An efficient method for the stereoselective synthesis of cis-3-substituted prolines: Conformationally constrained α-amino acids

Article abstract of DOI:10.1016/S0040-4020(02)01405-9

An efficient synthesis of enantiomerically pure cis-3-substituted prolines is reported. Key steps involve the stereoselective organocuprate addition to the (E)-α,β-unsaturated ester 1, obtained from the Garner's aldehyde, and expedient oxidation-cyclizati

Full text of DOI:10.1016/S0040-4020(02)01405-9

Tetrahedron 58 (2002) 10475–10484
An efficient method for the stereoselective synthesis of
cis-3-substituted prolines: conformationally constrained
a-amino acids
*
´ ` ´
Celine Flamant-Robin, Qian Wang, Angele Chiaroni and N. Andre Sasaki
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 24 June 2002; revised 8 October 2002; accepted 24 October 2002
Abstract—An efficient synthesis of enantiomerically pure cis-3-substituted prolines is reported. Key steps involve the stereoselective
organocuprate addition to the (E)-a,b-unsaturated ester 1, obtained from the Garner’s aldehyde, and expedient oxidation–cyclization
sequences. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Conformationally constrained a-amino acids have gained
significant attention in recent years. This may be due to the
observations that incorporation of such amino acids into
peptides induces the conformational change and thus may
serve as useful means for obtaining information on receptor
recognition.1 It also provides peptide mimetics that can be
used as new drugs.2 This type of amino acids per se exhibits
interesting biological activities.3 For designing such amino
acids, construction of a proline analogue with a functional
Scheme 1.
group at a specific position of the pyrrolidine framework has
become a major strategy. Among these chimeric amino
acids, the most intensively investigated one is the 3-sub-
epimerizing to thermodynamically more stable trans-
stituted prolines in terms of conformational studies,4
isomers.
biological activities5 and synthetic methodologies.6a–z
Although some of the methods described so far are very
efficient and can provide optically pure final products, it is
still worthwhile developing a simple approach that can lead
2. Results and discussion
to a variety of chimeric amino acids. In the previous papers,
we have described an unprecedented method for the
As part of our continuing pursuit for an easy access to
asymmetric synthesis of 2,3-disubstituted pyrrolidine
optically pure chimeric a-amino acids, we have established
derivatives via the ‘dianion [N–C–C]þbis-electrophile
an efficient method which gives only the desired cis-
[C–C]’ annelation protocol (Scheme 1).7 However, com-
pared with its excellent efficacity for the synthesis of
products starting from chiral oxazolidine a,b-unsaturated
ester (1) which is easily available from the Garner’s
aldehyde.8 (Scheme 2)
enantio- and diastereomerically pure 2,3-trans-disubstituted
pyrrolidines, this method has turned out to be somewhat less
satisfactory for the cis-isomers in terms of diastereo-
selectivity. Indeed, the preparation of cis-3-substituted
to the chiral oxazolidine a,b-unsaturated ester (1) in the
prolines is a challenging task due to their propensity of
It has been reported that the 1,4-addition of dialkylcuprate
presence of trimethylsilyl chloride provides the syn-
diastereomer with excellent diastereoselectivity.9,10 In
fact, the 1,4-addition of lithium dimethylcuprate to 1
provided the single syn-2a in 94% yield. The same addition
reaction with the divinylmagnesium cuprate also gave the
single syn-2b in 91% yield. However, in the case of the
Keywords: 3-cis-substituted proline; stereoselective; organocuprate;
conformationally constrained a-amino acid.
*
Corresponding author. Tel.: þ33-1-69-82-31-01; fax: þ33-1-6907-7247;
e-mail: andre.sasaki@icsn.cnrs-gif.fr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01405-9

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Scheme 2. Reagents and conditions: (i) for 2a: MeLi, CuI, Me3SiCl, THF, 2788C!rt, 94%; for 2b: CH2vCHMgBr, CuI, Me3SiCl, THF, 2788C!rt, 91%; for
2c: PhMgBr, CuCN, Me3SiCl, THF, 2258C!rt, 3 h, 64%. (ii) LiAlH4, THF, rt, 98% 3a, 98% 3b, 97% 3c. (iii) MsCl, Et3N, CH2Cl2, 08C, 87% 4a, 94% 4b,
96% 4c. (iv) (a) Jones oxidation, 08C, 4 h; (b) CH2N2, Et2O, 58% 5a, 70% 5b, 76% 5c. (v) NaH, DMF, 2258C, 78% 6a, 92% 6b, 76% 6c. (vi) 6N HCl, AcOH,
reflux, 4 h, 98% 7a, 90% 7b, 98% 7c.
preparation of adduct 2c, we encountered some difficulties.
In our hands, application of the same reaction conditions
described in the literature ended up with the recovery of the
starting material.10c,d Fortunately, the condition described
by Hruby10e provided the desired syn-2c as a single
diastereomer in 64% yield. Reduction of compounds 2
with LiAlH4 to 3 followed by treatment with mesylchloride
afforded oxazolidine mesylate 4 in excellent yields. Direct
Jones oxidation of 4 and subsequent treatment with
diazomethane provides the methyl esters 5. The yields
were 58, 70 and 76% for 5a–5c, respectively. Ester 5b was
subjected to cyclization by treatment with NaH in DMF at
08C to afford cis-3-vinyl proline derivative 6b in 90% yield
with 10% epimerization at C-2 position. Lowering the
reaction temperature to 2258C could simply surmount this
undesired epimerization. In this manner, cis-3-substituted
proline derivatives 6a, 6b, 6c were obtained in 78, 92 and
76% yield, respectively, as a single diastereomer judging
7 were obtained by purification with ion exchange column
chromatography. In order to confirm the stereochemical
integrity of the 2,3-disubstituted pyrrolidines obtained
according to the present method, the absolute stereo-
chemistry of 6c, deduced from that of the starting material,
was determined by single-crystal X-ray analysis. The Fig. 1
irrefutably shows the cis-configurational relationship
between the two functional groups at C-2 and C-3 positions.
Torsion angle values indicate that the pyrrolidine ring
exhibits an envelope conformation with carbon atom at C-4
1
from H and 13C NMR analyses. Potentiality of compound
6b as a starting material for other cis-3-substituted proline
derivatives was demonstrated in the synthesis of cis-3-
carboxyproline 7d (Scheme 3).
Thus, conventional ozonolysis followed by Jones oxidation
gave 6d in 50% yield. After the removal of the protecting
groups by treatment with 6N HCl, cis-3-substituted prolines
Scheme 3. Reagents and conditions: (i) (a) O3, CH2Cl2; PPh3; (b) Jones
oxidation, 08C, 4 h, 50%. (ii) 6N HCl, AcOH, reflux, 4 h, 98%.
Figure 1. ORTEP drawing of 6c. Displacement ellipsoids are shown at the
30% probability level.

C. Flamant-Robin et al. / Tetrahedron 58 (2002) 10475–10484
10477
Scheme 4. Reagents and conditions: (i) CeCl3·7H2O, (CO2H)2, CH3CN, rt, 2 h, 90% 8b. (ii) TBDMSCl, imidazole, DMF, rt, 83% 9b. (iii) NaH, DMF, 08C,
83% for three steps 10a, 90% 10b. (iv) Bu4NF, THF, rt, 15 h, 81% 11a, 81% 11b. (v) For 6a (a) Jones oxidation, 08C, 4 h; (b) CH2N2, Et2O, 08C, 58%; for 12b
Jones oxidation, 08C, 1.5 h, 56%.
˚
position deviating out of the mean plane by 0.571(3) A. The
dihedral angle between the pyrrolidine ring and the phenyl
group is 61.58.
cis-3-substituted prolines in six step sequences in 34–53%
overall yields. Transformation of 6b to other cis-3-
substituted prolines continues in this laboratory.
Initially, we transformed 4 to a-amino alcohol 811 that was
then cyclized to the pyrrolidines 10. Further deprotection-
oxidation protocol also provided desired cis-3-substituted
prolines 12 as illustrated in Scheme 4. Although the
preparation of cis-3-vinyl proline 12b by this route could
be carried out with ease, the conversion of 4a to 10a
required much precaution. The intermediates 8a and 9a
were found to be so unstable that they had to be used
immediately for the subsequent transformations. Since more
convenient route was established as shown in Scheme 1, we
did not pursue this route for the synthesis of N-Boc-cis-3-
phenyl proline.
4. Experimental
4.1. General
All reactions requiring anhydrous conditions or in an inert
atmosphere were conducted under an atmosphere of Argon.
Tetrahydrofuran, benzene were distilled from sodium-
benzophenone and methylene chloride from P2O5
immediately prior to use. Infrared (IR) spectra were
recorded on a Perkin Elmer Spectrum BX spectrometer.
1H and 13C NMR spectra were measured on Brucker
AM-300 and AC-250 (300 and 250 MHz, respectively)
spectrometers with tetramethylsilane as internal standard (d,
ppm). Flash chromatography was performed using
Kieselgel 60 (230–400 mesh, E. Merck) and usually
employed a stepwise solvent polarity gradient, correlated
with TLC mobility. Optical rotations were determined on a
JASCO P-1010 polarimeter at room temperature. HPLC
analyses were carried out on an Alliance (Waters 2690) onto
an analytical column (Hypercarb Thermohypersil,
4.6£100 mm, 5 m) with solvent mixtures of water (þTFA
0.1%) and acetonitrile (þTFA 0.1%). Eluted compounds
were detected by absorbance at 213 nm (Waters 996
Photodiode Array Detector) and by mass (Waters Micro-
mass ZQ). Mass spectra were run on a Kratos MS-80
spectrometer (CI), a Navigator of Thermo Quest spec-
trometer (ESI), an AEI MS-9 spectrometer (IE) and a
MALDI TOF spectrometer (high resolution) respectively.
Melting points were determined on a Bu¨chi melting
point apparatus and are uncorrected. Elemental analyses
were carried out by the microanalytical laboratory at the
ICSN.
Diastereomeric excess (de) of each final product was
1
assessed by H NMR spectroscopy and was determined to
be of 95–98%. This is further confirmed by the HPLC
analysis (vide infra in Section 4). In compound 7d, the
presence of its trans-diastereomer was detected in 1H NMR
spectra in 3–5% by integration. These figures were further
refined by HPLC analysis. In this case it is assumed that
epimerization has taken place at C-2 or C-3 position.
Enantiomeric excess (ee) of the final products, 7a and 7b, is
assumed to be that of the starting material, D-serine, that is
purchased as optically pure amino acid. It should be noted
that only one diastereomer was obtained during the
organocuprate addition to a,b-unsaturated ester 1.
3. Conclusion
Starting from easily available a,b-unsaturated ester 1, a
straight-forward method has been developed for the
synthesis of highly enantio- and diastereomerically pure

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4.1.1. (20E,4S)-4-(20-Ethoxycarbonyl-vinyl)-2,2-
dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
(1). To a solution of Garner’s aldehyde (11.1 g, 48.4 mmol)
in benzene (300 mL) was added ethyl (triphenylphosphor-
anylidene) acetate (18.9 g, 53.2 mmol). After stirring at rt
for 36 h, the reaction mixture was filtered through Celite, the
solvent was removed under vacuum and the residue was
purified by column chromatography on silica gel
(heptane/EtOAc¼4:1) to give 1 (12.4 g, 85%) as two
rotamers: mp 48–498C; [a]D¼þ60 (c 1.9, CHCl3), {lit.
[a]D¼þ54.3 (c 3.66, CHCl3) (Ref. 10a)); IR (CHCl3) n
3026, 2984, 2938, 2881, 1712, 1693, 1477, 1456, 1391,
1368, 1303 cm21; 1H NMR (300 MHz, CDCl3) d 6.83 (dd,
J¼7.7, 15.2 Hz, 1H), 5.91 (br t, J¼15.2 Hz, 1H), 4.56–4.37
(m, 1H), 4.25–4.15 (m, 2H), 4.08 (dd, J¼6.4, 9.0 Hz, 1H),
3.79 (dd, J¼2.6, 9.0 Hz, 1H), 1.64 (s, 1.5H), 1.60 (s, 1.5H),
1.53 (s, 1.5H), 1.49 (s, 1.5H), 1.42 (s, 9H), 1.28 (t, J¼
7.0 Hz, 3H); 13C NMR (62.5 MHz, CDCl3) d 166.1, 151.5,
145.8, 122.3, 94.2, 80.4, 67.3, 60.4, 58.0, 28.3, 27.3, 26.4,
24.6, 23.6, 14.2; MS (CI) m/z 300 [MþH]þ. Anal. calcd for
C15H25NO5: C 60.18; H 8.42; N 4.68. Found: C 60.05; H
8.64; N 4.88.
rotamers: [a]D¼þ10 (c 2.2, CHCl3); IR (CHCl3) n 3025,
3016, 2982, 2938, 1727, 1690, 1477, 1455, 1392, 1367,
1
1258 cm21; H NMR (300 MHz, CDCl3) d 5.77–5.56 (m,
1H), 5.15–5.01 (m, 2H), 4.07 (q, J¼7.2 Hz, 2H), 4.03–3.96
(m, 0.5H), 3.93–3.82 (m, 1.5H), 3.82–3.74 (m, 1H), 3.17–
3.03 (m, 1H), 2.48 (dd, J¼3.8, 15.3 Hz, 1H), 2.35–2.20 (m,
1H), 1.58 (s, 1.5H), 1.54 (s, 1.5H), 1.45 (s, 9H), 1.42 (s, 6H),
1.19 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
172.5, 152.9, 152.5, 137.6, 117.3, 117.0, 94.5, 94.0, 80.2,
64.7, 64.4, 60.4, 59.8, 43.0, 42.8, 35.2, 34.2, 28.4, 27.0,
26.3, 24.2, 22.7, 14.3; MS (ESI) m/z 328 [MþH]þ, 350
[MþNa]þ, 366 [MþK]þ, 677 [2MþNa]þ, 693 [2MþK]þ.
Anal. calcd for C17H29NO5: C 62.36; H 8.93; N 4.28.
Found: C 62.38; H 9.09; N 4.21.
4.1.4. (10S,4S)-4-(20-Ethoxycarbonyl-10-phenyl-ethyl)-
2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl
ester (2c). To a solution of 1 (1.01 g, 3.39 mmol) in THF
(10 mL) at 2258C was added CuCN (30 mg, 0.34 mmol).
This mixture was stirred for 10 min before TMSCl
(0.04 mL, 0.34 mmol) was added. After stirring for
25 min, phenyl magnesium bromide in Et2O (3 M,
1.24 mL, 3.72 mmol) was added dropwise. The cooling
bath was removed and the reaction mixture was stirred for
3 h. The reaction was quenched with NH4Cl and extracted
with Et2O. The ether extracts were washed with brine, dried
and evaporated. Column chromatography on silica gel
eluting with heptane/EtOAc (25/1) afforded compound 2c
(823 mg, 64%) as two rotamers: [a]D¼-31 (c 2.5, CHCl3);
IR (CHCl3) n 3023, 3019, 3016, 2982, 2937, 1727, 1691,
1392, 1376, 1367, 1257, 1169, 1107, 1089, 1061, 1031,
4.1.2. (10R,4S)-4-(20-Ethoxycarbonyl-10-methyl-ethyl)-
2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl
ester (2a). To a stirred suspension of CuI (20.5 g,
108 mmol) in THF (250 mL) at 08C was added methyl
lithium in Et2O (1.6 M, 134 mL, 215 mmol). This mixture
was cooled to 2788C for 15 min and TMSCl (13.7 mL,
108 mmol) and 1 (5.36 g, 18 mmol) in THF (100 mL) were
added dropwise respectively. The temperature was allowed
to reach rt gradually. The reaction was quenched with a
NH4OH/NH4Cl (1/9) pH 8 buffer solution and the mixture
was extracted with Et2O. The ether extracts were washed
with brine, dried and evaporated. Column chromatography
on silica gel eluting with heptane/EtOAc (10/1) afforded
compound 2a (5.32 g, 94%) as two rotamers: [a]D¼þ18 (c
2.0, CHCl3), (lit. [a]D¼þ19.8 (c 2.18, CHCl3) (Ref. 10a));
IR (CHCl3) n 3027, 2983, 2937, 2881, 1727, 1688, 1477,
1
852 cm21; H NMR (300 MHz, CDCl3) d 7.34–7.15 (m,
5H), 4.21–4.12 (m, 0.5H), 4.00 (q, J¼7.3 Hz, 2H), 4.05–
3.85 (m, 2.5H), 3.81–3.66 (m, 1H), 2.85–2.81 (m, 2H), 1.67
(s, 1.5H), 1.57 (s, 9H), 1.53 (s, 1.5H), 1.49 (s, 1.5H), 1.44 (s,
1.5H), 1.14–1.03 (m, 3H); 13C NMR (75 MHz, CDCl3) d
172.5, 152.8, 152.2, 140.4, 128.7, 128.2, 127.9, 126.9, 94.4,
94.3, 80.4, 64.1, 63.7, 61.9, 61.7, 60.3, 43.0, 33.8, 32.5, 28.5,
26.7, 26.2, 23.9, 22.5, 14.1; MS (ESI) m/z 400 [MþNa]þ, 416
[MþK]þ, 777 [2MþNa]þ. Anal. calcd for C21H31NO5: C
66.82; H 8.28; N 3.71. Found: C 66.56; H 8.47; N 3.53.
1
1456, 1392, 1367, 1257, 1174 cm21; H NMR (250 MHz,
CDCl3) d 4.14 (q, J¼7.2 Hz, 2H), 3.96–3.77 (m, 3H), 2.56–
2.46 (m, 2H), 2.20–1.96 (m, 1H), 1.63–1.37 (m, 15H), 1.26
(t, J¼7.2 Hz, 3H), 0.95 (d, J¼6.7 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3) d 173.2, 152.5, 94.3, 94.0, 80.0, 64.2,
61.2, 60.3, 37.1, 36.5, 33.0, 32.6, 28.4, 26.9, 26.3, 24.0,
22.7, 16.7, 16.5, 14.3; MS (ESI) m/z 316 [MþH]þ, 338
[MþNa]þ. Anal. calcd for C16H29NO5: C 60.93; H 9.27; N
4.44. Found: C 60.84; H 9.51; N 4.31.
4.1.5. (10R,4S)-4-(30-Hydroxy-10-methyl-propyl)-2,2-
dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
(3a). To a solution of 2a (5.32 g, 16.9 mmol) in THF
(170 mL) at 08C was added LiAlH4 (730 mg, 18.6 mmol).
After stirring at rt for 1.5 h, the mixture was cooled to 08C
and water (0.73 mL), 15% NaOH aqueous solution
(0.73 mL) and water (2.19 mL) were added sequentially.
The mixture was stirred for 30 min and filtered through
Celite/Na2SO4. The filtrate was evaporated in vacuo and
purified by chromatography on silica gel (heptane/EtOAc¼
2/1) to give 4.54 g (98%) of 3a as two rotamers: [a]D¼þ52
(c 2.2, CHCl3); IR (CHCl3) n 3467, 3012, 2979, 2881, 1686,
1477, 1456, 1393, 1378, 1367, 1254, 1172 cm21; 1H NMR
(300 MHz, CDCl3) d 3.94–3.58 (m, 5H), 2.17–2.10 (m,
2H), 1.82–1.71 (m, 1H), 1.59 (br s, 3H), 1.44 (s, 12H),
1.40–1.27 (br s, 1H), 0.91 (d, J¼7.2 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3) d 153.0, 152.8, 93.9, 93.7, 80.0, 79.6,
64.7, 61.7, 60.7, 34.5, 32.3, 28.3, 26.7, 26.3, 24.3, 22.8,
16.3; MS (CI) m/z 274 [MþH]þ. Anal. calcd for
C14H27NO4: C 61.51; H 9.96; N 5.12. Found: C 61.85; H
10.18; N 5.08.
4.1.3. (10S,4S)-4-(10-Ethoxycarbonylmethyl-allyl)-2,2-
dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
(2b). To a stirred suspension of CuI (19.1 g, 100 mmol) in
THF (200 mL) at 258C was added vinyl magnesium
bromide in THF (1 M, 200 mL, 200 mmol). After being
stirred at 258C for 15 min, the mixture was cooled to
2788C for 15 min and TMSCl (12.8 mL, 100 mmol) and 1
(5.0 g, 16.7 mmol) in THF (60 mL) were added dropwise.
The temperature was allowed to reach rt gradually. The
reaction was quenched with a NH4OH/NH4Cl (1/9) pH 8
buffer solution and extracted with Et2O. The ether extracts
were washed with brine, dried and evaporated. Column
chromatography on silica gel eluting with heptane/EtOAc
(15/1) afforded compound 2b (4.96 g, 91%) as two

C. Flamant-Robin et al. / Tetrahedron 58 (2002) 10475–10484
10479
4.1.6. (10S,4S)-4-[10-(200-Hydroxy-ethyl)-allyl]-2,2-
dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
(3b). To a solution of 2b (1.34 g, 4.1 mmol) in THF (20 mL)
at 08C was added LiAlH4 (192 mg, 4.9 mmol). After stirring
at rt for 2 h, the mixture was cooled to 08C and water
(0.25 mL), 15% NaOH aqueous solution (0.25 mL) and
water (0.75 mL) were added sequentially. The mixture was
stirred for 30 min and filtered through Celite/Na2SO4. The
filtrate was evaporated in vacuo and purified by column
chromatography on silica gel (heptane/EtOAc¼2/1) to give
3b (1.14 g, 98%) as two rotamers: [a]D¼þ23 (c 2.4,
CHCl3); IR (CHCl3) n 3629, 3482, 3024, 3009, 2981, 2938,
2882, 1685, 1477, 1455, 1392, 1367, 1254, 1223 cm21; 1H
NMR (300 MHz, CDCl3) d 5.77–5.57 (m, 1H), 5.14–5.02
(m, 2H), 4.01–3.75 (m, 3H), 3.73–3.64 (m, 1H), 3.61–3.52
(m, 1H), 2.64–2.52 (m, 1H), 2.18 (br s, 1H), 1.81–1.68 (m,
1H), 1.61–1.44 (m, 1H), 1.61 (s, 1.5H), 1.57 (s, 1.5H), 1.50
(s, 1.5H), 1.47 (s, 9H), 1.44 (s, 1.5H); 13C NMR (62.5 MHz,
CDCl3) d 152.8, 152.2, 139.0, 117.2, 116.7, 94.0, 93.6, 80.0,
79.7, 65.3, 60.6, 44.5, 44.3, 33.0, 32.6, 28.3, 26.9, 26.3,
24.4, 22.8; MS (EI) m/z 285 [M]þ, 230, 212. Anal. calcd for
C15H27NO4: C 63.13; H 9.54; N 4.91. Found: C 63.32; H
9.88; N 4.83.
16H), 0.94 (d, J¼7.0 Hz, 3H); 13C NMR (62.5 MHz,
CDCl3) d 153.0, 152.4, 94.0, 93.8, 80.1, 79.8, 68.6, 68.3,
64.2, 61.3, 37.3, 31.7, 30.8, 30.5, 28.5, 26.7, 26.1, 24.0,
22.5, 15.9; MS (EI) m/z 351 [M]þ, 278. Anal. calcd for
C15H29NO6S: C 51.26; H 8.32; N 3.99; S 9.12. Found: C
51.17; H 8.41; N 4.01; S 8.89.
4.1.9. (10S,4S)-4-[10-(200-Methanesulfonyloxy-ethyl)allyl]-
2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl
ester (4b). To a solution of 3b (1.13 g, 3.97 mmol) in
CH2Cl2 (23 mL) at 08C were added Et3N (0.72 mL,
5.15 mmol) and MsCl (0.37 mL, 4.76 mmol). After stirring
at rt for 1 h, the mixture was quenched with water and
extracted with CH2Cl2. The organic extracts were washed
with 1N HCl, water, saturated aqueous NaHCO3 solution,
brine, dried and evaporated. Column chromatography on
silica gel eluting with heptane/EtOAc (3/1) afforded
compound 4b (1.35 g, 94%) as two rotamers: [a]D¼þ33
(c 3.14, CHCl3); IR (CHCl3) n 3029, 3010, 2982, 2938,
2882, 1688, 1476, 1455, 1392, 1366, 1252, 1174 cm21; 1H
NMR (300 MHz, CDCl3) d 5.72–5.54 (m, 1H), 5.22–5.09
(m, 2H), 4.29 (dt, J¼6.2, 9.3 Hz, 1H), 4.14 (ddd, J¼4.5, 7.1,
9.8 Hz, 1H), 4.02–3.78 (m, 3H), 2.99 (s, 3H), 2.73–2.60
(m, 1H), 2.06–1.92 (m, 1H), 1.75–1.54 (m, 1H), 1.63 (s,
1.5H), 1.57 (s, 1.5H), 1.48 (s, 12H); 13C NMR (62.5 MHz,
CDCl3) d 152.9, 152.2, 137.5, 118.8, 118.2, 94.3, 93.8, 80.3,
80.1, 68.4, 68.2, 64.9, 60.4, 43.6, 43.5, 37.4, 29.2, 28.4,
27.0, 26.3, 24.3, 22.7; MS (EI) m/z 363 [M]þ, 308, 290, 264.
Anal. calcd for C16H29NO6S: C 52.87; H 8.04; N 3.85; S
8.82. Found: C 52.72; H 8.18; N 3.82; S 8.71.
4.1.7. (10S,4S)-4-(30-Hydroxy-10-phenyl-propyl)-2,2-
dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
(3c). To a solution of 2c (630 mg, 1.67 mmol) in THF
(10 mL) at 08C was added LiAlH4 (85 mg, 2.17 mmol).
After stirring at rt for 30 min, the temperature was cooled to
08C and water (0.09 mL), 15% NaOH aqueous solution
(0.09 mL) and water (0.27 mL) were added sequentially.
The mixture was stirred for 30 min and filtered through
Celite/Na2SO4. The filtrate was evaporated in vacuo and
purified by column chromatography on silica gel
(heptane/EtOAc¼4/1) to give 548 mg (97%) of 3c as two
rotamers: [a]D¼215 (c 1.5, CHCl3); IR (CHCl3) n 3627,
3480, 3025, 3015, 2982, 2938, 2885, 1688, 1494, 1477,
4.1.10. (10S,4S)-4-(30-Methanesulfonyloxy-10-phenylpro-
pyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-
butyl ester (4c). To a solution of 3c (91 mg, 0.28 mmol)
in CH2Cl2 (2 mL) at 08C were added Et3N (0.05 mL,
0.35 mmol) and MsCl (0.02 mL, 0.33 mmol). After stirring
at rt for 1 h, the reaction was quenched with water and
extracted with CH2Cl2. The organic extracts were washed
with 1N HCl, water, saturated aqueous NaHCO3 solution,
brine, dried and evaporated. Column chromatography on
silica gel eluting with heptane/EtOAc (6/1) afforded
compound 4c (108 mg, 96%) as two rotamers: [a]D¼25
(c 1.3, CHCl3); IR (CHCl3) n 3029, 3024, 3018, 2983, 1691,
1454, 1392, 1376, 1367, 1264, 1247, 1173 cm21; 1H NMR
(250 MHz, CDCl3) d 7.42–7.14 (m, 5H), 4.29–4.16 (m,
1H), 4.15–3.93 (m, 3H), 3.84–3.73 (m, 1H), 3.53–3.42 (m,
1H), 2.82 (s, 3H), 2.36–2.20 (m, 2H), 1.71–1.40 (m, 15H);
13C NMR (75 MHz, CDCl3) d 152.8, 152.3, 139.4, 129.0,
128.7, 128.6, 128.2, 127.1, 94.6, 94.1, 80.3, 68.7, 68.4, 64.0,
63.7, 62.1, 61.9, 43.1, 37.1, 28.4, 27.6, 26.7, 26.5, 26.1,
24.0, 22.4; MS (ESI) m/z 436 [MþNa]þ, 452 [MþK]þ.
Anal. calcd for C20H31NO6S: C 58.09; H 7.56; N 3.39; S
7.75. Found: C 58.27; H 7.51; N 3.31; S 7.49.
1
1454, 1392, 1368, 1248, 1171 cm21; H NMR (250 MHz,
CDCl3) d 7.38–7.18 (m, 5H), 4.12–4.05 (m, 1H), 3.99 (d,
J¼8.8 Hz, 1H), 3.82–3.73 (m, 1H), 3.68–3.58 (m, 1H),
3.53–3.39 (m, 2H), 2.34 (br s, 1H), 2.14–2.03 (m, 2H),
1.73–1.42 (m, 6H), 1.45 (s, 9H); 13C NMR (62.5 MHz,
CDCl3) d 152.8, 152.7, 140.8, 128.7, 126.8, 94.7, 94.2, 80.2,
64.5, 64.3, 62.3, 61.3, 43.6, 31.3, 30.1, 28.5, 26.8, 26.3,
24.3, 22.7; MS (ESI) m/z 336 [MþH]þ, 358 [MþNa]þ, 374
[MþK]þ. HRMS Calcd for C19H29NO4Na (MþNa):
358.19943. Found: 358.19954.
4.1.8. (10R,4S)-4-(30-Methanesulfonyloxy-10-methyl-pro-
pyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-
butyl ester (4a). To a solution of 3a (107 mg, 0.39 mmol)
in CH2Cl2 (2 mL) at 08C were added Et3N (0.07 mL,
0.51 mmol) and MsCl (0.04 mL, 0.47 mmol). After stirring
at rt for 1 h, the reaction was quenched with water and
extracted with CH2Cl2. The organic extracts were washed
with 1N HCl, water, saturated aqueous NaHCO3 solution,
brine, dried and evaporated. Column chromatography on
silica gel eluting with heptane/EtOAc (4/1) afforded
compound 4a (120 mg, 87%) as two rotamers: [a]D¼þ39
(c 4.5, CHCl3); IR (CHCl3) n 3022, 3016, 2981, 2936, 2881,
1685, 1476, 1456, 1392, 1366, 1255, 1211, 1174 cm21; 1H
NMR (250 MHz, CDCl3) d 4.39–4.18 (m, 2H), 3.97–3.74
(m, 3H), 3.01 (s, 3H), 2.25–1.92 (m, 2H), 1.64–1.45 (m,
4.1.11. (2S,3R)-2-tert-Butoxycarbonylamino-5-methane-
sulfonyloxy-3-methylpentanoic acid methyl ester (5a).
Jones reagent (2.67 M, 1.48 mL, 3.95 mmol) was added to a
solution of 4a (336 mg, 0.96 mmol) in acetone (10 mL) at
08C. After stirring at 08C for 4 h, the reaction was quenched
by addition of propan-2-ol. The mixture was stirred for
30 min and neutralized with saturated aqueous NaHCO3 to
pH 4–5 and extracted with EtOAc. The organic layers were
washed with brine, dried and evaporated. The residue was

10480
C. Flamant-Robin et al. / Tetrahedron 58 (2002) 10475–10484
dissolved in Et2O and CH2N2 in Et2O was added to the
solution. The mixture was evaporated in vacuo and purified
by column chromatography on silica gel (heptane/EtOAc¼
6/1) to afford compound 5a (190 mg, 58%): [a]D¼þ20 (c
1.6, CHCl3); IR (CHCl3) n 3437, 3022, 2980, 1739, 1711,
C18H27NO7S: C 53.85; H 6.78; N 3.49; S 7.99. Found: C
53.81; H 7.09; N 3.81; S 7.51.
4.1.14. (2S,3R)-3-Methyl-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester (6a) from 5a. To a
suspension of NaH (55–65% in mineral oil, 45 mg,
1.11 mmol, washed with pentane) in DMF (2 mL) at
2258C was added 5a (190 mg, 0.56 mmol) in DMF
(2 mL). After being stirred at 2258C for 1 h, the reaction
mixture was quenched by addition of water and extracted
with ether. The combined ether layers were washed with
water and brine, dried, and evaporated. Column chroma-
tography on silica gel (heptane/EtOAc¼8/1) afforded
compound 6a (107 mg, 78%) as two rotamers: mp 46–
478C; [a]D¼þ12 (c 0.8, CHCl3); IR (CHCl3) n 3025, 3022,
3020, 3019, 3018, 3016, 3014, 2975, 1741, 1687, 1404,
1367, 1170, 1150, 1119 cm21; 1H NMR (250 MHz, CDCl3)
d 4.27 (d, J¼8.8 Hz, 0.4H), 4.20 (d, J¼8.8 Hz, 0.6H), 3.75–
3.58 (m, 4H), 3.38–3.23 (m, 1H), 2.60–2.37 (m, 1H), 2.00–
1.87 (m, 1H), 1.84–1.60 (m, 1H), 1.45 (s, 3.6H), 1.41 (s,
5.4H), 0.99 (d, J¼7.3 Hz, 3H); 13C NMR (62.5 MHz,
CDCl3) d 172.4, 154.4, 153.8, 79.8, 63.4, 62.9, 51.6, 51.5,
46.2, 45.8, 37.1, 36.3, 32.0, 31.2, 28.4, 28.3, 14.8; MS (EI)
m/z 244 [MþH]þ, 243 [M]þ, 184, 142. Anal. calcd for
C12H21NO4: C 59.24; H 8.70; N 5.76. Found: C 59.33; H
8.76; N 5.52.
1502, 1457, 1438, 1357, 1226, 1173 cm21 1H NMR
;
(250 MHz, CDCl3) d 5.14 (br d, J¼9.3 Hz, 1H), 4.48–
4.27 (m, 3H), 3.76 (s, 3H), 3.07 (s, 3H), 2.36–2.24 (m, 1H),
1.93–1.79 (m, 1H), 1.71–1.57 (m, 1H), 1.44 (s, 9H), 0.87
(d, J¼6.8 Hz, 3H); 13C NMR (62.5 MHz, CDCl3) d 172.4,
155.9, 80.1, 68.0, 56.1, 52.5, 37.3, 32.6, 32.4, 28.3, 14.4;
MS (ESI) m/z 340 [MþH]þ, 362 [MþNa]þ, 378 [MþK]þ.
HRMS Calcd for C13H25NO7SNa (MþNa) 362.12494.
Found: 362.12404.
4.1.12. (2S,3S)-2-tert-Butoxycarbonylamino-3-(20-meth-
anesulfonyloxyethyl)pent-4-enoic acid methyl ester
(5b). Jones reagent (2.67 M, 1.82 mL, 4.86 mmol) was
added to a solution of 4b (588 mg, 1.62 mmol) in acetone
(16 mL) at 08C. After stirring at 08C for 4 h, the reaction was
quenched by addition of propan-2-ol. The mixture was
stirred for 30 min and neutralized with saturated aqueous
NaHCO3 to pH 4–5 and extracted with EtOAc. The organic
layers were washed with brine, dried and evaporated. The
residue was dissolved in Et2O and CH2N2 in Et2O was
added to the solution. The mixture was evaporated in vacuo
and purified by flash column chromatography on silica gel
(heptane/EtOAc¼6/1) to afford compound 5b (393 mg,
70%): [a]D¼þ48 (c 0.7, CHCl3); IR (CHCl3) n 3434, 3021,
2983, 2956, 1743, 1712, 1501, 1364, 1226, 1213,
4.1.15. (2S,3S)-3-Vinyl-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester 2-methyl ester (6b). To a suspension of
NaH (55–65% in mineral oil, 172 mg, 4.29 mmol, washed
with pentane) in DMF (10 mL) at 2258C was added 5b
(753 mg, 2.14 mmol) in DMF (10 mL). After being stirred
at 2258C for 1 h, the reaction mixture was quenched by
addition of water and extracted with ether. The combined
ether layers were washed with water and brine, dried, and
evaporated. Flash column chromatography on silica gel
(heptane/EtOAc¼15/1) afforded compound 6b (563 mg,
92%) as two rotamers: [a]D¼þ34 (c 1.5, CHCl3); IR
(CHCl3) n 3024, 3022, 3019, 2980, 2953, 1743, 1685, 1401,
1174 cm21 1H NMR (300 MHz, CDCl3) d 5.56 (ddd,
;
J¼9.1, 10.3, 17.0 Hz, 1H), 5.23–5.12 (m, 2H), 5.06 (br d,
J¼8.8 Hz, 1H), 4.46 (dd, J¼3.7, 8.8 Hz, 1H), 4.37–4.26 (m,
1H), 4.26–4.17 (m, 1H), 3.75 (s, 3H), 3.02 (s, 3H), 2.88–
2.76 (m, 1H), 2.06–1.94 (m, 1H), 1.86–1.73 (m, 1H), 1.44
(s, 9H); 13C NMR (62.5 MHz, CDCl3) d 171.6, 155.7,
134.7, 119.6, 80.1, 67.7, 56.4, 52.3, 42.8, 37.2, 30.1, 28.2;
MS (EI) m/z 352 [MþH]þ, 351 [M]þ, 278. HRMS Calcd for
C14H25NO7SNa (MþNa): 374.12494. Found: 374.12581.
1
1367, 1169, 1129 cm21; H NMR (300 MHz, CDCl3) d
4.1.13. (2S,3S)-2-tert-Butoxycarbonylamino-5-methane-
sulfonyloxy-3-phenyl-pentanoic acid methyl ester (5c).
Jones reagent (2.67 M, 1.33 mL, 3.55 mmol) was added to a
solution of 4c (490 mg, 1.18 mmol) in acetone (12 mL) at
08C. After stirring at 08C for 4 h, the reaction was quenched
by addition of propan-2-ol. The mixture was stirred for
30 min and neutralized with saturated aqueous NaHCO3 to
pH 4–5 and extracted with EtOAc. The organic layers were
washed with brine, dried and evaporated. The residue was
dissolved in Et2O and CH2N2 in Et2O was added to the
solution. The mixture was evaporated in vacuo and purified
by flash column chromatography on silica gel
(heptane/EtOAc¼4/1) to afford compound 5c (360 mg,
76%): [a]D¼þ49 (c 1.8, CHCl3); IR (CHCl3) n 3432, 3029,
3020, 3016, 2982, 2954, 1743, 1711, 1496, 1455, 1437,
5.74–5.59 (m, 1H), 5.20–5.10 (m, 2H), 4.37 (d, J¼8.1 Hz,
0.4H), 4.29 (d, J¼8.8 Hz, 0.6H), 3.77–3.64 (m, 4H), 3.43–
3.30 (m, 1H), 3.13–2.98 (m, 1H), 2.14–1.91 (m, 2H), 1.46
(s, 3,6H), 1.40 (s, 5.4H); 13C NMR (75 MHz, CDCl3) d
171.9, 153.7, 134.6, 117.5, 80.1, 63.0, 62.5, 51.5, 46.3, 46.0,
45.7, 45.4, 29.3, 28.5, 28.3; MS (EI) m/z 256 [MþH]þ,
255[M]þ, 196, 154. Anal. calcd for C13H21NO4: C 61.16; H
8.29; N 5.49. Found: C 61.11; H 8.33; N 5.43.
4.1.16. (2S,3S)-3-Phenyl-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester (6c). To a suspension
of NaH (55–65% in mineral oil, 54 mg, 1.36 mmol, washed
with pentane) in DMF (2 mL) at 2258C was added 5c
(273 mg, 0.68 mmol) in DMF (2 mL). After being stirred at
2258C for 50 min, the reaction mixture was quenched by
addition of water and extracted with ether. The combined
ether layers were washed with water and brine, dried, and
evaporated. Flash column chromatography on silica gel
(heptane/EtOAc¼8/1) afforded compound 6c (158 mg,
76%) as two rotamers: mp 90.48C; [a]D¼þ91 (c 1.5,
CHCl3); IR (CHCl3) n 3026, 3021, 3017, 3011, 2981, 1741,
1688, 1477, 1455, 1436, 1402, 1367, 1179, 1133, 997,
1393, 1367, 1174, 990, 971, 933, 920 cm21 1H NMR
;
(300 MHz, CDCl3) d 7.35–7.24 (m, 3H), 7.15–7.10 (m,
2H), 4.92 (br d, J¼9.2 Hz, 1H), 4.67 (dd, J¼4.1, 9.2 Hz,
1H), 4.31–4.22 (m, 1H), 4.11–4.02 (m, 1H), 3.68 (s, 3H),
3.49–3.38 (m, 1H), 2.89 (s, 3H), 2.35–2.12 (m, 2H), 1.42
(s, 9H); 13C NMR (75 MHz, CDCl3) d 171.3, 155.6, 137.3,
129.7, 128.1, 127.8, 80.0, 67.8, 57.0, 52.1, 43.9, 36.9, 30.9,
28.1; MS (EI) m/z 402 [MþH]þ, 346. Anal. calcd for
1
908 cm21; H NMR (250 MHz, CDCl3) d 7.35–7.18 (m,

C. Flamant-Robin et al. / Tetrahedron 58 (2002) 10475–10484
10481
5H), 4.55 (d, J¼8.8 Hz, 0.4H), 4.46 (d, J¼8.5 Hz, 0.6H),
3.96–3.80 (m, 1H), 3.75–3.56 (m, 1H), 3.53–3.39 (m, 1H),
3.27 (s, 1.8H), 3.24 (s, 1.2H), 2.69–2.46 (m, 1H), 2.16–2.04
(m, 1H), 1.48 (s, 3.5H), 1.40 (s, 5.5H); 13C NMR
(62.5 MHz, CDCl3) d 171.8, 153.8, 136.9, 136.8, 128.5,
128.4, 128.0, 127.9, 127.6, 127.5, 80.2, 80.1, 64.4, 64.0,
51.4, 51.3, 48.1, 47.2, 46.3, 45.9, 28.5, 28.4, 27.6; MS (ESI)
m/z 306 [MþH]þ, 328 [MþNa]þ, 344 [MþK]þ. Anal. calcd
for C17H23NO4: C 66.86; H 7.59; N 4.59. Found: C 66.68; H
7.57; N 4.39.
column was washed thoroughly with water and the amino
acid was eluted with 2 M NH4OH to give 7c (10 mg, 98%):
mp 216–2248C (decomp.), (lit. mp 214–2208C (Ref. 6f));
[a]D¼þ82 (c 0.5, 6 M HCl), (lit. [a]D¼þ63.7 (c 4.5, 6 M
HCl) (Ref. 6f)); 96% de (HPLC, water/acetonitrile¼92:8,
flow rate 0.6 mL/min, major diastereomer 22.6 min, minor
diastereomer 21.3 min); IR (hydrochloride, nujol) n 3413,
1
1723 cm21; H NMR (300 MHz, D2O) d 7.43–7.25 (m,
5H), 4.31 (d, J¼9.2 Hz, 1H), 3.88 (q, J¼8.1 Hz;1H), 3.74
(ddd, J¼4.4, 7.6, 12.0 Hz, 1H), 3.48–3.27 (m, 1H), 2.53–
2.39 (m, 1H), 2;37–2.23 (m, 1H). 13C NMR (75 MHz, D2O)
d 170.9, 137.1, 129.5, 128.8, 128.7, 64.5, 46.7, 46.2, 30.2;
MS (ESI) m/z 192 [MþH]þ, 214 [MþNa]þ, 230 [MþK]þ.
HRMS Calcd for C11H13NO2Na (MþNa) 214.08440.
Found: 214.08365.
4.1.17. (2S,3R)-3-Methyl-pyrrolidine-2-carboxylic acid
(7a). A solution of 6a (19 mg, 78 mmol) in HCl (6N,
1.3 mL) and acetic acid (0.3 mL) was refluxed for 4 h. The
volatile was evaporated. The residue was dissolved in
EtOH. The solution was treated dropwise with propylene
oxide under heating and evaporated to dryness. The residue
was dissolved in water and passed through a column of
Dowex 50WX8-200 ion-exchange resin (Hþ form). The
column was washed thoroughly with water and the amino
acid was eluted with 2 M NH4OH to give 7a (10 mg, 98%):
mp 226–2278C, (lit. mp 2258C (Ref. 6k)); [a]D¼228 (c 0.4,
0.1 M HCl), {lit. [a]D¼230.5 (c 0.19, 0.1 M HCl) (Ref.
6k)); 99% de (HPLC, water, flow rate 0.8 mL/min, major
diastereomer 3.0 min, minor diastereomer 4.0 min); IR
4.1.20. (2S,3R)-Pyrrolidine-1,2,3-tricarboxylic acid
1-tert-butyl ester 2-methyl ester (6d). Ozone was intro-
duced to a solution of 6b (50 mg, 0.20 mmol) in CH2Cl2
(4 mL) at 2788C. Ozonization was continued until the
reaction was complete (until the mixture turned blue). PPh3
(103 mg, 0.39 mmol) was added, the mixture was stirred
overnight at rt and evaporated in vacuo. Jones reagent
(2.67 M, 0.22 mL, 0.59 mmol) was added to a solution of
the above obtained residue in acetone (2 mL) at 08C. After
stirring at 08C for 4 h, the reaction was quenched by addition
of propan-2-ol. The mixture was stirred for 30 min and
neutralized with saturated aqueous NaHCO3 to pH 4–5 and
extracted with EtOAc. The organic layers were washed with
brine, dried and evaporated. The residue was purified by
preparative TLC on silica gel (heptane/EtOAc¼2/1) to
afford compound 6d (27 mg, 50%) as two rotamers:
[a]D¼þ4 (c 1.1, CHCl3); IR (CHCl3) n 3505, 3028, 2982,
2955, 1748, 1694, 1477, 1454, 1436, 1397, 1369 cm21; 1H
NMR (250 MHz, CDCl3) d 7.41 (br s, 1H), 4.63 (d,
J¼8.1 Hz, 0.4H), 4.53 (d, J¼8.1 Hz, 0.6H), 3.79–3.65 (m,
4H), 3.50–3.25 (m, 2H), 2.48–2.26 (m, 1H), 2.24–2.07 (m,
1H), 1.46 (s, 3.6H), 1.42 (s, 5.4H); 13C NMR (75 MHz,
CDCl3) d 175.3, 171.1, 154.2, 153.6, 80.7, 80.6, 60.7, 60.3,
52.3, 52.1, 47.2, 46.3, 45.7, 45.4, 28.4, 28.2, 27.2, 26.4; MS
(ESI) m/z 274 [MþH]þ, 296 [MþNa]þ, 312 [MþK]þ.
HRMS Calcd for C12H19NO6Na (MþNa): 296.11101.
Found: 296.11103.
(hydrochloride, nujol) n 3379, 1723 cm21
;
1H NMR
(250 MHz, D2O) d 4.11 (d, J¼7.7 Hz, 1H), 3.55 (dt,
J¼7.4, 11.9 Hz, 1H), 3.36 (ddd, J¼6.1, 8.4, 11.8 Hz, 1H),
2.79–2.71 (m, 1H), 2.29–2.14 (m, 1H), 1.86–1.75 (m, 1H),
1.03 (d, J¼7.2 Hz, 3H); 13C NMR (75 MHz, D2O) d 173.3,
66.0, 44.9, 35.2, 32.2, 14.8; MS (ESI) m/z 130 [MþH]þ, 152
[MþNa]þ, 168 [MþK]þ. HRMS Calcd for C6H11NO2Na
(MþNa) 152.06875. Found: 152.06878.
4.1.18. (2S,3S)- 3-Vinyl-pyrrolidine-2-carboxylic acid
(7b). A solution of 6b (48 mg, 0.19 mmol) in HCl (6N,
1.3 mL) and acetic acid (0.3 mL) was refluxed for 4 h. The
volatile was evaporated. The residue was dissolved in
EtOH. The solution was treated dropwise with propylene
oxide under heating and evaporated to dryness. The residue
was dissolved in water and passed through a column of
Dowex 50WX8-200 ion-exchange resin (Hþ form). The
column was washed thoroughly with water and the amino
acid was eluted with 2 M NH4OH to give 7b (24 mg, 90%):
mp 201–2128C (decomp.); [a]D¼218 (c 0.45, H2O); 95%
de (HPLC, water, flow rate 0.8 mL/min, major diastereomer
5.9 min, minor diastereomer 8.4 min); IR (nujol) n 3390,
4.1.21. (2S,3R)-Pyrrolidine-2,3-dicarboxylic acid (7d). A
solution of 6d (21 mg, 77 mmol) in HCl (6N, 1.3 mL) and
acetic acid (0.3 mL) was refluxed for 4 h. The volatile was
evaporated. The residue was dissolved in EtOH. The
solution was treated dropwise with propylene oxide under
heating and evaporated to dryness. The residue was
dissolved in water and passed through a column of Dowex
50WX8-200 ion-exchange resin (Hþ form). The column
was washed thoroughly with water and the amino acid was
eluted with 2 M NH4OH to give 7d (12 mg, 98%):
mp.3008C; [a]D¼239 (c 0.5, H2O), (lit. [a]D¼240.8 (c
0.1, H2O) (Ref. 6n)); 97% de (HPLC, water, flow rate
0.6 mL/min, major diastereomer 3.8 min, minor diastereo-
1
1611 cm21; H NMR (300 MHz, D2O) d 5.84–5.70 (m,
1H), 5.34–5.22 (m, 2H), 4.42 (d, J¼8.1 Hz, 1H), 3.70–3.33
(m, 3H), 2.38–2.25 (m, 1H), 2.14–2.01 (m, 1H); 13C NMR
(75 MHz, D2O) d 170.4, 133.1, 118.7, 63.8, 44.7, 43.9, 29.0;
MS (ESI) m/z 142 [MþH]þ, 164 [MþNa]þ, 180 [MþK]þ.
HRMS Calcd for C7H11NO2Na (MþNa) 164.06875. Found:
164.06887.
4.1.19. (2S,3S)-3-Phenyl-pyrrolidine-2-carboxylic acid
(7c). A Solution of 6c (18 mg, 59 mmol) in HCl (6N,
1.3 mL) and acetic acid (0.3 mL) was refluxed for 4 h. The
volatile was evaporated. The residue was dissolved in
EtOH. The solution was treated dropwise with propylene
oxide under heating and evaporated to dryness. The residue
was dissolved in water and passed through a column of
Dowex 50WX8-200 ion-exchange resin (Hþ form). The
mer 7.3 min); IR (nujol) n 3406, 1611 cm21 1H NMR
;
(300 MHz, D2O) d 4.12 (d, J¼6.6 Hz, 1H), 3.56 (ddd,
J¼8.1, 9.2, 11.8 Hz, 1H), 3.42 (ddd, J¼3.7, 9.4, 11.8 Hz,
1H), 3.33–3.26 (m, 1H), 2.40 (ddt, J¼7.7, 9.6, 13.6 Hz,
1H), 2.26–2.14 (m, 1H); 13C NMR (62.5 MHz, D2O) d
180.1, 173.5, 65.5, 48.4, 44.7, 29.8; MS (ESI) m/z 160

10482
C. Flamant-Robin et al. / Tetrahedron 58 (2002) 10475–10484
[MþH]þ, 182 [MþNa]þ. HRMS Calcd for C6H9NO2Na
(MþNa) 182.04293. Found: 182.04288.
Et2O. The ether extracts were washed with 1N HCl, water,
saturated aqueous NaHCO3 solution, brine, dried and
evaporated. Column chromatography on silica gel eluting
with heptane/EtOAc (10/1) afforded compound 9b (609 mg,
83%) as two rotamers: [a]D¼þ5 (c 2, CHCl3); IR (CHCl3) n
3443, 3020, 2956, 2931, 2858, 1707, 1499, 1471, 1392,
4.1.22. (2S,3R)-2-tert-Butoxycarbonylamino-5-methane-
sulfonyloxy-3-methyl-1-pentanol (8a). To a solution of 4a
(505 mg, 1.14 mmol) in acetonitrile (10 mL) at 08C were
added CeCl3·7H2O (1.07 g, 2.88 mmol) and oxalic acid
(6.4 mg, 0.07 mmol). After stirring at rt for 2 h, the mixture
was neutralized with saturated aqueous NaHCO3 solution,
filtered through Celite/Na2SO4 and evaporated. The crude
product 8a was used directly for the next reaction without
purification: 1H NMR (250 MHz, CDCl3) d 4.80 (br d,
J¼7.9 Hz, 1H), 4.38–4.18 (m, 2H), 3.68–3.55 (m, 3H),
2.98 (s, 3H), 2.75 (br s, 1H), 2.03–1.76 (m, 2H), 1.66–1.46
(m, 1H), 1.39 (s, 9H), 0.88 (d, J¼6.7 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3) d 156.6, 79.7, 68.4, 63.5, 55.1, 37.3,
33.0, 30.4, 28.4, 14.5; MS (EI) m/z 312 [M]þ, 280, 238.
1362, 1256, 1225, 1217, 1174, 1101 cm21 1H NMR
;
(250 MHz, CDCl3) d 5.58 (dt, J¼9.6, 17.1 Hz, 1H), 5.19–
5.06 (m, 2H), 4.50 (br d, J¼9.2 Hz, 1H), 4.30–4.11 (m, 2H),
3.71–3.46 (m, 3H), 2.96 (s, 3H), 2.59–2.47 (m, 1H), 2.00–
1.85 (m, 1H), 1.80–1.65 (m, 1H), 1.40 (s, 9H), 0.86 (s, 9H),
0.02 (s, 6H); 13C NMR (62.5 MHz, CDCl3) d 155.8, 136.4,
118.8, 79.4, 68.3, 63.2, 54.1, 41.0, 37.3, 30.5, 28.4, 25.9,
18.2, 25.5; MS (EI) m/z 437 [M]þ.
4.1.26. (2S,3R)-2-(tert-Butyl-dimethyl-silanyloxy-
methyl)-3-methyl-pyrrolidine-1-carboxylic acid tert-
butyl ester (10a). To a suspension of NaH (55–65% in
mineral oil, 230 mg, 5.75 mmol, washed with pentane) in
DMF at 08C (5 mL) was added 9a (611 mg, 1.44 mmol) in
DMF (5 mL). After being stirred at rt for 50 min, the
reaction mixture was quenched by addition of water and
extracted with ether. The combined ether layers were
washed with brine, dried, and evaporated. Column chroma-
tography on silica gel (heptane/EtOAc¼30/1) afforded
compound 10a (395 mg, 83% for three steps) as two
rotamers: [a]D¼229 (c 2.5, CHCl3); IR (CHCl3) n 3006,
2957, 2882, 2858, 1681, 1472, 1456, 1407, 1366, 1256,
1175, 1133, 1122, 1101 cm21; 1H NMR (300 MHz, CDCl3)
d 3.94 (dd, J¼3.6, 10.7 Hz, 0.5H), 3.75 (dd, J¼4.4, 10.3 Hz,
0.5H), 3.69–3.46 (m, 2H), 3.40–3.13 (m, 2H), 2.31–2.12
(m, 1H), 1.85–1.70 (m, 2H), 1.41 (s, 9H), 1.07 (d,
J¼6.6 Hz, 3H), 0.83 (s, 9H), 20.01– 20.05 (m, 6H); 13C
NMR (75 MHz, CDCl3) d 154.4, 79.0, 78.7, 61.6, 61.1,
61.0, 60.9, 46.4, 46.0, 36.5, 35.7, 32.5, 31.5, 28.7, 28.6,
25.9, 18.1, 14.3, 14.2, 25.3, 25.6; MS (ESI) m/z 330
[MþH]þ, 352 [MþNa]þ, 368 [MþK]þ, 681 [2MþNa]þ.
Anal. calcd for C17H35NO3Si: C 61.96; H 10.70; N 4.25.
Found: C 61.48; H 11.04; N 4.34.
4.1.23. (2S,3S)-2-tert-Butoxycarbonylamino-5-methane-
sulfonyloxy-3-vinyl-1-pentanol (8b). To a solution of 4b
(120 mg, 0.33 mmol) in acetonitrile (2 mL) at 08C were
added CeCl3–7H2O (246 mg, 0.66 mmol) and oxalic acid
(1.5 mg, 0.01 mmol). After stirring at rt for 2 h, the mixture
was neutralized with saturated aqueous NaHCO3 solution,
filtered through Celite/Na2SO4 and evaporated. Flash
chromatography on silica gel (heptane/EtOAc¼1/1)
afforded compound 8b (95 mg, 90%) as two rotamers:
[a]D¼þ23 (c 1.9, CHCl3); IR (CHCl3) n 3488, 3025, 3008,
2982, 2936, 1706, 1500, 1466, 1393, 1340, 1234,
1174 cm21 1H NMR (300 MHz, CDCl3) d 5.62 (dt,
;
J¼9.7, 16.7 Hz, 1H), 5.27–5.15 (m, 2H), 4.72 (br d,
J¼8.8 Hz, 1H), 4.36–4.28 (m, 1H), 4.24–4.15 (m, 1H),
3.73–3.60 (m, 3H), 3.01 (s, 3H), 2.64–2.48 (m, 1H), 2.44–
2.20 (br s, 1H), 2.08–1.94 (m, 1H), 1.82–1.67 (m, 1H), 1.44
(s, 9H); 13C NMR (62.5 MHz, CDCl3) d 156.4, 136.4,
119.3, 79.9, 68.1, 63.9, 54.7, 41.5, 37.4, 30.7, 28.4; MS
(ESI) m/z 324 [MþH]þ, 346 [MþNa]þ, 362 [MþK]þ.
Anal. calcd for C13H25NO6S: C 48.28; H 7.79; N 4.33; S
9.91. Found: C 48.31; H 7.91; N 4.23; S 9.89.
4.1.24. (2S,3R)- 2-tert-Butoxycarbonylamino-5-methane-
sulfonnyloxy-1-(tert-butyl-dimethyl-silanyloxy)-3-methyl-
pentane (9a). To a solution of crude product 8a (447 mg,
1.14 mmol) in DMF (15 mL) were added imidazole
(247 mg, 3.6 mmol) and TBDMSCl (243 mg, 1.58 mmol).
After stirring at rt for 2 h, the mixture was diluted with
water, extracted with Et2O. The ether extracts were washed
with 1N HCl, water, saturated aqueous NaHCO3 solution,
brine, dried and evaporated. The crude product 9b was used
directly for the next reaction without purification: 1H NMR
(250 MHz, CDCl3) d 4.60 (br d, J¼8.5 Hz, 1H), 4.36–4.20
(m, 2H), 3.68–3.52 (m, 3H), 2.97 (s, 3H), 2.10–1.76 (m,
2H), 1.66–1.48 (m, 1H), 1.41 (s, 9H), 0.91–0.83 (m, 12H),
0.02 (s, 6H); 13C NMR (62.5 MHz, CDCl3) d 156.0, 79.3,
68.4, 63.3, 54.2, 37.3, 33.1, 30.5, 28.4, 25.9, 18.2, 14.5,
25.4, 25.5.
4.1.27. (2S,3S)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-
3-vinyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(10b). To a suspension of NaH (55–65% in mineral oil,
10 mg, 0.67 mmol, washed with pentane) in DMF at 08C
(2 mL) was added 9b (73 mg, 0.17 mmol) in DMF (1mL).
After being stirred at rt for 3 h, the reaction mixture was
quenched by addition of water and extracted with ether. The
combined ether layers were washed with brine, dried, and
evaporated. Flash column chromatography on silica gel
(heptane/EtOAc¼30/1) afforded compound 10b (52 mg,
90%) as two rotamers: [a]D¼211 (c 2.7, CHCl3); IR
(CHCl3) n 3007, 2979, 2956, 2930, 2884, 2858, 1682, 1471,
1
1404, 1367, 1256, 1175, 1123 cm21; H NMR (300 MHz,
CDCl3) d 6.01–5.86 (m, 1H), 5.15–5.03 (m, 2H), 3.98 (dd,
J¼2.9, 10.7 Hz, 0.5H), 3.79 (dd, J¼3.9, 10.5 Hz, 0.5H),
3.76–3.70 (m, 0.5H), 3.68–3.62 (m, 0.5H), 3.57 (d,
J¼10.7 Hz, 1H), 3.49–3.37 (m, 1H), 3.35–3.19 (m, 1H),
2.94–2.74 (m, 1H), 2.19–1.98 (m, 1H), 1.89–1.75 (m, 1H),
1.44 (s, 9H), 0.86 (s, 9H), 0.02 (s, 1.5H), 0.01 (s, 1.5H),
20.01 (s, 1.5H), 20.02 (s, 1.5H); 13C NMR (75 MHz,
CDCl3) d 154.2, 137.6, 137.4, 116.5, 116.3, 79.1, 78.9, 61.5,
62.0, 61.3, 46.7, 46.3, 46.0, 30.7, 29.6, 28.6, 25.9, 18.1,
25.5, 25.6; MS (EI) m/z 342 [MþH]þ, 341 [M]þ, 296, 268.
4.1.25. (2S,3S)-2-tert-Butoxycarbonylamino-5-methane-
sulfonyloxy-1-(tert-butyl-dimethyl-silanyloxy)-3-vinyl-
pentane (9b). To a solution of 8b (543 mg, 1.68 mmol) in
DMF (10 mL) were added imidazole (289 mg, 4.20 mmol)
and TBDMSCl (284 mg, 1.85 mmol). After stirring at rt for
5 h, the mixture was diluted with water, extracted with

C. Flamant-Robin et al. / Tetrahedron 58 (2002) 10475–10484
10483
Anal. calcd for C18H35NO3Si: C 63.30; H 10.33; N 4.10.
Found: C 63.26; H 10.73; N 4.05.
4.1.31. (2S,3S)-3-Vinyl-pyrrolidine-1,2-dicarboxylic acid
1-tert-butyl ester (12b). Jones reagent (2.67 M, 1.78 mL,
4.75 mmol) was added to a solution of 11b (360 mg,
1.58 mmol) in acetone (25 mL) at 08C. After stirring at 08C
for 1.5 h, the reaction was quenched by addition of propan-
2-ol and stirred for 30 min. The mixture was neutralized
with saturated aqueous NaHCO3 and extracted with EtOAc.
The organic layers were washed with brine, dried and
evaporated. The residue was purified by flash chromato-
graphy on silica gel (heptane/EtOAc¼5/1) to afford
compound 12b (212 mg, 56%) as two rotamers:
[a]D¼þ34 (c 0.6, CHCl3); IR (CHCl3) n 3691, 3505,
3026, 2981, 2932, 2888, 1720, 1690, 1477, 1455, 1401,
4.1.28. (2S,3R)-2-Hydroxymethyl-3-methyl-pyrrolidine-
1-carboxylic acid tert-butyl ester (11a). To a solution of
10a (258 mg, 0.78 mmol) in THF (8 mL) was added
tetrabutylammonium fluoride in THF (1 M, 1.58 mL,
1.58 mmol) at rt. After stirring for 15 h, the solvent was
evaporated, and the residue was separated in EtOAc and
saturated aqueous NaHCO3. The aqueous layer was
extracted with EtOAc. The organic extracts were washed
with brine, dried and evaporated. Column chromatography
on silica gel eluting with heptane/EtOAc (4/1) afforded
compound 11a (136 mg, 81%) as two rotamers: [a]D¼218
(c 0.5, CHCl3); IR (CHCl3) n 3363, 3008, 2975, 2933, 2883,
1664, 1476, 1456, 1409, 1368, 1170, 1119 cm21; 1H NMR
(300 MHz, CDCl3) d 4.45–4.37 (m, 0.5H), 3.90–3.82 (m,
0.5H), 3.75–3.66 (m, 1H), 3.53–3.45 (m, 1H), 3.40–3.32
(m, 1H), 3.29–3.19 (m, 1H), 2.47 (br s, 1H), 2.32–2.17 (m,
1H), 1.89–1.79 (m, 1H), 1.62–1.48 (m, 1H), 1.47 (s, 9H),
1.03 (d, J¼6.6 Hz, 1H), 0.95 (d, J¼6.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 157.1, 80.0, 63.9, 62.3, 46.3, 36.3, 35.5,
32.0, 31.4, 28.5, 14.1; MS (ESI) m/z 216 [MþH]þ, 238
[MþNa]þ, 254 [MþK]þ, 453 [2MþNa]þ. HRMS Calcd for
C11H21NO3Na (MþNa) 238.14191. Found: 238.14139.
1
1368, 1227, 1170, 1150, 1131, 927, 858 cm21; H NMR
(300 MHz, CDCl3) d 9.13 (br s, 1H), 5.85–5.68 (m, 1H),
5.23–5.11 (m, 2H), 4.38 (d, J¼8.4 Hz, 0.4H), 4.28 (d,
J¼8.4 Hz, 0.6H), 3.77–3.62 (m, 1H), 3.44–3.31 (m, 1H),
3.17–3.01 (m, 1H), 2.10–1.92 (m, 2H), 1.46 (s, 3.4H), 1.42
(s, 5.6H); 13C NMR (75 MHz, CDCl3) d 177.0, 176.2,
154.7, 154.0, 134.5, 134.4, 117.8, 117.7, 80.6, 80.4, 63.0,
62.5, 46.1, 45.8, 46.3, 45.3, 29.3, 28.6, 28.5, 28.3; MS (ESI)
m/z 242 [MþH]þ, 264 [MþNa]þ, 280 [MþK]þ. Anal. calcd
for C12H19NO4: C 59.73; H 8.09; N 5.80. Found: C 59.73; H
7.94; N 5.59.
4.2. Crystallographic data
4.1.29. (2S,3S)-2-Hydroxymethyl-3-vinyl-pyrrolidine-1-
carboxylic acid tert-butyl ester (11b). To a solution of
10b (347 mg, 1.02 mmol) in THF (10 mL) was added
tetrabutylammonium fluoride in THF (1 M, 1.53 mL,
1.53 mmol) at rt. After stirring for 15 h, the solvent was
evaporated, and the residue was separated in EtOAc and
saturated aqueous NaHCO3. The aqueous layer was
extracted with EtOAc. The organic extracts were washed
with brine, dried and evaporated. Column chromatography
on silica gel eluting with heptane/EtOAc (10/1) afforded
compound 11b (224 mg, 81%) as two rotamers: [a]D¼214
(c 1.7, CHCl3); IR (CHCl3) n 3384, 3084, 3022, 3009, 2981,
2933, 2887, 1668, 1476, 1455, 1405, 1368, 1223,
Colorless crystal of 0.18£0.42£0.57 mm, crystallized from
a mixture dichlorometane/heptane. C17H23NO4. Ortho-
rhombic system, space group P212121, Z¼4 (four molecules
in the unit cell), Mw¼305.36; a¼6.085(6), b¼11.853(7),
3
c¼23.500(20) A, V¼1695 A , dc¼1.196 g cm23, F(000)¼
˚
˚
1600, l (Mo Ka)¼0.71073 A, m¼0.086 mm21. Data were
˚
measured with a Nonius Kappa-CCD area-detector diffract-
ometer, using graphite monochromated Mo Ka radiation, in
phi scans, up to u¼31.28. Thus, 4089 data were collected
leading to 2248 unique reflections, of which 1759 were
considered as observed having I$2sigma (I). The structure
was refined by full-matrix least-squares, based upon unique
F 2 with program SHELXL93. The hydrogen atoms, located
in difference Fourier maps, were fitted at theoretical
positions and treated as riding, and assigned an isotropic
displacement parameter equivalent to 1.2 that one of the
bonded atom. Thus, refinement of 203 parameters con-
verged to R1(F)¼0.0380 for the 1759 observed reflections
and wR2(F 2)¼0.0854 for all the 2248 data with a goodness-
of-fit S factor of 1.042. The residual electron density was
1
1169 cm21; H NMR (250 MHz, CDCl3) d 5.85–5.71 (m,
1H), 5.23–5.08 (m, 2H), 4.24–4.16 (m, 0.5H), 4.08–3.96
(m, 0.5H), 3.79–3.67 (m, 1H), 3.61–3.42 (m, 2H), 3.42–
3.31 (m, 1H), 2.97–2.83 (m, 1H), 2.50 (br s, 1H), 2.06–1.82
(m, 2H), 1.48 (s, 9H); 13C NMR (62.5 MHz, CDCl3) d
156.7, 136.3, 135.5, 116.8, 80.1, 79.9, 64.1, 64.0, 62.2,
61.6, 46.1, 45.9, 45.1, 29.6, 29.4, 28.4; MS (EI) m/z 228
[MþH]þ, 227[M]þ, 172, 154, 140. Anal. calcd for
C12H21NO3: C 63.41; H 9.31; N 6.16. Found: C 63.56; H
9.38; N 6.01.
found between 20.10 and 0.11 e A23. In the crystal
˚
packing, only van der Waals contacts are observed.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 187565. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44-(0)1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.1.30. (2S,3R)-3-Methyl-pyrrolidine-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester (6a) from 11a.
Jones reagent (2.67 M, 0.44 mL, 1.17 mmol) was added to a
solution of 11a (84 mg, 0.39 mmol) in acetone (5 mL) at
08C. After stirring at 08C for 4 h, the reaction was quenched
by addition of propan-2-ol. The mixture was stirred for
30 min and neutralized with saturated aqueous NaHCO3 to
pH 4–5 and extracted with EtOAc. The organic layers were
washed with brine, dried and evaporated. The residue was
dissolved in Et2O and CH2N2 in Et2O was added to the
solution. The mixture was evaporated in vacuo and purified
by column chromatography on silica gel (heptane/EtOAc¼
8/1) to afford compound 6a (56 mg, 58%).
Acknowledgements
´ `
We thank Marie-Therese Adeline and Vincent Guerineau
for their assistance in HPLC and HRMS analyses.

10484
C. Flamant-Robin et al. / Tetrahedron 58 (2002) 10475–10484
Johnstone, A. N. C.; North, M. Tetrahedron 1995, 51,
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