Classics in Tetrahedron Letters Jeremy Richter Baran Group Meeting: 9/24/03 The Plan • • • • Methodology Protecting Groups Natural Products Syntheses Methodology Oxidation of Vicinal Diols HO OH R 1. Cl2, DMSO, CH2Cl2, -78oC H R' R'' HO O R 2. Et3N, RT R' R'' Can selectively oxidize the secondary alcohol in the presence of the tertiary alcohol without cleavage. Corey. 1974, 287 cis-Hydroxylation of alkenes O CN Br HO TsCl Py/CH2Cl2 HO Br 1. 5:1 THF:1N HCl NaH O HO OH O O 2. K2CO3, MeOH CN Allows selectivity during bromohydrin formation Corey. 1982, 4217 O CN Indole Synthesis Li Br E E 1. MeLi H N R Li 2. tBuLi N R N R Biselectrophiles used: a-chloroketones, a,b-epoxyketone (Li enolate), and enediones Also used 5-substituted anilines R is a general protecting group: best results with BOC Yields: 50-90% Wender. 1981, 1475 An Interesting Reaction: H H 1. ClNHODNP B NH H 2. H2O2/NaOH H H OH acid or heat H Mueller. 1976, 2925 Mueller. 1979, 1991 CrO3/H2SO4/H2O H H N N H H Alcohol Oxidations Collins Reagent1 PCC2 Collins. 1968, 3363 Corey. 1975, 2647 Corey. 1979, 399 PDC3 Protecting Groups N,N-Diallyl Br R N RNH2 Hunig's Base (Ph3P)3RhCl "Wilkinson's Catalyst" Acid/Base Stable and Nucleophile Inert Ganem. 1981, 1483 RNH2 MEM1 and MTM2 MEMCl Hunig's Base O O R O ZnBr2 or TiCl4 ROH ROH 1. NaH 2. MTMI 1Corey. 2Corey. 1976, 809 1975, 3269 O R S HgCl2 or AgNO3 Protection for Alkynes Fe3+ Co2(CO)8 (OC)3Co Co(CO)3 Alkyne now protected from reagents which can affect alkenes or alkynes. Nicholas. 1971, 3475 Not New, But Improved: Thioacetals R' S O R PIFA S R R' Improved method of removal which is selective for thioacetals. Stork. 1989, 287 O O RO BOB1 Protection: 1. Fisher Esterification 2. Mitsunobo Esterification 3. Jacobsen Asymmetric Epoxide Opening with Carboxylic acids, catalyzed with Co(salen)2 Deprotection: 1. Hydrogenolysis/lactonization: H2, Pd/C then KOtBu Protecting Capability: 1. Assumed similar to other esters 2. Can remove in presence of other esters 1Ganem. 2000, 9523 1997, 773 2Jacobsen. Natural Products Reported in Tetrahedron Letters Natural Products Br CO2Me O O O CH3 O Cl H3C O H OH Br Johnstonol 3, 1972, 195 O OH OH Pseudopterane Metabolite, 36, 1991, 4661 OMe HO H3C O H OH OH O CH3 CH3 Blazeispirol A 40, 1999, 329 H H H H HO H O H O CH3 H O H H CH3 OH OH Blepharocalyxin A 40, 1996, 7283 H3CO OH CH3 Natural Products OH OH O Br H O O HO OH O OH O O O O Br HO O Floreside 4 44, 2003, 1243 Arabidopside A 44, 2003, 5553 O O HO O OH O O O H Brazilide A 43, 2002, 1731 O O O O OH O Coleophomone A 41, 2000, 8705 Syntheses (±)-Decaline O H H O H N O OMe OMe Arata. 1973, 2355 (±)-Decaline H O O H N O HO NaOH + H2O HN MeO Br Br OR OMe H H (MeO)2SO2, NaOH RO R=H R=Me, 76% (2 steps) H N IrCl4, HCl,Me3P, iPrOH, 84% Br "Henbest catalyst" OMe OMe Ac2O, Py Arata. 1973, 2355 R=H R=Ac 9:1 axial:equitorial Proc. Chem. Soc. 1964, 361 Org. Synth. 1970, 13 (±)-Decaline H H AcO OMe H CO2R O N H H R'O OH H CuO, Py 34% Br N "Ullman Condensation" O OMe OMe OMe O OMe H H NaOH, H2O O R=Me, R'=Ac R=R'=H H N pTSA, PhH O D, 55% (2 steps) OMe (±)-Decaline Arata. 1973, 2355 OMe (±)-Bakkenolide A O O H Evans. 1973, 4691 (±)-Bakkenolide A 1. OsO4, NaIO4, t-BuOH/H2O, 93% O 2. KOtBu, tBuOH/Et2O, 65% 3. H2, Pd/C, EtOH O H Li 1. 70% 2. PBr3 3. TosHNN SNa SMe 75% S NaH, THF, heat MeS 60% H S TosHNN Evans. 1973, 4691 SMe H (±)-Bakkenolide A Sigmatropic RAR Tos H N S N Tos N S N SMe SMe S MeS S Evans. 1973, 4691 SMe (±)-Bakkenolide A O S 1. HgO, HgCl2, 75% MeS O 2. SeO2 H H (±)Bakkenolide A Evans. 1973, 4691 Echinulin O H NH H HN CH3 N H Kishi. 1971, 4665 O Echinulin NH2 N NH2 ZnCl2 Kishi. 1971, 4661 Echinulin NH2 O O O OEt Br EtO N H 1. LAH 2. Ac2O-DMSO 3. Ph3P=CH2 N NHEt2, HCOH N H Kishi. 1971, 4665 "Mannich" N H Echinulin O MeO2C N O MeO2C NH H NH HN HN O H CH3 N H O 1. 0.1N NaOH/Dioxane 2. Heat 3. Resolution O H NH H HN CH3 N H Kishi. 1971, 4665 CH3 O dl-Cepharamine OCH3 HO O H3CO N Kitano. 1969, 1611 dl-Cepharamine OCH3 OCH3 H3CO H3CO I CN NC O O MVK, NaOH OCH3 OCH3 H3CO H3CO NC NaOEt O O HN Kitano. 1969, 1611 O OH dl-Cepharamine OCH3 OCH3 H3CO H3CO 1. Ethylene glycol 2. NaH, MeI O O HN O O N O H2NNH2-H2O KOH OCH3 OCH3 RO AcO R R 1. Hydrolysis 2. Br2, AcOH O N Kitano. 1969, 1611 O Freshly Fused NaOAc in HOAc O R=Br R=O O N R=H R=Ac O dl-Cepharamine OCH3 OCH3 AcO AcO O methanol O BF3 O N H3CO O N OCH3 LAH HO O dl-Cepharamine H3CO N Kitano. 1969, 1611 O (-)-Bilobalide O OH OH tBu O O O O O Corey. 1988, 3423. Racemic synthesis originally presented in J. Am. Chem. Soc. 1987, 7534 (-)-Bilobalide CO2M CO2M DIBALCl1 88%, 99% de MO2C CO2M 1. LDA M= 2. t-Bu O CO2Ph 91% Co2M tBu CO2M H tBu KHMDS 80% CO2M CO2M O Corey. 1988, 3423. 1Developed by Yamamoto. 1986, 4507 O (-)-Bilobalide Co2M tBu BH3-THF H N CO2M Co2M O tBu Ph Ph O B CO2M H 45% 10:1 desired isomer OH 1. O3, NaHCO3 DCM/MeOH 2. DMSO 3. pTsOH, MeOH 75% MeO tBu MeO 1. LAH, THF, 55oC, 84% 2. i) Oxalyl Chloride, DMSO MeO ii) Et3N, -78oC to -40oC O O O O 3. 1N HCl/THF, 0oC 4. PCC, 4A mol siv, DCM 62% tBu MO2C MO2C O OMe Corey. 1988, 3423. OMe (-)-Bilobalide RO tBu tBu O O Hunig's Base O O 75% (3 steps) OMe OMe KOH MeSO2Cl O O O O R=OMe R=OH R=Cl O2N COOOH 10eq NO2 NaHCO3, DCM, 95% AcO OAc O tBu tBu O O 1. 0.5 N HCl/H2O/THF, O 2. Ac2O, DMAP, DCM, RT 89% O O Corey. 1988, 3423. O 60oC OMe O O O O OMe AcO (-)-Bilobalide O OAc OAc tBu tBu O O O 1. 0.5N HCl/AcOH/THF, 80oC O O 2. PCC, DCM, 96% O O O O O R R' O R=H, R'=OMe R=R'=O mCPBA, BF3-Et2O 92% O trimethylsilane Tol, 300 oC, 90% O OR OAc tBu OH tBu O R' OsO4, Py, Et2O O O O O MeO2COCCl, Hunig's, 100% Bu3SnH, AIBN, 55% 3N HCl, reflux, 36 hrs, 70% O O O O Corey. 1988, 3423. O R=Ac, R'=OH R=Ac, R'=OCOCO2CH3 R=Ac, R'=H R=R'=H (-)-Bilobalide Conclusions
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