Vancomycin CD and DE macrocyclization and atropisomerism studies

Article abstract of DOI:10.1021/jo980880o

Continued studies on the synthesis and atropisomerism of the vancomycin CD and DE ring systems based on aromatic nucleophilic substitution macrocyclization reactions for formation of the biaryl ethers are detailed in efforts that further define substituent effects, explore the impact of protecting groups, and establish the stereochemical integrity of peripheral substituents. These have led to the identification of a previously unrecognized site of epimerization within our original approach to the DE ring system and the introduction of significant improvements in the approach that will find utilization in syntheses of the vancomycin CDE ring system and of the natural product itself. The preparation of a complete set of DE ring system isomers bearing the unnatural stereochemistry at the labile C8, C11, and C14 sites was accomplished for comparison and established that C8 is prone to epimerization to the more stable, unnatural S versus R absolute stereochemistry if it bears an ester, but not a carboxamide, substituent. Additionally, an improved synthesis of the CD ring system, enlisting a C14 carboxamide versus ester substituent, is disclosed and establishes the stereochemical integrity of our prior approach which incorporated a C14 ester. A set of fully functionalized CD and DE ring systems were prepared and include the development of conditions for the final deprotections required for incorporation into efforts on the natural product. The examination of the antimicrobial activity of these key substructures of vancomycin is detailed.

Full text of DOI:10.1021/jo980880o

70
J . Org. Chem. 1999, 64, 70-80
Va n com ycin CD a n d DE Ma cr ocycliza tion a n d Atr op isom er ism
Stu d ies
Dale L. Boger,* Steven L. Castle, Susumu Miyazaki, J ason H. Wu, Richard T. Beresis, and
Olivier Loiseleur
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
Received May 8, 1998 (Revised Manuscript Received October 23, 1998)
Continued studies on the synthesis and atropisomerism of the vancomycin CD and DE ring systems
based on aromatic nucleophilic substitution macrocyclization reactions for formation of the biaryl
ethers are detailed in efforts that further define substituent effects, explore the impact of protecting
groups, and establish the stereochemical integrity of peripheral substituents. These have led to
the identification of a previously unrecognized site of epimerization within our original approach
to the DE ring system and the introduction of significant improvements in the approach that will
find utilization in syntheses of the vancomycin CDE ring system and of the natural product itself.
The preparation of a complete set of DE ring system isomers bearing the unnatural stereochemistry
at the labile C8, C11, and C14 sites was accomplished for comparison and established that C8 is
prone to epimerization to the more stable, unnatural S versus R absolute stereochemistry if it
bears an ester, but not a carboxamide, substituent. Additionally, an improved synthesis of the CD
ring system, enlisting a C14 carboxamide versus ester substituent, is disclosed and establishes
the stereochemical integrity of our prior approach which incorporated a C14 ester. A set of fully
functionalized CD and DE ring systems were prepared and include the development of conditions
for the final deprotections required for incorporation into efforts on the natural product. The
examination of the antimicrobial activity of these key substructures of vancomycin is detailed.
Vancomycin (1, Figure 1), which was isolated in 1956
of the biaryl ethers and detailed an indirect solution to
the control of the atropisomer stereochemistry, enlisting
a selective DE versus CD atropisomer isomerization.9-11
Herein, we provide full details of studies that further
define the scope of the approach to the DE and CD ring
systems which were conducted in an effort to optimize
conditions for cyclization, to examine the effect of differ-
ent protecting groups, to confirm and establish the
stereochemistry, and to define thermal atropisomerism
substituent effects. These studies have resulted in sig-
nificant improvements in the approach and have identi-
from Streptomyces orientalis1 and whose structure was
secured 25 years later,2 is the prototypical member of a
class of clinically important glycopeptide antibiotics.3 It
is the therapeutic agent of choice for the treatment of
methicillin-resistant Staphylococcus aureus and is rou-
tinely used against enterococci and bacterial infections
in patients allergic to â-lactam antibiotics.4 The struc-
tural complexity of vancomycin, the interest in defining
structural features it possesses that are responsible for
inhibition of cell-wall biosynthesis in sensitive bacteria,5
and the emergence of clinical resistance6 have provided
renewed interest in the total synthesis of 1 and related
agents.7-14 In recent studies, we disclosed the synthesis
of appropriately functionalized vancomycin CD, DE, and
CDE ring systems on the basis of aromatic nucleophilic
substitution macrocyclization reactions with formation
(8) For recent disclosures: (a) 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. (b) Konishi, H.; Okuno, T.; Nishiyama, S.; Yamamura, S.;
Koyasu, K.; Terada, Y. Tetrahedron Lett. 1996, 37, 8791. (c) Pearson,
A. J .; Zhang, P.; Bignan, G. J . Org. Chem. 1997, 62, 4536. (d) 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. (e) Bois-Choussy, M.; Vergne, C.; Neuville, L.; Beugelmans,
R.; Zhu, J . Tetrahedron Lett. 1997, 38, 5795. (f) Nicolaou, K. C.; Boddy,
C. N. C.; Natarajan, S.; Yue, T.-Y. Li, H.; Bra¨se, S.; Ramanjulu, J . M.
J . Am. Chem. Soc. 1997, 119, 3421.
(9) Boger, D. L.; Beresis, R. T.; Loiseleur, O.; Wu, J . H.; Castle, S.
L. Bioorg. Med. Chem. Lett. 1998, 8, 721.
(10) Boger, D. L.; Loiseleur, O.; Castle, S. L.; Beresis, R. T.; Wu, J .
H. Bioorg. Med. Chem. Lett. 1997, 7, 3199.
(11) 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.
(12) Boger, D. L.; Borzilleri, R. M.; Nukui, S. J . Org. Chem. 1996,
61, 3561.
(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. Williamson, M. P.; Williams, D. H. J . Am. Chem. Soc. 1981,
103, 6580. Sheldrick, G. M.; J ones, P. G.; Kennard, O.; Williams, D.
H.; Smith, G. A. Nature (London) 1978, 271, 223. Williams, D. H.;
Kalman, J . R. J . Am. Chem. Soc. 1977, 99, 2768.
(3) Nagarajan, R. J . Antibiot. 1993, 46, 1181. Cooper, R. D. G.;
Thompson, R. C. Annu. Rep. Med. Chem. 1996, 31, 131. Malabarba,
A.; Nicas, T. I.; Thompson, R. C. Med. Res. Rev. 1997, 17, 69.
(4) Weidemann, B.; Grimm, H. In Antibiotics in Laboratory Medi-
cine; 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) Reviews: Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S.
Chem. Rev. 1995, 95, 2135. Evans, D. A.; DeVries, K. M. In Glycopep-
tide Antibiotics; Nagarajan, R., Ed.; Marcel Dekker: New York, 1994;
pp 63-104.
(13) Boger, D. L.; Nomoto, Y.; Teegarden, B. R. J . Org. Chem. 1993,
58, 1425.
(14) For additional studies, see: Beugelmans, R.; Singh, G. P.; Bois-
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.
10.1021/jo980880o CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/09/1998

Vancomycin CD and DE Ring Systems
J . Org. Chem., Vol. 64, No. 1, 1999 71
Sch em e 1
ee)11,12 provided 10 as a single detectable diastereomer
(76%). N-CBZ deprotection (H2, Pd/C, 95%) followed by
coupling with N-BOC-3-(2R,3R)-hydroxy-3-(4-fluoro-3-
nitrophenyl)alanine11,15c (12) provided 13 accompanied by
a significant amount of the diastereomer derived from
C14 epimerization.17 Without optimization, subjection of
13 to macrocyclization by treatment with K2CO3/CaCO3
(5.0 equiv/7.5 equiv, 2 wt equiv of 4 Å MS, 0.008 M DMF,
45 °C, 49 h) provided a separable 1.3:1 mixture of the
two atropisomers of 14 with the unnatural M atropisomer
predominating slightly.18 Although not examined in
detail, the ring closure appears slower and lower yielding
than that used to prepare 4.11 The comparison of (M)-
and (P)-14 with both atropisomers of 4 and the minor
C8 diastereomer19 of 4 confirmed they were distinct and
that the macrocyclization enlisted in the preparation of
4 proceeded without detectable C11 epimerization.20
C14 Dia ster eom er of th e DE Rin g System . During
the course of prior studies, ample quantities of the minor
diastereomer 15,11 derived from coupling of tert-butyl (S)-
(â-cyano)alanyl-(R)-(3,5-dihydroxy-4-methoxyphenyl)gly-
F igu r e 1.
fied a previously unrecognized site of epimerization15
within our prior approach to the DE ring system. Since
the DE ring system of vancomycin incorporates four of
the five key H-bonding sites for NAc-D-Ala-D-Ala binding,
the biological evaluation of a set of fully functionalized
DE and CD ring systems was conducted and constitutes
the examination of key substructures of the natural
product.
C11 Dia ster eom er of th e DE Rin g System . In the
course of efforts on the preparation of the DE ring system,
the C11 and C14 centers emerged as sites that are
susceptible to epimerization when activated for coupling
at the adjacent carboxylate. Typically, the couplings that
link C13 to N12 or enlist the N-terminus dipeptide when
constructing C10-N9 require effort to minimize racem-
ization, suggesting that substrates incorporating the
dipeptide may be prone to epimerization. To ensure that
such an epimerization at either site does not accompany
macrocyclization, both 14 and 16 were prepared for
comparison.
(16) N-CBZ-D-(â-cyano)alanine (9) was prepared following the pro-
cedure detailed for the L enantiomer: CBZNH-D-Asn (1.0 equiv DCC,
pyridine, 55%), Ressler, C.; Ratzkin, H. J . Org. Chem. 1961, 26, 3356.
For D-9: [R]25 +43 (c 0.5, DMF). (S)-8 was prepared by enlisting the
D
(DHQ)2PHAL ligand in the AA reaction following the procedure
detailed11,12 for the R enantiomer. For (S)-8: [R]25 +54 (c 0.27, CH3-
D
OH). (S)-41: [R]25 +74 (c 0.8, CH3OH), was prepared as an intermedi-
D
ate en route to (S)-8 and converted to 43: [R]25 +13 (c 0.08, CHCl3)
D
EDCI-HOAt, CH2Cl2-DMF 4:1, 4 °C, 18 h, 85%, [R]25 +142 (c 0.4,
D
CHCl3); H2, Pd/C, CH3OH-EtOAc 1:1, 25 °C, 5 h, 98%.
(17) Upon completion of this work, we have established that the
predominant extent of C14 epimerization occurs upon hydrolysis of
the precursor methyl ester rather than during the amide coupling
reaction. This can be minimized by conducting the hydrolysis at 0 °C
for a minimum reaction period.
The preparation of 14 is detailed in Scheme 1. Thus,
coupling of N-CBZ-(R)-(â-cyano)alanine (9)16 with tert-
butyl (R)-(3,5-dihydroxy-4-methoxyphenyl)glycine (8, g99%
(18) In preceding reports, we believe we have reversed the M and P
stereochemical representations which may be attributed to ambiguities
in the assignment of the pilot atom and its orientation for assignment
of M and P: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; pp 1120-1122 versus Cahn, R.
S.; Ingold, C.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1966, 5, 385.
For the present assignments, the pilot atoms selected are the C15 OR
(CD) and C15 OR (DE) substituents, and the chiral plane (the C ring
for CD, the E ring for DE) is viewed from the point of view of the pilot
atom (i.e., the pilot atom is placed above the chiral plane).
(15) For examples of such epimerizations preceding or accompanying
macrocyclization with biaryl ether formation: (a) Pearson, A. J .; Zhang,
P.; Bignan, G. J . Org. Chem. 1997, 62, 4536. (b) 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. (c) Boger, D. L.;
Zhou, J .; Borzilleri, R. M.; Nukui, S.; Castle, S. L. J . Org. Chem. 1997,
62, 2054. (d) For observations analogous to those described herein,
see: Pearson, A. J .; Chelliah, M. V. J . Org. Chem. 1998, 63, 3087.

72 J . Org. Chem., Vol. 64, No. 1, 1999
Boger et al.
Sch em e 2
cine with 12, were accumulated. Without optimization,
subjection of 15 to macrocyclization with K2CO3/CaCO3
(5.0 equiv/7.5 equiv, 2 wt equiv of 4 Å MS, 0.008 M DMF,
48 °C, 24 h) provided a 4:1 mixture of the two separable
atropisomers of 16 (43%) in which the unnatural M-
isomer was favored (Scheme 2), and the closure proceeded
at a rate analogous to that observed with 4. The com-
parison of 4 and its minor C8 diastereomer19 with the
two atropisomers of 16 confirmed that they are distin-
guishable and that the preparations of 4 proceeded
without detectable C14 epimerization.20 Attempts to
cyclize 15 with CsF (5 equiv, 0.005 M DMF or DMSO,
25 °C) provided a much more polar set of atropisomers
in yields as high as 75% containing isomers which were
easily distinguishable from 4 or 16. These possessed a
higher molecular weight, indicative of further substrate
reactions, and although their identification was not
pursued, more detailed studies with 4 implicated C8
oxidation.21
enlisting the corresponding nitrile. A (4,4’-dimethoxy-
diphenyl)methyl (Ddm)22 protected L-Asn was also ex-
amined in light of its use in related efforts8,14 to assess
whether it might favorably impact the macrocyclization
reaction. In particular, we were interested in establishing
whether the liberated fluoride might prove sufficiently
basic to promote â-elimination through R-deprotonation
of the nitrile, thus lowering the apparent effectiveness
of our original approach. Thus, coupling of N-CBZ-N’-
Ddm-(S)-Asn22 (17) with (R)-8 cleanly provided the
dipeptide 18 (92%) as a single detectable diastereomer
(Scheme 3). N-CBZ deprotection (H2, Pd/C, 100%) fol-
lowed by coupling of the free amine 19 with 12 (2.2 equiv
of EDCI, 1.2 equiv of HOBt, DMF, 0-4 °C, 15 h, 73%)
provided the tripeptide 20 as a separable 1.8:1 mixture
of diastereomers without optimization.17 Under compa-
rable conditions, the L-(â-cyano)alanine-containing dipep-
tide provided a more favorable 6:1 ratio of C14 diaster-
eomers.11 Macrocyclization upon treatment with K2CO3/
CaCO3 (5.0 equiv/7.7 equiv, 2 wt equiv of 4 Å MS, 0.008
M DMF, 45 °C, 47 h) provided a mixture of the two
atropisomers of 2120 in a yield (47% versus 59%) and
atropisomer diastereoselectivity (1:1.3 versus 1:1.3 M:P)
comparable, but not superior, to the substrate bearing a
nitrile. Analogous to observations made with 16 and in
our prior efforts,11 attempted closure of 20, enlisting CsF
Alter n a tive L-Asn Resid u es. In our prior studies, the
L-Asn residue in the DE ring system was protected
(19) Trace amounts (<7-8%) of a C8 diastereomer were detected
and isolated when the macrocyclization leading to 4 was prematurely
quenched. The diastereomer, not detected in the closure of 23, rapidly
and completely epimerized to 24 upon treatment with base. Thus,
treatment of (P)-30 or (P)-24 with 2 equiv of DBU (THF-d8, 25 °C) or
3 equiv of K2CO3 (DMF-d7, 25 °C) provided a 3-5:95-97 mixture of
(P)-30:(P)-24 in the time that it takes to immediately record the 1H
NMR. Conformational searches conducted on both atropisomers of the
8R and 8S diastereomers 30/24, 28/29, 37/45 (MacroModel BatchMin
6.0, OPLSA Force Field) revealed a preference for the unnatural 8S
diastereomer (∆E ) 2.3-3.9 kcal/mol) which is consistent with the
experimental observations, the epimerization of 30 to 24, and the
assigned stereochemistries. The natural 8R-37 proved more resistant
toward C8 epimerization than 30. Thus, treatment of 37 with 2 equiv
of DBU (THF, 25 °C, 40 min), 5 equiv of K2CO3 (DMF, 45 °C, 12 h), or
5 equiv CsF (DMF, 25 °, 8 h) led to generation of 20%, 58%, and 5%,
respectively, of the C8 diastereomer 45 and the equilibrium ratio of
8S:8R was established to be 95:5. Data for tert-butyl (M)- and (P)-(8R,-
11S,14R,15R)-14-[N-[(tert-butyloxy)carbonyl]amino]-11-(cyanomethyl)-
5, 15,-dihydroxy-10,13-dioxo-4-methoxy-18-nitro-9,12-diaza-2-oxatricyclo-
[14.2.2.13,7]heneicosa-3,4,7(21),16,18,19-hexaene-8-carboxylate (30) follow.
(M)-30 (the less polar isomer): [R]25 +78 (c 0.22, CH3OH); 1H NMR
D
(acetone-d6, 400 MHz) δ 8.28-8.21 (m, 1H), 8.20 (s, 1H), 8.16 (s, 1H),
7.96 (d, 1H, J ) 8.1 Hz), 7.53-7.47 (m, 1H), 7.44 (d, 1H, J ) 8.4 Hz),
6.60 (s, 1H), 6.27 (d, 1H, J ) 8.4 Hz), 5.46 (d, 1H, J ) 1.9 Hz), 5.27 (s,
1H), 5.14-5.06 (m, 1H), 4.99 (d, 1H, J ) 7.0 Hz), 4.73-4.68 (m, 1H),
4.62-4.55 (m, 1H), 3.95 (s, 3H), 2.93-2.77 (m, 2H), 1.44 (s, 9H), 1.40
(s, 9H); IR (neat) νmax 3326, 1660, 1537, 1341, 1249, 1158 cm-1
;
FABHRMS (NBA-CsI) m/z 804.1529 (M+ + Cs, C31H37N5O12 requires
804.1493). The 2D 1H-1H ROESY NMR spectrum (CD3OD, 600 MHz,
25 °C) of (M)-30 exhibited the following diagnostic NOE cross-peaks:
H-20/H-19 (s, δ 7.75/7.35), H-20/H-15 (s, δ 7.75/5.15), H-20/H-14 (s, δ
7.75/4.56), H-15/H-14 (s, δ 5.15/4.56), H-6/H-8 (m, δ 6.50/4.77), H-11/
CH2CN (m, δ 4.48/2.84 and 4.48/2.71). For (P)-30 (the more polar
(21) The chemical shifts of C6-H, C21-H, C8-H, and N9-H shift
dramatically (>1 ppm) and the signals previously attributable to C8-H
and N9-H collapse to singlets versus doublets. For the major atropi-
somer derived from 15: [R]25D -11.6 (c 0.01, CHCl3); 1H NMR (acetone-
d6, 400 MHz) δ 9.22 (s, 1H), 8.21 (d, 1H, J ) 8.2 Hz), 8.11 (s, 1H), 7.76
(d, 1H, J ) 8.7, 2.2 Hz), 7.36 (d, 1H, J ) 2.1 Hz), 7.26 (br s, 1H), 7.13
(s, 1H), 7.11 (d, 1H, J ) 7.2 Hz), 6.76 (br s, 1H), 6.47 (d, 1H, J ) 8.3
Hz), 5.47 (d, 1H, J ) 4.2 Hz), 5.11-5.09 (m, 1H), 4.77-4.71 (m, 1H),
4.35 (t, 1H, J ) 8.5 Hz), 3.92 (s, 3H), 3.05 (dd, 1H, J ) 17.1, 5.3 Hz),
2.93 (dd, 1H, J ) 17.1, 7.6 Hz), 1.56 (s, 9H), 1.30 (s, 9H); IR (film) νmax
3313, 2923, 1676, 1539, 1349, 1246, 1133 cm-1; FABMS (NBA-NaI)
m/z 710 (C31H37N5O12 requires 694). For the product derived from 20
(40%): 1H NMR (acetone-d6, 400 MHz) δ 9.09 (s, 1H), 8.18-8.14 (m,
2H), 7.97 (d, 1H, J ) 8.0 Hz), 7.77 (dd, 1H, J ) 8.8, 2.1 Hz), 7.35 (d,
1H, J ) 2.0 Hz), 7.28 (s, 1H), 7.19-7.16 (m, 4H), 7.12-7.08 (m, 2H),
6.88-6.82 (m, 4H), 6.55 (s, 1H), 6.22 (d, 1H, J ) 9.2 Hz), 6.10 (d, 1H,
J ) 8.3 Hz), 5.80 (d, 1H, J ) 3.5 Hz), 4.94-4.90 (m, 1H), 4.78-4.74
(m, 1H), 4.33 (t, J ) 8.6 Hz), 3.86 (s, 3H), 3.76 (s, 3H), 3.75 (s, 3H),
1.54 (s, 9H), 1.23 (s, 9H); FABMS (NBA-NaI) m/z 955 (M+ + Na,
isomer): [R]25 +65 (c 0.18, CH3OH); 1H NMR (acetone-d6, 400 MHz)
D
δ 8.25 (s, 1H), 8.20 (s, 1H), 7.94 (d, 1H, J ) 5.6 Hz), 7.82 (d, 1H, J )
7.3 Hz), 7.76 (d, 1H, J ) 8.4 Hz), 7.26 (d, 1H, J ) 8.6 Hz), 6.66 (s, 1H),
6.34 (d, 1H, J ) 7.6 Hz), 5.69 (s, 1H), 5.31-5.26 (m, 1H), 5.13 (d, 1H,
J ) 7.8 Hz), 5.07 (d, 1H, J ) 6.8 Hz), 4.68-4.60 (m, 1H), 4.56 (d, 1H,
J ) 5.6 Hz), 3.94 (s, 3H), 2.85-2.75 (m, 2H), 1.44 (s, 9H), 1.38 (s, 9H);
IR (neat) νmax 3410, 3287, 1668, 1634, 1537, 1254, 1158 cm-1
;
FABHRMS (NBA-CsI) m/z 804.1529 (M+ + Cs, C31H37N5O12 requires
804.1493). The 2D 1H-1H ROESY NMR spectrum (CD3OD, 600 MHz,
25 °C) of (P)-30 exhibited the following diagnostic NOE cross-peaks:
H-17/H-15 (s, δ 8.12/5.14), H-17/H-14 (s, δ 8.12/4.41), H-20/H-19 (s, δ
7.79/7.17), H-19/H-21 (m, δ 7.17/5.62), H-15/H-14 (s, δ 5.14/4.41), H-6/
H-8 (s, δ 6.53/4.79), H-11/CH2CN (m, δ 4.52/2.78 and 4.52/2.70).
(20) Tentative C8 stereochemical assignments for 16 and 21 are also
the unnatural, epimerized 8S stereochemistry. A conformational search
of both atropisomers of the C8 diastereomers of 16 (MacroModel
BatchMin 6.0, OPLSA) established that the unnatural 8S diastereo-
mers were substantially more stable (∆E ) >2.5 kcal/mol). For 21,
this is analogous to observations made with 4 and further supported
by its relative ease of atropisomerism, see Table 2. Product 14 has
been tentatively assigned the natural 8R stereochemistry on the basis
of a conformational search (MacroModel, BatchMin 6.0, OPLSA)
conducted on both atropisomers of the C8 diastereomers in which the
natural, nonepimerized 8R configuration was established to be more
stable (∆E ) 1.1-2.7 kcal/mol).
C
46H53O15N5 requires 939). For the products derived from 31 (70%):
1H NMR (acetone-d6, 400 MHz) δ 9.09 (s, 1H), 8.19 (d, 1H, J ) 7.8
Hz), 8.14 (s, 1H), 7.77 (dd, 1H, J ) 8.5, 2.2 Hz), 7.35 (d, 1H, J ) 2.0
Hz), 7.35-7.33 (m, 1H), 7.12 (s, 1H), 7.11 (d, 1H, J ) 8.6 Hz), 6.78-
6.76 (m, 1H), 6.31 (d, 1H, J ) 9.0 Hz), 5.61 (d, 1H, J ) 3.1 Hz), 5.01
(d, 1H, J ) 9.0 Hz), 4.80-4.76 (m, 1H), 4.43 (t, 1H, J ) 9.0 Hz), 3.92
(s, 3H), 2.98-2.82 (m, 2H), 1.56 (s, 9H), 1.18 (s, 9H); IR (film) νmax
3313, 2923, 2246, 1676, 1539, 1349, 1133 cm-1; FABMS (NBA-NaI)
m/z 710 (M+ + Na, C31H37O12N5 requires 694).
(22) Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 2041. Prepared by
treatment of CBZNH-Asn with bis(4-methoxyphenyl)carbinol (cat. H2-
SO4, HOAc, 25 °C, 13.5 h, 84%).

Vancomycin CD and DE Ring Systems
J . Org. Chem., Vol. 64, No. 1, 1999 73
Sch em e 3
Sch em e 4
complicated by what proved to be a concentration-
dependent 1H NMR behavior attributable now to its
dimerization or oligomerization in relatively nonpolar
solvents.15 Conformational analyses19 of 4 and 24 re-
vealed a significant preference for the unnatural 8S
diastereomer, consistent with an unrecognized epimer-
ization that accompanied cyclization to provide 4. As
outlined below, this was further implicated in deliberate
epimerization studies of a minor diastereomer isolated
along with 4 and verified by the correlations of 24, our
prior samples of 4, and its minor diastereomer19 with the
C8 hydroxymethyl and N-methyl carboxamide cyclization
products 28 and 37/45, which were established to close
without significant competitive epimerization.
(5 equiv, 25 °C, 0.008 M) in either DMF (48 h) or DMSO
(24 h), provided only low yields of 21 (21%, 1:1 mixture
of atropisomers) and afforded, predominately, a much
more polar cyclized product (40%)21 that possessed a
molecular weight 16 mass units higher than the desired
products. Although the identity of this undesired cycliza-
1
tion product was not established, analysis of the H NMR
indicated potential epimerization and oxidation of the C8
center under the reaction conditions.21 Important for our
considerations, this established that the failure of the
CsF-promoted closure with 411 was not attributable to a
fluoride-induced â-elimination within the nitrile-contain-
ing L-Asn subunit. Unlike samples of 4, a sample of 21
was only partially resolved by chromatography (3.5%
CH3OH-CHCl3, PTLC) into a 1.8:1 mixture enriched in
the less polar M atropisomer and a 1:3.2 mixture enriched
in the more polar P atropisomer. This difficulty in
separating the two atropisomers coupled with the slightly
lower macrocyclization conversions and the failure to
withstand CsF-promoted closure suggests no immediate
advantage to the use of 20 and a Ddm-protected Asn.
C8 Dia ster eom er of th e DE Rin g System . The
acidic C8 center on the central phenylglycine had been
anticipated to be problematic, and our efforts to promote
the closure to 4 with CsF versus K2CO3 were not
successful11 and provided products implicating additional
reactions at this center. This behavior required the
preparation and comparison of the C8 diastereomer 24
in order to unambiguously establish the expected stere-
ochemical assignments. Thus, coupling of 2211 with (S)-
816 provided 23 (72%) accompanied by a separable minor
diastereomer derived from C11 epimerization (Scheme
4). Macrocyclization of 23 upon treatment with K2CO3/
CaCO3 (5.0 equiv/7.5 equiv, 2 wt equiv of 4 Å MS, 0.008
M DMF, 45 °C, 35 h) cleanly provided a 1:1.5 mixture of
the separable atropisomers of 24 (44% unoptimized)
whose atropisomer stereochemistries were established by
Esta blish m en t of th e C8 Ster eoch em istr y. The C8
stereochemistry was unambiguously established by ex-
amining the (8R)-hydroxymethyl derivative 28, incapable
of epimerization upon cyclization of 27 (Scheme 5), and
its correlation with the reduction products derived from
24 and with its C8 diastereomer.19 N-CBZ and benzyl
ether deprotection of 2511,12 (H2, Pd/C, 100%) followed by
coupling of the free amine 26 with 2211 provided 27 (57%).
Macrocyclization of 27 upon treatment with CsF (DMSO,
25 °C, 24 h) provided 28 as a separable 1.3:1 mixture of
atropisomers (Scheme 5).
LiBH4 reduction23 of samples of (M)-4 which were
identical with (M)-24 did not provide (M)-28 establishing
their C8 stereochemistry as the unnatural 8S configu-
ration. In contrast, the minor C8 diastereomer19 (P)-30
did provide (P)-28 upon reduction, establishing its 8R
stereochemistry and the strong thermodynamic prefer-
ence for the unnatural 8S stereochemistry (Scheme 5).
Th e DE Rin g System : A C-Ter m in u s Ca r boxa m -
id e. Independent of these efforts and providing the
impetus for the studies described above, the potential for
epimerization at the central amino acid phenylglycine C8
site was first implicated in unsuccessful efforts at closing
4. Prior macrocyclization attempts at the formation of 4
with CsF (5 equiv, 0-25 °C, DMSO, DMF) instead of K2-
CO3/CaCO3 provided the desired products in low conver-
1
2D H-1H NMR along with recovered starting material
(51%). Ultimately, the putative C8 diastereomer 24
proved identical to our prior samples of 4, indicating C8
epimerization to provide a single dominant, albeit unas-
signed, C8 diastereomer.19 This comparison was initially
(23) Brown, H. C.; Narasimhan, S. J . Org. Chem. 1982, 47, 1604.

74 J . Org. Chem., Vol. 64, No. 1, 1999
Boger et al.
Sch em e 5
Sch em e 6
unnatural 8S stereochemistry. Deprotection of the tert-
butyl ester 3211 (HCO2H, 100%) followed by N-methyla-
mide formation (EDCI/HOBt, DMF, 4 °C, 84%) provided
34 as a single detectable diastereomer (Scheme 6). N-CBZ
deprotection (H2, Pd/C, 99%), followed by coupling of the
free amine 35 with 12 (EDCI/HOAt, DMF, 4 °C, 68%),
provided the macrocyclization substrate 36. Macrocy-
clization of 36 upon treatment with K2CO3/CaCO3 (5.0
equiv/7.5 equiv, 2 wt equiv of 4 Å MS, 0.008 M DMF, 45
°C) was unusually sluggish, providing no product after
24 h, little product after 48 h, and approximately 20%
37 after 110 h. However, CsF-promoted macrocyclization
proved successful, affording a 1.2:1 mixture of separable
P and M diastereomers in 65% yield (5.4 equiv CsF, 0.008
M DMSO, 25 °C, 11.5 h), favoring the natural atropiso-
mer. Conducting this reaction in DMF led to substantial
amounts of recovered starting material, and the use of
DMSO significantly increased the rate of cyclization. In
contrast to the closure leading to 4, the closure of 36
proceeded, without significant C8 epimerization, to pro-
vide 37 accompanied by e10% of 45. Reduction of (P)-37
(H2, Pd/C, CH3OH, 98%), diazotization (1.3 equiv of HBF4,
1.3 equiv of t-BuONO, CH3CN, 0 °C, 1-1.5 h), and
Sandmeyer substitution (60 equiv of CuCl2, 20 equiv of
CuCl, H2O, 25 °C, 1.5 h, 76%) provided (P)-40 available
for final conversion to a fully functionalized vancomycin
DE ring system. Notably, the conversions for introduction
of the DE aryl chloride have improved considerably over
our initial disclosure,11 as our technical experience with
them has matured.
sions (ca. 20%) and the major products isolated (70%)
implicated additional reactions at the C8 center (eq 1).
The chemical shifts of C6-H, C21-H, C8-H, and N9-H of
the major cyclized products moved by >1 ppm relative
to those of 4, the doublets observed for C8-H and N9-H
in 4 collapsed to singlets, and the product atropisomers
possessed a molecular weight 16 mass units higher than
that of the desired product, suggesting deprotonation and
oxidation of the C8 center.21 These observations contrast
those of both Evans and Zhu who have disclosed the use
of CsF under mild conditions to promote related macro-
cyclizations in systems where the C8 center was not
substituted with an ester.8,14
Similarly, coupling of (S)-43, derived from (S)-41,16
with 2211 provided 44 (79%), Scheme 7. CsF-promoted
macrocyclization (DMSO, 25 °C, 12 h) provided 45 (73%),
possessing the unnatural 8S stereochemistry, as a sepa-
rable 1.3:1 mixture of M:P atropisomers which were
readily distinguishable from 37.
In efforts that define the source of these distinctions,
(8R)-N-methylcarboxamide 37 and its unnatural (8S)-
epimer 45 were prepared. The correlation of 45, not 37,
with 4 served as the first indication that 4 possessed the
Correlation of 4 and its minor C8 diastereomer 3019
with 45 and 37, respectively, first established the previ-

Vancomycin CD and DE Ring Systems
J . Org. Chem., Vol. 64, No. 1, 1999 75
Sch em e 7
Sch em e 8
opportunities for thermal atropisomerism of the CD ring
system that were not accessible with the labile free
alcohol.10,11 Since the atropisomerism instability of the
free alcohol was attributable in part to a thermal retro
aldol reaction, a substrate bearing a less acidic C14
center might survive the thermal atropisomerism condi-
tions without such a deliberate alcohol protection.
In addition, efforts to promote the macrocyclization of
49 with CsF (DMF or DMSO, 25 °C, 24 h) failed to
provide the desired cyclization products and appeared to
provide epimers and/or retro aldol products instead.11,25
Thus, in conjunction with our thermal atropisomerism
studies and as a consequence of the success of the DE
macrocyclization with substrates bearing a C8 carboxa-
mide, we examined the macrocyclization substrate 54
substituted with a C14 carboxamide. Low-temperature
methyl ester hydrolysis of 4911 provided the carboxylic
acid 52 (85%) (Scheme 9). Coupling with methylamine
(EDCI-HOBt, DMF, 0-5 °C, 24 h, 64%) cleanly afforded
53 with no evidence of epimerization. TBDMS deprotec-
tion in the presence of HOAc (6 equiv of Bu4NF, 5 equiv
of HOAc, THF, 0-25 °C, 1.5 h, 83%) provided the
cyclization substrate 54 without competitive retro aldol
or initiation of the macrocyclization reaction. Closure of
53 or 54 under the K2CO3/CaCO3 conditions (5.5 equiv/
5.5 equiv, 2 wt equiv of 4 Å MS, DMF, 45 °C) was much
slower than the corresponding methyl ester substrate (14
h, 45 °C, 60%),11 and after 48 h (45 °C), the separable
atropisomers of 57 and 55 were isolated in 43% and 32%
yield with 22% and 50% of the unreacted starting
material recovered, respectively. In the case of the closure
of 53, this occurred without OTBDMS deprotection. In
contrast, CsF (5.6 equiv) proved more effective at pro-
moting the cyclization of 54 (0.008 M DMSO, 25 °C, 11
ously unrecognized C8 epimerization of 4 (Scheme 7) and
led to the initiation of the preceding studies. More
importantly, the distinguishable properties of 37 and 45
coupled with their successful correlations with 30/4/24
and, ultimately, 28/29 confirmed that the macrocycliza-
tions of the N-methyl carboxamides 36 and 44 proceeded
without significant C8 epimerization. Completion of the
preparation of the fully functionalized DE ring system
involved N-BOC deprotection of 40 (3 M HCl/EtOAc, 25
°C, 0.5 h, 100%), coupling the amine hydrochloride 46
with BOCNMe-D-Leu (EDCl/HOAt, 4:1 CH2Cl2/DMF, 0
°C, 2 h, 65%), and nitrile hydration of 47 under acidic
conditions enlisting moist, saturated HCl/Et2O,24 which
also served to deprotect the N-BOC group providing 48
(Scheme 8).
CD Rin g System Cycliza tion . In preceding studies,
we also disclosed the macrocyclization of 49,11 enlisting
K2CO3/CaCO3 under conditions where the C15 TBDMS
protecting group was not removed (eq 2). Although this
(25) Treatment of 49 with CsF (5.0 equiv, DMSO, 65%, 4:1, 25 °C,
15 h) provided two diastereomeric cyclization products that did not
correlate with 51, and conducting the reaction in DMF provided a
second pair of diastereomers (70%, 2.5: 1) that also did not correlate
with 51. For the product derived from the DMF reaction: 1.5:
1
mixture of rotamers: [R]25D +7 (c 0.019, CHCl3); 1H NMR (acetone-d6,
400 MHz) δ 8.37 (m, 1H), 8.19 (d, 1H, J ) 2.1 Hz), 8.03 (m, 1H), 7.90
(dd, 1H, J ) 8.4, 1.9 Hz), 7.01 (m, 1H), 7.41 (dd, 1H, J ) 8.4, 2.0 Hz),
7.12 (d, 1H, J ) 8.5 Hz), 6.69 (m, 1H), 5.74-5.67 (m, 2H), 5.53-5.37
(m, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.73 (s, 3H), 1.22 (s, 9H), 0.44 (s,
9H); IR (film) νmax 3410, 2956, 1742, 1710, 1680, 1580, 1530, 1495,
1343, 1255, 1100 cm-1; FABHRMS (NBA) m/z 907.0471 (M+ + Cs,
was similarly successful employing the free alcohol, this
closure to provide 2 highlighted the effective scavenging
of the liberated fluoride by the added CaCO3 and provided
(24) Garcia Ruano, J . L.; Martin Castro, A. M.; Rodriguez, J . H. J .
Org. Chem. 1992, 57, 7235.
C
33H35O13N14Br requires 907.0438).

76 J . Org. Chem., Vol. 64, No. 1, 1999
Boger et al.
Sch em e 9
Th er m a l Atr op isom er ism . We have disclosed that
the thermal interconversion of the CD and DE ring
system atropisomers proceeds rapidly at temperatures
of g155 °C and more slowly at 140 °C. This allows the
undesired atropisomers to be thermally equilibrated,
chromatographically reisolated, and recycled to provide
the desired atropisomers. The precursor CD and DE nitro
derivatives were found to equilibrate more rapidly than
the corresponding chloro atropisomers, and the rate of
isomerization could be controlled not only by the choice
of temperature but also by the choice of solvent. Signifi-
cantly, the equilibration of the DE atropisomer occurred
much more rapidly than that of the CD ring system. This
suggested that it would be possible to equilibrate the DE,
as opposed to the CD, atropisomers within an intact CDE
ring system or the ABCDE ring system of vancomycin
itself and that this would be best conducted with a DE
aryl nitro intermediate containing the installed CD aryl
chloride.11 This has been successfully implemented10,27
and suggested a preferred order to the synthetic intro-
duction of the CD and DE ring systems in which the CD
ring system is assembled first and the atropisomer
stereochemistry set with equilibration of its aryl nitro
derivative. Following conversion to the CD aryl chloride,
introduction of the DE ring system and subsequent
selective DE atropisomer equilibration provides a unique
solution to the control of vancomycin CDE atropisomer
stereochemistry.9 Consequently, the thermal atropisom-
erism of the substituted CD and DE ring systems
disclosed herein was examined to further define its scope.
The thermal equilibration of 55 and 57 was examined
for comparison with 2, 3, and 51. In preceding studies,10,11
the protected alcohols 2 and 3 were found to most rapidly
equilibrate in DMSO and DMF and to do so much more
slowly in o-Cl2C6H4 (Table 1). Even in DMSO, little or
no equilibration was observed at 120 °C, slow equilibra-
tion was observed at 140 °C, and rapid equilibration was
observed at 155 °C. The nitro derivative 2 equilibrated
more rapidly than the corresponding chloro derivative
3. In contrast, the free alcohol 5111 failed to undergo clean
atropisomerism in either DMSO or o-Cl2C6H4 (140 °C).10
Although this was not investigated in detail, retro aldol
ring cleavage contributed in part to this instability. The
retro aldol product (>10%) and five additional minor
products appear early in the thermal isomerism, and
comparable side reactions are not observed with 2 or 3.
This led to initial adoption of a synthetic approach to the
CD and CDE ring systems that incorporates and pre-
serves protection of the C15 alcohol despite challenges
this introduces for macrocyclization via biaryl ether
formation.9,11,27 One important element of thermal atro-
pisomerism that we wanted to examine with 55 was the
potential impact that the lower acidity of the C14
position, resulting from the carboxamide substitution,
would have on the competitive retro aldol reaction of the
free alcohol. Like 51, thermal equilibration attempts with
55 in DMSO (140 °C) provided only retro aldol products,
and no atropisomer was detected by 1H NMR. In contrast
to 51, 55 was found to cleanly thermally equilibrate in
o-Cl2C6H4 without competitive retro aldol, to do so slightly
more rapidly than the corresponding TBDMS-protected
alcohol, and to provide a slightly more favorable ratio of
atropisomers. All three of these attributes of the thermal
atropisomerism of 55, along with its slow rate relative
h, 95%; 0.008 M DMF, 25 °C, 34 h, 53%), providing a
1:1.3 mixture of separable atropisomers with the M
isomer predominating slightly. Similarly, subjecting 53
to CsF promoted macrocyclization (8 equiv, DMSO, 25
°C, 15 h) and also provided the same 1:1.3 mixture of 55
atropisomers (64%) resulting from both ring closure and
TBDMS deprotection. The atropisomer stereochemistry
and confirmation of the maintained C15/C14 stereochem-
istry was established by 2D 1H-1H NMR of (P)-55, which
exhibited diagnostic H-17/H-15 (s) and H-17/H-14 (s)
NOE’s as is characteristic of the natural atropisomer
stereochemistry and lacked H-20/H-15, H-20/H-14 NOE’s
as is diagnostic of the unnatural atropisomer. The
integrity of the remaining stereocenters was established
by conversion of authentic (P)-2 to (P)-55 (Scheme 9).26
This provided independent confirmation of the stereo-
chemical integrity of 2 and the improved C14 carboxa-
mide cyclization (CsF, DMSO, 95%) provides second-
generation improvements in the synthesis of the van-
comycin CD ring system, applicable to the natural
product itself. Consistent with prior observations, the CD
ring closure typically is better than the DE ring closure,
and the relative effectiveness of the 36 and 54 macrocy-
clizations reflect this trend.
(26) The stereochemical integrity of the C14 center was indepen-
dently established by preparation and cyclization of the C14 hy-
droxymethyl derivative corresponding to 50 and the correlation of the
product atropisomers with 51. Details are provided in supporting
information.
(27) Boger, D. L.; Miyazaki, S.; Loiseleur, O.; Beresis, R. T.; Castle,
S. L.; Wu, J . H.; J in, Q. J . Am. Chem. Soc. 1998, 120, 8920.

Vancomycin CD and DE Ring Systems
J . Org. Chem., Vol. 64, No. 1, 1999 77
Ta ble 1
Ta ble 2
compd
conditions
k (h-1
)
t1/2 (h)
2
2
2
3
3
155 °C, DMSO
140 °C, DMSO
0.27
1.06
3.52
9.77
4.03
44.0
14.2
2.52a
0.082
0.029
0.071
0.0065
0.0156
0.086
b
0.034
0.041
c
140 °C, o-Cl2C6H4
140 °C, DMSO
140 °C, o-Cl2C6H4
150 °C, o-Cl2C6H4
140 °C, DMSO
140 °C, o-Cl2C6H4
135 °C, o-Cl2C6H4
140 °C, o-Cl2C6H4
140 °C, DMSO
3
51
51
55
55
55
57
8.34
6.56
140 °C, o-Cl2C6H4
0.031
9.22
a
Accompanied by decomposition, data approximate. b Extensive
decomposition. c Only retro aldol observed.
to the DE ring system and the improved macrocyclization
(95%), define significant improvements for second-
generation syntheses of the CDE ring system and of the
natural product itself.
The thermal atropisomer equilibrations of the new
series of DE ring system derivatives as well as the
previously disclosed derivatives10,11 are summarized in
Table 2. Among these are the authentic 8R derivatives,
the initial 8S derivatives incorporating the Asn residue
carboxamide protected as a nitrile, as well as the deriva-
tives disclosed herein incorporating the free and Ddm-
protected carboxamide. Unlike the CD ring system, all
the derivatives which contain the free C15 alcohol were
found to withstand thermal atropisomerism conditions
without evidence of competitive retro aldol ring cleavage.
Analogous to observations made with the CD ring system,
the nitro derivatives equilibrate more readily than the
corresponding chloro derivatives. Unlike the CD ring
system, the equilibration was remarkably rapid and
proceeded readily even at 110-130 °C, and the unnatural
8S derivatives isomerize more rapidly than the natural
8R derivatives. Because of the rapid rates, the choice of
solvent has a less pronounced effect on the apparent ease
of atropisomerism. The nature of the Asn-residue sub-
stituent had little impact on this rapid rate of atropi-
somerism, and the Ddm-protected carboxamide 21 as well
as the free carboxamide 5828 isomerized at rates compa-
rable with 4. In fact, the rate of isomerization of the free
carboxamide 58 was slightly faster than that of the
corresponding nitrile (t1/2 5.5 min, 140 °C, DMSO). This
compd
conditions
k (h-1
)
t1/2 (h)
4
4
4
4
5
130 °C, DMSO
140 °C, DMSO
130 °C, o-Cl2C6H4
140 °C, o-Cl2C6H4
140 °C, DMSO
120 °C, DMSO
130 °C, DMSO
140 °C, DMSO
130 °C, DMSO
140 °C, DMSO
125 °C, DMSO
140 °C, DMSO
140 °C, DMSO
130 °C, DMSO
140 °C, DMSO
130 °C, DMSO
140 °C, DMSO
130 °C, DMSO
140 °C, DMSO
0.66
1.05
0.70
1.15
0.52
0.58
1.5
1.7
0.90
1.5
0.88
2.06
1.28
0.17
0.33
0.28
0.49
0.16
0.32
0.23
0.17
0.29
0.15
0.39
0.43
0.17
0.15
0.29
0.16
0.28
0.092
0.11
1.6
21
21
21
29
29
58
58
45
30
30
28
28
37
37
0.83
1.0
0.59
1.9
1.0
thermal atropisomerism of the free carboxamide 58 was
observed without competitive Asn-isoaspartate rear-
rangement analogous to that observed in the acidic,
(28) The amide 58 was prepared by treatment of 24 with H2O2/K2-
CO3 (4 equiv/2.3 equiv, 2:1 DMSO/H2O, 45 °C, 1.5 h, 64%) without
competitive ester hydrolysis. Katritzky, A. R.; Pilarski, B.; Urogdi, L.
Synthesis 1989, 949.

78 J . Org. Chem., Vol. 64, No. 1, 1999
Boger et al.
Ta ble 3. An tim icr obia l Activity, MIC (m g/m L)
(10% CH3OH/CHCl3) and concentrated in vacuo. PTLC
(SiO2, 10% CH3OH/CHCl3, three elutions) afforded 37 as
a separable 1.2:1 mixture of diastereomers (5.9 mg, 9.1
mg theoretical, 65%). For the major, more polar P
diastereomer: white film (3.2 mg, 35%); [R]25 +8.3 (c
D
0.12, CH3OH); 1H NMR (CD3OD, 400 MHz) δ 8.15 (s, 1H),
7.81 (dd, 1H, J ) 2.0, 8.5 Hz), 7.18 (d, 1H, J ) 8.5 Hz),
6.57-6.55 (m, 1H), 5.60-5.58 (m, 1H), 5.15 (d, 1H, J )
3.2 Hz), 4.89-4.86 (m, 1H, partially obscured by H2O),
4.60 (m, 1H), 4.32 (d, 1H, J ) 3.3 Hz), 3.96 (s, 3H), 2.80
(dd, 1H, J ) 6.7, 16.7 Hz), 2.73-2.67 (m, 1H), 2.69 (s,
3H), 1.48 (s, 9H); 13C NMR (CD3OD, 100 MHz) δ 171.5,
171.2, 169.2, 154.7, 152.5, 150.0, 144.2, 140.8, 138.0,
133.3, 133.1, 129.5, 127.3, 124.6, 117.5, 110.9, 106.0, 81.2,
73.9, 61.7, 60.6, 59.0, 51.1, 28.7 (3C), 26.7, 21.7; IR (film)
νmax 3289, 2930, 1653, 1534, 1349, 1239, 1164, 1086, 1027
cm-1; FABHRMS (NBA-CsI) m/z 761.1157 (M+ + Cs, C28-
H32N6O11 requires 761.1183). The 2D 1H-1H ROESY
NMR spectrum (CD3OD, 600 MHz, 40 °C) of (P)-37
displayed the following diagnostic NOE cross-peaks:
C17-H/C15-H (s, δ 8.15/5.15), C17-H/C14-H (s, δ 8.15/
4.32), C20-H/C19-H (m, δ 7.81/7.18), C6-H/C8-H (m, δ
6.57-6.55/4.89-4.86), C15-H/C14-H (m, δ 5.15/4.32),
C11-H/CH2CN (w, δ 4.60/2.80 and 4.60/2.73-2.67).
For the minor, less polar M diastereomer: white film
(2.7 mg, 30%); [R]25D +35 (c 0.14, CH3OH); 1H NMR (CD3-
OD, 400 MHz) δ 8.16 (s, 1H), 7.80-7.77 (m, 1H), 7.38 (d,
1H, J ) 8.3 Hz), 6.51-6.49 (m, 1H), 5.46-5.42 (m, 1H),
5.16 (d, 1H, J ) 3.7 Hz), 4.90-4.87 (m, 1H, partially
obscured by H2O), 4.61-4.56 (m, 1H), 4.45 (d, 1H, J )
3.7 Hz), 3.96 (s, 3H), 2.83-2.78 (m, 1H), 2.76-2.71 (m,
1H), 2.70 (s, 3H), 1.48 (s, 9H); IR (film) νmax 3290, 2921,
2849, 1652, 1539, 1507, 1153 cm-1; FABHRMS (NBA-
CsI) m/z 761.1158 (M+ + Cs, C28H32N6O11 requires
Staphylococcus
aureusa
Enterococcus
faeciumb
Enterococcus
faeciumc
compd
1
48
59
60
61
62
1.25
>1050
1250
>940
>1500
>2100
2.5
>1050
>2500
>940
>1500
>2100
250
>1050
>2500
>940
>1500
>2100
a
b
ATCC 25923. ATCC 35667. c Vancomycin resistant.
thermal degradation (pH 4.2, 70-80 °C, 40 h) studies of
vancomycin leading to CDP-12 and, in part, may be
attributed to a rapid isomerism precluding competitive
rearrangement.27 The observation that the natural 8R
derivatives isomerize more slowly than the 8S derivatives
is consistent with our disclosure that DE atropisomerism
within both the intact CDE ring system9 and within
vancomycin27 proceeds slowly and at a rate ca. 3× slower
than in 37 itself. This may now be attributed in part to
the (8R)-carboxamide stereochemistry present in the
CDE ring systems.
An tim icr obia l Activity. Three fully functionalized
DE ring systems incorporating the aryl chloride, the
natural atropisomer stereochemistry, the Asn free car-
boxamide, and the MeNH-D-Leu side chain including the
analogues bearing the natural C8 N-methylcarboxamide
and the unnatural C8 hydroxmethyl and tert-butyl ester29
substituents as well as two fully functionalized CD ring
systems were tested for antimicrobial activity in vanco-
mycin-sensitive and -resistant bacteria. In all cases, they
were g1000× less potent than vancomycin, and only 59
exhibited a detectable activity at this level (Table 3).
1
761.1183). The 2D H-1H ROESY NMR spectrum (CD3-
OD, 600 MHz, 40 °C) of (M)-37 displayed the following
diagnostic NOE cross-peaks: C20-H/C19-H (s, δ 7.80-
7.77/7.38), C20-H/C15-H (s, δ7.80-7.77/5.16), C20-H/
C14-H (s, δ 7.80-7.77/4.45), C6-H/C8-H (m, δ 4.90-4.87/
6.51-6.49), C11-H/CH2CN (w, δ 4.61-4.56/2.83-2.78 and
4.61-4.56/2.76-2.71).
N-Met h yl (P )-(8R,11S,14R,15R)-18-Am in o-14-[N-
[(ter t-bu tyloxy)ca r bon yl]a m in o]-11-(cya n om eth yl)-
5,15-d ih yd r oxy-10,13-d ioxo-4-m eth oxy-9,12-d ia za -2-
oxa t r icyclo[14.2.2.13,7]h en eicosa -3,4,7(21),16,18,19-
h exa en e-8-ca r boxa m id e (38). A solution of (P)-37 (3.0
mg, 0.0048 mmol) in anhydrous CH3OH (0.3 mL) was
treated with 10% Pd/C (0.4 mg, 0.13 wt equiv) and stirred
at 25 °C under H2 (1 atm) for 4 h. The reaction mixture
was filtered through a pad of Celite (washed with 10%
CH3OH/CHCl3) and concentrated in vacuo to afford 38
(2.8 mg, 2.9 mg theoretical, 98%) as a white film: 1H
NMR (CD3OD, 400 MHz) δ 6.85-6.83 (m, 1H), 6.80-6.78
(m, 1H), 6.76 (s, 1H), 6.50 (d, 1H, J ) 2.1 Hz), 5.70-5.67
(m, 1H), 5.02 (s, 1H), 4.93 (d, 1H, J ) 5.6 Hz), 4.65-4.60
(m, 1H), 4.25 (d, 1H, J ) 3.4 Hz), 3.97 (s, 3H), 2.81 (dd,
1H, J ) 6.4, 16.9 Hz), 2.72 (dd, 1H, J ) 6.2, 16.9 Hz),
2.70 (s, 3H), 1.48 (s, 9H); FABHRMS (NBA-CsI) m/z
731.1462 (M+ + Cs, C28H34N6O9 requires 731.1442).
N-Meth yl (P )-(8R,11S,14R,15R)-14-[N-[(ter t-Bu -
tyloxy)car bon yl]am in o]-18-ch lor o-11-(cyan om eth yl)-
5,15-d ih yd r oxy-10,13-d ioxo-4-m eth oxy-9,12-d ia za -2-
oxa t r icyclo[14.2.2.13,7]h en eicosa -3,4,7(21),16,18,19-
h exa en e-8-ca r boxa m id e (40). A solution of 38 (4.2 mg,
0.0070 mmol) in anhydrous CH3CN (0.25 mL) at 0 °C was
treated with HBF4 (0.1 M solution in CH3CN, 91 µL,
Exp er im en ta l Section
N-Meth yl (P )- a n d (M)-(8R,11S,14R,15R)-14-[N-
[(ter t-Bu tyloxy)ca r bon yl]a m in o]-11-(cya n om eth yl)-
5,15-d ih yd r oxy-10,13-d ioxo-4-m e t h oxy-18-n it r o-
9,12-d ia za -2-oxa tr icyclo[14.2.2.13,7]h en eicosa -3,4,7-
(21),-16,18,19-h exa en e-8-ca r boxa m id e (37). A solution
of 36 (9.4 mg, 0.014 mmol) in anhydrous degassed DMSO
(1.8 mL) was added to a vial charged with predried (130
°C, 0.1 mm Hg, 12 h) CsF (12.0 mg, 0.079 mmol, 5.4
equiv). The mixture was stirred at 25 °C for 11.5 h. The
resulting mixture was filtered through a pad of Celite
(29) Details of the preparation of 59 and 60 may be found in the
Supporting Information.

Vancomycin CD and DE Ring Systems
J . Org. Chem., Vol. 64, No. 1, 1999 79
0.0091 mmol, 1.3 equiv), and the resulting solution was
stirred at 0 °C for 10 min before being warmed to 25 °C
and stirred for 30 min. The reaction mixture was recooled
to 0 °C, treated with tert-butyl nitrite (0.1 M solution in
CH3CN, 91 µL, 0.0091 mmol, 1.3 equiv), and stirred at 0
°C for 1 h. The solvent was removed in vacuo at 0 °C,
and the residue containing 39 was treated with a solution
of CuCl2 (57 mg, 0.42 mmol, 60 equiv) in H2O (0.55 mL).
The resulting mixture was stirred at 25 °C for 5 min,
treated with CuCl (14 mg, 0.14 mmol, 20 equiv), and
stirred at 25 °C for 1.5 h. Saturated aqueous NH4Cl (1.5
mL) was added to the mixture, and it was extracted with
EtOAc (5 × 1.5 mL). The combined organic extracts were
washed with H2O (2.5 mL), saturated aqueous NH4Cl (2.5
mL), and saturated aqueous NaCl (2.5 mL), dried (Na2-
SO4), and concentrated in vacuo. PTLC (SiO2, eluted
twice with 10% CH3OH/CHCl3) afforded 40 (3.3 mg, 4.3
4.57 (m, 2H), 3.97 (s, 3H), 2.81-2.74 (m, 1H, partially
obscured), 2.79 (s, 3H), 2.72-2.67 (m, 1H, partially
obscured), 2.71 (s, 3H), 1.75-1.69 (m, 2H), 1.51-1.44 (m,
1H, partially obscured), 1.51 (s, 9H), 1.00-0.93 (m, 6H);
IR (film) νmax 3820, 3743, 3674, 1771, 1717, 1699, 1652,
1558, 1539, 1506 cm-1; FABHRMS (NBA-CsI) m/z
877.1970 (M+ + Cs, C35H45N6O10Cl requires 877.1940).
N-Meth yl (P )-(8R,11S,14R,15R)-14-[N-(N-Meth yl)-
D-leu cyl]a m in o-18-ch lor o-11-et h a n a m id o-5,15-d i-
hydroxy-10,13-dioxo-4-methoxy-9,12-diaza-2-oxatricyclo-
[14.2.2.13,7]h en eicosa -3,4,7(21),16,18,19-h exa en e-8-
ca r boxa m id e (48). A vial charged with 47 (1.1 mg,
0.0015 mmol) at 0 °C was treated with a saturated
solution of HCl in Et2O (0.4 mL) followed by H2O (10 µL),
and the mixture was stirred at 25 °C for 73 h. The
mixture was cooled to 0 °C, concentrated under a stream
of N2, and purified by reverse-phase HPLC (C18, CH3-
CN-0.07% aqueous TFA 23:77 as eluant) to afford 48
mg theoretical, 76%) as a white film: [R]25 +23 (c 0.1,
D
CH3OH); 1H NMR (CD3OD, 400 MHz) δ 7.60 (s, 1H), 7.47
(dd, 1H, J ) 1.9, 8.4 Hz), 7.07 (d, 1H, J ) 8.5 Hz), 6.53
(d, 1H, J ) 1.8 Hz), 5.49-5.46 (m, 1H), 5.05 (d, 1H, J )
2.8 Hz), 4.96 (s, 1H), 4.62-4.58 (m, 1H), 4.28 (d, 1H, J )
3.5 Hz), 3.97 (s, 3H), 2.79 (dd, 1H, J ) 6.8, 16.4 Hz),
2.73-2.67 (m, 1H), 2.71 (s, 3H), 1.48 (s, 9H); IR (film)
(0.9 mg, 1.0 mg theoretical, 90%) as a white film: [R]25
D
1
+16 (c 0.070, CH3OH); H NMR (CD3OD, 400 MHz) δ
7.60-7.57 (m, 1H), 7.53-7.49 (m, 1H), 7.11 (d, 1H, J )
8.5 Hz), 6.55 (d, 1H, J ) 1.8 Hz), 5.46 (d, 1H, J ) 1.8
Hz), 5.08-5.05 (m, 1H), 5.00 (s, 1H), 4.90-4.87 (m, 1H,
obscured by H2O), 4.68-4.63 (m, 1H), 4.57 (d, 1H, J )
3.6 Hz), 3.97 (s, 3H), 2.71 (s, 3H), 2.67 (s, 3H), 2.58-2.53
(m, 1H), 2.50-2.44 (m, 1H), 1.79-1.64 (m, 2H), 1.38-
1.31 (m, 1H), 1.07 (d, 3H, J ) 6.4 Hz), 1.03 (d, 3H, J )
6.4 Hz); IR (film) νmax 3319, 1673, 1650, 1434, 1205, 1138
cm-1; FABHRMS (NBA-CsI) m/z 795.1542 (M+ + Cs,
C30H39N6O9Cl requires 795.1521).
νmax 3302, 2919, 1658, 1512, 1237, 1161, 1038 cm-1
;
FABHRMS (NBA-CsI) m/z 750.0919 (M+ + Cs, C28H32
-
N5O9Cl requires 750.0943).
N-Meth yl (P )-(8R,11S,14R,15R)-14-Am in o-18-ch lor o-
11-(cyan om eth yl)-5,15-dih ydr oxy-10,13-dioxo-4-m eth -
oxy-9,12-d ia za -2-oxa t r icyclo[14.2.2.13,7]h en eicosa -
3,4,7(21),16,18,19-h exa en e-8-ca r boxa m id e (46). A vial
charged with 40 (3.3 mg, 0.0053 mmol) was treated with
3 M HCl/EtOAc (0.5 mL), and the resulting mixture was
stirred at 25 °C for 30 min. The mixture was concentrated
in vacuo to afford 46 (2.8 mg, 2.8 mg theoretical,
quantitative) as a white film which was used directly in
the next reaction: 1H NMR (CD3OD, 400 MHz) δ 7.56
(d, 1H, J ) 1.9 Hz), 7.49 (dd, 1H, J ) 2.1, 8.3 Hz), 7.11
(d, 1H, J ) 8.4 Hz), 6.51 (d, 1H, J ) 2.2 Hz), 5.64 (d, 1H,
J ) 2.1 Hz), 5.19 (d, 1H, J ) 4.3 Hz), 4.78 (s, 1H), 4.46-
4.43 (m, 1H), 4.16 (d, 1H, J ) 4.3 Hz), 3.98 (s, 3H), 2.91
(dd, 1H, J ) 6.5, 17.1 Hz), 2.82 (dd, 1H, J ) 4.6, 17.1
Hz), 2.70 (s, 3H).
(2S,3R)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-[N-[(R)-
N-[(R)-N-[(ter t-bu tyloxy)ca r bon yl]-(3,5-d ih yd r oxy-
4-methoxyphenyl)glycyl]-(3-bromo-4-methoxyphenyl)-
g ly c y l]a m i n o ]-3-(4-flu o r o -3-n i t r o p h e n y l)-p r o -
p ion ic Acid (52). A solution of 4911 (180 mg, 0.198 mmol)
in t-BuOH/H2O (2:1, 6.0 mL) was treated with LiOH‚H2O
(16.6 mg, 0.40 mmol, 2.0 equiv) at 0 °C under Ar for 3 h.
The reaction mixture was quenched with the addition of
15% aqueous citric acid (5 mL) at 0 °C and the volatiles
were removed in vacuo. The aqueous phase was extracted
with EtOAc (3 × 10 mL). The combined organic phases
were washed with H2O (10 mL) and saturated aqueous
NaCl (10 mL), dried (Na2SO4), and concentrated in vacuo.
PTLC (SiO2, 10% CH3OH/CHCl3) afforded 52 (150 mg,
N-Meth yl
(P )-(8R,11S,14R,15R)-14-[N-[N-[(ter t-
85%) as a pale yellow solid: [R]25 -31 (c 0.71, CH3OH);
Bu t yloxy)ca r b on yl]-N-m et h yl]-D-leu cyl]a m in o-18-
ch lor o-11-(cyan om eth yl)-5,15-dih ydr oxy-10,13-dioxo-
4-m e t h o x y -9,12-d ia za -2-o x a t r ic y c lo [14.2.2.13,7]-
h e n e icosa -3,4,7(21),16,18,19-h e xa e n e -8-ca r b oxa -
m id e (47). A solution of 46 (2.6 mg, 0.0050 mmol) in CH2-
Cl2/DMF (4:1, 0.38 mL) at 0 °C was treated with BOC-
NMe-D-Leu (1.8 mg, 0.0073 mmol, 1.5 equiv) and NaH-
CO3 (0.5 mg, 0.006 mmol, 1.2 equiv) and stirred at 0 °C
for 10 min. The mixture was then treated with HOAt (1.5
mg, 0.011 mmol, 2.2 equiv) and EDCI‚HCl (1.9 mg,
0.0099 mmol, 2.0 equiv) and stirred at 0 °C under Ar for
2 h. The mixture was treated with H2O (1 mL) and
extracted with EtOAc (5 × 1.5 mL). The combined organic
extracts were washed with H2O (2 mL) and saturated
aqueous NaCl (2 mL), dried (Na2SO4), and concentrated
in vacuo. PTLC (SiO2, eluted twice with 10% CH3OH/
CHCl3) afforded 47 (2.4 mg, 3.7 mg theoretical, 65%) as
a white film: [R]25D +46 (c 0.095, CH3OH); 1H NMR (CD3-
OD, 400 MHz) δ 7.60 (d, 1H, J ) 1.8 Hz), 7.51-7.47 (m,
1H), 7.08 (d, 1H, J ) 8.4 Hz), 6.52 (d, 1H, J ) 1.8 Hz),
5.49 (d, 1H, J ) 1.6 Hz), 5.06 (d, 1H, J ) 3.3 Hz), 4.93 (s,
1H), 4.90-4.87 (m, 1H, partially obscured by H2O), 4.62-
D
1H NMR (acetone-d6, 400 MHz) δ 8.01 (s, 2H), 7.77 (d,
1H, J ) 8.1 Hz), 7.59 (d, 1H, J ) 8.1 Hz), 7.48 (br s, 2H),
7.30-7.22 (m, 2H), 7.18-6.81 (m, 2H), 6.59 (s, 1H), 6.55
(s, 1H), 6.36 (s, 1H), 5.60 (s, 1H), 5.45 (s, 1H), 5.19 (br s,
1H), 4.58 (d, 1H, J ) 9.0 Hz), 3.90 (s, 3H), 3.76 (s, 3H),
1.36 (s, 9H), 0.77 (s, 9H), -0.06 (s, 3H), -0.20 (s, 3H); IR
(neat) νmax 3292, 2947, 1687, 1678, 1603, 1537, 1497,
1366, 1259, 1165 cm-1; FABHRMS (NBA-CsI) m/z
1027.1463 (M+
1027.1454).
+
Cs, C38H48N4O13BrFSi requires
N-Meth yl
(2S,3R)-3-[(ter t-Bu tyld im eth ylsilyl)-
oxy]-2-[N-[(R)-N-[(R)-N-[(ter t-b u t yloxy)ca r b on yl]-
(3,5-d ih yd r oxy-4-m eth oxyp h en yl)glycyl]-(3-br om o-
4-m eth oxyp h en yl)glycyl]a m in o]-3-(4-flu or o-3-n itr o-
p h en yl)p r op ion a m id e (53). A solution of 52 (53 mg,
0.060 mmol) in anhydrous DMF (2.0 mL) was treated
sequentially with HOBt (20.5 mg, 0.15 mmol, 2.5 equiv),
CH3NH2‚HCl (20 mg, 0.30 mmol, 5.0 equiv), NaHCO3 (25
mg, 0.30 mmol, 5.0 equiv), and EDCI (28 mg, 0.144 mmol,
2.4 equiv) at 0 °C under Ar and stirred for 24 h. After
removal of the solvent in vacuo, H2O (5 mL) and EtOAc

80 J . Org. Chem., Vol. 64, No. 1, 1999
Boger et al.
(5 mL) were added to the residue. The aqueous phase
was extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with H2O (10 mL) and
saturated aqueous NaCl (10 mL), dried (Na2SO4), and
concentrated in vacuo. PTLC (SiO2, 5% CH3OH/CHCl3)
(d, 1H, J ) 3.8 Hz), 5.15 (br s, 1H), 4.54 (d, 1H, J ) 3.8
Hz), 3.96 (s, 3H), 3.91 (s, 3H), 2.77 (s, 3H), 1.43 (s, 9H);
1H NMR (acetone-d6, 600 MHz) δ 8.29 (s, 1H), 8.06 (d,
1H, J ) 1.8 Hz), 7.79 (d, 1H, J ) 9.0 Hz), 7.66-7.61 (m,
2H), 7.47 (m, 2H), 7.34 (d, 1H, J ) 8.5 Hz), 7.11 (d, 1H,
J ) 8.5 Hz), 6.76 (s, 1H), 6.71 (m, 1H), 6.39 (s, 1H), 6.22
(m, 1H), 5.55 (dd, 1H, J ) 5.6, 2.4 Hz), 5.47 (d, 1H, J )
8.0 Hz), 5.18 (d, 1H, J ) 7.8 Hz), 5.12 (d, 1H, J ) 4.9
Hz), 4.62 (d, 1H, J ) 5.5 Hz), 3.94 (s, 3H), 3.91 (s, 3H),
2.73 (d, 3H, J ) 4.6 Hz), 1.38 (s, 9H); IR (neat) νmax 3304,
2978, 2926, 1652, 1575, 1532, 1505, 1456, 1436, 1349,
1258, 1164, 1086, 1022 cm-1; FABHRMS (NBA-CsI) m/z
906.0627 (M+ + Cs, C33H36N5O12Br requires 906.0598).
The 2D 1H-1H ROESY NMR spectrum (CD3OD, 600
MHz, 25 °C) of (P)-55 displayed the following diagnostic
NOE cross-peaks: H-17/H-15 (s, δ 8.05/5.34), H-17/H-14
(s, δ 8.05/4.54), H-15/H-14 (s, δ 5.34/4.54), H-2’/H-11 (m,
δ 7.48/5.38), H-6’/H-11 (s, δ 7.37/5.38), H-8/H-6 (s, δ 6.65/
5.15).
afforded 53 (35 mg, 65%) as a yellow solid: [R]25 -16 (c
D
1
0.60, CHCl3); H NMR (acetone-d6, 400 MHz) δ 8.07 (d,
1H, J ) 7.2 Hz), 8.02 (s, 2H), 7.95 (s, 1H), 7.67 (d, 1H, J
) 9.1 Hz), 7.63 (br s, 1H), 7.52 (m, 1H), 7.47 (d, 1H, J )
2.1 Hz), 7.18-7.12 (m, 2H), 6.90 (d, 1H, J ) 8.4 Hz), 6.46
(s, 2H), 6.30 (d, 1H, J ) 7.1 Hz), 5.57 (s, 1H), 5.44 (d,
1H, J ) 6.4 Hz), 5.15 (d, 1H, J ) 6.0 Hz), 4.54 (dd, 1H,
J ) 8.7, 2.3 Hz), 3.90 (s, 3H), 3.74 (s, 3H), 2.73 (d, 3H, J
) 4.7 Hz), 1.36 (s, 9H), 0.87 (s, 9H), 0.02 (s, 3H), -0.11
(s, 3H); IR (neat) νmax 3316, 2931, 2859, 1660, 1600, 1537,
1498, 1349, 1287, 1259, 1164 cm-1; FABHRMS (NBA-
NaI) m/z 930.2334 (M+ + Na, C39H51N5O12BrFSi requires
930.2369).
N-Methyl (2S,3R)-2-[N-[(R)-N-[(R)-N-[(tert-Butyloxy)-
ca r bon yl]-(3,5-d ih yd r oxy-4-m eth oxyp h en yl)glycyl]-
(3 -b r o m o -4 -m e t h o x y p h e n y l )g l y c y l ]a m i n o ]-3 -
h yd r oxy-3-(4-flu or o-3-n it r op h en yl)p r op ion a m id e
(54). A solution of 53 (16 mg, 0.017 mmol) in THF (5.3
mL) was treated with HOAc (1/100 v/v in THF, 5.5 µL,
0.096 mmol, 5.0 equiv) and Bu4NF (1.0 M in THF, 116
µL, 0.116 mmol, 6.0 equiv) at 0 °C under Ar, warmed to
25 °C, and stirred for 1 h. The reaction mixture was
quenched with the addition of saturated aqueous NaH-
CO3 (5 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with saturated
aqueous NH4Cl (2 × 5 mL), dried (Na2SO4), and concen-
trated in vacuo. PTLC (SiO2, 10% CH3OH/CHCl3) af-
For (M)-55 (the more polar isomer): [R]25D -29 (c 0.12,
1
CHCl3); H NMR (CD3OD, 400 MHz) δ 8.21 (d, 1H, J )
1.6 Hz), 7.70 (d, 1H, J ) 2.2 Hz), 7.68 (d, 1H, J ) 2.1
Hz), 7.36 (d, 1H, J ) 8.5 Hz), 7.31 (d, 1H, J ) 8.4 Hz),
7.06 (d, 1H, J ) 8.6 Hz), 6.60 (m, 1H), 5.99 (m, 1H), 5.37
(m, 2H), 5.17 (s, 1H), 4.64 (d, 1H, J ) 3.0 Hz), 3.98 (s,
3H), 3.90 (s, 3H), 2.78 (s, 3H), 1.41 (s, 9H); 1H NMR
(acetone-d6, 600 MHz) δ 8.33 (s, 2H), 7.68 (s, 3H), 7.43
(d, 1H, J ) 8.6 Hz), 7.26 (d, 1H, J ) 7.9 Hz), 7.05 (d, 1H,
J ) 8.2 Hz), 6.66 (s, 2H), 6.15 (m, 1H), 5.94 (m, 1H), 5.33
(s, 2H), 5.49 (d, 1H, J ) 7.6 Hz), 5.31 (d, 1H, J ) 8.8
Hz), 4.88 (m, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 2.68 (s, 3H,)
1.39 (s, 9H); IR (neat) νmax 3319, 2971, 2930, 1692, 1649,
1582, 1535, 1499, 1346, 1286, 1263, 1227, 1165, 1082,
forded 54 (11.6 mg, 83%) as a pale yellow solid: [R]25
D
1
-10 (c 0.20, CHCl3); H NMR (acetone-d6, 600 MHz) δ
1040 cm-1; FABHRMS (NBA-CsI) m/z 906.0558 (M+
+
8.01 (dd, 1H, J ) 7.2, 2.0 Hz), 7.89 (d, 2H, J ) 4.4 Hz),
7.79 (d, 2H, J ) 8.9 Hz), 7.54 (m, 2H), 7.50 (d, 1H, J )
2.2 Hz), 7.47 (br s, 1H), 7.19 (dd, 1H, J ) 8.5, 2.2 Hz),
7.12 (dd, 1H, J ) 11.0, 8.7 Hz), 6.86 (d, 1H, J ) 8.5 Hz),
6.49 (s, 2H), 6.17 (br s, 1H), 5.48 (d, 1H, J ) 6.4 Hz),
5.41 (d, 1H, J ) 2.2 Hz), 5.15 (d, 1H, J ) 5.8 Hz), 4.66
(dd, 1H, J ) 8.8, 2.4 Hz), 3.89 (s, 3H), 3.78 (s, 3H), 2.72
(d, 3H, J ) 4.6 Hz), 1.37 (s, 9H); IR (neat) νmax 3296, 2964,
1659, 1637, 1536, 1500, 1347, 1286, 1260, 1163, 1056
cm-1; FABHRMS (NBA-NaI) m/z 816.1469 (M+ + Na,
C33H37N5O12BrF requires 816.1504).
Cs, C33H36N5O12Br requires 906.0598). The 2D 1H-1H
ROESY NMR spectrum (CD3OD, 600 MHz, 25 °C) of (M)-
55 displayed the following diagnostic NOE cross-peaks:
H-20/H-15 (s, δ 7.67/5.38), H-20/H-14 (s, δ 7.67/4.65),
H-14/H-15 (m, δ 4.65/5.38), H-6′/H-11 (w, δ 7.33/5.29),
and H-8/H-6 (m, δ 5.15/6.62).
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(CA41101), the award of a NSF predoctoral fellowship
(S.L.C., GER-9253922), the award of NIH postdoctoral
fellowships (R.T.B., CA71102; J .H.W., AI09847), the
award of a Swiss National Foundation postdoctoral
fellowship and a Ciba-Geigy J ubilau¨ms Stiftung (O.L.),
and a sabbatical leave for S.M. (J apan Tobacco). We are
especially grateful to Dr. Qing J in for the antimicrobial
testing (Table 3).
N-Met h yl (P )- a n d (M)-(8R,11R,14S,15R)-11-(3-
Br om o-4-m eth oxyp h en yl)-8-[N-[(ter t-bu tyloxy)ca r -
bon yl]a m in o]-5,15-d ih yd r oxy-9,12-d ioxo-4-m eth oxy-
18-n itr o-10,13-diaza-2-oxatr icyclo[14.2.2.1]h en eicosa-
1(18),3(21),4,6,16,19-h exa en e-14-ca r boxa m id e (55). A
solution of 54 (4.1 mg, 5.1 µmol) in anhydrous degassed
DMSO (0.63 mL, 0.008 M) was treated with CsF (4.3 mg,
28 µmol, 5.6 equiv) at 25 °C under Ar and stirred for 11
h. The reaction mixture was filtered through Celite
(EtOAc wash) and concentrated in vacuo. PTLC (SiO2,
5% CH3OH/CHCl3) afforded (P)-55 (1.6 mg, 41%) as a
pale yellow solid, and (M)-55 (2.1 mg, 54%) as a white
solid.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and characterization of 10, 11, 13, 14, 16, 18-21, 23-
24, and 26-29, the correlations of (P)-30 with (P)-28, of 24 with
45, of 30 with 37, 33-36, 44-45, the conversion of (P)-2 to (P)-
55, 55-60, and the preparation, cyclization, and correlation
of the product atropisomers of the CO C14 hydroxymethyl
derivative. Copies of the 1H NMR of all compounds reported
herein are also provided (77 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
For (P)-55 (the less polar isomer): [R]25 -12 (c 0.065,
D
1
CHCl3); H NMR (CD3OD, 400 MHz) δ 8.05 (d, 1H, J )
2.1 Hz), 7.69 (d, 1H, J ) 8.0 Hz), 7.48 (m, 1H), 7.37 (d,
1H, J ) 8.6 Hz), 7.28 (d, 1H, J ) 8.5 Hz), 7.10 (d, 1H, J
) 8.6 Hz), 6.65 (m, 1H), 6.27 (m, 1H), 5.38 (s, 1H), 5.34
J O980880O