Preparation and applications of fluorinated propargyl phosphonate reagents

The invention provides new fluorinated .gamma.-tri-substsituted silylpropargyl phosphonates and methods for their use to generate a variety of diverse fluorine-containing compounds. The new fluorinated phosphonate synthons contain a novel juxtaposition of four different functional groups: fluoro, alkynyl, tri-substituted silyl, and phosphonato groups. The latter three of these groups provide convenient handles for the construction of fluorine-containing organic molecules.

BACKGROUND OF THE INVENTION 
The invention relates to the preparation of and methods of using versatile 
fluorinated phosphonate synthons for constructing fluorine-containing 
organic compounds. 
The use of fluorine in biologically active molecules is well known. One 
area of interest is the use of partially fluorinated phosphonates as 
phosphate mimics. The isosteric substitution of a hydrolytically labile 
ester oxygen of phosphate biomolecules by monofluoro- or difluoromethylene 
groups allows the latter to mimic the biological activity of the parent 
phosphates. 
Recent reports of the antiviral and anticancer activities of partially 
fluorinated unsaturated phosphonucleosides have increased the demand for 
new methods for their synthesis (Harnden, M. R., et al. J. Med. Chem. 36, 
1343-55, 1993; Megati, S., et al. J. Org. Chem. 57, 2320-27, 1992). 
Syntheses of .alpha.,.alpha.-difluorophosphonates have been carried out in 
the past, mainly by utilizing the diethyl ester of difluoromethylene 
phosphonate. Other syntheses have made use of phosphonyl radical addition 
reactions and electrophilic fluorination. 
SUMMARY OF THE INVENTION 
The invention is based on the discovery that new fluorinated propargyl 
phosphonate synthons can be used to generate a variety of diverse 
fluorine-containing compounds. The new synthons contain a novel 
juxtaposition of four different functional groups: fluoro (which provides 
the desired fluorine), alkynyl, tri-substituted silyl, and phosphonato 
groups. The latter three of these groups provide convenient handles for 
the construction of a wide variety of fluorine-containing organic 
molecules. The invention provides novel fluorinated .gamma.-alkyl- and 
.gamma.-arylalkylsilylpropargyl phosphonates, methods for the preparation 
of these compounds, as well as methods of using such phosphonates to 
construct useful fluorine-containing organic molecules. 
In general, the invention features fluorinated propargyl phosphonates, 
e.g., trisubstituted .gamma.-alkyl- and .gamma.-arylalkylsilylpropargyl 
phosphonates, having the structure 
##STR1## 
wherein R.sub.1, R.sub.2, and R.sub.3 are, independently, alkyl or aryl; X 
is H or F; and each R, independently, is the same as or different than 
each other R, and is an alkyl or is an organic linker. For example, each 
of R.sub.1, R.sub.2, and R.sub.3 can be, independently, methyl, isopropyl, 
phenyl, or tertiary butyl, and both Rs can be ethyl or 
2,2,2-trifluoroethyl. In addition, R.sub.1, R.sub.2 and R.sub.3 can be 
either all methyl, all isopropyl, or, independently, two can be methyl and 
the other can be isobutyl. The organic linker can be linked to a polymer. 
In another aspect, the invention features a method of preparing the new 
fluorinated propargyl phosphonates by (a) oxidizing 
.gamma.-tri-substituted silylpropargyl alcohol for a sufficient time and 
under conditions which allow the formation of a .gamma.-tri-substituted 
silylpropargyl aldehyde; (b) reacting the .gamma.-tri-substituted 
silylpropargyl aldehyde with diethyl phosphite for a time and under 
conditions sufficient to produce a .gamma.-tri-substituted 
silylpropargyl-.alpha.-hydroxyphosphonate; and (c) fluorinating the 
.gamma.-tri-substituted silylpropargyl-.alpha.-hydroxyphosphonate for a 
time and under conditions sufficient to produce the fluorinated propargyl 
phosphonate. This method can include a further step of reacting the 
fluorinated propargyl phosphonate with a fluorinating agent to produce 
.alpha.,.alpha.-difluoropropargyl phosphonate. 
An alternative method can be carried out by (a) sequentially reacting a 
1-tri-substituted silylpropyne with an organometallic compound and a 
halophosphonate for a time and under conditions sufficient to form a 
propargylphosphonate; and (b) reacting the propargylphosphonate with a 
fluorinating agent for a time and under conditions sufficient to form the 
fluorinated propargyl phosphonate. This method can also include the 
further step of reacting the .alpha.-fluoropropargyl phosphonate with a 
fluorinating agent to produce .alpha.,.alpha.-difluoropropargyl 
phosphonate. 
In another aspect, the invention features a method of preparing a 
fluorine-containing organic compound by reacting a new fluorinated 
propargyl phosphonate synthon with reagents for a time and under 
conditions sufficient to form a fluorine-containing organic compound. For 
example, the fluorinated propargyl phosphonate can be reacted with an 
alkylating agent to form a .alpha.-alkyl-.alpha.-fluoropropargyl 
phosphonate, reacted with a carbonyl compound to produce an 
.alpha.-fluoroenyne, reacted with an activated carbonyl compound to form a 
fluorinated .gamma.-ketoalkylpropargyl phosphonate, reacted with a diene 
to form a fluorinated Diels-Alder adduct, or reacted with an unsaturated 
compound to form a fluorine-containing photochemical adduct. 
The invention also includes new fluoroenediynes having the structure: 
##STR2## 
wherein R.sub.1, R.sub.2, and R.sub.3 are, independently, alkyl or aryl; 
and each R and R', independently, are the same as or different than each 
other, and are an alkyl, an aryl, or hydrogen. The invention includes a 
method of preparing the new fluoroenediynes by reacting a 
.alpha.-fluoropropargyl phosphonate with a propargyl carbonyl compound for 
a time and under conditions sufficient to form a fluoroenediyne. 
The invention further features a method of preparing a peptidomimic by (a) 
obtaining a new .alpha.-fluoroenyne; (b) carrying out a disilylation 
reaction to produce a desilylated .alpha.-fluroenyne; and (c) 
incorporating a .psi.(Z)-CF.dbd.CH! isomer of desilylated 
.alpha.-fluoroenyne into a peptide chain to form the peptidomimic. The 
invention also includes fluorine-containing organic compound prepared by 
the new methods, e.g., cancer-treating drugs, pharmaceuticals, 
anti-inflammatory drugs, nucleosides, peptidomimics, and insect sex 
pheromones. 
A "fluorinating agent" is a chemical reagent which introduces fluorine into 
a chemical compound under specific conditions. A "peptide" is a chain of 
natural or unnatural amino acids, regardless of length or 
post-translational modification (e.g., glycosylation, phosphorylation), 
and thus includes polypeptide and proteins. 
A "petidomimic" is a compound, e.g., a synthetic compound, having a 
three-dimensional conformation (i.e., a "peptide motif") that is 
substantially the same as the three-dimensional conformation of a selected 
peptide. The primary and secondary structure of the peptidomimic can be 
similar to, or different than, that of the naturally occurring peptide. 
The peptide motif enables the peptidomimic to modulate cellular responses 
with an activity that is greater than, similar to, or lesser than the 
activity of the peptide from which the peptidomimic was derived. 
An "organic compound" is a molecule comprised of carbon, hydrogen, 
nitrogen, oxygen, sulphur, or phosphorus atoms, or any combination 
thereof. An organic compound can be a cyclic or acyclic compound formed 
entirely of carbon and hydrogen, or it can contain one or more heteroatoms 
including oxygen, nitrogen, sulfur, halogens, or phosphorus. 
A "functional group," "functional moiety," "sidechain," or "substituent" is 
an organic group of atoms comprised of carbon, oxygen, hydrogen, halogens, 
nitrogen, sulfur, or phosphorus, and combinations thereof. 
An "electron withdrawing group" is a moiety covalently attached to a 
reactant, and that is capable of decreasing the electron density in other 
parts of the reactant. Non-limiting examples of these are nitro, acid 
halide, haloalkyl, alkylcarbonyl, arylcarbonyl, aldehyde, cyano and 
sulfone groups. 
All reagents are commercially available (e.g., Aldrich Chemical Company, 
Inc., Milwaukee, Wis.) and may be used after suitable purification (e.g., 
crystallization, distillation, sublimation, chromatographic separation). 
Unless otherwise defined, all technical and scientific terms used herein 
have the same meaning as commonly understood by one of ordinary skill in 
the art to which this invention belongs. Although methods and materials 
similar or equivalent to those described herein can be used in the 
practice or testing of the present invention, suitable methods and 
materials are described below. All publications, patent applications, 
patents, and other references mentioned herein are incorporated by 
reference in their entirety. In case of conflict, the present 
specification, including definitions, will control. In addition, the 
materials, methods, and examples are illustrative only and not intended to 
be limiting. 
The invention provides a number of advantages. The new fluorinated 
phosphonate synthons presented offer excellent building blocks for the 
creation of mono- or difluorine-containing phosphate mimics. They also 
provide convenient common starting points for the synthesis of a wide 
variety of complex fluorine-containing organic compounds. Thus, the 
invention provides simple synthetic pathways to vinyl fluorines, 
fluoroenynes, and fluoroenediynes. The presence of the alkyne 
(carbon-carbon triple bond) allows the facile introduction of both Z- and 
E- double bonds at the .beta.-carbon, under different reduction 
conditions. Variations in the phosphonate ester groups allow control over 
the double bond stereochemistry at the .alpha.-carbon. The synthetic 
methods are simple and provide for both mono- and difluoro phosphonate 
synthons in good yields. Also provided is a method for polymer-based 
syntheses of vinylfluorine compounds which have not been reported. 
Other features and advantages of the invention will be apparent from the 
following detailed description, and from the claims. 
DETAILED DESCRIPTION OF THE INVENTION 
New fluorinated propargyl phosphonate synthons include a number of 
convenient "handles" (functional groups) that enable the preparation of a 
variety of diverse fluorine-containing compounds. The new synthons can be 
easily prepared as described below, and can be used in simple methods to 
construct useful fluorine-containing organic molecules. 
Fluorinated Phosphonate Synthons 
The new fluorinated phosphonate synthons contain a novel juxtaposition of 
four different functional groups or functionalities: fluoro, alkynyl, 
tri-substituted silyl, and phosphonato groups. The latter three of these 
are convenient handles for the construction of other fluorine-containing 
organic molecules, including complex .alpha.-fluorophosphonates and 
.alpha.,.alpha.-difluorophosphonates. Fluorine itself is important for 
biological studies, serving as an analog of hydrogen, and --OH. 
Incorporation of fluorine into biological molecules has illuminated many 
enzymatic mechanisms. The invention provides starting materials for the 
synthesis of such molecules, as well as methods for converting these 
starting materials into useful endproducts. 
The new synthons are precursors of complex fluorinated phosphonates, an 
important group of biological phosphate mimics, as well as analogs of 
phosphonate-containing molecules that have biological activity. 
Phosphate-containing molecules are ubiquitous in biological processes 
including signalling pathways, information storage and energy transfer. 
The isosteric substitution of a hydrolytically labile ester oxygen of 
phosphate biomolecules by monofluoro- or difluoromethylene groups allows 
the latter to mimic the biological activity of the parent phosphate. 
Phosphonate-containing molecules having biological activity include 
inhibitors of EPSP synthase, HIV protease, renin, and PTPases. 
Phosphonates can exhibit important biological properties due to their 
similarity to phosphates. Phosphonates possess greater stability under 
physiological conditions than phosphates because the carbon-phosphorus 
bond of phosphonates is not subject to hydrolysis as is the 
oxygen-phosphorus bond of phosphates. In addition, alkyl phosphonate 
esters of nucleosides are generally more stable toward nucleases and have 
greater permeability into cells. Nevertheless, such analogs are still able 
to form stable complexes with complementary sequences. 
The ability of monofluorophosphonates in compounds created from the new 
synthons to mimic the chemical properties of phosphates arises from the 
electronic similarity of the monofluoromethylene linkage to the phosphate 
oxygen which links phosphorus to the alkyl group. This linkage more 
closely resembles the phosphate linkage than either methylene (CH.sub.2) 
or difluoromethylene (CF.sub.2). For example, the pK.sub.a for the second 
ionization of alkylphosphates (6.4) is virtually the same as that for 
monofluorophosphonates (6.5), while the pK.sub.a of the methylene analog 
is higher (7.6) and that of the difluoromethylene analog is lower (5.4). 
This has been recognized as an important electronic factor in the binding 
of such analogs to enzymes. 
Difluorophosphonates have great utility in the development of therapeutic 
agents. For example, a difluoromethylenephosphonate inhibitor for 
phosphatidylinositol-specific phospholipase C has been designed as a 
isosteric phosphonate substrate analog (Vinod, et al., Tet. Lett. 35, 
7193-6, 1994). Fluorinated nucleosides are strong inhibitors of, for 
example, purine nucleoside phosphorylase (Halazy et al., J. Am. Chem. Soc. 
113, 315-7, 1991). 
The new synthons also provide a scaffold for the construction of 
organofluoro compounds. Fluoroenynes have been used to study the 
perception processes in insects, since they serve as analogs of sex 
pheromones in insects. 
The fluorinated phosphonate synthons include the four above-mentioned 
functional groups in the following structural relationship: 
##STR3## 
in which R.sub.1, R.sub.2, and R.sub.3 are, independently, alkyl or aryl; 
X is H or F; and each R independently, is the same as, or different than, 
the other R and is alkyl, haloalkyl, or an organic linker. This 
juxtaposition allows the facile construction of other fluorine-containing 
organic molecules. 
The presence of these functional groups acts to stabilize the 
.alpha.-carbanion, as well as activating the .gamma.-carbon for attack by 
electrophiles. Thus, the synthon exhibits enhanced reactivities of the 
.alpha.-carbon, the .gamma.-carbon, the triple bond, and the phosphonate 
moiety toward electrophiles, nucleophiles, transition metal-catalysed 
coupling reactions, and Diels-Alder cycloadditions. 
Fluorine-containing compounds are of interest because of the unusual 
properties that compounds acquire upon introduction of fluorine 
substituents. The new synthons contain either one or two fluorine atoms on 
the .alpha.-carbon of the propargyl system. Although the Van der Waals 
radius of fluorine is larger than hydrogen, experimental evidence suggests 
that, generally, only small geometric and steric perturbations are 
introduced upon substitution of a single fluorine for hydrogen in 
methylenes. In biological systems, binding of fluorinated enzyme substrate 
analogs is usually not inhibited, although the electronic effect of 
fluorine can lead to dramatic mechanistic consequences. These can lead to 
mechanistic deviations and enzyme inhibition. 
Replacement of both methylene hydrogens by fluorine can lead to more 
dramatic effects, most likely due in part to conformational differences 
(i.e., angle widening of adjacent atoms from the normal sp.sup.3 
tetrahedral angle of 109.5.degree. to about 115-119.degree. in --CF.sub.2 
--). The electronic properties of fluorine also result in its being a 
relatively poor hydrogen bond acceptor, with a hydrogen bond strength of 
about half of that for oxygen. 
Incorporation of a tri-substituted silyl group attached to the 
.gamma.-carbon of fluoropropargyl phosphonates activates the C--Si bond 
towards electrophilic attack and stabilizes the .alpha.-carbanion. The 
presence of this group greatly increases the versatility of the synthon 
with respect to substituents at the .gamma.-carbon and reactions at the 
.alpha.-carbon. Previous methods involving acetylenic deprotonation and 
alkylation of propargyl alcohols required a completely new synthesis each 
time a new .gamma.-carbon substituent was desired. With the new synthons, 
a variety of substituents can be directly introduced at the .gamma.-carbon 
without remaking the synthon. These substituents are introduced via such 
reactions as electrophilic additions and transition metal couplings. 
The trialkylsilyl, diarylalkylsilyl, aryldialkylsilyl or triarylsilyl group 
also plays a role in stabilizing the carbanion at the .alpha.-carbon 
through hypercovalency on the silicon via a cumulene-type resonance with 
the .alpha.-carbanion. This effect can counteract a possible negative 
resonance contribution on that carbanion by the fluorine. 
The alkyl groups attached to silicon can be chosen from short chain (i.e., 
1 to 5 carbons) alkyl groups, such as methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl, t-butyl, and the like. The groups may be all the same, 
some the same, or all different. Further examples of tri-substituted silyl 
substituents useful in the present invention are trimethylsilyl (TMS), 
triusopropylsilyl (TIPS), diphenylmethylsilyl (DPMS), and 
t-butyldimethylsilyl (TBDMS) substituents. 
The nature of the phosphonate ester substituents can influence the 
stereoselectivity of the Horner-Wadsworth-Emmons (HWE) reactions 
(discussed below). Electron withdrawing substituents reinforce the 
electron-withdrawing character of the phosphonate. Suitable substituents 
are alkoxy groups substituted with electron-withdrawing groups such as 
halogens, e.g., bis(2,2,2-trifluoroethoxy). 
The phosphonate ester groups can alternatively be attached via a linker 
group to a polymer. Reactions carried out in this way enable the solid 
state syntheses of many of the fluorinated compounds discussed herein. 
Solid state syntheses are rapidly carried out and provide pure compounds. 
Such methods can be used to develop combinatorial libraries of 
structurally related compounds, e.g., combinatorial libraries of 
fluorine-containing compounds. These libraries could be used, for example, 
in the discovery of drugs for use in the treatment of cancer, immune 
disorders, and inflammation, as well as in agricultural biology 
applications, in bioseparations, and in the development of other types of 
pharmaceuticals. 
For reactions carried out with at least one of the reagents immobilized on 
either a solid support or a soluble polymer, the polymer will generally 
include a cleavable or noncleavable linker which connects the reagent to 
the solid support or soluble polymer. Suitable linkers include organic 
linkers e.g., alkyl or aryl chains substituted with ester, amide, ether, 
thioester, thioether linkages, or any other linker that can be easily 
cleaved if so desired. Alternatively, the linker can be noncleavable, so 
as to enable the synthesis of fluorine-containing organic compounds bound 
to the solid support or soluble polymer. 
The polymer can be either a solid state resin such as a Wang resin, or a 
soluble polymer such as non-cross-linked chloromethylated polystyrene 
(NCPS). This polymer shows excellent properties, such as solubility in 
tetrahydrofuran (THF), dichloromethane, chloroform, and ethyl acetate, 
even at low temperatures (-78.degree. C.). NCPS is insoluble in water and 
methanol. These features allow traditional organic chemistry techniques 
such as solvent extraction, and methanol precipitation. Suitable polymers 
include hydroxyl-containing polymers such as Wang resin, or poly(ethylene 
glycol) PEG. Other examples of suitable polymers are non-cross-linked 
polystyrene type polymers, such as non-cross-linked chloromethylated 
polystryene (NCPS). 
The presence of a carbon-carbon triple bond (i.e., the propargyl group) 
allows a variety of reactions to yield, for example, cis and trans double 
bonds, Diels-Alder-type electrocyclic products, and photocycloaddition 
products. This group also provides additional stabilization of the 
.alpha.-carbocation through electronic resonance. 
Carbon-carbon triple bonds can be reduced to give cis-double bonds by 
hydrogenation with diisobutylaluminum hydride (DIBALH), hydrolysis of 
boranes, or a variety of catalysts including activated zinc, palladium, 
and other palladium based catalysts such as Pd--CaCO.sub.3 --PbO 
(Lindlar's catalyst). These reactions yield cis-alkenes. Hydrazine, Li- or 
Na-liquid NH.sub.3, LiAlH.sub.4, and chromium (II) salts such as chromous 
sulfate pentahydrate give trans-alkenes upon reaction with alkynes. 
Methods of Preparing the New Synthons 
The new synthons are .gamma.-tri-substituted silyl-.alpha.-fluoro- or 
.alpha.,.alpha.-difluoropropargyl phosphonates, and are synthesized by 
starting with propargyl alcohol. A solution of propargyl alcohol is 
treated with 2 equivalents of an alkylmagnesium halide (or other Grignard 
reagent). Tri-substituted silicon chloride is added, yielding 
.gamma.-tri-substituted silyl propargyl alcohol. Typically, propargyl 
alcohol is protected as its tetrahydropyranyl ether before silylation. 
The alcohol is oxidized to the aldehyde in a non-polar, non-protic solvent 
(e.g., dichloromethane) by Dess-Martin periodinane (aromatic iodonium 
triacetate salt). Alternatively, the oxidation can be carried out with 
oxalyl chloride according to Swern oxidation procedures (dimethylsulfoxide 
and triethylamine). The .gamma.-tri-substituted 
silyl-.alpha.-hydroxypropargyl phosphonate is prepared by reacting the 
aldehyde with dialkyl phosphite and potassium fluoride dihydrate 
(alternatively triethylamine or alkali metal salts of 
bis(trimethylsilyl)amide) overnight for a time long enough to achieve 
complete phosphorylation. Generally, this takes from 2 to 20 hours. 
Another suitable time range is from 6 to 12 hours. If 
bis(2,2,2-trifluoroethoxy phosphite is used, a Lewis acid, such as 
AlCl.sub.3, should be utilized to promote addition of phosphite to the 
carbonyl. 
At this point, if a .alpha.,.alpha.-difluoropropargyl phosphonate is the 
desired product, the .alpha.-hydroxypropargyl phosphonate can be subjected 
to modified Pfitzner-Moffatt oxidation. The reaction is carried out by 
adding 1-(3-dimcthylaminopropyl)-3-ethylcarbodiimide hydrochoride (2-10 
equivalents) and dichloroacetic acid (0.5-3 equivalents) to a cold 
solution (0.degree. C.) of the hydroxyphosphonate, to give the 
.alpha.-keto phosphonate. This step was followed by treatment with from 10 
to 30 equivalents of diethylaminosulfurtrifluoride (DAST) at low 
temperatures (below 0.degree. C., for example from 0.degree. C. to 
-80.degree. C.) under a dry, inert atmosphere (N.sub.2 or Ar) to give the 
desired difluoropropargyl phosphonate. 
Alternatively, treatment of the monofluorinated product with DAST or the 
Ishikawa reagent (PCR, Gainesville, Fla.) yields the desired 
.gamma.-tri-substituted silyl-.alpha.-fluoropropargyl phosphonate 
(conditions as above). 
The .gamma.-tri-substituted silyl-.alpha.,.alpha.-difluoropropargyl 
phosphonate can also be prepared with the monofluoro phosphonate as a 
starting material by fluorinating the same with alkali metal salts of 
bis(trimethylsilyl)amide, and N-fluorobenzenesulfonimide (NFSI) or 
SELECTFLUOR.TM. (Air Products & Chemicals, Inc., Allentown, Pa.). 
This reaction pathway is shown in Scheme 1 . 
##STR4## 
Alternatively, the synthesis can carried be out in a slightly different 
manner. Propargyl alcohol is reacted with para-toluenesulfonic acid (PPTS) 
and a protecting group such as a trialkylsilyl or diphenylalkylsilyl group 
or dihydropyran (DHP) in a polar, aprotic solvent. This is followed by 
treatment with n-butyllithium and tri-substituted silyl chloride at low 
temperature (0.degree. C. or below, such as between 0.degree. C. and 
-20.degree. C.). This is followed by treatment with PPTS in a polar, 
protic solvent such as an alcohol. Ethanol is suitable for this purpose. 
This is followed by oxidation with pyridinium chlorochromate (PCC) in a 
nonpolar aprotic solvent at room temperature. Methylene chloride is 
suitable for this purpose. Reaction with diethylphosphite and a basic 
reagent such as potassium difluoride hydrate (KF.sub.2 H.sub.2 O), 
triethylamine (TEA), or sodium bis(trimethylsilyl)amide yields 
.gamma.-tri-substituted silyl-.alpha.-hydroxypropargyl phosphonate. This 
product can be subjected to modified Pfitzner-Moffatt oxidation. The 
reaction is carried out by adding 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochoride (2-10 
equivalents) and dichloroacetic acid (0.5-3 equivalents) to a cold 
solution (0.degree. C.) of the hydroxyphosphonate, to give the 
.alpha.-keto phosphonate. This is followed by treatment with DAST in an 
aprotic, nonpolar solvent such as methylene chloride (under an inert 
atmosphere (N.sub.2 or Ar) and anhydrous conditions, at 0.degree. C. or 
below, for example 0.degree. C. to -80.degree. C.) to give 
.gamma.-triakylsilyl-.alpha.,.alpha.-difluoropropargyl phosphonate. 
As described above, the .alpha.-hydroxypropargyl phosphonate itself can be 
reacted with DAST in in an aprotic, nonpolar solvent such as methylene 
chloride at low temperatures under a dry, inert atmosphere to give 
.gamma.-tri-substituted silyl-.alpha.-fluoropropargyl phosphonate. 
The .gamma.-tri-substituted silyl-.alpha.-fluoropropargyl phosphonate can 
also be synthesized by reacting 1-tri-substituted silyl-l-propyne with a 
sodium, lithium, or potassium salt of bis(trimethylsilyl)amide, lithium 
diusopropylamide, or n-butyl lithium in tetrahydrofuran (THF) at 
-20.degree. C., followed by the addition of diethyl chlorophosphate. After 
workup with saturated aqueous ammonium chloride, ether extraction, drying, 
and chromatographic separation, the product .gamma.-tri-substituted 
silylpropargyl phosphonate is isolated. The product can be subsequently 
added as a THF solution to a solution of sodium bis(trimethylsilyl)amide 
in THF at -80.degree. C. A fluorinating agent such as SELECTFLUOR.TM. (Air 
Products & Chemicals, Inc., Allentown, Pa.) or solid 
N-fluorobenzenesulfonimide (NFSI) can be added, the mixture is then 
allowed to warm, is poured into water, and finally extracted into ether. 
The extracts are dried, concentrated, and purified by chromatography. The 
resulting product is .gamma.-trisubstituted silyl-.alpha.-fluoropropargyl 
phosphonate, which is used to make the .alpha.,.alpha.-difluoro 
phosphonate via fluorination, as described above. 
This reaction pathway is shown in Scheme 2. 
##STR5## 
Reactions of the New Synthons 
The new fluorine-containing synthons can be used to provide a plethora of 
fluorine-containing organic compounds through a variety of synthetic 
methods. These methods include reactions providing modifications at the 
.alpha.-carbon, the .gamma.-carbon, the triple-bond, and the phosphonate 
moiety, or combinations of these modifications. 
Nucleophilic Alkylations at the .alpha.-Carbon 
The .gamma.-tri-substituted silyl-.alpha.-fluoropropargyl phosphonates 
allow considerable stabilization of the .alpha.-carbanion due to the 
synergistic effect of the combined electronic characters of the fluorine, 
phosphonate, carbon-carbon triple bond, and tri-substituted silyl groups. 
This feature greatly facilitates nucleophilic addition of the 
.alpha.-carbanion to a variety of alkylating agents, yielding new 
carbon-carbon bonds. 
These alkylating agents include substituted or unsubstituted compounds in 
the following classes: haloalkanes, alkyl tosylates, alkyl brosylates, 
alkyl nosylates, alkyl mesylates, and other compounds containing groups 
recognized in the art as being good leaving groups, as well as 
allylhalides, benzylhalides, and other compounds able to stabilize the 
positive charge developed in electrophilic addition. 
The products are .gamma.-tri-substituted 
silyl-.alpha.-alkyl-.alpha.-fluoropropargyl phosphonates and have the 
following structures: 
##STR6## 
in which R.sub.1, R.sub.2, and R.sub.3 are, independently alkyl or aryl, 
each R is the same or different than the other R and is alkyl, haloalkyl 
or an organic linker, and R' is alkyl, aryl or alkylaryl. 
These reactions are generally carried out by reacting the 
.gamma.-tri-substituted silyl-.alpha.-fluoropropargyl phosphonate with an 
alkylating reagent in the presence of a base, in a solvent, at low 
temperature. Suitable bases include sodium ethoxide, potassium t-butoxide, 
and sodamide. Suitable solvents include polar, aprotic solvents such as 
dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane or 
tetrahydrofuran (THF). The reaction is generally carried out at low 
temperatures, such as below 0.degree. C. The reactions can also be carried 
out at lower temperatures such as -20.degree. C. to -100.degree. C. 
Electrophilic Substitution at the .gamma.-Carbon 
The .gamma.-carbon of the new synthons is vulnerable to attack by 
electrophiles. Typically useful electrophiles are activated 
carbonyl-containing organic compounds, including substituted and 
unsubstituted organic aldehydes, such as benzaldehyde, pentanal, 
2-buteneal, and 2-octynal, substituted and unsubstituted carboxylic acids 
and acid anhydrides, as well as acyl halides, such as benzoyl chloride. 
The product is a conjugated ynone. 
The products are fluorinated .gamma.-ketoalkylpropargyl phosphonates having 
the following structure: 
##STR7## 
in which E is ketoalkyl, ketoaryl or ketoalkylaryl, X is F or H, and each 
R is the same as, or different than, the other R and is alkyl, haloalkyl 
or is linked to a tether. 
This reaction is facilitated by the presence of Lewis acid catalysts, such 
as metal halides. Useful examples are aluminum trihalides, e.g., 
AlCl.sub.3. This reaction can be carried out at low temperatures, such as 
below 0.degree. C. Other suitable temperature ranges include from 
0.degree. C. to -100.degree. C., or from -20.degree. C. to -80.degree. C. 
Reactions with Carbonyls 
Homer-Wadsworth-Emmons (HWE) reactions of the .gamma.-tri-substituted 
silyl-.alpha.-fluoropropargyl phosphonates with substituted or 
unsubstituted aliphatic, aromatic, or propargyl aldehydes result in the 
formation of conjugated fluoroenynes and fluoroenediynes, respectively, as 
does the reaction with substituted or unsubstituted aliphatic, aromatic, 
or propargyl ketones. Typically useful aliphatic aldehydes are pentanal 
and 3-chloropent-2-enal. Typically useful aromatic aldehydes are 
benzaldehyde and p-hydroxybenzaldehyde. Substitutents can be any 
containing alkyl, carboxylic acid, amine, amide, alcohol, cyano, nitro, 
heterocyclic or amino acid groups. Typically useful aliphatic ketones 
include cyclopenanone and methylvinyl ketone. Typically useful aromatic 
ketones include benzophenone and p-hydroxyacetophenone. Substitutents can 
be any containing alkyl, carboxylic acid, amine, amide, alcohol, cyano, 
nitro, heterocyclic or amino acid groups. The fluoroenyne products are 
extremely useful as peptide isosters. 
Typically useful propargyl aldehydes and ketones include 2-octynal and 
non-3-yn-2-one. The fluoroenediyne products can serve as models for the 
active enediyne moiety recently found in naturally occurring antibiotics 
and anticancer agents including esperomicin a.sub.1 and calicheamicin 
.gamma..sub.1. The Bergman rearrangement of enediynes leads to p-diradical 
benzene structures. The use of fluoroenediynes is expected to illuminate 
the reaction mechanism by altering the rate of the rearrangement. 
The .gamma.-tri-substituted silyl-.alpha.-fluroenyne products have the 
following general structure: 
##STR8## 
in which R.sub.1, R.sub.2, and R.sub.3 are, independently alkyl or aryl, 
and R and R' are alkyl or hydrogen. 
The .gamma.-tri-substituted silyl-a-fluoroenediyne products have the 
following general structure: 
##STR9## 
in which R.sub.1, R.sub.2, and R.sub.3 are, independently alkyl or aryl, 
and R and R' are alkyl or hydrogen. 
The reaction is generally carried out in the presence of a base, such as 
sodium ethoxide, alkali metal salts of bis(trimethylsilyl)amide or 
sodamide, in a polar, non-protic solvent such as THF, DMSO or HMPA. The 
reactions are carried out at low temperatures, for example below 0.degree. 
C. Suitable temperature ranges are from 0.degree. C. to -100.degree. C., 
or from -20.degree. C. to -80.degree. C. The reagents are mixed and 
allowed to warm up to room temperature overnight. 
In the HWE reaction path, the trans-fluoroalkene moiety, 
.psi.(Z)-CF.dbd.CH!, is a potentially useful peptidomimic. That is, it is 
viewed as a functional substitute for the amide bond in peptides, based on 
its planar geometry, molecular weight, and direction of polarization. The 
synthons developed herein play a critical role in the synthesis of peptide 
mimics because they are equipped with the necessary elements for 
interconversion into .psi.(Z)-CF.dbd.CH! via the HWE reaction, assuming 
the stereoselectivity of the resulting enzyme can be controlled. 
As mentioned above, the stereoselectivity of the HWE reaction can be 
influenced by the nature of the phosphonate ester substituents. Increasing 
the electron-withdrawing power of the phosphonate ester substituents 
results in increasing the proportion of (Z) alkenes. Substituents which 
can accomplish this are substituted alkoxy groups, and good examples are 
the halogenated alkoxy substituents. For example, this can be accomplished 
with bis(2,2,2-trifluoroethoxy) groups. 
Solid Phase Condensations with HWE 
The HWE reaction can also be used in the solid phase to obtain conjugated 
fluoroenynes. Fluoroenynes have been used to investigate the perception 
processes of insects, as analogs of sex pheromones in insects. The solid 
phase syntheses of organic compounds is important in the field of 
combinatorial chemistry. The HWE reactions outlined above can be adapted 
to the solid phase synthesis of fluoroenynes. This provides the first 
example of the solid phase synthesis of vinylfluoro compounds. 
The preparation is carried out by reacting a hydroxy-containing resin 
(e.g., a Wang resin) with a halophosphorin, such as 
2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one, in CH.sub.2 Cl.sub.2 
/pyridine, followed by cleavage with NaHCO.sub.3 -TEA to produce a 
triethylamine salt of a polymer-linked phosphite. Reaction of this salt 
with pivaloyl chloride, and subsequent reaction with a nucleophile (e.g., 
an alcohol) yields a polymer-linked phosphonate ester which is used as a 
common precursor to synthesize fluorine-containing organic compounds in 
the solid state. 
Reaction of the polymer-linked phosphonate ester with a unsubstituted or 
.gamma.-substituted propargyl aldehyde yields a polymer-linked 
.alpha.-hydroxypropargyl phosphonate. Treatment of this species with a 
fluorinating agent, e.g., diethylaminosulfurtrifluoride (DAST) or 
SELECTFLUOR.TM. (Air Products & Chemicals, Inc. Allentown, Pa.) at low 
temperatures (below 0.degree. C., for example 0.degree. C. to -80.degree. 
C.) in a dry, inert atmosphere (N.sub.2 or Ar), yields the polymer-linked 
.alpha.-fluoropropargyl phosphonate. HWE reaction of this species with a 
carbonyl compound, such as a ketone or aldehyde, under basic conditions 
cleaves the product fluoroenyne from the polymer. The E:Z stereochemistry 
of this reaction is roughly 1:1. 
Reactions with Transition Metal Complexes 
The silylalkyne moiety can be targeted for use as a platform for coupling 
reactions using Pd, Zr (e.g., Cp.sub.2 ZrHCl; Schwartz's reagent) and Ru 
catalysts. Palladium reagents are exemplified by bis(PPh.sub.3)PdCl.sub.2. 
Another useful reagent is ruthenium tetrakis(PPh.sub.3).sub.4. The 
reactions are generally carried out in polar, aprotic solvents like THF, 
DMSO, or hexamethylphosphoramide (HMPA) at low temperatures such as 
0.degree. C. to -100.degree. C. or from -20.degree. C. to -80.degree. C. 
The products of metal coupling reactions have the following general 
structure: 
##STR10## 
in which M is a metal complex such as bis(cyclopentadienyl)zirconium 
hydrochloride, tetrakis(triphenylphosphine) ruthenium, 
bis(triphenyl-phosphine) palladium dichloride, or 
tetrakis(triphenylphosphine) palladium, X is F or H, and each R is the 
same as, or different than, the other R and is alkyl, haloalkyl, or an 
organic linker. 
The reactions are generally carried out by first desilylating the synthon. 
This is accomplished by reaction with a halide, such as fluoride, followed 
by hydrometallation with one of the metal complexes named above, to give 
the fluorinated .gamma.-propenyl phosphonate metallocomplex. This species 
serves as a useful gateway for a wide variety of transformations such as 
reactions with Michael acceptors in the presence of Ni(AcAc).sub.2, 
iodination to produce vinyliodide phosphonates, and copper coupling 
reactions followed by reaction with epoxides or Michael acceptors to 
produce a variety of fluorophosphonate hydroxides and ketones, 
respectively. All of the above transformations can be carried out with 
either the mono- or difluorophosphonates described above. 
Cyclizations with Alkenes (Diels-Alder and Photocycloadditions) 
The triple bond is a convenient framework for cyclization reactions. The 
Diels-Alder reaction can be carried out with mono- or difluorinated 
propargyl phosphonates using cyclic and acyclic dienes with and without 
inverse electron demand. 
Reaction of fluorinated .gamma.-tri-substituted silylpropargyl phosphonates 
with cyclic dienes such as cyclopentadiene, and cyclopentadienone result 
in bicyclic fluorophosphonates. The subsequent decarbonylation of the 
cyclopentadienone adduct provides a facile entry into the realm of 
substituted benzylic fluoro- and difluorophosphonates. These classes of 
compounds represent an important mimic of O-phosphotyrosyl residues, key 
factors in signal transduction pathways. Reaction with acyclic dienes 
containing electron-withdrawing groups such as esters is also 
contemplated. For example, reaction of fluoropropargyl phosphonates with 
ethyl pentadienoate is quite suitable. These reactions are generally 
carried out at elevated temperatures such as 30.degree. C. to 100.degree. 
C., or for example, 50.degree. C. to 80.degree. C. Lewis acid catalysts 
such as AlCl.sub.3 can be used. Solvents useful for these reactions 
include polar, aprotic solvents such as DMF, DMSO, and CH.sub.3 CN, as 
well as nonpolar, aprotic solvents such as methylene chloride. 
Photocycloadditions with the fluorinated propargyl compounds are also 
possible. Such reactions include 2+2! photocycloadditions with alkenes to 
yield substituted cyclobutenes. These reactions can be carried out through 
either direct or sensitized excitation of either the alkynyl or alkenyl 
moiety. Generally, energy sufficient to excite the .pi.,.pi.* transition 
is required. This typically requires the equivalent of light energy in the 
150 nm to 400 nm region. These reactions can be carried out in polar, 
protic solvents such as alcohols, polar aprotic solvents such as 
acetonitrile, apolar aprotic solvents such as methylene chloride. 
Applications for the Products 
Peptide Isosters 
The terminal conjugated fluoroenynes produced by HWE reactions can be used 
to synthesize peptide analogs in which the amide linkage is replaced by a 
trans alkene (.psi.E-CH.dbd.CH!) to produce peptidomimics. The new 
peptidomimics typically have a backbone that is partially or completely 
non-peptide, but with side groups identical to the side groups of the 
amino acid residues that occur in the peptide on which the peptidomimic is 
based. This isosteric replacement can be used, for example, to prepare 
renin inhibitors. 
On the basis of its planar geometry, molecular weight, and direction of 
polarization, the trans-fluoroalkene moiety has been regarded as a 
potentially useful peptidomimic. The new synthons described herein can be 
pivotal intermediates in peptidomimic synthesis, because they are equipped 
with the necessary elements for interconversion into .psi.Z-CH.dbd.CH! 
via HWE reactions, assuming the stereochemistry of the resulting enzyme 
can be controlled. This can be accomplished through control of the nature 
of the phosphonate ester substituents. 
Use of the fluoroenynes as peptidomimics can be accomplished by reacting 
the .psi.(Z)-CF.dbd.CH! isomer of a .gamma.-tri-substituted 
silyl-.alpha.-fluoropropargyl phosphonate with a substituted amino 
aldehyde to give a substituted amino .gamma.-tri-substituted silyl 
fluoroenyne with .psi.(Z)-CF.dbd.CH! stereochemistry. Removal of the 
tri-substituted silylpropargyl group with dicyclohexylborane hydride and 
hydrogen peroxide yields the desired substituted fluoroene amino acid. The 
fluoroene unit is located in the backbone of the amino acid. Subsequent 
incorporation of the fluoroene amino acid in a peptide allows the use of 
the compound as a peptidomimic. 
Biological Phosphate Mimics 
The new fluorinated propargyl phosphonates and products of reactions 
thereof are useful as biological phosphate mimics. Fluorinated propargyl 
phosphonates can be transformed into fluorine-containing phosphonic 
analogs of nucleotides, and fluorine-containing analogs of binding 
partners of phosphorylases and phosphokinases. For example, the disodium 
salt of 2-hydroxy phosphonyl difluoromethyl propenoic acid, an isopolar 
and isosteric analog of phosphenolpyruvate (PEP), can be readily prepared 
using the new synthons. Non-fluorinated PEP is a ubiquitous compound in 
biological systems, and plays an important role in glycolysis. Fluorinated 
PEP analogs do not have transferrable phosphates and illuminate glycolysis 
mechanisms through inhibition of the enzymes responsible for phosphate 
transfer. 
In addition, purines linked to phosphates by 1,1-difluoro-2-butenyl chains 
can be prepared by .gamma.-carbon desilylation/alkylation and triple-bond 
reduction procedures.

EXAMPLES 
The invention will be further described in the following examples, which do 
not limit the scope of the invention described in the claims. The examples 
illustrate the syntheses and methods of using new fluorinated propargyl 
phosphonates. Also presented are typical reactions of the new phosphonates 
with representative classes of reagents to produce fluorine-containing 
organic molecules. 
Example 1 
Synthesis A of .gamma.-(TIPS)-propargyl-.alpha.-fluorophosphonate 
A solution of trilsopropylsilyl (TIPS)-propargyl alcohol (10.323 g, 48.6 
mmol) in dichloromethane (50 mL) was added dropwise to a solution of 
Dess-Martin periodinane (22.63 g, 53.35 mmol) in dichloromethane (200 mL). 
A mildly exothermic reaction ensued and the mixture was stirred at room 
temperature for 30 minutes. The reaction mixture was quenched by pouring 
it into a mixture of aqueous NaOH (500 mL, 1 M) and ether (900 mL). The 
organic phase was dried (MgSO.sub.4) and concentrated in vacuo. 
Distillation of the crude product afforded TIPS-propargyl aldehyde. The 
boiling point was 70-73.degree. C. at 0.45 torr (9.8235 g, 96%). The 
proton nuclear magnetic resonance spectra (.sup.1 H NMR) were recorded in 
deuterochloroform (CDCl.sub.3) and gave the following signals: .delta. 
1.10 (m, 21H), 9.21 (s, 1H); .sup.13 C (CDCl.sub.3) 11.2, 18.6, 101.0, 
104.7, 176.8; IR (film, NaCl) v 2950, 2870, 2150, 1670, 1465, 1000, and 
890 cm.sup.-1. Analysis calculated for C.sub.12 H.sub.22 OSi: C: 68.51, H: 
10.54. Found: C: 68.26, H: 10.45. 
A mixture of TIPS-propargyl aldehyde (9.8169 g, 46,66 mmol), diethyl 
phosphite (6.2 mL, 48.13 mmol) and potassium fluoride dihydrate (11.0 g, 
116.8 mmol) was stirred overnight. The reaction was taken up in ether (200 
mL) and washed with water (3.times.50 mL). The ethereal extract was dried 
(MgSO.sub.4) and concentrated in vacuo to afford a thick oil which changed 
to a waxy solid upon storage at low temperature (15.6105 g, 96%). This 
material (TIPS-propargyl-.alpha.-hydroxyphosphonate) was judged 
homogeneous by analytical TLC (50% ethyl acetate/hexanes): .sup.1 H NMR 
(CDCl.sub.3) .delta. 1.09 (s, 21H), 1.35 (m, 6H), 4.23 (m, 4H), 4.71 (d, 
J=15.9 Hz, 1H); .sup.31 P NMR .delta. 17.9. Analysis calculated for 
C.sub.16 H.sub.33 O.sub.4 PSi: C: 55.14, H: 9.54. Found: C: 54.87, H: 
9.65. 
A solution of TIPS-propargyl-.alpha.-hydroxyphosphonate (3.1438 g, 9.02 
mmol) in dichloromethane (50 mL) was added dropwise via cannula to a 
solution of diethylaminosulfurtrifluoride (DAST) (6.6 mL, 48.5 mL) in 
dichloromethane (100 mL) at -80.degree. C. and the resulting reaction 
mixture was allowed to reach room temperature slowly overnight. The 
reaction was quenched carefully with saturated aqueous sodium bicarbonate 
(100 mL), the organic layer was separated and the aqueous layer was 
extracted with dichloromethane (2.times.50 mL). The combined organic 
extracts were dried (MgSO.sub.4) and concentrated in vacuo to give a dark 
red oil. Purification of the crude product by flash chromatography (10-30% 
ethyl acetate/hexanes+4% triethylamine) afforded 1.3027 g (41%) of 
TIPS-propargyl-.alpha.-fluorophosphonate: .sup.1 H NMR (CDCl.sub.3) 
.delta. 1.09 (s, 21H), 1.37 (t, J=7.1 Hz, 6H), 4.28 (m, 4H), 5.35 (dd, 
J=47.0, 12.5 Hz, 1H); .sup.19 F NMR .delta. -196 (d, J=79 Hz); .sup.31 P 
NMR .delta. 11.4 (d, J=79 Hz); Infrared spectra (IR) were recorded with 
the sample as a film, on NaCl plates, and gave the following results: v 
2950, 2870, 2180, 1460, 1275, 1060, 1020 and 885 cm.sup.-1. Analysis 
calculated for C.sub.16 H.sub.32 FO.sub.3 PSi: C: 54.83, H: 9.20. Found: 
C: 54.77, H: 9.23. 
Example 2 
Synthesis B of .gamma.-(TIPS)-propargyl-.alpha.-fluorophosphonates 
To a cold solution (-20.degree. C.) of 1-triisopropylsilyl-1-propyne 
(0.8878 g, 98%, 4.43 mmol) in tetrahydrofuran (15 mL) was added 
n-butyllithum (2.9 mL of a 1.53 M solution in hexanes, 4.44 mmol). After 
15 minutes, the resulting solution was transferred via cannula to a 
solution of diethylchlorophosphonate (1.0 mL, 97%, 6.71 mmol) in THF (5 
mL) at -80.degree. C. After the addition was completed, the reaction 
mixture was allowed to warm up to room temperature overnight. The reaction 
was poured into saturated aqueous ammonium chloride (50 mL) and extracted 
with ether (3.times.30 mL). The combined organic extracts were dried 
(MgSO.sub.4) and concentrated. Flash chromatography (30% ethyl acetate in 
hexanes) of the residue afforded the desired phosphonate (0.200 g, 14%). 
.sup.1 H NMR (300 MHz, CDCl.sub.3) .delta. 1.07 (s, 21H), 1.35 (t, J=7.3 
Hz, 6H), 2.85 (d, J=22.2 Hz), 4.19 (m, 4H); .sup.31 P NMR .delta. 21.9 
(s). 
To a solution of sodium bis(trimethylsilyl)amide (0.70 mL of a 1 M solution 
in THF) in THF (1.3 mL) at -80.degree. C. was added a solution of 
TIPS-propargylphosphonate (0.1966 g, 0.59 mmol) in THF (1 mL). After 1 
hour, solid N-fluorobenzenesulfonimide (NFSI, 0.280 g, 0.89 mmol) was 
added in one portion. The reaction mixture was allowed to warm up to room 
temperature, poured into water (10 mL), and extracted with ether 
(3.times.10 mL). The combined organic extracts were dried (MgSO.sub.4) and 
concentrated in vacuo. The residue was triturated with hexanes, filtrated 
and concentrated. The resulting oil was purified by flash chromatography 
(30% ethyl acetate in hexanes) to afford the desired 
TIPS-propargylfluorophosphonate (0.106 g, 51%). .sup.1 H NMR (CDCl.sub.3) 
.delta. 1.09 (s, 21H), 1.37 (t, J=7.1 Hz, 6H), 4.28 (m, 4H), 5.35 (dd, 
J=47.0, 12.5 Hz, 1H); .sup.19 F NMR .delta. -196 (d, J=79 Hz); .sup.31 P 
NMR .delta. 11.4 (d, J=79 Hz); IR (film, NaCl) v 2950, 2870, 2180, 1460, 
1275, 1060, 1020, and 885 cm.sup.-1. 
Example 3 
Synthesis A of .gamma.-(TIPS)-propargyl-.alpha.,.alpha.-difluorophosphonate 
A cold solution (0.degree. C.) of (0.5 mmol) 
.gamma.-(TIPS)-propargyl-.alpha.-hydroxyphosphonate in DMSO-toluene is 
reacted with 1-(3-dimethylaminopropyl)-3-ethylcarbodlimide hydrochloride 
(2.5 mmol) and dichloroacetic acid (0.75 mmol)(Pfitzner-Moffatt 
conditions). The reaction is stirred for five hours after which the 
reaction is quenched with water and extracted with chloroform (3.times.25 
mL). The organic layers are combined, washed with saturated NaHCO.sub.3 
(3.times.20 mL), dried over MgSO.sub.4, filtered, and concentrated. The 
resulting oil is dissolved in dry methylene chloride (10 mL) and treated 
with DAST (0.01 mol) at 0.degree. C. after which the stirred mixture is 
allowed to warm to room temperature. After stirring at 25.degree. C. for 
12 hours, the mixture is diluted with methylene chloride and transferred 
dropwise into KOH solution at 0.degree. C. The aqueous layer is separated 
and the organic layer washed with saturated NaHCO.sub.3 (3.times.20 mL). 
Organic layers are combined, dried over MgSO.sub.4, filtered, and 
concentrated to yield 
.gamma.-(TIPS)-propargyl-.alpha.,.alpha.-difluorophosphonate. 
Example 4 
Synthesis B of .gamma.-(TIPS)-propargyl-.alpha.,.alpha.-difluorophosphonate 
To a solution of .gamma.-(TIPS)-propargyl-.alpha.-fluorophosphonate (0.6 
mmol in 1 mL THF), is added 1.1 molar equivalents of solid 
N-fluorobenzenesulfonimide (NFSI) in one portion. The reaction mixture is 
allowed to warm up to room temperature, poured into water (10 mL) and 
extracted with ether (3.times.10 mL). The combined organic extracts are 
dried (MgSO.sub.4) and concentrated in vacuo. The residue is triturated 
with hexanes, filtrated, and concentrated. The resulting oil is purified 
by flash chromatography (30% ethyl acetate in hexanes) to afford the 
desired .gamma.-(TIPS)- propargyl-.alpha.,.alpha.-difluorophosphonate. 
Example 5 
Olefination of Benzaldehyde with TIPS-propargyl fluorophosphonate 
To a solution of diisopropylamine (0.130 mL, 0.93 mmol) in tetrahydrofuran 
(5 mL) at 0.degree. C. was added dropwise n-butyllithium (0.60 mL of a 
1.53 M solution in hexanes, 0.92 mmol). After 5 minutes, the solution was 
cooled to -80.degree. C. and a solution of TIPS-propargylfluorophosphonate 
(0.2862 g, 0.82 mmol) in tetrahydrofuran (1 mL) was added dropwise. After 
the addition was completed, benzaldehyde (1.1 equivalents) was added neat 
and the reaction mixture was allowed to reach room temperature. The 
reaction mixture was poured into saturated aqueous ammonium chloride (10 
mL) and extracted with ether (3.times.15 mL). The combined organic 
extracts were dried (MgSO.sub.4) and concentrated in vacuo. Products were 
purified by flash chromatography using silica gel and hexanes containing 
4% of triethylamine as eluent. 
Obtained in 90% yield as a circa 1:1 mixture of isomers: .sup.1 H NMR 
(CDCl.sub.3) .delta. 1.09-1.20 (m, 21H), 6.06 (d, J=34.9 Hz, vinylic 
hydrogen of Z isomer), 6.59 (d, J=17.1 Hz, vinylic hydrogen of E isomer), 
7.25-7.36 (m, 3H), 7.50 (d, J=7.4 Hz, corresponding to 2H aromatic of one 
of the isomers), 7.70 (d, J=6.9 Hz, corresponding to 2H aromatic of one of 
the isomers); .sup.19 F NMR .delta. -102 (s) and -105 (s); IR (film, NaCl) 
v 3060, 3030, 2950, 2870, 2150, 1690, 1470, 1135, 925 and 890 cm.sup.-1. 
Analysis calculated for C.sub.19 H.sub.27 FSi: C: 75.44, H: 9.00. Found: 
C: 75.52, H: 8.89. 
Example 6 
Olefination of 2-octynal with TIPS-propargyl fluorophosphonate 
The reaction was carried out as in Example 2, using 2-octynal as the 
carbonyl compound. Obtained in 87% yield as a circa 1:1 mixture of 
isomers: .sup.1 H NMR (CDCl.sub.3) .delta. 0.87-0.92 (m, 3H), 1.07-1.19 
(m, 21H), 1.25-1.39 (m, 4H), 1.48-1.57 (m, 2H), 2.29-2.39 (m, 2H), 5.32 
(dt, J=28.8, 2.4 Hz, 1H Z isomer), 5.67 (dt, J=8.0, 2.5 Hz, 1H E isomer); 
.sup.19 F NMR .delta. -97 (s) and -102 (s); IR (film, NaCl) v 2940, 2870, 
2220, 2150, 1615, 1460, 1185, 1150 and 885 cm.sup.-1. Analysis calculated 
for C.sub.20 H.sub.33 FSi: C: 74.94, H: 10.38. Found: C: 74.95, H: 10.31. 
Example 7 
Olefination of Cyclopentanone with TIPS-propargyl fluorophosphonate 
The reaction was carried out as in Example 2, using cyclopentenone as the 
carbonyl compound. Obtained in 74% yield: .sup.1 H NMR (CDCl.sub.3) 
.delta. 1.10 (apparent s, 21H), 1.68-1.73 (m, 4H), 2.38-2.45 (m, 4H); 
.sup.19 F NMR .delta. -114 (s); IR (film, NaCl) v 2960, 2865, 2145, 1675, 
1460, 1245, 1155 and 885 cm.sup.-1. 
Example 8 
Olefination of 2-butenal with TIPS-propargyl fluorophosphonate 
The reaction was carried out as in Example 2, using 2-butenal as the 
carbonyl compound. Obtained in 84% yield as a circa 1:1 mixture of 
isomers: .sup.1 H NMR (CDCl.sub.3) .delta. 1.09-1.14 (m, 21H), 1.75-1.80 
(m, 3H), 5.71-5.86, 6.16-6.20 and 6.30-6.40 (three multiplets accounting 
for 3H); .sup.19 F NMR .delta. -111.9 (s) and -112.4 (s); IR (film, NaCl) 
v 3040, 2950, 2870, 2150, 1610, 1460, 1270, 1140, 970 and 885 cm.sup.-1. 
Example 9 
Olefination of Methyl Benzyl Ketone with TIPS-propargyl fluorophosphonate 
The reaction was carried out as in Example 2, using methyl benzyl ketone as 
the carbonyl compound. Obtained in 81% yield as a circa 1:2 mixture of E:Z 
isomers: .sup.1 H NMR (CDCl.sub.3) .delta. 1.00 (m, corresponding to 21H 
of isomer Z), 1.14 (m, corresponding to 21H of isomer E), 2.11 (d, J=4.0 
Hz, corresponding to 3H of isomer Z), 2.20 (d, J=3.4 Hz, corresponding to 
3H of isomer E), 7.23-7.36 (m, 3H), 7.41-7.50 (m,2H); .sup.19 F NMR 
.delta. -108 (s) and -112 (s); IR (film, NaCl) v 3060, 3030, 2950, 2870, 
2150, 1645, 1465, 1195, 1065 and 890 cm.sup.-1. Analysis calculated for 
C.sub.20 H.sub.29 FSi: C: 75.89, H: 9.23. Found: C: 75.88, H: 9.28. 
Example 10 
Olefination of Pentanal with TIPS-propargyl fluorophosphonate 
The reaction was carried out as in Example 2, using pentanal as the 
carbonyl compound. Obtained in 89% yield as a circa 1:1 mixture of E:Z 
isomers. However, flash chromatography afforded a few fractions containing 
only one of the isomers. Isomer E: .sup.1 H NMR (CDCl.sub.3) .delta. 0.90 
(t, J=7.1 Hz, #H), 1.10 (m, 21H), 1.29-1.42 (m, 4H), 2.12-2.19 (m, 2H), 
5.61 (dt, J=14.7, 8.2 Hz, 1H); .sup.19 F NMR .delta. -109 (s). Isomer Z: 
.sup.1 H NMR (CDCl.sub.3) .delta. 0.90 (t, J=7.1 Hz, #H), 1.09 (m, 21H), 
1.33-1.39 (m, 4H), 2.15-2.18 (m, 2H), 5.24 (dt, J=33.5, 7.8 Hz, 1H); 
.sup.19 F NMR .delta. -112 (s). IR (film, NaCl) v 2950, 2870, 2160, 1655, 
1460, 1115 and 885 cm.sup.-1. Analysis calculated for C.sub.17 H.sub.31 
FSi: C: 72.27, H: 11.06. Found: C: 72.37, H: 11.04. 
Other Embodiments 
It is to be understood that while the invention has been described in 
conjunction with the detailed description thereof, the foregoing 
description is intended to illustrate and not limit the scope of the 
invention, which is defined by the scope of the appended claims. Other 
aspects, advantages, and modifications are within the scope of the 
following claims.