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Asymmetric Morita Baylis Hillman Reaction Lalit Kumar Lalit Kumar Medicinal & Process chemistry Medicinal & Process chemistry Division Division CDRI CDRI

Lalit Kumar

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Page 1: Lalit Kumar

Asymmetric Morita Baylis Hillman

Reaction

Lalit KumarLalit Kumar

Medicinal & Process chemistry DivisionMedicinal & Process chemistry Division

CDRICDRI

Page 2: Lalit Kumar

2

O NH

O

N

N Ph

O

O

NH

OMe

O

OAc

OCH3

O

O

HH

O

OHH2N

MeMe

O

NH

HN

HO2C

OMeO2SHN

H2N

CO2H

OH

Pregabalin(Neuropathic pain)

Sampatrilat(Vasopeptidase inhibitor)

N

N

O

R1HN

Ph

COOMe

OR2

R1 = PhCH2OCO, R2 = 4-(NO2)PhCO

R1 = PhCH2OCO, R2 = PhCO

R1 = PhCH2OCO, R2 = CH3CO

Anti-malarial agents

Antiproliferative agent

Drugs & biological active moleculesDrugs & biological active molecules synthesized by using Baylis Hillman strategysynthesized by using Baylis Hillman strategy

Page 3: Lalit Kumar

Introduction

Two most fundamental reactions in synthetic organic chemistrysynthetic organic chemistryfunctional group transformations Carbon-carbon bond formation

Morita-Baylis-HillmanMorita-Baylis-HillmanAldol reactionReformatsky reactionClaisen rearrangements Friedel-Crafts reaction Grignard reaction Diels-Alder reaction Wittig reaction Heck reactionSuzuki coupling Grubb’s RCM

Some C-C bond forming reactions are-Some C-C bond forming reactions are-

O

Aldol

1,2-Addition

1,4-addition

Baylis Hillman

Diels-Alder

Five possible ways of constructing C-C bonds with MVK

3

Page 4: Lalit Kumar

“A carbon-carbon bond is formed between the α -position of activated alkenes such as α,β-unsaturated esters, amides, nitriles, ketones and electron-deficient sp2 carbon atom of various aldehyde under the catalytic influence of a tertiary bicyclic amine such as DABCO, pyrrocoline (indozoline) or quinuclidine, producing highly functionalized product”

Baylis, A.B.; Hillman, M.E.D.; German Patent 2155113, 1972

Chem. Abstr. , 19721972, 77, 34174q

Original patent information

4

R H

O EWG+

tert-amineOH

EWGR

EWG = COOR`, CONEt2, CN, COR``R, R` = Alkyl or Aryl; R`` = Alkyl

NNtert-amine =

N N

DABCO Indozoline Quinuclidine

C-C bond formed

Page 5: Lalit Kumar

A plausible mechanistic pathway

Basavaiah, D., Rao, A. J., Satyanarayana,T., Chem.Rev.,2003,103,811

Michael addition of the nucleophilic catalyst to the activated olefin.

Quenching the zwitterionic adduct with an electrophile.

Proton transfer and elimination of the catalyst

Me

O

NN

NN

Me

O

Ph H

O

NN

Me

OO

H

Ph H

NN

Me

OOH

H

Ph

Me

O

Me

OOH

Ph

NN

Me

O

O

MeH

NN

Me

O

OH

Me

Me

O

O

Me

MajorMinor

Path IPath II

5

Page 6: Lalit Kumar

Three essentials components

(1) Activated alkenes (acyclic or cyclic) allenes alkyne

R

OCN

N XRSO3Ph

SO2Ph

O OR

R`

OEtO

S S

O NO2

Ar`R

R

O

R = H, Alkyl, Vinyl, etc. R` = Alkyl, Vinyl, etc. X = O, S

PO(Et)2 ORORO

O OR

O O O

O

O

O

O

NH

NH

O

O

O

O

X

O

O

XO

n n

n = 0, 1, 2, etc. X = H, Me, Halide, etc.

OR

O OR

6

Page 7: Lalit Kumar

7

(2) Electrophiles

R H R CF3R COOR X3C COOR EtOOC COOEt

EWG

RRR H

O O O O O

EWG

Br

OAc

EWGNEWG

F3C CF3

NEWGO

NR

OOOO

O

O

O

X

XX

R = Alkyl, Aryl, H, etc, X = H, halide, NO2, etc. n = 0, 1, 2 EWG = COR, COOR, CN, SO2Ph, SO3Ph, Ts, POPh2,

,

I2(iodine), RCH(OMe)2

Page 8: Lalit Kumar

8

(3) Catalyst (Amine or Non-amine)

N

NN N

N

N N

OH

N

OAc

N

O

N

N

Aq/ Methanolic Me3N; etc

N

NH N

HN

benzimidazole

NN

NH

DMAP DBUIndozoline DABCO

QD 3-HQD

(C2H5)3N

Imidazole triazole

3-AQD 3-OQD

TiCl4 / Chalcogenides; BF3.OEt2 / Tetrahydrothiophene derivatives; BBr3 / Me2S; R3P; NaOMe; MgI2; MgBr2. etc.

NN

P

N

Page 9: Lalit Kumar

9

R

O

R1

OH

*

Chiral Center

R

O

R1

HO

*

R

O

R1

HO

*

S- isomer

R- isomer

Baylis Hillman adduct

Introduction of asymmetry

Introduction of Asymmetry

Page 10: Lalit Kumar

(1) Enantiopure (enriched) activated alkene

VariousVarious chiral chiral

auxillariesauxillaries

Me Me

N

SOO

O O

Me Me

N

NOO

Ph

O

Ph O

OPh

H

PhO

SiMe3OPh

OSO2N(c-Hex)2

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

OH

OO

O

O

O

O

OH

OO

O

O

O

O

10

Page 11: Lalit Kumar

N

O

RO

PhO

n

R = Vinyl, ethynyl

OMeH

O

Cr(CO)3

O

OH

O

Ph

N

O

O PMP

OO

PMP = 4-(OMe)C6H4

(2) Enantiopure (enriched) electrophile

CHO

PhO2SN-phenylsulfonyl-L-prolinal

R CHO

NR`R``

N-acylaminoaldehyde

Basavaiah, D.,Venkateswara, R., Reddy, R. J.,Chem.Soc.Rev.,2007,36,1583

CHO

OCH2Ph

(S)-3-benzyloxybutyraldehyde

O

O CHO

HIsopropylidene (R)-glyceraldehyde

CHO

OPG

PG = protecting group(S)-O-protected lactaldehyde

OHC

(R)-myrtenal

11

Page 12: Lalit Kumar

(3) Chiral catalyst

NH

N

NH

S

CF3

CF3 OH

OH

N

N

N

OH

O

N

OH

PPh2

BINOL-derivedQuinidine derived

Binaphthyl-derived amine thiourea organocatalyst

BINOL-derived

12

Page 13: Lalit Kumar

13

(4)Enantiopure catalytic sources (additives)

Induce high enantioselectivity Interact with activated alkene or electrophile either by H-bonding or by coordination Differentiate the diastereomeric transition state in the presence of posphine or tertiary amine catalyst.

NNH

But

But

HO

NH

S

OBn

MeBut

Page 14: Lalit Kumar

Brzeinski, L.J.; Rafel, S.; Leahy, J.W.; J.Am.Chem.Soc.1997, 119, 4317

Chiral Michael acceptors in Asymmetric MBH

Me Me

N

SO

+H R

O NN

CH2Cl2, O oC

O O

O

O

O

RR

33-98%( 99% ee)

Me Me

NS

OO O

DABCO

Me Me

NS

O

O

NR3

O

RCHO

RCHO

Me Me

NS

O

O

NR3O

RCHO

RCHO

O

H

R

NR3O

XcN

H

R

O

XcN

R3N

O

NR3

O

XcN

O R

RO

O

O

NR3

RR

O

O

O

O

addition to re face

More stable

14

Page 15: Lalit Kumar

Chiral glyoxylates as electrophiles

Bauer, T.; Tarasiuk J.; Tett. Asymm.; 2001,12, 1741

H

O

OH

O

O H

O

O

OH

H

O

O

HO

O O

+ +Me2S (0.2 eq)

TiCl4 (1 eq)

0oC, CH2Cl2

(-)-menthyl glyoxylate 2-cyclohexenone 45% yield, de: 8.7%

(-)-8-phenylmenthylglyoxylate

2-cyclohexenone 78% yield, de.> 95%, config.(S)

S R

O

OO

Me2S

O

H

Cl3Ti

re

si

OH

O

O

si

re

Me2S

O

TiCl3

O

OO

Me2S

O

H

Cl3Ti

re

si

A B Cs-cis s-cis s-trans

In all case bottom side of reacting formyl group is blocked by phenyl ring.

15

Page 16: Lalit Kumar

Hatakeyama, et al.; Org. Lett., 2003 , 17, 3103

β-Isocupreidine-catalized reaction of Imines

N

H

R

OAr

O CF3

CF3O

O CF3

CF3

NH

Ar

R

SDMF, -55 oC

+

(S)-enriched adductee: >91%HFIPA

N

OH

O

N

-ICD

N

OH

O

N

O

OR`

N

H

R

Ar

+N

O

O

N O

OR`

H Ar

HNR

N

O

O

N O

OR`

H H

ArNR

O

O

CF3

CF3

Ph

NHR

( S )- product

O

O

CF3

CF3

Ph

NHR

( R )- product

fast Slow

N

H HH

CO2R`

A

B

C

D

HH

More stable

16

Page 17: Lalit Kumar

17

O

HO

R

O CF3

CF3 O

O CF3

CF3

HO

R R

N

OH

O

DMF, -55 o C+

N

HFIPA> 91% ee

-ICD

(R)-enriched adduct

β-Isocupreidine-catalized reaction of aldehyde

N

OH

O

N

O

OR`

N

O

O

N O

OR`H

HRO

O

O

CF3

CF3

R

OH

( S )- product

O

O

CF3

CF3

R

OH

( R )- product

H HH

CO2R`

N

A

BC

H

H

RCHORCHO

X

Y

O

N

O H

N

O

O

N O

OR`H

H

RO

H

More stable

Hatakeyama, et al .; J. Am. Chem. Soc. 1999, 121, 10219

Page 18: Lalit Kumar

N ORCH3

R = H, CH3

N-methylprolinol as chiral base catalyst

Krishna, P. R.; Kannan, V.; Reddy P. V. N. Adv. Synth. Catal. 2004, 346, 603

OEt

O

N

Me

OH+ N

OH

OEt

OMe

Ar H

O

NMe

O

OOEt

OAr

H

AB

NMe

O

OOEt

OAr

H

C

Ar H

O

OEt

O

Ar OEt

HO O

15-78% ee

dioxane-water 1:1

+

OEtAr

HO O

(R)

More stable

18

(R)

Page 19: Lalit Kumar

19

Free hydroxy group in the chiral amineplays a major role in chirality induction

HAr

O

NH

CO2H N CO2

O

NO2N

OH

NMe2

OH

( 1R, 2R)-(-)-tert.amine O

O

NNO2

OH

OH

Ar H

O

N O

O

NNO2

OH

OH

ArH

ON O

O

NNO2

OH

OH

OO

ArAr

HO OH

(R)-(S)-

Favored unfavored

-H2O

Tang, H.; Zhao, G.; Zhao, Z.; Geo, P.; He, L.; Tang, C.; Eur. J. Org. Chem. 2008, 126

Chiral Tertiary Amine/L-Proline as Cocatalyst

Page 20: Lalit Kumar

Shi, Y. L.; Shi, M.; Adv. Synth. Catal.; 2007, 349, 2129

Chiral Thiourea-Phosphine Organocatalyst

NH

PPh2

NH

S

Ph O

+

PhCO2H

N

PPh2

N

S

Ph

Me

O

HH O

Ph

ON

PPh2

N

S

Ph

Me

O

H

H

O

Ph

OH H

A B

N

Ph2P

N

SPh

N

HTs

O

PhO

H

C

H

H

Ph

H

O

N

Ph2P

N

SPh

N

HTs

O

PhO

H

D

H

Ph

H

H

O

HN

HPh

O

PPh2

N

N

SPh

Ts H

H

OPh

O

H

HN

PhH

O

PPh2

N

N

SPh

Ts H

H

OPh

O

H

side viewE

favored

side viewF

disfavored

ONHTs

Ph S

ONHTs

Ph R

UP 1

20

Page 21: Lalit Kumar

Conformational lock in a Brønsted acid–Lewis base organocatalyst

The acid–base functionalities help in substrate activation and fixing of the organocatalyst conformation to promote the reaction with high enantioselectivity.

R1

O

H R2

NR3

R1

NHR3

R2

O+

Michaelreaction

OH

LB

OR1O

H

H R2

NR3 Mannichreaction

OH

LB

OR1O

H

R2

NR3

ImineAllyl amine

retro-michaelreaction-elimination

Bifunctional Organocatalyst

β

Proposed catalytic cycle for the bifunctional organocatalyst-mediated aza-MBH reaction

BrØnsted acid unitOH

OH

LB

Lewis base unitspacer

BINOL Unit

Concept of chiral bifunctional organocatalyst

Mataui, K., Tanaka, K., Horii, A., Takizawa, S., Sasai, H.; Tett. Asym., 2006, 17, 578

1a: (S)-3-[4-(dimethylamino)pyridin-2-yl]BINOL1b: (S )-3-[4-(dimethylamino)pyridin-3-yl]BINOL1c: (S)-3-[3-(dimethylamino)pyridin-5-yl]BINOL2a: (S)-3-(N-methyl-N-3-pyridinylaminomethyl)BINOL2b: (S )-3-(N-methyl-N-2-pyridinylaminomethyl)BINOL2c: (S)-3-(N-methyl-N-4-pyridinylaminomethyl)BINOL

OH

OH

OH

OH

OH

OH

N

Me2NN

NMe2

33 N

Me

N

1a-b, 1c, 2a-c Novel chiral organocatalyst 21

Page 22: Lalit Kumar

Novel chiral sterically congested phosphane-amide bifunctional Lewis base

Guan, X. Y., Jiang, Y.Q., Shi, M.; Eur. J. Org. Chem.; 2008, 2150

H

NTs

+O OTsHN

solvent

L1(10mol%)

(1.0 eq) (2.0eq)

DCM, 0oC, y: 90%, ee: 80%, SDCM, 20oC, y: 88% , ee: 73%, S

H

NTs

+O

DCM, rt, 24 h

(1.0 eq) (2.0eq)Cl

PPh2

NMe2

20 mol %No Reaction

HN C

O

CHN

O

Ph2P

PPh2

L 1

22

Page 23: Lalit Kumar

Why bi-functional organocatalyst so important ?

Amines covalently attached to a protic function several carbon away.

Suitable positioning of H-bond donors for selective intramolecularproton transfer of one of the alkoxide diastereomers , not the others.

The alkoxide diasteremers that undergoes the fast selective proton-transfer reaction may also be the diastereomers that is preferentially formed, but this is not a prerequisite.

Bi-functional catalysts give good selectivites only if no other protic additives.

23

Page 24: Lalit Kumar

Me

Me

Me

Me

O OH

N N

OHO

Me

Me

Me

Me

O OH

N N

OHO

Me

Me

Me

Me

O OH

N N

OHO

Me

Me

Me

Me

O OH

N N

OHO

Yang, K. S.; Lee, W.D.; Pan, J. F.; Chen, K.; J. Org. Chem. 2003, 68, 915

Chiral Lewis Acid-Catalyzed

O

O

R3N

O

H R

La

N N

Me

Me

MeMe

O

O

O

O

The stereocontrol elements for achieving enantioselective carbon-carbon bond formation depends on the proper choice of metal and chiral ligands.

Structures of camphor derived chiral ligand

Lewis acid

Yb(OTf)3

La(OTf)3

Yield(%)

7275

%ee

1784

confign

SS

24

Page 25: Lalit Kumar

New and improved bis(thio)urea catalyst

derived from isophoronediamine (IPDA)

Berkessel, A.; Roland, K.; Neudo1rl, J. M. Org. Lett. 2006, 8, 4195

F3C

F3C

NH

S HN

HN H

N

S

F3C

CF3

CH3H3C

CH3

Catalyst 1

TMIPDA: (N,N,N’,N’)-tetramethylisophoronediamine25

H

O O

+

20 mol % cat. 1

TMIPDA, toluene10oC

OH O

yield: 75%, ee: 96%, (R)-enriched2-Cyclohexene-1-one Cyclohaxenecarbaldehyde

Page 26: Lalit Kumar

26

The dendrimer supportedchiral phosphine Lewisbases can be easily and Reused.

Polyether dendrimer supported chiral Lewis bases (R)-DPLBs

Lewis base (R)-DPLB3

OH

PPh2

OO

O

R

R

n

(R)-DPLB3, n=2, R= Bn

OH

P(O)PH2

After reaction

Cl

NTs

O

+

ONHTs

Cl

(R)-DPLB3( mol 10%)

solvent

Liua, Y. H.; Shia, M.; Adv. Synth. Catal. 2008, 350, 122

93% ee (S)

Page 27: Lalit Kumar

27

Chiral ionic liquids as reaction media

Presence of the hydroxyl group on chiral ILs is propitious for the transfer of chirality

Ar H

O

MeO

O

DABCO, ILAr

OH

Ome

O+

*

Pe´got, B.; Vo-Thanh G.; Gori, D.; Loupy, A.; Tett. Lett.; 2004, 45, 6425

NRMe

Me

Ph

HOX

IL: Ionic Liquid

R= C4H9, C8H17, C10H21, C16H33

X= OTf, PF6

(R)

Page 28: Lalit Kumar

28

Hill and Isaacs Mechanism

Based on pressure dependence, rate, and kinetic isotope effect (KIE) data.ESMS and Tandem mass spectrometry.No α-proton cleavage occurs in the rate-determining step (RDS). Addition of the enolate to the aldehyde was the RDS.

Hill, J. S.; Isaacs, N. S.; J. Phys. Org. Chem. 1990, 3, 285

Ph

R3N

OMe

O O

R3N

OMe

O

OMe

O

Ph OMe

OH O

NR3

Proposed RDS

Int 1Int 2 Ph H

O

Page 29: Lalit Kumar

Robiette, R.; Aggarwal, V. K.; Harvey, J. N.; J. Am. Chem. Soc., 2007, 129, 15513

Mechanism of MBH reaction – based on computational method

O

OMe

TS 1

NMe3

O

OMe

Me3N

O

OMe

Me3N

Ph

OH

Int 2

O

OMe

Me3N

Ph

OH

O

Ph

Hemi 1

O

OMe

Me3N

Ph

O H

OPh

RDS

TS3-hemi

O

OMe

Me3N

Ph

O

OH

Ph

Hemi 2

O O

Ph O

Ph

O

OMe

Ph

O

OH

Ph

Hemi 3

Non-alcohol catalyzed

O

OMe

Me3N

Ph

OH

MeOH

TS 2-MeOH

Ph

OHOMe

Ph

Me3N

COOMe

O

HO

Me

H

TS3-MeOH

RDS

Ph

Me3N

OH

O

OMe

HOMe

Int-MeOH

OH OMe

OPh

Int 2 -MeOH

Alcohol catalyzed

29

PhCHOPhCHO

Int.1

Page 30: Lalit Kumar

Hindered bases with high pKa Higher the pKa of the conjugate acid of the amine higher the rate of reaction.(leading to increased concentrations of the intermediate ammonium enolate)e.g.; Quinuclidine (highest pKa), DBU.

Improvement of reaction rate Important landmarks

Hydrogen-bonding additives or solventshelp the proton-transfer step.e.g.; MeOH/t-BuOH/H2O

Lewis acids with alcohol-based ligandsThe Lewis acid-alcohol complex results in increased acidity of the OH groups, which promotes proton-transfer events.

30

Page 31: Lalit Kumar

31

XHY`R

R*

Three functional groupsThree functional groupsVia the functional group manipulation develop opportunities in organic synthesis

Chiral centerChiral centerFor asymmetric versionasymmetric version offers

challenge to develop efficient catalyst

Intra-molecular versionIntra-molecular versionOffers challenges to design and synthesize novel class of substrates with several combinations of activated olefinic and electrophilic groups thereby

leading to develop various cyclic frameworks of synthetic importance

X= O, NRY= Electron withdrawing group

Offers challenge to develop novel activated alkenes,

electrophiles and catalyst

Page 32: Lalit Kumar

32

Pfizer, Pregabalin, Drugs Future, 2002, 27, 426

Me

HMe

O

+

NC DBU, DBP Me

Me

NC

OHAcCl, Ac2O

Me

Me

NC

OAc

Py

OEtNC

O

MeMe

KOHO KNC

O

MeMe

O t-BuNH3NC

O

MeMe

HCl

t-BuNH2

Pd(OAc)2Ph3P

CO, EtOH

Chiral (R,R)-Rh catalystH2

Chiral (R,R)-Rh catalystH2

O O

NC NC O K

MeMe

MeMe

O t-BuNH3

sponge Ni catalystKOH, H2

O

OHH2N

MeMe

Pregabalin (Lyrica)Used in: Fibromyalagia

spinal cord injuryNeuropathic pain

Baylis Hillman reaction

(S)-3-(aminomethyl)-5-methylhexanoic acid

Synthesis for Pregabalin

/

Page 33: Lalit Kumar

33

Synthesis of Sampatrilat

CO2But

+H H

O 3-Quinuclidinol (0.25 eq)

H2O, CH3CN,HO

CO2But

ClCO2ButSOCl2 (0.88 eq)

Et3N (1.02eq)Py (0.1 eq)

NH

Ph

Ph

(S,S)(0.66 eq)

Et3N, 81%

ButO2C

N

Ph

Ph

CO2H

(1.1 eq)

LDA (2.2 eq)

THF -30 to 20 OCCO2H

N

ButO2C

Ph

Ph

de > 98%

NH

OCO2H

OH

HO2C

HN

O

NHSO2Me

H2N

Sampatrilat

(1.6eq) Baylis Hillman ReactionBaylis Hillman Reaction

Vasopeptidase inhibitorVasopeptidase inhibitorInhibits the angiotensin Inhibits the angiotensin converting enzyme (ACE)converting enzyme (ACE)

Dunn, et al; Organic Process Research & Development, 2003, 7, 244

Page 34: Lalit Kumar

O

OHN CHO

+MeOOC DABCO

O

OHN COOMe

OH

88%

O

OHN COOMe

DEAD, Ph3P

AcOH, THF 77%

H3N COOMe

OAc OAc

Dry HClEt2O

99%ClO N

H

O

N

N Ph

COOH

O

DCC, HOBT, DMAP, CHCl3, 79%

O NH

O

N

N Ph

O

O

NH

OMe

O

OAc

Baylis Hillman Reaction

The antimalarial efficacy of compound is comparable to that of chloroquine with IC50 6-8ng/mL against D-6

Synthesis of Novel Pyrimidinyl Peptidomimetics

Zhu, S.; Hudson, T.H.; Kyle, D.E.; Lin, A.J.; J. Med. Chem. 2002, 45, 3491

34

Potential Antimalarial Therapeutic Agents

Page 35: Lalit Kumar

N

N

O

R1HN CHO

Ph+

COOMe DABCO

N

N

O

R1HN

PhOH

COOMe

DEAD, Ph3P4-(NO2)PhCOOH orPhCOOH orCH3COOHN

N

O

R1HN

Ph

COOMe

OR2 R1 = PhCH2OCO, R2 = 4-(NO2)PhCO

R1 = PhCH2OCO, R2 = PhCO

R1 = PhCH2OCO, R2 = CH3CO

Anti-malarial compound

Baylis Hillman reaction

Zhu, S.; Hudson, T.H.; Kyle, D.E.; Lin, A. J. J. Med. Chem. 2002, 45, 3491

Antimalarial Therapeutic Agents

35

Page 36: Lalit Kumar

H3C H OCH3

O O

+

DABCO, 7 days, rt90%

OCH3

O

HO

NBS, (CH3)2S,

OoC to rt, 24 h, 92%

O

Br

OCH3

COOH

OH

CH2OH

OH

LiAlH4, THF

reflux 6h50%

CH2OH

OCH3

CH3I, acetone

K2CO3, 95%

CHO

OCH3

PCC, CH2Cl21.5 h, rt,90%

OCH3

O

O

HH

Sn, (CH3CH2)2O, HOAc,

p-(TsOH), C6H6, reflux9h, 70%

Baylis Hillman reaction

J. Bermejo et al, J. Med. Chem. 2002, 45, 2358

Synthesis of Antiproliferative Agent

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Simplicity of this reaction in the easy construction of the carbon- carbon bond.

Conclusions

Morita Baylis Hillman adduct is an excellent source for various stereochemical transformation methodologies.

Several natural products and biologically active molecules have also been synthesized using Morita Baylis Hillman strategy.

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AcknowledgementAcknowledgement

Dr. V.L. SharmaDr. V.L. Sharma

&&

All my friendsAll my friends

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TThhaannkk yyoouu