Enrichment tertiary

Until recently, chemical and enzymatic approaches toward the synthesis of enantiomerically enriched aldols have been applied almost exclusively to the synthesis of secondary aldols. Conversely, we found no general methods, either chemical or enzymic, for the preparation of enantiomerically enriched tertiary aldols, even though tertiary aldols are structural motifs common to many bioactive natural products, such as Vineomyci-none B2 (14), Dicrotaline (15), Torosachrysone (16), Mevalonolactone (17), and Mycarose (18). Application of natural enzymes toward the synthesis of enantiomerically enriched tertiary aldols might partially be hindered by the fact that no known natural aldolase catalyzes the synthesis of tertiary aldols (List et al., 1999). 

Alkylation of pseudoephedrine a-fluoropropionamide can be used to prepare enantiomerically enriched tertiary alkyl fluoride centers (eq 27). In contrast to the alkylation of pseudoephedrine a-fluoroacetamide, alkylation of pseudoephedrine a-fluoropropionamide proceeds with high diastereoselectivity when LDA in used as the base in the reaction and low diastereoselectivity when LHMDS is used. In these reactions, deprotonation of pseudoephedrine a-fluoropropionamide with LDA, proposed to occur under kinetic control, is believed to form the corresponding... 

Knochel and co-workers58 reported Baeyer-Villiger oxidation of a-trisubstituted aldehydes 116 in the preparation of tertiary chiral alcohols 117. The fact that the reaction proceeds with retention of configuration of the migrating group permits the utility of this reaction. Several optically enriched, tertiary alcohols were prepared using this simple 3-step method from optically-enriched allylic tetrafluoroborates 115. 

The asymmetric arylation or alkylation of racemic secondary phosphines catalyzed by chiral Lewis acids in many cases led to the formation of enantiomerically enriched tertiary phosphines [120-129]. Chiral complexes of ruthenium, platinum, and palladium were used. For example, chiral complex Pt(Me-Duphos)(Ph)Br catalyzed asymmetric alkylation of secondary phosphines by various RCH2X (X=C1, Br, I) compounds with formation of tertiary phosphines (or their boranes) 200 in good yields and with 50-93% ee [121]. The enantioselective alkylation of secondary phosphines 201 with benzyl halogenides catalyzed by complexes [RuH (/-Pr-PHOX 203)2] led to the formation of tertiary phosphines 202 with 57-95% ee [123, 125]. Catalyst [(R)-Difluorophos 204)(dmpe]Ru(H)][BPh4] was effective at asymmetric alkylation of secmidaiy phosphines with benzyl bromides, whereas (R)-MeOBiPHEP 205/dmpe was more effective in the case of benzyl chlorides (Schemes 65, 66, and 67) [125—127]. 

The arylatiOTi of secondary phosphines with aryl halogenides, catalyzed by chiral complexes of platinum [116-126], mthenium [127-129], and palladium [130-139], in many cases proceeded with good enantioselectivity and can be considered as raie of methods for preparatimi of enantiomerically enriched tertiary phosphines [ 109-113]. For example, the reaction of aryl iodides with secondary arylphosphines 201, catalyzed by chiral complex Pd((R,R)-Me-Duphos) (fraiw-stilbene), furnished tertiary phosphines 206 with enantioselectivities up to 88% ee [112, 115, 118, 130]. 

The arylation of secondary phosphines 201 with ortho-aiy iodides, catalyzed by generated in situ complex Pda (dba>3 x CHQ3, containing chiral ligand Et,Et-FerroTANE 207 and LiBr, led to the formatiOTi of corresponding tertiary phosphines with enantioselectivity of 90% cc [ 132,137]. The palladium complex 209 also showed high enantioselectivity in arylation of secondary phosphines [131,132]. Some examples of arylation reaction of secondary phosphines with low ee were described. The asymmetric arylation of phosphine boranes with anisyl iodide, catalyzed by chiral complex of oxazoline phosphine 208, led to the formation of enantiomerically enriched tertiary phosphines 206 with 45% ee [134]. The Pd complex 210 of (R )-t-Bu-JOSlPHOS ligand catalyzed arylation of PH(Me)(Ph)(BH3) by o-anisyl iodide with the formation of PAMP-BH3 with 10% ee (Table 3) [112]. 

In 2003, both Walsh and Yus reported independently on a titanium-mediated phenyl transfer to alkyl-aryl ketones 23 (Scheme 8.8) [22]. The role of the titanium alkoxide was not only to form the active chiral catalytic species, but also to sequester the tertiary alkoxide generated during the catalytic cycle. Yus has discussed the possibility of using either arylboronic acids or Ph3B as precursors for the aryl transfer, and in certain cases ee-values greater than 99% were observed [23]. It is worth highlighting at this point that Walsh also used a similar protocol for the aryl transfer to a,P-unsaturated ketones to produce optically enriched tertiary alcohols [24]. 

N-acyl imines [144]. A slightly modified chiral Br0nsted acid 185 was found to catalytically induce addition of indoles to N-Boc-protected enecarbamates ISK) in high yields and enantioselectivities (Scheme 8.51) [145]. In a related study, Zhou demonstrated the use of a-aryl enamides to obtain optically enriched tertiary amine products [146]. 

In 2007, Glueck s group reported a catalytic DKR process in which secondary phosphines were converted into the corresponding enantio-enriched tertiary phosphines through palladium-catalysed asymmetric hydrophosphination of aryliodides using secondary phosphines. The key intermediates were diaster-eomeric phosphide complexes with chiral ancillary ligands (L Pd PRR ). Their relative rates of P-inversion and phosphorus-carbon bond formation controlled the enantioselectivity of the prodnct formation. As shown in Scheme 2.63, the reaction allowed moderate enantioselectivities of up to 70% ee to be achieved. 

Although a variety of secondary aldols can be prepared by aldolase antibody 38C2-catalyzed cross-aldol reactions, tertiary aldols are typically not accessible via intermolecular cross-aldol reactions. For preparation of enan-tiomerically enriched tertiary aldols, aldolase antibody 38C2-catalyzed retro-aldol reactions can be used (Section 6.3.2). 

While general access to optically active tertiary aldols is not available by traditional synthetic methods, a variety of enantiomerically enriched tertiary aldols can be prepared by aldolase antibody-catalyzed kinetic resolution. Significantly, the aldolase antibodies process not only keto-aldols but also aldehyde-aldols for example, the reaction to provide (S)-40. 

Enantiomerically enriched, tertiary alcohols could also be constructed by addition of Al(2-thienyl)3(THF), mediated by the same catalyst system [93]. Several aryl,methyl ketones and an enone could frequently be transformed in almost quantitative yields and with ee s exceeding 90%. Again, 2-methoxyacetophenone furnished only a moderate ee of 45%, and unfortunately, alkyl,methyl ketones (alkyl = nPr, Pr, nBu) were transformed all in 96% yield but with less than 17% ee. Conducting the reactions in toluene led to better results than in THF, and the optimized conditions allowed the stereoselective total synthesis of the anticholinergic/spasmolytic drug tiemonium iodide (50) in 84% yield over three steps from 48 (Scheme 9). 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

Interestingly, certain chiral tertiary bases, viz., the Cinchona alkaloids, result in an asymmetric 1,3-elimination to give enantiomerically enriched azirine esters 29 (Scheme 15). The best results were obtained with quinidine in toluene as the solvent at a rather high dilution (2 mg mL ) at 0 °C. In an alcoholic solvent no asymmetric conversion was observed. It is of importance to note that the pseudoenantiomers of the alkaloid bases gave opposite antipodes of the azirine ester, whereby quinidine leads to the predominant formation of the (k)-enan-tiomer (ee = -80%). To explain this asymmetric Neber reaction, it is suggested... 

The enrichments and depletions displayed in Figure 1 are concordant with what would be expected if disorder were encoded by the sequence (Williams et al., 2001). Disordered regions are depleted in the hydrophobic amino acids, which tend to be buried, and enriched in the hydrophilic amino acids, which tend to be exposed. Such sequences would be expected to lack the ability to form the hydrophobic cores that stabilize ordered protein structure. Thus, these data strongly support the conjecture that intrinsic disorder is encoded by local amino acid sequence information, and not by a more complex code involving, for example, lack of suitable tertiary interactions. 

Cathodic deprotection of tosylates of chiral alcohols was achieved without racemization by cleavage of the O—SO2 bond [351]. Optically active quaternary arsonium [352, 353] and phosphonium salts [354] are cathodically cleaved to tertiary arsines and phosphines respectively, with retention of the configuration. The first enantiomer enriched chiral phosphines have been prepared this way. 

A series of pseudo-C or pseudo-C2 symmetric complexes 168-171 (Fig. 27) exhibited isotactic predominance P = 0.50-0.75) however, the isotacticity is compromised in solvent-free bulk polymerization at 130 °C [129]. Fluorous tertiary alcohol ligands with electron-withdrawing CF3 group are weakly basic and thus expected to reduce the possibility of catalyst deactivation by bridged species formation. Al complexes 172 and 173 offered highly isotactic-enriched stereoblock PLA (Pm = 0.87) from ROP of rac-lactide [168]. 

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

Hoft reported about the kinetic resolution of THPO (16b) by acylation catalyzed by different lipases (equation 12) °. Using lipases from Pseudomonas fluorescens, only low ee values were obtained even at high conversions of the hydroperoxide (best result after 96 hours with lipase PS conversion of 83% and ee of 37%). Better results were achieved by the same authors using pancreatin as a catalyst. With this lipase an ee of 96% could be obtained but only at high conversions (85%), so that the enantiomerically enriched (5 )-16b was isolated in poor yields (<20%). Unfortunately, this procedure was limited to secondary hydroperoxides. With tertiary 1-methyl-1-phenylpropyl hydroperoxide (17a) or 1-cyclohexyl-1-phenylethyl hydroperoxide (17b) no reaction was observed. The kinetic resolution of racemic hydroperoxides can also be achieved by chloroperoxidase (CPO) or Coprinus peroxidase (CiP) catalyzed enantioselective sulfoxidation of prochiral sulfides 22 with a racemic mixmre of chiral hydroperoxides. In 1992, Wong and coworkers and later Hoft and coworkers in 1995 ° investigated the CPO-catalyzed sulfoxidation with several chiral racemic hydroperoxides while the CiP-catalyzed kinetic resolution of phenylethyl hydroperoxide 16a was reported by Adam and coworkers (equation 13). The results are summarized in Table 4. 

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