Total synthesis of the teicoplanin aglycon [16]

Full text of DOI:10.1021/ja001663j

7416
J. Am. Chem. Soc. 2000, 122, 7416-7417
Scheme 1
Total Synthesis of the Teicoplanin Aglycon
Dale L. Boger,* Seong Heon Kim, Susumu Miyazaki,
Harald Strittmatter, Jian-Hui Weng, Yoshiki Mori,
Olivier Rogel, Steven L. Castle, and J. Jeffrey McAtee
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California, 92037
ReceiVed May 15, 2000
Teicoplanin1,2 is a complex of five antibiotics isolated from
Actinoplanes teichomyceticus that are related to vancomycin3-8
which is enlisted as the drug of last resort for treatment of resistant
bacterial infections or for patients allergic to â-lactam antibiotics.6
It is 2-8-fold more potent, possesses a lower toxicity, exhibits a
longer half-life in man (40 vs 6 h), and is easier to administer
and monitor than vancomycin.
Herein we describe the first total synthesis of the teicoplanin
aglycon (1).9-12 Although teicoplanin bears the identical ABCD
for macrocyclization and formation of the 16-membered DE diaryl
ether and a macrolactamization14 of the N-terminus amide for
closure of the 14-membered FG ring system. With the respective
order of closures, the choice of substrates, and the conditions
enlisted, no epimerization of the sensitive C23 center was observed.
3
Because of the facile C2 epimerization observed within the
confines of the teicoplanin FG ring system,13 the FG diaryl ether
was formed using an intermolecular nucleophilic aromatic
substitution reaction with acyclic phenylglycinol substrates in-
capable of epimerization. Thus, coupling of 215 and 316 (6 equiv
of K2CO3, 5 equiv of 18-c-6, 0.1 M DMSO, 14 h, 25 °C) provided
4 (70%), Scheme 1. Reactions conducted in DMSO were
substantially faster than those conducted in DMF and the
ring system and the same CDE atropisomer stereochemistry as
vancomycin, it contains a DE ring system that lacks the â-hydroxy
group of the vancomycin E-ring substituted phenylalanine (C2
residue) and incorporates an especially racemization prone
substituted phenylglycine C3 residue.13 Most significantly, it
contains the additional 14-membered FG ring system not found
in vancomycin. Key elements of the approach include sequential
DE and FG ring system introductions onto the common vanco-
mycin/teicoplanin ABCD ring system providing a late stage
divergent total synthesis of the two classes of glycopeptide
antibiotics. The ring systems were introduced enlisting a nucleo-
philic aromatic substitution reaction of an o-fluoronitroaromatic
(10) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue,
T.-Y.; Natarajan, S.; Chu, X.-J.; Bra¨se, S.; Ru¨bsam, F. Chem. Eur. J. 1999,
5, 2584. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes,
R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Bra¨se, S.; Solomon, M. E.
Chem. Eur. J. 1999, 5, 2602. Nicolaou, K. C.; Koumbis, A. E.; Takayanagi,
M.; Natarajan, S.; Jain, N. F.; Bando, T.; Li, H.; Hughes, R. Chem. Eur. J.
1999, 5, 2622. Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Bando, T.; Hughes,
R.; Winssinger, N.; Natarajan, S.; Koumbis, A. E. Chem. Eur. J. 1999, 5,
2648. Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger, N.; Hughes,
R.; Bando, T. Angew. Chem., Int. Ed. Engl. 1999, 38, 240. Nicolaou, K. C.;
Takayanagi, M.; Jain, N. F.; Natarajan, S.; Koumbis, A. E.; Bando, T.;
Ramanjulu, J. M. Angew. Chem., Int. Ed. Engl. 1998, 37, 2717. Nicolaou, K.
C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes, R.; Solomon, M. E.; Ramanjulu,
J. M.; Boddy, C. N. C.; Takayanagi, M. Angew. Chem., Int. Ed. Engl. 1998,
37, 2708. Nicolaou, K. C.; Jain, N. F.; Natarajan, S.; Hughes, R.; Solomon,
M. E.; Li, H.; Ramanjulu, J. M.; Takayanagi, M.; Koumbis, A. E.; Bando, T.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2714.
(11) 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.; Loiseleur, O.; Jin, Q. J. Am. Chem. Soc.
1999, 121, 10004.
(12) Nicolaou, K. C.; Boddy, C. N. C.; Bra¨se, S.; Winssinger, N. Angew.
Chem., Int. Ed. Engl. 1999, 38, 2096. Rao, A. V. R.; Gurjar, M. K.; Reddy,
K. L.; Rao, A. S. Chem. ReV. 1995, 95, 2135.
(13) Barna, J. C. J.; Williams, D. H.; Strazzolini, P.; Malabarba, A.; Leung,
T.-W. C. J. Antibiot. 1984, 37, 1204.
(1) Parenti, F.; Beretta, G.; Berti, M.; Arioli, V. J. Antibiot. 1978, 31, 276.
(2) Hunt, A. H.; Molloy, R. M.; Occolowitz, J. L.; Marconi, G. G.; Debono,
M. J. Am. Chem. Soc. 1984, 106, 4891. Barna, J. C. J.; Williams, D. H.;
Stone, D. J. M.; Leung, T.-W. C.; Doddrell, D. M. J. Am. Chem. Soc. 1984,
106, 4895.
(3) McCormick, M. H.; Stark, W. M.; Pittenger, G. E.; Pittenger, R. C.;
McGuire, J. M. Antibiot. Annu. 1955-1956, 606.
(4) Harris, C. M.; Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983,
105, 6915. Williamson, M. P.; Williams, D. H. J. Am. Chem. Soc. 1981, 103,
6580.
(5) Malabarba, A.; Nicas, T. I.; Thompson, R. C. Med. Res. ReV. 1997,
17, 69.
(6) Wiedemann, B.; Grimm, H. In Antibiotics in Laboratory Medicine;
Lorian, V., Ed.; Williams and Wilkins: Baltimore, 1996; pp 900-1168.
(7) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. Engl. 1999, 38,
1172.
(8) Walsh, C. T.; Fisher, S. L.; Park, I.-S.; Prahalad, M.; Wu, Z. Chem.
Biol. 1996, 3, 21.
(9) Orienticin C aglycon: Evans, D. A.; Barrow, J. C.; Watson, P. S.; Ratz,
A. M.; Dinsmore, C. J.; Evrard, D. A.; DeVries, K. M.; Ellman, J. A.;
Rychnovsky, S. D.; Lacour, J. J. Am. Chem. Soc. 1997, 119, 3419. Evans, D.
A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.; Barrow, J. C. J. Am. Chem.
Soc. 1997, 119, 3417. Vancomycin aglycon: Evans, D. A.; Wood, M. R.;
Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2700. Evans, D. A.; Dinsmore, C. J.; Watson, P. S.;
Wood, M. R.; Richardson, T. I.; Trotter, B. W.; Katz, J. L. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2704.
(14) Chakraborty, T. K.; Reddy, G. V. J. Org. Chem. 1992, 57, 5462.
Pearson, A. J.; Shin, H. J. Org. Chem. 1994, 59, 2314. Pearson, A. J.; Belmont,
P. O. Tetrahedron Lett. 2000, 41, 1671.
(15) (a) Prepared by Sharpless AA of 4-fluoro-3-nitrostyrene15b (3 equiv
of BocNClNa, 0.04 equiv of K2OsO2(OH)4, 0.06 equiv of (DHQD)2PHAL,
75%, 90% ee). (b) Rama Rao, A. V.; Gurjar, M. K.; Lakshmipathi, P.; Reddy,
M. M.; Nagarajan, M.; Pal, S.; Sarma, B. V. N. B. S.; Tripathy, N. K.
Tetrahedron Lett. 1997, 38, 7433.
10.1021/ja001663j CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/14/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7417
Scheme 2
epimerization (Scheme 2). Macrocyclization upon treatment of
15 with CsF (15 equiv, 0.007 M DMSO, 25 °C, 10 h) proceeded
in superb conversions (74-80%) to provide a separable 3:1
mixture of P:M atropisomers favoring the natural stereochemistry.
Under these conditions, N-Teoc deprotection was effected provid-
ing the amine 17 directly and only trace quantities of the
corresponding N-Teoc derivative 16 were isolated (6-13%).19
Protection of the secondary alcohol as its OTBS ether (30 equiv
of CF3CONMeTBS, CH3CN, 10 h, 25 °C, 89%), N-Troc
formation (2 equiv of TrocCl, 30 equiv of NaHCO3, CH2Cl2, 1.5
h, 25 °C, 93%), nitro reduction and O-benzyl deprotection (H2-
10% Pd/C, 1% Cl3CCO2H-CH3OH, 1 h, 25 °C), diazotization
(1.3 equiv of t-BuONO and HBF4, CH3CN-H2O, 5 min, 0 °C),
and Sandmeyer substitution (50 equiv of CuCl, 160 equiv of
CuCl2, H2O, 45 min, 0-25 °C) provided the key intermediate 21
(66% from 19) and set the stage for FG ring closure.
Two-step primary alcohol oxidation (10 equiv of Dess-Martin
periodinane, CH2Cl2; 15 equiv of NaClO2, aqueous NaH2PO4-
t-BuOH, resorcinol, 2 h, 25 °C) cleanly provided 22 (79%), which
was subjected to N-Troc deprotection (10% Zn-Pb,20 1 N aqueous
NH4OAc/THF, 10 h, 25 °C, 89%) to provide 23, the key amino
acid for FG macrolactamization. The closure was conducted with
slow addition of 23 (1 h, 0.001 M final concentration) to a solution
of PyBop (66%) or FDPP (62%) in the presence of NaHCO3
which provided excellent conversions to 24 (10-50% DMF-
CH2Cl2) with only a trace of C21 epimer generation. In each case,
the use of i-Pr2NEt versus NaHCO3 led to competitive or extensive
1
C2 epimerization. MEM deprotection (10 equiv of B-bromo-
catecholborane, CH2Cl2, 2.5 h, 0 °C) followed by protection of
the N-terminus amine with Boc2O (3 equiv, aqueous NaHCO3, 1
h, 25 °C) provided 25 (76%, 2 steps). Two-step alcohol oxidation
(10 equiv of Dess-Martin periodinane, CH2Cl2, 3 h, 25 °C;
NaClO2, NaH2PO4, DMSO-H2O, resorcinol, 30 min, 25 °C)
provided the carboxylic acid 26 (79%). The use of resorcinol in
DMSO proved superior to isobutene/t-BuOH and prevented
competitive aromatic chlorination. Exhaustive deprotection of 26
enlisting AlBr3-EtSH9 (25 °C, 3 h), which served to cleave the
six aryl methyl ethers, the C36 OTBS ether, and the N-BOC group,
provided the teicoplanin aglycon (48%) identical in all respects
with authentic material.
Acknowledgment. We gratefully acknowledge the financial support
of the National Institutes of Health (CA41101), the Skaggs Institute for
Chemical Biology, the sabbatical leaves of Y.M. (Mitsubishi-Tokyo
Pharmaceuticals, Inc. 1999-2000) and S.M. (Japan Tobacco, 1997-99),
and the award of a Novartis Stiftung to H.S., and a NIH postdoctoral
fellowship to J.J.M. (AI10367).
Supporting Information Available: Full characterization data for
1-4, 6-13, 15-19, and 21-26 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA001663J
(16) (a) Prepared by Sharpless AA of 3-benzyloxy-5-methoxystyrene16b (3
equiv of CbzNClNa, 0.04 equiv of K2OsO2(OH)4, 0.05 equiv of (DHQ)2PHAL,
78%, 80% ee) followed by (i) 6 equiv of MEMCl, 8 equiv of i-Pr2NEt, CH2Cl2,
0-25 °C, 20 h, 92%; (ii) H2, 10% Pd/C, MeOH, 1 h, 25 °C.; (iii) 2 equiv of
TFAA, 3 equiv of pyridine, 0-25 °C, 2.5 h, 93% for 2 steps. (b) Prepared in
two steps from 3-hydroxy-5-methoxybenzaldehyde (Ben, I.; Castedo, L.; Saa´,
J. M.; Seijas, J. A.; Suau, R.; Tojo, G. J. Org. Chem. 1985, 50, 2236): 1.5
equiv of BnBr, 1.5 equiv of K2CO3, DMF, 3 h, 60 °C, 89%; 2.8 equiv of
Ph3PdCH2, THF, -78 to 25 °C, 2 h, 87%.
(17) (a) Prepared by N-Teoc protection of (R)-4-fluoro-3-nitrophenylalanine
methyl ester17b (1.5 equiv of Teoc-OBt, 1.5 equiv of Et3N, 50% dioxane-
H2O, 25 °C, 19 h, 92%) followed by methyl ester hydrolysis (1.3 equiv of
LiOH‚H2O, 33% H2O-t-BuOH, 0 °C, 30 min, 100%). (b) Bois-Choussy, M.;
Neuville, L.; Beugelmans, R.; Zhu, J. J. Org. Chem. 1996, 61, 9309.
(18) Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Org.
Lett. 1999, 1, 91.
(a) CF3CONMeTBS, 89%. (b) TrocCl, 93%. (c) H2, Pd/C, 1%
Cl3CCO2H-MeOH. (d) t-BuONO, HBF4; CuCl-CuCl2, 66% from 19.
(e) Dess-Martin; NaClO2, 79%. (f) 10% Zn-Pb, 89%. (g) B-Bromo-
catecholborane; Boc2O, 76%. (h) Dess-Martin; NaClO2, 79%.
(19) An analogous treatment of the unnatural C23 diastereomer derived from
coupling 14 with diastereomerically impure 13 provided the C23 diastereomer
of 17 as a mixture of two atropisomers (75%, ca. 1:1 P:M) which were
chromatographically and spectroscopically distinguishable from 17 ensuring
conversions improved with inclusion of 18-c-6, 4 Å MS, or
CaCO3. Conversion of 4 to 10, coupling with 11,17 and subsequent
oxidation of 12 to the carboxylic acid 13 as detailed in Scheme
1 provided the key EFG tripeptide.
3
that the closure of 15 proceeds without detectable C2 epimerization.
(20) Overman, L. E.; Freerks, R. L. J. Org. Chem. 1981, 46, 2833.
(21) Boger, D. L.; Miyazaki, S.; Loiseleur, O.; Beresis, R. T.; Castle, S.
L.; Wu, J. H.; Jin, Q. J. Am. Chem. Soc. 1998, 120, 8920.
Coupling of 13 with 1411 was effected by DEPBT18 (3.5 equiv,
THF, 0 °C, 2 h, 83%) in good conversion without detectable