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In the second year of the funding period the previously initiated projects were further developed, contributing to the established program in the area of the organic synthesis. 3 graduate and 11 undergraduate students were involved in research. The PI started participating in programs to involve high school students (“Pilot-to-Lab”) and Native American students (NATURE programs) in research. 8 presentations on international conferences were made, 4 peer reviewed articles were published acknowledging the support of the ACS PRF grant.

Three projects were performed: 1) development of C-H insertion on sulfonyl compounds as a synthetic method 2) synthesis of Plakortethers, and 3) approach to the synthesis of Terpiodiene.

The previously discovered C-H insertion on sulfonyl compound was explored in the direction of its synthetic application. We've previously started the study of the alkylation of the C-H inserted products. We went on to discover that the high stereoselectivity, observed in alkylation of the six-membered products also is observed in the alkylation of the five-membered cyclic products. The stereochemistry of the alkylation products was determined by NOE correlations. Chlorination using C₂Cl₆ was also possible. It was additionally found that the alkylation products can be rearranged by treatment with NaHMDS, and converted to promising cyclopentene intermediates, such as 1.1, by Ramberg-Baecklund reaction (Scheme 1).

Scheme 1

Experimentation on sulfonates revealed that reductive scission of the C-S bond was possible using SmI₂/DMPU at prolonged reaction times (Scheme 2).

Scheme 2

Then we proceeded by application of the reaction in synthesis. The first synthetic target was selected to be hepatoprotective antibiotic Bakuchiol. The challenging element in its structure is the quaternary chiral center. Using the developed methodology it could be created from a tertiary center of a commercially available (-)-citronellol, using the sulfonate modification to effectively control regioselectivity.

Using the developed sequence, sulfonate 3.1 was prepared from citronellol (Scheme 3). The initially planned SmI₂ desulfonation was, unexpectedly, quite ineffective, causing formation of multiple byproducts. Alkylation of 3.1 was possible. However, this direction required decarboxylation that was not expected to be easy. Meanwhile, it was found that DIBALH reduction would provide alcohol 3.2 in high yield. This alcohol could be converted to alcohol 3.4 by treatment with Ph₃P/NBS, and then Zn in DME, albeit in low yield. An alternative high-yielding method was found via elimination and desulfonation of the resulting vinylic sulfonate, 3.3. Of the reagents attempted (Li/NH₃, BuMgCl-Ni(acac)₂, BuMgCl-Ni(acac)₂, SmI₂, SmI₂/DMPU, Na-EtOH-THF) the best results were obtained using Bu₃SnLi. The resulting alcohol, after oxidation, was converted to Bakuchiol as previously described. Mosher ester study also confirmed that no loss of optical purity took place.

Scheme 3

The second project was the synthesis of Plakortethers – secondary metabolites from marine sponge Plakortis Simplex (Scheme 4). We previously developed a sequence for the synthesis of the key intermediate, 4.1, via taking advantage of the symmetry in the molecule. We went on to optimize the aldol condensation step. Additionally, on closer analysis it was revealed that the ¹³C spectrum of the prepared Plakortether G has several deviations from the reported values. To conclusively prove the structure, additional studies were performed. NOE correlations confirmed relative configuration around the tetrahydrofuran ring. Confirmation of the side chain configuration, however, was not available. Several attempts to obtain crystalline derivatives for X-Ray analysis were unsuccessful. Finally, it was learned that both Plakortethers F and G, upon treatment with pyridinium tosylate, convert to the same bicyclic product, 4.2. This confirmed the identical configurations of all the centers in both compounds outside the acetal center. The NOE study of the cyclized product confirmed configuration of the centers in the side chain. After communication with the authors of the original isolation paper, we were provided with a copy of the ¹H spectrum of Plakortether G, which was a nearly photographical match to our compound. This lead us to believe the two compounds were identical, despite the ¹³C spectrum differences.

Scheme 4

Synthesis of other Plakortethers as well as Simplakidine A is now being performed. Additionally, an agreement has been achieved on a collaborative project involving biological testing of Plakortethers, synthetic intermediates and possible analogs to explore and optimize their biological activity.

Finally, studies on the synthesis of Terpiodiene, an isolate from an Okinawan sponge Terpios hoshinota with cytotoxic activity, were continued.

Scheme 5

The previously discovered route for preparation of alkene 5.1 provided very low yields. Attempts to optimize it (via a change of solvent – to THF, DMF, DMSO) and base (K₂CO₃, KOt-Bu, LDA) were not successful. The constant complication kept being overelimination, leading to aromatization (Scheme 5). Attempts to use sulfo and selenocyclization instead of iodocyclization also proved difficult and low yielding.

An alternative route based on intramolecular aldehyde allylation was concocted (Scheme 6). It is hoped that the possible competing elimination can be suppressed by a choice of metal and conditions. So far preparation of the key substrate proved heavily complicated by an extremely easy aromatization.

Scheme 6

Currently, alternative approaches to this intermediate using C-H insertion and olefin metathesis are being explored, as well as a possibility of using other reaction besides the allylation to construct the same bond (such as radical processes) to avoid the use of substrates and conditions conducive of elimination and aromatization.

In conclusion, with the support of the ACS Petroleum Research Fund we were able to establish a research program in the area of synthetic organic chemistry featuring both development of new synthetic methods and targeted synthesis of natural products. 4 peer reviewed publications have been published and 8 international conference presentations have been made with the results of the ongoing projects. The established program is well positioned for further advancement and diversification.