Total Synthesis of Angucyclines, 4. Synthesis of rac‐Tetrangomycin

Abstract

The synthesis of racemic tetrangomycin (11) is reported. In the key step the hexahydrobenz[α]anthraquinone 8 is generated in a regioselective Diels‐Alder reaction of diene 5 with bromonaphthoquinone 7. The conversion of 8 into 11 involves only three operations: treatment with diethyl ether–boron trifluoride, hydrogen peroxide and photooxygenation.

Angucyclines: Total syntheses, new structures, and biosynthetic studies of an emerging new class of antibiotics

“…The conjugate addition of lithium pentamethyldisilane (73) to cyclic enones is a general reaction (e.g., 74 and 76) and required no conversion to the corresponding copper species. The yields of the adducts 75 and 77 range from 50 % to 60% [68].…”

Biomimetic-Type Synthesis of the Racemic Non-Aromatic Angucyclinones of the SF 2315 and SS 228Y Types

“…Virtually no reaction occurred below -35°C and a very slow conversion was observed above -25°C in 0.2  methanolic KOH. This yielded only the aromatic angucyclines 8-deoxytetrangomycin (8b) and 8-deoxytetrangulol (9b), identical with samples from previous biomimetic [26] and Diels-Alder reactions [28] (Scheme 2).…”

Studies toward the synthesis of angularly-oxygenated angucyclines antibiotics

“…Since the double bond in the carbon side-chain would allow other reactions to compete with the desired cyclization, we introduced the A ring tertiary 3-OH group, or a function convertible into it before carrying out the cyclization. Inspired by Krohn's work on the synthesis of angucyclinones, 6,7,42 we wanted to install a silyl group as a hydroxyl group surrogate at position 3 (Scheme 5). 43 We first verified the feasibility of the conjugate addition of a silyl cuprate onto a β,β'-disubstituted enal: …”

“…Only two total syntheses of such angucyclines have been reported: Krohn's synthesis of the racemic 8-deoxy analogue of WP 3688-2 (6) 34 and the first total synthesis of aquayamycin (2), described by the Suzuki group. [35][36][37] In both cases, the key A ring annulation step was a pinacoltype coupling.…”

“…Until now, most synthetic efforts have been directed toward angucyclines with an aromatic B ring. In most cases, the strategy used for constructing the benz[a]anthracene framework is based on the Diels-Alder reaction, [3][4][5][6][7][8][9][10][11][12] but other synthetic approaches also have been described. [13][14][15][16][17][18][19][20][21][22] However, angucyclines bearing two hydroxy groups at the AB ring junction positions ( Figure 1) hold a special status among these targets because (1) their total synthesis still constitutes a real challenge and (2) their biological activities [23][24][25][26][27][28][29] are the most therapeutically significant ones e.g., exhibiting antitumor activity against adriamycin-and doxorubicin-resistant P388 leukemia cells.…”