Industrial enamine synthesis

Perhaps the most successful industrial process for the synthesis of menthol is employed by the Takasago Corporation in Japan.4 The elegant Takasago Process uses a most effective catalytic asymmetric reaction - the (S)-BINAP-Rh(i)-catalyzed asymmetric isomerization of an allylic amine to an enamine - and furnishes approximately 30% of the annual world supply of menthol. The asymmetric isomerization of an allylic amine is one of a large and growing number of catalytic asymmetric processes. Collectively, these catalytic asymmetric reactions have dramatically increased the power and scope of organic synthesis. Indeed, the discovery that certain chiral transition metal catalysts can dictate the stereo-... 

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. 

Isomerization is a frequent side-reaction of catalytic transformations of olefins, however, it can be a very useful synthetic method, as well. One of the best-known examples is the enantioselective allylamine enamine isomerization catalyzed by [Rh (jR)-or(S)-BINAP (COD)] which is the crucial step in the industrial synthesis of L-menthol by Takasago [42]... 

The ultimate test of any method lies in its applicability in challenging contexts, snch as total synthesis of natnral products and industrial settings. While the indnstrial applications of enamine catalysis are still mostly under development, asymmetric enamine catalysis has already been used in several instances for the synthesis of natural products. This area has been recently reviewed by Christmann [19]. 

There are rather few reactions that can be described as fully atom economical , i.e. when there are no co-products and all the atoms in the starting material(s) appear in the product(s). However, all isomerisation reactions necessarily fall into this category. The use of a transition metal to catalyse such a process with an appropriate substrate brings the possibility of effecting asymmetric isomerisation, a very efficient method to generate enantiomerically enriched products. Indeed, the asymmetric Rh-catalysed isomerisation of an allylamine to an enamine, which proceeds in over 96% ee, was scaled up a number of years ago for industrial production. The enamine product forms a multi-tonne feedstock for menthol and perfumery synthesis. In contrast, the cyclo-isomerisation of dienes, an equally atom-economical process that generates synthetically useful cyclic products, has seen relatively little development despite the reaction having been known for some 30 years. 

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... 

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. 

Here lies the first roadblock. Although the large scale preparation of some related vinyl derivatives such as enol ethers from acetylene itself has been used in the chemical industry for years, these syntheses usually require catalysis by mercuric salts and yields are often quite poor. Similarly, enamines have been claimed to be intermediates in the synthesis of amines from alkynes, but this process also requires mercuric ion catalysis. ... 

The diversity requirement of chiral amines in the synthesis of natural products and chiral drugs is everlasting and the most studies about the catalytic asymmetric hydrogenation of enamines have dealt with simple substrates to date. Hence, it is necessary to explore highly efficient enantioselective protocol to provide more complex and also industrially useful chiral amines. We are confident that the easily accessible and changeable monodentate phosphorus hgands will find a wide appli cation in this field. 

Cationic rhodium(I) complexes catalyze the isomerization of tertiary ally-lamines E-11.17 and Z-11.17 to enamines 11.18. In THF at 80°C, these enamines are readily hydrolyzed to provide aldehydes. When the rhodium ligand is a chiral diphosphine such as (R)- or (6)-binap 3.43 (Ar = Ph), or better yet, (R)- or (S)-tolbinap 3.43 (Ar = 4-MeC6H4), (R) or (5)-enamines 11.18 are obtained with an excellent enantiomeric excess. This method is used in industry for the synthesis of optically active dtronellol and menthol [811, 812, 853, 889], Biphemp 3.45 is also a highly potent ligand for the isomerization of Z-11.17, and ee s as high as 99.5% are observed [905]. The absolute configuration of the enatnine product... 

P-Pinene, a byproduct of the wood and paper industry, is the starting material for an enantioselective synthesis of (i )-citronellal Thermal cycloreversion leads to myrcene. The allylamine obtained by lithiation of myrcene with butyllithium and diethylamine involving an intermediate lithium chelate rearranges stereoselectively in the presence of a chiral catalyst containing the BlNAP-ligand (2,2 -bis-(di-phenylphosphino)-l,r-binapthyl = BINAP) (telomerization) to the enamine, which then readily undergoes acid-catalyzed hydrolysis to (7 )-(+)-citronellal with high enantiomeric excess. 

The oxidative functionalization of olefins through ir-olefin complexes of palladium also has a long history, including the industrial production of acetaldehyde and vinyl acetate. Related reactions, including the conversion of olefins to vinyl ethers and enamines, have been studied in more recent times for fine chemical synthesis. These oxidative C-0 and C-N bond formations have been conducted with a variety of oxidants, including Oj, and have been studied as both intermolecular and intramolecular processes. 

The Rh-catalyzed asymmetric isomerization of diethylgeranylamine to the enamine, which is a key step of the industrial synthesis of menthol, is similarly initiated by C— activation of the amine to form iminium-rhodium hydride rr-complex. ... 

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