The first asymmetric synthesis of alpha-sulfanylphosphonates.

Article abstract of DOI:10.1021/ol005937j

[reaction: see text] Diastereoselectivity of up to 88% was achieved for the synthesis of an alpha-mercapto gamma-unsaturated phosphonate using the readily available chiral dimenthylphosphonyl ester group and a carbanionic [2,3]-sigmatropic rearrangement.

Full text of DOI:10.1021/ol005937j

ORGANIC
LETTERS
2000
Vol. 2, No. 24
3757-3759
The First Asymmetric Synthesis of
r-Sulfanylphosphonates
Patrice Marchand, Mihaela Gulea, Serge Masson,* Monique Saquet, and
Noe1l Collignon†
Laboratoire de Chimie Mole´culaire et Thio-organique, UMR 6507-ISMRA-UniVersite´
de Caen, 6 Bd du Mare´chal Juin 14050 Caen Cedex, France
masson@ismra.fr
Received April 12, 2000 (Revised Manuscript Received November 2, 2000)
ABSTRACT
Diastereoselectivity of up to 88% was achieved for the synthesis of an r-mercapto γ-unsaturated phosphonate using the readily available
chiral dimenthylphosphonyl ester group and a carbanionic [2,3]-sigmatropic rearrangement. Absolute configuration of the newly formed chiral
center of this nonracemic thiol was determined, and the corresponding phosphono thiolane and thiolane S-oxide were also stereoselectively
prepared.
R-Heterosubstituted phosphonates have focused interest due
to their potential biological activities1 (as antibacterial,
antiviral, or herbicidal agents) and synthetic applications.2
Among these compounds, R-hydroxy and R-amino phos-
phonates have been extensively studied and their syntheses
(racemic or chiral) have been recently reviewed.3 However,
R-mercapto (or sulfanyl) phosphonates have been more
scarcely described.4
We have previously reported on the preparation of racemic
R-mercaptophosphonates via carbanionic [2,3]-sigmatropic
rearrangements of (allylthiomethyl)phosphonates.5 Herein we
report an asymmetric version of this rearrangement which
allowed us to synthesize the first chiral nonracemic mer-
captophosphonate and some of its derivatives including a
chiral cyclic sulfoxide (potent useful Wittig-Horner reagent).
[2,3]-Sigmatropic rearrangements which lead to the regio-
selective formation of carbon-carbon bonds have found wide
application in the synthesis of complex organic molecules.6
Moreover, applications of these rearrangements in the
synthesis of chiral compounds usually proceed with a high
level of stereo- or enantiocontrol.6
Moreover, to the best of our knowledge, no enantioselec-
tive synthesis of chiral R-mercaptophosphonates or sulfides
have so far been proposed.
† Present address: Laboratoire d’He´te´rochimie Organique, UPRESA
CNRS 6014 INSA de ROUEN-IRCOF Rue Tesnie`re, F-76821 Mont Saint
Aignan, France.
(1) (a) Engel, R. Chem. ReV. 1977, 77, 349. (b) Tashma, Z. J. Org. Chem.
1982, 47, 3012 and cited references. (c) Kafarsky, P.; Lejczak, B.
Phosphorus, Sulfur Silicon 1991, 63, 193.
(2) (a) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961,
83, 1733. (b) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. (c)
Mikolajczyk, M.; Balczewsky, P. AdVances in Sulfur Chemistry; JAI Press
Inc.: 1994, Vol. V1, p 41.
(3) (a) Wiemer, D. F. Tetrahedron 1997, 53, 16609. (b) Kushar, V. P.;
Soloshonsk, V. A. Phosphorus, Sulfur Silicon 1994, 92, 239.
(4) (a) Mikolajczyk, M.; Crzejszczak, S.; Chefczynska, A.; Zatorsky, A.
J. Org. Chem. 1979, 44, 17, 2967. (b) Zimin, M. G.; Burilov, A. R.; Islamov,
R. G.; Pudovik, A. N. Zh. Obsh. Khim. 1983, 53, 46.
Good diastereoselectivities (respectively 99% and 92% de)
for the [2,3]-sigmatropic rearrangement of lithiated allyl-
oxymethylphosphonates using additional chiral auxiliaries
have been previously reported by both Denmark7 and our
laboratory.8
(5) (a) Makomo, H.; Saquet, M.; Masson, S.; Putmann, D.; Simeon, F.;
About-Jaudet, E.; Collignon, N. Phosphorus, Sulfur Silicon 1996, 112. (b)
Makommo, H.; Saquet, M.; Masson, S. Tetrahedron Lett. 1993, 34, 7257.
(6) (a) Naka¨ı, T.; Mikami, K. Chem. ReV. 1986, 86, 885. (b) Mikami,
K.; Naka¨ı, T. Synthesis 1991, 594. (c) Bru¨kner, R. Kontakte (French ed.)
1993, 3; 1994, 2.
10.1021/ol005937j CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

Our successful results in the asymmetric synthesis of an
R-hydroxyphosphonate by using a C2-symmetry dimenthyl-
phosphonyl group incited us to keep this readily accessible
and cheap chiral auxiliary in the present study.
Scheme 3
Starting from the L-dimenthyl phosphite,8 we first prepared
the easily accessible (yield 72-85% on a 10 g scale)
phosphonodithioformate 1 (according to the method of
Grisley,9 Scheme 1) using HK as a base in THF.
Scheme 1
resulting methylsulfanyl derivative 4 was obtained with a
lower diastereoisomeric excess (cf. Scheme 3, yield 85%,
de ) 70%).
The reduction of dithioformate 1 by an excess of sodium
borohydride in ethanol followed by addition of allyl bromide
led us to (allylsulfanyl)methylphosphonate 2 in 95% yield
(Scheme 2).
We were able to deduce the configuration of the sulfur-
substituted carbon (C1) of the main diastereoisomer 3a from
that of the corresponding alcohol 5 of known configuration.8
Starting from the R-hydroxy phosphonate 5 (de ) 96%, 1R
from (-)-L-dimenthyl phosphite) and using thiolacetic acid
under the Mitsunobu conditions,11 we prepared the R-
acetylsulfanyl phosphonate 6b with 1R configuration (25%
yield, de ) 96%) with full inversion of configuration
(Scheme 4).
Scheme 2
Scheme 4
Owing to the dramatic steric effect of the two bulky
menthyl groups, the next step of the synthesis required us
to find appropriate conditions for the generation and re-
arrangement of the carbanion R to the phosphorus. Among
the bases we have tested,10 only alkyllithiums were found
to be efficient and, at low temperature, a large excess was
necessary to obtain a fast and complete deprotonation. The
best results were obtained by using 5 equiv of (sec-BuLi/
HMPA) in THF at -75/-72 °C and with a reaction time of
75 min. After acidic hydrolysis and extraction with pentane,
we obtained the rearranged R-mercaptophosphonate 3 (3a/
3b, 94:6) (cf. Scheme 3) with a diastereoisomeric excess of
up to 88% (according to 31P NMR) and a yield of 95%.
The thiol was found to be relatively unstable during
chromatography (disulfide formation occurred) and thus was
used in crude form (purity >90% according to NMR spectra)
for subsequent transformations.
Comparison of the 31P NMR spectra of 6b (1R; 31P )
24.1) and 6a (31P ) 24.2) (obtained by acetylation of the
crude thiol 3a, 94% yield, de ) 88%) showed that these
compounds are epimers. Therefore, an S configuration can
be attributed to the R-carbon of 6a and of its precursor, the
major diastereoisomer 3a.
The radical intramolecular cyclization of crude thiol 3 into
the 2-phosphonothiolane 7a,b was then performed (using UV
irradiation and a catalytic amount of AIBN).
This cyclization occurred without any epimerization (de
) 88%) and the yield was 60% after silica gel chromatog-
raphy (Scheme 5). Crystallization at -60 °C in pentane
allowed us to isolate a nearly pure sample of epimer 7a (de
) 96% by 31P NMR, yield 30%) with an S configuration
(compound isoster of L-proline esters).
Instead of acidic hydrolysis, methyl iodide was also used
to trap the intermediate lithiated thiolate. Probably due to
the excess of base, a partial racemization occurred and the
(7) Denmark, S. E.; Miller, P. C. Tetrahedron Lett. 1995, 36, 6631.
(8) Gulea-Purcarescu, M.; About-Jaudet, E.; Collignon, N. Tetrahedron
Lett. 1995, 36, 6635.
(9) Grisley, D. W., Jr. J. Org. Chem. 1961, 26, 2544.
(10) HNa, HK, HLi, LiHMDS, LDA, and tBuOK/BuLi in various
conditions (temperature, solvent, reaction time).
(11) Hughes, D. L. Org. React. 1992, 42, 335 and cited references.
Org. Lett., Vol. 2, No. 24, 2000
3758

Scheme 5
Scheme 7
Previous work has shown that the addition of N-bromo-
succinimide to a thiol leads to the formation of a sulfenyl
bromide.12 In particular, when a double bond is present, the
sulfenyl bromide spontaneously adds to the double bond and
such a reaction was recently used for the preparation of 5-
or 6-membered sulfurated rings.13 Thus, addition of the crude
thiol 3 to a solution of N-bromosuccinimide in chloroform
at -50 °C led to the formation of the 4-bromo-2-phospho-
thiolane 8 in 65% yield (Scheme 6). As expected11 and as
R-carbon to the sulfur (Scheme 7). The relative configuration
of 9 was established by comparison with its racemic
analogue, 2-phosphonothiolane S-oxide 11, obtained under
the same oxidation conditions from thiolane 10; the X-ray
study of a crystal of this sulfoxide has proven the relative
trans configuration of the C-P and S-O bonds.14 Conse-
quently, since the carbon of 9a is S, an R configuration can
be attributed to the sulfur atom of the major diastereomer
9a.
Scheme 6
In conclusion, this paper describes the first asymmetric
synthesis of an R-mercapto γ-unsaturated phosphonate and
of its cyclic derivatives 7, 8, and 9. Moreover, owing to the
stereoselectivity of the S-oxidation of thiolane 7, sulfoxide
9 can be considered as a new potential asymmetric Horner-
Wadsworth-Emmons reagent for the synthesis of asym-
metric vinylic sulfoxides.
1
shown by 13C and H NMR spectra of the thiolane 8, the
cyclization and bromination reactions were highly stereo-
selective.
Starting from the thiol 3 (de ) 80%), the phosphono-
bromothiolane 8 (probably trans as previously observed in
such cyclizations)12 was isolated with the same diastereo-
meric excess.
Acknowledgment. We thank the Re´seau Inter-Re´gional
Normand de Chimie Organique Fine (RINCOF, Contrat de
Plan Etat-Bassin Parisien-Re´gions Haute-Normandie-Basse-
Normandie) for financial support and for a grant to P.
Marchand.
We then performed the oxidation of 2-phosphonothiolane
7a,b (de ) 88%) using m-chloroperbenzoic acid. The
corresponding sulfoxide was obtained quantitatively. The
oxidation was found to be totally stereoselective and so
allows a complete transfer of the asymmetry from the
Supporting Information Available: Detailed descrip-
tions of experimental procedures and NMR data for com-
pounds 1-9. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL005937J
(12) Seliger, H.; Go¨rtz, H.-H. Synth. Commun. 1980, 10, 175.
(13) Ren, X.-F.; Turos, E.; Lake, C. H.; Churchill, M. R. J. Org. Chem.
1995, 60, 6468.
(14) Marchand, P.; Masson, S.; Saquet, M.; Averbuch-Pouchot, M. T.
To be published.
Org. Lett., Vol. 2, No. 24, 2000
3759