Biomedical subjects

R Daniel Little

Publications and source records attributed to R Daniel Little.

8 recordsLinked to original sources

PubMed2006

7,11-epi-thyrsiferol: completion of its synthesis, evaluation of its antimitotic properties, and the further development of an SAR model.

We (a) describe the completion of a total synthesis of 7,11-epi-thyrsiferol (4), (b) compare the antimitotic activities of thyrsiferol (2), Delta15,28-dehydrothyrsiferol (3), and 7,11-epi-thyrsiferol (4), (c) evaluate the synergistic behavior of the title compound and colchicine to inhibit cell proliferation, and (d) describe the results of conformational searches that provide additional insight concerning the SAR profile of the thyrsiferol family of natural products.

Animals↗

PubMed2005

Indirect electroreductive cyclization and electrohydrocyclization using catalytic reduced nickel(II) salen.

[Chemical reaction: See text] We describe efforts to achieve the electroreductive cyclization (ERC) and the electrohydrocyclization (EHC) reactions using catalytic nickel(II) salen as a mediator. While nickel(II) salen proved effective, the analogous cobalt complex as well as nickel(II) cyclam were not. The transformations were achieved in yields ranging from 60 to 94% using either a mercury pool or an environmentally preferable reticulated vitreous carbon (RVC) cathode. These examples represent the first instances wherein a nickel salen complex has been used in this manner. Clear differences between the voltammetric behavior of the ERC and EHC substrates were observed. The bisenoate 14, for example, displays a substantially larger catalytic current. When the structurally modified mediator 31 was used, the electron-transfer pathway shuts down. Instead, the reduced form of 31 behaves as an electrogenerated base, leading to the formation of the intramolecular Michael adduct 23. Presumably, the methyl groups of the modified ligand diminish the ability of the reduced form of the complex to serve as a nucleophile but not as a base. Aldehyde 23 was also characterized as a side product of the nickel(II) salen mediated electroreductive cyclization of 11. Given that it is absent from nonmediated processes, its formation is linked to the presence of the mediator. To account for the results, we favor the existence of a mechanistic continuum involving an equilibrium between nickel(II) salen (15) and two reduced forms, one being the metal-centered species 16, the other being a ligand-centered species 17. We postulate that one form may be more prominently involved with the chemistry than another, depending upon the electronic properties/requirements of the substrate, and suggest that the equilibrium will shift to accommodate the need. Thus, for a hard electrophile like an alkyl halide, the properties of 16 ought to dominate, whereas 17 ought to predominate as the reactive species accounting for the chemistry described herein since it properly matches a soft ligand-centered nucleophile with a soft electron deficient alkene.

Journal Article↗

PubMed2005

From C-glycosides to pyranopyrans: an approach to thyrsiferol using titanium(III)-promoted redox couplings.

An approach to the pyranopyran ring system that is found in many natural products, including thyrsiferol, is described. The route entails the assembly of an alpha,beta-unsaturated ketone (11) from geraniol and dihydropyran (23) from acetyl acetaldehyde dimethyl acetal (19) and their titanium(III)-promoted coupling to afford a respectable 60% yield of keto alcohol 26. The sigma-bond formed in this process corresponds to the pro-C(9)-C(10) bond of thyrsiferol (4). Attempts to invert the stereochemistry at the pro-C(11) center were thwarted by the congestion imparted by the presence of the vicinal TBS-ether. Consequently, cyclization of the coupling adduct under conditions developed by Olah and Prakash and co-workers led to the cis-fused pyranopyran 27. X-ray analysis of this crystalline material confirmed each of the stereochemical assignments. After much effort, it was determined that the hydroxyl group at C(12) could be removed by treating the derived methyl xanthate with a tri-n-butylphosphine-borane complex under radical-forming conditions. The reaction sequence worked well, despite the hindered working environment and the presence of a potentially labile C-Br bond.

Catalysis↗

PubMed2005

Remote substituent effects upon the rearrangements of housane cation radicals.

The rearrangement of a series of housane-derived cation radicals was investigated. Surprisingly, 2-aryl-substituted systems rearranged regioselectively and in a process whose selectivity proved to be independent of the electronic character of para substituents. The major reaction pathway is suggested to be the one that allows maximum delocalization, and allows it to be maintained for as long as possible. Bridging is invoked to account for the regio- and stereoselectivity. When a nonbridging trimethylsilylmethyl substituent is appended to C2, the regioselectivity is eroded entirely. B3LYP/6-31G(d) calculations corroborate the notion that bridging plays a role. While bridging ought to stabilize an intermediate by allowing delocalization of the charge/spin, there should be an accompanying entropic penalty. To determine the relative importance of enthalpic and entropic factors in determining the product selectivity, the rearrangement of the p-methoxyphenyl-substituted housane was investigated as a function of temperature. Enthalpic factors dominated over the entire temperature range that was explored. Overall, the results indicate that it is possible to influence the direction of migration in housane-derived cation radical rearrangements even when the regiochemical control unit is not directly appended to the migration terminus. This finding suggests that there may be other substituents that can be placed at C2 that could do the same, perhaps more efficiently.

Journal Article↗

PubMed2004

From dimerization, to cycloaddition, to atom transfer cyclization: the further chemistry of TMM diradicals.

We describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely tethered aldehyde, [b] the effect of a Lewis acid upon the course of TMM chemistry, [c] examples of exclusive intramolecular cycloaddition, competitive cycloaddition and ATC, and exclusive ATC, and [d] a set of predictive guidelines with which to assess whether cycloaddition or ATC will be the preferred path, and when the two processes will be competitive. Remarkably, a wide variety of structures can be obtained simply by varying the length of the tether within the diazenes investigated. DFT calculations were used to probe the energy surfaces for both atom transfer and cycloaddition. The transition structure for atom transfer involving the captodative system indicates that it occurs earlier along the reaction coordinate than for a system having only one radical stabilizing group. This is consistent with the existence of an exothermic process leading from the initial diyl to the captodatively stabilized distonic diyl. Gratifyingly, theory agrees with observation and provides substantial insight into the chemistry.

Cyclization↗

PubMed2003

Titanocene(III)-promoted Reformatsky additions.

[reaction: see text] A novel method for the promotion of Reformatsky-like reactions is presented. The technique employs titanocene(III) chloride as a mild and homogeneous single-electron reductant. The reactions are rapid, operationally simple, and compatible with a wide range of functionalities. These additions are also anti diastereoselective.

Journal Article↗

PubMed2003

Vanadium haloperoxidase-catalyzed bromination and cyclization of terpenes.

Marine red algae (Rhodophyta) are a rich source of bioactive halogenated natural products, including cyclic terpenes. The biogenesis of certain cyclic halogenated marine natural products is thought to involve marine haloperoxidase enzymes. Evidence is presented that vanadium bromoperoxidase (V-BrPO) isolated and cloned from marine red algae that produce halogenated compounds (e.g., Plocamium cartilagineum, Laurencia pacifica, Corallina officinalis) can catalyze the bromination and cyclization of terpenes and terpene analogues. The V-BrPO-catalyzed reaction with the monoterpene nerol in the presence of bromide ion and hydrogen peroxide produces a monobromo eight-membered cyclic ether similar to laurencin, a brominated C15 acetogenin, from Laurencia glandulifera, along with noncyclic bromohydrin, epoxide, and dibromoproducts; however, reaction of aqueous bromine with nerol produced only noncyclic bromohydrin, epoxide, and dibromoproducts. The V-BrPO-catalyzed reaction with geraniol in the presence of bromide ion and hydrogen peroxide produces two singly brominated six-membered cyclic products, analogous to the ring structures of alpha and beta snyderols, brominated sesquiterpenes from Laurencia, spp., along with noncyclic bromohydrin, epoxide, and dibromoproducts; again, reaction of geraniol with aqueous bromine produces only noncyclic bromohydrin, epoxide, and dibromoproducts. Thus, V-BrPO can direct the electrophilic bromination and cyclization of terpenes.

Catalysis↗

PubMed2002

Preparation of alpha-C-glycosides from glycals.

[reaction: see text]. A novel approach to simple C-glycosides is reported. Reductive ring opening of 1,2-anhydro sugars with titanocene(III) chloride produces an anomeric radical that can be trapped with a variety of agents. The reaction stereospecifically affords alpha-glycosides and produces a free C-2 hydroxyl group allowing for further elaboration.

Calcium Gluconate↗