Alcohol Dehydrogenases and N‐Heterocyclic Carbene Gold(I) Catalysts: Design of a Chemoenzymatic Cascade towards Optically Active β,β‐Disubstituted Allylic Alcohols

Abstract

The combination of gold(I) and enzyme catalysis is used in at wo-step approach, including Meyer-Schuster rearrangement of as eries of readily available propargylic alcohols followed by stereoselective bioreduction of the corresponding allylic ketone intermediates,toprovide optically pure b,b-disubstituted allylic alcohols.T his cascade involves ag old N-heterocyclic carbene and an enzyme,d emonstrating the compatibility of both catalyst types in aqueous medium under mild reaction conditions.T he combination of [1,3bis(2,6-) and aselective alcohol dehydrogenase (ADH-A from Rhodococcus ruber,K RED-P1-A12 or KRED-P3-G09) led to the synthesis of as eries of optically active (E)-4-arylpent-3-en-2ols in good yields (65-86 %). The approach was also extended to various 2-hetarylpent-3-yn-2-ol, hexynol, and butynol derivatives.T he use of alcohol dehydrogenases of opposite selectivity led to the production of both allyl alcohol enantiomers (93-> 99 %ee) for ab road panel of substrates.

Gold and Biocatalysis for the Stereodivergent Synthesis of Nor(pseudo)ephedrine Derivatives: Cascade Design Toward Amino Alcohols, Diols, and Diamines

“…To develop a regioselective access towards ketone derivatives 3 and 4 , the gold(I) NHC complex [1,3‐bis(2,6‐diisopropylphenyl)imidazole‐2‐ylidene][bis(trifluoromethanesulfonyl)imide] gold(I) (IPrAuNTf 2 ) was selected as catalyst for the hydration of propargylic acetate 1 and acetamide 2 (Scheme 2). Initial reaction conditions involved the use of propan‐2‐ol (2‐PrOH, 20% vol) as organic cosolvent but also as hydrogen donor in the subsequent ADH‐catalyzed bioreduction step for cofactor recycling purposes, and a compromise temperature of 40 °C since both gold(I) and enzyme can be simultaneously active under these conditions [11d,e] . Interestingly, after studying the influence of the gold(I) catalyst loading (2–6 mol%) and the reaction time (2–6 h), the amount of IPrAuNTf 2 could be reduced to 2 mol% for the synthesis of racemic keto ester 3 requiring just 6 h to achieve a quantitative conversion (see Table S1 in the SI for more details), expanding the potential of gold(I) catalysis previously disclosed using other species [16] .…”

Merging Gold(I) Catalysis with Amine Transaminases in Cascade Catalysis: Chemoenzymatic Transformation of Propargylic Alcohols into Enantioenriched Allylic Amines

“…After enzyme screening of the biotransamination of ketones 2 b – h (Tables S10 to S16 in SI), the scope of the sequential chemoenzymatic cascade was next explored using seven additional propargylic alcohols 1 b – h bearing different pattern substitutions at the aromatic ring, which were selected since they are known to be good substrates for their [Au(IPr)(NTf 2 )]‐catalysed Meyer‐Schuster rearrangements (Figure 3). [10d] The best [Au(IPr)(NTf 2 )]‐ATA pairs were identified (Table S18 in SI), allowing the preparation of both amine enantiomers 3 b – h (97 to >99% ee ) in good to excellent conversions (70–95%). Absolute configurations were assigned based on the known ATA stereoselective preference, [20–26] finding that the ( R )‐enantiomers released first in the HPLC analyses (see Section X in SI).…”

“…Therefore, the use of easily accessible and inexpensive amine donors is required, and nowadays two main strategies are employed, the use of a large excess of i PrNH 2 (forming acetone as by‐product), or using a small excess of alanine (Ala) with in situ removal of the resulting pyruvate, [15] although other possibilities such as the use of the so‐called “smart” amine donors in almost equimolecular amounts with regard to the carbonyl substrate can be an alternative [16] . The addition of various reactants needed for the enzymatic step was explored taking as an initial set of conditions our previously optimised gold‐catalysed Meyer‐Schuster rearrangement of racemic alcohol 1 a to provide preferentially the ketone isomer ( E )‐ 2 a [10d] . This included different amine donors ( i PrNH 2 and L‐Ala), an ATA and PLP required as enzyme cofactor (Table 1).…”

“…The combination of gold catalysts and enzymes has attracted recent attention, disclosing elegant examples for multi‐step transformations. Among the biocatalysts used, lipases and esterases from the hydrolase family, [8] and redox enzymes including monoamine oxidases (MAOs), [9] and alcohol dehydrogenases (ADHs), [10] have provided access to different families of organic compounds, although the performance of concomitant strategies has been scarcely demonstrated using either lipases [8a] or ADHs [10d,e] . Very recently, two one‐pot alkyne amination strategies have been reported based on the gold hydration of terminal alkynes to produce methyl ketones as amine precursors [11,12] .…”

Chemoenzymatic Cascades Combining Biocatalysis and Transition Metal Catalysis for Asymmetric Synthesis

“…Au complexes can catalyze this reaction under mild conditions, being compatible with the reaction of ADHs and ATAs. In this context, our research group successfully developed a concurrent cascade to synthesize fifteen optically active (hetero)aryl and aliphatic ( E )‐β,β‐disubstituted allylic alcohols in good yields (37–86 %) [50] . The approach consisted of the transformation of racemic propargylic alcohols with a NHC‐Au I complex and ADH‐A or LBADH at 40 °C in a predominantly aqueous medium and 2‐PrOH as organic cosolvent and as hydrogen donor (Scheme 10A).…”