Asymmetric synthesis of quaternary alpha-amino phosphonates using sulfinimines.

Article abstract of DOI:10.1021/ol015945f

The addition of lithium diethylphosphonate to enantiopure ketosulfinimines is highly diastereoselective (>95%), affording the first examples of quaternary alpha-alkyl alpha-amino (arylmethyl)phosphonates.

Full text of DOI:10.1021/ol015945f

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1757-1760
Asymmetric Synthesis of Quaternary
r-Amino Phosphonates Using
Sulfinimines
Franklin A. Davis,* Seung Lee, Hongxing Yan, and Donald D. Titus
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@astro.ocis.temple.edu
Received April 5, 2001
ABSTRACT
The addition of lithium diethylphosphonate to enantiopure ketosulfinimines is highly diastereoselective (>95%), affording the first examples of
quaternary r-alkyl r-amino (arylmethyl)phosphonates.
Notwithstanding the fact that the phosphonic and carboxylic
acid groups differ substantially with respect to shape, size,
and acidity, R-amino phosphonic acids are important struc-
tural analogues of R-amino acids.1 As a consequence 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 anti-HIV agents,9 and botryticides.10
The increased importance of unnatural R-amino acids in the
modification of peptides to improve bioactivity and stability
and their utility in peptide therapeutics make the asymmetric
synthesis of R-amino phosphonic acids a significant objec-
tive. Although a number of procedures have been described,11
there are few reports of the asymmetric synthesis of
quaternary derivatives. Studer and Seebach reported the
synthesis of several 1,2-diaminoalkane-2-phosphonic acids
via the alkylation of an enantiopure imidazolidine phos-
phonate ester,12 and we prepared (S)-(-)-R-methylphospho-
phenylalanine by a regiocontrolled ring opening of a
sulfinimine (N-sulfinyl imine)-derived aziridine-2-phospho-
nate.13 A rhodium-catalyzed enantioselective Michael addi-
tion to vinyl ketones gives a phosphorus-substitute quaternary
carbon, which in a series of reactions furnishes R-alkyl
R-amino alkylphosphonates.14 The asymmetric alkylation of
R-acetamido â-keto phosphonates has recently been de-
scribed.15
(1) For a review on the biological activity of amino phosphonic acids,
see: Kafarski P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991,
63, 193.
(2) Smith, A. B., III; Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc.
1995, 117, 10879.
(3) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med.
Chem. 1989, 32, 1652.
(9) (a) Camp, N. P.; Hawkins, P. C. D.; Hitchcock, P. B.; Gani, D. Bioorg.
Med. Chem. Lett. 1992, 2, 1047. (b) Haebich, D.; Hansen, J.; Paessens, A.
Eur. Pat. Appl. EP 472077, 1992, Bayer AG; Chem. Abstr. 1992, 117,
27161z. (c) Powers, J. C.; Boduszek, B.; Oleksyszyn, J. PCT Int. Appl.
WO 95 29691, 1995, Georgia Technology Research Corp.; Chem. Abstr.
1996, 124, 203102m. (d) Alonso, E.; Alonso, E.; Solis, A.; del Pozo, C.
Synlett 2000, 698.
(4) (a) Ding, J.; Fraser, M. E.; Meyer, J. H.; Bartlett, P. A.; James, M.
N. G. J. Am. Chem. Soc. 1998, 120, 4610. (b) Smith, W. W.; Bartlett, P. A.
J. Am. Chem. Soc. 1998, 120, 4622 and references therein.
(5) Bird, J.; Mello, R. C. D.; Harper, G. P.; Hunter, D. J.; Karran, E. H.;
Markwell, R. E.; Miles-Williams, A. J.; Rahman, S. S.; Ward, R. W. J.
Med. Chem. 1994, 37, 158.
(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.
(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.
(8) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med. Chem. 1986,
29, 29.
(10) Maier, L. Phosphorus, Sulfur Silicon 1990, 53, 43.
(11) For reviews see: (a) Dhawan B.; Redmore, D. Phosphorus, Sulfur
Silicon Relat. Elem. 1987, 32, 119. (b) Kukhar, V. P.; Soloshonok, V. A.;
Solodenko, V. A. Phosphorus, Sulfur Silicon Relat. Elem. 1994, 92, 239.
(c) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9, 1279.
(12) Studer, A.; Seebach, D. Heterocycles 1995, 40, 357.
(13) Davis, F. A.; McCoull, W.; Titus, D. D. Org. Lett. 1999, 1, 1053.
10.1021/ol015945f CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/05/2001

Table 1. Addition of Lithium Diethyl Phosphite to Ketosulfinimines (S)-1
R-amino
phosphonates (2)
entry
ketosulfinimine
(E:Z)a
(SS,R):(SS,S)b
% de
yieldc (%)
31P (δ)
[R]20 (CHCl3)
D
1
2
3
4
5
6
7
(+)-1a Me, p-MeOPh
(+)-1b Me, p-MePh
(+)-1c Me, Ph
(+)-1d Et, Ph
(+)-1e Me, p-NO2Ph
+)-1f Me, t-Bu
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
3:1
99:1
99:1
99:1
99:1
99:1
99:1
82:18
>95
>95
>95
>95
>95
>95
64
73
91
92
93
93
97
71
22.95
22.91
22.66
22.55
21.36
26.53
22.6
-14.6
-5.8
+5.6
-2.9
-45.7
+139.0
+70.3
(+)-1g Me, n-Bu
a E:Z ratio of the ketosulfinimines. b From the1H and 31P of the crude reaction mixture. c Yield of major diastereoisomer
Herein we disclose the first asymmetric synthesis of
R-alkyl R-amino(arylmethyl)phosphonate derivatives from
enantiopure ketosulfinimines 1.16 The analogous quaternary
R-amino acids are of considerable value because incorpora-
tion into peptides has been found to increase rigidity and
resistance to protease enzymes and enhance bioactivity.17 Our
process involves the stereoselective addition of 2 equiv of
lithium diethyl phosphite, prepared in situ by treatment of
diethyl phosphite with LiHMDS, to an enantiopure keto-
sulfinimine (S)-(+)-1 at -78 °C (Scheme 1). After 1-3 h
Ketosulfinimines 1 are prepared by condensation of
commercially available (S)-(+)-p-toluenesulfinamide (p-
TolylS(O)NH2) with the appropriate ketone in the presence
of 10 equiv of Ti(OEt)4.17,18 Sulfinimines 1a-f were isolated
as single E-isomers, whereas 1g, derived from 2-butanone,
exists as an inseparable 3:1 mixture of isomers. These results
are summarized in Table 1.
The addition of lithium diethyl phosphite to ketosulfin-
imines (S)-(+)-1a-f is remarkably stereoselective, and only
a single isomer was detected in the 1H and 31P NMR spectra
of the crude reaction mixtures. This selectivity is independent
of electronic factors as long as the ketosulfinimine exists as
a single isomer (Table 1, entries 1-6). However, in line with
the 3:1 ratio of E:Z isomers for (+)-1g is the 82:12 mixture
of diastereoisomers for 2g, undoubtedly resulting from
phosphite addition to both isomers (Table 1, entry 7).
Reversibility in the addition of phosphites to sulfinimines is
a consideration,19 and two experiments were designed to
reveal whether the addition is under kinetic or thermo-
dynamic control. First, diastereomeric pure (SS,R)-(+)-2g was
treated, under the reaction conditions, with LiHMDS fol-
lowed by addition of LiP(O)(OEt)2. The isomeric amino
phosphonate (SS,S)-2g was not detected, and (SS,R)-(+)-2g
was recovered unchanged. Next, (SS,R)-(-)-2b was treated
with lithium dimethyl phosphite. None of the crossover
product (SS,R)-3 was observed, and the substrate was
quantitatively recovered (Scheme 2). These experiments
Scheme 1
Scheme 2
the reaction mixture was quenched with saturated NH4Cl
solution, and the N-sulfinyl amino phosphonates 2 were
isolated by flash chromatography.
(14) Sawamura, M.; Hamashima, H.; Ito, Y. Bull. Chem. Soc. Jpn. 2000,
73, 2559.
(15) Kuwano, R.; Nishio, R.; Ito, Y. Org. Lett. 1999, 1, 839.
(16) The chiral HPLC separation of (+)-1-(amino-1-phenylethyl)phos-
phonic acid (41%) has been reported; see: Zarbl, E.; Lammerhofer, M.;
Hammerschmidt, F.; Wuggenig, F.; Hanbauer, M.; Maier, N. M.; Sajovic,
L.; Lindner, W. Anal. Chim. Acta 2000, 404, 169.
(17) For leading references, see: Davis, F. A.; Lee, S.; Zhang, H.; Fanelli,
D. L. J. Org. Chem. 2000, 65, 8704.
suggest that addition of metallo phosphites to ketosulfin-
imines at -78 °C is under kinetic control and may be a
consequence of the amino anion stabilizing ability of the
N-sulfinyl group.20 However, at higher temperatures revers-
ibility cannot be ruled out since decomposition occurs.
1758
Org. Lett., Vol. 3, No. 11, 2001

Because there is confusion in the literature regarding the
stereochemistry for addition of metallo phosphites to sulfin-
imines (vide infra) it was necessary to rigorously establish
the absolute stereochemistry of our amino phosphonate
products 2. The stereochemistry of (-)-2d was determined
to be (SS,R) by single-crystal X-ray analysis. The reasonable
assumption is that the stereochemistry of 2a-c and 2e-g
are also (R).
Scheme 4
The N-sulfinyl group in 2b, 2e, and 2f was selectively
removed, in excellent yield, to give the corresponding amino
phosphonate esters 4 (Scheme 3). Phosphonate esters are
Scheme 3
to rationalize the chiral recognition for addition of organo-
metallic reagents to sulfinimines. Enolates, Grignard reagents
(allyl and alkyl), DIBAL-H, Et2AlCN, and lateral lithiated
amides and nitriles are all believed to react with sulfinimines
via six-membered chairlike transition states where the metal
ion is chelated to the sulfinyl oxygen.21-23 On the other hand,
steric arguments have been evoked to explain the stereo-
chemical preference for additions of benzyl Grignard,24
R-metallo phosphonates,25 chloromethyl phosphonate an-
ions,26 1,3-dipoles,27 and glycine iminoester enolates28 to
sulfinimines. The situation is less clear for additions of
metallo phosphites. For example, Lefebvre and Evans
reported that lithium diethyl phosphite affords the (SS,S)
diastereoisomer on addition to aldehyde-derived sulfin-
imines.29 It was suggested that the preferred product results
from coordination of the Li ion to the nitrogen lone pair with
delivery of the phosphorus atom to the carbon center from
the face opposite the sulfinyl oxygen. For similar substrates
Mikolajczyk et al. reported the major diastereoisomer as
(SS,R) but gave no rationalization.19 To resolve these issues
we repeated the results of Lefebvre and Evans, adding lithium
diethyl phosphite to (S)-(+)-N-(benzylidene)-p-toluenesul-
finamide (9) and obtained (+)-10 as described by these
authors, to which they had assigned the (SS,S) configuration
on the basis of a literature reference (Scheme 5).2 However,
we found that hydrolysis of (+)-11 with 8 N HCl furnished-
(+)-R-amino (phenylmethyl)phosphonic acid (12) having the
(R)-configuration.30 We conclude that the earlier literature29
often preferred over the free acids because further elaboration
of latter can be problematic; they are insoluble in H2O and
common organic solvents.2 The acids 5 were obtained by
refluxing 2 with 10 N HCl. They were isolated, following
concentration, by dissolving the residue in hot EtOH and
precipitating the acid with propylene oxide. Racemization
is unlikely as a result of the quaternary nature of 4, and the
stereochemistry was confirmed by converting (R)-(+)-5b into
the methyl ester (R)-(+)-6 with diazomethane and comparing
it to that prepared independently from (+)-3 (Scheme 3).
Attempts to prepare the Mosher amide of (+)-5 failed.
The opposite sense of stereoinduction is reported to occur
on addition of diamido phosphites to aldehyde-derived
sulfinimines.19 Using the standard protocol, (SS)-(+)-1b and
lithium bis(N,N-diethylamino)phosphite afforded (-)-7 in
78% yield and >95% de (Scheme 4). Unfortunately, attempts
to hydrolyze 7 to the acid to establish its absolute configu-
ration was unsuccessful under a variety of conditions, and
decomposition occurred. For example, stirring with 6 N HCl
for 8 h produced a phosphorous acid and 4′-methylaceto-
phenone (8) in 42% and 51% yields, respectively
(21) Davis, F. A.; Andemichael, Y. W. J. Org. Chem. 1999, 64, 8627
and references therein.
(22) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W.
Org. Lett. 2000, 2, 3901.
(23) Chan, W. H.; Lee, A. W. M.; Xia, P. F.; Wong, W. Y. Tetrahedron
Lett. 2000, 41, 5725.
(24) (a) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396. (b)
Bravo, P.; Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron Lett. 1998,
39, 7771.
With regard to the participation of the stereogenic sulfinyl
group, steric and chelation-control arguments have been used
(25) Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J.; Wieczorek, M. W.;
Blaszczyk, J. Chem. Commun. 1996, 1503.
(18) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1403. (b) Fanelli, D. L.; Szewczyk,
J. M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A. Org. Synth.
1999, 77, 50.
(19) Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J. Tetrahedron: Asymmetry
1997, 8, 3991.
(20) For reviews on the chemistry of sulfinimines, see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. Syntheses and Reactions of Sulfinimines. In
AdVances in Sulfur Chemistry; Rayner, C. M., Ed.; JAI Press: Stamford,
CT, 2000; Vol 2; pp 249-282. (b) Hua, D. H.; Chen, Y.; Millward, G. S.
Sulfur Reports 1999, 21, 211. (c) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem.
Soc. ReV. 1998, 27, 13.
(26) (a) Davis, F. A.; McCoull, W., Titus, D. D. Org. Lett. 1999, 1,
1053. (b) Davis, F. A.; McCoull, W. Tetrahedron Lett. 1999, 40, 249.
(27) Viso, A.; de la Pradilla, R. F.; Guerrero-Strachan, C.; Alonso, M.;
Martinez-Ripoll, M.; Andre, I. J. Org. Chem. 1997, 62, 2316.
(28) Viso, A.; de la Pradilla, R. F.; Garcia, A.; Alonso, M.; Guerrero-
Strachan, C.; Fonseca, I. Synlett 1999, 1543.
(29) Lefebvre, I. M.; Evans, S. A., Jr. J. Org. Chem. 1997, 62, 7532.
(30) The absolute configuration of (R)-(+)-R-amino (phenylmethyl)-
phosphoninc acid (12) was established by X-ray crystallography: Glowiak,
T.; Sawka-Dobrowolski, W.; Kowalik, J.; Mastalerz, P.; Soroka, M.; Zon,
J. Tetrahedron Lett. 1977, 3965.
Org. Lett., Vol. 3, No. 11, 2001
1759

Scheme 5
Scheme 6
oxygens in a seven-membered twisted chairlike transition
state.33 By contrast the twisted-chair transition state leading
to the minor product has the bulky aryl and p-tolyl groups
in the energetically unfavorable axial positions. This model
can also be extended to the addition of phosphite to aldehyde-
derived sulfinimines.
In summary, the first asymmetric synthesis of quaternary
R-alkyl R-amino (arylmethyl)phosphonates was accom-
plished by the highly diastereoselective addition of lithium
diethylphosphonate to enantiopure ketosulfinimines. For the
addition of metal phosphites to sulfinimines, a unified
asymmetric induction model involving coordination of the
metal ion to both the sulfinyl and phosphonate oxygens in a
seven-membered twisted chairlike conformation is proposed.
was in error and that (+)-10 and (+)-11 have the (SS,R)-
and (R)-configuration, respectively.31
Resolution of this inconsistency means that metallo
phosphite addition to aldehyde- and ketone-derived (S)-
sulfinimines occurs with the same sense, re-face addition,
and it is now possible to put forth a unified model for these
additions. It is worth noting that this same sense of addition
is also observed for the analogous addition of CN in the
sulfinimine-mediated Strecker synthesis, as well as for most
organometallic reagents. In these examples coordination of
the metal ion to the sulfinyl oxygen is thought to play a
central role. On the basis of these considerations and
assuming that the sulfinimine has the favored E geometry,32
a plausible rationalization for the preferential formation of
(SS,R)-2 is depicted in Scheme 6. In this representation the
lithium cation is chelated to the sulfinyl and phosphite
Acknowledgment. We appreciate helpful discussions
with Professor A. B. Smith III, University of Pennsylvania.
This work was supported by a grant from the National
Institutes of Health (GM57870).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all compounds and X-ray
data for (-)-2d. This material is available free of charge
via the Internet at http://pubs.acs.org.
(31) Upon re-analysis Smith et al. have confirmed that the configuration
assigned to the phospho-phenylglycine derivatives (+)-12 is indeed R.
Ambiguous representation of the C1 (R carbon) stereochemistry reported
by Soroka and co-workers (ref 30) allowed this error to go previously
undetected.
OL015945F
(32) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555.
(33) For a discussion of the conformations of cycloheptanes, see: Bocian,
D. F.; Pickett, H. M.; Rounds, T. C.; Strauss, H. L. J. Am. Chem. Soc.
1975, 97, 687.
1760
Org. Lett., Vol. 3, No. 11, 2001