Total synthesis of prenylated acylphloroglucinols: faberiones A, B, and E

The first total synthesis of acylphloroglucinol-based natural products faberiones A, B, and E is reported, which were isolated from Hypericum faberi . Total syntheses of faberiones A and B are accomplished in six linear steps from commercially accessible 1,3,5-trimethoxybenzene (methyl protected form of phloroglucinol) in overall yields of 31 and 33% respectively, via simple and straightforward approaches that include acylation, o-methoxy deprotection, selective iodination and tandem-Sonogashira cyclization followed by C-geranylation. Faberione E is achieved in two linear steps from acylphloroglucinol with an overall yield of 57% via geranylation followed by benzopyran formation reaction.


Introduction
In the ancient past, natural products worked as a major source of drugs, and many of the pharmaceutical compounds today are derived from natural products. 1They have been proven to be a noble source of biologically active compounds for centuries. 2][5] Phloroglucinol based natural products are a major class of secondary metabolites with various biological properties such as antimicrobial, anticancer, antiviral, antibacterial, anti-analgesic, etc. 6 They are widely present in various families like Guttiferae, Hypericaceae, Euphorbiaceae, Myrtaceae, Cannabinaceae, Aspidiaceae, Clusiaceae, Lauraceae, Fagaceae, etc. [5][6][7] Recently, Gang Xu and coworkers isolated six new acylphloroglucinol based natural products faberiones A-F (1-6, Figure1) from the whole plant of Hypericum faberi.Out of these, faberiones A-D (1-4) considered as rare styrene substituted acylphloroglucinol based natural products.Faberione B (2) was found to be cytotoxically active against the pancreatic cell line (PANC-1) with IC50 value of 6.2 µM. 8 Due to prominent biological properties and attractive skeleton of these natural products, we were prompted to explore the chemical synthesis of faberiones A, B and E. Herein, we describe efficient and straight forward approaches with good overall yields.

Results and Discussion
Retrosynthetic analysis of 1 and 2 is depicted in Scheme 1. Faberiones A and B could be achieved via Cgeranylation of 7 and it was expected to be obtained from 8 by usual demethylation of aromatic methoxy groups.Polysubstituted benzofuran 8 could be derived from 9 by tandem Sonogashira cyclization with phenylacetylene.Compound 9 could be synthesized via selective iodination of 10, which could be obtained by ortho-demethylation of 11.

Scheme 1. Retrosynthetic analysis of faberiones A and B.
As shown in Scheme 2, we began our synthetic investigation toward faberiones A and B using commercially accessible 1,3,5-trimethoxybenzene (methyl protected form of phloroglucinol).Synthesis of compound 11a/11b from 1,3,5-trimethoxybenzene via acylation in presence of isobutyryl or 2-methylbutanoyl chloride with AlCl3 in DCM was accomplished in good yield (93/95%) by following reported protocol. 9,10heme 2. Synthesis of compounds 7a and 7b.© AUTHOR(S) .12The selective iodination of 10a/10b occurred using KI and KIO3 in AcOH at room temperature to produce 9a/9b in good yield (95/98%). 13,14The polysubstituted benzofuran 8a/8b was prepared in 75/64% yield via copper catalyzed tandem-Sonogashira reaction between 9a/9b and phenylacetylene in dioxane as solvent at 125 o C (Scheme 2). 15ompound 8a/8b was demethylated in presence of BBr3 in DCM at 0 o C to room temperature to give 7a/7b in 73/77% yield. 16,17When 7b was treated with geranyl bromide in presence of K2CO3 in acetone as solvent at reflux, 18 it was observed that reaction yielded two products 2 (faberione B) and 12 (Scheme 2).The desired product 2 was obtained in 5% while O-geranylation in 75% yields respectively.They were distinguished on the basis of 1 H and 13 C NMR spectra in which geranyl-CH2 peak was observed at 3.54 ppm and 39.7 in case of 2, due to C-C connectivity.However, O-C connectivity in product 12, it was observed at 4.70 ppm and 65.7.In order to get the C-alkylated product in good yield, we optimized geranylation reaction using compound 7b with geranyl bromide to obtain C-alkylated compound as major product.When compound 7b reacted with geranyl bromide in presence of K2CO3 (1 equiv) and acetone as solvent at room temperature, both C-alkylated 2 and O-alkylated 12 products were obtained in 12 and 35% yields respectively (Table 1, entry 1).Using 2.5 equivalents of K2CO3 at room temperature, yielded 2 and 12 in 41% and 15% yields (entry 2).When the solvent was switched to THF, improvement in the formation of 2 was observed (entry 3).With an effort to improve yield of 2, other bases (LiOH, DBU and Cs2CO3) were tried but unfortunately no significant result was observed with respect to yield of 2 (entries 4-6).The notable result was observed, when NaI (1 equiv) was used with K2CO3 (2.5 equiv) in THF at room temperature, yielded compound 2 in 70% due to insitu exchange of bromide by iodide as leaving group (entry 7).Moreover, excess NaI (2.5 equiv) also tested and 2 along with 12 were obtained in 62 and 7% yields respectively (entry 8).Among the optimized conditions, entry 7 was found to be best for the selective synthesis of C-alkylated product 2. Using optimized conditions, biologically active natural products faberiones A and B were synthesized from 7a/7b in 66 and 70% yields respectively (Scheme 3).

Scheme 3. Synthesis of faberiones A and B.
Retrosynthetic analysis of 3 is depicted in Scheme 4. Faberione E could be achieved from 13 via benzopyran formation with citral.Compound 13 could be derived from 14 by the geranylation of acylated phloroglucinol 14 (Scheme 4).

Scheme 4. Retrosynthetic analysis of faberione E.
As shown in Scheme 5, we commenced our synthetic investigation toward faberione E using commercially available phloroglucinol, which was converted to acylated phloroglucinol 14 in presence of AlCl3 in 78% yield by following reported protocol. 19,20Compound 13 was prepared by the geranylation of 14 using K2CO3/NaI with geranyl bromide in THF at room temperature.Then, compound 13 was subjected for the synthesis of faberione E via benzopyran ring formation in presence of citral and EDDA at room temperature. 21,22Faberione E was obtained in overall yield of 57% (Scheme 5).
Due to interesting biological properties and attractive structures of faberiones A, B and E, we were interested in synthesizing their analogues.Here, 1a and 1b were synthesized via alkylation of 7a and 2b from 7b using optimized condition.Derivatives 3a and 3b were prepared from 14 and 14b by following benzopyran ring formation protocol (Scheme 6).

Conclusions
In conclusion, we have accomplished the total synthesis of faberiones A, B six linear steps and E over two linear steps with overall yields of 31, 33 and 57% from commercially accessible starting materials.Five analogues of faberiones A, B and E were synthesized in moderate to good yields by following standard reaction conditions.

Experimental Section
General.All reactions were performed using oven-dried glassware.Commercial grade solvents and reagents were distilled before use.The reaction progress was examined by TLC by using silica gel GF 254 on a microscopic glass slide coated with silica gel.Melting points were recorded in open capillary tubes using electrothermal melting point apparatus.Purification of products were carried out by flash chromatography using Merck silica gel with ethyl acetate and hexane solvent mixture as eluent. 1 H and 13 C NMR spectrum were recorded at ambient temperature using Bruker 400 and 600 MHz spectrometers.The samples were prepared by dissolving the compounds in CDCl3/DMSO-D6 and TMS as internal standard.Chemical shift (δ) in ppm and coupling constant (J) in Hz are reported.HRMS was recorded on an Agilent spectrometer using electrospray ionization (ESI-TOF).

Synthesis of 1a, 1b and 2b
To a stirred solution of 7a/7b (1 equiv, 0.1 mmol) in THF (2 ml) was added NaI (1 equiv, 0.1 mmol) followed by K2CO3 (2 equiv, 0.2 mmol) and stirred at room temperature.After the completion of SM (monitored by TLC), diluted by water and extracted by EtOAc (3 x 20 ml).The combined organic layers were washed by brine, dried