The least well-precedented part of the synthesis involves
the methylenediamine moiety in the L-alanyl fragment. Most
work concerning the synthesis of such N-(1-aminoalkyl)-
amides focuses on their role as intermediates in carboxyl-
terminal peptide sequencing.2 Only a few examples exist
where such geminal amino amides were directly synthesized.3
The one precedent for synthesizing such an N-(1-amino-
methyl)amide in a peptidic molecule had an overall yield of
only 14%.4 Following Loudon’s procedure employing [I,I′-
bis(trifluoroacetoxy)iodo]benzene (PIFA) to affect an acidic
Hofmann rearrangement, we were able to synthesize the
desired amine (3) from the CBZ-L-alanylglycinamide deriva-
tive (2) in 48% yield (Scheme 1). The N-(1-aminomethyl)-
Scheme 2
Scheme 1
tion-elimination reaction leads to a loss of both stereo-
chemistry and regiochemistry. The triflate gives the desired
substitution reaction with predominant inversion. A 5:1
diastereoselective ratio as was observed by the anisotropic
shifts in the 1H NMR of the (S)-mandelate derivative of 7.7
A single-crystal X-ray structure of 6, using anomalous
diffraction to fix the absolute configuration, confirmed the
stereochemical assignments. Finally, the selective cleavage
of the p-methoxybenzyl ester gives 7 in essentially quantita-
tive yield.
amides are remarkably stable to hydrolysis, surviving under
a large range of acidic (pH g 1) as well as moderately basic
conditions (pH e 11).5
The two fragments were then coupled using a water-
soluble carbodiimide and N-hydroxybenzotriazole yielding
8 in 73% yield (Scheme 3).
The malic acid derived portion of pantocin B proved to
be more synthetically challenging due to the acidity of the
methylene protons. The choice of protecting groups had to
allow for selective deprotection under conditions mild enough
to prevent unwanted side reactions. After some experimenta-
tion, the benzyl and p-methoxybenzyl esters were selected.
Malic acid was selectively converted to 2-hydroxysuccinic
acid 1-benzyl ester (4) following Miller’s procedure (Scheme
2).6
Scheme 3
The use of triflate as a leaving group in the substitution
reaction is essential to avoid a competing elimination-
addition reaction, observed with both the mesylate and the
tosylate under a variety of conditions. The unwanted addi-
(1) Brady, S. F.; Wright, S. A.; Lee, J. C.; Sutton, A. E.; Zumoff, C.
H.;, Wodzinski, R. S.; Beer, S. V.; Clardy, J. C. J. Am. Chem. Soc. 1999,
121, in press.
(2) (a) Zervas, L.; Bergmann, M. J. Biol. Chem. 1936, 113, 341. (b)
Loudon, G. M.; Parham, M. E. Tetrahedron Lett. 1978, 5, 437. (c) Loudon,
G. M.; Parham, M. E. Biochem. Biophys. Res. Commun. 1978, 80, 1.
(3) (a) Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.; Blodgett,
J. K.; Boutin, R. H. J. Org. Chem. 1984, 49, 4272. (b) Einhorn, A.; Schupp,
G. Justus Liebigs Ann. Chem. 1906, 343, 252. (c) Goodman, M.; Chorev,
M.; Willson, C. G. J. Am. Chem. Soc. 1977, 99, 8075. (d) Goodman, M.;
Chorev, M. Acc. Chem. Res. 1979, 12, 1.
(4) Ikeda, Y., et al. J. Antibiot. 1986, 39, 476.
(5) Loudon, G. M.; Almond, M. R.; Jacob, J. N. J. Am. Chem. Soc. 1981,
103, 4508.
(6) Miller, M. J.; Bajwa, J. S.; Mattingly, P. G.; Peterson, K. J. Org.
Chem. 1982, 47, 4928.
320
Org. Lett., Vol. 2, No. 3, 2000