Chiral enolates alkylation

Synthetic applications of the asymmetric Birch reduction and reduction-alkylation are reported. Synthetically useful chiral Intermediates have been obtained from chiral 2-alkoxy-, 2-alkyl-, 2-aryl- and 2-trialkylsllyl-benzamides I and the pyrrolobenzodlazeplne-5,ll-diones II. The availability of a wide range of substituents on the precursor benzoic acid derivative, the uniformly high degree of dlastereoselection in the chiral enolate alkylation step, and the opportunity for further development of stereogenic centers by way of olefin addition reactions make this method unusually versatile for the asymmetric synthesis of natural products and related materials. 

Progress in the enantioselective synthesis of amino acids has been made, most notably this year by Seebach s research group. Simple amino acids, such as (S)-alanine, are converted into cis-(29) and trans-(29) imidazolidinones. These heterocycles undergo deprotonation to afford chiral enolates, alkylation of which takes... 

Chiral oxazolines were the first ehiral auxiliaries used for asymmetrie enolate alkylations. Subsequent studies led to the development of a number of other ehiral auxiliaries (34-38) ineluding those reported by Evans, Myers, Enders, Sehollkopf, and others, whieh are now widely used in asymmetrie synthesis. Although these new auxiliaries frequently provide higher yields and enantioseleetivities than the oxazolines originally developed by Meyers, the pioneering work of Meyers laid the groundwork for these later studies. 

Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereochemistry.) The most frequently used are the A-acyloxazolidinones.89 The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respectively, and the c -4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90... 

A number of other types of chiral auxiliaries have been employed in enolate alkylation. Excellent results are obtained using amides of pseudoephedrine. Alkylation occurs anti to the a-oxybenzyl group.93 The reactions involve the Z-enolate and there is likely bridging between the two lithium cations, perhaps by di-(isopropyl)amine.94... 

Scheme 1.9. Diastereoselective Enolate Alkylation Using Chiral Auxiliaries...

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

The asymmetric alkylation of a carbonyl group is one of the most commonly used chirality transfer reactions. The chirality of a substrate can be transferred to the newly formed asymmetric carbon atom through this process. In surveying chiral enolate systems as a class of nucleophile, three general subdivisions can be made in such asymmetric nucleophilic addition reactions intra-annular, extra-annular, and chelation enforced intra-annular. 

E. J. Corey, F. Xu, M. C. Noe, A Rational Approach to Catalytic Enantioselective Enolate Alkylation Using a Structurally Rigidified and Defined Chiral Quaternary Ammonium Salt under Phase Transfer Conditions , J. Am. Chem. Soc, 1997,119,12414-12415. 

Asymmetric introduction of azide to the a-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 and displacement of optically active trifluoromethanesulfonates,4 p-nitrobenzenesulfonates,5 or halides.6 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,5 and the Mitsunobu displacement using zinc azide.7 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the a-hydroxy esters are available, this would be the simplest method to introduce azide. 

Backes, B.J., Dragoli, D.R. and Ellman, J.A., Chiral A-acyl-tert-butanesulfinamides the safety-catch principle applied to diastereoselective enolate alkylations. J. Org. Chem., 1999, 64, 5472-5478. 

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. 

Although the results are easily rationalised in the case of the a-alkylation (attack of the electrophile at the Re face, i.e., attack from the less hindered a face), in the aldol condensation it is somewhat more difficult to rationalise and several factors should be considered. According to Evans [14] one possible explanation for the diastereofacial selection observed for these chiral enolates is illustrated in Scheme 9.14. In the aldol reactions, the more basic carbonyl group of the aldehyde partner interacts with the chelated boron enolate 45 to give the "complex" A which may... 

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

Suitably protected chiral tetrahydro-l,4-oxazin-2-ones can be deprotonated at the 3-position and the resulting enolates alkylated to give, after oxazine hydrolysis, a-amino acids. The advantage of the method shown in Scheme 13 using compound 170 to give 163 is that it can be used in the synthesis of a-quaternary amino acids <1999EJ01967>. 

In the case of the per-O-methylated /)-D-glucopyranosyl group as chiral auxiliary, alkylation with iodomethane gave the isomeric enol ethers 2 and 3 without efficient regiocontrol in a 3-4 1 ratio. Diastereoselectivity was also moderate (d.r. 60 40-80 20). In the less polar solvent diethyl ether or toluene, induction increased (d.r. 90 10), but chemical yield decreased (34%). 

Rotation is hindered in the enolate. Thus, if the a-substituent R1 4= R2, the enolate can exist in two forms, the syn- and anti-forms (enolates 2 and 3, respectively, if R2 has higher priority than R1). Attack of an electrophile on either face of the enolates, 2 or 3, leads to a mixture of the alkylated amides, 4 and 5. If R1 and R2 and the A-substituents R3 and R4 are all achiral, the two alkylated amides will be mirror images and thus a racemate results. If, however, any of the R substituents are chiral, enolate 2 will give a certain ratio of alkylated amide 4/5, whereas enolate 3 will give a different, usually inverted, ratio. Thus, for the successful design of stereoselective alkylation reactions of chiral amide enolates it is of prime importance to control the formation of the enolate so that one of the possible syn- or anti-isomers is produced in large excess over the other,... 

One of the most important factors for successful diastereoselection in chiral amide enolate alkylation reactions is the presence of strongly chelated ionic intermediates1 3. The chelation serves the purpose of locking the chiral auxiliary in a fixed position relative to the enolate. The metal counterion is chelated between the enolate oxygen and an additional polar group, anionic, carbonyl or ether oxygen attached to the chiral auxiliary. 

The 3-acyl-2-oxazolidinones are readily deprotonated by strong, sterically hindered amide bases in dry telrahydrofuran at low temperature to afford the. vyn-enolates. Alkylation then provides products with induced chirality in the a-position of the amide with good to excellent di as tereo selectivities. 

Table 12. Chiral 2-Alkyl-t-alkanols by Alkylation of the Enolates from -fv-3-AcyI-l,5-dimcthyI-4-phenyl-2-imidazoIidmones, Followed by Cleavage...

Reaction of the chiral enolate of 6 with the chiral bromide 7 proceeds with excellent double asymmetric induction to provide the alkylated product (R,S)/(S,R)-866. However, the yield of this transformation is quite low due to decomposition via competitive debromination of ester 7. 

The cyclic cobalt-acyl complex 1 undergoes a-proton abstraction from the least-hindered face opposite the phosphane ligand upon treatment with lithium hexamethyldisilazide at 0 °C to generate the chiral enolate species 283. Treatment of 2 with primary iodoalkanes diastereoselec-tively produces the alkylated cobaltocycles 3 also via attack of the reagent on the face opposite the bulky phosphane. 

Seebach and Naef1961 generated chiral enolates with asymmetric induction from a-heterosubstituted carboxylic acids. Reactions of these enolates with alkyl halides were found to be highly diastereoselective. Thus, the overall enantioselective a-alkyla-tion of chiral, non-racemic a-heterosubstituted carboxylic acids was realized. No external chiral auxiliary was necessary in order to produce the a-alkylated target molecules. Thus, (S)-proline was refluxed in a pentane solution of pivalaldehyde in the presence of an acid catalyst, with azeotropic removal of water. (197) was isolated as a single diastereomer by distillation. The enolate generated from (197) was allylated and produced (198) with ad.s. value >98 %. The substitution (197) ->(198) probably takes place with retention of configuration 196>. 

The oxazolidinones have been used as chiral auxiharies for enolate alkylation and aldol reactions in enantioselective and total syntheses The interest in these substrates is largely known for iyw-diastereoselective aldol reactions with chlorotitanium or diaUcylboron oxazilidinone enolates (equation 114). 

Enantioselectire alkylation of amides. Two laboratories12 have used (S)-prolinol as the chiral auxiliary for a synthesis of chiral amides. Alkylation of the enolate of the amide 1 (prepared with LDA or f-butyllithium) proceeds with pronounced... 

Scheme 17 Chiral Enolates for a-Alkylated y-Amino-p-hydroxy Acids...

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