University of Groningen Dynamic transfer of chirality in photoresponsive systems Pizzolato, Stefano Fabrizio

Dynamic transfer of chirality in photoresponsive systems

Pizzolato, Stefano Fabrizio

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Pizzolato, S. F. (2017). Dynamic transfer of chirality in photoresponsive systems: Applications of molecular photoswitches in catalysis. University of Groningen.

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Chapter 6

Chapter 5

Phosphoramidite-Molecular

Switches

as

Photoresponsive Ligands Displaying Multifold

Transfer of Chirality in Dynamic Enantioselective

Metal Catalysis

Transfer and amplification of chirality in biological and artificial systems is a fundamental process that allows dynamic control of structure and functions. Only few responsive systems harness the dynamic transfer of chirality and can act as photoswitchable chiral inductors. In this chapter we demonstrate that photoresponsive phosphoramidite ligands based on a chiral light-driven biaryl-substituted molecular switch can be used to alter the activity and invert the stereoselectivity of a copper-catalyzed asymmetric conjugate addition. The phosphoramidites were obtained as pairs of diastereoisomers, each displaying a distinctive catalytic activity and opposite stereoselectivity as results of photo-triggered matched-mismatched chiral interactions among the multiple stereochemical elements featured by the ligand. The result is an elegant balance of two competing catalysts, of which the complementary catalytic performance is tunable via internal dynamic transfer of chirality upon alkene photoisomerization.

This chapter will be published as: S. F. Pizzolato, P. Štacko, J. C. M. Kistemaker, T. van Leeuwen, Prof. B. L. Feringa, manuscript in preparation.

6.1 Introduction

The precision and efficiency with which nature controls the interplay and metabolic function of chiral biological structures has spurred and inspired the development of artificial switchable systems capable of displaying dynamic chirality upon external triggering.1–3 The exquisite selectivity realized by enzymes relies among others on the dynamic conformational properties produced by molecular folding to communicate structural information over large distances to the active site.4 In contrast, synthetic catalysts generally depend on static, proximal structural information for selectivity.5 Notably, examples of chirality-responsive helical polymers for control of catalytic functions have been disclosed.6 The quest for biomimetic molecules that exploit a chiral, folded secondary structure in asymmetric catalysis remains as a highly challenging objective in the search for function in artificial systems.7–9 Achieving this objective would minimally require the amplification and relay of local stereochemistry to the reactive/catalytic site via an intervening secondary structure. In recent years, the development of stimuli-responsive catalysts has attracted considerable attention and important efforts have been devoted to ON–OFF switching of catalytic activity.10–12 Remarkable reversal of enantioselectivity in asymmetric catalysis has been achieved using solvent responsive helical polymers,13 light-triggered organocatalysts14,15 and redox sensitive metal complexes.16 However, a highly desirable feature of an ideal responsive stereoselective catalyst is the ability to readily modify the chiral configuration of its active form in a non-invasive manner. In the case of homogenous catalysts based on metal complexes, some of the previously described systems rely on the isomerization of photoresponsive coordination ligands before the addition of the metal source.17,18 Such an approach is exploited because the formation of the active catalyst might impede the efficient reconfiguration, either due to slow metal-ligand dissociation processes in multi-dentate complexes19 or quenching of the photo-generated excited state via internal energy transfer influenced by the metal center.20 Moreover, the use of multi-dentate responsive ligands characterized by a large variation in geometry and distance of coordination sites between the interchangeable states, may lead to the reconfiguration among mono- and oligomeric structures with divergent catalytic performances.17,18 On the other hand, the optimal stereoselective metal-based catalyst should feature a limited number (ideally two) of isomers, e.g. enantiomeric or pseudoenantiomeric active forms. The latter should also be interchangeable in their coordinated states, providing access to chiral catalysts that could perform multiple enantioselective transformation in a sequential manner without the need of an intermediate metal-decomplexation step. Although it is difficult to switch the chirality of conventional ligands, artificial light-driven molecular motors and switches provide a unique platform to achieve this goal.21–23 Unidirectional rotary molecular motors based on overcrowded alkenes (Scheme 6.1a) can intrinsically act as multistage chiral switches as we have recently shown in the design of three-stage organocatalysts14,15 and phosphine ligands for metal catalysts.18 The photochemical and thermal isomerizations resulting in unidirectional rotation around the central overcrowded alkene bond provide stepwise control over the helicity of the bifunctional catalyst or bidentate ligand and spatial distance between these two interacting sites (Scheme 6.1b). As the photochemically-generated isomer [e.g. (P,P)-Z] and subsequent thermally-triggered isomer [e.g. (M,M)-Z] are pseudo enantiomers, chiral products with opposite absolute configuration are obtained when these isomers are used in a catalytic asymmetric transformation (Scheme 6.1). However, the thermally induced process of helix inversion between the pseudoenantiomeric (P,P)-Z and (M,M)-Z forms is not per se reversible. Indeed, starting from the (M,M)-Z isomer, three consequent isomerization (light-heat-light) are required to recover the initial (P,P)-Z isomer.24 Hence, fully reversible switching the handedness of chiral inductors remains highly challenging so far. Addressing this, we anticipated that light might allow non-invasive and dynamic control of multistage ligand chirality, introducing simple yet efficient designs of programmable coordination complexes.25 Fascinating prospects in the control of functions would arise from such a strategy (note that dynamic chiral metal complexes were recently used in chiral recognition,26,27 transmission of chirality,28 chiral amplification29 and asymmetric catalysis16–18). The design used to date is based on first generation molecular motors (Scheme 6.1a),24 of which core is composed of two identical halves each bearing one functional group of the catalytic pair (Scheme 6.1b). However, bridging the two

halves to construct a cyclic ligand structure would impede the characteristic isomerization cycle. Herein, we report molecular-switch-phosphoramidite30 hybrid structures based on second generation molecular motors (see Scheme 6.2b)31 in which, for the first time, the two-stage switching process of chirality via multifold coupled chirality transfer within monodentate tricyclic ligands can be driven by light in a fully reversible manner. As proof of concept, application in external modulation of catalytic activity and stereoselectivity of a copper-catalyzed asymmetric conjugate addition32 is demonstrated.

Scheme 6.1. Schematic representation of chiral photoresponsive bi-functional catalyst based on molecular

motors. a) Example of molecular motors of first (top) and second (bottom) generation. b) Schematic representation of unidirectional four-step rotary cycle of bi-functionalized molecular motor, comprising two photochemical E-Z isomerizations (PEZI) and two thermal helix inversions (THI).

6.2 Results and discussion

6.2.1 Design

In Chapter 5 we reported a photoresponsive molecular switch 1 featuring a versatile 2,2‘-biphenol motif in which chirality is transferred across three stereochemical elements (Scheme 6.2a). The isomer (S,M=,Ma)-1

is selectively obtained from synthesis being the global minimum due to the thermodynamically more favored pseudoaxial orientation adopted by the methyl group at the stereogenic center. The photochemical

E-Z isomerization (PEZI) of the helical-shaped central alkene bond towards the isomer (S,P=,Pa)-1 less

thermodynamically favored pseudequatorial orientation adopted by the methyl substituent allows via coupled motion the reversible control of the helical and axial chirality of the biaryl motif. In our previous study, we demonstrated that the specific switch core of 1 (6-membered ring upper half, 5-membered ring lower half)33 displayed high photostationary states (PSS) in the reversible photoisomerization process. In addition, it is characterized by an unprecedented thermal bi-stability,34 which increases its usefulness as dynamic chiral inductor in applications where thermal stability is desired.

Compared with previously reported molecular motor based systems, the reduction from four (Scheme 6.1) to two isomerization stages (Scheme 6.2a) featured by such a biaryl-functionalized design provides a

constructed and isomerized without disrupting the bridged biaryl unit or affecting its flexibility, nor obstructing the motion of the photoswitchable alkene unit.

Scheme 6.2. Design of chiral photoresponsive phosphoramidite ligands. a) Chiral 2,2‘-biphenol-substituted

switch 1 described in Chapter 5. b) Front structural view of photoswitchable phosphoramidite-biphenyl-substituted overcrowded alkene-derivative L with axial helicity and chirality (black) of the 2,2‘-biphenyl core coupled to helicity (blue) and point chirality (red) of the molecular switch scaffold. Point chirality on phosphorus (green) is not reversed. Descriptors are based on the structure of compound (S,SP )-L (for explanation of the chiral descriptors, vide infra). d) Schematic top-down view after metal-)-L

complexation: two metal-ligand complexes with opposite alkene and biaryl coupled helicity (M or P) can be selectively addressed by irradiation with UV-light: (S,SP,M=,Ma)-L and (S,SP,P=,Pa)-L. The descriptor

for the biaryl axial chirality Ra/Sa is inextricably dictated by the helicity of the alkene and of the bridged

biaryl structure (hence omitted in the rest of the manuscript for simplicity). The descriptor for the chirality of phosphorus in the complex matches that of the free ligand; naturally complexation of a metal with higher priority than oxygen would invert the absolute stereodescriptor.

Phosphoramidites38–40 have emerged as a highly versatile and readily accessible class of chiral ligands, showing exceptional levels of stereocontrol in homogeneous catalysis.30,32 In this context, we decided to explore the application of 1 as the chiral biaryl module in photoresponsive chiral phosphoramidite ligands for metal-catalyzed transformations (Scheme 6.2b). The system described herein features five stereochemical elements: i) the first element is the fixed stereogenic carbon center (R or S) of the switch

(highlighted in red); ii) the second element is the helicity of the overcrowded alkene (blue), which can be inverted upon photoisomerization between right-handed (P=) or left-handed (M=); the third and fourth

elements are, respectively, iii) the helical geometry (Pa or Ma) and iv) axial chirality (Ra or Sa) of the biaryl

unit (black), which is dictated by the helicity of the alkene (vide infra) due to steric interaction and can be assigned according to the CIP rules;41,42 v) the fifth element is the fixed stereogenic phosphorus center (RP

or SP) of the phosphoramidite motif (green) as dictated upon synthesis (vide infra). The barrier for

phosphine pyramidal inversion is high enough to prevent inversion occurring appreciably at room temperature.43,44 When coordinated to transition metal centers, enhanced configuration stability can be expected.45 Moreover, BINOL-based phosphoramidite ligands with asymmetric substitution pattern on the binaphthyl unit have been previously reported to be obtainable as stable and separable diastereoisomers at room temperature, which also displayed distinctive catalytic activity and selectivity.46

Similar to the previously described coupled transfer of dynamic chirality displayed by 1, the true helicity (and consequently the axial chirality) of the biaryl is inextricably connected to the helicity of the overcrowded alkene chromophore, and is identical to it in each of the isomers. Therefore, three stereodescriptors (R/S,RP/SP,P/M) will be sufficient for the assignment of any expected isomer reported in

this work. So for isomer (S,SP,M)-L: S = fixed configuration at C-stereogenic center, SP = fixed

configuration at P-stereogenic center, P = dynamic helicity of alkene chromophore and biaryl moiety. The doubly expressed P-stereodescriptor (RP/SP) throughout the text denotes a mixture of diastereoisomers with

identical absolute stereochemistry at the C-stereocenter and configurational helicity of the switch module but opposite absolute stereochemistry at the P-stereocenter [e.g. (S,SP/RP,M)-L means a mixture of

(S,SP,M)-L and (S,RP,M)-L]. When not expressed otherwise, L indicates the thermodynamic mixture of

diastereoisomers as obtained from synthesis without subsequent separation. For simplicity, we kept the descriptor for the chirality at phosphorus of the metal complex matching that of the free ligand – naturally complexation of a metal with higher priority than oxygen would invert the absolute stereodescriptor. Scheme 6.2c illustrates the delicate interplay of dynamic stereochemical elements of monodentate ligand (S,SP)-L after metal complexation and the light-triggered switching process between the two proposed

diasteroisomeric species.47 We envisioned a large variation of axial chiral induction and net steric hindrance provided around the coordinated metal center upon photochemical isomerization of the responsive ligand.

6.2.2 Synthesis

Biphenol switch (S)-1 was prepared from 8-bromo-7-methoxytetralone and 2-methoxyphenyl boronic acid via Suzuki cross coupling, subsequent Barton-Kellogg coupling of the corresponding hydrazone derivative with thiofluorenone, followed by chiral resolution of the deprotected biphenol intermediate with cinchona ammonium salt, according to synthetic methodology recently described by van Leeuwen.48 The synthesis of molecular switch-based ligands L1-5 is presented in Scheme 6.3. Starting from pure (S,M=,Ma)-1, ligands L

were obtained regarding their switch module only as (S,M=,Ma)-isomers (or (R,P=,Pa)-isomers in case of L3,

starting from (R,P=,Pa)-1), i.e. without loss of their helical purity. However, it should be noted that the

chiral switch structure features a C1-symmetry, as opposed to the C2-symmetry of BINOL-based

phosphoramidite ligands. As a consequence, ligands L1-5 were obtained as pairs of diastereoisomers due to the P-stereogenic center generated upon derivatization of 1, of which the distinctive relative ratio [dr, for instance (S,SP)-L:(S,RP)-L] is influenced by the steric requirements of the specific amine substituent.

46,49,50

N,N-dimethyl-substituted ligand L1 [(S,SP)-L1:(S,RP)-L1 = 56:44, 80% yield] was obtained from (S)-1

upon reaction with tris(dimethylamino)phosphine. Ligands L2-5 were obtained from either (S)-1 (99% ee) or (R)-1 (96% ee) via reaction with phosphorus trichloride followed by coupling with the correspondent secondary amine. Ligand L2 features the achiral N,N-diisopropylamine substituent, which upon comparison with L1 would allow investigating the influence of more sterically hindered phosphoramidite functionality

additional fraction with lower dr [(S,SP)-L2:(S,RP)-L2 = 60:40]. An important property of phosphoramidite

ligands is that different combinations of chiral diol and chiral amine allow tuning of the stereodiscrimination for the envisaged catalytic system.30 These features also result in matched/mismatched effects of the different diastereoisomers, of which distinct stereodiscrimination is exploitable to optimize the enantioselectivity in asymmetric reactions. Ligands L3 [(R,RP)-L3:(R,SP)-L3 = 95:5, 52% yield] and L4

[(S,SP)-L4:(S,RP)-L4 = 92:8, 40% yield] were synthesized from (R)-1 and (S)-1, respectively, in

combination with the chiral bis((R)-1-phenylethyl)amine.51 The latter is an established motif in various phosphoramidite ligands, first and foremost its BINOL-derivative which achieved remarkable results in many metal-catalyzed asymmetric transformations.30,32 It should be noted that in ligands L3 and L4 the number of stereochemical elements is raized up to seven [two additional fixed chiral centers (R1N,R

2

N) in

the amine unit]. Lastly, ligand L5 [(S,SP)-L5:(S,RP)-L5 = 60:40, 55% yield] was synthesized from (S)-1 and

tetrahydroquinoline (THQuin), which compared with L2 could provide insights on the influence of a non-symmetric achiral amine functionality on the catalytic performance. All molecular switches-based ligands

L1-5 were characterized by 1H, 13C and 31P NMR, UV-vis absorption and CD spectroscopy (see Experimental section for further details).

Scheme 6.3. Reagents and conditions for the synthesis of ligands L1-5. a) L1: P(NMe2)3, NH4Cl, benzene,

reflux, 16 h, 91:9 dr after recrystallization from Et2O-pentane. b) L2: PCl3, i-Pr2NH, NEt3, THF, then (S)-1,

0 °C to rt, 16 h, major diastereoisomer (S,SP):(S,RP) = 98:2 isolated by column chromatography. c) L3:

PCl3, (R)-[PhCH(CH3)]2NH, NEt3, THF, then (R)-1, 0 °C to rt, 16 h. d) L4: PCl3, (R)-[PhCH(CH3)]2NH,

NEt3, THF, then (S)-1, 0 °C to rt, 16 h. e) L5: PCl3, tetrahydroquinoline (THQuin), NEt3, toluene, 80 °C,

then (S)-1, THF, -78 °C to rt, 16 h. Ligands were obtained maintaining the helicity present in the starting biphenol 1. For all ligands L1-L5 only the major diastereoisomer is shown with a diastereoisomeric ratio as obtained from synthesis before isomer separation indicated below the structure. Structural view of diastereoisomers L with opposite point chirality on phosphorus reported in the box. Isolated yield (%) of diastereoisomeric mixture.

6.2.3 Photochemical isomerization

With the switchable ligands in hand, their photochemical and thermal isomerization properties were investigated. The reversible photochemical isomerization process of pure major diastereoisomer (S,SP ,M)-L2 in dichloromethane was monitored by UV-vis absorption, CD and 1H/31P NMR spectroscopy (Figures 6.1 and 6.2, see Experimental section for L1-3-4-L5). The forward photoisomerization step was achieved by irradiation at 365 nm, which resulted in a significant decrease in the intensity of the absorption band at 340 nm and the appearance of a new absorption band at 380 nm with clear isosbestic points (Figure 6.1b).

This red shift is indicative of the formation of the diastereoisomer (S,SP,M)-L2. 331

H and 31P NMR studies in CD2Cl2 also confirmed this structure as is evident from the downfield chemical shift of all the aliphatic

ring protons in 1H NMR and the shift of the phosphorus resonances in 31P NMR from 150.3 ppmto 145.4 ppm (Figure 6.2a-c). After reaching the photostationary state at 365 nm (PSS365), a ratio of (S,SP ,M)-L2:(S,SP,P)-L2 = 26:74 was established by 1H and 31P NMR spectroscopy (Figure 6.2c). The observed changes in the CD spectrum also support that the M to P helix inversion occurs during this step (new band at 410 nm, Figure 6.1c). The subsequent backward photoisomerization step was performed by irradiation at 420 nm of the previous PSS365 mixture, which largely regenerated the initial (S,SP,M)-L2. After reaching

the PSS420, a ratio of (S,SP,M)-L2:(S,SP,P)-L2 = 87:13 was established (Figure 6.2d). The excellent

reversibility and high PSS ratios are highly beneficial in applications of catalytic asymmetric reactions and dynamic control of chiral space. Complete photochemical isomerization study was also performed on ligands L1-3-4-L5 with similar results (see Experimental section for further details). Notably, photo-switching was successfully performed both with the free ligands and as the copper complexes (see Catalysis tests, vide infra) without a significant difference in stability or selectivity.

Figure 6.1. Photochemical isomerization study of (S,SP,M)-L2 by UV-vis absorption and CD spectroscopy. a) Photochemical E-Z isomerization of (S,SP,M)-L2 to (S,SP,P)-L2. b) UV-vis absorption spectral changes

of the switching process of L2 (CH2Cl2, 5.5·10−5 M). Starting isomer (S,SP,M)-L2 (black). Irradiation at

365 nm towards (S,SP,P)-L2 afforded a PSS365 mixture (red). Irradiation at 420 nm of the previous PSS365

mixture resulted in reversed E-Z isomerization affording a new PSS420 mixture (blue). Insert displays

irradiation cycles between the two PSS mixtures. c) Corresponding experimental CD spectral changes of previous sample.

Figure 6.2. Photochemical isomerization study of (S,SP,M)-L2 by 1H NMR and 31P NMR spectroscopy. a) Photochemical E-Z isomerization of (S,SP,M)-L2 to (S,SP,P)-L2 with labelled H and P atoms. d)

1 H/31P NMR spectra of L2 [(S,SP):(S,RP)= 98:2, 4.0 mg in 0.65 mL of CD2Cl2], 25 °C). e) 1 H/31P NMR spectra of PSS365 mixture [(S,SP,M)-L2:(S,SP,P)-L2 = 26:74]. d) 1 H/31P NMR spectra of PSS420 mixture [(S,SP

,M)-L2:(S,SP,P)-L2 = 87:13]. Residual solvent peak region (5.80–4.80 ppm) cut for clarity. Complete

6.2.4 Assignment of 1H NMR absorptions of (M) and (P) isomers of L2 via 1D-2D NMR techniques

Full assignment of the 1H NMR absorptions of major diastereoisomer (S,SP,M)-L2 (98:2 dr) was achieved

by comparing the 1H NMR (Figure 6.3), gCOSY (Figure 6.4) and NOESY (Figure 6.5) spectra here reported with the calculated NMR spectra (reported in Experimental section). Structure optimization of diastereoisomers (S,SP,M)-L2 and (S,RP,M)-L2 was executed with DFT (b3lyp/6-31g(d,p)) in gas-phase

(see Experimental section for further details on calculation study and comparison between experimental and calculated spectra). Insert with corresponding magnification of the aromatic protons range is reported in each spectrum. Individual absorptions assignments are indicated by single letters in the 1H-NMR spectrum, while cross-peaks are indicated by double letters in the gCOSY and NOESY spectra. In the current sample of (S,SP,M)-L2, coupling through space via NOE effect was observed via cross-peaks between protons A-L,

A-T, B-T and U-I. Notably, no coupling through space via NOE effect was observed via cross-peak between protons U-H. This experimental evidence supports the proposed stereochemical assignment to be diastereoisomer (S,SP,M)-L2, in which the diisopropylamine substituent is syn with the stereogenic center

of the upper half (rotor). The X-ray structure of the opposite diastereoisomer (S,RP,M)-L2 (see Figure 6.7),

which possesses opposite chirality on the phosphorus atom, clearly shows the close proximity of the diisopropylamine substituent with the protons M and N located in the fluorenyl lower half (stator). Indeed, no coupling through space would be expected between protons U-H for the latter diastereoisomer (S,RP ,M)-L2. Likewise, no U-H cross-peak would be expected for the photo-generated isomer (S,SP,P)-L2, due to the inverted axial chirality of the biaryl unit which results in an increased distance between protons U and H if compared with starting compound (S,SP,M)-L2.

Figure 6.3. 1H NMR (400 MHz, CD2Cl2) of (S,SP,M)-L2 with expansion of aromatic region; residual

The NMR analysis and assignment of the absorption peak was also performed on the photo-generated isomer (S,SP,P)-L2 (Figures 6.6 and 6.7). The starting sample was diluted in CH2Cl2 (20 mL), purged with

nitrogen for 5 min and irradiated at 365 nm until PSS was reached ((S,SP,M)-L2:(S,SP,P)-L2 = 26:74) (see

Experimental section for details). The suboptimal quality of the NMR spectrum and inherent incomplete conversion at the PSS365 did not allow recording a clear NOESY spectrum. Indeed, a complex spectrum

with no significant cross-peak was obtained (not reported).

Figure 6.6. 1H NMR (400 MHz, CD2Cl2) of PSS365 mixture, absorptions highlighted for (S,SP,P)-L2;

Figure 6.7. gCOSY (400 MHz, CD2Cl2) of (S,SP,P)-L2.

6.2.5 X-ray crystallography

Single crystals of L1 obtained upon crystallization from pentane/Et2O of the thermodynamic mixture of

diastereoisomers (S,SP)-L1:(S,RP)-L1 = 56:44 as obtained from synthesis were analyzed by X-ray

crystallography (Figure 6.1g, see Experimental section for further details). The reconstructed unit cell of the lattice was shown to contain only the minor diastereoisomer (R,P,Sa)-1, which may be characterized by a

lower solubility in the crystallization solvent. The experimental data confirmed the proposed model of coupled helical-to-axial transfer of helicity, demonstrating the most favored conformation of the lower aryl substituent to be parallel to the fluorenyl lower half of the switch core (synclinal) in the crystal lattice. The resolved structure also allows assessing the close proximity of the amine substituent to the fluorenyl group. Such structural restraint generates the distinctive diastereoisomeric ratio observed for the ligands, for which more sterically demanding amine substituents lead to higher dr. Lastly, the dihedral angle over the biaryl motif determined from the X-ray structure in the solid state was found to be 46.03°.

Figure 6.7. Schematic representation and X-Ray structure of (S,RP,M)-L1. Left: side view; right: top-down view through biaryl bond. Ellipsoids set at 50% probability. Torsional angle of biaryl unit: 46.03°.

6.2.6 Switchable asymmetric catalysis

Having confirmed the structures and two-stage photo-switching process of phosphoramidites L1-5, we investigated their performance as chiral switchable ligands in asymmetric catalysis. We selected copper(I)-catalyzed conjugate addition of diethylzinc to 2-cyclohexen-1-one (2) (Scheme 6.4a and Table 6.1), a well-established model reaction to determine the enantiodiscrimination abilities of chiral ligands.32 The reaction was carried out with 2 mol% of CuTC, 2 mol% of L in Et2O at -30 °C, either by using the copper-ligand

mixture as such [comprising of a single helicity, dr ratio reported in 3rd column of Table 6.1] or after irradiation at 365 nm [mixture of (M)- and (P)-isomers, determined by HPLC analysis, see 4th column of Table 6.1]. Notably, the presence of the copper salt did not affect the switching properties of photoresponsive ligands L. After addition of decane as internal standard, 1.2 equiv of Et2Zn (solution in

Et2O) and 0.25 mmol of 2-cyclohexen-1-one, the conversion was monitored over time by GC-MS analysis,

while enantiomeric excess was determine by chiral GC analysis of isolated product 2-ethylcyclohexan-1-one (3). To our delight, the reaction proceeds with high chemoselectivity affording high conversion towards product 3. Notably, upon comparison of the results of reactions conducted with almost pure (S,SP,M)-L2

using, respectively, the non-irradiated catalyst (see 3rd-4th columns in Table 6.1) and the catalyst mixture after irradiation (see 5th-7th columns), a large variation in enantioselectivity in favor of only (S)-3 was observed (from 5% to 69% ee, respectively, entry 2). When a mixture of L2 with gradually lower (S,SP):(S,RP) dr was used, an increasing preference for (R)-3 was observed in the reactions conducted with

non-irradiated catalyst (26% and 49%, entries 3-4). In addition, a decreasing enantioselectivity for (S)-3 was obtained in the reactions conducted with the irradiated catalyst mixture upon lowering the dr of the ligand (from 69% to 66% and 55%, entries 2-3-4). As general trend, when using mixtures of ligands with a low (S,SP):(S,RP) dr (namely L1, L2, and L5, entries 1-3-4-7) comparison of reactions conducted,

respectively, with a non-irradiated catalyst mixture, and the catalyst mixture after irradiation, displayed a net reversal of stereoselectivity, yielding 3 with stereochemistry of opposite configuration. On the other hand, when a mixture of ligands with a distinctively high dr was used (namely (S,SP,M)-L2, L3, and L4,

entries 2-5-6), a large variation in enantioselectivity in favor of a single enantiomer of 3 was observed. Moreover, the lower the dr of the ligand, the larger was the net variation of ee achieved (entries 2-3-4). The distinctive stereoselectivity of opposite diastereoisomers of conventional phosphoramidite ligands featuring

C1-symmetrical biaryl components was previously reported. 48

We suggested that an initially poorly performing (S,SP,M)-L2 can be converted to a chiral ligand with significant enantioselectivity for (S)-3

when converted to (S,SP,P)-L2 upon irradiation (entry 2). On the other hand, addition of the opposite

diastereoisomer (S,RP,M)-L2 (entry 4) provides a species more selective for (R)-3 in the non-irradiated

catalyst mixture, which strikingly appears to favor (S)-3 even upon irradiation due to the presence of the more active photo-generated (S,SP,P)-L2 isomer (Scheme 6.4b). An equivalent trend was observed for L5.

Scheme 6.4. Switchable asymmetric catalysis. a) Stereodivergent copper-catalyzed conjugate addition of

diethylzinc to 2-cyclohexen-1-one by switching the chirality of ligands L (only the major diastereoisomer is shown) upon photochemical isomerization (irradiation performed on copper-ligand mixtures in Et2O, see

Table 6.1 for details). b) Schematic top-down view of Cu-L complexes: for each (S,SP) or (S,RP)

diastereoisomer two metal-ligand complexes with opposite coupled helicity (M or P) can be selectively addressed by irradiation with UV-light. For simplicity, the descriptor for the chirality of phosphorus in the complexes matches that of the free ligand (see Scheme 6.2). In species Cu-(S,SP,M)-L and Cu-(S,RP,P)-L

the copper center is proposed to experience an unfavorable steric hindrance, which affects catalyst activity and enantioselectivity.

Table 6.1. Reaction scope of stereodivergent conjugate addition of diethylzinc to 2-cyclohexen-1-one with L1-5. Entrya L (S,SP,M):(S,RP,M) dr of Lb ee of 3 with non-irradiated catalyst mixture (%)c (M):(P) ratio of irr. cat. mix.d

(S,SP,M):(S,RP,M):

(S,SP,P):(S,RP,P) dr of irr. cat. mix.d

ee of 3 with irr. cat. mix.

(%)c 1 L1 55:45 22 (R) 28:72 15:13:40:32 12 (S) 2 L2 98:2 5 (S) 14:86 14:traces:84:2 69 (S) 3 L2 86:14 26 (R) 14:86 12:2:74:12 66 (S) 4 L2 60:40 49 (R) 14:86 8:6:52:34 55 (S) 5e L3 (R,RP,P):(R,SP,P) = 95:5 67 (S) 85:15 (R,RP,P):(R,SP,P): (R,RP,M):(R,SP,M) = 14:1:81:4 21 (S) 6 L4 92:8 43 (S) 60:40 55:5:37:3 97 (S) 7 L5 60:40 57 (R) 19:81 11:8:49:32 49 (S) a

General reaction conditions: 5 μmol of CuTC (copper(I)-thiophene-2-carboxylate), 5 μmol of (S,SP/RP,M)-L, 63 μmol of decane (int. std.), Et2O (1.0 mL), 0.30 mmol of Et2Zn (1.0 M in hexane), 0.25

mmol of 2-cyclohexen-1-one, -30 °C, 6 h.All isolated yield ranged within 70-84%, as determined by GC-MS analysis upon comparison with internal standard. b Determined by 1H/31P NMR analysis of isolated ligand mixtures from synthesis. c Determined by chiral GC analysis of isolated product. d Reaction with irradiated mixture of catalyst: mixture of CuTC and L irradiated with UV-light (365 nm) over 3 h. Ratio

It should be noted that the absolute preference of a ligand species for a specific enantiomer of 3 is dictated by the fixed point chirality on phosphorus [e.g. only (S)-3 using (S,RP)-L, entry 2], while the magnitude of

the enantioselectivity is governed by the reversible helicity of the switchable unit upon irradiation (e.g. from 5% to 69% ee for (S)-3 upon irradiation of (S,SP,M)-L2 towards (S,SP,P)-L2, entry 2). Overall, a

tunable matched-mismatched interaction of the fixed point chirality on phosphorus with the dynamic chiral induction provided by the stereogenic elements of the molecular switch can be observed. These results were supported by kinetic experiments, performed by monitoring the conversion of 2 vs. time (Figure 6.8). Comparison of reactions starting with pure (S,SP,M)-L2 proved that a strong increase in catalytic activity

[turnover frequency (TOF) from 57 h-1 to 281 h-1] is observed upon irradiation to 50% of (S,SP,P)-L2 with a

simultaneous increase in enantioselectivity (from 6% to 64% ee) (Figure 6.8a). On the other hand, dual stereocontrol can be achieved upon irradiation when employing an almost equimolar ratio of diastereoisomeric ligands like L5 [(S,SP):(S,RP)-L5 = 60:40], while maintaining comparable reaction rates

(Figure 6.8b). The more active outward facing complex (S,RP,M)-L5 then favors formation of (R)-3 (58%

ee), while after irradiation the majorly active complex (S,SP,P)-L5 is enantioselective for (S)-3 (43% ee).

This agrees fully with the results of L1 and L2 (entries 1 and 4, Table 6.1), in that (S,RP,M)-L is selective

for (R)-3 and (S,SP,P)-L favors (S)-3. However, the results obtained from reactions conducted with L3 and L4 show a clear preference for enantiomer (S)-3 in each experiment. This suggests that the common

bis((R)-1-phenylethyl)amine dominates the observed stereodescrimination in favor of (S)-3, despite opposite axial chiralities provided by the enantiomeric switch scaffold in L3 and L4. In spite of this, a

matched-mismatched interaction of the stereogenic elements of the chiral amine substituent and the

molecular switch can be observed. Precedent studies on conventional biaryl-based phosphoramidites showed significant increase in ee due to the additional chirality of the amine group.30 Based on such precedence and on the selectivities observed in the other ligands described hereto one expects the minor but presumably more active ligands (R,SP,P)-L3 and (S,SP,P)-L4 both to favor (S)-3 due to the likewise

matched interaction of (S)-chirality of the phosphorus center with (P)-helicity of the biphenol unit, but to a

different extent as the latter is featured, respectively, by the non-superimposable (R,P)-form (non-irradiated) or (S,P)-form ((non-irradiated) of the switch unit, which is reflected in a higher enantioselectivity for (S)-3 in the former with respect to the latter. Furthermore, irradiation of the ligands affords the more active pseudoenantiomeric complexes (R,RP,M)-L3 and (S,SP,P)-L4 in greater dr (81% and 37%, respectively),

resulting in an increase in the difference as well as an inversion of their respective enantioselectivities for (S)-3. Noteworthy, even an incomplete irradiation of L4 [(M):(P) = 60:40] provided from (S,SP,M)-L4 the

remarkably selective and active species (S,SP,P)-L4, which yielded (S)-3 with 97% ee which is attributed

due to the optimal matched interactions of seven chiral elements (i.e. (S,SP,R

1

N,R

2

N,P=,Pa,Sa)-L4). Although

(R,SP,P)-L3 displays a similar P-helical twist of the biaryl motif, the overall matched interaction is not

equally satisfied as in the photo-generated isomer. Such performance suggest that the chiral induction provided by (S,SP,P)-L4 most closely resembles the conventional

bis((R)-1-phenylethyl)amine-(S)-BINOL-derived phosphoramidite,52,53 a well-established ligand in copper-catalyzed asymmetric transformation which features the optimal combination of amine and biaryl chirality (S,R,R) if compared with its diastereoisomer (R,R,R).30 Based on this analysis, the proposed more active species for each mixture of ligands have been indicated in Table 6.1 (see bold text in 3rd and 6th columns).

Figure 6.8. Catalysis reaction kinetics. a) Reaction kinetics of copper-L catalyzed conjugate addition

followed by measuring substrate conversion and enantiomeric excess (ee) via GC-MS and chiral GC analysis. Comparison of conversion plots with non-irradiated (left) and irradiated catalyst mixture (right). Top: reactions performed with single diastereoisomer (S,SP,M)-L2 (as such and irradiated at 365 nm to an

(M):(P) = 50:50 mixture). Bottom: reactions performed with diastereoisomeric mixture of (S,SP ,M)-L5:(S,RP,M)-L5 = 60:40 (as such and irradiated at 365 nm to an (M):(P) = 21:79 mixture).

6.3 Conclusions

A selection of photoresponsive chiral phosphoramidite-molecular switch derivatives L1-5 in which chirality is dynamically transferred across from five to seven stereochemical elements [e.g. from (S,SP,M=,Ma,Ra)-L2 to (S,SP,P=,Pa,Sa)-L2] has been designed and successfully synthesized. The unique

combination of a light-triggered molecular switch featuring a bridged biaryl-derived monodentate ligand moiety allows reversible photo-switching between two stereochemical forms with distinct ligand properties. The ligands were used to alter the activity and invert the stereoselectivity of the copper–catalyzed conjugate addition of diethylzinc to 2-cyclohexen-1-one. Catalysis results supported by kinetic experiments suggest that each diastereoisomer of the ligand provides a distinctive activity and opposite stereoselectivity in the asymmetric catalytic event. This results in an elegant balance of two competing diasteroisomeric catalysts, of which complementary catalytic performance is tunable upon photoisomerization due to the reversible matched-mismatched interaction between the dynamic chirality of the switch unit and the fixed chirality of the phosphoramidite ligand site. Coupling of reversible switching to catalytic function, as demonstrated here, may prove to be a key design tool in the construction of future chiral catalysts that can perform multiple tasks in a sequential manner or can be used to ―up-or-down regulate‖ catalytic pathway non-invasively. These findings bring additional insights in the growing family of responsive chiral switches, not only for application as tunable catalysts into the vast domain of phosphorus-based ligands for transition metal catalysis,5,54 but more importantly as an additional step towards more sophisticated artificial systems for responsive control of chirality.55,56

6.4 Acknowledgements

The author would like to thank P. Štacko J. C. M. Kistemaker, T. van Leeuwen and Prof. E. Otten for their fundamental contribution to this work. Design was performed in collaboration with P. Štacko and J. C. M. Kistemaker. Computational study was performed by J. C. M. Kistemaker and T. van Leeuwen.. X-ray structure determination was performed by Prof. E. Otten.

6.5 Experimental section

6.5.1 General methods

Chemicals were purchased from Sigma Aldrich, Acros or TCI Europe. CuTC was prepared according to the literature procedure.57 Compound 1 was synthesized and resolved according to procedure reported in Chapter 5. Solvents were reagent grade and distilled and dried before use according to standard procedures. Dichloromethane, ether and toluene were used from the solvent purification system using an MBraun SPS-800 column. Tetrahydrofuran was distilled over sodium under a nitrogen atmosphere prior to use. NEt3 was

freshly distilled over CaH2 prior to use. PCl3 was freshly distilled at reduced pressure prior to use. Column

chromatography was performed on silica gel (Silica Flash P60, 230–400 mesh, mixtures of pentane with EtOAc, Et2O or CH2Cl2 were used as eluent as reported for each case).Components were visualized by UV

and phosphomolybdic acid or potassium permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890 – MS, HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). NMR spectra were recorded on a Varian Gemini-200, a Varian Mercury 300, a Varian AMX400 or a Varian Unity Plus 500 spectrometer, operating at 200 MHz, 300 MHz, 400 MHz, and 500 MHz for 1H NMR, respectively. Chemical shifts are denoted in δ values (ppm) relative to CDCl3 ( 1 H: δ = 7.26; 13 C: δ = 77.00) or CD2Cl2 ( 1 H: δ = 5.32; 13 C: δ = 54.00). Unless mentioned otherwise, all NMR spectra were recorded at 25 °C. For 1H NMR, the splitting parameters are designated as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), sext (sextet), m (multiplet) and b (broad). When mixtures of diastereoisomers are described (unless otherwise specified), the integral value of an absorption assignable for a specific diastereoisomer is reported as the corresponding fraction of the total number of nuclei of a specific chemical position. Mass spectra were obtained with an AEI MS-902 spectrometer (EI+) or with a LTQ Orbitrap XL (ESI+). Melting points were measured on a Büchi Melting Point B-545 apparatus. Optical rotations were measured on a Perkin Elmer 241 Polarimeter with a 10 cm cell (c given in g/100 mL). Chiral HPLC analysis was performed using a Shimadzu LC 10ADVP HPLC equipped with a Shimadzu SPDM10AVP diode array detector using a Chiralpak (Daicel) AD-H column. Elution speed was 0.5 mL/min, with mixtures of HPLC-grade heptane and isopropanol (BOOM) as eluent and column temperature of 40 °C. Sample injections were made using an HP 6890 Series Auto sample Injector. Chiral GC analysis was performed using a HP6890, equipped with capillary column Astec G-TA, 30m x 0.25mm, He-flow 1.0 mL/min, equipped with a flame ionization detector. UV-vis absorption spectra were measured on a SPECORD S600 Analityk Jena spectrophotometer. CD spectra were measured on a Jasco J-815 CD spectrophotometer. All spectra were recorded at 20 °C using Uvasol-grade dichlorometane (Merck) as solvent. Irradiation was performed using Thorlabs M365F1 (365 nm) and M420F2 (420 nm) fibre-coupled coupled high power LEDs. Room temperature (rt) as mentioned in the experimental procedures, characterization and computational sections is to be considered equal to 20 °C. The chiral descriptors for each species described in this work (e.g. (S,SP,M)-L) indicate respectively: the absolute

stereochemistry of the stereogenic center in the molecular switch core (R or S), the absolute stereochemistry of the phosphorus center (RP or SP), and the configurational helicity and axial chirality of the switch core (P

or M). The doubly expressed point P-chirality stereodescriptor (RP/SP) throughout the text denote a mixture

of diastereoisomers with identical absolute stereochemistry and configurational helicity in the switch core but opposite point chirality in the phosphorus center (e.g. (S,SP,M)-L indicates a mixture of (S,SP,M)-L and

6.5.2 Synthetic procedures

(M)-(12S)-13-(9H-fluoren-9-ylidene)-N,N,12-trimethyl-10,11,12,13-tetrahydrobenzo[d]naphtho[1,2-f][1,3,2]dioxaphosphepin-6-amine (L1)

Compound L1 was prepared from 1 by a modified procedure previously reported.58 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar and charged with racemic 1 (160 mg, 0.38 mmol), NH4Cl (4 mg, 0.07 mmol, 0.2 equiv), dry benzene (3 mL) and

tris(dimethylamino)phosphine (75 mg, 84 µL, 0.46 mmol, 1.25 equiv). The reaction mixture was heated at reflux for 5 h. The mixture was concentrated under reduced pressure affording a solid residue. The crude residue (56:44 mix. of diastereoisomers based on 1H/31P-NMR) was re-dissolved in dry Et2O (2 mL) and pentane (4 mL) was slowly added until

precipitation occurred. The precipitate was filtered on a glass fritted funnel P4 under vacuum and washed with pentane to yield racemic L1 (85 mg, 0.173 mmol, 45%, (S,SP)-L1:(S,RP)-L1 = 91:9 dr) as yellow

powder containing a few mono-crystals. The same procedure was performed on an enantioenriched fraction of (S,M)-1 (50 mg, 0.120 mmol, 90% ee) to yield enantioenriched (S,M)-L1 (90% ee, 91:9 dr) as yellow powder. m.p. 196–198 °C. 1H NMR (400 MHz, CDCl3, (S,SP)-L1:(S,RP)-L1 = 91:9 dr, absorptions of only

major diastereoisomer are reported) δ 7.95–7.86 (m, 1H), 7.59–7.52 (m, 1H), 7.37 (dd, J = 7.8, 1.9 Hz, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.28–7.24 (m, 3H), 7.06 (td, J = 7.4, 1.0 Hz, 1H), 6.90 (td, J = 7.7, 1.3 Hz, 1H), 6.81 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.69–6.59 (m, 2H), 4.21 (hept, J = 6.8 Hz, 1H), 2.74–2.64 (m, 1H), 2.53 (d, J = 8.9 Hz, 6H), 2.48–2.34 (m, 2H), 1.60 (d, J = 6.9 Hz, 3H), 1.33–1.21 (m, 1H). 13C NMR (75 MHz, CDCl3, (S,SP)-L1:(S,RP)-L1 = 91:9 dr, absorptions of only major

diastereoisomer are reported) δ 151.4 (d, J = 6.5 Hz), 149.4, 142.5, 140.7, 139.4 (d, J = 1.6 Hz), 138.5, 138.0, 137.5, 136.7, 134.6, 132.1 (d, J = 3.9 Hz), 130.6 (d, J = 1.1 Hz), 128.6 (d, J = 1.1 Hz), 128.3 (d, J = 2.0 Hz), 127.6, 127.10, 126.9, 126.6, 126.5, 124.8, 124.3, 122.1 (d, J = 2.2 Hz). 122.0, 121.4, 119.2, 118.0, 36.0, 35.8, 34.6, 31.5, 29.4, 21.7. 31P NMR (162 MHz, CDCl3, (S,SP)-L1:(S,RP)-L1 = 91:9 dr) δ 146.1

(major), 145.5 (minor). HRMS (ESI, m/z): calcd for C32H29NO2P [M+H] +

: 490.1930, found: 490.1917. [ ] = -104 (c 0.2, CHCl3) for (S,M)-L1 (90% ee, (S,SP)-L1:(S,RP)-L1 = 91:9 dr).

(M)-(12S)-13-(9H-fluoren-9-ylidene)-N,N-diisopropyl-12-methyl-10,11,12,13-tetrahydrobenzo[d]naphtho[1,2-f][1,3,2]dioxaphosphepin-6-amine (L2)

Compound L2 was synthesis according to a modified published procedure.59 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar and charged with THF (1 mL) and Et3N (0.16 mL,

1.18 mmol, 7 equiv). The reaction mixture was cooled at 0 °C and PCl3

(0.016 mL, 0.18 mmol, 1.1 equiv) was added via syringe under stirring. A flame-dried, 25 mL Schlenk tube was charged with diisopropylamine (0.026 mL, 0.18 mmol, 1.1 equiv) and THF (0.5 mL). This mixture was added dropwise to the above mentioned PCl3 solution at 0 °C. After the addition was complete, the reaction mixture was let to stir at

room temperature over 2 h. A flame-dried, 25 mL Schlenk tube was charged with (S,M)-1 (70 mg, 0.17 mmol, 99% ee) and THF (1 mL). This mixture was added dropwise to the mixture of PCl3 and

secondary amine at 0 °C. The resulting mixture was warmed up to room temperature and stir overnight, then filtered through celite, and washed with cold Et2O (2x5 mL). The organic phase was concentrated at

reduced pressure. The product was purified by column chromatography (SiO2, pentane:CH2Cl2 = 3:1) and

stripped from CHCl3 (2x10 mL) to yield L2 (62 mg, 0.11 mmol, 62%, 99% ee, (S,SP)-L2:(S,RP)-L2 = 86:14

dr) as a yellow foam. m.p. 125–126 °C. 1H NMR (400 MHz, CD2Cl2, (S,SP)-L2:(S,RP)-L2 = 86:14 dr) δ

7.99–7.92 (m, 1H), 7.63–7.56 (m, 1H), 7.48–7.39 (m, 2H), 7.36 (d, J = 8.0 Hz, 0.85H), 7.34–7.24 (m, 3H), 7.07 (t, J = 7.4 Hz, 1H), 6.98–6.82 (m, 2H), 6.74 (dd, J = 8.0, 5.6 Hz, 1.6H), 6.68 (t, J = 7.6 Hz, 1H), 4.30– 4.05 (m, 1H), 3.77 (dhept, J = 10.7, 6.6 Hz, 0.3H, minor d.), 3.37 (dhept, J = 10.6, 6.8 Hz, 1.70H, major d.),

2.71 (dt, J = 13.9, 3.4 Hz, 1H), 2.53–2.43 (m, 1H), 2.37 (td, J = 13.5, 4.9 Hz, 1H), 1.63 (d, J = 7.0 Hz, 2.50H), 1.59 (d, J = 7.0 Hz, 0.5H), 1.37 (dd, J = 6.8, 1.8 Hz, 1.8H), 1.32–1.24 (m, 1.5H), 1.20 (d, J = 4.2 Hz, 5.1H), 1.18 (d, J = 4.1 Hz, 5.1H). 13C NMR (100 MHz, CD2Cl2, (S,SP)-L2:(S,RP)-L2 = 86:14 dr) δ 152.5 (d, J = 8.3 Hz), 150.7, 144.2, 144.1, 141.0,140.0 (d, J = 1.5 Hz), 139.2, 139.0, 138.8, 138.5, 138.2, 138.1, 137.2 (d, J = 1.3 Hz), 134.8, 132.9, 132.92(d, J = 3.8 Hz), 131.6 (d, J = 1.0 Hz), 131.5 (d, J = 1.9 Hz), 129.1 (d, J = 1.2 Hz), 128.7 (d, J = 1.4 Hz), 128.2, 128.2, 127.8 (d, J = 1.4 Hz), 127.8, 127.7, 127.3, 127.3, 127.2, 127.2, 127.1, 125.7, 125.6, 124.7, 124.6, 123.1 (d, J = 1.6 Hz), 122.9, 122.9 (d, J = 2.5 Hz), 122.7, 122.1, 122.0 (d, J = 1.0 Hz), 119.8, 119.7, 118.8, 118.7, 45.4 (d, J = 12.5 Hz), 45.2 (d, J = 12.6 Hz), 35.6, 35.5, 32.1, 31.9, 30.0, 30.0, 24.8, 24.8, 24.7, 22.3, 22.3. 31P NMR (162 MHz, CD2Cl2,

(S,SP)-L2:(S,RP)-L2 = 86:14 dr) δ 149.7 (major), 147.8 (minor). HRMS (ESI, m/z): calcd for C39H33NO2P

[M+H]+: 546.2556, found: 546.2549.

The mixture of diastereoisomers of L2 ((S,SP)-L2:(S,RP)-L2 = 86:14 dr) was further purified by column

chromatography (SiO2, pentane:CH2Cl2 = 6:1) to yield L2 as two fractions with different dr (1 st

fraction: 31 mg, 0.056 mmol, (S,SP)-L2:(S,RP)-L2 = 98:2 dr; 2nd fraction: 30 mg, 0.055 mmol, (S,SP)-L2:(S,RP)-L2 =

60:40 dr). 1H NMR (400 MHz, CD2Cl2, (S,SP)-L2:(S,RP)-L2 = 98:2 dr, absorptions of only major

diastereoisomer are reported) δ 7.99–7.89 (m, 1H), 7.63–7.57 (m, 1H), 7.45 (dd, J = 7.8, 1.6 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.34–7.25 (m, 3H), 7.07 (td, J = 7.4 Hz, 1H), 6.92–6.85 (m, 2H), 6.74 (dd, J = 8.0, 5.3 Hz, 2H), 6.68 (t, J = 7.4 Hz, 1H), 4.22 (sest, J = 7.3 Hz, 1H), 3.37 (dp, J = 10.7, 6.8 Hz, 2H), 2.71 (ddd, J = 14.0, 4.1, 2.8 Hz, 1H), 2.52–2.26 (m, 2H), 1.63 (d, J = 6.9 Hz, 3H), 1.33–1.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H), 1.19 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CD2Cl2, (S,SP)-L2:(S,RP )-L2 = 98:2 dr, absorptions of only major diastereoisomer are reported) δ 152.5 (d, J = 8.4 Hz), 150.7, 144.1,

141.0, 140.0 (d, J = 1.7 Hz), 139.0, 138.5, 138.1, 137.2 (d, J = 1.7 Hz), 134.8, 132.9 (d, J = 3.8 Hz), 131.6 (d, J = 1.3 Hz), 128.7 (d, J = 1.4 Hz), 128.2 (2, J = 1.1 Hz), 127.7, 127.3, 127.2, 127.2, 125.6, 124.7,122.9 (d, J = 2.4 Hz), 122.1, 122.0 (d, J = 1.4 Hz), 119.7, 118.65, 45.3, 45.2, 35.6, 32.1, 30.0, 24.8, 24.7, 22.3. [ ] _{= -201 (c 0.2, CHCl} 3) for (S,M)-L2 (>99% ee, (S,SP)-L2:(S,RP)-L2 = 98:2 dr). (P)-(12R)-13-(9H-fluoren-9-ylidene)-12-methyl-N,N-bis((R)-1-phenylethyl)-10,11,12,13-tetrahydrobenzo[d]naphtho[1,2-f][1,3,2]dioxaphosphepin-6-amine (L3)

Compound L3 was synthesis according to a modified published procedure.59 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. The Schlenk tube was charged with THF (0.5 mL) and Et3N (0.27 mL, 1.9 mmol,

10 equiv). The reaction mixture was cooled at 0 °C and a solution of PCl3 (0.017 mL, 0.19 mmol, 1 equiv) in CH2Cl2 (0.1 mL) was added

via syringe under stirring. A flame-dried, 25 mL Schlenk tube was charged with bis[(R)-1-phenylethyl]amine (0.043 mL, 0.19 mmol, 1 equiv) and THF (1 mL). This mixture was added dropwise to the above mentioned PCl3 solution at 0 °C. After the addition was complete, the reaction

mixture was stirred at room temperature over 2 h and then CH2Cl2 (1 mL) was added. A flame-dried,

25 mL Schlenk tube was charged with (R,P)-1 (80 mg, 0.19 mmol, 96% ee) and THF (0.8 mL + 0.4 mL for rinsing). This solution was added dropwise to the mixture of PCl3 and secondary amine at

0 °C. The resulting mixture was let to warm up to room temperature and stir overnight, then filtered through celite and washed with cold Et2O (2x5 mL). The organic phase was concentrated at reduced

pressure. The product was purified by column chromatography (SiO2, pentane:CH2Cl2 = 3:1) and

6.94–6.83 (m, 3H), 6.70–6.62 (m, 2H), 4.47 (dq, J = 13.9, 7.1 Hz, 2H), 4.18 (h, J = 7.4, 6.5 Hz, 1H), 2.68 (dt, J = 14.0, 3.5 Hz, 1H), 2.49–2.40 (m, 1H), 2.35 (td, J = 13.5, 5.0 Hz, 1H), 1.84 (d, J = 7.1 Hz, 0.5H, chiral amine methyl peak of minor diastereoisomer), 1.67 (d, J = 7.1 Hz, 6H), 1.61 (d, J = 6.9 Hz, 3H), 1.33–1.19 (m, 2H). 13C NMR (100 MHz, CD2Cl2, (R,RP)-L3:(R,SP)-L3 = 95:5 dr, absorptions of only major

diastereoisomer are reported) δ 151.6 (d, J = 9.2 Hz), 149.4, 143.4, 143.2, 140.4, 139.8 (d, J = 1.7 Hz), 138.4, 137.9, 137.4, 136.7 (d, J = 1.7 Hz), 134.3, 132.4 (d, J = 3.9 Hz), 131.4 (d, J = 1.2 Hz), 128.3 (d, J = 1.6 Hz), 127.9, 127.9, 127.8, 127.7 (d, J = 1.4 Hz), 127.7, 127.4 (d, J = 2.2 Hz), 127.2, 126.8, 126.7, 126.6, 126.6, 126.5, 125.0, 124.9, 124.0, 122.4 (d, J = 2.7 Hz), 121.5 (d, J = 1.3 Hz), 121.5, 119.1, 118.1, 52.1 (d,

J = 12.1 Hz), 35.0, 31.5. 31P NMR (162 MHz, CD2Cl2, (R,RP)-L3:(R,SP)-L3 = 95:5 dr) δ 143.4 (major),

142.6 (minor). HRMS (ESI, m/z): calcd for C46H41NO2P [M+H] +

: 670.2868, found: 670.2869. [ ] = +296 (c 0.2, CHCl3) for (R,P)-L3 (>99% ee, (R,RP)-L3:(R,SP)-L3 = 95:5 dr).

(12S)-13-(9H-fluoren-9-ylidene)-12-methyl-N,N-bis((R)-1-phenylethyl)-10,11,12,13-tetrahydrobenzo[d]naphtho[1,2-f][1,3,2]dioxaphosphepin-6-amine (L4)

Compound L4 was synthesis according to a modified published procedure.59 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar and charged with THF (0.5 mL) and Et3N (0.27 mL, 1.9 mmol, 10 equiv). The reaction

mixture was cooled at 0 °C and a solution of PCl3 (0.017 mL, 0.19 mmol,

1 equiv) in CH2Cl2 (0.1 mL) was added via syringe under stirring. A

flame-dried, 25 mL Schlenk tube was charged with bis[(R)-1-phenylethyl]amine(0.043 mL, 0.19 mmol, 1 equiv) and THF (1 mL). This mixture was added dropwise to the above mentioned PCl3 solution at 0 °C. After the addition was complete, the reaction mixture was let to

stir at room temperature over 2 h and then CH2Cl2 (1 mL) was added. A flame-dried, 25 mL Schlenk tube

was charged with (S,M)-1 (80 mg, 0.19 mmol, 99% ee) and THF (0.8 mL + 0.4 mL for rinsing). This mixture was added dropwise to the mixture of PCl3 and secondary amine at 0 °C. The resulting mixture was

let to warm up to room temperature and stir overnight, then filtered through celite and washed with cold Et2O (2x5 mL). The organic phase was concentrated at reduced pressure. The product was purified by

column chromatography (SiO2, pentane:CH2Cl2 = 3:1) and stripped from CHCl3 (2x10 mL) to yield L4

(50 mg, 0.08 mmol, 40%, 99% ee, (S,SP)-L4:(S,RP)-L4 = 92:8 dr) as a yellow foam. m.p. 213–215 °C. 1

H NMR (400 MHz, CD2Cl2, (S,SP)-L4:(S,RP)-L4 = 92:8 dr) δ 7.96–7.88 (m, 1H), 7.61–7.52 (m, 1H), 7.45

(d, J = 7.8 Hz, 1H), 7.43–7.37 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.32–7.24 (m, 2H), 7.20–7.11 (m, 9H), 7.07 (t, J = 7.3 Hz, 1H), 6.86 (q, J = 7.5, 6.9 Hz, 1H), 6.76–6.69 (m, 3H), 6.63–6.57 (m, 1H), 4.46–4.34 (m, 2H), 4.20 (h, J = 7.4 Hz, 1H), 2.71 (dt, J = 14.2, 3.4 Hz, 1H), 2.51–2.31 (m, 2H), 1.84 (d, J = 7.1 Hz, 0.5H, chiral amine methyl peak of minor diastereoisomer), 1.69 (d, J = 7.1 Hz, 6H), 1.62 (d, J = 6.9 Hz, 3H), 1.27 (d, J = 7.1 Hz, 2H). 13C NMR (100 MHz, CD2Cl2, , (S,SP)-L4:(S,RP)-L4 = 92:8 dr) δ 152.1 (d, J = 11.6 Hz),

149.7, 143.4, 143.2, 143.2, 140.4, 139.9, 138.5, 137.9, 137.4, 136.7, 134.3, 132.6, 131.6, 131.6, 128.3 (d, J = 1.9 Hz), 128.1 (d, J = 3.1 Hz), 128.0, 127.9, 127.9, 127.8, 127.8, 127.7, 127.6, 127.2, 126.8, 126.7, 126.6, 126.6, 125.1, 125.0, 124.0, 123.8, 122.5 (d, J = 2.8 Hz), 121.7, 121.2, 119.2, 119.2, 54.1 (d, J = 10.9 Hz), 35.0, 31.6, 29.7, 29.4, 22.6 (d, J = 12.1 Hz), 21.7. 31P NMR (162 MHz, CD2Cl2, (S,SP)-L4:(S,RP)-L4 = 92:8

dr) δ 148.8 (major), 147.3 (minor). HRMS (ESI, m/z): calcd for C46H41NO2P [M+H] +

: 670.2868, found: 670.2869. [ ] = +106 (c 0.2, CHCl3) for (S,M)-L4 (>99% ee, (S,SP)-L4:(S,RP)-L4 = 92:8 dr).

(M)-(1-((12S)-13-(9H-fluoren-9-ylidene)-12-methyl-10,11,12,13-tetrahydrobenzo [d]naphtho[1,2-f][1,3,2]dioxaphosphepin-6-yl)-1,2,3,4-tetrahydroquinoline (L5)

Compound L5 was synthesis according to a modified published procedure.60 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. The Schlenk tube was charged with toluene (2 mL) and PCl3 (13 µL, 0.15 mmol, 1.1 equiv),

and then cooled at 0 °C. A flame-dried, 25 mL Schlenk tube was charged with 1,2,3,4-tethrahydroquinoline (19.7 mg, 0.15 mmol, 1.1 equiv), toluene (0.35 mL), and Et3N (35 µL, 0.25 mmol, 1.85 equiv). This mixture

was added dropwise to the above mentioned PCl3 solution at 0 °C. After the addition was complete, the

reaction mixture was heated at 80 °C for 6 h, and then was cooled at -78 °C slowly. A flame-dried, 25 mL Schlenk tube was charged with (S,M)-1 (56 mg, 0.135 mmol, 99% ee) and Et3N (65 µL, 0.47 mmol) in

toluene (1.25 mL) and THF (0.4 mL). This mixture was added dropwise to the mixture of PCl3 and

secondary amine at -78 °C. The resulting mixture was let to warm up to room temperature and stir overnight, then filtered through celite and washed with cold Et2O (2x5 mL). The organic phase was

concentrated at reduced pressure. The product was purified by column chromatography (SiO2,

pentane:CH2Cl2 = 5:1) and stripped from CHCl3 (2x10 mL) to yield L5 (43 mg, 0.074 mmol, 55%, 99% ee,

(S,SP)-L5:(S,RP)-L5 = 60:40 dr) as a yellow foam. m.p. 165-167 °C. 1 H NMR (500 MHz, CD2Cl2, (S,SP )-L5:(S,RP)-L5 = 60:40 dr) δ 8.01–7.96 (m, 0.4H), 7.96–7.91 (m, 0.6H), 7.64–7.56 (m, 1H), 7.50–7.40 (m, 3H), 7.38 (d, J = 8.1 Hz, 0.6H, major d.), 7.35–7.27 (m, 3.2H), 7.20 (d, J = 8.0 Hz, 0.4H, minor d.), 7.16– 7.04 (m, 3H), 7.02 (d, J = 7.9 Hz, 0.4H, minor d.), 6.98–6.82 (m, 3.4H), 6.80 (d, J = 7.9 Hz, 0.6H), 6.77– 6.71 (m, 1H), 6.68 (d, J = 8.0 Hz, 0.6H, major d.), 4.32–4.17 (m, 1H), 3.99–3.91 (m, 0.4H, minor d.), 3.36– 3.23 (m, 1H), 2.95–2.82 (m, 0.8H, minor d.), 2.78–2.64 (m, 3.2H) 2.52–2.44 (m, 1H), 2.40 (td, J = 13.4, 4.8 Hz, 1H), 2.08–1.91 (m, 0.8H, minor d.), 1.71–1.65 (m, 1.4H), 1.62 (d, J = 7.0 Hz, 1.8H, major d.), 1.58 (d, J = 6.9 Hz, 1.2H, minor d.), 1.35–1.17 (m, 2H). 13C NMR (126 MHz, CD2Cl2, (S,SP)-L5:(S,RP)-L5 = 60:40 dr) δ 151.80 (d, J = 6.8 Hz), 151.2 (d, J = 7.1 Hz), 150.9, 149.6, 143.8, 143.7, 142.7, 142.5, 141.0, 140.9, 140.6, 140.6, 139.7 (d, J = 1.0 Hz), 139.3, 139.1, 138.5, 138.5, 138.2, 138.0, 137.5 (d, J = 1.1 Hz),135.0, 135.0, 131.6, 131.6, 131.5, 131.5,130.5, 130.4, 129.3 (d, J = 1.2 Hz), 129.3, 128.8 (d, J = 1.8 Hz), 128.4, 127.9, 127.8, 127.7, 127.5, 127.5, 127.4, 127.3, 127.3, 126.8 (d, J = 2.6 Hz), 126.6 (d, J = 2.2 Hz), 126.6, 125.7, 127.7, 125.6, 124.7, 124.6, 123.7 (d, J = 1.1 Hz), 122.8 (d, J = 0.9 Hz), 122.7 (d, J = 2.3 Hz),122.9, 122.5 (d, J = 2.4 Hz),122.2 (d, J = 1.4 Hz), 122.1 (d, J = 1.7 Hz), 122.0, 119.9, 119.8, 119.0, 119.0, 118.9,118.8, 118.8, 118.7, 43.2 (d, J = 3.9 Hz), 42.4 (d, J = 2.9 Hz), 35.4, 35.4, 32.0, 31.8, 30.0, 30.0, 27.9, 27.4, 24.4, 24.0, 22.24, 22.1. 31P NMR (162 MHz, CD2Cl2, (S,SP)-L5:(S,RP)-L5 = 60:40 dr) δ

140.4 (major d.), 138.6 (minor d.). HRMS (ESI, m/z): calcd for C39H33NO2P [M+H] +

: 578.2243, found: 578.2240. [ ] _{= +167 (c 0.2, CHCl}

3) for (S,M)-L5 (>99% ee, (S,SP)-L5:(S,RP)-L5 = 60:40 dr). 6.5.3 X-ray Crystallography

A racemic fraction of compound L1 (56:44 dr) was recrystallized from a solution of diethyl ether upon addition of pentane as reported in the experimental procedure. Among various non-crystalline agglomerates, a single crystal of (S,RP,M)-L1 was obtained. The single crystal was mounted on top of a

cryoloop and transferred into the cold nitrogen stream (100 K) of a Bruker-AXS D8 Venture diffractometer. Data collection and reduction was done using the Bruker software suite APEX3.61 The final unit cell was obtained from the xyz centroids of 9994 reflections after integration. A multiscan absorption correction was applied, based on the intensities of symmetry-related reflections measured at different angular settings (SADABS).The structures were solved by direct methods using SHELXT62 and refinement

Table 6.2. Crystallographic data for (S,RP,M)-L1.

6.5.4 Atropisomers assignment via comparison of calculated and experimental NMR spectra

Structure optimization of diastereoisomers (S,SP,M)-L2 and (S,RP,M)-L2 was executed with DFT

(b3lyp/6-31g(d,p)) in gas-phase. The 1H-NMR signals were predicted using GIAO (mPW1PW91/6-311+g(2d,p)) method with chloroform SMD solvation model, using literature reported scaling factors.64 Calculated 1H NMR spectra of stable isomers (S,SP,M)-L2 and (S,RP,M)-L2 were compared with corresponding

experimental spectra (Figures 6.10 and 6.11). Figures 6.9b,c illustrate the corresponding calculated optimized geometries of predominant conformers with labelled atoms for NMR absorption assignment listed in Table 6.3.

Calculated 1H NMR multiplet reports:

(S,SP,M)-L2: 1H NMR (400 MHz, CDCl3) δ 7.75 (1H, T) , 7.49 (1H, Q), 7.46 (1H, L), 7.36 (1H, P), 7.18 (1H, G), 7.17 (1H, H), 7.16 (1H, S), 7.13 (1H, R), 6.94 (1H, O), 6.80 (1H, J), 6.77 (1H, N), 6.74 (1H, I), 6.69 (1H, M), 6.66 (1H, K), 4.16 (1H, B), 3.31 (2H, V), 2.61 (1H, E), 2.37 (1H, D), 2.27 (1H, F), 1.57 (3H, A), 1.14 (12H, U), 1.20 (1H, C). (S,RP,M)-L2: 1 H NMR (400 MHz, CDCl3) δ 7.78 (1H, T), 7.52 (1H, Q), 7.43 (1H, L), 7.36 (1H, ), 7.16 (1H, G), 7.29 (1H, H), 7.21 (1H, S), 7.17 (1H, R), 6.96 (1H, O), 6.81 (1H, J), 6.83 (1H, N), 6.76 (1H, I), 6.90 (1H, M), 6.65 (1H, K), 4.18 (1H, B), 3.75 (2H, V), 2.67 (1H, E), 2.39 (1H, D), 2.27 (1H, F), 1.55 (3H, A), 1.37 (12H, U), 1.19 (1H, C).

Based on calculated chemical shifts, the experimental absorption were assigned to the major diastereoisomer (S,SP,M)-L2 and minor diastereoisomer (S,RP,M)-L2, respectively (structures depicted in

Figure 6.9a). More precisely:

 the protons (from 62-H to 76-H, assigned to absorption peak U in experimental 1H NMR spectrum) on the four methyl substituents on the diisopropyl groups of (S,SP,M)-L2 (experimental chemical shift:

1.20–1.19 ppm, average calculated value: 1.14 ppm) resonate at lower frequency than (S,RP,M)-L2

(experimental chemical shift: 1.37 ppm, average calculated value: 1.26 ppm);

 the two tertiary protons (58-H and 60-H, assigned to absorption peak V in experimental 1H NMR spectrum) on the diisopropyl groups of (S,SP,M)-L2 (experimental chemical shift: 3.37 ppm, average

chem formula C32 H28 N O2 P

µ(Mo K



Mr 489.52 F(000) 516

cryst syst triclinic temp (K) 100(2)

color, habit light yellow, block  range (deg) 2.967 – 27.872 size (mm) 0.25 x 0.21 x 0.08 data collected (h,k,l) -12:12, -13:13, -17:17

space group P -1 no. of rflns collected 47480

a (Å) 9.6686(15) no. of indpndt reflns 5852

b (Å) 10.4782(15) observed reflns _{5017 (Fo  2}



c (Å) 13.3775(18) R(F) (%) 3.92

V (Å3) 1229.7(3) wR(F2) (%) 10.32

, deg 106.231(6) GooF 1.030

, deg 94.610(7) Weighting a,b 0.0490, 0.7448

, deg 106.368(6) params refined 328

Z 2 restraints 0

calc, g.cm

calculated value: 3.31 ppm) resonate at lower frequency than (S,RP,M)-L2 (experimental chemical

shift: 3.77 ppm, average calculated value: 3.75 ppm);

 the protons (from 45-H to 47-H, assigned to absorption peak A in experimental 1H NMR spectrum) on methyl substituent at the stereogenic center of (S,SP,M)-L2 (experimental chemical shift: 1.63 ppm,

average calculated value: 1.57 ppm) resonate at higher frequency than (S,RP,M)-L2 (experimental

chemical shift: 1.59 ppm, average calculated value: 1.55 ppm).

Figure 6.9. a) Schematic structure representation of diasteroisomers (S,SP,M)-L2 (amine substituent sin with methyl substituent in the switch unit) and (S,RP,M)-L2 (amine substituent anti with methyl substituent

in the switch unit), proton labelled according to assignment via analysis of experimental NMR spectra (vide