Convenient route to both enantiomers of chiral 5-hydroxypyrrolidin-2-one and 5-hydroxy-1,5-dihydropyrrol-2-one: Reverse enantioselectivity in lipase-catalyzed kinetic resolution

Article abstract of DOI:10.1016/S0040-4039(00)01745-7

High enantioselectivity was achieved in the lipase-catalyzed kinetic resolution of 5-hydroxypyrrolidin-2-one and 5-hydroxy-1,5-dihydropyrrol-2-one derivatives. Lipase PS and Novozym 435 were the successful catalysts (E=>1000). The acetylation of the N-pro

Full text of DOI:10.1016/S0040-4039(00)01745-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9859–9863
Convenient route to both enantiomers of chiral
5-hydroxypyrrolidin-2-one and
5-hydroxy-1,5-dihydropyrrol-2-one: reverse enantioselectivity
in lipase-catalyzed kinetic resolution
Kunihiko Takabe,a,* Masahisa Suzuki,a Toshiki Nishi,a Masaomi Hiyoshi,a
Yasuaki Takamori,b Hidemi Yodaa and Nobuyuki Masea
aDepartment of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku,
Hamamatsu 432-8561, Japan
bIwata Chemical Co., Ltd., Nakaizumi, Iwata 438-0078, Japan
Received 28 August 2000; accepted 29 September 2000
Abstract
High enantioselectivity was achieved in the lipase-catalyzed kinetic resolution of 5-hydroxypyrrolidin-2-
one and 5-hydroxy-1,5-dihydropyrrol-2-one derivatives. Lipase PS and Novozym 435 were the successful
catalysts (E=>1000). The acetylation of the N-protected 5-hydroxy-1,5-dihydropyrrol-2-one derivative
gave the (R)-acetate with high enantioselectivity, while, without N-protection, the (S)-acetate was
obtained. © 2000 Elsevier Science Ltd. All rights reserved.
Chiral 5-hydroxypyrrolidin-2-one and 5-hydroxy-1,5-dihydropyrrol-2-one derivatives are valu-
able building blocks for the asymmetric synthesis of natural products.1 Enantioselective reduc-
tion of succinimide derivatives is an effective method to lead to chiral
3,4-disubstituted-5-hydroxypyrrolidin-2-one derivatives, in which bicyclic derivatives give rise to
moderate to high enantioselectivities, whereas monocyclic derivatives show moderate enantio-
selectivities (Fig. 1).2,3 Kinetic resolution of 5-hydroxypyrrolidin-2-one and 5-hydroxy-1,5-dihy-
O
O
O
Enantioselective
Reduction
R1
R2
R1
R2
R1
R2
Kinetic Resolution
N R3
N R3
OH
Figure 1. Enantioselective reaction to 5-hydroxylactam
N R3
OH
Previous report
O
* Corresponding author. Tel/fax: +81-53-478-1148; e-mail: tcktaka@ipc.shizuoka.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01745-7

9860
dropyrrol-2-one derivatives is a more practical method. Recently, we reported the first asymmet-
ric synthesis of (R)-(−)-5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one (jatropham), which is an
antitumor alkaloid, using kinetic resolution of the racemic jatropham.4 We report5 herein highly
enantioselective kinetic resolution of 5-hydroxypyrrolidin-2-one and 5-hydroxy-1,5-dihydro-
pyrrol-2-one derivatives catalyzed by lipase6 (Fig. 1).
Lipase PS (Amano, Pseudomonas cepacia) catalyzed transesterification of 5-acetoxy-1-benzyl-
pyrrolidin-2-one 1 to give the (R)-hydroxylactam 2 and the recovered (S)-acetate 1 in a good
enantiomeric ratio of E7=23.8 after 192 hours stirring (Scheme 1).
O
O
O
Lipase PS
+
Bn
Bn
Bn
N
N
N
EtOH, i-Pr2O
15 °C, 192 h
E value = 23.8
OAc
1
OH
(R)-2
OAc
(S)-1
y. 43%
y. 43%
85% ee
52% ee
Scheme 1. Lipase PS-catalyzed transesterification of 5-acetoxy-1-benzylpyrrolidin-2-one 1
The enantioselectivity was increased to E=41.9 in the acetylation8 of 1-benzyl-5-hydroxy-
pyrrolidin-2-one 2 with vinyl acetate in 1,4-dioxane solution after 48 hours (Table 1, entry 3).
Furthermore, we found that the recovered 5-hydroxylactam (S)-2 was stable without racemiza-
tion after 10 days, while the acetate (R)-1 was easily racemized after a few days at room
temperature.9
Table 1
Enantioselective acetylation of 1-benzyl-5-hydroxypyrrolidin-2-one 2
Lipase PS
OAc
O
O
O
+
Bn
Bn
Bn
N
N
N
15 °C
OH
2
OAc
(R)-1
OH
(S)-2
Entry
Solvent
Time (h)
Acetate 1
Alcohol 2
E value
Yield (%)
Eea (%)
Yield (%)
Eea (%)
1
2
3
–
72
120
48
40
26
49
51
83
88
40
51
47
99
48
99
4.2
14.3
41.9
i-Pr2O
1,4-Dioxane
a Determined by chiral HPLC using Chiralcel OD (flow rate: 0.5 mL/min, eluent: hexane/i-PrOH=80/20).
High enantioselectivity was observed in the monocyclic succinimide derivatives above. Next,
we examined the kinetic resolution of maleimide and citraconimide derivatives. Results are
shown in Table 2. The transesterification of the 5-acetoxylactam 3a proceeded to give the
(R)-alcohol 4 and the recovered (S)-acetate 3 in a high enantiomeric ratio of E=>501 (entry 1).
The 4-methyl-5-acetoxylactam 3b did not react with ethanol, whereas the 3-methyl-5-acetoxylac-
tam 3c gave the (R)-alcohol 2 with high enantioselectivity (entries 2 and 3).

9861
Although high enantioselectivity was obtained in the transesterification of 3, the reactivity was
relatively low. On the other hand, enhanced reactivity was observed in the acetylation of the
5-hydroxylactam 5a–c with vinyl acetate as shown in Table 3. The reaction of the 1-benzyl-5-
hydroxylactam 5a in the presence of lipase PS gave the (R)-acetate 6a and the recovered
(S)-alcohol 5a with extremely high enantioselectivity (E=>1057, entry 1). Novozym 435 (Novo
Nordisk, Candida antarctica) was also a practical catalyst for the kinetic resolution (E=>752,
entry 2). The 1-allyl-5-hydroxylactam 5b was effectively resolved under similar conditions
(entries 3 and 4). Interestingly, reverse enantioselectivity was observed in the reaction of the
5-hydroxylactam 5c (R=H, entries 5–6); thus, the enantioselectivity depends upon N-protection.
These resolved compounds are stable at room temperature, and racemization was not observed.
Table 2
Enantioselective transesterification of the 5-acetoxylactam 3
O
O
O
R1
R2
R1
R1
a: R1 = H, R2 = H
b: R1 = H, R2 = Me
c: R1 = Me, R2 = H
Lipase PS
+
Bn
Bn
N
Bn
N
N
EtOH, i-Pr2O
25 °C
R2
R2
OAc
3
OH
(R)-4
OAc
(S)-3
Entry
Substrate
Time (h)
Alcohol 4
Ee (%)a
Acetate 3
E value
Yield (%)
Yield (%)
Ee (%)a
1
2
3
3a
3b
3c
72
480
120
45
Trace
26
\99
–
\99
49
99
62
90
–
43
\501
–
\280
a Determined by chiral HPLC using Chiralpak AS (flow rate: 0.3–1.0 mL/min, eluent: hexane/EtOH=90/10-98/2).
This approach is even successful with the citraconimide derivatives 5d–g. The (R)-1-benzyl-4-
methyl-5-acetoxylactam 6d (98% ee) was obtained but in 20% conversion after prolonged
reaction time (entry 7). This low reactivity was due to the steric interaction of the 4-methyl
group. In the case of the 1-benzyl-3-methyl-5-acetoxylactam 5e the acetylation smoothly
proceeded to give the (R)-acetate 6e (>99% ee) and the recovered (S)-alcohol 5e (>99% ee)
(entry 8). Reverse enantioselectivity was also observed in the acetylation of 5g without
N-protection in the presence of Lipase PL (Meito, Alcaligenes sp.) (R3=H, entry 10).
In conclusion, we have discovered that racemic hydroxylactams are easily resolved by lipase,
and that enantioselectivities depended upon the presence or absence of N-protection. Although
the mechanism of the enantioselectivity is not clear at this stage, probably, a hydrogen bonding
between the amide-hydrogen and the hydrogen acceptor near the reaction site plays an
important role in leading to the reverse enantioselectivity.
Acknowledgements
Thanks to Amano Pharmaceutical Co., Ltd, Novo Nordisk Bioindustry Co., Ltd., and Meito
Sangyo Co., Ltd. for a generous gift of some enzymes. This work was partially supported in part
by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and
Culture, Japan.

Table 3
Enantioselective acetylation of the 5-hydroxylactam 5
a: R1 = H, R2 = H, R3 = Bn
Lipase
OAc
O
O
O
b: R1 = H, R2 = H, R3 = Allyl
c: R1 = H, R2 = H, R3 = H
d: R1 = H, R2 = Me, R3 = Bn
e: R1 = Me, R2 = H, R3 = Bn
f: R1 = Me, R2 = H, R3 = Ally
g: R1 = Me, R2 = H, R3 = H
R1
R2
R1
R2
R1
R2
R3
R3
+
R3
N
N
N
1,4-Dioxane
25 °C
OH
OAc
OH
5
6
5
Entry
Substrate
R3
Lipase
Time (h)
Yield 6 (ee)a (%)
Config.
Yield 5 (ee)a (%)
Config.
E value
1
2
3
4
5a
5a
5b
5b
Bn
Bn
Allyl
Allyl
Lipase PS
Novozym 435
Lipase PS
24
20
6
50 (\99)
49 (\99)
42 (96)
R
R
R
R
48 (\99)
48 (\99)
50 (70)
S
S
S
S
\1057
\752
102
Novozym 435
20
48 (81)
47 (93)
21.2
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
5
6
5c
5c
H
H
Lipase PL
Novozym 435
5
20
49 (75)
43 (75)
S
S
32 (\99)
44 (99)
R
R
14.9
12.3
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
7
8
9
5d
5e
5f
Bn
Bn
Allyl
Lipase PS
Novozym 435
Novozym 435
240
20
20
20 (98)
49 (\99)
46 (79)
R
R
R
67 (38)
48 (\99)
48 (81)
S
S
S
126
\752
16.0
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
10 5g Lipase PL 53 (50) 35 (98) 5.1
H
6
S
R
a Determined by chiral HPLC using Chiralpak AS (flow rate: 0.5–1.0 mL/min, eluent: hexane/EtOH=80/20-98/2).

9863
References
1. (a) Dijkink, J.; Cintrat, J.-C.; Speckamp, W. N.; Hiemstra, H. Tetrahedron Lett. 1999, 40, 5919–5922. (b) Yoda,
H.; Kitayama, H.; Katagiri, T.; Takabe, K. Tetrahedron 1992, 48, 3313–3322. (c) Koot, W.-J.; Ginkel, R. v.;
Kranenburg, M.; Hiemstra, H.; Louwrier, S.; Moolenaar, M. J.; Speckamp, W. N. Tetrahedron Lett. 1991, 32,
401–404. (d) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc. 1989, 111, 2588–2595.
2. (a) Ostendorf, M.; Romagnoli, R.; Pereiro, I. C.; Roos, E. C.; Moolenaar, M. J.; Speckamp, W. N.; Hiemstra, H.
Tetrahedron: Asymmetry 1997, 8, 1773–1789. (b) Kang, J.; Lee, J. W.; Kim, J. I.; Pyun, C. Tetrahedron Lett. 1995,
36, 4265–4268. (c) Matsuki, K.; Inoue, H.; Ishida, A.; Takeda, M.; Nakagawa, M.; Hino, T. Chem. Pharm. Bull.
1994, 42, 9–18. (d) Romagnoli, R.; Roos, E. C.; Hiemstra, H.; Moolenaar, M. J.; Speckamp, W. N.; Kaptein, B.;
Schoemaker, H. E. Tetrahedron Lett. 1994, 35, 1087–1090.
3. We tried to achieve high stereoselectivity in the enantioselective reduction of N-benzylmaleimide to the 5-hydroxy-
1,5-dihydropyrrol-2-one derivative with BINAL-H; however, low enantioselectivity was observed.
4. Mase, N.; Nishi, T.; Takamori, Y.; Yoda, H.; Takabe, K. Tetrahedron: Asymmetry 1999, 10, 4469–4471.
5. A part of this work was presented at the 5th International Kyoto Conference on New Aspects of Organic
Chemistry (Kyoto, 12 November, 1991) and the 4th Symposium on Biotransformation of Organic Compounds
(Otsu, 22 January, 1992).
6. (a) Drauz, K.; Waldmann, H. Enzyme Catalysis in Organic Synthesis; VCH: Weinheim, 1995. (b) Wong, C.-H.;
Whitesides, G. M. Enzymes in Synthetic Organic Chemistry; Pergamon: Oxford, 1994. (c) Drueckhammer, D. G.;
Hennen, W. J.; Pederson, R. L.; Carlos, F.; Barbas, I.; Gautheron, C. M.; Krach, T.; Wong, C.-H. Synthesis 1991,
499–525. (d) Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl. 1989, 28, 695–707.
7. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294–7299.
8. Typical procedure: a solution of imide derivatives 1 (50 mg) and lipase (50 mg) in vinyl acetate (500 mg) was
stirred for an appropriate time; then, lipase was removed through filtration, and concentrated to give a crude,
which was purified by column chromatography (silica gel, eluent: hexane–AcOEt) to give the acetate 2 and the
recovered alcohol 1.
9. Recently, Feringa and Kellogg reported that lipase-catalyzed esterification and transesterification of 1-acetoxy
maleic anhydride and 1-acetoxymaleimide derivatives gave the chiral 1,5-diacetoxylactone and 1,5-diacetoxylactam
with >99% enantioselectivity and 100% yield due to spontaneous racemization of 5-hydroxylactone and 5-hydroxy-
lactam. van der Deen, H.; Cuiper, A. D.; Hof, R. P.; van Oeveren, A.; Feringa, B. L.; Kellogg, R. M. J. Am.
Chem. Soc. 1996, 118, 3801–3803.
.