The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.

Reaction of serine derived 1-alkoxy-2-azadienes with dehydroalanine derived dienophiles results in Diels-Alder reaction and aromatisation to give 2,3,6-trisubstituted pyridines, thereby establishing the viability of the proposed biosynthetic route to the pyridine ring of the thiopeptide antibiotics originally proposed by Bycroft and Gowland.

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SummaryAromatic compounds bearing an ortho-directing substituent may be deuterated by exchange with deuterium oxide in the presence of a range of cycloocta-1,5-dienyliridium(I)1,3-dionate catalysts. The exchange takes place in several dipolar aprotic solvents and is directly applicable to the deuteration of polar compounds. Isotope incorporation is efficient and regiospecific. The method is applicable to a wide range of ortho-directing groups some of which are only weak directors for alternative ortho-labelling approaches. In addition, the application of microwaves enables labelling within minutes even with sub-stituents which are poor directors.

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A detailed NMR study of the thiopeptide amythiamicin D establishes its solution conformation and the presence of a single intramolecular hydrogen bond involving NH13 and O28, and also provides the first evidence for self-association of thiopeptides in solution.

SUMMARY.In a group ofelderly patients with osteoporosis and femoral neck fracture, osteocalcin concentrations rose significantly in the first week after fracture fixation. The changes in osteocalcin correlated well with the changes in plasma 1,25-dihydroxycholecalciferol (P < 0'001).Osteomalacia is an important':" but uncommon] treatable accompaniment of femoral neck fracture. Current biochemical screening tests which rely on measurements of serum calcium and alkaline phosphatase have a high false positive rate." This is largely because alkaline phosphate arises from both bone and liver: hepatic dysfunction is common in the elderly fracture po pulation. ' The recent availability of radioimmunoassays for osteocalcin, a bone specific protein that is released during osteoblastic activity-7 and is stimulated by 1,25-dihydroxyvitamin D (1,25-(OH)2D)8.9 raises the possibility that it may be a more specific test for osteomalacia than serum alkaline phosphatase. The problem is that there is no information about changes in osteocalcin concentration during the immediate post-fracture period when it might be used for screening.In the present study we describe the changes in osteocalcin concentration which occur in the first week after a femoral neck fracture and its fixation. We have also examined its relationship to alkaline phosphatase, 1,25-(OHhD and bone histomorphometry. Patients and methodsThe study was based on 26 consecutive patients (3 male, 23 female; mean age 78·2 years, range 58-92 years) who had sustained a traumatic fracture of the femoral neck. Perioperative iliac crest bone biopsies had excluded osteomalacia in all cases: osteoid area < 3'5%; surface extent of osteoid < 25%, osteoid seam thickness index Fasting blood samples were taken pre-operatively, within 24 h of the fracture in all patients, and were repeated one week later by which time all fractures had been treated by internal fixation.Blood samples were collected into lithium heparin tubes and the plasma stored at -20°C until assay. Plasma calcium, phosphate, creatinine, albumin concentrations and alkaline phosphatase were measured by standard autoanalyser techniques. 10 Calcium concentrations were adjusted to a plasma albumin of 40 g/L.12Plasma osteocalcin concentrations were measured by radioimmunoassay (CIS(UK) Ltd, London, UK) using a rabbit antibody raised against bovine osteocalcin. 1,25-(OH)2D was extracted from plasma and purified by straight phase high performance liquid chromatography on a Zorbax-Sil column. I] The 1,25-(OH)2D peak was collected and quantitated by a competitive protein binding assay using calf thymus cytosol." Vitamin D binding protein (DBP) concentrations were measured by radial immunodiffusion.tv's The free 1,25-(OH)2D index was calculated as the molar ratio of 1,25-(OHhD/DBP x 10 5 • This gives a good estimate of the free 1,25-(OH)2D concentration." Parathyroid hormone (PTH) concentrations were measured using a C-terminal assay."Reference values for osteocalcin, 1,25-(OH)2D and DBP were derived from a group of health...