Chemoenzymatic Synthesis of 13-Oxoverruculogen

Abstract

Verruculogens are rare fumitremorgin alkaloids that contain a highly unusual eight-membered endoperoxide. In this paper, we report a concise chemoenzymatic synthesis of 13-oxoverruculogen using enzymatic C–H peroxidation and rhodium-catalyzed C–C bond activation reactions to install the eight-membered endoperoxide and the pentacyclic core of the natural product, respectively. Our strategy involves the use of 13-epi-fumitremorgin B as a substrate analog for endoperoxidation by verruculogen synthase, FtmOx1. The resulting product, 13-epi-verruculogen, is the first unnatural endoperoxide generated by FtmOx1 and is used in the first synthesis of 13-oxoverruculogen. This strategy enables a 10-step synthesis of this natural product from commercially available starting materials and illustrates a hybrid approach utilizing biocatalytic and transition-metal-catalyzed reactions to access challenging alkaloid architectures. Moreover, this work demonstrates the use of native enzyme promiscuity as a viable strategy for the chemoenzymatic synthesis of natural products.

Multienzymatic Cascades and Nanomaterial Scaffolding—A Potential Way Forward for the Efficient Biosynthesis of Novel Chemical Products

“…Another example in this vein specifically exploited substrate promiscuity in a mixed chemoenzymatic approach to produce a verruculogen, a class of rare fumitremorgin alkaloids containing a highly unusual eight‐membered endoperoxide group that have shown toxicity toward several specific cancer cell lines along with reversing multidrug resistance in certain breast cancers. [ 201 ] Structurally, these natural fungal‐produced alkaloids have a diketopiperazine core that is formed from proline and tryptophan with the prenyl side chains attached to the tryptophan indole embedded within the eight‐membered endoperoxide ring. The Ting group utilized the verruculogen synthase FtmOx1 isolated from Aspergillus fumigatus (E.C.…”

“…This represented the first successful use of this enzyme acting on a non‐natural analog of its native substrate, fumitremorgin B. Reflecting the thesis of this review, the authors state “Our strategy highlights the use of native enzyme promiscuity in the chemoenzymatic synthesis of natural products, where substrate analogs are utilized rather than the native substrate.” [ 201 ]…”

Recent Advances in Total Synthesis of Prenylated Indole Alkaloids by Transition Metal-Catalyzed Reactions as the Key Step

“…2023 年, Ting 课题组 [41] 报道了一种新颖的化学酶法 合成天然产物异戊烯基吲哚生物碱(＋)- 16 Wang's asymmetric total synthesis of (-)-spirotryprostatin A 18-crown-6 条件下进行选择性的异戊二烯化反应, 以两 步 反 应 45% 的 收 率 得 到 ( ＋ )-13-epi-Fumitremorgin B (159). 随后, 通过对 159 的酶促 C-H 过氧化反应的优 化, 以 FtmOx1(铁/α-酮戊二酸依赖型过氧桥环合酶)作 为催化剂, 以 62%的收率得到天然产物(＋)-13-epi-Verruculogen (160), (＋)-13-epi-Verruculogen 在 DDQ 条件下 进行氧化反应, 以 55%的收率得到另外的一个天然产物 (＋)-13-Oxoverruculogen (11) (Scheme 17).…”

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

“…P450 catalysis during the oxidation phase enabled the total synthesis of mitrephorone A [ 12 ], chevalone A [ 13 ], polysin [ 14 ], excolide B [ 15 ], and gedunin [ 16 ]. Fe(II)/2OG-dependent dioxygenases, such as FtmOx1, were employed as versatile catalysts in the synthesis of 13-oxoverruculogen [ 17 ]. The use of prenyltransferase NotF and flavin monooxygenase BvnB allowed the synthesis of eurotiumin A [ 18 ].…”