Diels-Alder reactions disconnection approach

Diels-Alder reactions offer an excellent strategy for synthesis of polycyclic systems consisting of 6-membered rings, and it is not therefore surprising that such approaches have been widely applied to the synthesis of anthracyclines. Six of the eight possible vertical disconnections (a-d,f,g) in 98 have been employed, while a seventh (e) has been investigated in a model study [78], but has yet to be applied to the synthesis of anthracyclinones. 

Vogel has developed an unusual synthetic approach to polycyclic compounds based on the observation that the bicycloheptane 114 reacts with dienophiles at a much faster rate than does the resulting mono adduct with the same dienophile. It is therefore possible to perform sequential Diels-Alder reactions with different dienophiles, and this has been exploited in the synthesis of 118, a precursor of 4-demethoxydaunomycinone 6, through construction of rings A and C (disconnections g and b in 98) in consecutive annulations [86]. An analogous approach to daunomycinone 5 yielded a mixture of regioisomers from which the major 4-methoxy analogue was obtained by recrystallisation [87]. 

A similar computer-assisted approach was also elaborated envisioning the choice of the Diels-Alder transform as a strategic reaction. The task of the program in this case is to suggest the retrosynthetic transformations of the target structure leading to the creation of the cyclohexene moiety amenable to the retro-Diels-Alder disconnection. The general coiu e of these pursuits is shown in Scheme 3.50. ... 

Whereas the foregoing Diels-Alder based strategies involve vertical disconnections a recent approach to 11-deoxyanthracyclinones employs a diagonal disconnection [125]. Lewis acid catalysed reaction of the acryloyl quinone 164 with various pentadienyl tins resulted in a tandem Michael/Diels-Alder sequence to give the tetracyclic products 166 in one step. These were converted to ( )-11-deoxyanthracyclinones via the epoxides 167. Another diagonal ... 

Abstract A problem-solving approach to retrosynthesis is introduced. Basic principles for good disconnections are postulated. Examples of interconversion and disconnection of carbinols, alkenes, ketones and nitro compounds are discussed. Concepts of retro-Diels-Alder and re/ro-Wittig disconnections are presented and the mechanisms of reactions explained. Application of the Wittig reaction on the industrial scale is exemphfied by the synthesis of the analog of bombykol, the principal of pear odor and anti-appelizer chlorphentermine. 

A problem-solving approach to retrosynthesis is introduced with examples selected according to the functional group that participates in C-C bond disconnection or is interconverted. The key retrosynthetic steps suggest important synthetic reactions, such as Diels-Alder, cyanhydrin, Wittig and Nef reactions. An argumentation is presented for the feasibility of the Wittig reaction on the industrial scale and its acceptability from the environmental aspect. 

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