A Total Synthesis of Bifidenone - The Journal of Organic Chemistry

Mar 29, 2017 - The first total synthesis of bifidenone, a novel natural tubulin polymerization inhibitor, has been achieved in 12 steps starting from ...
0 downloads 25 Views 1MB Size
Download PDF
Article pubs.acs.org/joc

A Total Synthesis of Bifidenone Zhongping Huang,*,† Russell B. Williams,‡ Mark O’Neil-Johnson,‡ Gary R. Eldridge,‡ John E. Mangette,† and Courtney M. Starks‡ †

Albany Molecular Research Inc., 1001 Main Street, Buffalo, New York 14203, United States Sequoia Sciences, Inc., 1912 Innerbelt Business Center Drive, St. Louis, Missouri 63114, United States

‡

S Supporting Information *

ABSTRACT: The first total synthesis of bifidenone, a novel natural tubulin polymerization inhibitor, has been achieved in 12 steps starting from commercially available 1,4dioxaspiro[4.5]decan-8-one. The synthesis includes a newly developed method to generate the dihydrobenzodioxolone core by palladium-catalyzed aerobic dehydrogenation. The three stereocenters were installed with an AD-mix-β dihydroxylation step followed by a late-stage palladiumcatalyzed decarboxylation−allylation procedure. The absolute stereochemistry of 3 was determined via 13a by single-crystal X-ray analysis.

■

thesis of tricycloillicinone.2 Unfortunately, for the route to prepare bifidenone, the attempt to convert A or B to C using these conditions resulted in the generation of only small amounts of elimination byproducts (Scheme 1).

INTRODUCTION Bifidenone (Figure 1) is a natural product that was first identified from a plant of the genus Beilschmiedia that was

Scheme 1. Initial Strategies for Formation of the Dihydrobenzodioxolone Ring System in Bifidenone

Figure 1. Structure of bifidenone.

collected in the Kwassa region of Gabon.1 It has submicromolar antiproliferation activity against a range of human cancer cell lines, making it an attractive candidate for development as a cancer drug. Unfortunately, bifidenone was found in extremely low quantities in the plant, so isolating enough compound for further in vivo and in vitro testing would have been impractical. Furthermore, only 79 μg of bifidenone has been isolated to date, and all of it has been used in biological screens. Thus, it was essential that any further studies would be pursued via total synthesis of bifidenone. The synthesis of bifidenone was made difficult by its unique structural features, in particular, the dihydrobenzodioxolone ring system and the sterically crowded cis configured allyl and arylpropyl substituents. To date, there have been only a few reports describing the preparation of the dihydrobenzodioxolone ring system. Terashima and Furuya used paraformaldehyde and catalytic dl-camphorsulfonic acid in cyclohexane to generate the ring system from (R)-3-ethoxy-6-hydroxy-6-(3(trimethylsilyl)prop-2-yn-1-yl)cyclohex-2-enone in the syn© 2017 American Chemical Society

The Lewis acid methylaluminum bis(4-bromo-2,6-di-tertbutylphenoxide) (MABR)-catalyzed3 or photoinduced rearrangement of an alkoxy benzodioxolone, as reported by Danishefsky and co-workers,4 also failed to provide the desired E needed for bifidenone (Scheme 2). After an extensive investigation, it was discovered that palladium-catalyzed aerobic dehydrogenation5 could effectively Received: January 25, 2017 Published: March 29, 2017 4235

DOI: 10.1021/acs.joc.7b00202 J. Org. Chem. 2017, 82, 4235−4241

Article

The Journal of Organic Chemistry Scheme 2. Initial Strategies for Formation of the Dihydrobenzodioxolone Ring System by MABR or UV Irradiation

generate the dihydrobenzodioxolone ring system from 5 (Scheme 3), using a palladium(II) catalyst and 1 atm of

Scheme 4. Synthesis of Intermediate 7

Scheme 3. Retrosynthetic Analysis of Bifidenone

enantiomeric purity of compound 4a. The dihydroxylation was slow. In our experiments, with the addition of toluene and methanesulfonamide and vigorous stirring, the conversion, diastereoselectivity, and enantiomeric purity were significantly improved. Methylenedioxy ring formation starting with a mixture of 6a and 6b gave 5a and 5b in 75% yield using paraformaladehyde and catalytic p-toluenesulfonic acid in dichloromethane (Scheme 6). The most challenging aspect of the synthesis was generating the dihydrobenzodioxolone ring system. After the common dehydrogenation protocols 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ),9a 2-iodoxybenzoic acid (IBX),9b and PhSO2SPh/m-CPBA9c failed to provide 4, we were pleased to observe that palladium-catalyzed aerobic dehydrogenation could generate 4 at 80 °C.10 The transformation was regioselective, affording compound 4 as the sole dehydrogenation product. Reaction optimization indicated that DMSO was the best solvent among those tested (DMSO, DMF, 1,4-dioxane) and that the ligand 4,5-diazafluoren-9-one could improve the yield and reduce decomposition. While the reaction was slow below 60 °C, the rate of decomposition

oxygen at 80 °C. The three stereocenters were generated with an AD-mix-β dihydroxylation step followed by a late-stage palladium-catalyzed decarboxylation−allylation procedure. A retrosynthetic analysis of bifidenone is illustrated in Scheme 3.

■

RESULTS AND DISCUSSION The synthesis started with reaction of commercially available 1,4-dioxaspiro[4.5]decan-8-one with isopropenylmagnesium bromide to provide 8 in quantitative yield (Scheme 4). Subsequent Heck reaction6 with 5-bromo-2-methoxyphenol, catalyzed by a palladium acetate/dicyclohexylamine catalyst system, afforded 9 in 63% yield. Hydrogenation of the double bond of 9 with palladium hydroxide in methanol provided 10 in quantitative yield. Benzyl protection of 10 gave 11 (67%) and was followed by dehydration with thionyl chloride in pyridine7 below 5 °C to afford 7 in 92% yield. Next, dihydroxylation with AD-mix-β8 generated the desired stereocenters at the C4 and C8 positions, giving a 2.8:1 ratio of 6a:6b based on 1H NMR (Scheme 5). The enantiomeric purity of 6a was 76% based on the subsequent determination of the 4236

DOI: 10.1021/acs.joc.7b00202 J. Org. Chem. 2017, 82, 4235−4241

Article

The Journal of Organic Chemistry Scheme 5. Chiral Center Formation at the C4 and C8 Positions with AD-mix-β

Scheme 6. Preparation of the Key Intermediate 2

Scheme 7. Completion of the Synthesis of Bifidenone

significantly increased over 80 °C. The best conditions employed palladium acetate (0.5 equiv) and 4,5-diazafluoren9-one (0.5 equiv) under 1 atm of oxygen at 80 °C for 7 h to afford 4 in 55% yield as a mixture of diastereomers. Enantiomer 4a was isolated from 4 by preparative HPLC using a chiral stationary phase (Chart S1). Subsequent hydrogenolysis to

remove the benzyl group provided 3, and methylation (92% yield) provided 2. In an initial attempt to prepare the final product, direct allylation of 2 generated only the trans-isomer 12 (Scheme 7), presumably because of unfavorable steric interactions in formation of the desired cis product. Instead, the cis-isomer was prepared via allylic ester 1 by palladium-catalyzed 4237

DOI: 10.1021/acs.joc.7b00202 J. Org. Chem. 2017, 82, 4235−4241

Article

The Journal of Organic Chemistry decarboxylation−allylation.11 Catalytic tetrakis(triphenylphosphine)palladium(0) induced decarboxylation and subsequent intramolecular allylation to generate a 78:22 ratio of cisisomer to trans-isomer in 78% yield. The major product was isolated, and its NMR spectra matched those previously reported for the isolated natural product.1 The cis relationship of the allyl and arypropyl was previously established by Williams et al. via ROESY spectroscopy which showed enhancement between the C8 methine proton and one of the C17 methylene protons.1 Because of the limited amount of material, the optical rotation of plant-derived bifidenone was not obtained. However, it was possible to measure the optical rotation of both enantiomers produced via synthesis and compare the observed biological activities to those of the natural product (Table 1). The potency of the (+)-enantiomer was equivalent

(Scheme 8). Crystals of 13a were grown from ethanol and analyzed by X-ray diffraction to allow assignment of the C4 and C8 stereocenters as R and S, respectively. This information taken together with the aforementioned ROESY data firmly established the absolute configurations of the three stereocenters of bifidenone.

■

CONCLUSION We have reported the first total synthesis of bifidenone in 12 steps starting from 1,4-dioxaspiro[4.5]decan-8-one. Particularly noteworthy are the efficient method to generate the dihydrobenzodioxolone core by palladium-catalyzed aerobic dehydrogenation and the palladium-catalyzed decarboxylation− allylation to generate the cis-isomer. The absolute stereochemistry of intermediate 3 was determined by a single-crystal X-ray analysis of 13a. This synthesis has supported further biological evaluations of bifidenone that were used to guide decisions regarding further development. It also paved the way for medicinal chemistry efforts which will be presented in a forthcoming publication.

Table 1. Optical Rotation and Antiproliferation Activity of Bifidenone and Synthetic Compounds entry

compound

1 2

bifidenone synthetic (+)-enantiomera synthetic (−)-enantiomerb

3

optical rotation

activity against NCI-H460 cancer cell line (IC50, μM)

− (+)-200

0.26 0.23

(−)-140

1.8

■

EXPERIMENTAL SECTION

General Experimental Procedures. All reactions were conducted under an inert nitrogen atmosphere with dry solvents unless otherwise noted. Reactions were monitored by TLC. Solvents and chemicals were purchased from commercial suppliers and used as received without further purification. All new compounds were characterized by 1H NMR, 13C NMR, and HRMS. Copies of the 1H NMR and 13C NMR spectra are included in the Supporting Information. 1H NMR spectra were acquired on a Bruker AV 500 or 600 MHz spectrometer equipped with a Bruker BioSpin TCI 1.7 mm MicroCryoProbe, and chemical shifts were recorded relative to protiated solvents (SiMe4 in CDCl3 or CD3OD: δ 0.00 ppm). 13C NMR spectra were obtained at 125 MHz. Chemical shifts were recorded relative to protiated solvents (CHCl3 in CDCl3: δ 77.0 ppm or CD3OD in CD3OD: δ 49.2 ppm). Optical rotations were measured on PerkinElmer 241 polarimeter equipped with sodium vapor lamp at 589 nm, and sample concentrations are denoted as c. High-resolution mass spectrometry data were obtained by high-resolution electrospray

a

The enantiomeric excess (ee) of (+)-enantiomer is 98%; c = 1.2, MeOH. bThe ee of (−)-enantiomer is 82%; c = 0.5, MeOH.

to that of the natural product, while the (−)-enantiomer was found to be much less active. Thus, bifidenone was deduced to be the (+)-enantiomer. Because bifidenone is an oily compound, crystals could not be grown for single-crystal X-ray assignment of absolute stereochemistry. Instead, stereochemistry of the C4 and C8 centers was determined by X-ray analysis after derivatization of the intermediate 3. A sample of 3 was converted to derivative 13a in 92% yield by reaction with (1S)-(−) camphanic chloride Scheme 8. Absolute Stereochemistry of 3 Assigned by 13a

4238

DOI: 10.1021/acs.joc.7b00202 J. Org. Chem. 2017, 82, 4235−4241

Article

The Journal of Organic Chemistry

(silica gel, hexanes to 40% EtOAc/hexanes, gradient elution) to afford 11 as an off-white solid (7.5 g, 67%). Mp: 97−99 °C. 1 H NMR (500 MHz, CDCl3): δH 7.44 (d, J = 7.0 Hz, 2H), 7.37 (t, J = 7.0 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 10.5 Hz, 1H), 6.68 (s, 1H), 5.13 (s, 2H), 3.99−3.93 (m, 4H), 3.86 (s, 3H), 2.97 (dd, J = 13.5, 3.0 Hz, 1H), 2.08 (t, J = 11.0 Hz, 1H), 1.95−1.91 (m, 2H), 1.80−1.75 (m, 2H), 1.66−1.62 (m, 5H), 1.05 (s, 1H), 0.75 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δC 147.0, 146.9, 136.4, 133.4, 127.5, 126.8, 126.5, 120.8, 114.7, 110.9, 107.9, 71.7, 70.2, 63.3, 63.2, 55.2, 44.7, 35.9, 31.5, 30.4, 29.5, 29.4, 12.5. HRMS (ESI) m/z: [M + NH4+]+ calcd for C25H36O5N, 430.2593; found, 430.2578. 8-(1-(3-(Benzyloxy)-4-methoxyphenyl)propan-2-yl)-1,4dioxaspiro[4.5]dec-7-ene (7). To a solution of 11 (6.2 g, 15.0 mmol) in pyridine (40 mL) was added thionyl chloride (2.1 mL, 30.0 mmol, 2 equiv) below 5 °C. After complete addition, stirring was continued at 5 °C for 2 h. After this time, pyridine was removed under reduced pressure, and the residue obtained was diluted with ethyl acetate (200 mL) and water (40 mL). The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo to dryness. The crude product was purified by chromatography (silica gel, hexanes to 30% EtOAc/hexanes, gradient elution) to afford 7 as a brown oil (5.4 g, 92%). 1 H NMR (500 MHz, CDCl3): δH 7.44 (d, J = 7.0 Hz, 2H), 7.36 (t, J = 7.0 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.68−6.66 (m, 1H), 5.20 (s, 1H), 5.13 (s, 2H), 3.96 (s, 4H), 3.86 (s, 3H), 2.68 (dd, J = 13.5, 6.0 Hz, 1H), 2.38−2.34 (m, 2H), 2.25−2.17 (m, 4H), 1.74−1.67 (m, 2H), 0.91 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δC 147.1, 147.0, 140.4, 136.7, 133.2, 127.8, 126.7, 126.6, 121.0, 116.9, 114.7, 111.1, 107.4, 70.3, 63.6, 55.3, 41.8, 40.7, 35.3, 30.6, 25.1, 18.1, 17.0. HRMS (ESI) m/z: [M + H]+ calcd for C25H31O4, 395.2222; found, 395.2207. (7R,8R)-8-(1-(3-(Benzyloxy)-4-methoxyphenyl)propan-2-yl)1,4-dioxaspiro[4.5]decane-7,8-diol (6). A mixture of AD-mix-β (21.2 g) in t-BuOH (75 mL) and H2O (75 mL) was stirred in an ice bath for 1 h. A solution of 7 (5.4 g, 13.7 mmol) in toluene (15 mL) was added, followed by methanesulfonamide (1.3 g, 13.7 mmol, 1 equiv). The reaction mixture was vigorously stirred at room temperature for 11 days. After this time, MTBE (250 mL) was added. The layers were separated, and the organic phase was washed with saturated Na2S2O3 and brine, dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by chromatography (silica gel, hexanes to 60% EtOAc/ hexanes, gradient elution) to afford the mixture of diastereomers 6 as a brown oil [3.2 g, 92% based on the recovered starting material (2.2 g)]. [α]25D = −2.7 (c 0.77, MeOH). 1 H NMR (500 MHz, CD3OD): δH 7.44 (d, J = 7.0 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 6.87−6.85 (m, 2H), 6.75− 6.73 (m, 1H), 5.08 (s, 2H), 3.97−3.91 (m, 4H), 3.81 (s, 3H), 3.09 (d, J = 11.5 Hz, 0.26H), 2.88 (dd, J = 13.0, 3.0 Hz, 0.74H), 2.21−2.05 (m, 1H), 2.04−1.98 (m, 2H), 1.84−1.79 (m, 2H), 1.61−1.51 (m, 3H), 0.74 (d, J = 7.0 Hz, 2.2H), 0.71 (d, J = 7.0 Hz, 0.8H). 13C NMR (125 MHz, CD3OD): δC 149.4, 138.9, 136.9, 136.2, 129.4, 128.9, 123.4, 117.2, 113.6, 110.3, 76.1, 75.8, 70.3, 65.4, 56.8, 42.6, 41.9, 40.4, 40.1, 38.6, 37.3, 30.6, 26.8, 26.0, 14.2, 13.1. HRMS (ESI) m/z: [M + NH4+]+ calcd for C25H36O6N, 446.2543; found, 446.2563. (3aR,7aR)-7a-(1-(3-(Benzyloxy)-4-methoxyphenyl)propan-2yl)tetrahydrobenzo[d][1,3]dioxol-5(6H)-one (5). To a solution of 6 (1.8 g, 4.20 mmol) and paraformaldehyde (3.8 g, 126 mmol, 30 equiv) in methylene chloride (150 mL) was added p-toluenesulfonic acid monohydrate (80 mg, 0.42 mmol, 0.1 equiv) at room temperature, and the mixture was stirred at room temperature for 24 h. After this time, the excess of paraformaldehyde was removed by filtration and washed with methylene chloride. The filtrate was concentrated to dryness, and the crude product was purified by chromatography (silica gel, hexanes to 40% EtOAc/hexanes, gradient elution) to afford a mixture of diastereomers 5 as a colorless oil (1.2 g, 75%). [α]25D = +53.4 (c 0.4, MeOH). 1 H NMR (500 MHz, CD3OD): δH 7.44 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.0 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H),

ionization mass spectrometry using an LCT time-of-flight mass spectrometer with an electrospray interface (Waters). Enantiopurity was assessed by chiral phase high-performance liquid chromatography. Chiral analysis and preparative HPLC isolations were performed on Chiralpak AD (4.6 × 250 mm, 5 μm, flow 1.0 mL/min, detection UV 254 nm) or Chiralpak AD (50 × 250 mm, 10 μm, flow 100 mL/min, detection UV 254 nm), respectively. 8-(Prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (8). To a solution of isopropenylmagnesium bromide (0.5 M in THF, 1.8 L, 0.90 mol, 1.3 equiv) was added a solution of 1,4-dioxaspiro[4.5]decan8-one (100 g, 0.64 mol) in THF (200 mL) at a rate to maintain the reaction temperature below 5 °C. After complete addition, the reaction mixture was stirred for 2 h. After this time, saturated ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (2 L). The organic phase was washed with brine (300 mL, ×2), dried over MgSO4, and concentrated in vacuo to afford 8 as a brown solid (126 g, >99%). The product was used without further purification. Mp: 46−48 °C. 1 H NMR (500 MHz, CDCl3): δH 5.05 (s, 1H), 4.84 (s, 1H), 3.99− 3.93 (m, 4H), 2.02−1.93 (m, 4H), 1.82 (s, 3H), 1.64−1.62 (m, 4H), 1.16 (s, OH). 13C NMR (125 MHz, CDCl3): δC 151.3, 109.5, 108.6, 72.9, 64.3, 33.6, 30.5, 19.1. HRMS (ESI) m/z: [M − H2O + H]+ calcd for C11H17O2, 181.1228; found, 181.1224. (E)-8-(1-(3-Hydroxy-4-methoxyphenyl)prop-1-en-2-yl)-1,4dioxaspiro[4.5]decan-8-ol (9). A mixture of 8 (500 mg, 2.52 mmol), 5-bromo-2-methoxyphenol (769 mg, 3.78 mmol, 1.5 equiv), Pd(OAc)2 (112 mg, 0.50 mmol, 0.2 equiv), and dicyclohexylamine (777 mg, 4.28 mmol, 1.7 equiv) in 1,4-dioxane (12 mL) and water (2.4 mL) was heated at reflux for 24 h. After this time, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (300 mL) and brine (100 mL). The solids were removed by filtration, and the filter cake was washed with ethyl acetate. The filtrate was washed with brine, dried over MgSO4, and concentrated in vacuo to dryness. The crude product was purified by chromatography (silica gel, hexanes to 30% EtOAc/hexanes, gradient elution) to afford 9 as an off-white solid (510 mg, 63%). Mp: 148−150 °C. 1 H NMR (500 MHz, CDCl3): δH 6.85 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.74 (dd, J = 8.5, 2.0 Hz, 1H), 6.60 (s, 1H), 5.55 (s, 1H), 4.00−3.94 (m, 4H), 3.89 (s, 3H), 2.06−2.00 (m, 4H), 1.90 (s, 3H), 1.70−1.65 (m, 4H), 1.20 (s, 1H). 13C NMR (125 MHz, CDCl3): δC 145.1, 145.0, 143.1, 131.8, 122.9, 121.1, 110.3, 108.6, 73.8, 64.3, 64.2, 56.0, 33.6, 30.6, 14.5. HRMS (ESI) m/z: [M + NH4]+ calcd for C18H28O5N, 338.1967; found, 338.1963. 8-(1-(3-Hydroxy-4-methoxyphenyl)propan-2-yl)-1,4dioxaspiro[4.5]decan-8-ol (10). To a solution of 9 (460 mg, 1.12 mmol) in MeOH (80 mL) was added Pd(OH)2/C (20 wt %, 80 mg), and the mixture was stirred under 1 atm of hydrogen for 1.5 h. After this time, the reaction mixture was filtered through a pad of diatomaceous earth, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to afford 10 as an off-white solid (360 mg, >99%). Mp: 128−130 °C. 1 H NMR (500 MHz, CDCl3): δH 6.76 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.64 (dd, J = 8.0, 2.0 Hz, 1H), 5.53 (s, 1H), 3.99− 3.93 (m, 4H), 3.86 (s, 3H), 2.99 (dd, J = 13.5, 3.0 Hz, 1H), 2.11 (t, J = 11.0 Hz, 1H), 1.96−1.94 (m, 2H), 1.81−1.78 (m, 2H), 1.70−1.62 (m, 5H), 1.07 (s, 1H), 0.83 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δC 145.4, 144.7, 135.2, 120.5, 115.2, 110.5, 108.8, 72.7, 64.3, 64.2, 56.0, 45.6, 36.8, 32.4, 31.4, 30.4, 30.3, 13.5. HRMS (ESI) m/z: [M + NH4+]+ calcd for C18H30O5N, 340.2124; found, 340.2137. 8-(1-(3-(Benzyloxy)-4-methoxyphenyl)propan-2-yl)-1,4dioxaspiro[4.5]decan-8-ol (11). To a mixture of 10 (8.8 g, 27.3 mmol) and K2CO3 (5.1 g, 37.2 mmol, 1.4 equiv) in acetone (160 mL) was added benzyl bromide (3.2 mL, 27.2 mmol, 1.0 equiv) at room temperature, and the mixture was stirred for 48 h. After this time, the reaction mixture was concentrated to remove acetone under reduced pressure. The residue obtained was diluted with ethyl acetate (300 mL) and water (50 mL). The layers were separated, and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo to dryness. The crude product was purified by chromatography 4239

DOI: 10.1021/acs.joc.7b00202 J. Org. Chem. 2017, 82, 4235−4241

Article

The Journal of Organic Chemistry

113.9, 112.9, 101.8, 100.0, 86.4, 56.3, 56.2, 40.2, 37.5, 34.1, 30.9, 15.4. HRMS (ESI) m/z: [M + Na]+ calcd for C18H22O5Na, 341.1365; found, 341.1354. (3aR,5R)-Allyl 3a-((S)-1-(3,4-dimethoxyphenyl)propan-2-yl)6-oxo-3a,4,5,6-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (1). To a solution of 2 (82 mg, 0.25 mmol) in THF (8 mL) was added LiHMDS (1.0 M in THF, 0.39 mmol, 1.5 equiv) at −78 °C, and the reaction mixture was stirred for 30 min. Allyl cyanoformate (43 mg, 0.38 mmol, 1.5 equiv) was added, and the reaction mixture was allowed to warm to 0 °C over 2 h. After this time, H2O (0.1 mL) and EtOAc (50 mL) were added. The organic phase was washed with brine, dried over MgSO4, and concentrated to dryness under reduced pressure. The crude product was purified by chromatography (silica gel, hexanes to 40% EtOAc/hexanes, gradient elution) to afford 1 as a brown oil (95 mg, 95%). [α]25D = +239.6° (c 0.2, MeOH). 1 H NMR (500 MHz, CD3OD): δH 6.88−6.85 (m, 2H), 6.78 (dd, J = 8.0, 2.0 Hz, 1H), 5.94−5.90 (m, 1H), 5.73 (s, 1H), 5.67 (s, 1H), 5.50 (s, 1H), 5.35 (dd, J = 14.0, 3.0 Hz, 1H), 5.24 (dd, J = 10.5, 1.5 Hz, 1H), 4.63 (d, J = 2.5 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.60 (dd, J = 12.5, 5.0 Hz, 1H), 3.03 (dd, J = 14.0, 5.0 Hz, 1H), 2.73 (dd, J = 12.5, 5.0 Hz, 1H), 2.55 (dd, J = 13.5, 9.0 Hz, 1H), 2.30−2.28 (m, 1H), 2.27 (t, J = 12.5 Hz, 1H), 0.98 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CD3OD): δC 195.0, 179.5, 171.5, 150.6, 149.2, 134.3, 133.3, 122.6, 118.7, 114.1, 113.3, 102.6, 99.9, 86.2, 67.1, 56.6, 52.0, 41.2, 39.0, 35.2, 16.2. HRMS (ESI) m/z: [M + H]+ calcd for C22H27O7, 403.1757, found, 403.1776. (6S,7aR)-6-Allyl-7a-((S)-1-(3,4-dimethoxyphenyl)propan-2yl)-7,7a-dihydrobenzo[d][1,3]dioxol-5(6H)-one (Bifidenone). To a solution of 1 (92 mg, 0.23 mmol) in DMF (3 mL) was added Pd(PPh3)4 (27 mg, 0.023 mmol), and the reaction mixture was stirred for 2 h. After this time, ethyl acetate (50 mL) was added, and the mixture was washed with brine, dried over MgSO4, and concentrated to dryness under reduced pressure. The crude product was purified by chromatography (silica gel, hexanes to 40% EtOAc/hexanes, gradient elution) to afford bifidenone as a colorless oil (50 mg, 60%). [α]25D = +200° (c 1.2, MeOH). 1 H NMR (600 MHz, CD3OD): δH 6.89 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.74 (dd, J = 8.0, 2.0 Hz, 1H), 5.94−5.85 (m, 1H), 5.68 (s, 1H), 5.62 (s, 1H), 5.50 (s, 1H), 5.18−5.14 (m, 2H), 3.81 (s, 6H), 3.11 (dd, J = 14.0, 4.0 Hz, 1H), 2.90−2.87 (m, 1H), 2.70 (d, J = 14.0 Hz, 1H), 2.63 (m, 1H), 2.44 (dd, J = 14.0, 11.0 Hz, 1H), 2.26− 2.24 (m, 1H), 2.13 (dd, J = 14.0, 10.0 Hz, 1H), 2.00−1.97 (m, 1H), 0.86 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CD3OD): δC 201.4, 178.1, 151.0, 149.4, 138.0, 134.1, 121.9, 117.0, 114.5, 112.9, 102.2, 98.9, 86.3, 56.0, 44.0, 43.1, 37.1, 36.3, 31.8, 14.6. HRMS (ESI) m/z: [M + H]+ calcd for C21H27O5, 359.1858; found, 359.1862. (1S,4R)-2-Methoxy-5-((S)-2-((R)-6-oxo-3a,4,5,6-tetrahydrobenzo[d][1,3]dioxol-3a-yl)propyl)phenyl 4,7,7-trimethyl-3oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate (13a). To a solution of 3 (40 mg, 0.13 mmol) and pyridine (0.032 mL, 0.39 mmol, 3 equiv) in methylene chloride (1 mL) was added (1S)(−)-camphanic chloride (35 mg, 0.16 mmol), and the reaction mixture was stirred at room temperature for 12 h. After this time, volatiles were removed under reduced pressure, and the crude product was purified by chromatography (silica gel, hexanes to 30% EtOAc/hexanes, gradient elution) to afford 13a as a white solid (57 mg, 92%). The product (57 mg) was recrystallized from ethanol (2 mL) to afford the crystalline product. [α]25D = +95.2° (c 0.1, MeOH). Mp: 172−174 °C. 1 H NMR (500 MHz, CD3OD): δH 7.15 (dd, J = 8.5, 2.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 5.69 (s, 1H), 5.63 (s, 1H), 5.45 (s, 1H), 3.81 (s, 3H), 3.06 (dd, J = 14.0, 4.5 Hz, 1H), 2.65−2.46 (m, 5H), 2.27−2.22 (m, 1H), 2.15−2.08 (m, 2H), 2.03− 2.00 (m, 1H), 1.70−1.68 (m, 1H), 1.25 (s, 3H), 1.22 (s, 3H), 1.09 (s, 3H), 0.95 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CD3OD): δC 197.4, 177.9, 176.2, 165.4, 149.1, 138.9, 132.6, 127.6, 123.0, 112.5, 100.4, 100.2, 91.1, 85.1, 55.8, 54.9, 54.6, 39.4, 36.4, 33.4, 30.9, 30.2, 29.0, 16.7, 16.6, 15.2, 9.8. HRMS (ESI) m/z: [M + H]+ calcd for C27H33O8, 485.2175; found, 485.2164.

6.82−6.74 (m, 2H), 5.10 (s, 2H), 5.08 (s, 0.3H), 5.04 (s, 0.7H), 4.79 (s, 0.3H), 4.75 (s, 0.7H), 4.33 (t, J = 3.0 Hz, 0.7H), 4.18 (t, J = 3.0 Hz, 0.3H), 3.82 (s, 3H), 3.12 (dd, J = 13.0, 2.5 Hz, 0.3H), 2.78 (dd, J = 13.5, 3.0 Hz, 0.7H), 2.67−2.64 (m, 2H), 2.42−2.38 (m, 1H), 2.26− 2.19 (m, 2H), 2.00−1.93 (m, 3H), 0.86 (d, J = 7.0 Hz, 2.1H), 0.77 (d, J = 7.0 Hz, 0.9H). 13C NMR (125 MHz, CDCl3): δC 212.8, 149.7, 149.3, 138.9, 135.2, 134.6, 129.4, 128.9, 128.8, 123.3, 117.4, 113.6, 93.6, 93.4, 83.7, 79.6, 79.3, 72.4, 56.7, 44.0, 43.9, 43.2, 43.0, 38.3, 37.8, 34.7, 26.5, 25.7, 14.3, 13.5. HRMS (ESI) m/z: [M + NH4+]+ calcd for C24H32O5N, 414.2280; found, 414.2260. (R)-7a-((S)-1-(3-(Benzyloxy)-4-methoxyphenyl)propan-2-yl)7,7a-dihydrobenzo[d][1,3]dioxol-5(6H)-one (4a). A mixture of 5 (1.1 g, 2.77 mmol), Pd(OAc)2 (312 mg, 1.38 mmol, 0.5 equiv), and 4,5-diazafluoren-9-one (251 mg, 1.38 mmol, 0.5 equiv) in DMSO (36 mL) was heated at 80 °C under oxygen atmosphere for 7 h. After this time, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (300 mL). The organic phase was washed with brine, dried over MgSO4, and concentrated to dryness under reduced pressure. The crude product was purified by chromatography (silica gel, hexanes to 30% EtOAc/hexanes, gradient elution) to afford a mixture of diastereomers 4a and 4b as a white solid (600 mg, 55%). The diastereomers were separated by a Chiralpak AD column (50 × 250 mm) eluted with 15% EtOH/heptane to afford the desired enantiomer (+)-4a (300 mg) as a white solid, opposite enantiomer (−)-4a (40 mg), diastereomer (+)-4b (55 mg), and opposite diastereomer (−)-4b (25 mg). 4a: [α]25D = +149.3 (c 0.3, EtOH). Mp: 96−98 °C. 1 H NMR (500 MHz, CD3OD): δH 7.41 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.0 Hz, 2H), 7.28 (t, J = 6.0 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.75 (s, 1H), 6.74 (d, J = 6.0 Hz, 1H), 5.65 (s, 1H), 5.61 (s, 1H), 5.43 (s, 1H), 5.11 (s, 2H), 3.82 (s, 3H), 2.96 (dd, J = 13.5, 4.0 Hz, 1H), 2.55− 2.51 (m, 1H), 2.42−2.36 (m, 3H), 2.08−2.07 (m, 1H), 1.99−1.94 (m, 1H), 0.82 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CD3OD): δC 201.0, 179.8, 149.9, 149.2, 138.8, 134.3, 129.5, 128.9, 128.7, 123.3, 117.3, 113.6, 102.2, 100.2, 86.7, 72.2, 56.6, 40.7, 37.7, 34.4, 31.3, 15.6. HRMS (ESI) m/z: [M + H]+ calcd for C24H27O5, 395.1877; found, 395.1872. (R)-7a-((S)-1-(3-Hydroxy-4-methoxyphenyl)propan-2-yl)7,7a-dihydrobenzo[d][1,3]dioxol-5(6H)-one (3). A mixture of 4a (230 mg, 0.58 mmol) and Pd(OH)2/C (20% on carbon, 46 mg) in ethyl acetate (10 mL) was stirred under 1 atm of H2 for 40 min. After this time, the reaction mixture was filtered by a pad of diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 3 as a white solid (177 mg, >99%). [α]25D = +260.4° (c 0.25, MeOH). Mp: 48−50 °C. 1 H NMR (500 MHz, CDCl3): δH 6.78 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.62−6.60 (m, 1H), 5.61 (s, 1H), 5.58 (s, 1H), 5.56 (s, 1H), 5.50 (s, 1H), 3.87 (s, 3H), 2.99 (dd, J = 13.5, 3.5 Hz, 1H), 2.59−2.49 (m, 2H), 2.44−2.34 (m, 2H), 2.18−2.14 (m, 1H), 2.06− 2.00 (m, 1H), 0.94 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CD3OD): δC 201.0, 179.8, 147.6, 134.6, 121.3, 117.1, 112.9, 102.2, 100.3, 86.8, 56.5, 40.8, 37.7, 34.4, 31.2, 15.7. HRMS (MM: ESI) m/z: [M + H]+ calcd for C17H21O5, 305.1389; found, 305.1378. (R)-7a-((S)-1-(3,4-Dimethoxyphenyl)propan-2-yl)-7,7a-dihydrobenzo[d][1,3]dioxol-5(6H)-one (2). Iodomethane (0.04 mL, 0.64 mmol, 1.5 equiv) was added to a mixture of 3 (130 mg, 0.42 mmol) and K2CO3 (116 mg, 0.84 mmol, 2.0 equiv) in acetone (4 mL), and the mixture was stirred at room temperature for 72 h. After this time, ethyl acetate (100 mL) and water (10 mL) were added, and the layers were separated. The organic phase was washed with brine, dried over MgSO4, and concentrated to dryness under reduced pressure. The crude product was purified by chromatography (silica gel, hexanes to 30% EtOAc/hexanes, gradient elution) to afford 2 as a white solid (120 mg, 92%). [α]25D = +179.4° (c 0.3, MeOH). Mp: 134−136 °C. 1 H NMR (500 MHz, CD3OD): δH 6.87 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.0, 2.0 Hz, 1H), 5.69 (s, 1H), 5.63 (s, 1H), 5.44 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.03 (dd, J = 13.5, 4.0 Hz, 1H), 2.61 (dd, J = 13.0, 2.0 Hz, 1H), 2.49−2.44 (m, 3H), 2.28− 2.24 (m, 1H), 2.03−2.01 (m, 1H), 0.94 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CD3OD): δC 200.7, 179.4, 150.2, 148.7, 134.2, 122.2, 4240

DOI: 10.1021/acs.joc.7b00202 J. Org. Chem. 2017, 82, 4235−4241

Article

The Journal of Organic Chemistry

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00202. Experimental details for data acquisition (PDF) X-ray data (CIF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Zhongping Huang: 0000-0001-8408-7243 Russell B. Williams: 0000-0003-4534-3173 Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS We thank Dr. Zhen Wei (University at Albany) for crystal Xray analysis. REFERENCES

(1) Williams, R. B.; Martin, S. M.; Lawrence, J. A.; Norman, V. L.; O’Neil-Johnson, M.; Eldridge, G. R.; Starks, C. M. J. Nat. Prod. 2017, 80, 616−624. (2) Furuya, S.; Terashima, S. Tetrahedron Lett. 2003, 44, 6875. (3) Nonoshita, K.; Banno, H.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 316. (4) Lei, X.; Dai, M.; Hua, Z.; Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6383. (5) (a) Izawa, T.; Pun, D.; Stahl, S. S. Science 2011, 333, 209. (b) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566. (c) Diao, T.; Pun, D.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 8205. (6) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320. (7) Bradley, P. J.; Grayson, D. H. J. Chem. Soc. Perkin Trans. 1 2002, 1, 1794. (8) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. (9) (a) Muramatsu, W.; Nakano, K. Org. Lett. 2014, 16, 2042. (b) Nicolaou, K. C.; Montagnon, D. S.; Baran, D. S.; Zhong, Y. L. J. Am. Chem. Soc. 2002, 124, 2245. (c) Trost, B. M.; Rigby, J. H. J. Org. Chem. 1976, 41, 3217. (10) (a) Diao, T.; Pun, D.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 8205. (b) Pun, D.; Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 8213. (c) Theissen, K. J. J. Org. Chem. 1971, 36, 752. (11) (a) Tsuji, J.; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.; Shimizu, I. J. Org. Chem. 1987, 52, 2988. (b) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381. (c) Shimizu, I.; Tsuji, J. J. Am. Chem. Soc. 1982, 104, 5844.

4241

DOI: 10.1021/acs.joc.7b00202 J. Org. Chem. 2017, 82, 4235−4241