Menthol asymmetric hydrogenation

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. 

Takasago has patented an alternate route to /-menthol (22) (Scheme 12.36).131 Chirality is set by the rhodium catalyzed asymmetric hydrogenation of piperitenone (108). Although many chiral biaryl bisphosphines catalysts have been used, DTMB-SegPHOS (107c) produced pulegone (109) in 90% yield and 98% ee with an S/C ratio of 50,000.131... 

Before leaving asymmetric hydrogenation reactions, we should mention one other related process that has acquired immense importance, again because of its industrial application. You have come across cit-ronellol a couple of times in this chapter already the corresponding aldehyde citronellal is even more important because it is an intermediate in the a synthesis of L-menthol by the Japanese chemical company Takasago. Takasago manufacture about 30% of the 3500 ton annual worldwide demand for L-menthol from citronellal by using an intramolecular ene reaction (a cycloaddition you met in Chapter 35). 

Like the synthesis of L-DOPA by asymmetric hydrogenation, the manufacture of L-menthol hy Takasago Company is also one of the early examples of an industrial process where asymmetric isomerization is a key step. The desired isomerization reaction is one of the steps of the overall synthetic scheme. The synthesis of L-menthol from diethyl geranylamine is shown by 9.2. The formal electron pair pushing mechanism for the isomerization of the allylic amine to the enamine proceeds according to reaction 9.3. 

Reduction of 2-acylamino acrylates to give aminoacids Hydrogenation with C2-Symmetrical BINAP Rh and Ru Complexes Asymmetric Hydrogenation of Carbonyl Groups Regioselective asymmetric hydrogenation ofenones Asymmetric reduction of ketones with kinetic resolution A Commercial Synthesis of Menthol... 

Asymmetric hydrogenation was boosted towards synthetic applications with the preparation of binap 15 by Noyori et al. [55] (Scheme 10). This diphosphine is a good ligand of rhodium, but it was some ruthenium/binap complexes which have found spectacular applications (from 1986 up to now) in asymmetric hydrogenation of many types of unsaturated substrates (C=C or C=0 double bonds). Some examples are listed in Scheme 10. Another important development generated by binap was the isomerization of allylamines into enamines catalyzed by cationic rhodium/binap complexes [57]. This reaction has been applied since 1985 in Japan at the Takasago Company for the synthesis of (-)-menthol (Scheme 10). 

In the area of asymmetric hydrogenation chiral dighosphines have played a center role since and many applications have been developed. Important new ligands that have been introduced comprise Noyori s BINAP [28], DuPhos (Burk) [29], Takaya s BINAPHOS [30], and Ci-symmetric ferrocene-based ligands introduced by Togni [31]. Industrial products, of which the synthesis uses enantioselective phosphine-derived metal-catalysts are for instance menthol, metolachlor, biotin, and several alcohols, e.g. (R)-1,2-propanedioI, For details about the applications the reader is referred to reviews and references therein [32, 33]. Substituents and backbones have an enormous influence on the performance of the ligands, but usually rationalizations are lacking. 

Early work in asymmetric hydrogenation by Knowles [30] and Horner [31] was accompanied hand in hand by important breakthroughs by Kagan [32] and Knowles [33]. Two ligands feature prominently in this regard the tartrate-derived bidentate ligand DIOP (5, Equation 1) [32] and the chiral monophosphine CAMP (8, Equation 2), which can be prepared by resolution with menthol [33]. 

Asymmetric catalysis allows chemicals to be manufactured in their enantiomer-ically pure form and reduces derivatisation and multiple purification steps that would otherwise be required. The 2001 Nobel Prize was awarded for two of the most important asymmetric reactions hydrogenations and oxidations. A variety of ligands suitable for asymmetric reductions are available commercially including BINAP, Figure 3.16. A BINAP Rh complex is used in the commercial production of 1-menthol to enantioselectively hydrogenate an alkene bond (Lancaster, 2002). Ru BINAP complexes can be used in asymmetric reductions of carbonyl groups (Noyori, 2005 Noyori and Hashiguchi, 1997). 

The cationic BINAP-Rh complexes catalyze asymmetric 1,3-hydrogen shifts of certain alkenes. Diethylgeranylamine can be quantitatively isomerized in THF or acetone to citronellal di-ethylenamine in 96-99% ee (eq 17). This process is the key step in the industrial production of (-)-menthol. In the presence of a cationic (R)-BINAP-Rh complex, (5)-4-hydroxy-2-cyclopentenone is isomerized five times faster than the (R) enantiomer, giving a chiral intermediate of prostaglandin synthesis. ... 

The terpene menthol is widely used in organic synthesis, and serves as a chiral auxiliary for several asymmetric reactions [39]. (-)-Menthol 53 could be produced in one step from isopulegol 55 by hydrogenation of the carbon-carbon double bond, and the latter compound could be prepared by a Lewis acid-induced carbonyl-ene reaction [40] of f-(y )-citronellal 54. Nakatani and Kawashima examined that the ene cyclization of citronellal to isopulegol with several Lewis acids in benzene (Sch. 22) [41]. The zinc reagents were far superior to other Lewis acids for obtaining... 

The discovery of the chiral atropisomeric ligand, BINAP, greatly expanded the number of asymmetric homogeneous hydrogenation catalyses. Rhodium and ruthenium complexes that contain BINAP and similar ligand systems have demonstrated an amazing versatility in the reduction of a wide variety of substrate classes in excellent stereoselectivities and reactivities. (-)-Menthol, a variety of... 

Synthesis from Citronellal. Citronellal can be hydrogenated to citronellol by the use of special catalysts and/or special hydrogenation techniques, e.g. [47]. The citronellal which is used as starting material may originate from synthetic production or from isolation of essential oils. Citronellal from citronella oil yields (+(-citronellol the corresponding material from citronellal from Eucalyptus citriodora oil is racemic. Pure (+(-citronellol is also obtained from (+)-citronellal which is produced as an intermediate of (-(-menthol (see p. 55-58). By this asymmetric technology, pure (-(-citronellal and therefore pure (-(-citronellol is also available. 

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. 

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. 

From a historical perspective, the Monsanto process for the preparation of (l.)-DOPA in 1974 laid the foundation stone for industrial enantioselective catalysis. Since then it has been joined by a number of other asymmetric methods, such as enantioselective Sharpless epoxidation (glycidol (ARCO) and disparlure (Baker)), and cyclopropanation (cilastatin (Merck, Sumitomo) and pyre-throids (Sumitomo)). Nevertheless, besides the enantioselective hydrogenation of an imine for the production of (S)-metolachlor(a herbicide from Syngenta), the Takasago process for the production of (-)-menthol remains since 1984 as the largest worldwide industrial application of homogeneous asymmetric catalysis. [124]... 

Natural (-)-menthol is synthesised commercially on a multi-ton scale from the inexpensive achiral precursor myrcene in an elegant application of the asymmetric 1,3-hydrogen shift (see section 6.4.2). The synthesis is so good that it competes with the traditional isolation method from oil of wintergreen. 

Fig. 8.36. As the asymmetric center of citronellal is unaffected by the reactions, all of the isopulegol and menthol isomers formed have the correct stereochemistry at Cl of the /i-menthane skeleton. There are therefore two strategies for recycling unwanted isomers. The first is to purify the ( )-isopulegol (172) by crystallization and recycle (178-180) back to citronellal by pyrolysis [221, 223, 224]. The second is to hydrogenate the mixture, separate the (—)-menthol by crystallization and treat the remainder with aluminium isopropoxide, which converts all of them, by Oppenauer oxidation, enoliza-tion, reketonization and Meerwein-Ponndorf-Verley reduction, to (—)-menthol, which is the thermodynamically most stable isomer (225).

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