5- Hydroxy-3-methylpentanoic acid

STEREOSELECTIVE ALDOL REACTION OF DOUBLY DEPROTONATED (RM+)-2-HYDROXY-1,2,2-TRIPHENYLETHYL ACETATE (HYTRA) (R)-3-HYDROXY-4-METHYLPENTANOIC ACID (Pentanoic acid, 3-hydroxy-4-methyl-, (R)-)... 

Preparation of (R)-(+)-3-hydroxy-4-methylpentanoic acid has been reported previously by the submitters.5 Alternative syntheses of (R)-(+)- or (S)-(-)-3-hydroxy-4-methylpentanoic acid rely on aidoi reactions of chiral ketone, ester, or amide enolates,2 8 10 and Lewis-acid mediated additions of chiral silyl ketene acetals to Isobutyraldehyde.3 11 Since both enantiomers of HYTRA are readily available this method enables one to prepare (S)-3-hydroxy-4-methylpentanoic acid as well. 

Potent inhibitors of aspartyl proteases have been prepared by incorporating hydroxy-methylene transition-state analogues modified in the a-position. The a-methylene moiety is either functionalized by a heteroatom 16,71 72 or it is dihalogenated)15,73,74 Alkyl substituents in that position are found in several residues present in compounds of natural origin, such as dolaproine (8) in dolastatin 10 and 4-amino-3-hydroxy-2-methylpentanoic acid (9) in bleomycin D (Scheme 1). This position is also substituted in synthetic, conformationally constrained six-membered-ring analogues)75 77 ... 

Stereochemically controlled synthesis of this subunit, which contains five stereogenic centers, is important to an efficient bleomycin synthesis. (2S,3S,4i )-4-(/er/-Butoxycarbonyl-amino)-3-hydroxy-2-methylpentanoic acid (15) was obtained via a stereoselective syn aldol addition of a boron Z-enolate with (27 )-2-(tert-butoxycarbonylamino)propanal (Scheme 4). Similarly, the L-threonine subunit 18 was prepared by diastereoselective syn aldol addition of an N- acy I ox azo I i di n one stannous Z-enolate with acetaldehyde. The bithiazole unit 19 was prepared using a direct DCC-promoted condensation of 3-(methylsulfanyl)propylamine. Convergent access to tetrapeptide S was obtained by coupling of acid 15 and deprotected 18 to give dipeptide 20, followed by further coupling with the bithiazole 19 to ultimately give tetrapeptide S (21). 

S,4S,5 E,7E)-3-Amino-4-hydroxy-6-methyl-8-(4-bromophenyl)-octa-5,7-dienoic acid [Aboa = Br-Ahmp, Br-Apoa], (2S,3S,8S,9S)-3-Amino-9-methoxy-2,6,8-trimethyl-10-phenyl-deca-4,6-dienoic acid (Adda). 3-Amino-2,4-dimethylpentanoic acid (Admpa). (2S,3R,5S)-3-amino-2,5,9-trihydroxy-10-phenyldecanoic acid (Ahda). j3-Aminoisobutyric acid (jS-AiB). (3S,4S,5E,7E)-3-Amino-4-hydroxy-6-methyl-8-phenylocta-5,7-dienoic acid [Ahmp (Faulkner) or Apoa (Fusetani)]. (2S,3R,5R)-3-Amino-2,5-dihydroxy-8-phenyloctanoic acid (Ahoa). 3-Aminopentanoic acid (Apa /5-Apa). (2R,3R)-3-Amino-2-methylbutanoic add (Amba). 3-Amino-2-methylhexanoic acid (Amha). 3-Amino-2-methyl-7-octynoic add (Amoa, Amoya). 3-Amino-7-octynoic add (Aoya). (2S,3R)-3-Amino-2-methylpentanoic acid (Map). http // www.ncbi.nlm.nih.gov/ Taxonomy/ tax.html... 

Acid hydrolysis affords two residues of L-2-amino-6-hydroxyamino-hexanoic acid, (-)-3-hydroxy-2-methylpentanoic acid, CO2, m-cresol and... 

Degradation procedures analogeus to those used for mycobactin P (see above) showed the aromatic residue to be salicylic acid (2-hydroxy-6-methylbenzoic acid in mycobactin P) and the hydroxy acid to be (+)-( -hydroxybutyric acid ((-)-3-hydroxy-2-methylpentanoic acid in mycobactin P). Fatty acid side chains substantially different from those in mycobactin P a minor component contains a s-octadec-2-enoic acid (identical to the principal product in mycobactin P). The major substituents in the fatty acid side chain are Cis to C21 fragments of unknown constitution. 

Commercially available C. boidinii-FDH was used to recycle the NADH cofactor in stereospecific reductions by (/ )-2-hydroxyisocaproate dehydrogenase from L. casei [174]. Enantiomerically pure (R)-2-hydroxy-4-methylpentanoic acid was obtained with 88% yield. The broad substrate specificity of this enzyme enables the synthesis of a broad range of enantiomerically pure ot-hydroxy acids with aliphatic or aromatic side chains. 

C. Mevalonolactone-2-13C. In a 250-mL Paar hydrogenation bottle are placed 50 mL of 95% ethanol, 0.107 g (0.001 mol) of palladium black (Note 14), and 0.519 g (0.00217 mol) of 5-benzyl-oxy-3-hydroxy-3-methylpentanoic acid-2-13C. The bottle is attached to a Paar hydrogenation apparatus (Note 15), charged to 50 psig with hydrogen, and shaken at room temperature for 2 hr. The... 

Stereoselective Aldol Reactions. The (R)- and (S)-2-hydroxy-1,2,2-triphenylethyl acetates (HYTRA) offer a simple soludon for a stereoselecdve aldol addition of a-unsubstituted enolates. When a suspension of HYTRA is treated in THF with 2 equiv of Lithium Diisopropylamide, a clear soludon of the enolate forms (eq 1). Subsequent dilution with 2-methylbutane followed by the addition of 2-methylpropanal affords predominantly the (R,R)-diastereomeric adduct. Alkaline hydrolysis not only delivers (/ )-3-hydroxy-4-methylpentanoic acid in 86-94% ee but also liberates the optically pure auxiliary reagent (/ )-1,2,2-triphenylethane-1,2-diol, which can be removed and reused (eq 1). - ... 

Dihydroxyacid dehydratase (E.C. 4.2.1.9) is a ubiquitous enzyme that is involved in the biosynthesis of the branched-chain amino acids (lie, Leu and Val) and of pantothenic acid and coenzyme A. The enzyme catalyzes the elimination of water from 2,3-dihydroxyalkanoic acids (23) to 2-hydroxy-2-alkenoic acids (24), which tautomerize to 2-ketoalkanoic acids (25). The enzyme from spinach has the highest activity towards 2,3-dihydroxy-3-methylbutanoic acid (Val precursor, Scheme 11.5-4) but also accepts other substrates1341. Thus, 2,3-dihydroxybutanoic acid, 3-cyclopropyl-2,3-dihydroxybutanoic add as well as 2,3-dihydroxy-3-methylpentanoic acid are substrates. With the latter substrate a slight preference for (2R,3S)-2,3-dihydroxy-... 

The optical purity of 3-hydroxy-4-methylpentanoic acid is determined by shift measurements on the methyl ester. Chemical purity exceeds 98% according to GC. The submitters report consistent ee of 92-94% the checker s experience is recorded in the procedure. 

A superb example of this approach is the total synthesis of bleomycin A2 (252) reported by Hecht. Bleomycin was isolated by Umezawa and co-workers Q nd shown to be a potent anticancer agent.l69 While determining the structure, it was shown that hydrolyses and other chemical manipulations of 252 gave nine identifiable fragments (a) aminopropyldimethyl sulfonium (253) (b) 2-aminoethyl-2, 4-bithiazole-4 -carboxylic acid (254) (c) L-threonine (255) (d) (2f ,3S,4R)-4-amino-3-hydroxy-2-methylpentanoic acid (256) (e) L-eryr/zro-(3-hydroxyhistidine (258) (f) (3-amino-P-(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propionic acid (259) (g) a rearrangement product, L- 3-aminoalanine (257) (h) gulose (260) and, (j) carbamoyl mannose (261). 

The four diastereomers of 2-bromo-3-hydroxy-4-methylpentanoic acid are shown below, with the configuration of each stereocenter identified. 

Biosynthesis 0-Hydroxyethy )-TPP formed from pyruvic acid condenses with 2-oxobutanoic acid to give 2-acetyl-2-hydroxybutanoic acid. The latter is rearranged and reduced by acetolactate mutase (EC 5.4.99.3.) and NAD(P)H-dependent reductase to 2,3-di-hydroxy-3-methylpentanoic acid. Dehydration then furnishes 2-oxo-3-methylpentanoic which is finally transaminated to He. 

The structure elucidation of BLM was not straightforward because of the noncrystalline nature of the molecule [36]. An extensive degradation study indicated that BLM contains novel amino acid constituents and an unusual disaccharide, i.e., pyrimidoblamic acid (1), rytfcro-P-hydroxy-L-histidine (2), (2S, 35,4/ )-4-amino-3-hydroxy-2-methylpentanoic acid (3), 2 -(2-aminoethyl)-2,4 -bithiazole-4-carboxylic acid (4), and 2-0-(3-0-carbamoyl-a-D-mannopyranosyl)-a-L- u/opyranose (5) (Fig. 9). The sequence of the peptide bonding and the glycoside linkage was established by selective partial hydrolysis and, in 1978, the total structure was eventually determined by Takita et al. on the basis of further direct and indirect evidence (Fig. 1) [2]. 

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