Valine derivatives

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

Furthermore, rwri-/ -hydroxy-L-histidine can be synthesized starting from the (R)-valine derived bromoacetate (see above). The diastereomeric purity of this acid is 30 1 (desired isomer/sum of all others)100. 

Use of the valine derived (4S )-3-acetyl-4-isopropyl-1,3-oxazolidine (8)92, the C2-symmetric reagents (2.5,55)-l-acetyl-2,5-bissubstituted pyrrolidine 994, or the doubly deprotonated acetyl urea /V-acetyl- V..V -bis[(.S)-l-phcnylethyl]urea (10), also does not lead to sufficient induced stereoselectivity combined with acceptable chemical yield. When the acetyl urea enolate is reacted with aliphatic and aromatic aldehydes, the diastereomeric adducts (ratios ranging from 1 1 to 3 1) may be separated by column chromatography to give ultimately both enantiomers of the 3-hydroxy acids in 99% ee110. 

The reaction of the imines, formed from 2-methylpropanal and (S )-a-methylbenzylamine with tert-butyl isocyanidc and benzoic acid under widely varied conditions, delivers the valine derivatives with only moderate diastcrcoselectivity (ratio of diastereomers less than 4 l)67. 

A decisive improvement in the stereoselective performance of the Ugi reaction was achieved by the use of 1-ferrocenylalkylamines, in particular, l-ferrocenyl-2-methylpropylamine. as the inducing chiral auxiliary 18, S7. The iminc formed from the (/ )-enantiomer and isobutyralde-hyde reacts at — 78 °C with tm-butyl isocyanidc and benzoic acid to give the (S )-valine derivative with a diastereoselectivity of about 100 1. 

The Ugi reaction has been successfully applied to the synthesis of oligopeptide derivatives, c.g.. in the construction of a pure tetra-L-valine derivative69. The 2-methylpropanaldimine 2 of (/7)-l-ferroccnyl-2-rnethylpropylarnine with /V-formyl-L-2-amino-3-methylbulanoic acid (3) as the carboxylic acid component and methyl A/-[(.S)-2-isocyano-3-mcthyl-l -nxo-buLyl -L-2-aiuino-3-inethylbutanoate (4) furnishes the diastereomeric valyl-valyl-valyl-valine derivatives in a ratio (S,S[R],S,S)i(S,R[R],S,S) of 91 9. The stereoselectivity of the process can be enhanced to 98.5 1.5 when two equivalents of tetraethylammonium A -formylvalinate are added. 

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.

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

A valine-derived oxazaborolidine derivative has been found to be subject to activation by Lewis acids, with SnCl4 being particularly effective.98 This catalyst combination also has reduced sensitivity to water and other Lewis bases. 

Helmchen and colleagues used equimolar amounts of L-valine derived oxazaboroli-dine 361a to catalyze the reaction of methacrolein with cyclopentadiene (equation 103). Cycloadduct 322 was obtained with 64% ee229. The enantioselectivity was increased to 86% ee by using 60 mol% of 361a and donor solvents like THF. The same catalyst afforded the endo cycloadduct of crotonaldehyde and cyclopentadiene with 76% ee. 

The action of the valine derivatives 87 on the diene 86 under EtAlCU catalysis resulted in a mixture of cycloadducts 88, which on hydrolysis with aqueous methanolic sodium carbonate furnished a mixture of the dihydro-2-pyridones 89 and 90 and the esters 91 and 92. In the case of imines derived from aliphatic aldehydes, e.g. 87 (R = Pr), all four types of product were isolated, whereas imines from aromatic aldehydes, 87 (R = Ph, 3-CIC6H4 etc.), gave only the esters 91 and 92 (equation 55). All products were formed in yields of 64-84% and in high de49. 

Later, Maikov and Kocovsky reported the asymmetric reduction of imines with A -methyl L-valine derivative 37 with high yield and enantioselectivity (Scheme 29) [103]. 

The phenylalanine-derived oxazolidinone featured here enjoys three practical advantages over the valine-derived oxazolidinone developed earlier in this laboratory. First, both the intermediate g-amino alcohol and the derived oxazolidinone are crystalline solids which can be purified conveniently by direct crystallization. Second, the oxazolidinone contains a UV chromophore which greatly facilitates TLC or HPLC analysis when it is employed as a chiral auxiliary. Finally, both enantiomers of phenylalanine are readily available, enabling stereocontrol in either sense simply by using the oxazolidinone derived from the appropriate enantiomer. 

Yamamoto had earlier reported that Lewis acid activation of valine-derived oxazaborolidine 60 yielded a highly reactive and moisture-tolerant LLA catalyst 61 for the Diels-Alder reaction (Scheme 5.76) [145]. In later studies, activation of 60 with the super Bronsted acid, C,sF5CHTf2, was found to produce the even more reactive catalytic species BLA 62. During studies toward an enantioselective route to Platensimycin [146], BLA 62 was found to catalyze the Diels-Alder reaction between various monosubstituted dienes and ethyl acrylate to afford adducts... 

Valine-derived (5)-2-ethoxy-4,5-dihydro-4-isopropyloxazole, obtained by alkylation of 4-isopropyl-2-oxazolidinone with Meerwein s reagent, has been used to convert secondary tion and alkylation occurs smoothly to give alkylated derivatives I, which can be deprotected to give tetrahydroisoquinolines 2 with recovery of the chiral auxiliary28. 

Depending on the nature of the imine, deprotonation and alkylation occurs either at the amine residue or at the carbonyl part of the molecule. Deprotonation of the amine residue (chiral auxiliary), as observed in the reaction of valine derived imines, can be excluded by choosing optimized metalation conditions3. 

The co-polymerization of D-alanine-derived A-propargylamide 22, L-valine-derived 23, and pyrene-based monomer 24 gives helical poly(22 -< o-23-c -24) carrying pyrene. The secondary structure of the co-polymer is tunable by the composition of the optically active amino acid units and solvent, which makes it possible to control the direction of the pyrene groups in the side chain. The interaction between the pyrene groups is small when the co-polymer takes a helical structure. The pyrene groups are regularly positioned in the polymer side chain. The co-polymer emits weak... 

The chiral auxiliaries H-A developed by Evans et al. 176) were derivatives of naturally occurring amino acids. The (S)-proline-derived amide enolates (164) as well as the (S)-valine-derived amide enolates (166) and imide enolates (165) have proven to be exceptionally versatile chiral nucleophiles. 

Oxazolin-5-ones have also proven to be important intermediates in the homologation of carboxylic acids (71AG(E)655). The IV-acyl-DL-valine derivative (402), prepared from the acid chloride of the carboxylic acid and DL-valine by the Schotten-Baumann procedure, was treated with excess acetic anhydride to afford (403). Reaction of (403) with acrylonitrile and triethylamine led to (404) in good yield. Hydrolysis of (404) with dilute alkali or acid gave the y-keto nitrile or y-keto acid (Scheme 89). 

A vast array of chiral catalysts have been developed for the enantioselective reactions of diazo compounds but the majority has been applied to asymmetric cyclopropanations of alkyl diazoacetates [2]. Prominent catalysts for asymmetric intermolecular C-H insertions are the dirhodium tetraprolinate catalysts, Rh2(S-TBSP)4 (la) and Rh2(S-DOSP)4 (lb), and the bridged analogue Rh2(S-biDOSP)2 (2) [7] (Fig. 1). A related prolinate catalyst is the amide 3 [8]. Another catalyst that has been occasionally used in intermolecular C-H activations is Rh2(S-MEPY)4 (4) [9], The most notable catalysts that have been used in enantioselective ylide transformations are the valine derivative, Rh2(S-BPTV)4 (5) [10], and the binaphthylphosphate catalysts, Rh2(R-BNP)4 (6a) and Rh2(R-DDNP)4 (6b) [11]. All of the catalysts tend to be very active in the decomposition of diazo compounds and generally, carbenoid reactions are conducted with 1 mol % or less of catalyst loading [1-3]. 

Hashimoto has shown that the the valine-derived catalyst Rh2(S-BPTV)4 (5) is effective in intermolecular tandem cyclization/intermolecular cycloaddition resulting in the formation of 46 in 92% ee (Eq. (26) [10]. More recent studies have broadened the range of substrates that can be used in the reaction although the enantioselectivity is variable [38,39],... 

Analogously, the l-valine derived nitrones 103 react with methyl acrylate (104) to produce the corresponding diastereomeric 3,5-disubstituted isoxa-zolines 105-108. In the case of the dibenzyl-substituted nitrones, in addition to 3,5-disubstituted isoxazolines, the 3,4-disubstituted isoxazolines were also obtained in low yields. High pressure just served to decrease the reaction time. The major products 105 were found to have the C-3/C-6 erythro and C-3/C-5 trans relative configuration (Scheme 30) [74]. 

Scheme 30 13DPRs of L-valine derived nitrones 103 with methyl acrylate (104) [74]... 

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