Total Synthesis of Vancomycin—Part 3: Synthesis of the Aglycon

Abstract

The total synthesis of the vancomycin aglycon (2, Figure 1) is described. Construction of the key intermediate, tricyclic triazene 3 a (Figure 2), was accomplished in the orderThe C-O-D ring system 18 a (Scheme 2) was formed by using the triazene ring-closure methodology from a precursor (17) already possessing the AB biaryl fragment 6, synthesized by a Suzuki coupling reaction. At this point, a macrolactamization reaction furnished the AB ring system. Tripeptide 5 was incorporated in the main framework and the triazene ring-closure methodology was applied again to achieve the formation of D-O-E ring system, providing tricyclic triazene 3 a (Scheme 6). The latter was converted to the fully protected vancomycin aglycon 45 a by first introducing the phenolic moiety (derivative 43 a) and then oxidizing the AA-7 side chain (Scheme 12). Finally, global deprotection afforded vancomycins aglycon (2). Atropisomerization was successfully performed for D-O-E ring systems.

The cyclization of peptides and depsipeptides

“…However, their key macrocyclization steps illustrate important themes. In the Evans et al [198,199] approach to vancomycin aglycone synthesis, the A-B diphenyl link was accomplished using vanadyl trifluoride oxidative cyclization, while the diphenyl [200][201][202][203] saw the A-B system effected by the Suzuki conditions [Pd(Ph 3 P) 4 ]/Na 2 CO 3 for coupling an iodoaryl compound to a boronic acid aryl group, while diphenyl ethers were produced via their in-house triazene-based technology (Scheme 21).…”

Biomimetic Synthesis of Azole‐ and Aryl‐Peptide Alkaloids

“…The first, developed by the group of K. C. Nicolaou [146][147][148], is based on a triazene driven copper-mediated coupling reaction of 109 to form the C-O-D ring 110 (Scheme 9.23) [149][150][151]. This coupling was not atropisomer-selective, but the undesired isomer could be separated.…”

“…Scheme 9.23Ring closures in Nicolaou's synthesis of vancomycin[146][147][148][149][150][151]. Reagents and conditions: (i) CuBr · Me 2 S, K 2 CO 3 , pyridine, MeCN; and (ii) FDPP, iPr 2 NEt, DMF.…”

The Essence of Total Synthesis

“…As a final set of examples related to the theme of how challenging molecular connectivities of natural products can lead to new methodology, we mention our recent forays toward diazonamide A, a natural product whose originally proposed structure (48) (27). At first, however, initial experiments led to the observation of an unintended cyclofragmentation cascade leading to the highly desirable 3-arylbenzofuran nucleus (53), a privileged structural motif found in numerous clinically used pharmaceuticals.…”

“…Achieving the first of these objectives required the development of new synthetic methodology because the tests provided by the unique conglomeration of vancomycin's sensitive functional groups (including seven epimerizable arylglycines) and stereochemical complexity (including 18 chiral centers and three axes of atropisomerism) were rather rigorous. Most noteworthy among these discoveries was a triazene-driven aryl ether forming reaction catalyzed by copper salts to generate the two 16-membered macrocyclic rings of the target molecule, a transformation with broad synthetic scope (45)(46)(47)(48)(49). The second task, preparing vancomycin analogs with improved activity, was accomplished by means of an inventive use of a process known as dynamic combinatorial screening (also known as targetdriven combinatorial synthesis).…”