title: 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.
authors.affiliation: Department of Chemistry, Oregon State University, Corvallis, OR 97331 (USA).
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Emerson
authors.forename: Lev N
authors.initials: LN
authors.lastname: Zakharov
authors.forename: Paul R
authors.initials: PR
authors.lastname: Blakemore
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008094:Lithium / Q000737:chemistry*; D008968:Molecular Conformation; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013454:Sulfoxides / Q000737:chemistry
chemical_list: D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009942:Organometallic Compounds; D011725:Pyridines; D013454:Sulfoxides; D008094:Lithium; C082748:epibatidine
keywords: alkaloid synthesis; boronic esters; carbenoids; homologation; sulfoxide-lithium exchange