Carbonylative N-Heterocyclization via Nitrogen-Directed C-C Bond Activation of Nonactivated Cyclopropanes.

Under Rh-catalyzed conditions, secondary amines and anilines function as directing groups to facilitate regioselective C-C bond activation of nonactivated cyclopropanes. The resulting amino-stabilized rhodacycles undergo carbonylative C-N bond formation en route to challenging seven- and eight-membered lactams. The processes represent rare examples where C-C bond oxidative addition of nonactivated cyclopropanes is exploited in reaction design.

Thermodynamic and Structural Behavior of α-Galactosylceramide and C6-Functionalized α-GalCer in 2D Layers at the Air-Liquid Interface.

α-Galactosylceramide (α-GalCer; KRN7000) is a ligand for the glycoprotein CD1d that presents lipid antigens to natural killer T cells. Therefore, KRN7000 as well as some modified versions thereof have been widely investigated as part of novel immunotherapies. To examine the impact of structural modification, we investigated KRN7000 and C6-modified KRN7000 at the air-liquid interface using monolayer isotherms, BAM, IRRAS, GIXD, and TRXF. The amino group has no influence on the highly ordered sub-gel structures found at lateral pressures relevant for biological membranes. Neither lateral compression nor the protonation state of the amino group has a measurable effect on the lattice structure, which is defined by strong and rigid intermolecular hydrogen bonds. However, the first-order phase transition found for the C6-functionalized α-GalCer is connected with an extraordinary surface-inhibited nucleation. Our study demonstrates that KRN7000 can be functionalized at C6 without significantly changing the structural properties.

Modular Access to Eight-Membered N-Heterocycles by Directed Carbonylative C-C Bond Activation of Aminocyclopropanes.

Aminocyclopropanes equipped with pendant nucleophiles undergo carbonylative heterocyclization triggered by C-C bond activation to generate eight-membered N-heterocycles. In these processes, intramolecular "capture" of a rhodacyclopentanone intermediate by an aryl or N-based nucleophile is followed by C-C or C-N bond-forming "collapse" to the targets. These studies demonstrate how the combination of cyclopropane strain release and the templating effect of catalytically generated metallacycles can be harnessed to enable otherwise challenging medium ring closures.

Improving vaccines against Streptococcus pneumoniae using synthetic glycans.

Streptococcus pneumoniae remains a deadly disease in small children and the elderly even though conjugate and polysaccharide vaccines based on isolated capsular polysaccharides (CPS) are successful. The most common serotypes that cause infection are used in vaccines around the world, but differences in geographic and demographic serotype distribution compromises protection by leading vaccines. The medicinal chemistry approach to glycoconjugate vaccine development has helped to improve the stability and immunogenicity of synthetic vaccine candidates for several serotypes leading to the induction of higher levels of specific protective antibodies. Here, we show that marketed CPS-based glycoconjugate vaccines can be improved by adding synthetic glycoconjugates representing serotypes that are not covered by existing vaccines. Combination (coformulation) of synthetic glycoconjugates with the licensed vaccines Prevnar13 (13-valent) and Synflorix (10-valent) yields improved 15- and 13-valent conjugate vaccines, respectively, in rabbits. A pentavalent semisynthetic glycoconjugate vaccine containing five serotype antigens (sPCV5) elicits antibodies with strong in vitro opsonophagocytic activity. This study illustrates that synthetic oligosaccharides can be used in coformulation with both isolated polysaccharide glycoconjugates to expand protection from existing vaccines and each other to produce precisely defined multivalent conjugated vaccines.

A Semi-synthetic Oligosaccharide Conjugate Vaccine Candidate Confers Protection against Streptococcus pneumoniae Serotype 3 Infection.

The identification of immunogenic glycotopes that render glycoconjugate vaccines protective is key to improving vaccine efficacy. Synthetic oligosaccharides are an attractive alternative to the heterogeneous preparations of purified polysaccharides that most marketed glycoconjugate vaccines are based on. To investigate the potency of semi-synthetic glycoconjugates, we chose the least-efficient serotype in the current pneumococcal conjugate vaccine Prevnar 13, Streptococcus pneumoniae serotype 3 (ST3). Glycan arrays containing synthetic ST3 repeating unit oligosaccharides were used to screen a human reference serum for antibodies and to define the recognition site of two ST3-specific protective monoclonal antibodies. The glycan array screens identified a tetrasaccharide that was selected for in-depth immunological evaluation. The tetrasaccharide-CRM197 carrier protein conjugate elicited protective immunity as evidenced by opsonophagocytosis assays and protection against pneumonia caused by ST3 in mice. Formulation of the defined protective lead candidate glycotope has to be further evaluated to elicit optimal long-term immunity.

One-pot catalytic asymmetric borylation of unsaturated aldehyde-derived imines; functionalisation to homoallylic boronate carboxylate ester derivatives.

The ß-borylation reaction of α,ß-unsaturated aldehyde-derived imines, formed in situ, has been studied using a one-pot methodology, as a route to ß-boryl aldehydes. The instability of the ß-boryl aldehydes meant that derivatisation was required and routes to both acetal derivatives and homoallylic boronates were examined. ß-Boryl acetals were also found to be unstable, however, the formation of homoallylic boronate derivatives using an in situ imine hydrolysis-Wittig olefination protocol was found to be suitable, resulting in an efficient synthesis with high enantiomeric excesses.

Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach.

We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,ß-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated ß-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee).

Understanding α,ß-unsaturated imine formation from amine additions to α,ß-unsaturated aldehydes and ketones: an analytical and theoretical investigation.

A combination of in situ IR spectroscopy (ReactIR) and DFT calculations have been used to understand what factors govern the selectivity in the addition of primary amines to α,ß-unsaturated aldehydes and ketones, i.e., 1,2- versus 1,4-addition. It has been found that the 1,2-addition products (α,ß-unsaturated imines following addition and elimination) usually predominate for most systems. However, exceptions, such as methyl vinyl ketone, selectively give 1,4-addition products. This has been rationalized by DFT calculations that show that major conformational effects are involved, controlled mainly by steric effects of carbonyl substituents, resulting in a model that provides simple and predictable preparation of α,ß-unsaturated imines for in situ utilization in synthesis.

A selective transformation of enals into chiral γ-amino alcohols.

A one-pot synthesis of chiral amino alcohols from α,ß-unsaturated aldehydes is reported which circumvents competitive 1,2- versus 1,4-boryl addition, by means of using a sterically hindered amine-derived imine. In addition to the complete chemoselectivity, modification of the Cu(I) catalyst with readily available chiral diphosphines, such as (R)-DM-BINAP, gave the 1,4-boryl addition products with high levels of asymmetric induction.

Novel transformation of α,ß-unsaturated aldehydes and ketones into γ-amino alcohols or 1,3-oxazines via a 4 or 5 step, one-pot sequence.

An efficient, 4-step, one-pot, highly stereoselective route to γ-amino alcohols has been developed via an in situ α,ß-unsaturated imine formation, ß-boration, reduction (C=N) and oxidation (C-B) sequence and especially for certain water-soluble γ-amino alcohols, a further step can be added to directly access the corresponding 1,3-oxazine derivatives.

Catalytic methodologies for the ß-boration of conjugated electron deficient alkenes.

The area of boron conjugate addition via diboration (ß-boration) has grown rapidly since the first examples appeared in the late 1990s. This article aims to give a comprehensive review of the current advances in ß-boration (of electron deficient alkenes), providing a commentary upon the development of the asymmetric version. To date, many mechanistic models have been put forward to explain the experimental observations and this review surveys some of these key ideas. Recently, the development of organocatalytic methodologies that facilitate ß-boration have also been demonstrated and current ideas regarding the mechanisms of such processes are examined.