A

h2n-

-NHTs

Ar Me high pH low pH

HCOOH:Et3N X J (1.2:1.0 mol ratio) pH 5 ^^ H2O,40 °C 2 X = C, 100%, 97% ee

77-94%, 89-94% ee n = 1, 93%, 95% ee n = 2, 97%, 94% ee

F

_| SO42-

H2 If

H2O N

^F

^F

CF3SO2

F

(S,S)-17

Scheme 3.4 Asymmetric transfer hydrogenation of ketones (a) and nitroalkenes (b) with unmodified DPEN ligands in neat water

14 cycles (tested in acetophenone reduction) with only 0.4% mol of metal leaching into the organic phase during the extraction of the product.

Quite unexpectedly, Xiao and coworkers found sensible rate acceleration of ATH of ketones using unmodified TsDPEN-Ru(p-cymene) complex in neat water [27], this behaviour being also observed with several of the ligands active in organic solvents [28] and TsDPEN-Ir(III)- or Rh(III)-complexes [29]. Using the ''on water'' protocol (substrate and catalyst are insoluble) or micellar catalysis [30] up to 10,000 S/C ratios became feasible and reactions could be performed without inert gas protection to give a variety of simple and functionalized secondary alcohols in high chemical and optical yields. Mechanistic investigation of Ru-(R,R)-TsDPEN promoted ATH of acetophenone in water with HCOOH/triethylamine azeotrope revealed a marked dependence of reaction rate and catalyst enantioselectivity with solution pH, so that the adjustment of initial pH to 5 was required in order to achieve results comparable with those obtained using HCOONa as hydrogen source. It has been suggested that the concerted mechanism proposed by Noyori through a cyclic hydride intermediate could be operative at high pH, with formic acid mainly existing in its dissociated form, whereas at acidic pH the protonation of the coordinated ligand could lead to uncyclic and less-organized transition states giving rise to decreased selectivity [31] (Scheme 3.4a).

More recently ATH has been extended to C-C unsaturated bond and in the reduction of a series of b, b-disubstituted nitroalkenes using different aqueous conditions [32, 33] the highest enantioselectivities were obtained with Ir(III)-aquacomplex 17 (Scheme 3.4b), a catalyst shown to be effective also in the reduction of a-cyano and a-nitroacetophenones [34].

Enantioselective carbon-carbon bond forming reactions are usually carried under Lewis acid catalysis and the use of aqueous solvents has been long precluded since many metals react with water, that act as Lewis base, rather than with substrates. Strictly anhydrous conditions and suitable protection of reactive functional groups are often required for such reactions, but a substantial breakthrough in this field was achieved by Kobayashi and coworkers that developed Sc(III)-, Yb(III)- and Ln(III)-triflates as water-compatible Lewis acids and demonstrated an activation role of water in the Mukayama aldol reaction between benzaldehyde and trimethylsilyil enol ether of cyclohexanone, for which only 10% substrate conversion had been observed in THF with Yb(OTf)3 [35].

The catalytic activity of several metal perchlorates, triflates and chlorides in a model aldol reaction was correlated with hydrolysis constants (Kh) and water exchange rate constants (WERC) for substitution of inner sphere water ligands. The screening revealed that other than rare earth metals also Fe(II), Cu(II), Zn (II), Ag (I), Mn(II) and In(III) worked as Lewis acid in aqueous medium, the optimal pKh ranging from 4 to 10 with WERC values greater than 3.2 x 106 M-1s-1 [36]. Within these intervals, cations are stable to hydrolysis maintaining sufficient Lewis acidity to activate the aldehyde, that can be coordinated to the metal only if a fast exchange with hydrating water molecules occurs.

Many triflates of the above metals have then been used in aldol reactions with moderate to good enantioselectivity in water-organic cosolvent mixtures [37-40] and sensible acceleration rate was observed in the presence of surfactants [41]. Taking this evidence, Lewis acid-surfactant combined (LASC) catalysts were developed by using dodecylsulphate (DS) as counterion for the active metal cations, the most common of which was scandium. The resultant M(DS)3 salts formed stable emulsions and micellar aggregates (1 im diameter) able to promote the concentration of organic substrates by hydrophobic interactions, so that effective reactions could be performed in water without the need of any organic solvent [42].

It has been recently found that also the reaction of silyl enol ethers with a hydrophilic reagent as formaldehyde can be positively carried out using LASC catalysts as Sc(DS)3/bipyridine 18 (Scheme 3.5a) and it has been suggested that the salt could play a key role on the reactivity through Lewis acid-Lewis base interactions with HCHO leading to increased amount of the aldehyde in the hydrophobic environment [43]. The use of water-tolerant Lewis acids, compatible with commercial aqueous solution of HCHO, allows to avoid the tedious

x v=N N=/ ,

Sc(DS)3 = Sc3+( j

/oh ho \

(S,S)-18

aq. HCHO

OSiMe3

H2O, rt

R = Me, R1 = Sf-Bu 73%, 91% ee R = Et, R1 = Sf-Bu 65%, 90% ee R = Me, R1 = 3-MePh 73%, 90% ee

H2O, rt

PK>OH

Ph Ph

H2O, rt

Scheme 3.5 Examples of Sc(DS)3-promoted asymmetric reactions and harmful procedures required to generate the anhydrous aldheyde offering a notable simplification in hydroxymethylation reaction, an efficient method to introduce a Cl-functional group at the a-position of carbonyls. The same system Sc(DS)3/18 catalyzed the ring opening of meso-epoxides with aromatic amines to afford optically active b-aminoalcohols without diol formation [44] and also C-, O- and S-nucleophiles reacted with comparable high yield and enantioselectivity [45] (Scheme 3.5b, c).

Among other examples involving Lewis acids in water, the Mannich-type reaction of enolsilanes and N-acylhydrazones, chosen as water stable surrogates of imines, in the presence of ZnF2/ligand 19 and CTAB as surfactant gave nearly enantiopure b-aminoketones and the stereospecificity toward syn- or anti-adducts was found dependent on the enolate geometry [46] (Scheme 3.6a). In the addition of alkynes to imines promoted by Cu(OTf)2/pybox-ligand 20 the use of stearic acid as additive was found essential for obtaining remarkable rate acceleration and high

OSiMe3 ^Ph

NNBz

OSiMe3 ^Ph

Ph"

R = Me 93%, 96% ee, syn:anti94:6 R = Et 76%, 96% ee, syn.anti 96:4

stearic acid (10% mol) H2O, rt

Me3SiO

Scheme 3.6 Reactions with water-tolerant or ligand stabilized Lewis acids enantioselectivity [47] (Scheme 3.6b). The discovery that some water-sensitive Lewis acids can be beneficially stabilized upon coordination with chiral basic ligands made feasible Mukayama aldol reactions in the presence of Bi(OTf)3 or Ga(OTf)3 (Scheme 3.6c) and further application of this concept could expand the portfolio of asymmetric reactions in aqueous media [48].

In the organocatalysis field, besides chiral phase transfer catalysts yet discussed in Sect. 2.3 and used in biphasic water-organic solvent systems, the study of reactivity in aqueous media has been mainly focused on enamine based reactions and, in this context, proline could appear an ideal candidate for its availability and water solubility. However, proline-catalyzed aldol reactions in water or water/ surfactant systems proceeded with low stereoselectivity and the addition of an organic solvent, an acid co-catalyst or large excess of the ketone subtrate was often necessary to improve catalyst performances. On the contrary, the introduction of large apolar substituents on proline skeleton in order to better promote hydrophobically directed assembling of catalyst with reagents proved to be a successful strategy to enhance catalytic activity. A number of 4-acyloxyprolines [49, 50] and O-protected 4-hydroxyprolines [51, 52] have been synthesized

NH2 nh2 h oh

(S,R)-21a R = iBuSiPh2 (TBDPS) (S,R)-22 R = H (S,R)-21b R = 4-tBu-Ph (S,S)-23 R = CH3

OBn O Ph ^ " _ Ph HI' ^-Ph NH2 H OH (R,S,R)-24

OH O

OH O

TBSO OTBS

HQ COOMe

H2O, rt

HQ COOMe

Brine, rt

O OH

TBSO OTBS

R = Ph, 83%, 96% ee, syn:anti 7:1 R = n-Pr, 77%, 95% ee, syn:anti 11:1

O HN

pOMePh

Scheme 3.7 Organocatalysts for enamine based reactions in water

and used ''on water'' in the direct aldol reaction of ketones with aromatic aldehydes or b, y-unsaturated a-ketoesters [53] providing higher yields and stereoselectivities than those obtained in organic solvents (Scheme 3.7a, b). It has been suggested that stereoselectivity in such reactions is controlled by the apolar sub-stituents since the aldehyde, in its approach toward the enamine, preferentially lies in the hydrophobic region of the catalyst rather than in the hydrophilic one [50].

With the same approach, O-hydrophobically substituted threonine [54] or serine [55] as well as some peptide-type derivatives [56-58] have been prepared as useful catalysts for aldol condensation of ketones or silyl-protected hydroxyacetone and their performances were improved by addition of an acid co-catalyst to stabilize enamine formation or using brine as reaction medium to promote concentration of catalyst and reagents by salting-out effect (Scheme 3.7c). More recently the catalytic activity of natural aminoacids in aldol reactions has been screened and those bearing more apolar residues, as trypthophan, leucine or isoleucine, displayed satisfactory selectivity further increased in some cases with 2,4-dinitrophenol additive [59, 60]. Three-component Mannich reactions of hydroxyacetone with aldehydes and p-anisidine were also performed with excellent yield and selectivity in the presence of threonine derivative 23 using water as sole reaction medium [61] (Scheme 3.7d).

Some proline-containing amides, sulphonamides and thioureas as 26-29 have been designed in order to have a secondary amino group for enamine formation, an amide group on a chiral center for hydrogen-bond directed stereocontrol and a hydrophobic group to promote aggregation of catalyst with reactants in water environment. All these elements contributed to fruitful catalysis in aldol and Michael reactions in aqueous systems [62] and even if the role of water was not fully rationalised [63] its positive effects could be ascribed to the increased acidity of amidic NH bond due to the hydrogen-bonding between the carbonyl of amide and water free hydroxyl groups at the hydrophobic interface of the catalyst. In some specific cases it has been proposed that the formation of an organized transition state could beneficially occur through a water molecule engaged in two hydrogen bonds bridging the catalyst on one side and the aldehyde approaching to the enamine on the other one [64, 65].

In the group of 2-substituted pyrrolidines, diamine salt 30 bearing long alkyl chains can be considered a hybrid surfactant-organocatalyst and it promoted aldol reactions in bulk water with excellent selectivity and high yields, remarkably obtained with reagents in stoichiometric ratio (Scheme 3.8a) [66]. More recently it has been reported that the aldol condensations valuably proceeded with only 1% mol of 30 in the presence of stearic acid; the reactions occurred in an emulsion rather than a biphasic system [67] and the products could be easily isolated by centrifugal separation leaving the catalyst to be recycled in water. Compound 30 was also active as catalyst in Michael addition of nitrostyrene to ketones in brine and in a multigram scale synthesis of adduct 31 the enantiopure product was isolated in good chemical yield by simple precipitation from reaction mixture and subsequent recrystallization [68] (Scheme 3.8b).

Although iminium activation seems to be less compatible with aqueous reaction media, the enantioselective addition of different nucleophiles to enals in water in the presence of benzoic acid as additive has been successfully achieved with prolinol catalysts 32a-c [69, 70] or the water-soluble derivative 32d, whose excellent stereoselectivity was maintained for at least six cycles adding fresh reactants to the aqueous phase after extraction of the reaction product with Et2O:hexane 1:8 mixture (Scheme 3.9a) [71]. Perchlorate salt of 32c also catalyzed Diels-Alder reaction of cyclopentadiene with aldehydes and the amount of water was crucial for high yield and selectivity (Scheme 3.9b). Since the stirring was not found essential, it was proposed that the reaction presumably occurred in the organic phase generated by reactants and catalyst rather than at the interfacial surface with water [72]. Water-soluble C2-symmetrical bipyrrolidine catalyst 33,

O OH

O OH

O Ph

O Ph

recrystallization (EtOAc)

73% syn isomer,>99% ee Scheme 3.8 Hydrophobic organocatalysts and related reactions in water specifically designed for its easy recovery and recycle, also displayed good selectivity in the same asymmetric transformation and diiminium intermediate 33/cynnamaldehyde was structurally characterised by X-ray analysis [73].

The activity of hydrogen-bonding and Bronsted acid organocatalysts, that exert stereocontrol through non-covalent interactions, could appear quite limited in aqueous medium since the strong hydrogen donor/acceptor character of water makes it competitive in the coordination with the chiral catalyst with respect to the reagents. However, following the approach to maximize the hydrophobic effect in order to overcome the competitive influence of water [74], BINOL phosphoric acid 34 was designed and successfully used in transfer hydrogenation of quinolines as the first example of asymmetric Bronsted acid catalysis in water (Scheme 3.10). Carrying out the reaction in deuterated water it was demonstrated that protons from solvent were specifically involved in 1,2-hydride addition step and the

(a)

Ph^CHO

H2O, rt

(0.8 eqv)

0 0

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