Continuum of Mechanisms for Nucleophilic Substitutions of Cyclic Acetals

Abstract

The effect of nucleophile strength on diastereoselectivity in the nucleophilic substitution of cyclic acetals was explored. Stereoselectivity remained constant and high as nucleophilicity increased until a threshold value was reached. Beyond this point, however, selection of Lewis acid determined whether stereochemical inversion or erosion was observed.The development of stereocontrolled glycosylation reactions is complicated by the fact that these processes may proceed via S N 1-like 1-3 or S N 2-like 4-10 mechanisms. Changes in the glycosyl donor, 11,12 nucleophile, 13,14 activator, 15 and solvent 16 can alter selectivity unpredictably. This report documents the relationship between nucleophile strength and stereoselectivity for the substitution reactions of cyclic acetals; we describe dramatic changes in stereoselectivity and provide mechanistic rationales for these findings. This study provides insight applicable to the development of new stereoselective glycosylation reactions.Acetal 1 was treated with a panel of nucleophiles having known nucleophilicity parameters (N) 17 in the presence of Me 3 SiOTf (Table 1). A nucleophile's N value is a direct measure of reactivity: it correlates logarithmically with its rate of reaction with carbocationic electrophiles. 17 Reactions with π-nucleophiles spanning more than four orders of magnitude of nucleophilicity led to selective formation of 1,4-trans products (entries 1 and 2). A roughly one hundred-fold further increase in N, however, associated with application of silylketene acetal nucleophiles 9-11, resulted in reversal of diastereoselectivity: 1,4-cis products were formed selectively (entries 3-5). This dichotomy in stereochemical outcomes suggests a change in reaction mechanism. 18We have reported previously an electrostatic model to explain the trans selectivities observed in the reactions of acetal 1 with weak nuceophiles (e.g., 7 and 8). 19,20 These reactions occur by S N 1-type mechanisms involving oxocarbenium ion intermediate I (Scheme 1). 21 Axial attack on the electrostatically preferred axial conformer I ax affords trans products via a chairlike transition state. This model, however, does not account for the cis selectivities observed when strong nucleophiles 9-11 react with 1. It is unlikely that the 1,4-cis ester products cis-(4-6) arise from disfavored equatorial conformer I eq because increased nucleophile strength should not alter the conformational equilibrium of the oxocarbenium ion. Moreover, the selectivities of reactions of I ax and I eq should be independent of nucleophile reactivity unless reaction rates approach the diffusion limit. 22 kwoerpel@uci.edu. The stereochemical inversion observed in Me 3 SiOTf-activated reactions of electrophile 1 with silylketene acetals 9-11 can be explained by S N 2-like substitutions 23-27 of triflate-trapped contact ion-pairs 28 II via transition state III (Scheme 2). Transition state III is consistent with the electrostatic model. As the triflate group departs from the axial orientation, the trans...

Correlations Between Nucleophilicities and Selectivities in the Substitutions of Tetrahydropyran Acetals

“…Purification by flash chromatography (10:90 EtOAc/hexanes) afforded the product as a colorless, clear oil (0.094 g, 80%). Characterization matches reported values 36 and is reported for the isolated isomers cis - 29 and trans - 29 .…”

“…34 These stereochemical models fail when the rates of nucleophilic addition to the intermediate oxocarbenium ion approach the diffusion limit. 35,36 …”

Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions

“…1) (20–23). Catalysts promoting stereoselective glycosylation via S N 1 pathways would have to bias the addition of the nucleophilic partner to either diastereotopic face of an oxocarbenium intermediate generated by ionization of the electrophilic partner (Fig.…”

Do Glycosyl Sulfonium Ions Engage in Neighbouring‐Group Participation? A Study of Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity

“…The steric bulk of the nucleophile should have no effect on the conformational equilibrium of an oxacarbenium ion. [48] However, the two-conformer hypothesis (Scheme 6) assumes that the b-glycoside initially forms in a 1 C 4 conformation in which there are unfavourable 1,3-diaxial interactions. Therefore, less reactive/more bulky nucleophiles should be less inclined to react with oxacarbenium ions in the 3 H 4 conformation, and may display greater stereoselectivity than would be predicted by simply calculating the relative abundance of 3 H 4 and 4 H 3 conformers.…”

“…In this case, the b-glycoside could not result from a 3 H 4 intermediate as the conformation of the sugar ring is locked by the benzylidene acetal; therefore, it probably arises from a change in mechanism to involve an a-triflate intermediate. [15,48] Nevertheless, such an intermediate would presumably also be the product of an S N 1-like opening of the oxathiane ring.…”