Enantioselective synthesis of α-hydroxyacids through oxidation of terminal alkenes with AD-mix/TEMPO

Article abstract of DOI:10.1016/S0040-4039(00)00352-X

α-Hydroxyacids can be enantioselectively prepared by means of a two- step oxidation process, involving first the asymmetric dihydroxylation of a terminal alkene and subsequent oxidation with TEMPO/NaOCl/NaClO₂ in good to excellent yields. No fragmentation of the glycol intermediate was detected. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00352-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3209–3213
Enantioselective synthesis of α-hydroxyacids through oxidation
of terminal alkenes with AD-mix/TEMPO
F. Javier Aladro, Francisco M. Guerra, F. Javier Moreno-Dorado, Jesús M. Bustamante,
Zacarías D. Jorge and Guillermo M. Massanet ∗
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Apartado 40, 11510 Puerto Real,
Cádiz, Spain
Received 16 December 1999; revised 17 February 2000; accepted 28 February 2000
Abstract
α-Hydroxyacids can be enantioselectively prepared by means of a two-step oxidation process, involving first the
asymmetric dihydroxylation of a terminal alkene and subsequent oxidation with TEMPO/NaOCl/NaClO2 in good
to excellent yields. No fragmentation of the glycol intermediate was detected. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: TEMPO; asymmetric dihydroxylation; α-hydroxyacids; oxidation.
In the course of our research programme aimed at the synthesis of eudesmanolides from Umbelliferae
plants, we envisaged the retrosynthetic analysis depicted in Fig. 1, to access the α-hydroxy-γ-lactone
moiety.
Fig. 1.
As is well known, 1,2-diols are very prone to undergo fragmentation reactions under oxidative
conditions. However, if these conditions were mild enough, their oxidation would provide us with the
required α-hydroxyacids in a simple manner. Being aware of such a difficulty, we undertook a search for
a method which allowed the oxidation of glycols while avoiding the oxidative cleavage of the molecule.
α-Hydroxyacids are important in the field of organic synthesis for several reasons.1 For instance,
mandelic acid and many of its derivatives are used as chiral intermediates and resolving agents of
alcohols and amines.2 The C2-symmetry backbone of tartaric acid has long been recognised as a valuable
chiral ligand in numerous asymmetric processes, especially the Sharpless epoxidation.3 MTPA (Mosher’s
∗
Corresponding author. E-mail: francisco.guerra@uca.es (G. M. Massanet)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00352-X
tetl 16632

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reagent) and MPA have been used in the determination of the absolute configuration of amines and
secondary alcohols by NMR.4 α-Hydroxyacids also find applications in the cosmetics industry as anti-
ageing factors.5
Even though several synthetic routes have been developed,6 α-hydroxyacids are usually obtained from
natural sources, either directly or after some transformations.
Since the asymmetric dihydroxylation of a terminal double bond provides an optically active glycol, we
thought that subsequent oxidation of the primary alcohol would produce the corresponding homochiral
α-hydroxyacid (Fig. 2).
Fig. 2.
The Sharpless asymmetric dihydroxylation (AD) is a well-known process. The availability of the AD-
mix (α and β), the high enantiomeric excess and the simplicity of the work-up make this reaction an
excellent choice to provide optically active material for many synthetic processes.7
The problem is in the oxidation of the glycol. As was previously pointed out, oxidation of the
primary alcohol in the presence of a vicinal tertiary alcohol leads in most cases to fragmentation of the
molecule. Any oxidation process involving esters of metals as intermediates (M=Cr, Mn, Os, Ru) leads
to decarboxylative rearrangements. We tried different oxidation reagents. The Swern oxidation produced
in most substrates an intractable mixture of products. The NMR analysis of this mixture displayed the
presence of the aldehyde proton, but any attempt at isolation was unsuccessful.8 IBX oxidation9 led
us to the same result. Dess–Martin periodinane is described to fragment glycols9 and oxidation with
NaOCl/NaOCl2 also gave negative results.
Our attention was then drawn to a paper by Zhao et al., which described the oxidation of primary
alcohols to carboxylic acids with sodium chlorite catalysed by TEMPO and bleach.10 The TEMPO
radical is oxidised to an N-oxoammonium ion which is the active species in the oxidation of the primary
alcohol. The proposed mechanism suggested to us that no fragmentation product should be produced.
This fact prompted us to investigate the oxidation of the glycols under those conditions. To our delight,
we observed that in most cases, the oxidation proceeded smoothly yielding the α-hydroxyacids in good
yields. In many cases, the reaction needed to be mildly heated to reach completion. The results are
displayed in Table 1. The nature of the terminal alkene prevents epimerisation at the carbon bearing the
tertiary hydroxyl group, as no hydrogen is available at that position to be removed. The ee/de are thus
determined by the effectiveness of the Sharpless asymmetric dihydroxylations.11
The presence of an electron-withdrawing group enhances the yield of the process, as observed in
entries 1 and 2. Entry 2 accounts for the preparation of the precursor of the Mosher’s reagent. The
oxidation is also possible when the aromatic ring bears an amino group, as long as it is protected
(entry 3). As expected, when no acetate group was present, the yields lowered to 25–30%. Marked
differences were observed for the benzyl methacrylate (entry 6) when treated with AD-mix-α (good
yield in the TEMPO oxidation step, 85%) or AD-mix-β (only moderate yield, 51%), but in both cases, the
dicarboxylic derivative could be isolated.12 Finally, entries 7 and 8 constitute two interesting examples. In
both cases, the major diastereomer was the same for any oxidising mixture. In the case of the 6-hydroxy-
cyperone (entry 8), we were surprised that the allylic secondary alcohol remained unaltered, allowing
after lactonisation, the synthesis of several 11-hydroxy-eudesmanolides.

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Table 1

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This procedure could even be successfully applied when the double bond is monosubstituted as long
as some precautions are taken. When the glycols from styrene and allylbenzene were submitted to the
same conditions, cleavage of the diol was observed. Nevertheless this problem was easily solved by the
selective protection of the secondary hydroxyl group (Fig. 3). This route provided us with optically active
mandelic and phenyllactic acids.
Fig. 3.
In conclusion, this procedure allows for the direct and easy conversion of terminal alkenes into
optically active α-hydroxyacids avoiding the common glycol cleavage observed in this kind of substrate
under most oxidative conditions. In this way, valuable compounds like mandelic, atrolactic or phenyllac-
tic acids can easily be synthesised.
General procedure. The general procedure is based on those described by Sharpless (AD)11 and
Anelli (TEMPO),13 although some modifications were introduced: 1 mmol of olefin was dissolved in
t-BuOH:H2O (1:1, 10 mL) and 1.49 g of AD-mix was added. The mixture was stirred at rt for 18 h.
Then, the reaction was quenched by adding 500 mg of sodium sulfite and it was stirred for 10 min. t-
BuOH was removed under vacuum and the aqueous layer was extracted with EtOAc (25 ml×3). The
organic layer was dried over sodium sulfate and the solvent was removed under vacuum. The resulting
residue was dissolved in acetonitrile (5 mL) and sodium phosphate buffer (4 mL, pH=6.5). Then, 0.25
mmol of TEMPO, sodium chlorite (2 mmol) and diluted bleach (0.02 mmol, 4% active chlorine) were
added and the mixture was heated to 55°C.
After four days, the reaction was allowed to cool down to rt and water (10 mL) was added. The pH was
set to 8 with 1N NaOH and cool aqueous sodium sulfite (0.4 g in 8 ml of water) was added. The pH was
lowered to 2 with 1N HCl and the mixture was extracted with EtOAc (25 ml×3). The organic layer was
dried over sodium sulfate and the solvent removed by rotary evaporation. The resulting crude mixtures
contained only the desired α-hydroxyacids, although in some cases some TEMPO-derived impurities
remained.
The optical purity was determined by esterification of the resulting α-hydroxyacid with (+)-menthol
using O,O0-di(2-pyridyl) thiocarbonate (DPTC) as coupling reagent.14

3213
Acknowledgements
Support for this work by the DGICYT (PB97-1360) is gratefully acknowledged. F.J.A. and J.M.B.
thank the University of Cádiz and the Ministerio de Educación for providing fellowships.
References
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