Substrate controlled chiral amine

Substrate-Controlled Chiral Amine Synthesis via C H Amination... 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

The substrate-controlled diastereoselective addition of lithiated alkoxyallenes to chiral nitrones such as 123, 125 and 126 (Scheme 8.32) furnish allenylhydroxyl-amines as unstable products, which immediately cydize to give enantiopure mono-orbicyclic 1,2-oxazines (Eqs 8.25 and 8.26) [72, 76]. Starting with (R)-glyceraldehyde-derived nitrone 123, cydization products 124 were formed with excellent syn selectivity in tetrahydrofuran as solvent, whereas precomplexation of nitrone 123 with... 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

Apart from cyclic or acyclic transition state geometry further distinctions of diastereoselec-tion have to be made with respect to the way in which the chiral center is attached to the reactive site. The term auxiliary control is used if a chiral subunit, e.g., an alcohol or an amine, is fixed covalently to the unsaturated substrate and then removed by bond cleavage after the addition. In contrast, if the stereogenic center remains part of the molecule after the addition, the term substrate control is applied (these definitions are given in Section A. 1.). 

The use of substrate control in rhodium catalyzed C H aminations is covered in detail in Espino and Du Bois recent review of rhodium catalyzed oxidative amina tion [51]. A brief summary of relevant material is provided here, leading to a discussion of recent advances in the synthesis of chiral amines from achiral substrates. Rhodium catalyzed C H amination proceeds via a concerted insertion process rendering it a stereospecific transformation. Thus, the appropriate choice of an enantioenriched starting material can facilitate the synthesis of enantioenriched amines, which would often be particularly difficult to access in any other manner. As exemplified in Scheme 12.9, the C H insertion reaction of enantiomerically pure carbamate 9 was accomplished with complete retention of configuration providing the chiral oxazolidinone 10 in greater than 98% ee [13]. 

Either ammonia or a variety of amine substrates can be used to prepare the product 2, widely called a Betti base. Various substitution patterns are tolerated on both the naphthol and aryl aldehyde component. While the reaction was classically performed in ethanol, a variety of solvents, and using the substrates neat are also possible. Increased rates have been observed using acid catalysis. The reaction results in a product 2 with a benzylic chiral center, which as such can be resolved into its enantiomers. Alternatively, chiral amines can be used to control the stereoselectivity of the process. Enantiomerically pure Betti bases have shown potential as chiral auxiliaries and as ligands in asymmetric reactions. ... 

Substrate-controlled diastereoselective hydroboration of protected chiral allylic alcohols [25-27] or amines [28, 29] with 9-BBN gives almost always anti selective products. On the other hand, catalyzed hydroboration in most of the cases using catecholborane as hydroborating agent tends to be syn selective [28-30] (Eq. 5.9). 

Finally, Kibayashi used aqueous versions of the intramolecular acyl-nitroso Diels-Alder reaction to good effect in his stereocontrolled syntheses of (-)-swainsonine (6.28) [78] and (-)-pumiliotoxin C (6.34) [79] (Schemes 1.13 and 1.14). In each case, oxazinolactam cycloadducts (cf. 6.32 and 6.38) served as key functional chiral building blocks for the remaining synthetic operations. For example, retrosynthetic analysis of the trihydroxy-indohzidine system of swainsonine (6.28) reveals that the pyrrolidine ring of this target can be formed by amine alkylation (cf. 6.29) while the vicinal diol can be installed via substrate-controlled cw-hydroxylation of a (Z)-allyl... 

Substrate control is another approach for synthesis of anti-Mannich products. The proline-catalyzed Mannich reaction between aldehydes and pre-formed N-Boc-imines affords the syn-Mannich product with exceptionally high diastereoselectivi-ties and enantioselectivities [44]. In contrast, the reaction of aldehyde 83 with N-Boc-imines, generated in situ from the stable a-amido sulfone 84, catalyzed by the commercially available chiral secondary amine 85 provides antt-Mannich product 86 with 96% ee (Scheme 28.7a) [45]. Cyclic iminoglyoxylate 88, readily prepared from commercially available starting materials, is a useful alternative imine electrophile its configuration is locked in the (Z)-form. Because of the (Z)-configuration of imine 88, the anti-selective Mannich reaction proceeds (Scheme 28.7b) [46]. 

Intramolecular rhodium-catalyzed carbamate C-H insertion has broad utility for substrates fashioned from most 1° and 3° alcohols. As is typically observed, 3° and benzylic C-H bonds are favored over other C-H centers for amination of this type. Stereospecific oxidation of optically pure 3° units greatly facilitates the preparation of enantiomeric tetrasubstituted carbinolamines, and should find future applications in synthesis vide infra). Importantly, use of PhI(OAc)2 as a terminal oxidant for this process has enabled reactions with a class of starting materials (that is, 1° carbamates) for which iminoiodi-nane synthesis has not proven possible. Thus, by obviating the need for such reagents, substrate scope for this process and related aziridination reactions is significantly expanded vide infra). Looking forward, the versatility of this method for C-N bond formation will be advanced further with the advent of chiral catalysts for diastero- and enantio-controlled C-H insertion. In addition, new catalysts may increase the range of 2° alkanol-based carbamates that perform as viable substrates for this process. 

The chiral enolate-imine addition methodology was examined in detail (Thiruvengadam et al., 1999). Enolate formation proceeds to completion within an hour at temperatures from — 30 to 0°C with either 1 equiv. TiCl4 or TiClaO-iPr (preformed or prepared in the presence of substrate by addition of TiCl4 and followed by a third of an equivalent Ti(0-iPr)4 and two equivalents of a tertiary amine base). Unlike the aldol process with the same titanium enolate, the nature of the tertiary amine base had no effect on the diaster-eoselectivity. The diastereoselectivity is maximized by careful control of the internal temperature to below — 20°C during the imine addition (2 equiv.) as well as during the acetic acid quench. The purity of the crude 2-amino carboxamide derivatives (17a or... 

An asymmetric version of aminoallylation has been developed via a transfer aminoallylation protocol. This methodology involves the initial aminoallylation of camphorquinone 207 with 5-allylpinacol boronate 177 in alcoholic ammonia, furnishing the a-aminoketone 208 stereoselectively, which upon treatment with an aldehyde 209 and achiral allyl boronate 177 leads to the in situ formation of chiral imine 210 followed by allylation to yield the homoallylic amines 212 (Scheme 35) <2006JA11038>. Excellent levels of enantio- and diastereo control were observed for the allylation of a wide array of aldehyde substrates. 

Asymmetric organocatalytic Morita-Baylis-Hillman reactions offer synthetically viable alternatives to metal-complex-mediated reactions. The reaction is best mediated with a combination of nucleophilic tertiary amine/phosphine catalysts, and mild Bronsted acid co-catalysts usually, bifunctional chiral catalysts having both nucleophilic Lewis base and Bronsted acid site were seen to be the most efficient. Although many important factors governing the reactions were identified, our present understanding of the basic factors, and the control of reactivity and selectivity remains incomplete. Whilst substrate dependency is still considered to be an important issue, an increasing number of transformations are reaching the standards of current asymmetric reactions. 

In another approach to control the absolute configuration of enone photocycloaddition products, an intermediate iminium ion with a chiral secondary amine was employed by Mariano et al. (Scheme 6.28) [80]. Irradiation of substrate 73 at relatively short wavelength (direct nn excitation) led, via intermediate 74, to the chiral... 

The nitrido complex was applied to the direct asymmetric animation with a silyl enol ether as a substrate. Although several examples for achiral aminations of silyl enol ethers have been reported [32], an asymmetric version of reagent-controlled reaction has not appeared except for the one recent example [33] and the diastereoselective reactions with silyl enol ethers having a chiral auxiliary [34], The amination, which is presumed to take place via an aziridine intermediate [5g, lid,32], proceeded smoothly to give the A-tosylated a-aminoketone in 76% yield with 48% ee. When the same silyl enol ether was treated with complex 15 under Carreira s condition, the TV-trifluoroacetylated a-aminoketone was obtained in 58 % yield with 79 % ee (Scheme 24). 

The synthesis of y-fluoroalkylated allylic alcohols and amines like 51 starting with chiral fluorinated allylic mesylates 50 has also been reported (Eq. 3) [134]. In this case, the regiochemistry of the addition is controlled by the substrate and the addition of the nucleophile occurs distal to the fluorinated alkyl chain. 

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