U.S. patent application number 12/507073 was filed with the patent office on 2010-01-28 for reaction and separation methods.
Invention is credited to Dennis P. Curran, Oscar de Frutos Garcia, Yoji Oderaotoshi.
Application Number | 20100018920 12/507073 |
Document ID | / |
Family ID | 24015980 |
Filed Date | 2010-01-28 |
United States Patent
Application |
20100018920 |
Kind Code |
A1 |
Curran; Dennis P. ; et
al. |
January 28, 2010 |
REACTION AND SEPARATION METHODS
Abstract
A method of separating compounds that includes the steps of:
tagging at least a first organic compound with a first tagging
moiety to result in a first tagged compound; tagging at least a
second organic compound with a second tagging moiety different from
the first tagging moiety to result in a second tagged compound; and
separating the first tagged compound from a mixture including the
second tagged compound using a separation technique based upon
differences between the first tagging moiety and the second tagging
moiety. Preferably, the separation technique is based upon
difference in the fluorous nature of the first tagged compound and
the second tagged compound, differences in total charge between the
first tagged compound and the second tagged compound, differences
in size between the first tagged compound and the second tagged
compound, and/or differences in polarity between the first tagged
compound and the second tagged compound. The present invention also
provides a method for carrying out a chemical reaction including
the steps of: tagging a plurality of compounds with different
tagging moieties to create tagged compounds, conducting at least
one chemical reaction on a mixture of the tagged compounds to
produce a mixture of tagged products, and separating the mixture of
tagged products by a separation technique based upon differences in
the tagging moieties.
Inventors: |
Curran; Dennis P.;
(PITTSBURGH, PA) ; de Frutos Garcia; Oscar;
(MADRID, ES) ; Oderaotoshi; Yoji; (ONOJOU,
JP) |
Correspondence
Address: |
BARTONY & HARE, LLP
1806 FRICK BUILDING, 437 GRANT STREET
PITTSBURGH
PA
15219-6101
US
|
Family ID: |
24015980 |
Appl. No.: |
12/507073 |
Filed: |
July 22, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10831087 |
Apr 23, 2004 |
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12507073 |
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09506779 |
Feb 18, 2000 |
6749756 |
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10831087 |
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Current U.S.
Class: |
210/635 ;
210/668 |
Current CPC
Class: |
G01N 2030/8845 20130101;
C07B 63/00 20130101; G01N 27/44726 20130101; G01N 2030/884
20130101 |
Class at
Publication: |
210/635 ;
210/668 |
International
Class: |
B01D 15/08 20060101
B01D015/08 |
Goverment Interests
GOVERNMENT INTERESTS
[0002] This invention was made with government support under grant
number Grant No. GM33372 awarded by the National Institutes of
Health. The government has certain rights in this invention.
Claims
1. A method for carrying out a liquid phase chemical reaction,
comprising: tagging a plurality of compounds with different tagging
moieties to create tagged compounds, conducting at least one
chemical reaction on the tagged compounds to produce a mixture of
tagged products in a liquid phase, and physically separating at
least one of the tagged products from the mixture of tagged
products by a method based upon differences in the tagging
moieties.
2. The method of claim 2 further including the step of removing the
tagging moieties from the tagged products.
3. The method of claim 2 wherein the tagging moieties are fluorous
moieties that differ in fluorous nature.
4. The method of claim 3 wherein the fluorous tagging moieties
differ in fluorine content or structure.
5. The method of claim 3 wherein the tagged products are separated
by using fluorous reverse phase chromatography.
6. The method of claim 1 wherein a first plurality of compounds is
tagged with a first tagging moiety and mixed with other tagged
compounds that are tagged with tagging moieties different from the
first tagging moiety.
7. The method of claim 6 wherein the separation of the tagged
products provides mixtures of product compounds bearing the same
initial tag.
8. The method of claim 1 wherein the tagged compounds are reacted
with a mixture of different starting compounds.
9. The method of claim 1 wherein the tagged compounds are
selectively tagged with different tagging moieties such that the
tagged products separate into fractions of known identity as
determined by the tagging moieties.
10. A method for carrying out a liquid phase chemical reaction,
comprising: tagging a plurality of compounds with different
fluorous tagging moieties to create tagged compounds, conducting at
least one chemical reaction on the tagged compounds to produce a
mixture of tagged products in a liquid phase, and physically
separating at least one of the tagged products from the mixture of
tagged products by a method based upon differences in the fluorous
nature of the tagging moieties.
11. The method of claim 10 further including the step of removing
the fluorous tagging moieties from the tagged products.
12. The method of claim 10 wherein the fluorous tagging moieties
differ in fluorine content or structure.
13. The method of claim 12 wherein the tagged products are
separated using fluorous reverse phase chromatography.
14. The method of claim 10 wherein a first plurality of compounds
is tagged with a first tagging moiety and mixed with other tagged
compounds that are tagged with tagging moieties different from the
first tagging moiety.
15. The method of claim 10 wherein the separation of the tagged
products provides mixtures of product compounds bearing the same
initial tag.
16. The method of claim 10 wherein the tagged compounds are reacted
with a mixture of different starting compounds.
17. The method of claim 10 wherein a first plurality of compounds
is tagged with a first fluorous tagging moiety and mixed with other
tagged compounds that are tagged with fluorous tagging moieties
different from the first tagging moiety.
18. The method of claim 17 wherein the separation of the tagged
products provides mixtures of product compounds bearing the same
initial tag.
19. The method of claim 18 wherein the tagged compounds are reacted
with a mixture of different starting compounds.
20. The method of claim 10 wherein the tagged compounds are
selectively tagged with different tagging moieties such that the
tagged products separate into fractions of known identity as
determined by the tagging moieties.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 10/831,087, filed Apr. 23, 2004, which
is a divisional application of U.S. patent application Ser. No.
09/506,779, filed Feb. 18, 2000, now U.S. Pat. No. 6,749,756, the
disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0003] The present invention relates to methods of carrying out
reactions and separations, and, especially, to reactions and
separations involving tagging.
BACKGROUND OF THE INVENTION
[0004] Interest in expediting the synthesis of organic compounds
for use as potential drugs, agricultural agents, catalysts, ligands
and other uses has led to the development of a number of methods
for synthesis that use "mixtures" of organic compounds rather than
pure organic compounds. Simple mathematics demonstrates the
potential power of mixture synthesis. For example, to execute a
parallel (or sequential) n-step synthesis starting from m different
starting materials requires n.cndot.m individual reactions with all
the attendant equipment (for example, reaction vessels) and
manipulations (transfers, workups, chromatography, etc). However,
if the m compounds are mixed at the beginning, and then carried
through the n-step synthesis and separated, only n separate steps
are required.
[0005] The value of mixture synthesis has recently been
demonstrated in the area of solid phase synthesis with techniques
of split synthesis. For example, by using "one bead/one compound"
techniques, large libraries of compounds can be made in relatively
few steps. See, for example, Lam, K. S., et al., "The
`One-Bead-One-Compound` Combinatorial Library Method," Chem. Rev.,
96, 411-488 (1996); Thompson, L. A. and Ellman, J. A., "Synthesis
and Applications of Small Molecule Libraries," Chem. Rev., 96,
555-600 (1996). Each bead is effectively a kind of reaction vessel
that permanently holds its "contents" (substrates and their
products) by chemical bonds. The beads are mixed, not the
compounds. Likewise, methods such as using "tea bags", "microkans",
and other physical equipment have been introduced to facilitate
mixture synthesis. However, in all those solid phase synthesis
techniques it is the container of the supported substrates that is
mixed. The substrates themselves are polymer-bound and are not
mixed. Such solid phase synthesis techniques are typically limited
by difficulty in developing suitable reaction conditions for
generally biphasic reactions.
[0006] Organized mixtures of organic molecules (libraries) have
also been generated by using solution phase chemistry. See, for
example, Houghten, R. A., "Mixture-Based Synthetic Combinatorial
Libraries," J. Med. Chem., 42, 3743-3778 (1999). Although such
libraries can be made in different ways, a common thread in that
approach is that no effort is made to separate the mixture into
individual pure components. Instead, libraries and sub-libraries
are constructed and assays are conducted such that an active
component (or components) can be identified by a process of
deconvolution. Deconvolution processes are generally methods which
attempt to identify the most active members of a library of
compounds without isolating the individual components of the
library. In general, mixtures of compounds are tested to measure an
average activity of the mixture. Mixtures can be separated by HPLC
fractionation or other standard techniques for separation of
organic molecules, but the separation typically does not provide
pure components since mixture components overlap. See, for example,
Griffey, H. Y., "Rapid Deconvolution of Combinatorial Libraries
Using HPLC Fractionation," Tetrahedron, 54, 4067-4076 (1998).
Further, the outcome of the separation (that is, which fractions
are pure and which are mixtures, as well as which fraction contains
which compound(s)) is not generally known in advance.
[0007] It is very desirable to develop improved reaction and
separation systems to, for example, enhance the utility of mixture
synthesis.
SUMMARY OF THE INVENTION
[0008] In general, the present invention provides a method of
separating compounds that includes the steps of: tagging a first
organic compound with a first tagging moiety to result in a first
tagged compound; tagging at least a second organic compound with a
second tagging moiety different from the first tagging moiety to
result in a second tagged compound; and separating the first tagged
compound from a mixture including the second tagged compound using
a separation technique based upon differences between the first
tagging moiety and the second tagging moiety. Preferably, the
separation technique is based upon difference in the fluorous
nature of the first tagged compound and the second tagged compound,
differences in total charge between the first tagged compound and
the second tagged compound, differences in size between the first
tagged compound and the second tagged compound, and/or differences
in polarity between the first tagged compound and the second tagged
compound.
[0009] As used herein, the term "tagging" refers generally to
attaching a moiety or group (referred to as a "tagging moiety" or
"tagging group") to a compound to create a "tagged compound".
Preferably, the tagging moiety is attached via covalent bond.
However, other strong attachments such as ionic bonding or
chelation can also be used. In the present invention, different
tagging moieties are preferably used on different compounds to
facilitate separation of such tagged compounds.
[0010] For example, the tagging moieties can be fluorous moieties
that differ in fluorine nature (for example, fluorine content
and/or structure). 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, fluorohydrocarbons, fluorinated ethers
and fluorinated amines). The term "fluorous substrate," thus refers
generally to a substrate 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. The attachment of
fluorous moieties to organic compounds is discussed in U.S. Pat.
Nos. 5,859,247 and 5,777,121, the disclosures of which are
incorporated herein by reference.
[0011] Separation of the tagged compounds of the present invention
is achieved by using separation techniques that are complementary
to (based upon differences between) the tagging moieties. For
example, in the case that compounds are tagged with fluorous
moieties that differ in fluorine content, the tagged compounds may
be separated using a fluorous separation technique (for example,
fluorous reverse phase chromatography).
[0012] 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 based predominantly on the fluorous
nature of molecules (for example, size and/or structure of the
fluorous molecule or domain). 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.RTM.
and Fluophase.TM. columns available from Keystone Scientific, Inc.
(Bellefonte, Pa.), and FluoroSep.TM.-RP-Octyl from ES Industries
(Berlin, N.J.). Other fluorous separation techniques include
liquid-liquid based separation methods such as countercurrent
distribution with a fluorous solvent and an organic solvent.
[0013] As indicated above, a number of tagging strategies other
than fluorous tagging are suitable for use in the present
invention. In general, any tagging strategy that facilitates
separation of the tagged compounds based on differences in the tag
is suitable. If compounds that are tagged are to undergo one or
more reactions to produce tagged product compounds that are to be
separated, the tagging moieties preferably do not substantially
interfere with the reaction(s) and are not cleaved during the
reaction(s). In that regard, the product compounds must be tagged
to achieve separation based upon differences in the tagging moiety.
As will be discussed further below, the manner/order of steps in
which the tagged product compounds become tagged is
unimportant.
[0014] In addition to tagging moieties that differ in fluorine
content, tagging moieties that, for example, differ in total charge
can also be used in the present invention. Such tagged compound
can, for example, be separated by electrophoresis. The tagging
moieties can also be oligomers, polymers, or dendrimers that differ
in size. In the case that the tagging moieties are oligimers,
polymers or dendrimers, the tagged compounds can, for example, be
separated by size exclusion chromatography. As used herein, the
terms, "oligomers" and "polymers" refer generally to molecules that
are made by linking together repeating units of one or more small
molecules called monomers. Generally, oligomers include fewer
monomer units than polymers, although the precise border between an
oligomer and a polymer in not well defined. In the present
invention, so-called "soluble" oligomers and polymers are
preferred. Soluble polymers are discussed in, for example, Gravert,
D. J. and Janda, K. D., "Organic Synthes is on Soluble Polymer
Supports: Liquid-phase Methodologies," Chem. Rev., 97, 489-509
(1997). Through use of soluble oligimer or polymer tags, substrates
or products can be attached to oligomer or polymer tags of
different molecular weights or molecular weight ranges and then the
tagged substrates can be mixed to generate a true mixture which
can, if desired, be reacted in standard solution phase organic
reactions prior to separation. An example of a suitable family of
oligomer/polymer tags is polyethylene glycol (PEG,
H(OCH.sub.2CH.sub.2).sub.nOH). PEG is soluble in an assortment of
organic solvents, has two terminal hydroxyl groups for
attachment/detachment of compounds and products, and can be
purchased in a range of sizes (for example, average molecular
weights of 1,000, 1,500, 2,000, 4,600, etc).
[0015] As used herein, the term "dendrimer" refers generally to
branched or hyperbranched molecules that are synthesized in
generations by attachments of successive sets of building blocks to
a core (or the inverse). See, for example, Dendrimers, F. Vogtle,
Ed., Springer-Verlag Berlin: Heidelberger Platz 3/W-1000 Berlin
33/Germany, 1-18 (1998). Unlike traditional oligomers and polymers,
dendrimers can be made largely as pure molecules each bearing the
same number of building blocks. To the contrary, oligomers and
polymers are generally available only as mixtures of molecules with
a distribution of sizes centered around an average. Different
generations of dendrimers make convenient families of tags. For
example, the various generations of the commercially available
"DAB" polypropylene amine dendrimers (tetraamine, octaamine,
hexadecamine, etc.) vary widely in size and molecular weight and
provide increasing numbers of amines for attachment. Starburst.RTM.
(PAMAM) dendrimers provide another example of a family of
dendrimers tags.
[0016] The tagging moieties can also differ in polarity, in which
case the tagged compounds can, for example, be separated by
standard or, preferably, reverse phase chromatography.
[0017] The present invention also provides a method for carrying
out a chemical reaction including the steps of: tagging a plurality
of compounds with different tagging moieties to create tagged
compounds, conducting at least one chemical reaction on the tagged
compounds to produce a mixture of tagged products, and separating
the mixture of tagged products by a separation technique based upon
differences in the tagging moieties. The method may further include
the step of removing the tagging moieties from the tagged products
after separation. The tagging moieties are removable using standard
reactions as known in the art. The tagging strategies described
above can be used.
[0018] The order or sequence of steps in which the tagged products
are produced is unimportant. In one embodiment of the present
invention, for example, compounds are tagged and then mixed. In
other embodiments, the tagging step itself generates the tagged
compound mixture. In still other embodiments, the compounds are
already mixed prior to the tagging. In these embodiments, each tag
is preferably attached to a single compound by using selective
reactions known to those skilled in the art. In general, selective
reactions are those in which one component or subset of components
of a mixture reacts faster than another component or subset of
components. Selective reactions can, for example, be based on
differences in reacting functional groups, steric effects,
electronic effects, and stereoelectronic effects, among other
things. For example, if a mixture contains a secondary and a
primary alcohol, it is possible to use the higher reactivity of the
primary alcohol to selectively attached a first tag to it, and then
attach a second tag to the remaining secondary alcohol. If a
mixture contains two enantiomers, it is possible to selectively tag
one enantiomer with a first tag using a chiral catalyst or reagent,
and then tag the remaining enantiomer with a second tag. In these
types of reactions, it is preferable that each tagging reaction be
selective for its target component(s) of the mixture to a level of
at least approximately 80%. More preferably, the level of
selectivity is at least approximately 90%.
[0019] The present invention is particularly useful in conjunction
with mixture synthesis or combinatorial synthesis. It is thus
beneficial to briefly discuss a number of terms commonly used in
such synthetic schemes. As used herein, the term "substrate" refers
generally to a reaction component that is a starting material of a
synthetic reaction, normally purchased prepared in a prior step.
The terms "product" or "target product" refer generally to the
target or desired molecule(s) of a transformation derived by
reaction of the substrate with the other reaction component(s) in a
reaction medium. The terms "side product" or "byproduct" refer
generally to a product derived from any component(s) of the
reaction medium which is not the target product and is preferably
separated therefrom.
[0020] The term "reagent," as used herein refers generally to a
chemical entity that is required for a reaction but contributes
either an invariant piece or no piece to the products of a mixture
synthesis or a combinatorial synthesis. The term "reactant," as
used herein refers generally to a type of molecule that contributes
a variable piece to the products of a mixture synthesis or a
combinatorial synthesis. The distinction between the terms
"reactant" and "reagent" in "common" (non-mixture and
non-combinatorial) organic syntheses is vague, but those skilled in
the art often refer to a reaction component as a reagent if it
contributes no piece, a rather small piece, or a piece without
carbon atoms therein to the target product. As used herein, the
term "reagent" includes a catalyst if used in a substoichiometric
quantity. Both substrates and reactants are sometimes referred to
as starting materials or starting compounds.
[0021] In common organic synthesis, individual steps are conducted
sequentially until the final target molecule or product is made. In
combinatorial organic synthesis, the target is not a single
molecule but instead a "library" of several to millions of
molecules. Combinatorial synthesis can be carried out by parallel
synthesis of individual pure compounds or synthesis of
mixtures.
[0022] Once again, the manner in which a product compound is tagged
in a mixture synthesis or combinatorial synthesis in the present
invention is unimportant. For example, a tagging moiety can be
incorporated into a substrate, reactant and/or reagent to create a
tagged product. Likewise, individual or mixed, untagged product
compounds can be directly tagged with tagging moieties to create
tagged product compounds. It is important that the different
products or subsets of products have different tags.
[0023] In mixture and combinatorial synthesis, multiple reactions
are conducted either together or in parallel to provide multiple
products. In mixture synthesis and combinatorial synthesis, the
premium of simple methods of purification is even higher than in
normal synthesis. For this reason, combinatorial synthesis is now
commonly conducted on the solid phase, where purification can be
effected simply by filtration. However, conducting such reactions
can be difficult because the solid-bound reaction component never
truly dissolves in the reaction solvent.
[0024] There are a number of advantages afforded by carrying out
mixture or combinatorial synthesis in a liquid phase as enabled by
the present invention. For example, many reactions are preferably
conducted in a homogenous liquid phase. This is in direct contrast
to solid phase syntheses, where true homogeneity is never
obtained.
[0025] Moreover, unlike deconvolution methods, the methods of the
present invention can be used to readily provide pure product
compounds for testing. In the case of deconvolution methods,
mixtures of product compounds are tested to identify the highest
average activity. Much valuable information can be lost in such
deconvolution methods. For example, even testing of non-optimal
(with respect to biological activity, for example) pure compounds
provides valuable information.
[0026] Furthermore, unlike standard separation techniques, the
separation of a mixture of tagged compounds in the present
invention is determined primarily by the nature of the tag rather
than the component/compound that is tagged. Preferably, the tagging
compounds of the present invention are chosen such that they are
separable in a predetermined manner via a complementary separation
technique. For example, compounds of different fluorine content
will separate in a predetermined order during chromatography over
solid fluorous phases. Because compounds are preferably selectively
tagged with certain tagging moieties in the present invention, the
manner (for example, order) in which specific tagged compounds will
separate is predetermined, thereby potentially eliminating the need
to chemically identify the results of the separation.
[0027] In general, the present invention provides substantially
universal methods for synthesizing and separating organic
compounds. The methods are particularly useful in mixture and
combinatorial synthesis techniques, but find use in substantially
any reaction and/or separation requiring separation of one organic
compound from another organic compound.
[0028] Typically, known standard (non-tagged) reactions can be
carried out under the present invention with one or more tagged
compounds within the range of reaction conditions used in the
corresponding standard (non-tagged) reactions. The present
invention is equally applicable, however, to newly developed
organic reactions.
[0029] Transformations under the method of the present invention
thus generally parallel the transformations of known "non-tagged"
substrates with the advantages that the tagged products are more
easily separated from untagged reaction components and from each
other.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1a illustrates a general mixture synthesis with
fluorous tags using a mixture of tagged compounds.
[0031] FIG. 1b illustrates a general mixture synthesis with
fluorous tags using a mixture of tagged compounds and a mixture of
reactants.
[0032] FIG. 1c illustrates a general mixture synthesis with
fluorous tags using fluorous tagged reactants and a substrate.
[0033] FIG. 2 illustrates a representative example of a synthesis
with a mixture of flourous tagged compounds and a mixture of
reactants.
[0034] FIG. 3 illustrates a representative HPLC trace of a library
of compounds produced in the synthesis of FIG. 2.
[0035] FIG. 4 illustrates preparation of precursors for a mixture
synthesis of mappicine analogs.
[0036] FIG. 5 illustrates mappacine mixture synthesis and
separation.
[0037] FIG. 6 illustrates synthesis of tagged compounds for a
mappacine mixture synthesis.
DETAILED DESCRIPTION OF THE INVENTION
[0038] The present invention provides methods for the synthesis
and/or separation of mixtures of organic compounds based on a
tagging strategy. The methods allows the final mixture to be
separated into components in an organized fashion based on the tag.
The invention is especially useful as an alternative to the
traditional methods of organic synthesis in which a single compound
is taken through a series of reactions and purifications one step
at a time to make a single product. The invention is broadly
applicable to many types of reactions and reaction conditions with
the full range of organic compounds and products, including but not
limited to, carbocycles, heterocycles, acyclic molecules, aromatic
molecules, peptides, carbohydrates and so on. The methods of the
present invention can be used, for example, to make an organic
compounds such as a natural product and its enantiomer and/or other
stereoisomers through a sequence of chemical reactions followed by
separation. It can also be used to make a series of compounds
bearing different substituents.
[0039] In several embodiments, the methods of the present invention
are applied in the synthesis of mixture and/or combinatorial
libraries by manual or automated methods. By multiplying the number
of compounds to be synthesized with only a small amount of
additional effort, the present invention expedites both traditional
synthesis and combinatorial library synthesis.
[0040] In one embodiment, the present invention provides a method
of tagging at least two organic compounds with one among a family
of tags designed to control separation at a later stage. Each
compound (or mixture of compounds) is tagged with a different tag.
The tagged compounds are then combined to generate a mixture, which
is processed through one or more chemical reactions to form a
mixture of tagged products. The mixture of tagged products is then
separated into fractions by a separation method that complements
the tag. In other words, the separation of the mixture is
determined primarily by the nature of the tag rather than the
component that is tagged.
[0041] In another embodiment, a series of tagged starting compounds
are added individually or as a mixture to one or more tagged or
untagged compounds to produce a mixture of tagged products. After
removal of the tags, the untagged products are chemically different
from the untagged starting compounds.
[0042] The tags are generally organic compounds that contain a
suitable site of attachment, such as but not limited to, a hydroxyl
group, an amino group, a silyl group, an alkyl group or an acyl
group, to which an organic substrate is attached through a covalent
chemical bond. Tags may have attached thereto a single compound or
they may have attached thereto multiple copies of the same or
different compounds that are preferably attached and detached in
substantially the same way. Likewise, a single substrate may have
attached thereto a single or multiple tagging moieties. As used
herein, a "family" of tags is a series of similar molecules that
differs in some "regular" or predetermined fashion to allow for the
separation of tagged products based on the nature of the tag. In
one embodiment, the predetermined difference between tags is
"incremental." For example, members of a family can be charged tags
that differ by one (or two, or more) negative or positive charges.
Members of a family can be dendrimers that vary by generation
(second generation, third generation, etc.). Members of a family
can be oligomers or soluble polymers that differ in size. Members
of a family can be linear hydrocarbons that differ in chain length.
Members of a family of fluorous tags can vary in the number of
fluorines, and so on. It is not necessary that the increment of
variation be constant. Nor is it necessary that the variation
between members of a family of tags be incremental provided that
the variation is sufficiently different to control the separation
of the tagged compounds.
[0043] Members of an example of an incremental family of fluorous
tags include: --Si(Me).sub.2CH.sub.2CH.sub.2C.sub.4F ,
--Si(Me).sub.2CH.sub.2CH.sub.2C.sub.5F.sub.11,
--Si(Me).sub.2CH.sub.2CH.sub.2C.sub.6F.sub.13,
--Si(Me).sub.2CH.sub.2CH.sub.2C.sub.7F.sub.15,
--Si(Me).sub.2CH.sub.2CH.sub.2C F.sub.17, --Si(Me)
(CH.sub.2CH.sub.2C.sub.5F.sub.11).sub.2,
--Si(Me)(CH.sub.2CH.sub.2C.sub.6F.sub.13).sub.2, etc. Additional
"non-incremental" tags can be generated without changing the
numbers of fluorines on the tag by changing the size or nature of
the "spacer" functionality (in this example, "CH.sub.2CH.sub.2") or
grafting organic groups onto the tag to modify its behavior
relative to an ungrafted tag.
[0044] In several embodiments of the invention, the following steps
are carried out: compound tagging, mixing of the tagged compounds,
conducting one or more chemical reactions on the compound mixture
to make a new product mixture, separating the mixture by a method
that complements the tags, and removing the tags. Two embodiments
of the invention are shown schematically in FIGS. 1a and 1b. FIG.
1a shows the synthesis of a mixture library where all the members
are reacted identically; in other words n starting materials give n
products. Starting materials S.sup.1-S.sup.n are attached to a
sequence of "tags" T.sup.1-T.sup.n. In FIG. 1a, the tags are
fluorous tags that are represented as F.sup.1-F.sup.n. The tagged
substrates are then mixed and taken through a step or sequence of
steps to provide the mixture of tagged products
F.sup.1P.sup.1-F.sup.nP.sup.n. This mixture is then separated by a
separation technique complementary to the tag (for example,
fluorous reverse phase chromatography). Finally, the tagged
products are preferably individually cleaved (or detagged) to give
the target products. The method is designed to separate the
products based on the tag placed on the initial substrate. For
example, certain organic reactions are well known to produce
mixtures of stereoisomers and/or regioisomers or even non-isomeric
products. Even though separations of these products may sometimes
occur, the invention is designed primarily to separate the
product(s) derived from one substrate bearing one tag from the
product(s) derived from different substrates bearing different
tags.
[0045] In a variant of the above embodiment, a mixture of
substrates is tagged with the same tag and then mixed with other
different substrates or mixtures of different substrates tagged
with different tags. The separation of the tagged products then
provides mixtures of product compounds bearing the same initial
tag.
[0046] In FIG. 1b, tagged substrates are reacted in at least one of
the following steps with a mixture of reactants (as opposed to a
single reactant). If there are n substrates and o reactants and all
reactions succeed, then n.cndot.o products result. Separation by
the method complementary to the tag will then provide groups of
products rather than individual pure products. Each group of
products has the same fluorous tag. In some cases, the members of
these groups of products may actually be separated from each other
during the tagged-based separation, or they could be separated by
traditional means after detagging. For some applications, final
separation to pure components is not desirable, and the method is
instead used to divide a library into known sub-libraries based on
the original tag. Such ordered sub-libraries are useful in various
methods of deconvolution.
[0047] The steps of tagging, mixing and reacting can be conducted
in various orders or even combined. For example, in the embodiment
in FIG. 1c, a single substrate can be reacted with a mixture of
tagged reagents added either together or individually to give a
mixture of tagged products. Subsequent separation of the mixture
based on the tag (possibly after additional reactions) separates or
sorts the products by tag. Detagging then gives the final
products.
[0048] In a preferred embodiment of this invention, the tags are
fluorinated groups (for example, F.sup.1-F.sup.n in FIGS. 1a-1c)
and the separation method is fluorous reverse phase chromatography.
Fluorous reverse phase chromatography separates primarily by
fluorine content, so tags F.sup.1-F.sup.n vary by the number of
fluorines.
[0049] In many embodiments of the present invention, tagging also
aids in the separation of the tagged products from any excess
reagents, reactants, catalysts, or their by-products because all of
those components are untagged.
[0050] In one embodiment, the tags are charged groups such as
ammonium salts, carboxylates, phosphates, etc. that differ in the
total number of charges in each tag and the complementary
separation method is electrophoresis or a related technique. When
the molecules are generally similar in size, electrophoresis and
related techniques generally separate by the total charge of a
molecule, so members of the family of tags contain increasing
numbers of positive or negative charges. After generating a mixture
of tagged products, the mixture is separated with the tagged
products being separated in order of charge. In a preferred
embodiment of this aspect of the invention, the charged functional
groups are masked with protecting groups during the tagging and/or
reaction states. The protecting groups are preferably removed prior
to the separation stage to reveal the charged groups on the tags.
Charged groups are undesirable in many common types of organic
reactions.
[0051] Protecting groups are commonly used in chemical synthesis
schemes to mask (protect) reactive functionalities so that
reactions can be selectivity carried out at other sites. Examples
of common protecting groups include benzyl, acyl, trialkylsilyl and
carbamate, among many others. See, for example, Greene, T. W., and
Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd ed.;
Wiley-Interscience: New York, (1999).
[0052] In another embodiment, the tags are oligomers, polymers, or
dendrimers, and the complementary separation method is size
exclusion chromatography. Size exclusion chromatography separates
by molecular size, so members of the family of tags in this
embodiment are increasingly larger. It is preferable in this
embodiment that the tags be much larger that the initial substrate
to be tagged, so that the tag and not the substrate dominates the
difference in size between the family of tagged products.
[0053] In another embodiment, the tags are non-polar organic groups
such as linear hydrocarbons, and the complementary separation
method is standard or, preferably, reverse phase chromatography.
Reverse phase chromatography separates primary by polarity, so a
family of tags should be increasingly more (or less) polar. It is
preferable in this method that the product component of the tagged
products be generally similar in polarity, so that the tag and not
the tagged component dominates the chromatographic separation. Or
in the case in which the polarity of the products is known or can
be estimated in advance, the less polar products are preferably
attached to the less polar tags and vise-versa. In this way, the
tagged-base separation is enhanced.
[0054] The tags of the present invention can, for example, be
attached to the substrates through any kind of standard covalent
bond. The tags themselves and the method of tagging are preferably
chosen so that both the tags and the bond(s) attaching the tags to
the substrates are stable to the conditions used in any subsequent
reaction(s). In one embodiment, the tags play a dual role as
protecting groups and serve both during the reaction sequence to
protect a labile, sensitive, or problematic group and after the
reaction to control the separation. In another embodiment, the tags
serve as "traceless units". Traceless units are groups that can
generally be replaced leaving no functional group trace of the
attachment. During the detagging reactions, the tags can be cleaved
by standard reactions, including reactions that further
functionalize or diversify the products.
[0055] In addition to being attached directly to the substrate, the
tags can also be attached through the intermediacy of a linker.
Linkers are bifunctional (or polyfunctional) molecules that are
used to bridge the tag and the substrate. They can be attached
first to the tag and then to the substrate or first to the
substrate and then to the tag. Linkers are commonly used, for
example, in solid phase synthesis. The use of linkers in the
attachment of fluorous groups or moieties to organic compounds is
described in U.S. Pat. Nos. 5,859,247 and 5,777,121
[0056] The molecular weights of the compounds/substrates prior to
attachment to the tags in the present invention are preferably less
than about 1,000, more preferably less that about 750, and even
more preferably less than 600. The molecular weights of the
products after detachment of the tags are preferably less than
about 2,000, more preferably less than about 1,500, and even more
preferably less than 1,000.
[0057] A number of the features of the present invention are
illustrated by the synthesis and separation of the three mixture
libraries shown in FIG. 2. These examples, wherein a mixture of
three substrates was reacted with four reactants, clearly subsume
applications in which the mixture is reacted with only one of the
four reagents. Three libraries of 12 compounds were made, as
illustrated in FIG. 2. The reaction of the tagged substrates was
the conjugate addition of aromatic thiols to unsaturated esters.
The esters were chosen as the fluorous tagged components. All
possible combinations of the three tags (x, y, z) with the three
esters (1, 2, 3) were made to demonstrate that the separation was
dictated primarily by the tag and not by the molecule that was
tagged or the thiol.
[0058] An initial mixture library was made by tagging acids 1, 2,
and 3 with tags x, y, and z, respectively. The tagged adducts 1x,
2y, and 3z were mixed and reacted with the four untagged thiols a-d
resulting in a mixture of 12 adducts in 4 sets of three (with
respect to the tag). To accomplish the separation by fluorous
reverse phase chromatography, the mixture was then injected on a
commercial Fluofix column and the HPLC trace was recorded with UV
detection. The retention times of the products (as assigned by
comparison to authentic, pure samples) are shown in FIG. 2 as
library 1. FIG. 3 shows a raw HPLC trace of a similar library. The
compounds elute in order of the fluorine content of the tag; a
first group of peaks corresponds to all the products with the
C.sub.6F.sub.13 tag (18-24 min); a second group of peaks
corresponds to all the products with the C.sub.8F.sub.17 tag (29-33
min), and a third group of peaks corresponds to all the products
with the C.sub.10F.sub.21 tag (34-35 min). Within these groups, the
separation of peaks was surprisingly good. Indeed, as many as 11 of
the 12 possible peaks were observed with only two compounds
overlapping (see FIG. 3). The compounds eluted reliably in order
based on the appended thiol: c before b before a before d. The
t-butyl-bearing compounds d always eluted well after the other
three, which were closely spaced. In a preparative separation, a
reasonable fractionation into six samples was obtained in the
following order: 1x-c, 1d, 2ya-c, 2d, 3za-c, 3d. Thus, instead of
obtaining three fractions of four compounds, three fractions of
three compounds each and three fractions of one compound each were
obtained. After detagging, the mixed fractions could be separated
to give pure products.
[0059] To demonstrate that the primary separation is by the tag,
two complementary sets of tagged precursors where the tags and the
acid substrates were mixed and matched were prepared as follows:
1y/2z/3x and 1z/2x/3y. These sets were again reacted with the four
thiols (libraries 2 and 3) with similar results to the first
library. The primary separation was by the fluorous tag (all x
before all y before all z) with a secondary separation by thiol. A
close inspection of the data showed that there was an effect of the
ester as well (comparison of samples across libraries is needed for
this determination). These results show that compounds can be
reliably tagged, mixed, reacted, and then separated in a fashion
predetermined by the initial tag selection.
[0060] FIGS. 4 and 5 show an example of mixture synthesis of
analogs of the natural product mappicine. This also illustrates the
use of a "null tag" (a tag with no fluorines). The compound with
the null tag emerges first in the final mixture separation, prior
to all of the tagged compounds. The use of one or more null tags is
advantageous because it allows more compounds to be separated than
the number of tags. The synthesis is an improvement over a prior
route to mappicine. Josien, H. and Curran, D. P., "Synthesis of
(S)-mappicine and mappicine ketone via radical cascade reaction of
isonitriles", Tetrahedron 53, 8881-8886 (1997). The preparations of
the precursors shown in FIG. 4 are described in the Examples
section and in FIG. 6.
[0061] The five precurscors 4a-e shown in FIG. 4 were each tagged
with a different silyl group on the free alcohol. The null tag
(octyldimethylsilyl) was attached to 4a, and fluorous tags of
increasing fluorine content were tagged to 4b-e. The fluorous silyl
bromides and triflate in FIG. 4 were prepared in situ by treatment
of the corresponding silanes (RfCH.sub.2CH.sub.2(Me).sub.2SiH) with
dibromine or with triflic acid. These preparations are described in
the Examples section along with the preparation of the silanes.
[0062] Equimolar amounts of the five silyl ethers 5a-e were mixed,
and reacted under standard conditions for the cascade radical
annulation reaction of with a p-tolyl isonitrile (see FIG. 5). See,
U.S. Pat. No. 5,859,247; U.S. Pat. No. 5,777,121; and Josien, H.
and Curran, D. P., "Synthesis of (S)-mappicine and mappicine ketone
via radical cascade reaction of isonitriles", Tetrahedron 53,
8881-8886 (1997). After completion of the reaction, the solvent was
evaporated and the mappicine mixture was separated from the tin
by-products by silica gel chromatography. The mappicine mixture was
then separated by HPLC on a Fluofix column to give individual
samples of 6a-e which eluted in order of the tag from the null tag
up to the C.sub.10F.sub.21 tag. Elution times and yields are
summarized in FIG. 5. Products 6a-e from the mixture experiment
were identical to samples of these products prepared by conducting
individual reactions of each precursor 5a-e with p-tolyl
isonitrile. The final products 6a-e can be detagged under standard
conditions for cleavage of silyl ethers to provide new analogs of
the natural product mappicine.
EXAMPLES
Example 1
Synthesis of the Fluorous Silane Tags for FIG. 2
Example 1a
1-Bromo-4-(2-perfluorohexyl)ethylbenzene
[0063] To zinc powder (1.63 g, 25.0 mmol) under argon was added THF
(4 ml) and 1,2-bromoethane (0.100 ml). The mixture was heated at
reflux at 5 min and then cooled to room temperature.
Chlorotrimethylsilane (0.100 ml) was added and the resulting
mixture was stirred for 15 min at room temperature. A THF solution
(20 ml) of 1-iodo-1H,1H,2H,2H-perfluorooctane (10.0 g, 21.00 mmol)
was added to the reaction mixture at 30.degree. C. The reaction
mixture was stirred for 15 h at room temperature. The mixture was
added to a THF solution (20 ml) of
tetrakis(triphenylphosphine)palladium (0.850 g, 0.735mmol) and
1-bromo-4-iodobenzene (6.09 g, 21.5 mmol). The mixture was heated
at 45.degree. C. for 12 h, cooled, and partitioned between
dichloromethane (20 ml) and FC-72 (40 ml). The organic layer was
washed two times with FC-72 and evaporated. Purification of the
residue by distillation under high vacuum (0.2 mmHg, 120.degree.
C.) afforded 5.06 g (48%) of desired product as colorless solid: mp
33-34.degree. C.; IR (KBr) 2954, 1485, 1236, 1145, 1004, 974, 851,
697, 570, 535, and 507 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta.
7.46 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H), 2.90-2.85 (m, 2H),
and 2.45-2.20 (m, 2H); .sup.13C NMR (CDCl.sub.3) .delta. 138.15,
131.99, 130.15, 120.69, 120-110 (m), 32.83 (t), and 26.05; .sup.19F
NMR (CDCl.sub.3, relative to CCl.sub.3F) .delta. -79.61 (3F),
-113.45 (2F), -120.73 (2F), -121.71 (2F), -122.34 (2F), and -124.99
(2F); Mass (EI) (rel intensity, %) m/z 505 (6), 504 (33), 503 (7),
502 (32, M.sup.+), 423 (7), 172 (7), 171 (base peak), 170 (8), 169
(99), 153 (6), 133 (5), 109 (37), 104 (10), 103 (5), 90 (20), and
89 (7); HRMS Calcd for C.sub.14H.sub.8F.sub.13Br: m/z 501.9602.
Found: m/z 501.96134.
Example 1b
1-Bromo-4-(2-perfluorooctyl)ethylbenzene
[0064] The compound was prepared according to the procedure for the
preparation of 1-bromo-4-(2-perfluorooctyl)ethylbenzene (example
1a). A THF solution (40 ml) of 1-iodo-1H,1H,2H,2H-perfluorodecane
(12.1 g, 21.00 mmol) was added to the suspension of zinc. After
workup, removal of palladium residue from the crude product by
column chromatography on silica gel with hexane/ethyl acetate=19/1
gave a mixture of product and 1-bromo-4-iodobenzene (6.75 g,
product/starting compound=75/25, 46% yield). This mixture was used
for the following transformation: Colorless solid; mp 45-48.degree.
C.; IR (KBr) 2998, 1723, 1370, 1224, 998, 804, 669, and 527
cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta. 7.46 (d, J=8.3Hz, 2H),
7.11 (d, J=8.3Hz, 2H), 2.90-2.86 (m, 2H), and 2.45-2.18 (m, 2H);
.sup.13C NMR (CDCl.sub.3) .delta. 138.16, 132.00, 130.14, 120.70,
120.00-100.00 (m), 32.85 (t), and 26.06;.sup.19F NMR (CDCl.sub.3,
relative to CCl.sub.3F) .delta. -79.52 (3F), -113.39 (2F), -120.47
(2F), -120.69 (4F), -121.51 (2F), -122.25 (2F), and -124.89 (2F);
Mass (EI) (rel intensity, %) m/z 606 (6), 602 (7, M.sup.+), 523
(7), 172 (6), 171 (98), 170 (6), 169 (base peak), 153 (7), 133 (5),
109 (42), 104 (9) 91 (6), 90 (14), 89 (5), and 69 (6); HRMS Calcd
for C.sub.16H.sub.8F.sub.17Br: m/z 601.9538. Found: m/z
601.951328.
Example 1c
1-Bromo-4-(2-perfluorodecyl)ethylbenzene
[0065] This was prepared according to the procedure for the
preparation of 1-bromo-4-(2-perfluorooctyl)ethylbenzene (example
1a). A THF solution (40 ml) of 1-iodo-1H,1H,2H,2H-perfluorododecane
(14.2 g, 21.00 mmol) was added to a suspension of zinc. After
workup, removal of palladium residue from the crude product by
column chromatography on silica gel with hexane/ethyl acetate=19/1
gave a mixture of product and 1-bromo-4-iodobenzene (8.09 g,
product/starting compound=52/48, 40% yield). This mixture was used
for the following transformation: Colorless solid; mp 64-69.degree.
C.; IR (KBr) 2951, 1489, 1347, 1204, 1145, 1073, 1018, 883, 808,
756, 650, 562, and 523 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta.
7.45 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 2.92-2.79 (m, 2H),
and 2.45-2.26 (m, 2H); .sup.13C NMR (CDCl.sub.3) .delta. 138.16,
132.00, 130.16, 120.69, 120.00-100.00 (m), 32.84 (t), and 26.05;
19F NMR (CDCl.sub.3, relative to CCl.sub.3F) .delta. -79.54 (3F),
--113.41 (2F), -120.86 (10F), -121.52 (2F), -122.27 (2F), and
-124.92 (2F); Mass (EI) (rel intensity, %) m/z 705 (15), 704 (83),
703 (20), 702 (91,M.sup.+), 682 (8), 683 (10), 623 (13), 314 (26),
169 (43), 153 (17), 152 (base peak), 151 (29), 150 (13), 126 (13),
109 (14), 76 (7), and 75 (5); HRMS Calcd for
C.sub.18H.sub.8F.sub.21Br: m/z 701.9474. Found: m/z 701.9536.
Example 1d
4-(2-Perfluorohexyl)ethylbenzylalcohol
[0066] A 1.7M solution of n-butyllithium in hexane (1.17 ml, 1.99
mmol) was added dropwise to THF solution (2 ml) of
1-bromo-4-(2-perfluorohexyl)ethylbenzene (0.500 g, 1.99 mmol) at
-40.degree. C. under argon. The resulting mixture was stirred for
20 min at -40.degree. C. N,N-Dimethylformamide (0.154 ml, 1.99
mmol) was added dropwise to the mixture. After 30 min, diluted
hydrochloric acid was added, and the mixture was extracted with
dichloromethane three times. The organic layer was dried with
anhydrous sodium sulfate, and evaporated.
[0067] To the above residue was added ethanol (2 ml) and sodium
borohydride (75.2 mg, 1.99 mmol). This mixture was stirred at
25.degree. C. for 16 h. The mixture was diluted with hydrochloric
acid, and then extracted with dichloromethane three times. The
organic layer was dried over sodium sulfate and evaporated.
Purification of the residue by column chromatography on silica gel
with hexane/ethyl acetate=3/1 afforded 0.366 g (81%) of product:
Colorless solid; mp 33-35.degree. C.; IR (neat) 3889, 2954, 2871,
1367, 1318, 1235, 1140, 1083, 1101, 837, and 697 cm.sup.-1; .sup.1H
NMR (CDCl.sub.3) .delta. 7.34 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz,
2H), 4.96 (s, 2H), 2.96-2.90 (m, 2H), 2.47-2.28 (m, 2H), and
1.80-1.50 (br, 1H); .sup.13C NMR (CDCl.sub.3) .delta. 139.47,
138.71, 128.63, 127.62, 120.00 -103.00 (m), 65.17, 33.07 (t), and
26.27; .sup.19F NMR (CDCl.sub.3, relative to CCl.sub.3F) .delta.
-79.54 (3F), -13.46 (2F), -120.73 (2F), -121.71 (2F), -122.34 (2F),
and -124.97 (2F); Mass (EI) (rel intensity, %) m/z 454
(21,M.sup.+), 121 (18), 109 (7), 106 (13), 107 (base peak), 105
(5), 93 (7), 91 (31), 79 (47), 78 (7), 77 (22), and 60 (5); HRMS
Calcd for C.sub.15H.sub.11F.sub.13O: m/z 454.0602. Found: m/z
454.0589.
Example 1e
4-(2-Perfluorooctyl)ethylbenzylalcohol
[0068] This was prepared according to the procedure for the
preparation of 4-(2-perfluorohexyl)ethylbenzylalcohol (Example 1d).
Use of 1.7 M of n-butyllithium in hexane (14.6 ml, 24.9 mmol),
N,N-dimethylformamide (1.93 ml, 24.9 mmol), THF (16 ml), and sodium
borohydride (0.941 g, 24.9 ml) for treatment of the mixture (5.00
g) of
1-bromo-4-(2-perfluorooctyl)ethylbenzene/1-bromo-4-iodobenzene=75:25)
afforded 2.70 g (68%) of product: Colorless solid; mp 68-69.degree.
C.; IR (KBr) 3394, 2996, 1612, 1343, 1152, 1081, 1006, 883, 646,
and 554 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta. 7.36 (d, J=8.0
Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 4.96 (s, 2H), 2.96-2.90 (m, 2H),
2.47-2.28 (m, 2H), and 1.90-1.70 (br, 1H); .sup.13C NMR
(CDCl.sub.3) .delta. 139.47, 138.70, 128.63, 127.62, 120.00 -103.00
(m), 65.16, 33.06 (t), and 26.25; .sup.19F NMR (CDCl.sub.3,
relative to CCl.sub.3F) .delta. -79.55 (3F), -113.39 (2F), -120.53
(2F), -121.71 (2F), -122.29 (2F), and -124.91 (2F); Mass (EI) (rel
intensity, %) m/z 555 (24), 554 (base peak, M.sup.+), 553 (23), 552
(15), 551 (30), 537 (10), 536 (8), 535 (27), 525 (5), 167 (5), 121
(16), 109 (10), 108 (8), 107 (94), 105 (8), 91 (29), 79 (18), and
77 (6); HRMS Calcd for C.sub.17H.sub.11F.sub.17O: m/z 554.0538.
Found: m/z 554.0527.
Example 1f
4-(2-Perfluorodecyl)ethylbenzylalcohol
[0069] This was prepared according to the procedure for the
preparation of 4-(2-perfluorohexyl)ethylbenzylalcohol (Example 1d).
Use of 1.7 M of n-butyllithium in hexane (15.1 ml, 25.6 mmol),
N,N-dimethylformamide (1.98 ml, 25.6 mmol), THF (16 ml), and sodium
borohydride (0.968 g, 25.6 ml) for treatment of the mixture (6.00
g) of
1-bromo-4-(2-perfluorodecyl)ethylbenzene/1-bromo-4-iodobenzene=52:48)
afforded 3.04 g (75%) of product: Colorless solid; mp 95-97.degree.
C.; IR (KBr) 3366, 2958, 1706, 1370, 1335, 1208, 1149, 1081, 1013,
828, 700, 653, and 558cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta.
7.35 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 4.70 (s, 2H),
3.00-2.90 (m, 2H), 2.47-2.19 (m, 2H), and 1.80-1.50 (br, 1H);
.sup.13C NMR (CDCl.sub.3) .delta. 139.47, 138.72, 128.63,
121.00-100.00 (m), 65.17, 33.06 (t), and 26.26; .sup.19F NMR
(CDCl.sub.3, relative to CCl.sub.3F) .delta. -79.51 (3F), -113.41
(2F), -120.54 (2F), -121.48 (10F), -122.25 (2F), and -124.91 (2F);
Mass (EI) (rel intensity, %) m/z 655 (6), 654 (30,M.sup.+), 653
(7), 652 (20), 635 (11), 121 (18), 109 (9), 108 (7), 107 (base
peak), 105 (8), 91 (28) and 79 (18); HRMS Calcd for
C.sub.19H.sub.11F.sub.21O: m/z 654.0474. Found: m/z 654.0463.
Example 2
Synthesis of Unsaturated Esters
Example 2a
4-(2-Perfluorohexyl)ethylbenzyl crotonate (1x)
[0070] Sodium hydride (about 1 mg) and ethyl crotonate (27.4 .mu.l,
1.10 mmol) were added to a benzene solution (2 ml) of
4-(2-perfluorohexyl)ethylbenzylalcohol (0.100 g, 0.220 mmol), and
then the mixture was heated at reflux for 1 h. Benzene was
distilled out at atmospheric pressure to give a residue. The
residue was quenched with dilute hydrochloric acid, and this
mixture was extracted with dichloromethane. The organic layer was
dried over anhydrous sodium sulfate and evaporated. Purification of
the residue by column chromatography on silica gel with
hexane/ethyl acetate=19/1 afforded 84 mg (73%) of product:
Colorless oil; IR (neat) 2953, 1724, 1654, 1448, 1320, 1243, 1177,
1142, 1022, 975, 847, 808, and 711 cm.sup.-1; .sup.1H NMR (CDCl3)
.delta. 7.34 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.03 (dq,
J=15.3 Hz and J=7.0 Hz, 1H), 5.90 (dq, J=15.3 Hz and J=1.6 Hz, 1H),
5.18 (s, 2H), 2.96-2.85 (m, 2H), 2.47-2.28 (m, 2H), and 1.89 (dd,
J=7.0 Hz and J=1.6 Hz, 3H); .sup.13C NMR (CDCl.sub.3) .delta.
166.43, 145.38, 139.24, 134.85, 128.60, 128.60, 122.54,
120.00-103.00 (m), 65.74, 33.02 (t), 26.28, and 18.10; 19F NMR
(CDCl.sub.3, relative to CCl.sub.3F) .delta. -79.62 (3F), -113.51
(2F), -120.75 (2F), -121.73 (2F), -122.38 (2F), and -125.01 (2F);
Mass (EI) (rel intensity, %) m/z 522 (13, M+), 477 (10), 439 (26),
117 (10), 104 (13), 91 (12), and 69 (base peak); HRMS Calcd for
C.sub.19H.sub.15F.sub.13O.sub.2: m/z 522.0864. Found: m/z
522.0873.
Example 2b
4-(2-Perfluorohexyl)ethylbenzyl 2-hexenoate
[0071] (2x): This was prepared according to the procedure for the
preparation of 4-(2-perfluorohexyl)ethylbenzyl crotonate
[0072] (1x): Colorless oil; IR (neat) 2960, 1724, 1654, 1464, 1375,
1239, 1173, 1014, 975, 812, 707, and 653 cm.sup.-1; .sup.1H NMR
(CDCl.sub.3) .delta. 7.35 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz,
2H), 7.02 (dt, J=15.5 Hz and J=7.0 Hz, 1H), 5.87 (d, J=15.5 Hz,
1H), 5.16 (s, 2H), 2.96-2.86 (m, 2H), 2.50-2.30 (m, 2H), 2.29-2.05
(m, 2H), 1.65-1.44 (m, 2H), and 0.94 (t, J=7.4 Hz, 3H); .sup.13C
NMR (CDCl.sub.3) .delta. 166.66, 150.20, 139.25, 134.84, 128.88,
128.62, 121.10, 120.00-105.00 (m), 65.79, 34.38, 33.01 (t), 26.27,
21.33, and 13.78; .sup.19F NMR (CDCl.sub.3, relative to CCl.sub.3F)
.delta. -79.60 (3F), -113.48 (2F), -120.72 (2F), -121.70 (2F),
-122.35 (2F), and -124.97 (2F); Mass (EI) (rel intensity, %) m/z
550 (28, M+), 494 (10), 438 (19), 437 (base peak), 117(25), 104
(29), 97 (99), 91 (32), 77 (10), and 56 (11); HRMS Calcd for
C.sub.21H.sub.19F.sub.13O.sub.2: m/z 550.1177. Found: m/z
550.1202.
Example 2c
4-(2-Perfluorohexyl)ethylbenzyl methacrylate
[0073] (3x): This was prepared according to the procedure for the
preparation of 4-(2-perfluorohexyl)ethylbenzyl crotonate
[0074] (1x): Colorless oil; IR (KBr) 2959, 1720, 1634, 1456, 1320,
1243, 1014, 940, 816, 704, and 650 cm.sup.-1; .sup.1H NMR
(CDCl.sub.3) .delta. 7.36 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz,
2H), 6.17 (s, 1H), 5.60 (s 1H), 5.19 (s, 2H), 2.97-2.64 (m, 2H),
2.47-2.29 (m, 2H), and 1.98 (s, 3H); .sup.13C NMR (CDCl.sub.3)
.delta. 167.44, 139.34, 136.44, 134.90, 128.79, 128.70, 126.03,
120.00 -105.00 (m), 66.28, 33.10 (t), 26.37, and 18.52; .sup.19F
NMR (CDCl.sub.3, relative to CCl.sub.3F) .delta. -79.73 (3F),
-113.55 (2F), -120.78 (2F), -121.77 (2F), -122.41 (2F), and
--125.06 (2F); Mass (EI) (rel intensity, %) m/z 523 (15), 522
(73,M.sup.+), 504 (10), 478 (13), 477 (61), 453 (18), 451 (13), 438
(21), 437 (base peak), 118 (16), 104 (18), 91 (29), and 69 (80);
HRMS Calcd for C.sub.19H.sub.15F.sub.13O.sub.2: m/z 522.0864.
Found: m/z 522.0852.
Example 2d
4-(2-Perfluorooctyl)ethylbenzyl crotonate (1y)
[0075] This was prepared according to the procedure for the
preparation of 4-(2-perfluorohexyl)ethylbenzyl crotonate (1x):
Colorless solid; mp 33-34.degree. C.; IR (KBr) 2934, 1710, 1651,
1450, 1378, 1200, 1145, 1105, 1022, 986, 804, 741, 665, and 554
cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta. 7.34 (d, J=8.0 Hz, 2H),
7.22 (d, J=8.0 Hz, 2H), 7.03 (dq, J=15.5 Hz and J=6.9 Hz, 1H), 5.90
(dq, J=15.5 Hz and J=1.4 Hz, 1H), 5.14 (s, 2H), 2.96-2.89 (m, 2H),
2.46-2.28 (m, 2H), and 1.89 (dd, J=6.9 Hz and J=1.4 Hz, 3H);
.sup.13C NMR (CDCl.sub.3) .delta. 166.45, 145.42, 139.24, 134.83,
128.84, 128.61, 122.53, 120.00-105.00 (m), 65.76, 33.03 (t), 26.47,
and 18.13; .sup.19F NMR (CDCl.sub.3, relative to CCl.sub.3F)
.delta. -79.55 (3F), -13.46 (2F), -120.52 (2F), -120.73 (4F),
-121.54 (2F), -122.30 (2F), and -124.94 (2F); Mass (EI) (rel
intensity, %) m/z 627 (14), 622 (27, M.sup.+), 604 (13), 577 (23),
553 (13), 551 (11), 538 (16), 537 (72), 309 (20), 308 (75), 265
(43), 223 (44), 180 (28), 179 (21), 178 (34), 165 (19), 117 (14),
104 (12), 91 (16), 69 (base peak), and 57 (12); HRMS Calcd for
C.sub.21H.sub.15F.sub.17O.sub.2: m/z 622.0800. Found: m/z
622.0808.
Example 2e
4-(2-Perfluorooctyl)ethylbenzyl 2-hexenoate (2y)
[0076] This was prepared according to the procedure for the
preparation of 4-(2-perfluorohexyl)ethylbenzyl crotonate (1x):
Colorless solid; mp 33-34.degree. C.; IR (neat) 2950, 2712, 1653,
1460, 1373, 1330, 1217, 1145, 978, 704, 656 and 561 cm.sup.-1;
.sup.1H NMR (CDCl.sub.3) .delta. 7.36 (d, J=8.0 Hz, 2H), 7.23 (d,
J=8.0 Hz, 2H), 7.03 (dt, J=15.6 Hz and J=7.0 Hz, 1H), 5.97 (d,
J=15.6 Hz, 1H), 5.17 (s, 2H), 2.96-2.90 (m, 2H), 2.47-2.28 (m, 2H),
2.23-2.09 (m, 2H), 1.57-1.44 (m, 2H), and 0.95 (t, J=7.4 Hz, 3H);
.sup.13C NMR (CDCl.sub.3) .delta. 166.64, 150.16, 139.25, 134.85,
128.86, 128.59, 121.10, 120.00-103.00 (m), 65.77, 34.36, 33.01 (t),
26.26, 21.32, and 13.72; .sup.19F NMR (CDCl.sub.3, relative to
CCl.sub.3F) .delta. -79.80 (3F), -113.60 (2F), -120.64 (2F),
-120.87 (4H), -121.68 (2F), -122.41 (2F), and -125.10 (2F); Mass
(EI) (rel intensity, %) m/z 650 (3, M.sup.+), 594 (5), 590 (5), 551
(9), 538 (17), 537 (base peak), 178 (15), 177 (10), 176 (13), 115
(7), 102 (5), and 98 (5); HRMS Calcd for
C.sub.23H.sub.19F.sub.17O.sub.2: m/z 650.1113. Found: m/z
650.1125.
Example 2f
4-(2-Perfluorooctyl)ethylbenzyl methacrylate (3y)
[0077] This was prepared according to the procedure for the
preparation of 4-(2-perfluorohexyl)ethylbenzyl crotonate (1x):
Colorless oil: IR (neat) 2953, 1724, 1638, 1456, 1371, 1200, 1154,
944, 812, and 657 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta. 7.36
(d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 6.17 (s, 1H), 5.60 (s
1H), 5.19 (s, 2H), 2.96-2.80 (m, 2H), 2.48-2.28 (m, 2H), and 1.99
(s, 3H); .sup.13C NMR (CDCl.sub.3) .delta. 167.44, 139.34, 136.44,
134.90, 128.79, 128.69, 126.02, 124.00-106.00 (m), 66.28, 33.11
(t), 26.38, and 18.51; .sup.19F NMR (CDCl.sub.3, relative to
CCl.sub.3F) .delta. -79.74 (3F), -113.56 (2F), -120.60 (2F),
-120.83 (4H), -121.64 (2F), -122.38 (2F), and -125.06 (2F); Mass
(EI) (rel intensity, %) m/z 622 (8, M.sup.+), 577 (33), 551 (23),
538 (20), 537 (base peak), 165 (13), 129 (17), 128 (23), 116 (12),
115 (26), 103 (34), 89 (23), 84 (12), and 83 (17); HRMS Calcd for
C.sub.21H.sub.15F.sub.17O.sub.2: m/z 622.0800. Found: m/z
622.0804.
Example 2g
4-(2-Perfluorodecyl) ethylbenzyl crotonate (1z)
[0078] This was prepared according to the procedure for the
preparation of 4-(2-perfluorohexyl)ethylbenzyl crotonate (1x):
Colorless solid; mp 46-48.degree. C.; IR (KBr) 2939, 1715, 1655,
1450, 1196, 1149, 986, 887, 646, 558, and 531 cm.sup.-1; .sup.1H
NMR (CDCl.sub.3) .delta. 7.35 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz,
2H), 6.98 (dq, J=15.7 Hz and J=7.0 Hz, 1H), 5.90 (dq, J=15.7 Hz and
J=1.5 Hz, 1H), 5.15 (s, 2H), 2.96-2.90 (m, 2H), 2.60-2.44 (m, 2H),
and 1.88 (dd, J=7.0 Hz and J=1.5 Hz, 3H); .sup.13C NMR (CDCl.sub.3)
.delta. 166.45, 145.41, 139.25, 134.84, 128.84, 128.60, 122.53,
120.00 -105.00 (m), 65.75, 33.01 (t), 26.25, and 18.11; .sup.19F
NMR (CDCl.sub.3, relative to CCl.sub.3F) .delta. -79.67 (3F),
-113.52 (2F), -120.65 (10F), -121.59 (2F), -122.35 (2F), and
-125.02 (2F); Mass (EI) (rel intensity, %) m/z 722 (11, M.sup.+),
704 (14), 678 (13), 677 (53), 676 (14), 654 (23), 651 (25), 638
(22), 637 (base peak), 171 (14), 167 (18), 166 (11), 165 (28), 163
(10), 154 (10), 148 (14), 147 (15), 144 (15), 133 (17), 130 (14),
129 (11), 128 (26), 127 (12), 126 (16), 125 (12), 105 (11), 104
(43), 103 (19), 102 (13), and 89 (22); HRMS Calcd for
C.sub.23H.sub.15F.sub.21O.sub.2: m/z 722.0736. Found: m/z
722.0729.
Example 2h
4-(2-Perfluorodecyl)ethylbenzyl 2-hexenoate (2z)
[0079] This was prepared according to the procedure for the
preparation of 4-(2-perfluorohexyl)ethylbenzyl crotonate (1x):
Colorless solid; mp 36-38.degree. C.; IR (neat) 2958, 1719, 1655,
1465, 1382, 1223, 1150, 978, 879, 645, and 554 cm.sup.-1; .sup.1H
NMR (CDCl.sub.3) .delta. 7.35 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz,
2H), 7.03 (dt, J=15.5 Hz and J=7.0 Hz, 1H), 5.88 (dd, J=15.6 Hz and
J=1.5 Hz, 1H), 5.16 (s, 2H), 2.96-2.85 (m, 2H), 2.50-2.33 (m, 2H),
2.23-2.13 (m, 2H), 1.56-1.40 (m, 2H), and 0.95 (t, J=7.4 Hz, 3H);
.sup.13C NMR (CDCl.sub.3) .delta. 166.58, 150.10, 139.19, 134.76,
128.80, 128.52, 121.02, 120.00-105.00 (m), 65.71, 34.30, 32.94 (t),
26.20, 21.25, and 13.66; .sup.19F NMR (CDCl.sub.3, relative to
CCl.sub.3F) .delta. -79.58 (3F), -113.46 (2F), -120.58 (10F),
-121.53 (2F), -122.30 (2F), and -124.95 (2F); Mass (EI) (rel
intensity, %) m/z 750 (5, M.sup.+), 725 (6), 653 (10), 638 (18),
637 (91), 537 (9), 223 (6), 179 (28), 178 (base peak), 164 (43),
121 (23), 117 (18), 115 (12), 104 (14), 97 (59), 91 (32), 68 (15),
and 56 (14); HRMS Calcd for C.sub.25H.sub.19F.sub.21O.sub.2: m/z
750.1049. Found: m/z 750.1054.
Example 2i
4-(2-Perfluorodecyl)ethylbenzyl methacrylate (3z)
[0080] This was prepared according to the procedure of the
preparation of 4-(2-perfluorohexyl)ethylbenzyl crotonate (1x):
Colorless solid; mp 55-56.degree. C.; IR (KBr) 2950, 1897, 1723,
1652, 1450, 1374, 1212, 1149, 1081, 880, 642, and 558 cm.sup.-1;
.sup.1H NMR (CDCl.sub.3) .delta. 7.35 (d, J=8.0 Hz, 2H), 7.23 (d,
J=8.0 Hz, 2H), 6.17 (s, 1H), 5.60 (s, 1H), 5.19 (s, 2H), 2.97-2.90
(m, 2H), 2.45-2.28 (m, 2H), and 1.98 (s, 3H); .sup.13C NMR
(CDCl.sub.3) .delta. 167.37, 139.24, 136.31, 134.77, 128.70,
128.61, 125.99, 122.00-100.00 (m), 66.19, 33.01 (t), 26.27, and
18.45; .sup.19F NMR (CDCl.sub.3relative to CCl.sub.3F) .delta.
-79.59 (3F), -113.50 (2F), -120.59 (10H), -121.56 (2F), -122.31
(2F), and -124.96 (2F); Mass (EI) (rel intensity, %) m/z 722
(19,M.sup.+), 677 (15), 637 (27), 537 (10), 177 (19), 178 (68), 169
(17), 167 (16), 166 (10), 165 (44), 121 (18), 199 (13), 117 (31),
104 (31), and 69 (base peak); HRMS Calcd for
C.sub.23H.sub.15F.sub.21O.sub.2: m/z 722.0736. Found: m/z
722.0719.
Example 3
General Procedure for the Synthesis of Individual Michael
Adducts
[0081] Twelve separate acceptor solutions (4 each of 1x, 2y, and
3z) were prepared by diluting an acceptor (0.05 mmol) with THF (50
ul). One of the four thiols (0.25 mmol, benzenethiol,
2-naphthalenethiol, 4-methoxybenzenethiol, and
4-tert-butylbenzenethiol) was added to each of the twelve acceptor
solutions such that all possible combinations of three acceptors
and four thiols were generated. Triethylamine (6.1 .mu.l, 0.05 mol)
was added to each mixture. The mixtures were stirred for 15 h at
room temperature. The reaction mixtures were charged on to 3.00 g
of fluorous reverse phase silica gel in twelve short columns with
methanol/water=4/1. The columns were eluted with methanol/water=4/1
(12 ml), and then they were eluted with ethyl acetate (12 ml).
Removal of solvent of the ethyl acetate fractions gave the twelve
individual Michael adducts. These were used as standards to
characterize the mixture library. The characterization data of
4-(2-perfluorodecyl)ethylbenzyl 2-methyl-3-phenylthiopropanate
(3az) are representative: 4-(2-perfluorodecyl)ethylbenzyl
2-methyl-3-phenylthiopropanate (3az): Colorless solid; mp
51-52.degree. C.; IR (KBr) 2954, 1731, 1592, 1236, 887, 816, 737,
650, and 554 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta. 7.39-7.17
(m, 9H), 5.10 (s, 2H), 3.29 (dd, J=13.2 Hz and J=7.3 Hz, 1H), 2.96
(dd, J=13.2 Hz and J=7.0 Hz, 1H), 2.95-2.85 (m, 2H), 2.80-2.70 (s,
1H), 2.50-2.25 (m, 2H), and 1.30 (d, J=7.1 Hz, 3H); .sup.13C NMR
(CDCl.sub.3) .delta. 174.86, 139.33, 135.76, 134.52, 130.19,
129.10, 128.76, 128.62, 126.61, 120.00-105.00 (m), 66.25, 39.92,
37.47, 32.98 (t), 26.28, and 16.88; .sup.19F NMR (CDCl.sub.3,
relative to CCl.sub.3F) .delta. -79.60 (3F), -113.46 (2F), -120.59
(10H), -121.55 (2F), -122.31 (2F), and -124.96 (2F); Mass (EI) (rel
intensity, %) m/z 833 (10), 832 (30, M.sup.+), 638 (16), 637 (93),
205 (14), 196 (13), 195 (base peak), 177 (12), 152 (31), 149 (37),
139 (16), 137 (19), 131 (21), 124 (46), 120 (12), 118 (40), 110
(16), 109 (49), 107 (12), 105 (21), and 104 (35); HRMS Calcd for
C.sub.29H.sub.21F.sub.21O.sub.2S: m/z 832.0944. Found: m/z
832.0947.
Example 4
Representative Procedure for Michael Addition of 4 Thiols with 3
Acceptors (LC-Mass Analysis)
[0082] Benzenethiol (20.6 .mu.l, 0.200 mmol), naphthalenethiol
(32.1 mg, 0.200 mmol), 4-methoxybenzenethiol (24.6 .mu.l, 0.200
mmol), 4-tert-butylbenzenethiol (33.6 .mu.l, 0.200 mmol), and
triethylamine (18.3 .mu.l, 0.15 mmol) were added to a THF solution
(150.0 .mu.l) of the three acceptors (1x,2y,3z, 0.05 mmol each).
The mixture was stirred for 15 h at room temperature. The reaction
mixture was then charged on to 5.00 g of fluorous reverse phase
silica gel in short column wetted with methanol/water=4/1. The
column was eluted first with 20 ml of methanol/water=4/1, and then
with 20 ml of ethyl acetate. Evaporation of the ethyl acetate
fraction gave the mixture of Michael adducts. The mixture was
analyzed by LC-MS (APCI, positive mode) with a Fluofix 120E (1E415,
150.times.4.6 mm) column (MeOH/H.sub.2O=4/1 gradient to MeOH only
for 40 min, flow rate 1.0 ml/min). All twelve adducts were present
as evidenced by the presence of the molecular ions in the MS.
Retention times for the peaks are shown in FIG. 2 as entry 1.
Example 5
General Procedure for Michael Addition of 3 Thiols with 3 Acceptors
to Form a Mixture Library (Separation by HPLC)
[0083] Naphthalenethiol (8.0 mg, 0.050 mmol), 4-methoxybenzenethiol
(6.2 .mu.l, 0.0500 mmol), 4-tert-butylbenzenethiol (8.4 .mu.l,
0.050 mmol), and DBU (7.5 .mu.l, 0.050 mmol) were added to a THF
solution (150.0 .mu.l) of 3 acceptors (0.05 mmol of 1y,2z,3x). The
mixture was stirred for 5 h at room temperature. The reaction
mixture was then charged onto 5.00 g of fluorous reverse phase
silica gel in short column wetted with methanol/water=4/1. The
column was eluted with 20 ml of methanol/water=4/1, and then with
20 ml of ethyl acetate. Evaporation of the ethyl acetate fraction
gave the mixture of Michael adducts.
[0084] This mixture was separated into 6 fractions: 1) a mixture of
3xb, and 3xc, 2) 3xd, 3) a mixture of 1yb, and 1yc, 4) a mixture of
1yd, 5) a mixture of 2zb, and 2zc, 6) 2zd] by HPLC (Fluofix 120E,
1EW125, 250.times.10.0 mm, NEOS Co. Ltd.) (MeOH/H.sub.2O=4/1
gradient to MeOH only for 60 min, flow rate 3.0 ml/min). The
mixtures 1), 3), and 5) were further separated by HPLC (Nova-pack
250.times.100 mm, Waters Corp.) (MeOH/H.sub.2O=19/1 to MeOH only
for 30 min, flow rate 5.0 ml/min) into the individual
components.
[0085] Two other libraries were prepared similarly using different
combinations of tags and esters, as shown in FIG. 2. Data for the
products follow:
[0086] 1xa: .sup.1H NMR (CDCl.sub.3) .delta. 7.46-7.20 (m, 9H),
5.10 (s, 2H), 3.66-3.60 (m, 1H), 2.96-2.90 (m, 2H), 2.69 (dd,
J=15.7 Hz and J=6.1 Hz, 1H), 2.49 (dd, J=15.7 Hz and J=8.5 Hz, 1H),
2.45-2.30 (m, 2H), and 1.33 (d, J=6.9 Hz, 3H). 1xb: .sup.1H NMR
(CDCl.sub.3) .delta. 8.00-7.19 (m, 11H), 5.09 (s, 2H), 3.80-3.74
(m, 1H), 2.95-2.89 (m, 2H), 2.74 (dd, J=15.6 Hz and J=6.2 Hz, 1H),
2.54 (dd, J=15.6 Hz and J=8.3 Hz, 1H), 2.49-2.30 (m, 2H), and 1.38
(d, J=6.8 Hz, 3H).
[0087] 1xc: .sup.1H NMR (CDCl.sub.3) .delta. 7.43-7.21 (m, 6H),
6.87-6.79 (m, 2H), 5.06 (s, 2H), 3.81 (s, 3H), 3.49-3.42 (m, 1H),
2.96-2.88 (m, 2H), 2.64 (dd, J=15.5 Hz and J=6.3 Hz, 1H), 2.44 (dd,
J=15.5 Hz and J=8.2 Hz, 1H), 2.48-2.28 (m, 2H), and 1.21 (d, J=6.9
Hz, 3H).
[0088] 1xd: .sup.1H NMR (CDCl.sub.3) .delta. 7.47-7.17 (m, 8H),
5.10 (s, 2H), 3.63-3.58 (m, 1H), 2.96-2.90 (m, 2H), 2.70 (dd,
J=15.6 Hz and J=6.1 Hz, 1H), 2.47 (dd, J=15.6 Hz and J=8.4 Hz, 1H),
2.52-2.34 (m, 2H), 1.32 (d, J=6.8 Hz, 3H), and 1.31 (s, 9H).
[0089] 2ya: .sup.1H NMR (CDCl.sub.3) .delta. 7.52-7.10 (m, 9H),
5.09 (s, 2H), 3.53-3.48 (m, 1H), 2.95-2.89 (m, 2H), 2.70-2.55 (m,
2H), 2.45-2.30 (m, 2H), 1.70-1.40 (m, 4H), and 0.90 (t, J=6.9 Hz,
3H).
[0090] 2yb: .sup.1H NMR (CDCl.sub.3) .delta. 7.90-7.17 (m, 11H),
5.07 (s, 2H), 3.70-3.61 (m, 1H), 2.95-2.88 (m, 2H), 2.69-2.60 (m,
2H), 2.49-2.30 (m, 2H), 1.70-1.27 (m, 4H), and 0.92 (t, J=7.0 Hz,
3H).
[0091] 2yc: .sup.1H NMR (CDCl.sub.3) .delta. 7.42-7.20 (m, 6H),
6.85-6.78 (m, 2H), 5.10 (s, 2H), 3.80 (s, 3H), 3.33-3.29 (m, 1H),
2.96-2.89 (m, 2H), 2.60-2.49 (m, 2H), 2.48-2.30 (m, 2H), 1.70-1.40
(m, 4H), and 0.89 (t, J=6.8 Hz, 3H).
[0092] 2yd: .sup.1H NMR (CDCl.sub.3) .delta. 7.47-7.20 (m, 8H),
5.09 (s, 2H), 3.50-3.43 (m, 1H), 2.96-2.90 (m, 2H), 2.70-2.55 (m,
2H), 2.50-2.30 (m, 2H), 1.70-1.40 (m, 4H), 1.31 (s, 9H), and 0.90
(t, J=6.6 Hz, 3H).
[0093] 3za: Colorless solid; mp 51-52.degree. C.; IR (KBr) 2954,
1731, 1592, 1236, 887, 816, 737, 650, and 554 cm.sup.-1; .sup.1H
NMR (CDCl.sub.3) .delta. 7.39-7.17 (m, 9H), 5.10 (s, 2H), 3.29 (dd,
J=13.2 Hz and J=7.3 Hz, 1H), 2.96 (dd, J=13.2 Hz and J=7.0 Hz, 1H),
2.95-2.85 (m, 2H), 2.80-2.70 (s, 1H), 2.50-2.25 (m, 2H), and 1.30
(d, J=7.1 Hz, 3H); .sup.13C NMR (CDCl.sub.3) .delta. 174.86,
139.33, 135.76, 134.52, 130.19, 129.10, 128.76, 128.62, 126.61,
120.00-105.00 (m), 66.25, 39.92, 37.47, 32.98 (t), 26.28, and
16.88; .sup.19F NMR (CDCl.sub.3, relative to CCl.sub.3F) .delta.
-79.60 (3F), -113.46 (2F), -120.59 (10H), -121.55 (2F), -122.31
(2F), and -124.96 (2F); Mass (EI) (rel intensity, %) m/z 833 (10),
832 (30, M.sup.+), 638 (16), 637 (93), 205 (14), 196 (13), 195
(base peak), 177 (12), 152 (31), 149 (37), 139 (16), 137 (19), 131
(21), 124 (46), 120 (12), 118 (40), 110 (16), 109 (49), 107 (12),
105 (21), and 104 (35). HRMS Calcd for
C.sub.29H.sub.21F.sub.21O.sub.2S: m/z 832.0944. Found: m/z
832.0947.
[0094] 3zb: .sup.1H NMR (CDCl.sub.3) .delta. 8.00-7.05 (m, 11H),
5.07 (s, 2H), 3.40 (dd, J=13.3 Hz and J=7.2 Hz, 1H), 3.07 (dd,
J=13.3 Hz and J=6.8 Hz, 1H), 2.94-2.90 (m, 2H), 2.90-2.75 (m, 1H),
2.50-2.25 (m, 2H), and 1.33 (d, J=7.0 Hz, 3H).
[0095] 3zc: .sup.1H NMR (CDCl.sub.3) .delta. 7.39-7.20 (m, 6H),
6.86-6.79 (m, 2H), 5.08 (s, 2H), 3.80 (s, 3H), 3.16 (dd, J=13.3 Hz
and J=7.5 Hz, 1H), 2.96-2.80 (m, 3H), 2.72-2.63 (m, 1H), 2.51-2.30
(m, 2H), and 1.26 (d, J=7.0 Hz, 3H). 3zd: .sup.1H NMR (CDCl.sub.3)
.delta. 7.51-7.19 (m, 8H), 5.09 (s, 2H), 3.26 (dd, J=13.3 Hz and
J=7.3 Hz, 1H), 2.97-2.90 (m, 3H), 2.80-2.70 (m, 1H), 2.60-2.34 (m,
2H), 1.31 (s, 9H), and 1.27 (d, J=6.7 Hz, 3H).
[0096] 3xb: .sup.1H NMR (CDCl.sub.3) .delta. 7.82-7.15 (m, 11H),
5.09 (s, 2H), 3.38 (dd, J=13.3 Hz and J=7.2 Hz, 1H), 3.05 (dd,
J=13.3 Hz and J=6.8 Hz, 1H), 2.95-2.90 (m, 2H), 2.90-2.75 (m, 1H),
2.50-2.30 (m, 2H), and 1.32 (d, J=7.0 Hz, 3H).
[0097] 3xc: .sup.1H NMR (CDCl.sub.3) .delta. 7.38-7.21 (m, 6H),
6.85-6.80 (m, 2H), 5.09 (s, 2H), 3.80 (s, 3H), 3.16 (dd, J=13.4 Hz
and J=7.4 Hz, 1H), 2.96-2.90 (m, 2H), 2.84 (dd, J=13.4 Hz and J=6.7
Hz, 1H), 2.72-2.63 (m, 1H), 2.50-2.30 (m, 2H), and 1.20 (d, J=7.1
Hz, 3H).
[0098] 3xd: .sup.1H NMR (CDCl.sub.3) .delta. 7.38-7.20 (m, 8H),
5.08 (s, 2H), 3.25 (dd, J=13.3 Hz and J=7.2 Hz, 1H), 2.95-2.88 (m,
3H), 2.80-2.70 (m, 1H), 2.50-2.30 (m, 2H), 1.30 (s, 9H), and 1.27
(d, J=7.0 Hz, 3H).
[0099] 1yb: .sup.1H NMR (CDCl.sub.3) .delta. 7.90-7.00 (m, 11H),
5.08 (s, 2H), 3.80-3.72 (m, 1H), 2.95-2.88 (m, 2H), 2.73 (dd,
J=15.6 Hz and J=6.1 Hz, 1H), 2.53 (dd, J=15.6 Hz and J=8.3 Hz, 1H),
2.39-2.20 (m, 2H), and 1.37 (d, J=6.9 Hz, 3H).
[0100] 1yc: .sup.1H NMR (CDCl.sub.3) .delta. 7.43-7.20 (m, 6H),
6.88-6.79 (m, 2H), 5.09 (s, 2H), 3.81 (s, 3H), 3.50-3.40 (m, 1H),
2.96-2.89 (m, 2H), 2.63 (dd, J=15.5 Hz and J=6.4 Hz, 1H), 2.44 (dd,
J=15.5 Hz and J=8.0 Hz, 1H), 2.55-2.37 (m, 2H), and 1.27 (d, J=7.1
Hz, 3H).
[0101] 1yd: .sup.1H NMR (CDCl.sub.3) .delta. 7.39-7.20 (m, 8H),
5.09 (s, 2H), 3.62-3.53 (m, 1H), 2.96-2.89 (m, 2H), 2.47 (dd,
J=15.6 Hz and J=8.1 Hz, 1H), 2.38 (dd, J=15.6 Hz and J=7.9 Hz, 1H),
2.37-2.20 (m, 2H), 1.31 (d, J=7.0 Hz, 3H), and 1.31 (s, 9H).
[0102] 2zb: .sup.1H NMR (CDCl.sub.3) .delta. 7.89-7.10 (m, 11H),
5.07 (s, 2H), 3.66-3.60 (m, 1H), 2.94-2.88 (m, 2H), 2.70-2.59 (m,
2H), 2.50-2.30 (m, 2H), 1.70-1.40 (m, 4H), and 0.90 (t, J=7.0 Hz,
3H).
[0103] 2zc: .sup.1H NMR (CDCl.sub.3) .delta. 7.41-7.10 (m, 6H),
6.85-6.80 (m, 2H), 5.09 (s, 2H), 3.80 (s, 3H), 3.33-3.28 (m, 1H),
2.96-2.89 (m, 2H), 2.57-2.50 (m, 2H), 2.50-2.20 (m, 2H), 1.70-1.40
(m, 4H), and 0.89 (t, J=7.0 Hz, 3H).
[0104] 2zd: .sup.1H NMR (CDCl.sub.3) .delta. 7.38-7.20 (m, 8H),
5.09 (s, 2H), 3.50-3.40 (m, 1H), 2.96-2.89 (m, 2H), 2.70-2.50 (m,
2H), 2.50-2.30 (m, 2H), 1.70-1.40 (m, 4H), 1.31 (s, 9H), and 0.90
(t, J=6.8 Hz, 3H).
[0105] LC-Mass (M+1)
[0106] 1xa=633; 1xb=683; 1xc=663; 1xd=689
[0107] 2ya=761; 2yb=811; 2yc=791; 2yd=817
[0108] 3za=833; 3zb=883; 3zc=863; 3zd=889
[0109] 2xa=661; 2xb=711; 2xc=691; 2xd=717
[0110] 3ya=733; 3yb=783; 3yc=763; 3yd=789
[0111] 1za=833; 1zb=883; 1zc=863; 1zd=889
[0112] 3xa=633; 3xb=683; 3xc=663; 3xd=689
[0113] 1ya=733; 1yb=783; 1yc=763; 1yd=789
[0114] 2za=861; 2zb=911; 2zc=891; 2zd=917
Example 6
General Procedure for the Deprotection of the Michael Adducts
[0115] Titanium tetraisopropoxide (12.5 mg, 0.0439 mmol) was added
to a suspension of each Michael adduct (0.0240 mmol) in anhydrous
2-propanol (0.5 ml) under argon. The mixture was heated at reflux
temperature for 6 h, cooled to room temperature, and was quenched
with dilute hydrochloric acid. The resulting mixture was extracted
with ethyl ether three times. The organic layer was dried over
sodium sulfate and evaporated. The residue in a minimum amount of
acetonitrile was charged on to 2.00 g of fluorous reverse phase
silica gel in a short column wetted with methanol/water=4/1. The
column was eluted with 8 ml of methanol/water=4/1 and then it was
eluted with 8 ml of ethyl acetate to give fluorous tagged
benzylalcohols. Removal of solvent from the first eluate and the
second eluate afforded deprotected product and fluorous tagged
benzylalcohol, respectively. 1-Methylethyl
2-methyl-3-phenylthiopropanate is a representative deprotected
product.
[0116] 1-Methylethyl 2-methyl-3-phenylthiopropanoate: Colorless
oil; IR (KBr) 2979, 2929, 1728, 1585, 1458, 1315, 1211, 1170, 739,
and 691 cm.sup.-1; .sup.1H NMR (CDCl.sub.3) .delta. 7.40-7.20 (m,
5H), 5.08-5.00 (m, 1H), 3.26 (dd, J=13.2 Hz and J=7.3 Hz, 1H), 2.92
(dd, J=13.2 Hz and J=6.9 Hz, 1H), 2.69-2.58 (m, 1H), and 1.27-1.22
(m, 6H); .sup.3C NMR (CDCl.sub.3) .delta. 174.59, 136.02, 130.04,
129.07, 126.50, 68.11, 40.01, 37.46, 21.94, and 16.94; Mass (EI)
(rel intensity, %) m/z 238 (7, M.sup.+), 123 (8), 88 (14), 86 (71),
and 84 (base peak) ; HRMS Calcd for C.sub.13H.sub.18O.sub.2S: m/z
238.1044. Found: m/z 238.1016.
Example 7
Synthesis of the Iodopydridone Precursors for the Experiments in
FIGS. 4 and 5 (See Flow Scheme Summary in FIG. 6)
Example 7a
4-Iodo-2-methoxy-3-methyl-6-trimethylsilylpyridine
[0117] To a solution of
4-iodo-2-methoxy-6-trimethylsilyl-3-pyridinecarboxaldehyde (1282
mg, 3.83 mmol) and Et.sub.3SiH (1.6 mL, 6.13 mmol) cooled to
0.degree. C. was added dropwise BF.sub.3OEt.sub.2 (1.26 ml, 6.13
mmol). The mixture was stirred 2 h at 60.degree. C. After cooling,
brine was added, the aqueous layer was extracted with Et.sub.2O and
the organic layer was dried (MgSO.sub.4) and evaporated. The
residue was purified by flash chromatography (hexanes) to give the
iodopyridine as a colorless oil (896 mg, 73%); .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.47 (s, 1H), 3.96 (s, 3H), 2.33 (s, 3H),
0.29 (s, 9H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 162.2,
160.9, 132.6, 124.3, 112.8, 53.7, 20.8, -1.9; HRMS (EI) m/z calcd
for C.sub.1OH.sub.16INOSi (M.sup.+) 321.0034, found 321.0046; EIMS
m/z 321 (M.sup.+, 57), 306 (100).
Example 7b
General Procedure for Grignard Formation and Addition to
Aldehydes
[0118] To a solution of the iodopyridine (3 mmol) in THF (10 mL) at
-40.degree. C. was added dropwise .sup.iPrMgCl (1.3 equiv. 2.0 M in
THF). The solution was stirred at that temperature for 30 min and
then the appropriate aldehyde (1.6 equiv) was added neat and the
reaction was stirred 1 h at -40.degree. C. and 15 min at 23.degree.
C. It was diluted with Et.sub.2O and washed with brine and
extracted with Et.sub.2O. The combined organic layers dried with
Et.sub.2O and evaporated and the residue was subjected to flash
chromatography.
[0119]
1-[2-Methoxy-3-methyl-6-(trimethylsilanyl)pyridin-4-yl]-propan-1-ol-
: Colorless oil (87%), flash chromatography (hexanes-EtOAc 20:1):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.22 (s, 1H), 4.88 (t,
J=6.4 Hz, 1H), 3.98 (s, 3H), 2.13 (s, 3H), 1.92 (br s, 1H), 1.71
(quint, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H), 0.29 (s, 9H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 65.0, 164.5, 154.1,
122.3, 119.5, 74.9, 56.7, 34.1, 14.2, 13.7, 1.7; HRMS (EI) m/z
calcd for C.sub.13H.sub.23NO.sub.2Si (M.sup.+): 253.1499, found
253.1498; EIMS m/z 253 (M.sup.+, 25), 238 (100).
[0120]
1-[2-Methoxy-3-methyl-6-(trimethyl-silanyl)-pyridin-4-yl]-2,2-dimet-
hyl-propan-1-ol: Colorless oil (74%), flash chromatography
(hexanes-EtOAc 15:1): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.21 (s, 1H), 4.75 (d, J=3.1 Hz, 1H), 3.96 (s, 3H), 2.13 (s, 3H),
1.87 (d, J=3.1 Hz, 1H), 0.90 (s, 9H), 0.28 (s, 9H); .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 61.7, 159.6, 148.4, 121.5, 118.1,
76.3, 53.3, 36.9, 26.1, 12.4, -1.7; HRMS (EI) m/z calcd for
C.sub.15H.sub.27NO.sub.2Si (M.sup.+): 281.1811, found: 281.1800;
EIMS m/z 281 (M.sup.+, 23), 266 (36), 225 (100).
[0121]
1-[2-Methoxy-3-methyl-6-(trimethylsilanyl)pyridin-4-yl]-2-phenyleth-
anol: Colorless oil (69%), flash chromatography (hexanes-EtOAc
15:1): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.38-7.23 (m, 6H),
5.10 (dd, J=8.6, 3.8 Hz, 1H), 4.01 (s, 3H), 3.00 (dd, J=13.9, 3.8
Hz, 1H), 2.85 (dd, J=13.8, 8.6, 1H), 2.13 (s, 3H), 2.09 (br s, 1H),
0.28 (s, 9H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 161.7,
161.3, 149.9, 138.0, 129.6, 128.8, 126.9, 119.0, 116.0, 71.3, 53.4,
44.5, 10.9, -1.6; HRMS (EI) m/z calcd for
C.sub.18H.sub.25NO.sub.2Si (M.sup.+): 315.1654, found: 315.1650;
EIMS m/z 315 (M.sup.+, 16), 300 (33), 224 (26), 73 (100).
Example 7c
Representative Procedure for Iododesilylation.
4-(1-Hydroxy-1-propyl)-6-iodo-2-methoxy-3-methylpyridine
[0122] A sonicated solution of ICl (297 mg, 2.3 mmol) in CCl.sub.4
(1.5 mL) at 0.degree. C. was added to a solution of
4-(1-hydroxy-1-propyl)-2-methoxy-3-methyl-6-trimethylsilylpyridine
(231 mg, 0.91 mmol) in CH.sub.2Cl.sub.2 (2 mL) at 0.degree. C., and
the mixture was stirred protected from light for 24 h. The solution
was diluted with CH.sub.2Cl.sub.2 and washed with aqueous
Na.sub.2S.sub.2O.sub.3 and brine, dried (Na.sub.2SO.sub.4),
evaporated and the residue purified by flash chromatography
(hexanes-EtOAc 25:1) to afford unreacted silane (89 mg, 39%) and
the iodide (135 mg, 48%) as a white solid, mp 57-58.degree. C.:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.41 (s, 1H), 4.75 (t,
J=6.4 Hz, 1H), 3.90 (s, 3H), 2.12 (br s, 1H), 2.03 (s, 3H), 1.64
(quint, J=7.3 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H); .sup.13C NMR (75
MHz, CDCl.sub.3) .delta.0 161.6, 154.8, 124.7, 119.7, 116.2, 110.1,
70.8, 54.5, 30.6, 10.9, 10.2; HRMS (EI) m/z calcd for
C.sub.10H.sub.14NO.sub.2I (M.sup.+): 307.0069, found: 307.0057;
EIMS m/z 307 (M.sup.+, 100), 278 (27), 151 (31).
[0123]
1-(6-Iodo-2-methoxy-3-methylpyridin-4-yl)-2,2-dimethyl-propan-1-ol:
White solid (56% iodide and 41% of recovered silane), flash
chromatography (hexanes-EtOAc 25:1), mp 64-65.degree. C.: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta.7.37 (s, 1H), 4.62 (s, 1H), 3.89
(s, 3H), 2.23 (s, 1H), 2.03 (s, 3H), 0.90 (s, 9H); .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 161.6, 152.6, 126.9, 118.1, 109.1, 75.7,
54.4, 37.0, 26.0, 12.5; HRMS (EI) m/z calcd for
C.sub.12H.sub.18INO.sub.2 (M.sup.+): 335.0375, found: 335.0382;
EIMS m/z 335 (M.sup.+, 25), 279 (100).
[0124] 1-(6-Iodo-2-methoxy-3-methylpyridin-4-yl)-2-phenyl-ethanol:
Pale yellow solid (49% iodide and 37% of recovered silane), flash
chromatography (hexanes-EtOAc 25:1); mp 69-70.degree. C.: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.50 (s, 1H), 7.35-7.25 (m, 3H),
7.21-7.18 (m, 2H), 4.98 (dd, J=8.8, 4.1 Hz, 1H), 3.93 (s, 3H), 2.92
(dd, J=13.8, 4.1 Hz, 1H), 2.78 (dd, J=13.8, 8.8 Hz, 1H), 2.22 (br
s, 1H), 2.04 (s, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
61.7, 153.8, 137.3, 130.0, 128.9, 127.2, 124.6, 116.1, 110.3, 70.7,
54.5, 44.4, 10.8; HRMS (EI) m/z calcd for C.sub.15H.sub.16INO.sub.2
(M.sup.+) 369.0226, found: 369.0219; EIMS m/z 369 (M.sup.+, 100),
277 (74).
Example 7d
General Procedure for Iodopyridone Formation.
4-(1-Hydroxypropyl)-6-iodo-3-methyl-1H-pyridin-2-one
[0125] To a solution of
4(1-hydroxy-1-propyl)-6-iodo-2-methoxy-3-methylpyridine (334 mg,
1.09 mmol) and NaI (262 mg, 1.75 mmol) in CH.sub.3CN (3.5 mL) was
added chlorotrimethylsilane (0.19 mg, 0.22 mL, 1.75 mmol) and
H.sub.2O (10 .mu.L, 0.55 mmol). The mixture was heated at
65.degree. C. for 5 h protected from light. After cooling, it was
washed with aqueous Na.sub.2S.sub.2O.sub.3 and brine and extracted
with EtOAc-MeOH, dried (MgSO.sub.4) and evaporated and the residue
subjected to flash chromatography (CH.sub.2Cl.sub.2--MeOH 9:1)
affording the iodopyridone (261 mg, 82%) as a white solid, mp
174-175.degree. C.: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 6.96
(s, 1H), 4.69 (t, J=6.5 Hz, 1H), 2.02 (s, 3H), 1.62 (quint, J=7.3
Hz, 2H), 0.96 (t, J=7.3 Hz, 3H); .sup.13C NMR (75 MHz, CD.sub.3OD)
.delta. 166.2, 157.3, 123.1, 118.9, 93.0, 71.5, 31.1, 11.5, 10.5;
HRMS (EI) m/z calcd for C.sub.9H.sub.12NO.sub.2I (M.sup.+):
292.9913, found: 292.9909; EIMS m/z 293 (M.sup.+, 100), 275 (35),
148 (24).
[0126]
4-(1-Hydroxy-2,2-dimethylpropyl)-6-iodo-3-methyl-1H-pyridin-2-one:
Pale yellow solid (92%), flash chromatography
(CH.sub.2Cl.sub.2-MeOH 9:1), mp 186-187.degree. C.; .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 6.91 (s, 1H), 4.55 (s, 1H), 2.02 (s,
3H), 0.91 (s, 9H) ; .sup.13C NMR (75 MHz, CD.sub.3OD) .delta.
166.1, 155.2, 125.4, 121.2, 91.1, 76.5, 37.9, 26.8, 13.5; HRMS (EI)
m/z calcd for C.sub.11H.sub.16INO.sub.2 (M.sup.+) 321.0226, found
321.0232; EIMS m/z 321 (M.sup.+, 25), 238 (100).
[0127]
4-(1-Hydroxy-2-phenyl-ethyl)-6-iodo-3-methyl-1H-pyridin-2-one:
White solid (76%), flash chromatography (CH.sub.2Cl.sub.2-MeOH
9:1); mp. 166-167.degree. C.: .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.25-7.20 (m, 3H), 7.13-7.10 (m, 2H), 6.98 (s, 1H), 4.97
(dd, J=6.9, 6.7 Hz, 1H), 2.96 (dd, J=13.4, 6.9 Hz, 1H), 2.82 (dd,
J=13.4, 6.7 Hz, 1H), 1.74 (s, 3H); .sup.13C NMR (75 MHz,
CD.sub.3OD) .delta. 166.1, 154.7, 137.3, 129.3, 127.8, 126.1,
122.3, 117.5, 70.0, 43.3, 9.8; HRMS (EI) m/z calcd for
C.sub.14H.sub.14NO.sub.2I (M.sup.+): 355.0069, found: 355.0074;
EIMS m/z 355 (M.sup.+, 7), 301 (8), 197 (24), 91 (100).
Example 7e
Representative Procedure for N-Alkylation.
4-(1-Hydroxypropyl)-6-iodo-3-methyl-1-prop-2-ynyl-1H-pyridin-2-one
(4b)
[0128] To a solution of
4-(1-hydroxypropyl)-6-iodo-3-methyl-1H-pyridin-2-one (200 mg, 0.69
mmol) in DME (2.4 mL) and DMF (0.6 mL) at 0.degree. C. was added
portionwise NaH (30 mg, 0.76 mmol, 60% in mineral oil). After 10
min, LiBr (120 mg, 1.38 mmol) was added and the cooling bath
removed. Propargyl bromide (170 mg, 0.16 mL, 80% in toluene) was
added 10 min later and the mixture was heated at 70.degree. C. for
14 h protected from light. The reaction was cooled, diluted with
EtOAc. This was washed with brine, dried (Na.sub.2SO.sub.4) and
evaporated. The residue was purified by flash chromatography
(CH.sub.2Cl.sub.2-EtOAc 9:1) to yield 4b (195 mg, 86%) as a pale
yellow solid. mp 126-127.degree. C.; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.05 (s, 1H), 5.01 (d, J=17.0, 1H), 4.92 (d,
J=17.0, 1H), 4.68-4.64 (m, 1H), 2.39 (t, J=2.6 Hz, 1H), 1.94 (s,
3H), 1.58 (quint, J=7.3 Hz, 2H), 0.90 (t, J=7.3 Hz, 3H); .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 162.6, 153.4, 124.2, 118.7, 94.7,
73.1, 70.6, 44.4, 30.0, 12.3, 10.2 (one signal is not observed);
HRMS (EI) m/z calcd for C.sub.12H.sub.14NO.sub.2I (M.sup.+):
331.0069, found: 331.0067; EIMS m/z 331 (M.sup.+, 100), 302
(20).
[0129]
1-[3-(tert-Butyldimethylsilanyl)prop-2-ynyl]-4-(1-hydroxy-2-phenyl--
ethyl)-6-iodo-3-methyl-1H-pyridin-2-one:
[0130] Pale yellow solid (79%), mp 98-99.degree. C.: .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.28-7.22 (m, 3H), 7.16-7.14 (m, 2H),
7.12 (s, 1H), 5.05 (br s, 2H), 4.93-4.85 (m, 1H), 3.17 (br s, 1H),
2.84 (br d, J=7.2 Hz, 2H0, 1.87 (s, 3H), 0.93 (s, 9H), 0.09 (s,
6H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 162.3, 151.9, 137.1,
129.5, 128.6, 126.9, 124.1, 118.2, 99.8, 94.8, 88.6, 70.5, 60.5,
44.7, 43.5, 26.1, 21.1, 16.7, 14.3, 12.2, -4.7; HRMS (EI) m/z calcd
for C.sub.23H.sub.30INO.sub.2Si (M.sup.+): 507.1091, found:
507.1099; EIMS m/z 507 (M.sup.+, 14), 450 (100).
[0131]
4-(1-Hydroxypropyl)-6-iodo-3-methyl-1-(3-phenylprop-2-ynyl)-1H-pyri-
din-2-one (4e): White solid (69%), mp 156-157.degree. C.: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.46-7.42 (m, 2H), 7.29-7.23 (m,
3H), 7.11 (s, 1H), 5.32 (d, J=17.0 Hz, 1H), 5.16 (d, J=17.0 Hz,
1H), 4.62 (t, J=6.5 Hz, 1H), 3.42 (br s, 1H), 1.89 (s, 3H),
1.65-1.53 (m, 2H), 0.83 (t, J=7.3 Hz, 3H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 162.8, 153.5, 132.0, 128.8, 128.4, 124.3,
122.5, 118.9, 94.9, 84.7, 83.3, 70.4, 45.0, 30.0, 12.2, 10.0; HRMS
(EI) m/z calcd for C.sub.18H.sub.18NO.sub.2I (M.sup.+) 407.0382,
found: 407.0400; EIMS m/z 407 (M.sup.+, 40), 378 (7), 115
(100).
[0132]
4-(1-Hydroxy-2,2-dimethyl-propyl)-6-iodo-3-methyl-1-prop-2-ynyl-1H--
pyridin-2-one (4c): Pale yellow solid (68%); mp 105-106.degree. C.:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.07 (s, 1H), 5.14 (d
system, J=17.0, 1H), 4.97 (d, J=17.0, 1H), 4.51 (s, 1H), 2.89 (s,
1H), 2.34 (t, J=2.1 Hz, 1H), 1.96 (s, 3H), 0.93 (s, 9H); .sup.13C
NMR (75 MHz, CDCl.sub.3) .delta. 162.5 151.3, 126.6, 120.8, 93.0,
75.7, 73.1, 44.3, 37.1, 26.2, 13.9.
4-(1-Hydroxy-2-phenylethyl)-6-iodo-3-methyl-1-prop-2-ynyl-1H-pyridin-2-on-
e (4d): Pale yellow solid (62%), mp 112-113.degree. C.: .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.32-7.27 (m, 3H), 7.23-7.17 (m, 2H),
7.15 (s, 1H), 5.06 (d, J=17.0, 1H), 4.99 (d, J=17.0, 1H), 4.91-4.88
(m, 1H), 2.98 (s, 1H), 2.83 (d, J=6.5 Hz, 2H), 2.27 (s, 1H), 1.86
(s, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 162.5 152.3,
137.2, 129.5, 128.7, 127.0, 124.3, 118.4, 94.8, 73.1, 70.5, 44.4,
43.5, 12.0.
Example 8
Diisopropyl-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)silane
[0133] To a solution of 1,1,1,2,2,3,3,4,4-nonafluoro-6-iodo-hexane
(1.0 g, 2.67 mmol) in Et.sub.2O (10 mL) at -70.degree. C. was added
tBuLi (4.0 mL, 2.1 equiv, 1.7 M in pentane). The bath temperature
was raised to -40.degree. C. over 30 min. It was then cooled again
to -70.degree. C. and chlorodiisopropylsilane (420 mg, 493 .mu.L,
2.40 mmol) was added. The mixture was warmed to 23.degree. C. and
stirred for 12 h. Water was added and the mixture was extracted
with Et.sub.2O. The Et2O layer was dried (MgSO.sub.4) and
evaporated. The residue was purified by flash chromatography
(hexanes) to give the fluorous silane (805 mg, 83%) as a colorless
oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.50 (s, 1H),
2.24-2.01 (m, 2H), 1.09 (s, 12 H), 0.94-0.79 (s, 3H); .sup.13C NMR
(75 MHz, CDCl.sub.3)_ .delta. 123.2-110.8 (m, 4C), 27.1 (t, (J=23.2
Hz), 18.6 (d, J=26.0 Hz), 10.4, -2.2; .sup.19F NMR (282.4 MHz,
CDCl.sub.3) .delta. -80.0 (3F), -115.6 (2F), -123.2 (2F), -125.02
(2F).
[0134] The following compounds were prepared by similar
procedures:
[0135]
(3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl)diisopropylsilane:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.50 (s, 1H), 2.24-2.02
(m, 2H), 1.08 (s, 12 H), 0.91-0.82 (s, 3H); .sup.13C NMR (75 MHz,
CDCl.sub.3)_ .delta. 22.4-109.7 (m, 6C), 27.4 (t, J=23.3 Hz), 18.7
(d, J=25.8 Hz), 10.6, -1.9; .sup.19F NMR (282.4 MHz, CDCl.sub.3)
.delta. -81.7 (3F), -117.0 (2F), -122.5 (2F), -123.4 (2F), -123.9
(2F), -126.7 (2F).
[0136]
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluoro-decyl)diisopr-
opylsilane: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.3.49 (s, 1H),
2.21-2.09 (m, 2H), 1.05 (s, 12 H), 0.87-0.83 (s, 3H); .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 121.8-107.4 (m, 8C), 27.4 (t, J=23.4
Hz), 18.8 (d, J=25.9 Hz), 10.6, -1.9; .sup.19F NMR (282.4 MHz,
CDCl.sub.3) .delta. -80.9 (3F), -117.9 (2F), -122.4 (6F), -123.4
(2F), -123.8 (2F), -126.6 (2F).
[0137]
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heneicosafluorodo-
decyl)-diisopropylsilane: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.3.50 (s, 1H), 2.18-2.09 (m, 2H), 1.06 (s, 12 H), 0.86-0.82
(s, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 121.7-108.5 (m,
10C), 27.4 (t, J=23.0 Hz), 18.8 (d, J=25.9 Hz), 10.6, -1.9;
.sup.19F NMR (282.4 MHz, CDCl.sub.3) .delta. -81.3 (3F), -117.0
(2F), -122.3 (8F), -123.4 (2F), -124.8 (2F), -127.4 (2F).
Example 9a
1-[3-(tert-Butyldimethylsilanyl)-prop-2-ynyl]-4-[1-(dimethyloctylsilanylox-
y)-2-phenylethyl]-6-iodo-3-methyl-1H-pyridin-2-one (5a)
[0138] To a solution of
1-[3-(tert-butyldimethylsilanyl)prop-2-ynyl]-4-(1-hydroxy-2-phenylethyl)--
6-iodo-3-methyl-1H-pyridin-2-one 4a (60 mg, 0.12 mmol) and
4-dimethylaminopyridine (2 mg, 1.2 .mu.mol) in CH.sub.2Cl.sub.2 (2
mL) was added NEt.sub.3 (49 mg, 66 .mu.L, 0.48 mmol) and
chlorodimethyloctylsilane (62 mg, 77 .mu.L, 0.3 mmol). The
resulting mixture was stirred for 12 h. The solvent was evaporated
and the residue was purified by flash chromatography (hexanes-EtOAc
15:1) to afford 5a (41 mg, 51%) as a yellow oil. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.7.32-7.24 (m, 3H), 7.15-7.12 (m, 2H), 7.08
(s, 1H), 5.14 (d, J=17.0, 1H), 5.09 (d, J=17.0, 1H), 4.79 (t, J=6.4
Hz, 1H), 2.79 (d, J=6.4 Hz, 2H), 1.98 (s, 3H), 1.39-1.11 (m, 14H),
0.94 (s, 9H), 0.90-0.87 (m, 3H), 0.10 (s, 6H), -0.17 (s, 3H), -0.18
(s, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.162.3, 152.0,
137.8, 129.7, 129.1, 128.3, 127.5, 127.2, 126.6, 118.6, 88.4, 44.6,
33.5, 32.0, 29.4, 29.3, 26.1, 23.2, 23.0, 22.7, 17.9, 16.5, 14.2,
12.0, -0.19, -2.05, -4.78.
Example 9b
4-{1-[Diisopropyl-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)silanyloxy]propyl}-6--
iodo-3-methyl-1-prop-2-ynyl-1H-pyridin-2-one (5b)
[0139] To a solution of
4-(1-hydroxypropyl)-6-iodo-3-methyl-1-prop-2-ynyl-1H-pyridin-2-one
4b (44 mg, 0.13 mmol) and 4-dimethylaminopyridine (2 mg, 1.2
.mu.mol) in CH.sub.2Cl.sub.2 (2 mL) was added NEt.sub.3 (53 mg, 74
.mu.L, 0.52 mmol) and
bromodiisopropyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)silane (147 mg,
0.33 mmol, prepared by mixing
diisopropyl-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)silane and Br.sub.2)
and the mixture was stirred for 12 h. The solvent was evaporated
and the residue was purified by flash chromatography (hexanes-EtOAc
15:1) to afford 5b (75 mg, 82%) as a colorless oil: .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 6.99 (s, 1H), 5.12 (d, J=16.5, 1H),
5.00 (d, J=16.5, 1H), 4.75 (t, J=6.0 Hz, 1H), 2.33-2.31 (m, 1H),
2.07-1.99 (m, 2H), 2.06 (s, 3H), 1.84-1.60 (m, 2H), 1.00 (s, 14H),
0.88 (t, J=7.4 Hz, 3H), 0.83-0.79 (m, 2H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 162.4, 152.5, 123.7, 118.6, 94.2, 72.8, 71.5,
44.3, 31.1, 25.3, 17.5, 12.6, 9.4, 0.3.
Example 9c
4-{1-[Diisopropyl-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-silanylox-
y]-2,2-dimethyl-propyl}-6-iodo-3-methyl-1-prop-2-ynyl-1H-pyridin-2-one
(5c)
[0140] To a solution of
4-(1-hydroxy-2,2-dimethylpropyl)-6-iodo-3-methyl-1-prop-2-ynyl-1H-pyridin-
-2-one 4c (31 mg, 0.09 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added
2,6-lutidine (37 mg, 40 .mu.L, 0.36 mmol) and
(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)diisopropyl silyl
trifluoromethanesulfonate (158 mg, 0.27 mmol, prepared by mixing
(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)diisopropyl silane
and TfOH at 0.degree. C. and stirring for 12 h) and the mixture was
stirred for 12 h. The solvent was evaporated and the residue was
purified by flash chromatography (hexanes-EtOAc 15:1) to afford 5c
(36 mg, 49%) as a colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.6.97 (s, 1H), 5.10 (d, J=17.0, 1H), 5.01 (part B of AB
system, J=17.0, 1H), 4.60 (s, 1H), 2.33-2.31 (m, 1H), 2.12-1.91 (m,
2H), 2.09 (s, 3H), 1.08 (s, 9H), 0.90 (s, 14H), 0.64-0.57 (m, 2H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 162.2, 150.6, 126.2,
120.6, 93.0, 72.8, 44.2, 38.0, 26.3, 25.1, 17.6, 14.1, 12.8,
0.6.
Example 9d
4-{1-[(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)diisoprop-
ylsilanyloxy]-2-phenyl-ethyl}-6-iodo-3-methyl-1-prop-2-ynyl-1H-pyridin-2-o-
ne (5d)
[0141] To a solution of
4-(1-hydroxy-2-phenyl-ethyl)-6-iodo-3-methyl-1-prop-2-ynyl-1H-pyridin-2-o-
ne 4d (65 mg, 0.17 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added
4-dimethyaminopyridine (2 mg, 17 .mu.mol), NEt.sub.3 (70 mg, 96
.mu.L, 0.68 mmol), and
bromo-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)diisopro-
pylsilane (277 mg, 0.43 mmol, prepared by mixing
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)diisopropylsil-
ane and Br.sub.2) and the mixture was stirred for 12 h. The solvent
was evaporated and the residue was purified by flash chromatography
(hexanes-EtOAc 15:1) to afford 5d (116 mg, 70%) as a colorless oil:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.27-7.22 (m, 3H),
7.12-7.10 (m, 2H), 7.02 (s, 1H), 5.10 (d, J=16.5, 1H), 5.01 (d,
J=16.5, 1H), 4.93 (t, J=6.5 Hz, 1H), 2.84-2.82 (m, 2H), 2.33-2.32
(m, 1H), 1.93-1.83 (m, 2H), 1.93 (s, 3H), 0.90 (s, 14H), 0.64-0.57
(m, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 162.2, 152.0,
136.9, 129.7, 128.5, 127.0, 123.7, 118.3, 114.8, 94.4, 72.8, 72.2,
44.9, 44.3, 25.1, 17.4, 12.5, 11.9, 0.1.
Example 9e
4-{1-[(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heneicosafluorodod-
ecyl)diisopropylsilanyloxy]propyl}-6-iodo-3-methyl-i-(3-phenylprop-2-ynyl)-
-1H-pyridin-2-one (5e)
[0142] To a solution of
4-(1-hydroxypropyl)-6-iodo-3-methyl-1-(3-phenylprop-2-ynyl)-1H-pyridin-2--
one 4e (100 mg, 0.25 mmol) in CH.sub.2Cl.sub.2 (3 mL) was added
4-dimethyaminopyridine (3 mg, 25 .mu.mol), NEt.sub.3 (76 mg, 105
.mu.L, 0.75 mmol) and
bromo-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heneicosafluorodo-
decyl)diisopropylsilane (365 mg, 0.50 mmol, prepared by mixing
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heneicosafluorododecyl)-
diisopropylsilane and Br.sub.2) and the mixture was stirred for 12
h. The solvent was evaporated and the residue was purified by flash
chromatography (hexanes-EtOAc 15:1) to afford 5e (118 mg, 75%) as a
colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.47-7.45
(m, 2H), 7.30-7.27 (m, 2H), 7.04 (s, 1H), 5.42 (d, J=17.1, 1H),
5.19 (d, J=17.1, 1H), 4.77 (t, J=6.0 Hz, 1H), 2.23-2.03 (m , 2H),
2.08 (s, 3H), 1.70-1.62 (m, 2H), 1.02 (s, 14H), 0.90 (t, J=7.4 Hz,
3H), 0.88-0.82 (m, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
162.5, 152.5, 132.0, 128.6, 128.2, 123.6, 122.6, 118.7, 94.4, 84.5,
83.3, 71.6, 44.8, 31.1, 25.3, 17.4, 12.5, 9.5, 0.3.
Example 10
General Procedure for the Radical Cyclization to Make Authentic
Samples
[0143] A Mixture of N-alkylated pyridone 5g and 4-methylphenyl
isonitrile (3 equiv, 1M in benzene) and hexamethylditin (1.5 equiv)
was irradiated with a 275W GE sunlamp for 5 h. After cooling, the
solvent was evaporated and the residue was purified by flash
chromatography (gradient
CH.sub.2Cl.sub.2.fwdarw.CH.sub.2Cl.sub.2-EtOAc 50:1) to yield the
corresponding silyl mappicine 6.
Example 10a
12-(tert-Butyldimethylsilanyl)-7-[1-(dimethylnonylsilanyloxy)-2-phenyl-eth-
yl]-2,8-dimethyl-11H-indolizino[1,2-b]quinolin-9-one (6a)
[0144] Pale yellow solid (45%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.15 (d, J=8.6, 1H), 8.01 (s, 1H), 7.66 (s, 1H), 7.60 (d,
J=8.6 Hz, 1H), 7.31-7.16 (m, 5H), 5.29 (s, 2H), 5.01-4.99 (m, 1H),
2.94-2.88 (m, 2H), 2.59 (s, 3H), 2.34-2.32 (m, 1H), 2.06 (s, 3H),
1.26-1.15 (m, 12H), 1.01 (s, 9H), 0.85-0.81 (m, 3H), 0.70 (s, 6H),
0.41-0.37 (m, 2H), -0.16 (s, 6H); MS m/z 668 (M.sup.+, 5), 575
(12), 496 (83), 405 (100).
Example 10b
7-{1-[Diisopropyl-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)silanyloxy]propyl}-2,-
8-dimethyl-11H-indolizino[1,2-b]quinolin-9-one (6b)
[0145] Pale yellow solid (67%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.23 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.66-7.61 (m, 2H),
7.49 (s, 1H), 5.24 (s, 2H), 4.99 (t, J=6.3 Hz, 1H), 2.59 (s, 3H),
2.28 (s, 3H), 2.21-2.05 (m, 2H), 1.83-1.77 (m, 2H), 1.06 (s, 14H),
0.93 (t, J=7.4 Hz, 3H), 0.89-0.82 (m, 2H); MS m/z 660 (M.sup.+,
36), 409 (43), 303 (100).
Example 10c
7-{1-[Diisopropyl-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silanyloxy-
]-2,2-dimethylpropyl}-2,8-dimethyl-11H-indolizino[1,2-b]quinolin-9-one
(6c)
[0146] Pale yellow solid (30%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.22 (s, 1H), 8.14 (d, J=8.6 Hz, 1H), 7.65-7.60 (m, 2H),
7.49 (s, 1H), 5.24 (s, 2H), 4.99 (s, 1H), 2.58 (s, 3H), 2.33 (s,
3H), 2.05-1.97 (m, 2H), 1.06 (s, 9H), 1.01 (s, 14H), 0.84-0.75 (m,
2H) ; MS m/z 808 (M.sup.+, 16), 752 (16), 205 (100).
Example 10d
7-{1-[(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)diisoprop-
ylsilanyloxy]-2-phenylethyl}-2,8-dimethyl-11H-indolizino[1,2-b]quinolin-9--
one (6d)
[0147] Pale yellow solid (64%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.25 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.67-7.62 (m, 3H),
7.25-7.15 (s, 5H), 5.25 (s, 2H), 5.17-5.15 (m, 1H), 3.03-2.96 (m,
2H), 2.60 (s, 3H), 2.07 (s, 3H), 2.05-1.86 (m, 2H), 1.01 (s, 14H),
0.66-0.61 (m, 2H); MS m/z 942(M.sup.+, 23), 851 (27), 205
(100).
Example 10e
7-{1-[(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heneicosafluorodod-
ecyl)diisopropylsilanyloxy]propyl}-2,8-dimethyl-12-phenyl-11H-indolizino[1-
,2-b]quinolin-9-one (6e)
[0148] Pale yellow solid (46%) :.sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.17 (d, J=8.6 Hz, 1H), 7.63-7.59 (m, 4H), 7.54 (s, 1H),
7.44-7.42 (m, 2H), 5.05 (s, 2H), 4.99 (t, J=6.1 Hz, 1H), 2.47 (s,
3H), 2.26 (s, 3H), 2.13-2.05 (m, 2H), 1.87-1.78 (m, 2H), 1.06 (s,
14H), 0.94 (t, J=7.4 Hz, 3H), 0.87-0.82 (m, 2H); MS m/z 1056
(M.sup.+, 37), 485 (37), 379 (100).
Example 11
Synthesis and Separation of a Representative Mixture Library
[0149] A mixture of 5a (4.8 mg, 7.0 .mu.mol), 5b (4.9 mg, 7.1
.mu.mol), 5c (5.2 mg, 6.3 .mu.mol), 5d (6.3 mg, 6.6 .mu.mol), 5e
(7.0 mg, 6.8 .mu.mol) and 4-methylphenyl isonitrile (3 equiv 1M in
benzene) and hexamethylditin (1.5 equiv) was irradiated with a 275W
GE sunlamp for 5 h. After cooling, the solvent was evaporated and
the residue purified by flash chromatography (CH.sub.2Cl.sub.2,
then CH.sub.2Cl.sub.2-EtOAc 50:1) to yield the silyl mappicine
mixture. This was separated by preparative HPLC with a Fluofix.TM.
column using the following step gradient: MeOH:H.sub.2O 80:20, 0-5
min, MeOH:H.sub.2O 90:10, 5-25 min; MeOH, >25 min. Isolated
yields of silyl mappicines are listed in order of elution: 6a (1.6
mg, 36%), 6b (2.0 mg, 41%), 6c (1.5 mg, 29%), 6d (2.2 mg, 36%), 6e
(3.0 mg, 43%). These products were identical to the authentic
samples prepared in Example 10.
[0150] Although the present invention has been described in detail
in connection with the above examples, it is to be understood that
such detail is solely for that purpose and that variations can be
made by those skilled in the art without departing from the spirit
of the invention except as it may be limited by the following
claims.
* * * * *