Organocatalytic Enantioselective Vinylogous Pinacol Rearrangement Enabled by Chiral Ion Pairing

Abstract

An enantioselective pinacol rearrangement of functionalized (E)-2-butene-1,4-diols was developed. In the presence of a catalytic amount of a chiral BINOL-derived N-triflyl phosphoramide, these 1,4-diols rearranged to b,g-unsaturated ketones in excellent yields and enantioselectivities. The formation of a chiral ion pair between the intermediary allylic cation and the chiral phosphoramide anion was postulated to be responsible for the highly efficient chirality transfer. These chiral building blocks were further converted into enantioenriched polysubstituted tetrahydrofuran and tetrahydronaphthalene derivatives.Pinacol rearrangements, which convert 1,2-diols into ketones under acidic conditions, are a blueprint for a group of carbenium-based molecular reorganization processes.[1] As such reactions generate a new stereogenic center, the ability to control the stereochemical outcome would significantly expand their synthetic utility. However, several factors intrinsic to the reaction mechanism have made this endeavor highly demanding. First, the regioselective generation of one of the two possible carbenium intermediates under strongly acidic conditions is difficult. Second, differentiation of the prochiral faces of highly reactive planar carbocation intermediates is a formidable challenge as it falls out of the reach of typical Lewis acid and Brønsted acid catalysis. As a matter of fact, Antillas chiral phosphoric acid (CPA) catalyzed rearrangement of indolyl diols is the only example of an enantioselective pinacol rearrangement to date (Scheme 1 a).[2] In this transformation, the benzylic cation is generated regioselectively and stabilized in the form of conjugated iminium species A, [3] thereby facilitating the transfer of chiral information. Indeed, imines are the most widely exploited substrates in CPA-catalyzed asymmetric transformations. [4,5] To circumvent the aforementioned challenges, a number of efficient catalytic enantioselective semipinacol rearrangements have been developed. [6][7][8] Two key structural elements have been strategically incorporated into the substrates of these reactions in order to a) regioselectively generate the cationic intermediate or its equivalent and b) render the 1,2-CÀC bond shift a ring-strain-releasing process (Scheme 1 b). While the synthetic significance of these transformations is self-evident, constraints imposed on the substrate structure have nevertheless limited the full exploitation of the pinacol rearrangement. In connection with our ongoing studies of organocatalytic enantioselective transformations, [9] we became interested in the chiral contact ion pairs [10] formed between a CPA and cationic intermediates other than iminium species, [11,12] and we chose allylic cations [13] as our playground. We herein report a catalytic enantioselective vinylogous pinacol rearrangement of 1,4-diols 1 to b,gunsaturated ketones 2 (Scheme 1 c) and provide evidence that supports the hypothesis that chiral allylic contact ion pair B is a key intermediate for the transfer ...

Advances and Perspectives in Pinacol Rearrangement Reactions: A Comprehensive Review

“…The paper titled "Organocatalytic Enantioselective Vinylogous Pinacol Rearrangement Enabled by Chiral Ion Pairing" published in Angewandte Chemie describes an innovative organocatalytic approach for achieving enantioselective vinylogous pinacol rearrangement using chiral ion pairing. The study focuses on the development of a highly efficient method for the synthesis of chiral carbonyl compounds with high enantioselectivity [44]. The authors emphasize the significance of vinylogous pinacol rearrangement as a powerful transformation for the construction of carbonyl compounds.…”

Expanding the Cation Cage: Squalene-Hopene Cyclase-Mediated Enantioselective Semipinacol Rearrangement

“…In contrast, the potential of noncovalent carbocation control in a cation cage was earlier recognized in small-molecule catalysis and exploited in myriad types of Brønsted-acid catalyzed reactions, e.g. , Michael additions, Pictet–Spengler cyclizations, cycloadditions, or pinacol rearrangements. − The asymmetric semipinacol rearrangements are among the most important cationic rearrangement reactions found in chemistry as they provide chiral access to quaternary (spiro-)­stereocenters which are broadly distributed in nature and are privileged scaffolds for medicinal chemistry (Figure B). ,− Despite the boundless creativity in synthetic tactics, including vinylogous, arylative, halogenative, , or aza-semipinacol rearrangements, the most simple Brønsted-acid-catalyzed type is limited to few examples with low catalytic performances (up to 40 TTN, Figure S1). , Moreover, enzymes for these challenging reactions just recently emerged in the literature and act on very specific substrates. , …”

Organoiodine‐Catalyzed Enantioselective Alkoxylation/Oxidative Rearrangement of Allylic Alcohols

“…[1] In most cases,t he reactions are usually initiated by either the protonation, halogenation, expoxidation, or arylation of the double bond and further driven by aring-strain-releasing process,therefore representing unconventional strategies for the difunctionalization of alkenes.Over the last decade,the enantioselective rearrangement of allylic alcohols has been extensively investigated, benefiting from the rapid growth of asymmetric catalysis (Scheme 1a). [2][3][4][5] Among them, chiral phosphoric acids (CPA) and bis(quinine) derivatives,s uch as (DHQ) 2 PYR, are privileged chiral catalysts for the asymmetric semipinacol rearrangement. [2] In sharp contrast, to the best of our knowledge,c hiral-organoiodine-catalyzed enantioselective rearrangements of allylic alcohols remain underdeveloped.…”