Asymmetric Catalysis Route to <i>anti</i>,<i>anti</i> Stereotriads, Illustrated by Applications

A short sequence based on asymmetric catalysis, chirality transfer, and an optimized carbometallation protocol gave an anti,anti stereotriad building block in six steps. Both enantiomers of the chirality source, N-methyl ephedrine, are inexpensive, and the auxiliary is recoverable. In one chiral series, the building block was converted to the “B-2” intermediate in Miyashita's synthesis of scytophycin C; in the enantiomeric series, it was converted to a key intermediate for aplyronine A and to the polyketide “cap” for the callipeltins

A Relay Ring-Closing Metathesis Synthesis of Dihydrooxasilines, Precursors of (<i>Z</i>)-Iodo Olefins

A convenient Grubbs II metathesis provides dihydrooxasilines by relay RCM (RRCM). Dihydrooxasilines undergo ring opening to give Z-vinyl silanes. These can then be converted to Z-vinyl iodides. This sequence provides a short, high yield, and convenient route to trisubstituted Z-vinyl iodides, useful intermediates for the preparation of polypropionate antibiotics

Process Development and Synthesis of Birinapant: Large Scale Preparation and Acid-Mediated Dimerization of the Key Indole Intermediate

Birinapant/TL32711 (<b>1</b>) is a novel bivalent antagonist of the inhibitor of apoptosis (IAP) family of proteins which is currently in clinical development for the treatment of cancer and hepatitis B virus (HBV) infection. In this report, we present a detailed description of the <b>1</b> drug substance synthesis used to support our ongoing clinical studies. Key transformations in this process included the development of a scalable, high-yielding route to acyl indole <b>14</b> as well as a two-step dimerization/oxidation of indole <b>19</b> that afforded biindole <b>21</b> in excellent yield and purity (70% yield, 2 steps; >95 area% purity by HPLC analysis). In addition, partial defluorination of <b>21</b> was observed following hydrogen-mediated benzyloxycarbonyl (Cbz) protective group removal which was obviated by the use of HBr/HOAc for this transformation. The use of commercially available amino acid derivatives afforded related impurities which proved difficult to purge in subsequent steps. Thus, defining the impurity specification for these reagents was critical to providing <b>1</b> drug substance of >99 area% chemical purity. Using this process, we have successfully prepared <b>1</b> drug substance multiple times on >500-g-scale in support of our clinical development program