Tricyclic marine alkaloid

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

The first total synthesis of the tricyclic marine alkaloid (+)-fasicularin was completed by the research team of C. Kibayashi." The secondary alcohol functionality was inverted using the Mitsunobu protocol. The resulting p-nitro benzoate was readily hydrolyzed under basic conditions. 

Total synthesis of bioactive tricyclic marine alkaloids with A-heterocyclic fragments, lepadiformine, and related compounds 03BCJ2059. 

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

Total synthesis of tricyclic marine alkaloids (—)-lepadiformine, (+)-cylin-dricine C, and (—)-fasicularin 07Y805. 

In contrast to the previous examples, the preferred formation of linear aldehydes was the main target in some syntheses to construct a cyclic derivative with an appropriate ring size in the next step or for simply elongating a carbon chain. The linear aldehydes are the proper intermediates for the synthesis of indolizidine alkaloids [11], the tricyclic marine alkaloid lepadiformine [12], ACE inhibitors such as MDL 27210 and its analogues [13,14], and bryostatin, a remarkably potent anticancer agent [15]. Rhodium complexes of bisphosphite ligands provide one of the best known classes of linear-selective hydroformylation catalysts for simple ot-olefins. Except for the lepadiformine intermediate, where hydroformylation was carried out in the presence of the Rh(acac)(CO)2/P(OPh)3 catalyst system, in other... 

Schar, P., Cren, S., and Renaud, P. (2006) Tricyclic marine alkaloids synthetic approaches to cylindridnes, lepadrformine, and fasdcularin. CHIMIA Int.J. Chem., 60,131-141. 

Kibayashi, C., Aoyagi, S., and Abe, H. (2003) Total synthesis of bioactive tricyclic marine alkaloids, lepadiformine and related compounds. Bull. Chem. Soc. Jpn, 76, 2059-2074. 

The ring system 413 is an intermediate in the synthesis of the tricyclic core of the marine alkaloids sarains A-C (Scheme 32) <1998JOC8096>. 

Synthesis of a tricyclic core of marine alkaloid variolin B has been achieved in three steps. The key reaction involves tandem deoxygenation and cylization of a triarylmethanol 187 using a combination of trifluoroacetic acid (TFA) and triethylsilane (TES). The use of 4.3equiv of TFA and 8.1 equiv of TES minimizes the formation of side products 188, 189 and allows the formation of the desired product 190 in 34% yield (Scheme 5) <2005JOC6204>. 

While 1- and 2-oxygenated tricyclic carbazole alkaloids were isolated primarily from higher plants, various tricyclic carbazole alkaloids, which are 3-oxygenated or 3,4-dioxygenated, were obtained from alternative natural sources, such as microbial, marine, and mammalian sources. 

The marine alkaloid sarain A 383 features an exceptionally challenging pentacyclic architecture (Figure 6). To date, 383 has not succumbed to a total synthesis. Two groups however have completed the tricyclic core of 383 and have annulated the western 13-membered ring using quite similar RCM approaches. " The results obtained with... 

Although marine organisms produce a large number of isocyanates, isothiocyanates, and formamides, the corresponding thiocyanates have rarely been encountered. Indeed, the thiocyanate functionality has only been found in six sesquiterpenes (263-268), in four tricyclic quinoline alkaloids (271-274), and in psamaplin B (172) (included in the bromotyrosine derivatives discussed in the disulfide/polysulfide section). They have been found in marine sponges, as well as in nudibranches and tunicates. 

The carbodiimide mediated preparation of tricyclic pyrido[3, 2 4,5]pyrrolo[l,2-cjpyrimidine is a key step in the preparation of the marine alkaloid variolin... 

S.M. Weinreb and co-workers were surprised to find that the convergent stereoselective synthesis of marine alkaloid lepadiformine resulted in a product that gave a totally different NMR spectra than the natural product. This finding led to the revision of the proposed structure of lepadiformine. In the final stages of the synthesis, they exposed a tricyclic piperidone intermediate to Ciemmensen conditions to remove the ketone functionality. Under these conditions the otherwise minor elimination product (alkene) was formed predominantly however, it was possible to hydrogenate the double bond to give the desired alkane. 

An intramolecular allyl silane/N-sulfonyl iminium ion cyclization has also been used as a pivotal step in an approach to the tricyclic core of the unique marine alkaloid sarain A [46]. The starting material was aziridine ester 129 (Scheme 25) which was elaborated to amide 130. An important step in the synthetic strategy was thermolysis of 130 to an azomethine ylide, which underwent stereospecific intramolecular 1,3-dipolar cycloaddition with the Z-alkene to produce bicyclic lactam 131 [47]. This compound was then elaborated into allyl silane 132. It was then possible to replace the lactam N-benzyl functionality with a tosyl moiety, leading to 133, and subsequent reduction of the carbonyl group afforded the desired cyclization precursor a-hydroxy sulfonamide 134. Exposure of 134 to ferric chloride promoted cyclization to a single stereoisomeric tricyclic amino alkene 136 having the requisite sarain A nucleus. It is believed that the intermediate N-sulfonyl iminium ion cyclizes via the conformation shown in 135. 

Guanidine metabolites of Ptilocaulis spiculifer and related compounds (marine alkaloids with tricyclic guanidine fragment) isolation and synthesis 00CSR57. 

A notable application of the photosensitized oxidation of furan, reported in 2004, is the construction of the ABC ring system of the marine alkaloid norzoanthamine. As illustrated below, the furan moiety was oxidized to a Z-y-keto-a,p-unsaturated silyl ester intermediate, which was then converted to the stable methyl ester. This key intermediate was elaborated to the tricyclic compound via an intramolecular Diels-Alder reaction <04SCI495>. 

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. 

In the 1980s Muratake and Natsume (202) in a number of reports presented a new, interesting approach to the synthesis of substituted indole derivatives that focused on their use as intermediates in the preparation of a variety of clavine alkaloids and mycotoxins. The method elaborated by the authors consisted of constructing the specifically substituted benzene portion of the indole nucleus, with 1-methoxycarbonylpyrrole being the starting material. The functionalized 4-alkylindole thus obtained was transformed to a tricyclic indole derivative which appeared to be a common intermediate for the synthesis of several ergot alkaloids, as exemplified by the synthesis of ( )-dihydrosetoclavine (203-205) (Scheme 42). Recently, the application of this method was extended by the authors (206) to the syntheses of a series of marine alkaloids, the hapalindoles. Most of these alkaloids have a tetracyclic framework made up of 3,4-substituted tryptamine and two isoprene units. 

The synthesis of the tricyclic core of the cytotoxic marine alkaloid Madangamine required an efficient method to generate the central quaternary carbon function. Weinreb employed an aza-Claisen rearrangement in the presence of a palladium catalyst [21c]. After treatment of ketone 116 subsequently with TOSMIC and DIBALH, the formed carbaldehyde 117 was reacted with diallylamine in the presence of Pd(OCOCFj)2/PPh,. Initially, the enamine 118 was formed, which underwent diastereoselective aza-Claisen rearrangement The unsaturated imine 119 was cleaved with aqueous HCl and the corresponding aldehyde 120 was isolated in 68% yield. Several further steps allowed one to complete the synthesis of the core fragment 121 of the natural product (Scheme 10.27). 

The 3-aza-Cope rearrangement is successfully applied to the key step in a concise approach to the tricyclic core of a marine alkaloid. A requisite quaternary center and attendant stereochemistry are established by condensation of the corresponding aldehyde with diallylamine followed by 3-aza-Cope rearrangement via a Tr-allylpalladium intermediate (Scheme 9). ... 

Tricyclic core of the cytotoxic marine alkaloid madangamine A, was prepared by Weinreb using aza enone as a dienophile partner in the Diels-Alder reaction (Scheme 46) [69]. Although a [4+2] cycloaddition of enone 189 with butadiene could not be effected xmder thermal conditions, the desired c/s-keto azadecalin derivative 190 could be formed at high pressure (12 kbar) in good yield. Attempted cycloaddition of enone 189 with butadiene using Lewis acids gave low yields of a mixture of cis- and frans-azadecalins that could only be separated by HPLC [70]. 

Marine alkaloids (-f)-batzelladine A and ( )-batzel-ladine D. Nine novel tricyclic guanidine marine alkaloids were isolated as metabolites of the Crambe genus. Members of the batzelladine alkaloid class exhibit potential antiviral activity in the inhibition of HIV gp 120-Human CD4 binding, as well as potential immunosuppressive... 

Sorek, H., Rudi, A., Gueta, S., Reyes, F., Martin, M.J., Aknin, M., Gaydou, E., Vacelet, J., and Kashman, Y. (2006a) Netamines A-G seven new tricyclic guanidine alkaloids fiom the marine sponge Biemna laboutei. Tetrahedron, 62, 8838-8843. 

Molina, P., Eresneda, P.M., and Delgado, S. (2003) Carbodiimide-mediated preparation of the tricyclic pyrido[3, 2 4,5]pyrrolo[l,2-c] pyrimidine ring system and its application to the synthesis of the potent antitumoral marine alkaloid variolin B and analog. J. Org. Chem., 68, 489-499. 

Chao, W., Mahajan, Y.R., and Weinreb, S.M. (2006) An approach to total synthesis of the cylindridne B pyridoquinoline subclass of tricyclic marine asddian alkaloids. Tetrahedron Lett., 47, 3815-3818. 

The number of natural products containing these tricyclic systems is relatively small, viz. a few alkaloids from marine (compound 293), fungal (compound 282), amphibian (compound 395), insect (compound 387), and plant sources (compound 288) and also some iridoid molecules (compounds 98-100). Some of those Myrmkaria alkaloids (from ants Section 12.16.6.5.2) which contain the 5 5 6 fused-ring system are perhaps the most extensively studied of these natural products, with several successful syntheses now recorded. 

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