lenes in organic synthesis: a concise synthesis of (±)-epi-picropodophyllin obert D. C. Pullin, Jonathan D. Sellars, and Patrick G. Steel* rg. Biomol. Chem., 2007, 5, 3201-3206 H H C Adam Hoye Current Literature ct. 27th, 2007 Adam Hoye @ Wipf Group 1 10/29/2007
Classic organosilicon chemistry H + tbu 2 Cl imidazole, DMF 2 tbu 3 Li 3 CH 3 E + 3 Et X - (- 3 X) E 3 E + 3 E X - (- 3 X) E 3 E + 3 E X - (- 3 X) E n 2 X 2 H 2 H H -H 2 n Adam Hoye @ Wipf Group 2 10/29/2007
ecent advances in organosilicon chemistry -Denmark (J. Am. Chem. Soc., 2007, 129, 2774) Bn Bn TES Li 2 HCl 89% [ucl 2 (p-cymene)] 2 H 2 = H TES = H, 84% I Piv Pd 2 (dba) 3 CHCl 3 82% Bn TES Piv Bn H H H H H H Papulacandin D -Woerpel (J. Am. Chem. Soc., 2005, 127, 2046) 1 2 AgCCF 3 (1-5 mol%) 2 1 1 2 1 2 96% (93:7 d.r.) Adam Hoye @ Wipf Group 3 10/29/2007
lenes: a brief history -In 1912 Schlenk and enning reported silene synthesis by dehydration of a silanol (release of H 2 ) -Kipping showed product was actually a siloxane and concluded multiple bonds to were not a realistic objective -1967 Gusel nikov and Flowers: 450 C -CH 2 =CH 2 H H H 2 3 H 3 3-1981 Brook (photolysis of acylsilanes)- steric bulk on the carbon atom key to moderating silene reactivity (stability) 3 ( 3 ) 3 hv 3 3 unchanged after several years although if exposed to air disappears in a puff of smoke ttosson, H.; Steel, P. G. Chem. Eur. J. 2006, 12, 1576-1585 Brook et al. J. Am. Chem. Soc. 1982, 104, 5667-5672 Adam Hoye @ Wipf Group 4 10/29/2007
lenes: a brief history -Steric stabilization of silenes 2 3 2 3 -Electronic stabilization of silenes: reversed =C bond polarity (that is δ- =C δ+ instead of δ+ =C δ- ) leads to lower release of energy upon dimerization; slower rates of addition to silicon dative stabilization silenolates 3 N 2 2 3 3 N 2 3 3 3 3 3 3 -Extension into allenyl and aryl systems: CH( 3 ) 2 ( 3 ) 2 HC CH( 3 ) 2 ttosson, H.; Steel, P. G. Chem. Eur. J. 2006, 12, 1576-1585 Adam Hoye @ Wipf Group 5 10/29/2007
lenes: preparation and general reactivity Common methods of preparation: General silene reactivity: 3 3 3 hv 3 TMS 3 Nu-H Nu! X C' 2 ' ' X 2 ( 3 ) 3 Li 3-3 Li 3 Cl Li - LiCl 2 3 3 3 K 3 3 K 3 3 K -40 C H ( 3 ) 2 (94%) ttosson, H.; Steel, P. G. Chem. Eur. J. 2006, 12, 1576-1585 3 3 TMS 2 C 180 C C 2 TMS C 2 ( 3 ) 2 C 2 Adam Hoye @ Wipf Group 6 10/29/2007
Tetralin lignan lactones 1 2 1 2 1 2 Podophyllotoxin 1 = H, 2 = H Isopodophyllotoxin 1 = H, 2 = H Epipodophyllotoxin 1 = H, 2 = H Epiisopodophyllotoxin 1 = H, 2 = H Podophyllotoxin is a potent antimitotic agent, but highly toxic. H H S H H Picropodophyllotoxin Epipicropodophyllotoxin 1 = H, 2 = H 1 = H, 2 = H N 2 H H HN H H H Etoposide Tenoposide DNA topoisomerase II inhibitors (used clinically, but poor solubility and growing drug resistance) Sellars, J. D.; Steel, P. G., Eur. J. rg. Chem., 2007, 3815 GL-331 In phase II trials (more potent, less resisted) Adam Hoye @ Wipf Group 7 10/29/2007
Lignan syntheses Typical strategies to construct the core: MsCl, Et 3 N 56% C 2 H C 2 H H Ar Ar 1 2 A B C D H! H 2 C C 2 H C 2 Ar Ar 90% Ar C 2 S S S S LDA 79% Ar Ar H Vanderwalle et al., Tetrahedron, 1991, 47, 4675 Charlton, J. L., Koh, K., J. rg. Chem., 1992, 57, 1514 Harrowven, D. C., Tetrahedron, 1993, 49, 9039 Florio et al., rg. Lett., 2005, 7, 4895 H Li W(C) 1. 5 2. pyridine N-oxide 52-83% H Adam Hoye @ Wipf Group 8 10/29/2007
Previous work in the Steel group ( 3 ) 3 1. KtBu or Li, THF, rt, 2 or 18 h 2. MgBr 2, Et 2 3 MgBr 3 CH H Et 2, -78 C 3 3 = (52%), C 3 H 7 (74%), (49%), i-bu (58%), t- Bu (37%), c-c 6 H 11 (38%), (68%) H ( 3 ) 2 BuLi/Li LiBr 3 H Li LiBr -TMSLi Li TMS Li Br ( 3 ) 2 3 TMS 3 Sanganee, M. J.; Steel, P. G.; Whelligan, D. K., rg. Biomol. Chem., 2004, 2, 2393 Adam Hoye @ Wipf Group 9 10/29/2007
Previous work in the Steel group 1 H 3 3 Diene n-buli, Et 2, rt, then -78 C, LiBr, warming to -30 C 22 h 4 3 3 1 2 3 3 3 3 3 3 i Pr i Pr i Pr i Pr 50% (83:9:8) 42% (83:17) 28% (89:7:4) 45% (74:20:6) 38% (86:9:4:1) 28% (80:14:4:2) 3 BF 3 2AcH, F 3 H 2 2, KF, H CHCl 3 KHC 3, THF/H 74% H 2, Pd/C 3 BF 3 2AcH, CHCl 3 3 F H 2 2, KF, KHC 3, THF/H 43% (2 steps) H TPAP, NM H 76% 85% (2 steps) (92:8 d.r.) Berry, M. B.; Griffiths,. J.; Sanganee, M. J.; Steel, P. G.; Whelligan, D. K., rg. Biomol. Chem.2004, 4, 2381 Berry, M. B.; Griffiths,. J.; Sanganee, M. J.; Steel, P. G.; Whelligan, D. K., Tetrahedron Lett., 2003, 44, 9135 Sanganee, M. J.; Steel, P. G.; Whelligan, D. K., rg. Biomol. Chem., 2004, 2, 2393 Adam Hoye @ Wipf Group 10 10/29/2007
Sakurai reactions with cyclic allyl silanes With electron-rich aromatics: 3 CH() 2, BF 3 Et 2, DCM, 0 C 60% F 3 3 F 3 BF 3 i. 4-()C 6 H 4 CH() 2, BF 3 ˇEt 2 ii. H 2 2, KHC 3 2 X 27% (5:1 d.r.) H 2 X H 2 2, KHC 3, THF/H 80% product oxidation 2 X H H Sellars, J. D.; Steel, P. G.; Turner, M., Chem. Commun., 2006, 2385 Steel et al. rg. Biomol. Chem., 2007, 5, 2841 Adam Hoye @ Wipf Group 11 10/29/2007
Current paper ( 3 ) 3 i. KtBu, THF ii. MgBr 2 Et 2 iii. CH, Et 2 40% i. n-buli, KtBu ii. B() 3, -78 C iii. H 2 2, NaH iv. TBSCl, Imidazole 43% H 3 3 TBS nbuli, LiBr, THF, -20 C 60% = TBS = Ac 3 i. ptsh ii. AcCl (45 %) Ac 3 i. BF 3 Et 2, DCM, 0 C ii. H 2 2, KHC 3, THF/H H H H 53% (20 : 1 d.r.) s 4 (cat.), NaI 4 2,6-lutidine, THF/H 2 58% H H 3:1 mixture of anomers H formed if unprotected alcohol used Adam Hoye @ Wipf Group 12 10/29/2007
Current paper H H NIS, Bu 4 NI (0.4 eq.), DCM H 63% epi-picropodophyllin HCl, THF KHMDS H H Adam Hoye @ Wipf Group 13 10/29/2007
Conclusions -Access to tetralin lignan lactone family using silene cycloaddition/cyclic allylsilane Sakurai reactions -Highly modular synthesis; facilitates future analogue development -Truly concise synthesis (9 steps, 2.2% overall yield) H H H 3 3 Adam Hoye @ Wipf Group 14 10/29/2007