Asymmetric Enzymatic Hydration of Unactivated, Aliphatic Alkenes

Abstract

The direct enantioselective addition of water to unactivated alkenes could simplify the synthesis of chiral alcohols and solve a long‐standing challenge in catalysis. Here we report that an engineered fatty acid hydratase can catalyze the asymmetric hydration of various terminal and internal alkenes. In the presence of a carboxylic acid decoy molecule for activation of the oleate hydratase from E. meningoseptica, asymmetric hydration of unactivated alkenes was achieved with up to 93 % conversion, excellent selectivity (>99 % ee, >95 % regioselectivity), and on a preparative scale.

Rational Engineering of Hydratase from Lactobacillus Acidophilus Reveals Critical Residues Directing Substrate Specificity and Regioselectivity

“…Hauer and coworkers demonstrated hydration of short to medium chain 1-alkenes (C5 to C10) using a combined approach of semi-rational engineering and decoy molecule strategy 31 . When heptadecanoic acid or similar chain length acids were used as decoy molecules (to activate enzyme through binding of carboxylic acid moiety), 1-decene was hydrated efficiently by the wild-type enzyme in a highly enantio-and regio-selective manner to produce (S)-2-decanol.…”

“…Castor plants are used to produce the most common industrial HFA, ricinoleic acid, but they do not provide any further product diversity and accumulate toxic ricin 19,21,28 . Due to poor reactivity of water, chemical methods for hydration of isolated carbon-carbon double bonds often require harsh reaction conditions such as transition metal and/or acid-base catalysts, high temperatures and hazardous organic solvents [29][30][31] . Besides, chemical methods lead to a variety of undesired side reactions and do not offer the necessary stereo-and regio-selectivity to unlock the full potential of HFAs 20,32 .…”

“…Although other enzymatic routes are present for hydration of activated α, βunsaturated carbonyl compounds, FAHs can efficiently act on non-activated carbon-carbon double bonds 20 . Moreover, regio-and stereo-selective hydration of non-fatty acid substrates, including terminal and internal alkenes as well as fatty acid derivatives, have been recently demonstrated by engineered FAHs 31,40 . Although no redox chemistry is involved, FAD is essential for this reaction and most likely plays a structural or charge-stabilization role 41 .…”

Directed Evolution of a Ketone Synthase for Efficient and Highly Selective Functionalization of Internal Alkenes by Accessing Reactive Carbocation Intermediates

“…Such conversions of unactivated internal alkenes to chiral alcohols and amines are a particular challenge in catalysis (Fig. S2-S3) with only limited catalytic solutions [24][25][26][27][28][29] . There are natural enzymes that catalyze direct hydroaminations of internal alkenes, yet, due to their underlying mechanism they depend on activated internal alkenes such as a,b unsaturated carboxylic acids 41,42 .…”

“…1c) of internal alkenes, reactions that are particularly sought after with only limited catalytic solution (Fig. S2-S3) [24][25][26][27][28][29] .…”