A Representative Synthetic Route for C5 Angucycline Glycosides

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A Representative Synthetic Route for C5 Angucycline Glycosides: Studies Directed toward the Total Synthesis of Mayamycin Soumen Chakraborty, and Dipakranjan Mal J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02833 • Publication Date (Web): 12 Dec 2017 Downloaded from http://pubs.acs.org on December 12, 2017

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The Journal of Organic Chemistry

A Representative Synthetic Route for C5 Angucycline Glycosides: Studies Directed toward the Total Synthesis of Mayamycin

Soumen Chakraborty and Dipakranjan Mal* Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India Supporting Information Placeholder

ABSTRACT: The study discloses an efficient synthetic route for the regiospecific construction of a C5 glycosidic angucycline representative of mayamycin. The key steps are intramolecular aldol condensation and Hauser annulation. The precursor for the aldol reaction is accessible through utilization of α-lithiation of a vinyl ether.

INTRODUCTION Carbohydrates in which a carbon atom of an aryl moiety replaces the glycosidic oxygen are defined as C-aryl glycosides.1 There are a wide variety of structurally diverse natural products with a C-aryl glycoside fragment, many of which are reported to exhibit significant antibiotic and anticancer activities.2 The C-aryl glycosides, synthetic or natural, are of great significance in medicinal chemistry due to their stability toward acidic and enzymatic cleavage compared to the O-glycosides.3 Among the C-aryl glycosides, quinone containing molecules are well known DNA intercalators. Angucycline antibiotics4 represent a unique class of polyaromatic polyketides, which exhibit diverse bioactivities, namely, antibacterial, anticancer, antiviral and enzyme inhibitory properties. Mayamycin (1), one such angucycline was isolated in 2010 from the cultures of marine sponge Halichondria panacea.5 It was found to exhibit potent cytotoxic activities with IC50 values ranging between 0.13–0.33 µM against eight human cancer cell lines. In addition, it showed activity against several bacteria including antibiotic-resistant strains. The most attractive structural feature of the molecule is

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the unusual site of the carbohydrate residue. Angucyclines having a carbohydrate residue at C5 position are rare. The significant biological activities and the inherent novel architecture prompted us to undertake the total synthesis of mayamycin. There are various strategies in the literature for the synthesis of C-aryl glycosides.6‒8 Till date only two synthetic approaches have been reported for the total synthesis of mayamycin. There is no total synthesis reported for the molecule. The first synthetic approach on mayamycin is due to Zhang et al.9 The total synthesis of the target could not achieved due to the failure of C5 glycosylation of benz[a]anthracene derivative 2 with mesyl sugar 3 to give mayamycin motif 4 (Scheme 1).

Scheme 1. Zhang approach for mayamycin9

The second approach is due to Mal et al.10 It was based upon the Hauser annulation between a naphthalenone 8 and a cyanophthalide 9 to give C5 glycosyl benz[a]anthraquinone 10 (Scheme 2). While this approach was applicable for A-ring unsubstituted C5 angucycline glycosides, it was found unsuitable for the total synthesis. It was primarily due to the failure in the obvious glycosylation of β-naphthol 11 with azido sugar 5 to give 12, prohibiting the synthesis of naphthalenone 13. We attributed the failure of the glycosylation to the steric effect of C7 methyl group in βnaphthol.11


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Scheme 2. Mal’s first approach to C5 angucycline glycoside and Problem in glycosylation of naphthol 1110, 11

Considering the pitfalls of the above approaches, we revised our plan which is shown in Scheme 3. Mayamycin 1 was thought to be assembled by the Hauser annulation12 of fully decorated naphthalenone 14. Intramolecular aldol reaction of 15 was considered for the synthesis of the naphthalenone 14. Thus, the key difference between this approach and our previous one10 is the fabrication of sugar-naphthalenone hybrid 14. Herein, we report a synthesis of sugar-naphthalenone (cf. 14) and its Hauser annulation leading to a C5 angucycline glycoside. Scheme 3. Retrosynthesis of mayamycin (1)

RESULTS AND DISCUSSION For the synthesis of a sugar containing naphthalenone (cf. 14), we chose easily accessible galactose aldehyde 1613 (Scheme 4). It was reacted with the Grignard reagent, prepared by



treating bromoarene 1714 with magnesium metal in refluxing tetrahydrofuran (THF), to furnish alcohol 18 as a 7:10 mixture of diastereoisomers. Oxidation of the alcohol 18 with pyridinium chlorochromate (PCC) in dichloromethane (DCM) gave ketone 19 in 73% isolated yield. Treatment of the ketone 19 with vinylmagnesium bromide followed by Omethylation with MeI and NaH provided alkene 20 via 21 in 87% yield as a single isomer. However, the crucial selective benzylic oxidation of methyl ortho to methoxy group in 20, posed a serious problem. All attempts, namely Bhatt oxidation (K2S2O8, CuSO4),15a oxidation with 3,6-bis(triphenylphosphonium) cyclohexene peroxodisulfate (BTPCP),15b oxidation with t

BuOOH15c and oxidation with 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO),15d

failed to give aldehyde 22. Thus the synthesis of keto aldehyde 23 was not possible. Since most of the benzylic oxidations proceed through radical mechanism, the vinyl group in 20 probably interfered the selective oxidation to give the aldehyde 22. Vinyl groups are known to be susceptible to radical polymerization.

Scheme 4. First approach for model compound 23 by selective benzylic oxidation

In the next approach ozonolysis of an advanced diene intermediate was attempted to arrive at keto aldehyde 23. But, it was prohibited due to the inefficiency of the ozonolysis.16


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The exceptional failure of the oxidative cleavage of the double bonds prompted us to examine Wacker oxidation17 of alkene 2418 to produce ketone 25 (Scheme 5). We examined various reaction conditions and reagents such as (i) PdCl2, CuCl, O2 (ii) PdCl2, CrO319a and (iii) PdCl2, Fe2(SO4)319b for the Wacker oxidation. For all the cases, the starting material 24 was recovered, except with Dess-Martin periodinane (DMP) and Pd(OAc)2,20 for which cyclized product 26 was obtained. The formation of unusual indanone product 26 is explained by Wacker type oxidation followed by cyclization through C–H activation in the presence of Pd(OAc)2. The structure of 26 was first assigned from its NMR spectral data. The absence of 1 aromatic ‘H’ in 1H NMR spectrum and the absence of 1 aromatic ‘CH’ in dept-135 spectrum indicated the product as a cyclic one. The presence of a peak at 203.3 ppm in

13

C

NMR spectrum clearly indicated the presence of ketonic carbonyl. The appearance of two ‘H’ separately as doublets (2.70 and 3.42 ppm) in 1H NMR spectrum and one extra ‘CH2’ (41.8 ppm) in dept-135 spectrum confirmed the presence of ‘CH2’ moiety in the molecule. Finally the structure was confirmed from its HRMS spectral data, which was in good agreement with the calculated ones. The plausible mechanism for the formation of 26 is shown in Scheme 5. At first complexation of the substrate with the catalyst takes place to form 27 and then addition of water occurs to generate 28a, which undergoes nuclear palladation to give 28b. Finally, reductive elimination of “Pd” from 28b takes place to form 29. Oxidation of the secondary alcohol 29 in the presence of DMP leads to the formation of the indanone 26.



Scheme 5. Unprecedented cyclization in the Wacker type oxidation of 24

Considering the difficulties in the previous approaches (Scheme 4‒5), we decided to adopt ring closing metathesis (RCM) for the construction of naphthalenone 30 (Scheme 6). Accordingly, arylmagnesium bromide prepared from aryl bromide 3121 was reacted with the aldehyde 16 to give alcohol 32 as a 3:10 mixture of diastereoisomers. Oxidation of the alcohol 32 with PCC furnished ketone 33 in 68% isolated yield. To execute the plan for RCM, the diene 34 was prepared from 33 by the treatment with allylmagnesium bromide in 87% isolated yield as a single isomer. RCM of the diene 34 in the presence of Grubbs-II in refluxing toluene gave cyclized product 35 in 45% yield, suggesting the success of RCM to give 36 which immediately lost water for aromatization. To prevent the aromatization, alcohol 34 was protected as its methyl ether 37 and then the RCM of 37 was performed under the same conditions as earlier. This time the yield of the reaction was excellent resulting in dihydronaphthalene 38. Unfortunately, allylic C–H oxidation22 of 38 to 30 posed severe problems. All the attempts, namely (i) PCC (ii) tert-butyl hydroperoxide (TBHP) (iii) pyridinium dichromate (PDC) (iv) SeO2 and (v) Mn3(OAc)2 were unsuccessful. This may be due to the competing reactivity of allylic and benzylic carbon. Since most of the allylic


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oxidations proceed through radical mechanism, the double bond isomerization of 38 probably interfered the oxidation.

Scheme 6. Fourth approach: RCM for the construction of naphthalenone 30

Considering the failure in converting 38 to 30, we planned for applying RCM to ketonic diene23,

24

to avoid the problem of installing keto functionality as in 38. However, the

attempted RCM in the presence of Grubbs-II or Hoveyda-Grubbs-II were unsuccessful leading to complete recovery of starting material

Finally, we exploited the enol-ether chemistry to construct key aldol precursor 23 (Scheme 4). As shown in Scheme 7, α-lithiated species generated from ethyl vinyl ether 39 was reacted with ketone 4018 to give intermediate alcohol 41. Interestingly, the hydrolysis of enol 41 with 1 M HCl resulted in the desired ketone 42 in 82% yield over two steps as a 6:10 mixture of diastereoisomers. Methylation of α-hydroxy ketone 42 by NaH and MeI provided ketone 25 in 86% yield. Deprotection of the benzyl group in ketone 25 furnished unexpected product 43 instead of 44. This probably resulted from intramolecular acetonide exchange. The driving force could be the product stability. The absence of ‘3H’ of one ‘CH3’ in 1H



NMR spectrum and absence of ‘C=O’ and one ‘CH3’ in

13

C NMR spectrum suggested the

structure of compound 43, and finally it was confirmed by HRMS spectral data.

Scheme 7. Successful incorporation of ketone moiety in 25

Having failed to obtain 44, we combined enol-ether chemistry with oxidative cleavage to transform the ketone 33 into the precursor 23 (Scheme 8). The ketone 33 was treated with αlithiated species of ether 39 to furnish ketone 45 in 79% yield as a single isomer via 46. The α-hydroxy ketone 45 was protected as its methyl ether by MeI providing ketone 47 in 84% isolated yield. Treatment of the alkene 47 with ozone initially furnished molozonide 48. It was fully characterized by 1H NMR and 13C NMR spectral data. The characteristic signals are two singlets at 5.24 and 5.35 ppm in the 1H NMR spectrum and one ‘CH2’ peak at 95 ppm in the dept-135 spectrum for ‘CH2’ of the ozonide motif. The ozonide 48, on treatment with Me2S, resulted in the aldehyde 23 in 90% yield. The keto aldehyde 23 was then treated with KtOBu in tBuOH to yield our desired napthalenone 30 in almost quantitative yield via intramolecular aldol condensation. In the 1H NMR spectrum of 30, the presence of two doublets at 6.08 and 7.84 ppm with coupling constant 10.2 Hz confirmed the presence of cyclic enone in the molecule.


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Scheme 8. Synthesis of sugar appended naphthalenone 30

Having been successful in synthesizing naphthalenone 30, we submitted it to the Hauser annulation with 7-methoxy-3-cyanophthalide 4925 in the presence of LiOtBu in THF to furnish annulated product 50 (Scheme 9). On standing, the quinol 50 was converted to quinone 51 by aerial oxidation. To construct the benz[a]anthraquinone the naphthol 50 was treated with 2 M HCl. Unfortunately, aromatization occurred with the loss of the sugar moiety giving quinone 52.26 Finally, the hurdle in the aromatization step was overcome by the use of oxalic acid. Treatment of the quinol 50 with oxalic acid in a mixture of THF and H2O at room temperature gave our desired angucycline core of natural product i.e. quinone 53.



Scheme 9. Synthesis of a C5 angucycline glycoside by Hauser annulation

CONCLUSION In conclusion, a facile regiocontrolled route is developed for the synthesis of 53, a C5 glycosidic angucyclinone, which features mayamycin-like angucyclines specially the A-ring substitution pattern. The key features of the route are (i) step-wise preparation of glycosyl naphthalenone 30 via a classical yet robust aldol condensation and (ii) its Hauser annulation in regiospecific manner. The failure of C-glycosylation of β-naphthols in the previously published routes9, 11 could be avoided by the present synthetic route. The application of this methodology to complete the total synthesis is underway. Also presented is a palladium catalysed cyclization to a 2-indanone.

EXPERIMENTAL SECTION General Procedures. All commercially available reagents were used without further purification. Melting points were determined in open-end capillary tubes and are uncorrected. Solvents were dried prior to use following the standard procedures. TLC were carried out on pre-coated plates (Merck silica gel 60, GF254), and the spots were visualized with UV, fluorescent light or by staining with 10% H2SO4 in methanol. Flash Column chromatography


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was performed on silica gel (230–400 mesh). 1H and 13C NMR spectra for all the compounds were recorded at 400/600 and 100/150 MHz (Bruker Avance II 400 and Bruker Ascend 600), respectively, and the chemical shifts are reported in ppm downfield of tetramethylsilane and referenced to residual solvent peak (CHCl3; δH = 7.26 and δC = 77.23). Multiplets are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra were recorded with a Perkin–Elmer FTIR instrument using a KBr pellet. Mass spectra were taken on MS-TOF mass spectrometer. The assignment in 13C NMR data was done on the basis of dept-135. The phrase ‘usual work-up’ or ‘worked up in usual manner mentions to washing of the organic phase with water (2×1/4 the volume of organic phase) and brine (1×1/4 the volume of organic phase), and drying (anhydrous Na2SO4), filtration, and concentration under reduced pressure. In most of the cases yields refer to isolated yields after purification. General procedure for reaction of arylmagnesium bromide with aldehyde 16 An oven dried, three-necked 50 mL round-bottomed flask was equipped with a magnetic stirring bar, a condenser, and an addition funnel, to which pre activated magnesium turnings (4.5 mmol, 108 mg) were added. The flask was then sealed with a rubber septum, evacuated, and refilled with N2. Freshly distilled THF (10 mL) was added to the flask with stirring and the addition funnel was charged with aryl bromide (3 mmol) and THF (5 mL). The aryl bromide solution was added dropwise to the flask with stirring. Upon complete addition, the reaction mixture was heated to 65 °C and allowed to reflux for 2 h. The formed Grignard solution was added, via cannula, to a solution of sugar aldehyde 16 (258 mg, 1mmol) in THF (5 mL) at –78 °C. The reaction mixture was stirred at the same temperature for 2 h and then allowed to warm to room temperature. The reaction was then quenched with saturated ammonium chloride solution (10 mL) and THF was evaporated under reduced pressure. The residue was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude alcohol. This was then purified by flash column chromatography using EtOAc/hexane as eluent to obtain pure alcohol. General procedure for PCC oxidation of alcohol to ketone To a stirred solution of alcohol (1 mmol) in anhydrous DCM (10 mL) was added 4 Å MS (100 mg) followed by PCC (323 mg, 1.5 mmol) at room temperature under N2 atmosphere.



The reaction mixture was heated at reflux for 4 h until there was no starting material in TLC. Then the reaction mixture was filtered through celite-pad and the residue was washed several times with DCM. The combined organic part was concentrated under reduced pressure and the residue was purified by flash column chromatography using EtOAc/hexane as eluent to obtain pure keto compound. General procedure for Grignard reaction of ketone To a stirred solution of ketone (1 mmol) in anhydrous THF (5 mL) at –40 °C was added commercially available Grignard reagent (2 mmol) under N2 atmosphere. The reaction mixture was stirred at the same temperature for 2 h and then allowed to warm to room temperature. The reaction was then quenched with saturated ammonium chloride solution (10 mL) and THF was evaporated under reduced pressure. The residue was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude alcohol which was purified by flash column chromatography using EtOAc/hexane as eluent to give desired alcohol.

General procedure for methylation of alcohol to methyl ether To a stirred solution of alcohol (1 mmol) in anhydrous THF (5 mL) at 0 °C was added NaH (1.5 mmol, 60% in oil) under inert atmosphere and the reaction was stirred at same temperature for 30 min. MeI (1.3 mmol) was then added dropwise to the reaction mixture and stirring was continued at room temperature for 12 h. The reaction mixture was cooled to 0 °C and MeOH was added to quench excess NaH. Then THF was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude methyl ether which was purified by flash column chromatography using EtOAc/hexane as eluent to give the methyl ether. (3-Methoxy-2,5-dimethylphenyl)((3aS,5S,8bS)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)methanol (18). The general procedure for reaction of arylmagnesium bromide with aldehyde 16 was followed using 1-bromo-3-methoxy-2,5dimethylbenzene (17) (642 mg, 3 mmol), Mg turnings (108 mg, 4.5 mmol) and aldehyde 16 (258 mg, 1 mmol). The crude product was purified by flash column chromatography on silica gel (25% EtOAc/hexane as eluent) to afford 18 as a yellow semisolid (256 mg, 65%) as


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mixture of two isomers. IR (KBr): ν̃ = 2934, 1218, 1145, 1068, 1000, 901 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.01 (s, 1H), 6.90 (s, 0.7H), 6.615 (s, 0.7H), 6.607 (s, 1H), 5.62 (d, J = 4.9 Hz, 0.7H), 5.56 (d, J = 5.1 Hz, 1H), 5.21 (t, J = 5.6 Hz, 1H), 5.12 (d, J = 8.3 Hz, 0.7H), 4.54 (dd, J = 8.1, 2.3 Hz, 1H), 4.44 (dd, J = 8.0, 2.2 Hz, 0.7H), 4.35 (dd, J = 8.1, 1.8 Hz, 1H), 4.27–4.29 (m, 1.7H), 3.94 (dd, J = 8.3, 1.5 Hz, 0.7H), 3.90 (dd, J = 5.9, 1.7 Hz, 1H), 3.80 (s, 6H), 3.53–3.50 (m, 0.7H), 2.33 (s, 3H), 2.31 (s, 2.2H), 2.23 (s, 2.2H), 2.16 (s, 3H), 1.57 (s, 2.2H), 1.55 (s, 3H), 1.48 (s, 5.2H), 1.35 (s, 3H), 1.33 (s, 2.2H), 1.29 (s, 3H), 1.23 (s, 2.2H). 13

C NMR (150 MHz, CDCl3) δ 157.7, 157.5, 140.1, 138.2, 136.1, 136, 122.9, 121.2, 120.3

(CH), 119.0 (CH), 111.0 (CH), 110.5(CH), 109.7, 109.4, 108.9, 108.6, 96.9 (CH), 96.7 (CH), 72.2 (CH), 71.6 (CH), 71.5 (CH), 71.4 (CH), 71.3 (CH), 71.1 (CH), 71.0 (CH), 70.7 (CH), 69.4 (CH), 68.5 (CH), 55.7 (OCH3), 55.6 (OCH3), 26.4 (CH3), 26.2 (CH3), 26.1 (CH3), 25.2 (CH3), 25.0 (CH3), 24.4 (CH3), 24.3 (CH3), 21.8 (CH3), 21.8 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C21H30O723Na 417.1889; Found 417.1891. (3-Methoxy-2,5-dimethylphenyl)((3aS,5R,8bS)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)methanone (19). The general procedure for PCC oxidation of alcohol to ketone was followed using alcohol 18 (394 mg, 1 mmol) and PCC (323 mg, 1.5 mmol). The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford ketone 19 as an off-white solid (286 mg, 73%). This compound could not be purified to a satisfactory level, some amount of impurities are present (as reflected from melting point and 1H NMR spectrum). mp 162–168 °C; [α]35D = –64 (c 0.4, CHCl3); IR (KBr): ν̃ = 2935, 2363, 1712, 1578, 1458, 1243, 1069, 1006, 900 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.76 (s, 1H), 6.74 (s, 1H), 5.68 (d, J = 5.0 Hz, 1H), 4.87 (d, J = 2.3 Hz, 1H), 4.62 (dd, J = 7.8, 2.6 Hz, 1H), 4.55 (dd, J = 7.7, 2.3 Hz, 1H), 4.37 (dd, J = 5.0, 2.6 Hz, 1H), 3.81 (s, 3H), 2.33 (s, 3H), 2.17 (s, 3H), 1.59 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H), 1.28 (s, 3H).

13

C NMR (150 MHz, CDCl3) δ 201.4, 158.1, 139.3, 135.9, 122.8, 119.3

(CH), 113.5 (CH), 110.1, 109, 97.0 (CH), 73.4 (CH), 72.3 (CH), 71.1 (CH), 70.6 (CH), 55.8 (OCH3), 26.3 (CH3), 26.0 (CH3), 25.0 (CH3), 24.8 (CH3), 21.7 (CH3), 12.2 (CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H29O7 393.1913; Found 393.1910. 1-(3-Methoxy-2,5-dimethylphenyl)-1-((3aS,5R,8bS)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)prop-2-en-1-ol (21). The general procedure for Grignard reaction of ketone was followed using ketone 19 (394 mg, 1 mmol) and commercially available vinylmagnesium bromide solution (2 mL, 1M in THF i.e. 2 mmol).



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The crude product was purified by flash column chromatography on silica gel (30% EtOAc/hexane as eluent) to afford 21 as a colourless gum (357 mg, 85%). [α]35D = –53.5 (c 0.2, CHCl3); IR (KBr): ν̃ = 2928, 2371, 1377, 1578, 1219, 1068, 995 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.34 (s, 1H), 6.68 (s, 1H), 6.42 (dd, J = 17.4, 10.8 Hz, 1H), 5.75 (d, J = 5.1 Hz, 1H), 5.23–5.18 (m, 2H), 4.78 (s, 1H), 4.45–4.43 (m, 2H), 4.29 (dd, J = 5.1, 2.2 Hz, 1H), 3.89 (dd, J = 8.1, 1.6 Hz, 1H), 3.82 (s, 3H), 2.36 (s, 3H), 2.17 (s, 3H), 1.57 (s, 3H), 1.53 (s, 3H), 1.34 (s, 3H), 1.18 (s, 3H).

13

C NMR (150 MHz, CDCl3) δ 158.1, 142.4, 139.5 (CH),

136.0, 120.2 (CH), 119.7, 116.7 (CH2), 110.6 (CH), 109.7, 108.7, 97.6 (CH), 79.2, 72.5 (CH), 71.5 (CH), 70.6 (CH), 67.3 (CH), 55.7 (OCH3), 26.3 (CH3), 26.0 (CH3), 24.9 (CH3), 24.1 (CH3), 22.0 (CH3), 15.3 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C23H32O723Na 443.2046; Found 443.2050. (3aS,5R,8bS)-5-(1-Methoxy-1-(3-methoxy-2,5-dimethylphenyl)allyl)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran (20). The general procedure for methylation of alcohol to methyl ether was followed using alcohol 21 (420 mg, 1 mmol), NaH (60 mg, 60% in mineral oil) and 0.1 mL of MeI. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford methyl ether 20 as yellow oil (377 mg, 87%). [α]35D = –67.5 (c 0.3, CHCl3); IR (KBr): ν̃ = 2919, 1609, 1583, 1461, 1380, 984, 895, 747 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.49 (s, 1H), 6.67 (s, 1H), 6.41 (dd, J = 18, 11.4 Hz, 1H), 5.72 (d, J = 5.4 Hz, 1H), 5.08 (d, J = 11.4Hz, 1H), 4.68 (dd, J = 7.8, 1.8 Hz, 1H), 4.64 (d, J = 18 Hz,1H), 4.56 (d, J = 7.8 Hz, 1H), 4.52 (s, 1H), 4.38 (t, J = 2.4 Hz, 1H), 3.83 (s, 3H), 3.09 (s, 3H), 2.37 (s, 3H), 2.18 (s, 3H), 1.62 (s, 3H), 1.49 (s, 3H), 1.40 (s, 6H).

13

C NMR (150 MHz, CDCl3) δ 158.2, 140.4, 140.0 (CH), 134.9,

123.7, 122.4 (CH), 115.5 (CH2), 110.6 (CH), 109.5, 108.6, 97.6 (CH), 84.5, 71.4 (CH), 71.3 (CH), 70.6 (CH), 69.11 (CH), 55.5 (OCH3), 51.2 (OCH3), 25.9 (CH3), 25.7 (CH3), 24.9 (CH3), 24.7 (CH3), 21.4 (CH3), 13.5 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H34O723Na 457.2202; Found 457.2220. 7-(Benzyloxymethyl)-1,6-dimethoxy-4-methyl-1-((3aS,5R,8bS)-2,2,7,7-tetramethyltetrahydro3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)-1H-inden-2(3H)-one

(26).

To

a

stirred

solution of olefin 24 (270 mg, 0.5 mmol, 1.0 equiv) in CH3CN (3.5 mL) and H2O (0.5 mL) were added Pd(OAc)2 (6 mg, 0.025 mmol, 5 mol %) and DMP (255 mg, 0.6 mmol, 1.2 equiv) at room temperature. The reaction mixture was warmed to 50 °C and stirred for 4 h under nitrogen atmosphere. The reaction mixture was then filtered through a small silica gel pad


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and washed with EtOAc, and the filtrate was concentrated. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford ketone 26 as a yellow semisolid (139 mg, 50%). [α]35D = –48.1 (c 0.5, CHCl3); IR (KBr): ν̃ = 2931, 1702, 1603, 1577, 1457, 1342, 1260, 1105, 901, 754 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40–7.27 (m, 5H), 6.75 (s, 1H), 5.30 (d, J = 4.9 Hz, 1H), 4.81 (d, J = 8.8 Hz, 1H), 4.71–4.55 (m, 5H), 4.21–4.14 (m, 1H), 4.09 (s, 1H), 3.90 (s, 3H), 3.42 (d, J = 19.1 Hz, 1H), 3.18 (s, 3H), 2.70 (d, J = 19.1 Hz, 1H), 2.64 (s, 3H), 1.48 (s, 3H), 1.37 (s, 3H), 1.25 (s, 3H), 1.18 (s, 3H).

13

C NMR (150 MHz, CDCl3) δ 203.3, 163.6, 154.5, 140.7, 138.7, 130.1, 128.4 (CH),

128.2 (CH), 127.7 (CH), 120.8, 114.8 (CH), 109.2, 108.1, 96.4 (CH), 84.2, 73.7 (CH2), 71.3, 71.2, 71.1, 70.5, 62.8 (CH2), 56.3 (OCH3), 51.5 (OCH3), 41.8 (CH2), 26.2 (CH3), 26.0 (CH3), 24.8 (CH3), 24.3 (CH3), 19.6 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C31H38O923Na 577.2414; Found 577.2437. (3-Methoxy-5-methyl-2-vinylphenyl)((3aS,5S,8bS)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)methanol (32). The general procedure for reaction of arylmagnesium bromide with aldehyde 16 was followed using 1-bromo-3-methoxy-5-methyl2-vinylbenzene 31 (681 mg, 3 mmol), Mg turnings (108 mg, 4.5 mmol) and aldehyde 16 (258 mg, 1 mmol). The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford 32 as a yellow semisolid (248 mg, 61%). IR (KBr): ν̃ = 2934, 1457, 1382, 1255, 1217, 1167, 1068, 999 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 6.95 (s, 0.3H), 6.81 (dd, J = 17.9, 11.7 Hz, 0.3H), 6.78–6.63 (m, 2.3H), 5.65–5.57 (m, 1.7H), 5.50–5.47 (m, 2.3H), 5.35 (t, J = 5.2 Hz, 1H), 5.20 (d, J = 7.3 Hz, 0.3H), 4.54 (d, J = 7.9 Hz, 1H), 4.44 (d, J = 8.0 Hz, 0.3H), 4.37 (d, J = 8.1 Hz, 1H), 4.27–4.24 (m, 1.3H), 3.97 (dd, J = 13.7, 7.1 Hz, 1.3H), 3.87 (d, J = 8.1 Hz, 0.3H), 3.78 (s, 4H), 3.46–3.44 (m, 1H), 2.34 (s, 4H), 1.53 (s, 1H), 1.50 (s, 6H), 1.49 (s, 1H), 1.33 (s, 3H), 1.31 (s, 1H), 1.27 (s, 3H), 1.21 (s, 1H).

13

C NMR (100 MHz, CDCl3) (Major isomer) δ 157.1, 140.0, 137.9, 130.1 (CH),

123.6, 120.58 (CH2), 119.4 (CH), 110.9 (CH), 109.5, 108.5, 96.7 (CH), 71.4 (CH), 71.0 (CH), 70.6 (CH), 70.1 (CH), 68.9 (CH), 55.6 (OCH3), 26.0 (CH3), 26.0 (CH3), 24.9 (CH3), 24.4 (CH3), 21.9 (CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H31O7 407.2070; Found 407.2074. (3-Methoxy-5-methyl-2-vinylphenyl)((3aS,5R,8bS)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)methanone (33). The general procedure for PCC oxidation of alcohol to ketone was followed using alcohol 32 (407 mg, 1 mmol) and PCC



(323 mg, 1.5 mmol). The crude product was purified by flash column chromatography on silica gel (15% EtOAc/hexane as eluent) to afford ketone 33 as a white solid (275 mg, 68%). mp 182–184 °C; [α]35D = –93.3 (c 0.4, CHCl3); IR (KBr): ν̃ = 2997, 1717, 1602, 1458, 1387, 1002, 891, 766 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.90 (dd, J = 17.8, 11.3 Hz, 1H), 6.77 (d, J = 1.2 Hz, 1H), 6.75 (d, J = 1.2 Hz, 1H), 5.60 (d, J = 5.0 Hz, 1H), 5.42–5.36 (m, 2H), 4.80 (d, J = 2.2 Hz, 1H), 4.58 (dd, J = 7.8, 2.6 Hz, 1H), 4.45 (dd, J = 7.8, 2.3 Hz, 1H), 4.32 (dd, J = 5.0, 2.6 Hz, 1H), 3.83 (s, 3H), 2.35 (s, 3H), 1.53 (s, 3H), 1.43 (s, 3H), 1.32 (s, 3H), 1.29 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 203.5, 156.8, 139.6, 138.8, 131.5 (CH), 123.0, 120.4

(CH2), 120.2 (CH), 113.3 (CH), 110.0, 109.0, 96.9 (CH), 73.7 (CH), 72.1 (CH), 71 (CH), 70.6 (CH), 55.8 (OCH3), 26.1 (CH3), 26 (CH3), 25.1 (CH3), 24.8 (CH3), 21.8 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H28O723Na 427.1733; Found 427.1730. 1-(3-Methoxy-5-methyl-2-vinylphenyl)-1-((3aR,5S,5aR,8aS,8bR)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)but-3-en-1-ol (34). An oven dried, three-necked 50 mL round-bottomed flask was equipped with a magnetic stir bar, a condenser, and an addition funnel to which pre activated magnesium turnings (4.5 mmol, 108 mg) were added. The flask was then sealed with a rubber septum, evacuated, and refilled with N2. Freshly distilled Et2O (10 mL) was added to the flask with stirring and the addition funnel was charged with allyl bromide (363 mg, 0.26 mL, 3 mmol) and Et2O (5 mL). The allyl bromide solution was added dropwise to the flask with stirring in such a rate to maintain gentle reflux. Upon completed addition, stirring was continued for 1 h. The so-formed Grignard solution was added, via cannula, to a solution of ketone 33 (405 mg, 1mmol) in Et2O (5 mL) at 0 °C. The reaction mixture was stirred at the same temperature for 1 h and then allowed to warm to room temperature. The reaction was then quenched with saturated ammonium chloride solution (10 mL) and THF was evaporated under reduced pressure. The residue was then extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude alcohol. The crude product was purified by flash column chromatography on silica gel (25% EtOAc/hexane as eluent) to afford alcohol 34 as yellow oil (389 mg, 87%). [α]35D = –32.6 (c 0.3, CHCl3); IR (KBr): ν̃ = 2929, 2372, 1579, 1388, 1001, 893, 758 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.34 (br s, 1H), 6.71–6.66 (m, 2H), 5.71 (d, J = 5.1 Hz, 1H), 5.62–5.45 (m, 2H), 5.31 (d, J = 17.8 Hz, 1H), 4.98 (dd, J = 17.1, 2.0 Hz, 1H), 4.92–4.84 (m, 1H), 4.44–4.42 (m, 2H), 4.27 (dd, J = 5.2, 2.2 Hz, 1H), 3.97 (d, J = 8.1 Hz, 1H), 3.77 (s, 3H), 2.95 (ddd, J = 14.4, 7.4, 1.3 Hz, 1H), 2.77 (s, 1H), 2.36 (s, 3H), 1.62 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H), 1.16


Page 16 of 32

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(s, 3H). 13C NMR (150 MHz, CDCl3) δ 157.2, 142.4, 137.6, 133.9 (CH), 133.0 (CH), 121.5 (CH2), 121.2 (CH), 121.1, 117.1 (CH2), 111.3 (CH), 109.5, 108.7, 97.2 (CH), 79.4, 72.3 (CH), 71.4 (CH), 70.7 (CH), 68.3 (CH), 56.0 (OCH3), 41.6 (CH2), 26.6 (CH3), 26.0 (CH3), 25 (CH3), 24.1 (CH3), 22.2 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H34O723Na 469.2202; Found 469.2179. (3aS,5S,8bS)-5-(5-Methoxy-7-methylnaphthalen-1-yl)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran (35). Compound 34 (about 446 mg, 1 mmol) in degassed toluene (10 mL) was added via syringe to a stirred solution of Grubbs–II catalyst (10 mg) in degassed toluene (10 mL) under an argon atmosphere. The resultant dark brown solution was refluxed under a nitrogen stream for 5 h. The reaction mixture was then concentrated under reduced pressure and kept at room temperature for 6 h and then purified by flash column chromatography (20% EtOAc/hexane as eluent) to give the product 35 (180 mg, 45% isolated yield after two steps) as a colourless clear oil. [α]35D = –84.8 (c 0.5, CHCl3); IR (KBr): ν̃ = 2922, 1372, 1253, 1212, 1168, 1104, 994, 888 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.29 (s, 1H), 6.64 (s, 1H), 5.81 (d, J = 4.9 Hz, 1H), 5.63 (s, 1H), 4.80 (d, J = 8.0 Hz, 1H), 4.62 (d, J = 7.9 Hz, 1H), 4.51–4.44 (m, 1H), 3.97 (s, 3H), 2.51 (s, 3H), 1.66 (s, 3H), 1.49 (s, 3H), 1.42 (s, 3H), 1.26 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 156.2, 136.1, 131.6, 131.5, 126.7 (CH), 124.2, 124.0

(CH), 121.8 (CH), 113.8 (CH), 109.5, 108.9, 105.8 (CH), 97.5 (CH), 73.1 (CH), 71.6 (CH), 71.1 (CH), 66.2 (CH), 55.7 (OCH3), 26.5 (CH3), 26.2 (CH3), 25.3 (CH3), 24.5 (CH3), 23.1 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C23H28O623Na 423.1784; Found 423.1770. (3aR,5S,5aR,8aS,8bR)-5-(1-Methoxy-1-(3-methoxy-5-methyl-2-vinylphenyl)but-3-enyl)2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran (37). The general procedure methylation of alcohol to methyl ether was followed using alcohol 34 (447 mg, 1 mmol), NaH (60 mg, 60% in mineral oil) and 0.1 mL of MeI. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford methyl ether 37 as colourless oil (415 mg, 90%). [α]35D = –39.4 (c 0.3, CHCl3); IR (KBr): ν̃ = 2993, 1602, 1458, 1365, 1254, 1002, 906 cm-1, 1H NMR (600 MHz, CDCl3) δ 7.32 (s, 1H), 7.05 (dd, J = 17.8, 11.6 Hz, 1H), 6.69 (s, 1H), 5.68 (dt, J = 17.1, 8.4 Hz, 1H), 5.64 (d, J = 5.1 Hz, 1H), 5.48 (dd, J = 17.9, 2.7 Hz, 1H), 5.41 (dd, J = 11.6, 2.6 Hz, 1H), 4.93–4.86 (m, 1H), 4.75 (d, J = 10.4 Hz, 1H), 4.60–4.54 (m, 1H), 4.46 (d, J = 8.0 Hz, 1H), 4.33 (s, 1H), 4.27 (dd, J = 5.1, 1.9 Hz, 1H), 3.77 (s, 3H), 3.35 (dd, J = 15.7, 5.7 Hz, 1H), 3.19 (s, 3H), 3.08 (dd, J =



15.5, 7.9 Hz, 1H), 2.34 (s, 3H), 1.51 (s, 3H), 1.45 (s, 3H), 1.34 (s, 6H). 13C NMR (150 MHz, CDCl3) δ 157.6, 140.8, 137.0, 136.4 (CH), 132.7 (CH), 124.1, 122.8 (CH), 119.1 (CH2), 115.2 (CH2), 111.9 (CH), 109.3, 108.4, 97.2 (CH), 83.7, 71.8 (CH), 71.6 (CH), 71.3 (CH), 71.2 (CH), 56.0 (OCH3), 52.4 (OCH3), 39.3 (CH2), 26.2 (CH3), 26.1 (CH3), 25 (CH3), 24.4 (CH3), 21.9 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C26H36O723Na 483.2359; Found 483.2346. (3aS,5R,8bS)-5-(1,5-Dimethoxy-7-methyl-1,2-dihydronaphthalen-1-yl)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran (38). Compound 37 (230 mg, 0.5 mmol) in degassed toluene (10 mL) was added via syringe to a stirred solution of Grubbs–II catalyst (6 mg) in degassed toluene (10 mL) under an argon atmosphere. The resultant dark brown solution was refluxed under a nitrogen stream for 3 h. The reaction mixture was then concentrated under reduced pressure and then purified by flash column chromatography (20% EtOAc/hexane as eluent) to give the product 38 (201 mg, 93%) as clear oil. [α]35D = –55.4 (c 0.4, CHCl3); IR (KBr): ν̃ = 2986, 1628, 1583, 1513, 1461, 1069, 899, 832 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 6.73 (d, J = 10.1 Hz, 1H), 6.62 (s, 1H), 5.96–5.92 (m, 1H), 5.64–5.63 (m, 1H), 4.35 (d, J = 8.2 Hz, 1H), 4.18 (d, J = 4.8 Hz, 1H), 4.08 (d, J = 8.3 Hz, 1H), 4.02 (s, 1H), 3.82 (s, 3H), 3.25 (s, 3H), 3.01 (dd, J = 18.2, 5.4 Hz, 1H), 2.68 (d, J = 17.8 Hz, 1H), 2.36 (s, 3H), 1.52 (s, 3H), 1.5 (s, 3H), 1.28 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 154.8, 137.7, 135.4, 125.7 (CH), 121.6, 120.3 (CH), 120.1 (CH), 111.1 (CH), 108.9, 108.1, 97.5 (CH), 80.2, 71.9 (2×CH), 70.3 (CH), 68.0 (CH), 55.7 (OCH3), 51.8 (OCH3), 28.0 (CH2), 26.4 (CH3), 26.3 (CH3), 25.0 (CH3), 23.8 (CH3), 22.2 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H32O723Na 455.2046; Found 455.2033.

1-(2-(Benzyloxymethyl)-3-methoxy-5-methylphenyl)-1-hydroxy-1-((3aS,5R,8bS)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)propan-2-one (42). To a solution of ethyl vinyl ether 39 (0.3 mL, 3.5 mmol) in THF (5 mL) at –78 °C was added t

BuLi (0.55 mL 1.6 M, 0.88 mmol) dropwise. The solution was protected from light and

stirred for 30 min. at –78 °C. The resulting solution was warmed to 0 °C for 10 min. then cooled back to –78 °C. After that, ketone 40 (125 mg, 0.25mmol) in THF (5 mL) was added. The mixture was stirred at –78 °C and followed to completion by TLC (45 min.). The reaction was then quenched with saturated ammonium chloride solution (10 mL) and THF was evaporated under reduced pressure. The residue was then extracted with ethyl acetate


Page 18 of 32

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(3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude alcohol 41 which was used directly in next step. To a stirred solution of alcohol 41 (obtained from previous step) in THF:H2O (10 mL, 3:1) at room temperature was added 5 mL of 1 M HCl and the reaction was stirred at room temperature for 2 h. Then THF was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude ketone 42. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford ketone 42 as a colourless semisolid (111 mg, 82% over two steps). [α]35D = –56.9 (c 0.3, CHCl3); IR (KBr): ν̃ = 2930, 1717, 1461, 1380, 1254, 1206, 1065, 1006 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42–7.23 (m, 12H), 6.71 (s, 1H), 6.69 (s, 0.7 H), 5.64 (d, J = 4.8 Hz, 1H), 5.56 (d, J = 5.1 Hz, 0.6H), 5.37 (s, 0.6H), 4.93–4.28 (m, 14H), 3.78 (s, 5.5H), 2.36 (s, 3H), 2.34 (s, 2H), 2.16 (s, 3H), 2.13 (s, 2H), 1.79 (s, 3H), 1.53 (s, 3H), 1.51 (s, 2H), 1.39 (s, 2.7H), 1.38 (s, 3H), 1.36 (s, 2.4 H), 1.30 (s, 2H), 1.14 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 209.1 (CO),

207.6 (CO), 159.4, 159.3, 139.6, 139.5, 139.2, 139.0, 128.3, 128.2, 127.5, 127.4, 112.1, 110.1, 109.5, 109.2, 108.8, 97.2 (CH), 97.0 (CH), 85.6, 84.8, 72.9 (CH), 72.7 (CH), 71.2 (CH), 62.5 (OCH3), 56.0 (OCH3), 26.5 (CH3), 26.4 (CH3), 26.2 (CH3), 26 (CH3), 25.9 (CH3), 25.3 (CH3), 25.2 (CH3), 25.0 (CH3), 24.3 (CH3), 24.2 (CH3), 22.2 (CH3), 22.0 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C30H38O923Na 565.2414; Found 565.2412. 1-(2-(Benzyloxymethyl)-3-methoxy-5-methylphenyl)-1-methoxy-1-((3aS,5R,8bS)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)propan-2-one (25). To a stirred solution of α-hydroxy ketone 42 (136 mg, 0.25 mmol) in anhydrous THF (5 mL) at – 20°C was added NaH (15 mg, 0.38 mmol, 60% in oil) under inert atmosphere and the reaction was stirred at same temperature for 30 min. MeI (0.32 mmol) was then added dropwise to the reaction mixture and stirring was continued at 0 °C for 4 h. MeOH was added to quench excess NaH. Then THF was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude methyl ether. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford ketone 25 as a yellow semisolid (119 mg, 86%). [α]35D = –57.4 (c 0.3, CHCl3); IR (KBr): ν̃ = 2934, 1724, 1606, 1461, 1384, 1213, 1077, 758 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.43–7.25 (m, 5H), 6.74 (s, 1H), 5.76 (d, J = 5.0 Hz, 1H), 4.68– 4.57 (m, 4H), 4.56 (d, J = 9.2 Hz, 1H), 4.49 (d, J = 9.1 Hz, 1H), 4.43–4.32 (m, 2H), 3.80 (s,



Page 20 of 32

3H), 3.01 (s, 3H), 2.39 (s, 3H), 2.10 (s, 3H), 1.65 (s, 3H), 1.42 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 204.5, 159.6, 139.6, 139.5, 128.2 (CH), 128.1 (CH),

127.2 (CH), 123.9, 123.8, 122.7 (CH), 112.7 (CH), 109.6, 109.1, 97.6 (CH), 86.7, 73.0 (CH2), 71.2 (CH), 71.0 (CH), 70.6 (CH), 68.9 (CH), 61.8 (CH2), 55.9 (OCH3), 52.3 (OCH3), 29.2 (CH3), 25.9 (CH3), 25.7 (CH3), 25.1 (CH3), 24.2 (CH3), 21.8 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C31H40O923Na 579.2570; Found 579.2554. 5-(2-(Hydroxymethyl)-3-methoxy-5-methylphenyl)-5-methoxy-2,2,6-trimethylhexahydro-3aH[1,3]dioxolo[4,5-e]furo[3,2-b]pyran-8-ol (43). To a stirred solution of ketone 25 (70 mg, 0.12 mmol) in 3:1 MeOH:EtOAc (10 mL), 10% Pd-C (10 mg) was added and the reaction mixture was hydrogenated for 6 h. The reaction mixture was filtered through celite, solvent was evaporated under reduced pressure and purified by flash column chromatography on silica gel (25% EtOAc/hexane as eluent) to afford 43 as colourless gum (33.2 mg, 65%). [α]35D = –67.3 (c 0.5, CHCl3); IR (KBr): ν̃ = 2927, 1461, 1376, 1217, 1062, 1006, 780 cm-1; 1

H NMR (400 MHz, CDCl3) δ 6.90 (s, 1H), 6.58 (s, 1H), 5.39 (d, J = 4.7 Hz, 1H), 4.87 (d, J

= 16.4 Hz, 1H), 4.70–4.64 (m, 2H), 4.49 (d, J = 6.2 Hz, 1H), 4.40–4.35 (m, 3H), 3.79 (s, 3H), 3.40 (s, 3H), 2.37 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H), 1.28 (s, 3H).

13

C NMR (100 MHz,

CDCl3) δ 154.5, 137.8, 131.7, 120.4 (CH), 110.1 (CH), 109.4, 106.1, 97.2 (CH), 85.9, 77.7 (CH), 77.4, 75.4 (CH), 73.8 (CH), 63.5 (CH), 62.2 (CH2), 55.3 (OCH3), 53.9 (OCH3), 26.2 (CH3), 25.1 (CH3), 22.2 (CH3), 17.5 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C21H28O823Na 431.1682; Found 431.1673. 1-Hydroxy-1-(3-methoxy-5-methyl-2-vinylphenyl)-1-((3aS,5R,8bS)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)propan-2-one (45). To a solution of ethyl vinyl ether 39 (1.2 mL, 14 mmol) in THF (15 mL) at –78 °C was added t

BuLi (2.2 mL, 1.6 M, 3.5 mmol) dropwise. The solution was protected from light and stirred

for 30 min. at –78 °C. The resulting solution was warmed to 0 °C for 10 min then cooled back to –78 °C. After that, ketone 33 (405 mg, 1 mmol) in THF (5 mL) was added. The mixture was stirred at –78 °C and followed to completion by TLC (1 h). The reaction was then quenched with saturated ammonium chloride solution (20 mL) and THF was evaporated under reduced pressure. The residue was then extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude alcohol 46. This alcohol was unstable, easily converted to its keto form. We were only able to record crude 1H NMR. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 6.77–


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6.70 (m, 2H), 5.61–5.59 (m, 1H), 5.46 (dd, J = 11.5, 2.4 Hz, 1H), 5.33 (dd, J = 17.9, 2.4 Hz, 1H), 5.02 (s, 1H), 4.59 (d, J = 4.4 Hz, 1H), 4.51 (dd, J = 8.0, 2.4 Hz, 1H), 4.27 (dd, J = 4.9, 2.3 Hz, 1H), 4.21 (d, J = 8.0 Hz, 1H), 3.76–3.69 (m, 6H), 2.37 (s, 3H), 1.75 (s, 3H), 1.45 (s, 3H), 1.36 (s, 3H), 1.28–1.20 (m, 6H). To a stirred solution of alcohol 46 (obtained from previous step) in THF:H2O (20 mL, 3:1) at room temperature was added 8 mL of 1 M HCl and the reaction was stirred at room temperature for 2 h. Then THF was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude ketone 45. The crude product was purified by flash column chromatography on silica gel (25% EtOAc/hexane as eluent) to afford ketone 45 as colourless gum (354 mg, 79% over two steps). [α]35D = –85.3 (c 0.5, CHCl3); IR (KBr): ν̃ = 2934, 1728, 1602, 1458, 1372, 1295, 1254, 1076, 758 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 6.77–6.68 (m, 2H), 5.60 (d, J = 4.8 Hz, 1H), 5.46 (dd, J = 11.5, 2.3 Hz, 1H), 5.33 (dd, J = 17.9, 2.4 Hz, 1H), 5.02 (d, J = 1.2 Hz, 1H), 4.60 (s, 1H), 4.50 (dd, J = 8.1, 2.3 Hz, 1H), 4.27 (dd, J = 4.9, 2.3 Hz, 1H), 4.21 (dd, J = 8.0, 1.6 Hz, 1H), 3.76 (s, 3H), 2.37 (s, 3H), 2.11 (s, 3H), 1.75 (s, 3H), 1.45 (s, 3H), 1.35 (s, 3H), 1.20 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 205.9, 157.5, 138.0, 137.8,

131.5 (CH), 124.4, 120.5 (CH), 120.5 (CH2), 112.7 (CH), 109.5, 109.4, 97.0 (CH), 84.6, 71.8 (CH), 71.2 (CH), 70.9 (CH), 68.3 (CH), 56.1 (OCH3), 26.1 (CH3), 26.0 (CH3), 25.3 (CH3), 25.3 (CH3), 24.1 (CH3), 22.0 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H32O823Na 471.1995; Found 471.2010. 1-Methoxy-1-(3-methoxy-5-methyl-2-vinylphenyl)-1-((3aS,5R,8bS)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)propan-2-one (47). To a stirred solution of α-hydroxy ketone 45 (449 mg, 1 mmol) in anhydrous THF (15 mL) at –20 °C was added NaH (60 mg, 1.5 mmol, 60% in oil) under inert atmosphere and the reaction was stirred at same temperature for 30 min. MeI (1.3 mmol) was then added dropwise to the reaction mixture and stirring was continued at 0 °C for 4 h. MeOH was added to quench excess NaH. Then THF was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude methyl ether. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford ketone 47 as a yellow semisolid (388 mg, 84%). [α]35D = –72.4 (c 0.5, CHCl3); IR (KBr): ν̃ = 2932, 2360, 1727, 1382, 1292, 1255, 1164, 998 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 6.77–6.70 (m, 2H), 5.73 (d, J = 5.0 Hz, 1H), 5.58 (dd, J = 17.8, 2.7 Hz, 1H),



5.39 (dd, J = 11.8, 2.6 Hz, 1H), 4.65–4.66 (m, 3H), 4.36 (dd, J = 5.1, 1.6 Hz, 1H), 3.78 (s, 3H), 3.06 (s, 3H), 2.39 (s, 3H), 2.02 (s, 3H), 1.66 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H), 1.32 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 203.8, 157.8, 137.9, 135.2, 130.1 (CH), 125.1, 123.1

(CH), 120.7 (CH2), 113 (CH), 109.6, 109.0, 97.7 (CH), 86.8, 71.2 (CH), 71.0 (CH), 70.6 (CH), 68.7 (CH), 55.9 (OCH3), 52.0 (OCH3), 29.0 (CH3), 26.0 (CH3), 25.7 (CH3), 25.1 (CH3), 24.3 (CH3), 21.8 (CH3). HRMS (ESI-TOF) m/z: [M–MeOH+H]+ Calcd for C24H31O7 431.2070; Found 431.2082. 1-Methoxy-1-(3-methoxy-5-methyl-2-(1,2,4-trioxolan-3-yl)phenyl)-1-((3aS,5R,8bS)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)propan-2-one (48). The alkene substrate 47 (463 mg, 1mmol) was dissolved in dry CH2Cl2 (20 ml) in a flame-dried flask under N2. The solution was cooled to –78 °C, at which point a stream of O3 was introduced through a disposable pipet for a period of 5 min. Once complete, the reaction was purged with O2 and then N2. After half an hour stirring, the solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (10% EtOAc/hexane as eluent) to afford ozonide 48 as a white semisolid (434 mg, 85%). [α]35D = – 44.3 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 6.82 (s, 1H), 6.66 (s, 1H), 5.73 (d, J = 5.0 Hz, 1H), 5.35 (s, 1H), 5.24 (s, 1H), 4.67–4.63 (m, 3H), 4.37 (dd, J = 5.1, 2.0 Hz, 1H), 3.82 (s, 3H), 3.19 (s, 3H), 2.40 (s, 3H), 2.05 (s, 3H), 1.64 (s, 3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 204.3, 160.8, 142.5, 139.1, 123.2 (CH), 116.3, 114.3 (CH), 109.7, 109.2, 99.3 (CH), 97.6 (CH), 95.0 (CH2), 86.7, 71.1 (CH), 70.8 (CH), 70.6 (CH), 69.3 (CH), 56.4 (OCH3), 52.7 (OCH3), 28.5 (CH3), 26.0 (CH3), 25.6 (CH3), 25.1 (CH3), 24.2 (CH3), 21.9 (CH3). 2-Methoxy-6-(1-methoxy-2-oxo-1-((3aS,5R,8bS)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)propyl)-4-methylbenzaldehyde (23). The ozonide 48 (255 mg, 0.5mmol) was dissolved in dry CH2Cl2 (10 ml) in a round bottom flask under N2 with stirring. The solution was cooled to –78 °C, and Me2S (0.3 mL, 4 mmol) was added. After 2 h stirring the solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (15% EtOAc/hexane as eluent) to afford keto aldehyde 23 as a white solid (209 mg, 90%). [α]35D = –67.1 (c 0.3, CHCl3); mp 178–180 °C; IR (KBr): ν̃ = 2931, 2362, 1727, 1718, 1381, 1293, 1165, 998 cm-1; 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 6.95 (s, 1H), 6.75 (s, 1H), 5.65 (d, J = 4.9 Hz, 1H), 4.76 (s, 1H), 4.44 (dd, J = 8.0, 1.9 Hz, 1H), 4.25 (dd, J = 5.0, 1.9 Hz, 1H), 3.89 (d, J = 8.3 Hz, 1H), 3.83 (s, 3H), 3.39 (s,


Page 22 of 32

Page 23 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3H), 2.35 (s, 3H), 2.23 (s, 3H), 1.73 (s, 3H), 1.43 (s, 3H), 1.36 (s, 3H), 1.19 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 204.9 (CO), 193.2 (CHO), 159.8, 143.0, 138.0, 124.5, 121.0 (CH), 112.6 (CH), 109.2, 109.0, 97.1 (CH), 88.8, 71.5 (CH), 71.4 (CH), 70.9 (CH), 69.6 (CH), 56.2 (OCH3), 54.9 (OCH3), 27.0 (CH3), 26.1 (2×CH3), 25.2 (CH3), 24.0 (CH3), 22.4 (CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H33O9 465.2125; Found 465.2119. 1,5-Dimethoxy-7-methyl-1-((3aR,5S,5aR,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)naphthalen-2(1H)-one (30). The keto aldehyde 23 (232 mg, 0.5 mmol) was dissolved in tBuOH (10 mL) in a round bottom flask under N2 with stirring. Then KOtBu (67 mg, 0.6 mmol) was added. After 5 min stirring the solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (15% EtOAc/hexane as eluent) to afford naphthalenone 30 as a yellow solid (219 mg, 98%). [α]35D = –56.3 (c 0.3, CHCl3); mp 160–162 °C; IR (KBr): ν̃ = 2362, 1663, 1604, 1458, 1381, 1307, 1218, 1069 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 10.2 Hz, 1H), 7.18 (s, 1H), 6.65 (s, 1H), 6.08 (d, J = 10.2 Hz, 1H), 5.49 (d, J = 5.0 Hz, 1H), 4.42 (dd, J = 7.8, 2.3 Hz, 1H), 4.23–4.16 (m, 2H), 3.99 (d, J = 1.4 Hz, 1H), 3.86 (s, 3H), 3.08 (s, 3H), 2.37 (s, 3H), 1.51 (s, 3H), 1.26 (s, 3H), 1.17 (s, 3H), 1.04 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 200.3 (CO), 156.4, 140.9, 140.8, 139.3 (CH), 123.1 (CH), 122.3 (CH), 119.6, 110.9 (CH), 109.2, 108.6, 96.9 (CH), 84.6, 75.0 (CH), 71.4 (CH), 70.9 (CH), 70.5 (CH), 55.7 (OCH3), 53.4 (OCH3), 26.0 (CH3), 25.2 (CH3), 24.9 (CH3), 24.5 (CH3), 22.1 (CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H31O8 447.2019; Found 447.2017. 1,5,8-Trimethoxy-3-methyl-5-((3aR,5S,5aR,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aHbis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)tetraphene-6,7,12(5H)-trione (51). A solution of cyanophthalide 4925 (50 mg, 0.25 mmol) in dry THF (5 mL) was added to a suspension of LiOtBu (72 mg, 0.9 mmol) in dry THF (5 mL) at –60 °C under an inert atmosphere. The resulting solution was stirred at –60 °C for 30 min after which a solution of naphthalenone 30 (134 mg, 0.3 mmol) in dry THF (5 mL) was added to it. The reaction mixture was then stirred for another 30 min at –60 °C followed by 6 h at room temperature. The reaction was then quenched with saturated ammonium chloride solution and THF removed under reduced pressure. The residue was then extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude product 50. This compound was unstable, easily converted to its quinone form. We were only able to record its 1H NMR data. 1H NMR (400 MHz, CDCl3) δ 13.90 (s, 1H), 8.11



Page 24 of 32

(s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.36 (s, 1H), 6.95–6.92 (m, 2H), 5.28 (d, J = 5.0 Hz, 1H), 4.31 (dd, J = 8.0, 1.9 Hz, 1H), 4.22 (d, J = 8.1 Hz, 1H), 4.02‒4 (m, 5H), 3.97 (s, 3H), 3.31 (s, 3H), 2.46 (s, 3H), 1.16 (s, 3H), 1.15 (s, 3H), 1.06 (s, 3H), 0.82 (s, 3H). From the 1H NMR data it was clear that the crude product was pure enough for further use. Crude 50 obtained from previous reaction was dissolved in 15 mL chloroform and left the solution stand for 2 h. The compound entirely converted to 51. Evaporation of the solvent resulted in quinone 51 as a deep yellow semisolid (140 mg, 92% over two steps). [α]35D = – 76.8 (c 0.4, CHCl3); IR (KBr): ν̃ = 2925, 1718, 1592, 1466, 1211, 1115, 907 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.62 (t, J = 8.1 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.24 (s, 1H), 7.07 (s, 1H), 6.75 (s, 1H), 5.34 (d, J = 4.9 Hz, 1H), 4.42 (s, 2H), 4.11 (d, J = 5.0 Hz, 1H), 3.95 (s, 4H), 3.79 (s, 3H), 3.22 (s, 3H), 2.40 (s, 3H), 1.38 (s, 3H), 1.20 (s, 3H), 1.16 (s, 3H), 1.12 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 196.5, 187.0, 179.3, 159.1, 157.9, 150.2, 143.6, 138.9, 136.7, 134.4 (CH), 128.7, 121.2 (CH), 121.0, 117.9 (CH), 117.7 (CH), 116.5, 113.2 (CH), 110.0, 108.7, 96.9 (CH), 86.9, 75.6 (CH), 71.2 (CH), 71.1 (CH), 70.0 (CH), 56.6 (OCH3), 56.2 (OCH3), 54.4 (OCH3), 26.0 (CH3), 25.7 (CH3), 25.0 (CH3), 24.4 (CH3), 22.5 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C33H34O1123Na 629.1999; Found 629.1998. 6-Hydroxy-1,5,8-trimethoxy-3-methyltetraphene-7,12-dione (52).26 To a stirred solution of naphthol 50 (152 mg, 0.25 mmol) in THF:H2O (10 mL, 3:1) at room temperature was added 4 mL of 2 M HCl and the reaction was stirred at room temperature for 6 h. Then THF was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude quinone 52. The crude product was purified by flash column chromatography on silica gel (15% EtOAc/hexane as eluent) to afford quinone 52 as a deep red semisolid (47 mg, 50%). IR (KBr): ν̃ = 2925, 1635, 1450, 1387, 1344, 1295, 1043, 971 cm-1; 1H NMR (400 MHz, CDCl3) δ 12.47 (s, 1H), 7.74–7.65 (m, 2H), 7.50 (s, 1H), 7.27 (s, 1H), 6.68 (s, 1H), 4.10 (s, 3H), 4.06 (s, 3H), 3.92 (s, 3H), 2.51 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 189.4, 185.8, 160.1, 157.3, 148.8, 145.6, 141.2, 139.4, 136.3 (CH), 134.6, 131.4, 120.4, 120.3, 118.9 (CH), 116.6 (CH), 116.3, 113.1 (CH), 109.2 (CH), 61.2 (OCH3), 56.8 (OCH3), 56.2 (OCH3), 22.8 (CH3). 6-Hydroxy-1,8-dimethoxy-3-methyl-5-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)tetraphene-7,12-dione

(53).

To

a

stirred

solution of naphthol 50 (76 mg, 0.125 mmol) in THF:H2O (5 mL, 3:1) at room temperature


Page 25 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


was added oxalic acid (12 mg, o.125 mmol) and the reaction was stirred at room temperature for 3 h. Then THF was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude quinone 53. The crude product was purified by flash column chromatography on silica gel (10% EtOAc/hexane as eluent) to afford quinone 53 as a deep red semisolid (57 mg, 80%). The [α] value could not be determined because of its opacity27 even at 0.001 concentrations. IR (KBr): ν̃ = 2923, 1639, 1450, 1343, 1295, 1076, 999 cm-1; 1H NMR (400 MHz, CDCl3) δ 12.92 (s, 1H), 8.25 (s, 1H), 7.71 (t, J = 8 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.27 (overlap with CHCl3, 1H), 6.60 (s, 1H), 6.06 (d, J = 1.8 Hz, 1H), 5.82 (d, J = 5.1 Hz, 1H), 4.80 (dd, J = 8.0, 2.2 Hz, 1H), 4.59 (dd, J = 8.0, 1.9 Hz, 1H), 4.49 (dd, J = 5.2, 2.3 Hz, 1H), 4.05 (s, 3H), 3.87 (s, 3H), 2.45 (s, 3H), 1.67 (s, 3H), 1.39 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 189.0, 186.7, 160.1, 156.7, 154.5, 139.7, 139.5, 139.3, 138.6, 136.9, 136.2, 122.9, 120.7, 118.8, 118.0, 116.7, 116.6, 114.9, 109.2, 108.3, 97.2, 73.3, 71.6, 70.9, 65.5, 56.8, 56, 28.2, 26.2, 26.0, 25.4, 23.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H33O10577.2074; Found 577.2070. (3aS,5R,8bS)-5-(1-Methoxy-1-(3-methoxy-5-methyl-2-vinylphenyl)-2-methylallyl)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran (54). The general procedure for Grignard reaction of ketone was followed using ketone 33 (405 mg, 1 mmol) and commercially available isopropenylmagnesium bromide solution (4 mL, 0.5 M in THF i.e. 2 mmol). The crude product was directly used in the next step. The general procedure for methylation of alcohol to methyl ether was followed using the crude alcohol, NaH (60 mg, 60% in mineral oil) and 0.1 mL of MeI. The crude product was purified by flash column chromatography on silica gel (15% EtOAc/hexane as eluent) to afford methyl ether 54 as colourless oil (415 mg, 93%). [α]35D = –98.1 (c 0.5, CHCl3); IR (KBr): ν̃ = 2920, 1610, 1584, 1462, 1382, 897, 749 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 6.93 (dd, J = 17.8, 11.8 Hz, 1H), 6.70 (s, 1H), 5.66 (d, J = 5.1 Hz, 1H), 5.61 (s, 1H), 5.47 (d, J = 17.9 Hz, 1H), 5.33 (dd, J = 11.6, 2.5 Hz, 1H), 5.22 (s, 1H), 4.60 (s, 1H), 4.39 (d, J = 7.9 Hz, 1H), 4.19 (d, J = 4.9 Hz, 1H), 3.95 (s, 1H), 3.77 (s, 3H), 3.36 (s, 3H), 2.35 (s, 3H), 1.59 (s, 3H), 1.54 (s, 3H), 1.48 (s, 3H), 1.33 (s, 3H), 1.20 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 157.1, 142.9, 140.8,

136.7, 131.5 (CH), 123.0, 122.4 (CH), 119.0 (CH2), 117.9 (CH2), 111.6 (CH), 108.8, 108.1, 97.3 (CH), 84.0, 77.4 (CH), 71.8 (CH), 71.4 (CH), 71.3 (CH), 55.8 (OCH3), 53.1 (OCH3), 26.3 (CH3), 26.1 (CH3), 24.9 (CH3), 24.2 (CH3), 21.9 (CH3), 20.7 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C26H36O723Na 483.2359; Found 483.2365.



Page 26 of 32

2-Methoxy-6-(methoxy(2-methyloxiran-2-yl)((3aR,5S,5aR,8aS,8bR)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)methyl)-4methylbenzaldehyde (55). The alkene substrate 54 (230 mg, 0.5 mmol) was dissolved in a mixture of dry CH2Cl2 (10 mL) and MeOH (3 mL) in a flame-dried flask under N2. The solution was cooled to –78 °C, at which point a stream of O3 was introduced through a disposable pipet for a period of 5 min. Once complete, the reaction was purged with O2 and then N2. After 5 min of stirring, Me2S (0.15 mL, 2 mmol) was added. After 6 h stirring the solvent was evaporated and the crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford epoxy aldehyde 55 as a white gum (36 mg, 15%). [α]35D = –56.1 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 6.84 (s, 1H), 6.67 (s, 1H), 5.57 (d, J = 4.7 Hz, 1H), 4.38 (d, J = 8.0 Hz, 1H), 4.22 (s, 2H), 4.07 (s, 1H), 3.78‒3.74 (m, 4H), 3.58 (s, 3H), 2.60 (d, J = 5.2 Hz, 1H), 2.35 (s, 3H), 1.67 (s, 3H), 1.44 (s, 3H), 1.34 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 194.8 (CHO), 156.7, 142.1, 140.1, 127.2 (CH), 118.8, 111.6 (CH), 109.4, 109.3, 97.2 (CH), 83.2, 72.2 (CH), 71.5 (CH), 71.0 (CH), 69.9 (CH), 58.2, 56.1 (OCH3), 53.6 (CH2), 53.5 (OCH3), 26.4 (CH3), 26.1 (CH3), 25.4 (CH3), 24.6 (CH3), 22.3 (CH3), 19.7 (CH3). (2-(Benzyloxymethyl)-3-methoxy-5-methylphenyl)((3aS,5R,8bS)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)methanone

(40).

The

general procedure for reaction of arylmagnesium bromide with aldehyde 16 was followed using aryl bromide 56 (970 mg, 3 mmol), Mg turnings (108 mg, 4.5 mmol) and aldehyde 16 (258 mg, 1 mmol). The crude product (1H and HRMS spectra given in SI) was pure enough to use in the next step. The general procedure for PCC oxidation of alcohol to ketone was followed using the crude alcohol and PCC (323 mg, 1.5 mmol). The crude product was purified by flash column chromatography on silica gel (10% EtOAc/hexane as eluent) to afford ketone 40 as a white solid (324 mg, 65% over two steps). [α]35D = –55.9 (c 0.4, CHCl3); mp 158–160 °C; IR (KBr): ν̃ = 2986, 1717, 1598, 1461, 1376, 1328, 1243, 895, 821 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.33–7.25 (m, 5H), 6.83 (s, 1H), 6.74 (s, 1H), 5.60 (d, J = 4.7 Hz, 1H), 4.85 (s, 1H), 4.71–4.61 (m, 4H), 4.46 (s, 2H), 4.35–4.30 (m, 1H), 3.78 (s, 3H), 2.35 (s, 3H), 1.47 (s, 3H), 1.40 (s, 3H), 1.32 (s, 6H).

13

C NMR (100 MHz, CDCl3) δ 203.6,

156.7, 140.1, 138.6, 138.3, 128.2 (CH), 127.8 (CH), 127.3 (CH), 122.3, 119.8 (CH), 112.9 (CH), 109.7, 108.9, 96.8 (CH), 74.1 (CH), 72.3 (CH2), 72.2 (CH), 70.9 (CH), 70.5 (CH), 64.4 (CH2), 55.7 (OCH3), 25.9 (CH3), 25.9 (CH3), 25.0 (CH3), 24.6 (CH3), 21.7 (CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C28H34O823Na 521.2151; Found 521.2155.


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(3aS,5R,8bS)-5-(1-(2-(Benzyloxymethyl)-3-methoxy-5-methylphenyl)-1-methoxyallyl)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran (24). The general procedure for Grignard reaction of ketone was followed using ketone 40 (495 mg, 1 mmol) and commercially available vinylmagnesium bromide solution (2 mL, 1 M in THF i.e. 2 mmol). The crude product was directly used in the next step without purification. To a stirred solution of alcohol obtained from previous step in anhydrous THF (5 mL) at 0°C was added NaH (60 mg, 60% in oil) under inert atmosphere and the reaction was stirred at same temperature for 30 min. MeI (0.1 mL, 1.3 mmol) was then added dropwise to the reaction mixture and stirring was continued at room temperature for 12 h. The reaction mixture was cooled to 0 °C and MeOH was added to quench excess NaH. Then THF was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude benzyl ether. The crude product was purified by flash column chromatography on silica gel (10% EtOAc/hexane as eluent) to afford alkene 24 as oil (449 mg, 83% over two steps). [α]35D = –75.2 (c 0.5, CHCl3); IR (KBr): ν̃ = 2934, 1605, 1578, 1454, 1381, 1254, 1211, 1166, 999, 898, 698 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.42–7.25 (m, 5H), 6.73 (s, 1H), 6.52 (dd, J = 17.6, 10.9 Hz, 1H), 5.70 (d, J = 4.8 Hz, 1H), 5.07 (d, J = 11.0 Hz, 1H), 4.72–4.48 (m, 8H), 4.40–4.34 (m, 1H), 3.84 (s, 3H), 3.17 (s, 3H), 2.36 (s, 3H), 1.60 (s, 3H), 1.49 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.9, 141.7, 141.2 (CH), 139.6, 138.2, 128.1 (CH), 127.8 (CH), 127.2 (CH), 123.5, 122.5 (CH), 116.8 (CH2), 111.9 (CH), 109.6, 108.7, 97.7 (CH), 84.5, 73.1 (CH2), 71.5 (CH), 71.4 (CH), 70.7 (CH), 69.4 (CH), 65.7 (CH2), 55.9 (OCH3), 52.4 (OCH3), 26.0 (CH3), 25.8 (CH3), 25.1 (CH3), 24.9 (CH3), 21.8 (CH3). HRMS (ESI-TOF) m/z: [M–MeOH+H]+ Calcd for C30H37O7 509.2539; Found 509.2521. 1-Hydroxy-1-(3-methoxy-5-methyl-2-vinylphenyl)-1-((3aR,5S,5aR,8aS,8bR)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)but-3-en-2-one (57). 1Methoxyallene (0.10 mL, 75.6 mg, 1.08 mmol) was dissolved in dry THF (5 mL) and nBuLi (0.37 mL, 2.50 M in hexane, 0.9 mmol) was added at –40 °C in an inert atmosphere. After 30 min, the mixture was cooled to –78 °C and a solution of ketone 33 (202 mg, 0.5 mmol) in THF (7 mL) was added. The mixture was stirred for 3 h, H2O (5 mL) was added, and after warming to room temperature, the layers were separated. THF was evaporated under reduced pressure. The residue was then extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the



Page 28 of 32

crude allene. This compound was unstable, easily converted to its keto form. To a stirred solution of the crude allene (obtained from previous step) in THF:H2O (10 mL, 3:1) at room temperature was added 5 mL of 1 M HCl and the reaction was stirred at room temperature for 2 h. Then THF was evaporated under reduced pressure and the residue was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (3×1/3 vol.), dried (Na2SO4) and concentrated to provide the crude ketone 57. The crude product was purified by flash column chromatography on silica gel (20% EtOAc/hexane as eluent) to afford unsaturated ketone 56 as colourless gum (175 mg, 90% over two steps). [α]35D = –35.4 (c 0.2, CHCl3); IR (KBr): ν̃ = 2927, 1706, 1606, 1458, 1380, 1258, 1210, 1065, 991 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 6.82–6.60 (m, 3H), 6.32 (dd, J = 17.3, 2.1 Hz, 1H), 5.61 (d, J = 4.7 Hz, 1H), 5.55 (dd, J = 10.4, 2.1 Hz, 1H), 5.45 (dd, J = 11.5, 2.2 Hz, 1H), 5.34 (dd, J = 17.8, 2.3 Hz, 1H), 5.06 (s, 1H), 4.69 (s, 1H), 4.51 (dd, J = 8.1, 2.2 Hz, 1H), 4.27 (dd, J = 4.9, 2.3 Hz, 1H), 4.19 (d, J = 8.1 Hz, 1H), 3.75 (s, 3H), 2.38 (s, 3H), 1.78 (s, 3H), 1.43 (s, 3H), 1.36 (s, 3H), 1.20 (s, 3H).

13

C NMR (100 MHz, CDCl3) δ 194.7, 157.5, 138.1, 137.3,

131.6 (CH), 131.3 (CH), 128.9 (CH2), 124.4, 120.7, 120.6 (CH2), 112.8 (CH), 109.6, 109.4, 97.1 (CH), 83.6, 71.9 (CH), 71.3 (CH), 70.9 (CH), 68.2 (CH), 56.1 (OCH 3), 26.2 (CH3), 26.0 (CH3), 25.3 (CH3), 24.2 (CH3), 22.1(CH3). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H32O823Na 483.1995; Found 483.1999. 1-Hydroxy-1-(3-methoxy-5-methyl-2-vinylphenyl)-1-((3aR,5S,5aR,8aS,8bR)-2,2,7,7tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-5-yl)butan-2-one

(60).

CeCl3•7 H2O (91 mg, 0.25 mmol, 1.1 equiv) was added to a solution of ketone 57 (106 mg, 0.23 mmol, 1 equiv) in MeOH (3 mL) at 0 °C. After 30 minutes, NaBH 4 (10 mg, 0.26 mmol, 1.2 equiv) was added and the mixture was stirred for 2 h at 0 °C. Saturated aqueous NaHCO 3 was added and the mixture was extracted with Et2O (3x10 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Ketone 60 was obtained as colorless oil (69 mg, 60%) after purification by column chromatography (20% EtOAc/hexane). [α]35D = –67 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 6.76 – 6.69 (m, 2H), 5.61 (d, J = 4.8 Hz, 1H), 5.46(dd, J= 11.6, 2.4 Hz, 1H), 5.33 (dd, J = 17.9, 2.4 Hz, 1H), 5.02 (s, 1H), 4.65 (s, 1H), 4.50 (dd, J = 8.1, 2.3 Hz, 1H), 4.27 (dd, J = 5.0, 2.3 Hz, 1H), 4.18 (dd, J = 8.1, 1.6 Hz, 1H), 3.76 (s, 3H), 2.66 – 2.56 (m, 1H), 2.53 – 2.42 (m, 1H), 2.37 (s, 3H), 1.77 (s, 3H), 1.45 (s, 3H), 1.36 (s, 3H), 1.20 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H).

13

C NMR (100 MHz, CDCl3) δ 208.4, 157.5, 138.4, 138.0, 131.5 (CH), 124.5, 120.6

(CH), 120.4 (CH2), 112.6 (CH), 109.5, 109.4, 97.1 (CH), 84.5, 71.8 (CH), 71.3 (CH), 70.9


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(CH), 68.5 (CH), 56.2 (OCH3), 30.4 (CH2), 26.3 (CH3), 26 (CH3), 25.3 (CH3), 24.1 (CH3), 22 (CH3), 7.9 (CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H35O8 463.2332; Found 463.2322.

ASSOCIATED CONTENT Supporting Information 1 H and 13C NMR spectra of the synthesized compounds

AUTHOR INFORMATION Corresponding Author * E-mail for D.M.: [email protected]. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We gratefully acknowledge the Council of Scientific and Industrial Research (CSIR) for financial support (02(0183)/14/EMRII), and the Department of Science and Technology for instrumental facilities. S. C. thanks CSIR for his research fellowship. We are also thankful to Prof. M. K. Ghorai (IIT Kanpur) and Dr. S. C. Pan (IIT Guwahati) for HRMS data.

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A Representative Synthetic Route for C5 Angucycline Glycosides

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