Full details of a diastereoselective total synthesis of the vancomycin aglycon are described. Two key aromatic nucleophilic substitution macrocyclizations with formation of the 16-membered diaryl ethers were enlisted for sequential CD and DE ring formations, an effective macrolactamization was developed for closure of the 12-membered biaryl AB ring system, and the defined order of CD, AB, and DE ring closures permitted selective thermal atropisomerism of the newly formed ring systems or their immediate precursors. This indirect control of the atropisomer stereochemistry allowed all synthetic material to be funneled into the one of eight atropdiastereomers characterizing the natural product.

The degradation of vancomycin to a series of aglucovancomycin derivatives containing modifications in key functional groups and a study of their thermal atropisomerism are detailed. In all of the cases, selective isomerism of the DE ring system atropisomers was observed under conditions where the CD and AB stereochemistries were unaffected. Competitive retro aldol ring cleavage of the CD and DE ring systems (CD > DE) was observed but could be minimized by the choice of solvent and thermal conditions (DE ring system) or precluded by alcohol protection (CD ring system). Similarly, competitive main chain succinimide formation through the loss of ammonia from the Asn residue could be minimized by the choice of thermal conditions or prevented by carboxamide protection. Resynthesis of natural aglucovancomycin, (M,M,M)-2, and its unnatural DE atropisomer (P,M,M)-2 from 6 are described. The comparative antimicrobial activity of the key derivatives and their unnatural DE ring system P-diastereomers are disclosed.

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Teicoplanin 1,2 is a complex of five antibiotics isolated from Actinoplanes teichomyceticus that are related to vancomycin [3][4][5][6][7][8] which is enlisted as the drug of last resort for treatment of resistant bacterial infections or for patients allergic to -lactam antibiotics. 6 It is 2-8-fold more potent, possesses a lower toxicity, exhibits a longer half-life in man (40 vs 6 h), and is easier to administer and monitor than vancomycin.Herein we describe the first total synthesis of the teicoplanin aglycon (1). 9-12 Although teicoplanin bears the identical ABCD ring system and the same CDE atropisomer stereochemistry as vancomycin, it contains a DE ring system that lacks the -hydroxy group of the vancomycin E-ring substituted phenylalanine (C 2 residue) and incorporates an especially racemization prone substituted phenylglycine C 3 residue. 13 Most significantly, it contains the additional 14-membered FG ring system not found in vancomycin. Key elements of the approach include sequential DE and FG ring system introductions onto the common vancomycin/teicoplanin ABCD ring system providing a late stage divergent total synthesis of the two classes of glycopeptide antibiotics. The ring systems were introduced enlisting a nucleophilic aromatic substitution reaction of an o-fluoronitroaromatic for macrocyclization and formation of the 16-membered DE diaryl ether and a macrolactamization 14 of the N-terminus amide for closure of the 14-membered FG ring system. With the respective order of closures, the choice of substrates, and the conditions enlisted, no epimerization of the sensitive C 2 3 center was observed.Because of the facile C 2 3 epimerization observed within the confines of the teicoplanin FG ring system, 13 the FG diaryl ether was formed using an intermolecular nucleophilic aromatic substitution reaction with acyclic phenylglycinol substrates incapable of epimerization. Thus, coupling of 2 15 and 3 16 (6 equiv of K 2 CO 3 , 5 equiv of 18-c-6, 0.1 M DMSO, 14 h, 25°C) provided 4 (70%), Scheme 1. Reactions conducted in DMSO were substantially faster than those conducted in DMF and the (1) Parenti, F.; Beretta, G.; Berti, M.; Arioli, V. J. Antibiot. 1978, 31, 276. (2) Hunt, A. H.; Molloy, R. M.; Occolowitz, J. L.; Marconi, G. G.; Debono, M. J. Am. Chem. Soc. 1984, 106, 4891. Barna, J. C. J.; Williams, D. H.; Stone, D. J. M.; Leung, T.-W. C.; Doddrell, D. M. J. Am. Chem. Soc. 1984, 106, 4895. (3) McCormick, M. H.; Stark, W. M.; Pittenger, G. E.; Pittenger, R. C.; McGuire, J. M. Antibiot. Annu. 1955-1956, 606. (4) Harris, C. M.; Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983, 105, 6915. Williamson, M. P.; Williams, D. H. (10) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Bräse, S.; Rübsam, F. Chem. Eur. J. 1999, 5, 2584. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602. Nicolaou, K. C.; Koumbis, A. E.; Takayanagi, M.; Natarajan, S.; Ja...

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

Self-assembled monolayers (SAMs) of 4-pyridineethanethiol (4-PyEtS) formed on a Au(111) surface were investigated in aqueous electrolyte solutions by cyclic voltammetry and in situ scanning tunneling microscopy (STM). On the basis of reductive desorption of 4-PyEtS on Au(111), the reduction peak potential was found to be -0.86 V vs. Ag/AgCl (sat. KCl). The surface excess was calculated from the reductive desorption peak area to be 5.4 x 10(-10) mol cm(-2). High-resolution STM images revealed that a p(5 x radical3 R-30 degrees ) lattice including two molecules was found in 0.1 M NaClO(4), whereas the 4-PyEtS-SAMs formed a p(10 x radical3 R-30 degrees ) lattice constituting four molecules in 0.05 M HClO(4). The transition from a p(10 x radical3 R-30 degrees ) to a p(5 x radical3 R-30 degrees ) in the 4-PyEtS-SAMs was directly observed by changing pH of the electrolyte solution, indicating that the conformational change in 4-PyEtS-SAMs is driven by protonation/deprotonation. The present results obtained by STM observation are also supported by the clear pH dependence of the pyridine moiety in the surface-enhanced infrared spectrum.

The degradation of teicoplanin to a series of key aglycon derivatives, including those containing a cleaved FG ring system, and a study of their thermal atropisomerism are detailed. In all cases, selective equilibration of the DE ring system was observed to provide a 1:1 mixture of P:M atropisomers under conditions in which the AB and CD atropisomer stereochemistry were unaffected. The DE atropisomer equilibration was found to occur with an E a of 29.3 and 24.8-25.2 kcal/mol for 6a (FG ring system intact) and 10/12 (cleaved FG ring system), respectively, which is comparable to that of a vancomycin aglycon DE ring system (E a ) 23.6 kcal/mol) and more facile than the CD (E a ) 30.4 kcal/mol) or O-methylated AB ring system (E a ) 37.8 kcal/mol). Consistent with intuitive expectations, the intact teicoplanin FG ring system slowed the rate of isomerization, contributing ca. 4.0 kcal/mol to the E a (6a vs 10), and the bulky C 2 3 substituent on teicoplanin acyclo FG derivatives had a much less significant effect, contributing only 1-1.5 kcal/mol to the E a relative to the vancomycin aglycon. Neither precludes selective equilibration of the DE ring system, and neither had an effect on the thermodynamic ratio of the resulting atropisomers (1:1). Resynthesis of the teicoplanin aglycon (P,P,P-2) from 8 as a prelude to the synthesis of the teicoplanin aglycon unnatural DE atropisomer (M,P,P-17) from 13 is described and provides the final stages of a teicoplanin aglycon total synthesis and a key structural analogue. The comparative evaluation of 2 and 17 revealed that the DE atropisomer stereochemistry substantially impacts the antimicrobial activity (2 > 17, 50-fold) and the binding affinity for N,N′-Ac 2 -L-Lys-D-Ala-D-Ala (2 > 17, K a ) 2.4 × 10 6 vs 1.9 × 10 4 M -1 , 125 times).

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