Karlotoxin synthetic studies: concise synthesis of a C(42-63) B-ring tetrahydropyran fragment.

Starting from natural D-mannose, a C(42-63) B-ring tetrahydropyran fragment in karlotoxin 2 has been prepared via a common THP intermediate in a concise manner. E-selective Julia-Kocienski olefination efficiently assembled a C(51-63) chlorodiene subunit and a C(42-50) tetrahydropyran segment.

n-BuLi/LiCH2CN-mediated one-carbon homologation of aryl epoxides into conjugated allyl alcohols.

A series of styrene oxides in the presence of a 1:1 mixture of n-butyllithium (n-BuLi) and lithioacetonitrile (LiCH2CN) in THF are converted into one-carbon homologated allyl alcohols in an unusual regioselective manner.

One-pot synthesis of 2-aminoquinoline-based alkaloids from acetonitrile.

α-Diaminoboryl carbanions, readily prepared from acetonitrile, stereoselectively convert 2-nitrobenzaldehydes into nitrophenyl (Z)-acrylonitriles. Subsequent reductive cyclization leads to a series of 2-aminoquinoline derivatives. The entire procedure is practically operated in a single flask.

An α-diaminoboryl carbanion assisted stereoselective single-pot preparation of α,ß-disubstituted acrylonitriles.

An α-diaminoboryl carbanion-mediated one-pot olefination directly converts an acetonitrile or the homologous nitrile into a series of α,ß-disubstituted acrylonitriles in a stereoselective manner. The protocol involves the formation of an α-substituted α-diaminoboryl acetonitrile and subsequent olefination with an aldehyde. The use of an aryl or conjugated aldehyde preferentially leads to a (Z)-acrylonitrile, while an aliphatic aldehyde gave an (E)-isomer as a major product. Two complementary approaches, a linear method and a divergent method, are developed.

DIBAL-mediated reductive transformation of trans-dimethyl tartrate acetonide into ε-hydroxy α,ß-unsaturated ester and its derivatives.

Stepwise, selective DIBAL reduction of the acetonide diester derived from tartaric acid followed by the Horner-Emmons reaction effectively provided desymmetrized hydroxy mono-olefination products in a one-pot operation.

A facile, one-pot synthesis of beta-substituted (Z)-acrylonitriles utilizing an alpha-diaminoboryl carbanion.

A simple three-step single-pot procedure for Z-stereoselective synthesis of beta-monosubstituted acrylonitriles has been established. The reaction involves olefination of aldehydes with an in situ generated alpha-diaminoboryl carbanion species. Various aromatic and aliphatic aldehydes were smoothly converted into the corresponding (Z)-olefin products (up to 96:4 ratio) in good yields (80-98%).

Spongipyran Synthetic Studies. Evolution of a Scalable Total Synthesis of (+)-Spongistatin 1.

Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)-C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)-C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third- generation syntheses, designed with the goal of accessing one gram of (+)-spongistatin 1 (1), maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis-Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mgs of the EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.

Gram-scale synthesis of (+)-spongistatin 1: development of an improved, scalable synthesis of the F-ring subunit, fragment union, and final elaboration.

In a quest to develop an effective, scalable synthesis of (+)-spongistatin 1 ( 1), we devised a concise, third-generation scalable synthesis of (+)- 7, the requisite F-ring tetrahydropyran aldehyde, employing a proline-catalyzed cross-aldol reaction. Subsequent elaboration to (+)-EF Wittig salt (+)- 3, followed by union with advanced ABCD aldehyde (-)- 4, macrolactonization and global deprotection permitted access to >1.0 g of totally synthetic (+)-spongistatin 1 ( 1).

Physicochemical properties of highly conductive urea-EtMeImCl melts.

Urea-EtMeImCl mixtures have melting points from 333 to 363 K at 10-80 mol% urea, and, at temperatures >343 K, these melts show the highest conductivity reported to date for urea-based binary melts.