Facile inversion of configuration of N-Boc-β-aminoalcohols via S(N)2 cyclization to oxazolidinones

Article abstract of DOI:10.1016/S0040-4039(00)01753-6

Oxazolidinones are obtained by the cyclization of mesylates derived from N-Boc-β-Aminoalcohols. Hydrolysis of the N-Boc-Oxazolidinones regenerates the protected aminoalcohols with inverted configuration at the hydroxy group. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01753-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10071–10074
Facile inversion of configuration of N-Boc-b-aminoalcohols
via SN2 cyclization to oxazolidinones
Fabio Benedetti* and Stefano Norbedo
Department of Chemical Sciences, University of Trieste, via Giorgieri 1, I-34127 Trieste, Italy
Received 3 October 2000; accepted 9 October 2000
Abstract
Oxazolidinones are obtained by the cyclization of mesylates derived from N-Boc-b-aminoalcohols.
Hydrolysis of the N-Boc-oxazolidinones regenerates the protected aminoalcohols with inverted configura-
tion at the hydroxy group. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amino alcohols; oxazolidinones; inversion reactions; cyclization.
N-Boc-b-Aminoalcohols (1) readily cyclize to oxazolidinones (2) by a base catalyzed
intramolecular acyl transfer (Scheme 1).1 However, when the hydroxy group is converted into a
R
acyl transfer
R
HN
HN
O
t-Bu
OH
O
O
O
1
2
R
i NaH, (Boc)2O
ii Cs2CO3, MeOH/H2O
SN2
R
R
HN
HN
HN
O
t-Bu
X
t-Bu
OH
O
O
O
O
O
3
4
5
Scheme 1.
* Corresponding author. Fax: +39 040 6763903; e-mail: benedett@univ.trieste.it
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01753-6

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suitable leaving group, as in 3, cyclization can take place by an intramolecular SN2 displacement,
thus leading to the formation of the epimeric product 4.2–4 As oxazolidinones 4 can be readily
converted into N-Boc aminoalcohols 5,5 this reaction sequence (1“5) can be exploited to invert
the configuration of the hydroxy group (Scheme 1).
Recently this approach has been used by Ghosh in the synthesis of the core unit of ritonavir,
a potent HIV-protease inhibitor, and cyclization was obtained by treating the N-Boc aminoalco-
hol with thionyl chloride.6 This prompted us to report on a parallel study which we undertook
Table 1
Inversion of configuration of N-Boc aminoalcohols

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as part of an investigation into the synthesis of dipeptide isosteres. We have found that SN2
cyclization to oxazolidinones takes place smoothly when the b-aminoalcohol 1 is converted in
situ into the corresponding mesylate 3 (X=OMs, Scheme 1), thus avoiding the use of thionyl
chloride which may lead to undesired side reactions. The inverted N-Boc aminoalcohol is then
restored by t-butoxycarbonylation and hydrolysis of the N-Boc oxazolidinones with cesium
carbonate.5,7 The results on a representative series of N-Boc b-aminoalcohols are reported in
Table 1.8–14
It can be seen from the Table that cyclization of the N-Boc aminoalcohols is completely
stereospecific giving the oxazolidinones with inversion of configuration at C5, with the two
exceptions of entries 4 and 7. In the case of the threo aminoalcohol 1d (entry 4), the reaction
leads to a 6:1 mixture of isomeric oxazolidinones 4c and 4d12 with retention and inversion of
configuration, respectively. The main product 4c is identical to that obtained from the cycliza-
tion (with inversion of configuration) of the erythro aminoalcohol 1c. The SN2 pathway is
probably disfavoured in the threo isomer 1d by steric interactions between the syn phenyl
groups; formation of the anti oxazolidinone 4c is thus preferred, probably via a SN1 cyclization
of the benzylic mesylate. Competition between SN1 and SN2 mechanisms is also likely to be
responsible for the partial epimerization observed in the cyclization of the very reactive mesylate
derived from alcohol 1g (entry 7) leading to a 3:1 mixture of inverted and retained oxazolidi-
nones 4g and 2g, respectively. A similar result was obtained when the cyclization was carried out
with thionyl chloride.6 Entries 5–7 in Table 1 illustrate the application of our methodology to
the inversion of configuration of enantiopure 1,2-aminoalcohols. Thus, for example, N-Boc
aminoalcohol 1e ([h]2D5=−2.62, c=4, EtOH) was smoothly converted into its enantiomer 5e
([h]2D5=+2.53, c=4, EtOH) via known oxazolidinone 4e ([h]2D5=+23, c=4.3, EtOH)13 in 74%
overall yield and 97% e.e. (entry 5). In the case of the allylic alcohol 1f (entry 6), our
methodology proved superior to that described by Ghosh.6 When the cyclization of this alcohol
was performed with thionyl chloride, a 1:1 mixture of oxazolidinone 4f and the chloride derived
by a SN1 displacement at the allylic position was obtained, while under our conditions 4f is the
only product.
The synthetic utility of this method is further illustrated by the two-step synthesis of
N-methyl-pseudoephedrine 8 from N-Boc-ephedrine 6 (Scheme 2). The latter aminoalcohol,
when treated with methanesulfonyl chloride, readily cyclizes, at 25°C in 4 hours, to the known15
oxazolidinone 7, with complete inversion of configuration. Reduction of the oxazolidinone with
lithium aluminium hydride in THF gave N-methyl-pseudoephedrine 816 in quantitative yield.
Scheme 2.
1,2-Aminoalcohols are intermediates in the synthesis of biologically active products17–19 and
are widely used as chiral auxiliaries in asymmetric synthesis;1 the methodology described here
may offer a useful tool for the interconversion of stereoisomers of this important class of
compounds.

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