Carbonyl compounds chiral auxiliaries

Chapter 2 provided a general introduction to the a-alkylation of carbonyl compounds, as well as the enantioselective nucleophilic addition on carbonyl compounds. Chiral auxiliary aided a-alkylation of a carbonyl group can provide high enantioselectivity for most substrates, and the hydrazone method can provide routes to a large variety of a-substituted carbonyl compounds. While a-alkylation of carbonyl compounds involves the reaction of an enolate, the well known aldol reaction also involves enolates. 

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). 

Epoxides bearing electron-withdrawing groups have been most commonly synthesized by the Darzens reaction. The Darzens reaction involves the initial addition of an ct-halo enolate 40 to the carbonyl compound 41, followed by ring-closure of the alkoxide 42 (Scheme 1.17). Several approaches for inducing asymmetry into this reaction - the use of chiral auxiliaries, reagents, or catalysts - have emerged. 

Formation of C —C Bonds by Addition to Chiral Dicarbonyl Compounds Where One Carbonyl Group is Modified or Masked with a Chiral Auxiliary... 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Table 2-13 summarizes some useful chiral auxiliaries for a-alkylation of a carbonyl compound. 

TABLE 2-13. A Summary of Chiral Auxiliaries Reported To Be Useful in the a-Alkylation of Carbonyl Compounds... 

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

Allenamide 188 having a chiral auxiliary was successfully applied to stereoselective [4+2]-cycloaddition reactions with a,/3-unsaturated carbonyl compounds at 80 °C to give pyranyl heterocycles with high enantioselectivities [153],... 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

Figure 5. Chiral allylic boranes used as chiral auxiliary reagents in enantioselective additions to carbonyl compounds. (Only one isomer is shown for simplicity. For reagents 12 and 64-66, (—)-Ipc is shown.).

Asymmetric cw-dihydroxylations of a,p-unsaturated carbonyl compounds have been achieved using RuClj/aq. NaCIO yCH CN-EtOAc, using N-enoyl sultams as chiral auxiliaries [173]. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

One of the most successful auxiliaries for ot,p-unsaturated carbonyl compounds for not only 1,3-dipolar but also other cycloadditions is Oppolzer s chiral sultam (276). In particular, the acrylate 165 of Oppolzer s chiral sultam is one of the most frequently used substrates for asymmetric 1,3-dipolar cycloadditions, as shown in Scheme 12.52. 

In comparison to the alkylation reactions noted above, stereoselective alkylations of azaenolates derived from chiral auxiliaries and carbonyl compounds are more flexible concerning the variability of alkylation products. 

Numerous chiral amines are reported to be useful in the asymmetric alkylation reaction of carbonyl compounds via their imine derivatives (see Section 1.1.1.4.1.)2,4. The asymmetric alkylation of chiral imines was first reported using simple, commercially available amines such as a-methylbenzeneethanamine (amphetamine)1, benzeneethanamine1 5 and exo-l, 7,7-trimethyl-bicyclo[2.2.1]heptan-2-amine (isobomylamine). In the case of cyclohexanone alkylation using these chiral auxiliaries, enantiomeric excesses of up to 72% were obtained1. 

The highly selective alkylation reaction of chiral imines, which in some cases occurs under complete asymmetric induction, as well as the simple introduction and recovery of the chiral auxiliaries, ensures that asymmetric alkylation of carbonyl compounds via their corresponding imines is a valuable tool in organic chemistry. 

In summary, of the many chiral auxiliaries used in the asymmetric synthesis of carbonyl compounds via imines, those able to form a methoxymethyl-chclated azaenolate show the best enantioselectivities (see Tabic 7). The same is true for valine and im-leucine derivatives which form rigid chelates via their carboxyl groups. In particular, quaternary centers (see Table 6) and a-alkvl-/i-oxo esters arc effectively prepared using these chiral auxiliaries. 

Table 7. Chiral Auxiliaries Used in the Asymmetric Synthesis of Carbonyl Compounds by Alkylation of Imines...

Alkylated Carbonyl Compounds and Recovery of the Chiral Auxiliary by Cleavage of Alkylated SAMP/ RAMP-Hydraznnes General Procedure for Ozonolysis3 ... 

The formation of chiral alcohols from carbonyl compounds has been fairly widely studied by reactions of aldehydes or ketones with organometallic reagents in the presence of chiral ligands. Mukaiyama et al. 1081 obtained excellent results (up to 94% e.e.) in at least stoichiometric addition of the chiral auxiliary to the carbonyl substrate and the organometallic reagent. 

In late 1975, Enders et al.156) started a research project directed towards the development of a new synthetic method for asymmetric carbon-carbon bond formation. A new chiral auxiliary, namely the (S)-proline derivative SAMP (137), was allowed to react with aldehydes and ketones to give the hydrazones (138), which can be alkylated in the a-position in an diastereoselective manner 157,158). Lithiation 159) of the SAMP hydrazones (138), which are formed in excellent yields, leads to chelate complexes of known configuration 160). Upon treatment of the chelate complexes with alkyl halogenides the new hydrazones (139) are formed. Cleavage of the product hydrazones (139) leads to 2-alkylated carbonyl compounds (140). 

The lithium derivatives described above react with electrophiles such as alkyl halides, carbonyl compounds, and thiocarbonyl compounds, resulting in the corresponding 3-substituted derivatives (190). Hydrolysis of these products by dilute acid as described in Section B,1 gives the new nonproteinogenic amino acid ester (191) along with the original amino acid ester used as the chiral auxiliary. The chemical yields are above 80% (83MI1). 

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