Asymmetric base mediated

Further work by the Ye group has shown that NHCs derived from pre-catalyst 215 can also promote the asymmetric dimerisation of alkylarylketenes 193 to generate alkylidene P-lactones 216 in good diastereo- and enantio-selectivity [83], The asymmetric [4+2] addition of enones and alkylarylketenes to generate 8-lactones 218 in high ee has also been accomplished [84], as has the asymmetric esterification of alkylarylketenes to give esters 217 using benzhydrol, which is assumed to proceed via a Lewis-base mediated mechanism (Scheme 12.46) [85]. 

Asymmetric synthesis of the rocaglamides was accomplished by employing [3+2] photo-cycloaddition mediated by functionalized TADDOL based chiral Brpnsted acids. The synthesis consisted of a [3+2] dipolar cycloaddition, a base-mediated a-ketol rearrangement and a hydroxyl-directed reaction <06JA7754>. Asymmetric synthesis of 1,2-dihydrobenzo /j]furans was achieved by adamantylglycine derived dirhodium tetracarboxylate catalyzed C-H insertion <06OL3437>. 

The synthesis of menthol is given in the reaction scheme, Figure 5. 6. The key reaction [2] is the enantioselective isomerisation of the allylamine to the asymmetric enamine. It is proposed that this reaction proceeds via an allylic intermediate, but it is not known whether the allyl formation is accompanied by a base-mediated proton abstraction or hydride formation. 

Cook and co-workers suggested that partial racemization had occurred in the acid/base mediated isolation of (-)-tetrahydroroeharmine (41), Fig. (10) [35]. Proof was obtained by treating 41 with TFA/CH2CI2 at room temperature, which resulted in racemization of 41. In an experiment with TFA-rf, deuterium was incorporated only at C-5 and C-8, not at the epimeric centre, indicating that a mechanism analogous to Mechanism 1 was not active. Reddy and Cook, in contrast, proposed that the mechanism depicted in Scheme (10) was responsible for the racemization of (-)-tetrahydroroeharmine (41). This mechanism is analogous to Mechanism 3. Interestingly, compounds with more than one asymmetric... 

The asymmetric synthesis of 4-alkyl-4-carboxy-2-azetidinones 18 has been achieved through base-mediated intramolecular cyclization of the corresponding Af-a-chloroacetyl derivatives bearing (+)- or (-)-10-(W,A,-dicyclohexylsulfamoyl)isobomeol as chiral auxiliary (ee up to 82%) <02JOC3953> <02H501>. 

Asymmetric variants of imine reduction have also been developed towards enantiopure aziridines. Reduction of chiral /V-tert-butanesulfinyl a-halo imines afforded enantiopure aziridines in good to excellent yields <07JOC3211>. Enantioselective catalytic reduction of a-chloroimines utilizing metal-free L-valine-derived formamide 45 followed by base-mediated ring closure provided aziridines with preserved enantiopurity <07AG(I)3722>. 

Bandraege, S, Josephson, S, Moerch, L, Vallen, S, Asymmetric synthesis of p-hydroxyesters by Reformatsky reactions and amide base mediated condensations, Acta Chem. Scand. Ser. B, 35, 273-277, 1981. 

Considerable work has been published on stoichiometric asymmetric routes to a-functionalised phosphonate esters. One of the most commonly exploited methods is the phosphonylation of a chiral aldehyde or imine by a phospho-rus(ni) ester (Scheme lb) or a by a hydrogen phosphonate (Scheme la). Thus, a team from Bristol-Myers Squibb reported the base-mediated addition of dimethyl H-phosphonate (DMHP) to a chiral aldehyde (Scheme 2) as a key step in their synthesis of renin inhibitors [6j. Subsequently, work from the Hoechst AG laboratories in Frankfurt used a related approach to the building of HIV protease inhibitor frameworks (Scheme 3) [9]. 

Development of novel catalytic asymmetric reactions mediated by chiral Pd complexes as acid-base catalysts and their application to synthesis of drug candidates 06CPB1351. 

The cyclopropanation of a, (3-unsaturated carbonyls can be achieved using metal-free ylides. This is an attractive strategy avoiding the use of expensive metal-based catalysts and potentially hazardous diazo compounds. Two main approaches to the asymmetric ylide-mediated cyclopropanation have been developed, both utilising enantiopure amines as catalysts. 

A prominent example of this catalytic methodology is the Stetter reaction. Although numerous NHC-organocatalysed versions of this reaction have been developed, it is only very recently that a mechanistic investigation has been detailed in the literature. The intramolecular asymmetric Stetter reaction of substrates (102) catalysed by triazolinylidene-based NHC (103) has been employed as the model reaction and the experimental results obtained have evidenced that the [l,2]-proton shift giving precisely Breslow intermediate (101) is not only slow but above all, the first irreversible step of the transformation. Also noteworthy is that (102) precursors are prone to cyclize not only to the expected six-membered Stetter products (104) but also to benzofurans (105), the latter resulting from a base-mediated mechanism related to the basic feature of the catalyst. 

The above synthesis gives an example of the high synthetic value of 1-substituted TosMICs (p-toluenesulfonyl methylisocyanides). TosMIC 1600 has been created by van Leusen, who describes syntheses of some chiral sulfonylmethyl isocyanides as TosMIC analogues [1201]. Most of the isocyanides 1600-1605 are prepared by dehydration of the corresponding formamides with phosphoryl chloride, whereby yields of 60-85% are obtained. The chiral isocyanides are compared in terms of their ability to achieve asymmetric induction in base-mediated reactions with... 

Asymmetric transformation mediated by chiral lithium amide bases has been used to advantage in an enantioselective pathway for formation of 8-oxanorcocaines (22) by deprotonation of 8-oxabicyclo[3.2.1]octan-3-one (21) and subsequent carbomethoxy-lation reaction with methyl cyanoformate (Scheme 2) ... 

Porco et al. reported the synthesis of ( ) methyl rocaglate using [3 + 2] dipolar photocycloaddition reaction of an oxidopyrylium betaine derived from excited state intramolecular proton transfer reaction of 3-hydroxyflavin and methyl cinnamate [144]. Methyl rocaglate was obtained by a base-mediated a-ketol rearrangement followed by hydroxy-directed reduction sequence. They subsequently succeeded in the asymmetric synthesis of methyl rocaglate using functionalized TADDOL derivative (34) (Figure 2.30) as a chiral Bronsted acid (Scheme 2.77) [145]. 

In 2003, Bonini et al. reported a new synthesis of ferrocenyloxazolines based on an iodide-mediated ring expansion of A-ferrocenoyl-aziridine-2-carboxylic esters. The thus-formed ligands were successfully employed as palladium chelates for the test reaction, since they allowed the product to be formed in quantitative yields and good to high enantioselectivities (Scheme 1.69). According to the results, it seemed that the additional chiral centre present in the oxazoline backbone of these ligands did not play a major role for the asymmetric induction and the activity of the corresponding catalysts. 

Chiral Ketone from Carbohydrate. Tu et al.100 reported a dioxir-ane-mediated asymmetric epoxidation based on the ketones derived from the low cost material D-fructose (Scheme 4-47). 

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