Asymmetric Total Synthesis of (+)- and ent-(−)-Yatakemycin and Duocarmycin SA:  Evaluation of Yatakemycin Key Partial Structures and Its Unnatural Enantiomer

Abstract

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, eg. 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 IC 50 = 5 pM) with its unnatural enantiomer (IC 50 = 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 (k rel = 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.

Oxidative coupling of sp 2 and sp 3 carbon–hydrogen bonds to construct dihydrobenzofurans

“…Cross-coupling of the ortho -chloro substituent to give phenylated dihydrobenzofuran proceeded in excellent yield 35 . The carboxylic group could be transformed into an NH 2 group ( 8) through Curtis rearrangement 36 . Last but not the least, with methyl substituents, further benzylic C–H activation and lactonization took place to produce a tricyclic compound ( 9 ) in a moderate yield 37 .…”

Asymmetric Synthesis of a CBI-Based Cyclic N-Acyl O-Amino Phenol Duocarmycin Prodrug

“…Analogous to observations made in an asymmetric synthesis of CBI itself, 13c formation of the aryl Grignard reagent by metal–halogen exchange (2.0 equiv of EtMgBr, 23 °C) is followed by the rapid intramolecular epoxide ring opening to give near exclusively 8 , the result of intramolecular 6- endo versus 5- exo addition to the epoxide with only detection of trace amounts of the isomeric product (>13:1, <5%). A similar but technically more demanding protocol, entailing metal–halogen exchange ( i -PrMgCl, THF, −40 °C, 20 min) followed by transmetalation with CuI–PBu 3 (−78 °C, 1 h), 15 also provided 8 (−40 °C, 30 min, 68%) in comparable conversions. O-Debenzylation of 8 , accomplished by transfer hydrogenolysis (cat.…”

Asymmetric Synthesis and Biological Evaluation of Glycosidic Prodrugs for a Selective Cancer Therapy

“…[27] Alkylation reactions using a glycidyl-nosylate [28] had been shown to proceed regioselectively. [29] Thus, reaction of 18 with the nosylate (+)-(S)-29 afforded (+)-(2'R)-30 in 95 % yield, which in the following metal mediated opening of the epoxide delivered the five-membered ring system (+)-(1S)-31 as the main product in 58 % yield in a stereoselective manner without any loss of stereo integrity. Transformation of (+)-(1S)-31 employing an Appel reaction led to the benzyl protected seco-CBI precursor (À)-(1S)-19 (Scheme 4).…”