John G. Cumming

The total synthesis of swinholide A. Part 3: A stereocontrolled synthesis of (−)-pre-swinholide A.

Two coupling strategies for (−)-pre-swinholide A were devised based on the analysis in Scheme 1. In the first route, a boron-mediated aldol reaction between the ethyl ketone 19 and the aldehyde 3 was used to construct the C15-C16 bond with moderate diastereoselectivity. In the second route, a Mukaiyama aldol reaction between the methyl ketone 54 and the aldehyde 4 introduced the C18-C19 bond with complete stereocontrol.

Studies in marine macrolide synthesis: Boron and silicon-mediated coupling strategies for Swinholide A

Abstract Reaction of aldehyde 6 with enol borinates 7 gives adduct 10 preferentially, whereas the allylsilane 18 provides the epimeric adduct 11 with 95% ds. Aldehyde 2 reacts mainly by si -face attack with simple Z enol borinates, which can be overturned by reagent control from (+)- 25 .

Automated QSAR with a Hierarchy of Global and Local Models.

We present an automated QSAR procedure that is used in AstraZeneca’s AutoQSAR system. The approach involves automatically selecting the most predictive models from pools of both global and local models. The effectiveness of this QSAR modelling strategy is demonstrated with a retrospective study that uses a diverse selection of 9 early stage AstraZeneca drug discovery projects and 3 physicochemical endpoints: LogD; solubility and human plasma protein binding. We show that the strategy makes a statistically significant improvement to the accuracy of predictions when compared to an updating global strategy, and that the systematic biases inherent in the global model predictions are almost completely removed. This improvement is attributed to the model selection aspect of the strategy.

Dynamically resolved peri-substituted 2-formyl naphthamides: a new class of atropisomeric chiral auxiliary

Formyl-N,N-dialkylnaphthamides are chiral, atropisomeric compounds, provided they are substituted peri to the amide group. They may be obtained as single enantiomers by dynamic resolution on formation of diastereoisomeric aminal derivatives and used as chiral auxiliaries in a new addition/rearrangement strategy. Nucleophilic attack by vinyl anion equivalents in the presence of Lewis acids leads atroposelectively to single diastereoisomers of allylic alcohols, whose derivatives undergo stereospecific (3,3)-sigmatropic rearrangements. Reductive ozonolysis of the rearrangement product returns an enantiomerically pure functionalised alcohol and in principle allows recovery of the atropisomeric auxiliary.

A stereocontrolled synthesis of a C19-C32 / C17-C30 Segment for swinholide A and misakinolide A, Cytotoxic dimeric macrolides from theonella swinhoei.

The C19-C32/C17-C30 segment (-)-5 of swinholide A / misakinolide A was prepared in 15 steps (6% yield) from (±)-13. Key steps include the Sharpless epoxidation, 13 → 14, the acetal allylation, 12 → 16, the anti aldol, 17 + 11 → 9, and the alkene hydroboration, 19 → 20.

Towards the synthesis of swinholide A and scytophycin C. A highly stereocontrolled synthesis of (−)-pre-swinholide A

Abstract The fully protected monomeric unit 19 of the marine macrodiolide, swinholide A ( 1 ), was obtained with > 97% ds by a Mukaiyama aldol reaction between 16 and 5 , followed by a boron-mediated reduction to give the syn 1,3-diol 18 . Deprotection gave (−)-pre-swinholide A ( 2 ), the putative biosynthetic precursor of 1 .

Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis

Modifications to a series of potent and selective substituted 1-(3,3-diphenylpropyl)-piperidine phenylacetamide CCR5 antagonists were explored with the aim of reducing affinity at the hERG cardiac ion channel. Replacement of one aromatic ring in the diphenylpropyl region with less lipophilic, saturated heterocyclic rings and subsequent optimisation of the other phenyl ring led to the identification of clinical compound AZD5672 which retained excellent potency while reducing hERG affinity. Modulating lipophilicity affected the interplay between potency, hERG affinity and absorption. AZD5672 was found to have an acceptable balance of these properties and was progressed to a phase II clinical trial to test the hypothesis that inhibition of CCR5 will bring benefits in the treatment of rheumatoid arthritis.

(S)-2-(Dibenzylamino)-3-phenylpropanal as a chiral auxiliary: a new strategy for the asymmetric synthesis of 2-substituted alcohols

Abstract The high levels of 1,2-stereocontrol observed in nucleophilic additions to ( S )-2-(dibenzylamino)-3-phenylpropanal (available in three high-yielding steps from l -phenylalanine) can be converted to remote 1,4-stereocontrol by a stereospecific rearrangement if the nucleophile is a vinyl anion equivalent. Ozonolysis of the product followed by reductive work-up returns an enantiomerically pure 2-substituted alcohol, along with the ( S )-2-(dibenzylamino)-3-phenylpropan-1-ol precursor to the starting aldehyde, which functions as a chiral auxiliary. The sequence provides a new strategy for the use of aldehydes as chiral auxiliaries in the synthesis of chiral alcohols bearing oxygen- or carbon-based 2-substituents.

The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis

Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.

Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis

A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics.