Synthesis of (+)-Vitepyrroloid A and (+)-Vitepyrroloid B by Late-Stage Ni-Catalyzed C(sp2)–C(sp3) Cross-Electrophile Coupling

Abstract

A concise and scalable five-step synthesis of vitepyrroloids A and B, two cytotoxic labdane diterpenoid alkaloids from Vitex trifolia, is reported. The presented approach features a Ni-catalyzed cross-electrophile coupling between a (+)-sclareolide-derived alkyl iodide and 3-bromo-2-cyanopyrrole.

A Process Chemistry Benchmark for sp2–sp3 Cross Couplings

“…Although we were encouraged by the identification of effective conditions for the sp 2 –sp 3 Suzuki coupling of alkyl bromide 7 and indole boronic acid 5a , we recognized that an additional gain in synthetic efficiency could be achieved if bromoindole 2a was directly coupled with a suitable alkyl halide or pseudohalide partner. We were encouraged by pioneering reports from Weix, with subsequent work from Gong, Christman, and Molander expanding the scope to include heterocyclic coupling partners. − We chose to begin our investigations with the cross-electrophile coupling of aryl bromide 2a and N -Boc alkyl bromide 7 .…”

Formal Synthesis of Actinoranone Using a Racemization-Free One-Pot Semipinacol Rearrangement/Wittig Reaction

“…Treatment with sulfuric acid in methanol resulted in a one-pot methanolysis of the lactone followed by elimination of the resulting tertiary alcohol at C8. [26][27] Subsequently, the ratio of  7,8 -alkene,  8,9 -alkene, and exocyclic  8,19 -alkene was optimized by screening different reaction temperatures and times. After three days at 23 °C, a mixture of alkene-isomers ( 7,8 ,  8,9 ,  8,19 = 1.0:0.2:0.7) with  7,8 -alkene 8 as the major product was obtained.…”

“…Likewise, we envisioned that 2 could be obtained from the sesquiterpenoid sclareolide. [17][18][19][20][21][22][23][24][25][26] In contrast to Ye and Pastre, we anticipated aldehyde 3 to be accessible from ester 4. For the synthesis of this intermediate, a semipinacol rearrangement/Wittig reaction sequence starting from silyl ether 6 was considered.…”

“…Rf = 0.44 (n-pentane/Et2O = 8:1); [α]D26 = +8.15 (CHCl3, c = 0.75); IR: ṽ = 835, 1154, 1204, 1429, 1462, 1595, 1733, 2856, 2930, 2953 cm -1 ; 1 H (500 MHz, CDCl3): δ = 6.34 (d, J = 2.2 Hz, 2H), 6.32 (t, J = 2.6 Hz, 1H), 4.08 (qd, J = 7.1, 1.0 Hz, 2H), 3.77 (s, 6H), 3.73 -3.63 (m, 2H), 2.71 -2.62 (m, 1H), 2.24 -2.15 (m, 3H), 1.87 -1.79 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 0.86 (s, 9H), -0.01 (s, 3H), -0.03 (s, 3H) ppm; 13 C (125 MHz, CDCl3): δ = 173.8, 160.9 (2C), 144.8, 106.4 (2C), 98.5, 67.9, 60.3, 55.4 (2C), 48.5, 32.5, 27.3, 26.0 (3C), 18.4, 14.4, -5.3 (2C) ppm; HRMS (ESI): [M+Na] + calculated for C21H36O5SiNa + : 419.2224, found: 419.2218; [M+K] + calculated for C21H36O5SiK + : 435.1964, found: 435.1949.4.11 Synthesis of (S)-5-((tert-butyldimethylsilyl)oxy)-4-(3´,5´dimethoxyphenyl)pentanal (14)To a solution of ester 13 (73.0 mg, 0.184 mmol, 1.0 equiv) in anhydrous CH2Cl2(1.8 mL), was added DIBAL-H (1.0M in CH2Cl2; 0.20 mL, 0.202 mmol, 1.1 equiv) at -78 °C. After stirring for 1 h, the reaction was quenched by the addition of saturated aqueous potassium sodium tartrate (5.0 mL), stirred for 30 min and extracted with EtOAc (3 x 20 mL).…”

Formal Synthesis of Actinoranone Using a Racemization-Free One-Pot Semipinacol Rearrangement/Wittig Reaction

“…Treatment with sulfuric acid in methanol resulted in a one-pot methanolysis of the lactone followed by elimination of the resulting tertiary alcohol at C8. [26][27] Subsequently, the ratio of  7,8 -alkene,  8,9 -alkene, and exocyclic  8,19 -alkene was optimized by screening different reaction temperatures and times. After three days at 23 °C, a mixture of alkene-isomers ( 7,8 ,  8,9 ,  8,19 = 1.0:0.2:0.7) with  7,8 -alkene 8 as the major product was obtained.…”