The Mechanics of the Bicycle Pedal Photoisomerization in Crystalline \u3cem\u3ecis,cis-\u3c/em\u3e1,4-Diphenyl-1,3-butadiene

Direct irradiation of crystalline cis,cis-1,4-diphenyl-1,3-butadiene (cc-DPB) forms trans,trans-1,4-diphenyl-1,3,-butadiene via a concerted two-bond isomerization called the bicycle pedal (BP) mechanism. However, little is known about photoisomerization pathways in the solid state and there has been much debate surrounding the interpretation of volume-conserving isomerization mechanisms. The bicycle pedal photoisomerization is investigated using the quantum mechanics/molecular mechanics complete active space self-consistent field/Amber force-field method. Important details about how the steric environment influences isomerization mechanisms are revealed including how the one-bond flip and hula-twist mechanisms are suppressed by the crystal cavity, the nature of the seam space in steric environments, and the features of the bicycle pedal mechanism. Specifically, in the bicycle pedal, the phenyl rings of cc-DPB are locked in place and the intermolecular packing allows a passageway for rotation of the central diene in a volume-conserving manner. In contrast, the bicycle pedal rotation in the gas phase is not a stable pathway, so single-bond rotation mechanisms become operative instead. Furthermore, the crystal BP mechanism is an activated process that occurs completely on the excited state; the photoproduct can decay to the ground state through radiative and non-radiative pathways. The present models, however, do not capture the quantitative activation barriers, and more work is needed to better model reactions in crystals. Last, the reaction barriers of the different crystalline conformations within the unit cell of cc-DPB are compared to investigate the possibility for conformation-dependent isomerization. Although some difference in reaction barriers is observed, the difference is most likely not responsible for the experimentally observed periods of fast and slow conversion

Enantioselective Synthesis of Piperidines through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies

An enantioselective intramolecular chiral phosphoric acid‐catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two‐step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous S N 2′‐like displacement to yield the product with stereoselectivity in agreement with experimental observations. Eine enantioselektive Cyclisierung ungesättigter Acetale mit einem chiralen Phosphorsäurekatalysator führt zu funktionalisierten Piperidinen. Die dabei erhaltenen chiralen Enolether durchlaufen anschließend in situ eine Enantiomerenanreicherung. Eine neue Rechenmethode wurde genutzt, um den Mechanismus und die Stereoselektivität dieser Transformation zu beleuchten. Cbz=Benzyloxycarbonyl; S =Anreicherungsfaktor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109322/1/ange_201405128_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/109322/2/11376_ftp.pd

Enantioselective Synthesis of Piperidines through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies

An enantioselective intramolecular chiral phosphoric acid‐catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two‐step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous S N 2′‐like displacement to yield the product with stereoselectivity in agreement with experimental observations. A rich seam : An enantioselective chiral phosphoric acid‐catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment. A new computational method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Cbz=benzyloxycarbonyl; S =resolution.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109355/1/anie_201405128_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/109355/2/11194_ftp.pd

Afadin orients cell division to position the tubule lumen in developing renal tubules

In many types of tubules, continuity of the lumen is paramount to tubular function, yet how tubules generate lumen continuity in vivo is not known. We recently found the F-actin binding protein Afadin is required for lumen continuity in developing renal tubules, though its mechanism of action remains unknown. Here we demonstrate Afadin is required for lumen continuity by orienting the mitotic spindle during cell division. Using an in vitro 3D cyst model, we find Afadin localizes to the cell cortex adjacent to the spindle poles and orients the mitotic spindle. In tubules, cell division may be oriented relative to two axes, longitudinal and apical-basal. Unexpectedly, in vivo examination of early stage developing nephron tubules reveals cell division is not oriented in the longitudinal (or planar polarized) axis. However, cell division is oriented perpendicular to the apical-basal axis. Absence of Afadin in vivo leads to misorientation of apical-basal cell division in nephron tubules. Together these results support a model whereby Afadin determines lumen placement by directing apical-basal spindle orientation, which generates a continuous lumen and normal tubule morphogenesis

Toward one‐pot olefin/thiophene block copolymers using an in situ ligand exchange

Block copolymers containing both conducting and insulating segments are of interest due to their enhanced electrical properties arising from their increased crystallization. Yet few methods exist for generating these copolymers, because the reaction conditions for synthesizing each block are often incompatible. Herein, efforts toward identifying a one‐pot, living polymerization method for synthesizing block copolymers of 1‐pentene and 3‐hexylthiophene is described. An in situ ligand exchange enables the optimal catalyst to be utilized for synthesizing each block. Even under these conditions, however, only homopolymers are observed. Computational studies modeling the ligand exchange reveal that the added stabilizing ligands likely inhibit propagation of the second block. These results suggest an ancillary ligand‐based “goldilocks” effect wherein catalysts that are stable yet still reactive are required. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1601–1605Combined experimental and computational studies revealed unexpected challenges in applying sequential catalysis for the streamlined synthesis of insulating/conducting block copolymers.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150553/1/pola29426_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150553/2/pola29426.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150553/3/pola29426-sup-0001-AppendixS1.pd

Experimental and Computational Studies on Regiodivergent Chiral Phosphoric Acid Catalyzed Cycloisomerization of Mupirocin Methyl Ester

This article presents a new strategy for achieving regiocontrol over the endo versus exo modes of cycloisomerizations of epoxide- containing alcohols, which leads to the formation of five- or six- membered cyclic ethers. Unlike traditional methods relying on achiral reagents or enzymes, this approach utilizes chiral phosphoric acids to catalyze the regiodivergent selective formations of either tetrahydrofuran- or tetrahydropyran- containing products. By using methyl ester of epoxide- containing antibiotic mupirocin as the substrate, it is demonstrated that catalytic chiral phosphoric acids (R)- TCYP and (S)- TIPSY could be used to achieve the selective formation of either the six- membered endo product (95:5 r.r.) or the five- membered exo product (77:23 r.r.), correspondingly. This cyclization was found to be unselective under the standard conditions involving various achiral acids, bases, or buffers. The subsequent mechanistic studies using state- of- the- art quantum chemical solutions provided the description of the potential energy surface, which is fully consistent with the experimental observations. Based on these results, highly detailed reaction paths are obtained and a concerted and highly synchronous mechanism is proposed for the formation of both exo and endo products.endo vs. exo: Chiral phosphoric acid catalysts are used for achieving regiocontrol over the endo vs. exo modes of cycloisomerizations of epoxide- containing antibiotic mupirocin methyl ester. This approach utilizes chiral phosphoric acids to catalyze the regiodivergent selective formations of either tetrahydrofuran- or tetrahydropyran- containing products. The mechanism of these reactions is investigated by using state- of- the- art quantum chemical solutions.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154885/1/chem201905222-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154885/2/chem201905222_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154885/3/chem201905222.pd

Integrin-dependent control of translation: engagement of integrin alphaIIbbeta3 regulates synthesis of proteins in activated human platelets.

Integrins are widely expressed plasma membrane adhesion molecules that tether cells to matrix proteins and to one another in cell-cell interactions. Integrins also transmit outside-in signals that regulate functional responses of cells, and are known to influence gene expression by regulating transcription. In previous studies we found that platelets, which are naturally occurring anucleate cytoplasts, translate preformed mRNA transcripts when they are activated by outside-in signals. Using strategies that interrupt engagement of integrin alphaIIbbeta3 by fibrinogen and platelets deficient in this integrin, we found that alphaIIbbeta3 regulates the synthesis of B cell lymphoma 3 (Bcl-3) when platelet aggregation is induced by thrombin. We also found that synthesis of Bcl-3, which occurs via a specialized translation control pathway regulated by mammalian target of rapamycin (mTOR), is induced when platelets adhere to immobilized fibrinogen in the absence of thrombin and when integrin alphaIIbbeta3 is engaged by a conformation-altering antibody against integrin alphaIIbbeta3. Thus, outside-in signals delivered by integrin alphaIIbbeta3 are required for translation of Bcl-3 in thrombin-stimulated aggregated platelets and are sufficient to induce translation of this marker protein in the absence of thrombin. Engagement of integrin alpha2beta1 by collagen also triggered synthesis of Bcl-3. Thus, control of translation may be a general mechanism by which surface adhesion molecules regulate gene expression

Butter Composition and Texture from Cows with Different Milk Fatty Acid Compositions Fed Fish Oil or Roasted Soybeans

Nutritional and physical properties of dairy products can be improved by changing milk fatty acid composition toward more unsaturation. Diet of cows, e.g., feeding supplemental fish oil (FO) or roasted soybeans (RSB), and cow selection can improve the nutritional and physical properties of dairy products and their acceptability to consumers. We examined whether feeding supplemental FO or RSB to cows that had a more unsaturated milk fatty acid composition acted additively to produce butter with improved fatty acid composition and texture. Multiparous Holstein cows chosen for producing either more or less unsaturated milk fatty acid composition (n = 6 in each group) were fed for three 3-week periods a control diet and two experimental diets that included additionally 0.9% of FO or 5% of RSB. The milk, collected in the third week of feeding, was used to make butter, which was analyzed for its fatty acid composition and physical properties. Dry matter intake, milk yield, and milk composition were not significantly affected by cow diet or by cow selection. Cows that produced, prior to the feeding study, a more unsaturated and healthful milk fat using a “health-promoting index” (HPI = [sum of % of unsaturated fatty acids] / [%C12:0 + 4 x %C14:0 + %C16:0]) maintained during the feeding study a higher HPI in their butter than did cows with a low HPI. Milk from cows fed supplemental FO or RSB yielded more unsaturated butters with higher HPI. This butter also was softer when the cows were fed RSB. Feeding RSB to cows chosen for their high milk HPI yielded the most unsaturated butter with the highest HPI and softest texture. Thus, selecting cows with a more healthful milk fatty acid composition and feeding cows supplemental RSB additively improved butter fatty acid composition and texture

Clinical and Economic Effectiveness of an Inpatient Anticoagulation Service

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90256/1/phco.19.13.1064.31591.pd