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ITY LIBRARIES

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This is to certify that the

dissertation entitled

Cyclobutanes in Organic Synthesis
Part I : Regio and Stereoselective Rearrangements of
Stereoisomeric 7—0Xirylbicyclo [4.2.0] Octan-7—ols
Part II: Solvol'ytic Stfidies bf Ester Derivatives of
Bicyclo [n.2.0] Alkanbls (n = 3 or 4)

presented by

Chrong—Shiong Hwang

has been accepted towards fulfillment
of the requirements for

Ph.D. degree in Chemistry

 

 

Mam

Major professor

Date 3/24/33

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CYCLOBUTANES IN ORGANIC SYNTHESIS
Part I : REGIo AND STEREOSELECTIVE REARRANGEMENTS OF
STEREOISOMERIC 7-OXlRYLBICYCLO[4.2.0]OCTAN-7-0LS
Part II : SOLVOLYTIC STIDIES OF ESTER DERIVATIVE OF
BICYCLO[n.2.0]ALKANOLS (n = 3 0R 4)
BY

Ch rong-Shiong Hwang

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1988

Siifi'LU

ABSTRACT

CYCLOBUTANES IN ORGANIC SYNTHESIS
Part I : REGID AND STEREOSELECTIVE REARRANGEMENTS OF
STEREDISDMERIC 7-OXIRYLBICYCLO[4.2.0]OCTAN-7-OLS
Part II : SOLVOLYTIC STIDIES OF ESTER DERIVATIVE OF
BlCYCLO[n.2.0]ALKANOLS (n = 3 0R 4)

By

Chrong-Shiong Hwang

Part I : The four racemic diastereomers of the title compound
have been prepared by epoxidation of the related vinylcyclobutanols.
Mild treatment of these isomers with boron trifluoride induced
regio- and stereoselective rearrangement to ring-expanded
hydroxymethyl bicyclo[4.2.0]nonanones. Curiously, one of the
diastereomers did not react under these mild conditions. Other
Lewis acids such as Ti(i-PrO)4, SnCl4 and MgBrz-EtzO have also been
examined. However, the results were not promising from a synthetic
point of View. When the pair of diastereomers having an endo
hydroxyl group (1 : 1 mixture) were treated with trifluoroacetic
acid, rearrangement of the methine group occurred exclusively,
followed by dehydration to cis-7-methylenebicyclo[4.3.0]nonan-8-

one (A).The physical properties of this enone and its 8-methylene-7-

Chrong-Shiong Hwang

one regioisomer (B) were established by independent syntheses.
Elimination of the hydroxymethyl products from the initial
rearrangement gave A or B, thus identifying the regioselectivity of
each rearrangement.

Several sequential reactions were then carried out to
characterize the hydroxymethyl configurations. First, sodium
borohydride reduction, followed by acetylation and hydroboration of
A and 8 gave a pair of cis 1,3-diols, assuming normal convex facial-
selectivity. Second, reduction of appropriate hydroxymethyl
products with sodium triacetoxyborohydride gave a pair of trans
1,3-diols. Finally, the cis or trans configurations of these diols

were confirmed by the relative rates of acetonide formation.

Part II : A two-carbon ring expansion involving solvolyses of
6-bicyclo[3.2.0]heptyl esters and 7-vinyl-7-bicyclo[4.2.0]octyl
esters has been explored. Acetolysis of benzoates or 1,3-
dinitrobenzoates in glacial acetic acid or aqueous acetic acid with
an acetate buffer afforded 3-cycloheptenyl or 3-cyclooctenyl
derivatives in good to excellent yields. The latter solvolysis

required the addition of LiClO4 for best results.

To My Grandmother And Parents

ACKNOWLEDGEMENTS

The author wishes to express his sincere appreciation to
professor William Reusch for guidance and encouragement
throughout the course of work and for his critical reading of this
manuscript.

Appreciation is extended to his colleagues for their friendship
and discussion. Special thanks are also extended to Judy Shu Jen
Hsieh for her love, concern and encouragement.

Finally the author would like to thank Michigan State
University and Walter R. Yates Scholarship Fund for financial

support.

TABLE OF CONTENTS

Part I : Regio and Stereoselective Rearrangements of
Stereoisomeric 7-Oxirylbicyclo[4.2.0]octan-

7-ols
Page
Introduction .......................... 1
Results and Discussion ................... 10
Preparation of Diastereomeric Epoxycyclobutanols ..... 10
Reactions of Epoxycyclobutanols with Lewis Acids and
Bronsted Acids ................... 19

Synthesis of Regioisomeric Methylene Cyclopentanones . . 24

Identification of Stereoisomeric Hydroxymethyl

Cyclopentanones ................... 29
Experimental .......................... 62
General ........................... 62
Cycloaddition of Cyclohexene with Dichloroketene ..... 63

Dechlorination of Dichlorocyclobutanone 16 with Zinc

Dust ......................... 63
Preparation of Vinyl Alcohol 18a ............. 64
Wittig Reaction of Ketone 17 in Toluene Solution ..... 64

Wittig Reaction of Ketone 17 in Dimethyl Sulfoxide
Solution .......... . ............. 65

Preparation of Epoxy Alcohols 9 .............

Preparation of Bromohydrins 38 .............

Base-Induced Cyclization of Bromohdrins 38 Epoxy

Cyclobutanols 9 ..................

Boron Trifluoride-Catalyzed Rearrangement of 9 . . . .

Trifluoroacetic Acid (TFA)-Catalyzed Rearrangement

of9 ........................

Preparation of Enones 34 from Ketols 29 ........

Preparation of Enones 348 from Dichlorocyclobutanone

16 .........................
Preparation of Cis-Diols 35 from Enones 34 ......
Reduction of Ketols 29 with NaB(OAc)3H ........

Preparation of Acetonides 40 .............

Part 2 : Solvolytic Studies of Ester Derivatives of

Bicyclo[n.2.0]alkanols (n = 3 or 4)

Introduction .........................
Results and Discussion ..................

Preparation of Ester Derivatives of Cyclobutanols . . .

Acetolysis of 6-Alkenyl Bicyclo[3.2.0]heptyl-6 Ester

Derivatives ....................

Acetolysis of 6-Alkyl Bicyclo[3.2.0]heptyl-6 Ester

Derivatives .....................

Acetolysis of 7-Vinyl Bicyclo[4.2.0]octyl-7 Ester

Derivatives ....................

Page
.66

.67

.69

.69

.70

.37

..43
..43

..46

..52

..58

Page
Experimental .......................... 78

General Procedure for the Preparation of Cyclobutanones . .78

General Procedure for the Addition of Grignard Reagents

to Cyclobutanones .................. 79

General Procedure for the Preparation of Dinitrobenzoates

(or Benzoates) of Cyclobutanols ........... 81

Acetolysis of Dinitrobenzoates (or Benzoates) in Glacial

Acetic Acid Containing Triethylammonium Acetate . .85

Acetolysis of Dinitrobenzoates (or Benzoates) with TEAA-

LiCIO4 In aqueous Acetic Acid ............ 86

Diels-Alder Reaction of Diane 66c and Maleic
Anhydride ...................... 93
Oxidation of 82 to 83 ................... 94
Appendix ............................ 95
Bibliography .......................... 224

vi

Table

VI
VII
VIII
IX

XI

LIST OF TABLES

Page
Temperature Effect on Epoxidation of Olefin 25 . . 15
Based-Induced Rearrangement of Olefin 25 ..... 16
Solvent Effect on Epoxidation of Alkylidenecyclo-
alkane Oxides 24 ................. 18
Reactions of 9a and 9b with Lewis Acids ...... 19
Dihedral Angle in the Most Stable Conformer of
9a through 9d .................. 35
Cycloaddition of Dichloroketene and Olefins . . . . 44
Yields of Cyclobutanols and Ester Derivatives . . . 45
Production Distribution from Solvolyses of 55. . . 47
Production Distribution from Solvolyses of 57a . . 50
Production Distribution from Acetolyses of 57b . . 51

Production Distribution from Solvolyses of 653 . . 60

vii

Figure

(Document-soc

10
11
12
13
14
15
16
17

LIST OF FIGURES

Page

Transition State of Lil-Induced Rearrangement of
Epoxides 1a and 1p ................... 3

Transition State of Ales-Induced Rearrangement of

Epoxyl Alcohols 13-erythro and 13-threo ...... 7

Diagram of Potential Energy vs. Dihedral Angle in 93 . . 95

Diagram of Potential Energy vs. Dihedral Angle in 9b . . 96

Diagram of Potential Energy vs. Dihedral Angle in 9c . . 97

Diagram of Potential Energy vs. Dihedral Angle in 9d . . 98

Infrared Spectrum of 18b ................ 99
Infrared Spectrum of 29a ............... 100
Infrared Spectrum of 34a ............... 101
Infrared Spectrum of 34a ............... 102
Infrared Spectrum of 35 ............... 103
Infrared Spectrum of 47 ................ 104
Infrared Spectrum of 55 ................ 105
Infrared Spectrum of 668 ............... 106
Infrared Spectrum of 66b ............... 107
Infrared Spectrum of 66c ............... 108
Mass Spectrum of 18a ................. 109

viii

Figure
18
19
20

21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43

Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
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
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
of
of
of
of
of
of
of
of

of

Page
18b ................. 109
9c ................. 110
9d ................. 110
29a ................. 111
29c ................. 111
29d ................. 112
35a ................. 112
34a ................. 113
34b ................. 113
35b ................. 114
35c ................. 114
35d ................. 115
35a ................. 115
47 ................. 116
52 ................. 116
55 ................. 117
62 ................. 117
57a ................. 118
57b ................. 118
63 ................. 119
69b ................. 119
60 ................. 120
64b ................. 120
64a ................. 121
65 ................. 121
663 ................. 122

Figure

45
46
47
48
49
50
51
52
53
54
55
56
57

58
59

60
61
62
63
64
65
66
67
68

69

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

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

of

NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum

1H NMR Spectrum

Page
66b ................. 122
66c ................. 123
66d ................. 123
67a ................. 124
67c ................. 124
68a ................. 125
68d ................. 125
69a ................. 126
70a ................. 126
71a ................. 127
71b ................. 127
73a ................. 128
73b ................. 128
74a ................. 129
74c ................. 129
of18a ............... 130
of18b ............... 131
of9a ................ 132
of9b ................ 133
of9c ................ 134
of9d ................ 135
of29a ............... 136
of29c ............... 137
of29d ............... 138
of34a ............... 139
of34b ............... 140

Figure
7 0
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95

NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum

Page
of34e ............... 141
of35a ............... 142
of 35b ............... 143
of35c ............... 144
of 35d ............... 145
of 35e ............... 146
of 36a ............... 147
of 36b ............... 148
of 36c ............... 149
of 37a ............... 150
of 37b ............... 151
of 38a ............... 152
of 38b ............... 153
of 38c ............... 154
of 38d ............... 155
of 40a ............... 156
of 40b ............... 157
of 45 ................ 158
of 46 ( cis ) ............ 159
of 46 ( tran ) ............ 160
of 47 ................ 161
of 50 ................ 162
of 52 ................ 163
of 53 ................ 164
of 55 ................ 165
of 563 ............... 166

x i

Figure
96

97

98

99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
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119
120
121

NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum

NMR Spectrum

NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum
NMR Spectrum

Page

of56b ............... 167
of57a ............... 168
of57b ............... 169
of60 ................ 170
of62 ................ 171
of63 ................ 172
of64a ............... 173
of64b ............... 174
of65 ................ 175
of66a ............... 176
of66b ............... 177
of66c ............... 178
of66d ............... 179
of67a ............... 180
of67c ............... 181
of683 ............... 182
of68d ............... 183
of 68a 4- 68a ............ 184
of69a ............... 185
of69b ............... 186
of70a ............... 187
of71a ............... 188
of71b ............... 189
of72a ............... 190
of 72c + 73d ............ 191
of73a ............... 192

Figure
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136

137
138
139
140
141
142
143
144
145
146
147

Page
1H NMR Spectrum of 73b ............... 193
1H NMR Spectrum of 74a ............... 194
1H NMR Spectrum of 74c ............... 195
13c NMR Spectrum of 18a ............... 196
13C NMR Spectrum of 18b ............... 196
13C NMR Spectrum of 9a ............... 197
13c NMR Spectrum of 9b ............... 197
13c NMR Spectrum of 9c ............... 198
130 NMR Spectrum of 90 ............... 19a
130 NMR Spectrum of 29a ............... 199
130 NMR Spectrum of 29c ............... 199
130 NMR Spectrum of 29d ............... 200
13c NMR Spectrum of 34a ............... 200
13C NMR Spectrum of 34a ............... 201
13c NMR Spectrum of 34b ............... 201
13C NMR Spectrum of 356 ............... 202
13c NMR Spectrum of 35b ............... 202
130 NMR Spectrum of 35c ............... 203
130 NMR Spectrum of 35d ............... 203
13C NMR Spectrum of 36a ............... 204
13c NMR Spectrum of 36b ............... 204
130 NMR Spectrum of 37a ............... 205
130 NMR Spectrum of 37b ............... 205
130 NMR Spectrum of 38a ............... 206
130 NMR Spectrum of 386 ............... 206
130 NMR Spectrum at 38c ............... 207

xiH

Figure
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173

13C NMR Spectrum
136 NMR Spectrum
13C NMR Spectrum
130 NMR Spectrum
13C NMR Spectrum
13C NMR Spectrum
130 NMR Spectrum
13C NMR Spectrum
130 NMR Spectrum
13c NMR Spectrum
13C NMR Spectrum
13C NMR Spectrum
13C NMR Spectrum
13C NMR Spectrum
130 NMR Spectrum
130 NMR Spectrum
13C NMR Spectrum
130 NMR Spectrum
13c NMR Spectrum
136 NMR Spectrum
130 NMR Spectrum
13C NMR Spectrum
130 NMR Spectrum
13C NMR Spectrum
13C NMR Spectrum
130 NMR Spectrum

Page
of38d ............... 207
of40b ............... 208
of40a ............... 208
of47 ............... 209
of52 ............... 209
of55 ............... 210
of62 ............... 210
of57a ............... 211
of57b ............... 211
of60 ............... 212
of 64b ............... 212
of64a ............... 213
of65 ............... 213
of66a ............... 214
of66b ............... 214
of66c ............... 215
of66d ............... 215
of67a ............... 216
0f67c ............... 216
of68a ............... 217
of68d ............... 217
of69a ............... 218
of69b ............... 218
of70a ............... 219
of71a ............... 219
of71b ............... 220

xiv

Figure
174
175
176
177
178
179
180

13C NMR Spectrum
130 NMR Spectrum
13C NMR Spectrum
130 NMR Spectrum
130 NMR Spectrum
130 NMR Spectrum
13C NMR Spectrum

of 53 ............... 220
of 72c 4- 73d ........... 221
of 723 ............... 221
of73b ............... 222
of 63 ............... 222
of 74a ............... 223
of 74c ............... 223

XV

CYCLOBUTANES IN ORGANIC SYNTHESIS
PART I
REGIO AND STEREOSELECTIVE REARRANGEMENTS
OF 7-OXIRYLBICYCO[4.2.0]OCTAN-7-OLS

lntroductlon

The importance of carbocations as reactive intermediates in
organic chemistry is well documented in both synthetic and
mechanistic studies.1 Prominent examples of reactions involving
carbocation intermediates include biogenetic-Iike polyene
cyclizations2 and molecular rearrangements such as those involving
steroid3 or terpene“ substrates.

The ring expansion of cyclobutane derivatives to cyclopentanes
is an important transformation that normally proceeds via
carbocation intermediates.5 This has emerged as a powerful
synthetic method which in some cases may proceed with good
regio- and stereoselective control. The popularity of cyclobutane
derivatives in syntheses may be attributed to several factors. First,
cyclobutane derivatives are readily prepared by [211 +211]
cycloaddition of olefins with ketenes,6 [211 + 211] photocyclization
of olefins7 together with several other facile methods8 such as ring
expansion of cyclopropane derivatives and ring closure by double

alkylation of 1,3-dithiane with bromochloropropane. Second, the

high strain energy in cyclobutane rings (26.9 kcaI/mole)9 provides a
thermodynamic driving force for ring cleavage or expansion. Finally,
cyclopentane derivatives occur in a variety of natural products,
including jasmones, pyrethrins,1° prostaglandins11 and triquinane
sesquiterpenes.12

An instructive example of such ring expansion was reported by
Hart and Comte.13 Bicyclic ketones (2 and 3), which have been
extensively used in the synthesis of prostacyclin analogues, were
prepared by regiocontrolled ring expansions from epimeric epoxides
la and 10 respectively. Rearrangement of epoxide let proceeded
rapidly in a regioselective manner (lithium iodide, THF, 20 °C, 4 hr)
to yield ketone 2 (68%) and its Isomer 3 (10%). In contrast to the
cleavage of let, epoxide 10 underwent a slow, regioselective

rearrangement to afford ketone 3 in 71% yield and less than 10% of

 

 

 

 

ketone 2.
Lil/THF
Rau- : R""° O
0 °C, 2 hr
R 2
O
Lil/THF
O : R‘IIII-
20 C, 60 hr
3

R‘ .. -OSiMe2‘Bu
R = -CH=CHCH05H11
DSiMezt'Bu

The regioselectivity of these epoxide-carbonyl rearrangements
has been attributed to steric Interactions and torsional strain
inherent in the bicyclo[3.2.0]heptane system. For example, epoxide
let, being readily susceptible to nucleophilic attack, may form a
five-membered anti-periplanar transition state 4, which then
undergoes a synchronous rearrangement to give ketone 2. However,
owing to steric congestion at the concave Ot-face, this path is not
available to 10, which has been thought to give ketone 3 via

transition state 5.

   

5 a
Li—"
RI!-
4 5
Figure 1

Another application of ring expansions of cyclobutane
derivatives has been used recently to prepare a key bicyclic
intermediate (8) for a total synthesis of the sesquiterpene (1)-
coriolin by Knapp et al.14 Treatment of ketone 6 with (CH38)3CLI
led to a single product 7, which was smoothly expanded to the keto
thioketal 8 without formation of its regioisomer (80% overall) by
treatment with CuBF4-CH30N in toluene solution.

CHas

 

 

..ém C(SCHala SCHS
.-0 (CH38)sCI.i CuBF4 CH3CN
95% OSEM 84% .
OSEM :
OSEM
6 7

The high regioselectivity in this case (where either a
methylene or methine carbon may migrate) has been attributed to
the formation of a highly stabilized cationic intermediate, followed
by a transition state in which there is substantial charge
delocalization on the migrating carbon. On the other hand, examples
of ring expansions with less15 or even reversed16 regioselectivity
have been also reported. Since these reactions involve less
stabilized cationic intermediates, the difference in electron-
donating ability of the migrating atoms is not significant.

Recognizing that epoxides are excellent initiating groups for
reactions proceeding via carbocation intermediates, such as polyene
cyclizations2 and molecular rearrangements,3 we decided to examine
the behavior of a group of stereoisomeric epoxycyclobutanols having

the general structure 9.

OH

Surprisingly, a survey of the literature revealed only few
examples of acid-catalyzed rearrangement of epoxy alcohols. Cheer
and Johnson17 found that monocyclic epoxyl alcohols 10 underwent
acid-catalyzed rearrangements induced by BF3-0Et2 or acidic

alumina to give hydroxymethyl ketone 11 in moderate yields

 

(Scheme ll).
, 0
(CH2) n OH BF3 . OEtz = (MCHW
CHZCIZ CH3
O
10 11

a : n = 0 63%

b : n = 1 49%

c : n = 2 15%

Scheme II

This study demonstrated that , as in the case of Tiffeneau-
Demjanov rearrangement,18 such rearrangements are a function of
ring size, giving decreasing yield with increasing ring size. More
significantly, the best yield was observed for the acid-catalyzed
rearrangement of epoxycyclobutanol 108, affording hydroxymethyl
cyclopentanone 11a in 63% yield.

To investigate the stereochemical character of this
rearrangement, Cheer and Johnson further examined the acid-
catalyzed rearrangement of the diastereomeric epoxyl alcohols 13-
erythro and 13-threo, derived from the epoxidation of 1-

isopropenyI-1-indanol.1 9

 

 

 

  

 

O
0 OH
OH
.© 14a 14b
H ,
a )b BF3 032 e 23 : 77
0 CH3
AI203
13-erythro ' 90 10
BFa‘OEtZ _ 10 : 90
Ho 7
H3 “203 , 10 90
1 3-threo
Scheme Ill

The erythro- and threo- epoxy alcohols on treatment with
BF3-OEt2 afforded hydroxymethyl ketones 14b and 14a in a ratio of
77 : 23 and 90 : 10 respectively (Scheme Ill). The ratio of 14a to
14b obtained in this study is probably best explained in terms of
migratory aptitudes, in this case phenyl (path b) shifts
preferentially over the primary alkyl group. On the other hand, the
corresponding alumina-catalyzed rearrangement of 13-erythro and
13-threo gave 14a and 14b in a ratio of 90 : 10 (67%) and 10 : 90
(66%) respectively. Because of this high regioselectivity, the

authors suggested that the alumina-catalyzed rearrangement

proceeded through a " surface-adsorbed " transition state, as shown

in Figure 2.

O\ O
/ H r/
3% A I 2 03

Figure 2

In this dissertation we present the results of our study of
Lewis and Bronsted acid-catalyzed rearrangements of the four
diastereomeric epoxycyclobutanols (9a, 9b, 90, and 9d). Our
interest in this subject is related to Johnson and Cheer‘s study. If
previously determined migratory aptitudes are dominant, the
methine residue should migrate preferentially and we would expect
to obtain hydroXymethyl cyclopentanones 293 or 29c as major
products. In contrast, a coordination-controlled pathway should
favor regioselective and stereoselective rearrangements. Four
possible regio- and stereoisomers, 29a, 29b, 29c and 29d, are
formally possible from rearrangements of the isomers of 9 (Scheme
IV).

A. Migratory Aptitude-Controlled Pathway

 

 

---------- -> @O
29a,c
;OH
O
29a,c
9H 0 OH O O
? ...\. \
I H + .I ----—
OH
9b 9d 29b,d
Scheme IV

Hydroxymethyl ketones 29a and 29c can be distinguished from
29b and 29d by dehydration to methylene cyclopentanones 34a or

34b under suitable conditions.

a: an

29a,c 34a

0 (i;
OH

29b,d 34”

Ot-Methylene ketones, such as 34a and 34b, are particularly
attractive intermediates In synthetic organic chemistry. Quite a
few natural products, such as the sesquiterpene chiloscyphoneZO and
the antibiotic methylenomycin A,21 possess this feature. Moreover,
the potential synthetic utility of the highly reactive unsaturated
carbonyl system (-C=C-C=O) has been demonstrated repeatedly in
organic syntheses, including extended enolate alkylations,22

reductive alkylations23 and especially Michael addition reactions.24

   

"COOH

Chiloscyphone Methylenomycin A

Results and Discussion

Preparation of Diastereomeric Epoxycyclobutanols
Cyclobutanone 17 is an obvious precursor to cyclobutanol 183.
Several methods of preparing cyclobutanones have been described.25
Among these the [211 + 211] cycloaddition26 of ketenes with alkenes
is one of the most direct and simplest, and dichloroketene has been
demonstrated to be particularly effective for this purpose.27 Thus
in situ cycloaddition of dichloroketene, prepared by the zinc
dechlorination of trichloroacetyl chloride, with cyclohexene gave
dichlorocyclobutanone 16 in 89% yield. Reductive removal of the
chlorine atoms from 16 with zinc in acetic acid was easily
accomplished to afford cyclobutanone 17 in excellent yield.
Subsequent addition of vinyl magnesium bromide to 17 yielded
a single diastereomeric product (vinyl cyclobutanol 18a). The
stereochemistry at the C(7) center, as indicated in structure 18a,
was assigned on the basis of preferred reagent attack at the less
hindered convex side of the substrate. Epoxidation of
vinylcyclobutanol 189 with MCPBA then provided
epoxycyclobutanols 9a and 9b in 93% yield as a 1 : 1 mixture of

diastereomers (determined by 1H NMR). Unfortunately, these

10

11

isomers could not be separated by fractional distillation or flash

chromatography (Scheme V).

 

 

 

 

O
Zn(Cu)
+ Clac—l'I—CI : “a
89% C.
1 6
O fiMgBt
Zn/HOAc .. 4—
‘: 83%
90%
1 7
OH
E MCPBA
7 —>
93%
18a 1 1

 

However, a pure sample of each isomer was eventually
obtained from the derived bromohydrins, 38a and 38b respectively,

by treatment with methanolic base.

12

 

 

OH OH OH
. 1 eq. KOl-I/MeOl-l WO
5 H
Br
38a 98% 9a
9H ‘OH OH O
OjFH 1eq. KOH/MeOH Oj—{u‘r
Br : H
75%
38b 9b

With epoxycyclobutanols 9a and 9b in hand, we continued our
effort to prepare the vinylcyclobutanol 18b, a precursor of the other
two diastereomeric epoxycyclobutanols (9c and 9d).

Brown and Fallis28 have reported a procedure for converting
the endo vinyl alcohols 19 and 20 into the corresponding exo vinyl
alcohols 22 and 23, via allylic sulfoxides 21a and 21b. A [2,3]
sigmatropic rearrangement of the sulfoxide moiety was assumed to
occur preferentially across the less hindered exo faces of the double
bond (Scheme VI).

Since treatment of vinylcyclobutanol 188 with either
phenylsulfenyl chloride or thionyl chloride led to complicated
mixtures, an alternative procedure was devised, as shown in Scheme
VII. Of central importance to this approach was the ability to carry
out a stereoselective epoxidation of ethylidenecyclobutane 25,
followed by a regioselective p-elimination of the resulting epoxides.
We anticipated that a peracid reagent would prefer to attack olefin
25 from the less hindered convex side, thus leading to the desired

p-epoxides.

13

h n-BuLi A O
PhSCI / 'S'

 

 

 

 

 

Ph
0H \ 45%
1 9 21 a
P(OMe) 3
: OH
3 2 2
SOCI2 'I. PhSNa _
\ 40% / Cl 2. MCPBA
OH
86%
2 0
NaSPh
(r). = jOH
/ S 51 o/o
‘Ph , /
2 3
2 1 b
Scheme Vl

In the event, alkene 25 was prepared as a 1 : 1 E/Z mixture
from cyclobutanone 17 by a Wittig reaction. Epoxidation of alkene
25 with MCPBA in methylene chloride solution yielded a
diastereomeric mixture of epoxides 26. Finally, base-catalyzed

elimination of this epoxide mixture with lithium diisopropylamide

14

(LDA) yielded vinylcyclobutanols 18b and 188 in a 4 : 1 ratio
(Scheme VII).

 

 

O EtPPh 3 Br
NaH/DMSO
:
48%
1 7 2 5
O OH OH
MCPBA LDA ‘
= ——» +
CHZCIZ 94%
1 8 a
87% 2 6 1 8 b
Scheme Vll

Of the many reported procedures for effective Wittig
reactions, we found that the conditions suggested by Schow and
McMorris32 (potassium tert-amylate In refluxing benzene or toulene)
worked well in this case. In order to reduce the loss of the volatile
olefin product (25) during workup, it was not purified and
epoxidation was conducted on the crude product mixture. Thus, the
effect of temperature changes on epoxidation stereoselectivity was
studied in this solution. Table I summarized the results of this
study, which provided the best experimental conditions for the
desired exo-face epoxidation. The overall yield for conversion from
17 to 18b was greater than 50%, which was nearly double that of

the previous procedure (Table l).

15

o
EtPPhaBr: .I/ MCPBA/Toluene
t'AmOK Temperature T

 

 

 

1 7 Toluene 2 5
O OH OH
2 5 18b 18a
Scheme Vlll

Table l. Temperature Effect on Epoxidation of Olefin 25

 

 

 

 

m 92215142 “it?" “W"
L t. 70.6 54 3.3
0 °C 61.6 49.3 4.8
-78 °C 65.1 49.9 4.1

 

 

 

 

 

 

* : Overall yield from 1 7 to 18b

The exclusive formation of tertiary alcohols (188 and 18b)
from epoxides 26 reported here should be contrasted with work of
Thummel and Rickborn,29 in which the base-induced rearrangement
of propylidenecycloalkane oxides to allylic alcohols exhibited

marked regioselectivity for endocyclic olefin products (Table II). An

16

exception was propylidenecyclohexane oxide, which gave 95% of the

alternative product.

Table II. Base-Induced Rearrangement of Akylidenecycloalkane
Oxides 24

 

A O
(CH2)n-1 CM Base (0% Hfic/OH
V2 4 2 V \A

OH
H I..2 I .(C
\J

 

 

 

 

 

 

n = 4 77 15
5 100 0
6 5 95
7 98 2
8 100 0
12 84

 

 

 

On the other hand, the same authors also reported30 a highly
selective base-induced rearrangement involving proton abstraction
from the least substituted p-carbon atom of unsymmetrically
substituted epoxides. Since there was no experimental data
available for base-induced rearrangements of ethylidenecyclobutane
oxide, we carried out our own study involving treatment of epoxides
27 with either lithium diisopropylamide (LDA) or lithium
diethylamide in ether solution to afford allylic alcohols 283 and
28b in a ratio of 10 : 1 (90%) and 12 : 1 (83%), respectively. These
results indicated a balance between the preference for endocyclic

olefin formation and the preference for base attack at the less

17

substituted p-carbon in the case of epoxide derivatives of

alkylidenecyclobutanes.

OH

 

 

27 283 28b

It has been noted31 that hydroxylic solvents such as t-BuOH
may form hydrogen bonds with peracids, resulting in a decrease of
the rate of epoxidation. With this in mind, we decided to explore the
medium effect. We hoped that association of additional polyhydroxyl
reagents or hydroxylic solvents with the peracid would increase the
bulkiness of this reagent and the facial selectivity of the
epoxidation of 25. The results of this study are listed in Table III.

As shown in Table III , the addition of a polyhydroxyl co-
reactant did not increase the facial selectivity. On the other hand,
the facial selectivity Increased to 6.5 : 1 when the epoxidation was
carried out in methanol solution. Unfortunately, the lower yield of
the reaction in MeOH offset this improvement.

Finally, epoxycyclobutanols 9c and 9d were obtained by
epoxidation of 18b with MCPBA in methylene chloride solution.
Unlike their diastereomers (9a and 9b), 9c and 9d were easily

separated by flash chromatography.

18

 

 

 

 

 

 

 

 

 

 

 

 

Table III. Solvent Effect on Epoxidation of Olefin 25

Yield(%#) Yield(%) + ++

maniac 18b# 18""83 ”hm“

CHZCIZ I 75. 5 I 59. 7 I 3. 8 I4

CH20l2

ROH‘ 62I 59.3 I35 I:

ether I7 74.8 I 57 8 I3 43'

ether
77. 2

ROH’ 4I 58.8 I32 I

MdH I6 55.7 I6 5'6

 

 

 

*

#

+

: 1,1,1-Tris(hydroxymethyl) ethane

ot‘H NMR

: Overall yield from 25 to 183 + 18b
: The ratios were determined by the integrations

+ : The ratios were determined by the isolated yields

 

19

Reactions of Epoxycyclobutanols with Lewis Acids and
Bronsted Acids

With the epoxycyclobutanols 93, 9b, 9c and 9d in hand, we
proceeded to study the Lewis acid-catalyzed rearrangement of these
isomers. Since boron trifluoride rapidly converted a 1 : 1 mixture of
93 and 9b to a complex decomposition mixture at 0 0C in methylene
chloride solution, milder acids such as SnCl4, Ti(i-PrO)4, Ti(i-
PrO)3Cl and MgBrg were investigated. As noted in Table IV, ring
expansion products (343 and 34c) and halohydrins (383 and 38b)
were identified and obtained in amounts that varied markedly with

the Lewis acids used and the conditions of the reaction.

Table IV. Reactions of Epoxycyclobutanols (93 + 9b) with Lewis Acids

 

 

 

 

 

 

 

 

 

 

 

 

 

w , 9“ OH OH é,OH
Yields(%) 05H? 0 m E I1 )
m 348 34° 38 a x 3” x
X a: CI X 3 Cl
Cat. Snot, I 33 I < 3 6.4 5,4
. . 1 0 < 3 X = C' X 7 Cl
Cat. Ti(I-Pro )3 CI I 3.7 3,6
. X = CI X 3 Cl
1.1eq.TI(i-Pro)30l I 50 50
Ti(i-PrO)4 I 27 I < 3
X 3 Br X - Bl’
1.1 sq. MgBr2 I 50 50

 

 

 

20

Although these Lewis acid-catalyzed reactions of 93 and 9b
proved to be unpromising from a synthetic point of view, several
conclusions may be drawn from the data. First of all, reactions of
epoxycyclobutanols 93 and 9b with one or more equivalents of
Lewis acids which incorporate nucleophilic halogens gave
halohydrins in near quantitative yields. Secondly, with catalytic
amounts of such Lewis acids, low yields of enones 343 and 34c
together with small amounts of halohydrins were obtained. Finally,
an examination of the reaction of 93 and 9b with the weak Lewis
acid, Ti(i-PrO)4, revealed that diastereomer 9b was substantially
less reactive than 93. Similar results were observed for Ti(i-PrO)4

catalyzed rearrangement of 9c and 9d, as shown in Scheme IX.

 

 

 

 

9H !0\ 9H {0
i . ._ E \
I Ti(l PI’O)4t 0+ I
H r.t. 24 hr H
93 & 9b(1 : 1) 343 21% 33% (4 : 1) mixture
OH

  

 

 

0 Ti(i-PrO)4
: 0 1‘ S.M

r.t. 4 days

90 34a 16% 29%
O
T' ._

I(I PrO)4 : + S.M.

r.t. 4 days
34b 10% 75%

 

Scheme IX

21

Better conditions for the conversion of 93 and 9b into enones
(34a and 34c) were achieved by replacing the Lewis acid catalysts
with the nonnucleophilic Bronsted acid, trifluoroacetic acid (TFA).
Thus treatment of the 1 : 1 mixture of epoxycyclobutanols (93 and
9b) with 1.1 equivalents of TFA in chloroform solution gave enones
343 (68.5%), 34c (7%) and 34d (3%).

lower yields of enones and recovery of starting material.

9“ o
? TFA/CHCI
o- a mo ««0#
H reflux, 24 hr

Shorter reaction times gave

 

 

 

93 8t 9b(1 :1 343 68. 5% 340 7% 34d 3%
OH
, o TFA/CHCI
3 : . O + .3 O
H reflux, 48 hr
9c 343 20% 34c 2 0 %
OH 0
‘ t O + o .M.
H reflux, 48 hr .3 +
343 28% 340 13.6% 36.8%

Scheme X

22

Not surprisingly, the migratory aptitudes displayed in these
rearrangements favor the more substituted ring residue. In the case
of Ot-epoxy alcohols 93 and 9b, the ratio of migratory aptitudes of
the methine and methylene carbons is 11 : 1. On the other hand,
methine carbon migration occurs almost exclusively in the reaction
of p-epoxy alcohols 9c or 9d with TFA (Scheme X).

Since the ratio of recovered epoxycyclobutanols (93 :9b)
remained unchanged, the reactivities of 93 and 9b with
trifluoroacetic acid , unlike Ti(i-PrO)4, are roughly the same. The
more thermodynamically stable enones 34c and 34d may be derived
from enones 34a and 34b, respectively, through keto-enol
tautomerization and double bound isomerization under acidic
conditions. Finally, the much slower rate of the reaction of 9c and
9d with TFA encouraged us to examine stronger Lewis acids, such as
BF3°OEt29 under milder conditions.

Remarkably, treatment of 9c with 1.1 equivalents of BF3-OEt2
in CHzclz at -17 oC gave a single ketol 29c in excellent yield.
Under equivalent conditions, ketol 29d was obtained in 74% yield
from 9d. We then examined the reaction of BF3-OEt2 with 93 and 9b
at lower temperatures. Surprisingly, treatment of 93 and 9b (1 : 1
mixture) with catalytic amounts of BF3-OEt2 at ~78 00 gave ketol
293 (45%) together with recovered 9b (43%). On more vigorous
treatment (higher temperature or equimolar boron trifluoride), 9b
was transformed to an intractable mixture including polymeric

products (Scheme XI).

93 8t 9b(1:1)

 

23

 

/OH
9“ 0
arm. - ‘4.)
... 0+ I
-78 °C H

 

 

298 45% 9b 43%
OH
BF3 . OEt2
: . O
-17 °C
290 7 4 °/o
O
BF3 . OEt2
-17 °C
OH
29d 8 8 %

Scheme XI

24

Our interpretation and rationalization of the highly selective
reactivity of stereoisomers 93, b, c and d with BF3 etherate was
complicated by the fact that none of the key compounds, including
93 through 9d, 343, 34b and 293 through 29d, had been reported
previously. Furthermore, although each of the diastereomers 93
through 9d exhibits characteristic properties, the corresponding 1H
and 13C NMR spectra cannot be assigned unambiguously to a specific
configuration. In addition, attempts to effect selective epoxidation
of vinyl alcohols 183 or 18b with either m-chloroperbenzoic acid
at low temperature (-78 0C) or titanium-mediated epoxidation with
tert-butylperoxide33 also gave a 1 : 1 ratio of diastereomeric
epoxycyclobutanols. Consequently, a series of chemical correlations
and interconversions were undertaken, which led ultimately to the

structural assignments presented in Scheme XVIII.

Synthesis of regioisomeric Methylene cyclopentanones
Greene and Depres have examined the ring expansion reactions
of certain alkyl-substituted cyclobutanones with diazomethane
(Et20-MeOH, room temperature).34 In the case of X - Y - H ( Scheme
XIII) the ring expansion proceeded quite smoothly to afford the
corresponding cyclopentanones; however the regioselectivity of the
migration was poor. The presence of or-chlorine substituent(s) (X, Y
- H, Cl or X - Y - Cl) not only accelerated the rate of reaction, but
also served to favor pathway 3 over pathway b, presumably due to
stabilization of the positive charge which must be shared in the
transition state. Although epoxide formation is generally observed

in the reaction of larger ring ketones with CH2N2,35 the reaction

25

with cyclobutanones gave ring expansion products exclusively. The
driving force in this case is probably the release of strain energy in

the four-membered ring.

OIH) JxNgfla/tm‘

R o R
x
R RI
‘ Y Y Path b
Scheme XIII

This reaction then served as the basis for our efforts to
synthesize regioisomeric enones (34a and 34b). Thus, ring
expansion of dichlorocyclobutanone 16 with diazomethane, followed
by zinc reduction, gave cyclopentanone 32 in excellent yield.
Subsequent methylenation of 32 by Gras‘ procedure36 [s-trioxane,
N,N‘-dimethylanilinium trifluoroacetate (TAMA) in dioxane or
tetrahydrofuran solution] failed, returning starting material.
Alternative procedures were then sought. A similar approach to
methylene ketones has been reported by Paquette, et al.37 Treatment

of bicyclic ketone 30 with paraformaldehyde and TAMA in dioxane

26

solution provided the corresponding enone 31. However, In our

hands, this method also failed to give the desired enone 343.

(HCHO) n

 

PhNH2m3'
CF3CID-

30 31

Eventually 343 was obtained in poor yield by a Mannich
reaction of ketone 32 with ammonium salt 12, prepared from the
reaction of N, N, N‘, N‘-tetramethyl diaminomethane (aminal) and
acetyl chloride in ether solution.66 As noted , dimethylene ketone
343 was the major product, even though less than one equivalent of

12 was used in the methylenation.

27

o 1. CH2N2
CI 2. Zn/HOAc’ 0
Cl
1 6 3 2

 

85.7%

 

 

 

' CI
4.
HZC=N(CH3)2 12_ 0 + .. o
343 34c
19%: 29°/°
PhaP-CHZ [O]
O :
UVISO :7
68%
3 2 3 3
Scheme XII

Attempts to effect allylic oxidation of olefin 33, obtained by
Wittig reaction of ketone 32 with methylenephosphorane, through
the action of either $60238 or CrOa-Pyridine39 resulted in complete
recovery of starting material.

Treatment of ketol 293 with Dowex 50x8-100 acidic ion
exchange resin and molecular sieve 4A in refluxing chloroform
yielded enone 34a. Curiously, equivalent reactions of ketols 29c or
29d with the acidic ion exchange resin were sluggish under similar
conditions. An alternative procedure, involving mesylation of ketol
29c followed by elimination with 1,5-diazabicyclo[5.4.0]undeca-5-
ene (DBU), gave enone 34a in excellent yield (Scheme XIV). By the

same procedure, enone 34b was obtained from 29d in 94% yield.

28

The characteristic properties of enone 343 derived from
dehydration of either ketol 293 or 29c were identical with the
enone prepared by methylenation of cyclopetanone 32. This result
indicated that ketols 29a and 29c are epimeric isomers. The
observed chemical shifts of the methylene protons of enone 343 (6
6.15, 5.15) and enone 34b (6 6.03, 5.30) enabled us to easily

distinguish these two regioisomeric enones.

Dowex 50x8-100
acidic ion exchange

resin
m: Molecular sieve 4A

 

 

 

293 343 75“
OH
1. MSCl/EtaN
.0 = to
2. DBU
78%
29c 343
O O
.. 1. MSCl/EtaN ..
OH 2. DBU 940/
29d 34 b °

Scheme XIV

29

Identification of Stereoisomeric Hydroxymethyl
Cyclopentanones

Having established the characteristics of enones 343 and 34b,
we proceeded to define their stereoisomeric ketol precursors. Since
the isomers 293, 29c and 29d could not be assigned configurations
based on their spectroscopic characteristics alone, we planned to
convert these ketols to 1,3-di0ls which would be defined as cis or
trans from the expected stereoselectivity of the reaction. These
assignments could then be checked by observing the rates of
acetonide formation.

For this purpose we used sodium triacetyl borohydride, a
highly selective reducing agent which reduces ketones only when a
neighbouring hydroxyl group serves as a ligand for intramolecular
delivery of hydride to the carbonyl function.4° Of the three ketols
obtained from the boron trifluoride-catalyzed rearrangements, both
29c and 29d have their hydroxymethyl group projecting from the
convex face of the cis-bicyclononane ring system. In these cases we
expected the normal convex facial-selectivity of the reduction
would be enhanced by the neighbouring group effect. In the event,
sodium triacetyl borohydride reduction of 29c or 29d gave high
yields of diols 35c or 35d, respectively, which in each case were
assigned trans configurations. On the other hand, isomer 293 has a
concave-face oriented hydroxymethyl group which, because of steric
hindrance, is less easily bound to the reducing agent. Here reduction
proceeded sluggishly at both faces of the carbonyl function and

yielded both cis 353 and trans 35e diols.

30

By comparison, sodium borohydride (NaBH4) reduction of ketols

29c or 29d each gave a Single product in lower yield. When ketol

293 was treated with NaBH4 in methanol solution, more than three

 

 

/OH /OH
3 5 a 3 5 e
N a B H 4 230/0 200/0 8°/o
NaB(OAc)3H 31% 25%
OH OH
O : ""IOH
29c 35c
NaBH4 810/0
NaB(OAc)4H -100%
O OH
OH : : OH
29d 35d
NaBH4 78%
NaB(OAc)3H 84%

Scheme XV

31

compounds, including 353 (31%),35e (25%)along with other
unidentified diols (8%), were obtained. This was attributed to the
epimerization of 293 under the reaction condition (Scheme XV).
Alternative preparations of these diols from enones 34a and
34b were also explored. Reduction of enone 343 with NaBH441 gave
a 9 : 1 ratio of epimeric allylic alcohols 363 and 36c which were
separated by flash chromatography. Subsequent acetylation of the
major alcohol 363 followed by hydroboration/hydrogen peroxide
oxidation gave dioI 353 in 42% overall yield from 343. Diol 35b
was also obtained in 50% yield from 34b by this same procedure.
This sequence of reactions, beginning with carbonyl reduction and
ending with hydroboration oxidation, was assumed to proceed
predominantly at the less hindered convex face, leading to the

formation of cis-diols (Scheme XVI).

 

 

 

 

CaeBHCI3
83%
6c
OH OH
+ O
*C’NaBH CeCI3
33% 20 : 1
36b 36d
=/OH
Ac 0 3
“...-OH ,2 . “""OAC 1. BZHG : ...-00H
Pyridine 2. 'OH/H202
720/0 0°
36 3 72/ 35a
9H 9H
A0201.BzH6 ‘ [OH
Pyridine. 2. 'OH/H202
90°/o 00
36b 58/ 356

Scheme XVI

Diol 35c was also prepared by an independent sequence of
reactions. Thus, carboxymethylation of 32 followed by sodium
borohydride reduction, dihydropyran protection, lithium aluminum
hydride reduction and deprotection gave the trans-diol 35c as a

predominant product (72% yield overall). The trans configuration

33

assigned in this case can be rationalized on the basis of steric

considerations.42 Of course, this diol was found to be identical to
the diol, derived from NaB(OAc)3H reduction of ketol 29¢ (Scheme

xvn).

COzMe

 

 

CO(OMe) 2 NaBH 4
O t O :
NaH

32

(302148

aolllOH

As expected,

 

CHZOH

1. DHP
2. LAH .

+ > ""OH + Diols
3. H

35c
Overall 72% 1 0%
Scheme XVII

the cis-diols 358 and 35b readily formed

acetonide derivatives 40a and 40b respectively, on treatment with

anhydrous copper sulfate in acetone solution43 (> 50% yield in 2 hr at

25 °C). The trans isomers 35c and 35d reacted sluggishly, giving

less than 5% acetonide's under equivalent conditions.

34

 

 

(OH ..
03 03 X
"HIGH : ..IIIO
Acetone
35a 408
9H 05‘—
? HO f 0
Acetone
35b 40b

At this stage, we had established reasonable structures and
configurations for regioisomeric enones 34a and 34b as well as
stereoisomeric ketols 356, 35c and 35d. To rationalize the
selective behavior of isomers 9a through 9d in the boron
trifluoride-catalyzed rearrangements, we made the plausible
assumption that the preferred transition state will have an anti-
periplanar orientation of the oxirane CH-O bond and the migrating
residue of the four-membered ring. Dihedral angles, calculated by
MM2,44 between the anti-periplanar ring residue and the CH-O bond
of the most stable conformation in each epoxycyclobutanol are
shown in Table V. Using this information together with Dreiding
models and the assumption thst transition state energy difference
will reflect ground state conformational energy difference, we

propose the configurational relationships depicted in Scheme XVIII.

35

Table V. Dihedral Angle in the Most Stable Conformer of
9a through 9d

 

 

 

 

 

 

 

Compound Potential Energy Dihedral Angle
(Kcal/mole) (Degree)*
9a 44.0 176.26'7’9'12
9b 44.4 177.4‘3'7'9'12
9c 44.7 172.1‘5'7'9'12
9d 44.3 175.0’3'7'9'12

 

 

 

* : atom number

OH

6 I7 /\o.2

9
8

 

 

Scheme XVIII

CYCLOBUTANES IN ORGANIC SYNTHESIS
PART II
SOLCOLYTIC STUDIES OF ESTER DERIVATIVES OF
BlCYCLO[n.2.0]ALKANOLS (n - 3 OR 4)

Introduction

This study began with an attempt to oxidize vinylcyclobutanol
45 by treatment with ceric ammonium nitrate in acetonitrile at
reflux. Unexpectedly, we obtained the rearranged vinylcycloheptenyl

nitrate 44b (23%) together with a complicated mixture (35%), and

0
446

were not able to detect any 443.

9H
E (NH4I209(N03)6

X
.I
45\ \Q/

0N02

 

44b 23%

The ring-opened compound 44b appeared to be a solvolytic
product of 45 (N03- as nucleophile, OCe(N03)5 as leaving group).

Consequently, it seemed to us that better controlled conditions (pure
substrates, specific media) should lead to better yields of useful

cycloheptenyl derivatives.

37

38

9H =0C6(NC)3)5
—»
45
NO'
_. . / .3.» \.l /
+ (me 446

Previous solvolytic studies of constrained cyclobutane
derivatives demonstrated that the configuration of the four-
membered ring and ionizing substituent were major factors in
determining reactivity as well as product distribution.45 A system
in which epimeric esters showed different reactivity and gave
different products was reported by Wibergfl6 In the case of exo-
bicyclo[4.2.0]ctyI-7 tosylate (75b) the formation of a
vinylcyclohexyl ion occurs with a conformational change of the
initially flattened cyclohexane ring into a normal chair form, and is
an energetically favorable process. In the event, solvolysis of 75b
yielded only trans-2-vinylcyclohexyl tosylate and acetate. On the
other hand, a similar reaction of 75a proceeds with conversion of
the cyclohexane ring to a higher energy boat conformation, and the
vinylcyclohexyl products should not be favored. Alternatively, a
disrotatory opening of the internal cyclobutane bond in 75a would
relieve strain without increasing nonbonded steric interactions. In
this fashion, the solvolysis of 75a gave 3-cyclooctenyl acetate and

bicyclo[5.1.0]octyl-2 acetate along with only a small amount of

39

vinylcyclohexyl products. The rate enhancement of the latter
reaction was attributed to release of strain and anchimetric

assistance in the ionization process (Scheme XX).

iOTs O O I O +
°“ K Ac/H Ac +
: 0
OR
OAc

 

 

75a RsAcorTs 0”
3.2% 64% 33.1 %
OTs I I
KOAc/HOAc : . + .
OTs OAc

7 5 b

53% 47%

Scheme XX

The effect of configuration on the rates and products of
solvolysis of bicyclo[3.2.0]heptyl-6 and bicyclo[4.1.0]heptyl-2
dinitrobenzoates in 80% aqueous acetone has been also studied.47
The endo isomer (596) has the configuration suitable for a concerted
rearrangement while 59b does not. This is reflected by the fact that
59a solvolyzes faster than 59b. However, a similar product
distribution is observed for the solvolyses of 54, 54a, 59a and 59b
(Scheme XXI). On the basis of these observations, the authors
assumed that the I-methyl bicyclo[4.1.0]heptyI-2 cation
intermediate is formed in each of these cases and is a common

intermediate leading to all the products.

40

OH OH
‘9H3 3- .QHa 9H
'. °. : CH3
. + , + + CH3
:H 'rH HO
49d 4 9 c 49a 69c

 

 

90MB
' CH3 140 °C
——> 46% 15% 9% 26%
59 a 12 hr
9H3
‘ ODNB o
160 c
—— 47% 15% 6% 23%
593 12 hr
ODNB
,CH
a" 3 85 °c
.y : 60% 21% 2% 17%
z, 4 I‘ll’
'H
5 4
QDNB
'z' $9Ha 85 °c
. 4 h > 59% 20% 2% 20%
°. I'
’H
544:

Reaction condition : 80% aqueous acetone

Scheme XXI

Wiberg‘s studies have shown that in the cases of endo
cyclobutyl derivatives, solvolysis proceeds with 0 -bond
participation, and the ring opening of the cyclobutane occurs so as to
ensure maximum overlap between the orbital of bond being broken

and the developing orbital. Thus the rate of endo isomer is faster

than that of exo isomer.

41

In contrast, Meinwald et al.“8 has found that certain epimeric
cyclobutanes under solvolytic conditions gave different products,
but showed the same reactivity. For example, acetolysis of 76a
gave pleiadiene 77 (1.2%) and acetate 78 (45%), while in the case of
76b a hydrocarbon fraction (9.5%) and three-component acetate
fraction (56%) were obtained. On the other hand, the reactivity of
epimeric esters (76a and 76b) was found to be nearly the same.
This is contrary to observation by Nelson“, involving the solvolysis
of bicyclo[3.2.0]heptyl-6 tosylates, wherein the endo isomer has a
solvolytic rate at least 500 times larger than that of the exo
isomer. The anomalously slow reaction rate of 76a as well as the
absence of cyclopropyl carbinyl products led Meinwald to question
whether anchimetric assistance by o-bond participation was

involved in this solvolysis.

 

 

 

 

 

.&OMs
_ 0 OAc
7 6 a 77 1.2% 78 45%
’OSOZCFa OAC

I— I
/ \ KOAC/HOAC: . +
\ ' / 00 ~

766 79 , so

 

 

 

 

+ Others

 

56% 9.6%
Scheme XXII

42

Continuing studies50 have yielded additional insight into the
relationship of reactivity and product distribution with the
conformation of cyclobutane rings. In this respect, prompted by our
earlier observation in the oxidation of vinylcyclobutanol 45, we
proceeded to study the solvolysis of ester derivatives of bicyclo-
[n.2.0]alkanols (n - 3 or 4) as a general synthesis of substituted

cycloheptenols or cyclooctenols (Scheme XXIII).

 

O
o_lL_a-
R .
(CH2)n Solvolysrs ‘ (0)42)" l
T R
Nu
n = 3 or 4 n = 3 or 4

Scheme XXIII

Results and Discussion

Preparation of Ester Derivatives of Cyclobutanols

The in situ cycloaddition26 of dichloroketene with an olefin to
give a dichlorocyclobutanone, followed by reductive removal of the
chlorine atoms with zinc and acetic acid is illustrated below for
cyclopentene. Other related compounds used in this investigation

are shown in Table VI.

0 O O
O + 013 CI M, ma Zn/HOAC: m
CI

41

 

Subsequent addition of Grignard reagents to these
cyclobutanones afforded cyclobutanols in good to excellent yields.
Finally, benzoates (or dinitrobenzoates) was prepared by treatment
of the cyclobutanols with 2 equivalents of benzoyl chloride (or 1, 3-
dinitrobenzoyl chloride) in pyridine solution in the presence of
catalytic amounts of 4-dimethylaminopyridine (DMAP). The yields of

specific products are listed in Table VII.

43

44

Table VI. Cycloadducts of Dichloroketene and Olefins

 

Olefin Cycloadduct Reduction Product Yield (%)

<3 (113 of. ..

<1 9f: if; as
O

 

 

 

 

0 O

0;: ..
CI

9\
I
\
.6
N

 

 

 

Attempts were made to convert vinylcyclobutanol 45 to the
corresponding tosylate or methanesulfonate. However, these
reactions did not proceed smoothly, probably due to steric hindrance
of the endo tertiary alcohol and/or the extreme reactivity of 3°-

allylic sulfonate ester.

45

Table VII. Adducts of Grignard Reagents with Cyclobutanones

and their Ester Derivatives

Product( yield %)

 

Dinotrobenzoate( yield %) Benzoate( yield%)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

= (75) QDNB (77)
<33") On 55
ODNB
(82) (65) O 00
Cum... Ctr—Ms. Cthgg
0
g” (92) 9MB (55) gJ—O
< [I < 47 57a Ctr-<(gglb
OH ODNB
‘-' 92 (83)
CIT" ‘49; CUM“
9H (82) ODNB (79)
r E:
mar 50 0:- 60
OH ODNB
5' (60) 3 (85)
OTQ 51 Ctr—O 61
9H QDNB
' (85) 83
<11“ 52 Cm
so” I 92) §°DNB (86
0.. l 53 ©.. I 63’
O
OH
: (83) 90616 (86) .9 II I: ]
$63
‘:ODNB

: 3,5-Dinitrobenzoate

46

Acetolysis of 6-Alkenyl Bicyclo[3.2.0]heptyI-6 Ester
Derivatives

Solvolytic reactions of 55 were carried out under various
conditions, the best consisting of glacial or aqueous acetic acid
solutions containing potassium acetate or triethylammonium
acetate (TEAA) at 80 OC. The results of these experiments are
summarized in Table Vlll.

Much to our surprise, the only products formed under all
reaction conditions were 3-vinyl cycloheptenol-3 (660) and its
ester derivatives (666 and 66b). The structure of 666 was
assigned from spectroscopic data as well as chemical reactions.
Thus, cycloaddition of 66c with maleic anhydride provided a 1 : 1
ratio of diastereomeric DieIs-Alder products (82), indicating the
conjugated diene character of 66c. Oxidation of 82 with pyridinium
dichromate (P00) in DMF solution gave a single isomer (83), which
was assigned the endo configuration on the strength of Alder‘s

rule.51

0 o
z
Q\/+¢O Ben ene (“\ch
reflux :.0 ' ’00
10
HO O GHBOA: 5 /o ——:).

55° 62 63

 

47

gone

 

 

 

 

 

 

 

 

’ 80 ° + + _
(IR ——2- QJ/ / 07694
12 hr
OAc ODNB OH
5 5 666 66b 66c 66d
Table VIII. The Product Distribution from Solvolyses of Benzoate 55
Yield(%)
Reaction Condition
666 66b 66¢ 66d
4 eq. KOAc/HZO 5 43
4 eq. KOAc/HOAc 32 21
10 eq. KOH 43
HOAc : H20 (6/1)
2 eq. ' OAc 66 8
HOAc
2 eq. ' OAc' 54 28
HOAcszO (3/1)
2 eq. ‘ OAc‘
4 eq' ”CD 4 24 5 4 7 26 2
HOAc : H20 (3/1) ' ' '
4 eq. LiClO4
H20 55

 

 

 

* :0.1 M EtaNHOAc in HOAc

48

Heterogeneous hydrolysis of 55 with 4 equivalents of LiCIO4
in H20 yielded the interesting bicyclic ether 66d, presumably by
internal trapping of allylic cation intermediate A by the oxygen

atom of the hydroxyl group, as shown in Scheme XXIV.

HO HO HO A
660
@‘7’
66d

Scheme XXIV

For the solvolysis of 566 and 56b, the same conditions which
gave the best results for 55 were used. Thus, buffered acetolysis of
566 (cis : trans = 2.5/1) with TEAA in aqueous acetic acid afforded
acetate 67a and alcohol 67c. A similar result was obtained in the
case of 56b (Scheme XXV) That dienyl acetate 676 was a single
stereoisomer was confirmed by its 130 NMR spectrum, and the trans
configuration was indicated by the vicinal coupling constant (J -

15.1 Hz) of the olefinic protons in the 1H NMR spectrum.

49

Emma 2 eq. TEAA
m T /
HOAc : H20(3/1)

 

 

R0
566 cisztrans(2-5/1) 676 3R = Ac 67c: R .. H
o 51% 14%
O—u—Ph 2 eq. TEAA
2 \ —: /
HOACIH20(3/1) R0
56b 67a=R=Ac 67czR-H
38% 21%

Scheme XXV

The product distribution from solvolysis of 57a and 57b was
dependent on the reaction conditions, as shown in Table IX and Table
X, respectively. Two points should be noted . First, 576 solvolyzed
faster than 57b in agreement with the fact that dinitrobenzoate is a
better leaving group than benzoate. Second, The formation of
isomerized diene 686 (or bicyclic ether 68d) probably proceeds by
way of the stable carbocation intermediate B, generating by
protonation of 686 (or 686). It should be noted that the ether

product was only formed when aqueous solvent systems were used.

 

 

, x @3
w
H“ 0“ 68d
—> ll
.. - h —
680 R8 H \ - C
686 R- Ac /
OR OAc

686

50

ODNB

 

, 2 eq. TEAA _ _
. = o +
Solvent
OAc
57a 68d 686

Table IX. The product Distribution from Solvolyses of Benzoate 57a

 

 

 

 

 

 

 

 

 

 

 

R t' C d't' S l t Yield(%)
eac ton on iron( oven) 68d 686
HOAc 85
HOAczH20(14/1) 25 61
HOAczH20(14/1) 35 53
4 eq. LiClO4
HOAczH20(3/1) 42 27
HOAc : H2 0(3/1) 53 27.3
HOACZH20(1/1) 76 18
Reaction Cndition
H2 0 >90

 

 

51

 

 

 

 

 

 

 

 

 

 

 

 

 

o
P" 2 eq. TEAA @ —
110 °C A o
C
Solvent OAc
57b 68d 686 68c
Table X. The Product Distribution from Solvolyses of Benzoate 57b
Yield(%)
Reaction Condition(Solvent) 533 53g 539
HOAc 48.3 43.4
HOAczHZO (14/1) 39-1 2715
4 eq. LiClO 4
HOAczHZO (3/1) 61-9 28-2
HOAcszO (3/1) 52.8 35.2
HOAc:HzO (1/1) 63 20.1
HOAczHZO (1/2) 77 12.4
HOAczHZO (1/3) 75.7 7
4 eq. LiClO4 80
HOAczHZO (3/1)
Reaction Condition
H20 76.6
4 eq. LiClO4 69
HZO

 

 

 

52

Acetolysis of 6-Alkyl Bicyclo[3.2.0]heptyl-6 Ester
Derivatives

Our finding that 6-alkenyl bicyclo[3.2.0]heptyl-6 esters (55
through 57) solvolyze with facile ring expansion to dienyl alcohols
and their derivatives prompted us to explore the generality of this
rearrangement by extending our study to the group of esters (58
through 61). The results are summarized in Scheme XXVI.
Significantly, in all of these cases except 58, ring expansion
products were obtained without significant formation of
unrearranged compounds, and yields ranged from 81 to 86%.

On consideration of the facts summarized in Scheme XXVI,
several interesting points emerge. First of all, the high KCH3/KH
ratio is probably a reflection of the difficulty of forming the
cyclobutyl cation in the absence of stabilization by substitution.
Secondly, since both 596 and 59b led to the same products, although
at different rates, both compounds probably react via the same
ion(s) on the way to products. Thirdly, a factor of at least 5 was
observed in the rate ratio of endo/exo 59, indicating some
anchimetric assistance by o-bond participation. Finally, the
formation of only 716 and 71b in the case of 61 was striking.
Wiberg reported47 that solvolysis of 61 in 80% aqueous acetone gave
almost equal amounts of rearranged and unrearranged products.
Consequently, Wibergproposed that a phenyl group is able to
stabilize the charge at the Ca position sufficiently to suppress
rearrangement. This view was supported by the Olah‘s observation52
that ionization of 6-phenyl bicyclo[3.2.0]heptan-6-ol in
FSOaH/SOzCIF at -149 0C gave the unrearranged parent ion by 13C

53

NMR spectroscopy. Thus it is clear that solvolysis conditions have a

marked effect on product distribution.

 

 

 

QDNB ODNB OAc gAc
= H 2 eq. TEAA ? H H
HOAc
5 8 58 60% 586 10% 58c 10%
*5 OAc
’ OAc
+ .>
58b 10% 58d 10%
QDNB 2 eq. TEAA Q
CIT” = *
HOAc AcO R ODNB R
596: R - Me 696 72% 69b 9%
60 : R - Et 70a 88%
61 : R = Ph 716 80% 71b 6.7%
ODNB
ODNB
2 . TEAA

....CHa eq : Q + m'mcw

59b 696 596
14% 55%

Scheme XXVI

54

 

goNe on Ph '
t P“ 80% aq. acetone ? Ph 5 OH
. ... . .
100 C
43% 8%
6' OH (Ref. 47)
- OH
? Ph Ph
. i .>
H H
18% 31%

As described in the introduction, orbital symmetry
considerations indicated53 that the conversion of a cyclobutyl ion
into a cyclopropyl carbinyl ion or a homoallylic ion should occur by
disrotatory ring opening, and steric factors that hinder such a
process are found to decelerate cyclobutyl solvolysis. Thus in the
case of 59a, to overlap the orbital of the bond being broken with the
back side of the developing p orbital, movement occurs in such a way
as to move the bridgehead hydrogens away from each other (pathway
a). However, in 59b, the same process would require that the
bridgehead hydrogens move toward each other, and this is
energetically unfavorable. Consequently, the solvolysis of 59b
probably proceeded through a classical ion which then undergoes a
thermodynamically controlled process leading to homoallylic
products (pathway b). Thus, both 596 and 59b solvolyzed to give
the same products, but 596 solvolyzed faster than 59b (Scheme
XXVII).

55

 

 

exo- -59b——- +E>R.—>Products
+ R
F

Scheme XXVII

To obtain a better understanding of the solvolysis mechanism,
dinitrobenzoates (54,62 and 63) were synthesized by a slight
modification of published procedures,54 or by methods described in
the previous section. For example, 54 was prepared from 2-chloro-
2-methyl cyclohexanone by the following sequence
dehydrochlorination (LiCl in DMF), reduction (lithium aluminum
hydride), cyclopropanation (CH2I2, Zn/Cu) and benzoylation (3,5-
dinitrobenzoyl chloride in pyridine, catalytic amounts of DMAP) in
7.8% yield overall.

Acetolysis of 54 was carried out with 0.1M TEAA in glacial
acetic acid at 90 °C, and the results are summarized in Scheme
XXVIIl. The data reported by Wiberg and Chen47 for the same

56

substrate in aqueous acetone are given for comparison. The
formation of ring opened acetate and dinitobenzoate in the less
nucleOphilic acetic acid medium is consistent with a longer lived
carbotion intermediate.

In studying the solvolyses of 55, 62 and 63, we found that 63
showed the lowest reactivity. A similar relationship has also been
observed by Meinwald,48 who found that acenaphthylene-fused
cyclobutane 766 has a rate at least 100 times smaller than that of
any other endo esters of fused cyclobutanes. The nearly comparable
reactivity of 55 and 62 was interesting, since the methyl group at
the C1 position should stabilize carbocation intermediate Fin
Scheme XXVII and facilitate ionization assisted by o-bond

participation.

57

 

 

 

ODNB
:é-CHS 2 eq. TEAA Q + Q
.. HOAc ' CH3 ODNB CHS
"H reflux OA"
5 4 698 55% 69b 31%
ODNB OH 9H CH
Ema 80% aq. Acetone .~“CH3 , a“ 3
O . 5 O +
.H 80 0 2H '4... ( Ref. 47)
5 4 49d 60% 49c 21 %
9H 96
499 17% 496 2%
gone
: 2 e . TEAA
m HqOAc 4 / + /
CH
CH3 80 °C CH3 OAc 3 cone
6 2 726 43.5% 726 5.7%

 

 

6 3 ' 73a 25.3% 736 34.5%

Scheme XXVlIl

58

Acetolysis of 7-Vinyl Bicyclo[4.2.0]octyI-7 Ester
Derivatives.

Effecting the acetolysis of 7-vinyl endo bicyclo[4.2.0]octyl-7
dinitrobenzoate (646) to a vinyl cyclooctenyl derivative proved to be
challenging. Treatment of 646 with 0.1M TEAA in glacial acetic
acid as in the earlier studies afforded not only 746 (10-15%) but
also 74f (SO-75%). A variety of ester derivatives of
vinylcyclobutanol 186, such as the trifluoroacetate, acetate,
benzoate and p-nitrobenzoate were examined under different
reaction conditions; however, in all cases the desired dienyl acetate

(746) was obtained in only poor yield (10-15%).

? 2eq.TEAA 3 CM
0- x : +
HOAc, 80°C
OAc

/
64 741‘ 746
60-75% 1 0-1 5%

 

R - CF3, CH3, Phenyl, p-Nitrophenyl, 3,5-Dinitrophenyl

We speculated that 74f was derived by an SN2‘ mechanism
with nucleophilic attack at the 1°-carbon occurring in preference to
conventional 8N2 displacement. In order to obtain a better yield of
ring opened products, we decided to modify the reaction medium so
as to enhance the formation of a carbocation intermediate in the
solvolysis. The so-called " special salt effect " proposed by

Winstein55 for the acetolysis of organic halides or

59

benzenesulfonates is well-suited to this purpose. Added salts, such
as lithium perchlorate or lithium bromide, not only increase the
solvolysis rate of alkyl bromides56 or benzenesulfonatesfi7 but also
trap the solvent-separated ion pair intermediate to form R+|| CIO4-
which then goes on to products.

When ester 646 was treated with TEAA in aqueous acetic acid
in the presence of 2 equiv. of LiBr, an improved yield (ZS-35%) of
cyclooctenyl derivatives was obtained. However, allylic acetate
74f was still the predominant product (40-45%). Further analysis
of the cyclooctenyl products by 1H NMR indicated a complicated
mixture, including not only acetates but also bromides. A similar
result was also observed with lithium chloride. We then turned our
attention to lithium perchlorate, an anion having little nucleophilic
character, as the added salt for the solvolysis reactions. Promising
results were obtained and are described in Table XI. With as little
as 2 equivalents of LiClO4 the derived vinylcyclooctenyl derivatives
(746, 74c) were the major product. With larger amounts of salt,
allylic icetate 74f could not be detected, and 746 together with
74c were obtained in almost 70% yield (run 3). With 8 equivalents
of added LiClO4, the yield of the thermodynamically favored isomers

(74d and 74e) increased to roughly 20% at the expense of 74c.

 

HOAC: H 20(3/1) CM
646 746

ODNB OQ—‘OH74C
CI]_\2 eq. TEAA QJ+
746

Table XI. The Product Distribution from Solvolyses of Benzoate 656

 

 

 

 

 

 

 

 

' 0
Run Reaction Condition Y'e|d(/°)
74a 74d 74c 74e 74f
1 2 eq. LiClO4 36.3 <2 14 3 14.5
2 4 eq. LiCIO4 40.8 <2 20.5
3 6 eq- LiClO4 42.8 <2 26.6
4 8 eq. LiClO4 45.9 16.4 6.2 4.6

 

 

Not surprisingly, on treatment with TEAA and LiClO4 in
aqueous acetic acid, exo ester 65 reacted slower than endo ester
64a to give 746 (20.3%), 74c (17.4%), and 74a (3%) along with 741
(3.2%). This was consistent with our previous observation in the
acetolysis of bicyclo[3.2.0]heptyl-6 systems. Finally the most
effective procedure for preparing the desired vinycyclooctenyl
compoundswas the acetolysis of benzoate 64b. This afforded vinyl

cyclooctenyl derivatives in over 85% yield without any formation of
74f (Scheme XXIX).

61

ACOH20
’ /

4.
09 0v» 0:)

 

OAc OH 0”
74a 74c 74e 74'
ODNB Zeq. TEAA
4 98° “(3'04 : 20.3% 17.4% 3% 3.3%
HOAc:H%O(3/1)
6 5 100 C

O
2 eq. TEAA
04"?“ 4 eq. LiClO4

Oj—\ , 65% 21.6% 4.1%
HOAczHZO(3/1)

0
64,, 100 c

 

Scheme XXIX

In summary, we have identified conditions for the conversion
of a variety of bicyclo[3.2.0]heptyI-6 derivatives to their
corresponding cycloheptenol derivatives. The analogous 7-vinyl
bicyclo[4.2.0]octyI-7 esters have also been converted to vinyl
cyclooctenol derivatives in good to excellent yields. An advantage
of this method is the facility with which alkyl or alkenyl
cycloheptenols and their derivatives can be prepared from readily
available bicyclo[3.2.0]heptanone-6 by three simple operations
(Grignard reagent addition, benzoylation and acetolysis). In
particular, The two ring functionalities (double bond and OR group)
created in this process. should allow further synthetic elaboration to

proceed in any of several directions.

CYCLOBUTANES IN ORGANIC SYNTHESIS
PART I
REGIO AND STEREOSELECTIVE REARRANGEMENTS
OF 7-OXIRYLBICYCO[4.2.0]OCTAN-7-OLS

Experimental Section

Unless otherwise indicated, all reactions were conducted
under a dry argon or nitrogen atmosphere, using solvents distilled
from appropriate drying agents. Reactions were monitored by thin
layer chromatography (Silica Gel 60 F254, E. Merck or Al Sil
G/UV254, Whatman) with visualization by ultraviolet fluorescence or
chemical reagents (30% aqueous H2SO4 or ammonium molybdate in
10% aqueous H2SO4) followed by heating. Analytical samples were
prepared by flash chromatography using Merck Silica Gel (230-400
mesh), as described by Still et al.53

Melting points were determined on either a Hoover-Thomas
apparatus or a Reichert hot-stage microscopic, and are uncorrected.
Infrared (IR) spectra were taken on a Perkin-Elmer 237 B or a
Perkin-Elmer 599 spectrophotometers in dichloromethane solution
unless indicated otherwise. 1H NMR spectra and 13C NMR spectra
were taken in deuteriochloroform solution and recorded on a Bruker
250 MHz spectrometer operating at 69.8 MHz for carbon, and were
calibrated in parts per million (5) from tetramethylsilane (TMS) as
an internal standard. UV absorption spectra (in 95% EtOH or CH30N)
were measured with a Perkin-Elmer 200 spectrophotometer. Mass
spectra (MS) were obtained with a Finnigan 400 GC/MS spectrometer
and recorded as We vs relative intensity. High resolution mass
measurements were made on a JEOL-HX 110 mass spectrometer.
Elemental analyses were conducted by Spang Microanalytical

Laboratory, Eagle Harbor, MI.

62

63

Cycloaddition of Cyclohexene with Dichloroketene

A solution of freshly distilled trichloroacetyl chloride (2.8 ml,
25 mmol) in dry ether (250 ml) was added over 4 hr to a stirred,
refluxing mixture of cyclohexene (2.6 ml, 25 mmol) and activated
zinc27 (5 g) in Eth (250 ml). The reaction mixture was stirred at
reflux overnight, then filtered through a pad of Celite. The filtrate
was concentrated to ca. 25% of its original volume, an equal amount
of pentane was added, and this mixture was washed with cold water,
cold saturated aqueous NaHCOa, brine and dried over Na2SO4.
Kugelrohr distillation of the product afforded dichlorocyclobutanone
16 (4.2 g, 87%).
Characteristic properties of 1659: IR, 1600 cm-1; 1H NMR. 3.90
(1 H, m), 2.93 (1 H, m), 1.02-2.18 (8H, m).

Dechlorination of Dichlorocyclobutanone 16 with Zinc Dust
A stirred solution of ketone 16 (2.0 g, 10.4 mmol) in glacial
acetic acid (25 ml) was cooled and stirred while zinc dust (2.5 g, 38
mmol) was added portionwise. The reaction mixture was warmed to
75 °C, stirred overnight and then filtered through Celite. The
filtrate was mixed with ether, washed several times with cold
water,followed by aqueous sodium bicarbonate, and dried. Kugelrohr
distillation of the product (40-45 °C, 0.3 mmHg) afforded
cyclobutanone 17 (1.15 g, 90%).
Characteristic properties of 1759: IR, 1780 cm‘I; 1H NMR, 3.27
(1H, m), 3.13 (1H, m), 2.50 (1H, m), 2.44 (1H, m), 2.15 (1H, m), 1.95
(1H, m), 1.10-1.80 (6H, m).

64

Preparation of Vinyl Alcohol 186

To a stirred solution of Grignard reagent, prepared by treating
vinyl bromide (7.7 mi, 10.8 mmol) in tetrahydrofuran (20 ml)
solution with magnesium (3.18 g, 12.9 mmol), activated by 1,2-
dibromoethane (0.3 ml), was added a solution of cyclobutanone 17
(5.34 g, 4.3 mmol) in THF (20 ml). The mixture was stirred overnight
at room temperature, then quenched by addition of saturated aqueous
ammonium chloride. Extraction with ether, followed by conventional
workup and Kugelrohr distillation (43-50 00, 025 mmHg), gave
vinylcyclobutanol 186 (4.433 g, 83%).
Characteristic properties of 1866°3 IR, 3450-3600 cm'1: 1H NMR.
6.15 (1H, dd, J = 10.7 & 17.4 Hz), 5.25 (1H, dd, J - 17.4 & 1.2 Hz),
5.00 (1H, dd, J - 10.7 a 1.2 Hz), 0.84-2.10 (13H, m); 13C NMR, 143.5,
111.0, 73.1, 42.5, 37.1, 25.9, 23.5, 22.6, 21.7, 21.5.

Wittig Reaction of Ketone 17 in Toluene Solution

A mixture of ethyltriphenylphosphonium bromide (30 g, 81
mmol) with 0.5M t'AmOK in toluene (180 ml, 90 mmol) was refluxed
for 30 min. A solution of cyclobutanone 17 (2.55 g, 21 mmol) in
toluene (10 ml) was then added dropwise, and this mixture was
refluxed for 2 hr, cooled and poured into ice water (100 ml)., The
resulting mixture was extracted with toluene, and the extracts were
washed with 10% aqueous HCI, saturated aqueous NaHCOa, brine and
dried over Na2SO4,

To one-third of the ethylidenecyclobutane solution thus
obtained, cooled to 0 °C,was added m-chloroperbenzoic acid (MCPBA).

The progress of this reaction was followed by TLC, and additional

65

MCPBA was occasionally added in order to complete the reaction.
The reaction was quenched with 10% aqueous N62803, brine and
dried over Na2SO4, Removal of the solvent followed by flash
chromatography of the residue (1 : 5, ether/hexane) gave a mixture
of epoxides 26 which was used immediately in the next step.

To 1.55M n-butyl lithium in hexane (6.5 ml, 10.1 mmol) at 0 0C

was added a solution of diisopropylamine (1.5 ml, 10.4 mmol) in
ether (20 ml) . After 20 min., a solution of the epoxides 26 in ether
(10 ml) was added. This mixture was then stirred at reflux for 2 hr,
and the reaction was quenched with MeOH and diluted with ether and
water. The organic layer was washed with cold 10% aqueous HCI,
brine and dried over Na2SO4, Evaporation of the solvent followed by
flash chromatography (3 : 1 pentane/ether) gave various ratios of
vinylcyclobutanols 18a and 18b, depending on the reaction
temperature. These results are listed in Table III.
Characteristic properties of 166 : IR, 3300-3650 cm-i; 1H NMR,
6.09 (IH, dd, J = 10.7 & 17.0 Hz), 5.23 (1H, dd, J - 17.0 8. 1.5 Hz), 5.12
(1H, J - 10.7 & 1.5 Hz), 2.62 (1H, m), 2.42 (1H, m), 2.18 (1H, m),1.92
(1H, m), 0.76-1.66 (9H, m); 13c NMR, 1415,1137, 44.2, 36.4, 26.9,
25.8, 23.2, 22.4, 22.0; MS, 152 (2), 135 (49), 109 (13), 81 (31), 70
(100), 55 (80); High resolution MS, calculate for C1oH1eO,
152.1206, found, 152.1198.

Wittig Reaction of Ketone 17 in Dimethyl Sulfoxide
Solution

A solution of dismyl sodium was prepared by heating a
suspension or sodium hydride (0.612 g, 25.5 mmol) in DMSO (60 ml)

66

at 60 0C for 1 hr. After cooling to room temperature, a solution of
ethyltriphenylphosphonium bromide (9.5 g, 25.5 mmol) in DMSO (30
ml) was added dropwise, the resulting red solution was stirred for
45 min., and a solution of cyclobutanone 17 (1.1926 g, 9.6 mmol) in
DMSO (15 ml) was added. The resulting mixture was heated at 60 °C
for 65 hr, cooled, poured into ice water (100 ml) and extracted with
hexane. The hexane extracts were washed with cold 10% aqueous
HCI, water, brine and dried over N62804 . Evaporation of the solvent
followed by chromatography on silica gel (hexane) gave a 1 : 1 E/Z
mixture of ethylidenecyclobutanes 25 (0.628 g, 48%).

Characteristic properties of 25 : 1H NMR, 5.12 (1H, m), 2.93 (1H, m),
2.52 (1H, m), 2.04-2.40 (2H, m), 0.80-1.96 (11H, m).

Preparation of Epoxy Cyclobutanols 9

Vinylcyclobutanols 186 and 18b were epoxidized by MCPBA. A
solution of the substrate (1.00 g, 6.6 mmol) in methylene chloride
(20 ml) was cooled (ice bath) and treated with MCPBA (ca. 10 mmol)
by dropwise addition of a methylene chloride solution of the peracid.
Following an overnight reaction period (25 °C), the reaction mixture
was filtered and washed with 10% aqueous Na2SO3 and brine. The
dried solution yielded an oily product which was purified by
chromatography (1 : 3 pentane/ether) to give 1.028 g of a 1 : 1
mixture of
diastereomeric epoxycyclobutanols 9c and 9d (93%).
Characteristic properties of 9c: IR, 3400-3650 cm'I; 1H NMR,
3.25 (1H, m), 2.74 (2H, m), 2.48 (2H, m), 1.10-2.30 (11H, m); 13C
NMR (acetone, d-6), 75.5, 52.5, 43.3, 42.2, 33.2, 27.0, 26.1, 23.2,

67

22.6, 22.2; MS, 168 (2), 149 (30), 139 (100), 66 (20); High
resolution MS, calculated for C1oH1302, 168.1151; found, 168.1160.
Characteristic properties of 9d : IR, 3450-3600 cm-i: 1H NMR,
3.26 (1H, dd, J =- 4.1 a 2.6 Hz), 2.65 (1H, dd, J .- 5.2 a 2.6 Hz), 2.75
(1H, dd, J a 5.2 a 4.1 Hz), 2.60 (1H, m), 2.36 (1H, m), 2.20 (1H, m),
1.20-2.20 (10H, m); 13C NMR, 76.5, 54.3, 44.2, 43.3, 34.1, 27.1, 25.7,
22.4, 22.3, 21.9; MS, 168 (2), 167 (13), 149 (100), 123 (35), 108
(33), 97 (70), 73 (45); High resolution MS, calculated for C1oH1302,
166.1151; found, 166.1156.

lsomers 9a and 9b were prepared from the corresponding
bromohydrins (386 and 38b) after chromatography separation, as
described below.
Characteristic properties of 9a : IR, 3500 cm-1; 1H NMR, 3.21 (1H,
dd, J =- 4.0 a 2.9 Hz), 2.63 (1H, dd, J .- 5.0 a 2.8 Hz), 2.76 (1H, dd, J -
5.0 a 4.0 Hz), 1.01-2.45 (13H, m); 13C NMR, 70.7, 56.7, 44.4, 39.5,
36.1, 26.1, 24.3, 22.6, 21.7, 21.1.
Characteristic properties of 96 : IR, 3500 cm-1; 1H NMR, 3.27 (1H,
dd, J =- 25 6 5.0 Hz), 2.82 (1H, dd, J - 2.5 & 5.0 Hz), 2.77 (1H, dd, J -
5.0 a 5.0 Hz), 0.91-2.45 (13H, m); 13C NMR, 71.5, 56.8, 44.1, 40.0,
35.1, 27.0, 24.6, 23.3, 22.4, 21.9.

Preparation of Bromohydrins 38

A solution of an epoxycyclobutanol isomer, 9abcd, (0.3323 g,
2.0 mmol) in THF (10 ml) was stirred at room temperature while
magnesium bromide etherate (0.68 g, 2.4 mmol) was added. Thirty
minutes later the reaction mixture was quenched with water and

carefully acidified by the addition of 1N hydrochloric acid. Ether

68

extraction in the usual manner gave crude bromohydrin which was
purified by chromatography (1 : 3 pentane/ether). From a 1 : 1
mixture of 9a and 9b the respective bromohydrins (386 and 38b)
were obtained, each in 46% each isolated yield. The other isomers
(38c and 38d) were obtained from 9c and 9d respectively in > 95%
yield.

Characteristic properties of 386 : Rf = 0.30 (1 : 3 pentane/ether);
mp, 110-112 0C; IR (KBr), 3500 cm“; 1H NMR, 3.88 (1H, m) , 3.62
(1H, dd, J - 2.3 & 10.6 Hz), 3.49 (1H, dd, J - 10.6 & 9.6 Hz), 1.03-2.51
(14H, m); 13c NMR (DMSO, d-6), 76.2, 75.6, 39.6, 37.6, 35.5, 27.3,
24.8, 23.2, 22.2, 20.8.

Characteristic properties of 380 : Rf :- 0.58 (1 : 3 pentane/ether);
mp, 142-143 0C; IR (KBr), 3550 cm-1; 1H NMR, 3.91 (1H, dd, J - 10.1
& 2.3 Hz), 3.65 (1H, dd, J - 10.7 & 2.3 Hz), 3.51 (1H, dd, J - 10.1 &
10.7 Hz), 0.93-2.63 (14H, m); 13C NMR, 76.8, 75.6, 36.2, 37.0, 35.9,
27.0, 24.8, 22.0, 21.4, 21.1.

Characteristic properties of 38c : mp, 138-140 0C; IR (KBr), 3300-
3650 cm'I; 1H NMR, 3.92 (1H, dd, J - 9.3 & 2.9 Hz), 3.50 (1H, dd, J a
10.8 & 9.3 Hz), 3.43 (1H, dd, J = 10.8 & 2.9 Hz), 1.01-2.90 (14H, m);
13C NMR (acetone, d-6), 78.9, 76.2, 43.0, 36.9, 36.7, 27.3, 26.8, 23.5,
23.1, 22.1.

Characteristic properties of 380 : mp, 97-98 00; IR (KBr), 3250-
3600 cm-1; 1H NMR, 3.97 (1H, dd, J 7.6 a 4.8 Hz), 3.47 (2H, m),
102-2.90 (14H, m); 13c NMR (acetone, d-6), 78.5, 75.0, 44.6, 36.3,
34.3, 26.8, 23.5, 23.1, 22.2.

69

Base-Induced Cyclization of Bromohydrins 38 to
Epoxycyclobutanols 9

A stirred solution of bromohydrin 386 (95 mg, 0.38 mmol) in
methanol (5 ml) was treated with 1N sodium hydroxide in methanol
(0.4 ml, 0.4 mmol). After 24 hr the reaction mixture was
neutralized with dilute aqueous hydrochloric acid and diluted with
ether. The organic layer was washed and dried; removal of the
solvent gave 63 mg (98%) of epoxycyclobutanol 9a.

In a similar reaction bromohydrin 38b gave 9b in 75% yield.

Boron Trifluoride-Catalyzed Rearrangement of 9

The following procedure is typical. To a stirred solution of 9a
and 9b (0.331 g, 2 mmol) in CH20I2 (10 ml), cooled to -78 °C, was
added ca. 0.2 mmol of BF3-OEt2 via syringe. This mixture was
stirred for 90 min., quenched with water and mixed with more
CH2CI2. Conventional workup and evaporation of the solvent gave a
residue which was purified by chromatography (1 : 3 pentane/ether)
to provide ketol 296 (0.15 g, 42.7%, Rf . 0.2), and recovered 9b
(0.16 g, 49.5%, Rf - 0.39).
Characteristic properties of 29a : IR, 3300-3650, 1705 cm‘I; 1H
NMR, 3.90 (1H, dd, J - 11.2 3. 7.4 Hz), 3.62 (1H,dd, J - 11.2 a 6.9 Hz),
2.59 (1H, m), 2.03-2.52 (5H, m), 1.31-1.83 (8H, m); 130 NMR, 221.3,
58.9, 58.3, 38.6, 38.2, 33.3, 26.2, 24.5, 23.4, 19.8; MS, 168 (5), 108
(50), 95 (11), 67 (48), 55 (47), 41 (100); High resolution MS,
calculated for C1oH1302, 168.1151; found 168.1160.
Characteristic properties of 29c : Yield, 88%; IR, 3350-3600, 1710
cm-1; 1H NMR, 3.64 (1H, dd, J - 10.8 a 5.2 Hz), 3.67 (1H, dd, J - 10.8

7O

6 6.4 Hz), 0.65-2.59 (14H, m); 13C NMR, 222.3, 62.9, 50.4, 47.6,
34.6, 29.5, 29.1, 24.4, 22.9, 22.7; MS, 168 (10), 150 (5), 12 (15), 95
(27), 81 (75), 67 (100), 55 (53), 41 (95).

Characteristic properties of 29d : Yield, 73.8%; IR, 3450-3600,
1725 cm-1; 1H NMR, 3.79 (1H, dd, J =- 4.3 6 11.7 Hz), 3.59 (1H, dd, J
g, 6.1 & 11.7 Hz), 2.10-2.51 (6H, m), 0.85-1.80 (8H, m); 13C NMR,
222.3, 60.5, 50.4, 45.8, 36.7, 33.7, 28.5, 25.6, 24.3, 20.4; MS, 168
(5), 150 (5), 122 (6), 108 (58), 93 (21), 79 (38), 67 (58), 55 (50),
41 (100).

Trifluoroacetic Acid (TFA)-Catalyzed Rearrangement of 9
To a stirred solution of 96 and 9b (1.0987 g, 6.4 mmol) in
CHCI3 (50 ml) was added TFA (0.6 ml, 7.8 mmol). The mixture was
refluxed with stirring for 24 hr, then quenched with water.
Conventional workup followed by removal of the solvent gave an oil

which was purified by chromatography, using 1 : 3 ether/pentane as
eluent, to provide enones 346 (622 mg, 68.5%, Rf - 0.5), 34c (29

mg, 3%, Rf - 0.2) and 34d (63.7 mg, 7%, Rf - 0.3).

Characteristic properties of 346 : IR, 1720, 1640 cm'I; UV (EtOH),
xmax 236 (an..." 6000); 1H NMR, 6.15 (1H, d, J =- 3 0 Hz), 5.15 (1H, dd,
J - 3.0 6 1.0 Hz), 0.64-2.37 (12H, m); 13C NMR, 207.0, 146.6, 115.6,
44.1, 40.6, 33.3, 26.5, 25.8, 23.7, 20.4; MS, 150 (20), 108 (96), 93
(53), 79 (73), 41 (100), 39 (90); High resolution MS, calculated for
C1oH14O, 150.1045; round, 150.1039.

Characteristic properties of 34c61: IR, 1675, 1625 cm-1; uv
(EtOH), xmax 240 (am, 6500); 1H NMR, 2.61 (1H, m), 2.49 (2H, m),
1.56 (3H, s), 0.76-2.16 (8H, m).

71

Characteristic properties of 34d62 : IR, 1685, 1645 cm'I; UV
(EtOH), xmax 237 (emax 7600); 1H NMR, 2.71 (1H, m), 1.13 (3H, d, J =
6.0 Hz), 1.10-2.42 (10H, m).

In a similar procedure, the reaction of 9c with TFA in CHCI3
gave enones, 346 (20%) and 34c (20%). Treatment of 9d with TFA
in CHCI3 afforded 34a (28%) and 34c (13.6%), along with recovery

of 9d (36.8%).

Preparation of Enones 34 from Ketols 29

Method 1 : A mixture of ketol 29a (75 mg, 0.45 mmol),
Dowex 50x8-100 ion acidic exchange resin (50 mg) and molecular
sieve 4A in CHCI3 (20 ml) was refluxed overnight. Filtration,
followed by evaporation of the solvent afforded enone 346 (50.2 mg,
75%).

Method 2 : To a cold solution (ice bath) of ketol 29d (159.5

mg, 0.95 mmol) and Et3N (0.5 ml) in CH2CI2 (20 ml) was added
methanesulfonyl chloride (0.5 ml). This mixture was stirred for 2 hr
at 0-5 00 before it was quenched by the addition of water (2 ml) and
saturated aqueous ammonium chloride. The organic layer was
washed with 10% aqueous citric acid, saturated aqueous NaHCOs,
brine and dried over Na2SO4. Evaporation of the solvent and
chromatography. of the crude product afforded mesylate (elution
with 1 : 3 hexane/ether, Rf = 0.22).
Characteristic properties of mesylate of 29d : IR, 1740, 1352,
1175 cm-1; 1H NMR, 4.42 (1H, dd, J .- 4.8 6 9.7 Hz), 4.32 (1H, dd, J ..
4.4 8 9.8 Hz), 2.95 (3H, s), 085-253 (13H, m); 13C NMR, 217.0, 69.0,
50.1, 44.9, 36.6, 33.8, 29.2, 28.6, 24.0, 22.4.

72

To this mesylate in ether (20 ml) was added DBU (0.5 ml) at 0

°C. The mixture was stirred at the same temperature for 2 hr, and
quenched with cold 10% aqueous HCI. Following workup, the crude
product was chromatographed to give 134.5 mg of enone 34b (94%
yield overall).
Characteristic properties of 34b : IR, 1710, 1636 cm'I; UV (EtOH),
kmax 235 (cmax 8500); 1H NMR, 6.03 (1H, m), 5.30 (1H, m), 2.65 (1H,
m), 2.95 (1H, m), 204-2.43 (2H, m), 0.80-1.75 (8H, m); 13C NMR,
206.8, 144.0, 117.9, 49.6, 34.3, 33.4, 29.2, 24.0, 22.8, 22.5; High
resolution MS, calculated for C10H14O, 150.1045; found, 150.1036.

Ketol 29c was converted to a mesylate derivative and then

eliminated by DBU treatment, as above. Chromatography of the
crude product gave 346 in 78% overall yield.
Characteristic properties of the mesylate derived from 29c : IR,
1745, 1360, 1160 cm-1; 1H NMR, 4.43 (1H, dd, J = 10.0 6 4.0 Hz),
4.28 (1H, dd, J = 10.0 & 3.8 Hz), 2.92 (3H, s), 1.12-2.50 (13H, m);
130 NMR, 216.6, 66.7, 47.4, 45.4, 36.5, 36.3, 33.1, 28.1, 25.0, 24.2,
19.8.

Preparation of Enone 346 from Dichlorocyclobutanone 16
To a solution of CH2N2 in ether, prepared by the reaction of
KOH (5.6 g) with N-methyI-N-nitroso-p-toluenesulfonamide (10.7 g,
50 mmol) in 1 : 3 diethyleneglycoI/ether (60 ml) solution,65 was
added a solution of ketone 16 (5.0416 g, 26 mmol) in Et20 (10 ml),
followed by MeOH (10 ml). Immediately, a brisk evolution of nitrogen
ensued. After 30 min., excess diazomethane was destroyed with a

few drops of AcOH. The solvent was evaporated to afford crude

73

dichlorocyclopentanone which was used immediately in the next
step.

To a stirred solution of the foregoing crude product in glacial
acetic acid (40 ml) was added zinc dust (10 g) in portion. The
reaction mixture was raised to 70 °C, stirred for 3 hr and filtered
through Celite. The filtrate was mixed with ether, washed several
times with cold water followed by aqueous sodium bicarbonate and
dried_ Kugelrohr distillation of the crude product gave
cyclopentanone 32 (2.95 g, overall 86%).

Characteristic properties of 3253 : IR, 1740 cm‘I; 1H NMR, 1.88-
2.36 (6H, m), 1.07-1.66 (8H, m).

An acetonitrile solution of ketone 32 (820.4 mg, 5.94 mmol)

and N, N-dimethyl(methylene)ammonium chloride66 (1.66 g, 19
mmol) was refluxed with stirring for 6 hr. After addition of K2C03 ,
this mixture was stirred for 6 hr at room temperature. Removal of
the solvent and the residue was diluted with ether and aqueous
N6H003 The organic layer was dried over Na2SO4. Evaporation of the
solvent yielded an oily residue, which was purified by flash
chromatography using 1 : 6 ether/hexane as eluent. This afforded
enone 346 (171.9 mg, 19%, Rf = 0.34), and dimethylene ketone 34e
(27.5 mg, 29%, Rf = 0.23).
Characteristic properties of 346 : IR, 1700, 1640 cm'1; 1H NMR,
6.04 (2H, dd, J a 1.0 8: 0.8 Hz), 5.27 (2H, dd, J = 1.0 8: 0.5 Hz), 2.29
(2H, m), 1.24-1.73 (8H, m); 130 NMR, 195.6, 149.0, 116.5, 39.4, 27.4,
22.0.

74

Preparation of Cis-Diols 35 from Enones 34

To enone 34b (351 mg, 2.34 mmol) was added 0.4M CeCI3-6H2O

in methanol solution (6 ml, 2.4 mmol), followed by addition of NaBH4
(15 mg, 3 mmol)at 0 °C. The reaction mixture was allowed to react
for 20 min., and then quenched with cold 5% aqueous HCI. After
conventional workup, the residue was purified by chromatography (1
: 1 ether/pentane) to give allylic alcohol 36b (308.4 mg, 88.4%) and
its epimer 36d.
Characteristic properties of 36b : IR, 3560 cm'I; 1H NMR, 5.05
(1H, dd, J =- 2.5 & 5.0 Hz), 4.94 (1H, dd, J - 2.5 8 5.0 Hz), 4.41 (1H, m),
0.70-2.40 (13H, m); 13c NMR, 154.2, 107.0, 78.2, 42.7, 32.2, 31.0,
26.6, 24.3, 20.7.

A solution of 36b (108 mg, 7.1 mmol) in pyridine (10 ml) was

mixed with acetic anhydride (2 ml, 19 mmol), and this mixture was
refluxed with stirring for 3 hr, cooled, and poured onto ice (20 ml).
The aqueous solution was extracted twice with ether and the
combined extracts were washed with 10% aqueous HCI, saturated
aqueous NaHCOs, and brine. The dried extract solution yielded an oily
product which was chromatographed to give allylic acetate 37b
(137 mg, 98%).
Characteristic properties of 37b : IR, 1725, 1235 cm“ 1H NMR,
5.42 (1H, m), 5.02 (2H, m), 2.11 (3H, s), 0.90-2.50 (12H, m); 13C NMR,
170.8, 148.8, 108.6, 79.1, 40.6, 33.1, 31.1, 26.5, 24.2, 21.5, 20.9,
20.7.

To a stirred solution of allylic acetate 37b (63 mg, 0.32
mmol) in THF (5 ml) was added 1M B2H3 in THF (1 ml, 1 mmol) at 0

oC. The reaction mixture was stirred at 0 0C for 3 hr, then quenched

75

with 10% aqueous NaOH (10 ml) and 30% H202 (3 ml). Extraction
with ether, followed by conventional workup and chromatography
gave cis-diol 35b (32.1 mg, 58%).

Characteristic properties of 35b : IR, 3200-3600 cm'I; 1H NMR,
4.42 (1H, m), 3.76 (2H, m), 2.38 (4H, m), 1.98 (2H, m), 1.00-1.77 (9H,
m); 13C NMR, 77.6, 64.2, 43.6, 44.4, 35.7, 29.6, 27.9, 24.8, 22.0, 21.8;
MS, 168 (3),152 (13), 108 (27), 95 (23), 81 (72), 67 (84), 55 (76), 41
(100).

In a similar procedure, reduction of 346 with NaBH4-CeCI3 in
MeOH gave allylic alcohols 366 (74.7%) and 360 (8.3%).
Characteristic properties of 366 : IR, 3575 cm'1; 1H NMR, 5.18
(1H, dd, J - 2.2 8 2.2 Hz), 5.00 (1H, dd, J - 2.2 8 2.2 Hz), 4.52 (1H, m),
2.42 (1H, m), 1.00-2.12 (12H, m); 13c NMR, 149.0, 97.4, 64.2, 42.6,
39.0, 36.2, 29.0, 28.4, 24.0, 23.8.

Characteristic properties of 36c : IR, 3560 cm-1; 1H NMR, 5.22
(1H, dd, J - 2.1 8 1.8 Hz), 5.00 (1H, dd, J - 2.1 8 2.0 Hz), 4.56 (1H, 111),
090-270 (13H, m); 13C NMR, 125.7, 108.4, 74.2, 42.3, 39.4, 36.8.
28.2, 26.7, 23.8, 22.0.

Characteristic properties of acetate 37a, derived from 366 : IR,
1725, 1225 cm-1; 1H NMR, 5.52 (1H, m), 5.02 (1H, m), 5.14 (1H, m),
2.11 (3H, s), 1.18-2.50 (12H, m); 13C NMR, 171.8, 153.7, 109.0, 75.8,
43.1, 36.8, 36.0, 29.2, 27.0, 24.0, 22.4, 21.1.

Characteristic properties of 356, derived from 376 : mp, 68-69 00;
IR, 3500 cm'I; 1H NMR, 4.23 (1H, m), 3.82 (1H, dd, J - 10.1 8 6.2
Hz), 3.71 (1H, dd, J = 10.1 8 9.0 Hz), 2.40 (1H, broad), 0.82-2.22 (14H,
rn); 13C NMR, 73.0, 59.7, 52.4, 41.3, 38.6, 38.3, 27.5, 26.4, 24.3, 21.5;

76

MS, 152 (9), 123 (8), 108 (56), 93 (29), 81 (44), 67 (54), 55 (57), 41
(100).
Reduction of Ketols 29 with NaB(OAc)3H

The following is a typical procedure. Sodium borohydride (0.2
g, 5.1 mmol) was added portionwise to chilled glacial acetic acid
(15 oC) and stirred until gas evolution ceased. Ketol 29d (73 mg,
0.43 mmol) was added, and the mixture was stirred at room
temperature for 4 hr. Following quenching with water and
extractionby ether, the crude product was chromatographed to trans
diol 35d (77.5 mg, quantitative).
Characteristic properties of 35d : mp, 78-80 00; IR, 3550 cm'1;1H
NMR, 4.00 (1H, dd, J = 5.7 8 2.1 Hz), 3.80 (1H, dd, J =- 5.7 8 4.4 Hz),
3.63 (1H, dd, J = 8.0 8 8.7 Hz), 1.10-2.31 (15H, m); 13C NMR, 80.1,
67.1, 45.8, 43.9, 34.3, 27.7, 26.9, 24.6, 22.0, 21.0; MS, 152 (21), 121
(13), 108 (28), 93 (23), 81 (58), 67 (76), 55 (74), 41 (100).
Characteristic properties of 35c : 64% yield; IR, 3580 cm-1; 1H
NMR, 4.07 (1H, ddd, J a 8.3, 5.7 8 2.5 Hz), 3.75 (1H, dd, J - 10.4 8 4.9
Hz), 3.43 (1H, dd, J - 10.4 8 9.0 Hz), 3.06 (broad, OH), 1.10-2.12 (14H,
m); 13C NMR, 77.6, 65.5, 52.2, 39.7, 39.5, 36.6, 29.1, 26.9, 24.1,
22.5; MS, 152 (6), 108 (46), 93 (25), 79 (42), 67 (53), 55 (55), 41
(100).

Preparation of Acetonides 40

A solution of diol 35b (79.6 mg, 0.47 mmol) in dry acetone (10
ml) was mixed with anhydrous copper sulfate (200 mg) and stirred
at room temperature for 2 hr. Filtration and chromatography of the

crude product from the filtrate resulted in some loss of the volatile

77

acetonide. In this case recovered 35b amounted to 7 mg (9%) and
the acetonide yield was 43 mg (44%).

Characteristic properties of 40b : 1H NMR, 4.07 (1H, dd, J - 5.2 8
5.2 Hz), 3.87 (1H, dd, J =- 11.3 8 5.2 Hz), 3.48 (1H, dd, J - 11.3 8 5.8
Hz), 1.32 (3H, s),1.27 (3H, s), 090-202 (13H, m); 13C NMR, 98.4,
75.5, 62.4, 43.0, 38.5, 37.1, 33.1, 30.6, 28.2, 24.0, 23.7, 21.1.
Characteristic properties of 406 : 52% yield; 1H NMR, 4.24 (1H, m),
3.84 (1H, dd, J =- 7.0 8 11.7 Hz), 3.74 (1H, dd, J = 6.4 8 11.7 Hz), 1.32
(3H, s), 1.26 (3H, s), 0.96-2.02 (13H, m); 13C NMR, 96.0, 71.2, 56.6,
43.3, 41.1, 37.0, 34.7, 26.9, 26.4, 25.7, 24.6, 21.4, 20.7.

CYCLOBUTANES IN ORGANIC SYNTHESIS
PART u
SOLCOLYTIC STUDIES OF ESTER DERIVATIVES OF
BlCYCLO[n.2.0]ALKANOLS (n =- 3 OR 4)

78

General Procedure for the Preparation of Cyclobutanones

A solution of freshly distilled trichloroacetyl chloride (3
mmol) in dry ether (30 ml) was added over 20 min. to a stirred,
refluxing mixture of olefin (3 mmol), dry ether (30 ml) and activated
zinc27 (0.6 g). The reaction mixture was stirred at reflux for an
additional 16 hr after the addition was complete. The excess zinc
was filtered and the filtrate was then concentrated to about 20 ml,
and mixed with pentane (40 ml). Finally, the pentane solution was
decanted from the precipitated zinc salts and evaporated to give a
crude product which was used immediately in the next step.

To a cooled stirred solution of the previous product in glacial
acetic acid (10 ml) was added zinc dust (0.5 g) portionwise. The
reaction mixture was heated to 75 °C, stirred overnight and then
filtered through Celite. The filtrates were mixed with ether,
washed several times with cold water followed by aqueous sodium
bicarbonate and dried over N62804. After removal of the solvent, the
residue was purified by Kugelrohr distillation or flash
chromatography.

Characteristic properties of 4159:Yield, 62%; IR, 1775 cm'I; 1H
NMR, 3.55 (1H, m), 3.21 (1H, m), 2.89 (1H, m), 2.48 (1H, m), 1.42-2.08
(6H, m).

Characteristic properties of 4267: Yield, 35%; IR, 1776 cm-1; 1H
NMR, 2.98 (1H, m), 2.81 (1H, dd, J =- 18.1 8 4.4 Hz), 2.65 (1H, dd, J =
18.1 8 2.9 Hz), 1.45-1.98 (6H, m), 1.41 (3H, 5).

Characteristic properties of 4367: Yield, 57%; IR, 1770 cm-1; 1H
NMR, 7.17 (4H, m), 4.02 (2H, m), 3.58 (1H, m), 3.29 (1H, d, J = 17.4

79

Hz), 3.08 (1H, m), 2.67 (1H, d, J - 17.4 Hz); 130 NMR, 211.9, 144.4,
142.6, 127.2, 125.2, 124.6, 62.6, 55.4, 36.4, 33.6.

General Procedure for the Addition of Grignard Reagents to
Cyclobutanones
To a stirred solution of Grignard reagent, prepared by treating

the appropriate alkenyl or alkyl bromide (7.5 mmol) in THF (10 ml)
solution with magnesium (9 mmol), was added a solution of the
cyclobutanone (3 mmol) in THF (10 ml). This mixture was stirred
overnight at room temperature, and then quenched by addition of
saturated aqueous ammonium chloride. Extraction with ether,
followed by conventional workup and purification by flash
chromatography yielded the corresponding cyclobutanol.
Characteristic properties of 456°: Yield, 75%; IR, 3330-3650,
1640, 998, 920 cm'I; 1H NMR, 6.15 (1H, dd, J - 17.3 8 10.6 Hz),
5.20 (1H, dd, J - 1.2 6 17.3 Hz), 5.00 (1H, dd, J - 1.2 8 10.6 Hz), 2.71
(1H, m), 2.27-2.52 (2H, m), 1.76-2.02 (3H, m), 1.35-1.62 (5H, m);
13c NMR, 146.7, 109.0, 71.0, 49.6, 39.4, 33.0, 30.9, 26.3, 26.0.

Characteristic properties of 46 : Yield, (cis +tr6ns), 82%;
trans: IR, 3350-3650, 1442, 1020 cm-1; 1H NMR, 5.75 (1H, m),
5.64 (1H, m), 2.53 (1H, m), 2.35 (1H, m), 2.26 (1H, m), 1.58 (3H, d, J =-
5.4 Hz), 136-2.01 (8H, m); cis : 1H NMR, 5.76 (1H, m), 5.52 (1H,
m), 2.57 (1H, m), 2.42 (2H, m), 2.04 (1H, m), 1.73 (3H, dd, J . 7.3 8
1.7 Hz), 1.36-1.92 (7H, 'm).
Characteristic properties of 47: Yield, 92%; IR, 3300-3650, 1642,
899 cm'I; 1H NMR, 5.01 (1H, m), 4.82 (1H, m), 2.70 (1H, m), 2.50
(1H, m), 2.41 (1H, m), 1.84 (3H, m), 1.72 (2H, m), 1.38-1.52 (6H, m);

80

13C NMR, 149.6, 106.2, 73.5, 47.2, 37.9, 32.5, 31.0, 26.2, 25.8, 17.8;
MS, 152 (2), 135 (17), 64 (70), 69 (100), 55 (31).

Characteristic properties of 49647: Yield, 92%; IR, 3350-3650
cm-i; 1H NMR, 2.46 (1H, m), 2.34 (1H, m), 2.06 (1H, m), 1.30-1.54
(4H, m), 1.64-1.92 (4H, m), 1.34 (3H, s).

Characteristic properties of 50 : Yield, 82%; IR, 3370-3650, 1440,
996 cm-1; 1H NMR, 2.46 (1H, m), 2.32 (1H, m), 2.15 (1H, m), 1.32-
1.88 (10H, m), 0.92 (3H, t, J =- 6 Hz).

Characteristic properties of 5147: Yield, 62%; IR, 3350-3650,
1604, 1496, 1075 cm-1; 1H NMR, 7.20-7.66 (5H, m), 2.97 (1H, m),
2.53 (2H, m), 142-2.17 (8H, m).

Characteristic properties of 52 : Yield, 85%; IR, 3320-3610 cm-I;
1H NMR, 6.14 (1H, dd, J .- 10.7 8 17.2 Hz), 5.20 (1H, dd, J - 17.2 6 0.9
Hz), 5.02 (1H, dd, J .-. 10.7 6 0.9 Hz), 2.64 (1H, broad), 2.25 (1H, dd, J
= 1.7 6 8.4 Hz), 2.06 (1H, dd, J =- 2.8 6 14.9 Hz), 1.29 (3H, s), 1.59-
2.03 (7H, m); 130 NMR, 145.6, 109.6, 69.3, 52.9, 44.9, 41.0, 37.8,
26.6, 25.6; MS, 152 (0.6), 135 (2), 109 (9), 63 (23), 70 (100), 67
(38), 55 (76).

Characteristic properties of 53 : Yield, 92%; IR, 3350-3650 cm'I;
1H NMR, 6.92-7.21 (4H, m), 6.01 (1H, dd, J .. 17.2 6 10.7 Hz), 5.13
(1H, dd, J =- 17.2 6 1.2 Hz), 4.93 (1H, dd, J = 10.7 6 1.2 Hz), 3.39 (1H,
m), 3.27 (1H, dd, J =- 17.8 6 2.7 Hz), 3.08 (1H, m), 2.99 (1H, dd, J .
17.6 6 9.6 Hz), 2.65 (1H, ddd, J =- 12.6, 10.6 6 2.2 Hz), 1.93 (1H,
broad), 1.63 (1H, ddd, J 12.6, 5.0 6 0.9 Hz); 13c NMR, 147.4, 144.2,
126.4, 124.7, 123.9, 110.6, 73.2, 47.6, 43.5, 37.9, 31.6; MS, 186
(0.51), 167 (1.5), 116 (100), 91 (10), 55 (24).

81

General Procedure for the Preparation of Dinitrobenzoates
or Benzoates of Cyclobutanols

To a stirred solution of the selected cyclobutanol (2 mmol) and
4-dimethylaminopyridine (20 mg) in pyridine (15 ml) was added 3,5-
dinitrobenzoyl chloride or benzoyl chloride (3 mmol). This mixture
was stirred overnight, then poured into ice (50 ml) and extracted
with ether. The combined ether layers were washed with cold 5%
aqueous HCI and dried. Removal of the solvent and purification by
flash chromatography gave the corresponding dinitrobenzoate or
benzoate derivatives.
Characteristic properties of 55 : Yield, 77%; mp, 84-85 0C; IR,
1730, 1550, 1350, 900 cm-1; 1H NMR, 9.23 (1H, t, J .- 2.0 Hz), 9.17
(2H, d, J = 2.0 Hz), 6.28 (1H, dd, J - 17.4 8 10.8 Hz), 5.35 (1H, d, J .
17.4 Hz), 5.26 (1H, d, J - 10.8 Hz), 3.17 (1H, m), 2.56-2.82 (2H, m),
1.52-2.12 (7H, m).; 13C NMR, 160.7, 148.6, 139.7, 134.5, 129.2,
122.2, 113.8, 81.0, 49.0, 36.8, 32.4, 32.2, 27.2; MS, 332 (0.05), 315
(0.09), 247 (1.7), 195 (36), 120 (42), 92 (37), 68 (100); High
resolution MS, calculated for C13H13N203; 332.1008, found,
332.1002.
Characteristic properties of 566 : Yield, 58%; mp, 160-165 00; IR,
1730, 1550, 1350, 1275, 900 cm-1; 1H NMR (cis), 9.27 (1H , m),
9.08 (2H, m),6.08 (1H, dd, J - 12.4 8 1.7 Hz), 5.61 (1H, m), 3.05 (1H,
m), 2.30 (2H, m), 1.69 (3H, dd, J - 1.7 8 7.1 Hz), 1.42-2.19 (7H, m).
1H NMR (trans), 9.27 (1H, m), 9.13 (2H, m), 5.84 (1H, m), 5.55 (1H,
m), 3.22 (1H, m), 2.30-2.81 (2H, m), 1.76 (3H, dd, J = 1.2 8 4.3 Hz),
1.42-2.19 (7H, m).

82

Characteristic properties of 56b : Yield, 84%; IR, 1710, 1602,
1450, 1335, 1275, 1113, 992 cm-1; 1H NMR (cis), 7.39-6.45 (5H,
m), 6.07 (1H, dd, J = 10.9 8 1.7 Hz), 5.53 (1H, dq, J a 10.9 8 7.2 Hz),
3.05 (1H, m), 2.51 (2H, m), 1.50-2.24 (7H, m), 1.64 (3H, dd, J =- 1.7 8
7.2 Hz); 1H NMR (trans), 739-845 (5H, m), 5.93 (1H, d, J - 15.5 Hz),
5.73 (1 H, dq, J - 15.5 8 6.3 Hz), 3.05 (1 H, m), 2.51 (2H, m), 1.72 (3H,
dd, J = 1.4 8 6.3 Hz), 1.50-2.24 (7H , m).

Characteristic properties of 57a : Yield, 55%; mp, 116-118 00; IR,
1730, 1550, 1349, 1275, 900 cm-1; 1H NMR, 9.23 (1H, t, J - 2.2
Hz), 9.12 (2H, d, J - 2.2 Hz), 5.20 (1H, m), 5.05 (1H, m), 3.10 (1H, m),
2.86 (1H, m), 2.62 (1H, m), 1.50-220 (7H, m), 1.76 (3H, m); 13C NMR,
160.5, 148.4, 144.6, 134.5, 129.1, 122.2, 110.4, 83.4. 48.3, 36.0,
32.6, 32.4, 27.4, 25.7, 17.9; MS, 346 (0.21), 317 (0.20), 276 (1.6),
195 (44), 119 (36), 67 (100); High resolution MS, calculate for
C17H13N203, 346.1165; found, 346.1171.

Characteristic properties of 57b : Yield, 66%; IR, 1725, 1275 1050
om-1;1H NMR, 6.06 (2H, m), 7.74 (1H, m), 7.54 (2H, m), 5.15 (1H, m),
4.97 (1H, m), 2.98 (1H, m), 2.85 (1H, m), 2.56 (1H, m), 2.13 (1H, m),
1.74 (3H, m), 1.50-1.98 (6H, m); 130 NMR, 164.6, 142.2, 132.6,
130.8, 129.3, 128.2, 109.4, 80.7, 48.5, 36.0, 32.5, 25.5, 17.9; MS,
188 (9), 151 (1.5), 135 (4), 105 (100), 77 (34).

Characteristic properties of 58 : Yield, 84%; mp, 114-115 00; 1H
NMR, 9.26 (1H, t, J =- 2.1 Hz), 9.15 (2H, d, J - 2.1 Hz), 5.40 (1H, m),
3.22 (1H, m), 2.66 (1H, m), 135-1.96 (6H, m).

Characteristic properties of 59647: Yield, 83%; mp, 129-131 0C;
IR, 1727, 1632, 1550, 1350, 1275, 926 cm'I; 1H NMR, 9.21 (1H, t, J

83

=- 2.2 Hz), 9.11 (2H, d, J - 2.2 Hz), 2.91 (1H, m), 2.58 (1H, m), 2.44
(1H, m), 1.74 (3H, s), 1.54-2.05 (7H, m).

Characteristic properties of 59b47: mp. 116-118 0C; IR, 2820-
3056, 1725, 1550, 1350 cm-1; 1H NMR, 9.20 (1H, t, J - 2.1 Hz), 9.15
(2H, d, J - 2.1 Hz), 3.05 (1H, m), 2.89 (1H, m), 2.11 (1H, m), 2.02-
2.45 (7H, m), 1.57 (3H, s).

Characteristic properties of 60 : Yield, 79%; mp, 103-105 0C; IR,
2660-3150, 1726, 1548, 1346 cm-1; 1H NMR, 9.14 (1H, t, J - 2.1
Hz), 9.04 (2H, d, J - 2.1 Hz), 2.88 (1H, m), 2.22-2.63 (2H, m), 2.08
(1H, m), 2.09 (2H, q, J - 7.4 Hz), 142-2.92 (6H, m), 0.65 (3H, t, J -
7.4 Hz); MS, 317 (0.44), 305 (2), 267 (6), 195 (60), 122 (16), 66
(100).

Characteristic properties of 6147: Yield, 85%; mp, 114-116 0C;
IR, 1725, 1630, 1450, 1348, 1275, 1170 cm-1; 1H NMR, 9.11-9.18
(3H, m), 7.12-7.60 (5H, m), 2.92 (1H, m), 2.43-2.69 (3H, m), 1.38-
2.02 (6H, m).

Characteristic properties of 62 : Yield, 83%; mp, 112-114 00; IR,
1723, 1545, 1345, 1270 cm-1; 1H NMR, 9.22 (1H, t, J - 2.1 Hz), 9.12
(2H, d, J - 2.1 Hz), 6.30 (1H, dd, J - 17.4 8 10.7 Hz), 5.36 (1H, d, J -
10.7 Hz), 5.30 (1H, d, J = 17.4 Hz), 2.65 (1H, m), 2.49 (1H, dd, J - 13.6
8 3.2 Hz), 2.22 (1H, d, J - 13.8 Hz), 1.29 (3H, s), 150202 (6H, m).
13c NMR, 160.7, 148.6, 139.9, 129.1, 122.1, 114.6, 79.6, 52.6, 42.3,
40.9, 39.6, 28.1, 26.5, 24.6; MS, 346 (0.03), 331 (0.29), 304 (1.1),
290 (0.53), 195 (12), 134 (13), 62 (100), 67 (25).

Characteristic properties of 63: Yield, 86%; IR, 1723, 1542, 1342
cm-1; 1H NMR, 8.98 (1H, t, J - 2.1 Hz), 6.63 (2H, d, J - 2.1 Hz), 6.94-
7.20 (4H, m), 6.24 ( 1H, dd, J - 10.6 6 17.4 Hz), 5.32 (1H, d, J - 17.4

84

Hz), 5.22 (1H, d, J =- 10.8 Hz), 3.49 (2H, m), 3.33 (1H, m), 2.96-3.24
(2H, m), 2.33 (1H, dd, J - 4.8 6 13.1 Hz); 13c NMR, 160.5, 146.4,
146.2, 144.2, 136.7, 134.1, 129.0, 126.7, 124.6, 123.6, 122.0, 114.7,
62.3, 46.4, 40.8, 39.1, 33.1; MS, 380 (0.12), 212 (1.5), 166 (27), 116
(100), 105 (7).

Characteristic properties of 64a : Yield; 57%; mp, 103-104 0C; IR,
1725, 1550, 1350 cm-1; 1H NMR, 9.20 (1H, t, J - 2.1 Hz), 9.11 (2H,
d, J - 2.1 Hz), 6.29 (1H, dd, J - 10.8 6 17.4 Hz), 5.42 (1H, d, J - 17.4
Hz), 5.30 (1H, d, J - 10.6 Hz), 2.72 (1H, m), 136-2.50 (2H, m), 2.27
(1H, m), 102-1.94 (6H, m); 13c NMR, 160.9, 148.4, 137.6, 134.6,
129.2, 122.1, 113.3, 81.9, 42.6, 34.9, 25.1, 25.0, 22.4, 22.0, 21.4;
MS, 317 (0.05), 290 (0.1), 212 (0.2), 195 (27), 134 (10), 62 (77), 67
(94), 55 (100).

Characteristic properties of 64b : Yield, 93%; IR, 1715, 1275,
1110 cm-i;1H NMR, 7.96 (2H, m), 7.46 (1H, m), 7.37 (2H, m), 6.25
(1H, dd, J - 17.3 8 10.7 Hz), 5.29 (1H, dd, J . 0.9 8 17.3 Hz), 5.16 (1H,
dd, J - 0.9 6 10.7 Hz), 2.64 (1H, m), 2.41 (2H, m), 2.25 (1H, m), 1.02-
1.94 (8H, m); 13c NMR, 165.1, 139.0, 132.7, 130.9, 129.5, 128.2,
113.7, 79.6, 42.7, 35.2, 25.4, 25.2, 22.5, 22.0, 21.5; MS, 256 (0.08),
151 (0.61), 135 (2.4), 105 (100), 77 (51); High resolution MS,
calculated for C17H2oO2, 256.1463; found, 256.1477.

Characteristic properties of 656 : Yield, 84%, mp, 121-123 0C; IR,
1725, 1550, 1335 cm-1; 1H NMR, 9.12 (1H, t, J a 2.1 Hz), 9.05 (2H,
d, J .- 2.1 Hz), 6.16 (1H, dd, J =- 17.4 6 10.7 Hz), 5.30 (1H, broad), 5.23
(1H, dd, J =- 10.7 6 1.0 Hz), 2.79 (1H, m), 1.45 (2H, m), 1.12-1.64 (9H,
m); 13c NMR, 161.2, 148.6, 136.0, 134.9, 129.3, 122.0, 117.6, 66.1,
42.3, 35.0, 27.0, 26.5, 22.6, 22.2, 22.0; MS, 346 (0.06), 303 (0.31),

85

290 (0.33), 212 (0.13), 195 (19), 134 (20), 82 (100), 67 (93), 55
(39).

Acetolysis of Dinitrobenzoates or Benzoates in Glacial
Acetic Acid Containing Triethylammonium Acetate

The following is a typical procedure. A solution of benzoate
55 (166 mg, 0.5 mmol) in 0.1 M triethylammonium acetate in glacial
acetic acid (10 ml) was stirred at 80 °C for 12 hr. The reaction
mixture was cooled, quenched with water and extracted with ether.
The organic extracts were washed with saturated aqueous sodium
bicarbonate, and dried. Evaporation of the solvent followed by flash
chromatography gave dienyl acetate 666 (59.4 mg, 66%) and dienyl
dinitrobenzoate 66b (13.3 mg, 8%).
Characteristic properties of 666 : IR, 2800-3150, 1730, 1500,
1350, 1175, 925 cm-1; uv (EtOH), xmax 232 (Emax 15600); 1H NMR,
6.29 (1H, dd, J - 10.8 8 17.4 Hz), 5.95 (1H, dd, J - 6.7 8 7.1 Hz), 5.11
(1H, d, J - 17.4 Hz), 4.92 (1H, d, J = 10.8 Hz), 4.66 (1H, m), 2.54 (2H,
m), 2.00 (3H, s), 1.29-2.28 (6H, m); 13c NMR, 170.3, 139.4, 136.4,
133.6, 111.3, 73.7, 31.4, 29.2, 27.2, 21.2; MS, 180 (0.5), 120 (21),
105 (33), 92 (31), 79 (33), 43 (100).
Characteristic properties of 66b : mp, 96-99 00; IR, 2840-3150,
1730, 1550, 1349, 1265, 1172 cm-1; uv (CH30N), xmax 232 (am,
15000); 1H NMR, 9.26 (1H, t, J = 2.0 Hz), 9.23 (2H, d, J = 2.0 Hz), 6.35
(1H, dd, J = 17.4 8 10.8 Hz), 6.07 (1H, dd, J = 7.0 8 6.9 Hz), 5.13 (1H,
d, J a 17.4 Hz), 5.07 (1H, m), 4.95 (1H, d, J = 10.8 Hz), 2.28 (2H, m),
1.46-2.33 (6H, m); 13C NMR, 160.8, 147.7, 136.9, 135.2, 134.6,

86

133.6, 128.4, 121.2, 110.0, 73.0, 35.9, 30.6, 26.4, 22.3; MS, 212 (5),
195 (42), 149 (36), 120 (79), 105 (100), 92 (75), 79 (54).

Acetolysis of Dinitrobenzoates or Benzoates with
Triethylammonium Acetate - Lithium Perchlorate in
Aqueous Acetic Acid

To a solution of LiClO4 (213 mg, 2 mmol) in water (3.3 ml) was
added a solution of 0.1M triethylammonium acetate in glacial acetic
acid (10 ml), followed by benzoate 55 (166 mg, 0.5 mmol). This
mixture was stirred at 80 0C for 12 hr, then cooled and quenched
with water. After conventional workup and chromatography of the
product, acetate 666 (22.1 mg, 24.5%), benzoate 66b (7.8 mg, 4.7%)
and alcohol 66c (18.1 mg, 26.2%) were obtained.

The studies of product distribution in acetolysis of benzoate
55 under different reaction conditions are listed in Table VIII.

The studies of product distribution in acetolysis of benzoate
576 under different reaction conditions are listed in Table IX.

The studies of product distribution in acetolysis of benzoate
57b under different reaction conditions are listed in Table X.
Characteristic properties of 66c : IR, 3250-3650, 2810-3100,
1638, 1606, 1036, 996 cm-1; uv (EtOH), xmax 234 (em...x 14000); 1H
NMR, 6.32 (1H, dd, J - 17.4 8 10.7 Hz), 5.97 (1H, dd, J - 7.0 8 6.8 Hz),
5.16 (1H, d, J . 17.4 Hz), 4.88 (1H, d, J - 10.7 Hz), 3.65 (1H, m), 2.48-
2.57 (2H, m), 2.09-2.20 (2H, m), 1.29-2.30 (5H, m); 13C NMR, 140.2,
136.9, 135.6, 110.6, 68.4, 41.0, 35.0, 27.8, 23.4; MS, 138 (4), 120
(29), 105 (54), 91 (45), 79 (100), 67 (49); High resolution MS,
calculated for CgH14O, 138.1045; found, 138.1049.

87

Characteristic properties of 66d : IR, 2800-3080, 1549, 1110,
1016, 667 cm-1; 1H NMR, 5.30 (1H, m), 4.46 (2H, m), 2.66 (1H, m),
2.33 (1H, m), 1.66 (3H, d, J - 6.1 Hz), 1.30-1.98 (6H, m); 13C NMR,
140.6, 112.7, 78.6, 75.1, 33.2, 32.5, 30.6, 16.0, 14.7; MS, 138 (40),
121 (52), 109 (100), 95 (76), 81 (61), 67 (52).

Characteristic properties of 686 : IR, 2810-3050, 1725, 1430,
1372, 1238, 1027 cm-1; uv (EtOH), xmax 236 (Ema, 22600); 1H
NMR, 6.26 (1H, d, J .. 11.2 Hz), 5.56 (1H, m), 4.99 (1H, m), 1.96 (3H,
s), 1.69 (3H, s), 1.67 (3H, s), 155-2.78 (6H, m); 130 NMR, 170.6,
131.6, 129.1, 125.9, 73.3, 35.5, 32.0, 24.3, 21.4, 20.6; MS, 194 (3),
152 (5), 134 (31), 119 (69), 91 (87), 78 (22), 56 (26), 43 (100).
Characteristic properties of 68d : IR, 2820-3100, 1550, 1172,
1010, 880, 669 cm-1; 1H NMR, 4.68 (1H, m), 4.42 (1H, m), 1.64 (3H,
m), 1.58 (3H, s), 1.20-2.72 (8H, m); 13C NMR, 134.7, 120.0, 76.4,
75.4, 34.8, 30.7, 30.2, 21.1, 20.4, 16.4; MS, 152 (43), 135 (52), 109
(100), 95 (40), 61 (62), 67 (43), 55 (24); High resolution MS,
calculated for C1oH150, 152.1211; found, 152.1206.

Acetolysis of dinitrobenzoate 566 and 56b was carried out
with two equivalents of 0.1M triethylammonium acetate in aqueous
acetic acid (HOAc : H2O =- 3/1) at 110 0C for 12 hr. Conventional
workup and chromatography of the produCt from 566 gave acetate
67a (51%) and alcohol 67c (14%).

Conventional workup and chromatography of the product from
56b gave acetate 67a (38%) and alcohol 67c (21%).

Characteristic pr0perties of 67a : IR, 2820-3085, 1725, 1370,
1235, 1025, 970 cm-1; uv (EtOH), xmax 233 (emax 13000); 1H NMR,
6.01 (1H, d, J - 15.1 Hz), 5.84 (1H, dd, J .- 6.7 6 6.9 Hz), 5.64 (1H, m),

88

4.65 (1H, m), 2.57 (2H, m), 2.01 (3H, s), 1.76 (3H, d, J - 6.5 Hz), 1.31-
2.20 (6H, m); 130 NMR, 170.2, 136.4, 134.4, 131.9, 122.2, 71.3, 37.2,
32.9, 27.4, 23.9, 21.2, 18.0; MS, 194 (2), 152 (3), 134 (100), 119
(99), 106 (45), 91 (48), 43 (79); High resolution MS, calculated for
C12H13O2, 194.1307; found, 194.1310.

Characteristic properties of 67c : IR, 3300-3600, 2875-3035,
1450, 1035, 975 cm'1; UV (EtOH), Xmax 237 (emax 15200); 1H NMR,
6.05 (1 H, dd, J - 0.6 8 15.6 Hz), 5.86 (1H, dd, J - 6.9 8 6.9 Hz), 5.70
(1 H, m), 3.68 (1H, m), 2.57 (2H, m), 2.00-2.25 (4H, m), 1.76 (3H, dd, J
- 0.5 8 6.3 Hz), 1.30-1.88 (3H, m); 13c NMR, 136.4, 134.9, 132.3,
122.1, 68.4, 41.0, 36.0, 27.7, 23.6, 18.0; MS, 152 (35), 134 (39), 119
(100), 106 (52), 91 (88), 79 (59), 65 (20); High resolution MS,
calculated for C1oH130, 152.1202; found, 152.1207.

Acetolysis of dinitrobenzoate 596 was carried out with two
equivalents of 0.1M triethylammonium acetate in acetic acid at 110
0C for 24 hr. Conventional workup and chromatography of the
product gave acetate 69a (72%) and benzoate 69b (9.0%).
Characteristic properties of 69a : IR, 2800-3100, 1722, 1550,
1370, 1235, 1026 cm-1; 1H NMR, 5.66 (1H, m), 4.71 (1H, ddd, J .-
10.0, 3.6 8 2.3 Hz), 2.52 (2H, dd, J . 10.8 8 9.8 Hz), 2.04 (3H, s), 1.78
(3H, s), 1.50-2.18 (6H, m); 13C NMR, 170.3, 134.1, 127.6, 71.2, 39.3,
37.4, 27.3, 26.1, 24.1, 21.3; MS, 125 (1), 109 (100), 93 (58), 67 (8),
43 (53). %

Characteristic properties of 69b : IR, 1725, 1550, 1350, 1235 cm'
1; 1H NMR, 9.23 (1H, t, J .- 2.1 Hz), 9.13 (2H, d, J - 2.1 Hz), 5.78 (1H,
m), 5.10 (1H, m), 2.74 (1H, m), 1.40-2.42 (7H, m), 1.62 (3H, s); 13c

89

NMR, 161.7, 148.6, 134.6, 133.4, 129.4, 128.4, 122.2, 74.4, 39.1,
27.3, 27.2, 26.2, 24.0; MS, 195 (3), 108 (100), 93 (52), 80 (10).

Acetolysis of dinitrobenzoate 59b was carried out with two
equivalents of 0.1M triethylammonium acetate in acetic acid at 110
0C for 24 hr. Conventional workup and chromatography of the
product gave acetate 696 (14%) and starting material (56%).

Acetolysis of dinitrobenzoate 60 was carried out with two
equivalents of 0.1M triethylammonium acetate in acetic acid at 110
°C for 24 hr. Conventional workup and chromatography of the
product gave acetate 706 (88%).
Characteristic properties of 706 : IR, 2810-3100, 1725, 1550,
1235 cm-1;1H NMR, 5.62 (1H, m), 4.64 (1H, m), 2.51 (2H, m), 2.00
(3H, s), 1.52-2.22 (8H, m), 0.96 (3H, t, J - 7.3 Hz); 13C NMR, 170.3,
139.8, 126.2, 71.7, 38.1, 37.7, 32.8, 27.3, 24.3, 12.5; MS, 122 (39),
107 (27), 93 (75), 79 (26), 55 (11), 43 (100); Elemental analysis,
calculated for C11H1302 : C, 72.48; H, 9.96

found : C, 72.33; H, 9.91

Acetolysis of dinitrobenzoate 61 was carried out with two
equivalents of 0.1M triethylammonium acetate in acetic acid at 110
0C for 24 hr. Conventional workup and chromatography of the
product gave acetate 716 (80%) and dinitrobenzoate 71b (6.7%).
Characteristic properties of 716 : IR, 2820-3100, 1725, 1369,
1226, 1024 cm-1; uv (EtOH), xmax 247 (smax 17600), 205 (am,
12900); 1H NMR, 7.12-7.40 (5H, m), 6.19 (1H, dd, J =- 7.6 8 7.2 Hz),
4.84 (1H, ddd, J = 9.7, 3.4 8 2.6 Hz), 2.86 (2H, m), 2.03 (3H, s), 1.40-
2.38 (6H, m); 13C NMR, 170.3, 143.9, 138.5, 131.7, 128.1, 126.5,

90

125.7, 71.4, 36.2, 37.7, 27.6, 23.6, 21.3; MS, 230 (1), 170 (43), 155
(34), 142 (66), 129 (40), 91 (36), 77 (16).
Characteristic properties of 71b : mp. 93-95 00; IR, 2860-3100,
1728, 1540, 1350, 1275, 1072 cm-1; uv (EtOH), xmax 238 (em.x
26000), 206 (em...x 32000); 1H NMR, 6.99 (1H, t, J - 2.1 Hz), 6.96 (2H,
d, J - 2.1 Hz), 6.9-7.27 (5H, m), 6.15 (1H, dd, J .- 7.0 6 6.8 Hz), 5.06
(1H, m), 3.00 (1H, dd, J =- 14.3 8 10.0 Hz), 2.83 (1H, d, J - 14.3 Hz),
1.42-2.36 (6H, m); 13C NMR, 161.7, 148.4, 143.4, 137.7, 134.1,
132.1, 129.2, 128.1, 126.6, 125.5, 122.0, 74.3, 37.7, 27.7, 23.5; MS,
382 (4), 195 (17), 170 (100), 155 (61), 142 (93), 129 (44), 115 (29),
91 (56), 75 (37);
Elemental analysis, calculated for C20H13N203 : C, 62.81; H 4.75.
found : C, 62.98; H, 4.70
Acetolysis of dinitrobenzoate 62 was carried out with two
equivalents of 0.1M triethylammonium acetate in acetic acid at 110
0C for 24 hr. Conventional workup and chromatography of the
product gave trienes 72c and 72d (25%, 3.5 : 1 ratio), acetate 726
(43.5%) and dinitrobenzoate 72b (4.5%).
Characteristic properties of 726 : IR, 1728, 1250 cm'1; UV (EtOH),
xmax 234 (am, 17000); 1H NMR, 6.24 (1H, dd, J - 10.6 6 17.4 Hz),
5.65 (1H, dd, J - 6.6 6 6.6 Hz), 5.14 (1H, d, J =- 17.4 Hz), 4.88 (1H, d, J
. 10.8 Hz), 2.87 (1H, d, J = 14.2 Hz), 2.68 (1H, d, J =- 14.2 Hz), 1.93
(3H, s), 1.44 (3H, s), 1.45-2.03 (6H, m); 13C NMR, 170.4, 140.4,
137.3, 134.2, 111.0, 82.0, 42.6, 35.8, 23.7, 22.5, 22.3.
Characteristic properties of 72b : 1H NMR, 9.07 (1H, t, J =- 2.1 Hz),
9.02 (2H, d, J = 2.1 Hz), 6.37 (1H, dd, J = 10.8 8 17.4 Hz), 5.96 (1H,
dd, J - 6.8 8 6.8 Hz), 5.24 (1H, d, J = 17.4 Hz), 5.03 (1H, d, J - 10.8

91

Hz), 3.03 (1H, d, J = 14.2 Hz), 2.82 (1H, d, J = 14.2 Hz), 1.66 (3H, s),
1.45-2.10 (6H, m).

Characteristic properties of 720 : 1H NMR, 6.25 (1H, dd, J - 10.8 8
17.4 Hz), 5.76 (1H, dd, J = 6.8 8 6.9 Hz), 5.44 (1H, m), 5.04 (1H, d, J =-
17.4 Hz), 4.85 (1H, d, J - 10.6 Hz), 2.92 (2H, broad), 2.06-2.31 (4H,
m), 1.70 (3H, d, J - 0.7 Hz); 13C NMR, 140.9, 133.3, 133.0, 124.6,
110.1, 109.5, 30.1, 29.7, 26.7, 25.9.

Characteristic properties of 72d : 1H NMR, 6.26 (1H, dd, J - 10.3 3,
17.4 Hz), 5.76 (1H, m), 5.10 (1H, d, J =- 17.4 Hz), 4.92 (1H, d, J - 10.8
Hz), 4.65 (1H, broad), 1.42-2.42 (6H, m), 1.39 (3H, s).

Acetolysis of dinitrobenzoate 63 was carried out with two
equivalents of 0.1M triethylammonium acetate in acetic acid at 110
°C for 24 hr. Conventional workup and chromatography of the
product gave acetate 736 (34.5%) and dinitrobenzoate 73b (25.3%).
Characteristic properties of 73a : IR, 1725, 1250 cm-1; uv (EtOH),
xmax 233 (emax9100); 1H NMR, 6.98-7.32 (4H, m), 6.26 (1H, dd, J .-
3.9 8 10.0 Hz), 6.20 (1H, dd, J = 10.8 8 17.5 Hz), 5.86 (1H, t. J - 7.0
Hz), 4.94 (1H, d, J = 17.5 Hz), 4.82 (1H, d, J = 10.8 Hz), 3.66 (1H, d, J
a 17.0 Hz), 3.36 (1H, dd, J .- 17.0 6 7.0 Hz), 2.70 (1H, d, J =- 14.5 Hz),
2.53 (1H, d, J - 14.5 Hz), 2.11 (3H, s); MS, 168 (26), 153 (5), 129
(10), 116 (100).

Characteristic properties of 73b : UV (EtOH), Xmax 236 (emax
17400),276 (em, 4100); 1H NMR, 7.03-7.32 (5H, m), 6.66 (1H, d, J -
11.8 Hz), 6.29 (1H, dd, J = 10.8 8 17.5 Hz), 5.74 (1H, dd, J - 7.0 8 7.1
Hz), 5.16 (1H, d, J = 17.5 Hz), 4.96 (1H, d, J = 10.8 Hz), 3.02 (2H, d, J
= 7.1 Hz); 13C NMR, 137.4, 135.5, 130.0, 128.6, 126.5, 127.4, 126.7,

92

126.2, 125.7, 113.0, 34.2; MS, 166 (67), 167 (100), 152 (32), 141
(32), 115 (51), 96 (16), 63 (26).

The studies of product distribution in acetolysis of benzoate
646 were carried out with 0.1M triethylammonium acetate and
lithium perchlorate in aqueous acetic acid. The results under
different reaction conditions are listed in Table XI.
Characteristic properties of 74a : IR, 1725, 1640, 1608, 1242, 903
cm-1; uv (EtOH), xmax 232 (am, 13200); 1H NMR, 6.33 (1H, dd, J -
17.5 8 10.9 Hz), 5.78 (1H, dd, J - 8.3 8 8.2 Hz), 5.30 (1H, d, J - 17.5
Hz), 4.98 (1H, d, J - 10.9 Hz), 4.95 (1H, m), 2.61 (2H, m), 2.04 (3H, s),
2.01-2.22 (2H, m), 1.32-1.78 (6H, m); 13c NMR, 170.5, 139.5, 136.5,
133.8, 111.4, 73.9, 31.3, 29.1, 27.0, 21.7, 21.4; MS, 194 (3), 134
(37), 119 (39), 105 (41), 91 (35), 43 (100).
Characteristic properties of 740 : IR, 3320-3630, 1638, 1607,
1075, 902 cm-1; uv (EtOH), xmax 236 (smax14000); 1H NMR, 6.36
(1H, dd, J =- 17.4 8 10.8 Hz), 5.76 (1H, dd, J =- 8.3 8 8.3 Hz), 5.25 (1H,
d, J - 17.4 Hz), 4.96 (1H, d, J - 10.7 Hz), 3.8 (1H, m), 2.58 (2H, m),
2.26 (2H, m), 1.15-1.66 (7H, m); 13c NMR, 140.2, 136.8, 133.6,
110.7, 71.2, 34.9, 32.3, 28.8, 26.8, 21.2; MS, 152 (37), 134 (40), 123
(60), 119 (100), 105 (49), 93 (95), 91 (89), 79 (78 ), 55 (37).
Characteristic properties of 74d :1H NMR, 16.14 (1H, d, J - 12.0 Hz),
5.67 (1H, q,'J . 5.7 Hz), 5.37 (1H, ddd, J - 12.0, 8.5 8 3.4 Hz), 5.04
(1H, m), 2.81 (2H, dd, J = 6.8 8 16.4 Hz), 2.42 (2H, m), 2.06 (3H, s),
1.82 (3H, d, J - 5.7 Hz), 1.44-1.90 (4H, m).

Acetolysis of benzoate 64b was carried out with 2 equivalents
of 0.1M triethylammonium acetate in aqueous acetic acid at 110 0C

for 24 hr. Conventional workup and chromatography of the product

93

gave dienyl acetate 74a (65%), dienyl alcohols 74c (21.6%) and 746
(4%).

Acetolysis of benzoate 656 was carried out with 2 equivalents
of 0.1M triethylammonium acetate in aqueous acetic acid at 110 CC
for 24 hr. Conventional workup and chromatography of the product
gave dienyl acetate 746 (20.3%), dienyl alcohols 74c (17.4%) and
746 (3%), and allylic acetate 74f (3.2 %).

DieIs-Alder Reaction of Diene 66c and Maleic Anhydride

A solution of dienyl alcohol 66c (92.6 mg, 0.67 mmol) and
maleic anhydride (131.5 mg, 1.34 mmol) in benzene (25 ml) was
refluxed with stirring for 16 hr. The solvent was removed, and the
residue was purified by flash chromatography to yield cycloadduct
products 826 and 82b (107.2 mg, 68%, 1 : 1 mixture).
Characteristic properties of 826 : mp, 119-122 0C; IR (CH3CI),
3200-3600, 1646, 1779, 1264, 1226, 966 cm-1; 1H NMR, 5.63 (1H,
m), 3.72 (1H, broad), 3.58 (1H, ddd, J = 1.6, 9.3, 8 7.0 Hz), 3.50 (1H,
dd, J - 5.1 6 9.3 Hz), 3.40 (1H, m), 2.57 (1H, ddd, J - 15.5, 7.0 6 1.7
Hz), 2.48 (1H, m), 1.88-2.42 (7H, m ), 1.12-1.64 (2H, m); 13C NMR,
175.9, 173.7, 143.8, 123.8, 73.6, 47.7, 46.8, 42.6, 42.1, 40.8, 29.6,
26.2, 25.6; MS, 236(4.6), 218 (4), 190 (39), 145 (100), 118 (52), 93
( 58), 71 (58).
Characteristic properties of 82b : mp, 103-107 0C; IR (CH30I),
3290-3610, 1846, 1776 cm-1; 1H NMR, 5.73 (1H, m), 4.02 (IH, m),
3.58 (1H, ddd, 1.8, 9.0 8 7.0 Hz), 3.51 (1H, m), 3.19 (1H, broad), 2.35
(1H, ddd, J = 7.0, 1.7 6 14.9 Hz), 1.42-2.48 ( 10H, m ); 13c NMR,
176.2, 173.8, 143.5, 124.9, 68.2, 76.6, 42.8, 42.6, 41.8, 38.1, 30.3,

94

25.5, 23.9; MS, 236 (1.3), 218 (5.5), 190 (56), 145 (100), 118 (30),
93 (29).

Oxidation of 82 to 83

A mixture of epimeric alcohols 826 and 82b (45 mg, 0.19
mmol) was added to a stirred solution of pyridinium dichromate
(P00, 144 mg, 0.4 mmol) in dimethylformamide (DMF, 10 ml). After
stirring overnight at room temperature, the solution was diluted
with water and extracted with ether. The extract was washed with
brine and dried over magnesium sulfate. Evaporation of the solvent
yielded ketone 83 (22.8 mg, 51%) as a yellowish solid. An analytical
sample was prepared by recrystallization (ethyl acetate) to give 83
as a colorless solid : mp, 136-137 0C; IR (CH3CI), 1849,
1761,1707, 1224, 1212 cm-1; 1H NMR, 5.70 (1H, m), 3.46 (2H, m),
3.16 (1H, d, J = 15.0 Hz), 2.63 (1H, d, J =- 15.0 Hz), 2.13-2.52 (4H, m),
1.68-2.10 (5H, m), 1.39 (1H, m); 13C NMR, 206.6, 175.6, 173.6,
138.5, 125.1, 50.9, 47.0, 43.6, 41.1, 40.3, 28.5, 24.6, 20.1; MS, 234
(50), 206 (32), 188 (34), 118 (51), 105 (61), 91 (100), 68 (72); High
resolution MS, calculated for C13H14O4, 234.0892, found, 234.0898.

APPENDD(

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».‘ . a .

Infrared Spectrum of 29a

8.

Figure

101

 

1800 1600 1400 1200 1000 800

2000

_ . z . . . .
m 0 O O O O
8 . 6 4 2

'IIOUENCY zCM‘

 

1500

2000

2500

3000

 

 

3500

 

 

 

 

4000

O 0 0
8 .0 4

.o\0.muz<:_<<mz<5

20
0

Infrared Spectrum of 34a

Figure 9.

102

100

so:

   
  
 

0
O

TRANSMIIIANCEWB)
5
O

N
O

2000 1800 1600 1400 1200 1000 800

 

4000 3500 3000 2500 2000 1500

Figure 10. Infrared Spectrum of 34a

103

.$.wuz<:.imz<5

 

.... -....T

5
8 .
1 2
b
5
3
f
O
2
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..e ..o. m
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3

1600

11.

Figure

1800
35

4

 

104

 

WAVCNUMBER (CM ’i

Figure 12, Infrared Spectrum of 47

‘NSMN

20

3500

Figure

3000

13.

 

105

2500

Infrared Spectrum of 55

2000

     

1000

 

106

 

600 .. 1400 1200 1000 800 600

 

2 500 2000 1.00

0
4000 3500 3000
WAVENUMDERKM")

Figure 14. Infrared Spectrum of 66a

 

107

 

3000 '
wwwumsatcw )

Figure 15. Infrared Spectrum of 661)

v‘..'11Atht"/.i

 

80

O
O

40

20

0
4000

1400

3500

108

1200 1000 800
WAVENUMBEI‘CM")

3000 2500
WAVENUMBENCM")

Figure 16. Infrared Spectrum of 66c

600

2000

400

 

 

 

 

 

 

 

109

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

mus-l ' i-
1 i
1 't
!
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1" 111 1'1! 1 131111 i 1
1.111111 J1 1111111111111111111. 1111 11111.;11111111111111I111111111111 1.1%41g11111‘11711gv11111111f1v13r1
H E 3131.. 148 1613
Figure 17. Mass Spectrum of 183
inch 7° 1-
55 L
OH
4 57 m 1
r
18b
50.94 1:15 .
1 8‘ b
43
93 .
| ...
4 h 1
tie
l 1 11 l l l
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n: «a so so in no no use

Figure 18.

Mass Spectrum of 18!)

110

108.0 ~ ‘39 -
25 ELECYRO1 U115

56.8-1 >-

I 03

1 16?

1 ' 1 I 11111, 11.L.--1l.11 I

lvvvv'VVvV'vvvv'vv vl‘vvv'vv'v'vv v'wvv'- vv lvvvv vv ‘vv'vw' 'vvvv'vvv

HE 413 80 88 1913 ‘0 150 180 2%

Figure 20. Mass Spectrum of 9d

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

199.0 - 1319

OH

 

 

 

513.1." -4

9c

0.)
£71

125
156

 

 

 

 

 

 

 

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I l l v 1 I I . "1""' -.-," -... 1 ".....,.--.'... ...-..,... .--“..- """""l""'. n," .,....l. -,-...,.---,-..-

n 'E 43 $41 so we in no ice . use 209

Figure 19. Mass Spectrum of 9c

111

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

189.6- ‘1 -
1 r
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29a
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ffi Vii "Ii' " ‘f'fif "I"' fi"'[""Y*""""Uf'r'1#*"' I
n: «a so 33 we :20 no 160 we
Figure 21. Mass Spectrum of 29a
new 4.1 "
1 P
I on .
' .0 .
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I 55
I r-
ancid 29¢
79 1
I
33 ,
‘ 61 as 122 150 168
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2., '1" "r" ""“ ‘ ' - 39 '13-)
n E 413 £13 £53 1'13 129 140 “’0 1 ‘
Figure 22.

Mass Spectrum of 29c

 

 

 

 

112

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

180.0 1 67 ..
41
I I
I ,
81
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55 “We"
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I 95 P
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I ‘68 b
I 113 ‘59
137
AV 1* I J] 'I'Il' -ll‘ £L'Ij TIIIVJI ‘h' JAIL 'I' IIIVIIr'uIJ II I;1'J [TL Jth‘LI‘ovvvllilrvvvIrvv-vv'v1I***'t*" v
'14 4e 5% 301mb 180 19:) cm
Figure 23. Mass Spectrum of 29d
[00.03 - “ -
4 P
I P
(on
I 5‘ .00.”
$03.14 I :3 I.
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1 35a
I 3:: >
N
I
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I" ' I I I I “ I ‘
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f“) '*T f"" fi' 'r' 1""T*“ r"' I'VV'Y‘ "***t ‘ f V I.
"i E ~30 3|" 3|? It}? 129 1‘3 IE4} 181'

Figure 24.

Mass Spectrum of 35a

 

 

 

 

 

 

 

 

 

 

 

 

 

 

113

 

 

 

 

 

 

 

 

“3&8 ‘1 "I 1* {-
I ’t'QI
-. r
I r
79
,
to .
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4 I” >
n
31
51 I P
1
47 .‘t L
II, III. II , ,IIL, I ,,
N E ‘0 68 3% 10$ 12% 140 15%
Figure 25. Mass Spectrum of 34a
- . 39
lUUJJfi ‘
I

€3.04

 

 

 

 

 

 

 

 

 

 

 

 

 

150
lfiS
I ' 93
12!
I
I
I I I ~ I III "5
'1 .;l‘.vlvv.‘.lv‘r‘tl-- 111-ff In: -I 1 J1 L I 11.]. 1‘6 I-
. . r~1rvv .- .-,-'ff,v-.. - Vi

 

Figure 26.

.1-

'VVTVI- v

vvr'vv

Mass Spectrum of (MD

vv'vv—yrrvvvvrvv

- ‘114

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

“Lam -, “II I
I
I
67
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"'T‘ '1'“ “"["*" ' 1' 1" *1" r I Y I 1 1 -1
H E W 80 9‘3 1""? [2‘3 HI" IE»? 1‘45? .193
Figure 27. Mass Spectrum of 35b
mew - “I

56253-4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

I
I I I “J 121 13‘
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I I . ILIJ' “.1 :- 3hr- III-11 - .llll I-II- -
. I .T- I .TI I-

I "'1'
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“0

Figure 23, Mass Spectrum of 35c

143

158

 

IN

 

 

 

 

 

""1
[$13

16?

 

1‘5.“

OH
..I lg
‘ I

9"

35d

 

 

l [43

 

115

 

 

 

 

Mass Spectrum of 35d

33
I

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 29,

 

 

 

 

 

 

 

 

 

 

 

OH

2‘13

 

(on
O
35e

H3

103

 

 

es.

Mass Spectrum of 35e

rvw v
t

I {it

 

cc,

.I.I.I.III. .

 

Figure 30,

 

100.0 - ‘9

 

 

 

 

 

 

 

 

 

 

116

 

 

r.
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< 84 : ; r
I
47
50.0? ,..
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55
I 95 m ’
1 I I II I 1I0 ‘23 I
152
I II I II II II I I IIIIIL IJIII 39L A1
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IVE ‘0 60 80 I“ 12. H. I“ I.

Figure 31.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Mass Spectrum of 47

 

 

133.9 - 7° I
4 r
55 P
03
q-Lh I
59.0 -« g _
52
I -, ,
b!‘
I
83

‘ r

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7""! ' "' '"'l' ' "'I"" " ‘I""I"" ' """""""""" ""‘I """""""" ' """"" I‘ """" | """ ‘ ' w" r ...

H/E ‘0 '30 a I” 12. I40 I“ I“ 200

Figure 32.

Mass Spectrum of 52

twee -'

50.0 -*

 

H/E

 

HIE

 

$0

 

 

 

 

 

 

 

1‘17

 

 

 

 

 

 

 

 

 

 

 

[— 28.0X -
gone
£35
120
32 ,
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an
x»
a. an
I‘I‘“- 2?: A 21‘ I 3}3 3;2
we :50 23' ””TTWZSO 'T-w .350 ........ 3.1%

Figure 33. Mass Spectrum of 55
[— 25.“ I.
P
I
I
L

62?

30‘ b
I

113 134 ‘95 290
33: '

m2
§§j§8154l 1”? aw

.Tv..vvv...rrrv...v.r1 wrr,Tvyc..Tv.,
an an an xw a»

 

Figure 34.

Mass Spectrum of 62

 

100.6-

 

H/E

1&3 H

56.81

 

H I’E

6?

 

63

77

 

106

 

HIS
0
9.1L”
57b
:88
SI 135
"B I I?! ‘i' JP I
m "",§."' ......th .2“
Figure 36. Mass Spectrum of 57b
[— 5.8x
195 57a
1119
134
278

 

 

118

'—

 

 

 

Figure 35.

 

 

 

 

 

 

l
fTV'TTvvi'v‘rI I-v—v r7'v1
350 400

Mass Spectrum of 57a

119

3m 0‘ “6 r- «max

 

50.0 4
I.

 

 

 

 

 

 

 

 

 

 

 

 

 

as ,4: I
I -I- 2'33 333 I I
«E 5.3 1 c fir“'"Y'f""T'Tfiri"*""*‘tr*1'*vvvr

1 LI) 1 .43 an) 239 m 359 s...)

Figure 37. Mass Spectrum of 63
ieo.o- ‘39 _.
“ p
25 ELECTRW IKLTS >

can: C,"
69b
93
50.0‘ h-
I b
4 P
1 b
‘r
.--.fiww .--.-c-...,......-..T....--
HE $0 I" 150 $ 25. )3!)

Figure 38. Mass Spectrum of 69!:

IN.0H

543.0‘

 

198.01

 

nus

 

 

h-..—.——.———

 

7?

 

    

Figure 39.

Figure 40.

120

l 95

122

 

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.
L
I
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60 F
267 I
27? 305
I 222 I 3"
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38 359

Mass Spectrum of 60

14176

 

 

Mass Spectrum of 64!)

105 [- l0.0( ,-
0
C135?” I
'64b
13:
187
I? 210 22L? 22‘ I . fl
7'"- T r V 1 FT T V 7' ‘I’ ‘I Y j ‘V I Y T I fi fi'T
we use 200 250 390

121

 

 

 

 

 

 

 

 

meme _
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i
I I: I] \\ I
we- 643 p
I .-
134 ’
BS .37 up

an

‘5‘ I I I I
at we in an in aw «m

Figure 41. Mass Spectrum of 64a
meo~ 32 r—zmmr F
4 r
I .ooue . '
1 I
539- 65; _
I $5 r

3 I

. 5 .

 

 

 

 

 

 

n'E

Figure 42. Mass Spectrum of 65

MEGA“:

 

nE

153.0‘

 

 

 

 

 

 

92

 

 

1‘5

 

 

 

 

 

 

I49

 

150

Figure 43.

155 I79

122

 

—-——T-‘

 

 

 

 

 

 

 

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663
I
I.
I
1:34 169
I u ' r ' """"" I
250 250
Mass Spectrum of 663
I
ODNB
I-
135 66b“
212
( 23 a- m .L
... 2.. as. «‘3.

Figure 44. Mass Spectrum of 66b

 

 

 

 

 

123

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 46. Mass Spectrum of 66d

103.6 ‘1 73 ..
I
I ,
I
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In“ /
J on
543.04 9f ..
. 9* 66c
I I .
I . 3 I I .
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I II I II
I I I _‘ '
I II I I
I III! I ‘
I ' I I I ‘“
IIIIIIIII. . II.-. I... . ................. , ............. . ............ ,
n: 40 so so we :29 m 150 we tors
Figure 45. Mass Spectrum of 66c
103.0- :99 I‘
95
.
67 1'“
50.04 66d
. :38
105
I 55
91
u I! '''' I- III! vvvvvvvvvv v vvvvvv Ill ----------- I ' r 'I I "r I 'I' I ' |‘ "'"""' ""1
not 40 so so I 120 m :60 too 200

3%.0I

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1N.0-I

 

HIE

I43

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

124

 

 

 

 

Figure 48. Mass Spectrum of 67c

91
106
673
p
79 .
55 S7
152 194
"3 . . L. , ......... .
50 m ISO 2" 250
Figure 47. Mass Spectrum of 67a
1 9
91
67 OH
79
m 67c
55
134
152

' I

I II II
I rrrr fijrrT'rjrvf1fw‘v' ‘fi—Iy—v—v—vvj

50 l ‘ :50 2” 250 3

 

 

 

 

 

 

 

 

 

125

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

180.0 - ‘3 P
‘ 91 I
113
I c J h
seen OAc I-
68a
134
I." L
Jb
73 ms
67
p
I 152 ‘9‘
... . - ”WI .
"If $0 I“ 150 T 2&9 ;
Figure 49. Mass Spectrum of 683
169.9- "'3 ..
1 I-
‘ b
s:
. 68d .
ms
se.o« _
67 132
I 95 .
I 123
s: I
1 b
I I II I ”9 I
I. IIIIII. LI IL. I I. - I I I I I -.III I - I :45 |
'U '7" ' ' ""'I' "I" 'I"' "I"' V ' ' """" I"' ""'l"""' l""""' """' ""‘ "I"""""" 'I ‘I"" ""I"' I """"

H4 40 so so :5 m m 160 m 2‘:

Figure 50.

Mass Spectrum of 68d

126

 

 

 

 

 

 

 

Ieo.a - -
I I
I b
1 h
.
I 93 I
OAc
43 C")
53.0 -‘ p-
69a
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so
1 67 h
I 5’ .I. I II
VI ..--.-,:.I:I,: -.-m,-...,....,.-..ll.l.‘. .- 1 ----1.. 3.-- . ”If -
so so

I 'I"" I I" """I"' I" 'I" """I'"" "'I" "' "I""""'I"' l' "I "'I""l'"'!
1% 120 140 160 I” 2”

Figure 51. Mass Spectrum of 698

 

 

 

 

 

 

 

 

 

 

100.8 q 43 r— s.“ ,-
P
93
0A t
I c E! I
50.0 "I 703 I-
. 122 ‘
I b
79 HI?

‘ P

S?

55

1 r
I" ‘l'll ‘l E“! MW

' ‘I""U""I""|""I"'

HIE 40 50 N I“ 12. MO 150 I“

Figure 52. Mass Spectrum of 703

IUJ‘

 

 

 

 

 

 

 

 

HIE

130.0-

 

 

127

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

I-
142
OAc Ph
170 71a
:29 .
9‘ :55
HS
77 ms
5: .
65
97 I87 {-1- 29 l
- . . r .- - . T .........
so m m 200 250 309
Figure 53. Mass Spectrum of 718
179
I-
142
I
./
91 con Ph
1:29 71b
75
II: .
195
"I"
‘79 2 3
VVTV‘Ylvv—IVV'VVYfr'Vf' TTTVV'[V'VYVIV‘VVVITVVV'fVTa
too :50 200 250 an 350

Figure 54. Mass Spectrum of 71b

 

128
167

I

73a

 

 

 

 

 

 

 

 

 

 

 

 

I L
_ IIs
$I.~.o« Isz -
I
m I
r. 5,3
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II I I' 70' I '
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"'1 a m 623 we :29 :40 :60 I38 2‘33
Figure 55. Mass Spectrum of 73a
190.9— “5 ,

I OAc '
$0.6 « 73b _
I we '

 

 

 

 

 

 

I I ~33 9}: 91 :93
l I V‘ I I I I v I I ' 1 I
P‘- E ‘7»? I”

Figure 56. Mass Spectrum of 73b

INJ-

 

 

 

129

11 9
,—
93
79 '
67
‘m “’3

(0

Ln
.-
a
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v-vv'vwv' I'vi'v v v'vvvv' 'wvvlvvvv v ‘v‘v'vv' vv 'vvvv'vv 'v v

60 fl :8 120 140 160 I“ 2"
Figure 57. Mass Spectrum of 74a

[— 5.0x

25 ELECTRW MTS

 

 

 

 

 

 

OAc
105
“I9 134 ‘ 74C
91
79
194
S7
is: is: m
I I l 1 ' |
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I“ IS. 2“ 1’30

Figure 58. Mass Spectrum of 74c I

130

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210.0 IBQIU ISQJB 120.0 SMJB 68.8 333.3 3.0

PPM

Figure 125. 13C NMR Spectrum of 18a

 

 

 

 

 

 

 

 

 

 

 

OH
18b
l
J1 JL 1 JLJLJJL.”
I I I I I I I I I I I I I I I I I I I I I I I T
210.0 156.33 1576.8 120.3 90.6 5315 33.6 3J3

PPI‘I

Figure 126. 13C NMR Spectrum of 18!)

 

 

 

 

I I I I I I

I IIIIIIIIIIII
Zlflllefin

l
ISBJ'B 12m.n gran sec 36.0
Pm

Figure 128. 13c NMR Spectrum of 9b

 

 

 

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‘. ...o
H
9a
I
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|
I
I
i
I
-- -- _ ”w... --. -- .w. - - -.r-.._.IL,_ “l.
I I I I I I I I l I I I I I I I l I I I I
21mm 15mm Isra.ra 12mg 9:312: 5mm mm
P r1

Figure 127. 13C NMR Spectrum of 9a

198

 

 

 

 

 

 

 

 

 

 

 

f EV { V Y Y 1 l V Y V T r W V Y 7— ‘ Y T v f

200 ISO I00 50
fI’r‘

Figure 129. 13C NMR Spectrum of 9c

 

 

 

 

 

 

 

 

 

 

 

OH O
8
{I
g L - L
l’ I I I I I r I - I I I I I I I 1 y , 1 {

mm

Figure 130. 130 NMR Spectrum of 9d

   

 

199

 

 

 

 

 

 

 

 

 

::--OH
~=o
29a
‘~ 4 A? JK‘JL’JUJM
I Y— j I W l j I fl I 1 ~
200 [50 me 50 2

ZOO

rrn

Figure 131. 13C: NMR Spectrum of 29a

 

 

 

 

 

 

 

 

 

 

H.“

Figure 132. 13C NMR Spectrum of 29c

 

200

 

 

 

 

 

 

 

 

 

 

i
l V fi fi ' i i Y ' ' i fl I T 1 w l
200 1573 Him So 0

f’t'n

Figure 133. 13c NMR Spectrum of 29d

 

 

 

 

 

 

2130 IS@ lflfl SB 0
Mn

Figure 134. 13c NMR Spectrum of 34a

34b

201

 

 

 

 

 

 

 

 

Figure 135.

 

 

r

um 55
rm

130 NMR Spectrum of 34a

 

L L -‘JJ

 

 

 

 

 

202

 

'5“ mm

B
mm

Figure 137. 13C NMR Spectrum of 35a

0H

35b

 

 

Figure 138. 13c NMR Spectrum of 35b

OH
®... 0“

35¢

WWJLJWJUU

i""l'T

20w ism

Figure 139.

CH

35d

Figure 140.

203

 

 

 

 

 

‘33“ SM
H’r‘!

13C NMR Spectrum of 35c

 

 

 

 

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T T T I I I I r I

tiara sra
t'f’r“

130 NMR Spectrum of 35d

 

 

 

 

 

 

 

 

210 (a

204

 

 

 

 

tem.m ism.m 12m.e 9p.e 6p_p
PPH

Figure 141. 130 NMR Spectrum of 36a

 

 

 

 

 

 

 

 

9n
36b
L Li ¥
T I I v T v { v v v v I v v v v I
anl ‘5“ la“ 5“

mm

Figure 142. 13C NMR Spectrum of 36b

 

 

 

 

 

 

i

37a

205

 

 

 

 

 

 

 

 

 

 

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W

 

 

 

 

 

 

 

 

 

 

 

 

 

wwwucwflrfiwvcflr WY 2.. *‘r‘wuwgr, 4.:{2:.:::;; LJ
I i I i I I I I I l I I i
200 150 H30 SB 8
mm
Figure 143- 13C NMR Spectrum of 373
9c
37b
A_.. 1_ J ++ 4L id fidL‘JULULW
I I I i I i I i I i I I I I l
2‘30 150 [era SG 0
fi’l‘i
Figure 144. 130 NMR Spectrum of 37b

206

 

 

 

 

 

 

 

 

 

 

 

 

 

 

<2" .0" I I j;
Oj’\3r l I“
5 it
i
‘I I I I I I I I I I I I I I I I I I I I I I I I
2H3.B IBIB Ia ISIUIB 120‘” 5313 60 a 3Q.B U a
Figure 146. 13C NMR Spectrum of 38b
i I
9“ OH
1.
38a
I I I I I I I I r I I I I I I I I I I I I I
ISQ 2 I53 I3 IIIDJB 7m 3 3%.[5 0J3

PPrI

Figure 145. 13C NMR Spectrum of 38a

207

OH OH

Br

38d

 

 

 

 

 

L_

i

i
5::
it

1 I
773? | S-‘d 30'?
— ’Pr

Figure 148. 13c NMR Spectrum of 38:!

OH OH

38c

 

 

 

 

 

Zran L30. 11': 3.3

fl-I...

Figure 147. 130 NMR Spectrum of 38c

208

 

 

 

 

200 150 “III SE D

Figure 149. 13C NMR Spectrum of 40b

 

 

 

 

Figure 150_ 13C NMR Spectrum of 40a

209

 

 

 

 

 

 

 

 

 

 

9H

47
gmw A} - L h wJL II JULILLJL‘,
PT] I I WWI
210.9 IBQJU ISO.B 12$.“ 90.6 63.0 30 0 9.

mm

Figure 151 13C NMR Spectrum of 47

cafe

52 I]

~ L— Lguuut.

«1
WI!” WWW ' I .. I
zpmra return izrara 3mm erarc dram

f’i'i‘1

Figure 152, 130 NMR Spectrum of 52

 

 

 

 

 

 

 

 

 

 

 

21()

gene

.55

 

 

 

 

 

 

 

 

uiiu u A

 

 

 

 

 

i....iIII'iI‘"II'III

20¢ 15g too 50 e
rrrt

Figure 153. 13C NMR Spectrum of 55

gene ’

 

62

 

 

 

 

IYIII [III III
I I I IIIIIIIIIIIIIIII‘IIIIIIIIIIIIIIIIITYTIIIII

ZII ‘3 17m ra

IIIIJI'IIII'IIWIIIIIIIYI'IIIIIIIIIIIIIIYIIYIIIIII
l i I

IIIIIIII'le
133 p 33 c em a
rrn

3,3 .3 B 0

Figure 154. 13C NMR Spectrum of 62

211

gone

 

 

 

 

 

 

 

 

u _ ‘_L III WIL

 

 

 

 

210.6 no.0 136.0 sea em a 30.2:
rr'n

Figure 155. 13C NMR Spectrum of 57a

VOL"
05%

57b

 

 

 

 

 

 

 

 

 

 

 

 

 

 

200 150

Figure 156. 13C NMR Spectrum of 57b

 

 

 

212

 

 

 

 

 

 

 

 

 

 

 

 

 

gone
60
”ATVVAA _; A AgifL Lg. A 4_V‘ LL
210.0 Hera 130.0 Sta Ia See an.

f’I’l‘“

Figure 157. 13C NMR Spectrum of 60

 

 

 

 

 

 

 

 

 

 

O
(In
64b
J _. _IL _
leafb 170,0 130.33 3'3 I'd SIB.” 3‘3 ‘1‘

rrn

Figure 158. 13c NMR Spectrum of 64!)

 

213

 

 

 

 

 

 

 

 

 

 

 

 

 

 

QDNB
03“
643
A- , f IL LL I IuWUL.‘
r—w I T 1 Isla 1 1IOIQ 5L jAOT

mm

Figure 159. 13C NMR Spectrum of 64a

ODNB

 

 

 

 

65

 

 

 

 

 

 

 

 

 

 

1“ AL v

216 6 179.0 130.0 3G 0 80.0 30.6 0,8
FFH

A‘ M ALLA—.AA . . l- l L ‘A
I' ' V " 1' WV ‘

A ‘ AAA“
7'11er “T—W

.-

Figure 160. 13C NMR Spectrum of 65

 

 

214

 

 

 

 

 

OAc
663 I
I
“I.“ L - _ 'JWWW'IWW
~r~ I I I I II
2am ism rm to: 5'3
Figure 161. 13c NMR Spectrum of 66a
/
ODNB
66b
“M
I 7* V 1 ‘V I. 1 v V ‘7’ 1 V f v Y _l
200 tsn tan so s

Frfi

Figure 162. 13C NMR Spectrum of 66b

215

 

 

 

 

 

 

 

 

 

 

 

on
66c
Wm¢%‘fia‘rr v-inWMW 'M
I I i I i I I l I I i I l
ZOO ISM mm 5‘? 0

Figure 163. 13C NMR Spectrum of 66c

 

 

 

 

 

210 B 1733 I3 IBIBJB 30.0 60.0 30.

Pm

Figure 164. 130 NMR Spectrum of 66d

 

 

 

216

 

 

 

 

 

 

 

 

 

 

 

 

 

673
L IJJLJg LL... (ULIJUIIL.
l I l i l l i l I t l l I IWWWWW
215.0 18@.B ISQQ 120.0 3@.G 60.0 35.3 0.3

rm

Figure 165. 13C NMR Spectrum of 67a

"0

67c

 

 

 

 

 

 

 

 

 

 

 

 

 

ZIII.O IBQJU I50.“ 120.0 ”.0 CIIJI 30.0 I.”
rrn

Figure 166. 13C NMR Spectrum of 67c

 

 

217

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OAc
68a
i
fi____.~_* #LL _f A- L JJ, LII _
IIIIIITIIIII‘I'IIIITIIIIII
21013 map I‘m n 3a II cn u an a n a I
H'r‘
Figure 167. 13C NMR Spectrum of 68a
I
*
68d
WM...” .4_ -LLWJI Hg... I...“
210.0 170 0 ~ 130.0 90.0 60,0 30.0 a 0

f’f’fl

Figure 153, 13c NMR Spectrum of 68d

 

218

 

 

 

 

 

 

 

 

 

 

 

 

 

 

cm

69a

L e L. l - L_
I I I I I I I I I I I I ""'l""""1"""'1"""'l""" TV I I I I I
21“, 0 17“,.G ‘3“! fl SMIJI Ball; 3“! m 0 la

mm

Figure 169. 13C NMR Spectrum of 69a

ODNB !

 

 

 

 

 

 

CH)
69b
aquuiflwyhuuuo*~wJ~m~L——JbL4 ;::;::¢ ,_
210.0 11m.m Ijm.m rrn am.m cm.m 3m.m a.z

Figure 170. 13c NMR Spectrum of 69b

219

OAc E!

70a

 

 

 

 

 

 

 

 

 

 

 

 

 

 

WWI ...l. TW
0 a

130.0 30.0 60.0

2m.ra 17° 9’
rr‘n

Figure 171. 13C NMR Spectrum of 703

 

 

 

 

 

 

 

 

 

 

 

OAc P"
713
- L I L I LI.
210.0 170.0 - 130.0 30.0 6" 0 30 0
--. . 0

I'm

Figure 172. 13C NMR Spectrum of 71a

 

220

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

”
ODNB Ph
711)
210.0 170.0 130.3 sea 52.9 3mg
cm
Figure 173. 13C NMR Spectrum of 71b
53
1 fl
2'.” ‘3 17m.13 1313.13 30.13 313.13 313 0

mm

Figure 174. 13C NMR Spectrum of 53

 

221

72d 72C

 

 

 

(—

 

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211‘." 11".“ 13“.“ 3“.“ 6“.“ 3“." 0.13
rrn

Figure 175. 13C NMR Spectrum of 72c + 73d

. -

OAc

72a

 

WWW WWW

210.0 170 I3 I'm In an»: era re 30 re a 2
rrn

Figure 176 13C NMR Spectrum of 72a

 

 

 

222

73b

 

 

 

 

 

210 0 170.0 130.0 ' 30.0 60.0 30.0 0.0
rm

Figure 177. 13C NMR Spectrum of 730

63

 

 

 

 

 

LIIII LL -

 

A A__ A A A _.__‘

I I 1 I I I 1 I 1 I I I I I 1 I I I I I 1 I I I
210.0 I70 0 1‘30 0 30,0 :0 n 30 0 B 3
Fl’f‘

Figure 178. 13C NMR Spectrum of 63

 

 

223

OAc

74a

 

 

rrn

Figure 17g 130 NMR Spectrum of 74a

03
74c

 

 

 

 

 

 

 

 

 

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I l 1 I l I 1 I 1 r I I 1 I l I

200 t50 t00 50 a
rrn

Figure 180. 13C NMR Spectrum of 74c

 

 

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