Synthetic Approach to the ABCD Ring System of Anticancer Agent Fredericamycin A via Claisen Rearrangement and Ring-Closing Metathesis as Key Steps

Abstract

A new synthetic strategy to the ABCD ring system of the anticancer agent fredericamycin A (NSC-305263) was realized by the Diels–Alder reaction and olefin metathesis as key steps. The tactics developed here for the construction of the ABCD ring system also involve double Claisen rearrangement followed by a retro-Diels–Alder reaction and ring-closing metathesis. The metathesis approach performs a key role in the construction of A and D rings of the ABCD core unit. More importantly, ABCD fragment synthesis was accomplished without the involvement of protecting groups.

Synthesis and Acid Catalyzed Rearrangement of Cage Propellanes

“…Later, the compound 15 was treated with allyl bromide in the presence of NaH in THF to deliver the diallyl compound 23 in excellent yield. Finally, the indanone derivative 23 was subjected to RCM via Grubbs catalyst (G‐II) to generate the ring‐closure product 19 (89%) . The structure of the RCM product 19 has been confirmed by 1 H NMR, 13 C NMR and HRMS data (Scheme ).…”

“…To create diverse cage frameworks, we focussed our efforts towards the synthesis of other functionalized cage propellanes 17 , 18 , and 33 bearing the spiro linkage. [4n, ° ] Towards this goal, the RCM product such as tricyclic spiro compound 19 on treatment with CAN at 0 °C in acetonitrile/water mixture delivered the quinone derivative 31 which acts as a potent dienophile for DA reaction with cyclopentadiene ( 25 ). Later on, [4+2] cycloaddition of quinone 31 with a freshly prepared cyclopentadiene ( 25 ) provided the DA adduct 32 in excellent (92%) yield.…”

“…[4n, ° ] Towards this goal, the RCM product such as tricyclic spiro compound 19 on treatment with CAN at 0 °C in acetonitrile/water mixture delivered the quinone derivative 31 which acts as a potent dienophile for DA reaction with cyclopentadiene ( 25 ). Later on, [4+2] cycloaddition of quinone 31 with a freshly prepared cyclopentadiene ( 25 ) provided the DA adduct 32 in excellent (92%) yield. The DA adduct 32 underwent [2+2] photocycloaddition smoothly in the presence of UV light (125 W‐homemade) irradiation for 1 h in dry ethyl acetate under nitrogen atmosphere gave the required cage trione 20 (Scheme ).…”

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…Kotha and co‐workers revealed the protecting‐group‐free synthesis of fredericamycin A tetracyclic spiro fragment 618 (Scheme 95). Fredericamycin A is an anticancer agent, extracted from the fermentation broth of the strain Streptomyces griseus (ATCC 49344, FCRC‐48) [276] . In this synthetic strategy, Kotha's group bestowed twice an RCM reaction to construct 5‐ and 6‐membered rings.…”

“…Fredericamycin A is an anticancer agent, extracted from the fermentation broth of the strain Streptomyces griseus (ATCC 49344, FCRC-48). [276] In this synthetic strategy, Kotha's group bestowed twice an RCM reaction to construct 5-and 6membered rings. Double C-allylation of indanone derivative 613 with allyl bromide in presence of NaH furnished a diene 614, as a RCM precursor, which encountered RCM in presence of G-II catalyst 2 and delivered a spiro compound 615 in 89% yield.…”