Selective approach toward multifunctionalized lactams by lewis acid promoted PhSe group transfer radical cyclization.

We have developed a regiospecific and highly stereoselective strategy for constructing the five-/six-membered monocyclic and bicyclic nitrogen heterocycle skeletons using PhSe group transfer radical cyclization of alpha-phenylseleno amido esters promoted by a Lewis acid (e.g., Yb(OTf)(3)) under UV irradiation. We obtained 5-/6-exo-trig mode cyclization products for the N-allyl/homoallyl substrates, whereas the enamide substrate gave 5-endo-trig ring closure.

Chiral alpha-aminoxy acid/achiral cyclopropane alpha-aminoxy acid unit as a building block for constructing the alpha N-O helix.

The monomer 1 derived from achiral 1-(aminoxy)cyclopropanecarboxylic acid (OAcc) and oligopeptides 2-9 consisting of a chiral alpha-aminoxy acid and an achiral alpha-aminoxy acid such as OAcc were synthesized and their structures characterized. The eight-membered-ring intramolecular hydrogen bond, namely the alpha N-O turn, was formed between adjacent residues independent of their chirality. However, the helix formation was sequence-dependent. Dipeptide 2 bearing chiral alpha-aminoxy acid (d-OAA) at the N-terminus and achiral OAcc at the C-terminus preferentially adopted a right-handed 1.8(8) helical structure, but dipeptide 3 (OAcc-d-OAA) did not. Theoretical calculation results, in good agreement with experimental ones, revealed that the biased handedness of alpha N-O turn found in OAcc residue depends on its preceding chiral residue. It was then found that the helical conformation was destroyed in the case of oligopeptides 6 and 7 [OAA-(OAcc)(n), n = 2, 3]. The crystal structure of tripeptide 8 ((i)PrCO-d-OVal-OAcc-d-OVal-NH(i)Bu) further disclosed the helical structure formed by three consecutive homochiral alpha N-O turns. This study has uncovered achiral aminoxy acid residues such as the OAcc unit as a useful building block to be incorporated into chiral aminoxy peptides to mimic chiral helix structure.

Synthesis and conformational studies of gamma-aminoxy peptides.

We have synthesized a series of gamma-aminoxy acids, including unsubstituted and gamma4-Ph-, gamma4-alkyl-, and gamma(3,4)-cyclohexyl-substituted systems. Coupling of these monomers to oligomers can be realized using EDCI/HOBt (or HOAt) as the coupling agent. gamma-Aminoxy peptides can form 10-membered-ring intramolecular hydrogen bonds-so-called "gamma N-O turns"-between adjacent residues, the extent of which is controlled by the nature of the side chain of each gamma-aminoxy acid residue, increasing from the unsubstituted gamma-aminoxy peptide to the gamma4-alkyl aminoxy peptides to the gamma4-phenyl- and gamma(3,4)-cyclohexyl-substituted aminoxy peptides. The presence of two consecutive homochiral 10-membered-ring intramolecular hydrogen bonds leads to the formation of a novel helical structure. Theoretical studies on a series of model peptides rationalize very well the experimentally observed conformational features of these gamma-aminoxy peptides.

Disulfide bond creates a small connecting loop in aminoxy peptide backbone.

Disulfide-bond formation between the side chains of cysteine-cysteine pairs is often critical to the folding behavior, stability, and functionality of proteins. In this paper, we report that sulfur atoms can be introduced into the amide groups of aminoxy peptides to form a novel type of disulfide bridge, which creates a connecting loop in the peptide backbone.

The galloyl moiety of green tea catechins is the critical structural feature to inhibit fatty-acid synthase.

It has been reported that inhibition of fatty-acid synthase (FAS) is selectively cytotoxic to human cancer cells. Considerable interest has developed in identifying novel inhibitors of this enzyme complex. Our previous work showed that green tea (-)-epigallocatechin gallate can inhibit FAS in vitro. To elucidate the structure-activity relationship of the inhibitory effects of tea polyphenols, we investigated the inhibition kinetics of the major catechins and analogues. Ungallated catechins from green tea do not show obvious inhibition compared with gallated catechins. Another gallated catechin, (-)-epicatechin gallate, was also found as a potent inhibitor of FAS and its inhibition characteristics are similar to (-)-epigallocatechin gallate. Furthermore, the analogues of galloyl moiety without the catechin skeleton such as propyl gallate also showed obvious slow-binding inhibition, whereas the green tea ungallated catechin not. Atomic orbital energy analyses suggest that the positive charge is more distinctly distributed on the carbon atom of ester bond of galloyl moiety of gallate catechins, and that gallated forms are more susceptible for a nucleophilic attack than other catechins. Here we identify the galloyl moiety of green tea catechins as critical in the inactivation of the ketoacyl reductase activity of FAS for the first time.

ß N-O turns and helices induced by ß2-aminoxy peptides: synthesis and conformational studies.

Herein, we report an efficient route for the asymmetric synthesis of ß(2)-aminoxy acids as well as experimental and theoretical studies of conformations of peptides composed of ß(2)-aminoxy acids. The nine-membered-ring intramolecular hydrogen bonds, namely, ß N-O turns, are generated between adjacent residues in those peptides, in accordance with our computational results. The presence of two consecutive homochiral ß N-O turns leads to the formation of ß N-O helical structures in solution, although both helical (composed of two ß N-O turns of the same handedness) and reverse-turn (composed of two ß N-O turns with opposite handedness) structures are of similar stability, as suggested by theoretical studies. Nevertheless, two slightly different conformations, with the same handedness, of ß(2)-aminoxy monomers have been observed in the solid state and in solution according to our X-ray and 2D NOESY studies.

Remote substituent effects on N-X (X = H, F, Cl, CH3, Li) bond dissociation energies in para-substituted anilines.

UB3LYP/6-311++g**//UB3LYP/6-31+g* and ROMP2/6-311++g**//UB3LYP/6-31+g* methods were used to calculate (i) N-X bond dissociation energies (BDE) in 4-YC6H4NH-X and (ii) N-H BDEs in 4-YC6H4NU-H, where Y = H, Me, OCH3, SMe, NH2, NMe2, SiMe3, F, Cl, CN, COOH, CF3, and NO2, X = H, CH3, F, Cl, and Li, and U = H, F, and CH(3). It was found that N-H BDEs of 4-YC6H4NH2 have a positive correlation with the substituent sigma(p+) constants. The slope (rho+) is about 3.0-4.3 kcal/mol, which is in good agreement with the experimental results. It was also found that the substituent effects on N-X BDEs of 4-YC6H4NH-X change considerably when X changes. rho(+)values for N-CH3, N-F, N-Cl, and N-Li BDEs were calculated to be 3.1-4.6, 1.3-1.9, 1.8-2.6, and 4.9-6.8 kcal/mol, respectively. The reason for the variation of substituent effects was proposed to be the ground-state effect, i.e., the interaction between the intact NH-X moiety and the parasubstituents. Finally, alpha-substitution was found to be able to significantly change the substituent effects. rho(+)values for N-H BDEs of 4-C6H4NCH3(-)H and 4-C6H4NF-H are 2.5-4.0 and 1.7-1.9 kcal/mol, respectively.

Effects of alpha-ammonium, alpha-phosphonium, and alpha-sulfonium groups on C-H bond dissociation energies.

C-H bond dissociation energies of alpha-ammonium-, alpha-phosphonium-, or alpha-sulfonium-substituted methanes and toluenes were calculated to a precision of 1-2 kcal/mol. It was found that alpha-ammonium, alpha-phosphonium, and alpha-sulfonium groups all destabilize a methyl radical. alpha-Ammonium also destabilizes a benzyl radical, whereas alpha-phosphonium and alpha-sulfonium either slightly stabilize or destabilize a benzyl radical depending on their alkylation state.

Remote substituent effects on bond dissociation energies of para-substituted aromatic silanes.

UB3LYP/6-31G(d) and ROMP2/6-311++G(d,2p) methods were used to calculate the Si-X bond dissociation energies (BDEs) of a number of para-substituted aromatic silanes (4-Y-C(6)H(4)-SiH(2)X, where X = H, F, Cl, or Li). It was found that the substituent effect on the Si-H BDE of 4-Y-C(6)H(4)-SiH(3) was small, as the slope (rho(+)()) of the BDE- regression was only 0.09 kJ/mol. In comparison, the substituent effect on the Si-F BDE of 4-Y-C(6)H(4)-SiH(2)F was much stronger, whose rho(+ )()value was -2.34 kJ/mol. The substituent effect on the Si-Cl BDE of 4-Y-C(6)H(4)-SiH(2)Cl was also found to be strong with a rho(+)() value of -1.70 kJ/mol. However, the substituent effect on the Si-Li BDE of 4-Y-C(6)H(4)-SiH(2)Li was found to have a large and positive slope (+9.12 kJ/mol) against. The origin of the above remarkably different substituent effects on the Si-X BDEs was found to be associated with the ability of the substituent to stabilize or destabilize the starting material (4-Y-C(6)H(4)-SiH(2)X) as well as the product (4-Y-C(6)H(4)-SiH(2)* radical) of the homolysis. Therefore, the direction and magnitude of the effects of Y-substituents on the Z-X BDEs in compounds such as 4-YC(6)H(4)Z-X should have some important dependence on the polarity of the Z-X bond undergoing homolysis. This conclusion was in agreement with that from earlier studies (for example, J. Am. Chem. Soc. 1991, 113, 9363). However, it indicated that the proposal from a recent work (J. Am. Chem. Soc. 2001, 123, 5518) was unfortunately not justified.