Cardiovascular effects of lepadiformine, an alkaloid isolated from the ascidians Clavelina lepadiformis (Müller) and C. moluccensis (Sluiter)

Juge, Marcel; Grimaud, Nicole; Biard, Jean-François; Sauviat, Martin-Pierre; Mohamed, Nabil; Verbist, Jean-François; Petit, Jean‐Yves

doi:10.1016/s0041-0101(01)00079-4

Cited by 55 publications

(48 citation statements)

References 19 publications

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“…2 The early syntheses 3 utilised cycloaddition methodology for construction of the pivotal tertiaryaza stereogenic centre of the trans-1-azadecalin A/B ring junction. More recently, Weinreb has demonstrated the application of an intramolecular spirocyclisation of an Nacyliminium ion with an allylsilane to accomplish the first enantioselective synthesis 4 of the alkaloid, thus establishing its absolute configuration.…”

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Synthesis of the Tricyclic Core of the Marine Alkaloid Lepadiformine

Hunter¹,

Richards²

2003

Synlett

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A stereoselective synthesis of the tricyclic core in racemic form of the marine alkaloid Lepadiformine is described from 4-methoxy-3-pyrrolin-2-one (methyl tetramate). Key steps involve 5,5-dialkylation of the tetramate, metathesis closure to an A/C 1-azaspirocycle and stereoselective hydrogenation for the trans A/B 1-azadecalin system. Considerable interest has been shown recently in the synthesis of the marine alkaloid Lepadiformine 1, a tricyclic perhydropyrrolo[2,1-j]quinoline isolated 1 from the tunicate Clavelina lepadiformis and reported to have moderate in vitro cytotoxic activity against certain tumour cell lines, 1 as well as various cardiovascular effects in vivo and in vitro. 2 The early syntheses 3 utilised cycloaddition methodology for construction of the pivotal tertiaryaza stereogenic centre of the trans-1-azadecalin A/B ring junction. More recently, Weinreb has demonstrated the application of an intramolecular spirocyclisation of an Nacyliminium ion with an allylsilane to accomplish the first enantioselective synthesis 4 of the alkaloid, thus establishing its absolute configuration. A key intermediate in Weinreb's synthesis was a 1-azaspiro[4.5]decyl unit used as an A/C ring-system template. Recent publications on the construction of the natural products FR901483 5 and (-)-TAN1251A 6 have highlighted the use of substituted 1-azaspiro[4.5]decanes, and in this communication we disclose a novel strategy for accessing this ring system as a 6-ketone 7 with subsequent conversion of it in moderate stereoselectivity to the tricyclic core of Lepadiformine in racemic form (Figure 1).Our strategy centred around a sequence involving 5,5-dialkylation of a tetramate derivative, followed by chain extension and metathesis to the substituted azaspirocycle. 5-Alkylation of the lithium dienolate of N-protected tetramates with primary alkylating agents is well established in the literature, 8 however in our hands allylation of 1-benzyl-4-methoxy-3-pyrrolin-2-one produced significant quantities of the a-alkylation product. Thus we resorted to using a procedure reported by Jones 8a involving allylation of the dianion of 4-methoxy-3-pyrrolin-2-one 2 with one equivalent of allyl bromide. 5-Allyltetramate 3a was obtained in 79% isolated yield after column chromatography. Phase transfer 9 protection of the lactam nitrogen of 3a produced the N-protected derivative 3b in excellent yield setting the stage for construction of the pivotal tertiaryaza centre (Scheme 1). Scheme 1 Reagents and conditions: (a) n-BuLi (2 equiv), THF, -78°C, allyl bromide (1 equiv), 79%; (b) KOH, Bu 4 NHSO 4 , THF, 88%.Given the poor regioselectivity of alkylation of the tetramate lithium dienolate, we opted to investigate the use of the much softer silyl dienol ether (2-silyloxypyrrole). Although N-Boc-2-tert-butyldimethylsilyloxypyrrole from N-Boc-3-pyrrolin-2-one has been demonstrated by Casiraghi 10 to be a versatile building block in natural product synthesis for 5-regioselective alkylation reactions, no equivalent studies have been carried out...

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Synthesis of the Tricyclic Core of the Marine Alkaloid Lepadiformine

Hunter¹,

Richards²

2003

Synlett

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“…[49][50][51][52][53][54] Since the first members were reported in 1993, 11 cylindricines A-K have been identified from the Tasmanian ascidians Clavelina cylindrica as new marine alkaloids [55][56][57] with a tricyclic ring system unprecedented among natural products, possessing a perhydropyrroloquinoline or a perhydropyridoquinoline. Shortly after the first isolation of cylindricines A (56a) and B (56b) 55) the isolation and structure elucidation of a closely related marine alkaloid, named lepadiformine, from the ascidian Clavelina lepadiformis collected in the Mediterranean near Tunisia 58) in 1994 and later from Clavelina moluccensis found along the Djibouti coast 59) was reported by Biard and co-workers. It was found to be moderately cytotoxic toward various tumor cell lines in vitro.…”

Section: Total Syntheses Of Tricyclic Marine Alkaloidsmentioning

confidence: 98%

“…Moreover, a recent study indicated that lepadiformine is very active in the cardiovascular system in vivo and in vitro and suggested that it has antiarrhythmic properties. 59) On the basis of extensive spectral analysis, this alkaloid was assigned the unusual zwitterionic structure 58.…”

Section: Total Syntheses Of Tricyclic Marine Alkaloidsmentioning

confidence: 99%

“…Having developed an extremely efficient approach to lepadiformine (59) utilizing the spirocyclic alcohol 80 stereoselectively derived from the enone 79, we next attempted to exploit this intermediate 80 for the synthesis of the related marine alkaloid cylindricine C (56c). [87][88][89][90][91][92] Cylindricine C (56c), possessing the perhydropyrroloquinoline framework, is intimately related to lepadiformine (59) differing structurally only in the cis/trans stereorelationship of the B/C ring system and the functionality at C-7.…”

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confidence: 99%

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Development of New Synthetic Methods and Its Application to Total Synthesis of Nitrogen-Containing Bioactive Natural Products

Kibayashi

2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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A group of naturally occurring substances containing nitrogen is widely distributed in plants as well as in fungi, animal, marine organisms, and insects, and many exhibit significant biological activity. These natural products with a huge variety of chemical structures include antibiotics, antitumor agents, immunostimulants, drugs affecting the cardiovascular and central nervous systems, analgesics etc. The diverse activities and low natural abundance of this group of natural products when coupled with their molecular complexity warrant development of new and efficient synthetic methods and strategy for the total synthesis of these products, in particular alkaloids. The purpose of this review is to describe some of our achievements in the total synthesis of the naturally-occurring bases including the Dendrobatid alkaloids pumiliotoxin B and allopumiliotoxin A, the anitibiotic streptazolin, the tricyclic marine alkaloids isolated from the ascidians such as fasicularin, lepadiformine, and cylindricine C, and the dimeric monoterpene alkaloid incarvillateine as well as the formal total synthesis of the spirocyclic marine alkaloids halichlorine and pinnaic acid, which are isolated from the Japanese marine sponge and the Okinawan bivalve, respectively.

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“…Among them, lepadiformines (A-C, 1-3) isolated from the tunicate Clavelina lepadiformis and Clavelina moluccensis by Biard and co-workers ( Figure 1), 3 exhibit modest cytotoxic activity towards various cardiovascular effects in vitro and in vivo. 3b,4 In 2000, Kibayashi and co-workers revised the originally proposed structure of lepadiformine (4) to structure 1 by their first total synthesis. 5a Because of the unique azaspirocyclic skeleton with four asymmetric stereocenters, these compounds have been attractive targets for the synthetic community.…”

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confidence: 99%