Tetrahedron: Asymmetry 21 (2010) 1135–1146

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Tetrahedron: Asymmetry

journal homepage: www.elsevier .com/locate / tetasy

Tetrahedron: Asymmetry Report Number 132

Highlights of the Rh-catalysed asymmetric hydroformylation of alkenesusing phosphorus donor ligands

Aitor Gual a, Cyril Godard a, Sergio Castillón b,*, Carmen Claver a,*

a Department de Química Física i Inorgànica, Universitat Rovira i Virgili, C. Marcel.li Domingo, s/n, 43007 Tarragona, Spainb Department de Química Analítica I Química Orgànica, Universitat Rovira i Virgili, C. Marcel.li Domingo, s/n, 43007 Tarragona, Spain

a r t i c l e i n f o a b s t r a c t

Article history:Received 2 April 2010Accepted 15 May 2010Available online 28 June 2010

Dedicated to Professor Henri Kagan on theoccasion of his 80th birthday

0957-4166/$ - see front matter � 2010 Elsevier Ltd. Adoi:10.1016/j.tetasy.2010.05.037

* Corresponding authors. Tel.: +34 977 559556; fax+34 977 559574; fax: +34 977 559563 (C.C.).

E-mail addresses: sergio.castillon@urv.cat (S. Cast(C. Claver).

Rhodium is currently the metal of choice to achieve high enantioselectivities in the hydroformylation of arelatively high variety of alkene substrates. The elucidation of the different steps of the catalytic cycle andthe characterisation of the resting state, together with the discovery of several types of ligands that areable to provide high enantioselectivities, have made the rhodium-catalysed hydroformylation a synthet-ically useful tool. For years, ligands containing phosphite moieties such as diphosphites and phosphine–phosphites were considered the most successful ligands to achieve high enantioselectivies in this process.In fact, the phosphite–phosphine BINAPHOS 43 and its derivatives are even today the most successfulligands in terms of selectivity and scope. Recently however, diphosphine derivatives were shown to pro-vide high levels of selectivity. It can consequently be concluded that the key to achieve high enantiose-lectivities is not the type the phosphorus function involved in the coordination to the metal, but theparticular spatial arrangement of the coordinated ligand.

� 2010 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11352. Rh-catalysed hydroformylation mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11363. Rh-catalysed asymmetric hydroformylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1137

3.1. Rh-catalysed asymmetric hydroformylation of monosubstituted alkenes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1137

3.1.1. 1,3-Diphosphite ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11373.1.2. Phosphine–phosphite ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11393.1.3. Bisphospholane ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11403.1.4. Bis-phosphonite ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11403.1.5. Monodentate phosphorus ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1141

3.2. Rh-catalysed asymmetric hydroformylation of disubstituted alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1141

3.2.1. Linear 1,2-disubstituted alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11413.2.2. Monocyclic 1,2-disubstituted alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11423.2.3. Bicyclic 1,2-disubstituted alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11433.2.4. 1,10-Disubstituted alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1143

4. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1145References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1145

1. Introduction

The hydroformylation of alkenes, which was originally discov-ered by Otto Roelen in 1938,1 nowadays is one of the most important

ll rights reserved.

: +34 977 558446 (S.C.); tel.:

illón), carmen.claver@urv.cat

industrial applications of homogeneous catalysis (Scheme 1).2,3 To-day, over 9 million tons of so-called oxo-products are produced peryear, a number which is still rising. The majority of these oxo-prod-ucts are obtained from the hydroformylation of propene 1, which is afraction of the steam-cracking process. The resulting products n-butanal 2 and iso-butyraldehyde 3 are important intermediates forthe production of esters, acrylates and 2-ethylhexanol.2

From a synthetic point of view, the reaction is a one-carbonchain elongation caused by the addition of carbon monoxide and

R R*

R+ CHOCHOcatalyst

CO/H2

5favored for

R= Aryl, OAc, etc.

6favored forR= Alkyl.

R* CHO

R*+ R´

catalystCO/H2R´ R

R´

CHO

RCHO

catalystCO/H2 *

R

R´ R´

R* CHO

catalystCO/H2

*R

R´R´

R´´R´´

4

8 97

11 1210

+ *R

R´OHC

14 1513

+*

R

R´R''

OHC

Scheme 2. Regioselective trends on hydroformylation of different alkenes.

Rh RhC

C

CO

LLCO

L LO

O

H2Rh COL

LH

Rh COL

CO

LH

Rh LL

HOC

RhOC L

LH

RhL

CO

LH

Rh COL

LRhCOOC L

L RhL

CO

L CO

Rh COL

LCO

RhCOOC L

LC

O

RhL

CO

LC

CO

O O

H

H2

CO

23 16 eq-ax 16 eq-eq

22 eq-ax 22 eq-eq 17

18 eq-ax 18 eq-eq

1920 eq-ax 20 eq-eq

21

COCO

CO

OC

Scheme 3. Mechanism of the Rh-catalysed asymmetric hydroformylation inpresence of bidentate ligand (L–L).

+ CHOCHOcatalyst

CO/H2

2 31

*

Scheme 1. Hydroformylation of propene.

1136 A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146

hydrogen across the p system of a C@C double bond.4,5 As a pureaddition reaction, the hydroformylation reaction meets all therequirements of an atom economic process.6 Furthermore, the syn-thetically valuable aldehyde function is introduced, which allowssubsequent skeleton expansion that may even be achieved inone-pot sequential transformations.7,8

In 1968, Wilkinson discovered that phosphine-modified rho-dium complexes display a significantly higher activity and selectiv-ity compared to the first generation of cobalt catalysts.9 Since thistime, ligand modification of the rhodium catalyst has been themethod of choice in order to influence the catalyst activity andselectivity.10

In the asymmetric hydroformylation of alkenes, the first exam-ples of high levels of enantioselectivity (ee’s up to 90%) wereachieved by Stille and Consiglio using chiral Pt-diphosphine sys-tems.11 However, these catalysts suffered several disadvantagessuch as low reaction rates, tendency to hydrogenate the substratesand low regioselectivity for the branched products. Later, these is-sues were mainly overcome by the use of Rh-based catalysts.12

In the low-pressure hydroformylation of internal alkenes, thechemoselectivity (and simultaneously regioselectivity) is one ofthe remaining problems to be solved in industry. This issue origi-nates from the exponential drop of alkene reactivity with increas-ing number of alkene substituents. The known hydroformylationcatalysts for internal alkene hydroformylation operating underlow-pressure conditions rely on the use of strong p-acceptor li-gands such as bulky phosphites and phosphobenzene systems.13

However, the high activity of the corresponding rhodium catalystsis always associated with a high tendency towards alkene isomeri-sation, which renders a position-selective hydroformylation of aninternal alkene so far impossible.

The regioselectivity of the hydroformylation of alkenes is a func-tion of many factors. These include inherent substrate preferences,directing effects exerted by functional groups as part of the substrate,as well as catalyst effects. In order to appreciate substrate inherentregioselectivity trends, alkenes have to be classified according tothe number and nature of their substituent pattern (Scheme 2).4,5

The regioselectivity issue usually only arises for terminal and1,2-disubstituted alkenes 7. For alkyl-substituted terminal alkenes4 there is a slight preference for the linear product 6. For terminalalkenes 4 containing electron-withdrawing substituent the forma-tion of the branched product 5 is favoured, and is sometimes theexclusive product. This tendency is more or less unaffected bythe catalyst structure. Both 1,1-disubstituted 10 and trisubstituted13 alkenes generally provide only one regioisomer (11 and 14,respectively) based on Keuleman’s rule, which states that the for-myl group is usually added in order to avoid the formation of aquaternary carbon centre.14

Asymmetric hydroformylation is a very promising catalyticreaction that produces chiral aldehydes from inexpensive feed-stock (alkenes, syngas) in a single step under essentially neutralreaction conditions. Even though asymmetric hydroformylation of-fers great potential for the fine chemical industry, this reaction hasnot yet been utilised on an industrial scale due to several technicalchallenges.2 Among the most significant issues are (a) the low reac-tion rates at low temperature where good selectivities are usuallyobserved, (b) the difficulty to control simultaneously the regio- andthe enantioselectivity and (c) the limited substrate scope for anysingle ligand.

2. Rh-catalysed hydroformylation mechanism

In Scheme 3, the well-known mechanism of the Rh-catalysedhydroformylation mechanism proposed by Heck is described forbidentate ligands.15 It corresponds to Wilkinson’s so-called disso-ciative mechanism.9 The associative mechanism involving 20-elec-tron intermediates for ligand/substrate exchange will not beconsidered. In this process, a great understanding of the mechanismhas been possible due to the observation and structural character-isation of the resting state of the catalyst by in situ spectroscopictechniques (HP-IR and HP-NMR).10 For bidentate ligands (L–L),the common starting complex is the [RhH(L–L)(CO)2] species 16,containing the ligand coordinated in equatorial positions (denotedeq–eq throughout the scheme) or in an apical-equatorial positions(complexes denoted eq–ax).

R R*

R+ CHOCHOcatalyst

CO/H2

5 64

Scheme 4. Asymmetric hydroformylation of monosubstituted alkenes.

R R*

CHORh/LCO/H2

A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146 1137

Dissociation of equatorial CO from 16 leads to the square-planarintermediate 17, which associates with alkene to give complexes18, where the ligand can again be coordinated in two isomericforms eq–ax and eq–eq, having a hydride in an apical positionand alkene coordinated in the equatorial plane. On the basis ofexperimental results and theoretical calculations, it has been pro-posed that the regioselectivity is determined by the coordinationof the alkene to the square planar intermediate 17 to give thepentacoordinate intermediates 18.16 This step is also crucial indetermining the enantioselectivity since the enantioface discrimi-nation occurs between 17 and 19, and particularly from 17 to 18.The CO dissociation from 16 was shown to be much faster thanthe overall hydroformylation process, indicating that the rate ofthe reaction is dominated by the reaction of 17 with either CO oralkene to form 16 or 18.17 It has not been established experimen-tally whether alkene complexation is reversible or not; although inthe Scheme 3, all steps are described as reversible except the finalhydrogenolysis. Experiments using deuterated substrates suggestthat alkene coordination and insertion into the Rh–H bond canbe reversible, certainly when the pressures are low. Complexes18 undergo migratory insertion to give the square-planar alkylcomplex 19. This species can undergo b-hydride elimination, thusleading to isomerisation, or can react with CO to form the trigonalbipyramidal (TBP) complexes 20. Thus, under low pressure of COmore isomerisation may be expected. At low temperatures(<70 �C) and a sufficiently high pressure of CO (>10 bar) the inser-tion reaction is usually irreversible and thus the regioselectivityand the enantioselectivity in the hydroformylation of alkenes aredetermined at this point. Complexes 20 undergo the second migra-tory insertion (see Scheme 3) to form the acyl complex 21, whichcan react with CO to give the saturated acyl intermediates 22 orwith H2 to give the aldehyde product and the unsaturated interme-diate 17. The reaction with H2 involves presumably oxidative addi-tion and reductive elimination, but for rhodium no trivalentintermediates have been observed.18 At low hydrogen pressuresand high rhodium concentrations, the formation of dirhodium dor-mant species such as 23 becomes significant.19

O OP POO O

O

(2R, 4R)-24

OO

binaphthyl

OR1

R2

R2

R1O

biphenyl

O O O O

R

R

Ph Ph

O OP POO O

O

(2R, 4R)- 27

O OP POO O

O

(2S, 4S)- 28

O OP POO O

O

(2R, 3R)- n =0 25

(2R, 5R)- n =2 26

n

O O

OO

pentane-2,4-diol

5a R= Ph

5b R= CH2CN

5c R= OAc

99 90

87 13

99 58

Rh/L Product Regio (%) ee (%)

4a-c

24a,d

24a

24a

5a-c

3. Rh-catalysed asymmetric hydroformylation

As mentioned above, the catalytic hydroformylation of alkenesis one of the largest applications of homogeneous organotransitionmetal catalysis today. Due to the robustness of the process and thewide availability of alkene substrates, enantioselective hydrofor-mylation provides great possibilities to obtain a great variety ofenantiomerically pure aldehydes. The first Rh-based systems thatwere reported in the asymmetric hydroformylation containeddiphosphine ligands that provided low to moderate enantioselec-tivities.12 With this type of ligand, the highest ee value wasreported using styrene as a substrate and bdpp (bis-diphenylphos-phino pentane) as a ligand (ee’s up to 64%).20 Later, higher enanti-oselectivities were achieved using more sophisticated diphosphiteand phosphine–phosphite ligands.3–5,10

In the following sections, the most relevant results reported inthe asymmetric Rh-catalysed hydroformylation of alkenes are de-scribed. The reactions are classified by degree of substitution ofthe substrates in order to highlight the issue of the substrate/ligandcompatibility in this process.

e (R/S)ax; R = Si(alkyl)3

f (R)ax ; R = Si(alkyl)3

g (S)ax ; R = Si(alkyl)3

a R1= tBu; R2= OMe

b R1= R2 = tBu

c R1= R2 = H

d R1= Si(alkyl)3; R2= H

h (2R, 4R)

i (2S, 4S)

Scheme 5. Rh-catalysed asymmetric hydroformylation of styrene using ligands 24–28.

3.1. Rh-catalysed asymmetric hydroformylation ofmonosubstituted alkenes

The hydroformylation of monosubstituted alkenes (Scheme 4)was extensively studied due to the interest in the synthesis oflinear aldehydes (non-chiral) or the enantioselective synthesis of

2-substituted branched aldehydes using chiral hydroformylationcatalysts.2–5

For example, the hydroformylation of vinylarenes (R = aryl) isused as a model for the synthesis of 2-aryl propionaldehydes,which are intermediates in the synthesis of 2-aryl propionic acids,the profen class of non-stereoidal drugs. Nowadays, the applicationof the Rh-catalysed asymmetric hydroformylation to obtain enan-tiomerically pure chiral aldehydes is growing. The Rh-catalysedasymmetric hydroformylation of several other monosubstituted al-kenes, such as allyl cyanide and vinyl acetate, was successfully car-ried out.3–5 In general, 1,3-diphosphite and phosphine–phosphiteligands provided the best results in these processes.10 However,the use of bisphophacyclic ligands has recently emerged as an effi-cient alternative.3–5

3.1.1. 1,3-Diphosphite ligandsThe use of disphosphite ligands was intensively studied in this

process as they provide high levels of selectivity with these sub-strates.21 The initial success in the rhodium-catalysed asymmetrichydroformylation of vinylarenes came from Union Carbide withthe discovery of the diphosphite ligand (2R,4R)-pentane-2,4-diol24 (Scheme 5).22

OO

binaphthyl

e (R/S)ax; R = Si(alkyl)3

f (R)ax ; R = Si(alkyl)3

g (S)ax ; R = Si(alkyl)3

OR1

R2

R2

R1O

biphenyl

a R1= tBu; R2= OMe

b R1= R2 = tBu

c R1= R2 = H

d R1= Si(alkyl)3; R2= H

OO

OO R

R= =

O

OO

OPPO

29

O

OO

OPPO

30

O

OO

O

31

O

OO

PO

32

O

OO

PO

33

O

OO

34

OP

POPOPO

OP

OO

OO

OO

OO

OO

OO

OO

OO

OO

OO

OO

OO P

O

OR

OPPOO

OC16H33

OPPO

38

OO

OO

OO

OO

O

OO

OPPO

39 R1=R2 = H; R3= CH2CH2CH3

40 R1=R2 = CH3; R3= H

41 R1=R2 = CH3; R3= CH2CH2CH3

OO

OO

OR3

R1R2

35 R= C4H9

36 R= C14H29

37 R= C16H33

R R*

CHO

5a R= Ph

5c R= OAc

99 93

99 73

Rh/L Product Regio (%) ee (%)

4a,c

CO/H2

30a,d

30a

5a,c

Rh/L

Scheme 6. Rh-catalysed asymmetric hydroformylation of styrene using ligands29–41.

1138 A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146

Good chemo-, regio- and enantioselectivities (ee up to 90%)were obtained with (2R,4R)-pentane-2,4-diol diphosphite deriva-tives 24c but only when the reaction was performed around roomtemperature. Inspired by these excellent results, other researchgroups synthesised a series of diphosphite ligands 25–28 in orderto study the effect of structural modifications on the Rh-catalysedasymmetric hydroformylation of vinylarenes (Scheme 5).23,24

The influence of the bite angle of these ligands was studied withdiphosphite ligands (2R,4R)-pentane-2,4-diol 24, (2R,4R)-butane-2,4-diol 25 and (2R,4R)-hexane-2,4-diol 26.23b In general, the li-gand 24, which contains a three carbon atoms bridge, providedhigher enantioselectivities than ligands 25 and 26, which have atwo and four carbon atoms bridge, respectively.

The effect of different phosphite moieties was studied with li-gands 24a–g.23 In general, sterically hindered phosphite moietiesare necessary to achieve high enantioselectivities. The results indi-cated that varying the ortho and para substituents on the biphenyland binaphthyl moieties has also a great effect on the asymmetricinduction. The highest enantioselectivity (ee up to 90% at 20 bar ofsyngas and 25 �C) in the Rh-catalysed asymmetric hydroformyla-tion of styrene was obtained by using the ligands 24a and 24d.

The influence of the backbone was studied by comparing the re-sults obtained with the ligands 24 and 27.23 Surprisingly, the li-gand 27, which contains a more sterically hindered phenyl group,provided lower enantioselectivity than ligand 24.

A cooperative effect between the different stereogenic centresof the phosphite ligands 24f–i and 28f–i was demonstrated. Ini-tially, van Leeuwen et al. studied the cooperative effect betweenthe chiral ligand bridge and the axially chiral binaphthyl phosphitemoieties by comparing ligands 24f,g and 28f,g. The hydroformyla-tion results indicated a suitable combination for ligand 24g (ee’s upto 86%).23 Later, Bakos et al. found a similar matched-mismatchedeffect between the chiral ligand bridge and the chiral phosphitemoiety of the ligands 24h,i and 28h,i.24a Interestingly, the hydro-formylation results obtained with ligands 24a and 24d, that areconformationally flexible and contain axially chiral biphenyl moie-ties, are similar to those obtained with ligand 24g. This indicatedthat diphosphite ligands containing these biphenyl moieties pre-dominantly exist as a single atropoisomer in the hydridorhodiumcomplexes [RhH(CO)2(diphosphite)] when bulky substituents arepresent in ortho positions.23 It is therefore not necessary to useexpensive conformationally rigid binaphthyl moieties.

To investigate whether a relationship exists between the solu-tion structures of the [RhH(CO)2(diphosphite)] species and cata-lytic performance, van Leeuwen and co-workers extensivelystudied the [RhH(CO)2(diphosphite)] (diphosphite = 24, 28) speciesformed under hydroformylation conditions by high pressure NMRtechniques (HP-NMR).5,10 From these trigonal bipyramidal (TBP)complexes, two isomeric structures are possible: one containingthe diphosphite coordinated in a bis-equatorial (eq–eq) fashionand the other containing the diphosphite in an equatorial-axial(eq–ax) fashion (Scheme 3). The results indicated that the stabilityand catalytic performance of the [RhH(CO)2(diphosphite)] (diphos-phite = 24, 28) species strongly depend on the configuration of thepentane-2,4-diol ligand backbone and on the chiral biaryl phos-phite moieties. Thus, ligands 24a, 24d and 24g, which form well-defined stable bis-equatorial (eq–eq) complexes, lead to goodenantiomeric excesses. In contrast, with ligands 24i and 28g, whichform mixtures of complexes, lead to low enantioselectivities.23,25

The ligand 24a was also evaluated in the Rh-catalysed asymmetrichydroformylation of allyl cyanide 4b and vinyl acetate 4c but lowto moderate enantioselectivities (13% and 58%, respectively) wereobtained with these substrates.3a

1,3-Diphosphite ligands derived from 1,2-O-isopropyliden-a-D-xylofuranose 29, 32 and 6-deoxy-1,2-O-isopropyliden-a-D-glucofuranose 30, 31, 33 and, 34 were successfully applied in

the Rh-catalysed asymmetric hydroformylation of vinylarenes(Scheme 6).26

The use of diphosphite ligands 30a,d and 34a,d in the Rh-cata-lysed asymmetric hydroformylation of styrene provided the (S)-and (R)-enantiomers of the product with high enantioselectivies(ee up to 93%) and excellent regioselectivity (Scheme 6).26c,d Theligand 30b was also tested in the hydroformylation of vinyl acetateobtaining excellent regioselectivity (99%) with an enantioselectivi-ty of 73%.27b

Recently, related C1-symmetry diphosphite ligands conforma-tionally more flexible 35–38 or incorporating an increase in sterichindrance at the C-6 position 39–41 were synthesised (Scheme 6).27

These ligands were probed in the hydroformylation of styrene 4aand vinyl acetate 4c with good regio- and enantioselectivity (upto 81% and 68%, respectively), but these selectivities resulted tobe lower than with ligand 30. Therefore, the bicycle structure andthe methyl substituent at C-5 position seem to be required toachieve high enantioselectivity in the hydroformylation of styreneand vinyl acetate when using 1,3-diphosphites derived fromcarbohydrates.

(R,S)-BINAPHOS 43(S,R)-BINAPHOS 44

R R*

CHORh/LCO/H2

Product

R

Regio (%)

ee (%)

5a 5d 5c 5b 5e 5f 5g 5h

Ph C6F5 OAc CH2CN CF3 Et Phth S(4-tolyl)

90 96 86 72 95 21 89 96

94 98 92 66 93 83 85 74

4a-h 5a-h

PPh2OP

OO

Scheme 8. Rh-catalysed asymmetric hydroformylation of monosubstituted alkenesusing (R,S)- and (S,R)-BINAPHOS (43) and 44.

A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146 1139

In summary, the results obtained in the Rh-catalysed asymmet-ric hydroformylation of monosubstituted alkenes indicate that (a)the absolute configuration of the product is governed by the con-figuration at the stereogenic centre C-3; (b) the level of enantiose-lectivity is influenced by the presence of stereocentres at C-3 andC-5 positions, where the phosphorus atoms are attached; (c) bulkysubstituents in ortho positions of the biaryl phosphite moieties arenecessary to achieve high levels of enantioselectivity and (d) pseu-do-enantiomer ligands such as 30 and 34 afford the same level ofenantioselectivity for both product enantiomers.

Interestingly, the ligands 30 and 34, for which only [RhH(CO)2(L)]species with eq–eq coordination were observed by HP-NMR tech-niques, provided higher enantioselectivity (ee up to 93%) than therelated ligands 31 and 33 (ee up to 64%), for which an equilibriumbetween the isomeric eq–eq and eq–ax [RhH(CO)2(L)] species wasobserved by HP-NMR and HP-IR techniques. Therefore, the presenceof a single coordination isomer, in this case with ligand coordinatedin an equatorial–equatorial eq–eq mode, was observed to producehigh levels of enantioselectivity in the Rh-catalysed asymmetrichydroformylation of styrene, as previously mentioned.26c,d,27

In contrast with the diphosphites previously mentioned, theKELLIPHITE ligand (42), which was developed by Dow ChemicalCompany, incorporates the chirality in the bisphenol unit, whilethe backbone is achiral (Scheme 7). The catalytic system containingthis ligand afforded very good enantioselectivity in the rhodium-catalysed hydroformylation of vinyl acetate and allyl cyanide,although low selectivities were obtained in the hydroformylationof styrene.28

OO

P

P

OO

OO

KELLIPHITE 42

O OO O tButBu

R R*

CHO

5a R= Ph

5b R= CH2CN

5c R= OAc

98 16

94 78

99 88

Product Regio (%) ee (%)

4a-c

Rh/42CO/H2

5a-c

Scheme 7. Rh-catalysed asymmetric hydroformylation of monosubstituted alkenesusing ligand KELLIPHITE 42.

PAr2OP

OO

45 Ar = 3-MeOC6H4

5a R= Ph 95

5i R= 2-vinylfuran

5j R= 3-vinylfuran

5k R= 2-vinylthiophene

5l R= 3-vinylthiophene

PPh2NP

OO

(R,S)-YANPHOS 46

5a R= Ph

5c R= OAc

Rh/45 Rh/46Regio(%) ee(%) Regio(%) ee(%)

89 99

93 96

97

79

99

93

91

R R*

CHORh/LCO/H2

4a,c,i-l 5a,c,i-l

Scheme 9. Rh-catalysed asymmetric hydroformylation of monosubstituted alkenesusing ligands 45 and 46.

3.1.2. Phosphine–phosphite ligandsThe discovery of the (R,S)-BINAPHOS 43 and (S,R)-BINAPHOS 44

ligands in 1993 by Takaya and Nozaki produced a real break-through in the Rh-catalysed asymmetric hydroformylation reac-tion (Scheme 8).29

These ligands allowed for the first time an increase in the scopeof this process since they provided high enantioselectivity in theRh-catalysed asymmetric hydroformylation of several classes ofmonosubstituted alkenes such as vinyl arenes, 1-heteroatom-func-tionalised alkenes and disubstituted 1,3-dienes (Scheme 8), andis still currently a reference in this area.30 Excellent regio- andenantioselectivities were achieved with most of these substrates,although the formation of the branched product (21%) was disfa-voured when but-1-ene was the substrate. In 2003, De Vries et al.reported the first Rh-catalysed asymmetric hydroformylation of

allylcyanide and although moderate regioselectivity was obtained(72%), the highest enantioselectivity (66%) by far was achievedusing the ligand 43.31 As a general rule, the presence of electron-withdrawing substituents such as phenyl or heteroatoms in the al-kene substrate leads to a control the regioselectivity in favour of thebranched product, independently of the ligand used.3a

It is noteworthy that (R,S)-BINAPHOS 43 or the (S,R)-BINAPHOS44 ligands yield the two enantiomers of the product with highenantioselectivity;32 however, the (R,R)- and (S,S)-BINAPHOS, dia-stereoisomers of ligands 43 and 44, yielded much lower enantiose-lectivity in this process, thus demonstrating the importance of thecombination of opposite configurations at the phosphine and phos-phite moieties.

In contrast with the previously mentioned diphosphite ligandswhich coordinate to the Rh centre in an eq–eq fashion, the BINA-PHOS ligand was found to coordinate to Rh in an eq–ax mode

1140 A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146

as a single isomer in the resting state [RhH(CO)2(L–L)] of theprocess.32

The second generation of BINAPHOS-type ligands (Scheme 9)was recently developed by the introduction of 3-methoxy substit-uents on the aryl phosphine units 45,30b,c and by replacement ofthe phosphite group by a phosphoramidite function, yielding theYANPHOS ligand 46 (Scheme 9).33 The Rh/45 increased the regio-and enantioselectivity in the asymmetric hydroformylation of sty-rene, vinylfuranes and thiophenes. (Scheme 9).

YANPHOS 46 provided higher enantioselectivity than the BINA-PHOS ligand 43 without altering the regioselectivity in the Rh-cat-alysed asymmetric hydroformylation of styrene and vinyl acetate(ee up to 99% and 96%, respectively). Recently, the efficiency ofthe ligand 46 was again demonstrated in the Rh-catalysed hydro-formylation of monosubstituted alkenes such as derivatives of sty-rene and vinylacetate, with ee’s up to 99% and 98%, respectively.34

Inspired by the excellent results obtained using 43 and 44, sev-eral new phosphine–phosphite ligands with different backboneswere developed in the last years but the catalytic results usingthese ligands provided lower enantioselectivity (from 20% to85%) than with the original BINAPHOS.35

3.1.3. Bisphospholane ligandsSeveral bisphospholane chiral ligands known as efficient li-

gands for asymmetric hydrogenation were recently evaluated inasymmetric hydroformylation (Scheme 10).36

Two ligands, namely (S)-BINAPINE 47 and (S,S,R,R)-TANGPHOS48, were found to give excellent enantioselectivities in the asym-metric hydroformylation of styrene, allyl cyanide and vinyl acetate

PP

Ph

Ph

Ph

Ph

(R,R)-Ph-BPE 49

P

(R,S)-BINAPINE 47

P

tBu

H

H

tBu

(S

R

Rh/LCO/H2

4a-c

Esphos 50

N PN

P NN

Ph

PhH

H

Product 5a 5b

Rh/L R= Ph R= C

47

48

49

50

51

90 94

93 90

98 94

97 89

8

8

8

8

Regio

Scheme 10. Rh-catalysed asymmetric hydroformylation of mon

(Scheme 10).36 It is noteworthy that the enantioselectivitiesachieved for product 5b with these ligands are the highest ever re-ported for the allyl cyanide substrate.

The discovery of the biphospholane scaffold as a new privilegedstructure for asymmetric alkene hydroformylation has triggerednew research efforts for novel and improved bisphospholane-typeligands. In this context, the (R,R)-Ph-BPE ligand 49 (Scheme 10),derivative of DuPhos, was identified as an outstanding ligand forasymmetric hydroformylation since excellent regio- and enanti-oselectivities were achieved for styrene, allyl cyanide and vinylacetate as substrates with this ligand.37 Several spacers betweenthe two phosphorus donor atoms were evaluated and the two car-bon bridge of 49 provided the highest selectivity for all threesubstrates.38

A series of bis-2,5-diazaphospholane ligands was also probed inthis process and the ESPHOS 50 proved to be optimal, with the bestresults being obtained in the hydroformylation of vinyl acetate (eeup to 89%) (Scheme 10).39 The bis-3,4-diazaphospholane ligand 51also provided excellent regio- and enantioselectivity (ee up to 96%)in this reaction (Scheme 11).40

3.1.4. Bis-phosphonite ligandsThe bis-phosphonite ligand 52 provided moderate selectivities

in the hydrofomylation of styrene and allyl cyanide. However, thisligand provided an excellent 91% ee in the hydroformylation of vi-nyl acetate.41 The related diphosphinite ligand derived from ferro-cene 53 was also recently reported by Ding et al. and its applicationin the Rh-catalysed asymmetric hydroformylation of styrene andvinyl acetate provided good conversion but lower enantioselectiv-

PPtBu tBu

H

H

,S,R,R)-TANGPHOS 48

R*

CHO

5a-c

Bis-3,4-diazaphospholane 51

P PNN N

NAr

Ar

Ar

Ar

O

O O

O

5c

H2CN R= OAc

7 94

8 93

8 90

3 87

97 87

97 83

99 82

94 89

98 96

(%) ee(%)

osubstituted alkenes using the diphosphine ligands 47–51.

NHP

OO

56

NN

Ph2P

NZnN NZnN OOO

O

tButButBu

tBu tBu

tButBu

tBu

R R*

CHORh/53CO/H2

4a R=Ph 5a R=Ph 90 74Regio (%) ee (%)

Scheme 13. Rh-catalysed asymmetric hydroformylation of styrene using thetemplated ligand 56.

R R*

CHORh/LCO/H2

P PO

ON

N

O

O

O

O N

N

O

O

4a-c 5a-c

PO

ON

N

O

O

PO

O

N

N

O

O

Fe

52

53

92 79

95 55

82 79 98 91

94 83

Regio (%) ee (%)

52

53

Product 5a 5b 5c

Rh/L R= Ph R= CH2CN R= OAc

Scheme 11. Rh-catalysed asymmetric hydroformylation of monosubstitutedalkenes with ligands 52 and 53.

A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146 1141

ities in the hydroformylation of styrene and vinyl acetate (up to55% and 83%, respectively).42

3.1.5. Monodentate phosphorus ligandsNowadays, despite the successful use of monodentate ligands in

many transition metal catalysed processes, there are only a few re-ports concerning their use in asymmetric hydroformylation.Achieving high enantioselectivies in this process using those li-gands remains a challenge.

Although the use of monodentate phosphorus donor ligandsusually provides higher catalytic activity than their bidentatecounterparts, only moderate to good enantioselectivities were re-ported in asymmetric hydroformylation processes so far. For in-stance, the ligand 54 was tested in the Rh-catalysed asymmetrichydroformylation of styrene and allyl cyanide and provided mod-erate enantioselectivities (Scheme 12).28 When vinyl acetate was

54

R R*

CHORh/LCO/H2

OO

tBu

tBu

P OR

55

OO

tBu

tBu

P NR2

4a-c 5a-c

54

55

94 38 84 43

96 80

93 8Regio (%) ee (%)

Product 5a 5b 5c

Rh/L R= Ph R= CH2CN R= OAc

Scheme 12. Rh-catalysed asymmetric hydroformylation of monosubstitutedalkenes using ligands 54 and 55.

the substrate, very poor ee’s were obtained (Scheme 12). However,in 2004, Ojima et al. reported the use of the phosphoramiditeligand 55 (Scheme 12), related to monophosphite 54, in theRh-catalysed asymmetric hydroformylation of allyl cyanide andachieved excellent regioselectivities together with the highestenantiomeric excess (80%) ever reported for this reaction with amonodentate ligand.43 These results, although still far from thoseobtained with bidentate ligands, clearly indicated that achievinghigh ee’s using monodentate ligands is possible.

In 2005, Breit reported an alternative approach to the classicalsynthesis of bidentate ligands for hydroformylation by using theself-assembly of bidentate ligands based on an A–T base-pair mod-el.44 This method presents the advantage of allowing the rapidscreening of various pairs of available monodentate ligands to ob-tain the most suitable combination for each substrate, overcomingthe typical synthetic limitations for new bidentate ligands. Later,van Leeuwen and Reek reported the template-induced formationof chelating heterobidentate ligands by the self-assembly of two dis-tinct monodentate ligands on a rigid bis-zinc(II)-salphen templatewith two identical binding sites (Scheme 13).45 The templated het-erobidentate ligand 55 induced much higher enantioselectivities(ee up to 72%) than any of the corresponding homobidentate ligandsor non-templated mixed ligand combinations (ee up to 13%) in theRh-catalysed asymmetric hydroformylation of styrene.

3.2. Rh-catalysed asymmetric hydroformylation ofdisubstituted alkenes

The Rh-catalysed asymmetric hydroformylation of disubstitutedalkenes has received much less attention than their monosubsti-tuted counterparts. To the best of our knowledge, only a fewexamples of asymmetric Rh-catalysed hydroformylation of 1,2-disubstituted and 1,1-disubstituted alkenes have been reported sofar (Scheme 2).12a,27b,46–58

3.2.1. Linear 1,2-disubstituted alkenesThe asymmetric hydroformylation of propenylbenzenes was

originally studied by Kollár using PtCl2(bdpp)/SnCl2 as catalyst.46

The reaction was performed using trans-anethole and estragoleas substrate in order to synthesise the branched chiral aldehydes8a and 9a (Scheme 14). However, the formation of the linear alde-hyde was observed due to the trans-anethole isomerisation into theterminal monosubstituted estragole. Furthermore, moderate to lowenantioselectivities were obtained (ee up to 27%). The 1,3-diphos-

1142 A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146

phite ligand 29 was used in the Rh-catalysed asymmetric hydrofor-mylation of trans-anethole 7a and estragole 7b (Scheme 14) butmoderate to low enantioselectivities were achieved (ee up to 15%).47

Ar Ar*

CHOM/LCO/H2 + Ar ∗

CHO

Ar

M/LCO/H2 + Ar CHO

trans-anethole

Estragole

Ar ∗

CHO

7a

7b

8a 9a

9a linear

Ar= p-MeOPh

Scheme 14. Isomerisation processes and asymmetric hydroformylation of trans-anethole and estragole.

Nozaki et al. reported the asymmetric Rh-catalysed hydrofor-mylation of trans-anethole 7a into 8a using the BINAPHOS ligand43 with excellent regioselectivity (98%) and a remarkable 80% ee.48

In the Rh-catalysed asymmetric hydroformylation of 1,2-alkyl-disubstituted alkenes (Scheme 15) as substrates, the BINAPHOSligand 43 provided the highest ee values.48 Interestingly, it was re-ported that the E-isomers 7d and 7f yielded lower enantioselectivitythan their Z-counterparts 7c and 7e.

R2 R3

*OHCRh/43CO/H2

H R1

7c-f 8c-f

R1

R2R3

Product

8c R1= H, R2=R3= Me

8d R1= Me, R2= H, R3= Me

8e R1= H, R2=R3= Et

8f R1= Et, R2= H, R3= Et

ee (%)

85

48

79

69

Scheme 15. Rh-catalysed asymmetric hydroformylation of di-substituted alkenes.

3.2.2. Monocyclic 1,2-disubstituted alkenesAmong monocyclic 1,2-disubstituted alkene substrates, five-

membered ring heterocycles such as dihydrofurans and dihydro-pyrroles have been the most studied. With these substrates, thesimultaneous control of the chemo-, regio- and enantioselectivityis a key issue since the presence of a heteroatom in the cycle fa-vours in some cases an isomerisation process in the presence of a

7g-i

X X

[Rh]-H

X

[Rh]

XCO

CO[Rh

7j-l

X X

[Rh]-HC

H-[Rh]

H-[Rh] X

[Rh]

X [Rh]

+

Scheme 16. Isomerisation processes observed during the Rh-asymm

metal-hydride species. Previous studies using achiral ligands dem-onstrated that the reaction conditions highly affected the chemo-and regioselectivity of this reaction.49 Indeed, allyl ethers wereshown to rapidly isomerise into their vinyl analogues under hydro-formylation conditions (Scheme 16). This isomerisation process isof critical importance since it has a direct influence not only onthe regioselectivity of the reaction but also on the enantioselectiv-ity since the opposite enantiomers of tetahydro-3-carbaldehydeare formed from the allylic 7g–i and vinylic 7j–l isomers of the sub-strate.50 It is therefore required to limit the isomerisation in orderto obtain high selectivities. In the Rh-catalysed asymmetric hydro-formylation of 2,5-dihydrofuran 7g, Nozaki and co-workers re-ported the first successful results using the BINAPHOS ligand 43which yielded total regioselectivity to the tetahydro-3-carbalde-hyde 8g with 68% ee (R) (Scheme 17).48,51 However, when the2,3-dihydrofuran 7j was tested with the same catalyst, no regiose-lectivity was observed and the ee obtained for the aldehyde 8g de-creased to 38% with (S)-configuration. This catalytic system wasthus suitable to avoid isomerisation of 7g into 7j but not selectivefor the hydroformylation of 7j. In the same study, the amine ana-logues 7h–i and 7k were also tested as substrates using the samecatalytic system (Scheme 17) and similar results were obtained.

Recently, the previously mentioned 1,3-diphosphites 30–41derived from carbohydrates were successfully applied in the Rh-catalysed hydroformylation of these substrates.52,27b The resultsindicated that ligands 30, 38–41, which have a glucose configura-tion, are the most appropriate to obtain high enantioselectiveinduction in the hydroformylation of these substrates. In the caseof the 2,5-dihydrofuran 7g, the highest enantioselectivity in thealdehyde 8g was obtained using ligand 38b [88% (S)]. Using thisligand, no isomerisation was observed under hydroformylationconditions. Interestingly, the presence of bulky substituents atC-5 such as in ligands 39b–41b was shown to increase the degreeof isomerisation. When the 2,3-dihydrofuran 7j was used as sub-strate, ee’s up to 84% (R) in aldehyde 8g were achieved usingligands 39b–40b, together with a regioselectivity of 80%. The 2,5-dihydropyrrole 7h was also tested with the Rh/30b system, achiev-ing comparable results to those previously reported using ligand43 (71% and 66%, respectively).

Very recently, Reek et al. described the synthesis and applica-tion of the ligand 57 (Fig. 1), containing a skeleton related to theXantphos diphosphine ligand, in the Rh-catalysed asymmetrichydroformylation of the dihydrofurans 7g and 7j (Scheme 17). Thissystem provided regioselectivities of 100% and 80%, respectively,and a remarkable enantioselectivity of 91% from both substrates.53

The asymmetric Rh-catalysed hydroformylation of dioxapines7l–m was reported using the BINAPHOS ligand 43 and 1,3-diphos-phite ligands derived from carbohydrates 58b (Scheme 18).48,52b

Using the ligand 43, total regioselectivity to 8l–m was achieved,together with ee’s up to 76%. Among the carbohydrate-derived

]

X

8g-i (S)

H2

CHO

+

XO

CO[Rh]

X

8g-i (R)

H2

CHO

+X CO[Rh] X

9g-i

CHO

[Rh]-H

[Rh]-H++

etric hydroformylation of five-membered heterocyclic alkenes.

R R R R

O O O OP PO

OO

O

58

Figure 1. Hemispherical diphosphite ligands 58 with a conical calixarene skeleton.

Rh/51CO/H2

O O

R R

*

O O

R R

CHO

7l,m 8l,m 9l,m

+*

O O

R R

CHO+

7n,o

O O

R R

O

OO

OPPO

58

OO

OO

TBDPSO

43

58b

99 76 (-)

99 68 (+)

99 70 (R)

99 55 (S)

Regio (%) ee (%)

Product 8l 8m

Rh/L R=H R= Me

Scheme 18. Rh-catalysed asymmetric hydroformylation of 7l,m.

Rh/43CO/H2

8p,q

+*

n n n

CHO

CHO

7p,q 9p,q

92 88

96 97

8p n=1

8q n=2

Product Regio (%)e e (%)

Scheme 19. Rh-catalysed asymmetric hydroformylation of bicyclic alkenes using(R,S)-BINAPHOS ligand 43.

Rh/LCO/H2

X

∗

X

CHO

Rh/LCO/H2

X

∗

X

CHO

+ ∗X CHO

+ ∗X CHO

7g-i 8g-i 9g-i

7j,k 8g-i 9g-i

Product 8g 8h 8i

Rh/L X=O X=NBoc X=NAc

30b

38b

43

57

9 75 (S)

99 88 (S)

99 68 (R)

99 91 (S)

99 73 (R)

99 71 (-)

99 66 (+)

Regio (%) ee(%)

30b

39b

40b

43

57

76 75 (R)

78 83 (R)

78 84 (R)

50 38 (S)

80 91 (R)

33 71 (S)

Regio (%) ee(%)

O

tBu tBu

PPh2 P

57

PPh2OP

OOO

OO

OPPO

30

OO

OO

43

Product 8g 8h

Rh/L X=O X=NBoc

Ph

OO

Ph

Regio (%) ee(%) Regio (%) ee(%)

Regio (%) ee(%)

9

Scheme 17. Rh-catalysed asymmetric hydroformylation of five-membered hetero-cyclic alkenes 7g–k.

A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146 1143

ligands that were tested, the ligand 58b provided the best results(Scheme 18), affording total regioselectivity to 8l,m and up to68% ee and thus indicating that no isomerisation of 7l,m hadoccurred.

3.2.3. Bicyclic 1,2-disubstituted alkenesThe Rh-catalysed asymmetric hydroformylation of substrates

7p and 7q was reported by Nozaki et al. using the ligand 43(Scheme 19).48 The results are really remarkable, in particular withsubstrate 7q, for which compound 8q was obtained with practi-cally total regio- and enantioselectivities (Scheme 19). The corre-

sponding products 8p and 8q are of interest since the aldehyde8p can be converted in a single step into the corresponding aminewhich exhibits hypotensive activity and the product 8q is a syn-thetic intermediate to produce a vasoconstrictor tetrahydrozo-line.54

Another bicyclic alkene substrate of interest for carbonylationreactions is the norbornene 7r and its derivatives. The first reportson the asymmetric Rh-hydroformylation of norbornene affordedlow enantiomeric induction with ee’s below 25%.55 In 2005, Buneland co-workers reported the first highly enantioselective Rh-cata-lysed hydroformylation of norbornene into the exo aldehyde withee’s up to 92% using the diphospholane ligands 48 and 49.56 Usingthese ligands, they also reported the hydroformylation of severalderivatives of this substrate with similar enantioselectivities(Scheme 20).

More recently, the hemispherical diphosphite ligands 58 (Fig. 1)with a conical calixarene skeleton was used in the asymmetric Rh-hydroformylation of norbornene, achieving enantioselectivities upto 61% with the exo aldehyde being the major product.57

3.2.4. 1,10-Disubstituted alkenesThe asymmetric hydroformylation of 1,10-disubstituted alkenes

differs from the classical asymmetric hydroformylation of mono-substituted terminal alkenes since the desired product is the linearaldehyde (Scheme 2).

Indeed, the Rh-catalysed asymmetric hydroformylation of 1,1-methylstyrene using diphosphite ligand 59 (Scheme 7) to formthe linear product was recently patented. The enantioselectivitywas however moderate (ee up to 46%).58

Interestingly, however, when dehydro amino acid deriva-tives 10b and dimethyl itaconate 10c were used as substrates(Scheme 21) in the presence of [RhH(CO)(PPh3)3] and 1–6 equivof the (R,R)-DIOP ligand 60, the formation of the branched productswas largely favoured with moderate enantioselectivity (ee’s up to59%). In this process highly functionalised quaternary carbons are

46% ee

CHORh/59CO/H2 *

59% ee

MeOCHN

Rh/60CO/H2

MeOOCNHCOMe*

COOMe

OHC

PPh2

PPh2

O

O60

95% Regio9% ee

MeOOCH 2C

Rh/60CO/H2

MeOOCCH2CO2Me*

COOMe

OHCCH2CO2Me*

H

COOMe

OHCH2C+

OO

P

P

OO

OO

59

O OO O

t-Bu

t-Bu

10a 12a

+

11a

CHO

10b 11b

10c 12c11c

Scheme 21. Rh-catalysed asymmetric hydroformylation of 1,10-disubstitutedalkenes.

R *

catalystCO/H2

R

R

CHOcatalystCO/H2

*R

R´

R´

*R

R´OHC

CHOR' R'

(a)

(b)

1

2

Scheme 22. Hydroformylation of 1,1- and 1,2-disubstituted alkenes.

Rh/48CO/H2 CHO

AcO

OAc

AcO

OAcCHO

OO

OOO

O CHO

NN

NN CHOR

RR

R

8r up to 92% ee

8u R= Cbz; up to 60% ee

8v R= Boc; up to 56% ee

Rh/48CO/H2

Rh/48CO/H2

Rh/48CO/H2

7r

8s up to 92% ee7s

8t up to 92% ee7t

7u R= Cbz

7v R= Boc

Scheme 20. Rh-catalysed asymmetric hydroformylation of norbornene usingligands 48.

1144 A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146

easily obtained from common products. This interesting reactiondeserves more attention by researchers in the field. It should benoted that when the a,b-unsaturated carboxylic compounds suchas 10c are hydroformylated in the presence of the [PtCl(SnCl3)](60), the only hydroformylation product obtained was the linearaldehyde with ee’s up to 82%.12a

4. Conclusions

Rhodium is currently the metal of choice to achieve high enanti-oselectivities in the hydroformylation of a relatively high variety ofalkene substrates. The elucidation of the different steps of the cat-alytic cycle and the characterisation of the resting state, togetherwith the discovery of several types of ligands that are able to pro-vide high enantioselectivities, and have made the rhodium-cata-lysed hydroformylation a synthetically useful tool.

In the catalytic cycle, the complex 16 has been identified as theresting state of the process. An important feature for bidentate li-gands is their possible coordination to the rhodium centre in eq–eq or eq–ax fashions. Indeed, although the enantioface discrimina-tion occurs at the alkene coordination step from the square-planarspecies 17, experimental observations showed that high enantiose-lectivity in asymmetric hydroformylation of alkenes is obtainedusing ligands that lead to the formation of only one isomer of theresting state 16. This fact could be attributed to the similitude inthe structures of the Rh hydride species 16 and 18. The co-exis-tence of the two possible isomers in solution was shown to alwaysprovide lower enantioselectivity.

Commonly, the synthesis of a chiral compound by asymmetrichydroformylation involves the introduction of a formyl group ina substituted olefinic carbon. This process has been widely studiedmainly for monosubstituted alkenes (Scheme 22a, R0 = H). How-ever, since the favoured process is usually the introduction of thisgroup in the less substituted carbon, this process is only useful forsubstrates containing electron-withdrawing group(s) (R = Ph, het-eroatom) which direct the introduction of the formyl group inthe most substituted carbon. Consequently, a regioselectivity prob-lem must be first considered. The presence of a functional group atthe allylic position, which contributes to stabilise the double bond,always supposes an additional issue, since isomerisation takesplace easily (see Schemes 14 and 16). This isomerisation can becontrolled by the appropriate choice of ligand and reaction condi-tions. For instance, increasing the CO pressure and/or decreasingthe reaction temperature reduce the degree of isomerisation.

Furthermore, low temperature conditions (<70 �C) are usuallyrequired to achieve high enantioselectivities although under theseconditions, reactions rates are usually low. A way to partially cir-cumvent this problem is increasing the H2 pressure thus shiftingthe equilibrium from the inactive complex 23 towards the activespecies 16 (see Scheme 3).

1,2-Disubstituted substrates are particularly challenging whensimilar substituents such as alkyl substituents are present in bothpositions (Scheme 22a, R0–H) (Scheme 15). However, higher regio-and enantioselectivity can be achieved when one of the substitu-ents direct the regioselectivity, as is the case of 2,3-dihydrofuran,dihydropyrrol, indene or 1,2-dihydronaphthalene (Schemes 17and 19). In the case of symmetrically substituted alkenes such as2,5-dihydrofuran and norbornene 7l,m, no regiocontrol is required,

A. Gual et al. / Tetrahedron: Asymmetry 21 (2010) 1135–1146 1145

high activities and enantioselectivities have been achieved inasymmetric hydroformylation (Schemes 17, 18 and 20).

1,1-Disubstituted or 1,1,2-trisubstituted are more challengingsubstrates (Scheme 22b). The general trend is the introductionof the formyl group onto the less substituted carbon, thus creat-ing the stereogenic centre at the more substituted carbon atom(Scheme 22b-l). This trend is respected in the hydroformylation ofsuch substrates using Pt catalysts, achieving high regio- and enanti-oselectivities. Interestingly, it is also possible to introduce theformyl group at the more substituted carbon using Rh catalysts,thus creating a highly functionalised chiral quaternary centre(Scheme 22b-2).

For years, ligands containing phosphite moieties such as diph-osphites and phosphine–phosphites were considered as the mostsuccessful ligands to achieve high enantioselectivies. For instance,diphosphite ligands 24, 30 and 42 are highly effective in the asym-metric Rh-catalysed hydroformylation of several alkene substratesand the phosphite–phosphine BINAPHOS 43 or its derivatives 45and 46 are still today the most successful ligands in terms of selec-tivity and scope. Recently however, diphosphines in which the Patoms are incorporated in a ring 45–49 have also shown to inducehigh levels of enantioselectivity in this process. It can consequentlybe concluded that the key to achieve high enantioselectivities isnot the type of phosphorus function involved in the coordinationto the metal, but the particular spatial arrangement of the coordi-nated ligand. It is also noteworthy that most of the successful li-gands incorporate phenyl rings in their structure with the onlyexception of TANGPHOS ligand 48.

As highlighted in this review, a variety of chiral products incor-porating a formyl unit can be enantioselectively prepared by Rh-catalysed asymmetric hydroformylation and this process is nowa-days considered as a powerful tool in organic synthesis.

Acknowledgements

We are grateful to the Spanish ‘Ministerio de Educación y Cien-cia’ (Consolider Ingenio 2010, Intecat-CSD2006-0003, CTQ2007-62288/BQU, CTQ2008-01569/BQU, Ramon y Cajal Fellowship toC.G.) and the Generalitat de Catalunya (2005SGR007777) for finan-cial support.

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