Enantioselective Syntheses of Various Chiral Multicyclic Compounds with Quaternary Carbon Stereocenters by Catalytic Intramolecular Cycloaddition

Abstract

The intramolecular cycloaddition of 1,n-diene-ynes (n = 4-6), where alkyne and alkene moieties are connected by a 1,1-disubstituted alkene, was examined using a chiral rhodium catalyst, and various types of cycloadducts with quaternary carbon stereocenter(s) were obtained in high to excellent enantiomeric excess. In the case of 1,4-diene-ynes, tricyclic, bicyclic, and spirocyclic compounds were obtained depending upon the substituents at the 2-position of the 1,4-diene moiety and those at their alkyne termini. On the other hand, 1,5- and 1,6-diene-ynes gave tricyclic and bicyclic compounds, which included medium-sized ring systems. The mechanistic considerations for different reaction pathways and the synthetic transformation of tricyclic products into functionalized spirocyclic compounds are also described. The reaction of enediynes, where two alkyne moieties are connected by a 1,1-disubstituted alkene, was also examined, and sterically strained tricyclic compounds with two carbon stereocenters were obtained.

Catalytic enantioselective synthesis of quaternary carbon stereocentres

“…For example, the cyclization of acyclic dienyne 30 with a Rh/tol-BINAP catalyst led to the formation of bridged azatricyclic product 32 in 88% yield and 99% ee . 30 This reaction presumably takes place via metallacyclic intermediate 31 , which undergoes alkene insertion and reductive elimination to furnish product 32 (Fig. 4d).…”

“…This reaction is suggested to take place via metallacyclic intermediate 31 , which undergoes alkene insertion and reductive elimination to furnish product 32 . 30 Ts, p -toluenesulfonyl; tol-BINAP, 2,2′-bis(di- p -tolylphosphino)-1,1′-binaphthalene; cod, 1,5-cyclooctadiene; L, ligand. e , The cyclization of tetraene aldehyde 33 in the presence of an imidazolone catalyst and a Cu(II) oxidant to form five rings and four quaternary stereocenters of hexacyclic product 35 .…”

Stereoselectivity of Metal-Catalyzed Cyclizations of 1,6-Dienes

“…14 The chiral ligand sphere enables the control of the absolute configuration of the sp 3 -hybridized stereogenic center during the oxidative cyclometalation affording intermediate 21.…”

Synthesis of Spirocyclic Ethers by Enantioselective Copper‐Catalyzed Carboetherification of Alkenols

“…[7g,8a,b,d,e] Aside from spiroketals, which can be made by intramolecular addition of two alcohols to a ketone, [8d] rarely are both rings of the spirocyclic ether formed in the same step, [7b, 9] and de novo formation of both rings of the spirocyclic ether with concomitant control of absolute stereochemistry at the quaternary carbon center is even more rare. [10] The spirocyclic ether synthesis strategy disclosed herein enables the enantioselective double intramolecular 1,2-difunctionalization of unactivated 1,1-disubstituted alkenes using a copper-catalyzed alkene carboetherification (Scheme 1b). This strategy forms both rings of the spirocyclic ether in one step and forms the fully substituted tertiary ether carbon center with control of absolute stereochemistry, thus expanding the repertoire of strategies available to the synthetic and medicinal chemist.…”