Anhydrides, enantioselective

The most common oxidatiou states and corresponding electronic configurations of rhodium are +1 which is usually square planar although some five coordinate complexes are known, and +3 (t7 ) which is usually octahedral. Dimeric rhodium carboxylates are +2 (t/) complexes. Compounds iu oxidatiou states —1 to +6 (t5 ) exist. Significant iudustrial appHcatious iuclude rhodium-catalyzed carbouylatiou of methanol to acetic acid and acetic anhydride, and hydroformylation of propene to -butyraldehyde. Enantioselective catalytic reduction has also been demonstrated. 

Lipase-catalyzed enantioselective transesterification of 0-substituted-l,2-diols is another practical route for the synthesis of P-blockers. Lipase PS suspended in toluene catalyzes the transesterification of (63) with vinyl acetate to give the (5)-ester in 43% yield and >98% ee (78). The desired product, optically pure (R)-ttitylglycidol, is then easily obtained by treating the ester with alcohoHc alkaU. Moreover, Pseudomonas Hpase catalyzes the acylation of oxazohdinone (64) with acetic anhydride in very good yield and selectivity (74). PPL-catalyzed transesterification of a number of /n j -norbomene derivatives proceeds in about 30% yield and 92% ee (79,80). 

Enantioselective alcoholysis of racemic, prochiral, or meso cyclic anhydrides can be catalyzed by hydrolases, yielding the corresponding monoesters (Eigure 6.25). In most cases, the enantioselectivity was moderate ]75-77]. Organometallic catalysts or organocatalysts such as cinchona alkaloids are often more efficient than enzymes for the stereoselective ring opening of cyclic anhydrides. 

Initial studies indicated that this ruthenium complex is an effective chiral catalyst for enantioselective metathesis. For example, desymmetrization of the anhydride 68 (Scheme 43) in the presence of 10 mol % of 65 and 10... 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

Enantioselective desymmetrization of meso-succinic anhydrides with diphenylzinc is catalyzed by Pd(OAc)2/chiral diphosphine 209 (Equation (113)).470... 

This chapter aims to provide an overview of the current state of the art in homogeneous catalytic hydrogenation of C=0 and C=N bonds. Diastereoselec-tive or enantioselective processes are discussed elsewhere. The chapter is divided into sections detailing the hydrogenation of aldehydes, the hydrogenation of ketones, domino-hydroformylation-reduction, reductive amination, domino hydroformylation-reductive amination, and ester, acid and anhydride hydrogenation. 

Researchers at Merck Co. [35] who, together with scientists from Solvias, had developed the enantioselective hydrogenation of unprotected enamine amides and esters [36], reported a more recent example of product inhibition. The product amine amide or ester was found to be an inhibitor of the catalyst, and indeed instances of catalyst poisoning by amines have been reported several times (see later). The authors also found an excellent solution to this problem the addition of BOC-anhydride to the hydrogenation reaction neatly reacts away all the amine to form the BOC-protected amine, whereas the enamine was left unreacted (Scheme 44.4). This addition resulted in a remarkable rate enhancement [35]. 

To a much smaller extent non-enzymic processes have also been used to catalyse the stereoselective acylation of alcohols. For example, a simple tripeptide has been used, in conjunction with acetic anhydride, to convert rram-2-acctylaminocyclohexanol into the (K),(R)-Qster and recovered (S),(S)-alcohol[17]. In another, related, example a chiral amine, in the presence of molecular sieve and the appropriate acylating agent, has been used as a catalyst in the conversion of cyclohexane-1(S), 2(/ )-diol into 2(S)-benzoyloxy-cyclohexan-1 f / j-ol1 IS]. Such alternative methods have not been extensively explored, though reports by Fu, Miller, Vedejs and co-workers on enantioselective esterifications, for example of 1-phenylethanol and other substrates using /. vo-propyl anhydride and a chiral phosphine catalyst will undoubtedly attract more attention to this area1191. 

Our final example is that of cyclic anhydrides, namely prochiral 3-sub-stituted glutaric anhydrides (7.101, R = Me, Et, or Pr). When incubated with lipase in an inert solvent in the presence of an alcohol (methanol, butan-l-ol, etc.), these compounds underwent nucleophilic ring opening with formation of a hemiester (7.102) of (/ -configuration (60-90% ee) [180]. This product enantioselectivity and, of course, the lack of reactivity in the absence of lipase show the enzymatic nature of the reaction. 

Progress of the reaction was monitored using a GC equipped with a FID on an achiral CP 1301 capillary column (30 m x 0.25 mm x 0.25 m film) and N2 as carrier gas. Enantiomeric purity of 2-octanol was analysed after derivatization with acetic anhydride (see below) using a CP-Chirasil Dex-CB column (25 m x 0.32 mm x 0.25 pm film, column B) and H2 as carrier gas. Enantioselectivities (expressed as the enantiomeric ratio E) were calculated from enantiomeric excess of the product and conversion as previously reported. Retention times and methods are listed in Table 3.1. 

The use of ethylene adduct lb is particularly important when the species added to activate catalyst la is incompatible with one of the reaction components. Iridium-catalyzed monoallylation of ammonia requires high concentrations of ammonia, but these conditions are not compatible with the additive [Ir(COD)Cl]2 because this complex reacts with ammonia [102]. Thus, a reaction between ammonia and ethyl ciimamyl carbonate catalyzed by ethylene adduct lb produces the monoallylation product in higher yield than the same reaction catalyzed by la and [Ir(COD)Cl]2 (Scheme 27). Ammonia reacts with a range of allylic carbonates in the presence of lb to form branched primary allylic amines in good yield and high enantioselectivity (Scheme 28). Quenching these reactions with acyl chlorides or anhydrides leads to a one-pot synthesis of branched allylic amides that are not yet directly accessible by metal-catalyzed allylation of amides. 

Alcoholysis of meso-cycYic anhydrides offers a versatile route to succinate and glu-tarate half-esters. Although a number of stoichiometric approaches to this problem have been investigated, a successful catalytic version of this reaction appeared as recently as 2003. ° Bolm and coworkers have developed a protocol for the metha-nolysis of a variety of succinic anhydrides using cinchona alkaloids [Eq. (10.50)]. The reaction may be made catalytic in alkaloid when pentamethylpiperidine is used as a stoichiometric additive. A moderate decrease in enantioselectivity is observed in a number of cases, although excellent selectivities are still attainable. More problematic is the reaction time (6 days under catalytic conditions) ... 

More recently, we have discovered that Pd-JOSIPHOS complexes effectively desymmetrize a variety of succinic anhydrides in excellent yield and enantio-selectivity [Eq. (10.54)]. The reaction proceeds at ambient temperature in some cases and can deliver aryl and alkylzinc reagents with equal facility. For reasons that are unclear, the latter protocol requires a styrenic additive for high enantioselectivity ... 

A catalyzed asymmetric alkylation of glutaric anhydrides has yet to appear. However, Fu has reported that stoichiometric amounts of sparteine efficiently mediate the addition of aryl Grignard reagents to 4-substituted glutaric anhydrides, providing the 5-ketoacids in good yields and excellent enantioselectivities ... 

Deng also showed that (DHQD)2AQN could catalyze the parallel KR (PKR) of a variety of monosubstituted succinic anhydrides via asymmetric alcoholysis [215]. The nature of the solvent was found to have a significant influence on the selectivity. Hence, increasing the size of the alcohol from methanol to ethanol resulted in increased levels of enantioselectivity, albeit with reduced reaction rates. In this context, 2,2,2-trifluoroethanol appeared to be the alcohol of choice as it allowed the ASD of 2-methyl succinic anhydride (58a) with a remarkable level of selectivity. Indeed, the use of (DHQD)2AQN (15 mol%) provided a mixture of two regioiso-meric hemiesters 59a and 60a in a 1 1 ratio with 93 and 80% ee respectively. 

Similarly, a variety of 2-alkyl and 2-aryl succinic anhydrides (58b-g) were resolved with good to excellent enantioselectivities (66-98% ee) (Table 11) [216],... 

It is remarkable that better enantioselectivities are achieved when CALB-catalyzed acylations of the alcohol are carried out in organic solvent rather than in water. Excellent enantioselectivities are obtained when the process is carried out with vinyl esters [22]. However, in some cases the use of vinyl or alkyl esters as acyl donors has the drawback of the separation of the ester (product) and the alcohol (substrate). A practical strategy to avoid this problem is the use of cyclic anhydrides [23]. In this case an acid is obtained as product, which can be readily separated from the unreacted alcohol by a simple aqueous base-organic solvent liquid-liquid extraction. This methodology has been successfully used for the synthesis of (-)-paroxetine as indicated in Scheme 10.11 [24]. 

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