Chiral amide enolates

Thus, in the above reactions of cither enantiomer of chiral aldehydes with the ketone enolate, as well as with the amide enolate, the stereochemical outcome in each case is largely determined by the inherent selectivity of the chiral enolate reagent. 

Reagent control This involves the addition of a chiral enolate or allyl metal reagent to an achiral aldehyde. Chiral enolates are most commonly formed through the incorporation of chiral auxiliaries in the form of esters, acyl amides (oxazolines), imides (oxazolidinones) or boron enolates. Chiral allyl metal reagents are also typically joined with chiral ligands. 

Substituted cyclohexanones, bearing a methyl, isopropyl, tert-butyl or phenyl group, give, on deprotonation with various chiral lithium amides in the presence of chlorotrimethylsilane (internal quench), the corresponding chiral enol ethers with moderate to apparently high enantioselec-tivity and in good yield (see Table 2)13,14,24> 29 36,37,55. Similar enantioselectivities are obtained with the external quench " technique when deprotonation is carried out in the presence of added lithium chloride (see Table 2, entries 5, 10, and 30)593. 

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,... 

SlLYL ENOL ETHERS Chiorotrimethylsilane-Zinc, 82 Lithium amides, chiral, 159 Lithium tri-sec-butylborohydride, 167 Organotin reagents, 211 Osmium tetroxide-Trimethylamine N-ox-ide-Pyridine, 223... 

Anions generated from tertiary amides preferentially assumed the Z-configura-tion. Reaction of MA-dimethylamides with 1 equiv. of LDA at -78 °C followed by addition of 1.5 equiv. of di(-)-isobomyl azodicarboxylate 97c gave in each case a 1 1 ratio of diastereomers (/ )-99 and (S)-99 (Table 3.10, entries 7 and 8). Double diastereoselection was tested with chiral enolates enantiomerically pure /V-acyloxazolidinone (S)-100 and its enantiomer (/ )-100 were aminated at -78 °C with 97c (Scheme 47). 

The asymmetric hydroxylation of ester enolates with N-sulfonyloxaziridines has been less fully studied. Stereoselectivities are generally modest and less is known about the factors influencing the molecular recognition. For example, (/J)-methyl 2-hydroxy-3-phenylpropionate (10) is prepared in 85.5% ee by oxidizing the lithium enolate of methyl 3-phenylpropionate with (+)-( ) in the presence of HMPA (eq 13). Like esters, the hydroxylation of prochiral amide enolates with N-sulfonyloxaziridines affords the corresponding enantiomerically enriched a-hydroxy amides. Thus treatment of amide (11) with LDA followed by addition of (+)-( ) produces a-hydroxy amide (12) in 60% ee (eq 14). Improved stereoselectivities were achieved using double stereodifferentiation, e.g., the asymmetric oxidation of a chiral enolate. For example, oxidation of the lithium enolate of (13) with (—)-(1) (the matched pair) affords the a-hydroxy amide in 88-91% de (eq 15). (+)-(Camphorsulfonyl)oxaziridine (1) mediated hydroxylation of the enolate dianion of (/J)-(14) at —100 to —78 °C in the presence of 1.6 equiv of LiCl gave an 86 14 mixture of syn/anti-(15) (eq 16). The syn product is an intermediate for the C-13 side chain of taxol. 

The stereoselection in the cyclization of each diastereomer was examined independently. The stereochemical outcome of the cyclization should be predictable based on our assumption regarding the relationship between enolate stereochemistry and cyclopropane stereochemistry, the principles of asymmetric, intermolecular alkylation of optically active amides (9-13) and the assumption that the mechanism of cyclopropane formation involves a straightforward back-side, %2 reaction. In the case of the major diastereomer, the natural tendency of the enolate to produce the cis-cyclopropane will oppose the facial preference for the alkylation of the chiral enolate. Consequently, poorer stereochemical control would be ejected in the ring closure. In the minor diastereomer these two farces are working in tandem, and high degrees of stereocontrol should result. 

The development of the asymmetric aldol reaction [2] has been dominated by the stereo-controlled addition of chiral, amide-derived enolates to, mainly, aldehydes. This constitutes an excellent method for the first step of many NARC processes. The pamamycins [3] and the nactins [4] are two groups of naturally-occurring ionophores. They contain tetrahydrofuran sub-units which have proved to be suitable targets for the application of the NARC process. 

In this section are discussed aldol reactions of achiral aldehydes with chiral enolates. In previous sections, many such examples have already been given for enolates derived from rigid cyclic ketones, lactones and lactams. The emphasis here is on reactions of the enolates of conformationally flexible, achiral ketones, esters and amides. 

Interligand asymmetric induction. Group-selective reactions are ones in which heterotopic ligands (as opposed to heterotopic faces) are distinguished. Recall from the discussion at the beginning of this chapter that secondary amines form complexes with lithium enolates (pp 76-77) and that lithium amides form complexes with carbonyl compounds (Section 3.1.1). So if the ligands on a carbonyl are enantiotopic, they become diastereotopic on complexation with chiral lithium amides. Thus, deprotonation of certain ketones can be rendered enantioselective by using a chiral lithium amide base [122], as shown in Scheme 3.23 for the deprotonation of cyclohexanones [123-128]. 2,6-Dimethyl cyclohexanone (Scheme 3.23a) is meso, whereas 4-tertbutylcyclohexanone (Scheme 3.23b) has no stereocenters. Nevertheless, the enolates of these ketones are chiral. Alkylation of the enolates affords nonracemic products and O-silylation affords a chiral enol ether which can... 

Amide and imide enolates. Scheme 5.31 illustrates several examples of asymmetric Michael additions of chiral amide and imide enolates. Yamaguchi [163] investigated the addition of amide lithium enolates to -ethyl crotonate, but found no consistent topicity trend for achiral amides. The three chiral amides tested are illustrated in Scheme 5.31a-c. The highest diastereoselectivity found was with the C2-symmetric amide shown in Scheme 5.3Ic. Evans s imides, as their titanium enolates, afforded the results shown in Scheme 5.31d and e [164,165]. The yields and selectivities for the reaction with acrylates and vinyl ketones are excellent, but the reaction is limited to P-unsubstituted Michael acceptors P-substituted esters and nitriles do not react, and 3-substituted enones add with no selectivity [165]. 

In a study on the electrophilic azide transfer to chiral enolates, Evans found that the use of potassium bis(trimethylsilyl)amide was crucial for this process. The KN(TMS)2 played a dual role in the reaction as a base, it was used for the stereoselective generation of the (Z)-enolate (1). Reaction of this enolate with trisyl azide gave an intermediate triazene species (2) (eq 4). The potassium counterion from the KN(TMS)2 used for enolate formation was important for the decomposition of the triazene to the desired azide. Use of other hindered bases such as Lithium Hexamethyldisilazide allowed preparation of the intermediate triazene however, the lithium ion did not catalyze the decomposition of the triazene to the azide.This methodology has been utilized in the synthesis of cyclic tripeptides. 

Unique H-Li couplings of 0.45 and 0.89 Hz through the Li-N-C-H network have been observed by Willard and co-workers in the spectrum of a chiral enolate aggregate containing a lithium enolate and a chiral lithium amide. This is a second example of such coupling reported in the literature. For the first time scalar coupling of 0.80 Hz between proton and lithium nuclei across the H-C-C-Li path was reported by Gunther and co-workers in 1993.2 ... 

Chiral Q , -unsaturated oxazolines can be obtained by a carbonylation-amidation of enol triflates or aryl halides with chiral amino alcohols (eq 36). The palladium catalyst can be either Pd(PPh3)4, bis(dibenzylideneacetone)palladium(0) and PPh3, or Pd(OAc)2 and dppp in the presence of triethylamine. 

Aside from Coreys phenylmenthyl propanoate 424, several chiral enolates have been utilized for Michael additions with substantial degrees of diastereoselectiv-ity. Yamaguchi s group developed a series of chiral amide enolates 436 and studied the conjugate addition to crotonates [210]. Another remarkable early contribution came from Oppolzer and coworkers who used dienolate 437 for diastereoselec-tive consecutive additions to cyclopentenone and allylation [211]. The auxiliaries 436 and 437 served for total syntheses of terpenoid natural products. Diastereos-elective Michael additions were also achieved by means of imidazolidinone-based lithium enolate 438 [212] - another showcase of the efficiency of imidazolidinone 118 [54] (Scheme 4.94). 

---