Chemoenzymatic Synthesis of O‐Containing Heterocycles from α‐Diazo Esters

Abstract

The synergy of biocatalysis and transition metal catalysis is rapidly moving forward, providing increasingly effective workflows in chemical synthesis. Here we present a facile way to prepare synthetically challenging O‐containing heterocycles bearing disubstituted stereogenic centers via catalytic chemoenzymatic transformation of α‐diazo carbonyl compounds. We demonstrate that keto‐α‐diazoesters can be enzymatically reduced to the corresponding alcohols with exquisite enantioselectivity and under retention of the diazo group using the ketoreductases LbADH and Gre2p. To further functionalize the resulting enantiopure (R)‐ and (S)‐hydroxyl α‐diazo esters, a variety of Cu and Rh catalysts were screened for intramolecular ring closure. Six‐ and seven‐membered rings with both, aliphatic and ester substituents, were obtained with up to 93 : 7 diastereomeric ratio and 81 % yield. Up to 98 % enantiomeric excess was obtained for both diastereomers, yielding the thermodynamically less favored α,ω‐trans‐oxepanes as the main products.

Microfluidic cultivation and analysis of productive biofilms

“…The EsPAD selectively converts HCA 4 to 4‐vinylphenol (VP) 5 (Figure 2c) (Peng et al, 2019). All three enzymes have been immobilized in isolated form in biocatalytic flow reactors in previous work and showed enzymatic activity for at least 40 h, highlighting the stability of these enzymes (Bitterwolf et al, 2019; Mittmann, Gallus, et al, 2019; Mittmann, Hu, et al, 2019; Peschke et al, 2018; Peschke, Rabe, et al, 2017; Peschke, Skoupi, et al, 2017).…”

“…The samples were centrifuged and the supernatant was analyzed by a reverse phase HPLC method (50% acetonitrile, 50% H 2 O containing 0.1% trifluoroacetic acid, flow rate: 1.0 ml/min, 35°C, Agilent Technologies® Eclipse XDB‐C18 5 µm, 4.6 mm × 150 mm). Absorption was detected at 285 nm (Mittmann, Hu, et al, 2019).…”

Reduction of the Diazo Functionality of α-Diazocarbonyl Compounds into a Methylene Group by NH3BH3 or NaBH4 Catalyzed by Au Nanoparticles

“…In the literature, it is well established that in the reduction of α-diazocarbonyl compounds with NaBH 4 , having an extra ketone carbonyl functionality, the diazo group remains intact [ 21 ]. The same holds in their reduction using biocatalytic conditions (ketoreductases, NADPH [ 22 ]). Notably, we found that in the absence of Au/TiO 2 , the reaction of 1l with NH 3 BH 3 or NaBH 4 yields a complex mixture of products, and this is quite reasonable given the expected instability of the anticipated α-diazo alcohol.…”

Stereoselective Bioreduction of α-diazo-β-keto Esters

“…In this context, remarkable chemoenzymatic transformations involving diazo compounds have been described in the past years [33][34][35]. However, the asymmetric reduction of ketones to alcohols in the presence of the diazo group had been completely neglected until very recently [36].Taking into account the importance of α-diazo-β-hydroxy esters in synthetic chemistry and chemical biology, and motivated by the absence of studies dealing with the asymmetric reduction of α-diazo carbonyl compounds, herein is presented the enantioselective synthesis of γ-functionalized α-diazo-β-hydroxy esters through the bioreduction of readily available α-diazo-β-keto esters by focusing on the screening of ketoreductases as versatile stereoselective biocatalysts of wide applicability.…”

“…In this context, remarkable chemoenzymatic transformations involving diazo compounds have been described in the past years [33][34][35]. However, the asymmetric reduction of ketones to alcohols in the presence of the diazo group had been completely neglected until very recently [36].…”