Versatile synthesis of alicyclic and acyclic compounds with alternate and remote C-methyl substitution patterns via asymmetric sequential olefination and ene reactions

Article abstract of DOI:10.1016/0040-4039(93)88009-8

Treatment of enantiomerically pure alkyl cyclohexane ethylidene derivatives with 2,3-di-O-benzyl D- and L-glyceraldehyde and related aldehydes in the presence of Lewis acids leads to enantiomerically pure or enriched branched alkylcyclohexenes. These can

Full text of DOI:10.1016/0040-4039(93)88009-8

Vol. 33. No. 50. pp. 7659-7662.1992
Britain
$5.00 +
in
PATTERNS VIA
SEQUENTIAL OLEFINATION AND
Stephen
and Serge Beaudoin
of Chemistry, de
P.O. Box 6128, Station A, Montreal, P.Q. CANADA,
Abstract: Treatment of
pure alkyl cyclohexane
derivatives with
and L-glyceraldehyde and related aldehydes in the presence of Lewis acids leads to enantiomerically pure or
enriched branched alkylcyclohexenes.
substitution pattern.
can be oxidized to acyclic motifs with a predetermined C-methyl
An impressively large number of natural products contain a wide array of carbon and
appendages
in their structures as a result of unique biosynthetic pathways. The C-methyl substitution pattern is ubiquitous in
many natural
relying for example, on
and a number of elegant chemical methods are available for the synthesis of such motifs,
processes,* and on approaches.3 In this letter, we report on a
novel approach to this problem based on the construction of chiral alicyclic cyclohexenes through the application
of sequential asymmetric and ene reactions5 of methyl Oxidative cleavage leads to
and
their acyclic counterparts containing stereochemically defined C-methyl groups with
relationships as exemplified in Figure 1.
Figure 1
We have previously reported on the asymmetric ethylidenation of methyl cyclohexanones using
unique chiral bicyclic phosphonamides, which are easily available from enantiomeric symmetrical
and
Here we show that treatment of 4-methylcyclohexanone with the chiral
phosphonamide reagent (R,R)- 2 leads after careful quenching with water to a mixture of

hydroxy phosphonamides
isomer 3 (55%). was established by direct analogy of the X-ray crystal analysis of the
Remarkably with the derivative 2, the anion attacks the ketone from the
reversing the previously observed trend with related
X-ray structure of
butyl group, while the pro-R face is relatively open, compared to the
which were separated flash chromatography. The structure of the major
side, thus
(ex. N-Me, N-Et, N-Bn, etc.).4 An
reagent 2 shows that the normally favored pro-S face of the anion is indeed shielded by the
analog.6
Treatment of 3
acetic acid produced
1).
ethylidene 4, with the highest recorded
Scheme 1
t-Bu
-78°C
290%
84%
+
Me
X-RAY
-47.5”
X-RAY
2, m.p.
2.
96%
1
4,
3,
2.
0
9 %
5.
7, [a], -2.8”
6,
m.p.
H (X-RAY)
Me
1.
2.
5
8%
NH,, 94%
Me
Me
10,
H (X-RAY), m.p.
1.0) at
a. Optical rotations recorded in CHC13
Reaction of 4 with
in the presence of stannic chloride, led to a major
product
in 63% yield (Scheme whose structure and absolute configuration was deduced from a
Thus, in addition to localizing the double bond, two new stereogenic
ray crystal structure analysis of the trio1 6.
centers were also generated in the ene reaction. Of interest is the
major product, which can be exploited as such, or after oxidative
orientation of the C-methyl groups.
of the C-methyl groups in the
to produce acyclic motif 7 an
of the
ethylidene (-71% e.e.) with the same aldehyde,
upon debenzylation gave the crystalline trio1 10. In
substitution pattern results in the cleaved and acyclic motif by virtue of
produced the ene product 9 and an isomer
this case, a
the position of the double bonds, in the cyclic product. The observed stereochemistry of the major products
and 9 can be rationalized (and predicted) by considering a sterically more favored enantiofacial approach of the
tin-chelated
on the
and
4 and 8 respectively (Scheme 1).

Application of the same protocol to
11 gave the ene product 12 in
82% yield (Scheme 2). Once again the structure was unambiguously established by X-ray crystallography of the
corresponding
13. In this case the oxidative cleavage was done using a sequence of reactions to produce
and ultimately an eight-carbon, differentially substituted diol
synthetically useful trisubstituted cyclohexanes,
17 in which a
substitution pattern is obtained.
An ene reaction between
ethylidene 18 and
gave a major product, whose structure is proposed to be 19, based on the precedents shown
above (Scheme 3). By virtue of the position of the double bond, the C-methyl groups are disposed in an
orientation after oxidative cleavage to the acyclic derivative 20. Finally, the ubiquitous propionate and
deoxypropionate motifs harboring
appropriately paired
or
arrangements of C-methyl groups can be obtained from
and D-or L-glyceraldehyde derivatives as shown in
ethylidene,
Scheme 4. Here the products are accompanied by starting material, possibly due to a steric crowding of the
chelated intermediate as depicted in Scheme 4. Oxidative cleavage in each case led to acyclic chains containing
and
The formation of chelated
positioning the double bond in these ene reactions. Thus, reaction of 0-benzyl glycolaldehyde with 18 gave two
products in which the double bond had the same position. resulting from a preferential abstraction to the
groups as in 23 and
is an important prerequisite for ensuring stereoselectivity and for
ethylidene group. As expected, there was no face selectivity in view of the absence of a stereocontrolling
element. The importance of chirality next to the aldehyde was demonstrated by the successful and highly
stereoselective ene reactions with
or (S)-lactaldehyde with 18.
Scheme
2
OH
1.
2.
2.
3.
77%
3.
4.
4
“Me
-78°C. 86%
11
60% overall
14,
-21
12,
13,
Bn,
H (X-RAY),
m.p.
-21
1.
2.
94%
m-CPBA
HO
OR
3. LAH, 29%
0
17, [a],
15,
[a], -4.0”
16,
Scheme 3
Me
20,
18
19,

7662
Scheme 4
OH
0
0
O H
2. Me&
51%
48%
19%
22,
24,
-28.4”
21
25,
It is clear that this methodology is uniquely suited for the synthesis of polysubstituted cyclohexenes and
Acyclic
related carbocycles, as well as their reduced variants, which are not readily available by other methods.
counterparts with
and anti-arrangements of C-methyl groups are accessible by oxidative
Application to natural product synthesis and in the design of enzyme inhibitors are evident.
cleavage.
Acknowledgments.
We wish to thank NSERCC, Merck
References and Notes.
and FCAR for financial assistance and for fellowships to S.B.
polyketideJb.iDos.yntihnesisC, oseme prehensive Organic Chemistry,
E .
E d . ,
Press. Oxford.
v. 5. 927.
s e e
For-some
Angew Chem. Int. Ed.,
Evans, D.A.
4 2 0 ; H e a t h c o c k , C . H . i n A s y m m e t r i c S y n t h e s i
Press, New York, NY, 1984, v. 3, p. 111 and references cited therein.
See for example Hanessian, S.
A
m
.
1
9
8
4
,
5 7 5 4 ;
C h i m i c u
1419; Hanessian, S.; Beaudoin. S. preceding paper and references cited therein.
For recent reviews, see Mikam1i, K.;9Terad9a, M.2; Naris,awa, S.; Nakai. T.
D
.
E
d
.
,
K
l
u
w
e
A
c
a
d
e
m
i
c
,
D o r
1988, p. 147; Whitesell, J.K.
1 9 8 0 .
426;
F . ;
S . B .
1 9 7 2 3,605; Asperger, R.G.; Liu, C.F.
Chem.. 1965.4, 1492; Kashiwabara, K.; Hanaki. K.; Fujita, J Bull. Chem.
Japan, 1980,
for a
L e t t . ,
Walborsky, H.M.; Banks, R.B.; Banks, M.L.A.; Durais6amy6. M.7
;
rotation value of
the resolved acid.
2 . 0 2 ,
V
i
a
Y.; Yoshimura, J.; Kono, M.;
T. Bull. Chem.
Japan,
2957.
1980.45. 2910.
T . - P . ;
A n g e w .
C h e mE .n g l . ,
For a recent review, see Schultz, A.G.
Chem. Res.. 1990,
207.
Obtained by Swem oxidation of the alcohol (using 2
of
W.T.; Canning, L.F.;
J . D . ; L i o u , R . ; D a v i e s , M . M . ; D e w i
A.K.;
9 2 6 .
Duraisamy. M.; Walborsky, H.M. Am. Chem. 1983, 3252.
V . J . ; S h e p p a r dA , m .
C h e m .