Synthesis of Abyssomicin C. Marie-Caroline Cordonnier Litterature Review 23/01/2009

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1 Synthesis of Abyssomicin C Marie-Caroline Cordonnier Litterature Review 23/01/2009

2 Isolation Isolated in 2004 from the actinomycete Verrucosispora strain collected from a sediment at a depth of 289m in the Japanese sea. (name: abyss) Discovered as a whole family but only abyssomicin C shows antibiotic activity. Süssmuth et al. Angew. Chem. Int. Ed. 2004, 43, 2574.

3 Biological activity Antibiotic activity against Gram-positive bacteria including methicilin - resistant (MRSA, MIC = 4 µg/ml) and vancomycin - resistant (VRSA, MIC = 13 µg/ml) Staphylococcus aureus strains. Inhibitor of the enzyme responsible for the conversion of chorismate to para-aminobenzoic acid as such it is a potential antibacterial drug. Süssmuth et al. Angew. Chem. Int. Ed. 2004, 43, 2574.

4 Biological activity Could be explained by the Michael system missing in the inactive compounds H 3 C H N H 3 C H 3 C H H H H Abyssomicin B Abyssomicin C Abyssomicin D Snider et al. rg. Lett. 2005, 7, 4939.

5 Total Syntheses Because of this intringuing system and of the biological activity several groups attempted the total synthesis of Abyssomicin C. B. B. Snider rg. Lett. 2005, 7, E. J. Sorensen Angew. Chem. Int. Ed. 2005, 44, K. C. Nicolaou Angew. Chem. Int. Ed. 2006, 45, 3256, and J. Am. Chem. Soc. 2007, 129, 429.

6 Challenging structural elements Strained 11-membered macrocyclic ring 7 stereogenic centers Potentially reactive α, β unsaturated ketone Novel fused tetronate oxabicyclo[2,2,2]octane core

7 Snider s Approach: Retrosynthesis Biomimetic route H 3 C H Abyssomicin C H 3 C Cyclisation 1 H Synthesis of the oxabicyclo[2.2.2]octane Epoxidation Deprotection Epoxidation of the more nucleophilic C=C from the less hindered face H 3 C Me Intramolecular Diels-Alder 2 H 3 C CH H 3 C Me 1. Maier et al. Synlett 2005, 314 and Maier et al. rg. Lett. 2005, 7, Yoshii et al. J. rg. Chem. 1987, 52, 4135.

8 Snider s Approach: Retrosynthesis Diels-Alder very risky The Key Step Creation of three stereocenters 4 possible products Endo and Exo products are possible Facial selectivity is also an issue Reactivity of the methylene butenolide as dienophile? Yoskii reported that reaction of a ten-atom tether proceeded under forcing conditions (180 C in o-dichlorobenzene) with a low yield and as a mixture of 4 cycloadducts. Yoshii et al. J. rg. Chem. 1987, 52, 4135.

9 Snider s Approach: Retrosynthesis Two encouraging factors The Key Step Presence of an acyl group in the tether dienophile more electron deficient Biosynthesis probably involves a similar Diels-Alder reaction under physiological conditions in which the stereochemistry of the product is controlled by the substrate rather than an enzyme.

10 Snider s Approach: Synthesis of the Diels-Alder Substrate Hoffmann et al. Tet. Lett. 1985, 26, Yoshii et al. E. J. Chem. Soc. 1989, 712. Paintner et al. Tet. Lett. 2000, 41, 9977.

11 Diels-Alder reaction ne single cycloadduct isolated Desired cycloadduct formed showed by NE in which C-16 is in endo position Novel and mild stereospecific Diels-Alder facile access to the carboxylic skeleton of Abyssomicin C

12 End of the synthesis Hydrolysis of the vinylogous carbonate with LiCl in DMS: 88% yield 1 Epoxidation of the cyclohexene double bond afforded complex mixture in which enone double bond had reacted m-cpba DMD Not surprising considering that this is probably the reason for Abyssomicin C s biological activity Yoshii et al. E. J. Chem. Soc. 1989, 712.

13 End of the synthesis Never completed because Sorensen published at the same time a full synthesis of Abyssomicin C

14 Sorensen s Approach: Retrosynthesis Convergent assymetric synthesis H 1. Stereoselective epoxidation 2. Demethylation 3. Intramolecular epoxide opening Me Abyssomicin C Intramolecular Diels-Alder H Intermolecular carbonyl additions Li Me Yoshii et al. Tet. Lett. 1986, 27, Yoshii et al. J. rg. Chem. 1990, 55, 3431.

15 Synthesis of the Diels-Alder substrate Lautens et al. rg. Lett. 2002, 4, Schick et al. Tetrahedron: Asymmetry. 1993, 4, 695.

16 Snider s Approach: Synthesis of the Starting Material H 1.DHP 2. DIBAL 94% THP Snider s preparation of the starting material is 63% yield H + Et 70% Sorensen s preparation is 50% yield Rh/Al 2 3 H 2 96% prepared on 100g scale from Andrus et al. J. rg. Chem. 1997, 62, 5542.

17 Synthesis of the Diels-Alder adduct Contains all carbons of Abyssomicin C But yields modest and variable Mixture of diastereomers Yoshii et al. J. rg. Chem. 1987, 52, 4135.

18 Cyclisation Step Sc(Tf) 3, DCM,0 C (65%) TBS Me Me Unstable trienone Me Toluene, 100 C (79%) TBS used as precursor of the trienone Trienone is an unstable compound one pot synthesis required

19 ptimised cyclisation step Is it really interesting? As the overall yield of the 2 Is it really interesting? As the overall yield of the 2 steps is 51%...

20 Completion of the synthesis Me DMD, Acetone 67% Me LiCl, DMS quant. p-tsh, LiCl, MeCN 50% H H

21 Nicolaou s Approach: Retrosynthesis Maier et al. Synlett 2005, 314 and Maier et al. rg. Lett. 2005, 7, Xu et al. Bioorg. Med. Chem. 1996, 4, 375.

22 Nicolaou s Synthesis: Studies toward the oxabicyclic core Abae et al. rg. Lett. 2000, 2, Maier et al. rg. Lett. 2005, 7, 3089.

23 Nicolaou s Synthesis: Studies toward the oxabicyclic core Kocienski, P. Phosphorus Sulfur 1985, 24, 97.

24 Nicolaou s synthesis: improved approach More efficient approach Me 2 C H Reductive elimination/ methylation H PhS H xidation Me Lewis-Acid templated Diels-Alder H PhS H PhS H

25 Nicolaou s synthesis: Improved synthesis Corey et al. J. rg. Chem. 1966, 31, Corey et al. Angew. Chem. Int. Ed. 1998, 37, Cohen et al. Acc. Chem. Res. 1989, 22, 152.

26 Nicolaou s synthesis: Synthesis of the oxabicyclic[2,2,2]octane core H C 2 Me t-buh V(Et) 3 93% Ac C 2 Me Ac 2 95% LHMDS aq.nh 4 Cl then TESCl 97%over2steps Dieckmann condensation H TES Sharpless et al. J. Am. Chem. Soc. 1974, 96, Evans et al. Synlett 1992, 269.

27 Nicolaou s synthesis Xu et al. Bioorg. Med. Chem. 1996, 4, 375. Maier et al. rg. Lett. 2006, 8, 1025.

28 Nicolaou s synthesis: fragment coupling Several oxidants were used but after 1st oxidation hemiketalization took place

29 Nicolaou s synthesis: synthesis of Abyssomicin C framework + 1. t-buli 2.(CH 2 SH) 2 TMSTf 76%over2steps H S S TES H 1.IBX 2. vinyl MgBr 65%over2steps H S S Grubb's II 85% H S S H H

30 Nicolaou s synthesis: completion of the synthesis H S S IBX 50% S S H H PhI(TFA) 2 71% CDCl 3 67% H H Abyssomicin C atrop-abyssomicin C

31 Abyssomicin C and atrop-abyssomicin C

32 Comparison of Sorensen s and Nicolaou s total syntheses Highlight the power of the Diels-Alder reaction Either intramolecular to form a strained macrocyclic system r intermolecular via a Lewis mediated templated transition state Both well-suited to synthesize new analogues to enable further studies of the structure-activity relationship

33 Comparison in numbers Sorensen s synthesis Nicolaou s synthesis Number of linear steps verall yield 2 % 4 %