Phlegmarines

Vinyl ethers and vinyl esters are not employed extensively in organic transformations. During the synthesis of phlegmarine, however, the stereogenic center at C-10 was to be introduced stereoselectively by catalytic hydrogenation-hydrogenolysis of the vinyl triflate (Scheme 4.7). 

The study above does not account for the extra six carbons acquired in the conversion of piperideine (8, 10 carbons) to phlegmarine (9, 16 carbons). It was initially proposed that the carbons were incorporated via pelletierine (12), which was incorporated twice into lycopodine resulting in two symmetrical halves of the alkaloid (Scheme 6.2). However, when 14C-labeled pelletierine (12, label at C2) was fed to the plant, degradation studies of lycopodine revealed that only one half consisted of the 14C label from pelletierine (the half containing C9-C16) [10]. The other half does not result from pelletierine 12 but must be something similar in structure since it does contain the piperideine unit (8) resulting from lysine. It was of interest then to determine the exact source of the three-carbon propionate unit in pelletierine (12). 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

Nyembo et al. [15] proposed in 1978 that the amino acid 34 and other compounds of general structure 35> known as phlegmarines, the stereochemistry of which is not specified, may be intermediates involved in the biosynthesis of Lycopodium alkaloids. 

Phlegmarine-type alkaloids possess a C16N2 skeleton that consists of a piperidine ring and a (decahydro)quinoline ring that are connected via a methylene group (Scheme 10). They might be the biogenetic intermediates of lycodine (49) We next describe the structure elucidation of this new class of alkaloids based on asymmetric total syntheses. 

Scheme 10 Hypothetical biogenesis of lycodine and phlegmarine-type alkalooids...

New alkaloids lycoposerramines-X (74) and -Z (75) are phlegmarine-type alkaloids consisting of a piperidine ring with a novel nitrone residue and a decahydroquino-line ring with four stereogenic centers [43] (Fig. 6). From spectroscopic analyses, 74 and 75 were found to be diastereomers at the C-13 position, but their absolute configuration could not established. Then we planned the asymmetric total syntheses of 74 and 75 to confirm their structures, including the absolute stereochemistry. 

As described above, we have achieved the asymmetric total syntheses of lyco-poserramines-V (50), -W (68), -X (74), and -Z (75) using cyclohexanol 59 as the common intermediate, which has enabled us to determine unambiguously the structures, including the absolute configurations, of the four new phlegmarine-type alkaloids (Fig. 7). 

Shigeyama T, Katakawa K, Kogure N, Kitajima M, Takayama H (2007) Asymmetric total syntheses of two phlegmarine-type alkaloids, lycoposerramines-V and -W, newly isolated from Lycopodium serratum. Org Lett 9 4069 072... 

Katakawa K, Kitajima M, Yamaguchi K, Takayama H (2006) Three new phlegmarine-type Lycopodium alkaloids, lycoposerramines-X, -Y and -Z, having a nitrone residue, from Lycopodium serratum. Heterocycles 69 223-229... 

The first lycopodium alkaloid was isolated from the club moss Lycopodium complanatum by Bodeker as early as 1881 [18] much later its structure was shown to be lycopodine [19]. Since the first comprehensive review on lycopodium alkaloids was published in 1968 [20], new structures have been isolated and the chemistry and biology of this class of compounds have been reviewed several times [6-9, 21], According to Ayer [6], the lycopodium alkaloids are generally considered to comprise of four major classes. Compounds 1-4 are representatives of each group lycopodine 1 (class 1), lycodine 2 (class IT), fawcettimine 3 (class III), and phlegmarine 4 (miscellaneous class IV). 

Lyconadin A (44) is a novel type of alkaloid consisting of five fused rings (one 5-membered and four 6-membered rings), while alkaloid 45 is the first lycodine analog with a hydroxy group at C-11 (37). A plausible biogenetic path for 44 and 45 is shown in Scheme 9 (37). Both alkaloids may be derived from L-lysine via pelletierine, followed by further cyclization of the phlegmarine skeleton (74,77). 

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