Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

Abstract

Four putative functionalized α-chloroakyllithiums RCH2CHLiCl, where R=CHCH2(18 a), CCH (18 b), CH2OBn (18 c), and CH[O(CH2)2O] (18 d), were generated in situ by sulfoxide-lithium exchange from α-chlorosulfoxides, and investigated for the stereospecific reagent-controlled homologation (StReCH) of phenethyl and 2-chloropyrid-5-yl (17) pinacol boronic esters. Deuterium labeling experiments revealed that α-chloroalkyllithiums are quenched by proton transfer from their α-chlorosulfoxide precursors and it was established that this effect compromises the yield of StReCH reactions. Use of α-deuterated α-chlorosulfoxides was discovered to ameliorate the problem by retarding the rate of acid-base chemistry between the carbenoid and its precursor. Carbenoids 18 a and 18 b showed poor StReCH efficacy, particularly the propargyl group bearing carbenoid 18 b, the instability of which was attributed to a facile 1,2-hydride shift. By contrast, 18 d, a carbenoid that benefits from a stabilizing interaction between O and Li atoms gave good StReCH yields. Boronate 17 was chain extended by carbenoids 18 a, 18 b, and 18 d in 16, 0, and 68% yield, respectively; α-deuterated isotopomers D-18 a and D-18 d gave yields of 33 and 79% for the same reaction. Double StReCH of 17 was pursued to target contiguous stereodiads appropriate for the total synthesis of (-)-epibatidine (15). One-pot double StReCH of boronate 17 by two exposures to (S)-D-18 a (≤66 % ee), followed by work-up with KOOH, gave the expected stereodiad product in 16% yield (d.r.~67:33). The comparable reaction using two exposures to (S)-D-18 d (≤90% ee) delivered the expected bisacetal containing stereodiad (R,R)-DD-48 in 40% yield (≥98% ee, d.r.=85:15). Double StReCH of 17 using (S)-D-18 d (≤90% ee) followed by (R)-D-18 d (≤90% ee) likewise gave (R,S)-DD-48 in 49% yield (≥97% ee, d.r.=79:21). (R,S)-DD-48 was converted to a dideuterated isotopomer of a synthetic intermediate in Corey's synthesis of 15.

Chain Extension of Boronic Esters with Lithiooxiranes Generated by Sulfoxide–Metal Exchange – Stereocontrolled Access to 2°/2°, 2°/3°, and 3°/3° Vicinal Diols and Related Compounds

“…Thus, for example, chlorosulfoxide 14 with 95 % ee gave cis ‐epoxide 16c exhibiting only 81 % ee by the illustrated route ( ee data for other epoxides are given in the Supporting Information). Loss of stereochemical integrity in reactions involving α‐chlorosulfoxide carbanions has previously been observed, but the phenomenon is not well understood 3c,15. Alternate methods for sulfinyl epoxide synthesis are available that deliver higher ee and dr if required 16…”

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

“…In fact, they allow the direct homologation of carbonyl compounds and imines leading to β-halo-alcohols and amines that are useful building blocks [29–31]. This work represents a remarkable example of flash chemistry, and has elements of sustainability considering that in batch macroreactors, in order to avoid metal-assisted α-elimination, in situ quenching, an excess of reagents, and very low temperature are required [32–33]. …”

Formation of Olefins by Eliminative Dimerization and Eliminative Cross‐Coupling of Carbenoids: A Stereochemical Exercise

“…entry 5), [8,14] deprotonation at the a-position (if aprotons are present) within the a-chloroalkyl sulfoxide starting material by the initiating organolithium competes with the desired process.The product carbenoid is itself basic enough to also deprotonate its precursor (leading to partial quenching of the carbenoid). [15] Unwanted proton exchanges do not complicate comparable sulfoxide-magnesium exchange reactions [16] and the interaction of simple Grignard reagents with a-chloroalkyl sulfoxides provides an incredibly efficient entry to configurationally stable stereodefined achloroalkylmagnesium chlorides in high yield (e.g.entry 6). [11] Notably,s ulfoxide-magnesium exchange is also chemoselective when applied to a-bromoalkyl sulfoxides,w hereas attempted sulfoxide-lithium exchange from the same substrates results in competition between the desired process, deprotonation, and bromine-lithium exchange.…”

“…Bpin = B(OCMe 2 CMe 2 O). [15] Scheme 4. Eliminative dimerization of a-haloalkyllithiums (and related species) derived from the corresponding stannanes by tin-lithium exchange.…”