1. Isolation of the Desired Product (III)
The ability of different hydroxyl group protectors on nerol to stay intact following a SeO2 oxidation and subsequent NaBH4 reduction
Tim Tetrault, Marc A. Boudreau
University of New Hampshire, Department of Chemistry, Durham, New Hampshire 03824
Introduction
Experimental Design
Isolation of the Desired Product (III)
Hydroxyl group protectors have been a crucial piece of synthetic chemistry for decades because of their ability to allow one to run further reactions on a compound, whilst retaining the hydroxyl group in the end. There are numerous hydroxyl group protecting reagents that vary in reactivity and stability, which leads to the necessity of properly choosing a protecting group for one’s specific synthetic scheme.1 Hydroxyl group protecting groups range from methoxy-substituted benzyl ethers, to silyl ethers, carbamates, and even diol protectors.2 The focus of this experiment will relate to the protecting groups in Figure 1.
SeO2 Oxidation and Subsequent NaBH4 Reduction
SeO2 as a reagent has the ability to oxidize multiple types of organic compounds such as aldehydes, nitrogen compounds, unsaturated aliphatic compounds, and many others.3 Nerol (Figure 2), being an unsaturated aliphatic compound, has the ability to be oxidized by SeO2 due to its methyl group adjacent to the double bond.
The NaBH4 reduction is a commonly used technique in synthetic chemistry to synthesize a primary alcohol from an aldehyde or a secondary alcohol from a ketone.
Prior to the oxidation and subsequent reduction, the hydroxyl group of nerol must be protected.
Factors to be Tested
The factors that will be accounted for are the ability to obtain the desired product in its pure form. Also, the yield and the cost will be accounted for.
Previously, the Boudreau group protected the hydroxyl group with O-TBDPS-protection and O-TBDMS-protection prior to undergoing the SeO2 oxidation and subsequent NaBH4 reduction.
It was found that b was efficiently purified and obtained following the oxidation and subsequent reduction with a 22% yield, within reach of the literature yield of 33%.4 When the same procedure was undergone with O-TBDMS protection, the desired product, d, was not obtained efficiently. The TLC analysis of the crude of b showed four bands with good separation that was easily purified via flash column chromatography on silica gel. The TLC analysis of the crude of d showed over ten bands with poor separation and the desired product was not able to be efficiently isolated via flash column chromatography on silica gel.
Testing of the O=TIPS Protecting Group
The experimental procedure was done in the same fashion as the reaction scheme in Scheme 2.
Purification of III
The crude product after the NaBH4 reduction had at least ten bands present upon TLC analysis (see Figure 3). The crude product was purified via flash column chromatography on silica gel (3:1 hexane:ethyl acetate) and three bands were isolated for further analysis. The three bands analyzed were band 1 (Rf = .55), band 2 (Rf = .45), and band 3 (Rf = .36). Upon the use of 1H NMR as an identification method, it was determined that band 1 may be the desired product.
NMR of Band 1
The 1H NMR spectrum of Band 1 (Figure 4) gave reason to believe that the band contained the desired product. The chemical shifts of the peaks were consistent with the expected spectrum of III, but the multiplet analysis showed that the multiplets did not appear as expected. A 13C NMR of Band 1 (Figure 5) was obtained to determine if there is more evidence that the desired product was present. The 13C NMR spectrum showed that the anticipated peaks of the desired product were present and that there are impurities present. Further TLC analysis was done to determine if the impurity could be removed via flash column chromatography on silica gel. The TLC analysis showed a large spot and a small spot with an insignificantly different Rf value. Multiple solvent systems were tested to attempt to increase the difference in Rf values. Figure 6 shows the different solvent systems tested and the inability to separate the two bands significantly to efficiently purify the product without advanced instrumentation.
Figure 4
Figure 5
The first reaction, the protection of nerol with TIPSCl, was significantly longer than the same reaction done in the previous protection reactions done by the Boudreau Group. This was due to the presence of starting material in the reaction mixture, which was most likely due to the TIPSCl reagent being impure. The starting material was removed from (I) via flash column chromatography on silica gel and (I) was isolated with a 94% yield. The 1H NMR of (I) showed success in the isolation of the desired product. The next two reactions in the scheme were done consistently with the corresponding reactions previously done by the Boudreau Group, without TLC analysis to monitor reaction progress. An 1H NMR of the intermediate produced after the SeO2 oxidation gave reason to move on to the reduction reaction, due to the presence of an aldehydic peak, which is consistent with the proposed intermediate.
Conclusion
References
The use of the triisopropyl silyl hydroxyl group protecting group on nerol during a selenium(IV) oxide oxidation and subsequent sodium borohydride reduction proved to be inefficient. While it appears the desired product was formed, it needs more advanced instrumentation to be purified. Also, the band isolated had a low yield (3.3%) and was still not yet pure. Lastly, the cost of the TIPSCl reagent is significantly larger than the TBDPSCl reagent, according to Sigma Aldrich.4 Future work could be to test non-silyl protecting groups, such as p-methoxy benzyl ether or the use of the acetate protecting group.
1. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons: Hoboken, New Jersey, 2007; pp
2. Waitkins, G. R.; Clark, C. W. Chem. Rev. 1945, 36 (3),
3. Liu, F.; Vijayakrishnan, B.; Faridmoayer, A.; Taylor, T. A.; Parsons, T. B.; Bernardes, G. J.; Kowarik, M.; Davis, B. G. Rationally designed short polyisoprenol-linked PgIB substrates for engineered polypeptide and protein N-glycosylation. J. Am. Chem. Soc. 2014, 136,
4. Sigma Aldrich. (accessed Decemeber 1, 2016).
Acknowledgements
Would
I would like to thank the UNH Department of Chemistry, the Boudreau Group, Bill Butler, and my Father.