Alkaloids protopine

Alkaloid isolation work is summarized in Table Samples of Argemone 

P Corydalis cava, ° C. ochotensis, C. ochotensis var. raddeana, Fumaria 

A new alkaloid, protothalipine (142 R = H), isolated from Thalictrum rugosum, gives muramine (142 R = Me) upon O-methylation. The location of the phenolic hydroxy-group was deduced with the aid of ASIS studies. 

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Reaction under solvolytic conditions such as in ethanol or aqueous tetrahydrofuran caused exclusive C-14—N bond cleavage and introduction of an ethoxyl or hydroxyl group at C-14, giving 30 in excellent yields (34). Addition of a base such as magnesium oxide to the reaction mixture was found to be useful to avoid the recovery of the starting material as the hydrobromide (35). The reaction was used for a synthesis of protopine alkaloids (Section V,E,5). 

The protopine alkaloids have been reviewed (1,2,7-10,190) and compiled (191). Although conversion of protoberberines to protopine alkaloids was achieved relatively early, only a few methods have since been developed. 

Scheme 72. Synthesis of protopine alkaloids through transannular oxygen transfer. Reagents a, peracid b, HC1.

Scheme 73. Synthesis of protopine alkaloids from tetrahydroprotoberberine JV-oxides. Reagents a, K2Cr07 b, Mel.

Bentley and Murray (201) reported another method for synthesis of protopine alkaloids allocryptopine (392) and cryptopalmatine (395) from tetrahydroprotoberberine /V-oxides (35a and 400) through oxidative rearrangement with potassium chromate (Scheme 73). 

Nalliah et al. (202,203) developed a novel entry to protopine alkaloids from a protoberberine. 13-Oxotetrahydroberberine (ophiocarpinone) metho salt (291) was reduced with zinc in 30% acetic acid to afford a new type of the protopine analog 401 (Scheme 74) (202). On the other hand, 291 gave 13-oxoallocryptopine (402) via the hydroperoxide on exposure to air in the presence of sodium hydride and potassium iodide in dimethoxyethane (203). 

Scheme 77. Synthesis of protopine alkaloids by photooxygenation of indenobenzazepines. Reagents a, hv, 02, Methylene Blue b, LAH c, Mn02.

The l-benzyl-tetrahydro-3H-3-benzazepin-2-one (130) with phosphorus oxychloride in boiling toluene cyclizes directly to the indenoazepine (131), a valuable intermediate for the synthesis of protopine alkaloids (80T317) (see Section 5.16.5). 

Certain berberine alkaloids can also be directly prepared from the appropriately substituted protopine alkaloid by photolysis in ethanol.387 Berberine itself (359) is obtained in this way from a-allocryptopine (360), and similar preparations of epiberberine and coptisine have been recorded. 

The protopine alkaloids have a 10-membered ring containing a carbonyl group and a tertiary nitrogen atom. Even though they do not have an isoquinoline ring they are properly classified in the isoquinoline family... 

Protopine alkaloids. A notably efficient route to protopanes is the photooxygenation (Rose Bengal or Methylene Blue) of an enamine such as 1 to give an amido ketone (2), which can be converted into 3 by reduction with lithium aluminum hydride in THF followed by oxidation with activated manganese dioxide. The overall yield is about 65%. 

The overall conversion of these tetrahydroberberine alkaloids to the 10-membered ring aminoketones has provided a good laboratory analogy for what is thought to be the biosynthetic route to the protopine alkaloids. 

Allocryptopine was demonstrated to enhance 3H-y-aminobutyric acid (GABA) binding to rat brain synaptic membrane receptors. Using this phenomenon as an in vitro paradigm, allocryptopine and other protopine alkaloids may be suggested to have benzodiazepine-like activity [175]. 

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