Chiral phosphite

The 4-thiazolidinyl phosphonates 143 (Scheme 44) are known for their therapeutical properties, in particular as anti-inflammatory agents [5,89]. Their asymmetric synthesis by hydrophosphonylation of 3-thiazolines has been described using various chiral auxiliaries chiral phosphites such as (2S,4i )-2H-2-oxo-5,5-dimethyl-4-phenyl-l,3,2-dioxaphosphorinane (de = 2-8%) [90] or BINOL-phos-phite (de = 65-90%) [91] and also chiral catalyst such as titanium or lanthanide chiral complexes (ee = 29-98%) [92]. Hydrophosphonylation of C2-chiral3-thi-azolines has also been performed (de = 32-38%) [93]. 

Since Pd complexes are well-known catalysts for enantioselective allylic substitution reactions, here the catalytic behaviour of palladium NPs for this reaction is examined (Scheme 1). One example involving a chiral phosphite with a carbohydrate backbone, able to coordinate firmly at the surface of NPs together with oxygen atoms capable to interact weakly with this surface, is presented. In particular. 

Table 5 Hydroboration of styrene using chiral phosphite ligands 48-53... 

The influences of the ligand-to-metal ratio, reaction temperature and syngas pressure on the enantioselectivity and regioselectivity were also studied. A multi-substrate screening approach has recently been used by Dow Chemical Company to identify the best catalyst for the hydroformylation of vinyl acetate. Here, the chiral phosphite Kelliphite, 5 (Fig. 1) gave enantioselectivity up 88% ee and excellent regioselectivity for the branched isomer [24,25]. 

Although the presence of BINOL in the ligands so far discussed has shown itself to be particular effective, modification of the diol moiety provides new classes of ligands for this addition reaction. Alexakis, screening a number of chiral phosphites in the Cu(OTf)2-catalyzed 1,4-addition, showed that an ee of 40% could be obtained for the addition of Et2Zn to 2-cyclohexenone and of 65% for addition to chalcone, by using cyclic phosphites derived from diethyl tartrate [51]. 

Reactions Catalyzed by Iridium Complexes of Chiral Phosphite Ligands... 

Scheme 3 Allylic alkylation catalyzed by [Ir(COD)Cl]2 and a chiral phosphite ligand...

A regio-, diastereo- and enantioselective synthesis of amino acids was reported by Takemoto and coworkers. The glycine equivalent ethyl diphenylimino glycinate was used as pronucleophile (Scheme 9.14), while the Hgand was a bidentate chiral phosphite, and 3-arylaUyl diethyl phosphates were employed as allylic substrates [39, 46]. 

Synthesis of Chiral Phosphite Esters with Phosphorus as the Primary Chiral Site... 

Yamamoto et al. reported the asymmetric (9-nitrosoaldol reaction using silyl enol ethers in the presence of the silver catalyst.32 In order to achieve this reaction, they developed a novel combination of silver and a chiral phosphite derived from BINOL. The disilanyl enol ether was used to ensure high yield and enantioselectivity. The reaction was conducted with disilanyl enol ether and nitrosobenzene in the presence of AgBF4 and the chiral phosphite ligand in THF to produce the O adduct with high regio- and enantioselectivity (Table 9.14). In addition, a chiral silyl enol ether could be used as a substrate. The reaction was conducted with chiral silyl enol... 

The reaction can be carried out asymmetrically, using nickel complexes of chiral phosphite ligands. Examples are the enantioselective hydrocyanation of norbomene using ligand (22-XVIII),48 and of vinylnaphthalene derivatives with (22-XIX).49 The latter is a precursor for the anti-inflammatory drug naproxen. 

The Ir-catalyzed enantioselective allylic substitution reaction can be used for the synthesis of -substituted a-amino acids . For example, the enantioselective Ir-catalyzed allylic substitution of 3-arylallyl diethyl phosphates 5.24 with pronucleophile diphenylimino gly-cinate 5.25 is achieved up to 98% ee by using bidentate chiral phosphite ligand 5.26. By changing the base, both diastereoisomeric substitution products 5.27a and 5.27b could be formed selectively. 

Enantioselective 1,4-Addition of Organozinc Reagents to Enones. Phosphite-oxazoline copper complexes are highly efficient catalysts for the 1,4-addition of organozinc reagents to 5-, 6- and 7-membered cyclic enones. Both the chiral oxazoline and the chiral phosphite unit have a significant influence on the enantioselectivity. 

The first asymmetric P-C bond formation under heterogeneous conditions has been achieved via a FeaOa-mediated conjugate addition of a chiral phosphite (175) to alkylidene malonates. The easy cleavage of the chiral auxiliary from the addition products (176) leads to optically active p-substituted p-phosphono malonates (177) in good yields and high enantiomeric excesses (Scheme 45). " ... 

Since the bisphosphine as well as a monophosphine greatly accelerate the copper-catalyzed reaction [59], a survey of the known diphosphine was carried out to find that 0.5% of copper(II) triflate and 0.5% of phosphine are sufficient, though enantioselectivity was at most 44% [60]. Chiral phosphite ligand bearing tartrate moiety 28 accelerated the reaction [61], but the ee was not so satisfactory at 40% (Eq. (12.30)) [62]. Chiral thiazolidinone 29 was developed as a chiral ligand to afford the product in 63% ee [63]. 

Miscellaneous. - Several new optically active tervalent phosphorus acid derivatives have been prepared for use as ligands in asymmetric metal catalysed reactions. These include the cyclic diaminophosphines 57, the cyclic bisamino-phosphine 58, and the compounds 59, 60, 61, and 62 containing a 1,1 -binaphthalene group as the chiral inducer. A new diphosphoramidite (63) has been used for improved regioselectivity of rhodium-catalysed hydroformylations of alkenes. A new sterically hindered chiral phosphite (64) derived from glucose and a Cu(I) complex of 64 have been prepared. ... 

In spite of the high level of interest in the asymmetric synthesis of a-amino phosphonic acids, less is known in the case of cyclic a-amino phosphonates. Although in recent years descriptions of promising pharmaceutical applications for cyclic compounds (and acylated derivatives thereof) have been published [61-64], until now no efficient general asymmetric route has been available to prepare this class of a-amino phosphonates. Several attempts at a diastereose-lective synthetic route which were made by the addition of a stoichiometric amount of chiral phosphites to cyclic imines, namely thiazolines, gave only limited diastereoselection ratios of dr=2 1 or below [75,76]. 

The complete regioselectivity, the absence of byproducts, the ready availability at low cost of the ligand employed, and the chemical and stereochemical efficiency of this reaction make it a good candidate to become the first catalytic, stereoselective industrial manufacturing of naproxen, even if the use of HCN can be a drawback. In this context, it must be remembered that Union Carbide Co. has recently patented a route to (S)-ibuprofen based on a Rh(CO)2(acac)/chiral phosphite-catalyzed hydroformylation of 4-isoutylstyrene that occurs in 82% e.e. [63,80]. 

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