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Asymmetric Morita Baylis Hillman
Reaction
Lalit KumarLalit Kumar
Medicinal & Process chemistry DivisionMedicinal & Process chemistry Division
CDRICDRI
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
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
“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
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
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
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
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
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
(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
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
(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
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
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
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
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
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
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)
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
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
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
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
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
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
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
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)
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)
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
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
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
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
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
/
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
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
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
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
36
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.
37
38
AcknowledgementAcknowledgement
Dr. V.L. SharmaDr. V.L. Sharma
&&
All my friendsAll my friends
39
TThhaannkk yyoouu