TETRAHEDRON:
ASYMMETRY
Tetrahedron: Asymmetry 14 (2003) 265–273 Pergamon
Chiral, non-racemic -hydroxyphosphonates and phosphonic acids
via stereoselective hydroxylation of diallyl benzylphosphonates
Danielle Skropeta*
,†
and Richard R. Schmidt
Fachbereich Chemie, Universitaet Konstanz, Fach M 725, D-78457 Konstanz, Germany
Received 28 October 2002; accepted 20 November 2002
Abstract—Chiral, non-racemic -hydroxyphosphonates have been prepared in high enantiomeric excess (96–98% ee), via
stereoselective oxaziridine-mediated hydroxylation of diallyl benzylphosphonates. The enantiomeric purity and absolute configura-
tion of the -hydroxyphosphonates was established from
1
H and
31
P NMR spectroscopy of the (S )-O-methylmandelate esters.
Deprotection of the diallyl -hydroxyphosphonates under neutral conditions furnished the corresponding free phosphonic acids,
retaining a high degree of stereochemical purity (90 to >98% ee). © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
-Hydroxyphosphoryl compounds are important bioac-
tive molecules known to inhibit a range of enzymes.
They are also attractive precursors to -aminophospho-
ryl isosteres of -amino acids. -Hydroxyphosphonic
acids are found to inhibit farnesyl protein transferase,
1
enolpyruvylshikimate-3-phosphate synthase,
2
tyrosine-
specific protein kinase
3
and HIV protease,
4
whereas
-hydroxyphosphonate esters are found to inhibit renin
angiotensin synthase.
5
Most bioactivity studies have
been performed using either free phosphonic acids
1–3
or
phosphonate diesters, however, those studies which
have compared the activities of both, have often
revealed a drastic difference in potency attributed to
additional hydrogen bond formation of the free acid, or
conversely, interaction of the ester groups with catalytic
moieties in the active site of the enzyme.
4,5
Further-
more, although the absolute configuration at the -cen-
tre has been shown to influence the biological
properties of -substituted phosphoryl compounds,
5
most bioactivity studies are performed employing
racemic compounds.
1–4
We were interested in a simple
and efficient stereoselective route that gives rise to both
enantiomerically pure -hydroxyphosphonates and
their corresponding phosphonic acids, as key precursors
in the asymmetric synthesis of potent sialyltransferase
inhibitors,
6
and as an essential tool for further investi-
gation into the role of -hydroxyphosphoryl com-
pounds in biological processes.
Chiral, non-racemic dialkyl -hydroxyphosphonates
have been prepared via several methods, as has been
recently reviewed,
7,8
including chiral variations of either
the Pudovik reaction
9
or the Abramov reaction,
10
chemical
11
or enzymatic resolution,
12
or employing cat-
alytic asymmetric methods.
8
On the other hand, enan-
tioenriched dialkyl -hydroxyphosphonic acids have
been prepared by enantioselective addition of aldehydes
to chiral phosphorous acid diamides
13
followed by
hydrolysis of the phosphonamides,
14
or more often by
hydrolysis of the corresponding non-racemic -hydroxy-
phosphonates prepared by one of the methods
described above.
The majority of these stereoselective routes are aimed
at the preparation of dialkyl -hydroxyphosphonates,
7,8
and yet, unlike their related carboxylate esters, simple
phosphonate dialkyl esters are not generally converted
in vivo to their corresponding free acids.
15
For the
majority of bioactivity studies, which require phospho-
nic acids, the harsh conditions necessary to liberate the
free acid from the dialkyl ester form, may lead to
substantial racemisation of the crucial, newly-formed,
non-racemic -centre.
11
Since their introduction as easily removable phospho-
nate protecting groups,
16
diallyl phosphonate esters
have been employed successfully in the synthesis of
sialyltransferase inhibitors,
6,17
in the field of solid-phase
peptide synthesis of phosphonic acid isosteres of -
amino acids
18
and also in the synthesis of ,-
* Corresponding author. Tel.: +49-(0)7531-88-2018; fax: +49-(0)7531-
88-3135; e-mail: danielle.skropeta@uni-konstanz.de
†
As of 12/02: University of Sydney, School of Chemistry, NSW,
2006, Australia. Tel.: +61-(0)2-9351-2297; fax: +61-(0)2-9351-3329;
e-mail: d.skropeta@chem.usyd.edu.au
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII:S0957-4166(02)00786-3