Asymmetric Synthesis of Chromans: Processes and Applications, Study notes of Organic Chemistry

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Asymmetric synthesis of chromans and their use as building blocks in some biologically important molecules Manasi Keni Department of Chemistry MSU Chromans O R1 R2 1 Benzopyrans saturated in the 2 and 3 position Biologically active compounds O OH O HO O H H O N H O OH OH (+)-Clusifoliol medicine for malignant tumor Siccanin antibacterial, antifungal, cytotoxic, insecticidal (S,R,R,R)-Nebivolol antihypertensive Outline of the seminar Asymmetric synthesis of compounds containing chroman moiety from Chiral pool Achiral starting material followed by resolution Enzymatically Chemically Achiral starting material followed by non asymmetric synthesis Conclusion Synthesis of Vitamin E O HO O HO O H Ph3P Br + Vitamin E O HO O H O O HO Me OH OH H HO Me OH O HO Me OH OH HO O OH O H OBn O O O H OBn O O H OBn O H BzO (S)-O-benzylglycidol acid Catalyzed cyclization Oxidative cleavage delactonization Asymmetric epoxidation Takano, S.; Shimazaki, Y.; Iwabuchi, Y.; Ogasawara, K. Tet. Lett. 1990, 31, 3619-3622. Synthesis of the chiral chroman adduct 30%H2O2, 6N NaOH, MeOH PhSeSePh, NaBH4, CH3CO2H, iPrOH i) LiAlH4 THF; ii) H2, Pd(OH)2-C, MeOH; iii) HIO4, H2O; iv) 2,5-dimethoxy -3,4,6-trimethyl- phenyl- magnesium bromide, THF, O0C CAN, aq. CH3CN (1:1), 2N-H2SO4, dioxane, reflux H2, Pd(OH)2-C, MeOH, cat. CHCl3 O H OBn O O BnO O OOH O OBn O OHO O O O H OBn H O OH O H OBn O OH O H OBn OMe MeO HO Me OH OH H O O HO Me OH OH H O O OH HO H HO O OH (1:1 epimers) *** * * ** Takano, S.; Shimazaki, Y.; Iwabuchi, Y.; Ogasawara, K. Tet. Lett. 1990, 31, 3619-3622. Construction of side chain and assemblage of Vitamin E (15 steps) MeLi, CuI, Et2O, 00C O H BzO (S)-O-benzylglycidol O H OBn O O O H BnO MeH H Me HO HMe ** * ** * Takano, S.; Shimazaki, Y.; Iwabuchi, Y.; Ogasawara, K. Tet. Lett. 1990, 31, 3619-3622. Me Me Me HO Me CHO H Ph3P HMe Br + O HO Vitamin E Lopresti, R. J.; Neukom, C.; Saucy, G. J. Org. Chem., 1976, 41, 3505-3511. Outline of the seminar Asymmetric synthesis of compounds containing chroman moiety from Chiral pool Achiral starting material followed by resolution Enzymatically Chemically Achiral starting material followed by non asymmetric synthesis Conclusion Outline of the seminar Asymmetric synthesis of compounds containing chroman moiety from Chiral pool Achiral starting material followed by resolution Enzymatically Chemically Achiral starting material followed by non asymmetric synthesis Conclusion Chromanethanol O HO OH (S)-Chromanethanol HO O OH OMOM BnO HO HO OMOM BnO OH O OMOM BnO OH OAc BnO O O OH BnO Double Inversion cyclization Sharpless epoxixdation acetylation Horner- Emmons- Wadsworth reaction Achiwa, K; Suzuki, T; Mizuguchi, F. Synlett 1996, 743-744. Synthesis of Chromanethanol using catalytic asymmetric epoxidation O OH BnO OAc BnO O OMOM BnO OH OMOM BnO OH O OMOM BnO HO HOHO O OH AcCl/Et3N, CH2Cl2, 72% D-(-)-DET, Ti(iPrO)4, TBHP/CH2Cl2, 98% i) Ph3CBF4, CH2Cl2, ii) H2, Pd-C, Et2O, 65%, 78% ee Horner- Emmons- Wadsworth reaction red-Al, Toluene, 99% (S)-Chromanethanol Achiwa, K; Suzuki, T; Mizuguchi, F. Synlett 1996, 743-744. Synthesizing the chiral diyne from a prochiral imine N Cl C2H5O2C CO2C2H5 TMS CO2C2H5 CO2C2H5 TMS TMS OH OH TMS OTBDMS OH TMS OTBDMSCHO H OTBDMS H3CO OCH3 CH3 Trost, B. M.; Fleitz, F. J.; Watkins, W. J. J. Am. Chem. Soc. 1996, 118, 5146-5147. 1st key step: Pd- Catalyzed Asymmetric Allylic Alkylation HO OMe MeO2CO HO OMeMeO2CO O OMe O OMe NH NH O PPh3 O NH NH O PPh3 O Ph3P Ph3P (S,S) 2 mol% [Pd2dba3.CHCl3] 6 mol % chiral ligand (S,S) HOAc (1 equiv), CH2Cl2 0.2 M, rt., 1 hr. 79% yield, 97% ee (R,R) 2 mol% [Pd2dba3.CHCl3] 6 mol % chiral ligand (S,S) HOAc (1 equiv), CH2Cl2 0.2 M, rt., 1 hr. 94% yield, 84% ee Trost, B.M.; Shen, H.C.; Surivet, J. Angew. Chem. Int. Ed. 2003, 42, 3943-3947 Catalytic cycle in Palladium-Catalyzed Asymmetric Allylic Alkylations or or complexation ionization-X Nu - Nucleophilic addition decomplexation L Pd L R R' X Pd LL R R' R R' Pd Pd L L L L R' Nu R Nu R'R Pd Pd L L L L R' Nu R R Nu R'* * * * X R' R * - 1 2 3 4 5 6 7 Trost, B.M.; Shen, H.C.; Surivet, J. Angew. Chem. Int. Ed. 2003, 42, 3943-3947 Synthesis of Diene for epoxidation O OMe O OMe O OH SO2Ph O OMe O SO2Ph + O OMe i) 4% aqueous OsO4, NMO, CH2Cl2, ii) NaIO4, acetone/H2O 94% i) PhSH, DIAD, PPh3, THF ii) Oxone, MeOH 89% i) nBuLi, then 5 ii) nBuLi, then Ac2O iii) 6% Na(Hg), Na2HPO4 93% Julia Olefination - 7 Trost, B.M.; Shen, H.C.; Surivet, J. Angew. Chem. Int. Ed. 2003, 42, 3943-3947 Mechanism of Radical Cyclization O MeO H H HO O MeO H H HO I O MeO H H HO O MeO H H O H O MeO H H O H O HO H H O H PhI(OAc)2, I2, PhH 65% EtSNa, DMF 82% Trost, B.M.; Shen, H.C.; Surivet, J. Angew. Chem. Int. Ed. 2003, 42, 3943-3947 (+)-Clusifoliol • Key step is Pd-cat. asymmetric allylic alkylation reaction of phenol allylic carbonates • Unusual effects of alkene geometry and additives on ee OMe O H Trost, B.M.; Shen, H.C.; Dong, L, Surivet, J J. Am. Chem. Soc. 2003, 125, 9276-9277 Retrosynthetically OH O H OH O H OMe O O H OMe OOCH2O2MeOH OMe OCH2O2MeOH OMe prenylation, [1,3] sigmatropic rearrangement modified Julia olefination oxidative cleavage regioselective O-allylic alkylationPd, L * Trost, B.M.; Shen, H.C.; Dong, L, Surivet, J J. Am. Chem. Soc. 2003, 125, 9276-9277 Unusual effects OCO2MeOH OMe OMe O i, 79%, 97% ee OCO2Me OH OMe i, 94%, 84% ee OMe O PPh3 O NH N H O Ph3P 1 Conditions: i) 2 mol% Pd2dba3, CHCl3, 6 mol% (R,R)-Ligand 1, 1-1.2 eq. HOAc, CH2Cl2, [C] = 0.1-0.2M, rt. Trost, B.M.; Shen, H.C.; Dong, L, Surivet, J J. Am. Chem. Soc. 2003, 125, 9276-9277 (-)-Calanolides A and B • Key structural feature is the trisubstituted Chroman ring • Challenging absolute and relative stereochemistry • Chirality introduced during Pd cat. O- alkylation which is both regioselective and enantioselective • Requires regioselective annulation of three rings onto phloroglucinol core, chromanol (ring D), chromene (ring C), coumarin (ring B) A B C D Calanolide A: R1= OH, R2= H; Calanolide B: R1= H, R2= OH. O O O O R2 R1 Retrosynthesis diastereoselective cyclization chemoselective hydration regioselective, enantioselective allylic alkylation chemoselective alkylation O O O O OH O O O O OH O O O O O OH O O H3CO2CO+ O OH OH CO2CH3 + HO OH OH Phloroglucinol Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 1998, 120, 9074-9075 Diastereoselective cyclization O O O O O O O O OH O O O O OH H O O O O H OH 9-BBN, THF then NaOH, H2O2 76% i) Dess-Martin Oxidation; ii) ZnCl2, ether 57% P(CH3)3, DEAD, ClCH2CO2H; K2CO3, MeOH 57% Calanolide B Calanolide A Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 1998, 120, 9074-9075 Synthesizing the Vitamin E core O HO O H3CO H3CO O electrophilic cycloaddition Vitamin E OCO2CH3 H3CO OH regioselective, enantioselective allylic alkylation Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 1998, 120, 9074-9075 Vitamin E HNNH OO PPh3 Ph3P OCO2CH3 H3CO OH H3CO O H3CO O H3CO O 1% Pd2dba3, 3% 4 85%, 92:8, 76%ee i) Catacolborane, ii) 2% (PPh3)3RhCl then NaOH, H2O2; iii) Tf2O, 2,6-di-tbutylpyridine, CH2Cl2 69% 3 Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 1998, 120, 9074-9075 A sequential anionic-pericyclic strategy for the synthesis of Rhododaurichromanic Acid A and B O O H NR2 R2 R3 X O O R2 R3 O O R2 R3 O OH R2 R3 O H H CO2Me HO H O H H CO2Me HO H Rhododaurichromanic Acid A and B Knoevenagel condensation 1-oxatrienes 1-oxadecalins A [3+3] cycloaddition for synthesis of Chromenes or Chromans 6π-electron electrocyclic ring-closure Hsung, R.P.; Kurdyumov, A.V.; Ihlen, K; Wang, J. Org. Lett. 2003, 21, 3935-3938 [3+3] cycloaddition DMSO, CH2Cl2, SO3-pyridine, Et3N 94% Piperidine, Ac2O, 900C, EtOAc, 1hr 71% HO O H O O O O O H 1:1 Hsung, R.P.; Kurdyumov, A.V.; Ihlen, K; Wang, J. Org. Lett. 2003, 21, 3935-3938 E-Daurichromenic ester LDA, THF, -780C, this was then added to NCCO2Me 71% O O O O O OMe OH O O OMe DDQ, toluene, reflux 44% E-Daurichromenic ester Hsung, R.P.; Kurdyumov, A.V.; Ihlen, K; Wang, J. Org. Lett. 2003, 21, 3935-3938