Scalable De Novo Synthesis of Aldgarose and Total Synthesis of Aldgamycin N

Abstract Since the accompanying study had shown that the introduction of the eponymous aldgarose sugar to the C5‐OH group of the macrocyclic aglycone of aldgamycin N is most difficult, if not even impossible, the synthesis route was revised and the glycosidation performed at an earlier stage. To mitigate the “cost” of this strategic amendment, a practical and scalable de novo synthesis of this branched octose was developed. The glycoside formation required mild conditions; it commenced with the reaction of the aglycone with the trichloroacetimidate donor to give a transient orthoester, which slowly rearranged to the desired aldgaropyranoside. The presence of the polar peripheral groups in the product did not impede the selective late‐stage functionalization of the macrolide ring itself: the contained propargylic alcohol entity was readily transformed into the characteristic acyloin motif of the target by a ruthenium‐catalyzed trans‐hydrostannation followed by a modified Chan‐Lam‐type coupling.


S4
The racemic sample was obtained following a literature procedure. 3 The analytical data are in agreement with those reported in the literature. 4

4-ol (9).
In a 100-mL two-necked flask, aqueous hydrogen peroxide solution (35% w/w, 2.5 mL) and aqueous sodium hydroxide solution (2 M, 0.55 mL) were sequentially added to a solution of compound 5 (1.24 g, 11.1 mmol) in methanol (52 mL) at −45 °C. Stirring was continued at that temperature for 2 h before the mixture was neutralized with acetic acid (0.07 mL) at −45 °C. Trimethyl phosphite (4.0 mL) was carefully added at this temperature and the mixture was allowed to warm to −20 °C over the course of 30 min. At this point, the same amount of trimethyl phosphite was added again. After stirring for another 30 min at 20°C, a peroxide test (Merck test strip) was negative. The mixture was warmed to ambient temperature and volatile components were removed under reduced pressure (10 -2 mbar, 30 °C). The residue was dissolved in ethyl acetate (40 mL) and the resulting solution was dried over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was removed under reduced pressure. Purification of the residue by flash chromatography (hexanes/EtOAc, 2:1) furnished a colorless gum (1.31 g), which was used in the next step without further characterization.
In a round-bottom flask, triisopropylsilyl chloride (3.4 mL, 16 mmol) and imidazole (1.28 g, 18.8 mmol) were added to a solution of this material in DMF (7.0 mL) and the resulting mixture was stirred for 15 h at room temperature. The mixture was diluted with tert-butyl methyl ether (40 mL) and washed with saturated aqueous sodium bicarbonate solution (40 mL). The aqueous phase was extracted with tert-butyl methyl S5 ether (4 × 15 mL) and the combined organic layers were washed with aqueous HCl (1 M, 30 mL), saturated aqueous sodium bicarbonate solution (30 mL) and brine (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, the drying agent was filtered off, and the solvent was removed under reduced pressure to give crude 8 as a colorless oil (3.83 g).
Vinylmagnesium bromide (1.0 M in THF,40 mL,40 mmol) was added to a solution of this material in diethyl ether (45 mL) at −78 °C. After stirring for 7 h at this temperature, reaction monitoring ( 1 H NMR) indicated full consumption of the starting material. The reaction was quenched with half-saturated aqueous ammonium chloride solution (75 mL), the mixture was warmed to room temperature with vigorous stirring until a clear, biphasic mixture was obtained. The aqueous phase was extracted with tert-butyl methyl ether (3 × 25 mL) and the combined organic layers were dried over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexanes/EtOAc, 90:1 → 70:1 → 60:1 → 50:1) to give the title compound as a colorless oil (1.77 g, 46% yield).  5, 114.1, 102.9, 75.6, 74.7, 66.7, 56.3, 43.5, 20.7, 18.4, 13.0. IR (film): 3551,2944,2894,2867,1465,1383,1347,1326,1310,1293,1246,1214,1164,1114,1095,1069,1052,1015,923,883,836,811,681,600,564 2.47 g,11.0 mmol) was added in one portion to a solution of allylic alcohol 9 (1.52 g, 4.41 mmol) in dichloromethane (40 mL) at 0°C. After stirring for 20 min at this temperature, the ice bath was removed and stirring was continued for 94 h. For work up, the flask was again immersed in an ice bath before aqueous sodium sulfite solution (10 w-%, 20 mL) was carefully added and the mixture was stirred for another 15 min. Half-saturated aqueous sodium carbonate solution (50 mL) was introduced and the mixture was warmed to room temperature under vigorous stirring. It was diluted with dichloromethane (20 mL), the layers were separated, and the organic layer was washed with half-saturated aqueous sodium carbonate solution (50 mL) and brine (20 mL). The aqueous phases were extracted with tert-butyl methyl ether (5 × 20 mL) and the combined organic layers dried over anhydrous sodium sulfate.

Methyl 2-O-acetyl-β-D-aldgaropyranoside (13a).
A solution of phosgene (20% w/w in toluene, 2.4 mL) was added to a vigorously stirred solution of triol 11 (617 mg, 2.99 mmol) in dichloromethane (7.5 mL) and pyridine (7.5 mL) at 0°C. The resulting white suspension was vigorously stirred for 2 h at this temperature before it was diluted with dichloromethane (25 mL) and washed with aqueous HCl (2 M, 2 × 15 mL). The aqueous phases were extracted with dichloromethane (4 × 10 mL) and the combined organic layers were dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. Remaining pyridine was removed by co-evaporation with toluene (8 mL).

1,2-Di-O-acetyl-D-aldgaropyranose (13b).
In a 10-mL round-bottom flask, a solution of concentrated sulfuric acid in acetic anhydride (1:99 v/v, 6.0 mL) was added to a solution of methyl glycoside 13a (482 mg, 1.76 mmol) in acetic anhydride (6.0 mL) at 0°C. After 5 min, the ice bath was removed and the mixture stirred for 1 h at room temperature. For work up, the mixture was diluted with ethyl acetate (30 mL) and carefully poured onto icecold water (25 mL) in a separatory funnel. After careful shaking of the two layers, saturated aqueous sodium bicarbonate solution was slowly added until all acid was destroyed (ca. 40 mL). After the gas formation had ceased, the layers were separated and the aqueous phase was extracted with ethyl acetate (6 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure. Most of the remaining acetic anhydride was destroyed by co-evaporation with ethanol (2 × 2 mL) followed by azeotropic removal with toluene (2 mL).
The aqueous phase was extracted with tert-butyl methyl ether (4 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, the drying agent was filtered off, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexanes/EtOAc, 2:1) to furnish the title compound as a colorless gum (40.3 mg, 78% yield; 1:2 mixture of α/β anomers), which formed a white wax upon standing. For analytical purposes, an aliquot was re-subjected to flash chromatography to give a pure sample of the β-anomer. The signals of the α-anomer were then assigned from the NMR spectrum of the mixture containing both anomers. Spectral data of the α-anomer  2983,2924,2851,1803,1756,1450,1374,1285,1228,1180,1158,1147,1079,1064,1022,943,919,828,803,773

6-Bromo-6-deoxy-D-isoascorbic acid (S2).
In a round-bottom flask, D-isoascorbic acid (21) (15.8 g, 89.6 mmol) was added to a solution of hydrogen bromide in acetic acid (33% w/w, 70 mL) at room temperature. The flask was covered with aluminum foil and the mixture stirred for 16 h before it was carefully poured onto ice-cold water (350 mL).
For work up, the pressure was carefully released and the mixture was concentrated under reduced pressure.
The 13 C resonance for C-17 was assigned by HSQC measurement (Figure S4), indicating that C-17 is overlapping with C-18 rather than with C-6' (however H-17 and H-6' overlap in 1 H NMR spectrum).

S27
The -OH 1 H resonances for the hydroxy groups at C-8, C-2', C-3', C-7' and C-4" varied for different samples. For C-7, C-10, C-13, C-14 and C-19, particularly broad 13 C{ 1 H} NMR signals were observed at 298 K (cf. copies of spectra). Measurements at 288 K and 308 K did not lead to any significant line sharpening.