Scalable Synthesis of Mycocyclosin

Abstract

We report herein the scalable total synthesis of the secondary metabolite, mycocyclosin, initially isolated from Mycobacterium tuberculosis. Mycocylosin bears a highly strained 3,3'-dityrosine biaryl system which arises biosynthetically from an intramolecular oxidative dehydrogenative cross-coupling of cyclo(l-Tyr-l-Tyr) (cYY) catalyzed by the P450 enzyme CYP121. CYP121 is found exclusively in M. tuberculosis. Scalable access to mycocyclosin and related derivatives via a Pd(II)-catalyzed macrocyclization is anticipated to facilitate the biological evaluation of these compounds as novel tuberculosis antimicrobials.

Oxidative Photocatalytic Homo- and Cross-Coupling of Phenols: Non-Enzymatic, Catalytic Method for Coupling Tyrosine

“…In particular, non-enzymatic catalytic methods for the direct oxidative ortho-ortho coupling of L-tyrosine have remained an elusive goal for chemists (Scheme 1 effect such a coupling, as it would engender a biomimetic approach to the dityrosine motif found in several natural products, including mycocyclosin 3 and RP-66453. 4 However, most efforts have culminated in Suzuki type crosscouplings to forge the biaryl bond, as is the case in all efforts to generate mycocyclosin (Scheme 1a), 3,21 a natural product that is also a key intermediate to the herqulines. [22][23][24] Notably, Baran deployed an intramolecular oxidative coupling of tyrosine and para-hydroxyphenylglycine by employing a stoichiometric Cu III -TMEDA complex (Scheme 1b).…”

Empowering Synthesis of Complex Natural Products

“…They believed this goal could be achieved through am acrocyclization of dimers or heterodimers. [40] To wards this goal, Schindler and co-workers began their synthesis with the methyl ester formation of 3-iodo-l-tyrosine (117)f ollowed by Boc protection and subsequent benzylation of the free phenol to yield variably protected tyrosine derivative 118.T he materialc ould then be split to selectively deprotect specific functionalities, that is,s aponification to reveal the carboxylic acid 119 or acid hydrolysis of the Boc group to furnish the amine salt 120.W ith the newly revealed functional handles, the tyrosine derivatives could be dimerized to form diketopiperazine 121 on 3.80 gs cale. The stage was set for the key macrocyclization event.…”

Bioinspired Syntheses of Herqulines B and C from Cyclodipeptide Mycocyclosin

“…In initial studies, we were able to build on the results of Hutton and coworkers to develop a scalable and reproducible synthesis of mycocyclosin (4). 12 Our detailed investigations of the cross-couplingconditions had revealed beneficial effects of H2O and exogenous air on the macrocyclization yield obtained. Based on these results, we considered a mechanism initiated by a palladium(II) peroxy species 13 formed upon oxidation of palladium(0) and water as a crucial additive to aid the formation of a palladium(II) hydroxyl complex to ultimately intercept the Suzuki-Miyaura reaction pathway.…”

“…2). Although the C2-symmetric piperazine 6 was expected to significantly facilitate synthetic efforts, four key challenges remained:(1) a scalable synthetic route to access gram-quantities of the strained cyclophane (4); (2) the development of a reliable protocol for diketopiperazine reductions in strained macrocycles; (3) a viable dearomatization strategy for highly strained and distorted biaryl systems 11,12 to selectively provide (4) the ,-enone over the corresponding ,-enone structural motifs. With these challenges in mind, we first focused on the development of a robust synthetic strategy to obtain gram-quantities of mycocyclosin (4).…”

“…Based on these results, we considered a mechanism initiated by a palladium(II) peroxy species 13 formed upon oxidation of palladium(0) and water as a crucial additive to aid the formation of a palladium(II) hydroxyl complex to ultimately intercept the Suzuki-Miyaura reaction pathway. 12 With a scalable synthetic strategy towards mycocyclosin secured, we next evaluated approaches to effect the selective reduction of the biaryl subunit. We were particularly inspired by Laguzza and Ganem who reported the formation of ,-enone 9 upon Birch reduction of N,N-diallyl-O-methyl-L-tyrosine (7) and subsequent aqueous hydrolysis of diene 8 (Fig.…”