Rahman Shah Zaib Saleem Michiggyan State …...Synthesis utilizing Povarov reaction= 6 (core synthesis= 4, total synthesis=2) gp • Biological evaluation: First non-peptide bradykinin

Rahman Shah Zaib Saleem

Michigan State Universityg y

October 24, 2007

Outline• INTRODUCTION• REACTION INSIGHT

Outline

• VARIANTS OF POVAROV REACTION• SINGLE ELECTRON MECHANISM• ASYMMETRIC CATALYSIS• CONCLUSIONS• CONCLUSIONS

Outline• INTRODUCTION

– HISTORYPOTENTIAL APPLICATIONS

Outline

– POTENTIAL APPLICATIONS• REACTION INSIGHT• VARIANTS OF POVAROV REACTION• SINGLE ELECTRON MECHANISMSINGLE ELECTRON MECHANISM• ASYMMETRIC CATALYSIS• CONCLUSIONS

Introduction: DiscoveryIntroduction: Discovery1962

Povarov and Mikhailov

Potential of generating 3 chiral centers in a single step

BF3.OEt2 pTsOH

R1=OR, SR

Considered as inverse electron demand aza-Diels Alder reactionConsidered as inverse electron demand aza-Diels Alder reaction

Reaction is also cited in the literature by the names:- Imino-Diels Alder reaction

A a Diels Alder reaction

Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656-670.

- Aza-Diels Alder reaction

Introduction: Reaction revisitedIntroduction: Reaction revisited

TFA

MeCN, r.t.

Grieco, P. A.; Bahsas, A. Tet. Lett. 1988, 29, 5855-5858.

Introduction: Reaction revisitedIntroduction: Reaction revisited

NXTFA

MeCN, r.t.

X

Grieco, P. A.; Bahsas, A. Tet. Lett. 1988, 29, 5855-5858.

Potential applications in total synthesisPotential applications in total synthesisHOOC Cl

N

OH NH OMe

VirantmycinMartinelline

O

NH

OHO

Helquinoline

y

NO

O

N

N

NO

HO O

ON

Isoschizogamine

CamptothecinDynemycin

Luotonin AMartinellic acidGalipinine


Outline

– MECHANISM– CONTROL OF REGIOSELECTIVITY– STEREOCHEMICAL OUTCOME

• ACYCLIC DIENOPHILE– MONOSUBSTITUTED– DISUBSITUTED

• CYCLIC DIENOPHILE• VARIANTS OF POVAROV REACTION• SINGLE ELECTRON MECHANISM• ASYMMETRIC CATALYSIS• CONCLUSIONS

Mechanism:Mechanism:

N

Mechanism: Concerted or stepwiseMechanism: Concerted or stepwise

Catalyst

R1=R2R R

Products that can be formed

by concerted mechanism


Catalyst

R1=R2R R

Product that can NOT be formed

by concerted mechanismby concerted mechanism


BF3.OEt2PhMe, r.t.

E d

+

ExoEndo Exo

Alves, M. J.; Azoia, N. G.; Fortes, A. G. Tetrahedron. 2007, 63, 727-734.

Mechanism: StepwiseMechanism: Stepwise

BF3.OEt2PhMe, r.t.

MeO MeO

NCO2Et

H

|+_BF3

N

CO2Et

H


ExplanationExplanationNH2 H

NN

TFA

HCHOTFA, MeCN

++

HN

NH

MeCN

NH2 HN

TFA, MeCN TFA, MeCN+

Mellor, J. M.; Merriman, G. D.; Riviere, P. Tet. Lett. 1991, 32, 7103-7106.

ExplanationPhOH

Explanation

O NH2 O HNPh

O NH

TFA

MeCN+ ++

O O O

r.t. 1.5h 56% 39%

Reflux 1.5h 82% 17%

O NH2

TFA

O

MeCN+

Mellor, J. M.; Merriman, G. D. Tetrahedron. 1995, 51, 6115-6132.

Control of regioselectivityControl of regioselectivity

BF3.OEt2+ +

4

r.t. 70 min

80%

2

Crousse, B.; Begue, J.; Bonnet-Delpon, D. J. Org. Chem. 2000, 65, 5009-5013.

Rationale for control of regioselectivityRationale for control of regioselectivity

O

O

LA= Lewis Acid

Stereochemical outcomeStereochemical outcome• Acyclic dienophiles

•Monosubsitituted•Monosubsitituted•Disubstituted

•Cyclic Dienophile

Stereochemical outcome li di hilStereochemical outcome- acyclic dienophile

OMe

N CO Et

OMe

MeOBF3.OEt2PhMe, r.t.+ +

NH

CO2Et,45 min44% Cis Trans

Axial substituent

less favoredH H

Equitorial

NH

MeO

COOEtMeO


substituent

more favoredCis Trans

Example from literatureExample from literature

InCl3 (10 mol%)

MeCN, r.t.

Entry R1 R2 R3 Time(h) Yield(%)

1 H OMe H 2 901 H OMe H 2 90

2 H Me H 2 71

3 H Me Cl 2 76

4 OMe H Cl 3 704 OMe H Cl 3 70

5 H Me OMe 2 72

6 H OMe OMe 2 80

7 Me Me Cl 3 79

Sridharan, V. Perumal, P. T. Avendaño, C. J. Menéndez, C. Org. & Biomol Chem 2007, 5, 1351-1353.

Example from literatureExample from literature

BF3.OEt2DCM, r.t.

Entry R1 R2 R3 Time(h) Yield(%) Cis:Trans1 H H H 2 98 98:2

Cis Trans

1 H H H 2 98 98:2

2 H H Me 2 96 96:4

3 H H OMe 2 90 96:4

4 OMe H OMe 3 94 98:24 OMe H OMe 3 94 98:2

5 H H Br 2 96 98:2

6 H H Cl 3 96 98:2

7 H H F 2 92 95:5

8 Me H H 3 89 90:10

Nikitina, E. V.; Kouznetsov, V. V.; Cruz, U. M.; Zubkov, F. I. Synthesis. 2007, 375-384.

Stereochemical outcome A li Di hilStereochemical outcome- Acyclic Dienophile

BF3.OEt2PhMe, r.t.

R= Aromatic, -OMe, -OAc

RR

H

R

R= Aliphatic, bulky group (-OTBS)


R

R

Stereochemical outcome C li di hilStereochemical outcome- Cyclic dienophile

O NH

O

CO2Et

BF3.OEt2PhMe, r.t.

+ +

H

O

H

RR

H

Chelation fovored


Sterically favored

Example from literature

OR4

Example from literature

NH

O

PhR1

R2

R3R4

CAN(5 mol%)MeCN, r.t.

+ + +

Entry R1 R2 R3 R4 Time(h) Yield(%) Cis:Trans1 H H H H 2 83 57:43

Cis Trans

1 H H H H 2 83 57:43

2 H H Cl H 2 80 55:45

3 H H Br H 1.5 79 55:45

4 H H F H 4 70 55:45

5 H H Me H 4 70 60:40

6 H Me H Me 4 75 55:45

7 Me H Me H 6 85 55:45

Sridharan, V.; Avendaño, C. J.; Menéndez, C. Synlett. 2007, 1079-1082 .


Outline

• VARIANTS OF POVAROV REACTION– ABC VS ABB TYPE REACTION

• SYNTHESIS OF MARTINELLINE– REVERSING THE REGIOSELECTIVITY

• SYNTHESIS OF LUOTONIN A– ALKYNYL DIENOPHILE

• SYNTHESIS OF CAMPTOTHECIN AND LUOTONIN A– DOUBLE POVAROV REACTION

• SYNTHESIS OF JULOLODINES• SINGLE ELECTRON MECHANISM• ASYMMETRIC CATALYSIS

CONCLUSIONS• CONCLUSIONS

ABB t tiABB type reaction

OGdCl3

(20 mol%)MeCN, r.t.

+ +

NH

Ph

A

eC , t

88%B C

InCl3(10 mol%)H2O, r.t.

85%

+ +

85%

A B B

Li, C.; Zhang, J. H. J. Org. Chem. 2002, 67, 3969-3971.

M h iMechanismIn+3 In+3

In+3

H2OOHO

N

In+3

OH

InCl3(10 mol%)H2O, r.t.+ +

A B B


E l f lit tExample from literature

InCl3(10 mol%)H2O, r.t.

Entry R Temp Time(h) Yield(%) Cis/Trans

Cis Trans

1 Me r.t. 4 84 81:19

2 OMe r.t. 4 81 87:13

3 F r.t. 10 81 86:14

4 NHPh t 10 65 86 144 NHPh r.t. 10 65 86:14

5 CN r.t. 24 46 69:31


E l f lit tExample from literatureCAN

(5 mol%)(5 mol%)MeCN, r.t.

Cis Trans

Entry R1 R2 R3 Time(min) Yield(%) Cis/Ttrans1 H H Et 60 75 89/11

2 H H nPr 60 73 91/92 H H Pr 60 73 91/9

3 H H nBu 60 76 91/9

4 OMe H Et 45 80 90/10

5 OMe H nPr 45 88 91/9

6 OMe H nBu 45 90 93/7

7 H Me Et 60 72 87/13

8 H OMe Et 120 75 85/15

Sridharan, V.; Avendaño, C. J.; Menéndez, C. Tetrahedron. 2007, 63, 673-681.

Application in total synthesisApplication in total synthesis

•Martinelline & Martinellic acid

Martinelline & Martinellic acidMartinelline & Martinellic acid• Source: Roots of Martinella iquitosensis (lowland Amazon rainforest plant) • Isolated by: Merck group1

Synthesis utilizing Povarov reaction= 6 (core synthesis= 4, total synthesis=2)

y g p• Biological evaluation: First non-peptide bradykinin receptor inhibitor2

Martinelline

M t i lli id

1Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Varga, S. L.; J. Am. Chem. Soc. 1995, 117, 6682–6685.2Xia, C. F.; Heng, L.; Ma, D.; Tet. Lett. 2002, 43, 9405-9409.

Matrinellic acid

Martinelline & Martinellic acidMartinelline & Martinellic acid

Approaches other than Povarov reaction to build the key intermediate:

Ma, D. Xia, C. Jiang, J. Zhang, J. Org. Lett. 2001, 3, 2189-2191.

Ma, D. Xia, C. Jiang, J. Zhang, J. Tang, W. J. Org. Chem. 2003, 68, 442-451.

19 steps

18 stepsSnider, B. B. Ahn, Y. O’Hare, S. M. Org. Lett. 2001, 3, 4217-4220.

p9 steps

Approaches using Povarov reaction to build intermediate

Powell, D. A. Batey, R. A. Org. Lett. 2002, 4, 2913-2916.

13 steps2 steps

Xia, C. F. Heng, L. Ma, D. Tet. Lett. 2002, 43, 9405-9409.

Martinelline & Martinellic acid

Cb

Martinelline & Martinellic acid

CO2Me

NCbz

2NH

MeO2CN

Cbz

N

MeO2CN

Cbz

NHCbzNHCbz

MeCN, r.t.48 h

NH2HN

H

Cat. Pd(OH)2, H2r.t. 5 h

Dy(OTf)3 92% 85 : 15CSA 74% 11 : 89

89%

Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913-2916.


Outline







2 3 Disubsitution2,3-Disubsitution

BF3.OEt2r.t.

OO

O

NH

CF3

OBF3.OEt2

r.t.

2 3 Disubsitution2,3-Disubsitution

R

NH

R'

RS S

NH

R'

RSc(OTf)3

MeCN, r.t.NiCl2/NaBH4

THF

’

1

Entry R’ R Time(h) Yield(%) 1(Trans/Cis)1 p-(C6H4)CO2Me Ph 3 81 23/1

2 Ph Bn 1 ¼ 82 28/1

3 iBu Bn 1 66 1/13 iBu Bn 1 66 1/1

4 iBu Ph 1 64 2/1

Cheng, D.; Zhou, J.; Saiah, E.; Beaton, G. Org. Lett. 2002, 4, 4411-4414.


Another example of 2,3-Disubstitution

•Luotonin A

Luotonin ALuotonin A

• Source: Peganum nigellastrum (Chinese medicinal plant )1• Source: Peganum nigellastrum (Chinese medicinal plant )• Isolated by: Hano and co-workers2

• Biological evaluation: Cytotoxic antitumor alkaloid

Synthesis Publications using Povarov reaction: 2

1 Osborne, D.; Stevenson, P. J. Tet. Lett. 2002, 43, 5469-5470. 2Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913-4916.

Luotonin ALuotonin A4 step total synthesis

i) Y(OTf)3 (3 mol%) AnilineMeCN, r.t. 12 h 97%

ii) HCl, MeCN, reflux, 1 h 78%

NaOEtEtOH78oC99%99%

Microwave, 7 min 85%

Osborne, D.; Stevenson, P. J. Tet. Lett. 2002, 43, 5469-5470.


Outline







Alk l di hil

R1

COOEtS

S

Alkynyl dienophile

N R2

R1CF3SO3HDCM, r.t.

5min

Entry R1 R2 Yield(%)1 Me 4-NO2-C6H4 59

2 Me 4-MeO-C6H4 72

3 Me 4-F-C6H4 63

4 Me 4-Cl-C6H4 68

5 H 4-MeO-C6H4 71

6 H 4-F-C6H4 63

7 Cl 3,4-CH2O2-C6H3 59

8 Cl 4-NO2-C6H4 57

Wang, S.; Zhao, Y. L.; Zhang, W.; Liu, Q. J. Org. Chem. 2007, 72, 4985-4988


•Camptothecin•Luotonin A

CamptothecinCamptothecin• Source: Camptotheca acuminata• Isolated by: Wall and co-workers• Biological evaluation: Potent antitumour alkaloid

Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H., Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888-3890.

CamptothecinCamptothecin

Dy(OTf)3 (10 mol%)

MeCN, 16 h, 50oC

71%

NN

O

Precursor used in the formal synthesis of camptothecin

NH CN

Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913-4916.

Luotonin ALuotonin A6 step total synthesisp y


Luotonin ALuotonin A6 step total synthesisp y

NH2

+ Dy(OTf)3 (10 mol%)

MeCN, 24 h, r.t.

51%



Outline







JulolodinesJulolodinesFluorescent probes, photoconductive materials, potential antidepressants and tranquilizers.

HN

R1

R2

N

R1

R2R3

TFE, r.t. 35% CH2O,

TFE, 1 h

i-Prn-C5H11i-Pr

N

OEtEtO

72%

N

OEtEtO

N

OEtO

35%

Legros, J.; Croousse, B.; Ourevitch, M.; Bonnet-Delpon, D. Synlett. 2006, 1899-1902.

72%80%35%


Outline


Single electron mechanismSingle electron mechanism

NH

NR1

ONO+BF4

-

DCM, r.t.H

R2

Wu, L.; Zhou, Y. L.; Jia, X.; Li, R.; Liu, Z.Tet. Lett. 2005, 46, 8937-8939.

Single electron mechanismSingle electron mechanism

O

N

NR1

2

O

N

O

R2

N O

N

NR1

R2

OH

R2


Single electron mechanismSingle electron mechanismN

1

O

NH

R1

R2

NO+BF4-

DCM, r.t.

Entry R1 R2 Time(h) Yield(%)1 OMe H 3 72

2 Me NO2 1.5 91

3 H OMe 2 89

4 H H 1 94

5 H NO 1 645 H NO2 1 64

6 Br H 1 95

7 Cl H 1 96



Outline

• VARIANTS OF POVAROV REACTION• SINGLE ELECTRON MECHANISM• ASYMMETRIC CATALYSIS

– ASYMMETRIC METAL CATALYSIS– ASYMMETRIC METAL CATALYSIS– ASYMMETRIC BRONSTED ACID CATALYSIS

• CONCLUSIONS

Asymmetric metal catalysisAsymmetric metal catalysis

Catalyst

OH

NH

Ph NH

Ph

OH

OH53% Yield, no chiral induction

N

Yb(OTf)3 Catalyst =

Ishitani, H.; Kobayashi, S. Tet. Lett. 1996, 37, 7357-7360.

Screening of additiveScreening of additive

Catalyst

OH

NH

Ph NH

PhOH OH

E t Additi ( l%) T (oC) Yi ld(%) Ci /T % (Ci )

OH

OHCatalyst = , DBUYb(OTf)3 Additive =

Entry Additive (mol%) Temp.(oC) Yield(%) Cis/Trans ee% (Cis)

1 DTBP (100) 0 67 99/1 61

2 DTBMP(100) -15 82 >99/1 70

3 DTBP(100) 15 92 >99/1 71


3 DTBP(100) -15 92 >99/1 71

Substrate scopeSubstrate scope

Yb Complex(10-20 mol%)

Additive (100 mol%)DCM, -15oC, MS4Ǻ

Entry R’ R Additive Catalyst Yield(%) Cis/Trans ee% mol% (Cis)

1 Ph Et DTBP 20 58 94/6 61

2 Ph Et DTBP 10 52 94/6 77

3 α Naphthyl Et DTBP 20 69 >99/1 863 α-Naphthyl Et DTBP 20 69 >99/1 86

4 α-Naphthyl Et DTBMP 20 74 >99/1 91

5 α-Naphthyl Bu DTBMP 20 80 66/34 70


Substrate scopeSubstrate scope

NH

R'

Yb Complex(10-20 mol%)

Additive (100 mol%)DCM, MS4Ǻ HOH

Entry R’ R Additive Catalyst mol%

Temp. (oC)

Yield (%)

Cis/ Trans

ee% (Cis)

DCM, MS4Ǻ

mol% ( C) (%) Trans ( )

1 α-Naphthyl Dihydrofuran DTBMP 20 -15 90 91/9 78

2 α-Naphthyl Dihydrofuran DPP 20 -15 67 93/7 86

3 α-Naphthyl Cyclopentadiene DTBMP 20 -15 69 >99/1 68

4 Cyclohexyl Cyclopentadiene DTBMP 20* -15 58 >99/1 73

*Sc(OTf)3 used


( )3

Explanation of enantioselectivityExplanation of enantioselectivityYb Complex(10-20 mol%)

Additive (100 mol%)Additive (100 mol%)DCM, MS4Ǻ


Asymmetric Bronsted acid catalysisAsymmetric Bronsted acid catalysis

ORCatalyst(10 mol%)

NH

R'OH

Toluene

Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070-13071.

Substrate scopeSubstrate scopeORCatalyst

(10 mol%)

T l NH

R'OH

Entry R’ R Temp. Yield(%) Cis/Trans ee(%) for Cis

Toluene

1 Ph Et -10oC 89 99/1 94

2 Ph nBu -10oC 82 99/1 96

3 Ph Bn 0oC 76 99/1 91

4 2-BrC6H4 Et -10oC 77 99/1 90

5 2-BrC6H4nBu -10oC 86 99/1 89

6 2-ClC6H4 Et -10oC 79 99/1 88

7 2-MeC6H4 Et 0oC 59 99/1 91

8 2-ClC6H4 Et 0oC 72 96/4 87

9 2-naphthyl Et 0oC 74 99/1 95

10 2 naphthyl nBu 0oC 80 99/1 8810 2-naphthyl nBu 0oC 80 99/1 88


Explanation of enantioselectivityExplanation of enantioselectivityORCatalyst

(10 mol%)

T l NH

R'OH

Toluene


Recent developmentsRecent developments

O NH

O

Catalyst

H

Woll, M. G.; Jacobsen, E. N. Manuscript in preparation

Recent developmentsRecent developments

ON

R' OCatalyst

ON

R NH

Catalyst=y

Entry R’ R Yield(%) Trans/Cis ee(%) for Trans1 H H 86 4:1 942 H OMe 90 3:1 883 H NO2 82 3:1 934 H Br 94 4:1 945 OMe H 92 3:1 93

Woll, M. G.; Jacobsen, E. N. Manuscript in preparation

6 Br H 85 5:1 91


Outline


ConclusionConclusion

•Highly regioselective reaction with good diastereoselectivity•Highly regioselective reaction with good diastereoselectivity.•Mild reaction conditions (mostly room temperature).•Potential to ability to generate 3 stereocenters at a time.•Good tool for building library of compounds.

•Future prospects•Work to be done in the asymmetric Povarov reaction.•Synthesis of natural products using asymmetric form of the reaction.

Rahman Shah Zaib Saleem Michiggyan State …...Synthesis utilizing Povarov reaction= 6 (core synthesis= 4, total synthesis=2) gp • Biological evaluation: First non-peptide bradykinin

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