Highlights in the Progress of Biomimetic Strategies for the Construction of Complex Natural Products. Chris Galliford 26 th August 2003

Transcription

1 ighlights in the Progress of Biomimetic Strategies for the Construction of Complex Natural Products Chris Galliford 26 th August 2003

2 The Biomimetic Approach Inspiration for biomimetic synthesis of a target compound generally comes from the biosynthetic pathway for that compound. apid generation of molecular complexity and challenging stereochemical environments are often created in a single stereogenic event. The symmetry or pseudo-symmetry of readily accessible starting materials is often exploited. An early example of this approach is obinson s 1917 biomimetic synthesis of tropinone.

3 Tropinone - Setting the Stage 2 C C 2 N N 2 tropinone Cl -2C 2 N C 2 N C 2 N C 2 C 2 C 2 2 C obinson,. J. Chem. Soc., 1917, 762

4 Carpanone A lignan obtained from the bark of the carpano tree. Possesses no element of symmetry and has five contiguous stereogenic centers. (±)-carpanone Chapman and co-workers had developed the reaction of o-quinone methide with electron-rich olefins: Chapman,. L.; Engel, M..; Springer, J. P.; Clardy, J. C., J. Am. Chem. Soc., 1971, 93, 24, 6696

5 Carpanone - etrosynthesis C-C bond rotation C 2 symmetric

6 Carpanone - Generation of the o-quinone Methide Precursors Pd o-quinone methide generated by Pdmediated oxidative phenolic coupling Carpanone formed only from conformation shown

7 Carpanone - Synthesis tbuk DMS PdCl 2 NaAc Me/ 2 [4+2] (±)-carpanone 48%

8 Panepophenanthrin ecently discovered inhibitor of the ubiquitin-proteosome pathway (UPP). Panepophenanthrin is the first example of a Ubiquitinactivating enzyme (E1) inhibitor. o Panepophenanthrin acemic synthesis: Baldwin, J.; Moses, J. E.; Commeiras, L.; Adlington,. M. rg. Lett., 2003, 5, 17, 2987 Asymmetric synthesis: Porco, J. A.; Lei, X.; Johnson,. P. Angew. Chem., Intl. Ed. Eng., 2003, 42, 3913

9 Panepophenanthrin - etrosynthesis o [4+2] o Pd-mediated coupling reaction

10 Panepophenanthrin - acemic Synthesis by Baldwin and Co-workers TESCl, imidazole rt 94% TES Bu 3 Sn Pd 2 (dba) 3, AsPh 3 toluene, reflux 75% TES one pot TBAF, Me 85% TES TES

11 Panepophenanthrin - Asymmetric Synthesis by Porco PPh 3, DIAD, 4-nitrobenzoic acid, -50 to 0 o C, 1 h NaMe (1M), Me rt, 0.5 h TBSCl, imidazole, DMF, rt 80% TBS 85% Bu 3 Sn Pd(Ac) 2, DMF 90 o C 75% 10 % F, CN/ C 2 Cl 2, rt 40% TBS

12 Torreyanic Acid C 2 Isolated as part of a program to explore the biosynthetic potential of endophytic fungi. Fungi residing in Florida torreya, (Torreya taxilofica), an endangered species of tree, closely related to the taxolproducing Pacific yew. C 2 The endophyte Pestalotiopsis microspora was identified and cultured. Several phytotoxic and antifungal secondary metabolites were isolated from this fungus, including Torreyanic acid 1. Dimeric quinone structure with selective cytotoxicity agaist human cancer cell lines. Lee, J. C.; Strobel, G.A.; Lobhovsky, E.; Clardy, J. J. rg. Chem., 1996, 61, 3232 Li, C.; Johnson,. P.; Porco Jr, J. A. J. Am. Chem. Soc., 2003, 125, 5095

13 Proposed Biosynthetic Pathway C 2 C 2 = C 2 Proposed biosynthesis via oxidative dimerization of monomeric precursors. oxaelectrocyclization/diels-alder cascade already demonstrated in an earlier racemic synthesis by the same authors.

14 etrosynthetic Analysis C 2 C 2 = C 2

15 etrosynthetic Analysis TBDPS C 5 11 C 5 11 C 5 11 TBDPS TBDPS TBDPS

16 Model Studies DMP C 5 11 C 2 Cl 2 rt C 5 11 C % 46%

17 Stereochemical ationale pentyl side chains restrict diene faceselectivity restrict epoxide chirality

18 Synthesis TBDPS PPTs Ph Ph 3 C 3, KMDS, TF 73% TBDPS 1. NM, s 4, acetone/ 2, 30 h 2. Pb(Ac) 4, TF, 5 min 3. Ph 3 P=C( )C 2 tbu 60% over three steps TBDPS C 2 tbu

19 Synthesis TBDPS C 2 tbu 1. Pd(PPh 3 ) 4, toluene, reflux 2. TBAF/Ac 3. 48% F, CN, 0 o C C 5 11 C 2 tbu C 2 C 2 tbu C 2 DMP C 2 Cl 2, rt, 1 h followed by TFA/ C 2 Cl 2 80% C 2 tbu

20 Summary Biomimetic approaches to complex natural products can be spectacularly successful, both in nature and at the lab bench. Advances in asymmetric processes have extended the scope of biomimetic strategies from being limited to mainly racemic syntheses, to enantioselective total synthesis - a powerful combination indeed.