James L. Leighton

A More Comprehensive and Highly Practical Solution to Enantioselective Aldehyde Crotylation

The enantioselective crotylation of aldehydes with 1,2-diaminochlorocrotylsilane reagents is effectively catalyzed by Sc(OTf)(3). The one significant limitation on the utility of these reagents--substrate scope--has thus been addressed. The net result is the most comprehensive and highly practical method for enantioselective aldehyde crotylation yet advanced.

Toward More “Ideal” Polyketide Natural Product Synthesis: A Step-Economical Synthesis of Zincophorin Methyl Ester

A highly efficient and step-economical synthesis of zincophorin methyl ester has been achieved. The unprecedented step economy of this zincophorin synthesis is principally due to an application of the tandem silylformylation-crotylsilylation/Tamao oxidation-diastereoselective tautomerization reaction, which achieves in a single step what would typically require a significant multistep sequence.

An Efficient Asymmetric Synthesis of Manzacidin C

A brief synthesis of manzacidin C based on a chiral silane-promoted diastereo- and enatioselective acylhydrazone-alkene [3 + 2] cycloaddition reaction has been achieved. This synthesis is the first synthesis of any of the manzacidins wherein the C(4) and C(6) stereocenters are established in a single highly stereoselective step.

Effects of MS-153 on chronic ethanol consumption and GLT1 modulation of glutamate levels in male alcohol-preferring rats.

We have recently shown that upregulation of glutamate transporter 1 (GLT1) in the brain is associated in part with reduction in ethanol intake in alcohol-preferring (P) male rats. In this study, we investigated the effects of a synthetic compound, (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), known to activate GLT1 on ethanol consumption as well as GLT1 expression and certain signaling pathways in P rats. P rats were given 24-h concurrent access to 15 and 30% ethanol, water and food for 5 weeks. On week 6, P rats received MS-153 at a dose of 50 mg/kg (i.p.) or a vehicle (i.p.) for 5 consecutive days. We also tested the effect of MS-153 on daily sucrose (10%) intake. Our studies revealed a significant decrease in ethanol intake at the dose of 50 mg/kg MS-153 from Day 1 through 14. In addition, MS-153 at dose of 50 mg/kg did not induce any significant effect on sucrose intake. Importantly, we found that MS-153 upregulated the GLT1 level in the nucleus accumbens (NAc) but not in the prefrontal cortex (PFC). In accordance, we found upregulation of nuclear NFkB-65 level in NAc in MS-153-treated group, however, IkBα was downregulated in MS-153-treated group in NAc. We did not find any changes in NFkB-65 and IkBα levels in PFC. Interestingly, we revealed that p-Akt was downregulated in ethanol vehicle treated groups in the NAc; this downregulation was reversed by MS-153 treatment. We did not observe any significant differences in glutamate aspartate transporter (GLAST) expression among all groups. These findings reveal MS-153 as a GLT1 modulator that may have potential as a therapeutic drug for the treatment of alcohol dependence.

Tandem asymmetric Aza-Darzens/ring-opening reactions: dual functionality from the silane lewis acid.

The addition of a stabilized sulfur ylide (generated by the rhodium-catalyzed reaction of Ph(2)S with ethyl diazoacetate) to N-acylhydrazones promoted by a chiral silane Lewis acid leads to the highly diastereo- and enantioselective synthesis of beta-chloro-alpha-hydrazido esters. The addition of electron-rich arenes and ZnCl(2) to the reaction mixture leads to the highly diastereo- and enantioselective one-pot synthesis of diarylalanine derivatives. In both cases, the silane Lewis acid responsible for the first reaction performs the second function of activating the aziridine intermediate toward nucleophilic attack.

Enantioselective (Formal) Aza-Diels-Alder Reactions with Non-Danishefsky-Type Dienes

Enantioselective (formal) aza-Diels-Alder reactions between acylhydrazones and non-Danishefsky-type dienes have been developed. The reactions are promoted by a simple and economical chiral silicon Lewis acid and are typically conducted at ambient temperature. Both glyoxylate- and aliphatic aldehyde-derived hydrazones may be employed, as may variously substituted dienes, leading to the synthesis of a diverse array of tetrahydropyridines with good to excellent levels of enantioselectivity.

A New Silicon Lewis Acid for Highly Enantioselective Mannich Reactions of Aliphatic Ketone-Derived Hydrazones

The first general method for the highly enantioselective Mannich reaction of aliphatic ketimines is reported. A new, second generation chiral silane Lewis acid has been developed that promotes the reaction between ketone-derived hydrazones and silyl ketene acetals, providing the beta,beta-disubstituted beta-amino esters with good enantioselectivity even for the hydrazone derived from 2-butanone (methyl vs ethyl, 91% ee). Several examples are provided, including a reaction with a substituted (propanoate-derived) silyl ketene acetal.

A Highly Step-Economical Synthesis of Dictyostatin†

In 1994 Petit reported the isolation and anti-cancer activity of the marine sponge-derived macrolide dictyostatin.[1] Wright subsequently isolated a sample that allowed initial biological characterization of dictyostatin as a potent inducer of tubulin polymerization,[2] and that was used by Wright and Paterson to make a full structural assignment in 2004.[3] This assignment was confirmed soon thereafter by total syntheses by Paterson[4] and Curran,[5] and the material thus obtained facilitated more detailed characterization of dictyostatin’s mechanism of action.[6,7] Total syntheses by Phillips[8] and Ramachandran,[9] formal syntheses by Micalizio[10] and Cossy,[11] a synthesis of C(9)-epi-dictyostatin by Gennari,[12] second generation syntheses by Paterson[13] and Curran,[14] and several fragment syntheses[15] followed these initial reports. In addition, the Paterson/Wright[16] and Curran/Day[17] teams have reported extensive SAR studies, while the Paterson/Diaz/Jimenez-Barbero[18] and Curran/Snyder[19] teams have advanced models for the interaction of dictyostatin with the taxane binding site on β-tubulin. Because dictyostatin and some of the prepared analogs are among the most potent microtubule-stabilizing agents characterized to date, there has been and continues to be intense interest in the possibility of advancing dictyostatin or an analog thereof into the clinic, a goal which might be facilitated by the development of a significantly more efficient and step-economical synthesis. As part of a larger program devoted to the development of new strategies and methods for the synthesis of complex and precious marine macrolides with high levels of step-economy, efficiency, and scalability,[20] we have developed and report herein a synthesis of dictyostatin that comprises just 14 steps in the longest linear sequence.

Direct and Highly Enantioselective Iso-Pictet–Spengler Reactions with α-Ketoamides: Access to Underexplored Indole Core Structures

Direct, one-pot, operationally simple, and highly enantioselective iso-Pictet-Spengler reactions are reported. The reactions involve the condensation of either (1H-indol-4-yl)methanamine or 2-(1H-Indol-1-yl)ethanamine with a variety of α-ketoamides, followed by the addition of a simple and commercially available chiral silicon Lewis acid. These reactions are the first asymmetric examples of these cyclization modes and provide access to 3,3-disubstituted-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolines and 1,1-disubstituted-1,2,3,4-tetrahydropyrazino[1,2-a]indoles, respectively, two relatively underexplored indole-based core structure motifs in medicinal chemistry.

Tandem Intramolecular Alkyne Silylformylation–Allylsilylation: A Case of Remote 1,5‐Asymmetric Induction

Two new C-C bonds as well as a remote stereocenter are formed in the title reaction. With remarkable efficiency, this new reaction provides, through remote 1,5-asymmetric induction, anti-1,5 diols that are useful synthons for polyol synthesis (see scheme; Hacac=acetylacetone).