Total Synthesis of Antheliolide A O H H H H O O H Antheliolide - PowerPoint PPT Presentation

Total Synthesis of Antheliolide A O H H H H O O H Antheliolide A Chandra Sekhar Mushti, Jae-Hun Kim and E.J. Corey JACS, ASAP 10/28/06 Bryan Wakefield @ Wipf Group 1 11/25/2006

Xenicane Family of Natural Products • A class of diterpenes and norditerpenes isolated from marine organisms • Have shown cytotoxicity, anti-inflammatory and antifungal activites. • First in the family was isolated in 1977 and since a hundred xenicanes have been discovered • This family can be divided into four main groups Liu, G.; Smith, T. C.; Pfander, H., Tet. Lett., 1995, 4979 Bryan Wakefield @ Wipf Group 2 11/25/2006

Synthesis of trans- Cyclononenes OTs NaH, DMSO OH O OTs O H MeO NaH, DMSO H H O OH 66% O H MeO O O PhO 2 S R KOH, MeOH O O O 95 °C, 87% R=CO 2 Me OH KHMDS or KH, 18-C-6, THF, -78 °C CO 2 Me O CO 2 Me 60% CO 2 Me CO 2 Me Corey, E. J.; Mitra, R. B.,;Uda, H. J. Am. Chem. Soc. 1964 , 485 Liu, G.; Smith, T. C.; Pfander, H. Tet. Lett. 1995, 4979 Kende, A. S.; Kaldor, I. Tet. Lett., 1989 , 7329 Von Zezschiwitz, P.; Viogt, K.; Noltemeyer, M.; de Meijere, A. Synthesis, 200, 1327 Bryan Wakefield @ Wipf Group 3 11/25/2006

Synthesis of Mixed Acetal 1. KH, THF, -40 °C then CuCN, THF then t BuLi, Et 2 O then Bu 3 SnCH 2 I OH Br BrMg O 2. ˆ n BuLi, THF, -78 °C Br OTBDPS Br OTBDPS 91% yield 90% yield HO CO 2 Me 1. DMP, DCM PPTS, 60-65 °C 2. HC(OMe) 3 , PPTS O OTBDPS OMe OTBDPS OH OTBDPS OMe CO 2 Me OMe 61% yield 85% yield O OTBDPS O OTBDPS O OTBDPS OTBDPS MeO 2 C O CO 2 Me CO 2 Me OMe CO 2 Me OMe Preparation of the Racemic Mixed Acetal Methyl Ester 7 . To a mixture of dimethyl acetal (4.15 g, 7.77 mmol) and methyl glycolate (9 mL, 116.6 mmol, 15 equiv), pyridinium tosylate (58 mg, 0.233 mmol, 3 mol %) was added and the reaction was heated in a preheated oil bath whose temperature was maintained between 60 to 65 o C. The biphasic reaction mixture was vigorously stirred and continuously purged with a slow stream of dry N 2 gas to remove the MeOH generated during the reaction. The reaction was continued at the same temperature until the reaction mixture became homogenous (usually within 1.5 to 2 h). ….. The residue was purified by flash column chromatography (silica gel, hexanes–EtOAc, 1:0 → 9:1 to give racemic mixed acetal methyl ester 7 (3.34 g, yield 73%) and 664 mg of starting dimethyl acetal 6 along with aldehyde, which can be recycled to the dimethyl acetal by treating methyl orthoformate and PPTS as before. Bryan Wakefield @ Wipf Group 4 11/25/2006

The “Magic” HPLC OTBDPS 1. LiOH, MeOH MeO H 2. p -TolCl, Et 3 N, O O OTBDPS O Toluene, reflux O OTBDPS H OMe CO 2 Me 66% yield OMe O OTBDPS OTBDPS 1. TMS-acetylene, n BuLi, CeCl 3 THF, -78 °C MeO H MeO H O O O 2. LiOH H H OH In 1 ml this is 7.2 M Bryan Wakefield @ Wipf Group 5 11/25/2006

Alkyne Oxidation OTBDPS OTBDPS PhS(O)Cl, Et 3 N, DMAP DCM, 0 °C Pd 2 dba 3 , Toluene, 60 °C MeO H MeO H O O H H OH O O S Ph 87% yield (3 steps) OTBDPS OTBDPS OTBDPS HCl Et 2 NH, DCM MeO H MeO H MeO H O O O NEt 2 SO 2 Ph H H H H O PhO 2 S SO 2 Ph OCO 2 Me 1. HF, pyr. MeO H 2.MeOCOCl, DMAP, DCM O SO 2 Ph H H O Bryan Wakefield @ Wipf Group 6 11/25/2006

An Unusually Pd-Allyl Ring-Closure OCO 2 Me Pd 2 dba 3 •CHCl 3 , 1,4 bisdiphenylphosphinobutane H MeO H DBU, THF, 55 °C MeO H O SO 2 Ph O H H H O O SO 2 Ph Pd H H H MeO MeO Pd MeO Pd H H H O O O H H H O O O SO 2 Ph SO 2 Ph SO 2 Ph Hu, T.; Corey, E.J., Org. Lett. 2002, 2441 Bryan Wakefield @ Wipf Group 7 11/25/2006

Absolute Stereochemistry by Comparing Optical Rotation H Al(Hg), THF, H 2 O, 88% Tebbe Reagent, 86% H H MeO MeO MeO H H H O O O H H H O O SO 2 Ph A (+)-A stereochemistry shown (-)-A oppisite stereochemistry H H X X=O X=CH 2 Bryan Wakefield @ Wipf Group 8 11/25/2006

Completion of the Synthesis PhSeAlMe 2 , DCM AgNO 3 , Acetone, H 2 O H H H HO PhSe MeO H H H O O 88% yield O H H H HO O 1. KHMDS, Davis Reagent, HO H H H TPAP, NMO NaIO 4 , DCM O O 90% yield H H H O H O O 93% yield H H 2. 1-bromo-1-propene, n BuLi, THF, 90% yield OH O Silica Gel, Benzene N H Piperidine, THF H r.t, 6 h N H H O O 98% yield O H H O O H [4+2] O H H 74% yield H H H O O H O O H Antheliolide A Bryan Wakefield @ Wipf Group 9 11/25/2006

Conclusion • This synthesis had a number of interesting steps as listed above. • The desire or need to separate the enantiomers at such an earlier stage (10 steps in to the synthesis, 15 steps remaining) is not addressed. • The origin of the selectivity and high yield of the Pd-allylation reaction needs to be addressed. Bryan Wakefield @ Wipf Group 10 11/25/2006