Asymmetric routes towards polyfunctionalized pyrrolidines: A short diastereoselective synthesis of polyhydroxylated pyrrolidines and an indolizidine

Article abstract of DOI:10.1055/s-1999-3434

Various (2S,3S,4R)-2-[(1R)-1-hydroxyalkyl]pyrrolidine-3,4-diols (11) have been prepared in 8 steps and 13-20% overall yield starting from (R)-(- )-phenylglycinol. This concise approach is based on the condensation of a chiral silyloxypyrrole with aldehydes which gave the (R,R)-aldol compounds in good yields and high diastereoselectivities. The cis-hydroxylation followed by reduction and deprotection gave the desired trihydroxylated pyrrolidines. The same strategy has been successively applied to a formal synthesis of 8a- epi-swainsonine.

Full text of DOI:10.1055/s-1999-3434

688
PAPER
Asymmetric Routes Towards Polyfunctionalized Pyrrolidines: A Short
Diastereoselective Synthesis of Polyhydroxylated Pyrrolidines and an
Indolizidine
Bruno Dudot,a Laurent Micouin,b Isabelle Baussanne,a Jacques Royer*a
a Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette cedex, France
b Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Université René Descartes, 4 avenue de l’Observatoire, F-75270 Paris cedex
06, France
Fax +33(1)69077247; E-mail: jacques.royer@icsn.cnrs-gif.fr
Received 6 January 1998; revised 14 October 1998
upon the choice of R group as exemplified in Scheme 2.
Abstract: Various (2S,3S,4R)-2-[(1R)-1-hydroxyalkyl]pyrrolidine-
Such pyrrolidines A bearing alkyl side chains are original
3,4-diols (11) have been prepared in 8 steps and 13–20% overall
compounds and to the best of our knowledge only one
yield starting from (R)-(–)-phenylglycinol. This concise approach is
based on the condensation of a chiral silyloxypyrrole with alde-
compound in this series: (2R,3S,4R)-2-[(1R)-1-hydroxy-
hydes which gave the (R,R)-aldol compounds in good yields and ethyl]pyrrolidine-3,4-diol has been synthesized8 and
high diastereoselectivities. The cis-hydroxylation followed by re-
proved to exhibit very potent enzyme inhibition. Herein
duction and deprotection gave the desired trihydroxylated pyrro-
we describe the synthesis of polyhydroxylated pyrro-
lidines. The same strategy has been successively applied to a formal
lidines of type A with different alkyl groups R = CH3,
synthesis of 8a-epi-swainsonine.
C6H13 and PhCH2CH2 which constitute new original com-
Key words: aldol condensation, OsO4 hydroxylation, polyhydroxy
pounds in this series, as well as the formal synthesis of 8a-
pyrrolidines and indolizidine, 8-epi-swainsonine
epi-swainsonine.
Aza sugars are attractive compounds which exhibit sever-
al potential therapeutic activities with antitumor and anti-
viral indications associated to their glucosidase inhibition
properties.1 They include polyhydroxylated piperidines,
pyrrolidines, indolizidines and pyrrolizidines. Numerous
syntheses2–4 have emerged in this area generally using
sugars as starting material although non-carbohydrate
routes have also been developed.
We recently reported the one-step preparation of lactam 15
[75% yield from (R)-(–)-phenylglycinol] which was
Scheme 2
found to be easily bis-alkylated a to the carbonyl group in
both high yield and diastereoselective excess.5 We have
We have reported earlier6 the aldol type condensation of
silyloxypyrrole 3 where the hydroxyl group of the chiral
appendage is protected as a methoxy group. We have now
investigated especially the influence of other protecting
groups which could give higher diastereoselectivity. After
some trials, the benzoyl group was found to be convenient
for our purpose; furthermore, it was easy to introduce di-
rectly onto the lactam 1 using standard conditions. Silyl-
oxypyrrole 6 was then prepared in 57% yield from 1 by re-
action with benzoyl choride in pyridine followed by treat-
ment with tert-butyldimethylsilyl trifluoromethane-
sulfonate (TBDMSOTf) in the presence of triethylamine
(Scheme 3).
also shown that the O-methylated lactam 2 could be easily
transformed into the chiral silyloxypyrrole 3 which under-
goes an aldol type reaction with achiral aldehydes6,7
(Scheme 1).
Scheme 1
The aldol condensation of 6 with various aldehydes in the
presence of 1 equivalent of BF3◊OEt2 occurred smoothly
at –78°C in CH2Cl2 (Scheme 3) and gave 7a–d [a mixture
of 2 diastereomers with (R,R) as major and (S,S) as minor
isomer] in good yields and with high diastereoselectivities
as shown in Table 1. The diastereoselectivities were nice-
We then planned to use these aldol type compounds for
the preparation of various polyhydroxylated pyrrolidines
A bearing alkyl side chains or indolizidines B depending
Synthesis 1999, No. 4, 688–694 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Routes Towards Polyfunctionalized Pyrrolidines
689
8c [R = (CH2)5CH3] was obtained diastereomerically pure
after simple purification on silica gel. The hydroxyl
groups were introduced trans relative to the side chain at
1
C-5 of the pyrrolidine ring as indicated by H NMR data
(no coupling between H-3 and H-4 was observed).
The 1,2-diol system of 8a (de 70%) and 8b (de 75%) was
protected as an acetonide to give 9a and 9b in quantitative
yield (Scheme 4). The carbonyl group reduction and the
cleavage of the benzoyl group were accomplished by the
use of LiAlH4 for 9a and through BH3◊THF reduction fol-
lowed by aqueous NaOH treatment for 9b (which bears a
sensitive primary chloride). The major diastereomer of
each amino alcohols 10a and 10b could be easily isolated
at this stage by simple flash chromatography on silica gel
and diastereomerically pure compounds were obtained in
both cases in 72% yield (Scheme 4).
Scheme 3
ly improved compared to our previous studies using the
silyloxypyrrole 3.9 The (R,R) configuration of the major
isomer was assessed by comparison with the major aldol
derivative obtained in our previous work,6 and by the
identity of (–)-12 with protected (–)-8a-epi-swainsonine
(vide infra). The major (R,R)-isomer of 7a–d could be iso-
lated by careful chromatography on silica gel, except in
the case of 7d, where it was found easier to effect the sep-
aration later in the reaction sequence on account of easy
preparative manipulation.
Table 1 Preparation of Compounds 7 and 8 According to Scheme 3
Entry
R2
Product 7
Product 8
yield
de (%)
yield
de (%)
( %)
(%)
Scheme 4
a
b
c
Me
Cl(CH2)3
Me(CH2)5 84
Ph(CH2)2 72
70
74
70
80
86
90
69
68
64
85
70
78
>95a
>95b
Diastereomerically pure 8c and 8d were reduced to pyrro-
lidines 10c (using LiAlH4) and 10d (using BH3◊THF re-
duction followed by NaOH treatment) without protection
(Scheme 4, Table 2).
d
aAfter purification of the crude (85% de) reaction mixture.
b From diastereomerically pure 7d.
Table 2 Reduction of Lactams 8c,d and 9a,b (cf. Scheme 4)
The transformation of these aldol-type derivatives 7 to
polyhydroxylated pyrrolidines was achieved through se-
quential bis-hydroxylation, carbonyl reduction and final
N-debenzylation. For these two last steps different reac-
tion conditions were used depending upon the alkyl sub-
stituent.
Lac-
tam
Reagent
Prod-
uct
R2
R3
Yield
(%)
9a
9b
8c
8d
LiAlH4
BH3◊THF
LiAlH4
10a
10b
10c
10d
Me
CMe2
CMe2
H
72
72
81
90
Cl(CH2)3
Me(CH2)3
Ph(CH2)2
BH3◊THF
H
Compounds 7a–d were subjected to catalytic OsO4 hy-
droxylation (N-methylmorpholine N-oxide, acetone/wa-
ter)11 to give the hydroxylated pyrrolidones 8a–d
(Scheme 3) in good yields (64–85%, Table 1) and with
complete diastereoselectivity. Pure isomer 7d (R =
CH2CH2Ph) gave the diol 8d with a de of >95%, while
7a–c with a de of 70–85% (Table 1) furnished compounds
8a–c as diastereomeric mixtures of the same diastereo-
meric ratio indicating a diastereospecific reaction. Triol
Completion of the asymmetric synthesis of polyhydroxyl-
ated pyrrolidines 11 necessitated the cleavage of the chiral
appendage. This was done by simple hydrogenolysis in
the presence of Pearlman’s catalyst followed by acid treat-
ment of 10a,c,d to give 11a,c,d as HCl salts in 90–98%
Synthesis 1999, No. 4, 688–694 ISSN 0039-7881 © Thieme Stuttgart · New York

690
B. Dudot et al.
PAPER
(2R)-2-[2-(tert-Butyldimethylsiloxy)pyrrol-1-yl]-2-phenylethyl-
benzoate (6)
yield. Starting from diastereomerically pure compounds
10, enantiomerically pure final pyrrolidines 11 were thus
obtained.
tert-Butyldimethylsilyl triflate (3.74 mL, 16.3 mmol) was slowly
added to a solution of benzoylated lactam 5 (5 g, 16.3 mmol) and
NEt3 (4.57 mL, 32.6 mmol) in CH2Cl2 (60 mL) and the mixture was
stirred at r.t. for 1 h. The solvent was evaporated in vacuo and the
residue purified by chromatography on alumina (heptane/EtOAc,
90:10) to yield 5.96 g (88%) of 6 as a white powder; mp 48 °C (hep-
tane/EtOAc); [a]D +24.0 (c = 0.99, CHCl3).
On the other hand, amino alcohol 10b bearing the chlori-
nated side chain was carefully hydrogenolyzed in MeOH
and in the presence of NaOAc. Indolizidine 12 ([a]D –49.0
(c = 0.5, CHCl3), Lit.13c [a]D +54 (CHCl3) for the enanti-
omer) was then obtained upon debenzylation followed by
cyclization14 in 65% yield (Scheme 5). This represents a
formal synthesis of (–)-8a-epi-swainsonine.13
IR (film): n = 1723 cm–1.
1H NMR (CDCl3, 300 MHz): d = –0.05 (s, 3 H), –0.2 (s, 3H), 0.9 (s,
9H), 4.8 (dd, J = 5.2, 11.7 Hz, 1H), 4.9 (dd, J = 11.7, 8.4 Hz, 1H),
5.3 (dd, J = 1.8, 3.5 Hz, 1H), 5.7 (dd, J = 5.2, 8.4 Hz, 1H), 6.05 (dd,
J = 3.3, 3.5 Hz, 1H), 6.45 (dd, J = 3.3, 1.8 Hz, 1H), 7.1–7.9 (m, 10
H).
13C NMR (CDCl3, 62.5 MHz): d = –4.7, –5.0, 18.1, 25.7, 56.1, 65.9,
87.7, 105.9, 110.0, 126.9, 127.9, 128.5, 128.8, 129.9, 133.2, 138.7,
142.6, 166.3.
Anal. calcd for C25H31NO3Si: C, 71.22, H, 7.41; N, 3.32; Found: C,
71.03; H, 7.38; N, 3.32
Aldol-type Reaction of Silyloxypyrrole 6, General Procedure
To a cooled (–78°C) solution of silyloxypyrrole 6 (2 g, 4.75 mmol)
in anhyd CH2Cl2 (20 mL) under argon were added the aldehyde
(14.25 mmol) and BF3◊OEt2 (14.25 mmol). The solution was stirred
at –78 °C for 3 h and allowed to warm to 0 °C. The reaction was
quenched by addition of H2O, the aqueous phase was separated and
extracted with CH2Cl2 (2 î 20 mL). The organic phases were com-
bined, dried (Na2SO4) and the solvent was removed in vacuo. The
resulting oil then obtained was purified by flash chromatography on
silica gel to furnish 7.
Scheme 5
In summary, the diastereoselective preparation of trihy-
droxylated pyrrolidines bearing different alkyl groups has
been achieved in few steps, showing the efficiency of the
newly developed methodology. Extension of this strategy
to indolizidine such as 8a-epi-swainsonine demonstrates
other potential generalization of our methodology.
(2R)-2-{(2R)-2,5-Dihydro-2-[(1R)-1-hydroxyethyl]-5-oxopyr-
rol-1-yl}-2-phenylethylbenzoate (7a)
From 6 (2 g, 4.75 mmol) and acetaldehyde (0.8 mL, 4.25 mmol)
Pyrrolidone 7a (1.18 g, 70%, 70% de) was obtained as a white
amorphous solid after flash chromatography on silica gel, eluent:
CH2Cl2/MeOH (96:4).
MS (CI): m/z = 352 (MH+).
IR (film): n = 3394, 1721, 1666, 1274 cm–1.
All reactions were carried out under an atmosphere of argon. The
solvents were distilled according to standard procedures (P2O5 for
CH2Cl2, Na/benzophenone for THF). H NMR spectra were ob-
tained at 200, 250 or 300 MHz. IR spectra were recorded as thin
film unless otherwise stated. Optical rotation measurements were
performed using a 1 dm path length cell at 20 °C. Elemental analy-
ses were carried out by the Service de microanalyse of the Institut
de Chimie des Substances Naturelles.
1
1H NMR (CDCl3, 300 MHz): (major isomer) d = 0.8 (d, J = 6.3 Hz,
3H), 3.8 (m, 1H), 4.3 (dt, J = 1.7, 5.4 Hz, 1H), 5.0 (dd, J = 11.2, 5.8
Hz, 1H), 5.3 (dd, J= 11.2, 9.0 Hz, 1H), 5.5 (dd, J= 9.0, 5.8 Hz, 1H),
6.25 (dd, J = 1.7, 6.0 Hz, 1H), 7.1 (dd, J =1.6, 6.0 Hz, 1H), 7.1–7.9
(m, 10H).
13C NMR (CDCl3, 75 MHz): (major isomer) d = 17.3, 55.0, 63.7,
67.2, 127.2, 127.8, 128.1, 128.2, 128.4. 129.3, 132.78, 136.6, 145.8,
166.1, 171.3.
(2R)-2-(2,5-Dihydro-2-oxopyrrol-1-yl)-2-phenylethylbenzoate
(5)
Benzoyl chloride (5 mL, 42 mmol) was added to a solution of lac-
tam 1 (7.8 g, 38.2 mmol) in pyridine (60 mL). The mixture was
stirred at 0 °C for 10 min. H2O (200 mL) was then added and the
precipitate was filtered, dried and purified by flash chromatography
on silica gel (CH2Cl2/MeOH, 98:2 as eluent) to give 3.85 g (65%)
of 5 as white crystals; mp 132 °C (CH2Cl2); [a]D –90.0 (c = 0.96,
CHCl3).
IR (film): n = 1669, 1712 cm–1.
MS (CI): m/z = 308 (MH+).
1H NMR (CDCl3, 300 MHz): d = 3.8 (ddd, J = 20.0, 1.7, 1.7 Hz,
1H), 4.1 (ddd, J = 20.0, 1.7, 1.7 Hz, 1H), 4.78 (dd, J = 11.4, 5.2 Hz,
1H), 5.05 (dd, J = 11.4, 9.0 Hz, 1H), 5.85 (J = 5.2, 9.0 Hz, 1H), 6.2
(ddd, J = 6.0, 1.7, 1.7 Hz, 1H), 7.05 (ddd, J = 6.0, 1.6, 1.7 Hz, 1H),
7.2–8.0 (m, 10H).
HRMS (CI, CH4): m/z calcd. for C21H21NO4: 352.1549; Found :
352.1546.
(2R)-2-{(2R)-2-[(1R)-4-Chloro-1-hydroxybutyl]-2,5-dihydro-5-
oxopyrrol-1-yl}-2-phenylethylbenzoate (7b)
From 6 (2 g, 4.75 mmol) and 4-chlorobutyraldehyde (1.51 g, 14.25
mmol) Pyrrolidone 7b (1.453 g, 74%, 80% de) was obtained as a
colorless oil after flash chromatography on silica gel, eluent:
CH2Cl2/MeOH (97:3).
IR (film): n = 1665, 1720, 3390 cm–1.
MS (CI): m/z = 414 , 416 (MH+).
13C NMR (CDCl3, 75 MHz): d = 49.7, 53.0, 63.6, 127.5, 128.3,
128.5, 129.1, 129.7, 133.2, 136.7, 143.5, 166.3, 171.7.
1H NMR (CDCl3, 300 MHz): (major isomer) d = 1.0 (m, 3H), 1.6
(m, 1H), 3.1 (t, J = 6.0 Hz, 2H), 3.5 (m, 1H), 4.3 (d, J = 3 Hz, 1H),
4.9 (dd, J= 11.3, 5.7 Hz, 1H), 5.1 (dd, J=11.3, 9.3 Hz, 1H), 5.6 (dd,
Anal. calcd for C19H17NO3 : C, 74.25; H, 5.57; N, 4.56. Found: C,
74.51; H, 5.69; N, 4.26.
Synthesis 1999, No. 4, 688–694 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Routes Towards Polyfunctionalized Pyrrolidines
691
J = 5.7, 9.3 Hz, 1H), 6.1 (dd, J = 6.0, 1.3 Hz, 1H), 7.1 (dd, J = 1.4,
(2R)-2-{(3S,4S)-3,4-Dihydroxy-(2R)-2-[(1R)-1-hydroxyethyl]-5-
6.0 Hz, 1H), 7.3– 8.0 (m, 10H).
oxopyrrolidin-1-yl}-2-phenylethylbenzoate (8a)
From 7a (2.09 mmol, 70% de), 0.325 g of 8a (69%, 70% de) was
obtained as an amorphous solid, after purification on silica gel
(CH2Cl2/MeOH, 92:8).
13C NMR (CDCl3, 75 MHz): (major isomer) d = 28.7, 29.4, 44.9,
54.6, 63.9, 67.5, 71.0, 127.9, 128.3, 128.6, 128.9, 129.3, 130.0,
133.7, 137.7, 146.4, 146.9, 166.8, 173.6.
IR (film): n = 1683, 1716, 3397.
MS(CI): m/z = 386 (MH+).
HRMS (CI, CH4): m/z calcd. for C23H24ClNO4: 414.1471; Found :
414.1447.
Anal. calcd for C23H24ClNO4◊0.25H2O: C, 66.03, H, 5.85; N, 3.38;
1H NMR (CDCl3, 300 MHz): (major isomer) d = 1.0 (d, J = 6.2 Hz,
3 H), 3.5 (d, J = 5.4 Hz, 1H), 3.7 (m, 1H), 4.3 (d, J = 4.9 Hz, 1H),
4.45 (d, J = 4.9 Hz, 1H), 4.9 (m, 2H), 5.25 (m, 2H), 7.3– 8.0 (m,
10H).
13C NMR (CDCl3, 75 MHz): (major isomer) d = 19.8, 57.6, 63.5,
66.8, 68.6, 69.2, 70.7, 127.7, 128.6, 128.9, 129.8, 137.5, 133.3,
166.7, 175.6.
Found: C, 66.02; H, 5.86; N, 3.18.
(2R)-2-{(2R)-2,5-Dihydro-2-[(1R)-1-hydroxyheptyl]-5-oxopyr-
rol-1-yl}-2-phenylethylbenzoate (7c)
From 6 (2 g, 4.75 mmol) and heptaldehyde (1.345 g, 11.8 mmol)
Pyrrolidone 7c (1.7 g, 84%, 86% de) was obtained as a colorless oil
after flash chromatography on silica gel, eluent: CH2Cl2/MeOH
(98:2). Careful separation on silica gel using the same eluent fur-
nished pure R,R diastereoisomer.
HRMS (CI, CH4): m/z calcd for C21H24NO6: 386.1603; Found :
386.1615.
Anal. calcd for C21H23NO6◊0.5H2O: C, 63.95; H, 6.13 ; N, 3.55 ;
Found: C, 63.87 ; H, 6.33 ; N, 3.43.
IR (film): n = 3418, 2929, 1721, 1663, 1272, 1124, 809, 712 cm–1.
MS (CI): m/z = 439 (MH+ + NH3), 422 (MH+), 325, 308, 225, 185.
1H NMR (CDCl3, 300 MHz): d = 0.75 (t, J = 7.1 Hz, 3H), 0.82–1.13
(m, 10H), 3.01 (m, 1H), 4.24 (ddd, J = 4.9, 1.7, 1.6 Hz, 1H), 4.89
(dd, J = 11.3, 5.6, 1H), 5.15 (dd, J = 11.3, 9.6 Hz, 1H), 5.57 (dd, J
=9.6, 5.6 Hz, 1H), 6.18 (dd, J = 6.0, 1.6 Hz, 1H), 7.04 (dd, J =6.0,
1.7 Hz, 1H), 7.12–7.52 (m, 8H), 7.94 (dd, J = 8.3, 1.4 Hz, 2H).
(2R)-2-{(2R)-2-[(1R)-4-Chloro-1-hydroxybutyl-(3S,4S)-3,4-di-
hydroxy-5-oxopyrrolidin-1-yl}-2-phenylethylbenzoate (8b)
From 7b (1.93 mmol, 80% de), 0.588 g of 8b (69%, 78% de) was
obtained as an oil, after purification on silica gel (CH2Cl2/MeOH,
96:4).
13C NMR (CDCl3, 75.43 MHz): d = 14.1, 22.6, 25.9, 29.1, 31.2,
31.8, 54.6, 63.7, 67.1, 71.6, 127.6, 128.0, 128.3, 128.6, 128.9,
129.6, 129.8, 133.4, 127.6, 146.7, 166.5, 173.4.
IR (film): n = 1683, 1713, 3382 cm–1.
MS(CI): m/z = 445, 448 (MH+).
1H NMR (CDCl3, 300 MHz): (major isomer) d = 1.0–1.4 (m, 3H),
1.7 (m, 1H), 3.3 (t, J = 5.4 Hz, 2H), 3.4 (m, 1H), 3.6 (d, J = 4.3 Hz,
1H), 4.3 (d, J = 4.6 Hz, 1H), 4.5 (d, J = 4.6 Hz, 1H), 4.9 (dd, J =
11.3, 6.2 Hz, 1H), 5.3 (dd, J = 11.3, 8.4 Hz, 1H), 5.4 (dd, J = 8.2,
6.2 Hz, 1H), 7.0– 8.0 (m, 10H).
13C NMR (CDCl3, 75 MHz): (major isomer): d = 28.9, 29.5, 44.2,
54.6, 62.8, 68.0, 68.2, 69.8, 70.2, 127.3, 128.1, 128.6, 129.4, 133.0,
136.2, 166.3, 175.1.
Anal. calcd for C26H31NO4 : C, 74.08; H, 7.41; O, 15.18; Found: C,
73.81; H, 7.34; N, 14.46.
(2R)-2-{(2R)-2,5-Dihydro-2-[(1R)-1-hydroxy-3-phenylpropyl]-
5-oxopyrrol-1-yl}-2-phenylethylbenzoate (7d)
From 6 (1.4 g, 3.36 mmol) and 3-phenylpropanionaldehyde (1.13 g,
8.4 mmol) Pyrrolidone 7d (1.05 g, 72%, 90% de) was obtained as a
colorless oil after flash chromatography on silica gel, eluent:
CH2Cl2/MeOH (98:2). Careful separation on silica gel using the
same eluent furnished pure R,R diastereoisomer; [a]D –141.0 (c =
0.88, CHCl3).
HRMS (CI, CH4): m/z calcd for C23H27ClNO6: 448.1527; Found:
448.1525.
(2R)-2-{(3S,4S)-3,4-Dihydroxy-(2R)-2-[(1R)-1-hydroxyheptyl]-
5-oxopyrrolidin-1-yl}-2-phenylethylbenzoate (8c)
From 7c (0.43 mmol, 86% de), 0.132 g of 8c (64%, >95% de) was
obtained as an oil, after purification on silica gel of the crude mix-
ture (85% de) (cyclohexane/EtOAc, 5:95); [a]D +44.0 (c = 0.95,
CHCl3).
IR (film): n = 3395, 3053, 2970, 1716, 1265, 859 cm–1.
MS (CI, NH3): m/z = 456 (MH+), 359, 353, 195.
IR (film): n = 3464, 2984, 1740, 1448, 1373, 1241, 1098, 1047, 938,
847, 786 cm–1.
MS (CI): m/z = 459 (MH+ + NH3), 442 (MH+), 325, 308, 223.
1H NMR (CDCl3, 300 MHz): d = 1.17–1.31 (m, 2H), 1.87 (m, 1H),
2.47 (m, 1H), 3.35 (br s, 1H), 3.64 (m, 1H), 4.39 (m, 1H), 4.96 (dd,
J = 11.4, 5.8 Hz, 1H), 5.16 (dd, J = 11.4, 9.3 Hz, 1H), 5.66 (dd, J =
9.3, 5.8 Hz, 1H), 6.14 ( dd, J = 6.1, 1.5 Hz, 1H), 6.91 (dd, J = 7.1,
1.5 Hz, 2H), 7.10–7.49 (m, 12H), 7.91 (dd, J = 7.1, 1.5 Hz, 2H).
1H NMR (CDCl3, 300 MHz): d = 0.75 (t, J = 7.1 Hz, 3H), 0.95–1.38
(m, 10H), 2.85 (br s, 1H), 3.41 (m, 2H), 3.62 (d, J = 4.9 Hz, 1H),
4.30 (d, J = 5.0 Hz, 1H), 4.49 (d, J = 5.0 Hz, 1H), 4.92 (dd, J = 10.3,
4.9 Hz, 1H), 5.28 (dd, J = 10.3, 8.7 Hz, 1H), 5.33 (dd, J = 8.7, 4.9
Hz, 1H), 7.27–7.56 (m, 8H), 7.94 (dd, J = 8.3, 1.4 Hz, 2H).
13C NMR (CDCl3, 75.4 MHz): d = 14.1, 22.6, 26.2, 29.1, 31.8, 32.8,
57.0, 63.3, 68.4, 68.8, 70.6, 70.9, 127.6, 128.5, 128.9, 129.7, 129.8,
133.3, 136.6, 166.6, 175.7.
13C NMR (CDCl3, 75.43 MHz): d = 32.3, 32.7, 53.8, 63.4, 67.0,
70.6, 125.9, 127.5, 128.2, 128.3, 128.5, 128.9, 129.4, 133.3, 137.5,
141.5, 147.0, 166.4, 173.4.
Anal. calcd for C28H27NO4: C, 76.17; H, 6.16; O, 14.49 Found: C,
75.78; H, 6.24; N, 14.63.
Bishydroxylation of Lactams 7; General Procedure
To a mixture of N-methylmorpholine oxide hydrate (0.212 g, 1.57
mmol) and OsO4 (0.10 g of a 2.5% solution in t-BuOH, 0.02 mmol)
in acetone (7.5 mL) and H2O (15 mL) was added the unsat. lactam
7 (1.0 mmol). The mixture was stirred at r.t. for 48 h and the solution
was treated with 1 N NaHSO3 solution (1 mL) and neutralized to pH
7 with a 1 N H2SO4 solution. The mixture was saturated with NaCl
before extraction with EtOAc. The organic phase was dried
(MgSO4) and the solvent removed in vacuo. The crude reaction
mixture was purified by flash chromatography on silica gel.
Anal. calcd for C26H33NO6◊0.5H2O: C, 67.22, H, 7.38, O, 22.38;
Found: C, 67.08, H, 7.47, O, 21.86.
(2R)-2-{(3S,4S)-3,4-Dihydroxy-(2R)-2-[(1R)-1-hydroxy-3-phe-
nylpropyl]-5-oxopyrrolidin-1-yl}-2-phenylethylbenzoate (8d)
From 7d (0.47 mmol, >95% de), 0.190 g of 8d (85%, >95% de) was
obtained as an oil, after purification on silica gel (CH2Cl2/MeOH,
90:10; [a]D +132.0 (c = 1.14, MeOH)..
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IR (film): n = 3400, 3055, 2972, 1720, 1448, 1265, 859, 743 cm–1.
(2R,3S,4S)-2-[(1R)-1-Hydroxyethyl]-1-[(1R)-2-hydroxy-1-phe-
nylethyl]-3,4-(2,2-dimethyl-1,3-dioxolyl)pyrrolidine (10a)
From lactam 9a (220 mg, 0.52 mmol, 70% de), pyrrolidine 10a (115
mg, 72%, >95% de) was obtained after separation from minor dias-
tereomer by flash chromatography on silica gel (CH2Cl2/MeOH,
96:4) as a colorless oil; [a]D –21.2 (c = 0.7, CHCl3).
1H NMR (CDCl3, 300 MHz): d = 1.51–1.68 (m, 2H), 2.16 (bd, J =
4.6 Hz, 1H), 2.23 (m, 1H), 2.63 (ddd, J = 13.9, 9.7, 5.4 Hz, 1H), 2.88
(br s, 1H), 3.38 (br s, 1H), 3.45 (m, 1H), 3.62 (d, J = 5.0 Hz, 1H),
4.26 (d, J = 5.0 Hz, 1H), 4.41 (m, 1H), 4.93 (dd, J = 10.0, 4.3 Hz,
1H), 5.36 (m, 2H), 6.97 (d, J = 6.6 Hz, 2H), 7.21–7.53 (m, 11H),
7.92 (d, J = 7.0 Hz, 2H).
MS (CI): m/z = 308.
13C NMR (CDCl3, 75.4 MHz): d = 33.5, 35.4, 57.5, 63.9, 69.0, 69.9,
70.6, 71.8, 126.7, 128.8, 129.2, 129.4, 129.8, 130.6, 134.2, 138.3,
142.9, 167.8, 177.0.
IR (film): n = 3394, 2982, 2933, 1377, 1209 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.3 (d, J = 5.4 Hz, 3H), 1.25 and
1.5 (2 s, 2 î 3H), 2.88 (dd, J = 6.1, 4.1 Hz, 1H), 2.95 (d, J = 6.1 Hz,
1H), 3.4 (m, 2H), 3.8 (d, J = 5.2 Hz, 2H), 4.4 (t, J = 5.2 Hz, 1H),
4.45 (d, J = 6.0 Hz, 1H), 4.6 (m, 1H), 7.3 (m, 5H).
HRMS (CI, CH4): m/z calcd for C28H30NO6 476.2063; found:
476.2061.
13C NMR (CDCl3, 75 MHz): d = 19.7, 23.9, 26.9, 54.2, 64.8, 65.7,
(2R)-2-{Tetrahydro-(4R)-4-[(1R)-1-hydroxyethyl)-2,2-dimeth-
yl-(1S,3R)-(1,3)-dioxolo[4,5-c]-6-oxopyrrol-5-yl]-2-phenylethyl-
benzoate (9a)
A solution of the diastereomeric mixture 8a (0.45 g, 1.17 mmol,
70% de), 2,2-dimethoxypropane (1.44 mL, 11.68 mmol), p-TsOH
(20 mg) in acetone (5 mL) was stirred at r.t. for 1.5 h. The mixture
was diluted with EtOAc and washed with sat. aq NaHCO3 solution,
then dried (MgSO4) and the solvent was evaporated. The acetonide
9a (495 mg, 99%, 70% de) was obtained as a yellow solid and used
without purification in the next step.
IR (film): n = 1685, 1719, 3425 cm–1.
MS(CI): m/z = 426 (MH+).
1H NMR (CDCl3, 300 MHz): (major isomer) d = 0.9 (d, J = 6.4 Hz,
3H), 1.2 and 1.3 (2 s, 6H), 3.9 (m, 2H), 4.8 (d, J = 5.4 Hz, 1H), 4.85
(J = 5.4 Hz, 1H), 4.9 (dd, J = 10.7, 4.7 Hz, 1H), 5.1 (m, 2H).
68.1, 73.2, 82.0, 83.9, 111.9, 128.0, 128.9, 129.0, 140.7.
Anal. calcd for C17H25NO4◊0.25H2O: C, 65.47; H, 8.24; N, 4.49;
Found: C, 65.43; H, 7.92; N, 4.68.
(2R,3S,4S)-2-[(1R)-1-Hydroxyheptyl]-1-[(1R)-2-hydroxy-1-
phenylethyl]-3,4-dihydroxypyrrolidine (10c)
From lactam 8c (120 mg, 0.36 mmol), pyrrolidine 10c (74 mg, 81%)
was obtained as an amorphous solid; [a]D –54.6 (c = 1.17, MeOH).
1H NMR (CDCl3, 300 MHz): d = 0.95 (m, 3H), 1.42–1.77 (m, 10H),
2.64 (t, J = 8.9 Hz, 1H), 2.96 (m, 2H), 3.55 (m, 1H), 3.78 (m, 1H),
3.91 (m, 1H), 4.03 (m, 2H), 4.16 (m, 1H), 7.25-7.48 (m, 5H).
13C NMR (CDCl3, 75 MHz): d = 14.5, 23.7, 27.5, 30.5, 33.1, 35.1,
53.2, 64.6, 69.4, 73.2, 74.0, 75.1, 128.5, 129.2, 130.2, 139.4.
IR (film): n = 3376, 2929, 1630, 1422, 1270, 1090, 738, 704 cm–1.
MS (CI): m/z = 338 (MH+), 228, 196.
13C NMR (CDCl3, 75 MHz): (major isomer) d = 17.6, 25.4, 26.6,
57.0, 63.1, 66.1, 74.4, 77.4, 111.5, 127.7, 128.0, 128.3, 128.7,
129.7, 133.2, 136.5, 166.4, 173.0.
(2R,3S,4S)-2-[(1R)-4-Chloro-1-hydroxybutyl]-1-[(1R)-2-hy-
droxy-1-phenylethyl]-3,4-(2,2-dimethyl-1,3-dioxolyl)pyrroli-
dine (10b)
Anal. calcd for C24H27NO6: C, 67.75; H, 6.40; N, 3.04; Found: C,
67.62; H, 6.31; N, 3.29.
To a solution of lactam 9b (0.25 g, 0.51 mmol) in THF (10 mL) was
added a 1 M THF solution of BH3 (1.53 mL, 1.53 mmol). The mix-
ture was heated to reflux under an argon atmosphere for 5 h, cooled
to r.t. and quenched with an excess of MeOH and evaporated to dry-
ness. The residue was dissolved in CH2Cl2 (10 mL) and H2O was
added (10 mL) and the two phase system stirred for 2 h. The organic
phase was decanted and the aqueous phase extracted several times
with CH2Cl2. The combined organic phases were evaporated to dry-
ness. The residual solid was dissolved in 2% NaOH solution in
MeOH (10 mL) and stirred for 15 min. The solvent was removed in
vacuo and the residue dissolved in CH2Cl2. The organic phase was
washed with H2O, dried (MgSO4) and the solvent was removed in
vacuo and the crude reaction mixture purified by flash chromatog-
raphy on silica gel (MeOH/CH2Cl2, 2:98) to give 10b as a colorless
oil (136 mg, 72%); [a]D –38.3 (c = 0.5, CHCl3).
(2R)-2-{Tetrahydro-(4R)-4-[(1R)-4-chloro-1-hydroxybutyl]-
2,2-dimethyl-(1S,3R)-(1,3)-dioxolo[4,5-c]-6-oxopyrrol-5-yl}-2-
phenylethylbenzoate (9b)
By using the same protocol, acetonide 9b was obtained (544 mg,
99%, 80% de) from 8b (500 mg, 1.12 mmol, 78% de).
1H NMR (CDCl3, 300 MHz): (major isomer) d = 1.0 and 1.2 (2 s,
6H), 1.2 (m, 4H), 1.7 (m, 1H), 3.1 (t, J = 6.0 Hz, 2H), 3.2 (m, 1H),
3.9 (d, J = 4.3 Hz, 1H), 4.8 (d, J = 5.5 Hz, 1H), 4.85 (J = 5.5 Hz,
1H), 4.9 (dd, J = 11.3, 5.6 Hz, 1H), 5.2 (dd, J = 11.3, 9.0 Hz, 1H),
5.35 (dd, J = 9.0, 5.6 Hz, 1H), 7.0–8.0 (m, 10H).
13C NMR (CDCl3, 75 MHz): (major isomer) d = 25.3, 26.5, 28.6,
29.1, 44.3, 55.9, 62.6, 65.3, 69.7, 74.4, 77.3, 101.6, 127.7, 128.3,
128.5, 128.8, 129.7, 133.3, 136.7, 166.4, 173.1.
MS (CI): m/z = 370, 372 (MH+).
IR (film): n = 1682, 1721, 3390 cm–1.
MS(CI): m/z = 488, 490 (MH+).
1H NMR (CDCl3, 250 MHz): d = 1.2 (s, 3H), 1.4–1.55 (m and s,
4H), 1.75–1.95 (m, 2 H), 1.95–2.1 (m, 1 H), 2.8 (dd, J = 14.3, 4.3
Hz, 1 H), 2.9 (d, J = 14.3 Hz, 1 H), 3.15 (dt, J = 6.2, 1.4 Hz, 2 H),
3.4 (d, J = 10.0 Hz, 1 H), 3.55 (m, 2 H), 3.75 (d, J = 6.0 Hz, 2 H),
4.35 (t, J = 4.6 Hz, 1 H), 4.4 (d, J = 6.1 Hz, 1 H), 4.55 (t, J = 4.5 Hz,
1H), 7.0–8.0 (m, 5 H).
13C NMR (CDCl3, 62.5 MHz) d = 23.59, 26.60, 29.10, 31.15, 45.19,
54.02, 65.59, 67.38, 68.06, 71.56, 81.87, 83.84, 111.62, 127.80,
128.68, 140.32.
Anal. calcd for C26H30ClNO6: C, 64.00; H, 6.20; N, 2.87; Found: C,
63.88; H, 6.07; N, 2.81.
LiAlH4 Reduction of Lactams 8c and 9a; General Procedure
To a stirred suspension of LiAlH4 (200 mg, 5.2 mmol) in anhyd
THF (10 mL) was added the appropriate lactam 8c or 9a (0.52
mmol) and the mixture was allowed to stir at r.t. for 12 h. The mix-
ture was treated sequentially with H2O (0.25 mL), aq 15% NaOH
solution (0.25 mL) and H2O (0.5 mL). The mixture was filtered on
a Celite pad and the Celite rinsed with Et2O. The filtrate was dried
(MgSO4) and the solvent removed in vacuo. Purification by flash
chromatography on silica gel afforded diastereomerically pure 10.
Anal. calcd for C19H28ClNO4: C, 61.70; H, 7.63; N, 3.79; Found: C,
61.62; H, 7.73; N, 3.53.
Synthesis 1999, No. 4, 688–694 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Routes Towards Polyfunctionalized Pyrrolidines
693
(2R,3S,4S)-1-[(1R)-2-Hydroxy-1-phenylethyl]-2-[(1R)-1-hy-
droxy-3-phenylpropyl]-3,4-dihydroxypyrrolidine (10d)
A 1 M solution of BH3◊THF (0.5 mL, 0.5 mmol) was slowly added
at r.t. to a solution of lactam 8d (40 mg, 0.085 mmol) in anhyd THF
(1.5 mL). The mixture was heated at 50 °C for 8 h, cooled to r.t. and
stirred for an additional 15 h. The reaction was quenched by the ad-
dition of 1 N NaOH (1 mL) at 0 °C and then extracted with EtOAc.
The solvent was removed in vacuo and the residue dissolved in 5 N
methanolic NaOH solution (5 mL). The solution was stirred at r.t.
overnight and after evaporation of the solvent, the residue was dis-
solved in H2O and extracted with EtOAc. After drying (MgSO4), the
solvent was removed in vacuo and purified by flash chromatogra-
phy to give pyrrolidine 10d (27 mg, 90%); [a]D –58 (c = 1.12,
MeOH).
HRMS (CI, CH4): m/z calcd for C11H24NO3Cl : 218.1756; Found:
218.1751.
(2R,3S,4S)-2-[(1R)-1-Hydroxy-3-phenylpropyl]pyrrolidine-3,4-
diol Hydrochloride (11d-HCl)
From 10d (27 mg, 0.075mmol), 11d-HCl was obtained as a white
powder (20 mg, 98%); [a]D +9.0 (c = 1.85, MeOH).
IR (film): n= 3374, 2946, 2835, 2214, 1654, 1449 cm–1.
1H NMR (CD3OD, 250 MHz): d = 1.97 (m, 2H), 2.78 (ddd, J = 13.5,
9.4, 7.0 Hz, 1H), 2.94 (ddd, J = 13.5, 9.4, 5.6 Hz, 1H), 3.31–3.42
(m, 3H), 3.46 (m, 1H), 3.91 (m, 1H), 4.20 (dd, J = 8.4, 3.8 Hz, 1H),
4.30 (bs, 1H), 7.23–7.43 (m, 5H).
13C NMR (CD3OD, 62.5 MHz): d = 32.6, 38.0, 51.2, 66.9, 68.2,
71.3, 74.0, 127.0, 129.5, 142.8.
IR (film): n = 3376, 2929, 1630, 1422, 1270, 1090, 738, 704 cm–1.
MS (CI, NH3): m/z = 358 (MH+).
HRMS (CI, CH4): m/z calcd for C13H20NO3 : 238.1432; Found:
238.1443.
1H NMR (CDCl3 300 MHz): d = 1.76–1.85 (m, 1H), 2.03–2.12 (m,
1H), 2.64 (t, J = 8.8Hz ,1H), 2.77 (m, 1H), 2.96 (m, 1H), 3.04 (m,
1H), 3.11 (dd, J = 5.7, 1.0 Hz, 1H), 3.57 (ddd, J = 11.2, 5.7, 2.2 Hz,
1H), 3.70 (m, 1H), 3.88 (dd, J = 4.7, 1.0 Hz,1H), 4.00 (m, 2H), 4.11
(ddd, J = 4.7, 4.4, 1.4 Hz, 1H), 7.15–7.48 (m, 10H).
13C NMR (CDCl3, 75 MHz): d = 33.4, 36.8, 53.2, 64.6, 69.5, 71.7,
73.0, 73.3, 74.8, 126.8, 128.5, 129.2, 129.4, 129.6, 130.1, 139.4,
143.6.
(1S,2R,8R,8aS)-1,2-O-Isopropylideneoctahydro-1,2,8-indoliz-
idinetriol (12)
Pyrrolidine 10b (60 mg, 0.168 mmol) was dissolved in MeOH (10
mL) and stirred under an H2 atmosphere at 1 bar and in the presence
of Pd(OH)2/C (20 mg, 28 mmol) and NaOAc (40 mg, 0.49 mmol) for
8 h. The mixture was filtered on a Celite pad and the solvent re-
moved under vacum (without heating since the product sublimes
quite easily). Indolizidine 12 was obtained as a white solid (22 mg,
65%) after flash chromatography on silica gel (MeOH/CH2Cl2,
8:92); [a]D –48.8 (c = 0.5, CHCl3) (Lit 13c [a]D 54.0 (CHCl3) for the
enantiomer).
Anal. calcd for C21H27NO4•0.5 H2O: C, 68.81; H, 7.71; N, 3.82
Found: C, 68.69; H, 8.04; N, 3.56.
Debenzylation of Pyrrolidines 10; General Procedure
A solution of pyrrolidine 10 (0.2 mmol) in MeOH (3 mL) contain-
ing 20% Pd(OH)2/C (20 mg, 28 mmol) was stirred under H2 (1 atm)
for 3 h. The mixture was filtered and the catalyst was washed with
MeOH (5 mL). The filtrate was acidified by the addition of 1 M HCl
(2 mL) and stirred at r.t. for 1.5 h. The solvent was evaporated under
reduced pressure and the white residue washed several times with
small amounts of Et2O. Extensive drying under vacum gave poly-
hydroxylated pyrrolidine as a white powder.
Anal. calcd for C11H19NO3: C 61.95, H 8.98, N 6.57 Found: C
61.73, H 8.31, N 6.43.
All other analytical data are identical to those reported in the litera-
ture.13c
Acknowledgement
The authors thank Prof. H.-P. Husson for helpful discussions.
(2R,3S,4S)-2-[(1R)-1-Hydroxyethyl]pyrrolidine-3,4-diol Hy-
drochloride (11a-HCl)
From 10a (60 mg, 0.2 mmol), 11a-HCl was obtained as a white
powder (34 mg, 99%); [a]D +54.0 (c = 0.4, EtOH).
1H NMR (CD3OD, 250 MHz): d = 1.2 (d, J = 6.3 Hz, 3H), 3.15 (m,
3H), 3.88 (dq, J = 6.3, 5.3 Hz, 1H), 4.02 (dd, J = 8.2, 4.0 Hz, 1H),
4.14 (m, 1H).
13C NMR (CD3OD, 62.5 MHz): d = 18.3, 58.2, 65.5, 67.4, 71.3,
73.8.
MS (FAB): m/z = 148 (MH+).
References
(1) (a) Elbein, A.; Molyneux, R. J. In Alkaloids, Chemical and
Biological Perspectives, Vol.V, Pelletier, S. W., Ed.; Wiley:
New York, 1990, pp 1–54.
(b) Look, G. C.; Fotsch, C. H.; Wong, C. H. Acc. Chem. Res.
1993, 26, 182.
(2) For a review see: Casiraghi, G.; Zanardi, F; Rassu, G; Spanu,
P. Chem. Rev. 1995, 95, 1677.
(3) More recent syntheses include:
(a) Ryu, Y.; Kim, G. J. Org. Chem. 1995, 60, 103.
(b) Marek, D.; Wadouachi, A.; Uzan, R.; Beaupere, D.;
Nowogrocki, G.; Laplace, G. Tetrahedron Lett. 1996, 37, 49.
(c) Rodriguez, R., Bermejo, F. Tetrahedron Lett. 1996, 37,
5581.
(d) Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.;
Romagnoli, R.; Zanirato, V. Tetrahedron Lett. 1996, 37, 7599.
(e) Moreaux, V.; Warren, H.; Williams, J. M. Tetrahedron
Lett. 1997, 38, 4455.
(f) McCort, I.; Duréault, A.; Depezay, J.-C. Tetrahedron Lett.
1998, 39, 4463.
(g) Godskesen, M.; Lundt, I. Tetrahedron Lett. 1998, 39,
5841.
Anal. calcd for C6H14ClNO3: C, 39.24, H, 7.69; N, 7.63; Found: C,
38.87; H, 7.45; N, 7.37.
(2R,3S,4S)-2-[(1R)-1-Hydroxyheptyl]pyrrolidine-3,4-diol Hy-
drochloride (11c-HCl)
From 10c (70 mg, 0.21 mmol), 11c-HCl was obtained as a white
powder (45 mg, 99%); [a]D –2.0 (c = 1.0, MeOH).
IR (film): n = 3362, 2946, 2834, 1654, 1450, 1114, 1027 cm–1.
MS (CI, CH4): m/z = 318 (MH+), 314, 300, 154.
1H NMR (CD3OD, 250 MHz): d = 1.7 (s, 3H), 2.1–2.57 (m, 10H),
3.87 (m, 2H), 4.12 (m, 1H), 4.22 (m, 1H), 4.53 (m, 1H), 4.63 (m,
1H), 5.1 (m, 1H), 5.13 (m, 1H).
(h) Blanco, M.-J.; Sardina, F. J. J. Org. Chem. 1998, 63, 3411.
(4) Meyers, A. I.; Andres, C. J.; Resek J. E.; McLaughlin, M. A.;
Woodall, C. C.; Lee, P. H. J. Org. Chem. 1996, 61, 2586.
13C NMR (D2O, 62.5 MHz): d = 15.5, 23.0, 26.6, 30.3, 33.1, 35.5,
61.2, 71.6, 72.1, 75.2, 78.3.
Synthesis 1999, No. 4, 688–694 ISSN 0039-7881 © Thieme Stuttgart · New York

694
B. Dudot et al.
PAPER
(5) Baussanne, I.; Chiaroni, A.; Husson, H.-P ; Riche, C.; Royer,
J. Tetrahedron Lett. 1994, 35, 3931.
(11) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 1973.
(6) Baussanne, I.; Royer, J. Tetrahedron Lett. 1996, 37, 1213.
(7) This strategy follows the pionnering work of Casiraghi and
Rassu which consisted of the condensation of achiral N-Boc-
2-(tert-butyldimethylsilyloxy)pyrrole and chiral aldehyde.
See Casiraghi, G.; Rassu, G. Synthesis 1995, 607.
(8) Eis, M. J.; Rule, C. J.; Wurzburg, B. A.; Ganem, B.
Tetrahedron Lett. 1985, 26, 5397.
(9) Under the same conditions O-methylated compound 3 reacted
with acetaldehyde to give 7a as a mixture of 4 compounds (51:
31: 8: 8), see Ref. 6.
(12) Ikota, N. Chem. Pharm. Bull. 1992, 40, 1925.
(13) for syntheses of 8a-epi-swainsonine, see:
(a)Tadano, K.; Hotta, Y.; Morita, M.; Suami, T.; Winchester,
B.; Centi di Bello, I. Bull. Chem. Soc. Jpn. 1987, 60, 3667.
(b) Kim, Y. G.; Cha, J. K. Tetrahedron Lett. 1989, 30, 5721.
(c) Keck, G. E.; Romer, D. R. J. Org. Chem. 1993, 58, 6083.
(14) Correia, C. R.; de Faria, A. R.; Carvalho, E. S. Tetrahedron
Lett. 1995, 36, 5109.
Synthesis 1999, No. 4, 688–694 ISSN 0039-7881 © Thieme Stuttgart · New York