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Hydrogen-Bond Catalysis

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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-Roberts 03/02/10

2 A brief history… Lewis acids has dominated enantioselective catalysis
acceleration of Diels Alder reaction with AlCl3 Yates P.; Eaton P., J.Am. Chem. Soc. 1960, 82, 4436 Wynberg reported asymmetric conjugate addition reactions with cinchona alkaloids bearing 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 days Hydrogen 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 catalysis The 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 1980s Diel Alder reaction accelerated by addition of AlCl3 Rate 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 catalysis Sigman, 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 ligand Lewis base/acid interactions are stronger Interactions are more directional H-bond catalysis Moderately tunable Active catalyst Potentially recoverable Lewis 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, 48 Role of H-bonds: DNA base pairing Ligand/receptor binding Strength 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, 1997 Most 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 catalysis General acid catalysis protonation of the electrophile in a prior to nucleophilic attack proton transfer to the transition state in the rate-determining step Specific acids catalysis is reversible and occurs in a pre-equilibrium step General acid catalysis involves proton transfer to the transition state in the RDS.

7 Modes of bonding Double H-bond donors
Increased strength and directionality e.g. Ureas, thioureas, Guanidinium and Amidinium ions There are three modes of H bonding Firstly double H-bonding…. X = O, S

8 Single H-bond donors Less strength than double H-bond donors
Less directionality e.g. Diols, biphenols, chiral phosphoric acids H-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 derivatives Lastly-Bifunctional species incorporate H-bond donors in addition to other Brønsted basic, nucleophilic, or acidic functional groups such 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= S c R1 = Bn, R2 = H, R3 = OCOtBu, X = O d R1 = R2 = CH3, R3 = OCOtBu, X =S e R1 = Bn, R2 = CH3, R3 = tBu, X = S Originally developed as ligands for lewis acidic metals. Most applicable class of chiral H-bond donors Can promote addition of a range of nucleophiles Imine activation The 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 donors Diels Alder reaction Wittkopp A.; Schreiner P. R., Chem. Eur. J. 2003, 9, Aza Baylis-Hillman reaction The DA reaction was catalysed by catalyst e It 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 activator The aza Baylis-Hillman reaction occurred in moderate yield with catalyst d Baylis-Hillman reaction: phosphine catalysed addition of electron deficient alkenes to aldehydes e R1 = Bn, R2 = CH3, R3 = tBu, X = S Raheem, I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005, 347, 1701

12 Asymmetric Strecker reaction
Double H-bond donors Asymmetric Strecker reaction Most 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 f the 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 synthesis Imines derived from alky, aryl, heteroaryl aldehydes Aqueous cyanide salts Robust catalyst Access to the (R)-enantiomer of tert-leucine Zuend S.J.; Coughlin M. P.; Lalonde M. P.; Jacobsen E. N., Nature, 2009, 461, 968

13 Asymmetric Pictet Spengler reaction
Double H-bond donors Asymmetric Pictet Spengler reaction Is the cyclization of electron-rich aryl or heteroaryl groups onto N-acyliminium ions This particular catalyst was used in the total synthesis of the indole alkaloid (+)-yohimbine The Jacobsen group proposed that the thiourea catalyst binds to the chloride counteranion of the charged electrophile Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558

14 Bifunctional Thiourea derivatives
1,4- additions Takemoto catalyst T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, – 12673 So 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 transfer Michael addition reactions Henry 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 group B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen, L.-S. Ding, Y. Wu, Synlett 2005, 4, 603 Aza-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-additions D. E. Fuerst, E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127, 8964 Other thiourea catalysts efficient catalyst for Baylis-Hillman reactions

16 Guanidinium and Amidinium ions
Double H-bond donors Guanidinium and Amidinium ions Capable of double H-bond interactions Are positively charged so result in increased H-bond donor abiltity. Strecker reaction Another 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 donors Amidinium catalysed reactions Nitro-Mannich reaction Diels Alder reaction Catalyst 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 reaction mechanistic proposal involves the generation of a guanidinium cyanide species from 7 and hydrogen cyanide, followed by H-bond-accelerated attack of the cyanide ion on the imine electrophile, with p-stacking interactions between substrate and catalyst playing a key role Presence of non-coordinating counter ions such as BArF4- have resulted in high catalyst activity. k Ar = 3,5-(CF3)2C6H3 Schuster 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 diols Huang Y.; Unni, A. K.; Thadani, A. N.; Rawal V.H., Nature, 2003, 424, 146 These 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 etc Baylis-Hillman reaction -Binol derivatives

19 Chiral phosphoric acids
Single H-bond donors Chiral phosphoric acids Mannich reaction Bifunctional Activation of imines by phosphoric acids also forms the basis for aza-Friedel–Crafts the presence of aryl substituents at the 3- and 3’- positions of the catalyst framework was crucial for high Enantioselectivity-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 – 1594 Angew. Chem. Int. Ed. 2004, 43, 1566 –1568 D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356 – 5357

20 Reductive amination Hantzsch ester acts as a hydrogen source
HEH = ethyl Hantzsch ester R. I. Storer, D. E. Carrera, Y. Ni, D. W. C. Macmillan, J. Am. Chem. Soc. 2006, 128, 84

21 Proline catalysed reactions
Bifunctional catalysis Proline catalysed reactions enatioselective aldol cyclizations Z. 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 analogues Proline-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 molecule H-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 donor Proline 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 solubility Tetrazole is a pharmacore for carboxylic acid

24 Cinchona alkaloids Bifunctional catalysis
Enatioselective conjugate additions Baylis-Hillman reaction Cinchona 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 base These 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, 381 Iwabuchi Y. et. al. J. Am. Chem. Soc. 1999, 121, 10219 Connon S.J., Chem. Comm., 2008, 2499

25 Oligiopeptides Bifunctional catalysis
Cyclo(l-phenylalanine-l-histidine) hydrocyanation of aldehydes High ee’s using electron rich benaldehydes substrates Some 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 proposed Uncertainty concerning mechanism S. Inoue, J.-I. Oku, J. Chem. Soc. Chem. Commun. 1981, 229 –230

26 Summary A dynamic and large area of research which is continuing to be explored Applicable to a wide number of transformations

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