The convergent total synthesis of cytotoxic homospisulosine and its 3-epi-analogue

A common strategy for the total synthesis of cytotoxic homospisulosine 7 and its 3-epi-analogue 10 was achieved in a stereoconvergent manner, from 3,5-di-O-benzyl-d-xylofuranose with the efficient use of rearranged products 14–17. The key transformations of this approach are [3,3]-heterosigmatropic rearrangements of allylic substrates 18 and 19 to establish a stereogenic amino group and regioselective intramolecular cyclization to form common oxazolidinones 28 and 29. Elongation of the side chain was accomplished via a Wittig reaction. Several compounds were evaluated for their in vitro antiproliferative/cytotoxic activity by the MTT method employing five different human cancer cell lines (Jurkat, MDA-MB-231, MCF-7, HCT-116 and Caco-2). The obtained data revealed that homospisulosine 7 exhibited the most significant inhibitory effects among all of the screened compounds on the panel of the tested cell lines with IC50 values comparable to those of conventional anticancer agents such as cisplatin and etoposide.

Figure optionsDownload as PowerPoint slide

Ethyl (4S,5R,6R,2E)-5,7-bis(benzyloxy)-4,6-(isopropylidenedioxy)hept-2-enoateC26H32O6[α]D24 = −22.7 (c 0.22, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4S,5R,6R,2E)

(4S,5R,6R,2E)-5,7-Bis(benzyloxy)-4,6-(isopropylidenedioxy)hept-2-en-1-olC24H30O5[α]D25 = +4.2 (c 1.28, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4S,5R,6R,2E)

(4R,5R,6S)-5-(Benzyloxy)-4-[(benzyloxy)methyl]-6-[(1′S)-1′-isothiocyanatoallyl)]-2,2-dimethyl-1,3-dioxaneC25H29NO4S[α]D25 = +52.7 (c 0.70, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4R,5R,6S,1′S)

(4R,5R,6S)-5-(Benzyloxy)-4-[(benzyloxy)methyl]-6-[(1′R)-1′-isothiocyanatoallyl)]-2,2-dimethyl-1,3-dioxaneC25H29NO4S[α]D25 = +2.9 (c 0.24, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4R,5R,6S,1′R)

N-{(1′S)-1′-[(4″S,5″R,6″R)-5″-(Benzyloxy)-6″-[(benzyloxy)methyl]-2″,2″-dimethyl-1″,3″-dioxan-4″-yl]allyl]-2,2,2-trichloroacetamideC26H30Cl3NO5[α]D24 = −47.1 (c 0.14, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (1′S,4″S,5″R,6″R)

N-{(1′R)-1′-[(4″S,5″R,6″R)-5″-(Benzyloxy)-6″-[(benzyloxy)methyl]-2″,2″-dimethyl-1″,3″-dioxan-4″-yl]allyl]-2,2,2-trichloroacetamideC26H30Cl3NO5[α]D24 = −28.3 (c 0.12, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (1′R,4″S,5″R,6″R)

(4S,5S)-5-[(1′S,2′R)-1′,3′-Bis(benzyloxy)-2′-hydroxypropyl]-4-vinyloxazolidine-2-thioneC22H25NO4S[α]D27 = −63.8 (c 0.34, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4S,5S,1′S,2′R)

(4R,5S)-5-[(1′S,2′R)-1′,3′-Bis(benzyloxy)-2′-hydroxypropyl]-4-vinyloxazolidine-2-thioneC22H25NO4S[α]D23 = +67.8 (c 0.37, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4R,5S,1′S,2′R)

(4S,5S)-5-[(1′S,2′R)-1′,3′-Bis(benzyloxy)-2′-hydroxypropyl]-4-vinyloxazolidin-2-oneC22H25NO5[α]D27 = −26.5 (c 0.26, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4S,5S,1′S,2′R)

(4R,5S)-5-[(1′S,2′R)-1′,3′-Bis(benzyloxy)-2′-hydroxypropyl]-4-vinyloxazolidin-2-oneC22H25NO5[α]D23 = +36.2 (c 0.26, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4R,5S,1′S,2′R)

N-[(3′S,4′S,5′R,6′R)-5′,7′-Bis(benzyloxy)-4′,6′-dihydroxyhept-1′-en-3′-yl]-2,2,2-trichloroacetamideC23H26Cl3NO5[α]D27 = −12.8 (c 0.32, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (3′S,4′S,5′R,6′R)

N-[(3′R,4′S,5′R,6′R)-5′,7′-Bis(benzyloxy)-4′,6′-dihydroxyhept-1′-en-3′-yl]-2,2,2-trichloroacetamideC23H26Cl3NO5[α]D28 = +34.7 (c 0.60, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (3′R,4′S,5′R,6′R)

(4S,5S)-4-Ethyl-5-[(1′S,2′R)-1′,2′,3′-trihydroxypropyl]oxazolidin-2-oneC8H15NO5[α]D23 = +6.3 (c 0.24, CH3OH)Source of chirality: d-xyloseAbsolute configuration: (4S,5S,1′S,2′R)

(4S,5R)-4-Ethyl-5-pentadecyloxazolidin-2-oneC20H39NO2[α]D24 = +5.1 (c 0.76, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4S,5R)

(3S,4R)-3-Aminononadecan-4-olC19H41NO[α]D24 = +14.0 (c 0.35, MeOH)Source of chirality: d-xyloseAbsolute configuration: (3S,4R)

(4R,5S)-3-Benzyl-5-[(1′R,2′R)-1′,2′,3′-tris(benzyloxy)propyl]-4-vinyloxazolidin-2-oneC36H37NO5[α]D24 = +77.0 (c 0.40, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4R,5S,1′R,2′R)

(4R,5S)-3-Benzyl-4-ethyl-5-[(1′S,2′R)-1′,2′,3′-trihydroxypropyl]oxazolidin-2-oneC15H21NO5[α]D23 = +74.2 (c 0.26, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4R,5S,1′S,2′R)

(4R,5R)-4-Ethyl-5-pentadecyloxazolidin-2-oneC20H39NO2[α]D24 = +40.0 (c 0.16, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (4R,5R)

(3R,4R)-3-Aminononadecan-4-olC19H41NO[α]D23 = +12.7 (c 0.22, CHCl3)Source of chirality: d-xyloseAbsolute configuration: (3R,4R)