Phorbol 3-A Kinder, Gentler Cyclization Phorbol 2 -The Hydroxypyrone Approach PhCH3200℃C,3da TBSO. Phorbol HcHS3,200°C,3days TBSO OTBS PhcH3,200°c Activation allows milder conditions TBSO TBSO CH2Cl2/DMF 18SO. Meotf 71% Wender, P A McDonald. F E. J Am. Chem. Soc. 1990. 112, 4956-4958 Wender, P. A: Mascarenas, J. L. J. Org. Chem. 1991, 56, Tetrahedron Lett. 1992, 33, 2115-2118.(Intermolecular t 35B-07 Ylides3/16/934:47PMActivation allows milder conditions: Phorbol 3 - A Kinder, Gentler Cyclization PhCH3, 200 °C, 3 days 74% only trace amounts (isomerization) PhCH3, 200 °C, 3 days TfO- + MeOTf CH2Cl2 CsF CH2Cl2 / DMF RT 3.8 : 1 84% 82% 3.8 : 1 RT MeOTf CH2Cl2 + TfO￾H Wender, P. A.; Mascareñas, J. L. J. Org. Chem. 1991, 56, 6267-6269. Tetrahedron Lett. 1992, 33, 2115-2118. (Intermolecular trapping) Phorbol 2 - The Hydroxypyrone Approach Phorbol - + PhCH3, 200 °C 71% Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112, 4956-4958 OH OH H OH OH OH H O O OTBS O TBSO O H O OTBS O H OTBS O TBSO O t-BuMe2Si O OTBS O O H O O OTBS O TBSO OTBS O TBSO O O OTBS O TBSO OTBS O TBSO O O OBz O TBSO O OBz MeO TBSO OTBS O TBSO O O OBz O HO O OBz MeO HO OTBS O MeO O N 35B-07 Ylides 3/16/93 4:47 PM