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130288-24-3Relevant academic research and scientific papers
An Enantioselective Total Synthesis of (+)-Duocarmycin SA
Schmidt, Michael A.,Simmons, Eric M.,Wei, Carolyn S.,Park, Hyunsoo,Eastgate, Martin D.
, p. 3928 - 3940 (2018/04/14)
An efficient, concise enantioselective total synthesis of the potent antitumor antibiotic (+)-duocarmycin SA is described. The invented route is based on a disconnection strategy that was devised to facilitate rapid and efficient synthesis of key core compounds to enable preclinical structure-activity relationship investigations. The key tricycle core was constructed with a highly enantioselective indole hydrogenation to set the stereocenter and a subsequent hitherto unexplored vicarious, nucleophilic-substitution/cyclization sequence to effectively forge a final indole ring. Additionally, the development of a stable sulfonamide protecting group capable of mild chemoselective cleavage greatly enhanced sequence yield and throughput. An understanding of key reaction parameters ensured a robust, reproducible sequence easily executable on decagram scales to this highly promising class of compounds.
ENANTIOSELECTIVE SYNTHESIS OF PYRROLOINDOLE COMPOUNDS
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, (2018/04/17)
Compounds according to formula (I) or (II), wherein R1, R2, and R3 are as defined in the specification, are versatile intermediates for the synthesis of DNA minor groove binder- alkylators having a cyclopropapyrroloindole (CPI) or seco-CPI alkylating subunit.
Systematic exploration of the structural features of yatakemycin impacting DNA alkylation and biological activity
Tichenor, Mark S.,MacMillan, Karen S.,Trzupek, John D.,Rayl, Thomas J.,Hwang, Inkyu,Boger, Dale L.
, p. 10858 - 10869 (2008/03/13)
A systematic examination of the impact of the yatakemycin left and right subunits and their substituents is detailed along with a study of its unique three subunit arrangement (sandwiched vs extended and reversed analogues). The examination of the ca. 50 analogues prepared illustrate that within the yatakemycin three subunit structure, the subunit substituents are relatively unimportant and that it is the unique sandwiched arrangement that substantially increases the rate and optimizes the efficiency of its DNA alkylation reaction. This potentiates the cytotoxic activity of yatakemycin and its analogues overcoming limitations typically observed with more traditional compounds in the series (CC-1065, duocarmycins). Moreover, a study of the placement of the alkylation subunit within the three subunit arrangement (sandwiched vs extended and reversed analogues) indicates that it not only has a profound impact on the rate and efficiency of DNA alkylation but also controls and establishes the DNA alkylation selectivity as well, where both enantiomers of such sandwiched agents alkylate the same adenine sites exhibiting the same DNA alkylation selectivity independent of their absolute configuration.
Asymmetric total synthesis of (+)- and ent-(-)-yatakemycin and duocarmycin SA: Evaluation of yatakemycin key partial structures and its unnatural enantiomer
Tichenor, Mark S.,Trzupek, John D.,Kastrinsky, David B.,Shiga, Futoshi,Hwang, Inkyu,Boger, Dale L.
, p. 15683 - 15696 (2007/10/03)
Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five-base-pair AT sequence, e.g., 5′-AAAAA), efficiency, relative rate, and reversibility of ent-(-)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nature of the DNA reaction, and comparisons of the cytotoxic activity of the natural product (L1210, IC50 = 5 pM) with those of its unnatural enantiomer (IC50 = 5 pM) and a series of key partial structures including those that probe the role of the C-terminus thiomethyl ester. The only distinguishing features between the enantiomers is that ent-(-)-yatakemycin alkylates DNA at a slower rate (krel = 0.13) and is reversible, whereas (+)-yatakemycin is not. Nonetheless, even ent-(-)-yatakemycin alkylates DNA at a faster rate and with a greater thermodynamic stability than (+)-duocarmycin SA, illustrating the unique characteristics of such "sandwiched" agents.
Total synthesis of the duocarmycins
Yamada, Ken,Kurokawa, Toshiki,Tokuyama, Hidetoshi,Fukuyama, Tohru
, p. 6630 - 6631 (2007/10/03)
The total synthesis of (+)-duocarmycin A and SA through a common indoline intermediate is described. The key reactions include selective lithiation of a 2,6-dibromoiodobenzene derivative and diastereoselective addition to a chiral nitroalkene, copper-mediated aryl amination, and addition of aryllithium to azlactones. Copyright
A novel synthesis of (+)-duocarmycin SA
Fukuda, Yasumichi,Terashima, Shiro
, p. 7207 - 7208 (2007/10/03)
The title synthesis was achieved in eight steps from (S)-5-aminoindoline (S)-4 by a method featuring sequential dehydrogenation, double bond isomerization, and oxidative cyclization of (S)-5-[(1-methoxycarbonylethyl)amino]indoline 5 as the key steps. The sequential reaction was effected by using MnO2-Pd(OAc)2 as the oxidizing agent in the presence of an acid catalyst.
Preparation of alkyl-substituted indoles in the benzene portion. Part 14. Synthesis of (±)-duocarmycin SA, natural (+)-duocarmycin SA and non-natural (-)-duocarmycin SA
Muratake,Abe,Natsume
, p. 67 - 79 (2007/10/03)
Total synthesis of duocarmycin SA (1), an extremely potent cytotoxic antibiotic, was achieved in the racemic form at first by effectively utilizing two reactions as key steps, (i) an intramolecular Heck reaction of the benzyl ether 21a, derived from a dihydropyridine 13a and a pyrrole derivative 11, to form tricyclic compounds 25a and 26a, and (ii) a modified Mitsunobu reaction on the diol derivative 40 for the construction of compound 41 having the pivotal pharmacophore of a cyclopropanoindolinone partial structure, which is critical for the high biological activities of 1. Next, optical resolution of an intermediary racemic secondary alcohol 50 was cleanly attained by derivatizing it to (R)-O-methylmandelates 52 and 53, and the resulting chiral alcohols (+)-50 and (-)-50 were respectively transformed into unnatural (-)-1 and natural (+)-1. Finally inversion of the secondary alcohol (+)-50 to the enantiomer (-)-50 was effected by using the Mitsunobu reaction. This constitutes an enantio-convergent total synthesis of natural duocarmycin SA (1) starting from a racemic compound.
Total synthesis of natural (+)-duocarmycin SA
Muratake,Matsumura,Natsume
, p. 1064 - 1066 (2007/10/02)
A total synthesis of natural (+)-duocarmycin SA (1) was achieved as shown in Chart 1, starting from L-malic acid (5) by using a Lewis acid-mediated indole formation reaction of a pyrrole precursor 14 to form the key compound 15.
Total Synthesis of an Antitumor Antibiotic, (+/-)-Duocarmycin SA
Muratake, Hideaki,Abe, Itsuko,Natsume, Mitsutaka
, p. 2573 - 2576 (2007/10/02)
A 12-step total synthesis of (+/-)-duocarmycin SA (1) was achieved from a readily available pyrrole 3 by way of 7,10/11,14 and 18, using a SnCl2-mediated reaction of a singlet oxygen adduct 6 with 5, as well as the Heck and Mitsunobu reactions on 9 and 16 as key steps.
Total synthesis and preliminary evaluation of (+)- and ent-(-)-duocarmycin SA
Boger, Dale L.,Machiya, Kozo,Hertzog, Donald L.,Kitos, Paul A.,Holmes, Daniel
, p. 9025 - 9036 (2007/10/02)
Concise total syntheses of natural (+)- and ent-(-)-duocarmycin SA (1) are detailed based on sequential regioselective nucleophilic substitution reactions of the unsymmetrical p-quinone diimine 3 in the preparation of a dihydropyrroloindole precursor to the left-hand subunit. In addition to constituting a new synthetic strategy for the preparation of natural or synthetic duocarmycins and related agents, both enantiomers of 2 (N-BOC-DSA) and its immediate synthetic precursors are made available by the approach. This provides access to synthetic analogs incorporating either enantiomer of the exceptionally stable and potent duocarmycin SA alkylation subunit. The comparative chemical properties of the agents are detailed in studies which reveal that N-BOC-DSA (t1/2 = 177 h, pH = 3; stable, pH = 7) is 4.8× more stable to chemical solvolysis than N-BOC-CPI (t1/2 = 37 h, pH = 3), the authentic alkylation subunit of CC-1065, and that the agents participate in a stereoelectronically-controlled solvolysis reaction with nucleophilic addition to the least hindered cyclopropane carbon. Consistent with this enhanced stability, (+)-N-BOC-DSA (2) proved to possess the most potent inherent cytotoxic activity of all natural and synthetic alkylation subunits examined to date including (+)-N-BOC-CPI, and its relative cytotoxic potency predictably follows a fundamental relationship between chemical stability and cytotoxic potency established in prior studies. In contrast to expectations based on past observations, the unnatural enantiomers of 1 and 2 as well as the natural enantiomers were found to constitute potent cytotoxic agents whose further examination should prove exceptionally interesting.
