Fukuyama coupling

Source: Wikipedia, the free encyclopedia.
Fukuyama coupling
Named after Tohru Fukuyama
Reaction type Coupling reaction
Identifiers
Organic Chemistry Portal fukuyama-coupling

The Fukuyama coupling is a

organozinc halide in the presence of a palladium catalyst. The reaction product is a ketone. This reaction was discovered by Tohru Fukuyama et al. in 1998.[1]

Advantages

The reaction has gained considerable importance in synthetic organic chemistry due to its high

functional groups such as ketones, α-acetates, sulfides, aryl bromides, chlorides, and aldehydes. This excellent chemoselectivity is attributed to the fast rate of ketone formation compared to oxidative addition of palladium to aryl bromides or the nucleophilic addition of zinc reagents to aldehydes.[1]

Mechanism

Although the Fukuyama cross-coupling reaction has been widely used in natural product synthesis, the reaction mechanism remains unclear. Various catalysts have been shown to promote reactivity, including Pd/C, Pd(OH)2/C, Pd(OAc)2, PdCl2, NiCl2, Ni(acac)2, etc.[2] The proposed catalytic cycle using Pd(OH)2/C (Pearlman’s catalyst) features the in situ generation of active Pd/C by reduction with a zinc reagent or zinc dust.[3] The active Pd/C species then undergoes oxidative addition with a thioester, followed by transmetallation with a zinc reagent and reductive elimination, to afford the ketone coupling product.

Reaction Conditions

Pd-catalyzed Fukuyama Coupling

Fukuyama et al. reported the PdCl2(PPh3)2-catalyzed coupling of ethyl thioesters with organozinc reagents in 1998.[4] Remarkably, α−amino ketones starting from thioester derivatives of N-protected amino acids can be synthesized without racemization in good to excellent yields (58-88%).

Ni-catalyzed Fukuyama Coupling

Aside from the use of palladium catalysts, the first nickel-catalyzed Fukuyama coupling was reported by Shimizu and Seki in 2002.[5] Ni(acac)2 was found to produce superior yields compared to other nickel catalysts.

Pd/C-catalyzed Fukuyama Coupling Employing Dialkylzinc Reagents

In 2004, the same group of researchers reported the Pd/C-catalyzed Fukuyama ketone synthesis. This reaction couples dialkylzinc reagents with various thioesters in the presence of zinc bromide, which is in situ generated from bromine and zinc dust.[6] The authors proposed that the inactive zinc bromide is shifted to the active RZnBr species via the Schlenk equilibrium. Additionally, DMF can be used as an additive to increase reaction yields.

Applications in Natural Product Total Synthesis

Biotin

The reaction has been used to shorten the synthesis of

deprotection
of the alkene intermediate according to the reported procedure afforded (+)-biotin in 73% yield over two steps. This Fukuyama coupling sequence provided (+)-biotin in 63% overall yield in three steps from the thiolactone 1, thus allowing practical access to the vitamin due the short sequence, high yield, mild conditions, and ready availability of the reagents.

Biotin synthesis utilizing Fukuyama coupling

Related Reactions

The reaction is conceptually related to Fukuyama Reduction[8] and the Fukuyama-Mitsunobu reaction.[9]

References

  1. ^
    ISSN 0040-4039
    .
  2. ISSN 1573-501X
    .
  3. ISSN 0022-3263
    .
  4. ISSN 0040-4039
    .
  5. ISSN 0040-4039
    .
  6. ISSN 0040-4039
    .
  7. ISSN 0040-4039
    .
  8. ISSN 0002-7863
    .
  9. ISSN 0040-4039
    .
Retrieved from "https://en.wikipedia.org/w/index.php?title=Fukuyama_coupling&oldid=1160851656"