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Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (>10:1, 76%) without problematic C(2)(3) epimerization provided the basicity of the reaction is minimized.

The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF, >/=95%) and diastereoselective (>/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.

Teicoplanin 1,2 is a complex of five antibiotics isolated from Actinoplanes teichomyceticus that are related to vancomycin [3][4][5][6][7][8] which is enlisted as the drug of last resort for treatment of resistant bacterial infections or for patients allergic to -lactam antibiotics. 6 It is 2-8-fold more potent, possesses a lower toxicity, exhibits a longer half-life in man (40 vs 6 h), and is easier to administer and monitor than vancomycin.Herein we describe the first total synthesis of the teicoplanin aglycon (1). 9-12 Although teicoplanin bears the identical ABCD ring system and the same CDE atropisomer stereochemistry as vancomycin, it contains a DE ring system that lacks the -hydroxy group of the vancomycin E-ring substituted phenylalanine (C 2 residue) and incorporates an especially racemization prone substituted phenylglycine C 3 residue. 13 Most significantly, it contains the additional 14-membered FG ring system not found in vancomycin. Key elements of the approach include sequential DE and FG ring system introductions onto the common vancomycin/teicoplanin ABCD ring system providing a late stage divergent total synthesis of the two classes of glycopeptide antibiotics. The ring systems were introduced enlisting a nucleophilic aromatic substitution reaction of an o-fluoronitroaromatic for macrocyclization and formation of the 16-membered DE diaryl ether and a macrolactamization 14 of the N-terminus amide for closure of the 14-membered FG ring system. With the respective order of closures, the choice of substrates, and the conditions enlisted, no epimerization of the sensitive C 2 3 center was observed.Because of the facile C 2 3 epimerization observed within the confines of the teicoplanin FG ring system, 13 the FG diaryl ether was formed using an intermolecular nucleophilic aromatic substitution reaction with acyclic phenylglycinol substrates incapable of epimerization. Thus, coupling of 2 15 and 3 16 (6 equiv of K 2 CO 3 , 5 equiv of 18-c-6, 0.1 M DMSO, 14 h, 25°C) provided 4 (70%), Scheme 1. Reactions conducted in DMSO were substantially faster than those conducted in DMF and the (1) Parenti, F.; Beretta, G.; Berti, M.; Arioli, V. J. Antibiot. 1978, 31, 276. (2) Hunt, A. H.; Molloy, R. M.; Occolowitz, J. L.; Marconi, G. G.; Debono, M. J. Am. Chem. Soc. 1984, 106, 4891. Barna, J. C. J.; Williams, D. H.; Stone, D. J. M.; Leung, T.-W. C.; Doddrell, D. M. J. Am. Chem. Soc. 1984, 106, 4895. (3) McCormick, M. H.; Stark, W. M.; Pittenger, G. E.; Pittenger, R. C.; McGuire, J. M. Antibiot. Annu. 1955-1956, 606. (4) Harris, C. M.; Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983, 105, 6915. Williamson, M. P.; Williams, D. H. (10) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Bräse, S.; Rübsam, F. Chem. Eur. J. 1999, 5, 2584. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602. Nicolaou, K. C.; Koumbis, A. E.; Takayanagi, M.; Natarajan, S.; Ja...

No abstract

Background: Fontan-associated liver disease (FALD) is an important late complication involving liver dysfunction, such as liver cirrhosis (LC) and hepatocellular carcinoma (HCC), in patients undergoing the Fontan procedure. However, the prevalence, clinical manifestation, and methods of diagnosis of FALD are still not well established. Methods and Results:This study comprised 2 nationwide surveys in Japan. First, the prevalence of LC and/or HCC in patients undergoing the Fontan procedure was determined. Second, clinical manifestations in patients with LC and/or HCC were analyzed, along with data from blood tests, echocardiography, and right heart catheterization. In the 1st survey, of the 2,700 patients who underwent the Fontan procedure, 31 were diagnosed with LC and/or HCC (1.15%), and 5 died due to liver diseases (mortality: 0.19%). In the 2nd survey, data were collected from 17 patients (12 with LC, 2 with HCC, and 3 with LC+HCC. Of these 17 patients, 5 died (mortality: 29.4%). The mean age at diagnosis of LC and HCC was 23 and 31 years, respectively. Computed tomography followed by ultrasound was most frequently used for diagnosis. Blood tests revealed low platelet counts, increased hemoglobin, aspartate aminotransferase, γ-guanosine triphosphate, and total bilirubin levels, and an elevated international normalized ratio of prothrombin time.Conclusions: LC and/or HCC in patients undergoing the Fontan procedure were not rare late complications and were associated with high mortality rates.

Long-term treatment with ACE inhibitors is effective in reducing not only LV volume overload but also LV hypertrophy in the hearts of growing children with LV volume overload.

yanotic congenital heart disease (CCHD) is associated with an increased risk of stroke and thromboembolism. 1 A recent study using contrast-enhanced computed tomography revealed a high prevalence of pulmonary thrombosis in patients with Eisenmenger syndrome. 2 The precise mechanisms of the increased incidence of thromboembolism in patients with CCHD have not yet been determined, but endothelial dysfunction, hemostatic abnormalities and platelet activation may be underlying factors causing hypercoagulability and thromboembolism. [3][4][5] Platelets interact with endothelial cells, leukocytes and other platelets. 6 Intravascular thrombus formation is enhanced by thrombin, which activates the coagulation cascade, platelets and the formation of neutrophil/platelet conjugates. 6-8 P-selectin is an adhesion molecule found in the secretory granules of platelets and Weibel -Palade bodies of endothelial cells, and is mobilized to the plasma membrane on activation. 6,9,10 P-selectin expressed on platelets may be a direct inducer of pro-coagulant activity associated with vascular and thrombotic diseases. 11 Although P-selectin is likely to play an important role in the thrombus formation, 6,11 there have been only a few studies evaluating Pselectin in CCHD. 4,12,13 Thrombomodulin is expressed mainly on the surface of vascular endothelial cells and prevents blood clotting on the internal surface of vessels. Endothelial thrombomodulin is a key component of the protein C anticoagulant pathway that facilitates the activation of protein C by thrombin. 14 Therefore, thrombomodulin acts as an intrinsic anticoagulant barrier between the blood and the endothelium. The plasma thrombomodulin level was elevated in disseminated intravascular coagulation and atheromatous arterial disease. 15,16 It may initially increase with acute vascular injury but decrease with subsequent downregulation of its production during chronic vessel injury. Several reports have shown that reduced thrombomodulin enhances thrombus formation. 17,18,19 We hypothesized that the decreased expression of protein C and the increased expression of Pselectin on platelets due to a reduced thrombomodulin level may contribute to the formation of thrombi in patients with CCHD. To test this hypothesis, we measured plasma levels of thrombomodulin and protein C, and the expression of Pselectin on platelets in patients with CCHD. The plasma thrombin -antithrombin complex III (TAT) level was also measured to evaluate coaguability. Methods PatientsWe enrolled 35 patients with CCHD. The inclusion criterion was the presence of cyanosis due to right-to-left shunt in patients with congenital heart disease. The demography of the patients is summarized in Table 1. There were 19 men and 16 women, with a mean age of 13±11 years, ranging from 1 to 37 years. Twenty-five patients had undergone palliative operations (Balock-Taussig shunt or bidirectional Glenn). Eight patients underwent definitive operations (Fontan operation in 7 and Rastelli operation in 1), but the Circ J 2007; 71: 948...