Transannular natural product synthesis

Note added in proof. ktotA synthesis of (-)-xialenon A using bicyclic alcohol 77 [Eq. (26)] represents the first application of enantioselective a-hthiation transannular C-H insertion of epoxides in natural product synthesis [78]. The first enantioselective generation - intermo-lecular nucleophile trapping of a lithium carbenoid has been described, via enantioselective a-deprotonation of the epoxides of oxa- and aza-bicyclic alkenes [e.g. 93 Eq. (30)] using alkyl-lithiums in the presence of (-)-sparteine or bisoxazoline 5 [Eq. (3)] [79]. Insertion of a second... 

In a subsequent investigation, Moriarty could demonstrate that primary sulf-amides 46 also undergo metal-free aziridination [35]. In these cases, stable aziri-dines 47 were obtained which could be isolated conveniently. The authors proposed an interesting mechanistic hypothesis of a [2 + 2] cycloaddition to encounter for the overall reaction, although it appears that this proposal has not been discussed further. Subsequent developments include the application of Phl(OAc)2 for intramolecular versions, in particular transannular aziridination reactions, which were of concern in natural product synthesis [36, 37]. 

Enantioselective desymetrization by a-deprotonation/tran-sannular C—H insertion of cyclooctene oxide (i.e., 173) was reported by Hodgson and co-workers for synthesis of bicycle[3.3.0] octanes, intermediates that are useful for pol-yquinane synthesis. The best yields and enantioselec-tivities of 175 were obtained when 173 was treated with j-PrLi and (—)-a-isosparteine (Scheme 20.42). Application of this reaction in natural product synthesis is yet to be reported. The same research group also reported expanding the scope of the reaction to synthesis of indolizidine 177 by a similar transannular reaction of 176. ... 

The synthesis of (-l-)-arteanniun M by Barriault and Deon provides an excellent demonstration of memory of chirality in natural product synthesis.Synthesized from enantio- enriched limonene (98% ee), the 1,2-divinyl cyclo-hexenol 186 underwent tandem oxy-Cope/transannular ene reaction to give 187 (Scheme 20.45). The reaction was highly diastereoselective as only one diastereomeric... 

Clarke PA, Reeder AT, Winn J. Transannular reactions in the synthesis of natural products. Synthesis 2009 691-709. 

Dell C. P. Cycloaddition in Synthesis Contemporary Organic Synthesis 1997 4 87 Keywords natural products, metal catalyzed, asymmetric reactions, Ionic reactions, transannular reactions, tethered reactions, tandem reactions, benzo-qulnones, quinodimethanes, hefero-Dlels-Alder reactions... 

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. 

A quite detailed review of transannular cyclizations was published201 wherein their important role in biomimetic syntheses of sesquiterpenes as well as explanation of the biogenetic formation of the polycyclic natural compounds from their monocyclic precursors is discussed. The great significance of these transformations for the synthesis of natural products is also emphasized in a series of reviews which describe the cyclizations to form terpene derivatives, e.g., of the germacrane and humulene systems202-206. 

The first total synthesis of (+)-arteannuin M was completed by L. Barriault et al. using a tandem oxy-Cope/transannular ene reaction as the key step to construct the bicyclic core of the natural product. The tandem reaction proceeded with high diastereo- and enantioselectivity. 

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. 

The scalable total synthesis of the cytotoxic natural product (+)-FR182877 was accomplished in the laboratory of E.J. Sorensen.The key steps of the synthetis were an intramolecular Tsuji-Trost allylation to prepare the 19-membered macrocyclic pentaene followed by a double transannular DIels-Alder cycloadditlon to obtain the desired pentacyclic structure. The allylic carbonate was exposed to 10 mol% of the Pd-catalyst under high dilution conditions in THF. The new bond between Cl and Cl 9 was formed with complete diastereoselectivity and in good yield, although the configuration at Cl 9 was not determined. 

Over the past 25 years longifolene (283) has been the focus of many aspects of chemical research—synthesis, molecular rearrangements, transannular reactions, and biosynthesis. All these and other details of longifolene chemistry have been thoroughly reviewed by Sukh Dev142 who himself has made many major contributions in this area of natural product chemistry. (+)-Longifolene can be converted into crystalline dilongifolylborane.143 This chiral dialkylborane can... 

A new approach to isocomene synthesis involving a transannular reaction has been described 2i. Rcgioselective oxirane ring opening after protonation initiates a stereoselective reaction to give the hydroxy ketone 15, w hich can be transformed into the natural product in several steps. 

Transannular cyclizations are an important class of radical reactions that are nowadays frequently used as a key step in the synthesis of polycyclic natural product... 

Biosynthesis of the polycychc diterpene intricarene (144) may occur from the natural product bipinnatin J (141) through transannular [5 - - 2] cycloaddition reaction. Based upon this proposed biosynthetic route, Tang et al. examined a synthesis of 144 [45]. Synthetic 141 was treated with VO(acac)2 and fert-butyl hydroperoxide, followed by acetic anhydride to give acetoxypyranone 142, which was subsequently heated in acetonitrile in the presence of DBU to give intricarene (144) (Scheme 7.32). 

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 group of Boger described the total synthesis of kopsinine, a member of the Aspidosperma alkaloids, using their landmark [4 + 2]/[3 + 2] cycloaddition cascade for the conversion of 44 to 45 (Scheme 16). An unusual Sml2-promoted transannular cyclisation of xanthate 46, formed the bicyclo[2,2,2]octane moiety and provided the highly compact core of the natural product 48 as a single diastereoisomer. Although 48 is the least stable diastereoisomer, its formation is consistent with a radical cyclisation mechanism followed by kinetic protonation of the samarium enolate 47 formed after a second electron transfer. 

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. ... 

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