Chiral Cyclic Imines

Only a few examples of U-3CRs involving chiral cyclic imines have been reported to date. 

Condensations employing 2-pyrrolines with the chirality on C-3 [8, 54] or C-5 [55] showed only moderate stereoselectivity. 

18) were therefore obtained, with the trans stereoisomer prevailing, employing a series of simple isocyanides and several acids or protected amino acids. However, when the bulky trityl group was present as protecting group on the pyrro-line alcohol (instead of SiMe2tBu) the reaction was almost completely non-stereoselective. 

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Traditionally, preformed or in JitM-formed acyclic imines (e.g., 15 see Scheme 7.4) have been used in the U-4CR. However, in 1989, Joullie and coworkers developed a unique 3CR using pyrrole-based chiral cyclic imine 15g (Figure 7.7). This version of the original U-4CRis commonly known as the Joullie-Ugi 3-CR (JU-3CR) [115]. The JU-3CR is one of the earliest diastereoseleetive versions of the original U-4CR and. 

Fifty years of established views of the Ugi reaction have been challenged by results of a theoretical study which suggests, for example, that the intermediate imine is not in equilibrium with its isocyanide adduct." An asymmetric three-component Ugi reaction has applied chiral cyclic imines in synthesis of morpholino- or piperazine-keto-carboxamide derivatives." ... 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

The same group extended this work to a cyclic imine (Scheme 5-47) better results were obtained with heterobimetallic lanthanide catalysts than with chiral titanium alkoxides. 

Scheme 5-47 Asymmetric hydrophosphonylation of a cyclic imine catalyzed by heterobimetallic rare earth/alkali metal/BI-NOL complexes or by chiral titanium alkoxide complexes...

Asymmetric hydrosilylation of the cyclic imine 17 (Approach A) was precedented on simpler substrates by Buchwald but the method requires an expensive and highly air-sensitive chiral htanocene catalyst (Scheme 8.5) [6]. 

The asymmetric hydrogenation of acyclic imines with the ansa-titanocene catalyst 102 gives the chiral amines in up to 92% ee.684,685 This same system applied to cyclic imines produces the chiral amines with >97% ee values.684,685 The mechanism of these reductions has been studied 686... 

The preparation of chiral isoquinoline derivatives continued to be investigated. Sulfanamide 59 was prepared by addition of a lateral lithiated o-toluonitrile with the corresponding sulfinimine. Treatment of 59 with MeLi followed by acidification afforded cyclic imine 60. Reduction of imine 60 with liAlHi/MejAl afforded the trans-1,3 derivative, and... 

Hoppe, I., Schollkopf, U., Nieger, M., and Egert, E., Asymmetric addition of a chiral cyclic phosphite to a cyclic imine — synthesis of phosphonic acid analogues of d- and L-penicillamine, Angew. Chem., Int. Ed. Engl., 24, 1067, 1985. 

Groeger, H., Saida, Y., Arai, S., Martens, J., Sasai, H., and Shibasaki, M., First catalytic asymmetric hydrophosphonylation of cyclic imines highly efficient enantioselective approach to a 4-thiazolidinylphosphonate via chiral titanium and lanthanoid catalysts,Tetrahedron Lett., 37, 9291, 1996. 

Another field where ATH catalysts have made an industrial impact is in the area of chiral amine synthesis by stereocontrolled reduction of imines. First demonstrated by Uematsu et the reduction of cyclic imines to yield chiral amines... 

Highly enantioselective hydrogenation of geometry-fixed cyclic imines has been achieved by the use of certain chiral Ti and Ir catalysts [14,17]. In particular, a chiral titanocene catalyst developed by Buchwald possess excellent enanti-odifferentiating ability for a variety of cyclic substrates [18]. 

Keywords Asymmetric hydrosilylation, optically active alcohols, amines, Chiral Titanocene Catalysts, Acyclic Imines, Cyclic Imines, Chiral Rhodium Catalysts, aromatic ketones... 

Several cyclic imines were reduced with phenylsilane as a reducing agent in the presence of the chiral titanocene catalyst 11 followed by a workup process to give the corresponding cyclic amines in excellent ee [26]. The hydrosilylation of 2-propyl-3,4,5,6-tetrahydropyridine with (R)-ll (substrate Ti=100 l) in THF at room temperature was completed in about 6 h (Scheme 14) [29]. The reaction mixture was treated with an acid and then with an aqueous base to afford (S)-coniine, the poisonous hemlock alkaloid, in 99% ee. 

The activity and enantioselectivity of chiral Ir catalysts have been tested by using 2,3,3-trimethylindolenine as a model substrate. Hydrogenation of the cyclic imine with [Ir(bdpp)Hl2 2 gives the corresponding chiral amine with 80% ce (Scheme 1.99) [350]. The stereoselectivity is somewhat better than that with acyclic substrates (see Scheme 1.94). A neutral BCPM-Ir complex with Bil3 effects asymmetric hydrogenation in 91% optical yield [354], A complex of MCCPM shows similar enantioselection [354], These complexes are not applicable to the reaction of other acyclic and six-membered cyclic imines. An MOD-DIOP-Ir complex is also usable with the aid of ( -C4H9)4NI [355], An Ir complex of BICP with phthalimide effectively... 

A water-soluble, recyclable ruthenium(II) complex including a chiral diamine ligand has been used for asymmetric transfer hydrogenation of cyclic imines and iminiums in water, with yields and ee up to 99%.49... 

The synthesis of 6-substituted pipecolic acid derivatives has been carried out, in most cases with excellent stereoselectivities (> 95 5 transicis) and yields, by U-3CR between six-membered cyclic imines 53, carboxylic acids and the convertible isonitriles 52. Representative examples are reported in Scheme 1.20. On the other hand, when the chirality was present only on the isocyanide no stereoselectivity was observed, as expected [57]. In situ treatment of enamides 54 with an appropriate nucleophile allowed the conversion into the final products. The same trend in stereoselectivity was observed when similar imines were condensed with isocyanoace-tic acid methyl ester and Boc-glycine to give a series of tripeptides [58]. 

Chiral amines can be prepared by asymmetric hydrogenation, transfer hydrogenation and hydrosilylation of imines. The piperidine 137 with 98% ee was obtained by highly efficient asymmetric hydrogenation of the cyclic imines 136 catalysed by the Ti catalyst 61 [82]. Pyrrolidine 139 with 99% ee was obtained in 34% after 50%... 

A chiral Ru hydride 23 is formed and it is assumed that the hydrogen transfer occurs via metal-ligand bifunctional catalysis. The N-H linkage may stabilize a transition state 24 by formation of a hydrogen bond to the nitrogen atom. Stereochemistry is determined by formal discrimination of the enantiofaces at the sp2 nitrogen atom of the cyclic imine. 

Chiral sodium acyloxy borohydride 554 prepared from NaBH4 and AyV-phthaloyl amino acid reduced cyclic imines in good enantioselectivity. Thiazazincolidine complex 555 was shown to be an excellent catalyst for the catalytic reduction of dihydroisoquinolines with BH3-THF (Equation (265)).1132-1134... 

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