Stereodynamic tetrahydrobiisoindole “NU-BIPHEP(O)”s: functionalization, rotational barriers and non-covalent interactions

Stereodynamic tetrahydrobiisoindole “NU-BIPHEP(O)”s: functionalization, rotational barriers and non-covalent interactions Golo Storch, Sebastian Pallmann, Frank Rominger and Oliver Trapp* Full Research Paper Address: Organisch-Chemisches Institut, Ruprecht-Karls Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany Open Access Beilstein J. Org. Chem. 2016, 12, 1453–1458. doi:10.3762/bjoc.12.141 Email: Oliver Trapp* - Received: 08 April 2016 Accepted: 28 June 2016 Published: 14 July 2016 * Corresponding author This article is part of the Thematic Series "Organometallic chemistry". Keywords: atropisomer; enantioselective DHPLC; ligand design; non-covalent interactions; Okamoto phases; phosphine ligand; stereodynamic ligands Guest Editor: B. F. Straub © 2016 Storch et al.; licensee Beilstein-Institut. License and terms: see end of document. Abstract Stereodynamic ligands offer intriguing possibilities in enantioselective catalysis. “NU-BIPHEPs” are a class of stereodynamic diphosphine ligands which are easily accessible via rhodium-catalyzed double [2 + 2 + 2] cycloadditions. This study explores the preparation of differently functionalized “NU-BIPHEP(O)” compounds, the characterization of non-covalent adduct formation and the quantification of enantiomerization barriers. In order to explore the possibilities of functionalization, we studied modifications of the ligand backbone, e.g., with 3,5-dichlorobenzoyl chloride. Diastereomeric adducts with Okamoto-type cellulose derivatives and on-column deracemization were realized on the basis of non-covalent interactions. Enantioselective dynamic HPLC (DHPLC) allowed for the determination of rotational barriers of ΔG‡298K = 92.2 ± 0.3 kJ mol−1 and 99.5 ± 0.1 kJ mol−1 underlining the stereodynamic properties of “NU-BIPHEPs” and “NU-BIPHEP(O)s”, respectively. These results make the preparation of tailormade functionalized stereodynamic ligands possible and give an outline for possible applications in enantioselective catalysis. Introduction Axially chiral biaryl compounds such as BINAP (2,2’-bis(diphenylphosphino)-1,1’-binaphthyl) represent widely used and highly efficient ligands that can be applied in a variety of enantioselective catalytic transformations. Unlike BINAP, the related stereodynamic BIPHEP (2,2’-bis(diphenylphosphino)1,1’-biphenyl) ligands have a significantly lower barrier of rota- tion around the central C–C bond regarding the conversion of the enantiomers into one another. This enables fast enantiomerization at room temperature. This, however, does not conflict with their usage in enantioselective catalysis. Noyori and Mikami reported the stereochemi- 1453 Beilstein J. Org. Chem. 2016, 12, 1453–1458. cal alignment of BIPHEP ligands in ruthenium complexes upon addition of chiral diamine co-ligands [1,2]. The resulting complexes were successfully employed in enantioselective ketone hydrogenation. Further examples of such systems are BIPHEP complexes of rhodium [3-6], palladium [7,8], platinum [9,10] and gold [11-13] in combination with chiral co-ligands or counter ions that are used after alignment of the ligand’s axial chirality. One major advantage of stereodynamic ligands is that there is no need for separate preparation of one ligand enantiomer as long as their chirality can be controlled by chiral additives or auxiliaries. In addition, the simultaneous presence of both axially chiral BIPHEP enantiomers can be beneficial as this allows bidirectional control of enantioselectivity depending on temperature [14,15]. In this approach, both product enantiomers of an enantioselective transformation can be addressed selectively by fine tuning of the conditions prior to and during catalysis. The rotational barrier around the central C–C bond of BIPHEP ligands is a key property of stereodynamic ligands that determines the temperature required for ligand enantiomerization as well as the half-life of isolated enantiomers. The latter are of particular importance if chiral co-ligands are cleaved off prior to catalysis and if the remaining stereochemically aligned BIPHEP complex fragment serves as the active species. Therefore, detailed knowledge of the interconversion barriers of stereodynamic ligands is crucial for the choice of conditions used for stereochemical alignment and subsequent application in catalysis. A rotational barrier of 92 kJ mol−1 for the unsubstituted BIPHEP was determined by NMR coalescence of a partially deuterated derivative [16]. However, this method does not fulfil the requirements for a reliable rapid screening of novel stereodynamic ligands due to harsh conditions such as isotope exchange. We recently reported the rotational barriers of 3,3’ and 5,5’ substituted BIPHEP and BIPHEP(O) compounds based on enantioselective DHPLC by evaluation of elution profiles using the unified equation [17-20]. Rotational barriers were found to be between = 86.8 kJ mol−1 (unsubstituted BIPHEP) and = 100.4 kJ mol−1. BIPHEP(O) derivatives (unsubstituted BIPHEP(O): = 88.6 kJ mol −1 ) were observed to exhibit slightly increased (approximately 2 kJ mol −1 ) barriers. Functionalization of stereodynamic BIPHEP ligands at the biaryl core offers multiple possibilities. The introduction of achiral, non-covalent interaction sites allows for ee determination of chiral analytes via NMR spectroscopy [21] as well as deracemization of the BIPHEPs with HPLC stationary phases [22]. However, introduction of functional groups which enable a modular derivatization approach is often hampered by long and tedious synthetic procedures. Doherty et al. reported a rhodium catalyzed double [2 + 2 + 2] cycloaddition strategy for a convergent synthesis of “NU-BIPHEP”s [23]. In this paper, we describe the application of Doherty’s synthetic strategy for the synthesis of stereodynamic tetrahydrobiisoindole “NU-BIPHEP(O)” compounds bearing secondary amino groups for functionalization. The attachment of a 3,5dichlorobenzoyl binding site is reported and non-covalent interactions as well as rotational barriers are studied in solution by (D)HPLC techniques. Results and Discussion Synthesis of tetrahydrobiisoindole “NU-BIPHEP(O)s” The rhodium catalyzed double [2 + 2 + 2] cycloaddition of 1,4bis(diphenylphosphinoyl)buta-1,3-diyne and a variable diyne compound is the key step in the preparation of “NU-BIPHEPs” [23] and related biaryls [24]. Doherty et al. reported the use of various diynes yielding for instance tetrahydrobiindene 1a and N-tosyl-protected tetrahydrobiisoindole 1b as the only N-heterocyclic compound (Figure 1A). Aiming at facile deprotection and enabling subsequent functionalization at the secondary amine position, we changed the strategy and used N-Boc dipropargylamine as the diyne compound (Figure 1A). The double cycloaddition product 1c was obtained in 77% yield. In accordance with the report of Doherty et al., very slow addition of the diyne compound via syringe pump was crucial. In contrast to 1a a (...truncated)