Isovanillin synthesis

A modification (142) of the synthesis of cryptopleurospermine (159) applied the O-benzoyl cyanohydrin of isovanillin benzyl ether (171) for nucleophilic... 

Arizonine (282), a tetrahydroisoquinoline alcaloid, has been recently synthesized in 35% yield from isovanilline, using a photochemical rearrangement like that depicted in Scheme 71. The yield of the photochemical step is 55%, and other byproducts (not shown in Scheme 71) are also formed [200]. The same authors reported the synthesis of caseadine following an analogous procedure. 

The asymmetric total synthesis of (+)-codeine, the unnatural enantiomer, was accomplished by J.D. White and coworkers using an intramolecular carbenoid insertion as the key step. The first stereogenic center that directed all subsequent stereochemical events was installed by the asymmetric hydrogenation of an alkylidene succinate that was obtained using the Stobbe condensation. Dimethyl succinate and isovanillin were reacted in the presence of excess sodium methoxide at reflux and the resulting reaction mixture was acidified to obtain the monomethyl ester. 

Crosby devised an interesting synthesis of scopoletin (V) which involves in the first step oxidation of commercial isovanillin (I, 1.28 moles) in ethyl acetate at 40° with 1,40 moles of peracetic acid in the same solvent. The product, 3-hydroxy-4-methoxyphenyl formate (II), distilled at 111-115°/1 mm. and, after two weeks at... 

In 2006 Fukuyama published a total synthesis of racemic morphine starting from isovanillin and a cyclohexene-epoxide [16, 17]. The key features in their synthesis are (1) a construction of the ether linkage between A and C rings by Tsuji-Trost coupling, (2) an intramolecular Heck reaction to construct A-C-E tricyclic system, and (3) an intramolecular Mannich-type reaction of a ketone with an aminal to provide the pentacyclic structure of morphine in a one-step reaction by double cyclization. 

Methylsalsoline, oxidized with permanganate, yields m-hemipinic acid. The position of the hydroxyl group was established by Spath, Orekhov and Kuffner (39) by synthesis, starting from isovanillin. Salsolidine was synthesized by Spath and Dengel (38). 

As outlined in Scheme 6, isovanillin (35) was converted to aryl iodide 36 via MOM-protection, protection of the aldehyde, and subsequent iodination. Hydrolysis of the acetal and Wittig olefination delivered phenol 37 after exposure of the intermediate aldehyde to methanolic hydrochloric acid. Epoxide 41, the coupling partner of phenol 37 in the key Tsuji-Trost-reaction, was synthesized from benzoic acid following a procedure developed by Fukuyama for the synthesis of strychnine [62]. Birch reduction of benzoic acid with subsequent isomerization of one double bond into conjugation was followed by esterification and bromohydrin formation (40). The ester was reduced and the bromohydrin was treated with base to provide the epoxide. Silylation concluded the preparation of epoxide 41, the coupling partner for iodide 37, and both fragments were reacted in the presence of palladium to attain iodide 38. 

Another synthesis (2) of cularine, specifically via cularimine, has also been reported. The dicarboxylic acid III, obtained by two different routes from isovanillin and veratraldehyde, was lactonized to IV (X = O) by heating with polyphosphoric acid this was convertible into the lactam IV (X = NH mp 216°) by treating with alcoholic ammonia. Reduction of the latter with lithium aluminum hydride followed by chromatography on alumina gave a base showing an IR-ketonic band. Clemmensen reduction generated d -cularimine (mp 128°) which was convertible into d(-cularine by methylation. 

The phosphodiesterase (PDE) IV inhibitor (109, Scheme 2.17) has been identified by Merck Research Laboratories as a potential lead for the treatment of asthma. Although an early synthesis of 109 relied on the use of Oppolzer s chiral sultam auxiliary, a more economic approach was subsequently developed that exploited an aminoindanol auxiliary. In the revised synthesis, the car-boxyhc acid 103 (available in two steps from isovanillin) is coupled with (15,2/ )-cis -aminoindanol 12 and subsequently converted into the amide 104. After protection of the amino alcohol, reaction of the resulting Michael acceptor 106 with phenyllithium 107 and subsequent... 

Hashimoto needed a step to remove the methoxycarbonyl group, Hu et al. proposed an alternative synthesis via the same approach. The a-diazoacetamide 5 prepared in four steps from the isovanillin 2 was treated in the presence of 1 mol% Rh2[(4/ )-MEOX]4 in methylene chloride to afford the expected lactam 6 in 64% yield albeit in lower enantiomeric excess (46% ee). After removal of the cumyl protecting group and two recrystallizations, 1 was isolated in 88% ee (Scheme 23.4). 

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