Methods and Applications in Atroposelective Chemistry

Home , Atropisomer

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

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

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

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 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

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. et. al. J. Med. Chem. 2011, 54, 7005. A Toolkit and a Renaissance

Boehringer Ingelheim and FDA (2011): collaboration to develop practical guide for atropisomerism in medicinal chemistry

Computational developments have enabled early-stage prediction of racemization rates based on structural elements

Laplante, S. et. al. J. Med. Chem. 2011, 54, 7005. Class I Atropisomers

‡ t1/2 < 1 min, ΔG < ~20 kcal/mol

Extremely rapid interconversion, cannot isolate in stereochemically enriched form

Often unaccounted for during synthetic planning!

Product of early stage reactions such as SNAr, cross-coupling, amide coupling, etc. (chiral axis arises downstream as functionality added)

t-Bu Top 200 Small Molecule Pharmaceuticals by Retail Sales in 2018 F Compiled and Produced by the Njarðarson Group (The University of Arizona) ● 1 Eliquis 2 Revlimid 3 Xarelto 4 Imbruvica 5 Lyrica 6 Genvoya 7 Tecfdera 8 Ibrance 9 Januvia 10 Xtandi 11 Triumeq 12 Zytiga 13 Mavyret 14 Gilenya 15 Advair 16 Truvada 17 Invega Sustenna 18 Symbicort 19 Spiriva 20 Jardiance estimated that ~15% F N (Apixaban) (Lenalidomide) (Rivaroxaban) (Ibrutinib) (Pregabalin) (Elvitegravir, Cobicistat, Emtricitabine, TAF) (Dimethyl Fumarate) (Palbociclib) (Sitagliptin) (Enzalutamide) (Abacavir, Dolutegravir, Lamivudine) (Abiraterone Acetate) (Glecaprevir, Pibrentasvir) (Fingolimod) (Salmeterol) (Emtricitabine, Tenofovir Disoproxil) (Paliperidone Palmitate) (Budesonide, Formoterol) (Tiotropium) (Empaglifozin)

$9.871 Billion $9.685 Billion $6.58 Billion $6.205 Billion $5.216 Billion $4.624 Billion $4.296 Billion $4.118 Billion $3.686 Billion $3.649 Billion $3.522 Billion $3.498 Billion $3.438 Billion $3.341 Billion $3.33 Billion $2.997 Billion $2.928 Billion $2.926 Billion $2.726 Billion $2.309 Billion Cardiovascular Diseases Oncology Cardiovascular Diseases Oncology Neurological Disorders Infectous Diseases Neurological Disorders Oncology Diabetes Oncology Infectous Diseases Oncology Infectous Diseases Neurological Disorders Respiratory Disorders Infectous Diseases Neurological Disorders Respiratory Disorders Respiratory Disorders Diabetes 21 Velcade 22 Sprycel 23 Janumet 24 Lipitor 25 Tivicay 26 Jentadueto 27 Alimta 28 Pomalyst 29 Afnitor 30 Nexium 31 Epclusa 32 Symtuza 33 Tasigna 34 Aubagio 35 Tagrisso 36 Cialis 37 Breo Ellipta 38 Prograf 39 Sensipar 40 Xeljanz H S (Bortezomib) (Dasatinib) (Metformin, Sitagliptin) (Atorvastatin) (Dolutegravir) (Linagliptin) (Pemetrexed) (Pomalidomide) (Everolimus) (Esomeprazole) (Sofosbuvir, Velpatasvir) (Darunavir, Cobicistat) (Nilotinib) (Terifunomide) (Osimertinib) (Tadalafl) (Fluticasone Furoate ) (Tacrolimus) (Cinacalcet) (Tofacitinib) of FDA approved drugs N $2.283 Billion $2.275 Billion $2.228 Billion $2.207 Billion $2.18 Billion $2.154 Billion $2.133 Billion $2.04 Billion $2.02 Billion $2.400 Billion $1.966 Billion $1.955 Billion $1.874 Billion $1.861 Billion $1.86 Billion $1.852 Billion $1.847 Billion $1.785 Billion $1.774 Billion $1.773 Billion Oncology Oncology Diabetes Cardiovascular Diseases Infectous Diseases Diabetes Oncology Oncology Oncology Gastrointestnal Disorders Infectous Diseases Infectous Diseases Oncology Neurological Disorders Oncology Sexual Health Respiratory Disorders Immunology Hormonal Disorders Immunology 41 Pradaxa 42 Latuda 43 Plavix 44 Otezla 45 Odefsey 46 Descovy 47 Gleevec 48 Farxiga 49 Abilify Maintena 50 Crestor 51 Ventolin 52 Mirena Family 53 Brilinta 54 Abraxane 55 Myrbetriq 56 Pulmicort 57 Galvus 58 Zetia 59 Orkambi 60 Keppra S (Dabigatran Etexilate) (Lurasidone) (Clopidogrel) (Apremilast) (Emtricitabine, Rilpivirine, TAF) (Emtricitabine, TAF) (Imatinib) (Dapaglifozin) (Aripiprazole) (Rosuvastatin) (Albuterol) (Levonorgestrel) (Ticagrelor) (Paclitaxel Protein Bound) (Mirabegron) (Budesonide) (Vildagliptin) (Ezetimibe) (Lumacaftor, Ivacaftor) (Levetiracetam) are Class I $1.679 Billion $1.648 Billion $1.627 Billion $1.608 Billion $1.598 Billion $1.581 Billion $1.561 Billion $1.514 Billion $1.491 Billion $1.433 Billion $1.377 Billion $1.342 Billion $1.321 Billion $1.292 Billion $1.287 Billion $1.286 Billion $1.284 Billion $1.271 Billion $1.262 Billion $1.254 Billion Blood Disorders Neurological Disorders Cardiovascular Diseases Dermatology Infectous Diseases Infectous Diseases Oncology Diabetes Neurological Disorders Cardiovascular Diseases Respiratory Disorders Sexual Health Cardiovascular Diseases Oncology Renal Disorders Respiratory Disorders Diabetes Cardiovascular Diseases Respiratory Disorders Neurological Disorders 61 Benicar 62 Vimpat 63 Harvoni 64 Opsumit 65 Atripla 66 Biktarvy 67 Promacta 68 Tafnlar + Mekinist 69 Isentress 70 Celebrex 71 Norvasc 72 Exjade 73 Chantix 74 Sutent 75 Esbriet 76 Faslodex 77 Entresto 78 Co-Diovan 79 Kyprolis 80 Kalydeco F O O (Olmesartan Medoxomil) (Lacosamide) (Ledipasvir, Sofosbuvir) (Macitentan) (Efavirenz, Emtricitabine, TDF) (Bictegravir, Emtricitabine, TAF) (Eltrombopag) (Dabrafenib, Trametinib) (Raltegravir) (Celecoxib) (Amlodipine) (Deferasirox) (Varenicline) (Sunitinib) (Pirfenidone) (Fulvestrant) (Sacubitril, Valsartan) (Hydrochlorothiazide, Valsartan) (Carflzomib) (Ivacaftor)

$1.242 Billion $1.241 Billion $1.222 Billion $1.215 Billion $1.206 Billion $1.184 Billion $1.174 Billion $1.155 Billion $1.14 Billion $1.129 Billion $1.111 Billion $1.099 Billion $1.084 Billion $1.049 Billion $1.041 Billion $1.028 Billion $1.028 Billion $1.023 Billion $1.012 Billion $1.008 Billion N Cardiovascular Diseases Neurological Disorders Infectous Diseases Cardiovascular Diseases Infectous Diseases Infectous Diseases Oncology Oncology Infectous Diseases Ant-Infammatory Cardiovascular Diseases Oncology Neurological Disorders Oncology Autoimmune Disorders Oncology Cardiovascular Diseases Cardiovascular Diseases Oncology Respiratory Disorders 81 Exforge 82 Jakavi 83 Letairis 84 Bridion 85 Doliprane 86 Nuvaring 87 Lupron 88 Rexulti 89 Vesicare 90 Lixiana 91 Invokamet 92 Lamictal 93 Lynparza 94 Premarin Family 95 Votrient 96 Brintellix 97 Edurant 98 Samsca 99 Nexavar 100 Flovent (Amlodipine, Valsartan) (Ruxolitinib) (Ambrisentan) (Sugammadex) (Acetaminophen) (Ethinyl Estradiol, Etonogestrel) (Leuprolide) (Brexpiprazole) (Solifenacin) (Edoxaban) (Canaglifozin, Metformin) (Lamotrigine) (Olaparib) (Conjugated Estrogens) (Pazopanib) (Vortioxetine) (Rilpivirine) (Tolvaptan) (Sorafenib) (Fluticasone Propionate)

$1.002 Billion $977 Million $943 Million $917 Million $911 Million $902 Million $892 Million $884 Million $884 Million $881 Million $881 Million $865 Million $834 Million $832 Million $828 Million $826 Million $816 Million $810 Million $805 Million $791 Million Cardiovascular Diseases Oncology Cardiovascular Diseases Neurological Disorders Ant-Infammatory Sexual Health Oncology Neurological Disorders Renal Disorders Blood Disorders Diabetes Neurological Disorders Oncology Sexual Health Oncology Neurological Disorders Infectous Diseases Cardiovascular Diseases Oncology Respiratory Disorders 101 Synthroid 102 Symdeko 103 Avodart 104 Augmentin 105 Ranexa 106 Zoladex 107 Baraclude 108 Noxafl 109 Risperdal Consta 110 Aprovel 111 Adempas 112 YAZ 113 Tarceva 114 Toprol 115 Cymbalta 116 Singulair 117 Glucobay 118 Nexplanon 119 Viagra 120 Adalat (Levothyroxine) (Tezacaftor, Ivacaftor) (Dutasteride) (Amoxicillin, Clavulanate) (Ranolazine) (Goserelin) (Entecavir) (Posaconazole) (Risperidone) (Irbesartan, Hydrochlorothiazide) (Riociguat) (Drospirenone, Ethinyl Estradiol) (Erlotinib) (Metoprolol) (Duloxetine) (Montelukast) (Acarbose) (Etonogestrel) (Sildenafl) (Nifedipine) NH2 ● another ~10% of drugs

$776 Million $769 Million $761 Million $758 Million $758 Million $752 Million $744 Million $742 Million $737 Million $737 Million $731 Million $722 Million $714 Million $712 Million $708 Million $708 Million $704 Million $703 Million $692 Million $690 Million N Hormonal Disorders Genetc Disorders Renal Disorders Ant-Bacterial Cardiovascular Diseases Oncology Infectous Diseases Ant-Fungal Neurological Disorders Cardiovascular Diseases Cardiovascular Diseases Sexual Health Oncology Cardiovascular Diseases Neurological Disorders Respiratory Disorders Diabetes Sexual Health Sexual Health Cardiovascular Diseases 121 Nexgard 122 Ganfort 123 Cellcept 124 Concerta 125 Uptravi 126 Complera 127 Azilva 128 Stribild 129 Alecensa 130 Bendeka 131 Anoro Ellipta 132 Aspirin Cardio 133 Vidaza 134 Lenvima 135 Dexilant 136 Emend 137 Sulperazon 138 Allegra 139 Bystolic 140 Ambisome (Afoxolaner) (Bimatoprost) (Mycophenolate Mofetil) (Methylphenidate) (Selexipag) (Rilpivirine, Emtricitabine, TDF) (Azilsartan) (Cobicistat, Elvitegravir, Emtricitabine, TDF) (Alectinib) (Bendamustine) (Umeclidinium, Vilanterol) (Acetylsalicylic Acid) (Azacitidine) (Lenvatinib) (Dexlansoprazole) (Aprepitant) (Cefoperazone, Sulbactam) (Fexofenadine) (Nebivolol) (Amphotericin B)

$689 Million $684 Million $676 Million $663 Million $663 Million $653 Million $647 Million $644 Million $643 Million $642 Million $633 Million $629 Million $617 Million $617 Million $617 Million $615 Million $613 Million $588 Million $586 Million $571 Million Parasitc Infectons Ophthalmology Immunology Neurological Disorders Cardiovascular Diseases Infectous Diseases Cardiovascular Diseases Infectous Diseases Oncology Oncology Respiratory Disorders Cardiovascular Diseases Oncology Oncology Gastrointestnal Disorders Oncology Renal Disorders Respiratory Disorders Cardiovascular Diseases Infectous Diseases 141 Pantoprazole 142 Invanz 143 Combigan 144 Tracleer 145 Inomax 146 Kombiglyze 147 Lo Loestrin 148 Ninlaro 149 Xalkori 150 Iressa 151 Takecab 152 Travoprost Group 153 Depakine 154 Vytorin 155 Nesina 156 Vraylar 157 Amitiza 158 Tamifu 159 Neupro 160 Jevtana are Class I-proatropisomeric Dabrafenib (Pantoprazole) (Ertapenem) (Brimonidine, Timolol) (Bosentan) (Nitric Oxide) (Saxagliptin, Metoprolol) (Norethindrone Acetate, Ethinyl Estradiol) (Ixazomib) (Crizotinib) (Geftinib) (Vonoprazan) (Travoprost) (Valproate) (Ezetimibe, Simvastatin) (Alogliptin) (Cariprazine) (Lubiprostone) (Oseltamivir) (Rotigotine) (Cabazitaxel)

$569 Million $554 Million $551 Million $546 Million $543 Million $543 Million $528 Million $526 Million $524 Million $518 Million $518 Million $517 Million $511 Million $497 Million $496 Million $487 Million $479 Million $478 Million $478 Million $477 Million Gastrointestnal Disorders Ant-Bacterial Ophthalmology Cardiovascular Diseases Respiratory Disorders Diabetes Sexual Health Oncology Oncology Oncology Gastrointestnal Disorders Ophthalmology Neurological Disorders Cardiovascular Diseases Diabetes Neurological Disorders Gastrointestnal Disorders Ant-Viral Neurological Disorders Oncology 161 Onf 162 Zyprexa 163 Uloric 164 Androgel 165 Sandimmune 166 Zepatier 167 Ultibro Breezhaler 168 Vasostrict 169 Hyzaar 170 Frontline 171 Strattera 172 Memary 173 Voltaren 174 Kuvan 175 Xeloda 176 Duodopa 177 Reyataz 178 Flomax 179 Medrol 180 Decapeptyl (Clobazam) (Olanzapine) (Febuxostat) (Testosterone) (Dexmethylphenidate) (Elbasvir, Grazoprevir) (Indacaterol, Glycopyrronium) (Vasopressin) (Losartan, Hydrochlorothiazide) (Fipronil) (Atomoxetine) (Memantine) (Diclofenac) (Sapropterin) (Capecitabine) (Carbidopa, Levodopa) (Atazanavir) (Tamsulosin) (Methylprednisolone) (Triptorelin) (chiral axis readily interconverts

$475 Million $471 Million $471 Million $469 Million $463 Million $455 Million $454 Million $454 Million $453 Million $451 Million $451 Million $450 Million $445 Million $434 Million $431 Million $430 Million $427 Million $427 Million $426 Million $421 Million oncology Neurological Disorders Neurological Disorders Autoimmune Disorders Hormonal Disorders Neurological Disorders Infectous Diseases Respiratory Disorders Renal Disorders Cardiovascular Diseases Parasitc Infectons Neurological Disorders Neurological Disorders Ant-Infammatory Renal Disorders Oncology Neurological Disorders Infectous Diseases Renal Disorders Immunology Hormonal Disorders 181 Seroquel 182 Vosevi 183 Multaq 184 Canasa 185 Vfend 186 Sevofurane 187 Injectafer 188 Amaryl 189 Incruse Ellipta 190 Nasonex 191 Bosulif 192 Cubicin 193 Halaven 194 Ambien 195 Aricept 196 Stivarga 197 Viibryd 198 Atozet 199 Tenelia 200 Madopar (Quetiapine) (Sofosbuvir, Velpatasvir, Voxilaprevir) (Dronedarone) (Mesalazine) (Voriconazole) (Sevofurane) (Ferric Carboxymaltose) (Glimepiride) (Umeclidinium) (Mometasone Furoate) (Bosutinib) (Daptomycin) (Eribulin) (Zolpidem) (Donepezil) (Regorafenib) (Vilazodone) (Ezetimibe, Atorvastatin) (Teneligliptin) (Levodopa, Benserazide) under biological conditions) $404 Million $396 Million $396 Million $394 Million $393 Million $391 Million $387 Million $379 Million $378 Million $376 Million $375 Million $367 Million $365 Million $363 Million $357 Million $356 Million $350 Million $347 Million $347 Million $344 Million Neurological Disorders Infectous Diseases Cardiovascular Diseases Gastrointestnal Disorders Ant-Fungal CNS And Anesthesia Blood Disorders Diabetes Respiratory Disorders Respiratory Disorders Oncology Ant-Bacterial Oncology Neurological Disorders Neurological Disorders Oncology Neurological Disorders Cardiovascular Diseases Diabetes Neurological Disorders

2 chiral axes, no separable diastereomers Key Oncology Neurological Disorders Diabetes Cardiovascular Diseases Infectous Diseases Respiratory Disorders Immunology Blood Disorders Sexual Health Miscellaneous

2018 sales data obtained from LePro PharmaCompass OPC Private Limited

Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Laplante, S. et. al. J. Med. Chem. 2011, 54, 7005. Class I Atropisomers

‡ t1/2 < 1 min, ΔG < ~20 kcal/mol

Class I compounds can exhibit heightened binding/potency from one axial orientation

Overlooked aspect in design of higher performance analogs

t-Bu F F N H S BRAF target N S O O F N binding

NH N 2

atroposelective binding observed despite rapid axial racemization!

Foster, S. A. et al. Cancer Cell 2016, 4, 477. Class III Atropisomers

‡ t1/2 > 1 year, ΔG > 30 kcal/mol

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

Indefinitely stable, can be developed and applied like point chiral drugs

Note: additional point chirality may be required to favor one diastereomer, stabilize chiral axis

Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Laplante, S. et. al. J. Med. Chem. 2011, 54, 7005. Class III Atropisomers

‡ t1/2 > 1 year, ΔG > 30 kcal/mol

MeO

MeO NHAc

O MeO

MeO

O MeO

‡ ΔG (rac) ~ 22 kcal/mol (racemizes in minutes)

Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Class II Atropisomers

‡ t1/2 ~ minutes–days, ΔG ~ 20–30 kcal/mol

Most challenging class for pharmaceutical development (almost never clinically successful)

● Prior to widespread computational modeling, challenging to predict

● Difficult preparation and unconventional pharmacokinetic profiles

Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Laplante, S. et. al. J. Med. Chem. 2011, 54, 7005. Class II Atropisomers

‡ t1/2 ~ minutes–days, ΔG ~ 20–30 kcal/mol

Most challenging class for pharmaceutical development (almost never clinically successful)

Best strategy: redesign as either Class III (best case) or Class I

OH OH O O O N O N structural O MeN MeN Me overhaul S O N S O N Me N i-Pr N i-Pr H

‡ ‡ ΔG (rot) = 24.6 kcal/mol ΔG (rot) = 20.1 kcal/mol observable atropisomers no detected atropisomers (Class I) enhanced ADMET properties

Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Laplante, S. et. al. J. Med. Chem. 2011, 54, 7005. Other Challenges: Detection and Purification

Common methods:

NMR linewidth X-ray Enzyme binding analysis crystallography studies

+ – SA

Only useful for diastereomer Kinetic resolution, equilibration rates non-preparative

Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Laplante, S. et. al. J. Med. Chem. 2011, 54, 7005. Other Challenges: Detection and Purification

Common methods:

Chiral HPLC

Ideal for enantiotopic atropisomeric compounds

Considerable effort must be spent on screening conditions (frequently requires low-temperature operations)

May not translate to preparative or process-scale conditions May not translate to process scale

Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Laplante, S. et. al. J. Med. Chem. 2011, 54, 7005. Other Challenges: Synthesis

To avoid setbacks from Class II compounds: simply increase ortho steric bulk ➞ Class III!

Not so fast…

OH OH O O O N O N structural O MeN MeN Me overhaul S O N S O N Me N i-Pr N i-Pr H

‡ ‡ ΔG (rot) = 24.6 kcal/mol ΔG (rot) = 20.1 kcal/mol observable atropisomers no detected atropisomers (Class I) enhanced ADMET properties

Not always a simple retrosynthetic disconnection!

If bond constructed in early stage, must overhaul entire route

Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Laplante, S. et. al. J. Med. Chem. 2011, 54, 7005. Other Challenges: Synthesis

To avoid setbacks from Class II compounds: simply increase ortho steric bulk ➞ Class III!

Not so fast…

Greater hindrance Challenging formation limits axial rotation of highly congested bond

New methods for late-stage, catalyst-controlled atroposelective synthesis are desirable

Toenjes, S.; Gustafson, J. Future Med. Chem. 2018, 10, 4109. Laplante, S. et. al. J. Med. Chem. 2011, 54, 7005. 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 Common Strategies in Atropisomer Synthesis

kinetic resolution

atroposelective R annulation

R' R'

Zilate, B.; Castgrogiovanni, A.; Sparr, C. ACS Catal. 2018, 8, 2981. Bringmann, G.; Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384. Organocatalytic Atroposelective Aldol Reactions

CHO N N N N N CHO H H O catalyst (5 mol%) O

CDCl3, 25 °C, 68 h

74% yield, 98% ee point-to-axial chirality transfer via Z-configured dienamine

N CHO N N HO O N N Me H H N(i-Pr)2 catalyst (5 mol%) Me

O KHCO3 Me CDCl , 25 °C, 30 min Me i-Pr 3 O N then NaBH4/EtOH 81% yield, 98% ee i-Pr

Faseke, V. C.; Sparr, C. Angew. Chem. Int. Ed. 2016, 55, 7261. Link, A.; Sparr, C. Angew. Chem. Int. Ed. 2014, 53, 5458. Common Strategies in Atropisomer Synthesis

kinetic resolution

atroposelective R annulation

R' R'

atroposelective DKR and arene functionalization desymmetrizations

Bringmann, G.; Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384. The Bringmann Lactone Concept

O O CONu Nu–H Nu–H CONu OH chiral cat. O O chiral cat. OH

NO2

O O HO catalyst (5 mol%) Me Me O Br O PhCF , 25 °C, 6 h Br NO2 3 OH

OMe OMe

99% yield, 96% ee

N H H N N CF3 H MeO S

CF3 N thiourea catalyst

Yu, C.; Huang, H.; Li, X.; Zhang, Y.; Wang, W. J. Am. Chem. Soc. 2016, 138, 6956. Bringmann, G.; Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384. Dynamtic Kinetic Resolution via Atroposelective Bromination

R R 10 mol% peptide cat. Me N N N-bromophthalimide (3 eq.) CO2H 2 CO2H Br Br NH O BocHN O O CHCl3/acetone (97:3) 25 °C, 18 h i-Pr NMe2 OH OH peptide catalyst Br

OMe O N 2 amide-mediated electrophilic bromination CO2H CO2H CO2H Br Br Br Br Br Br NMe2 i-Pr H OH OH OH O Br O N Br Br Br H 80% yield, 97:3 er 85% yield, 97:3 er 70% yield, 96:4 er O H Ph Br N O O F H H N O MeN CO2H BocHN CO2H Me CO2H Me Me Br Br Br Br Br Br pre-organization via

OH OH OH hydrogen bonding and Br Br Br salt bridge stabilization 65% yield, 96.5:3.5 er 85% yield, 87:13 er 77% yield, 85:15 er

Gustafson, J. L.; Lim, D.; Miller, S. J. Science 2010, 328, 1251. Common Strategies in Atropisomer Synthesis

kinetic resolution R

atroposelective atroposelective R cross-coupling annulation + R' R'

R' atroposelective DKR and arene functionalization desymmetrizations

Bringmann, G.; Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384. Common Strategies in Atropisomer Synthesis

M R M + R R' R + X + R' R' LG* redox-neutral

chiral couplings oxidative leaving groups couplings

R enantioselective

diastereoselective R'

chiral ortho chiral bridge substituent planar chiral auxiliary R

R * R + + * R' R'

Fe(CO)3 R' Suzuki-Miyaura, Ullmann-Goldberg, etc.

OBn OMe Lipshutz (2010):

OBn OMe I O PdI2 (4 mol%) CH2OTIPS BnO O SPhos (8 mol%) BnO CO2Ar NTs K PO (3 equiv.) NTs CH2OTIPS 3 4 B(OH) OBn Me n-BuOH, 25 °C, 24 h 2 OBn Me intramolecular -stacking π 72% yield, 11:1 dr distal chiral directing group (Ar = 1-naphthyl)

OH OMe

Me PCy 2 HO Me MeO OMe NH

OH Me SPhos (+)-korupensamine B 18 steps, 7% overall yield

Huang, S.; Petersen, T. B.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 14021. Common Strategies in Atropisomer Synthesis

M R M + R R' R + X + R' R' LG* redox-neutral

chiral couplings oxidative leaving groups couplings

R enantioselective

diastereoselective R'

chiral ortho chiral bridge substituent planar chiral auxiliary R

R * R + + * R' R'

Fe(CO)3 R'

M R M + R R' R + X + R' R' LG* chiral

chiral MLn* catalyst chiral

leaving groups MLn* catalyst

R enantioselective

diastereoselective R'

chiral ortho chiral bridge substituent planar chiral auxiliary R

R * R + + * R' R'

Fe(CO)3 R'

Three years after initial Kumada-Corriu reports (1975):

H MgBr Br Me O Me PPh2 Me Me NiCl2 • ligand (1 mol%) Me Me PPh O 2 H DIOP 32% yield, 2% ee

Further ligand optimization was achieved over the next 14 years:

PPh2 PPh2 NMe2 PPh2 OMe

Fe H Ph2P O Me Fe H H Me PPh2 O Me PPh2 Me PPh2 5% ee 13% ee 40% yield, 50% ee 69% yield, 95% ee

After these successes, no significant reports in redox-neutral cross-coupling over the next decade

Tamao, K.; Minato, A.; Miyake, N.; Matsuda, T.; Kiso, Y. Kumada, M. Chem. Lett. 1975, 4, 133. Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153. Hayashi,T.; Hayashizaki, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 215. Origins of Atroposelective Suzuki-Miyaura: Nicolau’s Vancomycin Synthesis

Design plan for Suzuki-Miyaura:

O C HO D Me HO HO O O O H Me OH N B OH O N H N + 2 O H A OMe O O MeO OMe Cl B O O I OMe 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 O O H Me HO C NH2 2 OH O O OH Me H H HO O N O N N N H H OMe O OMe O Challenge - stereoselective synthesis of AB ring system MeO OH in absence of bridging medium-sized ring HO OMe OMe OMe MeO MeO

Inherent bias for one atropisomer?

Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger, N.; Hughes, R.; Bando, T. Angew. Chem. Int. Ed. 1999, 1, 240. Origins of Atroposelective Suzuki-Miyaura: Nicolau’s Vancomycin Synthesis

O O O C D O O O O Pd(OAc) O H O H O H 2 N N N B OH N N N + Na2CO3 H H H A OMe O OMe O OMe O MeO OMe solvent B MeO OH HO I OMe OMe OMe OMe MeO MeO A B

entry ligand solvent temp (°C) time (h) Yield (%) Ratio (A:B)

1 PPh3 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

First report of catalyst-controlled stereoselective Suzuki-Miyaura biaryl coupling!

Nicolaou, K. C., et. al. Chem. Eur. J. 1999, 5, 2584. Expansion to Intermolecular Enantioselective Protocols

Cammidge (2000):

PPh2 O O PdCl2 (3 mol%) NMe2 B I PPFA (6 mol%) Me H Me Me Me Fe Me CsF (2 equiv.) DME, reflux PPh2 PPFA 1.1 equiv. 60% yield, 85% ee

Buchwald (2000):

Pd2(dba)3 • KenPhos Br O B(OH) 2 (0.2–10 mol%) Me NMe2 P(OEt) Me 2 P(O)(OEt)2 PCy2 K3PO4 (2 equiv.) toluene, 40-80 °C 98% yield, 87% ee KenPhos

Cammidge, A. N.; Crépy, K. V. L. Chem. Commun. 2000, 1723. Yin, J. J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051. Application to Stereoselective Synthesis of Michellamine B (Tang, 2014)

Me OH

O Me OH i-Pr O O Me OH OMe P P t-Bu N O O N MeO OMe O O OMe OH Me HO Me ligand BOPO–R Michellamine B NH anti-HIV activity OH Me OBn OMe

Br OBn OMe Pd(OAc)2 (1 mol%) BOPO CHO ligand (1.2 mol%) Me BOPO CHO K PO (3 equiv.) Me 3 4 toluene/H2O, 35 °C, 12 h OTBS B(OH)2 OTBS 1.1 equiv. 96% yield, 93% ee

First asymmetric synthesis after 20+ years of investigation

Xu, G.; Fu, W.; Liu, G. Senanayake, C. H.; Tang, W. J. Am. Chem. Soc. 2014, 136, 570. Expansion to Other Organometallic Nucleophiles

Espinet (2006): PPh2 Pd (dba) (5 mol%) NMe2 ZnAr Br 2 3 PPFA (20 mol%) Me H Me Me Me Fe Me THF, 60 °C, 24 h PPh2 PPFA 1.5 equiv. 95% yield, 85% ee

Denmark (2014):

Me Me OK Si Me Ph Ph Pd2(dba)3 • KenPhos Me (0.2–10 mol%) N N N N + K PO (2 equiv.) Br 3 4 Ph Ph toluene, 40-80 °C 98% yield, 87% ee ligand

Highly extensive investigation of mechanistic considerations in atroposelective redox-netural coupling

Swapping halide + silanol = identical ee, suggests stereodetermining reductive elimination (supported by DFT)

Genov, M.; Fuentes, B.; Espinet, P.; Pelaz, B. Tetrahedron: Asymmetry 2006, 17, 2593. Denmark, S. E.; Chang, W-T. T.; Houk, K. N.; Liu, P. J. Org. Chem. 2015, 80, 313. Oxidative Couplings: Fundamentals of Radical Approaches

metal catalyst (Cu, V, Ru, etc.) OH chiral ligand OH OH oxidant

dissociation tautomerization

L L L L L L L L Cu Cu Cu Cu O O SET O O

metal catalyst (Cu, V, Ru, etc.) OH chiral ligand OH OH oxidant

OH OH

Cu(NO3)2 OH

(S)-(+)-amphetamine sulfate 2 equiv. (S)-BINOL

85% yield, 95% ee

Brussee, J.; Jansen, A. C. A. Tetrahedron Lett. 1983, 24, 3261. Directing Groups Enhance Efficiency of Oxidative Couplings

CuCl (10 mol%) ligand (11 mol%) OH N H N Et OH Ph OH O2, CH2Cl2, 25 °C, 24 h ligand

yield (%) ee (%)

CO2Me 85 78

CO2Et 77 73

CO2Bn 77 76

CO2t-Bu 69 58 H 89 17 i-Pr 58 5 OBn 95 24

Nakajima, M.; Kanayama, K.; Miyoshi, I.; Hashimoto, S. Tetrahedron 1995, 36, 9519. Kozlowski: Divergent Perylenequinone Syntheses

OAc

MeO CO2Me H N OAc Cu I I OH MeO CO Me N 2 H OH (20 mol%) I OH

I OH O , 25 °C 2 MeO CO2Me OAc preparation: 33% over 5 steps 80% yield, 81% ee (>99% ee after trituration)

Synthetic intermediate to:

O OH O OH O OH O OH MeO MeO MeO MeO OR OH OH

Me OMe Me OMe Me O Me OMe HO OMe Me OMe Me OMe Me O Me OR’ OH OH O MeO MeO MeO O O OH O OH O OH Me O OH

(–)-Calphostins A-D (–)-Phleichrome Cercosporin Hypocrellin

Morgan, B. J.; Dey, S.; Johnson, S. W.; Kozlowski, M. C. J. Am. Chem. Soc. 2009, 131, 9413. Achieving Cross-Selectivity in Oxidative Heterocouplings

OBn Me Me CuCl (20 mol%) OH O O OBn CO2Ph PhBOX (6 mol%) OH N N Yb(OTf) (10 mol%) OH OH 3 Ph Ph O2, THF, –20 °C CO2Ph more better PhBOX electron-rich chelation 95% yield, 85% ee

L L L Yb O Cu n BnO O Cl O OPh

Electronic differentiation required for cross-selectivity

Habaue, S.; Temma, T.; Sugiyama, Y.; Yan, P. Tetrahedron Lett. 2007, 48, 8595. Progress in Oxidative C–H Arylation

i-Pr Pd(OAc)2 (10 mol%) B(OH)2 Me Me H L1 or L2 (10 mol%) i-Pr TEMPO (4 equiv.) or FePc (5 mol%) Me Me S S n-PrOH or DMA, 70 °C L1: 27% yield, 72% ee

L2: 61% yield, 61% ee

O O O

N N S N i-Pr i-Pr O i-Pr Me

L1 L2

Overall, underdeveloped strategy, requires substantial ligand development

Yamaguchi, K.; Kondo, H.; Yamaguchi, J.; Itami, K. Chem. Sci. 2013, 4, 3753. Ullmann-Goldberg: An Elusive Atroposelective Protocol

N I LnCu N N N N N Br thermal

oxidative addition rotation reductive elimination enantiopure racemic high temperatures (>100 °C)

More established than Buchwald-Hartwig for intramolecular, substrate-controlled cases (diastereoselective)

Forcing thermal conditions have prevented intermolecular utility

Frey, J.; Malekafzali, A.; Delso, I.; Choppin, S.; Colobert, F.; Wencel-Delord, J. Angew. Chem. Int. Ed. 2020 (pre-print). The First Atroposelective Intermolcular Ullmann-Goldberg (2020)

Me Me Mes I BF4 Cu(MeCN)4BF4 (10 mol%) N O O Me MeO CONH2 PhBOX (20 mol%) MeO CONH2 N N N H NEt3 (1 equiv.), BF3•(OEt2) (1 equiv.) Ph Ph Me OMe CH2Cl2/DMSO (4:1), 25 °C, 18 h OMe PhBOX 76% yield, >99:1 er

Requirements:

● indoline nucleophiles

● iodonium must contain ortho-amide substituent

Frey, J.; Malekafzali, A.; Delso, I.; Choppin, S.; Colobert, F.; Wencel-Delord, J. Angew. Chem. Int. Ed. 2020 (pre-print). The First Atroposelective Intermolcular Ullmann-Goldberg (2020)

a full mechanistic investigation is still underway

Noteworthy that these Cu catalysts are exceptionally active for C–N coupling

Among strongest positive non-linear effects observed in asymmetric copper catalysis

Frey, J.; Malekafzali, A.; Delso, I.; Choppin, S.; Colobert, F.; Wencel-Delord, J. Angew. Chem. Int. Ed. 2020 (pre-print). Organocatalytic Point-to-Axial Chirality Transfer in Oxidative Coupling

MeO2C OH HO OMe CO2Me 5 mol% (aR)-CPA MeO OH

CH2Cl2, –78 °C, 24 h O 95% yield, 85% ee

i-Pr i-Pr i-Pr i-Pr

i-Pr i-Pr O O O OH O O H

P P MeO2C O O O O i-Pr i-Pr H O OMe

i-Pr i-Pr i-Pr i-Pr (aR)-CPA

Chen, Y.-H.; Cheng, D.-J.; Zhang, J.; Wang, Y.; Liu, X.-Y.; Tan, B. J. Am. Chem. Soc. 2015, 137, 15062. Wang, J.-Z.; Zhou, J.; Xu, C.; Sun, H.; Kürti, L. s.; Xu, Q.-L. J. Am. Chem. Soc. 2016, 138, 5202. 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 Atropospecific Total Synthesis of Tryptorubin A

Tyr

O Ile CO2H NH Me O H N N Trp First approach: late-stage Me O NH amide coupling should enable O Me H Ala N diastereoselective macrocyclization H N NH H 2 O Tyr N

OH Trp

Tryptorubin A peptidic indole alkaloid unknown biological activity

Original structural disclosure: limited consideration of macrocyclic topology

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

O CO2H NH Me O H N N First approach: late-stage Me O NH O Me amide coupling should enable H N diastereoselective macrocyclization H N NH H 2 O N

Tryptorubin A peptidic indole alkaloid unknown biological activity

Original structural disclosure: limited consideration of macrocyclic topology

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

NsHN O O NH2 1. AcCl, MeOH (quant.) OMe HO2C HN 2. PMBOH, DIAD, PBu3 (81%)

3. NsTrp-OH, HATU, NH I DIPEA, DMF (91%) OH PMBO I

prepared in 5 steps 4. CuI/L (cat.)

Cs2CO3, LiOH 5. PivCl, NEt3; MeO C 2 THF/H2O/dioxane; then TFA, Et3SiH O 6. then allyl-OH, HCl DCM (99%) NH O (61%) OAllyl Br NTroc H OPiv O NTroc NH O H O O NsHN N OPiv AgSbF , DTBMP (55%) NHNs 6 H N H Troc Troc O N N 7. DDQ, EtOAc (88%) N PivO H NH OPiv

MeO2C

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

O O OAllyl OAllyl

8. p-BrPhSH, K2CO3; O NH then HATU, Z-Ala-OH CbzHN O O NH DIPEA (66%) NsHN N OPiv Me HN N OPiv 9. Zn, HCl, MeOH (64%) Troc Troc H H O N N O N N PivO PivO NH NH

MeO2C MeO2C

OPiv

10. Boc-Ile-OH, HATU, O CO2Me DIPEA, DCM; O NH H N N s-Bu then morpholine, Pd(PPh3)4; H2N then TFA (30%) HO C O Me 2 H N H N NHCbz H O N

OPiv

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

O O OAllyl OAllyl

8. p-BrPhSH, K2CO3; O NH then HATU, Z-Ala-OH CbzHN O O NH DIPEA (66%) NsHN N OPiv Me HN N OPiv 9. Zn, HCl, MeOH (64%) Troc Troc H H O N N O N N PivO PivO NH NH

MeO2C MeO2C

OPiv

O 10. Boc-Ile-OH, HATU, CO2Me DIPEA, DCM; O NH H N N s-Bu then morpholine, Pd(PPh3)4; H2N then TFA (30%) HO C O Me 2 H N H N NHCbz macrocyclization H O N disfavored

OPiv two aryl rotational axes

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

O O OAllyl OAllyl

8. p-BrPhSH, K2CO3; O NH then HATU, Z-Ala-OH CbzHN O O NH DIPEA (66%) NsHN N OPiv Me HN N OPiv 9. Zn, HCl, MeOH (64%) Troc Troc H H O N N O N N PivO PivO NH NH

MeO2C MeO2C OPiv

OPiv

CO2Me O O 10. Boc-Ile-OH, HATU, CO2Me NH O DIPEA, DCM; O NH torsional N NH H N N s-Bu s-Bu then morpholine, Pd(PPh3)4; equilibration H2N H2N then TFA (30%) HO C O Me 2 H N OPiv H N NHCbz H O macrocyclization HO C N NHCbz O 2 N disfavored better cyclization H N N H Me OPiv proximity H O Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

OPiv OH

CO2Me CO2H O O NH 11. PyAOP, DIPEA NH O MeCN (4%) N NH N NH O s-Bu 12. Pd/C, H2, MeOH; H H2N Me then LiOH, H2O (90%) Me H OPiv OH NH O O O HO2C N NHCbz N NH2

H N Me N N H N H Me H H O O

characterization data inconsistent with reference - synthesis was atroposelective, but absolute stereochemistry wrong!

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

OPiv OPiv

O CO2Me O CO2Me NH NH O 2nd generation O H H N N N N s-Bu s-Bu

H2N H2N HO C O Me HO C O Me 2 H 2 H N N H N NHCbz H N NHCbz H H O O N N H OPiv replace axis with “locking” point chirality OPiv

sp3 center of indoline prevents medium-sized ring torsion

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

OPiv OPiv

TrocN N CO2Me O CO Me Troc H 2 N NH 8. AgSbF6, DTBMP, DCM (62%) Br Troc TrocN N O O H O O Me O O Me H H H N N N NHCbz H N NHCbz H H O O OPiv N N H H OPiv OPiv

O CO2Me O NH prepared in 7 steps 9. Zn, HCl, MeOH/THF/H2O (84%) H N N s-Bu 10. Boc-Ile-OH, HATU; H2N Me HO C O then morpholine, Pd(PPh3)4; 2 H N then TFA (29%) No torsional H N NHCbz H O interconversion! N H OPiv

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

OPiv OH

O CO2Me 11. PyAOP, DIPEA O CO2H NH NH O MeCN (11%) O H H N N N N s-Bu 12. DDQ, TFA/MeCN s-Bu H2N O NH O Me microwave (42%) O Me HO2C H H N 13. Pd/C, H , MeOH; N H N NHCbz 2 H N NH H H 2 then LiOH, H2O(86%) O O N N H OPiv OH

biomimetic? Tryptorubin A

Subsequent genomics suggests 6-mer peptide synthesized ribosomally, downstream conversion is atroposelective

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. Atropospecific Total Synthesis of Tryptorubin A

OPiv OH

Tryptorubin A

Axial chirality doesn’t always resolve serendipitously!

Reisberg, S. H.; Gao, Y.; Walker, A. S.; Helfrich, E. J. N.; Clardy, J.; Baran, P. S. Science 2020, 367, 458. 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