An enantioselective synthesis of (1S,2S)-pseudoephedrine

Article abstract of DOI:10.1016/S0040-4039(99)02106-1

Synthesis of (1S,2S)-pseudoephedrine is described via reduction of an alanine-derived oxazolidinone followed by treating with phenyl magnesium bromide and chemoselective N-methylation in an efficient and practical manner. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02106-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 953–954
An enantioselective synthesis of (1S,2S)-pseudoephedrine†
G. Vidyasagar Reddy,∗ G. Venkat Rao, V. Sreevani and D. S. Iyengar ∗
Organic Division-II, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 28 June 1999; accepted 10 November 1999
Abstract
Synthesis of (1S,2S)-pseudoephedrine is described via reduction of an alanine-derived oxazolidinone followed
by treating with phenyl magnesium bromide and chemoselective N-methylation in an efficient and practical manner.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: enantioselection; amino alcohols; oxazolidinones; Grignard reagents; alkylation.
In recent years there has been considerable interest in the synthesis of optically pure amino alcohols
because of their wide occurrence in several biologically active molecules and also their application as
chiral building blocks, auxiliaries and ligands in asymmetric synthesis.1,2 Among this class, ephedrine
and pseudoephedrine have found wide application for a variety of purposes in organic synthesis.
Pseudoephedrine, especially, has been used extensively in asymmetric alkylations of corresponding
carboxamides.3,4 Recently, we have reported chemoselective reduction of N-protected oxazolidinones
to the corresponding lactol derivatives and their application in the synthesis of vicinal amino alcohols.5
In this paper, we wish to report a new approach for the synthesis of (1S,2S)-pseudoephedrine by using the
synthetic potential of our methodology. The key steps involved in the present synthesis are: (i) reduction
of the N-Cbz oxazolidinone derived from alanine (2 to 3); (ii) Grignard addition to the lactol to give the
amino alcohol (3 to 4); and (iii) chemoselective N-methylation (4 to 8) as shown in Scheme 1.
The oxazolidinone (2),6 readily obtained from N-Cbz-L-alanine (1) by reacting with paraformaldehyde
in the presence of catalytic PTSA, was treated with 1 equiv. of sodium borohydride to give the lactol 3‡
in excellent yield (95%) as a colourless syrup [α]D=−2(c 1, MeOH). Treatment of lactol (3) with phenyl
magnesium bromide afforded an inseparable diastereomeric mixture (4 and 5) in 92% combined yield,
1
ratio 95:5 from H NMR. The newly created stereocentre in the major isomer 4 was initially assumed
to be S by analogy with our earlier related work,5 and was confirmed by conversion into the known
∗
Corresponding author.
†
IICT Communication No. 4346.
‡
All the compounds were fully characterised by 1H NMR, IR, and mass spectrometry. Selected data for lactol derivative 3;
1H NMR (200 MHz, CDCl3): δ 1.10 (d, 3H, CH3), 3.45–3.70 (m, 2H, CHN and OH), 4.25–4.50 (m, 1H, CHOH), 4.90–5.20
(m, 4H, NCH2 and PhCH2O), 7.25–7.40 (m, 5H, Ph).
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02106-1
tetl 16034

954
Scheme 1. Reagents and conditions: (i) (CH2O)n, PTSA, benzene, reflux, 1 h; (ii) 1 equiv. NaBH4, MeOH, 2 h; (iii) PhMgBr,
THF, 0°C–rt, 3 h; (iv) (CH2O)n, PTSA, benzene, reflux, 1 h; (v) NaCNBH3/TMSCl, CH3CN, rt, 30 min; (vi) conc. HCl, reflux,
2 h
title compound. To circumvent the separation problem, the diastereomeric mixture was reacted with
paraformaldehyde in the presence of cat. PTSA to furnish oxazolines 6 and 7 in a combined yield of 96%.
Oxazoline 6 was easily separated from 7 by using column chromatography in 94% yield (based on crude 6
and 7) as a colourless syrup, [α]D=−21.5 (c l, MeOH). Treatment of oxazoline 6 with NaCNBH3/TMSCl
smoothly afforded the N-methyl amino alcohol 8 in 93% yield. Acidic hydrolysis of 8 afforded (1S,2S)-
pseudoephedrine hydrochloride as white crystalline solid in 92% yield. M.p. 184–186°C, [α]D=+59.8
(c 2, H2O) lit:7 m.p. 185–188, [α]D=+61 (c 1, H2O), thereby confirming the structure assignment and
configurations.
In summary, we have demonstrated an efficient new synthesis of pseudoephedrine in excellent yield.
This synthesis will be amenable to the syntheses of analogous compounds with ease. Further work is in
progress and will be reported in due course.
Acknowledgements
We thank Dr. K. V. Raghavan, Director IICT, for the facilities and encouragement. G. V. S. Reddy and
G. V. Rao thank CSIR (India) for fellowships.
References
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2. Reetz, M. T.; Rrewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 1141.
3. Myers, A. G.; Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995, 117, 8488.
4. Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361.
5. Reddy, G. V. S.; Rao, G. V.; Iyengar, D. S. Tetrahedron Lett. 1999, 40, 2653.
6. Ishai, D. B. J. Am. Chem. Soc. 1957, 79, 5736.
7. Aldrich Fine Chemical Catalog, 1998–1999, p. 1441.