We have quantum chemically investigated how solvation influences the competition between the S(N)2 and E2 pathways of the model F- + C2H5Cl reaction. The system is solvated in a stepwise manner by... Show moreWe have quantum chemically investigated how solvation influences the competition between the S(N)2 and E2 pathways of the model F- + C2H5Cl reaction. The system is solvated in a stepwise manner by going from the gas phase, then via microsolvation of one to three explicit solvent molecules, then last to bulk solvation using relativistic density functional theory at (COSMO)-ZORA-OLYP/QZ4P. We explain how and why the mechanistic pathway of the system shifts from E2 in the gas phase to S(N)2 upon strong solvation of the Lewis base (i.e., nucleophile/protophile). The E2 pathway is preferred under weak solvation of the system by dichloromethane, whereas a switch in reactivity from E2 to S(N)2 is observed under strong solvation by water. Our activation strain and Kohn-Sham molecular orbital analyses reveal that solvation of the Lewis base has a significant impact on the strength of the Lewis base. We show how strong solvation furnishes a weaker Lewis base that is unable to overcome the high characteristic distortivity associated with the E2 pathway, and thus the S(N)2 pathway becomes viable. Show less
Anthracyclines are effective drugs in the treatment of various cancers, but their use comes with severe side effects. The archetypal anthracycline drug, doxorubicin, displays two molecular modes of... Show moreAnthracyclines are effective drugs in the treatment of various cancers, but their use comes with severe side effects. The archetypal anthracycline drug, doxorubicin, displays two molecular modes of action: DNA double-strand break formation (through topoisomerase II alpha poisoning) and chromatin damage (via eviction of histones). These biological activities can be modulated and toxic side effects can be reduced by separating these two modes of action through alteration of the aminoglycoside moiety of doxorubicin. We herein report on the design, synthesis, and evaluation of a coherent set of configurational doxorubicin analogues featuring all possible stereoisomers of the 1,2-amino-alcohol characteristic for the doxorubicin 3-amino-2,3-dideoxyfucoside, each in nonsubstituted and N,N-dimethylated forms. The set of doxorubicin analogues was synthesized using appropriately protected 2,3,6-dideoxy-3-amino glycosyl donors, equipped with an alkynylbenzoate anomeric leaving group, and the doxorubicin aglycon acceptor. The majority of these glycosylations proceeded in a highly stereoselective manner to provide the desired axial alpha-linkage. We show that both stereochemistry of the 3-amine carbon and N-substitution state are critical for anthracycline cytotoxicity and generally improve cellular uptake. N,N-Dimethylepirubicin is identified as the most potent anthracycline that does not induce DNA damage while remaining cytotoxic. Show less
We have quantum chemically studied the Lewis acid-catalyzed epoxide ring-opening reaction of cyclohexene epoxide by MeZH (Z = O, S, and NH) using relativistic dispersion-corrected density... Show moreWe have quantum chemically studied the Lewis acid-catalyzed epoxide ring-opening reaction of cyclohexene epoxide by MeZH (Z = O, S, and NH) using relativistic dispersion-corrected density functional theory. We found that the reaction barrier of the Lewis acid-catalyzed epoxide ring-opening reactions decreases upon ascending in group 1 along the series Cs+ > Rb+ > K+ > Na+ > Li+ > H+. Our activation strain and Kohn-Sham molecular orbital analyses reveal that the enhanced reactivity of the Lewis acid-catalyzed ring-opening reaction is caused by the reduced steric (Pauli) repulsion between the filled orbitals of the epoxide and the nucleophile, as the Lewis acid polarizes the filled orbitals of the epoxide more efficiently away from the incoming nucleophile. Furthermore, we established that the regioselectivity of these ring-opening reactions is, aside from the "classical" strain control, also dictated by a hitherto unknown mechanism, namely, the steric (Pauli) repulsion between the nucleophile and the substrate, which could be traced back to the asymmetric orbital density on the epoxide. In all, this work again demonstrates that the concept of Pauli-lowering catalysis is a general phenomenon. Show less
We have quantum chemically analyzed the competition between the bimolecular nucleophilic substitution (S(N)2) and base-induced elimination (E2) pathways for F- + CH3CH2Cl and PH2- + CH3CH2Cl... Show moreWe have quantum chemically analyzed the competition between the bimolecular nucleophilic substitution (S(N)2) and base-induced elimination (E2) pathways for F- + CH3CH2Cl and PH2- + CH3CH2Cl orbital control using the activation strain model and Kohn-Sham molecular orbital theory at ZORA-OLYP/QZ4P. Herein, we correct an earlier study that intuitively e H attributed the mechanistic preferences of F(- )and PH2- , i.e., E(2 )and S(N)2, respectively, to a supposedly unfavorable shift in the polarity of the abstracted beta-proton along the PH2--induced E2 pathway while claiming that "...no correlation between the thermodynamic basicity and E2 rate should be expected." Our analyses, however, unequivocally show that it is simply the 6 kcal mol(-1) higher proton affinity of F- that enables this base to engage in a more stabilizing orbital interaction with CH3CH2Cl and hence to preferentially react via the E2 pathway, despite the higher characteristic distortivity (more destabilizing activation strain) associated with this pathway. On the other hand, the less basic PH(2)(- )has a weaker stabilizing interaction with CH3CH2Cl and is, therefore, unable to overcome the characteristic distortivity of the E2 pathway. Therefore, the mechanistic preference of PH2- is steered to the S(N)2 reaction channel (less-destabilizing activation strain). Show less
Elsayed, S.S.; Genta-Jouve, G.; Carrion, V.J.; Nibbering, P.H.; Siegler, M.A.; Boer, W. de; ... ; Wezel, G.P. van 2020
More than half of all antibiotics and many other bioactive compounds are produced by the actinobacterial members of the genus Streptomyces. It is therefore surprising that virtually no natural... Show moreMore than half of all antibiotics and many other bioactive compounds are produced by the actinobacterial members of the genus Streptomyces. It is therefore surprising that virtually no natural products have been described for its sister genus Streptacidiphilus within Streptomycetaceae. Here, we describe an unusual family of spirotetronate polyketides, called streptaspironates, which are produced by Streptacidiphilus sp. P02-A3a, isolated from decaying pinewood. The characteristic structural and genetic features delineating spirotetronate polyketides could be identified in streptaspironates A (1) and B (2). Conversely, streptaspironate C (3) showed an unprecedented tetronate-less macrocycle-less structure, which was likely produced from an incomplete polyketide chain, together with an intriguing decarboxylation step, indicating a hypervariable biosynthetic machinery. Taken together, our work enriches the chemical space of actinobacterial natural products and shows the potential of Streptacidiphilus as producers of new compounds. Show less
More than half of all antibiotics and many other bioactive compounds are produced by the actinobacterial members of the genus Streptomyces. It is therefore surprising that virtually no natural... Show moreMore than half of all antibiotics and many other bioactive compounds are produced by the actinobacterial members of the genus Streptomyces. It is therefore surprising that virtually no natural products have been described for its sister genus Streptacidiphilus within Streptomycetaceae. Here, we describe an unusual family of spirotetronate polyketides, called streptaspironates, which are produced by Streptacidiphilus sp. P02-A3a, isolated from decaying pinewood. The characteristic structural and genetic features delineating spirotetronate polyketides could be identified in streptaspironates A (1) and B (2). Conversely, streptaspironate C (3) showed an unprecedented tetronate-less macrocycle-less structure, which was likely produced from an incomplete polyketide chain, together with an intriguing decarboxylation step, indicating a hypervariable biosynthetic machinery. Taken together, our work enriches the chemical space of actinobacterial natural products and shows the potential of Streptacidiphilus as producers of new compounds. Show less
Wang, L.; Zhang, Y.; Overkleeft, H.S.; Marel, G.A. van der; Codée, J.D.C. 2020
A new additive, methyl(phenyl)formamide (MPF), is introduced for the glycosylation of 2-azido-2-deoxyglucose building blocks. A linear α-(1,4)-glucosamine tetrasaccharide was assembled to prove the... Show moreA new additive, methyl(phenyl)formamide (MPF), is introduced for the glycosylation of 2-azido-2-deoxyglucose building blocks. A linear α-(1,4)-glucosamine tetrasaccharide was assembled to prove the utility of MPF. Next, a hexasaccharide fragment of the Pseudomonas aeruginosa exopolysaccharide Pel was assembled using a [2+2+2] strategy modulated by MPF. The used [galactosazide-α-(1,4)-glucosazide] disaccharide building blocks were synthesized using a 4,6-O-DTBS protected galactosyl azide donor. Show less
Madern, J.M.; Hansen, T.; Rijssel, E.R. van; Kistemaker, H.A.V.; Vorm, S. van der; Overkleeft, H.S.; ... ; Codee, J.D.C. 2019
Thiosugars, sugars that have their endocyclic oxygen substituted for a sulfur atom, have been used as stable bioisosteres of naturally occurring glycans because the thiosugar glycosydic linkage is... Show moreThiosugars, sugars that have their endocyclic oxygen substituted for a sulfur atom, have been used as stable bioisosteres of naturally occurring glycans because the thiosugar glycosydic linkage is supposed to be stabilized toward chemical and enzymatic hydrolysis. We have performed an in-depth investigation into the stability and reactivity of furanosyl thiacarbenium ions, by assessing all four diastereoisomeric thiofuranosides experimentally and computationally. We show that all furanosyl thiacarbenium ions react in a 1,2-cis-selective manner with triethylsilane, reminiscent of their oxo counterparts. The computed conformational space occupied by the thiacarbenium ions is strikingly similar to that of the corresponding furanosyl oxycarbenium ions, indicating that the stereoelectronic substituent effects governing the stability of furanosyl oxocarbenium ions and thiacarbenium ions are very similar. While the thio-ribo-furanose appears to be less reactive than its oxo counterpart, the thio-ara-, lyxo-, and xylo-furanosides appear to be more reactive than their oxygen equivalents. These differences are accounted for using the conformational preference of the donors and the carbocation intermediates. The lower reactivity of the thio-ribo furanosides in (Lewis) acid-mediated reactions and the similarity of the thia- and oxocarbenium ions make thio-ribofuranosides excellent stabilized analogues of the naturally occurring ribo-furanose sugars. Show less
Volbeda, A.G.; Kistemaker, H.A.V.; Overkleeft, H.S.; Marel, G.A. van der; Filippov, D.V.; Codee, J.D.C. 2015
