Enantioselective Total Synthesis of the Marine Alkaloid Lepadin B

Toyooka, Naoki; Okumura, Maiko; Takahata, Hiroki

doi:10.1021/jo990141n

Cited by 49 publications

(30 citation statements)

References 17 publications

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“…The NMR data of our synthetic (−)‐lepadin B were coincident with those reported in the literature, while its specific rotation was in good agreement with the value reported for this compound 9a. The synthesis of (−)‐lepadin B consists of 19 synthetic steps from δ‐keto ester 3 and takes place in 7.6 % overall yield, which represents a significant improvement with regard to previous syntheses of this alkaloid.…”

Section: Resultssupporting

confidence: 88%

“…All these syntheses involve two phases: 1) construction of a protected 3‐hydroxy‐2‐methyl‐ cis ‐hydroquinoline platform, either functionalized at C5 or bearing an oxidized one‐carbon substituent at this position, and 2) installation of the appropriate C5 eight‐carbon chain. A variety of methodologies have been developed for the first phase: closure of the carbocyclic ring by aldol cyclization9a,b or a ring‐closing/ring‐opening metathesis sequence;9d closure of the piperidine ring by intermolecular [3+3]‐azacycloaddition,9f,g, 11 xanthate‐mediated free radical cyclization,10 or alkylative cyclization processes;9c and sequential one‐pot construction of both rings from an acyclic precursor by a tandem ene‐yne‐ene ring‐closing metathesis 9e…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, different strategies have been used to assemble the eight‐carbon chain at the DHQ C5 position: 1) starting from a C5 unsubstituted DHQ, direct introduction of an eight‐carbon chain (C 0 +C 8 strategy),9d or sequential introduction of either one carbon and a seven‐carbon chain (C 0 +C 1 +C 7 )9a,c or two and six carbons (C 0 +C 2 +C 6 );9c,f,g 2) starting from a DHQ bearing a functionalized one‐carbon substituent at C5, direct elongation of a seven‐carbon chain (C 1 +C 7 strategy)9e or sequential elongation of one carbon and a six‐carbon chain (C 1 +C 1 +C 6 ) 9b…”

Section: Introductionmentioning

confidence: 99%

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Enantioselective Synthesis of Lepadins A–D from a Phenylglycinol‐Derived Hydroquinolone Lactam

Amat

Pinto

Griera

et al. 2015

Chemistry A European J

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Abstract:The marine alkaloids (-)-lepadins A-C and (+)-lepadin D, belonging to two diastereoisomeric series, were synthesized from an (R)-phenylglycinol-derived tricyclic lactam via a common cisdecahydroquinoline intermediate. Crucial aspects of the synthesis are the stereochemical control in the assembly of the cisdecahydroquinoline platform, in the introduction of the C-2 methyl and C-3 hydroxy substituents, and in the generation of the C-5 stereocenter.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Enantioselective Synthesis of Lepadins A–D from a Phenylglycinol‐Derived Hydroquinolone Lactam

Amat

Pinto

Griera

et al. 2015

Chemistry A European J

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“…Other transformations will mainly be indicated as the number and nature of steps used to convert one intermediate into another. In 1999, Toyooka reported the first total synthesis of lepadin B using aldol cyclization as the key step [21,22]. The synthesis began from the racemic triketo compound 31, which was reduced with baker's yeast in high enantiopurity, correctly setting two stereocenters in one step.…”

Section: Synthetic Effortsmentioning

confidence: 99%

Stereocontrolled construction of decahydro quinoline ring systems: the case of lepadin alkaloids (Review)

Pelšs

Koskinen

2013

Chem Heterocycl Comp

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In this review the marine derived decahydroquinoline alkaloid chemistry and biology is described. A proposal is made for the biosynthetic relationships between acyclic and cyclic C-18 amino alcohol natural products.Keywords: amino alcohols, decahydroquinolines, asymmetric synthesis, biosynthesis, total synthesis. Decahydroquinoline (DHQ) alkaloids are unique natural products that can be divided into three distinct sets. The first group (more than 50 members) of these alkaloids are simple 2,5-disubstituted DHQs isolated from dart poison frogs and ants with the parent member being alkaloid cis-195A, also known as pumiliotoxin C [1]. These diverse cis-or trans-fused decahydroquinolines are equipped with various short alkyl and alkenyl side chains. The structurally related but biologically different lepadins 1-8 (Fig. 1) are on the other hand marine alkaloids isolated from three distinct ascidians: Clavelina lepadiformis (found in the North Sea), Didemnum, and Aplidium tabascum (both found in the Great Barrier Reef) [2][3][4][5]. The third group consists of more complex polycyclic alkaloids that besides the DHQ ring system, can contain several other heterocyclic ring systems fused into one molecule. Representative members of this group are gephyrotoxin and Lycopodium alkaloids [6,7]. This review will focus solely on the second group of DHQ alkaloids which, as distinct from the other two groups of DHQ-containing alkaloids, have not been reviewed in full so far [8]. Lepadin alkaloids differ from dendrobatin frog alkaloids in additional oxygenation at position 3, where the substituent may be a hydroxy or acyloxy group, as well as having eight-carbon long side chains of variable oxidation level at position 5 of the DHQ ring. There are three stereochemical groups of lepadins, each derived from distinct tunicate species (Fig. 1). Lepadin F is an exception, being present in both ascidians from the Great Barrier Reef. Lepadins possess some interesting biological activities: lepadins A and B -cytotoxicity against cancer cell lines, lepadins D-F -antiplasmodal and antitrypanosomal activity. Lately, lepadin B together with pictamine was found to block neuronal nicotinic acetylcholine receptors α4β2 and α7. However, the availability of only small quantities of these natural products has precluded further studies on the development into potential leads for nicotinic based therapies [9].

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“…[3] During the past five years, considerable effort has been directed towards the total synthesis of lepadins, and two successful protocols have resulted. [5,6] However, the requirement by both routes of lengthy reaction sequences to construct the left cyclohexane ring greatly diminished their synthetic efficiency. In 2002 Zard and co-workers described a short formal synthesis of racemic lepadin B, [7] but many more steps would evidently be necessary if this strategy was applied in an enantioselective synthesis.…”

mentioning

confidence: 99%

Total Synthesis of Lepadins B, D, E, and H; Determination of the Configuration of the Latter Three Alkaloids

2004

Angew Chem Int Ed

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Enantioselective Total Synthesis of the Marine Alkaloid Lepadin B

Cited by 49 publications

References 17 publications

Enantioselective Synthesis of Lepadins A–D from a Phenylglycinol‐Derived Hydroquinolone Lactam

Enantioselective Synthesis of Lepadins A–D from a Phenylglycinol‐Derived Hydroquinolone Lactam

Stereocontrolled construction of decahydro quinoline ring systems: the case of lepadin alkaloids (Review)

Total Synthesis of Lepadins B, D, E, and H; Determination of the Configuration of the Latter Three Alkaloids

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