Optical resolution of 1,16-dihydroxytetraphenylene by chiral gold(iii) complexation and its applications as chiral ligands in asymmetric catalysis

We report herein a novel approach involving optical resolution of (±)-1,16-dihydroxytetraphenylene (DHTP) by chiral gold(iii) complexation. This method features several key advantages, i.e., recyclability of chiral resolution reagents, feasibility of scaling up to gram quantities, and operational simplicity. On the basis of this method, which led to optically pure DHTP, a library of 2,15-diaryl (S)-DHTPs and several (S)-DHTP-derived phosphoramidite ligands were synthesized. Finally, the superior performance of a (S)-DHTP phosphoramidite ligand was demonstrated by efficient iridium-catalyzed asymmetric allylic alkynylation reactions.


Introduction
Tetraphenylene (1) 1 is a nonplanar saddle-shaped molecule, featuring four benzene rings that are arranged alternatively above and below its eight-membered ring (Scheme 1A). 2 As a molecule with a D 2d molecular symmetry, 1 is achiral in nature. However, chiral tetraphenylenes can be obtained by introducing appropriate substituents into the benzene rings due to the loss of D 2d symmetry, and also due to their extraordinarily high molecular inversion barrier. 3 Owing to their unique geometry and rigid molecular frameworks, chiral tetraphenylenes are endowed with great potential to function as excellent chiral ligands/catalysts and building blocks. 3b,4 It is therefore of great interest to design and prepare optically pure tetraphenylenes as novel ligands/catalysts for asymmetric reactions. 1c In 2005, our group reported for the rst time the use of tetraphenylene-derived phosphoramidite as chiral ligands in a Rh-catalyzed asymmetric hydrogenation. 4c As a result, a-acylaminoacrylates were hydrogenated, leading to quantitative yields with excellent enantioselectivities (94-99% ee). In 2010, we also designed and synthesized tetraphenylene-derived organocatalysts for the Diels-Alder cycloaddition reaction between anthrones and maleimides. 5 However, applications of chiral tetraphenylenes in asymmetric catalysis have still not been attractive, presumably due to the difficulty in obtaining enantiopure tetraphenylenes through asymmetric synthesis 3b,4a,6 or by chiral resolution. 4c,d,7 Over the past few decades, atropisomeric biphenols, such as BINOL (1,1 0 -bi-2-naphthol), H8-BINOL, SPINOL (1,1 0 -spirobiindane-7,7 0 -diol) and 6,6 0 -disubstituted-2,2 0 -biphenol (Scheme 1B), have been well-developed into privileged scaffolds for the design and synthesis of a variety of chiral ligands/catalysts. 8 Inspired by the architectural similarity of these structurally oppy biphenols, we opine that it is thought-provoking to apply structurally rigid 1,16-dihydroxytetraphenylene (DHTP) 4b,9 as a platform for comparison, in order to explore their application in asymmetric catalysis (Scheme 1C). Consequently, the development of enantiopure DHTPs as chiral ligands/catalysts in various asymmetric reactions, including asymmetric allylation, the Diels-Alder reaction, Michael addition and the Darzens reaction, has recently witnessed signicant progress. 10 Nonetheless, the utilization of chiral DHTPs in asymmetric catalysis is limited and still in its infancy because an efficient approach to enantiomeric (S)-DHTP and (R)-DHTP in large quantities is still challenging. 1d,e,g To the best of our knowledge, so far there are only two available pathways to access enantiopure (S)-DHTP and (R)-DHTP. The rst pathway is the diastereomeric separation of a pair of bis-(S)-camphorsulfonates of (AE)-DHTP by a conventional column chromatographic separation on silica gel (Scheme 2A). 4b This method suffers from the use of an expensive and non-recyclable chiral resolution reagent, as well as from the tedious and time-consuming chromatographic purication of the resulting diastereomeric camphorsulfonates. The second pathway is the enantiomeric separation of (AE)-DHTP on a chiral stationary phase by preparative high performance liquid chromatography (Scheme 2B). 10a Although this method is straightforward, avoiding multistep reactions, its high-cost due to the use of large amounts of expensive HPLC grade solvents is denitely discouraging, not to mention the lengthy chromatographic process. Furthermore, the primary limitation of this approach is that these preparative HPLC instruments and chiral columns, are usually available only in commercial laboratories. Therefore, attempts to look for practical and reliable methods to access enantiopure (S)-DHTP and (R)-DHTP in large quantities are urgent and essential. Herein we report a newly developed approach for the optical resolution of (AE)-DHTP by chiral gold(III) complexes (Scheme 2C). This method not only circumvents expensive and time-consuming chromatographic steps, but most importantly features noteworthy advantages including (a) the recyclability of chiral resolution reagents, (b) the feasibility of gram scale manipulation, and (c) the simplicity of the operation.
signicantly different: (S,R)-4 is almost insoluble in CH 2 Cl 2 , leading to the precipitate, while (R,R)-4 showed exceptional solubility in CH 2 Cl 2 . The precipitate was collected by ltration and washed with H 2 O and CH 2 Cl 2 to give (S,R)-4. Subsequently, (S,R)-4 was treated with 6 N HCl in CH 2 Cl 2 , followed by column chromatography to give (S)-DHTP in 44% yield and the recovered (R)-3 in 43% yield. 11a The optical purity of the obtained (S)-DHTP was determined to be 99% ee by HPLC analysis (Scheme 3B). 10a Then, treatment of the ltrate with 6 N HCl afforded (R)-DHTP in 49% yield with 90% ee, and (R)-3 was recovered in 51% yield. Notably, this optical resolution specically depended on the use of a benzyl (Bn) substituted chiral oxazoline-based gold(III) complex, because phenyl-, isopropyl-or tertiary butylsubstituted analogs did not lead to the formation of a precipitate, therefore optical resolution could not be realized.
An important advantage of employing (R)-3 instead of (S)-10camphorsulfonyl chloride is its recyclability. Based on recovered (R)-3 (14.8 g) from the 30 mmol reaction, the recyclability of (R)-3 was examined. A series of resolution steps for (AE)-DHTP in 25, 20, 15, 10 and 5 mmol quantities were carried out by using (R)-3 recovered from the last step, respectively (Table 1, entries 2-6). The results showed that (R)-3 could be repeatedly used for 6 cycles without any adverse effect on resolution performance to give (S)-DHTP in excellent yield (45-48%) and optical purity (99% ee), as well as in excellent recovery yield (98-99%) of (R)-3 in each cycle. It is noteworthy that the 10 mmol scale resolution process, providing (S)-DHTP in 46% yield with 99% ee and (R)-DHTP in 48% yield with 96% ee, was the optimal manipulation result (Table 1, entry 5). To our delight, (R)-3 was still recovered in 98% yield at the end of the 6th cycle. These results indicated that (R)-3 is extremely stable during the optical resolution process and could even be promisingly reused for many more cycles.
Scheme 7 Synthesis of (S)-DHTP derived phosphoramidite ligands. a X-ray crystal structures of (S)-L1, displacement ellipsoids are drawn at the 50% probability level and H atoms are omitted for clarity.
indicated that the olen moiety of the amine might be essential. When a SPINOL-based phosphoramidite (S)-L6 was used as the chiral ligand, slightly lower yield (79%) and enantioselectivity (97% ee) of 11a were achieved, as compared with those resulting from (S)-L1. For comparison, Carreira reported that the BINOL-derived phosphoramidite (S)-L7 gave 11a in 88% yield with 99% ee. 23 The results shown by (S)-L1 and BINOL-derived (S)-L7 encouraged us to expand the substrate scope to further evaluate the efficiency of (S)-L1 in this iridium-catalyzed enantioselective allylic alkynylation (Table 3). To our delight, a range of phenyl alkynyltriuoroborates bearing either electron-donating (methoxyl and t-butyl) or electron-withdrawing (F, Cl, and Br) groups reacted smoothly under the Ir/(S)-L1 catalytic system, affording the corresponding products 11b-f in good yields and excellent enantioselectivities. In addition, heteroaromatic (3thienyl) and aliphatic alkynyltriuoroborates also gave products 11g-k in high enantioselectivities although the yields were relatively low. It is noteworthy that substrates containing two allylic alcohol moieties proceeded smoothly, leading to the formation of the corresponding products 11l and 11m in good yields (57% and 56%) and in 99% ee. Moreover, a triallylic alcohol substrate also afforded the tris-alkynylation product 11n containing three chiral centers in good yield (55%) and excellent stereoselectivity (>99% ee with 43 : 1 dr). Even though relatively low yields of some cases were obtained, the high level of enantiocontrol indicates that (S)-L1 indeed exhibits excellent efficiency as BINOL-derived phosphoramidite (S)-L7 towards the enantioselective iridium-catalyzed allylic alkynylation reaction. The comparison of X-ray crystallographic structural data of (S)-L1 (CCDC 2124171 †) with those of SPINOL-derived (S)-L6 (CCDC 1439599) and BINOL-derived (S)-L7 (CCDC 694272) indicates that (S)-L1 has a larger dihedral angle (54.6 ) between the two phenol rings than the corresponding angles of (S)-L6 (53.2 ) and (S)-L7 (53.1 ). 24 The larger dihedral angle and the rigid skeleton of tetraphenylene might render (S)-L1 rather sensitive towards steric repulsion from the substrate, thereby leading to excellent enantiocontrol. This outcome points to the prospect that (S)-L1 might be a ne alternative to BINOL-derived (S)-L7 in asymmetric catalysis.

Conclusions
In summary, we have established a novel approach to optical resolution of (AE)-1,16-dihydroxytetraphenylene (DHTP) using chiral gold(III) complexes. This efficient and reliable method can provide (S)-DHTP and (R)-DHTP in large quantities. Accordingly, a library of 2,15-diaryl (S)-DHTPs and several (S)-DHTPderived phosphoramidite ligands were synthesized for the rst time. The outstanding performance of (S)-DHTP-derived phosphoramidite ligands was demonstrated by an iridium-catalyzed asymmetric allylic alkynylation reaction. It is envisioned that this practical and scalable approach to optically pure DHTP and well-established synthesis of 2,15-diaryl (S)-DHTPs will open a new synthetic avenue, leading to further development in the application of chiral DHTP-derived ligands/catalysts. In this connection, preparations of more (S)-DHTP-derived mono-and bis-phosphine ligands, as well as chiral phosphoric acid catalysts are currently underway in our laboratory.

Data availability
All experimental and characterization data, as well as NMR spectra are available in the ESI. † Crystallographic data for compounds (

Conflicts of interest
There are no conicts to declare.