An overview of chiral molybdenum complexes applied in enantioselective catalysis

Abstract

The aim of this contribution is to highlight the attractive applications of molybdenum in asymmetric catalysis. Even if molybdenum plays several biological roles mainly in metalloproteins, it has been less employed in catalysis in comparison with other transition metals. This perspective focuses on molybdenum complexes linked to chiral ligands applied in enantioselective processes. The versatility of molybdenum in terms of oxidation states and coordination geometries triggers its capability to catalyse different kind of processes such as carbon–carbon bond formation, olefin metathesis or alkene epoxidation among the most relevant transformations.

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1. Introduction

The synthesis of stereochemically pure compounds represents one of the key objectives for several domains of chemistry including the production of drugs, biologically active compounds, agricultural chemicals and materials.¹ Development of the organometallic enantioselective catalysis has been one of the most important hits of the last century, allowing the transformation of prochiral and racemic substrates into enantioenriched products. This successful research led to the Royal Swedish Academy of Sciences to award in 2001 W. S. Knowles, R. Noyori and K. B. Sharpless, pioneering chemists in the field of asymmetric catalysis, with the Nobel Prize in Chemistry.² At present, one of the challenges from an industrial and environmental point of view is to design highly active processes, inducing full control in chemo-, regio- and stereo-selectivity, decreasing the by-products and allowing the recycling of catalyst.³ The use of cheap and less toxic catalysts in relation to late transition metals signifies an attractive way for homogeneous catalysis. Although molybdenum plays several roles in biological transformations, it has been little applied in organometallic catalysis in relation to other transition metals. In the present perspective, we want to underline the successes and the limitations of chiral molybdenum complexes in asymmetric catalysis. The contribution is organized in three main sections where we discuss the role of molybdenum in asymmetric allylic alkylation, alkene metathesis and olefin epoxidation, emphasizing the type of complexes and in consequence the chiral ligands involved in each case. A few other relevant works are collected in a last “miscellaneous” section.

2. Asymmetric allylic alkylation

Transition-metal-catalyzed enantioselective allylic substitutions are a powerful synthetic tool to form carbon–carbon and carbon–heteroatom bonds.⁴ In particular, asymmetric allylic alkylations are catalyzed by a large variety of metal complexes,⁵ but those based on palladium are the most widely used in organic synthesis.⁶ A large variety of chiral ligands have been applied in enantioselective allylation reactions using different kinds of substrates, nucleophiles and reaction conditions, leading to high yields and excellent asymmetric inductions. However, when unsymmetrical substrates, mainly aryl-substituted allyl systems, are involved, palladium catalysts direct the nucleophilic attack to the less substituted allylic terminal carbon atom, giving the achiral regioisomer.⁷ In contrast, metals such as iridium,⁸ tungsten⁹ or molybdenum¹⁰ generally favour the nucleophilic attack at the more substituted terminus (Scheme 1). In this context, molybdenum represents an attractive alternative due to the relative low cost of its organometallic precursors (mainly [Mo(CO)₆], [Mo(CO)₃(EtCN)₃] and [Mo(CO)₃(C₇H₈)]) and the robustness of the corresponding complexes under catalytic reactions.¹⁰

Scheme 1 Allylic substitution catalyzed by Pd or Mo systems using unsymmetrical substrates (LG = leaving group).

The first highly regio- and enantio-selective catalytic asymmetric Mo-catalyzed allylic alkylation was reported by Trost and co-workers in 1998, achieving the best results with a C₂-symmetric bis(pyridyl-amide) ligand (1, X = N, R₁ = R₂ = H in Fig. 1),¹¹ which still remains the most efficient system for synthetic purposes;¹² some time before Faller and Murray independently reported stoichiometric alkylations using π-allylmolybdenum complexes.¹³ Since then, works concerning both the design of new ligands and comprehension of the mechanism have been carried out.

Fig. 1 Efficient representative chiral ligands applied in Mo-catalyzed allylic alkylation.

In Fig. 1, the most effective chiral ligands used in Mo-catalyzed allylic alkylation reactions are collected.¹⁴ In order to compare the regio- and the enantio-selectivity induced by these catalytic systems, cinammyl carbonate using dimethylmalonate (as a neutral nucleophile in the presence of a base or as the corresponding sodium salt, NaCH(COOMe)₂) is taken into account as a benchmark reaction. First Trost¹¹ (using type 1 ligand where R₁ = R₂ = H and X = N) and later Moberg¹⁵ (using type 1 ligands, both symmetrical and unsymmetrical derivatives) used bis(pyridyl-amide) ligands containing a trans-1,2-diaminocyclohexyl scaffold (type 1 ligands, Fig. 1), giving excellent enantioselectivity (of up to 99% ee) with regioselectivity up to 49 : 1 for the branched : linear regioisomer ratio (entries 1–4, Table 1); working under microwave heating, a cheaper and more stable molybdenum precursor, [Mo(CO)₆], could be used instead of [Mo(CO)₃(EtCN)₃] (entries 2–4 and 10, Table 1).¹⁵ When the trans-(1,2-diamino-1,2-diphenyl)ethyl skeleton is present in the ligand structure instead of the analogous cyclohexyl backbone (ligand 2, Fig. 1), the regioselectivity decreases maintaining high asymmetric induction (entry 5, Table 1).¹⁶ Based on these highly successful pyridyl-amides, Pfaltz developed new C₂-symmetrical bis(oxazolinyl-amide) ligands (types 3¹⁷ and 4,¹⁸Fig. 1). These Mo catalytic systems induced excellent enantioselectivity, but in both cases, the regioselectivity decreased (entries 6 and 7, Table 1). Kočovský and Lloyd-Jones designed C₁-symmetrical ligands of type 5 (Fig. 1) in order to study the effect of the chiral environment on the selectivity of the reaction.¹⁹ The high selectivity obtained (entry 8, Table 1) evidenced that one stereocentre on the ligand is enough to render efficient Mo catalytic systems. This result is in agreement with those obtained by Trost using ligands containing only one pyridyl group (entry 9, Table 1 and ligand 7, Fig. 2).¹⁶ More recently, Moberg and co-workers have synthesized new bis(pyridyl-amide) ligands containing a carbohydrate-based backbone instead of chiral 1,2-diamino scaffolds (type 6 ligands, Fig. 1).²⁰ The ligand coming from α-D-glucose gave the same regio- and enantio-selectivity as the ligand 1 (where R₁ = R₂ = H and X = N, Fig. 1), which represents one of the highest selective Mo system currently reported (entry 10 vs. 1, Table 1).

Table 1 Mo-catalyzed allylic alkylation of cinnamyl carbonate using dimethylmalonate as nucleophile

Entry (Ref.)	L	Mo precursor (mol%)	R1, R2	b : l (% ee)
a See Fig. 1. b Microwave heating.
1 (11)	1 (X = N)	[Mo(CO)3(EtCN)3] (15)	H, H	49 : 1 (99)
2 (15)	1 (X = N)	[Mo(CO)6] (4)^b	OMe, H	41 : 1 (>99)
3 (15)	1 (X = N)	[Mo(CO)6] (4)^b	Cl, H	74 : 1 (96)
4 (15)	1 (X = N)	[Mo(CO)6] (4)^b	NC4H8, H	88 : 1 (96)
5 (16)	2	[Mo(CO)3(EtCN)3] (10)	—	19 : 1 (99)
6 (17)	3	[Mo(CO)3(EtCN)3] (10)	iPr, —	14 : 1 (99)
7 (18)	4	[Mo(CO)3(EtCN)3] (10)	Pr, —	6 : 1 (98)
8 (19)	5	[Mo(CO)3(EtCN)3] (10)	(S)-iPr, —	38 : 1 (97)
9 (16)	1 (X = CH)	[Mo(CO)3(C7H8)] (10)	H, —	60 : 1 (99)
10 (20)	6	[Mo(CO)6] (10)^b	H, —	49 : 1 (99)

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Fig. 2 Three-coordination of bis(oxazoline) (top) and bis(amide) (down) ligands involved in carbonyl molybdenum complexes (ref. 18 and 21, respectively).

Concerning the coordination chemistry, Pfaltz and co-workers proved that the potential tetra-coordinated bis(oxazolinyl-amide) (type 4 ligand, Fig. 1) behaves as a tri-coordinated framework when reacting with carbonyl molybdenum precursors, giving [Mo(CO)₃(κ³-N,N′,O-4)] (for 4, R = Ph) (Fig. 2).¹⁸ Analogously, Trost and co-workers isolated the π-allyl Mo(II) complex containing mono-deprotonated pyridyl-bisamide ligand (type 1) starting from [Mo(CO)₆] in the presence of cinnamyl carbonate (Fig. 2).²¹ This tri-coordination mode of the chiral ligand agrees with the stereochemical requirements observed in the catalytic allylic alkylation (see above, entry 9 vs. 1 in Table 1).

From a mechanistic point of view, metal-catalyzed asymmetric allylic alkylations using stabilized nucleophiles mainly carry on in two steps: oxidative addition of the allylic substrate leading to a metal-allyl intermediate followed by nucleophilic attack to give the substitution product. Both steps can proceed with either retention or inversion. For Pd catalytic systems the overall stereochemistry is retention with the two steps undergoing inversion.²² For Mo, the overall reaction also takes place with retention,¹¹ but as proved by Kočovský and Lloyd-Jones the mechanism in this case proceeds by a retention-retention stepway.^19a,23

3. Asymmetric alkene metathesis

Olefin metathesis has been established as an indispensable method in organic synthesis for the preparation of a myriad compounds. Nowadays, Ru- and Mo-catalyzed olefin metathesis is routinely used to prepare an array of complex molecules, including small, medium and large rings.²⁴

During the last decade, research efforts have focused on the development of efficient catalytic enantioselective olefin metathesis reactions. Schrock, Hoveyda and co-workers have developed a series of enantiomerically pure chiral Mo-based arylimido alkylidene complexes that efficiently promote asymmetric ring-closing as well as ring opening metathesis reactions (ARCM and AROM, respectively). The majority of these catalysts are four or five-coordinate species bearing an imido functionality and a chiral diolate.²⁵ Representative chiral molybdenum alkylidene complexes are summarized in Fig. 3.

Fig. 3 Representative chiral alkylidene molybdenum complexes. OTBS = OSi(tBu)Me₂.

The first example of catalytic enantioselective metathesis was described by using the chiral biphen-Mo containing the 6,6′-dimethyl-3,3′-5,5′-tetra-tert-butyl-1,1′-biphenyl-2,2′-diol unit (type 8 complex in Fig. 3).²⁶ Type 8 complexes were proved to be highly effective catalysts in ARCM of 1,6-dienes affording five-membered carbo- and hetero-cycles in high optical purity. However, lower asymmetric induction was obtained in the reactions involving 1,7-dienes. Soon after, a new class of binol-based chiral Mo catalysts, complexes 9 in Fig. 3, were disclosed by the same authors. These new complexes were particularly effective in the enantioselective synthesis of chiral cyclohexenes, dihydropyrans and 1,7-dienes giving high enantiomeric excesses.²⁷

Since then, an impressive number of molybdenum-based alkylidene complexes bearing functionalized chiral binol ligands have been designed and applied in both ARCM and AROM transformations by Schrock, Hoveyda and co-workers. It has been proved that smooth modification of the chiral alkoxide leads to substantial improvement of selectivity. As an example, type 10 complexes (Fig. 3) share structural features with both biphen-8 and binol-9 based systems representing an hybrid between both 8 and 9 catalysts, and provides a unique selectivity profile, not observed using these latter systems.²⁸ From a practical point of view, catalysts 10 offer an important advantage because they can be prepared from commercially available starting materials and used in situ, without isolation, to attain enantioselective olefin metathesis.

The applicability of molybdenum-based catalysts in both ARCM and AROM reactions to obtain enantiopure products, unavailable by other methods, is now well demonstrated.²⁹ Substantial variations in reactivity and selectivity arises from subtle changes in catalyst structures. Structural modifications of the diolate ligands have proved to control both the selectivity and reactivity of the olefin metathesis reactions. Selected examples illustrating the importance of catalyst modularity and substrate specificity in asymmetric catalysis are depicted in Schemes 2 and 3. The binol-based catalyst 9a promotes the RCM of dienes I and II with outstanding levels of selectivity in contrast to complex 9b, that is not an efficient catalyst for the kinetic resolution of I and II (Scheme 2).

Scheme 2 Mo-catalyzed kinetic resolution of 1,7-dienes. For the corresponding complexes, see Fig. 3. TES = SiEt₃; TBS = Si(tBu)Me₂.

Scheme 3 Mo-catalyzed asymmetric desymmetrization of trienes. For the corresponding complexes, see Fig. 3.

The ARCM processes presented in Scheme 3 involve the catalytic desymmetrization of 1,6- and 1,7-dienes. Catalyst 9a is unable to initiate RCM of substrate III, complex 8b being the best choice for this transformation. In contrast, 9a readily promotes the conversion of silyl ether V to the six-membered ring allyl silane VI giving 99% ee with a 98% yield in 3 h. Biphen-based complex 9a is significantly less effective affording lower levels of enantioselection and low yield of product.²⁷

Structural changes of the catalysts have also been introduced taking into account the substituents on the imido ligand. Mo-biphen complexes bearing an alkylimido group (complex 11, Fig. 3) instead of arylimido displayed reactivity and enantioselectivity levels that are not accessible by the complexes previously described.³⁰ One illustrative example is the better performance of the alkylimido 11 in the asymmetric ring-opening/cross metathesis with triene VII compared to the arylimido 8a. As shown in Scheme 4, the reaction promoted by arylimido 8a gives significant amount of IX (an achiral by-product) and low enantioselectivities. However, under identical reaction conditions, catalyst 11 gives the desired product VIII with high yield and selectivity (96% ee, 82% isolated yield).^30b

Scheme 4 Mo-catalyzed asymmetric ring-opening/cross metathesis. For the corresponding complexes, see Fig. 3.

Catalytic AROM transformations have been developed as tandem processes involving the catalytic enantioselective C–C bond cleavage (ring opening) followed by an intramolecular ring closing metathesis (RCM) or intermolecular cross-metathesis (CM).³¹ As an example, Scheme 5 illustrates the tandem Mo-catalyzed AROM/CM reaction of a norbornyl ether with styrene to afford the corresponding cyclopentyl derivatives in high levels of selectivity and efficiency.³²

Scheme 5 Mo-catalyzed tandem AROM/CM reactions. For the corresponding complexes, see Fig. 3.

Recently, monoalkoxide pyrrolide (MAP) molybdenum species of the general formula [Mo(NR)(CHR′)(OR′′)(Pyr)] where Pyr is a pyrrolide or substituted pyrrolide ligand and OR′′ is an aryloxide, have attracted much interest in the field of enantioselective catalysis.³³ These new types of catalysts have a stereogenic metal centre, as a consequence of the four different ligands being covalently attached to molybdenum in a tetrahedral environment. The stereo-controlled molybdenum-based complexes were prepared by a ligand exchange process involving an enantiomerically pure aryloxide (Scheme 6).³⁴

Scheme 6 Diastereoselective synthesis of stereogenic-at-Mo complexes. OTBS = OSi(tBu)Me₂; d.r. = diastereomeric ratio.

The reactivity of MAP towards olefins is often much higher than that of bisalkoxides. Theoretical studies have predicted that high-oxidation-state complexes containing two electronically distinct ligands should be particularly effective promoters of alkene metathesis.³⁵ The stereogenic-at-Mo complex 12b reported by Schrock and Hoveyda represents a rare case of the successful use of a monodentate O-based chiral ligand in enantioselective catalysis. They demonstrated the applicability of the new catalysts in the enantioselective synthesis of an Aspidosperma alkaloid, (+)-quebrachamine, through an alkane metathesis reaction that cannot be promoted by any of the previously reported chiral catalysts (Scheme 7).³⁴

Scheme 7 Enantioselective synthesis of (+)-quebrachamine through an enantioselective RCM of a triene promoted by the stereogenic-at-Mo complex 12b (results from ref. 34a,b).

The proposed mechanism of metal-catalyzed olefin metathesis promoted by sterogenic-at-metal complexes implies that the configuration at the metal center is inverted in each olefin metathesis step. As illustrated in Scheme 8, the olefin attacks the metal in MAP species trans to the pyrrolide ligand to form an intermediate metallacyclobutane that contains the pyrrolide and two carbons of the resulting metallacycle in equatorial positions. The olefin then leaves trans to the pyrrolide to form the new alkylidene with the opposite configuration at metal. Therefore, the reactant olefin enters trans to the pyrrolide and the product olefin leaves trans to the pyrrolide, via an intermediate trigonal bipyramid with axial imido and aryloxide ligands, inverting the configuration at the metal in each metathesis step.³⁶ This mechanism is consistent with theoretical calculations performed by Eisenstein and co-workers.³⁵

Scheme 8 Proposed mechanism of metal-catalyzed olefin metathesis promoted by sterogenic-at-metal complexes.

4. Asymmetric alkene epoxidation

Oxomolybdenum(VI) complexes have been applied in asymmetric oxidation processes over the last 40 years after the Halcon and Arco processes,³⁷ mainly focused on olefin epoxidations. Although many contributions have been reported,³⁸ only some of them have induced good enantioselectivities at reasonably high conversions. In this section the most significant contributions in this field are underlined, organized by the nature of the chiral ligands employed. Most of them are N,O-hetero-donor ligands, mainly giving bidentate and tetradentate coordinations around the metal centre.

Chiral amides

Shurig and co-workers reported the first works related to the applications of chiral complexes in olefin epoxidations containing enantiopure hydroxyamides. The best catalytic system based on oxo-diperoxomolybdenum(VI) complexes gave 49% ee in the epoxidation of trans-but-2-ene.³⁹ Later Yoon et al. reported the epoxidation of styrene-based substrates getting 81% of enantiomeric excess for (E)-Ph–CH=CH–Me (Scheme 9); however, the asymmetric induction remained low (less than 40%) for cis-styrenes.⁴⁰

Scheme 9 Chiral oxo-bis(peroxo)molybdenum(VI) complexes applied in olefin epoxidations (results from ref. 40)

Molybdenum systems containing chiral bis(pyridyl-amide) ligands did not induce any enantioselectivity in the epoxidation of styrene and cyclohexene derivatives, in contrast to the excellent results obtained with this kind of ligands in Mo-catalyzed allylic alkylation (see above).⁴¹

Chiral hetero-donor alcohols: amino, pyridyl and imine derivatives

Zhou and co-workers have successfully applied chiral amino alcohols in the epoxidation of styrenes, obtaining more than 70% yield in the desired epoxide and enantiomeric excesses up to 84% (Scheme 10). However, the use of natural amino acids gave low conversions and very low enantioselectivity.⁴²

Scheme 10 Dioxo-molybdenum(VI) systems containing chiral amino alcohols applied in styrenes epoxidation (results from ref. 42).

In spite of the variety of scaffolds associated with chiral pyridyl alcohols (Fig. 4), their use in olefin epoxidation led to low enantiomeric excesses (<30% ee) for the epoxidation of different kinds of alkenes (styrenes, alkenes, pinenes…).⁴³

Fig. 4 Some representative examples of chiral pyridyl alcohols applied in Mo-catalyzed olefin epoxidation (from ref. 43).

However, pyridyl alcohols derived from camphor and fenchone (Fig. 4) led to full conversion and noticeable enantioselectivity (up to 80% ee) for the epoxidation of cis-1-propenylphosphonic acid to give the corresponding epoxide, a drug exhibiting antibiotic activity (Scheme 11).⁴⁴

Scheme 11 Synthesis of fosfomycin by Mo-catalyzed epoxidation (results from ref. 44).

Molybdenum complexes coordinated to chiral imino N,O,O′-tridentate ligands containing a carbohydrate backbone were first prepared by Rao et al.⁴⁵ and further applied in olefin epoxidation (Fig. 5).⁴⁶ Even if these systems gave high activities (up to 13 000 h⁻¹ for cyclooctene epoxidation), the enantioselectivity was low, getting 30% ee for the epoxidation of cis-β-methylstyrene using tert-butylhydroperoxide as oxidant.

Fig. 5 Dioxo-molybdenum(VI) complexes containing chiral N,O,O′-tridentate sugar-based ligands.

Chiral bishydroxamic acids

Enantiomerically pure bishydroxamic acids were first applied in vanadium-catalyzed epoxidation of allylic alcohols. Catalysts based on molybdenum containing this kind of ligands have also been applied in epoxidation of different kinds of olefins, obtaining the highest enantioselectivity described at present (up to 96% ee, Scheme 12). These catalytic systems also gave interesting regio- and enantioselectivity for the epoxidation of squalene (biogenetic precursor of steroids and terpenoids).⁴⁷

Scheme 12 Dioxo-molybdenum(VI) systems containing chiral bishydroxamic acids applied in olefin epoxidation (results from ref. 47).

Chiral oxazoline ligands

Oxazoline ligands have been extensively employed in metal-catalyzed asymmetric processes,⁴⁸ however their applications involving molybdenum systems have been less developed. Oxomolybdenum complexes containing chiral oxazolines have been applied in the epoxidation of limonene⁴⁹ and styrene derivatives^49c,50 (Fig. 6).

Fig. 6 Oxomolybdenum(VI) complexes containing chiral oxazoline ligands applied in asymmetric olefin epoxidation (ref. 49 and 50).

In relation to styrenes, no significant enantioselectivity was observed (less than 15% ee). However, interesting diastereoselectivity for the (R)-limonene epoxidation could be observed using oxazolinyl-pyridine ligands, favouring the formation of the corresponding trans-1,2-epoxide (Scheme 13).^49a Recently, the use of ionic liquid instead of organic solvent has allowed the exclusive formation of the trans epoxide.⁵¹

Scheme 13 Mo-catalyzed asymmetric epoxidation of (R)-limonene (results from ref. 49a and 51). Ionic liquid = butyl methyl pyrrolidinium bis(trifluoromethanesulfonyl)amide.

We have been interested in understanding the catalytic behaviour observed in Mo-catalyzed olefin epoxidation, in particular for those systems containing oxazoline ligands. Type 13 catalysts containing oxazolinyl-phenolato ligands (Fig. 6) were found to be highly active systems but without showing asymmetric induction. However, the bimetallic system 16 (Fig. 6) containing a oxazolinyl-pyridine ligand gave moderate activities and high diastereoselectivity for the epoxidation of (R)-limonene, in contrast to the inactivity observed using the oxo-bis(peroxo) monometallic system 15.^49a,b These results led us to carry out some NMR experiments, which have demonstrated the lability of the oxazoline moiety for the chiral phenolato ligand in the presence of the olefin and oxidant (complexes of type 13, Fig. 6). The catalytic inactivity of the oxo-bis(peroxo) complex 15 is attributed to the coordinative saturation of the complex, without any possibility to generate vacant positions. Actually, the robustness of the oxazolinyl-pyridine ligand was evidenced with complex 16, which was active (isothiocyanate acts as a labile ligand under catalytic conditions), inducing a high diastereoselectivity in the formation of the 1,2-epoxide of (R)-limonene (up to 100% selectivity in ionic liquid medium).⁵¹ These facts suggest that the metal interacts with the olefin as well as the oxidant, as postulated by Mimoun.⁵²⁹⁵Mo NMR monitoring of complex 16 with (R)-limonene evidenced the interaction of the olefin with the molybdenum centre, confirmed by theoretical calculations (Fig. 7).^49b

Fig. 7 X-Ray structure of 16 (right) and ⁹⁵Mo NMR spectra (left) (CDCl₃, 26 MHz): (a) complex 16; (b) 16 + (R)-limonene after 15 min of the olefin addition; (c) 16 + (R)-limonene after 48 h of the olefin addition.

Chiral N,N′- and O,O′-homo-donor ligands

Enantiopure diols and their phosphane derivatives, are very useful chiral ligands in stereoselective organic synthesis.⁵³ They have been also tested in Mo-catalyzed asymmetric epoxidation of alkenes, using both atropoisomeric diols⁵⁴ and those where the chirality resides in C-stereocentres of the backbone⁵⁵ (Fig. 8). Unfortunately these systems were not enantioselective.

Fig. 8 Dioxo-molybdenum(VI) complexes containing chiral diol (top, ref. 54 and 55) and diimine (bottom, ref. 57) ligands.

Chiral diimines, convenient ligands for several catalytic processes,⁵⁶ have been evaluated in alkene epoxidations using molybdenum catalysts (Fig. 8).⁵⁷ These systems gave high enantiomeric excesses (up to 85%) at low conversions of cis-β-methylstyrene (less than 10%); however the enantioselectivity strongly decreases at higher conversions.

Chiral cyclopentadienyl Mo(II) complexes

Besides oxo-molybdenum(VI)-based catalysts, Mo(II) complexes coordinated to cyclopentadienyl-based chiral ligands (complexes 19–21 in Fig. 9), have been also applied as catalytic precursors in alkene epoxidations, giving in all cases low selectivities. The highest enantiomeric excess (up to 25%) was achieved for the epoxidation of trans-β-methylstyrene using the catalyst 19 (Fig. 9).⁵⁸ The lack of asymmetric induction can probably be due to the lability of the cyclopentadienyl-based ligand under catalytic conditions.⁵⁹

Fig. 9 Chiral cyclopentadienyl-Mo(II) complexes applied in asymmetric olefin epoxidations (ref. 58 and 59).

5. Miscellaneous

In spite of the large variety of oxidation states of molybdenum (from −2 to +6) and the several geometries around the metal centre where different coordination modes of the ligands can be accommodated, the applications in asymmetric catalysis remain rather under-explored. In this section, the most relevant applications other than those mentioned above are underlined.

Oxygen transfer reactions represent the most significant applications for molybdenum catalysts, in particular concerning the enantioselective olefin epoxidation (see above). In the last years, the synthesis of chiral sulfoxides has experienced a great interest, not only from an academic point of view but mainly for synthetic purposes; the chiral sulfinyl group represents an asymmetric inductor for C–C and C–X bond formations.⁶⁰ Recently, Mo(VI) systems containing C₂-symmetric bishydroxamic acid ligands (see Scheme 12 for enantioselective epoxidation) have been applied in selective oxidations of pro-chiral sulfides to the corresponding sulfoxides using organic hydroperoxides as oxidants, giving from high (82% ee) to excellent (99% ee) asymmetric inductions (Scheme 14). High enantioselectivities were also achieved for the processes where sulfones were formed by oxidation of racemic sulfoxide substrates due to the different oxidation rate of both enantiomers under oxidative conditions.⁶¹ Mo(V) systems, starting from MoCl₅ in the presence of β-cyclodextrin ligands, have found interesting applications in the oxidation of methyl 1-naphthyl sulfide, giving high chemoselectivity but moderate enantioselectivity (up to 58% ee).⁶²

Scheme 14 Mo-catalyzed enantioselective oxidation of methyl phenyl sulfide (results from ref. 61). acac = acetylacetonate anion.

Dioxo-molybdenum(VI) complexes bearing tetradentate “salan” ligands (tetrahydro derivatives of salen related structures⁶³) have been successfully applied in enantioselective pinacol coupling of aldehydes, affording the corresponding diol compounds in high diastero- and enantio-selectivity (Scheme 15). Preliminary mechanistic studies proved the formation of Mo(IV) as catalytically active species.⁶⁴ However, related molybdenum complexes containing salalen ligands (dihydro derivatives of salen ligands) have not induced significant enantioselectivity in the hydrosilylation of prochiral ketones (<8% ee).⁶⁵

Scheme 15 Mo-catalyzed enantioselective pinacol coupling of aromatic aldehydes (results from ref. 64).

Other contributions of chiral molybdenum entities have been reported including stereoselective control in Pauson–Khand cyclizations⁶⁶ and applications in atom transfer radical polymerization of styrene.⁶⁷

Conclusions and perspectives

The present overview shows that chiral molybdenum complexes are convenient catalytic systems to induce chirality transfer in carbon–carbon bond formation processes. Undoubtedly enantioselective alkene metathesis reactions constitute the major success of molybdenum complexes in asymmetric catalysis, allowing the total synthesis of natural products. In particular, the results obtained using innovative stereogenic-at-metal complexes open fresh opportunities in future catalysts design. Moreover, Mo-catalyzed allylic alkylations of unsymmetrical substrates permit to obtain the chiral regioisomer with excellent asymmetric inductions.

Oxo-molybdenum complexes have been extensively applied in enantioselective alkene epoxidations, using different kinds of chiral ligands, containing N- and O-donor centres. Only a few of them have led to high enantioselectivities, due to the lability of the chiral spectators under catalytic conditions. The design of robust chiral ligands stable under oxidative conditions remains a challenge for the asymmetric induction in the oxidation of prochiral substrates using molybdenum catalytic systems.

Acknowledgements

Authors thank CNRS, Université Paul Sabatier and Fundação para a Ciência e Tecnologia (research project PTDC//QUI-QUI/098682/2008 and doctoral grant SFRH/BD/30917/2006 for JAB) for financial support.

Notes and references

1. Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley-VCH, New York, 2000; Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999.
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4. (a) B. M. Trost and C. Lee, in Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley-VCH, New-York, 2nd edn, 2000, pp. 593–650; (b) A. Pfaltz and M. Lautens, in Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and A. Yamamoto, Springer, Berlin, 1999, pp. 833–884.
5. Z. Lu and S. Ma, Angew. Chem., Int. Ed., 2008, 47, 258–297 and references therein.
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