Citronellal synthesis

A cursory inspection of key intermediate 8 (see Scheme 1) reveals that it possesses both vicinal and remote stereochemical relationships. To cope with the stereochemical challenge posed by this intermediate and to enhance overall efficiency, a convergent approach featuring the union of optically active intermediates 18 and 19 was adopted. Scheme 5a illustrates the synthesis of intermediate 18. Thus, oxidative cleavage of the trisubstituted olefin of (/ )-citronellic acid benzyl ester (28) with ozone, followed by oxidative workup with Jones reagent, affords a carboxylic acid which can be oxidatively decarboxylated to 29 with lead tetraacetate and copper(n) acetate. Saponification of the benzyl ester in 29 with potassium hydroxide provides an unsaturated carboxylic acid which undergoes smooth conversion to trans iodolactone 30 on treatment with iodine in acetonitrile at -15 °C (89% yield from 29).24 The diastereoselectivity of the thermodynamically controlled iodolacto-nization reaction is approximately 20 1 in favor of the more stable trans iodolactone 30. 

Terpenoid substances are of broad distribution and diverse function in insects. One set, elaborated by the mandibular glands of Acanthomyops claviger, acts both as a defensive secretion and as an alarm releaser. When fed Cu-labeled acetate or mevalonate, laboratory colonies of these ants produce radioactive citronellal and citral, providing unambiguous evidence for de novo synthesis of these terpenes by the ant. The incorporations of these precursors implicate the mevalonic acid pathway as the likely biosynthetic route. 

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

The one-electron oxidation of enol silyl ether donor (as described above) generates a paramagnetic cation radical of greatly enhanced homolytic and electrophilic reactivity. It is the unique dual reactivity of enol silyl ether cation radicals that provides the rich chemistry exploitable for organic synthesis. For example, Snider and coworkers42 showed the facile homolytic capture of the cation radical moiety by a tethered olefinic group in a citronellal derivative to a novel multicyclic derivative from an acyclic precursor (Scheme 8). 

Isomerization of allylic amines is another example of the application of the BINAP complex. Rh BINAP complex catalyzes the isomerization of N,N-diethylnerylamine 40 generated from myrcene 39 with 76-96% optical yield. Compound (R)-citronellal (R)-42. prepared through hydrolysis of (R)-41, is then cyclized by zinc bromide treatment.49 Catalytic hydrogenation then completes the synthesis of (—)-menthol. This enantioselective catalysis allows the annual production of about 1500 tons of menthol and other terpenic substances by Takasago International Corporation.50... 

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 intramolecular carbonyl ene reaction is a useful way to generate a C-C bond and has been well studied [49-52]. Of particular interest is the cyclization of citronellal to yield isopulegol, an important intermediate in an industrial synthesis... 

In a similar approach, Shishido et al. (241) used oxime 215 [derived from the monoterpene (+)-citronellal (214)] for the synthesis of (—)-mintlactone (218) and (+)-isomintlactone (219), sweet compounds isolated from some Mentha species (Scheme 6.89). Bicyclic isoxazoline 216 was obtained in good yield from the cycloaddition. As expected, the product possessing tra i-l,4-substimtion prevailed. Reductive hydrolysis of the major isomer of 216 using hydrogen-Raney Ni-trimethyl borate provided p-hydroxyketone 217. This compound was dehydrated to give an enone and this was followed by carbonyl reduction-lactonization to complete the synthesis of both lactones 218 and 219 (241). 

A striking example of the power of A -heterocyclic carbene (NHC)-bearing catalysts with sterically demanding substrates was disclosed by Chavez and Jacobsen, " who presented a route to several iridoid natural products, exemplified by the enantio- and diastereoselective synthesis of boschnialactone 31 outlined in Scheme 5. Chiral aldehyde 27, available from citronellal by Eschenmoser-methylenation in a single step, reacted despite the presence of an isoprenyl moiety and a gi OT-disubstituted double bond, in the presence of catalyst C smoothly to form... 

Synthesis of (+)- and ( )-Citronellol from the Citronellal Fraction of Essential Oils. (+)-Citronellal is obtained by distillation of Java citronella oil and is hydrogenated to (+)-citronellol in the presence of a catalyst (e.g., Raney nickel). Similarly, (zb)-citronellol is prepared from the ( )-citronellal fraction of Eucalyptus citriodora oil. 

Among the acyclic terpene aldehydes, citral and citronellal hold key positions as fragrance and flavor chemicals, as well as starting materials for the synthesis of other terpenoids. Hydroxydihydrocitronellal is one of the most important fragrance materials. Derivatives of these aldehydes, particularly the lower acetals, are also used as fragrance materials. Acyclic sesquiterpene aldehydes are not very important as such, but they contribute to the characteristic fragrance and aroma of essential oils, for example, in the case of a- and /3-sinensal in sweet orange oil. 

Pure citronellal is a colorless liquid with a refreshing odor, reminiscent of balm mint. Upon catalytic hydrogenation, citronellal yields dihydrocitronellal, citro-nellol, or dihydrocitronellol, depending on the reaction conditions. Protection of the aldehyde group, followed by addition of water to the double bond in the presence of mineral acids or ion-exchange resins results in formation of 3,7-dimethyl-7-hydroxyoctan-l-al (hydroxydihydrocitronellal). Acid-catalyzed cycli-zation to isopulegol is an important step in the synthesis of (-)-menthol. 

Synthesis from Geraniol or Nerol. ( )-Citronellal can be obtained by vapor-phase rearrangement of geraniol or nerol in the presence of, e.g., a barium-containing copper-chromium oxide catalyst [63]. 

Synthesis from Citronellol. ( )-Citronellal can also be obtained by dehydrogenation of citronellol under reduced pressure with a copper chromite catalyst [64]. 

Synthesis from Citral. Selective hydrogenation of citral to citronellal can be accomplished in the presence of a palladium catalyst in an alkaline alcoholic reaction medium [65]. 

Synthesis from Citronellal. One of the oldest routes to hydroxydihydrocitronellal is the hydration of the citronellal bisulfite adduct (obtained at low temperature) with sulfuric acid, followed by decomposition with sodium carbonate. A more recent development is hydration of citronellal enamines or imines, followed by hydrolysis [67]. 

Although a small amount of acyclic terpene acids such as geranic acid and citronel-lic acid occurs in many essential oils, often as esters, they are rarely used in perfume and flavor compositions. Methyl geranate is an intermediate in a-damascone synthesis and is sometimes needed in the reconstitution of essential oils. 

Individual compounds can be isolated from essential oils containing one or only a few major components by distillation or crystallization. Examples are eugenol from clove oil, menthol from commint oil, citronellal from Eucalyptus citriodora oil and citral from Litsea cubeba oil. These compounds are used as such or serve as starting materials for the synthesis of derivatives, which are also used as flavor and fragrance substances. However, the importance of some of these oils has decreased substantially because of the development of selective synthetic processes for their components. 

Uses and Reactions. The main use for citronellol is for use in soaps, deteigents, and other household products. It is also important as an intermediate in the synthesis of other important fragrance compounds, such as citronellyl acetate and other esters, citronellal, hydroxycitronellal, and menthol. 

Menthol can also be synthesized from optically active terpenoids such as (+)-citronellal, (-)- P-phellandtene, and (+)-3-carene. The synthesis from (+)-3-carene has already been discussed in the section on hydrocarbons. Such methods must avoid any racemization during the course of a usually multiple-step synthesis. One disadvantage of such methods is that the other menthol diastereoisomers must be equilibrated and recycled. 

A synthesis of optically active citronellal uses myrcene (7), which is produced from P-pinene. Reaction of diethyl amine with myrcene gives AyV-diethylgeranyl- and nerylamines. Treatment of the allylic amines with a homogeneous chiral rhodium catalyst causes isomerization and also induces asymmetry to give the chiral enamines, which can be readily hydrolyzed to (H-)-citronellal (151). 

The Rh(I)-catalyzed isomerization of prochiral allylic amines to optically active enamines is used for the giant-scale synthesis of citronellal, citronellol, menthol, and other fragrances (18)(Chapter 3). 7-Meth-oxydihydrocitronellal, thus prepared, is an insect growth regulator. All of these processes can be carried out economically and with extremely high optical yields. 

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