university of groningen dynamic transfer of chirality in ...8.1.1 design of natural and artificial...

University of Groningen

Dynamic transfer of chirality in photoresponsive systemsPizzolato, Stefano Fabrizio

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Citation for published version (APA):Pizzolato, S. F. (2017). Dynamic transfer of chirality in photoresponsive systems: Applications of molecularphotoswitches in catalysis. [Groningen]: University of Groningen.

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Chapter 8 Chapter 8

Study towards a Photoswitchable Chiral Bidentate

Phosphine Ligand based on an Overcrowded Alkene

for Metal-catalyzed Asymmetric Transformations

This chapter describes the study towards the synthesis and application of a photoswitchable chiral

bis(diphenylphosphine)-ligand based on a second generation molecular motor core. We envisioned a large

variation of axial chiral induction and steric hindrance induced around the coordinated metal center upon

photochemical isomerization of the responsive ligand. Derivatization of the 2,2’-bisphenol-functionlized

chiral molecular switch described in Chapter 5 provided the bis-triflate-intermediate. Several metal-

catalyzed aryl phosphination methodologies previously developed for conventional biaryl scaffold were

attempted. However, the target compound was not obtained. Experimental evidence suggests that the highly

hindered structure of the designed bidentate ligand may even preclude the proposed synthetic route at all.

An alternative proposal to develop a photoswitchable Brønsted acid catalyst based on an analogous

diphenylphosphine-hydroxyl derivative is presented.

Chapter 8

260

8.1 Introduction

8.1.1 Design of natural and artificial metal complexes

The ability to reversibly control the shape of structures at the nano-scale is a highly challenging and

attractive target of modern molecular design. Indeed, such molecular devices constitute powerful tools for

achieving switchable chiral induction. Chiral inversion and asymmetric induction processes play an

important role in host-guest chemistry, self-assembly and molecular recognition, as well as in nature.1–4

They are in fact known to affect the properties and functions of DNA5 and proteins.

6 Inspired by nature, the

dynamic cooperative effects and correlated motions of artificial chiral supramolecular structures held

together by weak intermolecular interactions such as hydrogen bonding, metal coordination, π-π

interactions, Coulomb forces, dipole-dipole interactions, and van der Waals forces have led to the

development of complex molecular assemblies that can be used for switching7–10

and amplification of

chirality.11–18

The versatile coordination chemistry and stereo-dynamics of chiral metal complexes that

exploit transfer of chirality from ligands to metal centers19

can be used to mimic such processes, to devise

chiral switches that respond to external stimuli, and to develop supramolecular architectures exhibiting

chiral amplification and memory.20–26

Since the first separation of enantiomeric octahedral cobalt complexes achieved by Werner in 1911,27

chemists have progressively developed deeper knowledge and control of chirality in coordination species.28

A major breakthrough was accomplished with the stereoselective synthesis of metal complexes via

introduction of chiral, non-racemic coordinating ligands. Several examples of supramolecular designs29

based on chiral organometallic structures have been crafted in the past decades, ranging from mononuclear

complexes to oligo- or polynuclear assemblies, helicates, catenanes, knots, rotaxanes,29,30

and polyhedral

three-dimensional structures.31,32

Chiral metal complexes are now extensively used in several

enantioselective catalytic synthetic methodologies by the pharmaceutical industry.33

Stereodiscrimination is

also an invaluable feature of modern chiral polymerization catalysts, which can give access to polymers

with highly controlled tacticity and consequent tailored mechanical properties.34

The ability to exert spatio-

temporal control in a polymerization process by means of a responsive stereodynamic catalyst is a concrete

example of industrial application of such an underdeveloped concept.2

8.1.2 Asymmetric transformation of stereodynamic biaryls

Biaryls such as BINOL35

and BINAP36

are certainly listed among the most widely recognized

atropisomeric inductors and constitute the main scaffold of several families of rigid chiral ligands exploited

in asymmetric synthesis. Their C2-symmetric 1,1‘-binaphthyl scaffold lacks of stereogenic centers, however

it features an element of axial chirality due to the restricted rotation around the aryl-aryl bond. The dihedral

angle between the two naphthyl halves is approximately 90°, which makes such framework capable of

providing a strong chiral induction. It is no coincidence that extensive development and application of

binaphthyl-based catalyst in asymmetric synthesis was achieved in the past decades.37–39

On the other hand,

several stereodynamic bidentate ligands that effectively amplify chirality at a metal center have been

reported to improve both selectivity and efficiency of asymmetric catalysts. A small selection of previously

reported catalysts based on metal complexes featuring stereolabile ligands is presented in Figure 8.1.40–49

Study towards a Photoswitchable Chiral Bidentate Phosphine Ligand based on an Overcrowded Alkene for

Metal-catalyzed Asymmetric Transformations

261

Figure 8.1. Previously reported catalysts based on metal complexes featuring stereolabile ligands.

The rotation energy barrier of biaryls can usually be explained on the basis of steric and electronic

substituent effects.50

Their conformational stability mainly depends on the presence of bulky ortho-

substituents. Meta-substituents further enhance steric hindrance to rotation through the so-called buttressing

effect: they reduce the flexibility of ortho-substituents and therefore enhance steric repulsion during

rotation about the chiral axis. The energy barrier to atropisomerization steadily increases with the steric

demand of the groups due to both enthalpic and negative entropic contributions. The latter originates from

the compromized rotational freedom of ortho-substituents in the crowded transition state. Electronic effects

play a secondary role due to enhanced CH/π-interactions, which becomes the predominant effect on the

rotational energy barrier upon promoting out-of-plane bending via less sterically hindered transition states.

The conformational stability of bridged biaryl units varies significantly with ring size. As a rule of thumb,

biaryls that possess one bridging atom are not stable to rotation to room temperature even if the remaining

two ortho-positions are occupied by bulky groups.51,52

An increase in bridge length enhances the torsion

angle between the two aryl rings and raises the energy barrier to racemization. Nevertheless, with a five- or

six-membered ring may still undergo rotation around the chiral axis, unless bulky ortho-substituents are

present in the bridged biaryl framework.53–59

Biaryl containing seven-membered or larger rings are

generally as stable as their unbridged analogs.60–63

By analogy with the stabilization of interconverting

axially chiral ligands by incorporation of a rigid bridge, coordination of a bidentate biaryl to a metal center

can significantly enhance the rotational energy barrier. Mikami,40,41,64

Jacobsen45

and Katsuki65

introduced

the concept of asymmetric activation of a stereolabile racemic catalysts derived from conformationally

unstable ligands with a non-racemic chiral activator. Such concept is based on rapidly interconverting chiral

catalysts, for example racemic BIPHEP-derived transition metal complexes, that are converted to a

diastereomerically enriched or pure catalytic species through addition of an enantiopure activator. For

example, 2,2‘-bis(diarylphosphino)biphenyls such as BIPHEP and DM-BIPHEP undergo rapid rotation

about the chiral axis at room temperature.66

However, the conformational stability of these diphosphines

increases upon metal complexation. The addition of enantiopure diamines to ruthenium and rhodium

Chapter 8

262

complexes of BIPHEP and DM-BIPHEP has been reported to give diastereoisomers that are stable to

isomerization at room temperature. Notably, the rapid racemization of BIPHEP is due to its ortho-

disubstituted biphenyl structure, as opposed to the conformationally stable ortho-tetrasubstituted biphenyl

ligand MeOBIPHEP (see Scheme 8.49). Achiral ligands can exist as a fluxional mixture of chiral and

enantiomeric conformers. Interaction with another chiral compound can render the equienergetic and

equally populated chiral conformation diastereomeric. Since diastereoisomers differ in energy, the ligand is

likely to preferentially occupy one chiral conformation. The presence of an enantiopure compound can

therefore induce a conformational bias in an achiral ligand resulting in amplification of chirality. In

contrast, Walsh‘s approach utilises stereolabile achiral activators, such as chiral diamine or diimine, to

optimize the performance of a chiral enantiopure BINOL-derived catalyst that is inherently stable to

racemization. 46–48

The preferential population of one chiral conformation of the stereolabile achiral

activator amplifies the asymmetric environment of the enantiopure catalyst, thus providing and

enhancement in asymmetric induction.

8.1.3 Photoswitchable metal complexes for asymmetric catalysis

The attractive prospects on the development and applications of stimuli-responsive catalysts have been

extensively explained throughout this thesis. Initial efforts were mainly devoted to the ON–OFF switching

of catalytic activity.67–69

Later, remarkable reversal of enantioselectivity in asymmetric catalysis has been

achieved using solvent responsive helical polymers,70

light-triggered organocatalysts71,72

and redox

sensitive metal complexes.73

As previously remarked in Chapter 6, a highly desirable feature of an ideal

responsive stereoselective catalyst is the ability to readily modify the chiral configuration of its active form.

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.74,75

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

complexes76

or quenching of the photo-generated excited state via internal energy transfer influenced by the

metal center.77

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.74,75

On the

other hand, the optimal stereoselective metal-based catalyst should feature a limited number (ideally two)

of 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

switches and motors provide a unique platform to achieve this goal.78–80

Branda and co-workers reported a

dithienylethene-based switch in asymmetric catalysis, which represents the first reported example of

modulation of stereoselectivity of a copper-catalyzed reaction by light (Scheme 8.1).81

They designed a

chiral bis(oxazoline) ligand with a switchable dithienylethene bridge unit, which allowed the selectivity of a

cyclopropanation reaction to be controlled with light. The approach exploited the differences in steric

interactions between the open and closed forms. In the open form o-L1, the two oxazoline moieties of the

ligand can bind copper(I) providing moderate enantioselectivities in the cyclopropanation of styrene (30–

50% ee). In the closed form c-L1, the two oxazolines are far apart, in an anti orientation, and cannot

provide bidentate coordination for the copper(I) atom. On using the ring-closed form, a significant drop in

enantioselectivity (5% ee) for the same catalyzed reaction was observed, although when a PSS mixture

consisting of 23% of the closed form was used, no significant drop in enantioselectivity was observed.

Unfortunately, this system is not effective in switching the selectivity in situ due to the low PSS. The same

group also developed a dithienylethene photoswitch bearing phosphine groups, displaying steric and

electronic differences between two photogenerated isomers.82

The coordination chemistry of this ligand



263

was demonstrated by preparing a gold(I) complex and a phosphine selenide. However, no catalytic

application was presented in the study.

Scheme 8.1. Photoswitching of a dithienylethane-based oxazoline ligand L1 that shows different

stereoselectivities in the copper-catalyzed asymmetric cyclopropanation of styrene developed by Branda

and co-workers.81

Craig and co-workers presented the first application of a photoswitchable bis-phosphine ligand in

enantioselective catalysis.83

Ligand L2 couples an achiral stilbene molecular photoswitch to the biaryl

backbone of a tetrasubstituted chiral bis-phosphine ligand analogous to MeOBiphep (Scheme 8.2).

Photochemical manipulation of ligand geometry is allowed without perturbing its electronic structure and

coordinating abilities. (E)-L2 and (Z)-L2 were isolated from the irradiated ligand mixture using column

chromatography. The changes in catalyst activity and selectivity displayed in palladium-catalyzed Heck

arylations and Trost allylic alkylations upon switching were attributed to intramolecular mechanical forces,

which varied the dihedral angle of the biaryl motif and consequently the catalyst performance. Although, in

all cases, the Z-isomer demonstrated higher selectivity than the E-isomer, reaction with either isomer

resulted in the same major enantiomer of the product (despite differing degrees of enantioselectivity). No

inversion of axial chirality of the biaryl bis-phosphine catalytic module was achieved upon switching of

such a stilbene actuator design, which resulted in the lack of stereoinversion when applied to the

asymmetrically catalyzed transformation.

Chapter 8

264

Scheme 8.2. Photoswitchable stilbene-derived biaryl bis-phosphine ligand L2 developed by Craig and co-

workers.83

Unidirectional rotary molecular motors based on overcrowded alkenes can intrinsically act as multistage

chiral switches as we have recently shown in the design of three-stage organocatalysts71,72

and bis-

phosphine ligands for metal catalysts.75

The design used to date is based on first generation molecular

motors,84

of which core is composed of two identical halves each bearing one functional group of the

catalytic pair. The photochemical and thermal isomerizations resulting in unidirectional rotation around the

central overcrowded alkene bond provide stepwise control over the helicity of the bifunctional bidentate

ligand L3 and spatial distance between the coordinating phosphine substituents. As the photochemically-

generated isomer (P,P)-(Z)-L3 and subsequent thermally-triggered isomer (M,M)-(Z)-L3 are pseudo

enantiomers, chiral products (3S,4R)-and (3R,4S)-toluensulfonyloxazolidinone with opposite absolute

configuration are obtained when these isomers are used in a palladium-catalyzed enantioselective allylic

substitution (Scheme 8.3).75

However, the thermally induced process of helix inversion between the

pseudoenantiomeric forms (P,P)-(Z)-L3 and (M,M)-(Z)-L3 is not per se reversible. Indeed, starting from

the isomer (P,P)-(Z)-L3, three consequent isomerization (light-heat-light) are required to recover the initial

isomer (M,M)-(Z)-L3.84

Hence, fully reversible handedness switching of chiral inductors remains highly

challenging so far. In case of non-labile coordination complexes, bridging the two halves to construct a

stable cyclic structure via metal complexation would also impede the characteristic isomerization cycle.

Further reversal of ligand chirality would require decomplexation of the active catalyst, for example upon

addition of a sequestering agent.



265

Scheme 8.3. Stereodivergent synthesis of (3S,4R)-and (3R,4S)-toluensulfonyloxazolidinone via palladium-

catalyzed enantioselective allylic substitution by switching the chirality of bis-phosphine ligand based on a

first generation molecular motor (Z)-L3 developed by Feringa and co-workers.75

In recognizing this, we decided to develop novel switchable bidentate bis-phosphine ligand based on the

scaffold of second generation molecular motors. Such a new design would feature a symmetrical fluorenyl

half, which would provide access to only two possible diastereoisomeric interconvertible forms and

consequently simplify the switching process. Light should allow non-invasive and dynamic control of

multistage ligand chirality, introducing simple yet efficient designs of programmable coordination

complexes.85

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,86,87

transmission of chirality,88

chiral amplification89

and asymmetric catalysis73–75

).

8.2 Results and discussion

8.2.1 Design

Chapter 5 describes the development of a photoresponsive molecular switch 1 featuring a versatile 2,2‘-

bisphenol motif in which chirality is transferred across three stereochemical elements (Scheme 8.4a).

Starting from the isomer (S,M=,Ma)-1, the photochemical E-Z isomerization (PEZI) of the helical-shaped

central alkene bond towards the isomer (S,P=,Pa)-1 allows via coupled motion the reversible control of the

helical and axial chirality of the biaryl motif. Successful application as stereodynamic chiral ligand in a

catalyzed asymmetric 1,2-addition of diethylzinc to benzaldehydes was demonstrated. Furthermore we

Chapter 8

266

previously proposed that such dynamic chiral selector could be derivatized to extend its applications into

more sophisticated catalytic systems. Indeed, in Chapter 6 we described the development of five chiral

photoresponsive phosphoramidite ligands derived from 1. The latter were successfully applied as tunable

ligands for copper-catalyzed asymmetric conjugate addition of diethylzinc to 2-cyclohexen-1-one. Control

over catalytic activity and stereoselectivity was achieved upon photo-induced isomerization using variable

diastereoisomeric mixtures of phosphoramidite-switch derivatives. Analogously, an attempt to develop a

switchable chiral phosphoric acid based on the same scaffold for application in photoswitchable

organocatalysis is presented in Chapter 7. Parallel to the last project, we envisioned such a biaryl-

functionalized core to be a promising candidate for developing the first bis-phosphine ligand based on a

second generation molecular switch 2, capable of providing light-triggered stereodynamic control in a

catalytic transformation upon metal complexation (Scheme 8.4b-c).

Scheme 8.4. Design of chiral photoresponsive bis-phosphine ligand 2. a) Previously described chiral 2,2‘-

bisphenol -susbtituted switch 1. b) Front structural view of metal complex with photoswitchable 2,2‘-

bis(phosphine) biphenyl-substituted overcrowded alkene-derivative 2 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. Descriptors are based on the structure of compound (S)-2 (for explanation of the chiral descriptors,

vide infra). c) Schematic top-down view of metal complexes MLn-(S)-2: two metal-ligand complexes with

opposite coupled helicity (M or P) can be selectively addressed by irradiation with UV-light: MLn-

(S,M,Ra)-2 and MLn-(S,P,Sa)-2.

In the photoresponsive bis-phosphine catalyst previously developed by our group,75

the cooperative

catalytic action was achieved by interaction of two ligating groups each attached to one half of a light-

driven unidirectional four-stage cycle first generation molecular motor.71,72,75

Such a design is limited to the

effective cooperative catalytic activity between two groups located on structurally distant points of the

photoresponsive scaffold only in the corresponding Z-isomers. Moreover, the four-stage cycle leads to a

complex mixture of four isomers upon multiple irradiation cycles, due to the incomplete conversion toward



267

the metastable isomer during each photochemical isomerization process. In comparison, we envisioned

metal complex of compound 2 to be switchable between only two possible forms displaying coupled alkene

and biaryl helicities (M and P, Scheme 8.4c). Due to the symmetric fluorenyl substituent, the design

described herein would display a strong reversible transfer of helicity to the biaryl motif with limited

variation in morphology of the switch unit. Consequently, we envisioned a sharp reversal of

stereoselectivity while retaining high catalytic activity, as opposed to previous switchable catalyst designs

based on first generation molecular motors featuring Z and E isomers with large differences in shape and

catalytic efficiency.

The system described herein features four stereochemical elements.90,91

The first element is the fixed

stereogenic center (R or S) of the switch unit (highlighted in red). The second element is the helicity of the

overcrowded alkene (highlighted in blue), which is under thermal control by the configuration at the

stereogenic center but can be inverted between right-handed (P=) or left-handed (M=) upon

photoisomerization. More precisely, the more stable diastereoisomer of the R enantiomer will adopt a P

helicity, while the photo-generated diastereoisomer with higher energy will adopt an M helicity. The third

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

biaryl unit (black), which are dictated via steric repulsion by the helicity of the alkene. In Chapter 5 we

showed that amongst the four theoretically possible conformations of a biaryl unit, only conformations in

which the non-annulated aryl group was parallel to the fluorenyl lower half were adopted. The other

conformations, with the aryl orientated perpendicular with respect to the lower half, were expected to

induce significant steric strain (see Scheme 8.5). Similar to the previously described coupled transfer of

dynamic chirality displayed by 1, the true helicity of the biaryl is inextricably connected to the helicity of

the overcrowded alkene chromophore, and is identical to it in each of the isomers. Analogously, two

atropisomers of 2 having identical alkene and biaryl helicity but opposite biaryl axial chirality are expected.

Therefore, three stereodescriptors (R/S, P/M and Ra/Sa) will be sufficient for the description of any expected

isomer reported in this work (unless indicated otherwise for more clear description). So for isomer (R,P,Sa)-

2: R = configuration of stereogenic center, P = helicity of alkene and biaryl, Sa = axial chirality of biaryl

(Scheme 8.4c). The doubly expressed axial stereodescriptor (Ra/Sa) throughout the text denotes a mixture of

rotamers with identical absolute stereochemistry at the stereocenter and configurational helicity (S,M,Ra/Sa

means a mixture of atropisomers S,M,Ra and S,M,Sa). Similarly to the phosphoramidite-switch derivatives

previously described in Chapter 6, our goal was to achieve reversible external control of chirality in a chiral

metal complex. We proposed that the tunable helicity (P or M) of the switch core in turn would dictate the

preferential axial configuration (Ra or Sa) of the desirable syn conformation of the biaryl moiety and

eventually, for instance, the configuration (R or S) of a newly formed stereogenic center when applied to an

enantioselective catalytic event.

Scheme 8.5 illustrates the envisioned interplay of dynamic stereochemical elements of bis-phosphine ligand

(S)-2 before and after metal complexation and the light-triggered switching process between the two

proposed diasteroisomeric species. Two rotamers, displaying syn or anti conformation of the biphenyl, are

expected for each helical diastereoisomer (S,M) and (S,P), respectively. Due to the steric hindrance caused

by the phosphine substituents, high energy barrier for biaryl axial inversion is envisioned in the free ligand

2. Thus no inversion of axial chirality is expected upon light-triggered inversion of helicity, namely M,Sa-

anti ⇄ P,Sa-syn and P,Ra-syn ⇄ P,Ra-anti. However, the helicity of the alkene and biaryl units are still

expected to convert through a coupled motion to accommodate the alkene bond isomerization (Scheme

8.5a). On the other hand, the bidentate metal complex is envisioned to permit the axial inversion of the

biaryl unit between the parallel and perpendicular conformations, respectively, for instance, between

M=,Ma,Ra-syn and M=,Pa,Sa-syn (Scheme 8.5b). If compared to monodentate anti-isomers, bidentate

coordination species are envisioned to have access to transition states with lower energy barrier for biaryl

axial inversion. Notably, both mono- and bidentate coordination species MLn-2 are possible. However, only

the isomers with syn conformation (torsion angle = 0°–±90°) were expected to efficiently bind a metal

center and successfully transfer the chirality within a catalytically active complex. Therefore, we

Chapter 8

268

envisioned that the parallel syn-conformer of the bidentate complex M=,Ma,Ra-syn would be largely

thermodynamically favored and be present as the major species at the equilibrium. In summary, isomers

with syn conformation and coupled helicity are expected to interconvert upon irradiation, while isomers

with anti conformation would either isomerize to corresponding energetically favored syn isomers or

spectate as catalytically inactive monodentate complexes (Scheme 8.5c). Overall, two main syn conformers

with opposite axial chirality would be selectively addressable by means of light-irradiation with appropriate

wavelength, giving access to a reversibly switchable chiral metal complex for catalytic applications.

Scheme 8.5. a) Schematic representation of switching process between the rotamers of free ligand (S)-2. b)

Depiction of the possible mono- and bidentate coordination species MLn-(S)-2. Only the isomer with syn

conformation (torsion angle = 0°–±90°) were expected to efficiently bind a metal center and successfully

transfer the chirality within a catalytically active complex. c) Schematic representation of switching process

between the rotamers of metal complexes MLn-(S)-2. Note: for monodentate coordination species, the

proposed metal coordination position at the upper phosphine moiety of the biaryl was arbitrary chosen.

8.2.2 Retrosynthetic analysis

The proposed retrosynthetic analysis of switchable metal complex with bis-phosphine ligand 2 from

bisphenol -derived switch 1 is presented in Scheme 8.6.

Scheme 8.6. Proposed retrosynthetic analysis of switchable bis-phosphine ligand 2 from bisphenol -derived

switch 1.

Metal complex MLn-2 could be obtained from free ligand 2 upon metal complexation. The target

photoresponsive ligand 2 was envisioned to be accessible via metal-catalyzed phosphination of bis-triflate

3. For comparison, BINAP is prepared from BINOL via nickel-catalyzed phosphination of its bis-triflate

https://en.wikipedia.org/wiki/1,1%27-Bi-2-naphthol

https://en.wikipedia.org/wiki/Triflate



269

derivative with diphenylphosphine.92

Similarly, bis-triflate 3 can be obtained from 1 upon reaction with

triflic anhydride.

8.2.3 Derivatization of resolved bisphenol derivative

The synthesis of bis-triflate switch derivative 3 starting from 2,2‘-bisphenol -derived molecular switch 1 is

illustrated in Scheme 8.7. A previously described, (S)-1 is obtained after resolution as a mixture of

interconverting conformers, i.e. (S,M,Ra)-1 and (S,M,Sa)-1 (hence, indicated as (S,M,Ra/Sa)-1; for synthesis

and chiral resolution of 1, see Chapter 5). Optically enriched (S,M,Ra/Sa)-1 (99% ee) was reacted with triflic

anhydride and pyridine in dichloromethane to yield a mixture of Ra-syn conformer (S,M,Ra)-3 and Ma-anti

conformer (S,M,Sa)-3 in a ratio of Ra-syn:Ma-anti = 40:60, as determined via 1H NMR analysis of the crude

mixture.

Scheme 8.7. Synthesis of conformers of bis-triflate switch derivative 3.

Chapter 5 describes the assignment of conformers (R,P,Sa)-1 and (R,P,Ra)-1 based on experimental and

calculated chemical shifts of the corresponding 1

H NMR spectra. Despite the difference in absolute

chemical shift value, the relative position of the experimentally assigned absorptions peaks for the

atropisomer in the experimental 1H NMR spectra are in full agreement with the corresponding calculated

absorption peaks. Notably, almost every resonance absorption of the syn isomer (R,P,Sa)-1 resonates at

higher frequency than the minor anti isomer (R,P,Ra)-1. By comparison with experimental 1H NMR spectra

of (S,M,Ra/Sa)-1 (Figure 8.2a), the isolated early (Figure 8.2b) and later fraction (Figure 8.2c) obtained after

flash column chromatography of the mixture were similarly assigned to the Ra-syn and Ma-anti conformers

of 3, (S,M,Sa)-3 and (S,M,Ra)-3, respectively, based on the relative position of each distinctive resonance

absorptions. Each single atropisomer was analyzed via 1H NMR spectroscopy before and after prolonged

heating (solution in toluene, 110 °C for 6 h). No isomerization towards the other conformer was observed.

Compared with bisphenol 1, bis-triflate 3 displayed a much higher thermal stability for the biaryl axial

isomerization, as no internal hydrogen bonding can take place between the two protected phenolic moieties

of the biaryl unit. This behavior is indicative of the importance of a cyclized intermediate which can give

access to a transition state with a low energy barrier for biaryl isomerization in order to achieve an efficient

coupled transfer of helicity within a reversible bidentate coordinating species.

Chapter 8

270

Figure 8.2. Comparison of 1H NMR spectra (CDCl3) of: a) interconverting atropisomers (S,M,Ra/Sa)-1 (see

Chapter 5 for full assignment); b) isolated atropisomer (S,M,Sa)-3; c) isolated atropisomer (S,M,Ra)-3.

8.2.4 Metal-catalyzed phosphorylation

Initial investigation of NiCl2(dppe)-catalyzed double phosphination or phosphorylation reactions with

either diphenylphosphine (Scheme 8.8a),92

diphenylphosphine-borane complex (Scheme 8.8a)93

or

diphenylphosphine oxide (Scheme 8.8b)94

were conducted on (S,M,Ra)-3 by modified procedures

previously reported for bis-triflate derivatives of BINOL. However, the tested conditions resulted in no

conversion towards either bis-diphenylphosphine derivative 2 or bis-diphenylphosphineoxide derivative 4.

Notably, substrate 3 was recovered in approximately 90% in all cases.



271

Scheme 8.8. Attempted NiCl2(dppe)-catalyzed phosphination and phosphorylation reactions of bis-triflate

derivative (S,M,Ra)-3.

Our experiments suggest that the procedure successfully implemented on naphthalene derivatives cannot be

extended to this less activated biphenyl substrate. We continued our endeavor by exploring the palladium-

catalyzed phosphorylation of aryl triflates in combination with phosphine oxide reduction. Previously

reported substituted BINAP and BIPHEP derivatives were synthesized via a four-step sequence of

phosphorylation (1) - phosphine oxide reduction (2) - phosphorylation (1) - phosphine oxide reduction (2)

(Scheme 8.9).38,95–97

As opposed to the Nickel-catalyzed processes, it appears that the first phosphine oxide

group deactivates the single substituted intermediate towards a second phosphorylation step. Upon

reduction of the phosphine oxide substituent, a second one can be subsequently installed. However, such

alternative route via a four-step sequence would be detrimental for the final yield of target compound 2.

Scheme 8.9. Retrosynthetic analysis of bis(diphenylphosphine) derivatives via four-step sequence of

palladium-catalyzed phosphorylation (1) of aryl triflates and phosphine oxide reduction (2).

Each conformer of bis-triflate 3 was successfully submitted to palladium-catalyzed phosphorylation with

diphenylphosphine oxide. Reactions were successfully conducted in presence of PdCl2(dppp) (dppp =

bis(diphenylphosphino)propane) (Scheme 8.10a-b) or PdOAc2 and dppb (dppb =

bis(diphenylphosphino)butane) (Scheme 8.10c) to yield the diphenylphosphino-triflate derivative 5 with

Chapter 8

272

moderate to good yield.98

Theoretically, substitution of a single triflate substituent could provide two

distinct regioisomers of the monophosphorylated biaryl derivative 5 (phosphine oxide on the upper ring and

triflate on the lower, and vice versa), each as a mixture of two conformers (syn and anti). Notably, a

common single isomer of the monosubstituted diphenylphosphine oxide-triflate product was obtained,

regardless of the starting bis-triflate conformer. By comparison with the 1H NMR spectra of the starting

materials, conformer (S,M,Ra)-5 was proposed as the obtained species. We hypothesized the opposite

conformer to be much more sterically hindered. Therefore, upon prolonged heating necessary to achieve

full conversion in the phosphorylation reaction, both conformers of 3 are transformed upon biaryl inversion

into the same most stable isomer of product (S,M,Ra)-5, either during or after the palladium-catalyzed

substitution. However, analysis with 2D-NMR techniques did not help to achieve full certainty about the

actual substitution pattern and conformation of the analyzed isomer among the four possible species.

Further investigation was not conducted due to interruption of the project (vide infra). On the other hand,

the proposed structure of 5 is consistent with the mechanism of base-promoted degradation of triflate

shown in Scheme 8.15 (vide infra).

Scheme 8.10. PdCl2(dppp)- and PdOAc2(dppb)-catalyzed phosphorylation reaction of bis-triflate 3 to

diphenylphosphine oxide-triflate 5.

8.2.5 Phosphine oxide reduction

Following the precedent literature, we proceeded with the reduction of the mono-substituted phosphine

oxide 5. Various conditions for phosphine oxide reduction of 5 were tested by modified procedures

previously reported.99

We suspected an inconvenient sensitivity of the overcrowded alkene functionality of

5 towards harsh reductive conditions. Hence, we initially opted for a highly selective and mild phosphine

oxide reduction methodology previously tested in our group for an analogous phosphine derivative based

on a first generation molecular motor.100

Beller and co-workers developed a highly chemoselective metal-

free reduction of phosphine oxides to phosphines in the presence of catalytic amounts of specific

phosphoric acid esters and methyldiethoxylsilane HSiMe(OEt)2.101



273

Scheme 8.11. Tested conditions for the phosphine oxide reduction of (S,M,Ra)-5 to (S,M,Ra)-6.

Other reducible functional groups such as ketones, aldehydes, olefins, nitriles, and esters are well-tolerated

under the reported optimized conditions. Basic workup with methanolic KOH was required to cleave the P-

Si bond of the phosphonium cation after reduction with silane species to isolate the phosphine products.

When such conditions were tested on 5 (Scheme 8.11a, Figure 8.3a), we observed major decomposition of

the overcrowded alkene functionality (see also Chapter 7). Analysis of the crude before basic workup via 1H/

31P NMR spectroscopy (Figure 8.3a-b, Figure 8.4) showed 45% conversion of 5 (δP = 27.8 ppm) (Figure

8.3a and Figure 8.4a) to a different unidentified species (δP = 19.0 ppm) (Figure 8.3b and Figure 8.4b),

which displayed phosphorus chemical shift not consistent with conventional phosphine ligands (0 ppm > δP

> -20 ppm). We supposed this observed new species to be a phosphorus-silane adduct, which was also

analyzed via 1H/

31P NMR spectroscopy (Figure 8.3c and Figure 8.4c) after purification. The target reduced

product diphenylphosphine-triflate 6 (δP = -12.9 ppm) was observed in the crude mixture only as minor

component (Figure 8.3b-c and Figure 8.4b-c). We continued our screening by testing the conditions for

deoxygenation of phosphine oxides using triphenylphosphine or triethylphosphite as an oxygen acceptor in

presence of large excess of trichlorosilane, as reported by Spencer and co-workers.102

Reaction of 5 with

triphenylphosphine resulted in no conversion of the substrate (Scheme 8.11b). On the other hand, reaction

of 5 with triethylphosphite afforded product 6 in moderate yield (30%) together with an inseparable side-

product (Scheme 8.11c), which appeared consistent with a by-product of tetrahydrofuranas suggested by 1H

NMR analysis of the isolated fraction (not shown). Another methodology for reduction of phosphine oxides

to phosphines uses a combination of titanium(IV) isopropylate and triethoxysilane, as reported by Lin and

Chapter 8

274

co-workers in the synthesis of 4,4′-substituted-xylBINAP ligands.38

No basic workup was reported for such

procedure, which was considered a promising approach to tackle the sensitivity to strong bases of the

switch scaffold described hereto. However, we observed no conversion of the substrate when applied to 5

(Scheme 8.11d). Eventually, we tested a conventional reduction methodology with diisopropylethylamine

and trichlorosilane in large excess.96

To our delight, very good selectivity was observed by analysis of the

crude with 1H/

31P NMR spectroscopy (Figure 8.3d and Figure 8.4d), which displayed high conversion (>

90%) of (S,M,Ra)-5 to (S,M,Ra)-6. The desired product was also obtained in good isolated yield (75%).

Figure 8.3. Comparison of 1H NMR spectra (CDC3) of: a) (S,M,Ra)-5; b) crude reaction mixture obtained

after reduction conditions indicated in Scheme 8.11a; c) columned fraction containing reduced phosphine

components from previous mixture; d) isolated (S,M,Ra)-6 obtained after conditions indicated in Scheme

8.11e.



275

Figure 8.4. Comparison of 31

P NMR spectra (CDCl3) of: a) (S,M,Ra)-5 (δP = 27.8 ppm); b) crude reaction

mixture obtained after reduction conditions indicated in Scheme 8.11a; c) columned fraction containing

reduced phosphine components (δP = 19.0 ppm and δP = -12.9 ppm) from previous mixture; d) isolated

(S,M,Ra)-6 (δP = -12.9 ppm) obtained after reduction conditions indicated in Scheme 8.11e (with

phosphoric acid as internal reference, δP = 0 ppm).

8.2.6 Attempted second metal-catalyzed phosphorylation

(S,M,Ra)-6 was subjected to the same conditions for palladium-catalyzed phosphorylation previously

described for 3 (Scheme 8.12).98

Unfortunately, the reaction yielded the oxidized substrate

diphenylphosphine oxide-triflate (S,M,Ra)-6 as major component. Oxidation of the substrate may have

occurred due to the oxidative properties of DMSO or via oxygen exchange with diphenylphosphine oxide at

high temperature. However, Spencer and co-workers reported that the latter pathway requires the presence

of trichlorosilane, as employed in their phosphine oxide reduction methodology.102

The detrimental

contamination of the reaction mixture with oxygen cannot be excluded either. Notably, no trace of the

expected diphenylphosphine-diphenylphosphine oxide 7 was detected by 1H/

31P NMR analysis. Such

phenomenon suggests that the highly hindered structure of the designed bidentate ligand and the low

reactivity of aryl triflate in metal-catalyzed substitution reactions may preclude the proposed synthetic route

employed so far.

Chapter 8

276

Scheme 8.12. Attempted conditions for PdOAc2(dppb)-catalyzed phosphorylation reaction of

diphenylphosphino-triflate 6 to diphenylphosphino-diphenylphosphine oxide 7.

In Chapter 3 we demonstrated how even the switch central scaffold (e.g. 5,8-dimethylthiochromene upper

half – fluorenyl lower half) plays an important role in the reactivity of their substituents. In the case

described in fact, the copper-catalyzed aromatic Finkelstein reaction allowed to exchange a bromine atom

for an iodine atom, incrementing significantly the conversion of the halogenated switch derivative in the

palladium-catalyzed Buchwald-Hartwig coupling. Therefore, in an attempt to exclude the low reactivity of

the triflate substituent of compound 6 towards the phosphorylation step among the plausible causes of its

failed conversion to 7, a triflate-halogen exchange step was considered. Indeed, metal-catalyzed

phosphorylation of aryl bromides and iodides is widely applied alternative methodology to synthesize

phosphine-based ligands.103,104

Hayashi and co-workers reported a solid methodology for transformation of

aryl triflates, alkenyl sulfonates and phosphates to aryl halides and alkenyl halides, respectively, by treating

them with LiBr/NaI and [Cp*Ru(MeCN)3]OTf in dimethylimidazolinone (DMI). Aryl triflates undergo

oxidative addition to a ruthenium(II) complex to form η1-arylruthenium intermediates, which are

subsequently transformed to the corresponding halides. For comparison, bis-triflate 3, diphenylphosphine

oxide-triflate 5, and diphenylphosphine-triflate 6 were treated according to the reported procedures. Bis-

triflate (S,M,Ra)-3 was successfully converted to what was assigned as the bromide-triflate (S,M,Ra)-8 (full

conversion, yield not determined, Scheme 8.13a), obtained by flash column chromatography together with

large amount of not removable DMI. It should be noted how only the triflate group on the upper phenyl

ring of the biaryl motif reacted to the tested conditions. On the other hand, diphenylphosphine oxide-triflate

(S,M,Ra)-5 gave no conversion towards either the corresponding diphenylphosphine oxide-bromide

(S,M,Ra)-9 or diphenylphosphine oxide-iodide (S,M,Ra)-10 (Scheme 8.13b). Lastly, diphenylphosphine-

triflate (S,M,Ra)-6 also gave no conversion towards the corresponding diphenylphosphine-iodide (S,M,Ra)-

11 (Scheme 8.13c). From the performed experiments, it appears that the triflate group on the lower phenyl

ring of the biaryl motif suffers from a general low reactivity towards metal-complex catalyzed substitution.

This could be due to its hindered position, almost sandwiched between the upper biaryl substituent and the

fluorenyl lower half of the switch module. The limited space may in fact not allow the catalyst to

successfully approach the aryl-triflate bond, thus preventing the oxidative addition and eventually any sort

of subsequent substituent exchange.



277

Scheme 8.13. Attempted conditions for [Cp*Ru(MeCN)3]OTf-catalyzed triflate-halogen exchange of bis-

triflate 3, diphenylphosphine oxide-triflate 5, and diphenylphosphino-triflate 6 to their corresponding

halogenated derivatives 8,9-10 and 11.

The synthesis of bis-diphenylphosphine ligand 2 was not accomplished according to the proposed synthetic

route (Scheme 8.6). A different approach could have been considered, possibly installing the phosphine

substituents on the biaryl unit before the creation of the overcrowded alkene function required for the

photoresponsive properties. However, such approach would need a totally different synthetic sequence and

would not exploit the already developed synthesis and chiral resolution of 2,2‘-bisphenol switch derivative

1 presented in Chapter 5. An alternative resolution strategy must be considered beforehand, for example via

formation of diastereoisomeric metal complexes of the target bisphosphine ligand with enantiopure

reusable resolving reagent as very last step (Scheme 8.14).105–107

Scheme 8.14. Proposed resolution of 2 with stoichiometric formation of diastereoisomeric palladium-

phosphine ligand complex.

Chapter 8

278

8.2.7 Development of photoswitchable chiral Brønsted acid

At this phase of the research project, a very small timeframe was left. Among the limited amount of

feasible options, we proposed to redirect the project goal to the development of a 2-diphenylphosphino-2‘-

hydroxy-1,1‘-biphenyl-derived overcrowded alkene 12 as a switchable chiral Brønsted acid (Figure 8.5).

Chiral Brønsted acid catalysis has been one of the growing fields in modern organic synthesis.108

Urea/thioureas,109

TADDOL,110

and phosphoric acids111,112

have been widely used as catalysts in various

asymmetric syntheses. Therefore, it would be interesting to extend the area of application of

photoswitchable chiral catalyst to the field of Brønsted acid catalysis. Our design was inspired by the

previously reported optically active (S)-2-hydroxy-2‘-diphenylphosphino-1,1‘-binaphthyl ((S)-HOP) and its

derivatives, which were successfully applied in asymmetric catalysis either as free organocatalysts or as

Lewis acid-assisted Brønsted acids (LBAs). Chen and co-workers described the application of 2-

diphenylphosphino-2‘-hydroxy-1,1‘-biphenyl as bifunctional organocatalyst for aza-Morita-Baylis-Hillman

(aza-MBH) reaction and domino reaction (aza-MBH followed by a Michael addition and aldol/dehydration

reaction) between N-sulfonated imines and acrolein.113

Shi and co-workers reported the use of (S)-HOP and

few of its functionalized derivatives as chiral phosphine Lewis bases in the catalyzed asymmetric aza-

Baylis-Hillman reaction of N-sulfonated imines with activated olefins.114

The study revealed that the phosphine

atom acted as a Lewis base to activate the Micheal acceptor, and the phenolic OH acted as a Lewis acid (BA) through

intramolecular hydrogen bonding with the oxygen atom of carbonyl group to stabilize the in situ formed key enolate

intermediate. In addition, the intramolecular hydrogen bonding between the phenolic OH and the nitrogen anion

stabilized by the sulfonyl group can give a relatively stable or rigid transition state for achieving high enantioselectivity

in the aza-Baylis-Hillman reaction. The same group later extended the catalytic methodology to a selection of chiral

phosphine Lewis bases bearing multiple phenol groups and closely related to HOP.115

Yamamoto and co-

workers developed a LBA derived from (S)-HOP with La(OTf)3 as a Lewis acid activator, which was

applied to the catalytic enantioselective protonation reaction of silyl enol ether of 2-aryl cyclic ketones in

the presence of methanol.116

Figure 8.5. Proposed design of photoswitchable chiral Brønsted acid 12, inspired by phosphine-hydroxyl-

biaryl Brønsted acid catalysts previously reported.

An alternative approach would be the synthesis of an analogue of the 2-(diphenylphosphino)-2‘-methoxy-

1,1‘-binaphthyl ligand (MOP) developed by Hayashi and co-workers upon methylation of (S)-12.117

Having already developed a synthetic route to phosphorylated intermediate 5, we hypothesized to prepare

12 via hydrolysis of the unreacted triflate substituent and subsequent reduction of the phosphine oxide

group. The hydrolysis of 5 was attempted using sodium hydroxide, a strong inorganic base, according a

modified procedure previously reported (Scheme 8.15).37



279

Scheme 8.15. Attempted conditions for hydrolysis of triflate substituent of 5 towards diphenylphosphine

oxide-hydroxyl derivative 15, which instead yielded the hypothesized by-products 16 and 16’ upon addition

of generated phenolate anion to the overcrowded alkene bond, according to the illustrated proposed

mechanism.

No conversion to the desired product 15 was observed as determined by NMR analysis of crude. Major

decomposition of the switch functionality occurred as determined by 1H NMR spectroscopy (Figure 8.6).

Complete hydrolysis of the triflate substituent was determined as observed by lack of any resonance peak in

the 19

F NMR spectrum. Notably, two sets of resonances with an approximate ratio of 70:30 were observed

in the 1H/

31P NMR spectra (Figure 8.6 and insert).

Figure 8.6. 1H NMR and

31P NMR (insert) spectra (CDCl3) of proposed atropisomers 16 and 16’ obtained

after hydrolysis of 5.

We proposed a mechanism involving initial hydrolysis of the triflate group to the corresponding phenolate

anion 13, followed by biaryl axial inversion and addition of the hydroxyl substituent to the upper carbon

atom of the overcrowded alkene bond to afford a tetracyclic anion intermediate 14 with a fluorenyl

substituent on the tetrasubstituted carbon of the newly formed pyranyl ring. Upon acid workup, the

Chapter 8

280

carbanion located on the position 9 of the fluorenyl substituent is then protonated to give a mixture of two

atropisomeric by-products 16 and 16’ (the sets of NMR resonances were not assigned to the corresponding

isomers). The driving force of such an unexpected decomposition mechanism is proposed to be the

decrease of steric hindrance and loss of torsion strain experienced by the overcrowded alkene bond, which

is consequently transmitted to the whole structure via tight coupled transfer of helicity. Moreover, the

fluorenyl anion substituent of 18 is expected to be highly energetically favored due to the aromatic

electronic configuration (14 electrons). In a comparative experiment, the same procedure described for the

attempted hydrolysis of 5 to 15 was applied to the deprotonation of bisphenol 1 and hydrolysis of bis-

triflate 3, respectively, affording in either case 19 upon reaction with sodium hydroxide (Scheme 8.16) or

potassium hydroxide.

Scheme 8.16. Decomposition of compounds 1 and 3 towards 19 upon reaction with sodium hydroxide.

Side: structural view of proposed most stable conformer of 19.

The same single set of absorptions was observed in the 1H NMR spectrum. No resonance was observed in

the 19

F NMR spectra of the crude obtained from reaction with 3. A common product as assigned to

structure 19 was suggested to be similarly obtained, after hydrolysis of triflate groups in case of 3, via

addition of phenolate anion to the alkene bond according to an analogous mechanism. Notably, unlike the

decomposition of 5, a single species was observed by 1H NMR analysis after reaction of 1 or 3 (Figure 8.7).

Figure 8.7. 1H NMR spectra (CDCl3)of product of obtained after treatment of 1 or 3 with strong inorganic

bases.



281

The characteristic resonances that support the proposed structure of 19 are the singlet at δ = 3.70 ppm,

assigned to the dibenzylic proton (Ha) in position 9 of the fluorenyl substituent, and the singlet at δ = 4.67

ppm, assigned to the single phenolic proton (Hb). Notably, the doublets at δ = 8.03 ppm and δ = 5.86 ppm

were assigned, respectively, to the aromatic protons in the positions 1 (Hc) and 8 (Hd) of the fluorenyl

substituent. The chemical shift of their absorption resonances were justified according to their distinctive

position relative to the central tetracyclic unit and consequent unusual magnetic environment. In particular,

it should be noted how the proton Hd is nearly facing the delocalized electronic orbital of the lower phenol

ring of the biaryl unit, thus experiencing a strongly shielding effect which lowers its chemical shift below

the expected range of common aromatic protons.

We proposed to circumvent issue of the instability of such phenol derivatives to strong bases by avoiding

the need of hydrolysing the unreacted triflate group. Upon careful dosage of triflic anhydride, we proposed

to convert bisphenol derivative 1 to a singly substituted triflate-hydroxyl derivative, which could be singly

phosphorylated without need of protecting the second phenol functionality. However, the reaction of

(R,P,Sa/Ra)-1 in such conditions (Scheme 8.17) yielded a mixture of two proposed rotamers of the product

in a ratio of 65:35, as analyzed by 1H/

19F NMR spectroscopy.

Scheme 8.17. Synthesis of conformers of triflate-hydroxyl derivative 20 from 1 (or proposed alternatively

substituted derivatives 21).

The structure of the observed species were assigned to conformers (R,P,Sa)-20 and (R,P,Ra)-20,

respectively, which feature the same substitution pattern of the biaryl unit but opposite biaryl axial chirality.

Such assignment was proposed by comparison of the 1H NMR spectra of substrate 1 (Figure 8.8a) with the

singly triflate-substituted products 20 (Figure 8.8b) and the corresponding isolated bis-triflate conformers 3

(Figure 8.8c-d), similarly to the previous cases (vide supra). However, a different regioisomeric structure

21 featuring opposite substituent position on the biaryl unit could also be consistently proposed. Notably,

the same ratio of conformers was observed in the starting material 1 and in the obtained product 20. This

could suggest that species 1 and 20 feature an equal difference in free energy between the corresponding

conformers (R,P,Sa) and (R,P,Ra). On the other hand, the substitution of the hydroxyl groups with non-

coordinating substituents (e.g. via hydrogen bonding) could in fact quench the biaryl axial isomerization,

thus fixing the ratio of the conformers displayed in 1 up to the derivatives 20 and 3. Interestingly, CSP-

HPLC analysis of the atropisomeric mixture of 20 displayed two sharp elution peaks, which may suggest

that no interconversion occurs between the two isomers at the tested analytical conditions. Moreover, when

a sample of the latter was subjected to EXSY experiment at 60 °C in CDCl3 to possibly observe a rapid

interconversion of the two coexisting species of 20, no exchange of excited resonance peaks was observed,

Chapter 8

282

which corroborates the lack of exchange between the two proposed atropisomeric structures even at slightly

higher than ambient temperatures. Such behavior is very different from what was observed for 1 (see

Chapter 5). This phenomenon could be explained via two hypotheses: 1) the energy barrier for biaryl axial

inversion of conformers 20 is higher than for 1 (see Chapter 5 for details) and could not be observed at the

applied conditions, as it would require higher temperatures; 2) the obtained product is a mixture of a single

conformer of 20 and 21, respectively, which are coincidentally also stable to biaryl axial inversion at such

conditions. However, the latter hypothesis seemed less likely. Regardless, no further investigation was

conducted to elucidate such point as it was not the main goal of the project.

Figure 8.8. Comparison of 1H NMR spectra (CDC3) of: a) (R,P,Sa/Ra)-1; b) mixture of conformers (R,P,Sa)-

20 and (R,P,Ra)-1; c) (S,M,Sa)-3; d) (S,M,Ra)-3.

The isolated mixture of conformers of 20 was submitted to the same conditions for palladium-catalyzed

phosphorylation previously described for 5 (Scheme 8.18). Unfortunately, the expected diphenylphosphine-

hydroxyl derivative 15 was not observed, while substrate 20 was not recovered. In fact, the reaction yielded

a complex mixture of by-products that could not be clearly identified even after 1H/

19F/

31P NMR analysis of

the various fractions obtained after column chromatography. Two early fractions displaying a single 19

F

NMR resonance absorption were lacking of the overcrowded alkene functionality resonances in the 1H

NMR spectra and of any 31

P NMR resonance absorption. The middle fraction, which displayed the



283

distinctive overcrowded alkene functionality resonances in the 1H NMR spectra and a single

19F NMR

resonance absorption was lacking of any 31

P NMR resonance absorption. The latter fraction, which

displayed five distinct 31

P NMR resonance absorptions and a single 19

F NMR resonance absorptions was

lacking of any overcrowded alkene functionality resonances as observed in the 1H NMR spectra. In

conclusion, the synthetic route towards the Brønsted acid 12 was not completed.

Scheme 8.18. Attempted synthesis of photoswitchable chiral Brønsted acid 12 via phosphorylation of 20

and consequent not tested phosphine oxide reduction of 15.

Due to the insurmountable complications encountered during the development of an effective switchable

bisphosphine ligand or Brønsted acid catalyst based on a reversibly photo-responsive bifunctional

overcrowded alkene, the venture of designing a novel phosphine-based catalyst for dynamic control of

light-assisted synthetic transformations was interrupted.

8.3 Conclusions

This chapter describes the study towards a bidentate biaryl bis(diphenylphosphine) ligand based on an

overcrowded alkene for photoswitchable asymmetric homogeneous metal-catalyzed transformation. The

design of the system implies a reversible change of helicity of the overcrowded alkene central scaffold

which produces a consequent inversion of helical and axial chirality of the biaryl unit. The absolute

stereochemistry is overall governed by the fixed point chirality sited in the stereocenter of the molecular

switch. An efficient coupled motion with effective inversion of the local chirality surrounding the

coordinated metal center is envisioned to occur only in the bidentate metal-ligand complex. The formation

of a seven-membered ring metallacyclic structure is key for lowering of the energy barrier for biaryl axial

inversion, as such species was expected to have access to a transition state characterized by a lower energy

if compared with the free ligand. We proposed a synthetic route of bisphosphine ligand 2 starting from 2,2‘-

bisphenol functionalized molecular switch 1 previously described in Chapter 5. Derivatization of the

bisphenol moiety to the corresponding bis-triflate 3 yielded a mixture of separable non-interconverting

atropisomers. Initial unsuccessful tests were conducted according to nickel-catalyzed phosphination or

phosphorylation methodologies previously reported for conventional binaphthyl-based scaffolds. The lower

reactivity of the biphenyl bis-trilate unit of 3 required a more robust yet laborious multi-step approach

comprising sequences of palladium-dppp/dppb-catalyzed phosphorylation and consequent phosphine oxide

reduction. Both atropisomers of 3 yielded a single isomer of singly phosphorylated derivative 5, which was

reduced to the corresponding diphenylphosphine-triflate 7 with trichlorosilane and ethyldiisopropylamine.

No substitution of the second triflate moiety was achieved by following the conditions of the previously

successful phosphorylation step. We attempted to enhance the reactivity of the lower leaving group via

ruthenium-catalyzed triflate-bromide/iodide exchange. Unfortunately, no conversion of 7 was observed. We

hypothesized that the steric hindrance around the lower triflate group caused by the molecular switch core

interferes with the catalytic system, thus precluding any further transformation via metal-catalyzed

substitution. The synthesis of the target bidentate ligand 2 was not accomplished. We proposed to redirect

the goal of the project to the development of a chiral photoswitchable Brønsted acid catalyst 12 featuring

diphenylphosphine and phenol functionalities on the biphenyl unit. Hydrolysis of the triflate group of 5

Chapter 8

284

with strong inorganic bases resulted in loss of the overcrowded alkene motif, possibly via addition of the

generated phenolate anion to the alkene bond to generate a tetracyclic structure. The same reactivity was

observed for bisphenol 1 and bis-triflate 3. Our hypothesis implies an energetically favorable loss of steric

strain and bond torsion that, unexpectedly, drives the addition of a phenolate to an alkene bond. Finally, we

also proposed to synthesize 12 via palladium-catalyzed phosphorylation of the monotriflate derivative 20.

However, this approach was found not fruitful, indicating a detrimental sensitivity of the phenol to tested

conditions. This study describes a novel approach to a truly reversible photoswitchable chiral bidentate

metal-complex. Notably, application of an externally triggered multistate chiral catalyst in tandem catalysis

is still an undisclosed achievement. Our investigation provides valuable insight into the requirements for

the design of more effective and complex responsive systems, which may allow the photocontrol of catalyst

activity and selectivity in multicomponent reactions. Key to the successful development of these future

catalysts will be a deeper understanding of the compatibility of ancillary functional groups with the stability

of the overcrowded alkene functionality and the introduction of more reactive substituent to ensure higher

versatility during the catalyst development and synthesis.



285

8.4 Experimental section

8.4.1 General methods

General experimental details can be found in Chapters 5 and 6.

8.4.2 Synthetic procedures

(1R,7S)-8-(9H-fluoren-9-ylidene)-7-methyl-1-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-5,6,7,8-

tetrahydronaphthalen-2-yl trifluoromethanesulfonate (3).

A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a

magnetic stirring bar. A solution of 2,2‘-bisphenol derived switch (S,M)-1 (400 mg,

0.96 mmol) in dry CH2Cl2 (4 mL) was injected under nitrogen. To this solution was

added dry pyridine (0.21 mL, 2.60 mmol, 2.7 equiv), followed by triflic anhydride

(0.34 mL, 2.02 mmol, 2.1 equiv) slowly at 0 °C . The reaction mixture was stirred

at 0 °C for 3 h, at which time TLC indicated that the reaction was completed. The

reaction mixture was diluted with CH2Cl2 (10 mL) and washed subsequently with aq. 1 M HCl (10 mL), aq.

1 M NaHCO3 (10 mL), and brine (10 mL). The organic phase was dried over anhydrous Na2SO4, filtered

and the solvent was removed under reduced pressure. The product was purified by column chromatography

(SiO2, pentane:CH2Cl2 = 5:1 to 1:1) to yield bis-triflate 3 (570 mg, 0.83 mmol, 86%) as a 40:60 mixture of

stable atropisomers as a yellow foam. The isolated early fractions were assigned to pure (S,M,Ra)-3 (190

mg, 0.28 mmol, 29%). The middle fractions were assigned to a mixture of (S,M,Ra)-3 and (S,M,Sa)-3. The

isolated later fractions were assigned to pure (S,M,Sa)-3 (300 mg, 0.44 mmol, 46%). (S,M,Ra)-3 (early

fraction): Rf: 0.82, pentane:CH2Cl2 = 5:1. m.p. 171.5 °C. 1H NMR (400 MHz, CDCl3) δ 7.73–7.57 (m, 3H),

7.55 – 7.44 (m, 2H), 7.34–6.99 (m, 8H), 6.83 (ddd, J = 8.2, 6.5, 2.1 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 3.96

(h, J = 7.3 Hz, 1H), 2.76 (dt, J = 15.8, 4.2 Hz, 1H), 2.51–2.32 (m, 2H), 1.36–1.18 (m, 1H), 1.27 (d, J = 7.0

Hz, 3H). 13

C NMR (100 MHz, CDCl3) δ 146.6, 146.5, 142.9, 142.9, 140.7, 140.6, 139.8, 138.7, 137.8,

136.4, 133.2, 130.4, 129.3, 128.4, 128.0, 127.9, 127.2, 127.0, 126.7, 126.6, 124.9, 124.5, 121.3, 120.1,

119.7, 119.5, 118.4 (q, J = 319.9 Hz), 118.3 (q, J = 319.9 Hz), 35.3, 31.8, 29.2, 20.3. 19

F NMR (282 MHz,

CDCl3) δ -74.15, -74.58. HRMS (ESI, m/z): calcd for C32H23F6O6S2 [M+H]+: 681.0835, found: 681.0830.

(S,M,Sa)-3 (later fraction): Rf: 0.65, pentane:CH2Cl2 = 5:1. m.p. 174.8 °C. 1H NMR (400 MHz,

CDCl3) δ 7.77 (dd, J = 6.7, 1.9 Hz, 1H), 7.56 (dd, J = 6.7, 1.9 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.47 (d, J =

8.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.32 (dd, J = 8.1, 1.9 Hz, 1H), 7.30–7.22 (m, 3H), 7.13 (t, J = 7.5 Hz,

1H), 7.08–7.03 (m, 1H), 7.00–6.90 (m, 3H), 6.67 (d, J = 7.9 Hz, 1H), 4.16 (h, J = 7.2 Hz, 1H), 2.82–2.72

(m, 1H), 2.53–2.40 (m, 2H), 1.43 (d, J = 6.9 Hz, 3H), 1.31–1.19 (m, 1H). 13

C NMR (100 MHz, CDCl3) δ

148.7, 146.4, 143.1, 140.9, 140.5, 139.9, 139.2, 137.8, 137.2, 136.4, 133.2, 130.2, 129.6, 128.9, 128.0,

127.7, 127.2, 127.0, 126.0, 125.4, 124.6, 123.9, 121.7, 119.7, 119.1, 119.0, 118.4 (q, J = 319.9 Hz), 118.4

(q, J = 319.9 Hz), 34.4, 30.8, 29.2, 21.9. 19

F NMR (376 MHz, CDCl3) δ -74.08, -74.23. HRMS (ESI, m/z):

calcd for C32H23F6O6S2 [M+H]+: 681.0835, found: 681.0830.

2-((1R,7S)-2-(diphenylphosphoryl)-8-(9H-fluoren-9-ylidene)-7-methyl-5,6,7,8-tetrahydronaphthalen-

1-yl)phenyl trifluoromethanesulfonate (5).

Diphenylphosphine oxide-triflate 5 was prepared from 3 by a modified procedure


A flame-dried Schlenk tube was equipped with

vacuum/nitrogen stopcock and a magnetic stirring bar. In a glovebox, the Schlenk

tube was charged with bis-triflate (S,M,Ra)-3 (90 mg, 0.132 mmol),

diphenylphosphine oxide (110 mg, 0.530 mmol, 4 equiv) and dichloro[1,3-

bis(diphenylphosphino)propane]palladium(II) [PdCl2(dppp)] (15.6 mg, 0.026

mmol, 0.2 equiv). The Schlenk tube was removed from the glovebox and attached to a nitrogen line. Dry

dimethyl sulfoxide (1 mL) and diisopropylethylamine (0.122 mL, 0.793 mmol, 6 equiv) were added by

syringe. The mixture was heated with stirring at 110 °C for 24 h. After being cooled to room temperature,

Chapter 8

286

the reaction mixture was concentrated under reduced pressure to give a dark brown residue, which was

diluted with EtOAc (10 mL). The organic phase was washed with aq. 3M HCl (10 mL), brine (10 mL),

dried over anhydrous MgSO4, filtered and the solvent was removed under reduced pressure. The product

was purified by column chromatography (SiO2, pentane:EtOAc = 5:1 to 2:1) to yield diphenylphosphine

oxide-triflate (S,M,Ra)-5 (63 mg, 0.085 mmol, 65%) as a yellow foam. The procedure was performed using

the other conformer (S,M,Sa)-3 (100 mg,0.147 mmol) as substrate to yield the same isomer of product

(S,M,Ra)-5 (90 mg, 0.122 mmol, 83%) as a yellow foam. Rf 0.23 in pentane:EtOAc = 4:1. m.p. 233-234 °C. 1H NMR (400 MHz, CDCl3) δ 7.78–7.69 (m, 2H), 7.66–7.50 (m, 5H), 7.50–7.43 (m, 3H), 7.43–7.34 (m,

3H), 7.30–7.23 (m, 3H), 7.23–7.13 (m, 3H), 6.99 (ddd, J = 8.6, 7.5, 1.7 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H),

6.28 (d, J = 7.9 Hz, 1H), 6.23 (t, J = 7.5 Hz, 1H), 6.11 (dd, J = 7.8, 1.7 Hz, 1H), 3.91 (q, J = 7.3 Hz, 1H),

2.70–2.60 (m, 1H), 2.41–2.30 (m, 2H), 1.21 (d, J = 7.0 Hz, 3H), 1.19–1.07 (m, 1H). 13

C NMR (100 MHz,

CDCl3) δ 149.0, 146.6 (d, J = 2.7 Hz), 144.4 (d, J = 0.7 Hz), 140.4, 140.2 (d, J = 10.4 Hz), 139.6, 139.2,

138.9 (d, J = 7.7 Hz), 137.8, 135.7, 134.6, 133.7 (d, J = 22.0 Hz), 133.3 (d, J = 12.7 Hz), 132.7, 132.6,

132.5, 132.4, 132.0, 131.9, 131.7 (d, J = 2.8 Hz), 131.5 (d, J = 2.9 Hz), 131.4, 131.3, 129.4 (d, J = 4.0 Hz),

129.2, 128.6, 128.4, 128.3, 128.2, 127.6, 127.3, 127.0, 126.6, 126.5 (d, J = 13.2 Hz), 124.7, 124.4, 123.9,

119.5 (d, J = 8.0 Hz), 118.3, 35.6, 31.7, 29.9, 20.2. 19

F NMR (282 MHz, CDCl3) δ -75.86. 31

P NMR (162

MHz, CDCl3) δ 27.70. HRMS (ESI, m/z): calcd for C43H33F3O4PS [M+H]+: 733.1784, found: 733.1774.

An alternative procedure for phosphine oxide coupling previously reported98

was also successfully

tested, using bis-triflate (S,M,Ra)-3 (68 mg, 0.10 mmol), palladium(II) acetate (0.2 equiv) and 1,3-

bis(diphenylphosphino)butane (dppb) (0.2 equiv) as a catalyst, to yield product (S,M,Ra)-5 (35 mg,

0.05 mmol, 50%) in a lower yield. The rest of the methodology was equal in all other details to the one

described above.

2-((1R,7S)-2-(diphenylphosphino)-8-(9H-fluoren-9-ylidene)-7-methyl-5,6,7,8-tetrahydronaphthalen-1-

yl)phenyl trifluoromethanesulfonate (6).

Diphenylphosphine-triflate 6 was prepared from 5 by a modified procedure


A Schlenk tube was charged with diphenylphosphine oxide-

triflate (S,M,Ra)-5 (40 mg, 0.055 mmol) and equipped vacuum/nitrogen stopcock

and a magnetic stirring bar. The tube was evacuated and backfilled with nitrogen

three times. Dry and degassed toluene (2 mL), diisopropylethylamine (0.29 mL,

1.64 mmol, 30 equiv) and trichlorosilane (0.06 mL, 0.546 mmol, 10 equiv) were

injected in the tube. The mixture was heated with stirring at reflux over 3 d. After cooling to rt, the reaction

mixture was diluted with CH2Cl2 (10 mL), sat. aq. Na2CO3 (10 mL) was carefully added and the mixture

was stirred over 1 h at rt. The organic phase was separated and washed with water (10 mL), brine (10 mL),

dried over anhydrous MgSO4, filtered and the solvent was removed under reduced pressure. The product

was purified by column chromatography (SiO2, pentane:EtOAc = 10:1) to yield diphenylphosphine-triflate

(S,M,Ra)-6 (30 mg, 0.041 mmol, 75%) as a yellow foam. Rf: 0.20, pentane:EtOAc = 10:1. m.p. 218.6-219.3

°C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.5 Hz, 1H), 7.58–7.54 (m, 1H), 7.48 (d, J = 7.5 Hz, 1H),

7.45–7.39 (m, 5H), 7.36 (d, J = 7.8 Hz, 1H), 7.32–7.27 (m, 3H), 7.24 – 7.16 (m, 5H), 7.10–7.00 (m, 3H),

6.70 (t, J = 7.6 Hz, 1H), 6.44 (td, J = 7.6, 1.5 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 6.36 (d, J = 7.7 Hz, 1H),

3.93 (h, J = 7.1 Hz, 1H), 2.72 (dt, J = 14.1, 3.8 Hz, 1H), 2.49–2.30 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H), 1.38–

1.18 (m, 1H). 13

C NMR (100 MHz, CDCl3) δ 146.1, 145.5, 143.4, 140.5, 140.3, 140.2, 140.1, 139.4, 139.2,

138.5, 138.4, 138.3, 138.1, 137.5, 137.4, 137.3, 135.4, 134.9, 134.6, 133.7, 133.5, 129.5, 129.0, 128.7,

128.6, 128.5, 128.4, 128.2, 128.0, 127.3, 127.2, 126.8, 126.5, 125.3, 124.7, 124.1, 119.8, 119.5, 119.1, 36.1,

32.0, 29.4, 20.6. 19

F NMR (376 MHz, cdcl3) δ -74.78. 31

P NMR (162 MHz, CDCl3) δ -12.91. HRMS (ESI,

m/z): calcd for C43H33F3O3PS [M+H]+: 717.1835, found: 717.1829.

Alternative tested conditions for phosphine oxide reduction of 5 were conducted by modified procedures

previously reported, resulting in poor or no conversion towards the desired product.



287

Attempted synthesis of (2-((1R,7S)-2-(diphenylphosphino)-8-(9H-fluoren-9-ylidene)-7-methyl-5,6,7,8-

tetrahydronaphthalen-1-yl)phenyl)diphenylphosphine oxide (7)

The synthesis of diphenylphosphine-diphenylphosphine oxide 7 from 6 was

attempted by a modified procedure previously reported.98

A flame-dried Schlenk

tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. In

a glovebox, the Schlenk tube was charged with diphenylphosphine-triflate

(S,M,Ra)-6 (30 mg, 0.042 mmol), diphenylphosphine oxide (17 mg, 0.084 mmol,

2 equiv), palladium(II) acetate (1.9 mg, 8.4 µmol, 0.2 equiv) and 1,3-

bis(diphenylphosphino)butane (dppb) (3.6 mg, 8.4 µmol, 0.2 equiv). The Schlenk

tube was removed from the glovebox and attached to a nitrogen line. Dry dimethyl sulfoxide (0.5 mL) and

diisopropylethylamine (0.026 mL, 0.167 mmol, 4 equiv) were added by syringe. The mixture was heated

with stirring at 110 °C for 24 h. After being cooled to room temperature, the reaction mixture was

concentrated under reduced pressure to give a dark brown residue, which was diluted with EtOAc (10 mL).

The organic phase was washed with aq. 3M HCl (10 mL), brine (10 mL), dried over anhydrous MgSO4,

filtered and the solvent was removed under reduced pressure. The residue was purified by column

chromatography (SiO2, pentane:EtOAc = 5:1 to 2:1) to yield the oxidized substrate diphenylphosphine

oxide-triflate (S,M,Ra)-6 as major component. No trace of the expected diphenylphosphine-

diphenylphosphine oxide 7 was detected by 1H/

31P NMR analysis.

General Procedure for Ruthenium-Catalyzed Transformation of Aryl Triflates to Halides.

The synthesis of compounds 8 from 3, 9 and 10 from 5, and 11 from 6, respectively, was attempted by a

modified procedure previously reported.118


vacuum/nitrogen stopcock and a magnetic stirring bar. In a glovebox, the Schlenk tube was charged with a

magnetic stirring bar, LiBr (3.0 equiv) or NaI (1.5 equiv), [Cp*Ru(MeCN)3]1OTf (0.1 equiv), aryl triflate

3, 5 or 6 and 1,3-dimethyl-2-imidazolidinone (DMI, ca. 10 mL/mmol of triflate). The resulting mixture was

heated under stirring under the reported conditions (NaI: 100 °C over 24 h; LiBr: 120 °C over 72 h). After

the reaction mixture was poured into water and extracted with Et2O (3 x 10 mL), the combined organic

layer was washed with water (3 x 15 mL) and brine (15 mL), and dried over MgSO4. After filtration and

concentration, the crude mixture was analyzed by 1H/

19F/

31P NMR spectroscopy. The crude was then

subjected to column chromatography on silica gel. Bis-triflate (S,M,Ra)-3 was successfully converted to

what was assigned as triflate-bromide (S,M,Ra)-8 (full conversion, yield not determined), obtained by flash

column chromatography (SiO2, pentane:EtOAc = 25:1 to 10:1) together with large amount of not

removable DMI. 8: 1H NMR (300 MHz, CDCl3) δ 7.69–7.59 (m, 2H), 7.56–7.22 (m, 10H), 7.20–7.03

(m, 4H), 6.89 (td, J = 8.4, 7.9, 1.8 Hz, 1H), 6.82 (t, J = 7.3 Hz, 1H), 6.17 (d, J = 7.8 Hz, 1H), 6.14 (t, J =

7.4 Hz, 2H), 6.00 (dd, J = 7.8, 1.7 Hz, 1H), 3.82 (h, J = 7.3 Hz, 1H), 2.82–2.51 (m, 1H), 2.32–2.19 (m, 2H),

1.11 (d, J = 7.0 Hz, 3H,) 1.10–0.95 (m, 1H). 19

F NMR (282 MHz, CDCl3) δ -76.01. Diphenylphosphine

oxide-triflate (S,M,Ra)-5 gave no conversion towards the corresponding diphenylphosphine oxide-bromide

(S,M,Ra)-9 or diphenylphosphine oxide-iodide (S,M,Ra)-10. Diphenylphosphine-triflate (S,M,Ra)-6 gave no

conversion towards the corresponding diphenylphosphine -iodide (S,M,Ra)-11.

Attempted synthesis of ((1R,7S)-8-(9H-fluoren-9-ylidene)-1-(2-hydroxyphenyl)-7-methyl-5,6,7,8-

tetrahydronaphthalen-2-yl)diphenylphosphine oxide (15) from 5

The synthesis of hydroxyl-diphenylphosphine oxide 15 from 5 was attempted

by a modified procedure previously reported.37

To a solution of

diphenylphosphine oxide-triflate (S,M,Ra)-5 (20 mg, 0.027 mmol) in a 2:1

mixture of l,4-dioxane and MeOH (0.2 mL) was added aq. 3N NaOH (0.1 mL,

0.33 mmol, 12 equiv) solution at ambient temperature. The reaction mixture

was stirred for 16 h, acidified (pH = 1) by addition of aq. 2N HCl, and then

extracted twice with EtOAc. The organic phase was dried over MgSO4 and

Chapter 8

288

concentrated under reduced pressure to give a pale brown residue. No conversion to the desired product 15

was observed as determined by NMR analysis of crude. Major decomposition of the switch functionality

occurred as determined by 1H NMR spectroscopy. Complete hydrolysis of the triflate substituent was

determined as observed by lack of any resonance peak in the 19

F NMR spectrum. Notably, two sets of

resonances with a ratio of 70:30 were observed in the 1H/

31P NMR spectra. Base-triggered addition of

lower hydroxyl substituent to the overcrowded alkene bond was proposed, affording a mixture of two

atropisomeric by-products 16 and 16’ (NMR resonances not assigned to corresponding isomer). 1H NMR

(400 MHz, CDCl3, A:B = 70:30 mixture of atropisomers) δ 8.90 (d, J = 8.0 Hz, 0.7H, A), 8.64 (dd, J = 7.9,

1.5 Hz, 0.3H, B), 7.94 (d, J = 6.9 Hz, 0.7H, A), 7.86–7.79 (m, 1.6H), 7.74–7.65 (m, 3H), 7.61 (d, J = 7.6

Hz, 0.7H, A), 7.55–7.40 (m, 6H), 7.41–7.29 (m, 6H), 7.28–7.08 (m, 3H), 7.07–7.01 (m, 1.6H), 6.96 (t, J =

6.8 Hz, 1H), 6.88 (t, J = 7.5 Hz, 0.7H, A), 6.81 (dd, J = 8.0, 1.4 Hz, 0.3H, B), 6.67–6.58 (m, 1.2H), 5.97 (d,

J = 7.7 Hz, 0.7H, A), 4.51 (s, 0.7H, A), 3.49 (s, 0.3H, B), 2.80 (t, J = 8.1 Hz, 0.7H, A), 2.69–2.60 (M,

0.9H), 2.35–2.22 (m, 1H), 2.15-2.09 (m, 0.8H), 1.35–1.20 (s, 3H), 1.11–1.02 (m, 1.2H), 0.97 (d, J = 6.9 Hz,

2H, A), 0.90–0.75 (s, 1.7H). 31

P NMR (162 MHz, CDCl3, A:B = 70:30 mixture of atropisomers) δ 29.80

(A), 29.18 (B).

(6S,6aR)-6a-(9H-fluoren-9-yl)-6-methyl-4,5,6,6a-tetrahydrobenzo[kl]xanthen-1-ol (19)

In a comparative experiment, the same procedure described for the attempted

hydrolysis of 5 to 15 was applied to the deprotonation of bisphenol 1 (30 mg,

0.072 mmol) and hydrolysis of bis-triflate 3 (25 mg, 0.037 mmol), affording

in either case the common species 19 (28 mg, 0.067 mmol, 94%, and 15 mg,

0.036 mmol, 97%, respectively) as a red-brown oil. A single set of absorptions

was observed in the 1H NMR spectrum. No resonance was observed in the

19F

NMR spectra from reaction with 3. 1H NMR (400 MHz, Chloroform-d) δ 8.54

(d, J = 8.0 Hz, 1H), 8.03 (d, J = 6.1 Hz, 1H), 7.79–7.67 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.43–7.35 (m,

2H), 7.35–7.26 (m, 3H), 7.20 (tt, J = 7.5, 0.9 Hz, 1H), 7.10–7.04 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.90 (td,

J = 7.6, 1.2 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.86 (d, J = 7.7 Hz, 1H), 4.67 (s, 1H), 3.70 (s, 1H), 2.57 (ddd,

J = 17.8, 11.0, 7.3 Hz, 1H), 2.15–1.98 (m, 2H), 1.08–1.00 (m, 1H), 0.95 (d, J = 6.9 Hz, 3H), 0.91–0.83 (m,

1H).

(1S)-8-(9H-fluoren-9-ylidene)-1-(2-hydroxyphenyl)-7-methyl-5,6,7,8-tetrahydronaphthalen-2-yl

trifluoromethanesulfonate (20).


vacuum/nitrogen stopcock and a magnetic stirring bar. A

solution of 2,2‘-bisphenol derived switch (R,P)-1 (100 mg,

0.24 mmol) in dry CH2Cl2 (2.5 mL) was injected under

nitrogen. To this solution was added dry pyridine (29 µL,

0.36 mmol, 1.5 equiv), followed by triflic anhydride (45 µL,

0.27 mmol, 1.2 equiv) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, at which time TLC

indicated that the reaction was completed. The reaction mixture was diluted with CH2Cl2 (10 mL) and

washed subsequently with aq. 1 M HCl (10 mL), aq. 1 M NaHCO3 (10 mL), and brine (10 mL). The

organic phase was dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced

pressure. The product was purified by column chromatography (SiO2, pentane:EtOAc = 10:1) to yield

hydroxyl-triflate 20 (120 mg, 0.22 mmol, 91%) as a thick yellow oil. The mixture contains two stable

atropisomers which were assigned by 1H/

19F NMR spectroscpy to (R,P,Sa)-20 and (R,P,Ra)-20 in a A:B =

65:35 ratio, respectively. Rf: 0.20 and 0.15, pentane:EtOAc = 10:1. 1H NMR (400 MHz, CDCl3, A:B =

35:65 mixture of atropisomers) δ 7.82 (dd, J = 6.1, 2.8 Hz, 0.65H, B), 7.74 (d, J = 7.7 Hz, 0.35H, A), 7.68–

7.64 (m, 0.35H, A), 7.62 (d, J = 7.5 Hz, 0.35H, A), 7.60–7.56 (m, 0.65H, B), 7.49 (d, J = 7.5 Hz, 0.65H, B),

7.47–7.43 (m, 1.8H, A+B), 7.35–7.20 (m, 3H, A+B), 7.24 (s, 1H), 7.17–7.11 (m, 1.3H, B), 7.02 (td, J = 7.6,



289

1.2 Hz, 0.35H, A), 6.98–6.88 (m, 1.3H, B), 6.88–6.82 (m, 1H, A+B), 6.72 (d, J = 7.8 Hz, 0.65H, B), 6.64 (t,

J = 7.5 Hz, 1H, A+B), 6.52 (d, J = 7.9 Hz, 0.35H, A), 6.45–6.38 (m, 1H, A+B), 4.53 (s, 0.35H, A), 4.49 (s,

1H, 0.65B), 4.22–4.11 (h, J = 7.1 Hz, 0.65H, B), 4.05 (h, J = 7.1 Hz, 0.35H, A), 2.80–2.69 (m, 1H, A+B),

2.53–2.32 (m, 2H, A+B), 1.51 (d, J = 7.0 Hz, 2H, B), 1.31 (d, J = 7.0 Hz, 1H, A), 1.32–1.20 (m, 1H, A+B). 13

C NMR (100 MHz, CDCl3, A:B = 35:65 mixture of atropisomers) δ 155.3, 154.2, 154.0, 149.5, 149.3,

145.2, 145.0, 144.3, 143.0, 142.8, 142.3, 141.8, 141.6, 141.6, 141.1, 140.2, 140.1, 139.9, 139.8, 138.0,

137.9, 134.3, 134.1, 132.1, 131.9, 130.5, 130.0, 129.8, 129.8, 129.7, 129.1, 129.0, 128.6, 127.0, 126.9,

126.7, 126.3, 126.2, 123.6, 123.3, 123.1, 122.2, 121.8, 121.5, 121.3, 119.0, 118.8, 117.3, 37.3, 36.8, 33.9,

33.3, 31.5, 31.2, 24.1, 22.8. 19

F NMR (376 MHz, CDCl3, A:B = 35:65 mixture of atropisomers) δ -74.18

(A), -74.44 (B). HRMS (ESI, m/z): calcd for C31H24F3O4S [M+H]+: 549.1342, found: 549.1331. CSP-HPLC

analysis of the atropisomeric mixture (Chiralpak AD-H, heptane:2-propanol = 95:5, flow rate =

0.5 mL/min, column temperature = 40 °C, Rt: 16.5 min for (R,P,Sa)-20 (A, minor), 21.4 min for (R,P,Ra)-20

(B, major)) showed sharp elution peaks for both species, which suggests no interconversion between the

two isomers at the tested analytical condition. EXSY experiment at 55°C showed no evidence of exchange

between the two atropisomers.

Attempted synthesis of ((1R,7S)-8-(9H-fluoren-9-ylidene)-1-(2-hydroxyphenyl)-7-methyl-5,6,7,8-

tetrahydronaphthalen-2-yl)diphenylphosphine oxide (15) from 20

The synthesis of hydroxyl-diphenylphosphine oxide 15 from 20 was attempted

by a modified procedure previously reported.98

A flame-dried Schlenk tube was

equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. In a

glovebox, the Schlenk tube was charged with diphenylphosphine oxide-triflate

(S,M,Ra)-5 (100 mg, 0.18 mmol), diphenylphosphine oxide (74 mg, 0.370 mmol,

2 equiv), palladium(II) acetate (8.1 mg, 36 µmol, 0.2 equiv) and 1,3-

bis(diphenylphosphino)butane (dppb) (14.4 mg, 36 µmol, 0.2 equiv). The Schlenk tube was removed from

the glovebox and attached to a nitrogen line. Dry dimethyl sulfoxide (2 mL) and diisopropylethylamine

(0.104 mL, 0.72 mmol, 4 equiv) were added by syringe. The mixture was heated with stirring at 110 °C for

24 h. After being cooled to room temperature, the reaction mixture was concentrated under reduced

pressure to give a dark brown residue, which was diluted with EtOAc (10 mL). The organic phase was

washed with aq. 3M HCl (10 mL), brine (10 mL), dried over anhydrous MgSO4, filtered and the solvent

was removed under reduced pressure. The residue was purified by column chromatography (SiO2,

pentane:EtOAc = 20:1 to 3:1) to yield five distinct fractions that were anaysed by 1H/

19F/

31P NMR

spectroscopy. No conversion to the desired product 15 was observed; instead decomposition of the

overcrowded alkene functionality was observed from the 1H NMR spectra.

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