gm 11-14-05 - atropisomerism · atropisomerism axial chirality in nature and synthesis kevin allan...
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AtropisomerismAxial Chirality in Nature and Synthesis
Kevin AllanStoltz Group Literature Meeting
Monday 11/14/20058 pm
147 Noyes
R
RMLn
*
R
R
O
O
OH
MeO
MeO
OH
OMe
OMe
OH
OH
O
O
OH OH
Me
OH
Me
O
MeO
MeO
*
*
*
*
O
OAl
OEt
HLi
N
NH
Me
OMe
OMe
Me
O
O
Nu
X
X
Y
Y
X
X
Y
Y
OO
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 i. Atropodiastereoselective Bridge Formation ii. Atroposelective Bridge Cleavage / The "Lactone Method"
IV. Atroposelective Construction of an Aromatic Ring
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: Bringmann, G.; Breuning, M.; Tasler, S. Synthesis, 1999, 4, 525-558. Bringmann, G.; Tasler, S.; Pfeifer, R.-M.; Breuning, M. J. Organomet. Chem. 2002, 661, 49-65.
Matthias BreuningUniversitat Wurzburg
Gerhard BringmannUniversitat Wurzburg
Motokazu Uemura (right) andKen Kamikawa (left)
Osaka Prefecture University
Albert I. MeyersColorado State University
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Atropisomerism is Everywhere
OHO
OH
HO OH
O
CH3(CH2)10
OH
Myristinin BMyristica cinnamomea
COX 2 inhibitor
HN
NH
OH OMe
MeO OH
HO
OH
OH
OH
Michellamine BAncistrocladus korupensis
Protein kinase C inhibitor, anti-HIV-1,2
O
O
O
NH
HN
O
O
O
HOHO
OH
O
OHHO
OH
Cl
Cl
OMe
NH2HO
Me
HN
O
HO2C
HO
NH
O HN
O
NH
OHO
Me
Me
NHMe
H
H2N
O
P
VancomycinAmycolatopsis orientalis
Antibiotic (Gram-positive)
P
M
Me
HO Me
HN
Atropisomerism is Everywhere
N N
Ph
O
Ph
O
Ru
Cl
NO
catalyzes asymmetric homo-couplingof 2-naphthols
Katsuki, T. Synlett, 2000, 1433-1436.
P P
N
N
HO
HOO
O
R
R
catalyzes enantioselectiveallylation of aldehydes
Hayashi, T. J. Org. Chem. 2003, 68, 6329-6337.
Me
Me
Me
Ph2P
M
P
catalyzes enantioselectivehydrosilations
Bringmann, G. Tetrahedron: Asymm. 1999, 10, 3025-3031.
Me
HO Me
HN
Me
OH
OH
HN
MMM
catalyzes enantioselectivealkylation of aldehydes
Bringmann, G. J. Org. Chem. 2003, 68, 6859-6863.
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AtropisomerismHistory & 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:
NO2HO2C
CO2HO2N
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.
AtropisomerismConditions 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).
• !G200 K = 61.6 kJ mol-1
• !G300 K = 93.5 kJ mol-1
• 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
HO OH
HO
OH
S = P
OH
OH
R = M
(P )-2,2'-dihydroxybiphenyl (M )-2,2'-dihydroxybiphenyl
HO OH
OHHO
HO OH
OH
OH
pro-P pro-M OHHO
HO OH
1
23
4
5 6
1'
2' 3'
4'
5'6'
OHHO
1
2 3
4
56
1'
2'3'
4'
5' 6'
Bringmann, G. Angew. Chem. I. E. 2005, 44, 5384-5427.
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Direct Atroposelective Aryl-Aryl CouplingDiastereoselective Coupling
XX
*
Chiral Tether Influences Configuration During Intramolecular Coupling
* *
MLn
Ortho Chiral Auxiliary Influences Configuration During Intermolecular
Coupling
Planar Chiral Element Influences Configuration During Intermolecular
Coupling
X
Y*
X
+
*
MLn
Y*
LnM'
X
X
+
MLn
*
LnM'
Central-to-axial transfer of chirality Central-to-axial transfer of chirality Planar-to-axial transfer of chirality
Diastereoselective Aryl-Aryl CouplingIntramolecular Coupling with Chiral Tethers - Toward Desertorin A-C
TBSO
TBSOOBn
OBn 3 steps
R
R O
O
OBn
OBn
Br
Me OMe
Br
MeO Me
S
S
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.
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Diastereoselective Aryl-Aryl CouplingIntramolecular Coupling with Chiral Tethers - Toward Desertorin A-C
TBSO
TBSOOBn
OBn 3 steps
R
R O
O
OBn
OBn
Br
Me OMe
Br
MeO Me
S
S
1. BuLi, -78 °C
2. CuCN, TMEDA-78 to -40 °C3. O2, -78 °C40% over 3 steps
O
O
P
OMe
Me
MeO
Me OBn
OBn
single diastereomer
O
O
O
O
OMeMe
RO
Me OR
MeO
Desertorin A-C
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 CouplingIntramolecular Coupling with Chiral Tethers - Toward Desertorin A-C
TBSO
TBSOOBn
OBn 3 steps
R
R O
O
OBn
OBn
Br
Me OMe
Br
MeO Me
S
S
1. BuLi, -78 °C
2. CuCN, TMEDA-78 to -40 °C3. O2, -78 °C40% over 3 steps
O
O
P
OMe
Me
MeO
Me OBn
OBn
H
O CH2OBn
H
CH2OBnO
Me
MeO
OBn substituents prefer gauche conformation as opposed to axial anti-coplanar
single diastereomer
O
O
O
O
OMeMe
RO
Me OR
MeO
Desertorin A-C
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.
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Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Asymmetric Suzuki Coupling
Broutin, P.-E.; Colobert, F. Org. Lett. 2003, 5(18), 3281-3284.
I
OMe
O I O
S
O
pTol
SpTolMe
LDA, THF80%
DIBAL
ZnCl2, THF74% I OH
S
O
pTolR1 R1 R1
O
Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Asymmetric Suzuki Coupling
Broutin, P.-E.; Colobert, F. Org. Lett. 2003, 5(18), 3281-3284.
I
OMe
O I O
S
O
pTol
B(OH)2
R2
R2
SpTolMe
LDA, THF80%
DIBAL
ZnCl2, THF74% I OH
S
O
pTol
I OH
S
O
pTol
+S
OH
R1
R1
O
pTolPd(OAc)2, dppf
CsF, dioxane70 °C
R1 R2 Yield (%) dr*
Me Me 60 70:30
Me OMe 27 90:10
OMe OMe 61 93:7
*determined by 1H NMR
(absolute configuration unknown)
R1 R1 R1
Entry
1
2
3
O
*
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Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Asymmetric Suzuki Coupling
I
OMe
O I O
S
O
pTolLDA, THF
80%
DIBAL
ZnCl2, THF74% I OH
S
O
pTolR1 R1 R1
NaH, MeIDMF, -20 °C
99%
I OMe
S
O
pTolR1
SpTolMe
O
Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113-1128.
Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Asymmetric Suzuki Coupling
I
OMe
O I O
S
O
pTolLDA, THF
80%
DIBAL
ZnCl2, THF74% I OH
S
O
pTolR1 R1 R1
NaH, MeIDMF, -20 °C
99%
I OMe
S
O
pTolR1
B(OR3)2
R2
+
Pd(OAc)2dppf or PPh3CsF, dioxane
70 °C
R2
S
OMe
R1
O
pTol
*
R4
R5
R1 R2 Yield (%) dr*
78 75:25
89 80:20
86 90:10
Entry
1
2
3
R3 R4 R5
4
5
6
7
8
Me Me CH2 H H
Me OMe CH2 H H
OMe Me CH2 H H
OMe OMe H H H 80 85:15
H Me H 99 >99:1
H OMe H 99 >99:1
Me H CH2 88 90:10
OMe H CH2 95:586
*determined by 1H NMR (absolute configuration unknown)
SpTolMe
O
Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113-1128.
R4
R5
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R Yield (%) dr (P :M )
90 20:80
75 40:60
80 42:58
79 90:10
73 93:7
CH2OMe
CH2OBn
Me
CH2OTBS
O
O
Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson, D. J.; Meier, A. Tetrahedron, 2004, 60, 4459-4473.
Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Aryl Grignard Coupling
O
N
MeO
Br
R
OMe
MeO
i-Pr+
Mg
THF, !
OMe
MeO
R
O
N
i-Pr
P
Grignard additions require EWG at ortho or para position to stabilize developing negative charge.
Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Aryl Grignard Coupling
O
N
MeO
Br
R
OMe
MeO
i-Pr+
Mg
THF, !
OMe
MeO
R
O
N
i-Pr
P
Grignard additions require EWG at ortho or para position to stabilize developing negative charge.
O
NMeOMeO Mg
Br
OMeR
i-PrO
NMeOMeO Mg
Br
i-Pr
OMeR
O
N
MeOMeO
Mgi-Pr
R OMe
Br
O
N
MeOMeO
Mgi-Pr
MeO R
Br
180° rotation
Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson, D. J.; Meier, A. Tetrahedron, 2004, 60, 4459-4473.
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Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Ullmann Homocoupling
Cu
DMF, 150 °C40 h
O
NBr
MeO
i-Pr
MeO
OMe
O
NMeO
i-Pr
MeO
OMe
O
NMeO
i-Pr
MeO
OMe
P
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 CouplingOrtho Chiral Auxiliaries - Ullmann Homocoupling
Cu
DMF, 150 °C1 h
O
NBr
MeO
i-Pr
MeO
OMe
O
NMeO
i-Pr
MeO
OMe
O
NMeO
i-Pr
MeO
OMe
P
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.
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O
NMeO
i-Pr
MeO
OMe
O
NMeO
i-Pr
MeO
OMe
P Cu
O
NMeO
i-Pr
MeO
OMe
O
NMeO
i-Pr
MeO
OMe
M Cu!
O
N
O
N
Cu
H
i-Pr
i-Pr
H
O
N
O
N
Cu
i-Pr
H
H
i-Pr
M P
Non-selective couplingthen
thermodynamic deracemization
Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Ullmann Homocoupling
Cu
DMF, 150 °C40 h
O
NBr
MeO
i-Pr
MeO
OMe
O
NMeO
i-Pr
MeO
OMe
O
NMeO
i-Pr
MeO
OMe
P
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 CouplingPlanar Arene-Metal Complexes - Asymmetric Suzuki Coupling
B(OH)2
Br
R1
R2 OMe
+Pd(PPh3)4, Na2CO3
MeOH/H2O
R1
R2 OMe
Cr(CO)3
Cr(CO)3
R1
MeO R2
(CO)3Cr
+
syn anti
P M
Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384.
major minor
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Diastereoselective Aryl-Aryl CouplingPlanar Arene-Metal Complexes - Asymmetric Suzuki Coupling
B(OH)2
Br
R1
R2 OMe
+Pd(PPh3)4, Na2CO3
MeOH/H2O
R1
R2 OMe
Cr(CO)3
Cr(CO)3
R1
MeO R2
(CO)3Cr
+
syn anti
!
toluene or xylenes
P M
Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384.
Diastereoselective Aryl-Aryl CouplingPlanar Arene-Metal Complexes - Asymmetric Suzuki Coupling
B(OH)2
Br
R1
R2 OMe
+Pd(PPh3)4, Na2CO3
MeOH/H2O
R1
R2 OMe
Cr(CO)3
Cr(CO)3
R1
MeO R2
(CO)3Cr
+
syn anti
!
toluene or xylenes
P M
Entry R1 R2 Yield (%) dr (P :M )
1
2
3
4
5
6
7
Me Me 96 100:0
Me CH2OH 77 100:0
OMe Me 94 97:3
CHO Me 95 0:100
CHO CHO 43 0:100
OMe CHO 85 4:96
Me CHO 82 100:0
Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384.
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Diastereoselective Aryl-Aryl CouplingPlanar Arene-Metal Complexes - Asymmetric Suzuki Coupling
B(OH)2
Br
R1
R2 OMe
+Pd(PPh3)4, Na2CO3
MeOH/H2O
R1
R2 OMe
Cr(CO)3
Cr(CO)3
R1
MeO R2
(CO)3Cr
+
syn anti
!
toluene or xylenes
P M
Entry R1 R2 Yield (%) dr (P :M )
1
2
3
4
5
6
7
Me Me 96 100:0
Me CH2OH 77 100:0
OMe Me 94 97:3
CHO Me 95 0:100
CHO CHO 43 0:100
OMe CHO 85 4:96
Me CHO 82 100:0
o-carbonyl substituents may result in chemical atropisomerization to the more thermodynamically stable (anti ) product.
Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384.
Diastereoselective Aryl-Aryl CouplingPlanar Arene-Metal Complexes - Asymmetric Suzuki Coupling
B(OH)2
Br
R1
R2 OMe
+Pd(PPh3)4, Na2CO3
MeOH/H2O
R1
R2 OMe
Cr(CO)3
Cr(CO)3
R1
MeO R2
(CO)3Cr
+
syn anti
P M
Entry R1 R2 Yield (%) dr (P :M )
1
2
3
4
5
6
7
Me Me 96 100:0
Me CH2OH 77 100:0
OMe Me 94 97:3
CHO Me 95 0:100
CHO CHO 43 0:100
OMe CHO 85 4:96
Me CHO 82 100:0
Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384.
h!, O2
R1
R2 OMe
R1
MeO R2+P M
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RS
OMe
Diastereoselective Aryl-Aryl CouplingPlanar Arene-Metal Complexes - Asymmetric Suzuki Coupling
Kamikawa, K.; Uemura, M. Synlett 2000, 7, 938-949.
H
R
OMe
RS
Cr(CO)3
Pd
Ph3P PPh3
R
H
OMe
RS
Cr(CO)3
Pd
Ph3P PPh3
Pd
H
R
PPh3
PPh3(CO)3Cr
RS
OMe
Pd
R
H
PPh3
PPh3(CO)3Crrotation to form the biaryl axis during reductive elimination occurs so as to minimize steric interactions with the bulky PPh3 ligands.
R
H
OMe
RS
(CO)3Cr
P
H
R
OMe
RS
(CO)3Cr
M
Diastereoselective Aryl-Aryl CouplingPlanar Arene-Metal Complexes - Asymmetric Suzuki Coupling
Kamikawa, K.; Uemura, M. Synlett 2000, 7, 938-949.
Entry R1 R2 Yield (%) dr (P :M )
1
2
3
4
5
6
7
OMe Me 88 100:0
OMe CHO 89 100:0
OMe 86 100:0
OMe Me 85 100:0
Me H 70 85:15
OMe H 71 71:29
Me H 78 97:3
R3
B(OH)2
Br
R3
R2 R1
+Pd(PPh3)4, Na2CO3
MeOH/H2O R2 R1
Cr(CO)3
Cr(CO)3
R1 R2
(CO)3Cr
+
syn anti
P M
R3 R3
H
H
CH2OH H
O
O
Me
Me
OMe
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Direct Atroposelective Aryl-Aryl CouplingEnantioselective Coupling
Chiral Leaving Group Influences Configuration During Intermolecular
Coupling
*
MLn
Central-to-axial transfer of chirality
X*
Y
+
X
Y
+
*
MLn*
Central-to-axial transfer of chirality
Redox-Neutral:• Kumada• Suzuki• Aryl-Lead Species
Oxidative:• Copper• Vanadium
Chiral Metal Complex Influences Configuration During Intermolecular Coupling
Enantioselective Aryl-Aryl CouplingChiral Leaving Groups
R*O
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.
O
NBr
R*ONa
DMF, 50 °C
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Enantioselective Aryl-Aryl CouplingChiral Leaving Groups
R*O
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.
THF, -20 °C
1-10 h
O
NBr
R*ONa
DMF, 50 °C
Li
OMe
N
O
OMe
M
Enantioselective Aryl-Aryl CouplingChiral Leaving Groups
R*O
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.
THF, -20 °C
1-10 h
O
NBr
R*ONa
DMF, 50 °C
Li
OMe
N
O
OMe
M
R* =O
O
O
N
O
MeO
N
H
N
HH
N
MeO
O
quinidinyl
quininyl
!-fenchyl
(R )-menthylbornyl
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Enantioselective Aryl-Aryl CouplingChiral Leaving Groups
R*O
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.
THF, -20 °C
1-10 h
O
NBr
R*ONa
DMF, 50 °C
Li
OMe
N
O
OMe
M
R* =O
O
O
N
O
MeO
N
H
N
HH
N
MeO
O
quinidinyl22% yield-84% ee
quininyl20% yield
87% ee
!-fenchyl88% yield
77% ee
(R )-menthyl68% yield>95% ee
bornyl67% yield
8% ee
Enantioselective Aryl-Aryl CouplingChiral Leaving Groups - Menthol
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.
CO2R
O
MgBr MgBr
OMe
THF, -20 °CPhH, 80 °C
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
P MOMe
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Enantioselective Aryl-Aryl CouplingChiral Leaving Groups - Menthol
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.
OO
OR
RLRM
H
Mg
Br
R
OO
OR
Mg
Br
R
RMRLH
OMe
O
RMRLH
O
ORMg
Br O
RMRLH
O
ORMg
Br
chelationcontrol
non-chelationcontrol
CO2RP
CO2RM
naphO
H
i-Pr
RM
RL
OMe
Enantioselective Aryl-Aryl CouplingOxidative Homocoupling - Copper
• Copper-amine complexes are the most widely investigated due to the ease of ligand screening.
H2N NH2
Ph Ph
H2N NH2NH
NEt
Ph NH
HN R1
R2
N N
N
N
R1
R2
OH
CO2Me CuI (2-10 mol%)diamine L* (2-10 mol%)
O2, CH2Cl248 h
OH
CO2Me
OH
CO2Me
M
Li, X.; Yang, J.; Kozlowski, M. Org. Lett. 2001, 3(8), 1137-1140.
Ligand Screen
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Enantioselective Aryl-Aryl CouplingOxidative Homocoupling - Copper
• Copper-amine complexes are the most widely investigated due to the ease of ligand screening.
H2N NH2
Ph Ph
H2N NH2NH
NEt
Ph NH
HN R1
R2
N N
N
N
R1
R2
OH
CO2Me CuI (2-10 mol%)diamine L* (2-10 mol%)
O2, CH2Cl248 h
OH
CO2Me
OH
CO2Me
M
Li, X.; Yang, J.; Kozlowski, M. Org. Lett. 2001, 3(8), 1137-1140.
Ligand Screen
Enantioselective Aryl-Aryl CouplingOxidative Homocoupling - Copper
• Copper-amine complexes are the most widely investigated due to the ease of ligand screening.
N
N
R1
R2
OH
CO2Me CuI (2-10 mol%)diamine L* (2-10 mol%)
O2, CH2Cl248 h
OH
CO2Me
OH
CO2Me
M
Li, X.; Yang, J.; Kozlowski, M. Org. Lett. 2001, 3(8), 1137-1140.
Ligand Screen
R1 = R2 = H
R1 = H, R2 = Me
R1 = R2 = Me
R1 = R2 = Bn
R1 = R2 = CH2CF3
60 91
53 79
43 3
72 22
% Yield % ee
NR
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Enantioselective Aryl-Aryl CouplingOxidative Homocoupling - Copper
• Copper-amine complexes are the most widely investigated due to the ease of ligand screening.
OH
CO2Me CuI (2-10 mol%)diamine L* (2-10 mol%)
O2, CH2Cl248 h
OH
CO2Me
OH
CO2Me
M
Li, X.; Yang, J.; Hewgley, B.; Mulrooney, C. A.; Yang, J.; Kozlowski, M. J. Org. Chem. 2003, 68, 5500-5511.
N
N
CuII
H
H
O
MeOO
N
N
CuI
H
H
O
MeOO
H
N
N
CuI
H
H
O
MeO O
H
CO2Me
OHN
N
CuII
H
H
HO
blocked
open
H2O O2
cat-Sub
cat
cat
rotation of aromatic ring away from ligand and tautomerization to binol
Enantioselective Aryl-Aryl CouplingOxidative Homocoupling - Vanadium
R1
R2 OH
R3
OH
R3
OH
R3R1
R2
R2
R1
VO(acac)2, O2
CH2Cl2
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.
Entry R1 R2 R3 % Yield
1
2
3
H H H 92
Br H H 90
H OMe H 76
4 H H CO2Me 35
Mechanism unknown
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Enantioselective Aryl-Aryl CouplingOxidative Homocoupling - Vanadium
R1
R2 OH
R3
OH
R3
OH
R3R1
R2
R2
R1
catalyst, O2
TMSCl or TMSOTfCH2Cl2
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.
O
V
N O
OBn
O
Me
H
catalyst
Entry R1 R2 R3 % Yield
1
2
3
H H H 82
Br H H 91
H OMe H 50
4 H H CO2Me trace
% ee
51
51
51
---
M
Mechanism unknown
Enantioselective Aryl-Aryl CouplingOxidative Homocoupling - Vanadium
R1
R2 OH
R3
catalyst, O2
TMSCl or TMSOTfCH2Cl2
Luo, Z.; Liu, Q.; Gong, L.; Cui, X.; Mi, A.; Jiang, Y. Angew. Chem. I. E. 2002, 41(23), 4532-4535.
catalyst
Entry R1 R2 R3 % Yield
1
2
3
H H H 62
Br H H 98
H OMe H 95
4
% ee
90
90
95
N
O
O
N
O
O
O
O
V
V
O
O
O
i-Bu
i-Bu
H OEt H 99 96
5 H On-Bu H 99 94
6 H OBn H 80 95
7 H H OBn trace ---
OH
R3
OH
R3R1
R2
R2
R1
M
Mechanism unknown
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Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Kumada Cross-Coupling
R2
MgBr
Br
R1
+R1
R2P
FePh2PR3
Me
4-10 mol%
NiBr2 (2-5 mol %)Et2O/toluene
< -15 °C
Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153-8156.
Entry R1 R2 R3 % Yield % ee
1
2
3
4
5
Me Me OMe 69 95
Me H OMe 25 16
H Me OMe 92 83
H Me OEt 82 68
H Me H 81 1
Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Kumada Cross-Coupling
R2
MgBr
Br
R1
+R1
R2P
FePh2PR3
Me
4-10 mol%
NiBr2 (2-5 mol %)Et2O/toluene
< -15 °C
Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153-8156.
Entry R1 R2 R3 % Yield % ee
1
2
3
4
5
Me Me OMe 69 95
Me H OMe 25 16
H Me OMe 92 83
H Me OEt 82 68
H Me H 81 1
MeOP
Mg
Me Br
R2
Fe
Ph
Ph
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Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Suzuki Cross-Coupling
• 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.
Me
B(OR2)2
I
R1
+R2
P6 mol%
PdCl2 (3 mol%)Ba(OH)2
DME/H2O, reflux
Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723-1724.
R1
FePh2PR3
Me
Entry R1 R2 R3 % Yield % ee
1
2
3*
OMe 74 14
H NMe2 44 63
Me NMe2 50 85
H
H
H
CH2
* used DME as solvent, CsF as additive, 6 days.
Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Suzuki Cross-Coupling
Me
B(OR2)2
I
R1
+R2
P6 mol%
PdCl2 (3 mol%)Ba(OH)2
DME/H2O, reflux
Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723-1724.
R1
FePh2PR3
Me
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Entry R1 R2 % Yield % ee*
1
2
3
98 87 (+)
Et 96 92 (+)
OEt 89 85 (+)
OEt
OEt
Me
i-Pr
Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Suzuki Cross-Coupling
R2
B(OH)2
Br
P
+R2Pd2(dba)3 (0.5-2 mol%)
K3PO4
toluene, 60-80 °C
Buchwald, S. L.; Yin, J. J. Am. Chem. Soc. 2000, 122, 12051-12052.
P
O
(OR1)2
*
PCy2
NMe2
0.8-3.3 mol%
4
5
OEt Ph 74 74 (+)
OMe Me 91 84 (+)
* absolute configuration undetermined.
O
(OR1)2
Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Aryl-Lead Triacetate
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.
OH
R
Pb(OAc)3
R'+pyr (xs)
OH
R
R'
+ Pb(OAc)2
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Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Aryl-Lead Triacetate
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.
OH
R
Pb(OAc)3
R'+pyr (xs)
OH
R
R'
O
R
Pb
R'
NAcO
AcO
+ Pb(OAc)2
Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Aryl-Lead Triacetate
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.
OLi
R
Pb(OAc)3
R'+brucine (6 equiv)
toluene, -40 °C
OH
R
R'
+ Pb(OAc)2
Entry Phenol Aryl-Lead Product% Yield
(dl:meso ) % ee
1
2
3
4
5
OH
OH
OH
MeO OMe
OH
Ph
Pb(OAc)3
Pb(OAc)3
Pb(OAc)3
Ph
i-Pr
Pb(OAc)3
Pb(OAc)3
Ph Ph
OH
OH
MeO OMePh Ph
OH
OH OH
Ph
OH
68(>99:1)
83
>99(2:1)
51
55(6.9:1)
93
99 85
99 20
N
MeO
MeO
N
O
H
H
H
H
H
O
brucine
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Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Aryl-Lead Triacetate
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.
OLi Pb(OAc)3
+brucine (6 equiv)
toluene, -40 °C
Pb OO
OO
O
Ph
OLiO
Ph
axial attack
brucine- AcOLi
pseudo-rotation PbO
Ph
L
L L
LL
-or-
L = brucine or AcO
O
Ph H
O
Ph
H
OH
Ph
R S
M fast
Pb O
Ph
L
LL
LL
Resolution/Desymmetrization of Prostereogenic Biaryls
Configurationally Stable, Axially Achiral
Introduction/Transformation of ArylSubstituent
(Desymmetrization)
Introduction of Chiral Bridge
(Resolution)
Atroposelective Cleavage of a Bridge(The Lactone Method)
(Resolution)
Configurationally Unstable, Axially Chiral
X X
Y
Z
CS-symmetric
Z X
Y
*
X
Y
A
A
X
Y
*
**
macroscopically achiral
X
Y
Nuc*H
X
Y
Nuc*
H
macroscopically achiral
*
• Biaryl axis formed non-selectively prior to introduction of axial chirality.
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Resolution/Desymmetrization of Prostereogenic BiarylsIntroduction/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.
Me Me
MeMe
N N
(-)-sparteine1. n-BuLi,
2. CO2
Me
Me
CO2H
HO2C
Engelhardt, L. M.; Leung, W.-P.; Raston, C. L.; Salem, G.; Twiss, P.; White, A. H. J. Chem. Soc. Dalton Trans. 1988, 2403-2409.
70% yield40% ee
P
Pd
N Cl
Cl
Me Me
Ph Ph
Me
PdCl2[(S )-alaphos]
Resolution/Desymmetrization of Prostereogenic BiarylsIntroduction/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.
R1
R2
TfO OTf
R3MgBr
LiBr or LiI
R1
R2
R3 OTfM
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.
Entry R1 R2 Yield (%) % ee
1
2
3
4
5
6
R3
H Me
H Me
H Ph
H Ph
Ph 85 95
87 85
Ph 80 94
88 99
Ph 92 94
88 92
Ph3Si
Ph3Si
Ph3Si
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Resolution/Desymmetrization of Prostereogenic BiarylsIntroduction of a Chiral Bridge
XO
O
RO
H2NOH
Ph
toluene, reflux
X
N
O
OMe
PhX
N
O
OMe
Ph
+
major minor
Penhoat, M.; Levachet, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517-9520.
X = CH2: 95%, >95% deX = N: 72%, >95% de
Resolution/Desymmetrization of Prostereogenic BiarylsIntroduction of a Chiral Bridge
XO
O
RO
H2NOH
Ph
toluene, reflux
X
N
O
OMe
PhX
N
O
OMe
Ph
+
major minor
O
HN Me
Ph
X
Ph rings oriented trans,axis rotates away fromoxazolidine Ph. O
N Me
Ph
X
Ph rings oriented cis,axis rotates away frombenzylic Me.
OOR
ORO H
XO
RO
XO
ROO
HN
O
HN
Ph
Ph
Me
Me
+
Penhoat, M.; Levachet, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517-9520.
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Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
O O
O O
Br
O
O
R
R
R
R
R
R
catalyst
NaOAcDMA
130 °C
catalyst A: Pd(OAc)2 (10 mol%) PPh3 (20 mol%)
catalyst B: (1 mol%)O
Pd
O O
Pd
O
Me
Me
P
PAr2
Ar2
Entry R A B
1
2
4
5
6
3
H 80 91
Me 75 87
Et 71 83
i-Pr 72 82
t-Bu 44 81
OMe 77 90
Coupling Yields
M P
Bringmann, G.; Breuning, M.; Henschel, P.; Hinrichs, J. Org. Synth. 2002, 79, 72-83.
Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
O O
O O
R
R
R
R
M P
OB
N
PhPh
H
Me
, BH3, THF, 30 °C
O
Al
O
OEt
HP
Li
KHN
Me MeNaO
Sp-Tol
OLi
RHO
R
OH
RHO
R
HN
O Me
S
MeHO
Me
O
O Me
OH
S
O
p-Tol
O
Me
Me
R = OMe: 70%, 82% deR = Me: 85%, 90% de
73%, 0% dechemically atropisomerizes
R = OMe: 97%, 76% deR = Me: 95%, 86% de
R = OMe: 94%, 95% deR = Me: 97%, 94% de
R = OMe: 88%, 91% deR = Me: 78%, 94% de
Bringmann, G. Org. Synth. 2002, 79, 72-83.Bringmann, G. Angew. Chem. I. E. Engl. 1992, 31, 761-762.Bringmann, G. Synthesis 1999, 525-558.Bringmann, G. Eur. J. Org. Chem. 1999, 3047-3055.Bringmann, G. Chem. Eur. J. 1999, 5, 3029-3038.
![Page 29: GM 11-14-05 - Atropisomerism · Atropisomerism Axial Chirality in Nature and Synthesis Kevin Allan Stoltz Group Literature Meeting Monday 11/14/2005 8 pm 147O Noyes R R MLn* R O O](https://reader035.vdocuments.us/reader035/viewer/2022063000/5f0d082c7e708231d43856e8/html5/thumbnails/29.jpg)
Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
Bringmann, G. Synthesis 1999, 4, 525-558.
O
O
R
R
OH
RHO
R
, BH3, THF, 30 °C
R = OMe: 88%, 91% deR = Me: 78%, 94% de
OB
N
PhPh
Me
H
M
Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
Bringmann, G. Synthesis 1999, 4, 525-558.
O
O
R
R
OH
RHO
R
, BH3, THF, 30 °C
R = OMe: 88%, 91% deR = Me: 78%, 94% de
OB
N
PhPh
Me
H
M
NB
O Me
B
O
O
R
R
H
H
H
Ph
Ph
Re
![Page 30: GM 11-14-05 - Atropisomerism · Atropisomerism Axial Chirality in Nature and Synthesis Kevin Allan Stoltz Group Literature Meeting Monday 11/14/2005 8 pm 147O Noyes R R MLn* R O O](https://reader035.vdocuments.us/reader035/viewer/2022063000/5f0d082c7e708231d43856e8/html5/thumbnails/30.jpg)
Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
O
O
O
O
Bringmann, G. Synthesis 1999, 4, 525-558.
eq
ax
ax
eq
R
R
R
R
H
H
H
H
Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
O
O
O
O
Bringmann, G. Synthesis 1999, 4, 525-558.
eq
ax
ax
eq
R
R
R
R
H
H
H
H
![Page 31: GM 11-14-05 - Atropisomerism · Atropisomerism Axial Chirality in Nature and Synthesis Kevin Allan Stoltz Group Literature Meeting Monday 11/14/2005 8 pm 147O Noyes R R MLn* R O O](https://reader035.vdocuments.us/reader035/viewer/2022063000/5f0d082c7e708231d43856e8/html5/thumbnails/31.jpg)
Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
O
O
O
O
Bringmann, G. Synthesis 1999, 4, 525-558.
O
H
O
OO
H
eq
ax
ax
eq
R
R
R
R R
R
R
R
Re face
attack
Si face
attack
H
H
H
H
Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
O
O
O
O
Bringmann, G. Synthesis 1999, 4, 525-558.
O
H
O
OO
H
eq
ax
ax
eq
H
O
O
R
R
R
R
R
R R
R
R
R
Re face
attack
Si face
attack
OH
O
R
R
RHO
R
H
O
major
OHR
R
H
O
minor
H+
H+
H
H
H
H
![Page 32: GM 11-14-05 - Atropisomerism · Atropisomerism Axial Chirality in Nature and Synthesis Kevin Allan Stoltz Group Literature Meeting Monday 11/14/2005 8 pm 147O Noyes R R MLn* R O O](https://reader035.vdocuments.us/reader035/viewer/2022063000/5f0d082c7e708231d43856e8/html5/thumbnails/32.jpg)
Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
O
O
O
O
Bringmann, G. Synthesis 1999, 4, 525-558.
O
H
O
OO
H
eq
ax
ax
eq
H
O
O
R
R
R
R
R
R R
R
R
R
Re face
attack
Si face
attack
OH
O
R
R
O
O
H
R
R
OH
O
R
R
RHO
R
H
O
major
OHR
R
H
O
minor
H+
H+
stereochemicalleakage
stereochemicalleakage
rate?
rate?
H
H
H
H
Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method
O
O
O
O
Bringmann, G. Synthesis 1999, 4, 525-558.
OO
H
eq
ax
ax
eq
H
O
O
R
R
R
R R
R
R
R
Re face
attack
RHO
R
H
O
major
H+
H
H
H
H
For optimal selectivity:• use a reactive nucleophile in cases involving an intermediate ketone or aldehyde, in order to avoid "stereochemical leakage"• use bulkier chiral nucleophiles for better facial selectivity.• optimal reactivity/selectivity with Me-CBS and catechol borane.
RHO
R
OH
major
[H]
OB
N
PhPh
H
Me
O
B
O
H
![Page 33: GM 11-14-05 - Atropisomerism · Atropisomerism Axial Chirality in Nature and Synthesis Kevin Allan Stoltz Group Literature Meeting Monday 11/14/2005 8 pm 147O Noyes R R MLn* R O O](https://reader035.vdocuments.us/reader035/viewer/2022063000/5f0d082c7e708231d43856e8/html5/thumbnails/33.jpg)
• Newest and least developed method for the formation of atropisomeric biaryls.• Most intermediates/transition states unknown.
Transfer of Chirality from Benzylic
sp3 Center to Biaryl Axis[2+2+2] Cycloaddition with Chiral Metal Complexes
*
*
M
*
Atroposelective Construction of an Aromatic Ring
Me
Cl
Cl
OH
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.
Me
Cl
Me
Cl
Cl
OH
TiCl4
CH2Cl2, -78 °C
TBSOTf
CH2Cl2, 0 °C
Atroposelective Construction of an Aromatic RingCentral-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols
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Me
Cl
Cl
OH
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.
Me
Cl
Me
Cl
Cl
OH
TiCl4
CH2Cl2, -78 °C
TBSOTf
CH2Cl2, 0 °C
Atroposelective Construction of an Aromatic RingCentral-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols
R1 R2 R2R1 R1
Entry % YieldR1 R2 % ee
1
2
3
4
5
Cl H 97 >99
Cl Cl 70 >99
OMe Me 71 >99
OMe Cl 65 >99
Me Cl 47 >99
Entry % YieldR1 R2 % ee
1
R2
Me H 41 45
Me
Cl
Cl
OH
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.
Me
Cl
Me
Cl
Cl
OH
TiCl4
CH2Cl2, -78 °C
TBSOTf
CH2Cl2, 0 °C
Atroposelective Construction of an Aromatic RingCentral-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols
R1 R2 R2R1 R1 R2
Me
Cl
Cl
OHR1 R2
TiCl4 Me
Cl
Cl
OHR1 R2
SiR3
OTf
R1 rotates away from
chelated TiCl4
R1 rotates away from
chelated TBSOTf
![Page 35: GM 11-14-05 - Atropisomerism · Atropisomerism Axial Chirality in Nature and Synthesis Kevin Allan Stoltz Group Literature Meeting Monday 11/14/2005 8 pm 147O Noyes R R MLn* R O O](https://reader035.vdocuments.us/reader035/viewer/2022063000/5f0d082c7e708231d43856e8/html5/thumbnails/35.jpg)
Me
Cl
Cl
OH
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.
Me
Cl
Me
Cl
Cl
OH
TiCl4
CH2Cl2, -78 °C
TBSOTf
CH2Cl2, 0 °C
Atroposelective Construction of an Aromatic RingCentral-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols
R1 R2 R2R1 R1 R2
Me
Cl
Cl
OHR1 R2
TiCl4 Me
Cl
Cl
OHR1 R2
SiR3
OTf
R1 rotates away from
chelated TiCl4
R1 rotates away from
chelated TBSOTf
Me
Cl Cl
R1 R2
rotation aroundpre-axis bond
(unknown mechanism)
Me
Cl
Cl
OH
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.
Me
Cl
Me
Cl
Cl
OH
TiCl4
CH2Cl2, -78 °C
TBSOTf
CH2Cl2, 0 °C
Atroposelective Construction of an Aromatic RingCentral-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols
R1 R2 R2R1 R1 R2
Me
Cl
Cl
OHR1 R2
TiCl4 Me
Cl
Cl
OHR1 R2
SiR3
OTf
R1 rotates away from
chelated TiCl4
R1 rotates away from
chelated TBSOTf
Me
Cl Cl
R1 R2
Me
R1 R2
ClCl
- H , - HCl
rotation aroundpre-axis bond
(unknown mechanism)
![Page 36: GM 11-14-05 - Atropisomerism · Atropisomerism Axial Chirality in Nature and Synthesis Kevin Allan Stoltz Group Literature Meeting Monday 11/14/2005 8 pm 147O Noyes R R MLn* R O O](https://reader035.vdocuments.us/reader035/viewer/2022063000/5f0d082c7e708231d43856e8/html5/thumbnails/36.jpg)
Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions
CN
OR1
R2
R2
catalysth! (" = 420 nm)
THF, 3 °C
R2R2
catalysth! (" = 420 nm)
THF, 3 °C
N
R2
R2N
R2
R2
R2
R2
Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797.
OR1 OR1
Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions
Co Co Co Co
CN
OR1
R2
R2
catalysth! (" = 420 nm)
THF, 3 °C
R2R2
catalysth! (" = 420 nm)
THF, 3 °C
N
R2
R2N
R2
R2
R2
R2
O
O
Co
O
O
Co
O
O
Catalyst Screen
Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797.
OR1 OR1
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Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions
Co Co Co Co
CN
OR1
R2
R2
catalysth! (" = 420 nm)
THF, 3 °C
R2R2
catalysth! (" = 420 nm)
THF, 3 °C
N
R2
R2N
R2
R2
R2
R2
O
O
Co
O
O
Co
O
O
Catalyst Screen
Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797.
OR1 OR1
Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions
CN
OR1
R2
R2
catalysth! (" = 420 nm)
THF, 3 °C
R2R2
catalysth! (" = 420 nm)
THF, 3 °C
N
R2
R2N
R2
R2
R2
R2
Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797.
Co
Catalyst
Entry
OR1 OR1
R1 R2 % Yield % ee Entry R1 R2 % Yield % ee
1 1
2
3
2
3
Me n-pentyl 33 38
Me n-Pr 8 32
Bn n-pentyl 7 39
Me Et 10 64
Bn Et 3 59
Me n-pentyl 2 63
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Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions
OR1
catalysth! (" = 420 nm)
THF, 3 °C
R2R2
catalysth! (" = 420 nm)
THF, 3 °C
N N
R2
R2
R2
R2
Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797.
Co
Catalyst
Entry
OR1 OR1
R1 R2 % Yield % ee Entry R1 R2 % Yield % ee
1 1
2
3
2
3
Me Me 88 88
Me Ph 86 89
Me t-Bu 74 88
Me Et 10 64
Bn Et 3 59
Me n-pentyl 2 63
R2
R2CN
Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions - Helicenes
Stara, I. G. Tetrahedron Lett. 1999, 40, 1993-1996.
• First reported asymmetric synthesis of a helicene derivative.
CO2Me
R = OHR = Br
PBr3, THF, 0 °C
THF, -78 °C
R
R
R = TIPSR = H
n-Bu4NF, THF, rt
CO2Me
Red-Al
toluene, 0 °C
R
R
Ni(cod)2
(S)-(-)-MOPTHF, -20 °C
tetrahydro[6]helicene
TIPS
Li
PPh2
(S)-(-)-MOP
![Page 39: GM 11-14-05 - Atropisomerism · Atropisomerism Axial Chirality in Nature and Synthesis Kevin Allan Stoltz Group Literature Meeting Monday 11/14/2005 8 pm 147O Noyes R R MLn* R O O](https://reader035.vdocuments.us/reader035/viewer/2022063000/5f0d082c7e708231d43856e8/html5/thumbnails/39.jpg)
Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions - Helicenes
Stara, I. G. Tetrahedron Lett. 1999, 40, 1993-1996.
• First reported asymmetric synthesis of a helicene derivative.
CO2Me
R = OHR = Br
PBr3, THF, 0 °C
THF, -78 °C
R
R
R = TIPSR = H
n-Bu4NF, THF, rt
CO2Me
Red-Al
toluene, 0 °C
R
R
Ni(cod)2
(S)-(-)-MOPTHF, -20 °C
tetrahydro[6]helicene
TIPS
Li
PPh2
(S)-(-)-MOP
P