Protecting groups KRZYSZTOF JAROWICKI and PHILIP KOCIENSKI Department of Chemistry, The Universiy, Southampton SO1 7 lBJ, UK Reviewing the literature published in 1994 1 2 2.1 2.2 2.3 2.4 3 4 5 6 7 7.1 7.2 8 9 10 Introduction Hydroxyl protecting groups Esters Silyl ethers Alkyl ethers Alkoxyalkyl ethers Thiol protecting groups Diol protecting groups Carboxyl protecting groups Phosphate protecting groups Carbonyl protecting groups 0,O-Acetals S, S-Acetals Amino protecting groups Books and Reviews References 1 Introduction The following review covers new developments in protecting group methodology which appeared in 1994. The review is not comprehensive but a selection of methods which we deemed interesting or useful. In addition to examples gleaned from casual reading, the references were selected through a Science Citation Index search based on the root words block, protect, and cleavage.The review is organized according to the functional groups protected with emphasis being placed on deprotection conditions. In the accompanying schemes, transformations for which the scale is specified imply that full experimental details were provided in the original reference. 2 Hydroxyl protecting groups 2.1 Esters Biotransformations continue to make significant contributions to protecting goup technology. For example, the acetyl esterase enzyme from the flavedo of oranges chemo- and regio-selectively removes acetyl groups from carbohydrates and nucleosides (Scheme l).' However, the exquisite gentleness and selectivity of the reaction exacts its price: 350 rnL of solvent are needed for 1 mmol of substrate.In another example, Fujii and co-workers2 reported a simple strategy for the generation of catalytic antibodies which can regioselectively and stereoselectively deprotect acylated carbohydrates. 0 OAc Acetyl esterase (20 units) 0.15 M NaCl(350 rnL) pH I 6.5 (adjusted with 0.02 M NaOH), r.t. 52% (1 rnmol scale) I 0 OH Scheme 1 Magnesium metal in methanol (i.e. magnesium methoxide) deprotects alkyl esters selectively by transesterification in the order p-nitro- benzoate > acetate >benzoate > pivaloate 9 trifluoroacetam ide (Scheme 2)3. 6 O M e HO Mg (3.0 eq.) NHCOCF3 BtO *oMe NHCOCF3 MeOH, 9196 r.t., 13 hr. * Scheme 2 Electrochemical methods are not a stock in trade of the typical synthetic chemist but two recent reports amply illustrate the potential of the method.In the first report, a new route to semisynthetic docetaxel analogues (Scheme 3) was accomplished by the selective electrochemical cleavage of the 2-benzoate as the key rea~tion.~ The optimized electrochemical reduction of 1 in a mixture of methanol and acetonitrile in the presence of tetraethylammonium acetate and acetate buffer at E-2.0 to -2.05 V versus SCE (5.5 F mol-' used) gave the 2-debenzoyl taxoid 2 in 79% yield on a 30 g scale. In the second example, electrochemical reductive cleavage was a ploy used to selectively remove only one of the tosyl groups from the bistosylate 3 during a synthesis of the furobenzofuran precursors of the carcinogenic aflatoxins 13' (Scheme 4). Jarowicki and Kocienski: Protecting groups 315FOCH20Me O A P h Q OMe 1 0 +2 e (-205 V ks SCE) c+ - 5.5 F mi-' EbNBF4 (0.1 M) EtNOAc (0.05 M) MeOH-MeCN (1:l) 79% (30 Q -1 FOCH20Me 2 OMe Scheme 3 TsO 0 $0- Pd(0Ac)flPTS (12) (5 d%) HNEt2 (5 q.) C3HFN (3 ml), H2O (0.5 ml) 20 min, r.t.1 1ooo/. (I mnol scale) 9" Ph+ Scheme 5 2.2 Silyl ethers Selective cleavage of primary and secondary TMS, TIPS, TBS, and TBDPS ethers has been accomplished with neutral alumina by stirring in the presence of a non-polar solvent like hexane.8 The deprotection rate depends on the steric bulk of the silicon substituents, following the order TMS + TBS -TIPS > TBDPS. The procedure can discriminate between different silyl groups located at equivalent positions of the same molecule, affording the corresponding monoprotected alcohols in very good yields.Potassium carbonate/Kriptofix 222 deprotects phenolic silyl ethers' and under these conditions the alkanolic silyl ethers remain unaffected. On the other hand PPTS or BF3 - OEt, removes only alcoholic silyl ethers (Scheme 6). -1 275 V TEAB, MeCN, 20 hr. 63X (3.62 mmol scale) i TsO Scheme 4 Genet and co-worker~~'~ have reported the removal of allyloxycarbonyl (Aloc) groups from protected alcohols using a water soluble Pd' catalyst [prepared in situ from Pd(OAc)* and trisodium 3,3',3"-phosphinetriyltribenzenesulfonate (TPPTS)] with diethylamine as ally1 scavenger. Scheme 5 illustrates the selective deprotection of an Aloc group without affecting a neighbouring dimethylallylcarbamate. The best result is obtained in a biphasic butyronitrile-water system with 5% of Pdo.Scheme 6 0 K&03 (0.5 mmol) Kryptofa 222 (0.065 mmol) MeCN (0.5 mL), 55 "C, 2 hr. 1 72% (0.13 mmol scale) PPTS (0.1 eq.) EtOH, 50 "C, 1 hr. or r.t., 70% BF@Et, (2 q.) 0 I 316 Contemporary Organic SynthesisPirrung and co-workers" reported a new method of deprotecting nucleosides and nucleotides bearing silyl protecting groups using commercially available triethylamine trihydrofluoride (Scheme 7). Work-up is accomplished by simple evaporation and chromatography thereby avoiding aqueous work-up. Excess triethylamine was added before work-up in some cases, but products of depurination were not observed even in its absence despite the seemingly acidic nature of the reagent. It is also harmless to pivaloyl, allyl, dimethoxybenzoin (DMB), and cyanoethyl protection.EtaNWF (4-10 q.) THF, 8-1 6 hr. 1 61% DMB = dimethoxybenzoin Scheme 7 During a recent synthesis of the antibiotic tunicamycin, Myers, and co-workers" required mild and efficient methods for the large-scale deprotection of anomeric TBS ethers. The first procedure (Scheme 8) uses triethylamine trihydrofluoride to accomplish the task in 97% yield. The second procedure effected deprotection of the pure a-glycoside 4 in quanatitative yield using the trihydrate of KF in MeOH but the product was obtained as a mixture of anomers (a : /.? = 2 : 1). Note the selective removal of the anomeric TBS ether in the case of 4. Kremsky and Sinha12 have reported that TBS and TIPS ethers can be removed from nucleosides under mild conditions by treatment with a mixture of potassium fluoride trihydrate and 18-crown-6 in DMF or THF at room temperature.Both acid and base-labile protecting groups are unaffected. are readily cleaved at room temperature using HF generated in situ from the reaction of BF3.0Et2 with 4-methoxy~alicylaldehyde.'~ The reaction time needed for complete deprotection is faster than t -Butyldiphenylsilyl ethers or triphenylsilyl ethers Et$+3HF (250 mmd) MeCN (120 mL) r.t., 6 hr. 67% (28.6 mmol scale) I 4 KF3H20 (1 27.5 mmd) MoOH (100 ml) rl., 6.5 hr. 100% (23.3 mmol scale) I OBOM O W BzO..flNPhth ym PhSel= 0 .'OH OLO* 0 OH a : g = 2 : 1 Scheme 8 TBAF or BF, - OEt, alone. t-Butyldiphenylsilyl ethers are usually more difficult to cleave than t-butyldimethylsilyl ethers - especially in acid - but Scheme 9 shows a selective deprotection of a primary TBDPS ether in the presence of a secondary TBS ether using 10% NaOH in relwring MeOH.14 Bu$Ae2Si0--{-r - OSi Ph2Bu' 10% NaOH in MeOH (I0 ml) A, 3 hr.87% (2 mmol scale) I Bu'Me2Si0 - - { -7 - - OH Scheme 9 A new silylation of base-sensitive alcohols has been described by Tanabe and co-worker~.'~ The procedure uses silazanes in the presence of a catalytic amount ( - 0.02 eq.) of tetrabutyl- ammonium fluoride (TBAF) (Scheme 10). The use of more hindered silazanes such as the bissilyl derivative of 5,5 -dimethylhydantoin allows regioselective TMS or TBDMS protection of primary hydroxy groups in the presence of secondary and tertiary ones. The same research group also found that hydrosilanes and disilanes can be used instead of silazanes in TBAF-catalysed protection of primary and secondary alcohols.'6 TMS protected alcohols can be prepared directly from carbonyl compounds via reductive silylation.l7 The procedure is limited to ketones and nonenolizable aldehydes and is accomplished by treating them with lithium hydride, TMSCl and a Jarowicki and Kocienski: Protecting groups 317O H 0 N ~ N T M S \-I 2 eq. TBAF (0.02 eq.) DMF, r f , 1 hr. 88% Scheme 10 0 lln (UH), (1.5 eq.) ?TMS -0"' &Sic1 (1.5 q.) Zn(OSOzMe)z (0.01 eq.) CH&h (30 mL), 28 "C, 50 hr. 50% (50.7 r n d scak) 1 mmol 5 <OH 6 7 L = coordinating liiand, X = CI, Br 8 catalytic amount of zinc salts or zinc powder (Scheme 11). groups in butane-1,2,4-triolS was achieved via st annanediyl acetal methodology.l8 Although stannanediyl acetal formation can give either 6 or 7, silylation (TBDMSC1, 1.2 eq.) occurs exclusively at the primary hydroxy of the 1,3-diol system to give 8 in ~ 9 9 % yield (Scheme 12); however, acylation, tosylation, and benzylation occur preferentially at the primary hydroxy group of the 1,2-diol system to give 9, 10, and 11 respectively. The silylation of hindered alcohols is greatly accelerated by the use of silyl triflates in place of the chlorides. The one silyl protecting group for which the triflate procedure is precluded is the t-butyl- diphenylsilyl group whose triflate cannot be prepared in the usual way owing to easy protiodesilylation of the aromatic rings. However, the rate of silylation with t-BuPh,SiCl can be boosted with the aid of silver nitrate." In the example shown in Scheme 13, silylation of an equatorial hydroxyl occurred preferentially over its adjacent axial neighbour.Regioselective protection of the primary hydroxy 2.3 Alkyl ethers Methyl aryl ethers can be demethylated" using 1,- Selectride and SuperHydride (Scheme 14). L- Selectride is the more effective reagent while electron-poor arenes work best. Ethyl ethers react 0 R = Ac, 71% 10 R = Ts, 72% 12 R=TBS,O% 11 R = Bn, 70% Scheme 11 Scheme 12 Bu'Ph#lCI (56 rnmd) AgN03 (52 rnmol) F'yr (0.215 mol) ''6- 'OMe THF 70% (20 (43 ml), mmol r.t., scale: 3 hr. Scheme 13 LiaHauS3 (1.1 eq.) in THF 67"C,3d 92% or b LIBHE13 (1.5 q.) in THF EtO 67 "C, 5 d EtO 88% Scheme 14 much slower than methyl ethers so selective deprotection is possible.the dynemicins, Myers and co-workers*' encountered problems with the lability of the dimethyl acetal function in 13 (Scheme 15) whilst removing the robust phenolic methyl group using sodium thioethoxide in hot DMF. These workers found that prior conversion of the free hydroxy function in the substrate into the magnesium salt 14 During a synthesis of quinone imine precursors to 3 18 Contemporaiy Organic Synthesis13 EtMgBr 1 1 14 Scheme 15 by reaction with EtMgBr afforded protection for the dimethylacetal under the strenuous conditions of nucleophilic demethylation. functions in polyoxygenated natural products and their precursors can be very inefficient. Evans and co-workers22 systematically investigated some of the known mild methods in the search for optimum conditions.Scheme 16 depicts two of the procedures which were especially fruitful. Both methods suffer from the high cost of the bases required. For all its simplicity, the 0-methylation of alcohol MeOTf (1 5 eq.) CHCI+ 60 "C, 6.3 hr. 2.&dCt-butyl4mthylWldi110 (30 bq.) R = M e Scheme 16 The allyl group in its various guises has gained favour as a hydroxyl protecting group due to its stability under basic and acidic conditions. Zhu and c o - ~ o r k e r s ~ ~ reported a way of removing this group from protected phenols using sodium borohydride and a catalytic amount of Pd(PPh3)4 (Scheme 17). A range of reducible functional groups are compatible like nitro groups, acetals, carboxylic acids, nitriles, carbamates, and imides.However, allyl esters are cleaved selectively in the presence of allyl ethers. Ph Ph NaBH, (0.287 ml) THF (2 mL) 1 hr., r.t. 97% (0.10 mmol scale) Pd(PPh& (0.02 w.) - Scheme 17 Ho$ph Benzyl ethers are amongst the oldest and most often used protecting groups typically removed by hydrogenolysis or dissolving metal reduction. A study on the oxidative debenzylation using dimethyldioxirane carried out by Csuk and co- w o r k e r ~ ~ ~ showed that the reaction proceeds well with benzyl ethers of primary and secondary alcohols and the method is compatible with silyl ethers (Scheme 18). Isopropylidiene acetals are stable but benzylidene acetals are cleaved. The deprotection of p-bromo, p-cyano and 2-naphthyl- methyl ethers can also be accomplished. Due to its R = -CH,Ph, -CHrpBr-CeH4 -CH2-2-Napht hyl -CH2-pCN-CeH, dimdhyldioxirane (60 ml of ca 0.1 M acetone Pdutkn) CH&12 (10 ml), 48 h, r.t.85-80% (1 mmd scale) Scheme 18 1,2-ck-arrangement and the stereoelectronically disfavoured anomeric equatorial C-0 linkage, construction of /?-mannosides based on conventional technology is difficult to achieve. Ito and Ogawa have recently devised an ingenious solution to the problem (Scheme 19) by using the well known oxidative lability of p-methoxybenzyl ethers to create a temporary anchor that fixes the position of the nucleophilic partner in a p-methoxyphenyl a~etal.*~ In the subsequent glycosidation step the Jarowicki and Kocienski: Protecting groups 319OMe I BnO BnO x F (0.16 mmol) Dw (0.10 mmol) 4 A MS (0.3 g) _____t CHZCI, (2.5 d) BnO \ BnO 74*& overall Scheme 19 ROH (0.121 mnol) _____c OMe I I &On (0.24 mnol). SnCl, (0.24 mmd) 2.6-difBu-4-Mepyr (0.24 mmo9 4 A MS (0.3 g), Et,O (I0 mL), r.t, 2.4 hr.OMe I + OMe BnO BnO BnO Bno neighbouring acetal ensures delivery of the nucleophilic partner from the P-face giving an intermediate whose capture by water results in stereospecific formation of the desired P-mannoside. A recent synthesis of the thrombin inhibitor cyclotheonamide B (15) was notable for the use of the simultaneous deprotection of an arginine 4-methoxy-2,3,6-trimethylbenzenesulfonyl group and a phenolic 2,6-dichlorobenzyl ether using trifluoroacetic acid in the presence of thioanisole as a carbocation scavenger.26 Both protecting groups survived dilute HCl in dioxane, LiOH in aqueous THF, TMSOTf (used to remove a Boc group), TBAF (used to cleave a trimethylsilylethyl ester), and a Dess-Martin oxidation (Scheme 20).Falck and c o - ~ o r k e r s ~ ~ have described a novel protecting group for primary and secondary alcohols prepared from commercial 1,1,1,3,3,3-hexafluoro- 2-phenylisopropyl (HIP) alcohol using DEAD and Ph3P (Scheme 21). The oustanding chemical resistance of the HIP group compares favourably with other standard ether protectors such as methyl, benzyl, and trityl. HIP ethers are stable over an unusually broad pH range as well as being resistant to oxidants, nucleophiles (MeLi, N2H4), Lewis acids (BF3 * OEt,), and various reducing agents. However, lithium aluminium hydride causes partial ( < 30%) cleavage of primary HIP ethers under forcing conditions.Results from the selective removal of several representative alcohol protecting groups in the presence of a HIP moiety are summarized in Table 1. The susceptibility of trifluoromethyl ethers to lithium naphthalenide (LiNaphth) can be exploited for the preferential deprotection of HIP ethers in the presence of other protecting groups. Many common functional groups such as amides, carboxylic acids, unconjugated olefins, and HN HNANH, 15 Scheme 20 320 Contemporary Organic Synthesis0- / PhcHo (1.2 eq.) I O- TMSOTf (2 q.) I I bMe PhC(CF&OH (1.2 MI) DEAD (1.5 mmol) Ph3P( 1.5 mmol) PhH (2 ml) 83% (1 mmol scale) 1 OH F3C CF3 x;DoXpn OM* Scheme 21 PhC(CF3)20-(CH&OPG -PG PM=(CF3)20-(CH2)80H - LIN apht h \ HO(CH2)eO-PG Table 1 PG removal ~~~ ~~ HIP' Yield removal Entry PG Reaction conditions Tmr.("A) yield ("A) I 1 Tr SnC12, CH2CI2 4 a9 a1 2 THP pTsOH,MeOH 1 93 89 3 MEM Me,SiiI,Nal/MeCN 6 88 86 4 Bn PdC, HAeOH 1 91 71 5 MPM DDQ,CH,CIf120 3 92 74 6 t-BuPh2Si Bu~NF, THF 1 95 73 7 Bz KOH, MeOH 97 0 'HIP = -C(CF&Ph acetylenes are compatible with the HIP deprotection conditions whilst others, e.g. esters, epoxides, ketones, and halides, are labile. With stoichiometric LiNaphth, deprotection is rapid ( < 1 h) even at - 78 "C; on a preparative scale, the cleavage is more conveniently conducted using Li sand and a catalytic amount of naphthalene, although the reaction requires more time to reach completion. ethers of primary and secondary alkyl alcohols has been reported by Hatakeyama and co-workers*' (Scheme 22).Ester, lactone, and glycosidic acetal functionalities are unaffected. of small organic molecules has stimulated a fresh Direct preparation of benzyl ethers from of TMS The growing interest in the solid phase synthesis Scheme 22 appraisal of traditional organic synthesis in a polymeric environment. One such recent study examined Horner-Emmons and conjugate addition chemistry on short aliphatic chains linked to a solid support (Scheme 23). Reaction of butane-1,4-diol with the tritylated3' polystyrene 16 gave the monoprotected alcohol 17 which was converted into the adduct 18 using traditional organic transformations without any penalty in efficiency. Release of the adduct was accomplished by simply treating the polymer beads with formic acid in THF at room temperature.Having validated the basic protocol, the authors extended their study to the generation of combinatorial libraries. 2.4 Alkoxyalkyl ethers Tetrahydropyranyl (THP) ethers can be selectively cleaved in the presence of TBS ethers, MOM ethers, benzyl ethers, and mesitylene acetals using RESIN Ph Ph 16 RESIN (i) PyrSOs DMSO (ii) PbP=CH-COMe * Ph RESIN I 17 PhSH, NaOMe (cat.) THF, r.t., 2 d REFIN THF H r.t.. 2 hr. 18 Scheme 23 Jarowicki and Kocienski: Protecting groups 32110 mol% BF3 - OEt, in dichloromethane containing EtSH as a carbocation scavenger; BBr3, ZnCl,, and H p o (i) ml,, cHZcl2, 0 “c, 50 ZnBr, also 24. OMEM 73% OH An example is shown in Scheme (19 pH 7.0 phosphate buffer EtSH4HZCIz (5% V/V) ../Oh 92% HA H ATBS Scheme 24 Tanemura and co-workers3’ have reported that THP ethers can be deprotected with DDQ in methanol-water solution giving the parent alcohols in very good yields.Sonnet’s33 one-pot direct conversion of tetrahydropyranyl ethers into bromoalkanes using Ph3P - Br, complex was used in quadruplicate for the conversion shown in Scheme 25.34 Ph3PBr2 (8.56 mmol) r.t., 16 hr. 81% (1.43 mmol scale) CHzCIz (40 ml) Scheme 25 A tetrahydropyranylation of primary and secondary alcohols using (zinc chloride)- impregnated alumina3’ is mild (room temperature), solvent free, and the procedure does not need an aqueous work-up. Deprotection of the homochiral MEM ether 19 was complicated by racemization owing to reversible intramolecular transesterification. Schroer and Welzel found that racemization could be prevented by using a phosphate buffer (pH 7.0) during work- up.36 Even then the product must be immediately used in the next step if the valuable stereogenicity is to be preserved (Scheme 26).During a synthesis of the antifungal polyene macrolide roxaticin (24) (Scheme 27), Rychnovsky and H ~ y e ~ ~ were faced with the daunting task of selectively releasing and distinguishing only the first two of the nine hydroxy functions (at C-1 and C-3) in the fully protected intermediate 20. The 19 no racemization I with buffer work-up I Scheme 26 successful three-step protocol involved first selective electrophilic cleavage of the terminal dioxane ring using TESOTf at elevated temperature thereby placing a TES group at C-1 and an isopropenyl ether at C-3.The isopropenyl ether was then cleaved in the second step using Os04 and finally the C-3 hydroxyl function was reprotected by reaction with 1,3-benzodithiolyl tetrafluoroborate (21) according to the procedure of Sekine and Hata.38. The resultant 1,3-benzodithiolan-2-yl (BDT) ether was stable to the conditions required to remove the TES ether of intermediate 22 in preparation for construction of the macrocycle in intermediate 23. In the final step of the synthesis, the remaining three dioxane rings and the BDT ether were cleaved using an acid ion-exchange resin in MeOH. 3 Thiol protecting groups For the synthesis of the highly labile antibiotic thiarubrine A (28) (Scheme 28), Koreeda and Yang3’ required a method for introducing a protected thiol which could be carried through the synthesis unscathed until the end.The 2-(trimethylsily1)ethyl group which had previously served well in the protection of esters and alcohols (in the form of the SEM group) was chosen for its robust character. Thus, a double base-catalysed addition of 2-(trimethylsily1)ethanethiol to the diyne 25 gave the symmetrical dienedithiol derivative 26 in excellent yield. After further elaboration to the triyne 27, the two thiol functions were released by treatment with TBAF and the construction of the 1,Zdithiine ring completed by oxidation with iodine to give the target in 53% yield for the two steps. Guibk and c o - ~ o r k e r s ~ ~ reported a new allylic protecting group for thiols in general and cysteine in paticular - allyloxycarbonylaminomethyl (Allocam).S-Allocam derivatives are readily prepared by acid- catalysed condensation of thiols with allyl N- hydroxymethyl carbamate 29 (Scheme 29). Deprotection can be achieved using a palladium catalyst, tributyltin hydride, and acetic acid - the latter being essential to prevent formation of allyl thioethers. The reaction leads to a mixture of the thiol, its tributyltin derivative, and minor amounts of disulfide. For the sake of convenience, the crude reaction mixtures were therefore treated with iodine and the deprotected products isolated as their disulfide derivatives. S-Allocam derivatives are stable under the basic deprotection conditions of 322 Contemporary Organic SynthesisI I TESOTf (318 mmd) Pt2NEt (530 mmol) CH2Cb (0.5 ml) 11o”c,2ohr. 20 I : I 22 \ I Q r 1 1 OsO, (30 pL of 2.5% inBu’OH) Pyr (20 pL), CDC13 (2.5 mL) 60% (53pmolscalc) J BF4- 21 I I I I 1 I I I i Dowex Wm-1x (10 mg) MeOH (2 mL) 1 .5 hr., r.t.23 24 Scheme 27 SiMe3 I I Me3SCHgHSH (2.2 eq.) I I KOH (cat.), DMF, r.t, 2 hr. [ 25 :: 87% -:$< 26 SiMe3 I I I I 28 Scheme 28 TBAF (8 eq.) 3A MS, THF, r.t., 1 hr. - I 2 (10 cq.) r.t., 30 mn. 53% 27 Fmoc derivatives but only marginally stable in the acidic conditions of But ester and Boc removal. 4 Diol protecting groups Selective cleavage of an acetonide in the presence of two MOM ethers, a Troc group, and a Boc group was accomplished with the aid of ferric chloride adsorbed onto silica gel (Scheme 30).4’ to efficiently cleave a terminal acetonide in the presence of an internal acetonide (Scheme 31).42 The Ley group has devised new methods for the simultaneous protection of two adjacent hydroxyl functions in carbohydrate derivative^.^^ For example, cyclohexane-1,2-diacetals allow protection of diequatorial 1 ,Zdiols especially in manno-type sugars where regioselective introduction of 3,4-protection is difficult.For rhamnosides4 this was, until now, only possible by a four-step sequence. In the example shown (Scheme 32), the requisite protection was accomplished by acid- cat alysed transacetaliza t ion between methyl a-mannoside (31) and 1,1,2,2-tetramethoxy- cyclohexane (30). In this case, vicinal protection Dowex 50W-X8 in 90% methanol has been shown Jarowicki and Kocienski: Protecting groups 32329 Bu3SnH (4.4 m 9 AcOH (8 mmol) CH&la 20 min, r.t.PdCldPPh& (0.08 mm~l) NHBoc T MeOOC &s.sOycoo-.. 4 I2 (0.5 -4.1 = Y O o M e NHBoc NHBoc 100% (2 mmol scale) FeCb / SiO, (0.3 mmol) CHC13, r.t., 15 hr. 86% (0.9 mmd scale) R = H, SnBu:, Scheme 29 Scheme 30 Scheme 31 DOWX 5ow-xa (110 w/w%) 80% MbOH 32 hr., r.t., 93% 1 A NH includes a minor amount of axial-equatorial protection of the 2,3-hydroxyls as well. The resultant cyclohexane-1,Zdiacetals 32 are readily deprotected on brief treatment with trifluoroacetic acid/water (19 : 1). On the other hand the protection of D-gluco- pyranose 34 (Scheme 33) presents problems, because here all secondary OH groups are trans- diequatorially arranged; thus tetramethoxy- cyclohexane 30 gives a mixture of 2,3- and 3,4-protected glucosides.If, however, the homochiral bis-dihydropyran 33 is used, one regioisomer (35) can be prepared in high yield.45 5 Carboxyl protecting groups The very high nucleophilicity of caesium phenylthi~late~~ was used to cleave both a hindered methyl ester and a methyl carbonate in the tetraprenylbenzoquinol derivative 36 (Scheme 34) under comparatively mild conditions (DMF, + HCIo3 OM9 OMe 24 4 mmal 17.8 mmol 30 31 HC(OM43 (2 ml) MeOH (25 mL) CSA (1.33 mmol), A T 698.77 7 6101.40 \ - Me&) I 11% 6 99.22 6111.23 32 (48%) Scheme 32 324 Contemporary Organic SynthesisPh I Scheme 33 OMe 36 PhSH (0.3 mL) 85 "c, 3 hr. 01% (0.3 ml scale) cw(se"mT' Yh OMe 37 Scheme 34 85 0C).47 The phenolic methyl ether in the product 37 survived unscathed. Chlorotetaine is an irreversible inhibitor of glucosamine-6-phosphate synthetase and thereby interferes with cell wall biosynthesis.The terminal steps of a synthesis of chlorotetaine are shown in Scheme 35 in which deprotection of an N-terminal amino group is a prelude to the final enzymatic hydrolysis of a methyl ester function.48 Critical to the success of the synthesis was the suppression of easy racemization at the ring juncture in the ester hydrolysis step by using porcine pancreatic lipase. deprotecting benzyl esters under neutral conditions using N-bromosuccinimide and dibenzoyl peroxide in carbon tetra~hloride.4~ It provides an alternative method to hydrogenolysis but it fails when the substrate contains a tertiary amide functionality. The 2-methoxyethoxy (MEM) group is a well known protector for alcohols but its use in the protection of carboxylic acids is rare.Scheme 36 depicts the deprotection of a MEM ester 38 under Anson and Montana reported a way of Scheme 35 (i) CF3COOH (3.1 mL) anisole (0.3 rrl) (ii) porcine pancreatic #pass pH 7.5 phosphate buffer 23 'c, 4.5 hr. 55% (0.62 mmol scale) CH&12 (0.6 ml), 0 "c, I h no racemization 0 COOH CbzHN OMe 38 MgBrz-EtzO ( 5 eq.) r.t.. 26 hr. ph\ CbzHN OMe OMe Scheme 36 mild conditions without harm to the Cbz or Boc groups and without racemization of the arylglycine units.50 MEM esters can also be cleaved readily on treatment with AlC1,-N,N-dimethylaniline in dichloromethane to give the parent carboxylic acid in high yield51 and the same conditions can be used to cleave methyl, benzyl, methoxymethyl, met hylt hiomethyl, and p-( trimet hylsilyl) ethoxymethyl esters as well.Jarowicki and Kocienski: Protecting groups 325The Kunz group has been at the forefront of development of new strategies and tactics for the synthesis of glycopeptides which compound all the difficulties inherent in manipulating acid-sensitive carbohydrates and base-sensitive peptides. A noteworthy new tactic from these workers52 uses lipase M from Mucor javanicw for the hydrolysis of the C-terminus of peptide components of glycopeptides as illustrated by the model shown in Scheme 37. 2-[2-Methoxyethoxy]ethyl (MEE) esters are especially valuable substrates because they confer wetability and solubility in water and so ensure that the esters of hydrophobic peptide sequences will be hydrolysable.Moreover, lipases generally lack protease activity making them selective for hydrolysis of ester functions only. Scheme 37 Reductive cleavage of 2,2,2-trichloroethyl esters and carbamates is usually accomplished with Zn in the presence of a proton source such as NH4Cl or acetic acid. However, in a recent synthesis of the potent phospholipase A2 inhibitor thielocin Alb, a 2,2,2-trichloroethyl ester was cleaved from the complex substrate 39 using cadmium in a mixture of DMF and acetic acid (Scheme 3!Q5' Of the many approaches toward the development of useful protecting groups for peptide synthesis, the concept of converting a stable protecting group into a labile protecting group (relay deprote~tion~~) has been fruitful. The same concept can be applied to linkers for solid phase peptide synthesis in which the linker also serves as a C-terminal protecting group.A recent synthesis of y-endorphin by Kiso and co- w o r k e r ~ ~ ~ adapted a relay deprotection strategy based on the p-(methylsulfiny1)benzyl (Msob) group of Samanen and Brandiess6 for the design of a new linker: 4 (2,5-dimet hyl-4-methylsulfinylpheny1)- 4-hydroxybutanoic acid (DSB) (40) (Scheme 39). The linker was appended to an aminomethylated polystyrene-resin and then coupled with C-terminal amino acid Boc-Leu to give 41. The acid stability of p(methylsulfiny1)benzyl type groups enabled selective removal of the Boc-protecting group from reagent 41 which could be used in solid phase peptide synthesis to prepare the protected resin- bound peptide 42. The deprotection of all protecting groups as well as the cleavage of the peptide from the resin was achieved in one-pot by reductive acidolysis using tetrachlorosilane, thioanisole, anisole, and trifluoroacetic acid.Under these conditions all Msob-derived protecting groups were smoothly reduced to the corresponding labile sulfide form and then cleaved by acidolysis to give y-endorphin in 62% yield. In a recent solid phase synthesis of arylacetic acids,57 a linker was required with the seemingly irreconcilable property of being stable towards the basic conditions of enolate alkylation and Suzuki coupling but also labile towards cleavage with hydroxide or amines. A relay deprotection approach based on Kenner's N-acylsulfonamide linker5* served the purpose as shown in Scheme 40.Under basic conditions the arylsulfonamide (pK, 2.5) is deprotonated and hence inert towards nucleophilic attack during the alkylation (43-+44) and Suzuki coupling (44 +45) steps. However, cleavage from the resin was accomplished by first converting the N-acylsulfonamide 45 into its N-methylated derivative 46 which is now quite labile towards nucleophilic attack. Cleavage of peptide segments linked to resins by allyl linkers using hydrostannolytic allyl transfer was originally reported by L ~ f f e t . ~ ~ Giralt and co- workersm showed that the procedure (which uses tributyltin hydride in presence of (Ph3P)4PdC12) is compatible with Fmoc protecting groups. Alternatively, the cleavage reaction may be carried out using N-methylaniline in a 2 : 2: 1 mixture of 0 Cd (50 q.), DMF-HOAc (1:l) 25 "C, 15 hr.R = H Scheme 38 326 Contemporary Organic Synthesis(i) HWESIN, PiflEt, BOP ( 8 ) B d e u , DIPCDI, DMAP \ HN Q. OH 41 SoYdPhaos i HN\o Pe#ide Synthesis i NH-RESIN I 0 Msob OMS& Msob Msob Msob I 1 1 I I I I Msz Boc-Tyr-Gl y-G l y - P h e - M e t - T h r S e r - G I ~ ~ r ~ l ~ T ~ - P ~ e ~ V a ~ T h r ~ e ~ 42 I I Msob Msz I HN\ SCb, thioanizds (100 eq.) aniook (100 q.), TFNCH& (9 : I) 25 "c, 3 hr., ( 6 s from 41) Msz I pMcSOC&t4CH,0C0 9 NH-RESIN Scheme 39 REFIN YHZ REFIN y 2 REFIN y 2 HNYo - Pd(PPhd4, hk&HCH*BN NafiO3 - Q Q THF, A (i) LDA, THF, 0 'c (ii) 43 44 I 45 A Ho% A Ho- Q 46 A Scheme 40 Jarowicki and Kocienski: Protecting groups 327DMSO/THF/OS M HCl in the presence of (Ph,P),Pd.The weaker basicity of the N-methyl- aniline compared with the usual morpholine suppresses competing deprotection of Fmoc groups. Genet and co-workers6 devised a water soluble Pdo catalyst [prepared in situ from Pd(OAc)2 and trisodium 3,3',3"-phosphinetriyltribenzenesulfonate (TPPTS)] which can be used to deprotect base sensitive penem allyl ester 47 (Scheme 41). The free carboxylic acid 48 was obtained in high yield and almost pure form by simple evaporation. and is thus compatible with other acid- or base- sensitive functional groups. Recently a comprehensive studyM revealed that bis(tributy1tin) oxide shows a high level of chemoselectivity between methyl and ethyl esters versus t-butyl esters and lactones. (Pivaloy1oxy)methyl carboxylates can also be cleaved in the presence of the base sensitive P-lactam moiety (Scheme 43).However, sterically hindered esters do not cleave and the method is not compatible with a fluoroalkyl group. 47 Pd(0AC)z (2 ml%) TPPTS (4 MI%), Et2NH (I0 eq.) MeCNIMcOWH20 1 hr., r.t, 03% I BmHND& 0 COOH (Bu,Sr1)~0 (0.2 mmol) Et@ (25 ml) 25 OC, 3 hr. 56% (0.1 mmd scale) Scheme 43 6 Phosphate protecting groups Scheme 41 Ally1 alk-2-ynoates can be readily converted into alk-2-ynoic acids by reaction with morpholine in the presence of a palladium-diphenylphosphinopropane catalyst, thus providing a deprotection of allyl esters of 2,2,3,3-tetradehydro-PGE1 (Scheme 42).6' Ruthenium-catalysed reductive cleavage of allylic esters with formic acid and triethylamine has also been reported.62 Bis(tributy1tin) oxide has been known for some time as a mild reagent for non-hydrolytic cleavage of carboxylic esters.63 The reaction is carried out in aprotic solvents under essentially neutral conditions dba = dibenzylideneacetone THF, 35 "C, 1 hr.0 -OH / T E S ~ dppp = 1,3-bis(diphenyIphosphino)propane Scheme 42 In 1971 Sheehad5 showed that 3',5'-dimeth- oxybenzoin (DMB) esters are photochemically cleaved with high quantum yield (0.64) to the corresponding carboxylic acid and the relatively inert 2-phenyl-5,7-dime t hoxybenzofuran (53). Givens66 and P i r r ~ n g ~ ~ have extended these observations to the protection of phosphotriesters. An asymmetric synthesis of 3',5'-dimethoxybenzoin (Scheme 44) via the benzaldehyde cyanohydrin minimizes the number of diastereoisomers created in the phosphorylation of chiral alcohols.Thus reaction of 49 with 2'-(cyanoethoxy)(N,N'- diisopropy1amino)chlorophosphine afforded the phosphoramidite 50 which then reacted with Boc- Ser-OMe to give the two diastereoisomeric phosphotriesters 51. Photodeprotection gave the desired phosphodiester 52 (85%) along with 53. Baldwin has used 3',5'-dimethoxybenzoin for the photolabile protection of inorganic phosphate.68 The allyl group in its many guises has rapidly gained favour for the protection of alcohols (allyl carbonates, allyl ethers), carboxylic acids (allyl esters), amines (allyl carbamates), and more recently, phosphate^.^^ Scheme 45 illustrates the value of the allyl group for the deprotection of complex substrates under very mild condition^.^' By using Pdo in a mixture of THF and acetic acid, 4 alcohol functions protected as their allyloxycarbonate (aloc derivatives) and two phosphotriesters protected and their allyl ester derivatives were deprotected simultaneously in 90% yield without injury to the remaining acid and base sensitive functionality.328 Contemporay Organic SynthesisMe0 g5% (8% e.e.) (1 80 m d scale) 85% (0.56 mmd scale) I MeO (i) hv (350 nm) PhH (10mL) 45 (ii) NEt:, Scheme 44 Scheme 45 I 51 Me0 (Ph2N-P(CI)OCH&H2CN (13.2 mmol) (PhpNEt (33 mmol) MeCN (50 mL), 0 "C, 1 hr. 66% (11 mmol scale) - (i) Boc-Ser-OMe (1.31 mmol) S@nitrophenyl)tetrazole (3.94 mmd) MeCN (30 ml), rA.. 30 min. (ii) 12, THF, 2,6-lutidine 45% (5 mmd scale) Me0 50 <NEt3 52 Mec, 53 OAll O-'f-ON 0 OH O.f-0" Jarowicki and Kocienski: Protecting groups 329The 2-(trimethylsily1)ethyl (TMSE) has been used successfully as a protecting group for phosphate monoester synthesis.71 It can be removed by treatment with tetrabutylammonium fluoride or HF in acetonitrile.Recently, Wada and Sekine have reported that TMSE is an effective protecting group for the internucleotidic phosphate in oligonucleotide ~ynthesis.~’ Reaction of protected phosphitylating reagent 55 (Scheme 46) with 5’-O-dimethoxy- tritylthymidine 54 afforded the phosphor- amidite building block 56 in 80-6% yield. The TMSE-phosphoramidite 56 was then condensed with thymidine 3’-O-succinate bound to controlled pore glass (CPG) 57 in the presence of 1 H- tetrazole. After oxidation with iodine and the subsequent capping reaction using acetic anhydride and DMAP, the protected dimer 58 was obtained in 99% yield.p-Nitrophenylethyl (Npe) groups are useful for phosphate protection during the preparation of oligonucleotides (Scheme 47).73 After phosphoramidite 59 was transformed into an oligonucleoside, the protecting group was removed using DBU. Npe protecting groups are superior to the 2-cyanoethyl group owing to diminished alkylation side-reaction during deprotection. 7 Carbonyl protecting groups 7.1 0,O-Acetals Aldehydes and ketones can be protected as p-me t hoxyp henyle t hylene ace t als and ke t als using DMTrO, OH 54 CHzCHzOH CH2CH20P(NPS& I I I 0 “c+ r.t.. 16 hr. I NO2 95% ( I 0 mmol scale) NO2 O M T ” W OH (0.66mmd) tetrazole (0.46 mmol) MeCN (I0 mL) 30 rnin., r.t.67% (0.83 mmd scale) 1 DMTrOtsl” 59 Scheme 47 bis-trimethylsilyl ether 60 and a catalytic amount of TMSI.74 Deprotection is accomplished under mild conditions with DDQ and water in dichloromethane. Other acetals and ketals are not affected (Scheme 48) ? TMSEO-P-NPS2 56 DMTr = 4,4’-dimethoxytrityl “w O-succinyCCPG 57 (i) 1Htetrazok (1 M in M N , 200 pmol), 5 min (i9 I2 (0.1 M in aqueous pyridine)), 1 min. (iii) Ac@, 0.1 M DMAP in pyridine, 2 mkr. >W %(using 20 pmol of 56 and 1 pmol57) ? TMSEO- k-okoJ” 0 bsuccinycCPG 58 Th = Thymine Scheme 46 330 Contemporary Organic SynthesisM e O w o m S oms Scheme 48 60 1.2 eq. TMSl (cat.), CH&lz (0.5 M) -78 + 0 "C 71% 82% HC(OMe)3 (376 mmol) PTSA (1.9 mmol) PhMe (50 mL) 97% (37.6 mmol scale) (€)-Me-CH=CH-CHO (51.8 mmol) PTSA (1.73 rnmol), PhMe (50 mL) r.t, 23 hr., r.t., 21 hr., 36% (34.6 mmol scale) 0 61 OH I MeO AD-mk-B (3.5 g) methanesulfonamide (2.50 mmol) BU'OH-H~O (1:1, 25 mL), rA., 48 hr.96% (250 mmol scale) + - Hz, Pd(OH)z. 50 p s i . MeOH, r.t., 48 hr. OH 0 OH Scheme 49 Wong and c o - ~ o r k e r s ~ ~ recently exploited the hydrogenolytic lability of 175-dihydro-3H-2,4-benzo- dioxepin derivatives for the preparation of some acid-labile dihydroxyaldehyde derivatives generated by the Sharpless asymmetric dihydroxylation as illustrated in Scheme 49. In the example shown, the required protected alkene 61 was generated in modest yield by acetal exchange with 3-methoxy- 1,5-dihydro-3H-2,4-benzodioxepin. Acid hydrolysis can also be used to release the aldehyde.The conversion of an aryl methyl group into a dioxolane is hardly a typical method but its feasibilty is illustrated by the two-step procedure shown in Scheme 50. The first step, a double radical bromination under photochemical conditions, converts 62 into the 172-dibromoalkane 63. In this case the bromination of the methyl group is accompanied by a small amount of bromination of the ester methylene function. In the second step, a double displacement of the bromine atoms in 63 by ethylene glycol at 160 "C produces the dioxolane 64 as a mixture of ethyl and hydroxyethyl esters.34 7.2 S,S-Acetals er I NBS (61.8 ml) CCl, (270 ml) - - 63 R = HI Br (85 : 1 5) cacos (75 ml) HO4H&H&H (120 ml) 160 "C, 3 hr. 5 48% (+29% Et ester) OH 64 Scheme 50 Direct conversion of the ketal function in 65 into a dithioketal moiety (Scheme 51)76 was accomplished with aluminium trichloride in order to minimalize the epimerization at C-(8) - a problem which attends other Lewis acids such as titanium tetrachloride.Deprotection of 173-dithianes to the corresponding carbonyl compounds has been achieved by treatment with 1.5 equivalents of DDQ in acetonitrile-water (9 : 1)77 and by irradiation Jarowicki and Kocienski: Protecting groups 331I 65 CFSCOOH (20 Id-) ankde (5.12 mmol) cH$3O,(l.l ml) r.t., 22 hr. 60% (1.28 mol scale) Small amount of C(8) epimer TBAF (1 .5 mmo9 DMF, 80 "c, 20 hr. 60% (0.5 mmol scale) H,NCH,CHflH, (0.15 mL) Scheme 51 ( y > 360 nm) of a dichloromethane solution of the dithioacetal or ketal with a pyrylium salt and molecular oxygen.78 8 Amino protecting groups Hydrazinolysis which is typically used to deprotect phthalimide derivatives can also be used to deprotect N-[ 1-(4,4-dimethyl-2,6-dioxocyclo- hexy1idene)ethyl (Dde) groups which are easily introduced by reaction of an amine (for example cadaverine as shown in Scheme 52) with 2-acetyldimedone (66).79 Dde groups are stable to 20% piperidine in DMF, the reagent frequently used to remove Fmoc groups, but is readily removed by 2% hydrazine in DMF within minutes.The driving force for the Dde deprotection is the formation of 3,6,6-trimethy1-4-0~0-4,5,6,7-tetra- hydro-lH-indazole and this can be monitored by the UV absorption at either 270 or 290 nm. The example shown in Scheme 52 comes from a synthesis of the spider toxins nephilatoxin-9 and -11. Two amine functions protected as their N- (3,4-dimethoxyphenyl)methyl derivatives in the pentacyclic tripyridine 67 (Scheme 53) were released on treatment with trifluoroacetic acid in the presence of anisole as a carbocation scavenger." [(trimethylsilyl)ethoxy]methyl (SEM) group from the indole derivative 68 (Scheme 54) using TBAF in THF gave poor yields" - a problem which had been previously encountered by others.82 The best and most consistent results were obtained by using Attempts to remove the 'COOEt Scheme 53 QyJyJ ' CN Scheme 54 66 Scheme 52 332 Contemporary Organic SynthesisTBAF in DMF in the presence of an excess of 0 eth~lenediamine.~~ (I) NaHMDS (4.4 mmo9 THF (4.4 mL), 15 min 929c (22 mmol scale) (4 eOc20 (2 ml) Waldman and co-workers reported’ the chemoselective enzymatic liberation of the amino functions present in the nucleobases of 0-acetylated nucleosides by penicillin G acylase mediated hydrolysis of the corresponding phenylacetamides (Scheme 55).Scheme 57 Pd(0Ac)pPTS (1:2,2.5 mot%) MeCN-Hfl (&I, 3.5 ml) HNEtz (5 -1) 30 m4. r.t. 0 OAc Penidlin G acylase pH 7.8, phosphate buffer 30 vol.% MeOH 0 I OAc Joulli6 and co-~orkers~’ reported that Fmoc can be removed from N-protected amino acids and dipeptides by potassium fluoride/l8-crown-6 in the presence of methyl, ethyl, t-butyl, benzyl, and p-methoxybenzyl esters. 2,2,5,7,8-pentamethylchroman-6-sulfonyl (pmc) group for the protection of the highly basic guanidine function in arginine based on earlier observations that electron donating substituents on arylsulfonamides greatly facilitate p r o t o n o l y ~ i s .~ ~ ~ ~ ~ Church and Young” have used the pmc group to activate an aziridine ring during nucleophilic cleavage with lithium trimethylsilylacetylide (Scheme 58). Simultaneous removal of the TMS, t-butyl ester, and pmc groups occurred in quantitative yield on treatment with trifluoroacetic acid to give the amino acid derivative 70. Ramage originally designed the Scheme 55 Allyloxycarbamate protected cephalosporin 69 (Scheme 56) are selectively and quantitatively cleaved using a Pdo water soluble catalyst [prepared in situ from Pd(OAc)2 and trisodium 3,3’,3’‘-phosphinetriyltribenzenesulfonate (TPPTS)] dimethylallyl carbo~ylate.~ A O H NH2 // under homogeneous conditions without affecting the 70 Scheme 58 okNf---- 0 Scheme 56 Aryl amines are converted into their Boc derivatives by treatment with two equivalents of sodium hexamethyldisilazide in THF followed by one equivalent of di-t-b~tylcarbonate.’~ This procedure works on a wide variety of both electron- rich and electron-deficient aryl amines (Scheme 57).A recent synthesis of spermine and spermidine analogues for use as tumour growth inhibitors made good strategic use of the trifluoromethanesulfonyl group as both a protecting group and an activating group (Scheme 59).89 The high acidity of the N- trifluoromethanesulfonamides of primary amines (pK, 7.5 compared with 11.7 for the corresponding tosyl derivatives) was sufficient to enable a double alkylation of the octane-198-diamine derivative 71 under Mitsunobu conditions.All four of the trifluoromet hanesulfonyl groups were then removed from the alkylation product 72 using sodium in a mixture of ammonia and t-BuOH to give the tetra- amine 73. Deprotection of N-( arylsulfony1)amines can be problematic. Electrolytic cleavage offers a method which tolerates a range of functionality. Thus, electrolysis of the N-tosylamide 74 (Scheme 60) gave the corresponding amine 75 in 90% yield.g0 Vedejs and Lin have also shown” that N-(arylsulfonyl) amines can be deprotected efficiently using Sm12 in a refluxing mixture of the substrate in THF and N, N ’-dimethylpropyleneurea (DMPU). Diary1 Jarowicki and Kocienski: Protecting groups 333\r?,s02cF3 LN/W2CF3 b o H CF@2 XN& (1 5 mmol) DEAD (1 5mnol) PhsP (15 mmOl) THF, r.t, 18 h 72% + NHS02C Fa I NHSO2CFa (yH2)6 71 (5 mmol) Na (OXC~OS), NH3 (106 mL) (em)@ (15 mnol), THF rR, 12 hr.54% overall (3 mmol scab) BdOH (!3 ml), -70 “c AH 73 Scheme 59 74 = Ts -1&55J 75 R=H (0.123 mmol scale) Scheme 60 disulfides and aryl mercaptans are amongst the sulfur-containing by-products. The study revealed that phenylsulfonyl groups cleave faster than tosyl groups but primary and secondary sulfonamides cleave at about the same rate. /?-Tosylethylamine 76 (Scheme 61) is a readily prepared reagent that can be used to synthesize N- tosylethyl-protected amido compounds, which can be deprotected with potassium t-buto~ide.~~ Thus, deprotection of /?-lactam 77 gave no evidence of ring-opening or epimerization. 9 Books and Reviews 1 ‘Protecting Groups’, P.J. Kocienski, 1994, Thieme Verlag, Stuttgart, 1994. 2 ‘Applications of Combinatorial Technologies to Drug Discovery, 1. Background and Peptide Combinatorial Libraries’, M.A. Gallop, R.W. Barrett, W. 3. Dower, S.P.A. Fodor, and E.M. Gordon, J. Med. Chem., 1994, 37, 1233. 3 ‘Applications of Combinatorial Technologies to Drug Discovery. 2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions’, E.M. Gordon, R.W. Barrett, W.J. Dower, S.P.A. Fodor, and M.A. Gallop, J. Med. 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