Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis.

A successful enone version of an intramolecular aza-[3 + 3] annulation reaction is described here. Use of piperidinium trifluoroacetate salt as the catalyst and toluene as the solvent appears to be critical for a successful annulation. We also demonstrated for the first time that microwave irradiation can accelerate aza-[3 + 3] annulation reactions. An attempt to expand the scope of the enone aza-[3 + 3] annulation was made in the form of propyleine synthesis as a proof of concept. While synthesis of the enone annulation precursor was successfully accomplished, the annulation proved to be challenging and was only modestly successful.

Total synthesis of (±)-phomactin A. Lessons learned from respecting a challenging structural topology.

Our struggles and ultimate success in achieving a total synthesis of phomactin A are described. Our strategy features an intramolecular oxa-[3 + 3] annulation to construct its unique ABD-tricyclic manifold. Although the synthesis would constitute a distinctly new approach with the 12-membered D-ring of phomactin A being assembled simultaneously with the 1-oxadecalin at an early stage, the ABD-tricycle represents a unique structural topology that would pose a number of unprecedented challenges. One challenge concerned elaborating this tricycle to have oxygenation at the proper carbon atoms. To overcome this, we would utilize a Kornblum-DeLaMare ring-opening of a peroxide bridge as well as a challenging late-stage 1,3-allylic alcohol transposition. Further, the structural intricacies of the ABD-tricycle were uncovered by a conformational analysis that would be critical for the C5a-homologation.

Constructing the Architecturally Distinctive ABD-Tricycle of Phomactin A through an Intramolecular Oxa-[3 + 3] Annulation Strategy.

Our efforts in constructing the ABD-ring of phomactin A through an intramolecular oxa-[3 + 3] annulation strategy is described. This struggle entailed finding a practical and efficient preparation of annulation precursor, and a realization of the unexpected competing regioisomeric pathway. The success entailed accessing the A-ring through Diels-Alder cycloaddition of Rawal's diene. Furthermore, the discovery that the regioisomers from the annulation existed as atropisomers with respect to the D-ring olefin and that they could be equilibrated to the desired ABD-tricycle, allowing large quantities of tricycle to be accessed.

An Enantioselective Synthesis of the ABD Tricycle for (-)-Phomactin A Featuring Rawal's Asymmetric Diels-Alder Cycloaddition.

An enantioselective synthesis of the ABD-ring of (-)-phomactin A is described here. The sequence features Rawal's asymmetric Diels-Alder cycloaddition. The overall length is significantly reduced from our previous attempt.

An Enantioselective Synthesis of the ABD Tricycle for (-)-Phomactin A Featuring Rawal's Asymmetric Diels-Alder Cycloaddition.

An enantioselective synthesis of the ABD-ring of (-)-phomactin A is described here. The sequence features Rawal's asymmetric Diels-Alder cycloaddition. The overall length is significantly reduced from our previous attempt.

Aza- and Carbo-[3 + 3] Annulations of Exo-Cyclic Vinylogous Amides and Urethanes. Synthesis of Tetrahydroindolizidines and An Unexpected Formation of Hexahydroquinolines.

[3 + 3] Annulations of exo-cyclic vinylogous amides and urethanes with vinyl iminium salts are described here. We observed an intriguing dichotomy in their reaction pathways. For pyrrolidine- and azepane-based vinylogous amides or urethanes, aza-[3 + 3] annulation would dominate to give tetrahydroindolizidines, whereas, unexpectedly, for piperidine-based vinylogous amides or urethanes, carbo-[3 + 3] annulation was the pathway, leading to hexahydroquinolines. The origin for such a contrast is likely associated with a switch in the initial reaction pathway between C-1,2-addition and C-1,4-addition.

Treatment of Distal Femur Nonunion Following Initial Fixation with a Lateral Locking Plate.

OBJECTIVE: To report and evaluate the outcomes of patients undergoing definitive treatment for distal femur nonunion after initial treatment with a locking plate. METHODS: Fourteen patients who had undergone definitive treatment at an academic Level 1 trauma center from May 2007 to December 2013 for distal femur nonunion were identified from a fracture database. Thirteen of them were female; the average age was 65 years (range, 50-84 years). Ten patients had sustained their injuries in falls at ground level, and four in motor vehicle accidents. Twelve patients were obese (body mass index ≥30), 10 had diabetes, none were current smokers, and one had an open fracture classified as type IIIa according to the Gustilo-Anderson classification system for open fractures. The fractures were classified according to the AO classification system for distal femur fractures; there were three type 33-A1, six 33-A2, two 33-A3 and three 33-C3 fractures. Methods of definitive treatment involved open reduction and internal fixation (ORIF) revision, medial plating, bone grafting and the use of other biologic materials. RESULTS: Eight of the 14 patients (57%) achieved union during follow-up. Definitive treatment for nonunion involved ORIF revision in 11 cases. Three patients who did not undergo ORIF revision were treated with iliac crest stem cell autografts, bone graft substitutes or recombinant human-bone morphogenetic protein-2 (rh-BMP-2). Other treatments included rh-BMP-2 (12 cases), iliac crest bone autograft (five), iliac crest stem cell autograft (two), crushed cancellous bone allograft (three), CaSO 4 and tricalcium phosphate bone graft substitute (two) and demineralized bone matrix (one). The average time from definitive treatment to union was 19 weeks (range, 12-51 weeks). Two of the 11 cases who underwent ORIF revision had medial plates added to improve biomechanical stability and prevent varus collapse. This was also performed in one patient with a grade III open type 33-C3 fracture and one with a closed 33-A2 fracture. Five study patients had comminuted fractures. Two had type 33-A3 and three type 33-C3 fractures. Both patients with 33-A3 fractures and 2 two with 33-C3 fractures had persistent nonunion at the end of follow-up. CONCLUSIONS: Definitive treatment of distal femur nonunion after initial treatment with a locking plate had a low rate of success in this study, suggesting that this procedure is ineffective as a definitive treatment for distal femur nonunion.

Systematic review of periprosthetic tibia fracture after total knee arthroplasties.

AIM: To investigate the known incidences, treatment options, and related outcomes of periprosthetic tibia fractures after total knee arthroplasty (TKA). METHODS: A literature search was done to identify studies that fit the inclusion criteria. The database search yielded 185 results, which were further reduced by the exclusion criteria to 13 papers, totaling 157 patients that met these criteria. Incidence rates of the different types of periprosthetic tibia fractures were determined and their treatments were subsequently analyzed based on the fracture's subclass, with patient outcomes being overall favorable. RESULTS: Of the 144 documented patients, 54 (37.5%) had a subclass C fracture, which are frequently seen in revision arthroplasties or when using cement intraoperatively. The fractures of subclasses A and B occur postoperatively. There were 90 subclass A and B fractures with incidences of 18.75% and 43.75% respectively. When broken down by type, 62 (55.36%) were type 1, 24 (21.4%) were type 2, 24 (21.4%) were type 3, and 2 (1.8%) were type 4. Furthermore, from the studies that included origin of injury, the types were further classified as having non-traumatic or traumatic origins. Type 1 had 78% (40/51) non-traumatic origin and 22% (11/51) traumatic origin. Fifteen fractures were type 2, but 5 were falls and 1 through a motor vehicle accident, giving a trauma causation of 40% (6/15). Of the 24 type 3 fractures, 12 were falls and 2 vehicular accidents, leading to a trauma causation of 58% (14/24). CONCLUSION: Type 1 fractures were the most common. Subclass A was treated with locking plates, B required a revision TKA, and C was treated intraoperatively or nonoperatively.

Asymmetric aza-[3+3] annulation in the synthesis of indolizidines: an unexpected reversal of regiochemistry.

An enantioselective and diastereoselective aza-[3+3] annulation of pyrrolidine-based exo-cyclic vinylogous amides and urethanes with chiral vinyl iminium salts is described. This asymmetric annulation manifold is possible because of an unexpected regiochemical reversal whereby head-to-tail annulations dominated over the predicted head-to-head. It should find prevalent synthetic applications in the enantioselective synthesis of indolizidines.

Total synthesis of phomactin A.

A total synthesis of (+/-)-phomactin A is described to highlight the final completion of a complex natural product target that had commenced with an intramolecular oxa-[3 + 3] annulation strategy in the construction of the ABD-tricycle. These efforts reveal structural intricacies of this ABD-tricycle with an illustrative example being the conformational analysis that was ultimately critical for the C5a-homolgation.