asymmetric organocatalysis through hydrogen … smith/austinlitsem.pdfasymmetric organocatalysis...

Asymmetric Organocatalysis through Hydrogen Bond Activation

Austin SmithUniversity of North Carolina at Chapel Hill

January 25, 2008

Outline

A. Introduction to Hydrogen Bond Donor Catalysts

B. Types of Catalysts: Structure

1. Thioureasa. Monofunctional Thioureasb. Bifunctional Thioureas

2. TADDOL and BINOL catalysts

3. Chiral Guanidinium and Amidinium Ions

F. Conclusion

Advantages/Disadvantages of Organic Small Molecule Asymmetric Catalysts

•Modular nature, flexible in design

•Exist as catalysts themselves

•Water and air stable

•Potentially recoverable and reusable

Disadvantages of hydrogen bond catalysis

•Higher catalyst loading required

•Separation required

Advantages of hydrogen bond catalysis

Advantages of metal-centered Lewis acid catalysis

Disadvantages of metal-centered Lewis acid catalysis

•Often generated in situ and employed directly

•Often unstable in air and water

•Non-recoverable

•Lower catalyst loading

•Flexibility in varying the counterion, the chiralligand, and the LA element

•Very strong Lewis acid/base interactions

Organic small molecule acid catalysts can accelerate organic reactions by two fundamentally unique mechanisms:

1) Reversible protonation of the electrophile in a pre-equilibrium step prior to nucleophilic attack (Specific Acid Catalysis) example:

2) Acidic activation of electrophiles, but not full protonation--Proton transfer in the transition state in the rate-determining step (General Acid Catalysis or Hydrogen Bond Catalysis) examples: S

NH

NH

R RO

O OH

OH

ArAr

ArAr

Ar

O P O

O

Ar

OH

Thiourea moiety TADDOL catalyst

Phosphoric Acids

Specific Acid Catalysis vs. General Acid Catalysis

1. Proline Derivatives:

NH

O

HN SArOO

NH

O

HN Ph

PhHO

NH

O

OH

2. Enantioselective protonation reactions of prochiral substrates (enantioselective proton transfer to enolates)

3. Hydrogen Bonding in Biological Catalysis: Serine Proteases

Type II Aldolases

4. H-bonding Phase Transfer Catalysis

5. RNA Catalysis

Hydrogen Bond Catalysis not covered

OUTLINE

A. Introduction





E. Conclusion

Jacobsen’s Thiourea Catalyst Discovery

•1998: Parallel library approach used to discover an optimal catalyst for the asymmetric hydrocyanation of imines (the Strecker reaction)

Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.Sigman, M.S.; Vachal, P.; Jacobsen, E.N.; Angew. Chem. Int. Ed. 2000, 39, 1279-1281.

Best catalyst from the library screens and optimization

A =

S

NH

NH

N

O N

HO

OtBu

O

tBu

N

CN

F3C

O

88% yield86% ee

tBu

N

CN

F3C

O

75% yield95% ee

N

CN

F3C

O

74% yield95% ee

N

CN

F3C

O

98% yield95% ee

MeO

N

CN

F3C

O

89% yield89% ee

Br

TBSCN

(1) 4 mol % catalystToluene, -70 ºC 15h

(2) TFAA

N

HN

CN

F3C

O

Cyanation of Ketoimines: Enantioselective Route to Quaternary Amino Acid Derivatives

Vachal, P.; Jacobsen, E.N. Org. Lett. 2000, 2, 867-870.

HNCN

Me

Ph

97% yield91% ee

Br

HNCN

Me

Ph

Me98% yield88% ee

HNCN

Me

Ph

Brquant. yield99.9% ee (afterrecryst)

HNCN

Me

Ph

97% yield90% ee

CO2HR2

R1 NH3Cl hydrolysis,deprotection

A =

S

NH

NH

N

O N

HO

OtBu

O

tBu

A (2 mol %), 15-90h, toluene, -75 ºC HN

CNR1 R2

NHCN

R1 R2

Ph Ph

A (2 mol %), 15-90h, toluene, -75 ºC HN

CNR1 R2

NHCN

R1R2

Where R1 and R2 are not Hup to 95% eeup to 98% yield

Ph Ph

How Does it Function?

Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012-10014.

• Ground state conformation (A) determined through ROESY and NOE experiments

• Reaction 1º order with respect to HCN and catalyst---> reversible formation of imine-catalyst complex

• imine interacts with the urea hydrogens

• imine in a bridging mode between the two urea hydrogens (basis for catalyst turnover)

•CN over diaminocyclohexane portion, away from the amino acid/amide portion (See C)

N N

O

H HN

Ar H

imine in bridging mode

R1

8.5 kcal/mol

NH

N

O

HN

Ar CN

R1

H

product singly-bonded to catalyst

5.0 kcal/mol

Further Reactivity of the Thiourea Catalyst

-Asymmetric Mannich reaction

-Asymmetric hydrophosphonylation of imines

Wenzel, A.G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964-12965.Joly, G.D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102-4103.

R OH

NH2 O

S

NH

NH

N

OX

N

HO

YtBu

C: X = Bn, Y = t-BuD: X = Me, Y = OCO-t-Bu

NO2

O P H

O

O

NO2

N

HR

PhO P

OR

HN

D (10 mol %)

Et2O, rt

93 % yield98 % ee

Bn

O

NO2

NO2

H2 (1 atm)Pd/C (20 mol %)

MeOH, 24-72 h rt

PO

HO OH

R

NH2

N

H R

Boc OTBS

OiPr R OiPr

1. C (5 mol %) toluene, 48 h

2. TFA, 2minNH OBoc

up to 99 % yieldup to 98% ee

Where R is aryl

Enantioselective Transformations of N-Acyl iminium ions

Taylor, M.S.; Jacobsen, E.N.; J. Am. Chem. Soc. 2004, 126, 10558-10559.

-very reactive intermediates, but activating these species through the use of chiral H-bond catalystsis a challenge due to weak Lewis basicity

-First example of N-acyliminium ions activated by chiral H-bond donors

NNH

S

NH

tBu

O

N

PhMeG

NH

N

RMe

OCl

NH

NAc

C5H1165% yield95% ee

NH

NAc

CH(CH2CH3)265% yield93% ee

NH

NAc

CH(CH3)2

67% yield85% ee

NH

NAc

CH2CH2OTBDPS

77% yield90% ee

NH

N

R NH

NAc

R

AcCl (1.0 equiv)

2,6-lutidine (1.0 equiv) Et2O -78 ºC---> -30 ºC

G (10 mol %)

65-81% yield75-95% ee

Mannich-type Reaction with Acylisoquinolinium Ions

Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2005, 44, 6700-6704.

NTroc

CO2iPr

Et3SiH, TFA

CH2Cl2, 0 ºC --> rtNTroc

CO2iPr

Zn, AcOH

THF/H2O, rtNH

CO2iPr86% ee90% yield

86% ee80% yield

NTroc

CO2iPr75% yield92% ee

Me

NTroc


NO2

NTroc


OTBS

NTroc


F3CO2SO

NTroc


Br

NNH

S

NH

tBu

O

N

PhMeG

N

1. TrocCl (1.1 equiv) Et2O, 0 C --> 23 ºC

2.

H2C

OTBS

OiPr(2.0 equiv)

G (10 mol %)Et2O, -78 ºC --> -70 ºC

NTroc

CO2iPr

80% yield86% ee

Enantioselective Pictet-Spengler-Type Cyclizations of Hydroxylactams

Raheem, I.T.; Thiara, P.S.; Peterson, E.A.; Jacobsen, E.N. J. Am. Chem. Soc.. 2007, 129, 13404-13405.

NH

N O

H88% yield96% ee

Br

NH

N O

Ph68% yield85% ee

NH

N O

Me84% yield91% ee

MeO

NH

N

H52% yield81% ee

O

NNH

S

NH

tBu

O

NMe

n-C5H11PhMe

NH

N

O

HO RNH

N O

R

G (10 mol %)TMSCl, TBME

-55 ºC or -78 ºC24-72 h

up to 92% yieldup to 98% ee


Evidence for Hydrogen-Bond Donor Catalysis by Anion Binding

NH

N O

R97% ee when X=Cl68% ee when X=Br<5% ee when X=I

NH

N O

RNH

N

O

HO R

TMSClH2O

NH

N

O

Cl R NH

NO

R

NH

N O

R

X

NH

N O

R

path BSN1-type

path A

NH

NO

RCl

A B D

SN2-type

C

NH

N

O

HO RNH

N O

R


-78 ºC

94% yield when R is Me12% yield when R is H

G (10 mol %)TMSX, TBME

-55 ºC


Evidence for Hydrogen-Bond Donor Catalysis by Anion Binding

Cl

N N

StBu

N PhH HMe

O

NMe

n-C5H11

NH

N O

R97% ee when X=Cl68% ee when X=Br<5% ee when X=I

NH

N O

RNH

N

O

HO R

TMSClH2O

NH

N

O

Cl R NH

NO

R

NH

N O

R

X

NH

N O

R

path BSN1-type

path A

NH

NO

RCl

A B D

SN2-type

C

NH

N

O

HO RNH

N O

R


-78 ºC

94% yield when R is Me12% yield when R is H

G (10 mol %)TMSX, TBME

-55 ºC

OUTLINE

A. Introduction





F. Conclusion

Bifunctional Hydrogen Bond Catalysis

-Catalyst structure allows for activation of both electrophile and nucleophile

-Catalysts usually possess an acidic and basic structural group--dual activation can lead tohigher yields and enantioselectivities.

Example:

-Acidic thiourea activates nitroolefin, basic tertiary amine enhances the nucleophilicity of the 1,3-dicarbonyl compound

-Chiral scaffold helps control approach of nucleophile

N N

S

H H

N

R1

OO

EtO

O

OEt

OHNR2 R3

chiral scaffold

Enantioselective Michael Reaction of Malonates to Nitroolefins

Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673. Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2004, 127, 119-125.

NO2

EtO2C CO2Et

86% yield93% ee

NO2

EtO2C CO2Et

F 87% yield92% ee

NO2

EtO2C CO2Et

95% yield92% ee

NO2

EtO2C CO2Et

74% yield90% ee

SC5H11

NO2

EtO2C CO2Et

78% yield81% ee

iBu NO2

EtO2C CO2Et

88% yield81% ee

CF3

F3C NH

NH

S

NMe2

R NO2EtO2C CO2Et

toluene, rt, 12-72 h(2 equiv) (10 mol %)

R NO2

EtO2C CO2Et

S

Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2004, 127, 119-125.

Reaction Mechanism: Malonate Addition to Nitroolefins

PDT.

EtO2C CO2Et

CF3

F3C NH

NH

S

NMe2

CF3

F3C NH

NH

S

NH OO

OEtEtO

A

1

NO2

CF3

F3C N N

S

N

N

E

E OOHH

D

H

CF3

F3C N N

S

NHHOO N

CF3

F3C N N

S

NHHOO N

C

EtOO

OEt

OH

EtOO

O

OEt

H

B

Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2004, 127, 119-125.

Application to the Total Synthesis of (-)Baclofen

CHO

Cl

MeNO2, NaOMe, MeOH

15 h, rt (90%) Cl

OHNO2

Cl

NO2

Cl

HO2C

NH2 HCl

(-)-Baclofen

6N HCl, 24 h, reflux

(94%)

six steps, 38% overall yield

MsCl, TEA, THF

1 h, rt (72%)

Cl

NH

OEtO

O

NiCl2•6H2O, NaBH4

MeOH, 7.5 h, rt (94%)

Cl

NO2

OEt

O

EtO

O

diethyl malonate, cat.

toluene, rt, 24 h (80%, 94% ee)

Cl

NH

O

1. NaOH, EtOH, 45 h, rt

2. toluene, 6.5 h, reflux (84%)

Takemoto’s Catalyst: Addition to Imides and Aldimines

Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem. Int. Ed. 2005, 44, 4032-4035.Okino, T.; Nakamura, S.; Furukawa T.; Takemoto, Y. Org. Lett. 2004, 6, 625-627.

CF3

F3C NH

NH

S

NMe2F

N

OO

Cl

CNNC

88% yield93% ee

N

OO

MeO

CNNC

77% yield85% ee

N

OO

tBu

CNNC

78% yield92% ee

N

OO

Me

CNNC

86% yield93% ee

NO2

H

HN P(O)Ph2

Cl76% yield67% ee

NO2

H

HN P(O)Ph2

O

85% yield76% ee

NO2

Me

HN P(O)Ph2

83% yield67% ee73:27 d.r.

F (10 mol %)CH2Cl2, rt

RCH2NO2N PO

PhPh

ArAr NO2

R

NH P(O)Ph2

N

OO

R CNNCF (10 mol %)toluene, rt N

OO

R(NC)2HC H

NO2

H

HN P(O)Ph2

87% yield67% ee

NO2

H

HN P(O)Ph2

78% yield70% ee

N

OO

O

CNNC

79% yield85% ee

Enantioselective Petasis-Type Reaction of Quinolines

Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686-6687.

Concept of the newly designed thiourea catalyst

N

R1 R2

H2O, NaHCO3, CH2Cl2

R4

R3

B(OH)2NCO2Ph

R4

R3

R2R1

PhOCOCl

NCO2Ph

H

OMe70% yield97% ee

NCO2Ph

59% yield82% ee

O

O NCO2Ph

H

OMe75% yield95% ee

HMe

NCO2Ph

H

OMe63% yield94% ee

Cl

NNH

NH

SAr

MeHO(H2C)2

(10 mol %)

N OR

O

N

S

NAr

N

O

Me

B

Ph

H HHO

Bifunctional thioureas possessing two acidic groups

Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004. 45, 5589-5592.

NH HN

S

HN

S

HN

CF3

CF3

CF3

F3C

E

H2NNH2

N CF3

CF3

CS

O O

R

OHE (40 mol %)

DMAP, -5 ºC, no solventR

19-90% ee33-99% yield

R H

O

OOH

88% yield33% ee

OOH

38% yield30% ee

CF3 OOH

88% yield19% ee

F3COOH

99% yield33% ee

F3C

OOH

67% yield60% ee

OOH

55% yield86% ee

OOH

72% yield90% ee

OOH

63% yield60% ee

Me

Proposed Transition State Derived from Product Results

• aldehyde and enone coordinate to thiourea groups through a double-hydrogen bond interaction

• aldehyde orients itself so that ‘R’ group is located on opposite side from the thiourea-enone complex, forming the R enantiomer preferentially

• bis-thiourea catalyst E is easily recoverable by silica-gel column chromatography

Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Let. 2004. 45, 5589-5592.

NN

HN

S

HAr

O

N

SAr

HH

R3N

R

O H

O

R

OH

R

Cinchona Alkaloid-Thiourea Bifunctional Catalyst

Vakulya, B.; Varga, S.; Csampai, A.; Soos, T.; Org. Lett. 2005. 7,1967-1970.

• Catalyst derived from epiquinine

• Analogous pseudoenantiomer quinine-derived catalyst was inactive in this system

• Proper conformation of the thiourea and the tertiary amine is crucial for effective catalysis

CF3F3C

NHSNH

N

OMeH N

H

O

no activityCH3NO2

CF3F3C

NHS

NHN

OMe

H

H

N

O(0.5-10 mol %)

CH3NO2toluene, rt

OO2N

R1 R289-98% ee94% yield

R

Cinchona-Based Catalyst in the Henry (Nitroaldol) Reaction

-While thioureas have shown to be excellent enantioselective catalysts in the aza-Henry reaction,(Takemoto), previous metal-free efforts in the parent Henry reaction did not exceed 54% ee.

Marcelli, T.; van der Hass, R.N.S.; van Maarseven, J.H.; Hiemstra, H. Angew.Chem. Int. Ed. 2006, 45, 929-931.

N

NH

NHS

O

N

Ph

CF3F3C

NO2

OH

94% yield89% ee

MeO

NO2

OH

90% yield92% ee

N

NO2

OH

91% yield86% ee

NO2

OH

99% yield85% ee

F

NO2

OH

99% yield92% ee

R H

OMeNO2

psuedo ent. (10 mol %), THF, -20 ºC

R NO2

OH

97% yield93% ee

R H

OMeNO2

cat. (10 mol %), THF, -20 ºC

R NO2

OH

Marcelli, T.; van der Hass, R.N.S.; van Maarseven, J.H.; Hiemstra, H. Angew.Chem. Int. Ed. 2006, 45, 929-931.

Proposed Mode of Action

N

N

S N

CF3F3C

O

Ph

NH O N

O

H

H O

H

R

R H

OMeNO2

cat. (10 mol %), THF, -20 ºCR NO2

OH

Si-face addition

Enantioselective Synthesis of Flavanones and Chromanones

Biddle, M.M.; Lin, M.; Scheidt, K. J. Am. Chem. Soc. 2007, 129, 3830-3831.

N

NH

NH

SAr

HN

H

H

BnO

H

H

O

O PhH

92% yield94% ee

H

H

O

O H83% yield90% ee Me

H

H

O

O H94% yield91% ee OMe

H

Me

O

O PhH

97% yield90% ee

H

H

O

O H89% yield91% ee

H

H

O

O H65% yield80% ee

R1

O

O RH

88% ee

O

CO2tBu

R

toluene, -25 ºC

cat. (10 mol %)

R1 R1

O

O RH

CO2tBu p-TsOH,toluene, 70 ºC

89% ee

OH

OH O

CO2tBu

R

R2R1

NH

NH

SAr

CF3

F3C

tolueneno cyclization

Biddle, M.M.; Lin, M.; Scheidt, K. J. Am. Chem. Soc. 2007, 129, 3830-3831.

Is Bifunctionality Necessary?

OH O

CO2tBu

R

R2R1

quinine R2

R1

O

O RH

CO2tBu

17% ee

OH O

CO2tBu

R

R2R1

NH

NH

SAr

CF3

F3C

quinine

R2

R1

O

O RH

CO2tBu

23% ee

Conjugate Hydroxylamine Addition using a Bifunctional H-bonding catalyst

Sibi, M.P.; Itoh, K. J. Am. Chem. Soc. 2007, 129, 8064-8065.

Stereochemical Model

CF3

NH

F3C

S

NH OH

R

O

NN

0 ºC, F3CC6H5

R

O

NNNH OR1

R1ONH2, MS 4 A(S)

CF3

F3C NS

NO H

R

ON

N

H H

H2NO

si face approach

R

CF3

NH

F3C

S

NH OH

61% yield, 19% ee

CF3

NH

F3C

S

NH

44% yield, <5% ee

CF3

NH

F3C

S

NH

81% yield, 2% eePh

Ph

OH

2

3

4

OUTLINE

A. Introduction





B. Conclusion

Acceleration of hetero-Diels-Alder reactions in H-bonding solvents

Huang, Y.; Rawal, V.H.; J. Am. Chem. Soc. 2002, 124, 9662-9663.

Reaction in acetonitrile-d3 at room temp. 10 times slower than in chloroform-d, despite being more polar

entry solvent Time (h)

1 chloroform 48

2 tert-butyl alcohol 24

3 isopropyl alcohol 3

4 ethanol 0.5

5 methanol 0.5

NMe2

TBSO

O

TBSO

NMe2

Ard-solvents, rt

OMe

OH

NMe2

TBSO O1) solvent, rt

2) AcCl, -78 ºC O

O

TADDOL Derivatives as Enantioselective H-Bonding Catalysts

Huang, Y.; Unni, A.K.; Thadani, A.N.; Rawal, V.H.; Nature, 2003, 424, 146.Thadani, A.N.; Stankovic, A.R.; Rawal, V.H.; Proc. Natl. Acad. Sci.2004, 101, 5846-5850.Du, H.; Zhao, D.; Ding, K. Chem. Eur. J. 2004, 10, 5964-5970.

TBSO

N(CH3)2

OH

O O

O Otoluene, -40 ºC

2) AcCl CH2Cl2/toluene, -78 ºC

OHArAr

O

O

Me

Me OHArAr

1)

10 mol %

67% yield92% ee

J

TBSO

N(CH3)2

Otoluene, -40 ºC

2) HF CH3CN, -80 ºC --> rt

1) 10 mol %

85% yield91% ee

CHOH3C

CH3

CHOJ

1) 10 mol %

67% yield83% ee

JPhH

O toluene, -60 ºC O

H3CO

O

PhOTMS

OCH3

H3CO

Rawal’s and Yamamoto’s BAMOL catalyst

Unni, A.K.; Takenaka, N.; Yamamoto, H.; Rawal, V.H. J. Am. Chem. Soc. 2005, 127, 1336-1337.

Evidence of single H-bond donation: Catalyst in a 1:1 association with benzaldehyde. Both intra- and inter- molecular H-bonds are observed.

Axially chiral BAMOL catalyst proved effective for a wide range of aliphatic and aromatic aldehydes

OHOH OH

ArAr

Ar ArOH

2,2'-biphenol

bis(diarylhydroxymethyl) functionality

OH

ArAr

Ar ArOH

TBSO

N(CH3)2

RH

O O

Otoluene, -40 ºC

2) AcCl CH2Cl2/toluene, -78 ºC

1)

20 mol %

>98% yield>99% ee

R

TADDOL in the Diastereo- and Enantioselective Mukaiyama Aldol Reaction

McGilvra, J.D.; Unni, A.K.; Modi, K.; Rawal, V.H. Angew. Int Chem. Ed. 2006, 45, 6130-6133.

O

H

94% yield15:1 d.r. (syn/anti)98% ee syn (84%)

O

H


O2N

O

H

84% yield>25:1 d.r. (syn/anti)96% ee syn

F3C

O

H


MeO

O

H


Br

N

OTBS

H

Me

Me

Me RCHO -78 C, toluene, 2 days

2. HF/CH3CN

OHArAr

O

O

R

R OHArAr

1.

N

O

Me

Me

Me

OH

R N

O

Me

MeOH

RMe

(10 mol%)

Ar= 1-napthyl, R= -(C5H10)-

O

H


S

O

H

47% yield9:1 d.r. (syn/anti)91% ee syn

O

H


OMe

McGilvra, J.D.; Unni, A.K.; Modi, K.; Rawal, V.H. Angew. Int Chem. Ed. 2006, 45, 6130-6133.

Amide reduction: Limited to no epimerization

TADDOL Crystal Structure: Evidence for Single-Point H-Bond Donation

Oxygen in redHydrogen in Blue

N

O

Me

MeOTBS

R

3 equiv [Cp2Zr(H)Cl]

CH2Cl2, rt, 0.5-2 hH

O OTBS

R4a: R = H, 35:1 syn:anti b: R = Cl, 24:1 syn:anti c: R = OMe, >50:1 syn:anti

5a: 88% yield, 30:1 syn:anti b: 84% yield, 24:1 syn:anti c: 85% yield, >50:1 syn:anti

Me Me

BINOL Derivatives as Enantioselective H-Bonding Catalysts

McDougal, N.T.; Schaus, S.E. J. Am. Chem. Soc. 2003, 125, 12094-12095.McDougal, N.T.; Trevellini, W.L.; Rodgen, S.A.; Kliman, L.T.; Schaus, S.E. Adv. Synth. Catal. 2004, 346, 1231-1240.

Precedent for the work: Yamada, T. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165-2169

Concluded that acidic additives such as phenols and napthols accelerate Morita-Baylis-Hillman reactions in high yields.

Proposed Catalytic Cycle

OOH

RO

R3P

OO

R

H

R3P

B

R

O

H

O

R3P

H B

B H

R3P

O O

Ph

OH

Ph H

O K (10 mol %)PEt3

THF, -10 ºC88% yield90% ee

Ar

OH

Ar

OH

Ar = 3,5-(CF3)2C6H3

K

Bifunctional BINOL Derivatives as Enantioselective H-Bonding Catalysts

-aza Baylis-Hillman reactions have been reported

-catalyst appears to play a bifunctional role: phenol hydroxy protons activate the electrophile while the pyridyl group functions as a nucleophile to generate the enolate

Matsui, K. Takizawa, S. Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680-3681.

L

OHOH

NN

iPr

O

CH3Ph

NTs

HPh

O

CH3

NHTs

93% yield87% ee

L (10 mol %)

toluene/c-C5H9OCH3 -15 ºC

Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 19, 4293-4296. Shi, Y-L.; Shi, M. Adv. Synth. and Catal. 2007, 349, 2129-2135.

Further Reactivity of the Bifunctional BINOL Derivatives

R

NTs O

>95% yield>90% ee

R

N

H

Ts O

(10 mol %)

CH2Cl2, rt5 mol % PhCO2H

NH

PPh2

S

NH

NH

NMe2

S

NH

O

R

O

HCH3CN, 0 ºC

(10 mol %)O

R

OH

up to 94% ee63-84% yield

CF3

CF3

Enamine Mannich Reaction

Tillman, A.L.; Dixon, D. Org. Biomol. Chem. 2007, 5, 606-609.

Derativization of ß-amino aryl ketone products

X

O

Ph

HN Boc

O

O

Ph

HN BocMeO

mCPBA, DCE, 60 ºC(X=OMe)

NH

O

Ph

HN Boc (X=H)1. NH2OH HCl, pyr. EtOH, rt2. TsCl, pyridine, benzene, rt

80% yield

82% yield

L-selectride

Me

Ph

HN BocOH

87:13, syn:anti90% yield

(X=Me)THF, -78 ºC

Ar1

N

O

Ar2

N

O

O toluene, -30 ºC, 48 h

2. H3O Ar1

O

Ar2

HN O

O

OHOH(20 mol %)


1.

OUTLINE

A. Introduction





F. Conclusion

Chiral Guanidinium Ions as H-Bond Catalysts

Corey, E.J.; Grogan, M.J.; Org. Lett.1999, 1, 157-160.

Proposed Mechanism

HNN

NPh

Ph

HNN

NPh

Ph

HCN

HC N

Ph

NPh2HCPh

NPh2HC

NN

NPh

Ph

HH

CN

pre-TS assembly

Ph

NHPh2HC

CNH

NN

NPh

Ph

N

Ph

Ph HN

Ph

Ph

CN

(10 mol %)

HCN (2 equiv)toluene, -40 ºC, 20 h

(R)

H3OCOOHH3N

80-99% yield50-88% ee

H

Activation of 1,3-Dicarbonyl Compounds using an Axially Chiral Guanidine Catalyst

Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454-1455.Terada, M.; Nakano. M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044-16045.

Ar = 3,5-(di-tert-butylphenyl)2C6H3

ArAr

NN

NH

H

H

(R)-2a

ArHN

Ar

NH

N

Me

Ar = 3,5-(di-tert-butylphenyl)2C6H3

(R)-1h

NO2

MeO

O O

OMeMeO

O O

OMeNO2

Et2O, -40 ºC

(R)-1h (2 mol %)

>99% yield>97% ee

OOEt

ONBoc N Boc

O

CO2Et

N Boc(R)-2a (0.05 mol %)

THF, -60 ºC, 4h

N H

Boc

+

quant. yield97% ee

Chiral Amidinium Ions as Catalysts Johnston’s chiral bisamidine catalyst:

Nugent, B.M.; Yoder, R.A.; Johnston, J.N. J. Am. Chem. Soc. 2004, 126, 3418-3419.Hess, A.S.; Yoder, R.A.; Johnston, J.N. Synlett. 2006, 1, 147-149.

NO2

HN Boc

57% yield60% ee

NO2

HN Boc

65% yield95% ee

O2N NO2

HN Boc

61% yield82% eeO2N

NO2

HN Boc

69% yield59% ee14:1 dr

CH3

NO2

HN Boc


CH3F3CO

NO2

HN Boc


CH3F3C

NO2

HN Boc


CH3

O2N

HN NHHH

N NH

OTf

R1C6H4

N

H

Boc NO2

R2 R1C6H4NO2

R2

HN Boc

toluene, -20 ºC

HQuin-BAM-HOTf

pKa = 5.78

Johnston’s chiral bisamidine catalyst: Anti diastereoselectivity

Singh, A.S.; Yoder, R.A.; Shen B.S.; Johnston, J.N. J. Am. Chem. Soc. 2007, 129, 3466-3467.

Ar H

N Boc CO2tBu

NO2Ar CO2

tBu

NH2

HN Boc1. 5 mol % M toluene, -78 ºC

2. NaBH4, CoCl2HN NH

HH

N N

OTf

H

M

CO2tBu

NH2

HN Boc

F81% yield93% ee7:1 dr

CO2tBu

NH2

HN Boc

F3C83% yield88% ee7:1 dr

CO2tBu

NH2

HN Boc

Me81% yield95% ee6:1 dr

CO2tBu

NH2

HN Boc


PhO CO2tBu

NH2

HN Boc


Cl CO2tBu

NH2

HN Boc


O

MeO

Conclusions

• Hydrogen bond donors are viable alternatives to metal-based Lewis acid catalysts

• Structural moieties provide easy flexibility in design

• Bifunctional catalysts have allowed for even greater yields and ee’s than their monofunctional counterparts via a dual activation mechanism.

• Lowering the catalyst loadings is necessary

Acknowledgements

• Jeff Johnson

• Johnson Research Group

Enantioselective Strecker Reaction Scope

Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.Sigman, M.S.; Vachal, P.; Jacobsen, E.N.; Agnew. Chem. Int. Ed. 2000, 39, 1279-1281.

(1) A (2 mol%) , 24h, toluene, -78 ºC

(2) TFAA

HCN (2 equiv) N

O

F3C

R CNR H

N

N

CN

F3C

O

93% yield77% ee

OMe

N

CN

F3C

O

99% yield95% ee

Me

Jacobsen’s Thiourea: A “Privileged” Chiral Catalyst

Wenzel, A.G.; Lalonde, M.P.; Jacobsen, E.N. Synlett, 2003, 12, 1919-1922. Yoon, T.P.; Jacobsen, E.N. Science, 2003, 29 9, 1691.

Strecker Reaction

Mannich Reaction

Catalyst A highly effective for both the Strecker and Mannich reactions, despite vast steric and electronic differences in the aldimine electrophiles --- Same mechanism of stereoinduction cannot be assumed

(1) A (2 mol%) , 24h, toluene, -78 ºC

(2) TFAAHCN (2 equiv) N

O

F3C

R CNR H

N


A =S

NH

NH

N

O N

HO

OtBu

O

tBu

N

H R

Boc OTBS

OiPr R OiPr

1. A (5 mol%) toluene, -40 ºC, 48 h

2. TFA, 2minNH OBoc


Where R is aryl

Wenzel, A.G.; Lalonde, M.P.; Jacobsen, E.N. Synlett, 2003, 12, 1919-1922.

Probe into Catalyst Structure

Variation of the Amino Acid

Catalyst Strecker

ee (%)

Mannich

ee (%)

1 96 51

2 91 22

3 92 38

Salicylaldimine Modifications

Catalyst Strecker

ee (%)

Mannich

ee (%)

4 92 97

5 92 97

6 91 96

7 94 91

8 64 82

Catalyst Strecker ee (%) Mannich ee (%)

9 98 80

10 No reaction No reaction

11 27 ( R ) 90

Effects of Diamine Structure and Stereochemistry

A = S

NH

NH

N

O

R

N

HO

OtBu

O

tBu

1: R= iPr (L-Val)2: R= Me (L-Ala)3: R= Ph (L-Phg)

Ph

A =S

NH

NH

N

O

tBu

N

R1O

R3R2

4: R1=H, R2=tBu, R3=tBu5: R1=H, R2=tPr, R3=tBu6: R1=H, R2=Me, R3=tBu7: R1=H, R2=H, R3=H8: R1=Me, R2=tBu, R3=tBu

Ph

A = S

NH

NH

N

O

tBu

N

HO

OtBu

O

tBu

9: R1=Ph, R2=Ph (R,R)10: R1=tBu, R2=tBu (R,R)11: R1,R2= -(CH2)4- (S,S)

Ph R2R1

Wenzel, A.G.; Lalonde, M.P.; Jacobsen, E.N. Synlett, 2003, 12, 1919-1922.

A Simpler Catalyst for the Mannich Reaction

Probing the catalyst involved led Jacobsen and coworkers to the development of a new catalyst for N-Boc aldimine activation

-new catalyst half the molecular weight of the original, with two fewer stereocenters

N

ONH

NH

SPh

tBu

Bn

Me

Ph

NBoc

OiPr

OTBS

H Ph OiPr

ONHBoc

>99% yield94% ee

(5 mol%)

2. TFA, 2 min

1.

-40 ºC, 48 h

Takemoto’s Catalyst in the Aza-Henry Reaction

F (10 mol%)Ch2Cl2, rt

RCH2NO2N PO

PhPh

ArAr NO2

R

NH P(O)Ph2

CF3

F3C NH

NH

S

NMe2F

NO2

H

HN P(O)Ph2

87% yield67% ee

NO2

H

HN P(O)Ph2

72% yield63% ee

NO2

H

HN P(O)Ph2

78% yield70% ee

NO2

H

HN P(O)Ph2

O

85% yield76% ee

NO2

Me

HN P(O)Ph2

83% yield67% ee73:27 d.r.

N

NO2

H

HN P(O)Ph2

91% yield68% ee

NO2

H

HN P(O)Ph2

Cl76% yield67% ee

Okino, T.; Nakamura, S.; Furukawa T.; Takemoto, Y. Org. Lett. 2004, 6, 625-627.

Effect of Catalyst: Is Bifunctionality Necessary?

entry additive time (h) % yield % ee

1 TEA 24 17 -

2 1b 24 14 35

3 TEA+1c 24 57 -

4 1d 48 29 91

5 1e 48 76 87

6 1f 48 58 80

7 1g 48 40 52

Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673

•For high yield and selectivity, catalyst must be bifunctional (Entries 1-3)•Substituents on the amino group greatly affect the yield, but marginally affect the % ee (Entries 4-5)•Decrease in N-H acidity of thiourea dramatically hinders the % ee and yield (Entries 6-7)

NAcHN

1b

HN

HN

S

F3C

CF3 1c

NHN

R1 R2HN

SAr

1d: Ar= 3,5-(CF3)2C6H3, R1 = R2 =o-(CH2)2C6H41e: Ar= 3,5-(CF3)2C6H3, R1= Me, R2= iPr1f: Ar= Ph, R1 = R2= Me1g: Ar= 2-(MeO)C6H4, R1 = R2 = Me

Dynamic Kinetic Resolution of Racemic Azlactones

Berkessel, A.; Cleemann, F.; Mukherjee, S.; Muller, T.N.; Lex, J. Agnew. Chem. Int. Ed. 2005, 44, 807-811.Berkessel, A.; Mukherjee, F. Cleemann, F.; Muller, T.N.; Lex, J. Chem. Commun. 2005, 1898-1900

-Mechanism here????

-Mention that a similar catalyst to 1 and 2 was used for the asymmetric silylcyanation of ketones (JACS, Jacobsen, 2005, 8964.)

NH

NH

S

NMe22O

MeNPh

tBuCF3

F3C NH

NH

S

NMe21

N O

Ph

iBuO

HOtoluene, rt

O

OHN

O

PhiBu

1 or 2 (5 mol%)

TADDOL Derivatives as Enantioselective H-Bonding CatalystsRegio- and Enantioselective Nitroso-Aldol Synthesis

Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 1080-1081.

-exclusive formation of a single regioisomer with proper choice of catalyst and enamine combination

ONOH

Ph

X = C, O n = 1

> 90% yield> 90% ee

OHArAr

O

O

Me

Me OHArAr

N

X

NO

Ph30 mol%

n

toluene-78 ºC, 2 h

O

OHOH

OO N

HPh

X = C n = 0, 1, 2> 90% yield> 92% ee

30 mol% Et2O-78 ºC, 12 h

Stereoselectivity Rationale

N

NNN H

H

H

HN C

-Phenyl group of catalyst undergoes π-stacking with a benzhydryl phenyl

-si face if the imine carbon blocked by other benzhydryl phenyl

-The aryl group π-conjugated to the imine fits into a vacant quadrant on guanidine face, experiences van der Waals attractions with the guanidine core

Corey, E.J.; Grogan, M.J.; Org. Lett.1999, 1, 157-160.

Guanidine-Thiourea Bifunctional Catalysts in the Henry Reaction

Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Adv. Synth. And Catal. 2005, 347, 1643-1648.

HN

S

HN N

HPh

N

NH

HN

C18H37 H

Ph S

HN CF3

CF3

F3C

CF3 1e

O

HNO2

OH 1e (10 mol%)CH3NO2 (10 equiv)

KOH (50 mol%) toluene-H2O (1:1)KI (50 mol%), 0 ºC, 24 h 91% yield

92% ee

NOO

H HNN

NHC18H37

N

N

S

Ar

H Ph

OH

R

H

H

anti conformation

R NO2R

OH

(Favored)

N OOH H

NN

NHC18H37

N

N

S

Ar

H Ph

OR

H

H

H

gauche conformation

R NO2

OH

S

(Disfavored)

Chiral Bicyclic Guanidine-Catalyzed Enantioselective Reactions of Anthrones

Shen, J.; Nguyen, T.T.; Goh, Y-P.; Ye, W.; Fu, X.; Xu, J.; Tan, C-H. J. Am. Chem. Soc. 2006, 128, 13692-13693.

HN NHHH

N N

OTf

H

toluene, rt

1.

5 mol%

Explaining the Diastereoselectivity

Ar CO2tBuHN Boc

NO2Ar CO2tBuHN Boc

NO2

Syn-diastereomer analysis determined its %ee to be Identical to the anti-precursor

Singh, A.S.; Yoder, R.A.; Shen B.S.; Johnston, J.N. J. Am. Chem. Soc. 2007, 129, 3466-3467.

asymmetric organocatalysis through hydrogen … smith/austinlitsem.pdfasymmetric organocatalysis...

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