Design and synthesis of (E)-1-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl-4-substitiited benzenes from 1-(2,6,6-trimethylcyclohex-1-enyl)ethanol

摘要

A novel strategy for synthesizing (E)-l-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl-4-substituted benzenes from l-(2,6,6-trimethylcyclohex-l-enyl)ethanoI 3 has been developed; the allylic alcohol 3 was treated with PPh_·HBr in methanol followed by aldehydes in the presence of a base and furnished the 1,3-dienes in moderate to good yields (79-86%).rnIn the context of an ongoing chemical biology project, studying the role of retinoic acid signaling pathways during zebrafish embryogenesis, we synthesized novel retinoid libraries. Retinoids (retinoic acid analogues) play key roles in embryo-genesis and for maintenance of various cellular processes such as cell growth and differentiation. Retinoids also have clinical value for cancer chemoprevention and therapy, although their use is limited by toxicity and teratogenecity at pharmacological doses. Retinoids exert their biological effects by activating nuclear receptors and modulating gene transcription. A clear understanding of the biological roles of the retinoid receptor families would greatly facilitate the design of retinoid analogues that could be targeted for specific diseases to improve the therapeutic index. A number of synthetic retinoids have been synthesized that interact selectively with its receptors. Understanding the importance of the retinoids we were keen to synthesize compounds la-c as new retinoic acid analogs by introducing a constrained phenyl ring system in the place of conjugated alkene backbone (spacers). In the process of synthesizing compound la, we encountered an unusual Wittig salt formation from the allylic alcohol 3 which involved the formation of the unusual 1,3-diene 2 when the Wittig ylide 4 was treated with aldehyde 5. The regio- and stereospecific synthesis of 1,3-dienes is of great importance in synthetic organic chemistry due to the frequent occurrence of these fragments in biologically active natural products, as well as to their utilization in numerous transformations such as the Diels-Alder reaction.