Menthol reaction

More than 15 preparations described in patents are variations of the above synthetic schane. hi particular, to obtain optically pure Emtricitabine, lipase-catalyzed enzymatic resolution, as well as chiral stationary phase HPLC was used [143]. However, the most effective procedure included separation of menthyl derivatives. This method evolved significantly since the first publication (which in fact relied on separation of all the 4 possible diastereomers) [144] one of the recent multigram preparations is shown in the Scheme 37 [145]. The first step of the synthesis included formation of methyl ester 159 from glyoxalic acid and L-menthol. Reaction of 159 with 1,4-ditiane 154 gave 1,3-oxathiolane 160 as a mixture of cis diastereomers. 

Three general methods exist for the resolution of enantiomers by Hquid chromatography (qv) (47,48). Conversion of the enantiomers to diastereomers and subsequent column chromatography on an achiral stationary phase with an achiral eluant represents a classical method of resolution (49). Diastereomeric derivatization is problematic in that conversion back to the desired enantiomers can result in partial racemization. For example, (lR,23, 5R)-menthol (R)-mandelate (31) is readily separated from its diastereomer but ester hydrolysis under numerous reaction conditions produces (R)-(-)-mandehc acid (32) which is contaminated with (3)-(+)-mandehc acid (33). 

AH (A)-menthol is made by synthetic methods. One method involves the cyclization of (+)-citroneIlal (68). Using a mild acid catalyst, (+)-citroneIlal [2385-77-5] undergoes an ene-reaction to produce a mixture of isopulegols (142). Catalytic hydrogenation of the isopulegol mixture gives a mixture of menthol and its isomers. The (A)-menthol is obtained after efficient fractional distillation and the remaining isomers can be equilibrated, usually with sodium menthol ate or aluminum isopropoxide. An equilibrium mixture is obtained, comprised of 62 wt % (A)-menthol, 23 wt % (+)-neomenthol, 12 wt % (+)-isomenthol, and 3 wt % (+)-neoisomenthol. The equilibrium mixture can be distilled to recover additional (+)-mentbol. 

The method for preparing (-)-menthol (73) from (+)-citroneUal (68), which can be fractionally distilled from citroneUa oU, is cyclization by the ene-reaction. The reaction can be done thermally or using alumina and silica catalysts (145—147). 

Danishefsky et al. were probably the first to observe that lanthanide complexes can catalyze the cycloaddition reaction of aldehydes with activated dienes [24]. The reaction of benzaldehyde la with activated conjugated dienes such as 2d was found to be catalyzed by Eu(hfc)3 16 giving up to 58% ee (Scheme 4.16). The ee of the cycloaddition products for other substrates was in the range 20-40% with 1 mol% loading of 16. Catalyst 16 has also been used for diastereoselective cycloaddition reactions using chiral 0-menthoxy-activated dienes derived from (-)-menthol, giving up to 84% de [24b,c] it has also been used for the synthesis of optically pure saccharides. 

CO2 reference standard. A special interface, employing the necessary oxidation and reduction reaction chambers and a water separator, was used employed. For standards of 5-nonanone, menthol and (/ )-"y-decalactone, they were able to determine the correct ratios, with relatively little sample preparation. The technical... 

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-... 

The interest in asymmetric synthesis that began at the end of the 1970s did not ignore the dihydroxylation reaction. The stoichiometric osmylation had always been more reliable than the catalytic version, and it was clear that this should be the appropriate starting point. Criegee had shown that amines, pyridine in particular, accelerated the rate of the stoichiometric dihydroxylation, so it was understandable that the first attempt at nonenzymatic asymmetric dihydroxylation was to utilize a chiral, enantiomerically pure pyridine and determine if this induced asymmetry in the diol. This principle was verified by Sharpless (Scheme 7).20 The pyridine 25, derived from menthol, induced ee s of 3-18% in the dihydroxylation of /rcms-stilbene (23). Nonetheless, the ee s were too low and clearly had to be improved. 

A similar but asymmetric variant of the reaction, involving the radical addition of alkyl iodides and trialkylboranes to chiral azirine esters derived from 8-phenyl-menthol and camphorsultam, in the presence of a Cu(i) catalyst, has subsequently been reported [64]. The diastereoselectivity of the addition is variable (0-92% de)... 

Solladie and coworkers avoided the use of a sulfinyl chloride when they prepared (— )-menthyl 1-naphthalenesulfinate in an overall yield of 45% by the reaction of thionyl diimidazole, obtained from imidazole and thionyl chloride, with 0.7 equivalent of ( — )-menthol followed by 1 equivalent of 1-naphthylmagnesium bromide (equation 4). 

Chiral alcohols have also been used in an asymmetric synthesis of sulphoxides based on halogenation of sulphides. Johnson and coworkers have found319 that the reaction of benzyl p-tolyl sulphide with JV-chlorobenzotriazole (NCBT) followed by addition of (—) menthol and silver tetrafluoroborate afforded diastereoisomeric menthoxysulphonium salts 267 which, upon recrystallization and hydrolysis, gave benzyl p-tolyl sulphoxide with 87% optical purity (equation 145). More recently, Oae and coworkers reported320 that optically active diaryl sulphoxides (e.e. up to 20%) were formed either by hydrolysis or thermolysis of the corresponding diaryl menthoxysulphonium salts prepared in situ from diaryl sulphides using ( —) menthol and t-butyl hypochlorite. 

The Diels-Alder reaction of simple alkoxy alkenylcarbene complexes leads to mixtures of endo and exo cycloadducts, with the endo isomer generally being the major one [96,97]. Asymmetric examples of endo Diels-Alder reactions have also been reported by the use of chiral auxiliaries both on the carbene complex and the diene. Thus, the reaction of cyclopentadiene with chiral alkenylcarbene complexes derived from (-)-menthol proceeds to afford a 4 1... 

BINAP is a versatile ligand the S-enantiomer, complexed with rhodium, is used in the commercial production of 1-menthol (Scheme 4.23). In this case the reaction involves isomerization of diethylgeranylamine to R)-citronellal enamine, which proceeds to approximately 99% ee. 

The 0-silylation reaction of alcohols is important as a protection method of hydroxyl groups. 0-Silylations of liquid or crystalline alcohols with liquid or crystalline silyl chlorides were found to be possible in the solid state. For example, when a mixture of powdered L-menthol (26), ferf-butyldimethylsilyl chloride (27), and imidazole (28) was kept at 60 °C for 5 h, 0-tert-butyldi-methylsilyl L-menthol (29) was obtained in 97% yield [8] (Scheme 4). Similar treatments of 26 with the liquid silyl chlorides, trimethyl- (30a) and triethylsilyl chloride (30b), gave the corresponding 0-silylation products 31a (89%) and 31b (89%), respectively, in the yields indicated [8] (Scheme 4). However, 0-silylation of triisopropyl- (30c) and triphenylsilyl chloride (30d) proceeded with difficultly even at 120 °C and gave 31c (57%) and 31d (70%), respectively, in relatively low yields. Nevertheless, when the solvent-free silylation reactions at 120 °C were carried out using two equivalents of 30c and 30d, 31c (77%) and 31d (99%) were obtained, respectively, in relatively high yields. 

The above system has been used for the reaction of EtjNH with myrcene to give a mixture of hydroamination products (53% yield) containing 80% of N,N-diethylgeranylamine [208], a key intermediate for the synthesis of industrially important monoterpenes [208, 209-211], including (-)-menthol (Tagasako process) [212]. 

On the contrary, the Lewis acid sites present on the snrface of sepiolite make the Cn/sepiolite catalyst extremely active in promoting the ene reaction of citronellal. Thns, citronellal never accnmnlates in the reaction mixtnre bnt it is com erted into isopulegol as soon as it forms. Hydrogenation of isopnlegol is very slow nnder these reaction conditions, bnt this simple catalyst is able to produce menthol in a one-pot-one-step reaction under very mild experimental conditions. Notably dehydration products, which give account of 40% of the reaction mixture obtained over Ni-H-MCM-41 [4], are kept under 20% over both Cu catalysts. 

Reaction with the hindered secondary alcohol menthol stops at the dialkyl sulfite ester. The examples reported do not establish the stereochemistry of the reaction. 

Differences in chirality of substrate, and nature of solvent, have no effect on the competitive nature of the displacement of 0-alkyl and S-methyl groups in the reactions between (+)-pinacolyl alkoxide and 0-ethyl (and methyl) S-methyl methylphosphonothioates (Scheme 23). For the (R)-( + ) esters, e.g. (210), the displacements are highly stereoselective and occur with configurational inversion,but the enantiomeric esters do not display such stereoselectivity. (-)-Menthol might be considered a mirror image of (S)-pinacol, and similar reactions with the sodium salt of (-)-menthol occur highly stereoselectively... 

Citronellol is formed through selective hydrogenation of the C=C bond activated by the presence of the OH group, whereas menthol 3 is the product of a three-functional process involving isomerization of the allylic alcohol 1 to citronellal 4, ene reaction to isopulegol 5 and final hydrogenation (Scheme 2). 

When the reaction is carried out over the 8% catalyst 2 and 5 are soon formed and in 2 hours also the hydrogenation of 5 to 3 is also complete, thus giving a 56% yield in 2 and about 30% in 3. In order to increase the yield in menthol, we carried out the reaction over a 5% Cu catalyst. In this case the... 

Clive and coworkers have reported a total synthesis of calicheamicinone, the aglycon of the antitumor agent calicheamicin starting from the Diels-Alder reaction of methyl 3-nitro-propenoate with ketene acetal (Eq. 8.32).54 An asymmetric Diels-Alder reaction between ketene acetal presented in Eq. 8.32 and 3-nitropropenoate derived from (-)-8-phenyl-menthol affords the optically pure adduct, which can be converted into either enantiomer of calicheamicinone (Eq. 8.33).55... 

The toluene layer, containing the menthol formed in the reaction, is saved for the recovery of both the toluene and the menthol, which are separated by distillation under atmospheric pressure. The /-menthol collected at 210-212° (corr.) amounts to 150-225 g. 

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