Chiral nitriles, diastereoselective addition

Scheme 1.11 Sequential diastereoselective addition to chiral nitriles.

The intermediate 139 formed following the addition of z-butylmagnesium chloride to the nitrile 138 was then treated with sulfoxide 137 to afford the sulfinyl ketimine 140. " Diastereoselective addition of hydride to the chiral imine 140 in the presence of Ti(0 Pr)4 afforded the chiral amine 142. This reaction may proceed via a closed-transition state (e.g., 141) in which the sulfoxide coordinates to the metal center and directs the stereoselective addition of hydride, as has been proposed for related reactions.Treatment of the sulfoxide 142 with acid and base effected removal of the auxiliary. 

An innovative development in the use of Enders chiral hydrazines involves reaction of the formaldehyde hydrazone 87 as a chiral formyl anion equivalent (Scheme 12.13) [93, 94]. Hydrazone 87 adds to nitroolefms to afford the corresponding adducts with excellent diastereoselectivity. Addition of 87 to nitroolefm 88, for example, proceeded to furnish 89 in 93 % yield and dr >99 1. The resulting adduct could subsequently be converted into aldehyde 91 (> 98 % ee) by ozonolytic cleavage or into nitrile [95] 92 (> 99 % ee) under mild oxidative conditions by treatment with magnesium monoperoxyphthalate (90) [94]. 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

The efficiency with which modified Cinchona alkaloids catalyze conjugate additions of a-substituted a-cyanoacetates highlights the nitrile group s stereoselective role with the catalyst. Deng et al. [60] utilized this observation to develop a one-step construction of chiral acyclic adducts that have non-adjacent, 1,3-tertiary-quatemary stereocenters. Based on their mechanistic studies and proposed transition state model, the bifimctional nature of the quinoline C(6 )-OH Cinchona alkaloids could induce a tandem conjugate addition-protonation reaction to create the tertiary and quaternary stereocenters in an enantioselective and diastereoselective manner (Scheme 18). 

Substituted 1,2,4-oxadiazoles were prepared by addition of nitrile oxides to imines or hydrazones. It has been reported that interaction of hydroximoyl chlorides 262 with chiral hydrazones 263 in the presence of EtsN leads to intermediates 264 with diastereoselectivity up to 97%. A subsequent N-N bond cleavage to remove chiral auxiliary by formic acid leads to 1,2,4-oxadiazolines 265 with ee up to 91% (equation 113). ... 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

Most of the approaches outlined in Figure 15.10 have been successfully realized on insoluble supports, either with the alkene or alkyne linked to the support, or with support-bound 1,3-dipoles (Table 15.16). Nitrile oxides are highly reactive 1,3-dipoles and react smoothly with both electron-poor and electron-rich alkenes, including enol ethers [200]. The addition of resin-bound nitrile oxides to alkenes (Entries 5 and 6, Table 15.16) has also been accomplished enantioselectively under catalysis by diisopropyl tartrate and EtMgBr [201], The diastereoselectivity of the addition of nitrile oxides and nitrones to resin-bound chiral acrylates has been investigated [202], Intramolecular 1,3-dipolar cycloadditions of nitrile oxides and nitrones to alkenes have been used to prepare polycyclic isoxazolidines on solid phase (Entries 7 and 9, Table 15.16). 

Michael Addition. Titanium imide enolates are excellent nucleophiles in Michael reactions. Michael acceptors such as ethyl vinyl ketone, Methyl Acrylate, Acrylonitrile, and f-butyl acrylate react with excellent diastereoselection (eq 21 ). - Enolate chirality transfer is predicted by inspection of the chelated (Z)-enolate. For the less reactive unsaturated esters and nitriles, enolates generated from TiCl3(0-j-Pr) afford superior yields, albeit with slightly lower selectivities. The scope of the reaction fails to encompass p-substituted, a,p-unsaturated ketones which demonstrate essentially no induction at the prochiral center. Furthermore, substimted unsamrated esters do not act as competent Michael acceptors at all under these conditions. 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

Low-valent Ru(II) [150] and Rh(I) complexes catalyze aldol and Michael reactions of 2-nitrilo esters. The sequence is thought to be initiated by nitrile complexation to the transition metal. This Lewis acid-activation is followed by an oxidative addition to give a metal hydride and a nitrile complexed enolate as shown in Sch. 36. Examples including diastereoselective Ru(II) catalyzed reactions [151] and enantioselective Rh(I)-catalyzed reactions [152-154] with the large trans-chelating chiral ligand PhTRAP are shown in Tables 8 and 9. 

Nitrile aldol reactions. P-Hydroxy nitriles are formed in the presence of CeCl3 7H20. Addition of a chiral ligand (BINOL) increases the diastereoselectivity. 

A variety of precursors of biologically relevant products have also been prepared by addition of nitrile oxides to chiral alkenes bearing a nitrogen substituted allylic stereocen-ter 37, i4°. rai. i46, iso. isi.155 obeyed diastereoselection is generally rather low and... 

Amide and imide enolates. Scheme 5.31 illustrates several examples of asymmetric Michael additions of chiral amide and imide enolates. Yamaguchi [163] investigated the addition of amide lithium enolates to -ethyl crotonate, but found no consistent topicity trend for achiral amides. The three chiral amides tested are illustrated in Scheme 5.31a-c. The highest diastereoselectivity found was with the C2-symmetric amide shown in Scheme 5.3Ic. Evans s imides, as their titanium enolates, afforded the results shown in Scheme 5.31d and e [164,165]. The yields and selectivities for the reaction with acrylates and vinyl ketones are excellent, but the reaction is limited to P-unsubstituted Michael acceptors P-substituted esters and nitriles do not react, and 3-substituted enones add with no selectivity [165]. 

Cho reported the addition of alkyl radicals from alkyl iodide to a,P-unsaturated ketones, esters, and nitriles mediated by indium in aqueous media. Recently, enantiomeiically pure natural and unnatural a-amino acids have been synthesized from a chiral methyleneoxazolidinone by such a highly diastereoselective 1,4-conjugate addition of alkyl iodides in aqueous media (Eq. 10.31). The zinc-copper conjugate addition reaction exhibits high chemoselectivity with the possibility of using functionalized iodides to afford a single diastereomer in short reaction times with good yields. 

Semmelhack s results in this area are centered on menthol derived chiral auxiliaries [23]. Product yields are good but diastereoselectivity in these reactions are modest (<48% ee). The example in Scheme 6 shows that higher enantiomeric excesses are obtained at elevated temperatures (0 °C as opposed to -78 °C) and this could be indicative of a change in the reaction from kinetic control at low temperature to thermodynamic control at the higher temperature. This is in keeping with the ready reversibiUty of nucleophilic addition of nitrile stabilized carbanions at temperatures above -70 °C [24,25]. 

The 1,3-dipolar cycloaddition of a variety of nitrile oxides, nitrones, ethyl diazoacetate, and azomethine ylide to the chiral furanone 174a was studied with respect to the present regio- and diastereoselectivity (93T8899). In the case of the azomethine ylide addition, three stereoisomeric adducts were obtained. However, in the case of the other dipoles only two stereoisomeric adducts were isolated the major product proved to be the an//-facial isomer. In this way, a number of multifunctional (lactone-annulated) isoxazolines 241 and 242, isoxazolidines 243 and 244, pyrazolines 245a,b, and pyrrolidines 248a,b,c could be synthesized (Scheme 65) (93T8899). 

The Strecker reaction of a dial with an amine and hydrogen cyanide, to produce a cyclic a,a -dicyanoamine, involves HCN addition to a cycUc imino nitrile intermediate as the final step. A highly diastereoselective synthesis of dihydro-5//-dibenz[c, ]azepines (80) from the biphenyldicarboxaldehyde exploits the chiral twist of the biaryl axis to achieve stereoselection. ... 

---