Enantioselective formation of quaternary carbon stereocenters in natural product synthesis: a recent update

Abstract

The enantioselective formation of quaternary carbon stereocenters in complex natural product synthesis in the latest six years is reviewed, with particular emphasis on the analysis of the stereochemical model of each enantioselective transformation.

All-carbon [3 + 2] cycloaddition in natural product synthesis

“…The syntheses of daphenylline (11) were reported by Li's group [42] and Zhai's group [43] independently in 2017 (Scheme 6B and Scheme 6C). In Li's synthesis, the common intermediate dienone 86 was subjected to a 1,1'-bis(diphenylphosphino)ferrocene-promoted [3 + 2] cycloaddition [41] with allenyl ketone 91 to give adduct 92a in 52% yield (Scheme 6B).…”

“…Exposure of freshly prepared 92b to triazabicyclodecene [45] led to a ring-expansion/aromatization/aldol cascade producing 93, which was reduced with Et 3 SiH/TFA smoothly to give indane 94 in 68% yield over two steps. The freshly prepared indane 94 was converted to daphenylline (11) in two steps. The preparation of daphnipaxianine A and himalenine D (not shown) were also disclosed in the same work but are not described here.…”

“…The highly-substituted, stereo-congested, five-membered carbocycle containing contiguous stereocenters is one of the most common structural features in many structurally complicated, biologically important natural products [1][2][3][4][5][6][7] (Figure 1). Meanwhile, the construction of quaternary carbon stereocenter(s) is, at present, a distinct challenge in modern synthetic chemistry [8][9][10][11]. Therefore, the synthesis of highly-substituted five-membered carbocycles bearing congested arrays of stereocenters within the polycyclic framework of complex natural products usually require a sophisticated synthetic planning.…”

“…(B) Enantioselective synthesis of marcfortine C (9) features a palladium-catalyzed asymmetric cyano-substituted TMM[3 + 2] cycloaddition[39].in place of ethyl 2,3-butadienoate (82) in the phosphine-catalyzed [3 + 2] cycloaddition. Ethyl 2-butynoate (85) enters the catalytic cycle by reacting with phosphine catalyst A to give H and C. Some total syntheses of hexacyclic Daphniphyllum alkaloids were reported by Li's group (longeracinphyllin A (10) [41] and daphenylline(11) [42]) and Zhai's group (daphenylline (11)[43]), applying Lu's[3 + 2] cycloaddition (Scheme 6). The synthesis of longeracinphyllin A (10), which was reported by Li and co-workers in 2017, used a 1,1'-bis(diphenylphosphino)ferrocene-promoted[3 + 2] cycloaddition[44] of enedione 86 and allenoate 87 to give adduct 88 in 45% yield.…”

Regioselective Markovnikov hydrodifluoroalkylation of alkenes using difluoroenoxysilanes

“…If 1,1-di-, tri-, and tetrasubstituted alkenes are used, Markovnikov regioselectivity will allow the construction of difluoroalkylated quaternary carbons. Because the selective incorporation of quaternary carbons to enhance conformational restriction has been recognized as an effective strategy to improve the properties of bioactive compounds 40 – 43 , it seems only logical that molecules bearing a difluoromethylated quaternary carbon are interesting targets for medicinal research. With these considerations in mind, it was postulated highly desirable to develop the Markovnikov hydrodifluoroalkylation of alkenes.…”