Pentafluorophenyl diphenylphosphinate (FDPP)

[138687-69-1]  · C18H10F5PO2  · (384.25)

(reagent used as carboxyl activating group and coupling agent in a wide variety of amide bond formations)

Solubility: soluble in most organic solvents.

Form Supplied in: white powder and chunks.

Handling, Storage, and Precautions: decomposition occurs upon prolonged exposure to moisture in air. Storage in a cool dry place extends the life of the reagent. The toxicological properties have not been thoroughly investigated; however, hazardous combustion products may include, but are not limited to, carbon monoxide, carbon dioxide, hydrogen fluoride, and phosphorus oxides. FDPP is incompatible with strong oxidizing agents.

Physical Data: mp 47-50 °C

Purification: silica gel chromatography (short column to minimize decomposition) eluting with 20% ethyl acetate in petroleum ether followed by drying under reduced pressure for 2 days over phosphorus pentoxide.

Preparative Methods: FDPP can be conveniently prepared by mixing equimolar amounts of diphenylphosphinic chloride, pentafluorophenol, and imidazole in anhydrous CH2Cl2 at room temperature (eq 1).1 There are slight procedural variations in the literature as to order of addition and reaction duration.2,3 It has been found that using an excess of the diphenylphosphinic chloride (1.5-2 equiv) to drive the reaction to completion simplifies the purification, as the residual hydrolyzed reagent adheres tightly to the silica gel column and is, therefore, easier to separate than residual pentafluorophenol.4

Coupling to Generate Linear Molecules

When Chen and Xu reported the new reagent, FDPP, in 1991,1 the use of diphenylphosphinic mixed anhydrides in peptide chemistry was known,5,6 as was the use of pentafluorophenyl esters.7-11 However, the need to preactivate amino acids or to prepare active esters was unattractive. FDPP can be used directly as a coupling reagent without preactivation.1 Chen and Xu demonstrated the utility of the reagent by preparing several small oligopeptides in solution and by preparing Leu-enkephalin via solid-phase synthesis.1 Their solution-phase protocol called for equimolar amounts of the carboxyl and amine hydrochloride components, 3 equiv of Hünig's base, and 1.2 equiv of FDPP in DMF at room temperature for 1.5 h. The yields of isolated products were all greater than 80%. Using HPLC12 (for the coupling product of Z-Gly-Phe-OH and Val-OMe·HCl) and the Young test13 (for the coupling product of Bz-Leu-OH and Gly-OEt·HCl), they observed almost no racemization with FDPP; whereas, pentafluorophenyl diphenylphosphate (FDP)14,15, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate/1-hydroxybenzatriazole (BOP/HOBt), and dicyclohexylcarbodiimide (DCC) all showed significant levels of racemization. In the solid phase protocol, they employed the chloromethyl resin and carried out the reactions with 3 equiv of Boc-amino acid, FDPP, and 9 equiv of Hünig's base. This method provided extremely high yields and proved superior to the DCC method because no insoluble by-product was generated.

The use of FDPP in the formation of a variety of dipeptides has been studied in comparison to BOP, HBTU, and isobutyl chloroformate (IBCF).3 Product yields, HPLC diastereomeric yields,12 and optical rotations were measured for each example. In general, FDPP did give high yields and good optical purity. When Fmoc was used as the nitrogen protecting group, significantly lower yields and lower optical purity resulted. FDPP gave excellent yields for the formation of proline methyl ester dipeptides, outperforming HBTU, BOP, and IBCF; however, these reagents provided better optical purity than FDPP. Overall, BOP was the most successful coupling reagent for the dipeptides studied.

The search for an economical synthesis of the b-hydroxyproline fragment found in the cyclopeptide alkaloids nummularine F and mauritine was the impetus for another comparative study of carboxyl activating reagents (eq 2).16 Relatively expensive isopropenyl chloroformate (IPCF) was used previously for this reaction. It was shown that the more affordable FDPP and BOP-Cl both possessed reactivity comparable to IPCF. In addition, the reactivity of FDPP in this reaction was shown to be greater than that of BOP, pentafluorophenol/DCC, phosgene, diphenylphosphinic chloride, DCC, N,N-carbodiimidazole, 2,4,6-trichlorobenzoyl chloride, pentafluorophenyl trifluoroacetate, and oxalyl chloride.

In the cryptophycin synthesis, FDPP was employed for the coupling shown in eq 3.2 The amine component was used as its TFA salt, and when DCC/HOBt or BOP-Cl was used, the desired product was contaminated with the trifluoroacetamide to varying degrees. The problem could be circumvented by exchanging the counterion for tosylate, but this replacement incurred significantly longer reaction times. FDPP gave a comparable yield of product uncontaminated by the trifluoroacetamide.

FDPP has also been employed in the coupling of N-protected amino acids to substituted g-thiapyrone amines (eq 4).17 When a-amino acids were used, the yields varied from 48-61% over a range of substitution patterns. The authors observed no signs of racemization in the 1H and 13C NMR spectra. Using Fmoc-protected b-amino acids, yields ranged from 39-46% for different substitution patterns, and longer reaction times (7-9 h) were required. Peptoid carboxyl components gave even lower yields at the same extended reaction time. It is unclear whether the low yields, with b-amino acids and peptoids, are due to the nature of these molecules or to the Fmoc protecting group, which is known to give lower coupling yields when used with FDPP.3

One way of immobilizing stationary phases onto silica gel involves amide bond formation; wherein the coupling partners are stationary phases derivatized with a free carboxylic acid and silica gel derivatized with an amino group. Low yields and racemization of chiral stationary phases often prove problematic, so Yang and co-workers investigated a variety of conditions and coupling reagents for this reaction.18 While model reactions in solution phase gave generally high yields, the extent of racemization encountered with FDPP was greater than that found when using diisopropylcarbodiimide/1-hydroxy-7-azabenzotriazole (DIC/HOAt), DIC/HOBt, diphenylphosphoryl azide (DPPA), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU), and benzotriazolyloxy-tris[pyrrolidino]-phosphonium hexafluorophosphate (PyBop). However, for aminopropylsilica gel couplings (eq 5), yields were generally much lower, and the extent of racemization was much greater with all reagents except EEDQ. In this particular coupling, FDPP performed similarly to DIC/HOAt, DIC/HOBt, DPPA, HATU, and PyBop.

The use of FDPP has also been investigated for the thioacylation of iminoacid residues with monothioacids (eq 6).19 FDPP gave a good yield of coupled product (81%) but a very low ratio of thio to oxo product. It was found that, for this reaction, coupling reagents with a leaving group bearing a delocalized charge, such as PfpO-, had inherently lower selectivity for thioamide formation. Polar solvents also lowered the selectivity, and FDPP couplings are usually performed in DMF.

FDPP has also shown utility in the coupling of N-protected amino acid residues to linear diamino substrates bearing a free secondary hydroxyl group. The desired hydroxy amides were obtained in good yields for testing as HIV-1 protease inhibitors.20

Macrocyclization

While it is not always the reagent of choice, FDPP often provides excellent yields in macrocyclizations over a wide variety of substrates. In Deng and co-workers' 1994 synthesis of the macrocyclic pentapeptide cyclotheonamide B, FDPP was used to accomplish the macrolactamization in >80 % yield (eq 7).21

In their 1996 approach to the same molecule,22 the WSCI/HOBt-mediated macrolactamization, which had been performed in 42% yield on an analog that had a vinylogous D-tyrosine in place of the vinylogous L-tyrosine, yielded only 16% for the desired substrate. DPPA and diethyl phosphorocyanidate (DEPC) gave only 8% and 12%, respectively, even after an extended reaction time of 3.5 days. The pentafluorophenyl ester also gave only 8% cyclized product. However, cyclization with FDPP gave 43% yield in only 4.5 h, and optimization increased the yield to 57% (eq 8).

Deng and co-workers had similar success using FDPP for the macrolactamization en route to alterobactin A, a siderophore from an open ocean bacterium.23,24 In this case, FDPP in the presence of NMM in DMF provided a 53% yield of cyclized product despite the relative steric congestion about the amino terminus (eq 9).

During the synthesis of new didemnin B analogs for investigation of the structure activity relationship of these cyclodepsipeptides,25 improvements were made to the original26 macrocycle synthesis. Among these modifications was the use of FDPP for the cyclization step. Previously, the best yields (42%) had been attained with DPPA after 72 h at 0 °C.26 The product of dimerization was always a major contaminant despite the use of very dilute conditions. The use of FDPP at room temperature for 3-4 h accomplished the cyclization in 68% yield (eq 10).3,25

In a 1995 synthesis of the cryptophycins, FDPP was used for the macrolactamization reactions, giving a 62% yield of cryptophycin D (eq 11).2,27,28

The same yield was achieved for a similar cyclization to give a product that proved not to be identical with cryptophycin C, leading to a revision of the structure of this natural product. The following year, a chemoenzymatic approach to the molecule was published by a different group in an effort to make the synthesis amenable to gram-scale preparation.29 A more hindered site of cyclization was chosen, and FDPP cyclized in >70% yield in each case examined. A representative example is shown in eq 12.

In the synthesis of astin G,30 FDPP was useful for the coupling of the dipeptide and tripeptide fragments to form the linear precursor, giving the same yield (80%) as BOP. However, cyclization to form the 16-membered ring was unsuccessful with both FDPP and DPPA. HBTU proved to be the best reagent for this difficult cyclization, which proceeded in only 16% yield (eq 13).

Cyclooligomerization

A less common use for FDPP is the cyclooligomerization reaction. Bertram et al. found that cyclic peptides containing thiazole moieties could be efficiently constructed in one step from the monomeric unit (eq 14).31 They found that FDPP gave consistently high yields of cyclic products. The optimum procedure employed 3 equiv of Hünig's base and 1.5 equiv of FDPP added to a suspension of the monomer at a concentration of about 50 mM in acetonitrile. The reaction duration was approximately 18 h at room temperature. The yields were consistently >80% under these conditions, and the major products were the cyclic trimer and tetramer, in a ratio of 5:2.

Couplings on Microarrays

In a recent adaptation of DNA microarray technology, Korbel et al. have used chiral fluorescent probes to measure the ee of tens of thousands of samples on reaction microarrays.32 Their protocol employed an FDPP-mediated coupling of an equimolar mixture of two pseudoenantiomeric fluorescent reporters to the immobilized amino acid samples. During the coupling, the ee information of the sample becomes coded as a ratio of the fluorescent probes that is observable upon measurement of fluorescent emission at the appropriate excitation wavelength for each fluorophore.

Related Reagents.

DCC, EDAC, IPCF, DPPA, BOP, BOP-Cl, HBTU, HATU, DEPBT.


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Michael S. Leonard & Madeleine M. Joullié

University of Pennsylvania, Philadelphia, PA, USA



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