Synthesis of Tetrahydroisoquinoline Alkaloids and Related Compounds through the Alkylation of Anodically Prepared α‑Amino Nitriles

α-Amino nitrile 2a was conveniently prepared
in two individual steps from chiral hexafluorophosphate salt isoquinolinium
(−)-8b including anodic cyanation as an efficient
means to activate the sp3 C1–H bond of the THIQ
nucleus. The lithiation of 2a was carried out in THF
at −80 °C in the presence of LDA to produce a stable α-amino
carbanion which was condensed on a large variety of alkyl halides.
The resulting quaternary α-amino nitriles were subjected to
a stereoselective reductive decyanation in ethanol in the presence
of NaBH4 as the hydride donor to yield N-Boc-1-alkyl-THIQs (+)-10a–g in
up to 97:3 er’s after removal of the chiral auxiliary group.
Examination of the ORTEP view of THIQ (+)-1f revealed
that the newly created stereogenic center had an absolute S configuration. Likewise, (−)-xylopinine was synthesized
in four workup steps in an overall 63% yield from α-amino nitrile
(+)-2b. In this process, crystallization of an enantioenriched
mixture (90:10) of (−)-norlaudanosine with 1 equiv of (−)-N-acetyl-l-leucine afforded the leucinate salt
(+)-13 (99:1 dr). Similarly, (+)-salsolidine was displaced
from its (−)-DBTA salt (−)-12 in 99:1 er,
which was determined by proton and carbon NMR spectroscopy in the
presence of thiophosphinic acid (+)-14 as the chiral
solvating agent.

α-氨基腈（α-Amino nitrile）2a可由手性六氟磷酸异喹啉鎓盐（chiral hexafluorophosphate salt isoquinolinium）(-)-8b通过两步独立反应便捷制备，其中以阳极氰化反应（anodic cyanation）作为活化四氢异喹啉（Tetrahydroisoquinoline, THIQ）母核sp3杂化C1-H键的高效手段。将2a于四氢呋喃（Tetrahydrofuran, THF）中、-80 ℃条件下以二异丙基氨基锂（Lithium diisopropylamide, LDA）为碱进行锂化反应，可得到稳定的α-氨基碳负离子（α-amino carbanion），该中间体可与多种烷基卤化物发生缩合反应。所得季铵型α-氨基腈（quaternary α-amino nitriles）在乙醇中以硼氢化钠（NaBH4）作为氢负离子供体，进行立体选择性还原脱氰反应（stereoselective reductive decyanation），随后脱去手性助剂，即可得到N-叔丁氧羰基（N-tert-butoxycarbonyl, N-Boc）-1-烷基四氢异喹啉类化合物(+)-10a~g，其对映体比例（enantiomeric ratio, er）最高可达97:3。对四氢异喹啉衍生物(+)-1f的ORTEP图（ORTEP view）进行分析后发现，新生成的手性中心（stereogenic center）具有绝对S构型（absolute S configuration）。同样地，以α-氨基腈(+)-2b为起始原料，经4步后处理操作即可合成(-)-xylopinine，总产率达63%。在该流程中，将90:10对映富集的(-)-去甲劳丹碱（norlaudanosine）与1当量的(-)-N-乙酰-L-亮氨酸（N-acetyl-l-leucine）进行结晶，可得到亮氨酸盐（leucinate salt）(+)-13，其非对映体比例（diastereomeric ratio, dr）为99:1。类似地，从其二(-)-二苯甲酰酒石酸（Dibenzoyl tartaric acid, DBTA）盐(-)-12中解离得到(+)-沙尔索定碱（salsolidine），其对映体比例为99:1；该结果通过以次膦酸（thiophosphinic acid）(+)-14作为手性溶剂化试剂（chiral solvating agent）的氢谱与碳核磁共振波谱法（proton and carbon NMR spectroscopy）得以确证。