Heterolytic Fragmentation. A Class of Organic Reactions

Grob, C. A.; Schiess, Peter

doi:10.1002/anie.196700011

Cited by 354 publications

(75 citation statements)

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“…We did not observe acrolein (by 1 H NMR or HPLC), 91, or 92 via Kitahara's decomposition pathway (b). 74 We also looked for acetate 93 that would be formed by a Grob fragmentation (c) 75,76 but have insufficient evidence to confirm this product formation. Hemiketal 64 exists as a 10:1 equilibrium mixture with linear ketoalcohol 64-open in both CD 2 Cl 2 and D 2 O, in accordance with Jacobsen's observation.…”

Section: Synthesis and Antitumor Activity Of Fr901464 A R T I C L E Smentioning

confidence: 99%

Total Syntheses, Fragmentation Studies, and Antitumor/Antiproliferative Activities of FR901464 and Its Low Picomolar Analogue

et al. 2007

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FR901464 is a potent anticancer natural product that lowers the mRNA levels of oncogenes and tumor suppressor genes. In this article, we report a convergent enantioselective synthesis of FR901464, which was accomplished in 13 linear steps. Central to the synthetic approach was the diene-ene cross olefin metathesis reaction to generate the C6-C7 olefin without the use of protecting groups as the final step. Additional key reactions include a Zr/Ag-promoted alkynylation to set the C4 stereocenter, a mild and chemoselective Red-Al reduction, a reagent-controlled stereoselective Mislow-Evans-type [2,3]-sigmatropic rearrangement to install the C5 stereocenter, a Carreira asymmetric alkynylation to generate the C4′ stereocenter, and a highly efficient ring-closing metathesis-allylic oxidation sequence to form an unsaturated lactone. The decomposition pathways of FR901464's right fragment were studied under physiologically relevant conditions. Facile epoxide opening by -elimination gave two enones, one of which could undergo dehydration via its hemiketal to form a furan. To prevent this decomposition pathway, a right fragment was rationally designed and synthesized. This analogue was 12 times more stable than the right fragment of the natural product. Using this more stable right fragment analogue, an FR901464 analogue, meayamycin, was prepared in 13 linear steps. The inhibitions of human breast cancer MCF-7 cell proliferation by synthetic FR901464 and meayamycin were studied, and the GI 50 values for these compounds were determined to be 1.1 nM and 10 pM, respectively. Thus, meayamycin is among the most potent anticancer small molecules that do not bind to either DNA or microtubule.

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Section: Synthesis and Antitumor Activity Of Fr901464 A R T I C L E Smentioning

confidence: 99%

Total Syntheses, Fragmentation Studies, and Antitumor/Antiproliferative Activities of FR901464 and Its Low Picomolar Analogue

et al. 2007

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“…Cl Ϫ elimination from adduct (C) then occurs via concerted transfer of 2 e Ϫ from the flavin to the leaving group, this being classic fragmentation as described by Grob and Schiess (34). For such fragmentations precise steric orientations of involved orbitals are necessary (in general, an antiparallel one) (34); the absence of this might be a possible reason for the absence or occurrence of ␤-elimination in related enzymes (4,26,35). In turn, the occurrence or absence of ␤-elimination in various enzymes might be dictated by the set-up of the active site, which determines the steric orientation of the ligand ␣-and ␤-substituents.…”

Section: Discussionmentioning

confidence: 99%

Revisitation of the βCl-Elimination Reaction of d-Amino Acid Oxidase

Ghisla

Pollegioni

Molla

2011

Journal of Biological Chemistry

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, which was later confirmed by others (2-4). Based on this, the mechanism depicted in Scheme 1 for the elimination reaction was put forward (1). In this reaction the substrate ␣H as H ϩ is abstracted to form a carbanion intermediate, which then releases Cl Ϫ to yield the final products pyruvate and NH 4 ϩ . In this reaction the redox state of the flavin cofactor remains unaltered."Normal" dehydrogenation of ␤Cl-D-Ala would yield ␤Cl-pyruvate (␤Cl-Py) as the final product and lead to reduction of the flavin cofactor (5). The initial experiment (1) provided the first clues for formulating a general concept for the mechanism underlying flavin dehydrogenation and represents the birth of the so-called carbanion mechanism. This concept then gained wide acceptance for decades to come. However, some doubts soon emerged (2, 6 -8); experiments by Hersh and Jorns (9) demonstrated that for a DAAO in which the flavin cofactor was replaced by 5-deaza-flavin, Cl Ϫ was not eliminated. This puzzle remained unanswered for a long time, as the flavin ought not to be involved directly in elimination. Later experiments based on the concept of the linear free energy relationship were not in favor of the carbanion mechanism either (10, 11). A way out of the conundrum emerged when the three-dimensional structure of two related DAAOs was identified (12, 13); these studies showed unambiguously that there is no functional group at the active center of the enzyme that could act as a base in abstracting the substrate ␣H as H ϩ . Furthermore, the structures of complexes of Rhodotorula gracilis D-amino acid oxidase (RgDAAO) with D-alanine or D-CF 3 -alanine show that the substrate ␣C-H points directly toward

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“…It had been anticipated that this product, upon treatment with sodium hydride in anhydrous toluene, would form the orthocarbonate aalt 116 which would then undergo a Grob type fragmentation (17) to yield the enol ether 117. ~is reaction was carried out and the product obtained had the expected spectroscopi~-properties for structure l![.…”

Section: Synthetic Studies Towards Anhydroryanodolmentioning

confidence: 99%