Diastereoselective total synthesis of the vancomycin aglycon with ordered atropisomer equilibrations [5]

Full text of DOI:10.1021/ja990189i

3226
J. Am. Chem. Soc. 1999, 121, 3226-3227
Diastereoselective Total Synthesis of the Vancomycin
Aglycon with Ordered Atropisomer Equilibrations
Dale L. Boger,* Susumu Miyazaki, Seong Heon Kim,
Jason H. Wu, Olivier Loiseleur, and Steven L. Castle
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Figure 1.
ReceiVed January 20, 1999
Scheme 1
Vancomycin (1) is the prototypical member of a class of
clinically important glycopeptide antibiotics1-3 enlisted as the
drugs of last resort for the treatment of resistant bacterial infections
or for patients allergic to â-lactam antibiotics.4 The structural
complexity of 1, the interest in defining the structural features
responsible for cell wall biosynthesis inhibition in sensitive bac-
teria,5 and the emergence of clinical resistance6 have generated
considerable interest in 1 and related agents.7-11 Complementary
to recent efforts,9,10 herein we detail a convergent total synthesis
of the vancomycin aglycon (2) (Figure 1). Having established
that the CD and DE ring systems are most effectively closed
through the formation of the diaryl ether linkage12 and having
explored,13 implemented,14 and improved15,16 methodology ame-
nable to macrocyclization of the sensitive vancomycin CD and
DE ring systems, we recently described an indirect strategy for
controlling the three stereochemical elements of atropisom-
erism14,15,17-19 and herein disclose methodology for the formation
(1) McCormick, M. H.; Stark, W. M.; Pittenger, G. E.; Pittenger, R. C.;
McGuire, G. M. Antibiot. Annu. 1955-1956, 606.
(2) Harris, C. M.; Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983,
105, 6915.
(3) Malabarba, A.; Nicas, T. I.; Thompson, R. C. Med. Res. ReV. 1997,
17, 69.
(4) Weidemann, B.; Grimm, H. In Antibiotics in Laboratory Medicine;
Lorian, V., Ed.; Williams and Wilkins: Baltimore, 1996; pp 900-1168.
(5) Williams, D. H.; Searle, M. S.; Westwell, M. S.; Mackay, J. P.; Groves,
P.; Beauregard, D. A. Chemtracts: Org. Chem. 1994, 7, 133.
(6) Walsh, C. T.; Fisher, S. L.; Park, I.-S.; Prahalad, M.; Wu, Z. Chem.
Biol. 1996, 3, 21.
(7) Review: Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S. Chem.
ReV. 1995, 95, 2135.
(8) 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.
(9) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.; Barrow,
J. C.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2700.
(10) Nicolaou, K. C.; Takayanagi, M.; Jain, N. F.; Natarajan, S.; Koumbis,
A. E.; Bando, T.; Ramanjulu, J. M. Angew. Chem., Int. Ed. 1998, 37, 2717.
(11) For related partial structures, see the following and references cited
therein: Konishi, H.; Okuno, T.; Nishiyama, S.; Yamamura, S.; Koyasu, K.;
Terada, Y. Tetrahedron Lett. 1996, 37, 8791. Pearson, A. J.; Zhang, P.; Bignan,
G. J. Org. Chem. 1997, 62, 4536. Rao, A. V. R.; 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. Bois-Choussy, M.; Vergne, C.; Neuville,
L.; Beugelmans, R.; Zhu, J. Tetrahedron Lett. 1997, 38, 5795.
(12) Boger, D. L.; Nomoto, Y.; Teegarden, B. R. J. Org. Chem. 1993, 58,
1425.
(13) Boger, D. L.; Borzilleri, R. M. Bioorg. Med. Chem. Lett. 1995, 5,
1187. Boger, D. L.; Zhou, J. J. Org. Chem. 1996, 61, 3938. Boger, D. L.;
Zhou, J.; Borzilleri, R. M.; Nukui, S. Bioorg. Med. Chem. Lett. 1996, 6, 1089.
Boger, D. L.; Zhou, J.; Borzilleri, R. M.; Nukui, S.; Castle, S. L. J. Org.
Chem. 1997, 62, 2054.
(14) Boger, D. L.; Borzilleri, R. M.; Nukui, S.; Beresis, R. T. J. Org. Chem.
1997, 62, 4721. Boger, D. L.; Borzilleri, R. M.; Nukui, S. Bioorg. Med. Chem.
Lett. 1995, 5, 3091.
(15) Boger, D. L.; Castle, S. L.; Miyazaki, S.; Wu, J. H.; Beresis, R. T.;
Loiseleur, O. J. Org. Chem. 1999, 64, 70.
of the 12-membered biaryl AB ring system. Thus, two aromatic
nucleophilic substitution macrocyclizations of the 16-membered
diaryl ethers were enlisted for sequential CD and DE ring
(16) For related studies, see: Zhu, J. Synlett. 1997, 133. Beugelmans, R.;
Singh, G. P.; Choussy, M.; Chastanet, J.; Zhu, J. J. Org. Chem. 1994, 59,
5535. Rao, A. V. R.; Reddy, K. L.; Rao, A. S. Tetrahedron Lett. 1994, 35,
8465. Rao, A. V. R.; Reddy, K. L.; Rao, A. S.; Vittal, T. V. S. K.; Reddy, M.
M.; Pathi, P. L. Tetrahedron Lett. 1996, 37, 3023. Evans, D. A.; Watson, P.
S. Tetrahedron Lett. 1996, 37, 3251.
(17) Boger, D. L.; Loiseleur, O.; Castle, S. L.; Beresis, R. T.; Wu, J. H.
Bioorg. Med. Chem. Lett. 1997, 7, 3199.
10.1021/ja990189i CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/19/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 13, 1999 3227
formations, an effective macrolactamization was developed for
closure of the 12-membered biaryl AB ring system, and the
defined order of CD, AB, and DE ring closures permitted selective
thermal atropisomerism of the newly formed ring systems or their
immediate precursors. This order permitted the recycling of the
undesired atropisomers and provided a solution to the control of
the stereochemistry funneling all synthetic material into the one
of eight atropdiastereomers characterizing the natural product. The
key to the recognition of this order was the establishment of the
thermodynamic parameters of atropisomerism: DE ring system
(Ea ) 21.1-23.6 kcal/mol) < AB biaryl precursor20 (Ea ) 25.1
kcal/mol) < CD ring system (Ea ) 30.4 kcal/mol).14,15,17-19
Preparation of 3 (4 steps from starting amino acids), equilibra-
tion and recycling of the unnatural atropisomer M-3, and
conversion to P-4 was accomplished as disclosed (Scheme 1).14,15
Both the ease of isomerization and thermodynamic ratio of the
atropisomers were more favorable with 3 versus 4 such that the
former was enlisted for equilibration while conversion to the latter
enhanced the thermodynamic stability of the CD ring system
throughout the synthesis. Suzuki biaryl coupling of 4 with 5 (0.3
equiv of Pd2(dba)3, 1.5 equiv of (o-tolyl)3P, toluene/CH3OH/1 N
aqueous Na2CO3 10/3/1, 80 °C, 15 min)21 provided a 1:1.3 mixture
of S:R 6 in superb yield (88%). Analogous to observations made
with a model AB precursor (eq 1), thermal equilibration of the
Scheme 2
EDCI, 2 equiv of HOAt, THF, 0 °C, 30 min, 57% from 10)
provided 13 and set the stage for DE macrocyclization. Diaryl
ether formation proceeded cleanly upon treatment with CsF (6
equiv, DMSO, 25 °C, 23 h, 75%) to provide a g6:1 mixture of
P:M 18 with the natural DE atropisomer predominating (Scheme
2).15 This preferential generation of the natural stereochemistry
was first disclosed by Evans8,9 with closely related substrates (5:
1) but contrasts with observations described by Nicolaou10 (1:3)
where the unnatural atropisomer predominated with an alternative
substrate and mode of closure. Notably, thermal atropisomerism
of 20 could be conducted without affecting the AB or CD
atropisomer stereochemistry analogous to our prior observations
with 22,19,20 and those conducted with 20 and 22 were much
cleaner than attempts with 18 due to suppressed competing retro
aldol reactions.19 Sandmeyer substitution with introduction of the
E-ring chloride was accomplished without loss of the DE
atropisomer stereochemistry (H2, 10% Pd/C, EtOAc, 25 °C, 3 h;
1.5 equiv of t-BuONO, 1.5 equiv of HBF4, CH3CN, 0 °C, 10
min; 60 equiv of CuCl2, 50 equiv of CuCl, H2O-CH3CN, 25
°C, 1 h, 50-60% overall).14 TBS protection of the secondary
alcohols (60 equiv of CF3CONMeTBS, CH3CN, 50 °C, 22 h;
aqueous citric acid, 25 °C, 13 h, 86%),19 MEM ether deprotection
(5.9 equiv of B-Br catecholborane, CH2Cl2, 0 °C, 2 h; 3.9 equiv
of Boc2O, 4.6 equiv of NaHCO3, 2:1 dioxane/H2O, 25 °C, 2.5 h,
60% for 2 steps), and two-step alcohol oxidation (3.7 equiv of
Dess-Martin periodinane, CH2Cl2, 0 °C, 15 min then 25 °C, 1
h; 9 equiv of NaClO2, 0.7 M NaH2PO4, isobutene/t-BuOH 1/4,
25 °C, 20 min), followed by methyl ester formation (TMSCHN2,
C6H6/CH3OH 4/1, 25 °C, 45 min) provided 22 (66%, 3 steps),
which was identical to material derived from natural vancomy-
cin.19 The final three steps in the conversion of 22 to 2 followed
our disclosed sequence,19 and significantly, the final step involved
clean cleavage of the methyl ester, four methyl ethers, and NBoc
deprotection.
separable atropdiastereomers under conditions where the CD
atropisomer was stable provided an equilibrium 3:1 ratio of S:R
6 in which the natural isomer predominated.20 The minor,
unnatural R-6 was recycled through the use of this thermal
equilibration. Silyl ether deprotection under conditions that
suppress retro aldol cleavage of the CD ring system (4 equiv of
Bu4NF, 4.8 equiv of HOAc, THF, 25 °C, 10 h, 87%),14 methyl
ester hydrolysis (2 equiv of LiOH, THF, 0 °C, 2 h, 96%), and
NCBZ deprotection (H2, cat 10% Pd/C, EtOAc/EtOH 2.5/1, 25
°C, 7.5 h, 99%) provided 9. By enlisting conditions developed
with the model tripeptide 1421 (eq 1), macrolactamization was
effected by treatment with EDCI/HOBt (5 equiv/5 equiv, CH2-
Cl2/DMF 5/1, 0.002 M, 0 °C, 16 h) to provide 10 (62%)
possessing the natural vancomycin ABCD atropisomer stereo-
chemistry (45% from 4 and 21% overall from constituent
subunits). Of the methods examined (eq 1), the EDCI/HOBt
conditions proved most effective with 9.
The longest linear synthetic sequence entailed the preparation
and incorporation of the central amino acid14,22 (31 steps), and
the convergent assemblage of 2 from the seven amino acid
subunits required 26 steps (0.5-1.0% overall). Given the modular
nature of the synthesis and its reliable control of the atropisomer
stereochemistry, it is especially suited for the preparation of
analogues, and such studies are in progress.
Selective NBOC deprotection of 10 (HCO2H-CHCl3 1:1, 25
°C, 5 h, 95%) followed by coupling of 11 with 1214 (2 equiv of
(18) Boger, D. L.; Beresis, R. T.; Loiseleur, O.; Wu, J. H.; Castle, S. L.
Bioorg. Med. Chem. Lett. 1998, 8, 721.
Acknowledgment. We acknowledge the support of NIH (CA41101),
a NSF fellowship (S.L.C., GER-9253922), a NIH fellowship (J.H.W.,
AI09847), a Swiss National Foundation fellowship (O.L.), and a sabbatical
leave for S.M. (Japan Tobacco).
(19) 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.
(20) Details may be found in the Supporting Information. The natural AB
atropisomers within the ABCD and ABCDE ring systems are also the
thermodynamically most stable (g95:5) ensuring that DE equilibration does
not affect the set AB stereochemistry.19
Supporting Information Available: Characterization of 5-24, 2 and
details of the preparations of 5 and 14 are provided (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(21) Brown, A. G.; Crimmin, M. J.; Edwards, P. D. J. Chem. Soc., Perkin
Trans. 1 1992, 123.
(22) Boger, D. L.; Borzilleri, R. M.; Nukui, S. J. Org. Chem. 1996, 61,
3561.
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