Design, synthesis, and investigation of protein kinase C inhibitors: total syntheses of (+)-calphostin D, (+)-phleichrome, cercosporin, and new photoactive perylenequinones

Abstract

The total syntheses of the PKC inhibitors (+)-calphostin D, (+)-phleichrome, cercosporin, and 10 novel perylenequinones are detailed. The highly convergent and flexible strategy developed employed an enantioselective oxidative biaryl coupling and a double cuprate epoxide opening, allowing the selective syntheses of all the possible stereoisomers in pure form. In addition, this strategy permitted rapid access to a broad range of analogues, including those not accessible from the natural products. These compounds provided a powerful means for evaluation of the perylenequinone structural features necessary to PKC activity. Simpler analogues were discovered with superior PKC inhibitory properties and superior photopotentiation in cancer cell lines relative to the more complex natural products.

Figure 1

Perylenequinone natural products.

Figure 2

Perylenequinone 3-D Helical Chirality and Atropisomerization.

Figure 3

Common enantiopure intermediates to allow evaluation of helical chirality.

Scheme 1

Retrosynthetic analysis of the calphostins.

Scheme 2

Common intermediate to the perylenequinone natural products.

Scheme 3

Retrosynthesis of cercosporin.

Scheme 4

Pathways to installation of the C7,C7′-stereoarray.

Scheme 5

Total synthesis of (+)-phleichrome and (+)-calphostin D.

Scheme 6

First total synthesis of cercosporin.

Scheme 7

Synthesis of C2,C2′-analogs.

Scheme 8

Use of common intermediates in the syntheses of C3,C3′,C7,C7′-analogs.