Chiral triazoles

Ma, D.Y, Wang, D.X., Zheng, Q.Y, et al. 2006. Nitrile biotransformations for the practical synthesis of highly enantiopure azido carboxylic acids and amides, click to functionalized chiral triazoles and chiral P-amino acids. Tetrahedron Asymmetry, 17 2366-76. 

Chiral triazoles have been synthesized by the desymmetrization of prochiral molecules. Thus, a PyBox ligand and CuCl have been used to furnish a highly... 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

Enantiomeric recognition of amino compounds by chiral macrocyclic receptors including pyridine or triazole subunits 97CRV3313. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

Finally, the chiral l,2,4-triazole-3,5-dione (131) has been used to resolve chiral dienes such as 1,2,3-trimethylcyclooctatetraene.225... 

Several relevant papers and review articles have appeared recently. These contain reports on the mechanism and kinetics of the ene reaction of ADC compounds,243-245 examples of four-membered ring formation,246-247 other cycloadditions of ADC compounds,248-252 the synthesis of azoalkanes,253 the use of chiral l,2,4-triazole-3,5-diones,254 and the use of the DEAZD/PI13P reagent in organic synthesis.255... 

Tandem azidination- and hydroazidination-Hiiisgen [3 +2] cycloadditions of ynamides are regioselective and chemoselective, leading to the synthesis of chiral amide-substituted 1,2,3-triazoles <06OBC2679>. A series of diversely l-substituted-4-amino-l,2,3-triazoles 132 were synthesized by the copper-catalyzed [3+2] cycloaddition between azides 130 and ynamides 131 <06T3837>. 

A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-l-substituted aryl-4-(l-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142,... 

Table 12 Reaction of chiral 4-amino-1,2,4-triazole derivatives with Grignard reagents (Equation 32)...

Stereoselective reduction of some triazolodiazines (derivatives of ring systems 33 and 37) bearing chiral terpene residues has been elaborated by Groselj el al. <2006TA79>. With catalytic hydrogenation, partial saturation of the six-membered ring was experienced, while reaction with borane-methyl sulfide resulted in formation of triazole-boron complexes. 

Following work on Michael addition of triazoles to nitro-olefins (discussed in Sect. 2.5), bifunctional chiral thiourea catalysts were used in the addition of triazoles to chalcones [83]. The catalytic system was applicable to enones bearing aromatic groups of varying electronic natures to provide good yields and moderate selectivity. a-Cyanoacetates [84] were also applied in Michael addition to chalcones under similar catalytic conditions (Scheme 33). 

Solid-phase library synthesis of triazolopyridazines via a [4+2] cycloaddition strategy has been accomplished <99TL619>. Intramolecular bis-Mannich reaction of 3-aryl-5-mercapto-13,4-triazole, formaldehyde and a-phenylethylamine yields chiral 5-aryltriazolo[3,4-ft]-[133]thiadiazine derivatives. These compounds have been screened for antibacterial activities and some of them show potent biological activity <99SC2027>. 

Dienes. (+ )-Camphor-derived 1 H-, 2,4-triazole-3,5(2//,4//)-dione 24 was used to determine the absolute configuration of chiral cyclooctatetraenes of type 23 and ent-23 by cycloadduct formation (compare with 25 and 26) and X-ray analysis (see also p 446)166. 

The amino ester 16 was then hydrolyzed to the carboxylic acid and isolated in 90% yield (Scheme 5.6). Subsequently, the amino acid was coupled with triazole 3 using EDC activation to afford the amide 17 in 90% assay yield. Removal of the chiral auxiliary was achieved via hydrogenolysis using Pd/C or Pd(OH)2 as catalyst to obtain sitagliptin in 83% assay yield. 

Overall, the chiral auxiliary approach to sitagliptin using (S)-PGA to install the amino group via diastereoselective hydrogenation resulted in a reduction of three chemical steps in the overall synthesis. This new synthetic approach essenhally followed the same convergent strategy (Route A on Scheme 5.8), but represented a big improvement over our previous route. The convergent approach made sense since the triazole heterocycle was a valuable intermediate that required an elaborate preparation with a modest yield of 26%. 

However, this approach required additional functional group manipulation steps since the chiral P-amino ester intermediate had to be hydrolyzed and activated to be converted to the desired amide. These steps could potentially be dirni-nated by introducing the triazole fragment much earlier in the synthesis and then introducing the chiral center on an enamine-amide instead of an enamine-ester (Route B on Scheme 5.8). 

With the improved route to prepare the triazole fragment 3 and the one-pot method to access keto amide 25 demonstrated, we set out to explore the chiral auxiliary strategy that had been demonstrated previously from keto ester 10. 

TABLE 8 Effects of Substituents on the Chiral Resolution of Aromatase Inhibitors (Triazole and Tetrazole Derivatives, Fig. 18) on a Chiralpak AD-RH CSP... 

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