Open-cyclic warfarin isomerism: 5-hydroxywarfarin

Addition of a 5-hydroxy substituent to warfarin [3-(1-phenyl-3-oxobutyl)-4-hydroxycoumarin] shifts the solution equilibrium in chloroform to favor the open isomeric form over the two cyclic diastereomeric hemiketals. X-ray diffraction analysis reveals 5-hydroxywarfarin crystallizes as the open isomer in contrast to the more than 20 warfarin and analog structures which occur ascis ortrans hemiketal forms in the solid. The two peri hydroxyl groups in the structure of 3-(1-phenyl-3-oxobutyl)-4,5-dihydroxycoumarin are intramolecularly H-bonded. Methyl kctal derivatives of 5-hydroxywarfarin and a close analog effectively model the minor cyclic hemiketal forms in solution. Structures of bothcis andtrans cyclic methyl ketals of 3-(4-oxopent-2-yl)-4,5-dihydroxy-coumarin have been determined and the aryl hydroxyls H-bond to the dihydropyranyl ring oxygens of the cyclic ketals. Nuclear magnetic resonance studies suggest that these intramolecular H-bonds persist in chloroform solution. Infrared spectroscopy on the series of compounds in KBr pellets is consistent with the crystallographically determined structures and H-bonding schemes.     

Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines

There are more than 400‐reported bisbenzylisoquinoline alkaloids, many with interesting biological activity, but the reported syntheses are long and low yielding. As a result, there have been no systematic attempts at exploitation of the potential therapeutic applications. The concept of a sulfur ‘stitch’, restricting the conformational freedom of intermediates in the synthesis, will potentially allow analogues of the natural products to be prepared using relatively efficient routes. The synthesis of intermediate sulfur heterocycles is reported, based on 2,8‐dimethylphenoxathiin, leading via 2,8‐bis(bromomethyl)phenoxathiin‐10,10‐dioxide to a synthesis of 3,4,8,9‐tetrahydro‐13‐oxa‐6‐thia‐2,10‐diazapentacene, a key potential intermediate on the route to a variety of macrocyclic bisbenzylisoquinolines.     

Synthesis of 8-(S)-methoxy-11-desmethyl laulimalide: a novel laulimalide analogue

A strategy is outlined which enables preparation of novel laulimalide analogues at C.8 and C.11. A representative analogue, 8-(S)-methoxy-11-desmethyl laulimalide, was synthesized via this route.     

Avoiding the classical resolution during the synthesis of MeO-BIPHEP and 3,3′-disubstituted derivatives

The Ullmann coupling of 1 (R = H) gives a 2:1 mixture of diastereomers 2 (R = H) in 81% yield that are easily separated by silica gel chromatography. This procedure avoids the generally cumbersome and sometimes difficult resolution step with DBTA. Similar Ullmann couplings and separation of the corresponding diastereomers are employed with other derivatives of 1 (R = OtBu, iPr, Ph, and mesityl) ultimately affording a new series of 3,3′-disubsituted-MeO-BIPHEP derivatives. The use of these new derivatives in palladium-catalyzed asymmetric Heck reaction, Pd-catalyzed polyene cyclizations and rhodium-catalyzed hydrogenations is also reported.     

Effects of acoustic parameters on bubble cloud dynamics in ultrasound tissue erosion (histotripsy)

High intensity pulsed ultrasound can produce significant mechanical tissue fractionation with sharp boundaries ("histotripsy"). At a tissue-fluid interface, histotripsy produces clearly demarcated tissue erosion and the erosion efficiency depends on pulse parameters. Acoustic cavitation is believed to be the primary mechanism for the histotripsy process. To investigate the physical basis of the dependence of tissue erosion on pulse parameters, an optical method was used to monitor the effects of pulse parameters on the cavitating bubble cloud generated by histotripsy pulses at a tissue-water interface. The pulse parameters studied include pulse duration, peak rarefactional pressure, and pulse repetition frequency (PRF). Results show that the duration of growth and collapse (collapse cycle) of the bubble cloud increased with increasing pulse duration, peak rarefactional pressure, and PRF when the next pulse arrived after the collapse of the previous bubble cloud. When the PRF was too high such that the next pulse arrived before the collapse of the previous bubble cloud, only a portion of histotripsy pulses could effectively create and collapse the bubble cloud. The collapse cycle of the bubble cloud also increased with increasing gas concentration. These results may explain previous in vitro results on effects of pulse parameters on tissue erosion.     

Hydrogenations at Room Temperature and Atmospheric Pressure with Mesoionic Carbene‐Stabilized Borenium Catalysts

1,2,3‐Triazolylidene‐based mesoionic carbene boranes have been synthesized in a convenient one‐pot protocol from the corresponding 1,2,3‐triazolium salts, base, and borane. Borenium ions are obtained by hydride abstraction and serve as catalysts in mild hydrogenation reactions of imines and unsaturated N‐heterocycles at ambient pressure and temperature.     

Palladium(II)‐Catalyzed Allylic C?H Oxidation of Hindered Substrates Featuring Tunable Selectivity Over Extent of Oxidation

The use of Oxone and a palladium(II) catalyst enables the efficient allylic C H oxidation of sterically hindered α‐quaternary lactams which are unreactive under known conditions for similar transformations. This simple, safe, and effective system for C H activation allows for unusual tunable selectivity between a two‐electron oxidation to the allylic acetates and a four‐electron oxidation to the corresponding enals, with the dominant product depending on the presence or absence of water. The versatile synthetic utility of both the allylic acetate and enal products accessible through this methodology is also demonstrated.     

Heterogeneous surface-to-air missile defense battery location: a game theoretic approach

In the context of an air defense missile-and-interceptor engagement, a challenge for the defender is that surface-to-air missile batteries often must be located to protect high-value targets dispersed over a vast area, subject to which an attacker may observe the disposition of batteries and subsequently develop and implement an attack plan. To model this scenario, we formulate a two-player, extensive form, three-stage, perfect information, zero-sum game that accounts for, respectively, a defender’s location of batteries, an attacker’s launch of missiles against targets, and a defender’s assignment of interceptor missiles from batteries to incoming attacker missiles. The resulting trilevel math programming formulation cannot be solved via direct optimization, and it is not suitable to solve via full enumeration for realistically-sized instances. We instead adapt the game tree search technique Double Oracle, within which we embed either of two alternative heuristics to solve an important subproblem for the attacker. We test and compare these solution methods to solve a designed set of 52 instances having parametric variations, from which we derive insights regarding the nature of the underlying problem. Enhancing the solution methods with alternative initialization strategies, our superlative methodology attains the optimal solution for over 75% of the instances tested and solutions within 3% of optimal, on average, for the remaining 25% of the instances, and it is promising for realistically-sized instances, scaling well with regard to computational effort.