Asymmetric aminoalkylation

Diastereoselective alkylation of lactams derived from 7 -(-)-phenylglycinol is an efficient method for the preparation of various substituted piperidines <961(52)7719, 961(52)7727, 961L(37)849>. Ihe asymmetric s mthesis of a series of 2-(l-aminoalkyl)piperidines using (-)-2-cyano-6-phenyloxazolopiperidine has been described <96JOC(61)6700>. 

Scheme 19 Asymmetric synthesis of 2-(l-aminoalkyl)pyrrolidines and 2,2 -dipyrrolidines from chiral imines and iminium ions...

Scheme 35 Asymmetric syntheses of 2-(l-aminoalkyl)piperidines and 3-aminoazepins by the CN(R,S) method...

Scheme 36 Asymmetric synthesis of 2-( l-aminoalkyl)azetidines from enantiopure 2-cyano-azetidines...

Asymmetric hydrogenation of a,fi-unsa turated acids.1 2- Aryl-3-methyl-2-bu-tenoic acids (2) undergo highly stereoselective hydrogenation catalyzed by a complex of rhodium with the chiral (aminoalkyl)ferrocenylphosphine (1), but not with... 

Hamada, T., Torii, T, Onishi, T, Izawa, K. and Ikariya, T. Asymmetric Transfer Hydrogenation of a-Aminoalkyl-a -Chloromethyl Ketones with Chiral Rh Complexes. J. Org. Chem. 2004, 69, 7391-7394. 

The methodology of the catalytic asymmetric aldol reaction has been further extended to the aldol-type condensation of (isocyanomethyl)phosphonates (12) with aldehydes, providing a useful method for the synthesis of optically active (l-aminoalkyl)phosphonic acids, which are a class of biologically interesting phosphorous analogs of a-amino acids (Scheme 8B1.6) [21,22], Higher enantioselectivity and reactivity are obtained with diphenyl ester 12b than with diethyl ester 12a (Table 8B1.6). 

Leautey, M. Jubault, P. Pannecoucke, X. Quirion, J.-C. Synthesis and evaluation of a broad range of new chiral (aminoalkyl)phos-phane ligands for asymmetric hydrogen-transfer reduction of prochiral ketones. Eur. J. Org. Chem. 2003, 3761-3768. 

Asymmetric Catalytic Aminoalkylations New Powerful Methods for the Enantioselective Synthesis of Amino Acid Derivatives, Mannich Bases, and Homoallylic Amines... 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

Scheme 3. Asymmetric catalytic aminoalkylation as key step in the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10) [20]. TBS = tert-butyldimethylsilyl, L = 1,2-dimethylimidazole, CAN = cerium ammonium nitrate.

The imines 12 (X = 4-CH3-QH4-SO2 (Ts), Ar, C02R, COR, etc.) preformed or generated in situ from N,0- or N,N-acetals or hemiacetals are another important class of Mannich reagents frequently used for diastereo- and/or enantioselective aminoalkylation reactions catalyzed by chiral Lewis acids (usually copper or palladium BINAP complexes such as 13). Among other things excellent results were obtained in the aminoalkylation of silyl enol ethers or ketene acetals [24], A typical example is the synthesis of Mannich bases 14 depicted in Scheme 5 [24b], Because of their comparatively high electrophilicity imines 12 could even be used successfully for the asymmetric aminoalkylation of unactivated alkenes 15 (ene reactions, see Scheme 5) [24h, 25], and the diastereo- and/or enantioselective aminoalkyla-... 

However, it could be shown that in principle simple imines can be used successfully as well for asymmetric aminoalkylation reactions catalyzed by chiral Lewis acids. The asymmetric allylation of simple imines 16 with allyltributylstannane (Scheme 6) catalyzed by the / -pinene derivative 17 [32a], for example furnished comparatively good results (for related asymmetric catalytic allylations of simple imines, see [32b-d]). Moreover, it was demonstrated on the basis of several Strecker-type syntheses [33-35] that catalysts such as the chiral aluminum complex 18 (Scheme 6) [33a—b] are also well suited for enantioselective aminoalkylations with simple imines. The mechanism indicated in Scheme 6 shows that the... 

Scheme 6. Asymmetric catalytic aminoalkylation of allyltributylstannane [32a] and MejSiCN [33a—b] with simple imines.

For two recent examples of asymmetric catalytic aminoalkylations of Reformatsky-type reagents, see a) Y. Ukaji, Y. Yoshida, K. Inomata, Tetrahedron ... 

Akiyama T, Saitoh Y, Morita H, Fuchibe K (2005b) Adv Synth Catal 347 1523 Akiyama T, Tamura Y, Itoh J, Morita H, Fuchibe K (2006a) Synlett 2006 141 Arend M (1999) Asymmetric catalytic aminoalkylations new powerful methods for the enantioselective synthesis of amino acid derivatives, Mannich bases, and homoallylic amines. Angew Chem Int Ed Engl 38 2873-2874 Arend M, Westermann B, Risch N (1998) Angew Chem Int Ed Engl 37 1045 Avemaria F, Vanderheiden S, Brase S (2003) Tetrahedron 59 6785 Babu G, Perumal PT (1998) Tetrahedron 54 1627... 

The transamidation-like reactions of the 2-(aminoalkyl)-l,2-thiazetidin-3-one 1,1-dioxides 172 in the presence of (piperidinomethyl)-polystyrene give the ring-enlarged eight-membered products 13 in 42-87% yields (Equation 35 <1999HCA354>). To prove the exclusive attack of the amine at the carbonyl rather than at the sulfonyl group, compound 13 (R = Me) and its stmcture with an asymmetrically situated methyl substituent was then established by X-ray crystallography (see Section 14.08.3.1.5). 

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