McDermott Todd S., Mortlock Andrew A., Heathcock Clayton H.
Department of Chemistry, University of California, Berkeley, California 94720.
J Org Chem. 1996 Jan 26;61(2):700-709. doi: 10.1021/jo951647i.
The pentacyclic marine alkaloids (-)-papuamine (1) and (-)-haliclonadiamine (2) have been prepared by total synthesis. The synthesis began with (-)-8, which was converted into diester 20 by way of bis-mesylate 17, dinitrile 18, and diacid 19. Dieckmann cyclization of 20 provided keto ester 21, which was transformed into acetal 22. After hydrolysis of the acetal, ketone 25 was subjected to reductive amination with 1,3-propanediamine and sodium triacetoxyborohydride to obtain diamines 26 and 27 as a 71:29 mixture of diastereomers, favoring the symmetrical isomer having the papuamine relative configuration. After transformation of the diamines to their t-Boc derivatives, the benzyl ethers were cleaved and the resulting diol was oxidized to dialdehyde 30. Application of the Seyferth procedure for conversion of aldehydes to alkynes gave a mixture of diynes 31 and 32. After removal of the t-Boc protecting groups from 31, diamino diyne 15 was treated with tributylstannane and azoisobutyronitrile to obtain the bis-vinylstannane 34. Treatment of this compound with Pd(II) and Cu(I) in the presence of air produced (-)-papuamine (1). (-)-Haliclonadiamine (2) was obtained from the unsymmetrical isomer, 32. The NMR spectra of the synthetic alkaloids were identical to those of authentic samples of the natural alkaloids.
五环海洋生物碱（-）-帕普胺（1）和（-）-哈立克隆二胺（2）已通过全合成制备出来。合成从（-）-8开始，它通过双甲磺酸酯17、二腈18和二酸19转化为二酯20。20的迪克曼环化反应得到酮酯21，其被转化为缩醛22。缩醛水解后，酮25与1,3-丙二胺和三乙酰氧基硼氢化钠进行还原胺化反应，得到非对映异构体比例为71:29的二胺26和27，其中以具有帕普胺相对构型的对称异构体为主。将二胺转化为它们的叔丁氧羰基衍生物后，苄基醚被裂解，所得二醇被氧化为二醛30。应用赛弗斯法将醛转化为炔烃，得到二炔31和32的混合物。从31中除去叔丁氧羰基保护基后，二氨基二炔15用三丁基锡烷和偶氮异丁腈处理，得到双乙烯基锡烷34。在空气中用钯（II）和铜（I）处理该化合物，得到（-）-帕普胺（1）。（-）-哈立克隆二胺（2）从不对称异构体32得到。合成生物碱的核磁共振谱与天然生物碱的真实样品的谱图相同。
