Zinc Chemistry

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Carbon-carbon bond formation plays a pivotal role in the assembly of drug candidates. The development of polyfunctionalized organozinc reagents facilitates the synthesis of complex molecules, which also avoid the protection and deprotection of functional groups.1

Functionalized aliphatic, aromatic or heteroaromatic organozinc reagents can be prepared via three approaches:direct zinc insertion between the iodide- or bromide-carbon bond, direct insertion of magnesium in the presence of Zn(II) salts to aryl or heteroaryl halides, or metalation of aryl or heteroaryl derivatives with the TMP2Zn.2MgCl2.2LiCl reagent as shown in Schemes 1 and 2.2

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Scheme 1

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 Scheme 2

The functionalized organozinc reagents are quite stable in solutions. Unfortunately, it has limited utility in organic synthesis because of its low reactivity with organic electrophiles. On the other hand, after the transmetallation to copper, palladium or nickel, organozinc reagents can be used for a wide variety of applications in organic synthesis as shown in Scheme 3.2

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 Scheme 3

This organozinc chemistry not only tolerates a variety of functional groups during carbon-carbon bond formation, but it also works extremely well in complex systems and under steric environments as shown in Scheme 4.2,3

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 Scheme 4

Organozinc reagents are more reactive than the corresponding organotin or organoboron reagents currently being used for organic synthesis. As a result, the organozinc reagents operate where organotin and organoboron reagents fail to provide the desired product, as shown in Schemes 5 and 6.

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 Scheme 5

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Scheme 6

Organozinc chemistry reduced the number of steps required for the synthesis of complex molecules, and also allowed structure activity relationship (SAR) studies to be completed much more quickly, as shown in Scheme 7.4

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Scheme 7

In summary, organozinc chemistry is one of the most powerful tools in carbon-carbon bond formation, and it has a tremendous range of applications in drug discovery research.

References:

  1. Knochel. P. et al Pure Appl. Chem.1992, 64, 361.
  2. Knochel, P. et al. Chem. Rev. 1993, 93, 2117-2188 and Angew. Chem. Int. Ed. 2011, 50, 9794-9824.
  3. Sidduri. A. et al. Bioorg. Med. Chem. Lett. 2013, 23, 1026-1031.
  4. Sidduri. A. et al. Bioorg. Med. Chem. Lett.2010, 20, 5673-5676.