Diastereoselective addition of Grignard reagents

As in all cases already mentioned, diastereoselective addition of Grignard reagents to j3-amino nitrones (a-aminoalkyl nitrones) is a key step in the stereo-controlled syntheses of O.,j3-diamino acids (Scheme 2.141) (565, 566), of unsym-metrical a-amino hydroxylamines and 1,2-diamines (Scheme 2.142) (209, 567). 

Variable levels of asymmetric induction or diastereoselectivity have been found with additions of or-ganometallics to a,0-unsaturated chiral amides (chiral auxiliary). For example, as shown in Scheme 26, Mukaiyama reports that the diastereoselective addition of Grignard reagents to -substituted a,p-un-... 

Fig. 10.41. Diastereoselective addition of Grignard reagents to a-chiral, a-oxygenated carbonyl compounds.

A simple and efficient stereoselective synthesis of aziridine-2-phosphonate 781 and phosphine oxide 782 was achieved by diastereoselective addition of Grignard reagents to 277-azirine phosphonate 779 and phosphine oxide 780. Addition of benzenethiol and heterocyclic amines proceeded in an analogous manner to yield functionalized aziridines 783 and 784 (Scheme 188). 

Silvani and coworkers have converted isatin to the chiral imines 94 and 97 that were employed as electrophiles for the diastereoselective addition of Grignard reagents [60]. As illustrated in Scheme 26, addition of allyl Grignard to 94 or 97 afforded the amino-substituted quaternary oxindoles 95 or 98 with good diastereos-electivity (80 20 and 89 11 dr, respectively). Grignard adducts 95 and 98 were further manipulated to afford the enantiomeric pair of 3-amino-3-allyloxindoles (5)-96 and (R)-99, respectively. 

Kant J, Schwartz WS, Fairchild C, Gao Q, Huang S, Long BH, Kadow JF, Langley DR, Farina V, Vyas D (1996) Diastereoselective Addition of Grignard Reagents... 

Of related interest is the diastereoselective addition of Grignard reagents to 2-acyl-l,3-dithiane 5-oxides [75], which gave results in accordance with chelated Cram-type transition states [76] involving equatorial sulfoxides (Scheme 3.46). 

Cornforth proposed a different explanation for the diastereoselective addition of Grignard reagents to a-chloro aldehydes and ketones. The underlying premise of this model is that electrostatic effects such as dipole-dipole interactions favor a reactant conformation in which the C=0 group and the C —Cl bonds are oriented anti-coplanar. The preferred path for approach of the nucleophile could then be predicted on the basis of the sizes of the other substituents on the a carbon (Figure 9.57). 

Palacios et al. described the stereoselective synthesis of fluoroalkyl-substituted aziridine-phosphine oxides by the diastereoselective addition of Grignard reagents to functionalized ketoxime-phosphine oxides. Aziridines were used as intermediates for the regioselective S5mthesis of fluorine containing P-aminophosphine oxides. Products of the latter type could also be obtained by reduction of the ketoxime-phosphine oxides with sodium borohydride (Scheme 39). ... 

The nucleophilic addition of Grignard reagents to a-epoxy ketones 44 proceeds with remarkably high diastereoselectivity70. The chelation-controlled reaction products are obtained in ratios >99 1 when tetrahydrofuran or tetrahydrofuran/hexamethylphosphoric triamide is used as reaction solvent. The increased diastereoselectivity in the presence of hexamethylphos-phoric triamide is unusual as it is known from addition reactions to a-alkoxy aldehydes that co-solvents with chelating ability compete with the substrate for the nucleophile counterion, thus reducing the proportion of the chelation-controlled reaction product (vide infra). 

The high diastereoselectivity which is found in the nucleophilic addition of Grignard reagents to chiral 2-0x0 acetals can be explained by a chelation-controlled mechanism. Thus, coordination of the magnesium metal with the carbonyl oxygen and the acetal moiety leads to a rigid structure 3A in the transition state with preferred attack of the nucleophile occurring from the S/-side. 

Enantiomerically pure of-dibenzylamino-/V-tosylimines 2 arc accessible from amino acids. Since they are not suitable for storage it is advantageous to prepare them in situ from the corresponding aldehydes 1 and A-sulfmyl-4-toluenesulfonamide immediately before use. Addition of Grignard reagents affords the protected 1,2-diamines 3 in good yields (57-95%) and diastereoselectivities (d.r. 85 15 >95 5)8. Deprotection is achieved without racenuzation by reductive methods, see 4-6. 

The diastereoselectivity of the reaction may be rationalized by assuming a chelation model, which has been developed in the addition of Grignard reagents to enantiomerically pure a-keto acetals7,8. Cerium metal is fixed by chelation between the N-atom, the methoxy O-atom and one of the acetal O-atoms leading to a rigid structure in the transition state of the reaction (see below). Hence, nucleophilic attack from the Si-face of the C-N double bond is favored4. 

Substantially high diastereoselectivity was accomplished by the conjugate addition of Grignard reagents to the amide 1 derived from 1-ephedrine32. The reagent attacked from the Re-face of the double bond, as shown in 2, via a chelated intermediate. Low asymmetric induction was observed when butyllithium was used instead of butylmagnesium bromide. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

O - P h e n y 1 - /V - e r y t h r o s y 1 nitrone (336), as a Ci,C i-bis-electrophile, when subjected to the double addition of Grignard reagents (in a domino style), leads to acyclic hydroxylamine (338) via the formation of open-chain nitrone (337 ). The reaction proceeds at 0°C with variable diastereoselectivity ranging from medium to good, depending on the organometalic reagent used (Scheme 2.140) (564). 

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) . ... 

When dienones such as 55 are subjected to the epoxidation conditions the electron-poorer C=C double bond is selectively epoxidized. The other C=C bond can be functionalized further, for example, it can be dihydroxylated, as shown in the synthesis of the lactone 56 (Scheme 10.11) [82]. Stannyl epoxides such as 57 (Scheme 10.11, see also Table 10.8, R1 = n-Bu3Sn) can be coupled with several electrophiles [72], reduction of chalcone epoxide 58 and ring opening with alkyl aluminum compounds provides access to, e.g., the diol 59 and to phenylpropionic acids (for example 60). Tertiary epoxy alcohols such as 61 can be obtained with excellent diastereoselectivity by addition of Grignard reagents to epoxy ketones [88, 89]. 

Diastereoselective 1,4- (conjugate) additions of Grignard reagents to a chiral a,3-unsaturated aminals afford optically active 3-substituted succinaldehydic acid methyl esters with 85-93% ee (eq 4). ... 

Diastereoselective 1,4-addition of Grignard reagent to a methylenemalonic acid derivative was promoted by NiCl2 [Eq. (158) 182,183]. Other metallic salts such as ZnCU, FeCl3, and Cul were less useful relative to the diastereoselectivity. 

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