Asymmetric citronellal

S )-citronellal 42 can also be prepared similarly from 40. Asymmetric hydrogenation of (R)-43 provides 44, which can be used to make the side chain of vitamins E and K (Scheme 6-22). 

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. 

The 1-pro-7 -hydrogen is lost on oxidizing geraniol with a cell-free extract from Cannabis sativa (Vol. 7, p. 9, ref. 96), asymmetric microbial reduction of ( )-citronellal to (-)-citronelloI is reported, and callus cultures of Nicotiana tabacum selectively hydroxylate linalool, dihydrolinalool, and the derived acetates at the -methyl group [e.g. to give (59)]. ... 

Olefinic double-bond isomerization is probably one of the most commonly observed and well-studied reactions that uses transition metals as catalysts [1]. However, prior to our first achievement of asymmetric isomerization of allylamine by optically active Co(I) complex catalysts [2], there were only a few examples of catalytic asymmetric isomerization, and these were characterized by very low asymmetric induction (<4% ee) [3], In 1978 we reported that an enantioselective hydrogen migration of a prochiral allylamine such as AVV-diethylgerany-lamine, (1) or N V-diethylnerylamine (2) gave optically active citronellal ( )-enamine 3 with about 32% ee utilizing Co(I)-DIOP [DIOP = 2,3-0-isopropylidene-2,3-dihydroxy-l,4-bis(diphenylphosphino)butane] complexes as the catalyst (eq 3.1). 

As described above, hydrolysis of the optically active enamine 3 proceeds without racemization and produces an optically active aldehyde, citronellal, with a very high optical purity (>98% ee). The optical purity of citronellal) available from natural sources is known to be no more than 80% ee [5], The present asymmetric isomerization of the allylamine 1 is utilized as the key step for the industrial production of (-)-menthol (Scheme 3.3). 

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... 

Noyori s BINAP catalysts deserve special attention because their chirality is based on the bulkiness of the naphthalene groups, rather than on carbon or phosphorus asymmetric centers (Figure 3.28, inset) [77]. One of the many examples of asymmetric catalysis using BINAP is the synthesis of (—)-menthol, an important additive for flavors, fragrances, and pharmaceuticals. Starting from myrcene, the process is carried out by Takasago International on a multi-ton scale. The key step is the isomerization of geranyldiethylamine to (R)-citronellal enamine [78], which is then hydrolyzed to (R)-citronellal with nearly 99% ee. 

Menthol is used in many consumer products, such as toothpaste, chewing gum, cigarettes, and pharmaceutical products, with an estimated worldwide consumption estimated at 4500 tons per year (Chapter 31)4143 (-(-Menthol (22) is manufactured by Takasago Co. from myrcene (23), which is available from the cracking of inexpensive P-pinene (Scheme 12.6)4244 The key step in the process is the asymmetric isomerization of /V,/V-diethylgcranylarninc (24) catalyzed by either [Rh(L2)(5 -BINAP)]+BF f (where L is diene or solvent) or Rh(.S -BINAP)2]+BF f to the diethyl enamine intermediate 25 in 96-99% ee.3645 Citronellal (26) is obtained in 100% ee after hydrolysis of the enamine intermediate natural citronellal has an optical purity of 80%.35 A stereospecific acid-catalyzed cyclization followed by reduction produces 22.42... 

S)-4 and/or its enantiomer (R)-4 have been prepared via resolution of an intermediate, starting from (RJ-citronellic acid,10 by stoichiometric asymmetric synthesis - 6 (76-88% ee), and by a microbiological method.17... 

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). 

Optically active polyaldehydes possessing optically active side chains, such as poly-(R)(+)-citronellal, poly-(R)(+)-6-methoxy-4-methylhexanal, and poly-(S)(+)-2-methylbutanal, have been prepared by Goodman (1, 22). The optical activity of the polymers was enhanced as compared with their model compounds. It was concluded that the enhancements of the optical activity arose from a conformational rigidity around the asymmetric center in the side chain of the polymer. From degradation studies of the polymers it was concluded that the optical activity of the monomer was unchanged, and no racemization had occurred during polymerization and degradation. 

The key step of this process is the asymmetric isomerization of (A,A)-diethyl-geranylamine or diethylnerylamine to give (7 )-citronellal ( )-diethylenamine. 

The first catalysts used were Co(I)-DIOP (DIOP, see Figure 11b) based systems. Up to 32% ee was achieved with 39% yield in the isomerization of (A, AO-diethylgeranylamine to (i )-citronellal. Subsequently, some rhodium (I)-DIOP or BINAP (BINAP = 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl) systems proved to be very active. In particular, cationic rhodium(I)-BINAP complexes show very high selectivities and catalytic activities for this isomerization. BINAP is an atropoisomeric diphosphine (Figure 20) which was first synthesized by Noyori and Takaya and since then its metal complexes have been extensively used as catalysts in a variety of asymmetric syntheses. 

This asymmetric Michael addition was used for synthesis of (S)-citronellic acid (6) from the chiral crotonate 5 and a 4-methyl-3-pentenylcopper reagent. 

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 system was also applicable to the cyclization of citronellal 54. Treatment of (f )- and (5)-citronellal with the chiral zinc reagent derived from (/ )- and (5)-BINOL 58 afforded the exclusive formation of /- and d-isopulegol 55, respectively. The asymmetric induction is totally controlled by the C-3 chiral center on the substrates and is independent of the chirality of the BINOL. 

The analogous cyclization of chiral imines occurs in high yield (75-85 %) with good asymmetric induction (36-65 % ee) [91]. For example, the cyclization of the aldimine derived from methyl citronellal, using SnCU, affords only the tram-substituted amino-cyclohexane in high yield (Eq. 57). exo Products are formed exclusively or preferentially over the thermodynamically favored endo products. 

The world s biggest application of asymmetric catalysis is Takasago Perfumery s synthesis of (-)-menthol from myrcene (see Sections 2.9 and 3.3.1) with about 1500 t/a (menthol and other chiral terpenic substances). The key step is the isomerization of geranyldiethylamine with an Rh -S-BINAP catalyst to citronellal ( )-enamine (eqs. (17)) (BINAP = 2,2 -bis(diphenylphosphine)-l,l -binaphthyl).The geometry of the double bond is 100% E. 

Oppolzer has developed a method of asymmetric synthesis based on the use of the chiral auxiliaries 39A and 39B derived respectively from (+ )-camphor [(+ )-40] and (- )-camphor [(- )-40]. Crotonylation of 39A gave the ester that was attacked by 4-methyl-3-pentenyllithium in the presence of copper iodide tributylphosphine and boron trifluoride from only one side of the molecule, the product 41 having the (S)-configuration (enantioselectivity 98.5%). The ester 42—similarly obtainable from 39B—was methylated under similar conditions, also yielding 41 with 92% enantioselectivity. (S)-Citronellic acid [(S)-36] or (S)-citronellol [(S)-33] were then obtained from 41 by the action of sodium hydroxide or lithium aluminum hydride (Scheme 6). Reduction of potassium... 

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