Endo cyclization natural products synthesis

The synthesis of cyclic ketones via acyl radical cyclizations represent by far the most frequently investigated approaches in the past two decades and such cyclizations are well discussed in a recent review [la]. Two recent examples of the application to natural product synthesis are given here. A seven-membered ring, a key compound in the overall synthesis of (-i-)-confertin, was prepared by Shishido and co-workers, utilizing 1-endo-trig acyl radical cyclization which occurred in a highly efficient manner (Scheme 4-39) [66]. 

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... 

Zard has developed the use of N-amidyl radicals. The precursors of the radical intermediates are 0-benzoyl hydroxyamines such as 37. Addition of a tributylstannyl radical to the carbonyl group of the benzoate moiety is followed by the cleavage of the weak N - O bond. A subsequent 5-exol6-endo tandem cyclization takes place to yield the skeleton of the natural product deoxyserratine (Scheme 12) [49]. Later, the same group disclosed a tin-free source of amidyl radicals that relies on the use of M-(0-ethyl thiocarbonyl-sulfanyl) amides and lauryl peroxide as initiator. Examples of polycyclization were also given [50]. On the occasion of a model study toward the synthesis of kirkine, the use of thiosemicarbazide precursors gave access to the tetracyclic structure of the natural product [51]. 

The total synthesis of pyrrolidinol alkaloid, (+)-preussin was achieved in five efficient transformations from commercially available fert-Boc-(S)-phenylalanine in the laboratory of S.M. Hecht. The key step involved the Hg "-mediated 5-endo-dig cyclization of ynone substrate affording the desired pyrrolidinone which, in two more steps, was converted into the natural product. 

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. 

The carbonylative coupling of an alkynyl zinc reagent 4.18 with a highly substituted, electron-rich aryl iodide 4.17 was used in a short synthesis of luteolin 4.20, a flavanoid natural product (Scheme 4.11). After the coupling, employing the PEPPSI catalyst, selective crr/tc-deprotection and 6-endo cyclization yielded the natural product."... 

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)... 

The acyl radical cyclizations have been cleverly applied to the synthesis of complex natural and unnatural products (Eq. (13.4)). In one example, tandem radical cyclization of 14 provides access to the steroidal skeleton. The reaction proceeds through a 6-endo-trig cyclization to form the A/B ring and a macrocycliza-tion/transannulation to establish the C/D ring [12]. More recently, a cascade cyclization initiated by an acyl radical has allowed for the establishment of fourteen chiral centers in a single step [13]. Once again the formation of the polycyclic compound 17 involves sequential 6-endo-trig reactions. 

Amidations of vinyl iodides have also been used to advantage in synthesis. Enamides such as 50-52 are representative of the procedures available (Scheme 1-3). By proper choice of nucleophile, annulations to either pyrroles 54 (15 examples) or pyrazoles 55 (10 examples) can be induced with Cul-catalysis after an initial amidation of enyne 53. " Subsequent 5-endo-dig cyclization produces the heteroaromatic products (Scheme 1-4). Several total syntheses have successfully applied this approach, as examples, to construction of key enamide antibiotic CJ-15,801 (56), and the naturally occurring cyclopeptide alkaloid paliurine F (57), where this methodology served as a tool for macrocyclization. " ... 

---