Target-oriented multifunctional organocatalysis for enantioselective synthesis of bicyclo[3.3.1]nona-2,6-dien-9-ones. A formal asymmetric synthesis of huperzine A

Synthetic approaches towards huperzine A and B

“…25 Another asymmetric version 26 of the aforementioned domino Michael-aldol sequence was implemented by employing a chiral cinchona base (11) which converted β-keto ester 3 into alcohol 4 in 64% ee. This asymmetric tandem Michael-aldol reaction has also been realized recently by Yao and coworkers 27 under the influence of the quinine-derived chiral thiourea organocatalyst 12 to give rise to the alcohol 4 in 92% enantiomeric excess. Kozikowski disclosed a second generation synthesis of huperzine A in which he exploited a palladium catalyzed annulation of β-keto ester 13 with 2-methylenepropane-1,3-diol diacetate (Scheme 2).…”

Trifunctional Organocatalysts: Catalytic Proficiency by Cooperative Activation

“…[38] Yao and co-workers reported a cinchona alkaloid derived multifunctional thiourea (86) for a tandem Michaelaldol reaction between β-oxo esters (87) and methacrolein (88) for the synthesis of Huperzine A precursors (89) (Scheme 13). [39] The reaction proceeded with low catalyst loading (10 mol-%) over 24 h at room temperature with good yields (75-88 %) and enantioselectivity (88-92 %, based on 90) for 7 examples. Compound 90 was prepared from 89 to facilitate chiral HPLC analysis.…”

“…Tandem Michael-aldol reaction for the formal synthesis of Huperzine A. [39] Lu et al reported a cinchona alkaloid inspired organocatalyst (94) for an enantio-and diastereoselective Michael addition between phthalide derivatives (95) to nitro olefins (96) to yield bicyclic lactams (97) (Scheme 14). [40] The reaction proceeded with excellent yields (65-95 %) and enantioselectivity (80-98 %) at room temperature over 12 h with relatively low catalyst loading (10 mol-%).…”

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

“…Employing the same catalyst as before, organocatalyst 27 , another synthesis of the bridged core 30 and specifically the bicyclo[3.3.1]nonadienone of (−)-huperzine was reported ( Scheme 11 ) [ 22 ]. The reagents were the analogue of pyridine 28 and an α,β-unsaturated aldehyde 29 .…”