Problematic dienes

With the C12,C13 disconnection producing an effective solution to the synthesis of epothilone A (4), it would seem likely that the metathesis approach could be extended readily to the preparation of epothilone B (5). However, installation of the desired C12 methyl group requires ring-closure of a diene precursor in which one of the olefins is disubstituted. Recently, such reactions have been shown to be problematic for Grubbs initiator 3 but more successful with Schrock s molybdenum initiator 1 [19]. Consistent with these reports, Danishefsky demonstrated that triene 38 would not undergo RCM with 3, whereas 1 was effective in promoting the transformation of 38 into a 1 1 mixture of 39a and 39b in good yield [14b] (Scheme 8). 

Although the selectivity exhibited by 269c is excellent for the systems investigated, its activity is less than optimal. The most reactive system, acryloylimide and cyclopen-tadiene, still requires 10 h to proceed to completion (-78°C). The least reactive dieno-phile examined, cinnamyl imide, requires 24 h at ambient temperature to provide the Diels-Alder adduct of the most reactive diene, cyclopentadiene. It was clear that a more active catalyst was necessary to handle problematic, less reactive dienes. 

One problem that is encountered in the use of DDQ is that either 1,4-dienes or hS-dienes" often interfere with deprotection, especially those that are have allylic heteroatoms. Trienes are even more problematic. The problem is less pronounced when there is an electron-withdrawing group conjugated to the diene. 

Evans and coworkers have reported that cationic copper(II)-bis(oxazoline) complexes derived from ferf-leucine are effective Lewis acids for a wide range of enantioselective Diels-Alder reactions. While initial investigations employed cy-clopentadiene as the diene and triflate catalyst 31a (Scheme 24) as the Lewis acid [82], subsequent studies revealed that the reaction rate is strongly dependent on the counterion X [83]. The hexafluoroantimonate catalyst 31b is approximately 20 times more reactive than 31a and is typically more stereoselective. The heightened reactivity and selectivity conferred by catalyst 31b allows access to more substituted adducts in uniformly high enantioselectivity. The active catalyst is easily prepared and robust exposure to air is not deleterious and the reactions may be conducted in the presence of free hydroxy groups. However, reduction of the metal center can be problematic with electron-rich dienes this side reaction may be controlled by a judicious choice of temperature. 

Initially, the reduction of ester 45 proved to be problematic (Scheme 14). When THF was used as solvent, a large excess of DIBAL was required (10 equiv.) and the yield for the desired alcohol was still very low, 50%, with the remainder being unreacted 45. Use of methylene chloride as solvent led to complete reduction along with unwanted TES removal. Finally, it was found that the use of ether with 2.5 equivalents of DIBAL provided the desired alcohol in 91% yield. Oxidation gave the enal intermediate, which was converted to the diene ester 47 with allyl phosphonate 46. The selectivity was 19 1 E,Z Z,Z) and the yield was an excellent 93%. Previously, the more common methyl ester corresponding to 47 was employed. Hydrolysis to the desired acid with this substrate was... 

Following this historical precedent, a sulfone was readily appended onto the diene system of 37, affording 38 in 91 % yield (Scheme 7). One should note that in this transformation both isomers obtained from the prior Wittig olefination were employed, resulting in the mixture of stereoisomers at C-9 in 38. Based on the assumption that eventual thermal extrusion of SO2 from either diastereomer would provide the requisite trans-substituted olefin in the diene desired for Diels—Alder reaction, this lack of selectivity was not deemed problematic. However, the pressing issue at this juncture remained the generation of the quinone. Fortunately, with the diene now protected, oxidative demethylation smoothly furnished 39 in 79 % yield with concomitant TBS deprotection. 

The preparation of tertiary amine-functionalized polydienes is less problematic than the situation for primary amine-functionalized polymers. 3-Dimethylaminopropyllithium can be prepared by lithiation of the corresponding alkyl chloride in hexane at 20 ° C, followed by replacement of the solvent by benzene. Using this initiator for butadiene polymerization in hexane at room temperature, a-dimethylaminopolybuta-dienes with high (76-86%) 1,4-microstructure were produced. It was noted that the amount of vinyl microstructure in the resulting polybutadienes increased with the amount of diamine impurity formed by Wurtz coupling during the synthesis of the initiator. 

Diels-Alder cycloadditons have been explored on solid supports, and Winkler and Kwak have demonstrated a chemoselective variant that affords a single reaction of a dienophile containing two reactive double bonds with a bis-diene. Utilizing bis-reactive Diels-Alder reagents in the absence of a solid support is problematic as competing oligomerization can occur. Thus, a dienophile was immobilized as 8 and reacted with the... 

However, the use of 1,1-diphenylalkyllithium initiators for initiation of styrene and diene monomers is more problematic, since addition of these monomers forms much less stable styryl and dienyl carbanions (see Table 2). Lee [109] has investigated and optimized these crossover reactions from polymeric 1,1-diphenylalkyllithiums to dienes and styrenes (see Scheme 8). 

The application of the one-pot conditions to (Z,Z)-substrate 199 was not as clean as the reactions of either 195 or 197 (Scheme 53). By subjecting 199 to a stepwise sequence where aminohydroxylation was followed by cyclization, the authors were able to conclude that the problematic step for the use of 199 was the oxidative cyclization to 201 rather than the aminohydroxylation to 200. Similar problems were found for the (Z, )-diene that corresponds to 199. 

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