A formal total synthesis of the cytotoxic macrolide amphidinolide E is reported. The strategic steps are three Julia-Kocienski reactions (J-K), for the formation of the C5-C6, C9-C10, and C17-C18 double bonds, a Suzuki-Molander C21-C22 bond formation reaction, and a Kita-Trost macrolactonization. The "instability" of the two dienic systems and of the stereocenter at C2 (allylic methine, α to the carboxy group) and the protecting groups at C17-OH and C18-OH have posed difficult challenges. Each Julia-Kocienski olefination has been systematically optimized to provide the highest possible E/Z ratios.
ABSTRACT:The use of the 2-(4-methylphenylsulfonyl)ethenyl (Tosvinyl, Tsv) group for the protection of the NH group of a series of imides, azinones (including AZT), inosines, and cyclic sulfonamides has been examined. The Tsv-protected derivatives are obtained in excellent yields by conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone). The stereochemistry of the double bond can be controlled at will: with only 1 mol % of Et 3 N or with catalytic amounts of NaH the Z stereoisomers are generated almost exclusively, while the E isomers are obtained using a stoichiometric amount of DMAP. Analogous phenylsulfonylvinyl-protected groups (with the Besvinyl or Bsv group instead of Tsv) are obtained stereospecifically by reaction with (Z)-or (E)-bis(phenylsulfonyl)ethene. For lactams and oxazolidinones, this last method is much better. The Tsv and Bsv groups are stable in the presence of non-nucleophilic bases and to acids. They can be removed highly effectively via a conjugate addition-elimination mechanism using pyrrolidine or sodium dodecanethiolate as nucleophiles.
A long series of Michael acceptors are studied computationally as potential alternatives to the maleimides that are used in most antibody–drug conjugates to link Cys of mAbs with cytotoxic drugs. The products of the reaction of methanethiol (CH 3 SH/MeSH, as a simple model of Cys) with N-methylated ethynesulfonamide, 2-ethynylpyridinium ion, propynamide, and methyl ethynephosphonamidate (that is, with HC≡C–EWG) are predicted by the M06-2X/6-311+G(d,p) method to be thermodynamically more stable, in relation to their precursors, than that of MeSH with N -methylmaleimide and, in general, with H 2 C=CH–EWG; calculations with AcCysOMe and t BuSH are also included. However, for the addition of the anion (MeS – ), which is the reactive species, the order changes and N-methylated 2-vinylpyridinium ion, 2,3-butadienamide, and maleimide may give more easily the anionic adducts than several activated triple bonds; moreover, the calculated Δ G ⧧ values increase following the order HC≡C–SO 2 NHMe, N -methylmaleimide, HC≡C–PO(OMe)NHMe, and HC≡C–CONHMe. In other words, MeS – is predicted to react more rapidly with maleimides than with ethynephosphonamidates and with propynamides, in agreement with the experimental results. New mechanistic details are disclosed regarding the advantageous use of some amides, especially of ethynesulfonamides, which, however, are more prone to double additions and exchange reactions.
The handicaps of the maleimides, the most commonly used reagents to link thiol groups (of Cys) to drugs, fluorescent labels, etc., prompted us to revise and develop an alternative, based on the known thia-Michael addition to activated triple bonds, which could be useful under physiological conditions. A drug with an amino group was converted into its propynamide and, in aqueous media at 37 ºC and pH 7.4, Cys derivatives were added, to afford rapidly the Z adduct. This chemical linker (the oxopropene-1,3-diyl group) showed advantages, in terms of following the reaction course: no diastereomers were formed; excellent selectivity (Svs. NH 2 , even at pH 10.0 and 12.0), without secondary reactions; no exchange with other thiols; and no incorporation of deuterium at the linker when the samples were dissolved in D 2 O to register their NMR spectra.Conventional cancer treatments that use cytotoxic compounds cause serious side effects due to their lack of selectivity for tumor cells.As known, a very promising strategy to avoid or alleviate these drawbacks is to conjugate cytotoxic drugs with antibodies (targeted therapy). 1 The preparation of antibody-drug conjugates (ADCs) requires efficient and reliable linkage protocols. 2 Most ADCs currently on the market (4 are currently FDA-approved) and in clinical development use the Michael addition reaction of a native or geneticallyengineered Cys in the antibody to a maleimide group to form the conjugate. 3 This transformation is widely used because the reaction is quantitative and fast under physiological conditions; however, the adducts may undergo thiol exchange in vivo causing off-site cytotoxicity and compromising the efficacy of the conjugate. 4,5 Other Cys conjugations have been reported (Scheme 1) 6 , including the addition to electron-deficient alkynes. 7Our long-standing interest in the conjugate addition of several nucleophiles to activated triple bonds 8 has recently led us to examine the possibility of going a step further: whether, under real physiological conditions, these reagents-specifically, propynamides-will or will not be useful to bind or link (as a linchpin or link pin) thiols and amines (Scheme 2). In other words, from our own work 8 and from that of our colleagues Arjona and Plumet, 9 we were aware that HC≡C-EWG compounds with strong EWGs such as SO 2 R and COOR are capable of reacting at rt even with very weak nucleophiles, in the presence of suitable catalysts. We did not know, however, if the reactions of Cys with HC≡C-CONHR would be sufficiently quick, complete, and stereoselective in aqueous solvents, without any additive, or if the
Amides from indole-3-glyoxylic acid and 4-benzoyl-2-methylpiperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the wellknown Cu(I)-catalyzed (3 + 2)-cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5-HIV-1 NLAD8 isolates. Thus, potential vaginal microbicides based on entry inhibitors, which can be called of 4 th generation, are reported here for the first time.
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