Catalytic Asymmetric Electrocyclizations: Early Investigations in an Emerging Field R. David Grigg Schomaker Group Organic Student Seminar University of.

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