Aromatic amines with a stereocenter a to the nitrogen atom are important structural motifs in a number of biologically active compounds.[1] Many of approaches to such structures have been investigated, but each method has limitations. Thus, a highly enantioselective procedure to prepare optically active aromatic amines would be valuable, and an enantioselective route to N-aryl allylic amines would be particularly useful because of the dual functionality in these compounds.Allylic substitution catalyzed by transition metals has emerged as a powerful tool for enantioselective formation of CÀC, CÀN, and CÀO bonds. [2][3][4] However, aromatic amines have not been used commonly in allylic amination, [5][6][7] presumably because they are less nucleophilic than the more commonly used benzylamine or stabilized anionic nitrogen nucleophiles. A general and highly enantioselective reaction between an aromatic amine without an activating group on the nitrogen atom and an achiral allylic ester or a racemic branched allylic electrophile has not been reported.Catalysts based on metals other than palladium [8][9][10][11][12][13][14][15][16] and its congeners often form the more hindered, branched product from nucleophilic substitution with unsymmetrical monosubstituted allylic esters. [17][18][19][20] This reactivity complements the regioselectivity of palladium catalysts, which tend to form the linear products. We previously reported asymmetric allylic substitution of achiral allylic carbonates with aliphatic amines and phenoxides to form branched allylic amines and ethers with high regio-and enantioselectivities in the presence of an iridium complex with a phosphoramidite ligand. [21,22] Reactions of aromatic amines did not occur under the conditions developed originally.Our mechanistic studies have shown that the cyclometalated complex 1, generated in situ by treatment of [{Ir(cod)Cl} 2 ] (cod = cycloocta-1,5-diene) and the ligand L 1 with an alkylamine base (Scheme 1), is likely to be the true catalyst in the allylic amination.[23] Reactions conducted with the isolated complex 1 as catalyst occurred faster and with broader scope than those with the combination of [{Ir(cod)Cl} 2 ] and L 1 .We proposed that the initial system failed to catalyze reactions of anilines because aromatic amines are not basic enough to induce cyclometalation, not because aromatic amines are too weakly nucleophilic to react with the iridium allyl intermediate. [23] If so, then the reactions of aniline should occur with a catalyst generated in situ by the action of a separate additive. Herein we report two convenient methods to generate the active catalyst in situ and the use of this catalyst to develop a general reaction of allylic carbonates with aromatic amines.[24] These reactions occur with a broad range of achiral, linear allylic carbonates to give branched chiral allyl aryl amines in excellent yields and with high regioand enantioselectivities (Scheme 2).The cyclometalated complex 1 was generated in pure form by reaction of [{Ir(cod)Cl} 2 ] and...

The ring-closing metathesis (RCM) step, a key reaction in our process to BILN 2061, was dramatically improved from the firstgeneration process by the selection of a more appropriate substrate as well as the use of a more effective catalyst. The two RCM reactions are compared in detail using criteria that are of high significance to the process chemist. † Dedicated to the memory of Chris Schmidt, a friend and esteemed colleague.

We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using 1H NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.

Elimination and racemization limit the synthesis of sterically hindered ethers, [1] such as a-chiral ethers, by the Willamson synthesis. Enantioselective transition-metal-catalyzed allylic substitution [2][3][4][5][6] could be used to prepare these materials from achiral or racemic allylic electrophiles, but intermolecular enantioselective reactions of allylic acetates or carbonates with alkoxides are limited. Enantioselective reactions of phenoxides are well documented, [7][8][9] but no metal catalyzes intermolecular enantioselective allylations of alkoxides with broad scope. [10][11][12][13] Lee and Kim [14] as well as Evans and Leahy [15] demonstrated that zinc and copper alkoxides were more reactive for allylic substitution with achiral palladium and rhodium catalysts than alkali metal alkoxides. The palladium-catalyzed reactions generated achiral ethers, but the rhodium-catalyzed reactions formed branched chiral ethers. Reactions of primary alkoxides with optically active allylic acetates occurred with predominant retention of configuration, but reactions of secondary and tertiary alkoxides were conducted with racemic allylic electrophiles. Because the products from reactions of primary alkoxides can be formed by alkylation of an optically active alcohol, but products from reactions of secondary alkoxides cannot, a catalyst that forms optically active products from hindered alkoxides and allylic carbonates is synthetically valuable. We report herein enantioselective reactions of primary, secondary, and tertiary alkoxides with achiral allylic carbonates to form branched chiral allylic ethers in high yields and with high stereoselectivity in the presence of an iridium catalyst containing a phosphoramidite ligand (Scheme 1). [16][17][18][19][20][21][22] To optimize the conditions for the allylation of aliphatic alkoxides with iridium-phosphoramidite catalysts, we studied the reactions of cinnamyl carbonate with benzyloxides (Table 1). Careful selection of carbonate, alkoxide counterion, and nitrogen substituents in the ligand was essential for high yields. Cinnamyl carbonates with small alkyl groups underwent transesterification in competition with etherification, but tert-butyl cinnamyl carbonate (1 a) provided the

[reaction: see text] The yields, enantioselectivities, and regioselectivities of the reactions of amines and phenoxides with allylic carbonates in the presence of a metallacyclic iridium catalyst were compared. These data show that both preactivation of the catalyst and the size of the ligand affect the yield, enantioselectivity, and regioselectivity. With the activated catalyst containing a bis-naphthethylamino group, the allylic amination and etherification of a broad range of allylic carbonates occurred in high yields and with high regioselectivities and enantioselectivities.