At sixes and sevens: The synthesis of [4.2.1]‐ and [3.2.1]‐fused bicyclic acetals by an intramolecular double alkoxylation of alkyne diols is reported. The course of the reaction depends on the substitution of the triple bond. Terminal alkynes give the [3.2.1]bicyclic product by a 6‐exo pathway, whereas aryl alkynes undergo almost exclusively a 7‐endo cyclization to give the [4.2.1]bicycles (see scheme, Ts=toluene‐4‐sulfonyl).

The AuCl3‐catalyzed double hydroalkoxylation of conjugated 7‐hydroxyheptynoates offers a convenient route for the synthesis of six‐membered cyclic acetals, which are common substructures of polyketide natural products. When conjugated 6‐hydroxyhexynoates are used as starting materials, either five‐membered cyclic E‐enol ethers or the corresponding acetals can be obtained by simply choosing the appropriate reaction solvent. NMR spectroscopic studies were carried out to determine the kinetics and pathway of the latterdomino 5‐exo cyclization–hydroalkoxylation reaction. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

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Despite the prevalence of morpholine derivatives and bridged heterocycles in medicinally relevant compounds, bridged bicyclic morpholines remain scarce because of the challenges associated with their synthesis. MRK A, an IDH1 mut inhibitor for the treatment of glioma, derives its potency in part from substitution of a zigzag 2,5-bicyclic morpholine, 2-oxa-5azabicyclo[2.2.2]octane, at C8. While existing entries suffered from low yields and lack of stereochemical control, we developed concise stereospecific routes toward both enantiomers of the zigzag morpholine antipode. The key common intermediate in the two routes was a chiral bicyclic lactone, which was readily synthesized following our previous synthesis of relebactam from optically pure (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (HPA). The desired (R,R) enantiomer for incorporation into MRK A required inversion of both stereocenters of the bicyclic lactone intermediate, which was accomplished by epimerization via a crystallizationinduced diastereomer transformation process followed by a key Ti(O i Pr) 4 -mediated intramolecular S N 2 ring closure. By this method, the (R,R)-zigzag morpholine was synthesized in six steps from HPA in 25% overall yield.

The development and execution of a practical asymmetric synthesis of the estrogen receptor beta selective agonist (8R,10aS)-6-(trifluoromethyl)-8,9,10,11-tetrahydro-8,10a-methanocyclohepta­[1,2]­indeno­[4,5-d]­[1,2,3]­triazol-7­(3H)-one is described. The optimized route features a key chiral auxiliary-mediated dialkylation approach to set the all-carbon quaternary center with exceptional stereocontrol. Overall, the chemistry has been used to prepare >30 kg of drug candidate in 21% overall yield through 13 longest linear steps and with >99% ee.