General Methods for the Synthesis of Difluoromethylphosphonates

Chapter 26

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General Methods for the Synthesis of Difluoromethylphosphonates Thierry P. Lequeux Laboratoire de Chimie Moléculaire et Thio-organique, UMR CNRS 6507, University of Caen, ENSICAEN, 6 Boulevard du Maréchal Juin, F14050 Caen, France

Due to the limitation of methylenephosphonates as biological models of phosphates, difluoromethylenephosphonates have been, and are still a center of interest as stable isopolar phosphate mimics. However, the major drawback to prepare potential enzyme inhibitors lies in the difficulties to introduce this function onto complex molecules. This chapter describes the most common methods reported in the literature to prepare such structures.

1. Fluorophosphonates as Isoacidic Analogs of Phosphates It has been shown that the replacement of the bridging oxygen atom of a phosphate by a difluoromethylene adequately maintain the acidity of the phosphonic moiety (J). Moreover, the difluoromethylenephosphonate group appears to approximate most closely the geometry of the phosphate group (2). In the alkyl- or benzyl-phosphonates series, the introduction of a single fluorine atom is often enough to restore the iso-acidic character (5, 4, 5, 6). It is generally assumed that the phosphate unit will be fully ionized on protein binding, and difluoromethylenephosphonates has emerged as excellent pyrophosphate and phosphate surrogates.

440

© 2005 American Chemical Society

In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

441


2. Synthesis of Difluoromethylenephosphonates Up to date, numerous efforts have been, and are still focus on the development of general synthetic methodologies to prepare a variety of structures containing the difluoromethylenephosphonate function. The most common routes presented here are: (a) the nucleophilic or free radical introduction of the difluoromethylenephosphonate unit; (b) the elaboration of this functional group from gem-difluoroalkenes; (c) the introduction of fluorine atoms by fluorination of (keto-) phosphonates; (d) the elaboration of complex structuresfrombuilding-blocks already fluorophosphorylated (figure 1).

(RO) (0)PCF —Y 2

2

Y = H, Met, Hal, S, Se

(a)

P(0)(OR)

2

l

(d)

(RO) (0)PCF 2

2

Figure 1,

2.1 The Direct Introduction of the Difluoromethylenephosphonate Unit Kondo's and Burton's groups have originally developed the direct introduction of the difluoromethylenephosphonate function from 7/3

56-79%

R = Bu, CH OH, C0 R, Ph, CONR Downloaded by NORTH CAROLINA STATE UNIV on September 29, 2012 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch026

2

2

2

Scheme 10. More recently, we showed that the addition of the phosphonodifluoromethyl radical onto alkenes, mediated with tributyltinhydride/initiator, allows the onestep synthesis of secondary phosphonates (57). Both secondary and primary difluoromethyl-phosphonates were prepared from alkylsulfanyl- or alkylselenyldifluorophosphonates. Using this approach, free radical addition onto dihydrofuran, afforded secondary phosphonofuran derivative in one step and in 47% yield (scheme 11).

47%

Scheme 11.

2.2 Construction of the Difluoromethylenephosphonate Function The construction of this function can be realized by carbon-phosphorus or by carbon-fluorine bond formations. The first method involves the addition of a phosphonyl radical onto difluoroalkenes, and the second the electrophilic or the nucleophilic fluorination of phosphonates.

2.2.1 Carbon-Phosphorus Bond Formation Few examples of carbon-phosphorus bond formation were reported. This method was applied to the synthesis of carbohydrates containing a difluoromethylenephosphonate. Products were obtained in a selective manner


447 by the addition of a dialkoxyphosphonyl radical onto 2,2-disubstituted gemdifluoroalkenes (58, 59) (scheme 12).


W J^I

ρ

+ HP(X)(QEt)

R = Ph, C9H R* = CH

2

19

/ B u Q Q C

Q

/ B U

( ) benzene 62°C/40h 60-72%

» V-CF P(X)(OEt) 2

2

3

x=o,s Scheme 12. From difluoroenol ethers the bimolecular homolytic substitution of diethoxyphosphonylphenyl selenide with tin radical furnished the best results (60, 61).

2.2.2 Carbon-Fluorine Bond Formation The fluorination of α-ketophosphonates has been explored in the synthesis of phosphotyrosine mimics, in which the bridging oxygen was replaced by a difluoromethylene (4). The reaction needed harsh conditions and best results were observed by running the fluorination neat in the presence of excess of DAST (scheme 13). Protected amino-acids were tolerated allowing a one-step synthesis of modified phosphotyrosine (62). NHBoc C0 Bz 2

Et NSF 2

neat 69%

ρ j^^C0 Bz

3 a

2

F^*J P(0)(OEt)

2

Scheme 13.

Another method is the fluorination of methylenephosphonates by using electrophilic fluorinating reagent (63). N-fluoro-benzenesulfonimide allows to obtain a variety of structures when the difluorination is conducted in two steps (64) (scheme 14). Nevertheless, from non-activated phosphonates, products were obtained in low yields (65). When F-TEDA was used, difluorination of activated phosphonates in one-pot sequence was preferred (66,67).


448

F

1 ) KDA

R"^P(0)(OR)

2

FF

)(PhS0 ) NF 61-70%

2

R

2 2

P (

°

R-H,CH ,Bu 3

) ( O R ) 2

^jî

9

b o c

^^(CH h 2


Scheme 14.

The synthesis of difluoromethylenephosphonate by using nucleophilic fluorinating reagents was less explored. The use of HF-base complex to introduce two fluorine atoms has been reported for the fluorination of sulfides through a halogen-exchange reaction or an electrolyticfluorination(15, 68). We showed that the chlore-fluor exchange can be performed with the non-corrosive 3HF-NEt3 complex in the presence of zinc bromide. This method allows to prepare alkylsulfanyl α,α-difluoromethylphosphonate in good yields (scheme 15), as new sources of both phosphonodifluoromethylfreeradical and carbanion (15,57). F F

1)S0 C1 2

RS

2

P(0)(0IPR)2

r-*°CF P(0)(OR) 2

RS*P(oxo.PorL ·ΟΡ ΟΚ 2Ρ{ΟΧ

R = Me, Et, Bu, Bz

2

Z n B r

)2

2

55-65%

Scheme 15.

2.3 The Building Block Approach Due to the difficulties to run the selective introduction of the difluoromethylenephosphonate function onto complex molecules, the buildingblocks approach can be used as alternative strategy to prepare fluorinated analogs of phosphates. Selected representative examples are described here.

Synthesis based on difluoromethylene-bisphosphonates and -phosphonoac The most used in the series is the difluoromethylenebisphosphonate (/, 12% which was directly incorporated into nucleotides, and terpenes (69). On the other hand, phosphonoacetate derivatives were involved in multi-step synthesis (Scheme 16). For example, thymidine analogs were prepared through their derivation into functionalized chiral phosphonoalcohols (70, 71). Its oxidative


449 cleavage, followed by a ring closure reaction of the intermediate aldehyde afforded the key lactones in good yield.

FF

F F

(EtO) (0)P^C0 Et Downloaded by NORTH CAROLINA STATE UNIV on September 29, 2012 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch026

2

(EtO) (0)PCF 2

2

(ΕΐΟ^Ο^^^Ν^

2

β

V°"j

Scheme 16.

Synthesis based on diethyl 2-oxo-l l-difluoroethylphosphonate hydrate t

The diethyl 2-oxo~l,l-difluoroethylphosphonate hydrate has been used as masked aldehyde (34). When involved in Horner-Wadworth-Emmons or Henry's reaction, a variety of activated difluoroallylic phosphonates were prepared (43, 72) (scheme 17). OH (EtO) (0)PCF -/ _ _ Z ^ 2

CF P(0)(OEt) f XJ 2

2

OH

p o hS

2

2

o

OH Y 1

/CF2

p

(0)(

OEt)

2

0-^So Ph 2

Scheme 17. These activated alkenes reacts with dienes to afford cyclic secondary difluoromethylenephosphonates as intermediate in the synthesis of DFMPAfunctionalized cyclohexene derivatives of biological interest (73, 74). Cyclohexene derivatives can be also prepared by cycloaddition carried out from electron-rich phosphonodifluoromethyl-homodienes (75).

Synthesis based on the diethyl difluorophosphonomethyldithioacetate Until recently, no multi-step syntheses were developed from fluorinated phosphonodithioesters. Derivation of the dithioacetate into thioamide was achieved in one-step from amines and amino-acids. By ring closure of intermediate amido-alcohols, we prepared functionalized thiazolines and thiazoles derivatives, which can be used as precursors of potent PNP inhibitors (76) (scheme 18).


450

(E«) (0)PCF SCH 2

2T

3

(EtO) (0)PCF 2

2

N

v


Scheme 18.

This activated dithioester can be also involved in hetero Diels-Alder reactions to prepare thiopyranosyl derivatives (77).

Synthesis based on allylic difluoromethylenenephosphonate derivatives The diethyl l,l-difluoro-3-butenylphosphonate, has been first derived into pivotal structures for the preparation glycerate analogs (78). Its use as free radical acceptor allows the preparation of thionucleotide analogs (79). The key step is the synthesis of a functionalized xanthate. The thiolactone was obtained by a ring closure reaction of the intermediate thiol (scheme 19). CF P(0)(OEt) 2

(I

C(S)OR

2

(EtO) (0)PCF/^^ 2

Scheme 19.

3. Conclusion As summarized herein, numerous efforts have been made to prepare analogs of phosphates by different methods. However due to the presence of fluorine atoms the synthesis of complex structures is rather difficult, and the known methods described for the preparation of methylenephosphonates cannot be applied. New reagents and building blocks are still needful for the preparation of analogs of bio-active compounds, and, in particular, reagents easy to handle, and methods opening a rapid access to secondary difluoromethylphosphonates.


451


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General Methods for the Synthesis of Difluoromethylphosphonates

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