1.Enantioselective carbolithiation of S-alkenyl-N-aryl thiocarbamates: kinetic and thermodynamic control.
Castagnolo D1, Degennaro L, Luisi R, Clayden J. Org Biomol Chem. 2015 Feb 28;13(8):2330-40. doi: 10.1039/c4ob02329c.
The addition of n-butyllithium to alkenylthiocarbamates in the presence of (-)-sparteine or the (+)-sparteine surrogate leads to asymmetric carbolithiation, and returns enantiomerically enriched thiocarbamate derivatives of secondary thiols. In THF, with the (+)-sparteine surrogate, in situ aryl migration leads to an enantiomerically enriched tertiary thiol derivative. Remarkably, the two pseudoenantiomeric chiral ligands do not always give enantiomeric products, probably as a result of a complex interplay of kinetic and thermodynamic control. In situ IR and NMR studies of a stable, hindered lithiated thiocarbamate demonstrated its chemical and configurational stability over a period of hours at 0 °C.
2.Alkaloid variation in New Zealand kōwhai, Sophora species.
McDougal OM1, Heenan PB2, Jaksons P3, Sansom CE4, Smallfield BM3, Perry NB4, van Klink JW5. Phytochemistry. 2015 Oct;118:9-16. doi: 10.1016/j.phytochem.2015.07.019. Epub 2015 Aug 6.
Alkaloid contents of leaf and seed samples of eight species of Sophora native to New Zealand, plus Sophora cassioides from Chile are reported. Fifty-six leaf and forty-two seed samples were analysed for alkaloid content by proton nuclear magnetic resonance spectroscopy, which showed major alkaloids as cytisine, N-methyl cytisine and matrine. GC analyses quantified these and identified further alkaloid components. The alkaloids identified were cytisine, sparteine, and matrine-types common to Sophora from other regions of the world. Cytisine, N-methyl cytisine, and matrine were generally the most abundant alkaloids across all species with seeds containing the highest concentrations of alkaloids. However, there was no clear taxonomic grouping based on alkaloid composition. A quantitative analysis of various parts of two Sophora microphylla trees showed that the seeds were the richest source of alkaloids (total 0.4-0.5% DM), followed by leaf and twig (0.
3.The First Modular Route to Core-Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)-Catalyzed Henry Reactions.
Scharnagel D1, Müller A2, Prause F1, Eck M3, Goller J1, Milius W4, Breuning M5. Chemistry. 2015 Aug 24;21(35):12488-500. doi: 10.1002/chem.201502090. Epub 2015 Jul 31.
The first modular and flexible synthesis of core-chiral bispidines was achieved by using an "inside-out" strategy. The key intermediate, a NBoc-activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified β-amino acid and 2-(acetoxymethyl)acrylonitrile in just five steps and good 48% yield. A simple addition-reduction protocol permitted a highly endo-selective introduction of substituents and, thus, a fast and variable access to 2-endo-substituted and 2-endo,N-fused bi- and tricyclic bispidines. The new diamines were evaluated as the chiral ligands in asymmetric Henry reactions. Excellent enantioselectivities of up to 99% ee and good diastereomeric ratios of up to 86:14 were reached with a copper(II) complex modified by a 2-endo,N-(3,3-dimethylpyrrolidine)-annelated bispidine. Its performance is superior to that of the well-known bispidines (-)-sparteine and the (+)-sparteine surrogate.
4.Toward ideality: the synthesis of (+)-kalkitoxin and (+)-hydroxyphthioceranic acid by assembly-line synthesis.
Balieu S1, Hallett GE1, Burns M1, Bootwicha T1, Studley J2, Aggarwal VK1. J Am Chem Soc. 2015 Apr 8;137(13):4398-403. doi: 10.1021/ja512875g. Epub 2015 Jan 27.
The iterative homologation of boronic esters using chiral lithiated benzoate esters and chloromethyllithium has been applied to the highly efficient syntheses of two natural products, (+)-kalkitoxin and (+)-hydroxyphthioceranic acid. The chiral lithiated benzoate esters (>99% ee) were generated from the corresponding stannanes, which themselves were prepared by Hoppe-Beak deprotonation of ethyl 2,4,6-triisopropyl-benzoate with s-BuLi in the presence of (+)- or (-)-sparteine and trapping with Me3SnCl followed by recrystallization. In addition, it was found that purification between several homologations could be avoided, substantially increasing both chemical and manpower efficiency. In the case of (+)-kalkitoxin, six iterative homologations were conducted on commercially available p-MeOC6H4CH2Bpin to build up the core of the molecule before the C-B bond was converted into the desired C-N bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative homologations were conducted on p-MeOC6H4Bpin with only four intermediate purifications before oxidation of the C-B bond to the desired alcohol.
