Studies toward the Asymmetric Synthesis of α-Amino Phosphonic Acids via the Addition of Phosphites to Enantiopure Sulfinimines

Full text of DOI:10.1021/jo971394o

7532
J . Org. Chem. 1997, 62, 7532-7533
Communications
Stu d ies tow a r d th e Asym m etr ic Syn th esis
of r-Am in o P h osp h on ic Acid s via th e
Ad d ition of P h osp h ites to En a n tiop u r e
Su lfin im in es
Sch em e 1
Isabelle M. Lefebvre and Slayton A. Evans, J r.*
The William Rand Kenan, J r. Laboratories of Chemistry,
The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina, 27599-3290
noaluminum reagents,10 Grignard reagents,11 and sulfur
ylides12). Among the most recent and stereochemically
illustrative examples, lithium ester enolates were added
to sulfinimines to form â-amino esters in high diastereo-
selectivities and excellent yields.13 In addition, the
reactions of R-metallo phosphonates with sulfinimines
have exhibited high diastereoselectivities as well.14
Received J uly 29, 1997
R-Amino phosphonic acids 1 serve as important sur-
rogates for R-amino carboxylic acids and therefore exhibit
a range of intriguing biological attributes.1 They usually
act as antagonists in the metabolism of amino acids.
Furthermore, R-amino phosphonic acids are potential
antibacterial agents,2 exhibit neuroactive characteristics,3
and have been employed as anticancer drugs4 and
pesticides.5 Generally, the biological activities of R-amino
phosphonic acids strongly depend on the stereogenicity
at the carbon center R to the phosphorus atom. One such
example is the high antibacterial activity of alafosfalin,
[N-(L-alanyl)-L-1-aminoethyl]phosphonic acid [(S,R) di-
astereomer], as compared to that of the other diastere-
oisomers [i.e., (R,R), (S,S), and (R,S)].2 Also, the (R)-
enantiomer of the phosphonic acid analog of leucine (i.e.,
(R)-LeuP) is a more potent inhibitor of leucine aminopep-
tidase than the (S)-isomer.6 As a consequence, consider-
able research has been devoted to the asymmetric
synthesis of R-amino phosphonic acids during the past
decades.7
These intriguing findings prompted us to study the
asymmetric synthesis of R-amino phosphonic acids via
the addition of metallo phosphites 4 to enantiopure
sulfinimines 3. The use of chiral sulfinimines as accep-
tors presented several unique advantages: (a) com-
mercial availability of the chiral auxiliary, (b) diverse
electronic and steric properties of the chiral sulfinyl
auxiliary which may encourage metal binding and unique
organizational requirements for substrate/reagent ap-
proach (i.e., stereodirecting functional group), and (c) the
possibility for recycling the auxiliary.13a
Our synthetic strategy illustrating an enantioselective
approach to R-amino phosphonic acids involved the
addition of metallo phosphites to enantiomerically ho-
mogeneous and configurationally restricted sulfinimines.
Enantiopure sulfinimines have found wide utility as
precursors in the asymmetric synthesis of amines8 and,
particularly, R-amino acids by utilizing the stereodirect-
ing capability of the chiral sulfinyl moiety. They were
used as activated imine acceptors in the “conjugate
addition” of various nucleophiles (e.g., hydrides,9 orga-
Chiral sulfinimines 3 were synthesized according to the
procedure reported by Davis et al. (Scheme 1).8
The additions of lithium and sodium dialkyl phosphites
4 to sulfinimines 3 were performed at -78 °C in tetrahy-
drofuran (THF) solvent. After quenching with a satu-
rated solution of ammonium chloride and extraction with
ether, N-sulfinyl-R-amino phosphonates15 5 were ob-
tained in excellent diastereoselectivity in all cases (Scheme
2 and Table 1).
Isolation of the major isomer 5a followed by transfor-
mation to the target R-amino phosphonate 6a allowed
for the assignment of the (S)-configuration to the new
stereogenic carbon center. Removal of the N-sulfinyl
auxiliary of diastereomer 5a was achieved by acid-
promoted methanolysis according to the procedure re-
(1) Kafarski, P.; Lejczak, B. Phosphorus Sulfur Silicon Relat. Elem.
1991, 63, 193.
(2) (a) Allen, J . G.; Atherton, F. R.; Hall, M. J .; Hassal, C. H.;
Holmes, S. W.; Lambert, R. W.; Nisbet, L. J .; Ringrose, P. S. Nature
1978, 272, 56. (b) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J .
Med. Chem. 1986, 29, 29.
(3) Collins, J . F.; Dixon, A. J .; Badman, G.; de Sarro, G.; Chapman,
A. G.; Hart, G. P.; Meldrum, B. S. Neurosci. Lett. 1984, 51, 371.
(4) (a) Klenner, T.; Valenzuele-Paz, P.; Keppler, B. K.; Angres, G.;
Scherf, H. R.; Winger, F.; Schmal, D. Cancer Treat. Rev. 1990, 17, 253.
(b) Klenner, T.; Winger, F.; Keppler, B. K.; Krempien, B.; Schmal, D.
J . Cancer Res. Clin. Oncol. 1990, 116, 341.
(5) Evans, R. H.; Watkins, J . C. Life Sci. 1981, 28, 1303.
(6) Giannousis, P. P.; Bartlett, P. A. J . Med. Chem. 1987, 30, 1603.
(7) (a) For a recent review, see: Kukhar, V. P.; Soloshonok, V. A.;
Solodenko, V. A. Phosphorus Sulfur Silicon Relat. Elem., 1994, 92, 239.
(b) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J . Org. Chem. 1995,
60, 6656. (c) Smith, A. B., III; Yager, K. M.; Taylor, C. M. J . Am. Chem.
Soc. 1995, 117, 10879.
(10) (a) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y.-H. J .
Org. Chem. 1996, 61, 440. (b) Davis, F. A.; Reddy, R. E.; Portonovo, P.
S. Tetrahedron Lett. 1994, 35, 9351.
(11) (a) Hua, D. H.; Miao, S. W.; Chen, J . S.; Iguchi, S. J . Org. Chem.
1991, 56, 4. (b) Yang, T. K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.; J iang,
Y.-Z.; Mi, A.-Q.; J ong, T. T. J . Org. Chem. 1994, 59, 914.
(12) (a) Davis, F. A.; Zhou, P.; Liang, C.-H.; Reddy, R. E. Tetrahe-
dron: Asymmetry 1995, 6, 1511. (b) Garcia Ruano, J . L.; Fernandez,
I.; Hamdouchi, C. Tetrahedron Lett. 1995, 36, 295.
(13) (a) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M. J . Org. Chem.
1995, 60, 7037. (b) Davis, F. A.; Szewczyk, J . M.; Reddy, R. E. J . Org.
Chem. 1996, 61, 2222 and references therein.
(8) 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 and references therein.
(9) (a) Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J . Tetrahedron:
Asymmetry 1995, 6, 349. (b) Hose, D. R. J .; Mahon, M. F.; Molloy, K.
C.; Raynhan, T.; Wills, M. J . Chem. Soc., Perkin Trans. 1 1996, 691.
(14) Mikolajcyk, M.; Lyzwa, P.; Drabowicz, J .; Wieczorek, M. W.;
Blaszcyk, J . Chem. Commun. 1996, 1503.
(15) The structures of products 5a -c have been assigned by 1H, 13C,
and 31P NMR spectroscopic techniques. The diastereoselectivities were
determined by 31P NMR. All products 5a -c gave satisfactory elemental
analysis.
S0022-3263(97)01394-7 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 22, 1997 7533
Ta ble 1. Dia ster eoselective Ad d ition s of Meta llo P h osp h ites 4 to Su lfin im in es 3 a t - 78 °C in THF
entry
phosphite 4: R
phosphite 4: M
sulfinimine 3
product
yield (%)
dea (%)
1
2
3
4
5
Et
Et
Et
Et
Li
Na
Li
Na
Li
3a
3a
3b
3b
3a
5a
5a
5b
5b
5c
85
80
50
50
82
84
93
84
90
97
i-Pr
a
All diastereoselectivities were determined by 31P NMR.
Sch em e 2
Sch em e 4
Sch em e 3
ported by Mikolajczyk et al. (Scheme 3).16 The desulfi-
nylation reaction occurs without epimerization of the
stereogenic carbon atom R to the nitrogen atom in 5a .16
Purification via flash chromatography afforded homoge-
neous R-amino phosphonate 6a .
The absolute configuration of R-amino phosphonate 6a
was established via the comparison of the sign of its
optical rotation with that reported in the literature.7c
1
the reaction conditions. The H NMR resonance of the
imino proton (δ 8.75 ppm) of sulfinimine 3a was invariant
between -66 °C and +80 °C, suggesting that the barrier
attending the E to Z equilibration of sulfinimine 3a was
greater than that for the sulfinimine derived from 4,4′-
dimethylbenzophenone, assuming that both have similar
transition-state energies. On the basis of the potentially
higher steric hindrance between the bulky Ar and the
S(O)-p-tolyl substituents in the Z-isomer, one might
anticipate that the E-isomer would be thermodynamically
more stable since these interactions are minimized in this
isomer. Consequently, from these limited data we con-
cluded that sulfinimine 3a exists in the single E-isomeric
form, and the same conclusion was drawn for compound
3b.
Mech a n istic Ra tion a le. Sulfinimines derived from
ketones reportedly interconvert rapidly at ambient tem-
peratures (∆G‡ ) 13-17 kcal/mol).17 However, Davis et
al.8 reported that sulfinimines derived from aldehydes
exist in a single isomeric form. The E-configuration of
the imino bond in 3a was established by single-crystal
X-ray analysis, and the assumption was made that all
aldehyde-derived sulfinimines possessed a similar geom-
etry. While this generalization may be valid, it seemed
appropriate to establish the boundaries for considering
the relevance of E- vs. Z-configurational lability18 under
While several transition-state models may be ap-
plicable, the preferred formation of diastereomer (SS, SC)-
5a may be rationalized by assuming a coordination of the
metal atom (i.e., Li) to the nitrogen lone pair, facilitating
the delivery of the phosphorus atom to the prochiral
trigonal carbon center from the face opposite to the
sulfinyl oxygen atom (Scheme 4). Such a transition-state
model rationalizes the greater diastereoselectivity ob-
served in the addition of diisopropyl phosphite to sulfin-
imine 3, relative to diethyl phosphite.
In conclusion, we reported that the addition of metallo
phosphites to chiral sulfinimines occurs with high dias-
tereoselectivity. The application of this novel reaction
has been demonstrated with the asymmetric synthesis
of R-amino phosphonate esters.
(16) Mikolajzcyk, M.; Drabowicz, J .; Bujnicki, B. J . Chem. Soc.,
Chem. Commun. 1976, 568.
(17) (a) Davis, F. A.; Kluger, E. W. J . Am. Chem. Soc. 1976, 98, 302.
(b) Davis, F. A.; Friedman, A. J .; Kluger, E. W. J . Am. Chem. Soc.
1974, 96, 5000.
(18) (a) J ennings, W. B.; Wilson, V. E. in Acyclic Organonitrogen
Stereodynamics; Lambert, J . B., Takeuchi, Y., Eds.; VCH Publishers:
New York, 1992; Chapter 6, pp 177-243. (b) Two mechanisms are
proposed for the syn-anti (Z-E) topomerization in imino compounds:
planar inversion (lateral shift) at the imino nitrogen atom, and
180˚rotation about the CdN bond.18a The DNMR evidence18a indicates
that the planar inversion pathway has preference over the rotational
option. We speculate that the N-sulfinimines from ketones have higher
ground-state energies than N-sulfinimines derived from aldehydes.
Therefore, it seems reasonable that the E- to Z-activation energies
would be higher for the latter, assuming similar transition state
energies.
Ack n ow led gm en t. We are grateful to the National
Science Foundation for support of this research.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure and compound characterization data for compounds
5a -c (20 pages).
J O971394O