Angewandte
Chemie
chromatography (CHCl3/MeOH/NH4OH, 14m; 95/5/1 v/v/v) and/or
semipreparative HPLC techniques.
Table 1: Site-selective reactions of erythromycin A with achiral catalyst
versus 7.
Received: April 14, 2006
Revised: June 12, 2006
Published online: July 21, 2006
Keywords: asymmetric catalysis · erythromycin · nucleophiles ·
.
peptides · site-selectivity
Cat.7[c]
8:9
(yield of
[1] J. Clardy, C. Walsh, Nature 2004, 432, 829 – 837.
[2] J. Y. Ortholand, A. Ganesan, Curr. Opin. Chem. Biol. 2004, 8,
271 – 280.
[3] U. Abel, C. Koch, M. Speitling, F. G. Hansske, Curr. Opin. Chem.
Biol. 2002, 6, 453 – 458.
[4] S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem.
1985, 97, 1 – 31; Angew. Chem. Int. Ed. Engl. 1985, 24, 1 – 30.
[5] J. M. McGuire, R. L. Bunch, R. C. Anderson, H. E. Boaz, E. H.
Flynn, H. M. Powell, J. W. Smith, Antibiot. Chemother. 1952, 2,
281 – 283.
Achiral
Entry
cat.[a]
8:9[b]
9)
1
1:9
(58%)
8a, 9a:
>10:1[b]
R=(CH2)6CH3
2
1:>10
8b, 9b:
5:1[b]
(53%)
[6] G. T. Copeland, S. J. Miller, J. Am. Chem. Soc. 2001, 123, 6496 –
6502.
R=(CH2)2NHBoc
[7] B. R. Sculimbrene, S. J. Miller, J. Am. Chem. Soc. 2001, 123,
10125 – 10126.
[8] J. W. Evans, M. B. Fierman, S. J. Miller, J. A. Ellman, J. Am.
Chem. Soc. 2004, 126, 8134 – 8135.
[9] P. H. Jones, E. J. Baker, E. K. Rowley, T. J. Perun, J. Med. Chem.
1972, 15, 631 – 634.
3
8c, 9c:
R=(CH2)2CH
CH2
1:5
(56%)
2:1[b]
=
4
1:3.5
(28%)
[10] For several lead references to the structure-nucleating effects of
d-Pro and Aib, see: a) T. S. Haque, J. C. Little, S. H. Gellman, J.
Am. Chem. Soc. 1996, 118, 6975 – 6985; b) I. L. Karle, S. K.
Awasthi, P. Balaram, Proc. Natl. Acad. Sci. USA 1996, 93, 8189 –
8193; c) C. Toniolo, M. Crisma, F. Formaggio, C. Peggion,
Biopolymers 2001, 60, 396 – 419.
[11] A table of the catalysts that were screened, reflecting their
diverse performance, may be found in the Supporting Informa-
tion.
[12] The ratios are supported by both NMR analysis and yields of
isolated products; see Supporting Information.
[13] J. R. Everett, E. Hunt, J. W. Tyler, J. Chem. Soc. Perkin Trans. 2
1991, 1481 – 1487.
[14] M. D. Burke, E. M. Berger, S. L. Schreiber, Science 2003, 302,
613 – 618.
8d, 9d:
R=Et
2:1[b]
[a] Reaction catalyzed by pyridine as solvent. Reactions catalyzed by NMI
provide similar ratios. [b] Reactions with pyridine or NMI are generally
sluggish and not preparatively useful. Consistent with the reports of
Abbott Laboratories,[9] the yields of 8 (R=Me) under conditions
promoted by pyridine is about 70% after 3 days reaction time. Yields
of 9 under catalysis by pyridine are extremely low and difficult to quantify.
Thus, peptide 7 provides unique access to 9. [c] Yields are determined
from isolated material after chromatography. In cases where co-elution
with minor components occurs, conversion into the corresponding C11-
monoester following methanolysis of the C2’-OH-ester delivers pure
compounds for full characterization. See Supporting Information for
details.
[15] For examples of mechanistic studies of asymmetric reactions
catalyzed by peptides related to 7, see: a) M. M. Vasbinder, E. R.
Jarvo, S. J. Miller, Angew. Chem. 2001, 113, 2906 – 2909; Angew.
Chem. Int. Ed. 2001, 40, 2824 – 2827; b) M. B. Fierman, D. J.
OꢀLeary, W. E. Steinmetz, S. J. Miller, J. Am. Chem. Soc. 2004,
126, 6967 – 6971.
Experimental Section
General procedure for the acylation of erythromycin A: Erythromy-
cin A (3, 100 mg, 0.136 mmol) was dissolved in CHCl3 (100 mm,
1.36 mL) in a flame-dried vial. Triethylamine (5 equiv, 93.0 mL,
0.681 mmol) and the catalyst (5 mol%, 20.0 mm in CH2Cl2,
0.340 mL, 6.81 mmol) were then added sequentially. For less reactive
anhydrides, 10 mol% catalyst is employed (see Supporting Informa-
tion for details.) Acetic anhydride (10 equiv, 128 mL, 1.36 mmol) was
added and the reaction was allowed to stir at 258C. Reaction progress
1
was monitored by H NMR (400 MHz) by removing 100 mL aliquots
followed by a methanol quench. The resulting solutions were passed
through a silica gel plug eluting with a CHCl3/MeOH (95/5 v/v)
solvent system and concentrated under high vacuum. After an
appropriate time interval, the full reaction mixture was quenched by
addition of methanol and passed through a silica gel plug and
concentrated to dryness. If complete cleavage of the labile 2’-acetyl
was desired, the unpurified reaction mixture was redissolved in
MeOH and allowed to stir for 72 h. After concentration of the
reaction mixture, reaction selectivity was analyzed by 1H NMR
(400 MHz). Individual products were isolated by silica gel column
Angew. Chem. Int. Ed. 2006, 45, 5616 –5619
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5619