Asymmetric Total Synthesis of Alkaloid-223A Through á-(N-Carbamoyl)alkylcuprate and á-[(N-Carbamoyl)alkyl]cyanocuprate Chemistry

Alkaloids with an indolizidine ring ([4.3] bicycle with bridgehead N-atom), are important targets in medicinal chemistry due their biological activity showing antitumor and neurological properties.   Alkaloid-223A (1) was discovered in the skin of tropical amphibians in the late 1990s and was the first trialkyl-substituted indolizidine alkaloid that, contained 4 chiral centers.   To date, 5 total syntheses for 1 have been reported, each having about 10 steps.   This target provides a good opportunity to use the chemistry developed in our laboratory for α-(N-Carbamoyl)alkylcuprates (R₂CuLi) 2 and α-[(N-Carbamoyl)alkyl]cyanocuprates (RCuCNLi) 3 in the total synthesis of 1.   These cuprates contain a pyrrolidinyl ring that can be prepared in an enantioenriched fashion using commercially available materials (with (-)-sparteine as chiral ligand).  Thus 2 and 3 were tested to undergo in allylic-S_N2’on allylic phosphates 4.   These allylic phosphates were prepared by a new synthetic route starting with ethyl glyoxylate (HCC(O)OEt) and triorganoalkynylzincs [(R¹-C≡C)₂ZnMeLi, R¹=C₄H₉, C₂H₅, C₆H₅] , followed by hydrogenation with Lindlar catalyst to produce (Z)-allylic alcohols [R¹-C=C-C(OH)COOEt] 5 in good yields (80-85%).  Then the alkoxide of 5 (deprotonation using LDA) was reacted with diphenyl phosphoryl chloride, (PhO)₂P(O)Cl,  to produce 4 in situ and at this point cuprate 2 or 3 was added to obtain the allylic substitution.  With R¹=C₂H₅, next steps will involve another catalytic hydrogenation followed by N-Boc deprotection and in situ cyclization, axial alkylation, treatment with EtMgBr and LiAlH₄ to obtain the enantiopure 1 in 7 steps.  Alkaloid-223A will be another example of nitrogen heterocycle synthesis through these cuprates.