Progress in the Chemistry of Cytochalasans
111
5.5 Total Synthesis of Asperchalasine A and Related
Derivatives
Recently, several unprecedented merocytochalasans were identified from the fermentation broth of Aspergillus flavipes by Zhang and coworkers, including asperchalasines A–D (455, 448–450) and epicochalasines A (461) and B (462) [193, 196].
Asperchalasine A (455), which is the first example of a cytochalasan heterotrimer
generated by the fusion of two cytochalasan molecules to an epicoccine, possesses an
unprecedented 13-oxatetracyclo[7.2.1.1
2,5 .0
1,6 ]tridec-8,12-dione core containing as
many as 20 chiral centers. Structurally, the dimeric and polymeric features of asperchalasine A (455) are sufficient to make it stand out from the large family of cytochalasans. More importantly, asperchalasine A (455) induced significant G1-phase cell
cycle arrest by selectively inhibiting cyclin A, CDK2, and CDK6 in cancerous,
but not normal cells, highlighting it as a potentially selective cell cycle regulator
against cancer cells. Recently, the synthesis of asperchalasine A (455) and its related
derivatives has become a topic of great interest in organic chemistry.
5.5.1 Total Synthesis of Asperchalasines A–E by Tang’s Group
The first total syntheses of asperchalasines A–E (455 and 448–451), a suite of
unprecedented merocytochalasans, was achieved by Tang and coworkers [198]. Key
to the success of a chemical synthesis approach that would deliver all these merocytochalasans was a convergent and scalable route to the key tricyclic monomer,
aspochalasin B (344). Aspochalasin B (344), was synthesized initially through a
unified approach that hinges on a Diels–Alder reaction and a ring-closing metathesis
reaction as shown in Scheme 14. The synthesis commenced with the preparation of
the fragment I5 through sequential acylation of the lactam G4 followed by selenation
and oxidative elimination, which was found to be quite unstable [277]. Thus, it had
to be promptly submitted in the subsequent Diels–Alder reaction with the diene I8
[288], which was prepared in one step from the known aldehyde I6 through Julia
olefination. (CuOTf) 2 ·PhMe was found to the best catalyst, and yielded I9 as a single
adduct in 63% yield [289, 290]. The 11-membered macrocycle was formed through
the RCM reaction using the Grubb’s second-generation catalyst, to afford tricyclic
intermediate I10 as a single (E)-isomer in 85% yield [291]. Dihydroxylation of the
double bond followed by removal of the N-benzoyl group afforded the trans-diol
I11. Then, selective protection of OH-17, oxidation of OH-18, and removal of the
protecting group converted I11 into I12, which was transformed into aspochalasin
P (358) by removal of the acetyl group. Finally, selenylation followed by oxidative
elimination afforded aspochalasin B (344) in 40% yield.
The bioinspired Diels–Alder reactions of aspochalasin B (344) with different
epicoccine precursors were then studied, which enabled the divergent synthesis of the
heterodimers asperchalasines B–E (448–451) and its related congeners (Scheme 15).
Treatment of aspochalasin B (344) with I14 [292] using CSA as acid smoothly
111
5.5 Total Synthesis of Asperchalasine A and Related
Derivatives
Recently, several unprecedented merocytochalasans were identified from the fermentation broth of Aspergillus flavipes by Zhang and coworkers, including asperchalasines A–D (455, 448–450) and epicochalasines A (461) and B (462) [193, 196].
Asperchalasine A (455), which is the first example of a cytochalasan heterotrimer
generated by the fusion of two cytochalasan molecules to an epicoccine, possesses an
unprecedented 13-oxatetracyclo[7.2.1.1
2,5 .0
1,6 ]tridec-8,12-dione core containing as
many as 20 chiral centers. Structurally, the dimeric and polymeric features of asperchalasine A (455) are sufficient to make it stand out from the large family of cytochalasans. More importantly, asperchalasine A (455) induced significant G1-phase cell
cycle arrest by selectively inhibiting cyclin A, CDK2, and CDK6 in cancerous,
but not normal cells, highlighting it as a potentially selective cell cycle regulator
against cancer cells. Recently, the synthesis of asperchalasine A (455) and its related
derivatives has become a topic of great interest in organic chemistry.
5.5.1 Total Synthesis of Asperchalasines A–E by Tang’s Group
The first total syntheses of asperchalasines A–E (455 and 448–451), a suite of
unprecedented merocytochalasans, was achieved by Tang and coworkers [198]. Key
to the success of a chemical synthesis approach that would deliver all these merocytochalasans was a convergent and scalable route to the key tricyclic monomer,
aspochalasin B (344). Aspochalasin B (344), was synthesized initially through a
unified approach that hinges on a Diels–Alder reaction and a ring-closing metathesis
reaction as shown in Scheme 14. The synthesis commenced with the preparation of
the fragment I5 through sequential acylation of the lactam G4 followed by selenation
and oxidative elimination, which was found to be quite unstable [277]. Thus, it had
to be promptly submitted in the subsequent Diels–Alder reaction with the diene I8
[288], which was prepared in one step from the known aldehyde I6 through Julia
olefination. (CuOTf) 2 ·PhMe was found to the best catalyst, and yielded I9 as a single
adduct in 63% yield [289, 290]. The 11-membered macrocycle was formed through
the RCM reaction using the Grubb’s second-generation catalyst, to afford tricyclic
intermediate I10 as a single (E)-isomer in 85% yield [291]. Dihydroxylation of the
double bond followed by removal of the N-benzoyl group afforded the trans-diol
I11. Then, selective protection of OH-17, oxidation of OH-18, and removal of the
protecting group converted I11 into I12, which was transformed into aspochalasin
P (358) by removal of the acetyl group. Finally, selenylation followed by oxidative
elimination afforded aspochalasin B (344) in 40% yield.
The bioinspired Diels–Alder reactions of aspochalasin B (344) with different
epicoccine precursors were then studied, which enabled the divergent synthesis of the
heterodimers asperchalasines B–E (448–451) and its related congeners (Scheme 15).
Treatment of aspochalasin B (344) with I14 [292] using CSA as acid smoothly