TABLE 1. Kinetic and DKR of Alcohols 8 and 9 with Novozyme
435
SCHEME 1. General Strategy for the Synthesis of Chiral
Nonracemic Pincer Ligands 4 and 5
(R)-acetate ee % (S)-alcohol ee %
entry substrate
E
conv. (%)
(yield %)a
(yield %)a
f
(()-8b >500
(()-9b >500
(()-8h
46c
44c
93i
92i
10 >99.9d (45)
8
9
79e (50)
-
1
2
3
4
11 >99d g (40)
10 >99.9 (70)
11 >99 (70)
86g (47)
,
(()-9h
a Product isolated after chromatographic purification. b Kinetic
resolution. Conditions: vinyl acetate, t-butyl methyl ether, rt.
c Calculated conversion. d After hydrolysis. e By chiral high resolution
gas chromatography (HRGC; ꢀ-cyclodextrine). f Lit.18 98%. g From the
1H NMR analysis of the corresponding Mosher’s ester. h DKR.
corresponding racemic mixtures9 and by the asymmetric reduc-
tion of prochiral ketones with isolated dehydrogenases10 or with
baker’s yeast (Saccharomyces cereVisiae).11 Herein, we describe
the application of these stereocomplementary biotransformations
to the synthesis of both enantiomers of 1-(6-phenylpyridin-2-
yl)ethanamine 4 (Scheme 1). (S)-4 was obtained via the lipase-
mediated kinetic resolution of the secondary alcohol (()-8, while
the baker’s yeast (Saccharomyces cereVisiae) reduction of the
ketone 6 gave access to the enantiomeric ligand (R)-4. This
approach was then extended to the synthesis of the novel chiral
1-(benzo[h]quinolin-2-yl)ethanamine CNN pincer ligands (R)-5
and (S)-5.
Conditions:
p-chlorophenylacetate,
toluene,
70
°C,
2%
Ru2(CO)4(µ-H)(C4Ph4-COHOCC4Ph4). i By HRGC.
tiospecificity was unsatisfactory, and harsh conditions were
required for the recovery of amines from the resolved aceta-
mides. Therefore, we decided to use CAL-B immobilized on
polyacrylamide (Novozyme) for the kinetic resolution of the
racemic alcohols 8 and 9 (Scheme 1).The alcohols were obtained
by the NaBH4 reduction of the corresponding ketones 6 and 7.
2-Acetyl-6-phenylpyridine 6 was obtained by the Suzuki
coupling of phenylboronic acid and 2-acetyl-6-bromopyridine,17
while the 2-acetylbenzo[h]quinoline 7 was synthesized from
2-chlorobenzo[h]quinoline as reported.1d
Candida antarctica lipase B (CAL-B) shows a very high and
general specificity for the (R)-enantiomer in the acylation of
chiral secondary alcohols12 which has been fully explained at
the molecular level.13 The enantiospecific acylation of chiral
amines by CAL-B has also been reported;14 however, while the
dynamic kinetic resolution (DKR)15 of racemic sec-alcohols is
well established, few protocols have been reported for the DKR
of amines.16 When we applied these conditions to the resolution
of 6-substituted 2-(1-aminoethyl)pyridines, the resulting enan-
The lipase-catalyzed asymmetric acetylation of 8, with
Novozyme and vinyl acetate in t-butylmethylether gave the
corresponding (R)-acetate 10 with excellent enantioselectivity
(enantiomeric ratio E > 500) and with recovery of the unreacted
alcohol (S)-8 (Table 1, entry 1), in agreement with literature
data.18 Similarly, the tricyclic alcohol 9 gave the corresponding
(R)-acetate 11 in 40% yield (44% conversion) and ee > 99%
(E > 500; Table 1, entry 2), while the recovered alcohol (S)-9
had 86% ee.
Although the optical purity of the resolved acetates (R)-10
and (R)-11 was excellent (Table 1), their yield is intrinsically
limited by the 50% maximum attainable in a kinetic resolution
and by the need for a chromatographic separation of the
enantioresolved alcohol and ester products. Both limitations were
overcome by applying to the lipase-catalyzed transesterification
of (()-8 and (()-9 the conditions developed by Ba¨ckvall et al.
for the dinamic kinetic resolution of sec-alcohols.19 When the
acetylation, with p-chlorophenylacetate as the acyl donor, was
coupled to the in situ racemization of the slow reacting
enantiomer with the Ru based redox catalyst [Ru2(CO)4(µ-
H)(C4Ph4-COHOCC4Ph4)] (Shvo’s catalyst), the reaction reached
complete conversion, enantioconverging to the (R)-acetates as
unique products. These were isolated in 70% yield (not
optimized) after column chromatography (Table 1, entries 3,
4).
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3548 J. Org. Chem. Vol. 74, No. 9, 2009