Synthetic studies on the DEF ring system of ristocetin A via ruthenium-promoted S(N)Ar reaction: Problems and solutions using arylserine-Ru complexes

Article abstract of DOI:10.1016/S0040-4039(00)00855-8

Ruthenium-promoted intramolecular S(N)Ar reaction has allowed the construction of the 16-membered DEF model macrocycle of ristocetin A that incorporates the required arylserine residue as the E ring. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00855-8

Tetrahedron Letters 41 (2000) 5991±5996
Synthetic studies on the DEF ring system of ristocetin A via
ruthenium-promoted SNAr reaction: problems and solutions
using arylserine±Ru complexes
Anthony J. Pearson* and Jung-Nyoung Heo
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA
Received 2 May 2000; revised 23 May 2000; accepted 24 May 2000
Abstract
Ruthenium-promoted intramolecular SNAr reaction has allowed the construction of the 16-membered
DEF model macrocycle of ristocetin A that incorporates the required arylserine residue as the E ring.
# 2000 Elsevier Science Ltd. All rights reserved.
The vancomycin group of antibiotics1 is of considerable interest because of its clinical
importance as well as the complexity of these molecules. Furthermore, the recent upsurge of
vancomycin-resistant strains of infectious bacteria2 provides the impetus for the development of
total syntheses3 of vancomycin analogues. Ristocetin A (1) has structural features that are similar
to vancomycin (2), but incorporates an additional 14-membered biaryl ether connection between
amino acid residues F and G. The construction of the biaryl ether linkage in these structures has
posed a considerable challenge due to the presence of base-sensitive amino acid residues,
especially arylglycine derivatives.4 Our group has extensively studied ruthenium-promoted SNAr
reactions for the formation of biaryl ethers.5 This chemistry allows: (1) complexation with
ruthenium under very mild conditions; (2) etheri®cation without appreciable racemization of aryl-
glycines as well as phenylalanine subunits; and (3) demetallation under simple photolytic conditions.
* Corresponding author. Fax: (+1)216-368-3006; e-mail: ajp4@po.cwru.edu
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00855-8

5992
The main objective of the study reported herein was to establish the feasibility of applying
ruthenium-promoted SNAr chemistry to arylserine substrates (5). For this purpose we designed
target molecule 3 (Scheme 1) in which the C-terminus of the central amino acid D would be
protected as its N-methyl amide to prevent the facile epimerization of this arylglycine,3a since
previous work has shown that the corresponding methyl ester is easily and totally epimerized
under basic conditions.6
Scheme 1.
The synthesis of arylserine derivative 12 corresponding to the ruthenium complex 5 was based
on the Sharpless asymmetric dihydroxylation reaction7 (Scheme 2). Ethyl (E)-4-chlorocinnamate
(7), prepared by Fischer esteri®cation of (E)-4-chlorocinnamic acid (6), was subjected to asymmetric
dihydroxylation by treatment with the AD-mix-b (1.4 g/mmol) reagent and CH3SO2NH2 (1.0
equiv.) in t-BuOH:H2O (1:1) to provide ethyl (2S,3R)-3-(4-chlorophenyl)-2,3-dihydroxy-
propionate (8) in good yield (80%, ‰ꢀŠ2D5=^14 (c 1.2, EtOH)) and high ee (74% ee, determined by
Mosher ester analysis).8 One recrystallization from 50% EtOAc±hexanes enriched 8 to >99% ee
(‰ꢀŠ2D5=^19ꢀ (c 1.0, EtOH)).
Scheme 2.

5993
Reaction of 8 with 4-nitrobenzenesulfonyl chloride (nosyl chloride, 1.0 equiv.) and Et3N (1.5
equiv.) in methylene chloride at 3ꢀC provided a-nosylate 9 (75%) resulting from the acidity
di€erence of the two alcohols.9 In addition, a small amount (12%) of the a,b-unsaturated ester
product, derived from elimination of the disulfonated intermediate, was isolated. Subsequent
azide replacement of the sulfonate (NaN3 (1.5 equiv), DMF, 50ꢀC, 10 h, 81%) gave 10 as a
syn:anti (1:9) mixture, which was separated by chromatography. Subsequent reduction of azide 10
(SnCl2 (2.0 equiv.), MeOH, 25ꢀC, 3 h) and Boc protection ((Boc)2O (2.0 equiv.), NaHCO3 (4.0
equiv.), THF:H2O (1:1), 25ꢀC, 23 h, 90% for two steps) provided 11, which was converted to the
arylserine 12 (LiOH (2.0 equiv.), THF:H2O (1:1), 0ꢀC, 2 h, 99%). Finally, complexation of 12
with [CpRu(CH3CN)3]PF6 was accomplished under the conventional reaction conditions
(ClCH2CH2Cl, re¯ux, 2.5 h) to provide Z6-arene-ruthenium complex 5 in good yield.10
With the arene-ruthenium complex 5 in hand, we investigated the ruthenium-promoted SNAr
chemistry as shown in Scheme 3. Our synthesis started with the azido acid 13, previously reported
by our group.11 The acid was masked as its methylamide (HOAt (1.5 equiv.), EDCI (1.2 equiv.),
CH3NH2 (3.0 equiv.), 0ꢀC (1 h) to rt (23 h), 91%) to provide 14. Subsequent azide reduction (H2,
Pd/C, 6N HCl, MeOH/THF, 12 h) and coupling with (S)-ZPhg in the presence of HOAt (1.5
equiv.), EDCI (1.2 equiv.), and TMP (2.0 equiv.) provided the dipeptide 4 (90%).
Scheme 3.
Several attempts to prepare the tripeptide-ruthenium complex 15 under standard coupling
conditions gave unsatisfactory results (less than 20% yield). In order to examine the coupling
reaction in more detail, we carried out the reaction of the dipeptide 4 and the arylserine 12, not
having the attached ruthenium, which gave the tripeptide 16 in excellent yield (Scheme 4). This
result indicated that the coupling reaction with the ruthenium complex 5 was likely proceeding
eciently, but the normal work-up procedure by extraction with propionitrile, we thought, could
be a problem because of the low solubility of the product. Accordingly, the DMF solvent was
removed in vacuo after the coupling reaction (HOAt (3.3 equiv.), EDCI (3.0 equiv.), DIPEA
(1.05 equiv.), DMF, 0ꢀC (3 h) to rt (21 h)) and the crude product was isolated by adding pro-

5994
pionitrile. The resulting dark brown solid was ®ltered, washed (cold H2O, ethyl ether), and dried
1
to give the desired product (58%). In addition to H NMR and FABHRMS to con®rm the
structure 15, demetallation reaction also furnished the same product 16 as synthesized from 4.
Intramolecular etheri®cation of 15 was achieved under basic conditions (potassium 2,6-di-t-
butylphenoxide (2.0 equiv.), 18-crown-6 (1.0 equiv.), DMF, ^78ꢀC to rt, 4 h) at low concentration
(10 mM) to give a cyclized ruthenium intermediate, which was subjected directly to photolysis
(350 nm, CH3CN, 24 h) to provide the cyclized biaryl ether tripeptide 3 in 30% overall yield. The
1
cyclization was easily con®rmed by the H NMR (CD3OD, 300 MHz) spectrum of 3, which
showed that one of the two aromatic protons at the central phenyl D was shifted up®eld due to
the shielding e€ect of the neighboring ether linked phenyl group (ꢁ 5.58 ppm).6 It is especially
noteworthy that epimerization among the chiral centers was not observed during this reaction
sequence. Nonetheless, the problems caused by low solubility of complexes such as 15 are cause
for concern, and we decided to investigate a means of ameliorating this situation.
Scheme 4.
In order to improve the solubility of the tripeptide-ruthenium complex 15, the benzylic hydroxy
group was converted to its silyl ether (Scheme 5). Thus, 11 was treated with TBSOTf (1.5 equiv.)
and 2,6-lutidine (2.0 equiv.) in CH2Cl2 to provide the TBS protected compound 17 in 79% yield.
Hydrolysis of ester 17 was carried out by using lithium hydroxide monohydrate (2.0 equiv.) in
t-buthanol:H2O (3:1) to obtain the acid 18 in 85% yield (‰ꢀŠ2D5=^45 (c 0.8, 95% EtOH); after
recrystallization from 20% EtOAc±hexanes). Compared to the hydrolysis of hydroxy ester 11, 17
required a more protic solvent system and increased reaction temperature. The resulting arylserine
18 was complexed with [CpRu(CH3CN)3]PF6 by using the same conditions as previous to give the
arene-ruthenium complex 19 in good yield. Prolonged reaction time (>2 h) led to the formation
of the desilylated side product 5.
Scheme 5.

5995
Coupling of the dipeptide 4 with the arene-ruthenium complex 19 provided tripeptide-ruthenium
complex 20 in good yield, and without epimerization, with signi®cant improvement of its solubi-
lity (Scheme 6). Now, the tripeptide ruthenium complex can be conveniently used in less polar
organic solvents such as THF and CH2Cl2. Treatment of 20 with Cs2CO3 (5 equiv.) in DMF (5±10
mM), followed by photolysis (Rayonet 350nm, 24 h) in CH3CN, e€ected its smooth conversion to
25
macrocycle 21 (‰aŠ = ^13.2ꢀ (c 0.6, MeOH)) in good yield without epimerization.
D
Scheme 6.
At this point we were concerned about the possibility of the complete inversion of con®guration
at the central amino acid D, as we had earlier noted in the case of the corresponding methyl ester
under the same basic conditions.6 Since this epimerization is thermodynamically driven to
completion, it would go unnoticed during the cycloetheri®cation. Therefore, we carried out the
same macrocyclization starting from racemic azido amide 14. Through all the coupling steps the
tripeptide ruthenium complex maintained its diastereomeric ratio (1:1). Cyclization under
standard conditions provided two macrocyclic products in 1:1 ratio arising from the original
amide-terminal mixture. These results establish that the N-methyl amide derivative is e€ective for
suppressing this epimerization, as a result of the lower acidity of the benzylic proton.
Conclusions: A 16-membered DEF model of ristocetin A was prepared by using ruthenium-
promoted intramolecular SNAr reaction under conditions that were mild enough to avoid
epimerization, when the C-terminal of the central amino acid D was protected as the N-methyl
amide linkage. Application of ruthenium-arylserine complex was successful for the construction
of the biaryl ether linkage. The e€orts developed here can be extended to the total synthesis of
ristocetin and related molecules.
Acknowledgements
We are grateful to the National Institutes of Health for ®nancial support of this research
(GM-36925), and to Mariappan Chelliah for preliminary work leading to this study.
References
1. (a) Williams, D. H. Acc. Chem. Res. 1984, 17, 364±369. (b) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed.
1999, 38, 1172±1193.
2. Walsh, C. T.; Fisher, S. L.; Park, I.-S.; Parhalad, M.; Wu, Z. Chem. Biol. 1996, 3, 21.

5996
3. (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±2707. (c) Nicolaou, K. C.; Natarajan, S.; Li, H.;
Jain, N. F.; Hughes, R.; Solomon, M. E.; Ramanjulu, J. M.; Boddy, C. N.; Takayanagi, M. Angew. Chem., Int.
Ed. 1998, 37, 2707±2714. (d) 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.
(e) Nicolaou, K. C.; Takayanagi, M.; Jain, N. F.; Natarajan, S.; Koumbis, A. E.; Bando, T.; Ramanjulu, J. M.
Angew. Chem., Int. Ed. 1998, 37, 2716±2719. (f) 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.
4. For reviews, see: (a) Evans, D. A.; DeVries, K. M. In Glycopeptide Antibiotics; Nagarajan, R., Ed.; Marcel
Dekker: New York, 1994; pp. 63±104. (b) Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S. Chem. Rev.
1995, 95, 2135±2167. (c) Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999,
38, 2096±2152.
5. (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.; Belmont, P. O. Tetrahedron Lett. 2000, 41, 1671±1675.
6. Pearson, A. J.; Chelliah, M. V. J. Org. Chem. 1998, 63, 3087±3098.
7. (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483±2547. (b) Sharpless, K. B.;
Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-
M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768±2771. (c) Boger, D. L.; Patane, M. A.; Zhou, J. J. Am.
Chem. Soc. 1994, 116, 8544±8556.
8. Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143±2147.
9. Fleming, P. R.; Sharpless, K. B. J. Org. Chem. 1991, 56, 2869±2875.
10. Pearson, A. J.; Park, G. W. J. Org. Chem. 1992, 57, 1744±1752.
11. Pearson, A. J.; Chelliah, M. V.; Bignan, G. C. Synthesis 1997, 536±540.