Enantioselectivity heterocyclic synthesis

In this chapter, the readers will be introduced in the different organocatalytic domino (or cascade) reactions that lead to the synthesis of C-C and C-heteroatom bonds. This type of reactions have found considerable applications in enantioselective heterocycle synthesis. The section has been organized by presenting first cascades initiated by a C-C bond formation and then presenting cascades initiated by a C-heteroatom bond formation. 

Gao, Y., Ren, Q., Wu, H., Li, M., Wang, J. (2010). Enantioselective heterocyclic synthesis of spiro chromanone-thiochroman complexes catalyzed by a bifunctional indane catalyst. Chemical Communications, 46, 9232-9234. 

Preliminary results on the enantioselective formation of sulfur and nitrogen mediumsized heterocycles by base-induced ring opening of hetero-oxabicyclic [3.2.1] and [3.3.1] systems have been reported.91 The reaction involves a deprotonation-C—O bond elimination sequence. The kinetics and mechanism of gas-phase unimolecular elimination reactions of some substituted aminoazoles have been studied as an aid to heterocycle synthesis.92... 

In an early step in an enantioselective total synthesis of certain prostaglandins <88T4989,92T10345>, application of the Prins reaction conditions to an unsaturated bicyclic lactone or ether (Equation (11)) afforded tricyclic heterocycles (31) containing cyclopentane-fused tetrahydrofuran and 1,3-dioxane units in 4-10% yield. The major products in each case were bicyclic diacetate derivatives of the starting material. 

An -carbonyi radicai cyciization was the key step in C.-K. Sha s enantioselective total synthesis of the alkaloid (-)-dendrobine. The five-membered nitrogen heterocycle was installed during the final stages of the synthetic effort. The bicyclic azido alcohol intermediate was oxidized using the Jones reagent to give the corresponding azido ketone, which was converted in three steps to the natural product. 

New approaches to nitrogen-containing heterocycles Enantioselective organocatalyzed synthesis of dihydropyridines, quinoHzidine derivatives, and dihydropyrimidines 12COC1754. 

Fustero S, Moscardo J, Jimenez D, Perez-Carrion MD, Sanchez-Rosello M, del Pozo C (2008) Organocatalytic Approach to Benzofused Nitrogen-Containing Heterocycles Enantioselective Total Synthesis of (-t-)-Angustureine. Chem Eur J 14 9868... 

The more challenging asymmetric iV-alkylation reactions of amines with alcohols was also developed in recent years. In 2009, by employing an Ir-catalyzed N-heterocyclization reaction as the key step, Trudell and co-workers first achieved the enantioselective total synthesis of both enantiomers of noranabasamine with >30 % overall yields and >80 % ee (Eq. 53) [175]. 

C-H alkylation and amination reactions involving metal-carbenoid and metal-nitrenoid species have been developed for many years, most extensively with (chiral) dirhodium(ll) carboxylate and carboxamidate complexes as catalysts [45]. When performed in intramolecular settings, such reactions offer versatile methods for the (enantioselective) synthesis of hetero- and carbocy-cles. In the past decade, Zhang and coworkers had explored the catalysis of cobalt(II)-porphyrin complexes for carbene- and nitrene-transfer reactions [46] and revealed a radical nature of such processes as a distinct mechanistic feature compared with typical metal (e.g., rhodium)-catalyzed carbenoid and nitrenoid reactions [47]. Described below are examples of heterocycle synthesis via cobalt(II)-porphyrin-catalyzed intramolecular C-H amination or C-H alkylation. 

Garrett, C.E. and Eu, G.C. (1998) Nucleophilic catalysis with m-bound nitrogen heterocycles synthesis of the first ruthenium catalysts and comparison of the reactivity and the enantioselectivity of ruthenium and iron complexes. J. Am. Chem. Soc., 120, 7479-7483. 

Toyota, M., Nishikawa, Y, and Fukumoto, K. (1998) A practical synthesis of the key intermediate for theopederins an enantioselective total synthesis of (+)-methyl pederate. Heterocycles, 47, 675-678. 

Enantioselective synthesis of bioactive 0-heterocycles related to plant protection and physiology 98YGK884. 

Zhang YR, He L, Wu X, Shao PL, Ye S (2008) Chiral N-heterocyclic carbene catalyzed Staudinger reaction of ketenes with imines highly enantioselective synthesis of W-Boc P-lactams. Org Lett 10 277-280... 

Asymmetric variants of these reactions are highly interesting since they provide access to chiral heterocycles. A recent comprehensive study by Stahl and coworkers reports the synthesis of various enantiopure [Pd( 4-C1)C1(NHC)]2 complexes and their application in asymmetric aza-Wacker cyclisations. The reactions generally proceed with low yields or enantioselectivity [43]. The best enantio-selectivity (63%) was achieved using complex 28 (Table 10.8). 

INAC reactions have also led to enantioselective syntheses of key intermediates in the synthesis of antibiotic l 3-Methylcarbapenem (724), to optically pure derivatives of tetrahydropyrano[2,3] cyclohexane (725a) to novel terahydro-isoxazolo-fused pyrano 2,3-/ quinolines (725b) and to a novel heterocyclic system, isoxazolo[3,4-d]thieno[2,3-b]pyridine (Scheme 2.229) (221). 

The development of Ir-chiral N,P ligand system opens another promising way for the hydrogenation of allylic alcohol and its derivatives. For example, a cationic Phox-Ir complex catalyzes the hydrogenation of ( )-2-methyl-3-phenyl-9-propen-l-ol in a highly enantioselective fashion.178 With 1 mol.% (5)-92-Ir catalyst, the hydrogenation proceeds completely to provide the chiral alcohol product in 96% ee. Under the same conditions, a para- Bu-substituted chiral alcohol derivative is obtained with 94% ee for the synthesis of lilial (Equation (59)). Heterocyclic N, P-ligand, HetPHOX 113, is also efficient for this reaction.191... 

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