Chiral azaenolates

Chiral imines derived from 1-phenylethanone and (I. Sj-exo-l, 7,7-trimethyIbicyclo-[2.2.1]heptan-2-amine [(S)-isobornylamine], (.S>1-phenylethanamine or (R)-l-(1-naphthyl) ethanamine are transformed into the corresponding (vinylamino)dichloroboranes (e.g., 3) by treatment with trichloroborane and triethylamine in dichloromethane. Reaction of the chiral boron azaenolates with aromatic aldehydes at 25 "C, and subsequent acidic hydrolysis, furnishes aldol adducts with enantiomeric excesses in the range of 2.5 to 47.7%. Significantly lower asymmetric inductions are obtained from additions of the corresponding lithium and magnesium azaenolates. Best results arc achieved using (.S )-isobornylamine as the chiral auxiliary 3. 

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

Metalation of 4,5-dihydro-2-[(7 )-sulfinylmethyl]oxazoles (e.g., 2) with butyllithium at -90 C and reaction of the chiral azaenolates with aldehydes furnishes the hydroxyalkylated sulfinylox-azole derivatives 3 which are desulfurized to give the 4,5-dihydro-2-(2-hydroxyalkyl)oxazoles 4. The corresponding 3-hydroxy acids 5 are obtained by acidic hydrolysis in 60-85% overall yield and 26-53% ee31. 

Addition of the chiral azaenolate obtained from metalation of (4A,55 )-4,5-dihydro-2-methyl-4-methoxymethyl-5-phenyloxazole (6, see Section D.1.1.1.4.3.3) to aldehydes shows lowdiastere-ofacial selectivity. Acidic hydrolysis of the aldol adducts gives 3-hydroxy adds 7 in 31 -87% yield and less than 25% ee18. 

Boron azaenolates, generated from achiral 2-ethyl-4,5-dihydro-4,4-dimethyloxazolc (10) and chiral diisopinocamphcylboryl trifluoromethanesulfonate [14, derived from (+)-a-pinene], selectively provide the //////-adducts (>90%) in 77 85% ee. These are converted to the corresponding methyl esters 16 in 22 -36% overall yield20,21. 

In contrast to the above boron azaenolates, those bearing the chiral information in the 4,5-di-hydrooxazole moiety (e.g., 17) furnish. ynt-adducts 18 in >97% selectivity and 40-60% ee. In these cases, the aldol adducts are hydrolyzed and esterified without prior purification20,21. 

This method was extended to the diastereoselective synthesis of amino acid derivatives from the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines to enones90. 

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. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

In these reactions one equivalent of chiral azaenolate remains unused. This can be overcome when a mixed azaenol cuprate 9 is employed with an acetylide as nontransferable ligand or when a mixed azaenol dimethylzincate 10 is used. Higher diastereoselectivities are achieved with zincates than with copper azaenolates and with (li ,2S )-2-methoxy-1,2-diphenylethanamine as auxiliary231. 

Boron triflates 45a and 45b are very useful chiral auxiliaries. Boron azaenolate derived from achiral35 and chiral36 oxazolines gives good stereoselectivity in the synthesis of acyclic aldol products, particularly for the rarely reached threo-isomers. By changing the chiral auxiliary, the stereochemistry of the reaction can be altered.37... 

As shown in Scheme 8-11, nucleophilic entry from the a-face (24a) may be hindered by the sterically bulky substituent R2 on the oxazoline moiety therefore entry from the / -face 24/ predominates. Free rotation of the magnesium methoxy bromide may be responsible for the sense of the axial chirality formed in the biaryl product. If the azaenolate intermediate 25 is re-aromatized with a 2 -methoxy substituent complexed to Mg, (iS )-biphenyl product is obtained. Upon re-aromatization of azaenolate 25B, (R)-product is obtained. 

The methodology was extended to an asymmetric introduction of snbstitnents to a naphthalene ring. When chiral naphthyloxazolines 13 were used as substrates, di- or trisubstituted dihydronaphthalenes 15 were obtained in high diastereomeric ratio (dr) after the treatment of intermediate azaenolate 14 with an electrophile (equation 7) °. Analogous reactions with a chiral naphthaldehyde imine were also reported . 

The highly selective addition was rationalized by a chelation control as shown in equation 8. Tetracoordinate organolithium can form complexes 16a and 16b with the chiral oxazoline. The addition, which can be viewed as a suprafacial 1,5-sigmatropic rearrangement, proceeds from 16b where the C—Li bond is parallel to the 7T-orbital of the naphthalene ring. The attack of an electrophile on the azaenolate 17 formed by the... 

On the other hand, asymmetric induction is observed in chiral azaenolates derived from chiral ketones and achiral amino derivatives. 

Few alkylations of chiral azaenolates according to the latter reaction sequence are known. An example is alkylation of the conformationally fixed 4-tert-butylcyclohexanone imine which furnished a single product. As evident from the 13C-NMR spectrum the introduced alkyl group is located exclusively in the axial position. The geometry of the C -N double bond is syn, however, after a period of time, the thermodynamically more stable auF-isomer appears. Upon hydrolysis of the imine partial epimerization to the more stable cquatorial-substituted ketone occurs28. 

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. 

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. 

In contrast to the variety of chiral auxiliaries which have been used in the asymmetric alkylation of imine-derived azaenolates (see Section 1.1.1.4.1Table 7), alkylations of the hydrazone analogues employ mainly (-)-(S)-l-amino-2-methoxymethylpyrrolidine (SAMP) and its opti-cal antipode (RAMP). r A oCH, O ... 

Rcgio- and diastereoselective deprotonation of chiral 5,6-dihydro-4H-l,2-oxazines, followed by alkylation of the azaenolate, furnishes only one of the two diastereomers4. 

As already demonstrated in the previous natural product synthesis, the alkylation of 2,2-dimethyl-l,3-dioxan-5-one SAMP/RAMP hydrazones is a reliable tool with which to synthesize chiral 4-substituted 2,2-dimethyl-l,3-dioxan-5-ones in gram quantities and with high enantiomeric excesses [68]. Thus, after metalla-tion of the RAMP hydrazone (R) -96 the corresponding lithio azaenolate was alkyl-... 

Aldol reactions.1 The chiral oxazolidine (1), formed from 3-pentanone and (-)-norephedrine, after conversion to the tin azaenolate reacts with aldehydes to give predominantly anti-aldols (2) in >90% ee. Reduction of the carbonyl group of the anti-aldol 2 provides (3S,4R)-4-methyl-3-heptanol (3) in 95% ee. 

Notable is the general enantioselective addition of organolithiums to chiral vinyloxazolines (38) in which the intermediate azaenolate (39) can be further alkylated with high diastereoselectivity (Scheme... 

The introduction of a chiral auxiliary on the nitrogen of an azaenolate offers the capability to perform asymmetric conjugate additions of chiral nucleophiles to achiral acceptors. This is in contrast to the typical asymmetric conjugate addition of achiral nucleophiles to chiral acceptors.137 For example, the con-... 

Use of the boron azaenolate 3, prepared from achiral 2-ethyl-4,4-dimethyloxazoline and the chiral boryl triflate, undergoes aldol condensation to give mainly threo-fi-hydroxy esters with enantioselectivity of about 80% (equation II). 

The aldimine of Figure 13.34 is a chiral and enantiomerically pure aldehydrazone C. This hydrazone is obtained by condensation of the aldehyde to be alkylated, and an enantiomerically pure hydrazine A, the S-proline derivative iS-aminoprolinol methyl ether (SAMP). The hydrazone C derived from aldehyde A is called the SAMP hydrazone, and the entire reaction sequence of Figure 13.34 is the Enders SAMP alkylation. The reaction of the aldehydrazone C with LDA results in the chemoselective formation of an azaenolate D, as in the case of the analogous aldimine A of Figure 13.33. The C=C double bond of the azaenolate D is fraws-configured. This selectivity is reminiscent of the -preference in the deprotonation of sterically unhindered aliphatic ketones to ketone enolates and, in fact, the origin is the same both deprotonations occur via six-membered ring transition states with chair conformations. The transition state structure with the least steric interactions is preferred in both cases. It is the one that features the C atom in the /3-position of the C,H acid in the pseudo-equatorial orientation. 

Electrophilic substitution. A number of chiral nucleophilic species have been described that result in optically active a-alkyl aldehydes, ketones, acids, and acid derivatives upon alkylation and (usually) subsequent hydrolytic cleavage. Enders provides a number of examples (Figure 3) one of which results in the ant alarm pheromone, 4-methyl 3-heptanone (26 2 7). Studies by A. I. Meyers of the chemistry of anions of chiral oxazolines (Figure 4) were the first of the genre, however ( 8 ). Related reactions of chiral anions of metalloenamines and hydrazones (29, 30, 31) have in common with the alkylation of oxazolines metallated azaenolate intermediates that predispose one face of an azaenolate double bond to reaction with the electrophile. 

FIGURE 5. Classical SAM and RAMP chiral vectors used for azaenolates alkylation410... 

Enders and Bhushan reported the preparation of a-benzyloxy aldehydes and a-acetoxy ketones 6 of high enantiomeric purity and in good overall yield by oxygenation of the azaenolates of chiral hydrazone 4 with 3-phenyl-2-(phenylsulfonyl)oxaziridine 282. The chiral auxiliary was removed without racemization by ozonolysis of the a-hydroxy hydrazone 5 at — 78 °C. 

Oxygenation of Chiral Lithium Azaenolates Using 3-Phenyl-2-(phenylsulfonyl)-... 

Further applications can be mentioned briefly. SAMP was used in the resolution of 4-demethoxy-7-deoxydaunomycinone/ in ee determinations (Scheme 1), as a chelate for tetracarbonylmolybdenum complexes/ in intramolecular Heck reactions, as polysilylated hydrazine, in the enantioselective synthesis of isoquinuclidines, and in the conversion of hydrazones to aldehydes and nitriles. The structure of a chiral lithium SAMP hydrazone azaenolate has been determined. In cases where SAMP did not lead to satisfactory inductions, a modified auxiliary, (S)-l-amino-2-dimethylmethoxymethylpyrrolidine (SADP), enhanced the stereochemical control. 

Chiral Cuprate Reagents. This chiral amine has also found application in asymmetric conjugate addition of copper azaeno-lates to cyclic enones. Lithium azaenolates of optically active acetone imines have been used in the preparation of chiral cuprate reagents. However, the asymmetric induction is low (17-28% ee) when this amine is employed (eq 5). ... 

Enders, D., Bachstaedter, G., Kremer, K. A. M., Marsch, M., Harms, K., Boche, G. The structure of a chiral lithium azaenolate monomeric intramolecular chelated lithio-2-acetylnaphthalene-SAMP-hydrazone. Angew. Chem., Int. Ed. Engl. 1988, 27,1522-1524. 

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