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This is to certify that the

dissertation entitled

51’oxide Rcowmngzmgni. as upgssiblc Hl’f‘m‘x‘
+0 C‘QdeQ'nc biRTPfines

presented by

Youse? M . 9560M eds

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Date ”“8256.

MSU is an Affirmative Action/Equal Opportunity Institution 0-12771

 

 

 

 

 

 

 

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EPOXIDE REARRANGEMENT AS A POSSIBLE APPROACH TO
CLERODANE DITERPENES

By

Yousef M. Abdallah

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1985

ABSTRACT

EPOXIDE REARRANGEMENT AS A POSSIBLE APPROACH TO
CLERODANE DITERPENES

By

Yousef M. Abdallah

We examined the rearrangement in Equation 1 as a
possible approach to clerodanes diterpenes. To demonstrate
the viability of such an approach, the Dials-Alder reaction
regioselectivity of dienes 100a and 100) with acetylenic
dienophiles, dimethyl acetylenedicarboxylate, ethyl
propiolate and ethyl tetrolate was studied. The
regioselectivity of the addition is *excellent and the
reaction proceeds in high yield (55-95%). The regio—
reversed Diels-Alder reaction of dienes 10011,!) with p-nitro-
¢,p-unsaturated esters 108 was examined and found to be
excellent, providing one isomer in good yield (57-783). An
improved synthesis of the diene 100a via CuSOq.5H20 mediated
dehydration of vinyl carbinol precursor was discovered.

_The epoxidation stereoselectivity of a number of 5,5-
dimethy1-3,5,6,7,8,8a-hexahydronaphthalenes . 104 with g-
chloroperbenzoic acid (MCPBA) and N-bromo-succinimide (NBS)

was investigated. Excellent epoxidation stereoselectivity

was observed with substrates containing a methyl at the C-
8a-ring junction. Treatment with MCPBA provided the «-
epoxides in high yields (82-90X). p-epoxides were obtained
as the major stereoisomer with substrates containing an H at
the ring junction in excellent yields (MCPBA). Epoxidation
of these substrates with NBS, aq. t-BuOH, proceeded with
high stereoselectivity providing the abepoxides as the
exclusive, or major, stereoisomer in high yields (60-94X).
Exposure of p-epoxides 110 to BFa-Etzo provided
excellent yields (79-92x) of rearranged fused indene
oxetanes 117. Treatment of abepoxides 109 with BFa-Etzo
yielded either the rearranged product 122 or the oxetanes
117 and the related alcohols 123 and 124 in good yields,
depending on the ring junction substituent. Treatment of
the 6-p-hydroxy-abepoxide 136'with BFs-Etzo resulted in ring
8 aromatization while 6-p-hydroxy-p—epoxides 137 provided a

gross mixture of product.

1MBLE¢HPCONHHHS

LIST OF SCHEMES.

LIST OF FIGURES.

LIST OF EQUATIONS.

LIST OF TABLES

INTRODUCTION

RESULTS AND DISCUSSION

I.

II. Regio-Reversed Dials-Alder Reactions.
III. Epoxidations.
IV. Epoxides Rearrangement Catalyzed by
BF3'Et20.
EXPERIMENTAL

Diels-Alder Reaction.

LIST OF REFERENCES

iv

Page

vii

ix

xi-

20

21

27

29

59

69

108

Scheme

Scheme

Scheme

Scheme

Scheme

Scheme

Scheme

Scheme

Scheme

Scheme

Scheme

Scheme

Scheme

II

III

IV

VI

VII

VIII

IX

XI

XII

XIII

LIST OF SCHEMES

An Approach to the

Synthesis
of Clerodanes Diterpenes . .

Biogenetic Pathway to Clerodane

Synthesis.

Halsall’s Approach to the
Clerodanes . . . . . . . .
Sarma’s Total Synthesis of (i)
Averol 12. . . . . . . . . .
Kakisawa’s Total Synthesis of
Ammonene 9 . . . . . .
Kende’s Total

Synthesis of
Ajugarin IV 6. . . . . . . .
trans-

Apsimon’s Route to

Clerodanes

Goldsmith’s Synthesis of the
Intermediate 48. . . . . .

deGroot’s Synthesis of epi—
Ajugarin I 60. . . . . . . . .

Ley’s Total Synthesis of Ajugarin
I 3. . . . . . . . . . . .
Tokorayama’s Total Synthesis of
Annonene 9 . . . . . . . .
Tokorayama’s Total

Synthesis of
the cis-Clerodane 10 . . .

Diels-Alder
Cyclohexenes

Reactions of l-vinyl

Page

10

11

11

13

14

16

16

17

Scheme

Scheme

Scheme

Scheme

XIV

XV

XVI

XVII

Goldsmith’s Approach to Ajugarin-I
via Diels-Alder Reaction . .

Kato’s Synthesis of a Clerodin
Homolog 96 . . . . . . . . . . .

Diels-Alder Reactions of 6,6-
dimethyl-l-vinyl cyclohexenes. .

Synthesis of 136 and 137 and
Rearrangements . . . . . .

vi

Page

18

19

68

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

1

5a

Selected

LIST OF FIGURES

Clerodanes Diterpenes and

Relative Compounds

1H-NMR

1H-NMR

(250 MHz) Spectrum of 110c .

(250 MHz) Spectrum of 110c

with Irradiation at 6 = 6.67 ppm

1H-NMR

(250 MHz) Spectrum of 110c

with Irradiation at 6 = 3.32 ppm

1H¥NMR

(250 MHz) Spectrum of 11°C

with Irradiation at 6 = 3.22 ppm

1H-NMR

(250 MHz) Spectrum of’ 11°C

with Irradiation at 6 = 2.76 ppm . . .

1H-NMR

(250 MHz) Spectrum of’ 110c

with Irradiation at 6 = 2.59 ppm

1H-NMR

(250 MHz) Spectrum of 11°C

with Irradiation at 6 = 2.10 ppm

IH¥NMR
with the

1H-NMR
with the

1H-NMR
with the

1H-NMR
with the

Proton
110c.

1H-NMR

(250 MHz) Spectrum of’ 110c
First Addition of Eu(fod)3.

(250 MHz) Spectrum of’ 110c
Second Addition of Eu(fod)3

(250 MHz) Spectrum of’ 110c
Third Addition of Eu(fod)3.

(250 MHz) Spectrum of 110c
Fourth Addition of Eu(fod)3

Chemical Shift Correlation of

(250 MHz) Spectrum of 109C .

vii

Page

31
32
33.
34
35
36
37
38
39
4o
41

42

45

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

5b

5c

5d

5e

5f

6a

6b

6c

6d

1H-NMR (250
Irradiation

1H-NMR (250
Irradiation

1H-NMR (250
Irradiation

1H—NMR (250
Irradiation

1H-NMR (250
Irradiation

1H-NMR (250

MHz)
at 6

MHz)
at 6

MHz)
at 6

MHz)
at 6

MHz)
at 6

MHz)

Spectrum of
= 6.47 ppm

Spectrum of
= 3.33 ppm

Spectrum of
= 3.01 ppm

Spectrum of
= 2.75 ppm

Spectrum of
= 2.52 ppm

Spectrum of

109C

109C

1090

109C

109C

109C

the First Addition of Eu(fod)3.

1H-NMR (250 MHz) Spectrum of 109c
the Second Addition of Eu(fod)3

1H-NMR (250 MHz) Spectrum of 109C
the Third Addition of Eu(fod)3.

1H-NMR (250 MHz) Spectrum of 109C
the Fourth Addition of Eu(fod)3

The ORTEP Plot of a
X-ray of 109C .

The ORTEP Plot of 8

X-ray of 1.

viii

with

with

with

with

with
with

with

with

with

Single Crystal

Single Crystal

Page

46
47
48
49
50
51
52"
53
54

55

58

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

5b

5c

5d

5e

5f

Ba

6b

6c

6d

1H-NMR (250 MHz) Spectrum of 1090
Irradiation at 6 = 6.47 ppm .

1H-NMR (250 MHz) Spectrum of 109c

Irradiation at 6 = 3.33 ppm

1H-NMR (250 MHz) Spectrum of'109c
Irradiation at 6 = 3.01 ppm

1H-NMR (250 MHz) Spectrum of 1mm:

Irradiation at 6 = 2.75 ppm

1H-NMR (250 MHz) Spectrum of'109c
Irradiation at 6 = 2.52 ppm

1H-NMR (250 MHz) Spectrum of’109c
the First Addition of Eu(fod)3.

1H-NMR (250 MHz) Spectrum of 109c
the Second Addition of Eu(fod)3

1H-NMR (250 MHz) Spectrum of 109c
the Third Addition of Eu(fod)3.

1H-NMR (250 MHz) Spectrum of 109c
the Fourth Addition of Eu(fod)3

The ORTEP Plot of a
X-ray of 109c .

The ORTEP Plot of a

X-ray of 1.

viii

with

with

with

with

with

with

with

with

with

Single Crystal

Single Crystal

Page

46
47
48
49
5o
51
52 '
53
54
55

58

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

Figure

6b

6c

6d

1H-NMR (250 MHz) Spectrum of 109c
Irradiation at 6 = 6.47 ppm

1H-NMR (250 MHz) Spectrum of 109c
Irradiation at 6 = 3.33 ppm

1H-NMR (250 MHz) Spectrum of 109c
Irradiation at 6 = 3.01 ppm

1H-NMR (250 MHz) Spectrum of’109c
Irradiation at 6 = 2.75 ppm

1H-NMR (250 MHz) Spectrum of’109c
Irradiation at 6 = 2.52 ppm

1I-I--NMR (250 MHz) Spectrum of 109c
the First Addition of Eu(fod)3.

1H-NMR (250 MHz) Spectrum of 109c
the Second Addition of Eu(fod)3

1H-NMR (250 MHz) Spectrum of 109c
the Third Addition of Eu(fod)3.

1H-NMR (250 MHz) Spectrum of 1mm:
the Fourth Addition of Eu(fod)3

The ORTEP Plot of a Single Crystal

X-ray of 109c .

The ORTEP Plot of a Single Crystal

X-ray of 1.

viii

with

with

with

with

with

with

with

with

with

Page

46
47
48
49
50
51
52'
53
54

55

58

Equation

Equation

Equation

Equation

Equation
Equation

Equation

Equation

Equation

Equation

Equation

Equation

Equation

10

11

12

13

LIST OF EQUATIONS

Epoxide 1 Rearrangement with BF3 Et20

Preparation

of 6,6-dimethyl-l-viny1
cyclohexene . . . . . . . . . . .

Preparation of 2, 6, 6-trimethyl-1-vinyl
cyclohexene . . . . . . . .

Diels-Alder Reaction of
hexene with Ethyl Propiolate. . .

Aromatization of 104C with DDQ.

Aromatization of 104d with DDQ.

Rearrangement of the Epoxide 111 with
BF3 Et20. . . . . . . .
Rearrangement of the Epoxide 113 with
BF3 EtzO. . . . . . . p
Rearrangement of the Epoxide 115 with
BF3 EtzO. . . . . . . .
Diels-Alder Reaction of l-vinyl
Cyclopentene with Dimethyl Acetykne
Dicarboxylate Followed by
Aromatization . . . . . . . . .
Oxetane 117a Opening with Sodium
Methoxide and by Aromatization with
PCC

Oxetanevll7a Treatment with Toluene

Sulfonic Acid and Acetic Anhydride in
py Benzene. . . . . . . . . . . .

Treatment of Acetates 125 and 126

with KOBut.

ix

l-vinylcyclo-

Page

20
21

23
24

24
59
60

60

63

64

65

65

Equation 14

Equation 15

A Proposed Mechanism for
epoxides 109 Rearrangement.

Preparation of Diene 131.

the

a—

Page

66

67

Table

Table

Table

Table

Table

II

III

IV

LIST OF TABLES

Diels-Alder Reactions of 1008,b with
Acetylenic Dienophiles. . . . .

Diels-Alder Reactions of 100a,b with
p-nitro-a,p-unsaturated esters.

Epoxidation of 104 with m—
chloroperbenzoic acid (MCPBA) and N-
Bromosuccinimide (NDS) in Aqueous
t-BuOH. .

Rearrangement of p-epoxides 110 with
BFa-EtzO.

Rearrangement of abepoxides 109 with
BF3°Et20.

xi

26

30
62

62

INTmDIBTION

ERREDUMHDN

Previously, we had investigated the Lewis acid

catalyzed rearrangement of the epoxide 1 as shown in

    

Equation 1. Rearranged alcohol 2 was the sole product
0M: om
02““ erg-0&2 02m
—* . \ . , (1)
OH
1 gnaw.)
obtained from this reaction, isolated in 76% yield. The

close structural relation of the C-3 to C—6 portion of the
rearranged product 2 and Clerodanes diterpenes suggested the
possibility of constructing 3-14 from such a rearrangement.
The presence of a C-3, C-4 double bond would allow
functionalization at C-3, C-4 and of C-4-CHa moiety.
However, the ring fusion CH3 group of 1 must be replaced by
an H without effecting the course of the reaction. Such an
approach to cis- or trans-, clerodane diterpenes and related

compounds (6-14) is illustrated in Scheme 1. Interest in

SCHEME |= An Approach to the Synthesis of CLerodone Diterpenes

  

___.._.- Ctorodonos

   

Clerodane diterpenes as targets for total synthesis stems
mainly from the range of biological activities exhibited by
a number of these compounds. For example, the neo-clerodane
diterpenes, Ajugarins (I-VI) 3-8, isolated from the leaves
of the East African medicinal plant, ajuga remote
(Labiatae), exhibit a potent insect antifeedant activity
against the desert locust, sebistocera wage:23 and shows, in
addition, insecticidal and insect-growth inhibiting
activities. Other Clerodanes of interest are annonene 92°,
1029, elongatolide-A 111”"i'h and the sesquiterpenes, Averol
122‘, illimaquinone 13,2i which exhibit antibacterial
activity, and arenarol 14.2i

Clerodane diterpenoids such as the ajugarins have a
rearranged labdane skeleton (15) and belong to a novel class

of natural products found in nature in ever-increasing

mvcsoaaoo o>fium~om
was moccasoufia monocouoao vouoodom H shaman

  

mvcsoaaoo o>wum~om
can moccasoufio mocmcouofio co~uo~om H ouamflm

  

mvcsoasoo o>wumdom
can mocoauoufia mocmvouofio couoofiom H magmas

 

4

numbers.3 These compounds, with both cis- and trans-ring
fusions, are believed to be formed biogenetically‘ from
geranyl geranyl pyrophosphate via a labdane precursor after
a series of backbone rearrangements involving hydrides and
methyl shifts are catalyzed enzymatically and are thought to
proceed these rearrangements as shown in Scheme II. This
process could account for both cis- and trans-Clerodanes

formation.

Scheme II Biogenetic Pathway to Clerodane
Synthesis.

 

opp

Trans-Clerodanes

   

C lav-Clerodanes

 

 

 

Synthesis and Synthetic Approaches

To date, four total syntheses of clerodane diterpenes
have been reported; and in addition, a number of approaches
to Clerodanes were attempted. None of these total syntheses
seemed to be sufficiently general or to provide for the
preparation of both the cis- and trans-Clerodanes. These
syntheses or synthetic approaches suffered from being either
lengthy, tedious, non-stereospecific, including very low
yield steps, or unable to achieve the goal. The major
obstacle to be overcome in any syntheses of a clerodane
diterpene is the construction of the decalin moiety with the
proper chiral centers. Three main pathways have been
utilized in the construction of the decalin framework: 8)
Wieland-Miescher ketones or related compounds, as the basic
skeleton, where all the asymmetry has to be introduced; b)
conjugate addition to an appropriate precursor .enone,
followed by cyclizations; and c) a Diels-Alder reaction; [4
+ 2] cycloaddition.

In the first synthetic approach by Halsall,5 the
decalin moiety was constructed by a Robinson annulation to
form 16 (Scheme III). Selective protection of 16, followed
by reductive alkylation, gave the desired trans-fused
compound 18. The C-8-CH3 was to be added via a Wittig
reaction; however, this sequence failed to methylenate the

hindered ketone 18. Methyl lithium was successfully added

Scheme III Halsall’s Approach to the
Clerodanes

 

a) NaOEt; b) 1,2-ethane diol; c) i) Li/NHa, ii) allyl

bromide; d) CRsLi

 

Scheme IV Sarma’s Total Synthesis of (i)
Averol 12.

a; g) Li/NRs, ii) ArCHzBr; b) PhaPCHz; c) Hz/Pd/C; d) PCC' e)
1 H3L1, 11) POC13,pyridine, iii) RhCla; iv) BuSLi-HMPA ’

to 18 to provide the alcohol 19; unfortunately, 19 could not
be converted to a clerodane derivative.

A similar Wieland-Miescher ketone-type approach to
Averol 12 was reported by Sarma.6 Reductive alkylation of
20, Scheme IV, gave the trans-decalol 21 which underwent a
Wittig reaction under forcing conditions providing the
corresponding exo-methylene compound. Hydrogenation of the
hindered exo-methylene compound followed by CHaLi addition
and dehydration afforded (t)Averol 12.

Kakisawa7 reported the first non-stereospecific total
synthesis of the clerodane diterpenes (i)-Annonene 9. Their
strategy utilized the Wieland-Miescher ketone to construct
the bicyclic framework, Scheme V. Dissolving metal
reduction of the enone 22 followed by cyano-hydrin formation
and dehydration resulted in a mixture (1:1) of the isomers
23. Separation of the mixture of olefins and reduction of
the nitrile 11; the intermediate aldehyde 24 gave the
alcohol 25. Treatment of 25‘with CHz=CH-OCH2CH3 under the
exchange conditions gave 26 which underwent the desired
Claisen rearrangement upon heating; leading to the aldehyde‘
27. This key step in the synthesis was stereoselective and
provided an exo-methylene at C-8. Hydrogenation of the C-8
exo—methylene afforded a mixture of 28 and its epimer at C-
8; further elaboration converted 28 to (i)annonene 9.

A total synthesis of the clerodane diterpene Ajugarin-

IV 6 (Scheme VI) was reported by Kende.8 These workers also

Kakisawa’s Total
Ammonene 9 .

Synthesis of

 

-- “dine; c) 1) Dibal, 1?
:;B§:{NH:) ethYl vinyl ether.Hg(0A§):3 3egu::?tifghium, ii)
’ .. .0. FCC; g - . . . o
NaBH" .11; Hgéggggi ;;1)1) 8+, ii) PhaPCHz; 1) d111th1um
Aczo, 111 . .
ethane-1,2-diam1ne

Scheme v

Kakisawa’s
Ammonene 9 .

Synthesis of

 

.. -dine; c) i) Dibal, ii)
. . b i) KCN’ 11) SOC121Pyr1. 00; f) 1)
§)B§1(NH:3 8tgy1 Viny1 ethergH8(0AC)§a 6% he?tifggium’ ii)
NZBH4’ ii) Hz/pd/C. iii) PCC; g) 1) 3‘ “FY

4:

0 'ii) Ca/NHs’ h) i) H’, ii) PhaPCHa; i) dilith1um
AC2 , 1 . ,
ethane-1,2-diam1ne

9

utilized the classical Wieland-Miescher ketone 29 as the
basic skeletal building block (Scheme VI). Selective
thioketalization, followed by a Wittig reaction, allowed the
introduction of the exo-methylene group at 0-4 and reductive
alkylation then gave 30. Oxygenation at C-6 was
accomplished by bromination-dehydrobromination to provide
the enone 31; CH3Li addition and 1,3-oxidative transposition
(CrOa-pyrz) gave the enone 32 in a low yield. Dissolving a
metal reduction of 32 in the absence of a proton source
resulted in a single isomer 33*with an equatorial methyl at
C-8. Lithium aluminum hydride reduction of the C-6 ketone
gave the C-6 equatorial alcohol 34. Hydroboration of 34-
under equilibrating conditions with disiamylborane resulted
in the conversion of the C-4 exo-methyl to the equatorial C-
4,CH20H group as well as the conversion of the Co-allyl
group to a proponal chain after oxidation (H202,‘OH).
Oxidation of the resulting dial to the diacid and
esterification resulted in 35. Selective hydrolysis of the
diester in 35 allowed the conversion of the least-hindered
side chain ester to the acid 36. The butenolide moiety was
introduced by reaction of the derived acid chloride from 36
with tris (trimethyl siloxy) ethylene, followed by heating
and acid hydrolysis, to provide the p-hydroxy ketone 37. A
ketenylidene triphenylphosphorane reaction with 37 provided
Ajugarin-IV 6.

Approaches to clerodanes that utilized the Robinson

annulation for the construction of the decalin substructure

10

Scheme VI Kende’s Total Synthesis of
Ajugarin IV 6.

 

Alma'ln-w (6)

a) i) 1,2—ethane dithiol,H+; ii) PhaPCHz; iii) HgClz-CdCOa;
iv) Li/NH3,ally1 bromide; b) i) base,MeaSiCl; ii) NBS; iii)
LiBr-L12003,DMF,ref1ux c) i) CH3Li; ii) Cr03-2py; d) i)
Li/NHa-THF; e) LAH; f) i) SiazBH,H202,OH‘; ii) PDC-DMF;
iii) NaC102; iv) CH2N2; g) i) KOH (1.1 equiv),CH30H; ii)
6NHC1; iii) AC20,Et3N,DMAP h) i) (COCl)2; ii)
[(CH3)3Si]2C=CHSi(CH3)3; iii) heat,H+ I) i) Ph3P=CH=C=O

 

ll

are discussed below. .Apsimon’ reported 'a route to the
trgng-clgrodgn. using an acid-catalyzed Michael addition and
aldol cyclodehydration of Z-methyl-l,3-cyclohexanedione with
enone 33 to give 33, Scheme VII. Monoprotected dione 33 was

hydrogenated stereospecifically to 40. Addition of CH3Li
and dehydration gave 41, which after thioketalization and
oxidation, gave 42. The conversion of 42 to trans-clerodane

has not yet been accomplished.

Seheae Aselmee' s Ieete trees.

Clerodanes .

cg—cfi'q‘}
4593—4?

a) none: 5) ls/sd-e: c) l) Ieflglr. ii) [Cl/HeOI: d) l) 1.3-
etbese dithiel.PTSOI. it) CrOs.syr

Goldsmith1° has reported an approach to Ajugarin-I 3

utilizing the strategy outlined in Scheme VIII.
Scheme VIII Goldsmith's Synthesis of the
Intermediate 4..
cum u
H
43 4: 4?, “'°z°°

3;; M? +52:

46

e) Ila-leICOs: b) lAI: c) methyl chloroformete, pyridine; d)
CrOs; e) Isl; f) P- -TSOI. ethyl vinyl ketone

 

12

Iodolactonization of 3—cyclohexene-l-carboxylic acid 43 gave
the iodolactone 44, which upon reduction (LAH) provided cis-
3-hydroxy methyl cyclohexanol 45. Selective acylation of
the 1°-0H with methyl chloroformate, oxidation to the
corresponding ketone 46 and NaH-induced cyclization afforded
the lactone 47. A Robinson-type annulation led to the cis-
fused lactone 48.

deGroot11 has reported the stereospecific synthesis of
the enone ether 52 as intermediates to clerodanes; more
recently,11c he has reported the conversion of 52 to 4-epi—
Ajugarin-I, Scheme IX. The p-ketoester 49 was condensed
with a-chloro-ethylacetate, then converted to the keto
diester 50. A Robinson annulation of 50 with ethyl vinyl
ketone provided 51 which, after enone protection, (LAH)
reduction, dehydration and hydrolysis, provided the key
intermediate, enone ether 52. Dissolving metal reductive
allylation of enone 52, CH3Li addition and dehydration gave
53. Hydroboration and conversion of the side chain to the
corresponding ester, followed by allylic oxidation of the
endocyclic double bond, gave the enone 54. Stereoselective
hydrogenation of the enone 54 resulted in the equatorial C-
8-methy1 and Li(t-Bu0)3A1H reduction of C-6-ketone provided the
equatorial C-6-OH which, upon acetylation, provided 55. The
tetrahydrofuran ring opening and acetylation gave 56. The

side chain was developed by a procedure analogous to that

13

discussed in Kende’s synthesis gig compounds 57, 58 and 59.
Epoxidation of 59‘with MCPBA gave only (ijepi-ajugarin-I 60.
Ley12 reported the first total synthesis of Ajugarin-I
3 (Scheme X) utilizing a conjugate addition, annulation
protocol. The enone 61, after protection of the aldehyde,
was converted to G! by conjugate addition. The A ring was
generated by hydroboration and oxidation of the butenyl side
chain followed by cyclization of the product keto-aldehyde
to form the enone 64. Stereospecific vinyl cuprate addition
and trapping of the resulting enolate with formaldehyde

allowed the insertion of the hydroxymethyl substituent at C-

5 to provide 65. Selective reduction of the ketone,
protection of the diol as' the acetonide, and
dethioketalization afforded the aldehyde 66. The

introduction of the side chain was accomplished by addition
of the lithium anion of phenyl sulfonyl (trimethylsilyl)
methane followed by acetylation, and Bu4NF treatment gave
the vinyl sulfone 67 which was reduced with LiEtsBH to
provide 33. The C-4-vinyl group was converted to the exo-
methylene group by ozonolysis, reduction, selenation and :-
elimination of the selenoxide to give 70. To the butenolide
precursor 69 was added the anion of 70 yielding 71 after

lactonization and desulfurization. Deprotection of the
acetonide to the diol epoxidation with m-chloroperbenzoic
acid, followed by acetylation, afforded a 1:3 mixture of

A.i‘ugarin-I 3 and 4—epi-Ajugarin-I 63 in 82* yield.

 

l3a

Scheme IX deGroot’s Synthesis of epi-

Ajugarin I 60.

 

a) i) C1CHzCOzEt; ii) NaOEt; iii) Na b) MeaN’BzOH c) i)
HC(OMe)3,BF3'Et20; ii) LAH; iii) H’ d) i) Li/NHa; ii) allyl
bromide; iii) CH3Li; iv) BFa'Etzo e) i) 9-BBN; ii) H202;
111) Jones; iv) CH2N2; v) CrOa/HOAC f) 1) H2; ii) Li (0-
F‘Bu)3HAl; iii) Aczo g) i) pyridium bromide,AczO h) i) KOH;
11) AczO i) i) oxalyl chloride; ii) CH2N2; iii) H20,SOz j)
PhaPC=C=O k) MCPBA '

Scl

13a

Scheme IX deGroot's Synthesis of epi-

Ajugarin I 60.

 

3) i) C1CH2C02Et; ii) NaOEt; iii) Na b) MeaN’Bzofl C) i)
HC(OMe)3,BF3-Et20; ii) LAH; iii) H’ d) i) Li/NHa; ii) allyl
l?romide; iii) CH3Li; iv) BFa'Etzo e) i) 9-BBN; ii) "202;
1ii) Jones; iv) CH2N2; v) CrOa/HOAC f) i) H2; ii) Li (0-
Fffiuhnu; 1'11) AczO g) 1) pyridium bromide,AczO h) 1) non;
11) AczO i) i) oxalyl chloride; ii) CH2N2; iii) H20,502 J)
PhaPC=C=O k) MCPBA '

l4 9

,Scheme X Ley’s Total Synthesis of Ajugarin

 

 

Aiuqorin-l ;_

a) i) 1,2-ethane dithiol, ‘Ht; ii) CdCOa-HgOAc; b) (5-
hexenyl)zCuMgBr; c) i) 8H3 (CH3)2)S; ii) NaOH,H202; iii)
py.SOa in camphorsulphonic acid; d) i) (vinyl)2CuLi; ii)
CH20; iii) t-Bu(CH3)2SiCl, e) LAH; iii) acetone, CuSOs; iv)
TI(OCOCF3)3,THF; f) i) (MeaSiCHSOaPh)Li+, ii) AC20,
‘pyr.DMAP, iii) Bu4NF, iv) LiEtaBH; g) i) 03,EtOH; ii) NaBH4;
iii) N-phenylselenium phthalimide n-BuaP; iv) EtzNH at
reflux; h) i) nBuLi; ii) t-Bu(Me)2Si-O-CsC-C02Et, iii)
BquF; I) 1) Na-Hg, 11) TFA, 111) MCPBA, iv) AczO

l4 1

 

.Scheme

Ahmode 31

a) i) 1,2-ethane dithiol, 'Ht; ii) CdCOa-HgOAc; b) (5-
hexenyl)2CuMgBr; c) i) BHa (CH3)2)S; ii) NaOH,H202; iii)
py.SOa in camphorsulphonic acid; d) i) (vinyl)3CuLi; ii)
CH20; iii) t-Bu(CH3)2SiCl, e) LAH; iii) acetone, CuSO4; iv)
TI(OCOCF3)3,THF; f) i) (MeaSiCHSOaPh)Li+, ii) AczO,
'pyr.DMAP, iii) Bu4NF, iv) LiEtaBH; g) i) 03,EtOH; ii) NaBH4;
iii) N-phenylselenium phthalimide n-BuaP; iv) EtzNH at
reflux; h) i) nBuLi; ii) t-Bu(Me)zSi-O-CsC-CozEt, iii)
Bu4NF; I) i) Na-Hg, ii) TFA, iii) MCPBA, iv) AczO

l5

Tokorayama13 has reported synthesis of both cis- and

trans-clerodanes. The synthesis involved the
stereoselective conjugate addition reactions to the
appropriate enone system. The cis-clerodane synthesis,

Scheme XI, started with (CH3)2CuLi addition to enone 72 and
trapping the resulting enolate with formaldehyde which led
to the exo-methylene enone 73 after dehydration. Reduction
of 73 with LiB(CHEtMe)3H in conjugate fashion and trapping
of the resulting enolate with (MezN)2PO-Cl according to
Irelandl‘ afford 74. Removal of the phosphoramide and
hydroboration and oxidation of the p-C-9-vinyl moiety gave
the aldehyde 75.‘ The addition of 3-fury1 lithium to 75
followed by acetylation and removal of the acetate group
provided 10.

The trans-clerodane annonene 9 was prepared13 by an
analogous pathway, as shown in Scheme XII.

Addition of Nagatta’sl5 EtzAlCN reagent to the enone 76
provided the trans nitrile 77. Protection of the ketone as
the corresponding ethylene ketal and hydroboration-oxidation
of the C-9-p-vinyl group gave the aldehyde 78. Addition of
3-furyl lithium acetylation and acetate removal provided 79.
Ketone reduction and dehydration, followed by nitrile
reduction and oxidation to the carboxylic acid 80,‘which had
previously been converted to annonene 6.

The third strategy employed in clerodane synthesis is

the Diels-Alder construction. The first approach reported

""“‘l"‘“

a)

111‘
111*
a

16

Scheme x1 Tokorayama’s Total Synthesis of
the cis-Clerodane 10 .

 

a) i) (CH3)2CuLi; ii) CH20; iii) CH3802CI; iv) DBN b) i)
LiB(CHMeEt)3H; ii) (MezN)2P-OC1 c) i) Bzfls; ii) H202,0H;
iii) Li/EtNH2,Bu*OH; iv) (COCl)2,DMSO d) i) 3-fury1 lithium;
ii) AczO,pyridine; iii) Li/Liq NHa

Scheme x11 Tokorayama’s Total Synthesis of
Annonene 9 .

 

a) i) EtzAICN b) 1,2-ethane diol,H+ c) i) Bsz; ii) HzOz,OH;
iii) DMSO,(COC1)2 d) i) 3-fury1 lithium; ii) AczO,pyridine;
iii) Li/NHs; iv) HCl,Acetone; v) Li B(CHMeEt)2H; vi)
POCla,pyridine e) i) BuzAle; ii) AcOH; iii) NaC102,NaH2P04

 

17

by Tokorayama16 utilized the [4 + 2] cycloaddition of
substituted maleic anhydrides such as Aconitic acid 81 and
chloromethyl maleic anhydride 82 and also crotonaldehyde I!
with 1-viny1cyclohexene 101. The addition of aconitic acid
81 to 1-vinyl-cyclohexene 101 afforded the exo-product 84
(Scheme XIII). However, chloromethyl maleic anhydride and

crotoraldehyde gave the expected end products 85 and 86.

Scheme XIII Diels-Alder Reactions of l-vinyl
Cyclohexenes .

o HOZf
e 00
(Q0 950 fif
@+
0
COZH
4

lg! g Q.
04..
ti; (13:53“
(L + . —~
” 0
§? E?
cno ' - H cuo
+ '- -————e
(::1\é7 \_—\ [::]:::r’
as a§

Goldsmith16 used the [4 + 2] cycloaddition protocol in
an approach to Ajugarin-I 3 (Scheme XIV). Cycloaddition of
2,4-pentadiene-l-ol 87 with l-carbomethoxy-P-benzo quinone
gave a mixture of hemiketals 88. Ketalization, ring-
junction isomerization 89 and zin-acetic acid reduction of
89 provided 90. Acetylation, followed by catalytic
hydrogenation, resulted in the production of 91. Alkylation
and lactonization of 91 provided 92; however, during this

sequence of reactions, the ring-junction hydrogen epimerized

l8

Scheme XIV

Goldsmith’s Approach to Ajugarin-I
via Diels-Alder Reaction

 

a) Mixing at room temperature in benzene b) DabCO c)
Ht/CHaofi d) Zn/HOAc e) i) AcaO; ii) Hz/pt. HOAC f) 1)
NaOCHa,HCOzMe; ii) n-BuSH; iii) Hz/Rany nickle g) 1) PhSeNa;

ii) CH2N2; iii) 03,Et2NH; h) i) LAH; ii) Aczo I) Jones
oxidation

l9

resulting in the isolation of the cis-fused 92. The lactone
moiety of 92 was opened (,SeNa) and the C-4-methy1ene group
was introduced gig selnoxide elimination to give 93.
Reduction and selective acetylation, followed by oxidation
of the 2°-alcohol 94, produced the desired intermediate 95.

Kato and Kojima17 synthesized a Clerodin homolog 96 in
18 steps 113 the Diels-Alder adduct 97, as shown in Scheme
XV. This sequence of reactions is similar to the synthesis

Scheme XV Kato's Synthesis of a Clerodin
Homolog 96 .

l.

1"-
O -
)(o

 

a) Ag20,SnCls b) i) Zn,HOAC; ii) NaOMe; iii) Hz/pd/C c) 1,2-
ethane diol,H’ d) i) LAH; ii) DHP,H’ e) TsMIC,BuOK f) i)
Acetone,H’; 11) Dibal; 111) PhaPCHz s) 1) MCPBA; 11) 3-furyl
lithium cuprate h) i) H'; ii) AcaO

reported previously by Goldsmith and will not be discussed

in detail.

RESULTS AND DISCIBSION

llBflHfliAflDlHBCEfiHDN

Our synthetic approach to the clerodane diterpene is
outlined in Scheme I. The construction of the decalin
moiety involves a Diels-Alder reaction of l-viny1-6,6-
dimethylcyclohexene 100a with an appropriate acetylenic
dienophile, a stereoselective epoxidation of the resulting
adducts and a Lewis acid catalyzed rearrangement of such
epoxides that should lead to C-5-methyl migration providing
substrates containing the required functionality for the
decalin portion of the clerodanes.

l-vinyl-6, 6-dimethy1cyclohexene 100a1 3" was readily

available (Equation 2) by alkylation of 2-methyl
==\
1__.-KH 4192'. .4194. ~ ~ . <2)
/ /
OZ‘MGI O .\ 6H

cyclohexanone 97 (RH,CHaI) to provide 2,2-dimethy1
cyclohexanone 98 (50-75%) yield after purification by
preparative liquid chromatography (prep. HPLC, Waters Prep.
500, ether-hexane, 2:98, 300 mL/min) followed by vinyl

magnesium bromide (1.5M) addition to 98 providing l-vinyl-

20

2]

2,2-dimethy1-cyclohexanol 99, 72% yield (BP13 80-8500).
Dehydration was smoothly accomplished with CuSO4.5H2019 (1
equiv.) in refluxing benzene (2 hrs.) with azeotropic
removal of water, a modification of the procedure of Ley to
provide l-vinyl-6,6-dimethyl cyclohexene 100a in 85% yield,
(BP11 50-51°C).

Another diene, l-vinyl-2,6,6-trimethyl cyclohexene19
10!!) will be required in order to investigate the generality
of the rearrangement protocol and this was available by
oxidation of p-ionone with sodium hypochloride 5.5% solution
followed by decarboxylation by heating in quinoline as shown

in Equation 3.18b

NdOCI 0e (3)

\
\ O \

L99."

 

 

Diels-Alder Reactions.2°

Inspection of the literature for the Dials-Alder
reaction of l-vinyl-6,6-dimethylcyclohexene 100a provided
only two examples with nonsymmetrical dienophiles,18 the [4
+ 2] cycloaddition with 2-methoxy benzoquinone and 3-
methylbenzofuran-4,7-quinone, illustrated in Scheme XVI.
These reactions were examined as part of the syntheses of
Tanshinone II, Tanshinone III and cryptotanshinone,

respectively. Both reaction, with ethylenic dienophiles,

22

.ms:oxe:o~o>c

_>:_>:_-_>;soaea

 

 

1w.w do m:omuume= mot—<Im~0«=
/ o
AYlI
o m \H
.muau .u
as
nzoo
/ 0
Au
0
/ o

~>x

mausom

 

23

provide excellent regiochemical control (l-isomer), but the
low yields obtained (40-503) were a cause for concern. The
related l-vinylcyclohexene 101 has been studied much more
extremely as a partner in the Dials-Alder reaction. We were
dismayed to discover a recent report by Markgraf21 (Equation

4) which indicated that l-vinylcyclohexene 101 and ethyl

0,51 0,5)
@ . -_-3—ch1 —-A-> (4)

IOI :02 L9}
“T' "’ (40%m24)
propiolate provided a 2:1 mixture of the ortho:meta

products, 102 and 103, in but 40* yield. This stands in

stark contrast to selectivities reported in an earlier
report by Anachenko22 where the reaction of 101 with
propiolic acid was claimed to provide a 10:1 ratio of ortho-
meta adducts. However, closer inspection of the primary
literature suggests that ortho to meta ratios are much
closer to those of Markgraf which were obtained as the bulk
in the reaction mixture and was reported as a ”mixture”.
Despite the low selectivity observed in the Diels-Alder
reaction of l-vinylcyclohexene with acetylenic dienophiles,
we examined the [4 + 2] cycloaddition of the dienes 100a and
Ill!) with a group of acetylenic dienophiles or equivalents

and studied the regioselectivities.2° The results are
contained in Table I. Diene 100a reacted exothermally with

dimethyl acetylenedicarboxylate and provided 104m in 952-

24

yield. The more encumbered diene 10(2) reacted sluggishly
with dimethyl acetylenedicarboxylate at 120°C to afford the
adduct.HMb in 87* yield. Excessive heating (>120°C) causes
aromatization of ring B of 1045.’ The less reactive
unsymmetrical dienophile, ethylpropiolate, reacted with
diene 100a at 110°C to provide the ortho:meta adducts
104c: 104d in a 3:1 ratio; the selectivity of this reaction

rose to 6:1 (80%) when the reaction temperature was lowered
to 50°C. The ratio of the adducts 104c:104d was determined
on the basis of 1H-NMR (250 MHz), high-pressure liquid
chromatography (HPLC) and capillary gas chromatographic (GC)
analysis. The identity of the adducts ‘104c and 104d was_
determined by separations on prep. HPLC eluted with
ether:hexane, 2:98. The pure regioisomers, 104c and 104d,

were each separately aromatized by treatment with 2,3-
dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) to provide 105

and 106, Equations 5 and 6. Compound 105 exhibited the

egg“ _ 0029!
' (5)

 

 

(6)

 

 

25

following resonances in 1H-NMR (250 MHz) 6 I: 7.56 (dd,
J=7.5,1.25Hz, 1H), 7.49 (dd, J=7.5,1.25Hz, 1R), 7.18 (t,
J=7.5Hz, 1H); while 106 exhibited the following signals: 6 =
7.83 (d, J=8.3Hz, 1H), 7.73 (br s, 1H), 7.36 (d, J=8.3Hz,
IR). A comparison of these spectral data with the 1H-NMR

spectrum of lane, 1H-NMR, 6 = 7.56 (br s, 1H), 7.62 (d,

 

complex, J=8Hz, 1H), 7.3 (d, J=8Hz, 1H), indicates that, as
expected, the assignment of the regiochemistry is correct.
The reaction of 10011 with ethyl propiolate was slow at
120°C; however, the adducts 104c and 104f were obtained in
SSX yield and in a 5:1 ratio. Methyl tetrolate reacted
slowly at elevated temperature (150°C) in a sealed stainless
steel reaction vessel with diene 100a to provide a 65% yield
of the adducts 104g and 10411 in a 9:1 ratio after 36 hours.
Methyl tetrolate failed to react at all with diene 1M; and
increasing the temperature of the reaction above 150°C,
resulted in destruction of the starting materials and/or
products. Furthermore, attempted Lewis acid catalysisz‘ of
the reaction of methyltetrolate with diene 10th was
fruitless. Strong Lewis acids like BFa-Etzo resulted in

instantaneous diene polymerization even at low temperatures,

Table l

 

Entry

Table

26

Diets - Alder Reactions of 1990.!) With Acetylenic Dienophiles

 

 

 

R R.
n __ A 1 R2
q/ R'-=-R2 v
100 0 R'H |O4
"' bR'Me
Diene R R. R2 TlC) Yield Adducllorlholmelo)
l000 .H cone coZMe RT 957. 104.: l_)
IOOb Me con. COZMe :20 87‘]. 1045 (--)
El H 4 6
lOOo H CO: so 007. IO c __
g H c023 1044 I
1005 Me C025! H '20 55,]. lO4e (1)
Me H 0026: 1041 .l
l000 H COZMe Me lO4q 9
' :50 55v. ‘T’
H .Me COzMe IO4h
ll. Dlels- Alder Reactions of lOOo.b with 19 - Niko-Esters I38
02“ . R R1
R u-Duels-Alder
ni \ ____.. R2
/ 22-080mm;
“ :29 IOB “ '29
Diane __R_ _l3_ _R_ TlC) Yield l04(0rlho/melo)
l000 H c025: H RT 73% l04cll04le/IOO)
lOOb Me CO'ZEl H NO 66% lO4e/l04llO/l00)
l000 H c0251 Me RT 577. l04q/l04ilO/IOO)

27

while the more moderate Lewis acids, EtAlClz and Et2A1C1,
were ineffective. Other Lewis acids which were reported by
Roush to be effective in catalyzing the intramolecular
Diels-Alderz‘ reaction, NbCls, WCls, MoC(O)s and ZnIz, were

unsuccessful in this case.

figgio-revggged DielsfiAlder Reaction.

Danishefsky25 has demonstrated that p-nitro conjugated
esters can be used in Dials-Alder reactions to provide
regio-reversed products,25 because the nitro group usually
predominates over an ester group and directs the
cycloaddition. These p-nitro-¢,fi-unsaturated esters are
acetylenic dienophile equivalents providing e,p-unsaturated
esters as products after elimination of the elements of
nitrous acid. We examined the reactions of p-nitroacrylate
108m and p-nitrocrotonate 105 with dienes 100a and 10a: and
the results are tabulated in Table II. These dienophiles
were quite reactive, readily providing [4 + 2] adducts in
accord with the observations of Danishefsky.

(E)-Ethy1-p-nitroacrylate 108a was reacted with 100m at
room temperature to provide a mixture of the endo- and exo-
adducts in 91% yield. The mixture was treated with 1,8-
diazabicyclo[5.4.0]undecane (DBU) in refluxing benzene to
provide 104d in 1002 regioselectivity and 78% overall yield.
The corresponding (E)-Ethyl-p-‘-nitrocrotonate 108: reacted
with diene 100a slowly at room temperature (12 hrs.) and

provided the Diels-Alder adduct, which, after nitrous acid

28

elimination, provided 104i as the sole regioisomer in 57%
overall yield.

The less-reactive diene 1005 reacted with p-
nitroacrylate 109m at 110°C (12 hrs.) and provided 1041
after treatment with DBU in 71% overall yield. The more
hindered dienophile, (E)-Ethyl-p-nitrocrotonate, did not
react with diene MED even at high temperature, 150°C; and
increasing the temperature above 150°C resulted in
destruction of the starting materials and/or products.

The marked increase in yield and regioselectivity
observed in the reactions of dienes 100a and 10(1) with
acetylenic dienophiles is noteworthy. The presence of, the
geminal dimethyl substituents at C-6 of 100a and 10!!) is the
major deviation from the previous studies of l-vinyl-
cyclohexe 101 with acetylenic dienophiles. As is well
known,28 the barrier for the conformational interconversion
in simple dienes is low (<6kca1/mole); and, in the absence
of the steric hindrance effects, the s-trans conformer is
more stable than the s-cis or s-skew conformer by $2; 2.1
kcal/mole.2° Reusch27 has recently examined the UV
absorption of diene 100a and l-vinylcyclohexane 101 and has
concluded that 1001: appears to chiefly assume the s—cis (or
s-skew) conformation and 1-vinylcyclohexene 101 exhibits an
apparent s-trans-s-cis equilibrium. This factor will likely
facilitate the [4 + 2] cycloaddition reaction for 100a,b

relative to the vinyl cyclohexene. Thus, the adducts 104

29

are available for a study of the stereoselectivity of the

epoxidation sequence and subsequent epoxide rearrangement.

EpoxidJaJion of Heflhydronfiaphthafileneglgi

We investigated28 the epoxidation stereochemistry of
the hexahydronaphthalene 104 available from the Diels-Alder
reactions (vide supra). The epoxidizing reagents employed
were: a) m-chloroperbenzoic acid (MCPBA) in Cfizclz and b) N-
bromosuccinimide (NBS) in aqueous t-butanol (1:2, H20:t—
BuOH). The epoxidation results, ratios of isomers and
yields, are reported in Table III.

Epoxidation‘ of ethyl-5,5-dimethyl-3,5,6,7,8,8a-
hexahydronaphthalene-l-carboxylate 104c with MCPBA (0°,
CH2C12, 1 hr.) gave a mixture of the ahepoxide 1m&:and the
p-epoxide 110c; (109c:110c = 1:9) in 828 total yield. The
ratio of these epoxides was determined by HPLC (lOu) silica;
ether:hexane; 1:4), gas chromatography (GC, carbowax
column), and 1H-NMR (250 MHz). The stereochemistry of these
epoxides was determined using lH-NMR techniques (decoupling
and shift reagent studies).

Compound 110c exhibited the following resonances in 1H-
NMR spectrum 6.67 (m, 1H), 3.32 (br s, 1H), 3.22 (d m,
J=12.2Hz, 1H), 2.75 (d m, J=20Hz, 1H), 2.59 (d m, J=20Hz),
2.10 (d m, J=12.2Hz). The decoupling results, illustrated
in Figure 2b to 2g, are as follows: Irradiation at 6 = 6.67

resulted in simplification and collapse of the signals at

30

once. cm gangs! .2 5N8 : So.

 

m9 : 2. <26: 0: .zaoo z :2 a
o H... o om «e3: .u~oo : .z :5. m
n “on .o 33: z .uNoo .2 :5. n
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5 an 2. «m3: 318 z x 3.0. e
o ”8. .5 538.82 x _ z 686 z . :5.

ca 6. No <26: : m~ou : 30. n
n ”mm S 33: .28... .zNoo a: 25. N
on he no «one: {moo oz~ou : 3o. .

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. ee -
NC O. NC .600003 N“
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. 10.5-. use-sac E .mozvouEEuoaaoEoemuz nee

 

 

 

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32

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36

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37

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38

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38

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38

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: .
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39

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comm do sacsumam Aux: came mzz-=1 pm unseen

e. o.~ an 9. on e.
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40

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0. O.
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-

 

 

 

 

 

HHOO . Homo

Adv manna o Ammav amnnm

 

42

 

o Amway mcnwoavo mdawnwos o Amway mcnwonpo manwnwos
N.Ho c.Nmm N.Hm o.mma
N.mm c.~wm N.mN o.NmA
N.qm o.~om N.qm o.N~o
w.NN o.nm< w.o~ c.mnh
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m.mq o.amo m.kq o.mwm

mwmcnn a” ormmwomw m5whnm ornsmnn awn: chwoavo madwnwos «o

How." man. anon and finance own—:2: arm?”
nonnmwmwwom 0». H86.

SD

43

3.22, 2.76 and 2.59. Irradiation at 6 = 3.32 resulted in
sharpening of the signals at 2.76 and 2.59 ppm. Irradiation
at 6 = 3.22 ppm resulted in simplification of the signals at
6.67, 2.76, 2.59 and 2.10 ppm. Irradiation at 6 = 2.76 ppm
effected the signals at 6.67, 3.32, 3.22 and 2.59 ppm.
Irradiation at 6 = 2.59 resulted in sharpening and
simplification of the signals at 6.67, 3.32, 3.22 and 2.76
ppm. Irradiation at 6 = 2.10 ppm resulted in sharpening the
resonance at 3.22 ppm. From these decoupling results and
consideration of chemical shifts, the connectivities of the
protons of the B-ring was determined to be that shown in
Figure‘.. The stereochemistry of the epoxide moiety was
made on the basis of (Eu(fod)3) studies. In these studies,
increments of Eu(fod)3 were added and the chemical shift
differences were measured; these results are presented in
Figures 5a-e. The resonance at 6 3.22 ppm, which had been
attributed to the C-8a-fl, shifted the most relative to the
other protons, indicating the close spatial proximity of
that hydrogen to the basic epoxide oxygen. Therefore, we
have concluded that the ring junction hydrogen (3.22 ppm)
and the epoxide oxygen are on the same face of the molecule.
The structure of 110 as a p-epoxide was secured by single x-
ray analysis.

The a—epoxide 109c was examined in a manner similar to
that of the p-epoxide to assign the stereochemistry.
Epoxide 109c exhibited the following signals in the 1H-NMR

spectrum: 6 (ppm) = 6.49 (m, 1H), 3.33 (br s, 1H), 3.01 (d

44

m, J = 12.0Hz), 2.75 (d m, J=20Hz, 1H), and 2.52 (d m,
J=20Hz). Decoupling was performed as follows in Figures 6a-
e. Irradiation at 6 = 6.47 effected the resonances at 3.01,
2.75 and 2.52 ppm. Irradiation at 6 = 3.33 sharpened and
simplified signals observed at 2.75 and 2.52 ppm.
Irradiation at 6 = 3.01 simplified those resonances at 6.47,
2.75 and 2.52 ppm. Irradiation at 6 = 2.75 simplified the
signals at 6.47, 3.33, 3.01 and 2.52 ppm. Irradiation at 6
= 2.52 simplified the peaks at 6.47, 3.33, 3.01 and 2.75
ppm. From a consideration of the observed chemical shifts
and the couplings relationship of the protons in 109c, the
following assignments can be made, Cz-H at 6.47 ppm, C4-p-H
at 3.33 ppm, C-8a-H at 3.01 ppm, Can-H at 2.75 ppm and Cap-H
at 2.52 ppm.

The epoxide stereochemistry was suggested to be ab by
shift reagent (Eu(fod)3) studies (Figures 6a-6e). The ring
junction hydrogen at 6 = 3.33 ppm was slightly shifted
relative to the other protons of 109c and in direct contrast
to the lanthanide-induced shift of the ring fusion hydrogen
of the p-epoxide. These data suggest an aborientation for
the epoxide moiety which is corroborated by single-crystal

x-ray crystallography; the ORTEP plot is shown in Figure'1A

45

.83 .8 5.58% 3:: of: mzzuf an 33:

... e. e e.

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:
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3 g 414

 

 

 

 

 

 

 

 

 

 

 

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5; 83 .8 5.383 352 33 ESL: .6 3st

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47

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64

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52

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:22: owe” me asuuumam 2N=z omwv mzzuzd

.. 3 ... 9. 3 ...
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53

o.
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54

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.33 92: .3 533on 3:: uni 5.21:. 3 33.:

.. .. ... ... o. 9. o. o.
___________._...___._._..__...___.h.PbP..bbpb»Lbbpbb—b.[bpbpp—bpppprbpp—brbptlrpr—L

 

 

 

 

55

 

Figure 7 The ORTEP Plot of a Single Crystal
X-ray of 109c .

56

Using the chelical shift and coupling precedents set in
the exanination of epoxides 109: and 110c, all other
renaining epoxide stereochenistries were established.
Epoxidation of loib with (MCPBA, 0°C) gave a sixture of
epoxides 1 and lldb in 95:5 ratio, 873. The stereocheaistry
of the epoxide l was deternined by lfi-NMR techniques
(decoupling and shift reagent studies) and secured by single
crystal x-ray crystallography. The ORTEP plot of epoxide l
is shown in Figure 8.

The stereoselectivity obtained in epoxidation of 101b-
is as expected. The a-face selectivity is likely due to
steric hindrance in the p-face approach by the axial nethyls
at C-4 and C-Ba. Such selectivity, favoring the a-epoxide
forsation, is also observed in the epoxidation of 104a and
1041 providing 109a and 109! in 81 and 90* yields,
respectively.

Epoxidation (MCPBA) of 104g provided a sixture of
epoxides 109g and 110g in 11:89 ratio, respectively and in a
78* overall yield which was separated by chromatography on
silica gel.

The stereoselectivity of MCPBA epoxidation dropped in
the epoxidation of 104a and 104d. In the case of 104a. a
nixture of epoxides, 10k and 110a, were obtained in a
45:55, «:3 ratio in 95! yield; however, these epoxides were

readily separable by fractional crystallization (30:70,

57

ether:hexane). Epoxidation of 104d with MCPBA provided a
mixture of epoxides 109d and 110d in a 33:67 ratio in 77%
yield.

The drop in facial selectivity in these last examples
was surprising. The only deviation from other substrates is
the substitution at 0-2 which might cause conformational
changes that would expose both the a- and p-face of the
4,4a-double bond.

From these results, we conclude that MCPBA provides
mainly the p-epoxides when the group at Cs. is a hydrogen,
while the selectivity turns around with substrates
containing a C-8a-methyl.

Clearly, the desired a-epoxides can be prepared in
small quantities at best with MCPBA as the epoxidation
reagent. An epoxidation sequence that should provide the
less available a-epoxides employs NBS in aqueous t-BuOH.
The yields and ratios of products obtained upon treatment of
dienes 104c to 104g with NBS in aq. t-BuOH as are present in
Table III. Treatment of 104c with 2.0 equivalents of NBS in
a 2:1 ratio of t-BuOH:water (2 hours) provided epoxide 109c
directly in 94% yield as the sole product. The obtention of
epoxides directly without the observation of an intermediate
was a surprising but general event (vide infra). Compound
104g, when subjected to the NBS-epoxidation conditions,
provided only 109g in 54% yield.’ Exposure of 104d to NBS

under the standard conditions yielded epoxides 109d and 110d

58

 

8 The ORTEP Plot of a Single Crystal

Figure

X—ray of l.

59

(85:15) in 60% yield. The selectivity dropped in this case
as it did with MCPBA as the epoxidizing reagent.

Attempts to obtain the p-epoxides 11G), 110e and 1101'
using the aq. NBS-tBuOH conditions resulted in a mixture of
decomposition products including B-ring aromatic materials.
Other attempts to convert the a—epoxide llOb to the ab
epoxide 11% via formation of an intermediate diol (830*)
also failed. With the epoxides 109 and 110 in hand, we
proceeded to investigate the rearrangement protomoted by

Lewis acids.

£2251Q§§_109_§gg_110 Rearran ement Catal zed b BFa-Etzo:28

Epoxides are well known to rearrange to a variety of
products upon Lewis acid treatment.29 Steroidal epoxides, in
which the epoxide moiety is part of a rigid system, have
been extensively examined as rearrangement substrates; often
with BFs-OEtz serving as the Lewis acid. A number of
instructive examples are illustrated in equation 7 to 9.
For example, treatment of 4,4-dimethyl-5m,6a—epoxy-
cholestane lll'with BFa-Etzo provided alcohol 112 resulting

from C4-CHa migration to C-5,291 Equation 7.

(7)

 

 

60

Halsa1129' studied the 4pehydroxy-4,4-dimethyl-5a,6a~
epoxy-cholestane 113 rearrangement with BFa-Etzo and
obtained 114 in 358 yield, a product stemming from
synochronous C-5-p-methyl, C—6-ahhydrogen migration

(Equation 8). Whitlock29h reported a similar rearrangement

(8)

 

of compound 115 to provide 116 in variable yields (21-34X)

as shown in Equation 9.

 

(9)

   

In all of these rearrangements, one might anticipate
that a stereoelectronically allowed synchronous C-4 to C-4a
methyl migration might energetically favor the release of
the 1,3-diaxial interaction between C-4-p-methyl and C-10-
angular methylzgllt'hl and the release of strain in the

three-membered epoxide ring.

61

With this background in mind and the necessary
substrates for the study in hand, we first investigated the
rearrangement with BF3 EtzO of the more available p-epoxides
110. In the steroid series, exposure of related C-4a-C-5 [-
epoxides to Lewis acids have generally given a gross mixture
of products. The results of p-epoxides 110 are listed in
Table IV.

Treatment of the p-epoxide 110a with BF3~Et20 (1.25
equiv. CHzClz, 0°C; 10 minutes) provided.117a in 92% yield.
The nature of’ 117m ‘was deduced from inspection of the
spectral data and subsequent chemical manipulation. The
first indications of a novel structure for the product of
the rearrangement of 110a came from 1H-NMR and 13C-NMH data.
In the 1I-I--NMR (250 MHz, CDCla) compound 117a exhibited
resonances at 6 = 4.75 (br m, 18), 1.80 (br t, J=8.3Hz, 18),
2.76 (dd, J=18.8,2.3Hz, 1H), 2.2 (dd, J=18.8,4.ZHz, 18),
1.44 (s, 3) and 1.22 (s, 3). These data are close to what
one might expect for the desired, but unexpected in this-
series, rearrangement products; however, the 6 between the
observed and expected chemical shift values for an olefinic
hydrogen (4.75 ppm vs. ca. 5.25 ppm) and a CHa- on an sp2
hybridized carbon (1.44 ppm vs. ca. 1.70 ppm) were cause for
concern.

Extensive decoupling (1H-NMR), shift-reagent and
nuclear Overhouser difference ( NOEDS) studies suggested the

C-9 and C-1- through C-4—arrangement with the

62

Table. IV. Rearrangement of B-Epaxldee [[9 with BF3-Et20°

 

R . RI .
R2 R2
BF3E'20

\\ ’ O

HO ' n7
Epoxide R R .R , Yield 1%)
ILOa H mm. cozm 92%
I101: H c026: H 80%
1194 H H . c0251 87%
L199. H cozuo Me 79%

Table V Rearrangement of a-Epaxldes 109 with 8F3 5120.

 

 

 

R “I R R; R R. R R1
R2 32 R2 ' 2 R2
813.82 + + .1.
g)” x 0 OH - / OH
129 g2 Ll] I_2_3 134
.- Weld"

m m ' B. 5. 52. '2_2 E L23 2:
I IOSa H COZMe COZMe — 53 30 8
2 109:: H COZEt H — so 30 —
3 l09d H H c0251 — 52 27 IO
“ 109. m c0251 H an — - --
5 109: Me H ' co Et 8? — — —-

63

stereochemistry shown in Table VI for 117a. The 13C-NMR
(68.9 MHz, CDCla) data for 117a demonstrated that there was
indeed reason for concern, for compound 117a exhibited but
two sp2 C=C resonances (142.2(s) and 129.0(3)) and two
signals (6 = 83.7 and 81.8 ppm) in an unusual chemical shift
region. These data, along with the observation of the
facile M’-58(C3H50) loss in EI/MS (70eV), suggested a
rearranged oxetane as the structure of compound 117. Some
support for this conclusion was provided by a comparison of
the EI/MS fragmentation of'117a after loss of C3860 with the
EI/MS (70eV) fragmentation pattern of dimethyl-2,3,3a,6-
tetrahydroindene-4,5-dicarboxylate 120 prepared as described,

in Equation 10.31 Additional support for the proposed

E E

29 IB' IZO
E3 COZMG

structure was supplied by a comparison of the 1H-NMR and
13C-NME resonances attributed to the oxetane portion of 117m
(IE-NMR 6 = 4.22 ppm, 13C-NMR 6 = 83.7,81.8 ppm) with data
for oxetanes previously reported.32

. The nature of the ring system was unequivocally
demonstrated by exposure of 117a to NaOMe,MeOH providing the
related l,3-diene-5-C(C83)20H ring-opened material 121 (75%,

Equation 11). Treatment of the dienol 121 with pyridinium_

 

64

’9‘: N7053——.M£. .O—L' 78% (ll)

I20
1.1.2 1.1 '7
E3COZMB
chlorochromate33 (PCC) afforded the expected

dihydroindenediester 120 which was identical in all respects
when compared to the literature data34 and an authentic
sample prepared as described in Equation 10. The obtention
of oxetanes 117 from the BFa-EtzO treatment of epoxides 110
was unexpected.?-9il"hbl:III However, ‘ an inspection of
molecular models and the x-ray data demonstrates the ideal
positioning of the C-3—C-4 ring bond of compounds 110 for
migration with respect to the breaking C-5-0-bond giving 117
after ring closure. Similarly, epoxides 110c, 110d and 110g

provided oxetanes 117C (80%), 117d (87X) and 117g (79%),

respectively.

Rearrangement of abEpoxides 109*with BFa-OEtg

 

As was mentioned previously, the abepoxide 1 provided
the CHa-migration product 2 (1.25 equiv. BFa-EtzO,CHzC12,'
0°) in 76% yield. Similar treatment of the.a-epoxides 109e
and 109f (Table V) provided 122a and 122! in 83% and 81%
yields, respectively. Despite this seemingly strong
precedent for OKs-migration, exposure of epoxides 109m,

109c, 109d, and 109g failed to give even trace quantities of

65

the desired products 122, yielding instead, oxetanes 117
(52-60X) and alcohols 123 (27-302) and 124 (0-103). The
oxetanes 117a, 117e, 117d and 117g were compared to those
isolated from rearrangement of epoxides 110 and were found
to be identical in all respects. Alcohols, 123 and 124,
were separated (chromatography) and acetylated
(AczO,py,DMAP) to give the acetates 125 and 126,
respectively. These acetates were compared to the 4-0Ac,5-
isopropenyl compounds derived from oxetanes 117 (P-

TsOH,AczO,PhH, reflux, 3 hours),35 shown in Equation 12.

 

E
P-TSOH ‘ E‘
. Aczp, PhHT '. (l2)

87%. 0A:

 

!L" ' 135

The acetates 125 prepared from the major alcohols 123 were
indistinguishable from those derived from the oxetanes 117.
The structures of alcohols 125‘were secured after conversion
of the acetates 125 and 126 into single trienes 127
(KOBu‘,THF, Equation 13); demonstrating that they differed

only in stereochemistry at the carbinol center.

E E
E f , E _ E E
.s new .0 K t-BuO ‘ ' -
/ ..
1_2_ 5 137

126

66

The conversion of epoxides 109 to oxetanes 117 requires
an inversion of configuration at C-4 and C-4a of the parent

compounds 1091with respect to the C-8a—H. Such a process

    
  

might occur as outlined in Equation 14. Rupture of the C-
R, ' R2
\‘ R3 sfioeu :
—~ .. -- "7.129.123

3

. 638:,

 

L23

4a-Q bond, accompanied by C-8a-H migration and cleavage of
the C-4a-C-4-ring bond, could provide the intermediate 128-
Further reaction of 128‘with BFa-Etzo could eventually lead
to 117. Some support for the ring cleavage and
recombination processes can be found in reports by
Whitlock29h and Demole31, respectively.

The processes described above illustrate the importance
of remote substituents C-8a-CH3 and the functional groups
(1,2-double bond) in directing the epoxidation of the dienes

104 and the rearrangement of the epoxides 109 and 110. In

order to facilitate the rearrangement of epoxides of the '

type 109 to clerodane intermediates 122, the C-8a-H must be

replaced with a hydrogen equivalent that will not interfere

with the rearrangement process. The group placed at C-8a
should be at least as large as a -CHa, must not eliminate,
or participate during the rearrangement and must be

transformed to the required hydrogen in later stages of the

(14)

67

synthesis. The carboakoxy group is a good candidate for
such substituents. An alternative to the introduction of a
functional group at the ring fusion might be the placement
of a substituent in the A-ring to facilitate CHa-migration
and/or impede oxetane formation. The group of choice might
be a 3p-hydroxy group.

The latter of these two possibilities was deemed the
simplest to examine and, therefore, was investigated first.
The required diene 130 was prepared as outlined in Equation

15 by the addition of vinyl magnesium ~bromide to 2,2-

qur CuSO4
————-o -——-D
THF-TB . / 68% / (I5)
\ 417. \OH \
13.9 ' '10 '3'
dimethyl-l,3-cyclohexanedione at -78°C followed by

dehydration with CuS04-5820 to provide 131. Although the
yield of alcohol 129*was modest (42%), attempts to add vinyl
magnesium bromide to the mono-protected diene3° resulted in
the recovery of the starting material unchanged.

The Dials-Alder reaction of 131 with dimethyl
acetylenedicarboxylate proceeded slowly at room temperature,
providing the adduct 132 in 52% yield (Scheme XVII).
Epoxidation of'132'with NBS aqueous, t-butanol provided a
1:6 mixture of epoxides 133 and 134 in 91% yield. Sodium
borohydride reduction of the epoxide 134 provided, as

expected, the equatorial alcohol 135 in 89% yield.

 

68

Rearrangement of 135 with BF3-Et20 resulted in the formation
of the related B-ring aromatic diester 136. The structure
of 136 was proved by comparison to an authentic sample,
prepared by treatment of’132 with 000 followed by sodium
borohydride reduction; these materials were found to be
identical in all respects.

Epoxidation of 132 with MCPBA provided exclusively the
epoxide 133 in 71% ‘yield which was reduced with NaBH4 to
provide 137. Treatment of 137 with BFa-Etzo resulted in the
formation of a large mixture of product which was
unidentified and which concludes that the perturbation in
the A ring was not good enough to direct the rearrangement

to the required pathway.

Scheme XVII Synthesis of 136 and 137 and
Rearrangements

0 (7'70)

 

 

0

d \
/ 137

E, COzMe a mixture of products

 

a) MCPBA 0°C' b) NBS a -
, , , q. t BuOH ooc,
gggfiq, 08308; d) BF: Et20. 0°C; ’

. 134:133= 6:1; c)’
e) 1) BBQ; 95%; ii) NaBflq,

Experimental Section

General: Tetrahydrofuran (THE) and benzene were dried
by distillation, under nitrogen from sodium benzophenone
ketyl. Petroleum ether refers to 30-60°C boiling point
fraction of petroleum benzin. Diethyl ether was purchased
from Mallinkrodt, Inc., St. Louis, Missouri, and used as
received. All other reagents were used as received unless
otherwise stated; all reactions were carried out under a
blanket of argon with the rigid exclusion of moisture from
all reagents and glassware unless otherwise mentioned.

Infrared spectra were recorded on a Pye-Unicam SP-lOOO
infrared spectrophotometer with polystyrene as standard.
Proton magnetic resonance spectra were recorded on a Varian
T-60 at GOMHz or a Bruker WM-250 spectrometer at 250MHz as
indicated, as solutions in deuterochloroform unless
otherwise indicated. Chemical shifts are reported in parts
per million on the 6 scale relative to a tetramethylsilane
internal standard. Data are reported as follows: chemical
shift [multiplicity (s = singlet, d = doublet, t = triplet,

q = quartet, m = multiplet, and br = broad), coupling

69

7O

constant (Hz), integration]. 13C magnetic resonance spectra
were recorded on a Bruker NM-250 spectrometer (68.9 MHz) and
are reported in parts per million from tetramethylsilane on
the 6 scale. Electron impact (EI/MS) and chemical
ionization (CI/MS) mass spectra were recorded on a Finnigan
4000 with an INCOS 4021 data system.

All chromatography was performed by the flash technique
according to the procedure of Still et s!” using the silica
gel mentioned and eluted with the solvents mentioned. The

column outer diameter (o.d.) is listed in millimeters.

6,6-Dimethyl-l-vinyl-cyclohexene 100a

To 15.4g (0.1 mol) of 2,2-dimethy1-l-vinyl-cyclohexanol
in 300 mL of benzene was added 24.9g (0.1 mol) of
CuSOe-(H20)5. The mixture was heated under reflux with
azeotropic removal of water for 2 hrs. After cooling to
room temperature, the copper sulfate was removed by
filtration and the filtrate was concentrated by distillation
of the benzene solvent at atmospheric pressure. The
residual oil was purified by distillation BPii = 50-5200,
providing 11.6g (87%) of late as a colorless liquid.
1H-NMR (250 MHz, CDCla): 6 6.30 (dd, J=l7.7,ll.682, l), 5.77
(t, J=3.97Bz, l), 5.26 (d, J=17.7Hz, l), 4.91 (d, J=ll.68z,
1), 1.65 (s, 6), 0.3-2.2 (m, s). EI/MS (70eV): 136 (H+,
34.5), 121 (48.9), 107 (24.7), 93 (73.5), 80 (base), 69

(28.5), 55 (32.3), 40 (47.3), 33 (84.8). IR (neat): 2990,

71

2950, 2915, 2850, 1610, 1450, 1375, 1355, 1260, 1120, 930,

765cm'1.

General Procedure for Diels—Alder Reactions.

Ethyl-5,5-dimethyl-3,5,6,7,8,8a-hexahydrongphthglene-l-

carboxylate 1m and 2-carboxylate 104d
To 2.0g (14.7 mmol) of lake was added 3.0g (30.6 mmol)

 

of freshly distilled ethyl propiolate; the mixture was then
heated in a 50°C oil bath for 12 hrs. The reaction mixture
was cooled to room temperature and the excess ethyl
propiolate was removed in vacua to provide a colorless oil.
The crude product was purified by preparative LC (Waters
Prep 500; 2 columns; ether-hexane, 2:98; 300 mL min'l)
providing 2.55g (74.1%) of 104c as a colorless viscous oil
and 0.36g (10.5%) of 104d as a colorless viscous oil.

Pfi: 1H—NMR (250 MHz, CDCla): 6 = 6.88 (br t, J=4.0Hz, l),
5.35 (br t, J=4.0Bz, l), 4.25 (m, 2), 3.28 (m, l), 2.77 (m,
2), 1.38 (t, J=8.0Hz, 3), 1.3-2.0 (m, 6), 1.10 (s, 6).
EI/MS (70eV): 234 (M’, 44.3), 219 (7.92), 205 (10.2), 187
(16.0), 173 (9.9), 166 (14.6), 145 (23.3), 135 (20.8), 119
(20.3), 105 (38.6), 91 (base).IR (neat): 2960, 2915, 2880,
1720, 1680, 1650, 1380, 1365, 1255, 1230, 1075, 985cm'1.
fl: lfi-NMR (250 MHz, CDCla): 6 = 6.76 (m, l), 5.45 (t,
J=3.3Hz, l), 4.20 (q, J=7.0ZHz, 2), 2.80-3.10 (m, 3), 1.45-
2.8 (m, 6), 1.29 (t, J=7.0282, 3), 1.09 (s, 3), 1.04 (s, 3).
EI/MS (70eV): 234 (M*, 39.6), 232 (6.5), 219 (26.6), 205

72
(9.4), 189 (20.8), 177 (10.5), 163 (13.7), 149 (22.0), 135
(32.7), 119 (26.2), 105 (54.4), 91 (base). IR (neat): 3010,
2960, 2920, 2870, 1716, 1650, 1460, 1380, 1353, 1290, 1253,

1240, 1110, 1090, 1030, 953, 915, 753, 740cm'1.

GmummllhmcuimeIn»?Beckriewumedlnehrifldurlhmduumm
-thyl-5,5-dimethyl-3,5,6,7,8,8a-hexahydronaphthalene-2-
garboxylgtgqlggl

To 0.5g (3.7 mmol) of 100m in 20 mL of dry benzene was
added 1.0g (6.9 mmol) of (Z)-ethyl-p-nitroacrylate3° 108m
(82:8). The resulting yellow-orange solution was allowed to
stir for 18 hrs. at room temperature, then the solvent was
removed in vacuo to give a yellow oil. The crude product
was filtered through a short column of silica gel (60-230
mesh, ether-pet. ether, 1:4) to afford the Diels-Alder
adducts (0.96g, 91%) as a pale yellow viscous oil.

To 0.6g (2.1 mmol) of the adducts in 20 mL of dry THF
was added 0.64g (4.2 mmol) of 080. The mixture was stirred
for 4 hrs. at room temperature, cast into ether (50 mL),
washed with 0.1N aq. BCl, saturated aq. NaHCOa and brine (50
mL each). The organic phase was dried (Na2804) and
concentrated in vacuo to provide the crude product as a
viscous pale yellow oil. The crude 104d was purified by
chromatography on a column of silica gel (20 mm 00; 230-400
mesh; ether-pet. ether, 1:4; 10 mL fractions) using the

flash technique37 to yield 10kl(0.42g, 86%).

73

Ethyl-5,5-dimethyl—5,6.7,8-tetrghydronaphthalene-l-

 

carboxylate 105
To a solution of 0.1g (0.4 mmol) of 104c in 10 mL of

benzene was added 0.17g (0.6 mmol) of 000. The mixture was
allowed to stir for 12 hours at room temperature; then was
filtered through a pad of celite which was rinsed with
benzene, and the combined eluate was concentrated in vacuo
to afford a pale yellow oil. The crude product was purified
by chromatography on a column of silica gel (20 mm 00; 60-
230 mesh; ether-pet. ether, 1:9; 7 mL fractions) giving
0.097g (98%) of 105 as a colorless viscous oil.

lfi-NMR (00013): 6 7.56 (dd, J=7.5,1.25Hz, l), 7.49 (dd,
J=7.5,1.25Hz, l), 7.18 (t, J=7.582, l), 4.34 (q, J=7.0Hz,
2), 3.02 (br t, J=6.SHz, 2), 1.6—1.85 (m, 4), 1.38 (t,
J=7.0Bz, 3), 1.28 (s, 6).EI/MS (70eV): 232 (M’, 68.8), 217
(90.5), 203 (17.3), 187 (48.0), 186 (84.3), 171 (base), 161
(20.1), 143 (39.1), 128 (64.3), 115 (52.9), 105 (11.0), 91
(33.6), 77 (19.5), 51 (16.1), 43 (32.3).IR (neat): 3065,
2960, 2935, 2875, 1720, 1560, 1475, 1450, 1385, 1365, 1275,

1210, 1185, 1150, 1100, 1025, 760, 7200m’1.

Ethyl-5,5-dimethyl-5,6.7.8-tetrghydrgngghthglene-g;
carboxylate 106

In a similar fashion to that described for the
preparation of 105, 0.1g of 104d yielded 0.084g (85%) of 113

as a viscous colorless oil.

74

1H-NMR (250 MHz, CDCla): 6 = 7.78 (br d, J=8.3Bz, l), 7.73
(br s, 1), 7.36 (d, J=8.3Hz, l), 4.35 (q, J=7.0Hz, 2), 2.80
(br t, J=6.682, 2), 1.6-1.85 (m, 4), 1.36 (t, J=7.0Hz, 3),
1.28 (s, 6). EI/MS (70eV): 232 (M’, 18.2), 217 (base), 203
(17.3), 187 (13.9), 171 (8.4), 159 (3.2), 145 (19.1), 128
(16.4), 115 (15.3), 105 (3.9), 91 (11.9), 77 (5.11), 51
(3.6), 43 (6.0), 41 (7.2). IR (neat): 3040, 2960, 2930,
2875, 1720, 1610, 1570, 1460, 1420, 1385, 1365, 1290, 1270,
1235, 1200, 1185, 1170, 1110, 1055, 1020, 915, 770, 730cm‘1.

Dimethyl-5.5-dimethyl-3,5,6,7,8,8a-hexahydronaphthalene-l,2-

dicarboxyl ate 1041:

According to the general procedure for Dials-Alder
reactions, 1.0g (7.3 mmol) of lab was mixed at room
temperature with 1.2g (8.5 mmol) of dimethylacetylene
dicarboxylate. An instantaneous exothermic reaction
occured; the reaction mixture was then stirred for an
additional 1 hour. Chromatography of the mixture on a
column of silica gel (50g, 60-230 mesh, 40 mm 00; 20 mL
fractions). Fractions 5 to 12 gave 1.93g of 104m as a
colorless oil (95%).
1H-NMR (250 MHz, C0013): 6 = 5.36 (t, J=3Hz, l), 3.76 (s,
3), 3.72 (s, 3), 3.0 (m, 3), 1.2-2.0 (m, 6), 1.06 (s, 3),
1.03 (s, 3). EI/MS (70eV): 278 (M‘, 2.5), 263 (2.3), 244
(base), 229 (46.9), 213 (5.05), 203 (11.4), 186 (19.8), 176

(7.4), 159 (12.3), 143 (13.9), 128 (17.9), 111 (61.0), 105

75

(22.8), 98 (11.6), 91 (37.9), 77 (24.9), 69 (26.2), 59
(61.7), 55 (45.8), 39 (95.6). IR (neat): 3020, 2950, 2930,
2870, 1725, 1430, 1260, 1100, 1040cm‘1.

Dimethyl-5,5,8a-triggthyl-3.5.6.7.8.8§:hexahydronaphtha1ene-

Li-dmfirbolefiatéabfiafl

According to the general procedure for the Diels-Alder
reaction, 5.0g (33.3 mmol) of diene lab was heated at 110°C
with 5.6g (35 mmol) dimethyl acetylene dicarboxylate for 12
hours. The mixture was. cooled to room temperature and
filtered through a short column of silica gel (ether:pet.
ether; 1:1). Purification of the resulting viscous oil on
prep. LC (ether:hexane, 8:92, 250 mL/minute) provided 8.1g
of 1041) as a colorless oil.
1B-NMR (250 MHz, CDCla): 6 = 5.70 (dd, J=3.0,6.0Hz, l), 3.8
(s, 3), 3.73 (s, 3), 3.20 (dd, J=6.0,2382, l), 2.78 (dd,
J=3.0,23Hz, l), 1.2-1.8 (m, 6), 1.43 (s, 3),' 1.18 (s, 3),
1.14 (s, 3). EI/MS (70eV): 292 (M’, 11.4), 261 (23.3), 260
(51.8), 245 (9.3), 233 (6.3), 217 (28.5), 210 (9.6), 203
(42.4), 189 (20.7), 178 (40.9), 176 (58.8), 163 (24.4), 149 .
(42.9), 83 (7.5), 69 (8.8), 55 (4.2), 40 (base). IR (neat):
3000, 2960, 2930, 2860, 1735, 1670, 1640, 1440, 1370,

l340cm‘1.

76

Ethyl-5,5,8a—trigethyl-3.5.6.7,8,8g-hexghydrongphthglene-l-
W

According to the general procedure for Diels-Alder
reactions, 1.0g (6.7 mmol) of diene 10th was mixed with 1.5g
(15.3 mmol) ethyl propiolate and heated at 120°C for 24
hours. Chromatography of the mixture on a column of silica
gel (70g, 230-400 mesh, ether-hexane, 5:95, 20 mL fractions)
0.77g (45.8%) of 104c as a colorless oil and 0.15g (9.1%) of
IDML
Lie: 1H-NMR (250 MHz, CDCla): 6 = 6.64 (t, J=4.ZHz, 1),
5.60 (t, J=4.le, l), 4.16 (q, J=7.0Rz, 2), 2.76 (t,
J=4.ZHz, 2), 1.46 (s, 3), 1.28 (t, J=7.0Bz, 3), 1.18 (s, 3),
1.11 (s, 3), 0.9-1.8 (m, 6). EI/MS (70eV): 249 (M', 5.97),
233 (47.5), 217 (15.9), 203 (12.1), 187 (40.5), 171 (19.8),
159 (28.9), 145 (41.3), 135 (25.5), 119 (base), 105 (92.4),
91 (78.0), 83 (8.9), 77 (26.8), 69 (15.6). IR (neat): 3060,
2960, 2920, 2870, 2820, 1715, 1670, 1630, 1460, 1385, 1370,

1230, 1180, 1060, 1025, 980cm‘1.

affordec

1041: 1H-NMR (250 MHz, CDCls): 6 = 6.58 (d, J=3.ZHz, 1), 5.65 (dd,

J=5.5,2.5Hz, 1), 4.22 (q, J=7.0Hz, 2), 3.01 (dd,
J=5.5,20.882, l), 2.83 (d t, J=2.5,20.882, 1), 1.3-2.0 (m,
6), 1.31 (t, J=7.0Hz, 3), 1.22 (s, 3), 1.18 (s, 3), 1.13 (s,
3). EI/MS (70eV): 248 (M*, 6.11), 233 (40.0), 217 (21.3),
203 (12.6), 187 (35.4), 171 (20.6), 159 (27.8), 145 (40.9),
129 (23.9), 119 (base), 105 (95.4), 91 (75.1), 77 (23.9), 69
(15.9). IR (neat): 3060, 2960, 2920, 2870, 2710, 1670,

77

1625, 1460, 1400, 1380, 1250, 1230, 1180, 1060, 1030,

980cm'1.

Ethyl-5,5,8a-triggthyl-3,5.6,].8.8a-hexahydronaphthalene-g;
carboxylate 104!

According to the general procedure for regio-reversed
Diels-Alder reactions, 1.5g ('10 mmol) of diene_ I!!!) was
treated with 1.5g (10.1 mmol) (E)-p-nitroacrylate 108m at
110°C for 12 hours. The crude product was purified by
chromatography on a column of silica gel (50g, 30 mm OD, 60-
230 mesh, ether-pet. ether, 5:95) gave 2.28g (78%) yield of
a mixture of exo- and endo-adducts. The adducts were
treated with 1.7g of (DBU) in 50 mL benzene and the mixture
was heated under reflux for 8 hours. Usual workup and
chromatography of the residue over silica gel (65g, 40 mm
OD, ether-Pet. ether, 2:98) provided 1.75g, 92%, of 104! as

a colorless liquid.

Methyl-2.5.5-trigethyl-3.5.6.7.8.8§:hexghydroggphthalene-l-
gmxyletefl

To 0.5g (3.6 mmol) of diene 100a was added 0.7g (7.1
mmol) methyl tetrolate, and the mixture was heated in a
sealed stainless steel cuvette at 150°C for 12 hours. The
resulting dark oil was purified by chromatography on a
column of silica gel (60g, 40 mm OD, ether-pet. ether, 3:97)
to give 0.495g of 104g (58%) as a colorless oil and 0.055g
of 1041: (6.4%).

78

_10_4‘: 111-mm (250 MHz, cnc13): a = 5.33 (t, J=3.4Hz, 1),
3.67 (s, 3), 2.0-3.2 (m, 3), 1.79 (s, 3), 0.99 (s, 6), 1.0-
2.0 (m, 6). BI/MS (70eV): 234 (M‘, 25.7), 219 (34.5), 203
(9), 187 (15.1), 175 (12.7), 159 (26.5), 145 (17.2), 131
(21.2), 119 (34.1), 105 (base), 91 (40.2), 77 (19.1), 59
(21.7). IR (neat): 2950, 2930, 2860, 1720, 1685, 1600,
1435, 1380, 1360, 1325, 1270, 1230, 1150, 1100, 1050,

870cm'1.

Ethyl-1,5,5-triggthyl-3.5.6.7.8.8a-hexahzdr0na2hthglene-g;
carboxylate 1041

According to the general procedure for regio-reversed
Diels-Alder reactions, 0.6g (4.4 mmol) of’loo and 0.7g (4.9
mmol) of ethyl-p-nitro crotonate reacted with 0.7g (4.9
mmol) 1081- in 30 m1. of benzene at room temperature for 12
hours. The usual workup provided 0.93g (74%) of a yellow
liquid of the nitro adducts. To 0.75g of the adducts was
added 0.76g of 080 (,8, 1 hr., RT) after the usual workup,
and purification of the residue by chromatography on a
column of silica gel (30g, 30 mm OD, ether-pet. ether, 3:97)
provided 0.57g (90% yield) of 1041. 1H-NMR (250 MHz,
00013): 6 = 5.38 (br t, J=3.4Hz, l), 4.11 (q, J=7.3Hz, 2),
2.7-2.89 (m, 3), 1.95 (br s, 3), 1.21 (t, J=7.3Hz, 3), 1.0
(s, 3), 0.97 (s, 3), 0.9-1.7 (m, 6). EI/MS (70eV): 248 (M’,
4.3), 175 (82.4), 159 (28.4), 133 (19.9), 119 (37.4), 105

(base), 91 (72.4). IR (neat): 3060, 2960, 2940, 2870, 1735,

79

1540, 1460, 1385, 1375, 1350, 1220, 1175, 1150, 1100, 1030,

860, 830cm‘1.

(knunflqfinnafinswflu-mimflmnmedunmah:Achi(Hanna
lpomhhnian
Ethyl-5,5-dimethxl-4-g,4a-Q-epoxy-3,4,4a,5,6,7,8,8a-
octahxdronaphthalene-l-carboxylate 110c and 4c~4a,s~epoxy
109:.

 

To a solution of 0.5g (2.1 mmol) of 104c in 20 mL dry
082012 at 0°C (ice water bath) was added a solution of 6.89g
(85%, 4.3 mmol) of m-chloroperbenzoic acid (MCPBA) in 20 mL
of dry CHzClz over a period of 1 hour. After stirring at
0°C for an additional 1 hour, a white precipitate was
formed. The reaction was quenched with 10% aq. NazSan (20
mL), then the mixture was cast into ether - 10% aq., NazSan
(100 mL each). The organic layer was separated, washed with
saturated aq. NaHCOa, water and brine (100 mL each), and
dried (Na2804). Concentration in vacuo provided 0.43g (81%)
of a mixture of 109c and 11°C. Purification of the mixture
on a column of silica gel (60g, 40 mm OD, ether-hexane,
5:95) to provide 0.387 (73%) of'110c as a colorless oil,
which solidified upon cooling (colorless crystals), m.p.
52°C. Further elution afforded 0.043g (8.1% yield) of’109c
as a white solid, m.p. 45-47°C. 110c: 1H-NMR (250 MHz,
CD013): 6 = 6.67 (br d, J=ZOHz, 1), 4.2 (m, 2), 3.32 (br s,
l), 3.22 (br d, J=12.282, l), 2.73 (dt, J=6.1,1.582, l),

80

2.10 (dt, J=12.2,l.5Hz, 1), 2.59 (dd, J=20,1.5nz, 1), 1.4-
1.3 (m, 6), 1.23 (t, J=7.2az, 3), 1.124 (s, 3), 0.31 (s, 3).
130-333 (6.9 MHz, 00013): a = 166.4, 132.5, 132.2, 66.3,
60.4, 54.5, 40.4, 34.6, 33.2, 27.1, 25.3, 22.1, 21.5, 14.2.
RI/MS (70eV): 250 (3+, 33.1), 235 (10.1), 222 (35.6), 217
(9.4), 205 (53.5), 139 (24.6), 179 (33.4), 177 (23.5). 171
(17.0), 161 (33.6), 154 (46.5), 149 (61.7), 139 (base). IR
(neat): 2930, 2360, 1720, 1660, 1470, 1390, 1372, 1305,
1270, 1250, 1100, 1050, 940, 900, 765cm'1. 109c: 13-333
(250 MHz, CD013): 5 = 6.47 (m, l), 4.21 (q, J=7.282, 2),
3.33 (br s, 1), 3.01 (dt, J=3,1zaz, 1), 2.75 (dm, J=2onz,
1), 2.52 (ddd, J=3,1.5,2082, 1), 1.3-2.2 (m, 6), 1.25 (t,
J=7.ZHz, 3), 1.15 (s, 3), 0.73 (s, 3). 130-333 (63.9 M82,
0001:): a = 167.3, 131.34, 131.37, 66.23, 50.24, 53.77,
37.30, 34.66, 32.72, 27.51, 26.93, 24.04, 22.27, 14.21.
31/33 (70eV): 250 (3+, 55.7), 235 (8.6), 222 (36.1), 217
(15.6), 205 (31.0), 139 (39.6), 179 (51), 171 (21.9), 161
'(6o.6), 154 (52.9), 69 (34.5), 55 (25.4), 41 (27.3). IR
(neat): 2970, 2930, 2370, 1740, 1695, 1440, 1390, 1365,

1280, 1260, 1210, 1120, 1100, 1070, 810cm'1.

Alflunrallfiocuhmethu-lint-unuxdmhddelhnmmmndanin
Amman-.bflhflmnol

Ethyl-5,5-dimeth11-4-s,4a-c—epoxy-3.414a,5,6,7,8,8a-

octahydronaphthaleng-l-carboxylate 109c
To 1.5g (6.4 mmol) of 104c in 30 II. of a mixture of t-

butanol-water (2:1) at room temperature was added 1.95g

81

(11.0 mmol) of N-bromosuccininide (NBS). (The mixture was
stirred at room temperature for 1 hour, and then was diluted
with water (100 mL). The solution was extracted ether (1x
00 mL); the combined organic phases were washed with
saturated aq. NaHCOa and brine (50 mL each) and dried
(NazSO4). Concentration in vacuo gave 1.5g (94%) of 109c as

a colorless oil which solidified upon cooling.

Methyl-2,5,5—trigethyl-41,4g1repoxy-3,4,4a,5,6,7,8,8a-
octahydronaphtLalene-l-carboxylate 110‘ and 4¢,4&¢ epoxy
1L9!

According to the general procedure for epoxidation with

 

MCPBA, 0.25g (1.06 mmol) of 104g were treated with a
solution of 0.33g (1.5 mmol) MCPBA, 85%. The usual workup
and chromatography of the crude product on a column of
silica gel provided 0.178g (68%) of 110g and 0.022g (8.5%)
of 109;

119‘: 1H-NMR (250 MHz, CD013): 6 = 3.71 (s, 3), 3.28 (d,
J=IHz, 1), 2.6 (br s, 2), 2.48 (m, 2), 1.97 (s, 3), 1.2-2.0
(m, 6), 1.59 (s, 3), 1.15 (s, 3), 0.79 (s, 3). EI/MS
(70eV): 250 (M’, 7.3), 235 (6.7), 219 (8.8), 207 (11.4), 185
(5.3), 176 (16.3), 163 (13.7), 157 (6.0), 91 (66.2), 77
(60.2), 69 (51.2), 55 (57.6), 41 (base). IR (neat): 2960,
2930, 1720, 1700, 1685, 1435, 1390, 1365, 1240, 1070cm'1.
199‘: 1H—NMR (250 MHz, 0D013): 5 = 3.73 (s, 3), 3.27 (br s,
1), 2.975 (dm, J=12.3Hz, 1), 2.61 (d, 3:19.582, 1), 2.53 (d,
3:19.582, 1), 1.22-2.2 (m, 6), 1.70 (br s, 3), 1.11 (s, 3),

82

0.73 (s, 3). 3I/Ms (70eV): 250 (M+, 11.51), 235 (15.0), 232
(6.1), 221 96.24), 219 (13.5), 191 (11.3), 176 (43.6), 163
(23.6), 153 (32.7), 147 (32.0), 133 (21.2), 121 (39.0), 117
(10.3), 103 (31.3), 91 (62.4), 69 (53.7), 41 (base). IR
(neat): 2960, 2930, 2360, 1720, 1700, 1685, 1430, 1330,
1365, 1240, 102063-1.

Dimethyl-5,5-dimethyl-4£-4a£-epoxz-3,4,4a,5,6,7,8,8a-
octahzdronaphthalene-l,2-dicarbox11ate 109a and dimethyl-
5,5-dimethyl-4s-4a«bepoxy-octahydronaphthalene-l,2-

dicarboleate 110:

According to the general procedure for epoxidation with
MCPBA, 7.0g (23.8 mmol) 10411 was epoxidized with MCPBA
(7.0g, 34.5 mmol, 85%) affording 6.73g (95%) of a mixture of
epoxides 109a and 110. in a ratio of 45:55. Fractional
crystallization from ether:hexane (3:7) gave 3.77g (52%) of
110 as white crystals, m.p. 74-76°0, and 3.03g of 109. (43%)
as white crystals, m.p. 112-113°C.

1195: lfl-NMR (250 MHz, CD013): 6 = 3.74 (s, 3), 3.71 (s, 3),
3.33 (br dd, J=19.0,2.lflz, 1), 2.12 (dt, J=13.7,2.582, 1),
1.61 (m, 3), 1.1-1.5 (m, 5), 1.08 (s, 3), 0.80 (s, 3).
RI/MS (70eV): 294 (M’, 1.5), 279 (0.7), 263 (26.5), 234
(51.7), 219 (36.4), 202 (23.0), 191 (30.0), 175 (20.8), 165
(base).' IR (neat): 1735, 1660, 1290, 1270, 1200, 1090,
1070, 1040, 940, 885, 870, 810, 785, 755cn'1.

L093: 111-NM}! (250 MHz, 0D013): 6 = 3.77 (s, 3), 3.70 (s, 3),

3.35 (t, J=1.5Hz, l), 3.08 (dm, J=19.Zflz, l), 3.05 (m, 1),

83

2.52 (dm, J=19.ZHz, 1), 1.2-1.8 (m, 6), 1.11 (s, 3), 0.8 (s,
3). BI/MS (70eV): 294 (M’, 4.5), 279 (7.5), 263 (21.7), 247
(13.2), 234 (51.5), 219 (27.9), 202 (17.3), 191 (21.9), 165
(base). IR (neat): 1730, 1720, 1650, 1260, 1090, 1070, 970,

955, 830, 760, 720cm‘1.

Ethyl-5.5-digethyl-4s,4a-a-epoxy-3,4,43,5,6,7,8.8;;

octahydronaphthalene-2-carboxylate 109d and 43,4a-g-epoxy
11m. '

According to the general procedure for.epoxidation with
NBS in aq. t-butanol, 0.2g (0.85 mmol) of 10441 was treated
with 0.23g (1.28 mmol) of N38 at room temperature to provide
0.11g (52%) of 109d and 0.0195g, 9%, of 110d after
purification by chromatography on a column of silica gel
(30g, 30 mm 0D, 230-400 mesh, ether-pet. ether, 2:98).
199g: 1H-NMR (250 MHz, CD013): 6 = 6.66 (dd, J=6.1,3.0Hz,
l), 4.2 (m, 2), 3.34' (br d, J-l.SHz, 1), 2.93 (dt,
J=18.5,l.5Hz, l), 2.79 (m, 1), 2.46 (ddd, J=18.5,1.5,3.0Hz,
l), 1.92 (m, 1), 1.3-1.7 (m, 6), 1.20 (t, J=7.282, 3), 1.0
(s, 3), 0.74 (s, 3). EI/MS (70eV): 250 (M‘, 26.6), 217
(48.4), 177 (19.5), 161 (80.5), 147 (39.1), 133 (25.0), 119
(46.1), 109 (63.3), 105 (63.3), 105 (64.1), 91 (base). IR
(neat): 2960, 2930, 2850, 2840, 1710, 1660, 1460, 1390,
1370, 1300, 1250, 1080, 1010, 895, 780, 740cm'1.
1499: lH-NMR (250 MHz, 0D013): 6 = 6.45 (t, J=3.3Hz, 1), 4.1
(q, J=7.28z, 2), 3.32 (br s, 1), 2.93 (dt, J=18.5,0.582, 1),
2.73 (dm, J=18.5Hz, l), 2.39 (dm, J=18.582, l), 1.25-1.8 (m,

84

l), 1.22 (t, J=7.ZHz, 3), 1.08 (s, 3), 0.78 (s, 3). EI/MS
(70eV): 250 (M’, 10.0), 235 (13.7), 221 (6.6), 204 (52.8),
189 (23.1), 176 (17.2), 161 (57.4), 147 (26.9), 133 (33.3),
123 (20.2), 107 (35.4), 96 (base). IR (0014): 2960, 2930,
2840, 1720, 1660, 1450, 1390, 1370, 1310, 1080, 1000, 895,

780cm'1.

Ethyl-5,5-dimethyl-4£,4a-£-epoxy-3,4,4a,5,6,7,8,8a-
oxtahzdronaphthalene-2-carboxylate 110d

According to the general procedure for epoxidation with

 

MCPBA, treatment of 0.2g (0.8 mmol) of 104d with 0.2g (0.95
mmol, 85%) of MCPBA at 0°C provided, after the usual workup
and chromatography on a column of silica gel (30g, 30 mm OD,
230-400 mesh, ether-pet. ether, 2:98), 0.11g (51%) of’llOd
as a colorless oil and 0.055g (26%) of 109d as a colorless

oil.

Ethyl-5,5,ggetrimethyl-4a,4a-a-epoxy-3.4,4g,5,§,7,8,83-
octahydronaphthalene-l-cgrboxylate 1093

According to the general procedure for epoxidation with
MCPBA, 0.14g (0.56 mmol) of 104c was treated with 0.17g
(0.84 mmol) of MCPBA at 0°C. After the usual workup,
purification by chromatography on a column of silica gel
(30g, 30 mm OD, 230-400 mesh, ether-pet. ether, 5:95) gave
0.12g (81%) of 109a.
lfl-NMR (250 MHz, 00013): 6 = 6.24 (dt, J=8.3,2.0Hz, l), 4.22

(q, J=7.0Hz, 2), 3.25 (br s, 1), 2.3-2.8 (m, 3), 1.46 (s,

85

3), 1.26 (t, J=7.0Hz, 3), 1.21 (s, 3), 0.81 (s, 3). EI/MS
(70eV): 264 (M’, 2.5), 249 (3.7), 235 (10.0), 219 (10.2),
203 (8.1), 191 (8,7), 175 (14.9), 163 (30.8), 147 (205), 133
(15.7), 123 (33.4), 107 (34.4), 91 (45.6), 81 (45.1), 69
(53.3), 55 (57.9), 41 (base). IR (neat): 2980, 2930, 2880,
1715, 1465, 1390, 1375, 1370, 1240, 1230, 1190, 1075, 1065,
1025, 975, 900cm'1.

fighyl-5,5,8§:tri;9thy1-45L4§;gbepoxy-3J4.4g,5.6,7.§4§g;
octahydrongphthglene-2-carboleate 109!

According to the general procedure for epoxidation with
MCPBA, treatment of 0.25g (1 mmol) of 1041' with 0136g (1.5-
mmol, 85%) of MCPBA provided, after chromatography on a
column of silica gel (35g, 30 mm OD, 230-400 mesh, ether-
pet. ether, 20:80) 0.24g (90%) of 109! as a colorless
viscous oil.
1H-NMR (250 MHz, CD013): 6 = 6.46 (d, J=3.3Hz, l), 4.16 (q,
J=7.ZHz, 2), 3.37 (m, 1), 3.31 (dd, J=18.7,3.3Rz, 1), 2.45
(dm, J=18.7, 1), 1.27 (t, J=7.ZHz, 3), 1.21 (s, 3), 1.14 (s,
3), 0.8 (s, 3), 1.1-1.8 (m, 6). EI/MS (70eV): 264 (M‘,
4.5), 249 (13.4), 235 (31.8), 218 (22.3), 203 (19.4), 189
(20.7), 175 (24.9), 266 (21.3), 161 (47.9), 147 (28.5), 133
(20.0), 123 (84.4), 107 (37.1), 91 (46.6), 79 (35.3), 69
(50.4), 55 (53.9), 41 (base). IR (neat): 2980, 2930, 2870,
2850, 1710, 1610, 1465, 1390, 1375, 1300, 1250, 1180, 1080,
1005, 975, 780, 740cm’1.

86

Atknunfl.anndmm:fimrlpmddelknnnmuulmmudthlflhdflao

Rearrangement of dimethyl-5,5-digethy1-4£,4a-Q-epoxy-
3,4,4a,5,6,7,8,8a-octahydronaphtha1ene-l,2-dicarboleate
jlgguwitthFa-fitgo

To a solution of 0.1g (0.42 mmol) of 110m in 20 mL of
dry methylene chloride, cooled to 0°C (ice water), was added
0.06g (0.42 mmol) BFa-tho in 5 mL 082012. The reaction
mixture was allowed to stir for 10 minutes at 0°C under
argon then was quenched with 5 mL of saturated aqueous
NaRCOa. The reaction mixture was cast into ether, saturated
aq. NaRCOa (50 mL each), and the organic layer was separated
and dried (Na2804). Concentration in vacuo and
chromatography of the residue on a column of silica gel
(30g, 30 mm OD, 60-230 mesh, ether-pet. ether, 1:1) provided
0.092g (92%) of oxetane 117a.
1H-NMR (250 MR2, 0D013): 6 = 4.76 (br t, J=ZHz, 1), 3.82 (s,
3), 3.76 (s, 3), 2.80 (br t, J=8.3Hz, l), 2.76 (dd, J=18.8,
2.382, 1), 2.26 (dd, J=18.8,4.282, 1), 2.12 (m, l), 1.90 (t,
J=8.3Rz, 2), 1.55 (m, 3), 1.44 (s, 3), 1.22 (s, 3). 13C-NMR
(68.9 MHz, 0D013): 6 = 169.4(s), 167.6(s), 142.2(s),
129.0(s), 83.7(s), 81.8(d), 53.1(s), 52.2(q), 52.1(q),
41.7(d), 33.7(t), 32.7(t), 30.3(t), 26.5(q), 24.5(q),
23.9(t). EI/MS (70eV): 295 (M’l, 0.6), 263 (5.9), 236
(1.4), 204 (m-60,55.4), 176 (base), 145 (32.4), 117 (42.9),

105 (50.8), 91 (31.7). IR (neat): 2945, 2860, 1720(br),

87

1645, 1430, 1375, 1360, 1260(br), 1190, 1105, 1070, 855,

830, 725cm'1.

Rearrangement of ethyl-5,5-dimethzl-4Q,4a-Lrepoxy-
3,4,4a,5,6,7,8,Ba-octahydronaphthgleng-l-carboxylate 110c
with §F3-§t20

To 0.5g (2 mmol) of epoxide 110c was added 0.31g (2.2
mmol) BF3'8t20 at 0°C according to the general procedure for
epoxide rearrangement. The usual workup and purification by
chromatography on a column of silica gel (60g, 40 mm OD,
230-400 mesh, ether-pet. ether, 3:7) provided 0.4lg (82%) of
oxetane 117c as a colorless oil.
1R-NMR (250 MHz, CD013): 6 = 7.03 (dm, J=7.ZHz, 1), 4.72 (br
s, 1), 4.24 (q, J=6.25Rz, 2), 3.02 (br t, J=9.0Rz, 1), 2.52
(ddd, J=19.5,7.2,1.7Hz, 1), 2.2 (br d, J=19.5Rz, 1), 2.08
(m, l), 1.43 (s, 3), l.5-2.0 (5), 1.12 (s, 3). 13C-NMR (68.9
M82, 0001:): a = 166.7, 135.5, 135.3, 33.9, 32.2, 60.4,
53.1, 38.2, 34.2, 38.4, 30.4, 26.7, 24.4, 23.9, 14.2. EI/MS
(70eV): 250 (M‘, 2.8), 233 (6.3), 217 (2.6), 205 (8.1), 192
(24.2), 76 (3.4), 163 (20.4), 147 (12.3), 133 (14.22), 119
(93.2), 105 (21.3), 91 (base). IR (neat): 2950, 2850, 1720,
1650, 1460, 1385, 1370, 1260, 1205, 1105, 1080, 950,

915cm'1}

88

Rearrangement of Methyl-2.5.5-trimethyl-4Q,4a-Q-epoxy-

3,4,5,6,7,8,8a-oxtahydrongphthglene-l-cgrboxylate 119g1with

 

BFg-Etgo

To 0.15g (0.6 mmol) of the p-epoxide 110g was added
0.128g (0.9 mmol) BFa-EtzO at 0°C according to the general
procedure for epoxide rearrangement. The usual workup and
purification by chromatography on a column of silica gel
(30g, 30 mm OD, 230-400 mesh, ether-pet. ether, 1:1)
provided 0.122g (81%) of oxetane 117g as-a colorless oil.
1R-NMR (250 MHz, CD013): 6 = 4.66 (t, J=2.582, l), 3.78 (s,
3), 2.80 (t, J=9.282, 1), 2.23 (m, 2), 2.14 (s, 3), 1.80 (t,
J=7.582, 2), 1.40 (s, 3), 1.17 (t, J=7.5Rz, 2), 1.14 (s, 3),
0.9-1.2 (m, 2). EI/MS (70eV): 250 (M‘, 2.9), 219 (7.5), 192
(39.4), 177 (50.4), 160 (15.2), 133 (89.9), 117 (23.1), 105
(98.4), 91 (40.9), 79 (26.5), 59 (36.6), 43 (base). IR
(neat): 2960, 2930, 2860, 1720, 1460, 1390, 1370, 1260,

1200, 1140, 1100, 1030, 975cm‘1.

Rearrangement of Ethyl-5,5-dimethyl-41,4a-g-epoxy-
3L4,4§,5,6,7,8,8g-octghygrongphthalene-Z-carboxylate 110d
with Bfg-Etzo

To 0.15g (0.6 mmol) of epoxide 110d was added 0.11g
(0.75 mmol) of BF3 EtzO at 0°C according to the general
procedure for epoxide rearrangement. The usual workup and

purification by chromatography on a column of silica gel

89

(30g, 30 mm OD, 230-400 mesh, ether-pet. ether, 1:1)
provided 0.13g (87%) of oxetane 117d.

1R-NMR (250 MHz, CD013): 6 = 7.40 (dd, 7.2,3.0Hz,l), 4.75
(m, 1), 4.18 (q, J=7.ZRz, 2), 2.82 (dd, J=18.75,1.0Rz, 1),
2.65 (dd, J=7.1,1.0Hz, 1), 2.14 (dt, J=18.75,4.0Rz, 1), 1.5-
2.1 (m, 6), 1.39 (s, 3), 1.30 (t, J=7.7Hz, 3), 1.125 (s, 3).
EI/MS (70eV): 250 (0.7), 217 (0.34), 205 (1.5), 192 (9.3),
163 (10.0), 119 (52.0), 91 (base). IR (neat): 3030, 2960,
2860, 1715, 1450, 1385, 1360, 1250cm'1.

Rearrangement of ggiggthyl-5,5-dimethyl-4a,4a-a-epoxy-
3,4,46,5,6,7,8,8a-octahydronaphtha1ene-1,2-dicarboxylate
1ggL

To 0.1g (0.34 mmol) of epoxide 10915 was added 0.059g
(0.42 mmol) BF3-Et20 according to the general procedure for
epoxide rearrangement. The usual workup and purification by
chromatography on a column of silica gel (30g, 30 mm OD,
230-400 mesh, ether-pet. ether, 1:1) gave 0.053g (53%) of
oxetane 117a, 0.030g (30%) of dimethyl-7p-hydroxy-7a,p-
isopropenyl-2,3,3a,6,7,7a-hexahydro-indene-4,5-dicarboxylate
123a and 0.008g (8%) of dimethyl-7u—hydroxy-7a-isopropeny1-
2,3,3a,6,7,7a-hexahydroidene-4,5-dicarboxy1ate :uum.
Q: 1H—NMR (250 MHz, CD013): 6 = 5.05 (m, 1), 4.84 (s, l),
3.77 (s, 3), 3.74 (s, 3), 3.85 (m, 1), 3.06 (t, J=8.282, l),
2.72 (dd, J=4.0,16.5Hz, l), 2.29 (ddd, J=2.0,8.2,16.5Hz, 1),
1.84 (br s, 3), 1.4-2.0 (m, 7). RI/MS (70eV): 276 (M‘, 820,.

90

2.1), 262 (13.9), 244 (11.3), 234 (43.3), 223 (23.5), 205
(14.9), 159 (13.2), 149 (base). IR (neat): 3600, 3030,
2960, 2930, 2360, 1725, 1600, 1440, 1340, 1250, 1170, 1150,
1100, 1050, 980cm'1.

__124g: 111-mm (250 MHz, cnc13): 6 = 5.02 (br s, 1), 4.94 (br
s, 1), 4.30 (m, 1), 3.30 (s, 3), 3.75 (s, 3), 3.0 (m, 1),
2.63 (ddd, J=18.5,4.0,1.5Hz, 1), 2.45 (ddd,
J=18.5,6.0,1.5Rz, 1), 1.30 (s, 3), 1.4-1.3 (m, 7). 31/33
(70eV): 294 (1.7), 276 (5.2), 261 (3.7), 245 (21.4), 237
(10.7), 221 (13.7), 213 (24.9), 201 (9.0), 139 (14.1), 161
(37.3), 145 (13.3), 123 (30.2), 105 (30.3), 91 (43.9), 43
(base). 13 (neat): 3600, 2960, 2330, .1735, 1650, 1600,

1460, 1330, 1250, 1200, 1150, 1100, 1035, 980cm‘1.

Rearrangement of ¥§thyl-4L4§-dimethyl-4¢,4a-s-epoxz-
3,4,4a,5,6,7,8,8a-octahydron4aphthfigene 109c with IBngjtzO

To 0.1g (0.40 mmol) of the repoxide 109c was added
0.07g (0.5 mmol) of BFa-EtzO according to the general
procedure for epoxide rearrangements. The usual workup and
purification by HPLC (Perkin Elmer Series 211 equipped with
a Waters Radial Compression Unit, lOu silica gel cartridge,
and a Perkin Elmer 7500 Variable Wavelength UV detector, nm,
eluted with ether-hexane, 1:4, 4 mL/min) gave 0.060g (60%)
of oxetane 117c and 0.030g (30%) of the p-alcohol LZ&L
1125: 1R-NMR (250 MHz, CD013): 6 = 6.79 (t, J=4.13Hz, 1),
5.03 (t, J=1.282, 1), 4.83 (br s, 1), 4.21 (m, 2), 3.82 (dd,
J=4.9,8.0Hz, 1), 3.09 (t, J=18.3Hz, 1), 2.50 (dt,

91

J=19.4,4.QHz, l), 1.05-1.35 (m, 3), 1.83 (br s, 3), 1.30 (t,
J=7.282, 3), 1.4-1.7 (m, 5). EI/MS (70eV): 250 (M‘, 1.5),
232 (10.0), 204 (30.6), 192 (32.7), 176 (19.7), 159 (35.8),
147 (29.4), 133 (60.4), 119 (67.5), 105 (43.5), 91 (79.6),
85 (base). IR (neat): 3450, 2950, 2860, 1710, 1650, 1450,
1375, 1240, 1200, 1100, 1060, 960, 900, 740cm'1.

Q: 1H-NMR (250 MHz, 00013): 6 = 6.78 (t, J=4.3Hz, 1),

5.03 (t, J=1.282, 1), 4.82 (br s, 1), 4.21 (m, 2), 3.82 (dd,
J=4.9,7.QRz, 1), 3.09 (t, J=8.3Hz, 1), 2.50 (dt,
J=19.2,4.9Rz, 1), 1.82 (br s, 3), 1.4-1.75 (m, 5), 1.05-1.35
(m, 3), 1.29 (t, J=7.0ZHz, 3). EI/MS (70eV): 250 (M‘,
13.5), 232 (10.0), 204 (30.6), 192 (32.7), 176 (19.7), 159
(35.2), 147 (29.4), 133 (60.4), 119 (67.5), 105 (43.5), 91
(76.6), 85 (base). IR (neat): 3450, 2950, 2850, 1710, 1650,

1450, 1375, 1240, 1200, 1100, 1060, 960, 900, 7400m‘1.

Dimethyl-2.3.3g.6-tetrahdro-indene-4,5-dicarboleate 119

According to the general procedure for Diels-Alder
reactions, 0.5g (5.3 mmol) of l-vinylcyclopentene 118 was
mixed with 1.5g (10.5 mmol) of dimethylacetylene
dicarboxylate and heated at 110°C for 24 hours. After
cooling to room temperature and purification by
chromatography on a column of silica gel (40g, 40 mm OD, 60-
230 mesh, ether-pet. ether, 1:4) gave 0.79g (63%) of 119 as
a colorless oil.
1R-NMR (250 MHz, 0D013): 6 = 5.46 (br t, J=2.ZHz, 1), 3.79
(s, 3), 3.75 (s, 3), 3.0 (m, 3), 2.32 (m, 2), 2.01 (m, 2),

92

1.4-1.7 (2). EI/MS (70eV): 236 (M*, 0.2), 204 (45.1), 176
(base), 145 (43.8), 117 (70.4), 105 (72.9), 91 (35.9). IR
(neat): 3040, 2960, 2870, 1725, 1650, 1590, 1445, 1265,

1040cm'1.

Rearrangement of Methyl-2.5.5-trimethyl-4a,4a-¢-epoxy-

3,4,4a,5,6,7,8,8a-octahydronaphthalene-l-carboxylate 199;
To 0.05g (0.2 mmol) of epoxide 109g *was added 0.057g

 

(0.40 mmol) of BF3 BtzO according to the general procedure
for epoxide rearrangements. The usual workup and
purification by chromatography on RPLC (15:85, ether:hexane,
4 mL/min) provided 0.028g (56%) oxetane 117g, 0.011g (22%)-
p-alcohol 123g and 0.005g (10%) of ralcohol 124g.

fig: 1H--NMR (250 MHz, CD013): 6 = 5.01 (br s, l), 4.83 (br
s, l), 4.27 (br s, 1), 3.97 (m, l), 3.74 (s, 3), 3.10 (t,
J=BHz, 1), 2.17 (s, 3), 1.81 (s, 3), 1.1-2.2 (m, 8). RI/MS
(70eV): 250 (M’, 16.0), 232 (12.1), 227 (6.2), 218 (16.5),
207 (25.4), 191 (23.6), 185 (27.3), 173 (27.6), 147 (32.0),
133 (37.7), 119 (31.6), 109 (50.2), 105 (43.8), 79 (42.6),
77 (35.5), 55 (46.8), 41 (base). IR (neat): 3500, 3030,
2980, 2960, 2860, 1720, 1650, 1450, 1320, 1260, 1150cm‘1.
a-alcohol gggg: 1H-NMR (250 MHz, CD013): 6 = 4.96 (br s, l),
4.94 (br s, 1), 3.80 (s, 3), 3.10 (m, 1), 2.4-2.8 (m, 2),
2.20 (s, 3), 1.32 (s, 3), 1.0—2.0 (m, 3). BI/MS (70eV): 250
(2.9), 232 (1.6), 219 (7.5), 192 (39.4), 177 (50.5), 160

(15.2), 133 (89.9), 117 (23.11), 105 (98.4), 91 (40.9), 79

93

(26.5), 59 (36.6), 43 (base). IR (neat): 3500, 3030, 2980,
2960, 2860, 1720, 1650, 1450, 1250, 1150, 1070, 980cm'1.

Rearrangement of Ethyl-5,5-dimethyl-4a,4a-abepoxy-
3,4,4a,5,6,7,8,Ba-octahydronaphthalene-Z-carboxylate lggg
with BF; Eth

To 0.06g (0.24 mmol) of 109d was added 0.043g (0.3
mmol) BFa-Btzo according to the general procedure of epoxide
rearrangement. The usual workup and 'purification by
chromatography on HPLC (15:85, ether:hexane, 4 mL/min)
provided 0.0131g (52%) of oxetane 117d, 0.017g (27%) of "'_
alcohol 123d and 0.005g (8%) of m-alcohol 124d.
Q-alcohol fl: 1H-NMR (250 MHz, 0D013): 6 = 6.92 (m, l),
5.09 (br s, 1), 4.80 (br s, 1), 4.21 (q, J=7.2Rz, 2), 3.93
(t, J=4.5Rz, 1), 2.95 (m, 1), 2.4-2.8 (3), 1.83 (s, 3), 1.25
(t, J=7.le, 3), 1.05-2.0 (6). BI/MS (70eV): 250 (M’, 9.6),
237 (5.1), 219 (8.9), 205 (14.1), 192 (81.7), 177 (50.6),
163 (47.0), 147 (22.3), 133 (76.3), 119 (base). IR (neat):
3500, 3030, 2960, 2930, 2860, 1725, 1650, 1450, 1360, 1280,
1150, 1100, 920, 840cm‘1.
ralcohol fl: 1I-I-NMR (250 MHz, 0D013): 6 = 7.22 (m, l),
5.01 (br s, 1), 4.93 (br s, 1), 4.2 (m, 2), 3.90 (dd,
J=6.2,9.0Rz, l), 3.09 (m, 1), 1.82 (s, 3), 1.29 (t, J=7.0Hz,
3), 1.1-1.75 (m, 7). EI/MS (70eV): 250 (M‘, 5.9), 237
(3.6), 205 (20.4), 192 (45.7), 163 (42.4), 147 (21.2), 135

94

(15.5), 119 (base). IR (neat): 3500, 3030, 2960, 2860,

1730, 1650, 1430, 1360, 1280, 1100, 920, 840cm‘1.

Treatment of Oxetgne :lyflLwith p-Tolgenggglfonic agidgggg
5519

To a solution of 0.05g (0.2 mmol) of oxetane 117a, in
20 mL benzene, was added 0.5 mL acetic anhydride and 0.1g
(0.52 mmol) p-toluene sulfonic acid monohydrate. The
mixture was heated under reflux for 4 hours, cooled to room
temperature and cast into ether saturated aq. NaHCOa (100 mL
each). The organic phase was separated and washed with
water, brine (30 mL each) and dried (Na2804). Concentration
in vacuo and chromatography, a column of silica gel (20g, 20
mm OD, 230-400 mesh, ether-pet. ether, 3:7) gave 0.051g
(87%) of 127 as a colorless oil.
121: 1H-NMR (250 MHz, CD013): 6 = 4.97 (dd, J=10,5Hz, l),
4.86 (br s, 1), 4.70 (br s, 1), 3.71 (s, 3), 3.63 (s, 3),
2.95 (br t, J=8.3Hz, 1), 2.65 (br dd, J=17.5,5Hz, 1), 2.21
(ddd, J=17.5,10,1.67Rz, 1), 1.99 (s, 3), 1.77 (br s, 3),
1.5-2.1 (6). EI/MS (70eV): 302 (M*-ROAc, 1.5), 276 (2.2),
262 (5.1), 244 (6.2), 216 (6.1), 203 (9.4), 187 (5.0), 176
(7.8), 157 (7.12), 145 (7.4), 131 (6.7), 105 (11), 91
(13.2), 43 (base). IR (0014): 2950, 2880, 1740, 1730, 1650,
1430, 1290, 1270, 1100, 1040, 900cm'1.

95

(15g, 20 mm OD, 230-400 mesh, ether-pet. ether, 1:4)
provided 0.023g (76%) of triene 127.

1R-NMR (250 MHz, 0D013): 6 = 6.15 (d, J=8.4Hz, 1), 5.70 (d,
J=8.4Rz, 1), 4.77 (br s, l), 4.70 (br s, l), 3.82 (s, 3),
3.80 (s, 3), 2.90 (t, J=8.282, 1), 1.88 (br s, 3), 1.2-2.0
(m, 6). RI/MS (70eV): 276 (M’, 1.4), 245 (0.88), 234
(1.18), 204 (62.4), 176 (base), 161 (3.4), 145 (26.0), 131
(3.9), 117 (20.5). IR (neat): 3030, 2960, 2930, 2860, 1720,

1640, 1595, 1580, 1400, 1260, 1080, 1030, 960cm‘1.

Dimethyl-7a-Q-l2-hydroxy-igopropyll—g.3,3a,7a-tetrahydro
indene-4.5-dicgrboleate 121

To 4.3 mmol of NaOMe, prepared from 0.1g (4.3 mmol) of
sodium metal, in methanol (10 mL) was added 0.020g (0.065
mmol) of oxetane 117a in methanol (5 ml.) over five minutes.
The resulting solution was stirred at room temperature for 4
hours, then cooled to 0°C; 5 mL of water was added slowly,
followed by 10 mL of 1N aq. 801. The methanol was removed
off in vacuo and the aqueous layer was extracted with 50 ml.
of ether. The organic layer was separated and washed with
saturated aq. NaRCOa, brine (50 mL each), and dried'
(Na2804). Concentration in 'vacuo gave a colorless oil which
was purified, by chromatography on a column of silica gel
(15g, 20 mm OD, 230-400 mesh, ether-pet. ether, 30:70) to

provide 0.015g (75%) of 121.

 

96

Dimethyl-7Q-acetoxnyng‘i§223222§11;§.3.39.6.7,73;
hexahydroindene-4.5-dicgrboxylgtefi;g§_

To a solution of 0.02g (0.65 mmol) of the p-alcohol
123a in 20 ml. benzene was added acetic anhydride (1 mL),
pyridine (1 mL) and a few crystals of 4-N,N-dimethyl-
aminopyridine (DMAP). The mixture was stirred at room
temperature for 8 hours then was quenched with IR aq. R01
(10 mL). The mixture was cast into ether -1N aq. 801 (50
mL each). The organic layer was separated, washed with
water (20 mL), saturated aq. NaRCOa (50 mL), brine (50 mL)
and dried (Na2804). Concentration in vacuo and purification -
by chromatography on a column of silica gel (15g, 20 mm OD,
230-400 mesh, ether-pet. ether, 1:1) provided 0.019g (84%)

of p-acetate 125.

Dimethyl-7a-3-isopropenyl-2,3,3a,7a-tetrahydro indene-4,5-

dicarboxylate 127
To a solution of 0.037g (0.11 mmol) of a mixture of the

¢~ and p-acetates 125 and 126 in benzene (20 mL) was added
0.020g (0.178 mmol) of KOBut. The resulting mixture was
stirred at room temperature for over night; then cast into
ether -1N aq. R01 (50 mL each). The organic layer was
separated, washed with saturated aq. NaHCOa, brine (30 mL
each), and dried (NazSO4). Concentration in vacuo and

purification by chromatography on a column of silica gel

97

1R-NMR (250 MHz, CD013): 6 = 6.19 (d, J=10.07Hz, 1), 5.71
(d, J=10.07Rz, 1), 3.80 (s, 3), 3.78 (s, 3), 3.00 (br t,
J=8.7Hz, l), 2.27 (m, 2), 1.51 (m, 5), 1.21 (s, 3), 1.15 (s,
3). EI/MS (70eV): 263 (0.7), 236 (3.6), 204 (11.3), 176
(base). IR (neat): 3520(br), 2950, 2870, 1715(br), 1640,

1595, 2580, 1430, 1260(br), 1080, 1030, 950cm'1.

 

Dimethyl-2,3-dihdry-indene-4,5-dicarboleate 120
To a solution of 0.01g (0.037 mmol) of 121 in 15 mL

082012 mixed with 0.3g of celite was added 0.2g (0.9 mmol)
of P00.33b The resulting suspension was stirred at room
temperature for 3 hours, then the solids were removed by
filtration through a pad of celite which was rinsed with
082012 (20 mL). The solvent was removed .in vacuo to provide

a yellow residue which was purified by chromatography on a
column of silica gel (10g, 10 mm OD, 230-400 mesh, ether-
pet. ether, 30:70) to provide 0.0062g (78%) of 120. 1H-NMR
(250 MR2, 06D6): 6 = 7.64 (d, J=8.3Hz, 1), 6.69 (d, J=8.3Rz,
l), 3.68 (s, 3), 3.46 (s, 3), 2.82 (t, J=7.3Hz, 2), 2.43 (br
t, J=7.3Hz, 2), 1.60 (m, 2). EI/MS (70eV): 234 (M’, 3.1),
203 (43.8), 202 (base), 201 (20.9), 175 (2.8), 187 (11.1),
144 (9.8), 115 (25.1). IR (neat): 3010, 2960, 2900, 2850,

1730, 1600, 1440, 1250, 1120, 1040, 890, 830, 790, 680cm‘1.

98

Dimethyl-2,3-dihydro-ingggg-4.5-dicgrboxy1§£§_lgg_

To a solution of 0.015g (0.064 mmol) of 119 in benzene
(20 mL) was added 0.1g (0.36 mmol) of DDQ. The resulting
mixture was stirred for 10 hours at room temperature, then
filtered through a pad of celite, and the solvent removed in
vacuo to give a yellow oil. The crude product was purified
by chromatography on a column of silica gel (15g, 20 mm OD,
230-400 mesh, ether-pet. ether, 30:70) to provide 0.012g

(81%) of 120.

Rearrangement of digethyl-SLS.8g-triggthy1-4ab4a-s—epoxyf
3,4,49,5,6,7,8,8géoctahydronaphthalene-l,2-dicarboxylate 1
To 0.5g (1.62 mmol) of 1 in 082012 (30 mL) was added
0.35g (2.48 mmol) of BFa-Etzo according to the general
procedure for epoxide rearrangements. The usual workup and
purification by chromatography on a column of silica gel
(60g, 40 mm OD, 60-230 mesh, ether-pet. ether, 20:80) gave.
0.43g (86%) of 2 as a colorless viscous oil. 1H-NMR (250
MHz, 0D013): 6 = 5.76 (m, 1), 3.92 (m, l), 3.80 (s, 3), 3.75
(s, 3), 2.63 (d, J=4.0Rz, 2), 1.2-2.3 (m, 5), 1.70 (br s,
3), 1.02 (s, 3), 0.95 (s, 3). EI/MS (70eV): 308 (M*, 8.2),
276 (base), ~258 (20.4), 244 (71.3), 230 (13.9), 215 (28.2),
199 (34.8), 189 (20.6), 171 (42.2), 156 (26.3), 91 (70.7).
IR (0014): 3570, 2970, 2950, 2880, 1740, 1720, 1620, 1430,
1395, 1390, 1290, 1250, 1200, 1100, 1080, 1060, 1030,

875cm‘1.

99

Rearrangement of Ethyl-5.5183-trimethyl-4a,4a-a—epoxx-

 

3,4,4a,5,6,7,8,8a-octah1dronaphtha1ene—l-carboxylate 1093
To 0.1g (0.379 mmol) of 109a was added 0.081g 0.568

mmol) of BF3 EtzO, according to the general procedure for
epoxide rearrangements. The usual workup and purification
by chromatography on a column of silica gel (25g, 20 mm OD,
230-400 mesh, ether-pet. ether, 1:1) gave 0.081g (81%) of
alcohol Huh:as a viscous colorless oil. 1H-NMR (250 MHz,
00013): 6 = 6.73 (t, J=4.0Hz, l), 5.79 (m, 1), 4.16 (m, 2),
3.84 (m, l), 2.45 (m, 3), 1.70 (br s, 3), 1.57 (s, 3), 1.29
(t, J=7.0Hz, 3), 1.15 (br s, 3), 0.9-1.3 (m, 4). EI/MS
(70eV): 264 (M’, 13.9), 246 (4.7), 231 (14.6), 218 (26.7),
205 (13.0), 190 (13.6), 185 (63.2), 173 (13.9), 157 (20.0),
135 (7.9), 121 (20.9), 105 (33.0), 91 (47.5), 55 (75.1), 43
(base). IR (neat): 3500, 3030, 2960, 1730, 1430, 1260,

1090, 1060cm'1.

Rearrangement of Ethyl-5,5,8a-trimethyl-4a,4a-ahepoxy-

314a4gi5461748.8§eoctahydronaphthalene-2-carboxylate 109!
To 0.06g (0.227 mmol) of 109! at 0°C was added 0.048g

 

(0.34 mmol) of 8F3 OEtz according to the general procedure
for epoxide rearrangements. The usual workup and
purification by chromatography on a column of silica gel
(15g, 20 mm 00, 230-400 mesh, ether-pet. ether, 1:1)

provided 0.05g (83%) of 1221’.

100

IR-NMR (250 MHz, 00013): a = 6.57 (br s, 1), 5.66 (br s, 1),
4.12 (q, J=7.2Rz, 2), 3.89 (t, J=4.3Hz, 1), 2.2-2.5 (m, 2),
1.65 (br s, 3), 1.23 (t, J=7.ZRz, 3), 1.13 (s, 3), 1.04 (s,
3), 1 1-2.0 (m, 5). EI/MS (70eV): 264 (M’, 17.4), 246
(11.5), 231 (22.7), 213 (23.4), 205 (34.7), 190 (13.6), 135
(base), 173 (42.9), 157 (19.3). 121 (27.6), 91 (53.2). IR
(neat): 3600, 3030, 2930, 2960, 2350, 1730, 1650, 1430,
1360, 1250, 1200, 1175, 1100, 1050, 980cm’1.

ngynigethyl-3-hydroxy-3-vinyl-cyclohexanone 130

To a solution of 2.0g (28.6 mmol) 2,23dimethyl-l,3-
cyclohexane dione in dry THF (50 mL), cooled to ~78°0 (dry
ice-iPrOR), was added 34.32 mL of vinyl magnesium bromide in
THF (34.32 mmol) over 1 hour. After the addition was
complete, the mixture was stirred for an additional 5
minutes at -78°C then carefully quenched with 30 mL of
saturated aq. N8401. The mixture was diluted with 60 mL of
ether, the organic layer was separated, washed with
saturated aq. NaRCOa, water, brine (50 mL each), and dried
(MgSO4). Concentration in vacuo gave a colorless liquid
that was purified by chromatography on a column of silica
gel (120g, 50 mm 00, 60-230 mesh, ether:pet. ether, 1:1) to
provide 1.0g (42%) of’130. ‘
1R-NMR (250 MHz, 00013): 6 = 5.98 (dd, 11.0,17.0Rz, 1), 5.26
(dd, J=1l.O,l.2Rz, l), 5.14 (dd, J=17.0,1.282, 1), 1.65-2.75

(m, 7), 1.09 (s, 3), 1.02 (s, 3). EI/MS (70eV): 168 (M’,

101

17.0), 151 (4.7), 150 (1.8), 140 (1.79), 135 (1.73), 125
(10.3), 107 (4.7), 98 (99.7), 86 (26.8), 83 (82.9), 20
(28.4), 67 (25.4), 55 (base). IR (neat): 3600, 3020, 2985,
2840, 1705, 1460, 1380, 1365, 1315, 1200, 1130, 985, 960,

920, 850, 830, 730cm‘1.

6,6-0imethyl-l-viny1-5-ogo-cyclohgxél-eng_§flL

To a solution of 0.5g (2.97 mmol) of 130 in 60 mL
benzene was added 0.74g (2.97 mmol) 0u804-5820. The
solution heated under reflux with azeotropic removal of
water for 3 hours. The mixture was cooled to room
temperature and filtered through a short column of silica
gel. The filtrate was washed with water (30 mL) and dried
(Mg804). The solvent was removed by distillation to provide
0.3g (68%) of diene 131 as colorless oil.
1H—NMR (250 MHz, 00013): 6 = 6.27 (ddd, J=l.2,10.7,17.1Hz,
1), 5.95 (t, J=4.1Rz, 1), 5.40 (dd, J=1.83,17.le, l), 5.06
(dd, J=1.83,10.7Hz, 1), 2.54 (m, 2), 2.47 (t, J=4.BRz, 2),
1.24 (s, 6). EI/MS (70eV): 150 (M’, 21.8), 135 (3.7), 121
(16.1), 108 (30.1), 93 (base), 85 (7.4), 79 (45.6), 39
(77.0). IR (neat): 3020, 2965, 2925, 2875, 1710, 1468,

1445, 1380, 1360cm'1.

Dimethyl-5,5-dimethyl-6-oxg-3,5,6,7,8,8grhexahydronaph-

thalene-l,2-dicarboxylate 132
To 0.4g (2.6 mmol) of 130 was added 1.0g (7.0 mmol) of

dimethyl acetylenedicarboxylate. The mixture was stirred at

102

room temperature for 2 hours, or could be heated at 110°C
for 15 minutes. The reaction mixture was purified by
chromatography on a column of silica gel (50g, 40 mm 00, 60-
230 mesh, ether-pet. ether, 1:1) to provide 0.4g (52%) of
132 as a white solid, m.p. 76-77°0. 1H-NMR (250 MHz,
00013): 6 = 5.55 (dd, J=3.36,3.6682, 1), 3.79 (s, 3), 3.74
(s, 3), 3.59 (m, 1), 3.07 (dm, J=17.0Rz, 2), 2.74 (m, l),
2.43 (dm, J=17.0Rz, 1), 2.21 (m, 1), 1.51 (m, l), 1.31 (s,
3), 1.26 (s, 3). EI/MS (70eV): 292 (M’, 24.9), 260 (44.4),
245 (4.6), 232 (base), 217 (24.2), 205 (89.6), 189 (55.0),
177 (69.6), 163 (20.5), 145 (25.0). IR (neat): 2980, 2945,
2875, 1720, 1680, 1650, 1540, 1435, 1385, 1360, 1260, 1235,

1225, 1105, 1080, 965cm'l.

_;!ethy1-5,5-digethyl-4¢,4a-c—epoxy-S-oxo-3,4,4a,5,6,7,8,8a-
octahydrongphthglene:1,2-dicarboxxlgte:;§§

To a solution of 0.1g (0.34 mmol) of 132 in 9 mL of
mixture of t-BuOR:water (2:1), cooled to 0°C (ice water),
was added 0.12g (0.68 mmol) of N08 in one portion. The
mixture was stirred for 3 hours at 0°C, then diluted with
water (20 mL) and cast into ether (100 mL) and water '(30
mL). The organic phase was separated and washed with
saturated aq. Na8003, water (10 mL each), and dried (MgSO4).
Concentration and purification of the residual oil by
chromatography on a column of silica gel (25g, 20 mm 00,
230-400 mesh, ether-pet. ether, 7:3) provided 0.014g (13%)
of 133 and 0.082g (78%) of 134.

103

133: 1H-NMR (250 MHz, 00013): 6 = 3.78 (s, 3), 3.76 (s, 3),
3.62 (br s, l), 3.46 (dm, J=9.282, 1), 3.10 (br d, J=9.282,
1), 2.85 (t, J=5.0Hz, 2), 2.81, 1.69 (s, 3), 1.34 (s, 3).
BI/MS (70eV): 308 (M‘, 1.7), 276 (16.3), 267 (2.0), 248
(3.0), 235 (base), 217 (8.1), 203 (17.6), 189 (10.9), 177
(45.3), 163 (12.4), 145 (15.3), 159 (6.3), 41 (83). IR
(0014): 2980, 2960, 2880, 1720, 1660, 1435, 1380, 1360,
1270, 1250, 1160cm‘1.

135: 1H-NMR (250 MHz, 00013): 6.: 4.31 (m, 1), 4.83 (s, 3),
3.76 (s, 3), 3.36 (dt, J=19.2,3.97Rz,. l), 2.88 (ddd,
J=19.2,1.83,1.53Rz, 1), 2.69 (m, l), 2.55 (dm, J=l3.6282,
1), 2.15 (br s, 1), 1.93 (m, 2), 1.58 (s, 3), 1.20 (s, 3).
EI/MS (70eV): 277 (M+-0083, 31.9), 259 (17.9), 245 (4.4),
235 (12.3), 217 (18.1), 204 (9.9), 189 (8.0), 177 (9.0), 91
(20.3), 59 (43.0), 43 (base). IR (neat): 2980, 2945, 2875,

1720, 1650, 1550, 1445, 1260, 1105, 1080, 1050, 910cm‘1.

imethyl-5,5-di!§thyl-4Q,4a—Qrepoxyé6-gxo-3,4,4a,5,6,7,8,8a-

octahydrongghthalene-l 2-dicarboxylgte 133

 

To a solution of 0.04g (0.136 mmol) of 132 in 082012,
cooled to 0°C, was added 0.1g (0.5 mmol) of MCPBA in 082012
(5 mL). The mixture was stirred at 0°C for 1.5 hours, then
quenched with saturated aq. NaRCOa (10 mL) and diluted with
30 mL ether. The organic phase was separated, washed with
10% aq. Na28203, saturated aq.’ NaRCOa, water (20 mL each),
and dried (Mg804). Concentration .in vacuo provided 0.03g

(71%) of 133 as a colorless oil.

104

Dimethyl-5,5-dimethyl-4s,4a-¢—epoxy-6g-hydroxy-

 

3,4,4a,5,6,7,8,8a-octahydronaphthalene-1.2:dicarboxylate 135

 

To a solution of 0.075g (0.24 mmol) of 134 in methanol
(10 mL), cooled to 0°C, was added 0.02g (0.5 mmol) of sodium
borohydride in portions over 15 minutes. The mixture was
stirred for 1 hour, then quenched by the careful addition of
10 mL of water. The mixture was extracted with 082012 (60
mL), the organic layer was separated and dried (Mg804).
Concentration in vacuo and purification of the resulting oil
by chromatography on a column of silica gel (20g, 20 mm 00,
230-400 mesh, ether) gave 0.067g (89%) of 135 as a colorless
oil.
1H-NMR (250 MHz, 00013): 6 = 3.78 (s, 3), 3.72 (s, 3), 3.61
(m, 1), 3.37 (br s, l), 3.06 (dm, J=19.5Hz, l), 3.05 (br s,
l), 2.55 (dm, J=19.582, l), 1.91 (m, l), 1.3-1.7 (m, 4),
1.05 (s, 3), 0.91 (s, 3). EI/MS (70eV):' 310 (M’, 4.9), 292
(0.61), 279 (15.3), 278 (20.0), 260 (12.3), 246 (9.2), 235
(14.9), 217 (14.4), 203 (19.7), 189 (16.5), 179 (22.2), 163
(16.4), 145 (19.6), 119 (21.4), 105 (5.9), 91 (49.5), 77
(40.5), 59 (79.2), 43 (base). IR (0014): 3500, 2940, 1720,
1650, 1430, 1380, 1360, 1260, 1240, 1190, 1060, 940, 890,
870, 825, 805, 760cm'1.

105

Dimethyl-5,54diggthyl-4Q,4a-g-epoxy-6Q-hydroxy-
3,4,43,5,6,7,8,8a-octahydronaphthalene-l,Z-dicarboxylate 137
To 0.02g (0.065 mmol) of 133 in methanol (10 mL) was
added 0.05g (0.13 mmol) of Na884 according to procedure
employed in the preparation of 135 to provide 0.015g (75%)
of 137.
1H-NMR (250 M82, 00013): 6 = 3.80 (s, 3), 3.73 (s,
3), 3.55 (m, 1), 3.30 (br s, 1), 3.16 (dm, J=9.582, 1), 3.13
(dm, J=l7.082, 1), 2.57 (dm, J=l7.082, l), 2.52 (dm,
J=9.582, l), 1.94 (m, 2), 1.58 (m, 2), 1.16 (s, 3), 0.98 (s,
3). BI/MS (70eV): 279 (Mt-0083, 15.6), 278 (13.3), 260
(8.3), 146 (6.4), 232 (13.7), 221 (15.5), 205 (35.5), 191
(30.2), 179 (14.3), 161 (12.9), 145 (17.4), 133 (12.6), 119
(18.3), 105 (25.9), 91 (33.1), 84 (base), 77 (25.6), 67
(19.5), 59 (55.7), 43 (71.3). IR (neat): 3500, 2960, 1720,

1650, 1430, 1380, 1360, 1260, 1190, 1060, 810, 740cm‘1.

Rearrangement of Afiwith 333-3th
To 0.008g (0.026 mmol) of 135 was added 1 drop of

BF3 Et20, according to the general procedure for epoxide
rearrangements. The usual workup and purification by
chromatography on a column of silica gel (30g, 30 mm 00,
230-400 mesh, ether:pet. ether, 7:3) provided 0.0074g (93%)
of 136.

1R-NMR (250 M82, 00013): 6 = 7.90 (d, J=8.582, 1), 7.46 (d,

J=8.582, 1), 3.96 (s, 3), 3.88 (s, 3), 3.76 (m, 1), 2.86 (m,

106

2), 2.0 (m, 2), 1.43 (s, 3), 1.39 (s, 3). lax/us (70eV): 292
(M*, 4.0), 277 (4.5), 260 (base), 245 (3.9), 227 (17.7), 217
(11.3), 200 (23.3), 135 (9.2), 157 (6.1), 145 (13.3), 129
(15.7), 115 (17.4). IR (neat): 3500, 2930, 1740, 1720,

1715, 1600, 1435, 1380, 1360, 1300, 1150, 970cm‘1.

Diggthyl-S.5-digethyl-6-oxo-5.6.7,8-tetrahydronaphtha1ene-
14§:dicgrboxy1§te:§gl

To a solution of 0.01g (0.034 mmol) of 132 in dry
benzene (20 mL) was added 0.04g (0.176 mmol) of 000. The
resulting mixture was heated under reflux for 5 hours then
cooled to room temperature and filtered through a plug of
silica gel, which was rinsed with benzene. Concentration in
vacuo provided 0.0095g (95%) of8138.
1H-NMR (250 M82, 00013): 6 = 7.91 (d, J=9.182, l), 7.47 (d,
J=8.5, l), 3.96 (s, 3), 3.90 (s, 3), 3.07 (dd, J=6.4,7.3Rz,
2), 2.68 (dd, J=7.3,6.482, 2), 1.45 (s, 3). EI/MS (70eV):
290 (M‘, 1.6), 258 (base), 243 (4.4), 236 (60.2), 215
(73.5), 199 (30.7), 187 (5.0), 172 (11.4), 158 (7.8), 144
(13.8), 128 (30.0), 115 (27.4). IR (neat): 2980, 2960,
1740, 1720, 1715, 1600, 1435, 1380, 1360, 1300, 1270, 1150,
970cm'1.

Dimethyl-5,5-diggthy1-6-géhydggxy-5,6,7,8-tetrahydronaph-
thalene-l,2-dicagboxylgte 136
To a solution of 0.005g (0.017 mmol) of 138 in dry

methanol (2 mL), cooled to 0°C (ice water), was added 0.005g

106

2), 2.0 (m, 2), 1.43 (s, 3), 1.39 (s, 3). lax/us (70eV): 292
(3+, 4.0), 277 (4.5), 260 (base), 245 (3.9), 227 (17.7), 217
(11.3), 200 (23.3), 135 (9.2), 157 (6.1), 145 (13.3), 129
(15.7), 115 (17.4). IR (neat): 3500, 2930, 1740, 1720,
1715, 1600, 1435, 1330, 1360, 1300, 1150, 970cm‘1.

Diggthy1-5,5-diggthYI-6-oxo-5.6.7.8-tetrahydronaphtha1ene-
ngjdicgrboxylgtegggL

To a solution of 0.01g (0.034 mmol) of 132 in dry
benzene (20 mL) was added 0.04g (0.176 mmol) of 000. The
resulting mixture was heated under reflux for 5 hours then
cooled to room temperature and filtered through a plug of
silica gel, which was rinsed with benzene. Concentration in
vacuo provided 0.0095g (95%) of'138.
1H-NMR (250 M82, 00013): 6 = 7.91 (d, J=9.182, 1), 7.47 (d,
J=8.5, 1), 3.96 (s, 3), 3.90 (s, 3), 3.07 (dd, J=6.4,7.382,
2), 2.68 (dd, J=7.3,6.482, 2), 1.45 (s, 3). EI/MS (70eV):
290 (M‘, 1.6), 258 (base), 243 (4.4), 236 (60.2), 215
(73.5), 199 (30.7), 187 (5.0), 172 (11.4), 158 (7.8), 144
(13.8), 128 (30.0), 115 (27.4). IR (neat): 2980, 2960,
1740, 1720, 1715, 1600, 1435, 1380, 1360, 1300, 1270, 1150,

970cm'1.

Dimethyl-5,5-dimethyl-6jlrhydr9xy-5,6,7,8-tetrahydronaph-
thalene-1,2-dicarboxylate 136
To a solution of 0.005g (0.017 mmol) of 138 in dry

methanol (2 mL), cooled to 0°C (ice water), was added 0.005g

106

2), 2.0 (m, 2), 1.43 (s, 3), 1.39 (s, 3). EI/MS (70eV): 292
(M’, 4.0), 277 (4.5), 260 (base), 245 (8.9), 227 (17.7), 217
(11.8), 200 (28.3), 185 (9.2), 157 (6.1), 145 (13.8), 129
(15.7), 115 (17.4). IR (neat): 3500, 2980, 1740, 1720,
1715, 1600, 1435, 1380, 1360, 1300, 1150, 970cm‘1.

giggthyl-S.5-diggthyl-6-oxo-5,6,7,8-tetrahydronaphtha1ene-
1,2edicgrboxylate:;gl

To a solution of 0.01g (0.034 mmol) of 132 in dry
benzene (20 mL) was added 0.04g (0.176 mmol) of 000. The
resulting mixture was heated under reflux for 5 hours then
cooled to room temperature and filtered through a plug of
silica gel, which was rinsed with benzene. Concentration in
vacuo provided 0.0095g (95%) of.138.
1H-NMR (250 M82, 00013): 6 = 7.91 (d, J=9.182, l), 7.47 (d,
J=8.5, l), 3.96 (s, 3), 3.90 (s, 3), 3.07 (dd, J=6.4,7.382,
2), 2.68 (dd, J=7.3,6.482, 2), 1.45 (s, 3). EI/MS (70eV):
290 (M’, 1.6), 258 (base), 243 (4.4), 236 (60.2), 215
(73.5), 199 (30.7), 187 (5.0), 172 (11.4), 158 (7.8), 144
(13.8), 128 (30.0), 115 (27.4). IR (neat): 2980, 2960,
1740, 1720, 1715, 1600, 1435, 1380, 1360, 1300, 1270, 1150,

970cm'1.

imethy1-5,5-diyethyl—6-L:hygroxy-5,6,7,8-tetrahydronaph-
thalene-l,2-dicarboxylate 136
To a solution of 0.005g (0.017 mmol) of 138 in dry

methanol (2 mL), cooled to 0°C (ice water), was added 0.005g

106

2), 2.0 (m, 2), 1.43 (s, 3), 1.39 (s, 3). 131/33 (70eV): 292
(3+, 4.0), 277 (4.5), 260 (base), 245 (3.9), 227 (17.7), 217
(11.3), 200 (23.3), 135 (9.2), 157 (6.1), 145 (13.3), 129
(15.7), 115 (17.4). IR (neat): 3500, 2930, 1740, 1720,

1715, 1600, 1435, 1380, 1360, 1300, 1150, 970cm'1.

Qiggthy1-5,5:g;!ethyl-6-oxo-5,6,7.8-tetrahydronaphthglene-
wicmoxwelfi

To a solution of 0.01g (0.034 mmol) of 132 in dry
benzene (20 mL) was added 0.04g (0.176 mmol) of 000. The
resulting mixture was heated under reflux for 5 hours then
cooled to room temperature and filtered through a plug of
silica gel, which was rinsed with benzene. Concentration in
vacuo provided 0.0095g (95%) of.138.
1H-NMR (250 M82, 00013): 6 = 7.91 (d, J=9.le, 1), 7.47 (d,
J=8.5, 1), 3.96 (s, 3), 3.90 (s, 3), 3.07 (dd, J=6.4,7.382,
2), 2.68 (dd, J=7.3,6.482, 2), 1.45 (s, 3). EI/MS (70eV):
290 (M’, 1.6), 258 (base), 243 (4.4), 236 (60.2), 215
(73.5), 199 (30.7), 187 (5.0), 172 (11.4), 158 (7.8), 144
(13.8), 128 (30.0), 115 (27.4). IR (neat): 2980, 2960,
1740, 1720, 1715, 1600, 1435, 1380, 1360, 1300, 1270, 1150,

970cm'1.

Dimethyl-5,5-digethyl—6-£:hydr9xy-5,6,7,8-tetrghydrongph-
thalene-IJgfdicarboxylate 136
To a solution of 0.005g (0.017 mmol) of 138 in dry

methanol (2 mL), cooled to 0°C (ice water), was added 0.005g

107

(0.13 mmol) of NaBH4. The mixture was stirred for 1 hour at
0°C, then quenched with saturated aq. Na8003 (5 mL). The
mixture was cast into ether (20 mL), the organic phase was
separated, washed with 820 (5 mL) and dried (MgSO4).

Concentration in vacua provided 0.0045g (89%) of 136.

LIST 0? was

LIST arm

Tanis, S. P.; Nakanishi, K. J. Am. Chem. Soc. 1979,
101, 4398.

For isolation and biological activities of some

clerodane diterpenes, see:

a) Kubo, 1.; Lee, Y.-W.; Balogh-Nair, I. V.; Nakanishi,
8.; Chapya, A. J. Chem. Soc. Chem. Ca-un. 1976,
949.

b) Kubo, 1.; Klocke, J. A.; Miura, 1.; Fukuyama, T. J.
Chem. Soc. Chem. 00.. 1932, 618.

c) Kubo, 1.; Fukuyama, 7.; Chapya, A. Chem. Lett. 1&3,
223.

d) Ferrai, M.; Pelizzoni, F.; Ferrari, G.
Phytochemjstry 1971, 10, 3267.

e) Niwa, M.; Yamamura, S. Tet. Lett. 1981, 22, 2789.

f) McCrindle, R.; Nakamura, R.; Anderson, A. B. J.
Chem. Soc. Perkin I 1977, 1590.

g) Anderson, T.; McCrindle, 8. Acta, Chem. Scand. 1m,
23, 1066.

h) Schmitz, F. J.; Lakshmi, V.;' Powel, 0. R.;
Vanderhelm, D. J. Org. Chem. 1&4, 49, 241.

i) Carté, 0.; Rose, 0. 0.; Raulkner, 0. J. J. Org.
Chem. 1935, 50, 2785.

Terpenoids and steroids, specialist periodical reports,
The Chemical Society, London, Vol. 1, 1971 to Vol. 13,
1983.

Miss, R.; Pandey, R. 0.; Dev S. Tetrahedron 1m, 49,
3751. '

Ardon-Jimenez, A.; Halsall, T. G. J. Chem. Soc. Perkin
I 1978, 1461.

a) Sarma, A. S.; Chattopadhyay, P. Tet. Lett. 1930, 21,
3719.

b) Sarma, A. S.; Chattopadhyay, P. J. Org. Chem. 1932,
47, 1727.

Takashi, S.; Kusumi, T.; Kakisawa, 8. Chem. Lett. 1979,
515.

108

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

109

Kende, A.; Roth, 8.; Kubo, I. Tet. Lett. 1982, 21,
1751.

Apsimon, J. W.; Yamusaki, K. Chem. Lett. 1977, 1453.

Goldsmith, 0. J.; John, T. R.; Vanmiddlesworth, F.
Synth. Cu. 1%, 10(7), 551.

a) Luteijn, J. M.; VanDoorn, M.; deGroot, A. Tet. Lett.
1&0, 2.1, 4127 and 4129.
b) Luteijn, J. M.; deGroot, A. J. Org. Chem. 1931, 146',

3448.

c) Luteijn, J. M.; deGroot, A. Tet. Lett. 1Ql, 21,
789.

d) Luteijn, J. M.; deGroot, A. Tet. Lett. 1932, 23,
3421.

Ley, S. V.; Simpkins, N. S.; Whittle, A. J. J. Chem.
Soc. Chem. Cancun. 1933, 503.

Tokoroyama, T.; Fujimori, 8.; Shimizu, J.; Yamagiwa, Y.
J. Chem. Soc. Chem. Commun. 1-, 1516.

Ireland, 8. 8.; Muchmore, 0. 0.; Hengarter, U. J. Am.
Chem. Soc. 1972,. .94, 5098.

Nagata, W.; Yoshioka, M. Org. React. 1977, 25, 255.

Goldsmith, D. J.; Srouji, 0.; Kwong, 0. J. Org. Chem.
1978, 43, 3182.

Kojima, Y.; Kato, N. Tet. Lett. 1930, 21, 5033.

a) Kakisawa, 8.; Ikeda, M. Nippon Kagaku Zasshi 1%7,
33, 476; Inouye, Y.; Kakisawa, 8. Bull. Chem. Soc.
Japan I”, 42, 3318.

b) Van del Tempel; Ruisman, 8. O. Tetrahedron 1%6, 22,
293.

This method which is a modification of that recently
reported by 1ey: Rollinshead, 0. M.; Howell, S. 0.;
Ley, S. V.; Mahon, M.; Ratcliffe, N. M.; Worthington,
P. A. J. Chem. Soc. Perkins I 1933, 1579.

Tanis, S. P.; Abdallah, Y. M. Synth. Comm. 1%, in
press. -

Markgraf, J. 8.; Greeno, E. W.; Miller, M. 0.; Zaks, W.
J.; Lee, G. A. Tetrahedron Lett. 1’, 24, 241. For a
recent example of the Diels-Alder reaction of 101 with

2-methy1 cyclopentanone, see: Ireland, R. 8.; Thompson,
W. J.; Mandel, N. S. J. Org. Chem. 1979, 44, 3583.

22.

23.

24.

25.

26.

27.

28.

29.

110

a) For a review, see: Onishchenko, A. S. in "Diene
Synthesis", Israil Program for Scientific
Translation, Jerusalem, 154.

b) Nazarov, I. N.; Anachenko, S. N.; Torgov, I. V.
Izv. Akad. Nauk SSS]? (Eng. Trans.) 159, 84 .

Julia, M; Malassine, B. Tetrahedron 1974, 30, 695.

Roush, W. R.; Gillis, R. 8.; 8o, A. I. J. Am. Chem.
Soc. 1932, 104, 2669.

a) Segal, G. M.; Rybkina, L. P.; Kucherov, V. F. 12v.
Akad. Nauk SSS]? (Eng. Trans.) 1”, 1368.

b) Danishefsky, 8.; Prisbylla, M. P.; Riner, S. J. Am.
Chem. Soc. 1978, 100, 2918.

c) Shin, 0.; Yamaura, M.; Inui, E.; Ishida, Y.;
Yoshimura, J. Bull. Soc. Chem. Japan 1978, 51,
2618.

a) Mui, P. W.; Grunwald, E. J. Am. Chem. Soc. 1932, 101,
6562.

b) Squillacote, M. E.; Sheridan, 8.; Chapman, 0. L.;’
Anet, F. A. L. ibid. 1978, 101, 3657.

c) Lipnick, R.; Garbish, E. W. ibid. 1973, 95', 6370.

Chenera, 8.; Reusch, W. Tetrahedron Lett. 1&4, 25,
4183.

Tanis, S. P.; Abdallah, Y. M.; Williard, P. G.
Tetrahedron Lett. 1%, 26', 3651.

a) Ramage, R.; Southwell, I. A. J. Chem. Soc. Perkin
Trans. I 1&4, 1323.

b) Bridge, A. W.; Morrison, 0. A. J. Chem. Soc. Perkin
Trans. I 1-, 2933.

c) Selover, S. J.; Crews, P. J. Org. Chem. 1930, 45,
69.

d) Maione, A. M.; torrini, 1.; Romeo, A. J. Chem. Soc.
Perkin Trans. I 1979, 775.

e) Ireland, 0.; Faulkner, 0. J.; Solheim, B. A.;
Clardy, J. J. Am. Chem. Soc. 1979, 100, 1002.

f) Ireland, R. E.; Beslin, P.; Giger, R.; Rengartner,
U.; Kirst, 8. A.; Maag, 8. J. Org. Chem.I 1977, 42,
1267.

g) Guest, 1. 0.; Marples, B. A. J. Chem. Soc. Perkin
Trans. I 1973, 900.

h) Whitlock, 8. W., Jr.; Olson, A. H. J. Am. Chem.
Soc. 1970, .93, 5383.

i) Blackett, B. N.; Coxon, J. M.; 8artshorn, M. P.;
Richards, K. E. Tetrahedron 1m, 25, 4999.

j) Rikino, R.; Kohama, T.; Takemoto, T. Tetrahedron
1%9, 25, 1037.

30.

31.

32.

33.

34.

35.

36.

37.

38.

111

k) Blunt, J. W.; Hartshorn, M. P.; Kirk, 0.
TeHQMBdnn719E&,.flZ 149.

1) Blunt, J. W.; 8artshorn, M. P.; Kirk, 0. N.
Chem.Sbc.(ZU hiih 635.

m) 8a1sa11, T. G.; Jones, E. R. 8.; Tan, E.
Chaudhry, G. R. J. Chem. Soc. (C) 1&6, 1374.

n) Coxon, J. M.; 8artshorn, M. P.; Rae, W.
Tetrahedron 1970, 26', 1091 .

Tanis, S. P.; Nakanishi, K. J. Am. Chem. Soc. 1979,
101, 4398.

Demole, E.; Enggist, P.; Borer, C. Helv. Chim. Acta
1971, 54, 1845.

N.

J.

Similar 18—NMR and 13C-NMR chemical shifts for oxetane
resonances have been previously reported, see, for

example:
a) Okuma, K.; Tanaka, Y.; Kaji, S.; Ohta, 8. J. Org.
Chem. 1&3, 48, 5133.

b) Garcia-Alvarez, M. 0.; Lukacs, 0.; Neszmelyi, A
Piozzi, F.; Rodriguez, 8.; Savona, G. J. Org.

Chem. 1&3, 48, 5123. See also:

c) Welch, S. 0.; Prakasa Rao, A. S. 0.; Lyon, J.
Assercq, J.-M. J. Am. Chem. Soc. 1&3, 105, 252;
and references cited therein.

T.‘

3) Burton, L. P. J.; White, J. D. J. Am. Chem. Soc.

1981, 103, 3226.
b) White, J. 0.; Burton, L. P. J. J. Org. Chem. 19$,
50, 357.

Prinzbach, 8.; Schmidt, 8.-G. Chem. Ber. I974, 107,
1988.

Stork, 0.; Atwal, K. S. Tet. Lett. 1983, 24, 3819.

a) Rajan, N.; Rajagopalan, K.; Swaminathan, S.

Tetrahedron Lett. 1&0, 21, 1577.
b) Geetha, K. V.; Rajagopalan, K.; Swaminathan,
Tetrahedron 1978, 34, 2201 .

Still, W. 0.; Mitra, A.; Khan, M. J. Org. Chem. 1978,
41, 2923.

a) Onezawa, S.; Shonosuke, 2. Bull. Chem. Soc. Japan
1&3, 1143.

b) McMurry, J. E.; Musser, J. 8. Org. Synth. 1977, 56',
65. -