R R * R MLn Me R OH O OH N OMe * Me Me Atropisomerism O * MeO OH N Axial Chirality in Nature and Synthesis H OMe Me MeO O X Y Y X OH O Y X X Y OMe MeO OH Kevin Allan O H MeO * OH Stoltz Group Literature Meeting Al Li Monday 11/14/2005 * O OEt 8 pm OMe 147 Noyes OH O O O O Nu O Nu Outline I. Introduction a. History and Background b. Conditions for Axial Chirality II. Direct Atroposelective Aryl-Aryl Coupling a. Diastereoselective Coupling b. Enantioselective Coupling III. Resolution/Desymmetrization of Prostereogenic Biaryls a. Configurationally Stable, Axially Achiral b. Configurationally Unstable, Axially Chiral Motokazu Uemura (right) and i. Atropodiastereoselective Bridge Formation Ken Kamikawa (left) ii. Atroposelective Bridge Cleavage / The "Lactone Method" Osaka Prefecture University IV. Atroposelective Construction of an Aromatic Ring Albert I. Meyers Colorado State University For a general review of biaryls in synthesis: Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. I. E. 2005, 44, 5384-5427. Biaryl cross-coupling: Stanforth, S. P. Tetrahedron. 1998, 54, 263-303. Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145-157. Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113-1128. Lactone Methodology: Gerhard Bringmann Matthias Breuning Bringmann, G.; Breuning, M.; Tasler, S. Synthesis, 1999, 4, 525-558. Universitat Wurzburg Universitat Wurzburg Bringmann, G.; Tasler, S.; Pfeifer, R.-M.; Breuning, M. J. Organomet. Chem. 2002, 661, 49-65. Atropisomerism is Everywhere OH HO HO HO O OH Me O Me O O NH2 O HO OH HO Cl O O CH3(CH2)10 HO Cl OH O O O O OH H H O N N NHMe OH N N N H H H Myristinin B O H Myristica cinnamomea HN O Me HN O COX 2 inhibitor HO2C P H2N Me OH OH M Vancomycin OH OH OMe HO Amycolatopsis orientalis Antibiotic (Gram-positive) MeO OH P HO NH OH Michellamine B Ancistrocladus korupensis Protein kinase C inhibitor, anti-HIV-1,2 Atropisomerism is Everywhere N NO N Ru Me P O Cl O Ph2P Me Ph P P Ph Me catalyzes enantioselective hydrosilations catalyzes asymmetric homo-coupling Bringmann, G. Tetrahedron: Asymm. 1999, 10, 3025-3031. of 2-naphthols Katsuki, T. Synlett, 2000, 1433-1436. R H H N N HO N H O M N M Me OH M M O HO Me HO N HO Me R OH Me catalyzes enantioselective catalyzes enantioselective Me allylation of aldehydes alkylation of aldehydes Hayashi, T. J. Org. Chem. 2003, 68, 6329-6337. Bringmann, G. J. Org. Chem. 2003, 68, 6859-6863. Atropisomerism History & Background Atropisomerism: a term coined by Richard Kuhn in 1933, it refers to stereoisomerism resulting from hindered rotation around a single bond such that the isolation of individual conformers is possible. From Greek: a - not tropos - to turn • The first atropisomer was reported in 1922 by G. H. Christie and J. Kenner. A single enantiomer of 6,6'-dinitro-2,2'-diphenic acid was isolated from the racemic mixture via diastereoselective crystallization with a chiral resolving agent: O2N CO2H HO2C NO2 Kuhn, R. "Molekulare Asymmetrie" in Stereochemie. Freudenberg, K. ed. Franz-Deutike: Leipzig-Wien, 1933, p. 803. Christie, G. H.; Kenner, J. J. Chem. Soc. 1922, 121, 614-620. Atropisomerism Conditions for Axial Chirality The Rules: • A generally accepted--though arbitrary--rule states atropisomers are considered physically separable when they have a half-life at room temperature of >1000 s (16.7 min). -1 • !G200 K = 61.6 kJ mol -1 • !G300 K = 93.5 kJ mol • Steric hindrance at the ortho positions (and to a lesser extent, electron donating/withdrawing character of each of the substituents around each aryl ring) determines the ability of a biaryl system to display atropisomeric behavior. • When referring to axial (helical) chirality, S and R notation become P (plus) and M (minus), respectively. • Hierarchy of functionality is identical to the determination of central (sp3 ) chirality (highest atomic number, etc.). • Hierarchy of aryl substitution is as follows: endocyclic ortho --> ortho --> meta --> para OH OH HO OH S = P R = M HO OH 3 2 2' 3' 3' 2' 2 3 1 1' 1' 1 4 4' HO OH 4' 4 5 6 6' 5' 5' 6' 6 5 (P )-2,2'-dihydroxybiphenyl (M )-2,2'-dihydroxybiphenyl OH HO OH pro-P pro-M HO OH HO OH HO OH HO OH OH Bringmann, G. Angew. Chem. I. E. 2005, 44, 5384-5427. Direct Atroposelective Aryl-Aryl Coupling Diastereoselective Coupling Chiral Tether Influences Configuration Ortho Chiral Auxiliary Influences Planar Chiral Element Influences During Intramolecular Coupling Configuration During Intermolecular Configuration During Intermolecular Coupling Coupling X X Y* LnM' X X + + * X X MLn MLn MLn LnM' * * * Y* * Central-to-axial transfer of chirality Central-to-axial transfer of chirality Planar-to-axial transfer of chirality Diastereoselective Aryl-Aryl Coupling Intramolecular Coupling with Chiral Tethers - Toward Desertorin A-C Me OMe Br TBSO R O S OBn 3 steps OBn OBn OBn TBSO R O S Br MeO Me Lipshutz, B. H.; Kayser, F.; Lui, Z.-P. Angew. Chem., I. E. Engl. 1994, 33, 1842-1844. Kyasnoor, R. V.; Sargent, M. V. Chem. Commun. 1998, 2713-2714. Diastereoselective Aryl-Aryl Coupling Intramolecular Coupling with Chiral Tethers - Toward Desertorin A-C Me OMe OMe Br TBSO R O S O OBn 3 steps OBn 1. BuLi, -78 °C Me OBn P OBn OBn MeO OBn TBSO R O S 2. CuCN, TMEDA O -78 to -40 °C Br 3. O2, -78 °C 40% over 3 steps Me MeO Me single diastereomer O O Desertorin A-C MeO Me OR RO O O Me OMe Lipshutz, B. H.; Kayser, F.; Lui, Z.-P. Angew. Chem., I. E. Engl. 1994, 33, 1842-1844. Kyasnoor, R. V.; Sargent, M. V. Chem. Commun. 1998, 2713-2714. Diastereoselective Aryl-Aryl Coupling Intramolecular Coupling with Chiral Tethers - Toward Desertorin A-C Me OMe OMe Br TBSO R O S O OBn 3 steps OBn 1. BuLi, -78 °C Me OBn P OBn OBn MeO OBn TBSO R O S 2. CuCN, TMEDA O -78 to -40 °C Br 3. O2, -78 °C 40% over 3 steps Me MeO Me single diastereomer O Me H O CH2OBn O Desertorin A-C MeO O CH2OBn MeO H Me OR RO O O OBn substituents prefer gauche conformation as opposed to axial anti-coplanar Me OMe Lipshutz, B. H.; Kayser, F.; Lui, Z.-P. Angew. Chem., I. E. Engl. 1994, 33, 1842-1844. Kyasnoor, R. V.; Sargent, M. V. Chem. Commun. 1998, 2713-2714. Diastereoselective Aryl-Aryl Coupling Ortho Chiral Auxiliaries - Asymmetric Suzuki Coupling Me pTol S O DIBAL OMe R1 R1 S pTol R1 S pTol LDA, THF ZnCl2, THF I O 80% I O O 74% I OH O Broutin, P.-E.; Colobert, F. Org. Lett. 2003, 5(18), 3281-3284. Diastereoselective Aryl-Aryl Coupling Ortho Chiral Auxiliaries - Asymmetric Suzuki Coupling Me pTol S O DIBAL OMe R1 R1 S pTol R1 S pTol LDA, THF ZnCl2, THF I O 80% I O O 74% I OH O R1 S pTol I OH O Entry R1 R2 Yield (%) dr* 1 pTol R S 1 Me Me 60 70:30 + Pd(OAc)2, dppf OH O CsF, dioxane * 2 2 Me OMe 27 90:10 B(OH)2 70 °C R R2 3 OMe OMe 61 93:7 *determined by 1H NMR (absolute configuration unknown) Broutin, P.-E.; Colobert, F. Org. Lett. 2003, 5(18), 3281-3284. Diastereoselective Aryl-Aryl Coupling Ortho Chiral Auxiliaries - Asymmetric Suzuki Coupling Me pTol S O DIBAL OMe R1 R1 S pTol R1 S pTol LDA, THF ZnCl2, THF I O 80% I O O 74% I OH O NaH, MeI DMF, -20 °C 99% R1 S pTol I OMe O Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113-1128. Diastereoselective Aryl-Aryl Coupling Ortho Chiral Auxiliaries - Asymmetric Suzuki Coupling Me pTol S O DIBAL OMe R1 R1 S pTol R1 S pTol LDA, THF ZnCl2, THF I O 80% I O O 74% I OH O NaH, MeI 5 DMF, -20 °C Entry R1 R2 R3 R4 R Yield (%) dr* 99% 1 Me Me CH2 H H 78 75:25 3 B(OR )2 4 2 2 Me OMe CH2 H H 89 80:20 R R + 3 OMe Me CH2 H H 86 90:10 R1 S pTol R5 4 OMe OMe H H H 80 85:15 I OMe O 5 H Me H 99 >99:1 6 H OMe H 99 >99:1 Pd(OAc)2 dppf or PPh 7 Me H CH 88 90:10 3 2 CsF, dioxane 70 °C R1 S pTol 8 OMe H CH2 86 95:5 OMe O *determined by 1H NMR (absolute configuration unknown) R4 * R2 R5 Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113-1128. Diastereoselective Aryl-Aryl Coupling Ortho Chiral Auxiliaries - Aryl Grignard Coupling R Yield (%) dr (P :M ) MeO R O Br 90 20:80 R OMe i-Pr O Mg + P N CH2OMe 75 40:60 i-Pr THF, ! MeO O CH OBn 80 42:58 OMe N 2 MeO Me 79 90:10 O CH2OTBS 73 93:7 Grignard additions require EWG at ortho or para position to stabilize developing negative charge. Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson, D. J.; Meier, A. Tetrahedron, 2004, 60, 4459-4473. Diastereoselective Aryl-Aryl Coupling Ortho Chiral Auxiliaries - Aryl Grignard Coupling MeO R Br R OMe i-Pr R OMe Mg O + P N i-Pr N THF, ! MeO O MeO i-Pr OMe N MeO Mg MeO O Br Grignard additions require EWG at ortho or para 180° rotation position to stabilize developing negative charge.