Atropisomerism Metal-mediated transformations to set biaryl chirality Nathaniel Kadunce Literature Meeting 12 December 2014 Atropisomerism • Atropos- the “inflexible” or “without turn” • Arise from hindered rotation about a single bond allowing for isolation of separate conformers HO2C NO2 HO2C NO2 HO2C NO2 HO2C NO2 Ra Sa 6,6'-dinitro-2,2'-diphenic acid, the first experimentally described atropisomeric compound Journal of the Chemical Society, Transactions 121: 614 First Evidence • Kaufler Hypothesis: cis and trans isomers explain op9cal proper9es • Supported by a series of misassignments in derivave studies • “It has been suggested by Carothers and by Mascarrelli that an objec9on to the Kaufler formula which has never been emphasized is the necessity of bending a bond to an angle of 90°. With a Kekule nucleus such a formula cannot be constructed, and each 9me that chemists adobt assump9ons that cannot be reconciled with the Kekule nucleus they encounter difficul9es.” –Adams, 1933 Rogers, A. and Yuan. H. C. Chem. Rev. 1933, 12, 261. First Evidence • Kaufler Hypothesis: cis and trans isomers explain op9cal proper9es • Supported by a series of misassignments in derivave studies • “It has been suggested by Carothers and by Mascarrelli that an objec9on to the Kaufler formula which has never been emphasized is the necessity of bending a bond to an angle of 90°. With a Kekule nucleus such a formula cannot be constructed, and each 9me that chemists adobt assump9ons that cannot be reconciled with the Kekule nucleus they encounter difficul9es.” –Adams, 1933 Rogers, A. and Yuan. H. C. Chem. Rev. 1933, 12, 261. Restricted Rotation 1926- The theory of restricted rotaon (Turner, Le Fevre, Bell, and Kenyon) • “Essen9ally, the theory states that subs9tuents in 2, 2’, 6, 6’ posi9ons in a diphenyl molecule can, by their interference, restrict the free rotaon of the two nuclei around the common axis, thus preven9ng the rings from becoming coplanar and thereby producing in the molecule an asymmetric configuraon.” –Adams, 1933 • Proven by resolu9on with alkaloids and subsequent racemizaon upon heang, studied extensively by dynamic NMR Rogers, A. and Yuan. H. C. Chem. Rev. 1933, 12, 261. Restricted Rotation • Extensive dynamic NMR studies by Sternhell show direct correlaon between van der Waals radii of subs9tuents and energe9c barrier to rotaon. • Increasing number of ortho- subs9tuents and van der Waals radius of each decreases the rate of racemizaon • Arbitrary defini9on of atropisomer is a half life of 1000 seconds at room temperature Strenhell, S. J. Am. Chem. Soc., 1980, 102, 5618. In Nature OMe Me OH O OMe O O OH MeO OH Me OH O O OH MeO OH HN OMe Me OH OMe Me OH O Me OH OMe (+)-orlandin (-)-phleichrome anti-plant growth photodynamic ROS generation OMe OH Me OMe OMe OH HO Me NH2 NH HO NH2 NH Me O OH Me HO Me HN O michellamine A NH anti-HIV1 and HIV2 CO2H OMe Me OH OH ancistrocladine biphenomycin A anti-malarial antibiotic Eudysmic Ratios i-Pr i-Pr Me OH HO Me CHO OH OH CHO HO OH OH HO OH CHO CHO OH HO Me Me OH i-Pr i-Pr (–)-gossypol (+)-gossypol “A potent inhibitor of the an9apopto9c B-cell lymphoma/leukemia-2 (Bcl-2) family of proteins such as Bcl-XL and that the (M)-isomer is some tenfold more cytotoxic than the (P)-isomer.” Eudysmic Ratios i-Pr i-Pr Me OH HO Me CHO OH OH CHO HO OH OH HO OH CHO CHO OH HO Me Me OH i-Pr i-Pr (–)-gossypol (+)-gossypol -Derivazaon led to increase in ac9vity and in eudysmic rao from 10 to 24. Ph Ph Me Me O NH HN O Me OH HO Me OH OH HO OH OH HO OH OH HO Me Me OH HN O O NH Me BI-97C1 (Sabutoclax) Me (R,M,R)- 0.1 µM Kd (R,P,R)- 2.4 µM Kd Ph versus Bcl-XL versus Bcl-XL Ph Pellecchia et al. J. Med. Chem. 2010, 53, 4166 and within. Atropchiral Ligands and Catalysts tBu O OMe Ph Ph Me O O Me O P tBu OH 2 N P P N P tBu OH O Me O O Me Ph Ph O OMe t Bu 2 (R)-BINOL Zhang's D2-symmetric (R)-DTBM-SEGPHOS phosphoramidite i-Pr i-Pr i-Pr PPh2 N O O O O P P OH PPh2 O O i-Pr i-Pr i-Pr (R)-QUINAP (R)-TRIP (R,S)-BINAPHOS Methods and Approaches Intramolecular Axial Coupling R Desymmetrization O X * X R O "The lactone concept" Chiral tether strategy Intermolecular Coupling OAux* O R R R' X N X M i-Pr Asymmetric cross-coupling Chiral auxilliary strategy Chiral leaving groups t-Bu O X S R R H Cr(CO)3 Asymmetric oxidative cross-coupling Methods and Approaches Intramolecular Axial Coupling Desymmetrization O X R * X R O "The lactone concept" Chiral tether strategy Intermolecular Coupling OAux* O R R R' X N X M i-Pr Asymmetric cross-coupling Chiral auxilliary strategy Chiral leaving groups t-Bu O X S R R H Cr(CO)3 Asymmetric oxidative cross-coupling Methods and Approaches Intramolecular Axial Coupling Desymmetrization O X R * X R O "The lactone concept" Chiral tether strategy Intermolecular Coupling OAux* O R R R' X N X M i-Pr Asymmetric cross-coupling Chiral auxilliary strategy Chiral leaving groups t-Bu O X S R R H Cr(CO)3 Asymmetric oxidative cross-coupling Methods and Approaches Intramolecular Axial Coupling Desymmetrization O X R * X R O "The lactone concept" Chiral tether strategy Intermolecular Coupling OAux* O R R R' X N X M i-Pr Asymmetric cross-coupling Chiral auxilliary strategy Chiral leaving groups t-Bu O X S R R H Cr(CO)3 Asymmetric oxidative cross-coupling Redox-Neutral Couplings 1. Enantioposition-selective cross-coupling of a difunctionalized achiral biaryl substrate 2. Dynamic kinetic asymmetric transformations via cross-coupling of a racemic substrate 3. sp2-sp2 Cross-coupling producing axial chirality in the bond-forming event Enantioposition-selective a) Kumada-Corriu cross-coupling of aryl Grignard reagent Me Me Me N PdCl2 P Ph (5 mol %) TfO OTf Ph Ph OTf PhMgBr (2 equiv) LiBr (1 equiv) Et2O/PhMe, −20 °C, 48 h (84% yield, 90% ee) b) Kumada-Corriu cross-coupling of alkynyl Grignard reagent Me Me Me N PdCl2 P Ph Ph TfO OTf (5 mol %) OTf Ph3Si MgBr Ph3Si (2.1 equiv) LiBr (1 equiv) Et2O/PhMe, 20 °C, 6 h (88% yield, 92% ee) c) Sonogashira cross-coupling of alkynes [PdCl(π-allyl)]2 (10 mol %) LX (12 mol %) Br Br CuI (10 mol %) Br Ph H Ph (1.5 equiv) Et3N (2.5 equiv) MeCN, 80 °C, 24 h O H (52% yield, 63% ee) N N Uozumi, Y., et al. J. Am. Chem. Soc. 1995, 117, 9101 Kamikawa, T.; Hayashi, T. Tetrahedron 1999, 55, 3455. PCy2 Kamikawa, T.; Uozumi, Y.; Hayashi, T. Tetrahedron Le?ers 1996, 37, 3161. Enantioposition-selective a) Kumada-Corriu cross-coupling of aryl Grignard reagent Me Me Me N PdCl2 P Ph (5 mol %) TfO OTf Ph Ph OTf PhMgBr (2 equiv) LiBr (1 equiv) Et2O/PhMe, −20 °C, 48 h TfO Ph (84% yield, 90% ee) k(R)/k(S) = 5 b) Kumada-Corriu cross-coupling of alkynyl Grignard reagent Me pro-R Me fast Me N slow PdCl (R)-XX 2 k(pro-S) k(R) P Ph Ph TfO OTf Ph Ph TfO OTf (5 mol %) OTf kinetic resolution Ph3Si MgBr Ph3Si (2.1 equiv) LiBr (1 equiv) k k Et O/PhMe, 20 °C, 6 h (pro-R) (S) 2 XX XX fast (88% yield, 92% ee) slow c) Sonogashira cross-coupling of alkynes Ph OTf k /k = 12 (85% ee) [PdCl(π-allyl)]2 (10 mol %) (pro-R) (pro-S) LX (12 mol %) Br Br CuI (10 mol %) Br Ph H Ph (S)-XX (1.5 equiv) major product Et3N (2.5 equiv) MeCN, 80 °C, 24 h O H (52% yield, 63% ee) N N Uozumi, Y., et al. J. Am. Chem. Soc. 1995, 117, 9101 Kamikawa, T.; Hayashi, T. Tetrahedron 1999, 55, 3455. PCy2 Kamikawa, T.; Uozumi, Y.; Hayashi, T. Tetrahedron Le?ers 1996, 37, 3161. DYKAT Hayashi, 2002 and 2004: Ni(cod)2 (3 mol %) i-PrPHOX (5 mol %) Ph O S SH PPh N PhMgX (10 equiv) 2 THF, 20 °C, 24 h iPr (92% yield, 95% ee) i-PrPHOX Ni(cod)2 (3 mol %) L (9 mol %) Me S SH MeMgX (10 equiv) PPh2 THF, 10 °C, 24 h L (97% yield, 68% ee) Shimada, T.; Cho, Y. H.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 13396. Cho, Y. H.; Kina, A.; Shimada, T.; Hayashi, T. J. Org. Chem. 2004, 69, 3811. DYKAT Hayashi, 2002 and 2004: Ni(cod)2 (3 mol %) i-PrPHOX (5 mol %) Ph O S SH PPh N PhMgX (10 equiv) 2 THF, 20 °C, 24 h iPr (92% yield, 95% ee) i-PrPHOX oxidative DYKAT addition fast NiLn NiLn S S Shimada, T.; Cho, Y. H.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 13396. Cho, Y. H.; Kina, A.; Shimada, T.; Hayashi, T. J. Org. Chem. 2004, 69, 3811. DYKAT Lassaletta, 2013: Pd2(dba)3 (5 mol %) Ph Ph TADDOL PNMe (5 mol %) − 2 O Me N CsCO (2 equiv) N Me O ϕ 3 P N OTf Ar Me O (ArBO)3 (1.5 equiv) O Me dioxane, 40 °C, 48 h Ph Ph (87% yield, 90% ee) Ar = p-MeOPh TADDOL-PNMe2 DYKAT slow N fast N ϕ [M]* [M]* Lassaletta, J. M., et al.