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An efficient stereoselective synthesis of the nuphar alkaloid, (-)-nupharamine, is reported. The key features include the Lewis acid catalyzed reaction of an α-chlorosulfide with a silyl ketene acetal for C-C bond formation, creation of the stereocenter at C2 by a diastereoselective reaction of allyl indium with a sulfinimine and reductive amination for the introduction of the C6 stereocenter of the piperidine ring.

An animalic note: The first total synthesis of the all-cis nupharamine 2, an alkaloid from beaver castoreum, is based on the stereoselective domino Mannich-Michael reaction of N-galactosylfurylaldimine to give 1 (Piv = pivaloyl), subsequent conjugate cuprate addition, and stereoselective protonation of the enolate. These reactions are all controlled by the carbohydrate. Protonation of the enolate after cleavage of the auxiliary leads to epimer 3.

A short and convergent synthesis of the naturally occurring sesquiterpenoid piperidine alkaloid (-)-nupharamine is presented starting from (-)-isopinocampheol via cross metathesis and reductive animation as the key steps.

Chiral synthesis of (−)-nupharamine and (+)-3-epinupharamine, based on elaboration of the intramolecular asymmetric Diels-Alder reaction of N-acylnitroso compounds and the introduction of the furyl group in a fully stereocontrolled manner, is described.

Enantiospecific syntheses of (–)-anhydronupharamine, (–)-nupharamine, (–)-nuphenine, and (+)-3-epinupharamine are achieved starting from (–)-or (+)-carvone as chiral sources, in which a regioselective reductive fragmentation of the cyclopentane derivatives and an intramolecular aza–Wittig reaction were involved as key reactions.

A simple and effective approach to the total synthesis of (-)-nupharamine (I) is presented, which allows to control the stereochemistry at C-3 by epimerization of the ethoxycarbonyl function. The key steps are reductive amination of the respective substituted 1,5-diketone V and enantiomer resolution of piperidine VI using (1S)-(-)-camphanic acid.

Enantiospecific syntheses of (–)-anhydronupharamine, (–)-nupharamine, (–)-nuphenine, and (+)-3-epinupharamine are achieved starting from (–)-or (+)-carvone as chiral sources, in which a regioselective reductive fragmentation of the cyclopentane derivatives and an intramolecular aza–Wittig reaction were involved as key reactions.

Reaction of the optically active alkenyloxirane with formic acid in the presence of palladium(0)-phosphine catalyst gave the homoallylic alcohol selectively, which was converted to (−)-nupharamine.

The alkaloids (±)-nupharamine and (±)-3-epinupharamine were synthesized using 3-acetylfuran as the starting material. The conditions for stereoselective reduction of pyridine derivatives are described.

Studying the synthesis of nupharamine, a minor alkaloid isolated from Nuphar japonicum DC, N-methylnupharamine was synthesized and its stereoisomers were characterized.

川骨のアルカロイドとしては,ヌファリジン,デスオキシヌファリジン,およびヌファラミンが知られているが,副アルカロイドをさらにアルミナクロマトグラフィーによって分離したところ,ヌファラミンーメチルエーテル,およびエチルエーテルを単離することができた。

A new alkaloid (I), C15H23O2N has been isolated from Nuphar japonicum DC. and named nuphamine. The compound (III) obtained by the catalytic reduction after the chlorination of I with thionyl chloride is completely in accordance with (-)-desoxynupharamine, derived from nupharamine (IX). By the catalytic reduction of I with palladium-carbon, dihydronuphamine (V), (-)-deoxynupharidine (VI-A) and allodeoxynupharidine (VI-B) were prepared. VI-A and VI-B were also prepared from V. Judging from these reactions and the nuclear magnetic resonance spectra, the structure of I has been determined to be presented by the fromula VIII. The steric chemical correlations among the alkaloids, (-)-desoxynupharidine (VI-A), (-)-nuphamine (VIII) and (-)-nupharamine (IX) isolated from Nuphar iaponicum have been also achieved.

The alkaloids (±)-nupharamine and (±)-3-epinupharamine were synthesized using 3-acetylfuran as the starting material. The conditions for stereoselective reduction of pyridine derivatives are described.