Fluorous tagging compounds and methods of use thereof

Details Fluorous tagging compounds and methods of use thereof Fluorous tagging compounds and methods of use thereof

2000-05-31

2004-01-06

Rotman, Alan L. (Department: 1625)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C570S241000

Reexamination Certificate

active

06673539

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to fluorous tagging or protecting compounds and to methods of use thereof, and especially, to fluorous tagging compounds suitable for use with hydyroxy- and amine-bearing organic compounds.
BACKGROUND OF THE INVENTION
In traditional organic chemistry, compounds are synthesized as pure substances through well-planned reactions and careful separation. However, in a number of fields, including drug discovery, catalyst design and new material development, tens of thousands of organic compounds must be synthesized and tested to discover a few active ones. In the pharmaceutical industry, for example, synthesizing such a large number of compounds in the traditional way is too slow compared to the rapid emergence of new biological targets. The productivity of orthodox solution (liquid) phase organic synthesis is severely limited by tedious separation processes for the purification of products. Techniques integrating organic reactions with rapid purification/separation procedures are thus highly desirable.
Recently, fluorous synthetic and separation techniques have attracted the interest of organic chemists. In fluorous synthetic techniques, reaction components are typically attached to fluorous groups or tags such as perfluoroalkyl groups to facilitate the separation of products. Organic compounds are readily rendered fluorous by attachment of an appropriately fluorinated phase label or tag. In general, fluorous-tagged molecules partition preferentially into a fluorous phase while non-tagged ones partition into an organic phase.
The fluorous tag preferably fulfills a double role as protective group and phase tag and is removed in the final step(s) of the synthesis. The viability of a fluorous synthesis plan depends greatly on the availability of suitable fluorous protecting groups, but only a few fluorous tags are currently available.
In that regard, the fluorous phase label or tag most often used in fluorous synthesis has been the silane (C
10
F
21
CH
2
CH
2
)
3
SiBr 1. In general, the silane is attached to alcohol-bearing substrates using standard conditions to result in a silyl ether, and can be cleaved with fluoride. The silane, however, cannot be recycled. In addition, the powerful electron withdrawing effect of three fluorous chains makes the silyl ether rather labile towards nucleophiles and other polar reactions. Thus, although fluorous synthetic and/or separation techniques are promising, such techniques are currently limited by a lack of availability of suitably versatile fluorous tags.
It is thus very desirable to develop improved fluorous tagging compounds.
SUMMARY OF THE INVENTION
For the further development of fluorous phase chemistry into a practical strategy in, for example, combinatorial and parallel synthesis, a variety of fluorous phase labels must be made available. The present invention provides fluorous tags that can be prepared in large quantity, can be installed and removed from a substrate using mild reaction conditions, and can be recyclable after cleavage. In addition, the fluorous tags of the present invention are tolerant, as a group, to a wide range of reaction conditions, such that an appropriate label can be chosen which is amenable to substantially any given sequence of reactions.
The resulting fluorous “tagged” compound can be used in a wide variety of fluorous reaction and/or separation techniques. Several fluorous reaction and separation techniques are disclosed, for example, in U.S. Pat. Nos. 5,859,247 and 5,777,121, the disclosures of which are incorporated herein by reference. The tagging compounds of the present invention are particularly suitable for tagging of compounds bearing hydroxyl groups or nitrogen groups such as amine groups.
As used herein, the term “fluorous”, when used in connection with an organic (carbon-containing) molecule, moiety or group, refers generally to an organic molecule, moiety or group having a domain or a portion thereof rich in carbon-fluorine bonds (for example, fluorocarbons or perfluorocarbons, fluorohydrocarbons, fluorinated ethers, fluorinated amines and fluorinated adamantyl groups). For example, perfluorinated ether groups can have the general formula —[(CF
2
)
x
O(CF
2
)
y
]
z
CF
3
, wherein x, y and z are integers. Perfluorinated amine groups can, for example, have the general formula —[(CF
2
)
x
(NR
a
)CF
2
)
y
]
z
CF
3
, wherein R
a
can, for example, be (CF
2
)
n
CF
3
, wherein n is an integer. Fluorous ether groups and fluorous amine groups suitable for use in the present invention need not be perfluorinated, however. The term “fluorous compound,” thus refers generally to a compound comprising a portion rich in carbon-fluorine bonds. As used herein, the term “perfluorocarbons” refers generally to organic compounds in which all hydrogen atoms bonded to carbon atoms have been replaced by fluorine atoms. The terms “fluorohydrocarbons” and “hydrofluorocarbons” include organic compounds in which at least one hydrogen atom bonded to a carbon atom has been replaced by a fluorine atom. A few examples of suitable fluorous groups Rf for use in the present invention include, but are not limited to, —C
4
F
9
, —C
6
F
13
, —C
8
F
17
, —C
10
F
21
, —C(CF
3
)
2
C
3
F
7
, —C
4
F
8
CF(CF
3
)
2
, —CF
2
CF
2
OCF
2
CF
2
OCF
3
, —CF
2
CF
2
(NCF
2
CF
3
)CF
2
CF
2
CF
3
, and fluorous adamantyl groups.
As used herein, the term “tagging” refers generally to attaching a fluorous moiety or group (referred to as a “fluorous tagging moiety” or “tagging group”) to a compound to create a “fluorous tagged compound”. Separation of the tagged compounds of the present invention is achieved by using fluorous separation techniques that are based upon differences between/among the fluorous nature of a mixture of compounds. As used herein, the term “fluorous separation technique” refers generally to a method that is used to separate mixtures containing fluorous molecules or organic molecules bearing fluorous domains or tags from each other and/or from non-fluorous compounds based predominantly on differences in the fluorous nature of molecules (for example, size and/or structure of a fluorous molecule or domain or the absence thereof). Fluorous separation techniques include but are not limited chromatography over solid fluorous phases such as fluorocarbon bonded phases or fluorinated polymers. See, for example, Danielson, N. D. et al., “Fluoropolymers and Fluorocarbon Bonded Phases as Column Packings for Liquid Chromatography,”
J. Chromat.,
544, 187-199 (1991). Examples of suitable fluorocarbon bonded phases include commercial Fluofix® and Fluophase™ columns available from Keystone Scientific, Inc. (Bellefonte, Pa), and FluoroSep™-RP-Octyl from ES Industries (Berlin, N.J.). Other fluorous separation techniques include liquid-liquid based separation methods such as liquid-liquid extraction or countercurrent distribution with a fluorous solvent and an organic solvent.
Preferably, the molecular weight of the fluorous tags of the present invention does not exceed about 2,500. More preferably, the molecular weight does not exceed about 1,750. Even more preferably the molecular weight does not exceed about 1200. Compounds may bear more than one fluorous tag of the present invention.
In one aspect, the present invention provides a method of increasing the fluorous nature of a compound, including the step of reacting the compound with at least one second compound having the formula:
wherein Rf is a fluorous group and m is 0, 1 or 2 (that is, the ring can be a five-, six-, or seven-membered ring) The fluorous group can, for example be a fluorohydrocarbon group (for example, fluorous alkyl groups, including fluorous adamantyl groups), a perfluorocarbon group, a fluorinated ether group or a fluorinated amine group. Perfluoroadamantyl group suitable for use in the present invention can, for example, have the following formulas:
As used herein, the terms “alkyl”, “aryl” and other substituent groups refer generally to both unsubstituted and substituted groups unless specified to

Affiliated with

Also associated with

Rating

Fluorous tagging compounds and methods of use thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Fluorous tagging compounds and methods of use thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fluorous tagging compounds and methods of use thereof will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3208059