A Short Diastereoselective Synthesis of the Putative Alkaloid Jamtine, Using a Tandem Pummerer/Mannich Cyclization Sequence

Treatment of 2-phenylhex-5-enal with benzylamine followed by sequential reaction with ethylthioacetyl chloride and sodium periodate oxidation afforded a E/Z mixture of α-sulfinylamides. As
anticipated from a 4π-conrotatory mechanism, cyclization of each olefin afforded fused isoquinoline
lactams as single diastereomers epimeric at the ethylthio position without any cross contamination.
Some preliminary studies were directed toward the synthesis of mesembrine using a 3,4-dimethoxy
aryl group. In this case, the Z-enamide prefers to undergo electrophilic aromatic substitution to
give a substituted azepinone as the preferred product in 87% yield. In contrast, the E-enamide
isomer provided the desired hydroindolone. The convergency and stereochemical control associated
with the tandem Pummerer /Mannich cyclization make it particularly suited for the assembly of
jamtine, a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties. The key step in
the synthesis involves a domino thionium/N-acyliminium ion cyclization to provide the tricyclic
ring skeleton 27a as the major diastereomer. Deprotonation of 27a with NaH gave 28a, which
contains the fully assembled skeleton of jamtine. Completion of the synthesis entailed installation
of the double bond and reduction of the lactam. Oxidation of a synthetic sample of jamtine with
MCPBA afforded the corresponding N-oxide, which does not match the spectral data reported in
the literature for this alkaloid. Our synthetic efforts raise the possibility of a revision of the earlier
assignment.

将2-苯基己-5-烯醛与苄胺（benzylamine）反应后，依次与乙硫代乙酰氯（ethylthioacetyl chloride）反应，再经高碘酸钠（sodium periodate）氧化，得到α-亚磺酰胺类化合物的E/Z异构体混合物。正如4π顺旋（4π-conrotatory）机理所预期，每种烯烃经环化反应后，均可得到仅在乙硫基位点存在差向异构的稠合异喹啉内酰胺类单一非对映异构体，无任何交叉污染。
本研究以3,4-二甲氧基芳基为取代基团，开展了美宾碱（mesembrine）的合成初步探索。在此反应体系中，Z型烯酰胺更易发生亲电芳香取代反应，以87%的收率得到目标取代氮杂卓酮产物。与之相反，E型烯酰胺异构体则可得到目标产物氢化吲哚酮。
串联Pummerer/曼尼希环化反应所具备的汇聚合成特性与立体化学调控能力，使其尤其适用于贾廷碱（jamtine）的骨架构建——贾廷碱是一类因具有治疗活性而备受关注的四氢异喹啉类生物碱。该合成路线的关键步骤为串联硫鎓离子/N-酰基亚胺离子环化反应，以主要非对映异构体形式得到三环骨架化合物27a。用氢化钠（NaH）对27a进行去质子化处理，得到化合物28a，其骨架已完全组装为贾廷碱的核心结构。完成该合成路线尚需引入双键以及还原内酰胺环两步操作。采用间氯过氧苯甲酸（MCPBA）对合成得到的贾廷碱样品进行氧化，得到相应的N-氧化物，但该产物的光谱数据与文献中报道的该生物碱的光谱数据并不一致。本合成研究结果提示，有必要对该生物碱早期的结构指认进行修正。