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My research group has benefited tremendously from the support of the ACS-PRF-UNI grant that we received. It has allowed me to fund three summer research students over the past two summers and purchase a variety of expendables that were needed for this project. Two of the students are currently beginning their senior year at ONU and both plan to attend graduate school in chemistry. Because of this support, my group has accumulated a lot of exciting results. I am very close to submitting two manuscripts for publication which will acknowledge ACS-PRF-UNI for its support. An undergraduate research student and myself presented two posters at the spring ACS National meeting in San Francisco, CA in March 2010 (abstract numbers ORGN 171 and ORGN 161). Below is a summary of my group's progress over the past fifteen months (June 1, 2009 through August 31, 2010).

The most commonly reported asymmetric free radical reaction involves an alkyl radical addition onto an enone or imine which makes the overall scope of products very limited.¹ Therefore, our goal was to develop a new asymmetric free radical method by switching the usual mode of reactivity by adding electrophilic radicals, generated from a-iodo carbonyl compounds, onto electron rich enol ethers (scheme 1). The products obtained from these reactions are 1,4-dicarbonyls which could be useful small molecule building blocks. By using a chiral catalyst, high levels of stereocontrol could be achieved. Since this reaction proceeds through a radical fragmentation pathway wherein a TMS radical propagates the chain, there is no need for the use of toxic alkyltin² reagents in this process.

In our initial studies on this project, we wanted to develop an optimized protocol for electrophilic radical additions onto electron rich alkenes at low temperatures (i.e. silylenol ethers). Table 1 shows a summary of the results for this radical fragmentation reaction using iodoethyl acetate (1) as the electrophilic radical precursor and 1-cyclohexenyloxy timethylsiloxane (2) as the acceptor.  We were pleased to find that this reaction proceeds at low temperature and without solvent (see entry 4). A brief study on radical precursors was also conducted and it was found that a-iodo esters, amides and ketones all give the target molecule in good yields. It was observed, however, that a-bromo precursors are very inefficient in this reaction (see entry 7, Table 1).

Table 1. Low temperature radical fragmentation reaction.

^a Isolated yield. ^b Reaction was run without solvent.

We next turned our attention to a diastereoselective method using chiral auxiliaries on the radical precursor. The reactions proceeded with moderate to good yields both at room temperature and -60 ûC. The products, however, showed little to no diastereoselectivity using the traditional Evan's chiral auxiliary (see Table 2). A more extensive auxiliary screening gave similar results with almost no dr observed (Scheme 2). We plan to continue this study broadening the chiral auxiliary screening. We have also begun investigating an enantioselective variant of this reaction. Only minimal amounts of stereocontrol are present in our initial attempts on this asymmetric reaction. Therefore, we propose to carry out an exhaustive CLA catalyst screening for this asymmetric radical process.

Table 2. Diastereoselective radical fragmentation reactions.

^aDetermined by ¹H NMR (200 MHz) ^b Isolated yield.

Scheme 2. Chiral auxiliary screening.

Our group is also investigating a tin-free radical project that utilizes simple silanes as hydrogen atom sources. In this study we screened a variety of silanes and Lewis acids in the radical additions onto 3-formylchromone (13), a commercially available starting material (Scheme 3). Interestingly we found that weaker Lewis acids such as Cu(OTf)₂ give product 14 after a one hour reaction time. If a stronger Lewis acid such as Yb(OTf)₃ is utilized, then the double addition product 15 is isolated as a single diastereomer. Even more interesting is the fact that triethylsilane serves as an efficient hydrogen atom source in this low temperature radical reaction. We completed a survey of silane reagents and found that triethylsilane was optimal in this reaction. We are currently investigating the asymmetric version of this reaction using a variety of chiral Lewis acid catalysts.

Scheme 3. Silane mediated radical additions.

References

1. For reviews on this topic see: (a) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263-3295. (b) Sibi, M. P.; Rheault, T. R. In Radicals in Organic Synthesis, Renaud, P., Sibi, M. P. Eds.; Wiley-VCH, Weinheim, 2001; pp 461-478. (c) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163-171. For other selected recent publications see: (d) Sibi, M. P.; Zimmerman, J.; Rheault, T. Angew. Chem. Int. Ed. 2003, 42, 4521-4523. (e) Sibi, M. P.; Petrovic, G.; Zimmerman, J. J. Am. Chem. Soc. 2005, 127, 2390-2391. (f) Sibi, M. P.; Patil, K. Org. Lett. 2005, 7, 1453-1456. (g) Sibi, M. P.; Zimmerman, J. J. Am. Chem. Soc. 2006, 128, 13346-13347.

2. For leading references on alternates to tin see: (a) Studer, A.; Amrein, S.; Schleth, F.; Schulte, T.; Walton, J. C. J. Am. Chem. Soc. 2003, 125, 5726-5733. (b) Jang, D. O.; Cho, D. H. Synlett 2002, 1523-1525. (c) Khan, T. A.; Tripoli, R.; Crawford, J. J.; Martin, C. G.; Murphy, J. A. Org. Lett. 2003, 5, 2971-2974. (d) Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.; Wood, J. L. J. Am. Chem. Soc. 2005, 127, 12513-12515. (e) Medeiros, M. R.; Schacherer, L. N.; Spiegel, D. A.; Wood, J. L. Org. Lett. 2007, 9, 4427-4429 (f) Pozzi, D.; Scanlan, E. M.; Renaud, P. J. Am. Chem. Soc. 2005, 127, 14204-14205.