Asymmetric copper-catalyzed alkylations and autocatalysis Pellegrini, Tilde
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Chapter 1
Introduction
Herein, asymmetric catalysis is introduced. After a general explanation of the asymmetric syntheses, metal-catalysis and organocatalysis are explained and examples are given. This introduction touches the topics of kinetic resolution and dynamic kinetic resolution to obtain enantioenriched compounds. Finally, we describe asymmetric amplification as a peculiar case of asymmetric catalysis.
4
1.1. Catalysis in asymmetric syntheses
Symmetry is beauty. Symmetric faces result more attractive to people than asymmetric ones.[1] However, synthetic organic chemists are rather attracted to asymmetry in
molecules. In fact, nature is an efficient asymmetric selector and homochiral molecules, for example, amino acids and sugars, compose living beings. Consequently, biological systems will interact differently with the two enantiomers and numerous pharmacological substances require to be composed by a single enantiomer to be administered to patients.[2]
Separations of enantiomers from racemic mixtures are commonly used, but their efficiency is limited by the fact than only half of the product can be utilized.[3–5] For this
reason, copious methods have been developed to obtain enantiopure compounds. The synthesis with chiral auxiliaries affords enantioenriched products, nevertheless it requires stoichiometric amount of chiral reagents that are often expensive and require to be separated from the product.[6] Due to the convenience of using chiral auxiliaries
in substoichiometric amount, enantioselective catalysis was widely developed during last century.[7,8]
1.2. Asymmetric metallic catalysis
Up to date, metallic catalysts are broadly used, both in laboratories and industrial processes.[9] In fact, these transformations usually require low catalyst loadings (less
than 10 mol%) and are easily tunable thanks to the possibility to vary the metal and to modify the ligand, carrier of the chiral information.[10,11]
In 2001, the Nobel Prize for chemistry was awarded to Knowles and Noyori (hydrogenations) and Sharpless (oxidations) for their contribution in asymmetric catalysis. The group of Knowles developed a convenient synthesis of (L)-DOPA, an amino acid employed in Parkinson Disease’s treatment via the enantioselective hydrogenation of 1 with a Rh/chiral phosphine complex (Scheme 1a).[12,13] Noyori et al. extended the scope of this reaction by using an atropoisomeric phosphine ligand
for the rhodium (BINAP, L2, Scheme 1b).[14,15] On the other hand, asymmetric
oxidations were established by Sharpless and coworkes: among others, the epoxidation of allylic alcohol by organic peroxides could be performed with Ti(Oi-Pr)4 and diethyl
tartrate (L3) as chiral additive. The use of the natural enantiomer (L)-L3 would have allowed the oxidation of the double bond from the enantiotopic face below (as drawn in Scheme 1c), independently from the substitution pattern.[16,17]
Introduction
5
Scheme 1 Asymmetric reductions and oxidations.
1.3. Asymmetric organocatalysis
Asymmetric metal-catalysis has enabled the creation of stereocenters in many different ways. However, some metals are expensive, air sensitive and/or toxic. Inspired by enzymatic catalysis, organocatalysts are small organic molecules that can catalyze organic transformations via H-bonding and ionic interactions (Non-covalent catalysis) or formation of covalent bonds, like NHC carbenes[18] or amines[19] (covalent catalysis).
These catalysts are generally inexpensive as they come from the chiral pool, but often require higher catalytic loadings.
The term organocatalysis was introduced by McMillan in 2000[20], however, the first
example dates back to 1912, when Bredig and Fiske reported that chichona alkaloids catalyze the addition of HCN to aldehydes with poor ees.[21] In 1960, O-Acetyl quinine
was used by Pracejus as an efficient catalyst for the addition of methanol to ketenes with 74% optical yield at -110°C (Scheme 2a). Interestingly, above -40°C, the reaction afforded the opposite enantiomer of the product.[22] Among the natural amino acids,
6
formation of imines or enamines[19] after the pioneering work of Wiechert et al.
concerning proline catalyzed intramolecular aldol reactions (Scheme 2b)[23].
Occasionally, asymmetric organocatalysis is combined with metal-catalysis to enable reactions that inactive organocatalyst would not be able to catalyze alone.[24]
Scheme 2 Asymmetric organocatalytic transformations.
1.4. Catalytic (dynamic) kinetic resolution
Another powerful method to obtain enantiopure compounds using chiral catalysts is through resolution of racemic mixtures, widely used in industrial processes. We refer with the term kinetic resolution to an asymmetric reaction where the conversion of the two enantiomeric substrates to products occurs with different rates (Scheme 3).[25] In
this way, after the reaction, one enantiomer is fully converted into the enantiopure product, while the other will be left as enantiopure substrate. Similar to other resolution methods, the upper yield limit for the kinetic resolution of a racemate is 50%. The enantioselectivity will instead depend on the ratio between the kinetic constants of the two asymmetric processes (s = krel = kfast/ kslow).[26]
Introduction
7 An example is the acylation of benzylic alcohols. (R,R)-Methyl-DUPHOS (17) promotes the selective benzoylation of (R)-14 and (R)-15 is obtained in 81% ee at 25% conversion while the unreacted (S)-14 is recovered with 28% ee at 81% conversion (Scheme 4).[27]
Scheme 4 Kinetic resolution of benzylic alcohol via acylation.[27]
However, if the two enantiomers can interconvert, the product of the resolution can be collected as a single enantiomer with yields higher than 50%. This process is termed
dynamic kinetic resolution (Scheme 5).[28]
Scheme 5 General scheme for dynamic kinetic resolution.[28]
For instance, chiral substituted acetyl acetates (18) can racemize via keto-enol tautomery. In the asymmetric hydrogenantion with Nickel Raney and tartaric acid, the reduction of the (S)-enantiomer is favored and the equilibrium between (S)-18 and (R)-18 is consequently shifted in this direction (Scheme 6).[29]
8
Scheme 6 Dynamic kinetic resolution in the hydrogenation of acetyl acetates.[29]
1.5. Non-linear effects in asymmetric catalysis
In asymmetric catalysis, the ee of the product (eeprod) is linearly correlated to the one
of the chiral auxiliary or catalyst (eeaux) by a constant that corresponds to the maximum ee that can be achieved with an enantiopure catalyst/auxiliary (eemax) (Equation 1;
Curve A, Plot 1 Source: review of Kagan and Girard[30]). However, there are cases
where the proportionality between the ee’s of the product and the auxiliary is lost, and we refer to that as non-linear effects (NLE). If the deviation from linearity is positive ((+)-NLE), the curve will resemble Curve B, Plot 1 while negative deviation ((-)-NLE) will generate a curve similar to Curve C, Plot 1.
Equation 1: eeprod= eemax*eeaux
Plot 1 Dependence of the eeprod on the eeaux. A) standard enantioselective reaction; B) (+)-NLE; C)
(-)-NLE. Source: Review of Kagan and Girard.[30]
Kagan and coworkers rationalized the non-linearity of enantioselectivity by different models that involve the formation of diastereomeric complexes or aggregates.[31]
Concerning metallic catalysis, the models are abbreviated with MLn or (ML)n where n
is the number of ligands or complexes that composes the species involved in the catalysis. The most recurring (and also the simplest) is the model ML2 or (ML)2. Other
Introduction
9 models will not be treated in detail in this thesis, but an extensive explanation can be found in a fascinating review of Kagan and Girard.[30]
The model ML
2or (ML)
2This model concerns the formation of dimeric complexes and is illustrated in Scheme
7 (Source: H. B. Kagan and T.O. Luukas, Chapter 4, Comprehensive Asymmetric
Catalysis I.[7]). Metal complexes containing two ligands that can have R or S
configuration (LR and LS) can be either homochiral (MLRLR and MLSLS) or heterochiral
(MLRLS). Each of the homochiral complexes catalyzes the reaction enantioselectively
with kinetic constant kRR = kSS, affording the product with a given eemax. MLRLS instead,
catalyzes a racemic reaction with kRS. The final relative concentration of the catalyst
are x, y and z and K is the equilibrium constant between homo- and heterochiral complexes, while β is the relative amount of heterochiral catalyst compared to the homochiral one.
Scheme 7 General scheme for the model ML2. Source: H. B. Kagan and T.O. Luukas, Chapter 4,
Comprehensive Asymmetric Catalysis I.[7]
The enantiomeric excess of the product can be expressed as function of the concentration of the catalytic species and of their kinetic constants in Equation 2.
Equation 2: eeprod= eemax*eeaux* 1+𝛽 1+𝑔𝛽
Non-linearity of asymmetric catalysis can be achieved when the following conditions are satisfied:
The rate of formation of the racemic product is slower than the one of the enantioenriched one (g ≤ 1)
The formation of the heterochiral complex is thermodynamically favored (K>>1). In fact, if the racemic complex is not formed (z=0), the value of β is null, and the correlation between ee of the product and the one of auxiliary is linear. In this case, the racemic portion of the catalyst is blocked via the formation of catalytically inactive species. On the other hand, the excess of one of the enantiomers of the chiral auxiliary catalyzes the enantioselective reaction. We can say that, in the model ML2, ligands behave like hands (that are the comparison par excellence for
10
The positive deviation from linearity in asymmetric catalysis is also referred to as
asymmetric amplification.
Scheme 8 Amplification of chirality in organometallic reactions.
Dimeric complexes (ML)2 can also cause non linearity of enantioselectivity according
to the same model by forming homo- (MLRMLR and MLSMLS) and heterodimers
(MLRMLS).[30] In the addition of dialkyl zinc to aldehydes with L4, reported by Noyori
et al., homochiral dimers easily dissociate to monomeric L4-ZnR, which can add
enantioselectively to aldehydes. Instead, the heterochiral dimers are stable inactive and, in this way, the chirality of the reaction is amplified (Scheme 8a).[32,33] Our group
reported a non-linearity effect in the asymmetric copper-catalyzed 1,2-addition of Grignard reagents to enones.[34] Homochiral dimers of CuBr·L5 complex are soluble
in MTBE[35] while heterochiral aggregates are not. For this reason, the racemic part of
the complex does not participate in the catalysis and asymmetric amplification is therefore achieved (Scheme 8b).
1.6. Thesis outline
Chirality, or rather chiral induction through asymmetric catalysis, constitutes the main thread of this thesis. Different cases of catalysis are discussed and the approach changes through the four Chapters.
Introduction
11 The first two Chapters address the enantioselective addition of Grignard reagents to symmetric diheteroaryl alkenes, reactive substrates towards the addition of organometallic reagents. Chapter 2 concerns the asymmetric conjugate addition of Grignard reagents to generic heteroaryl alkenes. The reactivity of this system and the consequent issues for enantioselectivity are discussed. Chapter 3 focuses on the addition of organomagnesium reagents to bispyridyl alkenes. The importance of pyridines is highlighted and the different behavior of substrates bearing 2-pyridyl or 4-pyridyl moieties is explained. A comparison between the ability of pyridine and benzoxazole to activate an alkene towards the conjugate addition is made.
The second part of the thesis concerns organic molecules that have a role in their own enantioselective synthesis. Chapter 4 regards autoinductive effects in the asymmetric 1,2-addition of Grignard reagents to enones. The product, an alkoxide, interacts with the copper/phosphine catalyst enabling a faster transmetallation that results in a better enantioselectivity. At the end, Chapter 5 describes the design or an organic asymmetric autocatalytic reaction inspired by Corey-Bakshi-Shibata reduction of ketones and imines with borane. The synthesis of the starting materials is reported and the prospects of asymmetric autocatalysis are discussed.
1.7. Bibliography
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