Recent Synthetic Developments in Polyquinane Chemistry [Reprint 2021 ed.] 9783112539286, 9783112539279

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L. A. Paquette Recent Synthetic Developments in Polyquinane Chemistry

L. A. Paquette

Recent Synthetic Developments in Polyquinane Chemistry

AKADEMIE-VERLAG • BERLIN 1984

Die Originalausgabe erscheint im Springer-Verlag Berlin • Heidelberg • New York • T o k y o in der Schriftenreihe "Topics in Current Chemistry", Volume 119 Vertrieb ausschließlich f ü r die D D R und die sozialistischen Länder

Alle Rechte vorbehalten © Springer-Verlag Berlin • Heidelberg 1984 Erschienen im Akademie-Verlag, D D R - 1 0 8 6 Berlin, Leipziger Straße 3—4 L i z e n z n u m m e r : 202 • 100/505/84 Printed in the G e r m a n Democratic Republic Gesamtherstellung: VEB Druckerei „ T h o m a s M ü n t z e r " , 5820 Bad Langensalza Umschlaggestaltung: Karl Salzbrunn LSV 1275 Bestellnummer: 763 338 2 (6816)

06800

Managing Editor: Dr. Friedrich L. Boschke Springer-Verlag, Postfach 105280, D-6900 Heidelberg 1

Editorial Board: Prof. Dr. Michael J. S. Dewar Department of Chemistry, The University of Texas Austin, TX 78712, USA Prof. Dr. Jack D. Dunitz

Laboratorium für Organische Chemie der Eidgenössischen Hochschule Universitätsstraße 6/8, CH-8006 Zürich

Prof. Dr. Klaus Hafner

Institut für Organische Chemie der T H Petersenstraße 15. D-6100 Darmstadt

Prof. Dr. Edgar Heilbronner

Physikalisch-Chemisches Institut der Universität Klingelbergstraße 80, CH-4000 Basel

Prof. Dr. Shö Ito

Department of Chemistry, Tohoku University, Sendai, Japan 980

Prof. Dr. Jean-Marie

Lehn

Institut de Chimie, Université de Strasbourg, 1, rue Blaise Pascal, B. P. Z 296/R8, F-67008 Strasbourg-Cedex

Prof. Dr. Kurt Niedenzu

University of Kentucky, College of Arts and Sciences Department of Chemistry, Lexington, KY 40506, USA

Prof. Dr. Kenneth N. Raymond

Department of Chemistry, University of California, Berkeley, California 94720, USA

Prof. Dr. Charles W. Rees

H o f m a n n Professor of Organic Chemistry, Department of Chemistry, Imperial College of Science and Technology, South Kensington, London SW7 2AY, England

Prof. Dr. Klaus Schäfer

Institut für Physikalische Chemie der Universität Im Neuenheimer Feld 253, D-6900 Heidelberg 1

Prof. Dr. Fritz Vögtie

Institut für Organische Chemie und Biochemie der Universität, Gerhard-Domagk-Str. 1, D-5300 Bonn 1

Prof. Dr. Georg Wittig

Institut für Organische Chemie der Universität Im Neuenheimer Feld 270, D-6900 Heidelberg 1

Table of Contents

I

Introduction

1

II

New Synthetic Developments A Annulation Reactions 1 Acid- and Base-Promoted Cyclizations 2 Intramolecular Ylide Additions 3 Weiss-Cook Condensations 4 [3 + 2] Cycloaddition Methodology 5 Silicon-Assisted Ring Closures 6 a-Diazo Ketone Decompositions B Ring Expansion, Contraction, and Cleavage Processes C Transannular and Intramolecular Cyclizations D Rearrangement Routes to Polyquinanes 1 Thermochemical Pathways 2 Carbocation-Based Approaches 3 Base-Promoted Isomerizations 4 Photochemical Reactions 5 Free Radical and Carbenic Avenues 6 Miscellaneous Schemes E Meta-Photocycloadditions F Trapping of 1,3-Diyls G Production of Tri- and Tetraquinanes

2 2 2 5 7 8 10 12 12 15 18 18 21 24 25 29 29 31 32 33

III

Functional Group Manipulation within Polyquinanes A Ring Opening of Tricyclo[3.3.0.0 2 8 ]octan-3-ones B Reactions Involving Ketonic Substrates C Use of Other Carbonyl Functional Groups D Reactions Involving Olefinic Centers E Miscellaneous Reactions

40 40 42 47 49 54

IV

Spectral Data on Bicyclo[3.3.0]octanes

57

V

Simpler Molecules of Theoretical Interest A Pentalene B Semibullvalenes

58 58 58

C D E F G H I J

Brexanes, Brendanes, and ijn/W/-Sesquinorbornanes Adamantane Isomers Propellanes Tricyclo[3.3.0.0 3,7 ]octanes Fenestranes (Z) 3 )-Trishomocubanes and Congeners Triquinacenes and Related Molecules Peristylanes

VI

Natural Products Chemistry A Isolation and Physical Properties B Chemical Transformations

VII

Synthesis of Diquinane Natural Products A Cedranoids B Gymnomitrol C Pentalenolactone D Pentalenolactone E Methyl Ester E Quadrone F Carbaprostacyclins

62 65 68 70 71 73 76 81

84 84 85

89 89 91 95 96 97 102

VIII Synthesis of Triquinane Natural Products A Linear Triquinanes 1 Hirsutine 2 The Capnellene Group 3 Coriolin 4 Hirsutic Acid B Angular Triquinanes 1 Isocomene 2 Silphinene 3 Pentalenene 4 Senoxydene 5 Pentalenic Acid 6 Retigeranic Acid C Propellane Structures 1 Modhephene

108 108 108 Ill 114 118 121 121 124 125 126 127 128 130 130

IX

135 135 135 136 137 139

The Quest for Dodecahedrane A C 16 -Hexaquinacene 1 Synthesis and Properties 2 Functionalization Reactions B Alternative Approach to C 16 -Hexaquinanes C Peristylenones and Norperistylenones

X

D C 2 -Dioxa-C 20 -octaquinane E Approaches to Higher Polyquinanes F Pentagonal Dodecahedranes 1 The 1,16-Dimethyl Derivative 2 Monomethyl Dodecahedrane 3 The Parent C 2 0 H 2 0 Hydrocarbon

140 142 143 143 145 146

References

148

Subject Index

159

Author Index Volumes 101-119

161

I Introduction

I Introduction

By the mid-1970's it had become clear that the area of polyquinane chemistry was on the verge of an explosive growth period. There were several underlying reasons for this surge of interest in molecules whose frameworks featured mutually fused cyclopentane rings. Perhaps the most evident was the realization that little attention had previously been paid to methodology for annulating one five-membered ring to another. The need for suitably efficient protocols of this type was arising on several fronts. On the one hand, new natural products were being isolated, the dior triquinane skeletons of which had not heretofore been appreciated as biogenetically derivable from farnesyl pyrophosphate or related precursors. Independently and with equal intensity, a growing fascination for the possibly unusual physical and chemical properties of yet unknown spherical compounds such as dodecahedrane was gaining rapid momentum. In addition, many novel polycyclopentanoid alicyclic systems of theoretical, interest were awaiting the implementation of ingenious routes to their acquisition in the laboratory. In 1979, we authored a review in Topics in Current Chemistry entitled "The Development of Polyquinane Chemistry" 1 '. Numerous early experimental investigations in this field were surveyed and compiled therein. In the few, short intervening years, the level of research activity dealing with polyquinanes has literally mushroomed. Accordingly, the writing of an updated, complementary review as a means of keeping oneself abreast of the many new and imaginative developments seemed entirely appropriate and even necessary. As before, the intention has been to gather together all relevant new facets of pertinent synthetic methodology in the polyquinane field with a view to stimulating yet more exciting future scientific ventures.

1

II N e w Synthetic Developments

II New Synthetic Developments

A Annulation Reactions 1 Acid- and Base-Promoted Cyclizations Although bicyclo[3.3.0]octenones lacking angular substituents can be generated under aldol conditions 2 , 3 ) , unsatisfactory yields are commonly encountered. The situation

x/T-^f0

N

°2

0

1. NoOH.EtOH

0.5 M NaOH

2.hci,h2o

e»oh

y^T^^A-Q

' (35%)

COOMe

COOMe

rs

0; MeO —}—OMe CHo3

S ( r\ 0

Ng0Me

MeOH

,

M e o V o ^ YX ' Me X CH 3 Me Ô

^a"' ¿i

r ^ i r\ ,( itlow - yield. . il) .

is rather dramatically altered and the process gains considerable preparative respectability when comparable cyclodehydration procedures are applied to suitably substituted analogues (Scheme I). It matters not whether the angular group is alkyl as in 1 4> and 2 5) or electron-withdrawing as in 3 6) and 5 7) . Until this phenomenon was recently appreciated, the simple bicyclic enone 4 had eluded synthesis.

i.A/Ci,

^

N H C6h6.û 1 TsOH ç f ^

2

A4-V0

2. Hg(OAc)2, ° ch EtOH.py 3

(30%) 30 % KOH MeOH

2

(60%)

A Annulation Reactions COOEt

COOEt

dX 0

C H

NoH toluene

3

A

1. 1 % N a O H , H2Q

db-
40 -» 41) has been described. 3 5 ) Noteworthily, the cyclization proceeds with high stereoselectivity and introduction of functionality highly conductive to further useful chemical transformation.

0

39

40

41 9

II New Synthetic Developments

5 Silicon-Assisted Ring Closures Conversion of cyclopentanones to their arenesulfonylhydrazones and sequential treatment with n-butyllithium and chlorotrimethylsilane in anhydrous tetramethylethylenediamine proceeds regiospecifically to afford the less substituted vinylsilanes (e.g., 42) in unsymmetrical c a s e s . 3 6 " 3 8 ' Friedel-Crafts acylation of such substrates with acryloyl chlorides in the presence of aluminum chloride proceeds exclusively via electrophilic attack at the silyl-substituted olefinic carbon to deliver cross-conjugated dienones. Subsequent N a z a r o v cyclization results in cyclopentenone annulation (Scheme I X ) . 3 9 ) Because acryloyl chloride polymerizes under the reaction conditions, use of P-chloropropionyl chloride and subsequent dehydrochlorination with D B U is recommended as a synthetic equivalent. In a complementary vein, cyclopentenecarbonyl chlorides react with vinyltrimethylsilane in the presence of stannic chloride to deliver fused cyclopentenones. With additional sulfur substitution of the vinylsilane as in 45 and 46, the cyclized

CH, \ZS> V-J

CH-3 um

1.PhS0 2 NHNH; 2. n - BuLi 3. Me3SiCI

3

,SiMe

H

3

CH3

COCI CH,

AICI 3 , -78°C C H^C12

42

CH3

SnCI 4 , CH2CI 2 , A c

CH3

\3

0

+ CH3 CH3

CH3"CH3

43

C2H5OH

a

COCI

R ^^COCI

XT

(R= H,CH3)

Me 3 s; +

SPh

C Hlg C12 (53%)

44

AgBF 4

if

CH

12 SPh

CICH2CH2CI

( 3 5 - 4 5 %)

45 R

10

J

Sn C I 4

CH 2 =CHS¡Me 3

0

0

H

1. CH3Li 2. HgCI2 , HgO h 3 O+

CH 3

A A n n u l a t i o n Reactions PhS

Me 3 Si

COCI

:>or

\

( R = H , CH3)

A1CI cich2ch2ci SPh

0

5

50°C

4Q

(40-55%)

2 equiv. MCPBA

1. ( C H 3 ) 2 C u L i 2. MCPBA 3. A ' (R = CH 3 )

( R = H)

0

PhSOo o

cK Scheme

IX

five-ring a, p-unsaturated ketone is more highly functionalized. 4 1 > The obvious migration of the phenylthio group which has materialized during the formation of 47 is of some synthetic value. With an additional variant of these concepts in mind, Denmark and Jones demonstrated that P-silyl substituted dienones such as 47 undergo Nazarov cyclization under full control by the silicon atom 4 2 ) . The result is a clean-cut introduction of the enone double bond into the thermodynamically less stable position (compare 43 and 44).

Me3

M-

Si Me

3

u

y

n V s i M e j i

SiMe 3

(311) 11

II New Synthetic Developments

6 a-Diazo Ketone Decompositions P,y-Unsaturated diazo ketones exemplified by 48 and 49,441 and aromatic systems such as 50 4 5 ) serve as useful templates for gaining access to diquinane systems (Scheme X). Under conditions of boron trifluoride or trifluoroacetic acid catalysis, the functional group in question comprises an effective initiator of olefinic cationic cyclization.

R

R

R

R

BF3- Et20 N,

R

(41-50%)

(R=H,CH3)

48

R

(10-30%)

0 CHN2

BF

3'Et2°

+

CH ^ C I ^

49

(30%)

CH3O

(13%)

CF3CO2H

N

2

V

CH2CI2

ch^

o (42%)

0

50 Scheme X

Positioning of the double bond in a y,S-relationship can also allow for intramolecular carbenoid cyclopropanation (e.g., 57 -> 52). 4 6 ) The rigid structure inherent in the product engenders overlap of the external cyclopropane bond with the carbonyl group. This electronic state of affairs permits nucleophilic opening to occur with full stereocontrol. This synthetically useful point is illustrated by the conversion of 52 to 53. 471

N?

COOMe

cCc0 51

y

COOMe

COOMe i

\

A 52

53

B Ring Expansion, Contraction, and Cleavage Processes In 1979, Greene and Depres introduced a versatile three-carbon annulation procedure which is based upon initial dichloroketene addition to an olefinic double bond. The readily available a,oc-dichlorocyclobutanones cleanly undergo highly regioselective 12

II New Synthetic Developments

6 a-Diazo Ketone Decompositions P,y-Unsaturated diazo ketones exemplified by 48 and 49,441 and aromatic systems such as 50 4 5 ) serve as useful templates for gaining access to diquinane systems (Scheme X). Under conditions of boron trifluoride or trifluoroacetic acid catalysis, the functional group in question comprises an effective initiator of olefinic cationic cyclization.

R

R

R

R

BF3- Et20 N,

R

(41-50%)

(R=H,CH3)

48

R

(10-30%)

0 CHN2

BF

3'Et2°

+

CH ^ C I ^

49

(30%)

CH3O

(13%)

CF3CO2H

N

2

V

CH2CI2

ch^

o (42%)

0

50 Scheme X

Positioning of the double bond in a y,S-relationship can also allow for intramolecular carbenoid cyclopropanation (e.g., 57 -> 52). 4 6 ) The rigid structure inherent in the product engenders overlap of the external cyclopropane bond with the carbonyl group. This electronic state of affairs permits nucleophilic opening to occur with full stereocontrol. This synthetically useful point is illustrated by the conversion of 52 to 53. 471

N?

COOMe

cCc0 51

y

COOMe

COOMe i

\

A 52

53

B Ring Expansion, Contraction, and Cleavage Processes In 1979, Greene and Depres introduced a versatile three-carbon annulation procedure which is based upon initial dichloroketene addition to an olefinic double bond. The readily available a,oc-dichlorocyclobutanones cleanly undergo highly regioselective 12

B Ring Expansion, Contraction, and Cleavage Processes

ring expansion when treated with diazomethane. The halogen substituents not only appear to accelerate the rearrangement, but serve more importantly to disfavor competitive migration of the carbon atom to which they are attached (Scheme XI) 4 8 ) . CUCHC0CI

1.CH2N2

O

peritane y^Y' ^JJ

OSiEtj 3 CI2CHC0CI Et3N '

E,

3Si?CI —M-CI

Pen,ane

54

HOC, 1. H , CH3OH x / M - f - c i 2. TsOH, ' / ^ A o CH3OH-THF

CI

HO CI HOAc

/ CH0N0 2 2 CI 0

55 Scheme

XI

Dechlorination can subsequently be realized, if desired, by conventional zinc reduction. Alternatively, when silyl enol ethers (e.g., 54) are involved, reduction leads ultimately to a-chloro enones (55) 49) . Regiospecific insertion of a functionalized carbon atom next to a carbonyl group can also be achieved starting from cyclobutanones 50) . Thus, treatment of 56 with tris(methylthio)methyllithium gives 57 resulting from attack on the convex face. With tetrakis(acetonitrile)copper(I) perchlorate in toluene, this intermediate experiences an exceptionally selective ring expansion with concomitant loss of a sulfur substituent to produce 58 exclusively.

(MeS)jCLi H

56

ÒAc

(MeS^C H

H OAc

57

toluene 75°C

58

Ring contraction methodology has also been utilized to arrive at key diquinane intermediates. The conversion of 59 by Favorskii rearrangement to 60, followed by two-step cyclization to generate 61, has recently been disclosed 51) . The crafting of the highly functionalized bicyclo[3.3.0]octane 64 from 62 has been described by Roberts and Schlessinger 52) . In this novel sequence, lactam 63 is first elaborated using a modified Beckmann approach and subsequently exposed to lithio dimethyl methylphosphonate at low temperatures. 13

II New Synthetic Developments

/ ^ r ^ ^

vv

0 OH Me II OHC 1.LiC^P(OCH3)2

0 I.MeNHOH-HCI, py

2. NoOAc.HOAc HpO.EtpO I 2 2 t-BuO

2 . T s C I , py

t-BuO

t-BuO

62

P(OMe)2

63

64

Potassium permanganate which is solubilized in dichloromethane through use of triethylbenzylammonium chloride smoothly oxidizes the inexpensive and plentiful endo-dicyclopentadiene to the dialdehyde 65 53). 1. KMn0 4 , TEBACI CH2CI2 , 0-3°C 2. NoOAc , HOAc H 2 0 (pH 3)

CHO

CD CHO

65 Along similar lines, Woodward oxidation of bicyclo[4.3.0]nonadiene 66 effects preferential oxidation of the cyclohexene double bond. Cleavage of the diol with alkaline periodate leads following spontaneous cyclization to a 1:1 mixture of the bicyclic aldehydes 54) . 1. AgOAc , l 2 H 2 0 , HOAc 2 . K O H , CHJOH

66 CHO

%

4

N0IO4 KOH,H^O

CQ

CHO

14

C Transannular and Intramolecular Cyclizations

C Transannular and Intramolecular Cyclizations Transannular bond formation within eight-membered rings continues to be a rich source of diquinane compounds. The lithium diethylamide-promoted cyclization of cyclooctene epoxide 67 55) , N-bromosuccinimide-induced closure of 1,5-cyclooctadiene to bromohydrin 68 56) , thiolation of the same diene in the presence of Lewis acids 5 7 ) , and its Me 2 AlCl-catalyzed ene reaction with formaldehyde to give 69 58) are new examples of this well-known behavior (Scheme XII).

OH

o

Li N E12 etherhexone

67

(21%)

(3%) OH *

•

• •

(71 %)

AICI

Br

cu

OH

CHgOH SH

CI

69

68 Scheme XII

Somewhat more unusilal is the study by Nagendrappa of the behavior of 1-trimethylsilylcyclooctane oxide to various acidic reagents 59) . With boron trifluoride etherate, bicyclic alcohol 70 is formed exclusively, while in aqueous or methanolic sulfuric acid, irani-cyclooctene derivatives appear as the major products.

UP

0

SiMe3

CO

OH

BFi

Et20

CH^C o°c

70 15

II New Synthetic Developments

Addition of n-butyllithium-tetramethylethylenediamine to 1,3-cydooctadiene delivers 71 in unspecified yield 60) , whereas bromination of semicarbazone 72 has been shown to furnish reasonable quantities of 73 61). 1. n - BuLi TMEDA ?

2. H30

+

CO 71 Br

Br2 , CaCOj CHCIj , - 60°C

N \ NHC0NH2

Ns

( 31 %)

72

N lQ

N H z

73

The response of cyclopropylsilane 74 to titanium tetrachloride in dichloromethane solution at —78 °C consists of efficient conversion to the stereochemically homogeneous bicyclo[3.3.0]octane 75 62).

CH2SiMe3

-78°C

74

CI

C

75

CH^SIMe3

6H6,W

In the presence of silver perchlorate and water or methanol, dibromide 76 is transformed into 77 63) . The overall process is believed to involve disrotatory cyclopropyl-allyl rearrangement in concert with halide ion removal, electrocyclization, and capture by solvent. OR

CK

.Br

76

AgCI04 ROH

/ V - - ^

(R = H , C H 3 )

0CH„ Li , t-BuOH THF

Br

(R = CH 3 )

77

Hudlicky and his coworkers have exploited the intramolecular carbenoid addition to conjugated dienes as a tool for the regio- and stereospecific formation of quaternary centers with concomitant closure of one or more five-membered r i n g s 6 4 " 6 6 ' . The initially formed vinylcyclopropanes are subsequently pyrolyzed to arrive at the desired polyquinane. Recently, the stereoselectivity of 1,5-ring closure within free radical intermediates has been accorded attention by two groups 6 7 , 6 8 ) . In Beckwith's example, cycli16

C Transannular and Intramolecular Cyclizations

N2

0

0,

R

Cu(acac)2 n6 C6K H

R = H , CH 3 0

N2

R

J? R = H , CH 3

zation of 78 was found to be relatively slow, to occur mainly in the e n d o m o d e (predominant formation of cis-fused bicyclics), and to be otherwise stereorandom. These results compare favorably with those observed by Wolff and Agosta for the 2-(but-3-enyl)cyclopentyl radical (79).

^

^

Bu3SnH

Br

78

CD- • CO™ + CD( 3 5 %)

(23%)

H ( 3.9%:

Br

CO 79

cr5 - a 5 A synthesis of 4 directly f r o m an acyclic starting material has been uncovered by Schore and Croudace 6 9 ) . In their strategy, dicobalt octacarbonyl served t o induce cyclization of enyne 80. HCH C(CH2)3CH = CH2

Co2(CO)g 95°C

80

( 31%)

4 17

II New Synthetic Developments

D Rearrangement Routes to Polyquinanes 1 Thermochemical Pathways The vinylcyclopropane rearrangement remains a frequently utilized synthetic procedure 70) . Several examples have been discussed earlier (Section II.C). The kinetics of a large number of these reactions, carried out in a micro stirred flow reactor, have been investigated 71) . The particularly relevant aspect of this study (Scheme XIII) OMe

^ Û

w

47.1

*

Ph

40.4

NMe2

40.2

38.9

-(350°C)

V^

V^

48.3 ± AG* ~ (350 C )

46.6

OMe

OSiMe*

v81^{

43.8

51.3

OSiMe3 AG*' „ 48.7 "(350 C) Scheme

43.8

XIII

is that the presence of an alkyl or aryl group, or a hetero atom at the 1'-position, facilitates the isomerization. The same principle holds true for the 2'-position. However, a hetero atom on the vinyl substituent as in 81 raises AG* significantly. Also, there is a reductance for migration to a center with a cis vinyl substituent 7 1 ~ 73) . Si Me3 SiMe3

84

-Si

>

~H

OC^ - C p 5

Scheme

IB

XIV

SiMej

83

D Rearrangement Routes to Polyquinanes

Paquette and coworkers have determined that a 1 '-trimethylsilyl group exerts a strong rate-retarding effect on this rearrangement. The kinetic order of Me 3 Si relative to H was established by the intramolecular competition depicted in Scheme XIV. T o the extent that the silicon substituted cyclopropane ring in 82 enters first into reaction, allylsilane 83 will ultimately result. Favored involvement of the unsubstituted three-membered ring will lead instead to vinylsilane 84. Experimentally, pyrolysis proceeds cleanly to give 84 exclusively 1 2 - 1 3 \ This methodology is usefully complementary to the enesilylation procedure (Section II.A.5) for producing regioisomerically pure bicyclic vinylsilanes. Application of the Shapiro-like sequence to 85 proceeds under conditions of clean kinetically controlled deprotonation to give only 86. On the other hand, treatment of cyclopentanone with the 1-trimethylsilylcyclopropyl anion, dehydration, and thermolysis produces 84 regiospecifically 7 2 , 7 3 ) .

a5 0

85

98

(ioo%)

99

^ co I90 C

100

O

2 Carbocation-Based Approaches Treatment of nitrosourea 101 with base in methanol leads predominantly to 102 and 10384). These reaction products and deuterium label distribution studies point to a mechanism which involves conrotatory opening of the diazonium intermediate to a geometrically well defined cyclooctatrienyl cation which subsequently experiences electrocyclization. The action of hot (100 °C) formic acid on tertiary carbinol 104 furnishes bicyclo[3.3.0]octyl products, but with low stereodiscrimination possibly, because of partial thermodynamic equilibration 85). 21

II New Synthetic Developments

OCH3

N-CONH2 No

2C03.

+

f

//

CH3OH OCH3

102

103 H 2 , Pt

CO

2, NaHCO^, CH 3 OH 3 . H 2 , Pt

C

O

•

C

O

OCH3

OCH3

HCOOH IOO°C OCH

104

Nee and Roberts have carried out a detailed analysis of the behavior of all six stereoisomeric 6-, 7-, and 8-bicyclo[3.3.0]oct-2-enyl tosylates under acetolysis conditions 86) . No carbon skeleton rearrangement was noted to occur except for low level amounts in the case of 105, thus indicating a greater degree of stability for the diquinane ring systems relative to framework isomers which might be produced by Wagner-Meerwein rearrangement. OTs //

HOAc

105

o5 - co OAc

NQOAC

108

107

CO = CO 109

(4 :1 )

110

111

COOCHGCHGOH HCI,H 2 O^ CH 3 OH

0 773(69%)

R

, R i MejSil

(27%)

0.

RT

0 114

CL

/

R = CH3, R' = H 1

R = H , R = CH3 R=CH = CH2,R'=H R = R' = C H 3

85%

15 %

10

90

>95 36

280 nm transforms 140 into the monocyclic products 141 which in turn photoisomerize to oxetanes 142 101) . Under conditions of triplet sensitization, 143 experiences 1,2-acyl shifting to give 144 as the less predominant of two new isomers 102) . Salomon has explored new avenues of polyquinane ring construction via coppercatalyzed photobicyclization and efficient syntheses of 145-149 by this technique have been reported (Scheme XIX) 103) . The particular attraction of this methodology is the rapid manner in which complex multicyclic carbon networks are arrived at and the presence in the photoproducts of a cyclobutylcarbinyl acohol moiety which can be subjected to independent solvolytic ring expansion. Photochemical reactions of 2,3-dialkyl and 2-alkyl, 2,3-dihydro-2,3-epoxy-l,4naphthoquinones in which a carbonyl group has intramolecularly abstractable 26

D Rearrangement Routes to Polyquinanes R

C=L

r

hV

0

140

141

142

R = H ,CH3

hv

144

143

,0H hV CuOTf

145 hv CuOTf OH

hv CuOTf HO'

SB-

+

148

149

Scheme XIX

y-hydrogen atoms have been reported to afford predominantly the cyclobutanols 150 via Norrish type II cyclization 104) . The cyclobutanols are prone to secondary photorearrangement leading to 151 and 152. Not unexpectedly, the P-diketones 152 are readily dehydrated to indenones 153 upon attempted chromatographic purification. When dilute solutions of benzene in furan are irradiated through Vycor, the novel 1,3-1,4 adduct 154 is formed in 30% yield amidst several other products 105) . On pyrolysis, 154 rearranges via a 1,4-vinyl migration to furnish 155 in low yield. 27

II N e w Synthetic D e v e l o p m e n t s

+

0

o

hV

ff

& 155

154

The observation has been made that irradiation of 6-cyano-l,3-dimethyluracil and cyclopentene in ethanol leads predominantly to 156 which on acidic workup produces 157 106). CH 3^

0

II CH,

3 156

157

Although cyclohexadiene photochemistry has been extensively scrutinized, the behavior of 158 has proven unusual in that polycyclic hydrocarbon 159 is formed in yields up to 17% alongside the ring-cleaved heptadiene 107) . Ph

Ph Ph Ph Ph

hv

+

I

I

I I

PhCH = C — C = C — C = C H C H ,

CH,

Ph Ph

158 When 1,5-cyclooctadiene is subjected to methyl benzoate-sensitized photolysis in the presence of acidic methanol, formation of the mono trans isomer occurs 28

D R e a r r a n g e m e n t R o u t e s to Polyquinancs

initially. Protonation of the more reactive double bond ensues to give a carbocation, much of which experiences transannular closure prior to solvent capture. The products 160-162 are isolated in a ratio of 2 : 3 : 2 108) . OMe

CD 160

c6 161

162

5 Free Radical and Carbenic Avenues X-ray irradiation of 7-formylnorbornadiene in an adamantane matrix at —196 °C leads to 163. Evidently, the acyl radical undergoes efficient intramolecular addition to the proximate double bond more rapidly than loss of carbon monoxide, perhaps because of the instability of the 7-norbornadienyl radical 1 0 9 ) .

163 1,5-Dihydropentalene is formed as the major product on treatment of 164 with methyllithium at —40 °C. This process has been rationalized in terms of a double ring expansion involving consecutive carbene-carbene rearrangements with 1,3-carbon and subsequent 1,2-hydrogen shifts, in agreement with double labeling experiments 110) .

Br2

CH3L' < - 40° C

Brc

164 6 Miscellaneous Schemes Photochemical decomposition of benzotriazole 165 in the presence of acrylonitrile leads to 166, the result of [8 (or 12) + 2] regio- and stereoselective cycloaddition to a reactive intermediate 111) . Four unexpected addition-rearrangement reactions have recently been reported (Scheme XX). Treatment of l,4-dipyrrolidinocyclohexa-l,3-diene with dimethyl 29

II N e w Synthetic Developments

hv C H 2 = CHCN

165

O

COOMe

COOMe I C

/>— COOMe

o

C I COOMe

o

N(C2H5)2

(C2H5)2N

CH,

N(C^5)2

c

N(C2H5)2

(C?H5)2N

,ch3

(C 2 H 5 ) 2 N

c

III

167

25°C

I CH,

173 Scheme 30

XX

174

E Meta-Photocycloadditions

acetylenedicarboxylate produces the substituted dihydropentalene 167 132) . Condensation of azulene with l-(diethylamino)propyne at room temperature gives 168 whose constitution has been established by x-ray analysis 113) . In the crystalline state, 168 exists as the dimer 169; however, both the Diels-Alder reaction leading to 168 and the cycloreversion have low activation energies. In the presence of catalytic quantities of glacial acetic acid at room temperature, 168 undergoes fast isomerization to 170 which ultimately proceeds onward at a slower rate to 171. Alternatively, 168 advances directly to 171 in boiling tetralin. In contrast to this behavior, 4,6,8-trimethylazulene reacts with the ynamine only in refluxing tetralin because of steric shielding by the methyl groups. The major product isolated proved to be 172 113). As expected, the bridged azulene 173 reacted much like the parent hydrocarbon to give 174 under mild conditions 114) . When 6,6-dialkylfulvenes are subjected to anionic polymerization, dianions such as 175 are observed 115.116>.

CH3 C

H

:

CH3

KH

2K

THF

E Meta-Photocycloadditions A plethora of new examples of photochemical cycloadditions of ethylenic compounds to benzene and its derivatives has been recently documented 117) . The processes which occur depend upon the ionization potential of the ethylene relative to that of the aromatic 118) . In general, meta-cycloaddition materializes in every case and often predominates. The process therefore serves as an excellent one-step route to dihydrosemibullvalenes. Ortho-cycloaddition tends mostly to occur with those ethylenes having lowest ionization potential and para-cycloaddition is seen with cyclobutene. In addition, acyclic ethylenes containing the Me 2 C = group can enter into ene-type chemistry. Importantly, all three cycloadditions proceed stereospecifically with respect to the ethylene. The photoreactions of vinyl acetate with benzene, toluene, anisole, fluorobenzene, and p-xylene yield meta-cycloadducts of type 176 119).

+

C H 2 = CHOAC

^

\

X

Y

176 While the meta-photoaddition of ethyl vinyl ether to 3-methylanisole yields six ethoxy substituted isomers of l-methoxytricyclo[3.3.0.0 2,8 ]oct-3-ene, 3-fluoroanisole affords only three 120>. Importantly, the methoxy group is invariably located at position 1. Completely analogous behavior is observed in the course of the photocycloaddition of cyclopentene to anisole 121) and o-methylanisole 122>. 31

E Meta-Photocycloadditions

acetylenedicarboxylate produces the substituted dihydropentalene 167 132) . Condensation of azulene with l-(diethylamino)propyne at room temperature gives 168 whose constitution has been established by x-ray analysis 113) . In the crystalline state, 168 exists as the dimer 169; however, both the Diels-Alder reaction leading to 168 and the cycloreversion have low activation energies. In the presence of catalytic quantities of glacial acetic acid at room temperature, 168 undergoes fast isomerization to 170 which ultimately proceeds onward at a slower rate to 171. Alternatively, 168 advances directly to 171 in boiling tetralin. In contrast to this behavior, 4,6,8-trimethylazulene reacts with the ynamine only in refluxing tetralin because of steric shielding by the methyl groups. The major product isolated proved to be 172 113). As expected, the bridged azulene 173 reacted much like the parent hydrocarbon to give 174 under mild conditions 114) . When 6,6-dialkylfulvenes are subjected to anionic polymerization, dianions such as 175 are observed 115.116>.

CH3 C

H

:

CH3

KH

2K

THF

E Meta-Photocycloadditions A plethora of new examples of photochemical cycloadditions of ethylenic compounds to benzene and its derivatives has been recently documented 117) . The processes which occur depend upon the ionization potential of the ethylene relative to that of the aromatic 118) . In general, meta-cycloaddition materializes in every case and often predominates. The process therefore serves as an excellent one-step route to dihydrosemibullvalenes. Ortho-cycloaddition tends mostly to occur with those ethylenes having lowest ionization potential and para-cycloaddition is seen with cyclobutene. In addition, acyclic ethylenes containing the Me 2 C = group can enter into ene-type chemistry. Importantly, all three cycloadditions proceed stereospecifically with respect to the ethylene. The photoreactions of vinyl acetate with benzene, toluene, anisole, fluorobenzene, and p-xylene yield meta-cycloadducts of type 176 119).

+

C H 2 = CHOAC

^

\

X

Y

176 While the meta-photoaddition of ethyl vinyl ether to 3-methylanisole yields six ethoxy substituted isomers of l-methoxytricyclo[3.3.0.0 2,8 ]oct-3-ene, 3-fluoroanisole affords only three 120>. Importantly, the methoxy group is invariably located at position 1. Completely analogous behavior is observed in the course of the photocycloaddition of cyclopentene to anisole 121) and o-methylanisole 122>. 31

II New Synthetic Developments OCI-b CH-3

o hv

cp OCH,

New spectral evidence has appeared showing that the cis-cyclooctene adducts of toluene and anisole have structures 777 1 2 3 ' 1 2 4 ) . When the aryl substituents are made bulkier, increasing levels of the 3-substituted isomer 178 result. The mechanistic implications of these observations have been discussed 125) .

Substantial advance has been made in elucidating the course of intramolecular photocycloaddition reactions involving phenylvinyl bichromophoric systems 125 - 126) and in the utilization of such processes in natural products synthesis (Sections VII and VIII).

F Trapping of 1,3-Diyls 5-Alkylidenebicyclo[2.1.0]pentanes enter into reaction with methyl acrylate, dimethyl maleate, and dimethyl fumarate at reduced temperatures in their trimethylenemethane biradical form (e.g., 179) to give adducts of general formula 180 and 181 127_129 >. The relative rates of cycloaddition involving 170 with various acceptor olefins have been determined by direct competition experiments and dissected into

singlet and triplet relative reactivities. As concerns the singlet species, the observed ordering is maleic anhydride > maleonitrile > fumaronitrile > dimethyl furmarate > acrylonitrile > methyl acrylate > dimethyl maleate. The results are thought to agree with concerted cycloadditions for the singlert and nonconcerted ones for the triplet 1 3 0 ) . The regiospecificity of the singlet cycloadditions have been evaluated in terms of frontier orbital control 1 3 1 ) . Salinaro and Berson have observed that condensation of allyl pinacolone with dimethyl diazomethylphosphonate leads to 182 which dimerizes readily by a [a + ir] 32

II New Synthetic Developments OCI-b CH-3

o hv

cp OCH,

New spectral evidence has appeared showing that the cis-cyclooctene adducts of toluene and anisole have structures 777 1 2 3 ' 1 2 4 ) . When the aryl substituents are made bulkier, increasing levels of the 3-substituted isomer 178 result. The mechanistic implications of these observations have been discussed 125) .

Substantial advance has been made in elucidating the course of intramolecular photocycloaddition reactions involving phenylvinyl bichromophoric systems 125 - 126) and in the utilization of such processes in natural products synthesis (Sections VII and VIII).

F Trapping of 1,3-Diyls 5-Alkylidenebicyclo[2.1.0]pentanes enter into reaction with methyl acrylate, dimethyl maleate, and dimethyl fumarate at reduced temperatures in their trimethylenemethane biradical form (e.g., 179) to give adducts of general formula 180 and 181 127_129 >. The relative rates of cycloaddition involving 170 with various acceptor olefins have been determined by direct competition experiments and dissected into

singlet and triplet relative reactivities. As concerns the singlet species, the observed ordering is maleic anhydride > maleonitrile > fumaronitrile > dimethyl furmarate > acrylonitrile > methyl acrylate > dimethyl maleate. The results are thought to agree with concerted cycloadditions for the singlert and nonconcerted ones for the triplet 1 3 0 ) . The regiospecificity of the singlet cycloadditions have been evaluated in terms of frontier orbital control 1 3 1 ) . Salinaro and Berson have observed that condensation of allyl pinacolone with dimethyl diazomethylphosphonate leads to 182 which dimerizes readily by a [a + ir] 32

G Production of Tri- and Tetraquinanes

pathway to deliver the unusual triquinane 183 132) . Metalation of 184 caused cyclization to 185 which dimerizes in an analogous manner to 186 or 187 133).

182

184

185

186

183

187

When an acetonitrile solution of azo compound 188 is refluxed in the presence of phenyl vinyl sulfone, bicyclic adduct 189 results from the trapping of 179 134). Desulfonylation of 189 with sodium amalgam in buffered methanol produces the hydrocarbon and sets the stage for ozonolytic cleavage and formation of 190 which has been elaborated into a C 1 0 modified prostaglandin precursor 134) . Alternatively, the oxidative desulfonylation of 189 provides a ready source of ketone 191 135).

191

G Production of Tri- and Tetraquinanes Working from a theoretical vantage point, Gund and Gund have evaluated the strain energy of a number of polyquinanes 1 3 6 ) . Previously discussed annulation schemes have been applied in imaginative ways to arrive at 192-194 7'79). 33

G Production of Tri- and Tetraquinanes

pathway to deliver the unusual triquinane 183 132) . Metalation of 184 caused cyclization to 185 which dimerizes in an analogous manner to 186 or 187 133).

182

184

185

186

183

187

When an acetonitrile solution of azo compound 188 is refluxed in the presence of phenyl vinyl sulfone, bicyclic adduct 189 results from the trapping of 179 134). Desulfonylation of 189 with sodium amalgam in buffered methanol produces the hydrocarbon and sets the stage for ozonolytic cleavage and formation of 190 which has been elaborated into a C 1 0 modified prostaglandin precursor 134) . Alternatively, the oxidative desulfonylation of 189 provides a ready source of ketone 191 135).

191

G Production of Tri- and Tetraquinanes Working from a theoretical vantage point, Gund and Gund have evaluated the strain energy of a number of polyquinanes 1 3 6 ) . Previously discussed annulation schemes have been applied in imaginative ways to arrive at 192-194 7'79). 33

II N e w S y n t h e t i c D e v e l o p m e n t s

Cd

Na H,NaT

Bi^N + F" THF

S0 2 Ph Me

3

Si

-^r0S02CH3

S0 2 PH

192

193 W o r k has been reported on the preparation of diketo acid 195 a by the Weiss-Cook procedure and the subsequent acid-promoted cyclization of this material to triketone

COOH I CH2 CH2

I

C= 0

COOR

COOMe 1.pH 8.3

+

I

C =0

I H

COOMe

naphthalene-Isulfonic acid , CgHg,dioxane,A Q

2.HCI, HOAc, A

X

COOH

o COOH

CHjOH

195a 195b

196

R = H R=CH3

nophthalene-lsulfonic acid CgHg , dioxane A

28 COOH

HOOC

0 V

30 Scheme

198

XXI

19629). In analogous fashion, 28 and 30 have been transformed into ¡97 and 198, respectively (Scheme XXI). Rather unfortunately, when all three products are heated to reflux in methanol, ring opening occurs in precisely the reverse m a n n e r to that used to prepare them. N o evidence could be found for cleavage in the other possible directions 29) .

34

G Production of Tri- and Tetraquinanes

Application of the intramolecular cyclopropanation-rearrangement sequence to dienic diazo ketones 199 and 201 has been shown to provide easy access to both linear (200) and angular triquinanes (202) (Scheme X X I I ) 6 6 , 1 3 7 ) 0 Cufococlg

' V

C

58CFC

H

6 6

200

199 1.H2, Pd-C 2 . Ph 3 P = CH 2

/

580-600t ,nnH EtOOC

202

201 ( R = H , COOEt)

"1.N0BH4 2. NoH . C S ^ C H j I 3 . ( n - Bu) 3 SnH nn H

Scheme

EtOOC

XXII

Whereas the intramolecular acid-catalyzed cyclization of rigid polycyclic P,yunsaturated diazomethyl ketones usually leads in excellent yield to the corresponding angularly fused cyclobutanones 1 3 8 ^ 1 4 0 ) , the pentalone-annulated tricyclic systems

CH3

COCHN 2

204

203

205

(R = H , OCH3 1. 4 8 % H B F 4 , CH3NO2 2.H2S04, CH3

COCHN2

c

Pd-C

H

6 6

206

35

II N e w S y n t h e t i c D e v e l o p m e n t s

203 undergo subsequent rearrangement to afford 204 141) . The saturated ketones 205 result from catalytic hydrogenation of the products. Bicyclic diazoketone 206 follows the same reaction course 141) . Little and his coworkers have reported on the utilization of 1,3-diyl trapping reactions to effect the regiospecific and highly regioselective synthesis of linearly

188

6

6 5 - 70°C H

207

208

209

1. B 2 H 6 2.OH", H 2 0 2 3. H 2 C r 2 0 7

1.H

2

,

COOH

Pd-C

2.0 3 3. Jones

213 H COPCH^ H \ / H

Scheme

XXIII

fused triquinanes. For example, heating bicyclic azo compound 188 in the presence of cyclopentenone affords the isomeric tricyclopentanoids 207-209 (ratio 1.3:1:3) in isolated yields of 90-98% (Scheme XXIII) 1 4 2 ». Isomer 207 was converted to diketone 210 in three steps to permit stereochemical assig' ^ n t s to be made. When azo compound 211 was utilized, the /?-CH 3 OC 6 H 4 group ol 212 allowed for {'¡¡nctionalization at C 8 as illustrated by the conversion to 213 142) . Intramolecular diyl 36

G Production of Tri- and T e t r a q u i n a n e s

trapping reactions hold particular promise. Their versatility can be seen in the fully stereocontrolled conversion of 214 to 215 143) and in applications to natural products synthesis discussed elsewhere (Section VIII). Excited state chemistry is recognized to play a useful role in gaining access to triquinanes. It will be recalled that alcohol 146 is readily accessible by copper-catalyzed photobicyclization 108) . Solvolytic ring expansion of its tosylate (216) in hot acetic acid and catalytic hydrogenation of the olefinic product offer an entry to 217.

216

217

Irradiation of the dicyclopentylmethane 218 in methanol leads to [2 + 2] cycloaddition and ensuing in situ addition of methanol to the presumed intermediate bicyclo[2.1.0]pentane (219) producing 220 in high yield 144) . Sequential treatment of this triketone with boron tribromide and ethanolic silver nitrate gives enone 221, hydrogenation of which produces the parent tricyclic undecanone 222. In a similar manner, irradiation of 223 gives rise to 224 containing the hirsutane carbon skeleton.

218

219

222

220

221

hy CH 3 OH

223 Mehta and his associates have implemented an interesting series of reactions for synthesizing higher polyquinanes 145 ~ 148 >. Their methodology is based upon the finding that photocyclized benzoquinone Diels-Alder adducts undergo thermolysis 37

II N e w Synthetic Developments

with alternate cleavage of the cyclobutane ring (Scheme XXIV). The conversion of 225 to 226 is exemplary of this seemingly general scheme. Furthermore, brief heating of 226 in ethyl benzoate causes partial isomerization to 227, a molecule which possesses the stereochemistry characteristic of hirsutene. These workers succeeded in transforming 227 to 230, thereby achieving a formal total synthetis of the natural product. With the goal of achieving stepwise enone transposition within these systems, diketone 231 was treated with methylmagnesium iodide and product 232 was oxidized to give 233 without event. However, exposure of 233 to methyllithium furnished a tertiary alcohol resistant to acid-catalyzed isomerization 146) . When the naphthoquinone-cyclopentadiene adduct was irradiated in benzene, 234 was formed. Reduction of this compound with zinc in acetic acid made 235 available. Exposure of 235 to strong base and subsequent treatment with sodium-potassium alloy in the presence of chlorotrimethylsilane led to uncaging and isolation of236, whose structural assignment was confirmed by single crystal x-ray diffraction studies 147) .

II

VJ o

W

C2H5C00C2H5

o

226

225

1.H 2 ,Pd-C 2.K0t-Bu,

CH 3 I

MeOCH£>

OH

230

232

233 1.NoOMe, MeOH , A 2.N0-K, H' Me 3 SiCI, toi uene

234 Scheme 38

XXIV

235

236

G Production of Tri- and Tetraquinanes

Oda has ingeniously arrived at 238 by treating the 2-cyclohexene-l,4-dione-cyclopentene photoadduct 237 with trimethylsilyl iodide 90) .

cte 0

Me3SiI (92%)

0

237

238

The ira«5-sulfonyl palladation product 239 can be dicarbonylated to provide either 240 or 241 149) . Chemical modification of these substances lead to unusual polyquinanes.

/

SO,R

SO,R

SOOR

CO , 25 otm CH3OH pyridine

OCH,

CH3OH

240 / CI

>¿,2

239

\CO , 25atm H 2 0 - THF pyridine

1. N a B H 4

2.H 1

39

Ill Functional G r o u p Manipulation within Polyquinanes

III Functional Group Manipulation within Polyquinanes

A Ring Opening of Tricyclo[3.3.0.02 bjoctan-3-ones As a direct consequence of favorable orbital overlap and thermodynamic factors, 133 and its derivatives experience ring cleavage predominantly at the peripheral cyclopropane bond. Thus, reaction of 133 with acetyl methanesulfonate and tetramethylammonium bromide or iodide gives a mixture of 242 and 243 150) . This is the lowest known level of regioselectivity. With the polymer-supported sulfonate NafionT M S 1 5 1 ) or trimethylsilyl iodide 152) , the proportion of 244 and 245 is very high. Also, acetyl methanesulfonate acts on 246 to give 247 almost exclusively 150) .

C

O 133

I a>

^

Me4N+ X Me4N+ X" X = Br ' I

V. >1 0 V—UHL h V - ^ yA c

242

1

+

/ f

\\ \\

243 (20%)

(80%)

0 A c

^ Me-a Si I ^ ^

Nofion-TMS

-

245 (95%)

244

A

(5%)

°

X AC0S02CH3 Me 4 N

+

OAc

X" '

CH3

246

^CHs

247

K a n and Isoe have applied this knowledge to the formolysis of 246 as a means of acquiring hydroxy ketal 248. This intermediate was subsequently employed as the starting material for a total synthesis of chrysomelidial (249, Scheme X X V ) 1 5 3 ) . Noting that methylation of 52 provides the homogeneous product 250, Vandewalle and coworkers proceeded to react this keto ester with lithium, dimethylcuprate and to t r a p the kinetic enolate with trimethylsilyl chloride following hydrolytic decarboxylation. With 251 in h a n d , ozonolysis and reductive w o r k u p with sodium borohydride afforded ( + )-isoiridomyrmecin (252) directly 4 7 '.

40

A Ring Opening of Tricyclo[3.3.0.0 2 - 8 ]octan-3-ones

246

HO^

HO

1. HCOOH 2. NoOMe 3. H O ^ O H , Ts OH

3

248 (80%)

1.Cr03-py 2.CH3U x

(20%)

3.TSÖH, oqTHF

HO.

HO. J

.OAc 1.P0CU 0t OAc py > ft

^ rrV

1.TSNHNH2

2. n-BuLi V-"*-»-/ 3 . 0s0 4 ;NqHS0 3 » 4 . Ac 2 0,py (major)

OH -OH

2.LÌAIH4 (major) NaI04 Et 2 0,H 2 0

CHO

HO Ac CHO H 2 0

249 Scheme XXV

COOMe

1.(CH3)2CuLi

OSiMe3

2. H30 + 3 . LDA , 250

Me

3sicl

251

1 '°3 2.NaBH4

252

Selected stereocontrolled transformations of 52 using nucleophiles and electrophiles have also been studied 46) . Acetolysis in the presence of sulfuric acid followed directly by sodium borohydride reduction afforded acetate 253 which was smoothly dehydrated with methanesulfonyl chloride and triethylamine. Following conventional conversion of 254 to keto ester 255, a second double bond was introduced as in 256. While selenation methodology proceeded in marginally acceptable (40%) yield and sulfenylation afforded the angular sulfide, the most satisfactory method involved palladium acetate oxidation of the kinetic silyl enol ether 47) . Indirect deconjugation of the double bond in the unsaturated ester moiety gave 257 as the major epimer. (±)-Verbenalol (258) was arrived at three steps later. Sulfuric acid-promoted acetolysis of alcohol 259 obtained from 52 by borohydride reduction led to a mixture of four products from which 260 could not be obtained pure. Inversion of its hydroxyl configuration followed by catalytic hydrogénation yielded lactone 261 as the major product 46) . 41

Ill Functional Group Manipulation within Polyquinanes COOMe

AcO

AcO

COOMe

1. K j C O j )

CH3SO2CI

MeOH

3N

2.Jones

254

253

«

COOMe

255

1. M e j S i C I , EtjN.DMF 2. Pd(OAc>2 COOMe

0

.0 w

.

ÖH

l.(CH 3 ) 2 CuLi

4

COOMe

COOMe

2. 0 -

1. N B S

3. Z n , HOAc

2. Z n , HOAc

256

257

258

COOMe

mOH

4

AcO

COOMe

HOAc (H2S04)

259

260

1. K2CO3, MeOH 2. Jones 3. N0BH4 4. H 2 , Pd-C

a> 261

B Reaction Involving Ketonic Substrates Although c«-bicyclo[3.3.(y|octan-3-one is conformationally mobile, its envelopeenvelope conformation can sometimes control the stereochemical course of a reaction. Recent work has shown that while good stereoselectivity is achieved in the Strecker reaction of this ketone (only 262 results), the Bucherer product is a mixture of 262 (60%) and 263 (40%) 1 5 4 ) . These findings compare well with the observation that oxymercuration-demercuration of, and phenylselenyl chloride addition to cisbicyclo[3.3.0]oct-2-ene proceeds with preferential hydration of the less congested 3-position, but with little exo/endo preference 155-169>.

H

KCN NH4CI

1

-N H H

H

r

/c=

0

C2H5OH H2O

262

H

KCN

(NH4)2Cq3 H'

H

0

C2H5OH" H2O

262 +

N-H

In the course of their study of ring size effects on the ketalization of a, (3-unsaturated ketones, Becker arid coworkers noted that 264 comprises 80 % of the mixture when a diquinane is involved 4) . 42

Ill Functional Group Manipulation within Polyquinanes COOMe

AcO

AcO

COOMe

1. K j C O j )

CH3SO2CI

MeOH

3N

2.Jones

254

253

«

COOMe

255

1. M e j S i C I , EtjN.DMF 2. Pd(OAc>2 COOMe

0

.0 w

.

ÖH

l.(CH 3 ) 2 CuLi

4

COOMe

COOMe

2. 0 -

1. N B S

3. Z n , HOAc

2. Z n , HOAc

256

257

258

COOMe

mOH

4

AcO

COOMe

HOAc (H2S04)

259

260

1. K2CO3, MeOH 2. Jones 3. N0BH4 4. H 2 , Pd-C

a> 261

B Reaction Involving Ketonic Substrates Although c«-bicyclo[3.3.(y|octan-3-one is conformationally mobile, its envelopeenvelope conformation can sometimes control the stereochemical course of a reaction. Recent work has shown that while good stereoselectivity is achieved in the Strecker reaction of this ketone (only 262 results), the Bucherer product is a mixture of 262 (60%) and 263 (40%) 1 5 4 ) . These findings compare well with the observation that oxymercuration-demercuration of, and phenylselenyl chloride addition to cisbicyclo[3.3.0]oct-2-ene proceeds with preferential hydration of the less congested 3-position, but with little exo/endo preference 155-169>.

H

KCN NH4CI

1

-N H H

H

r

/c=

0

C2H5OH H2O

262

H

KCN

(NH4)2Cq3 H'

H

0

C2H5OH" H2O

262 +

N-H

In the course of their study of ring size effects on the ketalization of a, (3-unsaturated ketones, Becker arid coworkers noted that 264 comprises 80 % of the mixture when a diquinane is involved 4) . 42

B Reactions Involving Ketonic Substrates

^

OH

CXX> + ^C V^a/ o

TsOH

264 Net unexpectedly, the generation of enamines from bicyclic ketones 265 and 266 leads to the lesser substituted product 2 ) .

>c6° ^

>cd"°

>cdo T,0H

265

266 1

0

>c4N-\

S TsOH t -

The same regioselectivity is achieved upon cyanohydrin dehydration as exemplified by the isolation of 267 and 268 54). CN

0 /—rA

1. KCN.HCN

ix>

—^^

H^V

2.P0CI 3 ,py

COOH 1.K0H,H 2 0 2 H

- 30+

267

0

CN

a$

a5

COOH

—

c6

268 The thiophenyl ketone 269, obtained by [3 + 2] annulation of 2-cyclopentenone 17) , offers a'practical synthetic entry to functionalized diquinanes as shown by its conversion to 270. PhS

269

0

1.NoH,CH3I 2.LI,NH 3 , EIOH

OH

OAc

1- AcgO , py 2.0s0 4 ,NaI0 4 t-Bu0H,H£>

~

*

270

The need to prepare the bicyclic enones 273, 278, and 279 caused Smith to treat 271 with riethyllithium. Even with excess organometallic, only monoalcohol 272 was obtained because of monoenolate formation following introduction of a methyl group. Conventional dehydration gave 273 (Scheme X X V I ) R e a c t i o n of its 43

Ill Functional Group Manipulation within Polyquinanes

tosylhydrazone with «-butyllithium in T M E D A followed by a trimethylsilyl chloride quench led to a 4 : 1 mixture of vinylsilanes 274 and 275. However, subsequent epoxi•dation occurred selectively at their methyl substituted double bonds, a reflection of the usually lower nucleophilicity of vinylsilanes. Alternatively, sequential treatment of the lithium enolates of 273 with diphenyl disulfide, sodium borohydride reduction, mesylation, and elimination with potassium zm-butoxide in dimethyl sulfoxide yielded vinyl sulfides 276 and 277 in near quantitative yield. Ensuing hydrolysis with mercuric chloride in aqueous acetonitrile afforded ketones 278 and 279 which were separated by VPC.

ch 3 L!

> o

TsOH H0 -

V----V A

272

271

273

1.TsNHNHz

/

2.n-BuLi,TMEDA 3. Me 3 SiCI /

1 LDA -phS^ph 2.NaBH4

3.CH^CI

(C^N 4. KOt-Bu, DMSO SPh

•SiMe-

274

+

- /

i

-SiMe,

275

HgCl2 CH3CN

276 +

- H2O

SPh

278 Scheme

279

277

XXVI

Docken has made the observation that dimethyl bromomalonate in methanolic sodium methoxide solution acts on Schroeter and Vossen's "red salt" (280) to produce 281, hydrolysj,s-decarboxylation of which gives 282 156) . This substance proves to be essentially nonenolic, unstable to base, and reactive toward diazonium ions. Its methylene protons exchange readily with deuterium and bis(tosylhydrazone) 283 forms readily in acidified methanol solution. Attempts to obtain pentalene by vacuum pyrolysis or photolysis of the dilithium salt of 283 failed. However, photolysis of a solution of 283 in aqueous sodium hydroxide solution produced 284. Treatment of 282 with zinc in tetrahydrofuran-acetic acid produced 285. 44

B Reactions Involving Ketonic Substrates MeOOC

COOMe

MeOOC

COOMe

V-T-SX BrCH(COOMe)2 HCI ^ Q = ° NcOMe ' N a o - ^ p ^ o MeOOC COOMe M e 0 H MeOOC COOMe A 280 281 / TSNHNH2

/-T=\ ° = C O °

+_ N

o

0

282 ' Zn, THFHOAC

C C H i^TsNHNNNHTs

°C

H2O

284

283

285

Selective transformations can be carried out on enedione 20. For example, treatment with lithium diisopropylamide generates a single kinetic enolate. Addition of trimethylsilyl chloride or phenylsulfenyl chloride produces 286 and 287 as the only detectable products 2 0 ) . The anions of 20 and 287 react with methallyl iodide (but not its 3-trimethylsilyl derivative 157) ) to give 288 and 289, respectively.

Me3SiO LDA Me3SiCI 286

tt> /

0 "

LDA

_ . . . » PhS PhSCI

287

20

'LDA ,

LDA,

PhS

288

289

Whereas epoxyketone 290 undergoes normal hydride reduction and oxirane ring cleavage in the presence of either boron trifluoride etherate or acetic anhydride in pyridine, ready fission of both of its five-membered rings occurs under other conditions 158) . Thus, methanolic sodium carbonate at ambient temperature converts 290 within 5 hours to keto ester 291. With hydrogen chloride in methanol, 291 is also produced, although chloro enone 292 predominates. Oxidation of the epimeric hydrazines 293 in the presence of base leads to the respective carbanions, the capture of deuterium by which in D z O and (CH 2 OD) 2 is nearly stereorandom 159) . Ketalization of the carbonyl group in these carbanions has little effect on this outcome. The stereochemistry of deuterium incorporation in 294 45

Ill Functional Group Manipulation within Polyquinanes

was established by conversion to a 1:1 mixture of epimeric alcohols with methyllithium, followed by lead tetraacetate oxidation to the tricyclic ether 295. Epimerization occurs during the latter reaction to enable both alcohols to cyclize. Opening of the tricyclic ether to a mixture of endo acetates with boron trifluoride-acetic anhydride and subsequent pyrolysis yielded a mixture of the two expected bicyclo[3.3.0]octadienes. Mass spectrometry demonstrated that the deuterium content remained constant throughout this series of conversions ; consequently, the stereochemical disposition of deuterium in the two compounds was assumed to be identical 1 5 9 ) .

1. CH3Li K I O

4

D ^ f t V o

O R " ROD

293a,X

293b-*=H

=

N H N H , Y

=

2

,

-

°

' .

CQCOJ C

Y = H

N H N H

2 Pb( AC 4

0

6H6

294

295

2

AC B F

2

0

3

ether 5 0 0 C D

AcO

An interesting regiochemical effect has been observed during Baeyer-Villiger rearrangement of the spirocyclobutanones 296 and 297. In the unsubstituted case, exclusive migration of the quaternary carbon takes place in customary fashion. In the case of 297, the oxidation conditions are critical. In the absence of base, 298 results; with potassium carbonate added, 299 is formed. Conversion to 300 occurs at more elevated temperatures 160) . The striking difference in regioselectivity is thought to be due to the fact that selenide oxidation is faster than Baeyer-Villiger oxidation in the absence of base.

46

C Use of Other Carbonyl Functional Groups

h2o2 NaOH J-y 296 0 h2O2 EtOH A

PhSe

PhSe 0.

//

T>

b~y 298

PhSe

h2o2, k 2 co 3 EtOH o°c

297

PhSe Q \

EtOH

J J 299

300

C Use of Other Carbonyl Functional Groups Bissulfenylation of lactones (e.g., 301) followed by monodesulfenylation with a Grignard reagent, cleanly delivers magnesium enolates carrying an a-phenylthio substituent suitable for aldol condensation 161

R0

~OC^

LDA

\ PhSS02Ph 9 v y j o ^ s p h SPh 301 ( R = H - S i - ) I 0

Q

1 c h m b

- 2 5 9 ;

2.CH3CH0 '

CXD-». ^ r

1-MCPBA 9 ) çj^sph HO

RO^OQ>

2. ca CO 3, CCI4,A0^

b~y 298

PhSe

h2o2, k 2 co 3 EtOH o°c

297

PhSe Q \

EtOH

J J 299

300

C Use of Other Carbonyl Functional Groups Bissulfenylation of lactones (e.g., 301) followed by monodesulfenylation with a Grignard reagent, cleanly delivers magnesium enolates carrying an a-phenylthio substituent suitable for aldol condensation 161

R0

~OC^

LDA

\ PhSS02Ph 9 v y j o ^ s p h SPh 301 ( R = H - S i - ) I 0

Q

1 c h m b

- 2 5 9 ;

2.CH3CH0 '

CXD-». ^ r

1-MCPBA 9 ) çj^sph HO

RO^OQ>

2. ca CO 3, CCI4,A0^ 00

H

305

306

307 (i-Bu) 2 AIH 2.03 3.Zn , HOAc \

COOCH?

Scheme

XXVII

D Reactions Involving Olefinic Centers The tricyclic dioxetane 309 has been isolated in crystalline form by cyclization of iodohydroperoxide in the presence of silver acetate. Thermolysis of 309 proceeds to give 1,5-cyclooctanedione with E a = 25.6 + 0.6 kcal/mol and AS* = 4 + 2 eu. The singlet 1 cp and triplet 3cp excited state product yields are 0.011 and 0.10, respectively 168) .

CO

1. diiodantin, H2Q2

,0 / v ^A^f

2. AgOAc

OH LiAIH

4 QH

309 49

Ill Functional Group Manipulation within Polyquinanes

The conversion of unsaturated carboxylic acids to bislactones in the presence of lead tetraacetate can be controlled to achieve efficient cis addition of two carboxylic oxygens to the double bond. The conversion of 310 to 311 is exemplary 170) . 0 HOOC

a>

àù

3

l HOOC

Î. r fj—0

310

° 311

The absolute configuration of ( + )-e«i/o-cw-bicyclo[3.3.0]oct-7-en-2-ol, resolved by chromatographic separation of diastereomeric camphanate esters, has been established by oxidation to 312 and conversion of this diacid to (—)-3-oxocyclopentaneacetic acid 171) .

a

HO

^

RuQ 2

V

NqI0 4

t

^ÇCOOH

1. H2SO4, MeOH ^2 .J J°onneeSs ,

^ OH y^cOOH

3. H CI, A

r-^COOH L j

312 Various Lewis acids promote the ene reaction of diethyl oxomalonate to olefins at or below room temperature 172) . The hydroxyl group in the product may be readily removed following acetylation 173) . The overall result is a regiocontrolled synthesis of diethyl allylmalonates from alkenes.

a

1. AC20,

^

o=c(cooEt) 2

y

SnCI4

"

DMAP

t 2.LÏ.NH, \ X 0

+

AgOAc

I

t( 1:101 1:10)

/— - AcOmi=0

314

«-"poO I

£0C> ¿COO 316

315

the lithium alkoxide of 324 was treated with dry carbon dioxide and an equivalent of bromine to produce bromo carbonate 325. Reduction of this intermediate with tri-nbutylin hydride gave carbonate 326 whose plane of symmetry is apparent in its 1 3 C N M R spectrum. These findings require that the action of hydroxide ion on 325 give 327 which is also obtained by borohydride reduction and cyclization of 318. With the intent of examining stacking interactions between aromatic rings, Gardette and Lhomme treated cw-bicyclo[3.3.0]octane-3,7-dione with the phenyl Grignard reagent and dehydrated the dihydroxy compound to a 1:1 mixture of dienes 328 and 329 which could be separated on silica gel impregnated with silver nitrate 177) . Hydroboration-oxidation gave 15:1 mixtures of 330aj330b and 33la/33lb. The tosy-

323a , R = THP 323b ,R= si-+DBU 0 +

320a , R = H 320b, R = THP 320c , R = si -+

319 o

0

DBU

321

322 51

Ill Functional G r o u p Manipulation within Polyquinanes

OH

0 o-^g

1. n-BuLi 2.C02

CO

0

O ' ^ - C O (Q-Bu),SnH

3. Br z

325

324

326

KOH,MeOH HO 1. NaBH4 318

2. KOH KOH,,

CH3OH

Scheme

'

C O "

327

XXVIII

lates of the major diols were reduced to 332 while minor diol 331b afforded cyclic sulfite 333 when treated with thionyl chloride in pyridine. Submission of 332 to electrophilic aromatic substitution revealed that a monoacylation/diacylation rate ratio of 5 prevails because of enforced proximity. In the absence of any charge on one benzene ring, however, it would appear that the system exists preferentially in conformations where the aryl groups do not interact.

»-a>

HO

Ph

1

b

H

- 2 6

OH

phi

miph

"


— C — CH^

COOEt hv > C D «

CH^ = C=CH'2 /

346

345

344 o

•

A /Nj^iMe » V \ r o

H

,CO 2 R

1.Ch 2.Me2S S

o R

NH

+

*R = H

348

X ^ / S ^ O

347a, R = H

347b, R = CH3

R=CHJ

) C

S ^ O

349

to 346. Ozonolysis of this methylenecyclobutane in methanol results in cleavage to 347b. Upon heating in acid, 347a gives only y-lactone 348; no evidence for 5-lactone formation was seen. In contrast, ammonia acts on 347a to deliver only 349 182).

E Miscellaneous Reactions The reaction of 1,5-cyclooctadiene with lead tetraacetate can be modified to produce either 350 or 351, both of which have been transformed into the bridged ether 352. Pyrolysis of diacetate 351 also serves as a useful method for preparing bicyclo[3.3.0]octa-2,6-diene 183) . 54

HI Functional Group Manipulation within Polyquinanes

Following introduction of a, P-unsaturation into bicyclo[3.3.0]oct-6-en-2-one to give 341, irradiation in the presence of 1,2-dichloroethylene and conventional dechlorination of the photoadduct furnished 342 as a 9:1 mixture of isomers which could be separated. The major (presumably cis-anti-cis) component was converted to bicyclobutane 343 via oxa-di-71-methane photorearrangement 1 8 0 ) . 1. hv,CICH = CHCI

CQ

2. hO-^ v - xOH . TsOH

hv acetone

3. No , NH 3 4. 2NHCI , ether

// o

341

343

342

Photoaddition of allene to diquinane-type a, P-unsaturated ketones proceeds with adherence to Wiesner's empirical rule 181) . In an attempt to arrive at pentalenolactone E, Magnus and coworkers prepared 345 and carried out is selective reduction hv Q

>


— C — CH^

COOEt hv > C D «

CH^ = C=CH'2 /

346

345

344 o

•

A /Nj^iMe » V \ r o

H

,CO 2 R

1.Ch 2.Me2S S

o R

NH

+

*R = H

348

X ^ / S ^ O

347a, R = H

347b, R = CH3

R=CHJ

) C

S ^ O

349

to 346. Ozonolysis of this methylenecyclobutane in methanol results in cleavage to 347b. Upon heating in acid, 347a gives only y-lactone 348; no evidence for 5-lactone formation was seen. In contrast, ammonia acts on 347a to deliver only 349 182).

E Miscellaneous Reactions The reaction of 1,5-cyclooctadiene with lead tetraacetate can be modified to produce either 350 or 351, both of which have been transformed into the bridged ether 352. Pyrolysis of diacetate 351 also serves as a useful method for preparing bicyclo[3.3.0]octa-2,6-diene 183) . 54

E Miscellaneous Reactions

AcO,

CQ

Pb(0Ac)4", PdCI2. ^ Li CI

Pb(OAc)^ Pd CI o

1.K2C03 MeOH - H 2 0 2.K0iBu, DMSO

CI

350

352 1. k 2 c o 3 Me0H-H 2 0 ' 2. DMSO , A

AcO

CO

600°C

OAc

CQ

351 The trimethylsilyl group in vinylsilane 84 directs the entry of incoming electrophiles. The course of acylation and bromination is illustrated 7 2 ' 7 3 ) . COCH,

Br

SiMe,

CH^COCI

C6

AI CI3 CH^Clg CI; -78°C

Br2

CH^C I ^

cd

84

The endo carboxylic acid 353 is readily transformed via its acid chloride to the diazo ketone. Heating of this intermediate in the presence of copper sulfate results in preferential carbene insertion into the C 8 /endo-H g bond to produce 2-ketoperhydrotriquinacene (354) 184). 1. CH2= PPhj 2. B2Hg. HgOg 3. [01

CO

1. s o c i 2 2. CH2N2 3.CUS04 i

TIOOH

353

354

The condensation of 355 with sodio dimethylmalonate proceeds anomalously to give 356 185).

Nq CH(C00Me)2 MeOOC

MeOOC

355

CH(C00Me)2

356 55

Ill Functional Group Manipulation within Polyquinanes

The diquinane unit has been incorporated into a macrocyclic polyether as in 357 and the host-guest complexing ability of the molecule has been examined 186) .

A,

0

0.

357

56

E Miscellaneous Reactions

IV Spectral Data on Bicyclo[3.3.0]octanes

13

C N M R data for a wide range of bicyclo[3.3.0]octanes, too extensive to compile here, have been reported 44 - 54 - 66 - 18? . 188 ). The influence of a variety of substituents on chemical shifts is now known. Furthermore, the basis for determining regio- and stereochemical features is now at hand. 13 C chemical shifts for a much more limited group of linearly fused tricyclopentanoids have also been published 6 6 , l 8 9 ) . Although similar tabulations of N M R data do not exist per se, it is clear that chemical shifts can be of considerable diagnostic value in structural assignment (see 91). Coupling constants as illustrated for pentalenolactone (358) 190) and 359 33) can likewise prove most helpful.

358

(JQb=9.0Hz)

359

(Jab=3-6Hz)

Distinction between (3,y- and y,5-unsaturated ketones is also feasible by UV spectroscopy. The enhanced absorption of the n -»• n* transition in the former is clearly apparent when the functional groups reside in different rings 4 4 ) . R

0

R

0

W R R

= H , A. 293(625) ' mo*

R =

CH

3 • ^max286

(6 75)

R-H.X. 298(689) ' max R = CH 3 , ^ m Q £ 9 8 ( 6 2 5 4 )

In a different context, ( + )-enJo-di-bicyclo[3.3.0]oct-7-en-2-ol has been shown to be an effective tool for determination of the absolute configurations of chiral acids I 9 1 ) .

57

V Simpler Molecules of Theoretical Interest

V Simpler Molecules of Theoretical Interest

A Pentalene While theoretical interest in pentalene expectedly persists 192) , some progress has been made in unraveling the nature of this electronically unusual alternant cyclic polyolefin. Since l,3,5-tri-/er/-butylpentalene (360) remains the only alkyl derivative

(CH 3 ) 3 C

360 so far which is stable at room temperature, provided that prolonged exposure to air is avoided, it has become a prime target for study. Its photoelectron (PE) and absorption (UV-VIS) spectra have been determined. The first four bands in the PE spectrum have been assigned by comparison with calculated orbital energies. Similar treatment of the absorption data indicates that bond alternance is operative 193) . The ESR spectra of the radical anion and cation of 360 have been reexamined under higher resolution and the coupling constants of all the protons were determined 194) . Since the experimental data agree with values predicted by the simple MO model, the n-spin distributions in 360~ and 360+ appear not to differ significantly from those of the parent species. However, the spectra of 360~ taken at low temperatures show no specific line broadening which could arise from bond-shifting between the two Kekulé forms. Proton hyperfine data have also been determined for the radical anions and cations of dibenzo[6/|pentalene and its 5,10-dimethyl derivative 195) . The coupling constants approximate closely the values obtained for the radical ions of 360. The mechanism of the dehydrogenative transannular ring closure of cyclooctatetraene in the presence of various inorganic reagents to provide complexes of pentalene has been the subject of debate 1 9 6 ' 1 9 7 ) .

B Semibullvalenes Serratose, et al., have succeeded in converting readily available lactone 361 to semibullvalene. The scheme, which involves no skeletal rearrangement, is based on diazoketone cyclization chemistry within an oxygenated cyclopentenyl derivative 198) . 58

V Simpler Molecules of Theoretical Interest

V Simpler Molecules of Theoretical Interest

A Pentalene While theoretical interest in pentalene expectedly persists 192) , some progress has been made in unraveling the nature of this electronically unusual alternant cyclic polyolefin. Since l,3,5-tri-/er/-butylpentalene (360) remains the only alkyl derivative

(CH 3 ) 3 C

360 so far which is stable at room temperature, provided that prolonged exposure to air is avoided, it has become a prime target for study. Its photoelectron (PE) and absorption (UV-VIS) spectra have been determined. The first four bands in the PE spectrum have been assigned by comparison with calculated orbital energies. Similar treatment of the absorption data indicates that bond alternance is operative 193) . The ESR spectra of the radical anion and cation of 360 have been reexamined under higher resolution and the coupling constants of all the protons were determined 194) . Since the experimental data agree with values predicted by the simple MO model, the n-spin distributions in 360~ and 360+ appear not to differ significantly from those of the parent species. However, the spectra of 360~ taken at low temperatures show no specific line broadening which could arise from bond-shifting between the two Kekulé forms. Proton hyperfine data have also been determined for the radical anions and cations of dibenzo[6/|pentalene and its 5,10-dimethyl derivative 195) . The coupling constants approximate closely the values obtained for the radical ions of 360. The mechanism of the dehydrogenative transannular ring closure of cyclooctatetraene in the presence of various inorganic reagents to provide complexes of pentalene has been the subject of debate 1 9 6 ' 1 9 7 ) .

B Semibullvalenes Serratose, et al., have succeeded in converting readily available lactone 361 to semibullvalene. The scheme, which involves no skeletal rearrangement, is based on diazoketone cyclization chemistry within an oxygenated cyclopentenyl derivative 198) . 58

B

0 0

361

TsO < q NS^ Ns^

1.S0CI 2 Ac0 - CH2No ''*r^\ COOH LA—firr v 3. Cu (acac)p, V=V 3.Cu(acac) 2, C 6 H 6 -hexane 4.NaOAc,H0Ac

Semibullvalenes

2

c

a> The synthesis of an optically active semibullvalene has been, realized for the first time 199) . Sequential reaction of methylcyclooctatetraene with one equivalent each of bromine and (—)-e«i/o-bornyltriazolinedione gave a mixture of Diels-Alder adducts which when debrominated afforded 362. Photocyclization to bishomocubane 363 allowed for chromatographic separation of the two diastereomers. Silver ion-

=\„CH

3

1. B r

hv

2

O^N-^O N=N 3. Zn-Cu

363

362

Ag NO3 KNO3

AgCI I60- I70°C 3 1. NaOH 'CH,

365

CHu

2.Mn0p

364

catalyzed rearrangement of the crystalline isomer delivered dextrorotatory 364 whose absolute configuration was elucidated by x-ray analysis. Hydrolysis-oxidation of (—)-364 gave ( + )-5. The higher Diels-Alder reactivity of 392 due to the presence of a norbornene double bond is responsible for this selectivity. .0

. Only two members of "adamantaneland" contain a /r. The C2v- and .^-symmetric tetraesters of tricyclo[3.3.0.0 3 - 7 ]octane (430 and 431) have been prepared by oxidation of diene 429251). To access the parent hydrocarbon (435), acid chloride 432 was transformed to the derived ketene which undergoes intramolecular [2 + 2] cycloaddition 252) . The resulting cyclobutanone (433) serves as precursor to perester 434 whose thermal decomposition proceeds with chain transfer in competition with cleavage 252) . The unique arrangement of the carbon atoms in 435 is such that the smallest rings are all five-membered. The highly symmetric structure may be viewed as a constrained cisoid bicyclo[3.3.0]octane (as well as the symbol of NATO).

G Fenestranes The synthesis of [4.4.4.4]fenestrane or "windowpane" has become an active area of research due to the aesthetic appeal of the hydrocarbon and the nature of its central quaternary carbon atom which is expected to be distorted from normal tetrahedral geometry 253) . Ongoing investigations have generated a number of ring-expanded triquinane and tetraquinane ([5.5.5.5]fenestrane) homologs. These molecules form the subject matter of the discussion which follows. The earliest pioneering work, due to Georgian and Saltzman 254) , began with Robinson annulation of 436 and intramolecular [2 + 2] photocyclization of the bicyclic enone.

436 Keese's group has achieved a more advanced stage of development beginning with 1,5-cyclooctadiene (Scheme XXXV) 255) . Following condensation with chloral and 71

V Simpler Molecules of Theoretical Interest

dehydrohalogenation to arrive at 437 256\ reaction with N-bromosuccinimide in the presence of water afforded a bromohydrin which in the presence of base afforded lactone 438. This intermediate could be elaborated into the lactone diester 439 where the side-chains are configurationally fixed. Dieckmann cyclization and hydrolytic

CCI2

1. C I 3 C C H O ,

AICI3

1.NBS , H20 2. O H -

2. KOH, C2H5OH

437

438 1.0H"

2.RUCI3, N0IO4 3.NAH , CH3I 4.H0~0H ,H 0

CH-£)OC

+

COOCH3 1. Li0^0 2. HGO ,H +

0

3.NaI04,RUCI3 4.CH2N2

1.LDA,

Br-"—^

|

^

p°2CH3

'

2.H3O+, acetone

439 1.Na N ( S i M e 3 ) 2 ,2.H,0+,A V

0

1.TSNHNH2 2 . KOH 3 . hv , di gly me

440 Scheme

XXXV

decarboxylation delivered 440. Photolysis of the potassium salt of the tosylhydrazone in diglyme yielded the tetraquinane 441. Beginning with dicyclopentadiene, it has also proven possible to prepare 442 which could serve in its own right as a tetraquinane precursor 2 5 7 ) .

H (Z) 3 )-Trishomocubanes and Congeners

The Dauben-Walker approach has yielded the smallest and most strained fenestrane known to date 258) . Following the intramolecular Wadsworth-Emmons cyclization of 443 which also epimerizes the butenyl sidechain to the more stable exo configuration, intramolecular photocycloaddition was smoothly accomplished to provide 444. Wolff-Kishner reduction of this ketone afforded the C 2 -symmetric hydrocarbon 445. Application of the photochemical Wolff rearrangement to a-diazo ketone 446 gave 447. o 2

*2C03 ,

18_cr_6'

\\

/

V

T

THF

443

OH"

H

H 0

C0 2 Me hv CH3OH

H

447

H

445

H (D3)-Trishomocubanes and Congeners (Z) 3 )-Trishomocubane (451) is a saturated pentacyclic cage compound whose carbon skeleton is made up of fused five-membered rings. The molecule, which is intrinsically chiral, possesses the rare D3 point group symmetry and is consequently of interest as a test system for chiroptic theories. Whereas racemic 451 has been known for more than a decade 2 5 9 - 2 6 1 ) > the enantiomers have recently become available and absolute configurational assignments made 2 6 2 ~264>. The approach used by Helmchen and Staiger involved conversion of diol 448 with hydriodic acid into 449a and 449b which were separated chromatographically as their diastereomeric (—)-camphanic acid esters (Scheme XXXVI). Subsequent zinc reduction, hydrolysis, and JonesKiliani oxidation furnished the optically active trishomocubanones 450a and 450b. The hydrocarbons were arrived at by Wolff-Kishner reduction. ' H N M R and x-ray methods were utilized to establish the absolute configurations 262) . Nakazaki's group also relied upon skeletal rearrangement, specifically that which occurs upon controlled acetylation of 452. With the diastereomeric cis monoacetates 453 in hand, they proceeded to ( + )-Z) 3 -trishomocubanol which was resolved via its acid phthalate as the ( + )-2-(l-aminoethyl)naphthalene salt. Collins oxidation and Wolff-Kishner reduction completed their scheme 263) . 73

H (Z) 3 )-Trishomocubanes and Congeners

The Dauben-Walker approach has yielded the smallest and most strained fenestrane known to date 258) . Following the intramolecular Wadsworth-Emmons cyclization of 443 which also epimerizes the butenyl sidechain to the more stable exo configuration, intramolecular photocycloaddition was smoothly accomplished to provide 444. Wolff-Kishner reduction of this ketone afforded the C 2 -symmetric hydrocarbon 445. Application of the photochemical Wolff rearrangement to a-diazo ketone 446 gave 447. o 2

*2C03 ,

18_cr_6'

\\

/

V

T

THF

443

OH"

H

H 0

C0 2 Me hv CH3OH

H

447

H

445

H (D3)-Trishomocubanes and Congeners (Z) 3 )-Trishomocubane (451) is a saturated pentacyclic cage compound whose carbon skeleton is made up of fused five-membered rings. The molecule, which is intrinsically chiral, possesses the rare D3 point group symmetry and is consequently of interest as a test system for chiroptic theories. Whereas racemic 451 has been known for more than a decade 2 5 9 - 2 6 1 ) > the enantiomers have recently become available and absolute configurational assignments made 2 6 2 ~264>. The approach used by Helmchen and Staiger involved conversion of diol 448 with hydriodic acid into 449a and 449b which were separated chromatographically as their diastereomeric (—)-camphanic acid esters (Scheme XXXVI). Subsequent zinc reduction, hydrolysis, and JonesKiliani oxidation furnished the optically active trishomocubanones 450a and 450b. The hydrocarbons were arrived at by Wolff-Kishner reduction. ' H N M R and x-ray methods were utilized to establish the absolute configurations 262) . Nakazaki's group also relied upon skeletal rearrangement, specifically that which occurs upon controlled acetylation of 452. With the diastereomeric cis monoacetates 453 in hand, they proceeded to ( + )-Z) 3 -trishomocubanol which was resolved via its acid phthalate as the ( + )-2-(l-aminoethyl)naphthalene salt. Collins oxidation and Wolff-Kishner reduction completed their scheme 263) . 73

V Simpler Molecules of Theoretical Interest

HI H2O

448 1.Zn,H0Ac 2 . K 0 H ,EtOH 3.[0L

1. Zn, HO Ac 2.K0H,Et0H 3.[0]

HONNHN

451a Scheme

451b

XXXVI OH

AcO.

AcO. Jones

AC2O py

453

452

H2NNH2L

1. C r 0 3 • py 2. H 2 N N H 2 , OH "

451 E a t o n a n d Leipzig chose to resolve racemic t r i s h o m o c u b a n o n e by reaction with /-ephedrine and s e p a r a t i o n of the diastereomers by fractional crystallization. Subsequent acid hydrolysis delivered the e n a n t i o m e r i c ketones 2 6 4 ) . Successive removal of a d i a g o n a l C H 2 bridge f r o m (—)-451 furnishes (—)-ditwistb r e n d a n e (C 2 symmetry) (454) a n d (—)-twist-brendane (C 2 symmetry) (455). Also, 74

H (D 3 )-Trishomocubanes and Congeners

(—)-451 may be regarded as a higher homologue of ( )-C 2 -bishomocubane (456). The preparation of all three hydrocarbons in optically active form has recently been realized and absolute configurations assigned 2 6 3 ' 2 6 5 , 2 6 6 1 .

«a

-•(%)

-

455

454

456

By rather analogous chemistry, Nakazaki and Naemura succeeded in gaining access to (—)-2-D 3 -trishomocubaneacetic acid (457). Esterification of this acid with l,3,5,7-tetrakis(hydroxymethyl)adamantane gave (-)-458a, believed to be the first T symmetric organic molecule with known absolute configuration 267) . This claim was shown to be incorrect by Mislow who pointed out that asymmetry was introduced by the C H 2 O C O C H 2 groups connecting the Td adamantane core to the C 3 -trishomocubane components 268) . However, Nakazaki has more recently arrived at ( + )-458b by coupling of 1,3,5,7-tetraethynyladamantane with ( + )-45 9 269). The highest attainable static and time-averaged dynamic symmetry of this molecule are T and (C 3 ) 4 ) .

C=C-Br

CH2COOH

-) - 457

(+)

R=-CH2OCCH2'

(-)-458a,

-459

o (+)-£> R = - ( C = C) 2

Irradiation of cis,syn,cis-enones 460 in ethyl acetate results in facile intramolecular cyclization to the trishomocubane diones 461. Interestingly, these substances undergo smooth cycloreversion to 460 when exposed to catalytic amounts of p-toluenesulfonic acid in benzene at 30 °C 270) .

0, ht/ R

0 460

TsOH , C6H6

° r

461

R = CH3 , CH2CH = CH2 , C 6 H 5 , CGH 4 0Me-p 75

V S i m p l e r M o l e c u l e s o f T h e o r e t i c a l Interest

I Triquinacenes and Related Molecules Full details have now appeared concerning the photoisomerization of triquinacene 271) , its bridgehead substitution via photochlorination 2 7 2 ) , and the S N 1 solvolytic reactivity of these halides 2 7 2 ) . The three deuterated, optically active 2,3-dihydrotriquinacenes 463 of known absolute configuration have been prepared from ( + )-462 (Scheme XXXVII) 273) . The dextrorotatory monodeuterated triquinacene 464 was

OSO2CH3

(+) -

462

L1AIR4, (C2H5)20.

AlgOj,

'

CH2CI2 " 25°C

25°C

463a,

R'= H , R = D

463b,

R'=D,R = H

463c,

R'= R = D

1.LÌAIH4

L I AL H 4 THF A CH3

2.NCS, CICH2

ME

2S

HOOC

465

466 Scheme

464

XXXVII

obtained from the same precursor and (—)-(15')-2-methyltriquinacene (466) from (—)-triquinacene-2-carboxylic acid (465) 273> . The absorption and circular dichroism spectra of these hydrocarbons have been measured and analyzed in terms of the contributions of the composite double bonds and peripheral substituents. By this technique, triquinacene is shown not to be homoaromatic 2 7 3 ) . 76

I Triquinacenes and Related Molecules

An alternative practical synthesis of triquinacene-2-carboxylic acid (as the dextrorotatory enantiomer) has been described by Deslongchamps and Soucy 2 7 4 ) . Their protocol begins with hydroxy ketone 467 and passes via the 2-methyl derivative (Scheme XXXVIII). Selenium dioxide oxidation of the h y d r o c a r b o n provided the aldehyde which was further oxidized and then hydrolyzed to arrive at the acid.

3

.0

1. A c 2 0 , py

H

2.CH3MgI

OH

1.CH 3 S0 2 CI, Et 3 N 2.AI203

OH

467

Se02 aq dioxane 1.Mn0 2 ,NaCN

QJ

/^.COOH

7

CH 3 0H, HO Ac

0

CH

2.K0H, H 2 0

465

I.NaH, Br(CH 2 ) 3 CI 2.AgBF4 C

6H6

468 Scheme

XXXVIII

Following resolution with (—)-quinine, ( + )-465 was transformed into the ( + )-2formamido derivative which was condensed with the acid chloride of ( + )-465 to give the secondary amide 468. F r o m this point, the cyclic imidate salt 469 was prepared, but cyclization to the dodecahedrane nucleus could not be realized 2 7 4 ) . With Thiele's acid as starting material, several routes to triquinacene and 2,3dihydrotriquinacen-2-one (462) have been developed 2 7 5 ) . Triquinacene reacts with MO(CO) 6 to give tricarbonyl(triquinacene)molybdenum (470) a n d with (CH 3 CN) 3 -

0

470 77

V Simpler Molecules of Theoretical Interest

W(CO)3 to give tricarbonyl(triquinacene)tungsten 276) . X-ray analysis has revealed 470 to possess the indicated structure. Following the preparation of 2,6-di(bromomethyl)triquinacene (471), dimercaptan 472 was synthesized conventionally. Coupling of these intermediates produced a 3.5 to 1 mixture of anti- and .vyw-triquinacenophanes 473 and 474. These [somers were separated chromatographically and identities established by x-ray structure determination of 473 211).

3. S e 0 2 , aq.dioxane

A. UAIH4 /

2. P h 3 P , C B r 4

S

S

S +

473

S

s

474

As part of a general study of the fate of perhydrotriquinacene 2-carbinyl cations, ketone 354 was converted to 475^477 184). Amidst the complex mixture of products formed upon trifluoromethanesulfonic acid-catalyzed skeletal rearrangement of tricyclo[6.2.1.02,7]undecane (478) has been found [3.3.3]propellane (479) and the methylated perhydrotriquinacene 480 and 481 278). Treatment of 482 as the ether or alcohol with magic acid generates carbocation 483 which rapidly isomerizes to 484 whose spectra are observable. Quenching experiments carried out with sodium bicarbonate suspensions in methanol or methyl mercaptan at —110 °C produced 485a and 485b. Dissolution of 485a in magic acid 78

I Triquinacenes and Related Molecules

C H o = PPh-a

1

-b2H6

2.H202> CH2

354

OH"

'''CH2OH 475

( major)

1.ÜAIH4 2.TsCI , py

CH,MgI

, 3 . KO t Bu 1. CO , H 2 , (Ph3P)3RhCI 2 . Li A I H 4 ch2oh

476

477 ch3

ch3

478

479

481

480

regenerated 484. Reduction of 485b with Raney nickel followed by hydrogénation over 10% palladium on charcoal gave 486 as the only detectable product 279) . Following the successful preparation of 3-methoxy-3a-methyl-3a//-indene (487), cycloaddition with dimethyl acetylenedicarboxylate was found to occur across the 3- and 4-positions to give 498 280) . Dissolution of 488 in a 1:1 mixture of concentrated sulfuric acid and methanol at 0 °C results in loss of the elements of methanol and conversion to a new tricyclic aromatic [10]annulene (Scheme X X X I X ) 2 8 1 ) . Diester 489 was subsequently transformed into the unsubstituted system (490). Catalytic hydro-

fso3h so2cif C D

or 482

2

C I

2

— I ?n°r

(r=h,ch3)

483

484 NaHC03 CH30H or CH3SH


. The latter ketone is subject to hydrogen-deuterium exchange only under basic conditions and appears to exist entirely in the keto form despite the ready formation of its anion and successful methylation on oxygen 285) . In agreement with the aromatic nature of 490, the hydrocarbon undergoes electrophilic substitution reactions 283) .

OMe

NoH

KH Me0S02F

CH3I

OMe

497

495

490 CU(N03)2, AC20 AC^D,CH2CI2,

,0°C

BF3-Et20

Isomer X =

N0

12

CI2CH0Bu-n , TiCI4,CH2CI2 X = COMe X =

CHO

2-

5-

6-

40

5

40

15

20

0

75

5

4

0 93

3

J Peristylanes Garratt and White have pointed out the similarities in the topologies of 498-500 and their more spherical counterparts 501-503 286) . Following Eaton's lead 287) , they proposed to name 498-500 as [3]-, [4]-, and [5]-peristylanes, respectively, to reflect 81

J Peristylanes

MeO

1.K,I-BuOH nh 3 2.CH3I

MeO

MeO " V

1. LDA,PhSeCI 2. H 2 0 2

OMe

sOCH? 3. CH2 = C^ 1.CH? ¡H^OCHf Nat CH3I 2.2 M HCI

¿£r

1. KOH , H20 OMe 2.(i-Bu)2AIH 3. (PhOJjPCHj I" 4. NaOH, H^O

TsOH CH2CI2

490 Scheme XL

The intermediate tricyclic ketones 495 and 496 have been transformed to the methoxy-substituted derivative 497 284'285>. The latter ketone is subject to hydrogen-deuterium exchange only under basic conditions and appears to exist entirely in the keto form despite the ready formation of its anion and successful methylation on oxygen 285) . In agreement with the aromatic nature of 490, the hydrocarbon undergoes electrophilic substitution reactions 283) .

OMe

NoH

KH Me0S02F

CH3I

OMe

497

495

490 CU(N03)2, AC20 AC^D,CH2CI2,

,0°C

BF3-Et20

Isomer X =

N0

12

CI2CH0Bu-n , TiCI4,CH2CI2 X = COMe X =

CHO

2-

5-

6-

40

5

40

15

20

0

75

5

4

0 93

3

J Peristylanes Garratt and White have pointed out the similarities in the topologies of 498-500 and their more spherical counterparts 501-503 286) . Following Eaton's lead 287) , they proposed to name 498-500 as [3]-, [4]-, and [5]-peristylanes, respectively, to reflect 81

V Simpler Molecules of Theoretical Interest

the size of the basal ring. T h e first m e m b e r of this series to yield t o synthesis was 498 and three a p p r o a c h e s are currently available. In expedient fashion, N i c k o n and P a n d i t pyrolyzed the sodium salt of the tosylhydrazone of n o r a d a m a n t a n - 2 - o n e 2 8 8 ) . Regiospecific C — H insertion leads directly and exclusively to 498. T h e synthetic entries devised by G a r r a t t and W h i t e both start f r o m carboxylic acid 504. Conversion t o tosylhydrazone 505 and pyrolysis of its s o d i u m salt a f f o r d e d azo c o m p o u n d 506 which itself on pyrolysis gave 498. Alternatively, 504 reacts with thionyl chloride t o provide chloro ketone 507. Once dichloride 508 was arrived at, reduction with sodium naphthalenide delivered 498. E a t o n ' s synthesis of [5]-peristylane (500)

287)

was discussed in o u r earlier review

1. Li AIH4

2.NCS,Me 2 S CO 2 H

f^X^l

3.TSNHNH 2 '

I.NaH 2.200-250°C N

TsNHN = CH

506

505

504 SOCI,

50tfC No+

1.NOBH4 2.SOCI?'

507

N

THF

498

A fully stereocontrolled p r e p a r a t i o n of 499 has recently been completed by Paquette a n d coworkers 2 8 9 ) . W h e n triene 508 was treated with />-toluenesulfonylacetylene, highly stereoselective addition f r o m the e n d o surface occurred t o deliver an a d d u c t which was directly epoxidized (Scheme XLI). T h e proximity of t h e t w o n b o n d s in 509 allows for ready photocyclization. Oxidative cleavage of 510 a f f o r d e d 82

J Peristylanes d i k e t o n e 511 which was desulfonylated after bisketalization. Stepwise r e d u c t i o n of 512 furnished the desired 499.

1.TsC = CH

hv CH3COCH3

2.MCPB A

(I eq)

508

509

510

Ts

HIO4 CH3OH,H2O

1. BF 3 ,Et 3 SiH 2.TsCI,py

>

II TsOH

3. L1AIH4

2.LI,ETNH2 3.H

499 Scheme

3

0+

512 XLI

A synthesis of a dimethyl derivative of 501 h a s also recently been a n n o u n c e d by H i r a o , et a l . 2 9 0 ) . F o l l o w i n g conversion of 513 t o its dimesylate, Lewis acid-catalyzed r e a r r a n g e m e n t gave dienedione 514 as the m a j o r p r o d u c t . H e a t i n g of the disemic a r b a z o n e of 514 with p o w d e r e d K O H f u r n i s h e d the diolefin which was t r a n s f o r m e d into 515 by ozonolysis. W h e n the d i t o s y l h y d r a z o n e of 515 was h e a t e d with p o t a s s i u m 0 fCU/OH

0 II 1.H 2 NNHCNH 2

1.CH 3 S0 2 CI, , 13-acetoxymodhephene (520) 294 \ 5-oxosilphiperfol-6-ene (521) 295>, 8-a-hydroxypresilphiperfolene (522) 296), 1-acetoxyisocomene (523) 297) , and several additional derivatives of this ring system 298) . From other laboratories have come the characterization of such interesting substances as magellanine (524) 299 \ paniculatine (525) 300) , arnicenone (526) 301 \ riolozatrione (527) 302) , stoechospermol (528) 304) , ptychanolide (529) 305) , yuzurimine (530) 306-307\ yuzurimine-A (531a) 3 0 7 ' 3 0 8 ) , macrodaphniphyllamine (531b) 309) , structurally related alkaloids of this family 3 0 6 _ 3 1 1 > ; laurenene (532) 312) , the only naturally occurring fenestrane molecule, and several oxygenated 1,7-diepicedrane sesquiterpenes 313) .

517

518

o

OAc

84

519

520

521

522

523

524

525

B Chemical Transformations

526 MeOOC

0 OAc

529

OR

530

'

531a , R = Ac 531b,R=H

532

B Chemical Transformations Cedrol (533a), its acetate (533b), and 8a//-cedrane (533c) undergo selective hydroxylation with ozone adsorbed on silica gel to produce 534a or b 314) . Cedrane oxide (555) gives the lactone 536 (30 %) and tertial alcohol 537, thereby revealing that —CH 2 0— and tertiary C—H groups are of similar reactivity. The conversion of 534b to C 1 4 -norcedrenol (538) has also been accomplished (Scheme XLII) 3 1 4 ) . With PhICl 2 , cedryl acetate affords the tertiary chloride corresponding to 534b. The autoxidation of 8J?-hydroxycedran-l 3-al has been reported 315) . Borohydride reduction of 9-oxo, 10-oxo- and 8-ene-10-oxo-cedranoids proceeds in general to give the (3-hydroxy epimer 316) . Details concerning the reductive ring opening of several cedrane oxides have been disclosed, as have the circular dichroism spectra of cedran-10-ones 3 1 7 ) . The configuration of the bromination product of dimethyl 8,13-epoxy-9-oxocedrane-12,15-dioate has also been established 318) . One of the sesquiterpene hydrocarbons previously obtained 319) by solvolysis of the /)-bromobenzenesulfonate of alio-cedrol has recently been shown to be identical with a-funebrene (539) 320) . The total synthesis of jalaric ester-I (540) has been accomplished through selective condensation of 16-hydroxy-(Z)-9-hexadecanoic acid and jalaric acid 3 2 1 , 3 2 2 ) . The possible importance of this compound in the elaboration of lac resin by insects has been pointed out. 85

B Chemical Transformations

526 MeOOC

0 OAc

529

OR

530

'

531a , R = Ac 531b,R=H

532

B Chemical Transformations Cedrol (533a), its acetate (533b), and 8a//-cedrane (533c) undergo selective hydroxylation with ozone adsorbed on silica gel to produce 534a or b 314) . Cedrane oxide (555) gives the lactone 536 (30 %) and tertial alcohol 537, thereby revealing that —CH 2 0— and tertiary C—H groups are of similar reactivity. The conversion of 534b to C 1 4 -norcedrenol (538) has also been accomplished (Scheme XLII) 3 1 4 ) . With PhICl 2 , cedryl acetate affords the tertiary chloride corresponding to 534b. The autoxidation of 8J?-hydroxycedran-l 3-al has been reported 315) . Borohydride reduction of 9-oxo, 10-oxo- and 8-ene-10-oxo-cedranoids proceeds in general to give the (3-hydroxy epimer 316) . Details concerning the reductive ring opening of several cedrane oxides have been disclosed, as have the circular dichroism spectra of cedran-10-ones 3 1 7 ) . The configuration of the bromination product of dimethyl 8,13-epoxy-9-oxocedrane-12,15-dioate has also been established 318) . One of the sesquiterpene hydrocarbons previously obtained 319) by solvolysis of the /)-bromobenzenesulfonate of alio-cedrol has recently been shown to be identical with a-funebrene (539) 320) . The total synthesis of jalaric ester-I (540) has been accomplished through selective condensation of 16-hydroxy-(Z)-9-hexadecanoic acid and jalaric acid 3 2 1 , 3 2 2 ) . The possible importance of this compound in the elaboration of lac resin by insects has been pointed out. 85

VI Natural Products Chemistry

~R

HO. 03,Si02

R=H

-78°C

HCOOH

533a, r=oh 533b, r = oac 533c , R = h O

534a,r = h 534b, R = Ac 03,si02

+

-78 °C H

HO.

R,

536

535

537

I.SeO^AcgO CHO ^OAc 2 . Li AI H 4

534b

OH (P^P^RhCI

OH

3, MnO-j

H

Scheme

538

XLII H \

H / c= c Vh2)5-ch20h

-COOH

OHC

CH2OH

539

540

The action of activated manganese dioxide on 541 gives the oxo-ether 542 as a single product in quantitative yield. On the other hand, 543 leads under analogous conditions to a mixture of six products 323>. The configurations of shellolic (544) and laccishelloic acids (545) have been correlated by conversion of the C 13 -hydroxymethyl function of the former into the methyl group of the latter via two routes involving reduction of an intermediate thioacetal and an iodo derivative, respectively 324) . Because of the absence of a suitably positioned C—H bond, the alkoxy radical derived from 546 cannot undergo heterocyclization. ^-Fragmentation therefore ensues to give 547 along with a small amount of parent ketone. An empirical predictive rule has been developed to account for the stereoelectronic control observed in such reactions 235) . Tricyclodehydroisohumulone (550), detected as a new bittering component present in beer and in stored hops, is formed in low yield by boiling aqueous humulone (549) in air. This highly functionalized triquinane, originally believed to possess an alternative structure 326) , is best prepared (30 %) by reaction of 549 with lead tetra86

B Chemical Transformations MeOOC

HO»

COOMe

COOMe MnQ2

Me

OO^

MeOOC

HO«.

,COOMe

CH2OH

__CH 2 OH

H

541

543 HO^^-cooh

HOOC ,

COOH

HOOC,

i™CH2OH

544

546

545

547

548

acetate 327) . On the basis of recent spectroscopic evidence the structural assignment to isohumulione A has been revised to 551 328). OH 0 Pb(0Ac) 4 HOAc 0°C

549

550

While the chirality of perezone (552) has been known for some time 329) , that of the a- (553) and (3-pipitzols (554) which are derivable from 552 by thermolysis was rigorously proven only recently by chemical transformation to cedrene and x-ray diffraction 330) . The cyclization of 552 has been shown to involve a concerted [4 + 2] cycloaddition which lacks stereochemical induction by the chiral center already present, since 553 and 554 are obtained in equimolar amounts 331) . However, a stepwise mechanism having higher stereoselectivity is followed by 552 in the presence 87

VI Natural Products Chemistry

of boron trifluoride ( 9 0 % of 553) 3 3 2 ) . T h e stereochemistries of the closely related cedranolides a-, (3-, and y-perezol have been assigned f r o m their respective O R D curves 330) OH

OH

,'J

H

552

553

554

Hydrogenation of endiandric acid (555) with an aged palladium catalyst afforded the dihydro derivative 556 which isomerized to the triquinane lactone '557 when heated with H B r in acetic acid 3 3 3 ) . Ph H

Ph H

H ch

Pd/C 2

co

2

h

555 Chemical modification of coriolin B (558) of rather extensive scope has been described 334 ' 335 >.

o—-

0C0(CH2)6CH3

558 Experimental studies delineating an extensive n u m b e r of chemical transformations of laurenene (532) 3 1 2 ' 3 3 6 ) , including the crystal structure analysis of a b r o m o derivative 3 3 7 ) , have been published.

88

A Cedranoids

VII Synthesis of Diquinane Natural Products

A Cedranoids Although cedranoid sesquiterpenes have earlier been synthesized, a renewed interest in alternative methods for elaborating these frameworks has arisen. The stereospecific approach to a-cedrene and a-patchoulene skeletons designed by Deslongchamps and summarized in Scheme XLIII is a case in point 338) . Beginning with the Stork-Clarke intermediate 559, the tetracyclic cyclopropyl diketone 560 was elaborated via a series of standard transformations. Treatment of 560 with three equivalents of sodium methoxide in methanol at room temperature for 20 min

COOEt 1.NaBH4 ,, \ >COOEt 2 . K 0 H , H ? 0 0=/ T Vf * AcO~< T X V^-yC H 3.AC 2 0,TSOH \ ^ / ' < H HO

1. NaOMe, M eOH

^-—-^.COOMe AcO~\ I X 2 . 2 0 0 - 210°C ^ ^ / C »

AcO 1.NaOH,H£>

559

2 . A C 2 0 , py

3. ( C OC I >2 4. C H 2 N 2 5. AG^D,

0 I^UN^

CH

•j

3 0

CH

560

561 Scheme

2. NoOH, 3

H

2

AcO

I

1. NoOH, HjP 2. A c 2 0 , p y "'H

0

3. J o n e s

CHN

2 3. (COCl) 2 4 . CH oNo

CHJOH

AcO

%

COOMe

562

XLIII 89

VII Synthesis of D i q u i n a n e N a t u r a l P r o d u c t s

gave the tricyclic enedione 561 (cedrene skeleton) as the only product. When the same reaction was carried out for 12 hr, the isomeric enedione 562 (patchoulene skeleton) was formed uniquely. Thus, 561 is the kinetic product and 562 the thermodynamic product. Yates and Stevens have devised an interesting synthesis of diketone 566 which is potentially adaptable to the introduction of additional functionality 339) . Taking advantage of the efficiency with which 563 enters into oxa-di-Tt-methane rearrangement and 564 undergoes homoconjugative addition, these workers gained access to 565. This keto ester was subjected to Rupe rearrangement conditions which led ultimately to 566 as shown.

563

564

565 1.NaCI,H£> DMSO 2.HC=CLi

KOtBu t-BuOH H

OX C02Me

H

1.HC00H, H 2 S0 4

Ts COMe

2. H 2 , Pt

q^r C02Me

OH

566 564

I.PhoCuLi

Ph

COOMe '

2. No CI , H20 DM SO

1. Et2AICN

o3,HOAcMeOOCv

2. H 2 0 2

COOMe '

3.CH 2 N 2 H

567 NC COOMe

2. No CI, H 2 0 DMSO

H2SO4 H

568 The viability of this synthetic approach to the introduction of a carboxylic acid function at C 2 has been demonstrated in two ways. Following lithium diphenylcuprate addition to 564, the newly introduced phenyl group is subsequently degraded by ozonolysis to provide 567. Alternatively, reaction of 564 with diethylaluminium cyanide in toluene gives 568 which is also conveniently transformed into 567 339,3401. Making elegant use of the intramolecular arene-olefin meta-cycloaddition reaction, Wender and Howbert have achieved a total synthesis of (±)-cedrene (5 73) 34 Irradiation of 569 led to an approximately equal mixture of 570 and 571 which 90

B Gymnomitrol

without separation were converted to cedren-11-one (572) by a bromination-reduction sequence. Wolff-Kishner reduction of this product gave 573 in 59% overall yield. OCH-A .OCH 3

hv

570

571 1. B r 2 ( I equiv), CH2CI2

2.( n - B u ) 3 S n H

H2NNH2 OH

573

572

B Gymnomitrol Gymnomitrol (579), a tricyclic sesquiterpenoid which occurs as a major metabolite of the liverwort Gymnomitrion obtusum (Lindb.) Pears, contains a rare 4,8-methanoazulene (diquinane) carbon skeleton with five adjacent chiral centers, three of them 1. R 2 N L i ,

> < t >

CN

CHOH

(EtO)2P(Q)CI

H2NOH

0

2 . H 2 , Pt / C 3 . N a H , HCOOEt

NoOMe

574

575 1.CH2=CHCH(0Et)2, C

6H6

A

2. H O ^ O H

1. Jones

.••\/CHO

2. A C 2 0 ,

0

HCIO4,

CH^CI ^

577

,H"

I.Li , N H 3 Me3SiCI 2.CH3U

c f c ^

0

CH3I

576

3 . 1.2 N H C I ,

acetone

1. ( ! - B U ) 2 A I H

2.H 2 Cr04 91

B Gymnomitrol

without separation were converted to cedren-11-one (572) by a bromination-reduction sequence. Wolff-Kishner reduction of this product gave 573 in 59% overall yield. OCH-A .OCH 3

hv

570

571 1. B r 2 ( I equiv), CH2CI2

2.( n - B u ) 3 S n H

H2NNH2 OH

573

572

B Gymnomitrol Gymnomitrol (579), a tricyclic sesquiterpenoid which occurs as a major metabolite of the liverwort Gymnomitrion obtusum (Lindb.) Pears, contains a rare 4,8-methanoazulene (diquinane) carbon skeleton with five adjacent chiral centers, three of them 1. R 2 N L i ,

> < t >

CN

CHOH

(EtO)2P(Q)CI

H2NOH

0

2 . H 2 , Pt / C 3 . N a H , HCOOEt

NoOMe

574

575 1.CH2=CHCH(0Et)2, C

6H6

A

2. H O ^ O H

1. Jones

.••\/CHO

2. A C 2 0 ,

0

HCIO4,

CH^CI ^

577

,H"

I.Li , N H 3 Me3SiCI 2.CH3U

c f c ^

0

CH3I

576

3 . 1.2 N H C I ,

acetone

1. ( ! - B U ) 2 A I H

2.H 2 Cr04 91

VII Synthesis of Diquinane Natural Products

CH3U

1 . POCI3 ,py 2 . Li AI Ha

0

579

578 Scheme

XLIV

quaternary. This molecule probably sets a record in that five different syntheses were reported in a span of only two months 342 ~347>. The Coates protocol (Scheme XLIV) centers about elaboration of hydroxymethylene ketone (574) into the tricyclic diketone (578). Alkylation of keto nitrile 575 proceeds exclusively cis to the angular methyl groups as does the subsequent reductive methylation. These authors were not able to achieve aldol cyclization of keto aldehyde 576 and consequently proceeded to enol lactone 5 77 342) . The addition of a methyl group to 578 could be achieved regioselectively. Subsequently dehydration gave 579 and its endocyclic isomer which were separated chromatographically. Paquette and Han chose to append their sidechain to 580 by preforming the a-methylene ketone 581 and carrying out a conjugate addition of a vinyl silane organo-

1. r O H . T s O H

-CO-

0^0

2 . WK 3.H30

+

PHNH2CH3 CFjCOCT

580

581 1. Me3Si ^ - ^ M g B r , CuBr'Me2S 2 . C H 3 I , HMPA

CHO

Me?

Si Me?

^MCPBA

CH30H

CH2CI2

582

576 2 % KOH, CH3OH

1.H2Cr04 ,0H

Scheme 92

XLV

2

-CH3U

1. P0CI 3 ,py

>0 H 2.UAIH41

CH

579

B Gymnomitrol

metallic reagent concurrent with methylation (Scheme XLV) 343) . Epoxidation and acid hydrolysis of 582 generated keto aldehyde 576 which they were able to cyclize with 2% potassium hydroxide in rhethanol. The remainder of the synthesis bears close similarity to the Coates approach. Welch's stereoselective synthesis centered about the tandem conjugate addition of a methyl group and allylation to produce 583 (Scheme XLVI) 3 4 4 ) . A second methylation, combined with oxidation of the allyl sidechain, gave 584 which was successfully cyclized under Claisen conditions. Trapping of the enolate as in 585 permitted differentiation between the two potential ketone carbonyl groups.

1. L D A ,

.Br c h 2 = C ; •CH Br 2

D ;

2.90% H 2 S0 4 KOH , EtOH

1. Me2CuLi

>-db

2.CH2=CHCH2CI 3-H 3 0 +

583 No H , CH 3 I

/ OSR

V

1. S i a 2 B H

LiN(SiMe

V V " ^

-4-Si — CI

2.H 2 0 2 ,0H~ CH

3°2

585

C

^

v

U=

''

Vf~

y;

3.Cr03,H^04 4.CH 2 N 2

sy^Vf"^ Ni—

584 1.NQBH4 2. CH 2 =C

/0CH3

POCIJ

3. Bu^N"*"F

1. Ph 3 P= CH2 2. 5 % HCI, CH30H R= -C(CH3)20CH3 Scheme

XLVI

579

In a clever adaptation of the acid-catalyzed addition of /»-quinone ketals to olefins J 4 5 ) , Biichi and Chu condensed 586 with 1,2-dimethylcyclopentene in the presence of stannic chloride and immediately reduced the two diastereomeric adducts with sodium borohydride 346) . The major alcohol 587 was separated, catalytically hydrogenated, and converted to the tetrahydropyranyl derivative 588 (Scheme XLVII). 93

VII Synthesis of Diquinane Natural Products

The subsequent conversion to gymnomitrol proved uneventful and the overall sequence is the most expedient yet devised.

586

587

& THRO

1.Ph 3 P = CH2 2. HOAc, H^D-THF

588 Co , N H ,

H

579 Scheme

XLVII

The last synthesis to evolve which is due to Ito and his coworkers is interesting in that it relies on a stereospecific skeletal rearrangement of a bicyclo[2.2.2]octane system which in turn was prepared by Diels-Alder methodology (Scheme XLVIII) 3 4 7 ) . Heating of a toluene solution of cyclopentene 1,2-dicarboxylic anhydride and 4methylcyclohexa-l,4-dienyl methyl ether in the presence of a catalytic quantity of />-toluenesulfonic acid afforded 589. Demethylation was followed by reduction and cyclization to sulfide 590. Desulfurization set the stage for peracid oxidation and arrival at 591. Chromatography of this intermediate on alumina induced isomerization to keto alcohol 592. Jones oxidation afforded diketone 593 which had earlier been •transformed into gymnomitrol.

CH

+

tol u e n e

3°

Q

1. B B r 3 , C H 2 C I 2

'

TsOH A

•0

OCH?

H0

2, Li Al H 4 3.CH3S02CI,py 4 . N a ^ , HM PA

590

589 1. Li, EtNH 2 2.MCPBA

1. J o n e s 2 . as above

579 Scheme 94

XLVIII

ai

2°3

C Pentalenolactone

C Pentalenolactone Pentalenolactone (593) is an antibiotic, t u m o r inhibitory agent whose provisional structural assignment was later revised on the basis of x-ray studies. Biosynthetic studies show pentalenolactone t o be of sesquiterpenoid origin 3 4 8 ) . T w o syntheses of 593, due t o Danishefsky 3 4 9 ) a n d Schlessinger 3 5 0 ) , have been reported t o date. In the first (Scheme IL), the operating strategy was t o arrive at keto ester 592 by DielsAlder cycloaddition. Following i n c o r p o r a t i o n of the essential stereochemical inform a t i o n in this manner, an additional five-membered ring was crafted and the cyclo-

J

Me02C Me02C

OMe

0 . Me^SiO ,x —

3. OH 4. EtOC= CH

MeO

Me^SiO'

1. BatOHig 2.NaHC0 3 , ch3i

592

3.OSO4

MeO

OH OH

1. Pb(OAc >4 2 . N 0 B H 4 ,OH~

H

T O^-H

H

.Pd-BoS04 3.Pd-BoS04 toluene, A toluene, A

n

H c

3.H 3 OyMeOH

X V0' H H

R02C

H

1.CH3CH = PPh 3 2. HCI 3. Jones 4. CH3OH,H + H COOMe H H ^ COOH Me

H

1.SOCI2 2. Al CI 3 , CH 2 CI 2

CO^e

1. PhgP= CH2 2.H 2 .(Phj^RhCI^ 3.(Me 2 N)^H0t_Bu , 95°C

Me

4. H 2 0 , s i l i c a gel

HO-HC V - ^ - H ^

'Me

1.NaBH4 2.CH3S02CI, py 3.DBU

593 Scheme

IL

95

VII Synthesis of Diquinane Natural Products

hexenone subunit was modified so as to become the epoxy lactone portion of the natural product. The quite different route implemented by Schlessinger commences with an expedient construction of the diquinane nucleus 594. This accomplishment is followed by an interclude of functional group reorganization. The concluding steps are concerned with appropriate introduction of carbon atoms 14 and 10 (Scheme L).

MeO

1.LDA,CH2=CHCH£I „ , „„ 2.LOA,

MeO

^COOEt rf

COOEt COOE COOEt

NqH OC(OMe) 2 DM E

^COOEt

1. N0BH4 2. CH 3 S0 2 CI, Et3N 3. col I i d ine, A

~V-CH(OMe) 2

MeO

1.03,Me2S 2.HC(OMe)3,

O, H

MeOH , H + 3. P h 3 P = CH2

CHO




Hg(OAc)2 2. 145 -150°C il. decalin

1. h 2 n n h 2

—

2.12, EtjN ,TH F

/ ^ ^ ^ ^ O LH-j

ch,

.

ch

598

597

596

3 Ni(C0)4 , NaOMe, MeOH OCH,

J,

^TiiiH n3

600

A

1. MeOMgOCC^Me

2.H,0+

CH,

3 3. HCHOjft^Hgl^NH^i ¿ c °3 HOAc.NaOAc dH3

^

1.10%H2S04 CH3 2.Jones COOCH3

CH 3 "

COOCH3

599

Scheme LI

E Quadrone Interest in the total synthesis of the Aspergillus terreus derived quadrone (606), an antitumor agent 354) , has been very intense. Success was first realized in Danishefsky's laboratory 355) . Once 601 was reached, its sidechain was elaborated and ring closure effected (Scheme LII). Condensation of 602 with 1 -;er/-butoxy-1 -;eri-butyldimethylsiloxyethylene in the presence of titanium tetrachloride and subsequent desilylation resulted in introduction of an angular acetic acid moiety. The two sidechains were next connected by intramolecular alkylation and the resulting keto acid was subjected to selenenylation in order to produce 603. The a, ß-unsaturated double bond was used to force enolization to the a' position. Indeed, 604 was 97

VII Synthesis of Diquinane Natural Products

obtained conventionally. However, upon exposure to /?-toluenesulfonic acid in refluxing benzene, 604 gave predominantly 605, an isomer of quadrone. On the other hand, heating 604 to 190-195 °C in the absence of the solvent induced proper lactonization and resulted in the formation of 606. hO^-OH,H + 2.B2H6

Xx

BrMg-^

3.H2O2 ,OH~

BU3P-CUI

4.CH 3 S0 2 CI,

C

MeO.

MeO

°2MeMe02C^°"

601

Br

5. Li Br,ace tone 6.H 3 0 +

COOMe NaOMe, MeOH,0°C

_H 1.1 M HCl, A HO 3. HO'"—OH, H+ MeO^C 4 . N a I .acetone

2

-Bu4N

+ F

"Me02C

602

1. L i N ( S i M e 3 ) 2 2. TsOH, acetone 3. PhSeCI 4. H 2 0 2 , py

Scheme

LII

The Helquist approach to quadrone begins in the same fashion and has many close similarities to the Danishefsky effort. Importantly, however, a key element of novelty in Scheme LIII is the deplopment of a lactone annulation procedure which bypasses the regiochemical complications earlier encountered 356) . 98

E Quadrone 1.CH,Li,

1.CH2= CHMgBr, CuBr • Me2S

BrCH2CH(OEt)=CHKQCH 3 ) 2 2.1 N HCI 3. NaH , DME ' ÒSI(CH3)3

2. Me^SiCI, Et3N

H.\

Li I 1. PhSCHCOOMe 2.CH 2 0 3.NaBH4 4.(CH 3 ) 2 C(OCH 3 ) 2 ,H +

x

1. 9-BBN 2.H202,0H-

CO,Me 2 3, TsCI , py 4. NaI , acetone

I! 1. Li , NH3 C0

^e

2.NH4CI

SPh C02Me

1. Li N( Si Me3'2 2. 1 N HCI 3. KOH 5. Ac 2 0, py

1. OH" 2. A C 2 0 , p y 3 PCC

OH ' C02Me Scheme

200° C CO2H

LIII

The starting material in Burke's phenomenologically different approach to quadrone was a spiro[4,5]decadienone which is readily available from 2-methyldimedone isobutyl ether (Scheme LIV) 357) Oxidative cleavage of the trisubstituted double bond in 606 set the stage for controlled intramolecular Michael addition (11->12) 12) . Once aldol cyclization to give 607 had been accomplished, the remaining major obstacle was installation of the lactone ring. The ester sidechain in 608 was introduced through combined application of Wharton and Claisen rearrangements and a one-carbon degradation scheme. Keto ester 608 linked up with both previous syntheses of quadrone. An interestingly short total synthesis of quadrone was developed by Kende and coworkers who made application of Pd(II)-mediated cycloalkenylation of silyl enol ethers (Scheme LV) 358) . Their point of departure was 609 which was converted directly to 610. Reaction of this silyl enol ether with palladium acetate in acetonitrile gave predominantly 611 which could be cyclized to 612. From this intermediate, it was possible to prepare the known keto acid. 99

VII S y n t h e s i s of D i q u i n a n e N a t u r a l P r o d u c t s 1.0s 0 4 ,

CHO

CT>H

CH-y

N /

2.NqI04

Ts O H ,

Me

C

6

h

6-

A

powdered NaOH, di b e n z o l8-crown-6 1.Et0CH=CH2, Hg(0Ac)2 2. xylene, A

1.

ho^-oh,H

+

2. t - BuOOH.OH"

H-

3. H 2 , Pd/C CHO

3. H 2 N N H 2

1. Ac^D, K O A c 2.0s04

1N0IO4

1.Jones ~C02Me

CHO 2 . C H 2 N 2

Scheme LIV

608

It is seemingly important that the lactone ring be formed last due to the strain present in the quadrone molecule. This conclusion is based upon Paquette's findings that cyclization of intermediates such as 613-617 could not be induced under a myriad of conditions 352) . The preparation of 620, a tricyclic intermediate suited for elaboration into quadrone, has been reported by Monti and Dean 359) . Following introduction of the proper C 5a stereochemistry by alkylation of 618 under kinetically controlled conditions, diketone 619 was subjected to acid-catalyzed rearrangement. After functional group manipulation, a tandem intramolecular aldol-pinacol rearrangement gave 620. A synthesis of descarboxylquadrone (621) has been described 360) . The presence of the a, (3-unsaturated carbonyl system causes this substance to be biologically active, presumably in parallel with the latent a-methylene cyclopentanone functionality believed responsible for the cytotoxic activity of quadrone. 100

E Quadrone 1.CH3CU•BF3

rv"

2.NaH,(MeO)2CO 3. NaH , BrCH^COOEt 4. L i I , 2 , 6 - lutidine

\

°

LDA |

Me 3 Si Q

COOEt OSiMe 3

COOEt

609 Pd(OAc)2, OUCN

Scheme

LV

OSi Me,

H\/OCH2Ph

H V-0CH2Ph H

CH

0Si(CH3)3

3

616

617 101

VII Synthesis of Diquinane Natural Products

1. LiN(SiMe 3 ) 2 , ICH 2 C = C H 2

HCOOH

2. Hg( OAc) 2> HCOOH 3. 10% HCl

HO H

H 1.H0' 2. NaH, -I—Si — CI I 3.10% HCl 4. Me2CuLi 5.(CH 3 ) 2 C = 0, H+

0

1.LDA, CH2=CHCH2Br 2. LDA, BrCH 2 C00Et 3. Me 2 CuLi

621

1.Sia 2 BH COOEt

0

^CHO .COOEt

2. ( COCI ) 2 , DMSO

1. HCl 2. P0CI 3 , py 3. H 2 , Pd/c

1. KOiBu

1.hs^-sh,BF3

2.LDA,CH 2 0

2. KOH , EtOH

3. H 2 , Pd/C 4. TsOH

3.CH 3 Li 4.Hg + 2 ,CH 3 CN

COOEt

F Carbaprostaglandins "Prostacyclin ( P G I 2 , 622) appears to play an i m p o r t a n t role in preventing stroke, thrombosis, and heart attack 3 6 1 , 3 6 2 ) . However, this substance is very unstable because of its labile enol ether linkage. This p r o p e r t y has p r o m p t e d intense research ,C0 2 H

622 102

VII Synthesis of Diquinane Natural Products

1. LiN(SiMe 3 ) 2 , ICH 2 C = C H 2

HCOOH

2. Hg( OAc) 2> HCOOH 3. 10% HCl

HO H

H 1.H0' 2. NaH, -I—Si — CI I 3.10% HCl 4. Me2CuLi 5.(CH 3 ) 2 C = 0, H+

0

1.LDA, CH2=CHCH2Br 2. LDA, BrCH 2 C00Et 3. Me 2 CuLi

621

1.Sia 2 BH COOEt

0

^CHO .COOEt

2. ( COCI ) 2 , DMSO

1. HCl 2. P0CI 3 , py 3. H 2 , Pd/c

1. KOiBu

1.hs^-sh,BF3

2.LDA,CH 2 0

2. KOH , EtOH

3. H 2 , Pd/C 4. TsOH

3.CH 3 Li 4.Hg + 2 ,CH 3 CN

COOEt

F Carbaprostaglandins "Prostacyclin ( P G I 2 , 622) appears to play an i m p o r t a n t role in preventing stroke, thrombosis, and heart attack 3 6 1 , 3 6 2 ) . However, this substance is very unstable because of its labile enol ether linkage. This p r o p e r t y has p r o m p t e d intense research ,C0 2 H

622 102

F

Carbaprostacyclins

in the preparation of a chemically stable analogue whose therapeutic potential is also high. One primary focus of attention has been 6a-carbaprostaglandin I 2 (623). Nicolaou's synthetic plan (Scheme LVI) begins with c/.s-bicyclo[3.3.0]octane-3,7dione and proceeds after monoketalization to append the lower sidechain as in 625 363).

i

1. H O ^ ' O H ,H + 2.H0AC, aq THF 3. NaH , OC(OMe >2

5

3Ph

MeOOC 1.NBS 2. PhSeNa , 3.H 2 0 2

3.CH 2 N 2 COOMe 4. PhCOOAg, CH30H

9

626

627 1.OSO4 ,

NQTO4 2. Jones 3.CH 2 N 2 4. HO/^OH, H+

r ^ 0^.0

623

Scheme LVII

several

OTHP

MeOOC /

COOMe /

1. IMaOMe, DMSO

3.

L1AIH4

628 103

VII Synthesis of Diquinane Natural Products

Involvement of 625 in a Wittig reaction with 4-carboxybutyl(triphenyl)phosphorane dissolved in dimethyl sulfoxide generates a mixture of double bond isomers rich in 623. The Kojima-Sakai approach, which makes use of trans-cis diester 626, is summarized in Scheme LVII 364) . This intermediate was homologated by the ArndtEistert method, converted to olefin 627, and oxidatively cleaved to produce ultimately the diester 628. Dieckmann condensation was used to construct the diquinane core which was subsequently transformed to 623 by standard reactions. The first synthesis of 623 in optically active form is due to Morton and Brokaw 365) . Reaction of resolved cyclobutanone 629 with dimethylsulfonium methylide and ring expansion with lithium iodide in tetrahydrofuran gave the isomeric cyclopentanones 630 and 631 (major) (Scheme XVIII). In the next step, 631 was reduced with sodium borohydride, acetylated, and hydrolyzed to endo aldehyde 632. This substance was then condensed with «-hexylidenetriphenylphosphorane, saponified, and oxidized to generate the presolvolysis ketone 633. Following hydroxylation, the isomeric cis glycols were treated with triethyl orthopropionate and rearranged in anhydrous formic acid. The formate mixture was hydrolyzed and exposed to sodium metaperiodate to give a keto diol which served as precursor to 623.

1.Me2S=CH2 2. Li I , THF H

H H

629 1. NaBH4

l.0s0 4 ,

c wT V ° "ch3

0

A

2.CH3CH2CH(0Et)2- C ^ k p ^ py. HCl H H H 3. HCOOH , 25°C

Scheme

LVIII

4. K 2 C 0 3 , aq CHjOH 5. N a I 0 4

633

2.AC20, py 3.88% HCOOH OAc 1. Ph3P=A/V 2.0H"

3.Jones

C ^ ^

0

H H H

632

The same feat was achieved by Hayashi and coworkers who began with the readily available, optically active lactone 634 (Scheme LIX) 366) . Cleavage of the oxygenated ring followed by reaction with excess lithio trimethylsilylacetate afforded the a, (3unsaturated ester 635. Hydrogénation, ring closure, and demethoxycarbonylation proceeded without event to furnish ketone 636 and its epimer which were separated 104

F Carbaprostacyclins

chromatographically. A second route to the same ketone was realized from the optically active hydroxy acid 637. The conversion of 636 to carbaprostacyclin followed established protocol. Ikegami has devised an interesting approach based upon 1,3-cyclooctadiene monoepoxide as starting material (Scheme LX) 3 6 7 ) . Transannular cyclization, Sharpless epoxidation, and silylation leads to 638 which is opened with reasonable regioselectivity upon reaction with l,3-bis(methylthio)allyllithium. Once aldehyde 639 had been accessed, «-amyllithium addition was found to be stereoselective, perhaps because of the location of the ;e/7-butyldimethylsilyloxy group. Nevertheless, 640 is ultimately produced in low overall yield. This situation is rectified in part by the initial formation of 641 and eventual decarboxylative elimination of 642 to arrive at 643. An additional improvement has appeared in the form of a 1,2-carbonyl transposition sequence which successfully transforms 641 into 644 368>.

A

1. NaOH MeOOCCH 1.H 2 ,Pd/C 2.CH2N2 Kj.-^COOMe 2-K0LBU< 3.Cr0 2 CI 2 , V - ^ ^ O ^ ^ P h 3.HMPA, I75 C t — BuOH,py OTHP OTHP 4.Me3SiCHC00Me

r f OTHP

634

635

. Ph

636

1. Bu3SnH, AIBN.hv 2 . Q ) H1 COOH

J OH

1.KOtBu 1. CH 3 T,K 2 C0 3 -COOEt 2.HMPA, 2.CH 3 C(0EI) 3 , a Ay"^COOMe 3.NBS ,Ph V - O ^ P h DM SO H20

637

\J

B

" 5 X o . OH

,Ph

Scheme LIX

Recently, more economical routes to carbaprostaglandins have been developed. Beginning with the commercially available, optically active lactone 645, Skuballa and Vorbrtiggen achieved a clever replacement of the ring oxygen atom by a methylene group (Scheme LXI) 3 6 9 ) . The subsequent conversion of 646 to 647 was accomplished in 88 % overall yield. After ketalization and sidechain oxidation of this intermediate, these workers prepared 648 which proved to be an analogue with the same pharmacological activity profile and efficacy as 623. This activity is not seen with many analogues 370) . Seemingly, Aristoff has designed the most practical synthesis of prostacyclin to date. In his ingenious approach to optically active 623, 648 was treated with 105

VII Synthesis of D i q u i n a n e N a t u r a l Products

0

1.LDA 2.t_-Bu00H, VO(acoc)2 3. H— Si CI, I imid

1.MeS^gfSMe ^V"'''! W 0

2.HgCI2 ,CoC03 h20,ch3cn

HCf

638

6 ste ps

1.Ü-CsH^Ü 2 . Q , H+ 3. Bu 4 N + F~

, c ^'C5H11 i 5 * -SiO -(— SiO thpo 1 I

641

-C5H11 thpo~'h

1.CH3S02CI,Et3N 2.KOH ,EtOH 3.MCPBA •C5H11 4.LiAIH4 THPO THPO H 5.Cr0 3 >2py

640

I.NaH , OC(OMe)2 \ 1 . T s N H N H 2 2 K 1BU

- ° ; I(CH2)4COOMe

2. n - BuLi

3.Bu44N+F- 4.

COOMe

CI-HA ^o \ COOMe

1. NaBH4 ,COOMe 2.CH3S02CI, iI .

1

^

642

CcH.. 2c0 5 11 3.NQ0H,H r u oh nL1 ch 3 4.CH2N2 1. NBS, DMSO - H20 2.Bu3SnH,AIBN 3. PCC I

THPO Scheme LX

644

OTHP

lithium dimethyl methylphosphonate and subjected to modified Collins oxidation (Scheme LXII) 371) . Cyclization of 649 could not be accomplished using standard methods. However, with potassium carbonate and 18-crown-6 in warm toluene, 650 106

F Carbaprostacyclins 1

/?

0 - f ^

1.+-

•

• -

1. J o n e s 2.DBN.THF

2. Li CHgCOOEt OH

OCOPh

3.TsOH,toluene

4.K2C03,CH30H

EtOOC

COOEt

Si-CI,imid.

psi^

3. N a B H 4

CO

OSi-

OH

646

645 1. D A B C O , toluene, H20, A 2 . P h COCI 3. H 2 0 , H O A C

COOH

severol steps OH

OCOPh

Scheme LXI

was obtained in 77% yield. Reduction with triethylammonium formate in the presence of palladium catalyst led to the cyclopentanone derivative which was transformed to 623 by sequential Wittig reaction with (4-carboxybutyl)triphenylphosphorane and hydrolysis.

HO

K OTHP

LiCH2P(OCH3)2

Cr03-2py

~ OTHP

OTHP

0 II CH,P(OCH,). 3;2

0 0 ^ch 2 cch 2 p(och 3 ) 2

OTHP

648 K2CO3 18-crown-6, toluene, A

623

i.Ph3P= 2.H30 +

,COOH

rf OTHP

HCOg HNEtj 5% Pd/C toluene , A

OTH-P

OTHP

Scheme LXII

107

VIII Synthesis of Triquinane Natural Products

VIII Synthesis of Triquinane Natural Products

A Linear Triquinanes 1 Hirsutine In 1976, Nozoe, et al. isolated and identified hirsutene {651) f r o m an extract of the mycelium of Coriolus consors. M a t s u m o t o has described the transformation of the protoilludene 652 3 7 2 3 7 3 1 and humulene {653) into 651 and other c o m p o u n d s possessing this c«,a«//,cw-tricyclo[6.3.0.0 2 , 6 ]undecane c a r b o n skeleton 3 7 4 '. Beyond this, hirsutene has proven to be a popular synthetic target and fertile testing ground for new and interesting synthetic protocols. F o r example, T a t s u t a ' s elegant stereoH CH2

H

H

H CH2

652

651

653

OAc

0

657 Scheme 108

656

655

654

LXIII

1. NaH , CSg , CH3I

4. Li Al H 4

A Linear Triquinanes

controlled synthesis (Scheme LXIII) began with the head-to-head photocycloaddition to 654 to 655 375) . Following functionality modification to give 656, skeletal rearrangement was effected in high yield by heating with potassium carbonate in aqueous acetone. This transformation is facilitated by the breaking of parallel C—C bonds. Once the norketone 657 was in hand, the formal synthesis was completed, since this substance had previously been transformed into 651 376>. For Greene, hirsutine proved to be a molecule which could be prepared by iterative application of his three-carbon annulation procedure 3 7 7 ) . 4,4-Dimethylcyclopentene was cycloadded to methylchloroketene and the resulting cyclobutanone was ring expanded with diazomethane (Scheme LXIV). Once a double bond was introduced as in 658, the sequence was repeated with dichloroketene to produce 659. Hydrolysis ultimately led to 657.

CI

H

s

>

CH 3 > A Ì Ì • C H 3 - ° c

h

3 ^

H

^ A Y H ^ Ô

2.CH2N2

1.N0BH4

C H 3 ' 2 . C r ( C I 0

4

)

CH 2

C H

3 V 3

^U

V ^ f v

H

Scheme

CH3

1

CI -CI>=-° 2.CH2N2

H

LXIV

Hudlicky saw in 651 an occasion to apply a-diazo ketone cyclization methodology 378) . With cyclopentene aldehyde 660 as the starting point, dienyl carboxylic acid 661 was elaborated and transformed into 662 (Scheme LXV). Cyclization, thermal isomerization, and catalytic hydrogénation gave 657 and ultimately hirsutine. 1. CH 2 = CHMgBr 2.CH3C(0Et)3,H CHO

+

1.(C0C1)2

Hg(OAc) 2 3 . KOH , H^D

660

COOH

2.CH 3 CHN 2

662

661

Cu(ocac)2 C6H6 , A

1. H 2 , 651

Pt 2. P h 3 P = CH 2

580 C

Scheme LXV 109

VIII Synthesis of Triquinane Natural Products

1. NaBH4

/ ° Y °

H

2.(i-Bu)2AIH

1. P h j P = CHCOOMe 2 -PCC

O COgMe ' H

'

CO,Me

663 1. I J A I H 4 2. - t - Si - CI , im id I 1. NoOMe, HCOOEt 2.n-BuSH

1.BH3-THF 2. PCC 3 . Bu 4 N + F~ 4 . PCC 5.(Ph 3 P) 3 RhCI

3. KOt- Bu, CH 3 I 4. KOH.HO—"'OH 5 . P h 3 P = CH 2

651

t

1.Mg 2.Cu Br • MegS 3. Br

COOMe

&

.0

MeOgC

. The mold metabolite has also been attained in clever fashion from 666 using meta-photocycloaddition methodology 382) . CuL! OSi -h) 2 2.EtjBzN CI" K F - 2 H20 3-TsCI , py

1. LiN(SiMe3)2 OTs

2. NQBH4 3 . N A H C H

,

3

C S 2 ,

I

4. BujSnH, AIBN

665

651 1. NaI04 2.(MeO) 3 P,

1.

R S O J H , C

AcO

1. hv 2.LiAIH4

6

H

6

, Û

2.PHSH ,A

r— SCgHg

3. Hg , [lr( cod)py PCy 3 >F 6

666 2 The Capnellene Group Capnellane is the generic name applied to a group of sesquiterpene alcohols and the hydrocarbon isolated from the soft coral Capnella imbricata 3 8 3 ) . A 9(12) -Capnellene (667), the presumed biosynthetic precursor of the capnellenols, was first synthesized in 1981 by Stevens and Paquette 384) . Their synthetic plan called for the construction of bicyclic ketone 668 and its appropriate annulation. The latter event was achieved by application of the Rupe rearrangement to 668, conjugate addition of a vinyl group to 669, ozonolysis, and cyclization (Scheme LXVIII). Hydrogénation and olefination completed the sequence. More recently, Little has synthesized 66 7 3 8 5 ) during his studies of the applicability of 1,3-diyl trapping reactions to the construction of tricyclopentanoids 3 8 6 ) . Capitalizing on a reversal of the " n o r m a l " regioselective mode of these transformations which gives rise to linearly fused triquinanes, he decomposed diazene 670 in refluxing acetonitrile and immediately subjected the product mixture to a hydroboration111

V I I I Synthesis of T r i q u i n a n e N a t u r a l P r o d u c t s

1. C H 2 = C H M g B r

Q

2.Mn02

1.HC =

3 . P 2 0 5 , CH3S03H

2 . HCOOH

4 . Me 2 C u Li

CH-,

CLi

(h2so4)

668

669

1 . C H 2 = CHMgBr 2.03-, Me2S 3 . HCOOH

1. h 2 , Pt

KOH

2.Ph 3 P = CH 2

667 Scheme

LXVIJI

oxidation sequence (Scheme LXIX). The less dominant ketone 671 gave A9(12)capnellene upon Wittig olefination.

¿6

SCHEME l

x n

H

1. CH 3 CN, A B2H6

9H2

3. H 2 0 2 , 0 H " 4.PCC

0

H

670 CH-3

CH3CH3

• .CH3 Ph3P=CH2

0

Scheme

CH 3 CH 3

LXIX

0

H

CH 3 CH 3

671

667

Oppolzer and Battig have prepared the marine sesquiterpene via ingenious application of iterative intramolecular "magnesium-ene" reactions 387) . Aldehyde 672 was converted to the allylic chloride 673, the Grignard of which was heated at 60 °C for 23 hours and subsequently treated with acrolein to furnish alcohol 674 (Scheme LXX). An analogous sequence transformed 675 to 676 and set the stage for final transformations which were patterned after earlier work. 112

A Linear Triquinanes Me

1. Mg 1.CH2=CHLI > ^ = 0

A-i-s

2.60°C

V+ii0H

2.S0CI2

H

673

672

674 I SOCI 2

Me

Me

!] CH3LI

Me

1.

Mg

2.

RT,20h

3. 0

2

H II

OH

676 1.03; Me2S 2 . KOH 3 . H 2 , Pt

CI

675

H

Me

4. P h 3 P = C H 2

HH

667

Scheme LXX

Two transannular cyclizations have been reported which lead to isomers of 677. Thus, treatment of 677 or 678 with boron trifluoride etherate gives rise to A8(9)capnellene (679) 388) . Also, conversion of humulene 6,7-oxide (680) to tricyclic epoxide 681 389) has provided the opportunity for trimethylsilyl triflate-promoted

B F 3 - EI- 2 O

BF3«Et20 C6H6,A

C6H6.A

677

680

678

several

1. T M S O T f

steps

t o l u ene 2 . 1 N HCI

681

682 several steps

683 113

VIII Synthesis of Triquinane Natural Products

isomerization to the methyl migrated product 682, from which A 7 -capnellene (683) was fashioned 390) . Pattenden and Teague have prepared tricyclic diol 684 which is epimeric to the naturally occurring A 9(12, -capnellene-8p,10a-diol (685)391'. Their strategy, which is summarized in Scheme LXXI, encompasses two critical cyclization steps. The first is the Lewis acid-catalyzed ring closure of enol acetate 686 and the second involves reductive closure of acetylenic ketone 687. It is of interest that the oxidation of 688 proved to be stereospecific.

¿ S * ^ to*" 686

SnCl4 moist CH 2 CI 2 1. KN( Si Me-j) CI 3 ' 2 2. L1AIH4

4.PCC H

OH

H

OH

t-BuOOH Se02

684

Scheme

LXXI

3 Coriolin Coriolin (689), a metabolite of the Basidiomycete Coriolus consors, has attracted widespread interest because of its unusual anti-tumor activity and highly functionalized triquinane structure. Accordingly, a number of syntheses of 689 have appeared on the scene. One of the earliest, due to Tatsuta, et al., begins with epoxide 690, whose preparation had been earlier realized in connection with their work on hirsutine (see Scheme LXIII). Deoxygenation of 690, hydrolysis, and cis-hydroxylation provided keto triol 691 (Scheme LXXII) 392) . The derived acetonide was transformed via 692 into tetraol 693 which could be selectively acetylated and dehydrated on both flanks of the carbonyl group. Deacetylation of 694 followed by epoxidation completed the synthesis. 114

A Linear Triquinanes

OCHoOCH-a

1.

NQI

,Zn

OH

1.(CH3)2C(0Me)?, H+

DMF

2.PCC

2-H30 + OH

3 . OSO4.,

C(r M°e=^P ° Me H

696 T.KOtBu 2.TS0H

Me

1.Li,NH3,

\ Me OH

2-MCPBA

^MetlnV HO'xH Me

1 . KOt Bu

MeOH

699

2 . HOAc 3. (j.-Bu)2AIH

698

697

1.PCC 2.LDA, PhSS02Ph

h2o

2

OH"

689

PhS

700 Scheme

LXXIII 115

VIII Synthesis of Triquinane Natural Products 1. (CH 3 ) 2 CUIJ

•SiO I 8 steps

H

3. L i , N H 3

Me Me

+

4. C Vl ' H 5. B U 4 N + F ~

701

Me

HO

2 . KOt B U , C H 3 I

H

OTHP

702 1

1.PCC

2 . Na H , 3. PdCI 2 ,CuCI,

02,DMF-H20

1. KOt Bu

3. L D A . P h S e C I 4. H 2 0 2

5.H30

Scheme

Me

2. L D A , C H 3 I

689

H

OTHP

+

703

LXXIV SiMe 3 1. K H ,CH 3 SSCH 3

SCH 3

Me

Me

2. KH, iJl^SiMej

jte

HO 1.MCPBA

2.BH4N+ F" CH 3 S'O 2

SCH 3

2CH3

707

706

705

S0

1. CH 2 l2, Et 2 Zn 2. H 2 , P t 3. S0CI2, py 4. MCPBA 1.Li, NH 3 2.MCPBA

..o

1. H-AO

2. DBU, C HgClg

CH3SO2

709 NSiMe, 2.LDA, Me 3 SiCI 3. CH2= N + Me 2 Cl 4. CH,I ; DBU X

708

several steps

Scheme 116

LXXV

>QXf> -y

689

o—\

SO 2 CH 3

A Linear Triquinanes

To arrive at racemic coriolin, Danishefsky and coworkers chose to add an acetonyl fragment to a bicyclic enedione by Diels-Alder chemistry (Scheme LXXIII) 393 . 394 >. Treatment of the resulting adduct 695 sequentially with a series of conventional reagents produced the key intermediate 696. Suitable aldolization delivered 697, the functionality in which was adjusted by deconjugation and reduction. Further reduction of .

.Me

0MeH

0

228

oOo

Me

1.CH 3 MgI 2.POCI 3 , py 3. Li, NH 3 4.MCPBA 5. BF 3 - Et^O

1.LDA,Me 3 SiCI 2.Pd(0Ac) 2 Me M • Me OH

3.H30+ o 4. LDA.PhSeBr 5.H202

1. LiAIH(OMe) 3 2.K01BU,CH3I

1, CICOOEt, py 2 . 0 3 -, Me g S

3. Li , NH 3

3.NOBH 4 4. -I— COCI, py

718 4 Hirsutic Acid T h e first stereocontrolled synthesis of ( + )-hirsutic acid (720) was achieved by T r o s t 4 0 0 ) . In this work, f o u r of the seven a s y m m e t r i c centers are fixed in the correct relative stereochemistry in bridged bicyclic c o m p o u n d 721 which in t u r n is f o r m e d by 118

A Linear Triquinanes

two intramolecular Michael addition reactions (Scheme LXX'VII). This key intermediate was reduced, hydrolyzed, and lactonized. Hydrolysis of the nitrile to give 722 set the stage for conversion of the double bond to methyl groups. Tricyclic lactone 723 was hydrolyzed and transformed conventionally to a known methyl ketone. Aldolization furnished 724 which earlier had been transformed to hirsutic acid. C0 2 M e

1.LDA) MejSi - = — CH^r

1. H3Q-f> 2.Et3N, toluene, -COOMe A

2. KOH , MeOH 3. LDA, C02 4.CH2N2

1.Hg, Pd/BaCOj 2. BrZnCH^COOEl CHO 1.NBS 2.L1Br,Li2C03 DM F 3. K2C03,Me0H 4. PCC

C02Me

Ch2OAc

1-NaOMe 2.BH3-THF MeOOC 3.AC20, py

DHTI , 1. K2C03, MeOH 2.NC1BH4 3-Ph3P =^NC00Et)2 4.HCI , MeOH

1.0 3 ; Me2S H 2. CH3SH,^ MeOOC BF3- Et20 3. RaNi . MeOOC 722

723 1.KOH 2.H30* 3. CH^i 4.CH2N2 5. PCC

' 720 Scheme

H'

H

7 2 4

LXXVII

Ikegami's successful synthesis of racemic 720 materialized by initial conversion of 701 to 725 via a 1,2-carbonyl transposition sequence (Scheme LXXVIII) 401 >. Treatment of 725 with methoxycarbene, deprotection, and oxidation provided 726. Acidpromoted cyclopropane ring cleavage and added functional group manipulation led to 727 which could be allylated stereoselectively. The tricyclic enone 724 was subsequently produced conventionally. 119

VIII Synthesis of Triquinane Natural Products

-I— Si I

1. TsNHNHg 2. NoOMe 3.Bu4N+F"

H 0

Me

4. R I I , H

1.NBS DMSO-HgO

-CD

TH PO

+

2.Bu3SnH AI BN , A

THPO

3.PCC

Me

- C D " Me

701

725 1.Ph3P= CH2 2.

Me

°-CH 3. HOAc, HjD 4. PCC

1. NaH, CH2=CHCH2Br 2. Pd (OAc)2, CuCI,02

3.K0t Bu

'

-cty

1.HCI,MeOH

Me

2.Jones

v"COOMe

y^-y Me H

^Tch^T OMe

Me

726

727

More recently, the same group achieved a simple, highly stereocontrolled total synthesis of ( + )-hirsutic acid (Scheme LXXIX) 402) . This chirally directed effort developed subsequent to reaction of dl-728 with ( + )-di-3-pinanylborane, alkaline hydrogen peroxide oxidation, chromatography, PCC oxidation, and hydrogenolysis. The dextrorotatory hydroxy ketone 729 was nicely crafted into keto aldehyde 730 from which 720 was readily obtained. Once again, the Wacker oxidation played an instrumental role in annulation of the third five-membered ring. The remainder of the asymmetric synthesis was completed as before.

0

PhCHgO

several sleps

a >

HO H

H

1. Ph3P = CHOMe 2.CH2I2 ,Zn-Cu 3. PCC " 4. HCl , MeOH

e

Ö H

730

-729

728

M

^

1. Jones 2.CH2N2

3 . C H 3 ü (leq)

COOH CH 2

(+)- 720 Scheme LXXIX 120

several steps

4.-H20 1. B2H6 2.PCC 3.N0H, tOOMe

4. Pd ( 0 A C ) Cu CI , 0 2 5. KOt Bu

2

,

fP
a> j^CHO

1. Na, NH3

1. CH3MgBr 2. 0 3 ;Me2S

2.H 3 0 +

3. HO^~-OH ,

CI

H+

762

763 1. SnCI4 , C6H6 2.PCC

//

1. LDA.PhSeCI 2.H 2 0 2

1.(Ph3P)3RhCI, Et,SiH

3.Me2CuLi 4. PhSeCI ; H2O2

2.H2NNH2, 0H-

764 Scheme

765 LXXXVI

4 Senoxydene In 1979, Bohlmann and Zdero reported the isolation and an unusual sesquiterpene hydrocarbon from Senecio oxyodonius 415) . This substance was formulated as 766 on the basis of its spectral characteristics and called senoxydene. However, Galemmo and Paquette have recently prepared this particular compound and determined that it is not identical to the natural product. Their pathway, which is summarized in Scheme LXXXVII, begins by transforming 4,4-dimethylcyclopentenone into bicyclic

766 126

B Angular Triquinanes

a, P-unsaturated ketone 767 which is hydrogenated to set the stereochemistry of the secondary methyl group 416) . A vinylsilane sidechain is next introduced which, after deblocking, is modified to introduce a second carbonyl group. Cyclization of diketone 768 delivers 769 which is subjected to dissolving metal reduction in order to fix the last chiral center appropriately. Finally, the double bond is generated regiospecifically. The finding that 766 is not senoxydene requires, of course, that structural revision be made and this action is currently pending.

/-A 1.

MgBr.Cu Pd/C

3. KOt Bu, t BuOH,A

767 1. KH,

OC(OEt) 2

2. n - Bu SH , H+ 3. LDA, Me3Si

KOt Bu

I.OtCHeCHgOHJg, KOH 2. MCPBA

1-BuOH THF

3. 20% H2SO4 , MeOH

Me 3 S

SBu

768

769 1. Li , NH3 2. Na BH4

POCh py

Scheme

LXXXVII

766

5 Pentalenic Acid The fermentation broth of various Streptomyces species can be separated into an acidic fraction shown to contain pentalenic acid (776)417). The somewhat less oxidized pentalenolactone precursor has been independently prepared from humulene from which is is probably derived biogenetically 4 1 8 ) . Thus, treatment of humulene with mercuric nitrate followed by aqueous potassium bromide solution gave two bromomercury derivatives which were oxygenated in the presence of sodium borohydride. The resulting pair of diols (770 and 771) were separately converted to exo methylene 127

VIII Synthesis of Triquinane Natural Products

derivatives 772 and 773, respectively, and 773 was transformed under standard conditions to 772 (Scheme LXXXVIII). Reduction of 772 with lithium in ethylamine furnished 774 which was cyclized under Lewis acid conditions. lOa-Hydroxypentalenene (775), formed (20%) alongside four other compounds, was subjected to conditions which oxidized its allylic methyl group first to the aldehyde level and ultimately to the methyl ester. Hydrolysis of this material delivered pentalenic acid, identical to the natural product.

1.Hg(N03)2, HgO-THF

HO h

2. KBr, HjO 3. NaBH4,02 DM F

HO CH \,>> 3

H

771 1. Ac^O, py 2.PBr3 ,ether 3. t - AmONa, DM SO

HO. H

HO.

H

1. Jones 2. NaBH4

**

774 BF3-Et20 CH2CI2, -IO°C

HO.

HO H

1. SeOg , H20 H

2. Mn02 , KCN,MeOH HOAc

COOMe

—COOH

776

775 Scheme

W '

HO H KO H MeOH H20

LXXXVIII

6 Retigeranic Acid A pentacyclic sesterterpene having eight chiral centers and five quaternary carbon atoms, retigeranic acid (777) is a topologically unique polyquinane system. Although its total synthesis has not yet been achieved, the lower triquinane segment of the molecule has been prepared in racemic and optically active form 4 1 9 ) . Enones 780 and 781 were obtained by initial conversion of 2-methylcyclopentanone to 778 followed by cyclopentannulation of this substrate to produce 779 (Scheme LXXXIX). With the indicated tricyclic a, (3-unsaturated ketones in hand, the proper fusion of rings D and E should be forthcoming. 128

B Angular Triquinanes

777

A

ch

3

1

ch 3 ^ ^CHBr ch 3 co toluene

ch 3

oV V ^ O

2.H20

ch 3

CH 3

CH3

CH 'OH

CH

30H

*4

fi

CH 3 H

778 CuBr•Me2S

2.H30 + CH?

No2Cr04 HOAc AC20

CH 3

05 ch 3

i.ch 3 -@-occi,

3.H 2 NNH 2 , OH"

H

780

CHjH

779 2.H 2 NNH 2 ,OH" 4. PCC

CH 3

1.LDA,

Chb

PhSeCI

2.H202

C?H 3

H

CH-3

781 Scheme

LXXXIX

For the optically active analogues, ( + )-pulegone (782) was utilized as the chiral pool source 4 1 9 ) . Since its methyl substituted carbon atom is not perturbed during the conversion to 783 and beyond (Scheme XC), this stereocenter is fixed. Three additional asymmetric centers were then introduced as previously outlined. 129

VIII Synthesis of Triquinane Natural Products

CH,

CHI

CH-3 Chf-

Br2 2.N00CH 3 ' 1.

CH 3 OH

eft,

0CH3 C0CH3

.0

1.0*

2.(CH3)2S

W M > r.tCOCH3 CH?

1. NaH , KH

782

2.0 3 ; Me2S *

CH,

CHi

severa I steps

1-NaH, toluene 2 . Li I ,

DMF

CH,

CH 3 C00CH 3

783 seve raI steps

,CH 3

K-J-*/ CH

H

Scheme XC

C Propellane Structures 1 Modhephene In 1977, Zalkow and associates reported the isolation and characterization of isocomene (784), a novel tricyclo[6.3.0.04,8]undecane featuring a bridged spirane arrangement of three cyclopentane rings 420) . At a later date, Bohlmann described the successful efforts of his group in isolating 784421Such a great deal of attention has been paid to the total synthesis of 784 that a detailed analysis of the convergency of the various pathways has been reported 422) . The strategy deployed by Smith and Jerris (Scheme XCI) converged upon formation of the [3.3.3]propellenone 786 which in turn was derived from acid-catalyzed rearrangement of tricyclic enones 7#5 423) . Following an alkylative 1,3-carbonyl transposition, conjugate addition of lithium dimethylcuprate, Wittig olefination, and double bond isomerization, 784 and its epimer were obtained. The approach chosen by Schostarez and Paquette (Scheme XCII) was fully regiocontrolled and designed to generate modhephene and epimodhephene independently 424) . Bicyclic enone 787 was transformed by conjugate addition into 788 or 789. When the first substrate was thermolyzed, ene chemistry locked the secondary methyl sub130

VIII Synthesis of Triquinane Natural Products

CH,

CHI

CH-3 Chf-

Br2 2.N00CH 3 ' 1.

CH 3 OH

eft,

0CH3 C0CH3

.0

1.0*

2.(CH3)2S

W M > r.tCOCH3 CH?

1. NaH , KH

782

2.0 3 ; Me2S *

CH,

CHi

severa I steps

1-NaH, toluene 2 . Li I ,

DMF

CH,

CH 3 C00CH 3

783 seve raI steps

,CH 3

K-J-*/ CH

H

Scheme XC

C Propellane Structures 1 Modhephene In 1977, Zalkow and associates reported the isolation and characterization of isocomene (784), a novel tricyclo[6.3.0.04,8]undecane featuring a bridged spirane arrangement of three cyclopentane rings 420) . At a later date, Bohlmann described the successful efforts of his group in isolating 784421Such a great deal of attention has been paid to the total synthesis of 784 that a detailed analysis of the convergency of the various pathways has been reported 422) . The strategy deployed by Smith and Jerris (Scheme XCI) converged upon formation of the [3.3.3]propellenone 786 which in turn was derived from acid-catalyzed rearrangement of tricyclic enones 7#5 423) . Following an alkylative 1,3-carbonyl transposition, conjugate addition of lithium dimethylcuprate, Wittig olefination, and double bond isomerization, 784 and its epimer were obtained. The approach chosen by Schostarez and Paquette (Scheme XCII) was fully regiocontrolled and designed to generate modhephene and epimodhephene independently 424) . Bicyclic enone 787 was transformed by conjugate addition into 788 or 789. When the first substrate was thermolyzed, ene chemistry locked the secondary methyl sub130

C Propellane Structures 1.hv CI2C = C C I 2

1. hv

2.H0-^0H ,

2. H O ^ — O H , H 3 . Nq , NH3 4. 2 % H 2 S 0 4

CI 2 C = C C I 2

3 . N o , NH3 4.2% H2S04

r

2

+

785 R-| = H , R R

1

=

c h

2

=

3>R2=

CH3 H

1. c h 3 l i

1. CH2= P P h 3

2. Jones

2.TS0H , CH^CIg

3 . Me 2 CuLJ

786 Scheme XCI

1. A 2. CH2= P P h 3 BFvEt?0

'

3.12

, CgHg

Û

787

MgCI 1.Me3Si — - -Cui , BF3- Et20

CH 3 'CH^

788

2.BU4N+F ~ 1 . Ph 3 P = C H 2 2.MCPBA

360 C

789 1.I2.C6H6 A 2.K2C03, h2nnh2 , A ch3ch

Scheme XCII

784

V I I I S y n t h e s i s of T r i q u i n a n e N a t u r a l P r o d u c t s

stituent into a syn relationship to the carbonyl group. Comparable pyrolysis of 789 led to the formation of 790 which was epoxidized and isomerized with full stereocontrol to give 791. Double bond isomerization and Wolff-Kishner reduction completed the synthesis.

o5

cp

1. KOH

1. K C N 2. C H 2 = P P h 3 _

2. S O C I ;

3. H 2 , P t

3.TMSC = CTMS, AlCh 4.Na2B407, CHJOH• H , 0

CN

792 620 C

«

several steps

786

784

Scheme XCIII

gBr, 1.

MeO

0

Cu Br • M e 2 S

1. ^ - ^ . M g B r 0

0

2. H , 0 +

2. HjO"1"

3

3. N a O H 4. Ms CI , py 5. D B N

793 250 C toluene

Hv,CH

3

1.CH 3 M g l ,

H^

.CH3

Cu B r • M e 2 S

3. H 2 0 2

3.H202

H

132

XCIV

Pd/C

2. L D A , P h S e B r

2. P h S e B r

Scheme

1.H;

784

CH3

H.

CH3

C Propellane Structures

Karpf and Dreiding arrived at modhephene by thermal a-alkynone cyclization (Scheme XCIII) 4 2 5 ) . The synthesis of key intermediate 792 was unfortunately plagued by isomer problems. Also, the pyrolysis of 792 did not afford 786 cleanly. With the availability of this last intermediate, arrival at modhephene followed earlier precedent. Oppolzer has designed two approaches to modhephene, both of which are based on the high level of stereochemical control attainable in intramolecular thermal ene reactions. In the first (Scheme XCIV), a, P-unsaturated ketone 793 is obtained by aldol methodology and heated at 250 °C in toluene to produce 794 4 2 6 ) . A methyl group and double bond are next introduced in standard fashion prior to arrival at the final sesquiterpene stage. The far more expedient pathway involves gaining direct access to 795 by cuprate addition-selenation and subsequent elimination (Scheme XCV). In this way, modhephene can be produced in only six steps.

784 Scheme XCV

Wender and Dreyer have demonstrated that meta-arene photocycloaddition chemistry can lead expediently to modhephene 4 2 8 ) . Acetate 796, a photoproduct derived from indane and vinyl acetate was converted to tetracyclic ketone 797 (Scheme XCVI). Because the enolate of 797 partakes of the dynamic behavior of semibullvalenes, it proved possible to trimethylate the substance to produce 798. A fourth methyl group was introduced by conjugate addition and the carbonyl was simultaneously converted to an olefinic center. Selective hydrogenation of 799 provided modhephene in seven steps. A regio- and stereospecific synthesis of modhephene has also been achieved beginning with the Weiss-Cook reaction 4 2 9 ) . As illustrated in Scheme XCVII, cyclopentane-l,2-dione can be readily crafted into a-diazo ketone 800, copper-catalyzed decomposition of which delivers tricyclic ketone 801. Following the dimethylation of this intermediate, carbomethoxylation was accomplished to give 802 and provide 133

VIII Synthesis of Triquinane Natural Products

1.K0 t Bu (15 equiv)

V

V

796

797

2.CH 3 I

V

(10 equiv)

798 'l.Me 2 CuLl 2.CIP(0XNMe 2 ) 2 3. Li , EtNH 2 THF

h2 Pt02

799

784 Scheme XCVI

the opportunity for controlled ring opening with lithium dimethyl cuprate. Once this final stereocenter had been introduced, conventional methodology was utilized to convert 803 to 784.

,co2ch3

a:

1. pH 6.8

2. HOAc, HCI

1. Li NtSiMe^g (EtOlgPOCI 2. H 2 ,Pt/C 3. NoOEt

I. MeoCuLi CH3

h 3 co 2 c

2.CH 3 I

-*Ch3

801

803 1. L1I , collidine

2.L1AIH4

3. S0CI2 , py

Scheme XCVII 134

2. t - BuLi 3. C0 2 ; CH 2 N 2

A C 1 6 -Hexaquinacene

IX The Quest for Dodecahedrane

A C 16 -Hexaquinacene 1 Synthesis and Properties When unstable 9,10-dihydrofulvalene (804) is allowed to react with dimethyl acetylenedicarboxylate, a separable mixture of the adducts 805 and 806 is produced 4 3 0 ) . The diacid derived from 805 can be readily transformed into diketone 807 and subsequently into triene dione 808 (Scheme XCVIII) 4 3 1 ' 4 3 2 ) . Once the intramolecular photocyclization of this intermediate has been carried out, two sigma bonds can be ruptured by reduction with zinc. X-ray analysis of 809 showed its three unsubstituted cyclopentane rings to be essentially planar and the other three to have half-chair conformations 4 3 3 ) .

COOMe

C in c COOMe

+ COOMe

805

804

806

1 .OH 2 . Li H , C H j L i 1.LDA,CuCI2 DMF

1.hv 2.Zn , HO A c

A

0

807

809 2 . T s C I , py 3. a c t i v a t e d

Scheme

XCVIII

810 135

I X The Quest for Dodecahedrane

When the remaining two double bonds are introduced to give 810, a high level of sphericality is achieved. However, the three sites of unsaturation do not engage in homoconjugative overlap 4 3 1 ' 4 3 2 ' 4 3 4 1 .

2 Functionalization Reactions Hales and Paquette have observed that sequential reduction and hydrolysis of 805 can lead efficiently to endo,endo diacid Hi 1 435>. Arndt-Eistert homologation, conventional elaboration of bis(thioether) 813, and exhaustive oxidation was utilized to arrive at 813. The plan was to deploy the dianion of 813 in a manner which would lead to 814. However, the principal product proved to be the unwanted 815. COOH

1.(C0CI)2

H

, j '

„COOCH, 3

2.Ts CI,

2.CH2N2 3. A g O A c , Et3N, MeOH

814

1. LiAIH4

COOCH3 3_pPhys-

813

SPh

815

818a , R = CN 818b , R = cooEt 136

B Alternative Approach to Hexaquinanes

The exhaustive hydroboration of C 16 -hexaquinacene (810) has been investigated and the isomeric