Structure elucidation of nigricanoside A through enantioselective total synthesis

Total synthesis enabled the assignment of relative and absolute stereochemistry of nigricanoside A, which was reported to show potent cytotoxicity.


H and 13 C NMR Data for synthetic Nigricanoside A Dimethyl Ester 2
S6-S7 Methods and Materials S8 Experimental procedures and characterization data Synthesis of the 20-C fatty acid 13 S9-S13 Synthesis of the 16-C fatty acid 14 S13-S16 Synthesis of nigricanoside A dimethyl ether epimer 32 S16-S26 Synthesis of nigricanoside A dimethyl ether 2 S27-S32 Figure S6.

-S7. Comparison of 4 diasteromeric triols (22-25) to nigricanoside A dimethyl ester 2
S33-S34 Figure S8. Selective TOCSY experiment of the mixture (23 (anti, anti) and 22 (syn, syn)) S35 NMR Spectra S36-S106 Electronic Supplementary Material (ESI) for Chemical Science. This journal is © The Royal Society of Chemistry 2015 S3 Figure S1. Comparison of synthetic nigricanoside A dimethyl ester 2 to natural product ( 1 H NMR). Spectrum of the natural product kindly provided by Prof. Raymond Andersen. Figure S2. Comparison of synthetic nigricanoside A dimethyl ester 2 to natural product ( 13 C NMR). Spectrum of the natural product kindly provided by Prof. Raymond Andersen.
S4 Figure S3. Comparison of synthetic nigricanoside A dimethyl ester 2 to natural product (6.20-5.00 ppm). Spectrum of the natural product kindly provided by Prof. Raymond Andersen. * = OH peak. Figure S4. Comparison of synthetic nigricanoside A dimethyl ester 2 to natural product (4.85-3.30 ppm). Spectrum of the natural product kindly provided by Prof. Raymond Andersen. * = OH peak.
Glycidyl ether (S)-6 was obtained from the reaction of commercially available (R)glycidol (from Aldrich) with NaH (60% in mineroil oil) and PMBCl in DMF following a known procedure 4 .
p-Toluenesulfonic acid (0.8 g, 1.33 mmol, 1.4 mol%) was added to a 100 mL round-bottomed flask containing a stirred solution of (R, R)-(-)-N,N'-bis (3,5-di-tert-butylsalicicylidene)-1,2-cyclohexanediaminocobalt (II) (0.27 g, 1.4 mmol, 1.5 mol%) in 20 mL DCM at room temperature. The reaction was allowed to stir open to air for 1 hour, after which the stir bar was removed and the solution was concentrated by rotary evaporation. The contents of the flask were placed under high vacuum for 1 hour to remove the remaining solvent. The stir bar was returned to the flask and racemic glycidaldehyde diethyl acetal (13.7 g, 93.7 mmol, 1.0 equiv) was added to the (salen)Co III -OTs catalyst at room temperature. The flask was capped and stirred vigorously for 24 hours. The epoxide was transferred to a -78˚C receiving flask by distillation (60˚C, 10 mmHg) to afford (S)-A (5.81 g, 40.1 mmol, 43% yield, 97% ee) as a clear liquid, which was stored over 4Å molecular sieves in the freezer. The ee of (S)-A (97%) was determined by chiral GC. 1
To a stirred solution of D (0.22 g, 0.654 mmol, 1.0 equiv) in 45 mL THF at 0 ºC was added a 15 mL freshly prepared solution of 10% HCl. Hydrolysis of the diethyl acetal was complete after 44 hours of stirring at 0 ºC, after which the solution was poured into a stirred solution of saturated aqueous NaHCO 3 at 0 ºC. The crude aldehyde E was extracted from the aqueous layer by washing once with EtOAc and twice with DCM. The organic layer was pooled, dried with MgSO 4 , filtered and concentrated. The crude aldehyde was unstable so it was purified quickly by flash chromatography (2.5-10% EtOAc in hexanes with 0.1% Et 3 N) afforded the aldehyde E (0.145 g, 85% yield) as a colorless oil. This α-hydroxy aldehyde E is very unstable and was used directly in the following reaction without being completely characterized.
Solid Cp 2 Zr(H)Cl (0.614 g, 2.26 mmol, 1.7 equiv) was added to a stirred solution of F (0.652 g, 2.00 mmol, 1.5 equiv) in 7 mL DCM at 0 ºC. The hydrozirconation was complete after 2 hours, at which time a solution of ZnBr 2 (2.0 M in toluene, 0.133 mL, 0.133 mmol, 0.1 equiv) was added to the reaction mixture. After stirring for an addition 15 minutes at 0 ºC, a solution of the aldehyde (E, 0.35 g, 1.33 mmol, 1.0 equiv) in 2 mL DCM was added at the same temperature. The aldehyde was allowed to react overnight at 0 ºC and the reaction was quenched with a 10% aqueous solution of citric acid. The organic layer was separated, and the aqueous layer was washed 3 times with DCM. The organic layer was combined, washed with brine, dried with MgSO 4 , filtered and concentrated to afford the desired alcohol as a mixture of diastereomers. The crude oil was taken directly into the Dess-Martin oxidation without further purification.
Hydrazine acetate (1.9 mg, 20.6 µmol, 3.0 equiv) was added to a stirred solution of the above product (7.6 mg, 6.8 µmol, 1.0 equiv) in 2.0 mL DMF at room temperature. After stirring for 3 h at room temperature, the reaction was quenched with saturated aqueous NaH 2 PO 4 , and extracted 3 times with EtOAc. The combined organic layer was washed with brine, dried with MgSO 4 , concentrated, filtered, and purified by a pipette column (5-60% EtOAc in hexanes) to afford the product (5.5 mg, 75% yield) as a colorless oil.