Stereodivergence in the Ireland–Claisen Rearrangement of α-Alkoxy Esters

Abstract

A systematic investigation into the Ireland-Claisen rearrangement of α-alkoxy esters is reported. In all cases, the use of KN(SiMe) in toluene gave rearrangement products corresponding to a Z-enolate intermediate with excellent diastereoselectivity, presumably because of chelation control. On the other hand, chelation-controlled enolate formation could be overcome for most substrates through the use of lithium diisopropylamide (LDA) in tetrahydrofuran (THF).

Scalable Total Synthesis, IP3R Inhibitory Activity of Desmethylxestospongin B, and Effect on Mitochondrial Function and Cancer Cell Survival

“…In preparation for the bis(macrolacram) assembly, the individual amino acid synthons were obtained by Ireland‐Claisen rearrangement (ICR) of two esters prepared from allylic alcohol 4 (Scheme 3 a and b) [11] . Intermediate 2 was obtained from ester 15 (82 % yield, dr 10:1) under reaction conditions developed specifically for α‐alkoxy esters, where we found that the best chelation‐controlled outcome is achieved with KN(SiMe3)2/PhMe combination, while, surprisingly, LDA/THF affords non‐chelation controlled diastereomer with good selectivity, despite the expected higher propensity of lithium to coordinate with oxygen Lewis bases [12] . ICR of ester 16 gave rise to carboxylic acid 17 (87 % yield, dr 6:1), which, after forming the methyl ester with Me 3 SiCHN 2 , was advanced to amino ester 3 by azide reduction with SnCl 2 /PhSH (82 % yield) [13] …”

“…[11] Intermediate 2 was obtained from ester 15 (82 % yield, dr 10:1) under reaction conditions developed specifically for a-alkoxy esters, where we found that the best chelation-controlled outcome is achieved with KN(SiMe3)2/PhMe combination, while, surprisingly, LDA/THF affords non-chelation controlled diastereomer with good selectivity, despite the expected higher propensity of lithium to coordinate with oxygen Lewis bases. [12] ICR of ester 16 gave rise to carboxylic acid 17 (87 % yield, dr 6:1), which, after forming the methyl ester with Me 3 SiCHN 2 , was advanced to amino ester 3 by azide reduction with SnCl 2 /PhSH (82 % yield). [13] Fragment union was achieved by amide formation from acid 2 and amine 3, followed by another azide reduction under the same conditions, ester hydrolysis, and macrolactamization.…”

Nickel-Catalyzed Alkylation or Reduction of Allylic Alcohols with Alkyl Grignard Reagents

“…Each of these Grignard reagents are known. − Their concentrations were titrated using Knochel’s method . Allylic alcohols were prepared according to the reported procedure . NMR spectra were recorded on a Bruker AV400 or Bruker AV300 spectrometer at 25 °C.…”

Stereodivergent routes in organic synthesis: marine natural products, lactones, other natural products, heterocycles and unnatural compounds

“…γ,δ-Unsaturated carboxylic acids bearing a tertiary alcohol at the α-position have been prepared by diastereodivergent Irelan-Claisen rearrangement studied by Zakarian and co-workers. 130 Starting from α-alkoxy-hydrocynnamic or lactic esters, and using KHMDS in toluene, the (Z)-enolate I was formed, which gave the syn-α,β-disubstituted hex-4-enoic acids (Scheme 85). On the other hand, using LDA the (E)-enolate II is formed, the chelation-controlled enolate generation being overcome, so providing anti-diastereomers.…”