Asymmetric Synthesis of a Key 1α,25-Dihydroxy-Vitamin D3 Ring A Synthon

Article abstract of DOI:10.1016/0040-4039(93)88021-A

An efficient and highly stereoselective synthesis of the A-ring synthon 4 of 1,25(OH)2-vitamin D3 (1) is deascribed.The aldehyde 12, which was used for an intramolecular ene reaction to form the main framework 18, was obtained by two different asymmetric

Full text of DOI:10.1016/0040-4039(93)88021-A

Vol. 33, No.
Britain
pp.
in
Asymmetric Synthesis of a Key
D3 Ring A
Synthon
Marek M.
Meinolf Lange, Peter M. Wovkulich and Milan R.
Roche Research Center, Hoffmann-La Roche Inc., Nutley. New Jersey 07110, USA
Summary: An efficient and highly
vitamin (1) is described The aldehyde 12, which was used for an intramolecular
main framework 18, was obtained by two different asymmetric approaches starting from oleftn 6.
synthesis of the A-ring synthon 4 of
reaction to form the
The ever growing volume of data regarding the biological activity of vitamin
and its metabolites continues
to stimulate vigorous research on the impact of these substances on basic cellular processes.* An essential
component of such programs is access to the
metabolites and especially their unnatural variants. In
with our development of a ring A + CD approach to the vitamin D system, as exemplified in the
formation of
derivative 3 (Scheme
(1) by coupling the ring A unit 2 with the Windaus-Grundmann ketone
we have investigated alternate syntheses of the ring A synthon 4. In this letter we
present a new synthesis of 4 which utilizes a highly stereoselective intramolecular
configuration for both the hydroxyl at Cl and for the Z double bond Two catalytic asymmetric routes to
this reaction substrate (12) described.
to set the proper
1
2 X =
18
12
4 X=OH
Scheme 1
The fiit approach engaged the catalytic system introduced by Mikami et.
reaction of methyl glyoxylate with olefins. Treatment of 6, readily accessible from pyranone
with methyl glyoxylate in the presence of 10 mol% of the Lewis acid obtained from
for the asymmetric

7703
81%
2)
94%
82%
1 3 R =
1 4 R =
88%
I
16
17
Scheme 3
12
For the next stage of the synthesis,
carbon bond formation. Exposure of akiehyde 12 to methoxymethylaluminum
-10 to “C) gave a mixture of the isomeric alcohols in high
reaction proceeded with extremely high stereoselectivity with respect to the newly formed
reaction chemistry was enlisted once again to effect the
(4
4). This
center at the ring fusion since alcohols 18 and 19 are epirneric at the hydroxyl center only and no other
Separation of the epimers was accomplished at the stage of the respective silyl
ethers 20 and 21. Having served its purpose of providing a rigid framework around which controlled bond
formation could take place, the pyran ring could now be cleaved. Allylic oxidation of 20 with
and
gave 22 (mp 112-116 which was smoothly reduced to diol 23 using
Differentiation of the two primary hydroxyl groups was accomplished by monosilylation
in DMF to give alcohol 24. Elimination of the primary hydroxyl was carried out by
with
tosylation, tosylate displacement with iodide
followed by elimination with DBU in DMF (80
to
give
25 in good overall yield. The final step entailed the selective removal of the
ether in the
presence of the secondary
ethers and was brought about with 10% KOH in methanol 6 h),
yielding allylic alcohol 4 in full accord, spectroscopically and analytically, with the previously prepared
material. The transformation of 4 to 2 has previously.2

7704
87%
2)
83%
18
19
20
OH,
H
=
H
21 = H,
R’ =
X
O H
2)
DMF
_
imidaxole. DMF
71%
81% 3 steps
4) KOH. 79%
24
Scheme 4
23
25 X =
4 X=OH
2 X =
References and Notes:
On leave from
Institute of
Chemistry, Poiiih Academy of Sciences, Warsaw, Poland.
Workshop Vitam. D. 8th (Vitamin. D:
New York, 1991.
For
and
in this area see:
Structure-Function
Application), W. de
J. A;
B.
M. R.. Am.
J. F.;
2945;
1986.51, 3098;
J. A.;
B. M.: Batcho, A. D.;
M.
Org.
P. M.;
M.; Nakai,
I. 1940.
M. R., Tetrahedron
K.;
1989.
Am.
1990.112, 3949.
K.;
M.;
Am.
containing
described in reference 3.
Olefii 6
at a much
rate than the non-he
acid esters of 7 produced asymmetrically and in
were prepared under
J. M.; Ko. S. Y.;
standard conditions. Dale, J. A.;
H. S.; Am.
1973.95.512.
T.;
H.;
K. B.; Am.
K. B., Am.
Gao, Y.: Hanson. R. M.;
and references therein.
was asses& by GC of the
V. S.;
R-MTPA ester of 15.
P.
S.;
K. B.;
S. M., Org.
1378;
J. M.; Kishi,
and has been
Y.,
w a s
fm m
chloride (1
and methanol
cf.
in
(0
utiiixed
a
reaction leading to a total
Org. 0000.
reactions of type, we
A. R.; Wovkulich, P. M.;
Uskokovic.
For
have not observed alcohols
N. K.: Batcho, A. D.;
at only the hydroxyl center,
J. C.; Uskokovic. M. R., Am.
see for example, Wovkulich. P. M.: Tang, P. C.:
1989,111.
Tetrahedron
could conceivably arise from
Salomond, W. G.; M. A.; Havens, J. L.: Org.
J. C.; Wovkulich, P. M.; Tang, P. C.: Batcho. A. D.: Uskokovic. M. R..
see
Snider, B. B.;
processes cf. Snider, B. B.; Goldman, B. E.,
1978.43. 2057.
E. A., Org.
1983.48, 1822. Alcohol 19
The bicyclic iactone related to 22 but epimeric at the ring fusion center has been reported previously, cf. Kobayashi, S.;
Shibata, J.;
were, however,
M.;
M., Tetrahedron
1990.31. 1577. Attempts to apply similar transformations to 22
(Received in USA 27 August 1992)