Synthesis of (+)-Disparlure via Enantioselective Iodolactonization

Abstract

The BINOL-amidine organic catalyst 1 was previously shown to promote highly efficient enantioselective halolactonization reactions of olefinic acids. As part of these studies, it was discovered that the enantioenriched iodolactones could be easily converted into enantioenriched cis-1,2-disubstituted epoxides. This halolactonization-epoxidation sequence was applied to the synthesis of (+)-disparlure, which resulted in the shortest catalytic enantioselective synthesis to date, requiring only five steps and proceeding in 33% yield.

Enantioselective Halolactonization Reactions using BINOL-Derived Bifunctional Catalysts: Methodology, Diversification, and Applications

“…This process was then applied in the syntheses of several synthons of the F ring subunit of the natural product kibdelone C ( vide infra ). 9a Iodolactonization of 58 could be effected using catalyst 20 , but the resultant iodolactone was unstable. On the other hand, the utility of 20 as a catalyst to promote kinetic resolutions of racemic olefinic acids is illustrated by the iodolactonizations of 60 and 62 to deliver the corresponding bicyclic iodolactones 61 and 63 in 83:17 er and 78:22 er, respectively (Equations 6 and 7).…”

“…A similar iodolactonization-epoxidation sequence was utilized in our concise enantioselective synthesis of (+)-disparlure ( vide infra ). 9b …”

“…8b The kibdelone fragments 67 and 73 9a and (+)-disparlure ( 74 ) 9b were synthesized according to our previously reported procedures.…”

“…5d Herein we report the details of our methodological studies directed toward the design and development of novel organic catalysts for enantioselective bromo- and iodolactonizations, 8 as well as the applications of these enantioselective halolactonizations to solving several synthetic problems in this account. 9 …”

Synthesis of disparlure and monachalure enantiomers from 2,3-butanediacetals

“…These methods use various approaches to ensure the required configuration of the asymmetric centers determining the biological activity of this compound. They include the use of naturally occurring chiral substrates, such as ʟ-glutamic acid [13], ʟ-tartaric acid [14][15][16], ᴅ-glucose [17], and sorbitol [18] as starting materials, as well as enantioselective reactions, such as the Sharpless epoxidation [19][20][21][22][23][24], asymmetric dihydroxylation [25,26], chloroallyloboronation [27], or iodolactonization [28]. Most recently a method using the asymmetric chlorination of dodecanal by LiCl in the presence of a chiral imidazolidinone catalyst has also been described [29].…”