Menthol, asymmetric synthesis

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. 

Scheme 12. The Takasago process for the asymmetric synthesis of (-)-menthol (1).

The interest in asymmetric synthesis that began at the end of the 1970s did not ignore the dihydroxylation reaction. The stoichiometric osmylation had always been more reliable than the catalytic version, and it was clear that this should be the appropriate starting point. Criegee had shown that amines, pyridine in particular, accelerated the rate of the stoichiometric dihydroxylation, so it was understandable that the first attempt at nonenzymatic asymmetric dihydroxylation was to utilize a chiral, enantiomerically pure pyridine and determine if this induced asymmetry in the diol. This principle was verified by Sharpless (Scheme 7).20 The pyridine 25, derived from menthol, induced ee s of 3-18% in the dihydroxylation of /rcms-stilbene (23). Nonetheless, the ee s were too low and clearly had to be improved. 

Chiral alcohols have also been used in an asymmetric synthesis of sulphoxides based on halogenation of sulphides. Johnson and coworkers have found319 that the reaction of benzyl p-tolyl sulphide with JV-chlorobenzotriazole (NCBT) followed by addition of (—) menthol and silver tetrafluoroborate afforded diastereoisomeric menthoxysulphonium salts 267 which, upon recrystallization and hydrolysis, gave benzyl p-tolyl sulphoxide with 87% optical purity (equation 145). More recently, Oae and coworkers reported320 that optically active diaryl sulphoxides (e.e. up to 20%) were formed either by hydrolysis or thermolysis of the corresponding diaryl menthoxysulphonium salts prepared in situ from diaryl sulphides using ( —) menthol and t-butyl hypochlorite. 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

Mckenzie carried out a number of asymmetric synthesis by reducing the keto groups in several ketoesters in which the ester group contained a chiral group. Thus he synthesized 1-mandelic acid from benzoyl formic acid by the following steps using 1-menthol... 

Quite recently, an asymmetric synthesis of alkoxyaminosulfonium salt 122 and diaminosulfonium salt 125 was accomplished (163) by way of menthoxysulfonium salt 126, obtained by treating A -p-toluene-sulftnylmorphoUne with 1-chlorobenzotriazole (NCBT), followed by menthol. The subsequent addition of methanol and sodium tetra-phenylborate gave the optically active salt 122 (Scheme 7). When 126 was treated with piperidine instead of methanol, the optically active diaminosulfonium salt 125 was formed. 

Production. Many industrial processes exist for the production of menthols. For (—)-menthol, isolation from peppermint oil (see Mint Oils) competes with partial and total syntheses. When an optically active compound is used as a starting material, optical activity must be retained throughout the synthesis, which generally consists of several steps. Total syntheses or syntheses starting from optically inactive materials require either resolution of racemic mixtures or asymmetric synthesis of an intermediate. Recently used processes are the following ... 

Allylic double bonds can be isomerized by some transition metal complexes. Isomerization of alkyl allyl ethers 480 to vinyl ethers 481 is catalysed by Pd on carbon [205] and the Wilkinson complex [206], and the vinyl ethers are hydrolysed to aldehydes. Isomerization of the allylic amines to enamines is catalysed by Rh complexes [207]. The asymmetric isomerization of A jV-diethylgeranylamine (483), catalysed by Rh-(5)-BINAP (XXXI) complex to produce the (f )-enaminc 484 with high optical purity, has been achieved with a 300 000 turnover of the Rh catalyst, and citronellal (485) with nearly 100% ee is obtained by the hydrolysis of the enamine 484 [208]. Now optically pure /-menthol (486) is commerically produced in five steps from myrcene (482) via citronellal (485) by Takasago International Corporation. This is the largest industrial process of asymmetric synthesis in the world [209]. The following stereochemical corelation between the stereochemistries of the chiral Rh catalysts, diethylgeranylamine (483), diethylnerylamine (487) and the (R)- and (5)-enamines 484... 

Although menthol (23) is a terpene available from natural sources (Chapter 5), asymmetric synthesis by the Takasago method now accounts for a substantial portion of the market. This synthesis is discussed in detail in Chapter 12. The key step is the asymmetric isomerization of an imine to an allyl amine (Scheme 31.18 ).224-225... 

A particularly effective method for the asymmetric synthesis of both aldehyde-and ketone-derived sulfinimines recently introduced by Davis and co-workers is the condensation of (5)-(+)-p-toluenesulfinamide (63) with aldehydes and ketones using activated 4-A molecular sieves or titanium ethoxide [Ti(OEt)4].46 This procedure avoids the problem of removing the menthol by-product of the one-pot procedure (see Section II.D) which is sometimes problematic.23 Importantly, this methodology affords ketone derived sulfinimines 66 which are difficult to prepare by other means. 

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. 

Scheme 1.13 Asymmetric synthesis of menthol by Takasago International Corporation...

Menthol is a well-known terpenoid from the essential oil of mint Mentha spp.) (15), and is described here as a representative of the different acyclic and cyclic plant monoterpenoids. Because of its pleasant odor, taste, and anesthetic and antimicrobial effects, (-)-menthol is an industrially important terpenoid and is produced commercially in large scale both from the essential oils of Mentha spp. and by asymmetric synthesis. The essential oil is produced in glandular trichomes, which are secretory cells that number in the thousands on Mentha leaves. The presence of these specialized cells, which easily can be separated physically from other cell types, has greatly facilitated studying (-)-menthol biosynthesis. 

Hamon and co-workers disclosed the asymmetric synthesis of non-proteinogenic a-amino acids [27], The authors used A -protected imino menthol esters as the building blocks (see Table 3, entry 3). They expected that 1,2-addition to the imine would take place, rather than attack at the nitrogen, because of the presence of the acyl group. The... 

A large excess of trimethylphosphite was required to achieve good yields of mono-substituted product 4. In the sequence 4 — 6, only the nicely crystalline phosphinic acid 6 was isolated. The fact that the acid chloride 7 can be converted into an 80 20 mix of (S) and (R) isomers means that the menthol preferentially reacts with one form while the other isomer rapidly racemizes. Thus, the catalyst preparation was greatly facilitated by an asymmetric synthesis of its own directed by (-)-menthol. 

One of Noyori s most remarkable achievements is a commercial synthesis of (-)-menthol 51 used since 1983 by the Takasago International Corporation on a scale of thousands of tonnes a year. This and related processes are discussed in detail by S. Akutagawa and K. Tani in chapter 3 of Ojima s Catalytic Asymmetric Synthesis. The process is summarised here ... 

Phenol, (-) menthol and diethyl aluminium chloride were reacted in toluene to produce the required intermediate for the ensuing asymmetric synthesis. Addition of chloral and stirring for 24 h at 25 °C gave the product. (-)-2-(2,2,2-trichloro-1 -hydrojqfethyl)phenol. 

This chapter summarizes some of the most characteristic results obtained with the use of mainly homogeneous metal complex eatalysts either in the industry or in processes recommended for practical use. These are large seale processes of asymmetric synthesis of the herbicide metolachlor, synthesis of optically pure menthol with the use of chiral iridium and rhodium phosphine complexes, consideration of the synthesis of ethyl 2-hydroxybutyrate as a monomer for the preparation of biodegradable polyesters with use of heterogeneous ehiral modified nickel catalyst, the manufacturing of (fJ)-pantolactone by means of a possible eata-IjTic systems for enantioselective hydrogenation of ketopantolactone, and catalytic systems for the preparation of other pharmaceuticals. 

Another important example for practical asymmetric synthesis is the manufacture of (-)-menthol produced by Tagasago Co. (Tani et ah ) on a... 

In the last 25 years or so, this subject has occupied more organic chemists than possibly any other, and we are now at a point where it is not only possible (and in fact essential because of strict regulatory rules) to make many drug molecules as single enantiomers, but it is also even possible to make many chiral molecules that are indigenous to nature more cheaply in the laboratory. By 2007, for example, at least 30% of the world s supply of menthol was not extracted from plants but made synthetically. A thousand tonnes of (-)-menthol a year is made by the company Takasago in Japan using the techniques of asymmetric synthesis that you will meet later in this chapter. 

Besides the more common reactions such as hydrogenation, isomerization, alkylation, and the Diels-Alder reaction. Sharpless epoxidation and dihydroxylation by asymmetrical catalysis are rapidly emerging as reactions with immense industrial potential. Table 9.7 lists some important syntheses based on asymmetric catalysis. These include processes for the pharmaceutical drugs (S)-naproxen, (S)-ibuprofen, (,S)-propranolol, L-dopa, and cilastatin, a fragrance chemical, L-menthol, and an insecticide (/ )-disparlure. Deltamethrin, an insecticide, is another very good example of industrial asymmetric synthesis. The total synthetic scheme is also given for each product. In general, the asymmetric step is the key step in the total synthesis, but this is not always so, as in the production of ibuprofen. Many of the processes listed in the table are in industrial production. 

Tsuruta et al. (1963) prepared optically active poly (propylene oxide) from one mole of diethylzinc and two moles of (- -)-bomeol or (—)-menthol. They interpreted the catalyst activity as due to monomeric or dimeric zinc dialkoxide and that anionic coordinated polymerization took place by a four-membered ring intermediate similar to (LXV). The proximity of the optically active alkoxide to the point of reaction was thought to cause the asymmetric synthesis. 

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