R-carbon, several approaches to enantioenriched R-amino-
phosphonic acids have been reported, which include re-
solution and chiral auxiliary based asymmetric synthesis.11
However, the catalytic asymmetric approaches12 based on
hydrophosphonylation of imines,13 nucleophilic addition
to or hydrogenation of R-iminophosphonates,14 electro-
philic amination of R-phosphonate carbanions,15 and
nucleophilic addition of phosphonate analogues of glycine
to electrophiles16,17 were more appealing. However, to our
knowledge, the generation of quaternary R-carbon centers
via catalytic asymmetric synthesis of R-amino phosphonic
acids remains scarcely explored.15,17
bis(binaphthoxide).19 Herein we report an organocata-
lyzed enantioselective synthesis of quaternary R-nitrophos-
phonates via Michael addition of R-nitrophosphonates to
enones using a new alkaloid derived thiourea catalyst.
Selected transformations of the quaternary R-nitrophos-
phonates to cyclic quaternary R-aminophosphonates are
also reported here.
As part of our ongoing research program on the stereo-
selective synthesis of aminophosphonates, we have re-
ported the diastereo- and enantioselective synthesis of
γ-nitrophosphonates via Michael addition of R-lithiated
phosphonates to nitroalkenes using cinchonine as the chiral
catalyst.18 Enantioenriched β-nitrophosphonates have also
been synthesized via Michael addition of dialkyl phosphites
to nitroalkenes in the presence of (S)-(À)-aluminum lithium
(11) For recent reviews: (a) Alfonsov, V. A. Phosphorus Sulfur
Silicon Relat. Elem. 2008, 183, 2637. (b) Kolodiazhnyi, O. I. Tetrahe-
dron: Asymmetry 1998, 9, 1279. For recent chiral auxiliary approaches:
(c) Kaur, P.; Wever, W.; Rajale, T.; Li, G. Chem. Biol. Drug. Des. 2010,
76, 314. (d) Palacios, F.; Olszewski, T. K.; Vicario, J. Org. Biomol. Chem.
2010, 8, 4255.
ꢀꢁ
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(13) (a) For a recent review: Merino, P.; Marques-Lopez, E.; Herrera,
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M.; Hirata, T. Tetrahedron 2009, 65, 4950. (i) Shi, F.-Q.; Song, B.-A.
Org. Biomol. Chem. 2009, 7, 1292. (j) Nakamura, S.; Nakashima, H.;
Yamamura, A.; Shibata, N.; Toru, T. Adv. Synth. Catal. 2008, 350, 1209.
(k) Alfonsov, V. A.; McKenna, C. E.; Bayandina, E. V.; Kashemirov,
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Angew. Chem., Int. Ed. 2008, 47, 5079. (m) Wilt, J. C.; Pink, M.;
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Goulioukina, N. S.; Bondarenko, G. N.; Lyubimov, S. E.; Davankov,
V. A.; Gavrilov, K. N.; Beletskaya, I. P. Adv. Synth. Catal. 2008, 350,
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Figure 1. Bifunctional organocatalysts screened.
In order to identify suitable reaction conditions, at the
outset, the asymmetric Michael addition of nitrophospho-
nate 2a20 to enone 1a21 was carried out in toluene at rt in
the presence of 10 mol % of catalysts C1ÀC8 (Figure 1 and
Table 1).22 The reaction in the presence of primary amines
C1 and C2 provided quaternary R-nitrophosphonate 3a in
good yield but poor selectivity (Table 1, entries 1À2). The
reaction remained incomplete even after 3 days when the
L-proline derived thiourea catalyst C3 was employed
(Table 1, entry 3). Subsequently, alkaloid based bifunc-
tional catalysts C4ÀC8 possessing a strong Lewis basic
moiety, such as quinuclidine, to activate the nitrophos-
phonate 2a, and a Brønsted acidic moiety, such as thiourea,
to activate the Michael acceptor enone 1a, were screened
(Table 1, entries 4À14).
Although the selectivity remained low with C4ÀC6
(26À31% ee, Table 1, entries 4À6), better selectivity was
(20) For general procedure for the preparation of nitrophosphonates
2: Zon, J. Synthesis 1984, 661. Also see the Supporting Information.
(21) For general procedure for the preparation of enones 1: Kundu,
N. G.; Dasgupta, S. K.; Chaudhuri, L. N.; Mahanty, J. S.; Shahinian,
A. H. Eur. J. Med. Chem. 1993, 28, 473. Also see the Supporting
Information.
(22) (a) C1, C2, C4, and C5: Vakulya, B.; Varga, S.; Csampai, A.;
Soos, T. Org. Lett. 2005, 7, 1967. (b) C3: Cao, C. L.; Ye, M. C.; Sun,
X. L.; Tang, Y. Org. Lett. 2006, 8, 2901. (c) C6: Chen, R. J.; Cao, J. Y.;
Zou, Q. Y.; Tan, F.; Zhu, Y. X.; Xiao, J. W. Org. Biomol. Chem. 2010, 8,
1275.
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Reference 13n.
(18) (a) Reference 9d. (b) Rai, V.; Namboothiri, I. N. N. Tetrahedron:
Asymmetry 2008, 19, 767.
(19) Rai, V.; Namboothiri, I. N. N. Tetrahedron: Asymmetry 2008,
19, 2335.
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