Chem 206D. A. Evans Matthew D. Shair Wednesday,December 11, 2002 http://www.courses.fas.harvard.edu/~chem206/ Reading Assignment for this Lecture: Introduction to Organosilicon Chemistry Chemistry 206 Advanced Organic Chemistry Lecture Number 33 Introduction to Organosilicon Chemistrya73 Silicon Bonding Considerations a73 The Silicon–Proton Analogya73 C=O Addition of Organosilanes a73 Sigmatropic Rearrangements of Organosilanesa73 Anionic (Brook) Rearrangements a73 Peterson Olefination Reactiona73 Survey of Silicon (and related) Protecting Groups Masse, C. E.; Panek, J. S. "Diastereoselective reactions of chiral allyl- and allenylsilanes with activated C-X pi-bonds." Chem. Rev. 1995, 95, 1293-1316. Ager, D. J. "The Peterson olefination reaction." Org. Reactions 1990, 38, 1-224 Fleming, I.; Barbero, A.; Walter, D. "Stereochemical control in organic synthesis using silicon-containing compounds." Chem. Rev. 1997, 97, 2063-2192. (Web) Moser, W. H. "The Brook Rearrangement in Tandem Bond Formation Strategies," Tetrahedron 2001, 57, 2065-2084 (handout) Colvin, E. "Silicon in Organic Synthesis," Butterworths, 1981 KHMDS THF, -78 °C Calter, M. A. Ph. D. Thesis, Harvard University, 1993. 94% Bu3Sn Bu3Sn OMe TBSO Me OH OMe OH OTBS Explain what drives this rearrangement. TBS = SiMe Me CMe3 OTMSRO P OR R P O O RO OR SiR3 R P OTMSO RO OR The C=O addition illustrated in eq 1 proceeds while the carbon analogue (eq 2) does not. Explain (1) R H O OMeRO P OR R P O O RO OR Me R P OMe O RO OR (2) Me OLi Me3Si O X Me H H O OSiMe3 XTakeda, Org. Lett, 2000, 2, 903-1905 Provide a mechanism for the indicated transformation Problems to Contemplate Bois, et al. "SiliconTethered Reactions" Chem. Rev. 1995, 95, 1253-1277. (Handout) Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part B Chapter 9, " C–C Bond Forming Rxns of Boron, Silicon & Tin", 595– 680. Chem 206D. A. Evans Bonding Considerations: Carbon vs Silicon Bonding Considerations: Carbon vs Silicon C–C C–Si83 76 Si–Si53 C–O Si–O 86 108 C–H Si–H83 76 C–F Si–F116 135 Average Bond dissociation eneregies (Kcal/mol) C–C C–Si1.54 1.87 C–O Si–O1.43 1.66 Average Bond Lengths (?) pi Si–Si = 23 kcal/molpi C–Si = 36 kcal/molpi C–C = 65 kcal/molThis trend is even more dramatic with pi-bonds: σ? C–Siσ? C–C σ C–Siσ C–C Bond length = 1.87 ?Bond length = 1.534 ? H3C–SiH3 BDE ~ 76 kcal/molH3C–CH3 BDE = 83 kcal/mol better than Group IV Electronegativities (Pauling) Carbon Silicon Germanium Tin Lead2.55 1.90 2.01 1.96 2.33 +2 Oxidation state becones increasingly more stable C Siδ+δ– Hypervalent 5-Coordinate Silicon Compounds Akiba, "Chemistry of hypervalent Compounds" Wiley-VCH, Chapters 4-5, 1999 Penta-coordinate silicates are commonly observed Nucleophilic substitution at Silicon F F–SiMe3+ OSiMe3 KOCMe3 O K Me3Si–OCMe3 Duhamel et al. J. Org. Chem. 1996, 61, 2232 OSiMe3 MeLi O Li Me3Si–Me Stork et al. JACS. 1968, 90, 4462, 4464 THF THF –20 ° 2h Thermal Rearrangements One may readily access divalent intermediates SiMeMe Si CH2MeMe H2C CH2thermolysis H SiMeMe thermolysis Si Me Me SiMe Me H Colvin, pp 7-9 C-SP3 Si-SP3 C-SP3C-SP3 SiC Si CCCCC MeSiF4 NEt4 Ph3SiF2 NR4 RO–SiMe3 RO K. Scheidt, D. A. Evans Chem 206Hypervalent Silicon Ate-Complexes 1.689 ? 1.647 ? Inorg. Chem. 1984, 23, 1378 J. Am. Chem.Soc. 1987, 109, 476 SiPhPh O F3C CF3 F SiF PhPh F CF3 F S(NMe2)3 J. Organomet.Chem. 1981, 221, 137. SiF FPh F F 1.668 ? 1.604 ? 1.597 ? Acta Crystallogr. Sect. C 1984, 40, 476 Cl Me O 2.104 ? 2.198 ? Chem 206D. A. Evans Bonding Considerations: Carbon vs Silicon Carbonyl addition Reactions1970 DAE Objective: Develop a reagent that will transform aldehydes into protected cyanohydrins in one step R H O SiR3 G+ R G OSiR3 H R G OSiR3 Li R3Si G Candidates Carbonyl Adducts R3Si CN R CNOSiR3H R3Si OSO2Ar R SO2ArOSiR3H R3Si OPR2 R POR2OSiR3H Carbonyl Anion EquivalentG = carbanion-stabilizing FG Thermal C=O addition of TMSCN is not a clean reaction + Me3Si CN C5H11 HOSiMe3CN50 C°Me HO C4H9 HOSiMe3+ ratio: 65:35 2-5 hr The prospect of catalysis was investigated C5H11 HOSiMe3CN1-5 min ZnI2 reaction was instaneous and quantiltative 1-5 min CN– Principle established that normally inaccessible cyanohydrin derivatives may now be accessed MeMeMe OTMS CN >95% yield(ZnI 2 catalysis) Me Me TMSO Me CN 92% yieldonly 1,2-addition (ZnI2 catalysis) O TMSO CN >95% yieldonly 1,2-addition (CN– catalysis) with Truesdale, Carroll, Chem Commun. 1973, 55; J. Org. Chem.. 1974, 39, 914Tetrahedron Lett 1973, 4929 (first discussion of Nu catalysis) + Me3Si CN Me H O "The Silicon Advantage" R R O X CN+ R R O–X CN ?HSi > ?HH From the preceding case, it is clear that ?HSi is more exothermic than ?HH R R ONucleophilic Catalysis C N R ROCN Me3Si CN R ROTMSCNC N + LiNR2 Chem 206D. A. Evans Carbonyl Addition Reactions-2 Explain the following observations O O C N+ OH OH CN THF/H2O O TMSO CN TMSCN O O + benzeneC N 1-4 addition 1-2 addition R1 R2OSiMe3SRRS–ZnI2R1 R2SRSR with Truesdale, Grimm, Nesbitt, JACS 1975, 97, 3229 JACS 1977, 99, 5009 Me3Si SR R1 R2 O + Me3Si OEtO N2R H O CN– or F– OEt O N2R OTMS 1-5 min with Truesdale, GrimmJOC 1976, 41, 3335 R H O OTMS RO POR + R P O O RO OR SiR3 R P OTMSO RO OR with Hurst, TakacsJACS 1978, 100, 3467 Non-catalyzed processes may also occur if a proper geometry for atom transfer can be achieved R O PO R ORTMSO RO R OTMS PORORO "The Proton–Silicon Correlation" a73 Organosilanes undergo carbonyl addition processes in direct analogy with their proton counterparts but with an attendant greater exothermicity. a73 Organosilanes undergo a range of thermal rearrangements processes in direct analogy with their proton counterparts. X H X H k(Si) =10+6 K(H) A. J. Ashe III, JACS 1970. 92, 1233 O OMe3SiOMe MeMe Me CO OSiMe3OMe Me Me Meheat Colvin, pp 37-8 a73 Organosilicon hydrides undergo transition metal catalyzed hydrosilylation processes in direct analogy with normal hydrogenation reactions R N O SiR 3 SiR3 R N O SiR3 SiR3 Yoder et al., JACS 1974. 96, 4283 ?G* 15-22kcal/mol Si transfer is intramolecular Me3Si C N C N SiMe3 rt H–HH–SiR3 R Me R Me HR Me SiR3 Rh(I) catalysis Rh(I) catalysis "Hydrosilylation of C–C Bonds". T. Hayashi In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol I, 319-332. Chem 206D. A. Evans Carbonyl [1,2] & [1,3] Sigmatropic Rearrangements "The Brook Rearrangement(s)"[1,3]-Sigmatropic Rearrangements Y C X R3Si R Y C XR R3Si Np Si Ph OMe Ph Y = C; X = O 110 °C Ph ONp Si Me Ph Np Si PhO Me Ph Complete retention of Si stereochemistry was noted. Ea = 28 kcal/mol A. G. Brook Accts. Chem. Research 1974, 7, 77-84 Brook speculates that a hypervalent Si intermediate might be involved in the rearrangement. Y = C; X = C Np Si CH2Me Ph H 500 °C H2C H Ph Si Me Np Inversion of Si stereochemistry was noted. Ea = 48 kcal/mol H. Kwart et al., JACS 1973. 95, 8678 Theoretical calculations lead to the conclusion that the concerted [1,3] sigmatropic rearrangement with retention of Si-configuration should represent the lower energy pathway. Yamabe, JACS 1997, 119, 808 At the present time these rearrangements are not well studied, A. G. Brook Accts. Chem. Research 1974, 7, 77-84 C OHR3SiPhPh C OHPhPh SiR3Et2NH DMSO Et2NH C OR3SiPhPh C O SiR3 PhPh Ea ~ 8-11 kcal/mol H N H Et Et H N H Et Et Brook has documented that retention at Silicon & inversion at Carbon occur. Transformations Involving the Brook Rearrangement Moser, W. H. "The Brook Rearrangement in Tandem Bond Formation Strategies," Tetrahedron 2001, 57, 2065-2084 R SiR3 O Acylsilanes Li R El(+) RR 3Si O R R O R Li R3Si Li El(+) R O R R3Si El [1,2] Si SiR3 O Cl O Li SiR 3 Cu(I)R R R2BH[Ox] SiR3R Chem 206D. A. Evans Transformations Involving the Brook Rearrangement Moser, W. H. "The Brook Rearrangement in Tandem Bond Formation Strategies," Tetrahedron 2001, 57, 2065-2084 R SiR3 O Li R El(+) RR 3Si O R R O R Li R3Si Li El(+) R O R R3Si El [1,2] Si ROR3Si s-BuLi ROR3Si Li ROLi SiR3 ROR3Si El El(+) OR These reagents are useful homoenolate anion equivalents R CH2(–)O "Metalated Allylic Ethers as Homoenolate Anion Equivalents". Evans, D. A.; Andrews, G. C.; Buckwalter, B. JACS 1974, 96, 5560. Si–Variant: Still & MacDonald JACS 1974, 96, 5561 Brook Equilibrium C OLiMe3SiPhPh C OLiPhPh SiMe3THF C OLiMe3SiHPh C OLiHPh SiMe3THF Reich JACS 1980, 102, 1423 (see footnote 8) Reich JACS 1980, 102, 1423 R SiR3 O Li (CH2)4–I R C OTMS R OH3O+ Intramolecular alkylations may be carried out: SiR3 O PhS R OLi OSiMe3 OHRPhS Takeda JACS 1993, 115, 9351; Synlett 1994, 178; SynLett 1997, 255 OPhS LiO SiR3 R [1,2] Si OPhS OSiMe3 R SiR3 O PhS OLi R OSiMe3 OLi R Me3Si PhS LiO SiR3 O R [1,2] Si PhS OSiMe3 O R PhS OSiMe3 OLi R [3,3] Tetrahedron 2001, 57, 2065-2084, footnote 16 Transformations Involving the Brook Rearrangement Chem 206D. A. Evans Transformations Involving the Brook Rearrangement Me OLi Me 3Si O X Me H H O OSiMe3 XTakeda, Org. Lett, 2000, 2, 903-1905 Me HRO CHO Me Me The natural product target: The key reaction The Peterson Olefination Reaction The key paper: Peterson, J. Org. chem. 1968, 33, 780-784 C NSi P It was Peterson's intent to find a silicon analog to the Wittig rxn.The reaction concept is outlined below: R R OMe 3Si CH2M OM R R Me3Si O R R Me3Si MOM R R Me3Si Me3Si CH2MgCl R RO O–MgCl R R Me3Si these adducts are quite stable Magnesium alkoxides: Stable Na & K alkoxides: Eliminate OH R R Me3Si KH R R OK (Na)Me 3Sirt Elimination could also be effected with dilute acid 10% H2SO4 R R OHMe 3Sirt analogy provided by Whitmore et al. JACS 1947, 69, 1551 Me3Si CH2 SMe nBuLiTMEDA Me3Si CH SMeLi Me3Si CH SMeLi OPh Ph C Ph Ph MeS carbanion-stabiizing groups facilitate elimination H OH R R Me3Si Mechanistic aspects of Beta-OH Elimination Me3Si OH PrH PrH H+ Pr H Pr H Anti Elimination Me3Si OK PrHPrH KH H Pr Pr H Syn Elimination Hudrlik et al. JACS 1975, 97, 1464 Colvin chapter 12, pp 141 Ager, D. J. "The Peterson olefination reaction." Org. Reactions 1990, 38, 1-224 R3Si OH PrHR HMe 3Si O PrH H KH RH PrH reaction is stereospecificnote site of nu attack. Why? The β-Effect (lecture 31) The β-Effect (lecture 31) R2CuLi Chem 206D. A. Evans The Peterson Olefination Reaction Boeckman, Tet. Lett 1973, 3437 a73 Simple Examples: Taken from Organic Rxns review NaH orTsOH This reagent is better that H2C=PPh3 for hindered ketones >90%O Me3Si CH2MgBr OH SiMe 3 CH2 Me OMeH HMeH2C Me Chan, Tet. Lett 1978, 2383 Nozaki, JACS 1974, 96, 1620 >95% >90% O Me3Si OEtO O OEt Me3Si SiMe3OH O O O O Me Me MeHOMe OHMe OH OH OMe OHMe O O Miyakolide (+)-1 HH O OPMB O OMeMe O Xp 1 9 O OPMB OMeMe O Xp 1 9 CO 2Me entry base solvent E : Z1 23 4 LDANaHMDS 73 : 2718 : 82 66 : 3366 : 33LDALDA TMS OMeO Conditions–78 °C 19-E with Ripin, Halstead, and Campos JACS 1999, 121, 6816-6826. Miyakolide presents an interesting olefin geometry challenge Chan, Chem. Commun 1982, 969 R OH SiMe3Me3Si B O O MeMe Me R Me R Hudrlik, JACS 1981, 103, 6251 Me3Si H n-Hexyl O OH CMe3 OLi n-HexylMe3Si CMe3 O O CMe3n-Hexyl OH CMe3n-Hexyl OH n-Hexyl Me3Si CMe3OH LiN(TMS)2 t-BuLiMgBr 2 SOCl2 THF Et2OTHFPhMe H+ KHRCHO BF3?OEt2 KH Chem 206D. A. Evans The Peterson Olefination Reaction O Me N O NO Me OTMSTMSO MeMe OTMS O O O Me OTMSTMSO MeMe OTMS O N O NO Me Me3Si KN(TMS)2 (E):(Z) = 13:1 O O Me OTMSTMSO MeMe OTMS O N O NO Me (t-Bu)Me2Si t-BuLi (E):(Z) = 1:7 Bell et al. Tetrahedron 1994, 50, 6643 Reaction may be altered significantly with an attendant chenge in stereoselection SiMe3R O O OH LiN(TMS)2 TMSClCH 2N2 R CO2Me SiMe3 OH syn:anti = 96:4 (See Lecture 15) Ireland Enolate Claisen Coupled to Peterson Olefination R CO2Me R CO2Me KH BF3?OEt2 Sato et al. Chem. Lett 1986, 1553 Application to Leucasandrolide: Rychnovsky JACS, 2001, 123, 8420 O OMe O Me OH Me Me O O O OMe O Me OH Me Me O HO The seco acid OH The Pivotal Step: O O Me OBn H O SiMe3 TBSO O OH O Me OBn OTBS BF3?OEt2 base, 78% 5.5:1 ratio Bunnelle-Peterson Allylsilane Synthesis R O R O Me3Si CH2M R 2 SiMe3 SiMe3 OH M = Li → M = CeCl2 silica gel R SiMe3 Me THPO SiMe 3 90% Ph SiMe3 Me93% TMSO SiMe3 TBSO TMSO O OEt TBSO TMSCH2MgCl CeCl3silica gel 87% Chem 206ROH Protecting GroupsJ. Leighton, D. A. Evans By far the two most common methods: 2 equiv of imidazole are required relative to R3SiCl. Silyl Ethers: trimethylsilyl triethylsilyl triisopropylsilyl tert-butyldimethylsilyl tert-butyldiphenylsilyl (TMS) (TES) (TBS or TBDMS) ndi-tert-butyldimethylsilylene Formation: R3Si-Cl, imidazoleDMF, R.T. CH2Cl2, 0 °CR3Si-OTf, 2,6-lutidine Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190. Corey, E. J. et al., Tetrahedron Lett. 1981, 22, 3455. Me Si ORMeMe Et Si OREtEt t-Bu Si ORMeMe t-Bu Si ORPhPh i-Pr Si ORi-Pri-Pr SiO O t-But-Bu R’R R OH R OSiR3 R OH R OSiR3 Cunico, R. F.; Bedell, L. J. Org. Chem. 1980, 45, 4797-4798. SiR3 76 min 137 min TBS TIPS Half-life THF, 22.5 °C2 equiv TBAF 5% NaOH in EtOH90 °C Half-life TBS TIPS TBDPS 1 h 14 h < 4 h SiR3 SiR3 < 1 min 18 min 244 min TBS TIPS TBDPS Half-life 22.5 °C1% HCl in EtOH Relative stabilities: TES ~102 times more stable to acidic hydrolysis than TMSTBS ~104 times more stable to acidic hydrolysis than TMS Me OSiR3 Me OH OSiR3 OH Me OSiR3 Me OH (TBDPS) (TIPS) (DTBS) Chem 206ROH Protecting Groups-2J. Leighton, D. A. Evans 77%CH2Cl2, 0 °C TESCl, DMAP Selective Protection: Askin, D.; Angst, D.; Danishefsky, S. J. Org. Chem. 1987, 52, 622. 91%CH2Cl2, -78 °C TBSOTf, 2,6-lutidine Evans et al.JACS 1999, 121, 7540-7552. 95%DMF, RT TBDPSCl, imidazole Donaldson, R. E.; Fuchs, P. L. J. Am. Chem. Soc. 1981, 103, 2108. 80%DMF, RT TBSCl, imid. Me Me OHOH MeMe Me Me OTBDPSOH MeMe Me OTMS H OH OH Me OTMS H OTBS OH HO HO SO2Ph HO TBSO SO2Ph MeO Me O OH OTIPS OH MeO Me O OH OTIPS OTES CH2Cl2, 0 °CTBSOTf, 2,6-lutidine 92% TMS-NEt2 has been reported to selectively protect equatorial alcohols in the presence of axial alcohols: Weisz, I. et al. Acta. Chim. Acad. Sci. Hung. 1968, 58, 189. TBSOTf, 2,6-lutidineCH 2Cl2, -78 °C71% White, J. D. et al., J. Am. Chem. Soc. 1989, 111, 790. TMS-NEt2acetone, -45 °C Yankee, E. W.; Bundy, G. L. J. Am. Chem. Soc. 1972, 94, 3651. OTBS Me CO2Me MeOTBS OHHO Me Me OTBS Me CO2Me MeOTBS OTBSHO Me Me HO HO CO2MeMe Me OH HO TMSO CO2MeMe Me OH NMe OOH OH Me Me NMe OOTBSOH Me Me O O Bn O O Evans, Ng JACS 1993, 115, 11446 Chem 206ROH Protecting Groups-3J. Leighton, D. A. Evans Evans, D. A.; Dart, M. J. Unpublished CH2Cl2, -10 °CTBSOTf, 2,6-lutidine 83% Selective Protection: TESCl, imidazoleDMAP CH2Cl2, -78 °C 98% > 80% TBSOTf, 2,6-lutidineCH 2Cl2, 0 °CMe NMe OOH OH Me Me Me N Me OOTBSOH Me Me O O Bn O O Bn Me N Me OOH OH Me Me Me N Me OOH OTBS Me Me O O Bn O O Bn O OO O MeO OMe H Me H O HOH Me OH Me MeO Me OO O MeO OMe H Me H HOH Me OTESMe MeO Me Evans, Ng JACS 1993, 115, 11446 Evans, Ratz JACS 1995, 117, 3448 Selective Deprotection: 100% Calter, M. A. Ph. D. Thesis, Harvard University, 1993 94% HF?pyr, pyridine O O Me OMe Me OTMSMe TMSO Me Me OMe O O Me OMe Me OHMe TMSO Me Me OMe O O PivO Me Me OTBS O OTBS Me OMe (NCCH2CH2O)2PO O O PivO Me Me OH O OTBS Me OMe (NCCH2CH2O)2PO Evans, Gage, Leighton JACS 1992, 114, 9434 K2CO3MeOH THF Chem 206ROH Protecting Groups-4J. Leighton, D. A. Evans Nakaba, T.; Fukui, M.; Oishi, T. Tetrahedron Lett. 1988, 29, 2219, 2223. 90% TBAF, THF Hart, T. W.; Metcalfe, D. A.; Scheinmann, F.J. Chem. Soc., Chem. ommun. 1979, 156. 76%4 h, 20 °C (8:8:1) 44 Selective Deprotection: CO2H C5H11H OTBSTESO HTESO CO2H C5H11H OTBSHO HTESO CO2MeO Me Me Me O O Me OTBS MeMe OTBSO N3 Me Me Me Me Me CO2MeO Me Me Me O O Me OTBS MeMe OHO N3 Me Me Me Me Me KHMDSTHF, -78 °C Calter, M. A. Ph. D. Thesis, Harvard University, 1993. 100% 1,2-Migration: Mulzer, J.; Schollhorn, B. Angew. Chem., Int. Ed. Eng. 1990, 29, 431-432. 1,3-Migration: 4:1 1. MeOTf,2. DIBAl-H, CH 2Cl2, -78 °C KHMDSTHF, -78 °C 94% 94%66% 80% ? Calter, M. A. Ph. D. Thesis, Harvard University, 1993. Bu3Sn Bu3Sn OMe OTBS Me OH OMe OH Me OTBS Me OH OTBDPS Me OTBDPS OH O OPiv H OTBS Me Bu3Sn OMe OH Me OTBS Bu3Sn MgBr Bu3Sn OH OTBS Me OPiv Bu 3Sn OMe OTBS Me OHNt-Bu t-BuMe RT AcOH:THF:H2O K2CO3MeOH Ref.Reagents Tetrahedron Lett. 1989, 30, 5713. J. Am. Chem. Soc. 1989, 111, 1923. Chem. Pharm. Bull. 1987, 35, 3880. BF3?OEt2, EtSH 1. BCl3, -78 °C to 0 °C.2. MeOH, -78 °C. TMSBr, C6H5SMe 3. Lewis Acids See Greene, p. 49. Synthesis 1981, 396. J. Org. Chem. 1978, 43, 4194. J. Org. Chem. 1979, 44, 3442. Tetrahedron Lett. 1986, 27, 2497 Cyclohexene Cyclohexadiene HCO2H i-PrOH Ref.Hydrogen Source Hydrogen Source Ag2O, BnBr4. Van Hijfte, L.; Little, R. D. J. Org. Chem. 1985, 50, 3940. Cruzado, C.; Bernabe, M.; Martin-Lomas, M. J. Org. Chem. 1989, 54, 465. Review: David, S.; Hanessian, S. Tetrahedron, 1985, 41, 643-663. 2. BnBr, N-methylimidazole1. (Bu3Sn)2O, PhMe, ↑↓ 3. Ar = 4-MeO-Ph: Ar = Ph: Yonemitsu, O. et al., Tetrahedron Lett. 1988, 29, 4139. Iversen, T.; Bundle, K. R.J. Chem. Soc., Chem. Commun. 1981, 1240. cat. TfOH 2. 2. BnBr/PMBBr1. NaH, DMF, 0 °C 1.Principle Methods for Benzylation of Alcohols: ROH Protecting GroupsJ. Leighton, D. A. Evans Chem 206 Ar = Ph: CH2Cl2 Ar = 4-MeO-Ph: Et2O n nCH2Cl2, 0 °CTakano, S. et al., Synthesis 1986, 811-817. Via Benzylidene Acetal: Principle Methods for Deprotection: 10% Pd on C, H2EtOH/EtOAc/AcOH1. Hydrogenation 2. Transfer Hydrogenation 10% Pd on C R OH R OBn R OH R OBn R PMB R PMB R OH R OBn R OH R OBn Ar O O NH CCl3 O R1 R2 Ar H OH O Ar R1 R2 R OBn R OH R OBn R OH R OBn R OH DMF DIBAl-H 20:1 CH2Cl2:H2O extended conjugated polyenesstyryl DDQ is incompatible with: Chem 206J. Leighton, D. A. Evans ROH Protecting Groups Selective Benzylation: NaH, BnBrDMF, -70 °C 97% Fukuzawa, A. et al. Tetrahedron Lett. 1987, 28, 4303. Cruzado, C.; Bernabe, M.; Martin-Lomas, M. J. Org. Chem. 1989, 54, 465. 2. BnBr, N-methylimidazole1. (Bu3Sn)2O, PhMe, ↑↓92% + +? ? -1 e- ? -1 e- ROH + ArCHO DDQ = 20:1 CH2Cl2:H2O PMB Deprotection: Yonemitsu, O. et al., Tetrahedron 1986, 42, 3021. n n DDQ, CH2Cl23 ? mol sieves * Other Oxidants: NBS, Br2, CAN ((NH4)2Ce(NO3)6).Acta Chem. Scand. Ser. B, 1984, B38, 419. J. Chem. Soc., Perkin Trans. I, 1984, 2371. Br OH Me H OH Br OH Me H OBn O OOH OHHO O OOH OBnBnO R O OMe O O CNCl Cl CN R O OMe R O OMe OH R O O R OPMBOH O OMe H R O OMe H R O OMe H R Ar R N C R Me Me Me R R’ OPMB R R’ ODDQ H2O DDQ -H+ Ng, H. P. Ph. D. Thesis,Harvard University, 1993 81% NaBH(OAc)3, AcOH Et2O, 0 °C(c-hex)2BCl, EtNMe2 14 10 84% 14 14 1010 (Xq) 48 C1-C8 Subunit 1 14 10 C9-C17 Subunit 17 33 11 Polypropionate Fragment Spiroketal Fragment 117 8 Rutamycin B(Streptomyces aureofaciens) 25 51 8 17 11 33 20 20 25 Chem 206J. Leighton, D. A. Evans ROH Protecting Groups 817 1 11 H Et O OH O Me OH O Me OH O Me Me H H MeH O MeHO Me OH CO2H B(OH)2Et OH I Me O Me OH Me OH Me O Me MeMe Me Me OH H Me OHOH Me OH H H X HMeMe OH Me OOR MeMe O Me OH CO2R' O O Me ON O HMe O CO2HOH Ph I Me O Bn Me Ph OH XqMeMe O O OH Me Me Xq OH Ph Me Me O Me OH Me OH Me O Me Me 14 1097%Swern Ox.1014 100% DIBAl-HCH2Cl2, 0 °C 100%CH2Cl2, 0 °C TBSOTf, 2,6-lut.14 10 91%CSA, DMF 1014 94%Et2O, 0 °C LiBH4, H2O 14 101014 Selective silylation was unsuccessful. ? 1014 ROH Protecting GroupsJ. Leighton, D. A. Evans Chem 206 14 10 20 33 11 17 8 1 5 25 25 5 1 8 17 11 33 20 HF?pyrpyridine, THF 99% 1. Cl3C6H2COCl DMAP, Et3N, benzene 2. (aq.) HF, CH3CN, H2O 84% Rutamycin B OOH Me Me Xq OH Ph Me OPMBO Me Me H TBSO Ph Me OOH Me Me Xq OH Ph Me OHOH Me Me O OH Ph Me O Me Me OH Ph Me PMPMeO OMe OMe OO Me Me TBSO Ph Me PMP OHPMBO Me Me TBSO Ph Me OPMBO Me Me TBSO Ph Me H Me MeTBSO Me TBSO Me OH Me OTESOH Me Me O OTBSMe O OTBS HH HO Me Et H O Me MeTBSO Me TBSO Me OH Me OHOH Me Me O OTBSMe O OTBS HH HO Me Et H O H Et O OH O Me OH O Me OH O Me Me H H MeH O MeHO Me OH Me Me After protonation of the amine, coulombic repulsion insulates against formation of another cationic site in the vicinity. 94% 20:1 CH2Cl2:H2OR = PMB R = H13 17 21 20:1 CH2Cl2:H2O 21 17 8 13 1 70%92 h(aq.) HF, CH3CN, H2O 21 25 17 8 37 33 30 26 13 1 No Reaction 24 h(aq.) HF, CH3CN, H2O Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453. ROH Protecting GroupsJ. Leighton, D. A. Evans Chem 206 1 13 26 3033 37 8 17 25 21 (+) Calyculin A Me2NMeO NHOH OH O Me N O O O OH Me OMe MeMe MeMe OHOH CN Me Me Me OP O(HO) 2 Me2NMeO OMe OMe OMeMe 2NMe2N TBSO TBSO O MeO MeOTESO TESO O OH OH O Me2NMeO NHOTES TESO O Me N O O O OTBS Me OMe MeMe MeMe OTBSOTBS CN Me Me Me O(PMBO)2P O O O OTBS Me OMe MeMe MeMe OTBSOTBS CN Me Me Me PMBO OTBS O O OTBS Me OMe MeMe MeMe OTBSOTBS RO OTBS PivO DDQ DDQ X DEIPS = Aloc = 30% overall 1. Pd(Ph3P)4, HCO2NH4, THF 2. Dess-Martin Periodinane 3. HF?pyr, pyridine, THF Romo, D.; Meyer, S. D.; Johnson, D. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 7906-7907. Rapamycin 74%THF, RTHF?pyr, pyridine Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001-7031. Cytovaricin ROH Protecting GroupsJ. Leighton, D. A. Evans Chem 206 O O Me OMe H H HMe H O MeHHH OOH OH HO O H MeO H H MeOH H Me OH Me OH OH Me OH O O Me TBSO Me SiO O H HMe H O MeHHH ODEIPSO TESO TESO O H MeO H H MeOTES H Me Me OTES Me O t-Bu t-Bu Me OMe O N O O OTBS Me OAloc H H OTIPSOAloc MeMe Me ODEIPS Me OAloc OMe Me OMe Me OMe O N O O O Me H H OHO MeMe Me OH Me O OMe Me OMe O H OH O O Et Si Et i-Pr ~97.5% per protecting group 35% 1. DDQ, t-BuOH-CH2Cl2; Ac2O, DMAP, pyr. 2. aq. HClO4, THF, 8 days 3. LiOH, H2O/MeOH/THF, RT, 20 h 4. TBAF, THF/DMF, RT, 90 h 5. AcOH, H2O, RT, 36 h Kishi, Y. et al., J. Am. Chem. Soc. 1989, 111, 7525, 7530. Palytoxin Carboxylic Acid ROH Protecting GroupsJ. Leighton, D. A. Evans Chem 206 MeO HO O O Me O O Me O O O O OH OHOOO H2N OH Me OH HO OH OHMe OH OH OH OH OH OH OH OH OH OHHO OHMe OHHO OH OH HO OH OH HO OH OHMe HOHO OH Me HO OHHO OH OH OH OHOH OH O O Me O O Me O O O O O OOOO N OAc Me OAc PMBO OPMB OPMBMe OMe OBz OBz OAc OTBS OTBS OTBS OTBS TBSO OTBSTBSO OTBSMe OTBSTBSO OTBS OTBS PMBO OPMB OPMB PMBO OPMB OPMBMe BzOBzO OAc Me TBSO OTBSTBSO OTBS OTBS OAc OTBSTBSO OTBS Me3Si(CH2)2O O H MeMe "That outpost of empire Australia,produces some curious mammalia, the kangaroo rat,the blood-sucking bat, and Aurthur J. Birch, inter alia."