Axially chiral enolate

Since the Boc and MOM groups at the nitrogen seem to be essential for the axial chirality in L and M, the reactions of V, V-diBoc derivatives 67 and 68 that do not generate axially chiral enolates were next investigated (Scheme 3.17). Upon a-methylation under conditions identical to those for 61... 

Stoodley and co-workers found retention of chirality in a cyclization reaction of 87.43 The reaction of 87 with triethylamine gave 89 in an enantiomerically pure form. They suggested that axially chiral enolate 88 with a chiral C(4)-N axis may be the origin of the asymmetric induction. Because of the high reactivity of the electrophilic diazo group, the cyclization of 87 would proceed before racemization of the axially chiral enolate. 

Piperidines with contiguous quaternary and tertiary stereocenters (for example 248) have been prepared in high enantiomeric purity by intramolecular conjugate addition of enolates generated from a-aminoacid (for example 249 derived from phenylalanine) derivatives (Scheme 74). An axially chiral enolate intermediate was proposed <050BC1609>. 

Advances in the use of enantiopure 3-lactams for the synthesis of biologically active compounds of medicinal interests 13THC(30)1. Asymmetric synthesis of multi-substituted p-lactams via C—N axially chiral enolates in intramolecular conjugate addition 12YGK1287. 

The deprotonation of the succinic imide 79 appears as a particularly elegant application of this concept. Thus, treatment with monohthiated base (78, Y = H) leads to the axially chiral enolate 80. Its enantioselective formation is proven indirectly by quenching with alkyl halides giving the a-substituted imide 81 in high enantiomeric excess only minor amounts (0—7%) of doubly alkylated products are formed (Scheme 2.22) [91]. 

Ghorai and co-workers reported on the synthesis of non-racemic amino aziridines 177 vmmemory of chirality (MOC) concept. The precursor 175 obtained from the addition of axially chiral enolate of amino acid ester to A7-sulfo-nyl imine following the concept of MOC. Reduction of 175 to the corresponding amino alcohol 176 followed by C—N cyclization produced the chiral aziridines 177 in good yields with excellent enatiomeric excess (Scheme 40.35). ... 

The creation of chiral oxazolidones with a tetrasubstituted chiral centre has been attributed to memory of chirality by an axially chiral enolate intermediate of the aldol reaction involved (Scheme 16). " ... 

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

Several applications of this methodology are known. For the determination of the relative configuration of the stereocenter and the axial chiral unit of 71, the product of a diastereoselective ester enolate Claisen rearrangement of 70, with AgBF4 a cycli-zation to 72 was initiated. Then the carboxylic acid was reduced to alcohol 73 and the position of the substituents was investigated by NMR and by the use of NMR shift-reagents (Scheme 15.16) [32], Control experiments ensured the stereospecifi-city of the cyclization and the reduction step. There are further examples of this strategy [33]. 

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and (41), the product of a retroaldol-acylation reaction. The selectivity is suggested to be directed by self-induced axial chirality, in which the enolate generated in the reaction has a stereochemical memory, being generated in an axially chiral form (42). The retroaldol step also exemplifies a stereoretentive protonation of an enolate. 

Next to phosphoramides, Denmark reported an axially chiral A -oxide to catalyze the asymmetric aldol reaction of trichlorosilyl enol ethers with ketones [99]. Hashimoto reported an aldol reaction with 3 mol% of another axially chiral A -oxide [100] which gave good yields and enantioselectivities. 

The formation of enolates or related compounds with a planar nucleophilic carbon atom by deprotonation of a center of asymmetry does not necessarily mean that the stereochemical information is lost. Examples have been reported in which the enolate remains chiral by assuming a different form of chirality (e.g. axial chirality) and the ensuing reaction with an electrophile proceeds with high enantioselectivity, despite the transient planarization of the stereogenic center (Scheme 5.72). 

Beagley, B. Betts, M. J. Pritchard, R. G. Schofield, A. Stoodley, R. J. Vohra, S. Hidden axial chirality as a stereodirecting element in reactions involving enol(ate) intermediates. Part 1. Cyclization reactions of methyl (4R)-3-(2-diazo-3-oxobutanoyl)thiazolidine-4-carboxyl-ate and related compounds. J. Chem. Soc. Perkin Trans. 1 1993, 1761-1770. 

Similar to the addition reactions of acceptor-substituted dienes (Scheme 16), the outcome of the transformation depends on the regioselectivity of the nucleophilic attack of the organocopper reagent (1,4- vs. 1,6-addition) and of the electrophilic capture of the enolate formed. The allenyl enolate obtained by 1,6-addition can afford either a conjugated diene or an allene upon reaction with a soft electrophile, and thus opens up the possibility to create axial chirality. The first copper-mediated addition reactions to Michael acceptors of this type, for example, 3-alkynyl-2-cyclopentenone 75,... 

Figure 3.2. Dynamic chirality of enolate structure (a) Axial chirality, (b) planar chirality.

NMR, Jab = 9.9 Hz, Avab = 228.4 Hz, Tc = 92°C). The restricted bond rotation brings about axial chirality in 54 (chiral C(l)-N axis), as shown in Scheme 3.13. The half-life to racemization of 54 was estimated to be 5 x 10-4 sec at 92°C, which corresponds to a half-life of about 7 days at —78°C.31 This implies that the corresponding potassium enolate could also exist in an axially chiral form with a relatively long half-life to racemization at low temperatures. 

Support for this novel mechanism was obtained from the reactions of 56 and 58 (Scheme 3.14). Upon a-methylation according to the protocol in Table 3.5, A/, A/ -diBoc derivative 56 (>99% ee) gave racemic 57 (95% yield). Similarly methylene acetal derivative 58 (>99% ee) gave racemic 59 (95% yield). These results are consistent with the conclusions above, since enolates G and H generated from 56 and 58, respectively, are not expected to be axially chiral along the C(l)-N axis. Enolate G is not axially chiral even if rotation about the C(l)-N bond is restricted at —78°C. The 2,3-dihydrooxazole ring in H is supposed to be nearly planar. 

Reactions like these, in which stereoselectivity is the consequence of steric hindrance to bond rotation, are most well known among the biaryls, and derivatives of binaphthyl have provided chemists with a valuable range of chiral ligands [4-6]. But the biaryls are only a small subset of axially chiral compounds containing two trigonal centres linked by a rotationally restricted single bond. Many others are known, some with much greater barriers to rotation than Fuji s enol ether [7]. Yet until quite recently there were no reports of reactions in which nonbiaryl atropisomers were the source, conveyor, or product of asymmetric induction. 

The diastereomerically pure thiazolium salt 509 which bears a 2-/i t7-butylphenyl substituent at the nitrogen atom was converted into a mixture of 510 and its atropisomer 510 (dr = 75 25) upon treatment with base (Scheme 128). The stereogenic center in the intermediate carbene favors one rotamer 510. Upon reaction with benzaldehyde, it accounts in a similar fashion for the formation of the major enol diastereoisomer 511 over 511, which, in turn, leads to the major enantiomer 512 rather than 512 observed in the benzoin condensation catalyzed by 509. The concept of axial chirality was proven to be viable for an efficient chirality transfer. Replacement of the isopropyl group at C-4 by the bulkier 2-phenyl-2-propyl substituent using 8-phenylmenthone is likely thought to increase the ee <2004EJ02025>. 

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