Chiral auxiliaries enantioselective Michael addition

This type of reaction attracted broad interest when it was discovered that high regioselectivity can also be effected with organoaluminum compounds and other nucleophiles in the presence of Lewis acids and that by employing chiral cyclic acetals (from optically active 1,2- or 1,3-diols) diastereoselective transformations can be realized. - Such reactions are synthetically very valuable when considering that the overall process represents an enantioselective Michael addition, where the chiral auxiliary can be recycled (Scheme 39). ... 

Some simple esters of proline have found applications as auxiliaries. Thus, the methyl ester 2 was used to form chiral amides for hydride reductions (Section D.2.3.3.). Methyl and benzyl esters 2 and 3 form amides with various types of carboxylic acids which are used in the addition of zinc or titanium species to carbonyl groups (Section D. 1.3.3.3 ). The amide of (S)-proline [(S)-4] has been used in enantioselective Michael additions (Section D.I.5.8.), and (5 )-Ar-tri-fluoroacetylproline [(.S)-5] is the only simple A-acyl derivative used as an auxiliary (Section D.l.1.2.2,). 

The diastereo- and enantioselective Michael addition of lithiated enantiopure sulfonates (454) bearing an inexpensive chiral sugar auxiliary to activated vinyl phosphonates (455) has produced a variety of functionalized phosphonates (456) in good diastereoselectivities (cfe = 55 73%) (Scheme 114). °... 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

The enantioselective aldol and Michael additions of achiral enolates with achiral nitroolefins and achiral aldehydes, in the presence of chiral lithium amides and amines, was recently reviewed354. The amides and amines are auxiliary molecules which are released on work-up (equation 90 shows an example of such a reaction). 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

The products are versatile auxiliaries not only for enantioselective deprotonation and elimination (Section C.), but are also valuable chiral ligands for complex hydrides in the enantioselective reduction of ketones (Section D.1.4.5.)- They are also applied in enolate reactions (Section D.l.5.2.1., D.1.5.2.4.). transition-metal-catalyzed Michael additions (Section D.l.5.8.), 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), and additions ofGrignard reagents (Section D.l.3.1.4.2.5.). (5 )-2-(Phenylaminomethyl)pyrrolidine has found most application and is also commercially available. Several methods exist for the preparation of such compounds. Two typical procedures for the synthesis of (.S)-2-(l-pyrrolidinylmcthyl)pyrrolidine are presented here. The methodology can be readily extended to other amides and alkylamino derivatives of proline. 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

NAP-MgO acts as a bifunctional heterogeneous catalyst for the Claisen-Schmidt condensation (CSC) of benzaldehydes with acetophenones to yield chalcones, followed by asymmetric epoxidation (AE) to afford chiral epoxy ketones in moderate to good yields and impressive enantioselectivities (ee s). NAP-MgO, in combination with the chiral auxiliary (11 ,21 )-(- -)-1,2-diphenyl-1,2-ethylenediamine (DPED), catalyzed the asymmetric Michael addition of malonates to cyclic and acyclic enones. 

A simple method for the enantioselective aziridination of a-substituted a,fl-unsaturated aldehydes CH2=C(R)CH=0 has been developed, based on the initial Michael addition of TsNHOTs catalysed by diarylpropinol trimethylsilyl ether (123b). The resulting Af-tosyl aziridines with a quaternary chiral centre were obtained in <90% ee. In a similar way, /3-substituted a,/8-unsaturated carbonyl compound with a chiral auxiliary RCH=CHCO-X (e.g. X = 1-menthopyrazole) has been... 

Conjugate addition of the lithium salt of a chiral amine to a -substituted a, 3-unsaturated ester leads to formation of a chiral, nonracemic amino acid. Addition of the chiral, nonracemic lithium amide 5.143 (contains a phenethyl auxiliary) to 5.142 gave the amino-ester.63 Catalytic hydrogenation removed both benzylic groups (the auxiliary and the benzyl group) and acid hydrolysis of the ester moiety led to 3-amino-3-(4-benzyloxyphenyl)-propanoic acid, 5.144. The initial Michael adduct was formed with >99% dr (dr is diastereomeric ratio), leading to high enantioselectivity in 5.144 after removal of the auxiliary. 

Michael Additions. Cu(OAc)2 in combination with chiral ligands has been extensively utilized as a catalyst for enantioselective conjugated-additions of organometallics and active methylene substrates to o , -unsaturated systems. The latter process, in particular, has been very useful synthetically, leading to the formation of quaternary chiral centers under mild, neutral conditions. Easily accessible natural a-amino acids or their derivatives were employed as efficient chiral auxiliaries and these could be recovered at the end of the reaction (eq 33). ... 

Chiral imidazolidin-4-ones-chiral secondary amines-had already been successfully used in asymmetric synthesis before they started their own career as organo-catalysts [1]. They were deployed as chiral auxiliaries for alkylation processes [2], Michael additions [3], and aldol reactions [4], For syntheses of this class of catalyst see Reference [5]. The ability to activate both carbonyl compounds by enamine formation as well a, 3-unsaturated carbonyl compounds by intermediate formation of iminium ions makes imidazolidin-4-ones a valuable class of organocatalysts in both series. Thus, they can roughly be divided by their mode of activation into enamine [6] or iminium [7] catalysis (Scheme 4.1). These catalysts were successfully deployed in a wide range of several important enantioselective C-C bond formation and functionalization processes. Figure 4.1 shows the chiral imidazo-lidinones covered in this chapter. 

A number of chiral auxiliaries has been designed for enantioselective 1,4-addition to a, -unsaturated carbonyl compounds. Chiral oxazolidinones are among the most efficient, affording the Michael-adducts with up to 99% ee. Asymmetric conjugate addition of an arylmagnesium reagent to cinnamoyloxazolidinone 151 is the key step in the synthesis of (+)-tolterodine 152, an important muscarinic receptor agonist (Scheme 2-58). 

Instead of using chloramine-T (pKa 13.5), the employment of more nucleophilic chloramine salt, A-chloro-A-sodiobenzyloxycarbamate (pKa 15.3), allows for an efficient aziridination of electron-deficient olefins (Michael acceptors) in the presence of a solid-liquid phase-transfer catalyst (Scheme 2.38) [57]. The reaction would involve an ionic pathway where the Michael-addition of chloramine salt to alkenes and the following back-attack of the resulting enolate at the electrophilic N-center to cyclize. This reaction was successfully extended to the asymmetric aziridination of the enones that have an auxiliary, to produce chiral aziridines with good enantioselectivities up to 87% ee. Another option to aziridinate electron-deficient alkenes is the utilization of... 

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