C O M M U N I C A T I O N S
Scheme 4
Supporting Information Available: Full experimental details and
characterization (PDF). This material is available free of charge via
References
(1) Cavalleri, B.; Pagani, H.; Volpe, G.; Selva, E.; Parenti, F. J. Antibiot.
1984, 37, 309. Pallanza, R.; Berti, M.; Scotti, R.; Randisi, E.; Arioli V. J.
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(2) Ciabatti, R.; Kettenring, J. K.; Winters, G.; Tuan, G.; Zerilli, L.; Cavalleri,
B. J. Antibiot. 1989, 42, 254. Kettenring, J. K.; Ciabatti, R.; Winters, G.;
Tamborini, G.; Cavalleri, B. J. Antibiot. 1989, 42, 268. Review: Parenti,
F.; Ciabatti, R.; Cavalleri, B.; Kettenring, J. Drugs Exptl. Clin. Res. 1990,
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(3) Review: Espersen, F. Curr. Opin. Anti-Infect. InVest. Drugs 1999, 1, 78.
(4) Somner, E. A.; Reynolds, P. E. Antimicrob. Agents Chemother. 1990, 34,
413. Bro¨tz, H.; Bierbaum, G.; Reynolds, P. E.; Sahl, H.-G. Eur. J.
Biochem. 1997, 246, 193. Review: Reynolds, P. E.; Somner, E. A. Drugs
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(5) Bro¨tz, H.; Josten, M.; Wiedemann, I.; Schneider, U.; Go¨tz, F.; Bierbaum,
G.; Sahl, H.-G. Mol. Microbiol. 1998, 30, 317.
(6) Lo, M.-C.; Men, H.; Branstrom, A.; Helm, J.; Yao, N.; Goldman, R.;
Walker, S. J. Am. Chem. Soc. 2000, 122, 3540. For dimerization of
ramoplanin, see: Lo, M.-C.; Helm, J. S.; Sarngadharan, G.; Pelczer, I.;
Walker, S. J. Am. Chem. Soc. 2001, 123, 8640.
(7) Jones, R. N.; Barry, A. L. Diagn. Microbiol. Infect. Dis. 1989, 12, 279.
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(10) Boger, D. L. Med. Res. ReV. 2001, 21, 356.
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M.; Holly, F. W.; Veber, D. F. J. Org. Chem. 1979, 44, 3101.
(13) EDCI ) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
HOAt ) 1-hydroxy-7-azabenzotriazole, PyBop ) benztriazol-1-yl-oxytris-
(pyrrolidino)phosphonium hexafluorophosphate, HATU ) 2-(1H-7-aza-
benzotriazol)-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate.
(14) DEPBT ) 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one: Fan,
C.-X.; Hao, X.-L.; Ye, Y.-H. Synth. Commun. 1996, 26, 1455. Li. H.;
Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Org. Lett. 1999,
1, 91.
(15) Beaulieu, P. L. Tetrahedron Lett. 1991, 32, 1031. Beaulieu, P. L.; Schiller,
P. W. Tetrahedron Lett. 1988, 29, 2019. Boc-L-aThr-OH was prepared
from L-aThr-OH by treatment with Boc2O, Na2CO3, THF/H2O (87%).
HCI‚H-D-aThr-OBn was prepared from Boc-D-aThr-OH by treatment with
BnBr, NaHCO3, DMF (89%); 4 N HCl-EtOAc (quant.).
(16) Boc-D-Orn(SES)-OH was prepared from Boc-D-Orn-OH as described in
the Supporting Information. Further treatment with BnBr, NaHCO3, DMF
(92%); HCl-EtOAc (quant.), provided HCl‚H-D-Orn(SES)-OBn. SES )
2-trimethylsilylethanesulfonyl.
(17) Boger, D. L.; Lee, R. J.; Bounaud, P.-Y.; Meier, P. J. Org. Chem. 2000,
65, 6770. The final steps in the preparation of 16 can be improved and
streamlined by treatment of Boc-L-HAsn(OTBS)-OBn directly with 4 N
HCl-EtOAc for simultaneous Boc and TBS deprotection followed by
treatment with FmocCl, dioxane-H2O (92%, 2 steps) and TrtOH, catalytic
H2SO4, HOAc, Ac2O (71%).
(18) Prepared from L-Chp-OH (Holdrege, C. T. U.S. Patent 3646024; Chem.
Abstr. 1972, 77, 34543) by treatment with Boc2O, Na2CO3, 25% H2O-
THF (98%); BnBr, NaHCO3, DMF (98%); CF3CONMeTBS, THF, 40-
45 °C (100%); H2, 10% Pd-C, EtOH (quant.).
conditions (8 equiv of Bu4NF, 10 equiv of i-PrOH, DMF, 25 °C,
1 h)22 that do not promote competitive Asn2 â-elimination, Asn1
acyl side chain introduction (42,23 20% CH2Cl2-DMF, 69% for 2
steps), and a single step HF deprotection24 of the trityl and SES
groups (HF, anisole, 0 °C, 90 min) or sequential trityl (5% H2O-
TFA, 25 °C, 5 h) and SES deprotection (HF, 83%) provided the
ramoplanin A2 and ramoplanose aglycon identical in all respects
with an authentic sample (1H NMR, HPLC, UV, MS).25
(19) Boger, D. L.; Chen, J.-H. J. Am. Chem. Soc. 1993, 115, 11624. Boger, D.
L.; Chen, J.-H.; Saionz, K. W. J. Am. Chem. Soc. 1996, 118, 1629. DMAP
) 4-(dimethylamino)pyridine.
(20) BCB ) B-bromocatecholborane: Boeckman, R. K., Jr.; Potenza, J. C.
Tetrahedron Lett. 1985, 26, 1411.
(21) Boger, D. L.; Miyazaki, S.; Kim. S. H.; Wu, J. H.; Loiseleur, O.; Castle,
S. L. J. Am. Chem. Soc. 1999, 121, 3226. Boger, D. L.; Miyazaki, S.;
Kim, S. H.; Wu, J. H.; Castle, S. L.; Loiseleuer, O.; Jin, Q. J. Am. Chem.
Soc. 1999, 121, 10004.
(22) Ueki, M.; Nishigaki, N.; Aoki, H.; Tsurusaki, T.; Katoh, T. Chem. Lett.
1993, 721.
(23) Prepared from 5-methylhex-2-enal (Vig, O. P.; Bari, S. S.; Puri, S. K.;
Dua, D. M. Indian J. Chem. 1981, 20B, 342) in three steps: (CF3CH2O)2-
POCH2CO2CH3, KHMDS, 18-c-6, THF; LiOH, CH3OH-H2O (86%, two
steps); 0.5 equiv of EDCI, CH2Cl2 (83%).
(24) Boger, D. L.; Ledeboer, M. W.; Kume, M. J. Am. Chem. Soc. 1999, 121,
1098. Boger, D. L.; Ledeboer, M. W.; Kume, M.; Searcey, M.; Jin, Q. J.
Am. Chem. Soc. 1999, 121, 11375.
(25) Prepared by degradation of the ramoplanin complex (mixture of A1-A3,
2.5%, HCl-BuOH, DMF, 75 °C, 20-31%). Derivatization of 41 (SESCl,
Et3N, DMF, -20 °C, 3 h, 20%) provided a correlation sample of 40 also
identical with synthetic material (1H NMR, HPLC, UV, MS).
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (CA41101) and The
Skaggs Institute for Chemical Biology. We wish to thank Dr. S.
Ichikawa for interim studies on the coupling of 15 and 26 and
macrocyclization studies of 37, Dr. P. Meier for contributing to
material supplies in interim studies, Dr. Mark O’Neil-Johnson
(Sequoia Sciences, San Diego, CA) for microscale 1H NMR spectra,
and Dr. Ciabatti (Biosearch Italia S.p.A.) for a supply of the natural
ramoplanin complex and a correlation sample of the ramoplanin
A2 aglycon.
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5290 J. AM. CHEM. SOC. VOL. 124, NO. 19, 2002