Chemo-enzymatic Total Syntheses of Jorunnamycin A, Saframycin A, and N-Fmoc Saframycin Y3

Abstract

The antitumor tetrahydroisoquinoline (THIQ) alkaloids share a common pentacyclic scaffold that is biosynthesized by nonribosomal peptide synthetases involving unique enzymatic Pictet-Spengler cyclizations. Herein we report concise and divergent chemo-enzymatic total syntheses of THIQ alkaloids by merging precise chemical synthesis with in vitro engineered biosynthesis. A recombinant enzyme SfmC responsible for the biosynthesis of saframycin A was adapted for the assembly of these natural products and their derivatives, by optimizing designer substrates compatible with SfmC through chemical synthesis. The appropriately functionalized pentacyclic skeleton were efficiently synthesized by streamlining the linkage between SfmC-catalyzed multistep enzymatic conversions and chemical manipulations of the intermediates to install aminonitrile and N-methyl groups. This approach allowed rapid access to the elaborated pentacyclic skeleton in a single day starting from two simple synthetic substrates without isolation of the intermediates. Further functional group manipulations allowed operationally simple and expeditious syntheses of jorunnamycin A, saframycin A, and N-Fmoc saframycin Y3 that could be versatile and common precursors for the artificial production of other antitumor THIQ alkaloids and their variants.

Lentzeacins A-E, New Bacterial-Derived 2,5- and 2,6-Disubstituted Pyrazines from a BGC-Rich Soil Bacterium Lentzea sp. GA3-008

“…Another route for pyrazine biosynthesis involves an uncommon monomodular NRPS with a terminal reductase domain (TD). Conversion of the amino acid to the reactive amino aldehyde allows for cyclization to form pyrazines [ 25 , 26 , 27 , 28 ]. The genome of Lentzea sp.…”

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

“…The methyl ester of dichotomine A (191, Scheme 23a), a stitchwort alkaloid, was enantioselectively acetylated by lipase QLM 37 to afford the (R)-acetate in 50% yield and 96% ee along with the (S)-alcohol in 45% yield and 96% ee (E ¼ 194). 99 Saponication of the methyl ester in (S)-191 gave (À)-dichotomine A (193), while aminolysis and a copper(I)-catalysed C-N-couplingamong other stepswere used to obtain (+)-dichotomide II (194) from (R)-192. The spectral characteristics and optical rotation of both target compounds matched those reported for material isolated from the natural source, 100 Scheme 22 Kinetic resolution of lactam 184, and structures of alkaloids prepared from its (R)-enantiomer.…”

“…Scheme 23 Lipase-catalysed kinetic resolution of sec-alcohol moieties in alkaloids: (a) kinetic resolution of rac-191 and its conversion into (À)-dichotomine A (193) and (+)-dichotomide II (194), (b) kinetic resolution of maleimycin (195) and its conversion into nitrosporeusines A and B (197,198). conrming that the two natural products 193 and 194 have opposite absolute conguration.…”

‐Aminonitriles: From Sustainable Preparation to Applications in Natural Product Synthesis

“…This example shows that besides their potential reactivity, aminonitriles can also serve as useful protecting groups in long synthesis sequences. In 2018, Oikawa, Oguri and co‐workers reported an impressive chemo‐enzymatic divergent total synthesis of saframycin A ( 262 ) and other THIQ derivatives with a pentacyclic scaffold such as (−)‐jorunnamycin A ( 263 ) through merging chemical and in‐vitro biological synthesis (Figure ), two disciplines with complementary strengths and weaknesses that have only rarely been combined in natural product synthesis so far . With this new strategy involving enzyme‐catalyzed construction of the skeleton, the group gained rapid access (only one single day of reaction time) to such pentacyclic scaffolds needed, without the necessity to isolate and purify every intermediate as compared to chemical multistep approaches.…”