Amines chiral bicyclic

Meyers and co-workers (143-146) studied the addition of azomethine ylides to the chiral bicyclic half-aminal 97 (Scheme 12.32). The diastereoselectivities of these reactions were highly dependent on the substituents of both 97 and... 

Following the pioneering work of Schultz and others on the solution phase photochemistry of linearly conjugated cyclohexadienones [13], we prepared the achiral benzo derivative 7a (Scheme 3) and studied the solid-state photochemistry of its salts with a series of optically pure amines [14]. Diazomethane workup afforded the expected chiral bicyclic photoproduct 8, whose optical purity was determined by chiral GC. The results are summarized in Table 2. 

Asymmetric synthesis of pyrrolidines and pyrrolinones. This chiral -hydroxy-amine (1) reacts with a y-keto acid in refluxing toluene to form a chiral bicyclic lactam 2 in 75-98% yield. Treatment of 2 with excess alane, generated from AlCly and LiAlH4,... 

At the same time Eder, Sauer and Wiechert of Schering A.G. in 1971 published a one-pot reaction for the asymmetric synthesis of chiral bicyclics. The group affected this transformation from prochiral triketones in the presence of chrial amines or amino acids such as proline (similar to Hajos and Parrish). The (5)-amine or (5)-amino acid induces (5)-configuration bicyclics, while the (/ )-configuration outcomes varies. The best results for this annulation are shown in the synthesis of 41 and 44. The reaction is performed in the presence of (5)-proline and perchloric acid. The reaction mixture is heated under reflux to give the products in good 87% and 83% yields, respectively, and 84% and 71% ee, respectively. 

In 2010, Jorgensen et al. developed an enantioselective tandem reaction of propargylated malononitriles with cyclic enones sequentially catalysed by a cinchona alkaloid-derived primary amine catalyst in the presence of (J )-mandelic acid as an additive for the first Michael step, and a gold catalyst for the second tandem exo-dig cyclisation-isomerisation reaction. " As shown in Scheme 7.62, the corresponding chiral bicyclic enones were achieved in good yields and high enantioselectivities of up to 96% ee, albeit low to moderate diastereoselectivities (34-66% de). 

The chiral primary amine catalyst 121 proved to be highly effective for the asymmetric Diels-Alder reaction of simple enones with 2-pyrone 120 to furnish chiral bicyclic structures (Scheme 1.44) [67]. 

In contrast to the alkaloid derived catalyst, some work groups focused their attention on synthetic amino alcohols as desymmetrization catalyst. In 2001, Uozomi et al, reported a series of A -chiral bicyclic tertiary amines 77 for the methanolysis of cyclohexane-1,2-dicarboxylic anhydride [83, 84]. In the presence of a stoichiometric amount of catalyst 77, the desymmetrization of the anhydride proceeds with up to 89% ee (Scheme 7.16). 

The enantioselectivity of Sn(II) enolate reactions can be controlled by chiral diamine additives. These reagents are particularly effective for silyl thioketene acetals.162 Several diamines derived from proline have been explored and l-methyl-2-(l-piperidinomethyl)pyrrolidine 21 is an example. Even higher enantioselectivity can be achieved by attachment of bicyclic amines to the pyrrolidinomethyl group.163... 

A parallel library of optically active bicyclic tertiary amines 127 bearing N-chiral bridgehead nitrogen atoms was readily prepared by condensation of primary amines, cyclic amino acids 126, and aldehydes. This method gives access to a large variety of substituted hexahydro-l/7-pyrrolo[l,2-/ ]imidazol-l-ones of type 127 (Scheme 16). These... 

A final example, from the work of Trost (49), represents the only case in which an intramolecular Michael reaction has been catalyzed by a chiral amine. When the achiral cyclohexanone is treated with (- )-quinine and heated in toluene solution, the bicyclic ketone is formed in 83% chemical and 30% enantiomeric yield (eq. [8]). 

Most of the useful auxiliaries are chiral amine or alcohol derivatives readily available from the chiral pool, and most of them possess rigid cyclic or bicyclic structures to allow efEcient differentiation of the two competing diastereomorphic transition states. In some cases, additional rigidity was achieved with the aid of an external chelating Lewis acid (entries 6, 10, 12). In certain cases, however, acyclic auxiliaries may also be useful (see entry 15). 

The scope of electrophiles was explored with malonates and p-ketoesters, providing chiral amine adducts in high yield and enantioselectivities (Scheme 57) [109]. Addition of cyclic P-ketoesters was also explored with hydrazines, providing cyclic and bicyclic chiral amines with quaternary centers in high enantiomeric ratios (Scheme 58). 

The chiral, nonracemic bicyclic lactams, used as starting materials for stereoselective alkylation reactions, are usually prepared by treating a mixture of the enantiomerically pure vicinal amino alcohol 1 with a 3-acylpropanoic or 4-acylbutanoic acid 2 (R4 = H) under acid catalysis in toluene with azeotropic removal of the resulting water1-17. When formation of the bicyclic aminal is complete, it is isolated as a diastereomeric mixture which is usually easy to purify and provides the major diastereomer 3. An alternative method for preparation of the bicyclic lactam uses the same conditions with a 2-substituted acid (R4 =1= H). This leads to a roughly 50 50 mixture of diastereomers 3 and 4 which can be used directly for the next step2,5,12. 

The prochiral aziridine 1 is easily prepared from cyclooctene. Paul Muller of the University of Geneva has shown (Helv. Chim. Acta 2004,87,227) that metalation of 1 in the presence of the chiral amine sparteine leads to the bicyclic amine 3 in 15% , by way of intramolecular C-H insertion by the intermediate chiral carbene 2. The sparteine can be recovered and recycled. 

The application of the desymmetrization method can be extended to a bicyclic system containing two primary acetate leaving groups (Scheme 8E.16). By using the chiral pyridine-phosphine ligand 49, the diacetate could be converted into the allylic amine in 93% yield and 89% ee [70],... 

A strictly nucleophilic approach can also be used for an [(N) + (C=C)] protocol Thus the chiral iodo-unsaturated bicyclic lactam 89 undergoes stereoselective conjugate addition with primary amines to give the tricyclic aziridine 90, which can be subsequently transformed into the chiral 3,4-aziridinopyrrolidine 91 by reductive cleavage. Yields of up to 90% can be achieved and facial selectivity is greater than 98 2 [95TL3491],... 

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