3470
J. Org. Chem. 1997, 62, 3470-3479
Transition Metal/Base-Catalyzed Aldol Reactions of Isocyanoacetic Acid Derivatives with Prochiral Ketones, a Straightforward Approach to Stereochemically Defined β,β-Disubstituted-β-hydroxy-r-amino Acids.1 Scope and Limitations Vadim A. Soloshonok,*,† Alexey D. Kacharov,‡ Dimitry V. Avilov,‡ Kohki Ishikawa,§ Nobuya Nagashima§ and Tamio Hayashi*,| National Industrial Research Institute of Nagoya, Hirate-cho 1-1, Kita-ku, Nagoya City, Aichi Prefecture 462, Japan, Institute of Bioorganic Chemistry and Petrochemistry, Ukrainian Academy of Sciences, Kiev 253160, Ukraine, Central Research Laboratories of Ajinomoto Co., Inc., Suzukicho, Kawasaki 210, Japan, and Department of Chemistry, Faculty of Science, Kyoto University, Sakyo, Kyoto 606-01, Japan Received December 13, 1996X
A systematic study of the transition metal/base-catalyzed aldol reactions of methyl isocyanoacetate with a wide range of prochiral ketones, giving rise to the 4-(methoxycarbonyl)-5,5-disubstituted2-oxazolines, has been made. The diastereoselectivity of these reactions was found to be influenced by a mix of several factors, including steric characteristic of the substituents, nature of the catalyst, electrostatic, and electron donor-acceptor type interactions. The former factor, a stereochemical discrimination between the substituents at the ketone carbon, was shown to be the most pronounced in controlling of the stereochemical outcome, which could be markedly improved with a proper choice of the catalyst. In particular, for the reactions of methyl isocyanoacetate with polyhaloalkyl aryl(alkyl) ketones, high diastereoselectivity (80-98% de) was achieved, thus allowing for straightforward and generalized access to the corresponding (2R*,3R*)-β,β-disubstituted-β-hydroxyR-amino carboxylic acid. Introduction Over the past 15 years the art of stereoselective aldol methodology has been advanced to the state that could rival enzymatic systems for the synthetic efficiency and control over relative and absolute stereochemistry of the products.2 However, the overwhelming majority of the strategies developed in this area are suitable for the additions to aldehydes, while the involvement of prochiral ketones in the stereoselective aldol reactions has yet to meet with such success.2,3 In particular, highly diastereoselective condensations between glycine R-anion equivalents and prochiral ketones are virtually unknown.4 It was recognized that poor electrophilicity and steric shielding of the carbonyl group, as well as greater difficulty in the stereodiscrimination between the two carbon-containing substituents in ketones, impose serious limitations on the control of chemo-, regio-, and stereoselective outcomes of the corresponding aldol addition
reactions. Apart from the methodological challenge, aldol reactions between the nucleophilic glycine equivalents and prochiral ketones attract our attention also because this approach would provide the most straightforward access to the sterically constrained β,β-disubstituted-βhydroxy-R-amino carboxylic acids, which are of exciting potential interest in the de novo design of peptides and peptidomimetics with specific conformational and physiological properties.5 Recently we have disclosed that trifluoromethyl ketones react with a Ni(II) complex of the Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone to afford the targeted aldol products in a highly diastereoselective manner (90-98% de) and in respected chemical yields (56-87%).6 Unfortunately, the scope of this approach was found to be limited to the reactions of the trifluoromethyl n-alkyl ketones, while sterically demanding aryl and sec-alkyl trifluoromethyl ketones and less electrophilic fluorine-free ketones failed to react with the Ni(II) complex.6c
†
National Industrial Research Institute of Nagoya. Ukranian Academy of Sciences. Central Research Laboratories of Ajinomoto Co. | Kyoto University. X Abstract published in Advance ACS Abstracts, May 1, 1997. (1) For preliminary communications, see: (a) Soloshonok, V. A.; Hayashi, T.; Ishikawa, K.; Nagashima, N. Tetrahedron Lett. 1994, 35, 1055. (b) Soloshonok, V. A.; Kacharov, A. D.; Avilov, D. V.; Hayashi, T. Tetrahedron Lett. 1996, 37, 7845. (2) For reviews of stereoselective aldol addition reactions, see: (a) Seebach, D. Angew. Chem. Int. Ed. Engl. 1990, 29, 1320. (b) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (c) Evans, D. A.; Nelson, J. V.; Taber, T. R. In Topics in Stereochemistry; Eliel, E. L., Allinger, N. L., Wilen, S. H., Eds.; Wiley Interscience: New York, 1982; Vol. 13, p 1. (d) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, Chapter 2. (e) Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic Synthesis. Additions to C-X π Bonds; Heathcock, C. H., Ed.; Pergamon Press: Oxford; 1991; Vol. 2, Part 2, pp 239-275. (f) Gennari, C. In Comprehensive Organic Synthesis. Additions to C-X π Bonds; Heathcock, C. H., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Part 2, pp 629-660. (g) Bach, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 417. (h) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317-416. (3) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24. ‡ §
S0022-3263(96)02340-7 CCC: $14.00
(4) For recent comprehensive reviews on asymmetric synthesis of R-amino acids, see: (a) Williams, R. M. Synthesis of Optically Active R-Amino Acids. In Organic Chemistry Series; Baldwin, J. E., Magnus, P. D., Eds.; Pergamon Press: Oxford, 1989; Vol. 7. (b) Duthaler, R. P. Tetrahedron 1994, 50, 1539. (5) (a) Peptide Chemistry: Design and Synthesis of Peptides, Conformational Analysis and Biological Functions; Hruby V. J.; Schwyzer, R., Eds.; Tetrahedron-Symposia-in-Print, 31; Tetrahedron 1988, 44, 661. (b) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244. (c) Robl, J. A.; Cimarusti, M. P.; Simpkins, L. M.; Weller, H. N.; Pan, Y. Y.; Malley, M.; DiMarco, J. D. J. Am. Chem. Soc. 1994, 116, 2348. (d) For general review on fluorine-containing amino acids, see: Fluorine-Containing Amino Acids. Synthesis and Properties; Kukhar, V. P.; Soloshonok, V. A., Eds.; Wiley: Chichester, 1994. R-Amino-β-hydroxy carboxylic acids are naturally occurring compounds. Some are proteinogenic and/or essential amino acids are involved in various physiological processes in living organisms; therefore, analogs of these amino acids are very interesting as biomedical tools or potential inhibitors. Other R-amino-β-hydroxy carboxylic acids are constituents of complex natural products such as cyclosporin, bouvardin, peptides, and glycopeptides, which usually possess high antibiotic activity. In addition, these amino acids are valuable precursors to β-lactam antibiotics.
© 1997 American Chemical Society
Transition Metal/Base-Catalyzed Aldol Reactions
Our experience in the aldol reactions clearly revealed that one serious obstacle to the successful condensation between a nucleophilic glycine equivalent and a ketone is the reversibility of the reaction, the equilibrium of which nearly entirely lies on the side of starting compounds. From this point of view, aldol-type reactions between isocyanoacetic acid derivatives and carbonyl compounds, one of the useful methods for preparing β-hydroxy-R-amino acids, hold an apparent advantage, as these condensations could proceed irreversibly, giving rise to the corresponding oxazolinecarboxylates.7 Moreover, these reactions were shown to be effectively catalyzed by certain transition metals that could allow for the rational influence of the regio- and diastereochemical outcomes of these transformations.8 This study gains also an additional impetus when considering the fact that for aldehyde series this method was brought to a high level of sophistication with the development of catalytic enantioselective synthesis of β-hydroxy-R-amino acids by use of a well-designed chiral ferrocenylbisphosphinegold(I)9,10 or -silver(I)11 catalyst. For the reactions of isocyanoacetic acid derivatives with prochiral ketones, only a handful of examples are extant.8,12 It was reported that certain alkyl R,β-alkenyl and R-chloroalkyl alkyl(aryl) ketones in the presence of Cu(I) (Cu2O, CuCl) smoothly react with the ethyl isocyanoacetate to afford a mixture of the corresponding trans/ cis-oxazolines with diastereoselectivity ranging from 0 to 80% de,12 while, under the similar reaction conditions, the condensation of acetophenone gives a 1 to 1 mixture of the diastereomeric products.8b In the work described here, following a systematic study, we have examined the diastereoselectivity of the transition metal/base-catalyzed reactions between methyl isocyanoacetate and a wide range of prochiral ketones 2a-z. Our study indicates that the stereochemical outcome of these reactions is influenced by a mix of several factors, including steric characteristic of the ketone substituents, the nature of the catalyst (metal and (6) (a) Soloshonok, V. A.; Kukhar’, V. P.; Galushko, S. V.; Svistunova, N. Yu.; Avilov, D. V.; Kuz’mina, N. A.; Raevski, N. I.; Struchkov, Yu. T.; Pysarevsky A. P.; Belokon’ Yu. N. J. Chem. Soc., Perkin Trans. 1 1993, 3143. (b) Soloshonok, V. A.; Avilov, D. V.; Kukhar’, V. P. Tetrahedron: Asymmetry 1996, 7, 1547. (c) Soloshonok, V. A.; Avilov, D. V.; Kukhar’, V. P. Tetrahedron 1996, 52, 12433. (7) For reviews: (a) Schollkopf, U. Angew. Chem., Int. Ed. Engl. 1977, 16, 339. (b) Matsumoto, K.; Moriya, T.; Suzuki, M. J. Synth. Org. Chem., Jpn. 1985, 43, 764. (8) (a) Ito, Y.; Matsumura, T.; Saegusa, T. Tetrahedron Lett. 1985, 26, 5781. (b) Saegusa, T.; Ito, Y.; Kinoshita, H.; Tomita, S. J. Org. Chem. 1971, 36, 3316, and references cited therein. (9) (a) Soloshonok, V. A.; Kacharov, A. D.; Hayashi, T. Tetrahedron 1996, 52, 245. (b) Soloshonok, V. A.; Hayashi, T. Tetrahedron Lett. 1994, 35, 2713. (c) Soloshonok, V. A.; Hayashi, T. Tetrahedron: Asymmetry 1994, 5, 1091. (d) Hayashi, T.; Sawamura, M.; Ito, Y. Tetrahedron 1992, 48, 1999. (e) Ito, Y.; Sawamura, M.; Hamashima, H.; Emura, T.; Hayashi, T. Tetrahedron Lett. 1989, 30, 4681. (f) Sawamura, M.; Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30, 2247. (g) Ito, Y.; Sawamura, M.; Hayashi, T. Tetrahedron Lett. 1988, 29, 239. (h) Ito, Y.; Sawamura, M.; Kobayashi, M.; Hayashi, T. Tetrahedron Lett. 1988, 29, 6321. (i) Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T. Tetrahedron Lett. 1988, 29, 235. (j) Ito, Y.; Sawamura, M.; Hayashi, T. Tetrahedron Lett. 1987, 28, 6215. (k) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. (10) (a) Pastor, S. D.; Kesselring, R.; Togni, A. J. Organomet. Chem. 1992, 429, 415. (b) Pastor, S. D.; Togni, A. Helv. Chim. Acta 1991, 74, 905. (c) Togni, A.; Blumer, R. E.; Pregosin, P. S. Helv. Chim. Acta 1991, 74, 1533. (d) Togni, A.; Pastor, S. D. J. Org. Chem. 1990, 55, 1649. (e) Pastor, S. D.; Togni, A. Tetrahedron Lett. 1990, 31, 839. (f) Togni, A.; Pastor, S. D. Tetrahedron Lett. 1989, 30, 1071. (g) Togni, A.; Pastor, S. D.; Rihs, G. Helv. Chim. Acta 1989, 72, 1471. (h) Pastor, S. D.; Togni, A. J. Am. Chem. Soc. 1989, 111, 2333. (11) (a) Hayashi, T.; Uozumi, Y.; Yamazaki, A.; Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron Lett. 1991, 32, 2799. (b) Sawamura, M.; Hamashima, H.; Ito, Y. J. Org. Chem. 1990, 55, 5935. (12) Heinzer, F.; Bellus, D. Helv. Chim. Acta 1981, 64, 2279.
J. Org. Chem., Vol. 62, No. 11, 1997 3471 Scheme 1
Scheme 2
base) employed, and, in some cases, the electrostatic, donor-acceptor type interactions. The resultant oxazoline diastereomer ratios appear to be determined primarily by the steric influence of the ketone substituents; however, they were found to be tunable depending on a proper choice of the catalyst. In particular, for the reactions of methyl isocyanoacetate 1 with polyhaloalkyl aryl(alkyl) ketones, a high, synthetically useful level stereoselectivity (80-98% de) was achieved, allowing straightforward and generalized access to the corresponding (2R*,3R*)-β,β-disubstituted-β-hydroxy-R-amino carboxylic acid of biomedicinal importance. Apart from the synthetic results, the data presented here shed light on some of the intricacies of these metal/base-catalyzed reactions, and should allow for the design of more general and practical catalytic and enantioselective aldol-type processes in the future. Results We have reacted methyl R-isocyanoacetate (1) (Scheme 1) with prochiral ketones 2a-z to give the corresponding diastereomeric oxazolines13 3,4a-z. The most represen-
3472 J. Org. Chem., Vol. 62, No. 11, 1997
Soloshonok et al.
Table 1. Catalytic Aldol Reactions of Ketones 2a-z with Methyl Isocyanoacetate 1aa catalyst,b
ketone entry
R
R1
1 (a) 2 (b) 3 (b) 4 (b) 5 (b) 6 (b) 7 (b) 8 (b) 9 (b) 10 (b) 11 (b) 12 (b) 13 (c) 14 (c) 15 (c) 16 (c) 17 (d) 18 (d) 19 (d) 20 (d) 21 (e) 22 (f) 23 (g) 24 (g) 25 (g) 26 (g) 27 (g) 28 (h) 29 (h) 30 (i) 31 (j) 32 (k) 33 (l) 34 (m) 35 (m) 36 (n) 37 (o) 38 (p) 39 (q) 40 (r) 41 (s) 42 (s) 43 (s) 44 (t) 45 (t) 46 (u) 47 (u) 48 (v) 49 (w) 50 (w) 51 (w) 52 (w) 53 (x) 54 (y) 55 (z)
C6H5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 C6H5 C6H5 C6H5 C6H5 4-CF3-C6H4 4-CH3O-C6H4 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 Me Me Me Me Me Me CH2Cl Me Me n-Hep n-Hep n-Hep n-Oct n-Oct c-Hex. c-Hex. C≡C-Ph CH2COOEt CH2COOEt CH2COOEt CH2COOEt Me Me Me
Me CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CH3 CH3 CH3 CH3 CF3 CF3 CF3 CF3 CF3 CF3 CClF2 CClF2 CClF2 CClF2 CClF2 C2F5 C2F5 n-C4F9 CN CH2OMe CH2F CH2Cl CH2Cl CHCl2 CCl3 CHCl2 CF3 n-C3F7 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 CF3 Et n-Pr c-Hex
ratiod
metal/base
mol %
time
Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Au(I)/NEt3 Ag(I)/NEt3 Ag(I)/i-Pr2NEt Ag(I)/NMe3f Ag(I)/PyH Ag(I)/PSg Cu(I) NEt3
10 10 10 1 1 1 1 1 1 10 25
24 he 10 min 10 h 4h 3.5 h 12 h 3.5 h 45 h 12 h 20 h 50 h 96 h 48 h 50 h 50 h 60 h 5h 5h 5h 7h 5h 6h 5h 10 h 5h 10 min 1h 6h 10 min 10 min 10 min 20 h 0.5 h 0.5 h 0.5 h 0.5 h 0.5 h 0.5 h 0.5 hh 0.5 hh 1h 1h 2h 1h 2h 5h 10 h 10 minh 0.5 h 1h 0.5 h 24 h 24 h 24 h 24 h
Ag(I)/NEt3 Cu(I)/NEt3 Au(I)/NEt3 Pd(II)/NEt3 Ag(I)/NEt3 Au(I)/NEt3 Rh(I)/NEt3 Cu(I)/NEt3 Ag(I)/NEt3 Ag(I)/NEt3 Ag(I)/NEt3 Rh(I)/NEt3 Pd(II)/NEt3 Cu(I)/NEt3 NEt3 Ag(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Ag(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Ag(I)/NEt3 NEt3 Ag(I)/NEt3 NEt3 Cu(I)/NEt3 Ag(I)/NEt3 Ag(I)/NEt3 Au(I)/NEt3 Cu(I)/NEt3 Ag(I)/NEt3 NEt3 Cu(I)/NEt3 Cu(I)/NEt3 Cu(I)/NEt3
1 1 1 1 1 1 1 10 1 1 1 1 1 10 200 1 10 10 10 10 10 10 2 10 10 10 10 10 10 2 200 5 200 10 5 2 2 10 2 100 10 10 10
yield,c 80 93 91 95 92 96 97 99 94 78 60 54 85 83 77 84 92 94 95 93 94 89 96 98 93 92 95 93 94 87 81 74 93 97 94 99 95 89 91 88 91 93 89 95 94 87 91 96 87 83 91 NR 37i 31i 24i
%
trans-3
cis-4
53 91 91 92 94 83 98 64 77 73 95 80 41 37 48 50 86 89 89 88 88 87 93 92 85 >99 94 95 >99 >99 18 56 71 74 79 92 >99 71 99 >99 76 90 86 91 84 35 43 >99 62 84 91
47 9 9 8 6 17 2 36 23 27 5 20 59 63 52 50 14 11 11 12 12 13 7 8 15
