Asymmetrization of meso-1,3-diols utilising Pseudomonas fluorescens lipase

Article abstract of DOI:10.1016/S0957-4166(98)00237-7

A convenient and enantioselective synthesis of monoacetates of meso- l,3-diols 2-substituted with an alkoxymethyl or a thiophenylmethyl group, by enzyme catalyzed acylation, is described, The absolute stereochemistries of two monoacetates were assigned by

Full text of DOI:10.1016/S0957-4166(98)00237-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2301–2310
Asymmetrization of meso-1,3-diols utilising Pseudomonas
fluorescens lipase
François-René Alexandre and François Huet ∗
Laboratoire de Synthèse Organique, UPRES A CNRS 6011, Faculté des Sciences, Université du Maine, Avenue Olivier
Messiaen, 72085 Le Mans Cedex 9, France
Received 14 April 1998; accepted 15 June 1998
Abstract
A convenient and enantioselective synthesis of monoacetates of meso-1,3-diols 2-substituted with an
alkoxymethyl or a thiophenylmethyl group, by enzyme catalyzed acylation, is described. The absolute
stereochemistries of two monoacetates were assigned by chemical correlation. © 1998 Elsevier Science Ltd. All
rights reserved.
1. Introduction
Enzyme catalyzed acylation by asymmetrization of meso-diols is a useful method for the preparation of
chiral building blocks.1 Several good results were recently described for the preparation of 2-substituted
1,3-propanediols bearing one2 or two3 hydroxy or alkoxy groups β to the hydroxyl groups with lipases
from Pseudomonas fluorescens (PFL) and from porcine pancreas (PPL) as catalysts (Scheme 1).
We have shown recently4 that 2-alkoxymethylmalonates 1 and 2 and the sulfur derivative 3 are
easily available by a short preparative method from diethyl methylenemalonate (Scheme 2) and we
anticipated that compounds such as 1 and 2 should be valuable starting materials for preparation of
asymmetrized tris(hydroxymethyl)methane2 b through reduction followed by lipase-mediated acylation.
We also planned to extend the investigation to the related compounds 3 and 4.
2. Results and discussion
Reduction of compounds 1, 2 and 4 in THF or diethylether gave the expected diols 5, 6 and 8. On
the other hand, reduction of the sulfur compound 3 with LiAlH4 in THF resulted in a mixture of the
∗
Corresponding author. E-mail: fhuet@aviion.univ-lemans.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00237-7

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F.-R. Alexandre, F. Huet / Tetrahedron: Asymmetry 9 (1998) 2301–2310
Scheme 1.
Scheme 2.
Table 1
expected diol 7 in only 34% yield together with 40% of 2-methyl-diethylmalonate 9 probably formed
by β-elimination of thiophenol in this basic medium, followed by conjugate reduction. Replacement of
LiAlH4 by NaBH4 in methanol led to an increased yield of 9 (90%) along with a very small amount of
7. Reduction with Ca(BH4)2 only yielded diol 10 from 9, and finally a satisfactory result was obtained
when using AlH35 obtained in situ from LiAlH4 (3 mol equiv.) and AlCl3 (1 mol equiv.) (Table 1).
When diols 5–8 were submitted to asymmetric enzymatic acylation, mixtures of monoacetates and
diacetates were obtained (Table 2). Enantiomeric excesses of monoacetates 11–14 were measured by
1H NMR either in the presence of (+)-Eu(hfc)3 (11, 12, 14) or by analysis of the (S)-O-acetyllactyl
ester derivative6 (13), or by chiral gas phase chromatography (11, 12) that led to coherent results. NMR

F.-R. Alexandre, F. Huet / Tetrahedron: Asymmetry 9 (1998) 2301–2310
2303
Table 2
analyses from 11 and 13 needed deconvolution of signals, by the Bruker Win NMR program, instead
of integration, as these signals were close to each other. All the NMR experiments were performed by
comparing the results for racemic products, obtained by reaction of diols with acetic anhydride and
pyridine, and the enantiomerically enriched monoacetates.
These analyses showed that enzymatic reactions with PFL led to poor results from 5 and 8. An
improvement was observed from 5 when the reaction time was increased (entry 2), however the yield
of 11 was then lowered due to conversion of a part of 11 into diacetate. The low selectivity from 6,
in the presence of PPL, contrasted with the good yield and enantiomeric excess with PFL (entry 4).
The predominant isomer had the S configuration in both cases, demonstrated below. The result was also
satisfying from 7, mainly when the reaction was run below room temperature (entry 6). In this case we
obtained the R product.
We also prepared (R)-12 in moderate yield and ee by hydrolysis of diacetate 15 (Scheme 3).
Scheme 3.
The S absolute configuration of monoacetate 12 (Table 2) was assessed by chemical correlation leading
to the known aminoalcohol (R)-21.7 The intermediate alcohol (R)-17 is a known product8 (Scheme 4).
The predominant monoacetate 13 had the R configuration as shown by chemical correlation leading to
the known (R)-239 (Scheme 5). As (S)-12 and (R)-13 correspond to the same selectivity, 11 and 14 are
probably the S products.
The configuration of monoacetate 13 could also be checked by conversion to (R)-21 through the
intermediate (S)-22 under conditions shown in Scheme 6.
As mentioned above, enantiomerically enriched protected tris(hydroxymethyl)methanes are interesting
synthetic intermediates that have been prepared efficiently, albeit in numerous steps, by several teams.
We propose here a new method, in two steps, for obtaining 12, for instance, starting from the easily
available 2. Thus our results constitute new examples of asymmetric acylation of meso-diols.

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F.-R. Alexandre, F. Huet / Tetrahedron: Asymmetry 9 (1998) 2301–2310
Scheme 4.
Scheme 5.
Scheme 6.
3. Experimental
Optical rotations were measured with a Perkin–Elmer 343 polarimeter. NMR spectra were recorded
on a Bruker AC 400 instrument at 400 and 100.6 MHz for 1H and 13C, respectively, in CDCl3 and using
TMS as the internal reference. Multiplicities in the 13C spectra were determined by DEPT experiments.
Chromatographic analyses were performed with a Hewlett Packard HP 6890 apparatus equipped with a
30 m Restek β-DEX-sm or a 25 m Chrompack Chirasil-DEX-CB column. IR spectra were recorded with
a Genesis Matteson infrared spectrophotometer. Melting points were measured on a Reichert apparatus
and are uncorrected. Elemental analyses were performed by the service de microanalyse, CNRS, ISCN,
Gif sur Yvette. Mass spectra were obtained by GPC/MS (Varian 3300 DB5 sm/ITD 800 Finnigan MAT)
or by HPLC/MS (Waters 510 Altech RP18 150 m×4.6 mm, Resil C18 5 µ/Fisons LCD MD 800) or with
a Varian mat 311 spectrometer (CRMPO, Rennes). The last instrument also led to high resolution mass
measurements.
3.1. Preparation of the starting materials 1–4
Compounds 1–3 were prepared as previously described.4 Crude compound 2 was not very stable and
it was distilled without delay after preparation to avoid decomposition. Diethyl 2-(tert-butoxymethyl)-2-
methylmalonate 4 was obtained in the following way. Diethyl 2-(tert-butoxymethyl)malonate 2 (4.78 g,
19.4 mmol) in dry THF (40 ml) was added dropwise, under argon, at 0°C and with stirring to sodium
hydride (855 mg of 60% dispersion in mineral oil, prewashed with cyclohexane then THF, 21.4 mmol).
The reaction mixture was stirred at room temperature for 1 h then a solution of methyl iodide (1.4 ml,
23.3 mmol) in dry THF (47 ml) was added dropwise. The reaction was allowed to proceed for 2 h at
room temperature then the reaction mixture was hydrolysed with brine (60 ml). Evaporation, extraction
by Et2O (3×60 ml), drying (MgSO4) then flash chromatography on silica gel (cyclohexane:AcOEt=7:3)
led to 4 as a colorless oil (4.90 g, 97%). 1H NMR δ 1.14 (s, 9H), 1.26 (t, 6H, J=7.1 Hz), 1.48 (s, 3H), 3.70
(s, 2H), 4.18 (q, 4H, J=7.1 Hz); 13C NMR δ 14.0 (2C, CH3), 18.4 (CH3), 27.3 (3C, CH3), 54.7 (quat. C),

F.-R. Alexandre, F. Huet / Tetrahedron: Asymmetry 9 (1998) 2301–2310
2305
61.0 (2C, CH2), 64.7 (CH2), 72.9 (quat. C), 171.0 (2C, CO); IR (film): 2979, 2940, 1735, 1259, 1083,
1025 cm−1; GPC/MS (chem. ionis. isobutane) m/z (rel. int.) 261 (MH+, 17), 205 (100), 177 (84), 115
(20); GPC/MS (EI) m/z (rel. int.) 261 (MH+, <2), 245 (4), 205 (100), 187 (30), 129 (67), 115 (36), 101
(27), 85 (20), 69 (21), 57 (77), 41 (85); anal. calcd for C13H24O5: C, 59.98; H, 9.29, found: C, 59.75; H,
9.43.
3.2. 2-(Methoxymethyl)propan-1,3-diol 5; 2-(tert-butoxymethyl)propan-1,3-diol 6; 2-(tert-butoxy-
methyl)-2-methyl-propan-1,3-diol 8
Compound 6 was obtained by adding dropwise, under argon, at room temperature and with stirring
diethyl 2-(tert-butoxymethyl)malonate (910 mg, 3.7 mmol) in dry THF (2 ml) to a suspension of LiAlH4
(351 mg, 9.3 mmol) in THF (9 ml). The reaction mixture was stirred for 30 min at room temperature
and then for 17 h at reflux. Hydrolysis with a small amount of water then Soxhlet extraction with THF
for 24 h led to an oil after evaporation. Flash chromatography on silica gel (cyclohexane:AcOEt=1:1)
yielded 6 as a colorless oil (426 mg, 71%). Compound 5, a known product,10 was obtained under
the same experimental conditions. Compound 8 was prepared with Et2O as solvent, and Soxhlet
extraction was replaced by suction filtration on a sintered-glass funnel then the solid was washed several
times with Et2O. Flash chromatography on silica gel (cyclohexane:AcOEt=1:1) or recrystallization
(cyclohexane:pentane) provided 8 as white crystals.
Data for 5: 1H NMR δ 2.00 (m, 1H), 3.09 (br s, 2H, OH), 3.35 (s, 3H), 3.53 (d, 2H, J=5.7 Hz), 3.77 (d,
4H, J=5.3 Hz); 13C NMR δ 42.7 (CH), 59.1 (CH3), 62.9 (2C, CH2), 73.0 (CH2); IR (film): 3367, 2881,
1095, 1037 cm−1
.
Data for 6: 1H NMR δ 1.20 (s, 9H), 1.95 (m, 1H), 2.86 (t, 2H, OH, J=5.3 Hz,), 3.56 (d, 2H, J=5.3 Hz),
3.78 (m, 4H); 13C NMR δ 27.3 (3C, CH3), 42.8 (CH), 63.0 (CH2), 63.3 (2C, CH2), 73.4 (quat. C); IR
(film): 3367, 2973, 1363, 1197, 1078, 1035 cm−1; MS (EI) m/z (rel. int.) 162 (M+, 0.4), 147 (15), 105
(15), 89 (24), 59 (96), 57 (100), 43 (24), 41 (47), 28 (78); HRMS calcd for C8H18O3 162.1256, found
162.1249.
Data for 8: mp 72.6–73°C; 1H NMR δ 0.82 (s, 3H), 1.19 (s, 9H), 2.97 (br s, 2H, OH), 3.36 (s, 2H),
3.55 (br d, 2H, JAB=11.1 Hz), 3.69 (d, 2H, JAB=11.1 Hz); 13C NMR δ 17.3 (CH3), 27.2 (3C, CH3), 40.1
(quat. C), 67.8 (2C, CH2), 68.2 (CH2), 73.4 (quat. C); IR (Nujol) 3324, 1463, 1363, 1058, 1037 cm−1
;
anal. calcd for C9H20O3: C, 61.33; H, 11.44, found: C, 61.37; H, 11.41.
3.3. 2-[(Phenylsulfanyl)methyl]propan-1,3-diol 7
LiAlH4 (1.454 g, 38.3 mmol) and AlCl3 (1.702 g, 12.8 mmol) in dry Et2O (50 ml) were stirred for 30
min under argon, at room temperature. Diethyl 2-[(phenylsulfanyl)methyl)]malonate (1.637 g, 5.8 mmol)
in Et2O (29 ml) was then added dropwise at 0°C. The reaction was allowed to proceed for 1.5 h at room
temperature. Hydrolysis with a small amount of water, addition of MgSO4, filtration on a sintered-glass
funnel then washing the solid several times with Et2O led to an oil. Flash chromatography on silica gel
(cyclohexane:AcOEt=1:1 then MeOH) yielded 7 as white crystals (908 mg, 79%), mp 45.0–45.5°C; 1H
NMR δ 1.94 (m, 1H), 2.63 (br s, 2H, OH), 2.99 (d, 2H, J=7.0 Hz), 3.82 (m, 4H), 7.18 (m, 1H), 7.28
(m, 2H), 7.34 (m, 2H); 13C NMR δ 32.2 (CH2), 41.6 (CH), 64.3 (2C, CH2), 126.1 (CH), 129.0 (2C,
CH), 129.2 (2C, CH), 136.1 (quat. C); IR (film): 3359, 2927, 2883, 1481, 1438, 1039, 740, 690 cm−1
;
HPLC/MS (EI) m/z (rel. int.) 198 (M+, 20), 123 (6), 110 (100); anal. calcd for C10H14O2S: C, 60.58; H,
7.12; S, 16.17, found: C, 60.48; H, 7.19; S, 16.01.

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F.-R. Alexandre, F. Huet / Tetrahedron: Asymmetry 9 (1998) 2301–2310
3.4. (−)-3-Methoxy-2-(hydroxymethyl)propylacetate 11; (S)-3-(tert-butoxy)-2-(hydroxymethyl)propyl-
acetate 12; (R)-3-hydroxy-2-[(phenylsulfanyl)methyl]propylacetate 13; 3-(tert-butoxy)-2-(hydroxymethyl)-
2-ethylpropylacetate 14
Compound (−)-11 was obtained by stirring 2-(methoxymethyl)propan-1,3-diol (149 mg, 1.24 mmol)
and PFL (15 mg) in vinyl acetate (3 ml) for 24 h, at room temperature. Enzyme was then removed
by filtration on a sintered-glass funnel. Washing (vinyl acetate), evaporation and flash chromatography
20
D
on silica gel (cyclohexane:AcOEt=1:1) provided (−)-11 (30 mg, 15%, 79% ee, [α] − 1.47 (CHCl3,
c=1.7)) as a colorless oil. Diacetate could also be isolated. Compound (S)-12 was obtained in the same
way from diol 6 (517 mg, 3.2 mmol), PFL (83 mg), vinyl acetate (10 ml), in 2 h. It was obtained as a
20
D
colorless oil (640 mg, 97%, 91% ee, [α] +1.8 (CHCl3, c=4.0)). In another experiment PFL was replaced
by PPL. Compound (S)-12 was thus obtained in 52% yield and 38% ee. Compound (R)-13 was obtained
by a similar procedure to (−)-11, in 3 h at 7°C, starting from diol 7 (105 mg, 0.53 mmol) and PFL
(10 mg) in vinyl acetate (5 ml). Flash chromatography (cyclohexane:AcOEt=6:4) provided (R)-13 as
20
D
a colorless oil (97 mg, 76%, 88% ee, [α] +14.7 (CHCl3, c=7.4)). Compound 14 was obtained by a
similar procedure as for (−)-11, in 3–7 days, starting from diol 8 (80 mg, 0.45 mmol) and PFL (15 mg)
in vinyl acetate (2 ml). Flash chromatography (cyclohexane:AcOEt=8:2) provided 14 as a colorless oil
20
(13 mg, 13%, 11% ee, [α] was very low and could not be measured).
D
1
Data for 11: H NMR δ 2.07 (s, 3H), 2.14 (m, 1H), 2.58 (br s, 1H, OH), 3.35 (s, 3H), 3.48 (dd, 1H,
J=9.3, 6.0 Hz), 3.53 (dd, 1H, J=9.3, 5.4 Hz), 3.71 (d, 2H, J=5.1 Hz), 4.18 (d, 2H, J=6.0 Hz); 13C NMR
δ 20.8 (CH3), 40.7 (CH), 59.1 (CH3), 62.2 (CH2), 62.5 (CH2), 72.4 (CH2), 171.3 (CO); IR (film): 3448,
2898, 1741, 1247, 1108, 1039 cm−1; GPC/MS (EI) m/z (rel. int.) 163 (MH+, <0.5), 145 (2), 131 (1), 84
(6), 71 (29), 61 (20), 57 (18), 45 (56), 43 (100); anal. calcd for C7H14O4+0.05H2O: C, 51.58; H, 8.65,
found: C, 51.39; H, 8.69.
1
Data for 12: H NMR δ 1.20 (s, 9H), 2.07 (s, 3H), 2.07 (m, 1H), 2.95 (m, 1H, OH), 3.49 (dd, 1H,
J=8.8, 5.9 Hz), 3.57 (dd, 1H, J=8.8, 4.7 Hz), 3.74 (m, 2H), 4.17 (d, 2H, J=6.5 Hz); 13C NMR δ 20.9
(CH3), 27.3 (3C, CH3), 40.5 (CH), 62.3 (CH2), 62.8 (CH2), 63.4 (CH2), 73.5 (quat. C), 171.2 (CO);
IR (film): 3453, 2973, 1741, 1243, 1039 cm−1; GPC/MS m/z (rel. int.) 205 (MH+, <0.5), 149 (39), 131
(100), 87 (16), 59 (27), 57 (27), 43 (90); anal. calcd for C10H20O4+0.2H2O: C, 57.73; H, 9.81, found: C,
57.79; H, 9.97.
Data for 13: 1H NMR δ 2.06 (s, 3H), 2.09 (m, 2H, OH and H-2), 2.96 (dd, 1H, J=13.5, 6.9 Hz), 3.02
(dd, 1H, J=13.5, 7.0 Hz), 3.69 (m, 2H), 4.24 (d, 2H, J=5.6 Hz), 7.18 (m, 1H), 7.28 (m, 2H), 7.36 (m,
2H); 13C NMR δ 20.8 (CH3), 32.3 (CH2), 40.3 (CH), 61.7 (CH2), 63.5 (CH2), 126.3 (CH), 129.0 (2C,
CH), 129.4 (2C, CH), 135.9 (quat. C), 171.4 (CO); IR (film): 3442, 3056, 2952, 2892, 1733, 1481, 1438,
1243, 1039, 740, 692 cm−1; HPLC/MS (EI) m/z (rel. int.) 240 (M+, 39), 149 (63), 131 (17), 123 (45),
110 (100), 109 (43); anal. calcd for C12H16O3S: C, 59.98; H, 6.71; S, 13.34, found: C, 59.62; H, 6.83; S,
12.98.
Data for 14: 1H NMR δ 0.85 (s, 3H), 1.18 (s, 9H), 2.08 (s, 3H), 3.24 (m, 1H, OH), 3.31 (d, 1H, J=8.7
Hz), 3.38 (d, 1H, J=8.7 Hz), 3.54 (m, 2H), 4.09 (d, 1H, J=11.0 Hz), 4.14 (d, 1H, J=11.0 Hz); 13C NMR
(CDCl3) δ 17.3 (CH3), 20.8 (CH3), 27.2 (3C, CH3), 39.1 (quat. C), 66.6 (CH2), 67.5 (CH2), 68.5(CH2),
73.4 (quat. C), 171.2 (CO); IR (film): 3455, 2973, 1733, 1365, 1243, 1199, 1085, 1039 cm−1
.
3.5. 3-(Acetyloxy)-2-(tert-butoxymethyl)propylacetate 15
This compound was obtained together with (ꢀ)-12 which was prepared to measure the ee of (S)-12.
Preparation of 15 was not optimised. Diol 6 (4.219 g, 26 mmol), Ac2O (2.5 ml, 26 mmol) and pyridine

F.-R. Alexandre, F. Huet / Tetrahedron: Asymmetry 9 (1998) 2301–2310
2307
(2.1 ml, 26 mmol) were stirred under argon, at room temperature for 3 h. Aqueous saturated NaHCO3
(90 ml) was then added. Extraction by CH2Cl2 (3×100 ml), washing of the combined organic phases
successively with 10% aqueous HCl (100 ml), H2O (100 ml), then brine (100 ml), drying (MgSO4),
evaporation and flash chromatography on silica gel (cyclohexane:AcOEt=7:3) led to (ꢀ)-12 (2.611 g,
49%) and to 15 (1.911 g, 30%) as colorless oils. Data for 15: 1H NMR δ 1.16 (s, 9H), 2.05 (s, 6H), 2.21
(m, 1H), 3.38 (d, 2H, J=5.8 Hz), 4.11 (dd, 1H, J=11.1, 6.2 Hz), 4.15 (dd, 1H, J=11.1, 5.9 Hz); 13C NMR
δ 20.8 (2C, CH3), 27.3 (3C, CH3), 38.6 (CH) 59.0 (CH2), 62.6 (2C, CH2) 72.8 (quat. C), 170.9 (2C,
CO); IR (film): 2973, 1747, 1365, 1234, 1039 cm−1; anal. calcd for C12H22O5: C, 58.52; H, 9.00, found:
C, 58.27; H, 9.19.
3.6. (R)-3-(tert-Butoxy)-2-(hydroxymethyl)propylacetate 12
Diacetate 15 (416 mg, 1.7 mmol) was stirred for 24 h with a mixture of pH 7 buffer solution (15 ml),
and of PFL (25 mg). Throughout this reaction, the pH was maintained at 7 by adding 1 M NaOH under
pH stat monitoring. Extraction by CH2Cl2 (3×15 ml), saturation of the aqueous phase with NaCl, other
extractions by CH2Cl2 (2×20 ml), drying of the combined organic phases (MgSO4), evaporation and
flash chromatography on silica gel (cyclohexane:AcOEt=1:1) provided (R)-12 (156 mg, 45%, 66% ee,
20
D
[α] −1.2 (CHCl3, c=2.75)).
3.7. (S)-3-(tert-Butoxy)-2-{[(methylsulfonyl)oxy]methyl}propylacetate 16
Compound (S)-12 (1.00 g, 4.9 mmol), Et3N (1.02 ml, 7.35 mmol) and CH2Cl2 (14 ml) were mixed
under argon at 0°C. Mesyl chloride (455 µl, 5.88 mmol) was then added dropwise. The reaction was
allowed to proceed for 2.3 h at the same temperature with TLC monitoring. CH2Cl2 was then added.
Washing of the organic phase (10% HCl), drying (MgSO)4, evaporation and flash chromatography on
20
D
silica gel (cyclohexane:AcOEt=1:1) led to (S)-16 as a colorless oil (1.292 g, 94%, 91% ee, [α] +1.5
(CHCl3, c=4.0)). 1H NMR δ 1.17 (s, 9H), 2.07 (s, 3H), 2.30 (m, 1H), 3.02 (s, 3H), 3.39 (dd, 1H, J=6.0,
9.1 Hz), 3.43 (dd, 1H, J=5.4, 9.1 Hz), 4.12 (dd, 1H, J=6.6, 11.3 Hz), 4.18 (dd, 1H, J=5.8, 11.3 Hz), 4.29
(dd, 1H, J=5.6, 9.6 Hz), 4.32 (dd, 1H, J=5.7, 9.6 Hz); 13C NMR δ 20.8 (CH3), 27.3 (3C, CH3), 37.1,
39.0, 58.3 (CH2), 61.9 (CH2), 67.7 (CH2), 73.1 (quat. C), 170.8 (CO); IR (film): 2975, 1733, 1359, 1243,
1178, 1083, 1043, 964, 835 cm−1; GPC/MS (chem. ionis. isobutane) m/z (rel. int.) 283 (MH+, 0.4), 227
(4), 209 (51), 131 (100); anal. calcd for C11H22O6S: C, 46.79; H, 7.85; S, 11.35, found: C, 46.78; H,
7.94; S, 11.21.
3.8. (R)-3-(tert-Butoxy)-2-methylpropan-1-ol 17
Compound (S)-16 (1.254 g, 4.45 mmol) in dry THF (5 ml) was added dropwise, under argon and with
stirring to a refluxing suspension of LiAlH4 (1.012 g, 26.7 mmol) in dry THF (5 ml). Reflux was pursued
for 5 min. Cooling, hydrolysis with a small amount of water, dilution with Et2O, filtration, washing of the
solid phase with Et2O, drying of the organic phase (MgSO4) and evaporation provided the crude (R)-17,
a known product,8 as a colorless oil that was used without further purification in the next step (458 mg,
20
20
1
70%, 91% ee, [α] +13.2 (CHCl3, c=2.6) (lit.8 [α] +0.49 (MeOH, c=4.0) for 100% ee)). H NMR
D
D
δ 0.84 (d, 3H, J=6.9 Hz), 1.20 (s, 9H), 1.99 (m, 1H), 3.30 (m, 2H), 3.57 (m, 3H, OH and next CH2);
13C NMR δ 13.4 (CH3), 27.3 (3C, CH3), 35.5 (CH), 68.0 (CH2), 69.1 (CH2), 73.3 (quat. C); IR (film):
3413, 2977, 2873, 1361, 1197, 1079, 1039 cm−1; GPC/MS (EI) m/z (rel. int.) 147 (MH+, 5), 131 (13),
91 (100), 73 (12), 59 (85), 57 (68), 41 (48).

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F.-R. Alexandre, F. Huet / Tetrahedron: Asymmetry 9 (1998) 2301–2310
3.9. (S)-3-(tert-Butoxy)-2-methylpropylmethanesulfonate 18
A mixture of compound (R)-17 (113 mg, 0.77 mmol), dry CH2Cl2 (2.5 ml) and Et3N (161 µl, 1.16
mmol) were stirred under argon and at 0°C. Mesyl chloride (72 µl, 0.93 mmol) was then added dropwise.
The reaction was allowed to proceed for 2.3 h at the same temperature with TLC monitoring then
CH2Cl2 was added. Washing of the organic phase (10% HCl), drying (MgSO4), evaporation and flash
chromatography on silica gel (cyclohexane:AcOEt=1:1) led to (S)-18 as a colorless oil (158 mg, 91%,
20
91% ee, [α] +8.5 (CHCl3, c=2.1)). 1H NMR δ 1.00 (d, 3H, J=6.9 Hz), 1.17 (s, 9H), 2.07 (m, 1H), 3.00
D
(s, 3H), 3.24 (dd, 1H, J=8.9, 7.1 Hz), 3.32 (dd, 1H, J=8.9, 5.0 Hz), 4.16 (dd, 1H, J=9.3, 5.8 Hz), 4.23
(dd, 1H, J=9.3, 5.3 Hz); 13C NMR δ 13.7 (CH3), 27.4 (3C, CH3), 34.1 (CH), 37.0 (CH3), 62.3 (CH2),
72.3 (CH2), 72.7 (quat. C); IR (film): 2973, 2879, 1353, 1176, 1081, 962, 829 cm−1; GPC/MS (EI) m/z
(rel. int.) 225 (MH+, <2), 209 (5), 170 (95), 151 (32), 97 (9), 79 (13), 73 (31), 57 (100), 41 (45); anal.
calcd for C9H20O4S: C, 48.19; H, 8.99; S, 14.29, found: C, 47.89; H, 9.01; S, 14.11.
3.10. (R)-1-Azido-3-(tert-butoxy)-2-methylpropane 19
Sodium azide (250 mg, 3.85 mmol) was added portionwise, with stirring, under argon and at room
temperature to a solution of compound (S)-18 (460 mg, 2.14 mmol) in DMF (4.5 ml). The reaction
mixture was stirred for 7.25 h at 75°C. Cooling, addition of water (10 ml), extraction (Et2O, 3×20 ml),
drying of the combined organic phases (MgSO4), evaporation then flash chromatography on silica gel
(light petroleum:Et2O=7:3) led to (R)-19 as a colorless oil (324 mg, 93%, 91% ee (estimated from (S)-
20
18), [α] +5.2 (CHCl3, c=1)). 1H NMR δ 0.95 (d, 3H, J=6.8 Hz), 1.17 (s, 9H), 1.90 (m, 1H), 3.23 (m,
D
3H), 3.36 (dd, 1H, J=12.0, 5.5 Hz); 13C NMR δ 14.9 (CH3), 27.4 (3C, CH3), 34.6 (CH), 54.8 (CH2),
63.6 (CH2), 72.4 (quat. C); IR (film): 2975, 2100, 1363, 1197, 1081 cm−1; GPC/MS (EI) m/z (rel. int.)
172 (MH+, <1), 144 (18) 128 (12), 116 (13), 86 (31), 70 (27), 57 (100), 41 (55).
3.11. (R)-3-(tert-Butoxy)-2-methyl-1-propanamine 20
A solution of compound (R)-19 (400 mg, 2.34 mmol) in dry THF (3.5 ml) was added dropwise under
argon, at 0°C and with stirring to a suspension of LiAlH4 (115 mg, 3.0 mmol), in dry THF (3 ml).
The reaction mixture was stirred for 6 h at room temperature. Hydrolysis with a small amount of water,
addition of Et2O, suction filtration on a sintered-glass funnel then washing the solid several times with
Et2O, drying the organic phase (MgSO4) and evaporation provided (R)-20 as a colorless oil that was used
20
without further purification in the next step (286 mg, 84%, 91% ee (estimated from (S)-18), [α] +4.3
D
1
(CHCl3, c=1,8)). H NMR δ 0.89 (d, 3H, J=6.8 Hz), 1.18 (s, 9H), 1.46 (br s, 2H, NH2), 1.69 (m, 1H),
2.56 (dd, 1H, J=12.6, 6.0 Hz), 2.74 (dd, 1H, J=12.6, 6.1 Hz), 3.22 (dd, 1H, J=8.8, 6.9 Hz), 3.25 (dd, 1H,
J=8.8, 5.9 Hz); 13C NMR δ 15.0 (CH3), 27.4 (3C, CH3), 37.1 (CH), 46.3 (CH2), 65.5 (CH2), 72.3 (quat.
C); IR (film): 3376, 2971, 2873, 1361, 1199, 1081 cm−1; GPC/MS (EI) m/z (rel. int.) 146 (MH+, 22),
130 (2), 90 (19), 88 (70), 72 (26), 57 (76), 41 (100).
3.12. (R)-3-Amino-2-methylpropan-1-ol 21
Sulfuric acid (160 µl of the 18 M reagent) was added dropwise, at room temperature and with stirring
to a solution of compound (R)-20 (157 mg, 1.08 mmol) in dry ethanol (3 ml). The reaction mixture was
heated to reflux and this temperature was maintained for 7 h. Cooling, evaporation, addition of water (0.5
ml), saturation with NaOH, extraction (CH2Cl2, 3×5 ml), drying the combined organic phases (MgSO4),

F.-R. Alexandre, F. Huet / Tetrahedron: Asymmetry 9 (1998) 2301–2310
2309
evaporation and flash chromatography on silica gel (CH2Cl2:MeOH:iPrNH2=85:10:5) led to the known7
20
(R)-21 as a colorless oil (59 mg, 63%, 91% ee (estimated from (S)-18), [α] +5.4 (MeOH, c=3.4) (lit.7
D
20
1
[α] +8.9 (MeOH c=22.6) for 100% ee)). H NMR δ 0.84 (d, 3H, J=6.9 Hz), 1.81 (m, 1H), 2.70 (dd,
D
1H, J=12.2, 8.6 Hz), 2.86 (br s, 3H, OH and NH2), 2.93 (dd, 1H, J=12.2, 3.8 Hz), 3.55 (dd, 1H, J=10.6,
8.2 Hz), 3.68 (dd, 1H, J=10.6, 4.0 Hz); 13C NMR δ 14.6 (CH3), 36.6 (CH), 47.9 (CH2), 69.0 (CH2); IR
(film): 3500–3000, 2906, 1602, 1463, 1037 cm−1
.
3.13. (S)-3-[(Methylsulfonyl)oxy]-2-[(phenylsulfanyl)methyl]propylacetate 22
Triethylamine (305 µl, 2.18 mmol) was added with stirring, at room temperature and under argon to a
solution of compound (R)-13 (349 mg, 1.45 mmol) in dry CH2Cl2 (4.5 ml). The mixture was cooled
to 0°C then mesyl chloride (135 µl, 1.74 mmol) was added dropwise. The reaction was allowed to
proceed for 1.5 h at room temperature, with TLC monitoring. CH2Cl2 was then added, the organic phase
was washed with 10% HCl then dried (MgSO4). Evaporation then flash chromatography on silica gel
(cyclohexane:AcOEt=6:4) led to (S)-22 as a colorless oil (462 mg, 99%, 88% ee (estimated from (R)-
20
1
13), [α] − 4.5 (CHCl3, c=1.9)). H NMR δ 2.05 (s, 6H), 2.30 (m, 1H), 2.99 (s, 3H), 2.99 (dd, 1H,
D
J=13.8, 7.3 Hz), 3.03 (dd, 1H, J=13.8, 6.8 Hz), 4.17 (dd, 1H, J=11.5, 6.4 Hz), 4.22 (dd, 1H, J=11.5, 5.4
Hz), 4.32 (dd, 1H, J=10.1, 5.0 Hz), 4.37 (dd, 1H, J=10.1, 5.3 Hz), 7.22 (m, 1H), 7.30 (m, 2H), 7.36 (m,
2H); 13C NMR δ 20.7 (CH3), 32.1 (CH2), 37.2, 37.8, 60.3 (CH2), 67.9 (CH2), 126.8 (CH), 129.2 (2C,
CH), 130.0 (2C, CH), 134.9 (quat. C), 170.5 (CO); IR (film): 3021, 2935, 1733, 1361, 1234, 1172, 1045,
962, 829, 744, 692 cm−1; HPLC/MS (EI) m/z (rel. int.) 318 (M+, 23), 222 (14), 209 (7), 162 (52), 161
(62), 149 (25), 147 (34), 135 (33), 129 (67), 123 (90), 110 (100), 109 (79); anal. calcd for C13H18O5S2:
C, 49.04; H 5.70; S, 20.14, found: C, 48.86; H, 5.61; S, 19.91.
3.14. (R)-2-Methyl-3-(phenylsulfanyl)propan-1-ol 23
A solution of compound (S)-22 (90 mg, 0.28 mmol) in dry THF (0.5 ml) was added dropwise, with
stirring and under argon to a refluxing suspension of LiAlH4 (64 mg, 1.70 mmol) in dry THF (3
ml). After 5 min stirring, the reaction mixture was cooled. Hydrolysis with a small amount of water,
addition of Et2O, suction filtration on a sintered-glass funnel then washing the solid several times
with Et2O, drying of the organic phase (MgSO4), evaporation then flash chromatography on silica gel
(cyclohexane:AcOEt=6:4) provided (R)-23, a known product,9 as a colorless oil (40 mg, 78%, 88% ee
20
20
(estimated from (R)-13), [α] −13.8 (CH2Cl2, c=3.0) (lit.9 [α] −17.0 (CH2Cl2, c=1) for 100% ee)).
D
D
1H NMR δ 1.04 (d, 3H, J=6.8 Hz), 1.71 (br s, 1H, OH), 1.94 (m, 1H), 2.83 (dd, 1H, J=12.9, 6.5 Hz),
3.07 (dd, 1H, J=12.9, 6.5 Hz), 3.61 (m, 2H), 7.17 (m, 1H), 7.27 (m, 2H), 7.34 (m, 2H); 13C NMR δ 16.4
(CH3), 35.5 (CH), 37.4 (CH2), 66.8 (CH2), 125.8 (CH), 128.9 (2C, CH), 129.0 (2C, CH), 136.7 (quat.
C); IR (film): 3353, 3058, 2956, 2878, 1583, 1481, 1438, 1033, 983, 738, 690 cm−1; GPC/MS (EI) m/z
(rel. int.) 182 (M+, 43), 165 (2), 149 (4), 123 (26), 110 (100), 77 (12), 65 (18), 57 (20), 51 (18), 45 (38),
39 (30).
3.15. (R)-3-Azido-2-[(phenylsulfanyl)methyl]propylacetate 24
Sodium azide (149 mg, 2.29 mmol) was added portionwise at room temperature, under argon and
with stirring to a solution of compound (S)-22 (404 mg, 1.27 mmol) in DMF (5 ml). The reaction was
allowed to proceed for 4 h at 75°C. Cooling, addition of water (10 ml), extraction (Et2O, 3×15 ml),
drying, evaporation and flash chromatography on silica gel (cyclohexane:AcOEt=7:3) provided (R)-24

2310
F.-R. Alexandre, F. Huet / Tetrahedron: Asymmetry 9 (1998) 2301–2310
20
1
as a colorless oil (291 mg, 86%, 88% ee, [α] −10.6 (CHCl3, c=2)). H NMR δ 2.05 (s, 6H), 2.12
D
(m, 1H), 2.97 (d, 2H, J=6.8 Hz), 3.49 (dd, 1H, J=12.4, 5.6 Hz), 3.53 (dd, 1H, J=12.4, 6.0 Hz), 4.13
(dd, 1H, J=11.4, 6.0 Hz), 4.16 (dd, 1H, J=11.4, 5.5 Hz), 7.20 (m, 1H), 7.30 (m, 2H), 7.36 (m, 2H); 13
C
NMR δ 20.8 (CH3), 33.0 (CH2), 38.0 (CH), 51.3 (CH2), 63.7 (CH2), 126.6 (CH), 129.1 (2C, CH), 129.7
(2C, CH), 135.4 (quat. C), 170.7 (CO); IR (film): 3073, 2933, 2103, 1741, 1234, 1039, 740, 692 cm−1
GPC/MS (EI) m/z (rel. int.) 237 (M+−N2, 3), 137 (51), 110 (34), 109 (45), 91 (27), 65 (21), 43 (100).
;
3.16. (R)-3-Amino-2-[(phenylsulfanyl)methyl]propan-1-ol 25
A solution of compound (R)-24 (159 mg, 0.6 mmol) in dry THF (0.8 ml) was added dropwise, under
argon, at 0°C and with stirring to a suspension of LiAlH4 (50 mg, 1.32 mmol), in dry THF (1.5 ml).
The reaction mixture was stirred for 2 h at room temperature. Hydrolysis with a small amount of water,
addition of Et2O, suction filtration on a sintered-glass funnel then washing of the solid several times with
Et2O, drying of the organic phase (MgSO4) and evaporation provided (R)-25 as a colorless oil that was
20
D
used without further purification in the next step (73 mg, 62%, 88% ee, [α] −10.4 (CHCl3, c=4,7)). It
could also be chromatographed (CH2Cl2:MeOH:iPrNH2=80:15:5). 1H NMR δ 1.85 (m, 1H), 2.60 (br s,
3H, OH and NH2), 2.89 (dd, 1H, J=13.1, 7.3 Hz), 2.92 (m, 1H); 2.95 (dd, 1H, J=13.1, 6.7 Hz), 3.07 (m,
1H), 3.81 (m, 2H), 7.17 (m, 1H), 7.27 (m, 2H), 7.34 (m, 2H); 13C NMR δ 33.4 (CH2), 41.0 (CH), 44.7
(CH2), 66.0 (CH2), 125.9 (CH), 128.9 (2C, CH), 129.0 (2C, CH), 136.4 (quat. C); IR (film): 3359, 3292,
3075, 1583, 1481, 1438, 1025, 740, 690 cm−1
.
3.17. Reduction of compound 25 by Raney nickel
A suspension of Raney nickel (3 g) in MeOH (10 ml) was obtained by washing with water several
times and decantations followed by replacement of water by MeOH. A solution of compound (R)-25
(105 mg, 0.53 mmol) in MeOH (1 ml) was then added to this suspension. The reaction mixture was
stirred for 1 h with TLC monitoring. Filtration on Celite, washing with MeOH and evaporation provided
20
D
(R)-21 (27 mg, 57%, 88% ee, [α] −1.7 (MeOH, c=1) (for the crude product)).
Acknowledgements
We thank the local section of Sarthe of the Ligue Nationale contre le Cancer for a fellowship to F.-R.
A.
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