Fluoride Ion‐Promoted α‐Ketol Rearrangement during Unmasking of Silyl‐Protected Medium‐Ring Dihydroxy Ketones

Abstract

Dedicated to Joe P. Richmond on the occasion of his 60 th birthday.Abstract: A new strategy for implementing a-ketol rearrangements under mild conditions is presented. The reactants are mono-and disilylated stereoisomers of a,a'-and a,b-dihydroxycycloheptanones and -cyclooctanones. Compounds of this class experience ready deprotection upon treatment with tetrabutylammonium fluoride. In certain examples, this process is accompanied by structural isomerization. Since the product diols are stable to the reaction conditions, these chemical changes have been attributed to kinetically controlled events following transient alkoxide generation resulting from cleavage of the O À Si bond proximal to the carbonyl group. The experimental findings are evaluated against a backdrop of calculated (MM3) steric energies of the siliconfree products and their response to equilibration under strongly basic conditions.Keywords: desilylation; fluoride ion; a-ketols; medium-sized rings; MM3 calculations; rearrangement Many a-hydroxy ketones have the capacity for conversion to an isomeric a-ketol. Catalysis by a base, [1] inorganic salt, [2] Br˘nsted acid, [3] or Lewis acid [4] is generally required. Two mechanistic pathways are possible depending on structural features. When the hydroxy group forms part of a tertiary carbinol, a 1,2-alkyl or aryl shift as depicted for operates.[5] Secondary a-keto carbinols can also isomerize via an enediol intermediate typified by 3.[6 ± 10] In both cases, the rearrangement is reversible, such that thermodynamic control is operative and the more stable isomer results. If the enthalpically advantaged member of the pair is already in hand, a chemical transformation will not likely operate under the predescribed conditions provided that the energy difference is sufficiently great.Extensive attention has been accorded to acyclic, cyclic, bridged, and steroidal a-ketols, such that ring-size effects and the impressively high levels of attainable selective bond migration are well appreciated.[5] In contrast, heteroatomic substituent effects in the vicinity of the carbonyl group appear not to have been given prior attention. The recent availability of monosilylated medium-ring a,a'-dihydroxycycloalkanones in our laboratory [11] has prompted a probe of the manner in which the individual cis-and trans-isomers react when desilylated. The generation of tautomeric a-ketol products has been found to occur under conditions sufficiently mild [1d,12] that the resulting dihydroxy ketones are not concurrently equilibrated. These observations constitute a previously unrecognized means for implementing a-ketol rearrangements.We first addressed the direct desilylation of 4 and its diprotected congener 5 with tetra-n-butylammonium fluoride (TBAF) in tetrahydrofuran at room temperature for 30 min. In the event, the dihydroxy ketones 6 and 7 were formed in an identical ratio of 2 : 1 in these examples. The structural assignments to the products are based upon direct spectral comparisons with authentic samples. The trans relat...

Applications of metal and non-metal catalysts for the synthesis of oxygen containing five-membered polyheterocylces: a mini review

“…The electrophilicity for an intramolecular nucleophilic attack was enhanced upon the coordination of the triple bond of propargylic alcohol to a suitable transition-metal catalyst. The oxonium ion intermediate triggered an irreversible 1,2-shift analogous to a formal α-ketol rearrangement, [162][163][164][165][166] and subsequently protonation of the carbontransition-metal bond occurred to regenerate the catalyst and provide the 3(2H)-furanones. The primary amines were used in situ condensation step to expand the diversity of structures obtained from propargylic alcohol, and finally a 1,2-migration occurred to the adjacent iminium ion to afford 3-pyrrolones.…”