A short-step synthesis of (2S,3R)-3-hydroxy-3-methylproline, a component of polyoxypeptins, using a tandem Michael-aldol reaction and optical resolution

Article abstract of DOI:10.1246/bcsj.77.1649

A short-step synthesis of (2S,3R)-3-hydroxy-3-methylproline, a component of polyoxypeptins, using a tandem Michael-aldol reaction followed by its optical resolution using (-)-cinchonidine has been achieved.

Full text of DOI:10.1246/bcsj.77.1649

ꢀ 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 1649–1653 (2004) 1649
A Short-Step Synthesis of (2S,3R)-3-Hydroxy-3-methylproline,
a Component of Polyoxypeptins, Using a Tandem Michael–Aldol
Reaction and Optical Resolution
ꢀ
Kazuishi Makino, Tatsuya Suzuki, and Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522
Received December 4, 2003; E-mail: hamada@p.chiba-u.ac.jp
A short-step synthesis of (2S,3R)-3-hydroxy-3-methylproline, a component of polyoxypeptins, using a tandem
Michael–aldol reaction followed by its optical resolution using (ꢁ)-cinchonidine has been achieved.
Polyoxypeptins A (1) and B (2) are novel 19-membered cy-
clic hexadepsipeptides isolated from the culture broth of Strep-
tomyces species by Umezawa and co-workers in 1998 (Fig. 1).1
O
Michael
reaction
They are known to show strong anticancer activity through the
induction of apoptosis against apoptosis-resistant human pan-
creatic adenocarcinoma AsPC-1 cells. In addition to their po-
tent biological activities, the structural complexity containing
a novel (2S,3R)-3-hydroxy-3-methylproline (3, HOMePro)
and other unusual amino acids have led several groups,2 in-
cluding ours,3 to investigate the total synthesis of polyoxypep-
tins and structurally related cyclodepsipeptides. We and others
have already reported the stereoselective synthesis of HOMe-
Pro.3e However, these methods require multi steps and give
low overall yields, and there is still need of a concise method
for large-scale production of this unique component. Recently,
we explored a concise synthetic route to racemic HOMePro
utilizing a tandem Michael–aldol reaction (Scheme 1).4 The
reaction was originally reported by Terry in 19625a and subse-
quently Lash in 19915b as a part of pyrrole synthesis. However,
no further investigation on the stereoselectivity and/or the
transformation to optically active HOMePro derivatives was
made. Herein, we describe a short-step synthesis of (2S,3R)-
3-hydroxy-3-methylproline from N-tosylglycine esters through
optical resolution using (ꢁ)-cinchonidine.
OH
OH
Aldol reaction
OR2
N
H
HN
R1
O
O
3
Scheme 1.
Results and Discussion
Our synthetic plan for racemic HOMePro is shown in
Scheme 1. The key reaction is the diastereoselective construc-
tion of the multi-substituted pyrrolidine ring in a single step
using a tandem Michael–aldol reaction between N-protected
glycine ester and 3-buten-2-one. We first searched for this type
of reaction under several conditions utilizing a phase-transfer
catalyst or a combination of various Lewis acids and bases.
All attempts failed, however, the reaction progressed in the
presence of a base (Table 1). Thus, the reaction of N-tosylgly-
cine ethyl ester and 3-buten-2-one using a catalytic amount of
t-BuOK (0.2 eq) in t-BuOH–Et2O afforded the Michael–aldol
adducts as a diastereomeric mixture of 55:45 in 49% combined
yield (entry 1). It is crucial to protect the amino group as a sul-
fonamide in this reaction (entry 2). To improve the chemical
yield and diastereoselectivity, the effect of the ester group
was examined. The use of N-tosylglycine t-butyl ester was ef-
fective in terms of yield (68%) but no diastereoselectivity was
observed (entry 3). The introduction of a benzyl group to N-to-
sylglycine increased the product selectivity (5c:6c = 69:31) in
good yield (entry 4). The treatment of 4c with 1,8-diazabicy-
clo[5.4.0]undec-7-ene5b (DBU, 1.0 equivalent) instead of t-
BuOK provided the Michael–aldol adducts with some im-
provement in yield (82% yield, 5c:6c = 69:31, entry 5). Fur-
thermore, we observed that this reaction progressed with a cat-
alytic amount of DBU (0.2 eq) with a similar yield (81%) and
diastereoselectivity (5c:6c = 66:34, entry 6). We also investi-
gated various solvents under conditions using DBU as a base.
Besides THF, other solvents such as PhCH3, DME, and 1,4-di-
oxane could be used for this reaction with similar results (en-
OH
O
OH
O
H
NH HN
N
H
O
H
N
H
HO
O
O
O
O
O
OH
N
H
N
R
HN
N
H
O
OH
R = OH: Polyoxypeptin A (1)
R = H:
Polyoxypeptin B (2)
Fig. 1. Structure of polyoxypeptins.
Published on the web September 10, 2004; DOI 10.1246/bcsj.77.1649

1650 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Short-Step Synthesis of (2S,3R)-HOMePro
Table 1. Diastereoselective Construction of Pyrrolidine Ring Using Tandem Michael–Aldol Reaction
OH
O
OH
OR2
base
OR2
+
R1HN
+
OR2
solvent
0 to 23 °C
N
N
R1
6
O
R1
4a: R = Et 4b: R = tBu
4c: R = Bn
O
syn
O
anti
5
RatiobÞ
syn:anti
Entry
R1
R2
Base/eq
Solvent
Time/h
Yield/%aÞ
1
2
3
4
5
6
7
8
9
Ts
Boc
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Et
Et
t-BuOK (0.2)
t-BuOK (0.2)
t-BuOK (0.2)
t-BuOK (0.2)
DBU (1.0)
DBU (0.2)
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.0)
DBU (1.0)
t-BuOH–Et2O
t-BuOH–Et2O
t-BuOH–Et2O
t-BuOH–THF
THF
THF
CH2Cl2
DMF
PhCH3
DME
1,4-dioxane
73
73
73
73
14
64
25
14
22
22
24
49
N.R.cÞ
68
65
82
81
75
81
74
55:45
—
t-Bu
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
50:50
65:35
69:31
66:34
39:61
43:57
66:34
60:40
63:37
10
11
82
81
1
a) Yields of isolated products. b) Determined by H NMR. c) No reaction.
OH Na, napthalene
OH
O
OH
H2, Pd-C
DBU
DME, -78 °C
+
CO2Bn
TsHN
MeOH
quant.
then CHCl3
64 %
THF
0 to 23 °C
82 %
then
Dowex50WX4
N
N
H
N
CO2H
CO2H
H
CO2Bn
7
Ts
Ts
8
( )-10
( )-11
60%
( )-9
syn : anti = 69 : 31
syn : anti = 95 : 5
ꢀ
ꢀ
Scheme 2. Synthesis of rac-(2S ,3R )-3-hydroxy-3-methylproline.
mother liquor
1N HCl
crystals
+
(-)-cinchonidine
(0.5 eq)
( )-10
(1.0 eq)
+
crystallized from
AcOEt
1N HCl
(-)-10
(+)-10
24 %, 61 % ee
76 %, 24 % ee
WSCI, DMAP
CH2Cl2
OH
1.
AcCl
MeOH
OH
*
O
*
*
N
then
crystallized
from AcOEt
2. 6N HCl
reflux
then Dowex50WX4
N
*
*
CO2H
N
H
*
O
CO2H
Ts
Ts
(-)-12
(-)-10
24 % ee
(2S, 3R)-13
97 % ee
25 %
75 %
ꢀ
ꢀ
Scheme 3. Optical resolution of rac-(2S ,3R )-3-hydroxy-3-methylproline.
tries 9–11). Interestingly, the use of CH2Cl2 or DMF gave the
anti isomer 6c as a major product (entries 7 and 8). With the
Michael–aldol adducts in hand, we next examined the separa-
Deprotection of the tosyl group was attained by using so-
dium napthalenide in DME. After treatment of the crude mix-
ture with Dowex 50WX4 ion exchange resin (Hþ form) eluted
with 2 M aqueous pyridine, the eluant was concentrated, and
the residue was recrystallized from H2O to give (2S ,3R )-
HOMePro as diastereomerically pure crystals.
Having established the short-step synthesis of 3-hydroxy-3-
methylproline as a racemic form, we next investigated the op-
tical resolution using a chiral amine (Scheme 3). The resolu-
tion was carried out by dissolving 1 equivalent of racemic
(ꢂ)-10 and 0.5 equivalent of (ꢁ)-cinchonidine in various sol-
vents with heating, followed by precipitating by cooling. It
seemed that the crystallization solvents were critical for the
formation of molecular crystals. In a solvent such as MeOH,
ꢀ
ꢀ
tion of their diastereomers and transformation to (2S ,3R )-
HOMePro (Scheme 2). After hydrogenolysis of the benzyl
ester in quantitative yield, diastereomerical purification was
achieved utilizing the difference in solubility in CHCl3 be-
tween the syn and anti diastereomers. The syn isomer was
more soluble in CHCl3 than the anti isomer. Thus, after the
mixture (syn:anti = 69:31) was suspended in CHCl3 and heat-
ed to reflux, the insoluble solid was filtered off, and the filtrate
was concentrated in vacuo to give the syn-rich mixture. This
cycle was repeated five times to give the diastereomerically
enriched (ꢂ)-10 (syn:anti = 95:5) in 65% yield.
ꢀ
ꢀ

K. Makino et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1651
wise DBU (1.40 mL, 9.38 mmol). After 14 h, the reaction was
quenched with 1 M HCl, and the resulting mixture was extracted
with ethyl acetate. The combined organic extracts were washed
with brine, saturated aqueous NaHCO3 solution and brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude
product was purified by silica-gel chromatography (hexane:ethyl
acetate = 1:1) to give the Michael–aldol adducts (ꢂ)-9 (3.66 g,
7.70 mmol, syn:anti = 69:31, 82%) as a pale yellow oil. The an-
alytical samples were obtained by purification using silica-gel
chromatography (hexane:ethyl acetate = 20:1). Syn adduct:
1H NMR (400 MHz, CDCl3) ꢂ 1.27 (3H, s, CH3), 1.74 (1H,
ddd, J ¼ 12:5, 7.5, 6.8 Hz, CH2), 2.08 (1H, ddd, J ¼ 12:5, 7.3,
6.0 Hz, CH2), 2.23 (1H, s, OH), 2.42 (3H, s, CH3), 3.39 (1H,
ddd, J ¼ 9:9, 7.7, 6.0 Hz, CH2), 3.56 (1H, ddd, J ¼ 9:9, 7.3,
6.8 Hz, CH2), 4.12 (1H, s, CH), 5.20 (2H, s, CH2), 7.28 (2H, d,
J ¼ 8:6 Hz, Ar), 7.31–7.42 (5H, m, Ar), 7.74 (2H, dt, J ¼ 8:4,
1.8 Hz, Ar); 13C NMR (100 MHz, CDCl3) ꢂ 21.6, 26.4, 38.9,
46.2, 67.3, 69.1, 79.0, 127.5, 128.3, 128.4, 128.6, 129.7, 135.0,
135.3, 143.8, 169.8; IR (neat, cmꢁ1) 3497, 3063, 3033, 2976,
2893, 1744, 1598, 1496, 1454, 1385, 1344, 1158, 1094; HRMS
(FAB); calcd for C20H24NO5S (M þ H) 390.1375, found
EtOH, Et2O, THF, and acetone, no crystallization was ob-
served. The solubility of (ꢂ)-10 in CH3CN, CHCl3, CH2Cl2,
i-PrOH, n-PrOH, and hexane was too poor to be used as the
solvent for the recrystallization. After a survey of several sol-
vents, we found that partial optical resolution occurred with
the use of ethyl acetate. The solids crystallized from ethyl ace-
tate were collected by filtration and treated with 1 M hydro-
23
chloric acid to liberate (þ)-10 (½ꢀꢃD þ52:9 (c 0.52, CHCl3),
61% ee) in 24% yield. The mother liquor containing the de-
sired (2S,3R)-stereoisomer was washed with 1 M hydrochloric
acid and evaporated in vacuo to yield (ꢁ)-10 (½ꢀꢃD ꢁ20:9 (c
1.1, CHCl3), 24% ee) as solids in 76% yield. For further enan-
tiomerical enrichment, (ꢁ)-10 was converted to ꢁ-lactone 12,
which was recrystallized from ethyl acetate to give highly
optically enriched (ꢁ)-12 with 97% ee in 25% yield. Meth-
anolysis of the ꢁ-lactone ring under acidic conditions and
the subsequent deprotection of the N-tosyl group with 6 M hy-
drochloric acid furnished (2S,3R)-HOMePro 13 as a p-toluene-
sulfonic acid salt. Purification of the crude salt with Dowex
50WX4 using 1 M aqueous pyridine as an eluant afforded pure
(2S,3R)-13 in 75% yield.
1
390.1360. Anti adduct: H NMR (400 MHz, CDCl3) ꢂ 1.17 (3H,
s, CH3), 1.76 (1H, s, OH), 1.82 (1H, dd, J ¼ 13:0, 6.6 Hz,
CH2), 2.07 (1H, ddd, J ¼ 12:8, 10.6, 8.6 Hz, CH2), 2.40 (3H, s,
CH3), 3.41 (1H, ddd, J ¼ 10:6, 8.8, 6.6 Hz, CH2), 3.62 (1H, dt,
J ¼ 8:8, 1.6 Hz, CH2), 4.11 (1H, s, CH), 5.12 (1H, d, J ¼ 12:3
Hz, CH2), 5.17 (1H, d, J ¼ 12:3 Hz, CH2), 7.27 (2H, d, J ¼ 8:1
Hz, Ar), 7.32–7.40 (5H, m, Ar), 7.72 (2H, dt, J ¼ 8:2, 1.8 Hz,
Ar); 13C NMR (100 MHz, CDCl3) ꢂ 21.5, 22.9, 38.2, 46.4, 67.2,
71.6, 79.9, 127.5, 128.5, 128.5, 128.6, 129.6, 134.7, 135.1,
143.6, 170.1; IR (neat, cmꢁ1) 3499, 3064, 3033, 2979, 2890,
1742, 1598, 1496, 1455, 1384, 1337, 1261, 1163, 1095; HRMS
(FAB); calcd for C20H24NO5S (M þ H) 390.1375, found
390.1344.
Conclusion
In conclusion, we have developed a concise method to con-
struct the multi-substituted pyrrolidine ring in one step using a
tandem Michael–aldol reaction catalyzed by DBU, and achiev-
ed a short-step synthesis of racemic (2S ,3R )-3-hydroxy-3-
methylproline. The enantiometically pure (2S,3R)-3-hydroxy-
3-methylproline was obtained by partial optical resolution
using (ꢁ)-cinchonidine and enantiomerical enrichment by
the recrystallization of its ꢁ-lactone derivative. Further studies
directed towards the total synthesis of polyoxypeptins are in
progress.
ꢀ
ꢀ
ꢀ
ꢀ
(2S ,3R )-3-Hydroxy-3-methyl-1-(p-tolylsulfonyl)-pyrroli-
dine-2-carboxylic Acids (ꢁ)-10. A mixture of the Michael–al-
dol adducts (3.66 g, 9.39 mmol, syn:anti = 69:31) and 5% Pd-C
(360 mg) in MeOH (38 mL) was stirred under a hydrogen atmo-
sphere (1 atm) at 23 ꢄC for 14 h. The reaction mixture was filtered
and concentrated in vacuo to give the carboxylic acid (10, 2.81 g,
9.39 mmol, quant.) as a pale yellow solid. After the crude carbox-
ylic acid was suspended in CHCl3 and heated to reflux, the insolu-
ble solid (anti product) was filtered off. The filtrate was concen-
trated in vacuo to give the syn-rich mixture. This cycle was re-
peated five times to give the syn product (ꢂ)-10 (1.80 g, 6.01
mmol, 64%, syn:anti = 95:5). Syn product: Mp 95–96 ꢄC;
1H NMR (400 MHz, CDCl3) ꢂ 1.29 (3H, s, CH3), 1.58 (1H, dt,
J ¼ 12:6, 7.7 Hz, CH2), 2.06 (1H, ddd, J ¼ 12:6, 6.8, 5.3 Hz,
CH2), 2.23 (1H, s, OH), 2.44 (3H, s, CH3), 3.38 (1H, ddd,
J ¼ 10:4, 7.7, 5.1 Hz, CH2), 3.64 (1H, dt, J ¼ 10:4, 7.1 Hz,
CH2), 4.01 (1H, s, CH), 7.35 (2H, d, J ¼ 8:1 Hz, Ar), 7.74 (2H,
dt, J ¼ 8:2, 2.0 Hz, Ar); 13C NMR (100 MHz, CDCl3) ꢂ 21.6,
26.1, 38.9, 46.8, 69.4, 79.5, 127.6, 129.9, 134.0, 144.3, 172.7;
IR (neat, cmꢁ1) 3437, 3355, 2981, 2875, 2648, 2550, 1694,
1419, 1387, 1343, 1281, 1246, 1207, 1159; HRMS (FAB); calcd
for C13H18NO5S (M þ H), 300.0906, found 300.0876. Anti prod-
uct: Mp 195–196 ꢄC (dec); 1H NMR (400 MHz, DMSO-d6) ꢂ 1.17
(3H, s, CH3), 1.71 (1H, dd, J ¼ 12:3, 6.0 Hz, CH2), 1.88 (1H, dt,
J ¼ 12:1, 8.2 Hz, CH2), 2.39 (3H, s, CH3), 3.16 (1H, ddd,
J ¼ 11:0, 8.2, 6.4 Hz, CH2), 3.42 (1H, t, J ¼ 8:1 Hz, CH2),
3.79 (1H, s, CH), 4.98 (1H, s, OH), 7.40 (2H, d, J ¼ 8:4 Hz,
Ar), 7.66 (2H, d, J ¼ 8:2 Hz, Ar), 12.78 (1H, bs, OH); 13C NMR
Experimental
General. Melting points were measured with a SHIBATA
NEL-270 melting point apparatus. IR spectra were recorded on
a JASCO FT/IR-230 spectrometer. NMR spectra were recorded
on JEOL JNM GSX400A and JNM ECP400 spectrometers.
FAB mass spectra were obtained with a JEOL JMS-HX-110A
spectrometer. Optical resolutions were determined on a JASCO
DIP-140 and JASCO P-1020 polarimeter. HPLC analyses were
performed using JASCO UV-970 and PU-980 high pressure liquid
chromatograph with an optically active column. Column chroma-
tography was carried out with silica gel BW-820MH (Fuji silysia).
Analytical thin layer chromatography was performed on Merck
Kieselgel 60F254 0.25 mm thickness plates. 3-Buten-2-one, 1,8-
diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, (ꢁ)-cin-
chonidine, 4-dimethylaminopyridine, acetyl chloride, and hydro-
chloric acid were purchased from Wako pure chemical industries,
Ltd. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydro-
chloride (WSCI) was purchased from Kokusan Chemical, Ltd.
N-Tosylglycine benzyl ester is commercially available from Sig-
ma-Aldrich Chemical Company, Inc., or is easily prepared from
glycine in 2 steps: a) TsCl, Na2CO3, Et2O, H2O, 122 h, 23 ꢄC,
91%; b) BnOH, TsOH, PhH, reflux, 22 h, quant.
ꢀ
ꢀ
ꢀ
ꢀ
(2S ,3R )- and (2R ,3S )-Benzyl 3-Hydroxy-3-methyl-1-
(p-tolylsulfonyl)-pyrrolidine-2-carboxylates (ꢁ)-9. To a stirred
solution of Ts–Gly–OBn 7 (3.00 g, 9.39 mmolꢄ) and 3-buten-2-one
(1.20 mL, 14.4 mmol) in THF (38 mL) at 23 C was added drop-

1652 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Short-Step Synthesis of (2S,3R)-HOMePro
(100 MHz, DMSO-d6) ꢂ 19.9, 22.1, 36.7, 45.4, 70.6, 77.0, 126.1,
128.5, 133.5, 142.0, 170.8; IR (neat, cmꢁ1) 3478, 3063, 2978,
2936, 2892, 2651, 2562, 1714, 1462, 1434, 1377, 1326, 1270,
1149, 1093; HRMS (FAB); calcd for C13H18NO5S (M þ H),
300.0906, found 300.0886.
mL/min, hexane/i-PrOH = 65:35, retention times 10.1 min for
(1S,5R)-(ꢁ)-12, 12.9 min for (1R,5S)-(þ)-12.
(2S,3R)-3-Hydroxy-3-methylproline 13. To a stirred solution
ꢄ
of (ꢁ)-12 (2.08 g, 7.39 mmol) in MeOH (37 mL) at 23 C was
added dropwise acetyl chloride (52.5 mL, 0.739 mmol). After 21
h, the reaction mixture was concentrated in vacuo. The residue
was purified by silica-gel chromatography (hexane:ethyl acetate
= 3:2) to give the methyl ester (2.03 g, 7.31 mmol, 99%) as a col-
ꢀ
ꢀ
(2S ,3R )-3-Hydroxy-3-methylprolines (ꢁ)-11. To a dark
green solution of Na (321 mg, 14.0 mmol) and napthalene (2.86
ꢄ
g, 22.3 mmol) in DME (14 mL) at ꢁ78 C was added dropwise
24
a solution of N-tosylamide (ꢂ)-10 (1.09 g, 2.79 mmol) in DME
(6.0 mL). After 15 min, the reaction was quenched with H2O,
and the resulting mixture was extracted with H2O. After the com-
bined aqueous extracts were neutralized with conc. HCl, the mix-
ture was charged on Dowex 50WX4 resin (Hþ form) and eluted
with 1 M aqueous pyridine to afford brown-white solids (ꢂ)-11
(366 mg, 2.73 mmol, 98%). The solids could be further purified
by recrystallization from H2O to give colorless crystals (243
mg, 60%ꢄ, 1.67 mmol). Mp 271 ꢄC (dec); 1H NMR (400 MHz,
D2O, 40 C) ꢂ 1.60 (s, 3H, CH3), 2.12–2.17 (2H, m, CH2), 3.45
(1H, ddd, J ¼ 11:0, 7.1, 4.7 Hz, CH2N), 3.55 (1H, dt, J ¼ 11:7,
8.8 Hz, CH2N), 3.85 (1H, s, CH); 13C NMR (100 MHz, D2O,
orless solid. Mp 134–135 ꢄC; ½ꢀꢃD ꢁ52:5 (c 0.61, CHCl3);
1H NMR (400 MHz, CDCl3) ꢂ 1.25 (3H, s, CH3), 1.71 (1H, dt,
J ¼ 12:4, 6.8 Hz, CH2), 2.10 (1H, dt, J ¼ 12:4, 6.8 Hz, CH2),
2.43 (3H, s, CH3), 2.71 (1H, bs, OH), 3.35 (1H, dt, J ¼ 11:2,
7.2 Hz, CH), 3.59 (1H, dt, J ¼ 9:6, 8.8 Hz, CH), 3.74 (3H, s,
CH3), 4.03 (1H, s, CH), 7.33 (2H, d, J ¼ 8:0 Hz, Ar), 7.74 (2H,
d, J ¼ 8:0 Hz, Ar); 13C NMR (100 MHz, CDCl3) ꢂ 21.5, 26.2,
38.7, 46.2, 52.3, 69.1, 78.7, 127.4, 129.6, 134.7, 143.8, 170.4;
IR (neat, cmꢁ1) 3500, 2976, 2954, 2898, 1745, 1598, 1439,
1342, 1158, 1093; HRMS (FAB); calcd for C14H20NO5S
(M þ H) 314.0984, found 314.1043.
A stirred mixture of the methyl ester (2.25 g, 7.18 mmol) in
6 M HCl (35 mL) was heated to reflux for 48 h. After cooling,
the reaction mixture was concentrated in vacuo. The residue
was charged on Dowex 50WX4 resin (Hþ form) and eluted with
1 M aqueous pyridine to give pure 13 (782 mg, 5.39 mmol, 75%)
60 ꢄC) ꢂ 24.3, 39.8, 43.8, 70.2, 78.8, 171.1; IR (KBr, cmꢁ1
)
3225, 3117, 2935, 2701, 2632, 2563, 1641, 1464, 1412; Anal.
Calcd for C6H11NO3: C, 49.65; H, 7.64; N, 9.65%. Found: C,
49.44; H, 7.69; N, 9.54%.
25
(2R,3S)- and (2S,3R)-3-Hydroxy-3-methyl-1-(p-tolylsulfo-
nyl)-pyrrolidine-2-carboxylic Acids (þ)-10 and (ꢂ)-10. A mix-
ture of racemic carboxylic acid (ꢂ)-10 (3.99 g, 13.3 mmol) and
(ꢁ)-cinchonidine (1.96 g, 6.66 mmol) was dissolved in ethyl ace-
tate (66.6 mL) with heating. After the clear solution was left for 12
h at 23 ꢄC, colorless solids were precipitated. The solids were col-
lected by filtration and treated with 1 M HCl to liberate (þ)-
as a colorless solid after evaporation. ½ꢀꢃD ꢁ42:3 (c 1.1, H2O).
The spectral data were identical with our previous reported
values.3e
This work was financially supported in part by a Grant-in-
Aid for Scientific Research on Priority Areas (A) ‘‘Exploita-
tion of Multi-Element Cyclic Molecules’’ from the Ministry
of Education, Culture, Sports, Science and Technology, and
a Sasakawa Scientific Research Grant from Japan Science
Society (to T.S.).
23
(2R,3S)-10 (½ꢀꢃD þ52:9 (c 0.52, CHCl3), 61% ee) as colorless
solids. The filtrate was washed with 1 M HCl and brine, dried over
Na2SO4, filtered, and concentrated in vacuo to give (ꢁ)-(2S,3R)-
10 (3.03 g, 10.1 mmol, 76%, 24% ee) as colorless solids, which
were used for the next reaction without further purification. The
enantiomeric excess was determined by chiral HPLC analysis
after transformation to the ꢁ-lactone 12.
References
1
a) K. Umezawa, K. Nakazawa, T. Uemura, Y. Ikeda, S.
(1S,5R)-(5-Methyl-2-(p-tolylsulfonyl)-6-oxa-2-aza-bicyclo-
Kondo, H. Naganawa, N. Kinoshita, H. Hashizume, M. Hamada,
T. Takeuchi, and S. Ohba, Tetrahedron Lett., 39, 1389 (1998).
b) K. Umezawa, K. Nakazawa, Y. Ikeda, H. Naganawa, and S.
Kondo, J. Org. Chem., 64, 3034 (1999).
[3.2.0]heptan-7-one (ꢂ)-12.
To a stirred solution of (ꢁ)-
ꢄ
(2S,3R)-10 (2.96 g, 9.88 mmol) in CH2Cl2 (50 mL) at 0 C was
added WSCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride) (2.08 g, 10.9 mmol) and DMAP (4-dimethyl-
aminopyridine) (302 mg, 2.47 mmol). After stirring the mixture
for 17 h at 23 ꢄC, the reaction was quenched with 10% citric acid
and extracted with ethyl acetate. The combined organic extracts
were washed with saturated aqueous NaHCO3 solution and brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The crude
product was purified by silica-gel chromatography (hexane:ethyl
acetate = 1:1) to give ꢁ-lactone as a colorless solid, which was
recrystallized from ethyl acetate four times to give (ꢁ)-12 (700
2
a) Y. Noguchi, T. Yamada, H. Uchiro, and S. Kobayashi,
Tetrahedron Lett., 41, 7499 (2000). b) Y. Noguchi, H. Uchihiro,
T. Yamada, and S. Kobayashi, Tetrahedron Lett., 42, 5253
(2001). c) M. Lorca and M. Kurosu, Tetrahedron Lett., 42, 2431
(2001). d) D.-G. Qin, H.-Y. Zha, and Z.-J. Yao, J. Org. Chem.,
67, 1038 (2002). e) D.-G. Qin and Z.-J. Yao, Tetrahedron Lett.,
44, 571 (2003). f) Y. Aoyagi, Y. Saitoh, T. Ueno, M. Horiguchi,
K. Takeya, and R. M. Williams, J. Org. Chem., 68, 6899 (2003).
g) J.-W. Shen, D.-G. Qin, H.-W. Zhang, and Z.-J. Yao, J. Org.
Chem., 68, 7479 (2003).
24
mg, 2.47 mmol, 25%, 97% ee) as a colorless solid. ½ꢀꢃD ꢁ128
(c 0.13, CHCl3); 1H NMR (400 MHz, CDCl3) ꢂ 1.68 (3H, s,
CH3), 1.83 (1H, dt, J ¼ 14:2, 11.5, 8.1 Hz, CH2), 2.22 (1H, dd,
J ¼ 14:4, 5.9 Hz, CH2), 2.44 (3H, s, CH3), 3.15 (1H, dt,
J ¼ 11:5, 5.9 Hz, CH), 4.00 (1H, dd, J ¼ 11:2, 7.6 Hz, CH),
5.08 (1H, s, CH3), 7.34 (2H, d, J ¼ 8:1 Hz, Ar), 7.79 (2H, d, J ¼
8:3 Hz, Ar); 13C NMR (100 MHz, CDCl3) ꢂ 20.6, 21.6, 35.1, 46.7,
3
a) N. Okamoto, O. Hara, K. Makino, and Y. Hamada,
Tetrahedron: Asymmetry, 12, 1353 (2001). b) K. Makino, N.
Okamoto, O. Hara, and Y. Hamada, Tetrahedron: Asymmetry,
12, 1757 (2001). c) K. Makino, Y. Henmi, and Y. Hamada,
Synlett, 2002, 613. d) N. Okamoto, O. Hara, K. Makino, and Y.
Hamada, J. Org. Chem., 67, 9210 (2002). e) K. Makino, A.
Kondoh, and Y. Hamada, Tetrahedron Lett., 43, 4695 (2002). f)
K. Makino, T. Suzuki, S. Awane, O. Hara, and Y. Hamada, Tetra-
hedron Lett., 43, 9391 (2002).
73.5, 87.3, 127.9, 130.0, 134.7, 144.5, 164.5; IR (neat, cmꢁ1
)
3093, 3063, 2983, 2938, 1832, 1595, 1479, 1455, 1390, 1354,
1264; HRMS (FAB); calcd for C13H17NO4S (M þ H) 282.0800,
found 282.0788. HPLC analysis: Daicel Chiralpac AD, flow 1.0
4
For excellent reviews of tandem reactions and Michael–

K. Makino et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1653
aldol reactions, see: a) L. F. Tietze, Chem. Rev., 96, 115 (1996). b)
K. Takasu, Yakugaku Zasshi, 121, 887 (2001).
Komis, J. Chem. Soc., 1965, 4389. b) T. D. Lash and M. C.
Hoehner, J. Heterocycl. Chem., 28, 1671 (1991).
5
a) W. G. Terry, A. H. Jackson, G. W. Kenner, and G.