Diastereoselective synthesis of (2S,3S,4S)-3-hydroxy-4-methylproline, a common constituent of several antifungal cyclopeptides

Article abstract of DOI:10.1016/S0040-4020(00)00117-4

(2S,3S,4S)-3-Hydroxy-4-methylproline 2 was synthesized from unsaturated γ-lactams 4 and 5 derived from (S)-pyroglutaminol. Starting from 5, haplophilic effect in the hydrogenation of a 4-exo-methylenic intermediate improved the diastereoselectivity of the synthesis, which was achieved in 19% yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00117-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2437–2448
Diastereoselective Synthesis of
(2S,3S,4S)-3-Hydroxy-4-methylproline,
a Common Constituent of Several Antifungal Cyclopeptides
*
Nicole Langlois and Felaniaina Rakotondradany
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 20 December 1999; accepted 7 February 2000
Abstract—(2S,3S,4S)-3-Hydroxy-4-methylproline 2 was synthesized from unsaturated g-lactams 4 and 5 derived from (S)-pyroglutaminol.
Starting from 5, haplophilic effect in the hydrogenation of a 4-exo-methylenic intermediate improved the diastereoselectivity of the synthesis,
which was achieved in 19% yield. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
albicans and Pneumocystis carinii.2,3 Numerous antifungal
semi-synthetic analogues of these lipopeptides retain HMP
as an aminoacid unit, particularly those containing a
modified polyaromatic side chain like LY303366 3 and its
derivatives.4
Echinocandins 1, isolated from Aspergillus, as well as some
related cyclohexapeptides (pneumocandins A, sporiofungin
A, mulundocandins), are constituted by five a-amino-b-
hydroxy acids including (2S,3S,4S)-3-hydroxy-4-methyl-
proline 2 (HMP), by ornithine or its 4,5-dihydroxy deriva-
tive, and by an acid with a lipophilic long chain (R3).1,2
They are inhibitors of 1,3-b-d-glucan synthase and exhibit
interesting specific fungicidal activities against Candida
Two syntheses of 2,5,6 and a synthesis of its methyl ester
hydrochloride,7 have already been described before this
study. As part of our program on the synthesis of bioactive
products from easily available (S)-pyroglutamic acid or
Scheme 1.
Keywords: 3-hydroxy-4-methylproline; antifungals; (S)-pyroglutaminol; nitrone [3ϩ2] cycloaddition; Cope elimination; stereoselective hydrogenation.
* Corresponding author. Tel.: ϩ33-1-69-82-30-68; fax: ϩ33-1-69-07-72-47; e-mail: nicole.langlois@icsn.cnrs-gif.fr
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00117-4

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N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
Scheme 2.
(S)-pyroglutaminol,8 several synthetic ways towards HMP,
starting from the g-lactams 4 or 5, were studied and our
main results are presented here (Scheme 1).9
The yield of this alkylation could be improved to 80% by
using a large excess of reagents (4 equiv. LDA, 4 equiv.
HMPA, 10 equiv. MeI), at the same temperature. However,
an inseparable mixture of 8 and dimethyl compound 9 was
obtained under these conditions. In the 1H NMR spectrum of
9, the additional methyl group gave rise to a singlet at
1.92 ppm indicating a quaternary bearing carbon. A depro-
tonation at the benzylic position of N-benzylpyrrolidin-2-
ones has been observed already18 and the formation of 9
could be explained by the loss of the proton at C-2. In our
case, noteworthy is the fact that only one diastereomer of the
dialkylated product was detected and its configuration at
C-2 (2R) was supported by NOESY data of the cis deriva-
tive 11 (see below). Since the N,O-protecting oxazolidine
will be removed, the lack of regiocontrol in this methylation
step was not a real drawback.
Results and Discussion
Sequential introduction of hydroxy and methyl groups
The first route involved sequential introduction of the
hydroxy and methyl groups on the bicyclic unsaturated
lactam 4 (Scheme 2). The g-lactam 4 was easily prepared
from (S)-pyroglutaminol,10 and its interest in the synthesis
of various enantiopure compounds was widely demon-
strated.11 Indeed, the rigid backbone of 4 induced a high
diastereoselectivity in several addition reactions on the
convex side of the molecule.11–13 Particularly, the epoxi-
dation of 48e was shown to be diastereospecific under the
conditions developed by Herdeis et al., and the epoxide 6
could be isolated in 87% yield.14 Furthermore, an efficient
and regiospecific cleavage of this oxirane with SmI2 was
carried out in our laboratory, leading to the (6S)-6-hydroxy
derivative 7 in 95% yield.8g The alcohol 7 therefore was
deprotonated and methylated at C-7 (Scheme 2). Obviously,
a-alkylation of dianions from b-hydroxy esters,15
lactones,16 and lactams17 are known to occur with high
trans diastereoselectivity, and the lithium enolate of the
resulting methylated product 8 was anticipated to be repro-
tonated with the same stereoselectivity to afford the desired
cis-6,7-disubstituted derivative 10. Thus, the dianion
obtained from 7 (LDA–THF–HMPA, Ϫ78ЊC) was alky-
lated with methyl iodide in excess (6 equiv.), giving rise
to trans derivative 8 (68%) as a single diastereomer.9 In
1H NMR, the observation of a nOe between the protons
H-7 and H-5 allowed to confirm the C-7 configuration.
To complete the synthesis of 2, the configuration of the
centre C-7 of 8 has to be inverted. The treatment of 8
with LDA–THF–HMPA, followed by quenching at
Ϫ78ЊC with pivaloic acid, afforded, in 73% yield, a separ-
able mixture (ca. 1:1) of 8 and cis diastereomer 10. Thus, the
epimerisation of 8 took place only in modest yield. Albeit
retro-aldolisation could not be excluded in this reaction, the
initial configuration at C-6 (6S) was retained. On the basis of
a deprotonation–protonation sequence, this result could be
explained by a competition between the trans orientation
induced by the vicinal alkoxide and an exo-protonation on
the less hindered convex face of the molecule, but this result
remains surprising owing to previous data. Studies of alky-
lations of a series of bicyclic g-lactams showed that the
diastereofacial selectivities are governed by electronic or
steric control depending upon the type and the position of
substituents.19 In the particular case of electrophilic
additions to the lithium enolate of the related bicyclic

N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
2439
Scheme 3.
g-lactam 12, the selectivity depends also upon the electro-
phile.10a,20 An endo-selectivity was observed in the electro-
philic addition of methyl iodide or proton, the nitrogen lone
pair directing the addition of these small electrophiles.20b
The nitrogen configurations in 8 and 12 were postulated to
be the same. Thus, a more selective endo kinetic protonation
of the lithium enolate from 8 to the cis derivative 10,
favoured by several factors, could be expected. The mixture
(8ϩ9) in the same conditions led to the mixture (10ϩ11,
44%) by partial epimerisation at C-7 (recovered 8ϩ9: 32%).
The compound 11 gave NOESY cross peaks between H-5
and CH3-7, H-7 and H-6 and between H-4 (endo) and H-6 as
well as CH3-2, supporting the configurations 2R, 6S, 7R
(Scheme 2).
lack of stereoselectivity in the deprotonation–protonation
sequence led us to research another route.
Cycloadduct of N-methylnitrone as an intermediate
It was anticipated that the hydroxy group of HMP 2 and
additional carbon of its methyl group could be both intro-
duced through 1,3-dipolar cycloaddition of methylnitrone to
the a,b-unsaturated g-lactam 5, which is conveniently
N-protected for final steps.12 A 3-(N-methyl)aminomethyl
derivative was expected to be formed by hydrogenolysis
of the N–O bond, allowing a subsequent conversion into a
methyl group after suitable protection of the vicinal hydroxy
group (Scheme 4).23
A synthesis of HMP 2 was achieved from the mixture
(10ϩ11) without separation as depicted in Scheme 3.9
Reduction with BH3-DMS led to the N-benzyl pyrrolidines
13 and 14 in 86% yield and a X-ray analysis of 14 confirmed
the previous deductions from the NOESY data of its pre-
cursor 11.21
The regio- and stereo-selective [3ϩ2] cycloaddition of
N-methylnitrone to the unsaturated pyrrolidinone 5 was
performed by heating in toluene at 110ЊC. During our pre-
liminary work,12 the N-methylnitrone was prepared as
described,24 except that benzene was replaced by toluene.
The cycloadducts were isolated in this case in 59% yield
(54% of 19 and 5% of the regioisomer), owing to com-
petitive conjugate addition (15%) of N-methylhydroxyl-
amine present in the reaction medium. The preparation of
N-methylnitrone with an excess of paraformaldehyde with
regard to N-methylhydroxylamine hydrochloride, and the
use of a slight excess of nitrone in the cycloaddition
(1.33 equiv., heating for 2 h) improved the yield of 19,
which was isolated (70%) together with the regioisomer
(9%), whereas the 1,4-addition product of N-methylhydroxyl-
amine was not detected. Unlike observed under other
Hydrogenolysis of the mixture (13ϩ14) and N-protection
with (Boc)2O furnished the N-Boc pyrrolidine 15 (92%).
The corresponding disilylated derivative 16 (75%) was
selectively deprotected into the primary alcohol 17 (70%)
which was oxidised under Sharpless conditions into 18
(80%).22 HMP 2 hydrochloride was then obtained in 90%
yield after acid hydrolysis with 6N HCl.
The steps leading from 15 to 18 were not optimised since the
Scheme 4.

2440
N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
Scheme 5.
conditions,13 the stereogenic centre of 5 (C-5) was
unaffected in this reaction. Thus, the enantiopurity of the
compound 19 was established after deprotection into the
primary alcohol 20 and preparation of the corresponding
Mosher’s esters. Several reagents were tested to cleave
between the substituents at C-3 and C-4 in 23a was
supported by the strong nOe between H-3 and H-4, while
in 23b, a nOe was observed between the methyl group and
1
H-4 and between H-4 and H-6. The H and 13C chemical
shifts of the methyl groups and adjacent H-3 are rather
different in the diastereomers a and b and characteristic of
the configuration at C-3 centre. In the cases of 21 and 23, the
cis diastereomers a were the major products of a deproto-
nation–protonation sequence with a ratio a:b about 2:1.
25
isoxazolidine N–O bond. Mo(CO)6 was inefficient and
the use of TiCl326 led only to the primary alcohol deprotec-
tion. In the major product obtained by the treatment of 19
with Raney nickel, the N-protective group was removed,
probably through the complexation of the two carbonyls
(Scheme 5).
For the next steps, a convenient protection of the hydroxy
group at C-4 was needed to allow a further selective depro-
tection of the primary alcohol and its oxidation into a
carboxyclic acid. Attempts to prepare the tert-butyldi-
methylsilyl derivative of 23 under the classical conditions
(t-BuMe2SiCl, Im, DMF)27 gave only moderate yield (50%).
The sensitivity of N-Boc-4-hydroxypyrrolidin-2-ones deriva-
tives towards b-elimination could be a drawback in this
protection step. For this reason, the lactams 21 were reduced
before the protection of the secondary hydroxy group. The
straightforward sequence depicted in the Scheme 5 was
applied to the mixture 21aϩ21b obtained from 19, without
separation of the intermediates leading to 25 and 26.
Finally, the isoxazolidine 19 was successfully hydro-
genolyzed over Pearlman’s catalyst into a complex mixture
after 16 h, which, by prolonged time of reaction (50 h),
gave rise to 3-methyl derivatives 21a and 21b in 72%
yield (Scheme 5). The ratio 21a:21b was evaluated as 2:3
by comparison of H-3 signals in 1H NMR. Thus, the
cleavage of the N–O bond was followed, under these con-
ditions, by elimination of methylamine and subsequent
hydrogenation. Similar results were obtained with the
acetate 22 which led to 23a and 23b (73%, total yield) in
the same ratio 2:3, determined by 1H NMR. A cis relationship
Scheme 6.

N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
2441
Scheme 7.
Accordingly, partial reduction of 21 with DIBAL-H28 led to
24 (98% yield) which was directly benzoylated. Subsequent
reduction with NaBH3CN in acetic acid, and concomitant
removal of EVE protection afforded the substituted pyrro-
lidines 25 and 26 (Scheme 5). The diastereomers 25 and 26
were separated by chromatography on silica gel with 32 and
36% overall yield, respectively, for the two steps. These
compounds gave poorly resolved 1H NMR spectra, presum-
ably due to conformational flexibility, but all other data
were fully consistent with these structures. The configu-
rations assigned at C-4 were confirmed by the conversion
of these alcohols into the amino acids 2 and 29 hydro-
chlorides (Scheme 6).
following step.31 Hydrogenolysis of the ammonium salt 32
in the presence of Pd(OH)2 afforded quantitatively the
dimethylaminomethyl derivative 33 as its methylsulfate
salt, which was converted to the base (97%) and then to
the benzoate 34 (93%). The compound 34 was in turn
oxidized into its N-oxide 35 (m-CPBA, 98%) which was
submitted to a Cope elimination by heating at 85ЊC in a
diluted mixture of THF and toluene (1:1) to furnish 36
(87%).32
It is known that the presence of some neighbouring groups,
particularly hydroxy groups can be responsible of the
stereoselectivity observed in heterogeneous catalytic hydro-
genation. This so-called ‘haplophilicity’ of hydroxy or
hydroxymethyl groups lead to addition of hydrogen from
the same face as these polar substituents.29,33 Thus, a selec-
tive reduction of the acetate in 36 was attempted with
DIBAL-H to perform a selective deprotection of the primary
alcohol, since benzoates can be stable in the presence of this
reagent. It gave rise to a mixture, from which 37 was
isolated in only 30% yield, together with 50% starting 36.
The primary alcohol of 36 was selectively deprotected to 37
more efficiently by smooth alkaline hydrolysis (0.05N
NaOH, MeOH, 72%) which was quenched by dilution
before completion, to minimise the formation of diol 38.
Hydrogenation of the methylenic compound 37 in EtOAc,
either with 10% Pd/C or PtO2 as catalyst, led to the 3,4-cis
derivative 25 as the major product. The last conditions using
PtO2 gave the best result and led to the diastereomer 25,
precursor of HMP 2, in 79% yield (Scheme 7).
This conversion was carried out by Sharpless oxidation of
25 and 26 respectively into 27 (88%) and 28 (75%),
followed by quantitative deprotection to 2 and 29 by heating
in 6 N HCl. Thus, the synthesis of 2, HCl from 5 could be
achieved in ca. 14% yield, despite the lack of selectivity in
the formation of the stereocentre bearing the methyl group.
This successful completion of the synthesis of 2 encouraged
us to seek conditions improving this stereoselectivity. Thus,
it was anticipated that the lactam carbonyl of the cyclo-
adduct 19 could be reduced at an early stage of the synthesis
to control the further methylamino group elimination. This
step could be followed by a stereoselective hydrogenation of
the resulting exo-methylene at C-4 controlled by a ‘haplo-
philic’ effect29 (Scheme 7).
Accordingly, 19 was successively reduced by DIBAL-H and
NaBH3CN in acetic acid to afford quantitatively the pyrro-
lidine 30 (Scheme 7). The primary alcohol was protected as
acetate (31, 78%). A protection as tert-butyldimethylsilyl
ether was avoided because this protecting group could be
unstable under hydrogenation conditions.30 The N-methy-
lation into 32 (92%) was then carried out with dimethyl-
sulfate, which gave better results than methyl iodide in the
Conclusion
HMP 2 was synthesized from either g-lactam 4 or 5, both
easily prepared from (S)-pyroglutaminol. The diastereo-
selectivity in the formation of C-4 stereogenic centre of 2
was improved by haplophilic effect in the hydrogenation of

2442
N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
the exo-methylenic compound 37. In this way, the synthesis
of 2 hydrochloride was achieved in 19% yield from 5.
CH3I. It led to 485 mg of a mixture of 8 and the dimethyl
derivative 9 (ratio about 3:7; ca. 80%) which could not be
1
separated. Data of 9: MS (EI): 247 (Mϩ⅐), 246. H NMR
(300 MHz): 7.46, 7.34 (H-Ar), 4.04 (dd, Ha-4), 3.80 (m,
Hb-4, H-6, H-5), 2.76 (m, H-7), 1.92 (s, CH3-2), 1.27 (d,
Jˆ7.5 Hz, CH3-7). 13C NMR (75.0 MHz): 173.28 (CO),
142.22 (qC, Ar), 95.03 (C-2), 80.00 (C-6), 67.81 (C-4),
65.17 (C-5), 49.17 (C-7), 26.02 (CH3-2), 12.51 (CH3-7).
Experimental
Melting points were taken on a Leitz microscope. Optical
rotations were measured on a Perkin–Elmer 241; the
concentrations in CHCl3 solution (unless otherwise indi-
cated) were given in g/100 mL. IR spectra (n cmϪ1
,
(2R,5R,6S,7R)-6-Hydroxy-7-methyl-2-phenyl-3-oxa-1-aza-
bicyclo[3.3.0.]octan-8-one 10. The compound 8 (40.8 mg,
0.17 mmol) in THF (0.67 mL) and HMPA (93 mL,
0.53 mmol) was added under Ar at Ϫ78ЊC to a solution of
LDA (0.52 mmol) in THF (0.45 mL). The mixture was
stirred at Ϫ78ЊC for 1 h and at Ϫ35ЊC for 1 h before
quenching with excess pivaloic acid. After addition of
Na2CO3 (10% v/w), extraction with Et2O and usual workup,
the products were separated by preparative TLC (eluent:
Et2O–EtOAc 6:4) to give 8 (14.8 mg, 36%) and 10
(15.2 mg, 37%) as white crystals. 10: Mp: 144–6ЊC,
[a]3D0ˆϩ206 (cˆ0.62). IR: 3688, 3608, 3420, 1709, 1603,
1450. MS (EI): 233 (Mϩ⅐), 232 (100%), 216, 203, 186, 176,
156, 148, 105, 91, 77. HRMS: Calcd for C13H15NO3 (Mϩ⅐):
233.1051. Found: 233.1019. 1H NMR (300 MHz): 7.37 (m,
5H, H-Ar), 6.35 (s, 1H, H-2), 4.38 (dd, 1H, J6,7ˆ7.5 Hz,
1
CHCl3) were recorded on a Nicolet 205 (FT). H NMR
spectra were obtained (CDCl3, Me4Si, dˆ0 ppm) from
Bruker AC250, AM300 or AM400 (s, d, t, dd and m
indicate singlet, doublet, triplet, doublet of doublets, and
multiplet respectively). 13C NMR spectra (d ppm relative
to the central signal of CDCl3 at 77.14 ppm) were recorded
on AC200 (50.0 MHz), AC250 (62.5 MHz) or AM300
(75.0 MHz). Mass spectra and high resolution mass spectra
(m/z) were respectively measured on an AEI MS50 or on a
Kratos MS80 spectrometer. Elemental analyses were
determined by the Microanalysis Laboratory at ICSN.
Flash chromatography was performed on silica gel (SDS
230–400 mesh) and preparative thin layer chromatography
on silica gel (Merck HF 254ϩ366). Usual workup means
that the organic layer was dried with magnesium sulfate,
filtered and evaporated under vacuum.
J5,6ˆ4.9 Hz, H-6), 4.23 (dd, 1H, J4a,4bˆ8.4 Hz, J4a,5
ˆ
6.8 Hz, Ha-4), 3.98 (ddd, 1H, J4a,5ϳJ4b,5ˆ6.8 Hz,
J5,6ˆ4.9 Hz, H-5), 3.69 (dd, 1H, J4a,4bˆ8.4 Hz, J4b,5
ˆ
(2R,5R,6S,7S)-6-Hydroxy-7-methyl-2-phenyl-3-oxa-1-aza-
bicyclo[3.3.0.]octan-8-one 8. To a solution of LDA
(5.75 mmol) in THF (5.75 mL), stirred under Ar at
Ϫ78ЊC, was added a solution of bicyclic lactam 7
(420 mg, 1.92 mmol) in a mixture THF (4.5 mL) and
HMPA (0.83 mL). After being stirred for 1 h at the same
temperature and for 1 h at Ϫ35ЊC, the mixture was cooled at
Ϫ78ЊC before the addition of CH3I (0.725 mL, 11.6 mmol).
The mixture was stirred at Ϫ78ЊC for 2 h. The reaction was
quenched at the same temperature by addition of a saturated
aqueous solution of NH4Cl (4 mL), an aqueous solution of
Na2CO3 (10% v/w, 4 mL) and the product was extracted
with Et2O. After purification by chromatography on silica
gel (eluent: Et2O–EtOAc 6:4), the compound 8 was
obtained as white crystals (304 mg, 68%). Mp: 134–6ЊC,
[a]2D5ˆϩ181 (cˆ1.02). IR: 3615, 3416, 1709, 1450. MS
(EI): 233 (Mϩ⅐), 232 (100%), 218, 203, 186, 156, 148,
105, 91, 77. Anal. Calcd for C13H15NO3: C, 66.93; H,
6.9 Hz, Hb-4), 2.80 (m, 1H, H-7), 1.34 (d, 1H, Jˆ7.5 Hz,
CH3). 13C NMR (75.0 MHz): 179.97 (CO), 138.11 (qC, Ar),
128.77, 128.61, 125.25 (CH, Ar), 87.51 (C-2), 72.50 (C-6),
69.18 (C-4), 65.15 (C-5), 45.77 (C-7), 10.44 (CH3).
(2R,5R,6S,7R)-6-Hydroxy-2,7-dimethyl-2-phenyl-3-oxa-
1-aza-bicyclo[3.3.0.]octan-8-one 11. Epimerisation under
the conditions described above of a mixture 8ϩ9
(402 mg) afforded a mixture of cis-derivatives 10ϩ11
(177 mg, 44%), together with the initial mixture 8ϩ9 (ca.
3:7, 127 mg, 32%), the two sets of products being separated
by chromatography (eluent: Et2O–EtOAc 6:4). The
compounds 10 and 11 were further separated by preparative
TLC (eluent: CH2Cl2–MeOH 98:2, then Et2O–heptane–
MeOH 14:5:1). Data of 11 (85 mg, 49%). Mp: 161–3ЊC.
[a]2D5ˆϩ296 (cˆ2.30). IR: 1710. MS (CI, isobutane): 248
[(MϩH)ϩ, 100%], 234, 121, 107. HRMS (CI, CH4): Calcd
1
for C14H18NO3 (MϩH)ϩ: 248.1287. Found: 248.1299. H
1
6.48; N, 6.01. Found: C, 66.71; H, 6.28; N, 5.92. H NMR
NMR (300 MHz): 7.44 (2H, H-Ar), 7.33 (m, 3H, H-Ar),
4.32 (dd, 1H, JϳJ0ϳ7 Hz, H-6), 4.06 (dd, 1H, Jˆ7 Hz,
J0ˆ6 Hz, Ha-4), 3.89 (ddd, 1H, H-5), 3.83 (dd, 1H,
Jˆ7 Hz, J0ˆ6 Hz, Hb-4), 2.83 (m, 1H, H-7), 1.92 (s, 3H,
CH3-2), 1.31 (d, 3H, Jˆ7 Hz, CH3-7). 13C NMR
(75.0 MHz): 175.60 (CO), 142.44 (qC, Ar), 128.61,
128.54, 128.21, 125.10 (CH, Ar), 94.93 (C-2), 73.19
(C-6), 67.80 (C-4), 65.37 (C-5), 47.52 (C-7), 26.01
(CH3-2), 10.29 (CH3-7). nOesy: cross peaks between H-5
and CH3-7; H-6 and H-7; H-6 and Hb-4; Hb-4 and CH3-2.
(300 MHz): 7.40 (m, 5H, H-Ar), 6.38 (s, 1H, H-2), 4.19 (dd,
1H, Jˆ9 Hz, J0ˆ6.5 Hz, Ha-4), 3.93 (m, 1H, H-5), 3.90
(masked m, 1H, H-6), 3.82 (dd, 1H, Jˆ9 Hz, J0ˆ5 Hz,
Hb-4), 2.86 (m, 1H, H-7), 2.72 (OH), 1.26 (d, 3H,
1
Jˆ7.5 Hz, CH3-7). H NMR (300 MHz, C6D6): 7.47 and
7.10 (2m, 5H, H-Ar), 6.56 (s, 1H, H-2), 3.68 (dd, 1H,
J4a,4bˆ8.5 Hz, J4a,5ˆ6.6 Hz, Ha-4), 3.36 (m, 1H, H-5),
3.25 (dd, 1H, J4a,4bˆ8.5 Hz, J4b,5ˆ5.3 Hz, Hb-4), 3.14 (m,
1H, H-6), 2.37 (m, 1H, H-7), 1.24 (OH), 1.06 (d, 3H,
Jˆ7 Hz, CH3-7). (400 MHz, C6D6, 40ЊC): nOe between
H-5 and H-7. 13C NMR (75.0 MHz, CDCl3): 177.02 (CO),
137.97 (qC Ar), 128.79, 128.61, 128.18 (CH, Ar), 87.28
(C-2), 80.87 (C-6), 69.86 (C-4), 64.37 (C-5), 48.10 (C-7),
12.33 (CH3).
(2R,3S,4S)-1-Benzyl-3-hydroxy-2-hydroxymethyl-4-methyl-
pyrrolidine 13, (2R,3S,4S)-1-(10-phenyl)ethyl-3-hydroxy-
2-hydroxymethyl-4-methylpyrrolidine 14 and (2R, 3S,4S)-
1-tert-butoxycarbonyl-3-hydroxy-2-hydroxymethyl-4-
methylpyrrolidine 15. A solution of BH3-DMS (2 M in
THF, 2.1 mL, 4.2 mmol) was added under Ar to a solution
The same reaction was carried out with 7 (548 mg, 2.5
mmol) using 4 equiv. LDA, 4 equiv. HMPA and 10 equiv.

N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
2443
of a mixture 10ϩ11 prepared as above (335 mg, ca.
1.38 mmol) in THF (32 mL) stirred at rt under argon. The
mixture was heated at 70ЊC for 2.25 h. After addition of 2N
HCl, the THF was evaporated under reduced pressure; 5N
HCl was added and the mixture was heated at 70ЊC for
10 min. After cooling at 0ЊC, 40% NaOH was added, the
cooling bath was removed and the product was extracted
with CH2Cl2. Usual workup afforded pyrrolidines 13ϩ14
(273 mg, ϳ86%). This product in methanol (16 mL) was
hydrogenolyzed with H2 (ca. 3.5 bars) in the presence of
Pd/C 10% (50 mg) for 16 h. The catalyst was filtered on
Celite᭨ and washed with MeOH and the solvent was evapo-
rated under vacuum. (Boc)2O (260 mg, 1.19 mmol) was
added to a solution of the residue in MeOH (20 mL) and
the mixture was stirred at rt for 2 h, evaporated to dryness
and purified by preparative TLC (eluent: CH2Cl2–MeOH
92:8) to afford the N-Boc pyrrolidine 15 as a colourless
oil (252 mg, 92%): [a]2D5ˆϪ38 (cˆ1.33). IR: 3608, 3402,
2977, 1669, 1410. MS (CI, isobutane): 232 (MϩH)ϩ, 176.
HRMS (CI, CH4): Calcd for C11H22NO4 (MϩH)ϩ:
232.1549. Found: 232.1580. 1H NMR (300 MHz,
CDCl3ϩD2O): 3.99 (d, 1H, J3,4ˆ2.8 Hz, H-3), 3.83 (dd,
1H, J2,6aϳJ2,6bˆ6 Hz, H-2), 3.69 (dd, 1H, J6a,6bˆ11 Hz,
J6a,2ˆ6 Hz, Ha-6), 3.53 (dd, 1H, J6a,6bˆ11 Hz, J6b,2ˆ6 Hz,
Hb-6), 3.45 (dd, 1H, J5a,5bϳJ5a,4ϳ9.5 Hz, Ha-5), 3.13 (dd,
1H, J5a,5bϳJ5b,4ϳ9.5 Hz, Hb-5), 2.27 (m, 1H, H-4), 1.45 (s,
9H, t-Bu), 1.05 (d, 1H, Jˆ7 Hz, CH3-4). 13C NMR
(75.0 MHz): 156.68 (NCO2), 80.23 (qC, t-Bu), 74.87
(C-3), 68.41 (C-2), 64.29 (C-6), 51.54 (C-5), 36.15 (C-4),
28.55 (CH3, t-Bu), 11.15 (CH3-4).
organic layer was separated and the aqueous layer was
extracted three times with CH2Cl2. After usual workup,
the product was purified by preparative TLC (eluent:
heptane–Et2O: 4:6) to afford the primary alcohol 17 as a
colourless oil (72.5 mg, 70%). [a]2D8ˆϪ27 (cˆ0.97). IR:
3688, 3389, 2957, 2931, 2858, 1669, 1410, 1370. MS (CI,
isobutane): 346 [(MϩH)ϩ, 100%], 290, 246. HRMS (CI,
CH4): Calcd for C17H36NO4Si (MϩH)ϩ: 346.2414. Found
1
346.2436. H NMR (300 MHz, C6D6): 4.04 (m, 1H, H-2),
3.7–3.6 (3H, H-3, OCH2), 3.29 (dd, 1H, J5a,5bˆ9.9 Hz,
J5a,4ϳ8 Hz, Ha-5), 3.17 (dd, 1H, ϳJ5b,4ϳJ5a,5bˆ9.9 Hz,
Hb-5), 1.77 (m, 1H, H-4), 1.41 (s, 9H, O-t-Bu), 0.88 (s,
9H, Si-t-Bu), 0.79 (d, 1H, Jˆ6.7 Hz, CH3-4), 0.00 (s, 3H,
SiCH3), Ϫ0.04 (s, 3H, SiCH3). 13C NMR (75.0 MHz):
157.12 (CO), 80.37, 80.28 (qC, O-t-Bu), 75.68, 75.12
(C-3), 68.73 (NCH), 65.29, 65.02 (CH2), 51.83, 51.58
(CH2), 36.93, 36.34 (C-4), 28.54 (CH3, t-Bu), 18.16 (qC,
Si-t-Bu), 11.64, 11.16 (CH3-4), Ϫ3.49 (SiCH3), Ϫ4.60,
Ϫ4.72 (SiCH3).
(2S,3S,4S)-1-tert-Butoxycarbonyl-3-tert-butyldimethyl-
silyloxy-4-methyl proline 18 and HMP 2. To a mixture of
alcohol 17 (44.2 mg, 0.128 mmol), CCl4 (0.25 mL), CH3CN
(0.25 mL) and H2O (0.37 mL) were successively added
under stirring NaIO4 (129.5 mg, 0.60 mmol) and RuCl3,
2H2O (3.0 mg). The mixture was vigorously stirred at rt
for 0.4 h, diluted with CH2Cl2 and H2O and the aqueous
layer was extracted three times with CH2Cl2. Et2O was
added to the residue obtained after usual workup and the
solution was filtered to afford the carboxylic acid 18 after
evaporation to dryness (36.8 mg, 80%). IR: 3396–2450
(broad), 2957, 2931, 2858, 1749, 1676, 1616. The product
was dissolved in 6N HCl (1.0 mL) and the mixture was
stirred at rt for 0.25 h and then at 118ЊC for 4 h. After
evaporation to dryness, the residue was washed twice with
Et2O, dissolved in H2O and the solution was filtered and
evaporated to dryness under reduced pressure to afford
(2R,3S,4S)-1-tert-Butoxycarbonyl-3-tert-butyldimethyl-
silyloxy-2-tert-butyldimethylsilyloxymethyl-4-methyl-
pyrrolidine 16. A solution of t-BuMe2SiCl (386 mg,
2.56 mmol) in DMF (0.6 mL) was added under Ar to a
solution of diol 15 (185 mg, 0.80 mmol) and imidazole
(218 mg, 3.2 mmol) in DMF (0.4 mL). The mixture was
stirred at 40ЊC for 18 h and diluted with Et2O after cooling.
An aqueous solution of NaHCO3 was added and the product
was extracted four times with Et2O. After washing of the
organic layers with H2O, usual workup and purification by
preparative TLC (eluent: heptane–Et2O 95:5), the disilyl-
oxy derivative 16 was obtained as a colourless oil (276 mg,
75%). [a]3D0ˆϪ23 (cˆ0.66). IR: 2964, 2931, 2858, 1682,
1410. MS (CI, isobutane): 460 [(MϩH)ϩ, 100%]. HRMS
(CI, CH4): Calcd for C23H50NO4Si2 (MϩH)ϩ: 460.3278.
HMP
2
hydrochloride (16.8 mg, 90%). [a]2D5ˆϩ12
(cˆ0.32, 5N HCl); literature: [a]Dˆϩ10 (cˆ0.40, 5N
HCl).1 MS (FAB, thioglycerol): 168 (Mϩ23), 146
[(MϩH)ϩ, 100%], 131, 105, 100. 1H NMR (300 MHz,
D2O: dˆ4.8 ppm): 4.47 (d, 1H, Jˆ3.6 Hz, H-3), 4.16 (s,
1H, H-2), 3.61 (dd, 1H, Jˆ11.5 Hz, J0ˆ7.9 Hz, Ha-5),
3.07 (dd, 1H, JϳJ0ϳ11.5, Hb-5), 2.28, (m, 1H, H-4), 1.06
(d, 3H, Jϳ6.8, CH3). 13C NMR (75.0 MHz, D2O, dioxane:
67.19 ppm): 170.96 (CO), 75.87 (C-3), 68.45 (C-2), 50.15
(C-5), 37.16 (C-4), 10.03 (CH3).
1
Found: 460.3318. H NMR (300 MHz, doubled signals):
4.12 (dd, 1H, Jϳ4 Hz, H-3), 3.8–3.2 (H2-6, H-2, Ha-5),
3.11, 3.02 (2dd, 1H, JϳJ0ˆ10.2 Hz, Hb-5), 2.26 (m, 1H,
H-4), 1.45 (s, 9H, t-Bu), 1.00, 0.98 (2d, Jˆ6.8 Hz,
CH3-4), 0.89 (s, 18H, 2×Si-t-Bu), 0.08, 0.07, 0.05, 0.04
(4s, 12H, 2×Si(CH3)2. 13C NMR (75.0 MHz): 154.96
(NCO2), 79.27, 79.0 (qC, O-t-Bu), 75.89, 75.46 (C-3),
68.45, 68.17 (C-2), 62.71, 61.99 (OCH2), 51.80, 51.15
(C-5), 36.39, 35.44 (C-4), 28.64 (CH3, t-Bu), 26.03, 25.88
(CH3, Si-t-Bu), 18.22 (qC, Si-t-Bu), 11.69 (CH3-4), Ϫ4.48,
Ϫ4.74 (SiCH3), Ϫ5.28, Ϫ5.35 (SiCH3).
(4S,5R)-1-tert-Butoxycarbonyl-5-(1-ethoxy)ethoxymethyl-
4-hydroxy-3-methylpyrrolidin-2-ones 21. Pd(OH)2 (200
mg) was added to a solution of cycloadduct 19 (760 mg,
2.22 mmol)12 in EtOAc–MeOH 5:1 (9.2 mL) and the
mixture was stirred under H2 atmosphere at rt for 50 h.
The catalyst was filtered on Celite᭨ and washed with
MeOH. The crude product obtained by evaporation to
dryness was purified by chromatography on silica gel
(eluent: CH2Cl2–MeOH 95:5) to afford the pyrrolidinones
21 (504 mg, 72%) amorphous. IR: 3613, 3470 (broad),
3014, 2983, 2938, 1783, 1747, 1712, 1476, 1457, 1371,
1313. MS (CI, isobutane): 318 (MϩH)ϩ, 262, 218, 216,
190, 172 (100%), 146. HRMS (CI): Calcd for C15H28NO6
(MϩH)ϩ: 318.1909. Found: 318.1917. 1H NMR (300
MHz): 4.77–4.62 (OCHO), 4.31 (H-4, dia a), 4.12 (H-5),
(2R,3S,4S)-1-tert-Butoxycarbonyl-3-tert-butyldimethyl-
silyloxy-2-hydroxymethyl-4-methylpyrrolidine 17. Disilyl-
derivative 16 (138 mg, 0.3 mmol) in a mixture AcOH–
THF–H2O 13:3:7 (2.0 mL)34 was stirred at 30ЊC for 12 h.
After dilution with CH2Cl2 and addition of Na2CO3, the

2444
N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
3.97 (H-5ϩH-4, dia b), 4.0–3.4 (2×OCH2), 2.92 (H-3, dia
a), 2.54 (H-3, dia b), 1.54 (s, 9H, t-Bu), 1.32 (CH3-3, dia b),
1.29 (OCHCH3), 1.20 (OCH2CH3, CH3-3, dia a). 13C NMR
(75.0 MHz): 175.93, 175.36 (CO), 150.11, 149.94 (NCO2),
100.38, 99.96, 99.73 (OCHO), 83.28, 83.01 (qC, t-Bu),
73.87, 73.58 (C-4, dia b), 70.19, 70.10 (C-4, dia a), 65.01,
64.89 (C-5), 64.50, 64.02 (OCH2), 64.02, 63.90 (C-5),
63.27, 62.98 (OCH2), 61.68, 61.50, 61.15, 61.06 (OCH2),
46.76 (C-3, dia b), 42.96, 42.84 (C-3, dia a), 28.09 (CH3,
t-Bu), 19.84, 19.64, 19.54 (OCHCH3), 15.29 (CH3-3, dia b),
13.85, 13.76 (OCH2CH3), 8.19 (CH3-3, dia a).
1.2 mmol) in anhydrous THF (2.9 mL), stirred at Ϫ78ЊC
under Ar, was dropwise added DIBAL-H (1 M in hexane,
3.6 mL). The mixture was stirred at Ϫ78ЊC for 30 min.
Na2CO3 (10% v/v, 14 mL) and saturated aqueous NH4Cl
solution (20 mL) were successively added at the same
temperature. After dilution with CH2Cl2 the cooling bath
was removed and the product was extracted four times
with CH2Cl2. Usual workup afforded a-hydroxycarbamates
24 (376 mg, 98%) as a colourless oil.
Benzoylation of 24: To a solution of a-hydroxycarbamates
24 (351 mg, 1.1 mmol) in CH2Cl2 (5.5 mL) cooled at 0ЊC
were successively added Et3N (367 mL) and PhCOCl
(130 mL). After being stirred for additional 24 h at 40ЊC,
the reaction medium was cooled at 0ЊC and diluted with
CH2Cl2 (20 mL). 2 N NaOH (10 mL) was added and the
mixture was stirred for 45 min. The aqueous layer was sepa-
rated and extracted with CH2Cl2 (three times). The organic
layers were stirred three times for 10 min. with 2N NaOH
and afforded after usual workup, a mixture which was
directly reduced as below.
(4R,7R,8S)-6-tert-Butoxycarbonyl-7-acetoxymethyl-2-
methyl-1-oxa-2,6-diazabicyclo[3.3.0]octane-5-one
22.
Acetic anhydride (2.0 mL) was added under Ar to a stirred
solution of alcohol 2012 (294 mg, 1.08 mmol) in pyridine
(5.8 mL) at 0ЊC. The mixture was stirred at rt for 2.75 h
and cooled again at 0ЊC before the addition of MeOH
(2 mL). After being stirred for 0.5 h at rt, the solvents
were removed under reduced pressure and the residue was
dissolved in CH2Cl2. After being washed with NaHCO3 (5%
w/v) the organic layers gave the crude acetate after usual
workup. It was purified by chromatography on silica gel
(eluent: CH2Cl2–MeOH 97:3) to afford 22 as a colourless
oil (321 mg, 95%): [a]2D6ˆϪ68 (cˆ0.73). IR: 2990, 1788,
1742, 1463, 1375. Anal. Calcd for C14H22N2O6: C, 53.49; H,
NaBH3CN reduction and primary alcohol deprotection:
NaBH3CN (470 mg, 7.47 mmol) was portionwise added at
rt to a stirred solution of the benzoylation crude product in
acetic acid (5.5 mL). After complete addition, the mixture
was stirred at 30ЊC for 1.5 h, cooled to 0ЊC, diluted with
CH2Cl2 (34 mL) and NaOH was added until pH 7.5. After
extraction with CH2Cl2 (four times) and usual workup, the
crude product was chromatographied on silica gel (eluent:
CH2Cl2–MeOH 96:4) to give 25 (more polar cis, 119 mg,
32%) and 26 (less polar, 133 mg, 36%) as colourless oils.
Overall yield 68% for 2 steps.
1
7.05; N, 8.91. Found: C, 53.45; H, 7.13; N; 9.13. H NMR
(300 MHz): 4.52 (mϩdd, 2H, H-8, Ha-9), 4.35 (m, 1H,
H-7), 4.20 (br d, Jϳ11 Hz, Hb-9), 3.53 (m, 2H, Ha-3,
H-4), 2.74 (masked m, 1H, Hb-3), 2.70 (br s, 3H, NCH3),
2.07 (s, 3H, COCH3), 1.55 (s, 9H, t-Bu). 13C NMR
(75.0 MHz): 173.89 (CO), 170.52 (CO), 149.19 (NCO2),
84.13 (qC, t-Bu), 75.33 (C-8), 63.52 (OCH2), 62.98
(NCH, C-7), 61.04 (NCH2, C-3), 52.83 (C-4), 44.95
(N-CH3), 28.11 (CH3, t-Bu), 20.78 (COCH3).
(2R,3S,4S)-1-tert-Butoxycarbonyl-3-benzoyloxy-2-hydroxy-
methyl-4-methylpyrrolidine 25. [a]2D5ˆϪ30.5 (cˆ1.34).
IR: 3684, 3400 (broad), 2988, 1717, 1687, 1602, 1469,
1462, 1409, 1367. MS (CI, isobutane): 336 (MϩH)ϩ,
292, 280, 236 (100%), 123, 114. Anal. Calcd for
C18H25NO5: C, 64.46; H, 7.51; N, 4.18. Found: C,
(4S,5R)-1-tert-Butoxycarbonyl-5-acetoxymethyl-4-hydroxy-
3-methylpyrrolidin-2-ones 23. The acetate 22 (201 mg,
0.64 mmol) was hydrogenolyzed as described with 19 to
afford, after chromatography on silicagel (eluent: CH2Cl2–
MeOH 96:4), the compounds 23 as a colourless oil (134 mg,
73%). IR: 3600, 2990, 1786, 1745, 1717 (sh), 1450, 1370,
1310. MS (CI, isobutane): 288 (MϩH)ϩ, 232, 188 (100%).
Anal. Calcd for C13H21NO6: C, 54.34; H, 7.37; N, 4.88.
1
64.32; H, 7.45; N, 4.13. H NMR (300 MHz): 8.05 (d,
2H, H-Ar), 7.60 (dd, 1H, H-Ar), 7.47 (dd, 2H, H-Ar),
5.36, 5.21 (2m, 1H, H-3), 4.10 (m), 3.85 (masked m):
H-2, 3.90, 3.75 (OCH2), 3.66 (m, 1H, Ha-5), 3.26 (m, 1H,
Hb-5), 2.60 (m, 1H, H-4), 1.47 (s, 9H, t-Bu), 1.10 (d,
3H, Jˆ6 Hz, CH3-4). 13C NMR (75.0 MHz): (CO not
visible), 133.36 (CH, Ar), 129.95 (qC, Ar), 129.74, 128.56
(CH, Ar), 80.57 (qC, t-Bu), 78.01 (C-3), 66.33 (C-2), 64.66
(OCH2), 52.35 (C-5), 35.65 (C-4), 28.50 (CH3, t-Bu), 11.48
(CH3-4).
1
Found: C, 53.99; H, 7.31; N, 4.84. H NMR (300 MHz):
4.50 (dd, Jˆ11.8 Hz, J0ˆ4.6 Hz, Ha-6, dia b), 4.36 (Ha-6,
dia a), 4.34 (Hb-6, dia b), 4.28 (m, H-4, dia a), 4.23 (Hb-6,
dia a, H-5, dia a), 4.03 (m, H-5, dia b), 3.93 (m, H-4, dia b),
3.26 (OH), 2.79 (m, H-3, dia a), 2.72 (OH), 2.58 (m, H-3,
dia b), 2.07 (splitted s, 3H, COCH3), 1.53 (s, 9H, t-Bu), 1.32
(d, Jˆ7 Hz, CH3-3, dia b), 1.22 (d, Jˆ7.2 Hz, CH3-3, dia a).
NOESY experiments (400 MHz) showed correlations
between H-3 and H-4 in 23a, CH3-3 and H-4 in 23b, as
well as H-4 and Hb-6 in 23b. 13C NMR (75.0 MHz):
175.47 (CO), 170.57 (CO), 149.87 (NCO2), 83.85, 83.70
(qC, t-Bu), 72.73 (C-4, b), 69.53 (C-4, a), 63.84 (C-5, a),
63.51 (C-5, b), 62.52 (C-6, a), 62.37 (C-6, b), 46.80 (C-3,
b), 42.73 (C-3, a), 28.02 (CH3, t-Bu), 20.86 (COCH3), 13.85
(CH3-3, b), 8.19 (CH3-3, a).
(2R,3S,4R)-Diastereomer 26. [a]2D4ˆϪ41 (cˆ1.81). IR:
1718, 1690. MS (CI, isobutane): 336 [(MϩH)ϩ, 100%],
292, 280, 236, 123. HRMS (CICH4): Calcd for C18H26NO5
(MϩH)ϩ: 336.1810. Found: 336.1809. 1H NMR
(300 MHz): 8.05 (d, 2H, H-Ar), 7.59 (dd, 1H, H-Ar), 7.45
(dd, 2H, H-Ar), 5.01 (m, H-3), 4.01 (m, H-2), 3.9 (Ha-6),
3.83 (Hb-6, Ha-5), 3.07 (m, 1H, Hb-5), 2.42 (m, 1H, H-4),
1.48 (s, 9H, t-Bu), 1.13 (d, 3H, Jˆ6 Hz, CH3-4). 13C NMR
(75.0 MHz): (CO not visible), 133.46, 129.83 (CH, Ar),
129.63 (qC, Ar), 128.55 (CH, Ar), 80.79 (qC, t-Bu), 80.18
(C-3), 65.80 (C-2), 65.14 (OCH2), 52.32 (C-5), 37.78 (C-4),
28.50 (CH3, t-Bu), 15.51 (CH3-4).
1-tert-Butoxycarbonyl-3-benzoyloxy-2-hydroxymethyl-
4-methylpyrrolidines 25 and 26. Reduction of 21 with
DIBAL-H: To a solution of the pyrrolidinones 21 (381 mg,

N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
2445
(2S,3S,4S)-1-tert-Butoxycarbonyl-3-benzoyloxy-4-methyl-
pyrrolidine-2-carboxylic acid 27. To a stirred biphasic
solution of alcohol 25 (54.0 mg, 0.16 mmol) in a mixture
of CCl4 (0.32 mL), CH3CN (0.32 mL), H2O (0.49 mL) were
successively added NaIO4 (107.4 mg, 0.50 mmol) and
RuCl3, 2 H2O (1.6 mg). The mixture was vigorously stirred
for 50 min. at rt, diluted with CH2Cl2 (15 mL) and H2O
(1.5 mL) and the layers were separated. The aqueous layer
was extracted three times with CH2Cl2. The organic layers
were washed with H2O (1 mL). After usual workup the
crude product was purified by preparative TLC (eluent
CH2Cl2–MeOH–CH3CO2H 92:8:0.05) to afford the
carboxylic acid 27 as a white solid (49.6 mg, 88%).
[a]2D6ˆϩ19 (cˆ2.1, MeOH). IR: 3450 (broad), 3030,
2990, 1716, 1682, 1616, 1417. MS (FAB, thioglycerol
dˆ67.19 ppm): 171.2 (CO), 79.3 (C-3), 65.4 (C-2), 50.4
(C-5), 40.6 (C-4), 14.04 (CH3-4).
(4R,7R,8S)-6-tert-Butoxycarbonyl-7-hydroxymethyl-2-
methyl-1-oxa-2,6-diazabicyclo[3.3.0]octane 30. A. Reduc-
tion of 19 with DIBAL-H: A solution of DIBAL-H in hexane
(1 M, 14.74 mL, 2.4 equiv.) was added dropwise under
argon to a stirred solution of 19 (2.11 g, 6.13 mmol) in
anhydrous THF at Ϫ78ЊC. The mixture was stirred
at Ϫ78ЊC for 35 min. At the same temperature were succes-
sively added an aqueous solution of Na2CO3 (10% w/v,
60 mL), a saturated aqueous solution of NH4Cl (85 mL)
and dichloromethane (100 mL) and then the cooling bath
was removed. CH2Cl2 (600 mL) was added and, after
being stirred, the layers were separated and the aqueous
layer was extracted three times with CH2Cl2. After
usual workup, the a-hydroxycarbamates were obtained
in 100% yield (2.12 g) and directly used in the next step: IR:
1700.
1
ϩHCl): 350 (MϩH)ϩ, 294, 250 (100%), 105. H NMR
(300 MHz, DMSO-d6): 7.95 (d, 2H, H-Ar), 7.66 (dd, 1H,
H-Ar), 7.53 (dd, 2H, H-Ar), 5.47 (m, 1H, H-3), 4.10, 4.02
(1H, H-2), 3.63 (m, Ha-5, OH), 3.04 (m, 1H, Hb-5), 2.61 (m,
1H, H-4), 1.41, 1.32 (2s, 9H, t-Bu), 0.94 (broad d, 3H,
CH3-4). 13C NMR (75.0 MHz, DMSO d6, dˆ39.52 ppm):
165.09 (CO), 153.85 (NCO2), 133.41 (CH, Ar), 129.67 (qC,
Ar), 129.09, 128.82 (CH, Ar), 80.3 (qC, t-Bu), 78.19, 77.85
(C-3), 51.06, 50.71 (C-5), 35.39, 34.44 (C-4), 28.24, 28.11
(CH3, t-Bu), 11.54 (CH3-4).
B. Reduction with NaBH3CN: NaBH3CN (2.33 g, 37.0
mmol) was portionwise added at rt to a stirred solution of
dried a-hydroxycarbamates (1.83 g, 5.29 mmol) in acetic
acid (26.4 mL). After complete addition, the mixture was
stirred at 30ЊC until completion (c.a. 1.3 h), cooled to 0ЊC
and diluted with CH2Cl2 (160 mL). After addition of NaOH
until pH 7.5 the mixture was extracted four times with
CH2Cl2 to afford, after usual workup, the compound 30
(amorphous, 1.365 g, 100%). [a]2D5ˆϪ27 (cˆ1.5). IRˆ
3415, 2990, 1689, 1483, 1463, 1410. MS (EI): 258 (Mϩ⅐),
185 (100%), 184, 157, 128, 127, 115, 112, 98. HRMS: Calcd
for C12H22N2O4 (Mϩ⅐): 258.1580. Found: 258.1569. 1H
NMR (300 MHz, very broad signals): 4.0, 3.8–3.4
(OCH2), 2.7 (3H, NCH3), 1.47 (s, 9H, t-Bu). 13C NMR
(75.0 MHz): 84.59 (weak, C-8), 80.3 (qC, t-Bu), 65.25
(NCH), 63.46 (CH2), 53.04 (CH), 51.74 (NCH2), 51.12
(NCH2), 45.04 (NCH3), 28.50 (CH3, t-Bu).
(2S,3S,4R)-1-tert-Butoxycarbonyl-3-benzoyloxy-4-methyl-
pyrrolidine-2-carboxylic acid 28. The less polar alcohol
26 (38.7 mg, 0.115 mmol) was oxidised following the same
protocol with NaIO4 (74.5 mg, 0.348 mmol) and RuCl3,
2 H2O (1.2 mg) for 40 min at rt. The same treatment as
before gave rise to the carboxylic acid 28 as a white solid
(30.2 mg, 75%). [a]2D6ˆϩ21 (cˆ2.15, MeOH). IR: 3350–
2600 (broad), 2975, 1719, 1702, 1686, 1630, 1455, 1410,
1375. MS (FAB, thioglycerolϩHCl): 350 (MϩH)ϩ, 294,
1
250 (100%), 105. H NMR (300 MHz, DMSO-d6): 7.95
(d, 2H, H-Ar), 7.68 (dd, 1H, H-Ar), 7.55 (dd, 2H, H-Ar),
5.23 (m, 1H, H-3), 4.13, 4.04 (1H, H-2), 3.67 (m, 1H, Ha-5),
3.05 (m, 1H, Hb-5), 2.25 (m, 1H, H-4), 1.44, 1.37 (2s, 9H,
t-Bu), 1.09 (broad d, 3H, CH3-4). 13C NMR (62.0 MHz,
DMSO-d6ˆ39.52 ppm): 165.3 (CO), 154.1 (NCO2), 133.4
(CH, Ar), 129.9 (qC, Ar), 129.15, 128.78 (CH, Ar), 85.0
(qC, t-Bu), 78.1, 77.9 (C-3), 66.8 (C-2), 51.8, 51.4 (C-5),
38.09 (C-4), 28.2 (CH3, t-Bu), 17.5 (CH3-4).
(4R,7R,8S)-7-Acetoxymethyl-6-tert-butoxycarbonyl-2-
methyl-1-oxa-2,6-diazabicyclo[3.3.0]octane 31. Acetic
anhydride (9.1 mL) was added at 0ЊC under argon to a solu-
tion of the compound 30 (1.34 g, 5.2 mmol, dried by
evaporation of toluene), in pyridine (26.0 mL). The mixture
was stirred at rt until completion of the reaction (5 h) and
cooled to 0ЊC before addition of methanol (16 mL). After
being stirred at rt for 0.5 h, the mixture was concentrated
under reduced pressure. After dilution with CH2Cl2
(200 mL) and washing with NaHCO3 (5% w/v, 10 mL),
the aqueous layer was extracted three times with CH2Cl2
(150, 100, 100 mL). After usual workup the organic layers
afforded the acetate 32 which was purified by chroma-
tography (eluent: CH2Cl2–MeOH 98:2) and obtained as a
colourless oil (1.22 g, 78%). [a]2D3ˆϪ41.5 (cˆ1.5). IR:
2900, 1743, 1690, 1407. MS (EI): 300 ((Mϩ⅐), 184
(100%), 125, 81, 80. Anal. Calcd for C14H24N2O5: C,
55.98; H, 8.05; N, 9.32. Found: C, 55.74; H, 7.98; N,
(2S,3S,4S)-3-Hydroxy-4-methylproline 2, hydrochloride.
The acid 27 (35 mg, 0.10 mmol) in 6N HCl (2 mL) was
heated at 80ЊC for 37 h and the mixture was evaporated to
dryness. The residue was washed with small amounts of
Et2O and dissolved in water. After filtration, the solvent
was removed under vacuum to provide quantitatively 2, as
hydrochloride salt.
(2S,3S,4R)-3-Hydroxy-4-methylproline 29, hydrochloride.
In the same conditions, the acid 28 (23.7 mg, 0.068 mmol)
was deprotected to give rise to the aminoacid 29 as its
hydrochloride salt (12.3 mg, 100%): [a]2D4ˆϪ4 (cˆ0.48,
MeOH). MS (FAB, thioglycerol): 147, 146 [(MϩH)ϩ,
1
9.41. H NMR (300 MHz, broad signals): 4.66, 4.46 (2m,
1H, H-8), 4.15 (OCH2), 3.7–2.8 (2×NCH2), 2.68 (3H,
NCH3), 2.07 (s, 3H, COCH3), 1.46 (s, 9H, t-Bu). 13C
NMR (75.0 MHz, broad signals): 170.48 (OCO), 153.78
(NCO2), 84.34 (C-8), 80.06 (qC, t-Bu), 65.19, 63.64
(CH2), 62.19–60.51 (NCH), 51.27 (NCH2), 44.89 (NCH3),
28.41 (CH3, t-Bu).
1
100%], 131, 100. H NMR (300 MHz, D2O:ˆ4.8 ppm):
4.20 (dd, 1H, JϳJ0ϳ6 Hz, H-3), 4.11 (d, 1H, Jϳ6 Hz,
H-2), 3.64 (dd, 1H, Jˆ12 Hz, J0ˆ7 Hz, Ha-5), 3.13 (dd,
1H, Jˆ12 Hz, J0ˆ9 Hz, Hb-5), 2.34 (m, 1H, H-4), 1.09 (d,
Jˆ7 Hz, CH3-4) 13C NMR (50 MHz, D2O, dioxane:

2446
N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
N, N-Dimethylisoxazolidinium and methyl sulfate 32.
Dimethyl sulfate (248 mL, 2.62 mmol) was added under
argon to a solution of acetate 31 (515 mg, 1.72 mmol) in
EtOAc (3.8 mL). The mixture was stirred at rt for 18 h and
the solvent and reagent in excess were eliminated under
reduced pressure and the white solid was crystallised in
MeOH–Et2O (673 mg, 92%). Mp: 158–160ЊC. [a]2D8ˆ
Ϫ15 (cˆ1.50, MeOH). Anal. Calcd for C16H30N2O9S: C,
45.05; H, 7.09; N, 6.57. Found: C, 44.69; H, 6.94; N,
was purified by chromatography on silica gel (eluent:
CH2Cl2–MeOH 95:5) and obtained as a colourless oil
(469 mg, 93%). [a]2D4ˆϪ22 (cˆ2.9). IR: 3030, 1750,
1730, 1700. MS (CI, isobutane): 421 [(MϩH)ϩ, 100%],
365, 186, 142, 123. Anal. Calcd for C22H32N2O6: C,
62.84; H, 7.47; N, 6.66. Found: C, 62.89; H, 7.47; N,
1
6.62. H NMR (300 MHz): 8.02 (d, 2H, Jϳ8 Hz, H-Ar),
7.60 (dd, 1H, H-Ar), 7.47 (dd, 2H, JϳJ0ϳ8 Hz, H-Ar),
5.43 (m, 1H, H-3), 4.32 (dd, 1H, Ha-6), 4.17 (Hb-6), 4.15,
4.00 (2m, 1H, H-2), 3.74, 3.33 (2m, 2H, NCH2), 2.75 (m,
1H), 2.58, 2.46 (2m, NCH2), 2.22 (s, 6H, N(CH3)2), 2.13 (s,
3H, COCH3), 1.47 (s, 9H, t-Bu). 13C NMR (75.0 MHz):
170.69 (OCOCH3), 165.74 (COPh), 155.0 (NCO2), 133.38
(CH, Ar), 129.88 (qC, Ar), 129.68, 128.57 (CH, Ar), 80.45,
80.14 (qC, t-Bu), 77.18, 76.30 (C-3), 63.18 (C-2), 62.78
(OCH2), 57.27, 56.93 (NCH2), 49.84, 49.54 (NCH2), 45.93
(N(CH3)2), 39.30, 38.47 (C-4), 28.48 (CH3, t-Bu), 20.95
(COCH3).
1
6.44. H NMR (300 MHz, D2O, HOD dˆ4.8 ppm): 5.40,
5.36 (m, 1H, H-8), 4.52 (Ha-3), 4.46 (Ha-9), 4.43 (m, H-7),
4.23 (Hb-9), 3.95 (m, 2H, Hb-3, H-4), 3.75 (masked m,
H2-5), 3.75, 3.68, 3.58 (3s, OCH3, 2×NCH3), 2.14 (s, 3H,
COCH3), 1.50 (s, 9H, t-Bu). 13C NMR (75.0 MHz, D2O
without reference): 173.60 (OCO), 155.26 (NCO2), 90.15,
89.22 (C-8), 82.84 (qC, t-Bu), 71.95 (CH2, C-3), 63.14,
62.42 (OCH2), 60.43, 60.13 (NCH), 56.06, 55.37, 54.49
(OCH3 sulfate, 2×NCH3), 49.75(C-5), 44.99, 44.22 (C-4),
27.52 (CH3, t-Bu), 20.21 (COCH3).
(2R,3S,4R)-2-Acetoxymethyl-4-(N, N-dimethyl, N-oxy)-
aminomethyl-3-benzoyloxy-1-tert-butoxycarbonylpyrroli-
dine 35. NaHCO3 (298 mg, 3.55 mmol) and mCPBA
(230 mg, 1.33 mmol) were successively added to a stirred
solution of benzoate 34 (371 mg, 0.88 mmol) in CH2Cl2
(17.7 mL) and the mixture was stirred for 5 min before the
addition of aqueous Na2CO3 (10% w/v, 7 mL). The N-oxide
was extracted three times with CH2Cl2 and the organic
layers were washed with 10% Na2CO3. Usual workup fur-
(2R,3S,4S)-2-Acetoxymethyl-4-(N, N-dimethyl)amino-
methyl-1-tert-butoxycarbonyl-3-hydroxypyrrolidine 33.
N,N-Dimethylisoxazolidinium 32 (653 mg, 1.53 mmol) in
MeOH (9.9 mL) was stirred under H2 atmosphere at rt in
the presence of Pd(OH)2 (130 mg) for 25 h. The catalyst was
filtered off on Celite᭨ and washed with MeOH. The solution
was evaporated to dryness to give the (N,N-dimethyl)-
aminomethyl derivative 33, as methylsulfate salt (660 mg,
100%). MS (CI, isobutane): 317 [(MϩH)ϩ, 100%], 261,
259, 142, 73. HRMS (CI): Calcd for C15H29N2O5
(MϩH)ϩ: 317.2076. Found: 317.2090. 1H NMR (300
MHz): 4.41 (m, 1H, H-3), 4.15 (2m, 2H), 3.95 (m, 1H),
3.75 (s, 3H, OCH3 sulfate), 3.55 (2 x NCH), 3.25 (m, 1H,
NCH), 3.04 (m, 1H, NCH), 2.94 (s, 6H, N(CH3)2), 2.74 (m,
1H), 1.47 (s, 9H, t-Bu). 13C NMR (75.0 MHz): 170.75 (CO),
154.35 (NCO2), 80.55 (qC, t-Bu), 71.74 (C-3), 65.06
(OCH2), 62.72 (C-2), 56.34 (OCH3), 55.11 (NCH2), 48.04
(NCH2), 44.49 (NCH3), 36.88 (C-4), 28.49 (CH3, t-Bu),
20.99 (COCH3). To this salt (608 mg, 1.42 mmol) and
CH2Cl2 (150 mL) was added an aqueous solution of
NaHCO3 (10% w/v, 7 mL). After stirring and separation
of the layers, the aqueous layer was extracted three times
with CH2Cl2. Usual workup afforded the compound 33
(435.5 mg, 97%). [a]2D6ˆϪ40 (cˆ0.75). IR: 3400, 3020,
1
nished the N-oxide 35 (379 mg, 98%) as a white foam. H
NMR (250 MHz): 8.00 (d, 2H, H-Ar), 7.61 (dd, 1H, H-Ar),
7.46 (dd, 2H, H-Ar), 5.57 (m, 1H, H-3), 4.4–3.3 (3m,
8H, H-2, OCH2, 2×NCH2, H-4), 3.22 (s, 6H, N(CH3)2),
2.15 (s, 3H, COCH3), 1.46 (s, 9H, t-Bu). 13C NMR
(62.5 MHz): 170.9 (OCO), 165.6 (OCO), 154.0
(NCO2), 133.8 (qC, Ar), 129.7 129.2, 128.7 (CH, Ar),
80.9, 80.5 (qC, t-Bu), 78.1 (C-3), 68.7 (OCH2), 62.8
(NCH3), 62.3 (NϩCH2), 60.8, 59.8, 59.5, 58.4 (C-2),
50.3, 50.0 (C-5), 36.0, 34.8 (C-4), 28.4 (CH3, t-Bu),
20.9 (COCH3).
(2R,3S)-2-Acetoxymethyl-3-benzoyloxy-1-tert-butoxycar-
bonyl-4-exo-methylenepyrrolidine 36. A solution of
N-oxide 35 (196 mg, 0.45 mmol) in a mixture THF–toluene
1:1 (70 mL) was heated under inert atmosphere at 85ЊC for
5 h. After cooling at 30ЊC, the solvents were evaporated
under reduced pressure and the residue was purified by
preparative TLC (eluent: heptane–Et2O 2:8) to afford the
compound 36, amorphous (147 mg, 87%). [a]2D7ˆϪ12.5
(cˆ2.36). IR: 3010, 1742, 1717, 1694, 1404. MS (EI):
375 (Mϩ⅐), 302, 260, 246, 215, 152 (100%), 105, 93, 56.
MS (FAB): 376 (MϩH)ϩ, 320, 276, 260, 198 (100%), 154,
91, 73. Anal. Calcd for C20H25NO6: C, 63.98; H, 6.71; N,
3.73. Found: C, 63.67; H, 6.64; N, 3.73. 1H NMR
(300 MHz): 8.02 (d, 2H, H-Ar), 7.59 (dd, 1H, H-Ar), 7.45
(dd, 2H, H-Ar), 5.66 (broad s, 1H, H-3), 5.54 (broad s, 1H,
vCHa), 5.36 (1H, vCHb), 4.34, 3.99 (2 broad d, OCH2),
4.21 (H-2), 2.07 (s, 3H, COCH3), 1.49 (s, 9H, t-Bu). 13C
NMR (75.0 MHz): 170.62 (OCO), 165.92 (OCO), 154.00
(NCO2), 142.91, 141.99 (C-4), 133.35 (qC, Ar), 129.77,
128.49 (CH, Ar), 115.21 (vCH2), 80.62 (qC, t-Bu),
77.58, 76.72 (C-3), 62.72, 62.47 (OCH2), 62.29, 61.91
(C-2), 49.69, 49.45 (C-5), 28.46 (CH3, t-Bu), 20.81
(COCH3).
1
1735, 1685 (broad). H NMR (300 MHz): 4.30 (1H), 4.21
(2H), 3.91 (1H), 3.80 (1H): H-3, H2-6, H-2, 3.40 (m, 1H,
NCH), 3.30–3.22 (1H), 2.69 (1H), 2.41 (m, 2H, NCH), 2.27
(s, 6H, N(CH3)2), 2.05 (s, 3H, COCH3), 1.48 (s, 9H, t-Bu).
13C NMR (75.0 MHz): 170.78 (OCO), 154.54 (NCO2),
80.14 (qC, t-Bu), 75.58, 74.28 (C-3), 63.44 (C-2), 63.12
(OCH2), 58.75 (NCH2), 48.76 (NCH2), 45.81 (NCH3),
36.80 (C-4), 28.47 (CH3, t-Bu), 20.93 (COCH3).
(2R,3S,4S)-2-Acetoxymethyl-4-(N, N-dimethyl)amino-
methyl-3-benzoyloxy-1-tert-butoxycarbonylpyrrolidine
34. Triethylamine (190 mL, 1.37 mmol) and benzoyl
chloride (159 mL, 1.37 mmol) were successively added to
a solution of 33 (379 mg, 1.2 mmol) in dry CH2Cl2
(4.85 mL) under stirring at 0ЊC. The mixture was stirred at
rt for 27 h. After dilution with CH2Cl2 and addition of
Na2CO3 (10% w/v, 25 mL) the mixture was stirred at rt
for 0.25 h and the aqueous layer was further extracted
twice with CH2Cl2. After usual workup, the benzoate 34

N. Langlois, F. Rakotondradany / Tetrahedron 56 (2000) 2437–2448
2447
4. (a) Debono, M.; Turner, W. W.; LaGrandeur, L.; Burkhardt,
F. J.; Nissen, J. S.; Nichols, K. K.; Rodriguez, M. J.; Zweifel,
M. J.; Zeckner, D. J.; Gordee, R. S.; Tang, J.; Parr, T. R. J. Med.
Chem. 1995, 38, 3271–3281. (b) For example: Jamison, J. A.;
LaGrandeur, L. M.; Rodriguez, M. J.; Turner, W. W.; Zeckner,
D. J. J. Antibiot. 1998, 51, 239–242. (c) Udodong, U. E.; Turner,
W. W.; Astleford, B. A.; Brown, Jr., F.; Clayton, M. T.; Dunlap, S.
E.; Frank, S. A.; Grutsch, J. L.; LaGrandeur, L. M.; Verral, D. E.;
Werner, J. A. Tetrahedron Lett. 1998, 39, 6115–6118.
5. (a) Kurokawa, N.; Ohfune, Y. J. Am. Chem. Soc. 1986, 108,
6041–6043. (b) Kurokawa, N.; Ohfune, Y. Tetrahedron 1993, 49,
6195–6222.
(2R,3S)-3-Benzoyloxy-1-tert-butoxycarbonyl-2-hydroxy-
methyl-4-exo-methylenepyrrolidine 37. To a solution of
acetate 36 (75.0 mg, 0.2 mmol) in MeOH (1.0 mL) was
added 0.05N NaOH (400 mL) and the mixture was stirred
at rt for 0.4 h, and diluted with EtOAc (40 mL) and with
H2O (3.0 mL). The aqueous layer was extracted three times
with EtOAc. After usual workup, the alcohol 37 was puri-
fied by preparative TLC (eluent: CH2Cl2–MeOH 96:4) and
obtained as a colourless oil (48.0 mg, 72%): [a]2D7ˆϪ39
(cˆ0.90). IR: 3013, 1716, 1689, 1603, 1477, 1453, 1409.
MS (CI, isobutane): 334 (MϩH)ϩ, 290, 278, 234 (100%),
123, 114. HRMS: Calcd for C18H24NO5 (MϩH)ϩ:
1
6. Mulzer, J.; Becker, R.; Brunner, E. J. Am. Chem. Soc. 1989,
111, 7500–7504.
7. Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1987, 109, 7151–
7157.
334.1655. Found: 334.1661. H NMR (300 MHz): 8.03 (d,
2H, H-Ar), 7.59 (dd, 1H, H-Ar), 7.46 (dd, 2H, H-Ar), 5.60
(m, 1H), 5.48 (broad s, 1H, vCHa), 5.32 (broad s, 1H,
vCHb), 4.25 (1H), 4.07, 3.80 (OCH2), 1.50 (s, 9H, t-Bu).
13C NMR (75.0 MHz): 142.31 (C-4), 133.49 (qC, Ar),
129.88, 128.58 (CH, Ar), 114.32 (vCH2), 80.90 (qC,
t-Bu), 65.41 (OCH2), 64.02 (C-2), 50.08 (C-5), 28.55
(CH3, t-Bu). In this reaction, starting acetate 36 (7.5 mg,
10%) was recovered and a more polar compound 38 was
isolated in small amount (7 mg, 15%). When the reaction
mixture was concentrated under reduced pressure before
extraction the yield of diol 38 was significantly improved.
Mp: 125ЊC. [a]2D7ˆϪ59 (cˆ2.08). IR: 3600, 3406 (broad),
3010, 2992, 2932, 1680, 1478, 1456, 1409, 1369. MS
(FAB): 230 (MϩH)ϩ, 198, 174 (100%), 156, 154, 147,
130. HRMS: Calcd for C11H20NO4 (MϩH)ϩ: 230.1392;
8. (a) Andriamialisoa, R. Z.; Langlois, N. Tetrahedron Lett. 1986,
27, 1149–1152. (b) Langlois, N.; Andriamialisoa, R. Z.
Tetrahedron Lett. 1988, 29, 3259–3262. (c) Langlois, N.;
Andriamialisoa, R. Z. Tetrahedron Lett. 1991, 32, 3057–3058.
(d) Langlois, N.; Favre, F.; Rojas, A. Tetrahedron Lett. 1993, 34,
4635–4638. (e) Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett.
1994, 35, 2889–2892. (f) Langlois, N.; Rojas-Rousseau, A.;
Decavallas, O. Tetrahedron: Asymmetry 1996, 47, 1095–1100.
(g) Panday, S. K.; Langlois, N. Synth. Commun. 1997, 27, 1373–
1384. (h) Calvez, O.; Langlois N. Tetrahedron Lett. 1999, 40,
7099–7100.
9. Preliminary communication: Langlois, N.; Brunet, D.;
Rakotondradany, F. Twelfth International Conference on Organic
Synthesis, 2nd July 1998, Venice, Italy.
10. (a) Thottathil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong,
M. K. Y.; Kissick, T. P. J. Org. Chem. 1986, 51, 3140–3143.
(b). Hamada, Y.; Hara, O.; Kawai, A.; Kohno, Y.; Shiori, T.
Tetrahedron 1991, 47, 8635–8652.
1
Found: 230.1387. H NMR (300 MHz): 5.30 (broad s, 1H,
vCHa), 5.14 (broad s, 1H, vCHb), 4.30 (1H), 4.15, 3.92 (2
broad d, OCH2), 3.85–3.60 (3H), 1.47 (s, 9H, t-Bu). 13C
NMR (50.0 MHz): 146.3 (C-4), 109.8 (vCH2), 80.8 (qC,
t-Bu), 74.5 (C-3), 67.5 (C-2), 63.9 (OCH2), 49.9 (C-5), 28.5
(CH3, t-Bu).
11. Nayera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245–
2303 and references cited therein.
12. Langlois, N.; Van Bac, N.; Dahuron, N.; Delcroix, J. M.;
Deyine, A.; Griffart-Brunet, D.; Chiaroni, A.; Riche, C.
Tetrahedron 1995, 51, 3571–3586.
13. Langlois, N.; Calvez, O.; Radom, M.-O. Tetrahedron Lett.
1997, 38, 8037–8040.
14. Herdeis, C.; Aschenbrenner, A.; Kirfel, A.; Schwabenla¨nder,
F. Tetrahedron: Asymmetry 1997, 8, 2421–2432.
Hydrogenation of 37–25. A solution of 37 (36.6 mg,
0.11 mmol) in EtOAc (3.7 mL) was stirred under H2 atmos-
phere in the presence of PtO2 (4 mg) for 1.5 h. The catalyst
was filtered off on Celite᭨ and washed with EtOAc.
Evaporation of the solvent under reduced pressure furnished
the crude dihydro derivative which was purified by prepara-
tive TLC (eluent–CH2Cl2–MeOH 96:4) to give 25
(29.0 mg, 79%).
15. Frater, G. Helv. Chim. Acta 1979, 62, 2825–2828.
16. For examples: (a) Chamberlin, A. R.; Dezube, M. Tetrahedron
´
Acknowledgements
Lett. 1982, 23, 3055–3058. (b) Chen, S.-Y.; Joullie, M. M. J. Org.
Chem. 1984, 49, 2168–2174. (c) Lee, J.; Marquez, V. E.; Lewin, N.
E.; Kazanietz, M. G.; Bahador, A.; Blumberg, M. Bioorg. Med.
Chem. Lett. 1993, 3, 1101–1106.
We thank J. F. Gallard for the nOe experiments.
17. (a) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
Lett. 1987, 28, 1581–1584. (b) Wittenberger, S. J.; Baker, W. R.;
Donner, B. G.; Hutchins, C. W. Tetrahedron Lett. 1991, 32, 7655–
7658.
18. Bren
˜a-Valle, L. J.; Sanchez, R. C.; Cruz-Almanza, R.
Tetrahedron: Asymmetry 1996, 7, 1019–1026.
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