Exploiting the Chiral Ligands of Bis(imidazolinyl)- and Bis(oxazolinyl)thiophenes—Synthesis and Application in Cu-Catalyzed Friedel–Crafts Asymmetric Alkylation

Five new C2-symmetric chiral ligands of 2,5-bis(imidazolinyl)thiophene (L1–L3) and 2,5-bis(oxazolinyl)thiophene (L4 and L5) were synthesized from thiophene-2,5-dicarboxylic acid (1) with enantiopure amino alcohols (4a–c) in excellent optical purity and chemical yield. The utility of these new chiral ligands for Friedel–Crafts asymmetric alkylation was explored. Subsequently, the optimized tridentate ligand L5 and Cu(OTf)2 catalyst (15 mol%) in toluene for 48 h promoted Friedel–Crafts asymmetric alkylation in moderate to good yields (up to 76%) and with good enantioselectivity (up to 81% ee). The bis(oxazolinyl)thiophene ligands were more potent than bis(imidazolinyl)thiophene analogues for the asymmetric induction of the Friedel–Crafts asymmetric alkylation.

The Use of Chiro-Inositols in Asymmetric Synthesis

<p>D- and L- chiro-inositols are readily and inexpensively available as their O-methyl ethers pinitol and quebrachitol. To date the use of the choro-inositols in synthesis has not been exploited as fully as that of the more common isomer myo-inositol. The chiro-inositols were protected as either the di-isopropylidene or the di-cyclohexylidene systems to give them more steric bulk and were subsequently evaluated in the three areas of asymmetric synthesis: as chiral reagents, as chiral auxiliaries, as chiral ligands. Outside of these areas was the successful application of methodology for the mono esterification of C-2 symmetric diols to these inositol systems. This allowed a series of molecules to be generated that proved useful in the areas outlined above. For the use of chiro-inositols as chiral reagents, two reagents were investigated. The first was a hydroboration reagent similar to pinenyl borane. The second was the generation of a strained silacycle for use as a reagent in the enantioselective allylation of aldehydes. In the area of chiral auxiliaries, these inositols were successfully used to give selectivity in the Michael reaction. Unfortunately this success was not repeatable in the aldol reaction. Investigations into the development of chiral ligands were unsuccessful in that we were unable to synthesize either a diamine or an amino alcohol from this system. A diol and an amino ether were trialed in asymmetric reactions but failed to provide any catalytic effect. This section of the project did lead to some interesting chemistry and a better understanding of this system that can be applied to future work.</p>

The Use of Chiro-Inositols in Asymmetric Synthesis

<p>D- and L- chiro-inositols are readily and inexpensively available as their O-methyl ethers pinitol and quebrachitol. To date the use of the choro-inositols in synthesis has not been exploited as fully as that of the more common isomer myo-inositol. The chiro-inositols were protected as either the di-isopropylidene or the di-cyclohexylidene systems to give them more steric bulk and were subsequently evaluated in the three areas of asymmetric synthesis: as chiral reagents, as chiral auxiliaries, as chiral ligands. Outside of these areas was the successful application of methodology for the mono esterification of C-2 symmetric diols to these inositol systems. This allowed a series of molecules to be generated that proved useful in the areas outlined above. For the use of chiro-inositols as chiral reagents, two reagents were investigated. The first was a hydroboration reagent similar to pinenyl borane. The second was the generation of a strained silacycle for use as a reagent in the enantioselective allylation of aldehydes. In the area of chiral auxiliaries, these inositols were successfully used to give selectivity in the Michael reaction. Unfortunately this success was not repeatable in the aldol reaction. Investigations into the development of chiral ligands were unsuccessful in that we were unable to synthesize either a diamine or an amino alcohol from this system. A diol and an amino ether were trialed in asymmetric reactions but failed to provide any catalytic effect. This section of the project did lead to some interesting chemistry and a better understanding of this system that can be applied to future work.</p>

Synthesis and Evaluation of C2-Symmetric SPIROL-Based bis-Oxazoline Ligands

This communication describes the synthesis of new bis-oxazoline chiral ligands (SPIROX) derived from the C2-symmetric spirocyclic scaffold (SPIROL). The readily available (R,R,R)-SPIROL (2) previously developed by our group was subjected to a three-step sequence that provided key diacid intermediate (R,R,R)-7 in 75% yield. This intermediate was subsequently coupled with (R)- and (S)-phenylglycinols to provide diastereomeric products, the cyclization of which led to two diastereomeric SPIROX ligands (R,R,R,R,R)-3a and (R,R,R,S,S)-3b in 85% and 79% yield, respectively. The complexation of (R,R,R,R,R)-3a and (R,R,R,S,S)-3b with CuCl and Cu(OTf)2 resulted in active catalysts that promoted the asymmetric reaction of α-diazopropionate and phenol. The resultant O–H insertion product was formed in 88% yield, and with excellent selectivity (97% ee) when ligand (R,R,R,R,R)-3a was used.