We have employed DFT protocols to calculate the NMR properties of the vannusals, a class of natural products whose structures have been the subject of recent investigations. The originally assigned structure of vannusal B was revised after a long synthetic journey which generated a series of closely related diastereomers. In this work we show how DFT calculations based on density functionals and basis sets designed for the prediction of NMR spectra (M06/pcS-2 level of theory) can be used to reproduce the observed parameters, thereby offering to the synthetic chemist a useful tool to discard or accept putative structures of unknown organic molecules.

Keywordsnatural products; vannusals A and B; samarium diiodide; ketyl-olefin cyclization Vannusals A (1a, Figure 1) and B (1b) are two marine natural products notable for their unusual molecular architectures. Isolated from the tropical interstitial ciliate Euplotes vannus strains Si121 and BUN3, these intriguing molecules include in their C30 molecular framework seven rings and thirteen stereogenic centers, three of which are quaternary. Their structures have been assigned on the basis of mass spectrometric and NMR spectroscopic data and chemical transformations. [1,2] Herein we report the total synthesis of structure 1b that proved that it does not represent the true structure of vannusal B.Our retrosynthetic analysis of the vannusal molecule dissected it as shown in Figure 2, revealing vinyl iodide 2 and aldehyde 3 as the key building blocks required for the projected total synthesis. The devised strategy anticipated their fusion through two carbon-carbon bond forming reactions, namely lithiation of 2 followed by addition of 3 to join them, and a samarium-induced ring closure of a subsequent intermediate to forge the final ring of the target molecule.Scheme 1 summarizes the construction of vinyl iodide 2 from the commercially available meso diol 4. Thus, dehydration of 4 through the action of POCl 3 (py, 90 °C) furnished conjugated diene 5 (97 % yield), [3] which was regio-and stereoselectively converted to the new meso diol 6 by a hydroboration-oxidation process (CyBH 2 ; H 2 O 2 , NaOH, 50 % yield). The latter compound was then desymmetrized through the enantioselective hydrolytic action of Lipase Amano PS[4] on its bis-acetate (prepared in quantitative yield by reaction of 6 with Ac 2 O in the presence of 4-DMAP), leading to the monoacetate 7 in 100 % yield and 99 % ee (determined by Mosher ester analysis). Silylation of 7 (TBDPSCl, imid., 98 % yield), followed by acetate cleavage (DIBAL-H, 98 % yield) and treatment of the resulting alcohol with Martin's sulfurane (Et 3 N, CH 2 Cl 2 , 91 % yield) afforded enantiomerically pure cyclopentene derivative 8. The planned stereoselective epoxidation of 8 was achieved through a two-step procedure that involved first iodohydrin formation (NIS, H 2 O), and then ring closure (K 2 CO 3 , MeOH) to give β-epoxide 9 in 90 % overall yield. This epoxide was then regio-and stereoselectively opened with 2-lithiopropene (generated from the corresponding bromide and tBuLi) in the presence of BF 3 •Et 2 O to afford hydroxy compound 10 (83 % yield), whose stereochemistry Figure 3) [7] of the crystalline p-bromophenyl carbamate 14 (m.p. 136-138 °C, EtOAc / hexanes) prepared from hydroxy compound 10 through reaction with pbromophenyl isocyanate, followed by TBAF-induced desilylation, in 80 % overall yield as shown in Scheme 1.Scheme 2 outlines the construction of building block 3 starting from intermediate 15 (racemic) [8] or 15a (enantiopure).[9] Thus, exposure of dihydroxy methyl ether 15 to Bbromocatecholborane, followed by selective monosilylation of the resulting triol (TIPS...

The total synthesis of the originally assigned structure of vannusal B (2) and its diastereomer (d-2) are described. Initial forays into these structures with model systems revealed the viability of a metathesis-based approach and a SmI 2 -mediated strategy for the key cyclization to forge the central region of the molecule, ring C. The former approach was abandoned in favor of the latter when more functionalized substrates failed to enter the cyclization process. The successful, devised convergent strategy based on the SmI 2 -mediated ring closure utilized vinyl iodide (−)-26 and aldehyde fragment (±)-86 as key building blocks, whose lithium-mediated coupling led to isomeric coupling products (+)-87 and (−)-88. These intermediates were separately converted to precursors (+)-25 and (−)-97, which cyclized under the influence of SmI 2 -HMPA to afford products (−)-90/(−)-91 and (+)-98, respectively. The former two intermediates were converted to vannusal B structure 2 while the latter gave rise to its diastereomeric structure d-2, neither of which exhibited the reported spectroscopic data of the natural product. These investigations led to the discovery and development of a number of new synthetic technologies that set the stage for the solution of the vannusal structural conundrum.

Vannusals A (1 a, Figure 1) and B (1 b) are two marine natural products notable for their unusual molecular architectures. Isolated from the tropical interstitial ciliate Euplotes vannus strains Si121 and BUN3, these intriguing molecules include in their C 30 molecular framework seven rings and thirteen stereogenic centers, three of which are quaternary. Their structures have been assigned on the basis of mass spectrometric and NMR spectroscopic data and chemical transformations. [1,2] Herein we report the total synthesis of structure 1 b that proved that it does not represent the true structure of vannusal B.Our retrosynthetic analysis of the vannusal molecule dissected it as shown in Figure 2, revealing vinyl iodide 2 and aldehyde 3 as the key building blocks required for the projected total synthesis. The devised strategy anticipated their fusion through two carbon-carbon bond-forming reactions, namely lithiation of 2 followed by addition of 3 to join them, and a samarium-induced ring closure of a subsequent intermediate to forge the final ring of the target molecule.Scheme 1 summarizes the construction of vinyl iodide 2 from the commercially available meso diol 4. Thus, dehydration of 4 through the action of POCl 3 (py, 90 8C) furnished conjugated diene 5 (97 % yield), [3] which was regio-and stereoselectively converted into the new meso diol 6 by a hydroboration-oxidation process (CyBH 2 ; H 2 O 2 , NaOH, 51 % yield). The latter compound was then desymmetrized through the enantioselective hydrolytic action of Lipase Amano PS [4] on its bis-acetate (prepared in quantitative yield by reaction of 6 with Ac 2 O in the presence of 4-DMAP), leading to the monoacetate 7 in 100 % yield and 99 % ee (determined by Mosher ester analysis). Silylation of 7 (TBDPSCl, imid, 93 % yield) followed by acetate cleavage (DIBAL-H, 98 % yield) and treatment of the resulting alcohol with Martins sulfurane (Et 3 N, CH 2 Cl 2 , 91 % yield) afforded enantiomerically pure cyclopentene derivative 8. The planned stereoselective epoxidation of 8 was achieved through a two-step procedure that involved first iodohydrin formation (NIS, H 2 O), and then ring closure (K 2 CO 3 , MeOH) to give b-epoxide 9 in 91 % overall yield. This epoxide was then regio-and stereoselectively opened with 2-lithiopropene (generated from the corresponding bromide and tBuLi) in the presence of BF 3 ·Et 2 O to afford hydroxy compound 10 (83 % yield), whose stereochemistry was inverted through application of a Mitsunobu (pNO 2 C 6 H 4 CO 2 H, Ph 3 P, DEAD) [5] /ester cleavage (DIBAL-H) protocol, leading to the desired hydroxy compound 11 in 90 % overall yield. With the proper stereochemistry now installed on 11, a BOM group was placed on the free hydroxy group (BOMCl, iPr 2 NEt) and the TBDPS group was removed (TBAF, 97 % overall yield) to furnish compound 12. The newly generated hydroxy group within 12 was then oxidized [NMO, TPAP (cat.), 96 % yield], and the resulting ketone was converted into its tris-hydrazone 13 (TrisNHNH 2 , 80 % yield). Finally, the targeted...