Efficient Asymmetric Synthesis of Unnatural β-Amino Acids

Abstract

The simple and highly enantioselective methanolysis of cyclic meso-anhydrides mediated by cinchona alkaloids leads to a broad variety of dicarboxylic acid mono-methyl esters with up to 99% ee. From these products, unnatural N-protected β-amino esters can be obtained by means of Curtius degradation of the corresponding acyl azides. Subsequent cleavage of the protecting groups leads to the free β-amino acids in excellent yields. By enantiomer differentiating opening of racemic anhydrides, synthetically highly useful regioisomeric amino acid esters become readily available.

Key words

asymmetric ring opening - chiral methyl esters - Curtius degradation - β-amino acids - enantiomer differentiating reaction

References

• 1 Review: Drey CNC. In Chemistry and Biochemistry of Amino Acids, Peptides and Proteins   Vol. 4:  Weinstein B. Marcel Dekker; New York: 1977.  p.242 
• 2 Review: Cole DC. Tetrahedron  1994,  50:  9517 
• 3a Matsunaga S. Fusetani N. J. Org. Chem.  1995,  60:  1177 
• 3b Trimurtulu G. Ohtani I. Patterson GML. Moore RE. Corbett TH. Valeriote FA. Demchik L. J. Am. Chem. Soc.  1995,  117:  1225 
• 4 Umezawa H. Aoyagi T. Suda H. Hamada M. Takeuchi T. J. Antibiot.  1976,  29:  97 
• Reviews:
• 5a Morin RB. Gorman M. Chemistry and Biology of β-Lactam Antibiotics   Academic Press; New York: 1982. 
• 5b Lukacs G. Ohno M. Recent Progress in the Chemical Synthesis of Antibiotics and Related Natural Products   Springer; Berlin: 1990. 
• 6 Review: Georg GI. Bioorg. Med. Chem. Lett.  1993,  3:  2135 
• 7 Burnett D. Caplen MA. Davis HR. Burrier RE. Clader JW. J. Med. Chem.  1994,  37:  1733 
• 8a Seebach D. Overhand M. Kühnle FNM. Martinoni B. Oberer L. Hommel U. Widmer H. Helv. Chim. Acta  1996,  79:  913 
• 8b Seebach D. Matthews JL. Chem. Commun.  1997,  2015 
• 8c Abele S. Vögtli K. Seebach D. Helv. Chim. Acta  1999,  82:  1539 
• 9a Appella D. Christianson LA. Karle IL. Powell DR. Gellman SH. J. Am. Chem. Soc.  1996,  118:  13071 
• 9b Appella D. Christianson LA. Klein DA. Powell DR. Huang X. Barchi J. Gellman SH. Nature  1997,  387:  381 
• 9c Appella D. Christianson LA. Karle IL. Powell DR. Gellman SH. J. Am. Chem. Soc.  1999,  121:  6206 
• 9d Barchi JJ. Huang X. Apella DH. Christianson LA. Durell SR. Gellman SH. J. Am. Chem. Soc.  2000,  122:  2711 
• 9e Huck BR. Langenhan JM. Gellman SH. Org. Lett.  1999,  1:  1717 
• 9f Appella DH. Barchi JJ. Durell SR. Gellman SH. J. Am. Chem. Soc.  1999,  121:  2309 
• 9g Wang X. Espinosa JF. Gellman SH. J. Am. Chem. Soc.  2000,  122:  4821 
• 9h Lee H.-S. LePlae PR. Porter EA. Gellman SH. J. Am. Chem. Soc.  2001,  123:  3597 
• 10a Review: Gellman SH. Acc. Chem. Res.  1998,  31:  173 
• 10b For recent references, see also: Winkler JD. Piatnitski EL. Mehlmann J. Kasparec J. Axelsen PH. Angew. Chem. Int. Ed.  2001,  40:  743 
• For biological studies of β-amino acid containing peptides and β-peptide, see:
• 11a Hintermann T. Seebach D. Chimia  1997,  51:  244 
• 11b Seebach D. Abele S. Schreiber JV. Martinoni B. Nussbaum AK. Schild H. Schulz H. Hennecke H. Wössner R. Bitsch F. Chimia  1998,  52:  734 
• 11c Werder M. Hauser H. Abele S. Seebach D. Helv. Chim. Acta  1999,  82:  1774 
• 11d Gademann K. Ernst M. Hoyer D. Seebach D. Angew. Chem. Int. Ed.  1999,  38:  1223 
• 11e Gademann K. Ernst M. Seebach D. Helv. Chim. Acta  2000,  83:  16 
• 11f Porter EA. Wang X. Lee H.-S. Weisblum B. Gellman SH. Nature  2000,  404:  565 
• 11g Hamuro Y. Schneider JP. De Grado WF. J. Am. Chem. Soc.  1999,  121:  12200 
• Reviews:
• 12a Cardillo G. Tomasini C. Chem. Soc. Rev.  1996,  117 
• 12b Sewald N. Amino Acids  1996,  11:  397 
• 12c Juaristi E. Enantioselective Synthesis of β-Amino Acids   Wiley-VCH; New York: 1997. 
• 12d Abele S. Seebach D. Eur. J. Org. Chem.  2000,  1 
• 13a Penke B. Czombos J. Baláspiri L. Petres J. Kovács K. Helv. Chim. Acta  1970,  53:  1057 
• 13b Podlech J. Seebach D. Liebigs Ann. Chem.  1995,  1217 
• 13c Podlech J. Seebach D. Angew. Chem., Int. Ed. Engl.  1995,  3:  471 
• 14a Bolm C. Gerlach A. Dinter CL. Synlett  1999,  195 
• 14b Bolm C. Schiffers I. Dinter CL. Gerlach A. J. Org. Chem.  2000,  65:  6984 
• For applications of the protocol reported in ref. 14, see:
• 15a Bernardi A. Arosio D. Dellavecchia D. Micheli F. Tetrahedron: Asymmetry  1999,  10:  3403 
• 15b Starr JT. Koch G. Carreira EM. J. Am. Chem. Soc.  2000,  122:  8793 
• For previous studies of this transformation, see:
• 16a Aitken RA. Gopal J. Tetrahedron: Asymmetry  1990,  1:  517 
• 16b Aitken RA. Gopal J. Hirst JA. J. Chem Soc., Chem. Commun.  1988,  632 
• 16c Hiratake J. Inagaki M. Yamamoto Y. Oda J. J. Chem. Soc., Perkin Trans. 1  1987,  1053 
• 16d Hiratake J. Yamamoto Y. Oda J. J. Chem. Soc., Chem. Commun.  1985,  1717 
• For recent modifications, see:
• 17a Chen Y. Tian S.-K. Deng L. J. Am. Chem. Soc.  2000,  122:  9542 
• 17b Uozumi Y. Yasashima K. Miyachi T. Nagai S.-i. Tetrahedron Lett.  2001,  42:  411 
• 18 For a general review on desymmetrization reactions: Willis MC. J. Chem. Soc., Perkin Trans. 1  1999,  175 
• 19 Alternatively, the enantiomerically enriched dicarboxylic acid monoesters can be prepared by enzyme-catalyzed hydrolysis of meso-diesters. For a recent review, see: Bornscheuer UT. Kazlauskas RJ. Hydrolases in Organic Synthesis - Regio- and Stereoselective Biotransformations   Wiley-VCH; Weinheim: 1999. 
• 21 Previously, difficulties in the separation of compound 4 from the excess of benzyl alcohol were reported (cf.: Appella DH. LePlae PR. Raguse TL. Gellman SH. J. Org. Chem.  2000,  65:  4766 ). All amino esters described here were purified by column chromatography (see experimental section)and NMR spectroscopy confirmed the complete removal of the alcohol
• 22 Martín-Vilà M. Minguillón C. Ortuño RM. Tetrahedron: Asymmetry  1998,  9:  4291 
• 24a Bondi A. J. Phys. Chem.  1964,  68:  441 
• 24b Allinger NL. Hirsch JA. Miller MA. Tyminski IJ. Van-Catledge F. J. Am. Chem. Soc.  1968,  90:  1199 
• For recent examples, see:
• 25a

  ref. 15a

• 25b Maruoka K. Akakura M. Saito S. Ooi T. Yamamoto H. J. Am. Chem. Soc.  1994,  116:  6153 
• 25c Borzilleri RM. Weinreb SM. J. Am. Chem. Soc.  1994,  116:  9789 
• 26 In the syntheses of S-1452 metabolites, ent-10 is a key intermediate. See: Watanabe F. Matsuura T. Shirahase K. Ohtani M. Chem. Pharm. Bull.  1991,  39:  2842 
• 27a Davies SG. Ichihara O. Walters IAS. Synlett  1993,  461 
• 27b Davies SG. Ichihara O. Lenoir I. Walters IAS. J. Chem. Soc., Perkin Trans. 1  1994,  1411 
• 28a Konosu T. Oida S. Chem. Pharm. Bull.  1993,  41:  1012 
• 28b Cimarelli C. Palmieri G. Tetrahedron: Asymmetry  1994,  5:  1455 
• 28c Cimarelli C. Palmieri G. J. Org. Chem.  1996,  61:  5557 
• 28d Kanerva LT. Csomós P. Sundholm O. Bernáth G. Fülöp F. Tetrahedron: Asymmetry  1996,  7:  1705 
• 28e Csomós P. Kanerva LT. Bernáth G. Fülöp F. Tetrahedron: Asymmetry  1996,  7:  1789 
• 28f Theil F. Ballschuh S. Tetrahedron: Asymmetry  1996,  7:  3565 
• 28g Evans C. McCague R. Roberts SM. Sutherland AG. Wisdom R. J. Chem. Soc., Perkin Trans. 1  1991,  2276 
• 30 Harmat NJS. Di Bugno C. Criscuoli M. Giorgi R. Lippi A. Martinelli A. Monti S. Subissi A. Bioorg. Med. Chem. Lett.  1998,  8:  1249 
• 31a Militzer HC, Matzke M, Mittendorf J, Schmidt A, Ziegelbauer K, and Schoenfeld W. inventors; Patent  DE4443890A1. 
• 33 Weygand F. Hunger K. Chem. Ber.  1962,  95:  1 
• 34 Patchornik A. Amit B. Woodward RB. J. Am. Chem. Soc.  1970,  92:  6333 
• 35 Carpino LA. Tunga A. J. Org. Chem.  1986,  51:  1932 
• 36a Canonne P. Akssira M. Dahdou A. Kasmi H. Boumzebra M. Tetrahedron  1993,  49:  1985 
• 36b Akssira M. Dahdou A. Kasmi H. Bull. Soc. Chim. Belg.  1993,  102:  227 
• 38 Pátek M. Drake B. Lebl M. Tetrahedron Lett.  1994,  35:  9169 
• 39a Seebach D. Jaeschke G. Gottwald K. Matsuda K. Formisano R. Chaplin DA. Tetrahedron  1997,  53:  7539 
• 39b See also: Jaeschke G. Seebach D. J. Org. Chem.  1998,  63:  1190 
• 39c Ramón DJ. Guillena G. Seebach D. Helv. Chim. Acta  1996,  79:  875 
• 40 Izumi Y. Tai A. Stereo-Differentiating Reactions   Kodansha Ltd.; Tokyo: 1977. 
• 41 Kagan HB. Croat. Chem. Acta  1996,  69:  669 
• 42a Alphand V. Archelas A. Furstoss R. Tetrahedron Lett.  1989,  30:  3663 
• 42b Petit F. Furstoss R. Tetrahedron: Asymmetry  1993,  4:  1341 
• 43 Bolm C. Schlingloff G. J. Chem. Soc., Chem. Commun.  1995,  1247 
• 44a Back TG. Nakajima K. Tetrahedron Lett.  1997,  38:  989 
• 44b Back TG. Nakajima K. J. Org. Chem.  1998,  63:  6566 
• 46a Frank RL. Emmick RD. Johnson RS. J. Am. Chem. Soc.  1947,  69:  2313 
• 46b Craig D. J. Am. Chem. Soc.  1950,  72:  1648 
• 47a Di Bugno C, Giorgi R, and Harmat N. inventors; Patent  WO9803540A2. 
• 48a Kobayashi S. Kamiyama K. Iimori T. Ohno M. Tetrahedron Lett.  1984,  25:  2557 
• 48b Kobayashi S. Kamiyama K. Ohno M. Chem. Pharm. Bull.  1990,  38:  350 

20

(a) See also: Martín-Vilà, M.; Muray, E.; Aguado, G.P.; Alvarez-Larena, A.; Branchadell, V.; Minguillón, C.; Giralt, E.; Ortuño, R.M. Tetrahedron: Asymmetry 2000, 11, 3569.
(b) Such a sequence has also been used for the preparation of acyclic β-amino acids. For a recent summary of citations, see within ref. 12d.

23

X-ray crystal structure analysis of 4: formula C₁₆H₁₉O₄N; M = 289.33, colorless crystal 0.3 × 0.3 × 0.3 mm, a = 5.3448(3), b = 15.878(2), c = 17.199(3) Å, V = 1459.6(8) ų, ρ_calcd = 1.317 gcm^-1, µ = 7.39 cm^-1, Z = 4, orthorhombic, space group P2₁2₁2₁ (No. 19), λ = 1.54179 Å, T = 180 K, ω/2θ scans, 3666 reflections collected, 3013 independent and 2371 observed reflections [I ≥ 2 σ(I)], 266 refined parameters, R1 = 0.057, wR2 = 0.052, residual electron density -0.35/0.39 eÅ^-3, hydrogens located and refined isotropically.

29

Attempts to hydrolyse the ester moiety of ent-2 under basic conditions led to epimerization.

32

MOZ = 4-MeO-C₆H₄CH₂CO₂-; (2-NO₂)-Z = 2-NO₂-C₆H₄CH₂CO₂-; hZ = C₆H₅CH₂CH₂CO₂-.

37

The failure of this reaction is in agreement with the observations by Gellman, see ref. 21.

45

X-ray crystal structure analysis of 26: formula C₁₇H₂₁O₄N; M = 303.35, colorless crystal 0.24 × 0.24 × 1.00 mm, a = 5.242(4), b = 9.344(4), c = 32.12(2) Å, V = 1573.28 ų, ρ_calcd = 1.281 gcm^-1, µ = 7.45 cm^-1, Z = 4, orthorhombic, space group P2₁2₁2₁ (No. 19), λ = 1.54179 Å, T = 150 K, ω/2θ scans, 3884 reflections collected, 3236 independent and 2924 observed reflections [I ≥ 2 σ(I)], 199 refined parameters, R1 = 0.064, wR2 = 0.085, residual electron density -0.57/0.45 eÅ^-3, hydrogens located in part. Us fixed at 1.5 times U of the relevant Leavy atoms prion to final refinement of the heavy atoms not refined.