Concise synthesis of truncated pachastrissamine (jaspine B) and its enantiomer

A short and efficient stereoselective synthesis of truncated pachastrissamine and its enantiomer have been achieved using the Wittig olefination, azidation through imidazole sulfonate ester and one-pot reductive hydrogenation as the key steps.


Introduction
(+)-Pachastrissamine 1a, a naturally occurring novel anhydrosphingosine derivative, has been isolated recently from the Okanawa marine sponge Pachastrissa sp (family calthropellidae) by Higa and co-workers 1 and found to posses cytotoxicity at a level of IC 50 0.01 µg/mL against P388, A549, HT29 and Mell 28 cell lines.Shortly thereafter, the Debitus research group 2 reported the isolation of the same natural product from a different marine sponge Jaspis sp.Pachastrissamine represents the first example of an anhydrosphingosine structural feature in a natural product.In anticancer assays, this novel sphingosine derivative exhibited submicromolar cytotoxic activity against human lung carcinoma cell line using the ATP lite assay.Jaspine B 1a proved to be the most potent compound yet isolated from the Jaspis genus on this cell lines, cf.pectenotoxin II (IC 50 > 10 µM), 3 bengamide Y (IC 50 = 12.8 µM), 4 bengamide Z (IC 50 = 10.5 µM).It has been reported that sphingosine 1-phosphate induces a rapid and relevant release of arachidonic acid and increase phospholipase D activity in A549 cells. 6The marine sponges even though have provided several bioactive leads, the consistent supply of these compounds has been limited.In order to gain rapid access to these products of biological interests, we have initiated a programme 7 to synthesise these scarce natural products and their analogues efficiently so that the supply for screening is uninterrupted.Herein we wish to report the concise synthesis of a truncated version of titled compound 2a and its enantiomer 2b.The same strategy can be also applied for the synthesis of jaspine B with original side chain.The present approach allows one to use various commercially available sugars and design new stereoanalogs with ease.To the best of our knowledge only three syntheses have been reported. 8

Results and Discussion
The retrosynthetic analysis depends on the conversion of hydroxyl group at C-2 to sulfuryl imidazylate followed by S N 2 displacement with N 3 group in the furanose sugar normally a difficult step owing to its vicinity to anomeric carbon.For (+) and (-) Jaspine (truncated), we began with commercially available L-xylose and D-glucose respectively which were converted to key aldehydes 3a and 3b.Our retrosynthetic approach is outlined in scheme 1.The (+) isomer, L-xylose was converted to aldehyde 3a through known sequence of reactions. 9The aldehyde 3a was subjected to Wittig olefination 10 with n-butyl triphenylphosphonium bromide in THF-HMPA and n-butyl lithium at -40 o C to give olefin 4a with Z/E ratio of more than 10:1 in 86 % yield.The hydrolysis of acetonide linkage and in situ formation of the methyl glycoside 5a was successfully achieved using catalytic CH 3 COCl in methanol. 11ith the alcohol 5a in hand, we tried several methods e.g.tosylation and mesylation for the S N 2 displacement of hydroxyl group at C-2 with N 3 group.But all efforts failed.Even more reactive triflate did not give good yield in nucleophilic substitution and resulted mainly in the elimination product.This problem was circumvented by treating 5a with N, N'sulfuryldiimidazole 12

Scheme 2
The reductive removal of the methoxy group of 6a with triethylsilane in the presence of BF 3 .OEt 2 14 proceeded smoothly to give the tetrahydrofuran derivative 7a in 94 % yield.Finally, reduction of the azide group as well as olefin hydrogenation and cleavage of the benzyl ether was successfully achieved in one-pot. 15A mixture of 7a and Pd / C in methanol was stirred under hydrogen atmosphere to furnish the target molecule 2a in good yield along with the formation of a minor product as benzyl ether 8a.The benzyl ether 8a was again subjected to hydrogenation under the same conditions to yield final compound 2a in complete conversion (scheme 2).The (-)-enantiomer of truncated pachastrissamine 2b was also synthesized from D-glucose as a replenishable starting material.Initially D-glucose was transformed to aldehyde derivative 3b employing already known set of reactions. 16All above reactions were strategically applied to this aldehyde 3b to furnish the (-)-enantiomer of truncated pachastrissamine, 2b in a stereoselective manner (scheme 3).

Conclusions
In conclusion, a practical and stereoselective total synthesis of truncated pachastrissamine 2a and its enantiomer 2b has been achieved using Wittig olefination, azidation through imidazole sulfonate ester and one-pot reductive hydrogenation as the key steps.Moreover, this synthetic approach is flexible and can be applied for the synthesis of other analogues with variety of side chain and different stereocentres.

Experimental Section
General Procedures.Optical rotations were measured with a JASCO DIP-360 Polarimeter at 26 o C and IR spectra were recorded with a Perkin Elmer FTIR spectrophotometer. 1 H NMR spectra were carried out using a Varian Gemini 200 or Varian Unity 400 or Bruker Avance 300 MHz spectrophotometer using TMS as an internal standard in CDCl 3 .Mass spectra were recorded on Micro mass VG-7070H for EI and VG Autospec M for FABMS mass spectrometers.The progress of all the reactions was monitored by thin-layer chromatography (TLC) using glass plates precoated with silica gel 60F 254 to a thickness of 0.25mm (Merck).Column chromatography was conducted by elution of columns with silica gel 60-120 mesh using ethyl acetate and hexane as eluents.

3-Azido-4-benzyloxy-2-methoxy-5-[1-penyenyl]-(3R,4S,5S)-tetrahydro furan (6a).
To a well stirred suspension of freshly activated NaH (0.51 g, 12.9 mmol, 60% w/v dispersion in mineral oil) in anhydrous DCM (5mL), a solution of alcohol 5a (2.5g, 8.6 mmol) in dry DCM was added dropwise at 0 o C and stirred for 30 min at room temperature.The reaction mixture was cooled to -40 o C and to this added a solution of sulfuryl diimidazole (2.5g, 12.9 mmol) in dry DCM (5 mL) at -40 o C and stirred for one hour at this temperature.To this added 0.01 mL of methanol at -40 o C and further stirred for 30 min at -40 o C. The reaction mixture was allowed to warm up to 0 o C and quenched with ice.The aqueous layer was extracted with DCM (3X20 mL).The combined organic extract was washed with water, brine, dried over Na 2 SO 4 and concentrated.To the solution of this crude product in dry DMF was added NaN 3 (0.046 g, 7.1 mmol) and tetrabutylammonium chloride (1.9 g, 7.1 mmol) and stirred for overnight at 110 o C. The reaction mixture was diluted with water and the aqueous layer extracted with ether (3X20 mL).The combined organic layer was washed with water, brine, dried over Na 2 SO 4 and concentrated.The crude product was purified by column chromatography to give 6a (0.71 g, 58 % for both steps) as colourless oil.[