Novel Hydroxamic Acid-Derived Ligands for Vanadium Catalysed Asymmetric Epoxidations

Research Paper (postgraduate), 2007

39 Pages, Grade: 1,0


Table of Contents



Table of Contents

1 Introduction
1.1 Sharpless Epoxidation
1.2 Yamamoto-Malkov Epoxidation
1.3 Camphor Derivatives
1.4 Phosphinamides
1.5 Sulfinamides

2 Project Objective

3 Results and Discussion
3.1 Camphor-derived hydroxamic acids
3.1.1 Synthesis of ligands
3.1.2 Application of ligand 3 to vanadium-catalyzed epoxidation
3.2 Hydroxamic acid based on diphenylphosphinamide moiety
3.2.1 Synthesis of ligand
3.2.2 Application of ligand 14 to vanadium-catalyzed epoxidation
3.3 Hydroxamic acids containing sulfinamide moiety
3.3.1 Synthesis of ligand 19 using direct method
3.3.2 Synthesis of ligand 19 using Nosyl protecting group
3.4 Synthesis of #-Benzhydryl-hydroxylamine

4 Conclusions and Future Aspects
4.1 General
4.2 Camphor derivatives
4.3 Sulfinamides
4.4 Phosphinamides
4.5 Anilides
4.6 Binaphthyls

5 Experimental
5.1 General Methods
5.2 Synthesis of hydroxylamine
5.3 Synthesis of Camphor-derived hydroxamic acids
5.3.1 Sulfonamides
5.3.2 Acid chlorides
5.3.3 Hydroxamic acids
5.4 Synthesis of Dpp-derived hydroxamic acid
5.5 Synthesis of sulfinamide-derived amino acid
5.6 Synthesis of #-Nosyl-(R)-phenylglycme
5.7 Epoxidation in water

6 References


First of all I would like to thank my supervisor Dr Andrei Malkov for his friendly tutelage, the interesting project, and the opportunity to work in his group.

Special thanks to Louise Czemerys for her friendly advice in the laboratory, her patient helpfulness, and finally for reading this report and correcting my English.

Many thanks go to all the other group members of laboratory A4-31 and A4-32 in Joseph Black Building for their steady assistance and support in everyday laboratory work, and for their open and friendly demeanour: Aneta, Claire, Frederic, Grant, Kveta, Jan, Marek, Mikhail and Sigitas.


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1 Introduction

1.1 Sharpless Epoxidation

Asymmetric epoxidation of olefinic double bonds has the potential to create two chiral centres in one step. Many research efforts have therefore been dedicated to the development of chiral metal catalysts that can perform asymmetric epoxidation.1 Most well-known is probably the Sharpless method, based on titanium tartrate complexes, for epoxidation of allylic alcohols. It was discovered in 1977 that a combination of VO(acac)2 and chiral hydroxamic acid (L* in Scheme 1) afforded optically active epoxides from the corresponding allylic alcohols and t-butyl hydroperoxide as oxidant with up to 50% ee. With a proline- derived hydroxamic acid as chiral ligand, higher enantioselectivities (up to 80% ee) could be achieved by the same authors a few years later.2

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Scheme 1. Asymmetric epoxidation according to Sharpless.3

Although this method is well understood and capable of delivering reliable and reproducible results, it still shows some disadvantages such as high catalyst loading, a tedious work-up and furthermore requires stringently anhydrous conditions.

1.2 Yamamoto-Malkov Epoxidation

In 2000, Yamamoto4 reported the successful use of amino acid-derived phthalimide ligands (A in Figure 1) in vanadium(V) systems which came close to Ti(lV) catalystsconcerning reactivity and enantioselectivity. At the same time, Maikov5,6 showed that phenylglycine derived sulfonamide ligands (B in Figure 1) exhibited high reactivity and promising enantioselectivity as well. But still, in both cases toluene was used as solvent and reactions had to be carried out under anhydrous conditions.

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Figure 1. Selected hydroxamic acids used as ligands so far.

Then it was discovered by the Maikov that the epoxidation reaction (Scheme 2) can successfully be carried out in water6, where the costly vanadium precursor VO(/-OPr)3 and anhydrous t-BuOOH can be replaced with much cheaper alternatives, such as VOSO4 and aqueous t-BuOOH.

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Scheme 2. Asymmetric epoxidation in water according to Maikov.

The reaction rate in water turned out to be generally slower than in organic solvents, and the Yamamoto ligand resulted in low conversions. However, the sulfonamides provided a reasonable level of reactivity, and enantiomeric excess values on a range of epoxidized allylic alcohols achieved up to 72 %.6 Another advantage of the application to aqueous systems consists of the very low catalyst loading needed (1 mol% or less).

So far, the coordination of ligands had lead to a significant deactivation of the catalyst in case of vanadium, resulting in a ligand-decelerating process. Applying the methodology mentioned above, it has been found that in water, vanadium catalysis turns into a ligand- accelerated process. Regarding the ligands, this effect can be attributed to the hydrogen bonding between the sulphonamide moiety and the incoming alcohol which brings and holds the reactants together. As well, transition states and active complexes have been studied6.

1.3 Camphor Derivatives

Chiral non-racemic monoterpenes derived from naturally occurring compounds have been widely used as chiral building blocks for the preparation of auxiliaries for asymmetric synthesis and ligands for asymmetric catalysis. Amongst monoterpenes a prominent position is occupied by optically active camphor, the framework of which has been incorporated into a variety of chiral ligands having homo- or heterodonor atoms.7 Interest in the chemistry of camphor and its derivatives has been continuous throughout the history of natural product chemistry. This interest is largely associated with the fact that (+)- or (-)-camphor is readily available and undergoes a wide variety of transformations, sometimes involving rearrangement processes. The range of functionalizations of the chiral moiety has been reviewed recently.8

Regarding applications in catalytic asymmetric synthesis, a class of camphor-based pyridine ligands have recently gained interest caused by improved methodology related to allylic substitution, allylic oxidation, cyclopropanation and hydrogenation (A, Figure 2).

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Figure 2. Selected camphor-based ligands for asymmetric synthesis.

Further applications of camphor-derived catalysts can also be found concerning carbonyl reductions, enantioselective deprotonations and a-hydroxylations9 (B and C, Figure 2), proving that camphor derivatives provide a valuable asset for reliable and versatile preparations of enantiopure compounds.

1.4 Phosphinamides

The chemistry of phosphinamides first gained interest in1976, as they were used as amino protecting groups in peptide synthesis by Kenner, Moore and Ramage.10 They designed a series of derivatives bearing similar reactivities as the well-known urethane protecting groups Boc (tert. -butyloxycarbonyl) and Bpoc (2-biphenyM-ylisopropyloxycarbonyl), which can be cleaved under mildly acidic conditions (Figure 3). For example, Dpp (Diphenylphosphino) is slightly more acid labile than Boc protecting group.11

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Figure 3. Different acid labile protecting groups.

To explain the particular acid lability of phosphinamides, the authors investigated the stereoelectronic properties of phosphinamides in comparison with amides. It was found that the nitrogen geometry in Ph2P(O)NMe2 and Ph2P(O)N(Me)CH2CH2Ph shows a flattened tetrahedron in which the lone pair on N is almost in the N-P-O plane, whereas in the amide bond, the lone pair of electrons on the trigonal N is orthogonal to the N-C-O plane.

The Dpp moiety turned out to be suitable as an amino protecting group even in oligopeptide synthesis and was stable during customary manipulations, which were found by the same authors a few years later.12

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Figure 4. Examples for phosphineamide-based ligands.

Nowadays, aside from its use as protecting group, phosphinamide moiety is mainly used in chiral ligands for asymmetric catalytic reactions, such as the asymmetric borane reduction of prochiral ketones13,14,15 (ligands A, B in Figure 4). Phosphinamide-based hydroxamic acids, which are considered in this work later on, have also found applications as inhibitors of matrix metalloproteinases16 (C in Figure 4).

1.5 Sulfinamides

A relatively rare class of ligands is that in which the stereogenicity resides not at the carbon atoms, but at a heteroatom such as sulfur. Over the last three decades, more than 40 different classes of chiral sulfur compounds have been described in the literature, accompanied by the development of a broad variety of useful procedures for the synthesis of enantiomerically pure sulfur compounds.17 Transition-metal complexes with chiral sulfur ligands are powerful catalysts in a considerable number of reactions, although, there have been several difficulties concerning chiral sulfinyl compounds, such as the formation of diastereomeric mixtures and the control of asymmetric induction in catalytic reactions.18 An appropriate summarizing review has recently been given by Fernandez and Khiar.19

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Figure 5. Illustrating the stereogenicity of sulfinamide moiety.

The structural key motif of sulfinamides consists of the sulfur atom in oxidation state (+11), which can also be found in sulfinimines, a class of ligands for asymmetric synthesis gaining interest since the 1990s.20 Considering the lone pair of sulfur, the structure can formally be regarded as tetrahedral (Figure 5), with activation parameters for pyramidal inversion of AH# = 35...42 kcal mol-[1] and AS# = 8 kcal K-[1] mol-[1] for related chiral sulfoxides. Thermal stereomutation can therefore be achieved at a fairly high rate at roughly 200 °C.21

From the view of metal complexation, chiral sulfinamide-containing scaffolds bear attractive features because of their ability to bind through nitrogen, sulfur, or oxygen to form a number of uniquely bonded motifs.22 Sulfinamides can be easily assembled from simple building blocks23 and are both structurally24 and optically stable, as mentioned above. Recent developments in improved synthetic approaches deliver a broad variety of possible stereoselective synthesis and reactions25, as well as successfully applied auxiliaries in catalytic asymmetric processes.26

2 Project Objective

The aim of this project was to carry out of the synthesis of three new classes of ligands ligand (Figure 6), each of which bearing different ways of influencing the product formation of vanadium(V)-catalysed asymmetric epoxidation in water. Since the amino acid backbone and the benzhydryl-amino moieties proved their suitability, these features will be preserved in the new ligands while varying the substituents on amide nitrogen.

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Figure 6. Target ligands of current project.

Design of ligands 3 incorporates the main features of the most successful ligand (B in Figure 1) and introduces an additional element of chirality (camphor) to the sulfonamide function. Both diastereomers of 3 are supposed to be prepared and the ligands will be tested in asymmetric epoxidation of model substrates.

Increasing the sterical extent of the amide moiety and, at the same time, exchanging sulfur for phosphorus, led to the development of ligand 14. Presuming a successful preparation, testing 14 in asymmetric epoxidation will represent the first application of phosphinamide derivatives to this reaction methodology.

In ligand 3, we have the sulphonamide moiety separating chiral amino acid from the chiral camphor scaffold. Therefore, another aspect one might consider is to decrease the distance of the second centre of stereogenicity to the amino acid backbone. The resulting ligand 19 bears a sulfinamide moiety, which introduces chirality caused by asymmetric substitution of sulfur. Synthesis of 19, separation of diastereomers and their application to the reaction mentioned above (Scheme 2) is considered as another target of this project.

3 Results and Discussion

3.1 Camphor-derived hydroxamic acids

3.1.1 Synthesis of ligands 3

The use of chiral camphor moiety is the reasonable continuation of the strategy that introduces ligand chirality by modifying the amino acid backbone. Enhancing the, so far non- chiral, sulfonamide moiety by addition of a stereogenic centre should enable the ligand (Figure 7) to influence the stereochemistry of asymmetric epoxidation in a way to reach higher enantiomeric excess. Also, the bulky quality of the bicyclic scaffold is supposed to influence the selectivity of product formation. Furthermore, the sulfonamide moiety is stable against strong acids and bases, and therefore easy to handle and useful substrates can be build even under harsh reaction conditions.

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Figure 7. Camphor-derived hydroxamic acid ligands.

Synthesis of each diastereomer (S, R)-3 and (S, S)-3 was accomplished in four convergent steps (Scheme 3). Starting from enantiopure (S)- or (R)-phenylglycine, which were coupled under aqueous conditions with commercially available (7S)-Camphor-10- sulfonic acid chloride to sulfonamides 1, the synthesis was continued by using phosphorus pentachloride in anhydrous ether to obtain acid chlorides 2.

To prevent the possible O-acylation in the next step, hydroxylamine 5 was protected in situ with chlorotrimethylsilane in presence of 2,6-lutidine, which acted as a non-nucleophilic base.

The subsequent coupling with 2, carried out in anhydrous THF, and O-deprotection with water furnished camphor-derived hydroxamic acids 3 in 44 - 73% yield.

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Scheme 3. Synthesis of ligands 3. Conditions: i) (S)- or (R)-phenylglycine, aq. NaOH, ether, r.t.; ii) PCl5, ether, r.t.; iii) chlorotrimethylsilane, 2,6-lutidine, THF, 0 °C; iv) 2,6-lutidine, THF, r.t.

3.1.2 Application of ligand 3 to vanadium-catalyzed epoxidation

Hydroxamic acids 3 were tested in two standard epoxidation runs in water, using allylic alcohols 6a-b as substrates (Figure 8). The catalyst consisted of vanadyl sulfate hydrate as the metal source and chiral ligand (S, R)-3 or (S, R)-3. More reaction conditions are given in Scheme 4.

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Scheme 4. Asymmetric epoxidation using ligands 3.

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Figure 8. Allylic alcohols used as substrates and appropriate epoxidation products.

Applying the reaction conditions optimized before6, we obtained moderate enantiomeric excess values (up to 46%) with camphor-derived hydroxamic acids 3 as ligands. The best results could be achieved when using ligand (S, S)-3 on substrate 6a (entry 3 in Table 1). The expected epoxidation product 7b of geraniol 6b appears to being opened instantly in presence of ligand (S, R)-3, therefore only the triol 8 could be detected after working up reaction mixture (entry 2 in Table 1).

Since epoxide ring opening occured as well in case of ligand (S, S)-3 and substrate 6a, even though in much lower quantity as with the other ligand diastereomer, the desired epoxide was detected as minor product (entry 3 in Table 1).

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Table 1. Summarized results of epoxidations using ligands 3. a detected by chiral GC (Supelco P-Dex 120 column; oven temp. 110 °C for 2 min, then 1 °C/min to 200 °C, tS,S = 34.66, tRR = 35.27); b Supelco a-Dex 120 column; oven temp. 110 °C for 2 min, then 1 °C/min to 200 °C, t^ = 21.67, tRR = 22.09.

The camphor moiety with its intrinsic chiral scaffold was apparently not able to introduce additional chirality into ligand backbone. It was probably too far away from the coordinating site and therefore not able to exert a sufficient effect on the product formed.


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Novel Hydroxamic Acid-Derived Ligands for Vanadium Catalysed Asymmetric Epoxidations
University of Glasgow  (Chemistry)
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Epoxidation, Ligand Synthesis, Vanadium, asymmetric catalysis
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Dominik Ohlmann (Author), 2007, Novel Hydroxamic Acid-Derived Ligands for Vanadium Catalysed Asymmetric Epoxidations, Munich, GRIN Verlag,


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