I. Completion of the synthesis of Kopsia lapidilecta alkaloid (+/-)-lapidilectine B. II. Synthesis of 1-azabicyclo[n.3.0]alkanes via [3+2] cycloadditions of nonstabilized azomethine ylides.

Abstract

The completion of the total synthesis of <italic>Kopsia lapidilecta</italic> alkaloid (+/-)-lapidilectine B is described. A key element of this synthesis includes installation of a pyrrolidine ring by a (2-azaallyl)stannane-derived nonstabilized 2-azaallyllithium (2-azaallyl anion) [3+2] cycloaddition with the acetylene equivalent phenyl vinyl sulfide. Closure of the 8-membered perhydroazocine ring is accomplished via the intramolecular S_N2 substitution of a mesylate to form a 1-azabicyclo[6.3.0]unadecane ring system. This constitutes the first synthesis of a member of the 5,6,12,13-tetrahydro-11a,13a-ethano-3<italic> H</italic>-pyrrolo[1<super>'</super>,2<super>'</super>:1,8]azocino[5,4-<italic> b</italic>]indole class of alkaloids. Nonstabilized azomethine ylides (i.e., those bearing only hydrogens or alkyl groups) were generated from (2-azaallyl)stannanes and (2-azaallyl)silanes through an intramolecular <italic>N</italic>-alkylation/demetallation cascade. The resulting ylides undergo [3+2] intermolecular cycloaddition with <italic> N</italic>-phenylmaleimide and intramolecular cycloaddition with unactivated olefins to yield 1-azabicyclo[n.3.0]alkanes in good yield. An in situ protocol allows for a one-pot, three-component synthesis of 1-azabicyclo[3.3.0]octanes (pyrrolizidines), 1-azabicyclo[4.3.0]nonanes (indolizidines), 1-azabicyclo[5.3.0]decanes, and 1-azabicyclo[6.3.0]unadecanes. The (2-azaallyl)stannanes tolerate enolizable hydrogens in these cycloadditions, while (2-azaallyl)silanes do not. The mechanism of the cycloaddition cascade was clarified by a series of control experiments. The ylide geometry (anti vs. syn) of 1,3-disubstituted and 1,1,3-trisubstituted azomethine ylides generated by this method was studied via analysis of the distribution of cycloadduct diastereomers. Addition of organolithium reagents to <italic>N</italic>-(tri-<italic> n</italic>-butylstannylmethyl)phthalimides yields <italic>N</italic>-(tri-<italic> n</italic>-butylstannylmethyl) cyclic carbinol amides, which form azomethine ylides upon treatment with HF&middot;pyridine and other electrophiles. This novel route to azomethine ylides allows rapid access to highly functionalized 1-azabicyclo[3.3.0]octanes (1,2,3,9b-tetrahydropyrrolo[2,1-<italic>a</italic>]isoindol-5-ones) through the inter- and intramolecular modes of cycloaddition.