Discovery of a multi-functional biocatalyst for asymmetric conjugate reduction-reductive amination

A major challenge in chemical synthesis is to develop catalytic systems that convert simple molecules to complex high-value products. Often these valuable compounds must be manufactured asymmetrically, as their biochemical properties can differ based on the chirality of the molecule. Of great interest are enantioenriched amine diastereomers, which are prevalent in pharmaceuticals and agrochemicals,1 yet their preparation often relies on low-efficiency multi-step synthesis.2 Herein, we report the discovery and characterisation of a multi-functional biocatalyst, which operates using a previously unreported conjugate reduction-reductive amination mechanism. This enzyme (pIR-120), identified within a metagenomic imine reductase (IRED) collection3 and originating from an unclassified Pseudomonas species, possesses an unusual active site architecture that facilitates an amine-activated conjugate alkene reduction followed by reductive amination. This enzyme enables the coupling of a broad selection of α,β-unsaturated carbonyls with amines for the efficient preparation of enantioenriched amine diastereomers. Moreover, employing a racemic substrate partner or conjugated dienyl-ketone provides a means of controlling additional stereocentres using the single catalyst. Mechanistic and structural studies have been carried out to delineate the order of individual steps catalysed by pIR-120 which have led to a proposal for the overall catalytic cycle. This work shows that the IRED family can serve as a platform for facilitating the discovery of further enzymatic activities for application in synthetic biology and organic synthesis.

Stereoselective Synthesis of the I–L Fragment of the Pacific Ciguatoxins

The I–L ring system found in all the Pacific ciguatoxins has been prepared from a tricyclic precursor in a highly stereoselective manner. Subtle differences in the reactivity of the enones present in the seven- and eight-membered rings of the tricyclic ether starting material have been exploited to allow selective protection of the enone in the eight-membered ring. Subsequent distereoselective allylation of the seven-membered ring has been accomplished by a palladium-mediated Tsuji-Trost reaction. The K-ring methyl and hydroxyl groups have been installed in a highly stereoselective manner by sequential conjugate reduction and enolate oxidation reactions. Ring L has been constructed by a use of a novel relay ring-closing metathesis reaction to complete the tetracyclic framework, which possesses the functionality necessary for elaboration of rings I and L and the introduction of ring M.

Copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters with chiral phenol–carbene ligands

A chiral phenol–NHC ligand enabled the copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters. The phenol moiety of the chiral NHC ligand played a critical role in producing the enantiomerically enriched products. The catalyst worked well for various (Z)-isomer substrates. Opposite enantiomers were obtained from (Z)- and (E)-isomers, with a higher enantiomeric excess from the (Z)-isomer.

Syntheses of cis- and trans-Jamtine and Their N-Oxides via a Benzyl Configuration-Inversion Approach

A novel synthesis of the tetrahydroisoquinoline alkaloid jamtine and its epimer is reported. The synthetic strategy hinges on a one-pot conjugate reduction/Robinson cyclization sequence and an efficient benzyl configuration inversion by an oxidation/reduction approach. The N-oxide derivatives of the jamtine isomers were also synthesized and identified by X-ray crystallographic analysis. Additionally, a density functional theory calculation for the four possible N-oxide structures was exploited to gain further insight into the structure of the natural product in comparison to those of the synthetic N-oxides, because the NMR data of the synthetic derivatives did not match those reported for natural jamtine N-oxide.

Implementation of an Off-Axis Digital Optical Phase Conjugation System for Turbidity Suppression on Scattering Medium

Due to the light scattering effect, it is difficult to directly achieve optical focusing and imaging in turbid media, such as milk and biological tissue. The turbidity suppression of a scattering medium and control of light through the scattering medium are important for imaging on biological tissue or biophotonics. Optical phase conjugation is a novel technology on turbidity suppression by directly creating phase conjugation light waves to form time-reversed light. In this work, we report a digital optical phase conjugation system based on off-axis holography. Compared with traditional digital optical phase conjugation methods, the off-axis holography acquires the conjugation phase using only one interference image, obviously saving photo acquisition time. Furthermore, we tested the optical phase conjugate reduction performance of this system and also achieved optical focusing through the diffuser. We also proved that the reversing of random scattering in turbid media is achievable by phase conjugation.

Total synthesis of dimeric Securinega alkaloids (−)-flueggenines D and I

The first total synthesis of dimeric securinega alkaloids (−)-flueggenines D and I was completed by a dimerization strategy that involves Stille reaction and stereoselective conjugate reduction.