Highly Stereoselective Reduction of β-Keto Amides: The First General and Efficient Approach to N-mono- and non-Substituted anti-α-Alkyl β-Hydroxy Amides

Abstract

The first general protocol for the anti-selective reduction of α-alkyl-β-keto amides is described. This simple and efficient methodology based on an open-chain Felkin-Anh model pathway, allows the isolation of N-mono- and non-substituted anti-α-substituted β-hydroxy amides in good yields and with high diastereo­selectivity.

stereoselectivity - β-keto amides - reduction - anti-β-hydroxy amides - Felkin-Anh model

References

For some reviews, see:

1a Heathcock CH. In Asymmetric Synthesis   Part B, Vol. 3:  Morrison JD. Academic Press; New York: 1984.  Chap. 2.

1b Kim BM. Williams SF. Masamune S. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991.  Chap. 1. p.239 

1c Evans DA. Nelson JV. Taber TR. Top. Stereochem.  1982,  13:  1 

1d Heathcock CH. Science  1981,  214:  395 

For recent direct catalytic asymmetric aldol reactions, see:

2a Northrup AB. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  6798 

2b List B. Lerner RA. Barbas CF. J. Am. Chem. Soc.  2000,  122:  2395 

2c Yoshikawa N. Kumagai N. Matsunaga S. Moll G. Oshima T. Suzuki T. Shibasaki M. J. Am. Chem. Soc.  2001,  123:  2466 

2d Trost BM. Ito H. J. Am. Chem. Soc.  2000,  122:  12003 

3 Greeves N. In Comprehensive Organic Synthesis   Vol. 7:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991.  p.1 

4a a-Alkyl b-hydroxy sulfones: Bartoli G. Bosco M. Cingolani S. Marcantoni E. Sambri L. J. Org. Chem.  1998,  63:  3624 

4b a-Alkyl b-hydroxy esters: Marcantoni E. Alessandrini S. Malavolta M. Bartoli G. Bellucci MC. Sambri L. Dalpozzo R. J. Org. Chem.  1999,  64:  1986 

4c a-Alkyl b-hydroxy ketones: Bartoli G. Bellucci MC. Bosco M. Dalpozzo R. Marcantoni E. Sambri L. Chem.-Eur. J.  2000,  14:  2590 

4d a-Alkyl b-hydroxy carbonitriles: Dalpozzo R. Bartoli G. Bosco M. De Nino A. Procopio A. Sambri L. Tagarelli A. Eur. J. Org. Chem.  2001,  2971 

5 Wild H. Kant J. Walker DG. Ojima I. Ternansky RJ. Morin JM. Georg GI. Ravikumar VT. In The Organic Chemistry of β-lactams   Georg GI. VCH Publishers; New York: 1993. ; and references therein

6a Mead KT. Park M. Tetrahedron Lett.  1995,  36:  1205 

6b Brown HC. Kulkarni SV. Racherla US. J. Org. Chem.  1994,  59:  365 

6c Hanessian S. Tehim A. Chen P. J. Org. Chem.  1993,  58:  7768 

7 Oishi T. Nakata T. Acc. Chem. Res.  1984,  17:  338 

8a For a synthesis of anti-N-mono- and non-substituted β-hydroxy amides via 2-iminooxetane, see: Barbaro G. Battaglia A. Giorgianni P. J. Org. Chem.  1992,  57:  5128 

8b For a recent asymmetric approach, see: Kitagawa O. Momose S.-i. Yamada Y. Shiro M. Taguchi T. Tetrahedron Lett.  2001,  42:  4865 

9 Ito Y. Katsuki T. Yamaguchi M. Tetrahedron Lett.  1985,  26:  4643 

10a Fujita M. Hiyama T. J. Am. Chem. Soc.  1985,  107:  8294 

10b Fujita M. Hiyama T. J. Org. Chem.  1988,  53:  5405 

For diastereoselective syntheses of N-disubstituted syn- or anti-β-hydroxy amides, see:

11a Ganesan K. Brown HC. J. Org. Chem.  1994,  59:  7346 

11b Denmark SE. Griedel BD. Coe DM. Schnute ME. J. Am Chem. Soc.  1994,  116:  7026 

11c Evans DA. Tedrow JS. Shaw JT. Downey CW. J. Am Chem. Soc.  2002,  124:  392 

11d Evans DA. Downey CW. Hubbs JD. J. Am Chem. Soc.  2003,  125:  8706 

The syn-reduction of β-keto amides is based on the preliminary formation of a chelate complex intermediate; see:

12a Bartoli G. Bosco M. Dalpozzo R. Marcantoni E. Massaccesi M. Rinaldi S. Sambri L. Tetrahedron Lett.  2001,  42:  8811 

12b Fujita M. Hiyama T. J. Org. Chem.  1988,  53:  5415 

12c Taniguchi M. Fujii H. Oshima K. Utimoto K. Tetrahedron  1993,  49:  11169 

13a Chérest M. Felkin H. Prudent N. Tetrahedron Lett.  1968,  2199 

13b Anh NT. Einsenstein O. Nouv. J. Chem.  1977,  1:  61 

14a Bürgi HB. Dunitz JD. Shefter EJ. J. Am. Chem. Soc.  1973,  95:  5065 

14b Bürgi HB. Dunitz JD. Lehn JM. Wipff G. Tetrahedron  1974,  30:  1563 

14c Bürgi HB. Lehn JM. Wipff G. J. Am Chem. Soc.  1974,  96:  1956 

15 Bartoli G. Bosco M. Dalpozzo R. Marcantoni E. Sambri L. Chem.-Eur. J.  1997,  3:  1941 ; for related systems, see ref. 4

16 Evans DA. Ennis MD. Le T. J. Am Chem. Soc.  1984,  106:  1154 

17 The use of a less hindered silylating agent results in a reduced anti-selectivity of the process. This is consistent with a Felkin-Anh model in which the presence of a bulky group on the oxygen of the intermediate 3 (Scheme 2) promotes the selective approach of the hydride anion to the b-carbonyl from the opposite side. For the importance of using bulky silylated reagents to effectively prevent chelation, see: Chen X. Hortelano ER. Eliel EL. J. Am Chem. Soc.  1990,  112:  6130 

18

Compound 4a was isolated by chromatography (pentane/Et₂O) in 87% yield, anti/syn>99/1. ¹H NMR (300 MHz, CDCl₃): δ = 0.86 (d, 3 H, J _HH = 7.2 Hz), 0.90-1.00 (m, 21 H), 2.45-2.50 (m, 1 H), 2.79 (d, 3 H, J _HH = 4.8 Hz), 4.91 (d, 1 H, J _HH = 7.8 Hz), 5.80 (br s, 1 H, NH), 7.20-7.35 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 12.3 (CH), 14.1 (CH₃), 17.7 (CH₃), 17.8 (CH₃), 26.0 (CH₃), 50.5 (CH), 77.4 (CH), 126.9 (CH), 127.5 (CH), 127.8 (CH), 142.7 (C), 175.1 (C).

19

A typical case is reported: ( R *, S *)-2-ethyl-3-hydroxy- N -methylhexanamide ( 2h). [20] The title compound was isolated by column chromatography (CH₂Cl₂/EtOAc) as a white solid (mp = 135-137 °C); yield 77%; anti/syn = 99/1. ¹H NMR (300 MHz, CDCl₃): δ = 0.85-0.95 (m, 6 H, 2 × CH₃), 1.30-1.55 (m, 4 H), 1.55-1.70 (m, 1 H, CH₂), 1.70-1.85 (m, 1 H, CH₂), 1.95-2.05 (m, 1 H, CH), 2.80 (d, 3 H, CH₃, J _HH = 4.8 Hz), 3.00 (bs, 1 H, OH), 3.60-3.70 (m, 1 H, CH), 6.00 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 12.0 (CH₃), 14.0 (CH₃), 19.2 (CH₂), 23.6 (CH₂), 25.9 (CH₃), 38.2 (CH₂), 53.5 (CH), 71.9 (CH), 176.2 (C). Anal. Calcd for C₉H₁₉NO₂: H, 11.05; C, 62.39; N, 8.08. Found: H, 11.36; C, 62.18; H, 7.90.

20

Descriptors R*, S* indicate that diastereomeric compounds are obtained as racemates. We prefer this terminology to avoid the ambiguities that could arise from syn-anti descriptors.