# US 2016/0355495 A1 · Preparation method of chiral multiple substituted tetrahydropyran

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- Number: US 2016/0355495 A1
- Document ID: US20160355495A1
- Status: Published application
- Kind: A1
- Application number: 14/872,619
- Filed: 2015-10-01
- Published: 2016-12-08
- Earliest claimed: 2015-06-04
- Assignees: National Taiwan Normal University
- Applicants: National Taiwan Normal University
- Inventors: Kwunmin Chen; Ramani Gurubrahamam; You-Song Cheng
- Web page: https://patentgrep.com/patent/US20160355495A1

## CPC

- C07D 309/10: Oxygen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

An organocatalytic kinetic resolution of racemic secondary nitroallylic alcohols via Michael/acetalization sequence to give fully substituted tetrahydropyranols is described. The process affords the products with high to excellent stereoselectivities. The highly enantioenriched, less reactive (S)-nitroallylic alcohols were isolated with good to high chemical yields. The synthetic application of the resolved substrate is shown toward the synthesis of enantioenriched (+)-(2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid.

## Claims

### Claim 1

A preparation method of a chiral multiple substituted tetrahydropyran derivative which comprises:
subjecting the compound represented by formula (I) and the compound represented by formula (II) to Michael addition/acetalization reaction in the presence of an organic catalyst, a solvent and an acidic additive to form a crude product; and
isolating the crude product by column chromatography to obtain a chiral multiple substituted tetrahydropyran derivative and to isolate a (S)-configuration compound represented by formula (II),
wherein, R is a C1-4 alkyl, or a C1-4 alkoxy substituted with a C6-10 aryl; Ar is an unsubstituted C6-10 aryl, a C4-10 heterocycloaryl, or a C6-10 aryl or a C4-10 heterocycloaryl substituted with at least one substituent selected from a group consisting of a halogen, a C1-4 alkyl, a C1-4 alkoxy, a C6-10 aryl, a C6-10 aryl C1-4 alkoxy, and a nitro; and the chiral multiple substituted tetrahydropyran derivative is represented by formula (III),
wherein R and Ar are of same definition as those of formula (I) and formula (II).

### Claim 2 (depends on 1)

The preparation method of claim 1, wherein the organic catalyst is (S)-(−)-α,α-diphenylprolinoltrimethylsiloxane.

### Claim 3 (depends on 1)

The preparation method of claim 1, wherein the amount of the organic catalyst is 5 to 20 mole %.

### Claim 4 (depends on 1)

The preparation method of claim 1, wherein the amount of the acidic additive is 5 to 20 mole %.

### Claim 5 (depends on 1)

The preparation method of claim 1, wherein the solvent is a chlorine-containing non-protonic solvent.

### Claim 6 (depends on 1)

The preparation method of claim 1, wherein the concentration of the solvent is 0.5 to 1.0 M.

### Claim 7 (depends on 1)

The preparation method of claim 1, wherein the reaction temperature of the Michael addition/acetalization reaction is −20 to 23° C.

### Claim 8 (depends on 1)

The preparation method of claim 1, wherein the stoichiometric ratio of the compound of formula (I) and the compound of formula (II) is 1:1.

### Claim 9 (depends on 1)

The preparation method of claim 1, wherein R is methyl, ethyl or benzyloxy.

### Claim 10 (depends on 1)

The preparation method of claim 1, wherein Ar is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylpheyl, 4-methoxyphenyl, 4-benzyloxyphenyl, 4-nitrophenyl, 3-methoxyphenyl, 3,5-dibromo-4-methxoyphenyl, 2-naphthyl, 2-thienyl, or 2-fluorophenyl.

### Claim 11 (depends on 1)

The preparation method of claim 1, wherein the compound of formula (II) is (±)-[ethyl 2-hydroxy-3-nitro-4-phenylbut-3(E)-enoate].

### Claim 12 (depends on 1)

The preparation method of claim 1, wherein the prepared chiral multiple substituted tetrahydropyran derivative is L-idose-derived (2R, 3S, 4S, 5R)-multiple substituted tetrahydropyran.

### Claim 13 (depends on 1)

The preparation method of claim 1, wherein the (S)-configuration compound of formula (II) is (S)-(E)-ethyl 2-hydroxy-3-nitro-4-phenylbut-3-enoate.

### Claim 14 (depends on 1)

A preparation method of precursor of HIV-I protease inhibitor, which comprises subjecting the (S)-configuration compound of formula (II) of claim 1 to reduction reaction.