Polymer-Supported Synthesis

A Phosphorane as Supported AcylanionEquivalent: Linker Reagents for Smooth andVersatile C�C Coupling Reactions**

Steffen Weik and J�rg Rademann*

Polymer supports are employed widely in diversity-orientedorganic chemistry, either in solid-phase synthesis in whichproducts are assembled on a cleavable linker moiety,[1] or inpolymer-assisted solution-phase (PASP) synthesis using poly-mer reagents and scavengers.[2–4] Recently, we introducednovel polymer reagents for important organic transforma-tions including alkylating[5] and oxidating polymers.[6, 7] Toestablish more complex reaction sequences including C�Ccoupling steps, polymer-supported carbanion equivalentswould be an ideal addition to the synthetic repertoire inpolymer-assisted synthesis. Lithiated dithioacetals[8–10] havebeen described as polymer-supported carbanion equivalents,however, these reagents are strongly basic and are thus of nouse for the efficient parallel synthesis of sensitive products.Ideally, the successful method should allow reactions witheasily available building blocks, under smooth, neutral con-ditions, and further derivatization after the C�C couplingstep.

To establish polymer-supported acyl anion equivalents 1,several different concepts were investigated (Scheme 1). Theresults for the reactions of polymer-supported thiazoliniumsalts (Y= 2-thiazolidenyl) and polymer-supported dialkylhydrazones (Y=NNR2) with amino acid electrophiles 2 willbe reported in due course. As a third approach, phosphoraneswere investigated as polymer-supported acyl anion equiva-lents (Y=P). The norstatine isostere 3 (Scheme 1) wasselected as a synthetic target for our study of carbanionequivalents as it represents a class of potent proteaseinhibitors of metallo and aspartate proteases.[11, 12]

Polystyrene-bound triphenylphosphane (4 ; Scheme 2;1.2 mmolg�1) is a classical polymer reagent,[13,14] which isroutinely employed in supported halogenation, Mitsunobu,

[*] Dr. J. Rademann, Dipl.-Chem. S. WeikInstitute for Organic ChemistryEberhard-Karls University T(bingenAuf der Morgenstelle 18, 72076 T(bingen (Germany)Fax: (+49)7071-29-5560E-mail: joerg.rademann@uni-tuebingen.de

[**] Part of this work was presented at the ORCHEM 2002 in BadNauheim (Germany). We gratefully acknowledge generous supportfrom Prof. G. Jung and from Prof. M. E. Maier, T(bingen, theStrukturfonds of the University of T(bingen, DFG project “ReactiveIntermediates in Polymeric Gels” (Ra 895/2), from the Fonds derChemischen Industrie, Novabiochem AG (LEufelfingen, Switzer-land), and Personal Chemistry GmbH (Konstanz (Germany)). Wethank Andreas Petri, Bojan Bister and Daniel Bischoff for analyticalsupport.

Supporting information (representative spectra of compounds 9–23) for this article is available on the WWW under http://www.angewandte.org or from the author.

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2491Angew. Chem. Int. Ed. 2003, 42, 2491 – 2494 DOI: 10.1002/anie.200351190 � 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

and Wittig reactions.[14, 15] To our knowledge this is the firstreport using it as a starting point for polymer-supported acylanion equivalents. Compound 4 was alkylated with bromo-acetonitrile in toluene under microwave irradiation (150 8C,15 min) yielding phosphonium salt 5 quantitatively (elemen-tal analysis; Scheme 2). Compound 5 was converted bytreatment with triethylamine into the stable and storablephosphorane 6 which has a characteristic yellow color.

The coupling of protected amino acids to 6 was inves-tigated employing various condensation agents. Reactionswere monitored by ATR-IR (ATR= attenuated total reflec-tion), yields could be quantified byspectrophotometric Fmoc-deter-mination. The success of the acyla-tions depended critically on therigorous exclusion of water (seeTable 1, entries 1 and 7), whichindicates the comparably lownucleophilicity of cyanophosphor-ane 6. The method of choice waspreactivation with EDC as con-densing agent with DMAP inCH2Cl2 yielding up to 90 % of theacylation product in single cou-plings. The base-labile Fmoc-pro-tecting group was not affected bythe phosphorane. Thus, theR1 position could be varied con-veniently starting from a selectionof representative amino acids(Table 2, entries 1–6). Fmoc-pro-tected acyl cyanophosphoranes7a–d were deprotected (25%piperidine, DMF) allowing for var-iations in the liberated amino posi-tion R2 (Table 2, entries 7–14).

Finally, the acyl cyanophos-phoranes were efficiently cleavedby oxidation, either employingozonolysis at �78 8C or by usingfreshly distilled 3,3-dimethyl diox-

irane[16] at room temperature (Scheme 3). Cleavage wasaccompanied by decoloration of the resin and released thea,b-diketo nitriles 8. Compounds 8 are highly activatedelectrophiles that were converted in situ with O-, N-, and S-nucleophiles, to give the a-keto esters 9–17, the a-keto amide18, and the a-keto thioester 19 (Table 2). Excess of non-volatile N-nucleophiles employed in this reaction was

Scheme 1. Three pathways to construct the novel acyl anion equiva-lents 1 were investigated to identify a general concept allowing for var-iations in positions R1, R2, and R3. Bestatin (3a) as well as allophenyl-norstatine (3b) represent the norstatine family 3 of potent proteaseinhibitors.

Scheme 2. Supported phosphorane 6 was constructed by alkylation oftriphenylphosphane resin 4 under microwave irradiation, followed byproton abstraction. Acylation of 6 to give the acylphosphoranes 7a–dwas best effected by activation with the condensing agent EDC.EDC=N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride,DMAP=4-N,N-dimethylaminopyridine, Fmoc=9-fluorenylmethoxycar-bonyl.

Table 1: Coupling yields to polymer-supported acylanion equivalents determined by spectroscopicquantification of Fmoc groups.

Entry Amino acid Conditions[a] Product Yield [%]

15 equiv AA, 5 equiv DIC, 5 equiv HOBt·H2O,0.75 equiv DMAP, CH2Cl2, RT

7a 0

25 equiv AA, 5 equiv DIC, 0.75 equiv DMAP, CH2Cl2,RT

7a 60

35 equiv AA, 5 equiv EDC, 0.75 equiv DMAP, CH2Cl2,RT

7a 90

45 equiv AA, 5 equiv EDC, 0.75 equiv DMAP, CH2Cl2,RT

7b 83

55 equiv AA, 5 equiv EDC, 0.75 equiv DMAP, CH2Cl2,RT

7c 81

65 equiv AA, 5 equiv EDC, 0.75 equiv DMAP, CH2Cl2,RT

7d 54

75 equiv AA, 5 equiv EDC, 0.75 equiv DMAP, CH2Cl2,RT

7e 0

[a] AA=amino acid, DIC=diisopropylcarbodiimide, HOBt=Hydroxybenzotriazol.

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removed by using polymer-sup-ported anhydride as a scavengerresin (7.5 equiv, 60 8C).

Products 9–18 were obtained inyields between 43 and 65% in five(9–14) to 11 (15, 16) synthetic steps.In all the examples this corre-sponds to an average of > 90%per step. Reversed-phase HPLC-MS revealed that the ketocarbonylproducts were in equilibrium withthe respective hydrate and cyano-hydrine adducts. The keto productscould be characterized by massspectrometry and by fully assignedNMR spectra (1H, 13C, HSQC, andCOSY) in CDCl3. The purities ofa-keto esters were generally above70%; purities of amide productswere determined after the reduc-tion step.[17]

In the final step, direct conver-sion of the a-keto compounds intothe a-hydroxy esters 20–23 and a-hydroxy amide 24 was accom-plished with the reducing polystyr-ylmethyl-bound trimethylammo-nium borohydride resin (10 equiv,12 h) (Scheme 3, Table 3).[18,19]

Under the selected conditions both diastereomers wereobtained in roughly equal amounts and could be fullyassigned by NMR spectroscopy after purification byreversed-phase HPLC. The asymmetric reduction of a-ketocarbonyl compounds has been reported in the litera-ture.[20]

In summary, we have established a powerful novelconcept of polymer-supported acyl anion equivalents thathas been demonstrated to allow the addition of a large varietyof easily accessible activated carboxylic acids. Diversity in allrelevant positions of the core structure 3 could be smoothlyobtained. The supported acyl anion reagents form a novelclass of reagent linkers, which combine the intermediaryimmobilization of a substrate with a C�C coupling astransformation step. Variations with respect to electrophiles,on-bead transformations, and the cleavage reaction arecurrently under investigation.

Experimental Section6 : Triphenylphosphane polystyrene(0.5 g, 1.2 mmolg�1, 0.6 mmol, 1%divinylbenzene, 100–200 mesh, Nova-biochem) was suspended in dry toluene(3 mL). After addition of bromoaceto-nitrile (199 mL, 3 mmol) the vial wassealed and heated by microwave irra-diation (15 min, 150 8C, PersonalChemistry Creator). Following coolingto room temperature the vial wasopened. The resin was collected by

Table 3: Reduction of ketoesters, and -amides.

Entry Product R1 R2 R3 Yield [%] Purity [%]

1 20 Ac OMe 76 (42 mg) 72

2 21 Ac-Ser(tBu)-Ile OMe 87 (25 mg) 84

3 22 Ac-Asp(tBu)-Val OMe 90 (6.3 mg) 79

4 23 Fmoc OMe >95 (37 mg) 62

5 24 Ac >95 (18.8 mg) 68

Scheme 3. Oxidative cleavage of acylcyanophosphoranes 7. The inter-mediary diketo nitriles 8 react with O-, N-, and S-nucleophiles yieldingthe respective a-keto esters 9–17, the a-keto amide 18, and the a-ketothioester 19. Reduction of the a-keto products gives the a-hydroxyesters 20–23 and the a-hydroxy amide 24.

Table 2: Variations of the a-ketocarbonyl products in the isosteric building block (R1 position), in theN-terminal (R2) and C-terminal (R3) positions.[a]

Entry Product R1 R2 R3 Yield [%] Purity [%]

1 9 Fmoc OMe 65 (32 mg) 88

2 10 Fmoc OMe 54 (24 mg) 86

3 11 Fmoc OMe 50 (29 mg) 72

4 12 Fmoc OMe 55 (28 mg) 88

5 13 Fmoc OMe 59 (43 mg) 99

6 14 Fmoc OMe 63 (31 mg) 87

7 15 Ac-Ser(tBu)-Ile OMe 30 (17 mg) 71

8 16 Ac-Asp(tBu)-Val OMe 43 (25 mg) 80

9 17 Ac 55 (28 mg) 80

10 18 Ac 53 (18 mg) 68[b]

11 19 Ac 38 (20 mg) 62

[a] Yields were determined by weight, purities were determined by HPLC (detection at 214 nm)combining the signals assigned to the product equilibrium. [b] Purities of amide products weredetermined after the reduction step.

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filtration, washed with dry toluene, CH2Cl2 and Et2O (3 C each) anddried. Elemental analysis (%) calcd: N 1.05; found: 1.02. Theobtained triphenylphosphonium bromide resin was suspended in dryCH2Cl2 (5 mL) and triethylamine (418 mL, 3 mmol) was added. Themixture was agitated (2 h, RT), the solid collected by filtration,washed (MeOH, THF, CH2Cl2), and dried in vacuo. IR (ATR): n=3057, 3024, 2923, 2851, 2150, 1945, 1751, 1600, 1492, 1452, 1437, 1261,1183, 1115, 1028, 749, 697, 539 cm�1. 7: EDC (101 mg, 0.525 mmol),DMAP (10 mg, 0.079 mmol), and Fmoc-protected amino acid(0.525 mmol) were dissolved in dry CH2Cl2 (3 mL) and stirred for5 min. Cyanophosphorane polystyrene 6 (100 mg, 1.05 mmolg�1,0.105 mmol) was added and the reaction mixture was agitated (12 h,RT). The resin was collected by filtration, washed (MeOH, DMF,THF, CH2Cl2, and Et2O), and dried in vacuo. Coupling yields weremeasured by spectroscopic Fmoc-determination (see Table 1).Oxidative cleavage of resins yielding a-ketomethyl esters or a-ketoamides 9–17: 7a–d were suspended in a mixture of dry CH2Cl2 and therespective alcohol (2:1) under N2-atmosphere. At �78 8C thesuspension was purged with ozone until a blue-green color remains(5–10 min). Excess ozone was removed by a stream of N2. Afterwarming to RT the mixture was stirred (4 h) and filtered. The resinwas washed (CH2Cl2) and the solvents were removed in vacuo. 18 :Ozonolytic resin cleavage was conducted as described with dryCH2Cl2 as the only solvent. After ozone removal at �78 8C, theprecooled solution of an amine (1.5 equiv in respect to the resinloading determined by Fmoc-cleavage, CH2Cl2, �78 8C) was added bysyringe. The reaction mixture was kept at �78 8C (30 min), was thenwarmed to RT and stirred for 2 h. Excess amine was scavenged in asealed vessel by the addition of macroporous anhydride resin(Novabiochem, 7.5 equiv, 60 8C, 12 h). The resin was collected byfiltration, washed with CH2Cl2, and the solvent was removed in vacuo.Products 9–19 were characterized by NMR spectroscopy and LC-MS;purities and yields are given in Table 2.

Received: February 17, 2003 [Z51190]

.Keywords: C�C coupling · carbanions · combinatorialchemistry · protease inhibitors · solid-phase synthesis

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