Dihydroxylation Studies of Isoquinolinones: Synthesis of the EF-Ring of Lysolipin I

Abstract

Inspired by the potent polycyclic xanthone antibiotic lysolipin I, a general study on asymmetric dihydroxylation reactions of variously substituted isoquinolinones was performed. Different isoquinolinones were efficiently prepared, either by a Pomeranz–Fritsch type condensation or a Curtius rearrangement. Under a broad variety of conventional oxygenation procedures, they proved very unreactive. However, either by suitable substitution of the appending aromatic ring or more forcing conditions a dihydroxylation could finally be performed, which allowed the synthesis of the EF-ring of lysolipin I.

The potent polyketide antibiotic lysolipin I (1, Scheme [1]),[2] presents a structurally unique polycyclic xanthone natural product[3] that is characterized by an unusual polyhydroxylated isoquinolinone moiety. These hydroxyl groups might have been introduced enzymatically by oxygenases from alkene precursors at a late stage of their biosynthesis.[4] [5] Mimicking this pathway, a related approach would rely on a selective oxidation of isoquinolinones of type 3 to access the desired hydroxylated derivatives 2 in a direct fashion. While various strategies for the synthesis of the parent isoquinolinones are available,[6] [7] [8] selective hydoxylation reactions for specific introduction of an oxygenation pattern have hardly been advanced.[9] As part of our studies to develop new approaches for highly unsaturated polyketide antibiotics,[10] [11] [12] [13] [14] [15] [16] we report herein a general study on asymmetric benzylic dihydroxylations of various isoquinolinones 3, which differ in the substitution and protective group pattern at C6 and C7 of the appending aromatic ring. Finally, we applied this strategy for the preparation of the authentic EF-ring system of lysolipin I.

During this study it became quickly apparent that the electronic situation in combination with the substitution pattern of the neighboring aromatic ring has a large impact on the envisioned oxygenation reaction. Therefore, variously substituted substrates with different electronic and structural properties were prepared. Their synthesis involved either a condensation reaction, mainly for the preparation of 7-hydroxylated substrates (Scheme [2]), or a Curtius rearrangement sequence for variation of the substation pattern at C6 (Schemes 4 and 5, vide infra).

As shown in Scheme [2], selected isoquinolinone 8 contains an additional C7-hydroxyl group that is in direct conjugation with the olefinic double bond and thus leads to a dramatic increase of the electron density at this alkene.

For its synthesis, we first evaluated a direct cyclization of readily available diacid 10 or diester 9 [17] with methylamine. However, useful degrees of conversion using different cyclization procedures could not be obtained, resulting mainly in decomposition at elevated temperatures.[7] Also, carboxylate activation with thionyl chloride, EDCI, or even harsher conditions with polyphosphoric acid were not successful.[18] Therefore, an intramolecular Pomeranz–Fritsch type condensation was applied.[19] Required acetal 7 was obtained in three steps from commercial 2,3-dihydroxybenzoic acid (4). After quantitative methylation and saponification of intermediate ester (98%, 2 steps), derived benzoic acid 5 was amidated with amino acetal 6 in the presence of EDCI[6] in moderate yield (55%), which could not be improved by other methods, such as CDI/DMAP or intermediate acid chloride formation. Amide 7, which resided as a mixture of two rotamers as evident from NMR analysis, then cyclized smoothly with 80% sulfuric acid giving the desired isoquinolinone 8 in high yield (90%). As shown in Scheme [2] (bottom part), the protective group pattern of 8 could then be selectively modulated. Treatment with sodium ethylthiolate resulted in a specific cleavage of the C8-hydroxyl methyl ether to give 11 in high yield (96%). Presumably, this selectivity originates from a pre-coordination to the carbonyl function and/or higher thermodynamic stability resulting from a strong hydrogen bond to the vicinal ketone. Full deprotection of 8 towards 12 in turn was accomplished by either lithium diphenylphosphide (80%)[20] or boron tribromide (96%).[21] Subsequently, selective introduction of variable groups at the C7 hydroxyl, for example, ethoxymethyl chloride (EOMCl) giving 13, was also accomplished with useful conversion (70%).

As shown in Scheme [3], an analogous strategy was applied for the synthesis of mono-hydroxylated as well as iodinated analogues 18 and 19. The required amides 16 and 17 were readily obtained from commercial methoxysalicylic acid 14 and halogenated equivalent 15 using the procedures evaluated above. In contrast, ring closure using 80% sulfuric acid resulted in no conversion (for 15) or decomposition (for 17). However, after exchanging the Brønsted acid with aluminum trichloride, the targeted heterocycles 18 and 19 were obtained with concomitant deprotection of the C-8 hydroxyl in moderate yields.[8]

For the synthesis of 6,8-bishydroxylated isoquinolinones of type 24 an alternative appraoch based on a reported Curtius rearrangement was pursued.[22] Accordingly, as shown in Scheme [4, 3],5-dimethoxybenzaldehyde (20) was first elaborated with malonic acid[23] and the resulting cinnamic acid derivative was converted to azide 21 by treament with thionyl chloride and NaN₃, following a reported protocol.[22] Thermal rearrangement then gave the desired isoquinolinone 22 with moderate conversion (42%). After N-methylation with dimethyl sulfate in the presence of K₂CO­₃ (89%), liberation of the phenolic hydroxyls of resulting 23 with BBr₃ gave 24 together with partially deprotected 25. Selective functionalization at the more reactive C6-hydroxyl was then possible giving TBS ether 26 and triflate 27 by treatment with TBSOTf and Tf₂NPh, respectively.

As shown in Scheme [5], 6-bromo analogues 31 and 32 were then synthesized in an analogous fashion. In detail, 3-bromo-5-hydroxybenzaldehyde (28), which was obtained in a reliable fashion from 3-nitrobenzaldehyde using a published protocol (four steps, 43% overall yield),[24] was elaborated by a Knoevenagel condensation with malonic acid to 29. While this cinnamic acid derivative was initially obtained as the trans-isomer, it gradually isomerized in solution to a 1:1 E/Z-ratio. This mixture was then used in the subsequent rearrangement, which resulted in a selective cyclization towards the desired isoquinolinone 30. Notably, likewise possible 8-bromo isomer was not obtained, presumably due to steric reasons. Nevertheless, only low degrees of conversion were obtained, which could not be improved by extended reaction times or elevation of the temperature. Presumably, this lower efficacy results from largely diminished +M effect of the bromine atom as compared to the methoxy group of 21. In general, due to low degrees of conversion, reproducibility, and scalability of this approach, this sequence was not extended to further analogues. Methylation of the amide function proceeded in high yield (82%) giving the desired 31 together with minor amounts of partially O-methylated derivative 32 (5%).

With these various substrates (Figure [1]) in hand, selective hydroxylation studies were then applied. While asymmetric olefin hydroxylations have been widely studied and various protocols have been reported,[25] [26] [27] [28] selective oxidations of electron-deficient substrates such as those discussed herein are less advanced.[9,29] In agreement with this observation, a broad range of well-established protocols for dihydroxylations and epoxidations, including Sharpless asymmetric dihydroxylations[25] (Table [1], entry 1), variations of the Upjohn protocol[26] (entries 2–4) or the Woodward dihydroxylation (Sudalai modification: entry 5)[27] [28] proved unsuccessful resulting mainly in no or very low degrees of conversion. Similarly, hydroxylations of electron-rich 7,8-dihydroxylated isoquinolinones 11–13 proved not promising. Also, various epoxidation reagents did not result in any conversions, including mCPBA,[30] H₂O₂,[31] Oxone,[32] or the Jacobsen procedure (not shown).[33] Similarly, also adjustment of the concentration of the catalyst and ligands resulted in no improvement of the outcome of the Sharpless dihydroxylation (entries 6–9).[34] [35] [36] Finally, only low degrees of conversion were obtained for the most electron-rich substrate by raising the temperature (entry 10). Consequently, this reagent combination was further modified and more forcing conditions were applied, including an excess of the oxidizing agents by using 7.2 g/mmol of AD-Mix β as well as additional 10 mol% of potassium osmate dihydrate and 50 mol% (DHQD)₂PHAL in a 1:1:2 mixture of water/butanol/DCM, which were already used for a quite similar system,[9] resulting in improved degrees of conversion (46%, entry 11). While under these conditions, also electronically more deficient substrates may be dihydroxylated, much lower conversions were observed (entry 12), demonstrating again the critical electronic impact of the appending aromatic system on the outcome of this reaction.

While all dihydroxylated products under modified conditions were obtained as diastereomeric mixtures (Table [1], entries 11, 12), the dihydroxylation with citric acid, being a ligand and puffer at the same time, led to a diastereomerically pure product with a significant increase in the yield (65%, entry 13 and 91%, entry 14). This is in accordance with the previous results of using citric acid for electronically deficient olefins.[37] [38] Subsequent to this results the diastereomeric mixture (entry 11) was analyzed in more detail. As shown in Scheme [6] only a slight diastereomeric bias in favor of the syn-isomer was obtained (3:2), presumably due to a concomitant C3-epimerization during the reaction.

Table 1 Studies on the Dihydroxylation of Variously Substituted Isoquinolinones

Entry	Substrate	Reagents	Conditions	ProductYield (%) (dr)
1	8/24–27/31/32	AD-Mix β (1.4 g/mmol)	H2O/t-BuOH (1:1), r.t.	–
2	19	OsO4 (30 mol%), NMO (2.0 equiv)	H2O/t-BuOH (1:1), r.t.	–
3	25	K2OsO4·2H2O (1 mol%), NMO (1.7 equiv)	DMF, r.t.	–
4	8	OsO4 (1 mol%), NMO (1.1 equiv)	H2O/t-BuOH acetone (5:3:3), r.t.	–
5	8/25	NaIO4 (30 mol%), LiBr (20 mol%)	AcOH, r.t.	–
6	25/27/31	K2OsO4·2H2O (1 mol%), K3Fe(CN)6, K2CO3, (DHQD)2AQN (5 mol%)	H2O/t-BuOH (1:1), r.t.	–
7	25/27/31	K2OsO4·2H2O (1 mol%), K3Fe(CN)6,K2CO3, (DHQD)2Py (5 mol%)	H2O/t-BuOH (1:1), r.t.	–
8	24/25/31/32	AD-Mix β (7.2 g/mmol), K2OsO4·2H2O (10 mol%), (DHQD)2PHAL (50 mol%)	H2O/t-BuOH (1:1), r.t.	–
9	24–27/31/32	AD-Mix β (1.4 g/mmol), K2OsO4·2H2O (1 mol%), (DHQD)2PHAL (5 mol%)	H2O/t-BuOH (1:1), r.t.	–
10	8	AD-Mix β (1.4 g/mmol), MsNH2 (1.5 equiv)	H2O/t-BuOH (1:1) r.t. to 100 °C	33; 2%
11	8	AD-Mix β (7.2 g/mmol), K2OsO4·2H2O (10 mol%), (DHQD)2PHAL (50 mol%), MsNH2 (1.8 equiv)	H2O/t-BuOH/DCM (1:1:2), r.t.	33; 46% (3:2)
12	19	AD-Mix β (7.2 g/mmol), K2OsO4·2H2O (10 mol%), (DHQD)2PHAL (50 mol%), MsNH2 (1.8 equiv)	H2O/t-BuOH/DCM (1:1:2), r.t.	34, 3%
13	8	K2OsO4·2H2O (0.2 mol%), citric acid (0.75 equiv), NMO (1.10 equiv)	H2O/t-BuOH (1:1), r.t.	33; 65% (>20:1)
14	19	K2OsO4·2H2O (0.2 mol%), citric acid (0.75 equiv), NMO (1.10 equiv)	H2O/t-BuOH (1:1), r.t.	34; 91% (>20:1)

Subsequent conversion into the N,O-acetal 35 (72%) by treatment with MeOH/scandium triflate resulted in a change of this ratio towards the anti-isomer (dr 3:1) and also resulted in a conformational fixation of C3. After protection of the C4 hydroxyl as TBDPS ethers, all four stereoisomers 36–39 could be separated by HPLC on a chiral phase. Their absolute configurations could then be assigned by Mosher ester analysis of the C-4 hydroxyls after TBDPS cleavage. This analysis revealed only very low enantioselectivities towards the desired C4 epimer (er ~2:1). While in principle, this sequence allows access to the authentic substitution pattern 38 of the EF ring of lysolipin, this strategy is limited by low yield and selectivity.

In summary, inspired by the substitution pattern of lysolipin I, a highly potent antibiotic of bacterial origin, a comprehensive study on asymmetric benzylic dihydroxylations of variously substituted isoquinolinones with a variety of different protocols has been conducted. These experiments revealed that most substrates are too electron-deficient to undergo a direct oxygenation under a wide variety of conventional procedures. It was shown that the electronic nature of the appending aromatic ring had a crucial influence on the outcome of the reaction. Thus, only the most electron-rich substrate bearing an additional methyl ether in the pendant aromatic ring (C-8) in direct conjugation with the benzylic olefin could be dihydroxylated with a useful conversion using harsh Sharpless dihydroxylation conditions. These involved an excess of the oxidizing agents by using 7.2 g/mmol of AD-Mix β as well as additional 10 mol% of potassium osmate dihydrate and 50 mol% (DHQD)₂PHAL in a 1:1:2 mixture of water/butanol/DCM. However, under these conditions only very low diastereoselectivities (syn/anti = 3:2) and enantioselectivities (er ~2:1) were obtained. On the contrary, a dihydroxylation with citric acid (0.75 equiv) shows a much higher activity and, consequently, a significant increase in conversion with a simultaneous decrease in catalyst loading (0.2 mol%). This effect is due to two important factors that keep the catalyst loading constant: On the one hand, due to the slightly acidic buffered solution in combination with the chelating effect, no disproportionation of the osmate takes place during the catalysis cycle, and on the other hand, the formation of a stable dioxoosmate complex can be prevented in the case of electron-deficient olefins.[37]

All reactions in anhydrous solvents were performed under an atmosphere of argon in flame-dried glassware. All flasks were equipped with rubber septa and reactants were handled using standard Schlenk techniques. Reactions were monitored via TLC on silica gel 60 F₂₅₄ precoated plates (0.2 mm SiO₂, Machery-Nagel) and visualized using UV light and/or staining with a solution of KMnO₄ (1.5 g KMnO₄, 10 g K₂CO₃, 1.25 mL 10% NaOH in 200 mL H₂O) and subsequent heating. For column chromatography, silica gel (pore size 60 Å, 40–63 μm) was used. ¹H and ¹³C NMR spectra were recorded on Bruker Avance I 400 MHz, Bruker Avance I 500 MHz, Bruker Avance III HD 500 MHz Prodigy, Bruker Avance III HD 700 MHz Cryo spectrometers. Chemical shifts (δ) are reported in ppm, coupling constants (J) in hertz (Hz) using standard abbreviations. High-resolution mass spectra (HRMS) were recorded on the following mass spectrometers: Bruker Daltonics micrOTOF-Q, Thermo Fisher Scientific Orbitrap XL and Bruker Daltonics­ Apex IV FT-ICR.

2,3-Dimethoxybenzoic Acid (5)

2,3-Dihydroxybenzoic acid (4; 2.00 g, 12.9 mmol) was dissolved in acetone (30 mL). K₂CO₃ (6.19 g, 44.8 mmol, 3.50 equiv) and dimethyl sulfate (4.25 mL, 44.8 mmol, 3.50 equiv) were added sequentially. The mixture was stirred overnight under reflux and was cooled to r.t. The carbonate was filtered off and washed with acetone. The filtrate was concentrated in vacuo and the crude methyl ether was used without further purification.

¹H NMR (400 MHz, CDCl₃): δ = 7.31 (dd, J = 7.2, 2.3 Hz, 1 H), 7.11–7.03 (m, 2 H), 3.90 (s, 3 H), 3.90 (s, 3 H), 3.88 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 166.9, 153.7, 149.3, 126.2, 124.0, 122.3, 116.0, 61.7, 56.2, 52.3.

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₀H₁₂O₄Na: 219.0628; found: 219.0631.

A solution of the crude product (1.91 g, 9.74 mmol) in THF (40 mL) and aq 1 N NaOH (21 mL, 21.0 mmol, 2.10 equiv) were refluxed for 4 h. Afterwards, the mixture was cooled to r.t. and THF was removed under reduced pressure. The aqueous phase was acidified to pH 1 with aq 1 N HCl and extracted with EtOAc (3 × 75 mL). The combined organic phases were dried (MgSO₄) and concentrated. The product 5 was obtained as a white solid and used without further purification; yield: 1.74 g (9.57 mmol, 98%).

¹H NMR (400 MHz, CDCl₃): δ = 7.74 (dd, J = 7.8, 1.8 Hz, 1 H), 7.24–7.14 (m, 2 H), 4.10 (s, 3 H), 3.93 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.2, 152.0, 148.1, 125.0, 123.9, 122.1, 117.5, 62.2, 56.2.

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₉H₁₀O₄Na: 205.0471; found: 205.0469.[36]

N-(2,2-Dimethoxyethyl)-2,3-dimethoxy-N-methylbenzamide (7)

To a solution of compound 5 (500 mg, 2.75 mmol) in anhyd DCM (40 mL) was added EDCI·HCl (1.10 g, 5.68 mmol, 2.07 equiv) in portions. After stirring at r.t. for 1 h, (methylamino)acetaldehyde dimethyl acetal (6; 0.73 mL, 5.68 mmol, 2.05 equiv) was added dropwise to the solution and stirred for another 18 h. The reaction was quenched by the addition of H₂O (40 mL). The phases were separated, and the aqueous phase was extracted with DCM (3 × 80 mL). The combined organic phases were dried (MgSO₄) and concentrated under reduced pressure. Purification of the crude product by silica gel flash column chromatography (cyclohexane/Et₂O 1:3) afforded 7 as a a yellow oil with 2:1 mixture of two rotamers A and B; yield: 429 mg (1.51 mmol, 55%).

¹H NMR (500 MHz, CD₂Cl₂): δ = 7.11–7.05 (m, 1 H, H_A and H_B), 6.95 (dd, J = 8.2, 1.5 Hz, 0.65 H_A), 6.94 (dd, J = 8.2, 1.5 Hz, 0.33 H_B), 6.77 (dd, J = 7.6, 1.5 Hz, 0.35 H_B), 6.75 (dd, J = 7.6, 1.5 Hz, 0.65 H_A), 4.63 (t, J = 5.5 Hz, 0.67 H_A), 4.29 (t, J = 5.5 Hz, 0.33 H_B), 3.86 (s, 2 H_A), 3.86 (s, 1 H_B), 3.80 (s, 2 H_A), 3.80 (s, H_B), 3.74–3.45 (m, 1.33 H_A), 3.43 (s, 4 H_A), 3.22 (s, 2 H_B), 3.23–3.14 (m, 0.66 H_B), 3.10 (s, 1 H_B), 2.86 (s, 2 H_A).

¹³C NMR (126 MHz, CD₂Cl₂): δ = 169.5 (C_B), 169.4 (C_A), 153.2 (C_B), 153.2 (C_A), 145.4 (C_A), 145.3 (C_B), 132.4 (C_A), 132.4 (C_B), 124.9 (C_A), 124.8 (C_B), 119.5 (C_B), 119.0 (C_A), 113.3 (C_A and C_B), 104.5 (C_B), 103.3 (C_A), 61.6 (C_B), 61.5 (C_A), 56.1 (C_A and C_B), 55.0 (C_B), 54.8 (C_A), 53.1 (C_B), 49.7 (C_A), 38.3 (C_A), 34.3 (C_B).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₂₂NO₅: 284.1492; found: 284.1493.

7,8-Dimethoxy-2-methylisoquinolin-1(2H)-one (8)

Dimethylacetal 7 (300 mg, 1.27 mmol) was dissolved in 80% H₂SO₄ (3.3 mL). After stirring the reaction mixture for 18 h at r.t., the mixture was poured onto ice (20 mL) and neutralized with sat. aq NaHCO_­3. The aqueous phase was extracted with DCM (2 × 120 mL), the combined organic phases were dried (MgSO₄), and the solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography (cyclohexane/Et₂O 1:3) to yield isoquinolinone 8 as a yellowish oil; yield: 250 mg (1.14 mmol, 90%).

¹H NMR (500 MHz, CD₂Cl₂): δ = 7.28 (d, J = 8.6 Hz, 1 H), 7.20 (d, J = 8.6 Hz, 1 H), 6.90 (d, J = 7.2 Hz, 1 H), 6.32 (d, J = 7.2 Hz, 1 H), 3.96 (s, 3 H), 3.91 (s, 3 H), 3.51 (s, 3 H).

¹³C NMR (125 MHz, CD₂Cl₂): δ = 160.7, 151.8, 149.6, 133.0, 130.7, 122.1, 121.0, 118.7, 61.7, 56.9, 37.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₄NO₃: 220.0968; found: 220.0973.

6-(Carboxymethyl)-3-(ethoxymethoxy)-2-methoxybenzoic Acid (10)

To a solution of diester 9 (2.90 g, 9.23 mmol) in THF (40 mL) was added aq 1 N NaOH (27.7 mL, 27.7 mmol, 3.00 equiv) and the mixture was refluxed for 2 h. After cooling to r.t., THF was evaporated and the aqueous phase was acidified to pH 1 with aq 1 N HCl. Extracting with DCM (3 × 50 mL), drying the combined organic phases (MgSO₄), and removing the solvent in vacuo gave dicarboxylic acid 10 as a yellowish oil; 2.39 g (8.40 mmol, 91%).

¹H NMR (500 MHz, CDCl₃): δ = 7.30 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 5.29 (s, 2 H), 3.99 (s, 3 H), 3.90 (s, 2 H), 3.76 (d, J = 7.1 Hz, 1 H), 1.24 (d, J = 7.1 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 176.2, 170.4, 150.2, 148.9, 128.1, 128.0, 125.3, 119.5, 93.9, 64.9, 62.3, 40.0, 15.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₃H₁₆O₇: 307.0788; found: 307.0782.

8-Hydroxy-7-methoxy-2-methylisoquinolin-1(2H)-one (11)

To a solution of isoquinolinone 8 (50.0 mg, 0.23 mmol) in DMF (2 mL) was added sodium ethylthiolate (25.1 mg, 0.30 mmol, 1.30 equiv). The mixture was heated to 100 °C and stirred for 30 min at this temperature. After cooling to r.t., the mixture was diluted with sat. aq NH₄Cl (10 mL) and DCM (20 mL). The solution was acidified to pH 1 by adding aq 1 N HCl and phases were separated. The aqueous phase was extracted with DCM (2 × 15 mL), the combined organic phases were washed with sat. aq NH₄Cl (10 mL), dried (MgSO₄), and the solvent was removed. The ortho-deprotected isoquinlinone 11 was obtained as a yellow oil; yield: 44.8 mg (2.18 mmol, 96%).

¹H NMR (500 MHz, CDCl₃): δ = 7.26 (d, J = 8.5 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 6.84 (d, J = 7.3 Hz, 1 H), 6.46 (d, J = 7.3 Hz, 1 H), 3,95 (s, 3 H), 3.55 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 166.1, 150.5, 145.4, 131.0, 129.6, 118.8, 115.2, 112.6, 108.1, 56.8, 36.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₂NO₃: 206.0812; found: 226.0807.

7,8-Dihydroxy-2-methylisoquinolin-1(2H)-one (12)

Method A: Diphenylphosphine (0.25 mL, 1.45 mmol) was dissolved in anhyd THF (1,5 mL) at 0 °C. To this solution was added n-BuLi (1.6 M, 1.00 mL, 1.60 mmol) dropwise and the red solution was warmed to r.t. over 20 min to form LiPPh₂. The LiPPh₂ solution (0.86 mL, 0.46 mmol, 2.00 equiv) was added dropwise to a solution of isoquinolinone 8 (50.0 mg, 0.23 mmol) in anhyd THF (2 mL). The mixture was stirred for 2 h and afterwards quenched with aq 1 N HCl (2 mL) and H₂O (2 mL). Extraction of the solution with EtOAc (3 × 7 mL), drying the combined organic phases (MgSO₄), and removing the solvent in vacuo gave a reddish crude product, which was purified by silica gel flash column chromatography (cyclohexane/EtOAc 2:3) to obtain double deprotected compound 12 as a yellowish oil; yield: 34.6 mg (0.18 mmol, 80%).

Method B: Isoquinolinone 8 (349 mg, 1.59 mmol) was dissolved in anhyd DCM (6 mL) and cooled to –78 °C. To this solution was added BBr₃ (1 M in DCM, 4.77 mL, 4.77 mmol, 3.00 equiv) dropwise. The cooling bath was removed, and the solution warmed to r.t. and stirred for 18 h. After cooling to 0 °C, the solution was diluted with phthalate buffer (pH 4, 12 mL) and extracted with EtOAc (3 × 25 mL). The combined organic phases were dried (MgSO₄) and concentrated under reduced pressure before purification by silica gel flash column chromatography (cyclohexane/EtOAc 1:9 + 2% AcOH) to afford compound 12 as a yellow oil; yield: 291 mg (1.53 mmol, 96%).

¹H NMR (700 MHz, CDCl₃): δ = 7.27 (d, J = 8.4 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 6.84 (d, J = 7.3 Hz, 1 H), 6.48 (d, J = 7.3 Hz, 1 H), 3.56 (s, 3 H).

¹³C NMR (175 MHz, CDCl₃): δ = 165.6, 146.6, 142.1, 130.4, 129.3, 121.2, 115.7, 112.1, 108.3, 36.1.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₀H₁₀NO₃: 192.0655; found: 192.0658.

7-(Ethoxymethoxy)-8-hydroxy-2-methylisoquinolin-1(2H)-one (13)

To a solution of dihydroxyisoquinolinone 12 (50.0 mg, 0.26 mmol) in anhyd DCM (1 mL) was added Hünig’s base (0.14 mL, 0.81 mmol, 3.10 equiv). After dropwise addition of EOMCl (64 μL, 0.65 mmol, 2.50 equiv), the mixture was stirred for 3 h and quenched with sat. aq NaHCO₃ (1 mL). The solution was extracted with DCM (3 × 6 mL) and the combined organic phases were dried (MgSO₄). The solvent was removed in vacuo and the crude product was purified by silica gel flash column chromatography (cyclohexane/EtOAc 1:1 + 2% i-PrNH₂) to give the mono-protected isoquinolinone 13 as a colourless amorphous solid; yield: 46.3 mg (0.18 mmol, 70%).

¹H NMR (500 MHz, CD₂Cl₂): δ = 13.10 (br s, 1 H), 7.44 (d, J = 8.3 Hz, 1 H), 6.92 (d, J = 8.3 Hz, 1 H), 6.92, (d, J = 7.3 Hz, 1 H), 6.49 (d, J = 7.3 Hz, 1 H), 5.27 (s, 2 H), 3.80 (q, J = 7.1 Hz, 2 H), 3.53 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 166.5, 152.1, 142.7, 133.3, 131.1, 125.2, 115.5, 113.4, 108.1, 95.4, 65.0, 36.6, 15.5.

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₃H₁₅NO₄Na: 272.0904; found: 272.0898.

N-(2,2-Dimethoxyethyl)-2-methoxy-N-methylbenzamide (16)

To a solution of 2-methoxybenzoic acid (14; 500 mg, 3.62 mmol) in anhyd DCM (30 mL) was added EDCI·HCl (1.41 g, 7.24 mmol, 2.00 equiv) in portions. After stirring for 1 h at r.t., (methylamino)acetaldehyde dimethyl acetal (6; 0.93 mL, 7.24 mmol, 2.00 equiv) was added dropwise to the solution and stirred for another 18 h. The reaction was quenched by the addition of H₂O (30 mL). The phases were separated, and the aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were dried (MgSO₄) and concentrated under reduced pressure. Purification of the crude product by silica gel flash column chromatography (cyclohexane/Et₂O 1:9) afforded 16 as a yellow oil with 2:1 mixture of rotamers A and B; yield: 366.8 mg (1.45 mmol, 40%).

¹H NMR (499 MHz, CD₂Cl₂): δ = 7.39–7.33 (m, 1 H, H_A and H_B), 7.20–7.16 (m, 1 H, H_A and H_B), 7.01–6.97 (m, 1 H, H_A and H_B), 6.96–6.93 (m, 1 H, H_A and H_B), 4.62 (t, J = 5.5 Hz, 0.64 H_A), 4.26 (t, J = 5.3 Hz, 0.37 H_B), 3.83 (s, 2 H_A), 3.83 (s, 1 H_B), 3.62–3.50 (m, 1.33 H_A), 3.44 (s, 4 H_A), 3.24–3.14 (m, 2.66 H_B), 3.09 (s, 1 H_B), 2.85 (s, 2 H_A).

¹³C NMR (126 MHz, CD₂Cl₂): δ = 169.7 (C_B), 169.7 (C_A), 155.6 (C_A), 155.4 (C_B), 130.6 (C_A), 130.6 (C_B), 128.5 (C_B), 128.0 (C_A), 127.1 (C_A), 126.9 (C_B), 121.2 (C_A), 121.1 (C_B), 111.3 (C_A and C_B), 104.5 (C_B), 103.6 (C_A), 55.9 (C_A), 55.8 (C_B), 54.8 (C_A and C_B), 52.9 (C_B), 49.9 (C_A), 38.0 (C_A), 34.2 (C_B).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₄H₁₉NO₄: 254.1387; found: 254.1390.

N-(2,2-Dimethoxyethyl)-4-iodo-2-methoxy-N-methylbenzamide (17)

To a mixture consisting of 2-methoxy-4-iodobenzoic acid (15; 700 mg, 1.85 mmol) and EDCI·HCl (0.72 g, 3.70 mmol, 2.00 equiv) in anhyd DCM (35 mL) was added (methylamino)acetaldehyde dimethyl acetal (6; 0.48 mL, 3.70 mmol, 2.00 equiv) dropwise. The reaction mixture was stirred for 17 h at r.t. and quenched by the addition of H₂O (20 mL). The phases were separated, and the aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with aq 1 HCl (20 mL) and sat. aq NaHCO₃ (20 mL). After drying (MgSO₄), the solvent was removed and the crude product was purified by silica gel flash column chromatography (cyclohexane/EtOAc 1:3) to give amide 17 as a yellow oil with a 2:1 mixture of rotamers A and B; yield: 378 mg (1.04 mmol, 56%).

¹H NMR (499 MHz, CD₂Cl₂): δ = 7.36 (dd, J = 7.8, 1.5 Hz, 0.65 H_A), 7.35 (dd, J = 7.9, 1.5 Hz, 0.35 H_B), 7.28 (d, J = 1.5 Hz, 0.66 H_A), 7.27 (d, J = 1.5 Hz, 0.33 H_B), 6.93 (d, J = 7.8 Hz, 0.66 H_A), 6.92 (d, J = 7.9 Hz, 0.34 H_B), 4.59 (t, J = 5.4 Hz, 0.65 H_A), 4.27 (t, J = 5.3 Hz, 0.35 H_B), 3.82 (s, 2 H_A), 3.81 (s, 1 H_B), 3.62–3.47 (m, 1.33 H_A), 3.42 (s, 4 H_A), 3.24 (s, 2 H_B), 3.21–3.14 (m, 0.71 H_B), 3.07 (s, 1 H_B), 2.84 (s, 2 H_A).

¹³C NMR (126 MHz, CD₂Cl₂): δ = 168.9 (C_B), 168.9 (C_A), 156.0 (C_A), 155.9 (C_B), 130.4 (C_A), 130.4 (C_B), 129.9 (C_B), 129.4 (C_A), 126.8 (C_A), 126.6 (C_B), 120.9 (C_A), 120.9 (C_B), 104.1 (C_B), 103.4 (C_A), 95.3 (C_A), 95.2 (C_B), 56.3 (C_A), 56.3 (C_B), 54.9 (C_A and C_B), 52.9 (C_B), 49.9 (C_A), 38.0 (C_A), 34.2 (C_B).

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₃H₁₈INO₄Na: 402.0173; found: 402.0169.

8-Hydroxy-2-methylisoquinolin-1(2H)-one (18)

To a solution of dimethylacetal 16 (300 mg, 1.18 mmol) in anhyd dichloroethane (15 mL) was added AlCl₃ (720 mg, 5.43 mmol, 4.60 equiv). The reaction mixture was stirred for 22 h and poured onto ice (20 mL). The mixture was neutralized with aq 40% NaOH and extracted with dichloroethane (3 × 30 mL). The combined organic phases were washed with brine (10 mL), dried (MgSO₄) and the solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography (cyclohexane/EtOAc 1:9) to give isoquinolinone 18 as a colorless oil; yield: 62.3 mg (0.36 mmol, 30%).

¹H NMR (700 MHz, CDCl₃): δ = 7.49 (dd, J = 7.9, 7.9 Hz, 1 H), 6.97 (d, J = 7.3 Hz, 1 H), 6.93 (dd, J = 7.9, 1.0 Hz, 1 H), 6.89 (dd, J = 7.9, 1.0 Hz, 1 H), 3.57 (s, 3 H).

¹³C NMR (175 MHz, CDCl₃): δ = 165.8, 161.3, 138.1, 134.4, 131.6, 115.5, 113.0, 112.1, 107.9, 36.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₀H₉NO₂: 176.0706; found: 176.0698.

8-Hydroxy-6-iodo-2-methylisoquinolin-1(2H)-one (19)

To a solution of dimethylacetal 17 (50.0 mg, 0.13 mmol) in anhyd dichloroethane (2 mL) was added AlCl₃ (98.4 mg, 0.74 mmol, 5.60 equiv) and stirred for 17 h at r.t. The reaction mixture was poured onto ice (7 mL) and quenched by the addition of aq 3N NaOH (2 mL). After extraction with dichloroethane (3 × 25 mL), the combined organic phases were dried (MgSO₄), and the solvent was evaporated under reduced pressure. Purification by silica gel flash column chromatography (cyclohexane/EtOAc 1:1) afforded isoquinolinone 19 as a colorless solid; yield: 14.2 mg (0.05 mmol, 36%).

¹H NMR (400 MHz, CD₂Cl₂): δ = 12.97 (s, 1 H), 7.39 (d, J = 1.5 Hz, 1 H), 7.24 (d, J = 1.5 Hz, 1 H), 7.08 (d, J = 7.4 Hz, 1 H), 6.46 (d, J = 7.4 Hz, 1 H), 3.56 (s, 3 H).

¹³C NMR (100 MHz, CD₂Cl₂): δ = 166.2, 161.9, 139.6, 133.7, 125.1, 122.2, 111.9, 106.8, 101.5, 36.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₀H₈INO₂: 301.9672; found: 301.9667.

6,8-Dimethoxyisoquinolin-1(2H)-one (22)

3,5-Dimethoxybenzaldehyde (20; 4.99 g, 30.0 mmol, 1.00 equiv) and malonic acid (4.70 g, 45.2 mmol, 1.51 equiv) were dissolved in pyridine (32 mL), followed by the addition of piperidine (1.1 mL, 11.1 mmol, 0.37 equiv). The solution was stirred under reflux for 5 h. After cooling down to r.t., pyridine and piperidine were removed under reduced pressure and the residue was diluted with cold H₂O, followed by acidification to pH 3 with aq 1 M HCl. The precipitate formed was collected by filtration, washed with cold H₂O, and recrystallized from EtOH to yield (E)-3-(3,5-dimethoxyphenyl)acrylic acid as a white crystalline solid (5.38 g, 25.9 mmol, 86%). SOCl₂ (8.20 mL, 113 mmol, 1.51 equiv) was added to a solution of the above prepared cinnamic acid derivative (15.6 g, 75.0 mmol, 1.00 equiv) in anhyd DCM (80 mL) and stirred under reflux for 3 h. After cooling down to r.t., SOCl₂ and the solvent were removed under reduced pressure. The residue was dissolved in 1,4-dioxane/THF (60 mL, 2:1) and added dropwise to a solution of NaN₃ (14.6 g, 225 mmol, 3.03 eq) in H₂O/1,4-dioxane (80 mL, 1:1) at 0 °C over a period of 1 h. After complete addition, the solution was stirred for an additional hour. The mixture was extracted with EtOAc (3 × 70 mL), the combined organic phases were dried (MgSO₄) and concentrated to a volume of 40 mL. The solution was diluted with Ph₂O (100 mL) and the remaining EtOAc/THF was removed in vacuo. Bu₃N (28 mL) and Ph₂O (80 mL) were heated up to 230 °C and the azide 21 was added dropwise over a period of 3 h. After complete addition, the reaction mixture was stirred for an additional hour at 230 °C, cooled down to 50 °C and n-hexane (500 mL) was added. The precipitate was collected by filtration, washed with n-hexane, and recrystallized from EtOAc/MeOH (9:1) to afford 22 as a light-yellow solid; yield: 6.44 g (31.4 mmol, 42%).

¹H NMR (499 MHz, DMSO-d ₆): δ = 10.68 (s, 1 H), 7.02 (dd, J = 7.0, 5.6 Hz, 1 H), 6.64 (d, J = 2.4 Hz, 1 H), 6.47 (d, J = 2.4 Hz, 1 H), 6.31 (d, J = 7.0 Hz, 1 H), 3.84 (s, 3 H), 3.79 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 162.6, 161.8, 160.0, 142.6, 129.9, 110.0, 104.2, 99.6, 97.7, 55.7, 55.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₂NO₃: 206.0812; found: 206.0813.

Spectroscopic data were consistent with that previously reported.[21]

6,8-Dimethoxy-2-methylisoquinolin-1(2H)-one (23)

To a stirred heterogeneous solution of 22 (270 mg, 1.31 mmol, 1.00 equiv) and K₂CO₃ in acetone (5 mL) was added dimethyl sulfate (250 μL, 2.62 mmol, 2.00 equiv). The mixture was heated up to 80 °C with vigorous stirring overnight, while the color changed from light yellow to pink. The reaction was quenched with aq 1 M NaOH (0.5 mL), stirred for an additional hour, and then diluted with H₂O (10 mL). The solution was extracted with EtOAc (3 × 10 mL), the combined organic layers were washed with brine (10 mL), dried (MgSO₄), and concentrated in vacuo. Purification of the residue by flash column chromatography (DCM/EE/MeOH 1:1:0.1) gave 23 as a colorless solid; yield: 255 mg (1.16 mmol, 89%).

¹H NMR (499 MHz, DMSO-d ₆): δ = 7.36 (d, J = 7.2 Hz, 1 H), 6.63 (d, J = 2.3 Hz, 1 H), 6.49 (d, J = 2.4 Hz, 1 H), 6.37 (d, J = 7.3 Hz, 1 H), 3.84 (s, 3 H), 3.79 (s, 3 H), 3.35 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 162.4, 161.7, 159.2, 141.8, 134.7, 109.4, 104.1, 99.4, 98.0, 55.8, 55.4, 36.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₄NO₃: 220.0968; found: 220.0972.

6,8-Dihydroxy-2-methylisoquinolin-1(2H)-one (24)

A solution of 23 (100 mg, 460 μmol, 1.00 equiv) in anhyd DCM (10 mL) was cooled to –78 °C and BBr₃ (1 M in DCM, 2.60 mL, 2.74 mmol, 6.00 equiv) was added. The mixture stirred for 1 h, heated up slowly to 60 °C, and stirred for an additional hour. After cooling down to r.t., the reaction was carefully quenched with MeOH (10 mL) and MeCN/H₂O (10 mL, 1:1) was added. After stirring for 1 h, the mixture was extracted with EtOAc (3 × 10 mL), the combined organic layers were washed with brine (10 mL), dried (MgSO₄), and the solvent was evaporated in vacuo. Purification of the residue by flash column chromatography (DCM/EtOAc 1:1) gave 24 and 25.

24

Colorless solid; yield: 66.0 mg (345 μmol, 75%).

¹H NMR (499 MHz, DMSO-d ₆): δ = 13.11 (s, 1 H), 10.26 (s, 1 H), 7.33 (d, J = 7.4 Hz, 1 H), 6.51 (d, J = 7.4 Hz, 1 H), 6.37 (d, J = 2.1 Hz, 1 H), 6.23 (d, J = 2.2 Hz, 1 H), 3.44 (s, 3 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 164.7, 162.7, 162.3, 139.7, 133.5, 106.6, 104.9, 100.9, 100.6, 35.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₀H₁₀NO₃: 192.0655; found: 192.0665.

8-Hydroxy-6-methoxy-2-methylisoquinolin-1(2H)-one (25)

Colorless solid; yield: 23.6 mg (115 μmol, 25%).

¹H NMR (700 MHz, DMSO-d ₆): δ = 13.14 (s, 1 H), 7.41 (d, J = 7.3 Hz, 1 H), 6.61 (d, J = 7.3 Hz, 1 H), 6.60 (d, J = 2.3 Hz, 1 H), 6.39 (d, J = 2.3 Hz, 1 H), 3.82 (s, 3 H) 3.47 (s, 3 H).

¹³C NMR (176 MHz, DMSO-d ₆): δ = 164.7, 164.0, 162.1, 139.7, 133.9, 106.8, 106.0, 99.7, 99.0, 55.5, 35.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₁NO₃: 206.0812; found: 206.0807.

6-[(tert-Butyldimethylsilyl)oxy]-8-hydroxy-2-methylisoquinolin-1(2H)-one (26)

To a solution of 24 (19.5 mg, 105 μmol, 1.00 equiv) and 2,6-lutidine (0.06 mL, 518 μmol, 4.95 equiv) in DCM (0.20 mL) was added TBSOTf (60.0 μL, 261 μmol, 2.50 equiv) at 0 °C. The reaction mixture was allowed to warm up to r.t., stirred for additional 2 h and was quenched with H₂O (2 mL). The solution was extracted with DCM (3 × 4 mL), the combined organic layers were dried (MgSO₄) and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (DCM/EtOAc 99:1) gave 26 as a colorless solid; yield: 30.2 mg (98.9 μmol, 95%).

¹H NMR (499 MHz, DMSO-d ₆): δ = 13.14 (s, 1 H), 7.40 (d, J = 7.3 Hz, 1 H), 6.61 (d, J = 7.3 Hz, 1 H), 6.53 (d, J = 2.2 Hz, 1 H), 6.28 (d, J = 2.2 Hz, 1 H), 3.47 (s, 3 H), 0.96 (s, 9 H), 0.24 (s, 6 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 164.7, 162.2, 160.2, 139.6, 133.7, 106.7, 106.5, 105.7, 104.7, 35.5, 25.5, 18.0, –4.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₆H₂₄NO₃Si: 306.1520; found: 306.1529.

8-Hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinolin-6-yl Trifluoromethanesulfonate (27)

To a stirred solution of 24 (18.9 mg, 98.9 μmol, 1.00 equiv), DMAP (1.30 mg, 10.6 μmol, 0.11 equiv), and NEt₃ (40.0 μL, 287 μmol, 2.90 equiv) in DCM (500 μL) was added Tf₂NPh (38.9 mg, 109 μmol, 1.10 equiv). The reaction mixture was stirred for 2 h and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (cyclohexane/EtOAc 3:2) gave 27 as a colorless solid; yield: 29.3 mg (90.6 μmol, 92%).

¹H NMR (499 MHz, CDCl₃): δ = 13.19 (s, 1 H), 7.09 (d, J = 7.4 Hz, 1 H), 6.85 (d, J = 2.3 Hz, 1 H), 6.77 (d, J = 2.3 Hz, 1 H), 6.53 (d, J = 7.4 Hz, 1 H), 3.59 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 165.3, 163.7, 153.1, 139.5, 133.6, 120.1, 117.6, 115.0, 111.9, 107.6, 107.6, 106.2, 36.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₉F₃NO₃S: 324.0148; found: 324.0159.

(E)-3-(3-Bromo-5-hydroxyphenyl)acrylic Acid (29)

3-Bromo-5-methoxybenzaldehyde (28; 221 mg, 1.10 mmol, 1.00 equiv) and malonic acid (172 mg, 1.66 mmol, 1.51 equiv) were dissolved in pyridine (2 mL), followed by the addition of piperidine (100 μL, 1.01 mmol, 0.92 equiv). The solution was stirred under reflux for 1 h and afterwards allowed to cool down to r.t. Pyridine and piperidine were removed under reduced pressure and the residue was diluted with cold H₂O, followed by acidification to pH 3 with aq 1M HCl. The mixture was extracted with EtOAc (3 × 15 mL), the combined organic phases were washed with brine (2 × 10 mL), dried (MgSO₄) and concentrated in vacuo. Purification of the residue by flash column chromatography (cyclohexane/EtOAc 2:1) gave 29 as a pale orange solid; yield: 250 mg (1.03 mmol, 93%).

¹H NMR (500 MHz, DMSO-d ₆): δ = 12.48 (s, 1 H), 10.08 (s, 1 H), 7.45 (d, J = 16.0 Hz, 1 H), 7.34 (t, J = 1.6 Hz, 1 H), 7.02 (t, J = 1.8 Hz, 1 H), 6.98 (t, J = 2.0 Hz, 1 H), 6.48 (d, J = 16.0 Hz, 1 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 167.3, 158.7, 142.5, 137.4, 122.3, 121.4, 120.7, 119.6, 114.1.

HRMS (ESI-TOF): m/z [M – H]^– calcd for C₉H₆BrO₃: 240.9506; found: 240.9499.

6-Bromo-8-hydroxyisoquinolin-1(2H)-one (30)

SOCl₂ (600 μL, 3.10 mmol, 1.25 equiv) was added to a solution of 29 (600 mg, 2.48 mmol, 1.00 equiv) in anhyd DCM (20 mL) and the mixture was stirred under reflux for 3 h. After cooling down to r.t., SOCl₂ and the solvent were removed under reduced pressure. The residue was dissolved in DMF (8 mL) and was added dropwise to a solution of NaN₃ (480 mg, 7.43 mmol, 3.00 equiv) in H₂O/1,4-dioxane (6 mL, 1:2) at 0 °C over a period of 1 h. After complete addition, the solution was stirred for an additional hour. The mixture was diluted with H₂O (5 mL), extracted with EtOAc (3 × 10 mL), the combined organic extracts were dried (MgSO₄), and concentrated in vacuo to a volume of 10 mL. The solution was diluted with Ph₂O (10 mL) and the remaining EtOAc/DMF was removed in vacuo. The azide prepared as above from 29 in Ph₂O (10 mL) was added dropwise over a period of 3 h to a mixture of Bu₃N (1 mL) and Ph₂O (10 mL) at 230 °C. After complete addition, the reaction mixture was stirred for an additional hour at 230 °C, cooled down to 50 °C and n-hexane (20 mL) was added. The precipitate was collected by filtration, washed with n-hexane, and concentrated in vacuo. Purification of the residue by flash column chromatography (cyclohexane/Et₂O 3:2) gave 30 as yellowish solid; yield: 92.9 mg (38.7 mmol, 16%).

¹H NMR (499 MHz, DMSO-d ₆): δ = 13.29 (s, 1 H), 11.89 (s, 1 H), 7.35 (d, J = 1.8 Hz, 1 H), 7.27 (d, J = 7.2 Hz, 1 H), 6.98 (d, J = 1.9 Hz, 1 H), 6.63 (d, J = 7.2 Hz, 1 H).

¹³C NMR (126 MHz, DMSO-d ₆): δ = 165.9, 161.8, 140.4, 129.9, 127.8, 118.2, 114.4, 110.6, 106.0.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₉H₇BrNO₂: 239.9660; found: 239.9655.

6-Bromo-8-hydroxy-2-methylisoquinolin-1(2H)-one (31)

To a heterogeneous solution of 30 (64.8 mg, 270 μmol, 1.00 equiv) and K₂CO₃ (149 mg, 1.08 mmol, 6.00 equiv) in acetone (2 mL) was added dimethyl sulfate (68.1 mg, 540 μmol, 2.00 equiv). The mixture was heated up to 80 °C under vigorous stirring for 1 h. After cooling down to r.t., the mixture was diluted with H₂O (5 mL). The solution was extracted with EtOAc (3 × 5 mL), dried (MgSO₄) and concentrated in vacuo. Purification of the residue by flash column chromatography (cyclohexane/Et₂O 3:2) gave 31 and 32.

31

Yellowish solid; yield: 56.3 mg (221 μmol, 82%).

¹H NMR (400 MHz, CDCl₃): δ = 12.93 (s, 1 H), 7.09 (d, J = 1.8 Hz, 1 H), 7.03 (d, J = 1.8 Hz, 1 H), 7.00 (d, J = 7.4 Hz, 1 H), 6.41 (d, J = 7.3 Hz, 1 H), 3.55 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 165.7, 162.1, 139.1, 133.0, 128.7, 118.4, 116.5, 111.1, 107.0, 36.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₀H₉BrNO₂: 253.9811; found: 253.9800.

6-Bromo-8-methoxy-2-methylisoquinolin-1(2H)-one (32)

Yellowish solid; yield: 3.62 mg (13.5 μmol, 5%).

¹H NMR (400 MHz, CDCl₃): δ = 7.19 (d, J = 1.8 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H), 6.97 (d, J = 1.8 Hz, 1 H), 6.26 (d, J = 7.3 Hz, 1 H), 3.97 (s, 3 H), 3.51 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 161.5, 160.9, 141.5, 134.4, 127.2, 120.8, 114.6, 111.8, 104.5, 56.6, 37.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₀BrNO₂: 267.9968; found: 267.9957.

3,4-Dihydroxy-7,8-dimethoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (33)

Method A: A mixture consisting of AD-Mix β (1.63 g), K₂OsO₄·2H₂O (1.02 mg, 23.0 μmol, 10 mol%), and (DHQD)₂PHAL (70.2 mg, 0.12 mmol, 50 mol%) in H₂O/t-BuOH (6 mL, 1:1) was stirred for 15 min at r.t. before MsNH₂ (39.0 mg, 0.41 mmol, 1.80 equiv) and isoquinolinone 8 (50.0 mg, 0.23 mmol) in DCM (6 mL) were added at 0 °C. The mixture was warmed to r.t. and stirred for 18 h. The reaction was quenched by the addition of Na₂S₂O₃ (2.20 g) and stirred for further 1 h. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 70 mL) and the combined organic phases were washed with brine (10 mL) and dried (MgSO₄). After evaporating the solvent in vacuo, the crude product was purified by silica gel flash column chromatography (EtOAc + 2% MeOH) to obtain the 2,3-diol 33 as an inseparable mixture of enantiomers and diastereomers (dr 1:1); colorless solid; yield: 36.8 mg (0.15 mmol, 46%).

Method B: To a solution of olefin 8 (100 mg, 456 μmol, 1.00 equiv) and citric acid (71.9 mg, 342 μmol, 0.75 equiv) in a 1:1 mixture of t-BuOH/H₂O (1 mL) was added K₂OsO₄·2H₂O (336 μg, 0.2 mol%) followed by NMO (67.8 mg, 502 μmol, 1.10 equiv). The reaction mixture was stirred for 36 h at r.t. The white precipitate was collected by filtration, washed with H₂O (3 × 2 mL) and dried in vacuo to obtain diastereomerically pure 2,3-diol 33 as a colorless solid, which could be used without further purification; yield: 75.1 mg (296 μmol, 65%).

syn-33

¹H NMR (700 MHz, DMSO-d ₆): δ = 7.20 (d, J = 0.9 Hz, 1 H), 7.20 (s, 1 H), 6.00 (d, J = 5.0 Hz, 1 H), 5.43 (d, J = 7.8 Hz, 1 H), 4.78 (dd, J = 5.0, 3.7 Hz, 1 H), 4.73 (dd, J = 7.8, 3.7 Hz, 1 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 3.01 (s, 3 H).

¹³C NMR (175 MHz, DMSO-d ₆): δ = 161.1, 152.6, 148.3, 132.7, 120.8, 120.4, 115.3, 83.2, 67.1, 60.7, 55.9, 33.1.

anti-33

¹H NMR (700 MHz, DMSO-d ₆): δ = 7.15 (d, J = 8.2 Hz, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 6.11 (d, J = 4.8 Hz, 1 H), 5.49 (d, J = 4.7 Hz, 1 H), 4.79 (dd, J = 4.8, 2.6 Hz, 1 H), 4.30 (dd, J = 4.6, 2.6 Hz, 1 H), 3.80 (s, 3 H), 3.73 (s, 3 H), 3.01 (s, 3 H).

¹³C NMR (175 MHz, DMSO-d ₆): δ = 160.8, 153.6, 148.6, 131.7, 124.8, 122.3, 115.1, 85.1, 68.5, 60.7, 55.9, 33.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₆NO₅: 254.1023; found: 254.1021.

syn-3,4,8-Trihydroxy-6-iodo-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (34)

To a solution of olefin 19 (500 mg, 1.66 mmol, 1.00 equiv) and citric acid (262 mg, 1.25 mmol, 0.75 equiv) in a 1:1 mixture of t-BuOH/H₂O (10 mL) was added K₂OsO₄·2H₂O (1.22 mg, 3.32 μmol, 0.2 mol%) followed by NMO (247 mg, 1.83 mmol, 1.10 equiv). The reaction mixture was stirred for 36 h at r.t. The white precipitate was collected by filtration, washed with H₂O (3 × 5 mL), and dried in vacuo to obtain diastereomerically pure 34 as a colorless solid, which could be used without further purification; yield: 505 mg (1.51 mmol, 91%).

¹H NMR (700 MHz, DMSO-d ₆): δ = 12.63 (s, 1 H), 7.32 (t, J = 1.4 Hz, 1 H), 7.21 (dd, J = 1.7, 0.9 Hz, 1 H), 6.47 (d, J = 5.6 Hz, 1 H), 5.76 (d, J = 7.9 Hz, 1 H), 4.88 (dd, J = 5.6, 3.9 Hz, 1 H), 4.85 (dd, J = 8.0, 3.8 Hz, 1 H), 3.03 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 167.5, 160.1, 143.1, 124.5, 124.1, 1085, 101.5, 83.4, 66.4, 32.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₀H₁₁INO₄: 335.9727; found: 335.9723.

4-Hydroxy-3,7,8-trimethoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (35)

Dihydroxyisoquinolinone 33 (10.0 mg, 0.04 mmol) was dissolved in anhyd MeOH (0,5 mL) and Sc(OTf)₃ (0.20 mg, 0.40 μmol, 1 mol%) was added. The mixture was stirred for 10 min at r.t. before the reaction was quenched with sat. aq NaHCO₃ (2 mL). After extraction with EtOAc­ (3 × 6 mL), the combined organic phases were washed with brine (2 mL) and dried (MgSO₄). The solvent was removed under reduced pressure and the product 35 was obtained as a colorless oil and could be used without any further purification; anti/syn = 3:1; yield: 7.60 mg (0.03 mmol, 72%).

Diastereomer A

¹H NMR (700 MHz, CD₃OD): δ = 7.17 (d, J = 8.3 Hz, 1 H), 7.12 (d, J = 8.3 Hz, 1 H), 4.68 (d, J = 2.5 Hz, 1 H), 4.55 (d, J = 2.5 Hz, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.38 (s, 3 H), 3.25 (s, 3 H).

¹³C NMR (175 MHz, CD₃OD): δ = 164.5, 155.7, 150.9, 132.4, 126.0, 122.8, 116.8, 95.0, 68.3, 61.8, 56.6, 56.6, 37.1.

Diastereomer B

¹H NMR (700 MHz, CD₃OD): δ = 7.30 (d, J = 8.4, 1.3 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 1 H), 4.94 (dd, J = 2.7, 1.3 Hz, 1 H), 4.66 (d, J = 3.7 Hz, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.44 (s, 3 H), 3.26 (s, 3 H).

¹³C NMR (175 MHz, CD₃OD): δ = 164.5, 154.5, 150.5, 133.7, 121.4, 121.3, 117.0, 94.0, 69.0, 61.8, 57.9, 56.6, 36.5

HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₃H₁₇NO₅Na: 290.0999; found: 290.0986.

4-[(tert-Butyldiphenylsilyl)oxy]-3,7,8-trimethoxy-2-methyl-3,4-dihydroisoquinolin-1(2H)-ones 36–39

The free alcohol 35 (64.3 mg, 0.24 mmol) was dissolved in anhyd DCM (4 mL) and imidazole (24.7 mg, 0.36 mmol, 1.50 equiv) and TBDPSCl (93.8 μL, 0.36 mmol, 1.50 equiv) were added. The reaction mixture was stirred for 22 h at r.t. and quenched with sat. aq NaHCO₃ (6 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL), the combined organic phases were washed with brine (5 mL), dried (MgSO_­4), and the solvent was removed. After purification by silica gel flash column chromatography (cyclohexane/EtOAc 1:3), the enatiomers and diastereomers were separated by HPLC to obtain the 3R,4R-product 38 (14.8 mg, 29.3 μmol, 12%), 3S,4S-product 37 (7.80 mg, 13.4 μmol, 5%), 3R,4S-product 36 (27.9 mg, 55.0 μmol, 23%), and the 3S,4R-product 39 (47.9 mg, 94.7 μmol, 39%). All products were obtained as colourless oil.

syn-Isomers

¹H NMR (700 MHz, CD₂Cl₂): δ = 7.81–7.80 (m, 2 H), 7.71–7.68 (m, 2 H), 7.52–7.49 (m, 2 H), 7.49–7.46 (m, 2 H), 7.46–7.43 (s, 3 H), 7.42–7.39 (s, 2 H), 7.11 (d, J = 8.4 Hz, 1 H), 5.07 (dd, J = 3.3, 1.3 Hz, 1 H), 3.87 (s, 3 H), 3.82 (s, 3 H), 3.73 (d, J = 3.3 Hz, 1 H), 3.16 (s, 3 H), 2.83 (s, 3 H), 1.19 (s, 9 H).

¹³C NMR (175 MHz, CD₂Cl₂): δ = 161.5, 153.3, 149.1, 135.8, 135.6, 133.8, 130.2, 130.2, 127.9, 127.9, 121.1, 119.6, 115.0, 91.8, 70.4, 61.2, 56.6, 56.0, 35.6, 26.8, 19.3.

anti-Isomers

¹H NMR (700 MHz, CD₂Cl₂): δ = 7.75–7.73 (m, 2 H), 7.55–7.52 (m, 1 H), 7.51–7.47 (m, 4 H), 7.45–7.42 (m, 2 H), 7.36–7.33 (m, 2 H), 6.78 (d, J = 8.2 Hz, 1 H), 6.41 (d, J = 8.2 Hz, 1 H), 4.59 (d, J = 2.7 Hz, 1 H), 4.44 (d, J = 2.7 Hz, 1 H), 3.93 (s, 3 H), 3.84 (s, 3 H), 3.27 (s, 3 H), 3.17 (s, 3 H), 1.02 (s, 3 H).

¹³C NMR (175 MHz, CD₂Cl₂): δ = 162.7, 155.0, 150.1, 136.4, 136.4, 133.9, 133.6, 130.8, 130.7, 130.3, 128.5, 128.1, 124.8, 123.5, 114.6, 94.3, 69.6, 61.9, 56.4, 56.4, 37.3, 27.1, 19.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₉H₃₆NO₅Si: 506.2357; found: 506.2371.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Andreas J. Schneider (University of Bonn) for excellent HPLC support.

• References

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Corresponding Author

Publication History

Received: 09 July 2021

Accepted after revision: 01 September 2021

Accepted Manuscript online:
01 September 2021

Article published online:
14 October 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Present address: CHEPLAPHARM Arzneimittel GmbH, Ziegelhof 24, 17489 Greifswald, Germany.
• 2 Drautz H, Keller-Schierlein W, Zähner H. Arch. Microbiol. 1975; 106: 175
  CrossrefPubMedSearch in Google Scholar
• 3 Winter DK, Sloman DL, Porco JA. Jr. Nat. Prod. Rep. 2013; 30: 382
  CrossrefPubMedSearch in Google Scholar
• 4 Bockholt H, Udvarnoki G, Rohr J, Mocek U, Beale JM, Floss HG. J. Org. Chem. 1994; 59: 2064
  CrossrefSearch in Google Scholar
• 5 Lopez P, Hornung A, Welzel K, Unsin C, Wohlleben W, Weber T, Pelzer S. Gene 2010; 461: 5
  CrossrefPubMedSearch in Google Scholar
• 6 LaBarbera CV, Bugni TS, Ireland CV. J. Org. Chem. 2007; 72: 8501
  CrossrefPubMedSearch in Google Scholar
• 7 Jangir R, Gadre SR, Argade NP. Synthesis 2014; 46: 1954
  Thieme ConnectSearch in Google Scholar
• 8 Perchonok CD, Lantos I, Finkelstein JA, Holden KG. J. Org. Chem. 1980; 45: 1950
  CrossrefSearch in Google Scholar
• 9 Ito M, Konno F, Kumamoto T, Suzuki N, Kawahata M, Yamaguchi K, Ishikawa T. Tetrahedron 2011; 67: 8041
  CrossrefSearch in Google Scholar
• 10 Herkommer D, Thiede S, Wosniok PR, Dreisigacker S, Tian M, Debnar T, Irschik H, Menche D. J. Am. Chem. Soc. 2015; 137: 4086
  CrossrefPubMedSearch in Google Scholar
• 11 Scheeff S, Menche D. Org. Lett. 2019; 21: 271
  CrossrefPubMedSearch in Google Scholar
• 12 Palm A, Knopf C, Schmalzbauer B, Menche D. Org. Lett. 2019; 21: 1939
  CrossrefPubMedSearch in Google Scholar
• 13 Schmalzbauer B, Herrmann J, Müller R, Menche D. Org. Lett. 2013; 15: 964
  CrossrefPubMedSearch in Google Scholar
• 14 Essig S, Bretzke S, Müller R, Menche D. J. Am. Chem. Soc. 2012; 134: 19362
  CrossrefPubMedSearch in Google Scholar
• 15 Li P, Li J, Arikan F, Ahlbrecht W, Dieckmann M, Menche D. J. Am. Chem. Soc. 2009; 131: 11678
  CrossrefPubMedSearch in Google Scholar
• 16 Altendorfer M, Menche D. Chem. Commun. 2012; 48: 8267
  CrossrefPubMedSearch in Google Scholar
• 17 Rathwell DC. K, Yang S.-H, Tsang KY, Brimble MA. Angew. Chem. Int. Ed. 2009; 48: 7996
  CrossrefPubMedSearch in Google Scholar
• 18 Mederski W, Baumgarth M, Germann M, Kux D, Weitzel T. PCT Int. Appl. WO2003097600A1, 2003
  PubMed
• 19 Cody JA, Ahmed I, Tusch DJ. Tetrahedron Lett. 2010; 51: 5585
  CrossrefSearch in Google Scholar
• 20 Bringmann G, Menche D, Brun R, Msuta T, Abegaz BM. Eur. J. Org. Chem. 2002; 1107
  Crossref
• 21 Ellerbrock P, Amanino N, Trauner D. Angew. Chem. Int. Ed. 2014; 53: 13414
  CrossrefPubMedSearch in Google Scholar
• 22 Dalton JT, Miller DD, Mohler ML, Wu Z, Hong S.-S. PCT Int. Appl WO 2008091555A2, 2008
  PubMed
• 23 Peterson JR, Russell ME, Surjasasmita IB. J. Chem. Eng. Data 1988; 33: 534
  CrossrefSearch in Google Scholar
• 24 Hartley CS, Elliott EL, Moore JS. J. Am. Chem. Soc. 2007; 129: 4512
  CrossrefPubMedSearch in Google Scholar
• 25 Sharpless KB, Amberg W, Bennani YL, Crispino GA, Hartung J, Jeong KS, Kwong HL, Morikawa K, Wang ZM. J. Org. Chem. 1992; 57: 2768
  CrossrefSearch in Google Scholar
• 26 Van Rheenen V, Kelly RC, Cha DY. Tetrahedron Lett. 1976; 1973
  Crossref
• 27 Woodward RB, Brutcher FV. Jr. J. Am. Chem. Soc. 1958; 80: 209
  CrossrefSearch in Google Scholar
• 28 Emmanuvel L, Shaikh TM. A, Sudalai A. Org. Lett. 2005; 7: 5071
  CrossrefPubMedSearch in Google Scholar
• 29 Becker H, Soler MA, Sharpless KB. Tetrahedron 1995; 51: 1345
  CrossrefSearch in Google Scholar
• 30 Sugisaki CH, Carroll PJ, Correia CR. D. Tetrahedron Lett. 1998; 39: 3413
  CrossrefSearch in Google Scholar
• 31 Qi B, Lu X.-H, Zhou D, Xia Q.-H, Tang Z.-R, Fang S.-Y, Pang T, Dong Y.-L. J. Mol. Catal. Chem. 2010; 322: 73
  CrossrefSearch in Google Scholar
• 32 Botman PN. M, Dommerholt FJ, de Gelder R, Broxterman QB, Schoemaker HE, Rutjes FP. J. T, Blaauw RH. Org. Lett. 2004; 6: 4941
  CrossrefPubMedSearch in Google Scholar
• 33 Jacobsen EN, Zhang W, Muci AR, Ecker JR, Deng L. J. Am. Chem. Soc. 1991; 113: 7063
  CrossrefSearch in Google Scholar
• 34 Blundell P, Ganguly AK, Girijavallabhan VM. Synlett 1994; 263
  Thieme Connect
• 35 Wang L, Sharpless KB. J. Am. Chem. Soc. 1992; 114: 7568
  CrossrefSearch in Google Scholar
• 36 Carreira EM, Kvaerno L. Classics in Stereoselective Synthesis . Wiley-VCH; Weinheim: 2009: 296
  Search in Google Scholar
• 37 Dupau P, Epple R, Thomas AA, Fokin VV, Sharpless KB. Adv. Synth. Catal. 2002; 344: 421
  CrossrefSearch in Google Scholar
• 38 Bobinski TP, Fuchs PL. Tetrahedron Lett. 2015; 56: 4151
  CrossrefSearch in Google Scholar

• Supplementary Material