Highly Efficient Phosphine-Free Pd(OAc)₂-Catalyzed Fukuyama Coupling Reaction: Synthesis of a Key Intermediate for (+)-Biotin under Low Catalyst Loading

Abstract

A phosphine-free catalytic system involving inexpensive Pd(OAc)₂ in conjunction with Zn dust and ZnBr₂ was unexpectedly found to effect the Fukuyama coupling reaction of thiolactone 2 with zinc reagent 3 to provide vinyl sulfide 6, a key intermediate for (+)-biotin (1), in high yield with a very tiny amount of Pd (up to 0.01 mol%, TON = 6800).

Key words

zinc - palladium - catalysis - cross-coupling - (+)-biotin

References

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4

The direct product of the present synthesis is ketone 5.

6

Synthesis of 6 from 2 (Table 1, Entry 8). To a suspension of zinc powder (3.57 g, 54.6 mmol) in a mixed solvent of THF (7.0 mL) and toluene (4.7 mL) was added bromine (0.72 mL, 14.0 mmol) below 40 °C for 5 min. After the mixture was stirred at 25 °C for 30 min, it was warmed up to 50 °C, and ethyl 5-iodopentanoate (4, 7.16 g, 28.0 mmol) was added at 50-55 °C for 30 min. The mixture was stirred at the same temperature for 1 h and cooled down to 30 °C. To the mixture were added thiolactone 2 (6.77 g, 20.0 mmol), toluene (9.3 mL), Pd(OAc)₂ (4.5 mg, 0.02 mmol) and DMF (1.7 mL, 22.0 mmol), and the mixture was stirred at 30-35 °C for 20 h. The mixture was cooled down to 5 °C, and 3 N HCl (21 mL) was added to the mixture below 20 °C. The mixture was stirred at 25 °C for 30 min and it was filtered. To the filtrate was added EtOAc (30 mL), and the organic layer was warmed up to 45 °C and evaporated. A part of the residue was analyzed by HPLC [L-Column, MeCN-THF-0.03 M phosphate buffer (K₂HPO₄/KH₂PO₄ = 1:1) = 40:8:52, 40 °C, 1 mL/min, 254 nm]. The assay yield of 6 was determined to be 90%. The residue was purified by silica gel column chromatography (toluene-EtOAc = 15:1) to give 6 as slight yellow oil (7.87 g, 87%). The spectroscopic data of the product were in complete accordance with those of the reported value. [3a]

7

A preliminary investigation has shown that the present protocol is applicable to the synthesis of multifunctional ketones from other thiol esters than 2.