# US 9,518,034 B2 · Synthesis of chiral enaminones, their derivatives, and bioactivity studies thereof

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- Number: US 9,518,034 B2
- Document ID: US9518034B2
- Status: Granted
- Kind: B2
- Application number: 14/514,001
- Filed: 2014-10-14
- Published: 2015-04-16
- Granted: 2016-12-13
- Earliest claimed: 2013-10-14
- Assignees: California Institute of Technology
- Applicants: California Institute of Technology
- Inventors: Brian M. Stoltz; Dennis A. Dougherty; Douglas Duquette; Noah Duffy
- Web page: https://patentgrep.com/patent/US9518034B2

## CPC

- C07D 295/116: with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring
- C07D 209/88: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention provides enantioenriched heterocyclic enaminone compounds with quaternary stereogenic centers and novel methods of preparing the compounds. Methods include the method for the preparation of a compound of formula (I): comprising treating a compound of formula (II): with a transition metal catalyst under alkylation conditions.

## Claims

### Claim 1

A method for the preparation of a compound of formula (I):
comprising treating a compound of formula (II):
with a transition metal catalyst under alkylation conditions, wherein, as valence and stability permit,
R1 and R2 are independently hydrogen or optionally substituted alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, or alkynyl; or
R1 and R2 are taken together to form an optionally substituted heterocyclic ring;
R3 is substituted or unsubstituted hydrogen, alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, alkenyl, alkynyl, or halo;
R4 is hydrogen, halogen, alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, alkenyl, or alkynyl;
R5, R6, R7, R8, R9, R10, R11, and R12 are independently selected for each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, arylalkoxy, heteroaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
W is CR13R13, O, S, or NR14;
R13 is selected, independently for each occurrence, from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, arylalkoxy, heteroaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
R14 is independently selected for each occurrence from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, or alkynyl;
wherein R2 and R4 may combine with the atoms to which they are attached to form an optionally substituted 4-9 membered heterocyclic ring, R4 and an occurrence of R13 may combine with the carbons to which they are attached to form an optionally substituted 3-8 membered ring, R4 and an occurrence of R14 may combine with the atoms to which they are attached to form an optionally substituted 4-8 membered heterocyclic ring, two occurrences of R13 may combine with the carbons to which they are attached to form a 3-8 membered ring, or an occurrence of R13 and an occurrence of R14 may combine with the atoms to which they are attached to form an optionally substituted 4-8 membered heterocyclic ring; and
n is an integer from 1-4.

### Claim 2 (depends on 1)

The method of claim 1, wherein R5,R6, R7, R8, R9, R10, R11, and R12 are each independently selected for each occurrence from hydrogen, halogen, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, and arylalkoxy.

### Claim 3 (depends on 1)

The method of claim 1, wherein R3 is selected from optionally substituted alkyl, aryl, aralkyl, haloalkyl, and hydroxyalkyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein W at each occurrence is CR13R13 and n is an integer from 1-3;and
wherein R13 is selected, independently for each occurrence, from hydrogen, halogen, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, and arylalkoxy.

### Claim 5 (depends on 1)

The method of claim 1, wherein R1and R2 taken together form an optionally substituted heterocyclic ring.

### Claim 6 (depends on 1)

The method of claim 1, wherein the transition metal catalyst comprises a transition metal selected from palladium, nickel, and platinum.

### Claim 7 (depends on 6)

The method of claim 6, wherein the transition metal catalyst comprises Pd2(dba)3 or Pd2(pmdba)3.

### Claim 8 (depends on 7)

The method of claim 7, wherein the transition metal catalyst is used in an amount from about 0.1 mol % to about 20 mol % total palladium relative to the compound of formula (II).

### Claim 9 (depends on 1)

The method of claim 1, wherein the transition metal catalyst further comprises an enantioenriched phosphine ligand.

### Claim 10 (depends on 9)

The method of claim 9, wherein the enantioenriched phosphine ligand is a phosphinooxazoline ligand.

### Claim 11 (depends on 10)

The method of claim 10, wherein the phosphinooxazoline ligand is selected from (S)—(CF3)3-tBuPHOX and (S)-tBuPHOX.

### Claim 12 (depends on 10)

The method of claim 10, wherein the ligand is used in an amount selected from 0.25 mol % to about 25 mol % relative to the compound of formula (II).

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound of formula (I) is enantioenriched.