I. Development of the In Situ Reductive Ozonolysis of Alkenes with Tertiary Amine N-Oxides. II. Progress toward the Asymmetric Synthesis of Peroxyplakoric Acid A3.

Ozone, first discovered in the mid 1800’s, is a triatomic allotrope of oxygen that is a powerful oxidant. For over a century, research has been conducted into the synthetic application and mechanism of reactions of ozone with organic compounds. One of the major areas of interest has been the ozonolysis of alkenes. The production of carbonyl compounds is the most common synthetic application of ozonolysis. The generally accepted mechanism developed by Rudolf Criegee for this reaction involves the 1,3-electrocyclic addition of ozone to the π bond of the alkene to form a 1,2,3-trioxolane or primary ozonide. The primary ozonide is unstable at temperatures above -100 °C and undergoes cycloreversion to produce the carbonyl oxide and carbonyl intermediates. These intermediates then recombine in another 1,3-electrocyclic addition step to form the 1,2,4-trioxolane or final ozonide. While the final ozonide is often isolable, most synthetic applications of ozonolysis require a subsequent reductive or oxidative step to form the desired carbonyl compound. During investigations into the nucleophilic trapping of the reactive carbonyl oxide, it was discovered that when amines were used as additives, an increased amount of reaction time was required in order to consume all of the starting material. Surprisingly, significant amounts of aldehydes and a suppression of ozonide formation also occurred which led to the discovery that amine N-oxides formed by the ozonation of the amine additives in the reaction were intercepting the carbonyl oxide. From the observed production of aldehydes, our proposed mechanism for the in situ reductive ozonolysis reaction with amine N-oxides involves the nucleophilic trapping of the carbonyl oxide intermediate to produce a zwitterionic adduct that fragments into 1O2, amine and the carbonyl thereby avoiding the formation of peroxidic intermediates. With the successful total syntheses of peroxyacarnoates A and D by Dr. Chunping Xu, the asymmetric total synthesis of peroxyplakorate A3 was investigated. The peroxyplakoric acids are cyclic peroxide natural products isolated from the Plakortis species of marine sponge that have been found to exhibit activity against malaria, cancer and fungi. Even though the peroxyplakorates differ from the peroxyacarnoates in the polyunsaturated tail and the head group, the lessons learned from the syntheses of the peroxyacarnoates have proven to be valuable in the asymmetric synthesis of peroxyplakorate A3. The challenges for the asymmetric synthesis of peroxyplakorate A3 include the stereospecific formation of the 3-methoxy-1,2-dioxane core with a propionate head group and the introduction of oxidation sensitive dienyl tail in the presence of a reduction sensitive 1,2-dioxane core. It was found that the stereochemistry of two of the chiral centers could be controlled by an anti-aldol reaction of a chiral propionate followed by the stereospecific intramolecular cyclization of a hydroperoxyacetal. The regioselective ozonolysis of a 1,2-disubstituted alkene in the presence of a terminal alkyne forms the required hydroperoxyacetal as a mixture of diastereomers. Finally, the dienyl tail is introduced by a hydrometallation/iodination of the alkyne to produce a vinyl iodide followed by a palladium catalyzed coupling reaction. While the coupling reaction was unsuccessful in these attempts, it is still believed that the intramolecular cyclization to introduce the 1,2-dioxane core could prove to be a general solution to many other cyclic peroxides natural products.

Rhodium-Catalyzed Hydroboration: Directed Asymmetric Desymmetrization

Rhodium-catalyzed asymmetric hydroboration in conjunction with directing groups can be used control relative and absolute stereochemistry. Hydroboration has the potential to create new C–C, C–O, and C–N bonds from an intermediate C–B bond with retention of stereochemistry. Desymmetrization resulting in the loss of one or more symmetry elements can give rise to molecular chirality, i.e., the conversion of a prochiral molecule to one that is chiral. Unsaturated amides and esters hold the potential for two-point binding to the rhodium catalyst and have been shown to direct the regiochemistry and impact stereochemistry in asymmetric hydroborations of acyclic β,γ-unsaturated substrates. In the present study, the pendant amide functionality directs the hydroboration cis in the cyclic substrates studied; the corresponding ester substrates do so to a lesser extent. The enantioselectivity is determined by regioselective addition to the re or si site of the rhodium-complexed alkene. The effect of catalyst, ligand and borane on the observed diastereoselectivity and enantioselectivity for a variety of cyclopentenyl ester and amide substrates is discussed.

The Somatic Chromosomes of Some North American Marmots (Sciuridae), with Remarks on the Relationships of Marmota browerii Hall and Gilmore

Karyotypes are defined for two nearctic species of marmots, Marmota olympus (2n = 40) and M. vancouverensis (2n = 42), and supplemental information is included on the karyotypes of M. flaviventris, M. monax ochracea, and M. marmota. The six North American species of Marmota (NF = 66) comprise a distinct group as compared with the middle Asian species (NF = 70) for which the karyotypes are known. Karyologic findings and zoogeographic evidence based upon the distribution of two nearctic species of host-specific cestodes indicate that M. broweri, in northern Alaska, is a pre-Würm relict. Its affinities appear to be with the North American caligata-group rather than with the northeastern Siberian M. camtschatica. The occurrence on M. broweri of the Asian flea, Oropsylla silantiewi, has not been explained. Some ecological and behavioral characteristics of M. broweri are briefly described and compared with those of other species. Family groups of M. broweri hibernate together in single winter dens that are plugged at the entrance; copulation takes place before the animals emerge from the winter den, near mid-May; face-glands are utilized in marking of territory. French abstract: Les auteurs définissent les caryotypes de deux espèces néarctiques de marmottes, Marmota olympus (2n=40) et M. vancouverensis (2n=42), et donnent des précisions sur les caryotypes de M. flaviventris, M. monax ochracea et M. marmota. Les six especes de Marmota (NF=66) d'Amérique du Nord forment un groupe distinct des espèces d'Asie centrale (NF=70) dont Ie caryotype est connu. Les données caryologiques et les preuves zoogéographiques basées sur la répartition de deux espèces néarctiques de cestodes spécifiques de I'hôte démontrent que M. broweri, dans l'Alaska septentrional, est une relicte du pré-Würm. Elle semble avoir plus d'affinités avec Ie groupe nord américain de caligata qu'avec M. camtschatica du nord de la Sibérie. La présence sur M. broweri de la puce asiatique, Oropsylla silantiewi, n'est pas expliquée. Quelques caractéristiques écologiques et éthologiques de M. broweri sont décrites brièvement et comparées avec celles d'autres espèces. Les groupes familiaux de M. broweri hibernent dans un meme terrier dont l'entrée est bouchée; la copulation à lieu avant que les animaux sortent de leur abri hivernal, it la mi-mai ; ils se servent de leurs glandes faciales pour marquer leur territoire.