Protective Groups in Synthetic Organic Chemistry OTBS OPMB O Lecture Notes O Me Key Texts O Me XX P. J. Kocienski, Protecting Groups (2nd Edition), 1994, Georg Thieme Verlag: Stuttgart, p. 260. P. J. Kocienski, Protecting Groups (3rd Edition), 2004, Georg Thieme: Stuttgart, p. 679. T. W. Greene, P. G. M. Wutz, Protective Groups in Organic Synthesis (3rd Edition), 1999, John Wiley and Sons: New York, p. 779. Key Reviews Selective Deprotections: T. D. Nelson, R. D. Crouch, Synthesis 1996, 1065. Protective Groups: Background and General Considerations "Protection is a principle, not an expedient" Benjamin Disraeli, British Prime Minister, 1845 "Like death and taxes, protecting groups have become a consecrated obstruction which we cannot elude" Peter Kocienski, Organic Chemist Remember: Every protecting group adds at least one, if not two steps to a synthesis They only detract from the overall efficiency and beauty of a route, but, without them, there are certainly transformations which we would not be able to do at all. Protective Groups: Temporary Protection Li Li O O N Li HO Ph Me O O O THF, -40 °C OLi aqueous O MeO O MeO work-up MeO N Ph Me Temporary protection involves the ideal for protecting groups when they are required: the protection step, desired reaction, and deprotection all occur in the same pot. Ene Reactions in Total Synthesis: Ene/Retro-Ene Sequence to Protect Indole O O H CO Me CH2Cl2, MeN H CO Me 2 O NH 2 0 °C, N NAc 1 min O N NAc NMe N N + NMe N N 150 °C, H O N 1 min N H Me Me O Me Me MTAD MTAD = N-methyltriazolinedione Me N MTAD, N OH Me Me N OH CH2Cl2, O MeH Me H 110 °C, MeH 0 °C, 1 h; N 30 min N N O H O O H 1 MeN NH H O2 H O (70% H O N N H O N (O2, O overall N methylene based on blue) r.s.m.) Retro N Ene N N H Me Me reaction Me Me Ene H Me Me reaction okaramine N P. S. Baran, C. A. Guerrero, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 5628. P. S. Baran, C. A. Guerrero, E. J. Corey, Org. Lett. 2003, 5, 1999. Protective Groups: Background and General Considerations Tactical considerations to consider for each protecting group selected in a synthesis: It should be easily and efficiently introduced. It should be cheap and readily available. It should be easy to characterize and avoid the introduction of new stereogenic centers. It should not afford so many spectroscopic signals that it hides key resonances for the substrate. It should be stable to chromatography. It should be stable to a wide range of reaction conditions. It should be removed selectively and efficiently under highly specific conditions. The by-products of deprotection shoud be easily separated from the substrate. Protective Groups: Something to be Very Carefully Considered OMe Cl O O TBSO Cl OTBS H O H O H O Boc N N N N N O N Me O H H O H Me NH O NHDdm Me MeO2C OMe OMe MeO (62% overall) 1. HF•py/py, THF, 0→25 °C, 12 h Global deprotections 2. AlBr3, EtSH/CH2Cl2 (1:1), 25 °C, 4 h OH Cl O O HO Cl OH H O H O H O H N N N N N O N Me O H H O H Me NH O NH2 Me HO2C OH vancomycin aglycon OH HO K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 1998, 37, 2708. Protective Groups: Orthogonal Sets of Protecting Groups Orthogonal Set = a groups of protecting groups whose removal is accomplished in any order with reagents and conditions that do not affect protecting groups in any other orthogonal set. TESO OBz Me Me Orthogonal Me TBSO Set #1 Me H O TBDPSO PvO OAc Orthogonal Set #2 In practice this concept is incredibly difficult to reduce to practice, but it is a useful framework and organizing principle to think about protecting group regimes for a complex molecule synthesis. Protective Groups: Orthogonal Sets of Protecting Groups 1. Cleavage by basic solvolysis O O O O O Cl Cl OH Cl RO RO ROH RO Me RO Cl RO Me Cl Cl krel 1 760 16,000 100,000 Protective Groups: Orthogonal Sets of Protecting Groups 1. Cleavage by basic solvolysis O O O O O Cl Cl OH Cl RO RO ROH RO Me RO Cl RO Me Cl Cl krel 1 760 16,000 100,000 2. Cleavage by acidic hydrolysis H O O O O HO OH RO OMe R R Other groups easily cleaved by acid Protective Groups: Orthogonal Sets of Protecting Groups 3. Cleavage by heavy metals S HgCl2 O S Protective Groups: Orthogonal Sets of Protecting Groups 3. Cleavage by heavy metals S HgCl2 O S 4. Cleavage by fluoride Me Me Me Me Me Me n-Bu NF 4 F H2O Si Si RO n-Bu4N ROH RO Me RO Me -[t-BuMe SiF] Me Me 2 n-Bu4N Strength of Si-F bond is 810 kJ/mol while Si-O bond is 530 kJ/mol Protective Groups: Orthogonal Sets of Protecting Groups 5. Reductive Elimination Cl H O O - Cl Cl Zn, AcOH ZnCl RO O RO O ROH Cl Cl -[CO2] Cl Cl Troc = trichloroethoxycarbonyl Protective Groups: Orthogonal Sets of Protecting Groups 5. Reductive Elimination Cl H O O - Cl Cl Zn, AcOH ZnCl RO O RO O ROH Cl Cl -[CO2] Cl Cl Troc = trichloroethoxycarbonyl 6. β-elimination O O Mild base R2N O R2N O R2NH2 + -[CO2] Fmoc = 9-fluorenylmethyl carbamate Protective Groups: Orthogonal Sets of Protecting Groups 7. Hydrogenolysis Ph OR H2, Pd/C + ROH O O R R benzyl ether Other examples of cleavable groups Protective Groups: Orthogonal Sets of Protecting Groups 7. Hydrogenolysis Ph OR H2, Pd/C + ROH O O R R benzyl ether Other examples of cleavable groups 8. Oxidation O O DDQ or CAN, Cl CN OR THF/H2O + ROH Oxidation via MeO MeO Cl CN Single-electron O p-methoxybenzyl transfer ether DDQ Protective Groups: Orthogonal Sets of Protecting Groups 9. Dissolving Metal Reduction Li/NH3, O OR t-BuOH + ROH OR Only other protecting group applicable to these conditions Protective Groups: Orthogonal Sets of Protecting Groups 9. Dissolving Metal Reduction Li/NH3, O OR t-BuOH + ROH OR Only other protecting group applicable to these conditions 10. Transition Metal Catalysis (i.e. Allyl-based protecting groups) Pd, morpholine RO or dimedone RO ROH PdL2 Can also use (Ph3P)3RhCl and acid Protective Groups: Orthogonal Sets of Protecting Groups 11. Light NO NO O 2 2 NO 2 N hν ROH + O OR O R OR O O O alcohol PG acid PG Protective Groups: Orthogonal Sets of Protecting Groups 11. Light NO NO O 2 2 NO 2 N hν ROH + O OR O R OR O O O alcohol PG acid PG 12. Enzymes O O O O OMe AcHN NHFmoc papain AcO cysteine wheat germ lipase buffer AcO OAc O O O O OH O O OMe AcHN AcHN NHFmoc AcO NHFmoc HO AcO HO OAc OH Protective Groups: Relay Deprotection SO Ph SO2Ph 2 SO2Ph Me Me Me Me Me Me 1. NaSPh NaBH Me Me 4 Me O 2. mCPBA O OH MeO MeO MeO O O OH MeO MeO MeO Me Me Me Cl SO2Ph Relay deprotection: when a protecting group that is stable under most conditions is transformed chemically into a new, and more labile, protecting group. Protective Groups: Mutual Protection "Une pierre, deux oiseaux" "Zwei Fleigen mit einer Klappe schlagen" "To kill two birds with one stone" Me Me py•HBr3 NC NC H pyridine H HO O Me (96%) Me TBSO TBSO Br CO Me HO CO2Me HO 2 OH Zn, OH O O AcOH HO HO O O H (96%) H HO O Me Me Br B. M. Trost, M. J. Krische, J. Am. Chem. Soc. 1999, 121, 6131. Protective Groups: Sometimes Not-So-Innocent Bystanders OTs OTs CN O NaCN, O NC DMSO O O 80 °C O OTs O Protective Groups: Sometimes Not-So-Innocent Bystanders OTs OTs CN O NaCN, O NC DMSO O O 80 °C O OTs O Br3B BBr3 Br MeO MeO Br O O O O O O Me O Me Me O Me Hydroxyl Protecting Groups: Silyl Ethers Me Et Me Ph i-Pr RO Si Me RO Si Et RO Si t-Bu RO Si t-Bu RO Si i-Pr Me Et Me Ph i-Pr trimethylsilyl triethylsilyl t-butyldimethylsilyl t-butyldiphenylsilyl triisopropylsilyl (TMS) (TES) (TBS or TBDMS) (TBDPS) (TIPS) Hydroxyl Protecting Groups: Silyl Ethers Me Et Me Ph i-Pr RO Si Me RO Si Et RO Si t-Bu RO Si t-Bu RO Si i-Pr Me Et Me Ph i-Pr trimethylsilyl triethylsilyl t-butyldimethylsilyl t-butyldiphenylsilyl triisopropylsilyl (TMS) (TES) (TBS or TBDMS) (TBDPS) (TIPS) Relative Acid Stability (t1/2 in 1% HCl/MeOH) 1 64 20,000 5,000,000 700,000 (<1 min) (<1 min) (<1 min) (255 min) (55 min) Relative Base Stability (t1/2 in 5% NaOH/MeOH) 1 10 - 100 20,000 20,000 100,000 (<1 min) (1 min) (> 24 h) (> 24 h) (> 24 h) Hydroxyl Protecting Groups: Silyl Ethers Formation: R SiCl, OH 3 imidazole, DMF OSiR3 R R R R or R3SiOTf, 2,6-lutidine, CH2Cl2 Cleavage: Common Fluoride Sources HF OSiR3 OH Fluoride source 3HF•NEt3 HF•pyr R R R R n-Bu4NF (TBAF)/AcOH HF•pyr/pyr n-Bu4NF (TBAF) Hydroxyl Protecting Groups: Silyl Ethers Selective Monosilylation of Diols is Possible: NaH (1 eq), THF; TBSCl, HO OH HO OTBS or n-BuLi (1 eq), THF; TBSCl, OTIPS OTIPS O O TESCl, O O OH N 2,6-lutidine, OTES N MeO MeO O CH2Cl2, O O Me -78 °C O Me O O TESO TESO N (97%) N OH OH O Me Me O Me Me O OH O OH TESCl/imid and TESOTf/2,6-lutidine gave bis-silylated product D.