TETRAHEDRON:
ASYMMETRY
Tetrahedron: Asymmetry 13 (2002) 2113–2115 Pergamon
Enantioselective synthesis of protected D-serine from
tetrahydrooxazin-4-one via a hetero Diels–Alder reaction
Mauro Panunzio,
a,
* Elisa Bandini,
b
Eileen Campana
b
and Paola Vicennati
b
a
ISOF -CNR, Dipartimento di Chimica ‘G. Ciamician’ Via Selmi 2, I -40126 Bologna, Italy
b
ISOF -CNR, Via Gobetti 101, I -40129 Bologna, Italy
Received 25 July 2002; accepted 30 August 2002
Abstract—Hetero Diels–Alder reaction between 2-aza-3-trimethylsilyloxy-1,3-diene and aldehydes gives rise to tetrahydrooxazin-4-
ones, useful intermediates in the synthesis of -amino--hydroxy acids. Herein we report the complete stereoselective synthesis of
D-serine Cbz-methyl ester. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Interest in the field of stereoselective synthesis of -
hydroxy--amino acids is in continuous growth because
of their presence in nature as metabolites or compo-
nents of biologically active compounds.
1
Moreover, due
to their high degree of functionalization, they find wide
use as chiral starting materials in asymmetric
synthesis.
2–4
Synthetic approaches to -hydroxy--amino acids are
based on condensation, possibly enzymatic,
5
of alde-
hydes with glycine derivatives;
6
Sharpless asymmetric
epoxidation/dihydroxylation;
7
electrophilic amination
of -hydroxy esters;
8
and the use of amino acids as
starting materials.
9
In the past few years we have started a detailed study
on 2-aza-3-trimethylsilyloxy-1,3-dienes, demonstrat-
ing that they can be useful intermediates in the stereo-
selective synthesis of nitrogen-containing biologically
interesting compounds: -lactams are accessible via
electrocyclic [2+2] ring closure;
10
-lactams can be syn-
thesized by a four-step one-pot process via addition of
cyano groups, followed by intramolecular ring closure
11
and tetrahydrooxazin-4-ones are obtained by hetero
Diels–Alder reaction with an appropriate dienophile.
12
We have already reported on the possibility of synthe-
sizing tetrahydrooxazin-4-ones as useful precursors of
-hydroxy--amino acids:
13
all stereoisomers of
threonine have been obtained starting from
(2R,5R,6R )-2-[(S )-1-[(triisopropyl)oxy]ethyl]-5-[(benzyl-
oxycarbonyl)amino]-6-methylperhydro-1, 3-oxazin-4-
one.
In order to demonstrate the utility of our approach in
the synthesis of non-proteinogenic amino acids, we
report herein the results obtained from the application
of our methodology to the enantioselective synthesis of
(+)-D-serine protected as N -Cbz-methyl ester. This
target is of interest as a result of its potential pharma-
ceutical application: D-serine has recently been found in
mammalian brain tissue, where it seems to be an
endogenous modulator of the N -methyl-D-aspartate
type (NMDA) glutamate receptors, which have well
known medical implications.
14–16
Besides being a possi-
ble drug, D-serine has additionally been used as a chiral
starting material for the asymmetric synthesis of a
number of -substituted--hydroxy--amino acids,
17
oxazolidinones,
18
pyrrolidines,
19
indolizidines.
20
2. Results and discussion
The synthesis of the azadiene 4 was carried out accord-
ing to the procedure previously reported, starting from
the N -(trimethylsilyl)imine 2 of (S )-lactic aldehyde 1
and acyl chloride 3 (Scheme 1).
12
Treatment of the azadiene
21
4 with formaldehyde
(obtained by thermal depolymerization of tri-
oxymethylene) in the presence of boron trifluoride
etherate in methylene chloride at -78°C followed by * Corresponding author. E-mail: panunzio@ciam.unibo.it
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
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