10 Selective protection of bifunctional compounds certain bifunctional compounds are extremely useful in Me have seen th: srganie synthesis. Nevertheless, the p ‘unctional groups in # molecule can sometimes be more of a hindrance han a help. Whea a molecule contains two reactive functional groups, the fien arises is how to carry out ing the other. Three dite of two or more reactive selective reaction on one nt situations © sroblem which offen cir reactivity then it should be possible to 1. if the 1wo groups differ i serform a reaction on the more reactive group (eqn 10.1) NH3 NHCOCH, = oo Ac, 7 . j aa u (0.1) HO* SS HO’ ct of reaction is less reactive possible to bring 2 ps arc identical but the prod: than the starting material th n it should be p about a selective reaction (eqns 10.2 and 10.3), NO, NH, . a | NaHS. (10.2) S ‘MeOH NO, NOe oO \. COMe Qo MOH, ( (103) ( COH oO nat the less reactive of Wwo 4 the more reactive 2. Wthe two grow 3. However, if we wish to carry out a reaction functional groups then we will usuuilly need 10 prover Sroup (scheme 10.1). a» Covegn Anu & olen Asetatsexive protection of bifunctional compaunels R d f \ LIA, Doon DS Scheme 10.1 10.1 Use of protecting groups tals can be used to protect J out elsewhere ir imple alcohols, Indeed they Idchyde oF ketone a molecule, As illustrated abow groups while transformations are ea ‘Acetals can also be used to protect diols and si ‘ire often preferable to simple ether protecting groups because they can be femoved under very miki conditions. Thus, the so-called tetrahydro- pycanyl (THP) aad methoxymethyl (MOM) ethers (eqns 10.4 and 1 are in ‘reality and can be readily removed by treatment with aqueous acid OQ = Om oO RO” cetatl ‘O (THP ether) ROT + Ch_LOMe —— | RO__OMe (10.5) (MOM ether) G ting the use of the THP protecting group is A short synthesis illust shown in scheme 10.2 CH,OH ‘Scheme 10.2[Aleohe!s can also be protected as trim rimethylsilyl ethers (eqn 16.6). Ti trimethybily! protecting group can be ee eabutstammonium Nuoride or aqueous HF. ea males ROH + ti MesSiCl ROSMey (10.6) (TNS ether) 40.2 Selective protection/deprotection of carbohydrates Onearca where aleohol (and exrhony protecting geo . exploited is in the chemistry of eacinimet mate been widely distinguishing between several very similar functional proups irsehienley iilustrates the use of acetal and ether eroups to eee fuels methylated glucose derivatives, pure two selectively HOH Ph: 0 ee a Qo ce eae ee on Ho. OMe ‘On methy! [3-O-glucoside | weviAg,0 lame . Ph: HOME. MeO" Q Ne Q MoO. OMe MeO. OMe ‘OMe oe | HO | HO" HOMe, HOH Meo: | HO Q MeO. OH MeO. OH ‘OMe eg 23.4.6tetra-Omethyl-{1-0-glucose 2,3-di-0 methylf-D-glucose Scheme 10.3 ‘on of amino acids no protecting nits CONTAIN ° 3 Selective protection/deprotect! “plide synthesis d «of carboxyl and a sis depends upon the use of carbons ups, since it involves joining together different monomer "e Carboxyl and amino groups. Forthermore, the protecting groups must inoue and remonea under conaitions whieh ‘Jo not cleave peptide bang ds and and do not lead to racernisatton retinal compounds 73ifimetionad compounds TA Selective protection of Carboxy! protection Fhe-use of methyl or ethyl esters as protecting groups is clearly poy citifretory sinee the strong alkali or aqueous acid nicedeel 10 Femove the alkyl group would lead to cleavage of the amide bonds and epimerisatiog of tiie stereogenic centres. Esters Ashich can be cleaved without hige treatment are therefore ideal protecting groups [6 this purpose. Bens} esters whieh can be cleaved by hydrogenol and rert-butyl esters which can be removed by treatment with ahydrous acid tdry HC! or fluoroacetic acid) are usually used ceqns 10. Tand 10.8). Oo ° fone TO meta R~ OH aw S07 Pn PHS Ae von ‘OH 7 R Amino protection “Fe use of a conventional acyl derivative (amide) ay san atnaine protecting ' r Ke & Cyt eee group suffers from the disadvantage t require the wee b strong alkali or aqueous acid to remove it, The bensyloxyearbony | and persce. ; Awyvo rbonyl (1-Boe) groups have therefore been developed for this © they can be readily removed under conditions which do not eeptide product (eqns 10.9 and 10.10. 9 monoSe AY pe He RNH, Spy wH ty ase Fi y ‘0 nS RNH, + CO, + PACH, A (105), Bulo” ct R. RNH, — in a ie N ANH, + CO, = (10.10) Peptide formation ynthesis involves not only protecting the functional groups not taking part in the reaction but also activating the Garboxyt group to bring about amide bond formation (eqn 10.11). However, atctivation of the carboxyl group enhances the possibility of epimeris:tion by increasing the acidity of the a-hydragen atom, and may also cause other side reactions 0 occur. Rt Re Rt , H ee + pa oor wae KL 008 ny Wane pot ipo protecting group bob X = carboxy! protecting group Y = activating group,Three methods which have bee, bond> ace illastrated Below. The first involves comverting oon groupintoan acy! azide (64 10.12). These derivatives are more usefat thee wept halides since, FOF FeYSONS which are not clear they do ni acemisation. ” Successfully used to make peptide 0 9° Ny we BONO, Rent Preeti wn! A AY ‘A-second approach involves the use of an a phenol, such as pentalluoropherol of 2.4 5-trichlorophenol, the anion of which provides a good leaving group, This a A Pproach is illustrated by a synthesis of the artifical sweetener aspartame (scheme 10.4) Cc sos, 9 TENN 2a Hes, phenol women meio wScoys AL PacHO~ N Ky H aspartic acid R activated ester derived from + phenylalanine methyl ester Ph Bifunctional compounds 1S H (10.12) cl 0. mo. COHPA ° 4H u * ANC Come x N, Hi — menos none § Pa-c. Hg ‘Asp-Phe-OMe Scheme 10.4 The third method uses dicyelohexylearbodiimide (DCCD, which has the eflect of converting the carboxylic acid into an activated intermediate ‘hich isnot isolated (eyn 10,14). The success of this method depends upon the fact 43 4 thermodynamically stable urea molecule is liberated when feacts with an amine. In DCI is usually used in Conjunction with N-hydroxysuecinimide or N-hydroxybenzotriazole, Which Facilinat ¥ same time minimisin, the les the coupling process while att the same time ie Ne risk of racemisation, ‘he interme, ° . Aue 7 Nhydroxysuccinimde 1 -hydroxybenzotriazole 4 Get NCONC Hs RaW16 Selective protection of bifune tional compounds A short dipeptide synthesis usin DCCLis shown in scheme 10.5. a CHy Oo CHy o fH Pncltococ! i OL NA —e : > N HA COs pncno~ ~N~ ~codt nea alanine " : NHR cHICH. CH(CH)2 | CHOH Sa HOH ye un cont We” un ~co,cH.Pn valine CH, oO GH + NCO; A J N, COCHPh HN’ aa . prcH,p~ NW aa YT, CHICH)2 Le) H(CHs)9 Ala-Val Scheme 10.5 Problems 1. Outline methods by which each of the following compounds may Pe synthesised from the suggested starting material ° 9 I Pr fom Pr . 40H Cost 9° ies from . - Ny \ r fr Oe i . 2. Suggest structures for the compounds AD in the following scheme. c 0 y MeOH, , SOCk, 4 MeN, — _heat DiC HNO 0