Valine scheme

Alternatively, diltiazem (30) has been prepared using the Evans auxiliary derivative 31 derived from L-valine (Scheme 23.7).55 After dehydration of the adduct from the condensation of 31 with anisaldehyde through the mesylate, the enol ether was formed with a Z E ratio of 4 1. This imide was then treated with 2-aminothiophenol in the presence of 0.1 equiv. 2-aminothiophenoxide with no change in the isomer ratio. The auxiliary was removed with trimethylaluminum, with concomitant formation of the lactam. After separation by crystallization, the correct diastereoisomer was converted to diltiazem in >99%ee. 

Valsartan (22) is an orally active, angiotensin II antagonist that is marketed under the name Diovan by Novartis for hypertension. Novartis has also developed a combination therapy, valsartan plus hydrochlorothiazide, for the second-line therapy of hypertension. The synthesis is straightforward from a stereochemical viewpoint because a chiral pool synthesis is used. The stereogenic center is derived from L-valine (Scheme 31.17).220 223... 

The polymer-supported chiral oxazaborolidinone catalyst 5 prepared from valine was found by Ituno and coworkers to be a practical catalyst of the asymmetric Diels-Alder reaction [7] (Scheme 1.12). Of the several cross-linked polymers with a... 

Scheme 4 Intramolecular Zn-MesSiCl-promoted reductive coupling of 0,0 -tethered bis(V-arylidene valinates)...

L-valine. The application of these ligands to the asymmetric addition of ZnEt2 to aldehydes provided the corresponding products with excellent enan-tioselectivities as high as 99% ee in almost all cases and with a catalytic loading as little as 0.02 mol% of the ligand depicted in Scheme 3.9. 

In 1998, Anderson et al. developed a new series of S/N ligands derived from L-valine and analysed these in the enantioselective addition of ZnEt2 to aromatic aldehydes. The use of these ligands allowed enantioselectivities of up to 82% ee to be obtained (Scheme 3.10). The results showed that the ligands possessing symmetrical nitrogen substituents did not perform as well as those... 

Scheme 3.9 L-Valine-derived P-amino thiol ligand for additions of ZnEt2 to aldehydes.

Scheme 3.10 L-Valine-derived P-amino thio ligands for addition of ZnEt2 to benzaldehyde.

In 2004, Yang and Tseng reported the synthesis of a series of new chiral amino thiol ligands derived from L-valine, which were further employed (1 mol%) in the enantioselective alkenylzinc addition to aldehydes, providing an efficient route for chiral ( )-allylic alcohols with enantioselectivities of up to >99% ee, as shown in Scheme 3.67. ... 

Scheme 5.26 L-Valine-derived arylsulfonamide ligands for B-catalysed Diels-Alder reactions.

In the same study, these authors also described the synthesis of other S/N ligands derived from various amino acids, such as proline, valine and cysteine. These dithioether and azathioether ligands were further tested as potential palladium ligands for the reduction of acetophenone, but no significant induction was observed in each case of ligand (Scheme 8.26). 

Originally, 1 was prepared by medicinal chemists from three key components, namely, a cyclopentanone moiety 2, a pyrazole moiety 3, and commercially available D-valine, as depicted in Scheme 2.1 [1], These synthetic disconnections provided an applicable and convergent route to 1, and consequently, were utilized in our strategy to develop an efficient and scalable synthesis of 1. 

Since preparation of pyrazole 3 was deemed straightforward (vide infra.) and D-valine tert-butyl ester was commercially available, our efforts focused on developing a synthesis of tbe more challenging cyclopentanone 2 [3], The original synthetic method for 2 by medicinal chemists is depicted in Scheme 2.2. 

The combination of a Mannich-3CR with an Ugi-4CR results in a seven-component reaction (7CR), as shown in Scheme 9.8. Reaction of dimethylamine, formaldehyde and isobutyraldehyde led to the 3-aminoaldehyde 9-40, which was treated with valine, methyl isocyanide, and methanol to give the anticipated product 9-41 [3],... 

The reaction of A-Boc protected amino acids alanine (184) and valine (185) with phenyldichlorophosphine in the presence of NEt3 was reported to lead to the clean formation of essentially one compound in each case, the P-chiral, tricoordi-nated, 1,3,2-oxazaphospholidinones 186 and 187 respectively (Scheme 52) [83],... 

A similar reaction of A-toluenesulfonyl derivatives of (.S )-alanine, phenylalanine, and valine (188-190) with PhPCl2 gave 4-methyl, benzyl, and isopropyl derivatives of 2-phenyl-1-p-toluenesulfonyl-l, 3,2-oxazaphospholidin-5-one, 191-193 in high yields (Scheme 53) [84], The ratios of the (2.V,4.V)/(2/f,4.V) diastereomers (which were designated as cis/trans isomers) were 1 1, 2 1, and 10 1 for 191a,b, 192a,b, and... 

BOC-L-valinal = ferf-butyl A/-[(1S)-1-(methylethyl)-2-oxoethyl]carbamate Scheme 9... 

The (5-lactam antibiotics are now so extensively described that we cannot attempt to summarize the literature. Since our emphasis is on sulfur, we note that the sulfur atoms of the thiazolidine or dihydrothiazine rings derive from a common tripeptide, 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine 1, ACV or Arnstein tripeptide . ACV is converted to a (5-lactam structure, isopenicillin N 2 and thereafter, the two pathways diverge, i.e. to benzylpenicillin 3 or to cephalosporin C 4 (Scheme 1). There have been extensive studies of the genes and enzymes involved in (5-lactam biosynthesis.18,19... 

Chiral nitrones derived from L-valine (62a-c) react with methyl acrylate to afford the corresponding diastereomeric 3,5-disubstituted isoxazolidines (565a-c) to (568a-c). The dibenzyl substituted nitrone (62a) also gave 3,4-disubstituted isoxazolidine (569) in 4% yield. The stereoselectivity was dependent on the steric hindrance of the nitrone and on reaction conditions. High pressure decreased the reaction time of the cycloadditions. The major products were found to have the C-3/C-6 erythro and C-3/C-5 Irons configuration (Scheme 2.262) (771). 

Selective hydroxylation of a-amino acids in water is achieved with the aid of K2PtCl4/CuCl2. The reaction of L-valine with K2PtCl4/CuCl2 at 160 °G for 10 h affords the cyclized lactones, which are converted to iV-Boc-lactones (Scheme 14).137... 

The main disadvantages of Evans auxiliaries 22 and 23 are that they are expensive to purchase and inconvenient to prepare, as the preparation involves the reduction of (5 )-valine 24 to water-soluble (b )-valinol, which cannot be readily extracted to the organic phase. The isolation of this water-soluble vali-nol is difficult and requires a high vacuum distillation, which is not always practical, especially on an industrial scale. Therefore, an efficient synthesis of Evans chiral auxiliary 25 has been developed, as depicted in Scheme 2-1930 ... 

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