New efficient synthesis of α-hydroxyesters from carbonyl compounds via α-chloroglycidic esters

Article abstract of DOI:10.1016/S0040-4039(00)01053-4

The chain extension with an α-hydroxyester unit of various carbonyl compounds was realized, in two steps, via α-chloroglycidic esters. Synthesis, results and expected mechanisms are reported. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01053-4

Tetrahedron Letters 41 (2000) 6571±6574
New ecient synthesis of a-hydroxyesters from carbonyl
compounds via a-chloroglycidic esters
Claude Grison,* Frederic Coutrot, Corinne Comoy, Claude Lemilbeau
and Philippe Coutrot
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Laboratoire de Chimie Organique 2, Institut Nanceien de Chimie Moleculaire, UMR 7565 SRSMC,
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Universite Henri Poincare ± Nancy I, BP 239, 54506 Vandoeuvre-les-Nancy, France
Received 18 April 2000; accepted 20 June 2000
Abstract
The chain extension with an a-hydroxyester unit of various carbonyl compounds was realized, in two
steps, via a-chloroglycidic esters. Synthesis, results and expected mechanisms are reported. # 2000
Published by Elsevier Science Ltd.
Keywords: chain extension; a-chloroglycidic esters; reduction; ring opening; a-hydroxyesters..
The target of our studies was to elaborate a new, ecient and convenient method which could
allow an interesting chain extension with a two-carbon unit, starting from easily available
carbonyl substrates to a€ord a-hydroxyesters (Scheme 1).
Scheme 1.
We considered a strategy based on previous results on the ring opening of glycidic esters with
nucleophilic or electrophilic assistance.1,2 In both cases, carbonyl precursors provided,
respectively, in two steps, b-halogeno-a-ketoesters or a-ketoesters which may lead to C-glycosyl-
a-aminoacid moieties.3,4
Recently, in connection with our research to mimic transition state of enzymatic reaction, we
described the nucleophilic opening of glycidic esters with trialkylphosphite to obtain, from
appropriate aldehydes, glucidic phosphoenol pyruvic acids.5
* Corresponding author. E-mail: claude.grison@lco2.uhp-nancy.fr
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01053-4

6572
In the present communication, we report the transformation of a carbonyl function into an
a-hydroxyester moiety including a chain extension with a two-carbon unit. The suggested
nucleophilic ring opening of a-chloroglycidic esters should be promoted by a reducing agent
which has to show a good nucleophilic character to perform this step, followed by the in situ high
chemoselective reduction of the non-isolated a-ketoesters.
We found that the mild hydride sodium cyanoborohydride (NaBH3CN) was able to open
oxiranes without any electrophile assistance, contrary to the current results reported in the
literature,6,7 and then reduced in situ the so formed a-ketoesters.
As outlined in Scheme 2, starting a-chloroglycidic esters 1a±g were easily prepared according to a
Darzens type condensation of appropriate carbonyl compounds with isopropyl dichloroacetate.3,4,8
Then, reaction of 2 equivalents of NaBH3CN and chloroepoxides 1a±g, in isopropanol, at 65ꢀC,
directly a€orded the expected a-hydroxyesters 2a±g in good yields (Table 1).9
Total conversions of 1a±e and 1g to 2a±e and 2g, respectively, were observed. In the galactosyl
series, after 20 h reaction time, a mixture in the ratio 15:85 of starting material 1f and product 2f
was collected. As a consequence, steric hindrance of the starting carbonyl compound might be a
limitating parameter in such a synthesis. Otherwise, in the case of the glucidic series, 2e±g were
obtained as a mixture of diastereomers revealing a lack of stereoselectivity.
Scheme 2.
Table 1
Reduction of 1a±g to 2a±g using NaBH3CN in iPrOH, at 65ꢀC

6573
For a comprehension of the reaction mechanism, two procedures were selected to detect the
di€erent species present in the reactional solution before the total conversion of 1 to 2. At ®rst,
chloroglycidic esters 1 were treated: (a) by only 1 equivalent of NaBH3CN, at 65ꢀC; and (b) on
the other hand, a reaction was performed using esters 1 and 2 equivalents of NaBH3CN, at 65ꢀC
for 2 h.
The results obtained according to (a) and (b) were similar. In both cases, a lack of hydride or a
shorter reaction time (except for 1e) did not provide 3 but a€orded a mixture of starting materials
1 and a-hydroxyesters 2, without any trace of a-ketoester intermediates 3.
The absence of 3 suggested that compounds 3 were fastly reduced to the corresponding alcohols
2, as soon as they were formed. Consequently, the oxirane ring openings appeared as being the
restrictive step of the sequence. Such results led us to the mechanism proposed below (Scheme 3).
The ®rst equivalent of hydride is used for the ring opening. The presence of a chlorine atom
facilitates the reaction and a rearrangement of the non-isolated alcoholate to a carbonyl group
with a displacement of Cl atom occurs. Then, the resulting non-isolated a-ketoesters 3 are easily
reduced to the hydroxycompounds 2. This mechanism was con®rmed by the reduction of
b-chloro-a-ketoester 4 (Scheme 4).
Scheme 3.
Scheme 4.
In the same conditions (65ꢀC, 20 h and 2 equivalents of NaBH3CN), a total reduction of 4 to
2d was not observed. The derivative 6 was obtained and characterized by NMR and IR
spectroscopies, showing that no reduction of the C±Cl bond occurred by NaBH3CN.
In conclusion, we have described a new method to introduce a a-hydroxyester moiety in aliphatic
carbonyl substrates or carbohydrates. Further studies to obtain pure enantiomers of a-hydro-
xyesters, according to this strategy, are under investigation. Such a sequence could be developed
on a large-scale, particularly for the synthesis of a-hydroxyesters which could be revealed as
important precursors for the preparation of derivatives with potent biological activity.

6574
References
1. Villieras, J.; Ferracutti, N. Bull. Soc. Chim. Fr. 1970, 2699±2701.
2. Coutrot, P.; Legris, C. Synthesis 1975, 118±120.
3. Coutrot, P.; Grison, C.; Coutrot, F. Synlett 1998, 393±395.
4. Coutrot, F. Thesis, University of Nancy I (France), 1999.
5. Coutrot, P.; Grison, C.; Tabyaoui, M.; Tabyaoui, B.; Dumarcay, S. Synlett 1999, 792±794.
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Á
6. Seyden-Penne. In Reduction par les alumino- et borohydrures en synthese organique; Technique et Documentation-
Lavoisier: Paris, 1988.
7. Hutchin, R. O.; Ta€er, I. M.; Burgoyne, W. J. Org. Chem. 1981, 46, 5214±5215.
8. Villieras, J.; Castro, B.; Ferracutti, N. Bull. Soc. Chim. Fr. 1970, 1450±1455.
9. Isopropyl 4,5:6,7-di-O-isopropylidene-2-hydroxy-d-arabino-hepto-uronate (2g): A solution of isopropyl 4,5:6,7-di-
O-isopropylidene-2-chloro-2,3-epoxy-d-arabino-hepto-uronate 1g (0.400 g, 1.10 mmol) in isopropanol (iPrOH) (7
mL) and NaBH3CN (0.166 g, 2.64 mmol) was stirred at 65ꢀC for 3.5 h (TLC eluent: AcOEt:hexane, 1:4). After
evaporation of iPrOH, diethyl ether was added to the residue. The resulting unsoluble solid was removed by
centrifugation, then the organic layer was concentrated and ®ltered quickly on silica gel chromatography. The
crude product was puri®ed by ¯ash chromatography on silica gel to give the expected hydroxyester 2g (0.240 g,
mixture of two diastereoisomers : 60:40), as an oil, in 65% yield: IR (®lm) ꢀ (cm^1): 3300±3500 (OH), 1725
(COOiPr). 1H NMR (CDCl3) ꢁ (ppm): 1.24±1.31 (m, 6H, CH3), 1.33±1.40 (m, 12H, CH3), 1.90±2.10 (m, 1H, CH2),
2.15±2.40 (m, 1H, CH2), 3.09 and 3.24 (d, 1H, OH, J=4.6 Hz), 3.54±3.71 (m, 1H, CH±O), 3.90±4.07 (m, 3H, CH2±
O, CH±O), 4.07±4.18 (m, 1H, CH±O), 4.30±4.40 (m, 1H, CH±OH), 5.05±5.20 (m, 1H, COOCH). 13C NMR
(CDCl3) ꢁ (ppm): 22.0 (2C, CH3), 25.4 (2C, CH3), 27.2 (2C, CH3), 29.9 (1C, CH2), 67.9 (1C, CH2), 68.7 (1C, CH±
O), 69.6 (1C, CH(CH3)2), 77.2 (2C, CH±O), 81.4 (1C, CH±O), 109.5 (1C, C(CH3)2), 109.9 (1C, C(CH3)2), 174.2
(1C, COO).