Synthesis of α-Amino Acids via a Carbolithiation Reaction on Acyclic Ene-Carbamates and an Internal N→C Alkyloxycarbonyl Migration

Abstract

A novel and efficient synthesis of precursors of α-amino acids is described. The key step involves a carbolithiation reaction on acyclic ene-carbamates generated from the corresponding vinylphosphates via a palladium cross-coupling reaction followed by a spontaneous internal N→C alkyloxycarbonyl migration.

non-natural amino acids - carbolithiation - ene-carba­mate - vinyl phosphate - alkyloxycarbonyl migration

References and Notes

<A NAME="RD09907ST-1A">1a</A> Williams RH. The Synthesis of Optically Active α-Amino Acids   Pergamon; New York: 1989. 

<A NAME="RD09907ST-1B">1b</A> Giannis A. Kolter T. Angew. Chem., Int. Ed. Engl.  1993,  32:  1244 

<A NAME="RD09907ST-1C">1c</A> Duthaler RO. Tetrahedron  1994,  50:  1539 

<A NAME="RD09907ST-1D">1d</A> Moutevelis-Minakakis P. Sinanoglou C. Loukas V. Kokotos G. Synthesis  2005,  933 

<A NAME="RD09907ST-2A">2a</A> Clayden J. Organolithiums: Selectivity for Synthesis   Pergamon; Oxford, UK: 2002.  p.273 

<A NAME="RD09907ST-2B">2b</A> Review: Mealy MJ. Bailey WF. J. Organomet. Chem.  2002,  646:  59 

<A NAME="RD09907ST-2C">2c</A> Cottineau B. O’Shea DF. Tetrahedron Lett.  2005,  46:  1935 

<A NAME="RD09907ST-3A">3a</A> Peters JG. Seppi M. Fröhlich R. Wibbeling B. Hoppe D. Synthesis  2002,  381 

<A NAME="RD09907ST-3B">3b</A> Norsikian S. Marek I. Poisson J.-F. Normant JF. J. Org. Chem.  1997,  62:  4898 

<A NAME="RD09907ST-3C">3c</A> Superchi S. Sotomayor N. Miao G. Joseph B. Campbell MG. Snieckus V. Tetrahedron Lett.  1996,  37:  6061 

<A NAME="RD09907ST-4A">4a</A> Klumpp GW. Recl. Trav. Chim. Pays-Bas  1986,  105:  1 

<A NAME="RD09907ST-4B">4b</A> Klein S. Mareck I. Normant J.-F. J. Org. Chem.  1994,  59:  2925 

<A NAME="RD09907ST-4C">4c</A> Mück-Lichtenfeld C. Ahlbrecht H. Tetrahedron  1996,  52:  10025 

<A NAME="RD09907ST-5A">5a</A> Marek I. Normant JF. Chem. Rev.  1996,  96:  3241 

<A NAME="RD09907ST-5B">5b</A> Beak P. Meyers AI. Acc. Chem. Res.  1986,  19:  356 

<A NAME="RD09907ST-6">6</A> Lepifre F. Cottineau B. Mousset D. Bouyssou P. Coudert G. Tetrahedron Lett.  2004,  483 

<A NAME="RD09907ST-7A">7a</A> Mousset D. Gillaizeau I. Hassan J. Lepifre F. Bouyssou P. Coudert G. Tetrahedron Lett.  2005,  21:  3703 

<A NAME="RD09907ST-7B">7b</A> Mousset D. Gillaizeau I. Bouyssou P. Coudert G. J. Org. Chem.  2006,  71:  5993 

<A NAME="RD09907ST-7C">7c</A>

Claveau, E.; Gillaizeau, I.; Blu, J.; Bruel, A.; Coudert, G. J. Org. Chem. 2007, accepted.

<A NAME="RD09907ST-8">8</A> Other strategy for the preparation of similar derivatives (N-acyl-α-arylvinylamines), see: Hansen AL. Skrydstrup T. J. Org. Chem.  2005,  70:  5997 ; and references cited therein

<A NAME="RD09907ST-9">9</A>

Representative Procedure for the Preparation of 7a-l
A solution of acyclic ene-carbamate 4a (0.100 g, 0.34 mmol) in THF (10 mL) was cooled to -78 °C under argon. Sub-sequently, MeLi (0.450 mL, 1.4 M in hexane, 0.71 mmol) was added dropwise. After stirring for 30 min at -78 °C, the reaction mixture was warmed up to 0 °C. After 1 h at 0 °C, the reaction was quenched by slow addition of H₂O. The aqueous phase was then extracted with EtOAc and the organic phase was washed with brine. The organic phase was dried over anhyd MgSO₄ and concentrated. Flash chromatography (PE-EtOAc, 98:2) afforded 7a (75%) as a white solid; mp 109-110 °C. IR (KBr): 3419, 2980, 1720, 1599, 1504, 1158 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 7.56 (d, J = 7.6 Hz, 2 H), 7.20-7.32 (m, 3 H), 6.95 (t, J = 7.8 Hz, 2 H), 6.57 (t, J = 7.6 Hz, 1 H), 6.35 (d, J = 7.8 Hz, 2 H), 5.35 (br s, 1 H), 2.51 (m, 2 H), 1.30 (s, 9 H), 0.84 (t, J = 7.2 Hz, 3 H). ¹³C NMR (62.9 MHz, CDCl₃): δ = 173.0 (s), 144.8 (s), 141.6 (s), 129.0 (d), 128.6 (d), 127.4 (d), 127.2 (d), 117.2 (d), 115.1 (d), 82.5 (s), 67.1 (s), 27.9 (q), 25.8 (t), 8.6 (q). MS (IS): m/z = 312 [M + 1]⁺.

<A NAME="RD09907ST-10A">10a</A> Houk KN. Rondan NG. Schleyer PVR. Kaufman E. Clark T. J. Am. Chem. Soc.  1985,  107:  2821 

<A NAME="RD09907ST-10B">10b</A> Bailey WF. Khnaolkar AD. Gavaskar K. Ovaska TV. Rossi K. Thiel Y. Wiberg KB. J. Am. Chem. Soc.  1991,  113:  5720 

<A NAME="RD09907ST-11">11</A> N→C Acyl migration: Rouden J. Ragot A. Gouault S. Cahard D. Plaquevent J.-C. Lasne M.-C. Tetrahedron: Asymmetry  2002,  13:  1299 

<A NAME="RD09907ST-12">12</A>

Analytical Data for 8
Brown solid; mp 72-73 °C. IR (KBr): 3404, 2967, 2933, 1600, 1498, 1491, 1446 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 7.24-7.29 (m, 5 H), 6.97-7.04 (m, 2 H), 6.59-6.66 (m, 1 H), 6.36-6.40 (m, 2 H), 4.00 (d, J = 11.0 Hz, 1 H), 3.91 (d, J = 11.0 Hz, 1 H), 2.05-2.16 (m, 1 H), 1.90-2.01 (m, 1 H), 0.79 (t, J = 7.6 Hz, 3 H). ¹³C NMR (62.9 MHz, CDCl₃): δ = 145.2 (s), 142.8 (s), 129.0 (d), 128.7 (d), 127.0 (d), 126.7 (d), 117.7 (d), 115.4 (d), 65.3 (s), 62.5 (s), 30.5 (s), 8.1 (q). MS (IS): m/z = 242 [M + 1]⁺.