Presentation on theme: "Hydrogen-Bond Catalysis"— Presentation transcript:
1 Hydrogen-Bond Catalysis For reviews see:M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45,A. G. Doyle, E. N. Jacobsen, Chem. Rev., 2007,Nadia Fleary-Roberts03/02/10
2 A brief history… Lewis acids has dominated enantioselective catalysis acceleration of Diels Alder reaction with AlCl3Yates P.; Eaton P., J.Am. Chem. Soc. 1960, 82, 4436Wynberg reported asymmetric conjugate addition reactions with cinchona alkaloidsbearing a free hydroxyl group.Metal-centred chiral lewis acids have dominated the field of enantioselective catalysis. Lewis acids, such as AlCl3 and TiCl4 accelerate Diels Alder reactions dramatically for example the DA reaction catalysed by AlCl3, with which the reaction take place in minutes. Without the lewis acid it would take several daysHydrogen bond catalysis has had little use in chemical synthesis- most reactions are promoted by complexes of Lewis acidic metal salts coordinated to chiral ligands. It was widely believed that H-bonding was insufficiently activating or directional enough to be of use in asymmetric catalysisThe concept of H-bond catalysis is not new. Diels alder reactions were found to be accelerated in protic additives such as carboxylic acids and phenols. The potential of H-bond catalysis was finally realised in the 1980’s when because of Wynberg reported conjugate addition of reactions catalysed by an alkaloid. This was followed by Jacobsen who reported the first H-bonding catalyst to mediate hydrocyanation of aldehydes.The ability of well-defined achiral hydrogen bond donors to catalyze useful organic transformations was discovered in pioneering studies beginning in the 1980sDiel Alder reaction accelerated by addition of AlCl3Rate acceleration with protic additives.Hiemstra H.; Wynberg H., J. Am. Chem. Soc. 1981, 103,
3 Jacobsen reported asymmetric hydrocyanation of aliphatic and aromatic aldehydes Jacobsen’s first generation catalysisSigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901
4 Lewis acid catalysis H-bond catalysis Highly tunable Can vary counter ion, chiral ligandLewis base/acid interactions are strongerInteractions are more directionalH-bond catalysisModerately tunableActive catalystPotentially recoverableLewis acid catalysts do have many advantages the main one being the ability to tunability i.e. You can design the catalyst-e.g. By varying the lewis acidic element itself, the counter ion or the chiral ligands that are used enabling you to fine tune the electronics and sterics of the catalyst.Another factor is that Lewis base/acid interactions are much stronger and more directional than H-bonds .EXPLAIN ADVANTAGES OF H-DONDING!!
5 What is a hydrogen bond?“An XH···A interaction is called a ,hydrogen bond', if 1. it constitutes a local bond, and 2. XH acts as a proton donor to A.”Steiner, Angew. Chem. Int. Ed. 2002, 41, 48Role of H-bonds:DNA base pairingLigand/receptor bindingStrength can vary from 0.4 to 40 kcalmol-1.H-bonding plays an important role in many biological processes e.g DNA base paring and with enzymes catalysed processes.H-BONDING plays a key role in electrophile activation. In catalysis H-bonding to an electrophile serves to decrease the electron density of this species thus, activating it toward nucleophilic attack.The bond strength can vary…A bond angle of 180 is preferred for strong H-bonds but with moderate to weak H-bonds this is slighlty relaxed, but in H-bond catalysis this is of moderate strength.G.A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford University Press, New York, 1997Most Hydrogen bonding in H-bond catalysis is of moderate strength
6 Specific acid catalysis General acid catalysis Brønsted acids can accelerate organic reactions by either of two fundamental mechanisms:Specific acid catalysisGeneral acid catalysisprotonation of the electrophile in a prior to nucleophilic attackproton transfer to the transition state in the rate-determining stepSpecific acids catalysis is reversible and occurs in a pre-equilibrium stepGeneral acid catalysis involves proton transfer to the transition state in the RDS.
7 Modes of bonding Double H-bond donors Increased strength and directionalitye.g. Ureas, thioureas, Guanidinium and Amidinium ionsThere are three modes of H bondingFirstly double H-bonding….X = O, S
8 Single H-bond donors Less strength than double H-bond donors Less directionalitye.g. Diols, biphenols, chiral phosphoric acidsH-bonds are already of moderate strength and directionality-this makes it a challenge to create a rigid....-but a number of catalysts have used additional noncovalent interactions and high ee’s can be obtained using these catalysts.
9 Bifunctional catalysis a single or dual H-bond donor site flanked by sites for secondary interaction with substrates.e.g. Proline and proline analogs, cinchona alkaloids and derivativesLastly-Bifunctional species incorporate H-bond donors in addition to other Brønsted basic, nucleophilic, or acidic functional groupssuch as aromatic, weakly basic or acidic, or strongly basic functionality
10 Ureas and Thioureas Double H-bond donors b R1 = Bn, R2 = H, R3 = OCH3, X= Sc R1 = Bn, R2 = H, R3 = OCOtBu, X = Od R1 = R2 = CH3, R3 = OCOtBu, X =Se R1 = Bn, R2 = CH3, R3 = tBu, X = SOriginally developed as ligands for lewis acidic metals.Most applicable class of chiral H-bond donorsCan promote addition of a range of nucleophilesImine activationThe most applicable class of double H-bond donor are ureas and thioureas and they have been applied to many asymmetric reaction. High enantioselectivity was observed in the absence of metals which was unanticipated. They can promote the addition of a wide range of nucleophiles ....Activation of imines by by forming a double H-bond between the acidic NH and the imine lone pair, thus activating the electrophile.
11 Aza Baylis-Hillman reaction Double H-bond donorsDiels Alder reactionWittkopp A.; Schreiner P. R., Chem. Eur. J. 2003, 9,Aza Baylis-Hillman reactionThe DA reaction was catalysed by catalyst eIt was found that Thioureas/ureas with electron withdrawing groups in the 3- and 5- positions experienced the greatest rate accelerations. The proposed explanation is that the EWG’s lower the pKa of the NH bonds thus increasing their acidity.diazabicyclo[2.2.2]octane (DABCO) acts as a nucleophilic activatorThe aza Baylis-Hillman reaction occurred in moderate yield with catalyst dBaylis-Hillman reaction: phosphine catalysed addition of electron deficient alkenes to aldehydese R1 = Bn, R2 = CH3, R3 = tBu, X = SRaheem, I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005, 347, 1701
12 Asymmetric Strecker reaction Double H-bond donorsAsymmetric Strecker reactionMost recently within the Jacobsen group: a scaleable catalytic asymmetric synthesis that provides an easier and safer route to enantiopure amino acids catalysed by thiourea g which enables a safer as well as easier synthetic route to amino acid (R)-tert-leucine which is the more expensive enanatiomer.Robust catalyst as it lacks sensitive functional groups and so can be used under aqueous or biphasic conditions.The Pictet spengler reaction catalysed by fthe catalyst (strecker reaction) can be reused without loss of either activity or enantioselectivity, and the catalyst can be immobilized on a polystyrene bead to facilitate Strecker product purification by simple filtration and solvent removal without impacting the enantioselectivity of the reaction.Scaleable catalytic synthesisImines derived from alky, aryl, heteroaryl aldehydesAqueous cyanide saltsRobust catalystAccess to the (R)-enantiomer of tert-leucineZuend S.J.; Coughlin M. P.; Lalonde M. P.; Jacobsen E. N., Nature, 2009, 461, 968
13 Asymmetric Pictet Spengler reaction Double H-bond donorsAsymmetric Pictet Spengler reactionIs the cyclization of electron-rich aryl or heteroaryl groups onto N-acyliminium ionsThis particular catalyst was used in the total synthesis of the indole alkaloid (+)-yohimbineThe Jacobsen group proposed that the thiourea catalyst binds tothe chloride counteranion of the charged electrophileTaylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558
14 Bifunctional Thiourea derivatives 1,4- additionsTakemoto catalystT. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, – 12673So called because they have an additional acidic or basic functionality.Bifunctional thiourea catalysts have been used for 3 fundamental reasons: 1,2 addition, 1,4 addition and acyl transferMichael addition reactionsHenry reaction is the nitro equivalent of the aldol reaction-it froms C-C bond between nitroalkanes and aldehyde/ketones.The catalyst serves to activate both nucleophile, by general base catalysis, and electrophile, by H-bonding to the nitro groupB.-J. Li, L. Jiang, M. Liu, Y.-C. Chen, L.-S. Ding, Y. Wu, Synlett 2005, 4, 603Aza-henry reaction-(addition of nitroalkanes to imines )T. Okino, S. Nakamura, T. Furukawa, Y. Takemoto, Org. Lett. 2004, 6, 625
15 Other thiourea catalysts 1,2-additionsD. E. Fuerst, E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127, 8964Other thiourea catalystsefficient catalyst for Baylis-Hillman reactions
16 Guanidinium and Amidinium ions Double H-bond donorsGuanidinium and Amidinium ionsCapable of double H-bond interactionsAre positively charged so result in increased H-bond donor abiltity.Strecker reactionAnother class of double h-bond donors are G and A ions. The positively charged nature of these species results in an increased hydrogen-bond donor ability relative to neutral ureas and thioureas but may result in non-productive binding to counterions.T. Steiner, Angew. Chem. 2002, 114, 50; Angew. Chem. Int. Ed. 2002, 41, 48 .
17 Amidinium catalysed reactions Double H-bond donorsAmidinium catalysed reactionsNitro-Mannich reactionDiels Alder reactionCatalyst j, derived from a bis-cinchona alkaloid ligand for osmium-catalyzed dihydroxylations, contains a protonated quinuclidine moiety for H-bond activation of the imine substrate.But with this positive charge comes the possibility of non-productive binding with the counteranion.With catalyst k there is a rate acceleration for the DA reactionmechanistic proposal involves the generation of a guanidiniumcyanide species from 7 and hydrogen cyanide, followedby H-bond-accelerated attack of the cyanide ion on the imine electrophile, with p-stacking interactions between substrate and catalyst playing a key rolePresence of non-coordinating counter ions such as BArF4- have resulted in high catalyst activity.kAr = 3,5-(CF3)2C6H3Schuster T.; Bauch M.; Durner G.; Gmbel M. W.; Org. Lett. 2000, 2, 179 – 181.
18 Diols and Biphenols Single H-bond donors Hetero Diels Alder reaction catalysed by chiral diolsHuang Y.; Unni, A. K.; Thadani, A. N.; Rawal V.H., Nature, 2003, 424, 146These catalysts were investigated after it was discovered that hetero DA reactions are accelerated by H-donor solvents such as 2-butanol and chloroform.Must mention TADDOL derivatives have been used to catalyse etcBaylis-Hillman reaction -Binol derivatives
19 Chiral phosphoric acids Single H-bond donorsChiral phosphoric acidsMannich reactionBifunctional Activation of imines by phosphoric acids also forms the basis for aza-Friedel–Craftsthe presence of aryl substituents at the 3- and 3’- positions of the catalyst framework was crucial for highEnantioselectivity-it suggests that aryl groups play an important role in orienting the bound substrate through p–p interactions.T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. 2004, 116, 1592 – 1594Angew. Chem. Int. Ed. 2004, 43, 1566 –1568D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356 – 5357
20 Reductive amination Hantzsch ester acts as a hydrogen source HEH = ethyl Hantzsch esterR. I. Storer, D. E. Carrera, Y. Ni, D. W. C. Macmillan, J. Am. Chem. Soc. 2006, 128, 84
21 Proline catalysed reactions Bifunctional catalysisProline catalysed reactionsenatioselective aldol cyclizationsZ. G. Hajos, D. R. Parrish, (Hoffman-La-Roche),German Patent DE , 1971 [Chem. Abstr. 1972, 76, 59072];A very general catalyst as it can be used to generate of carbon–carbon, carbon–nitrogen, carbon–oxygen, and carbon–halogen bonds a to ketone or aldehyde substrates.Its main advantage is that proline catalysed aldol cyclization can lead to natural products e.g. steroids/terpenoids) but a main disadvantage is its poor solubiltiy in organic solvents and poor reactivity. So there have been some recent development of proline/proline analoguesProline-catalyzed asymmetric aldol reactions exhibit first-order kinetic dependence upon catalyst concentration,and a linear relationship between the enantiomeric excess of catalyst and that of product is observed, indicating that the transition state incorporates a single proline moleculeH-bonding activation of the aldehyde electrophile may lower the activation barrier for aldol addition by as much as 17 kcalmol1
22 Proposed mechanism for proline catalysed transformations The secondary amine group of the catalyst undergoes a condensation reaction with the ketone substrate, resulting in the formation of a nucleophilic enamine intermediate. H-bonding to the carboxylic acid group serves to activate the electrophile towards attack by the enamine. The high enantioselectivity observed for reactions of a wide range of electrophile and nucleophile partners may be attributed to the highly ordered nature of this transition state assembly.Both the secondary amine and the carboxylic acid functional groups are crucial for high yield and selectivity.A. G. Doyle, E. N. Jacobsen, Chem. Rev., 2007,
23 Proline analogues u higher yields and selectivity compared to proline To aid with solubilty and reactivity a number of proline analogues have been developed. For example proline analogue b with an ammonium functional which likely assumes the role of the carboxylic acid as the H-bond donorProline analogs such as tetrazoles have been shown to outperform proline in terms of yield, reaction time, enantioselectivity, catalyst loadings, substrate scope. Whatsmore Tetrazole also imparts increased solubility in organic solvents and are pharmacores for carboxylic acids.x increased solubilityTetrazole is a pharmacore for carboxylic acid
24 Cinchona alkaloids Bifunctional catalysis Enatioselective conjugate additionsBaylis-Hillman reactionCinchona alkaloids and their derivatives have been used widely as chiral resolving agents and ligands for organocatalysis and transition metal catalysis.The quinuclidine N is very basic nucleophilic and acts as a lewis baseThese alkaloids have an acidic hydroxy group and it is those that experience significantly rate increase and enantioselectivity of conjugate addition. The catalyst activates the nuc by general base catalysis and the enone by H-bonding.Nakano A. et . al , 62, 381Iwabuchi Y. et. al. J. Am. Chem. Soc. 1999, 121, 10219Connon S.J., Chem. Comm., 2008, 2499
25 Oligiopeptides Bifunctional catalysis Cyclo(l-phenylalanine-l-histidine) hydrocyanation of aldehydesHigh ee’s using electron rich benaldehydes substratesSome uncertainity about the mechanism remains: Activation of the aldehyde electrophile by a H-bond, donated either from the secondary amide group or a protonated histidine moiety, has been proposedUncertainty concerning mechanismS. Inoue, J.-I. Oku, J. Chem. Soc. Chem. Commun. 1981, 229 –230
26 SummaryA dynamic and large area of research which is continuing to be exploredApplicable to a wide number of transformations