AN APPROACH TO THE SYNTHESIS OF NEOCLOVENE BY …
Transcript of AN APPROACH TO THE SYNTHESIS OF NEOCLOVENE BY …
AN APPROACH TO THE
SYNTHESIS OF NEOCLOVENE
BY
ANDREW MAR
B.Sc. (Hons.), U n i v e r s i t y of B r i t i s h Columbia, 1971.
A THESIS SUBMITTED IN PARTIAL FULFILMENT OF
THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE
i n the Department
of
CHEMISTRY
We accept t h i s t h e s i s as conforming to the
re q u i r e d standard
THE UNIVERSITY OF BRITISH COLUMBIA August, 1974
In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r
an advanced degree at the U n i v e r s i t y o f B r i t i s h Co lumb ia , I a g ree that
the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s tudy .
I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s
f o r s c h o l a r l y purposes may be g r a n t e d by the Head o f my Department o r
by h i s r e p r e s e n t a t i v e s . It i s u n d e r s t o o d tha t c o p y i n g o r p u b l i c a t i o n
o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i thou t my
w r i t t e n p e r m i s s i o n .
Department o f
The U n i v e r s i t y o f B r i t i s h Co lumbia Vancouver 8, Canada
D a t e flex:. <\
ABSTRACT ,
This thesis describes the i n v e s t i g a t i o n of two synthetic approaches
to the keto t o s y l a t e 90_, a key intermediate i n a proposed synthesis of
neoclovene. The f i r s t approach involved an e f f i c i e n t 9-step synthesis of
the epoxy acetals 152 and 153 from indan-l-one 142. D i a l k y l a t i o n of 142
with methyl iodide followed by the r e a c t i o n of the dimethyl ketone 143
with d i e t h y l cyanomethylphosphorane gave the n i t r i l e s 144 and 145. Successive
subjection of the n i t r i l e s to h y d r o l y s i s , hydrogenation, and reduction r e s u l t e d
i n the formation of the aromatic alcohol 141. Treatment of the l a t t e r with
l i t h i u m i n l i q u i d ammonia followed by r e g i o s e l e c t i v e hydrogenation of the
di s u b s t i t u t e d double bond of 149 with the homogeneous c a t a l y s t t r i s ( t r i p h e n y l -
phosphine)chlororhodium gave the o l e f i n alcohol 150. Epoxidation of the double
bond o£ the o l e f i n acetal 151, corresponding to .the alcohol 150, with
m-chloroperbenzoic acid gave a mixture of epoxy acetals 152 and 153 i n
quantitative y i e l d . However, a l l attempts to obtain the keto t o s y l a t e
90 from the epoxy acetals f a i l e d to give s y n t h e t i c a l l y useful y i e l d s of
the desired products. This precluded further use of t h i s approach.
The second approach involved the synthesis of the o l e f i n alcohol
179, a proposed intermediate i n the synthesis of the keto t o s y l a t e 90_. Thus,
a l k y l a t i o n of i s o b u t y r o n i t r i l e 165 with a l l y l bromide followed by ozonolysis
of the a l k y l a t i o n product gave the aldehydic n i t r i l e 167. Successive treatment
with cyclopentylidenetriphenylphosphorane, polyphosphoric acid, and
a l c o h o l i c sodium hydroxide afforded the ketone 170. The ketone 170 was
converted i n t o the epoxy ketone 171 and the l a t t e r was reacted with
methylenetriphenylphosphorane to y i e l d the epoxy o l e f i n 173. The l a t t e r
was subjected to hydroboration-oxidation to produce the epoxy alcohols
174 and 175. The a l c o h o l i c f u n c t i o n a l i t y was protected as the acetate
and the epoxide was reduced with tungsten hexachloride-n-butyllithium to
give the o l e f i n acetate 178 i n 90% y i e l d . Reduction of the o l e f i n
acetate with l i t h i u m aluminum hydride y i e l d e d the o l e f i n alcohol 179.
Unfortunately, due to the lack of time and m a t e r i a l , t h i s project was
concluded at t h i s point. A p o s s i b l e synthetic route to the keto t o s y l a t e
90 from the o l e f i n alcohol 179 i s given.
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TABLE OF CONTENTS
TITLE PAGE
ABSTRACT . 1 .
TABLE OF CONTENTS »
ACKNOWLEDGEMENTS
INTRODUCTION
1. Diorganocopper Reagents
2. Intramolecular A l k y l a t i o n
3. Or i g i n and S t r u c t u r a l E l u c i d a t i o n of Neoclovene . . . . o
4. Other Synthetic Approaches to Neoclovene .....
DISCUSSION
1. General
2. Attempted Synthesis of Keto Tosylate 90 ......
3. Second Attempted Synthesis of Keto Tosylate 90
EXPERIMENTAL
BIBLIOGRAPHY
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ACKNOWLEDGEMENT
I would like to express my thanks to Dr. Edward Piers for his
encouragement, invaluable advice, and consistent interest during the
course of this research and the preparation of this manuscript. I
would also like to thank a l l the members of Dr. Piers' research group
(past and present.) for their many helpful discussions and suggestions.
Special thanks are to Mrs. Diane Gray for the very capable typing
and to Mr. Marston Lee for drawing the many structural diagrams in this
thesis.
INTRODUCTION
H 2 0 ' II
1. Diorganocopper Reagents
The use of a catalytic amount of a copper salt in the reaction
of an a,8-unsaturated carbonyl compound with an organometallic reagent
o ' all
H \ . _ / C C H , R
V C = C A 4 R - M E T A L — — * - C H J C H C H = C - C H O
C H 3 / \ H I 3
1 n C MLTAL -i—. . . . . j_
R o I II
C H 3 C H C H 2 C C H 3
3.
to achieve a Michael (1,4) addition has been known since 1941.* It
was not until twenty-five years later that House, Respess, and 2
Whitesides experimentally showed that the reactive intermediate was
in fact an organocopper derivative. This derivative, preformed from
Cu(I) and an organometallic reagent or formed from the same reagents
in situ gave the same product upon reaction with E-3-penten-2-one 1. 3
Since 1966, extensive research has shown that diorganocopper
reagents can be used with a wide variety of substrates other than a,8-
unsaturated carbonyl compounds. The coupling reaction of organo-4-8 9_11 cuprates with alkyl halides " and tosylates has been shown to
H & U a CuLi 6,0%
M 6.5 % 0 = c
&/t 6 0 %
s 9
15%
11
C H 2 = C K C H 2 0 T S ^ C " L V
12 89%
C H 2 = C H C H 2
15
14
C u L i 4 C H 3 o T s
15 9 8 %
16
E ^ C H ^ C H o . 0 T « . IS 19
O O JL " M e o C u t i , II 9 C C H a C H ^ O T s — — — « ~ 9 C C H 2 C H 2 C H 3
2 0 21
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proceed not only i n high y i e l d but i n some cases with high stereo
s e l e c t i v i t y (see Chart 1). Other leaving groups have also been
displaced by organocuprate reagents. In the case of ethynylcarbinol
12 acetates, allenes are formed. O l e f i n s are formed s t e r e o s e l e c t i v e l y
13 from a l l y l i c acetates and B-alkoxy- and 3-alkylthio-a,B-unsatur'ated
14 15 carbonyl compounds ' (see Chart 2) and ketones are formed from
carboxylic a c i d c h l o r i d e s ' ^ (see Chart 3). Epoxide rings can al s o be 17-19
opened i n a n u c l e o p h i l i c manner by organocuprates. Although
organocuprate reagents react with the aforementioned substrates,
organic chemists have found these reagents to be most useful i n t h e i r - ' 2' unusually e f f e c t i v e conjugate addition to a , 8-unsaturated aldehydes,
ketones,^' e s t e r s , ^ ' and n i t r i l e s ^ 3 ' (see Charts 2 and 3).
involves e i t h e r p a r t i a l or complete electron t r a n s f e r from organo
cuprate, [RCu(I)Y] , to unsaturated substrate forming e i t h e r a charge-
tr a n s f e r complex or a r a d i c a l anion. Subsequent t r a n s f e r of an organic
r a d i c a l from a t r a n s i e n t organocopper(II) species to the end of the
conjugated anion r a d i c a l or collapse of the charge t r a n s f e r complex
[R:Cu(I)Y] R:Cu(II)Y Cu(I)Y
0 R 0 I)
-C=C-C-I I
-C-C=C- -C-C=C-
54 55 56
Y = R, halogen, CN
would complete the addi t i o n sequence and generate enolate 56 which i s
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24 2 5
CHART 2
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CN C C H o ) l o C o C l ' a ' 10
3£> R = 7lE>U 95%
CN ( CH</)lo CoR.
*7
-nC4Hcj 0 2 C C H 2 C H 1 C o C |
•?8
I ( C H ^ l o CoCl
40
n So»
R = nBu 93%
PL-nE>u 93%
* C 4 0aCCHaCH2CoR
1 CCH a ) 1 0 CoR •
41
M e 9 CuLi 8 8 %
42-O H 4 3
f> - C C H 2 ) 8 C o C H a C H 3 C H 2 C H CCH^g C0CH3
OH 4 4 45
• o
46 8 4 %
yy
4_7_
46 •5>7%
49
\ c = = c / MegCuLi,
50
cHo
CH 3 ^
/ C H 3
C = G
C H C 0 2 C H 2
c H 3
CH
CHART 3
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quenched on subsequent aqueous workup. The apparent requirements of
a net negative charge on the copper complex f o r e f f i c i e n t conjugate
ad d i t i o n has r e c e n t l y been confirmed. 26,27
Although enolates such as 56_ have been trapped as enol d e r i v a t i v e s 2
with acetyl c h l o r i d e , a c e t i c anhydride, and d i e t h y l phosphorochLori-
28 date and have been found to give only one double bond isomer, few
CH3
/ \ H ccH,
5 7
3°)
ccH3)2ca
H / cH
( C 2 H 5 0 ) a P o
II o
researchers have,* u n t i l r e c e n t l y , a l k y l a t e d these enolates i n s i t u
to f u r t h e r elaborate the carbonyl substrate.
Last year, Boeckman and Coates independently showed that organo-
copper enolates can be r e g i o s e l e c t i v e l y and, i n some cases, stereo-34 34-36 s e l e c t i v e l y a l k y l a t e d to y i e l d a - d i s u b s t i t u t e d and a,8-disubstituted
carbonyl compounds.
To date, the d i r e c t a l k y l a t i o n of the intermediate magnesium enolate formed from the copper-catalyzed conjugate addition of Grignard reagents to a,8-unsaturated ketones has been achieved by S t o r k 2 9 * 3 0 and Kretchmer. 3 1> 3 2 The a l k y l a t i o n of copper-lithium malonates has been reported by G r i e c o . 3 3
In his first' paper on this subject, BoeckmanJ'> was able to successfully
react some regio-stable copper enolates with various a-trimethyl-
s i l y l a,B-unsaturated ketones. It was found that in the case of
cyclic a,B-unsaturated ketones, the incoming a-trimethylsilyl vinyl
ketones add predominately anti to the previously introduced (from the
cuprate addition) alkyl group and therefore the overall annelation
reaction produces a highly stereoselective product. In the case of
enolate 6_2, the cyclohexene skeleton assumes a half-chair conformation
in which the allylic methyl group is in a pseudoaxial position to . fl 2)
relieve A ' ' strain. In this conformation, the steric requirements
favor alkylation on the a face. The resulting ratio (97:3) of the cis
octalone 64 to the trans octalone 65_ respectively shows the potential
of the conjugate addition-anneiation sequence in organic synthesis.
Boeckman has also added an isopropenyl group via the cuprate as shown
by his synthesis of hydrindenone 68_ (see Chart 4). In his second 36
paper on the alkylation of organocopper enolates, Boeckman turned his
attention toward the use of alkyl halides as the alkylating agents (see
Chart 4). This work showed that these metal enolates (formed in a regioselective manner), because of the covalent nature of the copper-
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oxygen bond, may be alkylated regiospecifically in unhindered cases
without a significant amount of polyalkylation. If the B position of
the carbonyl substrate is sterically hindered, as in ketone 71_ (see Chart 4),the metal enolates will undergo equilibration* at a significant _ Boeckman also proposed that reduction in the size of the alkyl halide would increase the ratio of alkylation to equilibration.
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rate r e l a t i v e to the rate of a l k y l a t i o n r e s u l t i n g i n loss of r e g i o -*
s p e c i f i c i t y , , 34
In a very s i m i l a r study, Coates investigated the conjugate
a d d i t i o n - a l k y l a t i o n of 2-n-butylthiomethylehe ketones as well as
other a,B-unsaturated ketones. Although the r e s u l t s obtained did not
show as high a degree of s t e r e o s e l e c t i v i t y as Boeckman1s work, he has
demonstrated a new method of acquiring a,a-disubstituted ketones. Thus,
37
double conjugate a d d i t i o n to 2-n-butylthiomethylene ketones (see
for example ketone 7£, Chart 4 ) , followed by a l k y l a t i o n of the copper-
li t h i u m enolate r e s u l t e d i n the formation.of cx-isopropyl-a-alkyl-
d i s u b s t i t u t e d ketones.
2. Intramolecular A i k y l a t i o n s
Intramolecular a l k y l a t i o n s play a very important r o l e i n synthetic
38
organic chemistry. With the advent and refinement of chromato
graphic techniques, p.m.r. spectrometers, and X-ray c r y s t a l l o g r a p h i c
techniques chemists are now able to i s o l a t e and determine the structure
of many natural products i n a r e l a t i v e l y short time. Most of these
compounds have complex, p o l y c y c l i c s t r u c t u r e s . In order to synthesize
these compounds from simpler mono-,.di-, or t r i - c y c l i c precursors,
more and more chemists have used intramolecular c y c l i z a t i o n s as an
i n t e g r a l step i n t h e i r synthetic sequence. This type of a l k y l a t i o n i s
a t t r a c t i v e because of the f a c i l i t y of intramolecular r e a c t i o n s . Also,
since i t i s k i n e t i c a l l y c o n t r o l l e d , t h i s process can lead to very
_ It must be remembered that other s t e r i c f a c t ors i n the c i s - d e c a l i n system also contribute to the rate o f a l k y l a t i o n .
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strained r i n g systems (vide i n f r a ) . In the synthesis of sesquiterpenes,
the f i r s t good examples of intramolecular a l k y l a t i o n are to be found 39 40 41 i n McMurry's synthesis of ( i ) - s a t i v e n e and Heathcock's synthesis '
of (i)-copaene and (i)-ylangene. Intramolecular c y c l i z a t i o n s have
been used not only i n the synthesis of sesquiterpenes but also i n the
synthesis of s t e r o i d s , diterpene a l k a l o i d s , t r i t e r p e n e s , and a l k a l o i d s . 42
In P i e r s ' synthesis of (i)-seychellene 81_, the keto t o s y l a t e 79_
(see Chart 5), upon treatment with base, gave i n excellent y i e l d (±)-
norseychellanone 80. This ketone was then converted by standard methods
into (i)-seychellene 81_. In the f i e l d of diterpene a l k a l o i d s Nagata 43
and co-workers, i n the synthesis of the p e n t a c y c l i c compound a t i s i n e , employed an intramolecular a l k y l a t i o n of ketone 82 to form the C-D
44
r i n g system of this complex compound. Piers and co-workers again
demonstrated the use of t h i s type of a l k y l a t i o n i n the synthesis of
(+)-copacamphor 85_ by base treatment of the keto-tosylate 84. The f i n a l 45
example i s taken from Corey's recent synthesis of (t)-q-copaene 88.
The keto t o s y l a t e 8_6 was converted to the ketone 87 thus e s t a b l i s h i n g
the required t r i c y c l i c skeleton. The isopropyl substituent was then
established to y i e l d (t)-q-copaene 88.
In view of the p o t e n t i a l synthetic u t i l i t y of the"conjugate
a d d i t i o n - a l k y l a t i o n r e a c t i o n and the importance of the intramolecular
a l k y l a t i o n i n organic synthesis, we were in t e r e s t e d i n combining
these two aspects i n one step. That i s to say, i t was proposed to
"tr a p " an organocopper enolate formed from a cuprate a d d i t i o n v i a
an intramolecular a l k y l a t i o n step. To demonstrate the a p p l i c a t i o n of
t h i s r e a c t i o n , we proposed to synthesize neoclovene 89. The key
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reaction f o r the proposed synthesis was the formation of the t r i c y c l i c
skelton v i a the organocopper enolate 91_. The expected stereochemistry
of the addition product, intermediate £1_ w i l l be discussed at a l a t e r
time (see p. 23 ).
3. O r i g i n and S t r u c t u r a l E l u c i d a t i o n of Neoclovene
Since t h i s t h e s i s i s p a r t i a l l y concerned with an approach to the
synthesis of neoclovene, i t i s pertinent to discuss the o r i g i n and
the work which led to the establishment of the structure and stereo
chemistry of t h i s compound. 46
Neoclovene was f i r s t i s o l a t e d by Parker, Raphael, and Roberts, '
when, i n an attempt to obtain a pure sample of (i)-clovene by the 48 well-known sulphuric acid-catalyzed rearrangement of caryophyllene,
they discovered a then unknown hydrocarbon as one of the two main
products i n t h i s r e a c t i o n . They subsequently characterized t h i s
hydrocarbon and showed i t s structure and absolute stereochemistry to
be as depicted i n structure 89_. This s t r u c t u r a l determination by
IO II
8<3?
Raphael and co-workers w i l l be summarized i n the following paragraphs.
Neoclovene fC, „.H„ . ) was shown to be t r i c y c l i c by c a t a l y t i c
hydrogenation over 10% palladium on charcoal to a f u l l y saturated
dihydro d e r i v a t i v e , neoclovane 93. The p.m.r. spectrum of neoclovene
indicated one v i n y l proton at x 4.19, three t e r t i a r y methyl groups
at x 8.80(3H) and x 8.99 (6H) and a v i n y l i c methyl group at x 8.41
(J = 1.5 Hz). Hydroboration followed by Jones oxidation gave two
epimeric ketones 9_4 whose carbonyl absorptions at 1712 cm * were
i n d i c a t i v e of cyclohexanones (see Chart 6). , Treatment of neoclovene
with osmium tetroxide followed by sodium metaperiodate cleavage of the
d i o l resulted i n the keto-aldehyde 9_5, the p.m.r. spectrum of which
showed a sharp s i n g l e t at x 7.98 (3H) confirming the presence of the
v i n y l i c methyl group. Further, the aldehydic proton at x 0.2 appeared
as a t r i p l e t (J =2.5 Hz) thus i n d i c a t i n g the presence of a neighbour
ing methylene group.
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C H A R T £»
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When the keto-aldehyde 95 was s e q u e n t i a l l y treated with chromium
t r i o x i d e , diazomethane, and t r i f l u o r o p e r a c e t i c a c i d , the r e s u l t a n t
acetoxy-methyl ester 9>6 was shown to possess a t e r t i a r y acetoxy group
due to a lack of resonance i n the x 5-6 region. In a d d i t i o n , none of
the three t e r t i a r y methyl groups showed any appreciable downfield
s h i f t to be expected i f one or two of them were substituted on the
carbon bearing the acetoxy-function.
Treatment of the hydroxy-ester 97_ corresponding to 96^ with excess
phenyl magnesium bromide, followed by a c e t i c anhydride dehydration
gave the diphenylene acetate 98. The v i n y l i c proton s i g n a l at T 3.89
was c l e a r l y resolved i n t o a t r i p l e t ( J = 8 Hz) demonstrating the
j u x t a p o s i t i o n of a methylene group. Treatment of 98_ with a c a t a l y t i c
n « - , n ; „ i t r,f - . » , ) ! , . r . . i'i i.-.v. .14 * w 5 A~ n-r\A r, „ ,-, •• ,. .C .1 4 . ..v. ,„.-.(-...-. -«4 r. A ~ UlllV/Ull \J S- J. \A UllUllX L ill \_i JL \J S*. JL. \JL ^ ClllWl Uil fA\.VJO \J JL. JUUXUill J1IV L.a .i. t . followed by methanolic sodium hydroxide, hyd r o l y s i s and e s t e r i f i c a t i o n
gave the nor-hydroxy-ester 99.
49
A second Barbier-Wieland sequence performed on 99_ afforded
i n i t i a l l y the nor-diphenyleneacetate 100 the p.m.r. spectrum of which,
revealed the v i n y l i c proton as a sharp s i n g l e t at T 3.62 i n d i c a t i v e of
a neighbouring quaternary c e n t e r In a d d i t i o n , one of the t e r t i a r y
methyl groups had moved downfield i n the conversion of 98_ to 100
suggesting that one of the substituents at t h i s quaternary center was
probably a methyl group. Conversion of this.product to the hydroxy-
ester 101 was achieved i n the same manner as f o r the higher homologue.
Lithium aluminum hydride reduction of 101 led to a 1,3-diol which was
transformed to the mono-tosylate 102. Base induced fragmentation of
102 y i e l d e d 4-isopropenyl-3,3-dimethylcyclohex-2-enone 103. This
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established the t r i c y c l i c system of neoclovene.
The assignment of the r e l a t i v e configuration of the t e r t i a r y methyl
group at with respect to the gem-dimethyl group at C g was proven
by the following method. Hydroboration of neoclovene gave two
epimeric alcohols 104 and 105 which were shown by p.m.r. to have
the structure shown. Jones oxidation of 104 gave ketone 106 the o.r.d.
curve of which showed a marked negative Cotton e f f e c t which i s
consistent with the p r e d i c t i o n of the octant r u l e . ' I f t h i s ketone
had possessed a structure i n which the C^ methyl group were a n t i to the
C c gem-dimethyl group then the Cotton curve would be expected to 8
show a p o s i t i v e e f f e c t .
The mechanism p r o p o s e d ^ f o r the rearrangement of caryophyllene
into neoclovene involves i n i t i a l l y the isomerization of the exo c y c l i c
double-bond followed by an acid-catalyzed c y c l i z a t i o n to the t r i c y c l i c
c a tion 109. A Wagner-Meerwein rearrangement of t h i s c a t i o n would
produce the bridge-head cation 110. A f i n a l Wagner-Meerwein rearrange
ment and subsequent proton loss would then generate neoclovene.
108 lo9
t
89 89
4. Other Synthetic Approaches to Neoclovene
There has been a number of approaches to the t o t a l synthesis of
52 53 neoclovene ' but, f o r the sake of b r e v i t y , the only successful one
53
w i l l be discussed. Parker and co-workers succeeded i n synthesizing
neoclovene by u t i l i z i n g a synthetic scheme which also added support
to h i s proposed mechanism f o r the rearrangement of caryophyllene i n t o
neoclovene (vide supra). Thus, the t r i - s u b s t i t u t e d double bond of
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caryophyllene 107 vv'as epoxidized with m-chloroperbenzoic acid followed
by oxidative cleavage of the ex o c y c l i c double bond with osmium
tetroxide-sodium periodate to give the epoxy-ketone 111 (see Chart 7).
Treatment of the l a t t e r with potassium hydroxide produced the ket o l
112. The carbonate ester 113, formed from the re a c t i o n of the ketol
112 with ethyl chloroformate, was pyrolyzed at 350° to give a 3:1
mixture of ketones 114 and 115 r e s p e c t i v e l y . Hydrogenation of t h i s
mixture over 10% palladium on charcoal y i e l d e d the saturated ketone
116. Treatment of the t r i c y c l i c ketone 116 with methylmagnesium
iodide afforded the t e r t i a r y alcohol 117 which, when treated i n ether
with concentrated sulphuric a c i d rearranged to neoclovene.
JL l a V H ^
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DISCUSSION
1. General
At the onset of t h i s p r o j e c t , we wished to apply the conjugate
addition-intramolecular a l k y l a t i o n sequence to the synthesis of
neoclovene. Because of the great d i v e r s i t y i n the number of t h e o r e t i c a l
pathways in which t h i s complex molecule could be constructed, a b r i e f
d iscussion of synthetic stratagem and methodology i s appropriate.
The f i r s t order of business i n planning a synthesis of a complex
molecule must be the reduction of the complex framework to simpler
r a t i o n a l precursors. A less complex r i n g structure may be obtained
by the t h e o r e t i c a l cleavage of a bond i n a complex bridged-ring
s t r u c t u r e . The c y c l i z a t i o n of the appropriately f u n c t i o n a l i z e d
intermediate would regenerate the desired p o l y c y c l i c skeleton. This 54
approach i s well i l l u s t r a t e d by Corey and co-workers, i n the
synthesis of longifolene 118. The t h e o r e t i c a l cleavage of the C^-C^
bond i n longifolene 118 produced a s i m p l i f i e d structure. 119 as
compared with 118. The appropriately f u n c t i o n a l i z e d intermediate 120
underwent an intramolecular Michael c y c l i z a t i o n to produce the t r i c y c l i c
diketone 121.
- 21 -
This same basic approach was used by McMurry i n h i s synthesis
39
of (t)-sativene 122. The key step i n t h i s synthesis involved the
intramolecular a l k y l a t i o n of an appropriately f u n c t i o n a l i z e d intermediate,
the b i c y c l i c keto t o s y l a t e 123, to a f f o r d the t r i c y c l i c ketone 124.
123 111
- 22 -
Following t h i s general o u t l i n e , the t h e o r e t i c a l cleavage of two
.carbon-carbon bonds i n neoclovene 89_ were considered (see Chart 8).
Cleavage of the C^-C.^ and C^-C^ bonds of neoclovene 89_ (see
numbering below) would lead to the hypothetical intermediates 125 and
126 r e s p e c t i v e l y . Bearing i n mind that the conjugate a d d i t i o n - .
c y c l i z a t i o n sequence involves, i n i t i a l l y , the addition of a methyl
group by an organocuprate reagent, the appropriately f u n c t i o n a l i z e d
intermediates that might be envisaged f o r the regeneration of the
required t r i c y c l i c skeleton were 90, 127, 128, and 129.
Upon analyzing the proposed intermediates, keto t o s y l a t e 127 was
rejected f o r lack of a "handle" on f o r the intr o d u c t i o n of the C^^
v i n y l methyl group. The ester t o s y l a t e 128 was also rejected not only
because of the- obvious d i f f i c u l t y i n •synthesizing t h i s complex
intermediate but also of the uncertainty i n the decarboxylation of
the c y c l i z e d product. Thus, our at t e n t i o n was focused on intermediates
90 and 129. There was an obvious l i m i t a t i o n i f 129 were to be the
b i c y c l i c precursor to neoclovene, since conjugate addition could
produce not only the desired trans hydrindenone 130 but also the c i s
isomer 131. Therefore, we believed that the keto t o s y l a t e 9_0 should
be our objective.
In a search of the current l i t e r a t u r e , several examples were found,
which led us to beli e v e that conjugate addition would occur a n t i to the
two carbon chain. In an i n v e s t i g a t i o n on some approaches to the
synthesis of cadinene sesquiterpenenes, P h i l l i p s found that, conjugate
addition to the dienones 132 and 135 occurred a n t i to the a x i a l
bridgehead substituents^^ to a f f o r d ketones 134 and 135. In a recent
- 23 -
130 131
paper, Zie g l e r and Wender° u reported that upon treatment of 3,4-
dimethylcyclohex-2-en-l-one 136 with l i t h i u m d i v i n y l c u p r a t e - t r i - n -
butylphosphine complex, the v i n y l ketone 137 was produced i n good
y i e l d free of i t s diastereomer. The cuprate reagent was proposed to f l 2") have added apt! to the pxial (due to A v ' interaction") C, methyl 4 -
group.
An examination of molecular models of keto t o s y l a t e 9_0 c l e a r l y
showed that, although the two carbon side chain i s i n a pseudo-axial
and not a purely a x i a l o r i e n t a t i o n , approach o f the cuprate reagent
from the 3 face would cause the reagent to be almost e c l i p s e d with the
C Q methylene group. This s t e r i c i n t e r a c t i o n should be almost
comparable i n magnitude to the i n t e r a c t i o n experienced by the cuprate
reagent i n the above examples (see Chart 9) and thus, attack from the
a face would be predicted. This would produce, a f t e r intramolecular
a l k y l a t i o n of the i n i t i a l l y formed enolate, the required stereochemistry
i n the product, ketone 97. The l a t t e r could be e a s i l y transformed
v i a the a l c o h o l 138 to neoclovene.
- 25 -
CHART «D
- 26 -
2. Attempted Synthesis of Keto Tosylate 90
At the outset of t h i s work, we had a v a i l a b l e a sample* of the
methoxy alcohol 139 which we attempted to reduce and hydrolyze to the
keto alcohol 140. Unfortunately, the l i t h i u m - l i q u i d ammonia
57 5 8 "
reduction, ' when attempted under a v a r i e t y of conditions (varying
temperature, amount of l i t h i u m and inverse a d d i t i o n ) , e i t h e r gave no
reduction products using mild r e a c t i o n conditions or a complex mixture
of saturated and unsaturated products using a greater amount of
l i t h i u m and a higher r e a c t i o n temperature. We therefore synthesized
the aromatic alcohol 141, the demethoxy analogue of 139 in the hopes
* We thank Dr. F. Kido f o r a generous sample of t h i s compound.
- 27 -
of introducing an oxygen functionality at the carbon atom of the
indane system at a later stage in the synthesis.
|39 UO \M
We chose as our starting material, indan-l-one 142 which was
alkylated with methyl iodide in the presence of potassium t-butoxide
to give an 86% yield of 2,2-dimethylindan-l-one 143 (see Chart 10).
The keto group of 145 was then used as a "handle" for the introduction
of the two carbon side chain. Initially considered for this purpose
was the reaction of 143 with the modified Wittig reagent, triethyl 59
phosphonoacetate. However, this reaction proved very sluggish and
even when carried out at elevated temperatures, produced no syntheti
cally useful results. Since i t was felt that the failure of this
reaction was due, at least in part, to the sterically hindered nature
of the carbonyl group in 145, i t was decided to attempt the use of a
reagent which was sterically less demanding, namely, diethyl cyano-
methylphosphonate.^"^ This approach proved successful. Thus,
reaction of ketone 143 with diethyl cyanomethylphosphonate in the 63
presence of methyl-sulfinyl carbanion in dimethyl sulfoxide at 105° for twenty hours produced a mixture* of Z and E isomers 144 and 145 _
A 65:35 mixture of the Z 144 and E 145 isomers was obtained as judged by g.l.c. analysis and by integration of the signals at T 4.36 and T 4.87 in the p.m.r. spectrum.
- 29 -
respectively in 93% yield.
The physical and spectral properties of the nitriles were in
agreement with structures 144 and 145. Thus the infrared spectrum
showed a nitrile absorption at 2238 cm * and olefinic absorptions at
1615 and 1600 cm *. This mixture of isomers were partially separated
by column chromatography to give a fraction that contained the major^*
Z_ isomer in 96% purity. From the p.m.r. spectrum of this fraction,
the proton resonances of the E isomer could be deduced. Of particular 64
interest was the anisotropic effect of the cyano group shown in
the p.m.r. spectrum. The C.7 proton (see Chart 10) of the Z_ isomer
was deshielded by the cyano group and appeared as a multiplet at
x 1.53-1.83. The gem dimethyl group appeared as a singlet at T 8.73
in the isomer while i t appeared at lower field (T 8.54), due to the
deshielding effect of the nitrile group, in the E isomer. The vinyl
proton of the E_ isomer, deshielded by the aromatic ring,appeared as
a singlet at T 4.36 while i t appeared at x 4.87 in the £_ isomer.
The mixture of nitriles 144 and 145 was hydrolyzed^^ to a mixture
of unsaturated acids 146 and 147 using a refluxing mixture of ethylene
glycol, water, and sodium hydroxide. The white crystalline product
exhibited physical properties in accord with those expected for a mixture
of compounds 146 and 147. Of particular interest in the infrared
spectrum was the absence of the nitrile absorption, the presence of
the hydroxyl absorption at 3600-2400 cm and an unsaturated carbonyl
absorption at 1690 cm-1. Again, the presence of the Z. 146 and 147
isomers were evident in the p.m.r. spectrum. The deshielding effect
of the acid group and the aromatic ring system caused the resonances of
the gem dimethyl group (x 8.45) and the vinyl proton (x 3.62) to appear
- 30 -
at lower field in the E_ isomer as compared to the corresponding signals
(T 8.72 and 4.15 respectively) of the Z_ isomer. The proton of the
Z isomer was also deshielded by the acid functionality and appeared as
a multiplet at T 1.14-1.42.
Hydrogenation of the mixture of acids (one equivalent of hydrogen)
over palladium on charcoal gave a 94% yield of the saturated acid 148.
The physical and spectral properties of the acid were in agreement
with structure 148. Thus the infrared spectrum showed a hydroxyl
absorption at 3500-2400 cm \ and a saturated carbonyl absorption at
1705 cm The presence of the acidic proton was evidenced in the
p.m.r. spectrum by a broad singlet at T -1.08. The doublet of doublets
at T 6.73 ( J = 6 Hz) was assigned to the benzylic methine proton and
the unresolved multiplet (AB of ABM system) between T 7.16 and T 7.68 wa
readily attributable to the methylene protons adjacent to the acid
functionality. The magnetic nonequivalence of methylene protons found
in an asymmetric environment is a well-established phenomenon,^ and
this therefore deserves no further comment. The sharp singlets at
x 9.08 and T 8.82 were attributed to the tertiary methyl groups.
The reduction of the aromatic acid 148 to the aromatic alcohol 141 67 68
was achieved by the reaction of the former with diborane ' in
tetrahydrofuran. The physical and spectral properties of the resulting
product (93% yield) were in accord with structure 141. The hydroxyl
group was evident due to an absorption at 3360 cm * in the infrared
spectrum and an exchangeable hydroxyl proton (broad singlet, T 6.50-
6.93) in the p.m.r. spectrum. The aromatic protons appeared as a
singlet at T 2.98. The triplet at T 6.27 (J = 6 Hz) was assigned to
the methylene protons a to the hydroxyl group. The geminal dimethyl
- 31 -
group appeared as singlets at x 8.89 and 9.05 while the singlet at
T 7.38 was attributed to the C 3 methylene protons.
With the achievement of our first synthetic objective, the
next step involved the reduction of the aromatic system and hopefully
the introduction of an oxygen functionality at the carbon atom 69
(vide supra). Since previous work in this laboratory showed that 70
'the allylic oxidation of the alcohol 154, under a variety of conditions,
yielded a number of a,6-unsaturated carbonyl products, we decided to
synthesize the epoxy ethers 152 and 153 (see Chart 10) and introduce
+ OTHER PRODUCT'S
the oxygen functionality via an allyl i c alcohol (vide infra).
Reaction of the aromatic alcohol 141 with lithium in liquid 72
ammonia afforded the diene alcohol 149 in 90% yield. This compound
showed the expected spectral properties. The infrared spectrum
showed a hydroxyl absorption at 3365 cm~* and an olefinic absorption
at 1645 cm In the p.m.r. spectrum the vinyl protons were evident
as a singlet at x 4.25. The C methylene protons appeared as a singlet
at T 7.38 while the triplet* at x 6.33 (J = 7 Hz) was assigned to the
methylene protons adjacent to the hydroxyl group. The exchangeable
hydroxyl proton appeared as a singlet at x 7.05, and the geminal
methyl group as singlets at T 8.92 and 9.03. v.
- 32 -
Regioselective hydrogenation of diene 149 was achieved by the
use of the homogeneous c a t a l y s t t r i s (triphenylphosphine)chloro-72
rodiunu A f t e r the uptake of one equivalent of hydrogen, the o l e f i n i c
alcohol 150 was i s o l a t e d i n 95% y i e l d . The s p e c t r a l properties of
t h i s compound were i n complete agreement with the assigned s t r u c t u r e .
There was an absence of o l e f i n i c absorptions due to the d i s u b s t i t u t e d
double bond i n the i n f r a r e d spectrum. The hydroxyl absorption
appeared at 3370 cm \ In the p.m.r. spectrum, the complete reduction
of the d i s u b s t i t u t e d double bond was evident due to the lack of
resonances i n the v i n y l proton region. The t r i p l e t at x 6.45 (J =
7 Hz) was assigned to the methylene protons adjacent to the hydroxyl
group while the s i n g l e t s at x 8.95 and x 9.08 were a t t r i b u t e d to the
gsminal methyl group. The exchangeable hydroxyl proton appeared as a .
broad s i n g l e t at x 6.05 to x 6„28.
The hydroxy f u n c t i o n a l i t y of 150 was protected as an a c e t a l . Thus treatment of the o l e f i n i c alcohol 150 with chloromethyl methyl
73 74
ether ' i n the presence of excess potassium t-butoxide afforded,
in 92% y i e l d , the o l e f i n i c a c e t a l . The p h y s i c a l and s p e c t r a l
properties of t h i s product were i n agreement with structure 151. Of
i n t e r e s t was the absence of hydroxyl absorptions i n the i n f r a r e d
spectrum. The p<,m0r. spectrum showed the methoxy group as a s i n g l e t
at T 6.73 while the methylene protons adjacent to the methoxy group
appeared as a s i n g l e t at x 5.48. The m u l t i p l e t at x 6.20 to x 6.66
was a t t r i b u t e d to the methylene protons. The two s i n g l e t s at x 8.95
and x 9.07 are due to the geminal methyl group.
The epoxy acetals 152 and 153 were formed by treatment of the
- 33 -
76 77
o l e f i n i c acetal 151 with m-chloroperbenzoic a c i d . ' This mixture
had s p e c t r a l properties that were almost i d e n t i c a l with those of
the corresponding o l e f i n i c acetal 151, except for the presence of the
epoxy absorption at 740 cm i n the i n f r a r e d spectrum. Gas-liquid
chromatographic analysis of the product revealed an 80:20 mixture of the
epimeric epoxy acetals 152 and 153 r e s p e c t i v e l y . This assignment
was based on the s t e r i c approach control p r i n c i p l e . The epoxidizing
reagent was assumed to have attacked from the less hindered side of
the double bond, a n t i to the two carbon chain, thus forming the major
isomer 152.
R - - C H a O C H 3
- 34 -
With the achievement of our second o b j e c t i v e , we now wished to
introduce an oxygen substituent at the p o s i t i o n . We therefore 77-79
reacted the epoxy acetals 152 and 153 with l i t h i u m diethylamide
i n tetrahydrofuran to produce a mixture of a l l y l i c alcohols 156 (two
diastereomers) and 157 (two diastereomers). The above ten t a t i v e
assignment was supported by a hydroxyl absorption at 3480 cm * i n the
i n f r a r e d spectrum and a broad s i n g l e t , assigned to the v i n y l proton,
at T 4.62 i n the p.m.r. spectrum. Although the four products, evidenced
by g a s - l i q u i d chromatographic a n a l y s i s , showed that t h i s sequence
would probably be s y n t h e t i c a l l y unproductive, we nevertheless decided
to continue with the sequence. 80
Upon treatment of t h i s mixture with aqueous hydrochloric a c i d ,
a diastereomeric mixture of the rearranged a l l y l i c alcohols 158 (two
diastereomers) and 159 (two diastereomers) were formed. This t e n t a t i v e
assignment was based on the disappearance of the v i n y l proton
resonance i n the p.m.r. spectrum and the presence of a m u l t i p l e t at x 5.84-6.17 which was assigned to the proton adjacent to the hydroxyl group. When the alcohols 158 and 159 were oxidized with C o l l i n s
8182
reagent, ' a mixture of ketones 160 and 161 were formed. This
tentative assignment was sustained by the presence of an a,3-unsaturated
ketone absorption at 1665 and 1630 cm - 1 i n the i n f r a r e d spectrum.
The presence of two major products were evident by g a s - l i q u i d
chromatographic a n a l y s i s .
Although t h i s sequence produced the desired ketone 160, i t was
not s y n t h e t i c a l l y useful due to the poor o v e r a l l y i e l d and the
expectation that the desired ketone 160 was the minor component. The
- 35 -
77 above expectation was due to the f a c t , established by Rickborn,
that the base induced rearrangement of epoxides occurs with the
abstraction of a proton that i s a and syn to the epoxide. Abstraction
of a proton at by the base would be s t e r i c a l l y hindered by the two
carbon side chain but, since t h i s s t e r i c i n t e r a c t i o n i s more pronounced
i n the minor epoxide, that i s epoxy a c e t a l 153, the attack by the base
at the psotion i s h i g h l y favored f o r only t h i s compound. Therefore,
the desired ketone 160 should be the minor isomer. Thus, we attempted
to synthesize the keto t o s y l a t e 90_ by another synthetic sequence.
2. Second Attempted Synthesis of Keto Tosylate 90
The d i f f i c u l t i e s encountered i n the reduction of the methoxy
alcohol 139 and i n the introduction of an oxygen-containing f u n c t i o n a l
group at the p o s i t i o n of the epoxy acetals 152 and 153 led us to
investigate a synthetic sequence i n which the i n t r o d u c t i o n of the oxygen
containing substituent at C. and the formation of the desired
b i c y c l i c system was r e a l i z e d i n the same r e a c t i o n . This could be
achieved through the base-catalyzed A l d o l c y c l i z a t i o n of the diketone
162. Upon examination of the p o s s i b l e c y c l i z e d intermediates of the
diketone 162, there are i n i t i a l l y four p o s s i b l e c y c l i z a t i o n products.
Two of these products have a four membered r i n g incorporated i n t h e i r
skeleton and the t h i r d product cannot be dehydrated to give an a,8-
unsaturated ketone. Since only the k e t o l 163 can be dehydrated to
the a,^-unsaturated ketone 164, the thermodynamically favored product,
ketone 164, would be r e a l i z e d i f the c y c l i z a t i o n were c a r r i e d out
under the proper conditions.
f
- 36 -
163 I&4
We chose, as our first objective, the ketone 170, which would
be an intermediate to the diketone 162. The starting material chosen
was isobutyronitrile 165 which was alkylated with
allyl bromide in the presence of lithium diisopropylamide to give a
83% yield of 2,2-dimethyl-4-pentenenitrile 166 (see Chart 11). The
physical and spectral properties of the olefinic nitrile were in
agreement with structure 166, and with the data reported in the 83 84
literature ' for this compound. Thus the infrared spectrum showed
the presence of the terminal olefinic functionality as bands at 3090,
1640, and 920 cm * and a nitrile absorption at 2245 cm In the p.m.r.
spectrum of 166, the vinyl group exhibited a multiplet at T 3.75-4.45
for the C 4 proton and a multiplet at x 4.63-5.06 for the C 5 protons.
The doublet (J = 7 Hz) at x 7.72 was assigned to the ally l i c C, protons
- 37 -
- 38 -
while, the s i n g l e t at T 8.67 was assigned to the t e r t i a r y methyl
groups.
Cleavage of the double bond of compound 166 was eff e c t e d by
85 ozonolysis i n 1% pyridine- dichloromethane s o l u t i o n at -78°, followed
8 6
by decomposition of the r e s u l t i n g ozonide with zinc and a c e t i c a c i d .
The r e s u l t i n g crude aldehyde n i t r i l e 167 was somewhat unstable and
prone to autoxidation and was therefore used i n the next r e a c t i o n
without further p u r i f i c a t i o n . However, the s p e c t r a l data obtained
from the crude product supported the assigned structure 167. The
in f r a r e d spectrum showed the presence of the aldehydic carbonyl
f u n c t i o n a l i t y with "absorptions at 2750 and 1720 cm ^ while the absorption
band at 2250 cm * indicated the presence of the n i t r i l e group. A
mul t i p l e t at T 0.10 i n the p.m.r. spectrum confirmed the presence of
the aldehyde fu n c t i o n a l i t y . - The t e r t i a r y methyl groups appeared as a
sharp s i n g l e t at T 8.50 while the methylene protons were evident as a
mu l t i p l e t at x 7.26.
The crude aldehyde n i t r i l e was then reacted with the W i t t i g 87
reagent cyclopentylidenetriphenylphosphorane i n dimethoxyethane to
give, i n 87% y i e l d , the o l e f i n i c n i t r i l e 168.* This compound showed * We attempted to synthesize compound 168 by an alternate route. Unfortunately, even at low temperatures, the Wit t i g reagent acted
o < T H 3
^ 3
as a base causing the formation of the A l d o l condensation product 1-cyclopentylidenec.yclopentanone.
- 39 -
the expected s p e c t r a l p r o p e r t i e s . The n i t r i l e group was evidenced
by the absorption at 2255 cm * i n the i n f r a r e d spectrum while the
o l e f i n i c absorption appeared at 1680 cm The p.m.r. spectrum showed
a sharp s i n g l e t at x 8.65 f o r the t e r t i a r y methyl groups while the
v i n y l proton appeared as a m u l t i p l e t at T 4.37-4.90. 88 8!
When the o l e f i n i c n i t r i l e was treated with polyphosphoric a c i d , '
i t underwent c y c l i z a t i o n and formed the b i c y c l i c imine 169.* The crude
imine was immediately hydrolyzed using a methanolic sodium hydroxide
s o l u t i o n to a f f o r d a 70% (overall) y i e l d of the desired product. The
phy s i c a l and s p e c t r a l properties of t h i s compound were i n complete
accord with structure 170. The u l t r a v i o l e t spectrum exhibited an
absorption at 248 mu (e = 14,300) which i s t y p i c a l of a f u l l y
substituted ft-unsaturated ketone. This was supported by the
in f r a r e d spectrum with absorptions at 1660 and 1640 cm In the
p.m.r. spectrum, the t e r t i a r y methyl groups appeared as a s i n g l e t at
x 8.90.
Having accomplished our f i r s t o b j ective, we next wished to
introduce a two carbon chain at the carbonyl carbon. 'Die so l u t i o n to
t h i s problem seemed to be the use of the modified W i t t i g reagent
t r i e t h y l phosphonoacetate. Unfortunately, a l l attempts at the r e a c t i o n
of the ketone 170 with t h i s reagent or the less s t e r i c a l l y demanding
reagent d i e t h y l cyanomethylphosphonate f a i l e d due to the e n o l i z a t i o n
In our hands, i t was found that the use of 10% phosphorous pentoxide-methanesulfonic acid^O was superior to that of polyphosphoric acid due to the d i f f i c u l t y i n s t i r r i n g a s o l u t i o n of the l a t t e r . The y i e l d s of ketone 170 was approximately the same i n both cases.
- 40 -
of the ketone. Various other attempts at the introduction of only
one carbon atom at the carbonyl carbon also f a i l e d . We, therefore,
decided to prevent the e n o l i z a t i o n of the ketone 170 by "blocking"
the double bond. The blocking group chosen had to p r o h i b i t e n o l i z a t i o n
and had to be susceptible to^removal to reform the double bond. -The
epoxide moiety seemed to meet both requirements. Thus treatment of the 91
ketone 170 with a mixture of hydrogen peroxide and sodium hydroxide
gave, i n 76% y i e l d , the epoxy ketone 171. An a n a l y t i c a l sample of
t h i s material was obtained by preparative g . l . c . and exhibited s p e c t r a l
data i n agreement with the assigned structure. Most notable i n the
in f r a r e d spectrum was the carbonyl absorption at 1700 cm In the
p.m.r..spectrum, the t e r t i a r y methyl groups now appeared as two
s i n g l e t s at Y 9.07 and T 5.92. One of the methyl groups was apparently 92
shielded by the oxygen atom of the epoxide r i n g thus causing it. to
resonate at a higher f i e l d .
With the establishment of the blocking group, we again attempted
to introduce the two carbon chain v i a the W i t t i g r e a c t i o n . Although
the r eaction of the epoxy ketone with t r i e t h y l phosphonoacetate was
unsuccessful, we were able to react the former with d i e t h y l cyano-
methylphosphonate at an elevated temperature (see page 27).
However, when we t r i e d to hydrogenate the double bond of the epoxy Q
n i t r i l e 172 (see Chart 11) with a v a r i e t y of c a t a l y s t s , hydrogenolysis
of the a l l y l i c C-0 bond occurred concurrently with the reduction of the
double bond. We therefore decided to i n s e r t the two carbon chain v i a
two one-carbon homologations.
The f i r s t carbon atom was introduced by means of the Witt i g
- 41 -
reaction. Thus, reaction of the epoxy ketone 171 with methylenetri-
phenylphosphorane resulted in an 88% yield of the epoxy olefin 173.
The spectral properties of this product were consistant with the
assigned structure. Of interest was the complete disappearance of the
carbonyl absorption and the presences of olefinic absorptions at
3120, 1635, and 890 cm"1 in the infrared spectrum. The vinyl protons
in the p.m.r; spectrum were evident as a singlet at x 4.73. The
signals at x 9.05 and 8.87 were assigned to the tertiary methyl groups.
In accord with our plans to convert this compound into the
next higher homologue, i t was necessary at this stage of the
synthesis to functionalize the terminal double bond into a primary
alcohol functionality. This was achieved by subjecting the epoxy
olefin 173 to hydroboration with diborane in tetrahydrofuran followed
by decomposition of the intermediate alkylborane with alkaline
hydrogen peroxide. The resultant ratio of the products (epoxy
alcohols 174 and 175) varied somewhat.from reaction to reaction but
the mixture of products, as judged by gas-liquid chromatographic
analysis, never contained less than 75% of the major isomer,* epoxy
alcohol 175. An analytical sample of this major isomer, collected
by preparative g.l.c, exhibited spectral properties in accord with
structure 175. Thus, the infrared spectrum showed a hydroxyl
absorption at 3460 cm In the p.m.r. spectrum, the tertiary methyl
groups were evident as sharp singlets at x 9.30 and 9.00. _
The assignment of the stereochemistry ot the two epimeric epoxy alcohols 174 and 175 is tentative and was based on examination of molecular models and the application of the steric approach control principle.
v.
- 42 -
The p r o t o n s a d j a c e n t t o t h e h y d r o x y l g roup appeared as a m u l t i p l e t
a t T 5 . 8 4 t o T 6 . 5 7 .
The a l c o h o l f u n c t i o n a l i t y was p r o t e c t e d as an e s t e r by t r e a t m e n t
o f t h e epoxy a l c o h o l s 174 and 175 w i t h a c e t i c a n h y d r i d e i n d r y
p y r i d i n e t o g i v e , i n 92% y i e l d , a m i x t u r e o f epoxy a c e t a t e s 176 and
177o The r a t i o o f t h e e p i m e r i c a c e t a t e s was dependent on t h e r a t i o
o f t h e m i x t u r e o f epoxy a l c o h o l s 174 and 175 u s e d . An a n a l y t i c a l
sample o f t h e ma j o r i s o m e r 1 7 7 , o b t a i n e d by p r e p a r a t i v e g . l . c ,
e x h i b i t e d s p e c t r a l p r o p e r t i e s i n a c c o r d w i t h t h e a s s i g n e d s t r u c t u r e .
The p r e s e n c e o f t h e a c e t a t e g r o u p was a p p a r e n t w i t h a b s o r p t i o n s a t
1740 and 1230 cm * . . i n t h e i n f r a r e d s p e c t r u m . I n t h e p.m.r. s p e c t r u m ,
t h e m u l t i p l e t a t T 5 . 4 7 - 6 . 4 0 was a s s i g n e d t o t h e p r o t o n s a d j a c e n t
t o t h e a c e t a t e f u n c t i o n a l i t y . The t e r t i a r y m e t h y l groups a p p e a r e d as
s i n g l e t s a t f 9 . 2 7 and T 8 . 9 7 w h i l e t h e a c e t o x y group a p p e a r e d as a
s i n g l e t a t T 7 . 9 7 .
A t t h i s t i m e , we f e l t t h a t i t would be a p p r o p r i a t e t o r e i n t r o d u c e
t h e d o u b l e bond by t h e r e d u c t i o n o f t h e e p o x i d e f u n c t i o n a l i t y .
A l t h o u g h t h e r e were many examples o f t h e r e d u c t i o n o f e p o x i d e s t o
o l e f i n s i n t h e l i t e r a t u r e , t h e r e was, a p p a r e n t l y , no example o f t h e
r e d u c t i o n o f a t e t r a s u b s t i t u t e d e p o x i d e . The a t t e m p t e d r e d u c t i o n o f
t h e epoxy a c e t a t e 176 and 177 w i t h c h r o m i u m ( I I ) e t h y l e n e d i a m i n e 94
complex i n d i m e t h y l f o r i n a m i d e y i e l d e d o n l y s t a r t i n g m a t e r i a l . The 95 96 r e d u c t i o n o f t h e e p o x i d e w i t h z i n c - c o p p e r * ' o r z i n c - s i l v e r c o u p l e
a t e l e v a t e d t e m p e r a t u r e s a l s o f a i l e d t o p r o d u c e any r e d u c t i o n p r o d u c t .
We were f i n a l l y a b l e t o e f f e c t t h e r e d u c t i o n by t h e t r e a t m e n t o f t h e
epoxy a c e t a t e s 176 and 177 w i t h t u n g s t e n h e x a c h l o r i d e and . n - b u t y l -
l i t h i u m i n r e f l u x i n g t e t r a h y d r o f u r a n . J 1 The desired o l e f i n i c acetate
178 was thus obtained i n 90% y i e l d . The p h y s i c a l and s p e c t r a l properties
were i n agreement with the assigned structure 178. Thus, the i n f r a r e d
spectrum showed carbonyl absorptions at 1740 and 1230 cm *. Of
p a r t i c u l a r i n t e r e s t was the p.m.r. spectrum i n which, due to the
removal of the s h i e l d i n g e f f e c t of the oxygen atom of the epoxide
r i n g , the t e r t i a r y methyl groups appeared as s i n g l e t s at x. 9.07 and
9.03. The acetoxy group was evident as a s i n g l e t at T 8.04 while the
m u l t i p l e t at T 5.66-6.31 was assigned to the protons adjacent to
acetate f u n c t i o n a l i t y .
In order to add another carbon atom to the side chain, the
acetate p r o t e c t i n g group was removed by the r e a c t i o n of the o l e f i n i c
acetate with l i t h i u m aluminium hydride.. The product, obtained i n 97%
y i e l d , exhibited s p e c t r a l properties in agreement with structure 179.
Thus, the i n f r a r e d spectrum showed a hydroxyl absorption at 3410 cm
In the p.m.r. spectrum,'the s i n g l e t s at x 9.14 and x 9.08 were
assigned to the t e r t i a r y methyl grups while the doublet (J = 4 Hz)
at x 6.40 was a t t r i b u t e d to the methylene protons adjacent to the
hydroxyl group.
At t h i s point i n the synthesis, we wished to homologate the o l e f i n i c
alcohol 179 according to the scheme shown i n Chart 12. The proposed
synthesis of the keto t o s y l a t e 90_ involved r e a c t i o n of the o l e f i n i c
t o s y l a t e 180, corresponding to the o l e f i n i c alcohol 179, with sodium 99
cyanide i n dimethyl s u l f o x i d e to give the o l e f i n i c n i t r i l e 181.
Base hydrolysis of the l a t t e r would a f f o r d the o l e f i n i c a c i d 182.
Subjection of 182 to ozonolysis and base-catalyzed cyclization''' <^ ,
- 44 -
would p r o d u c e t h e k e t o a c i d 184. S e l e c t i v e r e d u c t i o n o f t h e a c i d
f u n c t i o n a l i t y w i t h d i b o r a n e f o l l o w e d by t o s y l a t i o n o f t h e r e s u l t a n t
a l c o h o l would t h e n g i v e t h e d e s i r e d p r o d u c t , k e t o t o s y l a t e 90.
U n f o r t u n a t e l y due t o t h e l a c k o f t i m e and s t a r t i n g m a t e r i a l , t h e o l e f
a l c o h o l 179, t h e s y n t h e s i s o f t h e k e t o t o s y l a t e 90, as p r o p o s e d on
C h a r t 12, was n o t c a r r i e d o u t .
Thus, i n c o n c l u s i o n , an a t t r a c t i v e and q u i t e f e a s i b l e a p p r o a c h
t o t h e s y n t h e s i s o f n e o c l o v e n e has been d e v e l o p e d w h i c h i n c l u d e d t h e
a p p l i c a t i o n o f some r e c e n t s y n t h e t i c methods. The second and most
s u c c e s s f u l a p p r o a c h d e s c r i b e d o f f e r s t h e p o s s i b i l i t y t h a t f u r t h e r
development o f t h e s y n t h e t i c sequence c o u l d l e a d t o t h e s y n t h e s e s o f
n e o c l o v e n e i n t h e n e a r f u t u r e .
- 4 5 -
C H A R T \Z
EXPERIMENTAL
G e n e r a l
M e l t i n g p o i n t s , w h i c h were d e t e r m i n e d on a K o f l e r b l o c k , and
b o i l i n g p o i n t s a r e u n c o r r e c t e d . U l t r a v i o l e t s p e c t r a were measured
i n m e t h anol s o l u t i o n on e i t h e r a C a r y , model 14, o r a Unicam, model
SP 800, s p e c t r o p h o t o m e t e r . R e f r a c t i v e i n d i c i e s were t a k e n on a
O x j . J L C J . i i c : u a i j . i c u I v C x J . u u l i l c t C J . * J V U U L J . J J C i j i i i u i . U u I I ^ A V.
r e c o r d e d on a P e r k i n - E l m e r model 710 s p e c t r o p h o t o m e t e r w h i l e c o m p a r i s o n
s p e c t r a were r e c o r d e d on a P e r k i n - E l m e r model 457 s p e c t r o p h o t o m e t e r .
The p.m.r. s p e c t r a were t a k e n i n d e u t e r o c h l o r o f o r m o r c a r b o n t e t r a
c h l o r i d e s o l u t i o n on V a r i a n A s s o c i a t e s s p e c t r o m e t e r s models T-60
and/or HA-100, XL-100. L i n e p o s i t i o n s a r e g i v e n i n t h e T i e r s T s c a l e ,
w i t h t e t r a m e t h y l s i l a n e as i n t e r n a l s t a n d a r d ; t h e m u l t i p l i c i t y ,
i n t e g r a t e d peak a r e a s , and p r o t o n a s s i g n m e n t s a r e i n d i c a t e d i n
p a r e n t h e s e s . G a s - l i q u i d c h r o m a t o g r a p h y ( g . I . e . ) was c a r r i e d o u t on
e i t h e r an A e r o g r a p h A u t o p r e p model 700 o r a V a r i a n A e r o g r a p h , model
90-P. The f o l l o w i n g columns were employed:
- 47 -
Column Length S t a t i o n a r y Phase Support Mesh
A 10 f t x 1/4 i n 20% SE 30 Chromosorb W 60/80 B 11 20% Carbowax 20 M 11 11
C " 10% SE 30 II . . II D " 10% FFAP " ' " E " 10% OV-210 11 ' " F 10 f t x 3/8 i n 20% SE 30 " 11
G 11 10% OV-210 " " H 5 f t x 1/4 i n 20% SE 30 " "
The s p e c i f i c column used along with column temperature and c a r r i e r
gas (helium) f l o w - r a t e ( i n ml/min), are i n d i c a t e d i n parentheses. Column
chromatography was -performed us i n g f l o r i s i l ( F i s h e r S c i e n t i f i c Co.),
n e u t r a l s i l i c a g e l (Camag or Macheray, Nagel and Co.) or n e u t r a l alumina
(Ca map or Macher^yj Nagel and Co.) < The alumina was d e a c t i v a t e d as
r e q u i r e d by a d d i t i o n o f the c o r r e c t amount of water. High r e s o l u t i o n
mass s p e c t r a were recorded on an AEI type MS-9 mass spectrometer. M i c r o
analyses were performed by Mr. P. Borda, M i c r o a n a l y t i c a l Laboratory,
U n i v e r s i t y o f B r i t i s h Columbia, Vancouver.
P r e p a r a t i o n of 2,2-Dimethylindan-l-one 143
To an i c e - c o o l e d , s t i r r e d suspension of powdered potassium t -
butoxide (156.8 g, 1.4 moles) i n 1 £ of dry dimethoxyethane, kept under
an atmosphere of dry n i t r o g e n , was added a s o l u t i o n of 79.2 g (0.60
mole) of 1-indanone 142 i n 200 ml of dry dimethoxyethane. The r e s u l t i n g
mixture was s t i r r e d f o r 10 min, and then a s o l u t i o n o f 426 g (3 moles)
of methyl i o d i d e i n 300 ml of dry dimethoxyethane was added. The
mixture was warmed to room temperature and allowed to s t i r f o r 3 h.
The r e s u l t i n g mixture was d i l u t e d w i t h water and thoroughly e x t r a c t e d
- 48 -
with ether. The ethereal extracts were combined, washed with brine,
and dried over anhydrous magnesium sulfate. Removal of the solvent
gave an o i l which, upon d i s t i l l a t i o n under reduced pressure, afforded
78.2 g (86%) of the desired alkylated product 143, b.p. 47-49° at
0.2 mm [ l i t . b.p. 87-89° at 0.6 mm; n 1.5383]; m.p. 37-38°; n p
1.5442; u l t r a v i o l e t , X 246 my (e = 12,800); infrared ( f i l m ) , v max max
1706, 1610 cm \; p.m.r., T 8.80 (singlet, 6H, t e r t i a r y methyls),
7.OS (singlets, 2H, methylene protons), 2.17-2.85 (multiplet, 4H,
aromatic protons).
Anal. Calcd. for C1 1
H1 2
0 : C > 8 2- 4 6> H' 7' 5 5* F o u n d : c> 82.43;
H, 7.56.
Preparation of N i t r i l e s 144 and 14b
A s t i r r e d suspension of sodium hydride (16.8 g, 0.35 mole) in
400 ml of dry dimethyl sulfoxide was slowly heated, under an
atmosphere of dry nitrogen, to 75° and kept at t h i s temperature u n t i l
frothing had ceased (approximately 30 min). The solution was cooled
to room temperature and a solution of die t h y l cyanomethylphosphonate
(67.5 g, 0.38 mole) i n 100 ml of dry dimethyl sulfoxide was added.
The r e s u l t i n g solution was s t i r r e d for 15 min, and then a solution of
the ketone 143 (11.2 g, 70 mmole) i n 50 ml of dimethyl sulfoxide was
added. The reaction mixture was heated (bath temperature 105°) for
20 h, then cooled, d i l u t e d with water and thoroughly extracted with
ether. The combined extracts were washed- with water, saturated brine,
and then dried over anhydrous magnesium sulfate. Removal of the
solvent, followed by d i s t i l l a t i o n of the residual o i l under reduced
- 49 -
pressure afforded 11.75 g (93%) of a 65:35 mixture of £ and E isomers respectively as judged by p.m.r. and gas-liquid chromatographic analysis
(column E, 125°, 100). This mixture exhibited b.p. 96-98° at 0.25 mm;
infrared (film) v 2238, 1615, 1600 cm \ A sample was subjected to J max r . column chromatography using Camag Kieselgel for TLC (without binder)
and 98:2 petroleum ether (b.p. 68°)-ether as eluting solvent. A
positive pressure (air) was required to maintain a reasonable flow rate.
The ratio of compound to s i l i c a gel was 1:100. The major Z_ isomer was
thus obtained in 96% purity. It exhibited p.m.r., T 8.73 (singlet, 6H,
tertiary methyls), 7.13 (singlet, 2H, methylene protons), 4.87 (singlet,
1H, vinyl proton),-2.49-2.91 (multiplet, 3H, aromatic protons), 1.53-
1.83 (multiplet, 1H, proton). From the above, the p.m.r. spectrum
of the minor E isomer could be deduced. It showed p.ni.r.. 7 8.54
(singlet, 6H, tertiary methyls), 7.08 (singlet, 2H, methylene protons),
4.36 (singlet, 1H, vinyl proton), 2.43-2.90 (multiplet, 4H, aromatic
protons).
Anal. Calcd. for C^H^N: C, 85.21; H, 7.15; N, 7.64. Found:
C, 84.90; H, 7.08; N, 7.51.
Preparation of Acids 146 and 147
A mixture of nitriles 144 and 145 (24 g, 135 mmoles) was dissolved
in 540 ml of 5:1 ethylene glycol-water containing 100 g (2.5 mole) of
sodium hydroxide. The resulting solution was refluxed (bath temperature
140°) under an atmosphere of nitrogen for 20 h and then cooled to room
temperature. This mixture was diluted with 600 ml of saturated brine
and extracted with ether. The aqueous residue was acidified to pH 2
- 50 -
with 6 N hydrochloric acid and the resulting mixture was thoroughly
extracted with 600 ml of 1:1 petroleum ether (b.p. 68°)-ether. The
combined extracts were washed twice with brine and then dried over
anhydrous magnesium sulfate. Removal of the solvent gave 19 g (95%)
of white crystals. An analytical sample, obtained by recrystallization
from hexane, exhibited m.p. 114-115°; infrared (CHCl,), v 3600-2400,
I960, 1625 cm"1; ultraviolet, A 276 my (e = 12,150), 286 (e = 11,660), 1H3-X
302 (e = 10,400). The p.m.r. spectrum showed a 81:19 ratio of Z to E
isomers. The major 2_ isomer exhibited p.m.r., T 8.72 (singlet, 6H,
tertiary methyls), 7.12 (singlet, 2H, methylene protons), 4.15 (singlet,
IH, vinyl proton)2.35-2.85 (multiplet, 3H, aromatic protons), 1.14-
1.42 (multiplet, IH, Cj proton). The E_ isomer had p.m.r., T 8.45
(singlet, 6H, tertiary methyls), 7.01 (singlet, 2H, methylene protons),
3.62 (singlet, IH, vinyl proton), 2.46-2.96 (multiplet, 4H, aromatic
protons).
Anal. Calcd. for C1 3
H1 4
02
: c» 77.20; H, 6.98. Found: C, 77.04;
H, 7.20.
Hydrogenation of Acids 146 and 147
The acids 146 and 147. (16 g, 0.89 mole) in 350 ml of ethyl
acetate were hydrogenated over 2.0 g of 10% palladium on charcoal at
room temperature until the uptake of hydrogen was complete (approximately
10 h). The reaction mixture was filtered through celite and the
filtrate was evaporated to dryness to give a yellow o i l which was
distilled under reduced pressure (b.p. 140-142° at 0.05 mm). The
resulting pale yellow o i l (17.0 g, 94%) crystallized upon standing.
v
- 51 -
An analytical sample, obtained by recrystallization from hexane,
exhibited m.p. 74.5-75.5°; infrared (film) v 3500-2400, 1705 cm"1; r • ' *• 3 max ultraviolet X 260 my (e = 615), 267 my (e = 992), 273 my (e = 1145);
nicLX
p.m.r., x 9.08 (singlet, 3H, tertiary methyl), 8.82 (singlet, 3H,
tertiary methyl), 7.32 (singlet, 2H, C 3 protons), 7.16-7.68 (multiplet,
2H, -CH2C02H), 6.73 (doublet of doublets, 1H, methine proton, J =
6.0 Hz), 2.88 (singlet, 4H, aromatic protons), -1.08 (broad singlet, 1H,
-C00H). Anal. Calcd. for (L-H-.O.,: C, 76.44; H, 7.90. Found: C, 76.70;
IS ID I H, 8.10.
Preparation of Aromatic Alcohol 141
To a stirred solution cf acid 14S (16.2 g, 79 mmcles) in 30 ml
of dry tetrahydrofuran, cooled to 0°, was added 75 ml (100 mmoles) of
borane in tetrahydrofuran. The ice bath was removed and the resulting
solution was stirred under nitrogen for 1 h.. The excess hydride
was destroyed by careful addition of 50 ml of 1:1 tetrahydrofuran-
water and the aqueous phase was saturated with 15 g of anhydrous
potassium carbonate. The layers were separated and the aqueous phase
was extracted four times with 50 ml portions of ether. The combined
organic extracts were dried over anhydrous magnesium sulfate. The
concentrated yellow o i l was distilled under reduced pressure to afford 20
14.0 g (93%) of the desired alcohol b.p. 106-108° at 0.55 mm; n Q
I. 5318; ultraviolet A M A X 261 my (e = 668), 267 my (e = 1055), 274 my
(e = 1270); infrared (film) v 3360, 3110, 3060, 1040, 1010 cm"1; 3 max
p.m.r., T 9.05 (singlet, 3H, tertiary methyl), 8.89 (singlet, 3H,
- 52 -
t e r t i a r y methyl), 7.38 (singlet, 2H, methylene protons), 6.50-6.93
(broad s i n g l e t , IH, exchangeable, -OH), 6.27 ( t r i p l e t , 2H, -CH^OH, J =
6.0 Hz), 2.98 (singlet, 4H, aromatic protons).
Anal. Calcd. f o r n H O : C, 82.06; H, 9.53. Found:- C, 81.95; IS l o
H, 9.56.
Preparation of Diene Alcohol 149
To a s t i r r e d solution of lithium (2.15 g, 310 mmoles) i n 350 ml
of l i q u i d ammonia ( d i s t i l l e d from sodium metal) cooled to -78° was
added a solution of 11.8 g (62 mmole) aromatic alcohol i n 20 ml of
dry dimethyoxyethane and 8 ml of 95% ethanol. This solution was
s t i r r e d at -78° for 45 min aid then at -33° for 30 min. The blue color
was Hi scharged by the a d d i t i o n of 1 Q ml of 95% ethanol. The ammonia
was allowed to evaporate and 360 ml of.water was added. This mixture
was th r i c e extracted with ether. The combined organic extracts were
washed with saturated brine and dried over anhydrous magnesium sulfate.
Removal of the solvent, followed by d i s t i l l a t i o n of the residue, gave
10.5 g (90%) of the diene alcohol 149_ as a colorless o i l , b.p. 92-94°
at 0.2 mm. An a n a l y t i c a l sample, obtained by preparative g.l.c.
(column A, 160°, 100) exhibited infrared (film) v m a x 3365, 3055, 1645,
1045, 1015 cm - 1; p.m.r., T 9.03 (singlet,- 3H, t e r t i a r y methyl), 8.92
(singlet, 3H, t e r t i a r y methyl), 7.38 (s i n g l e t , 2H, C„ methylene
protons), 7.05 (singlet, III, exchangeable, -OH), 6.33 ( t r i p l e t , 2H,
-CH_20H, J = 7.0 Hz), 4.25 (singlet, 2H, v i n y l protons).
Anal. Calcd. f o r C jH^O: ' C, 81.20; H, 10.48. Found: .C, 81.27
H, 10.30.
- 53 -
Hydrogenation of Diene Alcohol 149
The hydrogenation of diene alcohol 149 (10.0 g, 52 mmoles) was
carried out i n benzene (200 ml) at room temperature and atmospheric pressure using tris(triphenylphosphine)chlororhodium (2.0 g) as catalyst.
One equivalent of hydrogen was consumed af t e r 11 h. The reaction
mixture was f i l t e r e d through a column of Camag Kieselgel a c t i v i t y I I I
neutral alumina (360 g) and eluted with 1 £ of ether. Removal of the
solvent and d i s t i l l a t i o n under reduced pressure afforded 9.5 g (95%)
of the o l e f i n i c alcohol as a colorless o i l , b.p. 94-96° at 0.5 mm. An
a n a l y t i c a l sample obtained by preparative g'.l.c. (column B, 200°, 100)
exhibited infrared"(film) v 3370, 1040, 1005 cm"1; p.m.r., x 9.08 max
(singlet, 3H, t e r t i a r y methyl), 8.95 (singlet, 3H, t e r t i a r y methyl),
6.45 ( t r i p l e t , 2H, -Ch\,GH, J = 7.0 Hz), 6.05-G.28 (broad s i n g l e t , III,
exchangeable, -OH).
Mol. Wt. Calcd. for C1 3
H 2 2 0 : 194.1670. Found (high resolution
mass spectrometry):' 194.1614.
Preparation of O l e f i n i c Acetal 151
To an ice bath cooled s t i r r e d s l u r r y of 8.27 g (72 mmoles) of
powdered potassium t-butoxide i n 200 ml of a7.hydrous ether was added
a solution of 7.4 g (38 mmoles) of o l e f i n i c alcohol 150 i n 50 ml of
anhydrous ether. After s t i r r i n g i n the cold for 15 min, a solution
of 6.45 g (80 mmoles) of chloromethyl methyl ether i n 30 ml of anhydrous
ether was added. The ice water bath was removed and the reaction
mixture was s t i r r e d under nitrogen for a further 15 min. Water was
then added and this mixture was thoroughly extracted with ether. The
- 54 -
combined ethereal extracts were washed with saturated brine and dried
over anhydrous magnesium s u l f a t e . The ether was removed in_ vacuo and
the residue d i s t i l l e d to yield"8.3 g (92%) of the o l e f i n i c acetal 151
as a c o l o r l e s s o i l , b.p. 92-94° at 0.4 mm. An a n a l y t i c a l sample, 20
obtained by preparative g . l . c . (column D, 130°, 100) exhibited n^
1.4820; i n f r a r e d (film) v 3060, 1140, 1100, 1025 cm"1; p.m.r., J max ' ' '
x 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.95 ( s i n g l e t , 3H, t e r t i a r y
methyl), 6.73 ( s i n g l e t , 3H, -Ci^OCH.,), 6.29-6.66 (multiplet, 2H,
-CH 2OCH 2OCH 3), 5.48 ( s i n g l e t , 2H, -Oq^OCIij). Anal. Calcd. f o r C , r H . , 0 _ : C, 75.58; H, 10.99. Found: C, 75.62;
l b 26 2 H, 10.91.
Preparation of Epoxy Acetals 152 and 153
To a cooled (0°) s t i r r e d s o l u t i o n of 500 mg (2„10 mmoles) o l e f i n i c
a c e t a l 151 i n 5 ml of methylene c h l o r i d e was added a s o l u t i o n of 905 mg
(5.25 mmoles) m~chloroperbenzoic acid i n 10 ml of methylene c h l o r i d e .
This mixture was s t i r r e d under dry nitrogen at 0° for 0.5 h and then at
room temperature f o r 2.5 h. The s o l u t i o n was poured onto 10 ml of 20%
sodium hydroxide s o l u t i o n and the layers were separated. The organic
extract was washed with a 10% sodium s u l f i t e s o l u t i o n , saturated brine
and d r i e d over anhydrous magnesium s u l f a t e . D i s t i l l a t i o n of the
concentrated o i l afforded a q u a n t i t a t i v e y i e l d of the desired
compounds as a c o l o r l e s s o i l b.p. (hot box) 130-135° at 0.4 mm. Gas-
l i q u i d chromatographic analysis (column E, 125°, 100) showed the
product to be an 80:20 mixture of epimeric epoxy acetals 152 and 153
respectively*, An a n a l y t i c a l sample of t h i s mixture, obtained by
- 55 -
preparative g. I.e. (column G, 160°, 200), exhibited infrared (film)
v 2990, 1140, 1100, 1030, 740 cm"1; p.m.r., T 9.02, 9.07 (singlet, J H c l X
s i n g l e t , 6H, t e r t i a r y methyls), 6.70 (singlet, 3H, -CH2OCH_3), 6.17-6.59
(multiplet, 2H, -CH^OCH^Ciy, 5.47 (singlets, 2H, -OCH_2OCH3).
Mol. Wt. calcd. for C H 0^: 2 3 8 • 1 9 3 2 • Found (high resolution
mass spectrometry): 238.1937.
Preparation of 2,2-Dimet.hyl-4-pentenenitrile 166
To an ice water bath cooled, s t i r r e d solution of diisopropylamine
(45.5 g, 0.45 moles) i n 75 ml of dry benzene was added 150 ml (0.375
moles) n-butyllithium i n hexane. After s t i r r i n g i n an inert atmosphere
for 5 min, a solution of 20.7 g (0.30 moles) of i s o b u t y r o n i t r i l e 165
in 45 ml of dry benzene was added dropwise. The cooling bath was
removed and t h i s mixture was s t i r r e d at room temperature f o r 5 min.
The reaction was again cooled to 0° and a solution of a l l y l bromide
(72.6 g, 0.6 mole) i n 75 ml dry benzene was added. The r e s u l t i n g
mixture was refluxed for 1.5 h and then cooled to room temperature.
Water was added and the layers were separated. The aqueous layer was
thoroughly extracted with ether. The organic extracts were combined,
washed with water, saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was removed under reduced pressure and the
residue d i s t i l l e d to give 27.0 g (83%) of the desired product b.p.
147-148°; n£ 1.4191 [ l i t . b.p/ 147-148.5°, n D 1.4180]; infrared
(film) V 3090, 2245, 1640, 920 cm"1; p.m.r., T 8.67 (singlet, 6H, IT13.X
t e r t i a r y methyls), 7.72 (doublet, 2H, methylene protons, J = 7 Hz),
4.63-5.06 (multiplet, 2H, C 5 pi'otons), 3.75-4.45 (multiplet, 1H, C 4
proton)„
- 56 -
Preparation of 3-Cyano-3,3-dimethyl propanal 1.67
A solution of 5 g (46 mmoles) of o l e f i n i c n i t r i l e 166 i n 80 ml of
a 1% pyridine-dichloromethane solution was treated with ozone at -78°
u n t i l the solution turned blue. The excess ozone was removed by bubbling
dry nitrogen through the solution. This mixture was poured onto 24 g
(370 mmoles) of zinc dust. Acetic acid (46 ml, 810 mmoles) was
immediately added and the r e s u l t i n g s l u r r y was slowly warmed to room
temperature. After the solution had been s t i r r e d for 1 h, i t was
f i l t e r e d , d i l u t e d with brine and extracted with methylene chloride.
The organic phase was washed with water, saturated sodium bicarbonate
solution, saturated brine, and dried over anhydrous magnesium s u l f a t e .
The solvent was removed to afford 3.5 g (70%) of the crude aldehyde
n i t r i l e .167- Due to t h e i n s t a b i l i t y of t h i s compound, i t was used
immediately i n the next reaction without further p u r i f i c a t i o n . A small
sample of the aldehyde n i t r i l e 167 was d i s t i l l e d and exhibited b.p. 90-
91° at 19 mm; infrared (film) v 2750,. 2250, 1720 cm"1; p.m.r., max
x 8.50 (singlet, 6H, t e r t i a r y methyls), 7.26 (multiplet, 2H, methylene
protons), 0.10 (multiplet, IH, -CHO).
This compound was characterized as i t s 2,4-dinitrophenylhydrazone
derivative, r e c r y s t a l l i z e d from ethanol, m.p. 153-154°.
Anal. Calcd. for C 2-H N 0 : C, 49.48; H, 4.50; N, 24.04.
Found: C, 49.66; H, 4.47; N, 23.85.
- 57 -
Preparation of Cycloperityltripheriylphdsphdriium Iodide
To a solution of 13.6 g (70 mmoles) of cyclopentyl iodide i n 50 ml
of xylene was added 39.3 g (150 mmole) of triphenylphosphine. This
mixture was refluxed f o r 17 h and then cooled to room temperature.
The precipitated s a l t was f i l t e r e d , washed with benzene, and dried
under vacuum overnight to afford 28.6 g (90%) of the desired compound
as a pale yellow c r y s t a l . It exhibited m.p„ 238-240°; infrared (CHCl^)
V 1590, 1440, 1110 cm"1, max Anal. Calcd. for C H 2 4IP: C, 60.28; H, 5.28; I, 27.68. Found:
C, 60.46; H, 5.55; I, 27.32.
Preparation of O l e f i n i c N i t r i l e 168
To a cooled (0°), s t i r r e d s lurry of 45.8 g (100 mmoles) of
cyclopentyltriphenylphosphonium iodide i n 250 ml of dry dimethoxy-
ethane was added 48.2 ml (92 mmoles) of a 1.9 M solution of n-butyl-
lithium i n hexane. The r e s u l t i n g blood red solution was s t i r r e d ,
under dry nitrognen, at room temperature for 15 min. A solution of
3.0 g (27 mmole) of crude aldehyde n i t r i l e 167 i n 20 ml of dimethoxy-
ethane was added.— After s t i r r i n g for 30 min, the mixture was poured
into 300 ml of water and thoroughly extracted with petroleum ether
(b.p. 30-60°). The organic extracts were combined, washed with
saturated brine, and dried over anhydrous magnesium s u l f a t e . Removal
of the solvent and d i s t i l l a t i o n of the residue gave 3.8 g (87%) of
the desired compound. An a n a l y t i c a l sample, obtained by preparative 2] ^
g.l.c. (column H, 135°, 100) exhibited b.p. 52-54° at 0.35 mm; n
1.4699; infrared (film) v 2255, 1680 cm ; p.m.r., T 8.65 (singlet,
- 58 -
6H, t e r t i a r y methyls), 4.37-4.90 (multiplet, 1H, v i n y l proton).
Anal. Calcd. for C H^N: C, 80.93; H, 10.50. Found: C, 80.95;
H, 10.72.
Preparation of Ketone 170
A s t i r r e d solution of 5.0 g (30.5 mmoles) of the o l e f i n i c n i t r i l e
and 75 g of polyphosphoric acid was heated, i n an inert atmosphere, at
125-130° for 30 min. This mixture was poured onto i c e , ba s i f i e d with a
20% sodium hydroxide solution, and extracted with chloroform.. The
organic extract was washed with saturated brine and concentrated to
y i e l d the crude imine 169 which exhibited infrared (film) v 1650, J J max ' 1600 cm ^. The imine 169 was immediately added to a solution of 184 ml
of ^0% sodium hydroxide solution and 180 ml of methanol and refluxed.
under a nitrogen atmosphere, for 2.5 h. The reaction mixture was
cooled and the methanol was removed at aspirator pressure. The residue
was dilu t e d with water and a c i d i f i e d with 6 N hydrochloric acid. This
mixture was thoroughly extracted with ether, the ether layer was
washed with saturated brine and dried over anhydrous magnesium su l f a t e .
Removal of the solvent, f i l t r a t i o n through a column of Camag Kieselgel
a c t i v i t y I I I neutral alumina (15 g), and elution with ether gave a
yellow o i l . D i s t i l l a t i o n of this material under aspirator pressure
gave 3.5 g (70%) of the ketone 170, b.p. 108-109° at 10 mm. An
a n a l y t i c a l sample was obtained by preparative g.l.c. (column A, 155°,
120), and i t exhibited n 1 9 , 51.5079; u l t r a v i o l e t X 248 my (e = 14,300) J D max ^ ' J
infrared (film) v 1660, 1640, 1390 cm"1; p.m.r., 8.90 (singlet, 611,
t e r t i a r y methyls).
- 59 -
Anal. Calcd. f o r C -.H.' 0: C, 80.44; H, 9.82. Found: C, 80.19; 1116
H, 9.60.
Preparation of Epoxy Ketone 171
To a s t i r r e d s o l u t i o n of 2.5 g (15.3 mmoles) of ketone 170 and 5 ml
(45.8 mmoles) of 30% hydrogen peroxide s o l u t i o n i n 50 ml of methanol
was added 15.3 ml (76.3 mmoles) of 20% sodium hydroxide s o l u t i o n .
The r e s u l t i n g mixture was s t i r r e d at room temperature f o r 2 h. Water
was then added and the mixture was thoroughly extracted with ether.
The organic layer was washed twice with saturated brine, d r i e d over
anhydrous magnesium s u l f a t e , and concentrated in_ vacuo. D i s t i l l a t i o n
of the residue under reduced pressure afforded 2.1 g (76%) of the epoxy
ketone 17i, b.p. 6i>-67° at 1.2 mm. An a n a l y t i c a l sample obtained by
preparative g . l . c . (column G, 130°, 200) exhibited i n f r a r e d (film)
v 1700 cm"1; p.m.r., x 9.07 ( s i n g l e t , 3H, t e r t i a r y methyl), 8.92 max ( s i n g l e t , 3H, t e r t i a r y methyl).
Mol. Wt. Calcd. f o r C ^ H ^ C y 180.1149. Found (high r e s o l u t i o n
mass spectrometry): 180.1140.
Preparation of Epoxy O l e f i n 173
To a cooled (0°), s t i r r e d s l u r r y of 19.1 g (53.5 mmoles) of
methyltriphenylphosphonium bromide i n 200 ml of anhydrous ether was
added 20.8 ml (50 mmoles) of a 2.4 M s o l u t i o n of n - b u t y l l i t h i u m i n
hexane. A f t e r the s o l u t i o n was s t i r r e d at room temperature, under an
atmosphere of dry nitrogen, f o r 10 min, a s o l u t i o n of epoxy ketone 171
(3.0 g, 16.7 mmoles) i n 20 ml of dry ether was added. This mixture
- 60 -
was refluxed for 4 h, cooled, poured into water, and thoroughly
extracted with ether. The ethereal extracts were combined, washed with
saturated brine, and d r i e d over anhydrous magnesium s u l f a t e . Removal
of the solvent and d i s t i l l a t i o n of the residue gave 2.6 g (88%) of the
epoxy o l e f i n 173. This sample was shown to be pure by g . l . c . analysis
(column E, 115°, 110). It exhibited b.p. 105-108° (hot box) at 10 mm;
i n f r a r e d (film) v _ 3120, 1635, 890 cm - 1; p.m.r., T 9.05 ( s i n g l e t , 3H,
t e r t i a r y methyl), 8.87 ( s i n g l e t , 3H, t e r t i a r y methyl), 4.73 ( s i n g l e t ,
2H, v i n y l protons).
Anal. Calcd. f o r C 1 0 H 1 0 0 : C, 80.85; H, -10.18. Found: C, 80.68; 12 l o
H, 10.33.
Preparation of Epoxy Alcohols 174 and 175
To a s o l u t i o n of 2.3 g (12.9 mmoles) of epoxy o l e f i n 173 i n 80
ml of dry tetrahydrofuran at 0° and under an atmosphere of dry nitrogen
was added 5.6 ml (7.4 mmoles) of 1.33 M borane i n tetrahydrofuran.
This s o l u t i o n was then s t i r r e d at room temperature for 1.5 h. The
r e a c t i o n mixture was again cooled to i c e temperature, and 16 ml of
20% sodium hydroxide s o l u t i o n was added slowly, followed by a d d i t i o n
of 26.6 ml of 30% hydrogen peroxide. The r e a c t i o n mixture was warmed
to room temperature and s t i r r e d f o r 1 h, then concentrated. The
r e s u l t i n g material was d i l u t e d with water then thoroughly extracted
with ether. The combined ether extracts were washed with a saturated
brine s o l u t i o n , and d r i e d over anhydrous magnesium s u l f a t e .
Removal of the solvent, followed by d i s t i l l a t i o n of the r e s i d u a l
material under reduced pressure (b.p. 105-107° at 0.4 mm) afforded
- 61 -
2.6 g (93%) of the desired epoxy alcohols 174 and 175 as a c o l o r l e s s
o i l . An a n a l y t i c a l sample of the major isomer was obtained by
preparative g . l . c . (column G, 165°, 200) and exhibited i n f r a r e d ( f i l m ) ,
v 3460, 1035 cm"1; p.m.r., x 9.30 ( s i n g l e t , 3H, t e r t i a r y methyl), nicix
9.00 ( s i n g l e t , 3H, t e r t i a r y methyl), 5.84-6.57 (multiplet, 2H,
-CH 20H).
Mol. Wt. Calcd. f o r C1 2
H 2 0 ° 2 : 1 9 6 - 1 4 6 3 - Found (high r e s o l u t i o n
mass spectrometry): 196.1459.
Preparation of Epoxy Acetates 176 and 177
To a s o l u t i o n of 2.1 g (10.7 mmoles) of epoxy alcohols 174 and
175 i n 14 ml dry p y r i d i n e was added 5.6 g (56 mmoles) of a c e t i c
anhydride. This s o l u t i o n v:as i r r p r i i- rp.nm i-p>m'nr'TT?i"iirf fcv* P. Ti ?rnd
then d i l u t e d with water. The ethereal extracts of t h i s mixture were
combined, washed with saturated brine, and dri e d over anhydrous
magnesium s u l f a t e . The solvent was removed under reduced pressure and
the residue was d i s t i l l e d at 99-101° at 0.5 mm to give 2.3 g (92%)
of the desired products. An a n a l y t i c a l sample of the major isomer
obtained by preparative g . l . c . (column G, 180°, 200) exhibited i n f r a r e d
(film) v 1740, 1230, 1030 cm"1; p.m.r., x 9.27 ( s i n g l e t , 3H, t e r t i a r y
methyl), 8.97 ( s i n g l e t , 3H, t e r t i a r y methyl), 7.97 ( s i n g l e t , 3H,
-0C0CH 3), 5.47-6.40 (multiplet, 2H, -CH_20Ac).
Anal. Calcd. f o r C H^o : C, 70.56; H, 9.30. Found: C, 70.43;
H, 9.50.
- 62 -
Preparation of O l e f i n i c Acetate 178
To a s t i r r e d solution of 12.0 g (30 mmoles) of tungsten hexachlorid
i n 40 ml of dry tetrahydrofuran, cooled to -78°, and under an
atmosphere of nitrogen was added 25 ml (60 mmoles) of 2.4 M i i-butyl-
lithium i n hexane. The solution was then warmed to room temperature
over a 20 min period. A solution of 1.9 g (8 mmoles) of epoxy acetates
176 and 177 i n 5 ml of dry tetrahydrofuran was then added. This green
solution was refluxed for 7 h, cooled to room temperature, and poured
into 350 ml of a solution that was 1.5 M i n sodium t a r t r a t e and 2 M
i n sodium hydroxide. This mixture was thoroughly extracted with ether
and the ethereal extracts were combined. This organic extract was
washed with saturated brine, dried over anhydrous magnesium sul f a t e ,
and then concentrated. The residue was d i s t i l J e d to afford 1.6 g (90%)
of the o l e f i n i c acetate 178 , b.p. 87-90° at 0.5 mm. An a n a l y t i c a l
sample, obtained by preparative g.l.c. (column F, 180°, 200) exhibited
infrared (film) v 1740, 1230, 1025 cm"1: p.m.r., T 9.07 and 9.03 v ; m a x
(singlets, 6H, t e r t i a r y methyls), 8.04 (singlet, 3H, ~0C0CH3), 5.66-
6.31 (multiplet, 2H, -CH_20Ac).
Mol. Wt. calcd. for C] 4
H2 2 ° 2 : 2 2 2.1619. Found (high resolution
mass spectrometry): 222.1583.
Preparation of the O l e f i n i c Alcohol 179
To a s t i r r e d solution of 1.2 g (5.4 mmole) of o l e f i n i c acetate
178 i n 10 ml of dry ether was added 100 mg (2.6 mmole) lithium
aluminum hydride. This mixture was refluxed, under an atmosphere of
dry nitrogen, for 1 h then cooled to room temperature. The excess
- 63 -
hydride was destroyed by the addition of powdered sodium sulfate
decahydrate and the reaction mixture was f i l t e r e d through c e l i t e .
The f i l t r a t e was concentrated and d i s t i l l e d at reduced pressure to
afford 900 mg (97%) of the o l e f i n alcohol 179, b.p. (hot-box) 82-
85° at 0.3 mm. An a n a l y t i c a l sample, obtained by preparative g.l.c.
(column G, 160°, 200) exhibited infrared (film) v 3410, 1025 cm"1
max p.m.r., x 9.14 and 9.08 (singlets, 6H, t e r t i a r y methyls), 6.40
(doublet, 2H, -CH^OH, J = 4 Hz).
Mol. Wt. calcd. for C H Q0:. 180.1514. Found (high resolution
mass spectrometry): 180.1511.
- 64 -
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