Synthesis of Enantiomerically Pure Cyclohex‐2‐en‐1‐ols: Development of Novel Multicomponent Reactions

Abstract

Multicomponent reactions of aldehydes, dienophiles, and alcohols or carboxylic acid anhydrides have been developed for the first time. In situ generation of 1-acyloxy- and 1-alkoxy-1,3-butadiene derivatives in toluene in the presence of electron-deficient dienophiles provides selective and efficient access to functionalized cyclohex-2-ene-1-ols in good yields. Subsequent enzyme-catalyzed kinetic resolution gave the corresponding enantiomers with high enantioselectivity.

Sequential Hydroformylation/Diels–Alder Processes: One‐Pot Synthesis of Polysubstituted Cyclohexenes, Cyclohexadienes, and Phthalates from Alkynes

“…The versatility of functionalized 1,3‐butadienes for Diels–Alder chemistry5 has also been demonstrated in the preparation of important natural products such as pumiliotoxin,6 gephyrotoxin,7 dendrobine,8 and tabersonine 9. Furthermore, we have demonstrated the synthetic applicability of MCRs in the preparation of highly substituted anilines, [10 ] bicyclo[2.2.2]oct‐2‐enes,11 enantiomerically pure cyclohexenols,12 and cyclohexenylamines,13 phthalic acids,14 luminol,15 phenanthridones16 as well as lactam derivatives 17…”

Orthoesters: Multiple Role Players in Organic Synthesis

“…Three‐component coupling reactions containing aldehydes, dienophiles, and orthoesters allow for a rapid entry to O ‐alkyl substituted cyclohexenes . The mechanism involves condensation of aldehydes with orthoesters to generate 1‐alkoxy‐1,3‐butadienes as key intermediates 156 , which subsequently are trapped by electron‐deficient dienophiles in a Diels‐ Alder reaction (Scheme , A ).…”

“…Unlike anhydrides and acid chloride, TMOF and TEOF act as water detracting reagents as well as alcohol donors without the need to use molecular sieves and/ or Na 2 SO 4 . This multicomponent reaction was developed for the preparation of hexahydroisoindole derivatives (Scheme , B ). Likewise, multisubstituted cyclohexene can be synthesized through condensation of TMOF with an alkyne and N ‐methylmaleimide as the dienophile (Scheme , C ).…”

“… Proposed mechanism for the formation of functionalized substituted cyclohexenes ( A ), Synthesis of hexahydroisoindole derivatives from orthoesters, unsaturated aldehydes and dienophiles ( B ), An example of hexahydroisoindole derivative prepared from TMOF, alkyne and dienophile ( C ) …”

Acrylonitrile

“…) 108. Silyl enol ethers and alkyl enol ethers will undergo [2 + 2] cycloadditions with acrylonitrile to form cyclobutanes.…”