Enantioselective Enzymatic Desymmetrizations in Organic Synthesis

García‐Urdiales, Eduardo; Alfonso, Ignacio; Gotor, Vicente

doi:10.1021/cr040640a

Cited by 488 publications

(192 citation statements)

References 271 publications

(303 reference statements)

Supporting

Mentioning

188

Contrasting

Unclassified

Order By: Relevance

“…Alcohols and amines are the most thoroughly investigated substrates in KR and DKR. [29][30][31][32][33][34][35][36][37][38] The production of chiral alcohols brought in 2002 more than 7 billion dollars in revenues worldwide and this was forecasted to be 14.9 billion dollars by the year 2009. 39 Although a tremendous number of biocatalytic reactions have been studied, [16][17][18][20][21][22][23][24][25][26] the operational parameters reported for most of them seem to be rather suboptimal.…”

Section: Introductionmentioning

confidence: 99%

Lipase-Catalyzed Kinetic Resolution of 1-(2-Hydroxycyclohexyl)Indoles in Batch and Continuous-Flow Systems

et al. 2014

View full text Add to dashboard Cite

The lipase catalysed kinetic resolution of three trans-1-(2-hydroxycyclohexyl)-indoles in both batch and continuous-flow systems is reported. Ring opening of cyclohexene oxide by the corresponding indole followed by enzymatic acylation with vinyl acetate resulted in novel, highly enantioenriched indole-substituted cyclohexanols and cyclohexyl acetates. The effect of the temperature on enantiomeric ratio (E) and productivity (specific reaction rate, r flow ) in the continuous-flow mode acylation was studied at analytical scale in the 0-70°C range.Preparative scale kinetic resolution of the three indole derivatives was performed in mixed continuous-and recirculation-flow mode resulting in almost complete conversion and good to excellent enantiomeric purity of the products.

show abstract

Section: Introductionmentioning

confidence: 99%

Lipase-Catalyzed Kinetic Resolution of 1-(2-Hydroxycyclohexyl)Indoles in Batch and Continuous-Flow Systems

et al. 2014

View full text Add to dashboard Cite

show abstract

“…cinchona alkoloid | desymmetrization | organocatalysis | general base catalysis | hydrogen bonding C omplementary to enantioselective transformations of planar functionalities, catalytic desymmetrization of meso compounds is another fundamentally important strategy for asymmetric synthesis (1)(2)(3)(4)(5). However, our understanding of how a chiral catalyst discriminates between two enantiotopic functional groups in a meso substrate at the molecular level is particularly lacking.…”

mentioning

confidence: 99%

Elucidation of the active conformation of cinchona alkaloid catalyst and chemical mechanism of alcoholysis of meso anhydrides

Liu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Complementary to enantioselective transformations of planar functionalities, catalytic desymmetrization of meso compounds is another fundamentally important strategy for asymmetric synthesis. However, experimentally established stereochemical models on how a chiral catalyst discriminates between two enantiotopic functional groups in the desymmetrization of a meso substrate are particularly lacking. This article describes our endeavor to elucidate the chemical mechanism and characterization of the active conformation of the cinchona alkaloid-derived catalyst for a desymmetrization of meso cyclic anhydrides via asymmetric alcoholysis. First, our kinetic studies indicate that the cinchona alkaloid-catalyzed alcoholysis proceeds by a general base catalysis mechanism. Furthermore, the active conformer of the cinchona alkaloid-derived catalyst DHQD-PHN was clarified by catalyst conformation studies with a designed, rigid cinchona alkaloid derivative as a probe. These key mechanistic insights enabled us to construct a stereochemical model to rationalize how DHQD-PHN differentiates the two enantiotopic carbonyl groups in the transition state of the asymmetric alcoholysis of meso cyclic anhydrides. This model not only is consistent with the sense of asymmetric induction of the asymmetric alcoholysis but also provides a rationale on how the catalyst tolerates a broad range of cyclic anhydrides. These mechanistic insights further guided us to develop a novel practical catalyst for the enantioselective alcoholysis of meso cyclic anhydrides.cinchona alkoloid | desymmetrization | organocatalysis | general base catalysis | hydrogen bonding C omplementary to enantioselective transformations of planar functionalities, catalytic desymmetrization of meso compounds is another fundamentally important strategy for asymmetric synthesis (1-5). However, our understanding of how a chiral catalyst discriminates between two enantiotopic functional groups in a meso substrate at the molecular level is particularly lacking. Our group reported a desymmetric alcoholysis of a wide range of meso cyclic anhydrides with modified cinchona alkaloids to generate highly enantiomerically enriched hemiesters (5-10). Thus, we have initiated mechanistic studies to investigate how the modified cinchona alkaloids are able to efficiently differentiate the two enantiotopic carbonyl groups while tolerating variations of the substituents of the anhydrides. Herein we describe the experimental results that have enabled us to construct a transition state model to answer these mechanistic questions and to develop a practical catalyst guided by insights gained from our mechanistic studies. Results and DiscussionIn order to shed light on the origin of the catalytic activity on the enantioselective alcoholysis of meso cyclic anhydrides, we carried out kinetic studies on the methanolysis of cis-2,3-dimethyl succinic anhydride (1a) (SI Appendix). Upon treatment with the mono cinchona alkaloid DHQD-PHN (3) and the bis cinchona alkaloid ðDHQDÞ 2 AQN (4) in diethyl ether at...

show abstract

“…The crucial step in this route is based on a previous study about desymmetrization of cyclohexadienones performed by the same research group [87]. In this occasion, the difficult task of controlling the sterically congested chiral arylated quaternary carbon center was reached by the use of bifunctional thiourea E, which facilitated the desymmetrization process [88] with high yield and enantioselectivity (91%, 97% ee).…”

Section: Xii32 (Thio)urea Organocatalyzed Processesmentioning

confidence: 99%