Enantioselective Synthesis of the Guaipyridine Alkaloid (+)- and (−)-Cananodine

Synthesis of both enantiomers of guaipyridine alkaloid cananodine was achieved. The stereocenter at C8 was set through an Evans alkylation, and the seven-membered carbocycle was constructed using an intramolecular Mizoroki–Heck reaction. Hydrogenation of an exomethylene set the C5 stereocenter. The optical rotation of each enantiomer matched the literature. The synthetic scheme is amenable to analogue preparation. (+)- and (−)-Rupestine G were also prepared.


■ INTRODUCTION
Cananodine (Figure 1) is a guaipyridine alkaloid isolated in small amounts from the fruit of Cananga odorata (ylang ylang) by Wu and co-workers, as reported in 2001. 1 It was initially reported to have submicromolar activity against two hepatocellular carcinoma cell lines.A more recent study has shown the bioactivity to be lower than initially reported. 2ananodine also has a modest activity against HeLa and MDA-MB-231 cell lines. 2Due to its biological activity, cananodine is the most prominent member of the guaipyridine alkaloids, which include the eponymous compound and the rupestines (Figure 1).The rupestines were isolated from the flowers and leaves of Artemisia rupestris, which is used in traditional Chinese medicine. 3The guaipyridines have a methyl group at C5 but varying substituents at C8 of the bicyclic core.
Guaipyridine alkaloids have long attracted the attention of synthetic chemists.Early studies by van der Gen 4 and Okatani 5 are best described as stereo-and regiorandom, yielding mixtures of constitutional isomers in the cyclization reaction to form the seven-membered ring.In 2006, Craig and Henry synthesized (+)-cananodine from (R)-(−)-citronellene and utilized a clever microwave-assisted decarboxylative Claisen rearrangement as the key step. 6In 2017, we reported the synthesis of all four stereoisomers of cananodine using the opening of a trisubstituted epoxide to construct the sevenmembered ring of the target. 7We subsequently synthesized (±)-cananodine, (±)-rupestine G, and (±)-rupestine D using an intramolecular Mizoroki−Heck reaction to form the sevenmembered carbocycle skeleton of the natural products. 8More recently, the Aisa group prepared (−)-cananodine and (−)-rupestine D from (S)-(+)-citronellene. 9 Finally, the Yusuf group made (±)-cananodine and separated the enantiomers using chiral HPLC. 2 Herein, we report the synthesis of (+)-and (−)-cananodine using an Evans alkylation to set the C8 stereocenter.There are a number of values given in the literature 1,2,6,9 for the optical rotation of cananodine, and our work making both enantiomers in sufficient quantities settles any dispute over optical rotation of the natural product.Making both mirror images also allows for further biological investigation of each enantiomer.

■ RESULTS AND DISCUSSION
The synthesis of (+)-cananodine (1) commenced with the alkylation 10 of oxazolidinone 4 12 with picolyl bromide 5 (prepared in 3 steps from 6-methylpyridin-3-ol) 8,11 to produce 3 in good yield and >96% diastereomeric excess (Scheme 2).We initially attempted this alkylation with the corresponding aryl triflate derivative of 5 instead of the allyl ether-protected phenol.The alkylation worked, but the purification of the product was exceedingly difficult, resulting in lower yields of pure material.Thus, we resorted to the allyl ether 5, which did not have these separation difficulties.
Despite Craig and Henry's report to the contrary on a similar oxazolidinone, 6 treatment of 3 with methoxide did not produce the methyl ester, but rather hydroxyamide 6. 13 Standard cleavage of the chiral auxiliary with basic peroxide readily produced the corresponding carboxylic acid 10,13 that was then subjected to Fischer esterification, which provided 7 in good yield and 99% enantiomeric excess, as determined by chiral GC analysis (Scheme 3).Deprotection of the allyl ether with catalytic Pd(PPh 3 ) 4 in basic methanol revealed the phenol, which was converted to the aryl triflate 2 without incident.The intramolecular Mizoroki−Heck reaction of 2 proceeded in excellent yield, provided that the Pd(PPh 3 ) 4 catalyst was washed with methanol immediately prior to the procedure to remove oxidized impurities, and provided bicyclic compound 8.
The next task was to hydrogenate the exocyclic methylene of 8. Consistent with prior results, 8 heterogeneous hydrogenation with Pd on carbon gave a 2:1 mixture of undesired (+)-rupestine G (9) and the desired intermediate 10.Utilizing Wilkinson's catalyst for the hydrogenation improved the ratio of 9 to 10 to 1:1 7 but also produced a significant amount of endocyclic alkene 11, evidenced by a resonance at 6.0 ppm (ddq, J = 6.9, 6.9, 1.6 Hz) in the 1 H NMR spectrum of the mixture. 14This isomer was resistant to reduction under one atm of hydrogen with Wilkinson's catalyst.Use of Crabtree's catalyst for the hydrogenation did not improve the diastereomeric ratio.Thus, we carried out a combination hydrogenation, first with Wilkinson's catalyst, followed by treatment with hydrogen over palladium on carbon to produce 9 ((+)-rupestine G) and 10 in essentially a 1:1 ratio in high yield.Separation of the diastereomers and exhaustive methylation of ester 10 gave (+)-cananodine (1).Chiral GC analysis of the product showed a 99% ee, and the optical  2 Using the procedures optimized for the preparation of (+)-cananodine, the synthesis of (−)-cananodine was straightforward (Figure 2).Initiated by alkylation of oxazolidinone ent-4 15 with picolyl bromide 5, and following the steps outlined in Schemes 2 and 3 provided (−)-cananodine (ent-1) in 99% ee by chiral GC analysis and an optical rotation that matched that previously reported: [α] D = −11.6 (c = 0.44, CHCl 3 ); lit 2 [α] D = −10.0,(c = 0.06, CHCl 3 ).

■ CONCLUSIONS
To summarize, we have accomplished the synthesis of both enantiomers of cananodine in nine steps and a 13% overall yield for (+)-cananodine (1) and a 9% yield for (−)-cananodine (ent-1).Key steps included a highly diastereoselective alkylation of the Evans auxiliary with picolyl bromide 5 and an intramolecular Mizoroki−Heck reaction to prepare the sevenmembered ring of the target molecules.This efficient and scalable synthesis will enable further biological studies of cananodine and should facilitate the synthesis of structural analogues for biological testing.

■ EXPERIMENTAL SECTION
All glassware was oven-dried and all reactions using airsensitive materials were carried out under an argon atmosphere.Also, when indicated, dry solvent from the Inert PureSolv solvent purification system (Et 2 O, THF, CH 2 Cl 2 , CH 3 CN) was used.All solvents that were not from the purification system were HPLC grade and used without further purification, with the exception of MeOH, which was dried over 3A molecular sieves (8−12 mesh, Acros Organics) and CHCl 3 , which was flushed through basic alumina (Sorbtech, pH = 10).Celite (EMD Chemicals) containing diatomaceous earth, quartz, and cristobalite was not acid-washed during manufacturing.
Each reaction involving extractive workup with the organic solvents and aqueous solutions detailed was washed with saturated NaCl (brine), dried over Na 2 SO 4 , and concentrated using rotary evaporation.All flash column chromatography was conducted using silica gel (230−400 mesh, Silicycle) handpacked with varying ratios of hexanes and ethyl acetate (hexanes/EtOAc) unless otherwise indicated.Silica G TLC plates (Sorbtech, polyester backed, thickness 200 μM, fluorescence UV 254 ) were used for monitoring the reaction progress and flash chromatography.
Infrared spectra (IR) were collected on a ThermoiS10 FT-IR spectrometer equipped with a single bounce diamond ATR.All tabulated signals are reported in cm −1 .Spectra acquired as "neat" were placed on the diamond ATR stage as a pure solid or liquid or occasionally as films from pure compounds dissolved in CDCl 3 or CH 2 Cl 2 and then evaporated.
Chiral gas chromatography (GC) was performed on a Varian CP3800 GC using an Agilent Cyclosil-B 30 m × 0.25 mm ID × 0.25 μm chiral column.All chiral samples were characterized using Method A. Method A: Hold 5 min at 60 °C, ramp 5 °C/min to 240 °C, hold 5 min.
Specific rotation was measured by using a Rudolph Digital Automatic polarimeter with a 10 cm quartz cell at room temperature (wavelength = 589 nm).
Detailed experimental procedures, characterization data, and copies of 1 H and 13 C{ 1 H} NMR spectra (PDF) ■ AUTHOR INFORMATION