Synthesis of a model bicyclic CDE ring system of ristocetin A and observation of a facile inversion of configuration in a 16-membered DE ring model

Article abstract of DOI:10.1021/jo980060b

Areneruthenium chemistry was used to effect intramolecular S(N)Ar reactions between phenoxide nucleophiles and chlorophenylalanine residues that are connected by a peptide chain, resulting in the construction of a bicyclic peptido aryl ether system that corresponds to the BCDF system of the glycopeptide antibiotics ristocetin A and teicoplanin. A facile and selective base-catalyzed complete inversion of configuration at the D ring arylglycine residue was observed when this unit is the carboxylate terminus on a 16- membered ring system corresponding to the DEF rings of the target molecules. The inversion appears to result from an overwhelming thermodynamic preference for the inverted system and is supported by molecular mechanics and semiempirical calculations on the minimized conformations of the epimeric molecules.

Full text of DOI:10.1021/jo980060b

J . Org. Chem. 1998, 63, 3087-3098
3087
Syn th esis of a Mod el Bicyclic CDE Rin g System of Ristocetin A
a n d Obser va tion of a F a cile In ver sion of Con figu r a tion in a
16-Mem ber ed DE Rin g Mod el
Anthony J . Pearson* and Mariappan V. Chelliah
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106
Received J anuary 13, 1998
Areneruthenium chemistry was used to effect intramolecular SNAr reactions between phenoxide
nucleophiles and chlorophenylalanine residues that are connected by a peptide chain, resulting in
the construction of a bicyclic peptido aryl ether system that corresponds to the BCDF system of
the glycopeptide antibiotics ristocetin A and teicoplanin. A facile and selective base-catalyzed
complete inversion of configuration at the D ring arylglycine residue was observed when this unit
is the carboxylate terminus on a 16-membered ring system corresponding to the DEF rings of the
target molecules. The inversion appears to result from an overwhelming thermodynamic preference
for the inverted system and is supported by molecular mechanics and semiempirical calculations
on the minimized conformations of the epimeric molecules.
In tr od u ction
macrocycles. Thus, vancomycin contains a 12-membered
biphenyl macrocycle and two 16-membered macrocyclic
ethers. During recent years, there has been observed an
increasing occurrence of vancomycin-resistant strains of
infectious bacteria.3 This, coupled with the challenge
presented by the structural complexity of these mol-
ecules, has promoted considerable interest in their
chemical synthesis.4
One of the challenges associated with the synthesis of
vancomycin and its relatives is the construction of the
diaryl ether linkages, since these must be formed in the
presence of quite sensitive amino acid and/or peptide
functionality. Of particular significance in this regard
are the arylglycine residues that are very labile under
basic conditions,5 which precludes the use of some of the
more classical approaches, such as Ullmann coupling.6
We have reported technology for ruthenium-promoted SN-
Ar reactions, which proceed under very mild conditions,
and that can be used either inter-7 or intramolecularly8
for the construction of diaryl ethers of the type found in
the vancomycin group. We describe in this paper ap-
Vancomycin (1) was isolated from Streptomyces orien-
talis in 1956 and is in clinical use as an effective
antibiotic, especially for the treatment of methicillin-
resistant infections.1,2 Following its isolation, more than
200 compounds having similar structural features, col-
lectively called glycopeptide antibiotics, have been iso-
lated. Other members of this family include orienticin-
A-D, ristocetin-A (2), aricidin, teicoplanin, and avoparcin.
In general, they have a core heptapeptide backbone
structure, containing amino acids made up of derivatives
of phenylglycine, tyrosine, leucine, methionine, and as-
paragine. The aromatic rings are cross-linked by either
biphenyl or by biaryl ether linkages, forming peptido
(1) (a) Isolation: McCormick, M. H.; Stark, W. M.; Pittenger, G. E.;
Pittenger, R. C.; McGuire, G. M. Antibiot. Annu. 1955-1956, 606. (b)
Structure elucidation: Williams, D. H.; Kalman, J . R. J . Am. Chem.
Soc. 1977, 99, 2768. Williamson, M. P.; Williams, D. H. J . Am. Chem.
Soc. 1981, 103, 6580. Harris, C. M.; Kopecka, H.; Harris, T. M. J . Am.
Chem. Soc. 1983, 105, 6915.
(2) (a) For reviews on the biological activity of vancomycin and
related compounds, see: Barna, J . C. J .: Williams, D. H. Annu. Rev.
Microbiol. 1984, 38, 339. Williams, D. H. Acc. Chem. Res. 1984, 17,
364. (b) For recent articles on mechanism of action, see: Waltho, J .
P.: Williams, D. H. J . Am. Chem. Soc. 1989, 111, 2475. Fesik, S. W.;
O’Donnell, T. J .; Gampe, R. T., J r.; Olejniczak, E. T. J . Am. Chem.
Soc. 1986, 108, 3165. Mueller, L.; Heald, S. L.; Hempel, J . C.; J effs, P.
W. J . Am. Chem. Soc. 1989, 111, 496. Prowse, W. G.; Kline, A. D.;
Skelton, M. A.; Loncharich, R. J . Biochem. 1995, 34, 9632.
(3) (a) Wright, G. D.; Walsh, C. T. Acc. Chem. Res. 1992, 25, 468.
Walsh, C. T. Science 1993, 261, 308. Walsh, C. T.; Fisher, S. L.; Park,
I.-S.; Prahalad, M.; Wu, Z. Chem. Biol. 1996, 3, 21. (b) The urgency of
the problem of vancomycin resistance is evidenced by numerous
references in medical bulletins and the popular press: Rowe, P. M.
Lancet 1996, 347, 252. Frieden, T. R.; Musiff, S. S.; Low, D. E.; Willey,
B. M.; Williams, G.; Faur, Y.; Eisner, W.; Warren, S.; Kreiswirth, B.
Lancet 1993, 342, 76. Lewis, R. FDA Consumer 1995, Sep 11. Williams,
D. H.; Westwell, M. S. Chemtech 1996, Mar 17. Begley, S.; Brant, M.
The End of Antibiotics? Science: A Medical Disaster in the Making.
Newsweek 1994 Mar. Roan, S. Bacterium’s Immunity to Powerful Drug
Bodes Ill. Los Angeles Times 1996, Feb 20. Boodman, S. G. Antibiotic-
Resistant Illnesses on the Rise. The Washington Post; Health News
Section 1996, J an 23. Altman, L. K After Causing Worry in the East,
A Germ Has Surfaced in the West. The New York Times 1995, Sep 19;
Dec 26. Bishop J . E. Bacteria Causing Ear Infection Grow Resistant
to Drugs. Wall St. J . 1994, J un 15. Day, K. The Germ of a Biotech
Boom? Firms Seek Products to Fight Antibiotic-Resistant Bacteria.
Washington Post 1995, Aug 19. Stinson, S. C. Chem. Eng. News 1996,
74(39), 75-94, 98-100.
(4) For recent reports, see: (a) Konishi, H.; Okuno, T.; Nishiyama,
S.; Yamamura, S.; Koyasu, K.; Terada, Y. Tetrahedron Lett. 1996, 37,
8791. (b) Rao, A. V. R.; Reddy, K. L.; Rao, A. S.; Vittal, T. V. S.; Reddy,
M. M.; Pathi, P. L. Tetrahedron Lett. 1996, 37, 3023. (c) Bois-Choussy,
M.; Vergne, C.; Neuville, L.; Beugelmans, R.; Zhu, J . Tetrahedron Lett.
1997, 38, 5795. Zhu, J . Synlett 1997, 133. (d) Boger, D. L.; Borzilleri,
R. M.; Nukui, S.; Beresis, R. T. J . Org. Chem. 1997, 62, 4721. (e)
Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T.-Y.; Li, H.; Braes,
S.; Ramanjulu, J . M. J . Am. Chem. Soc. 1997, 119, 3421. (f) Evans, D.
A.; Barrow, J . C.; Watson, P. S.; Ratz, A. M.; Dinsmore, C. J .; Evrard,
D. A.; DeVries, K. M.; Ellman, J . A.; Rychnovsky, S. D.; Lacour, J . J .
Am. Chem. Soc. 1997, 119, 3419.
(5) Smith, G. G.; Sivaka, T. J . Org. Chem. 1983, 48, 627.
(6) The standard Ullmann coupling reaction for the preparation of
diaryl ethers cannot be applied when both aromatic substrates have
protected amino acid or peptide side chains; see: Evans, D. A.; Ellman,
J . A. J . Am. Chem. Soc. 1989, 111, 1063. Boger, D. L.; Yohannes, D.
Tetrahedron Lett. 1989, 30, 2053. Crimmin, M. J .; Brown, A. G.
Tetrahedron Lett. 1990, 31, 2017.
(7) Pearson, A. J .; Park, J . G. J . Org. Chem. 1992, 57, 1744. Pearson,
A. J .; Lee, K. J . Org. Chem. 1995, 60, 7153. Pearson, A. J .; Zhang, P.;
Lee, K. J . Org. Chem. 1996, 61, 6581.
(8) Pearson, A. J .; Bignan, G.; Zhang, P.; Chelliah, M. J . Org. Chem.
1996, 61, 3940. Pearson, A. J .; Zhang, P.; Bignan, G. J . Org. Chem.
1997, 62, 4536. J anetka, J . W.; Rich, D. H. J . Am. Chem. Soc. 1995,
117, 10585.
S0022-3263(98)00060-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/07/1998

3088 J . Org. Chem., Vol. 63, No. 9, 1998
Pearson and Chelliah
III. The tetrapeptide intermediate III can be made by
condensing a phenylglycine to the cyclic tripeptide IV,
which can be made by an intramolecular SNAr reaction
of the corresponding linear tripeptide ruthenium complex
V.
Resu lts a n d Discu ssion
To implement the above strategy, we needed to prepare
a tripeptide ruthenium complex corresponding to the
intermediate V. Our synthesis started with the azido
acid 4 (Scheme 2), previously reported by us.9 The acid
was esterified using MeOH and p-toluenesulfonic acid
monohydrate to provide 5 in excellent yield. The azide
was reduced and coupled with (S)-ZPhg to provide the
dipeptide 6, also in excellent yield. The amine was then
deprotected and condensed with the ruthenium complex
7, reported by us previously,7,8 to provide the tripeptide
ruthenium complex 8 that was then used for cycloetheri-
fication studies.
The cyclization reaction conditions initially tested
(procedure A) involved addition, over 30 min, of a DMF
solution of the ruthenium complex to a cooled THF
solution (between -40 and -60 °C) of sodium 2,6-di-tert-
butylphenoxide (2 equiv) over a period of 30 min to 1 h,
followed by slow warming of the reaction mixture to 0
°C over a period of about 2 h, after which it was stirred
for about 1 h at 0 °C and 2-3 h at room temperature.
Thus, during the addition, an excess of base over complex
is present. The crude product was subjected to photoly-
sis, to disengage the RuCp moiety, and the product
fractions were separated by preparative TLC. Thus, the
phenolate of 8 was generated at low temperature and
allowed to warm slowly so as to undergo the desired
macrocyclization. The solution concentration was usually
around 5-10 mM.
The tripeptide ruthenium complex 8, when subjected
to these cyclization conditions, underwent smooth con-
version to two separable products in a ∼4:1 ratio with a
combined yield of 46% (Scheme 3). Both compounds
appeared to be cyclization products on the basis of their
1H NMR spectra, which showed clearly the expected
upfield shift of one of the ortho protons of ring D.10 This
was also confirmed by FABHRMS spectroscopy of each
fraction. The chromatographically more mobile com-
pound (TLC) was the major fraction and the less mobile
compound (TLC) was the minor fraction.
Since the minor component also appeared to be a
cyclization product, it suggested that partial epimeriza-
tion was taking place at one of the stereogenic centers,
most likely the amino acid residue D. Among the three
amino acid residues, both E and F contain amide carbo-
nyl, and only residue D contains the ester carbonyl, which
should make its R-CH comparatively more acidic. When
the cyclization was repeated, it was found that, depend-
ing on the reaction conditions, the ratio of the more
mobile to less mobile product varied to a great extent
(Table 1). By varying the procedure, one can produce
either the more mobile product as the major one (entry
1 and 3) or exclusively the less mobile product (entry 4).
plications of this chemistry to the synthesis of a model
bicyclic system, shown in structure 3, representing the
B/C/D/E/F rings of ristocetin and teicoplanin. This
system was chosen primarily because the presence of
three quite sensitive arylglycine residues would serve as
an excellent test of any methodology chosen for its
construction. We also disclose a thermodynamically
driven selective inversion of the D-ring arylglycine
residue when this is used as a carboxyl terminus. This
has important implications concerning the choice of
strategy for the general construction of these molecules,
and it appears to have gone unnoticed in previous studies
on these substances.
Our first retrosynthetic analysis of the target molecule
3 is presented in Scheme 1. This approach was chosen
on the basis of the known mechanism of biological activity
of vancomycin,2b which involves primarily the “right
hand” half of the molecule, and so it appeared most
expeditious to adopt a synthetic avenue that would
furnish carboxylate binding pocket analogues relatively
early in the sequence. By disconnecting the ether linkage
between the amino acid residues C and D, we arrive at
intermediate I. The target can be made by subjecting
this complex to an intramolecular SNAr reaction. Further
disconnection at the amide bond between residues C and
B results in the ruthenium complex II and the macrocycle
(9) (a) Pearson, A. J .; Chelliah, M. V.; Bignan, G. C. Synthesis 1997,
536. (b) See also: Beugelmans, R.; Bois-Choussy, M.; Vergne, C.;
Bouillon, J .; Zhu, J . J . Chem Soc., Chem. Commun. 1996, 1029. Boger,
D. L.; Borzilleri, R. M.; Nukui, S. J . Org. Chem. 1996, 61, 3561.
(10) Mann, M. J .; Pant, N.; Hamilton, A. D. J . Chem. Soc., Chem.
Commun. 1986, 158 and references therein.

Model Bicyclic CDE Ring System of Ristocetin A
J . Org. Chem., Vol. 63, No. 9, 1998 3089
Sch em e 1
Since the latter result is obtained when excess base is
not present during the reaction (as base is added slowly
to the complex), we suspected that the less polar product
is 9, wherein the stereochemistry is retained. Variation
of solvent has some effect on the outcome of the reaction
(entry 2 vs entry 1), and the use of cesium carbonate at
room temperature causes significant epimerization (entry
3; DMF was used as solvent to alleviate solubility
problems with cesium carbonate). The use of DMF might
be expected to promote epimerization, as a result of its
cation-coordinating ability leading to the presence of
“naked” phenolate, which would be a stronger base.
To confirm the site of epimerization, and which product
was the desired one, the carboxy-terminal epimer of 8
was prepared. During the asymmetric synthesis of 4, the
azido carboximide 11 was obtained as a minor product
(∼10%).9 Hydrolysis of this carboximide with LiOOH
provided the azido acid 12 with the required (S) absolute
configuration (Scheme 4), and this was esterified using
MeOH-PTSA to provide 13. The azide was reduced and
then coupled with (S)-ZPhg to provide the dipeptide 14,
which was then converted into the tripeptide ruthenium
complex 15. This complex was subjected to the standard
cyclization conditions (procedure A) using sodium 2,6-
di-tert-butylphenoxide as the base. Demetalation af-
forded a single macrocyclic product (Scheme 4), which
was in fact identical to the more mobile fraction 10
obtained from the cyclization of 8 (Scheme 3).
reveals that the more mobile, epimeric macrocycle 10 is
obtained as the major product when an excess of base is
present during cyclization (Table 1, entries 1-3, where
2 equiv or greater amount of base was installed prior to
addition of 8). We believe that cyclization of the tripep-
tide 8 results in the RuCp complex of 9, which undergoes
a facile base-promoted epimerization to provide the
thermodynamically more stable complex corresponding
to 10. Under the reaction conditions provided in entries
1 and 2 of Table 1, it is likely that the presence of excesses
of sodium 2,6-di-tert-butylphenoxide can drive this equi-
librium. To prevent this, we adopted procedure C (Table
1, entry 4) where the base is slowly added to a solution
of the ruthenium complex using a syringe pump. In this
way no excess of NaDTBP is present at any time, and
only the nonepimerized macrocycle 9 was obtained.
To test this proposition and further our understanding
of the configurational stability of these molecules, the
NMR psectrum of the macrocycle 9 (about 1.5 mg in
about 450 µL of 1:1 CD3CN-CDCl3) was recorded, and
the solution was then treated with 50 µL of 1:1 CD3CN-
CDCl3 containing DBU (5.0 equiv). The NMR spectrum
was immediately recorded, showing complete conversion
of 9 to 10 with no trace of residual starting material
remaining. Since the product ratio is >99:1, this corre-
sponds to at least 3 kcal/mol difference in free energy
between these two compounds. This is an extremely facile
and selective thermodynamically driven inversion of
configuration that probably also occurs with the inter-
mediate ruthenium complexes.
The absolute configurations of the two products 9 and
10 were thus confirmed by correlation with the product
from 15. Inspection of the product ratios in Table 1

3090 J . Org. Chem., Vol. 63, No. 9, 1998
Pearson and Chelliah
Sch em e 2
mixtures were not produced). There are a number of
reports in the literature11 of similar model systems that
have been constructed using more forcing conditions for
the SNAr process than those required for the Ru-promoted
reactions described herein. Our results indicate that any
inversion of configuration at the D-residue would probably
not be detected under such conditions and are a fore-
warning of a general problem that is likely to occur in
any approach to the target molecules that involve a
“right-to-left” strategy.
Molecu la r Mod elin g. Molecular Dynamics (Insight/
Discover molecular-modeling software package) simula-
tions were employed to obtain global minima for the
epimeric compounds 9 and 10. The molecule was con-
structed using the Insight program and was then sub-
jected to high-temperature MD simulation using the
Discover program and CFF91 force field. The molecule
was heated to 1000 K and equilibrated at this temper-
ature for 20 000 fs with an integral time step of 1 fs. The
temperature was maintained at 1000 K for 105 fs, and
the conformers were sampled at every 1000 fs. Each of
the resultant 100 conformers were then subjected to
minimization using Discover. The minimized conformers
were arranged in increasing order of total energy, and
the lowest energy conformer was selected. This structure
was further minimized using Discover, and the final
energy corresponding to this global minimum was taken.
The energy of the conformer corresponding to the global
minimum of 9 was found to be -4.79 kcal/mol using
CFF91. The energy corresponding to the epimer 10 was
found to be somewhat lower at -5.52 kcal/mol.
We also performed semiempirical calculations on these
molecules using the Spartan software package. The
coordinates corresponding to the global minima of 9 and
10 from the Insight/Discover molecular mechanics cal-
culations were imported into the Spartan program.
These structures were then subjected to semiempirical
minimization using the PM3, MNDO, and AM1 modules
of Spartan, and the results are summarized in Table 2.
Sch em e 3
The heats of formation of 9 and 10 were found to be
-245.82 kcal/mol and -248.76 kcal/mol (MNDO), respec-
tively, from these calculations. Both the strain energy
calculation using molecular mechanics and heat of for-
mation using semiempirical methods consistently show
that the epimeric macrocycle 10 is more stable than 9.
Even though the required macrocycle 9 could be
obtained as the sole product by choosing the appropriate
cyclization conditions (Table 1, entry 4) deprotection of
the methyl ester could not be realized with LiOH without
extensive epimerization of the C-terminal chiral center.
Acid-mediated removal of the methyl ester was not
expected to be successful due to the presence of the acid-
labile Boc group. Thus, we could not proceed satisfac-
torily to the intermediate III presented in Scheme 1.
Before abandoning the approach presented in Scheme 1,
we decided to prepare the macrocyclic tripeptide inter-
mediate VI with a (trimethylsilyl)ethyl carboxyl blocking
group, which can be removed under milder conditions.
The synthesis started with the azido acid 4, which was
esterified using DCC/HOAt to provide the ester 16 in
excellent yield (Scheme 5). The ester was converted to
As far as we are aware, this is the first reported
observation of such behavior during the construction of
subunits of the vancomycin family. Earlier, we have
reported the synthesis of 16-membered ring systems
related to 9 and 10, using both cycloamidation7 and
cycloetherification8 strategies. Comparison of the present
NMR spectra with our earlier data suggests that in both
cases we had obtained the products of inversion at the
carboxylate terminus, which went undetected (since
(11) Generally, the conditions used for nitro-group-promoted SNAr
reactions that lead to formation of diaryl ethers of this type require
the use of base at elevated temperature (ca. 40 °C) for extended periods
of time. For examples, see ref 4b-d.

Model Bicyclic CDE Ring System of Ristocetin A
J . Org. Chem., Vol. 63, No. 9, 1998 3091
Ta ble 1. Cycliza tion of 8 u n d er Differ en t Con d ition s
base
solvent
reaction condnsa
yieldb (%)
46
ratioc
4:1
1
NaDTBP
1:1 DMF-THF
procedure A: addition of complex 8 to 2 equiv of base over 30
min, then 2 h at -60 °C, warming to 0 °C, then 1 h
at 0 °C and 2 h at 20 °C
2
3
4
NaDTBP
Cs2CO3
2:5 DMF-THF
DMF
modified procedure A: 2 h at -60 °C to 0 °C then 1 h at
40
42
29
1:1
4:1
0:1
0 °C and 3 h at 20 °C
procedure B: addition of complex 8 to 5 equiv of Cs2CO3, then
6 h at rt
procedure C: addition of base by syringe pump to complex 8
over 2 h at 0 °C, then stirred for 30 min at 0 °C and 3 h at rt
NaDTBP
2:9 DMF-THF
a
b
See the Experimental Section for the detailed procedures. Yield represents the isolated yield after demtalation. c Ratio represents
the ratio of the more mobile to less mobile product.
Sch em e 4
Sch em e 5
Sch em e 6
Ta ble 2. Resu lts of Ca lcu la tion s on Str u ctu r es 9 a n d 10
calculated (kcal/mol)
property
method
9
10
rocyclic products arising from carboxyl-terminal epimer-
ization (Scheme 6). 1H NMR spectra of these products
showed patterns similar to 9 and 10. In contrast to the
cyclization of 8, we could not suppress the formation of
the epimeric macrocycle 20 during the cyclization of 18
by varying the reaction conditions.
1
2
3
4
strain energy
CFF91a
PM3b
-4.79
-279.27
-245.82
-265.05
-5.52
-280.27
-248.76
-265.47
heat of formation
heat of formation
heat of formation
MNDOb
AM1b
a
Molecular mechanics calculation using Insight/Discover pro-
gram.b Semiempirical calculations using Spartan program.
We also carried out TMSE deprotection and peptide
coupling on 19. When the ester 19 was treated with
tetrabutylammonium fluoride, the TMSE group was
cleaved to provide the acid. Analysis of the crude product
the dipeptide 17, which was then transformed into the
tripeptide ruthenium complex 18.
Cyclization of 18 under standard conditions with
sodium 2,6-di-tert-butylphenoxide also provided two mac-
1
by H NMR showed very little epimerization. Owing to

3092 J . Org. Chem., Vol. 63, No. 9, 1998
Pearson and Chelliah
Sch em e 7
difficulty in purifying this product, the crude material
was subjected immediately to peptide-coupling conditions
(EDCI/HOAt) with phenylglycine methyl ester. However,
analysis of the product showed extensive epimerization,
suggesting once again the extreme lability of the D-
residue stereogenic center. Thus, even if we could obtain
the acid 19 without epimerization we could not proceed
with the peptide coupling.
Th e “Left-to-Righ t” Str a tegy. Since the strategy
outlined in the preceding paragraphs met with numerous
tactical problems, we decided to construct the left side
macrocycle (C-O-D ring) first and then add the right
side macrocycle (D-O-E ring) as outlined in Scheme 7.
It may be noted that this is in fact the coupling direction
used by Evans in his synthesis of orienticin C.4 Here,
the synthesis requires the linear tripeptide X.
Our synthesis started with the (benzyloxy)carbonyl-
protected (R)-phenylglycine 21 (Scheme 8). (R)-ZPhg was
protected as its TMSE ester 22 using DCC/DMAP. The
Cbz group was then cleaved by hydrogenolysis to provide
the amine hydrochloride 23, which was coupled with the
azido acid 4 to furnish the dipeptide 24 in excellent yield.
The azide reduction was then carried out using SnCl2 to
provide the amine 25 in near-quantitative yield. This is
a clean reaction and provided the pure amine, which was
homogeneous by NMR without chromatographic purifica-
tion. Use of triphenylphosphine as the reducing agent
also worked well for this reaction, but product purifica-
tion was significantly more difficult. The amine was then
coupled with Boc-protected (S)-phenylglycine, prepared
by reaction of (S)-Phg with (Boc)2O in the presence of
NaHCO3 in THF-H2O mixture. The tripeptide 26 was
subjected to TMSE deprotection using TBAF to provide
the acid 27 in high yield, and debenzylation using H2/
Pd-C afforded 28.
It was found that the 1H NMR spectrum of the
tripeptide 26 in CDCl3 was markedly concentration-
dependent, showing two distinct NMR patterns at lower
and higher concentrations. For example, at very low
concentration (∼2 mg/mL), the benzylic methylene pro-
tons appeared as a singlet (4H), while at higher concen-
trations (∼40 mg/mL), they appeared as two (geminally
coupled) doublets. Similar changes were observed for
other resonances. This can be explained if the tripeptide
is undergoing noncovalent dimer formation (via hydrogen
bonding) in a relatively nonpolar solvent such as CDCl3.
At very low concentration only the monomer exists,
giving the spectrum where the benzylic protons appear
as a singlet. As the solution concentration is increased,
an equilibrium between monomer and dimer is set up.
The resultant NMR spectrum corresponds to a time-
averaged structure. As the concentration is further
increased it is possible that most of the molecules exist
as dimers, resulting in the limiting pattern observed at
higher concentrations, wherein restricted rotation about
the benzyl ether bonds causes inequivalence of the
methylene protons. It may be noted that many members
of the vancomycin family are known to exist as dimers

Model Bicyclic CDE Ring System of Ristocetin A
J . Org. Chem., Vol. 63, No. 9, 1998 3093
Sch em e 8
Sch em e 9
in solution,12 but the minimum structure that is required
for this phenomenon to occur has not been evaluated.
The tripeptide 28 was then converted to the tetrapep-
tide ruthenium complex 30 (Scheme 9). The ruthenium
complex 29 was prepared by complexation of the methyl
ester of (S)-N-Boc-4-chlorophenylalanine13 under the
conditions reported for the (R) enantiomer.7 The tert-
butoxycarbonyl group of the complex 29 was removed in
TFA-CH2Cl2 mixture, and the amine was then coupled
with the tripeptide 28 using HATU.14 In this case,
partial epimerization at the B-ring residue was observed,
since the peptide coupling is carried out at the C-terminal
phenylglycine, which contains an N-acyl unit. The
product mixture was subjected to cycloetherification,
affording two separable macrocycles in the ratio of ∼3:1.
When sodium 2,6-di-tert-butylphenoxide (DMF-THF)
was used as the base for cyclization, the yield was low
and purification was difficult, but when Cs2CO3 (DMF)
was used the macrocycles were obtained cleanly in 74%
overall yield for cyclization and demetalation.
photolytic decomplexation. The successful cyclization
was indicated by an upfield NMR shift of the second ortho
proton of the residue D, and the identity of this compound
was further confirmed by FABHRMS.
Su m m a r y
Ruthenium-promoted intramolecular SNAr reactions
can be successfully employed with structures of high
complexity to afford systems related to the vancomycin
group of antibiotics. The reaction conditions for the
cycloetherification process are sufficiently mild to avoid
epimerization of sensitive arylglycine residues except
when these are at the carboxyl terminus. An extremely
facile thermodynamically driven inversion at the D-ring
arylglycine residue was observed in the 16-membered
D-O-E macrocycle, which mandates a “left-to-right”
strategy for the synthesis of the target structures. The
chemistry developed here can now be extended to the
total synthesis of members of the vancomycin family of
antibiotics.
The major macrocycle 31 was then deprotected using
the TFA-CH2Cl2 mixture in the presence of dimethyl
sulfide, and the resultant amine was coupled with 7 to
provide the pentapeptide ruthenium complex 33 in high
yield (Scheme 10). This compound was treated with Cs2-
CO3 in DMF, resulting in a smooth intramolecular SNAr
reaction to afford the target molecule 3 in 70% yield after
Exp er im en ta l Section
General procedures are as described elsewhere.7,8
Meth yl (2R)-2-Azid o-2-[3,5-bis(ben zyloxy)-4-m eth oxy-
p h en yl]eth a n oa te (5). A solution of the azido acid 4 (520
mg, 1.24 mmol) and p-toluenesulfonic acid monohydrate (236
mg, 1.24 mmol) in 10 mL of MeOH was refluxed for 2.5 h. The
solvent was evaporated, and the residue was dissolved in 75
mL of CH2Cl2. The organic phase was washed with 2 × 30
mL of aqueous NaHCO3 and dried over Na2SO4. The solution
was filtered, the solvent evaporated, and the residue chro-
(12) Williams, D. H.; Searle, M. S.; Westwell, M. S.; Mackay, J . P.;
Groves, P.; Beauregard, D. A. Chemtracts: Org Chem. 1994, 7, 133.
(13) Lee, K. Ph.D. Dissertation, Case Western Reserve University,
1995.
(14) We used various coupling methods and found less epimerization
with those conditions described in this article, as reported by: Carpino,
L. A.; Ionesco, D.; El-Faham, A. J . Org. Chem. 1996, 61, 2460. Carpino,
L. A. J . Am. Chem. Soc. 1993, 115, 4397. Carpino, L. A.; El-Faham, A.
J . Org. Chem. 1994, 59, 695.
matographed (SiO2 gel, CH2Cl2) to obtain 510 mg of resin
1
(95%): Rf 0.30 (100% CH2Cl2); [R]20 -69° (c 1.7, CHCl3); H
D
NMR (CDCl3) δ 7.44-7.30 (10H), 6.64 (s, 2H), 5.13 (s, 4H),
4.81 (s, 1H), 3.89 (s, 3H), 3.66 (s, 3H); 13C NMR (75 MHz) δ

3094 J . Org. Chem., Vol. 63, No. 9, 1998
Pearson and Chelliah
r op h en yl)eth ylca r boxa m id o]-1-(p h en ylm eth yl)ca r boxa -
m id o}-2-(3,5-d ih yd r oxy-4-m et h oxyp h en yl)et h a n oa t e }-
r u th en iu m Hexa flu or op h osp h a te (8). A mixture of the
dipeptide 6 (84 mg, 0.17 mmol), 10% Pd-C (19 mg), and 6 N
HCl (84 µL, 0.5 mmol, 3.0 equiv) was stirred under 1 atm of
H2 (balloon) for about 12 h. The suspension was filtered
through Celite and evaporated. The residue was chased with
dry ether and dried under vacuum to obtain the amine
hydrochloride. To a flask containing the ruthenium complex
7 (103 mg, 0.17 mmol) and HOBt (34 mg, 0.25 mmol, 1.5 equiv)
in 0.75 mL of DMF at 0 °C was added EDCI (36 mg, 019 mmol,
1.1 equiv) and the mixture was stirred at 0 °C for 30 min. To
this was added a solution of the above amine hydrochloride
in 1.75 mL of DMF followed by DIPEA (30 µL, 0.17 mmol, 1.0
equiv). The mixture was stirred at 0 °C for 3 h and at room
temperature for about 12 h. The solution was poured into 25
mL of cold water and extracted with 3 × 10 mL of propionitrile.
The combined organic layer was washed with aqueous NaH-
CO3 (10 mL) and 1 M NaHSO4 (10 mL). The solution was
dried (Na2SO4), filtered, and evaporated to give a residue,
which was dissolved in 1 mL of 1:1 MeOH-MeCN and
reprecipitated by the addition of 50 mL of dry ether. The fine
precipitate was collected by filtration to give 90 mg (56%) of
dark brown solid: 1H NMR (CD3CN) δ 7.56 (d, 1H, J ) 6.6
Hz), 7.45 (d, 1H, J ) 6.4 Hz), 7.34 (bs, 5H), 6.95 (bs, 2H), 6.40-
6.30 (4H), 6.06 (d, 1H, J ) 5.4 Hz), 6.00 (d, 1H, J ) 6.0 Hz),
5.85 (bs, 1H), 5.43 (d, 1H, J ) 6.6 Hz), 5.36 (s, 5H), 5.22 (d,
1H, J ) 6.4 Hz), 4.29 (dd, 1H, J ) 13.7 Hz, 7.8 Hz), 3.74 (s,
3H), 3.66 (s, 3H), 2.86 (dd, 1H, J ) 13.8 Hz, 4.9 Hz), 2.86 (dd,
1H, J ) 13.8 Hz, 8.0 Hz), 1.35 (s, 9H); 13C NMR (CD3CN) δ
172.00, 170.78, 170.51, 156.62, 151.53, 138.98, 136.40, 133.00,
130.08, 129.67, 128.81, 108.13, 105.94, 102.35, 88.18, 84.12,
81.96, 81.17, 61.42, 58.12, 57.65, 56.35, 53.64, 37.29, 28.77;
FABHRMS (glycerol/NBA/CsI/NaI) m/z 773.2021 (M+ - PF6-
Cl), C37H41N3O9Ru requires 773.1880.
Sch em e 10
Cycliza tion of 8. P r oced u r e A. A stock solution of
sodium 2,6-di-tert-butylphenoxide was prepared by mixing 38
mg of 60% NaH (0.95 mmol) and 196 mg of 2,6-di-tert-
butylphenol (0.95 mmol) in 10 mL of THF. To a flask
containing 674 µL (0.064 mmol, 2.0 equiv) of this stock
solution, 2.4 mL of THF and 1.6 mL of DMF at -60 °C, was
added a solution of the ruthenium complex 8 (30 mg, 0.032
mmol) in 1 mL of DMF over a period of 30 min (final
concentration 5 mM). The solution was allowed to warm
slowly to 0 °C over a period of 2 h and stirred at 0 °C for 1 h
and then at room temperature for 2 h. The reaction was
quenched by the addition of 1 mL of 1 M NaHSO4 at 0 °C, and
the THF was evaporated under reduced pressure. The mixture
was diluted with 15 mL of H2O and extracted with 3 × 7 mL
of propionitrile. The combined organic layer was evaporated,
and the residue was dissolved in 20 mL of CH3CN, degassed
with Ar, and photolyzed (Rayonet, 350 nm) for 22 h. The
solution was concentrated and purified by preparative TLC
(0.5 mm thickness, SiO2 gel, 4:96 MeOH-CHCl3) to obtain 1.7
mg of 9 and 7.1 mg of 10 (46% combined yield).
P r oced u r e B. To a flask containing the ruthenium com-
plex 8 (94 mg, 0.099 mmol) and Cs2CO3 (161 mg, 0.49 mmol)
was added 9.9 mL of DMF (10 mM concentration), and the
mixture was stirred at room temperature for 6 h. The reaction
was quenched by the addition of aqueous citric acid at 0 °C
and diluted with 60 mL of propionitrile. The organic layer
was washed with 3 × 30 mL of H2O and evaporated to give a
residue, which was dissolved in 20 mL of CH3CN, degassed
with Ar, and photolyzed (Rayonet, 350 nm) for 24 h. The
solution was concentrated and purified by preparative TLC
(SiO2 gel, 0.5 mm thickness, 4:96 MeOH-CHCl3) to obtain 5
mg of 9 and 20.4 mg of 10 (42% combined yield).
169.28, 152.80, 140.14, 136.64, 128.81, 128.49, 127.89, 127.27,
107.26, 71.12, 65.10, 60.82, 52.84; IR (CHCl3) 2113, 1750, 1440
cm-1; HRMS (EI) m/z 433.1606 (M+), C24H23N3O5 requires
433.1638.
Meth yl (2R)-2-[(S)-1-{[(Ben zyloxy)ca r bon yl]a m in o]}-1-
(p h en ylm et h yl)ca r b oxa m id o]-2-(3,5-d ih yd r oxy-4-m et h -
oxyp h en yl)eth a n oa te (6). To a solution of the azide 5 (510
mg, 1.18 mmol) in 15 mL of THF-MeOH (1:1 v/v) was added
393 µL of 6 N HCl (2.36 mmol, 2.0 equiv) and 100 mg of 10%
Pd-C. The suspension was stirred under 1 atm of H2 (balloon)
for 18 h. The mixture was filtered through Celite, and the
solvent was evaporated. The residue was chased with dry
ether and dried under vacuum to obtain the crude amine
hydrochloride as a solid. To a solution of this amine hydro-
chloride, (S)-ZPhg (370 mg, 1.30 mmol, 1.1 equiv), and HOAt
(241 mg, 1.77 mmol, 1.5 equiv) in 12 mL of DMF-CH2Cl2 (1:2
v/v) at 0 °C was added EDCI (340 mg, 1.77 mmol, 1.5 equiv)
followed by TMP (156 µL, 1.18 mmol, 1.0 equiv). The mixture
was stirred at 0 °C for 2 h and at room temperature for 11 h.
The solution was diluted with 70 mL of EtOAc, and the organic
phase was successively washed with 1 N HCl (2 × 30 mL),
aqueous NaHCO3 (2 × 30 mL), and brine (30 mL) and dried
(Na2SO4). The solution was filtered, the solvent evaporated,
and the residue chromatographed (30 g of SiO2 gel, 5:95
MeOH-CHCl3) to obtain 590 mg of foam (98%): Rf 0.28 (5:95
1
MeOH-CHCl3); [R]22 -35° (c 1.3, CHCl3); H NMR (CDCl3)
D
δ 7.73 (d, 1H, J ) 3.3 Hz), 7.25-7.08 (10H), 6.83 (bs, 2H), 6.44
(s, 2H), 6.21 (d, 1H, J ) 9.2 Hz), 5.61 (d, 1H, J ) 7.7 Hz), 5.11
(d, 1H, J ) 4.8 Hz), 4.77 (d, 1H, J ) 12 Hz), 4.54 (d, 1H, J )
12 Hz), 3.67 (s, 3H), 3.58 (s, 3H); 13C NMR (CDCl3) δ 171.65,
170.77, 156.10, 149.75, 136.87, 135.72, 135.01, 130.27, 128.87,
128.34, 128.02, 127.79, 127.08, 107.08, 67.14, 60.54, 57.97,
57.12, 52.98; IR (CHCl3) 1741, 1712, 1677, 1513 cm-1; HRMS
(EI) m/z 494.1671 (M+), C26H26N2O8 requires 494.1689.
(η5-Cyclop en t a d ien yl){m et h yl (2R)-2-{(S)-1-[(1R)-1-
[(ter t -b u t oxyca r b on yl)a m in o]-2-((1,2,3,4,5,6-η)-4-ch lo-
P r oced u r e C. A stock solution of sodium 2,6-di-tert-
butylphenoxide was prepared by mixing 76 mg of 60% NaH
(1.94 mmol) and 400 mg of 2,6-di-tert-butylphenol (1.94 mmol)
in 15 mL of THF. To a flask containing the ruthenium
complex 8 (46 mg, 0.048 mmol) in 1 mL of DMF and 3.8 mL of
THF at 0 °C was added 763 µL (2.0 equiv) of the above stock
solution over a period of 2 h, using a syringe pump (∼9 mM
final concentration). The solution was stirred at 0 °C for 30

Model Bicyclic CDE Ring System of Ristocetin A
J . Org. Chem., Vol. 63, No. 9, 1998 3095
min and at room temperature for 3 h. The reaction was
quenched by the addition of 1 mL of 1 M NaHSO4 at 0 °C.
The mixture was diluted with 20 mL of H2O and extracted
with 3 × 7 mL of propionitrile. The combined organic layer
was evaporated, and the residue was dissolved in 20 mL of
CH3CN, degassed, and photolyzed (Rayonet, 350 nm) for 17
h. The solution was concentrated, and the residue was purified
by preparative TLC (SiO2 gel, 0.5 mm, 4:96 MeOH-CHCl3) to
obtain 7.8 mg of 9 (29%).
Meth yl (8R,11S,14R)-14-[(ter t-bu toxyca r bon yl)a m in o]-
5-h yd r oxy-4-m eth oxy-10,13-d ioxo-11-p h en yl-2-oxa -9,12-
d ia za t r icyclo[14.2.2.13,7]h en icosa -1(18),3,5,7(21),16,19-
h exa en e-8-ca r boxyla te (9): Rf 0.30 (4:96 MeOH-CHCl3);
[R]21Hg-578 -42° (c 0.3, CHCl3); 1H NMR (CD3CN-CDCl3) δ 7.37
(dd, 1H, J ) 8.3 Hz, 2.4 Hz), 7.32-7.14 (6H), 7.20-7.15 (2H),
7.02 (d, 1H, J ) 7.7 Hz), 6.91 (dd, 1H, J ) 8.3 Hz, 2.4 Hz),
6.46 (d, 1H, J ) 2.2 Hz), 5.71 (d, 1H, J ) 2.2 Hz), 5.48 (d, 1H,
J ) 5.0 Hz), 5.32 (d, 1H, J ) 7.7 Hz), 4.85 (d, 1H, J ) 6.8 Hz),
4.42-4.37 (m, 1H), 3.98 (s, 3H), 3.54 (s, 3H), 3.39 (dd, 1H, J )
13.8 Hz, 4.8 Hz), 2.87 (dd, 1H, J ) 13.8 Hz, 3.9 Hz), 1.44 (s,
9H); 13C NMR (CDCl3) δ 169.58, 169.46, 169.16, 155.57, 154.99,
152.74, 149.66, 136.14, 135.69, 134.21, 131.18, 130.34, 129.49,
129.13, 128.89, 127.35, 123.65, 122.66, 107.62, 106.31, 80.28,
61.45, 59.17, 55.80, 53.11, 39.14, 29.69, 28.30; FABHRMS
(glycerol/NBA/CsI/NaI) m/z 738.1444 (MCs+), C32H35N3O9Cs
requires 738.1424.
Meth yl (8S,11S,14R)-14-[(ter t-bu toxyca r bon yl)a m in o]-
5-h yd r oxy-4-m eth oxy-10,13-d ioxo-11-p h en yl-2-oxa -9,12-
d ia za t r icyclo[14.2.2.13,7]h en icosa -1(18),3,5,7(21),16,19-
h exa en e-8-ca r boxyla te (10): Rf 0.35 (4:96 MeOH-CHCl3);
[R]21Hg-578 +99° (c 0.4, CHCl3); 1H NMR (CD3CN-CDCl3) δ 7.47
(d, 1H, J ) 8.8 Hz), 7.38 (dd, 1H, J ) 8.5 Hz, 2.1 Hz), 7.35-
7.25 (6H), 7.17 (dd, 1H, J ) 8.5 Hz, 2.1 Hz), 7.08-7.03 (2H),
6.48 (dd, 1H, J ) 2.3 Hz, 1.0 Hz), 5.78 (dd, 1H, J ) 2.3 Hz, 1.0
Hz), 5.46 (bs, 1H), 5.43 (d, 1H, J ) 8.8 Hz), 5.34 (d, 1H, J )
7.2 Hz), 3.98 (s, 3H), 3.77 (s, 3H), 3.36 (dd, 1H, J ) 14.0 Hz,
2.8 Hz), 2.90 (dd, 1H, J ) 14.0, 2.8 Hz), 1.47 (s, 9H); 13C NMR
(CD3CN-CDCl3) δ 169.90, 169.81, 169.72, 155.94, 155.46,
153.58, 150.81, 138.43, 136.56, 133.49, 131.80, 131.47, 130.95,
128.98, 128.44, 126.81, 123.60, 122.31, 106.94, 106.86, 106.27,
80.58, 61.45, 56.97, 56.11, 54.97, 53.07, 36.84, 28.29; FAB-
HRMS (glycerol/NBA/CsI/NaI) m/z 628.2277 (MNa+),
12 using the procedure used for the preparation of 5: yield
87%; [R]24 +68° (c 1.5, CHCl3). The compound showed
D
spectral properties identical to its (R)-enantiomer 5.
Meth yl (2S)-2-[(S)-1-{[(Ben zyloxy)ca r bon yl]a m in o]}-1-
(p h en ylm et h yl)ca r b oxa m id o]-2-(3,5-d ih yd r oxy-4-m et h -
oxyp h en yl)eth a n oa te (14). This compound was prepared
from 13 using the procedure used for the preparation of 6:
yield 77% of foam; Rf 0.29 (4:96 MeOH-CHCl3); [R]24D +63° (c
0.5, CHCl3); 1H NMR (CDCl3), δ 7.91 (d, 1H, J ) 6.8 Hz), 7.42-
7.27 (10H), 6.65 (bs, 2H), 6.29 (s, 2H), 5.98 (d, 1H, J ) 7.9
Hz), 5.75 (d, 1H, J ) 7.9 Hz), 5.38 (d, 1H, J ) 6.8 Hz), 5.07 (d,
1H, J ) 12.2 Hz), 4.84 (d, 1H, J ) 12.2 Hz), 3.83 (s, 3H), 3.59
(s, 3H); 13C NMR (CDCl3) δ 171.09, 170.44, 156.28, 149.62,
136.80, 135.80, 134.99, 130.94, 128.92, 128.53, 128.39, 128.09,
128.02, 127.19, 106.77, 67.39, 60.55, 58.14, 56.42, 52.69; HRMS
(EI) m/z 494.1680 (M+), C26H26N2O8 requires 494.1689.
(η5-Cyclopen tadien yl){m eth yl (2S)-2-{(S)-1-[(1R)-1-[(ter t-
bu toxyca r bon yl)a m in o]-2-((1,2,3,4,5,6,-η)-4-ch lor op h en yl-
)et h ylca r b oxa m id o]-1-(p h en ylm et h yl)ca r b oxa m id o}-2-
(3,5-d ih yd r oxy-4-m e t h oxyp h e n yl)e t h a n oa t e }r u t h e n -
iu m Hexa flu or op h osp h a te (15). This compound was pre-
pared from 14 using the procedure employed for the prepara-
1
tion of compound 8: yield 59%; H NMR (CD3CN) δ 7.61 (d,
1H, J ) 7.5 Hz), 7.58 (d, 1H, J ) 9.0 Hz), 7.37 (bs, 5H), 6.39
(s, 2H), 6.36 (d, 1H, J ) 6.0 Hz), 6.28 (d, 1H, J ) 5.8 Hz), 6.03
(d, 1H, J ) 6.0 Hz), 5.98 (d, 1H, J ) 5.8 Hz), 5.86 (d, 1H, J )
7.0 Hz), 5.54 (d, 1H, J ) 6.1 Hz), 5.34 (s, 5H), 5.25 (d, 1H, J
) 7.0 Hz), 4.34 (bs, 1H), 3.76 (s, 3H), 3.58 (s, 3H), 2.83 (dd,
1H, J ) 13.5 Hz, 5.2 Hz), 2.62 (dd, 1H, J ) 13.5 Hz, 8.3 Hz),
1.32 (s, 9H); 13C NMR (CD3CN) δ 171.50, 170.50, 170.04,
156.29, 151.27, 138.63, 136.11, 132.98, 129.73, 129.34, 128.49,
107.86, 105.62, 101.94, 87.83, 83.78, 81.60, 80.81, 61.14, 57.48,
57.36, 56.02, 53.28, 37.07, 28.43; FABHRMS (NBA/glycerol)
m/z 808.1564 (M+ - PF6) C37H41N3O9ClRu requires 808.1568.
Cycliza tion of 15. A stock solution of sodium 2,6-di-tert-
butylphenoxide was prepared by mixing 34 mg of 60% NaH
(0. 85 mmol) and 176 mg of 2,6-di-tert-butylphenol (0.85 mmol)
in 10 mL of THF. To a flask containing 1.04 mL of the above
stock solution (0.9 mmol, 2.0 equiv), 1.2 mL of THF, and 0.7
mL of DMF at -60 °C was added a solution of the ruthenium
complex 15 (42 mg, 0.044 mmol) in 1.5 mL of DMF over a
period of few minutes (final concentration 10 mM). The
solution was allowed to warm to 0 °C over a period of 2 h and
stirred at 0 °C for 1 h and at room temperature for 2 h. To
the solution was added 1 mL of 1 N NaHSO4, the solution was
diluted with 20 mL of H2O, and the aqueous solution was
extracted with 3 × 7 mL of propionitrile. The combined
organic layer was evaporated, and the residue was dissolved
in 20 mL of CH3CN, degassed with Ar, and photolyzed
(Rayonet, 350 nm) for 24 h. The solvent was evaporated, and
the residue was subjected to preparative TLC (SiO2 gel, 0.5
mm thickness, 4:96 MeOH-CHCl3) to obtain 10 mg (38%) of
10.
C
32H35N3O9Na requires 628.2271.
(4R)-3-{(2S)-2-Azid o-2-[3,5-bis(ben zyloxy)-4-m eth oxy-
p h en yl]eth a n oyl}-4-ben zyl-1,3-oxa zolid in -2-on e (11): Rf
0.23 (15:15:70 EtOAc-CH2Cl2-hexanes); [R]20 +64° (c 2.7,
D
1
CHCl3); H NMR (CDCl3) δ 7.47 (d, 4H, J ) 7.4 Hz), 7.35 (t,
4H, J ) 7.4 Hz), 7.27-7.23 (5H), 6.94-6.91 (2H), 6.86 (s, 2H),
6.10 (s, 1H), 5.17 (ABq, 2H, J ) 12.2 Hz), 5.10 (ABq, 2H, J )
12.2 Hz), 4.76-4.68 (m, 1H), 4.20 (t, 1H, J ) 8.6 Hz), 4.08
(dd, 1H, J ) 9.1, 3.3 Hz), 3.97 (s, 3H), 2.89 (dd, 1H, J ) 13.6,
3.3 Hz), 2.40 (dd, 1H, J ) 13.6, 8.9 Hz); 13C NMR (CDCl3) δ
168.72, 152.76, 152.44, 140.12, 136.58, 134.28, 129.28, 128.72,
128.42, 127.90, 127.81, 127.16, 108.02, 70.93, 66.28, 62.88,
60.78, 54.59, 36.80; IR (CHCl3) 2110, 1782, 1709, 1593, 1443,
1391, 1371, 1119 cm-1; HRMS (EI) m/z 578.2192 (M+),
Equ ilibr a tion Stu d y on 9. A stock solution of DBU was
prepared by dissolving 20 mg of DBU in 500 µL of CD3CN-
CDCl3 (1:1 v/v) mixture. To an NMR tube containing 1.5 mg
(2.5 µmol) of 9 in ∼450 µL of CD3CN-CDCl3 (shimmed) was
added 50 µL of the above stock solution (13 µmol, 5.2 equiv).
The sample was shimmed, and the 1H NMR was taken
immediately. The NMR showed complete downfield shift of
CO2Me peak (from 3.54 to 3.71 ppm). The solution was
immediately diluted with 5 mL of EtOAc, washed with 1 N
HCl (2 × 5 mL) and brine (5 mL), and dried (Na2SO4). The
solution was filtered and evaporated, and the crude product
C
33H30N4O6 requires 578.2165.
(2S )-2-Azid o-2-[3,5-b is(b e n zyloxy)-4-m e t h oxyp h e n -
yl]eth a n oic Acid (12). A solution of the azido carboximide
11 (98 mg, 0.17 mmol), 30% H2O2 (77 mg, 0.68 mmol, 4.0
equiv), and LiOH‚H2O (15 mg, 0.36 mmol, 2.1 equiv) in 2 mL
of THF-H2O (3:1 v/v) was stirred at 0 °C for 1 h. The reaction
was quenched by the addition of a solution of Na2SO3 (108 mg,
0.86 mmol, 5.0 equiv) in 1 mL of H2O. The solution was stirred
for 5 min, and to this was added 5 mL of 0.5 M solution of
K2CO3 and 15 mL of H2O. It was then washed with ether (3
× 20 mL) and acidified with 10% HCl to ∼pH 2. The aqueous
phase was extracted with EtOAc (3 × 10 mL), and the
combined organic layer was washed with brine (10 mL) and
dried (Na2SO4). The solution was filtered and evaporated to
1
was analyzed by H NMR, which showed only the presence of
10.
2-(Tr im eth ylsilyl)eth yl (2R)-2-Azid o-2-[3,5-bis(ben zyl-
oxy)-4-m eth oxyp h en yl]eth a n oa te (16). To a mixture of the
azido acid 4 (208 mg, 0.50 mmol), (trimethylsilyl)ethanol (118
mg, 1.0 mmol, 2.0 equiv), and HOAt (68 mg, 0.50 mmol, 1.0
equiv) in 5 mL of CH2Cl2 at 0 °C was added DCC (154 mg,
0.75 mmol, 1.5 equiv), and the cloudy solution was stirred for
3 h at 0 °C and 12 h at room temperature. To the mixture
was added 2 mL of 1 N HCl at 0 °C and then 50 mL of EtOAc,
and the solution was filtered through a Celite plug to remove
obtain 60 mg of resin (85%), [R]24 +83° (c 1.3, CHCl3). The
D
compound showed spectral properties identical to its (R)-
enantiomer 4.
Meth yl (2S)-2-Azid o-2-[3,5-bis(ben zyloxy)-4-m eth oxy-
p h en yl]eth a n oa te (13). This compound was prepared from

3096 J . Org. Chem., Vol. 63, No. 9, 1998
Pearson and Chelliah
insolubles. The organic layer was washed with 1 N HCl (2 ×
25 mL) and brine (25 mL), dried (Na2SO4), filtered, and
evaporated under reduced pressure to a give a yellow residue
that was chromatographed (SiO2 gel, 3:7 hexanes-CH2Cl2) to
h (8 mM final concentration). The solution was allowed to
warm slowly to 0 °C over a period of 2 h and stirred at 0 °C
for 3 h. It was quenched with 1 mL of 1 N NaHSO4 at 0 °C,
the volatiles were removed under reduced pressure, and the
residue diluted with 15 mL of H2O. The aqueous phase was
extracted with 3 × 7 mL of propionitrile, and the combined
organic layer was evaporated. The residue was dissolved in
20 mL of CH3CN, degassed with Ar, and photolyzed (Rayonet,
350 nm) for 24 h. The solution was concentrated, and the
residue was subjected to preparative TLC (SiO2 gel, 0.5 mm
thickness, 2:98 MeOH-CHCl3) to obtain 5.2 mg of 19 and 2.6
mg of 20 (29% combined yield).
provide 248 mg of colorless resin (96%): Rf 0.38 (CH2Cl2); [R]20
D
1
-42° (c 1, CHCl3); H NMR (CDCl3) δ 7.44-7.32 (10H), 6.64
(s, 2H), 5.11 (s, 4H), 4.77 (s, 1H), 4.21-4.07 (2H), 3.88 (s, 3H),
0.95-0.89 (2H), -0.02 (s, 9H, TMS); 13C NMR (CDCl3) δ
168.83, 152.70, 139.98, 136.58, 128.98, 128.36, 127.76, 127.14,
107.19, 70.98, 65.12, 64.39, 60.66, 17.03, -1.73; IR (CHCl3)
2110, 1739, 1596, 1505, 1439, 1256, 1115 cm-1; HRMS (EI)
m/z 519.2195 (M+), C28H33N3O5Si requires 519.2189.
2-(Tr im eth ylsilyl)eth yl (2R)-2-[(S)-1-{[(Ben zyloxy)ca r -
bon yl]a m in o]}-1-(p h en ylm eth yl)ca r boxa m id o]-2-(3,5-d i-
h yd r oxy-4-m eth oxyp h en yl)eth a n oa te (17). A mixture of
the azide 16 (150 mg, 0.29 mmol), 6 N HCl (145 µL, 0.87 mmol,
3.0 equiv), and 35 mg of 10% Pd-C in 7 mL of 1:1 THF-MeOH
was stirred under 1 atm of H2 for 12 h. The slurry was filtered
through a Celite plug and evaporated, and the residue was
chased with dry ether and dried under vacuum to obtain the
amine hydrochloride. To a solution of the amine hydrochlo-
ride, (R)-ZPhg (83 mg, 0.29 mmol, 1.0 equiv), HOAt (59 mg,
0.43 mmol, 1.5 equiv), and TMP (38 µL, 0.29 mmol, 1.0 equiv)
in 3 mL of 1:2 DMF-CH2Cl2 at 0 °C was added EDCI (67 mg,
0.35 mmol, 1.2 equiv), and the solution was stirred for 3 h at
0 °C and 12 h at room temperature. The mixture was diluted
with 20 mL of EtOAc, and the organic layer was washed
successively with 1 N HCl (2 × 20 mL), aqueous NaHCO3 (2
× 20 mL), and brine (20 mL). The organic layer was dried
(Na2SO4) and filtered, and the solvent was evaporated to give
a residue that was chromatographed (SiO2 gel, 4:96 MeOH-
CHCl3) to obtain 150 mg of foam (89%): Rf 0.25 (4:96 MeOH-
2-(Tr im eth ylsilyl)eth yl (8R,11S,14R)-14-[(ter t-bu toxy-
ca r b on yl)a m in o]-5-h yd r oxy-4-m et h oxy-10,13-d ioxo-11-
p h e n yl-2-oxa -9,12-d ia za t r icyclo[14.2.2.13,7]h e n icosa -
1(18),3,5,7(21),16,19-h exa en e-8-ca r boxyla te (19): Rf 0.28
(2:98 MeOH-CHCl3); [R]21
) +116° (c 0.2, MeOH); 1H
Hg-578
NMR (CD3CN-CDCl3) δ 7.38 (dd, 1H, J ) 8.5 Hz, 2.3 Hz),
7.30 (bs, 5H), 7.28 (d, 1H, J ) 9.0 Hz), 7.20-7.15 (2H), 7.01
(d, 1H, J ) 7.6 Hz), 6.93 (dd, 1H, J ) 8.5 Hz, 2.3 Hz), 6.78 (s,
1H), 6.45 (d, 1H, J ) 2.1 Hz), 5.72 (d, 1H, J ) 2.1 Hz), 5.43
(bs, 1H), 5.29 (d, 1H, J ) 7.6 Hz), 4.78 (d, 1H, J ) 6.7 Hz),
4.40-4.34 (m, 1H), 4.05-3.96 (5H), 3.39 (dd, 1H, J ) 13.8 Hz,
4.8 Hz), 2.88 (dd, 1H, J ) 13.8 Hz, 4.0 Hz), 1.45 (s, 9H), 0.63
(t, 2H), -0.07 (s, 9H); 13C NMR (CD3CN-CDCl3) δ 169.96,
169.71, 169.30, 155.65, 155.52, 153.51, 150.25, 138.12, 136.33,
133.36, 132.01, 131.78, 130.78, 129.02, 128.55, 127.18, 123.41,
122.45, 109.61, 106.26, 80.40, 64.10, 61.58, 56.93, 56.59, 37.13,
29.95, 28.30, 17.25, -1.66; FABHRMS (NBA/CsI/NaI) m/z
692.3008 (MH+), C36H46N3O9Si requires 692.3003.
2-(Tr im eth ylsilyl)eth yl (8S,11S,14R)-14-[(ter t-bu toxy-
ca r b on yl)a m in o]-5-h yd r oxy-4-m et h oxy-10,13-d ioxo-11-
p h e n yl-2-oxa -9,12-d ia za t r icyclo[14.2.2.13,7]h e n icosa -
1(18),3,5,7(21),16,19-h exa en e-8-ca r boxyla te (20): Rf 0.22
(2:98 MeOH-CHCl3); [R]21Hg-578 ) +65° (c 0.4, CHCl3); 1H NMR
(CD3CN-CDCl3) δ 7.43 (d, 1H, J ) 8.7 Hz), 7.36 (dd, 1H, J )
8.4 Hz, 2.1 Hz), 7.32-7.22 (6H), 7.14 (dd, 1H, J ) 8.4 Hz, 2.1
Hz), 7.05-7.01 (2H), 6.88 (s, 1H), 6.49 (dd, 1H, J ) 2.2 Hz,
1.0 Hz), 5.75 (dd, 1H, J ) 2.2 Hz, 1.0 Hz), 5.46 (bs, 1H), 5.34
(d, 1H, J ) 8.7 Hz), 5.33 (d, 1H, J ) 7.3 Hz), 4.32-4.20 (3H),
3.95 (s, 3H), 3.33 (dd, 1H, J ) 13.9 Hz, 5.2 Hz), 2.87 (dd, 1H,
J ) 13.9 Hz, 2.8 Hz), 1.44 (s, 9H), 1.03-0.97 (2H), -0.02 (s,
9H); 13C NMR (CD3CN-CDCl3) δ 169.81, 169.77, 169.50,
155.99, 155.46, 153.59, 150.81, 138.49, 136.52, 133.52, 131.82,
131.62, 130.98, 128.99, 128.44, 126.80, 123.64, 122.34, 106.95,
106.29, 80.59, 64.88, 61.40, 56.98, 56.11, 55.10, 36.84, 28.30,
17.55, -1.60; FABHRMS (NBA/CsI/NaI) m/z 824.1979 (MCs+),
CHCl3); [R]20 -5.8° (c 1.3, CHCl3); 1H NMR (CDCl3) δ 7.62
D
(bs, 1H), 7.34-7.21 (10H), 6.48 (s, 2H), 6.06 (d, 1H, J ) 7.1
Hz), 5.61 (d, 1H, J ) 5.6 Hz), 5.14 (d, 1H, J ) 3.5 Hz), 4.86 (d,
1H, J ) 12.0 Hz), 4.68 (d, 1H, J ) 12.0 Hz), 4.33-4.24 (m,
1H), 4.17-4.08 (m, 1H), 3.81 (s, 3H), 0.97 (t, 2H), -0.02 (s,
9H); 13C NMR (CDCl3) δ 171.31, 170.70, 156.07, 149.72, 136.91,
135.75, 134.91, 130.30, 128.95, 128.83, 128.32, 127.96, 127.73,
127.05, 107.09, 67.05, 64.76, 60.52, 57.83, 57.47, 16.89, -1.69;
FABHRMS (glycerol/NaI/CsI) m/z 581.2298 (MH+), C30H37N2O8-
Si requires 581.2319.
(η5-Cyclop en t a d ien yl){2-(t r im et h ylsilyl)et h yl (2R)-2-
{(S)-1-[(1R)-1-[(ter t-bu toxycar bon yl)am in o]-2-((1,2,3,4,5,6-
η)-4-ch lor op h en yl)et h ylca r b oxa m id o]-1-(p h en ylm et h -
yl)ca r b oxa m id o}-2-(3,5-d ih yd r oxy-4-m et h oxyp h en yl)-
eth a n oa te}r u th en iu m Hexa flu or op h osp h a te (18). To a
solution of the dipeptide 17 (530 mg, 0.91 mmol) in 15 mL of
MeOH was added 115 mg of 10% Pd-C and 305 µL of 6 N
HCl, and the suspension was stirred under 1 atm of H2
(balloon) for about 16 h. The suspension was filtered through
Celite and evaporated, and the residue was chased with dry
ether and dried under vacuum to obtain the amine hydrochlo-
ride salt. This salt was taken along with the ruthenium
complex 7 (247 mg, 0.40 mmol, 1.0 equiv) and HATU (200 mg,
0.53 mmol, 1.3 equiv) in 4 mL of 1:1 DMF-CH2Cl2 and cooled
to 0 °C. To this was added DIPEA (212 µL, 1.22 mmol, 3.0
equiv), and the solution was stirred at 0 °C for 1 h and at room
temperature for 3 h. The mixture was poured into 50 mL of
ice-cold water and extracted with 4 × 15 mL of propionitrile.
The combined organic layer was washed with 1 N NaHSO4 (2
× 15 mL) and aqueous NaHCO3 (2 × 15 mL) and dried over
Na2SO4. The solution was evaporated, the residue was dis-
solved in 2 mL of CH3CN, and the product was precipitated
by the addition of 40 mL of dry ether. The precipitate was
filtered, washed with ether, and evaporated to give 337 mg of
dark brown solid (80%). Due to the difficulty in purifying
further, it was used for the next step as such.
C
36H45N3O9SiCs requires 824.1979.
2-(Tr im eth ylsilyl)eth yl (2R)-2-[(ter t-Bu toxyca r bon yl)-
a m in o]-2-p h en yleth a n oa te (22). To a flask containing 21
(500 mg, 1.75 mmol), (trimethylsilyl)ethanol (414 mg, 3.50
mmol, 1.2 equiv), and DMAP (214 mg, 1.75 mmol, 1.0 equiv)
in 15 mL of CH2Cl2 at 0 °C was added DCC (542 mg, 2.63
mmol, 1.5 equiv), and the mixture was stirred at 0 °C for 4 h.
The solution was quenched with aqueous HCl at 0 °C, diluted
with 100 mL of EtOAc, and filtered through a Celite pad. The
organic layer was washed with 2 × 50 mL of brine, dried over
Na2SO4, and filtered. The solution was concentrated and
chromatographed (SiO2 gel, 10:90 EtOAc/hexanes) to give 575
mg of resin (85%): Rf 0.19 (10:90 EtOAc/hexanes); [R]20D -68°
1
(c 2.7, CHCl3); H NMR (CDCl3) δ 7.36-7.28 (10H), 5.85 (d,
1H, J ) 6.7 Hz), 5.34 (d, 1H, J ) 6.7 Hz), 5.13 (ABq, 1H, J )
12.1 Hz), 5.07 (ABq, 1H, J ) 12.1 Hz), 4.32-4.11 (2H), 0.94
(t, 2H), -0.02 (s, 9H); 13C NMR (acetone-d6) δ 171.42, 156.43,
137.83, 129.41, 129.07, 128.97, 128.77, 128.56, 128.35, 127.20,
66.85, 64.13, 59.20, 17.58, -1.54; IR (CHCl3) 1729, 1724,1501,
1252, 1176, 1054 cm-1; FABHRMS (NBA/NaI/CsI) m/ z
386.1740 (M+), C21H28NO4Si requires 386.1788.
Cycliza tion of 18. A stock solution of sodium 2,6-di-tert-
butylphenoxide was prepared by mixing 40 mg of 60% NaH
(1.0 mmol) and 206 mg of 2,6-di-tert-butylphenol (1.0 mmol)
in 10 mL of THF. To a flask containing 770 µL (0.077 mmol,
2.0 equiv) of the stock solution, 1.7 mL of THF, and 1 mL of
DMF at -40 °C was added a solution of the ruthenium complex
18 (40 mg, 0.039 mmol) in 1.4 mL of DMF over a period of 1
[(R)-1-P h en yl-1-[2-[[(tr im eth ylsilyl)eth yl]oxy]ca r bon -
yl]m eth yl]a m m on iu m Ch lor id e (23). To a solution of 22
(518 mg, 0.74 mmol) and 6 N HCl (372 µL, 2.23 mmol, 3.0
equiv) in 15 mL of 1:1 MeOH-THF was added 55 mg of 10%
Pd-C, and the suspension was stirred under 1 atm of H2
(balloon) for 18 h. The suspension was filtered through a

Model Bicyclic CDE Ring System of Ristocetin A
J . Org. Chem., Vol. 63, No. 9, 1998 3097
Celite pad and evaporated. The residue was chased with dry
ether and dried under vacuum to obtain 370 mg of solid
(220 mg, 1.15 mmol, 1.5 equiv), and the mixture was stirred
at 0 °C for 2 h and at room temperature for 13 h. The reaction
was quenched with aqueous citric acid and diluted with 100
mL of EtOAc. The organic phase was washed successively
with 1 N HCl (2 × 50 mL), aqueous NaHCO3 (2 × 50 mL),
and brine (50 mL) and dried over Na2SO4. It was filtered and
evaporated, and the residue was chromatographed (SiO2 gel,
1:99 MeOH-CHCl3) to obtain 600 mg of white solid (91%): mp
158-161 °C; Rf 0.20 (1:99 MeOH-CHCl3); [R]24D ) -18° (c 2.5,
CHCl3); FABHRMS (glycerol/NBA/CsI/NaI) m/z 992.2918
(MCs+), C49H57N3O9SiCs requires 992.2919; 1H NMR (CDCl3,
2 mg/mL) δ 7.39-7.19 (20H), 6.95 (bs, 2H), 6.47 (s, 2H), 5.79
(bs, 1H), 5.41 (d, 1H, J ) 6.8 Hz), 5.30 (d, 1H, J ) 6.4 Hz),
5.17 (s, 1H), 4.81 (s, 4H), 4.23-4.03 (2H), 3.77 (s, 3H), 1.32 (s,
9H), 0.70 (dd, 2H, J ) 9.4 Hz, 7.7 Hz), -0.09 (s, 9H); 1H NMR
(CDCl3, 40 mg/mL) δ 8.14 (bs, 1H), 7.39-7.27 (19H), 7.12 (d,
2H, J ) 3.7 Hz), 6.54 (s, 3H), 5.92 (d, 1H, J ) 5.6 Hz), 5.37 (d,
2H, J ) 6.7 Hz), 4.60 (d, 2H, J ) 11.3 Hz), 4.44 (d, 2H, J )
11.3 Hz), 4.30-4.21 (m, 1H), 4.14-4.05 (m, 1H), 3.67 (s, 3H),
(96%): [R]20 -68° (c 0.9, MeOH); 1H NMR (CD3OD) δ 7.48
D
(bs, 5H), 5.12 (s, 1H), 4.35-4.28 (2H), 0.98-0.91 (2H); 13C NMR
(CD3OD) δ 169.58, 133.32, 133.11, 130.52, 129.27, 66.22, 57.65,
17.87, -1.57; FABHRMS (glycerol) m/z 252.1421 (M - Cl+)
C13H22NO2Si requires 252.1420.
2-(Tr im eth ylsilyl)eth yl (2R)-2-{(R)-1-Azid o-1-[[3,5-bis-
(ben zyloxy)-4-m eth oxyp h en yl]m eth yl]ca r boxa m id o}-2-
p h en yleth a n oa te (24). To a solution of the azido acid 4 (624
mg, 1.49 mmol), amine hydrochloride 23 (514 mg, 1.79 mmol,
1.2 equiv), HOAt (203 mg, 1.49 mmol, 1.0 equiv), and TMP
(236 µL, 1.79 mmol, 1.0 equiv) in 15 mL of CH2Cl2 at 0 °C was
added DCC (461 mg, 2.23 mmol, 1.5 equiv), and the cloudy
mixture was stirred at 0 °C for 3 h and at room temperature
for 12 h. The reaction was quenched with aqueous citric acid
and diluted with 150 mL of EtOAc. The suspension was
filtered through a Celite pad to remove the insolubles and then
washed successively with 1 N HCl (2 × 50 mL), aqueous
NaHCO3 (2 × 50 mL), and brine (50 mL). The solution was
dried (Na2SO4), filtered, and evaporated to give a crude product
that was chromatographed (SiO2 gel, 1:99 acetone-CHCl3) to
1
1.25 (s, 9H), 0.90 (t, 2H, J ) 8.7 Hz), -0.06 (s, 9H); H NMR
(DMSO-d6) δ 9.34 (d, 1H, J ) 6.7 Hz), 8.86 (d, 1H, J ) 8.6
Hz), 7.52 (d, 1H, J ) 7.9 Hz), 7.43-7.16 (20H), 6.77 (s, 2H),
5.66 (d, 1H, J ) 7.9 Hz), 5.46 (d, 1H, J ) 7.9 Hz), 5.42 (d, 1H,
J ) 6.7 Hz), 4.92 (ABq, 2H, J ) 11.5 Hz), 4.85 (ABq, 2H, J )
11.5 Hz), 4.15-4.00 (2H), 3.63 (s, 3H), 1.36 (s, 9H), 0.78 (t,
2H), -0.12 (s, 9H); 13C NMR (CDCl3, ∼40 mg/mL), δ 170.64,
170.08, 169.04, 154.79, 152.38, 150.40, 139.58, 138.18, 136.74,
132.94, 128.84, 128.61, 128.13, 127.99, 127.94, 127.67, 127.56,
127.19, 126.83, 104.51, 79.01, 69.98, 64.58, 60.45, 58.14, 57.22,
55.97, 27.95, 16.98, -1.81.
(2R)-2-{(R)-1-[(S)-1-[(ter t-Bu t oxyca r b on yl)a m in o]-1-
(p h en ylm et h yl)ca r b oxa m id o]-1-[[3,5-b is(b en zyloxy)-4-
m e t h oxyp h e n yl]m e t h yl]ca r b oxa m id o}-2-p h e n yle t h a -
n oa te (27). To a solution of the tripeptide 26 (595 mg, 0.69
mmol) in 7 mL of THF was added 1.39 mL of a 1 M solution
of TBAF in THF (1.39 mmol, 2.0 equiv), and the mixture was
stirred at room temperature for 8 h. The solution was poured
into 100 mL of 1 N HCl, and the aqueous slurry was extracted
with EtOAc (3 × 50 mL). The combined organic layer was
washed with brine (50 mL) and dried over Na2SO4. The
solution was filtered and evaporated to provide a foam that
was purified by chromatography (SiO2 gel, 3:97 MeOH-
EtOAc) to provide 488 mg (93%) of off-white solid: mp 156-
159 °C; Rf 0.43 (3:97 MeOH-EtOAc); [R]24D -34° (c 0.6, CHCl3);
1H NMR (DMSO-d6) δ 9.19 (d, 1H, J ) 5.4 Hz), 8.80 (d, 1H, J
) 8.0 Hz), 7.54-7.25 (20H), 7.17 (d, 1H, J ) 7.1 Hz), 6.76 (s,
3H), 5.67 (bs, 1H), 5.46 (d, 1H, J ) 8.0 Hz), 5.31 (d, 1H, J )
7.1 Hz), 4.90 (ABq, 2H, J ) 11.4 Hz), 4.82 (ABq, 2H, J ) 11.4
Hz), 3.62 (s, 3H), 1.36 (s, 9H); 13C NMR (DMSO-d6) δ 171.70,
169.70, 168.74, 154.75, 151.82, 139.00, 137.28, 136.78, 134.01,
130.26, 128.76, 128.64, 128.43, 128.14, 127.93, 127.84, 127.66,
127.46, 127.36, 105.33, 78.38, 70.08, 59.96, 57.21, 56.92, 56.88,
28.10; FABHRMS (glycerol/NBA/NaI/CsI) m/z 892.2225 (MCs+),
provide 874 mg (90%) of off-white solid: mp 106-109 °C; Rf
1
0.33 (1:99 acetone-CHCl3); [R]21 ) -120° (c 1.4, CHCl3); H
D
NMR (CDCl3) δ 7.50 (d, 1H, J ) 7.3 Hz), 7.41-7.25 (15H),
6.55 (s, 2H), 5.53 (d, 1H, J ) 7.3 Hz), 5.01 (ABq, 1H, J ) 11.8
Hz), 4.96 (ABq, 1H, J ) 11.8 Hz), 4.95 (s, 1H), 4.35-4.14 (2H),
3.84 (s, 3H), 0.99-0.93 (2H), -0.01 (s, 9H); 13C NMR (CDCl3)
δ 170.30, 167.10, 152.84, 139.93, 136.60, 136.34, 129.86,
128.93, 128.57, 128.43, 127.87, 127.34, 127.18, 107.15, 71.02,
66.86, 64.59, 60.73, 56.42, 17.06, -1.67; IR (CHCl3) 2116, 1736,
1685, 1596, 1505, 1499 cm-1; FABHRMS (NBA/CsI/NaI) m/z
652.2744 (M+), C36H40N4O6Si requires 652.2717.
2-(Tr im eth ylsilyl)eth yl (2R)-2-{(R)-1-Am in o-1-[3,5-bis-
(ben zyloxy)-4-m eth oxyp h en yl]m eth yl]ca r boxa m id o}-2-
p h en yleth a n oa te (25). A mixture of the azide 24 (509 mg,
0.78 mmol) and SnCl2 (296 mg, 1.56 mmol, 2.0 equiv) in 10
mL of THF-MeOH (2:3 v/v) was stirred at 0 °C for 15 min
and at room temperature for 5 h. The mixture was poured
into 100 mL of aqueous NaHCO3 and extracted with 3 × 50
mL of CHCl3. The combined organic layer was washed with
50 mL of brine, dried over Na2SO4, filtered, and evaporated
to give 480 mg (98%) of foamy resin that was homogeneous
by NMR: [R]24D ) -60° (c 1.1, CHCl3); 1H NMR (CDCl3) δ 8.17
(d, 1H, J ) 7.7 Hz), 7.42-7.28 (15H), 6.61 (s, 2H), 5.55 (d, 1H,
J ) 7.7 Hz), 5.03 (ABq, 2H, J ) 11.9 Hz), 4.97 (ABq, 2H, J )
11.9 Hz), 4.45 (s, 1H), 4.33-4.13 (2H), 3.83 (s, 3H), 0.96 (t,
2H, J ) 8.6 Hz), -0.02 (s, 9H); 13C NMR (CDCl3) δ 172.18,
170.51, 152.41, 138.62, 136.71, 136.54, 135.93, 128.61, 128.41,
128.16, 127.54, 127.10, 126.97, 106.05, 70.61, 63.95, 60.44,
59.26, 55.98, 16.81, -1.86; FABHRMS (glycerol/NBA/NaI/CsI)
m/z 759.1861 (MCs+), C36H43N2O6SiCs requires 759.1866.
(2S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-2-p h en yleth a n o-
ic Acid . A mixture of (S)-phenylglycine (804 mg, 5.3 mmol),
(Boc)2O (1.16 g, 5.3 mmol, 1.0 equiv), and NaHCO3 (671 mg,
8.0 mmol, 1.5 equiv) was stirred with 30 mL of THF-H2O
mixture (1:1 v/v) at room temperature for 21 h. The THF was
evaporated, and the mixture was diluted with 100 mL of H2O.
The aqueous solution was washed with 50 mL of ether,
acidified with 10% HCl, and extracted with 3 × 40 mL of
EtOAc. The combined organic layer was washed with 50 mL
of brine, dried over Na2SO4, filtered, and evaporated to give
C
44H45N3O9Cs requires 892.2207.
(2R)-2-{(R)-1-[(S)-1-[(ter t-Bu t oxyca r b on yl)a m in o]-1-
(p h en ylm eth yl)ca r boxa m id o]-1-[[3,5-d ih yd r oxy-4-m eth -
oxyph en yl]m eth yl]car boxam ido}-2-ph en yleth an oate (28).
To a solution of 27 (325 mg, 0.43 mmol) in 10 mL of 1:1 THF-
MeOH mixture was added 50 mg of 10% Pd-C and the
resulting mixture stirred under 1 atm of H2 (balloon) for 12 h.
The suspension was filtered through Celite and evaporated
to obtain 230 mg of off-white solid (93%): [R]21
-59° (c
Hg-578
1.26 g (94%) of white foam: [R]24 ) +135° (c 0.8, CHCl3); 1H
0.6, MeOH); 1H NMR (acetone-d6) δ 7.50-7.25 (13H), 6.47 (s,
2H), 5.54 (s, 2H), 5.41 (s, 1H), 3.74 (s, 3H), 1.37 (s, 9H); 13C
NMR (acetone-d6) δ 171.51, 170.29, 170.04, 151.08, 139.90,
138.05, 135.80, 134.44, 129.43, 129.18, 128.92, 128.47, 128.38,
128.26, 107.64, 79.53, 60.50, 59.35, 58.81, 57.32, 57.13; FAB-
HRMS (glycerol/NBA/CsI/NaI) m/z 712.1249 (MCs+),
D
NMR (CD3NO2) δ 7.48-7.36 (5H), 6.76 (bs, 1H), 6.03 (d, 1H,
J ) 5.7 Hz), 5.31 (d, 1H, J ) 5.7 Hz), 1.41 (s, 9H); 13C NMR
(CD3NO2) δ 173.94, 156.74, 138.46, 130.28, 129.92, 128.74,
81.38, 58.88, 28.60; FABHRMS (glycerol/CsI/NaI) m/z 252.1235
(MH+), C13H17NO4 requires 252.1236.
2-(Tr im et h ylsilyl)et h yl (2R)-2-{(R)-1-[(S)-1-[(ter t-Bu -
toxyca r bon yl)a m in o]-1-(p h en ylm eth yl)ca r boxa m id o]-1-
[[3,5-bis(ben zyloxy)-4-m eth oxyp h en yl]m eth yl]ca r boxa -
m id o}-2-p h en yleth a n oa te (26). To a solution of the amine
25 (480 mg, 0.77 mmol), (S)-N-Boc-Phg (231 mg, 0.92 mmol,
1.2 equiv), and HOAt (104 mg, 0.77 mmol, 1.0 equiv) in 7.5
mL of DMF-CH2Cl2 mixture (1:2 v/v) at 0 °C was added EDCI
C
30H33N3O9Cs requires 712.1268.
η6-{1-(2S)-2-[(ter t-Bu toxycar bon yl)am in o]-3-oxo-3-m eth -
oxy]p r op yl-4-ch lor o}ben zen e-η5-cyclop en ta d ien ylr u th e-
n iu m Hexa flu or op h osp h a te (29). A mixture of methyl ester
or (S)-N-Boc-4-chlorophenylalanine (300 mg, 0.96 mmol) and
[CpRu(CH3CN)3]PF6 (600 mg, 1.39 mmol) was refluxed in
dichloroethane for 4 h. The solution was cooled, filtered

3098 J . Org. Chem., Vol. 63, No. 9, 1998
Pearson and Chelliah
through a Celite pad, and evaporated. The residue was
dissolved in CH3CN and filtered through neutral alumina, and
the solution was evaporated to obtain 590 mg of dark brown
foam (98%). The compound showed spectral properties identi-
cal to the (R)-enantiomer reported earlier by us.
et h ylca r b oxa m id o]-1-(p h en ylm et h yl)ca r b oxa m id o}-5-
h yd r oxy-4-m et h oxy-9,12-d ioxo-11-p h en yl-2-oxa -10,13-
d ia za t r icyclo[14.2.2.13,7]h en icosa -1(18),3(21),4,6,16,19-
h exa en e-14-ca r b oxyla t e}r u t h en iu m H exa flu or op h os-
p h a te (33). A solution of 31 (17 mg, 16 µmol) in 1.1 mL of
7:3:1 mixture of CH2Cl2-TFA-DMS was stirred at 0 °C for 2
h, after which time the solution was evaporated. The residue
was dissolved in 1 mL of MeOH, and to this was added 1 drop
of 6 N HCl. The solvent was evaporated, and the residue was
chased with dry ether and dried under vacuum to obtain the
amine hydrochloride. To this was added 19 mg (31 µmol, 2.0
equiv) of ruthenium complex 7, 12 mg of HATU (32 µmol, 2.0
equiv), and 500 µL of DMF. The solution was cooled to 0 °C,
and to this was added 11 µL of DIPEA (63 µmol, 4.0 equiv).
The solution was stirred at 0 °C for 1 h and at 21 °C for 4 h.
The reaction was quenched with aqueous citric acid and
diluted with 15 mL of propionitrile. It was washed with 3 ×
10 mL of 1 N HCl and 2 × 10 mL of aqueous NaHCO3 and
dried over Na2SO4. The solution was filtered, concentrated,
and treated with dry ether and filtered to obtain 23 mg (81%)
of dark solid: 1H NMR (CD3CN-CDCl3) δ 7.52 (d, 1H, J )
8.2 Hz), 7.50 (d, 1H, J ) 8.3 Hz), 7.48-7.16 (12H), 7.13 (d,
1H, J ) 8.3 Hz), 7.12 (d, 1H, J ) 8.4 Hz), 6.87 (d, 1H, J ) 8.4
Hz), 6.86 (d, 1H, J ) 8.3 Hz), 6.40-6.33 (3H), 6.07 (d, 1H, J )
6.1 Hz), 5.95 (d, 1H, J ) 5.4 Hz), 5.76 (bs, 1H), 5.70 (d, 1H, J
) 2.0 Hz), 5.43-5.22 (7H), 5.04-4.95 (m, 1H), 4.83 (d, 1H, J
) 5.3 Hz), 4.31-4.24 (m, 1H), 3.94 (s, 3H), 3.70 (s, 3H), 3.46
(dd, 1H, J ) 13.8 Hz, 4.7 Hz), 3.17 (dd, 1H, J ) 12.6 Hz, 4.6
Hz), 2.73 (dd, 1H, J ) 13.8 Hz, 13.0 Hz), 2.53 (dd, 1H, J )
12.6 Hz, 8.2 Hz), 1.32 (s, 9H).
(η5-Cyclop en t a d ien -1-yl){m et h yl (2S)-2-{(R)-1-[(R)-1-
[(S)-1-[(ter t-Bu t oxyca r b on yl)a m in o]-1-(p h en ylm et h yl)-
ca r boxa m id o]-1-[(3,5-d ih yd r oxy-4-m eth oxyp h en yl)m eth -
y l]c a r b o x a m id o ]-1-(p h e n y lm e t h y l)c a r b o x a m id o}-3-
((1,2,3,4,5,6,-η)-4-ch lor op h en yl)p r op a n oa t e}r u t h en iu m
Hexa flu or op h osp h a te (30). To a flask containing the
complex 29 (220 mg, 0.35 mmol) was added 3 mL of CH2Cl2
followed by 1 mL of trifluoroacetic acid, and the solution was
stirred for 2 h at 0 °C. The solvent was evaporated, and the
residue was dissolved in ∼1 mL of MeOH. To this was added
120 µL of 6 N HCl (0.72 mmol, 2.0 equiv), and the solvent was
evaporated. The residue was chased with dry ether and dried
under vacuum to obtain the crude amine hydrochloride. To
this were added tripeptide 28 (0.32 mmol), HATU (159 mg,
0.42 mmol, 1.5 equiv), and 3.5 mL DMF. The solution was
cooled to 0 °C, and 128 µL of TMP was added (0.97 mmol, 3.0
equiv). The mixture was stirred at 0 °C for 1 h and at room
temperature for 2 h. It was quenched with aqueous citric acid
and diluted with 50 mL of propionitrile. The organic layer
was washed with 3 × 30 mL 1 N HCl and dried over Na2SO4.
The solution was filtered and concentrated. It was treated
with dry ether, and the resulting precipitate was collected by
filtration to provide 209 mg of dark brown solid. Due to
difficulty in purifying this product, it was used as such for the
next step.
Cycliza tion of 30. To a flask containing the ruthenium
complex 30 (40 mg, 37 µmol) and Cs2CO3 (60 mg, 0.18 mmol,
5 equiv) was added 4 mL of dry DMF, and the mixture was
stirred at 22 °C for 6 h. The solution was cooled to 0 °C,
quenched with aqueous citric acid, and diluted with 30 mL of
propionitrile. The organic layer was washed with 2 × 15 mL
of H2O and then evaporated. The residue was dissolved in 20
mL of CH3CN, degassed with Ar, and photolyzed for 22 h. The
solution was concentrated, and the residue was purified by
preparative TLC (SiO2 gel, 0.5 mm thickness, 5:95 MeOH-
CHCl3) to provide 15 mg of 31 (less mobile) and 5 mg of 32
(more mobile) (74% combined yield).
Meth yl (14S,17R,20R,23S,26R)-26-[(ter t-Bu toxyca r bo-
n yl)a m in o]-35-m e t h oxy-16,19,22,25-t e t r a oxo-17,23-d i-
p h e n y l-2,8-d i o x a -15,18,21,24-t e t r a a z a p e n t a c y c lo -
[26.2.2.29,12.13,7.05,20]p en t a t r ia con t a -1(30),3(35),4,6,9,11,
28,31,33-n on a en e-14-ca r boxyla te (3). To a flask containing
the ruthenium complex 33 (20 mg, 16 µmol) and Cs2CO3 (27
mg, 83 µmol, 5.0 equiv) was added 3.3 mL of DMF (∼5 mM
concentration), and the solution was stirred at 25 °C for 6 h.
The reaction was quenched with aqueous citric acid at 0 °C
and diluted with 15 mL of propionitrile. It was washed with
3 × 10 mL of H2O and evaporated, and the residue was
dissolved in 20 mL of CH3CN, degassed with Ar and photolyzed
(Rayonet 350 nm) for 22 h. The solution was concentrated,
and the product was purified by preparative TLC (SiO2 gel,
0.5 mm thickness, 4:96 MeOH-CHCl3) to obtain 10 mg (70%)
Met h yl (8R,11R,14S)-8-[(S)-1-a m in o-1-(p h en ylm et h -
yl)ca r b oxa m id o]-5-h yd r oxy-4-m e t h oxy-9,12-d ioxo-11-
p h e n yl-2-oxa -10,13-d ia za t r icyclo[14.2.2.13,7]h e n icosa -
1(18),3(21),4,6,16,19-h exa en e-14-ca r boxyla te (31): Rf 0.24
of 3: Rf 0.52 (4:96 MeOH-CHCl3); [R]21
-66° (c 0.2,
Hg-578
1
CHCl3); 1H NMR (CD3CN-CDCl3) δ 8.03 (bs, 1H), 7.62 (d, 1H,
J ) 8.0 Hz), 7.43-7.09 (15H), 7.04 (d, 2H, J ) 7.6 Hz), 6.73
(d, 2H, J ) 8.1 Hz), 6.35 (bs, 1H), 6.14 (d, 1H, J ) 6.9 Hz),
5.89 (s, 1H), 5.63 (s, 1H), 5.57 (d, 1H, J ) 6.9 Hz), 5.50 (d, 1H,
J ) 8.7 Hz), 5.13 (d, 1H, J ) 8.0 Hz), 5.08-4.99 (m, 1H), 4.66-
4.62 (m, 1H), 4.10 (s, 3H), 3.66 (s, 3H), 3.46 (dd, 1H, J ) 8.0
Hz, 6.5 Hz), 3.11 (dd, 1H, J ) 8.0 Hz, 7.1 Hz), 2.72 (dd, 1H, J
) 12.5 Hz, 10.1 Hz), 2.61 (t, 1H, J ) 12.5 Hz), 1.4 (s, 9H);
FABHRMS (glycerol/NBA/NaI/CsI) m/z 1016.2485 (MCs+),
(5:95 MeOH-CHCl3); H NMR (CD3CN-CDCl3) δ 7.51-7.15
(12H), 7.13 (d, 1H, J ) 8.3 Hz), 7.12 (d, 1H, J ) 8.3 Hz), 7.07
(d, 1H, J ) 5.7 Hz), 6.89 (d, 1H, J ) 8.3 Hz), 6.88 (d, 1H, J )
8.3 Hz), 6.37 (d, 1H, J ) 5.1 Hz), 5.82 (bs, 1H), 5.71 (d, 1H, J
) 2.1 Hz), 5.28 (d, 1H, J ) 8.2 Hz), 5.09 (1H, J ) 6.8 Hz), 4.99
(ddd, 1H, J ) 12.9 Hz, 10.3 Hz, 4.5 Hz), 4.89 (d, 1H, J ) 5.7
Hz), 3.96 (s, 3H), 3.73 (s, 3H), 3.45 (dd, 1H, J ) 12.9 Hz, 4.5
Hz), 2.70 (t, 1H, J ) 12.9 Hz), 1.34 (s, 9H); 13C NMR (CD3-
CN-CDCl3) δ 182.74, 171.72, 171.10, 169.02, 154.84, 154.12,
151.01, 150.61, 138.33, 134.34, 133.06, 132.10, 130.92, 129.32,
129.05, 128.77, 128.32, 127.72, 126.80, 122.73, 122.13, 118.55,
117.14, 111.28, 106.74, 61.34, 59.61, 59.18, 55.64, 53.13, 52.79,
38.15, 29.41, 28.31; FABHRMS (glycerol/NBA/CsI/NaI) m/z
871.1936 (MCs+), C40H42N4O10Cs requires 871.1952.
C
49H49N5O11Cs requires 1016.2486.
Ack n ow led gm en t. We are grateful to the National
Institutes of Health, General Medical Sciences, for
financial support (GM 36925). Special thanks are ex-
tended to Dr. Gilles Bignan for his early work on the
cycloetherification reactions employed in this work and
in developing the synthesis and peptide-coupling reac-
tions of ruthenium complex 29.
Met h yl (8R,11S,14S)-8-[(S)-1-a m in o-1-(p h en ylm et h -
yl)ca r b oxa m id o]-5-h yd r oxy-4-m e t h oxy-9,12-d ioxo-11-
p h e n y l-2-o x a -10,13-d i a z a t r i c y c lo [14.2.2.13 , 7 ]h e n i -
cosa -1(18),3(21),4,6,16,19-h exa en e-14-ca r b oxyla t e (32):
[R]21
-46° (c 0.3, CHCl3); 1H NMR (CD3CN) δ 7.70 (bs,
Hg-578
1H), 7.47 (d, 1H, J ) 8.3 Hz), 7.46 (d, 1H, J ) 8.3 Hz), 7.34-
7.26 (10H), 7.07 (d, 1H, J ) 8.2 Hz), 6.99 Hz (d, 1H, J ) 8.3
Hz), 6.98 (d, 1H, J ) 8.3 Hz), 6.66 (d, 1H, J ) 7.1 Hz), 6.23
(bs, 1H), 5.83 (s, 2H), 5.49 (d, 1H, J ) 8.2 Hz), 5.33 (d, 2H, J
) 5.4 Hz), 4.20-4.14 (m, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 3.47
(dd, 1H, J ) 14.0 Hz, 4.5 Hz), 2.89 (dd, 1H, J ) 14.0 Hz, 7.5
Hz), 1.34 (s, 9H); FABHRMS (glycerol/NBA/CsI/NaI) m/z
871.1952 (MCs+), C40H42N4O10Cs requires (871.1892).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for new compounds, including concentration effects on
the 1H NMR spectrum of tripeptide 26 (45 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.
(η5-Cyclop en ta d ien -1-yl){m eth yl (8R,11R,14S)-8-{(S)-1-
[(1R)-1-[(ter t-bu toxyca r bon yl)a m in o]-2-(4-ch lor op h en yl)-
J O980060B