Application of the Wittig Rearrangement of N-Butyl-2-benzyloxybenzamides to Synthesis of Phthalide Natural Products and 3-Aryl-3-benzyloxyisoindolinone Anticancer Agents

Abstract

Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO₂ provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents.

1. Introduction

In a recent paper [1], we reported that the N-butylamide group, C(=O)NHBu, was successful in promoting the [1,2]-Wittig rearrangement of substituted aryl benzyl ethers. While the diarylmethanol products resulting from rearrangement of 3- or 4-benzyloxy-N-butylbenzamides were stable, the products 2 derived from 2-benzyloxy-N-butylbenzamides 1 were found to cyclise slowly with loss of butylamine to give 3-arylphthalides 3, a process accelerated in the presence of p-toluenesulfonic acid (Scheme 1). More recently, we have described a similar pattern of reactivity for the isomeric benzyloxyphenyl phosphonamidates where the directing group, P=O(NHBu)OEt, gives stable Wittig-rearranged diarylmethanols for the 3- or 4- series [2], but in the 2-position results in cyclisation without rearrangement to give 1,3-benzoxaphospholanes [3].

There has been considerable recent interest in the synthesis and biological activity of 3-arylphthalide natural products, and a recent review lists over 40 such products, as well as describing in detail the methods developed for their synthesis [4]. The related 3-hydroxy-3-arylisoindolinones 4 are also of considerable interest [5], particularly since some simple derivatives have shown promising anticancer activity [6,7].

In this paper, we describe our attempts to apply the Wittig rearrangement route of Scheme 1 to the synthesis of three biologically active 3-arylphthalide natural products. In addition, we disclose for the first time a new oxidative workup of the reaction products 2 from [1,2]-Wittig rearrangement of 1, which offers a direct route to hydroxyisoindolinones 4 and its successful application to the synthesis of two anticancer compounds.

2. Results and Discussion

2.1. Synthesis of 3-Arylphthalide Natural Products

To investigate the applicability of the Wittig rearrangement–cyclisation approach to the synthesis of phthalides, we chose three examples: compounds 5, 6 and 7 (Figure 1). Chrycolide 5 was extracted from the leaves of Chrysanthemum coronarium [8] and shows activity as a plant growth inhibitor. Isopestacin 6, isolated from the endophytic fungus Pestalotiopsis microspora [9], has antifungal and antioxidant activity, and cryphonectric acid 7, isolated from Cryphonectrica parasitica [10], showed root growth inhibition.

Since our synthetic plans involved the final-stage deprotection of the phenolic OH groups carried through the syntheses as methyl ethers, we though it wise to first confirm the compatibility of the 3-arylphthalide functionality with the rather harsh conditions required for this deprotection. For this, a sample of the 5-methoxy compound 8, already obtained by the Wittig rearrangement–cyclisation approach [1], was treated with boron tribromide in dichloromethane to afford an essentially quantitative yield of the deprotected compound 9 with no evidence of unwanted side reactions (Scheme 2).

Encouraged by this result, we embarked on the synthesis of chrycolide, as summarised in Scheme 3. The starting material, methyl 2-hydroxy-6-methoxybenzoate 10, was readily prepared in 81% yield by mono de-methylation of methyl 2,6-dimethoxybenzoate [11] using boron trichloride and had properties in good agreement with the reported data [12]. This was converted into the N-butyl amide 11 by reaction with an excess of butylamine in boiling methanol. The O-alkylation of this with 2-bromomethylthiophene 12 and potassium carbonate in DMF afforded the target ether 13 in a disappointing 19% yield, most likely due to steric hindrance. In the key step, this was treated with 3.3 equivalents of n-butyllithium in THF, resulting in the Wittig rearrangement to the secondary alcohol 14. However, this was not isolated, since it was found to cyclise spontaneously on purification by preparative TLC with the loss of butylamine to afford the phthalide 15 in low yield. The final deprotection using boron tribromide proceeded in good yield to afford chrycolide 5, showing ¹H and ¹³C NMR data in good agreement with those of the natural product published by Tada and Chiba (see Supplementary Materials) [8]. As far as we are aware, there is only one other published synthesis of chrycolide reported by a group at Merck in 2013 [13].

The structure of isopestacin contains several features making it more challenging. The ring methyl group has to be introduced at the start and, more importantly, the presence of two ortho substituents on the 3-aryl group may make the Wittig rearrangement step difficult. The synthetic plan, summarised in Scheme 4, starts from orcinol 16 and makes use of an unusual carboxylation [14] analogous to the Kolbe–Schmitt reaction to form the dihydroxy-p-toluic acid 17. Exhaustive methylation of this gave a good yield of the dimethoxy ester 18, and this was readily mono de-methylated in excellent yield using boron trichloride to give 19, which had both melting point [14] and ¹H and ¹³C NMR data [15] in agreement with reported values. Conversion into the previously unknown N-butyl amide 20 was achieved in high yield. The final stage in the assembly of the substrate for the key Wittig rearrangement involved alkylation with 2,6-dimethoxybenzyl bromide 21. As we have already described elsewhere [16], this is a highly unstable compound, but by using the freshly prepared reagent immediately, the target compound 22 was obtained in reasonable yield. Unfortunately, all attempts to bring about the required Wittig rearrangement of this by treatment with n-butyllithium were unsuccessful. Even using 4.5 equivalents of butyllithium gave, after aqueous workup, mainly the recovered starting material accompanied by a low yield of the debenzylated product 20. We conclude that the benzyl carbanion formed from 22 is too hindered to undergo rearrangement and is simply reprotonated upon workup. This is a little surprising, since in our previous work [1], we were able to observe successful Wittig rearrangement with a 2-methoxy-1-naphthylmethyl ether. As far as we are aware, there is only one reported synthesis for both isopestacin and cryphonectric acid [17].

To apply the method to the synthesis of cryphonectric acid 7, we envisaged creating the carboxylic acid function by a late-stage oxidation of the methyl group, and so, the target for rearrangement and cyclisation became the ether 31 (Scheme 5). The required benzylic bromide 26 was not previously known, and since it was expected to be unstable like 21, no attempt was made to isolate it. The ester 18, already available from the previous synthesis, was subjected to lithium aluminium hydride reduction to afford 25 in good yield, and this was treated with phosphorus tribromide to generate 26 ready for immediate use.

In the meantime, the coupling partner 30 was prepared starting from trihydroxybenzoic acid 27 by exhaustive methylation to give 28, mono de-methylation using BCl₃ to give 29, and reaction with n-butylamine in methanol to give the new compound 30. Treatment of this with sodium hydride in DMF followed by the addition of freshly prepared 26 in DMF unfortunately gave mainly (~60%) recovered 30, together with just a trace (2%) of the desired product 31 in an impure form. It was clear that this approach to cryphonectric acid was not going to be viable, and the synthesis was abandoned. It is notable that cyclisation approaches to phthalides bearing a hindered 3-aryl group appear to be difficult, and a recently published new route to 3-arylphthalides does not include any examples with a 2,6-disubstituted aryl group [18].

2.2. Synthesis of 3-Aryl-3-hydroxyisoindolin-2-ones and Their Benzyl Derivatives

As mentioned in the introduction, compounds of this class have been of particular interest, since they were reported to have promising anticancer activity based on their inhibition of the MDM2-p53 protein–protein interaction [5,6]. Three main routes to the 3-hydroxy compounds required for conversion into the biologically active 3-benzyloxy derivatives have been developed (Scheme 6). The route used by Hardcastle and coworkers [5] exploits a method developed earlier by Golding and coworkers [19] and involves activation of 2-benzoylbenzoic acids with thionyl chloride followed by treatment with the requisite amine. An alternative approach developed much earlier is simply to treat the appropriate N-alkylphthalimide with an aryl Grignard reagent [20]. Most recently, a new method reported by Luzzio and coworker [21] involves reduction of the phthalimide, addition of the aryl group by electrophilic substitution, and a final oxidation using bipyridyl chlorochromate.

In our previous work, treatment of the 2-benzyloxy-N-butylbenzamide 32 with butyllithium led to Wittig rearrangement to afford the amide-substituted benzhydrol 33 [1]. This was found to be rather unstable and slowly converted with loss of butylamine into the corresponding phthalide, a process accelerated by heating in the presence of p-toluenesulfonic acid. We have now found that by stirring a solution of the crude product 33 in dichloromethane for 24 h with a ten-fold excess of manganese dioxide, it is possible to directly obtain the 3-hydroxy-3-phenylisoindolinone 34 in moderate overall yield (Scheme 7).

We decided to evaluate this new approach for the synthesis of some anticancer compounds and chose the two compounds 35 (IC₅₀ 82 ± 8 μM) and 36 (IC₅₀ 5.3 ± 0.8 μM) as targets (Figure 2). These are active as inhibitors of the MDM2-p53 protein–protein interaction [6,7]. It might be noted at this stage that the initial testing involved racemic compounds [6], as will be produced by our approach, but later studies showed that when the enantiomers of the most active compound were resolved, the activity resided predominantly in one enantiomer [7].

The route began by converting the readily available methyl salicylate 37 into its N-propyl amide 38 in high yield, and this was then O-alkylated with either benzyl bromide to give 39 or p-chlorobenzyl chloride to give 40 (Scheme 8).

In the key step of the synthesis, these were then treated with 3.3 equivalents of n-butyllithium in THF. Since the expected products 41 and 42 were prone to cyclisation, as mentioned earlier, no attempt was made to purify these. Instead, the crude products obtained after aqueous workup, extraction, drying, and evaporation were taken up immediately in CH₂Cl₂ and treated with a twenty-fold excess of manganese dioxide. After filtering off the solids, evaporation, and chromatographic purification of the residue, the desired 3-hydroxyisoindolinones 43 and 44 were obtained in moderate yield.

The NMR spectra of these were in full agreement with previously published values [20], but the ¹H NMR showed an interesting phenomenon: all four CH₂ protons within the n-propyl groups were non-equivalent and coupled to each other resulting in a highly complex pattern (Figure 3). Although these were described in the previous work simply as multiplets, we were able to analyse them and produce a successful simulation using the values shown in

Table 1. Chemical shift values (ppm) and coupling constants (Hz) used to achieve the simulation of Figure 3.

Proton (*)	δ	J*–H1b	J*–H2a	J*–H2b	J*–H3
H-1a	3.394	14	10	5.5	—
H-1b	2.912		5.5	10	—
H-2a	1.517			13	7.5
H-2b	1.393				7.5
3 × H-3	0.785

for the example of compound 43. The same feature was apparent in the spectra of the final products 35 and 36 and is clearly a consequence of the highly hindered environment of the propyl group adjacent to the stereocentre in these compounds.

For the final stage of the synthesis, we used the reported method [6], involving activation of the hydroxyisoindolinones 43 and 44 with thionyl chloride and treatment with the commercially available 4-hydroxy-3,5-dimethoxybenzyl alcohol 45 (“syringyl alcohol”) in the presence of triethylamine. This afforded the target anticancer compounds 35 and 36 in low and moderate yields, respectively, and these had spectroscopic data identical to the published values [6].

3. Experimental

3.1. General Experimental Details

NMR spectra were recorded on solutions in CDCl₃, unless otherwise stated, using Bruker instruments. Chemical shifts are given in ppm to high frequency from Me₄Si, with coupling constants J in Hz. The ¹H NMR spectra are referenced to internal Me₄Si, while the ¹³C NMR spectra are referenced to the solvent signal at 77.0 (CDCl₃). IR spectra were recorded on a Perkin Elmer 1420 instrument. Mass spectra were obtained using a Micromass instrument, and the ionisation method used is noted in each case. Preparative TLC was carried out using 1.0 mm layers of Merck alumina 60G, containing 0.5% Woelm fluorescent green indicator on glass plates. Column chromatography was carried out using silica gel (particle size 40–63 μm). Melting points were recorded on a Gallenkamp 50W melting point apparatus or a Reichert hot-stage microscope.

6-Methoxy-3-phenylisobenzofuran-1(3H)-one 8 was prepared, as previously described [1].

3.2. Trial Deprotection of a Methoxyphthalide

Preparation of 6-Hydroxy-3-phenylisobenzofuran-1(3H)-one 9

A solution of 6-methoxy-3-phenylisobenzofuran-1(3H)-one 8 (0.031 g, 0.13 mmol) in CH₂Cl₂ (1.5 cm³) was stirred under nitrogen, while boron tribromide (1 M, 0.45 cm³, 0.42 mmol) was added. The reaction was stirred under a nitrogen atmosphere for 18 h. CH₂Cl₂ (10 cm³) and ice water (10 cm³) were added, and the organic layer was separated, washed with 2M hydrochloric acid (10 cm³), dried over magnesium sulfate and concentrated in vacuo to afford 9 (0.029 g, 99%); mp 201–204 °C; ¹H NMR (300 MHz) δ_H 7.37 (4H, m ArCH), 7.26 (2H, m, ArCH), 7.20 (1H, d, J 8.5, ArCH-4), 7.15 (1H, dd, J 8.5, 2.5, ArCH-5), 6.36 (1H, s, 3-CH) and 5.50 (1H, br s, OH); ¹³C NMR (125 MHz) δ_C 170.4 (C=O), 156.8 (C–O), 142.1 (C), 136.5 (C), 129.3 (CH), 128.9 (2CH), 127.3 (C), 127.0 (2CH), 124.1 (CH), 122.8 (CH), 110.8 (CH), and 82.7 (CH); IR (ATR) ν_max/cm⁻¹ 3269 (OH), 1720 (C=O), 1321, 1308, 1065, 957 and 698; HRMS (ESI⁺) calcd. for C₁₄H₁₁O₃ (M+H) 227.0708, found 227.0697.

3.3. Synthesis of Chrycolide 5

3.3.1. Methyl 2-Hydroxy-6-methoxybenzoate 10

A solution of methyl 2,6-dimethoxybenzoate [11] (3.0 g, 15.29 mmol) in CH₂Cl₂ (90 cm³) was stirred at 0 °C while boron trichloride in hexane (1M, 45 cm³, 45.87 mmol) was added. After the addition, the mixture was allowed to warm to RT and stirred for 18 h. The solution was poured into ice water (50 cm³) and a precipitate formed. The organic layer was separated, and the aqueous phase was extracted with CH₂Cl₂ (3 × 30 cm³). The combined extract was dried over magnesium sulfate, and concentrated in vacuo to afford 10 as a brown oil (2.25 g, 81%); ¹H NMR (300 MHz) δ_H 11.52 (1H, s, OH), 7.32 (1H, t, J 8.4, ArC(4)H), 6.62 (1H, dd, J 8.4, 1.0, ArC(5)H), 6.43 (1H, dd, J 8.4, 0.8, ArC(3)H), 3.96 (3H, s, OCH₃) and 3.88 (3H, s, OCH₃). ¹H NMR spectral data were in accordance with those previously reported [12].

3.3.2. N-Butyl-2-hydroxy-6-methoxybenzamide 11

A solution of methyl 2-hydroxy-6-methoxybenzoate 10 (2.00 g, 10.98 mmol) and n-butylamine (5.69 cm³, 57.6 mmol) in methanol (25 cm³) was heated under reflux for 18 h. Methanol was evaporated, and 2 M hydrochloric acid was added until the pH was 1. The product was extracted with CH₂Cl₂ (20 cm³). The organic layer was washed with water (3 × 20 cm³), dried over magnesium sulfate, and concentrated in vacuo to afford 11 (2.00 g, 82%); mp 165–167 °C; ¹H NMR (300 MHz) δ_H 8.34 (1H, br s, NH), 7.25 (1H, t, J 8.4, 4-CH), 6.62 (1H, dd, J 8.4, 0.9, ArCH), 6.39 (1H, J 8.4, 0.9, ArCH), 3.93 (3H, s, OCH₃), 3.43 (2H, m, NCH₂), 1.61 (2H, m, NCH₂CH₂), 1.42 (2H, m, CH₂CH₂CH₃) and 0.97 (3H, t, J 7.2, CH₂CH₃); ¹³C NMR (125 MHz) δ_C 170.0 (C=O), 164.3 (C–O), 158.5 (C–O), 133.0 (CH), 111.7 (CH), 103.9 (C), 100.8 (CH), 56.2 (OCH₃), 39.0 (NCH₂), 31.3 (CH₂CH₂CH₂), 20.2 (CH₂CH₂CH₃) and 13.7 (CH₂CH₃); IR (ATR) ν_max/cm⁻¹ 3387 (NH), 1636 (C=O), 1587, 1541, 1437, 1238, 1086, 760 and 640; HRMS (ESI⁺) calcd. for C₁₂H₁₈NO₃ (M+H) 224.1287, found 224.1278.

3.3.3. N-Butyl-2-methoxy-6-(2-thienylmethoxy)benzamide 13

A solution of N-butyl-2-hydroxy-6-methoxybenzamide 11 (1.88 g, 8.42 mmol), 2-(bromomethyl)thiophene 12 (1.49 g, 8.42 mmol) and potassium carbonate (3.49 g, 6.67 mmol) in DMF (9 cm³) was stirred at 100 °C for 18 h. The solution was cooled to room temperature, then water (30 cm³) and CH₂Cl₂ (30 cm³) were added. The organic layer was separated, and the aqueous layer was washed with diethyl ether (3 × 30 cm³). The combined organic layers were washed with water (5 × 50 cm³). The resulting solution was dried over magnesium sulfate and concentrated in vacuo to afford a red solid. The solid was dissolved in diethyl ether (30 cm³) which was washed with 2 M sodium hydroxide (2 × 20 cm³), dried over magnesium sulfate, and concentrated in vacuo to afford a red solid. The product was further purified through column chromatography to afford 13 (0.46 g, 19%) as a yellow solid. mp 99–101 °C; ¹H (300 MHz) δ_H 7.28 (1H, m), 7.22 (1H, t, J 8.4), 7.06 (1H, m), 6.96 (1H, m), 6.62 (1H, d, J 8.4), 6.56 (1H, d, J 8.7), 5.72 (br t, J 4.8, NH), 5.22 (2H, s, OCH₂), 3.79 (3H, s, OCH₃), 3.41 (2H, m, NCH₂), 1.50 (2H, m, CH₂CH₂CH₂), 1.34 (2H, m, CH₂CH₂CH₃) and 0.89 (3H, t, J 7.3, CH₂CH₃); ¹³C (125 MHz) δ_C 165.2 (C=O), 157.4 (C–O), 155.6 (C–O), 138.9 (C), 130.2 (CH), 126.6 (CH), 126.5 (CH), 125.9(CH), 117.1 (C), 105.8 (CH), 104.5 (CH), 65.7 (OCH₂), 55.8 (OCH₃), 39.3 (NHCH₂), 31.4 (CH₂CH₂CH₂), 19.8 (CH₂CH₂CH₃) and 13.6 (CH₂CH₃); IR (ATR) ν_max/cm⁻¹ 3387 (NH), 1635. (C=O), 1589, 1541, 1437, 1238, 1086, 760 and 640; HRMS (ESI⁺) calcd. for C₁₇H₂₁NaNO₃S (M+Na) 342.1062, found 342.1127.

3.3.4. N-Butyl-2-methoxy-6-(2-thienyl(hydroxy)methyl)benzamide 14 and Cyclisation to 7-Methoxy-3-(2-thienyl)isobenzofuran-1(3H)-one 15

A solution of N-butyl-2-methoxy-6-(2-thienylmethoxy)benzamide 13 (0.3 g, 1.04 mmol) in dry THF (10 cm³) was stirred at RT under nitrogen while n-butyllithium (1.8 M in hexanes, 1.92 cm³, 3.45 mmol) was added dropwise. After the addition, the mixture was stirred at RT for 15 min then was quenched with saturated aqueous ammonium chloride (10 cm³) and the product was extracted with diethyl ether (3 × 20 cm³). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford a brown solid (0.16 g, 58%). A portion of the product (16 mg) was further purified through preparative TLC, which resulted in cyclisation to afford 15 (9.7 mg, 30%); ¹H NMR (300 MHz) δ_H 7.63 (1H, t, J 7.9, 5-H), 7.35 (1H, dd, J = 5.0, J = 1.1), 7.14 (1H, d, J = 3.5), 7.02–6.97 (3H, m), 6.57 (1H, s, 3-H) and 4.03 (3H, s, OCH₃); ¹³C (125 MHz) δ_H 167.7 (C=O), 158.4 (C), 151.4 (C), 139.1 (C), 136.5 (CH), 127.7 (CH), 127.3 (CH), 127.0 (CH), 114.7 (CH), 113.3 (C), 111.3 (CH), 76.8 (CH) and 56.1 (CH₃); IR (ATR) ν_max/cm⁻¹ 1759 (C=O), 1601, 1487, 1066 and 704; HRMS (ESI⁺) calcd. for C₁₃H₁₁O₃S 247.0429 (M+H), found 247.0415.

3.3.5. Chrycolide 5

To a stirred solution of 7-methoxy-3-(2-thienyl)isobenzofuran-1(3H)-one 15 (8.6 mg, 0.035 mmol) in CH₂Cl₂ (5 cm³) at rt under N₂ was added a 1.0 M solution of BBr₃ (60 μL, 0.070 mmol) in CH₂Cl₂, and the solution stirred at rt overnight. The reaction was quenched by the addition of ice-cold H₂O (5 cm³) and the layers separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 10 cm³), and the combined organic layers dried over MgSO₄ and concentrated to give, after purification via preparative TLC (hexane/Et₂O 3:2) at R_f 0.11, compound 5 (6.5 mg, 80%) as an orange solid; δ_H (500 MHz) 7.59 (1 H, t, J 7.9, ArH), 7.40 (1 H, dd, J 5.1, 1.2, ArH), 7.17 (1 H, d, J 3.4, ArH), 7.04 (1 H, dd, J 5.1, 3.6, ArH), 7.01 (1 H, d, J 8.3, ArH), 6.96 (1 H, dt, J 7.5, 0.8, ArH) and 6.68 (1 H, s, CHO); δ_C (125 MHz) 171.3 (C=O), 156.4 (C–O), 148.6 (C), 138.1 (C), 137.2 (CH), 128.3 (CH), 127.9 (CH), 127.1 (CH), 116.2 (CH), 114.6 (CH), 111.1 (C) and 79.0 (CH). The ¹H and ¹³C spectral data were in accordance with those previously reported [8].

3.4. Attempted Synthesis of Isopestacin 6

3.4.1. 2,6-Dihydroxy-4-methylbenzoic Acid 17

Following a literature procedure [14], a stirred solution of orcinol (1.32 g, 9.3 mmol) and KHCO₃ (2.30 g, 23.0 mmol) in glycerol (2.29 g, 24.9 mmol) was heated to 120 °C for 6 h. The solution was cooled to rt and H₂O (10 cm³) was added. The solution was acidified to pH 1 with conc. HCl and the resulting precipitate filtered off and dried to give 17 (1.28 g, 82%) as a brown solid which was used without further purification; mp (decomp.) 150 °C (lit. [22] 152 °C); δ_H (400 MHz) 6.35 (2 H, q, J 0.7, ArH) and 2.28 (3 H, t, J 0.7, CH₃). The ¹H spectral data were in accordance with those previously reported [23].

3.4.2. Methyl 2,6-Dimethoxy-4-methylbenzoate 18

To a stirred solution of 2,6-dihydroxy-4-methylbenzoic acid 17 (1.00 g, 5.9 mmol) and K₂CO₃ (2.40 g, 17.8 mmol) in Me₂CO (50 cm³) was added MeI (2.0 cm³, 4.52 g, 31.9 mmol) and the solution heated to reflux for 3 d. The reaction mixture was cooled to rt and filtered, and the filtrate concentrated. The crude residue was dissolved in EtOAc (30 cm³) and washed with H₂O (30 cm³) and 2 M NaOH (30 cm³). The organic layer was dried over MgSO₄ and concentrated to give 18 (1.12 g, 90%) as a brown solid, which was used without further purification; mp 74−76 °C (lit. [24] 79−81 °C); δ_H (400 MHz) 6.37 (2H, q, J 0.7, ArH), 3.88 (3H, s, COOCH₃), 3.79 (6H, s, 2 × OCH₃) and 2.34 (3H, t, J 0.7, CH₃); δ_C (100 MHz) 167.2 (C=O), 157.1 (2C), 141.7 (C), 110.1 (C), 104.6 (2CH), 55.8 (2CH₃), 52.2 (CH₃) and 22.2 (CH₃). The ¹H NMR spectral data were in accordance with those previously reported [23]. ¹³C NMR data are reported for the first time.

3.4.3. Methyl 2-Hydroxy-6-methoxy-4-methylbenzoate 19

To a stirred solution of methyl 2,6-dimethoxy-4-methylbenzoate 18 (1.00 g, 4.76 mmol) in CH₂Cl₂ (30 cm³) at 0 °C under N₂ was added BCl₃ (1.0 M hexanes, 7 cm³, 7.00 mmol) and the solution stirred at rt for 1 d. The reaction mixture was poured into ice-water (30 cm³) and extracted with CH₂Cl₂ (3 × 30 cm³). The organic layers were dried over MgSO₄ and concentrated to give 19 (0.91 g, 97%) as a brown solid, which was used without further purification; mp 86−88 °C (lit. [14] 94−95 °C); δ_H (400 MHz) 11.57 (1H, s, OH), 6.43 (1H, m, ArH), 6.23 (1H, m, ArH), 3.94 (3H, s, COOCH₃), 3.85 (3H, s, OCH₃) and 2.30 (3H, t, J 0.6, CH₃); δ_C (100 MHz) 171.6 (C=O), 163.5 (C–O), 160.6 (C–O), 146.6 (C), 110.5 (CH), 103.5 (CH), 100.4 (C), 56.1 (CH₃), 52.3 (CH₃) and 22.2 (CH₃). The ¹H and ¹³C NMR spectral data were in accordance with those previously reported [15].

3.4.4. N-Butyl-2-hydroxy-6-methoxy-4-methylbenzamide 20

To a stirred solution of methyl 2-hydroxy-6-methoxy-4-methylbenzoate 19 (0.88 g, 4.5 mmol) in MeOH (15 cm³) was added n-butylamine (2.31 cm³, 1.71 g, 23.4 mmol) and the solution heated under reflux for 8 h. The solution was cooled to rt and concentrated, then acidified to pH1 by the addition of 2 M HCl solution. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 cm³) and the combined organic layers dried over MgSO₄ and concentrated to give 20 (0.98 g, 92%) as a light brown solid which was used without further purification; mp 61−63 °C; δ_H (400 MHz) 8.26 (1H, s br, NH), 6.44 (1H, dq, J 1.5, 0.7, ArH), 6.20 (1H, d, J 1.5, ArH), 3.92 (3H, s, OCH₃), 3.41 (2H, td, J 7.1, 5.6, NHCH₂), 2.28 (3H, d, J 0.7, CH₃), 1.64−1.55 (2H, m, NHCH₂CH₂), 1.45−1.37 (2H, m, CH₂CH₃) and 0.96 (3H, t, J 7.3, CH₂CH₃); δ_C (100 MHz) 170.0 (C=O), 164.2 (C–O), 158.3 (C–O), 144.2 (C), 112.0 (CH), 102.1 (CH), 101.4 (C), 56.0 (OCH₃), 38.9 (NHCH₂), 31.4 (NHCH₂CH₂), 22.0 (CH₃), 20.2 (CH₂CH₃) and 13.7 (CH₂CH₃); ν_max/cm⁻¹ 3393 (N–H), 2959, 1641 (C=O), 1597, 1545 and 1224; HRMS (ESI⁺): calcd. for C₁₃H₂₀NO₃ (M+H) 238.1443, found 238.1429.

3.4.5. N-Butyl-2-(2,6-dimethoxybenzyloxy)-6-methoxy-4-methylbenzamide 22

To a solution of N-butyl-2-hydroxy-6-methoxy-4-methylbenzamide 20 (0.38 g, 1.62 mmol) in DMF (8 cm³), NaH (58 mg, 1.62 mmol) was added, followed after 30 min by a solution of 2,6-dimethoxybenzyl bromide 21 [16] (0.35 g, 1.51 mmol) in DMF (2 cm³). The mixture was stirred at rt for 18 h and then added to water (20 cm³) and CH₂Cl₂ (20 cm³). The organic layer was separated, and the aqueous layer extracted with diethyl ether (3 × 20 cm³). The combined organic layers were washed with water (5 × 20 cm³), then dried and evaporated. Purification via flash column chromatography (gradient elution 1:1 hexane/EtOAc to 100% EtOAc) gave, at R_f 0.10, 22 (0.19 g, 32%) as an orange oil ; δ_H (400 MHz) 7.26 (1H, t, J 8.4, ArH), 6.62−6.52 (3H, m, ArH), 6.37 (1H, s, ArH), 5.99 (1H, t, J 5.9, NH), 5.10 (2H, s, OCH₂), 3.803 (6H, s, 2 × OCH₃), 3.799 (3H, s, OCH₃), 3.25 (2H, td, J 7.0, 5.9, NHCH₂), 2.34 (3H, s, CH₃), 1.28−1.22 (2H, m, NHCH₂CH₂), 1.20−1.13 (2H, m, CH₂CH₃) and 0.76 (3H, t, J 7.2, CH₂CH₃); δ_C (100 MHz) 165.5 (C=O), 159.2 (2 C–O), 158.1 (C–O), 157.1 (C–O), 140.8 (C), 130.1 (CH), 113.0 (C), 112.6 (C), 106.3 (CH), 105.0 (CH), 103.8 (2CH), 60.0 (OCH₂), 55.9 (OCH₃), 55.8 (2 OCH₃), 39.2 (NHCH₂), 31.3 (NHCH₂CH₂), 22.1 (CH₃), 19.8 (CH₂CH₃) and 13.7 (CH₂CH₃); HRMS (ESI⁺): calcd. for C₂₂H₃₀NO₅ (M+H) 388.2124, found 388.2104.

3.5. Attempted Synthesis of Cryphonectric Acid 7

3.5.1. 2,6-Dimethoxy-4-methylbenzyl Alcohol 25

To a stirred suspension of LiAlH₄ (0.73 g, 19.02 mmol) in dry THF (20 cm³), a solution of methyl 2,6-dimethoxy-4-methylbenzoate 18 (1.99 g, 9.47 mmol) in tetrahydrofuran (2 cm³) was added dropwise and left to stir. After 2 days, water (7 cm³) and 2 M NaOH (7 cm³) were added carefully, affording a white precipitate. This precipitate was filtered off under suction using celite, and the filtrate concentrated in vacuo. The concentrated filtrate was extracted with CH₂Cl₂ (10 cm³) and the organic layer was dried over MgSO₄. The solvent was removed in vacuo, affording 25 (1.49 g, 87%) as a yellow solid, which required no further purification; mp 46–48 °C; δ_H (300 MHz) 6.38 (2H, s, ArH), 4.74 (2H, s, CH₂), 3.83 (6H, s, OCH₃) and 2.34 (3H, s, ArCH₃). The ¹H NMR spectral data were found to be consistent with those reported in the literature [25].

3.5.2. 2,6-Dimethoxy-4-methylbenzyl Bromide 26

To a solution of 2,6-dimethoxy-4-methylbenzyl alcohol 25 (0.5 g, 2.74 mmol) in diethyl ether (8 cm³), PBr₃ (0.107 cm³, 0.276 g, 1.02 mmol) was added at 0 °C and stirred for 30 min. Methanol (1.0 cm³) and water (10 cm³) were added, and the organic layer was collected. The aqueous layer was extracted with ether (8 cm³), and the combined organic layers were dried over MgSO₄. The filtrate was concentrated in vacuo, affording 28 (0.67 g, 100%) as an unstable solid. This was immediately dissolved in DMF (8.5 cm³) and was directly used for the synthesis of 31.

3.5.3. Methyl 2,4,6-Trimethoxybenzoate 28

Following a literature procedure adapted from Barrett and coworkers [26], to a stirred mixture of 2,4,6-trihydroxybenzoic acid 27 (6 g, 32 mmol) and K₂CO₃ (26.5 g, 192 mmol) in acetone (100 cm³), dimethyl sulfate (18 cm³, 190 mmol) was added. The mixture was stirred for 7 days at rt. The reaction was quenched with methanol (7.5 cm³) and concentrated aqueous ammonia (2.5 cm³) and stirred for 1 h. The mixture was filtered under suction, then concentrated aqueous ammonia (5 cm³) and saturated aqueous ammonium chloride (20 cm³) were added to the filtrate and stirred for 1 h. The aqueous filtrate was extracted with ether (3 × 30 cm³), then the combined organic layers were dried over MgSO₄, and then concentrated in vacuo, affording 28 (5.19 g, 72%) as colourless crystals which required no further purification; mp 65–67 °C (lit. [27] 67–70 °C); δ_H (300 MHz) 6.10 (2H, s, ArH), 3.87 (3H, s, OCH₃), 3.81 (3H, OCH₃) and 3.79 (6 H, s, OCH₃); δ_C (75 MHz) 166.9 (C=O), 162.5 (C), 158.6 (2C), 90.6 (2CH), 56.0 (OCH₃), 55.4 (OCH₃) and 52.2 (OCH₃). The ¹H and ¹³C NMR spectral data were found to be consistent with those reported in the literature [28].

3.5.4. Methyl 2-Hydroxy-4,6-dimethoxybenzoate 29

Following a literature procedure adapted from Barrett and coworkers [26], to a stirred solution of methyl 2,4,6-trimethoxybenzoate 28 (3.83 g, 17.06 mmol) in dry CH₂Cl₂ (75 cm³) under N₂ (g), at −78 °C, BCl₃ (19 cm³, 1 M, 19.00 mmol) was added dropwise, affording a cloudy precipitate. The reaction mixture was left to stir at rt overnight, then dilute HCl (45 cm³) was added, and the aqueous layer extracted with CH₂Cl₂ (3 × 15 cm³). The combined organic layers were washed with saturated aqueous NaHCO₃ (30 cm³) and then dried over MgSO₄. The solvent was then removed in vacuo, affording a mixture of 28 and 29. The crude product was partitioned between ether (30 cm³) and 2 M NaOH (30 cm³) and the organic and aqueous layers collected. The organic layer was dried over MgSO₄ and concentrated in vacuo to afford 28 (0.72 g). The aqueous layer was neutralised with 2M HCl, then extracted with ethyl acetate (2 × 30 cm³), then the combined organic layers were dried over MgSO₄ and concentrated in vacuo to afford 29 (2.26 g, 62%) as yellow crystals which required no further purification; mp 106–109 °C (lit. [27] 107–109 °C); δ_H (300 MHz) 12.01 (1H, s, OH), 6.10 (1H, d, J 2.4, ArH), 5.95 (1H, d, J 2.4, ArH), 3.90 (3H, s, OCH₃), 3.81 (3H, s, OCH₃) and 3.79 (3 H, s, OCH₃); δ_C (75 MHz) 171.6 (C=O), 165.9 (C), 165.3 (C), 162.1 (C), 96.5 (C), 93.4 (CH), 91.5 (CH), 56.0 (OCH₃), 55.4 (OCH₃) and 52.1 (OCH₃). The ¹H NMR spectra data were found to be consistent with those reported in the literature [29].

3.5.5. N-Butyl-2-hydroxy-4,6-dimethoxybenzamide 30

To a stirred solution of methyl 2-hydroxy-4,6-dimethoxybenzoate 29 (2.00 g, 9.4 mmol) in methanol (40 cm³), n-butylamine (4.55 cm³, 3.4 g, 46.0 mmol) was added dropwise, and the solution heated under reflux for 24 h. The solution was cooled to rt, concentrated in vacuo, and then acidified to pH 1 by adding 2 M HCl affording crystals. The mixture was extracted with CH₂Cl₂ (3 × 40 cm³), then the combined organic layers dried over MgSO₄, and then concentrated in vacuo to afford 30 (2.25 g, 94%) as a brown solid requiring no further purification; mp 65–69 °C; δ_H (300 MHz) 8.12 (1H, br s, OH), 6.12 (1H, d, J 2.4, ArH), 5.95 (1 H, d, J 2.4, ArH), 3.89 (3H, s, OCH₃), 3.78 (3H, s, OCH₃), 3.40 (2H, td, J 7.1, 5.5, NHCH₂), 1.64–1.54 (2H, m, NHCH₂CH₂), 1.47–1.34 (2H, m, NHCH₂CH₂CH₂) and 0.96 (3H, t, J 7.3, CH₂CH₃); δ_C (75 MHz) 170.0 (C=O), 166.2 (C), 163.4 (C), 159.7 (C), 97.5 (C), 94.5 (CH), 90.4 (CH), 56.0 (OCH₃), 55.3 (OCH₃), 38.8 (NHCH₂), 31.4 (CH₂), 20.2 (CH₂) and 13.7 (CH₃); ν_max/cm⁻¹ 3391, 2932, 2860, 1640, 1595, 1557, 1393, 1211, 1105, 914 and 820; HRMS (ESI⁺) calcd. for C₁₃H₁₉NaNO₄ (M+Na) 276.1212, found 276.1198; calcd. for C₁₃H₂₀NO₄ (M+H) 254.1392, found 254.1383.

3.5.6. N-Butyl-2,4-dimethoxy-6-(2,6-dimethoxy-4-methylbenzyloxy)benzamide 31

To a stirred solution of N-butyl-2-hydroxy-4,6-dimethoxybenzamide 30 (0.60 g, 2.74 mmol) in DMF (10.0 cm³), NaH (104 mg, 2.90 mmol) was added. Then 2,6-dimethoxy-4-methylbenzyl bromide 26 (0.6 g, 2.74 mmol) in DMF (8.5 cm³) was added to the reaction mixture and stirred at rt overnight. The reaction mixture was poured into water (30 cm³), and CH₂Cl₂ (30 cm³) was added, then the organic layer was collected. The aqueous layer was then extracted with ether (3 × 30 cm³), and the combined organic layers washed with water (5 × 30 cm³). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The product was purified by flash column chromatography and preparative TLC (3:1, hexane: ethyl acetate) to afford, in addition to the starting compound 30 (0.39 g), the impure product 31 (27.5 mg, 2%) as a yellow solid; HRMS (ESI⁺) calcd. for C₂₃H₃₁NaNO₆ (M+Na) 440.2049, found 440.2033.

3.6. Synthesis 3-Aryl-3-hydroxyisoindolin-1-ones and Their Benzyl Derivatives

3.6.1. Preparation of 2-Butyl-3-hydroxy-3-phenylisoindolin-1(3H)-one 34

A solution of 32 (1.41 g, 4.98 mmol) in dry THF (50 cm³) was stirred under nitrogen, while n-butyllithium in hexanes (2.5 M, 6.60 cm³, 16.4 mmol) was added dropwise. After 2 h, the mixture was added to saturated aq. ammonium chloride (50 cm³) and extracted with diethyl ether (3 × 30 cm³). Drying and evaporation gave the crude secondary alcohol 33 as an oil. This was taken up in CH₂Cl₂ (100 cm³) and stirred at rt with manganese dioxide (8.79 g, 0.101 mol) for 24h. The mixture was filtered, and the filtrate evaporated. The crude residue was purified by column chromatography (SiO₂, Et₂O/hexane 1:1) to give, at R_f 0.45, after subsequent recrystallisation (EtOAc/hexane 1:1), 34 (0.47 g, 34%) as colourless crystals; mp 158–161 °C; (lit. [20] 158–159 °C); δ_H (400 MHz) 7.75–7.71 (1H, m, ArH), 7.49–7.26 (8H, m, ArH), 3.66 (1H, s, OH), 3.45–3.35 (1H, m, NCHH), 2.99–2.87 (1H, m, NCHH), 1.50–1.40 (1H, m, NCH₂CHH), 1.35–1.25 (1H, m, NCH₂CHH), 1.25–1.15 (2H, m, CH₂CH₃) and 0.78 (3H, t, J 7.4, CH₃); δ_C (75 MHz) 167.9 (C=O), 149.1 (C), 138.9 (C), 132.3 (CH), 130.4 (C), 129.1 (CH), 128.3 (3CH), 126.1 (2CH), 123.0 (CH), 122.6 (CH), 91.2 (C(Ph)OH), 39.2 (NCH₂), 30.5 (NCH₂CH₂), 20.3 (CH₂CH₃) and 13.5 (CH₃); HRMS (ESI⁺): calcd. for C₁₈H₁₉NaNO₂ (M+Na) 304.1308, found 304.1302.

3.6.2. 2-Hydroxy-N-propylbenzamide 38

A mixture of methyl salicylate 37 (15.00 g, 98.6 mmol) and n-propylamine (40.5 cm³, 493.0 mmol) in methanol was heated to reflux for 18 h and concentrated in vacuo. The residue was acidified to pH 1 using 2 M HCl(aq) then extracted with CH₂Cl₂. The organic layers were washed with water, dried with MgSO₄ and evaporated to give 38 (16.2 g, 91%) as a waxy peach-coloured oil which was used without further purification. The spectral data were found to be in accordance with previously published data [30]; δ_H (400 MHz) 12.47 (1H, s, OH), 7.51 (1H, dd, J 8.0, 1.8, ArH), 7.35 (1H, ddd, J 8.6, 7.3, 1.6, ArH), 7.06 (1H, s, NH), 6.95 (1H, dd, J 8.3, 1.2, ArH), 6.80 (1H, ddd, J 8.1, 7.3, 1.2, ArH), 3.43–3.30 (2H, m, NCH₂), 1.71–1.53 (2H, m, CH₂) and 0.93 (3H, t, J 5.6, CH₃); δ_C (100 MHz) 169.9 (C=O), 160.8 (C–OH), 133.8 (CH), 125.8 (CH), 118.7 (CH), 118.0 (CH), 114.4 (C), 41.2 (NCH₂), 22.5 (CH₂) and 11.1 (CH₃).

3.6.3. 2-Benzyloxy-N-propylbenzamide 39

A solution of benzyl bromide (1.26 cm³, 10.6 mmol), 2-hydroxy-N-propylbenzamide 38 (1.79 g, 10 mmol) and K₂CO₃ (4.19 g, 30.3 mmol) in DMF (10 cm³) was heated at 100 °C for 18 h. It was then added to water (50 cm³) and extracted with CH₂Cl₂ (20 cm³) followed by diethyl ether (3 × 20 cm³). The combined extract was washed with water (6 × 20 cm³), dried, and evaporated. The residue was purified by column chromatography (SiO₂, EtOAc/hexane 1:1) to yield 39 (1.42 g, 53%) as a colourless oily solid, mp 15–16 °C. δ_H (500 MHz) 8.26 (1H, dd, J 7.8, 1.9, ArH), 7.93 (1H, s, NH), 7.49–7.36 (6H, m, ArH), 7.14–7.03 (2H, m, ArH), 5.16 (2H, s, OCH₂), 3.31 (2H, td, J 6.9, 5.4, NCH₂), 1.49–1.32 (2H, m, CH₂) and 0.75 (3H, t, J 7.4, CH₃); δ_C (100 MHz) 164.9 (C=O), 156.6 (C–O), 135.3 (C), 132.3 (CH), 132.0 (CH), 128.6 (2CH), 128.5 (CH), 127.9 (2CH), 121.5 (C), 121.2 (CH), 112.2 (CH), 71.1 (OCH₂), 41.2 (NCH₂), 22.1 (CH₂) and 11.1 (CH₃). HRMS (ESI⁺): calcd. for C₁₇H₁₉NO₂ (M+H) 270.1494, found 270.1482.

3.6.4. 2-(4-Chlorobenzyloxy)-N-propylbenzamide 40

The method of 3.6.3 was followed using 4-chlorobenzyl chloride (1.71 g, 10.6 mmol), 2-hydroxy-N-propylbenzamide 38 (1.79 g, 10 mmol) and K₂CO₃ (4.19 g, 30.3 mmol) in DMF (10 cm³). After extraction, washing, drying and evaporation, the product was obtained without further purification to yield 40 (2.83 g, 93%) as a colourless solid, mp 130–132 °C; δ_H (400 MHz) 8.24 (1 H, dd, J = 7.8, 1.9 Hz, ArH), 7.78 (1 H, s, NH), 7.45–7.34 (5 H, m, ArH), 7.11 (1 H, t, J = 6.8 Hz, ArH), 7.02 (1 H, d, J = 7.7 Hz, ArH), 5.14 (2 H, s, OCH₂), 3.34 (2 H, td, J = 6.9, 5.5 Hz, NCH₂), 1.48–1.36 (2 H, m, CH₂) and 0.78 (3 H, t, J = 7.4 Hz, CH₃); δ_C (100 MHz) 165.3 (C=O), 156.8 (C-O), 138.4 (C), 134.4 (C-Cl), 132.9 (CH), 132.8 (CH), 129.8 (2CH), 129.5 (2CH), 122.4 (C), 122.2 (CH), 70.9 (OCH₂), 41.8 (NCH₂), 22.8 (CH₂) and 11.7 (CH₃). HRMS (ESI⁺): calcd. for C₁₇H₁₉³⁵ClNO₂ (M+H) 304.1104, found 304.1096.

3.6.5. 2-(Hydroxy(phenyl)methyl)-N-propylbenzamide 41

A solution of 39 (0.539 g, 2.00 mmol) in dry THF (20 cm³) was stirred under nitrogen while n-butyllithium in hexanes (2.5 M, 2.60 cm³, 6.50 mmol) was added dropwise. After 2 h the mixture was added to saturated aq. ammonium chloride (20 cm³) and extracted with diethyl ether (3 × 10 cm³). Drying and evaporation gave 41 (0.440 g, 82%) as a brown viscous oil; δ_H (400 MHz) 7.47–7.19 (9H, m, ArH), 6.48 (1H, s, NH), 5.87 (1H, s, CHOH), 3.20–3.04 (2H, m, NCH₂), 1.35–1.27 (2H, m, CH₂) and 0.81 (3H, t, J 8.8, CH₃); δ_C (100 MHz) 170.8 (C=O), 143.0 (C), 142.7 (C), 135.8 (C), 130.5 (CH), 129.8 (CH), 127.74 (CH), 127.69 (2CH), 127.60 (CH), 126.6 (CH), 126.2 (2CH), 74.7 (CH–O), 41.6 (NCH₂), 22.2 (CH₂) and 11.2 (CH₃).

3.6.6. 2-(Hydroxy(4-chlorophenyl)methyl)-N-propylbenzamide 42

The method of 3.6.5 using n-butyllithium (2.60 cm³, 6.50 mmol), and compound 40 (0.608 g, 2.00 mmol) in dry THF (20 cm³) gave 42 (0.610 g, 100%) as a red sticky oil. δ_H (400 MHz) 7.42–7.18 (8H, m, ArH), 6.37 (1H, br t, J 5.5, NH), 5.93 (1H, s, OH), 5.76 (1H, s, CH–O), 3.26–3.13 (1H, m, NCH_AH), 3.13–3.01 (1H, m, NCHH_B), 1.36–1.28 (2H, m, CH₂) and 0.80 (3H, t, J 7.4, CH₃); δ_C (100 MHz) 170.9 (C=O), 143.2 (C), 141.6 (C), 135.7 (C), 132.5 (C), 130.9 (CH), 130.3 (CH), 128.00 (CH), 127.85 (2CH), 127.76 (2CH), 127.69 (CH), 74.8 (CH–O), 41.8 (NCH₂), 22.4 (CH₂) and 11.2 (CH₃).

3.6.7. 3-Hydroxy-3-phenyl-2-propylisoindolin-1(3H)-one 43

A solution of 41 (580 mg, 2.15 mmol) in CH₂Cl₂ (40 cm³) was stirred at rt with manganese dioxide (3.81 g, 43.8 mmol) for 24h. The mixture was filtered and the filtrate evaporated. The crude residue was purified by preparative TLC (SiO₂, Et₂O/hexane 1:1) to yield 43 (340 mg, 59%) as a yellow solid; mp 95–102 °C. δ_H (500 MHz, CDCl₃) 7.71 (1H, d, J 7.3, ArH), 7.50–7.23 (8H, m, ArH), 3.39 (1H, ddd, J 14, 10, 5.5, NCH_A), 2.91 (1H, ddd, J 14, 10, 5.5, NCH_B), 1.52 (1H, dddq, J 13, 10, 7.5, 5.5, CHH_C), 1.39 (1H, dddq, J 13, 10, 7.5, 5.5, CH_DH) and 0.78 (3H, t, J 7.5, CH₃). Coupling values derived by simulation to 3 decimal place shift accuracy—see Table 1. δ_C (100 MHz, CDCl₃) 167.7 (C=O), 148.9 (C), 138.6 (C), 132.5 (CH), 130.6 (C), 129.4 (CH), 128.45 (2CH), 128.40 (CH), 126.1 (2CH), 123.2 (CH), 122.6 (CH), 91.4 (C–OH), 41.3 (NCH₂), 22.1 (CH₂) and 11.7 (CH₃). The NMR spectroscopic data agree with literature values [21].

3.6.8. 3-(4-Chlorophenyl)-3-hydroxy-2-propylisoindolin-1(3H)-one 44

The method of 3.6.7 using manganese dioxide (3.53 g, 40.6 mmol) and 42 (608 mg, 2.00 mmol) in CH₂Cl₂ (40 cm³) followed by column chromatography (SiO₂, Et₂O/hexane 1:1) gave 44 (210 mg, 35%) as a peach solid, mp 201–202 °C (lit. [21] 188–190 °C). δ_H (400 MHz) 7.78–7.75 (1H, m, ArH), 7.49 (1H, td, J 7.6, 1.2, ArH), 7.46 (1H, td, J 7.2, 1.2, ArH), 7.37–7.27 (4H, m, ArH), 7.27–7.21 (1H, m, ArH), 3.41 (1H, ddd, J 13.9, 10.0, 5.8, NCH_AH), 3.17 (1H, s, OH), 2.92 (1H, ddd, J 13.9, 10.0, 5.7, NCHH_B), 1.58–1.35 (2H, m, CH₂) and 0.81 (3H, t, J 7.4, CH₃); δ_C (100 MHz) 167.6 (C=O), 148.4 (C), 137.2 (C), 134.5 (C), 132.7 (CH), 130.5 (C), 129.8 (CH), 128.7 (2CH), 127.7 (2CH), 123.4 (CH), 122.5 (CH), 91.0 (C–OH), 41.3 (NCH₂), 22.2 (CH₂) and 11.7 (CH₃). The NMR spectroscopic data agree with the literature values [21].

3.6.9. 3-(4-Hydroxy-3,5-dimethoxybenzyloxy)-3-phenyl-2-propylisoindolin-1(3H)-one 35

Thionyl chloride (0.278 cm³, 1.50 mmol) was added to a solution of 43 (200 mg, 0.75 mmol) in THF (10 cm³) with a catalytic amount of DMF, and the mixture was stirred at rt for 16 h before evaporating off the solvent. The residue was taken up in DMF (10 cm³) and 3,5-dimethoxy-4-hydroxybenzyl alcohol (276 mg, 1.5 mmol) and triethylamine (0.21 cm³, 1.5 mmol) were added. After stirring at rt for 20 h, the mixture was added to water (50 cm³) and extracted with ethyl acetate (3 × 20 cm³). The combined extracts were washed with water (6 × 30 cm³), dried and evaporated. The crude product was purified by preparative TLC (SiO₂, EtOAc/hexane 1:1) to yield 35 (10 mg, 5%) as a yellow oil. The spectral data were found to be in accordance with previously published data [6]. δ_H (400 MHz) 8.17 (1H, s, OH), 7.72–7.70 (1 H, m, ArH), 7.43–7.20 (8H, m, ArH), 6.60 (2H, s, ArH), 4.50 (2H, s, OCH₂), 3.78 (6H, s, OMe), 3.43–3.35 (1 H, m, NCH_AH), 2.91–2.84 (1H, m, NCHH_B), 1.53–1.35 (2H, m, CH₂) and 0.75 (3H, t, J 7.4, CH₃); δ_C (100 MHz) 167.6 (C=O), 152.0 (2C), 148.8 (C), 146.7 (C), 138.5 (C), 136.3 (C), 132.5 (CH), 130.6 (C), 129.6 (CH), 128.5 (2CH), 128.4 (CH), 126.1 (2CH), 123.3 (CH), 122.5 (CH), 105.1 (2CH), 91.4 (C), 56.2 (2OMe), 46.3 (OCH₂), 41.4 (NCH₂), 22.2 (CH₂) and 11.7 (CH₃).

3.6.10. 3-(4-Chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propylisoindolin-1(3H)-one 36

The method of 3.6.9 using thionyl chloride (0.278 cm³, 1.50 mmol) and 44 (200 mg, 0.66 mmol) in THF (10 cm³) with a catalytic amount of DMF followed by triethylamine (0.21 cm³, 1.5 mmol) and 3,5-dimethoxy-4-hydroxybenzyl alcohol (276 mg, 1.5 mmol) followed by preparative TLC (SiO₂, EtOAc/hexane 1:1) gave 36 (150 mg, 49%) as an orange oil. The spectral data were found to be in accordance with previously published data [6]. δ_H (400 MHz) 7.92–7.88 (1H, m, ArH), 7.52 (1H, td, J 8.0, 1.2, ArH), 7.48 (1H, td, J 8.0, 1.6, ArH), 7.35 and 7.30 (4H, AB pattern, J 8.8, 4ArH), 7.14–7.10 (1H, m, ArH), 6.46 (2H, s, 2ArH), 5.60 (1H, br s, OH), 4.15 (1H, d, J 11.4, OCH_AH), 3.92 (1H, d, J 11.4, OCHH_B) 3.35–3.26 (1H, m, NCH_AH), 3.16–3.06 (1H, m, NCH_BH), 1.62–1.46 (1H, m, CH_AH), 1.46–1.33 (1H, m, CH_BH) and 0.82 (3H, t, J 7.2, CH₃); δ_C (100 MHz) 168.2 (C=O), 146.8 (2C), 145.1 (C), 137.5 (C), 134.34 (C), 134.27 (C), 132.4 (CH), 131.8 (C), 129.8 (CH), 128.5 (2CH), 128.2 (C), 127.8 (2CH), 123.4 (CH), 123.1 (CH), 104.4 (2CH), 94.7 (C), 65.2 (OCH₂), 56.2 (2OMe), 41.4 (NCH₂), 21.6 (CH₂) and 11.7 (CH₃).

4. Conclusions

The application of our [1,2]-Wittig rearrangement approach to target syntheses of selected 3-arylphthalide natural products has revealed some limitations. While the method was successful in the case of crycolide, providing the only second synthesis of this compound, extension to examples such as isopestacin and cryphonectric acid bearing 2,6-disubstituted aryl groups failed, most likely due to the steric hindrance blocking either the alkylation or cyclisation stage. On the other hand, oxidative treatment of the crude Wittig rearrangement products provides a convenient new route to 3-aryl-3-hydroxyisoindolinones, and this allowed the synthesis of two anticancer compounds.