Principles and Applications of Asymmetric Synthesis

Scheme 6±53. Reprinted with permission by Royal Chem. Soc., Ref. 115.

Transition metal complexes with chiral phosphorous and nitrogen ligands have also been used for promoting asymmetric transfer hydrogenation. Moderate to good results have been obtained.114

Chiral b-amino alcohols, which can be used for enantioselective alkylation of carbonyl groups (see Chapter 2 for b-amino alcohol±mediated asymmetric alkylation), are also e¨ective chiral ligands in asymmetric transfer hydrogenation. Takehara et al.115 report Ru(II)-catalyzed asymmetric transfer hydrogenation in the presence of chiral amino alcohol. A particularly high ligand-acceleration e¨ect in the reduction of aromatic ketones was observed. Highly enantioselective results were achieved when using a chiral ligand with suitable con®guration and functionality.115 As shown in Scheme 6±53, excellent enantioselectivities are observed in the asymmetric transfer hydrogenations of aromatic ketones catalyzed by a combination of ruthenium complex and chiral b-amino alcohol

122 or 123.

Other amino alcohols have also been used as chiral ligands in asymmetric catalytic hydrogen transfer. Scheme 6±54 depicts another example. Ruthenium complex bearing 2-azanorbornyl methanol was used as the chiral ligand, and the corresponding secondary alcohols were obtained in excellent ee.116

The asymmetric transfer hydrogenation of ketones is further described elsewhere.117

384 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

Scheme 6±54. Reprinted with permission by Am. Chem. Soc., Ref. 116.

6.5ASYMMETRIC HYDROFORMYLATION

Thus far, we have discussed the transition metal complex±catalyzed hydrogenation of CbC, CbO, and CbN bonds. In this section, another type of transition metal complex±mediated reaction, namely, the hydroformylation of ole®ns, is presented.

Optically active aldehydes are important precursors for biologically active compounds, and much e¨ort has been applied to their asymmetric synthesis. Asymmetric hydroformylation has attracted much attention as a potential route to enantiomerically pure aldehyde because this method starts from inexpensive ole®ns and synthesis gas (CO/H2). Although rhodium-catalyzed hydrogenation has been one of the most important applications of homogeneous catalysis in industry, rhodium-mediated hydroformylation has also been extensively studied as a route to aldehydes.

Cobalt and rhodium complexes are the most important catalysts for hydroformylation. The latter is more favored because the cobalt complex±catalyzed reactions usually involve high temperature and high pressure (e.g., up to 190 C, 250 bar), which may not be desirable for industrial processes. Another advantage of using a rhodium complex may be the possibility of using a variety of phosphorous ligands to optimize the regioselectivity as well as the stereoselectivity of the reaction. Thus, the rhodium±phosphine-catalyzed hydroformylation reaction, which was ®rst reported by Evans et al.118 in the late 1960s, remains one of the most attractive homogeneous catalytic processes. The mechanism of rhodium±phosphine-catalyzed hydroformylation is shown in Scheme 6±55.

The mechanism of the hydroformylation reaction suggests that aldehyde regioselectivity is determined in the hydride addition step, which converts the ®ve-coordinated H(alkene)-Rh(CO)L2 into either a primary or a secondary four-coordinated (alkyl)Rh(CO)L2. For the linear rhodium alkyl species, this

Scheme 6±55

step is irreversible at moderate temperatures and su½ciently high pressures of CO. The structure of the alkene complex is therefore thought to play a crucial role in controlling the regioselectivity.119

The ®rst highly enantioselective asymmetric hydroformylation was the asymmetric hydroformylation of styrene.120 In 1991, Stille et al.121 reported the achievement of up to 96% ee using a chiral bisphosphine complex of PtCl2 as the catalyst in combination with SnCl2. However, the Pt(II)-catalyzed hydroformylation of arylethenes and some functionalized ole®ns has several disadvantages, such as low reaction rates, a tendency for the substrates to undergo hydrogenation, and poor branched-to-linear ratio.

A big problem in asymmetric hydroformylation is that the chiral aldehyde products may be unstable and may undergo racemization during the reaction. This problem is even more serious for the Pt catalyst systems, which are usually plagued by slow reaction rates. Stille et al.121 tackled this problem by using triethyl orthoformate to trap the aldehyde products as their diethyl acetals and consequently increased the product ee values signi®cantly.

Using a chiral diphosphine±Rh(I) complex as the catalyst, high catalytic activity and a good branched/linear ratio can be achieved, but in most cases the ee values remain moderate.122 The enantioselectivity of Rh(I)-catalyzed reactions depends on the amount of added chiral ligand because of the much higher catalytic activity of ligand-free rhodium species. Usually 4±6 equivalents

386 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

of the ligand relative to the Rh(I) species has to be applied to maintain reasonable stereoselectivity.122a

Phosphite ligands have attracted attention for Rh(I)-catalyzed hydroformylation because their complexes often show higher catalytic activity than do phosphine complexes.123 Bisphosphite ligands with bulky substituents are often used to produce linear aldehydes from 1-alkenes, while the hydroformylation of styrene using these ligands results in branched aldehydes as major products. A bis(triarylphosphite) Rh(I) catalyst system shows comparable enantioselectivity but superior catalytic activity when compared with the corresponding triaryl phosphine±Rh catalyst. One feature of the phosphite system that di¨ers from the corresponding bisphosphine ligand is that smaller amounts of chiral ligand are needed to attain the maximum ee.124

The stereoelectronic properties of phosphorous ligands have a dramatic in¯uence on the reactivity of hydroformylation catalysts. By using a series of p-substituted triphenylphosphines, Moser et al.125 investigated the e¨ect of phosphine basicity on the hydroformylation of ole®ns. Their study showed that less basic phosphines a¨orded higher reaction rates and a higher ratio of linear to branched product.125 Electron-withdrawing substituents on phosphines in the equatorial position give high linear/branched ratios, whereas electron-withdrawing substituents on phosphines in the apical position favor the production of branched aldehydes. Rossi and Ho¨mann's molecular orbital analysis126 of ligand electronic site preferences in ®ve coordinated d8 ML5 complexes suggests that weaker s-donor ligands prefer to stay at the equatorial position while strong s-donor ligands prefer to occupy the apical position.

In the mechanism proposed by Evans et al.,118 a ®ve-coordinated trigonal bipyramidal bis(phosphine)rhodium species is the most important intermediate. In this species, two phosphine ligands occupy either two equatorial sites or one equatorial and one apical site. Casey et al.119a,127 found that the intermediate in which both phosphorous atoms of the ligand occupy an equatorial position is essential for achieving high normal/iso selectivity in the hydroformylation of 1-hexene, whereas intermediate RhH(CO)2(bisphosphite), bearing both of the phosphorous atoms at equatorial positions, is the active species for achieving high branched/linear selectivity and high enantioselectivity for the hydroformylation of styrene.124f,g

van der Veen et al.128 studied the electronic e¨ect on rhodium±diphosphinecatalyzed hydroformylation by using a series of thixantphos 124 as ligands. They studied the catalytic performance and coordination chemistry of the diphosphine ligands in rhodium complexes. In this series of ligands, steric di¨erences are mininal, so purely electronic e¨ects can be investigated. In the hydroformylation of 1-octene and styrene, decreasing the phosphine basicity led to an increase in both linear/branched ratio and reactivity, while increasing the phosphine basicity gave the opposite result. Decreasing the phosphine basicity facilitates CO dissociation from the (diphosphine)Rh(CO)2H complex, hence enhancing the alkene coordination to form the (diphosphine)Rh(CO)H(alkene)

complex and therefore increasing the reaction rate. The weakening of the Rh± CO bond in the rhodium±carbonyl complex by electron-withdrawing substituents on the ligand can be visualized as an increase in the carbonyl stretching frequency. They argue that the natural bite angle of the ligand might not be as e¨ective as previously claimed.128

The asymmetric hydroformylation of aryl ethenes such as substituted styrene or naphthylethene is of industrial interest because the hydroformylation products of these substrates are precursors to important nonsteroidal antiin¯ammatory drugs such as (S)-ibuprofen and (S)-naproxen. Strong e¨orts have been made to improve the branched/linear ratio, as well as the enantioselectivity of the product.

Nozaki et al.129 report the asymmetric hydroformylation of aryl ethene using 125 as a ligand. The ligand has a new feature in that it contains both a phosphine and a phosphite moiety. High branched/linear ratio as well as enantioselectivity results when its Rh(I) complex is applied to the hydroformylation of styrene substrates. This study shows that 126 is the single species in the reaction. In this structure, phosphine occupies the equatorial position and the phosphite occupies the apical position, and the conversion of the equatorial± apical con®guration to the equatorial±equatorial con®guration is not observed. Indeed, this may be the cause of the high regioselectivity as well as enantioselectivity of the reaction.

The asymmetric hydroformylation of styrene and its derivatives is shown in Scheme 6±56. The results of the reaction are governed by several factors, such as solvent, temperature, reaction time, and con®guration of the ligand. The con®guration of the product, in turn, is governed mainly by the con®guration of the phosphine moiety (compare Entries 1 and 5 in Scheme 6±56). Low temperature gives a better branched/linear ratio, as well as better enantioselectivity, but normally it leads to a drop in reaction rate. The reaction is sensitive to the

388 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

Scheme 6±56. Reprinted with permission by Am. Chem. Soc., Ref. 129.

solvent used. Reactions carried out in an electron-donating solvent such as THF or methanol normally give poor results. The Rh catalyst 126 have given the best overall results thus far for the asymmetric hydroformylation of aryl ole®ns.

6.6SUMMARY

Homogeneous enantioselective hydrogenation constitutes one of the most versatile and e¨ective methods to convert prochiral substrates to valuable optically active products. Recent progress makes it possible to synthesize a variety of chiral compounds with outstanding levels of e½ciency and enantioselectivity through the reduction of the CbC, CbN, and CbO bonds. The asymmetric hydrogenation of functionalized CbC bonds, such as enamide substrates, provides access to various valuable products such as amino acids, pharmaceuticals, and

6.7 REFERENCES 389

important building blocks for organic synthesis. The asymmetric hydrogenation or reduction of ketones allows the production of a large number of useful chiral alcohols that are ubiquitous in nature and are in great demand for ¯avors and fragrances, for pharmaceuticals, and for agrochemicals.

In asymmetric hydrogenation, the pressure of hydrogen may have a substantial impact on both the rates and the stereoselectivities of the reaction. These e¨ects may be attributed either to the formation of di¨erent catalytically competing species in solution or to the operation of kinetically distinct catalytic cycles at di¨erent pressures.

The solvent employed in asymmetric catalytic reactions may also have a dramatic in¯uence on the reaction rate as well as the enantioselectivity, possibly because the solvent molecule is also involved in the catalytic cycle. Furthermore, the reaction temperature also has a profound in¯uence on stereoselectivity. The goal of asymmetric hydrogenation or transfer hydrogenation studies is to ®nd an optimal condition with a combination of chiral ligand, counterion, metal, solvent, hydrogen pressure, and reaction temperature under which the reactivity and the stereoselectivity of the reaction will be jointly maximized.

The asymmetric hydroformylation of aryl ethenes such as substituted styrene and substituted b-naphthyl ethene will lead to the intermediates for important pharmaceuticals. Much concerted e¨ort has been applied to achieve high enantioselectivity as well as high regioselectivity toward the branched aldehydes. The research work in this area is of great industrial interest, and it continues to be a dynamic ®eld of study.

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