Published on May 24, 2008
Asymmetric Morita Baylis Hillman Reaction Lalit Kumar Medicinal & Process chemistry Division CDRI
Pregabalin (Neuropathic pain) Sampatrilat (Vasopeptidase inhibitor) Anti-malarial agents Antiproliferative agent Drugs & biological active molecules synthesized by using Baylis Hillman strategy
Introduction Two most fundamental reactions in synthetic organic chemistry functional group transformations Carbon-carbon bond formation Morita-Baylis-Hillman Aldol reaction Reformatsky reaction Claisen rearrangements Friedel-Crafts reaction Grignard reaction Diels-Alder reaction Wittig reaction Heck reaction Suzuki coupling Grubb’s RCM Some C-C bond forming reactions are- 3
Two most fundamental reactions in synthetic organic chemistry
functional group transformations
Carbon-carbon bond formation
“ 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 sp 2 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 . , 1972 , 77 , 34174q Original patent information 4
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 5
Three essentials components (1) Activated alkenes (acyclic or cyclic) allenes alkyne 6
(3) Catalyst (Amine or Non-amine)
Baylis Hillman adduct Introduction of asymmetry Introduction of Asymmetry
(1) Enantiopure (enriched) activated alkene 10 Various chiral auxillaries
(2) Enantiopure (enriched) electrophile Basavaiah, D.,Venkateswara, R., Reddy, R. J., Chem.Soc.Rev ., 2007 , 36 ,1583 11
(3) Chiral catalyst BINOL-derived Quinidine derived Binaphthyl-derived amine thiourea organocatalyst BINOL-derived 12
(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.
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.
Brzeinski, L.J.; Rafel, S.; Leahy, J.W.; J.Am.Chem.Soc. 1997 , 119 , 4317 Chiral Michael acceptors in Asymmetric MBH More stable 14
Chiral glyoxylates as electrophiles Bauer, T.; Tarasiuk J.; Tett. Asymm .; 2001 , 12 , 1741 s-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 More stable 16
β -Isocupreidine-catalized reaction of aldehyde More stable Hatakeyama, et al .; J. Am. Chem. Soc. 1999, 121, 10219
N-methylprolinol as chiral base catalyst Krishna, P. R.; Kannan, V.; Reddy P. V. N. Adv. Synth. Catal . 2004 , 346 , 603 More stable 18 (R)
Free hydroxy group in the chiral amine plays a major role in chirality induction 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 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 . Mataui, K., Tanaka, K., Horii, A., Takizawa, S., Sasai, H.; Tett. Asym., 2006 , 17 , 578 1a : (S)-3-[4-(dimethylamino)pyridin-2-yl]BINOL 1b : (S )-3-[4-(dimethylamino)pyridin-3-yl]BINOL 1c : (S)-3-[3-(dimethylamino)pyridin-5-yl]BINOL 2a : (S)-3-(N-methyl-N-3-pyridinylaminomethyl)BINOL 2b : (S )-3-(N-methyl-N-2-pyridinylaminomethyl)BINOL 2c : (S)-3-(N-methyl-N-4-pyridinylaminomethyl)BINOL 21 β Proposed catalytic cycle for the bifunctional organocatalyst- mediated aza-MBH reaction Br Ø nsted acid unit Concept of chiral bifunctional organocatalyst 1a-b, 1c, 2a-c Novel chiral organocatalyst
Novel chiral sterically congested phosphane-amide bifunctional Lewis base Guan, X. Y., Jiang, Y.Q., Shi, M.; Eur. J. Org. Chem .; 2008 , 2150 DCM, 0 o C, y: 90%, ee : 80%, S DCM, 20 o C, y: 88% , ee : 73%, S 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 intramolecular proton 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
Yang, K. S.; Lee, W.D.; Pan, J. F.; Chen, K.; J. Org. Chem. 2003 , 68 , 915 Chiral Lewis Acid-Catalyzed 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(%) 72 75 % ee 17 84 confign S S 24
New and improved bis(thio)urea catalyst derived from isophoronediamine (IPDA) Berkessel, A.; Roland, K.; Neudo1rl, J. M. Org. Lett. 2006 , 8, 4195 Catalyst 1 TMIPDA: (N,N,N’,N’)-tetramethylisophoronediamine 25
New and improved bis(thio)urea catalyst
derived from isophoronediamine (IPDA)
Polyether dendrimer supported chiral Lewis bases (R)-DPLBs After reaction Liua, Y. H.; Shia, M.; Adv. Synth. Catal . 2008 , 350 , 122 93% ee ( S ) The dendrimer supported chiral phosphine Lewis bases can be easily and Reused. Lewis base (R)-DPLB3
Chiral ionic liquids as reaction media Presence of the hydroxyl group on chiral ILs is propitious for the transfer of chirality Pe´got, B.; Vo-Thanh G.; Gori, D.; Loupy, A.; Tett. Lett .; 2004 , 45, 6425 (R)
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
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.
Robiette, R.; Aggarwal, V. K.; Harvey, J. N.; J. Am. Chem. Soc ., 2007 , 129 , 15513 Mechanism of MBH reaction – based on computational method 29 PhCHO PhCHO Int.1
Hindered bases with high p K a Higher the p K a 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 p K a), DBU. Improvement of reaction rate Important landmarks Hydrogen-bonding additives or solvents help the proton-transfer step. e.g.; MeOH/ t -BuOH/H 2 O Lewis acids with alcohol-based ligands The Lewis acid-alcohol complex results in increased acidity of the OH groups, which promotes proton-transfer events. 30
Three functional groups Via the functional group manipulation develop opportunities in organic synthesis Chiral center For asymmetric version offers challenge to develop efficient catalyst Intra-molecular version Offers 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, NR Y= Electron withdrawing group Offers challenge to develop novel activated alkenes , electrophiles and catalyst
Synthesis for Pregabalin / Pfizer, Pregabalin, Drugs Future , 2002 , 27 , 426 Pregabalin ( Lyrica ) Used in: Fibromyalagia spinal cord injury Neuropathic pain Baylis Hillman reaction ( S )-3-(aminomethyl)-5-methylhexanoic acid
Synthesis of Sampatrilat Dunn, et al; Organic Process Research & Development , 2003 , 7, 244 Baylis Hillman Reaction Vasopeptidase inhibitor Inhibits the angiotensin converting enzyme (ACE)
Inhibits the angiotensin
converting enzyme (ACE)
34 Potential Antimalarial Therapeutic Agents Baylis Hillman Reaction The antimalarial efficacy of compound is comparable to that of chloroquine with IC 50 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
Potential Antimalarial Therapeutic Agents
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
J. Bermejo et al , J. Med. Chem. 2002, 45, 2358 Synthesis of Antiproliferative Agent 36 Baylis Hillman reaction
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
Simplicity of this reaction in the easy construction of the carbon-
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.
Acknowledgement Dr. V.L. Sharma & All my friends
T h a n k y o u
Lalit Kumar is an Indian medical oncologist, known to have contributed to the development of low cost medical facilities in Delhi. The Government of India ...
Nicht der Lalit Kumar, den Sie suchen? Lalit Kumar Business Head New Delhi
View Lalit Kumar’s professional profile on LinkedIn. LinkedIn is the world's largest business network, helping professionals like Lalit Kumar discover ...
Nicht der Lalit Kumar, den Sie suchen? Lalit Kumar Business Head New Delhi
View the profiles of people named Lalit Kumar on Facebook. Join Facebook to connect with Lalit Kumar and others you may know. Facebook gives people the...
Lalit Kumar CSM®s berufliches Profil anzeigen LinkedIn ist das weltweit größte berufliche Netzwerk, das Fach- und Führungskräften wie Lalit Kumar CSM ...
Lalit kumars berufliches Profil anzeigen LinkedIn ist das weltweit größte berufliche Netzwerk, das Fach- und Führungskräften wie Lalit kumar dabei ...
Lalit Kumar is on Facebook. Join Facebook to connect with Lalit Kumar and others you may know. Facebook gives people the power to share and makes the...
Profile der Personen mit dem Namen Manish Lalit Kumar auf Facebook anzeigen Tritt Facebook bei, um dich mit Manish Lalit Kumar und anderen Personen, die...
Lalit Kumar is the Founding Director of Himalaya Yoga Valley Centre and the Hon. Secretary for International Yoga Federation for Ireland and Dharamshala.