Domino Michael Aldol and Domino Michael Mannich Reactions: Highly Stereoselective Synthesis of Functionalized Cyclohexanes

Abstract

Enantiopure and highly functionalized cyclohexanes may be accessed in a single step and with high stereocontrol from the 7‐oxo‐2‐enimides 1 with use of the title reactions (see scheme). The bifunctional substrates 1 are available by a thermal [3.3]‐sigmatropic rearrangement of aldol products. Xc=chiral auxiliary; M=Cu, Al.

Diastereoselective Conjugate Additions to t-Leucine-Derived N-Enoyl 1,3-Oxazolidin-2-ones

“…5 On the other hand, Kunz and co-workers have reported diastereoselective conjugate addition reactions of dialkylaluminum chlorides to sugar-derived Nenoyl 1,3-oxazolidin-2-ones with very high levels of absolute stereocontrol. 6 In the course of our investigations to evaluate the synthetic potential of the products of the silyloxy-Cope rearrangement of syn-aldols 7 we have had the occasion to study conjugate addition reactions to chiral a,b-unsaturated imides. Because the chiral induction displayed by the standard 4-benzyl-1,3-oxazolidin-2-one was unsatisfactory in accordance to the results reported by others, we turned our attention to the bulkier 4-tert-butyl-1,3-oxazolidin-2-one derived from the unnatural amino acid t-leucine.…”

The Silyloxy-Cope Rearrangement of Syn-Aldol Products: Evolution of a Powerful Synthetic Strategy

“…When 19 was treated with 3 equiv of the monoorganocuprate BuCu×LiI in the presence of 3 equiv Me 2 AlCl at −78°C→ -40°C for 3 h the cyclohexanol 20 was obtained in 41% yield as a single stereoisomer (Scheme 12). 20 The principal side product produced in up to 20% yield originated from the double nucleophilic addition to the conjugate double bond and the aldehyde.…”

“…Whereas the ketone 21 gave rise to the expected amino-substituted cyclohexanol 25, the cyclohexyldiamines 26 were obtained in reactions with the aldehyde 19. 20 Apparently Al-N,O-hemiacetales were formed initially through addition of the amine in concert with Me 2 AlCl (or Me 2 AlNR 2 ) to the aldehyde moiety of 19 and collapsed to the iminium ions 27 at temperatures as high as 0°C. After the conjugate addition of a second equivalent of Me 2 AlNR 2 had occurred an intramolecular Mannich reaction of the imide enolate and the iminium ion commenced giving the final product.…”

“…The 7-oxo-2-enimides 11 turned out to be very versatile starting materials for straightforward syntheses of various complex organic structures. In this account our efforts will be described to use the Cope products as suitable substrates for syntheses of highly substituted and enantiopure oxygen 18 and nitrogen heterocycles, 19 functionalized cyclohexanes 20 as well as polyol chains 21 commonly found in polyene macrolide antibiotics. In addition, we accomplished a total synthesis of the monoterpenol (+)-lasiol from a Cope product.…”

Highly Stereoselective and Efficient Synthesis of Functionalized Cyclohexanes with Multiple Stereocenters

“…Furthermore, the Cope products 2 have proved to be versatile substrates for the straightforward synthesis of various complex organic structures, for example polyalkyl‐substituted tetrahydropyrans,2 piperidines,3 terpenols,4 and 1,3,5,…︁ polyol chains5 commonly found in the antifungal polyene macrolide antibiotics. We subsequently discovered that highly functionalized and enantiopure cyclohexanes may be obtained in one step from the Cope products using organocopper and organoaluminum reagents 6. In this article, we detail our observations on this powerful approach towards the assembly of six‐membered carbocycles with various functional groups and substituents attached to the ring.…”