14 research outputs found
Enantiospecific total synthesis of (-)-agelastatin a and evaluation of its biological properties.
No full text(-)-Agelastatin A (1) is a tetracyclic alkaloid recently isolated from the marine sponge Agelas dendromorpha. It has powerful antitumour properties in vitro and in vivo, and is a selective inhibitor of the ubiquitous enzyme, glycogen synthase kinase 3(3. It also exhibits insecticidal properties. In this thesis, we describe an enantiospecific total synthesis of the cyclopentenone (-)- 175, an advanced intermediate whose racemate had previously been converted into ( )-agelastatin A by Weinreb and co-workers. Our strategy exploited the chiral oxazolidinone 150 as a key intermediate, and commenced from the Hough-Richardson aziridine 234 (which is itself obtainable from D-glucosamine hydrochloride). Noteworthy reactions in the route to 150 include the regioselective trans-diaxial ring-opening of 234 with azide ion to set up the vicinal diamido functionality present in (-)-175, and the Grubbs-Hoveyda ring-closing metathesis reaction that is used to fashion its cyclopentene core. We also describe a new synthetic endgame for converting (-)-150 to (-)-agelastatin A via cyclopentenone 307. This new endgame has so far allowed 223 mg of (-)-agelastatin A to be prepared for detailed toxicological and biological evaluation. Some of the results of these studies are presented in this thesis
Total synthesis of dictyodendrin B
No full textA concise total synthesis of dictyodendrin B (1) is reported, a scarce marine alkaloid endowed with promising telomerase inhibitory activity. Key steps of the chosen route are a reductive cyclization of ketoamide 11 to indole 12 mediated by low-valent titanium (from TiCl3 and KC8) followed by a photochemical 6π-electrocyclization, which was performed in the presence of Pd/C and nitrobenzene to effect concomitant dehydrogenation/aromatization of the product initially formed. Regioselective bromination of the resulting pyrrolocarbazole 13 followed by lithium/bromine exchange and quenching of the resulting organolithium species with p-methoxybenzaldehyde installed the side chain at C2. Oxidation of the benzylic alcohol 15 thus obtained to ketone 17 was best achieved with catalytic amounts of tetra-n-propylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) in dilute CH2Cl2 solution to avoid the formation of undue amounts of the unsymmetrical dimer 16. Ketone 17 was elaborated into the natural product by selective cleavage of the isopropyl ether with BCl3, introduction of the sulfate moiety with the aid of trichloroethyl chlorosulfuric acid ester, deprotection of all lateral methyl ether groups, and final reductive cleavage of the trichloroethyl ester moiety. The spectroscopic data of synthetic dictyodendrin B thus formed matched those of an authentic sample in all regards. Moreover, it was shown that global deprotection of the peripheral −OH groups in pyrrolo[2,3-c]carbazole 13 is accompanied by spontaneous air-oxidation to form the quinone core of dictyodendrin C
Total Syntheses of the Telomerase Inhibitors Dictyodendrin B, C, and E
No full textConcise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2),
C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the
common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC
cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction
to generate an adjacent indole nucleus, and a photochemical 6π-electrocyclization/aromatization tandem
to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations
of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone
core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the
first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination
of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal−halogen exchange or
cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very
labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction
followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be
achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride
and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or
-stannanes met with failure
Total Syntheses of the Telomerase Inhibitors Dictyodendrin B, C, and E
No full textConcise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2),
C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the
common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC
cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction
to generate an adjacent indole nucleus, and a photochemical 6π-electrocyclization/aromatization tandem
to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations
of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone
core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the
first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination
of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal−halogen exchange or
cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very
labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction
followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be
achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride
and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or
-stannanes met with failure
Total Synthesis of Dictyodendrin B
No full textA concise total synthesis of dictyodendrin B (1) is reported, a scarce marine alkaloid endowed with promising telomerase inhibitory activity. Key steps of the chosen route are a reductive cyclization of ketoamide 11 to indole 12 mediated by low-valent titanium (from TiCl3 and KC8) followed by a photochemical 6π-electrocyclization, which was performed in the presence of Pd/C and nitrobenzene to effect concomitant dehydrogenation/aromatization of the product initially formed. Regioselective bromination of the resulting pyrrolocarbazole 13 followed by lithium/bromine exchange and quenching of the resulting organolithium species with p-methoxybenzaldehyde installed the side chain at C2. Oxidation of the benzylic alcohol 15 thus obtained to ketone 17 was best achieved with catalytic amounts of tetra-n-propylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) in dilute CH2Cl2 solution to avoid the formation of undue amounts of the unsymmetrical dimer 16. Ketone 17 was elaborated into the natural product by selective cleavage of the isopropyl ether with BCl3, introduction of the sulfate moiety with the aid of trichloroethyl chlorosulfuric acid ester, deprotection of all lateral methyl ether groups, and final reductive cleavage of the trichloroethyl ester moiety. The spectroscopic data of synthetic dictyodendrin B thus formed matched those of an authentic sample in all regards. Moreover, it was shown that global deprotection of the peripheral −OH groups in pyrrolo[2,3-c]carbazole 13 is accompanied by spontaneous air-oxidation to form the quinone core of dictyodendrin C
Chapter 11 Total synthesis and mechanism of action studies on the antitumor alkaloid, (-)-agelastatin a
No full textEnantiospecific Formal Total Synthesis of the Tumor and GSK‐3β Inhibiting Alkaloid, (‐)‐Agelastatin A.
No full textNew Total Synthesis of the Marine Antitumor Alkaloid (−)-Agelastatin A
No full textA new total synthesis of (−)-agelastatin A (1) has been achieved from the chiral oxazolidinone (−)-3. Although enone transposition was problematic
when the Michael ring closure of 2 was attempted with strong base, the desired cyclization could be effected with Hunig's base after the
pyrrole nucleus was brominated. Subsequent reduction and monobromination afforded synthetic (−)-agelastatin A (1)
New Total Synthesis of the Marine Antitumor Alkaloid (−)-Agelastatin A
No full textA new total synthesis of (−)-agelastatin A (1) has been achieved from the chiral oxazolidinone (−)-3. Although enone transposition was problematic
when the Michael ring closure of 2 was attempted with strong base, the desired cyclization could be effected with Hunig's base after the
pyrrole nucleus was brominated. Subsequent reduction and monobromination afforded synthetic (−)-agelastatin A (1)
