Chemistry, Organic

Herein, we discuss a novel method for the synthesis of decorated 2,5-dihydrofurans. The base promoted 5-endo-dig cyclization of non-Conia-ene propargyl ethers produces 2,2 disubstituted dihydrofurans. Central to the reaction is the presence of an acidic C–H bond which is activated by an adjacent aromatic heterocycle. The transformation is viable with a wide range of substituents, including N, O, and S containing heterocycles, substituted phenyl rings, and alkyl groups. The cyclization proceeds within 30 seconds at room temperature under the action of potassium tert-butoxide. This work stands apart from the current literature due to the absence of transition metal catalysts and/or harsh reaction conditions. A thorough mechanistic investigation is undertaken to better understand the nature of this unprecedented reaction.

In the present dissertation, we discuss the development of a stereoselective method for the production of phosphorus compounds that utilizes a phospha-Michael addition reaction. Separately, the design and synthesis of compounds that contain an all-carbon bridged bicyclic scaffold is reported; these compounds were used in initial SAR studies in different in vivo models. In Chapter one is presented a mechanistic framework to develop a highly diastereoselective method catalyzed by phase transfer chemistry leading to phosphinate compounds. In this method, phosphinate nucleophiles were added to various alkenyl ketones as Michael acceptors using crown ethers as phase transfer agents to obtain highly diastereoselective products with the generation of a carbon-based quaternary centers. A closed transition state mechanism is proposed to describe the diastereoselectivity observed in the reactions that is consistent with product outcome as established by X-ray crystallography. Analysis using the 31P NMR technique is also reported to ascertain the diastereomeric ratios in product formation. Using products obtained with the newly developed method, we disclose for the first time a novel phospha-heterocycle with high control of stereochemistry. Relative stereochemistry of the phosphorus containing heterocycle was reported using 2D NMR analysis. In Chapter two focus is placed on the use of acrylates as Michael acceptors in both the diastereoselective and enantioselective studies of phospha-Michael addition. In the asymmetric method development, screening of various chiral catalysts and development of HPLC method to quantify the enantiopurity of products obtained under reaction conditions are reported. The role of crown ether catalysts towards diastereoselectivity is reported.

A novel carbohydrate receptor based on the structure of the antibiotic polymxin B
was synthesized. The receptor was a cyclic heptapeptide. which was bridged
using 2, 2'-bi pyridine-5,5"- dicarboxylic acid. The association constants of the
receptor and a variety of sugars were determined using UV /Vis and fluorescence
spectroscopy and observed log K0 values are in the range from 3 .8 to 4.1 for the
pentoses, logKa 3.3 to 3.8 for the hexoxes and 0 to 2.9 logKa values from 0-2.9 for
disaccharides and logKa of2.6 to 3.11 for the charged sugars.
We demonstrated that polymixin based receptors are capable of binding various
monosaccharide substrates in aqueous media, displaying structure selectivity with
respect to monosaccharide ring size.

The ferrocenylrnethylation of the following compounds was studied
using (ferrocenylmethyl)trimethylammonium iodide: 1, 1-di(p-anisyl)-
ethene (I), 1, 1-di(p- anisyl)propene (II), 1- (p- anisyl)-1-phenylethene
(III), 1, 1- diphenylethene (IV), 1, 1- di(p- dimethylaminophenyl )ethene
(V) and 1, 1-di(p-dimethylaminophenyl)propene (VI). I is ferrocenylmethylated
exclu,sively on its side-chain, one or both vinyl hydrogens
being replaced by ferrocenylmethyl groups depending on the ratio of
ferrocenylmethylating agent to I, concentration of the reaction mixture,
reaction time, solvent and temperature. II is substituted only on its
side-chain to give a mono-ferrocenylmethylated product. III is ferrocenylmethylated
slowly. IV fails to react. Mono-ferrocenylmethylation
of V occurs principally on its side- chain; more extensive ferrocenylmethylation
occurs both on the side-chain and on the rings at the
position ortho to dimethylamino. VI reacts quite indiscriminately both
on the side-chain and on the rings.

Research directed toward renewable, non-destructive sources of bioactive marine derived compounds, is becoming more important everyday. Marine soft corals known as sea whips are a prolific source of such biologically active compounds. One particular organism, Eunicea fusca, possesses diterpene arabinose glycosides with potent antiinflammatory activity that rival the industry standard indomethicin. Fuscocide B is known to inhibit phorbol myristate acetate (PMA)-induced ear edema in murine models, is a minor secondary metabolite and it is therefore difficult to acquire in large quantities. Alternatively, fuscol and eunicol, are known to have similar antiinflammatory activity and are major secondary metabolites which are structurally similar to fuscocide B and are also produced by E. fusca. We have found that fuscol and eunicol can be extracted from the holobiont, and Symbiodinium (Symbiodinium sp.) cells isolated from E. fusca. Similarly, diterpene glycosides, known as pseudopterosins, have been isolated from the the holobiont, and purified Symbiodinium of Pseudopterogorgia elisabethae. Pseudopterosins are also known to possess anti-inflammatory and analgesic properties superior to that of existing drugs. Since many chemically unique metabolites demonstrating bioactive properties have been introduced into pre-clinical and clinical trials I-III5 and the supply issue has been duly highlighted, it has become advantageous to determine the source of these compounds in each of the above mentioned species and determine if a renewable, non-destructive source can be maintained. Data has been presented suggesting that the actual source of the pseudopterosins is not the coral, but actually the dinoflagellate symbiont associated with Pseudopterogorgia elisabethae. Therefore, we have examined cryopreservation of the dinoflagellate symbionts, induction of terpene biosynthesis in the dinoflagellate symbionts, as well as various cell culture techniques in order to better understand the ecological role of terpene biosynthesis in the symbionts and the host corals. The data obtained in the following studies reveals a bacterial source for the production of bioactive secondary metabolites from Eunicea fusca and lends support to a possible bacterial producing trend in gorgonians.

We report here the development of an efficient method for the conversion of a variety of conjugated alkynyl esters to alpha-substituted conjugated allenyl esters (racemic) through the use of strong amide bases. Substantially improved yields over typical enolate formation conditions were observed with the use of two equivalents of lithium diisopropylamide. Trapping studies indicate that the second equivalent of base likely leads to the dianion intermediate which upon addition of methyl iodide and trimethylsilyl chloride gives mixtures of alpha-substituted conjugated allenyl and beta,gamma-alkynyl deconjugated esters. Further optimization revealed that additive salts such as LiCl lead primarily to the allenyl product while the use of HMPA as a cosolvent gives the beta,gamma-alkynyl deconjugated alkylation product. The role of base, base concentration and electrophile on product yield and selectivity is also discussed. The optimized conditions resulting from our study of this reaction establishes this method as a viable synthetic tool for the production of alpha-substituted allenyl esters. A new method to prepare racemic alpha-tributylstannyl-alpha-allenyl esters from precursor conjugated alkynyl esters in good yields is reported. Key features of the optimized reaction conditions include the use of multiple equiv. of lithium diisopropylamide in THF with LiCl as a key additive. The allenyl tin reagent reacts with aldehydes in the presence of Lewis acid to give homopropargyl alcohol or allenyl alcohol products depending on the reaction conditions. The addition of boron trifluoride etherate to a solution of the allenyltin and aldehyde gives the homopropargyl alcohol. However, allenyl alcohol products are obtained exclusively with the addition of tin tetrachloride to the allenyl stannane rapidly followed by the addition of aldehyde. The effect of other Lewis acids and reaction variables such as solvent and temperature on the yield and relative stereochemistry of the products will also be described. The Mitsunobu coupling reaction of sterically hindered phenols and alcohols is greatly accelerated by the use of high reaction concentration in combination with sonication. The rate acceleration effect observed with our protocol may simply be based on the high concentration with the sonic waves providing efficient mixing of the highly viscous reaction mixture and generating localized hot spots, or in part, the result of an enhancement of a radical reaction pathway.

The pseudopterosins and seco-pseudopterosins are diterpene glycosides isolated from the marine soft coral, Pseudopterogorgia elisabethae . These compounds exhibit anti-inflammatory and analgesic activity greater than the industry standard, indomethacin. The overall goal of this research was to complete biosynthetic studies and enzymology related to the development of a biotechnological production method of the pseudopterosins and seco-pseudopterosins. We aimed to examine early steps in the biosynthetic pathway in order to gain detailed knowledge of the biosynthesis and enzymology of the system. Prior to examination of the biosynthetic pathway leading to the pseudopterosins, we developed both in vivo and in vitro systems to test putative precursors and demonstrated that pseudopterosin A is a precursor to pseudopterosins B--D. We also identified and confirmed the intermediacy of the pseudopterosin diterpene cyclase product using a radioactivity-guided isolation. The bicyclic structure of the diterpene cyclase product suggests that the pseudopterosins and seco-pseudopterosins are derived from this common bicyclic intermediate. The isolation of the pseudopterosin diterpene cyclase product provided us with an assay for the purification of the enzyme involved in its production. We identified the diterpene cyclase in aqueous extracts of P. elisabethae and plan to utilize the amino acid sequence for identification of the gene. This represents the first isolation of a biosynthetic enzyme from a marine coral. Moreover, various characterization studies indicated that the enzyme displays certain similar characteristics to other terpenoid cyclases isolated from terrestrial sources. In previous investigations, P. elisabethae was found only in the Bahamian and West Indian region, but we discovered P. elisabethae in the Florida Keys. Furthermore, due to the distinctive chemistry in the Florida Keys P. elisabethae, plausible early biosynthetic intermediates were isolated that are not present in the Bahamian population. We evaluated these compounds as intermediates in the biosynthesis of the pseudopterosins. The data obtained further supports the assumption of a common biosynthetic origin of the pseudopterosins and seco-pseudopterosins.