Birinapant/TL32711 (1) 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 1 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 14 as well as a two-step dimerization/oxidation of indole 19 that afforded biindole 21 in excellent yield and purity (70% yield, 2 steps; >95 area% purity by HPLC analysis). In addition, partial defluorination of 21 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 1 drug substance of >99 area% chemical purity. Using this process, we have successfully prepared 1 drug substance multiple times on >500-g-scale in support of our clinical development program.

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 Zvinyl iodides. This sequence provides a short, high yield, and convenient route to trisubstituted Zvinyl iodides, useful intermediates for the preparation of polypropionate antibiotics.Iodo olefins are important intermediates in organic synthesis. As key reactants in the convergent steps of many total syntheses, they are often the reagents of choice in Heck, Stille and Suzuki, Sonogashira, and Negishi coupling methods 1 as well as in the popular NozakiHiyama-Kishi (NHK) addition reaction. 2 Stereochemical homogeneity in the products of these transformations depends on the availability of geometrically clean iodo olefins as starting materials.We have been interested in the preparation of a 2-iodo (Z)-olefin of general structure 1 ( Figure 1) and, in particular, the iodoolefinic alkyne 2, 3 which we projected as a key intermediate in the synthesis of discodermolide (3). 4 Given the small number of approaches to vinyl iodides of this substitution pattern, 5 we considered the design of a new method that might be high-yielding and that would be easy to implement. We were especially motivated to prepare alcohol 4, an obvious precursor to alkyne 2 and a generally useful intermediate, from a precursor of general structure 5. Alcohols 5 are readily available from a short scheme based on asymmetric catalysis. 6 Thus we considered the possibility that the dihydrooxasiline 6 might serve as an intermediate in the desired conversion.Imagining the silyl ether 6 to be the product of a ring closing metathesis (RCM) reaction, we set out to attempt this cyclization. 7 Silylation of the known alcohol 5 (R, R = (CH 2 ) 5 , Scheme 2) with isopropenyldimethylsilyl chloride provided the desired 7. In this metathesis substrate, the functional group pattern should allow RCM to favor the formation of a 6-membered ring containing a trisubstituted olefin (not a cyclobutane and not a 5-membered ring containing a tetrasubstituted olefin). 8Attempted RCM with Grubbs's second generation catalyst (8) or with Schrock's catalyst 9 resulted in the recovery of starting material. We repeated both the Grubbs II and Schrock experiments under an atmosphere of ethylene, 9 recovering silyl ether 7 in both cases.In order to find conditions that would effect the desired closure, we prepared the model substrate 10 and subjected it to metathesis conditions (Scheme 3). Material recovered from the Grubbs II reaction showed two spots on tlc, one of which represented the starting material 10 and the other a new compound(s), which was clearly not the cyclized 11. 10 This result was not particularly surprising. The literature sports no examples of ruthenium catalyst-promoted ring closing olefin metathesis to 1,2-dihydrooxasilines; both Grubbs generation I catalyst 11 and Grubbs generation II catalyst (8) 11c are reported to fail with the relevant substrates. 12 On the other han...

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.

Organo-silicon compounds S 0060A Relay Ring-Closing Metathesis Synthesis of Dihydrooxasilines, Precursors of (Z)-Iodo Olefins. -The reaction of (I) is shown to be successful using the second generation Grubbs catalyst instead of the Schrock catalyst. Product (II) is transformed to the (Z)-vinyl iodides (V) and (VI), useful intermediates for the synthesis of antibiotics. -(XIE, Q.; DENTON, R. W.; PARKER*, K. A.; Org. Lett. 10 (2008) 23, 5345-5348; Dep. Chem., State Univ. N. Y., Stony Brook, NY 11794, USA; Eng.) -R. Steudel 17-175