The Ireland-Claisen rearrangement of allyl ester enolates has frequently been applied to the stereocontrolled C-C bond formation because of its high diastereo-selectivity. However, being "self-immolative", the reaction is not suited for the asymmetric induction. In order to develop a new methodology in asymmetric synthesis, we investigated the Claisen rearrangement of amide enolates and found that 1) the enolate derived from N-(2E)-butenyl-N-butylpropanamide rearranged with excellent internal asymmetric induction (syn:anti=199:1) (eq. 2), that 2) the reaction of amide enolates containing chiral alkyl groups (R^*) on the nitrogen proceeded with high selectivity in relative asymmetric induction in addition to the syn selectivity described above, and that 3) the rearrangement can be extended to the acetamides with a heteroatom at the α-position (Table 2). In order to test its applicability, (-)-verrucarinolactone and D-allo-isoleucine were synthesized (eq. 5 and 6). In a continuing effort to promote this potentially useful reaction, we attempted a synthesis of (-)-isoiridomyrmecin ((-)-1), a bioactive principle of Actinidia polygama with unique activity toward felids and an attractive target of many synthetic efforts because of the presence of the 4 contiguous chiral centers in a monoterpenoid carbon skeleton. Starting from dl-alcohol 6 derived from 2-methylcyclopentanone, (-)-1 was synthesized with excellent stereoselectivity in 6 steps utilizing the aza-Claisen rearrangement as a key step (eq. 7 and 8). Another notable feature is the introduction of N,N,N',N'-tetramethylazodicarboxamide (TMAD)-Bu_3P, a new Mitsunobu reagent system, applicable to the preparation of allylic secondary amines in general(eq. 7).
