Total synthesis of the alpha-glucosidase inhibitors schulzeine A, B, and C and a structural revision of schulzeine A

Abstract

The enantioselective total synthesis of the potent alpha-glucosidase inhibitors schulzeine A, B, and C and a revision of the proposed C20' configuration of schulzeine A are reported. The central feature of our convergent route to this family of novel marine natural products is the preparation of the common benzo[a]quinolizidine subunit through a substrate-controlled, diastereoselective Pictet-Spengler cyclocondensation.

Figure 1

(+)-Schulzeine A (revised structure) (1; C11b-H_β; R¹ = Me R² = H); (-)-schulzeine B (2; C11b-H_α; R¹, R² = H); (+)-schulzeine C (3; C11b-H_β; R¹, R² = H); (+)-schulzeine A (proposed structure) (4; C11b-H_β; R¹ = H; R² = Me).

Scheme 1. Synthesis of the Benzo[a]quinolizidine Subunit^a

aConditions: (a) i-BuOCOCl, NMM, CH₂Cl₂, -35 °C, 15 min, then 2-[3,5-bis(benzyloxy)phenyl]ethylamine, DMF, CH₂Cl₂, rt, 12 h; (b) NaBH₄, LiCl, THF, MeOH, 0 °C, 5.5 h; (c) HCl-Et₂O, CH₂Cl₂, rt, 2 h; (d) PhthCO₂Et, Na₂CO₃, THF, rt, 16 h; (e) Swern oxidation; (f) AcOH, CH₂Cl₂, rt, 2 h; (g) H₂NNH₂, EtOH, rt, 24 h; (h) Boc₂(O), CH₂Cl₂, rt, 1 h, cis-11 (57%), trans-11 (26%); (i) TFA, CH₂Cl₂, 0 °C, 1 h cis-12 (C11b-Ha, 98%), trans-12 (C11b-H_b, 85%).

Scheme 2. Total Synthesis of Schulzeine A (1).^a

aConditions: (a) Moffat-Swern oxidation; (b) (R)-(+)-1,1'-bi-2-napthol (10 mol%), Ti(O-i-Pr)₄, 4 Å m.s., CH₂Cl₂, reflux 1 h; then -78 °C, allyltri-n-butylstannane, -20 °C, 5 d; (c) TBSCl, imd, CH₂Cl₂, 0 °C®rt, 18 h; (d) 9-BBN, THF, 0 °C®rt, 14 h, then H₂O₂, NaOH, B(OH)₃, rt °C, 1 h; (e) 1-phenyl-1H-tetrazole-5-thiol, DIAD, Ph₃P, THF, 0 °C®rt, 12 h; (f) (NH₄)₆Mo₇O₂₄•4H₂O (20 mol%), H₂O₂, EtOH, 0 °C®rt, 14 h; (g) KHMDS, DME, -60 °C, 30 min, then (S)-3-methylundecanal, -60 °C®rt, 16 h, 16, 45%; KHMDS, DME, -60 °C, 30 min, then (R)-3-methylundecanal, -60 °C®rt, 16 h, 20, 75%, d.r. > 20:1; (h) HF, TBAF, THF, rt, 48 h; NaOH (1 M), EtOH, THF, reflux, 48 h, 17, 70%; 21, 84%; (i) EDC, CH₂Cl₂, rt, 16 h, 18, 73%; 22, 80%; (j) AD-mix a, MeSO₂NH₂, t-BuOH-t-BuOMe-H₂O-THF, 0 °C (1:1:1:1), 18 h, 19, 83%, d.r. = 4:1; AD-mix a, MeSO₂NH₂, t-BuOH-t-BuOMe-H₂O (1:1:1), 0 °C, 48 h, 23, 77%, dr = 91:9; (k) SO₃-pyr, DMF, rt, 2 h; (l) H₂, Pd/C, EtOH, rt, 8 h, 4, 88% (two steps); 1, 75% (two steps).