Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, April 4, 2011
Douglass F. Taber
University of Delaware

The Ma Synthesis of (-)-GB 13

An investigation of the activity of the Galbulimima alkaloids, exemplified by (-)-GB 13, led to the development of a series of potent thrombin receptor antagonists. Dawei Ma of the Shanghai Institute of Organic Chemistry devised (Angew. Chem. Int. Ed. 2010, 49, 5887. DOI: 10.1002/anie.201002299) a concise route to 3 based on the coupling of the chirons 1 and 2.

The starting point for the preparation of 1 was the unsaturated ester 4. Cyclization using the chiral enamine protocol developed by d’Angelo delivered the keto ester 6. Reduction with NaBH4 proceeded with substantial diastereocontrol to give an intermediate alcohol, that cyclized under acidic conditions to the lactone 1.

The preparation of 2 began with dihydroresorcinol 7. Condensation with the enantiomerically-pure amine 8 gave the enamine, that was converted to the bromide and cyclized to 9. Hydrogenation with substantial facial control set the ring fusion. Oxidation with 2-iodoxybenzoic acid (IBX) in DMSO introduced unsaturation with high regioselectivity, to give 2.

The ketene silyl acetal 10 derived from the lactone 1 added under Mukaiyama conditions across the open face of 2, to give the adduct 11. The same IBX oxidation protocol was used to introduce unsaturation, and the product was equilibrated to give 12. Hydrogenation, again across the open face of the bicyclic enone, then set the last stereogenic center of 13.

To construct the cyclohexenone 15, it was necessary to oxidize the diol 14 to the keto aldehyde. Others had found that the Swern modification of the Pfitzner-Moffatt oxidation worked well in such cases, minimizing competing lactone formation. Even more useful was the Boger protocol, that returned to the original Pfitzner-Moffatt conditions, activating DMSO with TFAA. Use of DBU in place of the more typical Et3N then cleanly delivered the aldol product, that was dehydrated and deprotected to give the enone 15.

The final ring closure was effected by reduction of the enone with SmI2. The initially-formed 16 was partially reduced to the diol under the reaction conditions, necessitating re-oxidation with the Dess-Martin reagent. The introduction of unsaturation with the Nicolaou IBX protocol was again successful, even in this more complex and fragile system. Deprotection then completed the synthesis of 3.

D. F. Taber, Org. Chem. Highlights 2011, April 4.