1992
R. Bhuniya, S. Nanda / Tetrahedron Letters 53 (2012) 1990–1992
attempted at the beginning, to our dismay the enantioselectivity in
the product alcohol was found to be very poor (only 20%).8 In gen-
eral none of the chiral boranes developed to date are efficient for
the enantioselective hydroboration of 1,1-disubstituted olefins
such as compound 13–15. At this point we have decided to change
our strategy and we thought to opt for the enzymatic kinetic reso-
lution (EKR) strategy, which will allow the synthesis of both the
enantiomers of venlafaxine in a straightforward way. Hydrobora-
tion of olefinic compound 13 with BH3ꢁSMe2 afforded the corre-
sponding racemic hydroxymethylated compound 16 in an 84%
yield. Compound 16 was subjected to lipase catalyzed EKR (transe-
sterification with active ester) with vinyl acetate. Lipase PS-D
(Burkholderia cepacia, lipase immobilized on diatomaceous earth)
was found to be the best lipase in terms of enantioselectivity.9 Sub-
sequently the fast reacting enantiomer of compound 16 was con-
verted to its (R)-acetate 19 (ee = 94%; yield = 48%) and the slow
reacting enantiomer (ee = 95%; yield = 46%; S) was recovered after
chromatographic separation. The absolute configuration was pre-
dicted by Kazlauskas empirical rule.10
authors (RB) is thankful to CSIR (New Delhi, India) for senior re-
search fellowship.
Supplementary data
Supplementary data (1H and 13C NMR spectra for all new com-
pounds) associated with this article can be found, in the online ver-
References and notes
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of (S)-22 with dimethyl amine (Me2NH, 40% aq solution)11 in a
closed vessel for 48 h at 80 °C followed by the removal of EOM
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anone. Overall yield of venlafaxine analogue 2 is 10.2% from
cyclopentanone and 3 is 12.8% from 4-methyl cyclohexanone).
The optical rotation value of our synthesized venlafaxine matches
well with the literature value, and that establishes the absolute
configuration of our synthesized venlafaxine.12 Deacetylation with
K2CO3–MeOH and the similar reaction sequences as described
above afforded (R)-venlafaxine from the (R)-acetate 19. The venla-
faxine analogues have also been synthesized by following similar
reaction sequences from (S)-17/18 and (R)-20/21 (Scheme 2).
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antidepressant agent venlafaxine and two of its analogues has been
reported here. The main highlight of our synthetic strategy was (S)-
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lipase-PS catalyzed kinetic resolution for creation of the stereocen-
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Chem. 1990, 33, 2899–2905. Literature
½
a 2D5
ꢂ
for (S)-venlafaxine = +27.6
(c = 1.07, EtOH); for (R)-venlafaxine ½a D25
ꢂ
ꢀ27.1 (c = 1.04, EtOH)..
We are thankful to DBT (New Delhi, India; Grant No: BT/
PR13830/PID/06/568/2010) for financial support. One of the