A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides. Furthermore, inline IR monitoring was used for the analysis of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details. The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the Grignard exchange reaction due to fast mixing and efficient heat transfer.

Shortly after the discovery of the proteasome it was proposed that inhibitors could stabilize proteins which ultimately would trigger apoptosis in tumor cells. The essential questions were whether small molecules would be able to inhibit the proteasome without generating prohibitive side effects and how one would derive these compounds. Fortunately, "Mother Nature" has generated a wide variety of natural products that provide distinct selectivities and specificities. The chemical synthesis of these natural products finally provided access to analogues and optimized drugs of which two different classes have been approved for the treatment of malignancies. Despite these achievements, additional lead structures derived from nature are under investigation and will be discussed with regard to their biological potential and chemical challenges.

The palladium-catalyzed asymmetric allylic alkylation (AAA) has proven to be a versatile method for the preparation of synthetically useful materials.[1] Vinyl epoxides have shown a broad utility in related dynamic kinetic asymmetric transformations (DYKATs), wherein a racemic starting material is converted into an enantioenriched product.[2] Only recently has the cycloaddition of vinyl aziridines with isocyanates to afford chiral imidazolidinones been reported.[3] Although this methodology provides the valuable chiral vicinal diamine moiety [4] in high ee, its synthetic utility has been limited owing to the difficult differentiation of the resulting amines. In recent studies with imide nucleophiles, we discovered an atom-economical [5] DYKAT for the efficient preparation of useful orthogonally protected chiral vicinal diamines through use of imido carboxylates that undergo a facile in situ acyl migration. Application of the AAA enabled the formal synthesis of the potent PKC inhibitor balanol and its cis diastereomer.By analogy to the DYKAT reactions with vinyl epoxides, [6] we first examined the asymmetric addition of phthalimide to the parent vinyl aziridine 1 with the use of diphosphine ligand 3 [Eq. (1)]. The addition of catalytic acetic acid, which was beneficial in the previous cycloadditions with isocyanates, [3] gave an increase in ee (47 to 82 % ee) with a concomitant drop in yield (99 to 55 %). The use of catalytic triethylamine instead provided a balance in improving the ee while affording a practical yield. A reasonable rationalization for the high enantioselectivity is the Curtin-Hammett kinetic amination of one diastereomeric h 3 -allyl Pd II complex from a pair which rapidly interconvert through a p-s-p mechanism. Regioselectivity can be rationalized by an analogous hydrogen-bonding interaction between the H À N group of the imide nucleophile and the amine of the h 3 -allyl Pd II intermediate, as well as the directing effect of the ligand.[1]When benzoyl imido carboxylates were examined as nucleophiles, a facile in situ acyl migration occurred, furnishing the protected N 1 -benzoyl-N 2 -tert-butoxycarbonyl vicinal diamine 7 in high enantioselectivity and yield [Eq. (2)]. The isomeric Boc acyl migration product was not observed, demonstrating the high selectivity for migration of the more electrophilic benzoyl group. Contrary to previous palladiumcatalyzed DYKATs with vinyl aziridines, [3] the enantioselectivity was high without the use of an additive.This dynamic kinetic asymmetric allylic amination and acyl migration proved general for a variety of benzoyl imido carboxylates to afford Boc-, Cbz-, ethoxycarbonyl-, and Trocprotected products (Table 1). Under current conditions, the reaction with acyl imido carboxylates affords only low yields. A similar highly enantioselective DYKAT and acyl migration was obtained with butadiene monoepoxide (Scheme 1). Saponification of ester 17 provided the known amino alcohol 18 [7] and established the absolute stereochemistry of the reaction. The products from ...

The first synthesis of the highly biologically active chivosazole F is described. It features an intramolecular Stille coupling for the macrolactone formation and thereby circumvents the problem of isomerization associated with the tetraene segment. Additionally, the synthesis confirms the structure which has been proposed based solely on a combination of NMR/computational methods and genetic analysis.