Asymmetric cyclopropanation of chiral (1-dimethoxyphosphoryl-2-phenyl)vinyl p-tolyl sulfoxide: A new synthesis of enantiomerically pure 2-amino-3-phenyl-1-cyclopropane-phosphonic acid - A constrained analog of phaclofen

Article abstract of DOI:10.1016/S0040-4039(02)00374-X

E-(S)-(1-Dimethoxyphosphoryl-2-phenyl)vinyl p-tolyl sulfoxide 3 was found to undergo cyclopropanation with sulfur ylides [dimethyl(oxo)sulfonium methylide, diphenyl sulfonium isopropylide and ethyl (dimethylsulfuranylidene)acetate (EDSA)] in a highly diastereoselective manner. The major diastereomer obtained in the reaction of E-(S)-3 with EDSA was converted into enantiopure (2R)-amino-(3R)-phenyl-(1R)-cyclopropane-phosphonic acid, a constrained analog of the GABA_B antagonist, phaclofen.

Full text of DOI:10.1016/S0040-4039(02)00374-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3061–3065
Asymmetric cyclopropanation of chiral
(1-dimethoxyphosphoryl-2-phenyl)vinyl p-tolyl sulfoxide: a new
synthesis of enantiomerically pure 2-amino-3-
phenyl-1-cyclopropane-phosphonic acid—a constrained analog of
phaclofen
Wanda H. Midura and Marian Mikołajczyk*
Centre of Molecular and Macromolecular Studies, Department of Heteroorganic Chemistry, Polish Academy of Sciences,
90-363 Ło´dz´, Sienkiewicza 112, Poland
Received 2 January 2002; revised 28 January 2002; accepted 21 February 2002
Abstract—E-(S)-(1-Dimethoxyphosphoryl-2-phenyl)vinyl p-tolyl sulfoxide 3 was found to undergo cyclopropanation with sulfur
ylides [dimethyl(oxo)sulfonium methylide, diphenyl sulfonium isopropylide and ethyl (dimethylsulfuranylidene)acetate (EDSA)] in
a highly diastereoselective manner. The major diastereomer obtained in the reaction of E-(S)-3 with EDSA was converted into
enantiopure (2R)-amino-(3R)-phenyl-(1R)-cyclopropane-phosphonic acid, a constrained analog of the GABAB antagonist,
phaclofen. © 2002 Published by Elsevier Science Ltd.
Aminoalkylphosphonic acids are important surrogates
for aminoalkylcarboxylic acids in which the planar
carboxylic group is replaced by a phosphonic acid or
related moiety having a tetrahedral configuration.
Aminophosphonic acids, both natural and synthetic,
have attracted considerable attention because of their
diverse and useful biological activities.1 Intensive
research aimed at the synthesis of phosphonic acid
analogs of protein and non-protein amino acids
resulted in new classes of drugs and other bioactive
compounds with a great variety of commercial applica-
tions, ranging from agriculture to medicine.
basic structural unit in a wide range of naturally occur-
ring compounds, both in plants and microorganisms,3
we turned our attention to aminocyclopropanephos-
phonic acids which are conformationally constrained
analogs of 1-, 2- and 3-aminoalkanephosphonic acids.
Although many articles have been published on the
preparation of this class of compounds, particularly on
1-aminocyclopropanephosphonic acids,4 the first and
only asymmetric synthesis of the enantiomerically pure
2-amino-3-phenyl-1-cyclopropane-phosphonic acid 1, a
constrained analog of the GABAB antagonist,
phaclofen 2, has recently been reported by Hanessian
and co-workers.5
Thus, amino phosphonic acids display promising
antibiotic and anti-cancer properties. They are strong
neuromodulators, plant growth regulators and herbi-
cides. This class of compounds also includes metal-
sequestering drugs, radiopharmaceuticals and NMR
imaging agents. Since the design and synthesis of con-
formationally constrained peptidomimetics has recently
been an important strategy in modern drug discovery
processes2 and the cyclopropyl group is found as a
Encouraged by our results on the asymmetric synthesis
of 1-amino- and 2-aminoalkylphosphonic acids medi-
ated by a chiral sulfinyl auxiliary,6 as well as on asym-
metric cyclopropanation of chiral a-phosphorylvinyl
Keywords: asymmetric cyclopropanation; chiral a-phosphorylvinyl
sulfoxides; aminocyclopropanephosphonic acid.
* Corresponding author. Fax: (+48-42) 684-71-26; e-mail:
marmikol@bilbo.cbmm.lodz.pl
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00374-X

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W. H. Midura, M. Mikołajczyk / Tetrahedron Letters 43 (2002) 3061–3065
sulfoxides,7 we decided to develop a new approach to
the synthesis of the enantiomerically pure 1. Our
method, is based on the highly diastereoselective cyclo-
propanation of chiral E-(S)-(1-dimethoxyphosphoryl-2-
phenyl)vinyl p-tolyl sulfoxide 3.
The major diastereomer of 6a (lP=19.4 ppm), isolated
by column chromatography was converted into the
corresponding methyl ester 6a% (l=19.5 ppm) in quan-
titative yield by transesterification with methanol under
basic conditions.
1
The starting reagent 3 was easily prepared in 60% yield
by treatment of (+)-(S)-dimethoxyphosphorylmethyl p-
tolyl sulfoxide8 with benzaldehyde in the presence of
piperidine (route A) or in 75% yield by reacting with
N-tosylsulfonyl benzylimine in the presence of a cata-
lytic amount of sodium hydride (route B)9 (Scheme 1).
Both geometrical isomers of (S)-3 formed in these
reactions were separated by column chromatography
[E-(S)-3: [h]D=+3.2 (c 3.2, acetone), lP=12.8 ppm;
Z-(S)-3: [h]D=−367.0 (c 2.6, benzene), lP=16.4
ppm].10
Analysis of the H and 13C NMR spectra of the prod-
ucts 4–611 revealed that the cis-relationship between the
phosphoryl group and phenyl substituent in the starting
E-(S)-3 is preserved in the cyclopropane ring and the
methoxycarbonyl group is trans-oriented to both of
them. Especially conclusive was the 13C NMR spectrum
3
of 6a% where a JCP coupling constant of 5.1 Hz for the
phenyl carbon and 2.0 Hz for the methyl ester carbonyl
carbon was observed indicating cis- and trans-orienta-
tions, respectively, between phosphorus and the two
carbon nuclei.12 The relative configuration ascribed to
6a% is in good agreement with the transition state model
for cyclopropanation of chiral a-phosphorylvinyl sul-
foxides proposed by us earlier,7 in which the approach
of EDSA to the carbonꢀcarbon double bond in E-(S)-3
takes place preferentially from the less hindered
diastereotopic face occupied by the lone electron pair of
sulfur (Scheme 3). Therefore, the two diastereomers of
6 obtained differ only in the configuration at the
methoxycarbonyl bearing carbon atom. Moreover,
based on this transition state model it is possible to
assign the absolute stereochemistry to the cyclopropane
ring in 6a and 6a% as (1S,2R,3R). The correctness of this
assignment was confirmed by the conversion of 6a% into
(2R)-amino-(3R)-phenyl-(1R)-cyclopropanephosphonic
acid 1 outlined below (Schemes 4 and 5).
In the preliminary experiments (Scheme 2) the cyclo-
propanation reaction was performed with two sulfur
ylides, namely dimethyl(oxo)sulfonium methylide and
diphenylsulfonium isopropylide. The corresponding
cyclopropanes 4 and 5 were obtained as mixtures of
only two diastereomers. However, while the cyclo-
propane 4 was formed with moderate stereoselectivity
(3:1 ratio), in the case of 5 a high level of asymmetric
induction was observed leading to a 92:8 mixture of
two diastereomers. The high level of diastereoselectivity
observed in the latter reaction prompted us to carry out
the cyclopropanation reaction of E-(S)-3 with ethyl
(dimethylsulfuranylidene)acetate (EDSA) in which
three new centers of chirality should be formed under
the control of the chiral p-toluenesulfinyl group. It was
gratifying to find that the cyclopropane 6 was formed
as a mixture of only two diastereomers in an 8:1 ratio.
In the first step of the synthesis of 1, the cyclopropane
6a% was treated with sodium amalgam in order to
Scheme 1.
Scheme 2.

W. H. Midura, M. Mikołajczyk / Tetrahedron Letters 43 (2002) 3061–3065
3063
Scheme 3.
Scheme 4.
methylmagnesium iodide at ca. −10 to −5°C. The ester
group in (+)-7a was then hydrolyzed to the correspond-
ing carboxylic acid (+)-8, which was in turn converted
by the well-known literature procedure15 into the
desired N-Boc derivative (+)-9. Final deprotection of
the amino and phosphonate groups afforded the enan-
tiomerically pure (+)-(2R)-amino-(3R)-phenyl-(1R)-
cyclopropanephosphonic acid 1.
remove the chiral sulfinyl moiety via reduction of the
carbonꢀsulfur bond. Under the reaction conditions
applied (Scheme 4), the cyclopropanephosphonate 7
was obtained as a 3:1 mixture of two diastereomers 7a
and 7b, which were easily separated by column
chromatography.
Based on the three-bond carbon–phosphorus coupling
constants as well as on the NOE measurements,13 cyclo-
propane phosphonates 7 were found to have a different
configuration at the a-phosphonate carbon atom,14 the
major diastereomer (+)-7a being formed with retention
of configuration. From the synthetic point of view, it is
relevant to emphasize that (+)-6a% was converted exclu-
sively into (+)-7a in 80% yield upon treatment with
Our synthesis afforded the dextrorotatory enantiomer
of 1 and in this way is complementary to the asymmet-
ric synthesis of the enantiomeric (−)-1 described by
Hanessian and co-workers5 involving the conjugate
addition of chiral a-chlorophosphonamide anions to
a,b-unsaturated esters. The synthesis of other optically

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W. H. Midura, M. Mikołajczyk / Tetrahedron Letters 43 (2002) 3061–3065
Scheme 5.
active isomers of 1 is currently being studied in our
laboratory.
Tetrahedron: Asymmetry 1997, 8, 3991–3994.
7. Midura, W. H.; Krysiak, J. A.; Wieczorek, M. W.;
Majzner, R.; Mikołajczyk, M. Chem. Commun. 1998,
1109–1110.
Acknowledgements
8. Mikołajczyk, M.; Midura, W. H.; Grzejszczak, S.;
Zatorski, A.; Chefczyn´ska, A. J. Org. Chem. 1978, 43,
473–478.
Partial financial support by the State Committee for
Scientific Research (Grant No Z-005/t09/99) is grate-
fully acknowledged.
9. For this new procedure of the Horner–Wittig reaction of
a-phosphoryl sulfoxides see: Shen, J.; Jing, G.-F. Synthe-
sis 2000, 99–102.
10. E-(S)-3: [h]D=+3.2 (c 3.2, acetone); 31P NMR (CDCl3):
12.8 ppm; 1H NMR (500 MHz, CDCl3): 2.39 (s, 3H),
3.28 (d, 3H, J=11.6 Hz), 3.47 (d, 3H, J=11.7 Hz),
7.27–7.29 (m, 3H), 7.41–7.43 (m, 2H), 7.65–7.67 (m, 2H),
7.75–7.77 (m, 2H), 8.09 (d, 1H, J=41.7 Hz). Calcd for
C17H19O4PS: C, 58.28; H, 5.47. Found: C, 58.37; H, 5.42.
Z-(S)-3: [h]D=−367.0 (c 2.6, C6H6); 31P NMR (CDCl3):
16.4 ppm; 1H NMR (200 MHz, CDCl3): 2.38 (s, 3H),
3.26 (d, 3H, J=11.5 Hz), 3.80 (d, 3H, J=11.6 Hz),
7.25–7.29 (m, 2H), 7.42–7.49 (m, 5H), 7.65–7.70 (m, 2H),
8.18 (d, 1H, J=21.8 Hz).
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1
11. 6a%: H NMR (200 MHz, CDCl3): 2.45 (s, 3H), 3.02 (d,
3H, J=11.4 Hz), 3.42 (dd, 1H, J=8.3, 16.9 Hz), 3.54 (d,
3H, J=11.1 Hz), 3.78 (dd, 1H, J=8.3, 13.4 Hz), 3.82 (s,
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relative configuration in cyclopropylphosphonates see:
;

W. H. Midura, M. Mikołajczyk / Tetrahedron Letters 43 (2002) 3061–3065
3065
Jubault, P.; Goumain, S.; Feasson, C.; Collignon, N.
Tetrahedron 1998, 54, 14767–14778 and references cited
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14. The desulfurization with sodium amalgam performed in
MeOD gave the cyclopropane 7 with deuterium incorpo-
rated at the a-phosphonate carbon atom. No exchange of
hydrogen by deuterium at the other cyclopropane carbon
atoms was observed.
3
3
13. For (+)-7a: JCarom–P=6.25 Hz, JC(O)–P=3.62 Hz; NOE:
H1“H3 6.5%.
For (+)-7b: 3JCarom–P=3.2 Hz, 3JC(O)–P=8.55 Hz; NOE:
H1“H2 5.75%.
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