Ving J. Lee

In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines.

N,N-Dimethylglycylamido (DMG) derivatives of minocycline and 6-demethyl-6-deoxytetracycline are new semisynthetic tetracyclines referred to as the glycylcyclines. The in vitro activities of the glycylcyclines were evaluated in comparison with those of minocycline and tetracycline against strains carrying characterized tetracycline resistance determinants and against 995 recent clinical isolates obtained from geographically distinct medical centers in North America. The glycylcyclines were active against tetracycline-resistant strains carrying efflux [tet(A), tet(B), tet(C), and tet(D) in Escherichia coli and tet(K) in Staphylococcus aureus] and ribosomal protection [tet(M) in S. aureus, Enterococcus faecalis, and E. coli)] resistance determinants. Potent activity (MIC for 90% of strains, < or = 0.5 microgram/ml) was obtained with the glycylcyclines against methicillin-susceptible and methicillin-resistant S. aureus, E. faecalis, Enterococcus faecium, and various streptococcal species. The glycylcyclines exhibited good activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to minocycline and tetracycline. The activities of the glycylcyclines against most organisms tested were comparable to each other. The in vivo efficacies of the glycylcyclines against acute lethal infections in mice when dosed intravenously were reflective of their in vitro activities. The glycylcyclines had efficacies comparable to that of minocycline against infections with methicillin-susceptible and methicillin-resistant S. aureus strains, a strain carrying tet(K), and a tetracycline-susceptible E. coli strain but exceeded the effectiveness of minocycline against infections with resistant isolates, including strains harboring tet(M) or tet(B). Levels of DMG-6-deoxytetracycline in serum were higher and more sustained than those of DMG-minocycline or minocycline. Our results show that the glycylcyclines have potent in vitro activities against a wide spectrum of gram-positive and gram-negative, aerobic and anaerobic bacteria, including many resistant strains. On the basis of their in vitro and in vivo activities, the glycylcyclines represent a significant advance to the tetracycline class of antibiotics and have good potential value for clinical efficacy.

N-Linked solid phase peptide synthesis

Abstract The synthesis of N-linked peptides on solid phase is accomplished using a resin bound Boc equivalent. The formation of the peptide bond is done by an activated 2, 4-dinitrophenyl ester intermediate and an unprotected amino acid at the C-terminus. Further extension of the peptide and cleavage of the resin is done using mild conditions.

1.2 – Conjugate Additions of Reactive Carbanions to Activated Alkenes and Alkynes

The 1,4-conjugate addition of stabilized carbanions (1,3-dicarbonyl class) to α,β-unsaturated carbonyl compounds was reported by Michael in 1887 and quickly became established as an efficient method for carboncarbon bond formation.1 Numerous stabilized nucleophiles (donors) have been found to participate efficiently in 1,4-conjugate additions to other activated alkenes (acceptors).2 In general, the reactivity of acceptors (a3-synthons) towards various stabilized carbanions follows: α,β-unsaturated aldehydes >> α,β-unsaturated ketones > α,β-unsaturated nitriles > α,β-unsaturated esters > α,β-unsaturated amides.3 Although the basic synthetic principles and reactivity were investigated in early years, limitations to this versatile form of carboncarbon bond formation were observed. For example, the addition of organolithiums or organomagnesium halides to α,β-unsaturated aldehydes affords exclusive 1,2addition, while additions to α,β-unsaturated ketones afford predominant 1,2-addition. During the last four decades intensive research in the use of unstabilized carbon nucleophiles for 1,4-conjugate additions was stimulated by three events. First, Kharasch and Tawney reported that preferential 1,4-conjugate addition of alkylmagnesium halides to isophorone was effected by catalytic amounts of copper(I) chloride,4 and second, House, Respess and Whitesides showed that the actual reactive species in the earlier work was an organocopper species.5 Third, Gilman and Kirby reported a comparative study of the addition of various aryl metallics to benzalacetophenone (1,3-diphenylpropene-1-one) in which several Group II (R2Cd and R2Zn) and Group III (R3Al) organometallics afforded exclusive 1,4-conjugate addition.6

A novel reagent for regioselective cleavage of 2,3-epoxyalcohols by fluoride - a synthesis of 3-fluoro-293-dideoxy-d-erythro-pentose.

Abstract The cleavage of the oxirane ring of 3,4-anhydro-2deoxy-D-threo-pentose diethyl acetal by (isopropoxy)-titanium fluorides is discussed. The high regioselectivity found with bis(isopropoxy)titanium difluoride is the basis for an enantioselective synthesis of 3-fluoro-2,3-deoxy-D-erythreo-pentose from a non-carbohydrate precursor.

Synthesis of novel tetracycline derivatives with substitution at the C-8 position

Abstract The C-8 functionalization of tetracycline derivatives via acid-catalyzed rearrangement of 7(or 9)azidotetracyclines is described. These compounds are the first to be prepared from an intact tetracycline nucleus.

Conjugate Additions of Carbon Ligands to Activated Alkenes and Alkynes Mediated by Lewis Acids

The conjugate addition of stabilized carbanions, nonstabilized carbanions and heteroanions to activated alkenes and alkynes has been discussed extensively in previous chapters in this volume (Chapters 1.1 and 1.2). In summary, the regioselectivity of carbanion additions is sensitive to: (i) the electronegativity of the metal center;1 (ii) the Hard and Soft Acid–Base (HSAB) characteristics of the metal center and the transferring ligand;2 (iii) the structure of the acceptor;3 and (iv) reaction conditions and solvent effects.4 The difference in electronegativity between a metal and carbon is reflected in the degree of ionic character imparted to the carbon–metal σ-bond and the direction of polarization.5 Thus the highly ionic Groups IA and IIA organometallics (RK, RNa, RLi and RMgX; Volume 4, Chapter 1.2) are extremely reactive, in contrast to the less ionic Group IIB organometallics (R2Cd and R2Zn; Volume 4, Chapter 1.2).

Synthesis of 3-substituted (azido, acylthio, chloro or fluoro)-2,3-dideoxy-D-erythro-pentoses and 3-methyl-3-substituted-2,3-dideoxy-D-erythro-pentoses

Abstract The enantioselective synthesis of 3-substituted and 3-methyl-3-substituted 2,3-dideoxy-D- erythro -pentoses from (3 R ,4 R )-1,1-diethoxy-3,4-epoxypentane-5-ol, (3 R ,4 R) -1,1-diethoxy-3,4-epoxy-3-methylpentane-5-ol and (2 R ,3 R )-2,3-epoxy-5-hexen-1-ol is reported. The key step is cleavage of the oxirane ring by Ti(O- i -Pr) 3 X class reagents followed by selective cyclization of the acyclic acetals to the furanosides. Fluorination with the complex of titanium (IV) iso -propoxide - titanium (IV) fluoride provides an enantioselective synthesis of 3-fluoro-2,3-dideoxy-D- erythro -pentose and 3-fluoro-3-methyl-2,3-dideoxy-D- erythro -pentose.

Effect of A(1,3)-cis strain on the asymmetric epoxidation of (E)- and (Z)-6,6-diethoxy-3-hexen-2-ols and 4-methyl-6,6-diethoxy-3-hexen-2-ols

The effect of A(1,3)-cis strain on the diastereoselectivity of epoxidation of (E)-and (Z)-6,6-diethoxy-3-hexen-2-ols and 4-methyl-6,6-diethoxy-3-hexen-2-ols is analyzed, with some empiric observations provided. Increased A(1,3)-cis strain results in increased amounts of racemic threo-epoxy alcohols, while high ees are found for the erythro-epoxy alcohols.

Synthesis and crystal structure of 3′-fluoro-3′-methyl-2′,3′-dideoxythymidine. inhibitory properties of 3′-fluoro-3′-methyl-2′,3′-dideoxythymidine-5′-triphosphate in the synthesis of DNA in cell-free media

Abstract The synthesis, physicochemical properties and chain-termination properties of 3′-fluoro-3′-methyl-2′-3-dideoxythymidine is described. The synthesis was accomplished b the coupling of bis(TMS)thymine with 3-fluoro-3-methyl-2,3-dideoxy-D-erythro-pentose which is obtained from non-carbohydrate precursors.

AN EFFICIENT DEGRADATION OF TAZOBACTAM, A BETA-LACTAMASE INHIBITOR, TO METABOLITE M-1

Abstract An efficient preparative degradation of tazobactam [(2S,3R,5S)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-yl-methyl)-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylic acid 4,4-dioxide] to the metabolite M-1 [[S-(R∗,R∗)]-2-amino-3-methyl-3-sulfino-4-(1H-1,2,3-triazol-1-yl)butyric acid] without intermediacy of a chromatographic procedure is described.