B-alkyl Suzuki coupling

Scheme 2.6 Late generation synthesis of desoxy epothilone B and epothilone B. The key steps in this total synthesis are a stereospecific aldol reaction, B-alkyl Suzuki coupling, and stereoselective Noyori reaction.

Condensation of 1 with 2 led to 3, setting the stage for the key macro ring closure. Happily, conditions could be developed to effect this important transformation, a B-alkyl Suzuki coupling. The ligand dppf is 1,1 -bisdiphenylphosphinoferrocene. The use of AsPh rather than a phosphine, as the supporting ligand was important, as was the use of the thallium base. 

Coupling reactions of alkyl boranes, formed by hydroboration of alkenes, with unsaturated halides (or triflates or phosphonates) is possible, and this reaction is finding increasing use in synthesis. For example, coupling of the alkyl borane derived from hydroboration (with 9-borobicyclo[3.3.1]nonane, 9-BBN) of the alkene 200 with the alkenyl iodide 201 gave the substituted cyclopentene 202, used in a synthesis of prostaglandin Ei (1.205). This type of B-alkyl Suzuki coupling reaction is very useful for the synthesis of substituted alkenes. 

The first total synthesis of epothilone A combines the two halves of the molecule via a B-alkyl Suzuki coupling [13] yielding the desired cyclization precursor. The critical cyclization was achieved by an intramolecular aldol reaction, utilizing KHMDS as base providing the natural configuration with a 6 1 ratio, 51% yield. 

B-Alkyl Suzuki coupling offers tremendous opportunities for one pot CTOSS-coupling between any alkene and aryl halides, as the intermediate alkylboranes are typically not isolated and can be used in situ for further cross-coupling. Some of the representative examples of this coupling include the synthesis of pyridyl alcohols 148 (Scheme 28.41), synthesis of alkyl arenes 149 (Scheme 28.42), and coupling of cyclopropyl boronic acid with aryl halides to obtain cyclopropyl arenes 153 (Scheme 28.43). ... 

Sasaki, M., Ishikawa, M., Fuwa, H., and Tachibana, K. (2002) A general strategy for the convergent synthesis of fused polycyclic ethers via B-alkyl Suzuki coupling synthesis of the ABCD ring fragment of ciguatoxins. Tetrahedron, 58,1889-1911. 

Synthesis of Natural and Unnatural Amino Acids via B-alkyl Suzuki Coupling of Functionalized Alkyl Boranes... 

B-alkyl Suzuki-coupling strategy for elongation of unsaturated side chains has been used as the key step in the synthesis of marine alkaloid (+)-halichlor-ine [138,139] and the related marine natural product pinnaic add, [140,141] an inhibitor of cytosolic phospholipase A2. Thus, the hydroboration of the common protected aminoalkene precursor 157 followed by Pd-mediated Suzuki coupling with iododienoic acid ester (158) afforded compound 159 that was converted into piimaic acid in several steps (Scheme 3.89). 

An intramolecular B-alkyl Suzuki coupling has been used to construct the core macrocyclic structure of benzolactone enamide salicylhalamide A [165], Thus, dia-stereoselective hydroboration of acyclic alkenyl iodide 183 with (dppf)PdCl2 cata-lyst/NaOH gave the macrocyclic lactone 184 in 48% yield. Because of the high dilution, a large amount of catalyst (20 mol%) was used. The steric hindrance at the ester group probably retards the cleavage of the lactone under basic conditions (Scheme 3.96). 

Xestocyclamine A, a polycyclic alkaloid isolated from xestospongia sp. is an inhibitor of PKC/3 and is of biomedical interest. During the course of the total synthesis of xestocyclamine A, Danishefsky has reported the elaboration of an ansa bridge using intramolecular B-alkyl Suzuki coupling as the key step. Thus, the intermediate 185 was obtained in 60% yield by regioselective hydroboration of 186 at the terminal alkenyl group followed by subsequent treatment with Pd(dppf)Cl2 catalyst in the presence of triphenylarsine and thallium carbonate as a base (Scheme 3.97) [166]. 

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