the mannich reaction: new light on an old story literature meeting julie côté november 27, 2007

The Mannich Reaction:New Light On An Old Story

Literature meeting

Julie CôtéNovember 27, 2007

The Mannich ReactionThe Mannich Reaction

H H

O+ R2NH + R

R'

OO

R'

R2N

R

Mannich base

Applications:

• Polymer chemistry (hardeners, cross-linkers and reaction accelerators)

• Plant protections

• Pharmaceutical area

Cribrochalina

Potent cytotoxic agent

Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky, S.J. J. Am. Chem. Soc. 2005, 127,4596-4598.

Dr. Ulrich Franz Carl Mannich Dr. Ulrich Franz Carl Mannich

Mechanism was discover in 1912

HNR2 HCl-HCl

+HClHNR2

-CH2O

+ CH2OHO NR2

-HCl, +H2O

+HCl, -H2O NR2CH2

Cl

1

1 R1

O

R2

R1

OH

R2R1

O

R2

NR2 HCl

Organic chemists in this area argue that this reaction has become the most important C-C bond-forming reaction!

Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

Limitation of the Mannich Reaction Limitation of the Mannich Reaction

R1

O

H R2

O+ +

R3

NH2

OR(NR2)

R1 H

N

R2

R3

R1

O HN

R2

R3

direct

indirect

This type was first used in early 20th century but neaded drastic reaction and long reaction time

The first methods developed were non-catalytic and employed preformed enolates and enamine with chiral

auxiliary control

O N

O

Bn

O

Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070. Enders, D.; Ward, D.; Adam, J.; Raabe, G. Angew. Chem. Int. Ed. Engl. 1996, 35, 981.

PresentationPresentation

Organocatalytic Mannich reaction• Proline catalyst• Cinchona alkaloids catalyst • Thiourea catalyst • Bronsted acid catalyst

Avancement in direct asymmetric mannich reaction• Aldimine MR• Anti-selective MR• Quaternary carbon center MR • Nitro MR• One pot three component MR

Indirect MR with Bronsted acid catalyst

Vinylogous MR

Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction : Unmodified Ketones Reaction : Unmodified Ketones

O

20 vol% N

MeO

R

S

NH

CO2H(20 mol%)

DMSO, rt, 24-48h

O

R

HN

MeO

O HN

MeO

45 %, 16 ee%

O HN

MeO

56 %, 88 ee%

O HN

MeO

NO248 %, 80 ee%

Very low yields and ee’s High amount of catalyst long reaction time

Notz, W. Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, III, C.F. Tetrahedron Lett. 2001, 42, 199-201.

Aldimine in direct asymmetric Mannich Aldimine in direct asymmetric Mannich Reaction : Unmodified Aldehyde Reaction : Unmodified Aldehyde

H

O

R H CO2Et

NPMP (L)-Proline (5 mol%)

Dioxane2-24h,rt

H

O

CO2EtR

HNPMP

(S)(S)

(1,5 eq)

H

O

CO2Et

HNPMP

H

O

CO2Et

HNPMP

H

O

CO2Et

HNPMP

H

O

CO2Et

HNPMP

H

O

CO2Et

HNPMP

81%, dr: 10:1, 93 ee% 72%, dr: 1.1:1, 99 ee% 81%, dr: 3:1, 99 ee%

71%, dr: 19:1, 99 ee% 89%, dr: 19:1, 99 ee%

H

O

CO2Et

HNPMP

MeO

O

CO2Et

HNPMP

NPMPO

CO2EtH H1) NaClO2, KH2PO4 2-methyl-2-butene t-BuOH/H2O

2) CH2N2, Et2O, 89%

1) LHMDS, THF, -20C 96%

B-lactam

NO

HN

Benzylpenicillin(Penicillin G)

NO SO3

HN

ONN

S

OO

OH

Monobactams(Azactam®)

NH2

S

HOO

NO

S

HOO

O

HH

HO

Carbapenems(Faropenem)Proceed smoothly with excellent enantioselectivity

Higher diastereoselectivities were achived with increased bulkiness of the substituents on the aldehyde

Cordova, A.; Watanabe. S. I.; Tanaka, F.; Notz, W.; Barbas, III, C. F. . J. Am. Chem. Soc. 2002, 124, 1866-1867.

Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction : Ionic LiquidsReaction : Ionic Liquids

N N BF4[bmin]BF4 =

- non volatile- Tunable polarity - High thermal stability- Great abily to dissolve catalyst- « Green » solvent

Faster reaction in ionic liquids: result from ionic based activation of the imine electrophile.

Solvent and catalyst are readily recycled

Can be performed on a multi-gram scale

R1

O

R2 H

N

CO2Et

PMP (L)-proline (5 mol%)

[bmim] BF4

30 min

R1

O

R2

HN

CO2Et

PMP

Chowdari, N.S.; Ramachary, D.B.; Barbas, III, C. F. Synlett, 2003, 12, 1906-1909.

H

O HN

CO2Et

PMP

90 %, dr: 5:1, 93 ee%

H

O HN

CO2Et

PMP

96 %, dr: 19:1, 99 ee%

Me

O

Me

HN

CO2Et

PMP

77 %, dr: 19:1, 99 ee%

H

O

CO2Et

HNPMP

81%, dr: 10:1, 93 ee%

87%, dr: 13:1, 99 ee%81%, dr: 3:1, 99 ee%

Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction : Protecting GroupReaction : Protecting Group

R1

O

R2 H R2

NBoc (S)-proline (20 mol%)

CH3CN, 0C8-12 h

R1

O

R3

R2

NHBoc

H

O NHBoc

91%, d.r. 99:1, e.r. 99:1

H

O NHBoc

OMe

80%, d.r. 99:1, e.r. 99:1 59%, d.r. 99:1, e.r. 98,5:1,5

H

O NHBoc

Cl

O NHBoc

73%, e.r. 99:1

R

HN

R2

PMP

R

HN

R2

BocR

NH2

R2

A

BA

Drastic oxidative condition Harmful reagents: (NH4)Ce(NO3)6,

(CAN)

B Easy clivage of Boc Provides stable crystalline compounds without purification

Initially homogenous

reaction mixture

After consumption of the starting

material : precipitation

Yang, J. W.; Stadler, M. List, B. Angew. Chem. Int. Ed. 2007, 46, 609-611.

Aldimine in Direct Asymmetric Aldimine in Direct Asymmetric Mannich Reaction :Anti-SelectiveMannich Reaction :Anti-Selective

H

O

R H

N

CO2Et

PMP NH

OMe

(20 mol%)

DMSO24-48h, rt

H

O

R

HN

CO2Et

PMP

(R)(S)

H

O HN

CO2Et

PMP

H

O HN

CO2Et

PMP

H

O HN

CO2Et

PMP

52 %, dr: 10:1, 82 ee% 68 %, dr: 19:1, 76 ee%78 %, dr: 10:1, 76 ee%

VS

Proline catalyst SMP catalyst

Plausible transition-states

Moderate yields and ee

Cordova, A.; Barbas, III, C.F. Tetrahedron Lett. 2002, 43, 7749-7752.

(E)-Enamine predominate

Si-face of imine is attacked by enamine si-face

Facial selection is controlled by proton transfer

Lacking the stereodirecting carboxylate of proline, the topicity is altered

Si-face of imine is now attacked by re-face of the enamine

Aldimine in Direct Asymmetric Mannich Aldimine in Direct Asymmetric Mannich Reaction :Anti-SelectiveReaction :Anti-Selective

H

O

R H CO2Et

NPMP

NH

CO2H35

H

O

RCO2Et

NHPMP

N

CO2H

HH

R

N

CO2H

R

HH

Structural features at the 5-position were installed to fix the enamine conformation

Acid position to affect control of enamine and imine facial selection

To avoid steric interaction between the substituents at the 5 the imine, substituents 3- and 5- are in trans -configuration

H

O

R1 H CO2R2

NPMP N

H

CO2H

H

O

RCO2R2

NHPMP

H

O

RCO2R2

NHPMP(1-5mol%)

DMSO

Entry R1 R2Time(h)

Yield( %)

dranti :syn

ee(%)

1 i-Pr Et 3 85 98 :2 992 n-Bu Et 1 71 97 :3 993 n-Pent Et 3 80 97 :3 >994 i-Pr i-Pr 1 92 97 :3 985 n-Pent i-Pr 1 85 96 :4 >99

Zhang, H.; Mifsud, M. Tanaka, F.; Barbas, III, C. F. J. Am. Chem. Soc. 2006, 128, 9630-9631.

N

H CO2Et

H

O

O

H

PMPH

Aldimine in direct asymmetric Mannich Aldimine in direct asymmetric Mannich Reaction :Anti-SelectiveReaction :Anti-Selective

R1

O

R2

NH

CO2H35

N

CO2H

R1H

R2

N

CO2H

R2

HR1

Ineffective in MR with ketones . Hypothesis: origined from the relatively slow formation of the enamine intermediates due to steric interaction with Me group of the catalyst

E1

O

R2 H

N

CO2R3

PMP

R1

O

R2

NHPMP

CO2R30.1 eq

2-PrOH, rt

NH

CO2H

Et

O

Me

NHPMP

CO2t-Bu

93%, dr: 99:1, 95 ee%

O NHPMP

CO2Et

96%, dr: 99:1, 96 ee%

Me

O NHPMP

CO2Et

85%, dr: 95:5, 91 ee%

S

O NHPMP

CO2Et

O

O NHPMP

CO2Et

78%, dr: 99:1, 99 ee% 82%, dr: 95:1, 86 ee%

Zhang, H.; Mifsud, M. Tanaka, F.; Barbas, III, C. F. J. Am. Chem. Soc. 2006, 128, 9630-9631.


R

O

HNH

H HEtO2C CO2Et

NH

Ph

OTMSPh

(10mol%)

benzoic acid (10 mol%)

CHCl3, -20 °C

R H

O

NH

CO2EtEtO2C

R

O

HNH

H HEtO2C CO2Et

NH

Ph

OTMSPh

(10mol%)

benzoic acid (10 mol%)

CHCl3, -20 °C

R H

O H CO2Et

NPMP

R CO2Et

HNPMP

OH4°C, 24 h

DMSO:CHCl3(R)-proline(35mol%) 80 %, 5:1 dr, 96% eeR= 2-naphtyl

Furnish three contiguous stereocenters in one step in good %The asymmetric reductive MTR proceed via a catalytic asymmetric domino reaction and furnish amino acid

Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.


Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.

N

H

R1 R2

Ar

ORAr

N

H

R1 R2

Ar

ORAr

N

H HEtO2C CO2Et

NH

EtO2C CO2Et

N

H

R1 R2

Ar

ORAr

NH

Ar

ORAr

H2O

O

H

R1 R2

H2O

O

H

R1 R2


N

H

R1 R2

Ar

ORAr

N

H

R1 R2

Ar

ORAr

N

H

R1 R2

Ar

ORAr

NH

Ar

ORAr

H2O

O

H

R1 R2

H2O

O

H

R1 R2

+ H+

NPMP

HEtO2C

NH

O

EtO

NH

O

EtOPMP

PMP

R1

NH

O

EtO

PMP

O H

R2

1,3-Dicarbonyls and Acyl Aldimines with 1,3-Dicarbonyls and Acyl Aldimines with Cinchona Alkaloids Catalyst Cinchona Alkaloids Catalyst

R1

O

OR2O

R3O N

O

PhHR1

O

Ph

HN

OR2O

OR3

O

10 mol%cinchonine

CH2Cl2-35 °C, 16h

N

H

HN

HO

cinchonine

O

Ph

HN

OO

OCH3

O

R1

O

Ph

HN

OCH3O

O

O

O

Ph

HN

OO

Ot-Bu

O

99%, 3:1 dr, 92% ee 85%, 3:1 dr, 80% ee 91%, 2:1 dr, 90% ee

H3C

O

Ph

N

OCH3O

O

O N NH

O

OCH3O

Bn

Ph

1) Pd(PPh3)4BnNCO

dimethylbarbituric acid

2) AcOH, EtOHmicrowave, 120°C

10 mins

Brandon, M. Lou, S.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256-11257.

Malonates and Acyl Aldimines with Malonates and Acyl Aldimines with Bifunctional Cinchona Alkaloids Catalyst Bifunctional Cinchona Alkaloids Catalyst

R H

NBoc

OR2

O

O OR2R

NHCOOR2

COOR2

Boc

(20 mol%)

-60 C, acetone36 h

catalyst

R2 = CH3, Bn, allyl up to 99 %, 99 ee%

R2 COOR

COOR

HNBoc

1) Pd/C, H2 MeOH, 10h

2) Toluene, reflux 2h

COORHN

Boc1) Pd(PPh3)4, THF morpholine, r.t., 3h

2) Dioxane, reflux 3h

COORHN

Boc

R=Bn, R2= H, 96%eeR=allyl, R2= vinyl, 96%ee

76%, 94 ee%72%, 96 ee%

Cinchona alkaloid derivatives bearing a thiourea functionnality might act as efficient bifunctional catalysts for malonates with simple imines

N

N

H3CO

HN

HN

S

CF3

CF3

thiourea cinchona alkaloid derivative

bridgehead nitrogen for activation of nucleophilic substrate

thiourea moiety for organisation/activation ofelectrophilic imine

Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048-6049.

Asymmetric Mannich Reaction Adducts Asymmetric Mannich Reaction Adducts with Quaternary Carbon Centerswith Quaternary Carbon Centers

H

OR2

R1 H CO2Et

NPMP L-proline (30 mol%)

DMSO, rt H

O

CO2Et

R1 R2

HNPMP

0,25-48h

H

O

CO2Et

Me Ph

HNPMP

66%, syn/anti: 85:15, ee (syn:anti) 86/25

H

O

CO2Et

HNPMP

99%, syn/anti: 96/4ee(syn/anti) 93/5

H

O

CO2Et

Me

HNPMP


S

H

O

CO2Et

Me

HNPMP

OO


H

O HN

CO2Et

PMP

94%, ee (syn:anti) 88/52

H

O HN

CO2Et

PMP1) NaClO2, NaH2PO4 2h

2) NaOH (1 eq)

3) HCl (1.1 eq) 5 min

NO PMP

CO2Et

80 %

spiro lactam

Chowdari, N. S.; Suri, J. F.; Barbas, III, C. F. Org. Lett. 2004, 6, 2507-2510.

R1 and R2 need to be very diffirent to access good syn/anti ratio


Ar

CN

CO2Bn

N

CO2R2

Boc(DHQD)2PYR

(5mol%)

-78° C, CH2Cl2Ar

HN

CO2R2NC CO2Bn

Boc

(DHQD)2PYRHN

CO2EtNC CO2Bn

Boc

98%, 89:11 dr, 97 ee%

HN

CO2EtNC CO2Bn

BocCl

99%, 80:20 dr, 91 ee%

HN

CO2EtNC CO2Bn

BocMeO

97%, 85:15 dr, 96 ee%

HN

CO2EtNC CO2Bn

Boc

95%, 18:82 dr, 11 ee%

Br

HN

CO2iPrNC CO2Bn

Boc

98%, 85:15 dr, 98 ee%

Br

Interesting solvent effect was demonstrated which gave drastic changes in stereoselectivity CH2Cl2 Toluene

Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M. Jorgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 2896-2899.


X

O O

YH

N

Ar

H3CO

O

CH2Cl2

5 mol%X

O HNAr

OCH3

O

OY

cinchonine

O HNOCH3

O

OH3CO

98%, 90 de%, 99 ee%

O HNOCH3

O

OH3CH2CO

98%, 94 de%, 98 ee%

O HNOCH3

O

OH3C

98%, 95 de%, 99 ee%

Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003-2006.

N

H

HN

HO

cinchonine

Asymmetric Nitro-Mannich Reaction Asymmetric Nitro-Mannich Reaction

Ar N PPh2

O CH3NO2

(5 eq)

[YbK(binaphoxide)2] (20mol%)

toluene/THF (7:1) -40 C

Ar NH

NO2

PPh2

O

41-93%, 69-91ee%15 h

Metal-free of the nitro-Mannich reaction have recently evolved

Limitations: proceeded smoothly with imine which contains an electron-withdrawing substituent and need prolonged reaction time with electron-donating group.

Aza-Henry Reaction

Yamada, K. I.; Harwood, S. J.; Gröger, H.; Shibasaki, M. Angew. Chem. Int. Ed. 1999, 38, 3504-3506.


Ar

NP(O)Ph2 RCH2NO2 (10 eq)

CH2Cl2, rt

Catalyst (0,1 eq)

Ar

HN

R

NO2

P(O)Ph2 F3C

CF3

HN

S

HN

N

thiourea derivative

HNNO2

P(O)Ph2 HNNO2

P(O)Ph2 HNNO2

P(O)Ph2

87%, 67 ee%

O

85%, 76 ee%

N

91%, 68 ee%

HNNO2

P(O)Ph2

83%, 67 ee%

Ar

NBoc

H ArNO2RCH3NO2

CH2Cl2, -20 °C, 24h

catalyst (10mol%) NHBoc

R

NO2

NHBocO

92%, 90/10 dr (syn/anti) 93 ee%

NO2

NHBocO

82%, 93/7 dr (syn/anti) 99%

NO2

NHBoc

94%, 97/3 dr (syn/anti) 92 %

F3C

Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org Lett. 2004, 6, 625-627. Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, T. Chem. Eur. J. 2006, 12, 466-476.


Future work includes the expansion of the methodology to different substrates and investigation of the synthetic utility of the addition products.

Ar

NBoc

H ArNO2RCH3NO2

CH2Cl2, -20 °C

catalyst (10mol%) NHBoc

R

Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, T. Chem. Eur. J. 2006, 12, 466-476.

The Thiourea moiety play a role in activation of N-Boc imine in the nucleophilic addition step and in nitroalkane deprotonation

Three-Component Mannich Reaction Three-Component Mannich Reaction

O

H R

ONH2

OMe

(L)-Proline (35 mol%)

12-48 h1.1 eq

O

R

HNPMP

O HNPMP

NO2

O HNPMP

O HNPMP

O HNPMP

O

O HNPMP O HN

PMP

50%, 94 ee% 35%, 96 ee% 82%, 75 ee%

90%, 93 ee% 74%, 73 ee% 56%, 70 ee%

List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337.

Three-Component Mannich Reaction Three-Component Mannich Reaction

JACS, 2002, 124 827

(S)-Proline (20 mol%)O

OHH

O

R

NH2

OMe1.1 eq

O

OH

HN

R

PMP

DMSO, rt, 3-24 h

10 vol% 1 eq

92%, dr = 20:1, 99 ee%

O

OH

HNPMP

NO2

O

OH

HNPMP

Br

90%, dr = 15:1, 98 ee%

O

OH

HNPMP

83%, dr = 9:1, 93 ee%

O

OH

HNPMP

OMe

88%, dr = 9:1, 61 ee%

O

OH

HNPMP

57%, dr = 17:1, 65 ee%

R H

ORNH2

OH

O

R

O

(S)-Proline

Sharpless AA

R

ONHR

OH

List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.

Mechanism of the Proline catalized Mechanism of the Proline catalized Mannich Reaction Mannich Reaction

N CO2H

XR

NAr

H R

O

H

N CO2

X

ArHN

R

H2O

O

X

ArHN

R

NH

CO2H

H2O

XO


Mechanism of the Proline catalized Mechanism of the Proline catalized Mannich Reaction Mannich Reaction

N

X

OO

H

N CO2H

X

R

O

H

AldolMannich

N

H R

MeO

ArNH2

H

O

X

ArHN

R

N

X

OO

H

O

R H

H

O

X

ArHN

Ranti

syn

enamine siimine si

enamine sialdehyde re


Three-Component Mannich Reaction Three-Component Mannich Reaction Optimization Optimization

O

H R

ONH2

OMe

(L)-Proline (30 mol%)

4-96 h1.1 eq

O

R

HNPMP

Water-Freezing (-20 C, 200 MPa)

DMSO

O HNPMP

NO2

O HNPMP

O HNPMP

O HNPMP

O HNPMP

50%, 94 ee% 35%, 96 ee% 0%, 0 ee%

0%, 0 ee% 23%, 4 ee%

58%, 91 ee% 64%, 91 ee% 65%, 95 ee%

OMe

OMe

NH

O

82%, 92 ee% 90%, 84 ee%

Accelerates the reaction but also suppresses side

reactions

Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125, 11208-11209.

Three-Component Mannich Reaction Three-Component Mannich Reaction Optimization Optimization

O

H

O

H

R

H2N

(S)-proline

DMSO

O

NH

R

microwave

Entry Rmol % of catalyst

Power (W)

Temp(°C)

Time(h)

Yield( %)

ee(%)

1 H 20 15 47 2 80 972 H 10 15 46 2,5 96 983 H 5 15 45 2,5 93 984 H 1 15 48 4 89 975 H 0,5 15 46 3 83 986 OMe 10 15 47 2,5 71 957 OMe 10 10 45 2,5 81 958 Ome 1 10 47 3 84 949 i-Pr 10 10 45 3 71 9710 i-Pr 5 15 51 3,5 88 9711 i-Pr 0,5 15 49 4 86 97

Reducing the time of reaction

Rodriguez, B.; Bolm, C. J. Org. Chem. 2006, 71, 2888-2891.

Access to Chiral 1,2- and 1,4 DiaminesAccess to Chiral 1,2- and 1,4 Diamines

O

N3

CO2Et

ONH2

PMP

NH

N NNN

30 mol %

DMSO, rt, 0.5 h

O

CO2Et

HN

N3

PMP

96%syn/anti 91/9, 99/99 ee%

O

NPhtCO2Et

ONH2

PMP

NH

N NNN

30 mol %

DMF, 4°C, 40h

O

CO2Et

HNPMP

83%90 % ee%

NPht

NN N

NN

NN

N

H

H R

N

MeO

NN N

NN

N

H

OOH R

N

MeO

NN N

NN

H

N OOH R

N

MeO

Protecting group dependent

regioselectivity

Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, III, C. F. Org Lett. 2006, 8, 2839-2842.

Green Green Three-Component Mannich Three-Component Mannich Reaction Reaction

R1

O

HR2NH2

O

H2O (5 mL), rt, 3-16 h

H3PW12O40 (10 mg)

O NHR2

R1

O NHR2

R1

syn anti

O HN

Cl

anti/syn 62 / 3880 %

O HN

OMe

OMe72 / 28

88 %

O HN

Cl

68 / 3283 %

Cl

Low loading of catalyst Good yields Clean reactionNeed vigourous stirringEnvironmentally benign

The reaction might take place at the

interface of organic materiels with water

in heterogeneous system.

Azizi, N.; Torkiyan, L.; Saidi, M.R. Org. Lett. 2006, 8, 2079-2082.

Synthesis of interesting 1,3-Diaryl-5-Synthesis of interesting 1,3-Diaryl-5-spirohexahydropyrimidinesspirohexahydropyrimidines

O

R1

NH2

R2

H H

O (S)-proline (20mol %)

DMSO, rt, 30 h

O

N

N

R2

R2R1

O

N

N

OMe

OMe

O

N

N

N

N

O

N

N

OMe

OMeO O80 % 67 %65 %

Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, Q. G.; Liang, M. Y. J. Org. Chem. 2007, 72, 8600.

Mechanism Mechanism

Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, Q. G.; Liang, M. Y. J. Org. Chem. 2007, 72, 8600.

N COOH

R1 R2

N COOH

R1 R2

NAr

CH2O ArNH2

H2ONAr

NH

COOH

H2O

O

R1 R2

H2O

O

R1 R2

NH

Ar

MechanismMechanismO

R1 R2

NH

Ar

NH

COOH

N COOH

R1 R2

NH

Ar

N COOH

R1 R2

NH

Ar

N ArH2O

O

R1 R2

HN

NH

Ar

Ar

CH2O

H2O

O

R1 R2

N

NAr

Ar

CH2O ArNH2

H2ONAr

Application in SynthesisApplication in Synthesis

HO

OH

CH3

NH3

O

NH

CO2O

HO OH

N NH

O

O

Nikkomycin

HO

OH

CH3

NH3

O

OH

OMeO

O

H3C NHBz

Antibiotic that inhibits the biosynthesis of chitin in cell wall by competitively

inhibiting chitin synthase

OH

OOTBS

NH2

O(L)- proline (10 mol%)

pyridine, NMP, -20 °C

NH

Me

O

H

TBSO

O

Without pyridine: 87%, 84 ee%With pyridine: 94%, 92 ee%

Hayashi, Y.; Urushima, T.; Shin, M.; Shoji, M. Tetrahedron 2005, 61, 11393-11404.

Bifunctional Bronsted Acid Activation of Bifunctional Bronsted Acid Activation of the Mannich Reaction the Mannich Reaction

R1

NR2XnM

Lewis acid catalysis

R1

NR2H

X

Bronsted acid catalysis

OO

PO

OH

Chiral phosphoric acid

NO2

NO2

N

Ph

OMe

OTMS

Ph OMe

OArHNcatalyst (30 mol%)

toluene, -78 C

(3.0 eq)

X

Entry X Time (h) Yields (%) ee (%)1 2-OH 13 98 892 4-OH 33 28 203 2-OMe 46 56 34 H 43 76 35

Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 21, 6756-6761.


Ph

NAr OTMS

OMe

catalyst (5mol%)

Toluene, -78 CPh OMe

ONHAr

OP

O

ArAr

ArAr

O

O

O

OH

Ar- p-CF3C6H4

TADDOL-derived phosphoric acid catalyst

O

OP

O

O

H

H

N

O

HO

O

F

F FF3C

F

FF

Nu

Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523.


Possible intramolecular hydrogen bonding

OMOM OMOM

BrNBS (1.1 eq)

AIBN (10 mol%)

CCl4reflux 5h

CF3SO2Na(2.0 eq)

pyridine (0.1 eq)DMA

100 C, 12h

OMOM

Tf

57 % in two step

1) BuLi (1.1 eq)Et2O, -78 C, 0,5h

2) Tf2O (0.6eq)

-78 C to rt, 2h

3) repeat 1 and two

OMOM

TfTf

Hconc. HCl

MeOH50 C, 12h

47 % in three step

Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 15, 3175-3178.


OH

TfTf

H

Chiral 2-bis(trifly)methyl-2'-hydroxy-1,1'-

binaphthyl

R

N OMe

OSiR33

(1.5 eq)

R1 OMe

ONHR4OSiR3

3

catalyst (10mol%)

tBuOH (100 mol%)

PrCl, -78 C, 24 h99% yield, 77 ee %

The addition of a stoichiometric achiral proton source is required to accomplish a

catalytic cycle of chiral bronsted acid catalyts

Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 15, 3175-3178.

Vinylogous Mannich Reaction Vinylogous Mannich Reaction

The VMR is rapidly emerging as an important process for the construction of derivatives of –aminocarbonyl compounds

Because the iminium and dienol components employed in this addition may be either acyclic or cyclic, a wide variety of adducts may be converted into a broad array of alkaloids and nitrogen heterocyclicles.

NR1

nOR2

Z

OOR2

NR1

n

NR1

n

H

Z

O

O OH

Nn

O

XH

X= H, OH

HON

ON

Vinylogous Mannich Reaction

OHN

O

N

Basic Mannich Reaction

Martin, S. F. Acc. Chem. Res. 2002, 35, 895-904.


OTBSO O

O

NHBn

OOH

NBn

OO

TBSOTf

CH2Cl2, -80°C

83%, 1:9

1) H2, Pd/C, THF

2) DBU, 80 °C

NH

O

OH OOH

NHBn

L.A

O O

O OTBS

Felkin-anh

Addition to the si-face of the imine

Access to lactam

Battistini, L.; Rassu, G.; Pinna, L.; Zanardi, F.; Casiraghi, G. Tetrahedron Asymmetry, 1999, 10, 765-773.


Ar

N

MeO

O

Me

OTMS

catalyst (5mol%)

AgOAc (5mol%)

undistilled iPrOH (1.1eq)undistilled THF, -78 °C, 18 h

in air

Ar

NH

O

Me

O

OMe

PPh2

N

sBu

O

HN

OMe

easily accessible chiral phosphine

NH

O

Me

O

OMe

NH

O

Me

O

OMe

NH

O

Me

O

OMe

MeO Cl

85%, 98% de, 87ee% 70%, 98% de, 83ee% 97%, 98% de, 90ee%

NH

OO

OMe

PhI(OAc)2, MeOH, 0 °C, 45 min;

1.0 M HCl, 0 °C to 22 °C, 1h;Na2CO3; CH2Cl2

PhI(OAc)2, MeOH, 0 °C, 45 min;

1.0 M HCl, 0 °C to 22 °C, 1h;Na2CO3; CH2Cl2,CbzCl, 4h

NH2

OO

NHCbz

OO

76%

76%

NH

OO

OMe

2) PhI(OAc)2, MeOH, 0 °C, 45 min;1.0 M HCl, 0 °C to 22 °C, 1h;

Na2CO3; CH2Cl2 71%

1) H2, 10% w/w Pd/C, EtOAc

2 h; 95%

3) DBU, 120 C, 18h, 70%

HN

O

OHPh

Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2006, 45, 7230-7233.

Lactam


Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2006, 45, 7230-7233.

1-Bidentate chelation with aldimine

2-The catalyst-bond imine may react with the siloxyfuran by an endo type addition

3- Intramolecular desilylation by the lewis basic amide

4-Product release is facilited by iPrOH


O

vinyloxirane

Vinyloxirane is a valuable and highly reactive species

Ring-opening and/or rearrangement processes are promoted by Lewis acids or transition-metal catalysts.

OLewis acid

ring opening

H

OLA

(1,2-hydride shift)

O

H

OH

aldehyde(electrophile)

dienol(nucleophile)

Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345-347.


R H

NCHPh2

Sc(OTf)3 (10mol%)

O (1.5 eq)

THF, 0 addition to 50 °C, 10-30 minR

HNCHPh2

CHO

EtOOC

HNCHPh2

CHO

74 %

HNCHPh2

CHO

70 %Cl

HNCHPh2

CHO

35 %MeO

EtOOC

HNCHPh2

CHO

Pd/CH2 (1atm)

N COOEtR

N COOEtCHPh2

solvent, rttime

unnatural amino acidC

A=H, B=CHPh2

Entry Solvent Time (h) A B C 1 MeOH 4 84 0 0 2 Benzene 24 trace 77 53 Benzene 1 0 trace 53

Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345-347.

Vinylogous Mannich Reaction: Application Vinylogous Mannich Reaction: Application in Synthesis in Synthesis

HN

NMeH

CO2H

HN

NMeH

Me OH

HN

NHMeH

O

OMe

lysergic acid setoclavine rugulovasines A and B

A=ß-HB=a-H

The indole alkaloids of Ergot family have attracted the attention of synthetic chemists for decades

The most well-known representative of this class is lysergic acid and rugulovasines A and B represent novel types within this family

HN

NHMeH

O

OMe

rugulovasines AHN

NHMeH

O

OMe

HN

OO

Me

NHMe

rugulovasines B

Liu, T. Y.; Cui, H. L.; Long, J.; Li, B. J.; Wu, Y.; Ding, L. S. Chen, Y. C. J. Am. Chem. Soc. 2007, 129, 1878-1879.

SummarySummary

Significant advancements have been reported in the direct asymmetric MR.

• High yields, dr and ee are possible using organocatalysis with relatively mild reaction conditions.

• Highly functionallized products are possible (ie. Nitro-Mannichs, quaternary carbon centers, 3 contiguous chiral centers).

•Usage in total synthesis still relatively rare.

•The use of the PMP protecting group remains widespread, although some work has been done to develop relatively <PMP-free protocols>.

the mannich reaction: new light on an old story literature meeting julie côté november 27, 2007

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