40 タミフル^[○!R]の触媒的不斉合成研究(口頭発表の部)

抄録

With increasing fear of a potential new influenza pandemic. the anti-influenza drug Tamiflu^[○!R]has become extremely important for protecting humans against this lethal flu. Here our third generation synthesis of Tamiflu^[○!R]is discussed. To quickly establish the synthetic route, we started our synthesis without chirality control (Figure 3.). Through the key transformations. 1) Diels-Alder reaction to construct the central carbon skeleton, 2) Curtius rearrangement of 14 to introduce the key 1,2-trans-diamide moiety, and 3) Ni-catalyzed conjugate addition of TMSCN to enone 4, we have produced Tamiflu^[○!R]successfully. We next developed the catalytic enantioselective Diels-Alder-type reaction for an asymmetric synthesis of Tamiflu^[○!R]. After intensive studies, we found that the desired cyclization proceeded in quantitative yield (endo: exo=2: 1) and 93% ee (endo) in the presence of 10mol% Ba(O^1Pr)_2. 10mol% Ligand I, and 10mol% CsF (Figure 4.). Preliminary mechanistic studies (Figure 5.) have led us to propose the mechanism shown in Figure 6. This reaction mechanism is completely different from the previously developed catalytic enantioselective Diels-Alder reactions which depend on chiral Lewis acids or Bronsted acids, and a new entry in the catalytic enantioselective Diels-Alder reaction has been developed. Thus, our third generation catalytic asymmetric synthesis of Tamiflu^[○!R]has been developed. Improvement of diastereoselectivity in the Diels-Alder-type reaction and further optimization in the late stage of the sythesis are now ongoing.