Chemo‐ and Stereodivergent Preparation of Terminal Epoxides and Bromohydrins through One‐Pot Biocatalysed Reactions: Access to Enantiopure Five‐ and Six‐Membered N‐Heterocycles

Abstract

Abstract. Different enantiopure terminal epoxides or bromohydrins have chemoselectively been synthesised in one-pot starting from the corresponding α-bromoketones through alcohol dehydrogenase (ADH)-catalysed processes adding an organic co-solvent and tuning appropriately the medium pH and the temperature. Thus, at neutral pH enantiopure bromohydrins were obtained while using basic conditions (pH 9.5-10) epoxides were isolated as the main product. Furthermore, by simple selection of the biocatalyst, chemo-and stereodivergent transformations were achieved to obtain, e.g. enantiopure prolinol or piperidin-3-ol.

Steric vs. electronic effects in the Lactobacillus brevis ADH-catalyzed bioreduction of ketones

“…In this sense, the use of α-haloand αor β-carbonyl ketones as hydrogen acceptors in nearly stoichiometric amounts has been utilized for synthetic purposes. [26][27][28][29][30] This behavior has been studied for LBADH obtaining excellent conversions with substrates bearing electron-withdrawing groups such halogen(s), azido, cyano, hydroxyl, and carbonyl. Although some of these derivatives appeared as poor substrates for this enzyme from a kinetic point of view, they could be converted into the alcohol products at high conversion, since these hydrogen transfer processes are mainly driven by thermodynamics.…”

“…For α-brominated ketones, 50 mM Tris-H 2 SO 4 buffer, pH 7.5 (600 µL, 1 mM NADPH, 1 mM MgBr 2 ) was used to avoid undesired S N 2 reactions. 28 Protocol using 2.5 equiv. of 2-propanol.…”

“…Concerning the substrate spectra, this ADH is able to accept a more variable (often aromatic) bulky moiety such as a large ketone substituent; 12,24 however, it has demonstrated a narrower acceptance for the small ketone substituent, accommodating preferentially methyl, ethyl, or chloromethyl groups. 12,25 The reduction of ketones coupled with the oxidation of alcohols in a hydrogen transfer (HT) fashion is a typical example where the redox potential between the hydrogen donor and the acceptor is not usually large enough to achieve quantitative conversions (conv), unless a huge excess of a sacrificial alcohol/ketone such as 2-propanol/acetone is used, 11 or activated ketones with an electron-withdrawing group at α-position such as chlorine, 26,27 bromine, 28 or a carbonyl moiety at α- 23 or β-position 23,29 are employed. In a recent contribution, 22 we observed that for some substrates LBADH activity did not correlate with the conversions obtained, appearing some remarkable exceptions, and suggesting that mainly thermodynamic effects were involved in these processes.…”

Biocatalyzed synthesis of both enantiopure fluoromisonidazole antipodes

“…Thus, following a typical procedure, 15 using a mixture of acetone/water (40:1 v v -1 ) at 0ºC afforded, by TLC, the desired compound, but when the solvent was evaporated under vacuum to obtain 10, the high volatility of this ketone avoided its adequate isolation. In order to circumvent this fact, the use of microwave conditions in the absence of an organic solvent employing just alcohol 9 with the Jones' reagent under different setups was done (see Supplementary Data).…”

Laccase/TEMPO-mediated system for the thermodynamically disfavored oxidation of 2,2-dihalo-1-phenylethanol derivatives

“…halohydrins. To date, Dess-Martin periodinane, 8 ruthenium 9 and iridium-based 10 catalysts, Swern, 11 tetrapropylammonium perruthenate (TPAP), 11,12 and Jones' reagent 13 Since the laccase/mediator system is able to oxidize primary and secondary benzylic alcohols, 7b,d,20 we reasoned that laccase/TEMPO could also lead to carbonylic compounds bearing electron-withdrawing groups at α-position under aerobic conditions. Therefore, several 2,2-dihalogenated 1-phenylethanol derivatives (1a-h) and 2-chloro-1-phenylethanol 1i (Scheme 1) were synthesized, and these compounds were tested as possible substrates.…”