Cylindricins

A total synthesis for (+)-cylindricines A and B has been achieved. Alkylation of -trifluoromethanesulfonyl ester 409 afforded 410 (93MI273)... 

Tasmanian collections of Clavelina cylindrica yielded the alkaloids cylindricines F (174) and G (175), the first thiocyanates isolated from an ascidian [169]. Cylindricines H-J (176-178) were later isolated from the same species [170]. 

Further examples of the endocyclic nitrone route to spirocyclic adducts are the total syntheses of (—)-histrionicotoxin (230) by Holmes and of cylindricines by Weinreb. Histrionicotoxin is one of many spiropiperidine alkaloids isolated from the poison-arrow frog Dendrobates histrionicus and has been the subject of many attempted total syntheses by a nitrone cycloaddition strategy that failed to provide the desired regioisomer, possibly through unfavorable steric interactions (265-268). Unlike these reports, Holmes and co-workers (101) found that the intermolecular reaction of nitrone (231), prepared by the 1,3-APT of the corresponding alkynyl-hydroxylamine carrying Oppolzer s chiral sultam auxiliary, afforded the styrene... 

The Tasmanian ascidian Clavelina cylindrica has yielded two interconvertible tricyclic alkaloids, cylindricine A (178) and B (179), which are toxic to brine shrimp [140]. 

The marine isothiocyanates, with more than 80 compounds isolated so far, form the largest group of naturally occurring isothiocyanates. This well-established group of marine natural products is constituted mainly by terpene metabolites present as sesquiterpene and diterpene derivatives. The non-terpene isothiocyanate compounds include two cylindricine alkaloids and a series of long-chain aliphatic metabolites. Marine sponges constitute the main source of these compounds, although they are also found in nudibranches and tunicates. 

Three novel related marine alkaloids, halichlorine (1148) from the sponge Halichondria okadai (1177, 1178) and pinnaic acid (1149) and tauropinnaic acid (1150) from the bivalve Pinna muricata (1179), have been the objects of much synthetic interest in view of their pronounced biological activity (inhibition of the vascular cell adhesion molecule-1) (1180). Synthesis of these alkaloids led to both revision and confirmation of the original structures (1181,1182). The syntheses of the previously known chlorine-containing cylindricines have been reviewed (1183). 

Weinreb SM (2006) Studies on Total Synthesis of the Cylindricine/Fasicularin/Lepadifor-mine Family of Tricyclic Marine Alkaloids. Chem Rev 106 2531... 

Short Syntheses of (+)-Cylindricine and Formal Synthesis of (-)-Lepadiformine... 

The synthesis of a borylcopper(i) reagent from bis(pinacolato)diboron (B2pin2) and GuOAc was developed. The reagent used for the 1,4-addition to a,/3-unsaturated ketone 146230 led to an intermediate for the total synthesis of cylindricine C and 2-epicyclindricine G (Equation (52)).231... 

The analogous intramolecular 1,3-dipolar cycloaddition of the cyclic nitrone 155, in an attempt to get to intermediates useful for the synthesis of the cylindricine or lepadiformine natural products, unexpectedly gave by lb/3a bonding the bridged cycloadduct oxazocine 117 in 49% yield with total diastereocontrol. From this reaction, the fused cycloadduct through la/3b bonding (41%) was also isolated (Equation 8) <2000TA2625>. 

Trost, B.M. and Rudd, M.T. (2003) Chemoselectivity of the ruthenium-catalyzed hydrative diyne cyclization total synthesis of (+ )-cylindricine C, D, and E. Organic Letters, 5, 4599-4602. 

Reductive cyclization. Azide redu addition of the resulting amine to a a assemblage of fused-bridged tricycles hai synthesis of (—)-cylindricine. 

The synthetic studies summarized here cover the partially developed and fully completed programs to build FR901483 and TAN1251 alkaloids, which together with the marine alkaloids cylindricines [80] and lepadiformine [81] are all the tricyclic natural products embodying the 1-azaspiro[4.5]decane ring to be isolated so far. 

Studies on total s5mthesis of the cylindricine/fasicularin/lepadiformine family of tricyclic marine alkaloids 06CRV2531. 

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