Diastereoselectivity imine additions

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... 

High yields and diastereoselectivities have also been observed for the addition of Grignard reagents to imines like 221 derived from phenylglycinol (222), which are existing in equilibria with 1,3-oxazolidines. Also, the imine derived from methoxyacetone affords amino-ethers with excellent diastereoselectivities. The addition of a Lewis acid (MgBr2) has a strong effect on both the yield and the selectivity (equation 151) . ... 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

The vinylogous Mannich reaction of 2 silyloxy furans and imines may also be catalyzed through chiral Brpnsted acids, as shown by Akiyama et al. [10]. Previously, Akiyama [11] and Terada [12] had independently discovered that 3,3 substituted BINOL based phosphoric acids were excellent Bronsted acids for a broad range of mainly imine addition reactions via protonation of the imines and in situ formation of chiral iminium contact ion pairs. Using the slightly modified phosphoric acid 28 as catalyst carrying additional iodine substituents in the 6,6 positions, the y amino substituted butenolides 27 were obtained in excellent enantioselectivity and variable diastereoselectivity (Table 5.4). 

This concept was extended to imines derived from a-amino acids. Several imines 8 react with cyclopentadiene (4) and 1,3-cyclohexadiene (9) yielding adducts 10 and 11 with good to excellent diastereoselectivity, while addition to acyclic dienes 12 proceeds with moderate selectivity68. 

A base-induced ring-opening imine isomerization/diastereoselective organometallic addition sequence on 4-substituted-2-perfluoroalkyl-l,3-oxazolidines 205 was developed for the asymmetric synthesis of perfluoroalkyl amino alcohols 207 via intermediates 206. Chiral compounds were obtained in good yields and high diastereoselectivity <04OL641>. 

The cycloaddition of ester enolates with imines is of continuing interest and potassium rert-butoxide may be used to generate the enolate (94S805) but more usually tin, titanium or zinc enolates are employed. When enolates are generated from 2-pyridylthioesters, the stereochemistry of the tin enolate may be greater than and, in some cases, opposite to that for titanium enolates (94T5821). The effect of the lithium, zinc or titanium on the diastereoselectivity in addition reactions of the enolates of a-... 

The chromium complex 46 of benzaldehyde imine is also a good substrate for asymmetric conjugate addition of organolithium reagents, where the reaction was mediated by a stoichiometric amount of chiral diether 18 in toluene to give, following propargylic electrophile incorporation, the cyclohexadienal 48 in up to 93% ee (Scheme 13) [38]. SAMP [(S)-l-amino-2-(methoxymethyl)pyrrolid-ine] hydrazones were used effectively in diastereoselective nucleophilic additions to (arene)Cr(CO)3 complexes [39]. 

The asymmetric lithiation of 0-benzyl carbamates 101-imine addition sequence using the s-BuLi/(-)-sparteine (19) complex has been studied [83]. The reactions proceeded with high diastereoselectivity, giving the three-amino alcohol derivatives 102 with modest to good ee (Scheme 30). 

Nelson and co-workers reported cinchona alkaloid-catalyzed [4-1-2] cycloaddition of ketenes and N-thioacyl imine, affording the 4,5-cw-disubstituted l,3-thiazin-6-one derivatives 146 with high enantioselectivities (>95% ee) and diastereoselectivities (>95 5 cis. trans). Scheme 3.47 [63], Ketene, in situ generated from acyl halide 143 and base, followed by addition to imine which was generated in situ via basic elimination of a-amido sulfone 144, providing the ketene-imine addition pathway toward the cycloadducts. 

An alternative approach is to have the chiral auxiliary on the enolate. Sweeney has reported the addition of bromoacyl sultam 102 to phosphonyl imines 103, which afforded the cis- or trans-aziridines with high levels of diastereoselectivity depending on the imine substituent (Scheme 1.30) [55]. 

For diastereoselective addition of pcrfluoroalkyl lithium generated in situ to imines and %-alkoxy imines in the presence of BF, OEt2. see refs 13 and 14. 

Addition of Grignard and organolithium reagents to imines 2. derived from enantiomerically pure (S)-valinol (1), provides a-substituted phenethylamines 3 in moderate to good yield and excellent diastereoselectivity (in each case only one diastereomer can be detected by NMR)15. By appropriate selection of imine and organometallic reagent both diastereomeric amines are accessible (see also refs 16 and 17). 

For diastereoselective addition of organometallic agents to imines attached to arene tricar-bonylchromium or ferrocenyl moieties, see refs 26 28 and Section 1.4.1.1.2.2. 

The diastereoselectivity of the addition of metalated croty] compounds 1 to the imine moiety has been constantly improved by changing the metal from magnesium over lithium, zinc, aluminum to boron and tin113 (see Table 7). With the latter a high selectivity in favor of the. vj M-product 3 was achieved. The unh-diastereomer 4 results exclusively from addition of boron reagents to A-arylimines 21. 

Auxiliary-Induced Diastereoselection I.4.3.3.I. Auxiliary Croup in the Enolate Addition to Imines or Iminium Salts... 

The mechanistic analogy to the Streckcr synthesis becomes obvious in the addition of the isocyanide to the imine to produce the a-amino nitrilium intermediate. Since all four components are involved in this step, it might be expected that every chiral component (chiral groups R1, R2, R3, R4) contributes to diastereofacial differentiation in the nucleophilic attack on the imine. However, in peptide syntheses by four-component condensation5, the chiral isocyanide or a chiral carboxylic acid component has only limited influence on the diastereoselectivity of the a-amino amide formation5. 

This method was extended to the diastereoselective synthesis of amino acid derivatives from the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines to enones90. 

Diastereoselective preparation of a-alkyl-a-amino acids is also possible using chiral Schiff base nickel(II) complexes of a-amino acids as Michael donors. The synthetic route to glutamic acid derivatives consists of the addition of the nickel(II) complex of the imine derived from (.S )-,V-[2-(phenylcarbonyl)phenyl]-l-benzyl-2-pyrrolidinecarboxamide and glycine to various activated olefins, i.e., 2-propenal, 3-phenyl-2-propenal and a,(f-unsaturated esters93- A... 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

Scheme 13 Diastereoselective addition of a-nitrocarbanions to chiral imines...

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