The development of efficient processes for the total synthesis of d-biotin (1), continues to be an attractive goal in synthetic organic chemistry, because of its unique structural features, significant biological properties and commercial importance. [2][3][4][5][6][7][8] Despite great advances [9][10][11][12][13][14][15][16][17][18][19][20][21] in total synthesis over the past 55 years, large-scale preparation of this vitamin employing the F. Hoffmann-La Roche lactone-thiolactone approach, developed by Goldberg and Sternbach in 1949, still retains technically and economic advantages.22) However, a long-standing problem in this synthesis has been the lack of an efficient and convenient procedure for the desymmetrization of dicarboxylic acid 2 to form (3aS,6aR)-lactone (6). Our recent strategy, using a polymer-supported oxazaborolidine catalyzed enantioselective reduction of mesocyclic imide approach, allowed us to prepare (3aS,6R,6aR)-hydroxylactam 5 from 2 in high yield and excellent enantiomeric excess.23) However, this procedure is impractical for large-scale synthesis due to the use of expensive and toxic BF 3 · Me 2 S as the reducing agent which requires a lot of precautions, and lack of a stable polymer-supported chiral ligand.24) These obstacles prompted us, as part of our strategy to develop a new oxazaborolidine-catalyzed reducing system that can easily be employed and that gives high enantiomeric excess for a large-scale conversion of 4 into 5 as a precursor for the formation of 6, to complete the asymmetric synthesis of 1.In the present paper, we describe an efficient and practical asymmetric total synthesis of 1 starting from commercially available dicarboxylic acid 2 through an improved enantioselective reduction of meso-cyclic imide 4 with the use of recoverable chiral polymer-supported oxazaborolidine as a catalyst.
Results and DiscussionThe asymmetric synthesis of 1 is presented in Chart 1. The known meso-cyclic-1,2-dicarboxylic anhydride 3 was prepared in almost quantitative yield by heating 2 in xylene with a catalytic amount of Ac 2 O with azeotropic removal of H 2 O for 13 h. Treatment of 3 with benzylamine in toluene under reflux for 6 h afforded the meso-cyclic imide 4 in a 90% yield.Next, we embarked upon the development of an efficient and convenient strategy for the large-scale asymmetric borane reduction of 4 into (3aS,6R,6aR)-hydroxylactam 5 using a chiral polymer-supported oxazaborolidine derived from polymer-supported ligand 10 25) (containing 0.39 mmol of diaryprolinol function units/g of polymer by elemental analysis) with in situ generated borane from cheap and convenient hydritic reagents and boron halide etherates. Thus, the mesocyclic imide 4 was treated with 80% NaH and BF 3 · Et 2 O in the presence of 10 under reflux in anhydrous THF to afford 5 in 82% yield. The enantiomeric excess of 5 was measured to be Ͼ98% by HPLC analysis using a Chiralcel OD column (eluent : hexane/2-propanol, 6 : 4, 0.7 ml/min).As pointed out in a number of studies, 26-32) one of the major advantages ...