Ketone Alkylation, enantioselective

Jiang et al.4 have recently succeeded in hydrogenating both aryl alkyl and dialkyl ketones. High enantioselectivity was obtained using PennPhos (19)-coordinated Rh complex as the catalyst. This success is based on the finding that a weak base (such as 2,6-lutidine) can facilitate the Rh-catalyzed hydrogenation of simple ketones (Scheme 6 35). 

Defined quaternary centers can also be constructed a to ketones, by enantioselective alkylation. Eric... 

Controlled oxidation of the a-pinenes with potassium permanganate leads to the enantiomeric 2-hydroxy-3-pinanones 38 29-31, while under forcing conditions, ring cleavage occurs, leading to cyclobutane derivatives 39. The hydroxy ketones 38 are useful auxiliaries forming imines with benzylic amines or glycine esters which can be alkylated enantioselectively via the enolates (Sections D.l. 1.1.1.3.2., D. 1.1.1.4.1. and D.I.5.2.4.). 

Defined quaternary centers can also be constructed a to ketones, by enantioselective alkylation. Eric N. Jacobsen of Harvard University has found (J. Am. Cliem. Soc. 2005, 127, 62) that tin enolates work particularly well with his Cr salen catalyst. A variety of activated alkylation agents give high ee from the alkylation. It works well for 5-, 6- and 7-membered rings. 

An in situ prepared mixture of [RuCl2(p-cymene)]2 and the binol-derived diphosphonite depicted in Figure 79 efficiently catalyzes the reduction of a family of methyl alkyl ketones (alkyl = c-CeHn, CH(CHs)2, n-CeHia, (CH3)2CHCH2, C6H5CH2CH2, re-C4H9) with 2-propanol as the hydrogen donor and in the presence of NaOH or KO Bu as a base (339). Conversions ranging from 83 to 90% with enantioselectivities up to 99% ee were achieved. 

Enantioselective alkylation of achiral enolates can provide an alternative to desymmetrization processes for the preparation of optically active Ca-substituted ketones. Alkylation of enolate 190 thus furnishes ketone 193 in 96 % ee and 76 % yield in the presence of chiral tetraamine 191 (Equation 14) (107). The reaction protocol prescribes the use of MeLi-LiBr for the generation of enolate 190 from enolsilane 189. The presence of lithium bromide was important, as it had a pronounced effect both on the subsequent rate of alkylation and on the stereoselectivity. Interestingly, the use of LiBr in combination with excess N,N,N, N -tetramethylpropylenediamine (192) enables the use of substoichiometric amounts of the chiral tetramine 191 (5mol%) (108). It has been suggested that diamine 192 functions as a trapping agent for LiBr, which otherwise complexes with and deactivates 191 in the course of the reaction. 

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

Arai and co-workers have used chiral ammonium salts 89 and 90 (Scheme 1.25) derived from cinchona alkaloids as phase-transfer catalysts for asymmetric Dar-zens reactions (Table 1.12). They obtained moderate enantioselectivities for the addition of cyclic 92 (Entries 4—6) [43] and acyclic 91 (Entries 1-3) chloroketones [44] to a range of alkyl and aromatic aldehydes [45] and also obtained moderate selectivities on treatment of chlorosulfone 93 with aromatic aldehydes (Entries 7-9) [46, 47]. Treatment of chlorosulfone 93 with ketones resulted in low enantioselectivities. 

Metalated SAMP- or RAMP-hydrazones derived from alkyl- or arylethyl ketones 3 add to arylaldehydes both diastereo- and enantioselectively. Substituted / -hydroxy ketones with relative syn configuration of the major diastereomer are obtained with de 51-80% and 70-80% ee. However, recrystallization of the aldol adducts, followed by ozonolysis, furnishes diastereo- and enantiomerically pure (lS, S )-. yn-a-mcthyl-/3-hydroxy ketones 5 in 36-51% overall yield. The absolute configuration of the aldol adducts was established by X-ray crystallographic analysis. Starting from the SAMP- or RAMP-hydrazone either enantiomer, (S,S) or (R,R), is available using this methodology16. 

Various aryl-alkyl ketones and dialkyl ketones could be reduced using the Rh(III) - NHC catalyst 55 in high yields (82-96%) and with good to excellent enantioselectivities (67-98% ee) (Scheme 34). 

An attractive alternative to these novel aminoalcohol type modifiers is the use of 1-(1-naphthyl)ethylamine (NEA, Fig. 5) and derivatives thereof as chiral modifiers [45-47]. Trace quantities of (R)- or (S)-l-(l-naphthyl)ethylamine induce up to 82% ee in the hydrogenation of ethyl pyruvate over Pt/alumina. Note that naphthylethylamine is only a precursor of the actual modifier, which is formed in situ by reductive alkylation of NEA with the reactant ethyl pyruvate. This transformation (Fig. 5), which proceeds via imine formation and subsequent reduction of the C=N bond, is highly diastereoselective (d.e. >95%). Reductive alkylation of NEA with different aldehydes or ketones provides easy access to a variety of related modifiers [47]. The enantioselection occurring with the modifiers derived from NEA could be rationalized with the same strategy of molecular modelling as demonstrated for the Pt-cinchona system. 

In addition, the most efficient mem-ligand depicted above was successfully applied, in 2006, to the alkynylation of ketones. Thus, Liu et al. showed that this ligand was able to catalyse the enantioselective addition of phenylacetylene to various ketones, using Cu(OTf)2 as the starting base in toluene. The results were excellent and homogeneous not only for substituted aryl alkyl ketones, but also for aliphatic methyl ketones (Scheme 4.6). 

In 2008, these authors reported a new strategy to attach chiral trans-l-arenesulfonylamino-2-isoborneolsulfonylaminocyclohexane to an achiral Frechet dendron (polyether having a repeated 3,5-dioxybenzyl structure) by a radical approach.The dendrimers obtained were successfully used in the enantioselective nucleophilic alkylation and arylation of ketones, providing... 

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