Biocatalytic Hydrogen-Borrowing Cascade in Organic Synthesis

Abstract

Biocatalytic hydrogen borrowing represents an environmentally friendly and highly efficient synthetic method. This innovative approach involves converting various substrates into high-value-added products, typically via a one-pot, two/three-step sequence encompassing dehydrogenation (intermediate transformation) and hydrogenation processes employing the hydride shuffling between NAD(P)⁺ and NAD(P)H. Represented key transformations in hydrogen borrowing include stereoisomer conversion within alcohols, conversion between alcohols and amines, conversion of allylic alcohols to saturated carbonyl counterparts, and α,β-unsaturated aldehydes to saturated carboxylic acids, etc. The direct transformation methodology and environmentally benign characteristics of hydrogen borrowing have contributed to its advancements in fine chemical synthesis or drug developments. Over the past decades, the hydrogen borrowing strategy in biocatalysis has led to the creation of diverse catalytic systems, demonstrating substantial potential for straightforward synthesis as well as asymmetric transformations. This perspective serves as a detailed exposition of the recent advancements in biocatalytic reactions employing the hydrogen borrowing strategy. It provides insights into the potential of this approach for future development, shedding light on its promising prospects in the field of biocatalysis.

Figure 1

General mechanism and catalysts of hydrogen-borrowing cascade.

Scheme 1. Biocatalytic Hydrogen-Borrowing Cascades for the Racemization of Alcohols

Relative rates were measured from the slope of the decline of ee versus time at the onset of the reaction (conversion <5%), values are expressed as % relative to the natural substrate (S)-2-hydroxy-4-methylpentanoic acid, which was set as standard (100%). Structures that are not racemized are shown in gray.

Scheme 2. Hydrogen-Borrowing Cascades for the Stereo-Inversion of Alcohols

Scheme 3. Three-Enzyme Cascades for the Conversion of Alcohols to Amines^,

employing crude enzyme. employing purified enzymes.

Scheme 4. Dual-Enzyme Hydrogen-Borrowing Cascades for the Conversion of Alcohols to Enantiopure Amines^,

Turner group’s double enzyme hydrogen borrowing system. Xu group’s double enzyme hydrogen borrowing system.

Scheme 5. Borrowing Hydrogen Reaction in Combination with Other Enzyme or Chemocatalysis

Scheme 6. Hydrogen-borrowing cascades for the alkylation of primary amines with alcohols^,

Biocatalytic hydrogen-borrowing cascades for the conversion of α-hydroxyl acids to chiral amino acids. Isolated yield cannot be stated due to impurities in the isolated material.

Scheme 7. Simultaneous Enzymatic Synthesis of (S)-3-Fluoroalanine and (R)-3-Fluorolactic Acid

Scheme 8. Conversion of Allyl Alcohols to Ketones

Scheme 9. Conversion of Allyl Alcohols to Ketones

Scheme 10. Conversion of bis-Aldehydes to Esters

Scheme 11. Conversion of α,β-Unsaturated Aldehydes to Acids