Natural product synthesis endo reactions

Side differentiating effects like allylic 1,3-strain [45] are also observed leading to exo/endo isomers. This effect is particularly expressed in the reaction of compound 42. In this case, a methoxy group is involved in the corresponding steric interaction (compare transition state Q). A lower side differentiation is observed in the reaction of compounds 52 and 58. In the latter case, the allylic 1,3-strain effect is located on the olefinic side chain and the only one of the hydrogen atoms at the methylene carbon is involved in the corresponding interaction (transition state R). The 1,3-allylic strain effect was particularly important in the application of the reaction to natural product synthesis (see below) since it diminish the number of isomers. 

The usefulness of aminosiloxy diene Diels-Alder chemistry to the preparation of different substituted cyclohexenones is demonstrated in Table 11.3 The functionality at the 4 and 5-positions of the cyclohexenones can be easily controlled by the substitution pattern in the dienophile. The differing endo-exo selectivity found in the initial cycloadducts does not impact the usefulness of this route to cyclohexenones, since the amino group is eliminated in the last step. Chiral versions of aminosiloxy dienes provide the opportunity for asymmetric synthesis. Indeed, the diphenylpyrrolidine-substituted diene allows the synthesis of a variety of cyclohexenones, with good to excellent ee s 2b The usefulness of aminosiloxy diene Diels-Alder reactions to natural product synthesis is exemplified through the stereocontrolled synthesis of the pentacyclic indole alkaloid tabersonine 2c... 

The synthesis of natural products containing the quinonoid stmcture has led to intensive and extensive study of the classic diene synthesis (77). The Diels-Alder cycloaddition of quinonoid dienophiles has been reported for a wide range of dienes (78—80). Reaction of (2) with cyclopentadiene yields (79) [1200-89-1] and (80) [5439-22-5]. The analogous 1,3-cyclohexadiene adducts have been the subject of C-nmr and x-ray studies, which indicate the endo—anti—endo stereostmcture (81). 

Sequences (or cascades) of radical reactions involving the 5-endo-trig cyclization of silyl radical to an allyloxy-type substituent as the key step have been developed and applied to the synthesis of natural products [7 11]. The concept and the sequence of radical reactions is outlined in Scheme 6.7. A radical of... 

In a similar approach, Garner et al. (78) made use of silicon-based tethers between ylide and dipolarophile during their program of research into the application of azomethine ylides in the total asymmetric synthesis of complex natural products. In order to form advanced synthetic intermediates of type 248 during the asymmetric synthesis of bioxalomycins (249), an intramolecular azomethine ylide reaction from aziridine ylide precursors was deemed the best strategy (Scheme 3.84). Under photochemically induced ylide formation and subsequent cycloaddition, the desired endo-re products 250 were formed exclusively. However, due to unacceptably low synthetic yields, this approach was abandoned in favor of a longer tether (Scheme 3.85). 

A synthesis of the well-known natural products, the inositols, begins with a Diels-Alder reaction between furan and vinylene carbonate (73JOC117). Both the exo and endo oxabicyclo[2.2.1]hept-5-ene-2,3-diol carbonate adducts were obtained. fraus-Hydroxyla-tion of the endo adduct via the epoxide (33) afforded D-l,4-anhydroinositol (34). Hydrolysis of this compound with acetic acid and a small amount of sulfuric acid yielded alio- (35) and myo-inositol (36 Scheme 7). 

The adducts resulting from Diels-Alder reaction of pyridyl sulfoxides with furan have been used in the synthesis of a number of natural products. Thus, a new procedure for the total synthesis of optically actives C-nucleosides was reported by Koizumi et al. [38], who prepared D-showdomycin (19) and (D)-3,4-0-isopropylidene-2,5-anhidroallose (20) from the endo(t) 18a adduct (Scheme 10). (-i-)-Methyl 5-epishikimate (21) [39] and pentaacetyl- -D-mannopyranose (22) [40] were also obtained starting from endo(t) 18a (Scheme 10), the cleavage of the oxygenated bridge being the key step of these transformations. 

The inter- and intramolecular Diels-Alder reactions of furans, and their applications to the synthesis of natural products as well as synthetic materials, were reviewed <1997T14179>. HfCU promoted the endo-seXccuve. inter-molecular Diels-Alder cycloadditions of furans with a,/3-unsaturated esters <2002AGE4079>. The cycloaddition between furan and methacrylate was also achieved under these conditions, providing, however the o-isomer as the major cycloadduct. A catalytic enantioselective Diels-Alder reaction between furan and acryloyl oxazolidinone to provide the < 46i-adduct in 97% ee was achieved by using the cationic bis(4-fer7-butyloxazoline)copper(ll) complex 55, as shown in Equation (41) <1997TL57>. 

Intramolecular Diels-Alder reaction can be used as a macrocyclization means. Thomas and Whitehead [167] apphed this approach to the synthesis of the 13-membered cytochalasan proxiphomin (280). As shown in Scheme 94, the long chain precursor 278 was heated in toluene at 100 °C for 5 h to give the 13-membered skeleton 279 and the endo adduct (52 48) in 52% yield. There are several other examples of the application of intramolecular Diels-Alder reaction to the synthesis of macrocyclic natural products [168]. 

The first total synthesis of the marine furanosesquiterpenoid tubipofuran was accomplished in the laboratory of K. Kanematsu. The c/s-fused furanodecalin system was constructed by the regioselective Diels-Alder cycloaddition reaction of benzofuran quinone and Danishefsky s diene in refluxing toluene. The reaction gave an 11 1 mixture of the desired ortho-endo adduct versus the undesired para-endo product in 98% isolated yield. The major isomer then was subjected to sequential radical deoxygenation reactions before it was finally converted to the natural product. 

DHPs and their equivalents are very beneficial in the synthesis of nitrogen-containing compounds as well as natural products [52]. The simplest 1,2-dihydropyridine unencumbered by perturbing substituents is V-methyl-1,2-DHP (53) which, on reaction with methyl acrylate, yields a mixture of endo and exo adducts (54a and 54b) (Scheme 1) [53,54]. 

The intramolecular Diels-Alder reaction has provided a large number of valuable intermediates for the synthesis of polycyclic compounds and has been used in the synthesis of a number of natural products [32,212-216], A distinct advantage of this reaction is the ability to construct the reactant to provide for either endo or exo attack, which allows for excellent stcreoselection [213,217-222],... 

The utility of such cycloadditions has been demonstrated by the elaboration of the cycloadducts to complex natural products [60]. For example, the adduct derived from a cyclopentadiene having a 2-bromoallyl sidechain has been converted to an intermediate employed in a previous (racemic) synthesis of gibberel-lic acid. As illustrated in Scheme 12, an exceptionally efficient synthesis of cassi-ol is realized by the successful execution of a rather difficult endo-selective Diels-Alder reaction using a slightly modified oxazaborolidine (11). The high catalyst loading is balanced by the fact that all the carbons and the quaternary center of the natural product are introduced in a single step. 

A number of oxacyclic natural products were synthesized via carbocycle-forming radical reaction of oxacyclic intermediates. An early example is the synthesis of (-)-dihydroagarofuran (170) by Biichi [109] (Scheme 58). The bridgehead chloride 168 obtained from the corresponding hydroxy ketone was amenable to radical cycliza-tion, and the tricyclic ether 169 was duly obtained. The aplysin synthesis [110] provides another example, and (—)-karahana ether (173) was synthesized via radical cyclization of the substrate 171 [111] (Scheme 59). Lactonic natural products (-1-)-eremantholide A [112], alliacolide [113], and (-)-anastrephin [114] were prepared via a variety of carbocycle-forming radical cyclization reactions. In the total synthesis of spongian-16-one (176) [115] (Scheme 60), the butenolide moiety in the substrate 174 served as the final radical acceptor for three consecutive 6-endo-. rig cyclizations. 

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