Progress in the Chemistry of Cytochalasans
101
5.1 Synthesis of Periconiasin G
Periconiasin G (412) was isolated in 2016 from the endophytic fungus Periconia sp.
F-31 was incubated in PDA medium by Dai and coworkers [15]. It has a unique 5/6/7fused ring system and is the smallest member so far discovered among the cytochalasans, showing weak anti-HIV activities. Nay and coworkers reported the total
syntheses of four stereoisomers of this seven-membered cytochalasan by biomimic
endo and exo IMDA cycloadditions [186]. After careful comparison, a revision of the
natural product structure (+)-periconiasin G (462) was achieved, and the stereocenter
of C-14 was revised as R.
The synthesis of periconiasin G (412) commenced from the protection of (R)citronellal with a 1,3-diol (Scheme 6) followed by dihydroxylation and oxidative
cleavage of the diol to deliver carboxylic acid E1. After esterification, the aldehyde E2 was readily obtained under the hydrolysis of the acetal. It was submitted
to a modified Takai olefination in the presence of anhydrous CrCl 2 and CHI 3 to
generate the iodoalkene E3, which was coupled with boronic acid E4 through a
Suzuki–Miyaura cross-coupling to afford diene E5. After hydrolysis, the carboxylic
acid was transformed into an acylimidazole. Then, the pre-lithiated N-benzoyl-5-isobutyl-pyrrolidin-2-one was added to acylimidazole E6 to provide the branched pyrrolidinone E7 in 65% yield. After deprotonation by LiHMDS, phenylselenation and
selenide oxidation afforded a highly sensitive linear IMDA substrate E8, which was
immediately engaged in a Diels–Alder reaction. The IMDA reaction was performed
at 100 °C in CHCl 3 and an inseparable mixture of endo and exo cycloadducts was
obtained in a 3:1 ratio. The removal of the protective benzoyl amide groups produced
a chromatographically separable mixture of periconiasin G (412) and E9. Supported
by X-ray crystallography, the proton NMR spectra and optical rotation of synthetic
periconiasin G (412) were in full accordance with those of the reported natural
product.
5.2 Syntheses of Cytochalasin B and L-696,474
Cytochalasin B (110, Fig. 23), together with cytochalasin A (109), was the first
isolated cytochalasan from Helminthosporium dematioideum [15]. In 1978, Stork
and coworkers reported the first total synthesis of cytochalasin B (110). The formation of the tricyclic ring was realized by a late-stage intramolecular Diels–Alder
condensation [268]. In 2004, Myers and coworkers reported an convergent synthesis
route in which the isoindolone core was constructed by a Diels–Alder reaction and
the macrocyclic ring was formed by an intramolecular Horner–Wadsworth–Emmons
(HWE) olefination ring closure with the macrocyclic appendage introduced at a latestage in the synthetic sequence [269]. Furthermore, using the same strategy, it is also
possible to synthesize cytochalasin L-696,474 (26, Fig. 23).
101
5.1 Synthesis of Periconiasin G
Periconiasin G (412) was isolated in 2016 from the endophytic fungus Periconia sp.
F-31 was incubated in PDA medium by Dai and coworkers [15]. It has a unique 5/6/7fused ring system and is the smallest member so far discovered among the cytochalasans, showing weak anti-HIV activities. Nay and coworkers reported the total
syntheses of four stereoisomers of this seven-membered cytochalasan by biomimic
endo and exo IMDA cycloadditions [186]. After careful comparison, a revision of the
natural product structure (+)-periconiasin G (462) was achieved, and the stereocenter
of C-14 was revised as R.
The synthesis of periconiasin G (412) commenced from the protection of (R)citronellal with a 1,3-diol (Scheme 6) followed by dihydroxylation and oxidative
cleavage of the diol to deliver carboxylic acid E1. After esterification, the aldehyde E2 was readily obtained under the hydrolysis of the acetal. It was submitted
to a modified Takai olefination in the presence of anhydrous CrCl 2 and CHI 3 to
generate the iodoalkene E3, which was coupled with boronic acid E4 through a
Suzuki–Miyaura cross-coupling to afford diene E5. After hydrolysis, the carboxylic
acid was transformed into an acylimidazole. Then, the pre-lithiated N-benzoyl-5-isobutyl-pyrrolidin-2-one was added to acylimidazole E6 to provide the branched pyrrolidinone E7 in 65% yield. After deprotonation by LiHMDS, phenylselenation and
selenide oxidation afforded a highly sensitive linear IMDA substrate E8, which was
immediately engaged in a Diels–Alder reaction. The IMDA reaction was performed
at 100 °C in CHCl 3 and an inseparable mixture of endo and exo cycloadducts was
obtained in a 3:1 ratio. The removal of the protective benzoyl amide groups produced
a chromatographically separable mixture of periconiasin G (412) and E9. Supported
by X-ray crystallography, the proton NMR spectra and optical rotation of synthetic
periconiasin G (412) were in full accordance with those of the reported natural
product.
5.2 Syntheses of Cytochalasin B and L-696,474
Cytochalasin B (110, Fig. 23), together with cytochalasin A (109), was the first
isolated cytochalasan from Helminthosporium dematioideum [15]. In 1978, Stork
and coworkers reported the first total synthesis of cytochalasin B (110). The formation of the tricyclic ring was realized by a late-stage intramolecular Diels–Alder
condensation [268]. In 2004, Myers and coworkers reported an convergent synthesis
route in which the isoindolone core was constructed by a Diels–Alder reaction and
the macrocyclic ring was formed by an intramolecular Horner–Wadsworth–Emmons
(HWE) olefination ring closure with the macrocyclic appendage introduced at a latestage in the synthetic sequence [269]. Furthermore, using the same strategy, it is also
possible to synthesize cytochalasin L-696,474 (26, Fig. 23).