Synthetic angucyclines, 3. First total synthesis of rac‐rabelomycin by Diels‐Alder reaction

Abstract

Conjugate addition of the 2-siloxydienes 5a and 5b to juglone (4a) or 3-chlorojuglone (4b) affords the products 6-8a and 8b, respectively. The reaction of 4a with furan 10 yields the substitution product 11, which is converted to the 5-hydroxybutenolide 12 by treatment with MCPBA. Hexamethyldisilane (13) is cleaved by treatment with methyllithium to afford lithium pentamethyldisilane (14), which adds to enone 15 in a Michael reaction to give the adduct 16. The diene 18 is constructed regioselectively from 16 by a Wittig-Homer reaction and silylation. The Diels-Alder reaction of 18 with juglone (4a) affords adducts 19a and 19b, which are converted to racemic rabelomycin (2) by hydroxylation and photooxygenation. The structures of four products (8a, 8b, 9, 12) were confirmed by X-ray structure determination.

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

“…The reaction proved to be of great value for angucycline synthesis because the fl-hydroxy group present in most natural products which is easily eliminated under basic or acidic conditions (see Scheme 2) and the carbonyl group at C-1 can thus be introduced under mild neutral conditions. We assume that the reaction is initiated by Norrish type II y-hydrogen abstraction of the excited carbonyl in 25 to yield a diradica126 as shown in Scheme 8 with 1-deoxyrabelomycin (25) as the example [39]. The H-abstraction requires a very definite steric environment in which the benzylic protons have to be in proximity of the excited carbonyl group.…”

“…In our group, we also investigated the reactions of naphthoquinones with siloxyfurans such as 64. However, instead of the expected [4+2] cycloaddition, a Michael addition that proceeded without catalyst occurred in the reaction with 3-chlorojuglone (63) [39]. Interestingly, both the Michael acceptor 63 and the donor 64 reacted in a 1,4-reaction mode.…”

“…A similar diene 66, prepared by reduction of the ketone 46 of Guingant and Barreto [53] [39] i.e., acetylation of 67) the racemic rubiginones [63] and emycin A [64]. The advantage offered by the diene 66 was that the adducts 67 with juglone 40 were relatively stable and did not spontaneously aromatize as observed by Guingant and Barreto [53].…”

“…The least substituted diene 83 was alternatively prepared from the triflate 82 in a Stille coupling with trialkylvinyl stannane [75] (Scheme 24), a reaction also used by Toshima et al [76]. With the required silyldienes 81, 83, and 85 in hand, the syntheses of most racemic angucyclines with aromatic ring B, such as rabelomycin (29) [39], tetrangomycin (2) and tetrangulol (3) [73] or the simple benzo[a]anthraquinone derivatives MM 47755 (isolation [77]) or X-14881 E (isolation [44]), could be prepared similarly as shown in Scheme 23 [74]. As a rule, the adducts using the ketene acetal 81 tend to rapidly eliminate one siloxy or alkoxy substituent generating a phenol or phenol ether.…”

Asymmetric Synthesis of Rubiginones A2 and C2 and Their 11‐Methoxy Regioisomers

“…A second hydrogen radical elimination from II could occur to give the angularly fused anthraquinone system III. As proposed by Krohn [44] in analoguous systems, an intramolecular hydrogen transfer from the C-1 situated in the g-position with respect to the C-12 carbonyl in III in a Norrish type II process would produce a new 1,4-biradical IV. This process must be easy due to the adequate geometric disposition of both the C À H bond at C-1 and the carbonyl group at C-12.…”