Hydroxy ketones from imines

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

A zinc-bis(BINOL) complex has been employed to effect chemoselective enolate formation from an a-hydroxy ketone (in the presence of an isomerizable imine) to give a Mannich-type product in high ee 1... 

The precursor to amidoacrolein 64, 1,3-dioxin 66, was prepared as follows [39] the imine derived from the condensation of 2,2-dimethyl-l,3-dioxan-5-one with aminoacetaldehyde dimethyl acetal was acetylated with acetic anhydride/triethylamine to afford dioxin 66 in 83% yield (Scheme 24). Retro Diels-Alder of dioxin 66 in warm benzonitrile (120 C, 16 h) generated the amidoacrolein 64, which was trapped in situ with the silyloxydiene 65 to afford the desired cycloadduct 63 (64%). An aldol cyclization between the acetamide and neighboring aldehyde functionalities within 63 proceeded smoothly (2 equiv. of KCh-Bu, 10 equiv. of EtOAc, THF, 0 °C, 40 min) and directly afforded the corresponding conjugated lactam. This product was of sufficient purity for the second aldol reaction, which was best accomplished under acidic conditions, presumably proceeding through the achiral keto aldehyde intermediate 62 enroute to the desired, but racemic, (3-hydroxy ketone 61 obtained in 79% yield after the two consecutive ring closures. 

The chemoselective enolate formation from hydroxyketone (245) and isomerizable aliphatic Ai-Dpp imines (246) has been described. The Et2Zn/linked-BINOL complex (247) effectively promoted the Mannich-type reaction, affording P-alkyl-P-amino-a-hydroxy ketones (248) in high enantioselectivity and good yield (Scheme 100). ... 

In the approaches toward a direct asymmetric Mannich reaction by enolate formation with the metal of the catalyst also, the well-proved systems of the analogous aldol reactions were widely applied. Here, it is referred to some of these protocols wherein a metal enolate is involved, as least as assumed and plausible intermediate [183]. Shibasaki and coworkers used a dinuclear zinc complex derived from linked BINOL ligand 371 for catalyst in direct Mannich reactions of a-hydroxy ketones 370 with Af-diphenylphosphinoyl imines 369 to give ti-configured a-hydroxy-P-amino ketones 372 in high yield, diastereoselectivity, and enantioselectivity (Scheme 5.97) [184]. The authors postulate the metal to form a chelated zinc enolate by double deprotonation of the a-hydroxy ketone. This enolate approaches with its Si-face to the Si-face of the imine, as illustrated by the transition state model 373, in agreement with the observed stereochemical outcome. It is remarkable that opposite simple diastereoselectivity arises from the Mannich reaction (anti-selective) and the previously reported syn-selective aldol reaction [185], although the zinc enolates... 

A number of chiral catalysts originally devised for aldol reactions (see Chapter 4) have also successfully been deployed in enantioselective Mannich additions. One such example is the dinuclear zinc complex 220 developed by Trost (Equation 18) [154]. The complex is generated in situ from Et2Zn and the corresponding chiral diamino triol ligand derived from prolinol. Excellent enantio- and diastereoselectivity were obtained in reactions with a-hydroxyketones such as 218. From imine 219, the syn a-hydroxy-/l-amino ketone 221 was isolated in > 99% ee and > 15 1 dr. Additional investigations revealed that appropriate choice of the N-substituent on the imine could selectively provide either the anti or the syn a-hydroxy- -amino ketones [155]. 

Originally, a C-20 amine (prepared from a bisnorcholanic acid) was converted into its 7V-chloro derivative, dehydrohalogenated to the imine, converted into the A-acetylenanime, reacted with perbenzoic acid, then hydrolyzed to the 17a-hydroxy-20-ketone ... 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

Heteroatom rings, such as that found in quinoline derivatives, can be generated from amino-ketones with [hydroxy(tosyloxy)iodo]benzene and perchloric acid. Cyclic imines are converted to pyridine derivatives with NCS and then excess sodium methoxide. ... 

Therefore, in principal, condensation of a primary amine with an enantiomerically pure ketone should allow asymmetric synthesis of a-substituted primary amines. This approach has been applied to the synthesis of a-amino acids, for example, using the imine prepared from a-amino esters and (l.S, 2,S ,5,S )-2-hydroxy-3-pinanone, via an amino-substituted ester enolate anion with some success39 40. Application of this approach to simple primary amines has seldom been reported. 

The carbonyl ylide generated from metal carbene can also add to C=0 or C=N bonds. The [2 + 3]-cycloaddition of carbonyl ylide with G=0 bond has been used by Hodgson and co-workers in their study toward the synthesis of zaragozic acid as shown in Scheme n 27a,27d Recently, a three-component reaction approach to syn-a-hydroxy-f3-amino ester based on the trapping of the carbonyl ylide by imine has been reported.The reaction of carbonyl ylide with aldehyde or ketone generally gives l,3-dioxolanes. Hu and co-workers have reported a remarkable chemoselective Rh2(OAc)4-catalyzed reaction of phenyl diazoacetate with a mixture of electron-rich and electron-deficient aryl aldehydes. The Rh(ii) carbene intermediate reacts selectively with electron-rich aldehyde 95 to give a carbonyl ylide, which was chemospecifically trapped by the electron-deficient aldehyde 96 to afford 1,3-dioxolane in a one-pot reaction (Equation (12)). 

These are the most favourable of all and the precursors, such as the hydroxy acids, e.g. 15, cannot usually be isolated, though the carboxylate salts are stable. The only important thing is to get the oxidation level of the precursor right. Using cyclic amines as examples, a fully saturated ring 45 would come from an alkylation reaction on 46 X = a leaving group. Imines 47 or enamines 49 would come from aldehydes or ketones 48. 

In 1993, Bolm reported that these reactions could be performed using catalytic quantities (10 mol%) of the chiral P-hydroxy sulfoximine.132 The enantiomeric purities of the product alcohols ranged from 52% (1-indanone) to 93% (PhCOCHjOSiRj). In many cases the enantiomeric purities were enhanced using sodium borohydride as reductant in the presence of chlorotrimethylsilane.133 These methods have been extended to the asymmetric reductions of imines.134 /V-SPh-substituted imines gave the highest enantioselectivities and these reductions proceeded in the same stereochemical sense as the reductions of ketones. 

As mentioned previously, the cyclization of phenethyl ketone oximes with [Bu4N]Re04 and CF3SO3H and the cyclic imine formation from 0-sulfonyl oximes both proceed by intramolecular S 2-type reaction on the nitrogen atom of the oximes (Scheme 33). ° In contrast, both of the E- and Z-isomers cyclized smoothly and only 8-hydroxyquinoline was obtained regioselectively without forming 6-hydroxy derivatives. These phenomena are not consistent with a nucleophilic substitution reaction, and the cyclization of 0-2,4-dinitrophenyloxime 80a seemed to proceed by another reaction pathway (Scheme 37). To check isomerization of the 0-2,4-dini-trophenyloxime 84, the Z-isomer was treated with NaH and m-cresol. The isomerization of (Z)-84 hardly occurred, but 4-phenylbutan-2-one azine (85) and 4-phenyl-2-butanone (86) were obtained in 27 and 11%... 

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