Exploring asymmetric catalytic transformations Guduguntla, Sureshbabu
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The work described in this thesis was carried out at the Stratingh Institute for Chemistry, University of Groningen, The Netherlands.
This work was financially supported by the NWO-CW NSF astrochemistry program and the University of Groningen.
Printed by Ipskamp Printing BV, Enschede, The Netherlands.
Cover design by Joana Romão and Sureshbabu Guduguntla.
ISBN: 978-94-028-0529-1 (printed version) ISBN: 978-94-028-0531-4 (digital version)
Exploring Asymmetric
Catalytic Transformations
PhD thesis
to obtain the degree of PhD at the University of Groningen
on the authority of the Rector Magnificus Prof. E. Sterken
and in accordance with
the decision by the College of Deans.
This thesis will be defended in public on
Friday 10 March 2017 at 16.15 hours
by
Sureshbabu Guduguntla
born on 4 June 1988 in Kavalakuntla, India
Supervisor: Prof. B. L. Feringa Assessment Committee Prof. W. R. Browne Prof. S. R. Harutyunyan Prof. F. P. J. T. Rutjes
1.2 Asymmetric autocatalysis and autoinduction 6
1.2.1 Asymmetric autoinduction 6
1.2.2 Asymmetric autocatalysis 8
1.3 Cu-catalyzed asymmetric allylic substitution 11
1.4 Thesis outline 13
1.5 References 14
Chapter 2 Synthesis of optically active β- or γ-alkyl substituted alcohols through copper-catalyzed asymmetric allylic alkylation with organolithium
reagents 21
2.1 Introduction 22
2.2 Results and discussions 23
2.3 Conclusions 29
2.4 Experimental section 29
2.4.1 General procedures 29
2.4.2 General procedure for the one-pot synthesis of β-alkyl substituted alcohols through Cu-catalyzed asymmetric allylic alkylation of allyl bromides with organolithium reagents followed by reductive
ozonolysis 30
2.4.3 General procedure for the synthesis of γ-alkyl substituted alcohols through Cu-catalyzed asymmetric allylic alkylation of allyl bromides with organolithium reagents followed by a
hydroboration/oxidation 37
2.4.4 General procedure for the one-pot synthesis of α-alkyl substituted aldehydes through Cu-catalyzed asymmetric allylic alkylation of allyl bromides with organolithium reagents followed by ozonolysis 41 2.4.5 General procedure for the synthesis of β-alkyl substituted aldehydes through the oxidation of γ-alkyl substituted primary alcohols with
Dess- Martin periodinane 42
2.4.6 General procedure for the synthesis of benzoate ester of the alcohols
Chapter 3 Chiral Diarylmethanes via Copper-Catalyzed Asymmetric
Allylic Arylation with Organolithium Compounds 47
3.1 Introduction 48
3.2 Results and discussions 50
3.3 Conclusions 56
3.4 Experimental section 57
3.4.1 General procedure 57
3.4.2 Preparation of allyl bromides 58
3.4.3 Procedure for the synthesis of chiral imidazolium salts 59 3.4.4 General procedure for the preparation of ArLi using lithium metal 64 3.4.5 Genral procedure for the preparation of ArLi using n-BuLi 64 3.4.6 General procedure for the copper-catalyzed asymmetric allylic arylation with organolithium reagents 65 3.4.7 General procedure for the hydroboration-oxidation of the
corresponding alkenes 65
3.4.8 Characterization and analysis of the molecules 66
3.5 References 88
Chapter 4 Enantioselective synthesis of di- and tri- arylated all-carbon quaternary stereocenters via copper catalyzed allylic arylations with
organolithium compounds 91
4.1 Introduction 92
4.2 Results and discussions 94
4.3 Conclusions 99
4.4 Experimental section 100
4.4.1 General procedures 100
4.4.2 GC-MS conditions 101
4.4.3 General procedure for the synthesis of (E)-allyl bromides 102 4.4.4 Procedure for the synthesis of (+)-CuClL16 106
4.4.5 General procedure for the synthesis of copper-catalyzed asymmetric allylic arylation with organolithium reagents 107 4.4.6 General procedure for the hydroboration-oxidation of the
corresponding alkenes 108 4.4.7 Characterization and analysis of the molecules 108
5.1 Introduction 128 5.1.1 Enantioselective synthesis of α-hydroxy phosphonates: nucleophilic addition of dialkyl phosphites to carbonyl compounds 129
5.2 Goal 131
5.3 Results and discussions 132
5.4 Conclusions 141
5.5 Experimental section 141
5.5.1 General procedures 141
5.5.2 Synthesis of (S)-diisopropyl hydroxy(phenyl)methylphosphonate
(9) 142
5.5.3 Synthesis of (R)-dimethyl hydroxy(phenyl)methylphosphonate
(12) 144
5.5.4 General procedure for the synthesis of chiral (racemic) non-
symmetrical dialkyl phosphites 145 5.5.5 General procedure for the entries in Table 1 146
5.5.6 General procedure for the entries 3, 4, 6, 7, 10, 11 and 12 in Table
2 147
5.5.7 General procedure for the entries 1, 2, 5, 8, 9 and 13 in Table
2 147
5.5.8 General procedure: Nucleophilic addition of diisopropyl phosphite 8 to benzaldehyde 7 in the presence of chiral Mg-alkoxide 13 148 5.5.9 General procedure: Nucleophilic addition of diisopropyl phosphite 8 to benzaldehyde 7 in the presence of chiral Li-alkoxide 14 148
5.5.10 General procedure: Nucleophilic addition of diisopropyl phosphite 8 to benzaldehyde 7 in the presence of chiral Al-alkoxide 15 149 5.5.11 General procedure: Nucleophilic addition of ethylmethyl phosphite 24 to benzaldehyde 7 in the presence of chiral Li-alkoxide 28 150
6.1 Introduction 158 6.1.1 Titanium-promoted catalytic enantioselective addition of Grignard
reagents to aldehydes 158
6.1.2 Asymmetric reduction of ketones using CBS-oxazaborolidine 162
6.2 Design 164
6.3 Results and discussion 165
6.4 Conclusions 172
6.5 Experimental section 173
6.5.1 General procedures 173
6.5.2 Synthesis of racemic 1-(hydroxy(phenyl)methyl)naphthalen-2-ol
(14) 174
6.5.3 Synthesis of (S)-1-(hydroxy(phenyl)methyl)naphthalen-2-ol (14) 175 6.5.4 Synthesis of 2-methoxy-1-naphthaldehyde (20) 178 6.5.5 Synthesis of (S)-(2-Methoxynaphthalen-1-yl)(phenyl)methanol
(21) 179
6.5.6 General procedure: nucleophilic addition of PhMgBr to aldehydes in the presence of a chiral ligand 180 6.5.7 Nucleophilic addition of PhMgBr to 2-hydroxy-1-naphthaldehyde 7 in the presence of (S)-14 with 92% ee 181 6.5.8 Nucleophilic addition of PhMgBr to 2-methoxy-1-naphthaldehyde 20 in the presence of (S)-21 with 94% ee (Table 1) 181 6.5.9 Nucleophilic addition of PhMgBr to 2-methoxy-1-naphthaldehyde 20 in the presence of (S)-BINOL 181 6.5.10 Asymmetric reduction of (2-hydroxynaphthalen-1-
yl)(phenyl)methanone 16 in the presence (S)-14 with 10% ee 182 6.5.11 Reduction of ketone 16 with borane 182
6.6 References 183
Chapter 7 Efforts towards the development of new asymmetric
autocatalytic reactions: H-bond donor approach 187
7.1 Introduction 188
7.1.1 Bifunctional urea or thiourea catalyzed Mannich reaction 188 7.1.2 Bifunctional urea or thiourea catalyzed Kabachnik–Fields (phospha-
7.5 Experimental section 200
7.5.1 General procedures 200
7.5.2 Synthesis of imine (16) 201
7.5.3 Synthesis of 4-(N,N-dimethylamino)picolinaldehyde (26) 204 7.5.4 Synthesis of 2-((N,N-dimethylamino)methyl)benzaldehyde (27) 204 7.5.5 General procedure for the Mannich reaction 205 7.5.6 General procedure for the three component (Kabachnik–Fields)
reaction 205
7.6 References 206
Samenvatting 211
Summary 217
The word chirality is derived from the Greek word for hand, χείρ (kheir). When a mirror image of an object or a system is not superimposable on its original it is called chiral. A chiral object and its mirror image are called enantiomorphs (Greek opposite forms) or, when referring to molecules, enantiomers. Enantiomers are also called optical isomers, which is due to their ability to rotate the plan of polarised light. In 1815,1 Jean-Baptiste Biot observed the rotation of plain polarised light in certain liquids and vapours of organic substances such as turpentine. Depending on which direction a chiral molecule rotate the plain polarised light, it is designated as d (clockwise; dextrorotatory) or l (anti-clockwise; levorotatory). In 1849,2,3 Louis Pasteur performed a famous experiment on the resolution of tartaric acids. He sorted the crystals by hand which gave two forms of the compound: solutions of one form rotate polarized light clockwise, while the other form rotates light anti-clockwise. In 1874,4 Jacobus Henricus van't Hoff and Joseph Achille Le Bel5 independently proposed that this phenomenon of optical activity in carbon compounds is due to the three-dimensional geometry of carbon- based compound when a carbon atom is connected with four different groups in a tetrahedral structure. This theory leads to another notation of chiral molecules based on the Cahn-Ingold-Prelog rules. By using these rules the absolute configuration of a molecule is assigned either R or S (Figure 1).6
Figure 1: (S)-(+)-Lactic acid (left) and (R)-(–)-lactic acid (right) are
non-superimposable mirror images of each other.
One of the most fundamental aspect of all the living organisms is self-replication. Self-replication arises from biologically active molecules like DNA and RNA, which have the ability to self-organize and interact dynamically in complex molecular networks. Therefore, considerable experimental efforts have been reported in attempts to elucidate how life began by mimicking prebiotic systems.7,8,9,10,11,12 Several mechanisms
In addition to self-replication, the essential biological molecules possess homochirality, which is also another key aspect of life on the Earth. Sugars such as deoxyribose and ribose are present in the most important biologically active molecules like DNA and RNA, which transfer the genetic information in living organisms, are right-handed. Amino acids that form the proteins that are essential for the structure and chemical transformations in cells are left-handed. The origin of homochirality in biomolecules is still one of the great current mysteries which is directly associated with the ˋorigin of lifeˊ question.14 There are several hypotheses reported in an attempt to explain possible prebiotic chemical pathways towards the asymmetric formation of the smallest chiral biomolecules.15 From a chemical point of view, molecular self-replication processes function via autocatalytic, cross catalytic or collectively catalytic pathways with an additional information transfer (templating) from the product to the reactants (Scheme 1).7-13,15 It was suggested that, in the earliest stages of life, a small enantiomeric excess might be amplified via auto- or cross- catalytic processes.15
Scheme1: a) Autocatalytic reaction, b) Cross catalytic reaction.
Up to now the asymmetric autocatalytic reaction reported by the group of Soai16 is the only reliable example known and its mechanistic aspects are still not fully understood.17 Therefore it would be a real challenge to find other reactions which show asymmetric autocatalytic behaviour.18
1.1 Design of a self-replicating system
In a self-replicating system, a molecule C acts as a template for the starting materials A and B that are bound by noncovalent interactions to
4
form a termolecular complex [A.C.B]. This complex allows components
A and B to organize in such a way that they can react to form a copy of
the original template molecule C. In this way an autocatalytic synthesis is accomplished (Scheme 2).
Scheme 2: General representation of a self-replicating system.
In 1986, von Kiedrowski19 reported the first non-enzymatic self-replicating system based on the formation of a hexa eoxynucleotide from two trideoxynucleotides. This system was designed based on the oligonucleotide (template) synthesis from monomers; reported by Orgel
et al.20 Studies21 on the von Kiedrowski system reveals that the highest efficiency based on a template mechanism was observed when the trimers and hexamer are completely complimentary to each other. Orgel
et al.22 reported a similar system by taking advantage of phosphoramidate backbone formation for the synthesis of a tetranucleotide template from dinucleotides. These early reported self-replicating systems suffered from low efficiency due to a strong binding between the product dimer, resulting in catalyst inhibition.23 By using the concept of phosphoramidate formation von Kiedrowski et al.24 reported a modified system (Scheme 3). In the presence of EDC, the trideoxynucleotide 3'-phosphate 1 reacts with the 5'-amino trideoxynucleotide 2 to give the hexameric 3'-5'-phosphoramidate 3. Compound 3 acts as a self-complementary unit for its own formation through a trimeric complex 4. This complex 4 allows components 1 and 2 to form a network of H-bonding with 3 and to organize in such a way that they can react to form a copy of the original template molecule 3. In this way an autocatalytic
Scheme 3: von Kiedrowski system using phosphoramidate chemistry.24
Achieving complete exponential replication in oligonucleotide based self-replicating systems has proven to be difficult.25 Exponential growth has been gained by attaching the oligonucleotides to a solid surface and
6
subsequently manually melting and annealing the strands, thereby avoiding product inhibition.26 There are many types of autocatalytic self-replicating systems based on peptides, small molecules etc. which are well reviewed by Bissette and Fletcher.11
It is worth to mention that in all of these synthetic self-replicating systems developed so far, homochirality has been predefined with the precursors employed being homochiral, i.e. no asymmetric centre is formed during the reaction. It was specified earlier that, biologically important molecules such as amino acids and sugars are homochiral in nature. So it is very important in this context to elucidate the origin of homochirality on earth.
1.2 Asymmetric autocatalysis and autoinduction.
For the first time the term asymmetric autocatalysis was introduced by Wynberg, who very early acknowledged the great potential of a system where the chiral product affects the stereoselectivity of that reaction.27 In 1989, Wynberg hypothesized that asymmetric autocatalysis would represent the next generation in asymmetric catalysis.27,28
1.2.1 Asymmetric autoinduction
In a chemical process where a chiral product that does not possess catalytic activity participates in the formation of a chiral complex with the enantioselective catalyst to effect the stereochemical outcome is called asymmetric autoinduction (Scheme 4).27,29
Scheme 4: Asymmetric autoinduction.
In asymmetric autoinduction, the product of the reaction modifies the course of the reaction by changing the nature of the reagent or the
Wynberg et al.27,28 reported the first example of asymmetric autoinduction, in the nucleophilic addition of ethyllithium to benzaldehyde (Scheme 5). The addition of stoichiometric enantioenriched product of the reaction (6, deuterated to distinguish it from the alcohol product) was found to influence the enantioselectivity of the reaction. The ee of the product 6 was found to be 17% in favour of the isomer with the same absolute configuration as that of added (Scheme 5).27,28
Scheme 5: Proof of asymmetric autoinduction in nucleophilic addition of EtLi to
benzaldehyde using stoichiometric amount of product.
However, the same effect was also demonstrated in a catalytic process (Scheme 6).27 The addition of diethylzinc to benzaldehyde is not a spontaneous reaction, but can be catalyzed by orthotitanates. When such a catalyst was prepared from TiCl4 and 6-d1, and used in the addition of diethylzinc to benzaldehyde, the product was produced in 32% ee again with the same absolute configuration as for the Ti ligands. There are many other reactions which shows asymmetric autoinduction, which have been reviewed by Todd.30
Scheme 6: Asymmetric autoinduction in the addition of Et2Zn to benzaldehyde using
1.2.2 Asymmetric autocatalysis
Biologically important molecules such as L-amino acids and D-sugars are the main carriers of homochirality in living organisms.31 One of the widely accepted hypothesis for the origin of homochirality is astrochemically relevant and based on the fact that only an excess of left-handed L-amino acids have been found in carbonaceous meteorites.32 Preferential excess of L-amino acid found in carbonaceous meteorites may indicate that the origin of life on the earth has an extraterrestrial input. But to get homochirality in life there would need to be some mechanism of transferring the single-handedness between different types of amino acids. An important question is how this initial preference was further amplified.
It has also been suggested that a weak electronic forces based on the principle of parity violation could be responsible for the symmetry breaking.33 However, it has often been argued that this force is too small to be effective.34 Another source of symmetry breaking is circular polarized light (CPL). CPL is capable of activating one enantiomer more than the other resulting in faster deterioration of this enantiomer, resulting in a small enantiomeric excess. In the universe large areas exist where CPL is present.35 This might be the origin of a small enantiomeric excess in organic compounds present on meteorites.36
Although these described processes of initial symmetry breaking lead to a small enantiomeric excess in a specific area, this is however not likely to be sufficient to induce homochirality in all living systems. Therefore these small initial enantiomeric excesses need to be amplified. One of the earliest hypothesis is that asymmetric autocatalysis11,16,37 (Scheme 1a) played an important role in the amplification of chirality. A reaction is classified as an autocatalytic reaction if the product acts as a catalyst for its own formation (Scheme 1a). If the product of an autocatalytic reaction is chiral and a selective catalyst, meaning that one enantiomer of the product catalyzes for its own production, an asymmetric autocatalytic reaction is obtained.
solution to catalyze the hydrolysis, providing an autocatalytic reaction.38 Additionally there have been a wide range of autocatalytic reactions to amplify an initially small signal.39 In general it was assumed that (asymmetric) autocatalytic reactions have played an important role in the origin of life. Autocatalysis provides a tool to obtain relevant compounds in sufficient amounts. Furthermore an autocatalytic reaction can be viewed as one of the simplest chemical metabolic cycles. Additionally as mentioned above, the asymmetric variant provides a tool to amplify not only the relevant compounds but also its chirality.
In 1953 Frank et al.37a proposed a theoretical model to understand the concept of amplification of chirality by means of asymmetric autocatalysis. According to his model, in order to achieve asymmetric amplification, the process of self-replication of a catalyst must be accompanied by the suppression of the activity of its enantiomer, referred to by Frank as mutual antagonism (Figure 2).37a
Figure 2: Schematic representation of Frank’s model.
R and S are the enantiomers which can act as autocatalysts for their own formation, by reacting with molecules of substrate.40 Together with this autocatalytic process, there is a mutual antagonism between R and S such that, when they react together, they deactivate and lose their self-replicating property. As shown in Figure 2, the self-replication of the enantiomers cause a change in the R:S ratio, which grows as long as there was a small initial imbalance at the beginning of the process. The cooperation of the autocatalysis and mutual antagonism propagate and
10
amplify the imbalance of the enantiomers. If the substrate pool is large enough, the process can be sustained and the selectivity towards the self-production of one enantiomer will dominate.41
For the first time as a proof of concept, Soai et al.42 (Scheme 7) reported an asymmetric autocatalytic reaction in 1995, which involves the nucleophilic addition of diisopropyl zinc to pyrimidine-5-carbaldehyde. This process satisfied the principles for an asymmetric autocatalytic reaction as proposed by Frank et al.37a In this reaction, the starting mixture was seeded with product that contained as little as 0.00005% ee, which allowed, after several cycles, each time using the slightly more enriched product of the previous round as seed, for the product to be obtained in >99.5% ee (Scheme 7).43
Scheme 7: Soai reaction.
Subsequently Soai et al. have shown that besides an initial enantiomeric excess also other chiral factors such as sodium chlorate salts,44 helicenes,45 quartz crystals,46 CPL,47 single wall carbon nanotubes48 and even isotopes of hydrogen,49 carbon,50 oxygen,51 and nitrogen52 are capable of directing the chirality of the Soai reaction.53 Carreira et al.54 demonstrated the versatility of the Soai reaction in synthetic chemistry, to produce the drug Efivarenze. By using an autocatalytic reaction, the transformation is not only catalyzed but because the catalyst is also the product the purification of the product becomes more efficient.
There are several attempts reported to understand the mechanism of Soai reaction but so far there is no clear explanation.55 Initially it was hypothesized that the Soai reaction operates with very high selectivity due to the formation of homochiral and heterochiral dimers. It was suggested that the homochiral dimers are capable of catalyzing the
proving that the dimer formation does not sufficiently explain the selectivity.55e Additional kinetic and 1H-NMR experiments suggested the formation of a tetrameric complex 9. During the enantioselective reaction, the association of this complex with the aldehyde forms a trimeric complex 10 (Scheme 8b).55f-i
Scheme 8: Proposed intermediates in Soai reaction.
Use of diisopropyl zinc makes the Soai reaction highly reactive towards water and therefore not very likely to have occurred under prebiotic conditions. Moreover the Soai reaction is in itself very interesting, but this transformation did not lead to any biological relevant molecules. Therefore, it remains very challenging and highly important to develop an autocatalytic reaction that can yield biologically relevant molecules, and to investigate if these reactions show enantioselectivity.
1.3 Cu-catalyzed asymmetric allylic substitution.
Transition metal catalyzed asymmetric transformation is a highly efficient tool for the construction of chiral molecules with control over
12
the absolute configuration, which is often a key factor determining the activity of pharmaceuticals.56 This strategy presents various advantages such as atom economy, reduction of by-product formation, functional group tolerance and the capability to provide the desired product with high levels of selectivity. Several transition metals have proven their efficiency in catalytic asymmetric processes.57 In particular, the use of copper provides cheaper and readily available catalyst systems while maintaining high activity and selectivity. Among the Cu-catalyzed enantioselective processes for asymmetric C-C bond formation, asymmetric allylic substitution (AAS) represents a useful and powerful methodology for the synthesis of chiral building blocks, in particular for the synthesis of pharmaceuticals and natural products.57,58 This transformation generally leads to the SN2′-functionalised product, through the reaction of a nucleophile and an allylic system, bearing a suitable leaving group, and provides a carbon-based stereocenter next to a terminal olefin (Scheme 9). This alkene moiety can be further converted into a variety of functionalities while preserving the stereochemical integrity of the starting material.59
Scheme 9: Cu-catalyzed AAS protocols.
Cu-catalyzed AAS represents a highly efficient catalytic process for the use of organometallic reagents, such as organozinc,60 organomagnesium,61 organoaluminium,62 organozirconium,63 organolithium64 compounds, etc.65,66,67 The AAS reactions, with these “hard” C-nucleophiles, are complementary to the well-known Pd-catalyzed asymmetric allylic substitutions which employs soft and stabilized nucleophiles.68 In Cu-catalyzed AAS, the organometallic
reductive elimination gives rise to the new C–C bond and the branched (SN2′) product (Scheme 10).69
Scheme 10: General mechanism for the Cu-catalyzed AAS reaction.
Detailed introduction about the various AAS reactions is discussed in Chapters 2, 3 and 4.
1.4 Thesis outline
In these thesis two main areas of research work has been described. The first half of the thesis involves Cu-catalyzed asymmetric allylic substitution reactions with organolithium reagents. The second half of the thesis describes efforts towards the development of new asymmetric autocatalytic reactions.
In Chapter 2, the synthesis of optically active β- or γ-alkyl substituted alcohols through copper-catalyzed asymmetric allylic alkylation with organolithium reagents are reported.
In Chapter 3, a route to chiral diarylmethanes via copper-catalyzed asymmetric allylic arylation with organolithium compounds is described.
In Chapter 4, the enantioselective synthesis of di- and tri-arylated all-carbon quaternary stereocenters via copper-catalyzed allylic arylations with organolithium compounds are presented.
In Chapter 5, efforts towards the development of a new asymmetric autocatalytic reaction based on nucleophilic addition of dialkyl phosphites to aldehydes are described. The goal was to take advantage of the aggregation behavior of metal alkoxides and to use them as catalysts to promote their own synthesis in a nucleophilic addition reaction.
In Chapter 6, efforts towards the development of a new asymmetric autocatalytic reaction based on a metal-ligand approach is discussed.
In Chapter 7, efforts towards the development of new asymmetric autocatalytic reactions based on H-bond donor approach and of an imine based autocatalysis using urea motifs, are discussed.
1.5 References
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Catal. 2010, 352, 2023. d) Fang, F.; Zhang, H.; Xie, F.; Yang, G.; Zhang, W. Tetrahedron 2010, 66, 3593. e) Magre, M.; Mazuela, J.; Diéguez, M.; Pàmies, O.;
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Tetrahedron 2010, 66, 676. c) Fañanás-Mastral, M.; Pérez, M.; Bos, P. H.;
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Reagents
An efficient one-pot synthesis of optically active β-alkyl-substituted alcohols through a tandem copper-catalyzed asymmetric allylic alkylation (AAA) with organolithium reagents and reductive ozonolysis is presented. Furthermore, hydroboration-oxidation following the Cu-catalyzed AAA leads to the corresponding homochiral γ-alkyl substituted alcohols.
This chapter is adapted from the original paper:
Guduguntla, S.; Fañanás-Mastral, M.; Feringa, B. L. J. Org. Chem. 2013,
2.1 Introduction
Chiral nonracemic alcohols (and derivatives) are very important building blocks in the synthesis of numerous biologically active compounds. In particular, optically active primary alcohols bearing alkyl substitution at
β- or γ-positions are key intermediates in the total synthesis of several
natural products including arundic acid,1 Lyrica,2 bongkrekic acids,3 gynnastatin A4 and vitamins E and K.5 There are a number of methods available for the synthesis of this type of alcohols based on chiral auxiliaries6 and enzyme-catalyzed kinetic resolution of racemic compounds.7 In 1995, Negishi reported a Zr-catalyzed asymmetric carboalumination of alkenes followed by a lipase catalyzed resolution method to access these building blocks in good yields with excellent enantiomeric excess.8 The development of alternative catalytic enantioselective protocols remains an important challenge in view of the potential of these highly versatile building blocks.
Cu-catalyzed AAA is among the most powerful enantioselective C-C bond-forming reactions.9 In sharp contrast with the well-known Pd-catalyzed asymmetric allylic alkylation reaction,10 which is characterized by the use of soft and stabilized nucleophiles, Cu-catalyzed asymmetric allylic alkylation is characterized by the formation of C–C bonds with organometallic reagents, resulting in a complementary method. The reaction usually proceeds with high SN2ꞌ selectivity and provides access to a carbon stereocenter next to a terminal olefin which can readily be further functionalized. Pioneered by Bäckvall and van Koten,11 Cu-catalyzed AAA has been widely studied and its synthetic utility has been shown in the total synthesis of several natural products and biologically active compounds.12 Recently, our group reported for the first time the use of highly reactive organolithium reagents in copper–catalyzed asymmetric allylic alkylation of allyl bromides with excellent regio- and enantioselectivity using Taniaphos as a chiral ligand.13 We also implemented this methodology for both allyl bromides and chlorides in the enantioselective synthesis of tertiary and quaternary stereocenters using phosphoramidite ligands.14
reaction. The direct use of organolithium reagents is also extended to the synthesis of γ-alkyl-substituted alcohols through Cu-catalyzed AAA of allyl bromides with RLi reagents followed by hydroboration-oxidation reactions (Scheme 1).15
Scheme1: Synthesis of optically active alcohols through copper-catalyzed asymmetric allylic alkylation with organolithium reagents
2.2 Results and Discussion
Our strategy is based on a tandem Cu-catalyzed AAA/reductive ozonolysis to achieve highly enantioenriched β-alkyl-substituted alkyl alcohols in a chemo-, regio- and enantioselective one-pot operation with no racemization. Using the well-established conditions for the Cu-catalyzed AAA with organolithium reagents,13,14 we optimized the conditions for the synthesis of highly enantioenriched β-alkyl-substituted alcohols in a one-pot protocol (Table 1). We started our study with commercially available cinnamyl bromide 1a. After Cu-catalyzed AAA of 1a,13 the reaction mixture was quenched with EtOH and purged with ozone for 20 min followed by purging with nitrogen. When 2.5 equiv of NaBH4 were added to reduce the ozonide, a mixture of desired alcohol 4a and aldehyde 5 was obtained in a 70:30 ratio (Table 1, entry 1). Doubling the amount of NaBH4 did not lead to full conversion towards the desired alcohol either (Table 1, entry 2), probably due to the formation of the
corresponding acetal in the reaction mixture which was hydrolyzed during the workup giving rise to aldehyde 5. In order to achieve full conversion to alcohol 4a, 10 equiv of NaBH4 and 10 equiv of water were used to hydrolyze the acetal in situ (Table 1, entry 3). Under these conditions, no aldehyde 5 was observed, and the desired alcohol 4a was obtained in good overall yield with very high enantioselectivity (see Table 2, entry 1).16
Table 1: Optimization conditions for the one-pot Cu-catalyzed asymmetric allylic alkylation followed by reductive ozonolysis
entry NaBH4 (x equiv) 4a : 5 (%)a
1 2.5 70:30
2 5 90:10
3b 10 >99:1
(a) The ratio was determined by 1H-NMR and GC–MS. (b) 10 equiv of water added to the reaction mixture. L1 = (+)-(R,Rp)-Taniaphos (see Table 2).
Having optimized conditions for the one-pot protocol for the synthesis of
β-alkyl-substituted alcohols, the scope of the reaction was examined. We
employed this tandem consecutive Cu-catalyzed AAA/reductive ozonolysis protocol with organolithium reagents such as MeLi, n-BuLi and n-HexLi on cinnamyl bromide 1a, achieving excellent enantioselectivities (98−99%) and good overall yields (60–85%) (Table 2, entries 1−3). More hindered reagents, such as i-BuLi, could also be used in this tandem application leading to the desired alcohol 4d in 70% overall yield with high ee of 84% (Table 2, entry 4). It is important to note that phosphoramidite ligand L217 had to be used in this case. To show the functional group tolerance of this protocol, we performed the reaction with p-bromo-substituted substrate 1b using different
halogen-lithium exchange) (Table 2, entries 5−7). The allyl bromide 1c bearing an aliphatic bromide (BrCH2 substituent) was converted with n-HexLi affording alcohol 4h in 60% yield and again with excellent enantioselectivity (97% ee) (Table 2, entry 8). A decrease in the enantioselectivity was observed when 1c was treated with MeLi as an alkylating source (Table 2, entry 9). The allyl bromide 1d bearing an acetal protected chiral 1,2-diol functionality upon the tandem application with MeLi and n-HexLi provided excellent diastereoselectivity (anti/syn ratios of >99:1) (Table 2, entries 10 and 11). An ester functionality is also tolerated, and the one-pot Cu-catalyzed AAA/reductive ozonolysis of 1e led to an exclusive SN2' substitution that provided the desired alcohol 4l in 73% yield with 97% ee (Table 2, entry 12).
Table 2: One-pot synthesis of β–alkyl-substituted alcohols through Cu-catalyzed asymmetric allylic alkylation of allyl bromides with organolithium reagents followed by reductive ozonolysis
(a) Reactions were run on a 0.2−0.5 mmol scale using 1.2 equiv of R'Li diluted with n-hexane (1.5 equiv diluted with toluene in the case of MeLi) which was added over 2 h using a syringe pump to a 0.1 M solution of substrate in CH2Cl2. (b) Ratio of SN2′:SN2
products was determined by GC−MS and 1
H-NMR analysis of a sample taken before ozonolysis. (c) The corresponding alcohol obtained from the SN2 product could be
separated by column chromatography unless otherwise noted (see experimental section). (d) Determined by chiral HPLC. (e) The low yield is due to volatility issues. (f) Dr determined by 1H-NMR. (g) 10% of double 1,2–addition product A was isolated in this case.
As the results summarized in Table 2 show, a highly versatile one-pot catalytic protocol to access a range of homochiral β-substituted alcohols is now available using common organolithium reagents and allyl bromides. This one-pot protocol, based on readily available compounds, avoids the isolation of the branched alkenes, which can be volatile (especially methyl-substituted compounds), thus affording better overall yields than the corresponding two steps version.
It is important to note that when the Cu-catalyzed AAA followed by ozonolysis was performed of 1d with subsequent Me2S treatment we
entrya 1 R' L 2:3 (%)b 4, yield (%)c 4, ee (%)d 1 1a Me L1 90:10 85 4a, 98 2 1a n-Bu L1 90:10 60 4b, 99 3 1a n-Hex L1 88:12 70 4c, 99 4 1a i-Bu L2 88:12 70 4d, 84 5 1b Me L1 90:10 84 4e, 99 6 1b n-Bu L1 85:15 75 4f, 97 7 1b n-Hex L1 87:13 90 4g, 99 8 1c n-Hex L1 100:0 60 4h, 97 9 1c Me L1 100:0 30e 4i, 72 10 1d n-Hex L1 90:10 65 4j, >99:1 (dr)f 11 1d Me L1 80:20 50 4k, >99:1 (dr)f 12g 1e n-Bu L1 100:0 73 4l, 97
Scheme 2: One-pot synthesis of α–alkyl-substituted aldehyde through Cu−catalyzed asymmetric allylic alkylation of allyl bromides with organolithium reagents followed by ozonolysis
We also explored a similar strategy for the synthesis of highly enantioenriched γ−alkylated alcohols via Cu-catalyzed AAA followed by a hydroboration/oxidation reaction. First, we performed the Cu-catalyzed AAA on cinnamyl bromide 1a using n-BuLi and n-HexLi. The corresponding olefins were formed in good yields of 88% and 86%,
respectively, with excellent enantioselectivity. The
hydroboration/oxidation reaction of these olefins using commercially available 9-BBN led to the corresponding γ-alkylated alcohols 6a and 6b in good yields (67% and 74%) without erosion of the enantiomeric excess (Table 3, entries 1 and 2). Olefins bearing a p-bromo substituent, obtained via Cu-catalyzed AAA from 1b, were converted in a hydroboration/oxidation sequence to the corresponding alcohols 6c and
6d in 70% and 90% yield, respectively, being enantiomerically pure
(99% ee) (Table 3, entries 3 and 4). Allyl bromide 1f, bearing a benzyl ether functionality, was also be subjected to the Cu-catalyzed AAA/ hydroboration/oxidation sequence providing the corresponding alcohols
6e and 6f in good yields (75% and 93%) albeit with slightly lower
enantioselectivities (81% and 88% ee, respectively) (Table 3, entries 5 and 6).
Table 3: Synthesis of γ-alkyl substituted alcohols through Cu-catalyzed asymmetric allylic alkylation of allyl bromides with organolithium reagents followed by a hydroboration/oxidation
(a) Reactions were run on a 0.2 mmol scale using 1.2 equiv of R'Li diluted with n-hexane (1.5 equiv diluted with toluene in the case of MeLi) which was added over 2 h using a syringe pump to a 0.1 M solution of substrate in CH2Cl2. (b) Ratio of SN2′:SN2
products was determined by GC–MS and crude 1H-NMR. (c) Calculated based on 2. (d) Determined by chiral HPLC.
As illustrated in Scheme 3, a β-alkyl-substituted aldehyde can also be readily synthesized. For instance, the oxidation of the corresponding primary alcohol 6e with Dess-Martin periodinane (DMP) provided aldehyde 8, an important intermediate in the total synthesis of danshenspiroketallactone.18 entrya 1 R′ L 2:3 (%)b (2+3), yield (%) 6, yield (%)c 6, ee (%) d 1 1a n-Bu L1 90:10 88 67 6a, 99 2 1a n-Hex L1 90:10 86 74 6b, 99 3 1b Me L1 90:10 90 70 6c, 99 4 1b n-Hex L1 87:13 93 90 6d, 99 5 1f Me L1 85:15 81 75 6e, 81 6 1f n-Bu L1 85:15 85 93 6f, 88
2.3 Conclusions
In summary, we have developed a highly enantioselective synthesis of β-alkyl-substituted alcohols through a one-pot Cu- catalyzed asymmetric allylic alkylation with organolithium reagents followed by reductive ozonolysis. The synthesis of γ-alkyl-substituted alcohols was also achieve through Cu-catalyzed asymmetric allylic alkylation with organolithium reagents followed by a hydroboration oxidation. These protocols do not compromise the stereochemical integrity and provide readily access to highly valuable chiral building blocks.
2.4 Experimental section
2.4.1 General Procedures
Flash column chromatography was performed on silica gel (230-400 mesh). Thin-layer chromatography was performed on silica plates. Compounds were visualized by UV and cerium/molybdenum or potassium permanganate staining. Progress and conversion of the reaction were determined by GC-MS and 1H-NMR. Mass spectra were recorded on a mass spectrometer using orbitrap analyzer. 1H- and 13 C-NMR were recorded on 400 MHz and 100.59 MHz using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: 7.26 for 1H, 77.0 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling
constants (Hz), and integration. Optical rotations were measured on a polarimeter with a 10 cm cell (c given in g/100 mL). Enantiomeric excesses were determined by chiral HPLC analysis using a diode array detector.
All reactions were carried out under a nitrogen atmosphere using oven-dried glassware and using standard Schlenk techniques. All the reagents, starting materials, and ligand L1 were purchased from commercial sources and used without further purification. Dichloromethane and toluene were used from the solvent purification system. n-Hexane was dried and distilled over sodium. Allylbromides 1b,19 1d,20 1e21 and 1f22 were prepared following literature procedures. Phosphoramidite ligand
L2 was prepared as reported in the literature.23
Racemic products were synthesized by reaction of the allyl bromides 1 and the corresponding organolithium reagent at -78 °C in CH2Cl2 in the presence of CuI (10 mol %) and PPh3 (20 mol %).
2.4.2 General procedure for the one-pot synthesis of β–alkyl-substituted alcohols through Cu-catalyzed asymmetric allylic alkylation of allyl bromides with organolithium reagents followed by reductive ozonolysis
A Schlenk tube equipped with septum and stirring bar was charged with
CuBr•SMe2 (0.01 mmol, 2.06 mg, 5 mol %) and the appropriate ligand (0.012 mmol, 6 mol %). Dry dichloromethane (2 mL) was added, and the solution was stirred under nitrogen at room temperature for 15 min. Then, allyl bromide 1 (0.2 mmol) was added, and the resulting solution was cooled to −80 °C. In a separate Schlenk tube, the corresponding organolithium reagent (0.24 mmol, 1.2 equiv) was diluted with n-hexane (toluene in the case of MeLi, combined volume of 1 mL) under nitrogen and added dropwise to the reaction mixture over 2 h using a syringe pump. Once the addition was complete, the mixture was stirred for another 2 h at −80 °C. The reaction was quenched with EtOH (2 mL), and then ozone was bubbled through the solution for 20 min. After being
after 10 min by the addition of H2O (10 equiv). Subsequently, the reaction mixture was warmed to room temperature and stirred overnight. The mixture was quenched by addition of extra water (5 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using different mixtures of n-pentane/Et2O as eluent.
Note: The SN2':SN2 ratio was determined by GC-MS and 1H-NMR analysis on a sample obtained after quenching with EtOH, which was passed through a short plug of silica gel to remove transition metal residues.
(R)-2-Phenylpropan-1-ol (4a): Purification by flash column chromatography (SiO2, 10 − 30% Et2O/pentane, gradient) afforded an inseparable mixture of 4a and benzyl alcohol in the ratio of 90:10 (51 mg, yield = 85%) as a colourless oil. 98% ee, [α]D20 = +5.0 (c = 1 in CHCl3); [lit.24 (97% ee): [α]D23 = +16.2 (c = 1 in CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.18 (m, 5H), 4.68 (s, 2H), 3.69 (d, J = 6.8 Hz, 2H), 2.9 – 3.0 (m, 1H), 1.63 (s, 1H), 1.28 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.7, 140.9, 128.6, 128.5, 127.6, 127.5, 127.0, 126.7, 68.7, 65.3, 42.4, 17.6; HRMS (APCI+, m/z): calculated for C9H11 [M-H2O]+: 119.08553, found: 119.08549. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OB-H column, n-heptane/i-PrOH 90:10, 40 °C, 217 nm, retention times (min): 10.40 (major) and 11.11 (minor).
(R)-2-Phenylhexan-1-ol (4b): Purification by flash column chromatography (SiO2, 5 − 20% Et2O/pentane, gradient) afforded 4b (25 mg, yield = 60%) as a colourless oil. 99% ee, [α]D20 = −11.0 (c = 1 in CHCl3); [lit.25 [α]D20 = −18.0 (c = 3.73 in CH2Cl2)]; 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.18 (m, 5H), 3.79 − 3.68 (m, 2H), 2.82 − 2.72 (m, 1H), 1.75 – 1.65 (m, 1H), 1.62 – 1.51 (m, 1H), 1.49 – 1.11 (m, 4H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.5, 128.6, 128.1, 126.7, 67.6, 48.7, 31.8, 29.5, 22.7, 14.0; HRMS (APCI+, m/z): calculated for C12H17 [M-H2O]+: 161.13248, found: 161.13245. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OJ-H column,
n-heptane/i-PrOH 95:5, 40 °C, 220 nm, retention times (min): 13.51
(major) and 14.17 (minor).
(R)-2-Phenyloctan-1-ol (4c) Purification by flash column chromatography (SiO2, 5 − 20% Et2O/pentane, gradient) afforded 4c (33 mg, yield = 70%) as a colourless oil. 99% ee, [α]D20 = −14.2 (c = 1 in CHCl3); [lit.26 (S)-enantiomer (92% ee): [α]D21 = +15.1 (c = 0.99 in CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.18 (m, 5H), 3.81 − 3.66 (m, 2H), 2.82 − 2.72 (m, 1H), 1.77 – 1.63 (m, 1H), 1.62 – 1.50 (m, 1H), 1.34 – 1.11 (m, 8H), 0.85 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.5, 128.6, 128.0, 126.6, 67.6, 48.7, 32.0, 31.7, 29.3, 27.3, 22.6, 14.0; HRMS (APCI+, m/z): calculated for C14H21 [M-H2O]+: 189.16378, found: 189.16372. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OJ-H column, n-heptane/i-PrOH 95:5, 40 °C, 220 nm, retention times (min): 10.63 (major) and 11.33 (minor).
(R)-4-Methyl-2-phenylpentan-1-ol (4d) Purification by flash column
chromatography (SiO2, 5 − 20% Et2O/pentane, gradient) afforded 4d (30 mg, yield = 70%) as a colourless oil. 84% ee, [α]D20 = −10.2 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.19 (m, 5H), 3.76 − 3.64 (m, 2H), 2.95 − 2.84 (m, 1H), 1.64 – 1.51 (m, 1H), 1.49 – 1.36 (m, 3H), 0.86 (t, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 142.4, 128.6, 128.1, 126.7, 68.0, 46.4, 41.1, 25.2, 23.5, 21.8; HRMS (APCI+, m/z): calculated for C12H17 [M-H2O]+: 161.13248, found: 161.13238. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel AD-H column, n-heptane/i-PrOH 95:5, 40 °C, 212 nm, retention times (min): 12.26 (major) and 13.04 (minor).
(R)-2-(4-Bromophenyl)propan-1-ol (4e) Purification by flash column
chromatography (SiO2, 10 − 20% Et2O/pentane, gradient) afforded an inseparable mixture of 4e and p-bromo benzyl alcohol in the ratio of 90:10 (27 mg, yield = 84%) as a colourless oil. 99% ee, [α]D20 = +8.6 (c = 1 in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 4.64 (s, 2H), 3.72 – 3.62 (m, 2H), 2.96 – 2.86 (m, 1H), 1.25 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.7, 139.8, 131.6, 131.6, 129.2, 128.6, 121.4, 120.4, 68.4, 64.5, 41.9, 17.5; HRMS (APCI+, m/z): calculated for C9H10Br [M-H2O]+: 196.99604, found: 196.99617. Enantiomeric excess was determined by chiral HPLC analysis, Chiralcel OB-H column, n-heptane/i-PrOH 95:5, 40 °C, 224 nm, retention times (min): 14.37 (minor) and 14.9 (major).
