Total synthesis of periploside A, a unique pregnane hexasaccharide with potent immunosuppressive effects

Abstract

Periploside A is a pregnane hexasaccharide identified from the Chinese medicinal plant Periploca sepium, which features a unique seven-membered formyl acetal bridged orthoester (FABO) motif and potent immunosuppressive activities. Here, we show the synthesis of this molecule in a total of 76 steps with the longest linear sequence of 29 steps and 9.2% overall yield. The FABO motif is constructed via a combination of Sinaÿ's and Crich's protocol for the formation of orthoester and acetal glycosides, respectively. The 2-deoxy-β-glycosidic linkages are assembled stereoselectively with judicious choice of the glycosylation methods. The epimer at the spiro-quaternary carbon in the FABO motif has also been elaborated in a stereo-controlled manner. This epimer, as well as the synthetic analogues bearing the FABO motif, retain largely the inhibitory activities of periploside A against the proliferation of T-lymphocyte, indicating the importance of the chemical connection of the FABO motif to their immunosuppressive activity.

Figure 1. Periploside A 1 and the retrosynthetic analysis.

Shadowed in pale blue are the FABO motifs that have been previously assigned; highlighted in red are leaving groups in donors and in blue are hydroxyl groups in acceptors. Ac, acetyl; CA, chloroacetyl; MP, 4-methoxyphenyl; TBDPS, tert-butyldiphenylsilyl; TBS, tert-butyldimethylsilyl.

Figure 2. Synthesis of tetrasaccharide donor 2.

Highlighted in red are the nascent glycosidic bonds. (a) Ph₃PAuNTf₂ (0.1 equiv), toluene, 4 Å MS, −40 °C; 95% and β only (for 12); 99% and β only (for 14 and 16); (b) TBAF, THF, 0 °C to RT; 99% (from 12); 94% (from 14); 96% (from 16); (c) CH₃(OMe)₃, p-TsOH, RT, 93% for (13); 91% (for 15); (d) ⁿBu₂SnO, MeOH, reflux; (e) BnBr, DMF, CsF, RT; (f) LiOH, THF, H₂O, RT; 87% (for three steps); (g) MeI, NaH, DMF, 0 °C to RT, 99%; (h) Pd(OH)₂/C, H₂ (1 atm), Et₃N, EtOAc, MeOH, 50 °C, 93%; (i) Ph₃PAuNTf₂ (0.2 equiv), toluene, 5 Å MS, −50 °C to RT, 93%, β/α=4/1; (j) Ag(DPAH)₂, CH₃CN, H₂O, 0 °C to RT, 95%; (k) o-cyclopropylethynylbenzoic acid, EDCI, DMAP, 4 Å MS, CH₂Cl₂, RT, 99%. DMAP, 4,4-dimethylaminopyridine; DPAH, bis(hydrogen dipicolinate); EDCI, N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride; MS, molecular sieves; TBAF, tetrabutylammonium fluoride.

Figure 3. Construction of the FABO motif and synthesis of C1′′-epi-periploside A (31).

Highlighted in red are the nascent glycosidic bonds. (a) PhSeCl, CH₃CN, −40 °C, 78%; (b) DAST, THF, −30 °C to RT; (c) PhSCH₂OH, SnCl₂, CH₂Cl₂, 4 Å MS, −40 °C to RT; 58% (for two steps); (d) NIS, TfOH, CH₂Cl₂, −30 °C, 75% (for 24), 20% (for 23); (e) MeONa, MeOH, CH₂Cl₂, RT, 93%; (f) NaIO₄, NaHCO₃, MeOH, CH₂Cl₂, H₂O, RT, 99%; (g) vinyl acetate, toluene, DIPA, Mw, 145 °C, 20 min, 85%; (h) BzCl, Et₃N, DMAP, CH₂Cl₂, 0 °C to RT, 99%; (i) Ag(DPAH)₂, CH₃CN, H₂O, 0 °C to RT, 90%; (j) N-phenyl-2,2,2-trifluoroacetimidoyl chloride, Cs₂CO₃, CH₂Cl₂, RT, 95%; (k) TBSOTf, CH₂Cl₂, 5 Å MS, −78 °C, 85%, β/α=3/1; (l) Et₃B, Bu₃SnH, toluene, RT, 97%; (m) MeONa, MeOH, CH₂Cl₂, RT, 99%; (n) Ph₃PAuOTf (0.8 equiv), TTBP, CH₂Cl₂, 4 Å MS, −20 °C to −10 °C, 64% (87% b.r.s.m.), β/α=2.1/1; (o) thiourea, pyridine, EtOH, 80 °C; (p) HF·py, pyridine; THF, 0 °C to RT; 91% (for two steps). DAST, (diethylamino)sulfur trifluoride; DIPA, diisopropylamine; TBSOTf, tert-butyldimethylsilyl trifluoromethane sulfonate; Mw, microwave; TTBP, 2,4,6-tri-tert-butylpyrimidine.

Figure 4. Construction of the FABO motif with the natural configuration.

Highlighted in red are the nascent glycosidic bonds. (a) DAST, THF, −30 °C to RT; (b) SnCl₂, Et₂O, 4 Å MS, 0 °C to RT; 85% (for two steps); (c) NaIO₄, NaHCO₃, MeOH, CH₂Cl₂, H₂O, RT, 99%; (d) vinyl acetate, toluene, DIPA, Mw, 140 °C, 40 min, 92%; (e) EtSCH₂OH, DCCl₃, Mw, 10 min, 110 °C, 81%; (f) H₂NNH₂·H₂O, pyridine, HOAc, 0 °C to RT, 92%; (g) BSP, Tf₂O, DTBP, 5 Å MS, Et₂O, −114 °C, 64% (for 37), 18% (for 38). BSP, 1-benzenesulfinyl piperidine; DTBP, 2,6-di-tert-butylpyridine; Lev, levuloyl; Mw, microwave.

Figure 5. Completion of the total synthesis of periploside A (1).

Highlighted in red are the nascent glycosidic bonds. (a) Ag(DPAH)₂, CH₃CN, H₂O, 0 °C, 91%; (b) N-phenyl-trifluoroacetimidoyl chloride, Cs₂CO₃, CH₂Cl₂, RT, 90%; (c) TBSOTf, CH₂Cl₂, 5 Å MS, −78 °C, 87%, β/α=6.1/1; (d) Et₃B, Bu₃SnH, toluene, RT, 95%; (e) MeONa, MeOH, CH₂Cl₂, RT, 96%; (f) Ph₃PAuOTf (0.8 equiv), TTBP, CH₂Cl₂, 4 Å MS, −10 °C, 80%, β/α=2/1; (g) thiourea, pyridine, EtOH, 80 °C; (h) HF·py, pyridine, THF, 0 °C to RT, 93% (for two steps).

Figure 6. Synthetic analogues of periplosides.

Shadowed in pale blue are the carbon centres with opposite configurations to those in the nature product.