Tetraethylphosphorodiamidate-Directed Metalation Group: Directed Ortho and Remote Metalation, Cross Coupling, and Remote Phospha Anionic Fries Rearrangement Reactions.

The linked directed ortho and remote metalation (DoM and DreM) and cross-coupling reactions of aryl phosphorodiamidates (Ar-OP(O)(NEt2)2) is reported. The o-iodo and o-boronato aryl tetraethylphosphorodiamidates 3, prepared by DoM, undergo orthogonal Ni- and Pd-catalyzed Suzuki-Miyaura cross coupling to furnish biaryls 4 and 5 in good to excellent yields. Silicon group protection of biaryl 4 via DoM followed by previously unobserved DreM phospha anionic Fries rearrangement affords biaryls 11 which, under acidic conditions, furnish oxaphosphorine oxides 12.

The Tetraethylphosphorodiamidate (OP(O)(NEt2)2) Directed Metalation Group (DMG). Directed ortho and Lateral Metalation and the Phospha Anionic Fries Rearrangement.

We report on the tetraethylphosphorodiamidate (-OP(O)(NEt2)2) group as an effective directed metalation group (DMG). Lithiation-electrophile quench of 1 provides a general synthesis of ortho-substituted aryl and naphthyl phosphorodiamidates 4-8. We also describe the phospha anionic ortho-Fries (AoF) rearrangement of the phosphorodiamidates 1a,1b → 2 or 3 and its vinylogous counterpart to the ortho-tolyl phosphorodiamidates 5b → 13. Intermolecular competition experiments demonstrate the approximately equal DMG strength of the -OP(O)(NEt2)2 and the most powerful OCONEt2 groups.

On the mechanism of the directed ortho and remote metalation reactions of N,N-dialkylbiphenyl 2-carboxamides.

A study concerning the mechanism of the LDA-mediated ortho and remote metalation of N,N-dialkyl-2-biphenyl carboxamides (e.g., 4a) is reported. On the basis of site-selective lithiation/electrophile quench experiments, including deuteration, the LDA metalation of 4 is proposed to involve initial amide-base complexation (CIPE) and equilibrium formation of 5, whose fast reaction with an in situ electrophile (TMSCl) to afford 6 prevents its equilibration with 7. In the absence of an electrophile, 5 undergoes equilibration via 4a with 7, whose fate is instantaneous cyclization to a stable tetrahedral carbinolamine oxide 8 which, only upon hydrolysis, affords fluorenone (3).

Directed ortho metalation-boronation and Suzuki-Miyaura cross coupling of pyridine derivatives: a one-pot protocol to substituted azabiaryls.

A general method for the synthesis of azabiaryls 19a-t by a one-pot procedure involving a Directed ortho metalation (DoM)-boronation-Suzuki-Miyaura cross coupling sequence is described. Aside from the three isomeric pyridyl carboxamides 15a-c, chloro-, fluoro-, and O-carbamoyl pyridines are adapted to this method providing a range of azabiaryls (Table 2). The method has an advantage in that it avoids the recognized difficult isolation of pyridyl boronic acids and their instability toward deboronation. The efficient synthesis of hydroxypicolinamides 12-14 (Scheme 3) by a one-pot metalation-boronation-oxidation sequence with the LDA-B(OiPr)3 in situ procedure that avoids self-condensation of incipient ortho-metalated species (Scheme 2) is delineated. The conversion of azabiaryls 19b,e,h,l into azafluorenones 20b,e,h,l by a directed remote metalation protocol is demonstrated (Table 3). A comprehensive survey of pyridyl boronates, of considerable interest in contemporary heterocyclic synthetic chemistry, is given (Figure 1).

Susceptibility to aflatoxin B1-induced carcinogenesis correlates with tissue-specific differences in DNA repair activity in mouse and in rat.

To investigate the mechanisms responsible for species- and tissue-specific differences in susceptibility to aflatoxin B(1) (AFB(1))-induced carcinogenesis, DNA repair activities of nuclear extracts from whole mouse lung and liver and rat liver were compared, and the ability of in vivo treatment of mice with AFB(1) to alter repair of AFB(1)-DNA damage was determined. Plasmid DNA containing AFB(1)-N(7)-guanine or AFB(1)-formamidopyrimidine adducts were used as substrates for the in vitro determination of DNA repair synthesis activity, detected as incorporation of radiolabeled nucleotides. Liver extracts from CD-1 mice repaired AFB(1)-N(7)-guanine and AFB(1)-formamidopyrimidine adducts 5- and 30-fold more effectively than did mouse lung, and approximately 6- and 4-fold more effectively than did liver extracts from Sprague-Dawley rats. The susceptibility of mouse lung and rat liver to AFB(1)-induced carcinogenesis correlated with lower DNA repair activity of these tissues relative to mouse liver. Lung extracts prepared from mice treated with a single tumorigenic dose of 50 mg/kg AFB(1) i.p. and euthanized 2 hours post-dosing showed minimal incision and repair synthesis activities relative to extracts from vehicle-treated mice. Conversely, repair activity towards AFB(1)-N(7)-guanine damage was approximately 3.5-fold higher in liver of AFB(1)-treated mice relative to control. This is the first study to show that in vivo treatment with AFB(1) can lead to a tissue-specific induction in DNA repair. The results suggest that lower DNA repair activity, sensitivity of mouse lung to inhibition by AFB(1), and selective induction of repair in liver contribute to the susceptibility of mice to AFB(1)-induced lung tumorigenesis relative to hepatocarcinogenesis.

The contrasting kinetics of peroxidation of vitamin E-containing phospholipid unilamellar vesicles and human low-density lipoprotein.

It is well established that alpha-tocopherol, TocH, is an outstanding lipid-soluble, peroxyl radical trapping antioxidant in homogeneous systems. It is also well established that TocH functions as a prooxidant in human low-density lipoprotein, LDL, subjected to attack by peroxyl radicals generated in the aqueous phase by, for example, thermal decomposition of the azo compound, ABAP. This tocopherol-mediated peroxidation, TMP, of LDL involves a three-step chain reaction, one step being hydrogen atom abstraction from the LDL lipids by the tocopheroxyl radical, Toc*. The occurrence of TMP has been attributed to three factors, (i) translocation by TocH of radical character from the aqueous phase into LDL lipid, (ii) isolation of the water-insoluble Toc* in the LDL particle in which it is formed for times sufficient to permit it to react with the lipid, and (iii) the small lipid volume of LDL which ensures that no particle can contain more than a single radical for a significant length of time. This consensus view of TMP implies that it should occur in any TocH-containing dispersion of small lipid particles. However, the present examination of the kinetics of the ABAP-initiated peroxidation of small unilamellar vesicles, SUVs, made from palmitoyllinoleoylphosphatidylcholine and cholesterol with a composition designed to mimic the surface coat of LDL, has shown that TocH functions as an antioxidant in such systems and that TMP does not occur under conditions where it would have occurred if the particles had been LDL. Several possible reasons for the kinetic differences between SUVs and LDL have been considered and ruled out by experiment. It is concluded that TMP can occur in LDL because these particles contain a lipid core in which the Toc* radical "hides" for much of its lifetime well away from the peroxyl radicals in the aqueous phase. In contrast, because SUVs have no lipid core, the Toc(*) radical is always "exposed" and available to aqueous peroxyl radicals with which it reacts rapidly and is destroyed before it can abstract a hydrogen atom from the lipid.