catalytic asymmetric electrocyclizations: early investigations in an emerging field r. david grigg...
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Catalytic Asymmetric Electrocyclizations: Early Investigations in an Emerging Field
R. David GriggSchomaker GroupOrganic Student SeminarUniversity of Wisconsin-MadisonOctober 14, 2010
140 oC
6 Cyclization
Background• Electrocyclic reactions
• Stereospecific cyclization
• Several drawbacks limit practical use of these reactions
H3C CH3
CH3 CH3
6 Thermal Disrotatory
cis Product
2
Woodward, R.B. and Hoffmann, R. The Conservation of Orbital Symmetry. Verlag Chemie, Weinheim, 1970.
H H
Electrocyclic Cycloaddition
Sigmatropic ene reactionRearrangement
R4R1
R2 R3
O Protic or Lewis acid
O
R1 R4
R2 R3
A Powerful Synthetic Tool
• Biomimetic syntheses of endiandric acids
• 8π-6π cascades
• Natural products isolated as racemates
3
Nicolaou, K.C.; Petasis, N.A.; Zipkin, R.E. J. Am. Chem. Soc. 1982, 104, 5560-5562.
CO2Me
Ph
1) H2, Pd/BaSO4, quinoline
2) Toluene, 100 oCCO2Me
Ph
CO2Me
PhPh
CO2Me
H H
Ph
CO2Me
H H
8
con
6
dis
endiandric acid D endiandric acid Emethyl ester methyl ester
[4+2]
CO2Me
H
HH
H
HPh
H
endiandric acid Amethyl ester
O
OMe
O Microwave, 150 oC
Toluene O
OMe
O O OMe
O
H+
() deoxytridachione () ocellapyrone A 32% 38%
Asymmetric Electrocyclization In Nature• Enzyme provides chiral environment for cyclization
4
Korman, T.P.; Hill, J.A.; Vu, T.N.; Tsai, S. Biochemistry 2004, 43, 14529-14538.Miller, A.K.; Trauner, D. Angew. Chem. Int. Ed. 2005, 44, 4602-4606.Díaz-Marrero, A.R.; Cueto, M.; D’Croz, L.; Darias, J. Org. Lett. 2008, 10, 3057-3060.
O
O
OMe
O
O
H
H
OMe
8
OOMe
O
Presumed Tetraene Precursor
condis
6O
O
H
H
OMe
O
O
elysiapyrone A
Nazarov CyclizationO
R1 R4
R2 R3Lewis acid
O
R1 R4
R2 R3
LA
pentadienyl cation oxyallyl cation
4
con
R2 R3
R1 R4
OLA
R2 R3
R1 R4
OLA
R2 R3
R1 R4
O
H
elimination protonation
R2 R3
R1 R4
OLA
kineticprotonation
thermodynamicprotonation R2 R3
R1 R4
O
R2 R3
R1 R4
O
cis trans
5
Nazarov, I.N.; Zaretskaya, I.I. Bull. Acad. Sci. U.R.S.S., Classe sci. chim. 1942, 200-209. Frontier, A.J.; Collison, C. Tetrahedron 2005, 61, 7577-7606.
• Earliest catalytic asymmetric examples with Nazarov cyclization
• 4π electrocyclization: controtatory
R2 R3
R1 R4
OLA
HH
either proton can eliminate
R2 R3
R1 R4
OLA
R2 R3
R1 R4
OLA
regioselectivity problem in the elimination
OR
Substrate-Controlled Torquoselectivity
• Favoring direction of orbital rotation (torquoselectivity)
• Torquoselectivity can be controlled by a stereocenter
O
R1 R4
R2 R3
LA
Clockwise OR Anti-Clockwise
R2 R3
R1 R4
OLA
R2 R3
R1 R4
OLA
4
con
6
Frontier, A.J.; Collison, C. Tetrahedron 2005, 61, 7577-7606Denmark, S.E.; Wallace, M.A.; Walker, C.B. J. Org. Chem. 1990, 55, 5543-5545
CR1
Me R3
H
R2
O
R1
Me R3
OLA LA
R1
Me R3
OLA
HR2
R2H
Favored
Disfavored
A1,3 Strain
OTMS FeCl3
CH2Cl2 , -50 oC
OFeCl2
OFeCl2
TMSTMS
H H
HO
H H
X
88% ee58% yield
88% ee
TMS
OFeCl2
H
NN
O
O
H
R
R
H
OO
H
Ph
Ph
R1
CuEt2N
Lewis Acid-Mediated Asymmetric Nazarov
• Chiral ligand (bisoxazoline) on Lewis acid could control torquoselectivity
CuO
OOMe
OMe
NN PhHO
O
H
R
R
H
R = tBu Evans (2000)
7
Evans, D.A.; Rovis, T.; Kozlowski, M.C.; Downey, C.W.; Tedrow, J.S. J. Am. Chem. Soc. 2000, 122, 9134-9142.Aggarwal, V.K.; Belfield, A.J. Org. Lett. 2003, 5, 5075-5078.
R1
Ph Ph
NEt2
O O
1 equiv CuBr2, AgSbF6
DCM, RT
O
Ph
NEt2
O
Ph
R1
NN
O O
tBu tBu
R3 LA equiv
Yield (%)
ee (%)
Ph 1.0 92 86
Ph 0.5 56 87
Me 1.0 72 84
Me 0.5 56 85
Lewis Acid-Mediated Asymmetric Nazarov
R1 R2 LA equiv
Yield (%)
ee (%)
Me Ph 1.0 73 76
Ph Ph 1.0 98 86
Me Me 1.0 35 3
Ph Me 1.0 86 42
8
R1
Ph R2
OEt
O O
CuBr2, AgSbF6
DCM, RT
O
R2
OEt
O
Ph
R1
NN N
O O
iPr iPr
OO
OEt
R2
PhR1
R2
O
Ph
R1EtO
ON
N
NO
O
CuiPr
iPr
• Bulky substituents critical to achieving high enantioselectivity
Aggarwal, V.K.; Belfield, A.J. Org. Lett. 2003, 5, 5075-5078.Evans, D.A.; Burgey, C.S.; Kozlowski, M.C.; Tregay, S.W. J. Am. Chem. Soc. 1999, 121, 686-699.
Cu-tris(oxazoline) Catalyst
• Polarized divinyl ketones cyclize with poor enantioselectivity using Cu(II)-PyBOX Lewis acids
• Desired less planar chiral ligand
• tris-oxazoline Pendant group on box ligand
OOMe
O O
Cu-iPr-PyBOX (100%)O
O
Ph
CO2MePh 94% Yield
27% ee- +
Pendant Group
9
He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2003, 125, 14278-14279.Hargaden, G.C.; Guiry, P.J. Chem. Rev. 2009, 109, 2505-2550.Cao, P.; Deng, C.; Zhou, Y.; Sun, X.; Zheng, J.; Xie, A.; Tang, Y. Angew. Chem. Int. Ed. 2010, 49, 4463-4466.
X =
O
N
ON ONN
NO
O
H
R
R
H
OO
H
R3OMe
R2
R1
Cu
X
Catalyst Design and Scope
Ligand Yield (%) ee (%)
1 85 78
2 74 88
3 73 85
4 90 92
5 69 86
O
N
ON ON
N N
OO
iPr iPr
N N
OO
1
2-4
1 & 2: X =
3: X = 4: X =
5: X = H
X
X
O
R
OMe
O O
Ligand (7.3 mol%)
CuCl2 (10 mol%)
NaB(ArF)4 (20 mol %)
HFIP (1.0 equiv.)
tBuOMe, RT
O
O
CO2Me
R
12 ExamplesYields: 45-96%
ee: 78-98%
R = Aryl or cyclohexyl
R = Ph for Catalyst Screening
10
Cao, P.; Deng, C.; Zhou, Y.; Sun, X.; Zheng, J.; Xie, Z.; Tang, Y. Angew. Chem. Int. Ed. 2010, 49, 4463-4466.
• Only minor improvement in selectivity with pendant group
• 10 mol% catalyst loading: Ionizing additive improved turnover
NN
MeO
O
OO
MeO
HCu
O
OO
MeOH
O
OO
MeO
HO
vs.+3.94 kcal/mol 0.00 kcal/mol
DFT Calculations: B3LYPBasis Sets: 6-31G (d), level, sddall (Cu)
NN
MeO
OCu N
N
O
OCu
X X X
Me
Stereochemical Model
• Double-bond isomerization prior to cyclization
• Steric effect identified for disfavored rotation (3.94 kJ mol-1)
• Role of sidearm not defined
?
11
Cao, P.; Deng, C.; Zhou, Y.; Sun, X.; Zheng, J.; Xie, Z.; Tang, Y. Angew. Chem. Int. Ed. 2010, 49, 4463-4466.He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2008, 130, 1003-1011.
Enantioselective Protonation in the Nazarov
• Cyclization of 2-alkoxy divinyl ketone with Sc-PyBOX catalyst
• Other substrates produced mixtures with low enantioselectivities
• Suspected poor control of torquoselectivity
• Protonation of enolate proposed to occur asymmetrically
O
O
N
N N
O O
Ph Ph
Sc(OTf)3
(20 mol%)
THF, rt
OO
H
H
53 % yield61 % ee
O
O
MeCN, molecular sieves
10 mol % Sc(OTf)3PyBOX OO
OO
Me
MeMe
Me
Yield: 62% 18%ee: 40% 79%
12
Mohr, J.T.; Hong, A.Y.; Stoltz, B.M. Nature Chem. 2009, 359-369.Liang, G.; Gradl, S.N.; Trauner, D. Org. Lett. 2003, 5, 4931-4934.
O
O
X
R
MeCN, molecular sieves
rt or 0 oC
10 mol % Sc(OTf)3PyBOX OO
R
Chiral scaf fold controls face of
enolate protonation
X = CH2 or OR = Alkyl or Aryl
OO
R
*M
NN N
O O
Sc(OTf)3
10 ExamplesIsolated Yields: 65-94%
ee: 72-97%
NN
O
N OSc
Proposed bindingto Sc through
Chelation
(OTf)3
Enantioselective Protonation in the Nazarov
• Simplified system improved enantioselectivity
• Direction of conrotatory electrocyclization did not affect stereochemical outcome
13
Liang, G. and Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544-9545.Evans, D.A.; Masse, C.E.; Wu, J. Org. Lett. 2002, 4, 3375-3378.
Summary:Lewis Acid-Promoted Nazarov Cyclizations
• Demonstrated viability of the transformation
• Control of torquoselectivity achieved
• Viable alternative: enantioselective protonation
• High catalyst loadings common
Ph
Ph Ph
OEt
O O
CH2Cl2, RT
O
Ph
OEt
O
Ph
Ph
98% yield86% ee
1 equiv Cu-PyBOX
N
N N
O O
iPr iPr
Cu
2+
2 SbF6-
14
Brønsted Acid-Promoted Nazarov Cyclizations
• Precedent: Enantioselective transformations of imines with chiral Brønsted acids
• Carbonyl activation could allow asymmetric Nazarov cyclization
• Control of torquoselectivity or enantioselective protonation
N
R1 R2
R Chiral Brønsted Acid
HB*
N
R1 R2
RH*B
NuH
-*BH
HN
R2R1
R
Nu*
ChiralIon Pair
ArOP
O
ArO OH
R1
R2
R3
R4
OHB*
R1 R3
R4HR2
OH B*
R1 R3
R4R2
O OArP
HO
OArOH
R1 R3
R4R2
O R1
R2 R4
R3O
*
*
15
Terada, M. Synthesis 2010, 1929-1982. Rueping, M.; Ieawsuwan, W.; Antonchick, A.P.; Nachtsheim, B.J. Angew. Chem. Int. Ed. 2007, 46, 2097-2100.
First Enantioselective Organocatalytic Electrocyclization
• Chiral BINOL phosphates
• N-triflyl phosphoramide improved reactivity
• Low diastereoselectivity
R1 Ar Yield (%)
cis/trans ee (cis), ee
(trans)
methyl phenyl 88 6:1 87, 95
n-pentyl phenyl 78 3.2:1 91, 91
n-propyl 4-methylphenyl
77 2.6:1 91, 90
n-propyl 4-bromophenyl
87 4.6:1 92, 92
O R1O
Ar
2 mol% *BH
CHCl3, 0 oC
OO
Ar
R1O
O
Ar
R1+O
OP
O
N
SO2CF3
H
Ar
Ar
Ar =
OO
R2
R1O
O
R2
R1
BasicAlumina
16
Rueping, M.; Ieawsuwan, W.; Antonchick, A.P.; Nachtsheim, B.J. Angew. Chem. Int. Ed. 2007, 46, 2097-2100.
Organocatalytic Enantioselective Protonation
• Octahydro-BINOL derivative improved selectivity for asymmetric enolate protonation
• No stereochemical model for either system
R1 R3
R2
O OArP
HN
OArOH
Potential forenantioselective protonation
SO2CF3
*
O
OP
O
N
SO2CF3
H
Ar
Ar
Ar =
O R
O5 mol% *BH
CHCl3, -10 oC
OO
R
R = alkyl orbenzyl groups
9 ExamplesYields: 44-93%ee: 67-78%
17
Rueping, M.; Ieawsuwan, W. Adv. Synth. Catal. 2009, 351, 78-84.
Bifunctional Organocatalyst Approach
• Asymmetric Nazarov for α-ketoenones
• Well-designed for interaction with a bifunctional organocatalyst
Ph
Me
O
O +
HN
NH3
OTf
25 mol% H2O
MeCN, rt, 7.5 d
60% Yield94% ee
Previous Report: Tius (2010)
N
NR
RMe
Ph Ph
OH
O
O
OH
Ar
R1
R2
RO2C
Acid
Base
Chiral
18
Bow, W.F.; Basak, A.K.; Jolit, A.; Vicic, D.A.; Tius, M.A. Org. Lett. 2010, 12, 440-443.Basak, A.K.; Shimada, N.; Bow, W.F.; Vicic, D.A.; Tius. M.A. J. Am. Chem. Soc. 2010, 132, 8266-8267.Shimada, N.; Ashburn, B.O.; Basak, A.K.; Bow, W.F.; Vicic, D.A.; Tius, M.A Chem. Commun. 2010, 46, 3774-3775.
MeN
NH
NH
CF3
CF3
S
O
Lacks Basic Amino GroupNo Reaction
NH
NH
NR1 R2
S
F3C
CF3
Me CO2Et
O
O
Ph
Me
For Screening
Thiourea Catalysts for Asymmetric Nazarov
• Bifunctional nature of catalyst crucial to enantioselectivity
• Product could inhibit turnover
• No well-defined stereochemical model
R1 R2 ee (%)
H H 82
Me Me 12
H Cyclohexyl
48
R4 CO2Et
O
O
Ar
R3 Catalyst (20 mol%)
toluene, rt
13 Examplesyields: 42-95%
ee: 80-97%
OH
O
R4CO2EtAr
O
O
HH
Potential for C3-C4 bondtorsion bycatalyst
Catalyst
19
Basak, A.K.; Shimada, N.; Bow, W.F.; Vicic, D.A.; Tius, M.A. J. Am. Chem. Soc. 2010, 132, 8266-8267.
Summary:Organocatalytic Asymmetric Nazarov
• Organocatalytic methods compare well to techniques utilizing Lewis acidic metals
• Alternative approaches have achieved lower catalyst loadings
• Attempts made to broaden substrate scope
• Mechanisms of stereoinduction not well-understood at present
O
O2 mol% *BH
CHCl3, 0 oC
2 h
OO
O
O
O
O
OO
O
O
83% yield1.5:1 dr
87% ee (cis)92% ee (trans)
20
6π Electrocyclizations: Beginnings
• Rate of thermal 6π electrocyclizations strongly dependant upon substrate electronics
• Lewis acid interaction with EWG could catalyze the reaction• DFT calculations identified significant activation barrier lowering for
ester at position 2
+24 kcal/mol +26 kcal/mol
+14 kcal/mol
+24 kcal/mol
CO2Me
CO2Me
E = -10 kcal/mol
CO2Me
CO2Me
OMeOLA O
OMe
LA
DFT: B3LYP / 6-31G**
12
3
45
6
21
Guner, V.A.; Houk, K.N.; Davies, I.W. J. Org. Chem. 2004, 69, 8024.Bishop, L.M.; Barbarow, J.E.; Bergman, R.G.; Trauner, D. Angew. Chem. Int. Ed. 2008, 47, 8100-8103
Me2AlCl
50 oC, C6D6
Ph
OEtO
Ph
OEtO
Catalytic Carba – 6π Electrocyclization
• t1/2 = 4 h at 50 °C without Me2AlCl
• t1/2 = 21 min at 50 °C with 1 equiv Me2AlCl
O
Ph
O
Ph
H
1 equiv. Sc(OTf )3-PyBOX2,6-Di-t-butyl-4
-methylpyridine (0.7equiv)
(CDCl2)2, 5 h, RT
57-77% ee
N
N N
O O
Sc(OTf)3Ph Ph
Uncatalyzed
1 equiv LA
0.43 equiv LA
• Cyclization & stereocontrol feasible with Sc(III) & Cu(II) Lewis acids
22
Bishop, L.M.; Barbarow, J.E.; Bergman, R.G.; Trauner, D. Angew. Chem. Int. Ed. 2008, 47, 8100-8103.Bishop, L.M.; Roberson, R.E.; Bergman, R.G.; Trauner, D. Synthesis 2010, 2233-2244.
N
R RR1
Base
Chiral Phase-Transfer Catalyst
HN
R1 RRPotential for
Cation-DirectedTorquoselectivity
N
R1 R R
6 π Electrocyclization: Indoline Synthesis
• 2-aza-pentadienyl anions found to be excellent substrates for facile electrocyclization
• Asymmetric phase transfer catalysis proposed as a route to asymmetric indoline synthesis
N
N
O
O
Bn
PhNH
N
O
O
Bn
Ph
EtOH/NaOEt
RT
91 % yield
Speckamp: 1981
23
Speckamp, W.N.; Veenstra, S.J.; Dijkink, J.; Fortgens, R. J. Am. Chem. Soc. 1981, 103, 4643-4645.Maciver, E.E.; Thompson, S.; Smith, M.D. Angew. Chem. Int. Ed. 2009, 48, 9979-9982.
CO2iPr
CO2iPr
NH2R1
1) R2CHO, MgSO4
toluene, rt
2) catalyst (10 mol%)
toluene, -15 oC
K2CO3 (aq)
R1 NH
iPrO2CCO2
iPr
R2N
H
N
OH
H Cl19 Examples
yields: 54-92%ee: 73-98%
Cyclization via Phase-Transfer Catalysis
CO2Me
CO2tBu
NF3C Ph
Catalyst (10 mol%)
Toluene, -15 oC
K2CO3 (aq) F3C NH
tBuO2CCO2Me
Ph
d.r. 3.5:1, ee(major): 83%, ee(minor): 66%
CO2iPr
CO2iPr
O2N Ph
No Reaction
24
Maciver, E.E.; Thompson, S.; Smith, M.D. Angew. Chem. Int. Ed. 2009, 48, 9979-9982.
Electrocyclization or Mannich?
• Possibility for an intramolecular Mannich-type reaction
• No cyclization with a substrate that could control enolate geometry
N
H
HO
N
N
iPrOO
cyclize awayf rom catalyst
NH
iPrO2CCO2
iPr
Ph
N N
R R
5-(enolexo)-endo trig 6π Disrotatory
CO2Me
NF3C Ph
N O
Bn
No Cyclization
R
R
25
Maciver, E.E.; Thompson, S.; Smith, M.D. Angew. Chem. Int. Ed. 2009, 48, 9979-9982. Corey, E.J.; Xu, F.; Noe, M.C. J. Am. Chem. Soc. 1997, 119, 12414-12415.
Chiral Brønsted Acid Catalysis: 6π
• α,β-unsaturated hydrazone rearrangement to give 2-pyrazoline is isoelectronic to a pentadienyl anion 6π electrocyclization
• Acid-promoted: might occur asymmetrically with chiral Brønsted acid
NHN
Me
R
A
NHNR
Me H A
Fischer: 1895
R R
Huisgen: Isoelectronic with 6 π Electrocyclization of Pentadienyl anion
H
R1
NN
HH
R2 OPO
O O*
Possible Controlof Torquoselectivityby Chiral Counterion
N N
F
MeO2S
N N
F
MeO2SCF3
(S)-(-)-E-6244
Patented COX-2 Inhibitors
26
Huisgen, R. Angew. Chem. Int. Ed. 1980, 92, 979.Müller, S.; List, B. Angew. Chem. Int. Ed. 2009, 48, 9975-9978.
R
O
NH
NH2
N N
R
+
1) molecular sieves 4 h, 50 oC
2) 10 mol% catalyst
70-96 h, 30 oC
2-Pyrazoline Synthesis via Electrocyclization
• Chiral phosphoric acids found to give optically active products with good yield and enantioselectivity
• Could form hydrazone intermediate in situ
R1
N10 mol% catalyst
N N
R1
R2
14 ExamplesYields: 85-99%ee: 76-96%
HN
R2
Chlorobenzene
30 oC, 70-96 h
O
OP
OH
O
Ar
Ar
Ar =
Chiral BINOL-Phosphoric Acid Catalyst
27
Müller, S.; List, B. Angew. Chem. Int. Ed. 2009, 48, 9975-9978.
Mechanistic Questions
• Two mechanistic scenarios
• Intramolecular Michael addition would be a disfavored 5-endo-trig
O
POHO
O
*
Ph NN
Ph
H
H
OP
O
OO
Ph N
NPhH
H
O
POO
O
*N
N
Ph
HH
OP
O
OO
Ph
N N
Ph
PhH H
PO
O
*
Product
6πDisrot.
α,β-unsaturated hydrazone
E-Z Iminium Isomerization
s-cis tos-trans
Isomerization
OO
*
N
N
H
H
NN
HH
Intramolecular Michael Addition5-endo-trig
6Electrocyclization
28
• Stereochemical model not proposed at present
Müller, S.; List, B. Synthesis 2010, 2171-2179.
6π Electrocyclization Summary
• High activation barrier limits scope to substrates with compatible electronics, though encouraging results have been obtained
• Methods have worked well for heterocycle formation▫ Approaches include phase-transfer catalysis & chiral Brønsted acid
catalysis▫ Mild conditions▫ Exact cyclization mechanisms not well understood
F3C N Ph
CO2iPr
CO2iPr
F3C NH
Ph
iPrO2C CO2iPr10 mol% A
K2CO3 (aq)
toluene, -15 oC
99% Yield97% ee
N
H
Ph
N
OH
ClA
29
Conclusions & Future Directions
• Catalytic asymmetric electrocyclizations have the potential for becoming key synthetic transformations
• Enantioselective reactions can be approached with Lewis acidic metals and organocatalysts
• Selectivity can be accomplished by control of torquoselectivity and through enantioselective protonation
• Future efforts will seek to cyclize more diverse polyene structures in both the Nazarov reaction and 6π systems
• Improving understanding of stereoinduction mechanism will be a key goal in future efforts
30
Acknowledgements
• Jennifer Schomaker
• Kat Myhre
• Practice Talk attendees• Alex Clemens• James Gerken• Jonathan Hudon• Michael Ischay• Liz Tyson• Dan Wherritt• Kevin Williamson• Gene Wong
31
• Luke Boralsky• Rachel Dao• Ally Esch• John Hershberger• Dagmara Marston
• Alan Meis• Simon Pearce• Jared Rigoli• Vitaliy Timokhin
Schomaker Group Members