Landscape of Lankacidin Biomimetic Synthesis: Structural Revisions and Biogenetic Implications

Abstract

In this report, a unified biomimetic approach to all known macrocyclic lankacidins is presented. By taking advantage of the thermolysis of N,O-acetal to generate the requisite N-acyl-1-azahexatriene species, we eventually realized the biomimetic Mannich macrocyclization, from which all of the macrocyclic lankacidins can be conquered by orchestrated desilylation. The reassignments of the reported structures of isolankacidinol (7 to 10) and the discovery of a recently isolated "lankacyclinol" found to be in fact 2,18-bis-epi-lankacyclinol (72) unraveled the previously underappreciated chemical diversity exhibited by the enzymatic macrocyclization. In addition, the facile elimination/decarboxylation/protonation process for the depletion of C1 under basic conditions resembling a physiological environment may implicate more undiscovered natural products with variable C2/C18 stereochemistries (i.e., 62, 73, and 75). The notable aspect provided by a biomimetic strategy is significantly reducing the step count compared with the two previous entries to macrocyclic lankacidins.

Stereodivergent Synthesis of Lankacyclinol and Its C2/C18-Congeners Enabled by a Bioinspired Mannich Reaction

“…The novel strategy presented herein is stereochemically complementary for synthesizing several scarce metabolites ( 7 = 6.3% yield from 11 ; 8 = 22.8% yield from 11 ; 9 = 15.0% yield from 11 ) as compared to our previous Mannich macrocyclization strategy ( 7 = 1.1% yield from 11 ; 8 = 4.0% yield from 11 ; 9 = 0.5% yield from 11 ). Together with the previous biomimetic approach, this intermolecular bioinspired Mannich reaction allows all known lankacidins to be conquered in considerable efficiency and provides comprehensive entries to systematically diversified analogues for future biological evaluation.…”

“…Although great synthetic efforts have been devoted by several research groups to solve the primary hurdles associated with the densely functionalized β-keto-δ-lactonic core structure, only Williams and, recently, our group accomplished the total synthesis of lankacyclinol ( 6 ). In a recent full account, we disclosed a biomimetic approach based on a mild thermolytic demethoxylative macrocyclization of an advanced long-chain N , O -acetal.…”

1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations, and Maybe Something More: A Review

“…Such transformations gained attention and were used for the preparation of substrates for α-amido sulfone-based intermolecular Mannich addition in the stereodivergent synthesis of lankacyclinol (Lankacidin antibiotics; Scheme 15 /B) [ 60 , 61 , 62 ].…”

The Fruit of Gold: Biomimicry in the Syntheses of Lankacidins

“…Org. Chem.2020851381813826 . This work describes the detailed evolution of the Mannich macrocyclization strategy that resulted in syntheses of eight naturally occurring lankacidins in 8–12 steps. ZhengK.ShenD.ZhangB.HongR. Zheng, K. Shen, D. Zhang, B. Hong, R. 10.1021/acs.joc.0c02443…”

“…Org. Chem.2020851381813826 . This work describes the detailed evolution of the Mannich macrocyclization strategy that resulted in syntheses of eight naturally occurring lankacidins in 8–12 steps.…”