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Frontiers Presentation Biaryls in Nature and Synthetic Approaches to Axial Chirality Frontiers of Chemistry 3/11/06 Erikah Englund M.C.Escher’s Drawing Hands Erikah Englund @ Wipf Group 1 3/11/2006 Outline Axial chirality in context Biaryls in nature Synthetic approaches to biaryl axial chirality Classical Selective conversion of pro-stereogenic biaryls Generation of second aromatic ring Conclusion Erikah Englund @ Wipf Group 2 3/11/2006 Timeline of Chirality 1848: Louis Pasteur studied the enantiomers of tartaric acid while investigating the mechanism by which wine goes sour. 1874: Van’t Hoff proposed the tetrahedral carbon CO H NO 1922: Christie and Kenner first 2 2 O2N CO2H CO H NO accurately described axial 2 2 CO2H NO2 chirality (J.Chem.Soc. 1922, 121, 614) cis 1933: Kuhn coined the term trans atropisomer (a=not, O2N O2N tropos=turn). Originally only CO2H CO2H referred to biaryl compounds O2N CO2H (Stereochemie, Frans Deuticke, Leipzig, 1933) CO2H NO2 Kaufler’s explanation for axial chirality (Ann. 1907, 151, 351) Erikah Englund @ Wipf Group 3 3/11/2006 Features of Chiral Biaryl Atropisomers Stability/rotational barrier factors (a half life of 16.7 min (1,000 s) is considered physically separable): Sterics (I>Br>Me>Cl>NO2>CO2H>OMe>F>H) 3 or 4 ortho substituents generally form stable atropisomers Existence, length and rigidity of bridges 5 membered rings freely rotate at r.t. A B Atropisomerization mechanisms A' B' Physical (e.g. heat) Photochemical Chemically induced Chirality criteria: Different substituents on both sides of the axis (A≠B and A’≠B’) Presence and location of hetero-atoms Different meta substituents Angew.Chem.Int.Ed. 2005, 44, 5384 Erikah Englund @ Wipf Group 4 3/11/2006 Assignment of Chirality M=Minus P=Plus Angew.Chem.Int.Ed. 2005, 44, 5384 Erikah Englund @ Wipf Group 5 3/11/2006 Biological Activity OH CHO OH HO OH OH CHO HO Gossypol (from gossypium hirsutum seeds) Discovered in 1899 (absolute stereochemistry determined in 1988) The (-) enantiomer is either the major or sole possessor of the following biological activity: Anti-fertility Anti-tumor Anti-amoebic Anti-HIV Phytochemistry,1991, 30, 2655 Erikah Englund @ Wipf Group 6 3/11/2006 Biological Activity (cont.) Antimicrobial Teicoplanin (actinoplanes teichomyceticus) 2-8 fold more potent than vancomycin and less cytotoxic The biological activity of the DE ring atropisomer was 50 fold less active than the parent compound in antimicrobial and cell free binding assays (Boger JACS, 2000, 122, 10047) Erikah Englund @ Wipf Group 7 3/11/2006 Biosynthetic Pathways Oxidative phenolic coupling OH O O O O O coupled biaryls Polyketide cyclization OH OH O O O RS O O HO OH Bringmann, Progress in the Chemistry of Organic Natural Products Vol. 82, 2001, 1-249 Erikah Englund @ Wipf Group 8 3/11/2006 Biosynthetic Pathways (cont.) Diels-Alder O HO Hydroxyanigorufone OH OH OH O OH OH Aldol type cyclizations OH OH O HO OMe O OH Terphenyllin HO O MeO O OH OH Erikah Englund @ Wipf Group 9 3/11/2006 Biaryls in Nature Wherever in nature phenolic aromatics can be found- be they derived from polyketide precursors, from aromatic amino acids and/or shikimic acid, or from terpenoids- the corresponding homo- or hetero–dimeric biaryls have to be expected. Bringmann Progress in the Chemistry of Organic Natural Products 2001, Vol. 82, 3 Erikah Englund @ Wipf Group 10 3/11/2006 Biaryl Ligands Ligand Review: Tetrahedron 2001, 57, 3809 Erikah Englund @ Wipf Group 11 3/11/2006 Synthesis “Classic concept” C-C bond formation between two aryl systems with simultaneous asymmetric induction Transformation of a “pro-chiral” biaryl system into a chiral system through chemical transformation Desymmetrization Generation of second aromatic ring from nonaromatic precursor with simultaneous generation of desired chirality Erikah Englund @ Wipf Group 12 3/11/2006 I. Classical Approaches Diastereoselective approaches: Chiral bridge linking the two coupling partners Bridge might or might not be present in final product Chiral auxiliary on the arene (usually ortho position) Incorporation of removable chiral unit (η6 chromium complex) Enantioselective approaches: Chiral leaving group Metal based reagents and chiral ligands Aryl-aryl bond formation review: Hassan, Chem.Rev.2002, 102, 1359 Erikah Englund @ Wipf Group 13 3/11/2006 Classical Approach- chiral tethers Pioneering Work: (Miyano, Bull. Chem. Soc. Jpn. 1981, 54, 3522) O R O O R Cu, DMF R KOH CO H X O 2 O X 30-80 %, 85-100 de O ~90% CO2H R' O O R' R' Modifications: (Lipshutz, Angew. Chem. Int. Ed. Engl. 1994, 33, 1842) Favored due to anomeric effect (Sargent, Chem.Comm, 1998, 2713) H RO CH2OBn 1. t-BuLi O 2. CuCN, TMEDA RO CH2OBn Br OBn H 3. O2 O OBn vs. Br OBn O OBn O 78%, 100%de CH2OBn RO H RO H CH2OBn Erikah Englund @ Wipf Group 14 3/11/2006 Additional Tethers Acetonide (Lipshutz, Tetrahedron Lett. 1997, 38, 753) Designed to allow access to BINOL derivatives CuCl(OH)TMEDA O O O OH O OH O OH O OH O CH2Cl2, O2, rt 90% O Lactone (Waldvogel, Angew. Chem. Int. Ed. 2002, 41, 2981) Structural motif in biologically active lignans (Charlton, J.Nat.Prod, 1998, 61, 1447) OMe OMe MeO MeO MoCl , CH Cl 5 2 2 O O 0 oC, 50% O O MeO MeO OMe OMe Erikah Englund @ Wipf Group 15 3/11/2006 Schreiber’s application to DOS A library of axially chiral biaryls (>400) was synthesized to screen for biological activity (Schreiber, JACS, 2000, 122, 5656) The kinetic product could be converted to the other atropodiastereomer by heating for 2 days. 1. t-BuLi O I 2. CuCN O 3. Oxidant N N R R I 55%, 6:1 P:M R= Si (CH2)5O 500-560 micrometer polystyrene beads Erikah Englund @ Wipf Group 16 3/11/2006 Schreiber’s DOS results 9 and 10-membered rings were synthesized (Org. Lett, 2004, 6, 4021) These analogues were submitted to protein-binding, chemical genetic, and phenotype assays. When entry l was tested in zebrafish, the P isomer had no activity while the M isomer affected the cardiovascular system during development (J.A.C.S, 2002, 124, 1354) Erikah Englund @ Wipf Group 17 3/11/2006 Total Synthesis Applications- Vancomycin Evans (JACS, 1993, 115, 6426) Cl Cl OPG OPG OH Cl O OH Cl O O NHCOCF3 O N O NHCOCF3 H VOF3, BF3, AgBF4 N NH OBn H MeHN HN 54% O OMe MeHN OMe MeO OMe MeO OMe Boger (JACS, 1999, 121, 3226) 95:5 OMe B(OH) OMe 2 O OH O OH R OMe TBSO NO2 TBSO NO2 O O H H N N OMe CO2Me N H CO2Me N H O O o Pd2(dba)3, P( tol)3, o Na2CO3, 80 C MeO Br 88% R OMe OMe MeO 1:1 3:1 Erikah Englund @ Wipf Group 18 3/11/2006 Vancomycin Derivatives Boger (J. Am. Chem. Soc. 2006; 128; 2885) The A-B ring system was constructed in the same fashion as the parent compound (Suzuki coupling followed by thermal equilibration) Ultimately, 5 exhibited antimicrobial activity against VanA-resistant microorganisms Erikah Englund @ Wipf Group 19 3/11/2006 Vancomycin- Chiral Ligands Nicolaou (Chem. Eur. J. 1999, 5, 2584-2601) O O O B OH O O H H N MeO OMe CO2Me N N H CO2Me N H O O Pd2(OAc)2, Na2CO3 MeO OH I OMe OMe MeO + atropisomer Entry Ligand Solvent Temp Time (h) Yield Ratio 1 PH3P PhMe 90 2 80 1:1 2 BINAP PhMe 90 12 Trace - 3 BINAP THF 65 12 Trace - 4 S-BINAP DMF 80 8 60 2.3:1 5 S-BINAP PhMe:THF (1:1) 70 5 40 95:5 6 R-BINAP PhMe:THF(1:1) 70 5 40 5:95 Erikah Englund @ Wipf Group 20 3/11/2006 Chiral Ortho Substituents Oxazoline and asymmetric Grignard addition (Meyers, JACS, 1985, 107, 682) Grignard reagent essential Low selectivity with aryllithium Good yields of tri-ortho substituted products. Tetra-ortho substituted products are produced in low yields R’ and R’’= Me, OMe, OMOM or OTBS, R=Ph MeO R Mg, THF Br MeO R N OMe N O O Erikah Englund @ Wipf Group 21 3/11/2006 Chiral Ortho Substituents (cont.) Suzuki (Colobert, Org. Lett. 2003, 5, 3281) Methoxy protection of chiral aux prevents hydrodehalogenation of substrate Mechanistic studies (Colobert, Org.Lett, 2005, 7, 3737) Diastereoselectivity when SO2pTol is replaced with: . H=60/40 . OMe or OBn=70/30 . NMe2=<95/5 Proposed palladacycle intermediate: Erikah Englund @ Wipf Group 22 3/11/2006 Removable Chiral Unit Chromium complex (Uemura, Synlett 2000, 938-949 ) Br R1 R2 Cr(CO)3 Used in: Pinacol coupling with SmI2 (J.O.C. 1996, 61, 6088) Enantiotopic lithiation (J.O.C. 2002, 67, 1929) Suzuki coupling (Org. Lett. 2001, 3, 2033) . Accelerates oxidative addition to aryl halide . Poor yields when chromium complexed to aryl boronic acid Chromium removed through photooxidative demetalation Disadvantages: laborious to get to single enantiomer of chromium complex toxic Erikah Englund @ Wipf Group 23 3/11/2006 Removable Chiral Unit Ruthenium complex (Uemura, Org.Lett. 2001, 3, 3667) Single diastereomer Reagents: (a) BH3·Me2S, (S)-oxazaborolidine b), (b) Pd(OAc)2, (c) [CpRu(CH3CN)3]PF6, (CH2Cl)2, reflux, (51%), (d) NaOMe, MeOH, (98%), (e) hv, CH3CN, (95%). Cyclophanes (Miyano Tetrahedron Lett. 1996, 37, 2057-2060) Used with Grignard reagents 82-85% yield and 91-99% ee O (CH2)10 CO iPr O 2 Erikah Englund @ Wipf Group 24 3/11/2006 Enantioselective Approaches Chiral leaving group: Initial studies found yields: 7-83% and optical purities: 10-95% (Wilson and Cram, J.
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