Dynamic Kinetic Resolution of Primary Alcohols with an Unfunctionalized Stereogenic Center in the β‐Position

Abstract

Primary alcohols with an unfunctionalized stereogenic center in the b-position undergo an enzyme-and metal-catalyzed dynamic kinetic resolution (DKR). The in situ racemization of the primary alcohol, required for the DKR, takes place via: (i) ruthenium-catalyzed dehydrogenation of the alcohol, (ii) enolization of the aldehyde formed, and (iii) ruthenium-catalyzed readdition of hydrogen to the aldehyde. The present method widens the scope of metal-and enzyme-catalyzed DKR, which has so far been limited to a-chiral alcohol and amine derivatives.Keywords: dynamic kinetic resolution; enzyme catalysis; metal catalysis; primary alcohols The development of efficient protocols for the synthesis of optically active compounds has attracted major attention in organic chemistry, because of the increasing demand for such compounds as building blocks in the pharmaceutical or agrochemical industry.[1] The most common way to prepare enantiomerically pure compounds in the chemical industry is still via resolution and separation of enantiomers from racemic mixtures.[2] In this respect, enzymatic resolution plays an important and dominant role [3] and a number of multi-ton industrial processes are based on enzymatic resolution.[4] A drawback with these kinetic resolutions (KR) is the maximum theoretical yield of 50 % leading to waste of half of the material. A solution to this problem is dynamic kinetic resolution (DKR), [5] which takes advantage of an in situ racemization of the remaining substrate enantiomer (Scheme 1). In this way a yield of up to 100 % of enantiopure material can be achieved.During the past decade, various DKR methods based on the combination of an enzyme and an additional racemization catalyst have been developed. [5d,6] In particular, the combination of an enzyme and a transition metal catalyst has proven to be useful for DKR of secondary alcohols.[5d] In the first efficient system developed, [7] Shvos ruthenium catalyst 1 (Scheme 2) was employed, and this catalyst requires a slightly elevated temperature. This procedure has been successfully applied to the DKR of various substituted secondary alcohols including diols [8] and allylic alcohols.[9] The method was recently extended to amines. [10] Further developments have led to room temperature procedures for DKR of secondary alcohols that employ a new type of racemization catalyst together with an enzyme. [11][12][13] In all these applications, the metal catalyst can be compared with the dehydrogenase/hydrogenase activity by enzymes having NAD(P)/ NAD(P)H as cofactor.All of the protocols for chemoenzymatic DKR of alcohols and amines described to date have been limited to substrates that are chiral at the a-carbon (A, Figure 1). An extension of chemoenzymatic DKR to alcohols and amines with a non-functionalized chiral carbon, for example, B (Figure 1) would significantly broaden the scope of the method. Scheme 1. Principle of a dynamic kinetic resolution (DKR).Adv. Synth. Catal. 2007, 349, 1577 -1581 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim...

Shvo’s Catalyst in Hydrogen Transfer Reactions

“…In one example reported by B€ ackvall and coworkers in 2007, Shvo's complex 1 was used [80]. The proposed mechanism for racemization begins with formation of A and 2, which create an equilibrium between primary alcohol and aldehyde via dehydrogenation/hydrogenation.…”

Asymmetric Synthesis of Bicyclic Diol Derivatives through Metal and Enzyme Catalysis: Application to the Formal Synthesis of Sertraline

“…[6] Our group has recently been involved in combined enzyme-and transition-metal-catalyzed DKR of secondary alcohols, [5a] primary amines, [6b,c] and primary alcohols [7] as well as the dynamic kinetic asymmetric transformation (DYKAT) [8] of acyclic diols. [9] In the DYKAT of acyclic diols, coupled resolution and epimerization of a dl/meso mixture of the diol occur in situ, thus resulting in one enantiomer of the diol diacetate.…”

Lipases: Valuable catalysts for dynamic kinetic resolutions

“…Since the pioneer work of Bäckvall (Larsson et al, 1997;Persson et al, 1999), 1 has been applied to the DKR of a wide range of substrates (Atuu and Hossain, 2007;Felluga et al, 2009;Hoyos et al, 2006Hoyos et al, , 2008Hoyos et al, , 2011aHoyos et al, , 2011bHuerta et al, 2000;Jung et al, 2000aJung et al, , 2000bKiełbasiński et al, 2005;Kim et al, 2001;Millet et al, 2010;Pàmies and Bäckvall, 2001, 2002a, 2002bRunmo et al, 2002;Strübing et al, 2007;Vallin et al, 2009;Verzijl et al, 2005) and new Ru (II)-based racemization catalysts compatible with lipases were discovered and developed, many of which are free from some drawbacks exhibited by 1 in DKR reactions, such as: the need for high temperatures, long reaction times and, in some cases, requirement of additives such as the substrate corresponding ketone (Larsson et al, 1997;Persson et al, 1999) or hydrogen sources to minimize substrate oxidation Pàmies and Bäckvall, 2002a;Runmo et al, 2002); incompatibility with the use of alkenyl esters such as vinyl acetate (Larsson et al, 1997;Persson et al, 1999) and instability under aerobic conditions. Several complexes of Ru (II) have been combined with lipases for DKR of alcohols, some of which are depicted in Fig.…”