Domino Stille/Diels—Alder

Martin and coworkers [93] described a highly efficient enantioselective total synthesis ofmanzamine A (6/1-177) with a concise domino Stille/Diels-Alder reaction to construct the tricyclic ABC ring core in 6/1-177 as the key step. Reaction of 6/1-178 with vinyl tributylstannane in the presence of (Ph3P)4Pd afforded the triene... 

The enantioselective total synthesis of the manzamine alkaloid ircinal A was completed in the laboratory of S.F. Martin utilizing a novel strategy. A domino Stille/Diels-Alder reaction was used to assemble the ABC ring core of the natural product. The vinyl bromide intermediate reacted with vinyl tributylstannane in the presence of Pd to afford the 1,3-diene moiety, which cyclized via an intramolecular Diels-Alder reaction to give the ABC core. 

The alkaloid (—)-galanthamine, isolated from Caucasian snow-drop Galanthus woronowii) and other plant sources, is a competitive and reversible acetylcholinesterase inhibitor and an allosteric modulator of the neural nicotine receptors for acetylcholine. Galanthamine hydrobromide (commercially available as Razadyne) finds application in the treatment of symptoms of Alzheimer s disease [101]. Since the isolation of galanthamine (256) from natural sources is quite expensive, several total syntheses have been developed to date. The synthetic strategy to galanthamine (256) developed by Cho et al. [102] includes a domino Stille/Diels-Alder reaction as the key step (Scheme 14.39). 

Scheme 14.39 Cho s total synthesis of racemic galanthamine (2S6) by a domino Stille/Diels—Alder reaction.

Domino transition metal-catalyzed processes can also start with a cross-coupling reaction most often, Suzuki, Stille and Sonogashira reactions are used in this context They can be combined with another Pd-catalyzed transformation, and a number of examples have also been reported where a pericydic reaction, usually a Diels-Alder reaction, follows. An interesting combination is also a Pd-catalyzed borina-tion followed by a Suzuki reaction. 

In those domino processes which start with a Stille reaction, the second step is usually a Diels-Alder reaction. However, there are two examples where an electrocycli-zation follows. 

Scheme 6/1.48. Domino Stille/transannular-Diels-Alder reaction.

The enantioselective syntheses of ircinol A (38) and the related manzamine alkaloids ircinal A and manzamine A were accomplished by Martin (Scheme 5.4.9). The concise synthesis of ircinol A (38) highlights the strategy for assembling the tricyclic ABC ring core via a domino Stille coupling/Diels-Alder reaction. 

Scheme 5.4.9 Domino Stille coupling/Diels-Alder reaction in one of the initial steps of the synthesis of ircinol A...

The cyclic a,/ -unsattirated ketone cyclohex-2-en-l-one (50) was used as building block in the one-pot domino cycloaddition of enol ether 14 and nitrostyrene 15a. At 15 kbar and 50 "C, nitroso acetal 51 was formed in 67 % yield, whereas nitroso acetal 54a was formed as a side product (Scheme 9.18). This result indicated that the 1,3-dipolar cycloaddition is still faster with the electron-poor substituted cyclohexenone 50 than with the electron-rich mono-substituted enol ether 14. The one-pot reaction of 52 with enol ether 14 and nitrostyrene 15a merely resulted in formation of nitroso acetal 54a instead of nitroso acetal 53. The unwanted side reaction was not observed in the one-pot three-component reaction with 14 and methyl-substituted nitrostyrene 15b and 52 (Scheme 9.19). The large difference in reactivity between the three components in both the Diels-Alder and the [3 + 2] cycloaddition resulted in the formation of 55 as the main product. The side reaction of 16b with 14 to form 54b was prevented, since 14 was completely consumed in the reaction with 15b to give nitronate 16b (15 kbar, 50 °C, 16 h). However, heating (50 °C) the reaction mixture for 76 h at 15 kbar was necessary to produce nitroso acetal 55, which was formed as a mixture of two major diastereomers (ratio 3 1) in 69 % yield. 

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