Total Syntheses of the Assigned Structures of Lituarines B and C

Abstract

The lituarines A-C comprise an architecturally novel, biologically active family of marine natural products (1-3; Figure 1) reported by Vidal and co-workers in 1992. 1a Isolated from the sea pen Lituaria australasaie, endemic to the western region of the New Caledonian Lagoon near the Baie de St. Vincent, their structures, including the connectivities and relative stereochemistries, were assigned on the basis of multidimensional NMR techniques; 1b the absolute stereochemistry remains undefined. From the biomedical perspective, the lituarines display significant cytotoxicities toward KB cells [(1): IC 50 ) 5.5-7.5 nM; (2): IC 50 ) 1-3 nM; (3): IC 50 ) 7-9 nM]. Intrigued both by the architecture and the biological activities of the lituarines, we initiated a research program directed toward the total synthesis of the lituarines. 2,3 The Robertson laboratory has also reported progress in this area. 4

Asymmetric synthesis of the C(6–18) bis(tetrahydropyran)spiroacetal fragment of the lituarines

“…The route summarised in Schemes 10 and 11, above, satisfied our immediate needs, with the low-yielding steps [29/(À)-54, (À)-55/(þ)-33 and (þ)-48a/(þ)-49] returning mostly unreacted starting materials to account for the mass balance in each case. However, Smith's report, during the course of this work, 3 that the structures of the lituarines are incorrectly assigned, adds to the list of 'molecules that were never there' 48 and a re-evaluation of the original structural data needs to be undertaken before further efforts are expended on this endeavour.…”

“…Flash chromatography (petrol/ether, 3:1/1:1) afforded the title compound (35) as a pale brown oil (0.11 g, 87%). R f 0.13 (petrol/ ether, 1:1); n max (thin film)/cm À1 3482br, 2952s, 2931s, 2854m, 1714s,1659s,1508m,1437s,1331m,1278s,1205s,1177s,1149s, 2953s,1738s,1439s,1373m,1344m, 1289s, 1261s, 1207s, 1169s, 1093s, 1011m; d H (400 MHz, CDCl 3 ) 1.36 (3H, s, CH 3 C(OR)), 1.86 (1H, ddd, J 13.5, 11.5, 5.0 Hz, CHH 0 C(CH 3 )), 1.91 (1H, ddd, J 13.5, 10.5, 6.5 Hz) and 2.09 (1H, dddd, J 13.5, 6.5, 4.0, 3.0 Hz, CH 2 CH 2 CO), 2.19 (1H, ddd, J 13.5, 11.0, 5.5 Hz, CHH 0 C(CH 3 )), 2.45e2.66 (5H, m, CH 2 CO and CH 2 CO 2 and FuCHH 0 ), 2.75 (1H, ddd, J 15.5, 11.0, 5.0 Hz, FuCHH 0 ), 3.73 (3H, s, OCH 3 À1 2953m,1737s,1508s,1373m,1288s, 1260s, 1210s, 1172s, 1089s, 1072s To a stirred solution of ketone 35 (0.10 g, 0.36 mmol) in dichloromethane (13.3 mL) at À78 C was added dropwise ZnCl 2 (0.48 mL, 1.0 M solution in ether, 0.48 mmol). After 0.5 h, L-Selectride (1.23 mL, 1.0 M solution in THF, 1.23 mmol) was added dropwise and stirring continued at À78 C for 1.5 h. The reaction was quenched by the careful addition of methanol (0.31 mL), water (0.16 mL), hydrogen peroxide (0.16 mL, 35% w/w aqueous solution) and aq NaOH (0.16 mL, 6.0 M) and the resulting solution warmed to rt before being diluted with water (5.0 mL) and extracted with dichloromethane (3Â15 mL).…”

“…However, Smith's group completed total syntheses of the structures proposed for lituarines B and C and found that the spectroscopic data for these compounds did not match those reported. 3 Thus, more recent synthetic efforts have been aimed at securing the correct structures for the lituarines.…”

Chemical exchange in novel spirobicyclic zwitterionic Janovsky complexes using dynamic 1H NMR spectroscopy

“…1 and their 1 Ha n d 13 C NMR assignments are listed in Table 1; the observed 1D 1 H NMR peak shapes for compounds 1 and 2 as a function of temperature are shown in Fig. 2 and Fig.…”

“…1) were acquired on a Jeol JNM GSX-270 spectrometer using Jeol Delta NMR 4.3.5 software operating at 270 MHz for 1 Hor a Varian MercuryPlus spectrometer operating at 200 MHz for 1 H. 1 H NMR spectra were acquired as d 3 -acetonitrile or d 6 -dimethyl sulfoxide (DMSO) solutions, whereas 13 C NMR spectra (50 MHz) were collected as d 4 -methanol solutions. All solutions had a concentration of 10−20 mg ml −1 .…”