Convergent total synthesis of kidamycin – KidamySyn

Three teams (Partners 1, 2 and 3) from 3 different universities collaborate to the KidamySyn project. The scientific program is organized around two main scientific tasks.
The first task concerns the synthesis of kidamycinone (kidamycin aglycone) via B-ring construction based on a Diels-Alder reaction between juglone and a well-suited diene. This task will be performed by partner 1. Two different syntheses to access to the diene could be proposed to increase the panel of available building blocks and to eventually offer an alternative route in case of failure of one of them. Each strategy possesses its own advantages in terms of efficiency and molecular diversity.
The second one, divided in four subtasks will concern the total synthesis of kidamycin starting from the preparation of dienophile bearing two C-glycoside moieties and followed by its reaction with dienes developed in the first task. The preparation of this dienophile will start by the synthesis of angolosamine precursors (lactone or glycal) by Partner 1. At the same time, Partner 2 will prepare the N,N-dimethylvancosamine precursor. Partner 3 will be in charge with the condensation of both precursors on a bis-protected 1,8-naphthalendiol platform by means of organometallic couplings (Heck, Suzuki, Stille...) respecting the appropriate stereoconfigurations. The final subtask consisting in the Diels-Alder reaction between bis-glycosylated dienophile and diene followed by few final functional transformations will be perform by Partner 1.

Partner 1 in Nantes as set up the synthesis of a first diene which, upon reaction with juglone, led us to reach before summer 2015 our first target : the synthesis of kidamycinone. Then, a first racemic synthesis of the angolosamine lactone has then been studied but neither yield nor stereoselectivity were satisfactory. A second strategy has been investigated conducing to a well-protected angolosamine lactone. Simultaneously, we have studied couplings tests between mono (or di-) protected 4-bromo-1,8-naphthalenediol (prepared by Partner 3) and lactone-type electrophiles.
The principal objective for Partner 2 at the begenning of the project was to synthesize in good amount the vancosamine fragment in order to quickly validate the coupling step with the naphthalenic platform and the stereospecific reduction of the glycal. After few reproductibility problems, the vancosamine precursor has been obtained and given to Partner 3. However, we have decided to propose an alternative to the synthesis of this fragment.
The first task of Partner 3 was to synthesize in good amount of mono (or di-) protected 4-bromo-1,8-naphthalenediol. The synthesis has been scaled up to a 30g scale.
Concerning the coupling of vancosamine to the naphthalenic platform (C10), investigations were carried out on different models showing difficulties in using Suzuki-type coupling with a borylated glycal. The reactivity of a stanylated glycal is now under investigations (Stille coupling). Concerning the anchorage of angolosamine at C8 position, after different tests, the Suzuki-type coupling has also shown to be difficult to carry. For this reason, Partner 3 is currently studying a Heck reaction between the bromonaphtol and an angolosamine glycal.

- Validate the coupling of both angolosamine and vancosamine precursors onto the mono (or di-) protected 1,8-naphthalenediol plateform.
- Propose an effcicient non-racemic synthesis of both precursors of angolosamine and vancosamine.
- Validate the stereospecific reduction onto the vancosamine part to set up the desired alpha link at C10.
- Undertake the Diels-Alder reaction between the bis-glycosylated dienophile (when obtained) and the diene and finish the kidamycin synthesis.

Publication :
«Total synthesis of (+,-)-gama-indomycinone«; M. Pantin, D. Zon, R. Vomiandry, L. Foulgoc, D. Sissouma, A. Guingant, S. Collet, Tetrahedron Lett. 2015, 56, 2110-2112.

Communications :
1– «Recent advances in the synthesis of kidamycin« G. A; Guerrero-Vasquèz, T. Mabit, A.Siard, F.Carreaux, G. Dujardin, S. Collet - Oral communication : Scientific symposium of the French Chemical Society, section «Bretagne Pays de la Loire« - 18-20 may 2015 – Nantes (44), France.
2 – «Synthèse totale de la kidamycinone” A. Siard, T. Mabit, F. Carreaux, G. Dujardin, S. Collet – Poster Communication : Scientific symposium of the French Chemical Society, section «Bretagne Pays de la Loire« - 18-20 may 2015 – Nantes (44), France.
3– «Synthèse totale de la kidamycinone” A. Siard, T. Mabit, F. Carreaux, G. Dujardin, S. Collet – Poster communication : 5th french Symposium on Total synthesis – 4-6 june 2015 – Strasbourg (67), France.
4 - «Total synthesis of kidamycinone” A. Siard, T. Mabit, M. Mathé-Allainmat, F. Carreaux, G. Dujardin, S. Collet – Poster Communication : 14th Symposium of the ICSN – 18-19th june 2015 – Gif sur Yvette (91), France.
5 – “ Common strategy for the synthesis of angucyclines, calothrixin et pluramycin skeletons“ S. Collet, D.Sissouma, A. Guingant ; Oral communication : IC3TC – 7-10th december 2015 – Lisbonne, Portugal.
6 - “ Recent advances in the synthesis of kidamycin“ G. Guerrero-Vasquez, A. Siard, T.Mabit, M. Mathé-Allainmat, J. Lebreton, F. Carreaux, G. Dujardin, et S. Collet ; Oral communication : IC3TC – 7-10th december 2015 – Lisbonne, Portugal.
7 – “ Total synthesis of kidamycinone “ T. Mabit, A. Siard, F. Carreaux, G.Dujardin, et S. Collet - Communication par affiche : 24th Young Researchers Days 15-17th february 2016 – School of Pharmacy, Lille (59), France

The KidamySyn project is built on the collaboration of three teams (Nantes, Rennes, Le Mans) and plans to achieve the first total synthesis of Kidamycin, a member of the Pluramycins family. This project submitted in 2013 has been selected on the additional list and received very good appreciations from the evaluation committee. This situation convinced the constituted consortium to resubmit the proposal in a revised form with a better distribution of tasks between the different partners and additional informations about the few remarks emphasised by the referees.
The pluramycins display a 4H-anthra[1,2-b]pyran-4,7,12-trione structure with attached C-glycoside moieties (D-angolosamine and L-vancosamine) and a remote epoxide or unsaturated lateral chain. Their core structure with four contiguous rings, one of which being angularly disposed, is clearly reminiscent of the angucycline class of natural compounds. Besides their remarkable structure, many members of the pluramycin family have promising biological activities, making it a particularly attractive target for organic chemists.
Following our common experience in the chemistry of angucyclines and in the development of innovative synthetic methodologies, our project aims to design and to realise the total synthesis of kidamycin following a convergent strategy that should be efficiently transposed in a second phase to the synthesis of analogues and pluramycin-related molecules with potential enhanced activities.
We will first focus our attention on the synthesis of kidamycin aglycone named kidamycinone. The pluramycinone skeleton will be elaborated in a highly convergent manner via B-ring construction by Diels-Alder cycloadditions involving novel dienes already possessing the lateral chains and juglone. This first task, based in part on the results already obtained in our laboratory, should enable to strengthen the viability of our synthetic plan towards the kidamycin.
The main goal of the project, the synthesis of kidamycin itself, will start by the preparation of the dienophile partner with its two C-glycoside appendages and its subsequent reaction with appropriate diene. Recent literature reports mention the difficulties encountered in installing the two unit sugars by direct C-glycosidation with the appropriate stereoconfiguration mainly for the L-vancosamine link. We therefore designed a new stereocontrolled approach based on a direct C-glycosidation with D-angolosamine followed by the critical introduction of L-vancosamine unit by univocal transformation of the corresponding glycal. Finally, the Diels-Alder strategy developed for kidamycinone will be applied to couple the two key fragments to afford kidamycin after a limited number of further functional transformations. This convergent route, associated with the potential structural diversity of the dienyl building blocks, would enable access to other pluramycin-related compounds and related simplified derivatives. Encouraging preliminary results indicate that the challenging objectives of this project, the total synthesis of kidamycin and the development of innovating synthetic strategies, should be reasonably achieved under the proposed schedule.