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Synlett 2009(10): 1635-1638  
DOI: 10.1055/s-0029-1217192
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© Georg Thieme Verlag Stuttgart ˙ New York

Catalytic Asymmetric Synthesis of Nitrogen-Containing gem-Bisphosphonates Using a Dinuclear Ni2-Schiff Base Complex

Yuko Kato, Zhihua Chen, Shigeki Matsunaga*, Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Fax: +81(3)56845206; e-Mail: mshibasa@mol.f.u-tokyo.ac.jp; e-Mail: smatsuna@ mol.f.u-tokyo.ac.jp;
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Publication History

Received 30 January 2009
Publication Date:
02 June 2009 (online)

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Abstract

A catalytic asymmetric synthesis of nitrogen-containing gem-bisphoshonates is described. A Lewis acid-Brønsted base bifunctional homodinuclear Ni2-Schiff base complex promoted catalytic enantioselective conjugate addition of nitroacetates to ethylidenebisphosphonates, giving products in up to 93% ee and 94% yield. Transformation of the product into a chiral α-amino ­ester with a gem-bisphosphonate moiety is also described.

Key words

asymmetric catalysis - asymmetric synthesis - bisphosphonates - Michael addition

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12

To demonstrate the stability of the Ni2-Schiff base 1 complex, the catalyst stored for 3 months was used in this study. Freshly prepared Ni2-Schiff base 1 complex showed comparable reactivity and enantioselectivity. For more detailed information of the Ni2-Schiff base 1 complex, see ref. 10c.

13

The absolute configuration of 6 was determined by comparing the sign of optical rotation with the literature data in ref. 4b. The enantiofacial selectivity of β-keto ester was same as that observed in the asymmetric Mannich-type reaction of β-keto ester using the Ni2-Schiff base 1 complex. The absolute configurations of 4 were tentatively assigned in analogy based on the enantiofacial selectivity of nitroacetate 3b in the asymmetric Mannich-type reactions.

15

General Procedure
5 Å MS (Fluka, powder, 20 mg) in a test tube was flame-dried prior to use under vacuum for 5 min. After cooling down to r.t., argon gas was refilled, and the Ni2-Schiff base 1 catalyst (6.4 mg, 0.01 mmol) and toluene (333 µL) were added. The mixture was cooled down to 0 ˚C, and nitro-acetate 3b (15.9 µL, 0.11 mmol) was added to the mixture. After stirring for 15 min at 0 ˚C, ethylidenebisphosphonate 2a (27.5 µL, 0.1 mmol) was added. The reaction mixture was stirred for 24 h at 0 ˚C. The mixture was filtered through a short pad of SiO2 (eluent: hexane-acetone = 1:3). The combined filtrate was concentrated under reduced pressure, and the residue was purified by SiO2 column chromatography (hexane-acetone = 4:1 to 2:1) to afford 4ab (39.7 mg, 0.083 mmol, 83% yield) as a colorless oil.
Compound 4ab: colorless oil. IR(neat): ν = 3473, 2982, 1746, 1555, 1251, 1023 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 1.29-1.40 (m, 12 H), 1.46 (s, 9 H), 1.76 (s, 3 H), 2.36-2.50 (m, 1 H), 2.77-3.01 (m, 2 H), 4.06-4.26 (m, 8 H). ¹³C NMR (125 MHz, CDCl3): δ =14.8, 16.1-16.4 (m), 19.0, 29.4, 30.3 (t, J = 154.0 Hz), 62.9-63.1 (m), 82.8, 90.6, 164.2. ³¹P NMR (202 MHz, CDCl3): δ = 20.4, 21.4. ESI-MS: m/z = 498 [M + Na]+. HRMS: m/z calcd for C17H36NO10P2 [M + H]+: 475.1814; found: 476.1811; [α]D ²².5 -19.8 (c 0.80, CHCl3). HPLC [DAICEL CHIRALPAK AD-H, hexane-
2-PrOH (95:5), flow 1 mL/min, detection at 210 nm]: t R = 21.8 min (major)and 20.2 min (minor).