Formation of Chiral C(sp³)−C(sp) Bond by Allylic Substitution of Secondary Allylic Picolinates and Alkynyl Copper Reagents

Abstract

To establish allylic substitution of secondary allylic alcohol derivatives with alkynyl copper reagents, allylic esters bearing the (2-pyridine)CO2-, (2-pyrazine)CO2-, (EtO)2PO2-, C6F5CO2-, o-(Ph2P)C6H4CO2-, MeOCO2-, or AcO- group were examined. First, picolinate (R1 = Me, R2 = CH2OPMB) was subjected to reaction with (TMS-C[triple bond]C)2CuLi.LiBr at 0degreesC. Although no substitution took place, MgBr2 (3 equiv) was found to promote the reaction to produce the anti SN2' product in 93% yield with 94% regioselectivity and 99% chirality transfer. In contrast, substitution of the other esters with the copper reagent in the presence of MgBr2 were less reactive ((2-pyrazine)CO2-) or marginally reactive (other cases). Generality of the substitution using picolinates was established with five picolinates (R1 = Me, Ph(CH2)2, PMBO(CH2)3; R2 = Me, CH2OPMB, CH2OTBS, C5H11, c-C6H11) and seven alkynyl copper reagents (R3 = TMS, Ph, p-TBSOC6H4, p- and o-MeOC6H4, p-MeC6H4, p-FC6H4), furnishing anti SN2' products in 61-93% yields with high regioselectivity (usually >90%) and high chirality transfer (usually >95%). In addition, transformation of the products was briefly studied.

Preparation of conjugated dienoates with Bestmann ylide: Towards the synthesis of zampanolide and dactylolide using a facile linchpin approach

“…Careful analysis of the product mixtures led to the realisation that silyl migration from the primary to the secondary hydroxy group was occurring in the reaction, leading to the C20-linked ester isomer in addition to the desired C19 ester 11g . In contrast, reactions of the PMB-protected variant 7b [ 43 – 45 ] with cinnamaldehyde afforded the product 11h in pure form and reasonable-to-good yields in THF and toluene ( Table 1 , entries 14 and 15, respectively).…”

“…The α,β,γ,δ-unsaturated ester 5a was formed as a mixture of diastereomers ( Scheme 3 ), as expected, but was again contaminated with the regioisomer resulting from silyl migration (2:1 ratio 5a :isomeric C20 ester). Employing the PMB-protected C19 alcohols 7b [ 43 – 45 ] and 7c [ 43 – 45 49 ] led to the desired products 5b and 5c , respectively. While the reaction of 7b with aldehyde 8 in THF took 11 h to go to completion (62% isolated yield of 5b ), the equivalent reaction in toluene required only 5 h (68% yield).…”

“…Although fragment syntheses vary, the late-stage fragment assembly of the dactylolide macrocycle has centred mostly around construction of the C1–C5 dienoate by Wittig-type olefination reactions followed by ester hydrolysis and esterification with the C19 hydroxy group, combined with metathesis to form the alkene at C8–C9. In our synthesis, the doubly unsaturated ester moiety will be formed through an efficient linchpin reaction between the C16–C20 fragment (alcohol 7 ) [ 42 – 45 ], the C3–C8 fragment (α,β-unsaturated aldehyde 8 ) and Bestmann ylide ( 1 , Scheme 1 ). We plan to then attach the C9–C15 aldehyde fragment 6 by asymmetric alkynylation, and form the pyran using an oxa-Michael addition, in a manner reminiscent of that employed by Uenishi and co-workers [ 34 ].…”

Total Synthesis of (+)‐Antofine and (–)‐Cryptopleurine

“…Preparation of Alkyne Ketone 16d by Sonogashira Coupling of Bromo Ketone Carbamate 12d with Optically Pure Alkyne 15. Enantiomeric Excess Assessment of 12d: A procedure analogous to that for 5a was used, starting from bromo ketone 12d (1 equiv., 85 mg, 0.150 mmol), ( R )‐(but‐3‐yn‐2‐yloxy)( tert ‐butyl)diphenylsilane 15 41 (4 equiv., 185 mg, 0.599 mmol), bis(triphenylphosphane)palladium(II) chloride (0.1 equiv., 11 mg, 0.015 mmol), copper(I) iodide (0.04 equiv., 1.1 mg, 0.006 mmol), and triphenylphosphane (0.2 equiv., 8 mg, 0.030 mmol). Compound 16d (98 mg, 82 %) was obtained as a pale yellow semi‐solid after chromatographic purification.…”

Derivatization of Secondary Aliphatic Alcohols to Picolinates – A New Option for HPLC Analysis with Chiral Stationary Phase

“…[7][8][9] Chelation of the carbonyl oxygen and the pyridyl nitrogen in the picolinoxy moiety to MgBr 2 , produced in situ from…”