Stereochemistry of 1,2-elimination reactions at the E2–E1cB interface—tert-butyl 3-tosyloxybutanoate and its thioester

Abstract

Experimental data on the stereoselectivity of base-catalyzed 1,2-elimination reactions that produce conjugated carbonyl compounds are scarce in spite of the importance of these reactions in organic and biochemistry. As part of a comprehensive study in this area, we have synthesized stereospecifically-deuterated beta-tosyloxybutanoate esters and thioesters and studied the stereoselectivity of their elimination reactions under non-ion pairing conditions. With the availability of both the (2R*,3R*) and (2R*,3S*) diastereomers the innate stereoselectivity could be determined unambiguously. (1)H and (2)H NMR data show that these substrates produce 5-6% syn elimination, the usual amount for acyclic substrates undergoing E2 reactions. Contrary to earlier suggestions, activation by a carbonyl group has virtually no influence upon the stereoselectivity. Elimination of the (2R*,3R*) diastereomer of the beta-tosyloxyester and thioester produces 21-25% of the (Z)-alkene, much more than observed with a poorer beta-nucleofuge. A relatively large amount of (Z)-alkene product seems to be a good marker for an E2 pathway, in which the transition state is E1cB-like, rather than an E1cB(irrev) mechanism. Syn KIE values were higher than those for anti elimination for the esters as well as the thioesters. Experimental challenges to the synthesis of stereospecifically-deuterated beta-tosyloxyesters are discussed.

Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors

“…According to Karplus equation, vicinal coupling constants present a strong correlation with the dihedral angle (θ) enabling correlation of the 3 J CH value with E (θ = 0°) or Z (θ = 180°) stereochemistry of the double bond [25,26]. Thus, in this case, the 3 J CH = 6.9 Hz was observed in the NMR experiment, which corresponds to θ around 0°, confirming the exclusive presence of isomer E as expected, due to the most favorable anti elimination in the E1cB reaction, giving rise to a more stable E -isomer [27].…”

Does Activation of the Anti Proton, Rather than Concertedness, Determine the Stereochemistry of Base-Catalyzed 1,2-Elimination Reactions? Anti Stereospecificity in E1cB Eliminations of β-3-Trifluoromethylphenoxy Esters, Thioesters, and Ketones

“…The (E)-alkenes were formed almost exclusively. 2,3 GC analysis of the elimination mixtures showed only 1.3% of tert-butyl (Z)-2-butenoate (9a) from 1a during the entire course of the reaction and no discernible amount of S-tert-butyl (Z)-2butenethioate (9b) from 1b. Under the reaction conditions for 1a, 29 ± 2% of 9a was shown to isomerize to 2a; thus, no more than 0.5% rearrangement could have taken place in the elimination reactions of 3a and 3b.…”

“…We already have insights into the stereoselectivity of the elimination reactions of stereospecifically deuterated tert-butyl β-trimethylacetoxyand β-tosyloxybutanoate and thiobutanoate esters for which 94−95% anti elimination occurs. 2,3 Liquid-phase density functional theory (DFT) calculations support a stepwise E1cB I pathway for these reactions, except for the elimination of TsOH from the tosyloxyester, which follows a concerted but asynchronous E2 pathway with an E1cB-like transition state. 4 It is generally recognized that anti elimination will dominate over syn elimination under normal conditions, where ion pairing or complex conformational factors of cyclic compounds do not play a major role.…”

Reaction mechanisms : Part (iii) Polar reactions

“…The stereochemistry of the 1,2-elimination reactions of tert-butyl 3-tosyloxybutanoate 55 and thioester analogue 56 (Scheme 16) have been studied by 1 H and 2 H NMR spectroscopy after stereospecific deuteration of both esters to yield single diastereomers. 39 It was observed that activation by a carbonyl group has virtually no influence on the stereoselectivity. All substrates gave 5-6% syn elimination.…”