Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

The efforts on developing efficient synthetic strategies to access macarpine never ceased during the last decades, and we have joined this meaningful research. Herein, a strategy involving the synthesis of an intermediate reported by Ishikawa in 1995 in the total synthesis of macarpine [12] is proposed via a Au(I)-catalyzed cycloisomerization reaction.

Retrosynthetically, the target molecule macarpine (1) could be disconnected into naphthol 12 (Scheme 3), a key intermediate reported by Ishikawa in the total synthesis of macarpine. This intermediate could be synthesized from silyl enol ether compound 10 via the Au(I)-catalyzed cycloisomerization reaction developed by our group [15]. The compound 10 could be constructed by the Sonogashira coupling reaction from readily prepared iodoarene 8 [12,16] and ketone 5, which could be synthesized by using cheap 6-bromopiperonal (2) as the starting material.

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Scheme 3: Retrosynthetic analysis of marcarpine precursor 12 for a partial synthesis.

To attempt the proposed synthetic strategy, ketone 5 and iodoarene 8 were prepared by following the synthetic route outlined in Scheme 4. Ketone 5 was prepared in a four-step procedure. Firstly, a Sonogashira coupling between 6-bromopiperonal (2) and trimethylsilylacetylene was performed to furnish aldehyde 3 [17,18] in 89% yield. A following nucleophilic addition reaction of aldehyde 3 by methylmagnesium bromide (MeMgBr) gave alcohol 4 in 99% yield, which was oxidized by pyridinium chlorochromate (PCC) leading to the formation of ketone compound and the deprotection of the silyl group was accomplished in the presence of potassium carbonate (K2CO3) and methanol to provide the terminal alkyne 5 in 96% yield in two steps. The iodoarene 8 [12,16] was facilely synthesized from sesamol (6) via methylation and iodination in an overall yield of 67%.

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Scheme 4: Syntheses of precursors 5 and 8.

With the building blocks 5 and 8 in hand, ketone 9 was prepared via a palladium-catalyzed Sonogashira coupling reaction in a yield of 95%. The precursor 10 for the gold(I)-catalyzed [19-24] cycloisomerization was then synthesized by treating ketone 9 with sodium bis(trimethylsilyl)amide (NaHMDS) and tert-butyldimethylsilyl chloride (TBSCl) (Scheme 5).

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Scheme 5: Synthesis of enol silyl ether 10.

To find the best cycloisomerization conditions, the 1,5-enyne substrate 10 was subjected to different reaction conditions as listed in Table 1. It was observed that [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I) chloride (IPrAuCl) itself failed to catalyze the cycloisomerization (Table 1, entry 1). Evaluation of a number of silver salts illustrated that silver hexafluoroantimonate (AgSbF6) was the optimal additive to activate the gold catalyst (Table 1, entries 2, 3, and 7). Screening of the other ligands of Au(I) catalysts, including triphenylphosphane (Ph3P), [1,1'-biphenyl]-2-yl-di-tert-butylphosphane (JohnPhos) dicyclohexyl(2',4'-diisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (BrettPhos) (Table 1, entries 4–6) revealed that 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) was still the best one (Table 1, entry 7). Neither decreasing nor increasing the loading of the catalyst gave better yields (Table 1, entries 8 and 9). Examination of the reaction time showed that 2 h was the shortest reaction time and that extending the reaction time did not help to increase the yield (Table 1, entries 10 and 11). Lowering or raising the reaction temperature resulted in lower yields (Table 1, entries 12 and 13). The solvent had less effect on the reaction, and combining various factors, DCM was used for the reaction (Table 1, entries 14 and 15). When AgSbF6 was utilized as the sole catalyst, not any product was generated indicating cationic Au(I) was the true catalyst (Table 1, entry 16). A control experiment using 2,6-di-tert-butylpyridine as a proton scavenger in the IPrAuCl/AgSbF6 system provided the product in good yield, which excluded the influence of trace amounts of acids on the reaction (Table 1, entry 17).

Table 1: Optimization of the Au(I)-catalyzed cycloisomerization conditions.

[Graphic 1] entry catalyst solvent additive T (°C) yield (%) 1 IPrAuCl DCM – 23 0 2 IPrAuCl DCM AgOTf 23 61 3 IPrAuCl DCM AgCO2CF3 23 23 4 Ph3PAuCl DCM AgSbF6 23 77 5 JohnPhosMeCNAuSbF6 DCM – 23 64 6 BrettPhosAuCl DCM AgSbF6 23 45 7 IPrAuCl DCM AgSbF6 23 82 8 IPrAuCl DCM AgSbF6 23 68a 9 IPrAuCl DCM AgSbF6 23 82b 10 IPrAuCl DCM AgSbF6 23 57c 11 IPrAuCl DCM AgSbF6 23 81d 12 IPrAuCl DCM AgSbF6 0 63 13 IPrAuCl DCM AgSbF6 40 72 14 IPrAuCl toluene AgSbF6 23 82 15 IPrAuCl THF AgSbF6 23 80 16 – DCM AgSbF6 23 0 17 IPrAuCl THF AgSbF6 23 80e

a3 mol % IPrAuCl and 3 mol % AgSbF6 were used. b10 mol % IPrAuCl and 10 mol % AgSbF6 were used. cThe reaction was run for 1 h. dThe reaction was run for 3 h. e5 mol % 2,6-di-tert-butylpyridine was added. IPr = [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]. JohnPhos = [[1,1'-biphenyl]-2-yldi-tert-butylphosphane]. BrettPhos = [dicyclohexyl(2',4'-diisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane].

The Au(I)-catalyzed cycloisomerization reaction of substrate 10 occurred under the catalysis of 5 mol % [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I) chloride (IPrAuCl) and 5 mol % silver hexafluoroantimonate (AgSbF6) [25,26] in anhydrous DCM at room temperature for 2 h forming a benzene ring smoothly, leading to the exclusive formation of biaryl intermediate 11 in a yield of 82%. It is worth noting that the methoxy substitution in the substrate played a crucial role in controlling the selectivity of the cycloisomerization according to our previous study [15]. It was rationalized that the electron-donating phenyl ring enabled the coordination of the alkyne with the Au+ complex in the α-position, which promoted the silyl ether to attack the β-position of the alkyne to promote a 6-endo-dig cyclization. Next, compound 11 was subjected to a solution of tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF), resulting in the formation of naphthol 12 [12,13], a key intermediate in the previous total synthesis of macarpine (1) reported by Ishikawa (Scheme 6).

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Scheme 6: Formal total synthesis of macarpine (1).

To simplify the synthetic procedure, a more straightforward strategy was proposed by using alkynyl ketone 9 [27-29] as the substrate for the gold-catalyzed cycloisomerization in the presence of protonic acid. It was supposed that alkynyl ketone 9 would undergo enolization under the acidic conditions, followed by a gold-catalyzed cycloisomerization to provide the naphthol 12.

To test the idea, alkynyl ketone 9 was subjected to different reaction conditions as listed in Table 2. It was observed that both the acids and the temperatures had a great influence on the cycloisomerization. An attempt was also made by using only p-toluenesulfonic acid (TsOH) in the cycloisomerization step, but no corresponding product was obtained. Finally, the optimal conditions for the Au(I)-catalyzed cycloisomerization of alkynyl ketone 9 were determined as to stir the substrate under the catalysis of 5 mol % IPrAuCl/AgSbF6 with 2 equiv of TsOH as the additive at 70 °C for 2 h (Table 2, entry 3). It is notable that our synthetic route to naphthol 9 is shorter and proceeds with higher yield (5 steps, 59% yield) than Ishikawa’s route (9 steps, 13% yield).

Table 2: Reaction condition optimization of the cycloisomerization of alkynyl ketone 9.

[Graphic 2] entry acid solvent T (°C) yield (%) 1 TsOH DCM 23 0 2 TsOH DCM 40 0 3 TsOH DCE 70 73 4 TFA DCE 70 50 5 AcOH DCE 70 24 6 PhCO2H DCE 70 39

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