2 Synthetic methods Part (v) Protecting groups Alan C. Spivey and Adrian Maddaford Department of Chemistry Brook Hill University of She.eld She.eld UK S3 7HF. E-mail a.c.spivey@she.eld.ac.uk Another excellent and comprehensive ‘update’ review of protecting group strategies in organic synthesis has appeared this year. Additionally a useful review focusing on enzymes as ‘reagents’ for protecting group manipulation (mainly esters and amides) has been published. O at 70°C (Kharasch—Sosnovsky 1 Hydroxy protecting groups The development of mild new methods for the cleavage of allyl ethers continues to attract attention. An interesting example is a new two-step procedure whereby sodium dithionate (Na S O )—sodium bicarbonate mediated (i.e.radical) addition of per- .uorohexyl iodide (C F I) in CH CN—H O (4 1) a.ords the corresponding -iodo- -per.uoroalkyl derivatives which undergo reductive elimination on treatment with Zn-powder and ammonium chloride in re.uxing EtOH to a.ord anomeric hemiacetals of carbohydrates, secondary alcohols and carboxylic acids from their respective allyl protected forms. Acetoxy and secondary hydroxy groups isopropylidene and benzylidene acetals thiophenyl ethers and trisubstituted double bonds are inert under these conditions (Scheme 1). Preliminary studies on the oxidative deprotection of allyl glycosides using tert-butyl hydroperoxide—copper(.) bromide in t-BuOH—H reaction via peroxyacetal intermediates) have also been disclosed but presently give moderate yields. Two new methods for the chemoselective O-methylation of phenols in the presence of alkyl alcohols have appeared LiOH·H O (1 equiv.) dimethyl sulfate (0.5 equiv.) in dry THF at 25 °C, and Cs CO (0.25 equiv.) in neat dimethyl carbonate at 120 °C. The former method which uses a minimum of dimethyl sulfate is compatible with benzylic primary amide and ester functionality and e.ciently methylates (R)-N-Boc tyrosine methyl ester without loss of optical purity.The latter avoids the use of dimethyl sulfate (which is toxic) and can also be applied to the preparation of methyl esters. 3-Pentyl ether protection of tyrosine has been advocated during segment coupling as it is compatible with both .uoren-9-ylmethyloxycarbonyl (Fmoc) and 83 Annu.Rep. Prog. Chem. Sect. B 1999 95 83—95 Scheme 1 tert-butoxycarbonyl (Boc) based peptide synthesis strategies. Introduction employs NaH then 3-bromopentane in N,N-dimethylformamide (DMF) (no racemisation observed for N-Boc tyrosine) and cleavage employs neat tri.uoroacetic acid (TFA) 25 °C. Cleavage could also probably be e.ected using AlCl in CH Cl which has been reported to selectively cleave isopropyl aryl ethers in the presence of methyl aryl ethers. Phenolic triisopropylsilyl (TIPS) ethers are not stable to these conditions. The Boc group has been shown to be a useful group for the protection of highly hindered phenols such as 2,6-di-tert-butylphenol. The group is introduced using di-tert-butyl dicarbonate (Boc and deprotected using 3M aq.HCl—dioxane (1 1) at re.ux. Deprotection using TFA was unsatisfactory due to competing dealkylation and o-and p-realkylation by the liberated tert-butyl cation. O)—N,N-dimethyl-4-aminopyridine(DMAP) inCH CN orCH Cl Trityl ethers are popular acid labile protecting groups and a new method for their CH Cl. The expected selectivity for primary over secondary alcohols introduction under almost neutral conditions employs stoichiometric benzyl trityl ether (BTE) and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) with 4Åmolecular sieves in ClCH is observed. Non-acidic deprotection of both trityl and monomethoxytrityl ethers can be e.ected using 1% iodine in MeOH allowing preservation of acetate and tertbutyldimethylsilyl (TBDMS) ethers providing the temperature is kept below 40 °C. A photo-labile trityl derivative the 9-phenylxanthen-9-yl (pixyl) group which undergoes heterolytic C—O bond cleavage on irradiation at 254 or 300nm in CH CN—H O in excellent yields has also been developed. Due to the enduring popularity of benzyl ether protection particularly in the .eld of oligosaccharide synthesis numerous new and selective methods for their deprotection continue to be reported.Of note is a new dual ‘primary benzyl ether deprotection and alkyl to thiophenylglycosyl’ conversion employing PhSSiMe ZnI Bu NI in ClCH CH Cl (a reagent combination introduced by Hanessian for the latter process).Of more general utility is the extensive work that has been reported this year on the e.ect of additives (both promoters and dopants) on palladium-catalysed hydrogenolysis. Thus Ti-loaded hexagonal mesoporous silica (TiHMS) signi.cantly accelerates the cleavage of primary and secondary benzyl ethers by hydrogen using 5% Pd—C in MeOH in the presence of acid-sensitive functionality such as TBDMS and 84 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 NAPO HO NAP = O O 10% Pd-C H2 EtOH 8 h BnO BnO BnO BnO 90% BnO OMe BnO OMe Scheme 2 tetrahydropyranyl (THP) ethers and dimethyl acetals. Elegant studies into the mechanistic details of hydrogenolysis with Pd—C (and homogeneous Pd systems) have highlighted the amphipolar nature of the Pd—H bond resulting in insights of use in synthesis. For example the use of speci.c amine dopants for tempering the reactivity of the Pd surface such that disubstituted alkenes benzyl esters and nitro functions can be reduced in the presence of phenolic benzyl ethers, mono- di- and tri-substituted alkene hydrogenation in the presence of O-benzyl and N-benzyloxycarbonyl (Cbz) groups, and the use of 2-naphthylmethyl (NAP) as a benzylic protecting group which is more labile to hydrogenolysis than the benzyl group thereby allowing sequential deprotection of the two (Scheme 2). Use of .uorous ‘tagged’ benzyl protecting groups during oligosaccharide synthesis has been shown to allow rapid .uorous-organic separation techniques although presently the yields of introduction of these groups leave much to be desired (51% for standard tribenzylation of a monosaccharide). Microwave thermolysis using clay supported ammonium nitrate (Clayan) in the absence of solvent o.ers a cost e.ective and environmentally benign method for the selective deprotection of alkyl and aryl p-methoxybenzyl (PMB) ethers in the presence of silyl ethers acetates esters double and triple bonds and benzyl ethers. O-2,4-Dimethoxybenzyl (DMB) protection of hydroxamic acids during parallel synthesis allows for clean deprotection by 5% TFA (triethylsilane as benzyl cation scavenger) in CH Cl . An economical method for the preparation of benzhydryl ethers would appear to be by re.uxing equimolar quantities of alcohol and benzhydrol with catalytic p-TSA in benzene in a Dean—Stark trap. In the area of ester protection of alcohols there have been further advances in non-enzymatic kinetic resolution of secondary alcohols via acylation using ‘synthetic’ chiral catalysts based on DMAP derivatives,— N-alkylimidazole containing tripeptides, TaCl —chiral diol complexes, and chiral diamines. Preparation of esters of highly hindered alcohols by reaction with an acid is frequently a challenging proposition but a number of excellent protocols have now been developed including the use of scandium tri.ate—DMAP and O,O-di(2-pyridyl) thiocarbonate —DMAP. An alternative protocol employs the acid anhydride with trimethylsilyl tri.ate (TMS-OTf). Selectivity for acylation of primary over secondary (or tertiary) alcohols is also challenging and stannoxane catalysed transesteri.cation with alkenyl esters (e.g.vinyl acetate), triphenylphosphine—carbon tetrabromide mediated transesteri .cation with ethyl acetate (or formate), and lanthanide tri.ate catalysed acylation with anhydrides all display useful levels of such selectivity. The utility of cerium(...) chloride (CeCl ) and copper(.) chloride for promoting selective C-10 [over C-7] acylation in 10-deacetylbaccatin III has also been investigated. Racemisation of optically labile secondary alcohols during esteri.cation can also prove troublesome and N-acylpyridinium tri.ates are recommended in such situations. Environment- 85 Annu.Rep. Prog. Chem. Sect. B 1999 95 83—95 Ph Ph O O O O O AcO O AcO Bu4NNO2 (4 equiv.) Ac2O (1.5 equiv.) pyridine 0 °C O OMe O OMe O O NPh NHPh O N 93% Ac2O (1.2 then 1 equiv.) 40 °C Ph O O O AcO HO OMe Scheme 3 ally benign methods for the per-O-acetylation of polyols (particularly sugars) include using neat acetic anhydride (Ac O) with either Montmorillonite K-10 or Zeolite HSZ-360, both of which are cheap solids which can be readily recycled. A new ester group the 2,2-dimethylpent-4-enoate has been introduced as an oxidatively labile pivaloate equivalent. Use of pivaloate protection particularly for tertiary alcohols is often limited by the vigorous hydrolysis conditions required to e.ect cleavage.The 2,2-dimethylpent-4-enoate however can be removed by intramolecular 6-exo-trig lactonisation following either hydroboration—oxidation [9-borabicyclo[3.3.1]nonane (9-BBN)—H O ] or dihydroxylation [OsO —N-methylmorpholine oxide (NMO)]. The transformation of alcohols into N-phenylcarbamates using e.g. N-phenyl isocyanate is rarely considered as a protection step because deprotection requires drastic conditions (e.g. LiAlH in re.uxing THF or sodium ethoxide in re.uxing EtOH). However N-nitrosation of alkyl N-arylcarbamates at 0 °C in pyridine using acetic nitrous anhydride [AcONO generated in situ from Ac O—tetrabutylammonium nitrite (Bu NNO )] followed by addition of further Ac O and heating to 40 °C allows for e.cient deprotection of -.-glucofuranose derivatives without acetyl benzoyl pivaloyl or TBDMS migration. This innovation makes N-phenylcarbamate protection of alcohols much more attractive in the context of organic synthesis (Scheme 3).Toluene-p-sulfonates are generally prepared to enable S 2 type substitution rather than as an alcohol protection strategy. However following the development of interesting asymmetric ketone -tosyloxylation and alkene 1,2-tosyloxylation protocols using hypervalent iodine reagents mild methods for accomplishing their ‘deprotection’ have been developed utilising magnesium in dry MeOH. Methods for the selective deprotection of various silyl ethers are legion. Useful additions to the synthetic repertoire disclosed this year include the use of 1% iodine in MeOH and catalytic scandium tri.ate in CH CN—H O for selective deprotection of alkyl trialkylsilyl ethers in the presence of aryl trialkylsilyl ethers.Both systems are also successful for distinguishing di.erent alkyl trialkylsilyl ethers in favourable 86 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 SiMe3 O Me3Si 'SIL' O Si O O BASE O R H H O H H O MeO O O O P 'ACE' O O N O R = cyclooctyl for guanosine and uridine R = cyclododecyl for adenosine and cytidine O O 'TES' Uridine TrO Si Si O O iPr iPr iPr iPr H H H O O O NC 'THP' H P O N Tr = trityl Scheme 4 cases. Carbon tetrabromide in re.uxing MeOH or PrOH is also useful in this regard and can be used for deprotection of primary TIPS ethers in the presence of secondary ones. Tris(dimethylamino)sulfonium di.uorotrimethylsilicate (TAS-F) a commercially available anhydrous solid also appears to be a useful reagent for mild silyl ether removal in extremely base sensitive situations where alternative .uoride sources fail. This reagent has been used in DMF at 23 °C to successfully deprotect TBDMS and triethylsilyl (TES) ethers in complex natural product synthesis when tetrabutylammonium .uoride (TBAF) and HF—pyridine methods failed.Cerium(...) chloride heptahydrate (CeCl ·7H O)—sodium iodide in CH CN is also a useful reagent combination for nearly neutral deprotection of trialkylsilyl ethers in the presence of THP ethers. The versatility of pyridinium toluene-p-sulfonate (PPTS) as a cheap mild and selective acid catalyst has been highlighted by its use for primary TBDMS ether deprotection in the presence of primary N-Boc carbamates. Silyl protecting groups are gaining popularity for protection of 5-hydroxy positions during RNA synthesis using the phosphoramidite method.Traditionally this position is protected as an acid labile dimethoxytrityl (DMT) ether and the 2-hydroxy by a .uoride-labile TBDMS group. The ‘reversal’ of this orthogonality by employing .uoride-labile 5-protection and acid-labile 2-protection appears to produce cleaner RNA. Both 5-O-SIL-2-OACE and 5-O-TES-2-O-THP ribonucleoside phosphoramidites (Scheme 4) have been advocated although the former presently appears superior since .uoridolytic cleavage of the TES group induces partial cleavage of the 2-cyanoethyl phosporamidite group.Oxidative cleavage of silyl ethers yields either aldehydes or ketones. DDQ is 87 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 probably one of the mildest methods available for this transformation and is useful for the preparation of labile ,-unsaturated aldehydes from allylic TBDMS ethers and benzaldehyde derivatives from benzylic TBDMS ethers. A more vigorous procedure employs dinitrogen tetraoxide complexes of iron() nitrate [Fe(NO)¡PNO] and copper() nitrate [Cu(NO)¡PNO] either neat in CHCl or in CCl at 25 ¢XC. These conditions also eect oxidative cleavage of THP ethers acetals and thioacetals to give aldehydes and ketones.4,6-O-Phenylboronate diester protection of thioethylglycosyl donors during Niodosuccinimide (NIS)¡Xtriic acid (TfOH) mediated glycosylation appears to oer an interesting alternative to benzylidene acetal protection.A particular advantage is the easy introduction of this grouping by reuxing with phenylboronic acid in benzene with a Dean¡XStark trap and easy deprotection using the borate selective resin Amberlite-IRA-743 in dry CHCN at room temperature. The 1,1,3,3-tetraisopropyl-1,3- disiloxanediyl group can also be used for this same 1,3-diol protection. The advantage of this mode of protection is the ability to eect partial ring-opening at the sterically less hindered 6-position using polyhydrogen uoride. This and the chemistry of this group in a broader setting have been reviewed.A selective one-pot protection of the secondary alcohol of 1,2-diols using BuLi then di-tert-butylchlorosilane to form a cyclic silyl ether followed by Si¡XO ring-opening with BuLi at 78 ¢XC has been developed. This aords 2-(butyldi-tert-butylsiloxy)alkan-1-ols with excellent regioselectivities and as such represents an interesting alternative to the more readily accomplished selective protection of the primary alcohol. Selective mono-protection of the primary (i.e. 1-) position of 1,2-diols can be achieved by trityl protection (by virtue of the steric bulk of this protecting group) or benzylative or benzoylative ring-opening of dibutylstannylene acetals. However the large quantities of dibutyltin oxide required to form the stannylene acetals invariably present unwanted purication problems and so a new procedure employing just catalytic quantities of dimethyltin dichloride for the in situ formation of dimethylstannylenes during benzoylation should nd wide utility in synthesis (Scheme 5).2 Carboxy protecting groups TMS chloride catalyses the selective formation of aliphatic methyl esters from their corresponding acids in the presence of aromatic acids using 2,2-dimethoxypropane¡XMeOH at 25 ¢XC. As the reagents are cheap and all the by products are volatile this represents an attractive method. An intriguing new method for the synthesis of benzyl esters from their corresponding acids by simply heating in toluene with O-benzyl-S-propargyl xanthate (propargylprop-2-ynyl) has been described. The conditions are essentially neutral making the procedure useful for sensitive substrates and also for benzylation of other suitably acidic (pK below 8¡X10) functionality such as phenols and tetrazoles.Transesterication is another popular method for the preparation of esters and further mechanistic details of the alkali-metal alkoxide cluster catalysed procedure have appeared. Titanium() ethoxide has also been shown to be an eective catalyst for the preparation of hindered menthyl esters from ethyl or methyl ester precursors although the reaction fails for highly hindered tert-triphenylmethyl ester formation. Cleavage of highly hindered tert-butyl esters is 88 Annu. Rep. Prog. Chem. Sect. B 1999 95 83¡X95OBz OH OH PhCOCl (1.2 equiv.) Me2SnCl2 (0.01 equiv.) K2CO3 (2 equiv.) THF 25 °C 12 h OH OBz OH Ph Ph Ph Me 5% 90% via Me O Sn O Ph Scheme 5 generally achieved using excess TFA either neat or in concentrated CH Cl or CH CN solutions with cation scavengers such as anisole MeOH or trialkylsilanes added.A new method employs just two equivalents of commercial 100% nitric acid in CH Cl at 0 °C. As the liberated tert-butyl cation is rapidly scavenged by nitrate as 1,2-dimethylethyl nitrate (cf. poor scavenging properties of tri.uoroacetate) the addition of supplementary scavengers is unnecessary. Catalytic transfer hydrogenolysis of p-nitrobenzyl (PNB) esters using 10% Pd—C in MeOH with ammonium formate (or aqueous phosphinic acid) acting as hydrogen donor allows for clean deprotection in 3-cephems. 3-Cephems are notoriously prone to alkene isomerisation (to give 2- cephems) which occurred in this case when employing alkali-or .uoride-mediated hydrolysis.Alkaline hydrolysis is also problematic for the deprotection of peptide methyl esters as very careful control of pH is required to minimise racemisation in most cases. Tetrabutylammonium hydroxide (40% aqueous) in DMF or THF at 0 °C now appears to be the method of choice for this application particularly for poorly soluble non-polar peptide esters. These often hydrolyse very slowly and with unacceptable levels of epimerisation using alkali metal hydroxide hydrolysis. 3 Carbonyl protecting groups A new type of acetal protective group for aldehydes and ketones has been introduced the methylenephenylsulfone appended ethylene acetal. These are formed from 3- phenylsulfonylpropane-1,2-diol by re.uxing in benzene with a catalytic quantity of PPTS and can be readily cleaved by -elimination on treatment with 1,8-diazabicyclo[ 5.4.0]undec-7-ene (DBU 1.2 equiv.) in CH Cl .Such deprotection is complementary to conventional acid or Hg salt mediated cleavage of the ‘parent’ ethylene acetals (1,3-dioxolanes) for which a new protocol employing copper(..) chloride dihydrate in CH CN at 25 °C has been described. Catalytic quantities of CuCl ·2H O su.ce but the conditions do appear to be substantially acidic causing concomitant deprotection of TBDMS and THP ethers. A neutral and anhydrous alternative is the use of (trimethylsilyl)bis(.uorosulfuryl)imide [TMSN(SO F) (1.1 equiv.)] in CH Cl at 0 °C. This reagent can also be used in catalytic quantities (5 mol%) for the deprotection of dimethyl acetals of aromatic carbonyl compounds at 78 °C and aliphatic counterparts at 0 °C.1,1-Diacetates (acylals) are useful protective groups for aldehydes as they are particularly stable in basic media. Classical preparative procedures employ Ac O in conjunction with Brønsted or Lewis acids. Scandium tri.ate (2 mol%) in nitromethane has now been shown to catalyse this reaction, as has TMS iodide in CH CN or CHCl (generated in situ from TMS chloride and sodium 89 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 iodide), and commercially available zeolite-Y in neat Ac O. Aldehydes and ketones are occasionally protected as oximes during synthesis and furthermore the formation of an oxime from a carbonyl compound can often expedite its puri.cation and characterisation.Mild methods for regeneration of the carbonyl function from its corresponding oxime are still being sought. This year two new methods have been described one using silica-supported chromium trioxide (SiO —CrO ) and the other using the Dess—Martin periodinane to e.ect oxidative cleavage of the C——N bond. The former method gives excellent yields and involves pre-adsorption of the oxime onto the derivatised silica microwave (MW) irradiation for 45 s in a domestic 750W MWoven and elution from the silica. The latter method also gives excellent yields and employs 1.1 equiv.of the Dess—Martin oxidant in wet CH Cl at 25 °C for less than half an hour. It seems likely that the essentially neutral Dess—Martin reagent would be preferred in an acid sensitive molecule of some complexity for which pre-adsorption on silica would not be recommended. 4 Amine protecting groups In impressive studies directed towards the controlled synthesis of polyamine toxins isolated from the venom of spiders and wasps an orthogonal set of .ve independently removable amine protecting groups has been developed. The groups in question are i) Boc ii) N-(trimethylsilyl)ethanesulfonyl (SES) iii) N-allyl iv) N-phthalimido (Phth) and v) N-pyridine-2-sulfonyl. The conditions for their selective removal are as follows i) TFA—CH Cl 25 °C ii) CsF—DMF 90 °C iii) Pd(PPh ) —N,N-dimethylbarbituric acid (NDMBA)—CH 1.83mV (having previously removed the N-Phth group and reprotected as the tri.uoroacetate using TFA—Et be selectively deprotected using potassium carbonate in MeOH at 25 °C (Scheme 6).Cl 30 °C iv) N H ·H O EtOH re.ux and v) electrolysis N—CH Cl 0 °C). The tri.uoroacetate group can also 2-N-Ac Protection of .-glucosamine (GlcNH ) derived glycosyl donors during the synthesis of -GlcNAc and -GalNAc containing glycoconjugates is unsatisfactory due to the poor reactivity and poor anomeric -/-stereocontrol this group imparts (due to neighbouring group participation to give a 1,3-oxazolinium intermediate).Consequently numerous alternative protecting groups for the primary 2-amino group have been investigated.N-Phth protection in this context is widespread because of the -directing in.uence which the 2-N-Phth unit imparts to the glycosyl donor. However deprotection by prolonged heating with N H ·H O or ethylenediamine is often problematic in complex carbohydrates. The 4,4,5,5-tetrachlorophthaloyl (TCPhth) and 4,5-dichlorophthaloyl (DCPhth) groups have been advocated as alternatives which retain the advantageous -directing in.uence but allow cleavage under milder conditions. The DCPhth group is more stable towards basic conditions than the TCPhth group and has now been shown to survive deacetylisation benzylation benzylidenation and Lewis acid- silver salt- and iodonium ion-promoted glycosylation.The dimethylmaleoyl (DMM) group has also been touted for this role and appears to be an attractive choice in view of its good -selectivity stability during TMS-OTf mediated trichloroacetimidate glycosylation and ease of removal by treatment with NaOH and then dilute HCl (pH 5). The 2,5-dimethylpyrrole group has also been evaluated for use as a protecting group at this position and gives high yields 90 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 N O O S O N N N N BocHN O S O SiMe3 O Scheme 6 and high -selectivity in TMS-OTf promoted trichloroacetimidate glycosylation. The group is readily introduced using hexane-2,5-dione—Et N in MeOH is removed using hydroxylamine hydrochloride and is signi.cantly more base stable than Phth DCPhth or TCPhth groups.Interestingly it is stable to conditions required for the removal of the N-Phth group. The enhanced stability towards basic conditions of the 2,5-dimethylpyrrole group relative to Phth type groups also make this the group of choice for protection of anilines during nucleophilic aromatic substitution (e.g. copper( .) chloride mediated methoxylation of iodoaniline derivatives). E.cient protection of the side-chain primary amino functionality of lysine and ornithine residues during automated solid-phase peptide synthesis (SPPS) in a manner which allows for mild cleavage is also a challenge for which the Phth group falls short and for which solutions are valuable given current interest in the synthesis of cyclic and branched peptides.Monomethoxytrityl (MMT) and dimethoxytrityl (DMT) groups have been suggested for this role when using Fmoc based procedures but are incompatible with Boc based procedures. However the 1-(4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl (Dde) group (the enamine of 2-acetyldimedone) is a promising alternative. It is stable to the acid (TFA) and base (20% piperidine—DMF) conditions employed during Boc and Fmoc based SPPS strategies but is readily removed with 2% v/v hydrazine in DMF. Furthermore providing allyl alcohol is added as a sacri.cial scavenger this hydrazinolysis is compatible with N-allyloxycarbonyl (Aloc) protection too. Two protecting groups closely related to Dde have been introduced this year the enamine of 2-isovaleroyldimedone (N-Ddiv), and the enamine of 2-acetyl-4-nitroindane-1,3-dione (N-Nde). The former displays slightly improved base stability and resistance to intramolecular NN migration relative to Dde and the latter has the advantage over Dde that its removal is readily monitored visually.All three groups show exquisite selectivity for introduction onto primary amines due to the formation of a strong intramolecular hydrogen bond making them attractive groups also for the synthesis of complex polyamines (e.g. spermidine derivatives) (Scheme 7). Another group which has been evaluated as a nitrogen protecting group which is orthogonal to Boc based peptide synthesis for the synthesis of cyclic peptides is the cyclohexyloxycarbonyl (Choc) group. This group is stable under the 1M TMSOTf —thioanisole/TFA Boc cleavage conditions but is removable with anhydrous HF.Selective N-benzoylation of less hindered amines in the presence of more hindered amines is possible using 2-chloro-N,N-dibenzoylaniline. The method is useful for discrimination between primary amines in sterically di.erent environments between primary amines and secondary amines and between secondary amines in sterically di.erent environments. The reagent which is an air-stable solid is readily prepared 91 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 Me Me O O H Me H Me Fmoc-(S)-Lys-OH FmocHN N O O R CO2H R O Dde R = Me Ddiv R = CH2CHMe2 H O O O Fmoc-(S)-Lys-OH H FmocHN N Me NO2 O O Me CO2H NO2 Nde Scheme 7 from 2-chloroaniline using BuLi¡Xbenzoic anhydride in THF at 25 ¢XC.A new and versatile method for the introduction of rigidifying constraints into amino acids and peptides is Ru-catalysed ring-closing metathesis. N-Allylation of amino acids and peptides is a relatively easy method for the introduction of the primary alkene functionality required for these reactions and has now been shown to be readily accomplished from N-Ts protected derivatives using allyl ethyl carbonate and 1 mol% allylpalladium chloride dimer. Should deprotection be required then a new method employing MeAl (3 equiv.) and (dppp)NiCl (4 mol%) in toluene can be employed. Diisobutylaluminium hydride (DIBAL 1.5 equiv.)¡X(dppp)NiCl (4 mol%) can be used for the analogous removal of N-allyl groups from primary or secondary amines.Deprotonated N-allyl- N-benzyl- and N-3,4-dimethoxybenzyl- methylbenzylamine are useful chiral ammonia equivalents for the synthesis of -amino acids via conjugate addition to acrylates. Selective deprotection to leave just the N-methylbenzyl group from these derivatives can be achieved by palladium or rhodium catalysed deallylation hydrogenolysis using Pearlman¡¦s catalyst [10% Pd(OH) on carbon] in MeOH and cerium() ammonium nitrate (CAN) in CHCN¡XHO or DDQ in CHCl¡XHO respectively. Further studies on the utility of the o-nitrobenzyl group as a photolabile benzyl protecting group have now established that this group can be eciently introduced onto (o-nitrobenzyl bromide¡XNaH¡XDMF) and removed from (h 300 nm) a number of indoles benzimidazoles and 6-chlorouracil.Carbamate protection remains one of the most valuable methods for the protection of amines both in natural product and peptide synthesis. Unsurprisingly therefore new methods for their introduction and removal continue to be developed. Of particular note is a new method for the introduction of common carbamate protecting groups simply by mixing the amine and appropriate chloroformate (ethyl isopropyl and benzyl) in benzene at 25 ¢XC in the presence of powdered zinc (1 equiv.). Excellent yields are observed and reaction times are generally under 20 min although electron decient anilines can take up to 6 h. Alkyl esters and tert-butyldiphenylsilyl (TBDPS) ethers are tolerated and the zinc can apparently be recovered and re-used. Six new 92 Annu. Rep. Prog.Chem. Sect. B 1999 95 83¡X95 methods for the deprotection ofN-Boc groups have been reported. Two closely related methods involving MW irradiation involve either pre-adsorption onto silica or pre-adsorption onto AlCl doped neutral alumina. Both methods are applicable to bothN-Boc amines and amides although the latter method appears to tolerate a wider range of potentially acid-and base-sensitive functionality (e.g. TBDMS ethers and benzyl ethers). A related method involving pre-adsorption onto Yb(OTf) doped silica followed by heating to 40 °C appears to be limited to the deprotection ofN-Boc amides which can be deprotected in the presence of N-Cbz carbamates and acetonides. Use of AlCl —anisole in CH Cl —MeNO (2 1) has been reported to successfully deprotect immobilised N-Boc-5-amino-2,5-dideoxynucleosides (on controlled pore glass CPG). The use of TFA in this instance resulted in unacceptable depurination at the 5-terminus.The use of TMS-OTf-2,6-lutidine in CH Cl at 25 °C is also su.ciently mild to allowN-Boc deprotection of peptides immobilised to resins via the Rink amide method (which is a TFA cleavable linkage). The strongly acidic ion-exchange resin Amberlyst-15 is also capable of deprotecting N-Boc amines and has the advantage that the released amino function becomes ionised and binds to the ion exchange resin thus allowing for separation and subsequent release from the resin by elution with ammonia-saturated methanol and evaporation. A specialised procedure for the introduction of carbamate protection onto the guanidino function of arginine via a silylated intermediate has also been disclosed. A one-pot conversion of N-Fmoc amino acids and dipeptides linked to Wang resin into N-Boc derivatives can be achieved in high yields using KF—Et N and either Boc O or S-Boc-2-mercapto-4,6-dimethylpyrimidine in DMF. This transformation is particularly valuable because unlike N-Fmoc derivatives N-Boc derivatives can be cleaved intact from Wang resin using trimethyltin hydroxide.A direct comparison of the e.cacy of the 2-(4-nitrophenylsulfonyl)ethoxycarbonyl (Nsc) group and the Fmoc group with respect to N()-amino protection during the automated SPPS of peptides on PEG—PS and Wang-PS using standard (benzotriazolyloxy)tris- (dimethylamino)phosphonium hexa.uorophosphate (BOP)—diisopropylethylamine (DIEA) protocols has appeared. There appears to be very little to choose between the groups which are both base labile (via -elimination) although the Nsc protected peptides are substantially more polar than their Fmoc counterparts.Sulfonamide deprotection has again come under the spotlight and in particular some limitations to the thiolate cleavage of p-nitrobenzenesulfonyl (p-NBS) groups have been highlighted. Thus it has been found that deprotection (via S Ar substitution ipso to the sulfonamide) using thiophenol—DIEA in DMF is accompanied by signi.cant (up to ca. 11%) substitution ipso to the nitro group. This side reaction which seems to be most severe for cyclic amines generates 4-thiophenylbenzenesulfonyl protected amines which are essentially uncleavable.It was noted that the corresponding o-nitrobenzenesulfonyl (o-NBS) group did not su.er from this side reaction. The o-NBS group has also been examined as an alternative to Fmoc for SPPS. Advantages are reported to include i) deprotection liberates a yellow chromophore which allows visual or spectrophotometric con.rmation/quantitation of deprotection ii) the possibility of selective N-methylation of N-o-NBS protected nitrogen during peptide synthesis iii) the o-NBS amino acid chlorides couple more e.ciently to hindered amines than Fmoc ones and iv) o-NBS chloride is 10 times cheaper than Fmoc chloride. Furthermore since o-NBS groups cannot form 93 Annu.Rep. Prog. Chem. Sect. B 1999 95 83—95 oxazolone intermediates it is possible that racemisation levels may be reduced. However it was noted that even for the automated synthesis of a hexapeptide a product of slightly lower purity relative to that prepared using Fmoc protection was obtained. Finally there has been an extensive study of methods for the cleavage of N-ptolylsulfonyl (N-Ts) from chiral aziridines (2-phenyl 2-benzyl and 2-carboxy-). Of the methods surveyed (M in liq. NH ,Mg in MeOH aromatic radical anions SmI hv) lithium with a catalytic amount of di-tert-butylbiphenyl (DTBB) in THF at 78 °C and Mg in MeOH at 25 °C with ultrasound were the best giving good yields of desulfonylated aziridines without detectable racemisation.Only the use of magnesium in MeOH was successful for the e.cient deprotection of sensitive 2-phenylaziridines. References 1 K. Jarowicki and P. Kocienski J. Chem. Soc. Perkin Trans. 1 1998 4005. 2 T. Pathak and H. Waldmann Curr. Opin. Chem. Biol. 1998 2 112. 3 B. Yu J. B. Zhang S. F. Lu and Y. Z. Hui Synlett 1998 29. 4 B. Yu B. Li J. B. Zhang and Y. Z. Hui Tetrahedron Lett. 1998 39 4871. 5 R. Krahmer L. Hennig M. Findeisen D. Muller P. Welzel Tetrahedron 1998 54 10 753. 6 A. Basak M. K. Nayak and A. K. Chakraborti Tetrahedron Lett. 1998 39 4883. 7 Y. Lee and I. Shimizu Synlett 1998 1063. 8 J. Bodi Y. Nishiuchi H. Nishio T. Inui and T. Kimura Tetrahedron Lett. 1998 39 7117. 9 M.G. Banwell B. L. Flynn and S. G. Stewart J.Org. Chem. 1998 63 9139. 10 M.M. Hansen and J. R. Riggs Tetrahedron Lett. 1998 39 2705. 11 M. Oikawa H. Yoshizaki and S. Kusumoto Synlett 1998 757. 12 J. L. Wahlstrom and R. C. Ronald J. Org. Chem. 1998 63 6021. 13 A. Misetic and M. K. Boyd Tetrahedron Lett. 1998 39 1653. 14 D. S. Liu R. Chen L. W. Hong and M. J. So.a Tetrahedron Lett. 1998 39 4951. 15 A. Itoh T. Kodama S. Maeda and Y. Masaki Tetrahedron Lett. 1998 39 9461. 16 J. Yu and J. B. Spencer J. Am. Chem. Soc. 1997 119 5257. 17 H. Sajiki K. Hattori and K. Hirota J. Org. Chem. 1998 63 7990. 18 H. Sajiki H. Kuno and K. Hirota Tetrahedron Lett. 1998 39 7127. 19 M.J. Gaunt J. Q. Yu and J. B. Spencer J. Org. Chem. 1998 63 4172. 20 D. P. Curran R. Ferritto and Y. Hua Tetrahedron Lett. 1998 39 4937.21 J. S. Yadav H. M. Meshram G. S. Reddy and G. Sumithra Tetrahedron Lett. 1998 39 3043. 22 B. Barlaam A. Hamon and M. Maudet Tetrahedron Lett. 1998 39 7865. 23 R. Paredes and R. L. Perez Tetrahedron Lett. 1998 39 2037. 24 A. C. Spivey T. Fekner and H. Adams Tetrahedron Lett. 1998 39 8919. 25 J. C. Ruble J. Tweddell and G. C. Fu J. Org. Chem. 1998 63 2794. 26 S. J. Taylor and J. P. Morken Science 1998 280 267. 27 S. J. Miller G. T. Copeland N. Papaioannou T. E. Horstmann and E. M. Ruel J. Am. Chem. Soc. 1998 120 1629. 28 G. T. Copeland E. R. Jarvo and S. J. Miller J. Org. Chem. 1998 63 6784. 29 S. Chandraekhar T. Ramachander and M. Takhi Tetrahedron Lett. 1998 39 3263. 30 T. Oriyama K. Imai T. Hosoya and T. Sano Tetrahedron Lett. 1998 49 397.31 T. Oriyama K. Imai T. Sano and T. Hosoya Tetrahedron Lett. 1998 39 3529. 32 R. B. Greenwald A. Pendri and H. Zhao Tetrahedron Asymmetry 1998 9 915. 33 K. Saitoh I. Shiina and T. Mukaiyama Chem. Lett. 1998 679. 34 P. A. Procopiou S. P. D. Baugh S. S. Flack and G. G. A. Inglis J. Org. Chem. 1998 63 2342. 35 A. Orita A. Mitsutome and J. Otera J. Org. Chem. 1998 63 2420. 36 H. Hagiwara K. Morohashi H. Sakai T. Suzuki and M. Ando Tetrahedron 1998 54 5845. 37 R. A. Holton Z. M. Zhang P. A. Clarke H. Nadizadeh and D. J. Procter Tetrahedron Lett. 1998 39 2883. 38 E.W. P. Damen L. Braamer and H. W. Scheeren Tetrahedron Lett. 1998 39 6081. 39 R. Wagner W. Gunther and E. Anders Synthesis 1998 883. 40 P.M. Bhaskar and D. Loganathan Tetrahedron Lett. 1998 39 2215.41 R. Ballini G. Bosica S. Carloni L. Ciaralli R. Maggi and G. Sartori Tetrahedron Lett. 1998 39 6049. 42 M.T. Crimmins C. A. Carroll and A. J. Wells Tetrahedron Lett. 1998 39 7005. 43 S. Akai N. Nishino Y. Iwata J. Hiyama E. Kawashima K. Sato and Y. Ishido Tetrahedron Lett. 1998 39 5583. 94 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95 44 M. Sridhar A. Kumar and R. Narender Tetrahedron Lett. 1998 39 2847. 45 B. H. Lipshutz and J. Keith Tetrahedron Lett. 1998 39 2495. 46 B. H. Lipshutz and J. Keith Tetrahedron Lett. [Corrigendum] 1998 4407. 47 T. Oriyama Y. Kobayashi and K. Noda Synlett 1998 1047. 48 A. S. Y. Lee H. C. Yey and J. J. Shie Tetrahedron Lett. 1998 39 5249. 49 K. A. Scheidt H. Chen B. C. Follows S. R. Chemler D. S. Co.ey and W.R. Roush J.Org. Chem. 1998 63 6436. 50 G. Bartoli M. Bosco E. Marcantoni L. Sambri and E. Torregiani Synlett 1998 209. 51 J. H. Zaidi A. H. Fauq and N. Ahmed Tetrahedron Lett. 1998 39 4137. 52 S. A. Scaringe F. E. Wincott and M.H. Caruthers J. Am. Chem. Soc. 1998 120 11 820. 53 I. Hirao M. Koizumi Y. Ishido and A. Andrus Tetrahedron Lett. 1998 39 2989. 54 I. Paterson C. J. Cowden V. S. Rahn and M.D. Woodrow Synlett 1998 915. 55 H. Fiiiirouzabadi N. Iranpoor and M.A. Zol.gol Bull. Chem. Soc. Jpn. 1998 71 2169. 56 G. G. Cross and D. M. Whit.eld Synlett 1998 487. 57 T. Ziegler R. Dettmann F. Bien and C. Jurisch Trends Org. Chem. (India) 1997 6 91. 58 K. Tanino T. Shimizu M. Kuwahara and I. Kuwajima J. Org. Chem. 1998 63 2422. 59 T. Maki F. Iwasaki and Y. Matsumura Tetrahedron Lett.1998 39 5601. 60 A. Rodriguez M. Nomen B. W. Spur and J. J. Godfroid Tetrahedron Lett. 1998 39 8563. 61 M. FaureTromeur and S. Z. Zard Tetrahedron Lett. 1998 39 7301. 62 M. G. Stanton C. B. Allen R. M. Kissling A. L. Lincoln and M.R. Gagne J. Am. Chem. Soc. 1998 120 5981. 63 P. Krasik Tetrahedron Lett. 1998 39 4223. 64 P. Strazzolini M.G. DallArche and A. G. Giumanini Tetrahedron Lett. 1998 39 9255. 65 D. Albanese M. Leone M. Penso M. Seminati and M. Zenoni Tetrahedron Lett. 1998 39 2405. 66 A. F. Abdel-Majid J. H. Cohen C. A. Maryano. R. D. Shah F. J. Villani and F. Zhang Tetrahedron Lett. 1998 39 3391. 67 S. Chandrasekhar and S. Sarkar Tetrahedron Lett. 1998 39 2401. 68 P. Saravanan M. Chandrasekhar R. V. Anand and V. K. Singh Tetrahedron Lett.1998 39 3091. 69 G. Kaur A. Trehan and S. Rehan J. Org. Chem. 1998 63 2365. 70 V. K. Aggarwall S. Fonquerna and G. P. Vennall Synlett 1998 849. 71 N. Deka R. Borah D. J. Kalita and J. C. Sarma J. Chem. Res. (S) 1998 94. 72 R. Ballini M. Bordoni G. Bosica R. Maggi and G. Sartori Tetrahedron Lett. 1998 39 7587. 73 P. M. Bendale and B. M. Khadilkar Tetrahedron Lett. 1998 395867. 74 S. S. Chaudhari and K. G. Akamanchi Tetrahedron Lett. 1998 39 3209. 75 J. K. Pak A. Guggisberg and M. Hesse Tetrahedron 1998 54 8035. 76 M. Lergenmuller Y. Ito and T. Ogawa Tetrahedron 1998 54 1381. 77 M. R. E. Aly J. C. CastoPalomino E. S. I. Ibrahim E. S. H. ElAshryr and R. R. Schmidt Eur. J. Org. Chem. 1998 2305. 78 S. G. Bowers D.M. Coe and G. J. Boons J.Org. Chem. 1998 63 4570. 79 J. A. Ragan T.W. Makowski M.J. Castaldi and P. D. Hill Synthesis 1998 1599. 80 S. Matysiak T. Boldicke W. Tegge and R. Frank Tetrahedron Lett. 1998 39 1733. 81 B. Rohwedder Y. Mutti P. Dumy and M. Mutter Tetrahedron Lett. 1998 39 1175. 82 S. R. Chhabra B. Hothi D. J. Evans P. D. White B. W. Bycroft and W. C. Chan Tetrahedron Lett. 1998 39 1603. 83 B. Kellam B. W. Bycroft W. C. Chan and S. R. Chhabra Tetrahedron 1998 54 6817. 84 G. Mezo N. Mihala G. Koczan and F. Hudecz Tetrahedron 1998 54 6757. 85 K. Kondo and Y. Murakami Chem. Pharm. Bull. 1998 46 1217. 86 F. L. Zumpe and U. Kazmaier Synlett 1998 1199. 87 T. Taniguchi and K. Ogasawara Tetrahedron Lett. 1998 39 4679. 88 S. G. Davies and O. Ichihara Tetrahedron Lett. 1998 39 6045. 89 T. Voelker T. Ewell J. Joo and E. D. Edstrom Tetrahedron Lett. 1998 39 359. 90 J. S. Yadav G. S. Reddy M.M. Reddy and H. M. Meshram Tetrahedron Lett. 1998 39 3259. 91 J. G. Siro J. Martin J. L. GarciaNavio M. J. Remuinan and J. J. Vaquero Synlett 1998 147. 92 D. S. Bose and V. Lakshminarayana Tetrahedron Lett. 1998 39 5631. 93 H. Kotsuki T. Ohishi T. Araki and K. Arimuta Tetrahedron Lett. 1998 39 4869. 94 K. D. James and A. D. Ellington Tetrahedron Lett. 1998 39 175. 95 A. J. Zhang D. H. Russell J. P. Zhu and K. Burgess Tetrahedron Lett. 1998 39 7349. 96 Y. S. Liu C. X. Zhao D. E. Bergbreiter and D. Romo J. Org. Chem. 1998 63 3471. 97 H. A. Moynihan and W. P. Yu Tetrahedron Lett. 1998 39 3349. 98 R. L. E. Furlan and E. G. Mata Tetrahedron Lett. 1998 39 6421. 99 A. N. Sabirov Y. D. Kim H. J. Kim and V. V. Samukov Protein Peptide Lett. 1998 5 57. 100 P. G. M. Wuts and J. M. Northuis Tetrahedron Lett. 1998 39 3889. 101 S. C. Miller and T. S. Scanlan J. Am. Chem. Soc. 1998 120 2690. 102 D. A. Alonso and P. G. Andersson J. Org. Chem. 1998 63 9455. 95 Annu. Rep. Prog. Chem. Sect. B 1999 95 83—95