Asymmetric synthesis of alpha-methylphosphophenylalanine derivatives using sulfinimine-derived enantiopure aziridine-2-phosphonates.

Article abstract of DOI:10.1021/ol990855k

[formula: see text] 2-Methylaziridine-2-phosphonates were prepared from enantiopure sulfinimines and were demonstrated to be versatile synthetic intermediates for the synthesis of novel alpha-disubstituted and alpha,beta-trisubstituted alpha-aminophosphon

Full text of DOI:10.1021/ol990855k

ORGANIC
LETTERS
1999
Vol. 1, No. 7
1053-1055
Asymmetric Synthesis of
r-Methylphosphophenylalanine
Derivatives Using Sulfinimine-Derived
Enantiopure Aziridine-2-phosphonates
Franklin A. Davis,* William McCoull, and Donald D. Titus
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@astro.ocis.temple.edu
Received July 23, 1999
ABSTRACT
2-Methylaziridine-2-phosphonates were prepared from enantiopure sulfinimines and were demonstrated to be versatile synthetic intermediates
for the synthesis of novel r-disubstituted and r,â-trisubstituted r-aminophosphonate derivatives. The first asymmetric synthesis of both
enantiomers of r-methylphosphophenylalanine is described.
The asymmetric synthesis of R-aminophosphonates has
become important due to their interesting biological proper-
ties. They have found widespread use as surrogates for
R-amino acids,1,2 enzyme inhibitors,3-5 haptens for catalytic
antibodies,6 antibacterial agents,7,8 and biotryticides.9 Gener-
ally, biological activity is strongly dependent upon the
chirality R to the phosphorus atom, and a number of
asymmetric syntheses of R-aminophosphonates have been
reported.10 Particularly, enantiopure sulfinimines (N-sulfinyl
imines) have been utilized in a direct R-aminophosphonate
synthesis11,12 and also via aziridinyl-2-phosphonates.13 How-
ever, to the best of our knowledge, there are no reports of
the asymmetric synthesis of R-disubstituted derivatives. The
analogous R-methyl R-amino acids are of considerable
interest because incorporation into peptides results in in-
creased rigidity, resistance to protease enzymes, and often
enhance bioactivity.14 The aziridine-2-phosphonate route is
especially attractive in that, like aziridine-2-carboxylates,15,16
it should allow incorporation of substituents at both the R-
and â-positions relative to phosphorus with control of
chirality.
(1) Kafarski P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991,
63, 193-215.
Herein, we disclose the first asymmetric synthesis of
R-methylphosphophenylalanine derivatives from enantiopure
(2) Smith, A. B., III; Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc.
1995, 117, 10879-10888.
(3) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med.
Chem. 1989, 32, 1652-1661.
(10) Reviews: Dhawan B.; Redmore, D. Phosphorus, Sulfur Silicon
Relat. Elem. 1987, 32, 119-144. Kukhar, V. P.; Soloshonok, V. A.;
Solodenko, V. A. Phosphorus, Sulfur Silicon Relat. Elem. 1994, 92, 239-
264. Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9, 1279-1332.
(11) Lefebvre I. M.; Evans, S. A., Jr. J. Org. Chem. 1997, 62, 7532-
7533.
(4) Bartlett, P. A.; Hanson, J. E.; Giannousis, P. P. J. Org. Chem. 1990,
55, 6268-6274.
(5) Bird, J.; Mello, R. C. D.; Harper, G. P.; Hunter, D. J.; Karran, E. H.;
Markwell, R. E. J.; Miles-Williams, A.; Rahman, S. S.; Ward, R. W. J.
Med. Chem. 1994, 37, 158-169.
(6) Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P. A.;
Taylor, S. D.; Yager, K. M.; Sprengler, P. A.; Benkovic, S. J. Science 1994,
265, 234-237.
(12) Mikolajczk, M.; Lyzwa, P.; Drabowicz, J. Tetrahedron: Asymmetry
1997, 8, 3991-3994.
(13) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249-252.
(14) See, for example: (a) Colson, P.-J.; Hegedus, L. S. J. Org. Chem.
1993, 58, 5919-5924. (b) Shao, H.; Zhu, Q.; Goodman, M. J. Org. Chem.
1995, 60, 790-791.
(7) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hasssal, C. H.; Holmes, S.
W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S. Nature 1978, 272, 56-
58.
(8) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med. Chem. 1986,
29, 29-40.
(9) Maier, L. Phosphorus, Sulfur Silicon 1990, 53, 43-67.
(15) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 596-619.
(16) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27,
13-18.
10.1021/ol990855k CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/09/1999

aziridine-2-phosphonates which are accessed via an aza-
Darzens reaction of sulfinimine (S)-(+)-117 and diethyl
1-chloroethylphosphonate (2).18 The reaction of (+)-1 with
2.2 equiv of the lithium anion generated from 2 at -78 °C
for 20 min afforded R-chloro â-amino adduct (+)-3 in 56%
isolated yield after chromatography and also an inseparable
mixture of 4 and 5 in 23% isolated yield (4:5, 68:32)
(Scheme 1).19
derived from (+)-3 using reactions of known stereochemical
outcome can thus be assumed. Cyclization using sodium
hydride to give aziridine (SS,2R,3R)-(+)-6 proceeded in 69%
yield (SN2 inversion R to phosphorus) and the sulfinyl
auxiliary was removed in 76% yield using TFA in acetone-
water to give (2R,3R)-(+)-7 (Scheme 2).19
Scheme 2
Scheme 1
Transfer hydrogenation (Pd/C, HCO2NH4, MeOH) pro-
ceeded with conservation of the stereochemistry R to
phosphorus to afford diethyl (R)-(+)-R-methylphospho-
phenylalanine (8) in 92% yield. Similarly, the minor product
mixture of 4/5 was converted to (S)-(-)-R-methylphospho-
phenylalanine (9) in 43% yield over three steps. After
removal of the sulfinyl group, the N-H aziridines were
separable by chromatography and the aziridine derived from
5 was characterized as the enantiomer of (+)-7. The C(2)
The stereochemistry of (+)-3 was established as (SS,1R,2R)
by single-crystal X-ray analysis since NOE experiments on
the derived aziridines proved inclusive. Figure 1 shows the
1
methyl displays a characteristic doublet H NMR signal
depending on whether it is cis (δ 1.0) or trans (δ 1.6) to the
C(3) phenyl substituent.
The formation of (+)-3 was rationalized through attack
by the phosphonate anion at the imine face opposite to that
sterically shielded by the sulfinyl oxygen in a six-membered
transition state (Figure 2). The anion was expected to adopt
Figure 1. ORTEP view of R-chloro â-amino adduct (+)-3.
corresponding ORTEP drawing with the appropriate atom
numbering. The stereochemistry of subsequent products
Figure 2. Proposed predominant transition state for phosphonate
anion addition to sulfinimine (+)-1.
(17) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1403-1406.
(18) Gajda, T. Synthesis 1990, 717-718.
a conformation similar to the analogous E enolate,20 but the
barrier to rotation around the P-C bond in such compounds
was expected to be low.21 Consequently, minor adduct 4 may
(19) Selected properties. (SS,1R,2R)-(+)-3: mp 102 °C, [R]20 24.3 (c
D
1.01, CHCl3), δP 19.42. (SS,2R,3R)-(+)-6: oil, [R]20 5.2 (c 1.4, CHCl3),
D
δP 24.32. (2R,3R)-(+)-7: oil, [R]20 26 (c 0.56, CHCl3), δP 28.50. ent-7:
D
oil, [R]20D -26 (c 0.56, CHCl3). (R)-(+)-8: oil, [R]20D 1.5 (c 0.75, CHCl3),
δP 30.94. (S)-(-)-9: oil, [R]20D -1.4 (c 0.77, CHCl3). (1R,2S)-(+)-10: oil,
(20) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996, 37,
5473-5476.
[R]20 63 (c 0.76, CHCl3), δP 29.66.
D
1054
Org. Lett., Vol. 1, No. 7, 1999

was removed at room temperature and thus provided an
alternative desulfinylation procedure for such compounds.
Second, in a significantly slower step the aziridine ring was
opened, presumably through BF3 activation on nitrogen
which required heating at 55 °C for 2 days.
Scheme 3
In summary, 2-methylaziridine-2-phosphonates were pre-
pared from enantiopure sulfinimines and were demonstrated
to be versatile synthetic intermediates for the synthesis of
novel R-disubstituted and R,â-trisubstitute R-aminophos-
phonate derivatives with control of the chirality at these
centers.
results from interconversion of the methyl and chlorine
positions, while the very minor adduct 5 results from the
less favored attack at the imine face shielded by the sulfinyl
oxygen.
Treatment of aziridine (+)-6 with methanol in the presence
of BF3‚OEt2 afforded the â-methoxy-R-methylphospho-
phenylalanine derivative 10 in 90% de with complete control
of the regiochemistry (Scheme 3).19 After chromatography
(1R,2S)-(+)-10 was obtained in 72% yield. The reaction
proceeded in two steps. In a fast step, the sulfinyl auxiliary
Acknowledgment. We thank Mr. George Kemmerer,
director of the Temple NMR facilities, for his assistance with
the 31P NMR spectra. This work was supported by grants
from the National Science Foundation and the National
Institutes of Health (GM51982).
Supporting Information Available: Full experimental
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Denmark, S. E.; Miller, P. C.; Wilson, S. R. J. Am. Chem. Soc.
1991, 113, 1468-1470.
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