Matrine synthesis

The reaction of 2-(a-pyridyl)alkylmalonic acid with J -piperideine leading to formation of 3-((x-pyridyl)quinolizidine-l-carboxylic acid on decarboxylation, has been used by Van Tamelen and Foltz (316) for the syntheis of the alkaloid lupanine (Scheme 20). A very elegant synthesis of matrine has been accomplished by Bohlmann et al. (317). 

Xanthates serve as a reliable source of electrophilic radicals, and this was exploited by Zard and coworkers for a short synthesis of ( )-matrine (3-304), a naturally occurring alkaloid which has been claimed to have anti-ulcerogenic and anticancer properties [116]. Heating a mixture of xanthate 3-299 and the radical acceptor 3-300 (3 equiv.) in benzene in the presence of lauroyl peroxide as initiator, gave 3-301 in 30% yield and a 3 1 mixture of the tetracylic products 3-302 and 3-303 in 18% yield (Scheme 3.76) [117]. The three compounds could be converted into the... 

Scheme 3.76. Domino radical sequence in the total synthesis of ( )-matrine (3-304).

In a formal total synthesis of matrine (116), Yamanaka and coworkers used the Sonogashira reaction of pyridyl halides as the means to form C—C bonds <86CPB2018>. For instance, bromonaphthyridinone 114 was coupled with 3-butyn-l-ol to furnish alkynylnaphthyridinone 115, an intermediate towards matrine (116). 

The total synthesis of matridine 110) and of matrine 107, 110, 111) have been detailed. 3-Ketoquinolizidine (CXLI), which was obtained by reacting ethyl pyridylacetate with ethyl j8-halogenpropionic ester, was... 

For the synthesis of matrine the penultimate intermediate was 2,6-dioxoquinolizidine (CXLV). The Schilf s base CXLII was reduced and converted to the lactam CXLIV. Dieckmann ring closure, hydrolysis, and decarboxylation gave CXLV which, following a double enamine synthesis with acrylonitrile, and final hydrogenation gave dZ-matrine. Hence the synthesis of dZ-leontine (CXXXVI) (allomatrine) is available. 

A synthesis of matrine under milder conditions although in poorer yield has also been reported 106). The ester half-aldehyde of glutaric acid was condensed to the Schiff base CXLVI with aminolupinane. Dehydrogenation conditions caused cyclization with the formation of a mixture which upon reduction yielded matrine, allomatrine, and lup-anine. 

The hydrogenated pyndo[3,2-//]-1,6-naphthyridin-6-one 305 was synthesized from l,6-naphthyridin-5(6i/)-one 306 in six steps (1986CPB2018). The key stage of the scheme consists in the Heck reaction of 8-iodo-l,6-naphthyridine 307 with ethyl acrylate. Reduction of the double bond in the resulting derivative 308 and cyclization of 309 under the action of sodium methoxide complete the synthesis. The structural fragment in 305 is present in the alkaloid matrine (sophocarpidine) found in dried roots of several plants belonging to the genus Sophora. 

The xanthate group may be reduced away using any of the methods described above for the Barton-McCombie reaction. The lauroyl peroxide/isopropanol system appears to be especially useful in this respect [32a]. This is demonstrated by the transformation in Scheme 16, a key step in the synthesis of (+)-matrine [32b]. Thus, upon heating in refluxing isopropanol with portion-wise addition of a stoichiometric amount of lauroyl peroxide, the double cyclization is followed by the reductive removal of the xanthate group. The reaction gives a 3 1 mixture of isomers, the minor having the relative stereochemistry of a//o-matrine. 

Matrine was isolated at the beginning of the twentieth century [1], and its plane structure was reported about 30 years later. However, it was a further 30 years before the absolute configuration of matrine was deduced by the total synthesis of (+)-matrine [3-5]. 

The total synthesis of -matrine was accomphshed [8], and the antit-richomonal activity of matrine was reported [9]. 

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