Fukuyama Reduction

What Is Fukuyama Reduction?

The Fukuyama reduction is a pivotal reaction in modern organic synthesis, enabling the selective reduction of thioesters to aldehydes under mild conditions. Developed by Tohru Fukuyama and colleagues in the 1990s, this reaction addresses the longstanding challenge of directly converting carboxylic acid derivatives to aldehydes without over-reduction to alcohols or requiring multi-step protocols.

Compared with the methods of DIBAL-H, Rosenmund, etc., which convert carboxylic acid derivatives such as esters or acyl chlorides into aldehydes, this method has milder conditions, and exceptional functional group tolerance and chemoselectivity.

• Reagents: Palladium on carbon (Pd/C) or Lindlar catalyst; triethylsilane (Et₃SiH); toluene or tetrahydrofuran (THF).
• Reactants: Thioesters (RCOSR').
• Products: Aldehydes.
• Reaction type: Catalyzed reduction.
• Related reactions: DIBAL-H reduction, Rosenmund reduction, Steglich esterification.
• Experimental tips:
• Amines, esters, ketones, acetals, silicon-based protecting groups, thioethers, β-lactams, etc. are not suitable for this reaction.
• Alkenes will also be reduced, but the reaction can be improved by adding excess terminal olefins using Lindlar catalyst.

Fig 1. Fukuyama reduction reaction and its mechanism. [1]

Mechanism of Fukuyama Reduction

The Fukuyama reduction reaction involves the reduction of thioesters using triethylsilane and a palladium catalyst, resulting in the formation of aldehydes without leading to the production of alcohols. The proposed mechanism includes two pathways.

• In Path A, the reaction begins with the oxidative addition of Pd(0) to the sp²-hybridized carbon of the thioester, resulting in the formation of a Pd(II) complex. Next, the acylpalladium complex undergoes transmetallation with triethylsilane, followed by reductive elimination from the acylpalladium hydride to yield the aldehyde.
• Path B suggests a direct hydrosilylation of the thioester to produce the aldehyde; however, this pathway was dismissed since intermediate compound was not observed in the reaction mixture.

Application Examples of Fukuyama Reduction

• Example 1-Total Synthesis of (+) Leinamycin: (+) Leinamycin 32 is a crucial anti-tumor agent extracted from the culture broth of Streptomyces sp. The first complete synthesis of leinamycin 32 was achieved in 1993 by Kanda and Fukuyama, utilizing the Fukuyama reduction as a pivotal step. Acid 29, derived from dioxalanone 28 through multiple steps, was transformed into thioester 30 with an 87% yield. Following the Fukuyama reduction, this thioester yielded aldehyde 31 in a 92% yield after two additional steps, ultimately leading to the synthesis of (+)-leinamycin 32 through further transformations.
• Example 2-Total Synthesis of Lipogrammistin A: Lipogrammistin-A 36 is an alkaloid extracted from the skin mucus of grammistid fish by Fusetani and Tachibana, featuring a polyamine lactam ring in its structure. Fujiwara et al. reported the total synthesis of lipogrammistin-A 36 employing the Ns-strategy and Fukuyama reduction. Their synthesis began with acid 33, which was converted to thiol ester 34 by replacing the Cbz protecting group with Boc, achieving a 70% yield over two steps. Subsequently, thiol ester 34 underwent Fukuyama reduction using triethylsilane and 10% Pd/C, resulting in aldehyde 35 with a 74% yield. Following several additional steps, lipogrammistin-A 36 was synthesized with an overall yield of 12% across 13 steps.

Fig 2. Synthetic examples via Fukuyama reduction reaction.

Related Products

CAS No.	Structure	Product
53092-86-7		Lindlarcatalyst
617-86-7		Triethylsilane
7440-05-3		Palladium
1264-52-4		Octanoyl coenzyme a
1866-16-6		S-Butyrylthiocholine iodide
41345-70-4		3-(Acetylthio)propionic acid
6038-19-3		Dl-homocysteinethiolactone hydrochloride
72-89-9		Acetyl coenzyme a trilithium salt trihydrate

References

1. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Fourth Edition, 2014, 270-271.
2. Sikandar, Sana, et al. Molecular Diversity, 2022, 26, 1-40.