Total synthesis of an indolizidine alkaloid, (+)-ipalbidine, by means of an intramolecular McMurry coupling reaction

An indolizidine alkaloid, (+)-ipalbidine, exhibiting a non-addictive analgesic activity, was synthesized in an optically active form, by employing an intramolecular McMurry coupling reaction as a key step.


Introduction
Indolizidine alkaloids, a large class of natural products, are popular synthetic targets because they exhibit attractive biological activity and also provide further opportunities for developing new synthetic methods and strategies for the nitrogen-heterocyclic ring systems.Among them, (+)-ipalbidine 1, isolated from the seeds of Ipomoea alba L. as the aglycone of ipalbine 2, has a relatively simple structural feature, which contains a 1-azabicyclo-[4.3.0]-non-3-enesystem with a phenolic substituent at the 3-position 1 (Figure 1).Ipalbidine 1 is known to be a non-addictive analgesic, and caused analgesia in mice which was not antagonized by naloxone. 2This alkaloid also showed inhibitory effects on respiratory burst of leukocytes and scavenged oxygen-free radicals. 3Owing to its interesting biological activity, a number of total syntheses for racemic ipalbidine has been reported by several groups. 4On the other hand, only one chiral synthesis for ipalbidine has appeared to date, 5 where, however, the specific optical rotation of the synthesized compound [α] D +54.1 (c=1, EtOH) was found to be much different from that of the optically resolved compound [α] D +190.5 (c=1, MeOH).4b As an extension of our work on the synthesis of analgesic agents, we are interested in a total synthesis of (+)-ipalbidine in an optically pure form starting from a readily accessible chiral source, (-)-pyroglutamic acid, in which we planned to utilize a carbon-carbon double bond formation as a crucial step.

Results and Discussion
(-)-Pyroglutamic acid was first converted into the corresponding alcohol 3 according to the known procedure. 6Treatment of 3 with p-toluenesulfonyl chloride gave the tosylate 4, which was further coupled with a higher-order cuprate reagent to afford the desired olefinic amide 5 in 93% yield (Scheme 1).Scheme 2. Preparation of the allylic bromide 9.
Preparation of the bromide 9, as an N-substituent for 5, was achieved starting from methyl 4benzyloxyphenylacetate 6 by condensation with paraformaldehyde in the presence of tris-[2-(2methoxyethoxy)ethyl]amine (TDA-1), 7 followed by reduction of the ester 7 with diisobutylaluminum hydride and bromination of the resulting alcohol 8 with CBr 4 and Ph 3 P as shown in Scheme 2.
Condensation of the amide 5 with the bromide 9 was carried out in THF-HMPA in the presence of sodium hydride as the base to give the diene 10 in 90% yield.Since the key material for the desired carbon-carbon double bond formation was thus synthesized, we attempted an intramolecular ring-closing metathesis (RCM) 8 by using Grubbs catalyst 9 or Hoveyda catalyst 10 under various reaction conditions; however, no cyclization product 11 could be isolated, unfortunately.For constructing a tetra-substituted alkene system by RCM, the Schrock catalyst 11 is recognized to be more effective than Grubbs catalyst; however, none of the desired product could be obtained even by the use of the active catalyst (Scheme 3).Since an intramolecular RCM was found to be ineffective for the desired carbon-carbon double bond formation in this synthesis, we decided to utilize an intramolecular McMurry coupling reaction 12 for this purpose.Thus, the diene 10 was converted into the diketone 12 by ozonolysis, followed by reductive work-up with methyl sulfide, in the usual manner.Treatment of 12 with titanium(0), prepared from titanium(III) chloride-THF complex and Zn-Cu couple, in DME at 80°C for 40 h, furnished the desired product 11 in 30% yield together with the cisdiol 13 and a stereochemically unidentified compound 14 in 15% and 15% yields, respectively (Scheme 4).The structure of the cisdiol 13, including its absolute stereochemistry, was unambiguously determined by single-crystal X-ray analysis as shown in Figure 2. On the other hand, the compound 14 was also supposed to have diol functions, based on its mass spectrum, and its NMR spectrum was quite similar to that of the cisdiol 13.Although we cannot confirm its structure at present, a diastereoisomeric β-cis-diol structure might reasonably be assumed, based on the reaction mechanism.When this coupling was carried out under the same reaction conditions for a shorter reaction time (5 h), the cisdiol 13 was isolated as the major product, in 66% yield, in addition to the diol 14 (6%).Since we could obtain the desired product 11 by the formation of a carbon-carbon double bond in relatively short steps, its conversion into (+)-ipalbidine 1 was further investigated as follows.Lithium aluminum hydride reduction of 11 afforded the amine 15 in 86% yield, which on debenzylation under hydrogenolysis conditions over 5% palladium hydroxide on carbon in MeOH furnished the natural product 1 (Scheme 5).The spectroscopic data for 1, mp 76-78°C (from benzene-cyclohexane) (lit.4b mp 82-84°C) were in agreement with those reported. 4Although some difference is observed between the specific optical rotation of the synthesized compound 1 ([α] D +158.6 (c=0.8,MeOH); +189.4 (c=1, CHCl 3 )) and those reported (lit.4b [α] D +190.5 (c=1, MeOH); lit. 5 [α] D +54.1 (c=1, EtOH)), and the accurate value is still obscure, we believe that our compound is in almost optically pure form, based on the synthetic strategy.
Although the direct formation of the alkene function from the diketone 12 by employing McMurry coupling as the key step gave the desired product, which led to the chiral synthesis of the target natural product, the yield was found to be unsatisfactory.We therefore investigated an alternative synthetic path to (+)-ipalbidine, in which elimination of the vic-diol function in 13 was involved as the key reaction.Thus, the reaction of the diol 13 obtained in 66% yield from 12 by McMurry coupling with a shorter reaction time, with trimethyl orthoformate and PPTS, afforded the orthoformate 16, which on treatment with acetic anhydride 13 brought about the desired elimination reaction to provide the olefin 11 in 75% yield from 13 (Scheme 6).In summary, we have succeeded in an alternative total synthesis of optically active (+)ipalbidine 1, in which intramolecular McMurry coupling of the diketone 12 with Ti(0) was employed as the key reaction, forming a carbon-carbon double bond directly.Elimination of the vic-diol of 13, obtained as the major product from the McMurry coupling of 12 under different reaction conditions, also afforded the desired product efficiently.The synthetic strategy developed here would be applicable to the synthesis of other biologically active phenanthroindolizidine and phenanthroquinolizidine alkaloids.

Experimental Section
General Procedures.Melting points were measured with a Yanagimoto MP apparatus and are uncorrected.IR spectra were obtained using a JASCO FT/IR-200 spectrophotometer. 1 H-and 13 C-NMR spectra were obtained on a JEOL LAMBDA-270 ( 1 H-NMR: 270 MHz, 13 C-NMR: 67.8 MHz) instrument for solutions in CDCl 3 , and chemical shifts are reported on the δ scale from internal TMS. 13 C multiplicities were determined with the aid of an APT sequence, separating methylene and quaternary carbons = up, from methyl and methine carbons = down.Mass spectra were measured with a JEOL JMS-D 300 spectrometer.Elemental analyses were performed using a Yanaco-MT5 instrument.

5-(2-Methyl-2-propenyl)pyrrolidin-2-one (5).
To a stirred solution of 2-bromopropene (7.99 mL, 90.0 mmol) in Et 2 O (180 mL) was slowly added 1.49 M tert-BuLi in pentane (113 mL, 180 mmol) over a period of 1 h at -78°C under argon.After being stirred for 3 h at the same temperature, 0.25 M lithium 2-thienylcyanocuprate in THF (360 mL, 90.0 mmol) was added to the solution, and the whole was stirred for a further 1 h at the same temperature.To this solution was added a solution of the tosylate (4) (8.07 g, 30.0 mmol) in THF (120 mL) over a period of 30 min at -78°C, and the resulting mixture was gradually warmed to 0°C and stirred for further 12 h at the same temperature.The mixture was treated with saturated aqueous NH 4 Cl solution, and the insoluble materials were removed by filtration through a pad of Celite.The filtrate was extracted with Et 2 O, and the extract washed with brine and dried over Na 2 SO 4 .Evaporation of the solvent gave a residue, which was subjected to column chromatography on silica gel.Elution with EtOAc-MeOH (70:1, v/v) gave the olefin (5) (3.89 g, 93%) as a pale yellowish oil.[α] D +13.6 (c=1.0,CHCl 3 ); IR ν max.3228, 1699 cm -1 ; 1   (7).To a stirred solution of methyl 4benzyloxyphenylacetate (6) (1.28 g, 5.00 mmol) in toluene (50 mL) were added paraformaldehyde (1.50 g, 50.0 mmol), cesium carbonate (6.52 g, 20.0 mmol) and tris-[2-(2methoxyethoxy)ethyl]amine (TDA-1) (0.16 mL, 0.50 mmol) at room temperature under argon.The whole mixture was heated at 85°C for 3 h, and the insoluble materials were removed by filtration through a pad of Celite.The filtrate was washed with water and dried over Na 2 SO 4 .Evaporation of the solvent gave a residue, which was subjected to column chromatography on silica gel.Elution with hexane-EtOAc (8:1, v/v) gave the acrylate (7)

2-(4-Benzyloxyphenyl)-3-bromoprop-1-ene (9).
To a stirred solution of the ester (7) (1.12 g, 4.18 mmol) in CH 2 Cl 2 (20 mL) was added 0.95 M DIBAL in hexane (9.68 mL, 9.19 mmol) at -78°C under argon, and the resulting mixture was stirred for a further 1 h at the same temperature.After treatment with saturated aqueous NH 4 Cl solution, the mixture was stirred for 1 h at room temperature, and the precipitated material was filtered off using a pad of Celite.The filtrate was concentrated to give the crude alcohol (8) (966 mg), which without further purification was used in the next reaction.To a stirred solution of the above crude alcohol (8)

McMurry coupling reaction of 12 (Method 2).
When the McMurry coupling reaction was carried out for 5 h under the same reaction condition as described above, the cis-diol (13) was obtained as a major product in 66% yield, together with 11 and 14 in 5 and 6% yields, respectively.X-Ray analysis of the cis-diol (13).C 22 H 25 NO 4 .3H 2 O, M=421.49,orthorhombic, space group P2 1 2 1 2 1 , a=7.666(1), b=42.539(5), c=6.7407(9)Å, V=2198.2(5)Å 3 , Z=4, Dc=1.27 g/cm 3 ; The data were collected at a temperature of 23±1°C using the ω scan technique to a maximum 2θ value of 136.0°.Omega scans of several intense reflections, made prior to data collection, had an average width at half-height of 0.18° with a take-off angle of 6.0°.Scans of (1.68+0.30tan θ)° were made at a speed of 16.0°/min (in ω).The weak reflections (I < 10.0σ (I)) were rescanned (maximum of 7 scans) and the counts were accumulated to ensure good counting statistics.Of the 4267 reflections that were collected, 4228 were unique (R int.= 0.000); equivalent reflections were merged.The intensities of three representative reflections were measured after every 150 reflections.No decay correction was applied.The structure was solved using MALTAN88.R=0.049, Rw=0.056.O-Benzylipalbidine (15).To a stirred suspension of LiAlH 4 (168 mg, 4.43 mmol) in THF (3.7 mL) was added a solution of the lactam (11) (246 mg, 0.74 mmol) in THF (2 mL) at 0°C, and the resulting mixture was stirred at room temperature for 1 h.After quenching the reaction by addition of 10% NaOH solution, the insoluble material was removed by filtration, and the filtrate was concentrated to leave a residue, which was subjected to column chromatography on silica gel.(+)-Ipalbidine (1).A solution of the amine (15) (165 mg, 0.52 mmol) in MeOH (2.6 mL) in the presence of Pd(OH) 2 on carbon (16.5 mg) was stirred under an atmospheric pressure of hydrogen for 1 h.After removal of the catalyst by filtration, the filtrate was concentrated to leave a residue, which was subjected to column chromatography on silica gel.Elution with EtOAc-MeOH (5:1, v/v) gave ipalbidine (1) (118 mg, 100%) as a colorless solid.Mp 76-78°C (benzenecyclohexane); [α] D +146.9 (c=0.75,EtOH); The spectroscopic data were identical with those reported. 4onversion of the cisdiol into the lactam 11.A solution of the diol (13) (64.0 mg, 0.17 mmol), trimethyl orthoformate (95.3 µL, 0.87 mmol) and PPTS (21.9 mg) in CH 2 Cl 2 (0.7 mL) was stirred for 24 h at room temperature.The mixture was filtered through a short column on silica gel, and the crude filtrate was dissolved into acetic anhydride (0.5 mL).The solution was heated at 140°C for 24 h.After treatment with saturated aqueous NH 4 Cl solution, the mixture was extracted with EtOAc, and the extract was washed with brine and dried over Na 2 SO 4 .Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel with hexane-EtOAc (1:2, v/v) as the eluent to afford the lactam (11) (43.6 mg, 75%) as a colorless solid.The lactam obtained here was identical with the authentic specimen.