Cylindricine A and

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

Blackman AJ, Li CP, Hockless DCR, Skelton BW, White AH (1993) Cylindricine A and Cylindricine B, Novel Alkaloids from the Ascidian Clavelina cylindrica. Tetrahedron 49 8645... 

Isomeric cylindricines A and B, isolated in 1993, are the two main alkaloids (Section 25-8) present in extracts from the Australian marine plant Clavelina cylindrica. The two compounds equilibrate to a 3 2 mixture. Formulate a mechanism for this process. (Hint Check Exercise 9-25.)... 

The overall structure contains an indolizidine or a quinolizidine attached to a cyclohexane, all forming a complex tricyclic system whose conformation has proved difficult to determine. The first two examples of these structures were cylindridnes A and B, whose structures were confirmed by X-ray analysis. These two molecules have a chlorine atom and are interconvertible through an aziridinium ion. At room temperature a solution of either of the two molecules will be found after six days to contain a mixture of 60% cylindricine A and 40% cylindricine B (Blackman et al., 1993). This equilibrium, however, occurs only with free bases at room temperature salts (picrates) are regarded as stable in solution. 

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. 

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... 

Mihara H, Shibuguchi T, Kuramochi A, Ohshima T, Shibasaki M (2007) Short Synthesis of (-t)-Cylindricine C and Formal Total Synthesis of (-)-Lepadiformine. Heterocycles 72 421... 

Removal of the Boc group in enone 418 with TFA resulted in a free amine that underwent an in situ Michael cyclization to provide the desired aza-tricycle 409, the common intermediate, in 72% yield (Scheme 12.105). Additionally, we isolated a second product, which after careful scrutiny, learned that the aza-tricycle underwent rapid epi-merization at C5 when exposed to silica gel, thereby giving the TBDPS-protected form of (-l-)-cylindricine C 386 as well as 387 in a 1 1 mixture. It turned out that TBAF-mediated deprotection of the silyl group in tran.r-azadecalin 409 concomitantly epimerized C5 of the aza-tricycle, providing (+)-cylindricine C 386 and importantly verified the link between cylindricines and lepadiformine. Subsequent chemical manipulations then afforded (-l-)-cylindricines D and E (387 and 388 in Scheme 12.106). 

Most cybndricines are related to cylindridnes A and B, which are almost always the major constituents of mixtures from spedes collected from various sites on the Tasman coast. Structural analysis was done by chemical spectroscopy and interconversion. Lepadiformine is related to cylindricine C, but with a different configuration at the jimction between indolizidine and cydohexane the final structure of this atypical alkaloid was confirmed by several total syntheses and X-ray analysis of its hydrochloride group (Abe, Aoyagi, and Kibayashi, 2000 Greshock and Funk, 2001 Sim, Sim, and Weinreb, 2001,2002 Weinreb, 2003). Lepadiformines B and C differ from lepadiformine A only in the carbon chains linked to the tricyclic system. Two other alkaloids related to lepadiformine A, polycitorols A and B, were isolated from an undetermined asddian of the family Polycitoridae of Indonesian origin (Issa et al, 2005). All currently known structures are presented in Figure 28.23. 

Fhck, A.C., Caballero, M.J.A., and Padwa, A. (2010) A conjrigate addition/dipolar-cydoaddition cascade sequence for the synthesis of ( )-cylindricine C. Tetrahedron, 66, 3643—3650. 

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... 

Reductive cycttzation. Azide reduction with CrCla is followed by intramolecular addition of the resulting amine to a cross-conjugated dienone system. This efficient assemblage of fused-bridged tricycles has been incorporated as the final and key step in a synthesis of (—)-cylindricine. 

In 2006, Shibasaki and co-workers [91] developed phase-transfer-catalyzed asymmetric Michael addition of glycine Schiff base 237 and dienone 238 to afford dienone 240 in 84% isolated yield and 82% ee for the total synthesis of (+)-cylin-dricine C (242) and a formal synthesis of (—)-lepadiformine (244), using a chiral two center organocatalyst 239 (TaDiAS Tartrate-derived Di-Ammonium Salt) (Scheme 17.41). (+)-cylindricine C (242) was achieved three steps from 240 using... 

A carbonylative coupling of a vinyl derivative was employed in a synthesis of cylindricine C 433 (Scheme 4.14). " In this case, the double Michael acceptor ability of the product was exploited to generate the tricyclic product, following protecting group manipulation and installation of nitrogen in the form of azide. Another synthesis of this molecule can be found in Scheme 11.89. 

The mthenacyclopentatrienes, obtained by the oxidative cyclization of diynes, can also undergo an attack of other reagents than unsaturated molecules. In the presence of the complex [CpRu(CH3CN)3]PF6 and water, a hydrative diyne cyclization took place leading to a,p-unsaturated ketones [46-49] [Eq. (18)]. This reaction was applied to the total synthesis of (-i-)-Cylindricine C, D, and E [49]. 

Wharton, P. S. Bohlen, D. H. Hydrazine Reduction of Epoxy Ketones to Allylic Alcohols /. Or. Chem. 1961, 26, 3615-3616. For a mechanistic study see Stork, G. Williard, P. G. Five- and Six-Membered-Ring Formation from Olefinic a,j8-Epoxy Ketones and Hydrazine /. Am. Chem. Soe. 1977, 99, 7067-7068. For a recent appUcation of the Wharton rearrangement see Liu, J. Hsung, R. P. Peters, S. D. Total Syntheses of (+)-Cylindricines C-E and (-)-Lepadiformine through a Common Intermediate Derived from an z -Prins Cyclization and Wharton s Rearrangement Oi. Lett. 2004, 6, 3989-3992. 

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