activation modes are enabled by priviledged catalyst...

Activation Modes Are Enabled by Priviledged Catalyst Achitectures

! Enamine ! Iminium

NH

N

t-Bu

O Me

Me

ImidazolidinoneProline-derived

NH

R

N

NMe Me

DMAP

R R

Carbene

! Electrophile Activation

Previous Lecture This Lecture – Broadened Activation Themes

Activation

Modes

New Reactions –

Enabling Valuable

Bond Disconnections

! Nucleophile Activation

S

NH

NH

RRP

O

OHRO

RO

Acids and Phase Transfers

NR4

Catalysis Platform / Concept Chemical Methodology

Catalyst

Design

Priviledged

AchitectureChiral

Pool

Phase Transfer Catalysis (PTC)

! Begining with Makosza and Brandstrom, Stark coined the term phase transfer catalysis

Cl

H2O, 105 °C

NaCN

hexCN

hex No Reaction

Starks, R. M. J. Am. Chem. Soc. 1971, 93, 195.

Phase Transfer Catalysis (PTC)

Cl

H2O, 105 °C

NaCN

hexCN

hex

Bu3P(CH2)15CH3 Cl

NaCl

Bu3P(CH2)15CH3 CN (Interface)

Aqueous Phase

Organic Phase

NaCN

High Yield

"The phenomenon of rate enhancement of a reaction between chemical species located in different phases by addition of a small quantity of an agent (called the 'phase-transfer catalyst') that extractsone of the reactants, most commonly an anion, across the interface into the other phase so thatreaction can proceed..." – IUPAC Gold book

Pioneering Studies at Merck

! In 1984 researchers at Merck published their work towards asymmetric alkylations

N

HN

OH

10 mol % cat

50% aq NaOH

toluene

20 °C, 18 h

MeCl

Br

Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446.

CF3

N

N

O

CF3

OCl

Cl

MeO

O

Ph

Cl

Cl

MeOMe

OCl

Cl

MeO

H

!"

#-stack

H-bond / ion pair

phase transfer catalyst

95% yield

92% ee



10 mol % cat

50% aq NaOH

toluene

20 °C, 18 h

MeCl


OCl

Cl

MeO

O

Ph

Cl

Cl

MeOMe

95% yield

92% ee

O

Ph

Cl

Cl

MeOMe

O

Ph

Cl

Cl

OMe

O

HO

60% overall

(+)-indacrinone

MK-0197



N

HN

OH

10 mol % cat

50% aq NaOH

toluene

20 °C, 18 h

MeCl

Br


CF3

N

N

O

CF3

OCl

Cl

MeO

O

Ph

Cl

Cl

MeOMe

OCl

Cl

MeO

H

!"

#-stack

H-bond / ion pair

phase transfer catalyst

95% yield

92% ee

Asymmetric Phase Transfer Catalysis

! The catalyst controls the orientation of the enolate alkylation

N

O

Ot-BuPh

Ph

N

HN

OH

Organic

Aqueous

Br

Glycine Imine Ester

Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.



N

O

Ot-BuPh

Ph

NaOH

Na

N

HN

OH

Organic

Aqueous

Br

Glycine Imine Ester


N

O

Ot-Bu

Ph

Ph



N

O

Ot-BuPh

Ph

NaOH

Na

N

HN

OH

Br

Cl

Organic

Aqueous

Br

–NaBr

Glycine Imine Ester


N

O

Ot-Bu

Ph

Ph

N

HN

OH

O

Ot-Bu

Re face open

ion

pairing

Si face sheilded

Ph

Ph



N

O

Ot-BuPh

Ph

N

O

Ot-BuPh

Ph

NaOH

Cl

Na

N

HN

OH

Br

Cl

Organic

Aqueous

Br

–NaBr

Glycine Imine Ester

Chlorophenylalanine


N

O

Ot-Bu

Ph

Ph

N

HN

OH

O

Ot-Bu

Re face open

ion

pairing

Si face sheilded

Ph

Ph



N

O

Ot-BuPh

Ph

N

O

Ot-BuPh

Ph

NaOH

Cl

Na

N

HN

OH

Br

Cl

Organic

Aqueous

Br

–NaBr

Glycine Imine Ester

Chlorophenylalanine


N

O

Ot-Bu

Ph

Ph

Switching Enantioselectivity Using Pseudoenantiomers

! Catalyst diastereomers give rise to the opposite product configuration

NH

Et

N

HN

OBn

OBn

N

N

O

Ot-BuPh

Ph

N

O

Ot-BuPh

Ph

10 mol % cat

50% aq KOH

toluene

20 °C, 18 h

A From cinchonine B From cinchonidine

PhCH2Br

N

O

Ot-BuPh

Ph

cat A

77% yield

86% ee

cat B

85% yield

94% ee

BrBr

Et


Advances in Catalyst Design

! Catalysts have been benchmarked using the benzylation of glycine imine:

N

N

O

Ot-BuPh

Ph

N

O

Ot-BuPh

Ph

10 mol % cat

50% aq KOH

toluene

20 °C, 18 h

PhCH2Br

Br

Shirakawa, S.; Marouka, K. Catalytic Asymmetric Synthesis. Hoboken: Wiley, 2010.

R = allyl

Lygo, Corey 1997

10 mol %

87% yield, 94% ee

N

Br

Ar

Ar

Maruoka 1999

1 mol %

91% yield, 98% ee

Ar = Ph

Ph

N

HN

OH

Ar = Ph

O'Donnell 1989

10 mol %

75% yield, 66% ee

Br

H

N

ORMaruoka 2005

0.05 mol %

0.05 mol % 18-crown-6

90% yield, 98% ee

Cocatalyst:

O

O

O

OO

O

18-crown-6

The PTC Activation Mode Beyond Alkylation Reactions

! PTC activation of carbonyls has enabled the developement of many different asymmetric reactions

N

O

Ot-BuPh

Ph

N

O

Ot-Bup-Cl-Ph

glycine–alkylation

Me

glycine alkylation–allylation

N

O

Ot-BuPh

Ph

CN

glycine–Michael

!-ketoester SNAr

O

Ot-Bu

NH2

glycine–aldol

OH

c-hex

83% 96:4 anti, 98% ee

85%, 91% ee85%, 98% ee90%, 98% ee

glycine–Mannich

95%, 9:1 syn 82% ee

O

Ot-Bu

NH2

NH

PMB

Boc O

CO2Et

O2N NO2

78%, 85% ee

Recent review: Ooi, T.; Maruoka, K. Angew. Chem. Int. Ed. 2007, 46, 4222.

Angew. Chem. Int. Ed. 2005, 44 , 625. J. Am. Chem. Soc. 2000, 122, 5228. Org. Lett. 2000, 2, 1097.

J. Am. Chem. Soc. 2004, 126, 9685. Angew. Chem. Int. Ed. 2005, 44, 4564. J. Org. Chem. 2006, 71, 4980.

The PTC Activation Mode Beyond Alkylation Reactions

! PTC activation of carbonyls has enabled the developement of many different asymmetric reactions

Recent review: Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656.

!-ketoester fluorination

Ph

O

PhO

enone epoxidation

O

t-BuO N

Ph

aziridation

HNSO2Mes

t-Bu CN

Strecker

O

CO2Et

NN NH

Boc Boc

!-ketoester amination

Ph H

Me SO2PhO

Darzens epoxidation

70%, 81% ee

94%, 84% ee

NH

O

F3C

F

MeO

Cl

79%, 84% ee

99%, 96% ee94%, 94% ee

O

Boc

99%, 92% ee

J. Am. Chem. Soc. 2004, 126, 6844.J. Am. Chem. Soc. 2006, 128, 2548.

Synthesis 2005, 2022.

Tetrahedron 2002, 58, 1407.

Angew. Chem. Int. Ed. 2008, 47, 9466.J. Org. Chem. 2003, 68, 2494.

Phase Transfer Catalysis

! Since the original reports the area continues to be a strong sector of organocatalysis research

! ISI web of knowledge references containing the key phrase "phase transfer catalysis" total 3698

Dolling’s

(+)-indacrinone

synthesis

Carbenes as Organocatalysts

! Carbenes were long suspected as catalytic intermediates



Breslow, R. J. Am. Chem. Soc. 1958, 14, 3719.



S

N

Me

N

N

H2N

Me

HO

H

S

N

Me

N

N

H2N

Me

HO

Nature's Carbene OrganocatalystThiazolium Salt of Thiamine Coenzyme (vitamin B1)

! For many years a carbene catalyst for the enantioselective benzoin condensation was elusive

OH

Ph

S NR

S NR

H

base

S NR

Ph O

S NR

Ph OH

S NR

Ph

OH

Ph

O

O

H Ph

O

Ph

O

H Ph

Benzoin Product

Breslow-type

Intermediate



S

N

Me

N

N

H2N

Me

HO

H

S

N

Me

N

N

H2N

Me

HO

Nature's Carbene OrganocatalystThiazolium Salt of Thiamine Coenzyme (vitamin B1)

! For many years a carbene catalyst for the enantioselective benzoin condensation was elusive

S NR

Ph OH

O

H Ph

Breslow-type

Intermediate

electrophilic

O

Ph

acyl anion synthon

! The newly proposed intermediate exhibits umpolung reactivity

cat

novel reactivty patternsBefore we can get new reactions

we need better catalysts


N NMes Mes

H Cl

KOtBuN N

Mes Mes

! Isolated in 1991 by Arduengo while working at DuPont

Bulky groups

prevent dimerization

! In 1995 Enders and Teles develop stable triazole-based carbenes

N

N

NPhPh

PhNaOCH3

CH3OH

70 °C

N

N

NPhPh

Ph

OCH3

80 °C

0.1 mbar

N

N

NPhPh

Ph

Arduengo III, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361.

Angew. Chem. Int. Ed. 1995, 34, 1021.

Asymmetric Carbene Catalysts

! 2002 Chiral triazole are made and are efficient and selective for the benzoin condensation

N

N

NPh

O

t-Bu

O

H Ph

10 mol %

KOt-Bu

THF

OH

Ph

O

Ph

83% 90% ee

2002 Enders

N

N

NPh

O

t-Bu

1997 Leeper

BF4Cl

80% ee

! The genesis of a new platform for asymmetric catalysis

1966 Sheehan Hunneman

S N

Ph

O

O

c-hex

22% ee

Sheehan, J.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666.

Knight, R. L.; Leeper, F. J. Tetrahedron Lett. 1997, 38, 3611.

Enders, D.; Kallfass, U. Angew. Chem. Int. Ed. 2002, 41, 1743.

Carbenes: Generic Activation Platform

! It was soon realized that carbenes activate carbonyls for a number of useful reactions

N

N

NPh

O

t-Bu

base

O

H Ph

Breslow-type Nucleophile

N

N

NPh

O

t-Bu

carbenetriazolium salt

N

N

NPh

O

t-Bu

Ph O

electrophile

! Generically activated towards electrophileselectrophile

N

N

NPh

O

t-Bu

Ph OH

! Alkene geometry controlled by bulky group

! Re face shielded by t-Bu

Recent Advance in Carbene Catalysis

! After the initial disclosures in the 1990's the Stetter reaction has been championed by Rovis

20 mol %

KHMDS

xylenes

N

N

N

O BF4

O

O O

O

94% yield

94% ee

Rovis 2002

OMe

CO2EtCO2Et

! The Rovis catalyst design has been have been proven to be excellent for many more reactions

20 mol %

KOt-Bu

THF

N

N

N Ph

O

BF4

O

H

Et

O

O

OHEt

88% yield

94% ee

Enders 2006

Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am Chem. Soc. 2002, 124, 10298.

Enders, D.; Niemeier, O.; Raabe, G. Synlett 2006, 2431.

Beyond the Stetter and Bezoin Reactions

! Azadiene Diels–Alder

10 mol %

DIPEA

toluene/THF

N

N

NMes

O

BF4

NS

O O

MeO Ph

O

O

OEtH N

O

Ph

90%, 50:1 dr 99% ee

Bode 2006

N

N

NMes

O

OH

OEt

O

N

N

NMes

O

OH

OEt

O

N

N

NMes

O

O

OEt

O

NS

Ph

O O

OMe

O

OEtPMBO2S

He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418.

Substrate Activation Towards New Reactivity

! !-chloroaldehydes provide access to alternate manifolds for e.g. esterification

N

N

NPh

OHCl

Ph

O

Cl

PhH

N

N

NPh

OH

Cl

Ph

N

N

NMes

O

N

N

NPh

Cl

N

N

NPh

O

Cl

Ph

O

PhOPh

NEt3

10 mol %

HO Ph

!-chloroaldehyde alcohol ester

O

CO2MeMe

O

O

Ph

CO2Me

88%, >20:1 dr, 99% ee

O

Cl

PhH

0.5 mol %

EtOAc, NEt3

Cl

Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518. He, M.; Uc, G. J.; Bode, J. W. J Am. Chem. Soc. 2006, 128, 15088.

! Oxy Diels–Alder reaction

Hydrogen-Bonding Catalysis

! Early examples using cinchonia alkaloidsas H-bonding catalysts

H-bond catalysis

Jacobsen–Akiyama

~30 new reactions

RN N

R

S

H H

R H

O

Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.

NH

N

O

cinchonidine

O

Me

Me

t-Bu

SH

H O

MeMe

S

H

t-Bu

1 mol %O

ArSMe

Me

75% ee

H!-

! Typically a 2-20 kcal/mol interaction

Me

O

S

NH

NH

CF3

CF3F3C

CF3

! Activates electrophiles

krel 8.8 times faster with catalystMe O

10 mol %

Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407.

Ph

Early Examples of Hydrogen Bonding Catalysis

! A small dipeptide was designed by Inoue to mimic oxynitrilase

Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181. Grogan, M. J.; Corey, E. J. Org. Lett. 1999, 1, 157.

NH O

O N

H

H

H

OPh NHHN

C NH Ph

O

HCN2 mol %, toluene, –20 °C

Ph CN

H OHHN

NH

O

O

N

HN

Ph

97%, 97% ee

! Asymmetric Strecker reaction using Corey's guanidine H-bonding catalyst

N

Ph

Ph

Ph

HCN

10 mol %

toluene, –40 °CHN

Ph

Ph

Ph

CNN

N

NH

PhPh

N

N

N

PhPh

HH CN

N

N

N

PhPh

H H

CNNR

Ph

Discovery of Acid Mediated Strecker Reactions – Jacobsen Thioureas

! Parallel synthetic ligand libraries were evaluated with various metals

TBSCN

! Modifed Schiff bases were prepared in a combinatorial fashion on a solid support

N

H

ligand library / metal N

CNTFA

F3C

O

O N

O

R R

R

M

Target Catalyst Architecture

HO

Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.

R3 R4

N

NH

NH

O

O

HN

O

NH 5

R1

R2

R2

12 MetalsNo Metal

59% conv 19% ee

Ru

69% conv 13% ee

Discovery of Acid Mediated Strecker Reactions – Jacobsen Thioureas

! The structure was quickly optimized to provide an efficient Strecker catalyst

HO

Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.

R3 R4

N

NH

NH

O

O

HN

O

NH 5

R1

R2

R2

78% conv 91% ee

Catalyst Lead

HO

t-Bu OMe

N

NH

NH

O

O

HN

t-Bu

Ph

TBSCN

N

H

2 mol % cat

N

CNTFA

F3C

O

toluene, –78 °C

Systematic

optimization

New Catalyst

How Do These New Catalysts Function?

! Knock-out studies show that the urea functional group is essential

Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 120, 10012.

HO

t-Bu OBz

N

NH

NH

O

O

HN

t-Bu

Ph

! Hydrogen bonding established as the activation mode

X

NH

NH

MeMe

X

N NMeMe

H H

NMe

Me

X = O –8.5 kcal/mol

X = S –10 kcal/mol

X

N NMeMe

H H

NHMe

Me CN

–5.0 kcal/mol

–6.3 kcal/mol

HCN

! Weaker product binding enables turnover

NMe

Me

DFT and NMR Studies:

Urea Stereochemical Model

Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 120, 10012.

HO

t-Bu OBz

N

NH

NH

S

O

N

t-Bu

Ph

Me

Ph Me

NCN

! With a better understanding of how these catalysts work new reaction methods can be developed

HCNt-Bu

N

R

Ph

1 mol % cat

t-Bu

N

CN

Ph

TFA

F3C

O

toluene, –78 °C

R = H

Strecker reaction with aldimine or ketoimine

R

R = Me

99% ee

86% ee

Urea Catalyzed Reactions

HO

t-Bu OCOt-Bu

N

NH

NH

S

O

HN

t-Bu

Ph

H Ph

NBoc

OTBS

Oi-Pr

5 mol % cat

toluene, 48 h

–40 °C

TFAi-PrO

O

Ph

NHBoc

90% conv, 91% ee

! Enantioselective Mannich Reaction

Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.

! Enantioselective Acyl Pictet–Spengler Reaction

N

NH

NH

S

O

N

t-Bu

NH

i-Bu

i-Bu

Me Ph

NAc

EtEt

NH

N

EtEt

Ac-Cl

lutidine

10 mol % cat

–78 °C

81% conv, 93% ee

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


NHAc

NH

NH

S

O

Me2N

t-Bu

H Ph

NBoc

10 mol % cat

toluene, i-Pr2NEt4 °C

4 Å MS

>95% conv, 91% ee

! Enantioselective Aza-Henry Reaction

Yoon, T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 124, 466.

! Enantioselective Hydrophosphorylation

Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4108.

HO

t-Bu OCOt-Bu

N

NH

NH

S

O

Me2N

t-Bu

EtNO2 Ph

NHBoc

Me

NO2

15:1 syn

P

O

OH

O

Ar = 2-nitrophenyl

N

Ph

PhAr

Ar

P

O

O

OAr

Ar HN

Ph

Ph10 mol % cat

4 °CEt2O

87% yield, 98% ee


NHAc

NH

NH

S

O

Me2N

t-Bu

H Ph

NBoc

10 mol % cat

toluene, i-Pr2NEt4 °C

4 Å MS

>95% conv, 91% ee

! Enantioselective Aza-Henry Reaction

Yoon, T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 124, 466.

! Enantioselective Hydrophosphorylation

Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102.

HO

t-Bu OCOt-Bu

N

NH

NH

S

O

Me2N

t-Bu

EtNO2 Ph

NHBoc

Me

NO2

15:1 syn

P

O

OH

O

Ar = 2-nitrophenyl

N

Ph

PhAr

Ar

P

O

O

OAr

Ar HN

Ph

Ph10 mol % cat

4 °CEt2O

87% yield, 98% ee

Bifunctional Urea Catalysts

! Enantioselective Michael Addition

10 mol % cat

toluene , 23 °C

Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 128, 12672.

NMe2

NH

NH

S

CF3

F3C

Me2N

NN

S

R

H H

ONu

H

NO2Ph

O

EtO OEt

O

NO2Ph

OEt

O

EtO

O

NMe2

AcHN

NH

NH

S

CF3

F3C

14%, 35% ee

10 mol % NEt3

57%, 0% ee 86%, 93% ee

NO

Ph

! Both thiourea and tertiary amine are needed

Urea Catalyzed Double Michael Cascade

! Enantioselective Double Michael Addition

10 mol % cat

toluene , –20 °C

Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tettrahdron Lett. 2003, 45, 9185.

NO2Ph

O

OEt

O

Me

O

OEt

O

Ph

NO2

Me

87% yield

O

OEt

O

Me

Ph

NO2

>99% de

92% ee

NMe2

NH

NH

S

CF3

F3C

catalyst =

Rawal's Discovery of H-Bonding Catalyzed Diels–Alder

! Observed that the hetero Diels–Alder reaction is accelerated in alcohol solvent

TBSO

NMeMe

H

O O

O

krel

THF 1

Benzene 1.3

t-BuOH

i-PrOH 630

280

solvent

solventOMe OMe

TBSO

NMeMe

H Ph

O O

O Ph

AcCl

AcCl

20 mol % cat

OH

OH

Ar Ar

Ar Ar

Me

Me

Ar =70% yield

99% ee

Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146.

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

! This observation was turned into an asymmetric reaction using a chiral H-donor catalyst

Mechanism of Rawal's H-Bonding Diels–Alder Reaction

! Is single or double point activation in operation?

R

H

O

O

H

OH

O

RH

O

H

O

H

O

RH

O

O

Ph Ph

Ph Ph

H

H

OH

OH

Ph Ph

Ph Ph

O

RH

Carbonyl

Activation

Single–Point Activation

Re–Face

Open

Single or Double–point activation

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

Chiral Phosphoric Acids

99% yield

95% ee

92% yield

12% ee

O

OP

O

OH

R

R

! Long used for chiral resolutions

! Used as a ligand for Lewis acid catalysis

! 2004 Terada and Akiyama use as Brønsted acid catalyst

NBoc

HPh

O O

MeMe

HN

Boc

Ph

Ac

Ac2 mol % cat

CH2Cl2

R =R = R =

95% yield

56% ee

H

R =

88% yield

90% ee

Akiyama, T.; Itoh, K.; Yokota, K.; Fuchibe, K. Angew Chem. Int. Ed. 2004, 43, 1566.

Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.

! Size of R group very important for enantioselectivity

New Reactivity – Imine Amination

Ph

Ph

O

OP

O

OH

Rowlan, G. B.; Zang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696.

N

Ph

Boc

H2N TsHN

Ph

Boc

HN

SO2Me

No known reaction

metal or

organocatalytic

enantioenriched aminal

(differentially protected)

Boc-imine tosyl-amine

5 mol % cat

Et2O, 1 h, 21 °C

86% yield

93% ee

(S)-VAPOL

Friedel–Crafts

CO2Et

Me2N OMe

Transfer Hydrogenation

O

Consideration of priviledged architecture and stereogenicity

B

A

X important

chiral synthon

important

chiral synthon

O

! Perhaps the most important stereogenicity for biomedical applications

biomedically

relevant center

Amine conjugate addition

O

NR2

Y

X

H

H Me

H

NH2

93–97% ee

There are vast technologies for the construction of amine stereogenicity

! Favourite: Ellman imine, most general–dogma breaking

N

SR

Me

MeS

O

Me

Me

Me HN

SR

Me

MeS

O

Me

Me

Me

tert-butanesulfinamide 20:1 dr, 86% yield

DIBAL

There are vast technologies for the construction of amine stereogenicity

! Favourite: Ellman imine, most general–dogma breaking

N

SR

Me

MeS

O

Me

Me

Me HN

SR

Me

MeS

O

Me

Me

Me

tert-butanesulfinamide 20:1 dr, 86% yield

DIBAL

! Reductive Amination: Simultaneous fragment coupling and C–N bond formation

N

OMe

NHMe

F

no enantioselective catalytic

reductive amination-coupling

Me

O

F

N

O

NH2

Me

NaBH4

–H2O

fragment 1 fragment 2

Organic Catalyzed Reductions in Biological Systems

! NADH: Natures Reduction (Hydrogenation) Reagent (Coenzyme)

NR

H

H

H2NO

NADH reduction

active site

N

R

H H

methyl NADH

enzyme

catalyst

CONH2

pyruvate

alanine transferase

MeOH

O

OMe

OH

NH2

O

Could this organocatalytic sequence be utilized in the redution of carbon–carbon double bonds

Selective reduction of pyruvate imines to create amino acids

alanine

OO

N

Me

H

HN

HN

HH

HNNH

NHR

R

+

His

Arg

NH3

Organic Catalyzed Reductions in Laboratory Systems

! Hantzsch ester as a useful surrogate for NADH reductions in the lab

NR

H

H

MeOO

organic iminium reduction

H-bonded or Bronsted acid

acetophenone NADH analog

catalyst

Me

O

Me

NHR

Can we develop a useful transformation on the basis of established Bronsted acid catalysts

Can we translate a biochemical concept to a laboratory reaction

phenylethyl amine

N

Me

H +

NH2R

R

O catalyst

N

H

H H

CO2MeMeO2C

Me Me

Me

Me

Organic Catalyzed Reductions in Laboratory Systems

! Hantzsch ester as a useful surrogate for NADH reductions in the lab

NR

H

H

MeOO

organic iminium reduction

H-bonded or Bronsted acid

acetophenone NADH analog

catalyst

Me

O

Me

NHR

Can we develop a useful transformation on the basis of established Bronsted acid catalysts

Can we translate a biochemical concept to a laboratory reaction

phenylethyl amine

N

Me

H +

NH2R

R

O catalyst

N

H

H H

CO2MeMeO2C

Me Me

Me

Me

O

OHX

Y

X

Y

O

OP

O

OH

simple carboxylic

or phosphonic acids

catalyst

Organocatalysis and the advent of Bronsted Acid/H-bonded catalysis

S

NN

CF3

CF3

Me2N

Jacobsen

H H

O

O

OH

OH

Ph Ph

Ph Ph

Rawal

O

OP

O

OH

Akiyama, Terada

YamamotoO

OHR

OH

OH

OH

Schaus

! Pioneers


acetophenone

80°C, toluene

Me

O

Me

NHPMPNH2PMP

N

H

H H

CO2MeMeO2C

Me Me

S

NN

CF3

CF3

Me2N

Jacobsen

H H

O

O

OH

OH

Ph Ph

Ph Ph

Rawal

O

OP

O

OH

Akiyama, Terada

YamamotoO

OHR

OH

OH

OH

Schaus

20 mol% catalyst

! Pioneers


acetophenone

80°C, toluene

Me

O

Me

NHPMPNH2PMP

N

H

H H

CO2MeMeO2C

Me Me

S

NN

CF3

CF3

Me2N

Jacobsen

H H

O

O

OH

OH

Ph Ph

Ph Ph

Rawal

O

OP

O

OH

Akiyama, Terada

YamamotoO

OHR

OH

OH

OH

Schaus

No reaction No reaction

No reaction

No reaction

43% yield

7%ee

20 mol% catalyst

! Pioneers

Attempts to develop a Bronsted Acid Catalyst for Reductive Amination

acetophenone

80°C, toluene

Me

O

Me

NHPMPNH2PMP

N

H

H H

CO2MeMeO2C

Me Me

O

OP

O

OH

20 mol% catalyst

ON

OMeH

H

7% ee


acetophenone

80°C, toluene

Me

O

Me

NHPMPNH2PMP

N

H

H H

CO2MeMeO2C

Me Me

O

OP

O

OH

20 mol% catalyst

ON

OMeH

H

R Yield

O

OP

O

OH

R

R

%ee

7% ee


acetophenone

80°C, toluene

Me

O

Me

NHPMPNH2PMP

N

H

H H

CO2MeMeO2C

Me Me

O

OP

O

OH

20 mol% catalyst

ON

OMeH

H

R Yield

O

OP

O

OH

R

R

%ee

43 7

Ph(NO2)2 45 16

2-Nap 56 40

Ph(CF3)2 39 65

7% ee

H


acetophenone

80°C, toluene

Me

O

Me

NHPMPNH2PMP

N

H

H H

CO2MeMeO2C

Me Me

O

OP

O

OH

20 mol% catalyst

ON

OMeH

H

R Yield

O

OP

O

OH

R

R

%ee

43 7

Ph(NO2)2 45 16

2-Nap 56 40

Ph(CF3)2 39 65

Ph3Si 90 85

7% ee

H

The impact of additives and temperature on the reductive amination

80°C, tolueneMe

O

Me

NHPMPNH2PMP

N

H

H H

CO2MeMeO2C

Me Me20 mol% cat

additive

O

OP

O

OH

TPS

TPS

--

H2O (1eq)

H2O (2eq)

catalyst

! What is the impact of the water biproduct

MgSO4

Na2SO4

Yield %ee

90 85

35 77

<10 72

79 83

83 85

Time

28 h

72 h

72 h

20 h

36 h

! What is the scope of this transformation with respect to ketones?

The impact of additives and temperature on the reductive amination

80°C, tolueneMe

O

Me

NHPMPNH2PMP

N

H

H H

CO2MeMeO2C

Me Me20 mol% cat

additive

O

OP

O

OH

TPS

TPS

--

H2O (1eq)

H2O (2eq)

5A mol sieves

catalyst

Temp Yield %ee

80° 85 90

60° 90 93

40° 86 95

Time

6 h

22 h

36 h

! What is the impact of the water biproduct

MgSO4

Na2SO4

Yield %ee

90 85

35 77

<10 72

79 83

83 85

Time

28 h

72 h

72 h

20 h

36 h

6 h 85 90

! What is the scope of this transformation with respect to ketones?

The scope of the reductive amination with respect to aryl ketones

40°C, tolueneMe

O NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst! Scope of the ketone component

! Are there other systems that are successful in this transformation?

5A mol sieves

60-85% yield

(o) 83% ee

X

Me

NHPMP

X

Me

Me

F

(m) 95% ee

(p) 94% ee

O

O

Cl

95% ee

75% yield

Me

O

O2N

95% ee

71% yield

Me

O

MeO

90% ee

77% yield

O

85% ee

75% yield

96% ee

73% yieldMe

O

The scope of the reductive amination

40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst

! Scope of the ketone-ketimine component

5A mol sieves

ON

OMe

97% ee

82% yield

ON

OR

OHN

OR


40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst


5A mol sieves

79% ee

27% yield

ON

OMe

97% ee

82% yield

ON

OEt

ON

OR

OHN

OR


40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst


! Stereochemical models are in accord with the observed reactivity

5A mol sieves

79% ee

27% yield

ON

OMe

97% ee

82% yield

ON

OEt

ON

OR

OHN

OR

Si-face exposed

Si-face blocked

Si-face

= Me

= H

MM3-Calculations Provide Good Prediction of Asymmetric Environment

MM3-structure

Si-face

MM3-Calculations Provide Good Prediction of Asymmetric Environment

5Å MS, 50 °C

10 mol% cat

benzene

Si-face

O2N

N

Me

OMe

O2N

HN

Me

OMe

HEH,

71% yield95% ee

Crystal grown in toluene at –20 ˚C in glove boxX-ray structureMM3-structure

Si-face


40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst



5A mol sieves

79% ee

27% yield

ON

OMe

97% ee

82% yield

ON

OEt

ON

OR

OHN

OR

Si-face exposed

Si-face blocked

Si-face

= Me

= H


40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst



5A mol sieves

79% ee

27% yield

ON

OMe

97% ee

82% yield

ON

OEt

ON

OR

OHN

OR

Si-face exposed

Si-face blocked

Si-face

= Me

= H

selective for

methyl versus ethyl ketones


40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst



5A mol sieves

ON

OR

OHN

OR

Si-face exposed

Si-face blocked

Si-face

= Me

= H

selective for



40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst



5A mol sieves

ON

OR

OHN

OR

Si-face exposed

Si-face blocked

Si-face

= Me

= H

selective for


Et

O

ND % ee

<15% yield

Me

O

93% ee

87% yield


40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst



5A mol sieves

ON

OR

OHN

OR

Si-face exposed

Si-face blocked

Si-face

= Me

= H

selective for



40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst



5A mol sieves

ON

OR

OHN

OR

Si-face exposed

Si-face blocked

Si-face

= Me

= H

selective for


MeMe

O

2-butanone

Me vs Et

on the same substrate

The scope of the reductive amination: alkyl ketones

40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst

! Scope of the alkyl ketone component

5A mol sieves

R Me

O

R Me

NHPMP

Et Me

O 91% ee

71% yield

The scope of the reductive amination: alkyl ketones

40°C, toluene

NH2PMP

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst

! Scope of the alkyl ketone component

5A mol sieves

Me

O

86% ee

49% yield

94% ee

75% yield

R Me

O

R Me

NHPMP

86% ee

50% yield

Me

O

Me

O 91% ee

72% yield

Et Me

O 91% ee

71% yield Me

NHPMP

BzO

92% ee

68% yield

O

Cl

! This reductive amination process appears to be general for methyl ketones

With Storer, Carrera, Ni. J. Am. Chem. Soc. 2006, 128, 84

The scope of the reductive amination: aryl amines

40°C, toluene

RNH2

N

H

H H

CO2MeMeO2C

Me Me10 mol% cat

O

OP

O

OH

TPS

TPS

catalyst

! Scope of the amine component

5A mol sieves

93% ee

73% yield

R Me

O

R Me

NHR

Me

HN

95% ee

55% yield

Me

HN

CF3

90% ee

92% yield

Me

HN

O

93% ee

90% yield

Me

HN

TsN

91% ee

70% yield

Me

HN S

N

90% ee

75% yield

Me

HN

TsN

Activation Modes Are Enabled by Priviledged Catalyst Achitectures

R R

Carbene, Phase Transfer

Activation

Modes

S

NH

NH

RR P

O

OHRO

RO

H-Bonding, Brønsted Acids

NR4

Catalysis Platform / Concept Chemical Methodology

Catalyst Design

Priviledged

AchitectureChiral

Pool

Novel Reactivity

Valuable New Bond

Disconnections

MacMiIlan, D. W. C. Nature 2008, 455, 304.

activation modes are enabled by priviledged catalyst...

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