Transannular natural product synthesis Diels-Alder reaction

The thermally and Lewis acid-promoted transannular Diels-Alder reactions have proven to be a powerful tool for the synthesis of steroids and other natural products [24]. A research team led by Takamura, Arimoto, and Uemura utilized this reaction to assemble the polycyclic skeleton of nakiterpiosin (1) [25]. Heating macrolide 39 at 160 °C gave 40 and 41 as a mixture of diastereomers in good yields. 

The first asymmetric total synthesis of (+)-maritimol, a diterpenoid natural product that possesses a unique tetracyclic stemodane framework was accomplished by P. Deslongchamps. To introduce the C12 stereocenter, the Enders SAMP/RAMP hydrazone alkylation was used. This stereocenter played a crucial role in controlling the diastereoselectivity of the key transannular Diels-Alder reaction later in the synthesis. The required SAMP hydrazone was formed under standard conditions using catalytic p-toluenesulfonic acid. Subsequent protection of the free alcohol as a f-butyidiphenylsilyl ether, deprotonation of the hydrazone with LDA and alkylation provided the product in high yield and excellent diastereoselectivity. The hydrazone was converted to the corresponding nitrile by oxidation with magnesium monoperoxyphthalate. 

In the remainder of this chapter, we will present another total synthesis in which transannular Diels—Alder reactions would appear to play an essential role in Nature s construction of a natural product. That work is the 2001 total synthesis of (—)-FR182877 (1) in which the Sorensen group at The Scripps Research Institute executed not one, but two transannular Diels—Alder reactions in a single cascade to establish five rings and seven stereogenic centers from a 19-membered macrocyclic pentaene precursor. 

In the course of a total synthesis of the diterpenoic tetraol (+)-aphidicolin, Des-longchamps and coworkers developed a domino transannular Diels-Alder/aldol reaction of macrocyclic trienyl oxo aldehyde 88, which closed four rings and assembled the entire skeleton of the natural product in one transformation. Heating 88 in a sealed tube in toluene at 230 °C for 24 h in the presence of triethylamine as proton scavenger first initiated the transannular Diels-Alder reaction, which was followed by the intramolecular aldol reaction to deliver tetracycle 90 in excellent yield and as a single diastereomer (Scheme 8.26) [47]. Three new carbon-carbon a-bonds and four new stereogenic centers were established with complete stereocontrol. 

The final type of intramolecular Diels-Alder reaction that finds wide use in natural product total syntheses is the transannular process. Danishefsky exploited the power of this transformation during an oxidative dearomatization/transannular Diels-Alder cascade in his synthesis of 11-0-debenzoyltashironin. Deslongchamps produced the tricyclic core of cassaine via a transannular intramolecular Diels-Alder reaction. The tricyclic c/5-decalin with appended macrocycle framework of superstolide A is also available using this strategy. Roush demonstrated the effectiveness of this approach by heating 140 in toluene to yield cycloadduct 141 that was transformed into superstolide A in four more steps. ... 

The intramolecular Diels-Alder cyclization of cyclohexadiene-l,2-dicarboxylic anhydride-derived diester-tethered triene (86) produces the cycloadducts in a ratio of 7 1 (Scheme 31). The intramolecular Diels-Alder reactions of amino acid-derived trienes (87) yield cycloaddition products (88) and (89) which are mainly cw-fused and derived from the exo-transition states (Scheme 32). A key reaction in the synthesis of the natural product momilactone A is the transannular Diels-Alder cyclization of the trans-trans-cis alkene (90) to the trans-syn-trans tricycle (91) (Scheme 33). The Diels-Alder cycloaddition of 1 l-oxapentacyclo[6,5,2,2 0 0 ]-heptadeca-4,14,16-triene-4,5-dicarboxylic anhydride (92) with cyclopentadiene proceeds with 5yn-facial selectivity to produce syn,endo and syn,exo cycloadducts (93) and (94)... 

In 2003, the group of Evans reported an asymmetric synthesis of the cytotoxic natural product (-)-FR182877 by using a sequence of stereoselective transannular Diels-Alder reactions (Scheme 13.16) [19]. This cascade reaction formed four new rings and seven new stereocenters in the pivotal construction event. 

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