enamine catalysis: fifty years in the making · 2016. 12. 24. · enamine catalysis: fifty years in...

Enamine Catalysis: Fifty Years in the Making

! Stork's landmark 1954 publication outlines benefits of enamines vs enolates

N

O

Me

Ph

CN

O

Ph

O

Alkylation

Acylation

Michael

Addition

Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.

Enamine Catalysis: Fifty Years in the Making

! Stork's landmark 1954 publication outlines benefits of enamines vs enolates

N

O

Me

Ph

CN

O

Ph

O

Alkylation

Acylation

Michael

Addition

Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.

Enamine Catalysis: Inspiration from Biology

! Mechanism of class I aldolases is proposed to involve enamine intermediates

Fructose bisphosphate aldolase

NH2

NH

O

OPO32–OH

HO

H

OPO32–

N

OH

OPO32–

O

HOPO3

2–

OH

2–O3PO

O

OH

OPO32–

2–O3PO

Rutter, W. J. Fed. Proc. Am. Soc. Exp. Biol. 1964, 23, 1248Lysine reside is required for catalytic activity

Enamine Catalysis: Early Adoption in Total Synthesis

! Woodward-Wieland-Miescher enamine cyclization for steroid synthesis

Wieland, P.; Miescher, K. Helv. Chim. Acta 1950, 33, 2215

O

Me

MeOH

OH

HH5IO6

O

Me

MeO

O

H NH

HOAcbenzene O

Me

H

CHO

Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223

O O

Me

O

Me

O

OH

O

HH

NH

NaOH OOH

OMe

O

HOOH

O

OMe

Hajos-Parrish-Eder-Sauer-Wiechart: Asymmetric Breakthrough

! Use of proline to deliver the Weiland-Miescher ketone in an asymmetric fasion

O

Me

OMe

proline

(200 mol%)

MeCN, HClO480 ºC

Me O

O

proline

(3 mol%)

DMF

Me O

OOH

98% ee 67% ee

J. Org. Chem. 1974, 39, 1615. Angew. Chem. Int. Ed. 1971, 10, 496.

German Patent DE2102623 (July 29, 1971) German Patent DE2014757 (Oct 7, 1971)

O

Me

OMe

proline

(200 mol%)

MeCN, HClO480 ºC

Me O

O

proline

(3 mol%)

DMF

Me O

OOH

98% ee 67% ee

97% ee

O

Me

OMe

proline

(200 mol%)

MeCN, HClO480 ºC

Me O

O

proline

(3 mol%)

DMF

Me O

OOH

98% ee 67% ee

97% ee

O

Me

OMe

proline

(200 mol%)

MeCN, HClO480 ºC

Me O

O

proline

(3 mol%)

DMF

Me O

OOH

98% ee 67% ee

97% ee

3210

Bifunctional Enamine Catalysis: Generic Induction Platform

! Use of proline or proline-type activation a widely exploited mode of ketone activation

R'

O

R

NH

O

OH

XY

H

N

H

R

O O

ketone

proline

Bifunctional

activation

N N

Cbz

R'

O

R

N

NHCbz

Cbz

Jørgensen JACS 2002, 124, 6254.

R'

O

R

List Org Lett 2001, 13, 2423.

O

H

Me

O Me

Me

OH

List Org Lett 2001, 3, 573.

X Y

Amination

Cross-Aldol

R'

PhNO2

Nitro-olefin

addition

NO2

Ph

R'

O

R

NH

O

OH

XY

H

N

H

R

O O

ketone

proline

Bifunctional

activation

N N

Cbz

R'

O

R

N

NHCbz

Cbz

R'

O

R

List Org Lett 2001, 13, 2423.

O

H

Me

O Me

Me

OH

X Y

Amination

Cross-Aldol

R'

PhNO2

Nitro-olefin

addition

NO2

Ph

R'

O

R

NH

O

OH

XY

H

N

H

R

O O

ketone

proline

Bifunctional

activation

N N

Cbz

R'

O

R

N

NHCbz

Cbz

R'

O

R

List Org Lett 2001, 13, 2423.

O

H

Me

O Me

Me

OH

X Y

Amination

Cross-Aldol

R'

PhNO2

Nitro-olefin

addition

NO2

Ph

R'

O

R

NH

O

OH

XY

H

N

H

R

O O

ketone

proline

Bifunctional

activation

N N

Cbz

R'

O

R

N

NHCbz

Cbz

R'

O

R

List Org Lett 2001, 13, 2423.

O

H

Me

O Me

Me

OH

X Y

Amination

Cross-Aldol

R'

PhNO2

Nitro-olefin

addition

NO2

Ph

Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 6722.

86%

5:1

TFA

86% 94%

Et2OMe

Me Me

5:1

97%

DMSO

73%

64%

97%

19:1 95%–78 to –40 ºC

–20 to +4 ºC

87%

95%

>19:1

–20 to +4 ºC

79%

95%

OH

OAc

OH

OBn

95%

Predictable Stereochemistry for Aldol and Mannich

! Use of proline or proline-type catalysts leads to anti-aldol or syn-Mannich

XY

H

N

H

R

O O

Bifunctional

activation

OH

N

H

R

O OH

R'

O

H R'

R

OHAldol

anti-selective

NH

N

H

R

O OR'

H

PMP O

H R'

R

NHPMPMannich

syn-selective

! Maruoka's binaphthyl catalyst is a significant advance to access opposite stereoisomers

NH

NHTf

N

NTf

H

R

O

HR'

N

NTf

H

R

N

R'H

O

H R'

R

OH

Syn-aldol: ACIEE 2004, 43, 6722

O

H R'

R

NHPMP

Anti-Mannich: JACS 2005, 127, 16408

Predictable Stereochemistry for Aldol and Mannich

! Use of proline or proline-type catalysts leads to anti-aldol or syn-Mannich

XY

H

N

H

R

O O

Bifunctional

activation

OH

N

H

R

O OH

R'

O

H R'

R

OHAldol

anti-selective

NH

N

H

R

O OR'

H

PMP O

H R'

R

NHPMPMannich

syn-selective

! Maruoka's binaphthyl catalyst is a significant advance to access opposite stereoisomers

NH

NHTf

N

NTf

H

R

O

HR'

N

NTf

H

R

N

R'H

O

H R'

R

OH

Syn-aldol: ACIEE 2004, 43, 6722

O

H R'

R

NHPMP

Anti-Mannich: JACS 2005, 127, 16408

Monofunctional Enamine Catalysis

! Bifunctional activation is not absolutely required for selective catalysis

H

O

Me

10 mol% catalyst

then, MeOH/CSAMeO

OMe

Me

N

NH

MeO

Bn •TCAMe

OH

4:1 (ant:syn)

94% ee

! Imidazolidinone and Jørgensen-type frameworks have been widely applied

N

NH

MeO

Bn

N

NH

MeO

Bn

NH

Ar

OTMSNH

Ar

ArMe

Me H

Enamine Chemistry with Jørgensen's Catalyst

Ar

ArOTMS

NH

Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kaersgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.

O

H

R

O

H

Bn

F

O

H

i-Pr

Br

O

H

Et

S Ph

O

H

Et

N

HN

CO2Et

O

H

Et

HN

CO2Et

PMP

O

H

Et

O

Me

74%, 94% ee

74%, 93% ee

83%, 93% ee

83%, 94% ee, 4:1 dr

79%, 90% ee

83%, 96% ee

Ar

ArOTMS

N

RE

O

H

Et

NBn2

84%, 90% ee

Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.

O

H

Bn

OH

70%, 87% ee

Ibrahem, I.; Zhao, G.-L.; Sunden, H.; Córdova, A. Tettrahedron Lett. 2006, 47, 4659.

Ar

ArOTMS

NH

O

H

R

O

H

Bn

F

O

H

i-Pr

Br

O

H

Et

S Ph

O

H

Et

N

HN

CO2Et

O

H

Et

HN

CO2Et

PMP

O

H

Et

O

Me

74%, 94% ee

74%, 93% ee

83%, 93% ee

83%, 94% ee, 4:1 dr

79%, 90% ee

85%, 96% ee

Ar

ArOTMS

N

RE

O

H

Et

NBn2

84%, 90% ee

O

H

Bn

OH

70%, 87% ee

Ar

ArOTMS

NH

O

H

R

O

H

Bn

F

O

H

i-Pr

Br

O

H

Et

S Ph

O

H

Et

N

HN

CO2Et

O

H

Et

HN

CO2Et

PMP

O

H

Et

O

Me

74%, 94% ee

74%, 93% ee

83%, 93% ee

83%, 94% ee, 4:1 dr

79%, 90% ee

85%, 96% ee

Ar

ArOTMS

N

RE

O

H

Et

NBn2

84%, 90% ee

O

H

Bn

OH

70%, 87% ee

Dienamine Activation: !-Amination of Enals

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

E

Ar

ArOTMS

NH

Ar = 3,5-(CF3)2C6H3

10 mol % PhCO2H

toluene

NN CO2Et

EtO2C

O

H

Me

O

H

Me

N

HN

CO2Et

10 mol %

56%, 89% ee

Bertelsen, S.; Marigo, M.; Brandes, S.; Dinér, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

E

Ar

ArOTMS

NH

Ar = 3,5-(CF3)2C6H3

10 mol % PhCO2H

toluene

NN CO2Et

EtO2C

O

H

Me

O

H

Me

N

HN

CO2Et

10 mol %

56%, 89% ee

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

Ar

ArOTMS

N

R

20.9 kcal/mol

13.0 kcal/mol

N

NEtO2C

CO2Et

Ar

ArOTMS

N

R

N

NH

EtO2C

S-product

(not observed)

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

Ar

ArOTMS

N

R

20.9 kcal/mol

13.0 kcal/mol

N

NEtO2C

CO2Et

Ar

ArOTMS

N

R

N

NH

EtO2C

S-product

(not observed)

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

Ar

ArOTMS

N

R

20.9 kcal/mol

13.0 kcal/mol

N

NEtO2C

CO2Et

Ar

ArOTMS

N

R

N

NH

EtO2C

S-product

(not observed)

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

Ar

ArOTMS

N

R

7.5 kcal/mol

Ar

ArOTMS

N

R

Ar

OTMSN

R

NCO2Et

6.7 kcal/mol

–23.5 kcal/mol0 kcal/mol

H2O

–cat

O

R

N

H NH CO2Et

CO2Et

R–product

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

Ar

ArOTMS

N

R

7.5 kcal/mol

Ar

ArOTMS

N

R

Ar

OTMSN

R

NCO2Et

6.7 kcal/mol

H2O

–cat

O

R

N

H NH CO2Et

CO2Et

R–product

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

Ar

ArOTMS

N

R

7.5 kcal/mol

Ar

ArOTMS

N

R

Ar

OTMSN

R

NCO2Et

6.7 kcal/mol

H2O

–cat

O

R

N

H NH CO2Et

CO2Et

R–product

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

Ar

ArOTMS

N

R

7.5 kcal/mol

Ar

ArOTMS

N

R

Ar

OTMSN

R

NCO2Et

6.7 kcal/mol

H2O

–cat

O

R

N

H NH CO2Et

CO2Et

R–product

Ar

ArOTMS

NH

O

H

Ar

ArOTMS

N

R

Ar

ArOTMS

N

R

–H2O –H+

Ar

ArOTMS

NH

Ar = 3,5-(CF3)2C6H3

10 mol % PhCO2H

toluene

NN CO2Et

EtO2C

O

H

Me

O

H

Me

N

HN

CO2Et

10 mol %

56%, 89% ee

HOMO-Raising Catalysis Beyond Enamine Activation

N

OR

N

OMe

Ph

Ph Ph

Ph PhFe

N

Me2N

! Enamine activation is extremely powerful, but does not extend to esters, amides, etc.

O

H

R

N

NH

O Me

Ph

N

O Me

Ph

R

O

X

R

X = OR, NR2

N

NH

O Me

Ph

N

O Me

Ph

R

X

O

X

R1

R2

Is there an alternative way to generatechiral ester enolate equivalents?

Chiral Ammonium Catalysis

Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596

No condensation

HOMO-Raising Catalysis Beyond Enamine Activation

N

OR

N

OMe

Ph

Ph Ph

Ph PhFe

N

Me2N

! Enamine activation is extremely powerful, but does not extend to esters, amides, etc.

O

H

R

N

NH

O Me

Ph

N

O Me

Ph

R

O

X

R

X = OR, NR2

N

NH

O Me

Ph

N

O Me

Ph

R

X

O

X

R1

R2

Is there an alternative way to generatechiral ester enolate equivalents?

Chiral Ammonium Catalysis

Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596

No condensation

Ketenes as Precursors for Ammonium Enolates

! Attack of nucleophilic tertiary amine on ketene leads directly to ammonium enolate

O

•

MeH

*NR3

O

Me

H

R3N*E+

O

R3N*

Me

E HNuc

O

Nuc

Me

E

Enantioselective ester/amide!-functionalization

! First asymmetric example by Wynberg in 1982 (first racemic by Sauer in 1947)

•O

H

H CCl3

O

N

OMe

OH

catalyst (4 mol%)

PhMe, –25 ºC

O

Cl3C

*NR3

O

H

R3N* H CCl3

O

Cl3C

O

NR3*

"-Lactone formation: internal nucleophile

catalyst

Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166

Sauer, J. C. J. Am. Chem. Soc. 1947, 69, 2444

Ketenes as Precursors for Ammonium Enolates

! Attack of nucleophilic tertiary amine on ketene leads directly to ammonium enolate

O

•

MeH

*NR3

O

Me

H

R3N*E+

O

R3N*

Me

E HNuc

O

Nuc

Me

E

Enantioselective ester/amide!-functionalization

! First asymmetric example by Wynberg in 1982 (first racemic by Sauer in 1947)

•O

H

H CCl3

O

N

OMe

OH

catalyst (4 mol%)

PhMe, –25 ºC

O

Cl3C

*NR3

O

H

R3N* H CCl3

O

Cl3C

O

NR3*

"-Lactone formation: internal nucleophile

catalyst

Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166

Sauer, J. C. J. Am. Chem. Soc. 1947, 69, 2444

Ammonium Enolates as Versatile Synthetic Intermediates

N

OR

N

OMe

Ph

Ph Ph

Ph PhFe

N

Me2N

Gaunt, M. J. Johansson, C. C. C. Chem. Rev. 2007, 107, 5596

or

•O

X

Y

O

Cl

Y

X

H

O

R3N*

Y

X

O

R

X

Y

O

R

TsN

O

R

X

Y

NTs

R

O

X

YR

O

•

R

"Cl+"

O

ROCl

X Y

[4+2]

NR

O O

X

Y

MeOH

O

MeOH

X Y

France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985

Ammonium Enolates as Versatile Synthetic Intermediates

N

OR

N

OMe

Ph

Ph Ph

Ph PhFe

N

Me2N

Gaunt, M. J. Johansson, C. C. C. Chem. Rev. 2007, 107, 5596

or

•O

X

Y

O

Cl

Y

X

H

O

R3N*

Y

X

O

R

X

Y

O

R

TsN

O

R

X

Y

NTs

R

O

X

YR

O

•

R

"Cl+"

O

ROCl

X Y

[4+2]

NR

O O

X

Y

MeOH

O

MeOH

X Y

France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985

Alternative Methods to Access Ammonium Enolates

N

OR

N

OMe

Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 4641

Et2N

O

Br

O

Phcatalyst (10 mol%)

CsCO3, MeCN, 80 ºC

! Alkylation of !-bromocarbonyls lead to chiral ammonium ylides

PhEt2N

O O

94% yield97% ee

catalyst

*NR3

Et2N

O

NR3*

CsCO3

O

Ph Et2N

O

NR3*

Ph

O

Nucleophilic cyclopropanation –*NR3

! Also applicable to Baylis-Hillman type reactivity

Asymmetric Ylides Formed from Chalcogenides

Furukawa, N.; Sugihara, Y.; Fujihara, H. J. Org. Chem. 1989, 54, 4222

! Combination with stronger bases/alkyl halides allows for asymmetric epoxide formation

! Vast array of structural types allows for epoxide, aziridine, cyclopropane formation, Baylis-Hillman

SMeOMe

BnBr

KOH, MeCN

SMeOMe

Ph

O

ArH

O

Ar

Ph

R2S

O

Ph Ar

With 10 mol% sulfide: 23% yield31%ee

S

S RR

S

N

Me Ph

Et

S

O Se MeMe Te EtEt

McGarrigle, E. M.; Myers, E. L.; Illa, O.; Shaw, M. A.; Riches, S. L.; Aggarwal, V. A. Chem. Rev. 2007, 107, 5841

"The Taxol Problem" An illustrative example

! Important ovarian, breast cancer treatment worldwide

! Originally available from Pacific Yew Taxus Brevifolia

(extraction killed the source)

! Structural core available from European Yew

Taxus Baccata allows semi synthesis, production

! Global demands exceed a metric tonne annually

! Now produced via fermentation

from Taxus Chinensis

! Wender, most expeditious, efficient chemical synthesis

! What if the European or Chinese Yew did not produce baccatin in the pine needles?

accomplished in 37 steps and 0.44% overall yield

OHO

BzO AcO

OHAcO

HO

O

11 Chemical steps 7 isolation steps

10-deacetyl baccatin III (renewable source)

OHO

BzO AcO

OHAcO

O

Ph

O

OH

NHPh

Taxol

OHO

BzO AcO

OHAcO

HO

O

OHO

BzO AcO

OHAcO

O

Ph

O

OH

NHPh

Taxol

OHO

BzO AcO

OHAcO

HO

O

OHO

BzO AcO

OHAcO

O

Ph

O

OH

NHPh

Taxol

OHO

BzO AcO

OHAcO

HO

O

OHO

BzO AcO

OHAcO

O

Ph

O

OH

NHPh

Taxol

OHO

BzO AcO

OHAcO

HO

O

OHO

BzO AcO

OHAcO

O

Ph

O

OH

NHPh

Taxol

The problem with a 40 step synthesis: Step Economy and Losses

! "Stop and Go" isolation can greatly diminsh the overall efficiency of processes with high yielding steps

50 % yield

! For every step (operation) involved = exponential decrease in efficiency

! Why is chemical synthesis able to produce complexity on small scale but not large

40 steps

! Problems with taxol production arose from "stop and go" synthesis

OHO

BzO AcO

OHAcO

HO

O

OHO

BzO AcO

OHAcO

O

Ph

O

OH

NHPh

10-deacetyl baccatin III Taxol

11 Chemical steps

7 isolation steps

50 % yield

40 steps

OHO

BzO AcO

OHAcO

HO

O

OHO

BzO AcO

OHAcO

O

Ph

O

OH

NHPh

11 Chemical steps

7 isolation steps

50 % yield

40 steps

OHO

BzO AcO

OHAcO

HO

O

OHO

BzO AcO

OHAcO

O

Ph

O

OH

NHPh

11 Chemical steps

7 isolation steps

Benchtop Synthesis vs. Biosynthesis : Why is Nature Winning?

! Nicolaou Synthesis of Taxol: Tour de force

OHO

BzO

HAcO

OHAcO

O

Ph

O

OH

NHBz

Taxol

55 Chemical steps

! Biology employs enzymatic cascade catalysis: Continuous process assembly lines

O6P2O

geranylgeranyl diphosphate

taxadiene

synthase

3 x enzyme benzoyl

transferasefunctionalizn

OHO

BzO

HAcO

OHAcO

O

Ph

O

OH

NHBz

Taxol

5 catalytic transformations

in one cascade process

H

OTIPS

O

55 isolation steps

OHO

BzO

HAcO

OHAcO

O

Ph

O

OH

NHBz

Taxol

55 Chemical steps

O6P2O

taxadiene

synthase

3 x enzyme benzoyl

OHO

BzO

HAcO

OHAcO

O

Ph

O

OH

NHBz

Taxol

H

OTIPS

O

55 isolation steps

OHO

BzO

HAcO

OHAcO

O

Ph

O

OH

NHBz

Taxol

55 Chemical steps

O6P2O

taxadiene

synthase

3 x enzyme benzoyl

OHO

BzO

HAcO

OHAcO

O

Ph

O

OH

NHBz

Taxol

H

OTIPS

O

55 isolation steps

! Why doesn't the field of chemical synthesis build complexity using cascade catalysis (biomimetic)

OHO

BzO

HAcO

OHAcO

O

Ph

O

OH

NHBz

Taxol

55 Chemical steps

O6P2O

taxadiene

synthase

3 x enzyme benzoyl

OHO

BzO

HAcO

OHAcO

O

Ph

O

OH

NHBz

Taxol

H

OTIPS

O

55 isolation steps

Design of Cascade–Catalysis Strategy: LUMO–HOMO Catalyst

O

RNH

R+ N

R

+•HCl

substrate catalyst LUMO–activation

O

RNH

R+ N

R

•HCl

substrate catalyst HOMO–activation

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

O OLALewis acid (LA)+

+

O

RNH

R+ N

R

+•HCl

O

RNH

R+ N

R

•HCl

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

+

O

RNH

R+ N

R

+•HCl

O

RNH

R+ N

R

•HCl

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

Aldehyde aldol

!-Oxy Aldol

Imidazolidinone aldol !-Oxyamination

Epoxidation

98% ee94% ee

99% ee

98% ee

94% ee

99% ee

Enamine activation strategy is useful for a variety of organocatalytic reactions

!-Chlorination

Aziridination

98% ee

!-Fluorination

99% ee

Two step sugars

JACS 2002, 124, 6798

Angew Chemie 2004, 43, 2152

Angew Chemie 2004, 43, 6722

Science 2004, 305, 1752

JACS 2004, 126, 4108

JACS 2003, 125, 10808

JACS 2005, 127, ASAP

95% eeH

Me

OHO

Me

H

OBn

OHO

OBn

MeO

Me

OHOMe

Me

O OHTIPSO

TIPSO

OH

NBOC

H

Cl

O

HPh

ONHPh

O

HPh

F

O

BnN

+

O

RNH

R+ N

R

+•HCl

O

RNH

R+ N

R

•HCl

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

+

O

RNH

R+ N

R

+•HCl

O

RNH

R+ N

R

•HCl

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

N

NH

O Me

Ph

Me

imidazolidinone

generation 1

! Can we merge LUMO-lowering and HOMO-raising catalysis using the same catalyst

N

O Me

R

N

O Me

R

N

NH

Ph

O Me

X– +

HX

N

NH

Me

imidazolidinone

! First step:

Iminium catalysis

! Second step:

Enamine catalysis

Ph Me

Merging LUMO-lowering and HOMO-raising with one catalyst

E+

O

MeMe

Nu O

Nu

Me

MeMe

Me

MeR

N

O Me

R

N

Ph

O Me

R

HX +

N

NH

Ph

O Me

N

Ph

O Me

+X–

R

X– +

Nu–

Nu O

Nu

Me

MeMe

Me

MeMe

R

N

Ph

O Me

R

X– +

Nu

Me

MeMe

Ph

E

R O Nu O

R

E

First Cycle

(Im)

Second Cycle

(En)

Ph

O

R

HX +

N

O Me

R

N

O Me

R

N

NH

Ph

O Me

X– +

HX

N

NH

Me

imidazolidinone

! First step:

Iminium catalysis

! Second step:

Enamine catalysis

Ph Me

E+

O

MeMe

Nu O

Nu

Me

MeMe

Me

MeR

N

O Me

R

N

Ph

O Me

R

HX +

N

NH

Ph

O Me

N

Ph

O Me

+X–

R

X– +

Nu–

Nu O

Nu

Me

MeMe

Me

MeMe

R

N

Ph

O Me

R

X– +

Nu

Me

MeMe

Ph

E

R O Nu O

R

E

First Cycle

(Im)

Second Cycle

(En)

Ph

O

R

HX +

N

O Me

R

N

O Me

R

N

NH

Ph

O Me

X– +

HX

N

NH

Me

imidazolidinone

! First step:

Iminium catalysis

! Second step:

Enamine catalysis

Ph Me

E+

O

MeMe

Nu O

Nu

Me

MeMe

Me

MeR

N

O Me

R

N

Ph

O Me

R

HX +

N

NH

Ph

O Me

N

Ph

O Me

+X–

R

X– +

Nu–

Nu O

Nu

Me

MeMe

Me

MeMe

R

N

Ph

O Me

R

X– +

Nu

Me

MeMe

Ph

E

R O Nu O

R

E

First Cycle

(Im)

Second Cycle

(En)

Ph

O

R

HX +

N

O Me

R

N

O Me

R

N

NH

Ph

O Me

X– +

HX

N

NH

Me

imidazolidinone

! First step:

Iminium catalysis

! Second step:

Enamine catalysis

Ph Me

E+

O

MeMe

Nu O

Nu

Me

MeMe

Me

MeR

N

O Me

R

N

Ph

O Me

R

HX +

N

NH

Ph

O Me

N

Ph

O Me

+X–

R

X– +

Nu–

Nu O

Nu

Me

MeMe

Me

MeMe

R

N

Ph

O Me

R

X– +

Nu

Me

MeMe

Ph

E

R O Nu O

R

E

First Cycle

(Im)

Second Cycle

(En)

Ph

O

R

HX +

N

O Me

R

N

O Me

R

N

NH

Ph

O Me

X– +

HX

N

NH

Me

imidazolidinone

! First step:

Iminium catalysis

! Second step:

Enamine catalysis

Ph Me

E+

O

MeMe

Nu O

Nu

Me

MeMe

Me

MeR

N

O Me

R

N

Ph

O Me

R

HX +

N

NH

Ph

O Me

N

Ph

O Me

+X–

R

X– +

Nu–

Nu O

Nu

Me

MeMe

Me

MeMe

R

N

Ph

O Me

R

X– +

Nu

Me

MeMe

Ph

E

R O Nu O

R

E

First Cycle

(Im)

Second Cycle

(En)

Ph

O

R

HX +

N

O Me

R

N

O Me

R

N

NH

Ph

O Me

X– +

HX

N

NH

Me

imidazolidinone

! First step:

Iminium catalysis

! Second step:

Enamine catalysis

Ph Me

E+

O

MeMe

Nu O

Nu

Me

MeMe

Me

MeR

N

O Me

R

N

Ph

O Me

R

HX +

N

NH

Ph

O Me

N

Ph

O Me

+X–

R

X– +

Nu–

Nu O

Nu

Me

MeMe

Me

MeMe

R

N

Ph

O Me

R

X– +

Nu

Me

MeMe

Ph

E

R O Nu O

R

E

First Cycle

(Im)

Second Cycle

(En)

Ph

O

R

HX +

Cascade catalysis with imidazolidinones: preliminary results

Me OOMe

O

ClCl

Cl

10 mol%

–50 °C, EtOAc

N

NH

OMe

Me

MeMe

BnIndole OMeO

Cl

Me

substrate electrophilenucleophile 86% yield 14:1 dr 99% ee

Me OOMe

O

ClCl

Cl

10 mol%

–50 °C, EtOAc

N

NH

OMe

Me

MeMe

BnIndole OMeO

Cl

Me

substrate electrophilenucleophile 86% yield 14:1 dr 99% ee

! Cascade-catalsysis appears general for a range of enal substrates

! Diastereoselectivity suggests that catalyst control is dominant in second cycle

R OOMe

O

ClCl

Cl

10 mol%

–50 °C, EtOAc

N

NH

OMe

Me

MeMe

BnIndole OMeO

Cl

R

substrate electrophilenucleophile

R ee%Yield syn:antiTemp °C

Me

Pr

CO2Et

CH2OAc

syn 99% ee

14:1

13:1

22:1

11:1

–50

–40

86%

74%

80%

82%

Enantioselective Organo–Cascade Catalysis

Me O

Im En syn:anti 25:1

99% ee

71% yield

N

NH

OMe

But Bnindole

! With a range of nucleophiles

OTESO

Cl

O

Cl Cl

10 mol% catalyst

•TFA

O

Im EnN

Cl

O

Cl Cl

Me O

Im Ensyn:anti 9:1

99% ee

97% yieldN

OTIPSOCl

Cl

O

Cl Cl

NaBH4;

NaOH

Me

N

O

OMe

Ph

Me

Cl

N

O syn:anti 12:1

99% ee

75% yield

Rapid development of molecular complexity from simple materials

! Processes are highly selective also using thiophenes, nitroalkanes

Me Me

Me

O

Me

Cl

O

H

Me

O

Me

Me O

Im En syn:anti 25:1

99% ee

71% yield

N

NH

OMe

But Bnindole

OTESO

Cl

O

Cl Cl

10 mol% catalyst

•TFA

O

Im EnN

Cl

O

Cl Cl

Me O

Im Ensyn:anti 9:1

99% ee

97% yieldN

OTIPSOCl

Cl

O

Cl Cl

NaBH4;

NaOH

Me

N

O

OMe

Ph

Me

Cl

N

O syn:anti 12:1

99% ee

75% yield

Me Me

Me

O

Me

Cl

O

H

Me

O

Me

Me O

Im En syn:anti 25:1

99% ee

71% yield

N

NH

OMe

But Bnindole

OTESO

Cl

O

Cl Cl

10 mol% catalyst

•TFA

O

Im EnN

Cl

O

Cl Cl

Me O

Im Ensyn:anti 9:1

99% ee

97% yieldN

OTIPSOCl

Cl

O

Cl Cl

NaBH4;

NaOH

Me

N

O

OMe

Ph

Me

Cl

N

O syn:anti 12:1

99% ee

75% yield

Me Me

Me

O

Me

Cl

O

H

Me

O

Me

Im En

Me O

Ph

anti:syn 16:1

99% ee

81% yield

NH

MeMe

RO2C CO2R

H H

O

H

F

PhS

NS

Ph

O O O O

F

syn:anti 9:1

99% ee

62% yieldO

H

F

catalyst

combination A

catalyst

combination B

Me

Im En

H

Cascade Catalysis Towards the Development of Modular Stereocontrol

N

NH

MeO

Me

catalyst

N

NH

MeO

catalyst

Me

Ph

(5S)-iminium (2R)-enamine

(7.5 mol%) (30 mol%)

N

NH

MeO

Me

catalyst

N

NH

MeO

catalyst

Me

Ph

(5S)-iminium (2S)-enamine

(7.5 mol%) (30 mol%)

catalyst combination A catalyst combination B

enamine catalyst and E

added after consumption of Nu

With Huang, Walji, Larsen. J. Am. Chem. Soc. 2005, 127, 15051

Im En

Me O

Ph

anti:syn 16:1

99% ee

81% yield

NH

MeMe

RO2C CO2R

H H

O

H

F

PhS

NS

Ph

O O O O

F

syn:anti 9:1

99% ee

62% yieldO

H

F

catalyst

combination A

catalyst

combination B

Me

Im En

H

N

NH

MeO

Me

catalyst

N

NH

MeO

catalyst

Me

Ph

(7.5 mol%) (30 mol%)

N

NH

MeO

Me

catalyst

N

NH

MeO

catalyst

Me

Ph

(7.5 mol%) (30 mol%)

N

NH

MeO

Me

catalyst

N

NH

MeO

catalyst

Me

Ph

(7.5 mol%) (30 mol%)

N

NH

MeO

Me

catalyst

N

NH

MeO

catalyst

Me

Ph

(7.5 mol%) (30 mol%)

Im En

Me O

Ph

anti:syn 16:1

99% ee

81% yield

NH

MeMe

RO2C CO2R

H H

O

H

F

PhS

NS

Ph

O O O O

F

syn:anti 9:1

99% ee

62% yieldO

H

F

catalyst

combination A

catalyst

combination B

Me

Im En

H

Im EnMe O

Ph

Me O

Ph

NH2

! Olefin hydroamination

H

Im En

anti:syn 17:1 99% ee

Me O

Ph

Me O

Ph

NNH

BOCBOC

NH

MeMe

EtO2C CO2Et

H H

BOCN

NBOC

Im En

H

6:1

CbzCbz

Im En

Me O

Ph

Me O

Ph

NNH

BOCCOB

Im En Me O

Ph

Me O

Ph

OH

! Olefin hydrolysis

H

6:1

hydrooxidation

CbzCbz

Im En

Me O

Ph

Me O

Ph

NNH

BOCCOB

Im En

Me O

Ph

Me O

Ph

ONH

Ph

! Olefin hydrolysis

H

NH

MeMe

EtO2C CO2Et

H H

Im En

ON

6:1

hydrooxidation

11:1

CbzCbz

Im En

Me O

Ph

Me O

Ph

NNH

BOCCOB

Im En

Me O

Ph

Me O

Ph

ONH

Im EnMe O

Ph

Me O

OH

NH2

! Olefin hydrolysis

! Olefin aminohydroxylation

6:1

hydrooxidation

11:1

CbzCbz

Im En

Me O

Ph

Me O

Ph

NNH

BOCCOB

Im En

Me O

Ph

Me O

Ph

ONH

Im En

Me O

Ph

Me O

ONH

Ph

NBOC OSiR3

! Olefin hydrolysis

! Olefin aminohydroxylation

Im En

ON

BOCNH

OSiR3

6:1

hydrooxidation

11:1

17:1

CbzCbz

Im En

Me O

Ph

Me O

Ph

NNH

BOCCOB

Im EnMe O

Ph

NNH

BOCBOC

syn:anti 8:1 99% ee

Im En

Me O

Ph

Me O

Ph

ONH

Im EnMe O

Ph

O

syn:anti 10:1 99% ee

Im En

Me OIm EnMe O

ONH

Ph

syn:anti 9:1 99% ee

NH

Ph Ph

NBOC OSiR3

Me O

ONH

Ph

NBOC OSiR3

6:1

11:1

17:114:1

CbzCbz

Cascade Catalysis: Merging Organo and Organometallic Catalysis

! The structural core of aromadendranediol in one step

Me

Ru Im En

O

86% yield

8:1 dr

92% ee

OTMSO Me

OO

HMeOH

Me

HO

O

! 4 contiguous

stereogenic centers

! 11 carbon

framework

N

Ph

O Me

X Iminium CycleMe

MeMeMe O

O

Me N

N

Ph

O Me

Me

MeMe

O

Me

H

O

Me

H

O

N

Ph

O Me

XMe

MeMe

N

NH

Ph

O Me

Me

MeMe

O

Me

H

O

HX

NCO2

Me

H

O

O Me

H

OHMe

Me O

O

H

OH

Me

O

H

O

NH

CO2H

+ H2O+ H2O

NCO2

+ H2O + H2O

Enamine Cycle

NHO2C

Cross-Metathesis

RuLxMe

LxRu

Me

O

RuLx

Me

O

LxRu

Me

O

H

Me

O

H

OOTMSMe

Me

O

[2+2]retro[2+2]

Cascade Catalysis:

Merging Organocatalysis

and Organometallic Catalysis

Triple cascade catalysis should allow

rapid access to complex bicycle

in one overall transformation

N

Ph

O Me

X Iminium CycleMe

MeMeMe O

O

Me N

N

Ph

O Me

Me

MeMe

O

Me

H

O

Me

H

O

N

Ph

O Me

XMe

MeMe

N

NH

Ph

O Me

Me

MeMe

O

Me

H

O

HX

NCO2

Me

H

O

O Me

H

OHMe

Me O

O

H

OH

Me

O

H

O

NH

CO2H

+ H2O+ H2O

NCO2

+ H2O + H2O

Enamine Cycle

NHO2C

Cross-Metathesis

RuLxMe

LxRu

Me

O

RuLx

Me

O

LxRu

Me

O

H

Me

O

H

OOTMSMe

Me

O

[2+2]retro[2+2]

Cascade Catalysis:

N

Ph

O Me

X Iminium CycleMe

MeMeMe O

O

Me N

N

Ph

O Me

Me

MeMe

O

Me

H

O

Me

H

O

N

Ph

O Me

XMe

MeMe

N

NH

Ph

O Me

Me

MeMe

O

Me

H

O

HX

NCO2

Me

H

O

O Me

H

OHMe

Me O

O

H

OH

Me

O

H

O

NH

CO2H

+ H2O+ H2O

NCO2

+ H2O + H2O

Enamine Cycle

NHO2C

Cross-Metathesis

RuLxMe

LxRu

Me

O

RuLx

Me

O

LxRu

Me

O

H

Me

O

H

OOTMSMe

Me

O

[2+2]retro[2+2]

Cascade Catalysis:

Me

Ru Im En

O

64% yield

5:1 dr

95% ee

OTMSO Me

OO

HMeOH

Me

HO

O

MeHO H

OHMe

H

Me Me

! Aromadendranediol

! Previous synthesis 22 steps

! Analgesic in folk medicine

5 steps

Me

Ru Im En

O

64% yield

5:1 dr

95% ee

OTMSO Me

OO

HMeOH

Me

HO

O

Cascade Synthesis of the Sytrchnos Alkaloid Minfiensine

N

PMB

NHBoc

SMe

NNBoc

O

SMePMB

O

Diels!Alder/amine

cyclization cascade

NH

N

Me

OH

minfiensine

! Strychnos alkaloid minfiensine and members of the akuammiline alkaloid family

! Key strategy for minfiensine involving an organocatalytic Diels!Alder cyclization cascade

Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606

minfiensine core

N

PMB

NHBoc

SMe

NNBoc

O

SMePMB

O

Diels!Alder/amine

cyclization cascade

NH

N

Me

OH

minfiensine

minfiensine core

N

PMB

NHBoc

SMe

NNBoc

O

SMePMB

O

Diels!Alder/amine

cyclization cascade

NH

N

Me

OH

minfiensine

minfiensine core

! Organocascade catalysis provides rapid access to the core structure of minfiensine

N

PMB

BocHN

SMe

N

OMe

Me

MeN

PMB

N

R

SMe

NHBoc

N

NH

OMe

Me

N

NH

OMe

Me

N

PMB

O

SMe

NHBoc

N

PMB

O

SMe

NHBoc

NNBoc

PMB

O

SMe

NNBoc

PMB

O

SMe

O

R2NH •HX

N

NH

OMe

Me

= R2NH •HX

Ar

N

OMe

tBuAr

H

•HX

X–

•HX

Iminium

Cycle Cycle

•HX

H+

[4+2]

endo

! Organocascade catalysis provides rapid access to the core structure of minfiensine

N

PMB

BocHN

SMe

N

OMe

Me

MeN

PMB

N

R

SMe

NHBoc

N

NH

OMe

Me

N

NH

OMe

Me

N

PMB

O

SMe

NHBoc

N

PMB

O

SMe

NHBoc

NNBoc

PMB

O

SMe

NNBoc

PMB

O

SMe

O

R2NH •HX

N

NH

OMe

Me

= R2NH •HX

Ar

N

OMe

tBuAr

H

•HX

X–

•HX

Iminium

Cycle Cycle

•HX

H+

[4+2]

endo

NH

N

OH

Me

(+)-minfiensine

9 steps, 21% overall

N

PMB

NHBoc

SMe NNBoc

PMB

OH

SMe87% yield

96% ee

cascade3 steps

NH

NHBoc

commercially available

NN

OTES

PMB

radical

cyclization2 steps

NN

PMB

OTES

SMe

StBu

2 steps

Diels!Alder

63%

! Diels!Alder/Bronsted acid cascade provides rapid access to the enantioenriched core of minfiensine

Organocascade Catalysis Inspired by Nature

strychnine

N

O O

H

O

OGluc

CHO

MeO2C

secologanin

NH

NH2

tryptamineN

N

H Me

MeO2C CH2OH

preakuammicine

NH

N

H Me

CHO

norfluorocurarine

NH

CO2Me

N

Et

didehydrosecodine

(Strychnos alkaloids)

Common Intermediate

NH

N

Me

vincadifformine

CO2Me

(Aspidosperma or Kopsia)

Natures employs transform specific enzymes in continous catalytic cascades to rapidly access common

biosynthetic intermediates and natural products.

strychnine

N

O O

H

O

OGluc

CHO

MeO2C

secologanin

NH

NH2

tryptamineN

N

H Me

MeO2C CH2OH

preakuammicine

NH

N

H Me

CHO

norfluorocurarine

NH

CO2Me

N

Et

didehydrosecodine

Common Intermediate

NH

N

Me

vincadifformine

CO2Me

strychnine

N

O O

H

O

OGluc

CHO

MeO2C

secologanin

NH

NH2

tryptamineN

N

H Me

MeO2C CH2OH

preakuammicine

NH

N

H Me

CHO

norfluorocurarine

NH

CO2Me

N

Et

didehydrosecodine

Common Intermediate

NH

N

Me

vincadifformine

CO2Me

Proposed Diels-Alder/Michael Catalytic Cycle

! Double cascade would enantioselectively construct a highly functionalized spirocycle

N

OMe

t-BuAr

N

NBoc

PG

O

N

NH

t-Bu

Me O

Ar

N

NH

t-Bu

Me O

Ar

PGN

BocHN

X First Cycle

(Im)

Second Cycle

(Im)

N

PG

Boc

NR2

N

PG

Boc

NR2

N

NH

PG

Boc

NR2

X

N

NH

PG

Boc

NR2

N

NHBoc

PG

•HA

A

N

PG

NHBoc

X

O

•HA

A

[4+2]

= HNR2

N

OMe

t-BuAr

N

NBoc

PG

O

N

NH

t-Bu

Me O

Ar

N

NH

t-Bu

Me O

Ar

PGN

BocHN

X First Cycle

(Im)

Second Cycle

(Im)

N

PG

Boc

NR2

N

PG

Boc

NR2

N

NH

PG

Boc

NR2

X

N

NH

PG

Boc

NR2

N

NHBoc

PG

•HA

A

N

PG

NHBoc

X

O

•HA

A

[4+2]

= HNR2

N

OMe

t-BuAr

N

NBoc

PG

O

N

NH

t-Bu

Me O

Ar

N

NH

t-Bu

Me O

Ar

PGN

BocHN

X First Cycle

(Im)

Second Cycle

(Im)

N

PG

Boc

NR2

N

PG

Boc

NR2

N

NH

PG

Boc

NR2

X

N

NH

PG

Boc

NR2

N

NHBoc

PG

•HA

A

N

PG

NHBoc

X

O

•HA

A

[4+2]

= HNR2

N

OMe

t-BuAr

N

NBoc

PG

O

N

NH

t-Bu

Me O

Ar

N

NH

t-Bu

Me O

Ar

PGN

BocHN

X First Cycle

(Im)

Second Cycle

(Im)

N

PG

Boc

NR2

N

PG

Boc

NR2

N

NH

PG

Boc

NR2

X

N

NH

PG

Boc

NR2

N

NHBoc

PG

•HA

A

N

PG

NHBoc

X

O

•HA

A

[4+2]

= HNR2

N

OMe

t-BuAr

N

NBoc

PG

O

N

NH

t-Bu

Me O

Ar

N

NH

t-Bu

Me O

Ar

PGN

BocHN

X First Cycle

(Im)

Second Cycle

(Im)

N

PG

Boc

NR2

N

PG

Boc

NR2

N

NH

PG

Boc

NR2

X

N

NH

PG

Boc

NR2

N

NHBoc

PG

•HA

A

N

PG

NHBoc

X

O

•HA

A

[4+2]

= HNR2

N

OMe

t-BuAr

N

NBoc

PG

O

N

NH

t-Bu

Me O

Ar

N

NH

t-Bu

Me O

Ar

PGN

BocHN

X First Cycle

(Im)

Second Cycle

(Im)

N

PG

Boc

NR2

N

PG

Boc

NR2

N

NH

PG

Boc

NR2

X

N

NH

PG

Boc

NR2

N

NHBoc

PG

•HA

A

N

PG

NHBoc

X

O

•HA

A

[4+2]

= HNR2

N

OMe

t-BuAr

N

NBoc

PG

O

N

NH

t-Bu

Me O

Ar

N

NH

t-Bu

Me O

Ar

PGN

BocHN

X First Cycle

(Im)

Second Cycle

(Im)

N

PG

Boc

NR2

N

PG

Boc

NR2

N

NH

PG

Boc

NR2

X

N

NH

PG

Boc

NR2

N

NHBoc

PG

•HA

A

N

PG

NHBoc

X

O

•HA

A

[4+2]

= HNR2

N

OMe

t-BuAr

N

NBoc

PG

O

N

NH

t-Bu

Me O

Ar

N

NH

t-Bu

Me O

Ar

PGN

BocHN

X First Cycle

(Im)

Second Cycle

(Im)

N

PG

Boc

NR2

N

PG

Boc

NR2

N

NH

PG

Boc

NR2

X

N

NH

PG

Boc

NR2

N

NHBoc

PG

•HA

A

N

PG

NHBoc

X

O

•HA

A

[4+2]

= HNR2

N

OMe

t-BuAr

N

NBoc

PG

O

N

NH

t-Bu

Me O

Ar

N

NH

t-Bu

Me O

Ar

PGN

BocHN

X First Cycle

(Im)

Second Cycle

(Im)

N

PG

Boc

NR2

N

PG

Boc

NR2

N

NH

PG

Boc

NR2

X

N

NH

PG

Boc

NR2

N

NHBoc

PG

•HA

A

N

PG

NHBoc

X

O

•HA

A

[4+2]

= HNR2

Bioinspired Cascade of a Common Intermediate for Indole Alkaloid Synthesis

N

NBoc

PMB

82%, 97% ee

N

PMB

NHBoc

SeMe

O

PhMe, –40 °C

to rt20 mol% cat.

N

NH

1-napMe

Me

OMe

TBA

akuammicine

strychnine

NH

N

HMe

aspidospermidine

kopsanone

kopsinine

NH

N

NH

N

CO2Me

O

N

O O

H

NH

N

CO2Me

H

H Me NH

N

Me

vincadifformine

CO2Me

KopsiaAspidospermaStrychnos

CHO

Bioinspired Cascade of a Common Intermediate for Indole Alkaloid Synthesis

N

NBoc

PMB

82%, 97% ee

N

PMB

NHBoc

SeMe

O

PhMe, –40 °C

to rt20 mol% cat.

N

NH

1-napMe

Me

OMe

TBA

akuammicine

strychnine

NH

N

HMe

aspidospermidine

kopsanone

kopsinine

NH

N

NH

N

CO2Me

O

N

O O

H

NH

N

CO2Me

H

H Me NH

N

Me

vincadifformine

CO2Me

KopsiaAspidospermaStrychnos

CHO

Synthesis of High Profile Alkaloids via Cascade Catalysis

akuammicine

strychnine

aspidospermidine

kopsanone

kopsinine

vincadifformine

organo-Im

Imcatalyst

common intermediate

NPG

X

NHBoc

NPG

CHO

NR1

NH

N

Me

CO2Me

NH

N

MeH

NH

N

Me

CO2Me

O

NH

N

O

NH

N

CO2Me

MeH

N

O O

HH

H

9 steps

11 steps

9 steps

12 steps

10 steps

11 steps

akuammicine

strychnine

aspidospermidine

kopsanone

kopsinine

vincadifformine

organo-Im

Imcatalyst

common intermediate

NPG

X

NHBoc

NPG

CHO

NR1

NH

N

Me

CO2Me

NH

N

MeH

NH

N

Me

CO2Me

O

NH

N

O

NH

N

CO2Me

MeH

N

O O

HH

H

9 steps

11 steps

9 steps

12 steps

10 steps

11 steps

akuammicine

strychnine

aspidospermidine

kopsanone

kopsinine

vincadifformine

organo-Im

Imcatalyst

common intermediate

NPG

X

NHBoc

NPG

CHO

NR1

NH

N

Me

CO2Me

NH

N

MeH

NH

N

Me

CO2Me

O

NH

N

O

NH

N

CO2Me

MeH

N

O O

HH

H

9 steps

11 steps

9 steps

12 steps

10 steps

11 steps

akuammicine

strychnine

aspidospermidine

kopsanone

kopsinine

vincadifformine

organo-Im

Imcatalyst

common intermediate

NPG

X

NHBoc

NPG

CHO

NR1

NH

N

Me

CO2Me

NH

N

MeH

NH

N

Me

CO2Me

O

NH

N

O

NH

N

CO2Me

MeH

N

O O

HH

H

9 steps

11 steps

9 steps

12 steps

10 steps

11 steps

akuammicine

strychnine

aspidospermidine

kopsanone

kopsinine

vincadifformine

organo-Im

Imcatalyst

common intermediate

NPG

X

NHBoc

NPG

CHO

NR1

NH

N

Me

CO2Me

NH

N

MeH

NH

N

Me

CO2Me

O

NH

N

O

NH

N

CO2Me

MeH

N

O O

HH

H

9 steps

11 steps

9 steps

12 steps

10 steps

11 steps

akuammicine

strychnine

aspidospermidine

kopsanone

kopsinine

vincadifformine

organo-Im

Imcatalyst

common intermediate

NPG

X

NHBoc

NPG

CHO

NR1

NH

N

Me

CO2Me

NH

N

MeH

NH

N

Me

CO2Me

O

NH

N

O

NH

N

CO2Me

MeH

N

O O

HH

H

9 steps

11 steps

9 steps

12 steps

10 steps

11 steps

akuammicine

strychnine

aspidospermidine

kopsanone

kopsinine

vincadifformine

organo-Im

Imcatalyst

common intermediate

NPG

X

NHBoc

NPG

CHO

NR1

NH

N

Me

CO2Me

NH

N

MeH

NH

N

Me

CO2Me

O

NH

N

O

NH

N

CO2Me

MeH

N

O O

HH

H

9 steps

11 steps

9 steps

12 steps

10 steps

11 steps

akuammicine

strychnine

aspidospermidine

kopsanone

kopsinine

vincadifformine

organo-Im

Imcatalyst

common intermediate

NPG

X

NHBoc

NPG

CHO

NR1

NH

N

Me

CO2Me

NH

N

MeH

NH

N

Me

CO2Me

O

NH

N

O

NH

N

CO2Me

MeH

N

O O

HH

H

9 steps

11 steps

9 steps

12 steps

10 steps

11 steps

7700 other alkaloids

akuammicine

strychnine

aspidospermidine

kopsanone

kopsinine

vincadifformine

organo-Im

Imcatalyst

common intermediate

NPG

X

NHBoc

NPG

CHO

NR1

NH

N

Me

CO2Me

NH

N

MeH

NH

N

Me

CO2Me

O

NH

N

O

NH

N

CO2Me

MeH

N

O O

HH

H

9 steps

11 steps

9 steps

12 steps

10 steps

11 steps

7700 other alkaloids

enamine catalysis: fifty years in the making · 2016. 12. 24. · enamine catalysis: fifty years in...

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