Catalytic asymmetric synthesis of the alkaloid (+)-myrtine

Abstract

A new protocol for the asymmetric synthesis of trans-2,6-disubstituted-4-piperidones has been developed using a catalytic enantioselective conjugate addition reaction in combination with a diastereoselective lithiation-substitution sequence; an efficient synthesis of (+)-myrtine has been achieved via this route.

Direct α‐Functionalization of Saturated Cyclic Amines

“…The described protocol has been used for diastereoselective lithiation to obtain trans-2,6-disubstituted-4-piperidones and the utility of the protocol was shown when applied to the asymmetric synthesis of the alkaloid (+)-myrtine (65) (Scheme 40). [38] The scope of the lithiation of 66, followed by electrophilic trap-ping, was explored with several electrophilic species. The authors anticipated a trans geometry in the products 67 a-e, as the a substituent of 66 must adopt an axial position to minimize pseudo-allylic strain with the Boc group, which facilitates equatorial lithiation at the least substituted a-carbon.…”

“…This was presumably due a lack of coordination of Fe to the substrate, which might also indicate that no imine intermediate is involved in this specific case. Despite the excess substrate required, the Cu-catalyzed methodology for the coupling of unprotected tetrahydroisoquinoline was extended to the coupling with pyrroles 316-318, yielding products 319-321 in moderate yield (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)Scheme 74). The role of the oxidant was examined and studies performed in the absence of oxi-dant with a stoichiometric quantity of Cu (irrespective of its oxidation state) or with TBHP as oxidant in the absence of Cu, showed no product formation, suggesting that the oxidant is not only required to reoxidize Cu I to Cu II in the catalytic cycle.…”

Synthesis of quinolizidine-containing lycopodium alkaloids and related natural products

“…36Scheme 12. Amat's Formal Synthesis of Cermizine C and Senepodine GMinnaard, Feringa and co-workers reported an enantioselective synthesis of myrtine(2.4) in 2008 (Scheme 13) 38. Their synthesis commenced with a catalytic enantioselective conjugate addition to Boc-protected 2,3-dehydro-4-piperidinone (13.1) using the chiral phosphoramidate ligand 13.2 and Me 3 Al to establish in high (96% ee) enantioselectivity.…”

Formation of Quaternary Stereogenic Centers by Copper‐Catalyzed Asymmetric Conjugate Addition Reactions of Alkenylaluminums to Trisubstituted Enones

“…The precise reason for the lower enantioselectivity is unclear but might partially be attributed to the strongly coordinating properties of THF, which allows for the generation of essentially monomeric aluminum species. [19] Formation of the Cu complex in methyl tert-butyl ether (MTBE) as the solvent gave rise to an increase in enantioselectivity compared with diethyl ether, albeit with lower conversion (Table 4; compare entries 5 and 8). Preparation of alane A3 in MTBE gave high enantioselectivity (93 % ee) and full conversion when the Cu complex was prepared in Et 2 O ( Table 4, entry 7).…”