Enantioselective total synthesis of (‒)-lucidumone enabled by tandem prins cyclization/cycloetherification sequence

The Ganoderma meroterpenoids are a growing class of natural products with architectural complexity, and exhibit a wide range of biological activities. Here, we report an enantioselective total synthesis of the Ganoderma meroterpenoid (‒)-lucidumone. The synthetic route features several key transformations, including a) a Cu-catalyzed enantioselective silicon-tethered intramolecular Diels-Alder cycloaddition to construct the highly functionalized bicyclo[2.2.2]octane moiety; b) Brønsted acid promoted tandem O-deprotection/Prins cyclization/Cycloetherification sequence followed by oxidation to install concurrently the tetrahydrofuran and the fused indanone framework; c) Fleming-Tamao oxidation to generate the secondary hydroxyl; d) an iron-catalyzed Wacker-type oxidation of hindered vinyl group to methyl ketone.

Enantioselective total synthesis of (-)-lucidumone enabled by tandem prins cyclization/cycloetherification sequence Xian-Zhang Liao 1,2,3 , Ran Wang 1,2,3 , Xin Wang 1,2 & Guang Li 1,2 The Ganoderma meroterpenoids are a growing class of natural products with architectural complexity, and exhibit a wide range of biological activities.Here, we report an enantioselective total synthesis of the Ganoderma meroterpenoid (-)-lucidumone.The synthetic route features several key transformations, including a) a Cu-catalyzed enantioselective silicon-tethered intramolecular Diels-Alder cycloaddition to construct the highly functionalized bicyclo[2.2.2] octane moiety; b) Brønsted acid promoted tandem O-deprotection/Prins cyclization/Cycloetherification sequence followed by oxidation to install concurrently the tetrahydrofuran and the fused indanone framework; c) Fleming-Tamao oxidation to generate the secondary hydroxyl; d) an iron-catalyzed Wacker-type oxidation of hindered vinyl group to methyl ketone.

Results
With an in-depth analysis of the chemical structure of lucidumone, we envisioned that the critical tetrahydrofuran-spiro-indanone framework (E-B-A rings of the natural product), a challenging task for synthesis, could be constructed via a pivotal cascade Prins cyclization/Cycloetherification followed by oxidation 30,31 .The precursor for this key transformation could be divided into two parts, the left bicyclo[2.2.2] octane moiety (highlighted in red) and right benzene (highlighted in blue), which would be connected through the transition metalcatalyzed C7'-C3 bond formation.Owing to the high regio-and stereoselectivity of intramolecular Diels-Alder cycloaddition than the intermolecular one, the silicon-tethered intramolecular Diels-Alder reaction gives us an excellent choice for the assembly of bicyclo[2.2.2] octane moiety [32][33][34][35] .In addition to the expected high degrees of regioand stereoselectivity, the silicon-tethered intramolecular Diels-Alder reaction could also provide suitable synthetic handles for the rapid generation of the requisite secondary alcohol and methyl ketone.

Retrosynthetic analysis
With the hypothesis in mind, we proposed our retrosynthetic analysis of (-)-lucidumone (-)−1 in Fig. 2. We envisioned to access (-)-1 from hexacyclic intermediate 7 via a sequence of Fleming-Tamao oxidation, Wacker oxidation and O-demethylation.The fused indanone framework could be constructed by a key O-deprotection/Prins reaction/Cycloetherification followed by oxidation sequence from 8, which in turn could be assembled via a Suzuki coupling between boronic acid 9 and vinyl triflate 10.The latter could be traced back to 11, the product of asymmetric intramolecular Diels-Alder reaction of 12, which could be accessed from the known diene 14 36 and the easily accessible silyl acrylate imide 13.

Synthesis of chiral bicyclo[2.2.2]octane
The synthesis of 1 commenced with the preparation of 12 (Fig. 3).Following the protocol developed by Sieburth 37 , exposure of the readily available silyl acrylate imide 13 to triflic acid, followed by the addition of the known primary alcohol 14 afforded silyl ether 12 in 91% yield.The Diels-Alder cycloaddition of 12 in the presence of Et 2 AlCl (0.1 equiv) at 0 °C proceeded smoothly to give the desired cycloadduct in 90% yield as a single endo diastereoisomer.Encouraged by this observation, we turned our attention to the catalytic asymmetric silicon-tethered intramolecular Diels-Alder reaction of 12 38,39 .Following Evans's pioneering work, diverse chiral C 2 -symmetric Box ligands were used in combination with different Cu(II) salt [40][41][42] .Screening the reaction  conditions by varying the reaction temperature, the ligands, and the copper sources led to the identification of the optimized reaction condition using Cu(OTf) 2 (10 mol%) and ligand (S,S)-L1 (11 mol%) at 50 °C (see Supplementary Table 1).Under these conditions, cycloadduct 11 was isolated in 96% yield with 92% ee.Performing the reaction at 3.0 mmol in the presence of Cu(OTf) 2 (0.3 mmol), (S,S)-L1 (0.33 mmol) afforded 11 without obvious erosion of yield and enantioselectivity (95% yield, 92% ee).The ee value of 11 could be further improved to 99% after recrystallization.The absolute configuration of 11 was determined by the X-ray diffraction analysis of its derivative (vide infra, compound 17).

Synthesis of hexacyclic intermediate
With the gram-scale synthesis of chiral bicyclo[2.2.2]octane intermediate 11 in hand, the synthesis of highly functionalized hexacyclic intermediate 22 was undertaken (Fig. 4).Hydrolysis of 11 (LiOH, H 2 O 2 , THF/H 2 O v/v = 2:1, 0 °C to RT) afforded the carboxylic acid 15 in 94%  yield.On the other hand, reduction of 11 with lithium borohydride (LiBH 4 ) provided the alcohol 16 in 85% yield.We surmised that the neighboring carboxylic acid group of 15 or the hydroxy group of 16 could be used to direct the hydroboration at C7' 43,44 .Treatment of 15 with BH 3 •THF (-30 °C to RT.) followed by the addition of NaBO 3 •4H 2 O furnished the mixed diol product resulting from the concomitant reduction of the carboxylic acid.Without purification, this diol was converted to ketone 17 and its regioisomer 18 in 89% overall yield (rr = 3.4:1) via a sequence of selective O-protection and oxidation.The absolute configuration of the tricycle ketone 17 was determined by X-ray crystallographic analysis.Therefore, the successful elaboration of 17 according to our synthetic plan would afford the levorotatory target molecular (-)-lucidumone (-)-1.Notably, applying the same conditions to alcohol 16, a mixture of two regioisomeric ketones was isolated in 1:1 ratio.These results indicated that carboxylic acid is a better-directing group in the hydroboration step.
We then turned our attention to build A-B-E rings of the natural product.Deprotonation of ketone 17 with potassium bis(trimethylsilyl) amide (KHMDS) at -78 °C followed by the addition of PhNTf 2 afforded the desired vinyl triflate 10 in 94% isolated yield.The Pd-catalyzed Suzuki-Miyaura cross-coupling between 10 and the known boronic acid 9 45 proceeded smoothly to afford the functionalized tetracycle 8 in 69% yield.The one-step conversion of 8 to 22, a strategic step in our synthesis, was sought next.This efficient transformation involved a hypothetical acid-catalyzed O-deprotection/Prins cyclization/Cycloetherification sequence 30,31,[46][47][48][49][50][51][52][53] .Model reaction was attempted first before the real substrate.The precursor 20, generated through Suzuki-Miyaura cross-coupling between 10 and commercially available 2-formylphenylboronic acid pinacol ester 19, was screened in various acidic conditions for the key transformation.Gratifyingly, the desirable 21 was obtained in the presence of HCl (10 equiv) in DCM at -10 °C in 89% yield with 20:1 diastereoselectivity (X-ray of major rac-21).However, tetracycle 8 is unstable and was decomposed when treated with the aforementioned identical condition.The realization of the transformation turned out to be a challenging task.The desired product as a pair of diastereoisomers 22 could be isolated under a series of acidic conditions with the concomitant formation of Prins cyclization product 23.To minimize the generation of by-products, different Brønsted acids [TFA, HCl, p-TsOH•H 2 O, (-)-CSA] and Lewis acids [BF 3 •Et 2 O, AlCl 3 , Sc(OTf) 3 , TBSOTf, TMSOTf, etc.] in different solvents at various temperatures were screened (Fig. 5).HCl was still identified as the most suitable promotor.The optimum reaction conditions consisted of stirring a DCM solution of 8 in the presence of an excess of HCl (2 M in ethyl acetate, 10 equiv) at -78 °C for 24 h (Fig. 5, Entry 11).Under these conditions, 22 was generated as a pair of diastereoisomers in 86% yield, which could also be directly oxidized by Dess-Martin periodinane to afford the desired product 7 in a one-pot sequence in 80% overall yield (Fig. 6).The structure and absolute configuration of 7 was confirmed by X-ray crystallographic analysis.We note that the reaction temperature and time have to be carefully controlled in order to avoid the formation of by-products.
Total synthesis of (-)-lucidumone Elaboration of hexacycle 7 to (-)-lucidumone (-)-1 was accomplished as shown in Fig. 6.The Fleming-Tamao oxidation of 7 (KF, H 2 O 2 , methanol/THF, v/v = 1:1) afforded diol 26 in 91% yield 54 .It was noted that by-product 23 could also be converted to diol 26 under the sequential Dess-Martin oxidation and the Fleming-Tamao oxidation via a spontaneous deprotection/oxa-Michael addition.Dehydration of 26 underwent smoothly to give the desired product 27 (X-ray) in 50% isolated yield according to Grieco's procedure 55 .As Kawamoto and Ito mentioned 29 , the late-stage Wacker oxidation of the vinyl group 27 to methyl ketone group 28 proved to be challenging.Under classic conditions, aldehyde resulting from the anti-Markovnikov addition was formed as a major product due presumably to the steric effect 56 .We then turned our attention to the iron-catalyzed Wacker-type oxidation of olefins to ketones developed by Han's 57 and Knӧlker's 58 groups, respectively.Gratefully, applying their standard conditions to 27 [Fe(dbm) 3 , PhSiH 3 , EtOH, RT], methylketone 28 was obtained in 65% yield.Finally, Lewis acid catalyzed double O-demethylation of 28 afforded (-)-lucidumone (-)-1 in 70% isolated yield.The physical and spectroscopic data of the synthetic (-)-lucidumone (-)-1 are identical to those reported for the natural product.In this work, an enantioselective total synthesis of (-)-lucidumone (-)-1 is accomplished.Our synthetic route to this natural product features several key transformations, including bis(oxazoline)copper(II) complex catalyzed enantioselective silicon-tethered intramolecular Diels-Alder reaction to construct the multi-functionalized bicyclo[2.2.2]octane moiety, a Brønsted acid promoted tandem O-deprotection/Prins reaction/Cycloetherification followed by oxidation to install concurrently the tetrahydrofurane and the fused indanone moieties, Fleming-Tamao oxidation to afford the secondary hydroxyl, and an iron-catalyzed late-stage Wacker-type oxidation of hindered vinyl group to methyl ketone.

Methods
Unless otherwise stated, reagents were purchased at the highest commercial quality and used without further purification.Solvents were purchased in HPLC quality, degassed by purging thoroughly with nitrogen, and dried over activated molecular sieves of appropriate size.Alternatively, they were purged with argon and passed through alumina columns in a solvent purification system (Innovative Technology).The conversion was monitored by thin layer chromatography (TLC) using Merck TLC silica gel 60 F254.Compounds were visualized by UV light at 254 nm and by dipping the plates in an ethanolic vanillin/sulfuric acid solution or a 72 aqueous potassium permanganate solution followed by heating.Flash column chromatography was performed over silica gel (230−400 mesh).
NMR spectra were recorded on a Bruker 500 and 400 MHz at room temperature, Chemical shifts (δ) were reported in parts per million (ppm) relative to residual solvent peaks rounded to the nearest 0.01 for proton and 0.1 for carbon.Coupling constants (J) were reported in Hz to the nearest 0.1 Hz.Peak multiplicity was indicated as follows s (singlet), d (doublet), t (triplet), q (quartet), m (multiple), and br (broad).The attribution of peaks was done using the multiplicities and integrals of the peaks.
IR spectra were recorded in a Perkin-Elmer 1000 series FT-IR spectrometer.The spectra were reported in cm −1 .
The accurate masses were measured by the mass spectrometry service of IMM, PUMC&CAMS on an Agilent 6244 Tof-MS using electrospray ionization (ESI).