Introduction

Clarithromycin, one of the semi-synthetic analogs of erythromycin A, has good acid stability in the stomach because of the incorporation of 6-OMe blocking the degradation process that involved original 6-OH and 9-keto.1 Recently, 3-keto derivatives of clarithromycin, termed ketolides, have been developed to combat the growing prevalence of MLSB resistance.2 Ketolides, the third-generation erythromycin derivatives, are represented by telithromycin (HMR3647),3 cethromycin (ABT-773)4 and TE-8025 (Figure 1).

Figure 1
figure 1

Structure of ketolide.

The success of ketolides disproved the long held belief that 3-O-cladinose was essential moiety for the antibacterial activity. In addition to ketolides, other macrolides with various substituents at C-3 instead of cladinose have also been designed and investigated over the past decade, such as acylide,6 3, 6-bicyclolide (Figure 2),7 2, 3-anhydrolide,8 2, 3-enol ether,9 3-deoxy,10 3-O-phenyl ether,11 3, 6-ketal12 and 3, 6-ether.13

Figure 2
figure 2

Structure of acylide, 3, 6-bicyclolide and alkylide.

In our search for novel erythromycin derivatives, we previously reported some alkylides (Figure 2) with improved activity against erythromycin-resistant pathogens.14 We speculated alkylides, characterized by 3-O-ether bond, might have a profile of higher acid stability and enzyme resistance compared with acylides.6 More importantly, an allyl group could easily be transformed into other functional groups.15 For this reason, we synthesized the alkylides to explore their structure-activity relationship. Consequently, we found that Heck isomerization occurred in the presence of palladium (II) acetate and tri(o-tolyl)phosphine, which led to a 3-O-(3-aryl-Z-prop-1-enyl) sidechain,14 which involved an allylic double-bond isomerization and concomitant configuration isomerization. In this study, we report further modification of the configuration of the linkers at 3-OH, as well as the skeleton of macrolides.

Results and discussion

3-O-(3-aryl-E-prop-2-enyl) clarithromycin derivatives were prepared by a multi-step synthesis, as illustrated in Scheme 1. Starting material 3-OH clarithromycin was produced by the acidic hydrolysis of commercially available clarithromycin.2 Without the addition of a base such as triethylamine or K2CO3, the 2′-acetate 1 (see ref. 2) was smoothly obtained by treatment of 3-OH-clarithromycin with acetic anhydride, as attributed to the catalytic function of neighboring 3′-tertiary amino group. Next, the 11, 12-carbonate 2 was easily obtained by the BTC (bis(trichloromethyl)carbonate) method reported by You.16

An initial attempt14 to convert 2 to the 3-O-allyl counterpart failed in the presence of allyl bromide and KOtBu. The major product in the resulting mixture was identified as 10, 11-anhydro-3-OH-6-O-methylerythromycin A 3 after methanolysis. In contrast, the 3-keto 4 resulting from the Corey–Kim oxidation17 of 2, successfully yielded corresponding the 2, 3-dehydro-3-O-allyl analog 5 in the presence of allyl bromide and KOtBu. A similar phenomenon was reported by Denis concerning four-atom-length and five-atom-length alkoxy linkers using NaH as the base.9

Meanwhile, the 11, 12-carbonate underwent smooth elimination in the presence of KOtBu and was converted to the 10, 11-olefin. Thus, in addition to previously reported DBU,16 KOtBu seemed to be effective in decarboxylation, but it is noted that the elimination of the 11, 12-carbonate under the same reaction condition would be hampered when the 9-keto was converted to an oxime ether.14

After the introduction of the allyl group, a three-atom-length allylic linker was formed to serve for further modification. In the presence of palladium (II) acetate and tri(o-tolyl) phosphine, an aryl group was attached to the allyl group. Interestingly, the Heck reaction yielded the expected 3-O-(3-aryl-E-prop-2-enyl) derivatives 6 without Heck isomerization. According to the crystal structure of the alkylide,14 we speculated that spatially neighboring 5-O-desosamine probably led to Heck isomerization of C-3 sidechain, whereas the introduction of 2, 3-olefin may change the conformation of skeleton of macrolide, and thus make the 3-O-allyl functional group be farther away from originally spatially neighboring 5-O-desosamine.14 However, this hypothesis would require further studies to be fully assessed. Finally, the target compound 7 was obtained by methanolysis. The selected aromatic rings included 3-quinolyl (a), 5-indolyl (b), 3-pyridyl (c) and 4-isoquinolyl (d) group.

The in vitro antibacterial activity of 7a7d was assessed against erythromycin-susceptible and erythromycin-resistant bacteria including Staphylococcus aureus and Streptococcus pneumoniae. Data are tabulated in Table 1 as the MIC, which was determined by the broth microdilution method, as recommended by the Clinical and Laboratory Standards Institute.18 The MIC test indicated that 7a7d were generally inactive to the selected pathogens, especially for S. pneumoniae. Only 7d (4-isoquinolyl) had a slightly higher activity against erythromycin-resistant S. aureus than the reference compound, clarithromycin. This antibacterial evaluation reconfirmed that position 2 of the skeleton of macrolides needs to remain tetrahedral to retain good activity.9 On the other hand, the formation of 10,11-olefin also proved to have negative effects on the activity of macrolides, but further transformation of 10, 11-olefin to 11, 12-carbamate could improve the activity dramatically.8 Nevertheless, the aryl sidechain appended at C-3 could improve the activity of macrolides, because compound 7 showed much higher activity against both susceptible and resistant strains compared with 2, 3; 10, 11-dianhydroclarithromycin, a 3-dealkyloxy version of 7 with abolished activity (all MICs>100 μg ml−1).8

Table 1 Antibacterial activity of 2, 3-dehydro-3-O-(3-aryl-E-prop-2-enyl)-10, 11-anhydroclarithromycin derivatives against selected respiratory pathogens

In conclusion, a series of 2, 3-dehydro-3-O-(3-aryl-E-prop-2-enyl)-10, 11-anhydroclarithromycin derivatives were synthesized via the allylation of the 3-keto precursor followed by Heck reaction. As the structure of 2, 3-olefin and 10, 11-olefin may contribute much to low activity, further efforts would be devoted to the synthesis of 3-O-(3-aryl-E-prop-2-enyl) clarithromycin derivatives without 2, 3-olefin and 10, 11-olefin to search for better efficacy against resistant bacteria.

Experimental procedure

All solvents and reagents were obtained from commercial sources and used without further purification unless otherwise noted. 1H and 13C NMR spectra were recorded in CDCl3 on a Bruker ARX 400 MHz, 600 MHz (Bruker, Switzerland) with tetramethylsilane (TMS) as an internal standard. The assignments of 7e were made based on 1H–1H COSY. HRMS were obtained with Bruker Apex IV FTMS (Bruker, USA). Column chromatography was performed with silica gel (Qingdao Haiyang, Qingdao, China; 200–300 mesh grade). NH3 H2O refers to 25% aqueous ammonium hydroxide.

scheme 1

Reagents and conditions: (a) Ac2O, CH2Cl2, 88.2%; (b) BTC (bis(trichloromethyl)carbonate) , pyridine, CH2Cl2, -5 °C, 94.2%; (c) allyl bromide, KOtBu, THF/DMSO, 0 °C, 50% (TLC), then MeOH; (d) NCS (N-chlorosuccinimide), DMS (dimethyl sulfide), CH2Cl2, −15 °C, 97.3%; (e) allyl bromide, KOtBu, THF/DMSO, 0 °C, 90.5%; (f) Pd(OAc)2, P(o-MePh)3, Et3N, acetonitrile, ArBr, 60 °C 1 h then 80 °C 24 h; (g) MeOH, 65 °C, 8.4–11.5% in two steps (7a–7d).

3-OH-6-O-CH3-erythromycin A

To a stirred solution, 80 ml of water and 4 ml of 36% aqueous HCl was added followed by 10 g of clarithromycin. The reaction was stirred at room temperature for 2 h, and then was adjusted to pH 9 with 25% aqueous NH3. The precipitate was collected by filtration, and washed with cold water to afford 6.8 g of 3-OH-clarithromycin2 (86.2%). HRMS (ESI) (M+H)+ m/z 590.3901, calculated for C30H56NO10 590.3898.

2′-O-Ac-3-OH-6-O-CH3-erythromycin A (1)

A solution of 3-OH-clarithromycin (5.4 g, 9.2 mmol) in CH2Cl2 (50 ml) was treated with acetic anhydride (2.0 ml, 20.7 mmol) at room temperature for 1 h. The reaction mixture was washed with saturated NaHCO3, water and brine. The organic layer was dried over MgSO4, filtrated and concentrated to yield 1 (see ref. 2) (5.1 g, 88.2%). 1H NMR (400 MHz, CDCl3) δ: 2.06 (s, 3H, 2′-COCH3), 2.25 (s, 6H, –N(CH3)2), 2.49–2.54 (m, 1H, H-8), 2.63–2.66 (m, 1H, H-2), 2.93 (s, 3H, 6-OCH3), 2.96 (q, 1H, H-10), 3.25 (s, 1H, 12-OH), 3.80 (s, 1H, H-11), 3.94 (s, 1H, 11-OH), 4.41 (dd, 1H, H-2′), 5.15 (dd, 1H, H-13).

2′-O-Ac-3-OH-6-O-CH3-11, 12-carbonate erythromycin A (2)

To a solution of 1 (10.2 g, 16.2 mmol) in CH2Cl2 (200 ml), pyridine (15.6 ml, 193.8 mmol) was added and then a solution of BTC (bis(trichloromethyl)carbonate) (9.6 g, 32.3 mmol) in CH2Cl2 (80 ml) was dropped over 2 h. The reaction mixture was stirred at −5 °C for 7 h. Then 200 ml of brine was added dropwise to the reaction mixture. The organic layer was washed with saturated NaHCO3, water and brine and then dried over MgSO4, filtrated and concentrated to yield 2 (see ref. 16) (10.0 g, 94.2%).

3-OH-6-O-CH3-10,11-anhydroerythromycin A (3)

The procedure described as below was originally designed to prepare 3-O-allyl-6-O-methylerythromycin 11, 12-carbonate, but unexpected results were observed.

To a solution of 2 (1.0 g, 1.5 mmol) in 10 ml of DMSO and 10 ml of THF, allyl bromide (0.25 ml, 3.0 mmol) and KOtBu (0.5 g, 3.0 mmol) was added. The mixture was stirred for 30 min at 0 °C, then quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over MgSO4, filtrated and concentrated. The crude product was heated to reflux in MeOH, and then the solution was concentrated. The residue was purified by column chromatography on silica gel (10:0.3:0.1 CH2Cl2/C2H5OH/NH3 H2O) to yield pure 3 (102 mg, 11.7%). HRMS (ESI) (M+H)+ m/z 572.37921, calcd for C30H54NO9 572.37931. 1H NMR (400 MHz, CDCl3) δ: 0.92 (t, J=7.3 Hz, 3H, 15-CH3), 1.02 (d, J=7.0 Hz, 3H, 8-CH3), 1.20 (d, J=6.4 Hz, 3H, 4-CH3), 1.26–1.29 (m, 7H, 12-CH3, 5′-CH3, H-4′ax), 1.33 (d, J=6.8 Hz, 3H, 2-CH3), 1.37 (s, 3H, 6-CH3,), 1.60–1.74 (m, 5H, H-14ax, H-7, H-4′eq, H-4), 1.91–1.97 (m, 1H, H-14eq), 2.04 (s, 3H, 10-CH3), 2.29 (s, 6H, -N(CH3)2), 2.54 (br, 1H, H-3′), 2.69–2.71 (m, 1H, H-2), 3.10 (s, 3H, 6-OCH3), 3.14–3.29 (m, 2H, H-2′, H-5′), 3.52-3.58 (m, 1H, H-8), 3.92 (m, 2H, OH, H-5), 4.03 (dd, J=4.2, 10.5 Hz, H-3), 4.45–4.51 (m, 2H, OH, H-1′), 4.96 (d, J=9.9 Hz, H-13), 6.47 (s, 1H, H-11). 13C NMR (100 MHz, CDCl3) δ: 207.7, 176.7, 141.5, 138.6, 106.8, 91.9, 80.8, 79.2, 77.6, 73.5, 70.5, 69.7, 65.5, 48.2, 44.3, 40.2, 38.3, 36.9, 36.4, 28.3, 21.3, 20.8, 20.3, 20.1, 16.1, 15.7, 12.9, 10.4, 7.6.

2′-O-Ac-3-keto-6-O-CH3-11,12-carbonate erythromycin A (4)

A solution of NCS (N-chlorosuccinimide) (3.25 g, 24.3 mmol) in CH2Cl2 (160 ml) was stirred at −15 °C for 10 min, and then DMS (dimethyl sulfide) (2.0 ml, 27.2 mmol) was added slowly to the solution . After stirring for 20 min, a solution of 2 (10.0 g, 15.2 mmol) in CH2Cl2 (80 ml) was added to the reaction mixture over 30 min. The reaction mixture was stirred at −15 °C. After 2–3 h, dropwise triethylamine (3.3 ml) was added to the reaction mixture. The solution soon became clear, and continued to be stirred at −5 °C for 1 h. The organic layer was washed with saturated NaHCO3, water and brine, concentrated to yield 4 (see ref. 16) (9.7 g, 97.3%). 1H NMR (400 MHz, CDCl3) δ: 0.88 (t, 3H, 15-CH3), 1.12–1.14 (m, 6H, 8-CH3, 4-CH3), 1.18 (d, 3H, 10-CH3), 1.23 (d, 3H, 5′-CH3), 1.30 (s, 3H, 6-CH3), 1.38 (d, 3H, 2-CH3), 1.53 (s, 3H, 12-CH3), 1.56–1.90 (m, 4H), 2.06 (s, 3H, 2′-COCH3), 2.23 (s, 6H, –N(CH3)2), 2.63–2.69 (m, 5H, H-3′, H-8, 6-OCH3), 2.92–3.03 (m, 2H, H-10, H-4), 3.49–3.56 (m, 1H, H-5′), 3.78 (q, 1H, H-2), 4.15 (d, 1H, H-5), 4.36 (d, 1H, H-1′), 4.61 (s, 1H, H-11), 4.72 (dd, 1H, H-2′), 4.99 (dd, 1H, H-13). 13C NMR (100 MHz, CDCl3) δ: 212.8, 203.9, 169.7, 169.0, 153.7, 101.3, 84.4, 80.8, 78.2, 78.1, 71.5, 69.1, 63.3, 51.0, 49.4, 47.4, 43.7, 40.6, 39.2, 38.0, 30.4, 22.3, 21.3, 20.9, 19.6, 17.8, 16.0, 14.0, 13.5, 12.4, 10.2.

2′-O-Ac-2, 3-dehydro-3-O-allyl-6-O-CH3-10, 11-anhydroerythromycin A (5)

To a solution of 4 (2.0 g, 3.0 mmol) in 20 ml of DMSO and 20 ml of THF, allyl bromide (0.51 ml, 6.0 mmol) and KOtBu (1.0 g, 6.0 mmol) was added. The mixture was stirred for 30 min at 0 °C, then quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over MgSO4, filtrated and concentrated to yield 5 (1.8 g, 90.5%). The structure of 5 was confirmed by the H-H COSY anal of 7e.

2, 3-Dehydro-3-O-allyl-6-O-CH3-10, 11-anhydroerythromycin A (7e)

The product 5 was heated to reflux in MeOH at 65 °C for 3 h. After the solvent was evaporated in vacuo, the residue was purified by column chromatography on silica gel (15:0.3:0.15 CH2Cl2/C2H5OH/NH3 H2O) to yield pure 7e. HRMS (ESI) (M+H)+ m/z 610.39584, calcd for C33H56NO9 610.39496. 1H NMR (400 MHz, CDCl3) δ: 0.96 (t, J=7.2 Hz, 3H, 15-CH3), 1.07 (d, J=6.6 Hz, 3H, 8-CH3), 1.17–1.34 (m, 10H, 12-CH3, 4-CH3, 5′-CH3, H-4′ax), 1.39 (s, 3H, 6-CH3,), 1.49 (s, 3H, 2-CH3), 1.53–1.55 (m, 2H, H-14ax, H-7), 1.83–1.98 (m, 2H, H-4′eq, H-14eq), 2.06 (s, 3H, 10-CH3), 2.12–2.21 (m, 1H, H-7), 2.41 (s, 6H, -N(CH3)2), 2.60–2.80 (m, 3H, -CH2-CH=CH2, H-3′), 3.13 (s, 3H, 6-OCH3), 3.32 (dd, 1H, H-2′), 3.39–3.60 (br, 3H, H-4, H-8, H-5′), 4.16 (br, 1H, H-5), 4.36 (br, 1H, H-1′), 5.05 (dd, 1H, H-13), 5.13–5.17 (m, 2H, -CH2-CH=CH2), 5.59–5.69 (m, 1H, -CH2-CH=CH2), 6.60 (br, 1H, H-11). 13C NMR (100 MHz, CDCl3) δ: 11.3, 13.3, 15.2, 20.0, 21.1, 21.4, 22.5, 23.1, 29.8, 35.0, 39.8, 40.4, 50.0, 60.3, 65.4, 69.2, 70.3, 78.6, 83.8, 119.5, 132.1, 172.6.

2, 3-Dehydro-3-O-[3-(3-quinolyl)-E-2-propenyl]-6-O-CH3-10, 11-anhydroerythromycin A (7a)

To a solution of 5 (1.4 g, 2.1 mmol), palladium (II) acetate (90.3 mg, 0.4 mmol) and tri(o-tolyl)phosphine (245 mg, 0.8 mmol) in acetonitrile (8 ml) were added followed by 3-bromoquinoline (0.55 ml, 4.0 mmol) and triethylamine (0.56 ml, 4.0 mmol). The mixture was flushed with nitrogen and sealed in a pressure tube. The reaction mixture was stirred at 60 °C for 1 h and then at 80 °C for 24 h. The reaction mixture was extracted with ethyl acetate, and washed with saturated NaHCO3 and brine. The organic phase was concentrated, and the residue was purified by column chromatography on silica gel (5:5:0.2 petroleum ether/acetone/triethylamine) to yield 6a (523 mg). The product 6a (523 mg) was heated to reflux in MeOH (10 ml) at 65 °C for 3 h. After the solvent was evaporated, the crude product was purified by column chromatography on silica gel (15:0.3:0.15 CH2Cl2/C2H5OH/NH3 H2O) to yield pure 7a (172 mg, 10.8% in two steps). HRMS (ESI) (M+H)+ m/z 737.43864, calcd for C42H61N2O9 737.43716. 1HNMR (CDCl3, 400 MHz), δ: 0.98 (t, 3H, 15-CH3), 1.08 (d, 3H, 8-CH3), 1.18–1.27 (m, 10H), 1.48 (s, 3H, 6-CH3), 1.52 (s, 3H, 2-CH3), 1.63–1.66 (m, 2H), 2.06 (s, 3H, 10-CH3), 2.16–2.22 (m, 1H), 2.27 (s, 6H, N(CH3)2), 2.45–2.50 (m, 1H), 2.84–2.88 (m, 1H, 3-O-CH2CH=CH-Ar), 2.84–3.00 (m, 1H, 3-O-CH2CH=CH-Ar), 3.09 (s, 3H, 6-OCH3), 3.23 (t, 1H, H-2′), 3.35 (s, 1H, 2′-OH), 3.35–3.55 (m, 3H, H-4, H-8, H-5′), 4.13 (br, 1H, H-5), 4.30 (br, 1H, H-1′), 5.07 (d, 1H, 13-H), 6.28–6.32 (m, 1H, 3-O-CH2CH=CH-Ar), 6.62 (d, J=15.8 Hz, 1H, 3-O-CH2CH=CH-Ar), 6.63 (br, 1H, H-11), 7.52 (t, 1H, quinoline), 7.63–7.68 (m, 1H, quinoline), 7.77 (d, 1H, quinoline), 7.99 (d, 1H, quinoline), 8.05 (d, 1H, quinoline), 8.90 (d, 1H, quinoline). 13CNMR (CDCl3, 100 MHz) δ: 11.5, 13.1, 15.6, 19.6, 21.2, 21.9, 22.6, 23.1, 28.7, 35.2, 40.1, 40.3, 50.2, 60.7, 65.4, 69.4, 70.3, 78.5, 127.0, 127.8, 127.9, 129.1, 129.2, 129.7, 130.9, 132.1, 147.4, 149.1, 172.5.

2, 3-Dehydro-3-O-[3-(5-indolyl)-E-2-propenyl]-6-O-CH3-10, 11-anhydroerythromycin A (7b)

Following the procedure for 7a, 6b (234 mg) was prepared as a yellow solid from 5 (0.9 g), and then deacetylated to give pure 7b (112 mg, 11.1% in two steps). HRMS (ESI) (M+H)+ m/z 725.43714, calcd for C41H61N2O9 725.43716. 1HNMR (CDCl3, 600 MHz), δ: 0.97 (t, 3H, 15-CH3), 1.09 (d, 3H), 1.21–1.30 (m, 10H), 1.47 (s, 3H, 6-CH3), 1.50 (s, 3H, 2-CH3), 1.66–1.68 (m, 1H), 2.07 (s, 3H, 10-CH3), 2.16–2.17 (m, 1H), 2.29 (s, 6H, N(CH3)2), 2.52 (m, 1H), 2.79–2.98 (m, 2H, 3-O-CH2CH=CH-Ar), 3.13 (s, 3H, 6-OCH3), 3.24–3.57 (m, 5H), 4.16 (br, 1H), 4.36 (br, 1H), 5.06 (dd, 1H, 13-H), 5.97 (t, 1H, 3-O-CH2CH=CH-Ar), 6.50 (s, 1H, indole), 6.57 (d, J=15.1 Hz, 1H, 3-O-CH2CH=CH-Ar), 6.68 (br, 1H, 11-H), 7.18–7.21 (m, 2H, indole), 7.31 (d, 1H, indole), 7.54 (s, 1H, indole), 8.63 (s, 1H, indole).

2, 3-Dehydro-3-O-[3-(3-pyridyl)-E-2-propenyl]-6-O-CH3-10, 11-anhydroerythromycin A (7c)

Following the procedure for 7a, 6c (205 mg) was prepared as a yellow solid from 5 (0.9 g), and then deacetylated to give pure 7c (80 mg, 8.4% in two steps). HRMS (ESI) (M+H)+ m/z 687.42278, calcd for C38H59N2O9 687.42151. 1HNMR (CDCl3, 600 MHz), δ: 0.90 (t, 3H, 15-CH3), 1.12 (d, 3H), 1.20–1.29 (m, 10H), 1.48 (s, 3H, 6-CH3), 1.55 (s, 3H, 2-CH3), 1.64–1.66 (m, 2H), 1.91 (br, 1H), 2.04 (s, 3H, 10-CH3), 2.04–2.07 (m, 1H), 2.27 (s, 6H, N(CH3)2), 2.44–2.48 (m, 1H), 2.83–2.84 (m, 2H, 3-O-CH2CH=CH-Ar), 3.02 (s, 3H, 6-OCH3), 3.21 (dd, 1H), 3.33–3.54 (m, 4H), 4.12 (d, 1H), 4.34 (br, 1H), 4.98 (dd, 1H, H-13), 6.19 (dt, 1H, 3-O-CH2CH=CH-Ar), 6.45 (d, J=15.8 Hz, 1H, 3-O-CH2CH=CH-Ar), 6.67 (br, 1H, H-11), 7.20–7.22 (m, 1H, pyridine), 7.61 (d, 1H, pyridine), 8.43–8.44 (m, 1H, pyridine), 8.54 (d, 1H, pyridine).

2, 3-Dehydro-3-O-[3-(4-isoquinolyl)-E-2-propenyl]-6-O-CH3-10, 11-anhydroerythromycin A (7d)

Following the procedure for 7a, 6d (257 mg) was prepared as a yellow solid from 5 (0.9 g), and then deacetylated to give pure 7d (117 mg, 11.5% in two steps). HRMS (ESI) (M+H)+ m/z 737.43888, calcd for C42H61N2O9 737.43716. 1HNMR (CDCl3, 600 MHz), δ: 0.87 (t, 3H, 15-CH3), 1.06 (d, 3H), 1.22–1.26 (m, 10H), 1.49 (s, 3H, 6-CH3), 1.63 (s, 3H, 2-CH3), 1.64–1.66 (m, 1H), 1.93 (br, 1H), 2.04 (s, 3H, 10-CH3), 2.06–2.10 (m, 1H), 2.27 (s, 6H, N(CH3)2), 2.44–2.47 (m, 1H), 2.91–3.02 (m, 2H, 3-O-CH2CH=CH-Ar), 3.05 (s, 3H, 6-OCH3), 2.21 (dd, 1H), 3.22–3.53 (m, 4H), 4.14 (d, 1H), 4.32 (br, 1H), 5.04 (dd, 1H, H-13), 6.25 (dt, 1H, 3-O-CH2CH=CH-Ar), 6.74 (br, 1H, H-11), 7.09 (d, J=15.8 Hz, 1H 3-O-CH2CH=CH-Ar), 7.61 (t, 1H, isoquinoline), 7.73 (t, 1H, isoquinoline), 7.95 (d, 1H, isoquinoline), 8.05 (d, 1H, isoquinoline), 8.54 (s, 1H, isoquinoline), 9.10 (s, 1H, isoquinoline). 13CNMR (CDCl3, 150 MHz) δ: 11.3, 13.4, 16.0, 19.6, 21.3, 21.6, 22.4, 28.7, 36.6, 40.1, 40.4, 41.5, 44.7, 50.1, 60.5, 65.5, 69.5, 70.5, 78.6, 83.2, 104.0, 123.0, 127.3, 128.1, 128.5, 128.6, 130.3, 130.6, 133.6, 138.8, 140.1, 142.6, 151.6, 171.3.