Total Syntheses of Hyperforin and Papuaforins A–C, and Formal Synthesis of Nemorosone through a Gold(I)‐Catalyzed Carbocyclization

Abstract

The remarkable biological activities of polyprenylated polycyclic acylphloroglucinols (PPAPs) combined with their highly decorated bicyclo[3.3.1]nonane-2,4,9-trione frameworks have inspired synthetic organic chemists over the last decade. The concise total syntheses of four natural products PPAPs; hyperforin and papuaforins A-C, and the formal synthesis of nemorosone are reported. Key to the realization of this strategy is the short and scalable synthesis of densely substituted PPAP scaffolds through a gold(I)-catalyzed 6-endo-dig carbocyclization of cyclic enol ethers for latestage functionalization.

Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity

“…The total syntheses of hyperforin ( 239 ) and papuaforins A-C ( 240 - 242 ) have been achieved by using a gold(I)-catalyzed Conia-type reaction from 1,5-enynes 237 (Scheme 74 ). 232 Similar cyclizations were used in the syntheses of the alkaloids (+)-lycopladine A ( 245 ) 233 and (+)-fawcettimine ( 249 ) (Scheme 75 ), 234 as well as in the total synthesis of platencin. 235 This reaction has also been applied to the cyclization of 1,7-enynes in the total synthesis of the marine sesquiterpene (±)-gomerone C 252 ( 236 ) and also in the total synthesis of Daphniphyllum alkaloid daphenylline 255 (Scheme 76 ).…”

Research Progress of Polycyclic Polyprenylated Acylphloroglucinols

“…The concise total syntheses of hyperforin (422) and its analogues, papuaforins A−C (478−480), were accomplished in 17 steps by Barriault and Bellavance (Scheme 8). 341 They provided a strategy of short and scalable synthesis of densely 167 HL-60 acute myeloid leukemia 2.4 μM SW480 human colon cancer 5.5 μM (−)-garmultin C (410) 167 HL-60 acute myeloid leukemia 3.2 μM SMMC-7721 human hepatocarcinoma 5.6 μM A-549 human lung carcinoma 4.4 μM MCF-7 human breast adenocarcinoma 5.9 μM SW480 human colon cancer 3.0 μM human erythroleukemia (HEL) cells 2.5 μM (+)-garmultin F (411) 167 HL-60 acute myeloid leukemia 5.4 μM A-549 human lung carcinoma 9.5 μM SW480 human colon cancer 4.3 μM (−)-garmultin F (412) 167 34 NO production in RAW264.7 cells 9.5 μM (IC 50 ) anti-inflammatory garcimultiflorone A (63) 77 superoxide anion (•O 2…”

“…) generation and elastase release 7.2 μM 6.0 μM garcimultiflorone G (317) 156 superoxide anion (•O 2 − ) generation 7.0 μM hyperattenin C (61) 71 HIV on C8166 cells 8.1 μM (EC 50 ) anti-HIV 1.65 (SI) hyperattenin B (88) 71 HIV on C8166 cells 9.9 μM, 0.97 hyperisampsin D (279) 149 HIV-1 in MT-4 cells 0.97 μM, 7.7 hyperisampsin A (281) 149 HIV-1 in MT-4 cells 3.0 μM, 4.8 hyperattenin K (331) 147 HIV-1 in MT-4 cells 3.4 μM, 3.5 hyperascyrone E (349) 161 HIV-1 in MT-4 cells 3.6 μM, 2.1 hyperascyrone B (360) 161 HIV-1 in MT-4 cells 4.2 μM, 0.36 hyperascyrone C (361) 161 HIV-1 in MT-4 cells 2.4 μM, 0.23 hyperascyrone F (373) 161 HIV-1 in MT-4 cells 2.4 μM, 5.6 coccinone C (174) 97 FcB1 (P. falciparum) 9.0 μM (IC 50 ) antiplasmodial coccinone D (175) 97 FcB1 (P. falciparum) 7.0 μM coccinone E (176) 97 FcB1 (P. falciparum) 4.9 μM 7-epi-isogarcinol (178) 97 FcB1 (P. falciparum) 5.1 μM 14-deoxy-7-epi-isogarcinol (179) 97 FcB1 (P. falciparum) 2.5 μM symphonone B (180) 123 FcB1 (P. falciparum) In addition, a formal synthesis of (±)-nemorosone (426) from 476 in 6 steps was also suggested. 341 This modular approach serves as a platform to quickly assemble PPAPs for further synthetic studies. 341…”

“…341 This modular approach serves as a platform to quickly assemble PPAPs for further synthetic studies. 341…”

Methoxycyclization of 1,5‐Enynes by Coinage Metal Catalysts: Is Gold Always Superior?

“…The ability of Au(I) catalysts to facilitate the intramolecular cycloisomerization of 1, n ‐enynes leading to increasingly complex cyclic species is well established in the literature [1–4] . Practically speaking, such cycloisomerization procedures have been used in the synthesis of complex natural products, [5] such as the angular triquinane ventricosene (1,6‐enyne), [6] as well as hyperforin, [7] papuaforins A–C, [7] nemorosone, [7] (+)‐lycopladine A, [8] (+)‐fawcettimine, [9] and platencin [10] (each involving 1,5‐enynes). As such, it is hardly surprising that considerable effort has been placed into establishing a detailed mechanistic understanding of such a versatile reaction [11–19] .…”