S_N2 Reactions at Tertiary Carbon Centers in Epoxides

Abstract

Described herein is anovel concept for S N 2reactions at tertiary carbon centers in epoxides without activation of the leaving group.Q uantum chemical calculations show why S N 2 reactions at tertiary carbon centers are proceeding in these systems.T he reaction allows flexible synthesis of 1,3-diol building blocks for natural product synthesis with excellent control of the relative and absolute configurations.Designing novel reactions based on mechanisms which are commonly considered as unfavorable is ac hallenging approach to research in chemistry.I ta llows us to overcome limitations in our mechanistic understanding and lays the basis for the discovery of novel synthetic strategies. S N 2r eactions at tertiary carbon atoms provide an attractive starting point for such as trategy.A sy et, S N 2 reactions at tertiary carbon centers require either destabilization of the cation to be formed for the competing S N 1 reaction, [1, 2] or substrates with very good leaving groups. [3, 4] A recent excellent example is the synthesis of isonitriles from tertiary trifluoroacetates and Me 3 SiCN catalyzed by Sc-(OTf) 3 [5] ,areaction that proceeds by stereoselective trapping of the contact ion-pair.Aslight erosion of the exclusive inversion of configuration was observed, however.T he reaction of epoxides with BF 3 and NaBH 3 CN is conceptually similar. [6] It results in ar ing-opening with hydride as nucleophile at the higher substituted carbon atom with inversion of configuration. Thes trong Lewis acid BF 3 may lead to rearrangements of the epoxide.Herein we report S N 2reactions at tertiary carbon centers of epoxides relying on enforcing af avorable "backside attack" of the nucleophile rather than on activating the leaving group.W ith unsymmetrically substituted epoxides typical S N 2r eactions occur at the less substituted carbon center and not at the more substituted carbon center. With our system, this selectivity is overcome by binding ap ronucleophile to the substrate,w ith subsequent activation of the intermediate formed by ac atalyst. In this manner,t he key feature of S N 2r eactions,t he complete inversion of configuration, is preserved, while side-reactions with activated leaving groups,such as skeletal rearrangements or erosion of stereochemical integrity by cation formation, are avoided.Thereductive opening of Sharpless epoxides [7] affords an efficient approach to the synthetically important 1,3-diol unit. Ther egioselective opening at tertiary centers remains unresolved. Here,w ec hose PhSiH 3 with catalytic amounts of tetrabutylammonium fluoride (TBAF) [8] to realize this goal by epoxide hydrosilylation. [9] This reagent combination does not open simple trisubstituted epoxides.I n1 ,2-disubstituted epoxides,hydroxy substitution is mandatory,asdemonstrated in asynthesis of 1,4-diols by S N 2reaction at secondary carbon centers,and occurs by formation of asilyl ether and activation of the silyl ether by fluoride.Opening of 1, 3,a nd 5 with PhSiH 3 /cat. TBAF results in exclusive formation of 1,3-diols wit...

Trifluoroethanol-Mediated Cyclization of Two-Carbon-Tethered Epoxide–N-Boc Pairs: Completely Regioselective Synthesis of 3,6-Disubstituted 1,3-Oxazinan-2-ones

“…However, preferential formation of products 2w′ and 2x′ over the regioisomeric products 2w and 2x (Scheme 5 ) raises the question as to why substrates 1w and 1x underwent S N 2-type cyclization in the 5- exo mode (via intermediates III ) instead of the 6- endo one (via intermediates IV ) (Scheme 6 B). From the conceptually related epoxide-opening reactions discussed in Gansäuer’s seminal work entitled ‘S N 2 Reactions at Tertiary Carbon Centers in Epoxides’, 18 we hypothesize that the preference of the S N 2 reaction at the tertiary epoxide carbon (instead of the secondary epoxide carbon) might be due to a better orbital overlap in the transition state according to the original Baldwin rules. 19…”

Stereospecific and stereoconvergent nucleophilic substitution reactions at tertiary carbon centers

“…In another example, nucleophilic ring opening of Sharpless epoxides was reported by Grimme and Gansa ¨uer (Scheme 6B). 20 A combination of PhSiH 3 and tetrabutylammonium fluoride (TBAF) was used to generate active hydride for the ring opening of epoxides. The hydride was selectively added to tertiary gem-Dichlorooxirane, an intermediate of Corey-Link reaction, can undergo ringopening reactions with nucleophiles.…”

Catalytic Reduction of Cyclic Ethers with Hydrosilanes

“…As an extension of work on fluoride catalysis, Gansäuer et al. reported the fluoride‐catalyzed stereospecific hydrosilylation of a range of α‐hydroxy epoxides (Scheme ) . The reaction with PhSiH 3 (4 equiv) proceeded at 25 °C through an intramolecular S N 2 hydride transfer in the presence of 20–50 mol % TBAF.…”