Fawcettimine alkaloids

Another highlight of the period under review is the report of the total synthesis of the tricyclic alkaloid fawcettimine (22) (Scheme 2).9 Lewis-acid-catalysed Diels-Alder addition of butadiene to 2-allyl-5-methylcyclohex-2-enone provided the ds-octalone (23), which was modified as indicated to give the dialdehyde (24). After considerable experimentation, conditions were defined which led to regioselective ring-closure in the desired direction. The unsaturated aldehyde was treated directly with the Wadsworth-Emmons reagent to provide... 

The structure of fawcettidine (10) was indicated from the similarity of its i.r. and n.m.r. spectra and basicity to those of serratinine.2 Transformation of a serratinine derivative (7) into fawcettidine was thus envisaged and ultimately achieved by the sequence outlined in Scheme 3. The required intermediate (8) for the reductive rearrangement to (9) and (10) was obtained in four conventional steps. On the basis of previous studies, the alkaloid fawcettimine had been assigned structure (9). Unfortunately, direct comparison of synthetic (9) with the natural product could not be effected. 

Lycoflexine (1), isolated from Lycopodium clavatum var. inflexum, is a representative of a new skeleton hitherto not encountered in this group of alkaloids. Lycoflexine showed in its mass spectrum a base peak at mje 84 which had not been previously encountered in mass spectra of Lycopodium alkaloids. The structure was solved by X-my crystallographic analysis of its hydrobromide derivative. Lycoflexine may be biogenetically related to the known fawcettimine (2), which also occurs in L. clavatum var. inflexum, by invoking an intramolecular Mannich reaction on an initially formed immonium salt (3). 

Fawcettimine-type alkaloids possess a CisNi skeleton and are considered to be derived from the lycopodine skeleton (Scheme 2). Initially, the nucleophilic attack of water on C-13 of the lycopodine skeleton, followed by C-13-N bond scission, would occur. Next, the Wagner-Meerwein rearrangement would proceed to form the fawcettimine skeleton. Fawcettimine (11) exists as an equilibrium mixture of the carbinolamine form and the keto-amine form. A number of fawcettimine-type alkaloids derived from each form have been isolated from nature. 

The structure of the new alkaloid 27, named lycoposeiramine-C [25], was deduced to be a fawcettimine-t3q3e alkaloid possessing a double bond at the C-6 and C-7 positions of fawcettimine (11), and was finally established by X-ray crystallographic analysis (Fig. 2). Although our preliminary biological screening indicated that 27 possesses potent AChE inhibitory activity, further examination of the activity has been restricted by its limited availability in nature. In order to develop an efficient synthetic route to 27 for further examination, we planned the asymmetric total synthesis of 27. 

Katakawa K, Kogure N, Kitajima M, Takayama H (2009) A new Lycopodium alkaloid, lycoposerramine-R, with a novel skeleton and three new fawcettimine-related alkaloids from Lycopodium serratum. Helv Chim Acta 92 445-452 and references cited therein... 

Nakayama A, Kitajima M, Kogure N, Takayama H (2009) First asymmetric total syntheses of fawcettimine-type Lycopodium alkaloids, lycoposerramine-C and phlegmariurine-A. Org Lett 11 5554-5557... 

Synthesis ofalkaloids using radical cyclizations 12YGK1413 13H(87)527. Syntheses of fawcettimine-type Lycopodium alkaloids utilizing the Pau-son—Khand reaction 12SL2014. 

Schemp 2.15 The total synthesis of the fawcettimine class alkaloids.

As already mentioned earlier (e.g. Scheme 35), Lycopodium alkaloids have always been interesting targets in natural product syntheses (129-133). In 2007, the group of Toste reported a 13-step total synthesis of (+)-fawcettimine (273) with... 

Katakawa K, Nozoe A, Koguie N, Kitajima M, Hosokawa M, Takayama H (2007) Fawcettimine-Related Alkaloids frinn Lycopodium serration. J Nat Prod 70 1024... 

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). 

A series of lycoposerramines isolated by Takayama et al. were fawcettimane-type and fawcettidane-type alkaloids from the same species Lycopodium serratum in Japan which contains huperzines in China. The structure of lycoposerramine-A (21), which has a l,2,4-oxadiazolidin-5-one residue in the molecule, was elucidated through spectroscopic data and X-ray analysis (31,32). Seven new alkaloids, lycoposerramines B (22), C (23), D (24), E (25), P (26), Q (27), S (28), and U (29), with novel, fawcettimine-related structures were isolated from the club moss Lycopodium serratum in Japan (33). Their relative and absolute stereochemistries were analyzed by spectroscopic data. X-ray analysis, and chemical correlations. The skeleton of lycoposerramine A (21) may be constructed by the incorporation of NH3, NH2OH, and a Ci unit into a fawcettimine-type skeleton. 

Ayer et al. proposed the pathway for the biogenesis of macleanine (68) (47). Most of the Lycopodium alkaloids known to date possess functionality at C-5. Fawcettimine (93) readily forms a transannular carbinolamine 93a. Macleanine (68) might be derived from fawcettimine (93) through reductive amination to generate 94, formation of the internal immonium ion 95, and subsequent transannular cycUzation (47). 

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