Total synthesis of (±)-halichlorine, (±)-pinnaic acid, and (±)-tauropinnaic acid

Abstract

The related marine natural products halichlorine, pinnaic acid, and tauropinnaic acid have been synthesized. The described route provided access to all three compounds from a common, late-stage intermediate. The synthesis began with 1-pyrrolidino-1-cyclopentene from which an intermediate possessing the three contiguous stereocenters of the natural products was synthesized in just four steps. Olefin cross metathesis followed by a hydrogenation͞hydrogenolysis reaction stereoselectively formed the piperidine ring. Use of a ␤-lactam group provided internal protection for the highly congested nitrogen atom during side-chain elaboration. The ␤-lactam was subsequently reduced directly to an amino aldehyde, which after the HornerWadsworth-Emmons reaction was elaborated to pinnaic acid. The same amino aldehyde was also transformed into halichlorine after a thiol-mediated cyclization sequence to form the dehydroquinolizidine ring system.

Synthetic approaches towards alkaloids bearing α-tertiary amines

“…A related apporach employing a different type of N-acyl iminium ion was used by Heathcock in 2004 for the synthesis of halichlorine, pinnaic acid and tauropinnaic acid (Scheme 49a). 312 Treatment of carbamate acetal 220 with allyl trimethylsilane and titanium tetrachloride furnished ATA-bearing carbamate 221 with a high degree of stereoselectivity. This key intermediate could be transformed into all three natural products.…”

“…Both groups explored an intramolecular carbene insertion into a C,H-bond to form the ve-membered heterocyclic core. Hayes converted the enantiomerically pure Scheme 49 Syntheses of halichlorine, pinnaic acid and tauropinnaic acid by Heathcock (2004) and Arimoto (2007). Cbz ¼ benzyloxycarbonyl, PMP ¼ p-methoxyphenyl, TMS ¼ trimethylsilyl.…”

Polycyclic ethers and an unexpected dearomatisation reaction during studies towards the bioactive alkaloid, perophoramidine

“…Increasing the number of equivalents of AlCl 3 and/or heating the reaction using conventional or microwave methods had no effect. Use of a ptoluenesulfonic acid-mediated protocol, that had been successful for the conversion of 14 to 26, did not work in the case of 25 (Scheme S3) Use of the Hosomi-Sakuri protocol 14 with AlCl 3 and allyltrimethylsilane as the nucleophile in dichloromethane enabled the synthesis of 29 and 30 from 16 and 17 respectively (Figures 2, S4 and S5). Again, the attempted reaction of 18 gave a complex mixture and, despite considerable efforts (Table S2), none of the desired products could be obtained when 10 and 25 were used under these conditions.…”

“…(KBr) ν max : 3320, 2143, 1555, 1469, 1452, 1206, 1059, 761, 702 cm -1 . 1 (±)-(3aR,13bR)-9-Benzyl-2,3,9,13b-tetrahydrofuro [3,2c]indolo [2,3-b]quinoline (14) To a solution of 15 (100 mg, 0.270 mmol) in pyridine (5 mL) was added p-toluenesulfonyl chloride (57 mg, 0.297 mmol) and the solution stirred at rt for 2h. The mixture was then heated to 60 °C for a further 5h before cooling to rt and adding 1M HCl [2,3b]quinolin- 11-ol (19) To a solution of 13 7 (360 mg, 0.977 mmol) in THF (12 mL) at 0 °C was added methylmagnesium bromide (3M in THF, 0.72 mL, 2.150 mmol).…”

Modular Asymmetric Synthesis of Functionalized Azaspirocycles Based on the Sulfoximine Auxiliary

“…10,11 In 2004, HEATHCOCK and co-workers reported the total synthesis of the racemates of 4 and 7. 12 Later some other groups published formal total syntheses of these marine alkaloids. 13,14,15 Theoretical part 7…”