Titanocene (III) chloride (Cp2TiCl), generated in situ, reduces N-O bonds of various substrates in good to excellent yields (72–95%). Reactions may be performed with stoichiometric Cp2TiCl or with catalytic Cp2TiCl.
By employing an intramolecular Pd(0)-mediated ring opening of an acylnitroso-derived cycloadduct, new hydroxamic acid containing benzodiazepines have been synthesized and have demonstrated biological activity in MCF-7 and PC-3 tumor cell lines. Subsequent N-O bond reduction of the hydroxamate has provided access to amide analogs for SAR studies. During the course of our syntheses, an intermediate oxazoline-N-oxide was isolated and gave insight into the mechanism of the key Pd(0)-mediated reaction.1,4-Benzodiazepines are important biomolecules with a wide array of biological activities and therapeutic functions. Benzodiazepines are primarily known for their actions in the central nervous system. In addition to their established anxiolytic activites, 1,4-benzodiazepines also demonstrate activities as antibiotics, 1 anti-malarial, 2 and anti-HIV 3 agents. Additionally, there have been several reports of benzodiazepines as anti-cancer agents, 4 including BMS-214662, 4a a known farnesyltransferase (FTase) inhibitor, and Bz-423, 4b which has antiproliferative effects through the regulation of the c-myc protein (Figure 1).Herein we report the synthesis of 1,4-benzodiazepines via a Pd(0)-mediated ring opening of cycloadduct 3a and subsequent elaboration and evaluation of their anti-cancer activity in MCF-7 and PC-3 tumor cell lines. In contrast to the benzodiazepines disclosed in the literature, the benzodiazepines synthesized from cycloadduct 3a contain a hydroxamate embedded within the core structure. This presents the possibility of direct metal binding with the benzodiazepine ring system and makes these compounds potential inhibitors of metalloenzymes such as the aforementioned farnesyltransferase protein. 5 Whereas BMS-214662 contains an imidazole group that coordinates to zinc (II) in the FTase active site, 6 our benzodiazepine derivatives may potentially bind to the active site of FTase through a monoanionic bidentate chelation of the hydroxamate to the zinc (II) ion.Acylnitroso-derived hetero-Diels-Alder adducts, generated from the reaction of transient acylnitroso species with cyclopentadiene, are synthetically important precursors to a variety of bioactive molecules. 7 Pd(0)-mediated ring openings of acylnitroso-derived cycloadducts have been employed to provide syn-1,4-disubstituted cyclopentene derivatives. 8 Construction of the appropriately functionalized cycloadducts 3a and 3b began with commercially available mmiller1@nd.edu. NIH Public AccessAuthor Manuscript Org Lett. Author manuscript; available in PMC 2010 April 2. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 2-nitrobenzoic acid 1 (Scheme 1), which was coupled with O-benzyl hydroxylamine and subsequently deprotected and reduced under hydrogenolysis conditions to yield hydroxamic acid 2. In situ oxidation of hydroxamic acid 2 in the presence of cyclopentadiene afforded the anthranilic acid based cycloadduct, which was reacted with the appropriate sulfonyl chloride to give cycloadducts 3a and 3b in 47% and 73% yiel...
Carbocyclic aminonucleosides and epi-4′-carbocyclic puromycin were prepared from an acylnitroso-derived hetero Diels-Alder cycloadduct. Pd(0)/InI-mediated allylations of a formyl species were used to install the 4′-hydroxymethyl group. A tethered aminohydroxylation strategy was employed to install the cis-2′,3′-aminoalcohol moiety with complete regio-and diastereocontrol.Puromycin is an aminonucleoside natural product that demonstrates broad spectrum antibiotic and antitumor activities (Figure 1).1 The 3′-aminoacyl moiety structurally resembles the aminoacyladenyl region of an aminoacyl tRNA2 and plays a crucial role in terminating protein biosynthesis. Specifically, the α-amino group is transferred to a carboxyl-activated peptidyl-tRNA to form a new peptide bond.3 However, subsequent aminoacyl-group transfer reactions are precluded due to the presence of an unreactive 3′-amide in the ribosomal acceptor site rather than an activated 3′-ester linkage. As a result, the nascent polypeptide chain is prematurely released from the ribosome.4Although puromycin effectively inhibits transpeptidation, the ribonucleoside is rapidly metabolized in vivo to inactive and toxic components.5 In order to circumvent enzymatic degradation and toxicity issues, carbocyclic puromycin and related analogs have been prepared and studied extensively.6 The carbocyclic aminonucleosides have the same mode of action as puromycin and retain antimicrobial activity.7 Also, carbocyclic nucleosides lack an enzymatically labile glycosidic bond and provide a more metabolically robust scaffold.8 Structure-activity relationships (SAR) revealed that the 4′-hydroxymethyl group was not required for activity9 and the 1′,2′,3′,4′,-diastereomer lacked biological function. The cis-2′, 3′-aminoalcohol stereochemistry was essential for activity. Additionally, replacement of the functionalized cyclopentane core with a cyclohexyl ring resulted in decreased inhibition of protein synthesis.10Our research group's continued interest in the syntheses of diverse carbocyclic nucleosides11 led us to investigate carbocyclic puromycin derivatives. By employing Pd(0)/ InI-mediated allylations of a formyl species, 4′-hydroxymethyl groups may be installed in the carbocyclic scaffold with regio-and diastereocontrol.12 Additionally, a N-
Homoallylic esters are obtained in a single transformation from allyl 2,2,2-trifluoroethyl malonates by using a Pd(0)-catalyst. Facile decarboxylation of allyl 2,2,2-trifluoroethyl malonates is attributed to a decrease in pK a compared to allyl methyl malonates. Subsequent reduction of the homoallylic 2,2,2-trifluoroethyl ester provides a (hydroxyethyl)cyclopentenyl derivative that represents a key intermediate in the synthesis of carbocyclic nucleosides. A select allyl 2,2,2-trifluoroethyl malonate undergoes a decarboxylative Claisen rearrangement to provide a regioisomeric homoallylic ester.Homoallylic esters are embedded in the core structures of several classes of natural products including macrolide polyketides, 1 α-linolenic acid metabolites and derivatives 2 and cyclopentenone prostaglandins. 3 Although homoallylic esters may be synthesized in several steps by functional group manipulation, 2a direct access to homoallylic esters has been achieved by Krapcho decarboxylation of malonates, 4 addition of vinyl radicals to α,β-unsaturated esters 5 and 1,4-addition of alkenylcopper reagents. 6 We considered metal-catalyzed decarboxylative allylations as an alternative method to directly prepare homoallylic esters under mild conditions. 7 Although α-cyano, α-nitro, α-keto 8 and α-sulfonyl 9 allyl esters readily undergo Pd(0)-catalyzed decarboxylative rearrangements to afford the corresponding homoallylic derivatives, allyl methyl malonates are much less reactive. Their diminished reactivity is attributed to the less stable methoxyethenolate that forms upon decarboxylation. α,α-Dialkyl allyl methyl malonates require harsh conditions (i. e., 120 °C in DMF) to effect Pd(0)-decarboxylative rearrangements. 8 Diallyl malonates undergo decarboxylative allylation at room temperature, but must possess an aryl group at the α-position. 10 To our knowledge, Pd(0)-decarboxylative rearrangements of α,α-unsubstituted allyl alkyl malonates have not been reported. In order to achieve decarboxylation, we envisioned replacement of the allyl methyl malonate with an allyl 2,2,2-trifluoroethyl malonate. The strong electron-withdrawing ability of the trifluoroethyl group would improve the stability of the transient alkoxyethenolate and promote decarboxylation. Herein, we disclose that α,α-unsubstituted allyl 2,2,2-trifluoroethyl malonates are suitable substrates for Pd(0)-catalyzed decarboxylative allylations and provide desired homoallylic 2,2,2-trifluoroethyl esters in high yields. Our group has previously reported Pd(0)-catalyzed allylic alkylations with cycloadduct 3 11 and related substrates as key steps en route to targeted carbocyclic nucleosides. 12 In order to access carbonucleoside targets 5′-homocarbovir 1b 13 and 5′-homoaristeromycin 2b ,14 we required a reliable method to install the requisite 5′-hydroxyethyl side chain. We envisioned a Pd(0) decarboxylative rearrangement to afford an α-allyl ester and subsequent reduction to the (hydroxyethyl)cyclopentyl core structure. Further elaboration would furnish 1b and 2...
Carbocyclic nucleosides (−)-5′-homocarbovir and (+)-epi-4′-homocarbovir were prepared from an acylnitroso-derived hetero Diels-Alder cycloadduct. A kinetic enzymatic resolution generated an enantiopure aminocyclopentenol and Pd(0)-mediated decarboxylative allylations of allyl 2,2,2-trifluoroethyl malonates were used to install the 4′-hydroxyethyl groups. Late stage derivatization gave access to the cyclopropylamine congenors, (−)-5′-homoabacavir and (+)-epi-4′-homoabacavir. All carbonucleoside target molecules were evaluated for antiviral activity.
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