An Efficient Asymmetric Route to 2,3-Diaminobutanoic Acids

Nonproteingenic amino acids have been uncovered in a growing number of naturally occurring compounds.1 Consequently, interest in their application as building blocks for peptidomimetics in medicinal chemistry efforts has also increased due to their protease resistance and potential conformational constraints.2 The R,â-diamino acid family constitutes a key structural element found in a variety of antibiotics,3 antifungal dipeptides,4 and other biologically active compounds.5 In particular, R,âdiaminobutanoic acids such as 1 (Figure 1) have attracted numerous synthetic efforts, since they are the simplest member of the R,â-diamino acid family yet form key elements in both peptide antibiotics and toxins.6 Several methods for the synthesis of R,â-diaminobutanoic acids have been reported. Noteworthy was a method reported by Schmidt and co-workers7 in which threonine or allo-threonine was exploited as starting materials and Mitsunobu reaction conditions were used for the installation of the second amino group. While this tact is reliable, only the anti isomers 1b and 1d are accessible from threonine, whereas the syn isomers 1a and 1c must be obtained from allo-threonine. In related studies, Shin6a,b described syntheses leading to all four isomers of 1 using Lor D-threonine as starting materials and double inversion chemistry to obtain the syn diastereomers 1a and 1c. Utilizing a completely different strategy, Davies and co-workers6c reported the synthesis of epimers 1a and 1d based on the asymmetric addition of a chiral lithium amide to tert-butyl crotonate, followed by the introduction of the second amino group using trisyl azide. Very recently, all four isomers of 1 were synthesized on the basis of the nucleophilic addition of methylmagnesium bromide to differentially protected nitrones that were derived from either Lor D-serine.8 Critical in this approach was the protecting group strategy used on the starting nitrone, as this dictated the stereochemical outcome of the reaction. Except for the approach outlined by Davies (vide supra), all syntheses of the R,â-diaminobutanoic acids have required the use of optically active R-amino acids as starting material. Furthermore, while Davies’s methodology is apt to apply toward the synthesis of other R,âdiamino acids, it requires stoichiometric quantities of chiral reagents for two key steps, a Michael and an electrophilic addition. Herein, we report an efficient stereoselective synthesis of R,â-diaminobutanoic acids that eliminates the drawbacks found in the previous syntheses. Our route utilizes the highly enantioselective Sharpless asymmetric aminohydroxylation (AA) reaction and regioselective ring opening of an aziridine functionality. Commercially available tert-butyl crotonate (2) was the starting point of our synthesis (Scheme 1). Crotonate 2 was functionalized using (DHQD)2PHAL and the benzylcarbamate-based Sharpless AA9 reaction gave 3 in high regioselectivity and enantioselectivity. The ratio of the regioisomer was about 9:1 based on 1H NMR spectrum of the crude product, and the initial ee of 90% could be easily raised to >99% by a single recrystallization from hexane/ethyl acetate. Ester 3 was converted to its methanesulfonate 4, which was successfully transformed to the anti-R-azido species with inversion of configuration at C-2.6c Catalytic hydrogenation and subsequent acidic hydrolysis of azide 5 gave enantiomerically pure diaminobutanoic acid 1b as its HCl salt {[R]D -8.9 (c 1.0, 6 N HCl), lit.10 [R]D -11.0 (c 1.0, 6 N HCl)}. For the synthesis of the syn isomer 1a, compound 4 was converted to aziridine species 6 in 80% yield with potassium tert-butoxide. For the ring opening of 6, solvent turned out to be a critical factor. Initial attempts with TMSN3 and MeOH in DMF11 gave no product, even after a prolonged reaction time (48 h), and reactions conducted in either THF or benzene showed no measurable change. However, use of MeOH as a solvent granted azide 7 as a single diastereomer (NMR), this by regiospecific C-3 ring (1) (a) Amino acids, Peptides and Proteins; The Chemical Society: Cambridge, 1968-1991; Vols. 1-22. (b) Hunt, S. Chemistry and Biochemistry of the Amino Acids; Barrett, G. C., Ed.; Chapman and Hall: London, 1985; p 55. (c) Wagner, I.; Musso, H. Angew. Chem., Int. Ed. Engl. 1983, 22, 816. (2) (a) Gante J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1699. (b) Hirschman, R. Angew. Chem. Int. Ed. Engl. 1990, 29, 1278. (c) Sherman, D. B.; Spatola, A. F. J. Am. Chem. Soc. 1990, 112, 433. (3) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. (4) Rane, D. F.; Girijavallabhan, V. M.; Ganguly, A. K.; Pike, R. E.; Saksena, A. K.; McPhail, A. T. Tetrahedron Lett. 1993, 34, 3201. (5) (a) Dunn, P. J.; Haner, R.; Rapoport, H. J. Org. Chem. 1990, 55, 5017. (b) Palomo, C.; Aizpurua, J. M.; Galaza, R.; Mielgo, A. J. Chem. Soc. Chem. Commun. 1996, 633. (6) (a) Nakamura, Y.; Shin, C. Chem. Lett. 1992, 49. (b) Nakamura, Y.; Hirai, M.; Tamotsu, K.; Yonezawa, Y.; Shin, C. Bull. Chem. Soc. Jpn. 1995, 68, 1369. (c) Burke, A. J.; Davies, S. G.; Hedgecock, C. J. R. Synlett 1996, 621. (7) (a) Schmidt, U.; Mundinger, K.; Mangold, R.; Lieberknecht, A. J. Chem. Soc, Chem. Commun. 1996, 1216. (b) Schmidt, U.; Mundinger, K.; Riedl, B.; Haas, G.; Lau, Palomo, C. Synthesis 1992, 1201. (8) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron Lett. 1997, 38, 1813. (9) (a) Gunther, S.; Sharpless, K. B. In Asymmetric Oxidation Reactions: A Practical Approach: Katsuki, T., Ed.; Oxforn University Press: London, 1998; in press. (b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2813. (10) Atherton, E.; Meienhofer, J. J. Antibiot. 1972, 25, 539. HoppeSeyler’s Z. Physiol. Chem. 1973, 354, 689. (11) (a) Legters, J.; Willems, J. G. H.; Thijs, L.; Zwanenburg, B.Recl. Trav. Chim. Pays-Bas 1992, 111, 59. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. Figure 1. The four enantiomers of 2,3-diaminobutanoic acid. 2045 J. Org. Chem. 1998, 63, 2045-2048