Atropisomerism: Axial Chirality in Nature and Synthesis

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

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

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

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 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

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.

Br O N R OMe MeO R MeO MeO Mg i-Pr O O N R OMe N MeO i-Pr MeO MeO Mg i-Pr MeO Mg

Br Br

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 - Ullmann Homocoupling

OMe MeO O i-Pr Br N MeO Cu N i-Pr MeO O P DMF, 150 °C N i-Pr 40 h MeO MeO O OMe MeO OMe 58% 93:7 dr

Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 3061-3062. Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 3259-3262.

Diastereoselective Aryl-Aryl Coupling Ortho Chiral Auxiliaries - Ullmann Homocoupling

OMe MeO O i-Pr Br N MeO Cu N i-Pr MeO O P DMF, 150 °C N i-Pr 1 h MeO MeO O OMe MeO OMe 56% 62:38 dr

Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 3061-3062. Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 3259-3262. Diastereoselective Aryl-Aryl Coupling Ortho Chiral Auxiliaries - Ullmann Homocoupling

OMe MeO O i-Pr Br N MeO Cu N i-Pr MeO O P DMF, 150 °C N i-Pr 40 h MeO MeO O OMe MeO OMe

OMe Non-selective coupling OMe MeO then MeO O thermodynamic deracemization O

MeO MeO N i-Pr ! N i-Pr M Cu P Cu N i-Pr N i-Pr MeO MeO

O H i-Pr O MeO O O MeO N N OMe M i-Pr H P OMe Cu Cu N i-Pr H N O O H i-Pr Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 3061-3062. Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 3259-3262.

Diastereoselective Aryl-Aryl Coupling Planar Arene-Metal Complexes - Asymmetric Suzuki Coupling

R1 B(OH) 2 1 1 Pd(PPh3)4, Na2CO3 R R + P + M 2 2 MeOH/H2O R OMe MeO R Br Cr(CO)3 (CO)3Cr R2 OMe

Cr(CO)3 syn anti major minor

Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384. Diastereoselective Aryl-Aryl Coupling Planar Arene-Metal Complexes - Asymmetric Suzuki Coupling

R1 B(OH) 2 1 1 Pd(PPh3)4, Na2CO3 R R + P + M 2 2 MeOH/H2O R OMe MeO R Br Cr(CO)3 (CO)3Cr R2 OMe

Cr(CO)3 syn anti

toluene or xylenes

Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384.

Diastereoselective Aryl-Aryl Coupling Planar Arene-Metal Complexes - Asymmetric Suzuki Coupling

R1 B(OH) 2 1 1 Pd(PPh3)4, Na2CO3 R R + P + M 2 2 MeOH/H2O R OMe MeO R Br Cr(CO)3 (CO)3Cr R2 OMe

Cr(CO)3 syn anti

Entry R1 R2 Yield (%) dr (P :M ) toluene or xylenes

1 Me Me 96 100:0

2 Me CH2OH 77 100:0

3 OMe Me 94 97:3

4 CHO Me 95 0:100

5 CHO CHO 43 0:100

6 OMe CHO 85 4:96

7 Me CHO 82 100:0

Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384. Diastereoselective Aryl-Aryl Coupling Planar Arene-Metal Complexes - Asymmetric Suzuki Coupling

R1 B(OH) 2 1 1 Pd(PPh3)4, Na2CO3 R R + P + M 2 2 MeOH/H2O R OMe MeO R Br Cr(CO)3 (CO)3Cr R2 OMe

Cr(CO)3 syn anti

Entry R1 R2 Yield (%) dr (P :M ) toluene or xylenes

1 Me Me 96 100:0

2 Me CH2OH 77 100:0

3 OMe Me 94 97:3

4 CHO Me 95 0:100 o-carbonyl substituents may result in chemical 5 CHO CHO 43 0:100 atropisomerization to the more thermodynamically stable (anti ) product. 6 OMe CHO 85 4:96

7 Me CHO 82 100:0

Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384.

Diastereoselective Aryl-Aryl Coupling Planar Arene-Metal Complexes - Asymmetric Suzuki Coupling

R1 B(OH) 2 1 1 Pd(PPh3)4, Na2CO3 R R + P + M 2 2 MeOH/H2O R OMe MeO R Br Cr(CO)3 (CO)3Cr R2 OMe

Cr(CO)3 syn anti

h!, O Entry R1 R2 Yield (%) dr (P :M ) 2

1 Me Me 96 100:0

2 Me CH2OH 77 100:0

3 OMe Me 94 97:3 R1 R1 P + M 4 CHO Me 95 0:100 R2 OMe MeO R2

5 CHO CHO 43 0:100

6 OMe CHO 85 4:96

7 Me CHO 82 100:0

Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384. Diastereoselective Aryl-Aryl Coupling Planar Arene-Metal Complexes - Asymmetric Suzuki Coupling

OMe H OMe R Ph3P PPh3 Ph3P PPh3 Pd Pd

RS R RS H Cr(CO)3 Cr(CO)3

OMe OMe H R PPh rotation to form the biaryl axis (CO) Cr 3 PPh3 3 Pd during reductive elimination occurs (CO)3Cr Pd PPh3 so as to minimize steric interactions RS PPh3 with the bulky PPh3 ligands. RS R H

H R RS RS P M

OMe OMe (CO)3Cr R (CO)3Cr H

Kamikawa, K.; Uemura, M. Synlett 2000, 7, 938-949.

Diastereoselective Aryl-Aryl Coupling Planar Arene-Metal Complexes - Asymmetric Suzuki Coupling

R3 B(OH) 2 3 3 Pd(PPh3)4, Na2CO3 R R + P + M 2 1 1 2 MeOH/H2O R R R R Br Cr(CO)3 (CO)3Cr R2 R1

Cr(CO)3 syn anti

Entry R1 R2 R3 Yield (%) dr (P :M )

1 OMe Me H 88 100:0

2 OMe CHO H 89 100:0

3 OMe CH2OH H 86 100:0 O 4 OMe Me 85 100:0 O 5 Me H Me 70 85:15

6 OMe H Me 71 71:29

7 Me H OMe 78 97:3

Kamikawa, K.; Uemura, M. Synlett 2000, 7, 938-949. Direct Atroposelective Aryl-Aryl Coupling Enantioselective Coupling

Chiral Leaving Group Influences Chiral Metal Complex Influences Configuration During Configuration During Intermolecular Intermolecular Coupling Coupling

X* X

+ +

Y Y

Oxidative: • Copper * Vanadium MLn MLn •

Redox-Neutral: • Kumada • Suzuki • Aryl-Lead Species * *

Central-to-axial transfer of chirality Central-to-axial transfer of chirality

Enantioselective Aryl-Aryl Coupling Chiral Leaving Groups

R*ONa O O DMF, 50 °C Br N R*O N

Wilson, J. A.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 881-884. Wilson, J. A.; Cram, D. J. J. Org. Chem. 1984, 49, 4930-4943. Enantioselective Aryl-Aryl Coupling Chiral Leaving Groups

O R*ONa THF, -20 °C O O DMF, 50 °C 1-10 h N Br N R*O N M OMe +

Li OMe

Wilson, J. A.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 881-884. Wilson, J. A.; Cram, D. J. J. Org. Chem. 1984, 49, 4930-4943.

Enantioselective Aryl-Aryl Coupling Chiral Leaving Groups

O R*ONa THF, -20 °C O O DMF, 50 °C 1-10 h N Br N R*O N M OMe +

Li OMe

N R* = O O H O MeO bornyl (R )-menthyl N quininyl H H O N !-fenchyl

MeO quinidinyl O

N Wilson, J. A.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 881-884. Wilson, J. A.; Cram, D. J. J. Org. Chem. 1984, 49, 4930-4943. Enantioselective Aryl-Aryl Coupling Chiral Leaving Groups

O R*ONa THF, -20 °C O O DMF, 50 °C 1-10 h N Br N R*O N M OMe +

Li OMe

N R* = O O H O MeO bornyl (R )-menthyl 67% yield 68% yield N 8% ee >95% ee quininyl H 20% yield H 87% ee O N !-fenchyl 88% yield MeO quinidinyl O 77% ee 22% yield -84% ee N Wilson, J. A.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 881-884. Wilson, J. A.; Cram, D. J. J. Org. Chem. 1984, 49, 4930-4943.

Enantioselective Aryl-Aryl Coupling Chiral Leaving Groups - Menthol

O OMe CO R MgBr 2 MgBr

PhH, 80 °C THF, -20 °C

OMe P M CO2R CO2R

% Yield % ee R % Yield % ee

95 80 i-Pr 92 97

93 76 (R )-menthyl 81 98

74 91 (R )-phenylethyl 85 91

Wilson, J. A.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 881-884. Wilson, J. A.; Cram, D. J. J. Org. Chem. 1984, 49, 4930-4943. Enantioselective Aryl-Aryl Coupling Chiral Leaving Groups - Menthol

RL R R H M non-chelation OR Br OR control

O O O Mg O Mg H R Br R RM L

chelation R control L RM H Br R L RM naphO H Br i-Pr O Mg OR H RL O Mg OR RM O

OMe O

OMe M P CO2R CO2R

Wilson, J. A.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 881-884. Wilson, J. A.; Cram, D. J. J. Org. Chem. 1984, 49, 4930-4943.

Enantioselective Aryl-Aryl Coupling Oxidative Homocoupling - Copper

• Copper-amine complexes are the most widely investigated due to the ease of ligand screening.

CO2Me CuI (2-10 mol%) CO2Me diamine L* (2-10 mol%) OH M O , CH Cl OH OH 2 2 2 48 h

CO2Me

Ligand Screen

H 1 Ph Ph Et N R N NH 2 H2N NH2 H2N NH2 Ph R N H R1 N

N N N R2

Li, X.; Yang, J.; Kozlowski, M. Org. Lett. 2001, 3(8), 1137-1140. Enantioselective Aryl-Aryl Coupling Oxidative Homocoupling - Copper

• Copper-amine complexes are the most widely investigated due to the ease of ligand screening.

CO2Me CuI (2-10 mol%) CO2Me diamine L* (2-10 mol%) OH M O , CH Cl OH OH 2 2 2 48 h

CO2Me

Ligand Screen

H N R1 Ph Ph Et N NH 2 H2N NH2 H2N NH2 Ph R N H R1 N

N N N R2

Li, X.; Yang, J.; Kozlowski, M. Org. Lett. 2001, 3(8), 1137-1140.

Enantioselective Aryl-Aryl Coupling Oxidative Homocoupling - Copper

• Copper-amine complexes are the most widely investigated due to the ease of ligand screening.

CO2Me CuI (2-10 mol%) CO2Me diamine L* (2-10 mol%) OH M O , CH Cl OH OH 2 2 2 48 h

CO2Me

Ligand Screen

% Yield % ee R1 1 2 N R = R = H 60 91 R1 = H, R2 = Me 53 79 R1 = R2 = Me 43 3 N R1 = R2 = Bn 72 22 2 1 2 R R = R = CH2CF3 NR

Li, X.; Yang, J.; Kozlowski, M. Org. Lett. 2001, 3(8), 1137-1140. Enantioselective Aryl-Aryl Coupling Oxidative Homocoupling - Copper

• Copper-amine complexes are the most widely investigated due to the ease of ligand screening.

CO2Me CuI (2-10 mol%) CO2Me diamine L* (2-10 mol%) OH M O , CH Cl OH OH 2 2 2 48 h CO Me H 2 N rotation of aromatic ring H O 2 II O2 away from ligand and HO Cu tautomerization to binol N H O H H cat CO2Me MeO N O H CuII N O MeO O N I open Cu H O H N MeO N H H O I Cu cat O N H H cat-Sub

blocked

Li, X.; Yang, J.; Hewgley, B.; Mulrooney, C. A.; Yang, J.; Kozlowski, M. J. Org. Chem. 2003, 68, 5500-5511.

Enantioselective Aryl-Aryl Coupling Oxidative Homocoupling - Vanadium

R1 R3

R1 R3 VO(acac)2, O2 R2 OH 2 CH Cl R OH R2 OH 2 2

R1 R3

Entry R1 R2 R3 % Yield

1 H H H 92

2 Br H H 90

3 H OMe H 76

4 H H CO2Me 35

Mechanism unknown

Hwang, D.-R.; Chen, C.-P.; Uang, B.-J. Chem. Commun. 1999, 1207-1208. Chu, C.-Y.; Hwang, D.-R.; Wang, S.-K.; Uang, B.-J. Chem. Commun. 2001, 980-981. Chu, C.-Y.; Uang, B.-J. Tetrahedron: Asymm. 2003, 14, 53-55. Enantioselective Aryl-Aryl Coupling Oxidative Homocoupling - Vanadium

R1 R3

R1 R3 catalyst, O2 R2 OH M 2 TMSCl or TMSOTf R OH R2 OH CH2Cl2 R1 R3

Entry R1 R2 R3 % Yield % ee

Bn O 1 H H H 82 51

N O 2 Br H H 91 51 V H 3 H OMe H 50 51 O O

Me 4 H H CO2Me trace --- catalyst Mechanism unknown

Enantioselective Aryl-Aryl Coupling Oxidative Homocoupling - Vanadium

R1 R3

R1 R3 catalyst, O2 R2 OH M TMSCl or TMSOTf R2 OH R2 OH CH2Cl2 R1 R3

i-Bu O Entry R1 R2 R3 % Yield % ee N O 1 H H H 62 90 V O O 2 Br H H 98 90 O O 3 H OMe H 95 95 V O 4 H OEt H 99 96 N O 5 H On-Bu H 99 94 i-Bu O 6 H OBn H 80 95 catalyst 7 H H OBn trace ---

Mechanism unknown

Luo, Z.; Liu, Q.; Gong, L.; Cui, X.; Mi, A.; Jiang, Y. Angew. Chem. I. E. 2002, 41(23), 4532-4535. Enantioselective Aryl-Aryl Coupling Redox-Neutral Coupling - Kumada Cross-Coupling

3 R1 R Ph2P Fe Br 4-10 mol% R1 P + 2 NiBr2 (2-5 mol %) R Et2O/toluene MgBr < -15 °C R2

Entry R1 R2 R3 % Yield % ee

1 Me Me OMe 69 95

2 Me H OMe 25 16

3 H Me OMe 92 83

4 H Me OEt 82 68

5 H Me H 81 1

Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153-8156.

Enantioselective Aryl-Aryl Coupling Redox-Neutral Coupling - Kumada Cross-Coupling

3 R1 R Ph2P Fe Br 4-10 mol% R1 P + 2 NiBr2 (2-5 mol %) R Et2O/toluene MgBr < -15 °C R2

Entry R1 R2 R3 % Yield % ee

1 Me Me OMe 69 95 Me Br Ph

2 Me H OMe 25 16 MeO P Fe Mg 3 H Me OMe 92 83 R2 4 H Me OEt 82 68 Ph

5 H Me H 81 1

Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153-8156. Enantioselective Aryl-Aryl Coupling Redox-Neutral Coupling - Suzuki Cross-Coupling

3 R1 R Ph2P Fe I 6 mol% R1 P + 2 PdCl2 (3 mol%) R 2 Ba(OH)2 B(OR )2 DME/H2O, reflux Me

• Suzuki cross-coupling is a convenient, versatile method for the formation of atropisomeric biaryls with a wide range of functionality due to the mild nature of boronic acids/esters as nucleophilic arene species.

Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723-1724.

Enantioselective Aryl-Aryl Coupling Redox-Neutral Coupling - Suzuki Cross-Coupling

3 R1 R Ph2P Fe I 6 mol% R1 P + 2 PdCl2 (3 mol%) R 2 Ba(OH)2 B(OR )2 DME/H2O, reflux Me

Entry R1 R2 R3 % Yield % ee

1 H H OMe 74 14

2 H H NMe2 44 63

3* Me CH2 NMe2 50 85 * used DME as solvent, CsF as additive, 6 days.

Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723-1724. Enantioselective Aryl-Aryl Coupling Redox-Neutral Coupling - Suzuki Cross-Coupling

O NMe2 P PCy2 1 Br (OR )2 O P 0.8-3.3 mol% 1 + (OR )2 Pd (dba) (0.5-2 mol%) * 2 3 R2 K PO B(OH) 3 4 2 toluene, 60-80 °C R2

Entry R1 R2 % Yield % ee*

1 OEt Me 98 87 (+)

2 OEt Et 96 92 (+)

3 OEt i-Pr 89 85 (+)

4 OEt Ph 74 74 (+)

5 OMe Me 91 84 (+)

* absolute configuration undetermined.

Buchwald, S. L.; Yin, J. J. Am. Chem. Soc. 2000, 122, 12051-12052.

Enantioselective Aryl-Aryl Coupling Redox-Neutral Coupling - Aryl-Lead Triacetate

OH Pb(OAc)3 OH R' pyr (xs) R + R' R + Pb(OAc)2

Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943-8944. Kano, T.; Ohyabu, Y.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 5365-5373. Enantioselective Aryl-Aryl Coupling Redox-Neutral Coupling - Aryl-Lead Triacetate

OH Pb(OAc)3 OH R' pyr (xs) R + R' R + Pb(OAc)2

AcO AcO N Pb O

R R'

Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943-8944. Kano, T.; Ohyabu, Y.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 5365-5373.

Enantioselective Aryl-Aryl Coupling Redox-Neutral Coupling - Aryl-Lead Triacetate

OLi Pb(OAc)3 OH R' brucine (6 equiv) R + R' R + Pb(OAc)2 toluene, -40 °C % Yield Entry Phenol Aryl-Lead Product (dl:meso ) % ee

OH Pb(OAc)3 OH Ph 1 68 83 Ph Ph (>99:1)

OH Pb(OAc)3 OH 2 >99 51 (2:1)

OH OH Pb(OAc)3 H N MeO 3 Ph 55 93 H Ph Ph (6.9:1) MeO N MeO OMe MeO OMe H H O O OH Pb(OAc)3 OH H 4 i-Pr 99 85 brucine Ph

Pb(OAc)3 OH 5 99 20 OH

OLi Pb(OAc)3 OH Ph M fast brucine (6 equiv) + toluene, -40 °C Ph

O O H axial attack Ph H R S Ph

Ph O O Pb O brucine Ph Ph - AcOLi O L L O L L O OLi pseudo-rotation O Pb -or- Pb O L L L L L L

L = brucine or AcO

Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943-8944. Kano, T.; Ohyabu, Y.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 5365-5373.

Resolution/Desymmetrization of Prostereogenic Biaryls

• Biaryl axis formed non-selectively prior to introduction of axial chirality.

Configurationally Stable, Axially Achiral Configurationally Unstable, Axially Chiral

Introduction/Transformation of Aryl Introduction of Chiral Bridge Atroposelective Cleavage of a Bridge Substituent (The Lactone Method) (Desymmetrization) (Resolution) (Resolution)

Y X X X X Y Y

CS-symmetric macroscopically achiral macroscopically achiral

A Z Nuc*H A *

Y X X Nuc* Z * X * Y * * Y H Resolution/Desymmetrization of Prostereogenic Biaryls Introduction/Transformation of an Ortho Substituent

• Very little investigation into this method. • Usually no rationalization of stereochemistry. • Most systems lack broad applicability due to substrate requirements or have low functional group tolerance.

N N

CO2H Me Me 1. n-BuLi, (-)-sparteine Me Me Me Me 2. CO2 HO2C

70% yield 40% ee

Engelhardt, L. M.; Leung, W.-P.; Raston, C. L.; Salem, G.; Twiss, P.; White, A. H. J. Chem. Soc. Dalton Trans. 1988, 2403-2409.

Resolution/Desymmetrization of Prostereogenic Biaryls Introduction/Transformation of an Ortho Substituent

R1 R1 R3MgBr R2 LiBr or LiI R2 M TfO OTf Me Me R3 OTf Me N Cl Pd P Cl Ph Ph PdCl2[(S )-alaphos]

Entry R1 R2 R3 Yield (%) % ee

1 H Me Ph 85 95

2 H Me Ph3Si 87 85

3 H Ph Ph 80 94

4 H Ph Ph3Si 88 99

5 Ph 92 94

6 Ph3Si 88 92

Hayashi, T.; Niizuma, S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc. 1995, 117, 9101-9102. Kamikawa, T.; Hayashi, T. Tetrahedron 1999, 55, 3455-3466. Resolution/Desymmetrization of Prostereogenic Biaryls Introduction of a Chiral Bridge

H2N O O X OH O O X X Ph Ph Ph RO N + N toluene, reflux O O Me Me

major minor

X = CH2: 95%, >95% de X = N: 72%, >95% de

Penhoat, M.; Levachet, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517-9520.

Resolution/Desymmetrization of Prostereogenic Biaryls Introduction of a Chiral Bridge

H2N O O X OH O O X X Ph Ph Ph RO N + N toluene, reflux O O Me Me

major minor

Ph Ph O O X HN Me HN RO X O Me OR + O Ph rings oriented trans, axis rotates away from Ph Ph oxazolidine Ph. O O X HN O N Me OR H RO O Me X Ph rings oriented cis, axis rotates away from benzylic Me. Penhoat, M.; Levachet, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517-9520. Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

O O O catalyst M P Br R O R O R O NaOAc DMA 130 °C R R R

Coupling Yields

catalyst A: Pd(OAc)2 (10 mol%) Entry R A B PPh3 (20 mol%) 1 H 80 91 Me

catalyst B: (1 mol%) Ar2 2 Me 75 87 P O O Pd Pd 3 OMe 77 90 O O P Ar2 4 Et 71 83 Me 5 i-Pr 72 82

6 t-Bu 44 81

Bringmann, G.; Breuning, M.; Henschel, P.; Hinrichs, J. Org. Synth. 2002, 79, 72-83.

Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

H N O Me

O Me O HO R HO Me KHN S

Me NaO Me R = OMe: 97%, 76% de R Me R = Me: 95%, 86% de R = OMe: 70%, 82% de R = Me: 85%, 90% de

O O H Ph Ph M P R O R O

N O , BH3, THF, 30 °C B Me R R R = OMe: 88%, 91% de R = Me: 78%, 94% de p-Tol S Li O

O H OH P Al O OEt HO R p-Tol R = OMe: 94%, 95% de Li S R = Me: 97%, 94% de O O Me OH R Bringmann, G. Org. Synth. 2002, 79, 72-83. Bringmann, G. Angew. Chem. I. E. Engl. 1992, 31, 761-762. 73%, 0% de Bringmann, G. Synthesis 1999, 525-558. chemically atropisomerizes Bringmann, G. Eur. J. Org. Chem. 1999, 3047-3055. Me Bringmann, G. Chem. Eur. J. 1999, 5, 3029-3038. Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

H Ph Ph

N O O B OH Me , BH3, THF, 30 °C M R O HO R

R R R = OMe: 88%, 91% de R = Me: 78%, 94% de

Bringmann, G. Synthesis 1999, 4, 525-558.

Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

H Ph Ph

N O O B OH Me , BH3, THF, 30 °C M R O HO R

R R R = OMe: 88%, 91% de R = Me: 78%, 94% de

Ph R O Me B O Ph N O Re H B H R H

Bringmann, G. Synthesis 1999, 4, 525-558. Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

eq H R R O

O H ax

ax R H

O O

H eq

Bringmann, G. Synthesis 1999, 4, 525-558.

Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

eq H R R O

O H ax

ax R H

O O

H eq

Bringmann, G. Synthesis 1999, 4, 525-558. Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

eq H R R Re face R R O attack O O

H O H ax

ax R H R Si face H R R attack O O O O

H eq

Bringmann, G. Synthesis 1999, 4, 525-558.

Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

O H+ R HO R R O H R O major eq H R R Re face R R O attack O O

H O H ax

ax R H R Si face H R R attack O O O O

H eq H O R R OH H+ R H O R O minor Bringmann, G. Synthesis 1999, 4, 525-558. Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

O H+ R HO R R

O rate? H R O major eq H R R R Re face R R R O attack O O O H

H O H O ax stereochemical stereochemical leakage leakage ax R R H R O Si face H R R R attack H O O O O O

H rate? eq H O R R OH H+ R H O R O minor Bringmann, G. Synthesis 1999, 4, 525-558.

Resolution/Desymmetrization of Prostereogenic Biaryls Atroposelective Cleavage of a Bridge - The Lactone Method

O H+ R HO R R O H R O major eq H For optimal selectivity: R R Re face • use a reactive nucleophile in cases R R involving an intermediate ketone or O attack O aldehyde, in order to avoid "stereochemical O leakage" use bulkier chiral nucleophiles for better O • H H facial selectivity. ax • optimal reactivity/selectivity with Me-CBS and catechol borane.

ax H Ph H R Ph O OH N O B H R B O Me [H] O O HO R H eq

R major

Bringmann, G. Synthesis 1999, 4, 525-558. Atroposelective Construction of an Aromatic Ring

• Newest and least developed method for the formation of atropisomeric biaryls. • Most intermediates/transition states unknown.

Transfer of Chirality from Benzylic [2+2+2] Cycloaddition with Chiral Metal Complexes sp3 Center to Biaryl Axis

* M

* *

Atroposelective Construction of an Aromatic Ring Central-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols

Cl Cl Cl

Cl Cl Me TiCl4 Me TBSOTf Me OH OH CH2Cl2, -78 °C CH2Cl2, 0 °C

Nishii, Y.; Yoshida, T.; Tanabe, Y. Tetrahedron Lett. 1997, 38(41), 7195-7198. Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126, 5358-5359. Atroposelective Construction of an Aromatic Ring Central-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols

Cl Cl Cl

Cl Cl Me TiCl4 Me TBSOTf Me R1 OH R2 R1 R2 R1 OH R2 CH2Cl2, -78 °C CH2Cl2, 0 °C

Entry R1 R2 % Yield % ee Entry R1 R2 % Yield % ee

1 Cl H 97 >99 1 Me H 41 45

2 Cl Cl 70 >99

3 OMe Me 71 >99

4 OMe Cl 65 >99

5 Me Cl 47 >99

Nishii, Y.; Yoshida, T.; Tanabe, Y. Tetrahedron Lett. 1997, 38(41), 7195-7198. Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126, 5358-5359.

Atroposelective Construction of an Aromatic Ring Central-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols

Cl Cl Cl

Cl Cl Me TiCl4 Me TBSOTf Me R1 OH R2 R1 R2 R1 OH R2 CH2Cl2, -78 °C CH2Cl2, 0 °C

Cl Cl

Cl Cl Me TiCl4 Me O OH 2 R2 R1 H R R1 SiR3 OTf

R1 rotates away from R1 rotates away from chelated TiCl4 chelated TBSOTf

Cl Cl Cl

Cl Cl Me TiCl4 Me TBSOTf Me R1 OH R2 R1 R2 R1 OH R2 CH2Cl2, -78 °C CH2Cl2, 0 °C

Cl Cl

Cl Cl Me TiCl4 Me O OH 2 R2 R1 H R R1 SiR3 OTf

R1 rotates away from R1 rotates away from Cl Cl chelated TiCl4 chelated TBSOTf rotation around Me pre-axis bond (unknown mechanism) 2 R1 R

Nishii, Y.; Yoshida, T.; Tanabe, Y. Tetrahedron Lett. 1997, 38(41), 7195-7198. Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126, 5358-5359.

Atroposelective Construction of an Aromatic Ring Central-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols

Cl Cl Cl

Cl Cl Me TiCl4 Me TBSOTf Me R1 OH R2 R1 R2 R1 OH R2 CH2Cl2, -78 °C CH2Cl2, 0 °C

Cl Cl Cl - H , - HCl Cl

Cl Cl Me TiCl4 Me Me 2 O 1 R OH 2 R R2 R1 H R R1 SiR3 OTf

R1 rotates away from R1 rotates away from Cl Cl chelated TiCl4 chelated TBSOTf rotation around Me pre-axis bond (unknown mechanism) 2 R1 R

R2 2 2 2 R 2 R R R CN N OR1 N R2 R2 R2 R2 R2 1 1 OR catalyst catalyst OR h! (" = 420 nm) h! (" = 420 nm) THF, 3 °C THF, 3 °C

Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797.

Atroposelective Construction of an Aromatic Ring [2+2+2] Cycloadditions

R2 2 2 2 R 2 R R R CN N OR1 N R2 R2 R2 R2 R2 1 1 OR catalyst catalyst OR h! (" = 420 nm) h! (" = 420 nm) THF, 3 °C THF, 3 °C

Catalyst Screen

Co Co Co Co

O O O

Co Co

Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797. Atroposelective Construction of an Aromatic Ring [2+2+2] Cycloadditions

R2 2 2 2 R 2 R R R CN N OR1 N R2 R2 R2 R2 R2 1 1 OR catalyst catalyst OR h! (" = 420 nm) h! (" = 420 nm) THF, 3 °C THF, 3 °C

Catalyst Screen

Co Co Co Co

O O O

Co Co

Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797.

Atroposelective Construction of an Aromatic Ring [2+2+2] Cycloadditions

R2 2 2 2 R 2 R R R CN N OR1 N R2 R2 R2 R2 R2 1 1 OR catalyst catalyst OR h! (" = 420 nm) h! (" = 420 nm) THF, 3 °C THF, 3 °C

Entry R1 R2 % Yield % ee Entry R1 R2 % Yield % ee

1 Me n-pentyl 33 38 1 Me Et 10 64 Co 2 Me n-Pr 8 32 2 Bn Et 3 59

3 Bn n-pentyl 7 39 3 Me n-pentyl 2 63

Catalyst

Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797. Atroposelective Construction of an Aromatic Ring [2+2+2] Cycloadditions

R2 R2 R2 R2

1 N 2 OR N R CN R2 R2 R2 1 1 OR catalyst catalyst OR h! (" = 420 nm) h! (" = 420 nm) THF, 3 °C THF, 3 °C

Entry R1 R2 % Yield % ee Entry R1 R2 % Yield % ee

1 Me Me 88 88 1 Me Et 10 64 Co 2 Me Ph 86 89 2 Bn Et 3 59

3 Me t-Bu 74 88 3 Me n-pentyl 2 63

Catalyst

Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797.

Atroposelective Construction of an Aromatic Ring [2+2+2] Cycloadditions - Helicenes

• First reported asymmetric synthesis of a helicene derivative.

R CO2Me Red-Al

toluene, 0 °C PPh2 CO2Me R

(S)-(-)-MOP PBr3, THF, 0 °C R = OH R = Br

TIPS Li R Ni(cod)2 THF, -78 °C R (S)-(-)-MOP THF, -20 °C

n-Bu4NF, THF, rt R = TIPS tetrahydro[6]helicene R = H

Stara, I. G. Tetrahedron Lett. 1999, 40, 1993-1996. Atroposelective Construction of an Aromatic Ring [2+2+2] Cycloadditions - Helicenes

• First reported asymmetric synthesis of a helicene derivative.

R CO2Me Red-Al

toluene, 0 °C PPh2 CO2Me R

(S)-(-)-MOP PBr3, THF, 0 °C R = OH R = Br

TIPS Li R Ni(cod)2 THF, -78 °C R (S)-(-)-MOP P THF, -20 °C

n-Bu4NF, THF, rt R = TIPS tetrahydro[6]helicene R = H

Stara, I. G. Tetrahedron Lett. 1999, 40, 1993-1996.