Oxidative dearomatic approach towards the synthesis of erythrina skeleton: a formal synthesis of demethoxyerythratidinone

A concise synthetic route leading to highly functional erythrina alkaloid skeletons has been developed. The key process is an oxidative carbon-carbon coupling followed by a conjugated addition. Based on this new strategy, a formal synthesis of demethoxyerythratidinone was completed in only 6 steps from 4-aminophenol.


Introduction
The genus Erythrina is widely distributed in tropical and subtropical regions and has been used in indigenous medicine. 1 Erythrina alkaloids are common constitutes isolated from this species. Representative structures of the erythrina alkaloid family are characterized by a tetracyclic ring system and featured with an 1-azaspiro[5.5]undecane unit (Figure 1). A variety of biological effects are associated with the erythrina skeleton including sedative, hypotensive, neuromuscular blocking and CNS activity. 1a,2 Because of its typical structure and interesting bioactivities, there has been much interest in the synthesis of these alkaloids and derivatives over the years. 3 An impressive strategy towards erythrina skeleton is biomimetic approach through an oxidative carbon-carbon bond formation. 4 Although numerous imaginative synthetic routes have been developed based on the oxidative coupling, 5 few meet adequate measures of flexibility and efficiency in terms of diversity oriented synthesis.
We recently initiated a research program towards the synthesis of structurally diverse compounds by using oxidative formation of carbon-carbon bond as the key reaction. The spiro cyclohexyldienonyl -lactams, oxindoles and structural unit for erythrina alkaloids were synthesized from the amide derivatives of 4-aminophenol. 6 In this paper, we reported the results towards the synthesis of analogues of erythrina alkaloids.

Results and Discussion
The retrosynthetic analysis is showed in Scheme 1. Starting from the commercially available 4-aminophenol (1kg/157USD), we speculated that a highly functional erythrina skeleton could be reached by a sequential oxidative dearomatization and a Michael addition. We began our research by an amidation of 4-aminophenol (1) with homoveratroyl chloride (2). 7 The product, amide (3), was then converted to amine by a reduction with lithium aluminium hydride in THF (83%). By treatment of amine (4) with ethyl 3-chloro-3-oxopropanoate in dichloromethane in the presence of pyridine, amide (5) was obtained in 71% yield over three steps. Other amides (10 and 11), aiming at the synthesis of erythraline and its analogues, were prepared in three or four steps by the same procedure as shown in Scheme 2. The key oxidative coupling process was attempted by treatment of amide (5) with iodobenzene diacetate (IBD) in methanol, a well-established dearomatization procedure. 8 To our disappointment, this oxidative condition only led to cyclohexyldienone (12). We then tried the oxidation with (bis(trifluoroacetoxy)iodo) benzene (PIFA) in trifluoroethanol at 40C. 9 To our delight, this oxidation provided the desire azaspiro cyclohexyldienone (13), after treatment with DBU in dichloromethane, the desire intermediate (14) with a highly functional erythrina skeleton was obtained in 72% yield. This two steps procedure was soon optimized to be an efficient "one-pot" reaction: after the oxidative coupling, potassium carbonate was directly introduced to the reaction mixture at room temperature, and compound 14 was obtained in 83% isolated yield. Although oxidative coupling of amides 10 and 11 proceeded under the same reaction condition, the yield (70% and 72% for 15 and 16) was relatively lower than that of amide 5, possibly due to the poor electron donating ability imposed by stereoelectronic effect of the methylenedioxy substituent. 10 This one-pot cyclization furnished the highly functional erythrina skeletons in an efficient way (4 steps for erythrina derivative 14 and 4~5 steps for erythrina derivatives 15 and 16).
Having successfully constructed the azaspiro cyclohexyldienone, we turned our attention next to convert compound 14 to the natural product, namely 3-demethoxyerythratidinone. Compound 14 was further manipulated, hydrogenation followed by decarboxylation, to a known intermediate for the synthesis of demethoxyerythratidinone (Scheme 4), thus furnished a formal synthesis of this natural erythrina alkaloid. 11 In conclusion, we have developed a practical and efficient method for the synthesis of erythrina skeletons. Based on this methodology, a formal synthesis of demethoxyerythratidinone was also completed. The highly functional erythrina derivatives could be used not only as intermediates for the synthesis of natural erythrina alkaloids but also be used as building blocks for the synthesis of erythrina alkaloid-like compounds.

Experimental Section
General Experimental Procedures. Melting points were obtained on a XT-4 melting-point apparatus and were uncorrected. Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded on a Bruker Avance 300 spectrometer at 300 MHz. Carbon-13 nuclear magnetic resonance ( 13 C NMR) was recorded on Bruker Avance 300 spectrometer at 75 MHz. Chemical shifts are reported as δ values in parts per million (ppm) relative to tetramethylsilane (TMS) for all recorded NMR spectra. Low-resolution mass spectra were recorded on a VG Auto Spec-3000 magnetic sector MS spectrometer. High resolution mass spectra were taken on AB QSTAR Pulsar mass spectrometer. Silica gel (200-300 mesh) for column chromatography and silica GF 254 for TLC were produced by Qingdao Marine Chemical Company (China). All air-or moisture-sensitive reactions were conducted under an argon atmosphere. Starting materials and reagents used in reactions were obtained commercially from Acros, Aldrich, Fluka and were used without purification, unless otherwise indicated.

Synthesis of Compound 3.
To a solution of 4-aminophenol (1, 546 mg, 5 mmol) in CH 2 Cl 2 (20 mL) and pyridine (2.02 mL, 25 mmol, 5.0 eq.) at 0°C, homoveratroyl chloride (2, 5.5 mmol, 1.1 eq.) in dichloromethane (5 mL) was added dropwise. The resulting mixture was then stirred at room temperature for 3-4 h. The reaction mixture was diluted with CH 2 Cl 2 (20 mL) and treated with 2N HCl (10 mL) for 10 min and the aqueous phase was separated and the organic phase was washed with water (2 × 15 mL). After dried over anhydrous Na 2 SO 4 and filtration, the solvent was removed under reduced pressure and the residue (1.43 g) was used in next step without further purification.