2 Synthetic methods Part (v) Protecting groups By ALAN C. SPIVEY and STEVEN J. WOODHEAD Department of Chemistry Brook Hill University of Sheffield Sheffield S3 7HF UK Another excellent and comprehensive ‘update’ review of protecting group strategies in organic synthesis has appeared this year.1 1 Hydroxy protecting groups The use of allylic protection of alcohols in the context of complex synthesis (mainly of oligosaccharides) has been reviewed.2 Sodium borohydride–iodine (THF at 0 °C) appears to be an attractive method for the reductive cleavage of both aryl and alkyl allyl ethers.3 An alternative reductive cleavage of allyl ethers employs naphthalene catalysed lithiation.4 This method uses an excess of lithium powder in the presence of catalytic naphthalene at low temperature and generally gives higher yields for the removal of benzyl ethers and is also e§ective for the de-sulfonylation of primary tosyl amides and tosyl or mesyl carboxamides.Deprotection of allyl ethers is also frequently achieved by a two step procedure involving base or transition metal complex mediated isomerisation to the corresponding vinyl ether followed by acid mercury(II) chloride or iodine assisted hydrolysis. Wacker type oxidation o§ers a mild alternative for this second step.5 Such oxidation is compatible with acid sensitive benzylidene acetals and proceeds with retention of configuration for anomeric vinyl ethers. Benzyltriethylammonium tetrathiomolybdate in acetonitrile e§ects selective deprotection of propargyl ethers in the presence of allyl and benzyl ethers and other easily reducible functionalities such as nitro aldehyde and keto groups under essentially neutral conditions.6 Two very similar new methods for the selective removal of p-methoxybenzyl ethers are ethanethiol–aluminium trichloride [or tin(II) chloride] and dimethylsulfide–magnesium bromide.7,8 The former method employs 0.2 equiv.of Lewis acid at ambient temperature and is tolerant of methyl and benzyl ethers p-nitrobenzoyl esters tertbutyldiphenylsilyl ethers (TBDPS) and isopropylidene acetals whilst the latter employs 3 equiv. of Lewis acid at ambient temperature and is tolerant of 1,3-dienes tert-butyldimethylsilyl (TBDMS) and benzyl ethers benzoyl esters and isopropylidene acetals. Commercially available and reusable HSZ zeolites o§er a useful and environmentally benign method for the large scale preparation of both alkyl and aryl tetrahydropyranyl ethers (THP) in neat dihydropyran (DHP).9 Selectivity for the former over the latter is also possible.The same zeolite catalyst can also be employed to e§ect 77 NC O O NaN(SiMe3)2 or LiN(Pri)2 (2.5 equiv.) THF–DMEU 185 °C sealed tube 95% NC OH OH Scheme 1 O OR OX O O Me PACH X = PACM X = PACLev X = OMe ROH O O H2–Pd(OH)2 (PACH and PACM) or NH2NH2–AcOH–pyridine (PACLev) + Scheme 2 quantitative deprotection in methanol as can anhydrous tin(II) chloride.10 An interesting method for the deprotection of methyl and benzyl aryl ethers in good to excellent yields employs sodium hexamethyldisilazide (NaHMDS) or lithium diisopropylamide (LDA) in THF–1,3-dimethyl-2-imidazolidinone (DMEU) at 185 °C in a sealed tube.11 NaHMDS is slightly less reactive than LDA and this can be exploited for the mono deprotection of o-dimethoxybenzenes.Of particular note is that either base can also be employed for the almost quantitative deprotection of the methylenedioxy functionality (Scheme 1). Partial resolution (39–97% ee) of the enantiomers of selected simple cis-diols has been achieved by acetal formation with a polymer-supported 7-keto-steroid followed by hydrolysis.12 In the area of ester protection of alcohols there has been exciting progress in the area of non-enzymatic kinetic resolution of secondary alcohols via acylation using a number of ‘synthetic’ chiral catalysts and this area has been briefly reviewed.13 The use of magnesium methoxide in methanol at ambient temperature has been advocated for the deprotection of alkyl acetates.14 Of note is the sensitivity of the procedure to steric hindrance thereby allowing the selective removal of primary acetates in the presence of secondary and tertiary acetates in complex substrates.Three 2-(2-oxyethyl)benzoate protecting groups PAC H PAC M and PAC L%7 have been introduced and their utility demonstrated for the preparation of phosphorylated inositol derivatives.15 These esters are generally introduced using DCC–DMAP and have cleavage properties dependent on the 2-oxyethyl ether substituent e.g. H 2 –Pd(OH) 2 or H 2 –PdCl 2 for the 2-benzyloxy- and 2-(4-methoxybenzyloxy)ethylbenzoyl groups (PAC H and PAC M ) and NH 2 NH 2 –AcOH–pyridine for the 2-(2-levulinoyloxy)ethylbenzoyl group (PAC L%7). PAC is an abbreviation for ‘proximately assisted cleavable group’ as the ester hydrolysis is facilitated by 6-exo-trig lactonisation (Scheme 2).A protecting group closely related to PAC L%7 is the 2-(levulinyloxymethyl)nitrobenzoyl group (LMNBz) which has been employed successfully as a 5@-hydroxy protecting group which suppresses depurination [cf. dimethoxytrityl (DMTr)] during automated ribonucleoside and 2@-deoxyribonucleoside 3@-phosphoramidite synthesis.16 Cleavage is via 5-exo-trig lactonisation using 0.5M imidazole in acetonitrile following ether cleavage using 0.5M NH 2 NH 2 in 1 4 AcOH–pyridine. 78 A. C. Spivey and S. J. Woodhead Two new carbonate type 5@-hydroxy protecting groups for ribonucleoside synthesis have been developed the 2-(2-nitrophenyl)ethoxycarbonyl group (NPEoc) is removed by photolysis (365 nm) and displays a ca.3-fold rate enhancement for cleavage relative to the 2-nitrobenzyloxycarbonyl group (NBoc).17 The (2-cyano-1-phenyl)ethoxycarbonyl group (CPEoc) is base labile (0.1M DBU in acetonitrile) and works e¶ciently in conjunction with 4-ethoxytetrahydropyran-4-yl 2@-hydroxy protection.18 Carbonate protection of the phenol of tyrosine as a 2,4-dimethyl-3-pentyloxycarbonyl group (Doc) has been proposed as an alternative to the 2-bromobenzyloxycarbonyl group (2-BrZ) during tert-butoxycarbonyl (Boc) solid phase synthesis.19 However although this group displays superior resistance to nucleophilic cleavage it is more acid sensitive and much less rapidly cleaved using 20% piperidine–DMF. The tris(trimethylsilyl)silyl group (Sisyl) has been introduced as a new fluoride resistant photolabile (medium pressure Hg lamp MeOH ca.30 min) protecting group for primary and secondary alcohols.20 These ethers are prepared from the corresponding chlorosilane using CH 2 Cl 2 –DMAP (1.2 equiv.). They are not stable towards certain nucleophiles (TBAF BuLi LiAlH 4 ) but are stable towards other fluoride sources (CsF KF–18-crown-6) Grignard and Wittig reagents (MeMgBr Ph 3 P––CH 2 ) oxidation (Jones’ reagent) and are more acid stable than TBDMS TBDPS and triisopropysilyl (TIPS) groups [p-TSA (1 equiv.) 0.2M HCl–acetone (1 1)]. These latter silyl ethers are photostable under the conditions which remove the Sisyl group. Primary TBDMS ethers can be selectively removed in the presence of secondary TBDMS ethers using LiBr–18-crown-6 in acetone at elevated temperatures.21 Additionally quinolinium fluorochromate has been shown to e§ect concomitant cleavage and oxidation of primary TBDMS ethers (including allyl and benzyl) to aldehydes in the presence of secondary TBDMS ethers (including allyl and benzyl).Primary methoxymethyl(MOM) THPand TBDPS ethers are stable to these conditions.22 The e¶cient one-pot deprotection–oxidation of primary and secondary trimethylsilyl ethers (TMS) using 3-carboxypyridinium chlorochromate in refluxing acetonitrile or dichloromethane to give aldehydes and ketones respectively has also been described.23 THP ethers also undergo this oxidation but more slowly. The susceptibility to cleavage by LiAlH 4 of TBDMS ethers 1,3- or 1,4-disposed to an unprotected hydroxy group has been demonstrated and is proposed to result from intramolecular hydride delivery from the alcohol-derived alkoxyaluminium hydride.24 2 Carboxy protecting groups Just 5mol% of potassium tert-butoxide believed to form highly reactive caged tetramers e§ects almost quantitative ester metathesis between methyl benzoate and tert-butyl acetate to give tert-butyl benzoate provided the volatile by-product (methyl acetate) is removed by application of an aspirator vacuum.25 The full scope of this procedure has yet to be established (Scheme 3).The p-acid tetracyanoethylene (TCNE) is an e§ective catalyst (20 mol%) for the esterification of lauric acid with a wide variety of alcohols (1° 2° benzyl allyl propargyl 2-trimethylsilylethyl) for the esterification of a-hydroxy- and N-benzyloxycarbonyl- (Cbz) or N-Boc-a-amino acids with methanol to give methyl esters and also for the transesterification of methyl laurate with a variety of alcohols (1° 2° 79 Synthetic methods Part (v) Protecting groups Ph O O Me Me O O But Ph O O But Me O O Me + + 5 mol% KOBu t neat 45 °C 30 min 98% Scheme 3 N S OH O H S O O S O 4.6 mol% Pd(PPh3)4 TolSO2Na (1.1equiv.) THF–MeOH 25 min 87% N S OH O H S OH O S O Scheme 4 benzyl allyl propargyl).26 These reactions are driven towards products by using the appropriate alcohol as solvent.Magnesium bromide etherate has been previously shown to cleave b-(trimethylsilyl)ethoxymethyl esters (SEM) and this methodology has now been extended to amino acid and peptide derivatives in the presence of protecting groups typically encountered in peptide chemistry [Boc Cbz fluoren-9- ylmethoxycarbonyl (Fmoc) and 2,2,2-trichloroethoxycarbonyl (Troc) carbonates and benzyl (Bn) But TBDMS ethers].27 Other fluoride sensitive protecting groups are stable to magnesium bromide.An extensive survey of allyl scavengers has been undertaken for the tetrakistriphenylphosphine catalysed deprotection of allyl esters.28 Toluenesulfinic acid was identified as the most e¶cient scavenger (better than carboxylic acids morpholine dimedone etc.) allowing e¶cient deprotection on sensitive penem substrates (Scheme 4). Salts of toluenesulfinic acid can also be employed and this allows the use of other palladium catalysts such as palladium acetate dichlorobis(acetonitrile)palladium triethylphosphite although these reactions are substantially slower. 2-Chloroallyl 2-methylallyl crotyl and cinnamyl esters are similarly e¶ciently scavenged and the process can also be extended to the deprotection of allyl carbonates allyl ethers allylamines and O-allyl oximes.3 Phosphate and sulfate protecting groups Non-hydrolytic deprotection of phosphite and phosphate alkyl esters is often accomplished using TMS iodide or TMS chloride. The reactive inorganic polymer silica chloride is an attractive alternative.29 tert-Butyl and benzyl esters are cleaved almost quantitatively at ambient temperature in chlorinated hydrocarbon solvents (CCl 4 CHCl 3 CH 2 Cl 2 ) in under an hour as are the corresponding sulfite esters. Isopropyl and phenyl esters however do not react and the reaction was shown to produce racemic 1-phenethyl chloride when using bis(S)-1-phenethylphosphite as substrate. The use of ammonia gas under pressure o§ers an e¶cient alternative to hot aqueous ammonium hydroxide for the deprotection and cleavage steps during the large scale synthesis of oligonucleotides and their phosphorothioate (PS) analogues prepared using N-pent-4-enoyl (PNT) protected nucleoside phosphoramidites (O-2-cyanoethyl 80 A.C. Spivey and S. J. Woodhead O MeO OMe O O montmorillonite K10 CH2Cl2 D 4 h 82% O O O O Scheme 5 N,N-diisopropyl) and H-phosphonates.30 Methylamine with or without added ammonium hydroxide has also been advocated for the same purpose when employing N-acetyl protected nucleoside phosphoramidites (O-2-cyanoethyl N,N-diisopropyl) and H-phosphonates.31 Use of N4-acetyldeoxycytidine (dCA#) was noted to suppress transamination relative to use of dCB; during this procedure. O-4-Cyanobut-2-enyl protection (CB) has been reported as an alternative to the ubiquitous O-2-cyanoethyl phosphoramidite protecting group.32 Deprotection by d-elimination is e§ected using aqueous ammonium hydroxide under identical conditions as the O-2-cyanoethyl analogues but the method is purported to be ca.60% less costly on a kilogram scale. Eight new S-protecting groups have been investigated for the synthesis of dithymidine phosphorothioates by the solution phase phosphotriester method.33 The best of these was the 4-chloro-2-nitrobenzyl group which allowed e¶cient coupling using 4-nitro-6- trifluoromethylbenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyFNOP 96% 15 min) and could be removed with a minimum of side reactions using thiophenolate. The trifluoroethyl ester has been demonstrated to be a useful protecting group for sulfate monoesters in carbohydrates.34 These esters are readily formed from the appropriate sulfate using trifluoroethyldiazoethane are stable to TFA but cleaved with mineral acids (dil.H 2 SO 4 ) stable to TBAF sodium methoxide in methanol and hydrogenation but selectively cleaved using potassium tert-butoxide in refluxing tert-butyl alcohol. 4 Carbonyl protecting groups Monomorillonite K10 in dichloromethne at ambient temperature has been found to be an extremely convenient mild and e¶cient method for the deprotection of acetals and ketals.35 Its utility has been demonstrated in the first synthesis of syn-4,8- dioxatricyclo[5.1.0.03,5]octane-2,6-dione and is e§ective not only for dimethyl acetals but also 1,3-dioxolanes and 5,5-dimethyl-1,3-dioxanes (Scheme 5).Monomorillonite K10 in refluxing dichloromethane is also e¶cient for the deprotection of 1,1-diacetates.36 Ferric chloride hexahydrate is a mild promoter of hydrolytic deprotection of acetals in dichloromethane at ambient temperature which appears to be more selective for this process (particularly with 1,3-dioxolanes) over interaction with other acid sensitive functionalities than alternative Lewis acids.37 Hydrogenolytic deprotection of 4-phenyl-1,3-dioxolane protected ketones and aldehydes simply using Pd-C–H 2 has been shown to be a very clean and e¶cient alternative to electrolytic deprotection.38 Cyclo-SEM has been introduced as a new 81 Synthetic methods Part (v) Protecting groups O O O O Me3Si H Me O O H Me O LiBF4 THF 66 °C 3 h >80% Scheme 6 fluoride labile acetal protecting group for carbonyl groups.39 Protection is accomplished at ambient temperature using a slight excess of 2-trimethylsilylpropane-1,3- diol in dry dichloromethane with activated powdered 3 or 4Å MS and catalytic camphorsulfonic acid (0.25 equiv.) and deprotection using LiBF 4 in THF (conditions which do not a§ect 1,3-dioxolanes Scheme 6).A rapid and e¶cient deprotection of a series of simple aryl aldehyde 1,1-diacetates catalysed by ‘expansive graphite’ in refluxing dichloromethane or benzene has been reported preceded by details of the synthesis of the catalyst.40 5 Amine protecting groups Amides are rarely used for amine protection in peptide synthesis due to their proclivity towards racemisation (via azalactones) and resistance to hydrolysis.The hydrolysis of N-trifluoroacetyl-a-amino acid tert-butyl esters to the corresponding tert-butyl ester hydrochlorides using liquid–liquid phase transfer catalysis [20% KOH triethylbenzylammonium chloride (10 mol%) H 2 O–CH 2 Cl 2 25–35 °C] followed by precipitation (HCl Et 2 O) has been reported but is accompanied by partial racemisation in the case of phenylalanine (23%) and complete racemisation for phenylglycine.41 The corresponding N-trifluoroacetyl-a-amino acids can be obtained using TFA (probably without racemisation although this was not verified). A more e§ective approach to amide deprotection employs enzymatic amide hydrolysis. The exquisite selectivity of N-phenylacetyl deprotection using immobilised penicillin G acylase (SeparaseG') under extremely mild neutral conditions allowed cleavage of an N-phenylacetyl ethanolamine phosphate heptosyl disaccharide42 (Scheme 7).Soluble penicillin G acylase has also been found to be e§ective for the deprotection of a controlled pore glass (CPG) bound TGGGG-pentanucleotide containing Nphenylacetyl protected bases.43 The synthetic scope of recombinant phthaloyl amidase for the mild unmasking of N-phthaloyl imides (Phth) following partial hydrolysis to their mono acids has also been further delineated.44 A range of primary amines can be deprotected and the enzyme exhibits modest chiral selectivity between diastereomeric dipeptides. An alternative solution to mild phthalimide deprotection is to employ a tetrachlorophthalyl group (TCP).45 Installation can be accomplished in two steps by treating the free base with commercially available TCP anhydride followed by ring closure with Ac 2 O–pyridine and the group is stable under conditions ranging from mildly basic to harshly acidic.Cleavage is e§ected by 2–4 equiv. of ethylenediamine at 60 °C in MeCN–THF–EtOH(2 1 ) conditions under which glycopeptides containing standard N-Phth and ester groups retain their constitutional and stereochemical integrity. trans-2-Hydroxycinnamic acid has been investigated as a photolabile protecting group for amines.46 Photolysis (low intensity 4W lamp 365 nm) of derived amides results in quantitative cleavage via trans to cis isomerisation and 6-exo-trig 82 A. C. Spivey and S. J. Woodhead O HO O OH O O HO HO O(CH2)3NH2 HO HO HO HO O HO O OH O O HO HO O(CH2)3NH2 HO HO HO HO P O NH PhAc O –O P O NH3 O –O SeparaseG® pH 7.5 1.5 h 93% Scheme 7 lactonisation.Secondary amides are cleaved more slowly than primary amides and in both cases the addition of a trace of acid to the organic solvent (e.g. MeOH–AcOH 70 1) is essential to assist lactonisation. The free phenol present in this protecting group was noted as a limitation but presumably this could be orthogonally protected if necessary. Allyl based protection strategies for the synthesis of peptides are attractive alternatives to Boc and Fmoc strategies for both solid and solution phase peptide synthesis particularly of sensitive glyco- nucleo- and sulfopeptides due to the extremely mild nature of the palladium catalysed deprotection conditions. This strategy has now been further refined for large-scale solution phase synthesis exploiting the chemoselective deprotection of N-allyloxycarbonyl-O-dimethylallyl-a-amino esters with a water soluble Pd0 catalyst generated in situ from Pd(OAc) 2 and triphenylphosphinotrisulfonate sodium salt (TPPS) with diethylamine as allyl scavenger.47 Care however needs to be taken to avoid N-terminal diketopiperazine (DKP) formation.This problem has been addressed in the context of allyl based solid phase protection strategies by employing phenyltrihydrosilane (PhSiH 3 ) as a neutral non-nucleophilic allyl scavenger.48 The allyloxycarbonyl group (Alloc) has also been shown to be a useful orthogonal protection group for the indolic nitrogen of tryptophan (preventing oxidation during global phosphorylation) during Fmoc–But solid phase synthesis providing the Fmoc groups are removed using DBU.49 C-terminal incorporation of a-trifluoromethyl substituted amino acids into Fmoc peptide acyl fluorides via in situ deprotection of N-(trimethylsilyl) ethoxycarbonyl (Teoc) derivatives using tetraethylammonium fluoride in acetonitrile at 50 °C has been described.50 a-Trifluoromethyl amino acids are notoriously non-nucleophilic at the a-nitrogen and this coupling is proposed to proceed via the ‘mixed anhydride’ of the Fmoc protected peptide and the Teoc derived carbamic acid.This subsequently extrudes CO 2 (Scheme 8). 83 Synthetic methods Part (v) Protecting groups TeocHN CO2Me CF3 –O O NH CO2Me CF3 TBAF 50 °C Fmoc-Xaa-F FmocHN O O O NH H R CO2Me CF3 –CO2 FmocHN O NH H R CO2Me CF3 Scheme 8 Since all the a-trifluoromethyl amino acids used in this study were racemic the configurational integrity of the a-trifluoromethyl residue during coupling could not be ascertained.The p-nitrobenzyloxycarbonyl group (PNZ) has been utilised in syntheses of b-GlcNAc terminating glycosides as an e¶cient participating group in the stereoselective formation of the 2-amino-b-glucosidic linkage and as an N-protecting group which can be removed either by hydrogenolysis or by reaction with dithionite under neutral conditions.51 Lewis acid mediated deprotection of Boc groups is well established but improved methods for their clean removal using boron trifluoride etherate in dichloromethane and for the deprotection of N,N@-bis(tert-butoxycarbonyl) protected guanidino groups using tin(IV) chloride have been reported.52,53 Interestingly,N-silated carbamates (e.g.N-Boc-N-TMS aliphatic benzyl and amino acids) are readily formed from the corresponding primary carbamates using silyl triflates are generally stable to silica chromatogrphy and provide a useful method for the temporary protection of the carbamate NH.54 Base sensitive carbamates such as Fmoc owe their reactivity to facile b-elimination.The b-elimination side-product dibenzofulvene is usually trapped out but occasionally this proves problematic. A new type of urethane protecting group the 1,1-dioxobenzo[b]thiophen-2-ylmethyloxycarbonyl group (Bsmoc) has been introduced as an alternative protecting group for solution and solid phase peptide segment synthesis which circumvents this limitation. 55 this group owes its base sensitivity to an ingenious Michael-type addition process whereby the deblocking event is simultaneously a scavenging event (Scheme 9).A variety of nucleophiles were investigated piperidine was preferred for solid phase synthesis whilst tris(2-aminoethyl)amine (TAEA) gave a water soluble side product making this the nucleophile of choice for solution phase work. The Bsmoc group was compatible with acyl fluoride and in situ ammonium or phosphonium salt based coupling methods and being UV active allows for accurate tracking and quantitation. The Bsmoc group is more sensitive to piperidine than Fmoc is stable to tertiary amines [pyridine diisopropylethylamine (DIEA) hydroxybenzotriazole (HOBt)–DIEA] stable to neat TFA or saturated HCl in EtOAc (but not HBr in AcOH) but is rapidly cleaved by thiols. Sulfonamide protection of amines has traditionally been plagued by their problematic deprotection in highly functionalised sensitive substrates.However in recent 84 A. C. Spivey and S. J. Woodhead NH-(Xaa) n- O O S O2 H2N-(Xaa) n- S O2 2–5% piperidine CH2 N + CO2 + S O2 N Scheme 9 years a number of sulfonamide protecting groups which are amenable to mild deprotection have been developed. Samarium iodide (SmI 2 ) has become widely used for selective arylsulfonamide deprotection particularly of amino sugars.56 2,4-Dinitrobenzenesulfonamides are readily deprotected using excess n-propylamine (20 equiv.) in dichloromethane at ambient temperature or more conveniently using HSCH 2 CO 2 H (1.3 equiv.) and triethylamine (2 equiv.) whereby the side-product 2,4-dinitrophenylthioacetic acid can be easily removed by washing with aqueous NaHCO 3 .57 This year a new sulfonamide analogue of the Boc group tert-butylsulfonyl (Bus) has been introduced which is stable to strong metallation conditions but readily cleaved using 0.1M triflic acid in dichloromethane.58 Introduction of this group requires a two step procedure employing tert-butylsulfinyl chloride followed by oxidation (m-CPBA or RuCl 3 –NaIO 4 ) since tert-butylsulfonyl chloride is unreactive and unstable.The group is stable towards BusLi–TMEDA 0.1M HCl–MeOH 0.1M TFA–CH 2 Cl 2 and pyrolysis neat at 180 °C for 3 h. Selective deprotection of Bus groups from secondary amines in the presence of primary amines (using triflic acid) is possible although the origin of this selectivity is unclear. The vinyl group has been reported to be an e¶cient and economical group for the protection of azole nitrogens in simple heterocyclic systems (e.g.imidazole).59 Protection is a one-pot two step process involving heating first with 1,2-dibromoethane –Et 3 N then aqueous NaOH to e§ect elimination and removal involves treatment with ozone in MeOH at [78 °C in the presence of dimethylsulfide. A methylene ‘bridge’ between the N-1 nitrogens of two 1,2,4-triazoles has also been advocated as a simple but e§ective protecting group during selective 4-alkylation.60 The 2-adamantyloxymethyl group (2-Adom) has been utilised for imidazole protection of histidine during peptide synthesis.61 Boc-His(Nn-2-Adom)-OH is prepared from Boc-His(Nn-2-Boc)-OMe by treatment with 2-adamantyloxymethyl chloride followed by saponification (NaOH). The group is stable to TFA 1M NaOH and 20% piperidine–DMF and easily removed by 1M trifluoromethanesulfonic acid–thioanisole or anhydrous HF.The o-nitrobenzyl group has been shown to function as a reasonably e¶cient photocleavable protecting group for indoles ben- 85 Synthetic methods Part (v) Protecting groups zimidazoles and 6-chlorouracil.62 The 1-thiophenylbenzyl group has been introduced as a b-lactam protecting group during the synthesis of N-unsubstituted b-lactams by [2]2] cycloaddition.63 Deprotection is via oxidation using potassium persulfate. The monomethoxytrityl group (MMTr) is frequently employed for alcohol protection in nucleoside chemistry but its utility as an amino protecting group is often overlooked. A rare instance of this group’s utility in this capacity is its application for the protection of a lysine side chain during the synthesis of complex cathespin B-sensitive maleimidocaproyl-Phe-Lys linked prodrugs.The favourable solubilising properties conferred by the lipophilic MMTr unit were noted.64 References 1 K. Jarowicki and P. Kocienski Contemp. Org. Synth. 1997 454. 2 F. Guibe Tetrahedron 1997 53 13 509. 3 R.M. Thomas G. H. Mohan and D. S. Iyengar Tetrahedron Lett. 1997 38 4721. 4 E. Alonso D. J. Ramon and M. Yus Tetrahedron 1997 53 14 355. 5 H.B. Mereyala and S. R. Lingannagaru Tetrahedron 1997 53 17 501. 6 V.M. Swamy P. Ilankumaran and S. Chandrasekaran Synlett 1997 513. 7 A. Bouzide and G. Sauve Synlett 1997 1153. 8 T. Onoda R. Shirai and S. Iwasaki Tetrahedron Lett. 1997 38 1443. 9 R. Ballini F. Bigi S. Carloni R. Maggi and G. Sartori Tetrahedron Lett.1997 38 4169. 10 K. J. Davis U. T. Bhalerao and B. V. Rao Indian J. Chem. Sect. B-Org. Chem. Med. Chem. 1997 36 211. 11 J. R. Hwu F. F. Wong J. J. Huang and S. C. Tsay J. Organomet. Chem. 1997 62 4097. 12 I. D. Clarke and P. Hodge Chem. Commun. 1997 1395. 13 P. Somfai Angew. Chem. Int. Ed. Engl. 1997 36 2731. 14 Y. C. Xu A. Bizuneh and C. Walker J. Org. Chem. 1996 61 9086. 15 Y. Watanabe and T.Nakamura Nat. Prod. Lett. 1997 10 275. 16 K. Kamaike K. Takahashi T. Kakinuma K. Morohoshi and Y. Ishido Tetrahedron Lett. 1997 38 6857. 17 A. Hasan K.-P. Stengele H. Giegrich P. Cornwell K. R. Isham R. A. Sachleben W. Pfleiderer and R. S. Foote Tetrahedron 1997 53 4247. 18 U. Mu� nch and W. Pfleiderer Nucleosides Nucleotides 1997 16 801. 19 K. Rosenthal A. Karlstrom and A. Unden Tetrahedron Lett.1997 38 1075. 20 M.A. Brook C. Gottardo S. Balduzzi and M. Mohamed Tetrahedron Lett. 1997 38 6997. 21 M. Tandon and T. P. Begley Synth. Commun. 1997 27 2953. 22 S. Chandrasekhar P. K. Mohanty and M. Takhi J. Org. Chem. 1997 62 2628. 23 I. Mohammadpoor-Baltork and S. Pouranshirvani Synthesis 1997 756. 24 P. Saravanan S. Gupta A. DattaGupta S. Gupta and V. K. Singh Synth. Commun. 1997 27 2695. 25 M.G. Stanton and M. R. Gange J. Am. Chem. Soc. 1997 119 5075. 26 Y. Masaki N. Tanaka and T. Miura Chem. Lett. 1997 55. 27 W.-C. Chen M.D. Vera and M.M. Joullie Tetrahedron Lett. 1997 38 4025. 28 M. Honda H. Morita and I. Nagakura J. Org. Chem. 1997 62 8932. 29 F. Mohanazadeh and Y. Ranjbar Iran. J. Chem. Chem. Eng. Int. Eng. Ed. 1996 15 35. 30 R. P. Iyer D. Yu J. Xie W. Zhou and S.Agrawal Bioorg. Med. Chem. Lett. 1997 7 1443. 31 M.P. Reddy N. B. Hanna and F. Farooqui Nucleosides Nucleotides 1997 16 1589. 32 V. T. Ravikumar Z. S. Cheruvallath and D.L. Cole Nucleosides Nucleotides 1997 16 1709. 33 A. Pu� schl J. Kehler and O. Dahl Nucleosides Nucleotides 1997 16 145. 34 A. D. Proud J. C. Prodger and S. L. Flitsch Tetrahedron Lett. 1997 38 7243. 35 E. C. L. Gautier A. E. Graham A. McKillop S. P. Standen and R. J. K. Taylor Tetrahedron Lett. 1997 38 1881. 36 T. S. Li Z. H. Zhang and C. G. Fu Tetrahedron Lett. 1997 38 3285. 37 S. E. Sen S. L. Roach J. K. Boggs G. J. Ewing and J. Magrath J. Organomet. Chem. 1997 62 6684. 38 S. Chandrasekhar B. Muralidhar and S. Sarkar Synth. Commun. 1997 27 2691. 39 B. H. Lipshutz P. Mollard C. Lindsley and V. Chang Tetrahedron Lett.1997 38 1873. 40 T. S. Jin Y. R. Ma Z. H. Zhang and T. S. Li Synth. Commun. 1997 27 3379. 41 D. Albanese F. Corcella D. Landini A. Maia and M. Penso J. Chem. Soc. Perkin Trans. 1 1997 247. 42 N. C. R. van Straten H. I. Duynstee E. de Vroom G. A. van der Marel and J. H. van Boom Liebigs Ann./Recueil 1997 1215. 43 H. Waldmann and A. Reidel Angew. Chem. Int. Ed. Engl. 1997 36 647. 86 A. C. Spivey and S. J. Woodhead 44 C. A. Costello A. J. Kreuzman and M. J. Zmijewski Tetrahedron Lett. 1997 38 1. 45 J. S. Debenham S. D. Debenham and B. FraserReid Biorg. Med. Chem. 1996 4 1909. 46 B. H. Wang and A. L. Zheng Chem. Pharm. Bull. 1997 45 715. 47 S. Lemaire-Audoire M. Savignac E. Blart J.-M. Bernard and J. P. Genet Tetrahedron Lett. 1997 38 2955. 48 N. Thieriet J. Alsina E. Giralt F.Guibe and F. Albericio Tetrahedron Lett. 1997 38 7275. 49 T. Vorherr A. Trzeciak and W. Bannwarth Int. J. Pept. Protein Res. 1996 48 553. 50 W. Hollweck N. Sewald T. Michel and K. Burger Liebigs Ann./Recueil 1997 2549. 51 X. P. Qian and O. Hindsgaul Chem. Commun. 1997 1059. 52 E. F. Evans N. J. Lewis I. Kapfer G. Macdonald and R. J. K. Taylor Synth. Commun. 1997 27 1819. 53 H. Miel and S. Rault Tetrahedron Lett. 1997 38 7865. 54 J. Roby and N. Voyer Tetrahedron Lett. 1997 38 191. 55 L. A. Carpino M. Philbin M. Ismail G. A. Truran E.M. E. Mansour S. Iguchi D. Ionescu A. ElFaham C. Riemer R. Warrass and M.S. Weiss J. Am. Chem. Soc. 1997 119 9915. 56 D. C. Hill L. A. Flugge and P. A. Petillo J. Organomet. Chem. 1997 62 4864. 57 T. Fukuyama M. Cheung C.-K. Jow Y. Hidai and T. Kan Tetrahedron Lett. 1997 38 5831. 58 P. Sun S. M. Weinreb and M. Y. Shang J. Org. Chem. 1997 62 8604. 59 D. J. Hartley and B. Iddon Tetrahedron Lett. 1997 38 4647. 60 E. DiezBarra A. delaHoz R. I. RodriguezCuriel and J. Tejeda Tetrahedron 1997 53 2253. 61 Y. Okada J. D. Wang T. Yamamoto T. Yokoi and Y. Mu Chem. Pharm. Bull. 1997 45 452. 62 T. Voelker T. Ewell J. Joo and E. D. Edstrom Tetrahedron Lett. 1998 39 359. 63 K. Karupaiyan V. Srirajan A. Deshmukh and B. M. Bhawal Tetrahedron Lett. 1997 38 4281. 64 G.M. Dubowchik and S. Radia Tetrahedron Lett. 1997 38 5257. 87 Synthetic methods Part (v) Protecting groups