1、Protection of Functional Groups,One classical example of selective protection and deprotection of OH group,A. Robertson and R. Robinson, J. Chem. Soc., 1460 (1928).,Selectivity?,Synthesis of callistephinchloride (氯代翠菊苷),NBS? HBr ?,Why are the protective groups needed?,The Synthesis of complex organi
2、c molecules demands the availability of a variety of protective groups to ensure the survival of reactive functional groups during synthetic operations.,Synthesis of colchicine (秋水仙碱),E. E. van Tamelen, T. A. Spencer, Jr., D. S. Allen, Jr., and R. L. Orvis, Tetrahedron, 14, 8 (1961).,Synthesis of Hi
3、mastatin (A Tumor Probe),A novel bisindolyl structure in which the two halves of the molecule are identical. Each half contains a cyclic peptidal ester that contains an L-tryptophanyl unit, D-valine, (S)-2-hydroxyisovaleric acid, D-(R)-5-hydroxylpiperazic acid, L-leucine, D-valine and D-threonine.,T
4、. M. Kamenecka and S. J. Danishefsky, Angew. Chem., Int. Ed. Engl., 37,2995 (1998).,The synthesis of himastatin which illustratesseveral important aspects of protective group usage.,Bisindolyl Unit A2,6-8,Peptidal Ester Unit B,19,Base,Protective groups used,CbzCl: benzyloxycarbonyl chloride (PhCH2OC
5、OCl)TBSCl: t-butyldimethylsilyl chlorideTESCl: triethylsilyl chlorideTMSCl: trimethylsilyl chlorideFMOC: fluorenylmethoxycarbonyl groupBoc: t-butoxycarbonyl groupTeocCl: 2-trimethylsilylethoxycarbonyl chlorideTrocCl: 2,2,2-trichloroethyl chlorideTrCl: Triphenylmethyl chloride,An ideal protective gro
6、up,To be desirable that the introduction of the “blocking” group is easy and that its reactions are complementary to other protecting groups.To combine stability under a wide range of conditions with susceptibility to facile removal (“deblocking ”) by a specific, mild reagent,“Protective Groups in O
7、rganic Synthesis”Third Edition. Theodora W. Greene, Peter G.M. WutsCopyright 1999 John Wiley 0-471-22057-4 (Electronic),PeptidesNucleotidesSaccharidesOther natural compounds,Protecting groups for alcohols R-OH,Substituted Methyl Ethers(Me-OR)Allyl Ether (Allyl-OR)Benzyl Ether (Bn-OR)Triphenylmethyl
8、Ether (Tr-OR)Benzyloxymethyl Ether (BOM-OR)THP: from 3,4-Dihydro-2H-pyran,Substituted Methyl Ethers,Methyl Ether: ROMe,FormationMe2SO4, NaOH, Bu4N+I-, org. solvent, 60-90% yield.MeI or Me2SO4,NaH or KH, THF. This is the standard method for introducing the methyl ether function onto hindered and unhi
9、ndered alcohols.CH2N2,Cleavage:,Me3SiI, CHCl3, 25, 6 h, 95% yield.BBr3, NaI, 15-crown-5.BBr3, EtOAc, 1 h, 95% yield.BBr3, CH2Cl2, high yields.,Mechanism for deprotection of methyl ether: Hard-soft acid and base principle,Methoxymethyl (MOM): CH3OCH2OR,Formation:CH3OCH2Cl, NaH, THF, 80% yield.CH3OCH2
10、Cl, i-Pr2NEt, O, 1 h 25, 8 h, 86% yield.,Selective formation of MOM ethers has been achieved in a diol system.,Cleavage:,Trace coned. HCl, MeOH, H2O, 15 min.6 M HCl, aq. THF, 50, 6-8 h, 95% yield. Concd. HCl, isopropyl alcohol (IPA), 65% yield.,CF3COOH, CH2Cl2, 85% yield.,2-Methoxyethoxymethyl Ether
11、 (MEM-OR): CH3OCH2CH2OCH2OR,Formation:NaH or KH, MEMCl, THF or DME, OC, 10-60 min, 95% yield,ZnBr2, CH2Cl2, 25, 2-10 h, 90% yield.TiCl4, CH2Cl2, O, 20 min, 95% yield. Me3SiCl, NaI, CH3CN, -20, 79%.,Cleavage:,Allyl Ether (Allyl-OR): CH2=CHCH2OR,Formation:CH2=CHCH2Br, NaOH, benzene, reflux, 1.5 h, or
12、NaH, benzene,90-100% yield.Allyl carbonates,0.1 N HCl, acetone-water, reflux, 30 minHgCl2/HgO, acetone-H2O, 5 min, 100% yield0.1 eq. TsOH, MeOH, 25, 2.5 h, 86% yield,Cleavage:,Benzyl Ether (Bn-OR): PhCH2OR,BnCl, powdered KOH, 130-140, 86% yieldNaH, THF, BnBr.NaH, THF, BnBr, Bu4N+I-, 20, 3 h, 1OO%.,F
13、romation:,Selectivity?,Na/ammonia or EtOHFeCl3, Ac2O, 55-75% yieldBF3, Et2O, NaI, CH3CN, 0, 1 h; rt, 7 h, 80% yieldSnCl4, CH2Cl2, rt, 30 minPd-C, EtOH, 95% yield,Cleavage:,Triphenylmethyl Ether (Tr-OR): Ph3C-OR,C6H5CCl, Pyr, 25, 5 days, 90%Ph3CCl, 2,4,6-collidine, CH2Cl2, Bu4N+CI-, 15 min, 97% yield
14、TrOTf, 2,6-lutidine, CH2Cl2, 0, 74% yield,Formation:,Formic acid, ether, 45 min, 88% yield90% CF3COOH, t-BuOH, 20, 2-30 minH2/Pd, EtOH, 20, 14 h, 80% yieldTsOH, MeOH, 25”, 5 hBF3.Et2O, CH2Cl2, MeOH, 2 h, rt, 80% yield,Cleavage:,Benzyloxymethyl Ether (BOM-OR): PhCH2OCH2OR,PhCH2OCH2Cl, (i-Pr)2NEt, 10-
15、20, 12 h, 95% yield. Bu4N+I- can be added to increase the reactivity for protection of more hindered alcohols.PhCH2OCH2Cl, NaI, proton sponge 1,8-bis(dimethylamino)naphthalene, 84% yield.,Formation:,HCl, MeOH, 56%Na, NH3, EtOHH2, 1 atm, Pd-C, EtOAc-hexane, 68%H2, 1 atm, 10% Pd-C, 0.01 N HClO4, in 80
16、% THF/H2O, 25,Cleavage:,ROTHP (3,4-Dihydro-2H-pyran),Formation:Acid-catalyzed (trace of HCl or p-toluenesulfonic acid) addition to alcohols to give 2-tetrahydropyrayl ethersCHCl3, ethers and DMF as solventsThe acetal system is stable toward bases, organometalic compounds, LAH and alkying agents.,Cle
17、avage: Aqueous acetic acid or 0. 1M HCl Disadvantage: To yield a new chiral center,Silyl Ether,Trimethylsilyl Ether (TMS-OR): ROSi(CH3)3Triethylsilyl Ether (TES-OR): Et3SiOR,Trimethylsilyl Ether (TMS-OR): ROSi(CH3)3,Formation:Me3SiCl, Et3N , THF, 25, 8 h, 90% yield.Me3SiCH2CO2Et, cat. Bu4N+F-, 25, l
18、-3 h, 90% yield.Me3SiCH2CH=CH2, TsOH, CH,CN, 70-80, 1-2 h, 90-95% yield.,Bu4N+F-, THF, aprotic conditionsK2CO3, anhydrous MeOH, O, 45 min, 100% yieldCitric acid, MeOH, 20, 10 min, 100% yield.BF3.Et2OK2CO3, anhydrous MeOH, O, 45 min, 100% yield.,Cleavage:,Triethylsilyl Ether (TES-OR): Et3SiOR,Formati
19、onEt3SiCl, PyrTriethylsilyl cyanideTriethylsilyl triflateAllyltriethylsilane,CleavageThe triethylsilyl ether is approximately l0-100 times more stable than the TMS ether and thus shows a greater stability to many reagents.,ESTERS,Acetate Ester (ROAc)Trichloroacetate Ester: RO2CCCl3Alkyl9-Fluorenylme
20、thyl Carbonate (Fmoc-OR):Alkyl 2,2,2-Trichloroethyl Carbonate (Troc-OR): ROCO2CH2CCl3,Acetate Ester (ROAc),Ac2O, Pyr, 20,12 h, 100% yieldCH3COCl, 25, 16 h, 67-79% yieldCH3COCl, CH2Cl2, collidine, 91% yield.Ac2O or AcCl, Pyr, DMAP, 24-80, 1-40 h, 72-95% yieldAcOH, TMSCl, 81% yield,Formation:,K2CO3, M
21、eOH, H2O, 20, 1 h, 100% yieldBF3.Et2O, wet CH3CN, 96% yieldSm, I2, MeOH, rt, 3-60 min, 95-100% yield,Cleavage:,Regioselective protection is geneally posssible if there are hydroxyl groups of different steric hindrance (prim sec tert; Equatorial carbonyl (cyclohexanone) cyclopentanone ,-unsaturated k
22、etone phenylketone,SelectiveProtection,1,3-Dioxolane(乙二醇缩酮,(R2C(OCH2)2),Formation: p-TsOH, HOCH2CH2OHStability: R2C(OCH3)2 R2C(OCH2)2Cleavage: acid,1,2-oxothioketal,Dicyanomethylene group,Formation: Knoevenagel condensation with malononitrile Cleavage: concentrated alkaline solutions,Protecting Grou
23、ps for carboxy acids,Mechanism for deblocking protective groups,Application in the synthesis of peptides,Reactive carbon-hydrogen and carbon-carbon bonds,Terminal alkynes (CH): Mostly used in organometallic synthesis and in oxidative coupling-Methylene groups of ketones with tertiary -carbon atomC =
24、 C double bonds,Terminal alkynes (CH) Formation: chlorotrimethylsilane Cleavage: silver nitrate in quantitative yield,-Methylene groups of ketones with tertiary -carbon atom,Formation: successive treatment with ethyl formate and butanethiolCleavage: KOH in boiling diethylene glycol,C = C Double bonds,Formation: epoxidationCleavage: removal of oxygen atom by treatment with zinc and sodium iodide in acetic acid,
