Approaches to the fully functionalized DEF ring system of ristocetin A via highly selective ruthenium-promoted SNAr reaction

Article abstract of DOI:10.1021/ol000180h

Ruthenium-promoted intramolecular S_NAr reaction has allowed the construction of the fully functionalized 16-membered DEF macrocycle 4 of ristocetin A that incorporates the required arylglycine and arylserine residues as the F and E ring, respectively.

Full text of DOI:10.1021/ol000180h

ORGANIC
LETTERS
2000
Vol. 2, No. 19
2987-2990
Approaches to the Fully Functionalized
DEF Ring System of Ristocetin A via
Highly Selective Ruthenium-Promoted
SNAr Reaction
Anthony J. Pearson* and Jung-Nyoung Heo
Department of Chemistry, Case Western ReserVe UniVersity, CleVeland, Ohio 44106
ajp4@po.cwru.edu
Received July 7, 2000
ABSTRACT
Ruthenium-promoted intramolecular SNAr reaction has allowed the construction of the fully functionalized 16-membered DEF macrocycle 4 of
ristocetin A that incorporates the required arylglycine and arylserine residues as the F and E ring, respectively.
Ristocetin A (1), a glycopeptide related to vancomycin (2),
is an antibiotic1 produced by the microorganism Nocardia
lurida (Figure 1). Vancomycin is currently in clinical use
and is well-known as the “antibiotic of last resort” in
hospitals. Ristocetin A was also clinically employed to treat
bacterial infections in the late 1950s, but undesirable side
effects led to its discontinuation. Teicoplanin (3) is a
potentially useful experimental drug. Recently, the increasing
incidence of vancomycin-resistant strains of infectious
bacteria,2 as well as the challenging molecular architecture
of these antibiotics, has evoked considerable interest in the
total synthesis of these compounds.
an additional 14-membered ring with biaryl ether connection
between amino acid residues F and G. Only recently have
total syntheses of vancomycin and its aglycon been
accomplished.4-6 Our own efforts have focused on construc-
(3) For reviews, see: (a) Nicolaou, K. C.; Boddy, C. N. C.; Bra¨se, S.;
Winssinger, N. Angew. Chem., Int. Ed. 1999, 38, 2096-2152. (b) Evans,
D. A.; DeVries, K. M. In Glycopeptide Antibiotics; Nagarajan, R., Ed.;
Marcel Dekker: New York, 1994; pp 63-104. (c) Rao, A. V. R.; Gurjar,
M. K.; Reddy, K. L.; Rao, A. S. Chem. ReV. 1995, 95, 2135-2167.
(4) (a) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.;
Barrow, J. C.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2700-2704.
(b) Evans, D. A.; Dinsmore, C. J.; Watson, P. S.; Wood, M. R.; Richardson,
T. I.; Trotter, B. W.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2704-
2708. (c) For an earlier synthesis of the orienticin C aglycon, see: Evans,
D. A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.; Barrow, J. C. J. Am.
Chem. Soc. 1997, 119, 3417-3418. 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-
3420.
(5) (a) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes, R.;
Solomon, M. E.; Ramanjulu, J. M.; Boddy, C. N. C.; Takayanagi, M. Angew.
Chem., Int. Ed. 1998, 37, 2708-2714. (b) Nicolaou, K. C.; Jain, N. F.;
Natarajan, S.; Hughes, R.; Solomon, M. E.; Li, H.; Ramanjulu, J. M.;
Takayanagi, M.; Koumbis, A. E.; Bando, T. Angew. Chem., Int. Ed. 1998,
37, 2714-2716. (c) Nicolaou, K. C.; Takayanagi, M.; Jain, N. F.; Natarajan,
S.; Koumbis, A. E.; Bando, T.; Ramanjulu, J. M. Angew. Chem., Int. Ed.
1998, 37, 2717-2719.
Molecules of this group generally have a heptapeptide
backbone structure with embedded biaryl ether and biphenyl
linkages.3 Both ristocetin A and teicoplanin have structural
features that are similar to vancomycin, but they incorporate
(1) (a) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38,
1172-1193. (b) Williams, D. H. Acc. Chem. Res. 1984, 17, 364-369.
(2) (a) Walsh, C. T.; Fisher, S. L.; Park, I.-S.; Parhalad, M.; Wu, Z.
Chem. Biol. 1996, 3, 21. (b) Henry, C. M. Chem. Eng. News 2000, 78(10),
41-43, 46-58.
10.1021/ol000180h CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/30/2000

Figure 1.
tion of the ristocetin and teicoplanin structures using
ruthenium-promoted SNAr reactions.7 Although we have
published Ru-based technology using a chloroarylserine-
RuCp complex as a key element for approaches to Ristocetin
synthesis,8 the work described herein represents a fairly
significant advance in this chemistry, allowing it to be used
successfully with a molecule that has competing functional-
ity. In the present work it is demonstrated that the DEF ring
system can be constructed using a fully functionlized F-ring
residue and without orthogonal protection steps, which sets
the stage for the final building of the entire ristocetin
molecule by using the “end-game” methodology that we have
reported. Herein we describe an efficient approach to the
fully functionalized DEF ring system (4) of ristocetin A that
will be useful for building on the final DEFG ring of
ristocetin and teicoplanin.9
dure,11 methyl ester 6 was obtained by Fischer esterification
[MeOH, p-TsOH‚H2O (0.2 equiv), reflux, 24 h, 80%].
Methylation of 6 [Me2SO4 (1.2 equiv), K2CO3 (2.0 equiv),
n-Bu4NI (0.2 equiv), reflux, acetone, 24 h] afforded the
monomethyl ether 7 (42%) along with the corresponding
bismethyl ether (33%). Subsequent benzylation of 7 [BnBr
(1.05 equiv), NaH (1.1 equiv), n-Bu4NI (0.1 equiv), THF,
room temperature, 2 h, 96%] provided 8, which was
subjected to reduction [LiAlH4 (1.5 equiv), THF, reflux, 2.5
h] and oxidation [PCC (3.0 equiv), CH2Cl2, room temper-
ature, 3 h] to give aldehyde 9 in 96% yield for two steps.
Methylenation of 9 via Wittig reaction [Ph3PdCH2 (2.0
equiv), THF, -78 °C to room temperature, 2 h, 95%]
afforded styrene 10, required for the Sharpless asymmetric
aminohydroxylation.
The terminal olefin 10 was converted to the corresponding
benzyloxyamino alcohol with a good regioselectivity (1°
alcohol 11:2° alcohol ) 4/1) and enantioselectivity (g90%
ee) under the typical reaction conditions [BnOCONH2 (3.1
equiv), t-BuOCl (3.05 equiv), NaOH (3.1 equiv), (DHQ)2-
PHAL (5 mol %), K2OsO2(OH)4 (4 mol %), n-PrOH/H2O/
Et2O (3:2:1), room temperatrue, 1 h, 80%]. In this reaction
the use of diethyl ether as cosolvent was necessary to
improve the solubility of styrene 10. The enantiomeric purity
of amino alcohol 11, separated by chromatography, was
determined by Mosher ester analysis.12 As a final step,
oxidation of 11 [TEMPO (1.05 equiv), NaOCl (2.0 equiv),
First, the requisite differentially protected F ring amino
acid was prepared by a Sharpless asymmetric aminohydroxy-
lation reaction10 (Scheme 1). Starting from 3,5-dihydroxy-
4-methylbenzoic acid (5), prepared by the literature proce-
(6) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Castle, S. L.;
Loiseleur, O.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 10004-10011.
(7) (a) Pearson, A. J.; Zhang, P.; Lee, K. J. Org. Chem. 1996, 61, 6581-
6586. (b) Pearson, A. J.; Bignan, G. Tetrahedron Lett. 1996, 37, 735-738.
(c) Pearson, A. J.; Lee, K. J. Org. Chem. 1995, 60, 7153-7160. (d) Pearson,
A. J.; Chelliah, M. V. J. Org. Chem. 1998, 63, 3087-3098.
(8) Pearson, A. J.; Heo, J.-N. Tetrahedron Lett. 2000, 41, 5991-5996.
(9) Pearson, A. J.; Belmont, P. O. Tetrahedron Lett. 2000, 41, 1671-
1675.
(10) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207-
1217.
(11) Borchardt, R. T.; Sinhababu, A. K. J. Org. Chem. 1981, 46, 5021-
5022.
2988
Org. Lett., Vol. 2, No. 19, 2000

Scheme 1
Scheme 2
KBr (0.14 equiv), 5% NaHCO3, acetone, 0 °C, 2.5 h] led to
carboxylic acid 12 in good yield ([R]25D ) +94, c 1.0, EtOH,
after recrystallization from Et2O). An alternative approach
for the oxidation of 12 was also successful using H5IO6/
CrO3 (66% yield).13
DMF] to provide the tripeptide-ruthenium complex 16 in
92% yield. It is noteworthy that little or no epimerization
was observed during the coupling reaction, according to the
1H NMR spectrum of 16.
With arylglycine 12 in hand, we have investigated the
synthesis of the fully functionalized DEF ring system as
shown in Scheme 2. Our synthesis started with azido amide
13, derived from the carboxylic acid previously reported by
our group.8,14 Simultaneous azide reduction and benzyl ether
deprotection of 13 (H2, Pd/C, 6 N HCl, MeOH/THF),
followed by coupling of the resulting amine salt with (S)-
arylglycine 12 [HOAt (1.5 equiv), EDCI (1.5 equiv), TMP
(2.0 equiv)]15 provided the dipeptide 14 in 91% yield. After
deprotection of both the benzyl carbamate and benzyl ether
of the dipeptide 14 (H2, Pd/C, 6 N HCl, MeOH/THF),
coupling with the arylserine-ruthenium complex 158 pro-
ceeded smoothly [HATU (2.0 equiv), TMP (2.2 equiv),
The macrocyclization using ruthenium-promoted SNAr
reaction on 16 could in principle lead to 16-membered and
13-membered diaryl ether rings by reaction of hydroxy
moieties on the D ring and on the F ring, respectively. Before
this step, of course, an orthogonally protected amino acid
corresponding to the F ring could be used to mask the free
hydroxy group. However, intramolecular cyclization was
expected to provide exclusively the 16-membered ring as a
result of the large ring strain of the 13-membered ring.
Computational studies16 predict a steric energy difference
of ∼18 kcal/mol favoring the 16-membered ring 4 (-26.775
kcal/mol) over 13-membered ring 17 (-8.508 kcal/mol).
Exposure of tripeptide-ruthenium complex 16 to Cs2CO3
(5.0 equiv) in DMF (5 mM), followed by photolytic
(12) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38,
2143-2147.
(13) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323-5326.
(14) Pearson, A. J.; Chelliah, M. V.; Bignan, G. C. Synthesis 1997, 536-
540.
(16) Molecular mechanics calculations were performed by using MM2
force field molecular modeling software, Chem3D.
(15) HOAt, 1-hydroxy-7-azabenzotriazole; EDCI, 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride; TMP, 2,4,6-trimethylpyridine;
HATU, O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexa-
flourophosphate.
(17) After this manuscript was submitted, a total synthesis of the
teicoplanin aglycon was disclosed by Boger et al.: Boger, D. L.; Kim, S.
H.; Mizayaki, S.; Strittmatter, H.; Weng, J.-H.; Mori, Y.; Rogel, O.; Castle,
S. L.; McAtee, J. J. J. Am. Chem. Soc. 2000, 122, 7416-7417.
Org. Lett., Vol. 2, No. 19, 2000
2989

to the hydroxyl are expected to show significant changes
upon etherification). One of the advantages of this selectivity
is that additional hydroxyl protection and deprotection steps
are not necessary, which will ultimately allow for construc-
tion of the DEFG ring system by intermolecular etherification
and intramolecular macroamidation as described by our
group.9,17
In summary, we have developed a convenient synthesis
of the fully functionalized DEF ring system of ristocetin A
using ruthenium-promoted SNAr chemistry. Indeed, the
regiospecific macrocyclization in favor of the 16-membered
ring promises an efficient approach to the final DEFG ring
system of ristocetin A and teicoplanin.
demetalation (Rayonet 350 nm, CH3CN) provided a single
compound, macrocycle 4 ([R]25D ) -19.1 (c 0.47, MeOH)),
1
in 61% yield. H NMR showed the characteristic chemical
Acknowledgment. We thank the National Institutes of
Health for financial support.
shift difference between the two ortho-protons on the D ring
corresponding to the 16-membered macrocycle, because Ha
is located within the shielding zone of the neighboring E
ring: δ 6.65 (d, 1H, J ) 1.5 Hz, Hb), 5.75 (d, 1H, J ) 1.5
Hz, Ha).7d,8 Another clear indication for formation of the 16-
membered ring is that the D-ring methoxy singlet is shifted
downfield approximately 0.2 ppm after cyclization, while
the F-ring methyl singlet remains unaffected (groups ortho
Supporting Information Available: Detailed experi-
mental procedures and spectral data for compounds 11, 12,
14, 16, and 4. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL000180H
2990
Org. Lett., Vol. 2, No. 19, 2000