Dattatraya H.
Dethe
*,
Nitin
Sharma‡
,
Sakshi
Juyal‡
,
Prabhakar
Singh
and
Salman A.
Siddiqui
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, 208016, India. E-mail: ddethe@iitk.ac.in
First published on 3rd June 2024
Enantioselective total synthesis of (+)-sapinsigin H, (+)-agallochaol C, and (+)-16α, 17-dihydroxy-atisan-3-one has been accomplished starting from enantiopure Wieland–Miescher ketone. Key features of the syntheses include a benzannulation step to construct the tricyclic core, an oxidative dearomatization step to generate the diene, and a Diels–Alder reaction with ethylene gas to establish the bicyclo[2.2.2]octane framework. Efficient late-stage functionalisation of the A-ring by aerobic oxidation and Baeyer−Villiger oxidation completed the atisane target molecules.
A plausible biogenetic pathway for 3,4-seco-atisane diterpenoids was proposed from the putative precursor A (Scheme 1). The initial transformation involves Baeyer–Villiger oxidation of precursor A, yielding the pivotal intermediate B. Subsequent hydrolysis and dehydration steps lead to the formation of 3,4-seco-atisane diterpenoids.
We planned our retrosynthesis for agallochaol C inspired by the biogenetic pathway of 3,4-seco-atisane diterpenoids. Our primary objective was to establish the tetracyclic atisane core. In a related context, Liu and coworkers undertook the racemic synthesis of atisane-type diterpenoids in 2015, employing the Diels–Alder reaction to form the bicyclo[2.2.2]octane skeleton with various dienophiles. However, their attempts using ethylene gas as a dienophile did not yield the desired product.11 In contrast, the Fukuyama group achieved successful Diels–Alder reactions with ethylene gas as the dienophile during the synthesis of lepenine in 2014.12
Inspired by these studies, we planned to construct the atisane framework using Diels–Alder reaction with ethylene gas. Our retrosynthesis commenced with the preparation of tetracyclic 10, which could be then converted to different atisane natural products. The bicyclo[2.2.2]octane moiety of 10 may result from a Diels–Alder reaction of 11 with ethylene gas. Further simplification of diene 11 revealed a bicyclic intermediate 12via benzannulation (6π electrocyclization) and dearomatization steps. Bicyclic intermediate 12 would be accessible via Heck coupling of triflate 13 with methyl acrylate, and 13 can be synthesised from the enantiopure Wieland–Miescher ketone derivative 14 (Scheme 2).
According to our retrosynthetic plan expounded above, our initial target was to procure diene 11, the Diels–Alder precursor, from the enantiopure Wieland–Miescher ketone derivative 14. Bicyclic keto intermediate 15 was prepared from 14 according to previously reported procedures in decagram scale. 15 on deprotonation using NaHMDS and the treatment of the resulting enolate with Comins’ reagent resulted in vinyl triflate 13. Heck reaction of triflate 13 with methyl acrylate using palladium acetate led to 12, which underwent saponification using LiOH to the corresponding acid derivative 16. We conducted the benzannulation of acid 16 utilizing propionic anhydride at 180 °C for a duration of 2 days, employing the methodology reported by Murali and Krishna Rao on simple carboxylic acid substrates.13 In this reaction, initial ε-deprotonation resulted in the corresponding ketene 16′ (Scheme 3 below) which underwent 6π electrocyclization and aromatization followed by protection of the resulting phenol to the corresponding propionate ester. Concurrently, the TBS group on another hydroxy group was deprotected during this reaction, which led to a free hydroxy group. Subsequent protection of this free hydroxy group with propionic anhydride led to the formation of the corresponding propionate ester, ultimately yielding the tricyclic compound 17. The entirety of this reaction process required 2 days for full conversion. The phenolic propionate was then subjected to selective deprotection using tetramethylguanidine, which was followed by PIDA-mediated oxidative dearomatization.14,15 Alongside the desired diene 11, an almost equal amount of para-quinol ether 18 was also formed, which was inseparable from the diene 11. Importantly, it is essential to note that using a temperature above 0 °C leads to the predominant formation of para-quinol ether, whereas temperatures below −10 °C result in a consistent 1:
1 ratio of the two products. This observation underscores the temperature sensitivity of the reaction, with the necessity to carefully regulate the conditions to achieve the desired product.
With the mixture of diene precursor 11 and para-quinol ether 18 in hand, we performed the key Diels–Alder reaction to build the bicyclo[2.2.2]octane moiety, thereby finalizing the atisane core 10. The ethylene gas only reacted with diene 11, and compound 18 remained unreacted. Initially, the reaction was carried out at 70 bar pressure and 140 °C for a duration of 5 days. Subsequently, we conducted further experimentation to refine the reaction conditions and determined that the reaction could be completed at 40 bar pressure and 110 °C in 24 hours. This Diels–Alder reaction shows endo-selectivity and gave the product in diastereomeric ratio of 5.5:
1. Compound 10 was then subjected to a reaction with samarium iodide, which cleaved the dimethyl acetal group present at the α position to the keto group. Subsequent diastereoselective hydrogenation of the resulting product produced keto-ester compound 19. Wittig olefination of 19 and reduction of the ester group using LiAlH4, followed by DMP oxidation of the resulting hydroxy group gave us compound 9 (X-ray). Hydrolysis of the ester group in the A-ring was first attempted using various acidic and basic conditions. However, these conditions resulted in poor yields. Therefore, we opted for LiAlH4 reduction, which gave an excellent yield.
Dihydroxylation of exomethylene alkene in 9 using osmium tetroxide gave inseparable diastereomers 20 and 21 in 3:
2 ratio, respectively. Employing AD-mix-α or AD-mix-β for this dihydroxylation also yielded the same 3
:
2 ratio. The acetate protection of primary alcohols in the diastereomeric mixture facilitated the column separation of the resulting acetates 22 and 23. Hydrolysis of acetate 22 using K2CO3/MeOH resulted in the formation of (+)-16α, 17-dihydroxy-atisan-3-one (1). Highly efficient aerobic oxidation of the α-carbon to carbonyl in compound 1 was performed using potassium tert-butoxide in tert-butanol under an oxygen atmosphere, which completed the total synthesis of (+)-sapinsigin H (3).16 The characterization data of our synthetic 1 and 3 were in good agreement with those of natural 1 and 3. The biomimetic strategy was used in the synthesis of (+)-agallochaol C (2). First, a Baeyer−Villiger oxidation and then an acid-catalyzed ring opening was employed, followed by acetate deprotection. Thus, completing the first total synthesis of (+)-sapinsigin H (3) and (+)-agallochaol C (2).17
In conclusion, the first total syntheses of three atisane natural products, (+)-16α, 17-dihydroxy-atisan-3-one (1), (+)-sapinsigin H (2), and (+)-agallochaol C (3), were completed using an 18–21 step longest-linear sequence starting from Wieland-Mischer ketone. A series of biomimetic transformations were employed to achieve the synthesis of these natural products. The aromatic core in the intermediate 17 was synthesized by benzannulation aromatization, followed by PIDA-mediated oxidative dearomatization, whereas the bicyclo[2.2.2]octane moiety was constructed by Diels–Alder reaction using ethylene gas. Further studies on the syntheses of novel diterpenoids using similar biomimetic approaches are ongoing in our laboratory.
D. H. D. directed the project and wrote the manuscript. N. S. and S. J. wrote the manuscript, prepared the ESI† and conducted most of the synthetic experiments. P. S. and S. S. provided the enantiopure Wieland–Miescher ketone.
Nitin and Sakshi thank IIT Kanpur for the research fellowship. Financial support from SERB Project No. CRG/2022/002967 is gratefully acknowledged. The authors thank Miss Archana Yadav for single crystal X-ray analysis.
Footnotes |
† Electronic supplementary information (ESI) available. CCDC 2334823. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4cc01982b |
‡ These authors contributed equally. |
This journal is © The Royal Society of Chemistry 2024 |