Macrolactonization iodide

The group of Samuel Danishefsky at the Sloan-Kettering Institute for Cancer Research in New York has also been active in the synthesis of the natural epothilones and biologically active analogs. One of these syntheses also uses the olefin metathesis reaction (not shown). The synthesis in Scheme 13.51 uses an alternative approach to create the macrocycle. One of the key steps is a Suzuki coupling carried out at step H-(l,2) between a vinylborane and vinyl iodide. The macrocyclization is an aldol addition reaction at step H-4. The enolate of the acetate adds to the aldehyde, creating the C(2)-C(3) bond of the macrolactone and also establishing the stereocenter at C-3. 

A Stille type coupling strategy has been utilised to complete a total synthesis of epothilone E. The vinyl iodide 30 and the thiazole stannane 31 were coupled to give the macrolactone 32 which is a precursor to natural epithilone E. The thiazole stannane 31 was prepared from 4-bromo-2-hydroxymethylthiazole via treatment of the lithiated protected 4-bromO 2-hydroxymethylthiazole with tributylstannyl chloride. This Stille coupling approach was also used to prepare a range of epothilone B analogues <99BMC665>,... 

Mukaiyama and coworkers [24] found that 2-chloro-3-methoxymethyl-l-me-tbylpyridinium iodide is also suitable for effecting macrolactonization. Furthermore [25], the cyclization mediated by the 2-chloropyridinium salts described above sometimes gives no satisfactory yields. It is mainly due to the decomposition of the pyridinium salts under the cyclization conditions by the attack of triethylamine to either the 1-methyl group or the 2-position of the pyridinium ring to form 2-chloropyridine or 2-ammoniopyridinium salts. To solve this... 

Another type of free-radical reaction was explored starting from a long-chain alkyl iodide for the synthesis of a macrolactone (eq. (15)). The reaction utilized (MesSiliSiH as a hydrogen transfer agent [54, 55]. 2,2 -Azoisobutyronitrile (AIBN) was used as a radical initiator. Furthermore, a CO pressure of 30 bar was required for the alkyl radical to trap CO. The resultant acyl radical reacted with the activated double bond to give desired product. 

Bauer and Maier synthesized the benzolactone 538, which has the core structure of salicylihalamide A, using intramolecular Suzuki reaction.228 Hydrobora-tion of the alkenyl iodide-alkene 537 with 9-BBN and subsequent Suzuki reaction in the presence of a palladium catalyst gave the macrolactone 538 in 48% yield (Scheme 160). The hydroboration proceeded with high diastereoselectivity. 

A variety of specialized reagents have been developed for macrolactonization reactions. Two of the more important are the Corey-Nicolaou reagent, 2,2 -dipyridyl disulfide (232)10 jjjg Mukaiyama reagent, which is 2-chloro-l-methylpyridinium iodide (233). A number of related reagents have been developed, including imidazole disulfide 234 [2,2 -dithio-(4-ferf-butyl-l-isopropylimidazole)]l 2 and imidazole 235 [N-(trimethylsilyl)imidazole].l 3 All of these reagents are effective for the cyclization of co-hydroxy acids, as shown in Table 6.1. For comparison, available cyclization results with DEAD and 234 are included. In this table, a hydroxy acid is converted to a lactone (219). 

The synthesis of 252 began with Brown s asymmetric crotylation to aldehyde 261. The resulting homoallyl alcohol was converted benzyl ester 262, which was reduced to give lactol acetate 263. Axial allylation to 263 formed 2,6-trans-tetrahydropyran 264, which was subjected to ozonolysis to give an aldehyde. Addition of alkenylzinc, prepared by hydrozircona-tion of an alkyne 265, to the aldehyde mediated by chiral ligand 266 yielded allyl alcohol 267 with a 5.1 1 diastereoselectivity [110]. The stereochemistry of the major isomer was found, unexpectedly, to be the S-form at Cl7, which rendered the macrolactonization to adopt the Mitsunobu reaction. The iodide 252, prepared from 267 in three steps, reacted with... 

In 1979, Tsuji s group [51] reported an alternative approach to macrolactonization. Inspired by their previous success in the preparation of recifeiolide and 9-decanolide, the authors envisioned that the dimethyl ether of zearalenone (6) could be obtained via olefination using the co-iodoalkyl phenylthioacetate 7 (Scheme 7.2). The Michael addition of diethyl malonate (11) to 10 followed by decarboxylation afforded an ethyl ester, which was reduced to alcohol and converted into the tosylate 12. Wacker-Tsuji oxidation of the terminal olefin was then followed by reduction of the ketone and conversion of the tosylate into iodide to provide 9. This was... 

Chemoselective carbonylation of a vinyl iodide 34 with alcohol containing a vinyl bromide moiety 35 has been successfully employed for the solid-phase synthesis of a macrosphelide precursor 36 [43]. After the 4-methoxyphenylmethyl (MPM) group was removed, the palladium-catalyzed carbonylative macrolactonization of the vinyl bromide 37 achieved the synthesis of the macrosphelide-supported derivative 38 (Scheme 9.13). The combinatorial synthesis of a 122-member macrosphelide library has been performed by the three-component strategy based on the palladium-catalyzed chemoselective carbonylation/macrolactonization reaction. 

CM reactions with vinyl boronates were first reported by Morril and Grubbs [16]. They are usually diastereoselective in favor of the E-isomer. Vincent and Prunet used this type of CM for the synthesis of the C1-C15 fragment of dolabelide C, a cytotoxic macrolactone isolated from the sea hare Dolabdla auricularia [17]. Hence, 1,1-disubstituted olefin 28 was reacted with 4 equiv. of vinyl boronate 29, and the resulting product was converted to the corresponding vinyl iodide in 89% yield for the two steps (Scheme 10.8). As it is often the case with 1,1-disubstituted... 

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