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
Water plays an indispensable role in manufacturing industry. However, discharge of polluted water containing heavy metal ions often appears in streams and causes serious damage to creatures and environment. Therefore, water-quality monitoring is essential to ensure both developments and safeties. To address this need, different approaches of metal ion detection include spectrophotometry, conductivity test, membrane electrode method and atomic emission spectroscopy. Nevertheless, the accuracy and efficiency of these approaches could still be improved. For these reasons, this study aims to develop an innovative water quality examination technique by using electrochemical impedance spectroscopy (EIS) measurements. By improving the sensitivity and reproducibility of the developed approach, this technique could contribute to metal ion detection. In this work, the main approach to detect the target ion, Cu2+, is surface modification for electrochemical impedance analysis method. To accomplish the development, first, the relationship between ion concentration and the impedance of solution was analyzed. CuCl2 solutions with a concentration between 10-2 to 10-6 M were used as samples for measurement. The experiment, in the Faradaic Mode, was carried out at a starting voltage of 0.34 V. The amplitude was 200 mV, with frequencies varied from 1 MHz to 1 Hz. The effect of temperature variations between 40 to 140 degree Celsius was also discussed. Then, the electrodes were respectively immersed in solutions which are 11-MUA (24 hours), 3-MPA (6 hours) and 2-thiobarbituric acid molecules (24 hours) to construct different exterior structures. Finally, histidine is connected to the electrode for capturing and recognizing copper ions [1]. With the modified electrode, the measured ion concentration was changed to 10-3 to 10-9 M. The same experimental parameters as mentioned above were used to measure Ca2+, Mg2+, Na+ and Cu2+, respectively. Also, the copper ion selectivity of each type of monolayers was evaluated. The diameter of the semicircle extrapolated in the Nyquist diagram represents the charge transfer resistance (Rct ) of the solution. In Faradaic mode, Rct should have a negative relationship with ion concentration [2]. By adopting the method proposed by Edward & Craig (2013), the copper ions can be identified by the Rct value obtained in this study. According to experimental results illustrated in Fig. 1, the diameter of the impedance diagram becomes smaller as the concentration increases, meaning a decrease of the Rct. Besides, as the temperature increases, Rct decreases gradually (Fig. 2). On the other hand, there is no significant difference between the trend of Rct when using electrodes with different modification materials (Fig. 3). The detection limit of the bare electrode or modified with planar structured thiolates falls on 10-6 M. However, the detection limit of the electrode with 11-MUA or 3-MPA is approximately reduced to 10-8 M (Fig. 4). Compared to other ions, Rct of Ca2+ and Mg2+ in specific concentration performs similarly when using 11-MUA modified electrode. The correlation coefficient of the calibration relationship between Na+ concentration and the resistance are lower than those in Cu2+ detection (Fig. 5). Based on the above results, it is illustrated that MUA modified electrode performs the best ion selectivity in Cu2+ detection. Finally, for the MPA electrode, the quadratic calibration function between ion concentration and Rct of Cu2+ can also be established as shown in Fig. 6. Based on this experimental result, MPA modified electrode also has high selectivity to Cu2+. In the study, it has been confirmed that the lower ion concentration results a higher impedance of the solution. Besides, the negative logarithm of the concentration (-log[Cu2+], pCu2+) is positively related to Rct in a quadratic form. Also, as the temperature increases, the ion migration rate becomes faster, and the Rct value gets lower; hence, the environmental temperature was controlled to be 25 degree Celsius during the experiments. By modifying 11-MUA and 3-MPA on the electrode, the measurement limit has been significantly reduced, verified by a smoother fitting trend. In conclusion, the proposed 11-MUA and 3-MPA modified approaches have a higher copper ion selectivity and concentration measurement accuracy. In other words, an efficient and sensitive ion detection approach becomes available for water quality examination by utilizing the method proposed in the study. [1] Perrin D. D. (1959). Histidine-Copper (II) Complexes. [2] Edward P, and Craig E (2013). Electrochemical impedance spectroscopy: an overview of bioanalytical applications, Analytical Methods, 2013(5), 1098–1115. Figure 1
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