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Total synthesis of veratrum alkaloids

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Title: Total synthesis of veratrum alkaloids
Author: Cable, John
Degree: Doctor of Philosophy - PhD
Program: Chemistry
Copyright Date: 1968
Subject Keywords Alkaloids;Veratrine
Issue Date: 2011-06-29
Publisher University of British Columbia
Series/Report no. UBC Retrospective Theses Digitization Project [http://www.library.ubc.ca/archives/retro_theses/]
Abstract: A synthetic approach to members of the Veratrum alkaloids and its application in the synthesis of verarine is described. The condensation of optically active 3β-acetoxy-5α-etiojerv-12-en-17-one (76), a known compound available from the degradation of hecogenin acetate, with the lithium derivatives of various substituted 2-ethylpyridines is outlined as a general scheme for synthesising the carbon skeleton of members of the Veratrum alkaloids. Condensation with the lithium derivative of 2-ethyl-5-methylpyridine (105) followed by acetylation of the product gave a mixture of four isomers possessing the verarine skeleton (106). The two major isomers designated "A" and "B" were separately converted to the ring D aromatic compounds (107) by heating with palladised charcoal and the products shown to be isomeric. Selective hydrogenation of the pyridine moiety in either ring D aromatised compound (107) gave a mixture of four isomers which contained the piperidine ring (108). These compounds were separated and then converted to the N-acetyl derivatives (110) via the 3-0,N-diacetyl derivatives (109). Degradation of veratramine (2) by a known procedure gave 3-0,N-diacetylverarine (117). Hydrogenation of the 5,6-double bond employing Adams catalyst in acetic acid gave a 1:1 mixture of the 5α,6- and 5β,6-dihydro compounds which were separated as the N-acetyl derivatives (120, 121). The N-acetyl derivative of one of the eight isomers obtained from hydrogenation of the isomeric aromatic compounds (107) has been identified as N-acetyl-5α,6-dihydroverarine (120). The conversion of this compound to verarine (Ӡ) was carried out on a quantity of material obtained from veratramine. Oxidation with Jones reagent led to N-acetyl-3-keto-5α,6-dihydroveiarine (111) which was converted to N-acetyl-Δ⁴-3-keto-5,6-dihydroverarine (112). Treatment of this α,β-unsaturated ketone with isopropenyl acetate gave the enol acetate (113) which was converted to N-acetylverarine (114). Removal of N-acetyl group gave verarine (3) which was identified by comparison with an authentic sample. This completes in a formal sense the total synthesis of verarine since hecogenin has been totally synthesised. The total synthesis of racemic 3β-acetoxy-5α-etiojervan-17-one from 6-naphthol by other members of this laboratory is mentioned and its comparison with the natural (+) 3β-acetoxy-5α-etiojervan-17-one is noted.
Affiliation: Science, Faculty of
URI: http://hdl.handle.net/2429/35823
Scholarly Level: Graduate

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