Methods and Applications in Atroposelective Chemistry HO Me HO HO Me OH O H N 2 O O Cl O O HO Cl OH O O H H H N N N H N NH O H H H O H O NHMe NH O O H Me HO C NH2 2 OH OH Me HO Nate Dow Group Meeting Literature Talk April 13, 2020 Outline Introduction and General Considerations ! Discovery and fundamentals ! Contributions to rotational barriers ! Pharmaceutical considerations Methods of (Catalytic) Synthesis ! Diastereoselective methods ! Dynamic kinetic resolutions and desymmetrization NMe2 i-Pr H O ! Redox-neutral cross-oupling O N Br H O ! Oxidative cross-oupling N O H O H H Applications N O BocHN Me Me ! Case Study: Tryptorubin A Formal Definitions of Atropisomerism Atropos (Greek) - “Without Turn” Atropisomers: stereoisomers caused by restricted rotation around a single bond (a subset of axially chiral compounds) ‡ HO2C NO2 O2N CO2H HO2C NO2 HO2C NO2 HO2C NO2 HO2C NO2 strained coplanar transition state Eliel, E. L.; Wilen, S.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley Interscience: New York, 1994, pp. 1119. Formal Definitions of Atropisomerism Atropos (Greek) - “Without Turn” Atropisomers: stereoisomers caused by restricted rotation around a single bond (a subset of axially chiral compounds) Requirement: t1/2 > 1000 seconds ΔG‡ > 22 kcal/mol (at 27 °C) HO2C NO2 HO2C NO2 HO2C NO2 HO2C NO2 C axially chiral, but no rotational interconversion! Eliel, E. L.; Wilen, S.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley Interscience: New York, 1994, pp. 1119. Formal Definitions of Atropisomerism Atropos (Greek) - “Without Turn” Atropisomers: stereoisomers caused by restricted rotation around a single bond (a subset of axially chiral compounds) Requirement: t1/2 > 1000 seconds ΔG‡ > 22 kcal/mol (at 27 °C) HO2C NO2 HO2C NO2 HO2C NO2 HO2C NO2 H H H H H H H H Ξ Me Me Ξ H Me Me H H Me Me H Me Me conformers: rotational interconversion, but barrier too low to produce stable stereoisomers! Eliel, E. L.; Wilen, S.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley Interscience: New York, 1994, pp. 1119. Formal Definitions of Atropisomerism Atropos (Greek) - “Without Turn” Atropisomers: stereoisomers caused by restricted rotation around a single bond (a subset of axially chiral compounds) Requirement: t1/2 > 1000 seconds ΔG‡ > 22 kcal/mol (at 27 °C) HO2C NO2 HO2C NO2 HO2C NO2 HO2C NO2 First reported atropisomeric compound (1922) Eliel, E. L.; Wilen, S.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley Interscience: New York, 1994, pp. 1119. Initial Discoveries via Alkaloid Resolution HO2C NO2 HO2C NO2 structural hypotheses planar parallel planes (Kauffler) non-planar internal symmetry planes, cannot be resolved common axis, but not coplanar chiral resolution possible Christie, G. H.; Kenner, J. J. Chem. Soc., Trans. 1922, 121, 614. Initial Discoveries via Alkaloid Resolution HO2C NO2 HO2C NO2 structural hypotheses planar parallel planes (Kauffler) non-planar internal symmetry planes, cannot be resolved common axis, but not coplanar chiral resolution possible Christie, G. H.; Kenner, J. J. Chem. Soc., Trans. 1922, 121, 614. Initial Discoveries via Alkaloid Resolution HO2C NO2 H2SO4/H2O (2 M) HO2C NO2 H N H MeO H mp = 230–231 °C O2C NO2 H H [α]D = +225.3° HO2C NO2 MeO N O N O H MeO H HO2C NO2 H H diastereomeric alkaloid salts HO2C NO2 MeO N O H O N H mp = 263 °C brucine MeO H O2C NO2 H H HO2C NO2 MeO N O O H SO /H O (2 M) HO2C NO2 2 4 2 HO2C NO2 Original theory: 2,2’,6,6’-tetrasubstituted biaryls possess this unique asymmetry mp = 230–238 °C [α]D = –169.7° Christie, G. H.; Kenner, J. J. Chem. Soc., Trans. 1922, 121, 614. Formal Definitions of Atropisomerism Me Me Excellent correlation between rotational barriers and van der Waals Me radii of ortho substituent can (roughly) paramaterize LFER via effective radii comparable to Charton values most commonly encountered scenario: biaryls containing at least two bulky ortho substituents, steric hindrance between substituents restricts rotation Bott, G; Field, L. D.; Sternhell, S. J. Am. Chem. Soc. 1980, 102, 5618. Formal Definitions of Atropisomerism Me Me Excellent correlation between rotational barriers and van der Waals Me radii of ortho substituent can (roughly) paramaterize LFER via effective radii comparable to Charton values However, many other factors contribute to the rotational barrier! Bott, G; Field, L. D.; Sternhell, S. J. Am. Chem. Soc. 1980, 102, 5618. Other Causes of Restricted Rotation Buttressing Effects ‡ CO2H HO2C I I I I HO2C HO2C H – ΔG‡ = 23.4 kcal/mol meta substitution prevents in-plane bending : I – ΔG‡ = 30.1 kcal/mol that could reduce ortho-ortho steric clash Electronic Effects F3C F3C ΔG‡ (kcal/mol) F3C F3C CF3 H 25.6 F3C OMe 24.9 X X 3 NO2 25.8 increased n ➞ !* donation increases sp -character at axial carbon, lowers rotational barrier Wolf, C.; Hochmuth, D. H.; König, W. A.; Roussel, C. Liebigs Ann. 1996, 357. Other Causes of Restricted Rotation Stereoelectronic Effects ϕ = 90° ϕ = 45° ϕ = 0° minimized tortional energy H H H H complete electronic no coplanar repulsion delocalization H H H H disrupted conjugation severe coplanar strain Leroux, F. ChemBioChem 2004, 5, 644. Other Causes of Restricted Rotation Stereoelectronic Effects ϕ = 90° ϕ = 45° ϕ = 0° H H ϕ = 90° ϕ = 45° ϕ = 0° ϕ = –90° maximum coplanar H strain H ϕ = ±180° Leroux, F. ChemBioChem 2004, 5, 644. Other Causes of Restricted Rotation Stereoelectronic Effects ϕ = 90° ϕ = 45° ϕ = 0° H H ϕ = 90° ϕ = 45° ϕ = 0° ϕ = –90° maximum coplanar strain Increased ortho steric bulk eventually overrides stereoelectronic effects, ground state favors orthogonal orientation Leroux, F. ChemBioChem 2004, 5, 644. Other Causes of Restricted Rotation Bond Length Effects OMe O N Me vs. Me Me N Me ΔG‡ = 30 kcal/mol shorter bond as chiral axis ΔG‡ = 36 kcal/mol t1/2 > 30 years ⬇ t1/2 ~ 800,000 years higher barrier to rotation rC–C = 1.49 Å rC–N = 1.37 Å Also must consider non-axial bond lengths: N N N N Me N S Me N O X = O Me N X X = S Me N S Me Me ‡ Me ‡ Me ΔG (rac) = ΔG (rac) = 27.9 kcal/mol 23.1 kcal/mol key resonance form more ground-state single bond character ➞ longer C–S bond, more readily distorted in coplanar transition state Kashima, C.; Katoh, A. J. Chem. Soc., Perkin Trans. 1980, 1599. Roussel, C.; Adjimi, M.; Chemlal, A.; Djafri, A. J. Org. Chem. 1988, 53, 5076. Determination of Absolute Axial Chirality Cahn-Ingold-Prelog notation (aR, aS) OR helical analogy (M - minus, P - plus) Br 1 MeO CHO OMe OMe 2 1 H Br H Br 2 CHO CHO Cahn-Ingold-Prelog: counter-clockwise = aS helical analogy: clockwise = P Eliel, E. L.; Wilen, S.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley Interscience: New York, 1994, pp. 1119. Examples of Atropisomeric Frameworks C–C bonds C(sp2)–C(sp2) C(sp2)–C(sp3) C(sp3)–C(sp3) Me O Cl i-Pr Cl N i-Pr H Me Me HO Cl H Cl ‡ ‡ ΔG (rac) = 33.3 kcal/mol ΔG (rac) = 23.5 kcal/mol C–N bonds C–O bonds C–S bonds O O N O S S O N N Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.; Sivarugu, J. Chem. Rev. 2015, 115, 11239. Atropisomers in Nature and Organic Synthesis Natural products Pharmaceuticals HO Me HO MeO HO Me OH O MeO H N 2 O O MeO Cl NHAc O O Vancomycin HO Cl OH O O antibiotic “of last resort” O H H H MeO N N N H N NH O H H H O H O NHMe Colchicine NH O O H Gout/anti-inflammatory Me HO C NH2 2 OH OH Me HO Ligands Organocatalysts Boc O Et H HN t-Bu HO NBoc O O O H PAr2 (R)-DTBM- HO P N O PAr2 OMe SEGPHOS O OH t-Bu H O Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.; Sivarugu, J. Chem. Rev. 2015, 115, 11239. Atropisomers Can Exhibit Potent Bioactivity 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 Eudysmic ratio: fold change in potency (cytotoxicity) between two enantiomers of an inhibitor Eudysmic ratio for (–)-gossypol to (+)-gossypol: 10:1 Pellecchia, M. et al. J. Med. Chem. 2010, 53, 4166. Atropisomeric Representation in Pharmaceuticals O NH MeO N N CO H Br S 2 S MeO N N Me MeO O NHAc N O N MeO Me Telenzepine Colchicine Lesinurad treatment for peptic ulcers Gout/anti-inflammatory urate transport inhibitor S S Me Me O O t1/2 (20 °C) ~ 1,000 years O O N N NH HN MeN N N NMe (+)-isomer: 500-fold greater activity Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Atropisomeric Representation in Pharmaceuticals O NH MeO N N CO H Br S 2 S MeO N N Me MeO O NHAc N O N MeO Me Telenzepine Colchicine Lesinurad treatment for peptic ulcers Gout/anti-inflammatory urate transport inhibitor examples exist of FDA-approved compounds with minimal or no detectable racemization Historically among chiral drugs, axial chirality is dramatically underrepresented Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Considerations in Small Molecule Racemization O O O –H+ + H+ H H ● bimolecular ● multi-step ● dependent on environmental conditions (pH, etc.) ● unimolecular ● single-step ● potentially accessible via ambient temperature thermal activation Potential racemization has overall suppressed efforts to design drugs with chiral atropisomeric axes Laplante, S.