Synthesis of seco-B-ring bryostatin analogue WN-1 via C-C bond-forming hydrogenation: critical contribution of the B-ring in determining bryostatin-like and phorbol 12-myristate 13-acetate-like properties.

The seco-B-ring bryostatin analogue, macrodiolide WN-1, was prepared in 17 steps (longest linear sequence) and 30 total steps with three bonds formed via hydrogen-mediated C-C coupling. This synthetic route features a palladium-catalyzed alkoxycarbonylation of a C2-symmetric diol to form the C9-deoxygenated bryostatin A-ring. WN-1 binds to PKCα (Ki = 16.1 nM) and inhibits the growth of multiple leukemia cell lines. Although structural features of the WN-1 A-ring and C-ring are shared by analogues that display bryostatin-like behavior, WN-1 displays PMA-like behavior in U937 cell attachment and proliferation assays, as well as in K562 and MV-4-11 proliferation assays. Molecular modeling studies suggest the pattern of internal hydrogen bonds evident in bryostatin 1 is preserved in WN-1, and that upon docking WN-1 into the crystal structure of the C1b domain of PKCδ, the binding mode of bryostatin 1 is reproduced. The collective data emphasize the critical contribution of the B-ring to the function of the upper portion of the molecule in conferring a bryostatin-like pattern of biological activity.

Acquired facial palsy with hypertension secondary to Guillain-Barre syndrome.

Most cases of facial nerve paresis are idiopathic (Bell's palsy). However, rare and potentially dangerous conditions may present in this manner. We report 2 children presenting with unilateral lower motor neuron facial nerve palsy and hypertension. A diagnosis of Guillain-Barre syndrome was made in both; literature linking facial nerve palsy in childhood with hypertension and Guillain-Barre syndrome is reviewed.

Phosphine-Catalyzed (4+1) Annulation: Rearrangement of Allenylic Carbamates to 3-Pyrrolines through Phosphonium Diene Intermediates.

We have developed a phosphine-catalyzed (4+1) annulative rearrangement for the preparation of 3-pyrrolines from allenylic carbamates via phosphonium diene intermediates. We employed this methodology to synthesize an array of 1,3-disubstituted- and 1,2,3-trisubstituted-3-pyrrolines, including the often difficult to prepare 2-alkyl variants. A mechanistic investigation employing allenylic acetates and mononucleophiles unexpectedly unveiled that a phosphine-catalyzed (4+1) reaction for the construction of cyclopentene products, previously reported by Tong, might not occur through a phosphonium diene, as had been proposed, but rather through multiple mechanisms working in concert. Consequently, our phosphine-catalyzed rearrangement is most likely the first transformation to involve the unequivocal formation of a phosphonium diene intermediate along the reaction pathway. To demonstrate the synthetic utility of this newly developed reaction, we have completed concise formal syntheses of the pyrrolizidine alkaloids (±)-trachelanthamidine and (±)-supinidine.

Highly efficient palladium-catalyzed hydrostannation of ethyl ethynyl ether.

The palladium-catalyzed hydrostannation of acetylenes is widely exploited in organic synthesis as a means of forming vinyl stannanes for use in palladium-catalyzed cross-coupling reactions. Application of this methodology to ethyl ethynyl ether results in an enol ether that is challenging to isolate from the crude reaction mixture because of incompatibility with typical silica gel chromatography. Reported here is a highly efficient procedure for the palladium-catalyzed hydrostannation of ethyl ethynyl ether using 0.1% palladium(0) catalyst and 1.0 equiv of tributyltin hydride. The product obtained is a mixture of regioisomers that can be carried forward with exclusive reaction of the beta-isomer. This method is highly reproducible; relative to previously reported procedures, it is more economical and involves a more facile purification procedure.

Neurogenic pulmonary edema in enterovirus 71 encephalitis is not uniformly fatal but causes severe morbidity in survivors.

During the Australian summer of 2000/2001, there was an outbreak of enterovirus 71 infection in Sydney. Between December 2000 and May 2001, approximately 200 children presented to Sydney Children's Hospital with hand-foot-and-mouth disease and 18 experienced neurologic complications. Four presented with acute invasive central nervous system disease and severe pulmonary edema. We describe the cardiorespiratory disturbances and intensive care management of these four consecutive children successfully treated for neurogenic pulmonary edema attributed to proven enterovirus 71 infection. All four survived the acute stage of the illness. However, all four have been left with significant debilitating morbidity. Epidemic enterovirus 71 brainstem encephalitis presenting as neurogenic pulmonary edema can be successfully managed in the pediatric intensive care unit but has great potential to yield a large number of handicapped toddlers and become "the poliomyelitis of the 21st century."

Enantioselective total synthesis of (+)-ibophyllidine via an asymmetric phosphine-catalyzed [3 + 2] annulation.

In this study we performed the total synthesis of the terpene indole alkaloid (+)-ibophyllidine through a pathway involving asymmetric phosphine catalysis, with our novel l-4-hydroxyproline-derived chiral phosphine mediating the key [3 + 2] annulation. Hydrogenation of the [3 + 2] adduct allowed the rapid formation of the stereochemically dense pyrrolidine ring of (+)-ibophyllidine in excellent yield with exceptionally high levels of both diastereo- and enantioselectivity. We constructed the remainder of the pentacyclic skeleton through an intramolecular alkylation and an intramolecular aza-Morita-Baylis-Hillman reaction.

Phosphine-catalyzed intramolecular γ-umpolung addition of α-aminoalkylallenic esters: facile synthesis of 3-carbethoxy-2-alkyl-3-pyrrolines.

An array of N-tosylated α-aminoalkylallenic esters was prepared and their cyclization under the influence of nucleophilic phosphine catalysts was explored. The α-aminoalkylallenic esters were prepared through aza-Baylis-Hillman reactions or novel DABCO-mediated decarboxylative rearrangements of allenylic carbamates. Conversion of these substrates to 3-carbethoxy-2-alkyl-3-pyrrolines was facilitated through Ph(3)P-catalyzed intramolecular γ-umpolung addition.