Approaches to the Synthesis of the Vancomycin Antibiotics. Synthesis of Orienticin C (Bis-dechlorovancomycin) Aglycon

Abstract

In the preceding paper, we described the synthesis of the vancomycin-related M(4-6)(5-7) bicyclic subunit 3 (Scheme 1), 1,2 a structural motif common to all members of this family of antibiotics exemplified by vancomycin aglycon (1). 3 Herein we describe the first synthesis of the vancomycin-related heptapeptide nucleus and the transformation of this intermediate to orienticin C (bis-dechlorovancomycin) aglycon (2). 4Our original strategy for the construction of the biaryl ethercontaining rings was based on a successful study that demonstrated that these macrocycles, in the absence of the biarylcontaining M(5-7) ring, could be constructed through a Tl(III)mediated oxidative cyclization. 5 In the current plan, the N-terminal tripeptide 4 incorporating the 4,4′-dimethoxydiphenylmethyl (Ddm)-protected asparagine was employed for the construction of the final M(2-4) macrocyclic subunit. The selection of this protecting group was predicated on its favorable impact on epimerization during the fragment coupling, 6 on suppression of the aspartate-iso-aspartate rearrangement, 6 and on protection of this residue during selective derivatization of the N-methyl amide at the end of the synthesis. Given the complexity of these natural products, orienticin C aglycon (2) 4 was chosen as our initial target.Deprotection of the Boc-protected bicyclic tetrapeptide 3 (30% TFA, DMS, CH 2 Cl 2 , 0°C) and fragment coupling with the N-terminal tripeptide 4 7 was carried out under standard conditions (1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), THF, 0°C) to afford heptapeptide 5 in excellent yield with no detectable epimerization (Scheme 1). Removal of the ring-2 allyl ether provided 6, which was cyclized under the optimized conditions developed for the M(2-4)(4-6) bicycle 5 (Tl(NO 3 ) 3 ‚3H 2 O, 30:1 CH 2 Cl 2 /MeOH, room temperature (rt); CrCl 2 , 0°C) to provide the desired tricycle 7 in approximately 20% yield as an inseparable mixture with two other unidentifiable byproducts. In spite of an extensive reevaluation of this methodology, no improvement in yield for this critical transformation could be achieved. We conclude that the enhanced rigidity of the biaryl-containing M(4-6)(5-7) bicycle, in comparison to that of the M(4-6) monocyclic counterpart employed in the model studies, 5,8 could be responsible for the failure of this transformation. A detailed investigation of this reaction will be published elsewhere. 9 Rather than proceeding with a substandard cyclization step, other diaryl ether-forming macrocyclization strategies were considered. On the basis of the existing precedent provided by Beugelmans, Rao, and Boger, 10 the nitroaromatic-based S N -Ar methodology was evaluated. Accordingly, the refunctionalization of bicyclic tetrapeptide 3 to phenol 8 was undertaken (Scheme 2). Protection of the ring-4 phenol as its derived allyl ether and subsequent deprotonation of the six amidic and alcoholic hydrogens with MeMgCl (18 equiv, THF/Et 2 O, 0°C, 2 h) was followed by lit...

Total Syntheses of Vancomycin and Eremomycin Aglycons

“…Use of Li 2 CO 3 in MeOH minimized this side reaction and provided 8 b, which was used in unpurified form after aqueous workup. Following Boc cleavage, coupling of 8 a and 8 b to amino acid 5 and subsequent protecting group exchange afforded tripeptides Oxidative cyclization of 10 a and 10 b according to our previously reported conditions (VOF 3 ) [9,10] provided the M(5 ± 7) cyclic tripeptides 11 a and 11 b as their unnatural R atropisomers (dr b 95:5). The reductive quench for this oxidation was modified to employ NaBH(OAc) 3 in place of zinc dust to avoid the unwanted reduction of the nitro group in ring 6.…”

“…Application of this methodology to the synthesis of bis-dechlorovancomycin (orienticin C) aglycon has recently been reported. [10] The most formidable synthesis challenges that the vancomycin skeleton presents are the three stereochemical elements of atropisomerism present in the structure as a consequence of hindered rotation in each of the cyclic tripeptide subunits. Our recent efforts have been directed toward the development of strategies for controlling these architectural features during the assemblage of the vancomycin skeleton.…”

“…As noted previously, the desired cleavage of the aryl benzyl ether in ring 5 was also observed under the reaction conditions. [9,10] We also investigated the analogous oxidative cyclizations of more conventional amino acid 7 ester analogues of tripeptide 10. However, these substrates exhibited significant levels of epimerization of the C-terminal amino acid residue during the cyclization process, a side reaction that was suppressed through use of the illustrated N-methyl amides.…”

Nonconventional Stereochemical Issues in the Design of the Synthesis of the Vancomycin Antibiotics: Challenges Imposed by Axial and Nonplanar Chiral Elements in the Heptapeptide Aglycons

“…Collectively, these three features of the aglycon architecture present the significant challenge of controlling atropisomerism in the construction of each of the three macrocyclic tripeptide subunits designated as M(2 ± 4), M(4 ± 6), and M(5 ± 7). [5] Hence, even with asymmetric syntheses of the amino acid constituents [6] and an assemblage strategy in hand, [7] one is still faced with the problem of producing the vancomycin aglycon skeleton as only one of eight possible atropdiastereomers.…”

“…[9,10] This stereochemical bias also extends to the more complex oxidative cyclization found in the orienticin C synthesis (Scheme 1 b). [7] A(1,3) strain [11] was implicated as the stereochemical control element in these cyclizations when it was found that the diastereomeric tripeptide 6, containing the epimeric arylglycine in position 5, underwent a highly diastereoselective oxidative ring closure to the natural atropisomeric product 7 with S configuration.…”