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STUDIES DIRECTED TOWARD THE SYNTHESIS
OF TETRACYOLIC TRITERPENES

By

Jacob Shya Tou

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1980

ABSTRACT

STUDIES DIRECTED TOWARD THE SYNTHESIS
OF TETRACYCLIC TRITERPENES

By
Jacob Shya Tou

Studies directed toward the synthesis of tetracyclic

triterpenes such as lanosterol l and euphol g from

perhydroindanedione 3 are presented.

 

Selective reactivity of the two carbonyl groups in‘g
was observed in reactions with tosylhydrazine and with the
strong base-lithium diisopropyl amide (LDA). Although 2’
was readily converted to the corresponding bis-tosylhydrazone
and bis-enolate when two equivalents of these reagents were
used, treatment with one equivalent of tosylhydrazine and
LDA gave the correSponding mono-tosylhydrazone‘fi, and a

mono-enolate which was trapped as its silyl enol ether

Jacob Shya Tou
derivative 3. On the other hand, base-catalyzed condensation
of 2 with benzaldehyde occurred preferrentially at the five—
membered ring to givelé. Differences in theJT-conjugation
of the alpha-keto benzylidene moieties may be a major factor

in the surprising predominance of this adduct.

 

Attempts to fuse six-membered rings to 2, so as to
generate the tetracyclic triterpene skeleton, are described
in part B of this dissertation. Two potentially useful

precursors, Z and g, were prepared.

 

Z 8 9

The most promising approach was found to be the Diels-

Alder reaction of diene‘2,with appropriate dienophiles.
However, the synthesis of 2’proved more difficult than

eXpected, because it readily isomerized to the transoid

Jacob Shya Tou
isomer £9 on treatment with acid. In situ trapping
experiments such as dehydration of carbinol l} in the
presence of maleic anhydride (MA), or a thermal reaction
between allyl chloride lg and MA gave modest yields of
adduct £9.

   

10 11 13 13

A successful preparation of 2'was achieved by
treatment of i} with boron trifluoride etherate in refluxing
benzene-THF solution. Diene 2 reacted on heating with a
variety of dienophiles to give crystalline alpha-endo
adducts, such as £2, £9 and 1;. Isomeric adducts £9, and
{2 were selectively prepared via Lewis acid-catalyzed
Diels-Alder reactions. The configurations of adducts lé-E,

have been confirmed by high resolution nmr and X-ray

analyses.

Jacob Shya Tou

 

Adducts a; and ;9 should be useful precursors for the
synthesis of lanostane natural products. Epimerization of
C-5 failed in l; and ;§, but epimerization of 0-10 in if
was successful. Synthesis of the mono enol-acetate ;§ from
lé not only proved that 0-5 is enolizable, but also
generates a dienone moiety in ring A, which might be useful
in the synthesis of euphane natural products by

epimerization of C-10.

 

In the third part of this dissertation, the selective
catalysis of Diels-Alder reactions will be discussed.
Several important directing effects of normal (thermal)

Diels-Alder reactions of substituted quinones are summarized.

Jacob Shya Tou
The regioselectivity of Diels-Alder reactions of 2-methoxy-
5-methyl benzoquinone £9 with isoPrene, piperylene and diene
2 was poor. However, this poor regioselectivity can be
directed to favor ortho/para adducts (lg, £9 and 2}) by
using boron trifluoride as the catalyst, or to favor meta
adducts (£3, £3 and E2) by using stannic chloride as the
catalyst:

Q
MeO O

C

19

gg R1=CH3, R2,R3,R“=H

 

21 R3=CH , R1,R2,R”=H
Av 3

a3 R”=CH3, R1,R2,R3=H
a; R2=CH3, R1,R3,R”=H

Two different catalyst-quinone complexes a9 and a;

are proposed to account for this remarkable regioselectivity.

 

DEDICATION

This dissertation is dedicated to my mother and to

the memory of my father.

ii

ACKNOWLEDGEMENTS

The author wishes to express his sincere appreciation
to Professor William H. Reusch for his guidance, conseling
and encouragement throughout this study, for his critical
reading of this manuscript and for numerous enlightening
and informative discussions. Appreciation is extended to
Professor E. LeGoff for being second reader and to
Professors H. Hart, A. Timnick and M. Rogers for their
helpful suggestions.

The author is also indebted to Dr. W. S. Knowles of
Monsanto Company for a generous gift of 5-methoxy-2-methyl-
p-benzoquinone, and to Dr. L. Shadoff of Dow Chemical
Company for high resolution mass Spectra. Many thanks also
go to Drs. D. Ward and H. Kung for their excellent work in
the X-ray analyses of compounds i3, éé and 22, and to Mr.
E. Oliver for his assistance in obtaining mass Spectra.

To his fellow students, Dr. K. Subrahamanian, Dr. J.
Shau, Y. Chang, J. Meinzer, J. Gibson, Balan Chenera, J.
Dickenson, W. Munslow, J. Christensen and L. Kolaczkowski,
the author wishes to extend his appreciation for their
friendship, assistance and many helpful discussions during
the past years.

The author is grateful to his brother Jim, and sister-

iii

in-law Jane, for their many years of insPiration and
encouragement. Special thanks also goes to his wife
Shannon, for her endless love, patience and understanding
and for her help in preparing this manuscript.
Appreciation is extended to Michigan State University
for a teaching assistantship and to the General Electric

Foundation for a summer term fellowship.

iv

TABLE OF CONTENTS

Page
INTRODUCTION. . . . . . . . . . . . . . . . . . . . . 1
RESULTS AND DISCUSSION. . . . . . . . . . . . . . . . 12
A. Selective Reac ions of trans 1,6-Dimethyl-
bicyclo [4,3,01-nonane-2,7-dione Q. . . . . 12
B. Approaches to B ring Synthesis. . . . . . 21
C. Selective Catalysis of Diels-Alder Reactions
of 2-methoxy-5-methyl-1,h-benzoquinone . . 51
EXPERIMENTAL. . . . . . . . . . . . . . . . . . . . . 68
General. . . . . . . . . . . . . . . . . . . . 68
Preparation of Bis- -tosylhydrazone 19 and mono-
tosylhydrazone 20.. . . . . . . . . . . 7O
Preparationo b1s- -silyl ether 22 and mono-
silyl ether 29. . . . . . . . . 70
Preparation of mono- silyl ehter 23 . . . . . . 72
Preparation of enedione 27 . . . . . . . . . . 73
Preparation of benzylidene adduct 28 . . . . 74
Preparation of benzylidene adducts 28 and 29 . 75
Preparation of cisoid diene 31 . . . . . . . 76
Preparation of transoid diene 3i . . . . . . 77
Preparation of nonconjugated di etone 33 . . . 78
Isomerization of 35 to conjugated diketone 2]. 78

Preparation of benzothiazole adduct 40 . . . . 79

Preparation of epoxide adduct 42 . . . . . . 80
Preparation of a, fl-unsaturated aldehyde 38 . 80
Preparation of allyl chloride Q; . . . . . 81
Preparation of maleic anhydride Diels-Alder

adduct 46. . . . . . . . . . . . . . . . . 82
Preparation of diester adducts 59 and i2 . . . 83
Preparation of p-benzoquinone Diels-Alder

adduct 51. . . . . . . . . . . . . . . . . 84
Preparation of Diels-Alder adduct i9 . . . . . 85
Preparation of Diels-Alder adduct fié . . . . . 86
Preparation of Diels—Alder adduct 37 . . 87
Thermal reaction of qu1none 5 and diene 31. . 88
Preparation of monoacetate 5 . . . . . . . . 89
Epimerization of adduct 57 f3 52 . . . . . . . 9O
Epoxidation of adduct i§"to Q3. . . . . . . . 90
Thermal reaction of qu1none g; and isoprene. . 91

Page

Thermal reaction of quinone 55 and piperylene . 91
Stannic chloride- -catalyzed reaction of quinone
and iSOprene . . . . . . . . . . . . . 91
Stannic chloride- -catalyzed reaction of quinone
55 and piperylene . . . . . . . . . . 92
Boron trifluoride- -catalyzed reaction of quinone
55 and isoprene . . . . . . . . . . . . . 92
Boron trifluoride- -catalyzed reaction of quinone
55 and piperylene . . . . . . . . . . . . . . 93
APPENDIX . . . . . . . . . . . . . . . . . . . . . . . 95
BIBLIOGRAPHY . . . . . . . . . . . . . . . . . . . . . 152

Vi

LIST OF TABLES

Table Page
I Aluminum chloride catalyzed Diels-Alder

reactions of 55 with 31 . . . . . . . . . . . . 60

II Dials-Alder reactions of 55 with piperylene . . 62

III Diels-Alder reactions of 55 with isoprene . . . 62

vii

Figure

10
11
12
13
14
15
16

17

LIST OF FIGURES

Conformational drawing and part of the pmr

Spectrum of adduct 46. . . . . . . .
Spin-Spin decoupling Spectrum of 46.

Stereodrawings illustrating adduct 54 as
determined by X-ray analysis . . . . . .

Coupling constants of HB in the isomeric
fl and 53. I O 0 O O O I O O O O D I O O

Stereodrawings illustrating adduct 56 as
determined by X—ray analysis . . . T“. .

Stereodrawings illustrating adduct 52 as

determined by X-ray analysis .

adducts

The stabilities between the two Diels-Alder
adducts 56/57 and the corresponding isomers

611.21.

molecular models

59 and 62, as predicted by Dreiding

Page

34
35

39

41

42

43

48

Different approaches of diene to a p-benzoquinone.55

The proposed quinone-Lewis acid complex and
its regio-reversal addition to a Substituted

diene. .

Infrared Spectrum of

Infrared
Infrared
Infrared
Infrared
Infrared
Infrared

Infrared

Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
Spectrum

Spectrum

of
of
of
of
of
of
of

65
95
96
97
98
99
100
101
102

Figure Page
18 Infrared Spectrum of 31. 103
19 Infrared Spectrum of 34. 104
20 Infrared Spectrum of 55. 105
21 Infrared Spectrum of 38. 106
22 Infrared Spectrum of 49. 107
23 Infrared spectrum of 42. 108
24 Infrared Spectrum of 45. 109
25 Infrared Spectrum of 46. 110
26 Infrared Spectrum of 59. 111
27 Infrared Spectrum of 5;. 112
28 Infrared Spectrum of 52. 113
29 Infrared Spectrum of 54. 114
30 Infrared Spectrum of 56. 115
31 Infrared Spectrum of 52. 116
32 Infrared Spectrum of 58. 117
33 Infrared Spectrum of 62. 118
34 Infrared Spectrum of 68. 119
35 Infrared Spectrum of 29. 120
36 Pmr Spectrum of 29 . . . 121
37 Pmr Spectrum of 29 . . . . . . . . . . . . . . . . 121
38 Pmr Spectrum of 22 . . . . . . . . . . . . . . 122
39 Pmr Spectrum of 23 . . . . . . . . . . . . . . . . 122
40 Pmr Spectrum of 24 . . . . . . . . . . . . . 123
41 Pmr Spectrum of 22 . . . . . . . . . . . . . . . 123
42 Pmr Spectrum of 28 . . . . . . . . . . . . . . . . 124
43 Pmr Spectrum of 29 . . . . . . . . . . . . . . . . 124
44 Pmr Spectrum of 51 . . . . . . . . . . . . . . . . 125

ix

Figure Page

45 Pmr Spectrum of 35. . . . . . . . . . . . . . . . 125
46 Pmr Spectrum of 34 . . . . . . . . . . . . . 126
47 Pmr Spectrum of 38 . . . . . . . . . . . . . 126
48 Pmr Spectrum of 49. . . . . . . . . . . . . . . . 127
49 Pmr Spectrum of 42 . . . . . . . . . . . . . . . 127
50 Pmr Spectrum of 45 . . . . . . . . . . . . 128
51 Pmr Spectrum of 48. . . . . . . . . . . . . . . . 128
52 Pmr Spectrum of 59. . . . . . . . . . . . . . . . 129
53 Pmr Spectrum of 52. . . . . . . . . . . . . . . . 129
54 Pmr Spectrum of 5}. . . . . . . . . . . . . . . . 130
55 Pmr Spectrum of 54 . . . . . . . . . . . . . 130
56 Pmr Spectrum of 58 . . . . . . . . . . . . . . . 131
57 Pmr spectrum of 52. . . . . . . . . . . . . . . . 131
58 Pmr spectrum of 58. . . . . . . . . . . . . . . . 132
59 Pmr Spectrum of 89 . . . . . . . . . . . . . . 132
60 Pmr Spectrum of 88. . . . . . . . . . . . . . . . 133
61 Pmr Spectrum of Z9 . . . . . . . . . . . . . . 134
62 Mass Spectrum of 19 . . . . . . . . . . . . . . 135
63 Mass Spectrum of 29 . . . . . . . . . . . . . . . 135
64 Mass Spectrum of 22 . . . . . . . . . . . . . . . 136
65 Mass Spectrum of 24 . . . . . . . . . . . . . 137
66 Mass Spectrum of 23 . . . . . . . . . . . . . . . 137
67 Mass spectrum of 22 . . . . . . . . . . . . . . . 138
68 Mass Spectrum of 34 . . . . . . . . . . . . . . . 138
69 Mass Spectrum of 28 . . . . . . . . . . . . . . . 139
70 Mass Spectrum of 29 . . . . . . . . 140

Figure

71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88

89

Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass

Mass

Spectrum
Spectrum
Spectrum
Spectrum

Spectrum

spectrum.

Spectrum
Spectrum
Spectrum
Spectrum
Spectrum
spectrum
Spectrum
Spectrum
Spectrum
spectrum

Spectrum

of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of

13C NMR Spectrum

13C NMR Spectrum

25 15 (‘63 28’. z“:

‘8 ($25

It’ll

BS {‘3 {‘61 (3.1 2X}

1

O\
M)

13183:

O
H)

xi

Page
140
141

. 141
. 142

143
143
144
145
146
146
147
147

. 148

148
149
149
150
151
151

INTRODUCTION

The tetracyclic triterpenes are mostly found in the

plant kingdom, and have a common perhydrocyclopentanophen-

1,2

anthrene Skeleton i:

 

1.

Because of their structural resemblance to steroids,
the tetracyclic triterpenes are also called methylsteroids
or 14—urmethyl analogs of steroids.3 A number of tetracyclic
triterpenes, such as the cucurbitacins, have been Shown to
have anti-tumor activity and some of their derivatives are
also found to be as physiogically active as steroids.

It is now known that the tetracyclic triterpenes and
steroids are formed in nature by an enzymatic cyclization
of squalene 2,3-oxide‘2.5 In these biosyntheses, enzymes
play an important role in folding the squalene oxide in two
different modes: one leads to the lanosterol/steroid system

via a chair-boat-chair-boat arrangement, and one to the

euphol system via the correSponding chair-chair-chair-boat

conformation:

 

lanosterol euphol

The tetracarbocyclic skeleton and stereochemical
complexities of the tetracyclic triterpenes pose a challenge
to synthetic organic chemists with many challenges. However,
a greater effort has been directed toward the total synthesis
of steroids than toward that of the tetracyclic triterpenes.
In fact, at the present time, only two distinct approaches
have been successful in achieving the total synthesis of a
tetracyclic triterpene. The first, developed by Woodward
et.al., used cholesterol as the starting meterial for a

lanosterol synthesis. The other entirely different approach

uses a biogenetically patterned reaction sequence, as
effected in van Tamelen's studies.

In Woodward's approach,6 a key step involved the
introduction of a 14-a-methyl group onto a 15-keto-
cholestane derivative 2, as Shown below. Lanosterol was

thus synthesized in over twenty five steps.

      

2:

The van Tamelen strateSY. on the other hand, involved

acid-catalyzed cyclization of a suitable polyene monoepoxide.
For example, acid treatment of a mono-carbocyclic derivative
of squalene oxide’4 and its C-3 epimer led to the total

syntheses of parkeol and isotirucallol, reSpectively:7

 

C—3 epimer of 1

 

isotirucal lol

Similarly, when polyene epoxide 5 having a preformed

CD ring is used, cyclization to a dihydrolanosterol

precursor8 took place:

 

dihyd rolanosterol

Although the lanostane skeleton has been successfully
constructed as noted above, a total synthesis of the related
euphanes and cucurbitacins has not yet been accomplished.
The euphane/tirucallane family will be difficult to prepared

by the versatile polyene cyclization approach, because

compounds of this kind suffer a facile acid-catalyzed
8.9

rearrangement to the isoeuphane system:

 

   

euphenol acetate isoeuphenol acetate

The bicyclic diketone trans-1,6-dimethyl-bicyclo

6 10

[4,3,0] nonan-2,7-dione A, has been prepared from

cyclohexa-1,3-diketone via the following scheme:

lli/NH3O
H0 v

   

This diketone incorporates a common Skeletal feature
found in the tetracyclic triterpenes. Thus, it should be
possible to use compound‘é as a CD synthon in a synthesis
of the above natural products. In order to achieve such a
total synthesis, two major transformations must be
accomplished. First, A and B rings must be attached to
the Six—membered ring of 6'in a regio- and stereoselective
manner. Second, an alkyl Side chain must be bonded to the

five-membered ring.

attach side chain

 

rings A and B

2

There are two important advantages to using compound 6’

as a starting material in tetracyclic triterpenes synthesis.
First, because of the presence of the 14—a-methyl group, the
tedious methylation steps in Woodward‘s synthesis will be
eliminated. Secondly, two possible stereo orientations of
the methyl group at C-10 are possible, i.e. alpha and beta.
Stereochemical control during the introduction of this
center would allow synthesis of both important families of

these triterpenes. If an alpha configuration is generated,

it can be used for the synthesis of euphane natural
products. On the other hand, if a beta configuration is
obtained, then the resulting product can be used for the
synthesis of lanostane natural products.

In developing methods for attaching rings A and B to 6,
it is helpful to examine related systems in which analogous
transformations have been achieved. In steroid synthesis,

11 generally have

three fundamentally different strategies
been used for the fusion of a two-ring fragment to an
existing two-ring moiety in order to build up the desired

tetracarbocycle:

1. CD -----> BCD -—-> ABCD

This notation indicates that ring B is first attached
to a preformed CD ring system. The ABCD Skeleton is
then constructed via addition of the A ring to the

newly formed BCD unit.

 

2. CD + A —> ACD ——-> ABCD
3. CD + A ———> ABCD or AB + D ) ABCD
12,13

Johnson's steroid synthesis is one of the best
examples of the first approach. As shown below, the B and
A rings were introduced stepwise via a Michael-Aldol

reaction sequence.

 

+' -
MeN(Et)2l
+-
0/
unsaturated
steroids <— <—
0
ABCD
Two examples of the A-I-CD —-> ACD ——> ABCD route may be
cited. In Birch's preparation of D-homosteroids,11+ an

enolate CD fragment was added to a bromide which
incorporated the A ring. The resulting ACD intermediate 8'

was then cyclized to the desired tetracyclic structure.

OMe
Br K
——>
“Aecdlliil\'14Eflllllliiill AfleC) j;
A CD A l

D— homosteroids

 

Johnson15 reversed the polarity of this process by

having the A ring moiety serve as an anionic Species. The
alkylation adduct ACD 9 was hydrogenated and then cyclized

to yield a tetracyclic compound 19 which eventually led to

a total synthesis of estrone methyl ether 2}.

 

The third approach is best accomplished by a Diels-
16

Alder reaction of a bicyclic diene and a monocyclic
dienophile. In principle, this type of Diels-Alder
reaction can put together all four rings in one step.
Surprisingly, the CD-t A -€>ABCD strategy has not yet been

11

used for a steroid synthesis. However, there are several

10

syntheses which utilize a Similar pathway, namely AB-+ D
-—€>ABCD, for the construction of the tetracyclic system.

17 is a notable

Johnson's estrone methyl ether synthesis
example. Quinone 13, after condensing with diene 12, gave
a cycloadduct 25, which served as a precursor for the total

synthesis of estrone methyl ether 2}.

   

R
—>
AB D ABCD
13 12 R::ri E? R==P1
1:} R=Me Ll; R=Me
18

More recently, Valenta and coworkers have achieved a
similar steroid synthesis by an elegant Lewis acid-directed
Diels-Alder reaction. For example, reaction of diene 22 and
substituted quinone 24 in.the presence of boron trifluoride
etherate gave cycloadduct 18, which was then transformed

to 1}. Similarly, adduct 28 was obtained from the reaction
of diene £2 and quinone 14. This cycloadduct was a key
intermediate in a total synthesis of saturated D-

homosteroids.18

11

 

/
.1
0
AB D ABCD
1] 15 13
V
.L

saturated D-homosteroids

In the first part of this dissertation, the relative
reactivities of the carbonyl functions in perhydroindandione
‘6 will be examined. In the second part, some methods of
fusing Six-membered rings to 8, so as to generate the
tetracyclic skeleton of the lanostane and/or euphane
triterpenes, will be tested. Finally, Lewis acid-
controlled low-temperature DielS-Alder reactions will be

discussed in the third part.

RESULTS AND DISCUSSION

A. Selective Reactions of trans 1,6- 19
Dimethylbicyclo (4,3JO)-nonane-2,7-dione

~

Before undertaking the selective annulation of AB ring
fragments to the six-membered moiety of‘é, it is necessary
to establish the relative reactivities of the two carbonyl
groups in the five- and six-membered rings. Indeed,
compound 8 is an excellent model compound for studying the

chemical behavior of cycloketones with respect to ring size.

 

2.

that the carbonyl group in

It is well known20

cyclohexanone is more reactive than that in cyclopentanone.

21

Also previous studies of compound_6 have shown that

nucleophilic reagents favor reaction at the Six-membered

carbonyl Site. Examples are sodium borohydride reduction,21a

21b

lithium phenylacetylide addition and vinyl magnesium

bromide addition21a:

12

13

NaBH4

¢?\Nbflr

 

 

lo

 

 

K Q-CsC-Li

 

All these selective reactions were reported to give
good yields without protection of the five-membered carbonyl
group. A Similar selectivity has now been observed in
reactions with tosylhydrazine.22 Both the carbonyl groups
in‘6,can undergo condensation reactions with tosylhydrazine
(TSNHNHZ), and with excess reagent bis-adduct 19 was
isolated in 66% yield. When 6,was treated with an equimolar
amount of tosylhydrazine, however, the reaction gave a
monoadduct (83% yield), which was identified as 29 on the

1

evidence of a strong carbonyl absorption at 1740 cm- in

the infrared.

14

7 excess >
i TsNHNH2

 

6 1 eq. \_
N K TsNHNH2I

 

 

The usefulness of‘é as an intermediate in the total
synthesis of natural products would be enhanced if the
formation of a selective enolate could be achieved. To
this end, reactions involving enolate formation from’é were
investigated. Both the carbonyl functions in‘é proved
readily converted to enolate Species when excess strong
base-lithium diisopropylamide (LDA)-was used. After
trapping the bis-enolate Species 2; with tert-butyl
dimethylchlorosilane (TDCS), the bis-silyl ether 22 was
obtained in 85% yield.

15

 

   

When 8 reacted with an equimolar amount of LDA, two
mono enolates were obtained as their silyl enol ether
derivatives in roughly quantitative yield. The infrared
Spectrum of the major product (>95fl) indicates the presence
of a five-membered ring carbonyl group (fihax=1740 cm'l).
This Spectral feature strongly supports the assignment of
structure 29 to this compound. 0n the other hand, the
infrared Spectrum of the minor isomer (ca. 1%) indicates
the presence of a six-membered ring carbonyl group,

1

absorption at 1715 cm' , and clearly suggests structure 24

for this product.

llJlA

N)
\/

 

16

The lithium enolate salts generated as described above
were found to be rather insoluble in THF. In order to
improve the reactivities of these bases at low temperature,
it was necessary to add hexamethylphOSphorous triamide
(HMPA) to the enolate solution before trapping with TDCS.
In fact, in the absence of HMPA the reactions were
heterogeneous, and yielded three products: the bis-silyl
ether 22 and mono-adducts 28 and 24 in varying proportion.

Since the formation of mono-adduct 29 was independent
of either the reaction temperature in the range 00 to 650
or the reaction time, it is assumed that 25 represents the
thermodynamically favored mono-enolate Species derived from
8, All attempts to trap a kinetically favored enolate at
a lower temperature (~—16°C) failed because of solubility
problems, even though a Significant amount of HMPA was
added.

In principle, enolate 25 could be alkylated, acylated
or sulfenylated, and would be potentially useful in
selective annulation reactions. In practice, it has been
found that reaction of diphenyl disulfide with 25 yielded
sulfide 28. Oxidation of 26 followed by elimination of

23

the resulting sulfoxide gave enedione 23. Alternatively,

enedione 27 was also prepared by selenium dioxide

oxidation:2h

17

 

l NalO
2 NaH
A
23
/\
$60: I

 

 

An unexpected result was observed in studies of
benzaldehyde condensations withlé. Base catalyzed reaction

of g with excess benzaldehyde gave bisadduct 28.

NaOH
09. QIYme

 

Ur

 

 

 

This demonstrates that both the alpha methylene groups
in the five- and six-membered rings can serve as enolate
donors. When one equilvalent of benzaldehyde was used,
however, two condensation adducts were isolated in a 1:2

ratio. One of the products was the bis-adduct 28 and the

18

other was a mono-adduct which, surprisingly, was identified
as five-membered ring adduct 29. It Should be noted that
none of the mono-adduct 39 was detected in this reaction.
Further studies showed that when the bis-adduct 28 was
treated with one equivalent of_8_under similar reaction

conditions, the same mixture of 28 and 29 was obtained.

 

 

 

 

As expected, mono-adduct 29 was the chief condensation
product when‘é'reacted with half an equivalent of

benzaldehyde:

3 + 0.59quiv. ¢CHO 02.?ng > .8 "' 2.9 + 3.?

ratio (52) = (7) = (57)

19

At first glance, the above condensation reactions seem
to conflict with the silyl enol ether trapping experiments
described above. However, this inconsistency may be
rationalized by the difference in fl-conjugation of thea-
keto benzylidene groupings in the five- and six-membered
rings. According to Dreiding molecular models, there is a
substantial dihedral angle (ca. 35°) between the Six-
membered carbonyl group and its alpha benzylidene grouping,
whereas the two functions are essentially coplanar when on

a five-membered ring. (see 28')

 

’23!

This suggests that a benzylidene group alpha to a five-
membered ring ketone has greater fl-conjugation than the
six-membered analog. Furthermore, the relatively higher
molar extinction coefficient (e=25,000) of the adduct 29
also implies greater coplanarity between carbonyl and the
abbenzylidene groups. For example,(x-benzylidenecyclo—
hexanones have molar extinction coefficients (£=16,000)
roughly 70% that of acyclic or five-membered analogues

(5:24,000).37

20

Since these condensations are reversible, the product
distribution Should reflect the thermodynamic equilibrium
of the two adducts. If the greater conjugation in 29 makes
it more stable than 39, the predominance of the former mono

adduct in these product mixtures is reasonable.

B. Approaches to AB ring,Synthesis

From the beginning, a Dials-Alder reaction between
diene 2} and a suitable dienophile appeared to be the most

direct means of fusing an AB ring unit to intermediate‘é:

 

In order to put this A + CD -€>ABCD approach into

practice it was first necessary to develop an efficient

psynthesis of diene 5; from 6, In initial studies by J.

21a

Martin, vinyl carbinol 52 was prepared in moderate

yield by treatment of dione 6,with vinyl Grignard reagent.
Dehydration of 32 in refluxing xylene containing a little
iodine gave a product initially believed to be the desired

21a

diene 31. However, no DielS-Alder adducts were obtained

22

from reactions of this product (33) with maleic anhydride,

tetracyanoethylene, p-benzoquinone and dimethyl acetylene

dicarboxylate under varying reaction conditions:21a

 

 

I
2 35%;) [ dehydrated diene]
:13;
22
various
dienophiles
v

No Dials—Alder Adduct

Epoxidation of diene 35 by m-chloroperbenzoic acid
has now been shown to yield enedione 34. This unexpected
product is not easily rationalized starting from diene 3},

suggesting that a reexamination of 33 be made.

MCPBA

 

 

23

A careful review of the pmr Spectrum of diene 22 now
shows it to be the rearranged transoid isomer 2;, resulting
from an acid-catalyzed rearrangement25 of cisoid diene 31

under the dehydration condition:

 

 

The correct structural assignment of diene 35 not

only explains the failure of attempted Diels-Alder
reactions,but also is consistent with the formation of the
unexpected enone 23. It is believed that epoxide 2g
undergoes a facile 1,2-hydride shift26 under the reaction
conditions to yield enone 25. In fact, this reaction is
best carried out by introducing a catalytic amount of
boron trifluoride etherate, which acts to catalyze the
rearrangement of intermediate epoxide zé. By this means,

enone 23 was obtained in 65% yield.

2#

 

 

 

The above findings led to two interesting follow-up
studies. First, although carbinol 23 did dehydrate under
the iodine-catalyzed treatment, the resulting transoid
diene 22 was not suitable for the Diels-Alder approach;
consequently, it was necessary to find suitable conditions
for generating cisoid diene 2a. A variety of dehydration
reactions of 25 were investigated and will be discussed
later in this dissertation. Second, sincelfi,7-unsaturated
ketone 25 could be obtained from 29 in good yield, it was
considered as a possible alternative in the AB ring
annulation.

Treatment of 23 with potassium t-butoxide in t-butanol
solution partially isomerized the double bond to give
conjugated enone 22. The product mixture from this
treatment proved to be 87% 22 and 13% 23, as evidenced

from pmr Spectroscopy.

25

 

(87) = (13)

That enone 22 is a potentially useful synthon for
subsequent annulation via the well-known Michael-Aldol
reaction sequence is clear from the reported studies of
Robinson and others on simpler systems.27 Unfortunately,
all attempts to effect the Michael addition of diethyl
malonate and Z-methyl-l,3-cyclohexadione to 22 failed.

In a related study, methods of preparing the
equivalent unsaturated aldehyde 2§ from é'were also
explored. Two potentially useful precursors to 2g were

prepared by taking advantage of the different reactivities

   

2,

26

of the two carbonyl functions in‘é. When compound é’was
treated with the lithium derivative of benzothiazole 2228
in THF, a single adduct, 29, was obtained in 70% yield.
However, efforts to effect dehydration of £9 under a variety
of conditions failed. These included treatment with
phOSphorous pentoxide in methane sulfonic acid,28 iodine
in refluxing xylene, boron trifluoride in benzene/THF and

p-toluenesulfonic acid in benzene.

 

 

A second approach to the synthesis of 2§ proved
successful. The lithium reagent fl}, derived from

29 was added to é,and yielded

chloromethyl phenyl sulfoxide,
ketoepoxide gg. This reaction apparently proceeds via an

addition to give Q2, followed by dehydrochlorination to
#2.

27

I
453%... \_

9 21

 

 

 

Compound fig underwent a facile thermal decomposition
reaction to yield the desired aldehyde 2§,29b which
exhibited a one proton triplet at 66.4 and a one proton

singlet at 69.2 in the pmr Spectrum.

   

Although 38 is a potentially useful synthon for

subsequent annulation, the failure of Michael addition

28

reactions to the similar unsaturated ketone 22 together with
the success of the Diels-Alder approach discouraged further
investigations with this intermediate.

Because of the superiority of the DielS-Alder approach,
the preparation of diene 23 by dehydration of 22 became the
subject of an extensive investigation. Unfortunately, this
transformation proved very sensitive to acid-catalyzed
isomerization of 23 to the undesired isomer 2;. Typical
examples were found in the iodine and ferric chloride/Silica
gel catalyzed dehydrations which gave the rearranged diene
2; exclusively. Treatment of 23 with p-toluenesulfonic acid
in refluxing toluene gave a 50:50 mixture of 2} and 2;.
Diene 2} is apparently the initial product of this
dehydration, since 2; is not isomerized to 21 under

equivalent conditions.

 

Studies also Showed that transoid diene 2; was

resistant to in Situ isomerization to cisoid diene 2}. No

Diels-Alder adduct was obtained when the reaction was

29

carried out in the presence of maleic anhydride (MA), which

served as a trapping reagent.

> No Diels-Alder Adduct

 

The Burgess reagent £9, a zwitterionic salt which has
been Shown to be useful for effecting acid-sensitive

33

dehydration reactions, gave a complicated mixture of

products when used for the dehydration of 23.
_ o ,
EtO-g-N-g-N (Et)3

44

~

The possibility of effecting dehydration of 22 under
basic conditions was next explored. Treatment of carbinol

34

23 with thionyl chloride in triethylamine, gave allyl

chloride 3; as a SNZ' rearranged product. Moreover, with

35

phOSphorouS oxychloride in refluxing pyridine, carbinol
22 produced the desired cisoid diene 2; as the only volatile
product. Unfortunately, the recovered yield of 2; was quite
low (ca. 20%), possibly because its volatility resulted in

loss during the removal of pyridine.

30

 

 

 

SOC|2 \
Et3N ’ 43
POCI3\

33 PY ’ :11

 

The proSpect for the DielS-Alder approach was improved
by successful trapping experiments. When carbinol 22 was
treated with an excess of maleic anhydride in refluxing
toluene containing a catalytic amount of PTSA, a crystalline
DielS-Alder adduct fig was obtained in 30-40% yield. The
same product also resulted from a reaction between allyl
chloride fig and maleic anhydride in refluxing xylene

solution.

 
 
  

PTSA/Tol-
MA . A

 

 

 

31

After considerable effort, a satisfactory procedure
for preparing 2} from 22 was finally discovered. This
involved treatment of 22 with boron trifluoride etherate

in refluxing benzene-THF solution,18b

followed by Kugelrohr
distillation of the crude product to yield essentially pure
cisoid diene 2} as a colorless low melting solid in 75-80%

yield.

 

 

With the availability of cisoid diene 23 assured, a
series of DielS-Alder reactions became the subject of study.
Reactions of 2} with dienophiles, Such as dimethyl
acetylene dicarboxylate, p-benzoquinone and maleic

anhydride, yielded cycloaddition adducts 50, 23 and fig.

32

 

C)

 

I/

 

 

C)

 

 

 

[O
_< I
—«O

 

These crystalline adducts were obtained in about #5-65%
yield as the only condensation products from the reactions.
The diester adduct 29 was found to undergo facile air

oxidation to the corresponding aromatized product 22.

 

 

33

Four diastereomeric structures are possible for the
Diels-Alder adducts derived from the symmetrical dienephiles
p-benzoquinone and maleic anhydride. These areca-endo flé,
a-exo 1:7, B-endo 92, and fi-exo 93, where a and 3 refer to

the bottom and top Side of the diene.

o ‘
0‘!
o

19

   

It is imperative to know which isomer if any is
favored in the 4+2 cycloaddition reactions reported here.
Accordingly, high-resolution pmr and 130 nmr Spectroscopic
analyses were conducted for each adduct. In particular,
adduct flé has unique pmr Spectroscopic characteristics
(Figure 1) which provide key evidence for the assigned
structure.

The Spin-Spin couplings of protons A through F with
each other have been elucidated by inSpection and decoupling
measurements (Figure 2). Dreiding models of the four
diastereomers of the maleic anhydride adduct were then
examined to determine how well each fit with established

geometrical relationships for these coupling constants.36

The¢y-endo configuration Shown in Figure 1 proved to have

34

.mM Posucm mo asapoomm use map mo yawn can mafizmgc Hmcoflmepoycoo .H opsmflm

 

 

 

 

QAD|¢
Omblv
ooh I.

mesa eI

n12. con cato>

 

 

 

 

 

 

 

, _ 2 a .3.
j . 2 ... as E
W. as u 3..
_.._ _ mg n 3..
_ s.o~ . cue
m.~ u 2.. ambush
8b ms u “We won
”3., _ tab N: 2 u a 93m:
25 2h

3% £33m:

 

35‘

and m: vm SOHPMHGMSMH .Ao .m: pm co“

.m: Pm coavacmuhH .AU .
pmflemngH .An .mm pm cofipmflemsaH .
afl no sznpomnm mzwamsoooc Sammucfl

a:

%m
m .N answflm

 

36

the best fit. Although quinone adduct 2} diSplayed fewer
well-defined coupling patterns in its pmr Spectrum, those
that could be unambiguously assigned were also consistent
with an a—endo configuration. Furthermore, X-ray
diffraction studies of substituted quinone adducts (see
below) confirm this assignment.

Thecx-endo configurations established for adducts fié,
23 and 23 raise a subtle but interesting paradox. According
to Dreiding molecular models, the C ring of allcx-endo
adducts is constrained in a twist-boat conformation whereas
that of the B-endo or exo adducts can have a more stable
chair conformation. Therefore,¢x-adduct flé Should be
thermodynamically unstable compared to the corre8ponding
flLadduct E2. 0n the other hand, molecular models of diene
2} Show that methyl (A) is tilted over the endocyclic
double bond while methyl (B) is tilted back-away from it.
This implies that the bottom (or arside) of the diene is
less hindered than the tOp Side, and that oraddition Should
be favored. The exclusive formation ofcx-adducts from
diene 2; suggests that "steric approach control" is a
stronger factor in the course of these cycloaddition
reactions than is product stability. However, DielS—Alder
reactions of simpler, less polar reactants are known to have

16

product-like transition states, which favor the more
stable cycloadducts. These conflicting results are
probably due to a wide "Spectrum" of Diels-Alder transition

states.

37

 

When an unsymmetrical dienophile reacts with Q; the
question of regioselectivity must be considered. Treatment

of quinone 5338

~

with 2} in refluxing xylene solution gave
adduct éfl in 58% yield. The 250 MHz pmr Spectrum of this
sharp-melting compound suggested high regio- and

stereoselectivity in this Diels-Alder reaction.

 

 

As expected from other cycloaddition reactions of 22,
the angular methyl group and the terminal diene substituent
were ortho to each other in the newly formed B ring. In

the pmr Spectrum of é& a long range coupling between HA

38

and H shows up as a. 65.58 doublet (J=1.5 Hz) for the

B
vinyl hydrogen HA' A one proton quartet at 66.21
accounts for HE’ which is coupled with HC’ HD and HF
(JEéVJEfiVJE§V2.7 Hz). The Similar magnitude of the
coupling constants between JEC and JED implies that the
'C-H o The

B C
structure of adduct 53 was firmly established by an X-ray

39

C-HE bond bisects the dihedral angle of H
diffraction analysis which is summerized by the
stereoscopic view shown in Figure 3. .

Unlike the regioselective thermal cycloaddition of
quinone 52 with 2}, the isomeric quinone 55 showed poor
selectivity in refluxing toluene solution. This reaction
gave two isolable cycloadducts in a 2:1 ratio. The major

adduct was identified as 5g, and the minor adduct was its

regioisomer 57.
~

 

39

 

fr‘b) ,4"
F\ A ’5‘ z‘ '
A ”N“ W , xx
, \J I 3
I

Figure 3. Stereodrawings illustrating adduct 59
as determined by X-ray analysis.

30

Except for the position of the methoxyl group, 5g is
structurally very Similar to 53. The pmr Spectra of these
two compounds reflect this similarity, the chief difference
being that the long range coupling between HA and HB
observed in 53 is no longer present in 5Q. The Splitting
patterns of HB in adducts 53 and 5g, as well as one of the
decoupling experiments are shown in Figure 3. An X-ray

diffraction study39

of 5g confirms the assigned structure,
a stereoscopic view of which is shown in Figure 5.

Adduct 52 displays a similar pmr Signal for vinyl
hydrogen HE as do the isomeric adducts 53 and 5§.
Unforturnately, the bridgehead C-10 hydrogen and the C-6
methylene hydrogens in 52 are not well resolved. However,
this structure was also established by an X-ray diffraction

39

analysis, and a stereoscopic view of the molecule is
shown in Figure 6.

Both adducts 53 and 5g are potentially useful
precursors for a total synthesis of tetracyclic triterpenes.
In fact, adduct 5g is probably the better of the two for
this purpose, but its usefulness is limited by the poor
selectivity of the thermal cycloaddition of 55 and 2}. It
was thus necessary to develop reaction conditions which
favor the selective formation of 5g. To this end, Lewis
acid-catalyzed low-temperature Diels-Alder reactions were
explored. Most of the important selective catalytic

effects that were discovered in this study will be

described in part C of this dissertation, but two results

31

H3 (82.95)

"' 3'50 “9-5“; ’V
FIBCAJ-S H:
hJBA‘El’Hg

Irradiation of HA

 

 

 

 

 

 

V

 

 

 

 

 
 

HB(J:.") “I
#359 ”K23
‘fikfifl

9—13 H: (EH3

\ . b
' \
Ho
HA 56

Figure 3. Coupling constants of H3 in the isomeric
adducts 53 and 5§.

a). Irradiation of HA in 53 resulted in the
collapse of the multiplet to a doublet of
doublets.

b). A similar doublet of doublets is observed
in 5é, in which the long range coupling
between HA and HE is not Significant.

32

 

Figure 5. Stereodrawings illustrating adduct 56
as determined by X-ray analysis. “’

33

 

Figure 6. Stereodrawings illustrating adduct 57
as determined by X-ray analysis. A“

33

are of Special interest.

Addition of 55 to diene 21 in the presence of stannic
chloride gave 53 as the only significant cycloadduct, based
on high-resolution pmr and 130 nmr analyses. Remarkably,
the corresponding boron trifluoride catalyzed reaction gave
a mixture of 56 and 52, in which the former predominated by
10:1. The minor isomer 52 can be easily removed by Slow
crystallization from methylene chloride-cyclohexane

solution.

   

a9 2,7

catalyst
used: SnCI 4 ’ <1 : >99 74%
BF3/Ef20 ’ 1o : 1 55%

Thus, successful selective additions of quinones 52
and 55 with diene 21 not only produce the desired

tetracyclic skeleton of the target molecule, but also

35

introduce the necessary 0-19 methyl group. The remaining
stages of a triterpene synthesis can now be outlined. The
configuration of 53 and 56 are clearly best Suited to a
synthesis of lanosterol or one of its olefinic isomers
such as parkeol. The transformations required to
accomplish this can be grouped into three operational
categories. First, the isolated double bond must be
shifted to the tetrasubstituted [36(9) position so that
the unnatural configuration at 0-9 is eliminated. A
necessary epimerization at C-5 might be effected at the
same time. Second, the functionality in ring A must be
changed to match that of lanosterol, and the gem-dimethyl
groups at C-3 introduced. The well known Woodward6
dimethylation procedure gives a [XS-unsaturated derivative
that can be hydrogenated to the desired AB-trans system.
Finally, the terpene side chain must be attached at 0-17

in a stereOSpecific fashion.

 

% 56 lanosterol

parkeol. = A99”

36

Surprisingly, compound 56 was found to be resistant to
either C-5 epimerization or double bond migration under
both acidic and basic conditions, Such as PTSA/benzene,

30 sodium bicarbonate/methanol and

Dowex 50-8/methanol,
sodium hydroxide/methanol. It Should be noted that the

C-3 carbonyl group of 56 is enolizable as evidenced from
a trapping experiment which gave a selective monoacetate

56 in 71% yield.

 

 

Thus the reluctance of 56 to epimerize clearly

indicates that a trans-fused AB ring junction is not
favored compared to the cis-fused 56. In contrast to
this, regio isomer 5Z was epimerized quite readily in

sodium bicarbonate/methanol solution to yield 52.

4?

 

 

An examination of Dreiding molecular models of 56,
53 and their isomers 52, 69, 6} and 6g is helpful in
explaining the difficulty encountered here (Figure 7).
In all cases having a 918-hydrogen configuration, the C
ring is always forced to be in a twist-boat conformation.
The ciS-syn conformation of 56 gives it a chair-like B
ring. On the other hand, its C-5 epimer, 69, would be
forced to have a boat-like B ring with H-9 and C-19
eclipsed. Therefore, compared to 56, structure 69 should
be less stable, and the failure of 56 to epimerize is
understandable. Both compound 52 and its C-1O epimer 52
have chair-like conformations of the B ring; however, the
A ring is fused in a diequatorial fashion in 52 instead of
the equatorial-axial fashion found in 52. This accounts
for the successful transformation of 52 to 52. It is also
expected from conformational analysis that structure 63

would be more stable than 6} for Similar reasons.

Figure 7.

38

 

 

 

 

 

The stabilities between the two Diels—
Alder adducts 56/57 and the corresponding

isomers 69, 61, 59 and 6;, as predicted
by Dreiding molecular models.

39

This conformational analysis suggests that a Shift
of theZ§7 double bond tozflfi should facilitate subsequent
epimerization at 0-5 to give compound 63. Since thel§7
double bond in 56 proved to be stable under both acidic
and basic conditions, an alternative means of transforming
this function was examined. Treatment of 56 with m-
chloroperbenzoic acid in methylene chloride yielded a
homogeneous product in quantitative yield. A rigorous
assignment of the stereochemistry of the epoxide ring is
not possible from the high-resolution nmr; however, a
doublet of doublets (J=11.9 and 5.2 Hz) at 62.83
suggests a beta-epoxide orientation, as in 6}. Compound
6; is a potentially useful intermediate which may lead
both to the formation of azgé double bond and epimerization

at C-5.

 

 

In subsequent elaboration of ring A functionality, a
conversionof'the enedione moiety to a BBLOH and
introduction of a 0-3 gem-dimethyl system are necessary.

There are Similar transformations of this type in the

50

31,32,33

literature,

and the most attractive of these is

that used by Woodward in his cholesterol synthesis,

illustrated below:

0 H
lAH a
Mao
O H

.152é2_€> IZn

 

PY O /
OAc

51

C. Selective Catalysis of DielS-Alder Reactions
of 2-methoxy:5-methyl-1L3-benzoquinoneuu

The DielS-Alder reaction has been used extensively

16 Because of its

for the formation of six-membered rings.
directness, it is frequently one of the most important
steps in the synthesis of fused ring structures, including
many natural products. Many dienophiles have been used
effectively in these reactions, but derivatives of p-
benzoquinone offer Special interest and advantage because

of their high degree of functionalization. This is

convincingly demonstrated by reported syntheses of
18,31 33 A5

36

steroids, gibberellic acid, dendrobine,

reserpine and trichodermol,47 excerpts from which are
shown in Schemes I—VI.

One advantage to using quinone dienophiles in total
synthesis is the stereoSpecific construction of a cis
configuration in the newly formed ring junction. When
a trans ring-fusion is required, a subsequent epimerization
can be carried out because of the adjacent carbonyl

functions (Schemes I and V). Furthermore, the quinone

moiety is highly functionalized and can be elaborated in

Scheme I.LL

 

Dendrobium (1973)

36

Scheme IV.

 

 

Scheme VI.

 

Trichodermol (1980)

53

many ways (Schemes I-VI). In Schemes I, II and III, the
quinone ring remains intact throughout the entire reaction
sequence and becomes part of the target molecule.
Woodward's reserpine synthesis (Scheme IV) provides an
interesting example in which the quinone ring first served
as a handle for stereochemical control of Sites on the
neighboring cyclohexane ring, following which it was
cleaved and eventually became part of a piperidine ring.
The formation of a five-membered carbocyclic system from
the quinone ring can be effected by the strategies shown
in Valenta's steroid (Scheme V) and Still's trichodermol
(Scheme VI) syntheses. It is also interesting to note
that in Kende's dendrobine synthesis (Scheme III), Six of
the seven asymmetric centers are precisely created on a
cyclohexane ring which is derived from the starting
quinone.

When substituted p-benzoquinones serve as dienophilies
with unsymmetrical dienes, four regio-isomers are possible.
As shown in Figure 8a, the diene can approach from Side A
or B to give two isomeric adducts. Furthermore, two
different diene orientations, C and D, are possible at

each side as shown in Figure 8b.

RI
\ R2
/ R
4
B
O L
“’0'“
R8 R6
0
a

55

R1
\R2
/R

4
/
\/f'

tr.”

Figure 8. Different approaches of diene to a p-
benzoquinone.

Several important directing effects concerning p-

benzoquinone Diels-Alder reactions have been noted in the

literature:

a) Electron donating substituents on the quinone

deactivate the double bond to which they are

attached (OCH3>CH3>H>COOR). Examples are

shown in equations 1, 2 and 5-7.

b) Substituents on the dienophilic double bond

usually direct addition reactions with

 

R R=H 65%
R=CH3 61%
R=H 6Q%
R=CH3 95%
R=H (major)

R= CHZOAC 80%
R: COOCH3 55%

85%

R: CH3 85%

R: CH OAC 85%

2

R=H , CH3 60%

(no isomer)

 

 

"‘ O :
MeO + OA‘ 307:0“c 30%

). complex product

 

 

E=COOMe 0 Z-Meo 70%

3-Me0 83%

58

1-Substituted dienes to give ortho adducts
(Equations 3 and 3) and additions with 2-
substituted dienes to the para adducts.55

c) A remote methoxy substituent exerts a strong

influence on the orientation of addition
reactions at the double bond on the other Side
of the quinone (Equation 5).

As shown in equation 5, the predominate adduct from
reaction of methoxy 1,3-benzoquinone with 1-Substituted
dienes is that in which the diene substituent is adjacent
to the ketone-like carbonyl group. The same orientation
was observed in the reaction of 2-methoxy-6—methyl-p-
benzoquinone 52 with dienes 63 and 65 (Equation 6). It
should be noted that in these cases directing effect (b)
acts in concert with effect (c) to give the observed ortho
adduct. However in 2-methoxy-5-methyl-p—benzoquinone 55,
directing effects (b) and (c) are opposed to each other,
and the observed selectivities in these reactions are
found to be very poor (Equation 7). This lack of
Specificity can be tipped in favor of the ortho adduct by
replacing the 1-alkyl substituent on the diene with an
electron withdrawing group (e.g. COOCHB), as Shown in
Equation 8, or in favor of the meta adduct by replacement
with an electron donating group (e.g. OCH3 in Equation 9).
In fact, the influence of the methoxy substituent on the
orientation of cycloaddition reactions seems to be

negligable if a strong electron withdrawing group (e.g.

59

COOCHB) is located on the reactive double bond of the
quinone. Examples are shown in Equation 10.

In the course of studies toward a total synthesis of
tetracyclic triterpenes, efforts were made to attach a
potential AB ring fragment to CD moiety 5} via a Diels-
Alder reaction (see Part B in this dissertation). As
suggested by the previous work, quinone 55 was observed
to undergo thermal cycloaddition with the bicyclic diene
23 to give a 2:1 mixture of adducts 56 and 53 in
approximately a 33% isolated yield. In contrast, 21
reacted with quinone 52 under similar conditions to afford

53 as the only detectable adduct in over 55% yield.

 

 

 

60

The poor regioselectivity of DielS-Alder reactions of
55 with diene 51 can be changed to favor either isomeric
adduct by using appropriate Lewis acid catalysts. Thus
mixtures of the two regioisomers 56 and 52 were obtained
from aluminum chloride catalyzed reactions of 51 and 55 at
-78°C. The composition of these mixtures varied as the
amount of aluminum chloride catalyst was changed. In
general, when a 1:2 ratio of AlClB: quinone was used, 56
was the favored adduct. As the amount of catalyst
increased, adduct 52 was found to be enriched. In the case
of a 2:1 ratio of catalyst: quinone, adduct 52 was the
major component in a 5:1 mixture with the other isomer

(Table 1).

Table 1. Aluminum chloride catalyzed DielS—Alder
reactionsof 55 with 51.

 

product ratio

A1013 Quinone 55 56:52

 

 

 

0.3 1 2:1
0.8 1 3:2
1.2 1 1:2

 

2.0 1 1:5

 

 

 

 

 

61

A dramatic improvement in selectivity was observed
when stannic chloride and boron trifluoride were used as
catalysts. For example, reaction of 51 and 55 in methylene
chloride solution at 0°C with stannic chloride as a
catalyst (1:1 catalyst:quinone), yielded adduct 52 in over
75% yield. None of the known regio- or stereo-isomers of
5] was detected in this reaction by pmr analysis. On the
other hand, the correSponding boron trifluoride catalyzed
reaction at -16°C gave a 50-55% isolated yield of 56,
contaminated by no more than 10% of 52.

These studies were then extended to Similar reactions
of 55 with piperylene and isoprene. Thermal cycloaddition
reactions of quinone 55 to piperylene and isoprene were
generally found to give a mixture of two regioisomeric
adducts in about 1:1 ratio. In contrast, stannic chloride
catalysis of reactions of 55 with piperylene and isoprene
gave mainly the meta adducts (66 and 69 reSpectively),
while the boron trifluoride catalyzed reactions favored
the ortho/para adducts (6] and 66). The results are shown
in Tables 2 and 3.

62

 

66, R4=CH3: R2’3’1=H
63, R1=CH3: R4'2'3=H
@g, R3=CH3: R1'2'4=H
63, R2=CH3: R1'3'“=H

Table 2. Diels-Alder Reactions of 55 with
Piperylene

Thermal(1000) Sn014(-16°) BF3(-16°)

 

66 1:1 1:20 3:1

)

Ratio 6

~

 

 

 

 

 

Yield (% 80 85 85

 

Table 3. DielS-Alder Reactions offi55with Isoprene

Thermal(1000) SnClu(-16O) BF3(0°)

 

Ratio 66:62 1:1 1:20 2.3:1

 

Yield (%) 70 80 70

 

 

 

 

 

In the stannic chloride catalyzed piperylene Diels-
Alder reaction, the meta adduct 66 was isolated as a solid
(mp 70—730) with a pmr Spectrum identical to that reported
by Bohlmann and coworkers};9 The meta orientation was
clearly indicated by the presence of a one proton doublet

at 6 2.99 (J=5.5 Hz) in the pmr Spectrum. This doublet is

63

assigned to the bridgehead hydrogen which is split by the
adjacent methine hydrogen. Mixtures of isomers 66 and 62
are difficult to separate, and are best analyzed by a
combination of gas chromatogrophy, 1H pmr and 13C nmr. A
pure sample of 62 was not obtained. However, when the
mixture of 66 and 62 was left standing at room temperature
for several days, a new compound Slowly crystallized. This
isomeric material was then identified as 29, an enol form
of 62. A possible regio isomer 2; was excluded, based on
the pmr Signals of the double-allylic protons HC and Hb at
62.76 and 63.30 reSpectively, and a quintet from the
allylic proton Hf, appearing at higher field ( 62.59).

The presence of a hydroxyl group was clearly indicated by
its facile exchange with D20, and infrared Spectroscopy
(ng 3300 cm'l). An absorption at Amax330 nm (ethanol)
(16:3300) in the UV is consistent with the presence of a
dienone moiety. The assignment of structure 29 was
confirmed by a series of decoupling experiments. This
unusual tautomerization, 62+>Z9, which has not been
observed in any of the other similar cases, may be due to

interaction between the methyl groups.

 

63

Our assignment of 62 as the major component of the
boron trifluoride catalyzed piperylene Diels-Alder reaction
is based primarily on its conversion to enol 29.

The assignments of the isoprene Diels-Alder adducts 66
and 69 are not obvious from Spectroscopy, because of their
structural Similarity. However, 69 isolated from the
stannic chloride catalyzed reaction proved to be a solid
having an identical melting point (116-118°) to that
56

reported by Ayer and coworkers. These workers claim that
the thermal cycloaddition of isoprene with 55 gives pure
69, in contradiction to the findings reported here, as well

as an unpublished study by W. S. Knowles.57a

The product
obtained by Ayer et. al. was well-characterized by their
degradative work, and this is the basis for our structure
assignment. A possible explaination for their
contradictory result is that a metal ion catalyst may
inadvertently have been incorporated in their experiments.
In such an event 69 might well be the only product
isolated, as in the stannic chloride catalyzed reaction
reported here. One possible source for such metal ion
contamination may be the preparation of quinone 55 by the
method of Ashley,38 which gives a product containing zinc

salts that are difficult to removefn‘

The major component
68 from the boron trifluoride catalyzed reaction of 55
and isoprene was isolated via recrystallization from an
ethyl acetate: pet ether solution. The melting point of

é§ (87-890) agrees well with that reported by Woodward.57b

65

It is well known that Lewis acid catalysts have a
profound influence on the rate of Diels-Alder reactions.58
However, the fact that they can change the regio chemistry
of these reactions was not known until the work of E.
Valenta and coworkers18 appreared in 1972. Valenta
reported an efficient regio-reversal in reactions of 2,6-
dimethyl-p-benzoquinone £3 with various dienes in the
presence of Lewis acid catalysts. The exclusive formation
of the "abnormal" (non-thermal) isomer was rationalized

by a Specific coordination of the Lewis acid with one of
the carbonyl groups of 13 to give a reactive quinone-Lewis
acid complex. The complexed quinone is assumed to have a
different electronic distribution than the uncomplexed
quinone, and this is believed to be reSponsible for the

659

orientation reversal effect (Figure 9

O

/ ‘\~ g
\\ ‘~“:lll||[/
o’ '

O\LA
1:!

Figure 9. The prOposed quinone-Lewis acid.complex and
its regio-reversal addition to a
substituted diene.

66

The present studies of 2-methoxy-5-methyl—p-
benzoquinone 55 provide more evidence for a selective
complexation of Lewis acids with unsymmetrical quinones.
The aluminum chloride-catalyzed eXperiments Show that the
regioselectivity is dependent upon the amount of Lewis
acid used. A possible explaination assumes that both
bis- and mono-complexs were formed between 55 and aluminum
chloride. When two equivalents of aluminum chloride were
used, the bis-complexed Species I predominates and the
activation at C-5 dominates the directing effects, thus

giving the meta-oriented adduct.

LA
‘0
I

5

MeQ
o

I

LA"

I

When a 1:1 ratio of quinone: Lewis acid was used,
selective complexation may occur. There are two types of
mono-complexation that should enhance Diels-Alder reactions.
First, the Lewis acid may complex at the C-1 carbonyl
group, in which case stabilization by chelation would be
possible, as shown in II. Second, the Lewis acid may

complex to the more basic ester-like C-3 carbonyl group

67

as in III. Complexes in which the Lewis acid moiety is
syn to the dienophilic double bond are not considered
because of their steric hinderance to the Diels-Alder

reaction.

In those reactions using one equivalent of boron
trifluoride or aluminum chloride catalysts, the type III
complex will be favored because of the poor chelating
ability of boron and aluminum. The activation of 0-6
in these complexes accounts for the formation of ortho-
or para- cycloadducts in the Diels-Alder reactions. On
the other hand, catalysts that have strong chelating
tendencies (e.g., stannic chloride and titanium chlorideéo)
tend to form type II complexes, which activate C-5.
Consequently, the meta-oriented cycloadducts will be

favored.

EXPERIMENTAL

General

Except as indicated, all reactions were conducted
under dry nitrogen or argon, using solvent purified by
distillation from suitable drying agents. Magnetic
stirring devices were used for most small scale reactions;
larger reactions were agitated by paddle stirrers. Organic
extracts were always dried over anhydrous sodium sulfate
or anhydrous magnesium sulfate before being concentrated or
distilled under reduced pressure. The progress of most
reactions was followed by thin layer chromatography (TLC)
and/or gas liquid phase chromatography (GLPC). Visualiza-
tion of the thin layer chromatograms was effected by Spray
reagents such as 5% p-anisaldehyde in ethanol and 30%
sulfuric acid with subsequent heating.

Analysis by GLPC was conducted with A-90-P3 or 1200
Varian-Aerograph instruments. Preparative layer chroma—
tography was carried out on 2 mm Silica gel F-253 adsorbent
on 20 X 20 cm glass plates. Visualization of the prepara-
tive plates was effected by ultraviolet light and/or
charring with a hot wire. Melting points were determined
on either a Hoover-Thomas apparatus (capillary tube) or
on a Reichert hot-stage microscope and are uncorrected.

Infrared Spectra (IR) were recorded on a Perkin-Elmer 237B

68

69

grating Spectrophotometer. Proton magnetic resonance
Spectra (PMR) were taken in deuterochloroform or CCln
solutions with either a Varian T-60, a Bruker 180 MHz or
a Bruker 250 MHz Spectrometer and are calibrated in parts
per million (8) downfield from tetramethylsilane as an
internal standard. Ultraviolet Spectra (UV) were recorded
on a Unicam SP-800 SpectrOphotometer. Mass Spectra (MS)
were obtained with either a Hitachi RMU 6 mass Spectrometer
or a Finnigan 3,000 GC/MS Spectrometer. Carbon magnetic
resonance Spectra (CMR) were taken in deuterochloroform
solution with a Varian CFT-20 Spectrometer and are cali-
brated in parts per million (6) downfield from tetramethyl-
silane as an internal standard.

Microanalyses were performed by Spang Microanalytical
Labs, Ann Arbor, Michigan, and Guelph Chemical Laboratories

Ltd., Guelph, Ontario, Canada.

70

 

Preparation of Bis-tosylhydrazone 29 and mono-
tosylhydrazone 29.

In a 50-mL flask, tosylhydrazine, 0.733 g (0.003 mol),
was dissolved in a minimum amount of ethanol containing 2
drops of concentrated HCl on steam bath. After the mixture
was cooled to room temperature, the diketone‘6,(0.18 g,
0.001 mol) was added in one portion. The reaction mixture
was then refluxed for 3 h. After cooling in the refrige—
rator, the white fine precipitate was filtered, giving
0.33 g (66%) of the bis-adduct 29, which displayed the
following properties: mp 233-235°C (dec): IR (Nujol) 3200,

1

1590, 1160 cm- : PMR (CF COOH) 6 0.85-O.9 (2s, 6H), 2.02

3
(s, 6H) 1.2-3.2 (m, 12H), 6.8-7.3 (q, 8H): MS (70 eV) (rel
intensity) m/e CI. 517 (M+1) (3). 361 (9). 343 (8). 173

(13). 157 (100). 139 (36). 93 (25)-

If 1.2 equiv of tosylhydrazine was used, the mono-
adduct 29 was obtained in 78% yield: mp 180-182°C: IR

(Nujol) 3180, 1730, 1610, 1590, 1160 cm"1

: PMR (00013) 180
MHz, 60.7 (S, 3H), 1.0 (s, 3H), 2.3 (S, 3H), 1.3-2.3 (m,
10H), 6.8-7.9 (m, 5H); MS (70 eV) (rel intensity) m/e 338
(3). 193 (36). 163 (25). 135 (20), 122 (100). 107 (25).

93 (9).

Preparation of bissilyl ether 22 and monosilyl ether 23.

A solution of LDA was prepared by reacting 0.61 mL
(3.3 mmol) of diisopropylamine in 10 mL of dry THF with
1.73 mL of 2.32 M n—butyllithium in hexane for 20 min at

71

-78°C. To this was added a solution of 0.36 g (2 mmol) of
dione 6,in 10 mL of THF, and the resulting cloudy mixture
was warmed to 0°C following the addition of 0.5 mL of HMPA
(hexamethylphoSphoric triamide). After this enolate
solution was quenched with tert~butyldimethylchlorosilane
(0.63 g in 5 mL of THF), the resulting mixture was warmed
to room temperature and worked up by addition to ice water
and extraction with ether. The combined ether extracts were
washed and dried before removal of the solvent. The
resulting yellow oil was purified by distillation (110°C,
10"3 torr), yielding 0.69 g (85%) of a low-melting solid.
Analysis of this product by GLC (3% QF-l, 180°C) and TLC
showed it to be chiefly the his adduct 22, containing ca.
2% of the mono adduct 23. A sample of 22 obtained by GLC
(5% PDEAS, 16000) had the following properties: mp 57—590C:
IR (0014) 1635 and 1620 cm‘1; PMR (0014) 6 0.15 (s, 12H),
0.9 (br s, 21H), 1.15 (s, 3H), 1.2-2.6 (m, 6H), 3.2 (m, 2H);
MS (70 eV), m/e (rel intensity) 308 (12), 393 (11). 351 (6),
277 (11). 75 (35). 73 (100). 69 (30). 61 (33).

52%;: Calcd for CZ3H3302812‘ C, 67.56: H, 10.87

Found: C, 67.58: H, 10.73

A sample of 23 was also obtained by GLC and diSplayed
the following properties: IR (CClu) 1720, 1620 cm-1: PMR
(001“) 6 0.15 (s, 6H), 0.9 (s, 12H), 1.3 (s, 3H), 1.3-2.8
(m, 8H), 3.2-3.3 (m, 1H): MS (70 eV), m/e (rel intensity)

293 (30). 279 (15). 251 (5). 237 (12). 223 (16). 75 (100).

72

73 (90)-

Preparation of monosilyl ether 23.

To a solution of LDA (1.1 mmol) in 10 mL of THF at
-78°C was added a solution of 180 mg of’6 (1.0 mmol) in
10 mL of THF. The resulting mixture was stirred for 20
min, warmed to 0°C (the enolate salt precipitates), and
then combined with 3 mL of HMPA to give a clear light-
yellow solution. This enolate solution was quenched at
0°C by addition of 0.233 g of tert-butyldimethylchlorosilane
(1.5 mmol) in 5 mL of THF. In a second experiment, the
enolate solution was refluxed for 3 h prior to quenching,
and the results were the same. Workup of the reaction
mixture by the previously described procedure gave, after
distillation (100°C, 10'3 torr), 0.278 g of a colorless
solid (95%) which proved to be 23 contaminated with ca.
1% 23. A sample of 23 obtained by GLC (5% PDEAS, 160°C)
had the following properties: mp 58-60°C: IR (CClu) 1730,

1635 om"1

:PMR (CClu) 60.15 (s, 6H), 0.9-1.1
(overlapping S, 15H), 1.2—1.5 (m, 8H), 3.3 (t, 1H): MS
(70 eV), m/e (rel intensity) 293 (26), 270 (20), 237 (38),
135 (37). 75 (100). 73 (78). 60 (53).
Aflél- Calcd for Cl7H3OOZSi: C, 69.32; H, 10.29
Found: C, 69.28; H, 10.27

73

Preparation of enedione 22.
(a) via Se02 reaction:

A solution of 0.18 g (0.001 m) of dione Q, 0.33 g (3
mmol) of selenium dioxide in 15 mL of t-BuOH and 1 mL of
glacial acetic acid was heated under reflux in an
atomOSphere of nitrogen for about 20 h. The resulting
mixture was then cooled, diluted with ether which was then
washed with water, brine and dried. Removal of the solvent
gave a yellowish oil which was distilled by Kugelrohr (50°C,
5 microns) afforded the enedione 22 (32 mg, 18%) as a
yellowish solid: mp lol-102°C; IR (00013) 3120, 2950, 1745,
1680, 1605 cm'1; PMR (00013) 6 1.1 (s, 3H), 1.2 (s, 3H),
1.3-2.7 (m, 6H), 5.7-6.1 (m, 1H), 6.5-6.9 (m, 1H): MS (70
eV) m/e (rel intensity) 178 (53), 163 (18), 150 (30), 123
(56), 68 (100).

Anal. Calcd for CllH1302: C, 73.13: H, 7.92

Found: C, 73.02; H, 7.86

(b) via enolate reaction:

To a monoenolate solution of the diketone 6,(0.18 g,
1 mmol) prepared as described before, was added a solution
of 0.327 g (1.5 mmol) of diphenyl disulfide in 5 mL of THF
at 0°C. The reaction mixture was stirred 30 min at this
temperature, followed by 3 h at room temperature. The
reaction was quenched by adding water dropwise at 000, and
the aqueous layer was extracted with ether. The combined

ether layer was washed with water, brine, and dried. The

73

crude product from the above step was oxidized overnight
by 0.53 g (1.5 mmol) of sodium periodate in 15 mL aqueous
methanol. The precipitate formed was filtered and washed
with ether. Solvents in the combined filtrate and washes
were removed under reduced pressure and the resulting oil
was dissolved in ether and washed with water, brine and
dried. The crude product obtained by removal of the
solvent was refluxed for 3 h in 25 mL toluene containing
0.11 g (1.3 mmol) of anhydrous sodium bicarbonate. The
oil obtained in usual was purified percolation through

25 g of silica (first eluted with pet ether, followed by
ether). Removal of the solvent, gave 0.15 g of a residue
which contained both the starting diketone‘é'and the
desired unsaturated ketone 22 with a ratio of 2:3 based
on GLC and NMR Spectral analyses. The yield of the

unsaturated ketone 27 was not optimized.

Preparation of benzylidene adduct 28.

A mixture of 0.18 g §,(1 mmol), 0.3 g of benzaldehyde
(2.5 mmol), and 30 mg of sodium hydroxide in 20 mL of 1:1
water-ethanol was refluxed for 30 h. The cooled reaction
mixture was filtered and the solid product washed with
aqueous ethanol. Recrystallization of the crude product
from ethyl acetate/pet ether gave 0.3 g (85%) of 28: mp
163-166°C; IR (CClu) 1720, 1695, 1630, and 1595 cm’l; PMR
(CDCl3) 61.2 (br 8, 6H), 1.3-3.6 (m, 6H), 7.2-7.5 (m, 12H);

MS (70 eV), m/e (rel intensity) 356 (30), 331 (31), 313

75

(36). 226 (70). 199 (100). 116 (97)-

Anal. Calcd for C C, 83.23; H, 6.79

25H2402‘
Found: C, 83.33; H, 6.87

Preparation of benzylidene adducts 28 and 22.

A mixture of 0.133 g of é,(0.8 mmol), 96 mg of
benzaldehyde (0.9 mmol), and 36 mg of sodium hydroxide in
25 mL of 2:3 water-glyme was refluxed for 35 h (the
reaction mixture remains homogeneous throughout). After
it was cooled, the reaction mixture was neutralized with
aqueous hydrochloric acid and concentrated under reduced
pressure. This concentrate was dissolved in a mixture of
water and ether, and the aqueous portion was extracted with
additional ether. The combined organic extracts were
washed and dried in the usual fashion. Evaporation of the
solvent gave a product mixture which was separated by
preparative TLC (silica gel, 30% ethyl acetate/cyclohexane).

The R =0.3 band yielded 58 mg (36% based on benzaldehyde)

f

of 28. A band at R =0.28 yielded 87 mg (36%) of mono

f
adduct 29, and a weak band at Rf=0.17 proved to be 26 mg
- of recovered‘é. Compound 22 exhibited the following

properties: mp 126-129°C; IR (00013) 1715 and 1630 om'1:
PMR (CDClB) 60.95 (S, 3H), 1.15 (s, 3H), 1.3-3.3 (m, 8H),
7.0-7.5 (m, 6H); MS (70 eV), m/e (rel intensity) 268 (35),
253 (12), 116 (100), 115 (35); Dmaxmtom 29L» nm (6:

25,000).

76

Anal. Calcd for °18H20°2: C, 80.56; H, 7.51
Found: C, 80.63; H, 7.53

In a parallel experiment, a mixture of 90 mg of‘é (0.5
mmol), 213 mg of 28 (0.6 mmol), and 36 mg of sodium
hydroxide in 25 mL of 2:3 water-glyme was refluxed for 32
h. Workup and separation as before gave 110 mg of 2§ (0.3
mmol), 101 mg of 29 (0.3 mmol), and 20 mg of 6.

Prepgration of cisoid diene 31.

The alcohol 32, 1.25 g (6 mmol), was dissolved in a
solution of 12 mL of dry THF and 38 mL of benzene in room
temperature. While stirring, 1 mL of boron trifluoride
etherate was added via syringe. The solution was stirred
and heated at reflux (bath temperature 90-9500) for about
20 h. The solution was then cooled and diluted with ether
and ice-cold water. The ether layer was washed sequentially
with 10% NaOH solution, water, and brine, and then dried.
Removal of the solvent, gave an oil residue which was
purified by Kugelrohr distillation (120°C, 35 microns, the
receiver was cooled at ice bath during distillation). The
colorless low melting solid 31 (0.86-0.97 g) was obtained
in 75-80% yield. This material showed the following
properties: IR (0014) 2950, 1750, 1665, 1625 om‘lgiimax
(EtOH) 235 nm (6:11.900) (Calcd. 223 nm); PMR (001“)

60.9 (s, 3H), 1.0 (s, 3H), 1.1-2.6 (m, 8H), 3.6-3.8 (d,
1H, J=11 Hz), 3.9-5.2 (d, 1H, J=17 Hz), 5.3 (t, 1H, J=3
Hz), 5.7-6.3 (dd, 1H, J=17, 11 Hz); MS (70 ev) m/e (rel

77

intensity) 190 (79): 175 (38). 133 (100). 119 (85). 105
(62). 91 (73). 79 (39).
Anal. Calcd for C13H18°‘ m/e 190.1358
Found: m/e 190.1335

Preparation of transoid diene 35.

A catalytic amount of iodine was added to a solution
of 1.03 g (5 mmol) of the enol 32 in 50 mL of p-xylene, and
this solution was refluxed for 3-3 days. The reaction
mixture was cooled to room temperature and washed
sequentially with 0.5 M sodium thiosulfate, water brine
and then dried. Evaporation of the solvent gave a colored
oily residue which was then eluted with ether through a
short column of silica gel and charcoal. The solvent was
again removed and the residue purified by Kugelrohr
distillation (60°C, 10 microns). The distillate crystallized
as a white solid, 0.89 g (93%), which displayed the
following pr0perties: mp 67-71°C: UV (95% ethanol) 235
nm (calcd. 235 nm): IR (0014) 3010, 1730, 1675 om‘l; PMR
(CD013) 60.75 (s, 3H), 0.85 (s, 3H), 1.6-1.8 (d, 3H,
J=5.88 Hz) 1.8-2.5 (m, 6H), 5.0-5.3 (q, 1H, J=5.88 Hz),
5.5-5.7 (m, 1H), 6.0-6.3 (m, 1H): MS m/e (rel intensity),
190 (43). 175 (16). 157 (8). 147 (10). 133 (37). 119 (100).
105 (28).

Anal. Calcd for °13H18° : C, 82.06; H, 9.53

Found: C, 82.22; H, 9.70

Preparation of nonconjugated diketone 33.

A solution of 75.93% m-chloroperbenzoic acid (1.05 g,
3.6 mmol) in methylene chloride (30 mL) was slowly added to
a solution of diene 3} (0.865 g, 3.5 mmol) in methylene
chloride (10 mL). The addition was carried out at room
temperature with constant stirring for about 23 h. Boron
trifluoride etherate (about 1 mL) was added and the reaction
mixture was then stirred for another two h. The reaction
mixture was diluted with methylene chloride, and then
washed with 20% sodium bisulfite solution, 10% sodium
bicarbonate solution and brine. After removal of the
solvent from the dried organic layer, 0.885 g (93%) of
crude reaction adduct was obtained. The crude material
was purified by preparative TLC (20 % ethyl acetate/
cyclohexane) to give 33vflflxflldi8played the following
properties: mp 75-77°C: IR (C014) 2950, 1735, 1700, 1680

om‘l, PMR (00013) a 0.8 (s, 3H), 1.1 (s, 3H), 2.3 (s, 3H),

1.0-2.8 (m, 6H), 3.2-3.3 (m, 1H), 5.7-5.8 (s, 2H): MS (70
eV) m/e (rel intensity) 206 (32), 163 (30), 163 (35), 149
(37). 136 (73). 131 (100). 119 (71). 93 (52). 91 (88)-
Ag§;. Calcd for 013H1802: c, 75.69: H, 8.80
Found: c, 75.78: H, 8.78

Isomerization of 33 to conjugated diketone 32.
The above crude nonconjugated ketone 33 was dissolved
in 20 mL of methanol in presence of 2 g of sodium hydroxide.

The reaction mixture was stirred at room temperature for

79

about 23 h. After neutralized with dil aqueous HCl
solution, methanol was removed in vacuo and the residue was
diluted with methylene chloride. The organic layer was
washed with dil sodium bicarbonate, water, brine and dried.
After removal of solvent, the oily residue was found
containing the isomerized conjugated ketone 3] (5:6.5 ppm,
t, 1H) and some unreacted material 33 in a 82:18 ratio as

evidenced from pmr Spectroscopy.

Preparation of benzothiazole adduct 39.

To a cold (-78°C) solution of 0.5 mL (1.2 mmol) of
2.32 M n-butyllithium (hexane solution) in 15 mL of dry
ether was added 0.135 g (1.2 mmol) of benzothiazole. After
20 min, a solution of 0.18 g (1.0 mmol) of‘é in 15 mL of
ether was added dropwise with stirring, and the reaction
mixture was then warmed to room temperature. Following a
1-h reaction period, the mixture was quenched with water
and extracted with ether. The combined ether extracts were
washed, dried, and condensed, yielding 0.22 g (70%) of the
adduct 39. Recrystallization from ether gave a pure sample:
mp 193-193.5°c: IR (CHClB) 3555, 3300, 2925 and 1725 om’l:
PMR (CDClB) 60.90 (S, 3H), 1.3 (S, 3H), 1.5-2.8 (m, 11H),
3.2 (s, 1H), 7.0-7.3 (m, 2H), 7.5-8.0 (m, 2H): MS (70 eV),
m/e (rel intensity) 315 (50), 300 (17), 203 (37), 178 (63),
139 (100), 136 (35).

gg§;. Calcd for C18H21NS0 : C, 68.53; H, 6.72; N, 3.33

2
Found: C, 68.67; H, 6.68; N, 3.33

80

Preparation of epoxide adduct 32.

To a solution of 0.36 g (2 mmol) of chloromethyl
phenyl sulfoxide in 15 mL of dry THF at -78°C was added
1.0 mL (2.3 mmol) of 2.32 M n-BuLi. After stirring for
35 min, the diketone‘é, 0.72 g (3 mmol) in 12 mL of THF,
was added via syringe, and the reaction mixture was allowed
to stir at this temperature for 30 min, then 1 h at -20°C.
After warming to room temperature, the reaction mixture
was quenched by adding saturated ammonium chloride solution.
The solution was extracted several times with ether. The
combined organic solution was washed with water, brine, and
dried. After removal of solvent, the residue was treated
with ether and placed in refrigerator. The colorless
epoxide 32 was then filtered off to give 0.335 g in 70%
yield: mp 131-133°C: IR (00013) 3050, 3000, 2950, 1730,

1580 cm"1

: PMR (00013) 180 MHz 6 1.09 (s, 3H), 1.11 (s, 3H),
1.3-2.6 (m, 10H), 3.58 (s, 1H), 7.3-7.7 (m. 5H): 130 NMR
(00013) 6 216.7, 131.9, 131.6, 129.5, 123.3, 72.9, 69.8,
52.9, 33.2, 32.6, 25.7, 23.9, 23.3, 22.0, 18.3, 17.7: MS
(70 eV) (rel intensity) m/e CI, 319 (M+1) (3), 193 (100),
175 (30). 165 (25). 137 (30). 133 (15).

Aflél- Calcd for C18H2203S: C, 67.88; H, 6.98

Found: C, 67.87; H, 6.97

Preparation ofaLB-unsaturated aldehyde 38.

A solution of epoxide 32 (0.318 g, 1 mmol) in 5 mL of

81

methylene chloride was evaporated onto 0.5 g of calcium
carbonate and the mixture was distilled by Kugelrohr
apparatus (150-160°C, 50 microns) to give 0.216 g of crude
distillate which was chromatographed on silica gel. The
crude material was eluted with pentane followed by 30%
ethyl acetate in hexane to furnish 0.132 g (69%) ofa,fi-
unsaturated aldehyde 32: IR (0014) 2950, 1750, 1695, 1625
cm‘l: PMR (celn) 00.83 (s, 3H), 0.88 (s, 3H), 1.0-2.7

(m, 8H), 6.3 (t, 1H), 8.9 (s, 1H): MS (70 eV) (rel
intensity) m/e 193 (15), 192 (100), 177 (25), 165 (10),
163 (18): 149 (22): 136 (30): 135 (60): 131 (35). 121 (70):
109 (75): 107 (83): 105 (30): 93 (68): 91 (70): 79 (63):
55 (50).

Preparation of allyl chloride 33.

A solution of 0.238 g (2 mmol) of thionyl chloride in
5 mL of carbon tetrachloride was added to a stirred solution
of 0.208 g (1 mmol) of the allyl alcohol 32 and 0.97 mL of
triethylamine in 10 mL of carbon tetrachloride at 0°C under
nitrogen. After refluxing for 3 h, the reaction mixture
was then cooled, diluted with water, and neutralized with
dilute hydrochloric acid. The neutral solution was
extracted twice with ether. The combined ether extracts
were washed with sodium bicarbonate solution, water and
brine. The dried solution was eluted through a Short column

which was packed with charcoal and Silica gel to remove the

82

impure colored materials. Evaporation of the solvent gave
0.193 g (86%) of the rearranged product 3; as a yellow-
brown oil, which diSplayed the following Spectral data:

IR (CClu) 2955, 1750, 1665 om‘l: PMR (CClu) o 0.8 (s, 3H),
1.0 (S, 3H), 1.0-2.8 (m, 10H), 3.8-3.1 (d, 2H), 5.1-5.5
(t, 1H): MS (70 eV, direct probe) m/e (rel intensity) 228
(10): 226 (28): 213 (9). 211 (23): 191 (50): 190 (53): 175
(32), 135 (88), 133 (81), 31 (100).

Preparation of maleic anhydride DielS-Alder adduct 38.

A solution consisting of 0.19 g (1 mmol) of diene 31,
0.185 g (2.5 mmol) of maleic anhydride and 10 mL of xylene
was refluxed for 23 h. The reaction mixture was then
concentrated, diluted with water, and extracted several
times with methylene chloride. The organic layer was then
washed with water, brine, and dried. It gave 0.3 g of
crude product on evaporation of the solvent. This crude
material was treated with ether to give 0.16 g (56-60%)
colorless solid which was further recrystallized from ethyl
acetate/petroleum ether to give colorless crystals 38: mp
221-222.5°c: IR (CD013) 2950, 1850, 1780, 1730, 1625 om‘l:
PMR (CD013) 250 MHz, 6 0.88 (S, 3H), 0.95 (s, 3H), 1.3-
1.82 (m, 10H), 2.80-2.90 (ddd, 1H, J=2.3, 8.8, 20 Hz),
3.32-3.38 (dd, 1H, J=12.5, 7.3 Hz), 3.33-3.52 (ddd, 1H,
J=2.3, 8.5, 12.5 Hz), 5.70-5.76 (dt, 1H, J=3.2, 8.8 Hz);
130 NMR (00013) 6 218.8, 173.2, 172.1, 138.9, 118.3, 51.5,
36.3, 33.5, 30.9, 33.0, 29.3, 23.9, 23.8, 23.7, 22.3,

83

18.7: MS (70 eV) m/e (rel intensity) 288 (10), 273 (19),
218 (8): 189 (8): 181 (18): 173 (11). 160 (9): 157 (25):

133 (20). 131 (37). 117 (35). 91 (100). 77 (33).

Anal. Calcd for Cl7H2003: C, 70.81: H, 6.99

Found: C, 70.57: H, 7.12

In a trapping experiment, a solution of allyl alcohol
32 (0.208 g, 1 mmol), p-toluenesulfonic acid (28 mg, 1.5
mmol) and excess of maleic anhydride (0.3 g, 3 mmol) in 30
mL of toluene was refluxed under nitrogen atomosphere.
Work-up as usual gave 0.12 g (35%) colorless solid 38 which
Showed the same properties as above.

Similar result was obtained from a reaction of allyl
chloride 3; and maleic anhydride in refluxing xylene

solution.

Preparation of diester adducts 39 ggg 32.

A solution of 0.323 g (0.0017 mmol) of diene 3} and
0.3 mL (3.1 mmol) of dimethyl acetylenedicarboxylate in
10 mL of benzene was refluxed under N2 for about 10 h.
After cooling to room temperature, the mixture was diluted
with ether and then washed with water, brine and dried.
After evaporation of the solvent, the resulting residue
was crystallized from ether/hexane to give 0.316 g (56%) as
an off-white solid 39 which gave the following properties;

IR (0014) 2920, 1760 (broad), 1660 cm“1

: PMR (CD013) 6'
100 (S: 3H): 1'1 (3! 3H): 103‘3-2 (m: 11H): 3-6‘3-7 (ZS:

6H), 5.5 (m, 1H); 130 NMR (00013) 6 218.2, 169.6, 166.1,

83

133.1, 132.6, 127.3, 118.1, 52.2, 51.0, 36.5, 35.5, 33.1,
30.7, 28.0, 27.1, 23.3, 23.7, 22.1: MS (70 eV) m/e (rel
intensity) 332 (3): 300 (67): 285 (37): 273 (36). 231 (50):
105 (82), 83 (100).

The above material was air oxidized to 32 during a
slow recrystallization from methylene chloride/cyclohexane
solution. Compound 32 diSplayed the following properties;
mp 123-5°C: IR (00013) 2950, 1730 (broad), 1595 om’l: PMR
(CD013) 250 MHz,.6 0.83 (S, 3H), 1.08 (S, 3H), 1.1-3.0
(m. 8H). 3.89 (8. 3H). 3.95 (8. 3H). 7.23-7-89 (AB quartet.
2H): MS (70 eV) m/e (rel intensity) 330 (1), 315 (2), 299
(26), 298 (100), 231 (38).

Anal. Calcd for C H2205: C, 69.08: H, 6.71

19
Found: C, 69.01: H, 6.75

Preparap;on ofp;benzoquinone Diels-Alder adduct 3}.

A solution of 0.216 g (2 mmol) of p-benzoquinone and
0.19 g (1 mmol) of diene 33 in 10 mL of xylene was refluxed
for about 20 h. The reaction mixture was added water and
then extracted with methylene chloride. The organic layer
was sequentially washed with water and brine and then dried.
After removal of the solvent, the residue was crystallized
from ethanol/pet ether to yield 0.132 g (33%) of light
yellow, crystalline 3}. An analytical sample of 31
diSplayed the following properties; mp 170-3°C: IR (CHClB)

1

1730, 1690, 1600 om‘ : PMR 180 MHz (00013) 6 1.05 (s, 3H),

85

1.2 (s, 3H), 2.3-3.3 (m, 13H), 5.2 (q, 1H , J=2.93 Hz),
6.39-6.56 (d of half of a AB quartet, 1H, J=1.22 Hz, 10.3
Hz), 6.59-6.65 (half of a AB quartet, 1H, J=10.3 Hz): 130
NMR (CD013) 6 219.2, 201.0, 198.9, 133.8, 131.0, 137.0,
115.6, 51.0, 50.3, 36.7, 35.3, 33.1, 30.6, 27.2, 26.3,
23.7, 23.7, 20.7: MS (70 eV) m/e (rel intensity) 298 (13),
282 (2). 265 (2): 255 (5). 189 (27). 161 (10). 135 (25):
131 (27). 123 (100). 105 (32). 91 (65). 77 (30).

Apgi. Calcd for C H 0 C, 76.39: H, 7.33

22 3’
Found: c, 76.58, H, 7.33

19

Prepgration of Digis-Alder adduct 33.

A solution of 0.57 g (3 mmol) of diene 33 and 0.912 g
(6 mmol) of 6-methoxy-2-methyl-benzoquinone 33 in 15 mL of
p-xylene was refluxed for 25 h. The solvent was then
removed in vacuo, and the crude yellow residue was stirred
in aqueous sodium bisulfite/methylene chloride solution.
The organic layer was then separated and the aqueous layer
was extracted with methylene chloride. The combined
organic layers were washed with water, brine and dried.
Removal of the solvent, gave a crude mixture which was found
to be mainly the adduct 33, with a small amount of 38 which
was formed by the contaimination of quinone 3; in the
starting dienophilic material. Pure sample of adduct 33
was obtained by the flash chromatographic column
separation (50 mm column diameter, packed with 30-63 um

Silica gel, using 50% ethyl acetate/pet ether as eluting

86

solvent). The fractions with Rf=0.20 were combined and
concentrated, giving 0.596 g (58%) of slight yellow solid
which was washed with ether to give 0.372 g (46%) of
colorless crystals; mp 227.5-230°c; IR (00013) 2950, 2875,

1735, 1715, 1670, 1650, 1601 cm‘1

; PMR (00013) 180 MHz 6
1.0 (s, 3H), 1.15 (s, 3H), 1.3 (s, 3H), 1.32-2.85 (m, 11H),
2.87-2.98 (ddd, 1H, J=10.5, 7.83, 1.37 Hz), 3.65 (s, 3H),
5.1 (q, 1H, J=2.93 Hz), 5.58 (d, 1H, J=1.37 Hz); 130 NMR
(00013) 6 219.3, 200.6, 196.5, 160.2, 133.3, 116.1, 107.2,
56.9, 56.5, 50.8, 50.7, 36.8, 32.1, 33.2, 30.8, 28.3, 25.6,
25.1, 23.6, 23.3, 17.8; MS (70 eV) m/s (rel intensity) CI
333 (M+1, 100), 325 (95), 315 (27), 307 (31); stereoscopic

views of 59 from X-ray crystallographic studies are shown

in page 38.

Preparation of Diel§:Alder adduct 56.

Quinone 55 (0.76 g, 5 mmol) was dissolved in 15 mL of
methylene chloride at 0°C. To this solution, 0.5 mL (3.5
mmol) of boron trifluoride etherate was added via syringe.
After stirring at this temperature for one h, the colored
solution was cooled to -16°C, and a solution of 0.57 g (3
mmol) of diene 31 in 15 mL of methylene chloride was slowly
introduced. After about four h stirring, water and
methylene chloride was added. The organic layer was washed
with saturated sodium bicarbonate solution, and then
condensed. The residue was stirred with aqueous sodium

bisulfite solution for one h. Methylene chloride was added

87

and the organic layer was then washed with water, brine,
and dried. Evaporation of the solvent in vacuo gave an off-
white solid which was triturated with ether and placed in
refrigerator. The white solid (562 mg, 55%) was filtered
and was identified to be mainly adduct 56 with small amount
of its isomer 52 (about 10:1 ratio). The minor adduct 53
can be removed by recrystallization from cyclohexane/
methylene chloride solution to furnish pure 56 which
diSplayed the following properties: mp 260-1°c: IR (CHClB)
2950, 1730, 1710, 1675, 1605 om‘l; PMR (00013) 180:MHz,5
1.01 (s, 3H), 1.15 (s, 3H), 1.39 (s, 3H), 1.40-2.8 (m, 11H),
2.94—3.04 (dd, 1H), 3.76 (s, 3H), 5.28-5.31 (q, 1H), 5.67
(s, 1H); MS (70 eV) m/e (rel intensity) CI 343 (M+1, 100),
325 (25). 315 (14). 285 (25). 189 (25). 181 (44). 171 (56).
167 (81), 153 (65): stereoscopic views of 56 from X-ray
crystallographic studies are shown in page 41.

Anal. Calcd for C21H2604: c, 73.66; H, 7.65

Found: C, 73.37: H, 7.70

Preparation of Diels-Alder adduct 57.

To a solution of 0.152 g (1 mmol) of quinone 55 in
8 mL of methylene chloride at 0°C was added 0.8 mL (0.8
mmol, 1 M solution in methylene chloride) of stannic
chloride, and this mixture was stirred for 1 h. A solution
of 0.114 g (0.6 mmol) of diene 31 in 9 mL of methylene
chloride was then added at 0°C. After stirring at this
temperature for about 1.5 h, the reaction mixture was

decomposed by the addition of 10 mL of water. After the

88

solution warmed up to room temperature, the organic layer
was separated and the aqueous layer was extracted with
methylene chloride. The combined organic extracts were
processed in the same manner as in the corresponding boron
trifluoride-catalyzed reaction giving 0.193 g of solid which
contained adduct 57 as the only detected Diels-Alder adduct.
This material was triturated in ether and the resulting
colorless solid was filtered,Recrystallization from
methylene chloride/ether gave 0.152 g (74%) of 53 which
displayed the following properties; mp 239.5-241.OOC; IR

(KBr) 2950, 1730, 1710, 1665, 1610 cm”1

: PMR (00013) a 1.05
(s, 3H), 1.2 (s, 3H), 1.5 (s, 3H), 1.6-3.0 (m, 13H), 3.7

(s, 3H), 5.2 (dd, 1H), 5.65 (s, 1H); 130 NMR (00013) .5
217.8, 201.3, 193.1, 161.8, 133.8, 115.5, 108.3, 56.3, 55.8,
51.0, 50.3, 36.8, 33.9, 33.2, 31.7, 30.6, 26.5, 25.0, 23.8,

21.3, 20.9. UV Dgax(Et0H) 268 nn5£=1.5 x 10“

3 MS (70 eV)
(rel intensity) m/e 332 (1), 327 (3), 313 (100), 299 (69),
281 (14). 105 (33). 91 (33). 69 (56).

Anal. Calcd for 021H2604: c, 73.66; H, 7.65

Found: C. 73-75: H. 7.75

Thermal reaction oquuinone 55 and diene 51.

A solution of 1.026 g (3 mmol) of diene 51 and 0.912
g (6 mmol) of quinone 55 in 15 mL of xylene was refluxed
for 26 h. The xylene was removed under reduced pressure
and the residue was treated with saturated aqueous sodium

bisulfite solution. The organic solution was then washed

89

with water, brine and dried. After removal of the solvent,
the residue was treated with ether. The resulting solid
was filtered to yield 0.35 g (34%) of two isomers 58 and

57 in a ratio of 2:1 as evidenced by pmr Spectroscopy.

Preparation of monoacetate 58.

A mixture of 0.1 g (0.29 mmol) of 58, 0.04 g (0.49
mmol) of sodium acetate, 5 mL of acetic anhydride, and 4
mL of benzene was refluxed for about 60 h. The solvent
was removed in vacuo, the residue was treated with methylene
chloride and was filtered. The filtrate was washed with
water, brine and dried. After removal of the solvent, a
brown oil was recovered which contained a mono acetate 58
and trace amount of starting material 58 as evidenced
from pmr Spectroscopy. This material was treated with
ether and the resulting white precipitate was filtered to
give 80 mg (71%) of 58. An analytical sample of 58
(recrystallized from ethyl acetate/pet ether) diSplayed
the following properties: mp 195-197°c; IR (00013) 2950,
1760, 1730, 1675, 1605 cm‘1; PMR (00013) 250 MHz, 6 0.97
(s, 3H), 1.26 (s, 3H), 1.50 (s, 3H), 2.26 (s, 3H), 1.6-3.1
(m, 11H). 3-75 (S. 3H). 5-43 (8, 1H). 5-56 (m. 1H): MS (70
eV) (rel intensity) m/e 385 (3), 384 (10), 343 (23), 342
(100). 327 (33). 309 (10). 207 (20). 181 (11). 167 (13).
166 (34).

Anal. Calcd for 0 H2805: m/e 384.1937
Found: m/e 384.1950

23

9O

(Epimerization of adduct 57 32.59.

A solution of 0.1 g (0.29 mmol) of 57 and 0.025 g
(0.25 mmol) of sodium bicarbonate in 7 mL of absolute
methanol was refluxed for 40 h. The solution was cooled
to room temperature and filtered. The filtrate was then
diluted with methylene chloride and washed with water,
brine and dried. After removal of the solvent, 0.08 g
(80%) of off-white solid was recovered. This material
contained a trace amount of starting material 57 and a
major product which is believed to be its epimer 59 as
evidenced from pmr Spectroscopy: (in CD013) 6 1.0 (s, 3H),
1.2 (s, 6H), 1.5-2.9 (m, 12H), 3.8 (s, 3H), 5.3 (m, 1H).
5.6 (S, 1H).

Epoxidation of adduct 58 :9 83.

To a solution of 0.12 g (0.35 mmol) of 58 in 5 mL of
methylene chloride at room temperature was added 0.092 g
(0.4 mmol, 75.52%) m-chloroperbenzoic acid in 5 mL of
methylene chloride. The reaction mixture was stirred for
24 h, and then sequentially washed with 10% sodium
bisulfite, dilute sodium bicarbonate, water and brine.

The organic layer was dried and the solvent was evaporated
to give an essentially pure solid in quantitative yield.
An analytical sample of 6} (recrystallized from methylene
chloride/cyclohexane) diSplayed the following properties:
mp 206-209°; IR (00013) 2950, 1730, 1720, 1675, 1605, and
1175 cm-1

3H). 1.35 (8. 3H). 1.4-2.8 (m. 13H). 3-65 (8. 3H). 5.6

; PMR (00013) 250 MHz, 6 1.03 (s, 3H), 1.07 (s,

91

(S, 1H); MS (70 eV) (rel intensity) m/e 358 (2), 340 (2),
325 (1). 167 (23). 84 (41). 69 (100). 55 (44).

Anal. Calcd for 021H26O C, 70.36; H, 7.32

5.
Found: C, 70.22; H, 7.32

Thermal reaction of quinone 55 and isoprene.

A solution of 0.56 g (3.7 mmol) of quinone 55 and 6.2
mL (62 mmol) of isoprene in 10 mL of benzene was heated at
90-1000 in a sealed tube for Six days. The solution was
then cooled to room temperature and the solvent was
evaporated in vacuo. Addition of pet ether to the resulting
oil gave 0.58 g (72%) of crude solid. This material was
found to be a mixture of adducts 88 and 83 (-1:1 ratio)

as analyzed by high resolution pmr and 13C nmr.

Thermalreacgion of quinone 55 and piperylene.

Quinone 55 (0.46 g, 3 mmol), piperylene (1 mL, mixture
of 50:50 cis:trans) and benzene (5 mL) were heated at 90—
1000 in a sealed tube for six days. Work-up as usual gave
0.532 g (81% yield) of mixed product 88 and 87 as evidenced
by high resolution pmr, 13c nmr and GLPC (3% SE-30 column).

Stannic chloride-catalyzed reaction ofgquinone 55 and

o N

lsoprene.
A solution 0.228 g (1.5 mm) of quinone 55 in 8 mL of

methylene chloride was stirred at 00 while 1.5 mL (1.5 mm)
of 1 M stannic chloride solution was added. The resulting
mixture was stirred for one h then cooled to -160

whereupon a solution of isoprene (0.5 mL, 5mm) in 8 mL of

92

methylene chloride was added. After stirring at -160 for
four h, the reaction mixture was decompored by the addition
of water. The organic layer was washed with dilute sodium
bicarbonate, sodium bisulfite solution, water and brine.
Crystallization of the condensed residue from pet ether
gave adduct 89 (0.205 g, 62%): mp (recrystallized from
ether/pet ether) 116-118o (lit. mp 115-118°).56
Stannicpghloride-catalyzed reaction of quinone 55 Egg
piperylene. 7“

Following the same reaction procedure as the
corresponding isoprene DielS-Alder reaction, the reaction
of piperylene (0.4 mL, excess, mixture of 50:50 cis:trans),
quinone 55 (0.228 g, 1.5 mmol) and stannic chloride (1.4
mL, 1 M) in methylene chloride solution gave 0.381 g of
crude oil. Recrystallization from ether/pet ether afforded
0.195 g of pure adduct 88 which diSplayed the following
properties: mp 70-730; IR, NMR, MS agree with literature

data.“9

Boron trifluoride-catalyzed reaction of_guinone 55 and
isoprene. “v

A solution of 0.456 g (3 mmol) of quinone 55 in 12 mL
of methylene chloride was stirred at 00 while 0.35 mL of
boron trifluoride etherate solution was added. The
resulting mixture was stirred at this temperature for one
h then a solution of is0prene (0.6 mL, 6 mm) in 6 mL of

methylene chloride was added slowly. After stirring at 00

93

for three hour, the reaction mixture was decomposed by the
addition of water. The organic layer was washed sequentially
with dilute sodium bicarbonate solution, sodium bisulfite
solution, water and brine. After drying, the solvent was
removed in vacuo to give quantitative amount of oil which
contained adduct 88 and 89 in approximately 2.4:1 ratio
based on 250 MHz nmr. This crude oil solidified on standing
at room temperature. The seperation of 88 and 82 was
achieved by recrystallization methods. The major adduct 88
was obtained by recrystallization from ether/pet ether
solution as a pure colorless solid which displayed the
following properties: mp 86-880; IR (CDClB) 1720, 1660 and

1610 cm-1

, PMR (00013) 250 MHz, 6 1.31 (s, 3H), 2.0 (s, 3H),
2.1-2.8 (m, 3H), 2.93 (t, 1H), 3.79 (s, 3H), 5.31 (m, 1H),
5.83 (s, 1H); MS (70 eV) (rel intensity) m/e 220 (5), 205
(6). 192 (72). 177 (100). 173 (19). 161 (8). 145 (20). 91
(37). 77 (21). 69 (72)-

Angl. Calcd for 017H1603: m/e 220.1099

Found: m/e 220.1090

The minor component, 83, was selectively crystallized
in pure from (mp 116-118°) in methylene chloride/cyclohexane.
Boron trifluoride-catalyzed reaction of quinone 55 Egg
piperylene. 7’

Quinone 55 (1.52 g, 0.01 mol, in 30 mL of methylene
chloride) and boron trifluoride etherate (1.2 mL, 10 mmol)
was complexed as described before. The reaction solution

was then cooled to -160 and a solution of piperylene (5 ml,

94

50 mmol, mixture of 50:50 cis:trans) in 10 mL of methylene
chloride was added. After stirring at -160 for 4 h, the
reaction was quenched by the addition of water. Work-up
as usual gave an orange colored oil which was purified via
Kugelrohr distillation (50 microns, 120°). The yellow oil
(1,982 g, 90%) obtained was found to be a mixture of
products 87 and 88 in a 4:1 ratio as evidenced by GLPC

(3% SE-3O column, 200°), GC/MS and high resolution pmr.
Attempts to separate the two isomers by preparative GLPC
(15% SE-30 column, 220°) and HPLC (neutral aluminum)
failed. However, when the mixture of 88 and 87 was left
standing at room temperature for several days, a new
compound Slowly crystallized. This material, 29, was then
isolated and displayed the following properties: mp 120-

123°c; IR (KBr) 3300, 1675, 1601 om"1

: PMR (00013) 250
MHz,So.71 (d, 3H), 1.30 (s, 3H), 2.59 (quintet, 1H), 2.76
(dt, 1H), 3.30 (ddd, 1H), 3.88 (s, 3H), 5.35 (s, 1H), 5.37
(s, 1H), 5.60 (dt, 1H). 5.65 (m, 1H); MS (70 eV) (rel
intensity) m/e 220 (100), 205 (38), 192 (29), 191 (28),
177 (43). 173 (32). 159 (26). 153 (38). 145 (36). 91 (79).

69 (90); UV Dmax(Et0H) 340 nm (6:3300) (Calcd.~350 nm).

APPENDIX

95

 

100

J
3

TRANSMITTANCE (%)
A o
O O

NNHTS ‘

 

n
o

TSNHN

 

 

 

4000 3500 3000 2500 : 2000 1500

mm (CAN)

TRANSMITTANCE(%)

 

2000 1800 1600 1400 1200 1000 800

F'FOUFhK‘Y (M ‘1

Figure 10. Infrared Spectrum of L9.

96

 

m
0

0
O

 

TRANSMITTANCE (72.)
#
O

 

M
o

 

 

 

 

 

 

0
4000 3500 3000“ 2500 2000 1500

"(QUINCY ( CM" )

 
   

TRANSMITTANCE(°/o)

      

0 V ,
2000 1800 1600 1400 1200 1000 800

FREQUENCY (CM ‘)

Figure 11. Infrared Spectrum of 83.

97

 

100

 

 

 

8
1
k
I
1
‘1
7..)

 

0
O

-—.---.‘
.-

 

TRANSMITTANCE (%)
n
o

3’
(1?-
+

M
O

35,,
g

 

 

 

0
4000 3500 3000 2500 2000 1500

momma (cu-I)

(%)

O
O

TRANSMITTANCE
A
O

20

     

2000 1800 1600 1400 1200 1000 800

‘REOUENCY (CM '1

Figure 12. Infrared Spectrum of 88.

98

100

 
  
  
  
  

:- o
C) c: 23

TRANSMITTANCE(%)

M
O

Jr'si-o

0
4000 3500 3000 2500 2000 1 500

FREQUENCY (CM ')

TRANSMITTANCE(%)

    

2000 1800 1600 1400 1200 1000 800

IIEOUEBK 1 tCM ‘\

Figure 13. Infrared Spectrum of 83.

 

«302412.525:

3000

3500

0

FREQUENCY (CM ')

 

1600 1400 1200 10 8

1800

FREQUENCY !CM '1

Infrared Spectrum of 24.

Figure 14.

100

 

100

80

 

 

0
O

b
O

 

TRANSMITTANCE (%) -

 

 

 

 

 

 

 

M
O

 

 

 

 

 

 

0
4000 3500 3000 2500 2000 1500

moumcv (cm)

on
O

......

(%fl

0
O

TRANSMITTANCE
5
o

20

 

o - : ' ; , i , .
2000 1 800 1 600 1400 1 200 1 000 800

FREQUfNCY 'CM '1

Figure 15. Infrared Spectrum of 87.

101

 

653025-335:

1500

0

25
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3000

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4000

 

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1600 1400 1200 1000
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Infrared Spectrum of 28.

Figure 16.

102

 

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1500

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3000 2500
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1400 1200 1000 800

1600

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Infrared Spectrum of 29.

Figure 17.

103

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

100
#fi'fi“. 1‘.- I
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Figure 18. Infrared Spectrum of 23.

 

Samuzfitingh

1500

800

2000

1000

25
rasoumcv (CM"1
1400 1200

3000

1600

3500

1800

 

4000

2000

MW . 0 0 0 0
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Infrared Spectrum of 34.

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F1

105

 

2500 2000 1500
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W 0
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Figure 20.

106

 

 

 

 

 

 

 

100
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4000 3500 3000 2500 2000 1500

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Figure 21. Infrared Spectrum of 38.

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100

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Figure 22. Infrared Spectrum OI 30.

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4000 3500 3000 2500 2000 1500

 
  

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Figure 23. Infrared spectrum of {+3.

109

 

 

 

 

 

 

 

 

 

 

 

 

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Figure 24. Infrared spectrum of fig.

110

100

 
 
 
 
 
 
 
 
 

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TRANSMITTANCE(%)

N
O

4000 3500 3000 2500 2000 1500

FREQUENCY (CM ')

TRANSMITTANCE(%)

 

1800 1600 1400 » 1200 1000 800

FIEOUENCV "CM '1

Figure 25. Infrared Spectrum of fig.

111

 

 

 

 

 

 

 

 

 

 

 

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Infrared Spectrum of 50.

Figure 26.

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N
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4000 3500 3000- 2500 2000 1500

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1800 1600 1400 1200 1000

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Figure 2?. Infrared Spectrum of 51.

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A

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2000

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Figure 28.

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4000 3500 3000 2500 2000 1500

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Figure 29. Infrared Spectrum of 21.

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Figure 30. Infrared spectrum of 56.

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4000 3500 3000 2500 2000 1500

maumcv (cu-u)

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2000 1500

4000 3500 3000 2500

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Figure 32 . Infrared spectrum of 53.

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1800 1600 1400 . 1200 1000 800

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Figure 33. Infrared Spectrum of i3.

119

 

 

 

 

 

 

 

 

 

 

 

 

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Infrared Spectrum of 70.

Figure 35.

 

 

 

 

 

 

 

 

 

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T ' ' ' ' l ' I r f! ' ' T ' '. ’
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Pmr Spectrum of £9.

 

 

 

 

 

 

 

 

2.37

Pmr Spectrum of 29.

 

 

 

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cm 01617 o

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

:00 ON m 200 IN 3":
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Figure 38. Pmr Spectrum of 22.
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500 000 300 700
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3 1
1 1 _
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L 1 1 1 1 1 . A 1 i 1 1 I A . 1 L
L A A 1 A A A A i A A A A I A J A A 1 l A A A 174A 1 LAL I J A A A 1 L . I 1 A A
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Figure 39. Pmr spectrum of 2;.

 

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A A I A A A A l A A A A I A AA A A I A A A A I A A A A I A A L A I A A AA A I A A A A L 4
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r' *‘I ' F
200 ‘m .“I

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Figure 41. Pmr Spectrum of 32.

v v

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._-_..._-

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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. 11_11i1 11,11111 11 11 11 .1 11 11 11 11 . .1 I1 11 11 11111 f1
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Figure #2. Pmr Spectrum of §§.
I i ' ' I r I * t r i 1 v ‘
:00 con .1; 7; KL | CI)":

 

 

 

 

 

 

 

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125

I
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20

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310

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126

 

 

 

 

 

 

 

 

 

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52- 5192

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128

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 51.

Pmr Spectrum of flé.

T ' V r I f l ' '
son a 3m 2!” i!” 2!“:
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3 l
c: “I
I
111. _J v _ _
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I0 70 so so m W no JO :0 vo 0
Figure 50. Pmr Spectrum of 45.
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m m m 200 Im 0H8
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Figure 62. Mass Spectrum of £2.
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RELATIVE INTENSITY

N

 

138

 

 

 

 

 

Ll ’ I - |I__C l ,I
in He no we 75 so Tho I]. IS. :7. 2.... JM: no A; no ’5‘:- oée 3:5 2.5: -,\~ m

Figure 67. Mass Spectrum of a2.

0

fl'

ALBUM i . ,1
.. w [:0 no no T 31’“

 

 

 

 

 

 

 

 

 

 

We

Figure 68. Mass Spectrum of 23.

139

 

I

my mm 1%

h

 

 

 

 

a a
L_____
E

”H

 

H

rhuaapuwmm

 

E

a

warm 1:. ram 1? (fl)
3‘ x

 

 

.
O
I.—
h
P
5.
*—

xlflibflpmnAFme

9°
C
v
i
I
H

Figure 69. Mass Spectrum of §§.

 

Mum MW” 1%

7‘1

5.

l 3 fl 1‘ 2‘

b

6

 

“Io.

REDTUE In TEVJTIY

 

.11 LL” ill“

60

1’40

 

 

 

 

 

Figure 70. Mass Spectrum of 29.

 

 

 

 

 

 

 

 

 

 

IM
30
6a
‘0
)0
l M I‘ll
C 172‘ 40 ' 60 "W mo [3.0 no 'tO [LB .aoo
’71).

Figure 71. Mass Spectrum of 2}.

b C

lawman r c v.)
'3

6:54.! lib

 

141

 

 

 

 

u/ n- 3. It .9 o. n {b n In II. no no N. 4;. (a "f, I“ .;a z. ‘. an. n. 1m u.
m a.

Figure 72. Mass Spectrum of 35.

 

‘1' Ink “5!»
8-
I
I
I
f
I

 

i:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

‘h '5." 8" "' ”3 - "to m I5“: 2..

. 8.
Figure 73. Mass spectrum of 2’

 

A
n

RELATIVE W51”
8

 

O

“E

3

EMU“ tum"
L

 

142

 

 

 

 

 

 

O

 

ILA.

a 5m $140

7%

Figure 74.

Mass Spectrum of i9.

1&3

 

 

 

    

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

13.3.31 193" - 117-338
' ll
1 :-
sa.o- I-
14701 l?5.l P
‘ 155.1 ’
. ”9'9 127133.1 ’
I 51.0 71.3 85-9 99-9 205.1 221.1 235.9
we so so 108 120 140 169 180 200 220 240
168.9- F'w'e" {mass
sata- '-
4 319.1 .
b
331.9
A 331.1128}: 1.. 31?:2
,1lfifi ,Irq,
me 250 233 390 320 340 360 333 409 420 448
° #2.
Figure 75. Mass Spectrum of A“
O
z
I 8
“9 Cl
gt.
a.
L-
p:
g“
‘2
5::
o if 4'6 to .50 I10 no I60 I50 loo ' no 240
We

Figure 76. Mass Spectrum of E3.

 

 

 

 

 

 

 

 

 

too.o~ 9‘
J
55
50.04
77
J
131
H?
I
I a i
;' . . "H
I: I? 7. iii 4 ’1;
it I I] I f: III
1 II? ”I '1 FI III II
J”: 1th I I L.Hl..!§lni iii. IMI
NE 50 1%

Figure 77.

14h

143

I

“I .‘i'él
' 150

 

 

181

173
189

218

Hm.

!=:
I .. ‘
”I? KIWI II" .

273 ~

288 .

 

 

 

III'T'I'

I rrfrvIfiI'r

MaSS Spectrum of i6.

NATIVE WWW

 

RELATIVE NW: r r

‘8

‘3‘

e

8

‘5

 

 

 

 

 

 

 

 

 

 

 

145

O
CHSOZC
C H302C

 

 

 

 

 

Figure 78.

I] .. ”whim“ II MIIJ ILJJ “IIIJL [Ll

Mass Spectrum of 29.

146

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

 

 

 

 

 

 

 

 

 

 

 

zoom-I "“5 r 113:
I
* r
4 I-
J I
* 183 238 I
33. 0 ~ ”
I45
1 I31 . F
51 I} ‘
i ‘ I.
I
< 255 -
. 35 -s: 139 ZI: 24x . .
I I I 255 "33
I i7 ihh
" 4: II! '1”
'I'Y'T I IIT‘I‘ITIrTIIr
5 SJ 1% 250 380
Figure 79. Mass Spectrum of 51.
(NI
Iea.o~— r IGETZ
4 L-
1 L
50.81 .
J ..§ .
102' 141 1‘3 215 ‘4. b
1 5 " I
48 55 153 183 1., . ..
s 91 98 n I JLL .. " * “
.lu. Al.[ Rim. ‘2 95.1 1 “IL; l?‘. In I11 I I. 41 - ,.JhliaI‘mg ITIL LIIL
g.nfihmrwqfiqmfifiqu,nrnwmv m TWWHW.HI.I-, t.r
H-"E 49 60 80 189 120 140 160 1'3 283 22“
,,
108.9 1 ‘93 - I:=‘;
I I-
. C) »

 

 

 

 

A
I .41 I
4 I-

561
4 ”'7‘ L
I I
F: .
g I, 475 :71 I _
I I C A
1113’ .4; - LJYJI .1 T 'I r L 1: T T -
YY V YV Y "Y' v—V T—Y_V"T_‘ WV r v—r r fiv v T . v 1 fi rrY
w r .49 ’50 .:n )u‘ 2:0 4* 3ea . .. I .

Figure 80. Mass Spectrum of 52.

~

 

 

 

 

 

147

 

 

 

 

 

 

108. 3 1 P
J L

+ P

< L-

4 u-
sa.a-4 _
i 167 '

. 171 ’

4 . ‘89 ”

4 147 ‘31

3 D

| 55 75 83 33 103 115 133 153 7 207 7 o 2 253 ‘

n22 89 130 129 149 160 188 ‘ 299 220 240 260
zoe.o- 325 343 ,
4 I-

- .:II a - P

397
w 315 -
T 371 {
........ ,,,,.,r..1[....,....r1..-1.. ,....,e...,....,....‘j..,,....I..-.,..-.,..-.,r1-.T...-....-r
n a 230 "30 329 343 350 333 m 429 440 45"

Figure 81. Mass spectrum of éfl.

 

 

 

 

 

 

 

 

  

 

 

 

100.C‘1 "
4 r
157
1 I-
‘ 153 ’
< 171 ~
53.6-4 191 —
.1 b
1 189 *
‘ ,, 131 .c. ‘
ss .:4 5:. 9.9 .. 2}?ng .11 L 1?? 1.- - I Li J 1. us 2’3 219 2:9 23724:. *1:
V—T‘qYVYfIY YTrYVV [YI’VVIYYYVIYYYYIVYV IYYTY—r V' ‘11 IV 7""YVVVI‘VVIY]'7'!'VYYYI’YYTY"TYYVITY'Y'I‘YvaI

use 90 100 128 140 168 186 200 220 240 268

109.0 3‘3

(D
,zfs 39‘ 323 *
l 315 '
-, 311 371 '
5 3?3 A -?31.. l- 1 I 355 1 3?J
4r. ,,.-. , ., if- . .r.r1-..e,....,--..,....,..--,.-..,.-..T.,..,.-,.TT..1T....,...-T....I.--.;T-

n s 23‘ 390 329 34a _ 3:n 333 495 4:3 443 vcn

Figure 82. Mass spectrum of éé.

£3136

 

 

148

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

100.0-a ’
4 es
5a.a-
41 r
91 165 _
‘ 55 131
. . 77 1x9 145
95 138 159 167 176 139 ..
‘ 197 2 1 225
are 40 60 so :03 129 140 160 180 290 220
180.0-1
.J F'
L-
i
293 -
(3+4 C) .
.3
EJ.&‘- _
‘ 281
239 , 257 26? L385 [ 32? 342 [
lmv%re-.*.9e.u-.v~quw.v.1»...ivrn393 v.1.fi1l W1: "
nvE 240 250 238 300 329 340 363 330 433 4;;
Figure 83. Mass Spectrum of 22.
I
. L
'57 3'1 "'
J 166 ‘
§
1
j
'1 113. ‘274‘L QSLI !??.h1?z.hn l
-. rev}, .vr,,.,,.,..,,... ...r-...r....,-.,.l....r1,.,l...
”.5 so so 160 128 148 168 180 200 2.9 240
,.. 5 342
A‘ o.j [-
s
I
, .
gt ItI-1 H i-
(3 :3 .
32?
1 L
I .
i 399 334 _
.g'q 9?? A"! E- :35
1 71.2. 4.. .L .1 l. I. I. 1
_i iii ,fir Vu.g-.. --rfi-qq.n, " 7,.q.,n,vu.ruww..”1hr. .H,.fi.1,fq.rfil
n e ‘53 :93 see 329 340 368 380 400 429 440

Figure 84.

Mass Spectrum of 2g.

«in
'1.

(u

(.‘I
(0
(CI

'—.
‘J
\

.
U

(in

173'

 

69

 

 

 

 

1&9

 

 

 

 

 

 

 

 

  

 

 

 

 

 

 

Figure 86.

Mass Spectrum of §§.

....e- -
1 p
9
‘I
I .
f‘.3-1 SS -
‘ a4
‘ 5:13 51
1 E: 75 ‘85- 119 13: ‘57
154 ’
‘ L J 111 123 .39 163 171 _
.3 1 ,1 l 1 l :79 196 213 f
- - ,T..,-tj ..I..
3.: 4a 50 so 109 120 149 160 180 200 220
3.3-3" r-
1! .
I C1430 -
Ii ' b
j .
inSIP? . 251 255- 2?9A237 2%? 337.4. 335 . 3?“ 3?8 '
~ _ ...::; -,,...rl-...,.-rfr.-..,..v. ,..-,....,....,...-,.-..T....,....,...-,,-..Tf...[.-..1....,..-,,
. : .44 2:0 239 300 320 340 350 339 . 430 429
Figure 85. Mass Spectrum of ég.
180.0- ‘7? f
T
59 :92
C) .
CHC)
3 o
50.9-- r
s
91 i
i
. L
3. 7- 3
53 I ”5 1.“: i
55 ’ !
;
. 161 1
l3? 149 I I 3 1'5“: ”I :?5 ~-. [r
*' ' fl :5 -7 '
fivfi I .ILALL! JJ [11”] 1 ”'1" 1"!!! )3} L .!
1 7 ' ' ' ' ' ' ' ' Y ' l V ' I
we 40 93 2:0 1:30 1:0 140 160 ° ‘ -‘ -.‘ _

19272

1827'2

185(3

“’)
-1... ' ....

199.0% ... ;_:_:

69

91

 

 

38.8‘

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

177
r.- Am: ,‘
77 :45 1”3 ‘3’ i
:73 - F
‘
107 1‘9 1‘10 :62 1 I
u . T is 5 3
. " 35 133 I ii i E Q
I r
t N : L '
. 43 I 143 {I .l .f :z
. . g 3 II .
* 1 HI I i' W "' W i?
99 "- 5 3'3- ,' .
33 . hMVHMHMmdumn.,tg Jhivil‘ i
n 5 49 ea 39 100 :sa 120 :50 ;;¢

Figure 87. Mass Spectrum of 29.

 

 

F'N’

 

 

 

Hr)

 

 

 

 

 

 

 

 

 

 

.II I p... (‘0..7UL ...cc9.a..o.c
I.II—)(¢3IDJ7.507.7409017°
.I...I...........lI....I.
- .4 c 7 7-‘.vfla cauéa ,..437°
’.. . - ol.0777t.5 on ‘6.)c.l)c..\(2cl
. --‘-'
.JI(l-’)Jn.°”o-I6-IJ.§7§2-
conclooooooooocIII-ooooolm
7. .. I.‘J-si9lo’u-.-9n)' 1.50
I20 ,‘Vl..)..l.\a¢bl§|0v¢5
J» l....- J'-°c¢u.h~a\-IJ“J
t. .actl‘-"'-‘

 

 

s.-.- o...‘ .
t .' Inl.d.d.o

9.. a-IIIJI 65.77
2.- 1:13 1.1....(33

 

I00
‘0
)I‘
3-
1|

 

 

 

.ll‘l . 6, JDfi-I.‘ 031..., u’dlqlJ‘la

II--"'|"II.00.Q‘.I.‘.‘

 

 

 

 

 

 

 

 

 

 

 

 

151

 

 

 

 

 

 

 

 

.b‘L

|714|~ .19

"“

13C NMR Spectrum of E§.

.tbc..~.l
0000.00.

 

 

I .1... .7 .13....J. .(7 .~:

""‘-"".PV

 

 

 

 

Figure 88.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N

13C NMR Spectrum of 54.

Figure 89-

BIBLIOGRAPHY

10.

ll.

BIBLIOGRAPHY

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P

K. G. Rutherford, 0. A. Mamer, J. M. Prokipcak and R.
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(

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28.

29.

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31.
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34.
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36.

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38.

39-

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Data for X- -ray determination of compounds 54, 58 andéZA
were obtained from a Picker FACS- I automatic
diffractometer using graphite- -monochromatized MoKa
radiation. Crystal data are: compound 54, a: 39. 983
(110A . b 7 584 (3)142 c=11 901 (8) 119.5 =91 52 (4) .
Spaceo group CZ/C; compound 58, a=14. 4803 (4)A , =6 835
(2) /A, C: 19. 084 (11) A), 3:107. O9 (3)0 Space group
P2 /n; compound 52, a=19. 152 (12) A, b= 6. 828 (6)A

Wi4 495 (8) AZ 5:107. 09 (4)°, Space group P21/a.
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(1952).

42.

43.

1,1,,

45.

46.

47.

48.

49.

50.
51.

52.

53-

54.

55-

56.

57.

58.

155

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§22-. 3505 (1954)-

(a) Knowles, W. 8., private communication. (b) A
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(1960).

 

156

59. (a) I. Fleming, "Frontier Orbitals and Organic
Chemical Reactions", Wiley-interscience, N. Y. (1976).
(b) Alston, P. V. and Ottenbrite. R. M. Ottenbrite,

J. Org. Chem., 48 1111 (1976). (c) Houk, K. N.,
Strozier, R. W. and Patterson, R. T., J. Amer. Chem.

Soc., 188,6531 (1978).

60. Kolaczkowski, L., recent observation in this
laboratory.