21704-86-9

Usage

Chemical Properties

Light Yellow Solid

Uses

Used as a treatment for type II diabetes

InChI:InChI=1/C6H13NO3/c1-3(4(2)8)5(7)6(9)10/h3-5,8H,7H2,1-2H3,(H,9,10)/t3-,4?,5-/m0/s1

Upstream product

• 600-18-0 2-Oxobutyric acid 
• 75-07-0 acetaldehyde 
• 55527-86-1 (3S,4R,5S)-3-amino-4,5-dimethyldihydrofuran-2(3H)-one 
• 55527-85-0 (3S,4R,5R)-3-Amino-4,5-dimethyl-dihydro-furan-2-one 
• 1093653-23-6 C₇H₁₁NO₃ 
• 885054-35-3 C₆H₁₁NO₂ 
• 71392-28-4 (3S,4S,5R)-3-amino-4,5-dimethyldihydrofuran-2(3H)-one 
• 916751-12-7 (2S,3S,4R)-2-(trichloromethylcarbonylamino)-3-methyl-4-methoxymethoxypentanoic acid 
• 911099-44-0 (3S,4S,5R/5S)-3-amino-4,5-dimethyltetrahydro-2-furanone 
• 942208-46-0 C₇H₁₂N₂O₃ 
• 168610-73-9 4-hydroxyisoleucine γ-lactone 
• 950204-60-1 (2R,4S,5R,6S)-5,6-dimethyl-2-phenyl-tetrahydro-2H-1,3-oxazin-4-carboxylic acid 

Downstream Products

• 71392-28-4 (3S,4S,5R)-3-amino-4,5-dimethyldihydrofuran-2(3H)-one 
• 55527-86-1 (3S,4R,5S)-3-amino-4,5-dimethyldihydrofuran-2(3H)-one 

Relevant academic research and scientific papers

An organocatalyzed enantioselective synthesis of (2S,3R,4S)-4- hydroxyisoleucine and its stereoisomers

A concise enantioselective total synthesis of (2S,3R,4S)-4- hydroxyisoleucine and its stereoisomers is described. A key feature of this protocol is a catalytic enantioselective mannich reaction that is either anti- or syn-selective as genesis of chirality.

Engineering Bacillus subtilis Isoleucine Dioxygenase for Efficient Synthesis of (2 S,3 R,4 S)-4-Hydroxyisoleucine

Isoleucine dioxygenase (IDO)-catalyzed hydroxylation of isoleucine is a promising method for the synthesis of the diabetic drug (2S,3R,4S)-4-hydroxyisoleucine [(2S,3R,4S)-4-HIL]. However, the low activity of IDO significantly limits its practical application. In this work, a high-throughput screening method was developed and directed evolution was performed on the IDO from Bacillus subtilis, resulting in a double mutant with improvements in specific activity, protein expression level, and fermentation titer of 3.2-, 2.8-, and 9.4-fold, respectively. l-Isoleucine (228 mM) was completely converted to (2S,3R,4S)-4-HIL by the best variant with a space-time yield of up to 80.8 g L-1 d-1, which is the highest record reported so far. With a further increase of the substrate loading to 1 M, a high conversion of 91% could also be achieved. At last, enzymatic synthesis of (2S,3R,4S)-4-HIL was successfully carried out on a 3 L scale, indicating tremendous potential of the IDO variant I162T/T182N for green and efficient production of (2S,3R,4S)-4-HIL.

New synthetic routes toward enantiopure (2S,3R,4R)-4-hydroxyisoleucine by 1,3-dipolar cycloaddition of a chiral nitrone to C4 alkenes

1,3-Dipolar cycloaddition reaction of a chiral nitrone derived from (-)-menthone to E/Z mixtures of crotonaldehyde or (Z)-but-2-en-1,4-diol opens, by simultaneous creation of three contiguous asymmetric centers, new access to enantiopure (2S,3R,4R)-4-hydroxyisoleucine, respectively in 13% (7 steps) and 34% (6 steps) overall yield. Georg Thieme Verlag Stuttgart.

Synthesis of hydantoin analogues of (2S,3R,4S)-4-hydroxyisoleucine with insulinotropic properties

The first synthesis of an optically pure (2R,3R,4S)-hydantoin 2, analogue of (2S,3R,4S)-4-hydroxyisoleucine, was achieved in two steps in un-optimized 35% overall yield from previously reported aldehyde synthon 1. (2R,3R,4S)-Hydantoin is stable at acidic pH. This solves the major drawback of (2S,3R,4S)-4-hydroxyisoleucine that easily cyclizes into inactive lactone. Furthermore, (2R,3R,4S)-hydantoin stimulates the insulin secretion by 150% at 25 μM compared with 4-hydroxyisoleucine and insulin secretagogue drug repaglinide. In view of its stability and biological activity, (2R,3R,4S)-hydantoin represents a good candidate for type-2 diabetes management and control.

1,3-Dipolar cycloaddition of a chiral nitrone to (E)-1,4-dichloro-2-butene: A new efficient synthesis of (2S,3S,4R)-4-hydroxyisoleucine

1,3-Dipolar cycloaddition of a chiral nitrone derived from (-)-menthone to (E)-1,4-dichlorobut-2-ene was the key step in a novel 5 step synthesis of (2S,3S,4R)-4-hydroxyisoleucine, obtained in 21% overall yield with high enantiopurity.

Repurposing Nonheme Iron Hydroxylases to Enable Catalytic Nitrile Installation through an Azido Group Assistance

Three mononuclear nonheme iron and 2-oxoglutarate dependent enzymes, l-Ile 4-hydroxylase, l-Leu 5-hydroxylase and polyoxin dihydroxylase, are previously reported to catalyze the hydroxylation of l-isoleucine, l-leucine, and l-α-amino-δ-carbamoylhydroxyvaleric acid (ACV). In this study, we showed that these enzymes can accommodate leucine isomers and catalyze regiospecific hydroxylation. On the basis of these results, as a proof-of-concept, we demonstrated that the outcome of the reaction can be redirected by installation of an assisting group within the substrate. Specifically, instead of canonical hydroxylation, these enzymes can catalyze non-native nitrile group installation when an azido group is introduced. The reaction is likely to proceed through C - H bond activation by an Fe(IV)-oxo species, followed by azido-directed C-N bond formation. These results offer a unique opportunity to investigate and expand the reaction repertoire of Fe/2OG enzymes.

Attempt to simultaneously generate three chiral centers in 4-hydroxyisoleucine with microbial carbonyl reductases

A panel of microorganisms was screened for selective reduction ability towards a racemic mixture of prochiral 2-amino-3-methyl-4-ketopentanoate (rac-AMKP). Several of the microorganisms tested produced greater than 0.5 mM 4-hydroxyisoleucine (HIL) from rac-AMKP, and the stereoselectivity of HIL formation was found to depend on the taxonomic category to which the microorganism belonged. The enzymes responsible for the AMKP-reducing activity, ApAR and FsAR, were identified from two of these microorganisms, Aureobasidium pullulans NBRC 4466 and Fusarium solani TG-2, respectively. Three AMKP reducing enzymes, ApAR, FsAR, and the previously reported BtHILDH, were reacted with rac-AMKP, and each enzyme selectively produced a specific composition of HIL stereoisomers. The enzymes appeared to have different characteristics in recognition of the stereostructure of the substrate AMKP and in control of the 4-hydroxyl group configuration in the HIL product.

A practical and efficient total synthesis of potent insulinotropic (2S,3R,4S)-4-Hydroxyisoleucine through a chiral N-protected γ-keto- α-aminoester

(2S,3R,4S)-4-Hydroxyisoleucine, which exhibits remarkable insulinotropic activity, is expected to be a potent drug to treat type II diabetes. We propose herein a four-step synthesis of the enantiopure natural product on the basis of successive Mannich condensation, catalytic epimerization, N-paramethoxyphenyl deprotection, and diastereoselective reduction. This compact economical and scalable sequence enables to perfectly control three contiguous chiral centers. It does not involve any chromatographic purification, and the desired compound is obtained in >99 % de, >99 % ee, and 22 % overall yield under our optimized conditions.

METHOD FOR PRODUCING 4-HYDROXY-L-ISOLEUCINE

A highly active L-isoleucine dioxygenase from Bacillus thuringiensis is provided. A method for manufacturing (2S,3R,4S)-4-hydroxy-L-isoleucine or a salt thereof by reacting L-isoleucine in an aqueous solvent in the presence of L-isoleucine dioxygenase and isolating (2S,3R,4S)-4-hydroxy-L-isoleucine is also provided.

METHOD FOR PURIFYING 4-HYDROXYISOLEUCINE

The present invention aims to provide a method of conveniently isolating and purifying as well as separating and removing (2S,3R,4S)-4-hydroxyisoleucine at a high purity and in a high yield. Specifically, the present invention discloses a purification method of (2S,3R,4S)-4-hydroxyisoleucine or a chemically acceptable salt thereof, which includes the following steps (a), (b) and (c): (a) a step of reacting (2S,3R,4S)-4-hydroxyisoleucine or a chemically acceptable salt thereof in a mixture with an aldehyde compound represented by the formula: Q-CHO wherein Q is an aryl group having a carbon number of 6 to 14, an alkyl group having a carbon number of 1 to 10, a cycloalkyl group having a carbon number of 3 to 10 or a 5- to 10-membered heterocyclic group, each of which optionally has substituent(s), or an equivalent form thereof to give a compound represented by the formula (1) wherein Q is as defined above, (b) a step of extracting the compound represented by the formula (1) with an organic solvent, and (c) a step of converting the compound represented by the formula (1) to (2S,3R,4S)-4-hydroxyisoleucine or a chemically acceptable salt thereof.