Chlorothricolide synthesis

This method of diene formation with definite E and Z structures has wide synthetic applications [518], particularly for the syntheses of natural products with conjugated polyene structures. Bombykol and its isomers (650 and 651) have been prepared by this method[5l9]. The synthesis of chlorothricolide is... 

The Diels-Alder cycloaddition is the best-known organic reaction that is widely used to construct, in a regio- and stereo-controlled way, a six-membered ring with up to four stereogenic centers. With the potential of forming carbon-carbon, carbon-heteroatom and heteroatom-heteroatom bonds, the reaction is a versatile synthetic tool for constructing simple and complex molecules [1], Scheme 1.1 illustrates two examples the synthesis of a small molecule such as the tricyclic compound 1 by intermolecular Diels-Alder reaction [2] and the construction of a complex compound, like 2, which is the key intermediate in the synthesis of (-)chlorothricolide 3, by a combination of an intermolecular and an intramolecular Diels-Alder cycloaddition [3]. 

Chlorothricolide, the aglycon of the chlorothricin antibiotic, is a complex molecule containing an octahydronaphthalene unit. Roush and Sciotti [121] recently reported the total enantioselective synthesis of chlorothricolide. The multiple Diels-Alder reaction between poliene 130 and chiral dienophile (R)-131 was the key step in the synthetic process (Scheme 2.50). The interaction... 

Diels-Alder reaction of 2-cyclohexen-l-one (37) with diene 38 mainly afforded the exo adduct 39, the key intermediate in the synthesis of the bottom half of chlorothricolide [14] (Equation 5.4). 

For clarification, individual transformations of independent functionalities in one molecule - also forming several bonds under the same reaction conditions -are not classified as domino reactions. The enantioselective total synthesis of (-)-chlorothricolide 0-4, as performed by Roush and coworkers [8], is a good example of tandem and domino processes (Scheme 0.1). I n the reaction of the acyclic substrate 0-1 in the presence of the chiral dienophile 0-2, intra- and intermolecular Diels-Alder reactions take place to give 0-3 as the main product. Unfortunately, the two reaction sites are independent from each other and the transformation cannot therefore be classified as a domino process. Nonetheless, it is a beautiful tandem reaction that allows the establishment of seven asymmetric centers in a single operation. 

Scheme 0.1. Synthesis of chlorothricolide (0-4) using a tandem process.

Kijanolide 117,76 tetronolide 118,76 and chlorothricolide 119,77 the agly-cones of the structurally novel antitumor antibiotics kijimicin, tetrocaricin A, and chlorothrimicin, are highly valued targets for total synthesis. All three structures share a similar octahydronaphthalene fragment 121, which can be obtained by cyclization of 120. Compound 120, appropriately functionalized 2,8,10,12-tetradecatetraene acid, can be constructed via aldol reactions. Two... 

This reaction was used for a synthesis of the hydronaphthalenecarboxylic acid 1, a subunit of the macrocyclic antitumor antibiotic chlorothricolide. 

During a synthesis of the Chlorothricolide, Roush and Sciotti encountered unexpected problems with the hydrolysis of the dimethyl acetal 54.1 [Scheme 2.54].112 Use of some of the standard hydrolysis conditions (oxalic acid, PPTS, PTSA, HO Ac, or trifluoroacetic acid — all in acetone) resulted in recovery of 54.1 or decomposition. Success was achieved by exploiting the mild Lewis acidic properties of the lithium cation under conditions first reported by Lipshutz and Harvey.113 Thus treatment of the dimethyl acetal 54,1 with lithium tetrafluoroborate in acetonitrile containing 2% water returned the desired aldehyde 54J in 97% yield after 2 h at room temperature. The reaction was also applied to the deprotection of a cyclic ketal in a synthesis of Pumi-liotoxin.114 115... 

A synthesis of (-)-Chlorothricolide was impeded by problems deprotecting the spirotetronate unit in 63 1 [Scheme 6.63].159 Early attempts to deploy 2-(tri-methylsilyl)ethoxymethyl or p-methoxy benzyl ethers failed because the product was unstable to the conditions of the deprotection. After much experimentation, a solution to the problem was found simultaneous deprotection of the spirotetronate and the carboxyl group was achieved with Pd(0) and dimedone in 94% yield. 

As the ester enolate Claisen rearrangement allows for a stoichiometric combination of alcohol and acid components, it has been used for the formation of strategically important C—C bonds by esteriflcation or lactonization and subsequent rearrangement, such as is elegantly demonstrated in the synthesis of the antibiotic chlorothricolide (Scheme 24)." Radical decomposition of the selenoester of (132) leads to... 

Roush, Nicolaou, and Evans have also demonstrated the efficiency of thallium hydroxide in tlie synthesis of an aglycone of the antibiotic kijanimicin [84], chlorothricolide [85], (5Z, 8Z, lOE", 12R, 14Z)-12-hydroxy-5,8,10,14-icosatetraenoic acid [(IZR)-HETE] [86], and a macrolide antibiotic, rutamycin B [87] (Scheme 2-30). 

Roush, W.R., and Sciotti. R.J., Enantioselective total synthesis of (-)-chlorothricolide via the tandem inter- and intramolecular Diels-Alder reaction of a hexaenoate intermediate, 7. Am. Chem. Soc., 120, 7411, 1998. 

This reaction was applied to the synthesis of many alkadiene structures including complex natural products such as palytoxin, chlorothricolide, ° and rutamycin A new synthesis of vitamin A with essentially complete control of regio- and stereochemistry has recently been reported. ... 

The trawi-selective cross-coupling of 1,1-dihaloalkenes exhibiting >98% stereoselectivity has found various interesting and attractive applications in natural products synthesis, as represented by those of lissoclinolide, (-)-chlorothricolide, and kijanolide.t These and other examples are summarized in Table 9. 

In addition, soon after Ireland s synthesis of chlorothricolide analog 228, Yoshii and coworkers [117] made one step further by presenting the synthesis of ( )-chlorothricobde as its 24-O-methyl derivative 251 (Scheme 1.37). Yoshii succeeded in utilizing the same strategy as in the total synthesis of irdnianin for the key... 

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