Citronellic acid 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. 

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... 

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. 

Methyl-3-propiolactone is useful as a four-carbon building block for terpenoid synthesis (eq 4). Citronellic acid (9) isprepared by reaction with the homoprenyl Grignard reagent pulegone (10), citronellol (11), geraniol, and nerol (12) can be obtained by further functional group manipulations. ... 

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... 

These compounds are often used by oxidative cleavage of the alkene to give a C7 unit with functionality at both ends, e.g. 78 from citronellic acid. Notice how the functional groups are carefully made different so that one end can be reacted selectively. This compound 78 was used by Mori in natural product synthesis.22... 

I will now outline the details of our second synthesis of 104 published in 1990.103 The purpose of our 1990 synthesis was to provide extremely pure products. In our 1978 synthesis of 104 all the stereoisomers were pheromonally active. In that synthesis, however, we employed (R)-citronellic acid of 92% ee as our starting material (cf. Figure 4.54). In our 1990 synthesis, we chose enantiomerically pure (R)-citronellol and ethyl (R)-3-hydroxybutanoate as our starting materials to ensure the preparation of the stereoisomers of 104 in 100% enantiomerically pure forms. Bioassay of the products then unambiguously would verily the previous conclusion that all the stereoisomers are bioactive. 

Cuprates containing a non transferable chiral group leads to induction of asymmetry, the optical yields being however moderate (15—50% enantiomeric excess) but the presence of a chiral center in the substrate can also govern an induction of asymmetry as shown in a synthesis of 5(—) citronellic acid [8]. 

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... 

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 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. 

EG acid-catalyzed cyclization of citronellal 70 in a CH2Cl2,/THF(7/1)—E NOTs/ LiC104—(Pt) system gives a 91% yield of the cyclized products 71, a precursor for the synthesis of menthofuran 73 via the ene-type chlorination product 72 (Scheme 3-26)... 

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 total synthesis of milbemycin-p developed by Williams et al. [124] involves construction of three units the spiroketal moiety (A), carbon chain with a remote chiral centre at C-12 (B) and the substituted benzoic acid (C). Unit (A) is prepared starting from citronellol (154), while unit (B) was prepared starting from (-)-(3S)-citronellal (162) (Scheme 20). A and B were joined after transmetalation of the tetrahydropyranyl ether 166 to give 167 (Scheme 21), which is allowed to react with the aldehyde A to give 168. Further steps are shown in scheme 22. 

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