STUDIES IN ASYMMETRIC OLEFINATIONS - THE SYNTHESIS OF ENANTIOMERICALLY PURE ALLYLIDENE, ALKYLIDENE, AND BENZYLIDENE CYCLOHEXANES

Article abstract of DOI:10.1016/0040-4039(93)88008-7

Treatment of alkyl cyclohexanones with topologically unique bicyclic phosphonamides derived from the C₂ symmetrical (R,R)- and (S,S)-N,N'-dimethyl 1,2-trans-cyclohexane diamine leads to enantiomerically pure allylidene and benzylidene alkylcycl

Full text of DOI:10.1016/0040-4039(93)88008-7

Vol. 33. No. SO, pp.
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+
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STUDIES IN ASYMMETR IC
E N A N T I O M E R I C A L L Y
THE SYNTHES IS OF
C YC L O H E X A N E S
Stephen Hanessian* and Serge Beaudoin
Department of Chemistry, de Mont&I
P.O. Box 6128, Station A, P.Q. CANADA,
Abstract: Treatment of alkyl cyclohexanones with topologically unique bicyclic phosphonamides derived
the symmetrical leads to enantiomerically
pure allylidene and
alkylcyclohexanes.
The past decade has witnessed a burgeoning activity in the area of asymmetric organic
increasing number of known bond-forming processes have their “asymmetric” counterparts, usually with
impressive levels of enantiomeric or diastereomeric purities.
Today, an
In spite of such developments in the field, the
subject of a direct asymmetric olefmation of cycloalkanones has received little attention.2
In 1984. we reported our preliminary results on the design and reactivity3 of anions derived from
topologically unique
stereoselectivity in the ethylidenation
reactions Ph, alkyl, CI,
substituted-a-alkylphosphonic acids. We now report further studies on the asymmetric
substituted cyclohexanones that lead to enantiomerically pure benzylidene, allylidene, and propylidene alkyl
bicyclic phosphonamides of the type shown in Figure 1.4 These showed high
of substituted cyclohexanones, and recently5 in alkylation
etc.) to produce enantiomerically pure (or highly enriched)
of alkyl
cyclohexanes. The potential for kinetic resolution in such
examples.
is also demonstrated with specific
Figure 1
0
Me,
Ph
SR
X=
alkyl
Ph, etc.
Me,
Ph, etc.
Me
Ben zyliden e alk yl cycloh exan es Reaction of 4-methylcyclohexanone 2 with the (R,R)-bicyclic
benzylphosphonamide quench, led to the corresponding
(4-methylcyclohexane) benzylidene in excellent yield and optimal enantioselectivity (Scheme 1). The facile
1
1
7655

7656
isolation of the intermediate
3 and its structure elucidation by single crystal X-ray
allowed a definitive assessment of the optical purity of the product after elimination.
It also led to some
important insights into the mechanism of the reaction with the following conclusions:
a. the disposition of the
phosphoryl appendage reflects a
orientation of the a-phenyl group is the one expected from an attack on the
“equatorial” attack on the
group as shown in 3. b. the
face of the anion by the
as originally predicted from the model (Figure 1). c. the enantiomeric purity of the olefin obtained
in one step is essentially identical to that resulting
a two-step sequence (via the
thus demonstrating the extremely high
in the
reaction.
Scheme 1
0
1.
-78°C
81%
l
,
2.
Me
2
Me
4
-37.9”
3. mp.
[a], -61.3”
Table 1 lists several examples of asymmetric benzylidenations of various alkyl cyclohexanones with the
a-benzylphosphonamide reagents
and
Table 1
Ketone
Yield*
91%
Ratio
Reagent
Product
Ph
0
1
-33.3” (c 1.12)
4
Ph
0
I
2
82%
06%
89%
-72.0” (c 1.08)
-86.0” (c 1
(c 1.39)
“Me
0
0
3
Me
Me
Ph
I
(c 0.98)
75%
66%
( W - 1
6
“Me
6
Me
a Isolated yields. b. Ratios evaluated by capillary
The inherent preference for the formation of the
respectively is evident, as predicted by the
c. Optical rotations measured at
and
alkyl cyclohexanes from
the
(entries l-5). A deviation can be

7657
seen in entry 6, where the proportion of the Z-olefinic product expected from the
diminished due to an unfavorable hetween the phenyl and groups.
Kinetic Resolution Based on the proposed model in Figure 1 and the result in entry 6, it was of interest to
is greatly
attempt asymmetric benzylidenations with
maximized in the transition state, thus allowing a kinetic resolution. Treatment of
alkyl cyclohexanones, where
could be
5
mmole) with the anion of
benzylidene 6. and the Z-isomer
(&X)-derivative was obtained in 67% yield,
mmole,
cap. GC, 63% based on the reagent) (Scheme 2). The enantiomeric
from the An identical reaction with
THF, 1
-78°C) gave
8 and the (R&)-reagent (0.5 mmole) gave the
dimethylcyclohexane) benzylidene via the corresponding Phydroxyphosphonamide 9 in 60% overall yield and
enantiomeric purity. Benxylidenation of
efficient, resulting in the formation of the
with the
reagent was less
cap.
and
GC, 53%).
Scheme 2
0
Ph
-78°C
67%
2.
-86.4’
6
7
Ph
0
M e
2.
8%
Me
[a],
m.p.
10
9
Allylidene and Propylidene Alkyl Cyclohexanes Elegant studies by Walborsky and coworkers9 have
led to the synthesis of isomers of enantiomerically pure (and enriched) allylidene alkyl cyclohexanes via the
intermediacy of alkylidene carboxylic acids which were resolved and further manipulated. We now show that
the treatment of alkyl cyclohexanones with the
and
allylphosphonamide reagents
Scheme 3
-141.6’
-155.9”

11 give, respectively, the corresponding enantiomerically pure allylidene alkyl cyclohexanes in one step.11
Scheme 3 lists a number of relevant examples where this trend is consistently observed, even in the case of a
substituted cyclohexanone (compare Table 1, entry 6).
A
and stereochemical correlation with allylic alcohols obtained
the resulting 4-methyl and cyclohexanone via selective hydroxylation of
followed by oxidative cleavage with periodate and reduction to
It is of interest that with one exception, all the shown in Scheme 3
the
was possible
the
double
allylic alcohol.
attack at the a-position
of the allylic
diene (55%.
to account for the major product. In the case of bulky ketones such as dihydrocarvone, the
was accompanied by another product resulting
attack of the
on the carbonyl
Asymmetric propylidenation of
corresponding to THF,
by NMR to have a de of
-10.0’ 1.03,
was best achieved using the
The crude
Recrystallization from hexane afforded a single isomer, mp.
reagent
was shown
1
then
at
Acknowledgments.
We wish to thank NSERCC, Merck
References
and FCAR for financial assistance and for fellowships to S.B.
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4
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12. Unless otherwise mentioned, optical rotations were measured at a concentration of 1.0. All products showed
the
analytical and spectroscopic characteristics.
(Received in USA 28 July 1992; accepted 2 September 1992)