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

Total Synthesis of Antheliolide A

Chandra Sekhar Mushti, Jae-Hun Kim and E.J. Corey JACS, ASAP 10/28/06

H H O H O O H H Antheliolide A

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

O OTs OH NaH, DMSO O O OTs OH O MeO H H NaH, DMSO O O H H MeO 66% KOH, MeOH 95 °C, 87% O O PhO2S O R R=CO2Me CO2Me CO2Me OH KHMDS or KH, 18-C-6, THF, -78 °C 60% CO2Me CO2Me O

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

BrMg CuCN, THF then Br Br Br

tBuLi, Et2O then

O OTBDPS OH OTBDPS

• 1. KH, THF, -40 °C then

Bu3SnCH2I

• 2. ˆnBuLi, THF, -78 °C

OTBDPS OH

• 1. DMP, DCM
• 2. HC(OMe)3, PPTS

OTBDPS OMe OMe HO CO2Me PPTS, 60-65 °C OTBDPS O OMe CO2Me 91% yield 90% yield 61% yield 85% yield

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 oC. The biphasic reaction mixture was vigorously stirred and continuously purged with a slow stream of dry N2 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.

OTBDPS OMe OTBDPS O OMe CO2Me OTBDPS O CO2Me OTBDPS O O CO2Me MeO2C

Bryan Wakefield @ Wipf Group 4 11/25/2006

The “Magic” HPLC

OTBDPS O OMe CO2Me

• 1. LiOH, MeOH
• 2. p-TolCl, Et3N,

Toluene, reflux O MeO O OTBDPS H H 66% yield OTBDPS O OMe O O MeO O OTBDPS H H

• 1. TMS-acetylene, nBuLi, CeCl3

THF, -78 °C

• 2. LiOH

O MeO OTBDPS H H OH

In 1 ml this is 7.2 M

Bryan Wakefield @ Wipf Group 5 11/25/2006

O MeO OTBDPS H H OH PhS(O)Cl, Et3N, DMAP DCM, 0 °C O MeO OTBDPS H H O S O Ph Pd2dba3, Toluene, 60 °C O MeO OTBDPS H H PhO2S Et2NH, DCM O MeO OTBDPS H H NEt2 SO2Ph O MeO OTBDPS H H SO2Ph O H 87% yield (3 steps) HCl

• 1. HF, pyr.

2.MeOCOCl, DMAP, DCM O MeO OCO2Me H H SO2Ph O H

Alkyne Oxidation

Bryan Wakefield @ Wipf Group 6 11/25/2006

Pd2dba3•CHCl3, 1,4 bisdiphenylphosphinobutane DBU, THF, 55 °C O MeO OCO2Me H H SO2Ph O H O MeO H H H O SO2Ph

An Unusually Pd-Allyl Ring-Closure

O MeO H H H O SO2Ph Pd O MeO H H H O SO2Ph Pd O MeO H H H O SO2Ph Pd

Hu, T.; Corey, E.J., Org. Lett. 2002, 2441

Bryan Wakefield @ Wipf Group 7 11/25/2006

Absolute Stereochemistry by Comparing Optical Rotation

O MeO H H H O SO2Ph Al(Hg), THF, H2O, 88% O MeO H H H O H H X X=O X=CH2 O MeO H H H Tebbe Reagent, 86% A (+)-A stereochemistry shown (-)-A oppisite stereochemistry

Bryan Wakefield @ Wipf Group 8 11/25/2006

Completion of the Synthesis

O MeO H H H PhSeAlMe2, DCM O PhSe H H H AgNO3, Acetone, H2O 88% yield O HO H H H TPAP, NMO O O H H H

• 1. KHMDS, Davis Reagent,

90% yield

• 2. 1-bromo-1-propene, nBuLi,

THF, 90% yield O H H H HO HO NaIO4, DCM 93% yield H H O O O Piperidine, THF 98% yield H H O O O N Silica Gel, Benzene r.t, 6 h H H O H H H O N OH H H O H O O [4+2] H H O H O O H H 74% yield 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