Aldehyde diacetates, reduction

One of the first practical methods for the manufacture of cinnamyl alcohol involved reduction of cinnamic aldehyde diacetate with iron filings in acetic acid. This approach suffered from low yields and Hberation of a significant amount of the starting aldehyde. 

The methyl substituent of 2-methyl-4,8-dihydrobenzo[l,2- 5,4-. ]dithiophene-4,8-dione 118 undergoes a number of synthetic transformations (Scheme 8), and is therefore a key intermediate for the preparation of a range of anthraquinone derivatives <1999BMC1025>. Thus, oxidation of 118 with chromium trioxide in acetic anhydride at low temperatures affords the diacetate intermediate 119 which is hydrolyzed with dilute sulfuric acid to yield the aldehyde 120. Direct oxidation of 118 to the carboxylic acid 121 proceeded in very low yield however, it can be produced efficiently by oxidation of aldehyde 120 using silver nitrate in dioxane. Reduction of aldehyde 120 with sodium borohydride in methanol gives a 90% yield of 2-hydroxymethyl derivative 122 which reacts with acetyl chloride or thionyl chloride to produce the 2-acetoxymethyl- and 2-chloromethyl-4,8-dihydrobenzo[l,2-A5,4-3 ]-dithiophene-4,8-diones 123 and 124, respectively. 

The reductive amination between aldehyde 45 and methyl O-methyl-L-tyrosine ester gave the amino phenol 41, which incorporates all carbon atoms of the synthetic target FR901483. The crucial transformation in the synthetic pathway was the following oxidative cyclization of aminophenol 41. After much experimentation, it was found that exposure of a solution of 41 in hexafluoro-2-propanol to iodobenzene diacetate at room temperature resulted in the formation of azaspiro[4.5]decadienone... 

Treatment of (31) with crotyl chloride-potassium carbonate in DMF afforded (33), which was converted into (34) by heating in a sealed tube. Methylation of the phenol (34) with methyl iodide-potassium carbonate gave (35). Osmic acid-sodium periodate oxidation produced the keto-aldehyde (36). Acetalization by standard methods gave the diacetal (37). Reduction of (37) with lithium in liquid ammonia and subsequent toluene-p-sulphonic acid work-up afforded (38) in a yield of 50 %. A vinylogous aldol condensation was effected with methan-olic potassium hydroxide. The resulting mixture was oxidized with chromium... 

An alternative route involves ozonolysis of 6-nitrosafrole followed by reductive conversion to an aldehyde which is converted into indole 18 by reduction, with or without prior conversion to a gfcm-diacetate (Scheme 9). Alternatively, 6-nitrosafrole can be reduced to the corresponding amine which is trifluoroacetylated, ozonized and allowed to cyclize by removal of the protecting group with diethylene triamine (86% yield of 18). This latter step is particularly clean, high yielding and easy to work up. 

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