A Mesoporous‐Silica‐Immobilized Oxovanadium Cocatalyst for the Lipase‐Catalyzed Dynamic Kinetic Resolution of Racemic Alcohols

Abstract

In the last decade, cooperative catalysis has received considerable attention as a powerful synthetic method. [1] Two or more catalysts function simultaneously or sequentially in a single reaction vessel to construct complicated molecules, which provides a means to perform unprecedented syntheses that cannot be achieved by a single catalyst. Various catalytic combinations involving transition metals, organocatalysts, and biocatalysts have been developed thus far. [2] A typical example is the combined use of lipases and transition metals to attain the dynamic kinetic resolution (DKR) of racemic secondary alcohols for producing single enantiomer products in up to 100 % yields, [3] in contrast to the use of lipases alone, which can only achieve maximum yields of 50 %. In this DKR process, the enzymatic enantioselective esterification of racemic alcohols is combined with the transition-metal-catalyzed continuous racemization of optically active alcohols, which remain intact during the enzymatic reaction, through a redox process. However, such cooperative cocatalysis often encounters crucial issues of low compatibility between the lipases and the transition metals. Although intense efforts have been devoted to developing highly active racemization catalysts, [4, 5] only a few ruthenium complexes have met both the requirement of sufficient compatibility with lipases and high racemization activity. [5] We recently reported that a combination of oxovanadium compounds (4 or 5) with lipases accomplished the efficient and direct conversion of racemic allylic alcohols (AE)-1 and (AE)-2 into optically active allyl esters (R)-3. [6] This method featured a unique racemization process wherein 4 (or 5) catalyzed the racemization of (S)-1 with 1,3-transposition of the hydroxy group of 1 or 2, while the lipases effected chemoand enantioselective esterification. This is significantly different from the above-mentioned ruthenium-catalyzed DKRs and offered a synthetic advantage in that both (AE)-1 and (AE)-2 were available as equivalent substrates. However, this method required further improvement in both catalytic activity and compatibility of the oxovanadium catalysts with the lipases. [7,8] Herein, we report the preparation of a novel oxovanadium catalyst (V-MPS) immobilized inside mesoporous silica (MPS) with pores of approximately 3 nm in diameter, which enabled a complete division of the racemization site and the enzymatic reaction site. The combined lipase-V-MPS catalyst is reusable and achieved DKR of a wide range of racemic alcohols with excellent chemical and optical yields (Scheme 1).The immobilization of oxovanadium species inside a solid carrier with microsized pores or multilayered structures [9] enables the minimization of interactions between the oxovanadium species and lipases while maintaining easy access of substrate molecules to the metal center. The solid carrier should be neutral and non-charged in order to exert little adverse effect on the lipases. Among the various potential solid carriers, [10,11] MPS,...

Dynamic Kinetic Resolution of Racemic Allylic Alcohols via Hydrolase–Metal Combo Catalysis: An Effective Method for the Synthesis of Optically Active Compounds

“…The overall yield of (R)-28 (68%) from less expensive 2-cyclohexen-1-one (33) was much higher than the previous case (31% overall yield from 29); thus, the enzymatic transformation demonstrated its synthetic advantages in terms of the step, atom, and redox economies (Scheme 8). 32 Another utility of our DKR was exhibited by the total synthesis of (R)-imperanene, in which the DKR of chlorohydrin («)-36, using V-MPS and B. cepacia lipase, was used to afford the optically pure intermediate (S)-37. The regio-and stereoselective nucleophilic addition of Grignard reagent 39 to oxirane (S)-38 followed by the deprotection afforded (R)-imperanene.…”

“…We then developed a new oxovanadium catalyst, V-MPS, in which the oxovanadium species is covalently attached to the inner surface of mesoporous silica (MPS) with a pore size of 3 nm ( Figure 1B). 32 In particular, its small pore size (3 nm) separated the large lipase outside the pore and completely divided the racemization and kinetic resolution sites ( Figure 1C). V-MPS (1 mol % of the vanadium amount) showed high racemization activity, which corresponded to the activity of 10 mol % 13B and significantly improved compatibility with lipases.…”

Why Leave a Job Half Done? Recent Progress in Enzymatic Deracemizations

“…[43] More recently, Akai et al have combined the use of an oxovanadium catalyst immobilized inside mesoporous silica (MPS), which ensured the compartmentalization between both metal-and biocatalysts (CAL-B or PS-IM). [44] Thus, (R)-acetylated derivatives from a series of aromatic and allylic alcohols were synthesized at 35 ºC using heptane or acetonitrile (MeCN) as solvents in very high conversions (>80%) and enantiomeric excess (>95%). Moreover, when starting from compounds bearing the alcohol at benzylic position (7, Scheme 3), the final (R)-acetate derivatives 8 could be attained as the sole products.…”

Expanding dynamic kinetic protocols: transaminase-catalyzed synthesis of α-substituted β-amino ester derivatives

“…Thus, performing a kinetic resolution on a substrate which simulta-20 neously can undergo racemization has led to efficient dynamic kinetic resolutions (DKRs). 2 While this methodology has extensively been employed with hydrolases (usually in combination with a metal-based racemization) 3 and oxidoreductases (often combined with a racemization in basic conditions), 4 for other 25 enzymes it has been scarcely exploited.…”

“…4a,d In a subsequent step, adapting a protocol described by Brandt and co- 60 workers, 13 ultrasonication of these derivatives under the presence of benzylamine at 30 ºC smoothly afforded the (Z)-N-benzylated enamine esters 4b-k in excellent yields. Then, the corresponding N-protected β-amino esters syn-5b-k and anti-6b-k were obtained as diastereoisomeric mixtures by reduction of the C=C double 65 bond with NaBH(OAc) 3 at 0 ºC in high yields. As previously described, the syn isomers were preferentially formed.…”