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Chemistry

Research project: Linclau: The synthesis of luminacin D

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Angiogenesis, the formation of new blood vessels, is a highly regulated process that plays an important role in a variety of functions such as wound healing and reproduction. Uncontrolled angiogenesis is associated with a variety of diseases such as rheumatoid arthritis, diabetic retinopathy (a major cause for blindness) and atherosclerosis. Tumor growth is also angiogenesis-dependent: the growth of new capillary blood vessels is essential for the tumor itself to grow. Furthermore, the new blood vessels in the tumor provide a gateway for tumor cells to enter the circulation, which results in the spread of the disease.

Hence, controlling angiogenesis is being investigated as a strategy for treating these disorders. A new family of 14 angiogenesis inhibitors, the luminacins, was isolated from Streptomyces species, from which Luminacin D is the most active one.

Luminacin D

In the current syntheses of Luminacin D, the introduction of the trisubstituted epoxide appears to be rather unselective. We have developed a synthesis of Luminacin D based on methodology that has been developed in our group.

Here we have shown that 1,3-dicarbonyl groups can be allylated with very high diastereoselectivity under chelation conditions:

Selective allylation of 1,3-dialdehydes under chelation conditions

This methodology is published in Angew. Chem. Int. Ed. 2012, 51, 1232.

Applied on Luminacin D, the allylation substrate has an epoxide ring

Key selective allylation reaction

The total synthesis based on this key allylation step is published in Chem. Eur. J. 2014, 20, 3306.

However, albeit very selective, the absolute configuration of the formed alcohol stereocentre was the undesired one, requiring a 2-step Mitsunobu inversion. Hence, a second generation synthesis was investigated involving a similar key step, but now with the correct stereoselectivity:

This total synthesis was published in J. Org. Chem. 2016, 81, 3818.

Related research groups

Organic Chemistry: Synthesis, Catalysis and Flow
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