Diastereoselective Diels-Alder reactions with sterically hindered dienophiles for the total synthesis of (+)-dihydrodrimenin and related drimane natural products

This dissertation adds to the current knowledge of chiral auxiliaries for diastereoselective Diels-Alder reactions and utilizes a series of novel, sterically hindered dienophiles as a means of obtaining high degrees of selectivity in the reaction. These diastereoselective Diels-Alder reactions are then applied to the total asymmetric synthesis of four natural products. A general synthetic route to the synthesis of drimane and related natural products is also reported.;In order to utilize these steric interactions in an advantageous manner, a class of natural products known as drimanes is targeted. To this end, a novel allene-containing chiral auxiliary is prepared from (1R,5 R,6R)-6-aminospiro[4.4]nonan-1-ol and is shown to undergo diastereoselective Diels-Alder reactions with a variety of dienes in the presence of either BCl3 or MeAlCl2 to afford exclusively endo-adducts in up to >99:1 dr. Unfortunately, this allenyl auxiliary is shown to be ineffective at undergoing a Diels-Alder reaction with a sterically hindered diene necessary for the synthesis of drimane natural products and a modified strategy is proposed.;An alternative Diels-Alder strategy towards the synthesis of drimane natural products is proposed that utilizes a novel crotonate dienophile functionalized in the allylic position. Using this strategy, diastereoselective Diels-Alder reactions are shown to proceed quickly between several chiral oxazolidinone auxiliaries and sterically hindered 1,3,3-trimethyl-2-vinyl-cyclohexene with high regio- and stereoselectivity to afford exo-adducts in up to >99:1 dr. The absolute configuration of these adducts are determined by x-ray crystallography. It is found that an allylic --OBn substituent is vital in obtaining exo-adduct selectivity due to a increased thermodynamic preference for the exo-adduct.;These exo-adducts are subsequently used in the first total synthesis of (+)-dihydrodrimenin using a hydroboration-oxidation then deoxygenation strategy in 45% overall yield. (+)-Dihydrodrimenin is also easily converted to (--)-dihydroisodrimeninol in 95% yield in one step, (+)-albicanol in 22% yield over four steps and (+)-albicanyl acetate in one step from (+)-albicanol in 95% yield.;A novel cyclopropenyl-containing chiral auxiliary is prepared from (1 R,5R,6R)-6-aminospiro[4.4]nonan-1-ol and is shown to undergo diastereoselective Diels-Alder reactions with a variety of dienes in the presence of either BCl3 or MeAlCl2 to afford exclusively endo-adducts in up to >99:1 dr. High degrees of regioselectivity are found due to steric interactions between the cyclopropenyl-moiety and several unsymmetrical dienes.