# US 8,541,625 B2 · Cyclopropenones and the photochemical generation of cyclic alkynes therefrom

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- Number: US 8,541,625 B2
- Document ID: US8541625B2
- Status: Granted
- Kind: B2
- Application number: 13/567,509
- Filed: 2012-08-06
- Published: 2012-11-22
- Granted: 2013-09-24
- Earliest claimed: 2009-02-19
- Assignees: University of Georgia Research Foundation, Inc.
- Applicants: Vladimir V. Popik; Andrei A. Poloukhtine; Geert-Jan Boons; Margaretha Wolfert
- Inventors: Vladimir V. Popik; Andrei A. Poloukhtine; Geert-Jan Boons; Margaretha Wolfert
- Web page: https://patentgrep.com/patent/US8541625B2

## CPC

- C07D 249/16: condensed with carbocyclic rings or ring systems
- C07C 41/18: by reactions not forming ether-oxygen bonds
- C07C 43/215: having unsaturation outside the six-membered aromatic rings
- C07C 43/23: containing hydroxy or O-metal groups
- C07C 49/753: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07D 495/04: Ortho-condensed systems
- C07C 2603/36: containing eight-membered rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Cyclic alkynes (e.g., cyclooctynes such as dibenzocyclooctynes) can be photochemically generated from cyclopropenones as disclosed herein. The cyclic alkynes can be reacted (e.g., in situ) with materials having alkyne-reactive groups (e.g., azide groups in a “click” reaction). In preferred embodiments, the generation and reaction of the cyclic alkyne can proceed in the absence of a catalyst (e.g., Cu(I)). These reactions can be useful, for example, for the selective labeling of living cells that are metabolically modified with azido-containing surface monosaccharides, or for light-directed surface patterning.

## Claims

### Claim 1

A compound of the formula:
wherein:
each Ar is a group independently representing a monocyclic or polycyclic, aromatic or heteroaromatic ring;
E represents O, NR6, or +N(R6)2;
each R4 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, a C1-C10 organic group, and a linking group; and
each R6 is independently hydrogen, a C1-C10 organic group, or a linking group.

### Claim 2 (depends on 1)

The compound of claim 1 wherein each Ar is a phenyl group.

### Claim 3 (depends on 2)

The compound of claim 2 wherein one or more carbon atoms of one or both phenyl groups are substituted with a substituent selected from the group consisting of alkyl, aryl, heteroaryl, halogen, nitro, cyano, hydroxyl, alkoxyl, aryloxyl, thio, mercapto, alkylthio, arylthio, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aldehyde, arylcarbonyl, alkylcarbonyl, iminyl, aryliminyl, alkyliminyl, sulfo, alkylsulfonyl, arylsulfonyl, hydroximinyl, aryloximinyl, and alkoximinyl; and
wherein two or more alkyl or heteroalkyl substituents of a phenyl group may optionally be combined to form fused aryl-alkyl or aryl-heteroalkyl ring systems.

### Claim 4 (depends on 2)

The compound of claim 2 wherein one or more carbon atoms of one or both phenyl groups are substituted with a PEGylated or biotinylated group.

### Claim 5 (depends on 4)

The compound of claim 4 wherein the biotinylated group has the formula:

### Claim 6

A compound of the formula:
wherein:
each Ar is a group independently representing a monocyclic or polycyclic, aromatic or heteroaromatic ring;
E represents an oxygen atom; and
each R4 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, a C1-C10 organic group, and a linking group.

### Claim 7 (depends on 6)

The compound of claim 6 wherein each Ar is a phenyl group.

### Claim 8 (depends on 7)

The compound of claim 7 wherein one or more carbon atoms of one or both phenyl groups are substituted with a substituent selected from the group consisting of alkyl, aryl, heteroaryl, halogen, nitro, cyano, hydroxyl, alkoxyl, aryloxy, thio, mercapto, alkylthio, arylthio, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aldehyde, arylcarbonyl, alkylcarbonyl, iminyl, aryliminyl, alkyliminyl, sulfo, alkylsulfonyl, arylsulfonyl, hydroximinyl, aryloximinyl, and alkoximinyl; and
wherein two or more alkyl or heteroalkyl substituents of a phenyl group may optionally be combined to form fused aryl-alkyl or aryl-heteroalkyl ring systems.

### Claim 9 (depends on 7)

The compound of claim 7 wherein one or more carbon atoms of one or both phenyl groups are substituted with a PEGylated or biotinylated group.

### Claim 10 (depends on 9)

The compound of claim 9 wherein the biotinylated group has the formula:

### Claim 11

A compound of the formula:
wherein:
each Ar is a group independently representing a monocyclic or polycyclic, aromatic or heteroaromatic ring;
E represents an oxygen atom;
R3 represents a organic group; and
each R4 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, a C1-C10 organic group, and a linking group.

### Claim 12 (depends on 11)

The compound of claim 11 wherein each Ar is a phenyl group.

### Claim 13 (depends on 12)

The compound of claim 12 wherein one or more carbon atoms of one or both phenyl groups are substituted with a substituent selected from the group consisting of alkyl, aryl, heteroaryl, halogen, nitro, cyano, hydroxyl, alkoxyl, aryloxyl, thio, mercapto, alkylthio, arylthio, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aldehyde, arylcarbonyl, alkylcarbonyl, iminyl, aryliminyl, alkyliminyl, sulfo, alkylsulfonyl, arylsulfonyl, hydroximinyl, aryloximinyl, and alkoximinyl; and
wherein two or more alkyl or heteroalkyl substituents of a phenyl group may optionally be combined to form fused aryl-alkyl or aryl-heteroalkyl ring systems.

### Claim 14 (depends on 12)

The compound of claim 12 wherein one or more carbon atoms of one or both phenyl groups are substituted with a PEGylated or biotinylated group.

### Claim 15 (depends on 14)

The compound of claim 14 wherein the biotinylated group has the formula:

### Claim 16

A method of photochemically inducing the reaction of two materials, the method comprising:
photochemically generating a cyclic alkyne from a cyclopropenone of the formnula:
wherein each Ar is a group independently representing a monocyclic or polycyclic, aromatic or heteroaromatic ring; E represents O, NR6, or +N(R6)2; each R4 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, a C1-C10 organic group, and a linking group; and each R6 is independently hydrogen, a C1-C10 organic group, or a linking group; and
contacting the cyclic alkyne with a material comprising an alkyne-reactive group under conditions effective for the cyclic alkyne and the material comprising the alkyne-reactive group to react.

### Claim 17 (depends on 16)

The method of claim 16 wherein each Ar is a phenyl group.

### Claim 18 (depends on 17)

The method of claim 17 wherein one or more carbon atoms of one or both phenyl groups are substituted with a substituent selected from the group consisting of alkyl, aryl, heteroaryl, halogen, nitro, cyano, hydroxyl, alkoxyl, aryloxyl, thio, mercapto, alkylthio, arylthio, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aldehyde, arylcarbonyl, alkylcarbonyl, iminyl, aryliminyl, alkyliminyl, sulfo, alkylsulfonyl, arylsulfonyl, hydroximinyl, aryloximinyl, and alkoximinyl; and
wherein two or more alkyl or heteroalkyl substituents of a phenyl group may optionally be combined to form fused aryl-alkyl or aryl-heteroalkyl ring systems.

### Claim 19 (depends on 16)

The method of claim 16 wherein the method photochemically induces the ligation of the cyclic alkyne and the material comprising the alkyne-reactive group.

### Claim 20 (depends on 16)

The method of claim 16 wherein the method forms a cyclic adduct.

### Claim 21 (depends on 20)

The method of claim 20 wherein the material comprising the alkyne-reactive group is a 1,3-dipole-functional compound.

### Claim 22 (depends on 21)

The method of claim 21 wherein the cyclic adduct is a heterocyclic compound.

### Claim 23 (depends on 22)

The method of claim 22 wherein the 1,3-dipole-functional compound is selected from the group consisting of azide-functional compounds, nitrile oxide-functional compounds, nitrone-functional compounds, azoxy-functional compounds, acyl diazo-functional compounds, and combinations thereof.

### Claim 24 (depends on 23)

The method of claim 23 wherein the 1,3-dipole-functional compound is an azide-functional compound, and the cyclic adduct is a triazole.

### Claim 25 (depends on 24)

The method of claim 24 wherein the azide-functional compound or the cyclic alkyne is bound to the surface of a substrate or integrated into a substrate layer.

### Claim 26 (depends on 25)

The method of claim 25 wherein the substrate is a solid substrate or a cell membrane.

### Claim 27 (depends on 25)

The method of claim 25 wherein the azide-functional compound is bound to the surface of a substrate or integrated into a substrate layer, and the cyclic alkyne is a ligand that binds to the azide.

### Claim 28 (depends on 27)

The method of claim 27 wherein the azide ligand or the cyclic alkyne ligand is a detectable label.

### Claim 29 (depends on 24)

The method of claim 24 wherein the azide-functional compound is selected from the group consisting of: an alkyl azide, a heteroalkyl azide, a cycloalkyl azide, a heterocycloalkyl azide, an alkylamino azide, a benzyl azide, an aryl azide, an alkyacyl azide, and an arylacyl azide.

### Claim 30 (depends on 24)

The method of claim 24 wherein photochemically generating the cyclic alkyne comprises irradiating the cyclopropenone with light having a wavelength selectively absorbed by the cyclopropenone, and substantially not absorbed by the cyclic alkyne or by the trizaole.

### Claim 31 (depends on 30)

The method of claim 30 wherein the wavelength of light is from about 220 nm to about 450 nm.

### Claim 32 (depends on 24)

The method of claim 24 wherein the triazole has the foimula:
wherein:
each Ar is a group independently representing a monocyclic or polycyclic, aromatic or heteroaromatic ring;
E represents O, NR6, or +N(R6)2;
R3 represents an organic group;
each R4 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, nitrate, nitrite, sulfate, a C1-C10 organic group, and a linking group; and
each R6 is independently hydrogen, a C1-C10 organic group, or a linking group.

### Claim 33 (depends on 20)

The method of claim 20 wherein the material comprising the alkyne-reactive group is a diene, and the cyclic adduct is a Diels-Alder adduct.

### Claim 34 (depends on 20)

The method of claim 20 wherein the material comprising the alkyne-reactive group is a nitrosoarene, and the cyclic adduct is an N-hydroxy indole.

### Claim 35 (depends on 20)

The method of claim 20 wherein the material comprising the alkyne-reactive group is a metal-containing compound.

### Claim 36 (depends on 35)

The method of claim 35 wherein the metal-containing compound is a four- or five-memebered platinacycle.

### Claim 37 (depends on 20)

The method of claim 20 wherein the material comprising the alkyne-reactive group is carbon monoxide, the method further comprising contacting the cyclic alkyne with an alkene, and the cyclic adduct is a [2+2+1] cycloaddition product.

### Claim 38 (depends on 16)

The method of claim 16 wherein the material comprising the alkyne-reactive group is a metal carbene complex, the method further comprising contacting the cyclic alkyne with an alkene under conditions effective to form a butadiene.

### Claim 39 (depends on 36)

The method of claim 36 wherein the method comprises enyne metathesis.

### Claim 40 (depends on 16)

The method of claim 16 wherein the material comprising the alkyne-reactive group is an alkyne, the method further comprising contacting the cyclic alkyne with a metal catalyst under conditions effective to form a different alkyne.

### Claim 41 (depends on 40)

The method of claim 40 wherein the method comprises alkyne metathesis.

### Claim 42 (depends on 17)

The method of claim 17 wherein one or more carbon atoms of one or both phenyl groups are substituted with a PEGylated or biotinylated group.

### Claim 43 (depends on 42)

The method of claim 42 wherein the biotinylated group has the formula:

### Claim 44 (depends on 25)

The method of claim 25 wherein the cyclic alkyne is bound to the surface of a substrate or integrated into a substrate layer, and the azide-functional compound is a ligand that binds to the cyclic alkyne.