Synthesis of the vancomycin CD and DE ring systems

Article abstract of DOI:10.1021/jo970560p

Full details of the synthesis of the fully substituted vancomycin CD and DE ring systems are described and a potential solution to the control of the atropisomer stereochemistry is defined.

Full text of DOI:10.1021/jo970560p

J . Org. Chem. 1997, 62, 4721-4736
4721
Syn th esis of th e Va n com ycin CD a n d DE Rin g System s
Dale L. Boger,* Robert M. Borzilleri, Seiji Nukui, and Richard T. Beresis
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 March 26, 1997X
Full details of the synthesis of the fully substituted vancomycin CD and DE ring systems are
described and a potential solution to the control of the atropisomer stereochemistry is defined.
Vancomycin (1)1 was isolated in 1956 from Streptomy-
ces orientalis and its structure and stereochemistry were
ultimately secured over 25 years later through a combi-
nation of chemical degradation,1b NMR,1d,e and X-ray
crystallography studies (Figure 1).1f It represents the
prototypic member of a large class of clinically effective
glycopeptide antibiotics,2-7 which now includes teico-
planin,2a ristocetin,2b â-avoparcin,2c actaplanin (A4696),2d
and A33512B,2e characterized by a polycyclic heptapep-
tide backbone composed of two 16-membered biaryl ether
ring systems (CD and DE). In addition, it possesses a
challenging 12-membered biaryl AB ring system which
imposes the cis secondary amide structure in the 16-
membered CD ring system, two sensitive â-hydroxy
3-chlorophenylalanines susceptible to retro-Aldol cleav-
age in the corners of central CDE ring system, three
substituted phenylglycines prone to epimerization in-
cluding a pivotal 3,4,5-trihydroxyphenylglycine central
to the CDE ring system, and a defined atropisomer
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) (a) McCormick, M. H.; Stark, W. M.; Pittenger, G. F.; Pittenger,
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stereochemistry resulting from the monochloro substitu-
tion of the aryl C and E rings, as well as an unusual
phenol glycosidic linkage capping off its structure. Teico-
planin and ristocetin possess an additional 14-membered
FG ring system and the former lacks the DE ring benzylic
hydroxyl group while the latter agent lacks the aromatic
chlorine substituents. Several congeners of vancomycin
have been disclosed and differ in the number and location
of its chlorine substituents and in the number, structure,
and position of the linked carbohydrates.3 Two especially
interesting variants on the vancomycin structure are
orienticin C,3c,d which lacks both aromatic chlorine sub-
stituents, thus simplifying the synthetic target, and
complestatin and the chloropeptins which incorporate an
aryl-indole linkage into the DE ring system in place of
the characteristic biaryl ether.4
Vancomycin has been in clinical use for over 35 years
and its use has increased steadily over the past 20 years.
Currently, it is the therapeutic agent of choice for the
treatment of Gram-positive bacterial infections caused
by methicillin-resistant Staphylococcus aureus, and is
routinely used against enterococci and bacterial infections
in patients allergic to â-lactam antibiotics. It inhibits
bacterial cell wall biosynthesis by selectively binding to
mucopeptides terminating in the sequence D-Ala-D-Ala.5,8
Consequently, the binding affinity and selectivity of
(8) Nieto, M.; Perkins, H. R. Biochem. J . 1971, 123, 789.
S0022-3263(97)00560-4 CCC: $14.00 © 1997 American Chemical Society

4722 J . Org. Chem., Vol. 62, No. 14, 1997
Boger et al.
vancomycin with the C-terminal D-Ala-D-Ala sequence
and related cell wall mimics have been the subject of
numerous investigations.5 As its use has increased, the
emergence of resistant bacteria insensitive to vancomycin
has also increased. This has serious clinical implications
and has been shown to be derived from transposition of
the normal D-Ala-D-Ala peptidoglycan termini of the
bacterial cell wall into a depsipeptide D-Ala-D-lactate
sequence which binds 1000 times less effectively with 1.9
As a result of the structural complexity of the vanco-
mycin family of antibiotics, the interest in defining the
fundamental principles underlying the structural basis
for its dipeptide binding affinity and selectivity, and the
importance surrounding the emergence of vancomycin
resistance in the clinic, a number of synthetic efforts7
directed toward this family of natural products have been
detailed. Efforts from the laboratories of Hamilton,10
Williams,11 Yamamura,12 Evans,13 Pearson,14 Brown,15
Rao,16 Reddy,17 Beugelmans,18 Gallagher,19 Danishef-
sky,20 Still,21 and Nicolaou21 as well as our own22-25 have
addressed aspects of this challenging problem. With one
exception,19 previous efforts to prepare model 16-mem-
bered CD or DE macrocyclic rings through conventional
macrolactamization techniques have been unsuccess-
ful11,14,16 or were found to proceed in low yields.10,14,15,22
lar oxidative phenol coupling procedure was used initially
to access a highly functionalized bicyclic species embody-
ing the CDE biaryl ether subunits of vancomycin as
symmetrical tetrahalogenated products. More recently,
this has been reported with unsymmetrical 2-bromo-6-
chlorophenol coupling partners providing access to the
biaryl ethers possessing a single chlorine substituent. In
complementary efforts, we disclosed the unusually suc-
cessful implementation of an Ullmann macrocyclization
reaction for the preparation of related and more refrac-
tory 14-membered biaryl ethers23 and its surprisingly
effective extension to the core 16-membered CD and DE
ring systems of vancomycin.22 Subsequent to this dem-
onstration, both Beugelmans and Rao have expanded on
the scope of such cyclization strategies through use of
aromatic nucleophilic substitution reactions of o-halonitro
aromatics. Initially examined in the intermolecular
preparation of vancomycin related biaryl ethers16,18 as
first described by Hamilton,10 the studies have been
extended to the key intramolecular macrocyclization
reaction for formation of 16-membered biaryl ethers
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Full details are provided in the Supporting Information.
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Vancomycin CD and DE Ring System Synthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4723
Sch em e 1
based on our Ullmann strategy. Complementary with
these later studies, we disclosed the effective synthesis
of the cycloisodityrosine 14-membered biaryl ether ring
system adopting the intramolecular nucleophilic substi-
tution reaction of an o-fluoronitro aromatic and its
extension to the vancomycin CD and DE ring systems.24
In addition to providing smooth access to the 16-
membered biaryl ethers, the activating nitro group serves
as useful functionality for the introduction of the single
aromatic chlorine substituents required of vancomycin.
In our efforts, which are complemented by the recent
studies of Evans,13 we also elected to pursue the prepara-
tion of the fully functionalized vancomycin CD and DE
ring systems complete with their sensitive â-hydroxy
3-chlorophenylalanines, assuring the applicability of the
approach to all members of this class of glycopeptide
antibiotics. In these studies, we anticipated determining
if there is any tactical advantage to the order of the
introduction of the 16-membered rings and whether the
atropisomer diastereoselectivity might be subject to
substrate control. Herein, we report full details of our
efforts,24 including a significant technical improvement
in the methodology, their extensions culminating in the
preparation of the fully functionalized 16-membered CD
and DE ring systems of vancomycin, and a potential
solution to the control of the atropisomer stereochemistry
(Figure 1).
Mod el Bia r yl Eth er Cycliza tion Su bstr a tes. In the
course of our investigations, we have examined a range
of systems reported to activate aromatic nucleophilic
substitution reactions. The three most promising options
included the o-fluoronitro aromatics16,18,24 and the o-
[[(trifluoromethyl)sulfonyl]oxy]nitro aromatics26-28 bear-
ing a nitro activating group as well aryldiazonium salts29
in which the diazonium salt serves as a powerful electron-
withdrawing substituent for activation of the aromatic
nucleophilic substitution reaction and as the immediate
in situ precursor to the vancomyin aromatic chlorine
substituent. For comparison purposes, the intramolecu-
lar variant of these reactions for the preparation of the
simplified vancomycin DE skeleton have been examined
(Scheme 1). Of these, the closure employing the o-
fluoronitro aromatic acceptor 2 proved most successful,24
and such observations were first disclosed by Beugel-
mans18 and Rao16 and more recently by Evans.13 In
contrast, the corresponding diazonium salt 5 prepared
in situ by diazotization (1.6 equiv of t-BuONO, 1.6 equiv
of HBF4, THF or CH3CN, 0 °C, 1 h) of the amine 4 failed
to provide evidence of ring closure upon exposure to base
(DBU or K2CO3, THF or CH3CN, 0-25 °C, 14 h),
affording modest conversions to the corresponding acyclic
aryl chloride 6 upon Sandmeyer quench of the reaction
mixture. Although this was not investigated in detail
due to the success with 2, the powerful electron-
withdrawing nature of the diazonium salt, which exceeds
that of a nitro group, along with its documented activa-
tion properties for aromatic nucleophilic substitution
suggested the stepwise sequence required for the conver-
sion of 2 to 8 ultimately may be combined into a single
step. Similarly, the aromatic triflate activated for dis-
placement by the o-nitro group in 9 or by the o-diazonium
salt in 12 failed to undergo the intramolecular closure
to the biaryl ether when subjected to similar reaction
conditions (K2CO3, DMF, 85-100 °C, 4-18 h; NaH, DMF,
0-25 °C, 1-3 h, THF, 45 °C, 15 h). With these observa-
tions in hand, we proceeded with efforts directed at the
vancomycin CD and DE ring systems recognizing that
the opportunity to further explore closures related to
those of 5, 9, and 12 could be conducted in these efforts.
Th e Va n com ycin CD Rin g System . Protection of
methyl (2S,3R)-â-hydroxy-â-(4-fluoro-3-nitrophenyl)alan-
inate (14)24,30 as its TBDMS ether 15 (4 equiv of TBDM-
SOTf, 4.5 equiv of 2,6-lutidine, CH2Cl2, 0 °C, 4 h, 85%),
which was isolated as the free amine upon chromatog-
raphy purification followed by coupling (3 equiv of EDCI,
3.3 equiv of HOBt, DMF, 0 °C, 5 h) with (R)-N-BOC-(3-
bromo-4-methoxyphenyl)glycine (17), provided 18 (80%),
(26) For reviews on aryl triflates, see: Ritter, K. Synthesis 1993,
735. Stang, P. J .; Hanack, M.; Subramanian, L. R. Synthesis 1982,
85.
(27) For examples of nucleophilic displacement of activated o-nitro
aryl triflates, see: Kotsuki, H.; Kobayashi, S.; Suenaga, H.; Nishizawa,
H. Synthesis 1990, 1145. For examples involving aromatic amines as
the nucleophile, see: Kraus, G. A.; Liu, P. Tetrahedron Lett. 1995, 36,
7595. For examples involving dimethyl malonate as the nucleophile,
see: Atkinson, J . G.; Wasson, B. K.; Fuentes, J . J .; Girard, Y.; Rooney,
C. S.; Engelhardt, E. L. Tetrahedron Lett. 1979, 19, 2857. For examples
of o-nitrobenzenesulfonamides with thiolates, see: Fukuyama, T.; J ow,
C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. For the related
displacement of a tosylate, see ref 10.
(28) For related studies and observations, see: Zhu, J .; Bigot, A.;
Dau, M. E. T. H. Tetrahedron Lett. 1997, 38, 1181.
(29) Review: Bunnett, J . F.; Zahler, R. E. Chem. Rev. 1951, 51, 273.
Lewis, E. S.; Suhr, H. J . Am. Chem. Soc. 1960, 82, 862. Brennan, J .;
Cadogan, J . I. G.; Sharp, J . T. J . Chem. Soc., Chem. Commun. 1976,
850.
[R]25 -55 (c 0.7, CHCl3), and a small amount of a
D
(30) Scho¨llkopf, U.; Nozulak, J .; Groth, U. Synthesis 1982, 868.
Scho¨llkopf, U.; Nozulak, J .; Grauert, M. Synthesis 1985, 55. Our two-
step preparation of 1424 has been improved by transmetalation of the
lithiated Scho¨llkopf reagent (1 equiv) with Cp2ZrCl2 (1 equiv) prior to
addition of 4-fluoro-3-nitrobenzaldehyde (1 equiv, -80 °C, 48 h, THF)
which provided a more favorable 5:1 ratio of separable alcohol
diastereomers (53% + 10%). Compound 14 has also been prepared by
a threonine aldolase catalyzed aldol reaction: Vassilev, V.-P.; Uchiya-
ma, T.; Kajimoto, T.; Wong, C.-H. Tetrahedron Lett. 1995, 36, 4081.
We thank Wilna J . Moree and Professor C.-H. Wong for providing
substantial quantities of 14.

4724 J . Org. Chem., Vol. 62, No. 14, 1997
Boger et al.
Sch em e 2
Sch em e 3
Sch em e 4
(18:1 diastereomeric mixture, 90% ee) occurred in route
to 17 as well as 36. Moreover, the 9% of the undesired
diastereomer of 18 obtained upon coupling (R)-17 with
15 may, in fact, be derived principally from the small
amount of contaminant (S)-17.31
N-BOC deprotection by a method that precludes O-
desilylation was effected by treatment of 18 with TB-
DMSOTf (2.7 equiv, CH2Cl2, 0 °C, 1.5 h, 99%) and cleanly
provided 19, [R]26 -25 (c 0.4, CHCl3), with no evidence
D
of racemization of the sensitive phenylglycine.33 Subse-
quent coupling (3 equiv of EDCI, 3.3 equiv of HOBt,
DMF, 0 °C, 12 h) of the free amine 19 with (R)-N-BOC-
(3,5-dihydroxy-4-methoxyphenyl)glycine (20, g94% ee)25
provided 21 (91%) accompanied by less than 5-7% of a
separable diastereomer (g10.5-11:1) derived from epimer-
ization of the intermediate activated carboxylate or
contaminant (S)-20. TBDMS ether deprotection of 21 (13
equiv of Bu4NF, 3 equiv of HOAc, THF, 25 °C, 12 h, 79%)
cleanly provided the alcohol 22. Comparable deprotec-
tions (5 equiv of Bu4NF, THF, 25 °C, 3 h) conducted in
the absence of added HOAc led to competitive macrocy-
clization providing both 22 (15%) and 25/26 (38%, 1:1.7
respectively). Alternatively, the free alcohol 22 could be
prepared by direct coupling of 38 (3 equiv of EDCI, 3.5
equiv of HOBt, DMF, -20 to 0 °C, 14 h, 70%) with (R)-
20 (g94% ee). In turn, 38 was derived from the direct
coupling of 14 with 17 (3 equiv of EDCI, 3.3 equiv of
HOBt, DMF, -20 to 4 °C, 18 h, 76%) followed by acid-
catalyzed N-BOC deprotection (Scheme 4).32
separable diastereomer (9%) derived from epimerization
at the phenylglycine center (Scheme 2). The preparation
of 17 was most conveniently conducted by direct O-
methylation (1.9 equiv of NaH, 1 equiv of CH3I, 1:1 THF-
DMF, 0 °C, 3.5 h, 70%) of the free acid 1615,31 and
attempts to prepare 17 from the corresponding methyl
ester of 16 suffered substantial racemization upon O-
methylation and ester hydrolysis (48% ee).
The optical purity of 17 and related intermediates was
assessed by methyl ester formation (6.7 equiv of TM-
SCHN2, 80% C6H6-CH3OH, 25 °C, 30 min), N-BOC
deprotection (30% TFA-CH2Cl2, 0-25 °C, 1.3 h), and
subsequent formation of the Mosher amide 36 (1.0 equiv
of (R)-MTPA-Cl, 1.0 equiv of pyridine, CH2Cl2, 0 °C, 1 h,
77% for three steps), (Scheme 3).32 1H NMR analysis32
(CDCl3, 400 MHz) established that minimal racemization
Both the alcohol 22 and the TBDMS ether 21 under-
went smooth macrocyclization upon treatment with K2-
CO3-CaCO3 (5 equiv of, 0.005 M DMF, 45 °C, 12.5 h for
21, 6 h for 22) in the presence of 4 Å molecular sieves to
provide 25 and 26 (1:1.7, 38%) or 23 and 24 (50-60%,
1:1), respectively, as separable mixtures of diastereomers.
Although this was not examined in extensive detail,
(31) The preparation of 16 from (R)-4-hydroxyphenylglycine was
more convenient and provided higher yields if the order of steps was
reversed: 1 equiv of BOC2O, 1.5 equiv of NaHCO3, 50% THF-H2O,
25 °C, 14 h, 88%; 1 equiv of Br2-py‚HBr, THF, 0 °C, 2 h, 70%)32 versus
(Br2, HBr-HOAc, 49%; BOC2O, 100%).15 This reversed order of steps
permitted the chromatographic separation of the dibrominated byprod-
uct and unreacted starting material that was only possible after N-BOC
protection.32 To date we have not been successful in enriching the
optical purity of 17 by recrystallization as it has only been isolated as
a foam.
(32) Full experimental details are provided in the Supporting
Information.
(33) Interestingly, when this reaction was worked up with
a
saturated aqueous NaHCO3 wash rather than direct chromatographic
purification, additional undesired and unidentified reaction products
were isolated.

Vancomycin CD and DE Ring System Synthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4725
macrocyclizations conducted in the presence of 18-
crown-6 or in the absence of CaCO3 led to much lower
conversions and consumption of the desired cyclization
products. Similarly, conducting the reaction in the
absence of 4 Å molecular sieves proved less satisfactory.
Presumably CaCO3 serves as an effective scavenger of
the liberated fluoride, which is sufficiently basic to
promote product decomposition, and the molecular sieves
serve to remove adventitious moisture. Consistent with
this expectation and in contrast to reactions run in its
absence, little or no TBDMS ether deprotection of 21 was
observed to accompany macrocyclization to 23 and 24 in
the presence of the added CaCO3 under the prescribed
reaction conditions. Moreover, under these conditions,
10-15% of the starting material is routinely recovered
and its examination revealed no evidence of substrate
epimerization under the reaction conditions. Anticipat-
ing appending the DE ring system onto the preformed
CD ring system and recognizing the inherent sensitivity
of the free alcohol, this development permitted us to
devote our efforts to conducting the cyclization of 21 to
provide 24 and to carrying this stable, protected material
forward. The sensitivity of the free â-hydroxyphenyla-
lanine subunit within the CD ring system became ap-
parent upon deprotection of 23 and 24 to provide the
corresponding free alcohols 25 and 26, respectively, which
were conducted to complete our structural correlations
and stereochemical assignments. Deprotection of 24
promoted by Bu4NF treatment (20 equiv of, THF, 25 °C,
3 h, 50%) conducted in the presence of HOAc (5 equiv)
cleanly provided 26, whereas conducting a similar reac-
tion on 23 proved more sensitive to the precise reaction
conditions. Treatment of 23 (5 equiv of Bu4NF, 6 equiv
of HOAc, 25 °C, 1 h, 60%) cleanly provided 25, whereas
conditions employing more Bu4NF and less HOAc (13
equiv of Bu4NF, 2 equiv of HOAc, 25 °C, 2 h, 61%) cleanly
provided the retro-Aldol product 3934 (eq 1). This selected
same retro-Aldol product 39 was observed in small
amounts in the macrocyclization closure of 21, which
provided 25 and 26 (40%, 1:1.7) directly along with 22
(15%). Thus, the ratio of 25 to 26 may well reflect a
diastereomeric sensitivity to the subsequent retro-Aldol
cleavage rather than a macrocyclization diastereoselec-
tivity. This same byproduct 39 derived from the desired
cyclization products was not observed with 21 unless the
reaction was conducted for prolonged reaction times
leading to contaminant TBDMS ether deprotection and
subsequent retro-Aldol cleavage.
Both 23 and 24 were independently converted to the
corresponding chlorides 29 and 33, respectively. Reduc-
tion of the nitro group to the aryl amines 27 and 31
without competitive removal of the aryl bromide was
effectively accomplished by H2/cat. Raney Ni (CH3OH,
-20 °C, 1.5 h, 100%). Alternative attempts employing
10% Pd-C (CH3OH, >90%) or a large excess of Raney
Ni (10 equiv) led to effective removal of the aryl bromide
as well as nitro reduction. Similarly, H2/cat. PtO2 and
Al(Hg) reduction (EtOH-Et2O-H2O 2:10:1, 25 °C, 1 h)
gave additional unidentified products, SnCl2 (EtOH, 40
°C) led to competitive N-BOC deprotection, Zn-HOAc
promoted decomposition of the substrate, and no reaction
was observed upon exposure to Na2S2O4 (THF-H2O, 25-
60 °C). Diazotization of 27 or 31 (1.3 equiv of t-BuONO,
1.3 equiv of HBF4, CH3CN, 0 °C, 1 h) followed by
Sandmeyer substitution of the corresponding diazonium
salts 28 and 32 with chloride (50 equiv of CuCl, 60 equiv
of CuCl2, CH3CN, 0 °C, 50-87%) cleanly provided 29 and
33 with virtually no competitive production of the reduc-
tion product 30. However, the success of the conversions
depended on the prescribed reaction conditions. The use
of larger amounts of HBF4 in the diazotization reaction
led to diminished conversions, presumably due to com-
petitive N-BOC deprotection. Similarly, the elimination
of the reduction product 30 required the use of large
excesses of both CuCl (50 equiv) and CuCl2 (60 equiv),
the use of CH3CN as a cosolvent, a minimal diazotization
reaction time with subsequent manipulation at 0 °C, and
the reverse addition of the diazonium salt to the aqueous
solution of CuCl-CuCl2 at 0 °C. Under these conditions,
33 (87%) could be generated in superb yield with no
competitive reduction to 30. In the course of optimizing
this reaction, the reduced byproduct 30 was obtained
from the sequences leading to both 29 and 33, confirming
that 23 and 24 and their subsequent products were
atropisomers and not diastereomers derived from epimer-
ization. More importantly, both 29 and 33 were prepared
free of the contaminant atropisomer indicating that the
isomerization of intermediates, particularly the diazo-
nium salts 28 or 32 and related Sandmeyer reaction
intermediates, was not observed through this sequence.
The assignment of the atropisomer stereochemistry
was accomplished by 2D 1H-1H ROESY NMR conducted
first on 23 (DMSO-d6, 600 MHz) and 24 (acetone-d6, 600
MHz) and later with the amines of 29 and 33. The
desired atropisomer 24 exhibited strong and diagnostic
NOE crosspeaks between H-15/H-17 (s) and H-14/H-17
(s) that were not observed with its diastereomer 23
(Figure 2). Instead, 23 exhibited diagnostic H-20/H-15
(s) and H-20/H-14 NOE (s) crosspeaks which in turn were
not observed with 24. Several additional strong (s) and
medium (m) NOE crosspeaks along with an unusually
small H-14/H-15 coupling constant (J ) 0 Hz) for both
23 and 24 established the rigid 16-membered ring
conformation which, unlike 1, adopts the more stable
sensitivity of the undesired atropisomer 25 to retro-Aldol
ring cleavage is surprising and suggests that caution
should be used in interpreting the origin of apparent
atropisomer diastereoselectivity observed in macrocy-
clization reactions conducted with such substrates. This
(34) For 39: 1H NMR (acetone-d6, 400 MHz) δ 10.05 (s, 1H), 8.52
(d, 1H, J ) 2.0 Hz), 8.20-8.15 (m, 1H), 8.12 (dd, 1H, J ) 2.0, 8.6 Hz),
7.98-7.90 (m, 1H), 7.65 (d, 1H, J ) 2.3 Hz), 7.44 (dd, 1H, J ) 2.3, 8.6
Hz), 7.13 (d, 1H, J ) 8.6 Hz), 7.08 (d, 1H, J ) 2.2 Hz), 7.01 (d, 1H, J
) 8.6 Hz), 6.92 (d, 1H, J ) 2.2 Hz), 6.60-6.53 (m, 1H), 5.52 (d, 1H, J
) 7.2 Hz), 5.35-5.30 (m, 2H), 3.93-3.90 (m, 2H), 3.86 (s, 3H), 3.74 (s,
3H), 3.61 (s, 3H), 1.28 (s, 9H); IR (neat) νmax 3327, 2955, 2924, 2853,
1726, 1658, 1571, 1494, 1462, 1377, 1260, 1163 cm-1; FABHRMS (NBA-
CsI) m/ z 907.0449 (M+ + Cs, C33H35N4O13Br requires 907.0438). For
42: [R]25D -14 (c 0.028, CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.59
(s, 1H), 7.42-7.35 (m, 2H), 7.30-7.25 (m, 3H), 7.02-6.95 (m, 1H), 7.01
(d, 1H, J ) 8.7 Hz), 6.71 (s, 1H), 6.59 (s, 1H), 6.25-6.17 (m, 1H), 5.85
(d, 1H, J ) 8.7 Hz), 5.50-5.40 (m, 2H), 4.58-4.50 (m, 1H), 3.96 (s,
3H), 3.83 (s, 3H), 3.74 (s, 3H), 1.39 (s, 9H), 0.79 (s, 9H), -0.01 (s, 3H),
-0.13 (s, 3H); IR (neat) νmax 3309, 2958, 2925, 2855, 1731, 1716, 1682,
1651, 1584, 1504, 1463, 1261, 1121, 1073, 1038, 800 cm-1; FABHRMS
(NBA-CsI) m/ z 932.1978 (M+ + Cs, C39H50N3O11ClSi requires 932.1957).

4726 J . Org. Chem., Vol. 62, No. 14, 1997
Boger et al.
Ta ble 1. Atr op isom er Isom er iza tion
agent
conditions
23:24 or 29:33
23
23
23
23
23
23
23
23
23
23
23
23
23
23
23
23
23
29
29
29
29
29
29
29
29
33
33
33
33
33
DMSO, 120 °C, 1 h
DMSO, 155 °C, 1.3 h
DMSO, 155 °C, 4 h
DMSO, 140 °C, 5 min
DMSO, 140 °C, 0.5 h
DMSO, 140 °C, 1 h
DMSO, 140 °C, 1.5 h
DMSO, 140 °C, 3.5 h
DMSO, 140 °C, 7 h
100:0
2:1
1.7:1 (72%)
>20:1
10:1
5:1
3.5:1
2:1
1.2:1
100:0
1.7:1
1.2:1 (57%)
>20:1
11:1
8:1
1.6:1
1.1:1
100:0
16:1
11:1
4:1
DMF, 120 °C, 1 h
DMF, 155 °C, 0.5 h
DMF, 155 °C, 1.1 h
o-C6H4Cl2, 140 °C, 20 min
o-C6H4Cl2, 140 °C, 2 h
o-C6H4Cl2, 140 °C, 3 h
o-C6H4Cl2, 140 °C, 16 h
o-C6H4Cl2, 140 °C, 56 h
DMSO, 120 °C, 0.25 h
DMSO, 140 °C, 1 h
DMSO, 140 °C, 1.5 h
DMSO, 140 °C, 3.5 h
DMSO, 140 °C, 4.5 h
DMSO, 140 °C, 6 h
F igu r e 2.
trans N13-C12 secondary amide stereochemistry. The
additional diagnostic H-1H NOEs for 24 include H-17/
1
H-13 (w), H-15/H-14 (s), H-13/H-20 (m), H-11/H-10 (m),
H-10/H-8 (s), H-10/H-21 (m), H-8/H-6 (s), H-8/H-21 (m),
and H-6/C5-OH (w). Notably, 24 failed to exhibit a strong
and diagnostic H-14/H-11 NOE crosspeak required of the
cis N13-C12 amide conformation. For 23, additional NOE
crosspeaks were observed for H-15/H-14 (s), H-14/H-13
(m), H-13/H-11 (m), H-11/H-10 (w), H-10/H-8 (s), H-10/
H-21 (w), H-6 and H-21/H-8 (m,s), H-8/NHBOC (m), H-6/
NHBOC (m), H-6/C5-OH (m), H-21/H-19 (w), and H-20/
H-19 (m). Similar observations were made with the
amines of 29 and 33. For the free amine of the desired
(M)-atropisomer 33 (CD3CN, 600 MHz), strong diagnostic
H-15/H-17 (s) and H-17/H-14 (s) NOE crosspeaks were
observed and those of H-15/H-20 and H-14/H-20 were
absent. Additional clear crosspeaks were observed for
H-15/H-14 (s), H-11/H-10 (m), H-10/H-21 (w), and H-20/
H-19 (s). In contrast, the HBr salt of the amine of the
undesired (P)-atropisomer 29 exhibited diagnostic H-15/
H-20 (s), and H-14/H-20 (m) NOE crosspeaks.
3:1
2:1
1.5:1
3:1
1:13
1:6
1:4
1:3
1:2
DMSO, 140 °C, 7 h
DMSO, 155 °C, 1.5 h
o-C6H4Cl2, 140 °C, 9.5 h
o-C6H4Cl2, 140 °C, 19.5 h
o-C6H4Cl2, 140 °C, 32 h
o-C6H4Cl2, 140 °C, 53 h
o-C6H4Cl2, 140 °C, 96 h
ate. As disclosed in the following section, the DE
atropisomer equilibration occurs more readily and the
aryl nitro intermediate similarly isomerizes more rapidly
than the corresponding aryl chloride. This suggests that
it may be possible to preferentially equilibrate the DE
versus CD atropisomers and that this may be best
conducted with a DE aryl nitro intermediate containing
the fully installed CD aryl chloride. Importantly, this
also implies that, once the CD atropisomer stereochem-
istry is set through equilibration of the aryl nitro deriva-
tive 24, its subsequent conversion to the aryl chloride 33
may be utilized to ultimately control the atropisomer
stereochemistry of a subsequently introduced DE ring
system.
Given the clean debromination of 24 that accompanied
reduction to the aryl amine upon hydrogenation using a
10% Pd-C catalyst or excess Raney Ni (10 equiv of,
conditions, 25 °C, 3 h, 100%), the conversion of 40 to the
corresponding aryl chloride 42 was also accomplished
(Scheme 5).34 The sample of 42 prepared through this
sequence was identical to that obtained by debromination
of 33 (H2, Pd-black, 2 equiv of NaOAc, CH3OH, 25 °C, 4
h, 74%).12
In contrast to past studies, the thermal interconversion
of the atropisomers 23 and 24 or 29 and 33 was examined
and found to proceed rapidly at temperatures of g155
°C and more slowly at 140 °C (Table 1). This productive
observation allows the undesired atropisomer 23 or 29
to be thermally equilibrated with 24 or 33, chromato-
graphically reisolated, and recycled to provide the desired
atropisomers. More importantly, the nitro-substituted
agents 23 or 24 equilibrated more rapidly than the
corresponding chloro atropisomers 29 or 33, and the rate
of atropisomerism could be controlled not only by the
choice of temperature but also by the choice of solvent.
These observations, in conjunction with similar observa-
tions on the atropisomer equilibration of the DE ring
system, provide the basis for the strategic plan to conduct
the synthesis in a manner that provides the fully
installed CD aryl chloride and DE aryl nitro intermedi-
Finally, in conjunction with projected efforts on the
synthesis of vancomycin itself, we also examined an
alternative order of amide coupling reactions for the
preparation of 21. That which was detailed in Scheme

Vancomycin CD and DE Ring System Synthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4727
Sch em e 5
Sch em e 7
Sch em e 6
2 uses progressive couplings requiring carboxylate acti-
vation of the sensitive phenylglycine derivatives at an
early stage and on intermediates that do not require a
preceding phenylglycine ester deprotection minimizing
the opportunity for adventious epimerization. In efforts
to establish whether this might not prove problematic,
the alternative coupling order for the preparation of 21
was examined (Scheme 6).32 Although coupling of 35
with 20 proceeded smoothly without problematic race-
mization of the sensitive phenylglycine center, conven-
tional efforts to hydrolyze the resulting methyl ester
(LiOH, THF-CH3OH-H2O, 25 °C) met with significant
racemization. This could be avoided by employing Bu2-
SnO, which cleanly provided 45 as a single diastereomer,
albeit in a low but unoptimized conversion. However,
its coupling with 16 to provide 21 also proved problematic
and was not further pursued.
cyanoalanine (4732 and 4835 ) with tert-butyl (R)-(3,5-
dihydroxy-4-methoxyphenyl)glycine (49, g94% ee)25 cleanly
provided 50 and 51 as single detectable diastereomers
(Scheme 7). Acid-catalyzed N-BOC deprotection of 50 (1
N HCl-EtOAc, 25 °C, 5 h, 60%) followed by NaHCO3
workup or hydrogenolysis of 51 (H2, Pd-C, CH3OH, 25
°C, 4 h, 98%) provided 52 as the free base. Hydrolysis
(2 equiv of LiOH, 2:1 t-BuOH-H2O, 25 °C, 0.5 h, 96%) of
methyl (2R,3R)-N-BOC-â-hydroxy-â-(4-fluoro-3-nitro-
phenyl)alaninate,24,30 [R]23D +21 (c 0.35, CHCl3), followed
by coupling (3 equiv of EDCI, 1.1 equiv of HOBt, DMF,
We also examined the potential of effecting the mac-
rocyclization reaction directly on the diazonium salt
derived from 21 (eq 2). Thus, reduction of 21 to the
0-25 °C, 14 h, 70%) of 53, [R]23 +6.9 (c 0.85, CH3OH),
D
with 52 provided 54. To date, the best conditions exam-
ined for effecting this coupling has provided a 6:1 mixture
of separable diastereomers, presumably derived from
partial epimerization of the intermediate activated car-
boxylate. Alternative methods including the use of DPPA
or BOPCl (0-25 °C, DMF, 12-36 h) were less successful.
Exposure of 54 to K2CO3-CaCO3 (5/7.5 equiv of, 0.005
M DMF, 45 °C, 6 h) cleanly provided 55 and 56 (59%) as
a separable 1:1.5 mixture of diastereomers with the (M)-
atropisomer possessing the natural stereochemistry being
preferentially formed. Thus, in sharp contrast to the
macrocyclization model studies of Zhu,18 which provide
only the unnatural atropisomer, the cyclization of 54
corresponding amine (H2, cat. PtO2, CH3OH, 25 °C, 91%),
diazotization (1.3 equiv of t-BuONO, 1.3 equiv of HBF4,
CH3CN, 0 °C, 1 h) followed by K2CO3-CaCO3 treatment
(7 equiv of each, 4 wt equiv of 4 Å MS, CH3CN, 0 °C, 48
h), and final Sandmeyer reaction (50 equiv of CuCl, 60
equiv of CuCl2, H2O, 1.5 h) failed to provide 29 or 33 or
evidence of macrocyclization (i.e. 30).
Th e Va n com ycin DE Rin g System . Coupling (2.2
equiv of EDCI or 1.3 equiv of DCC, 1.1 equiv of HOBt,
DMF, 0-25 °C, 16 h, 84%) of N-BOC or N-CBZ-L-â-
(35) Badet, B.; Vermoote, P.; Le Goffic, F. Biochemistry 1988, 27,
2282. For the dehydration procedure: Liberek, B.; Buczel, Cz.; Gr-
zunka, Z. Tetrahedron 1966, 22, 2303; Ressler, C.; Ratzkin, H. J . Org.
Chem. 1961, 26, 3356.

4728 J . Org. Chem., Vol. 62, No. 14, 1997
Boger et al.
Sch em e 8
F igu r e 3.
of both 70 and 71 provided 55 and 56, respectively,
establishing the correlation of atropisomers between the
two approaches.
Both 55 and 56 were independently converted to the
corresponding chlorides 59 and 63, respectively, without
atropisomer interconversion. Reduction of the nitro
group to the aryl amines 57 and 61 (H2, 10% Pd-C,
CH3OH, 25 °C, 2 h, 99%), diazotization (1.3 equiv of
t-BuONO, 1.3 equiv of HBF4, CH3CN, 0 °C, 1 h), and
Sandmeyer substitution of chloride for the diazonium salt
(50 equiv of CuCl, 60 equiv of CuCl2, CH3CN-H2O, 0-25
°C, 1.5 h) provided the chlorides 59 and 63. When the
Sandmeyer substitution was conducted in H2O (25 °C,
1.5 h) with more modest amounts of CuCl/CuCl2 (50/20
equiv) or with just CuCl (6 equiv) following diazotization
in THF (0 °C, 1 h) and low temperature removal of the
solvent (0-10 °C), significant or exclusive conversion to
the reduced product 60 was observed. In fact, conducting
the reaction with only 6 equiv of CuCl led to superb
conversion to 60 (76%). In these latter preliminary
studies, the isolation of the same reduction product 60
from the reactions of both 57 and 61 confirmed that the
diastereomers 55 and 56 and their corresponding deriva-
tive products were atropisomers and not isomeric at
alternative, epimerized sites.
provided preferentially the natural atropisomer, and
analogous observations have been disclosed by Evans and
co-workers.13 In the absence of CaCO3, exposure of 54
to K2CO3 (4 equiv of, 0.008 M DMF) provided recovered
starting material (25 °C , 14 h) or lower conversions to
55 and 56 (55-60 °C, 3 h) with extensive decomposition.
In the presence of 18-crown-6, treatment with only K2-
CO3 (10 equiv) in THF (25 °C, 0.008 M) provided
recovered starting material, while reactions in DMF (25
°C) or CH3CN (55 °C) underwent conversion to multiple
products. Na2CO3-CaCO3 (5/8 equiv), but not Li2CO3-
CaCO3 (9/6 equiv), was also effective at promoting the
cyclization reaction but required substantially longer
reaction times (DMF, 45 °C, 72-96 h), and CaCO3 alone
failed to provide evidence of ring closure. In a potentially
useful alternative, the use of DMSO versus DMF as the
reaction solvent provided a slightly faster cyclization
reaction. Thus, treatment with K2CO3-CaCO3 (7/10
equiv of, DMSO, 40 °C, 5 h) provided comparable cycliza-
tion results and when conducted in the presence of 18-
crown-6 (1 equiv of, DMSO, 25 °C, 8 h) led to cyclization
at room temperature with comparable results. However,
unlike the studies conducted in DMF, additional poten-
tially epimeric products were also detected. To date, CsF
(5 equiv of, DMF, 25 °C, 48 h) has failed to provide
cyclization, affording only recovered starting material,
although two independent studies13,18 have experienced
the best conversions with such conditions.
The TBDMS ether 69 was similarly examined (Scheme
8). However, the coupling of 67 with 52 proved more
problematic than that observed with 53. Although this
was not examined in detail, coupling of 67 with 52 under
the same conditions (3 equiv of EDCI, 1.1 equiv of HOBt,
DMF, 25 °C, 14 h, 56%) proceeded more slowly and
suffered more substantial racemization (1.5:1 mixture of
diastereomers). The TBDMS ether 69 underwent clean
closure to 70 and 71 upon treatment with K2CO3-CaCO3
(5/7.5 equiv of, 0.005 M DMF, 25 °C, 5 h). With this
substrate, the closure occurred under even milder condi-
tions (25 °C versus 45 °C) and the major diastereomer
was isolated in yields as high as 40%. Treatment of this
substrate with CaCO3 alone (5 equiv of, DMF, 70 °C, 6.5
h) led to only recovered starting material. Deprotection
The stereochemical assignments of the atropisomers
was accomplished by 2D 1H-1H ROESY NMR conducted
on nitro compounds 55 and 71 (acetone-d6, 500 MHz) and
subsequently with the corresponding chlorides 59 and 63
(acetone-d6, 600 MHz) (Figure 3). The desired TBDMS-
protected atropisomer 71 exhibited diagnostic NOE
crosspeaks between C15-H/C17-H (s) and C14-H/C17-H
(m) which were clearly not observed with 55. Instead,
55 exhibited C14-H/C20-H (s) and C15-H/C20-H (m) NOE
crosspeaks which in turn were not evident with 71.
Several additional strong (s) and medium (m) NOE
crosspeaks for both 55 and 71 established the rigid 16-
membered ring conformation which possesses two sec-
ondary trans-amides and confirmed the required C14
stereochemistry (the relative C14-C15 stereochemistry).
1
The additional diagnostic H-1H NOEs for 55 and 71
included C8-H/N9-H (m), N9-H/C21-H (m), N9-H/C11-H
(s), N12-H/C14-H (m), N12-H/C15-H (m), C14-H/NH-
BOC (s), C15-H/NHBOC (s), and C14-H/C15-H (s). For
55, additional strong NOE crosspeaks were observed for
C8-H/C21-H and C8-H/C6-H. Similar observations were
made with chloride atropisomers 59 and 63. For the
desired (M)-atropisomer 63, diagnostic NOEs were ob-
served between C15-H/C17-H (s) and C14-H/C17-H (m),
as well as C20-H/C15-OH (w). As expected for the unde-
sired (P)-atropisomer 59, strong diagnostic NOEs were

Vancomycin CD and DE Ring System Synthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4729
Ta ble 2. Atr op isom er Isom er iza tion
Ta ble 3. Atr op isom er Equ ilibr a tion Ra tes
compound
conditions
k (h-1
)
t1/2 (h)
CD ring system
155 °C, DMSO
140 °C, DMSO
140 °C, o-Cl2C6H4
140 °C, DMSO
23a
23a
23
0.27
1.06
3.52
9.77
4.03
53.0
0.082
0.029
0.071
29
29
140 °C, o-Cl2C6H4
0.0054
DE ring system
130 °C, DMSO
140 °C, DMSO
55b
55b
55
0.66
1.05
nd
0.23
0.17
<0.16
compound
conditions
55:56 or 59:63
140 °C, o-Cl2C6H4
55
55
55
55
55
55
55
55
55
55
55
55
55
55
59
59
59
59
59
DMSO, 115 °C, 20 min
DMSO, 130 °C, 5 min
DMSO, 130 °C, 10 min
DMSO, 130 °C, 15 min
DMSO, 130 °C, 30 min
DMSO, 130 °C, 50 min
DMSO, 140 °C, 3 min
DMSO, 140 °C, 7 min
DMSO, 140 °C, 11 min
DMSO, 140 °C, 15 min
DMSO, 140 °C, 20 min
DMSO, 140 °C, 30 min
DMSO, 140 °C, 60 min
o-C6H4Cl2, 140 °C, 10 min
DMSO, 115 °C, 20 min
DMSO, 140 °C, 20 min
DMSO, 140 °C, 40 min
DMSO, 140 °C, 60 min
o-C6H4Cl2, 140 °C, <2 h
100:0
5.6:1
4.6:1
3.0:1
1.7:1
1.2:1
6.1:1
2.6:1
2.0:1
1.6:1
1.3:1
1.1:1
1:1
59
140 °C, DMSO
0.67
0.35
Ea ) 26.6 kcal/mol, ∆Hq ) 27.0 kcal/mol, ∆Sq ) -1.7 eu. Ea
) 15.3 kcal/mol, ∆Hq ) 14.5 kcal/mol, ∆Sq ) -24.0 eu.
a
b
Sch em e 9
55:45
100:0
2.4:1
1.5:1
1:1
Sch em e 10
1:1
observed for C15-H/C20-H, C14-H/C20-H, and C17-H/
C15-OH; however, one additional weak NOE crosspeak
was also observed for C15-H/C17-H (w). This observation
along with the lack of the C15-H/C14-H crosspeaks would
indicate that the C15 proton is bisecting and orthogonal
to the E aromatic ring. Additional clear crosspeaks for
both 59 and 63 were observed for C8-H/C6-H (m), C8-H/
N9-H (m), N9-H/C21-H (m), N9-H/C11-H (s), and N12-
H/C14-H (s), while C11-H/C20-H (s) and C11-H/C21-H
(w) were observed only with 59, suggesting that the C11
proton may be positioned underneath the E aromatic
ring.
Analogous to studies with the CD ring system, the
thermal interconversion of the atropisomers 55 and 56
or 59 and 63 was examined and found to proceed rapidly
at 140 °C (Table 2). Consistent with analogous observa-
tions with the CD ring system, the isomerization of the
chloride atropisomers 59 and 63 was slower than that of
the corresponding nitro atropisomers 55 and 56. More
importantly, the DE ring system atropisomers equili-
brated much more rapidly than the CD ring system
atropisomers (DMSO or o-Cl2C6H4, 140 °C) under condi-
tions where little or no equilibration of the CD ring
system was observed. This distinction is especially true
in the comparisons of the more readily equilibrated DE
ring system nitro atropisomers (10 min, 140 °C, o-Cl2C6H4)
versus the more stable CD ring system chloride atropiso-
mers (30 min, 140 °C, DMSO, >16:1 or 140 °C, o-Cl2C6H4,
>20:1) (Table 3). Thus, it may be possible to control the
atropisomer stereochemistry of a newly appended DE
ring system via thermal equilibration while the appropri-
ate CD atropisomer stereochemistry is maintained during
the assemblage of the CDE substructure of vancomycin.
Significantly, this may be accomplished by employing DE
substrates bearing an L-â-cyanoalanine side chain versus
the L-asparagine carboxamide side chain, which can be
expected to suffer competitive backbone rearrangement
under comparable thermal treatment.
In an additional but concurrent study, exhaustive
treatment of 54 with TBDMSOTf (3 equiv of, 4 equiv of
Et3N, CH2Cl2, 0 °C, 3 h, 50%) provided 72 (Scheme 9).32
The intention with 72 was to determine whether it was
possible to selectively deprotect the phenol TBDMS
ethers and promote the in situ cyclization of the resulting
phenoxide potentially with and without deprotection of
the secondary alcohol. Although cyclization was not
observed, selective or exhaustive deprotection of 72 was
observed upon treatment with KF or Bu4NF, respectively.
Thus, although the conversion of 72 to either 55/56 or
70/71 was not realized, the selective deprotection of 72
to provide 69 offers alternatives to the key intermediate
syntheses as we address the natural product itself.
Similarly, the corresponding o-nitroaryl triflate 77 was
prepared32 and its potential closure to 70/71 examined
(Scheme 10). Treatment of 77 with K2CO3 (5-10 equiv
of, DMF, 70 °C, 5 h) resulted in epimerization of the
starting material and at temperatures below 70 °C
resulted only in recovered starting materials.
Finally, a more convergent assembly of the key cy-
clization precursor 54 was examined (Scheme 11). Con-
version of N-CBZ-â-cyano-L-alanine (48)35 to the corre-
sponding methyl ester 78 (1.3 equiv of TMSCHN2, 20%
CH3OH-C6H6, 25 °C, 1 h, 84%) and subsequent CBZ

4730 J . Org. Chem., Vol. 62, No. 14, 1997
Boger et al.
Sch em e 11
provide predominantly or exclusively the unnatural
atropisomers.18 The first disclosure of the thermal
equilibration of the stable atropisomers was also detailed.
Important substituent effects on the rate of thermal
equilibration were defined (C1 more stable than NO2).
Significantly, thermal equilibration of the DE ring system
proved substantially faster than the CD ring system,
suggesting a potential solution to the control of the
vancomycin CDE atropisomer stereochemistry. Exten-
sions of these efforts to the total synthesis of the
vancomycin CDE ring system and vancomycin itself are
in progress and will be disclosed in due course.
Exp er im en ta l Section
Meth yl (2S,3R)-2-Am in o-3-[(ter t-bu tyld im eth ylsilyl)-
oxy]-3-(4-flu or o-3-n itr op h en yl)p r op ion a te (15). A solu-
tion of 1425 (104 mg, 0.40 mmol) in CH2Cl2 (4 mL) was treated
with 2,6-lutidine (194 mg, 1.81 mmol, 4.5 equiv), TBDMSOTf
(0.37 mL, 1.6 mmol, 4 equiv) at 0 °C and the mixture was
stirred at 0 °C (4 h) before saturated aqueous NaHCO3 (2 mL)
was added. The resulting mixture was extracted with EtOAc
(2 × 9 mL), and the combined EtOAc extracts were washed
with saturated aqueous NaCl (2 × 3 mL), dried (Na2SO4), and
concentrated in vacuo. Flash chromatography (SiO2, 1.5 × 12
cm, EtOAc) afforded 15 (127 mg, 150 mg theoretical, 85%) as
a yellow film: [R]26D -6.1 (c 1.1, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 8.07 (dd, 1H, J ) 2.1, 7.1 Hz), 7.64 (ddd, 1H, J ) 2.1,
4.1, 8.6 Hz), 7.26 (dd, 1H, J ) 8.6, 10.5 Hz), 5.27 (s, 1H), 3.75
(s, 3H), 3.48 (br s, 1H), 0.86 (s, 9H), -0.01 (s, 3H), -0.17 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 173.5, 154.8 (d, J ) 264
Hz), 139.1, 136.9, 133.2 (d, J ) 10 Hz), 124.0, 118.1 (d, J ) 21
Hz), 74.3, 61.4, 52.2, 25.5 (3C), 18.0, -4.7, -5.5; IR (neat) νmax
2954, 2950, 2857, 1743, 1619, 1595, 1598, 1538, 1499, 1350,
1255, 1083, 835 cm-1; FABHRMS (NBA) m/ z 373.1607 (M+
+ H, C16H25N2O5FSi requires 373.1595).
hydrogenolysis (H2, 10% Pd-C, CH3OH, 25 °C, 5 h, 60%)
provided â-cyano-L-alanine methyl ester (79). Although
the direct coupling of 79 with the free acid 53 under a
variety of conditions (1.1-1.6 equiv of EDCI, DCC, or
HATU; 1.1 equiv of HOAt or HOBt; with or without 1.1
equiv of collidine, 64-82%) provided the desired dipeptide
81, it was typically accompanied by substantial epimer-
ization when this reaction was conducted at 25 °C (ca.
2:1). This could be minimized by first converting 53 to
the diastereomerically pure activated pentafluorophenol
ester 80 (64%), followed by room temperature coupling
with 79 in THF (3 h) in the absence of additional
reagents, providing 81 (58%) accompanied by a smaller
amount of the separable epimerized diastereomer (18%).36
However, the best conversions were ultimately obtained
by conducting the direct reaction of 79 with 53 at 0-5
°C (3 equiv of EDCI, 3.3 equiv of HOAt, 14 h), providing
81 (98%) as a 14:1 mixture of diastereomers. A single
recrystallization (30% i-PrOH/hexane) provided 81 as a
34:1 mixture of diastereomers suitable for direct use and
avoided an otherwise tedious chromatographic separa-
tion. Both the reaction temperature (0-5 °C) and the
use of HOAt proved critical to the success of this coupling
and suggests that the preceding results for the prepara-
tion of 54, 69, and 74 may be further improved by
adopting this reaction protocol. Although unappreciated
in the discussion of studies disclosed to date, epimeriza-
tion of this substituted phenylalanine R-center has
proven much more facile than could be predicted and
constitutes a stereocenter that should be closely moni-
tored.14,18,24 Methyl ester hydrolysis (2 equiv of LiOH,
2:1 t-BuOH-H2O, 0 °C, 45 min, 98%) and subsequent
coupling of 82 with 49 (2.2 equiv of EDCI, 1.1 equiv of
HOBt, DMF, 0 °C, 15 h, 58%) provided 54 identical in
all respects with our prior sample (cf. Scheme 7).
(R)-(3-Br om o-4-m eth oxyp h en yl)-N-[(ter t-bu tyloxy)ca r -
bon yl]glycin e (17). A suspension of 1615,31 (2.0 g, 5.8 mmol)
in DMF-THF (1:5, 35 mL) was treated with a suspension of
NaH (80% in oil, 330 mg, 1.1 mmol, 1.9 equiv) in DMF (23
mL) at -40 °C and the temperature was raised to 0 °C. The
reaction mixture was stirred for 15 min before CH3I (0.38 mL,
6.1 mmol, 1 equiv) was added and the mixture was stirred at
0 °C (3.5 h). Aqueous citric acid (pH 3, 5 mL) was added and
the resulting mixture was extracted with EtOAc (2 × 50 mL).
The combined EtOAc extracts were washed with saturated
aqueous NaCl (2 × 10 mL), dried (Na2SO4), and concentrated
in vacuo. Flash chromatography (SiO2, 2 × 20 cm, CH2Cl2-
CH3OH-HOAc, 90:2:1) afforded 17 (1.5 g, 2.1 g theoretical,
1
70%) as a white film: [R]26 -127 (c 0.5, CH3OH); H NMR
D
(CD3OD, 400 MHz) δ 7.56 (d, 1H, J ) 1.9 Hz), 7.34 (dd, 1H, J
) 8.5, 1.9 Hz), 7.01 (d, 1H, J ) 8.5 Hz), 5.07 (s, 1H), 3.86 (s,
3H), 1.43 (s, 9H); 13C NMR (CD3OD, 100 MHz) δ 173.8, 157.4,
157.3, 133.3, 132.4, 129.0, 113.1, 112.5, 80.8, 58.1, 56.7, 28.7
(3C); IR (neat) νmax 3333, 2974, 2929, 1713, 1602, 1496, 1359,
1257, 1163, 1054, 1019 cm-1; FABHRMS (NBA-CsI) m/ z
491.9435 (M+ + Cs, C14H18NO5Br requires 491.9423).
Meth yl (2S,3R)-2-[(R)-N-[(3-Br om o-4-m eth oxyp h en yl)-
N-[(ter t-bu tyloxy)ca r bon yl]glycyl]a m in o]-3-[(ter t-bu tyl-
d im et h ylsilyl)oxy]-3-(4-flu or o-3-n it r op h en yl)p r op ion -
a te (18). A solution of 15 (140 mg, 0.37 mmol), HOBt (160
mg, 1.2 mmol, 3.3 equiv), and 17 (140 mg, 0.39 mmol, 1.1
equiv) in DMF (7.4 mL) was treated with EDCI‚HCl (210 mg,
1.1 mmol, 3 equiv) at -20 °C, and the mixture was stirred at
-20 °C (15 min) and at 0 °C (15 h). The reaction mixture was
quenched with the addition of saturated aqueous citric acid
(pH 3) and extracted with EtOAc (2 × 12 mL). The combined
organic layers were washed with H2O (3 mL) and saturated
aqueous NaCl (2 × 5 mL), dried (Na2SO4), and concentrated
in vacuo. Flash chromatography (SiO2, 2 × 17 cm, 67%
EtOAc-hexane) afforded 18 (210 mg, 260 mg theoretical, 80%)
Con clu sion s. The fully functionalized vancomycin
CD and DE ring systems were prepared by employing
an aromatic nucleophilic substitution reaction for forma-
tion of the biaryl ether linkage and key macrocyclization
of the 16-membered rings. Closure to form the CD ring
system provided a 1:1 mixture of atropisomers, while
closure of the DE ring system exhibited a slight prefer-
ence for the natural atropisomer (1.5:1). This contrasts
the preferential closure of related simplified models to
as a white film and its separable diastereomer (6.7 mg, 74 mg
(36) Both the â-cyano-L-alanine methyl ester (79) and the pentafluo-
rophenyl ester 80 were enantiomerically and diastereomerically pure
going into the reaction.
1
theoretical, 9%). For 18: [R]26 -55 (c 0.7, CHCl3); H NMR
D
(acetone-d6, 250 MHz) δ 8.09 (d, 1H, J ) 5.9 Hz), 7.76 (d, 1H,

Vancomycin CD and DE Ring System Synthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4731
J ) 9.5 Hz), 7.60-7.55 (m, 1H), 7.50 (d, 1H, J ) 2.2 Hz), 7.22-
7.05 (m, 2H), 6.92 (d, 1H, J ) 8.5 Hz), 6.42-6.36 (m, 1H), 5.57
(d, 1H, J ) 1.9 Hz), 5.21 (d, 1H, J ) 7.9 Hz), 4.87 (dd, 1H, J
) 1.9, 9.5 Hz), 3.91 (s, 3H), 3.79 (s, 3H), 1.35 (s, 9H), 0.89 (s,
9H), 0.26 (s, 3H), -0.17 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
169.29, 169.26, 156.0, 154.8, 154.76 (d, J ) 264 Hz), 137.1,
136.7, 136.6, 132.6 (d, J ) 8 Hz), 131.8, 127.2, 123.3, 118.3
(d, J ) 21.0 Hz), 112.2, 112.0, 80.2, 77.2, 72.6, 58.3, 56.2, 52.9,
28.2 (3C), 25.4 (3C), 17.8, -4.8, -5.7; IR (neat) νmax 2951, 2926,
1714, 1693, 1682, 1538, 1495, 1349, 1259, 1166, 1094, 837
cm-1; FABHRMS (NBA-CsI) m/ z 846.0862 (M+ + Cs,
C30H41N3O9BrFSi requires 846.0834).
aqueous NH4Cl (1 mL) and extracted with EtOAc (2 × 5 mL).
The combined organic layers were washed with saturated
aqueous NH4Cl (2 × 2 mL), dried (Na2SO4), and concentrated
in vacuo. Flash chromatography (SiO2, 0.5 × 5 cm, 75%
EtOAc-hexane) afforded 22 (1.4 mg, 1.8 mg theoretical, 79%)
as a white film: Rf ) 0.20 (75% EtOAc-hexane); 1H NMR
(acetone-d6, 400 MHz) δ 8.03 (d, 1H, J ) 6.4 Hz), 8.00-7.93
(br s, 2H), 7.88-7.80 (m, 2H), 7.60-7.52 (m, 1H), 7.48 (s, 1H),
7.14 (d, 1H, J ) 8.6 Hz), 7.14-7.04 (m, 1H), 6.83 (d, 1H, J )
8.6 Hz), 6.48 (s, 2H), 6.34-6.26 (m, 1H), 5.50-5.38 (m, 3H),
5.12 (d, 1H, J ) 7.4 Hz), 4.96 (dd, 1H, J ) 2.2, 9.4 Hz), 3.88
(s, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 1.35 (s, 9H); IR (neat) νmax
3300, 2924, 2854, 1738, 1709, 1698, 1694, 1657, 1651, 1644,
1538, 1501, 1462, 1440 cm-1; FABHRMS (NBA-CsI) m/ z
927.0501 (M+ + Cs, C33H36N4O13BrF requires 927.0537).
F r om 38.32 A solution of 38 (5.2 mg, 10 µmol), HOBt (4.6
mg, 34 µmol, 3.3 equiv), and 20 (3.3 mg, 10 µmol, 1 equiv) in
DMF (0.3 mL) was treated with EDCI‚HCl (6.0 mg, 31 µmol,
3 equiv) at -20 °C and the mixture was stirred at -20 °C (15
min) and at 0 °C (15 h). The reaction mixture was quenched
with the addition of saturated aqueous citric acid (pH 3) and
extracted with EtOAc (2 × 5 mL). The combined organic
layers were washed with H2O (2 mL) and saturated aqueous
NaCl (2 × 2 mL), dried (Na2SO4), and concentrated in vacuo.
Flash chromatography (SiO2, 0.5 × 4 cm, 75% EtOAc-hexane)
afforded 22 (5.8 mg, 8.3 mg theoretical, 70%) as a white film.
Meth yl (P )- a n d (M)-(8R,11R,14S,15R)-11-(3-Br om o-4-
m eth oxyp h en yl)-15-[(ter t-bu tyld im eth ylsilyl)oxy]-8-[N-
[(ter t-b u t yloxy)ca r bon yl]a m in o]-5-h yd r oxy-4-m et h oxy-
18-n it r o-10,13-d ia za -2-oxa t r icyclo[14.2.2.13,7]h en eicosa -
1(18),3(21),4,6,16,19-h exa en e-14-ca r boxyla te (23 a n d 24).
A solution of 21 (350 mg, 0.385 mmol) in DMF (80 mL) was
treated with K2CO3 (267 mg, 1.93 mmol, 5 equiv), CaCO3 (193
mg, 1.93 mmol, 5 equiv), and 4 Å molecular sieves (700 mg),
and the mixture was stirred at 45 °C (14 h). The reaction
mixture was filtered through Celite (EtOAc wash) and con-
centrated in vacuo. Flash chromatography (SiO2, 2 × 14 cm,
67% EtOAc-hexane then 44% acetone-hexane) afforded 23
(95 mg, 347 mg theoretical, 27%, typically 21-29%) as a white
solid, 24 (84 mg, 347 mg theoretical, 24%, typically 20-26%)
as a white solid, and recovered 21 (53 mg, 15%, typically 10-
15%).
Meth yl (2S,3R)-2-[N-[((R)-3-Br om o-4-m eth oxyp h en yl)-
glycyl]am in o]-3-[(ter t-bu tyldim eth ylsilyl)oxy]-3-(4-flu or o-
3-n itr op h en yl)p r op ion a te (19). A solution of 18 (130 mg,
0.18 mmol) in CH2Cl2 (32 mL) was treated with TBDMSOTf
(110 µL, 0.50 mmol, 2.7 equiv) at 0 °C and the mixture was
stirred at 0 °C (1.5 h). The reaction mixture was directly
passed through a short column (SiO2, EtOAc). The combined
eluant was washed with saturated aqueous NaHCO3 (5 mL)
and saturated aqueous NaCl (2 × 5 mL), dried (Na2SO4), and
concentrated in vacuo. Flash chromatography (SiO2, 1.5 × 10
cm, EtOAc) afforded 19 (110 mg, 111 mg theoretical, 99%) as
1
a white film: [R]26 -25 (c 0.4, CHCl3); H NMR (acetone-d6,
D
400 MHz) δ 8.44 (d, 1H, J ) 10.2 Hz), 8.15 (dd, 1H, J ) 2.1,
7.2 Hz), 7.86 (ddd, 1H, J ) 2.1, 4.4, 8.6 Hz), 7.58 (d, 1H, J )
2.1 Hz), 7.47 (dd, 1H, J ) 8.6, 11.1 Hz), 7.32 (dd, 1H, J ) 2.1,
8.5 Hz), 6.99 (d, 1H, J ) 8.5 Hz), 5.63 (d, 1H, J ) 1.7 Hz),
4.73-4.66 (m, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 0.99 (s, 9H), 0.092
(s, 3H), -0.13 (s, 3H); 13C NMR (acetone-d6, 100 MHz) δ 171.2,
170.6, 156.1, 155.5 (d, J ) 260 Hz), 154.2, 139.6, 139.5, 134.7
(d, J ) 9.0 Hz), 133.0, 128.9, 124.9, 118.9 (d, J ) 21 Hz), 112.8,
111.6, 73.7, 67.0, 58.7, 56.5, 52.9, 26.0 (3C), 18.5, -4.5, -5.5;
IR (neat) νmax 3580, 2925, 2856, 1738, 1687, 1618, 1598, 1537,
1494, 1346, 1259, 1092 cm-1; FABHRMS (NBA-CsI) m/ z
746.0337 (M+ + Cs, C25H33N3O7BrFSi requires 746.0310).
Meth yl (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-
m eth oxyph en yl)glycyl](3-br om o-4-m eth oxyph en y)glycyl]-
a m in o]-3-(4-flu or o-3-n it r op h en yl)p r op ion a t e (21).
A
solution of 19 (520 mg, 0.846 mmol), HOBt (385 mg, 2.79
mmol, 3.3 equiv), and 2025 (265 mg, 0.846 mmol, 1 equiv) in
DMF (25 mL) was treated with EDCI‚HCl (488 mg, 2.54 mmol,
3 equiv) at -20 °C and the mixture was stirred at -20 °C (15
min) and at 0 °C (15 h). The reaction mixture was quenched
with the addition of saturated aqueous citric acid (pH 3) and
extracted with EtOAc (2 × 40 mL). The combined organic
layers were washed with H2O (25 mL) and saturated aqueous
NaCl (2 × 20 mL), dried (MgSO4), and concentrated in vacuo.
Flash chromatography (SiO2, 4 × 25 cm, 67% EtOAc-hexane)
afforded 21 (700 mg, 770 mg theoretical, 91%) as a white
film: [R]25D -63 (c 1.0, CHCl3); 1H NMR (acetone-d6, 400 MHz)
δ 8.07 (dd, 1H, J ) 2.0, 7.2 Hz), 7.97 (s, 2H, OH), 7.91 (d, 1H,
J ) 7.3 Hz), 7.81 (d, 1H, J ) 7.3 Hz), 7.55-7.49 (m, 1H), 7.50
(d, 1H, J ) 2.0 Hz), 7.17 (dd, 1H, J ) 2.0, 8.6 Hz), 7.04 (dd,
1H, J ) 8.7, 11 Hz), 6.89 (d, 1H, J ) 8.6 Hz), 6.46 (s, 2H), 6.27
(d, 1H, J ) 7.3 Hz), 5.53 (d, 1H, J ) 2.4 Hz), 5.49 (d, 1H, J )
7.3 Hz), 5.11 (d, 1H, J ) 7.3 Hz), 4.45 (dd, 1H, J ) 9.5, 2.4
Hz), 3.91 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 1.34 (s, 9H), 0.87
(s, 9H), 0.001 (s, 3H), -0.19 (s, 3H); 13C NMR (acetone-d6, 100
MHz) δ 170.41, 170.4, 170.1, 156.4, 155.51 (d, J ) 260 Hz),
155.5, 151.2 (2C), 138.8, 137.2, 135.8, 135.5 (d, J ) 8 Hz),
134.4, 133.4, 132.7, 128.3, 124.8, 118.4 (d, J ) 22 Hz), 112.5,
111.7, 107.4 (2C), 79.4, 73.7, 60.5, 58.9, 58.4, 56.4, 55.9, 52.8,
28.6 (3C), 25.9 (3C), 18.5, -4.6, -5.5; IR (neat) νmax 3331, 2954,
2857, 1742, 1703, 1693, 1678, 1659, 1651, 1599, 1537, 1497,
1350, 1260, 1164, 1055 cm-1; FABHRMS (NBA-CsI) m/ z
1041.1396 (M+ + Cs, C39H50N4O13BrFSi requires 1041.1365).
Meth yl (2S,3R)-2-[N-[(R)-N-[(R)-N-[(ter t-Bu tyloxy)ca r -
bon 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-h yd r oxy-3-(4-flu or o-3-
n itr op h en yl)p r op ion a te (22). F r om 21. A solution of 21
(2.0 mg, 2.2 µmol) in THF (0.2 mL) was treated with HOAc
(38 µL, 6.6 µmol, 3 equiv) and Bu4NF (1.0 M in THF, 29 µL,
13 equiv), and the mixture was stirred at 25 °C (10 h). The
reaction mixture was quenched with the addition of saturated
F or 23 (m or e p ola r isom er ): Rf ) 0.25 (67% EtOAc-
hexane); [R]25 -180 (c 0.5, CHCl3); 1H NMR (acetone-d6, 400
D
MHz) δ 8.24 (s, 1H, OH), 8.15 (d, 1H, J ) 2.1 Hz), 7.93-7.87
(m, 1H), 7.84-7.80 (m, 1H), 7.55-7.45 (m, 2H), 7.41 (d, 1H, J
) 8.5 Hz), 7.15 (d, 1H, J ) 8.3 Hz), 6.69 (d, 1H, J ) 2.0 Hz),
6.42 (d, 1H, J ) 2.0 Hz), 6.20-6.10 (m, 2H), 5.62 (s, 1H), 5.48
(d, 1H, J ) 7.7 Hz), 5.37-5.30 (m, 1H), 4.68-4.63 (m, 1H),
3.98 (s, 3H), 3.95 (s, 3H), 3.77 (s, 3H), 1.39 (s, 9H), 0.86 (s,
9H), 0.04 (s, 3H), -0.03 (s, 3H); 1H NMR (DMSO-d6, 400 MHz)
δ 8.97 (s, 1H), 8.51 (d, 1H, J ) 8.4 Hz), 8.25 (s, 1H), 7.70-
7.60 (m, 1H), 7.58 (d, 1H, J ) 2.0 Hz), 7.29 (dd, 1H, J ) 8.4,
2.0 Hz), 7.22 (d, 1H, J ) 8.4 Hz), 7.06 (d, 1H, J ) 8.4 Hz),
6.99 (d, 1H, J ) 8.4 Hz), 6.42-6.33 (m, 1H), 5.79 (br s, 1H),
5.56 (s, 1H), 5.40-5.33 (m, 1H), 5.12-5.04 (m, 1H), 4.80-4.75
(m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.70 (s, 3H), 1.39 (s, 9H),
0.92 (s, 9H), 0.09 (s, 3H), 0.04 (s, 3H); 13C NMR (DMSO-d6,
100 MHz) δ 168.9, 168.8, 155.3, 155.2, 152.1, 151.3, 148.3,
141.7, 138.5, 135.6, 134.3, 133.1, 131.2, 130.8, 128.0, 125.5,
123.5, 112.5, 110.7, 108.4, 103.0, 78.6, 71.5, 60.2, 59.0, 56.7,
56.3, 55.9, 55.8, 52.1, 29.6 (3C), 25.6 (3C), 17.7, -4.7, -5.5; IR
(film) νmax 3328, 2926, 2854, 1723, 1703, 1677, 1584, 1535,
1498, 1463, 1344, 1260, 1165, 1094, 838, 779 cm-1; FABHRMS
(NBA-CsI) m/ z 1021.1331 (M+ + Cs, C39H49N4O13BrSi requires
1021.1303).
The 2D 1H-1H ROESY NMR spectrum (DMSO-d6, 600
MHz) of 23 displayed the following diagnostic NOE cross-
peaks: C20-H/C15-H (s), C20-H/C14-H (s), C15-H/C14-H (s),
C14-H/C13-H (m), C13-H/C11-H (m), C11-H/C10-H (w), C10-
H/C8-H (s), C10-H/C21-H (w), C6-H/C8-H (m), C21-H/C8-H (s),
C8-H/NHBOC (m), C6-H/NHBOC (m), C6-H/C5-OH (m), C21-
H/C19-H (w), C20-H/C19-H (m).
F or 24 (less p ola r isom er ): Rf ) 0.70 (67% EtOAc-
1
hexane); [R]25 -34 (c 0.2, CHCl3); H NMR (acetone-d6, 400
D
MHz) δ 8.32 (s, 1H, OH), 8.16 (d, 1H, J ) 2.1 Hz), 7.68-7.62

4732 J . Org. Chem., Vol. 62, No. 14, 1997
Boger et al.
(m, 1H), 7.58-7.48 (m, 2H), 7.37 (d, 1H, J ) 8.6 Hz), 7.37-
7.32 (m, 1H), 7.18 (d, 1H, J ) 8.4 Hz), 6.76 (d, 1H, J ) 2.2
Hz), 6.68 (d, 1H, J ) 2.2 Hz), 6.35-6.25 (m, 1H), 5.90 (d, 1H,
J ) 8.5 Hz), 5.62 (s, 1H), 5.49 (d, 1H, J ) 7.4 Hz), 5.19-5.10
(m, 1H), 4.56 (d, 1H, J ) 8.5 Hz), 3.944 (s, 3H), 3.936 (s, 3H),
3.78 (s, 3H), 1.39 (s, 9H), 0.79 (s, 9H), 0.02 (s, 3H), -0.11 (s,
3H); 13C NMR (acetone-d6, 100 MHz) δ 169.8, 169.1, 168.5,
157.1, 152.8, 151.7, 151.4, 143.5, 138.7, 138.6, 133.6, 132.4,
130.3, 129.8, 124.60, 124.57, 122.9, 113.3, 113.2, 112.6, 109.9,
79.4, 74.2, 61.5, 61.3, 60.9, 58.2, 57.6, 56.7, 53.0, 28.5 (3C),
25.9 (3C), 18.3, -4.3, -5.7; IR (film) νmax 3408, 2956, 1742,
afforded 26 (0.65 mg, 1.3 mg theoretical, 50%) as a white film
identical in all respects with authentic material.
Meth yl (P )-(8R,11R,14S,15R)-11-(3-Br om o-4-m eth oxy-
p h en yl)-15-[(ter t-bu tyld im eth ylsilyl)oxy]-8-[N-[(ter t-bu -
tyloxy)ca r bon yl]a m in o]-18-ch lor o-5-h yd r oxy-4-m eth oxy-
10,13-d ia za -2-oxa t r icyclo[14.2.2.13,7]h e n e icosa -1(18),
3(21),4,6,16,19-h exa en e-14-ca r boxyla te (29). Following the
procedure detailed below for 33, 27 afforded 29 (47%) as a
1
white film: [R]25 -66 (c 0.4, CHCl3); H NMR (CD3CN, 500
D
MHz) mixture of two rotamers (rotamer A:B ) 4.8:1) δ (for
rotamer A) 7.61 (d, 1H, J ) 2.0 Hz), 7.40 (dd, 1H, J ) 8.5, 2.0
Hz), 7.31 (d, 1H, J ) 8.5 Hz), 7.30 (d, 1H, J ) 2.0 Hz), 7.17 (br
s, 1H), 7.12 (d, 1H, J ) 8.5 Hz), 7.11 (br s, 1H), 6.93-6.70 (m,
1H), 6.64 (d, 1H, J ) 2.0 Hz), 6.33 (br s, 1H), 5.82 (br s, 1H),
5.71 (d, 1H, J ) 9 Hz), 5.47 (s, 1H), 5.19 (d, 1H, J ) 5.5 Hz),
5.03 (br s, 1H), 4.69 (d, 1H, J ) 5.5 Hz), 4.01 (s, 3H), 3.91 (s,
3H), 3.73 (s, 3H), 1.40 (s, 9H), 0.78 (s, 9H), -0.01 (s, 3H), -0.11
(s, 3H); IR (neat) νmax 3419, 2930, 2857, 1709, 1674, 1588, 1499,
1434, 1341, 1259, 1168, 1094, 1058, 836, 779 cm-1; FABHRMS
(NBA-CsI) m/ z 1010.1083 (M+ + Cs, C39H49N3O11BrClSi
requires 1010.1063).
1709, 1677, 1582, 1530, 1495, 1343, 1252, 1166, 1101 cm-1
FABHRMS (NBA-CsI) m/ z 1021.1332 (M+ + Cs, C39H49N4O13
BrSi requires 1021.1303).
;
-
The 2D 1H-1H ROESY NMR spectrum (acetone-d6, 400
MHz) of 24 displayed the following diagnostic NOE cross-
peaks: C15-H/C17-H (s), C14-H/C17-H (s), C17-H/C13-H (w),
C15-H/C14-H (s), C13-H/C20-H (m), C11-H/C10-H (m), C10-
H/C8-H (s), C10-H/C21-H (m), C8-H/C6-H (s), C8-H/C21-H
(m), C6-H/C5-OH (w).
Meth yl (P )- a n d (M)-(8R,11R,14S,15R)-11-(3-Br om o-4-
m et h oxyp h en yl)-8-[N-[(ter t-b u t yloxy)ca r bon yl]a m in o]-
5,15-d ih yd r oxy-4-m et h oxy-18-n it r o-10,13-d ia za - 2-oxa -
tr icyclo[14.2.2.13,7]h en eicosa-1(18),3(21),4,6,16,19-h exaen e-
14-ca r boxyla te (25 a n d 26). F r om 21. A solution of 21 (3.8
mg, 4.2 µmol) in THF (0.2 mL) was treated with Bu4NF (1.0
M in THF, 21 µL, 5 equiv), and the mixture was stirred at 25
°C (3 h). The reaction mixture was quenched with the addition
of saturated aqueous NH4Cl and extracted with EtOAc (2 × 5
mL). The combined organic layers were washed with satu-
rated aqueous NH4Cl (2 × 2 mL), dried (Na2SO4), and
concentrated in vacuo. PTLC (SiO2, 75% EtOAc-hexane, then
56% acetone-hexane) afforded 22 (0.5 mg, 3.4 mg theoretical,
15%) as a white film, 25 (0.46 mg, 3.3 mg theoretical, 14%) as
a white film, and 26 (0.79 mg, 3.3 mg theoretical, 24%) as a
white film.
F or 25 (m or e p ola r isom er ): Rf ) 0.50 (56% acetone-
hexane); [R]25D -113 (c 0.09, CHCl3); 1H NMR (acetone-d6, 400
MHz) δ 8.39 (s, 1H), 8.30-8.20 (m, 2H), 7.90-7.75 (m, 2H),
7.68 (d, 1H, J ) 2.2 Hz), 7.44 (dd, 1H, J ) 8.7, 2.2 Hz), 7.28
(d, 1H, J ) 8.4 Hz), 7.03 (d, 1H, J ) 8.7 Hz), 6.67 (s, 1H),
6.20-6.12 (m, 1H), 5.98-5.88 (m, 1H), 5.72 (s, 1H), 5.60-5.50
(m, 1H), 5.54 (d, 1H, J ) 9.0 Hz), 5.31 (d, 1H, J ) 9.1 Hz),
5.12-5.06 (m, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.75 (s, 3H), 1.39
(s, 9H); IR (neat) νmax 3312, 2916, 2846, 1715, 1698, 1650, 1538,
1504, 1455, 1350, 1259, 1161, 1090, 1040 cm-1; FABHRMS
(NBA-CsI) m/ z 907.0464 (M+ + Cs, C33H35N4O13Br requires
907.0438).
Meth yl (8R,11R,14S,15R)-11-(3-Br om o-4-m eth oxyp h en -
yl)-15-[(ter t-b u t yld im e t h ylsilyl)oxy]-8-[N-[(ter t-b u t yl-
oxy)ca r bon yl]a m in o]-5-h yd r oxy-4-m eth oxy-10,13-d ia za -
2-oxa t r icyclo[14.2.2.13,7]h en eicosa -1(18),3(21),4,6,16,19-
1
h exa en e-14-ca r boxyla te (30): H NMR (CD3CN, 400 MHz)
mixture of two rotamers A:B ) 5:1) δ (for rotamer A) 7.36 (d,
1H, J ) 8.4 Hz), 7.20-7.17 (m, 3H), 7.11-7.06 (m, 4H), 6.84
(d, 1H, J ) 3.7 Hz), 6.60 (d, 1H, J ) 2.2 Hz), 5.72 (d, 1H, J )
9.2 Hz), 5.43 (d, 1H, J ) 2.0 Hz), 5.09 (d, 1H, J ) 4.8 Hz),
4.70-4.78 (m, 1H), 4.68 (d, 1H, J ) 9.6 Hz), 3.98 (s, 3H), 3.88
(s, 3H), 3.71 (s, 3H), 1.37 (s, 9H), 0.73 (s, 9H), -0.06 (s, 3H),
-0.20 (s, 3H); IR (neat) νmax 3304, 2929, 2855, 1699, 1651,
1588, 1504, 1259, 1164, 1087, 836 cm-1; FABHRMS (NBA-
NaI) m/ z 844.2476 (M+ + H, C39H50O11N3BrSi requires
844.2470).
Meth yl (M)-(8R,11R,14S,15R)-11-(3-Br om o-4-m eth oxy-
p h en yl)-15-[(ter t-bu tyld im eth ylsilyl)oxy]-8-[N-[(ter t-bu -
tyloxy)ca r bon yl]a m in o]-18-ch lor o-5-h yd r oxy-4-m eth oxy-
10,13-d ia za -2-oxa t r icyclo[14.2.2.13,7]h e n e icosa -1(18),
3(21),4,6,16,19-h exa en e-14-ca r boxyla te (33). A solution of
24 (50 mg, 0.055 mmol) in CH3OH (9 mL) was treated with
cat. Raney Ni at -20 °C and the mixture was stirred under
1 atm of H2 at -20 °C for 1 h. The reaction mixture was
filtered through a pad of Celite (CH3OH, 20 mL), the solvent
was removed under a stream of N2, and the product was dried
under vacuum to afford 31 (100%) as a crude residue which
was used directly.
A solution of crude 31 in anhydrous CH3CN (1.0 mL) was
treated with HBF4 (48% aqueous solution, 9.16 µL, 71.5 µmol,
1.3 equiv) at 0 °C under Ar, and the resulting solution was
stirred at 0 °C for 10 min before being warmed to 25 °C for 30
min. The reaction mixture was recooled to 0 °C and treated
dropwise with tert-butyl nitrite (9.0 µL, 71.5 µmol, 1.3 equiv),
and the resulting reaction mixture was stirred at 0 °C for 1 h.
The reaction mixture was cooled to -20 °C and added to the
aqueous suspension of CuCl (272 mg, 2.75 mmol, 50 equiv)
and CuCl2 (443 mg, 3.3 mmol, 60 equiv) in H2O (1.8 mL) at 0
°C. Additional CH3CN (2.0 mL) was used for transfer washing
the diazonium salt. The heterogeneous mixture was warmed
to 25 °C and stirred for 45 min. The reaction mixture was
quenched with the addition of 5% aqueous NaHCO3 (4 mL)
and extracted with EtOAc (3 × 10 mL). The combined EtOAc
extracts were washed with saturated aqueous NaCl (5 mL),
dried (MgSO4), and concentrated in vacuo. Chromatography
(SiO2, 3% CH3OH-CHCl3) afforded 33 (42 mg, 47 mg theoreti-
cal, 87%) as a white film: [R]25D -22 (c 0.27, CHCl3); 1H NMR
(CD3CN, 500 MHz) mixture of two rotamers (rotamer A:B )
7:1) δ (for rotamer A) 7.54 (d, 1H, J ) 2.0 Hz), 7.32 (s, 1H),
7.26 (dd, 1H, J ) 8.5, 2.0 Hz), 7.20 (d, 1H, J ) 8.5 Hz), 7.10
(d, 1H, J ) 8.5 Hz), 7.06 (dd, 1H, J ) 8.5, 2.0 Hz), 6.83 (d, 1H,
J ) 5.5 Hz), 6.66 (d, 1H, J ) 2.0 Hz), 6.33 (br s, 1H), 5.87 (br
s, 1H), 5.74 (d, 1H, J ) 9 Hz), 5.41 (s, 1H), 5.21 (d, 1H, J )
5.5 Hz), 4.90 (br s, 1H), 4.67 (d, 1H, J ) 5.5 Hz), 4.01 (s, 3H),
3.90 (s, 3H), 3.73 (s, 3H), 1.40 (s, 9H), 0.76 (s, 9H), -0.03 (s,
3H), -0.17 (s, 3H); IR (neat) νmax 2956, 2928, 1709, 1692, 1659,
F or 26 (less p ola r isom er ): Rf ) 0.55 (56% acetone-
hexane); [R]25 -25 (c 0.03, CHCl3); 1H NMR (acetone-d6, 400
D
MHz) δ 8.29 (s, 1H, OH), 8.12 (s, 1H), 8.05-7.90 (m, 1H), 7.93
(d, 1H, J ) 8.5 Hz), 7.78-7.60 (m, 2H), 7.48 (d, 1H, J ) 8.5
Hz), 7.36 (d, 1H, J ) 8.5 Hz), 7.06 (d, 1H, J ) 8.5 Hz), 6.68 (s,
1H), 6.22-6.13 (m, 1H), 5.93-5.80 (m, 2H), 5.63-5.56 (m, 1H),
5.57 (d, 1H, J ) 8.7 Hz), 5.30 (d, 1H, J ) 8.6 Hz), 5.03-4.98
(m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H), 1.36 (s, 9H); IR
(neat) νmax 3300, 2914, 2851, 1694, 1658, 1586, 1532, 1497,
1348, 1286, 1259, 1164, 1084, 1037 cm-1; FABHRMS (NBA-
CsI) m/ z 907.0414 (M+ + Cs, C33H35N4O13Br requires 907.0438).
F r om 23 a n d 24, Cor r ela tion of Isom er s. A solution of
23 (2.0 mg, 2.0 µmol) in THF (0.25 mL) was treated with HOAc
(1/100 v/v in THF, 63 µL, 11 µmol, 6 equiv) followed by Bu4-
NF (1.0 M in THF, 13 µL, 5 equiv). The solution was stirred
at 25 °C (1 h) and then quenched with the addition of saturated
aqueous NH4Cl (1.0 mL) and extracted with EtOAc (2 × 5 mL).
The combined organic layers were washed with saturated
aqueous NaCl (4 mL), dried (MgSO4) and concentrated in
vacuo. PTLC (SiO2, 75% EtOAc-hexane) afforded 25 (1.1 mg,
1.7 mg theoretical, 60%) as a white film.
A solution of 24 (1.5 mg, 1.7 µmol) in THF at 0 °C was
treated dropwise with a 0.17 M solution of HOAc in THF (49
µL, 8.4 µmol, 5 equiv) and a 1.0 M solution of Bu4NF in THF
(22 µL, 22 µmol, 13 equiv) under Ar. The resulting reaction
mixture was gradually warmed to 25 °C, stirred for 2 h, and
concentrated in vacuo. PTLC (SiO2, 75% EtOAc-hexane)

Vancomycin CD and DE Ring System Synthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4733
Ta ble 4. Rep r esen ta tive Resu lts of th e Con ver sion of 31
to 33
Meth yl (M)-(8R,11R,14S,15R)-8-[(ter t-bu tyloxyca r bon -
yl)a m in o]-11-(3-br om o-4-m eth oxyp h en yl)-18-ch lor o-5,15-
dih ydr oxy-4-m eth oxy-10,13-diaza-2-oxatr icyclo[14.2.2.13,7]-
h en eicosa -1(18),3(21),4,6,16,19-h exa en e-14-ca r boxyla te.
A solution of 33 (3.0 mg, 0.0034 mmol) in THF (0.25 mL) was
first treated with HOAc (1/100 v/v in THF, 97 µL, 0.017 mmol,
5 equiv) followed by Bu4NF (1.0 M in THF, 20 µL, 0.02 mmol,
5 equiv). The solution was stirred at 25 °C (1 h) and then
quenched with the addition of saturated aqueous NH4Cl (1.0
mL) and extracted with EtOAc (2 × 5 mL). The combined
organic layers were washed with saturated aqueous NaCl,
dried (MgSO4), and concentrated in vacuo. PTLC (SiO2, 75%
EtOAc-hexane) afforded the free alcohol (1.5 mg, 2.5 mg
theoretical, 59%) as a white film: 1H NMR (CD3CN, 400 MHz)
mixture of two rotamers (rotamer A:B ) 10:1) δ (for rotamer
A) 7.54-7.49 (m, 2H), 7.44 (dd, 1H, J ) 2.0, 0.7 Hz), 7.32-
7.26 (m, 2H), 7.25 (d, 1H, J ) 8.4 Hz), 7.05 (m, 1H), 7.01 (d,
1H, J ) 8.4 Hz), 6.92 (d, 1H, J ) 7.0 Hz), 6.53 (s, 1H), 5.81 (s,
1H), 5.66 (d, 1H, J ) 1.4 Hz), 5.32 (d, 1H, J ) 8.0 Hz), 5.13 (d,
1H, J ) 9.6 Hz), 5.04 (d, 1H, J ) 6.7 Hz), 4.76 (dd, 1H, J )
7.5, 4.4 Hz), 3.98 (s, 3H), 3.86 (s, 3H), 3.71 (s, 3H), 1.39 (s,
t-BuONO/HBF4
CuCl/CuCl2
(equiv)
solvent
(equiv)
result
THF
1.6/1.6
1.3/1.3
1.3/1.3
1.3/1.3
50/20
50/20
50/60
50/60
27% 33, 30% 30
36% 33, 12% 30
61-64% 33
CH3CN
CH3CN
CH3CN
87% 33a
a
Large scale.
1588, 1498, 1340, 1259, 1165, 1099, 1059, 835 cm-1; FAB-
HRMS (NBA-NaI) m/ z 878.2069 (M+ + H, C39H49N3O11BrClSi
requires 878.2087).
Representative results of a study of the conversion of 31 to
33 are summarized in Table 4.
Meth yl (M)-(8R,11R,14S,15R)-8-Am in o-11-(3-br om o-4-
m eth oxyph en yl)-15-[(ter t-bu tyldim eth ylsilyl)oxy]-18-ch lo-
r o -5-h y d r o x y -4-m e t h o x y -10,13-d ia za -2-o x a t r ic y c lo -
[14.2.2.13,7]h en eicosa -1(18),3(21),4,6,16,19-h exa en e-14-
ca r boxyla te. A solution of 33 (9.0 mg, 10 µmol) in CH2Cl2
(0.7 mL) was treated with a solution of B-bromocatecholborane
in CH2Cl2 (0.28 mL) at 0 °C, and the mixture was stirred at 0
°C for 2 h. The reaction mixture was directly passed through
a short column (SiO2, 0.5 × 2 cm, 20% CH3OH-CHCl3). The
combined eluant was washed with saturated aqueous NaHCO3
(3 mL), dried (Na2SO4), and concentrated in vacuo. Flash
chromatography (SiO2, 0.8 × 4 cm, EtOAc then 8% CH3OH-
CHCl3) afforded the title amine (7.3 mg, 93%) as a pale yellow
9H); IR (film) νmax 3311, 2917, 1651, 1495, 1260, 1089 cm-1
;
FABHRMS (NBA-CsI) m/ z 898.0212 (M+ + Cs, C33H35O11N3-
ClBr requires 898.0177).
Th e Th er m a l In ter con ver sion of Atr op isom er s (Ta bles
1 a n d 2). A solution of 23, 29, 33, 55, or 59 (2.0 mg, 2.3 µmol)
in DMSO-d6, DMF-d7, or o-Cl2C6D4 (0.63 mL) was warmed at
the indicated temperature in an NMR tube under Ar for the
indicated time and cooled to 25 °C. The ratio of 23 and 24
was determined by 1H NMR analysis (at 25 °C) by integration.
A solution of 23 (45 mg, 0.049 mmol) in dried and degassed
1,2-dichlorobenzene (30 mL) under Ar was warmed at 140 °C.
film: [R]25 +78 (c 0.32, CHCl3); 1H NMR (CD3CN, 400 MHz)
D
δ 8.00 (s, 1H), 7.53 (d, 1H, J ) 2.0 Hz), 7.21 (d, 1H, J ) 8.4
Hz), 7.20 (d, 1H, J ) 8.4 Hz), 7.05 (s, 2H), 6.80 (dd, 1H, J )
8.4, 1.6 Hz), 6.77 (s, 1H), 6.62 (s, 1H), 6.28 (s, 1H), 5.74 (d,
1H, J ) 9.8 Hz), 5.42 (d, 1H, J ) 2.0 Hz), 4.91 (dd, 1H, J )
9.8, 2.0 Hz), 4.89 (s, 1H), 4.22 (s, 1H), 4.02 (s, 3H), 3.87 (s,
3H), 3.75 (s, 3H), 0.72 (s, 9H), -0.04 (s, 3H), -0.23 (s, 3H);
13C NMR (CD3CN, 100 MHz) δ 171.8, 169.9, 169.7, 156.9,
154.1, 153.9, 151.2, 138.9, 138.3, 138.0, 133.1, 129.5, 128.9,
128.6, 128.3, 127.2, 123.9, 112.9, 112.3, 111.9, 108.5, 73.5, 62.3,
62.0, 60.1, 58.1, 56.9, 53.3, 25.8 (3C), 18.3, -4.5, -5.6; IR (neat)
νmax 3423, 2958, 2928, 2857, 1732, 1694, 1667, 1601, 1498,
1463, 1262, 1123, 1060, 833 cm-1; FABHRMS (NBA-CsI) m/ z
912.0596 (M+ + Cs, C34H41N3O9BrClSi requires 912.0637).
1
After 43 h, H NMR (400 MHz) analysis of a reaction aliquot
indicated the presence of 23 and 24 in a ratio of 1.5:1. The
solution was cooled and directly subjected to chromatography
(SiO2, 75% EtOAc-hexane) to afford 24 (less polar isomer, 14
mg, 31%; typically 25-35%) and recovered 23 (22 mg, 49%;
typically 68-49%).
ter t-Bu tyl (R)-N-[ter t-(Bu tyloxy)ca r bon yl]-N-[(S)-â-cy-
a n oa la n yl](3,5-d ih yd r oxy-4-m eth oxyp h en yl)glycin e (50).
A solution of 4925 (58 mg, 0.22 mmol) in anhydrous DMF (1.5
mL at 0 °C was treated sequentially with HOBt (32 mg, 0.24
mmol, 1.1 equiv), 4732 (69 mg, 0.32 mmol, 1.5 equiv) dissolved
in DMF (0.7 mL), and DCC (58 mg, 0.28 mmol, 1.3 equiv)
under Ar. The reaction mixture was warmed to 25 °C and
stirred under Ar for 14 h. After removal of the solvent in
vacuo, the crude residue was dissolved in CHCl3 (0.5 mL), and
Et2O (1.0 mL) was added. The insoluble salts which formed
were filtered and washed with Et2O (2 × 0.5 mL), and the
filtrate was concentrated in vacuo. Flash chromatography
(SiO2, 3.5 × 10 cm, 2-10% CH3OH-CHCl3 gradient elution)
1
The 2D H-1H ROESY NMR spectrum (CD3CN, 600 MHz)
displayed the following diagnostic NOE crosspeaks: C15-H/
C17-H (s), C17-H/C14-H (s), C15-H/C14-H (s), C11-H/C10-H
(m), C10-H/C21-H (w), C20-H/C19-H (s).
Meth yl (P )-(8R,11R,14S,15R)-8-Am in o-11-(3-br om o-4-
m eth oxyph en yl)-15-[(ter t-bu tyldim eth ylsilyl)oxy]-18-ch lo-
r o -5-h y d r o x y -4-m e t h o x y -10,13-d ia za -2-o x a t r ic y c lo -
[14.2.2.13,7]h en eicosa -1(18),3(21),4,6,16,19-h exa en e-14-
ca r boxyla te. A solution of 29 (6.1 mg, 6.9 µmol) in CH2Cl2
(0.68 mL) was treated with a solution of B-bromocatecholbo-
rane (0.19 mL, 38 µmol, 0.2 M solution in CH2Cl2) in CH2Cl2
(2.7 mL) at 0 °C and the mixture was stirred at 0 °C for 2 h.
The reaction mixture was directly passed through a short
column (SiO2, 0.8 × 6 cm, EtOAc then 20% CH3OH-CHCl3 to
provide the title amine‚HBr (4.6 mg, 75%) as a yellow film:
[R]25D +18 (c 0.2, CHCl3) for free amine; 1H NMR (CD3CN, 500
MHz) δ 7.59 (s, 1H), 7.39 (d, 1H, J ) 7.3 Hz), 7.28 (d, 1H, J )
7.3 Hz), 7.27-7.17 (m, 2H), 7.13-7.11 (m, 1H), 7.10 (d, 1H, J
) 8.4 Hz), 7.00 (s, 1H), 6.43 (s, 1H), 5.71 (d, 1H, J ) 8.4 Hz),
5.43 (s, 1H), 5.36 (br s, 1H), 4.87 (br s, 1H), 4.59 (d, 1H, J )
8.4 Hz), 4.02 (s, 3H), 3.90 (s, 3H), 3.73 (s, 3H), 0.85 (s, 9H),
0.04 (s, 3H), -0.15 (s, 3H); 13C NMR (CD3CN, 100 MHz) δ
170.0 (2C), 168.7, 157.5, 153.4, 151.8, 151.7, 142.9, 140.5,
137.9, 133.5, 131.5, 130.3, 129.6, 128.5, 128.0, 126.5, 125.6,
113.5, 112.8, 107.8, 74.1, 61.3, 60.9, 58.4, 58.1, 57.1, 53.4, 25.9
(3C), 18.4, -4.3, -5.6; IR (neat) νmax 3329, 2929, 2852, 1730,
afforded 50 (85 mg, 100 mg theoretical, 85%) as a foam: [R]25
D
1
-53 (c 0.16, CH3OH); H NMR (acetone-d6, 400 MHz) δ 8.13
(br s, 2H, OH), 7.80 (d, 1H, NH, J ) 7.1 Hz), 6.67 (d, 1H,
NHBOC, J ) 8.5 Hz), 6.45 (s, 2H), 5.12 (d, 1H, J ) 7.1 Hz),
4.58 (ddd, 1H, J ) 5.1, 8.5, 17.0 Hz), 3.77 (s, 3H), 3.00 (dd,
1H, J ) 5.1, 17.0 Hz), 2.86 (dd, 1H, J ) 8.8, 17.0 Hz), 1.43 (s,
9H), 1.37 (s, 9H); 13C NMR (acetone-d6, 100 MHz) δ 170.0,
169.4, 156.3, 151.5 (2C), 136.1, 133.2, 118.1, 107.4 (2C), 82.4,
80.4, 60.6, 57.9, 51.5, 28.5 (3C), 28.1 (3C), 20.9; IR (film) νmax
3328, 2979, 2935, 1666, 1600, 1524, 1455, 1392, 1369, 1254,
1158, 1058 cm-1; FABHRMS (NBA-CsI) m/ z 598.1140 (M+
Cs, C22H31N3O8 requires 598.1165).
+
ter t-Bu t yl (R)-N-[(Ben zyloxy)ca r b on yl]-N-[(S)-â-cy-
a n oa la n yl](3,5-d ih yd r oxy-4-m eth oxyp h en yl)glycin e (51).
A solution of 4925 (0.11 g, 0.41 mmol) in anhydrous DMF (4.1
mL) at 0 °C was treated sequentially with 4835 (0.11 g, 0.45
mmol, 1.1 equiv), HOBt (61 mg, 0.45 mmol, 1.1 equiv), and
EDCI‚HCl (0.17 g, 0.90 mmol, 2.2 equiv). The reaction mixture
was gradually warmed to 25 °C and stirred under Ar for 14 h.
H2O (10 mL) and EtOAc (10 mL) were added, the two layers
were separated, and the aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organic extracts were
washed with H2O (10 mL) and saturated aqueous NaCl (10
mL), dried (Na2SO4), and concentrated in vacuo. Flash chro-
matography (SiO2, 3.0 × 1.5 cm, 2-5% CH3OH-CHCl3 gradi-
1673, 1592, 1496, 1434, 1339, 1258, 1086, 1058, 838 cm-1
;
FABHRMS (NBA-CsI) m/ z 910.0510 (M+ + Cs, C34H41N3O9-
BrClSi requires 910.0538).
1
The 2D H-1H ROESY NMR spectrum (CD3CN, 600 MHz)
displayed the following diagnostic NOE crosspeaks: C15-H/
C20-H (s), C14-H/C20-H (s), C14-H/C15-H (s).

4734 J . Org. Chem., Vol. 62, No. 14, 1997
Boger et al.
ent elution) afforded 51 (0.17 g, 0.20 g theoretical, 84%) as a
afforded 54 (36 mg, 55 mg theoretical, 65%) and a second
separable minor diastereomer. For 54: white film (less polar
isomer, Rf ) 0.40, 5% CH3OH-CHCl3); [R]25D -13 (c 0.3, CH3-
OH); 1H NMR (acetone-d6, 400 MHz) δ 8.26-8.21 (m, 2H, two
NH), 8.13-8.10 (m, 3H), 7.91-7.88 (m, 1H), 7.45 (dd, 1H, J )
8.8, 11.0 Hz), 6.45 (s, 2H), 6.28 (d, 1H, NHBOC, J ) 9.4 Hz),
5.49 (s, 1H, OH), 5.18 (d, 1H, J ) 7.3 Hz), 4.99 (d, 1H, J ) 7.6
Hz), 4.94 (ddd, 1H, J ) 5.0, 6.4, 7.9 Hz), 4.44 (dd, 1H, J ) 7.6,
9.4 Hz), 3.76 (s, 3H), 3.08 (dd, 1H, J ) 5.0, 17.0 Hz), 2.96 (dd,
1H, J ) 7.9, 17.0 Hz), 1.40 (s, 9H), 1.24 (s, 9H); 13C NMR
(acetone-d6, 100 MHz) δ 171.7, 170.0, 168.8, 155.6, 155.4, (d,
J ) 260 Hz), 151.4 (2C), 140.0, 137.8, 135.5 (d, J ) 9.0 Hz),
135.0, 133.0, 125.5, 118.5 (d, J ) 21 Hz), 117.8, 107.5 (2C),
82.4, 79.6, 74.1, 60.5, 60.3, 58.1, 50.4, 28.2 (3C), 28.0 (3C), 20.9;
IR (film) νmax 3300, 2919, 2854, 2241, 1657, 1531, 1452, 1350,
1248, 1155 cm-1; FABHRMS (NBA) m/ z 692.2556 (M+ + H,
C31H38N5O12F requires 692.2579).
foam: [R]25 -46 (c 1.7, CH3OH); 1H NMR (acetone-d6, 400
D
MHz) δ 8.14 (br s, 2H, phenol OH), 7.87 (d, 1H, NH, J ) 7.11
Hz), 7.41-7.28 (m, 5H), 7.03 (d, 1H, NHCBZ, J ) 8.5 Hz), 6.46
(s, 2H), 5.15 (s, 1H), 5.14 (s, 2H), 4.70 (ddd, 1H, J ) 5.1, 8.5,
8.6 Hz), 3.77 (s, 3H), 3.03 (dd, 1H, J ) 5.1, 17.0 Hz), 2.89 (dd,
1H, J ) 8.6, 17.0 Hz), 1.39 (s, 9H); 13C NMR (acetone-d6, 100
MHz) δ 170.0, 169.1, 156.9, 151.5 (2C), 137.7, 136.2, 133.1,
129.2 (2C), 128.7 (2C), 128.6, 117.9, 107.6 (2C), 82.3, 67.2, 60.5,
58.0, 52.0, 27.9 (3C), 21.2; IR (film) νmax 3326, 2978, 2938, 1706,
1670, 1600, 1526, 1456, 1369, 1259, 1155 cm-1; FABHRMS
(NBA-CsI) m/ z 632.1011 (M+ + Cs, C25H29N3O8 requires
632.1009).
ter t-Bu tyl (R)-N-[(S)-â-Cya n oa la n yl](3,5-d ih yd r oxy-4-
m eth oxyp h en yl)glycin e (52). F r om 50. The dipeptide 50
(82 mg, 0.18 mmol) was treated with 1 N HCl-EtOAc (1.8 mL)
and the resulting mixture was stirred under Ar at 25 °C for 5
h. The volatiles were removed in vacuo, and the oily solid was
dissolved in saturated aqueous NaHCO3 (1.0 mL). The aque-
ous phase was extracted with EtOAc (4 × 5 mL), and the
combined organic extracts were washed with saturated aque-
ous NaCl (15 mL), dried (Na2SO4), and concentrated in vacuo.
The crude residue was triturated with CHCl3 (2 mL) to afford
52 (35 mg, 64 mg theoretical, 55%) as a colorless oil: 1H NMR
(CD3OD, 400 MHz) δ 6.33 (s, 2H), 5.00 (s, 2H), 3.70 (s, 3H),
3.63 (dd, 1H, J ) 5.4, 7.1 Hz), 2.75 (dd, 1H, J ) 5.4, 16.8 Hz),
2.64 (dd, 1H, J ) 7.1, 16.8 Hz), 1.35 (s, 9H); FABHRMS (NBA-
NaI) m/ z 310.1027 (M+ - tert-Bu, C13H15N3O6 requires
310.1039).
For the minor diastereomer: white film (more polar isomer,
Rf ) 0.35, 5% CH3OH-CHCl3); [R]25 -58 (c 0.8, CH3OH); 1H
D
NMR (acetone-d6, 400 MHz) δ 8.20-8.16 (m, 4H, phenol OH
and NH), 7.98 (d, 1H, J ) 7.2 Hz), 7.85-7.82 (m, 1H), 7.42
(dd, 1H, J ) 8.6, 11.1 Hz), 6.47 (s, 2H), 6.31 (d, 1H, NHBOC,
J ) 8.7 Hz), 5.54 (s, 1H), 5.15 (d, 1H, J ) 7.3 Hz), 5.09 (d, 1H,
J ) 7.5 Hz), 4.87 (ddd, 1H, J ) 5.4, 6.5, 7.4 Hz), 4.22 (dd, 1H,
J ) 7.5, 8.7 Hz), 3.77 (s, 3H), 3.03 (dd, 1H, J ) 5.4, 17.0 Hz),
2.96 (dd, 1H, J ) 7.4, 17.0 Hz), 1.40 (s, 9H), 1.26 (s, 9H);
13C
NMR (acetone-d6, 125 MHz) δ 171.6, 170.0, 168.6, 155.7, 155.5
(d, J ) 260 Hz), 151.5 (2C), 140.1, 137.7, 135.6 (2C), 133.0,
125.6, 118.7 (d, J ) 21 Hz), 117.8, 107.6 (2C), 82.4, 79.8, 73.7,
60.6, 60.4, 58.0, 50.4, 28.3 (3C), 28.0 (3C), 20.9; IR (film) νmax
3337, 2921, 2930, 2249, 1652, 1646, 1540, 1352, 1165, 1053
cm-1; FABHRMS (NBA) m/ z 824.1573 (M+ + Cs, C31H38N5O12F
requires 824.1555).
F r om 51. A solution of 51 (90 mg, 0.18 mmol) in CH3OH
(2.0 mL) at 25 °C was treated with 10% Pd-C (9.0 mg, 0.10
wt equiv) and was stirred under H2 (1 atm) for 4 h. The
reaction mixture was filtered through a pad of Celite (5% CH3-
OH-CHCl3, 3 × 10 mL) and the solvent was removed in vacuo.
The crude amine 52 (65 mg, 66 mg theoretical, 98%) was
sufficiently pure to use in the subsequent step.
F r om 82.32 A solution of 49 (1.0 mg, 3.4 µmol) in anhydrous
DMF (0.10 mL) at 0 °C was treated sequentially with 82 (1.6
mg, 3.4 µmol, 1.0 equiv), HOBt (0.6 mg, 4.1 µmol, 1.1 equiv),
and EDCI‚HCl (1.6 mg, 8.2 µmol, 2.2 equiv) under Ar. The
reaction mixture was stirred at 0 °C for 15 h before being
(2R,3R)-2-[N-[(ter t-Bu tyloxy)ca r bon yl]a m in o]-3-[(4-flu -
or o-3-n itr o)p h en yl]-3-h yd r oxyp r op ion ic Acid (53).
A
solution of 6525,32 (18 mg, 0.050 mmol) in t-BuOH-H2O (2:1,
1.5 mL) was treated with LiOH‚H2O (4.2 mg, 0.10 mmol, 2.0
equiv) at 25 °C for 0.5 h. The volatiles were removed in vacuo
before H2O (5 mL) and EtOAc (8 mL) were added to the
residue. The pH of the solution was adjusted to 5 by the
dropwise addition of 15% aqueous citric acid at 0 °C. The two
layers were separated, and the aqueous phase was extracted
with EtOAc (3 × 10 mL). The combined organic extracts were
washed with H2O (8 mL) and saturated aqueous NaCl (8 mL),
dried (Na2SO4), and concentrated in vacuo. The crude solid
was triturated with anhydrous Et2O (2 × 1 mL) and dried
thoroughly to afford 53 (16.5 mg, 17.1 mg theoretical, 96%) as
diluted with H2
O (0.5 mL). The solution was extracted with
EtOAc (5 × 0.5 mL) and the combined organic extracts were
washed with saturated aqueous NaHCO3 (2 × 1 mL), H2O (2
× 1 mL), and saturated aqueous NaCl (1 mL), dried (Na2SO4),
and concentrated in vacuo. PTLC (SiO2, eluted twice with 5%
CH3
as a white film.
OH-CHCl3) afforded 54 (1.5 mg, 2.6 mg theoretical, 58%)
ter t-Bu tyl (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 y-
d r oxy-10,13-d ioxo-4-m eth oxy-18-n itr 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 boxyla te (55 a n d 56). A solution of 54 (49 mg, 71 µmol)
in anhydrous degassed DMF (9 mL) was treated with a
predried (180 °C, 0.1 mmHg, 2 h) mixture of K2CO3 (50 mg,
0.37 mmol, 5.0 equiv), CaCO3 (55 mg, 0.55 mmol, 7.5 equiv),
4 Å molecular sieve powder (100 mg, 2 wt equiv) at 25 °C under
Ar. The reaction mixture was warmed at 48 °C for 24 h. The
resulting mixture was cooled to 25 °C, filtered through Celite
(EtOAc, 4 × 5 mL) and the solvent was removed in vacuo.
Flash chromatography (SiO2, 1.5 × 10 cm, 2-5% CH3OH-
CHCl3, gradient elution) afforded 55 and 56 (28 mg, 47 mg
theoretical, 59%) as a separable 1:1.5 mixture of diastereomers.
For the major diastereomer 56: white film (17 mg, 36%); (more
polar isomer, Rf ) 0.31, 5% CH3OH-CHCl3); [R]25D +85 (c 0.33,
CH3OH); 1H NMR (acetone-d6, 500 MHz) δ 8.43 (br s, 1H,
phenol OH), 8.21 (d, 1H, NH, J ) 8.5 Hz), 8.16 (s, 1H), 7.84
(dd, 1H, J ) 1.5, 8.5 Hz), 7.54 (d, 1H, NH, J ) 6.7 Hz), 7.32
(d, 1H, J ) 8.5 Hz), 6.67 (dd, 1H, J ) 1.1, 1.2 Hz), 6.24 (d, 1H,
NHBOC, J ) 6.0 Hz), 5.70 (d, 1H, J ) 1.1 Hz), 5.41 (dt, 1H, J
) 1.0, 8.9 Hz), 5.32-5.26 (m, 1H), 5.06-4.98 (m, 1H), 4.73 (dd,
1H, J ) 6.6, 13 Hz), 4.71-4.67 (m, 1H), 3.92 (s, 3H), 2.95-
a yellow film: [R]25 +6.9 (c 0.85, CH3OH); 1H NMR (acetone-
D
d6, 400 MHz) δ 8.19 (dd, 1H, J ) 1.7, 7.2 Hz), 7.89-7.85 (m,
1H), 7.46 (dd, 1H, J ) 8.8, 11.0 Hz), 6.20 (d, 1H, NH, J ) 8.6
Hz), 5.19 (d, 1H, J ) 6.2 Hz), 4.46 (dd, 1H, J ) 6.2, 8.6 Hz),
1.32 (s, 9H); 13C NMR (acetone-d6, 100 MHz) δ 171.6, 156.1,
155.3 (d, J ) 260 Hz), 140.1, 138.0, 135.0 (d, J ) 9.0 Hz), 125.0,
118.6, (d, J ) 21 Hz), 79.7, 73.4, 60.4, 28.3 (3C); IR (film) νmax
3423, 1670, 1636, 1540, 1349, 1251, 1159, 1052 cm-1; FAB-
HRMS (NBA-NaI) m/ z 367.0934 (M+ + Na, C14H17N2O7F
requires 367.0917).
ter t-Bu tyl (R)-N-[(2R,3R)-2-[N-[(ter t-Bu tyloxy)ca r bon -
yl]a m in o]-N-[(S)-â-cya n oa la n yl]-3-(4-flu or o-3-n itr op h en -
yl)-3-h yd r oxyp r op ion a m id o]-â-cya n o-L-a la n yl-N-(3,5-d i-
h yd r oxy-4-m eth oxyp h en yl)glycin e (54). F r om 52.
A
solution of 52 (29 mg, 0.079 mmol) in anhydrous DMF (1.0
mL) at 0 °C was treated sequentially with HOBt (12 mg, 0.087
mmol, 1.1 equiv), 53 (30 mg, 0.087 mmol, 1.1 equiv), and
EDCI‚HCl (40 mg, 0.21 mmol, 2.6 equiv) under Ar. The
reaction mixture was slowly warmed to 25 °C, stirred for 14
h, and concentrated in vacuo. EtOAc (5 mL) and H2O (5 mL)
were added to the residue, the two layers were separated, and
the aqueous layer was extracted with EtOAc (3 × 5 mL). The
combined organic extracts were washed with saturated aque-
ous NaHCO3 (2 × 5 mL), H2O (2 × 5 mL), and saturated
aqueous NaCl (5 mL), dried (Na2SO4), and concentrated in
vacuo. PTLC (SiO2, eluted twice with 5% CH3OH-CHCl3)
1
2.75 (m, 2H), 1.50 (s, 9H), 1.44 (s, 9H); H NMR (DMSO-d6,
400 MHz) δ 9.74 (br s, 1H, phenol OH), 8.97 (d, 1H, NH, J )
9.0 Hz), 8.06 (d, 1H, NH, J ) 6.8 Hz), 7.99 (d, 1H, J ) 2.0
Hz), 7.69 (dd, 1H, J ) 1.8, 8.5 Hz), 7.25 (d, 1H, J ) 8.5 Hz),
5.53 (s, 1H), 6.41 (d, 1H, NHBOC, J ) 8.2 Hz), 5.74-5.69 (m,
1H), 5.49 (s, 1H), 5.27 (d, 1H, J ) 8.8 Hz), 5.07 (s, 1H), 4.53
(dd, 1H, J ) 6.5, 13 Hz), 4.48-4.40 (m, 1H), 3.79 (s, 3H), 2.77-

Vancomycin CD and DE Ring System Synthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4735
2.62 (m, 2H), 1.47 (s, 9H), 1.41 (s, 9H); 13C NMR (acetone-d6,
125 MHz) δ 170.2, 168.1, 167.6, 155.3, 153.3, 151.5, 147.4,
142.6, 140.0, 136.3, 131.8, 131.3, 126.4, 124.4, 116.2, 107.5,
104.4, 82.9, 72.6, 60.6, 58.6, 55.2, 54.8, 49.7, 27.8 (3C), 27.4
(3C), 20.7; IR (film) νmax 3323, 2974, 2923, 2256, 1692, 1656,
1533, 1513, 1364, 1236, 1154 cm-1; FABHRMS (NBA-CsI) m/ z
804.1465 (M+ + Cs, C31H37N5O12 requires 804.1493).
For the minor diastereomer 70: colorless oil (1.6 mg, 22%);
(more polar product, Rf ) 0.40, 30% EtOAc-hexane).
Con ver sion of 71 to 56 (Cor r ela tion of Ma jor Isom er s).
A solution of 71 (1.8 mg, 2.2 µmol) in THF (0.2 mL) at 0 °C
was treated dropwise with a 1.0 M solution of Bu4NF in THF
(4.5 µL, 4.5 µmol, 2.0 equiv) under Ar. The resulting reaction
mixture was gradually warmed to 25 °C, stirred for 1 h, and
concentrated in vacuo. PTLC (SiO2, 5% CH3OH-CHCl3)
afforded 56 (1.2 mg, 1.5 mg theoretical, 80%) as a white film
identical in all respects with authentic material.
For the minor diastereomer 55: white film (11.0 mg, 23%);
(less polar isomer, Rf ) 0.34, 5% CH3OH-CHCl3); [R]25 +57
D
(c 0.30, CH3OH); 1H NMR (acetone-d6, 500 MHz) δ 8.43 (br s,
1H, phenol, OH), 8.24-8.21 (m, 2H, NH), 7.86 (dd, 1H, J )
1.8, 8.5 Hz), 7.46 (d, 1H, NH, J ) 7.1 Hz), 7.10 (d, 1H, J ) 8.2
Hz), 6.81 (dd, 1H, J ) 0.9, 2.2 Hz), 6.21 (d, 1H, NHBOC, J )
7.6 Hz), 5.60 (d, 1H, J ) 0.9 Hz), 5.40 (d, 1H, J ) 7.6 Hz),
5.24-5.22 (m, 1H), 4.94 (d, 1H, J ) 8.5 Hz), 4.80-4.75 (m,
2H), 3.96 (s, 3H), 2.81-2.70 (m, 2H), 1.45 (s, 9H), 1.43 (s, 9H);
1H NMR (DMSO-d6, 400 MHz) 11:1 mixture of conformational
isomers at 25 °C (signals coalesce at 55 °C), δ 9.74 (s, 1H,
phenol OH), 9.38 and 8.95 (two d, 1H, J ) 8.6 Hz), 8.13 and
8.12 (two d, 1H, J ) 1.4 Hz), 7.91 (d, 1H, J ) 7.2 Hz), 7.75
and 7.73 (two dd, 1H, J ) 1.8, 8.5 Hz), 7.20 and 7.15 (two d,
1H, J ) 8.5 Hz), 6.61 (d, 1H, J ) 1.2 Hz), 6.38 (d, 1H, J ) 8.2
Hz), 5.83-5.78 (m, 1H), 5.50 and 5.31 (two s, 1H), 5.21 and
5.19 (two d, 1H, J ) 8.1 Hz), 5.05 (s, 1H), 4.70-4.64 (m, 1H),
4.55 and 4.51 (two dd, 1H, J ) 7.4, 13 Hz), 3.91 and 3.83 (two
s, 3H), 2.74-2.68 (m, 2H), 1.44 (s, 9H), 1.41 (s, 9H); 13C NMR
(acetone-d6, 100 MHz) δ 170.5, 168.7, 168.4, 156.1, 153.6, 152.2,
148.8, 144.0, 140.8, 134.2 (2C), 132.1, 126.3, 123.0, 116.8,
108.9, 104.8, 83.5, 72.5, 61.3, 58.5, 56.3, 55.4, 49.7, 28.5 (3C),
27.9 (3C), 21.7; IR (film) νmax 3364, 2974, 2933, 2246, 1703,
1646, 1533, 1503, 1364, 1229, 1157 cm-1; FABHRMS (NBA-
CsI) m/ z 804.1471 (M+ + Cs, C31H37N5O12 requires 804.1493).
Con ver sion of 70 to 55 (Cor r ela tion of Min or Isom er s).
A solution of 70 (0.9 mg, 1.2 µmol) in THF (0.1 mL) at 0 °C
was treated dropwise with a 1.0 M solution of Bu4NF in THF
(2.3 µL, 2.3 µmol, 2.0 equiv) under Ar. The resulting reaction
mixture was gradually warmed to 25 °C, stirred for 1 h, and
concentrated in vacuo. PTLC (SiO2, 5% CH3OH-CHCl3)
afforded 55 (0.6 mg, 0.77 mg theoretical, 77%) as a white film
identical in all respects with authentic material.
ter t-Bu tyl (P )- a n d (M)-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 et h oxy-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 boxyla te (57 a n d 61). A solution of either 55 or 56 (6.0
mg, 9.3 µmol) in anhydrous CH3OH (1 mL) was treated with
10% Pd-C (1.2 mg, 0.2 wt equiv) at 25 °C and stirred under
one atmosphere of H2 for 4 h. The reaction mixture was
filtered through a pad of Celite (CH3OH wash), concentrated
in vacuo, and dried thoroughly under vacuum to afford 57 and
61 (5.9 mg, 5.9 mg theoretical, 100%) as colorless oils. Both
57 and 61 were somewhat unstable to storage and handling
but sufficiently pure to use immediately in the subsequent
reactions.
ter t-Bu tyl (P )-(8R,11S,14R,15R)-14-[N-[(ter t-Bu tyloxy)-
ca r bon yl]a m in o]-18-ch lor o-11-(cya n om eth yl)-5,15-d ih y-
d r oxy-10,13-d ioxo-4-m et h oxy-9,12-d ia za -2-oxa t r icyclo-
[14.2.2.13 ,7 ]h e n e i c o s a -3,4,7(21)16,18,19-h e x a e n e -8-
ca r boxyla te (59). Following the procedure detailed below for
The 2D 1H-1H ROESY NMR spectrum (acetone-d6, 500
MHz) of 55 displayed the following diagnostic NOE cross-
peaks: C14-H/C15-H (s), C14-H/N12-H (m), C14-H/C20-H (s),
C11-H/C21-H (w), C11-H/N9-H (s), C15-H/C20-H (w), C8-H/
C21-H (s), C8-H/C6-H (s), C8-H/N9-H (m), C21-H/N9-H (m),
C20-H/C19-H (s), C11-H/CH2CN (w).
63, 57 provided 59: [R]25 +52 (c 0.1, CH3OH); 1H NMR
D
(acetone-d6, 400 MHz) δ 8.33 (s, 1H, phenol OH), 8.25 (d, 1H,
J ) 8.2 Hz), 7.63 (s, 1H), 7.50 (d, 1H, J ) 7.1 Hz), 7.30-7.26
(m, 1H), 7.14 (d, 1H, J ) 8.3 Hz), 6.72 (s, 1H), 6.16 (d, 1H,
NHBOC, J ) 7.0 Hz), 5.52 (s, 1H), 5.34 (d, 1H, J ) 8.1 Hz),
5.16-5.10 (m, 1H), 5.86-5.74 (m, 2H), 4.69-4.61 (m, 1H), 3.96
(s, 3H), 2.77-2.69 (m, 2H), 1.48 (s, 9H), 1.44 (s, 9H); 1H NMR
(DMSO-d6, 400 MHz) δ 9.67 (s, 1H, phenol OH), 8.98 (d, 1H,
J ) 8.4 Hz), 7.77 (d, 1H, J ) 7.7 Hz), 7.54 (s, 1H), 7.39 (d, 1H,
J ) 8.6 Hz), 7.09 (d, 1H, J ) 8.6 Hz), 6.58 (s, 1H), 6.34 (d, 1H,
J ) 8.7 Hz), 5.64-5.61 (m, 1H), 5.31 (s, 1H), 5.20 (d, 1H, J )
8.4 Hz), 4.99 (dd, 1H, J ) 4.4, 8.7 Hz), 4.72-4.64 (m, 2H), 3.86
(s, 3H), 2.74-2.61 (m, 2H), 1.48 (s, 9H), 1.44 (s, 9H); IR (film)
ter t-Bu tyl (P )- a n d (M)-(8R,11S,14R,15R)-15-[(ter t-Bu -
tyldim eth ylsilyl)oxy]-14-[N-[(ter t-bu tyloxy)car bon yl]am i-
n o]-11-(cya n om eth yl)-10,13-d ioxo-5-h yd r oxy-4-m eth oxy-
18-n it r o-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 boxyla te (70 a n d 71). A
solution of 6932 (9.0 mg, 11 µmol) in anhydrous degassed DMF
(2.2 mL) was treated with a predried (180 °C, 0.1 mmHg, 2 h)
mixture of K2CO3 (7.7 mg, 55 µmol, 5.0 equiv), CaCO3 (8.4 mg,
84 µmol, 7.5 equiv), 4 Å molecular sieve powder (18 mg, 2 wt
equiv) at 25 °C under Ar. The reaction mixture was warmed
at 48 °C for 25 h. The resulting mixture was cooled to 25 °C
and filtered through Celite (EtOAc, 4 × 5 mL), and the solvent
was removed in vacuo. PTLC (SiO2, 30% EtOAc-hexane)
afforded 70 and 71 (3.6 mg, 50%; 7.0 mg theoretical based on
1.8 mg recovered 69, 62%) as a separable 1:1.3 mixture of
diastereomers. For major product 71: white film (2.0 mg,
νmax 3292, 2923, 2851, 2236, 1708, 1646, 1503, 1369, 1236, 1154
cm-1; FABHRMS (NBA-CsI) m/ z 793.1278 (M+ + Cs,
C31H37N4O10Cl requires 793.1253).
The 2D 1H-1H ROESY NMR spectrum (acetone-d6, 600
MHz) of 59 displayed the following diagnostic NOE cross-
peaks: C14-H/N12-H (s), C14-H/C20-H (s), C11-H/N12-H (s),
C11-H/C20-H (s), C17-H/C15-OH (s), C11-H/N9-H (s), C11-H/
C21-H (w), C15-H/C20-H (s), C15-H/C17-H (w), C8-H/C6-H
(m), C8-H/N9-H (m), C21-H/N9-H (w), C20-H/C19-H (s), C11-
H/CH2CN (s).
28%); (less polar isomer, Rf ) 0.75, 30% EtOAc-hexane); [R]25
D
+75 (c 0.085, CH3OH); 1H NMR (acetone-d6, 400 MHz) δ 8.45
(br s, 1H, C5-OH), 8.19 (d, 1H, J ) 9.0 Hz, N9-H), 8.13 (s, 1H,
C17-H), 7.78 (dd, 1H, J ) 1.8, 8.5 Hz, C20-H), 7.31 (d, 1H, J
) 8.5 Hz, C19-H), 7.22 (d, 1H, J ) 6.4 Hz, N12-H), 6.67 (dd,
1H, J ) 1.0, 2.2 Hz, C6-H), 5.82 (d, 1H, J ) 1.0 Hz, C21-H),
5.55 (d, 1H, J ) 8.7 Hz, NHBOC), 5.44 (dt, 1H, J ) 1.0, 9.0
Hz, C8-H), 5.35 (d, 1H, J ) 3.0 Hz, C15-H), 4.74 (dd, 1H, J )
3.0, 8.7 Hz, C14-H), 4.61 (ddd, 1H, J ) 4.7, 6.4, 10.0 Hz, C11-
H), 3.92 (s, 3H, OCH3), 2.91-2.74 (m, 2H, partially obscured
by H2O, CH2CN), 1.51 (s, 9H, t-BuO2C), 1.46 (s, 9H, NBOC),
1.00 (s, 9H, t-BuMe2Si), 0.20 (s, 3H, t-BuMe2Si), -0.05 (s, 3H,
t-BuMe2Si); FABHRMS (NBA-CsI) m/ z 918.2319 (M+ + Cs,
C37H51N5O12Si requires 918.2358).
The 2D 1H-1H ROESY NMR spectrum (acetone-d6, 500
MHz) of 71 displayed the following diagnostic NOE cross-
peaks: C19-H/C20-H (m), C11-H/N12-H (w), C11-H/N9-H (s),
C14-H/C15-H (s), C14-H/NHBOC (s), C14-H/N12-H (m), C14-
H/C17-H (m), C15-H/NHBOC (s), C15-H/N12-H (m), C15-H/
C17-H (s), C8-H/C6-H (w), C8-H/N9-H (m), C21-H/C19-H (m),
C21-H/N9-H (m).
Representative results of a study of the conversion of 57 to
59 is summarized in Table 5.
ter t-Bu tyl (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 i-
o x o -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 en eicosa -3,4,7(21),16,18,19-h exa en e-8-ca r boxyla te (60):
1
white film; [R]25 +67 (c 0.14, CH3OH); H NMR (acetone-d6,
D
400 MHz) δ 8.26 (s, 1H, phenol OH), 8.14 (d, 1H, J ) 8.3 Hz),
7.53 (d, 1H, J ) 8.6 Hz), 7.49 (d, 1H, J ) 8.1 Hz), 7.22 (d, 1H,
J ) 7.2 Hz), 7.09 (dd, 1H, J ) 2.4, 8.4 Hz), 7.00 (dd, 1H, J )
2.4, 8.4 Hz), 6.65 (dd, 1H, J ) 1.0, 2.2 Hz), 6.24 (d, 1H,
NHBOC, J ) 6.2 Hz), 5.65 (dd, 1H, J ) 1.0, 2.2 Hz), 5.34 (dt,
1H, J ) 1.0, 8.4 Hz), 5.14-5.07 (m, 1H), 4.78-4.70 (m, 1H),
4.63 (d, 1H, J ) 9.4 Hz), 4.59-4.57 (m, 1H), 3.94 (s, 3H), 2.78-
2.66 (m, 2H), 1.47 (s, 9H), 1.44 (s, 9H); 1H NMR (CD3OD, 400
MHz) δ 7.47 (dd, 1H, J ) 1.8, 8.4 Hz), 7.25 (dd, 1H, J ) 1.8,

4736 J . Org. Chem., Vol. 62, No. 14, 1997
Boger et al.
Ta ble 5. Rep r esen ta tive Resu lts of th e Con ver sion s of
57 a n d 61 to 59 a n d 63
2.2 Hz), 6.16 (d, 1H, NHBOC, J ) 7.0 Hz), 5.60 (s, 1H), 5.38
(d, 1H, J ) 8.6 Hz), 5.14-5.09 (m, 1H), 4.78 (d, 1H, J ) 8.4
Hz), 4.73 (dd, 1H, J ) 7.0, 7.4 Hz), 4.68-4.61 (m, 1H), 3.96 (s,
3H), 2.80-2.71 (m, 2H), 1.48 (s, 9H), 1.44 (s, 9H); 1H NMR
(DMSO-d6, 400 MHz) δ 9.67 (s, 1H, phenol OH), 8.94 (d, 1H,
J ) 8.8 Hz), 7.99 (d, 1H, J ) 7.8 Hz), 7.51 (s, 1H), 7.40 (d, 1H,
J ) 8.4 Hz), 7.19 (d, 1H, J ) 8.4 Hz), 6.56 (s, 1H), 6.33 (d, 1H,
J ) 8.6 Hz), 5.59-5.53 (m, 1H), 5.43 (s, 1H), 5.25 (d, 1H, J )
8.8 Hz), 4.96 (dd, 1H, J ) 4.4, 8.6 Hz), 4.64-4.56 (m, 2H), 3.87
(s, 3H), 2.72-2.59 (m, 2H), 1.49 (s, 9H), 1.44 (s, 9H); IR (film)
νmax 3286, 2971, 2920, 2849, 2240, 1699, 1648, 1506, 1363,
t-BuONO/HBF4 CuCl/CuCl2
compound solvent
(equiv)
(equiv)
result
76% 60
23% 59, 25% 60
30% 59, 0% 60
47% 63, 23% 60
54% 63, 0% 60
57
57
57
61
61
THF
THF
CH3CN
THF
CH3CN
1.6/1.6
1.6/1.6
1.6/1.6
1.3/1.3
1.3/1.3
6/0
50/20
50/60
50/25
50/60
1231, 1155 cm-1; FABHRMS (NBA-CsI) m/ z 793.1284 (M+
+
8.4 Hz), 7.00 (dd, 1H, J ) 2.5, 8.4 Hz), 6.84 (dd, 1H, J ) 1.8,
8.4 Hz), 6.51 (dd, 1H, J ) 1.0, 2.2 Hz), 5.48 (dd, 1H, J ) 1.0,
2.2 Hz), 5.22 (s, 1H), 4.96 (d, 1H, J ) 3.9 Hz), 5.54 (dd, 1H, J
) 6.3, 7.0 Hz), 4.37 (d, 1H, J ) 3.9 Hz), 3.85 (s, 3H), 2.64-
2.61 (m, 2H), 1.41 (s, 9H), 1.38 (s, 9H); IR (film) νmax 3288,
2974, 2925, 2247, 1702, 1648, 1587, 1506, 1368, 1330, 1212,
1160 cm-1; FABHRMS (NBA-CsI) m/ z 759.1664 (M+ + Cs,
C31H38N4O10 requires 759.1642).
Cs, C31H37N4O10Cl requires 793.1253).
The 2D 1H-1H ROESY NMR spectrum (acetone-d6, 600
MHz) of 63 displayed the following diagnostic NOE cross-
peaks: C14-H/N12-H (m), C14-H/C17-H (m), C11-H/N9-H (s),
C8-H/N9-H (m), C21-H/N9-H (m), C20-H/C15-OH (w), C17-H/
C15-H (s), C6-H/C8-H (w), C20-H/C19-H (s), C11-H/CH2CN (s).
Representative results of a study of the conversion of 61 to
63 are summarized in Table 5.
ter t-Bu tyl (M)-(8R,11S,14R,15R)-14-[N-[(ter t-bu tyloxy)-
ca r bon yl]a m in o]-18-ch lor o-11-(cya n om eth yl)-5,15-d ih y-
d r oxy-10,13-d ioxo-4-m et h oxy-9,12-d ia za -2-oxa t r icyclo-
[14.2.2.13,7]h e n e icosa -3,4,7(21),16,18,19-h e xa e n e -8(R )-
ca r boxyla te (63). A solution of 61 (6.2 mg, 9.7 µmol) in
anhydrous CH3CN (0.2 mL) was treated with HBF4 (48%
aqueous solution, 2.3 mg, 1.6 µmol, 12.6 µmol, 1.3 equiv) at 0
°C under Ar, and the resulting solution was stirred at 0 °C
for 10 min before being warmed to 25 °C for 30 min. The
reaction mixture was recooled to 0 °C and treated dropwise
with tert-butyl nitrite (1.3 mg, 1.5 µL, 12.6 µmol, 1.3 equiv )
and the resulting reaction mixture was stirred at 0 °C for 1 h.
The reaction mixture was cooled to -20 °C and immediately
added to an aqueous solution (0.4 mL) containing CuCl (48
mg, 0.48 mmol, 50 equiv) and CuCl2 (78 mg, 0.24 mmol, 60
equiv) at 0 °C, and the heterogeneous mixture was warmed
to 25 °C and stirred for 1.5 h. The reaction mixture was
poured into saturated aqueous NH4Cl (1 mL) and extracted
with EtOAc (4 × 1 mL). The combined organic extracts were
washed with saturated aqueous NH4Cl (2 mL), H2O (2 mL),
and saturated aqueous NaCl (2 mL), dried (Na2SO4), and
concentrated in vacuo. PTLC (SiO2, eluted twice with 5% CH3-
OH-CHCl3) afforded 63 (3.5 mg, 6.4 mg theoretical, 54%) as
a white film: [R]25D +49 (c 0.1, CH3OH); 1H NMR (acetone-d6,
400 MHz) δ 8.35 (s, 1H, phenol, OH), 8.17 (d, 1H, J ) 8.6 Hz),
7.63 (s, 1H), 7.50 (dd, 1H, J ) 0.8, 8.4 Hz), 7.49 (dd, 1H, J )
2.0, 8.4 Hz), 7.22 (d, 1H, J ) 8.4 Hz), 6.69 (dd, 1H, J ) 1.0,
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(CA41101), the award of NIH postdoctoral fellowships
(R.M.B., GM17548; R.T.B., CA71102), and a postdoc-
toral fellowship sponsored by Pfizer, Inc., J apan (S.N.).
We are especially grateful for the improvements in the
synthesis of 20 and 49 first examined by the Sharpless
group (cf. ref 25) and to Dr. O. Loiseleur for its large
scale adaptation detailed in the Supporting Information
and for his improvements in the preparation of 81. We
thank Dr. O. Loiseleur and S. L. Castle for the detailed
study of the atropisomerism of 55 found in Tables 2 and
3.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details and characterization for 16, 34, 36, improvements in
the preparation of 20/49, 37, 38, 44-47, 65-69, and 72-82,
and 1H NMR spectra of all intermediates detailed herein (83
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.
J O970560P