SuperQuat, (S)-4-benzyl-5,5-dimethyl-oxazolidin-2-one for the asymmetric synthesis of α-substituted-aldehydes

Article abstract of DOI:10.1016/S0957-4166(00)00333-5

Reduction of α-substituted-(S)-N-acyl-4-benzyl-5,5-dimethyl-oxazolidin-2-ones with DIBAL-H in CH₂Cl₂ affords α-substituted aldehydes with no loss of stereochemical integrity at their α-centre. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00333-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3475–3479
SuperQuat, (S)-4-benzyl-5,5-dimethyl-oxazolidin-2-one for
the asymmetric synthesis of a-substituted aldehydes
Steven D. Bull, Stephen G. Davies,* Rebecca L. Nicholson, Hitesh J. Sanganee and
Andrew D. Smith
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 2 August 2000; accepted 16 August 2000
Abstract
Reduction of a-substituted-(S)-N-acyl-4-benzyl-5,5-dimethyl-oxazolidin-2-ones with DIBAL-H in
CH2Cl2 affords a-substituted aldehydes with no loss of stereochemical integrity at their a-centre. © 2000
Elsevier Science Ltd. All rights reserved.
The generation of a-substituted aldehydes from a-substituted-N-acyl-oxazolidin-2-ones is
normally achieved via overreduction to the a-substituted alcohol followed by oxidation,1 or
conversion to either a Weinreib amide2 or ester/thioester3 and reduction. We have recently
reported that achiral N-acyl-5,5-dimethyl-oxazolidin-2-ones 1 can be reductively cleaved directly
to aldehydes 2 with DIBAL-H (Scheme 1).4 This, combined with the ability of the SuperQuat
4-benzyl-5,5-dimethyl-oxazolidin-2-one auxiliary 3 to control alkylations of attached enolate
fragments,5 suggested a direct stereoselective synthesis of a-substituted aldehydes which is
described herein.6
Scheme 1. Reagents and conditions: (i) DIBAL-H (2.0 equiv.), CH2Cl2, −78°C; (ii) NaOH, NaHSO3
Meyers et al. have reported an isolated example of the direct reduction of an N-acyl-oxazo-
lidin-2-one aldol product with Red-Al in THF at −78°C to afford the corresponding aldehyde
which was trapped in situ with the anion of triethylphosphonoacetate to give an a,b-unsaturated
ester in 32% yield.7 In order to investigate the suitability of Red-Al for the reduction of simple
* Corresponding author. E-mail: steve.davies@chemistry.ox.ac.uk
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00333-5

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N-acyl-oxazolidin-2-ones without a coordinating b-hydroxyl group in its N-acyl side-chain, the
sterically demanding N-acyl-oxazolidin-2-one 4 was reduced with Red-Al to afford a complex
mixture of products which was purified to afford starting material 4, (S)-4-benzyl-oxazolidin-2-
one 5, and 2-benzyl-3-phenyl-propanal 6, the product of endocyclic cleavage N-acyl-2-amino-
ethanol 7, and 2-benzyl-3-phenyl-propanol 8. Similarly, reduction of N-acyl-oxazolidin-2-one 4
with DIBAL-H in CH2Cl2 at −78°C gave a complex reaction product which was purified to
afford starting material 4, (S)-4-benzyl-oxazolidin-2-one 5, aldehyde 6, (S)-N-acyl-O-formyl-2-
benzyl-2-amino-1,1-dimethyl-ethanol 9 and (4S)-N-(1%-hydroxy-alkyl)-4-oxazolidin-2-one 10 as a
single diastereoisomer (C-1% stereocentre of 10 undefined) (Scheme 2).
1
Scheme 2. Ratio of products determined by integration of resonances in the 400 MHz H NMR spectra of the crude
product mixtures. Reagents and conditions: Red-Al, THF, −78 to −50°C or DIBAL-H, CH2Cl2, −78°C; NH4Cl(aq)
In contrast, while reduction of N-acyl-5,5-dimethyl-oxazolidin-2-one 11 with Red-Al gave a
complex mixture of products, reduction with DIBAL-H in CH2Cl2 at −78°C went to completion
affording cleanly a mixture of the desired reaction products which were purified to afford the
aldehyde 6 in 86% isolated yield and (S)-4-benzyl-5,5-dimethyl-oxazolidin-2-one 3 in 92%
isolated yield, with no evidence of any products arising from the endocyclic cleavage pathway
(Scheme 3).
Scheme 3. Reagents and conditions: (i) DIBAL-H, CH2Cl2, −78°C; NH4Cl(aq)
Attention was next directed towards investigating the reduction of a-substituted-N-acyl-4-ben-
zyl-5,5-dimethyl-oxazolidin-2-ones 13a–e to afford a-substituted aldehydes 15a–e. Thus, the
enolate of (S)-(N-hydrocinnamoyl)-4-benzyl-5,5-dimethyl-oxazolidin-2-one 12a in THF was
alkylated with methyl iodide, allyl bromide and 4-bromo-2-methyl-2-butene to afford (4S,2%S)-
N-[(2%-methyl)-dihydrocinnamoyl]-4-benzyl-5,5-dimethyl-oxazolidin-2-one 13a in 85% d.e.,

S. D. Bull et al. / Tetrahedron: Asymmetry 11 (2000) 3475–3479
3477
(4S,2%S)-N-[(2%-allyl)-dihydrocinnamoyl]-4-benzyl-5,5-dimethyl-oxazolidin-2-one 13b in 86% d.e.
and (4S,2%S)-N-[(2%-3,3-dimethyl-2-butene)-dihydrocinnamoyl]-4-benzyl-5,5-dimethyl-oxazolidin-
2-one 13c in 94% d.e. (Scheme 4). Similarly, alkylation of the enolates of (S)-(N-iso-valeroyl)-4-
benzyl-5,5-dimethyl-oxazolidin-2-one 12b or (S)-(N-butanoyl)-4-benzyl-5,5-dimethyl-oxazo-
lidin-2-one 12c with benzyl bromide gave (4S,2%R)-N-[(2%-benzyl)-iso-valeroyl]-4-benzyl-5,5-di-
methyl-oxazolidin-2-one 13d in 91% d.e., and (4S,2%R)-N-[(2%-benzyl)-butanoyl]-4-benzyl-5,5-di-
methyl-oxazolidin-2-one 13e in 94% d.e. All d.e.’s were calculated from integration of the
resonances corresponding to the major 13a–e and minor diastereoisomers 14a–e in the 400 MHz
1H NMR spectra of the crude reaction products.
Scheme 4. Reagents and conditions: (i) LHMDS, THF, −78°C, MeI; (ii) LHMDS, THF, −78°C, allyl bromide; (iii)
LHMDS, THF, −78°C, 4-bromo-2-methyl-2-butene; (iv) LHMDS, THF, −78°C, BnBr

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S. D. Bull et al. / Tetrahedron: Asymmetry 11 (2000) 3475–3479
The mixtures of diastereoisomers 13a–e/14a–e (85–94% d.e.) were reduced with DIBAL-H in
CH2Cl2 at −78°C to afford a mixture of (S)-4-benzyl-oxazolidin-2-one 3 and the enantiomerically
enriched aldehydes 15a–e which were separated via chromatography {silica, hexane:ether (12:1)}
(Scheme 5, Table 1). The enantiomeric excesses of the resulting aldehydes 15a–e were determined
by immediate reduction of the purified aldehydes 15a–e with LiAlH4 to afford alcohols 16a–e,
which were derivatised via treatment with (R)-Mosher’s acid chloride to afford diastereoisomeric
Mosher’s esters whose 19F NMR spectra were compared with authentic racemic esters. Authentic
racemic alcohols 16a–e required for determining the enantiomeric excess of the products of these
reductions were prepared via repetition of the enolate alkylation protocol described in Scheme
4 using analogous substrates derived from achiral N-acyl-5,5-dimethyl oxazolidin-2-ones 1,
followed by reduction of the resulting racemic a-alkylated-N-acyl-oxazolidin-2-ones with LiAlH4.
Comparison of the d.e.’s obtained for 19F NMR analysis of the Mosher esters of 2-alkyl alcohols
16a–e with the d.e.’s of the parent a-substituted-N-acyl-5,5-dimethyl-oxazolidin-2-ones 13a–e
employed for DIBAL-H reduction clearly revealed that no racemisation had occurred at the
stereogenic centres of aldehydes 15a–e under these conditions.
Scheme 5. Reagents and conditions: (i) DIBAL-H, CH2Cl2, −78°C; NH4Cl(aq); (ii) LiAlH4, THF, 0°C

S. D. Bull et al. / Tetrahedron: Asymmetry 11 (2000) 3475–3479
3479
Table 1
Yields and [h]2D3 for aldehydes 15a–e from reduction of N-acyl-oxazolidin-2-ones 13a–e and d.e.’s of Mosher’s
esters of 2-alkyl-alcohols 16a–e
N-acyl-SuperQuats
13a–13e
% Yield of
aldehydes 15a–e
[h]2D3 of aldehydes 15a–e
in CHCl3
D.e. of (R)-Mosher’s ester of
2-alkyl alcohols 16a–e
13a (85% d.e.)
13b (86% d.e.)
13c (92% d.e.)
13d (91% d.e.)
13e (94% d.e.)
15a 87
15b 76
15c 81
15d 95
15e 95
15a −1.10 (c 1.0)a
15b −28.4 (c 1.0)
15c −58.4 (c 1.0)
15d +24.9 (c 1.0)
15e +2.25 (c 2.0)
16a 87% d.e.
16b 87% d.e.
16c 94% d.e.
16d 91% d.e
16e 94% d.e.
a Literature value for [h]2D3 of (R)-15a (82% e.e.)=+4.0, c 1.25 in acetone.8
In conclusion, we have demonstrated that a-substituted-N-acyl-4-benzyl-5,5-dimethyl-oxazo-
lidin-2-ones 13a–e may be reduced with DIBAL-H in CH2Cl2 to afford a-substituted aldehydes
15a–e with no loss of stereochemical integrity at their a-centre.9 All novel compounds were fully
characterised including elemental analysis or HRMS.
Acknowledgements
We would like to thank AstraZeneca for the award of studentships (R.L.N. and H.J.S.).
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