A straight route towards glyceric chirons

Article abstract of DOI:10.1081/SCC-120016307

Glycidic esters react with alcohols in the presence of a catalytic amount of magnesium perchlorate to give enantiopure 3-alkoxy-2-hydroxy esters regioselectively.

Full text of DOI:10.1081/SCC-120016307

This article was downloaded by: [Northeastern University]
On: 08 October 2014, At: 10:04
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
A Straight Route Towards Glyceric Chirons
Mansour Haddad a & Marc Larchevêque a
a Laboratoire de Synthèse Organique Associé au CNRS ENSCP , Paris Cedex 05, France
Published online: 17 Aug 2006.
To cite this article: Mansour Haddad & Marc Larchevêque (2003) A Straight Route Towards Glyceric Chirons, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:5, 687-692, DOI:
10.1081/SCC-120016307
To link to this article: http://dx.doi.org/10.1081/SCC-120016307
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 5, pp. 687–692, 2003
A Straight Route Towards Glyceric Chirons
*
Mansour Haddad and Marc Larcheveque
Laboratoire de Synthese Organique Associe au CNRS
ENSCP, Paris Cedex 05, France
ABSTRACT
Glycidic esters react with alcohols in the presence of a catalytic
amount of magnesium perchlorate to give enantiopure 3-alkoxy-
2-hydroxy esters regioselectively.
Key Words: Epoxide opening; Optically active diols.
*Correspondence: Marc Larcheveque, Laboratoire de Synthese Organique
Associe au CNRS, ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex
05, France; Fax: þ(33) 1 43 25 79 75; E-mail: larchm@ext.jussieu.fr.
687
DOI: 10.1081/SCC-120016307
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
688
Haddad and Larcheveque
During the last years there has been increasing interest in the synthesis
of small chiral fragments which can be incorporated into compounds of
biological and synthetic importance.
Among the polyhydroxylated synthons, one of the most popular is
the acetonide derived from glyceraldehyde.[1] However, this synthon
suffers from several drawbacks. Only the R enantiomeris readily acces-
sible and the S isomer necessitates always multistep procedures.[2]
Moreover it is not very stable. Compounds derived from glyceric
acid are also of interest and may be prepared from D- or L-serine or
D-mannitol and D-isoascorbic acid.[3] Alternatively, they may also be
obtained by microbial oxidation.[4] However, due to the use of an
acetonide as protecting group, in all these compounds the two hydroxyl
functions cannot be differentiated.
We report here a very simple synthesis of monoprotected a,b-dihy-
droxy esters which allows such a differentiation by regioselective opening
of ethyl epoxyesters by alcohols.
These epoxides may be prepared in bulk quantities from R or S
serine.[5] Alternatively, they can be obtained by oxidation of chiral epoxy-
alcohols prepared by Sharpless enantioselective epoxidation of allylic
alcohols.[6] However, few is known concerning the reaction of epoxides
with alcohols. Some examples of epoxyalcohols opening in the presence
of titane tetraisopropylate, tin phosphates or perchlorates were
reported.[7,8,9] However, most of them are not applicable to epoxyesters
because they promote the concurrent reaction of transesterification. To
the best of ourknowledge, until now, the use of a mixture AlPO 4–Al2O3
only allowed the opening of glycidic esters.[10]
In order to access to various monoprotected a,b-dihydroxyesters, we
thought that it would be necessary to operate in the presence of a Lewis
acid both to avoid the transesterification and to generate an electrophilic
assistance. The first experiments were achieved with lithium perchlorate
and benzyl alcohol and we observed with ester 1 a totally regioselective
reaction at C3 position. Since the reaction was rather long, we tried
then to activate the epoxide with an othermetallic salt and we
were pleased to observe that good results were obtained with magnesium
perchlorate (Sch. 1).
The reaction was clearly more rapid than with the lithium salt and it
was then possible to operate with a catalytic amount of salt (25%). This
strategy was successfully extended to some other alcohols (Table 1). The
same regioselectivity was observed with the 3-substituted epoxyester 2
which afforded the 2-hydroxy esters 3 exclusively (Entries 4 and 5). To
achieve these reactions, the presence of a solvent was not necessary, and
satisfactory yields were obtained by simply heating an equimolecular

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Glyceric Chirons
689
Scheme 1.
Table 1. Synthesis of 3-alkoxyesters 3.
20
Method Yield (%) ½ꢀŠ (c in CH2Cl2)
Entry Epoxide
Alcohol
BnOH
t-BuOH
D
1
2
3
4
5
1
ent-1
A
B
B
A
B
75
78
74
68
63
þ9.7 (3.1)
þ2.2 (3.4)
þ4.7 (3.5)
þ30.5 (5.4)
þ21.8 (2.5)
1
2
2
3,5-(MeO)2BnOH
BnOH
3,5-(MeO)2BnOH
amount of alcohol and epoxide. The target molecules were isolated in
enantiomeric purities better than 98% without any racemization.
In conclusion, by using this economical and attractive method, both
enantiomers of monoprotected glyceric esters now become accessible
starting from readily available glycidic esters.
EXPERIMENTAL PROCEDURES
General Procedure
Products were purified by bulb to bulb distillation or by flash
chromatography (Kieselgel 60 Merck: 230–400 Mesh; solvent:
cyclohexane/EtOAc) and analyzed by GC (Chrompack BP5, 50 m
capillary column) or by TLC (Merck silica gel 60F 254). Nuclear
magnetic resonance spectra were recorded on a Bruker AC at 200 MHz
1
for H and 50 MHz for 13C. CDCl3 was used as solvent with TMS as
internal standard. Infrared spectra were recorded on a Perkin-Elmer 599
spectrophotometer. Mass spectra were recorded on a Ribermag R10-10C
instrument at 70 eV ionizing voltage; ammonia was used for chemical
ionization. Optical rotations were measured on a Jasco P-1010 polarimeter.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
690
Haddad and Larcheveque
The enantiomeric excesses were measured by GC after derivatization of
the a-hydroxyester with i-propylisocyanate on a 25 m Chirasil-D-Val
column (Chrompack)[11] orby HPLC on a 25 cm Chiarcel OD using
hexane-propan-2-ol (9/1) as eluent.
Method A. A mixture of epoxide (5 mmol), alcohol (10 mmol, 2
equiv.), and anhydrous Mg(ClO4)2 (1.25 mmol, 0.25 equiv.) was heated
to 50ꢀC for 48 h. Alternatively, the reaction was achieved with LiClO4
(6.25 mmol, 1.25 equiv.) by heating at 60ꢀC forthree days. Aftercooling,
the mixture was hydrolyzed with water (7 mL) and extracted with diethyl
ether. After elimination of the solvent in vacuo, the excess of alcohol
was removed by bulb to bulb distillation and the residue was purified by
flash-chromatography.
Method B. A mixture of epoxide (5 mmol), alcohol (6 mmol) (except
for Entries 3 and 5 where 4.5 mmol were used because the ester 3 and the
alcohol were difficult to separate by flash-chromaography) and
Mg(ClO4)2 (1 mmol, 0.25 equiv. or2.5 mmol, 0.5 equiv. forEntyr 2)
was heated to 45ꢀC for 24 h. After cooling, the mixture was hydrolyzed
with water(0.4 mL). Diethyl ether(10 mL) was then added to the
homogeneous mixture until the formation of two phases. The aqueous
phase was extracted with 3 Â 10 mL of diethylether. After drying
(MgSO4) and elimination in vacuo of the solvent, the ester 3 was purified
by flash-chromatography using a solvent containing 1% of Et3N.
20
Ethyl (R)-3-benzyloxy-2-hydroxypropanoate: ½ꢀŠ ¼ þ9.7 (c 3.1,
D
CH2Cl2); IR ꢁ (cmꢁ1) 3470, 3030, 2867, 1736, 1453, 1206, 1125, 1026;
1H NMR ꢂ 1.30 (t, 3H, J ¼ 7.1 Hz), 3.03 (br. s, 1H), 3.78 (d, 2H,
J ¼ 3.4 Hz), 4.28 (q, 2H, J ¼ 7.1 Hz), 4.55 and 4.65 (2d, 2H,
J ¼ 12.2 Hz), 7.35 (m, 5H);13C NMR ꢂ 13.87, 61.52, 70.54, 71.08, 73.17,
127.34, 128.09, 137.42, 172.35. MS (CI, NH3) m/z (relative intensity) 242
(100, M þ 18), 225 (5, M þ 1), 108 (8). Anal. calcd. forC 12H16O4: C,
64.27; H, 7.19. Found: C, 64.34; H, 7.15.
20
D
Ethyl (S )-3-t-butoxy-2-hydroxypropanoate: ½ꢀŠ ¼ þ2.2 (c 3.4,
CH2Cl2); IR ꢁ (cmꢁ1) 3470, 2975, 2936, 2875, 1746, 1365, 1233, 1194,
1124, 1095, 1022; 1H NMR ꢂ 1.16 (s, 9H), 1.24 (t, 3H, J ¼ 7.1 Hz), 3.10 (d,
1H, J ¼ 6.7 Hz), 3.64 (d, 2H, J ¼ 3.1 Hz), 3.78 (s, 6H), 4.25 (q, 2H,
J ¼ 7.1 Hz); 13C NMR ꢂ 14.05, 27.15, 61.27, 63.41, 70.75, 73.19, 172.67.
MS (CI, NH3) m/z (relative intensity) 191 (15, M þ 1), 152 (100). Anal.
calcd. forC H18O4: C, 56.82; H, 9.54. Found: C, 56.75; H, 9.50.
9
20
D
Ethyl (R)-3-(3,5-dimethoxybenzyloxy)-2-hydroxypropanoate: ½ꢀŠ
¼
þ4.7 (c 3.5, CH2Cl2); IR ꢁ (cmꢁ1) 3478, 2937, 2909, 2840, 1739, 1600,
1463, 1431, 1320, 1233, 1126, 1067, 1021; 1H NMR ꢂ 1.27 (t, 3H,
J ¼ 7.1 Hz), 3.31 (d, 1H, J ¼ 6.7 Hz), 3.75 (d, 2H, J ¼ 3.4 Hz), 3.78 (s, 6H),
4.25 (q, 2H, J ¼ 7.1 Hz), 4.45 and 4.55 (2d, 2H, J ¼ 12.4 Hz), 6.37 (m, 1H),

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Glyceric Chirons
691
6.48 (m, 2H); 13C NMR ꢂ 14.02, 55.15, 61.65, 70.73, 71.32, 73.25, 99.51,
105.20, 140.07, 160.75, 172.51. MS (CI, NH3) m/z (relative intensity) 316
(100, M þ 18), 299 (43, M þ 1), 278 (3), 232 (48), 169 (81), 151 (49). Anal.
calcd. forC 14H20O6: C, 59.14; H, 7.09. Found: C, 59.21; H, 7.13.
20
D
Ethyl (2R,3S )-3-benzyloxy-2-hydroxybutanoate: ½ꢀŠ ¼ þ30.5 (c 5.4,
CH2Cl2); IR ꢁ (cmꢁ1) 3490, 2980, 1740, 1454, 1375, 1205, 1075;
1H NMR[10] ꢂ 1.25 (t, 3H, J ¼ 7.1 Hz), 1.35 (d, 3H, J ¼ 6.2 Hz), 2.96
(d, 1H, J ¼ 8.0 Hz), 3.95 (dq, 1H, J ¼ 2.4 and 6.4 Hz), 4.04–4.35
(m, 3H), 4.48 and 4.57 (2d, 2H, J ¼ 12.4 Hz), 7.2–7.3 (m, 5H);
13C NMR ꢂ 13.90, 15.42, 61.45, 70.73, 71.32, 74.12, 127.21, 128.03,
137.07, 172.51. MS (CI, NH3) m/z (relative intensity) 256 (100,
M þ 18), 239 (8, M þ 1), 176 (3), 108 (34), 91 (40).
20
D
Ethyl (2R,3S)-3-(3,5-dimethoxybenzyloxy)-2-hydroxybutanoate: ½ꢀŠ
¼
þ21.8 (c 2.5, CH2Cl2); IR ꢁ (cmꢁ1) 3487, 2979, 2938, 2840, 1738, 1598,
1468, 1431, 1204, 1153, 1094, 1068; 1H NMR ꢂ 1.25 (t, 3H, J ¼ 7.2 Hz), 1.33
(d, 3H, J ¼ 8.4 Hz), 3.79 (s, 6H), 3.92 (dq, 1H, J ¼ 1.0 and 7.2 Hz), 4.04
(m, 1H), 4.25 (m, 2H), 4.35 and 4.56 (2d, 2H, J ¼ 12.0 Hz), 6.38 (m, 1H),
6.44 (m, 2H); 13C NMR ꢂ 14.00, 15.50, 55.18, 61.46, 70.69, 74.21, 75.05,
99.42, 105.34, 140.36, 160.67, 172.86. MS (CI, NH3) m/z (relative intensity)
285 (11, M þ 1), 279 (4), 222 (6), 180 (12), 169 (100), 152 (6). Anal. calcd.
forC 15H22O6: C, 60.39; H, 7.43. Found: C, 60.51; H, 7.46.
REFERENCES
1. Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447–488;
Schmid, R.; Bryant, J.R. Organic Synthesis 1995, 72, 6–13.
2. Hubschwerlen, C. Synthesis 1986, 962–964.
3. Lok, C.M.; Ward, J.P.; van Dorp, D.A. Chem. Phys. Lipids 1976, 16,
115–122; Hirth, G.; Walther, W. Helv. Chim. Acta 1985, 68,
1863–1871; Emons, C.C.H.; Kuster, B.F.M.; Vekemans, J.A.J.M.;
Sheldon, R.A. Tetrahedron: Asymmetry 1991, 2, 359–362.
4. Berthole, M.A.; Koger, H.S.; Phillips, G.T.; Marx, A.F.;
Claassen, V.P. EP 244912, 1987.
5. Petit, Y.; Larcheveque, M. Organic Synthesis 1998, 75, 37–43.
6. Denis, J.N.; Greene, A.E.; Serra, A.A.; Luche, M.J. J. Org. Chem.
1986, 51, 46–49.
7. Chong, J.M.; Sharpless, K.B. J. Org. Chem. 1985, 50, 1557–1560.
8. Otera, J.; Yoshinaga, Y.; Hirakawa, K. Tetrahedron Lett. 1985, 26,
3219–3222.
9. Chini, M.; Crotti, P.; Flippin, L.E.; Gardelli, C.; Giovani,
E.; Macchia, F.; Pineschi, M. J. Org. Chem. 1993, 58, 1221–1227.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
692
Haddad and Larcheveque
10. Riego, J.; Costa, A.; Saa, J.M. Chem. Lett. 1986, 1565–1568.
11. Konig, W.; Benecke, I.; Sievers, S. J. Chromatograph. 1982, 238,
¨
427–431.
Received in the Netherlands February 13, 2002