Chemoenzymatic synthesis of glycosylated enantiomerically pure 4- pentene 1,2- and 1,3-diol derivatives

Article abstract of DOI:10.1016/S0957-4166(98)00052-4

1-Dimethylthexylsiloxy-2-chloroacetoxy-4-pentene 2 and 1- dimethylthexylsiloxy-3-chloroacetoxy-4-pentene 3 were saponified with Pseudomonas lipase to give (R)-1-dimethylthexylsiloxy-4-pentene-2-ol (ee=99%) and (S)-2 (ee=99%) and (S)-1-dimethylthexylsiloxy

Full text of DOI:10.1016/S0957-4166(98)00052-4

Pergamon
Tetrahedron: Asymmetry 9 (1998) 781–790
Chemoenzymatic synthesis of glycosylated enantiomerically pure
4-pentene 1,2- and 1,3-diol derivatives
Frank Bien and Thomas Ziegler ∗
Institute of Organic Chemistry, University of Cologne, Greinstraße 4, D-50939 Cologne, Germany
Received 15 December 1997; accepted 4 February 1998
Abstract
1-Dimethylthexylsiloxy-2-chloroacetoxy-4-pentene 2 and 1-dimethylthexylsiloxy-3-chloroacetoxy-4-pentene 3
were saponified with Pseudomonas lipase to give (R)-1-dimethylthexylsiloxy-4-pentene-2-ol (ee=99%) and (S)-2
(ee=99%) and (S)-1-dimethylthexylsiloxy-4-pentene-3-ol (ee=99%) and (R)-3 (ee=98%), respectively. All enan-
tiomers were chemically transformed into the corresponding enatiomerically pure 2-benzoyloxy-4-pentene-1-ols
8 and 3-benzoyloxy-4-pentene-1-ols 14, respectively. Mannosylation of (R)-8 and (S)-14 with 2,3,4,6-tetra-O-
benzoyl-a-D-mannopyranosyltrichloroacetimidateafforded the correspondingmannopyranosides. © 1998 Elsevier
Science Ltd. All rights reserved.
1. Introduction
In the preceding paper,1 partially blocked enantiomerically pure 3-butene-1,2-diol derivatives for direct
glycosylation reactions were efficiently prepared from 1 using Schneiders approach2 via lipase-catalyzed
saponification. Since the thus-obtained 3-butene-1-hydroxy-2-yl glycopyranosides1 are thought to be
suitable precursors for aldolase-catalyzed preparation of novel disaccharides,3 the enzymatic resolution
of racemic alkenediols was extended here to the 4-pentene-1,2- and 1,3-diol derivatives 2 and 3,
respectively. Furthermore, optically active 4-pentene-1,3-diols were previously used as starting materials
for the synthesis of various deoxysugars4–6 and thus are ideal building blocks for the preparation of
carbohydrate derivatives.7,8
∗
Corresponding author. E-mail: Thomas.Ziegler@Uni-Koeln.de
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00052-4

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2. Results and discussion
Racemic 4-pentene-1,2-diol derivative 2 was conveniently prepared from ethyl 2-hydroxy-4-
pentenoate 4 which, in term, was easily accessible in 56% yield via Sn–Al promoted9 allylation
of ethyl glyoxylate. Next, reduction of 4 with NaBH4 in dioxane afforded diol 5 (94%) which was
regioselectively silylated at the primary alcohol to give 6 (85%; Scheme 1). Alternative preparations10–12
of racemic 5 and 6 were less efficient. Finally, chloroacetylation1 of compound 6 with chloroacetic
anhydride furnished racemic 2 in 99% yield. Since Pseudomonas lipase-catalyzed saponification of 1
was previously found to be more efficient than saponification with other enzymes.1 Pseudomonas lipase
was also used here for kinetic resolutions of 2 and 3. Thus, enzyme-catalyzed saponification of 2 was
accomplished on a 13 g scale exactly as previously described for compound 1.1,16 Alcohol (R)-6 (45%,
ee=99%) and unreacted (S)-2 (45%, ee=99%) were obtained. Although (R)-6 can be directly used for
glycosylation reactions at its secondary hydroxyl, further manipulations of the blocking groups of the
latter were performed as follows.
Scheme 1. (i) NaBH4, dioxane–EtOH, 25°C. (ii) Cl–SiMe2thex, imidazole, CH2Cl2, 0°C. (iii) Chloroacetic anhydride, pyridine,
0°C. (iv) Pseudomonas lipase, phosphate buffer (pH 7), 45% (S)-2 (ee=99%), 45% (R)-6 (ee=99%). (v) BzCl, pyridine, rt. (vi)
3% HF in MeCN, rt. (vii) (1) ethylenediamine, Et3N, MeOH, pyridine; (2) (v). (viii) Cat. TMSOTf, MeCN, −30°C
Benzoylation of (R)-6 first gave (R)-7 (98%), protodesilylation of which with HF in MeCN afforded

F. Bien, T. Ziegler / Tetrahedron: Asymmetry 9 (1998) 781–790
783
enantiomerically pure (R)-8 (99%). Similarly, (S)-2 was chemically dechloroacetylated, to first give
(S)-6. Here, deacylation was performed most efficiently with ethylene diamine13 since removal of the
chloroacetyl group by Candida lipase1 which was found to be optimal for compound 1 gave lower yields
with 2. Next, (S)-6 was first benzoylated and the resulting (S)-7 was once again desilylated with HF to
afford (S)-8. Thus, both enantiomers of regioselectively blocked 4-pentene-1,2-diol derivatives 6 and 8
were easily available on a multigram scale.
Direct glycosylation was further exemplified for compound (S)-8. Mannosylation proceeded smoothly
with mannosyl imidate14 9 to give crystalline 10 in 98% yield. The crystal structure15 of the latter showed
unambiguously the (S)-configuration at C-2 of the aglycon.
Enzymatic resolution of racemic 4-pentene-1,3-diol derivative 3 was performed according to that of
compound 2. First, known ethyl 3-hydroxy-4-pentenoate16 was converted into diol 11, regioselective
silylation of which furnished 12 (83%; Scheme 2). Next, chloroacetylation of the remaining hydroxyl
gave racemic 3; Pseudomonas lipase-catalyzed saponification of the latter then afforded (S)-12 (44%,
ee=99%) and (R)-3 (49%, ee=98%), respectively on a 21 g scale. Similar to the aforementioned 4-
pentene-1,2-diol derivatives, (S)-12 was converted via (S)-13 into (S)-14 and (R)-3 was converted via
(R)-12 and (R)-13 into (R)-14, respectively. For the dechloroacetylation of (R)-3, Candida cylindracea
lipase-catalyzed deacylation was superior to chemical procedures. Mannosylation of the (R)-14 with
mannosyl imidate 9 then afforded crystalline glycoside 15 (90%), the crystal structure of which15 proved
the (R)-configuration of the aglycon of compound 15. Finally, Zemplén deacylation of 15 furnished the
free 3-hydroxy-4-pentene-1-yl mannopyranoside 16 (90%) which is a suitable precursor for aldolase-
catalyzed preparation of novel saccharides as previously described for similar derivatives.3,17
3. Experimental
3.1. General
Optical rotations were performed with a Perkin–Elmer polarimeter 241 LC. Melting points were
determined with a Büchi SMP-20 apparatus. The NMR data were obtained from spectra measured in
CDCl3 solutions for blocked compounds (with Me4Si as an internal standard) and D2O for deblocked
compounds (with MeOH as an internal standard) at 25°C with a Bruker AC 250 F, a Bruker CXP 300
and a Bruker ARX 500 spectrometer. 1H NMR signals assignments were made by first-order analysis of
the spectra. 13C NMR assignments were made by mutual comparison of spectra, by DEPT spectra, by
1
comparison with spectra of related compounds and H–13C correlated spectra. GC for determination
of the enantiomeric excess: (a) Carlo Erba HRGC 5300 Mega Series with FID, Carlo Mega Series
integrator, 0.4–0.6 bar hydrogen, column 20 m, Bondex-un-Et-105 (β-cyclodextrin); (b) Fisons HRGC
8560 with FID, Mega Series 2 integrator, 0.4–0.6 bar hydrogen, column 20 m, Bondex-un-a-5,6-Et-
57 (α-cyclodextrin). Mass spectrometry was performed with a Finnigan mass spectrometer MAT 95 in
FAB mode. GC–MS was performed with a Hewlett–Packard 5890 GC, 0.4 bar hydrogen, column 30 m,
HP-5 MS and Finnigan MAT 95 mass spectrometer, CI, methane 0.5 torr. Thin-layer chromatography
(TLC) was performed on precoated plastic sheets, Polygram SIL UV254, 40×80 mm (Macherey–Nagel)
using appropriately adjusted mixtures of CCl4–acetone or petroleum ether–ethyl acetate for development.
Detection was effected with UV light, where applicable, iodine and by charring with 5% H2SO4 in EtOH.
Preparative column chromatography was performed with glass columns of different sizes packed with
silica gel S, grain size 0.032–0.063 mm (Riedel de Haen).

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Scheme 2. (i) Cl–SiMe2thex, imidazole, CH2Cl2, 0°C. (ii) Chloroacetic anhydride, pyridine, 0°C. (iii) Pseudomonas lipase,
phosphate buffer pH 7, 49% (R)-3 (ee=98%), 44% (S)-12 (ee=99%). (iv) BzCl, pyridine, rt. (v) 3% HF in MeCN, rt. (vi) (1) CC
lipase, phosphate buffer (pH 7.0); (2) (v). (vii) 9, cat. TMSOTf, MeCN, −30°C. (viii) cat. NaOMe, MeOH, rt
3.2. Ethyl 2-hydroxy-4-pentenoate 4
A 50% solution of ethyl glyoxylate in toluene (50 g, 0.15 mol) and allyl bromide (16.9 ml, 0.2 mol)
was dissolved in petroleum ether (50 ml). Water (25 ml), Sn dust (9.97 g, 0.084 mol), Al powder (4.72
g, 0.175 mol) and a catalytic amount of aq. HBr were added to the solution and the reaction mixture
was stirred for 1 h at room temperature and filtered through a layer of Celite. The solid residue was
extracted twice with petroleum ether and the combined organic layers were washed with 2 M aq. HCl and
NaHCO3 solution dried (Na2SO4) and concentrated. The residue was purified by Kugelrohr distillation,
1
to give 4 (11.78 g, 56%); bp: 100°C/15 mmHg (Kugelrohr oven temperature); H NMR (500 MHz):
δ=1.30 (t, 3H, OCH2CH3, J=7.2 Hz), 2.42–2.47 (m, 1H, 3-Hb), 2.56–2.61 (m, 1H, 3-Ha), 2.60 (d, 1H,
OH, J=4.6 Hz), 4.20–4.30 (m, 3H, 2-H, OCH2CH3), 5.13–5.18 (m, 2H, 5-Hcis, 5-Htrans), 5.81 (ddt, 1H,
4-H, J3a,4=J3b,4=7.0 Hz, J4,5cis=10.1 Hz, J4,5trans=17.1 Hz); 13C NMR (125 MHz): δ=14.2 (OCH2CH3),
38.7 (C-3), 61.7 (OCH2CH3), 70.0 (C-2), 118.7 (C-5), 132.5 (C-4), 174.5 (C-1). GC–MS, CI, m/z: 144
(M)+, 126 (M−H2O)+, 99 (M−OCH2CH3)+, 71 (M−COOCH2CH3)+.

F. Bien, T. Ziegler / Tetrahedron: Asymmetry 9 (1998) 781–790
785
3.3. 4-Pentene-1,2-diol 5
A solution of 4 (1.50g, 10.40 mmol) in dioxane:EtOH (10:1, 55 ml) was treated with NaBH4 (474 mg,
12.50 mmol) for 22 h at room temperature. After removal of the solvent, the residue was coevaporated
twice with MeOH and redissolved in MeOH. Ion-exchange resin (Dowex 50 WX8, H+) was added until
the solution became neutral. Filtration of the mixture, concentration of the filtrate and chromatography
1
(CHCl3:MeOH=3:1) of the residue afforded 5 (997 mg, 94%). H NMR (500 MHz): δ=2.21–2.29 (m,
2H, 3-Ha, 3-Hb), 2.95 (s, 2H, 2×OH), 3.47 (dd, 1H, 1-Hb, J1b,2=7.4 Hz, J1a,1b=11.3 Hz), 3.66 (dd, 1H,
1-Ha, J1a,2=2.9 Hz), 3.75–3.79 (m, 1H, 2-H), 5.12–5.16 (m, 2H, 5-Hcis, 5-Htrans), 5.82 (ddt, 1H, 4-H,
J
3,4=7.1 Hz, J4,5cis=10.1 Hz, J4,5trans=17.1 Hz); 13C NMR (125 MHz): δ=37.8 (C-3), 66.2 (C-1), 71.3
(C-2), 118.1 (C-5), 134.1 (C-3); GC–MS (CI) m/z: 102 (M)+, 85 (M−OH)+, 67 (C5H7)+.
3.4. 1-Dimethylthexylsilyloxy-4-pentene-2-ol 6
Thexyldimethylsilylchloride (9.3 ml, 47.4 mmol) was added at 0°C to a solution of 5 (4.60 g,
(45.04 mmol) and imidazole (7.66 g, 112.5 mmol) in CH2Cl2 (80 ml). After stirring for 1 h at room
temperature, the mixture was diluted with CH2Cl2, washed with aq. NaHCO3 solution, dried (Na2SO4)
and concentrated. Chromatography of the residue (petroleum ether:ethyl acetate=20:1) afforded 6 (9.06
g, 82%); 1H NMR (500 MHz): δ=0.11 (s, 6H, Si(CH3)2), 0.86 (s, 6H, Si(CH3)2C(CH3)2), 0.89 (d, 6H,
Si(CH3)2C(CH3)2CH(CH3)2, J=6.9 Hz), 1.63 (quint, 1H, Si(CH3)2C(CH3)2CH(CH3)2), 2.24 (t, 2H,
3-Ha, 3-Hb, J=6.8 Hz), 2.41 (d, 1H, OH, J=3.8 Hz), 3.44 (dd, 1H, 1-Hb, J1b,2=7.0 Hz, J1a,1b=10.0
Hz), 3.61 (dd, 1H, 1-Ha, J1a,2=3.7 Hz), 3.68–3.73 (m, 1H, 2-H), 5.09 (d, 1H, 5-Hcis, J=10.8 Hz),
5.12 (d, 1H, 5-Htrans), 5.73 (ddt, 1H, 4-H, J4,5cis=17.1 Hz); 13C NMR (125 MHz): δ=−3.5, −3.4
(Si(CH3)2), 18.5 (Si(CH3)2C(CH3)2CH(CH3)2), 20.3 (Si(CH3)2C(CH3)2), 25.1 (Si(CH3)2C(CH3)2),
34.2 (Si(CH3)2C(CH3)2C), 37.6 (C-2), 66.3 (C-1), 71.1 (C-2), 117.4 (C-5), 134.5 (C-4); anal. calcd for
C13H28O2Si (244.5): C, 63.88; H, 11.54; found: C, 63.87; H; 11.58.
3.5. 2-Chloracetoxy-1-dimethylthexylsilyloxy-4-pentene 2
A solution of 6 (10.54 g, 43.12 mmol) in pyridine:CH2Cl2 (1:13, 75 ml) was treated with chloroacetic
anhydride (7.74 g, 45.27 mmol) at 0°C. After 90 min water was added and the mixture was diluted
with CH2Cl2, washed with water, aq. 2 M HCl and NaHCO3 solution, dried (Na2SO4) and concen-
trated. The residue was chromatographed (petroleum ether:ethyl acetate=20:1) to give 2 (13.70 g,
1
99%); H NMR (500 MHz): δ=0.08 (s, 6H, Si(CH3)2), 0.83 (s, 6H, Si(CH3)2C(CH3)2), 0.87 (d, 6H,
Si(CH3)2C(CH3)2CH(CH3)2, J=6.9 Hz), 1.61 (sept, 1H, Si(CH3)2C(CH3)2CH(CH3)2), 2.28–2.50 (m,
2H, 3-Ha, 3-Hb), 3.66 (m, 2H, 1-Ha, 1-Hb), 4.04 (s, 2H, CH2Cl), 4.96–5.15 (m, 3H, 2-H, 5-Hcis, 5-
H
trans), 5.75 (ddt, 1H, 4-H, J3a,4=J3b,4=7.1 Hz, J4,5cis=10.1 Hz, J4,5trans=17.1 Hz); 13C NMR (125 MHz):
δ=−3.6 (Si(CH3)2), 18.5 (Si(CH3)2C(CH3)2CH(CH3)2), 20.2 (Si(CH3)2C(CH3)2), 25.1 (Si(CH3)2C),
34.2 (Si(CH3)2C(CH3)2CH(CH3)2), 34.9 (C-3), 41.0 (CH2Cl), 63.1 (C-1), 75.8 (C-2), 118,3 (C-5), 132.9
(C-4), 166.9 (CO); anal. calcd for C15H29ClO3Si (320.9): C, 56.14; H, 9.11; Cl: 11.05; found: C, 55.99;
H, 9.18; Cl, 11.03.
3.6. Kinetic resolution of compound 2
Racemic 2 (13.00 g, 40.51 mmol) was added to a suspension of Pseudomonas lipase (Amano PS)
(400 mg) in 0.1 M aq. phosphate buffer (pH 7.0; 100 ml). The mixture was vigorously stirred, with the

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F. Bien, T. Ziegler / Tetrahedron: Asymmetry 9 (1998) 781–790
pH maintained at 7.0 by addition of aq. 1.0 M NaOH. After 18 h, the reaction had consumed 19.798
ml of base. NaCl (40 g) was added and the solution was extracted several times with CH2Cl2. The
combined organic layers were dried (Na2SO4) and concentrated. Chromatography (petroleum ether:ethyl
acetate=25:1) of the residue afforded first (S)-(2) (5.82 g, 45%, ee=99%), [α]2D0=−2.3 (c=1.7, CHCl3).
Eluted next was (R)-(6) (4.45 g, 45%, ee=99%); [α]2D0=−1.7 (c=2.1, CHCl3).
3.7. (S)-1-Thexydimethylsilyloxy-4-pentene-2-ol (S)-(6)
A solution of (S)-2 (5.65 g, 17.61 mmol) in pyridine:methanol (1.5:1, 100 ml) was treated with
ethylenediamine (2.4 ml, 35.74 mmol) and triethylamine (12 ml) for 15 h at room temperature. The mix-
ture was diluted with CH2Cl2, washed with water, aq. 2 M HCl and NaHCO3 solution, dried (Na2SO4)
and concentrated. Chromatography (petroleum ether:ethyl acetate=20:1) of the residue afforded (S)-6
(3.92 g, 91%); [α]2D0=+0.9 (c=3.0, CHCl3).
3.8. (R)-2-Benzoyloxy-1-dimethylthexylsilyloxy-4-pentene (R)-(7)
Benzoyl chloride (2.4 ml, 20.69 mmol) was added to a solution of (R)-6 (4.20 g, 17.18 mmol) in
pyridine (40 ml) and the mixture was stirred for 3 h at room temperature. Water (2 ml) was added and
the mixture was extracted with CH2Cl2. The combined organic layers were washed with water, aq. 2
M HCl and NaHCO3 solution. After drying (Na2SO4) the solvent was removed and chromatography
(petroleum ether:ethyl acetate=20:1) of the residue afforded (R)-7 (5.87 g, 98%); [α]2D0=+9.0 (c=1.7,
1
CHCl3); H NMR (500 MHz): δ=0.07 (s, 6H, Si(CH3)2), 0.83 (s, 6H, Si(CH3)2CH), 0.85, 0.86 (2d,
6H, Si(CH3)2C(CH3)2CH(CH3)2, J=6.8 Hz), 1.60 (quint, 1H, Si(CH3)2C(CH3)2CH), 2.45–2.51 (m, 1H,
3-Hb), 2.53–2.59 (m, 1H, 3-Ha), 3.76–3.77 (m, 2H, 1-Ha, 1-Hb), 5.07 (dd, 1H, 5-Hcis, J4,5cis=10.1 Hz,
J
5cis,5trans=1.2 Hz), 5.13 (dd, 1H, 5-Htrans, J4,5trans=17.1 Hz), 5.16–5.20 (m, 1H, 2-H), 5.84 (ddt, 1H,
4-H, J3a,4=J3b,4=7.1 Hz, J4,5cis=10.0 Hz), 7.42–8.05 (m, 5H, C6H5); 13C NMR (125 MHz): δ=−3.6
(Si(CH3)2), 18.4, 18.5 (Si(CH3)2C(CH3)2CH(CH3)2), 20.2, 20.3 (Si(CH3)2C(CH3)2), 25.1 (Si(CH3)2C),
34.2 (Si(CH3)2C(CH3)2CH), 35.1 (C-3), 63.3 (C-1), 74.2 (C-2), 117.9 (C-5), 133.5 (C-4), 166.1 (CO);
anal. calcd for C20H32O3Si (348.6): C, 68.92; H, 9.25; found: C, 68.67; H, 9.36.
3.9. (S)-2-Benzoyloxy-1-dimethylthexylsilyloxy-4-pentene (S)-(7)
Treatment of (S)-6 (3.70 g, 15.14 mmol) as described for compound (R)-6 afforded (S)-7 (5.21 g,
99%); [α]2D0=−9.1 (c=2.4, CHCl3).
3.10. (R)-2-Benzoyloxy-4-pentene-1-ol (R)-(8)
40% aq. HF (4 ml) was added to a solution of (R)-7 (5.60 g, 16.07 mmol) in MeCN (80 ml). After
stirring at room temperature for 1.5 h, the reaction mixture was diluted with CH2Cl2, washed with water
and aq. NaHCO3 solution, dried (Na2SO4) and concentrated. Chromatography (CCl4:acetone=8:1) of
the residue afforded (R)-8 (3.29 g, 99%); [α]2D0=+8.7 (c=2.0, CHCl3); 1H NMR (500 MHz): δ=2.27 (t,
1H, OH, J=6.1 Hz), 2.52 (t, 2H, 3-Ha, 3-Hb, J=6.7 Hz), 3.79 (ddt, 1-Hb, J1b,2=6.0 Hz, J1a,1b=12.1 Hz),
3.84 (ddd, 1H, 1-Ha, J1a,2=3.6 Hz), 5.10 (d, 1H, 5-Hcis, J4,5cis=10.1 Hz), 5.15–5.19 (m, 1H, 5-Htrans),
5.19–5.22 (m, 1H, 2-H), 5.84 (ddt, 1H, 4-H), 7.42–8.05 (m, 5H, C6H5); 13C NMR (125 MHz): δ=35.3
(C-3), 64.3 (C-1), 75.2 (C-2), 118.4 (C-5), 133.2 (C-4), 166.7 (CO); anal. calcd for C12H14O3 (206.2):
C, 69.89; H, 6.84; found: C, 69.71; H, 6.88.

F. Bien, T. Ziegler / Tetrahedron: Asymmetry 9 (1998) 781–790
787
3.11. (S)-2-Benzoyloxy-4-pentene-1-ol (S)-(8)
Treatment of (S)-7 (900 mg, 2.58 mmol) as described for compound (R)-7 afforded (S)-8 (516 mg,
97%); [α]2D0=−9.7 (c=2.1, CHCl3).
3.12. 2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl trichloroacetimidate 9
DBU (500 µl, 3.40 mmol) was added to a solution of trichloroacetonitrile (6.7 ml, 67 mmol) and
2,3,4,6-tetra-O-benzoyl-D-mannopyranose14 (20.0 g, 33.5 mmol) in CH2Cl2 (150 ml) and the mixture
was stirred for 2 h at 0°C. The mixture was concentrated and the residue was chromatographed
(petroleum ether:ethyl acetate=2:1 with 1% Et3N) to afford 9 (18.62 g, 75%); [α]2D0=−37 (c=1.5,
1
CHCl3); H NMR (300 MHz): δ=4.62 (dd, 1H, 6-Hb, J5,6b=4.1 Hz, J6a,6b=12.2 Hz), 4.61–4.67 (m,
1H, 5-H), 4.74 (dd, 1H, 6-Ha; J5,6a=2.4 Hz), 5.95 (dd, 1H, 2-H, J1,2=1.9 Hz, J2,3=3.3 Hz), 5.99 (dd,
1H, 3-H, J3,4=9.9 Hz), 6.24 (1H, 4-H, J4,5=10.0 Hz), 6.58 (d, 1H, 1-H), 7.24–8.11 (m, 20H, C6H5),
8.87 (s, 1H, CNHCCl3); 13C NMR (75.5 MHz): δ=62.4 (C-6), 66.1 (C-4), 68.9 (C-3), 69.8 (C-2), 71.6
(C-5), 90.6 (CNHCCl3), 94.7 (C-1), 159.9 (CNHCCl3), 165.1, 165.4, 165.5, 166.0 (CO); anal. calcd for
C36H28NO10Cl3 (741.0): C, 58.43; H, 3.81; N, 1.89; Cl, 14.35; found: C, 58.49; H, 3.95; N, 1.64; Cl,
14.54.
3.13. (S)-2-Benzoyloxy-4-pentene-1-yl 2,3,4,6-tetra-O-benzoyl-α-D-mannopyranoside 10
A solution of TMSOTf (91 µl, 0.5 mmol) in CH2Cl2 (10 ml) was added at −30°C to a solution of (S)-8
(969 mg, 4.70 mmol) and 9 (3.60 g, 4.86 mmol) in CH2Cl2 (50 ml). After stirring for 50 min, the mixture
was neutralized with pyridine, filtered, washed with aq. 2 M HCl and NaHCO3 solution, dried (Na2SO4)
and concentrated. Chromatography (CCl4:acetone=15:1) of the residue afforded 10 (3.63 g, 98%), which
was crystallized from petroleum ether–acetone; mp: 114–116°C; [α]2D0=−27 (c=1.2, CHCl3); 1H NMR
(500 MHz): δ=2.59–2.66 (t, 2H, 31-Ha, 31-Hb), 3.82 (dd, 1H, 11-Hb, J11b,21=4.0 Hz, J11a,11b=10.6 Hz),
4.07 (dd, 1H, 11-Ha, J11a,21=6.1 Hz), 4.40–4.46 (m, 2H, 52-H, 62-Hb), 4.66–4.69 (m, 1H, 62-Ha), 5.15
(dd, 1H, 51-Hcis, J41,51cis=10.3 Hz, J51cis,51trans=1.3 Hz), 5.17 (d, 1H, 12-H, J12,22=1.5 Hz). 5.23 (dd, 1H,
51-Htrans, J41,51trans=17.1 Hz), 5.46–5.50 (m, 1H, 21-H), 5.76 (dd, 1H, 22-H, J22,32=3.1 Hz), 5.85 (dd,
1H, 32-H, J32,42=10.1 Hz), 5.87–5.93 (m, 1H, 41-H), 6.08 (t, 1H, 42-H); 13C NMR (125 MHz): δ=35.6
(C-31), 62.7 (C-62), 66.7 (C-42), 68.4 (C-11), 69.0 (C-52), 70.0 (C-32), 70.2 (C-22), 71.9 (C-21), 97.5
(C-12), 118.8 (C-51), 133.5 (C-41); anal. calcd for C46H40O12 (784.8): C, 70.40; H, 5.14; found: C, 70.37
H, 5.17.
3.14. 1-Dimethylthexylsilyloxy-4-pentene-3-ol 12
Thexyldimethylsilyl chloride (17.1 ml, 87.14 mmol) was added at 0°C to a solution of 114 (8.70
g, 85.18 mmol) and imidazole (14.50 g, 213.0 mmol) in CH2Cl2 (100 ml). The mixture was stirred
for 1 h, diluted with CH2Cl2, washed with aq. NaHCO3 solution, dried (Na2SO4) and concen-
trated. Chromatography (petroleum ether:ethyl acetate=15:1) of the residue afforded 12 (17.27 g,
1
83%); H NMR (250 MHz): δ=0.12 (s, 6H, Si(CH3)2), 0.85 (s, 6H, Si(CH3)2C(CH3)2), 0.89 (d, 6H,
Si(CH3)2C(CH3)2CH(CH3)2, J=6.9 Hz), 1.54–1.85 (m, 3H, Si(CH3)2C(CH3)2CH), 2-Ha, 2-Hb), 3.33 (d,
1H, OH, J=3.5 Hz), 3.78 (ddd, 1H, 1-Hb, J1b,2a=4.6 Hz, J1b,2b=7.2 Hz, J1a,1b=10.2 Hz), 3.88 (ddd, 1H,
1-Ha, J1a,2a=4.6 Hz), 4.31–4.40 (m, 1H, 3-H), 5.11 (dt, 1H, 5-Hcis, J4,5cis=10.4 Hz, J3,5cis=J5cis,5trans=1.6
Hz), 5.24 (dt, 1H, 5-Htrans, J4,5trans=17.2 Hz), 5.88 (ddd, 1H, 4-H, J3,4=5.4 Hz); 13C NMR (62.9 MHz):

788
F. Bien, T. Ziegler / Tetrahedron: Asymmetry 9 (1998) 781–790
δ=−3.6 (Si(CH3)2), 18.5 (Si(CH3)2C(CH3)2CH(CH3)2), 20.2 (Si(CH3)2C(CH3)2), 25.0 (Si(CH3)2C),
34.1 (Si(CH3)2C(CH3)2CH), 38.3 (C-2), 61.6 (C-1), 72.5 (C-3), 114.1 (C-5), 140.7 (C-4); anal. calcd for
C13H28O2Si (244.5): C, 63.88; H, 11.54; found: C, 63.64; H, 11.66.
3.15. 3-Chloroacetoxy-1-dimethylthexylsilyloxy-4-pentene 3
Chloroacetic anhydride (13.08 g, 76.5 mmol) was added to a solution of 12 (16.97 g, 69.4
mmol) in pyridine (8.1 ml) and CH2Cl2 (100 ml) and the mixture was stirred for 2 h at 0°C. The
mixture was diluted with CH2Cl2, washed with aq. 2 M HCl and NaHCO3 solution, dried (Na2SO4)
and concentrated. Chromatography (petroleum ether:ethyl acetate=15:1) of the residue afforded 3
1
(21.39 g, 96%); H NMR (250 MHz): δ=0.07 (s, 6H, Si(CH3)2), 0.84 (s, 6H, Si(CH3)2C(CH3)2),
0.88 (d, 6H, Si(CH3)2C(CH3)2CH(CH3)2, J=6.9 Hz), 1.61 (quint, 1H, Si(CH3)2C(CH3)2CH),
1.75–1.99 (m, 2H, 2-Ha, 2-Hb), 3.61–3.66 (m, 2H, 1-Ha, 1-Hb), 4.05 (s, 2H, CH2Cl), 5.22 (dt, 1H,
5-Hcis, J4,5cis=10.3 Hz, J3,5cis=J5cis,5trans=1.1 Hz), 5.30 (dt, 1H, 5-Htrans=17.2 Hz, J3,5trans=1.2 Hz),
5.47 (q, 1H, 3-H, J2a,3=J2b,3=J3,4=6.7 Hz), 5.81 (ddd, 1H, 4-H); 13C NMR (62.9 MHz): δ=−3.5
(Si(CH3)2), 18.6 (Si(CH3)2C(CH3)2CH(CH3)2), 20.4 (Si(CH3)2C(CH3)2), 25.1 (Si(CH3)2C), 34.2
(Si(CH3)2C(CH3)2CH), 37.1 (C-2), 41.6 (CH2Cl), 58.5 (C-1), 74.3 (C-3), 117.7 (C-5), 135.5 (C-4),
166.4 (CO); anal. calcd for C15H29ClO3Si (320.9): C, 56.14; H, 9.11; Cl, 11.05; found: C, 56.18; H,
9.20; Cl, 10.85.
3.16. Kinetic resolution of compound 3
A suspension of racemic 3 (21.00 g, 65.43 mmol) in aq. 0.1 M phosphate buffer (pH 7.0; 120 ml)
was treated with Pseudomonas lipase (400 mg) as described for compound 2. The reaction was stopped
after 37.821 ml of aq. 1 M NaOH solution had been consumed in 13 h and 40 min. Chromatography
(petroleum ether:ethyl acetate=20:1) afforded first (R)-3 (10.33 g, 49%, ee=98%); [α]2D0=+19.6 (c=3.0,
CHCl3).
Eluted next was (S)-12 (7.05 g, 44%, ee=99%); [α]2D0=+8.6 (c=2.45, CHCl3).
3.17. (R)-1-Dimethylthexylsilyloxy-4-pentene-3-ol (R)-(12)
Compound (R)-3 (10 g, 31.16 mmol) was added to a stirred suspension of Candida cylindracea lipase
(400 mg) in aq. 0.1 M phosphate buffer (pH 7.0; 120 ml) and the pH was maintained by addition of aq.
NaOH solution. After 116 h, the reaction mixture had consumed 30.944 ml of 1 M NaOH. NaCl (50 g)
was added and the mixture was extracted several times with CH2Cl2. The combined organic layers were
dried (Na2SO4) and the solvent was removed. Chromatography of the residue afforded (R)-12 (6.66 g,
87%); [α]2D0=−8.6 (c=2.8, CHCl3).
3.18. (R)-3-Benzoyloxy-1-dimethylthexylsiloxy-4-pentene (R)-(13)
Compound (R)-12 (6.50 g, 26.59 mmol) and benzoyl chloride (3.4 ml, 29.31 mmol) were dissolved in
pyridine (40 ml) and stirred for 3 h at room temperature. After the addition of water (2 ml), the solvent
was removed followed by coevaporation with toluene. The residue was redissolved in CH2Cl2, washed
with water, aq. 2 M HCl and NaHCO3 solution, dried (Na2SO4) and concentrated. Chromatography
of the residue (petroleum ether:ethyl acetate=20:1) afforded (R)-13 (9.00 g, 97%); [α]2D0=−1.2 (c=1.2,
CHCl3); 1H NMR (250 MHz): δ=0.05, 0.06 (s, 6H, Si(CH3)2), 0.83 (s, 6H, Si(CH3)2C(CH3)2), 0.87 (d,

F. Bien, T. Ziegler / Tetrahedron: Asymmetry 9 (1998) 781–790
789
6H, Si(CH3)2C(CH3)2CH(CH3)2, J=6.9 Hz), 1.60 (sept, 1H, Si(CH3)2C(CH3)2CH), 186–2.10 (m, 2H,
2-Ha, 2-Hb), 3.69–3.74 (m, 2H, 1-Ha, 1-Hb), 5.20 (dt, 1H, 5-Hcis, J4,5cis=10.5 Hz, J3,5cis=J5cis,5trans=1.1
Hz), 5.33 (dt, 1H, 5-Htrans, J4,5trans=17.3 Hz, J3,5trans=1.2 Hz), 5.59–5.67 (m, 1H, 3-H), 5.92 (ddd,
1H, 4-H, J3,4=6.3 Hz), 7.41–8.08 (m, 5H, C6H5); 13C NMR (62.9 MHz): δ=−3.5 (Si(CH3)2), 18.5
(Si(CH3)2C(CH3)2CH(CH3)2), 20.3 (Si(CH3)2C(CH3)2), 25.1 (Si(CH3)2C), 34.2 (Si(CH3)2C(CH3)2
CH), 37.4 (C-2), 58.8 (C-1), 72.1 (C-3), 116.6 (C-5), 136.5 (C-4), 165.7 (CO); anal. calcd for C20H32O3Si
(348.6): C, 68.92; H, 9.25; found: C, 69.14 H, 9.22.
3.19. (S)-3-Benzoyloxy-1-dimethylthexylsiloxy-4-pentene (S)-(13)
Treatment of (S)-12 (6.60 g, 27.00 mmol) as described for compound (R)-13 afforded (S)-13 (8.83 g,
94%); [α]2D0=+0.9 (c=2.4, CHCl3).
3.20. (R)-3-Benzoyloxy-4-pentene-1-ol (R)-(14)
Treatment of (R)-13 (8.85 g, 25.39 mmol) with aq. 40% HF (4.5 ml) in MeCN (150 ml) as described
for compound (R)-8 afforded (R)-14 (4.89 g, 93%); [α]2D0=−27 (c=1.8, CHCl3); 1H NMR (250 MHz):
δ=1.88–2.10 (m, 2H, 2-Ha, 2-Hb), 2.17–2.22 (m, 1H, OH), 3.63–3.78 (m, 2H, 1-Ha, 1-Hb), 5.23
(dt, 1H, 5-Hcis, J4,5cis=10.5 Hz, J3,5cis=J5cis,5trans=1.0 Hz), 5.38 (dt, 1H, 5-Htrans, J4,5trans=17.2 Hz,
J
3,5cis=J5cis,5trans=1.1 Hz), 5.67–5.75 (m, 1H, 3-H), 5.96 (ddd, 1H, J3,4=6.1 Hz), 7.41–8.08 (m, 5H,
C6H5); 13C NMR (62.9 MHz): δ=37.5 (C-2), 58.8 (C-1), 72.4 (C-3), 116.8 (C-5), 136.3 (C-4), 166.5
(CO); anal. calcd for C12H14O3 (206.2): C, 69.89; H, 6.84; found: C, 69.67; H, 6.95.
3.21. (S)-3-Benzoyloxy-4-pentene-1-ol (S)-(14)
Treatment of (S)-13 (8.00 g, 22.95 mmol) as described for (R)-13 afforded (S)-14 (4.96 g, 96%);
[α]2D0=+26 (c=2.77, CHCl3).
3.22. (R)-3-Benzoyloxy-4-pentene-1-yl 2,3,4,6-tetra-O-benzoyl-α-D-mannopyranoside 15
A solution of TMSOTf (181 µl, 1.0 mmol) in CH2Cl2 was added at −30°C to a solution of (R)-14
(2.0 g, 9.7 mmol) and 9 (8.15 g, 10.22 mmol) in CH2Cl2 (110 ml) containing molecular sieves 3 Å
(5 g). After 1.5 h the reaction mixture was neutralized with pyridine, filtered through a layer of Celite,
diluted with CH2Cl2 and washed with aq. 2 M HCl and NaHCO3 solution. The dried (Na2SO4) solution
was concentrated and the residue was crystallized from hexane–acetone to afford 15 (6.84 g, 90%); mp:
1
176–178°C; [α]2D0=−18 (c=1.4, CHCl3); H NMR (500 MHz): δ=2.18–2.28 (m, 2H, 21-Ha, 21-Hb),
3.67–3.70 (m, 1H, 11-Hb), 3.99–4.04 (m, 1H, 11-Ha), 4.26 (dd, 1H, 62-Hb, J52,62b=4.1 Hz, J62a,62a=12.2
Hz), 4.35 (ddd, 1H, 52-H, J42,52=10.1 Hz, J52,62a=2.6, J52,62b=3.7 Hz), 4.48 (dd, 1H, 62-Ha), 5.09 (d, 1H,
12-H, J12,21=1.4 Hz), 5.29 (d, 1H, 51-Hcis, J41,51cis=10.5 Hz), 5.45 (d, 1H, 51-Htrans, J41,51trans=17.2 Hz),
5.71 (dd, 1H, 22-H, J22,32=3.2 Hz), 5.82–5.85 (m, 1H, 31-H), 5.92 (dd, 1H, 32-H), 5.96–6.03 (m, 1H,
41-H), 6.11 (t, 1H, 42-H); 13C NMR (125 MHz): δ=34.2 (C-21), 62.5 (C-62), 64.4 (C-11), 66.6 (C-42),
68.8 (C-52), 70.2 (C-32), 70.4 (C-22), 71.9 (C-31), 97.7 (C-12), 117.1 (C-51), 136.1 (C-41); anal. calcd
for C46H40O12 (784.8): C, 70.40 H, 5.14; found: C, 70.49; H, 5.13.

790
F. Bien, T. Ziegler / Tetrahedron: Asymmetry 9 (1998) 781–790
3.23. (R)-3-Hydroxy-4-pentene-1-yl α-D-mannopyranoside 16
A solution of 15 (6.70 g, 8.95 mmol) in MeOH:toluene (5:1, 120 ml) and methanolic 1 M NaOMe (300
ml, 0.30 mmol) was kept for 7 days at room temperature. The mixture was neutralized by addition of ion-
exchange resin (Dowex 50 WX8, H+), filtered and concentrated. Chromatography (CHCl3:MeOH 3: 1) of
the residue afforded 16 (2.13 g, 90%); [α]2D0=+65 (c=1.0, CH3OH); 1H NMR (500 MHz): δ=1.72–1.79
(m, 2H, 2-Ha, 2-Hb), 3.48 (dt, 1H, J11b,21a=J11b,21b=6.0 Hz, J11a,11b=10.0 Hz), 3.52–3.80 (m, 6H, 11-Ha,
32-H, 42-H, 52-H, 62-Ha, 62-Hb), 3.84 (dd, 1H, 22-H, J12,22=1.3 Hz, J22,32=3.1 Hz), 4.16–4.20 (m, 1H,
31-H), 4.76 (d, 1H, 12-H), 5.09 (d, 1H, 51-Hcis, J41,51cis=10.3 Hz), 5.17 (d, 1H, 51-Htrans, J41,51trans=17.2
Hz), 5.81 (ddd, 1H, 41-H, J31,41=6.4 Hz); 13C NMR (125 MHz): δ=35.7 (C-21), 61.2 (C-62), 64.4 (C-11),
67.0 (C-42), 70.2 (C-22), 70.4 (C-32), 70.9 (C-31), 73.0 (C-52), 100.0 (C-12), 115.6 (C-51), 140.2 (C-41);
FAB-MS: 287 (M+Na)+.
Acknowledgements
We thank Dr. P. Fischer, Institute of Organic Chemistry, University of Stuttgart, Dr. H. Schmickler and
Dr. R. Tappe, Institute of Organic Chemistry, University of Cologne for performing the NMR spectra and
Dr. J. Opitz, University of Stuttgart for the elemental analyses. This work was financially supported by
the Bundesministerium für Bildung und Forschung (BMBF) and the Fonds der Chemischen Industrie.
Support by the Bayer AG and Boehringer Mannheim GmbH is also gratefully acknowledged.
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