Photoenolization Diels-Alder Reactions Application to the Total Synthesis of Hybocarpone and Hamigerans

Transcription

1 Photoenolization Diels-Alder Reactions Application to the Total Synthesis of ybocarpone and amigerans Group Meeting 01/08/04 Vijay References ybocarpone Nicolaou,K.C.; Gray, D. L.F. J.Am,Chem,Soc.2004,126 ASAP Nicolaou,K.C.; Gray, D. L.F.Angew.Chem.Int.Ed.2001,40,761 amigerans Nicolaou,K.C.; Gray, D. L.F.; Tae, Jinsung. J.Am,Chem,Soc.2004,126 ASAP

2 Photoenolization Diels-Alder Reaction: Introduction Benzophenone to Benzopinacol Dienol(α-ydroxy o-quninodimethane) Formation via Intramolecular hydrogen transfer Yang, N.; Rivas, C. J.Am.Chem.Soc.1961,83, 2213

3 ther methods for Dienol Formation C hν S 2 1 C C 2 R hν C 2 R 5A 3 R 2 C 5B C 2 R C 2 R C 2 R R = C2 Me C 3 6 Yields NR C 2 R C 2 R 5A C 2 R + C 2 R 7 8 C 2 R C 2 R Ts C 2 R + C 2 R 70 : 30 C 2 R C 2 R Charlton, J.; Koh, K.; Plourde, G. Tet.Lett.1989, 30, % Yield

4 Mechanism hν EWG Diels-Alder Trap EWG endo adduct shown Sammes,P. Tetrahedron 1976, 32, 405 Charlton, J.; Alauddin, M. Tetrahedron 1987, 43, 2873

5 Examples of PEDA and Applications Photochemical Synthesis of Estrone 3 C hν λ 340 nm Me-Cyclohexane 95 o C 2,6-dimethyl phenol Pyridine 3 C trans-anti-trans Major + cis-anti-trans Minor 2,6- Dimethyl phenol prevents light induced decomposition of dienol Pyridine increases the life time of (Z)-Dienol Quinkert, G.; Stark,.Angew Chem.Int.Ed.1983, 22, C C 3 (or) C 3 E / exo / β Z / exo / β favored E / endo / α disfavored Z / endo / α Pleurotin Analog Me Me C 1. hν Me Me Ag o C 50 % N 3 TF Kraus,G.A.; Chen,Li. Synth.Commun.23, 2041, 1993 Pleurotin

6 ybocarpone Isolated from lichen species Lecanora ybocarpa in Lousiana woodland Cytotoxic against murine mastocytoma P815 transplantable tumor cell line IC 50 of 150 ng/ml Possible DNA intercalation/dna damage pathway as viable mode of action Novel molecular architecture containing dinaphtho furantetraone skeleton possessing element of C 2 symmetry Closely structurally related to the naphthazarins

7 Tetralones as precursors to ybocarpone and Analogs

8 PEDA Approach to Tetralones

9 xidative Dimerization of Ketone Enolate 15

10 Ireland Claisen Rearrangement Approach -A Simple Model System

11 Biomimetic Approach

12 Possible diastereomers formed upon hydration/cyclization event

13 Synthesis of Napthazarins 3,4

14 Naphthazarins (Cont d) 41,42

15 Synthesis of Protected hybocarpone 21 Low yields for dimerization 36 % combined yield of 25&21 after three iterations using recovered starting material.longer reaction times and other reaction variables did not affect conversion and chemical yields

16 Completion of synthesis

17 Synthesis of ybocarpone Analogs Two isomeric compounds for 46 were isolated in 1:1 ratio. The other isomer doesn t interconvert in acidic conditions. More prone to decomposition

18 Substrate Scope For Intermolecular PEDA

19 Asymmetric Induction in PEDA

20 Intramolecular PEDA Approach to amigerans

21 Substrate scope of IMPEDA

22 Proposed Model to account for Stereoselectivity in (Z)-lefin

23 amigerans Isolated from amigera Tarangaensis in Newzealand Cytotoxic against P-388 leukemia cells [4-bromo-hamigeran B, IC 50 = 13.5µM Strong antiviral activity against herpes and polio viruses Substituted benzenoid nucleus fused to [4.3.0] or [5.3.0] bicyclic system

24 Retrosynthesis of amigerans

25 Synthesis of 80 via Jacobsen s ydrolytic kinetic resolution Tokunga, M.; Larrow, J.F.; Kakiuchi, F.; Jacobsen, E.N. Science 1997, 277,

26 Photocyclization of 71

27 5-epi amigeran A&B

28 Photoisomerization of Tricyle 88

29 Strain Energies of amigerans

30 Photocyclization of 72

31 Advanced intermediate 109

32 Unexpected Endo Attack Upon ydrogenation

33 ydrogenation Studies

34 6-epi-amigerans

35 ydroboration to set C-6 in 121

36 Construction of amigerans A and B

37 Ring Contraction of Tricycle 96

38 Mechanism for Ring Contraction

39 Synthesis of amigeran E

40 Conclusions Inter and Intramolecular PEDA reactions have been developed as versatile synthetic methodologies for construction of polycyclic natural products such as ybocarpone and amigerans. Norrish Type I fragmentation pathway led to isomerization of 88 and ring contraction leading to [3.3.0] bicyclic system 123 Barium hydroxide mediated cascade pathway was developed to facilitate interconversion to other members of amigerans ur Approach Alternative approach X Me Cr(C) 5 X Me X Me Me R Cr(C) 5 Me R Me Cr(C) 5 R Me Me a) Nucleophile b) oxidation R Cr(C) 5 Me amigeran Analogs