Catalytic asymmetric synthesis, production

We now turn to the Takasago Process for the commercial synthesis of (-)-menthol (1),4 one of the most successful industrial applications of catalytic asymmetric synthesis. This exquisite synthesis is based on the BINAP-Rh(i)-catalyzed enantioselecdve isomerization of allylic amines, and has been in operation for the commercial production of (-)-menthol since 1984. 

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

The utility and efficiency of this methodology is demonstrated by the first catalytic asymmetric synthesis of (—)-phaseolinic acid , a natural product displaying useful antifungal, antitumor and antibacterial properties, as illustrated in equation 110. 

Progress has also been made in asymmetric synthesis through the use of a chiral metal catalyst, so-called catalytic asymmetric synthesis, which is one of the most promising methods for obtaining optically active compounds, since a small amount of chiral material can produce a large amount of chiral product [4]. 

Recently, examples of catalytic asymmetric synthesis have been reported in which the enantiomeric purity of the product is much higher than that of the chiral catalyst. A positive nonlinear effect, that is, asymmetric amplification, is synthetically useful because a chiral catalyst of high enantiopurity is not needed to prepare a chiral product with high enantiomeric excess (% ee) (Scheme 9.1). 

This powerful quaternization method enabled the catalytic asymmetric synthesis of quaternary isoquinoline derivatives with 42 (R1 = Me) as a substrate. When 42 (R1 = Me) was treated with a,a -dibromo-o-xylene, CsOHH20 and (S,S)-le (1 mol%) in toluene at 0 °C, the transient monoalkylation product was rapidly produced, and subsequently transformed into the desired 44 (64%, 88% ee) during the work-up procedure. Catalytic asymmetric alkylation of 42 (R1 = Me) with functionalized benzyl bromide 45, followed by the sequential treatment with 1 M HC1 and then excess NaHC03, furnished the corresponding dihydroisoquinoline derivative 46 in 87% with 94% ee (Scheme 5.23) [25]. 

This method enables the catalytic asymmetric synthesis of differentially protected 3-aminoaspartate, a nitrogen analogue of dialkyl tartrate, the utility of which was demonstrated by the product syn-80 being converted into a precursor 81 of strepto-lidine lactam (Scheme 5.42). 

Despite the revolutionary advances achieved in the field of catalytic asymmetric synthesis, resolution methods both chemical and enzymatic are still probably the most used methods for preparation of optically pure organic compounds. This is especially true on large scale for the production of industrial fine chemicals. A very large number of chiral pharmaceuticals and pharmaceutical intermediates are manufactured by the process involving resolution. The reason behind the continued dominance of resolution in industrial production of optically pure fine chemicals is perhaps the reliability and scalability of these processes. 

This type of additive (or ligand) control of stereoselectivity has three advantages. First of all, after the reaction has been completed, the chiral additive can be separated from the product with physical methods, for example, chromatographically. In the second place, the chiral additive is therefore also easier to recover than if it had to be first liberated from the product by means of a chemical reaction. The third advantage of additive control of enantioselectivity is that the enantiomerically pure chiral additive does not necessarily have to be used in stoichiometric amounts catalytic amounts may be sufficient. This type of catalytic asymmetric synthesis, especially on an industrial scale, is important and will continue to be so. 

There is no doubt that catalytic asymmetric synthesis has a significant advantage over the traditional diastereomeric resolution technology. However, it is important to note that for the asymmetric hydrogenation technology to be commercially useful, a low-cost route to the precursor olefins is just as crucial. The electrocarboxylation of methyl aryl ketone and the dehydration of the substituted lactic acids in Figures 5 and 6 are highly efficient. Excellent yields of the desired products can be achieved in each reaction. These processes are currently under active development. However, since the subjects of electrochemistry and catalytic dehydration are beyond the scope of this article, these reactions will be published later in a separate paper. 

Sulfoximines are versatile reagents for diastereoselective and asymmetric synthesis. They continue to find many synthetic applications as both nucleophilic and electrophilic reagents. While the nucleophilic character of sulfoximine reagents has been well exploited,1 the use of the sulfoximine group as a nucleofuge is more recent and adds to the synthetic use of these compounds. The palladium(0)-catalyzed chemistry of allylic sulfoximines and the use of chiral sulfoximines as ligands in catalytic asymmetric synthesis are areas of recent development that have potentially useful applications. Further work is required to understand the factors that determine the diastereoselection and the stereochemical outcomes of these reactions. These studies will result in enhanced product diastereo- and enantioselectivities and make these reagents even more attractive to the wider synthetic chemistry community. 

With the enantioselective intramolecular benzoin reaction established as a synthetic tool, and in combination with our efforts in the synthesis of bioactive natural products bearing a quaternary a-hydroxy ketone unit (Davis and Weismiller 1990 Heller and Tamm 1981), such as the 4-chromanone derivative (S)-eucomol (Bohler and Tamm 1967 Crouch et al. 1999), a catalytic asymmetric synthesis of various 3-hydroxy-4-chromanones brought about by the chiral triazolium salts 127, 123b and 102 as pre-catalysts was investigated (Enders et al. 2006d). The sterically different pre-catalysts were chosen in order to adjust the catalyst system to the steric and electronic properties of the substrates 128. A screening of the reaction conditions indicated 10 mol% of the... 

An elegant example of a highly efficient catalytic asymmetric synthesis is the Takasago process [128] for the manufacture of 1-menthol, an important flavour and fragrance product. The key step is an enantioselective catalytic isomerisation of a prochiral enamine to a chiral imine (Fig. 1.44). The catalyst is a Rh-Binap complex (see Fig. 1.44) and the product is obtained in 99% ee using a sub-strate/catalyst ratio of 8000 recycling of the catalyst affords total turnover numbers of up to 300000. The Takasago process is used to produce several thousand tons of 1-menthol on an annual basis. 

Having succeeded in obtaining the first results from a catalytic asymmetric nitroaldol reaction, we attempted to apply the method to the catalytic asymmetric synthesis of biologically important compounds. The nitroaldol products were readily converted into /3-amino alcohols and/or ct-hydroxy carbonyl compounds and convenient syntheses of three kinds of optically active /1-blocker are presented in Sch. 8 [55-57]. 

The stereoselectivities seem to be kinetically controlled. In fact, the ee of the aldol product was constant during the course of the reaction. Thus, we have succeeded in performing the first catalytic asymmetric aldol reaction between aldehydes and unmodified ketones by using heterobimetallic or heteropolymetallic catalysts. Several reactions have already been synthetically useful especially for tertiary aldehydes, leading to the catalytic asymmetric synthesis of key intermediates en route to natural products [63]. Further studies are currently in progress. 

The Sharpless AE of allylic alcohols has become a benchmark classic in catalytic asymmetric synthesis [52a,b] and has found use in some industrial applications [52c]. Although this catalytic process seems to be well understood, a heterogeneous system would be advantageous as it could avoid a complicated separation of the product from the catalyst, which can lead to decomposition of the epoxide formed [52c]. However, only a few heterogeneous versions of this important reaction have been conducted successfully [43, 51c, 53]. 

The catalytic asymmetric synthesis of diarylmethylamines by a rhodium/phos phoramidite catalyzed addition of arylboronic adds to N,N dimethylsulfamoyl pro tected aldimines has been reported by de Vries and Feringa [118], The reaction produces very high yields and high enantioselectivities of the protected amine. Deprotection of the amine is achieved without any racemization upon heating the product in the microwave with 1,3 diaminopropane (Scheme 1.35). 

The best approach is to start with a natural optically active compound and modify it by reactions that will not racem-ize the product or intermediates. Unfortunately, this is possible in only a relatively few cases. Some of the problems mentioned in the foregoing might be solved if one could devise a catalytic asymmetrical synthesis for a desired compound.57 Activity in this field is intense. The many small companies in this field (plus some of their suppliers) include the following ... 

With respect to statements 2) and 3), these conditions are particularly easy to fulfill in catalytic asymmetric synthesis where 2) simply demands separation of the chiral product from the chiral catalyst and 3) is superseded by a requirement of reasonable turnover. (A turnover number of 100, modest by the stemdcurds of many catalytic reactions, is equivalent to a 99% recovery of chiral auxiliciry reagent, which is rarely achieved ) Catalytic asymmetric syntheses are therefore particularly attractive, but, of course, they are often not available Statement 3) may not apply when the chiral auxiliary reagent is very cheap (e.g. sucrose). 

A most impressive exam e of catalytic asymmetric synthesis forms the basis for still another and very efficient approach to 19-norsteroids (10,11). The exact mechanism responsible for the extremely high asymmetric induction noted in the crucial conversion of prochiral to ketol 11 and ( )-enedione 12 still needs to be clarified (12,13). Nonetheless, these tftlral aldol products serve very effectively as steroid CD-ring synthons (8,14-21). 

However, this facile epimerization phenomenon was viewed as an opportunity, rather than a liability, to dramatically refine the oxazinone route. Within our process research group, it is commonplace to consider a crystallization-driven racemization resolution protocol whenever an epimerizable stereocenter exists in a molecule. Such an approach towards diastereomerically pure substrates simply relies on differences in the solubility of the diastereomeric products and on the ability of the undefined stereocenter to epimerize under the conditions used in the crystallization. In fact, these processes can effectively rival catalytic asymmetric synthesis and the literature is replete with recent examples of resolution/racemization approaches to chiral molecules. ... 

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