Daring the Challenge and Thinking Big: The Value of Early Process R&D.

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding (<0.5% yield) and comprise many steps that are not acceptable for scale-up, a series of processes to 1 was developed to match the increasing requirements from first kg-batches to clinical supplies. The three routes are characterized by an individual asset. (1) The first route contains a scale-up of a Diels-Alder reaction with highly reactive reagents and afforded 90 kg enantiomerically pure 1. To mitigate safety risks, a flow reactor was developed for the high-temperature Diels-Alder reaction. This route relied on an efficient enantiomer separation on a »-ton scale by HPLC. (2) A Crystallization Induced Diastereomer Transformation (CIDT) during an intramolecular aldol reaction was the pivotal step of a first enantioselective route that starts with the Shibasaki reaction. (3) The 2(nd) enantioselective route represents a rare example of organocatalysis on scale and allowed to skip six out of nine steps with a significant impact on the cost of goods. This simple way to 1 opened up a short synthesis of Hayashi's chiral diene ligands (bod*) that were so far lacking an affordable access. Some of these novel C1-symmetrical dienes have shown very high enantioselectivities in Rh-catalyzed additions of arylboronates.

Scalable synthesis of enantiomerically pure bicyclo[2.2.2]octadiene ligands.

An operationally simple and scalable synthesis of enantiomerically pure bicyclo[2.2.2]octadiene (bod*) ligands relying on an organocatalytic one-pot Michael addition-aldol reaction with cheap 2-cyclohexenone and phenylacetaldehyde is presented. The crystalline bicyclic product 4a (6-hydroxy-5-phenylbicyclo[2.2.2]octan-2-one) is transformed into phenylbicyclo[2.2.2]oct-5-en-2-one 2, a versatile starting material for the 2-step synthesis of both symmetrical, such as Hayashi's Ph-bod* ligand, as well as novel unsymmetrical chiral dienes.

The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments.

Due to a combination of their promising anticancer properties, limited supply from the marine sponge source and their unprecedented molecular architecture, spirastrellolides represent attractive and challenging synthetic targets. A modular strategy for the synthesis of spirastrellolide A methyl ester, which allowed for the initial stereochemical uncertainties in the assigned structure was adopted, based on the envisaged sequential coupling of a series of suitably functionalised fragments; in this first paper, full details of the synthesis of these fragments are described. The pivotal C26-C40 DEF bis-spiroacetal was assembled by a double Sharpless asymmetric dihydroxylation/acetalisation cascade process on a linear diene intermediate, configuring the C31 and C35 acetal centres under suitably mild acidic conditions. A C1-C16 alkyne fragment was constructed by application of an oxy-Michael reaction to introduce the A-ring tetrahydropyran, a Sakurai allylation to install the C9 hydroxyl, and a 1,4-syn boron aldol/directed reduction sequence to establish the C11 and C13 stereocentres. Two different coupling strategies were investigated to elaborate the C26-C40 DEF fragment, involving either a C17-C25 sulfone or a C17-C24 vinyl iodide, each of which was prepared using an Evans glycolate aldol reaction. The remaining C43-C47 vinyl stannane fragment required for introduction of the unsaturated side chain was prepared from (R)-malic acid.

An Improved Impact Ratio for Identifying Critical Process Parameters in Pharmaceutical Manufacturing Processes.

The identification of critical process parameters in biologics and small molecule process development is a key element of quality by design. The objectivity and consistency of procedures to identify critical process parameters can be improved with the use of impact ratios. Impact ratios quantify a process parameter's practical effect on a critical quality attribute relative to the critical quality attribute's acceptance limits. If the impact ratio is large, i.e., exceeds a predefined impact ratio threshold, the recommendation is to classify the process parameter as a critical process parameter. This article introduces an improved and mathematically well-defined impact ratio. Benefits of this impact ratio are a consistent interpretation for many scenarios commonly encountered in practice, high suitability to automation, and the possibility of standardizing on a single impact ratio definition for pharmaceutical manufacturing.

Synthesis of two diastereomeric C1-C22 fragments of spirastrellolide A.

The optimisation of a synthetic strategy towards the ABC segment of the cytotoxic macrolide spirastrellolide A is reported, together with its application to the synthesis of two diastereomeric C(1)-C(22) fragments for stereochemical correlation purposes with a putative spirastrellolide degradation product.

Synthesis of the DEF-bis-spiroacetal of spirastrellolide A exploiting a double asymmetric dihydroxylation/spiroacetalisation strategy.

An efficient synthesis of the C(26)-C(40) tricyclic [5,6,6]-bis-spiroacetal segment of the marine macrolide spirastrellolide A has been developed, exploiting a novel double Sharpless asymmetric dihydroxylation/spiroacetalisation sequence.

Cu(OAc)2-catalyzed N-arylations of sulfoximines with aryl boronic acids.

[reaction: see text] A simple and mild copper salt-catalyzed N-arylation of sulfoximines in high yields is reported. Cu(OAc)(2) activates aryl boronic acids for the reaction with NH-sulfoximines without additional base or heating. Furthermore, this new method allows the preparation of N-arylated sulfoximines, which have previously been more difficult to access.

Copper-mediated cross-coupling reactions of N-unsubstituted sulfoximines and aryl halides.

[reaction: see text] Copper-mediated cross-coupling reactions of sulfoximines with aryl iodides and aryl bromides provide N-arylated sulfoximines in high yields. The method is complementary to the known palladium-catalyzed N-arylation and allows the preparation of N-arylated sulfoximines, which have previously been inaccessible.