Protecting‐Group‐Free Total Syntheses of Rubrolide R and S

Abstract

The two marine natural products rubrolide R (1) and S (2) were synthesised in only three linear steps starting from commercially available tetronic acid without using protecting‐group chemistry. Key steps in the syntheses were the Pd‐catalysed Suzuki–Miyaura cross‐coupling followed by a vinylogous aldol condensation. Both compounds have been tested for their antibiotic and antiviral activities. At a concentration of 10 µm rubrolide R (1) and S (2), a 2‐log and 1.5‐log reduction in virus titre has been detected for a seasonal influenza virus (H3N2) and the pandemic swine influenza virus (pH1N1), respectively.

Synthesis of Natural Rubrolides B, I, K, L, M, O and Analogues

“…With the β‐aryl butenolides 13 – 15 in hand, a vinylogous aldol condensation between commercially available benzaldehyde derivatives 16 – 18 was employed in order to synthesize the naturally occurring rubrolides B 1 , I 2 , K 3 , L 4 , M 5 , O 6 and nine rubrolide analogues 19 – 27 . As reported previously, [11,13,14,15,18] the vinylogous aldol condensation was conducted in a three‐step one‐pot synthesis, using TBSOTf, DIPEA (a) or Et 3 N (b) as base depending on the desired derivative and CH 2 Cl 2 at 0 °C for 30 min in the first step. Afterwards, the p‐ hydroxy benzaldehyde derivative ( 16 , 17 or 18 ) is added to the reaction mixture and stirred for another 24 h at room temperature.…”

“…Some of the natural abundant rubrolides were already synthesized employing various protocols, [11–25] since the biological activities, especially of higher halogenated rubrolides, is considered promising for the discovery of novel antiinfective agents. Therefore, a robust and divergent synthetic protocol for the construction of a suitable substance library is highly desirable.…”

“…The synthetic strategy employs the synthesis of privileged intermediates, which then can be transferred into halogenated analogues by simple procedures. Intermediate 9 can be synthesized in two steps employing a robust Suzuki‐Miyaura cross‐coupling reaction starting from tetronic acid 10 [11] . This product 9 can be selectively chlorinated in 3‐position of the furanone ring.…”

“…[2][3][4][5][6][7][8][9][10] These small molecules mostly differ in their halogenation grade at the aromatic substituents except rubrolides E, R and S, which are not halogenated at all. The biological activities of the members of the natural product class range from antibacterial, [2,3,5,7] antiinflammatory, [4] antiviral [8,11] to aldose-reductase inhibition [10] with a so far unknown mode of action. Most rubrolides contain brominated phenol groups, and some also have a chloro substituent in α-position of the furanone ring (Figure 1).…”

“…Most rubrolides contain brominated phenol groups, and some also have a chloro substituent in α-position of the furanone ring (Figure 1). Some of the natural abundant rubrolides were already synthesized employing various protocols, [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] since the biological activities, especially of higher halogenated rubrolides, is considered promising for the discovery of novel antiinfective agents. Therefore, a robust and divergent synthetic protocol for the construction of a suitable substance library is highly desirable.…”