Kinetic resolution of amino alcohol derivatives with a chiral nucleophilic catalyst: Access to enantiopure cyclic cis-amino alcohols

Article abstract of DOI:10.1039/b108753c

Acylative kinetic resolution of racemic cyclic cis-amino alcohol derivatives with a chiral nucleophilic catalyst proceeds enantioselectively (s = 10-21) at ambient temperature to give enantiopure recovered materials, and the % conversion of the acylation can be readily controlled by the amount of acid anhydride.

Full text of DOI:10.1039/b108753c

Kinetic resolution of amino alcohol derivatives with a chiral
nucleophilic catalyst: access to enantiopure cyclic cis-amino alcohols†
Takeo Kawabata,* Kensaku Yamamoto, Yashima Momose, Hiroshi Yoshida, Yoshie Nagaoka and
Kaoru Fuji
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
E-mail: kawabata@scl.kyoto-u.ac.jp
Received (in Cambridge, UK) 27th September 2001, Accepted 1st November 2001
First published as an Advance Article on the web 27th November 2001
Acylative kinetic resolution of racemic cyclic cis-amino
alcohol derivatives with a chiral nucleophilic catalyst
proceeds enantioselectively (s = 10–21) at ambient tem-
perature to give enantiopure recovered materials, and the %
conversion of the acylation can be readily controlled by the
amount of acid anhydride.
b-Amino alcohol functionality is found in many biologically
tective groups such as Boc and Cbz was resolved with moderate
active compounds and is therefore considered an important
pharmacophore.1 The asymmetric synthesis of b-amino alco-
hols has been extensively studied.2 Kinetic resolution3 is
another method of choice, and the enzymatic4,5 and non-
enzymatic6,7 kinetic resolution of racemic amino alcohol
derivatives has been reported. Since the theoretical maximum
yield is only 50%, kinetic resolution is worthwhile when it is
possible to prepare compounds with extremely high enantio-
meric purity, which would otherwise be unattainable by
asymmetric synthesis. To obtain enantiopure compounds by the
kinetic resolution of racemates, high selectivity factor3 (s) as
well as control of the % conversion of the reaction are
indispensable. We report here the preparation of nearly
enantiopure (!99% ee) cyclic cis-amino alcohol derivatives via
acylative kinetic resolution with a chiral nucleophilic catalyst.
Practically useful levels of enantioselectivity (s = 10–21) were
observed in reactions at ambient temperature and the %
conversion was readily controlled by the amount of the
acylating agent.
Kinetic resolution via enantioselective acylation of racemic
alcohols by artificial organic molecules has been a focus of
current synthetic attention.6,8,9 We have shown that chiral
nucleophilic catalyst 1 could effectively catalyze the acylative
kinetic resolution of racemic diol derivatives.10 Since acylation
of an amino group of amino alcohols readily takes place in the
absence of catalyst,11 the amino group was protected and the
effect of the protective group on kinetic resolution was
examined (Table 1). Racemic-2 with typical carbamate-pro-
enantioselectivity (s = 4.0–4.5) via acylation with 1 (entries 1
and 2). However, 2 with amide-protective groups showed better
selectivity (s = 8.7– > 13, entries 3–5). Enantiomers of a
substrate with a p-(dimethylamino)benzoyl group were again10
found to be most effectively differentiated by 1 (s = > 13, entry
5). The effects of the acylating agents on the efficiency of
kinetic resolution were re-investigated with the racemic-2
(PNCOC6H4-p-NMe2) under the conditions similar to those in
Table 1. The selected results are as follows: Ac2O (s = 12), (i-
PrCO)2O (s = 17), (t-BuCO)2O (s = 6.2), Bz2O (s = 6.5), i-
PrCO-OC6F5 (s
= 17), (2-MeO-C6H4CO)2O (s = 14),
(2,4,6-F3-C6H2CO)2O (s = 19). Among commercial acid
anhydrides, isobutyric anhydride gave the highest selectivity, as
previously observed.10 Although the use of the corresponding
pentafluorophenyl ester gave selectivity comparable to that with
isobutyric anhydride, it was much less effective in kinetic
resolution due to its low reactivity (25% conversion after 2
days). 2,4,6-Trifluorobenzoic anhydride gave the highest se-
lectivity, however, we decided to use isobutyric anhydride for
further investigation due to its ready availability.
The results of the kinetic resolution of several cyclic amino
alcohol derivatives 2a–6 are shown in Table 2. Treatment of
racemic-2a with 60 mol% of isobutyric anhydride in the
presence of 5 mol% of 1 at 20 °C led to the recovery of (1R, 2S)-
2a in 93% ee at 58% conversion (entry 1). Enantiopure 2a was
obtained with a minimum loss of chemical yield by increasing
the amount of acid anhydride to 65 mol% (entry 2). Even with
0.5 mol% of the catalyst (catalyst–substrate = 0.9 mg+131 mg),
the acid anhydride was almost completely consumed within 24
h and enantiopure 2a was recovered (entry 4). Addition of a
stoichiometric amount of collidine does not affect the efficiency
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b1/b108753c/
Table 1 Effects of protective group P on the kinetic resolution of racemic-2 with 1
Ee of recovered 2
Conversiona (%) (%)
Entry
P
Solvent
Reaction time/h
Ee of 3 (%)
Sb
1
2
3
4
5
CO2t-Bu
CO2CH2Ph
COCH3
COPh
COC6H4-p-NMe2
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
24
5
20
20
20
69
68d
69
70
68
72c
76c
96
98
> 99c
33
—
43
42
47
4.0
4.5
8.7
9.4
> 13
a Conversion was determined by the following equation; conversion (%) = ee (recovered 2)/ee (recovered 2) + ee (3).b S = k (fast-reacting enantiomer)/k
(slow-reacting enantiomer), see ref. 3.c Absolute congfiguration is (1R, 2S).d Conversion was determined from the ratio of 3 to recovered 2.
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Chem. Commun., 2001, 2700–2701
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b108753c

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Table 2 Kinetic resolution of racemic amino alcohol derivatives 2a–6 with 1a
Ee of
recovered Ee of
Reaction
substratec acylated
Entry
Substrate
1/mol% (i-PrCO)2O/mol% time/h
Conversionb (%) (%)
product (%) S
68
1
2a
2a
2a
2a
2a
2a
3
5
5
5
0.5
5
0.5
5
5
5
5
60
65
70
70
70
70
70
60
70
70
70
75
9
44
9
24
9
24
9
24
24
3
58
63
68
66
67
60
69
59
68
64
69
73
93
> 99
> 99
> 99
> 99
89
17 (54)h
> 18
> 14
> 15
> 14
11
> 12
21
> 13
17
2d
3
59
48
52
48
59
44
67
46
56
46
37
4
5e
6e
7
> 99
97
> 99
99
8f
9f
10g
11
12
4
4
5
6
5
5
9
9
97
99
10
10
6
a A 0.17 M solution of substrate (0.5 mmol) in CHCl3 was treated with isobutyric anhydride at 20 °C in the presence of a catalytic amount of 1 and 100 mol%
of collidine, unless otherwise stated.b See footnote a in Table 1.c Absolute configuration of 2a, 3, 4, and 6 is (1R, 2S) in each case and that of 5 is (1S,
2R).d Run in 0.05 M solution of substrate.e Run in the absence of collidinef Run in 0.03 M solution of substrate.g Run in CH2Cl2.h S value of the kinetic
resolution at 240 °C with 0.01 M solution of substrate.
of the kinetic resolution with 5 mol% of 1 (entries 3 vs. 5), while
it does affect the efficiency with 0.5 mol% of 1 (entries 4 vs. 6).
Enantiopure amino alcohol derivatives 3–6 were also recovered
at 64–73% conversion by similar treatment of the racemates (s
= 10–21, entries, 7, 9, 10, and 12). In each case, an alcohol with
S configuration preferentially underwent acylation. The amide-
protective group of (1S, 2R)-5 was removed by treatment with
6 M HCl to give (1S, 2R)-1-aminoindan-2-ol (68% yield),
which is the key component of the orally active HIV protease
inhibitor indinavir.12,13 In these acylations with 1, the %
conversion could be simply controlled by the amount of acid
anhydride so that enantiopure compounds were readily obtained
without careful monitoring of the progress of the reaction. This
is in contrast to enzymatic acylative kinetic resolution where
excess acylating agent is used.5,14 Even in the case of non-
enzymatic acylative kinetic resolution, acylating agents are not
always consumed completely within a reasonable reaction
time.9
The protocol for kinetic resolution was applied to acyclic
amino alcohol derivatives. Acylation of an anti-amino alcohol
derivative, racemic-7, under the standard conditions (Table 2,
footnote a) gave recovered 7 with 93% ee at 70% conversion (s
= 7.1), while the corresponding syn-derivative 8 showed
negligible selectivity (s = 1.0). Kinetic resolution of 9 with a
primary hydroxy group progressed with a selectivity factor of
6.8. Another syn-amino alcohol derivative 10 (taxol side-chain)
was poorly resolved with 1 (28% ee at 71% conversion, s =
1.6). Thus, the relative configuration of the b-hydroxyamine
critically affects the enantioselectivity of the kinetic resolution
promoted by 1.
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (No. 706 : Dynamic Control of
Stereochemistry) from the Ministry of Education (Monbusho),
Japan.
Notes and references
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Angew. Chem,. Int. Ed. Engl., 1996, 35, 2813.
3 H. B. Kagan and J. C. Fiaud, Top. Stereochem., 1988, 18, 249.
4 For a recent example of enzymatic de-acylative kinetic resolution: G.
Sekar, R. M. Kamble and V. K. Singh, Tetrahedron: Asymmetry, 1999,
10, 3663.
5 For a recent example of enzymatic acylative kinetic resolution:A. Luna,
A. Maestro, C. Astorga and V. Gotor, Tetrahedron Asymmetry, 1999,
10, 1969.
6 For a example of non-enzymatic acylative kinetic resolution: E. R.
Jarvo, G. T. Copeland, N. Papaioannou, P. J. Bonitatebus, Jr. and S. J.
Miller, J. Am. Chem. Soc., 1999, 121, 11638.
7 For an oxidative kinetic resolution of b-hydroxyamines: S. Miyano, L.
D.-L. Lu, S. M. Viti and K. B. Sharpless, J. Org. Chem., 1985, 50,
4350.
8 For a leading reference of catalytic asymmetric acylation of alcohols: J.
Ichikawa, M. Asamin and T. Mukaiyama, Chem. Lett., 1984, 949.
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10 T. Kawabata, M. Nagato, K. Takasu and K. Fuji, J. Am. Chem. Soc.,
1997, 119, 3169.
11 A pioneering work for catalytic enantioselective acylation of amines
was reported recently: S. Arai, S. Bellemin-Laponnaz and G. C. Fu,
Angew. Chem., Int. Ed., 2001, 40, 234.
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Fidanze and C. H. Senanayake, Synthesis, 1998, 937.
In summary, acylative kinetic resolution of several cyclic cis-
amino alcohol derivatives with 1 proceeds enantioselectively at
ambient temperature to give enantiopure unreacted materials
under proper control of the % conversion of the acylation.
Complete consumption of acid anhydrides at low catalyst
loading indicates that 1 has high catalytic activity. Kinetic and
mechanistic investigations are now under way.
14 For a review: C.-H. Wong, Chemtracts: Org. Chem., 1990, 3, 91.
Chem. Commun., 2001, 2700–2701
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