Diastereofacial selectivity preparation

In addition to the boron trifluoride-diethyl ether complex, chlorotrimcthylsilanc also shows a rate accelerating effect on cuprate addition reactions this effect emerges only if tetrahydrofuran is used as the reaction solvent. No significant difference in rate and diastereoselectivity is observed in diethyl ether as reaction solvent when addition of the cuprate, prepared from butyllithium and copper(I) bromide-dimethylsulfide complex, is performed in the presence or absence of chlorotrimethylsilane17. If, however, the reaction is performed in tetrahydrofuran, the reaction rate is accelerated in the presence of chlorotrimethylsilane and the diastereofacial selectivity increases to a ratio of 88 12 17. In contrast to the reaction in diethyl ether, the O-silylated product is predominantly formed in tetrahydrofuran. The alcohol product is only formed to a low extent and showed a diastereomeric ratio of 55 45, which is similar to the result obtained in the absence of chlorotrimethylsilane. This discrepancy indicates that the selective pathway leading to the O-silylated product is totally different and several times faster than the unselective pathway" which leads to the unsilylated alcohol adduct. A slight further increase in the Cram selectivity was achieved when 18-crown-6 was used in order to increase the steric bulk of the reagent. 

Nucleophilic addition reactions to A -monoprotected a-amino aldehydes 1 (Table 20) represent the beginning of the worldwide interest in peptide isosteres for the preparation of certain specific enzyme inhibitors (e.g., aspartylproteinase inhibition). Some examples of this reaction type show a relatively low diastereofacial selectivity, especially when the reactions are per-... 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

Ail extremely useful method for the asymmetric synthesis of substituted amino acids, in particular glutamic acids, is based on optically active bislactim ethers of cyclodipeptides. The lithium etiolates of bislactim ethers (which are prepared easily from amino acids) undergo 1,4-addition to various a,/ -unsaturated esters to give -substituted 2,5-dihydropyrazine-propanoates203-205 with high diastereofacial selectivity, ratio (R/S) > 140-200 1. 

As an example the enolatc of (5,)-2,5-dihydro-5-isopiopyl-3,6-diinethoxypyrazine, prepared from (S>valine and glycine, reacts with methyl (2s)-3-phenylpropenoate and the (2/ ,/ S)-iso-mer is obtained as the major diastereomer. The diastereofacial selectivity is reflected by a 2R/2S ratio of 99.6 0.4, whereas the high simple diastereoselectivity is shown by the diastereomeric ratio (syn/ami) of 91 9. Using methyl (Z)-3-phenylpropenoate the (2R, R)-isomer is formed... 

Chiral tricyclic compounds have been prepared by thermal and Eu(fod)j-catalyzed cycloadditions of furanosidic a,-unsaturated aldehydes 26-29 (Figure 3.4) with cyclopentadiene (18) [31]. The diastereofacial selectivity depends markedly on the stereochemistry of the anomeric benzyloxy and methoxy groups. 

Recently, two new axially chiral compounds 44 and 45 have been prepared [44, A-acryl-A-allyl-o-t-butylanilide 45, A-(o-t-butylphenyl)-2-methyl-maleimide]. This represents the first instance of using nonbiaryl axially chiral ligands in asymmetric Dield-Alder reactions. In the presence of iodine, high endo-facial and diastereofacial selectivities have been obtained in 44/45-medi-ated reactions.10... 

Chiral glycolates. The chiral dioxolanes 1 and 2 are prepared by reaction of 8-phenylmenthone with a protected derivative, (CH3)3SiOCH2COOSi(CH3)3, of glycolic acid catalyzed by trimethylsilyl triflate. They are obtained in about a 1 1 ratio and are separable by chromatography. Alkylation of the enolates of 1 and 2 proceeds with marked diastereofacial selectivity. After separation of the major... 

The diastereofacial selective imine-ene reactions with a-imino esters prepared from (—)-8-phenylmenthyl glyoxylate have provided an efficient entry to the asymmetric synthesis of a-amino acids, and a Lewis acid-mediated intramolecular imine-ene reaction has been used for the key spirocyclization step in a recent synthesis of (—)-perhydrohistrionicotoxin. Asymmetric azo-ene reactions have been effected using the chiral azo-enophile, di-(—)-(lR,2S)-2-phenyl-l-cyclohexyldiazenedicarboxylate. ... 

Treatment of the known nitroalkene 44 with the ylide indeed gave 41, but it was accompanied by a small proportion of the stereoisomer 4 (lA). Altljough the preparative yield was low (- <30%), the high diastereofacial selectivity of the methylene addition was remarkable. It becomes plausible on inspection of a molecular model, which points to hindered approach from one face, and unhindered approach from the other (Figure 7). 

The class of 3-silyl-substituted reagents provides, upon addition with aldehydes, allylic silanes that offer many options for further derivatization. Oxidative processes are described in previous sections (see the sections on Preparation of 1,2-Diols and 1,4-Diols). If the appropriate silicon substituents are chosen, formal [3+2] cycloadditions with aldehydes can be promoted under Lewis acid catalysis. For example, the mismatched addition of the Z-3-propyl-3-benzhydryldimethyl allylsilane 183 to an a-benzyloxy aldehyde proceeds with low diastereofacial selectivity in favor of product 184 however, after protection of the secondary alcohol, an efficient [3+2] annulation provides the polysubsubstituted furan 185 in good yield and acceptable stereoselectivity (Scheme 24). ° The latter is brought forward to a tricyclic unit found in the antitumor natural product angelmicin B. 

Chiral cyclobutanes can be prepared by cycloaddition of alkenes substituted with one or more chiral auxiliary groups. A diastereofacial selectivity of 95% was observed in the diethylalu-minum chloride catalyzed cycloaddition of 1,1-dimethoxyethene (36) with ( — )-dimenlhyl-3-yl fumarate (37).16 The chiral cyclobutane 38 has been used as an intermediate in the synthesis of carbocyclic oxetanocin analogs. 

The diastereofacial selectivity of radical hydrogen quenching applied to the synthesis of O-glycosides is discussed later, in connection with data from related methods concerning radical-mediated preparations of C-glycosyl compounds. 

In 1992 Ghosh and co-workers provided the first example of the utility of rigid cis-1 -amino-2-indanol-derived oxazolidinone 36 as the chiral auxiliary in the asymmetric. vv//-aldol reaction.60-61 Aldol condensation of the boron enolate of 37 with various aldehydes proceeded with complete diastereofacial selectivity. Effective removal and recovery of the chiral auxiliary was carried out under mild hydrolysis conditions (Scheme 24.6). As both enantiomers of the chiral auxiliary were readily available, both enantiomers of the. yyn-aldol could be prepared with equal asymmetric induction. 

Spirodienones are attractive intermediates for the preparation of calixarenes in which the intraanular hydroxy groups are partly replaced by hydrogen,93 amine 93 methyl,94 or halogen.95 The reaction with benzyne affords Diels-Alder adducts in high diastereofacial selectivity.92 No special use has been made of their chirality, however. 

The most direct method for the preparation of polyol frameworks is without doubt the aldol reaction. The diastereofacial selectivity of the reaction can be controlled by /J-alkoxy groups in both the methylketone enolate and the aldehyde. As investigations by Evans [6] and Paterson [7] and their groups have demonstrated, the correct selection of enolization conditions and the protective group for the )8-hydroxy group are important for the stereocontrol of the reaction. 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

Paterson et have prepared the enolate of 3-pentanone, an achiral ketone, with (-( )- or (-)-IpcaBOTf and have found that its aldol reactions with various aldehydes proceed with high syn.anti ratios (>9 1) and respectable enantioselectivities (5 1-20 1) (Scheme 44). High degrees of asymmetric induction are noted with unhindered aldehydes, llie combination of the chiral ethyl ketone (104) and (-t-)-Ipc2BOTf constitutes a matched pair, which enhances the diastereofacial selectivity of the resulting enolate (compared to that obtained with an achiral boron reagent), and provides via aldol reactions high... 

The aldol reactions of titanium enolates have been the best studied of all the transition metal enol-ates."- In many cases they show higher stereoselectivity and chemoselectivity in their reactions than lithium enolates and are easily prepared using inexpensive reagents. They also promote high levels of diastereofacial selectivity in reactions of chiral reactants. The Lewis acidity of the titanium metal center can be easily manipulated by variation of the ligands (chloro, alkoxy, amino, cyclopentadienyl, etc.) attached to titanium, which leads to enhanced selectivity in appropriate cases. Moreover, the incorporation of chiral ligands on titanium makes possible efficient enantioselective aldol reactions. 

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