Enantioselective Pd-Catalyzed α-Arylation of <i>N</i>-Boc-Pyrrolidine: The Key to an Efficient and Practical Synthesis of a Glucokinase Activator

Klapars, Artis; Campos, Kevin R.; Waldman, Jacob H.; Zewge, Daniel; Dormer, Peter G.; Chen, Cheng‐yi

doi:10.1021/jo8006804

Cited by 67 publications

(47 citation statements)

References 22 publications

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“…The benzimidazole N-H and pendant 2-pyridyl group appear to satisfy the requisite donor-acceptor pair. These structures generally resemble earlier disclosures from Banyu and Merck, with the exception of the ubiquitous representation of a gamma lactone at the 5-position of the benzimidazole scaffold [33,144]. The two enantiomers of compound 32 were separated and exhibited different potencies; while enantiomer A was reported to have an EC 50 value of 1.91 µM and an E max value of 541% at a 2.5-mM glucose concentration, enantiomer B was significantly more potent with an EC 50 of 0.24 µM and an E max of 588%.…”

Section: Glucokinase Activatorssupporting

confidence: 67%

Glucokinase Activators

Filipski

Futatsugi

Pfefferkorn

et al. 2012

Pharm. Pat. Analyst

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In this review we highlight recently disclosed progress in the field of small-molecule activators of the human glucokinase enzyme. Several of the reported chemotypes possess structural features that diverge from known leads; some of these modifications appear to be specifically designed to modulate tissue selectivity or discrete parameters of enzyme function (e.g., S0.5 v Vmax). This review will inform the reader of the extent of continued effort being directed toward discovery of a first-in-class drug for Type II diabetes mellitus that functions through this target. Patents were selected from those published in December 2009 up to November 2011; foreign filings were translated where possible to understand the claims and biological techniques utilized to characterize the reported glucokinase activators. Overall, there appears to be a recent trend leading to reduced patent filings for small-molecule glucokinase activators. There are many possible explanations for this trend; however, it is likely that the field has reached maturity and that the downturn of new disclosures represents the transition of many of these programs to the clinic.

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Section: Glucokinase Activatorssupporting

confidence: 67%

Glucokinase Activators

Filipski

Futatsugi

Pfefferkorn

et al. 2012

Pharm. Pat. Analyst

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“…Snyder and coworkers [28] developed the synthesis of (R)-(−)-pyrrolam A in three steps by using a (−)-sparteine-mediated asymmetric deprotonation of N-Boc pyrrolidine to control the stereochemistry in the final product (Scheme 7.21). More recently, the asymmetric arylation of N-Boc-2-lithio pyrrolidine has been applied to the preparations of a glucokinase activator and (R)-crispine A (Scheme 7.22) [29]. The asymmetric deprotonation followed by transmetallation with ZnCl 2 provides configurationally stable pyrrolidinyl zinc intermediates that undergo Pd-catalyzed cross-coupling reactions.…”

Section: Five-membered Rings: Lithiated Pyrrolidinesmentioning

confidence: 99%

“…29) [39]. The proposed lithiated intermediates involved in the synthetic pathways set the lithium atom in equatorial position because of A 1,3 strain and the reaction with the electrophiles occurs with retention of configuration [40].…”

mentioning

confidence: 99%

Nitrogen‐Bearing Lithium Compounds in Modern Synthesis

Degennaro¹,

Musio²,

Luisi³

2014

Lithium Compounds in Organic Synthesis

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IntroductionNitrogen-containing compounds are ubiquitous and are extremely important in synthesis. This chapter reports some general aspects of the generation, structure, and reactivity of nitrogen-bearing organolithiums showing the progress made over the last decade. The chapter does not cover comprehensively the field but the aim is to provide the reader with useful information on the generation, reactivity, and potential in synthesis of this kind of lithiated intermediates.Throughout the chapter, the name amino-organolithiums is used to describe reactive intermediates lithiated at sp 3 -hybridized carbon atoms adjacent (α) to a nitrogen atom that could be included also in a ring. Amino-organolithiums can be generated mainly in three different ways: (i) deprotonation of a parent amine or its derivative; (ii) transmetallation by using an alkyllithium; and (iii) reductive cleavage of C-heteroatom bond (e.g., C-S). Each way has advantages and disadvantages and in some cases they complement each other (Scheme 7.1).Direct deprotonation is a widely used strategy to generate amino-organolithiums even in chiral form, while tin-lithium exchange reactions are preferred when direct deprotonations are difficult (high kinetic barrier) or regiochemical issues apply. Concerning the direct deprotonation of amines, this is not a simple task because the corresponding lithiated intermediates suffer from destabilizing interactions that make this reaction very difficult unless a ''stabilizing group'' (SG) is introduced either on the nitrogen atom or on the lithium-bearing carbon (Scheme 7.2).The SG (Scheme 7.2) has a pivotal role, either reducing the kinetic barrier in the hydrogen/lithium permutation or stabilizing the organolithium mesomerically or by coordination. For these reasons, often, amino-organolithiums are classified as stabilized or unstabilized. The chemistry of unstabilized amino-organolithiums has been so far less developed however, lithiation of simple tertiary amines could be accomplished by two main strategies: (i) by tin/lithium exchange reaction and (ii) by deprotonation of quaternary ammonium complexes (Scheme 7.3).

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“…Enantioselective lithiation of N-Boc-pyrrolidine followed by transmetallation with ZnCl 2 provides the configurationally stable (even at rt) 2-pyrrolidinozinc reagent 347, which reacts with an array of aryl bromides in the presence of Pd(OAc) 2 and tBu 3 P·HBF 4 with perfect retention of configuration [252]. In the illustrative formation of 349, the direct use of unprotected 4-bromo-3-fluoroaniline 348 as electrophilic partner is worthy to note (Scheme 4.80) [253]. N-Boc-piperidines can also be α-arylated with aryl iodides by means of the Negishi coupling.…”

Section: And the Analogous Sphosmentioning

confidence: 99%