Tert asymmetric methylation

Aliphatic Ketones The asymmetric hydrogenation of simple aliphatic ketones remains a challenging problem. This may be attributed to the difficulty with which the chiral catalyst differentiates between the two-alkyl substituents of the ketone. Promising results have been obtained in asymmetric hydrogenation of aliphatic ketones using the PennPhos-Rh complex in combinahon with 2,6-lutidine and potassium bromide (Tab. 1.11) [36]. For example, the asymmetric hydrogenation of tert-butyl methyl ketone affords the requisite secondary alcohol in 94% ee. Similarly, isopropyl, Butyl, and cyclohexyl methyl ketones have been reduced to the corresponding secondary alcohols with 85% ee, 75% ee, and 92% ee respectively. 

The mode and extent of asymmetric induction strongly depends on the solvent used in tert-butyl methyl ether with an optimum temperature of 0°C mostly e-attack occurred (Method A), whereas in THF or THF/HMPA Si-attack is observed (Method B). 

In 2005, Ramachandran and coworker reported the asymmetric methylation of tert-butyl 2-(6-methoxynaphthalen-2-yl)acetate (67) using cinchoninium PTC 69 and strong base potassium fert-butoxide (Scheme 6.20) [45], The optically active methylated product 68 can be converted to naproxen, a nonsteroidal anti-inflammatory drug, by hydrolysis of ester. 

B. Wirz, S. Doswald, E. Kupfer, W. Wostl, T. Weisbrod, H. Estermann, Protease-Catalyzed Preparation of (S)-2-[(tert-butylsulfonyl)-methyl]-hydrocinnamic Acid for Rennin Inhibitor RO0425892, in H.-U. Blaser, E. Schmidt (Eds.), Asymmetric Catalysis on Industrial Scale, Wiley-VCH, Weinheim, 2004, pp. 385-398. 

Yamamoto has recently described a novel catalytic, asymmetric aldol addition reaction of enol stannanes 19 and 21 with aldehydes (Eqs. 8B2.6 and 8B2.7) [14]. The stannyl ketones are prepared solvent-free by treatment of the corresponding enol acetates with tributyltin methoxide. Although, in general, these enolates are known to exist as mixtures of C- and 0-bound tautomers, it is reported that the mixture may be utilized in the catalytic process. The complexes Yamamoto utilized in this unprecedented process are noteworthy in their novelty as catalysts for catalytic C-C bond-forming reactions. The active complex is generated upon treatment of Ag(OTf) with (U)-BINAP in THE Under optimal conditions, 10 mol % catalyst 20 effects the addition of enol stannanes with benzaldehyde, hydrocinnamaldehyde, or cinnamaldehyde to give the adducts of acetone, tert-butyl methyl ketone (pinacolone), and acetophenone in good yields and 41-95% ee (Table 8B2.3). 

Two pieces of chemical evidence support the three-membered ring formulation. The bifunctional oxazirane prepared from glyoxal, tert-butylamine, and peracetic acid (6) can be obtained in two crystalline isomeric forms. According to the three-membered ring formula there should be two asymmetric carbon atoms which should allow the existence of meso and racemic forms. A partial optical resolution was carried out with 2-7i-propyl-3-methyl-3-isobutyloxazirane. Brucine was oxidized to the N-oxide with excess of the oxazirane. It was found that the unused oxazirane was optically active. 

Ahlbrecht and coworkers showed that the stereoselective alkylation of Af-cinnamyl (5 )-2-methoxymethylpyrrolidine (STdR), followed by hydrolysis, affords enantiomerically enriched 3-substituted phenylpropionaldehydes, as shown in Scheme 45. This method is analogous to the asymmetric alkylation of S AMP/RAMP hydrazones, as the anions are isoelectronic. The mechanisms of asymmetric induction for the two systems are probably similar. For the lithio cinnamyl amine, methylation can be optimized up to 97.5% ds. Most of the procedures in this paper include potassium tert-butoxide, so the cation in these examples may be potassium. Under these conditions, methyl, primary and secondary alkyl iodides typically afford the products with selectivities in the 90-93% ds range. 

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

ASYMMETRIC HYDROGENATION OF METHYL (E)-3-ACETYLAMINO-2-BUTENOATE CATALYZED BY Rh(I)-(R,R)-2,3-BIS(tert-BUTYLMETHYLPHOSPHINO)QUINOXALINE... 

Enantioselective Michael addition of glycine derivatives by means of chiral phase-transfer catalysis has been developed to synthesize various functionalized a-alkyl-a-amino acids. Corey utilized 4d as catalyst for asymmetric Michael addition of glycinate Schiff base 1 to a,(3-unsaturated carbonyl substrates with high enantioselectivity (Scheme 2.15) [35,36]. With methyl acrylate as an acceptor, the a-tert-butyl-y-methyl ester of (S)-glutamic acid can be produced, a functionalized glutamic acid... 

The salient feature of le as a chiral phase-transfer catalyst is its ability to catalyze the asymmetric alkylation of glycine methyl and ethyl ester derivatives 4 and 5 with excellent enantioselectivities. Since methyl and ethyl esters are certainly more susceptible towards nucleophilic additions than tert-butyl ester, the synthetic advantage of this process is clear, and highlighted by the facile transformation of the alkylation products (Scheme 5.3) [8],... 

The first example of a catalytic asymmetric Horner-Wadsworth-Emmons reaction was recently reported by Arai et al. [78]. It is based on the use of a chiral quaternary ammonium salt as a phase-transfer catalyst, 78, derived from cinchonine. Catalytic amounts (20 mol%) of organocatalyst 78 were initially used in the Homer-Wadsworth-Emmons reaction of ketone 75a with a variety of phospho-nates as a model reaction. The condensation products of type 77 were obtained in widely varying yields (from 15 to 89%) and the enantioselectivity of the product was low to moderate (< 43%). Although yields were usually low for methyl and ethyl phosphonates the best enantioselectivity was observed for these substrates (43 and 38% ee, respectively). In contrast higher yields were obtained with phosphonates with sterically more demanding ester groups, e.g. tert-butyl, but ee values were much lower. An overview of this reaction and the effect of the ester functionality is given in Scheme 13.40. 

Aggarwal and coworkers have studied the electrophilic behavior of enantiomerically pure N-p-toluenesulfinimines and N-tert-butanesulfinimines in the asymmetric Baylis-Hillman reaction with methyl acrylate with and without Lewis acids [26], In the presence of In(OTf)3 good yields and high diastereoselectivities have been achieved providing an effective route to /i-amino-a-methylene esters. 

The conjugate addition of (K)-N-methyl-N-a-methylbenzyl amide 33 to tert-butyl cinnamate 34, followed by an asymmetric aldol reaction and subsequent N-oxidation/Cope elimination afforded the -substituted homochiral Baylis-Hillman product 39 in good yield (Scheme 7) [37]. This chemistry requires the use of stoichiometric rather than catalytic amounts of the chiral base. 

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