Natural products alkenyl-allyl coupling

Nozaki-Hiyama-Kishi (NHK) reactions215,216 are well known and often employed as a useful method for the synthesis of natural products by coupling of allyl, alkenyl, alkynyl, and aryl halides or triflates with aldehydes. The organochromium reagents are prepared from the corresponding halides or triflates and chromium(ll) chloride, and are employed in polar aprotic solvents (THF, DMF, DMSO, etc.). Subsequently, it was found that nickel salts exhibited a significant catalytic effect on the formation of the C-Cr bond217,218 (Equation (19)). 

Alkenylboronic acids and esters are also very useful substrates (Equation 71, Figure 1.38) [405], in particular to access substituted olefins and dienyl moieties commonly encountered in several classes of bioactive natural products [282, 406]. To this end, Kishi and co-workers examined the influence of the base, and developed an optimal variant using thallium hydroxide [281]. Recently, allylic alcohols were found to couple directly with alkyl and alkenyl boronic acids without the aid of a base [407]. In rare cases, the Suzuki reaction has been applied to the use of alkylboronic acids [296, 408], including cyclopropylboronic acids [409]. Hitherto notorious for their tendency to undergo [3-hydride elimination, alkyl bromides are now suitable as electrophiles under carefully optimized conditions that even allow Csp -Csp couplings with alkylboronic acids (Equation 72) [410]. The Suzuki reaction has also been applied very successfully in solid-phase chemistry and combinatorial library synthesis [411]. It has been applied industrially [412], especially in medicinal chemistry, e.g. in the production of the antihypertensive drug losartan [195]. 

The first syntheses of dendralenes by C2-C3 bond formation (Scheme 1.25) were reported by Tsuge and coworkers in 1985 and 1986, and proceed via substitution at either a bromide 160 or an epoxide 163, followed by elimination (Scheme 1.26) [116, 117]. Similar addition/elimination sequences to carbonyl groups or epoxides [120], and substitution reactions [121], followed. Such methods have been superseded by cross-coupling techniques that take place between a 2-functionalized 1,3-butadiene and an alkene (each can be either electrophilic or nucleophilic) or a 4-functionalized 1,2-butadiene and alkene, and occur with allylic transposition (Scheme 1.25). No doubt due to the ready availability of alkenyl halides and allenes, and the variety of increasingly mild and selective reaction variants, cross-coupling has provided access to a large number of diversely substituted dendralenes over the past 20 years, some of which have even been part of natural product syntheses [14,122,123]. 

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