155 synthèse du tubastrindole B (130)) plutôt que de biomimétisme. L’utilisation du terme

"biomimétique" est parfois source de désaccord.

Schéma 33 : Obtention d’un intermédiaire biosynthétique-clé.

Certains considèrent qu’il s’applique lorsque le mécanisme de la transformation est conforme au processus biologique supposé quels que soient les substrats en présence. D’autres (et c’est le cas ici), considèrent plus volontiers que ce terme doit être réservé aux transformations mettant en jeux des composés mimant (et donc très proches) des substrats naturels. Les conditions réactionnelles sont également à prendre en compte. Le recours à la lumière et aux monomères naturels était clairement biomimétique pour la synthèse du dictazole B (138). Ici, l’utilisation des micro-ondes à chaud ainsi que le choix du composé de type dictazole (140) non naturel cantonnent à l’utilisation du terme de bio-inspiration.

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4. Vision d’ensemble et exploration des variations de la famille des

aplysinopsines.

4.1. L’influence du motif hydantoïne dans la série aplysinopsine.

Avec la réalisation des premières synthèses totales du dictazole B (138) et du tubastrindole B (130), l’ensemble des squelettes connus au sein de la famille des aplysinopsines ont été atteints. Même si la généralisation de ces résultats est logique, une des variations usuelle de la série n’avait pas été explorée. En effet, le motif créatinine (et sa

pseudo-guanidine) est parfois remplacé par une hydantoïne (et sa pseudo-urée). On peut citer

parmi d’autres le monomère 120, les cycloaplysinopsines A et B (121-122) ou encore le tubastrindole H (136) (Figure 20).

Figure 20 : Substances présentant un motif hydantoïne (et sous motif urée).

À première vue, les structures dimériques présentées ci-dessus possèdent le même squelette. Cependant, si on les analyse plus finement, on constate que leurs stéréochimies relatives varient. L’extension de l’étude à ces derniers composés doit permettre de comprendre leur réactivité. De plus, une investigation plus profonde de la famille représente une occasion de mieux comprendre les liens qui unissent tous ces alcaloïdes tout en étoffant les données biosynthétiques accumulées sur ces métabolites spécialisées.

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4.2. Article.

2015

Adam Skiredj, Mehdi A. Beniddir, Delphine Joseph, Guillaume Bernadat, Laurent Evanno* and Erwan Poupon*

Abstract :

Aplysinopsin monomers are considered as plausible biosynthetic precursors of the wider aplysinopsin family of marine alkaloids. The idea of harnessing their intrinsic reactivity to undertake the synthesis of dictazoles or cycloaplysinopsins logically emerged from this status. These biosynthetic considerations led us to the first total syntheses of dictazole B and other valuable cyclobutanes. When further exploiting pre-encoded reactivity, our first total synthesis of tubastrindole B originated from the ring-expansion cascade of its dictazole-type precursor. Moreover, the isolation of a transient biosynthetic intermediate combined with dimerization outcomes of a hydantoin-containing monomer allowed us to explain the formation of cycloaplysinopsins A and B.

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1. Introduction

Some specific marine sponges and stony corals living in shallow waters are the sources of intriguing alkaloids that share quite obvious structural links with aplysinopsin (1).1 Hence, this rather simple alkaloid not only gives its name to the group of aplysinopsin monomers (over 20 similar compounds slightly differing from one another by N-demethylation or C6 bromination of 1 and 2, Figure 1),2 but it is also the eponym of the whole ‘aplysinopsin alkaloids family’ considered herein. The other congeners known to date, far more complex, define two distinct groups of dimeric compounds depending on their respective scaffolds: 1) dictazoles: remarkable spiro-fused cyclobutanes [e.g., dictazole B (3)] and 2) cycloaplysinopsins: spirocyclic tetrahydrocarbazole-type natural products [e.g., tubastrindoles B (4) and H (5) and cycloaplysinopsins A (6) and B (7)].3,4 Beyond the undeniable synthetic challenge represented by the access to these densely functionalized marine alkaloids (two indoles and up to eight nitrogens),5 the puzzling biosynthetic issues raised by their study prompted us to undertake the present work. Aiming to synthesize some of these complex natural products with high simplicity, if not spontaneously, we have previously reported the first total syntheses of (±)-dictazole B (3) and (±)-tubastrindole B (4).6 Intrigued by the reactivity of 2 and the variable stereochemical features of several related bis-hydantoin alkaloids of the family (see the structures of 5, 6, and 7 in Figure 1), we extended our study towards this subset of natural products.The new outcomes are reported herein in addition to our previous results related to this stunning series of marine alkaloids.

Figure 1 : Selected examples among the three skeletons encountered in the aplysinopsin alkaloid family.

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2. Easy access to dictazole cyclobutanes

In our view, from both biosynthetic and synthetic standpoints, the three different subgroups of alkaloids presented in Figure 1 should not be considered independently, but rather as a unique set of closely related congeners (Scheme 1). Indeed, these natural products have all been isolated and, therefore, naturally produced in similar environments. A common feature of the environments from which materials have been collected

attracted our attention: the shallow waters where all the relevant sponges and stony corals were collected are directly exposed to sunlight. Guided by this unifying idea, we turned to study the photochemical dimerization of aplysinopsin-type monomers. Prepared, as previously reported, by a trivial aldolization-dehydration step on a gram scale, the desired monomers 1, 2, 8, and 9 were exposed to artificial UV-enriched light under appropriate conditions.7 These experiments resulted in different outcomes summarized in Table 1.

Although common optimized conditions have been established (i.e., thin film of a 5 mM solution in DMF, hν,

14 h)8 by iterative screening followed by a kinetic study, the recourse to additives, and their respective efficiency, differs from one monomer to another.

As mentioned in our previous reports, and in contrast with the usual lack of selectivity observed in photochemical [2+2] processes, the self-condensation of 1 by [2+2] photocycloaddition is diastereoselective and leads exclusively to the anti-dictazole-type compound 10. Moreover, the addition of copper(I) triflate significantly enhanced the yield of this transformation, even if it also induced a slight erosion of diastereoselectivity, leading to the isolation of 14, a minor

syn-derivative (entries 1 and 2, Figure

2).9 Comparable results were observed

Scheme 1 : First issue: is a dimerization possible?

Table 1 : Compared [2+2] photochemical homodimerization results of aplysinopsin-type monomers.

160