α‐ and γ‐Regiocontrol and Enantiospecificity in the Copper‐Catalyzed Substitution Reaction of Propargylic Phosphates with Grignard Reagents

Abstract

The regioselectivity (r.s.) and enantiospecificity (e.s.) of the substitution reactions of secondary propargylic alcohol derivatives using reagents derived from ArMgBr and Cu salts were studied. First, the picolinate, 3‐methylpicolinate, and diethylphosphonate derivatives of Ph(CH2)2CH(OH)C≡CTMS were reacted with PhMgBr/CuCN in ratios of 2.5:2.7–2.5:0.25. The use of 2.5:0.25 ratio in THF/DME (6:1) at 0 °C for 1 h afforded the α‐substitution product from the phosphate with ≥98 % r.s. and 99 % e.s. CuBr⋅Me2S gave similar selectivity. The reaction system was then applied to phosphates derived from R1CH(OH)C≡CR2 and ArMgBr to obtain synthetically sufficient r.s. and e.s. values with R2=TMS, Ph, whereas iPr was borderline in terms of size as an R1 substituent. The presence of a substituent at the o‐position of Ar marginally affected the selectivity. We also found that the use of PhMgBr/Cu(acac)2 in a 2:1 ratio in THF produced the γ‐substitution products (allenes) with high r.s. and e.s.

Stereoselective Synthesis of (–)-Heliannuol E by α-Selective ­Propargyl Substitution

“…Scheme 6 Synthesis of (-)-heliannuol E (5) In conclusion, we have successfully synthesized (-)-heliannuol E (5) through an -selective propargyl substitution as the key step. Propargylic phosphate 18 was synthesized from D-malic acid (20) and subjected to copper-catalyzed -selective propargyl substitution to produce alkyne 17 efficiently and with high selectivity.…”

“…The -selective propargylic substitution of 18 with Grignard reagent 28 and CuBr•SMe 2 catalyst produced compound 17, which was deprotected to give diol 29 in 65% yield (Scheme 4). 5 The regioselectivity of the propargyl substitution was >99%, as determined by 1 H NMR spectroscopy (see the Supporting Information). 5 After removal of the TMS group with K 2 CO 3 /MeOH, the resulting alkyne was reduced by using Zn 9 to form olefin 31 in 88% yield.…”

“…5 The regioselectivity of the propargyl substitution was >99%, as determined by 1 H NMR spectroscopy (see the Supporting Information). 5 After removal of the TMS group with K 2 CO 3 /MeOH, the resulting alkyne was reduced by using Zn 9 to form olefin 31 in 88% yield.…”

“…Recently, we reported a copper-catalyzed -selective propargyl substitution of the propargylic phosphate 14 with Grignard reagents (Scheme 1). 5 The reaction proceeds with high regio-and stereoselectivity, irrespective of steric and electronic effects of the nucleophile. Optically active propargylic phosphates can be easily synthesized by the reduction of alkynones with a commercially available ruthenium catalyst.…”

“…Optically active propargylic phosphates can be easily synthesized by the reduction of alkynones with a commercially available ruthenium catalyst. 6 Considering these synthetic advantages, we carried out a stereoselective synthesis of heliannuol E (5). Our retrosynthetic analysis is shown in Scheme 2, where alkyne 17 is proposed to form (-)-heliannuol E ( 5) through an epoxidation and subsequent cyclization reaction.…”