Synthesis of the core structure of phalarine

Kazuya Douki a, Jun Shimokawa *ab and Masato Kitamura *a
aGraduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail: kitamura@os.rcms.nagoya-u.ac.jp
bDepartment of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. E-mail: shimokawa@kuchem.kyoto-u.ac.jp

Received 19th September 2018 , Accepted 29th September 2018

First published on 1st October 2018


The core skeleton of phalarine was rapidly synthesised through novel palladium-catalysed dearomative spirocyclisation and a palladium-catalysed Wacker-carbonylative cyclisation cascade. The two key steps allowed for the efficient construction of a tricyclic propeller skeleton bearing contiguous tetrasubstituted carbon centres, within 3 steps from a topologically planar precursor.


Efficient access to architecturally complex molecules is a crucial challenge in modern organic synthesis. Especially, a synthetic strategy for stereochemically diverse sp3-rich polycyclic compounds are eagerly desired for devising an ideal tailor-made design of future drugs or advanced molecular materials.1 Dearomative transformation has been one of the most important strategies for this purpose. It was often applied to the construction of three-dimensional molecular architecture by combining the efficient functionalisation of sp2-rich planar aromatics and strategic saturation to efficiently deliver cubic sp3-rich molecules.2 In particular, a transition metal-catalysed dearomatisation reaction has been intensively developed to enable the rapid propagation of the complexity from simple planar building blocks,3 and these methodologies have been applied to various target-oriented syntheses.4 Hereby we report the development of a new catalytic dearomatisation reaction and the application to the concise synthesis of the polycyclic core structure of the unique propeller-shaped alkaloid, phalarine.

Phalarine (1) was isolated from the perennial grass Phalaris coerulescens in 1999.5 Its structure was characterised by a unique tricyclic propeller core framework fused to a piperidine unit and a multiple functionalised indole moiety through consecutive tetrasubstituted stereogenic centres at C4a and C9a. Although the biological activity of 1 has not been reported, the characteristic structure fascinated a number of synthetic chemists6 and their endeavours have culminated in the seminal asymmetric total syntheses of 1 by Danishefsky7 and Chen.8 We herein aimed at the development of synthetic methodology to rapidly construct a propeller-shaped core framework in a racemic manner from an achiral sp2-rich precursor.

Scheme 1 shows our retrosynthetic analysis. Phalarine (1) would be derived by the late-stage construction of an indole unit from simplified intermediate 2 bearing the core propeller-shaped framework. We have set this molecule without the indole moiety as the primary target of the current synthetic study. The removal of the C1 unit next to the nitrogen functionality in 2 and the opening of the cyclic ether moiety at C4a leads to amide 3. This amide, in turn, could be derived by aminolysis of spirocyclic lactone 4 that was retrosynthetically excised at C9a to form the topologically planar aryl indole-2-carboxylate 5via pivotal dearomative spirocyclisation.


image file: c8ob02320d-s1.tif
Scheme 1 Retrosynthetic analysis.

Initially, the Heck-type dearomative spirocyclisation from Boc-protected o-iodoaryl indole-2-carboxylate (6) to 7 was investigated (Table 1). A similar method with the amide linkage, using o-bromoaryl indole-2-carboxamide was reported by Jia.9 The reaction was optimised by fixing our standard conditions as follows: 6 (100 μmol), palladium catalyst (10 mol%), NaOAc (1.5 equiv.), DMA (1.0 mL), 100 °C, and 18 h. Among the palladium species tested, Pd[P(t-Bu)3]2 showed insufficient reactivity (entry 1), while Buchwald's P(t-Bu)3 Pd G2 precatalyst10 gave 7 in 25% yield (entry 2). To our delight, [Pd(IMes)(NQ)]2 and Pd2(dba)3·CHCl3 catalysed the dearomative spirocyclisation and gave 7 in high yield (entries 3 and 4). Due to almost the same yields for these two conditions, the more easily available Pd2(dba)3·CHCl3 was employed in the current racemic scale-up synthesis.

Table 1 Optimisation of the reaction conditions for palladium-catalysed dearomative spirocyclisationa

image file: c8ob02320d-u1.tif

Entry Pd catalyst Yieldb (%)
a All reactions were carried out under standard reaction conditions: 6 (100 μmol), Pd catalyst (Pd: 10 mol%), NaOAc (1.5 equiv.), DMA (1.0 mL), 100 °C, and 18 h. b Determined by 1H NMR analysis using dimethyl sulfone as an internal standard. IMes = 1,3-dimesitylimidazol-2-ylidene, NQ = naphthoquinone, and dba = dibenzylideneacetone.
1 Pd[P(t-Bu)3]2 <1
2 P(t-Bu)3 Pd G2 25
3 [Pd(IMes)(NQ)]2 75
4 Pd2(dba)3·CHCl3 77


A plausible mechanism for this transformation is shown in Scheme 2. The oxidative addition of 6 to palladium(0) species generates intermediate 8 that is then subjected to migratory insertion to form the spirocyclic centre.9 Following β-hydride elimination from intermediate 9 releases olefin 7 in concomitance with hydrogen iodide to regenerate palladium(0) species.


image file: c8ob02320d-s2.tif
Scheme 2 Plausible reaction mechanism for palladium-catalysed dearomative spirocyclisation.

Subsequent transformation toward the propeller architecture involved the ring-opening of spirocyclic lactone 7, followed by the sequential introduction of the C1 unit during the cyclisations of two heterocycles (Table 2). This transformation would facilitate the formation of the C4a tetrasubstituted carbon centre. We eventually settled this task by a Wacker-carbonylative cyclisation cascade on the exocyclic double bond, to afford a β-alkoxy carbonyl moiety.11 An intriguing point for the current transformation was deemed the use of a secondary amide as a terminal nucleophile for the formation of a cyclic imide. Thus, spirocyclic lactone 7 was subjected to aminolysis with p-methoxybenzylamine, quantitatively affording the corresponding amide 10.12 Under various conditions, amide 10 was found to release an installed p-methoxybenzylamine to regenerate lactone 7. Fortunately, this undesired cyclisation was suppressed specially in DMSO. The appropriate reoxidant for the reaction from 10 to 11 was eventually confirmed to be NaIO4, a rare reoxidant for the palladium catalyst.13 Thus, the standard reaction conditions were fixed as follows: 10 (100 μmol), Pd(OAc)2 (10 mol%), NaIO4 (1.5 equiv.), DMSO (1.0 mL), CO (1 atm), 40 °C, and 18 h. Interestingly, the amount of water substantially affected the result of this transformation. Table 2 shows the summary of the effect of water on this reaction. Under strictly dehydrated conditions, a low yield of 11 was observed due to the formation of various byproducts (entry 1). In the presence of 0.1 equiv. of water, this undesired reaction path was suppressed and a moderate yield (56%) of 11 was observed (entry 2). Exocyclic olefin 10 was consumed in the presence of 1.0 equiv. of water, exclusively affording 11 in 81% yield (entry 3). The reactivity was reduced in the presence of 10 equiv. of water and was sluggish with 100 equiv. of water (entries 4 and 5). The added water (<1 equiv.) possibly inhibited the formation of potent highly oxidising species such as the HIO3–DMSO complex.14 Instead, an excess of water (>10 equiv.) would reduce the Lewis acidity of palladium(II) species probably via the formation of inactive Pd(OH)2 or PdO. Collectively, 1.0 equiv. of water (entry 3) was determined to be the best additive to this catalytic cascade reaction.

Table 2 Optimisation of the amount of water for the palladium-catalysed cyclisation cascadea

image file: c8ob02320d-u2.tif

Entry x (equiv.) Conversionb (%) Yieldb (%)
a All reactions were carried out under standard reaction conditions: 10 (100 μmol), Pd(OAc)2 (10 mol%), NaIO4 (1.5 equiv.), DMSO (1.0 mL), CO (1 atm), 40 °C, and 18 h. b Determined by 1H NMR analysis using dimethyl sulfone as an internal standard. PMB = p-methoxybenzyl.
1 0 85 36
2 0.10 85 56
3 1.0 >99 81
4 10 85 70
5 100 8 <1


The proposed reaction mechanism (Scheme 3) proceeds through alkoxypalladation on the exocyclic double bond to form alkyl palladium intermediate 12, to which carbon monoxide would be installed. The resultant carbonyl group was attacked by the nitrogen atom of the amide to lead to palladacycle 13. Reductive elimination would provide product 11 in concomitance with the palladium(0) species, that would be oxidised by NaIO4 to regenerate the palladium(II) species to finish the cycle.


image file: c8ob02320d-s3.tif
Scheme 3 Plausible reaction mechanism for the Wacker-carbonylative cyclisation cascade.

The synthesis of the propeller core 11 thus having been established was scaled up to verify its efficiency (Scheme 4). Methyl-2-oxo-butyrate (14) was converted to 3-methylindole-2-carboxylic acid (15) in 63% yield in 2 steps.15 The condensation of 15 with 2-iodo-5-methoxy phenol (16)16 followed by installation of the Boc group gave 6 in 83% yield in 2 steps. Palladium-catalysed dearomative spirocyclisation on 6 efficiently proceeded even on a 5 g scale, and provided 7 in 71% isolated yield. Aminolysis of lactone 7 by p-methoxybenzylamine quantitatively gave amide 10, which was subjected to the catalytic Wacker-carbonylative cyclisation cascade using the established Pd(OAc)2–NaIO4–DMSO system with 1.0 equiv. of water. These transformations successfully provided 11 with the propeller architecture on a 500 mg scale.


image file: c8ob02320d-s4.tif
Scheme 4 Scale-up synthesis of the core structure of phalarine (1). EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

Conclusions

We have efficiently constructed the propeller-shaped core structure of phalarine (1). Our synthesis consisted of two unique transformations: (1) a palladium-catalysed dearomatisation transformation of topologically planar indole 6 to indoline 7 with the formation of the tetrasubstituted C9a centre, and (2) a palladium-catalysed Wacker-carbonylative cyclisation cascade on olefin 10 to construct the core structure bearing the contiguous C4a–C9a tetrasubstituted carbon centres. These processes eventually provided the 3-step transformation of aryl indole carboxylate 6 to the tricyclic propeller framework of 11 on a 500 mg scale. The development of catalytic asymmetric dearomative spirocyclisation and further transformation of 11 to phalarine (1) will be reported in due course.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Kato Memorial Bioscience Foundation, a Mitsubishi Tanabe Pharma Award in Synthetic Organic Chemistry, Japan, JSPS KAKENHI Grant Numbers 15H05641, 16H02274, 17J06799, the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Advanced Catalytic Transformation Program for Carbon Utilization (ACT-C) from the Japan Science and Technology Agency (JST).

Notes and references

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Footnote

Electronic supplementary information (ESI) available: Experimental procedures and characterisation data. See DOI: 10.1039/c8ob02320d

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