Ruthenium enantiomerically pure

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

Enantioselective cyclopropanations using enantiomerically pure tungsten [54], iron [458,483,630], and ruthenium [581] carbene complexes have also been at-... 

The control of enantioselectivity in the reduction of carbonyl compounds provides an opportunity for obtaining the product alcohols in an enantiomerically enriched form. For transfer hydrogenation, such reactions have been dominated by the use of enantiomerically pure ruthenium complexes [33, 34], although Pfaltz and coworkers had shown by 1991 that high levels of enantioselectivity could be obtained using iridium(I) bis-oxazoline complexes [35]. 

Thus, a synthetic cycle for the formation of enantiomerically pure propargylic alkylated compounds from an achiral propargylic alcohol has been accomplished by starting from the ruthenium-BINAP complex 66 (Scheme 12). This stepwise reaction provides the first synthetic approach to highly enantioselective propargylic substitution reactions. 

A ruthenium(II) complex (5,5,55)-BrXuPHOS-Ru-DPEN (4) containing BINOL-based monodonor phosphorus ligand BrXuPHOS (1) has been prepared and applied as a catalyst (S/C = up to 10000) for the asymmetric hydrogenation of ketones, providing the enantiomerically pure secondary alcohols with up to 99 % ee. 

The asymmetric hydrogenation of 2-(6-methoxy-2-naphthyl)acrylic acid using ruthenium-BINAP complexes also yields enantiomerically pure naproxen. 

The syntheses of l,2,3,5,6,8a-hexahydroindolizine (1) and (-)-swainsonine were successfully carried out via a ROM-RCM strategy, and final CM with ethylene to free the ruthenium. Two different synthetic routes were implemented to achieve a similar compound. In the case of l,2,3,5,6,8a-hexahydroindolizine 1, the six-membered ring was established first using RRM and in the case of (-)-swainsonine, the five-membered ring was established first. In both cases, the ring rearrangement precursors were enantiomerically pure five-membered carbocycles, which can be synthesised efficiently from racemic starting materials. 

A similar type of cascade reaction has been carried out with cyclic alkenes bearing only one olefinic side chain to obtain substituted heterocycles via ruthenium-catalyzed ring closing-ring opening metathesis (RCM-ROM) reactions. The preparation of enantiomerically pure cis- or trans-a,a -disubstituted piperidines has been achieved in the same yield for the two diastereoisomers [35] (Scheme 17). This reaction has also been used as a key step for the synthesis of natural products [36-39]. 

Complex 376 can be prepared from enantiomerically pure rhenium precursor 381. The former can be deprotonated at low temperatures initiating the [2,3]-sigmatropic rearrangement to diastereomerically pure homoallylic sulfide complex 377. After S-alkylation, cyanide treatment releases the S ligand as product 379. As an extension of this work the authors showed that iron and ruthenium complexes can be used, too [219]. 

The ruthenium-catalyzed racemization of a-methylbenzyl alcohol was combined with an enzyme-catalyzed transesterification with lipase. Dinuclear ruthenium complex 64 effectively catalyzes the racemization of a-methylbenzyl alcohol and the combination of 64, p-chlorophenyl acetate, and enzyme N-435 in the reaction of racemic amethylbenzyl alcohol gave enantiomerically pure (R)-a-methylbenzyl acetate in the excellent yield (Eq. 12.26) [29]. 

Finally, the last few years have seen the first examples of the use of molecular-imprinted, polymer-supported catalysts for achieving product selectivity. The imprinted cavities are tailored in such a way that the course of a chemical reaction is directed towards one of the possible products. In the previous section it has already been shown that molecularly imprinted polymers used as microreactors are able to impart to a given reaction a different regio- and stereo-selectivity with respect to the same reaction in solution. Attempts towards an imprinted enantio-selective catalyst were reported by Gamez and co-workers who employed as template monomer an optically active, polymerisable ruthenium complex bearing in its coordination sphere an enantiomerically pure alkoxide [121]. After polymerisation, the alkoxide was split off and the resulting polymer-supported catalyst was used for enantio-selective hydride transfer reductions. The obtained selectivity was higher than for a polymer prepared without the optically active alkoxide but lower than for the same ruthenium complex in solution. 

Ruthenium(binap) complexes effectively catalyze asymmetric hydrogenation of a-amidocinnamic acids [172], allylic alcohols [173] and acrylic acids with almost quantitative enantiomeric excess [174]. For example, one of the largest-selling anti-inflammatory agents, Naproxen should be supplied as the enantiomerically pure 5-isomer, because the R-isomer is expected to be toxic to the liver. Asymmetric hydrogenation of the precursor by RuCL[(5)- binap] produces 5-Naproxen with 96-98 % ee (eq (47)) [175-176]. 

Using enantiomerically pure 4-hydroxy-2-alkynoate and 1,11-dodecadiene with CpRu(cod)Cl as catalyst, this reaction type was used in the synthesis of the acetogenin (+)-ancepsenolide, a bisbutenolide with a 12-carbon chain linking both lactone units "4. The primary addition step of this conversion represents an example of a ruthenium-catalyzed Alder-ene reaction (vide infra). Other examples of this type have been reported123. 

Enantiomerically pure ruthenium complexes [CpRuLL (CH2=Cll2)]PF6 17, where LL is (S,S)-Chiraphos or (-)-Diop, catalyze the cyclocondensation of benzaldehyde (2 a) with ( )-l-methoxy-3-trimethylsilyloxy-l,3-butadiene (16. Danishefsky s diene), albeit with low optical yields of 25% and 16% ee (18 as a major isomer), respectively39. 

When an enantiomerically pure catalyst is used in the directed hydrogenation of a racemic reactant then the enantiomers will react at intrinsically different rates since the transition states are diastereomeric. With some rhodium and ruthenium catalysts the difference [expressed as a selectivity factor S = k(fast)/k(slow)] is > 10 which makes the process synthetically useful. This is the case for all the x-hydroxyalkylacrylates described in Section 2.5.1.1.1. when complexes based on rhodium(DiPAMP)+ are employed as catalysts. The procedure is operationally simple in that the reaction is run to the point where the enantiomeric excess of recovered reactant is ca. 95% (57-65 % reaction) and the hydrogenation is then stopped. The starting material and product arc separated after removal of the catalyst. Similar results are obtained for a-hydro-xyalkyl-39, x-amidoalkyl-40 and a-carboxyalkylacrylatcs41 (entries 1-3, in the table below). 

The intermediate sulfonimide derived from saccharin by addition of an alkyllithium compound is also the starting material for sultams mimicking the behavior of camphorsultams. The sultams arc readily obtained from, e.g., 3-methylbenzisothiazole 1,1-dioxide, by ruthenium-catalyzed enantioselective reduction, using BINAP as a chiral ligand, in enantiomerically pure form 79. Thus, both enantiomers can be obtained by using the appropriate enantiomer of the control ligand. Like the camphorsultams, the saccharin derivatives readily form amides with carboxylic acids which can be alkylated via the carbanion (Section D.1.1.1.3.1.) or, if unsaturated carboxylic acids are used, may react as chiral dienophiles in Diels—Alder reactions (Section D.l.6.1.1.1.). 

The preparation of ruthenium bis(diimine)sulfoxide complexes by reaction of cis-[Ru(bipyridine)2(Cl)2] (165) with enantiomerically pure chiral sulfoxides 166 was described by Ait-Haddou [94] as a new concept in the preparation of optically active octahedral ruthenium complexes (Scheme 5.47). The reaction produces two dia-stereomeric complexes 167 and 168 and the microwave-irradiated reactions resulted in excellent yields and high reaction rates with a notable increase in the observed diastereomeric excess. 

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