Optical Activity and Helicity Enhancement of Highly Sensitive Dinaphthylmethane-Based Stereodynamic Probes for Secondary Alcohols.

Chirality transfer from circular dichroism (CD)-silent secondary alcohol (inductor) to the stereodynamic bichromophoric di(1-naphthyl)methane probe (reporter) led to the generation of intense, induced exciton-type Cotton effects (CEs) in the ultraviolet-visible absorption region. The di(1-naphthyl)methane probe exhibits extraordinarily high sensitivity to even small structural variations of the alcohol skeleton, that is, the probe is able to distinguish between an oxygen atom and a methylene group in a 3-hydroxytetrahydrofurane skeleton. Signs and amplitudes of the exciton couplets of 1Bb electronic transition might be correlated with the type of stereo-differentiating parts of the molecule flanking the stereogenic center, however, not with the absolute configuration. The origin of the induced CEs was established by means of experimental and theoretical methods. As a result, a mechanism of chirality transfer from the permanent stereogenic center to the bichromophore is proposed.

Introduction

Chirality, its generation, sensing, transfer, and amplification are of paramount significance for numerous processes occurring in natural and artificial systems.[1−4] Chirality transfer can be considered as transmission of information about the three-dimensional structure of a given substrate (inductor) or catalyst to the structure of the product(s), further appearing as an uneven population of diastereomers or enantiomers.[5−7] Electronic circular dichroism (ECD) has been widely used to determine the stereochemistry [i.e., absolute configuration (AC)] of chiral molecules.[8] Together with X-ray crystallography, ECD allows a full description of the stereochemistry of a chiral molecule or molecular system in all states of matter.[9] Despite some discrepancies,[10] the exciton chirality method is of particular value as it allows direct insight into the stereochemistry of the molecule if (at least) two chromophores, with the allowed π–π* electronic transitions, are present.[11−13] The geometrical relationship between the interacting electronic dipole transition moments (EDTMs), μi and μj (so-called coupled oscillators), can be easily related to the stereostructure of a given molecular system. In the simplest terms, the sign of the exciton couplet is the function of the dihedral angle ω between interacting EDTMs. In general, if the two interacting chromophores constitute a clockwise screw sense, the ECD shows a positive first exciton Cotton effect (CE) at a longer wavelength and a negative second CE at a shorter wavelength and vice versa.[12−14]

Among the natural and artificial chiral molecules, secondary alcohols remain one of the most abundant species. Usually, these compounds are characterized by the lack of suitable chromophore(s), which makes the stereochemical analysis with the use of ECD spectroscopy impossible. On the other hand, derivatization of the CD-silent chiral molecule (inductor) by the stereodynamic bichromophoric probe (reporter) led to the generation of intense, induced CEs through a mechanism of chirality transfer from a permanent chirality element.[15−19] Since the pioneering work of Nakanishi and Berova, a variety of achiral or dynamically racemic stereodynamic probes, introduced by Anslyn, Wolf, Taniolo, Canary, Borovkov, Bornhan, Gawroński, and others, have been utilized in chirality sensing of molecules usually having two or more functional groups.[20−63] Regardless of the chemical composition and the method of binding to the inductor, the probe’s mode of action can be defined as a dynamic adaptation of the chromophoric system to the chiral environment. However, a characteristic feature of the inductor molecules, tested so far, is the large sterical difference between substituents around the stereogenic center(s).

Literature review leads to the conclusion that the bichromophoric derivatives of monoalcohols still constitute a not fully explored class of compounds. This justifies the efforts to develop new or test existing stereodynamic chromophoric systems as effective chirality sensors.[57,64]

Recently, it has been shown that disturbing the local symmetry of triphenylmethane led to a generation of characteristic CD signals observed for a series of nonracemic O-trityl alcohols, N-trityl amines, triphenylacetic acid derivatives, and related compounds.[65−70] The structurally simpler diphenylmethane (benzhydryl) probe has been used for the determination of chirality of alcohols and hydroxyacids.[71−73] Because of the appearance of the observed induced CEs in the short-wavelength region of the phenyl 1B transitions, the applicability of the benzhydryl probe is limited.

A high-intensity electronic transition (1Bb) located at ca. 220 nm and its well-defined polarization along the long axis of the chromophore make naphthalene a particularly suitable chromophore for CD spectroscopy. Recently, we and others have proven the utility of 1-naphthalene derivatives in stereochemical studies with the use of chiroptical methods.[74−76] For instance, Borhan used di(1-naphthyl)methanol esters for the determination of absolute stereochemistry of carboxylic acids. Although the results were spectacular, the studied objects were characterized by a low structural diversity.[77]

Feeling that the problem of chirality sensing by stereodynamic reporters is not fully explored yet, we decided to show the usability, or its lack, of diarylmethane-based probes in stereochemical studies with the use of ECD spectroscopy. We anticipated that proper functionalization of the phenyl rings in benzhydryl or replacement phenyls by the naphthalene moieties would provide appropriate chromophoric systems capable of chirality sensing. In principle, the probes should be structurally as simple as possible but sensitive to small changes in the inductor structure. The mechanism of chirality transfer should be possible to be determined by means of experimental and theoretical methods. Solubility in the nonpolar environment, preferentially in hydrocarbons, which facilitates experimental/theoretical analysis, is an additional desired factor.

Results and Discussion

As it has been mentioned above, we have intended to show how the probes under study are sensitive to even small changes in the inductor structure. Because of the very small difference between methyl and ethyl substituents flanking the stereogenic center, we have selected (R)-2-butanol (1a, Chart ) as the model compound for preliminary study. Alcohol 1a has been functionalized by methoxy-substituted benzhydryl probes as well as by di(1- and 2-naphthyl)methyl groups providing respective diarylmethyl ethers 1b–1f (see Experimental section for details). Despite many attempts, we were not able to obtain benzhydryl-based probe substituted by methoxy groups in meta positions.

Chart 1

Structures of Alcohols 1a–10a and Their respective Diarylmethyl Ethers 1b–1f and 2b–10b Used in This Study and the Structure of the Model Compound 11a

Torsion angles α1, α2, β1, and β2 that characterize the molecular conformation and the definition of angle ω between interacting electric transition dipole moments μ1 and μ2. Sterodifferentiating groups flanking the stereogenic center are distinguished by colors.

The most convenient way to indicate sensitivity in chirogenesis, and therefore the advantage of a given chromophoric system over others, is to compare their dissymmetry factors, defined as the Δε/ε ratio at a given wavelength. However, the definition of the Δε/ε relationship is straightforward in situations where both the ultraviolet (UV) and CD curves reach the extreme at the same wavelength. In the case of exciton couplets, the UV maximum appeared at the wavelength at which the CD curve with the abscissa is intersected. Therefore, to avoid discussion on which of the exciton CEs should be applied to calculate the dissymmetry factors, for the purpose of this work, we introduced the sensitivity factor G, which used absolute values of the amplitude of exciton couplets (|A|) and is defined here as G = |A|/ε. The amplitude (A) of exciton CEs is defined as the difference between the first, long-wavelength CE (Δεlong) and the second, short-wavelength (Δεshort) CE (A = Δεlong – Δεshort).

It is clearly seen that all of the preliminarily tested probes are capable of chirality sensing. A more detailed look at the results led to the following conclusions. Bearing in mind the low structural diversity of the inductor, the induced CEs measured for the basic benzhydryl chromophore (1b) are relatively high. The amplitude of exciton CEs is negative and amounts to −9.1.

Methoxy groups have a diverse impact on the observed induced CD. The OMe groups at C2 positions enhanced the intensity of the CEs, as it is seen in 1c. On the other hand, the methoxy groups at C4 positions of the chromophore make the CD spectrum more complex and hence more difficult to interpret. Whereas the amplitude of exciton CEs (ECEs) estimated for 1c (A = −13.8) is higher than that of 1b, the change in the electronic structure of 1d caused a significant decrease in the amplitude (A = −4.6). In addition to the intensity of the relevant CEs, the position of the absorption bands needs to be taken into account. Because no significant UV absorption band shift is observed for either 1c or 1d, compared to 1b, the usability of methoxy-substituted probes is not much greater than the basic benzhydryl one.

The presence of naphthyl groups in 1e and 1f caused a significant red shift of the respective UV absorption maxima with simultaneous enhancement of the CEs observed at around 230 and 220 nm. The amplitudes of ECEs estimated for 1e and 1f are almost the same and amount to −38.8 and −40.2, respectively.

A direct comparison of the G factors provides valuable information on the induced optical activity in the given chromophore (see Table ). In the homologous series 1b–1f, the estimated G factors diminish in the order 1f ≥ 1e > 1c > 1b ≫ 1d. Although both naphthyl-based probes gave a similar CD output, our experience shows that the interpretation of results obtained for 1-naphthalene derivatives is easier. This is related to, for example, the less conformational freedom of such compounds.[74−76] Therefore, we have limited further studies to the di(1-naphthyl)methane derivatives (vide infra).

Table 1

UV (ε, in dm3·mol–1·cm–1) and ECD (Δε, in dm3·mol–1·cm–1) Data for 1b–1f and 2b–10b in Cyclohexane Solution and Estimated Sensitivity Factors G (|A|/ε)

compd	UV [ε (nm)]	CD [Δε (nm)]	|A|/ε × 10–4
1b	61 300 (189)	1.4 (224); −7.7 (198); 4.2 (187)	1.48
1c	52 000 (196)	1.9 (223); −11.9 (202)	2.65
1d	24 000 (234); 77 500 (196)	–1.3 (219); −2.9 (203); 1.7 (193)	0.59
1e	107 200 (227)	–21.9 (232); 16.9 (221)	3.62
1f	95 800 (234); 77 600 (219)	–18.4 (233); 21.8 (218)	4.19
2b	112 100 (226)	52.9 (231); −36.4 (220)	7.97
3b	127 900 (227)	4.4 (229); −0.3 (220); 1.5 (211); −2.1 (194)	0.37
4b	107 200 (223)	–217.7 (230); 127.0 (218)	32.1
5b	112 100 (226)	–6.9 (234); 18.0 (229); 12.4 (224); −8.8 (215)	2.21
6b	114 600 (227)	–1.8 (237); 21.4 (228); −3.5 (216)	2.17
7b	122 400 (226)	–10.0 (237); −48.2 (228); 54.9 (213)	8.42
8b	101 500 (226)	–28.1 (234); 47.9 (227); 46.6 (224); −25.5 (214)	7.49
9b	107 700 (227); 69 500 (188)	22.6 (236); −98.5 (227); 65.4 (214)	11.2
10b	112 700 (226)	–17.0 (235); 50.2 (228); −33.8 (217); 12.9 (195)	5.96

To investigate the analytical scope of the di(1-naphthyl)methane probe, we obtained a set of ethers 2b–10b (Chart ). Because of the formation of bis(di(1-naphthyl)methane) ether as a byproduct, the yields of ethers 2b–10b ranged from good to moderate. It is worth noting that under the same reaction conditions, the use of di(2-naphthyl)methanol as a substrate led to products with very low yields, thus confirming the legitimacy of choosing the di(1-naphthyl)methane probe as a privileged chromophoric system.

The 1H nuclear magnetic resonance (NMR) spectra measured at room temperature for ethers 2b–10b did not show any broadened peaks, which could indicate a hindered rotation within the di(naphthyl)methyl moiety.

The UV spectra of ethers 2b–10b exhibit intense absorption bands at around 230 nm because of π–π* electronic transition polarized along the long axis of naphthalene. Interactions between the EDTMs in chromophores within the di(1-naphthyl)methane moiety generate induced nonzero exciton CEs visible in the ECD spectra of 2b–10b (see Figure and Table ).

Figure 1

Exemplary ECD spectra of 1e, 4b, and 7b, experimental, measured in cyclohexane solution (solid black lines) and calculated on the TD-CAM-B3LYP/6-311++G(d,p) level and ΔΔG-based Boltzmann-averaged (dashed red lines). Wavelengths were corrected to match the experimental UV maxima. Δε values are in dm3·mol–1·cm–1. Rotatory strengths (in 10–40 erg esu cm Gauss–1) were calculated as dipole-velocity representation (Rvel).

Generally, the magnitudes of induced CEs depend on the structure of the inductor. For example, a simple elongation of the carbon chain in 2b causes more than 2-fold increase in the intensity of the absolute values of CEs compared to 1e. Because of the sterical congestion around the stereogenic center at the C1 carbon atom, the highest amplitude of the exciton couplet (A = −344.7) was found for menthol derivative 4b. The presence of other aromatic groups in inductor skeletons revealed in the generation of additional CEs originated from aryl–naphthyl interactions in the higher energy part of the spectrum.

By far, compounds 3b, 5b, and 6b constitute the most challenging tasks for the di(1-naphthyl)methane probe. Because it is in the parent compounds, citronellol, 3-hydroxytetrahydrofurane and cholesterol, there are no chromophores absorbing in the spectral region between 230 and 200 nm, and the observed CEs are apparently due to the induced helicity of the naphthyl groups in di(1-naphthyl)methane moieties. In the first case (3b), the stereodifferentiating methyl group is 3 carbon atoms away from the stereogenic center. Although the exciton CEs are of the lowest intensity within the whole series, they are still easily detectable. The estimated amplitude is A = 4.7, which corresponds to the sensitivity factor that equals 3.2 × 10–5.

For 3-hydroxytetrahydrofurane derivative 5b, the probe must distinguish the oxygen atom from the methylene group. However, the estimated amplitude (A = −24.9) is much higher than it was expected. This suggested that in the case of 5b, a rough and simple analysis of the inductor structure based only on the sterical factors might not be sufficient to explain the origin of the observed induced CEs.

The sensitivity of the di(1-naphthyl)methane probe to γ-substitution in the cyclohexane skeleton is also worth mentioning. Even for the equatorial position of C*(3)–O bond in 6b, the stereodifferentation between C1 and C10 groups is visible.

Di(1-naphthyl)methyl ethers under study are very well-soluble in cyclohexane and, to a limited extent, in polar solvents. However, to show the scope and limitation of this derivative as a probe, we measured the ECD spectra of 1e and 2b–10b in acetonitrile that is highly polar but transparent in the spectral region of interest. In the case of 1e, 3b, and 9b, we observed a small increase in the amplitudes of respective CEs, whereas for the remaining cases, the use of polar solvent reduces the amplitudes of respective CEs and/or reverses their signs. Because the steric requirements of the substituents remain the same irrespective of the solvent polarity, the reasons for changing the course of the CD curves can be twofold. First, the conformer population may change, and second, in cases where the conformation is determined by other than steric interactions (i.e., electrostatic), they might lose their importance in the polar environment. ECD spectra measured for selected cases, namely 6b, 7b, 8b, and 10b in ethanol, have a similar course to those measured in acetonitrile. The effect of the solvent on the chiroptical properties of various molecular and supramolecular systems has been reported previously.[78−84]

As the observed CEs have exciton character and EDTMs are polarized along the long axis of the chromophore, their signs are directly linked to the conformation (helicity) of the chromophore but not to the AC of the stereogenic center in a given compound. Strictly speaking, the origin of optical activity of all compounds under study relies on the generation of an unequal population of conformational diasteroisomers characterized by either P or M helicity of a chromophoric system. In the first, but very inexact approximation, the difference of the steric bulk of the groups flanking the stereogenic center might constitute the main reason for the induction of dynamic chirality in a chromophore. Therefore, neglecting the nuances of the inductor structure, helicity of dominant conformer(s) could be linked to the relative size of the substituents, as it has been shown in Figure . This, in principle, should allow correlation between the CD data and structure of the given compound with the use of simplified (semi)empirical approach (see below and the Supporting Information for details).

Figure 2

Correlation between the size of R1, R2, the dominant helicity of the probe, and the sign of the exciton CE.

In Table , the data comparing the relative size of the substituent, dominant helicity of the chromophoric system, and AC of C*–O stereogenic center in given compound have been juxtaposed.

Table 2

Relationships between the Size of Substituents R1, R2 Flanking the C*–O Stereogenic Center, the Dominant Helicity of the Probe, the Sign of ECE, and the AC of the C*–O Stereogenic Center Estimated for Ethers 1e, 2b, and 4b–10b on the basis of CD Data Recorded in Cyclohexane

compd	R1		R2	helicity	ECE	AC
1e	Me	<	Et	M	(−)	R
2b	Hex	>	Me	P	(+)	S
4b	–CH2–	<	–CH(i-Pr)–	M	(−)	R
5b	–OCH2–	<	–CH2CH2–	M	(−)	S
6b	–HC=C(R)CH2–	>	–CH2CH2C(Me)–	P	(+)	S
7b	–(Me)C–	<	–CH2CH2–	M	(−)	S
8b	MeOOC	<	–CH2COOMe	M	(−)	S
9b	Me	>	Ph	P	(+)	R
10b	MeOOC	<	Ph	M	(−)	S

The analysis of the data from Table leads to some unobvious conclusions. The larger steric power of the methyl group than that of the phenyl for induction of dynamic chirality has been reported previously.[68] As expected, the highest steric power for helicity induction within the whole series can be attributed to the −CH(i-Pr)– group, however, the dominant role of −C(15)H2C(16)H2– alkyl chain for helicity induction in testosterone derivative 7b can be surprising. The dominant role of the sp3-hybridized carbon atom over that of sp2 hybridization is seen for malic acid derivative 8b. Therefore, a purely empirical analysis that is based on sterical factors only, while neglecting other interactions, might not be enough in some demanding cases.

To shed light on the origin of optical activity of the di(naphthyl)methane probe and on the mechanism of chirality transmission from the chiral inductor to the reporter, we performed experimental and theoretical studies on the structure-chiroptical property relationships in ethers 1e and 3b–10b as well as for the model compound 11 (Chart ). Without wishing to obfuscate the discussion, all calculation details have been skipped to the Supporting Information. Note that as we compare the experimental results obtained in nonpolar cyclohexane (dielectric constant equals 2), the solvent model was not implemented in the calculations (see the Supporting Information for details).

The structures of individual conformers of all di(1-naphthyl)methane derivatives can be defined by a set of torsion angles α1, α2 (C2Ar–C1Ar–C–O), β1, β2 (H–C–O–C* and C–O–C*–H), and angle γ that defines the conformation of the carbon skeleton of an alcohol moiety. Additionally, we use the angle ω, which corresponds directly to the angle between interacting EDTMs, μ1 and μ2, polarized along the long axis of the naphthalene chromophore (see Chart ).

Contrary to the benzhydryl or trityl, the di(1-naphthyl)methyl chromophore has not been a subject of detailed studies.[73] For this reason, we started the study from establishing the detailed relationship between the structure of the model compound 11 and the sign and magnitude of the rotatory strengths of the 1Bb transition.

The potential energy surface for the change of angles α1 and α2 in 11 is shown in Figure a. The low-energy conformers are lying in the region characterized by the values of α1 angles ranging from −110° to 0°. The second naphthyl group adjusts its conformation to the conformation of the first one. In general, the low-energy conformers are characterized by the almost perpendicular orientation of aromatic rings (α2 angle is within the range from −30° to 30°).

Figure 3

(a) Molecular energy of 11 as a function of angles α1 and α2. Computed on the TD-CAM-B3LYP/6-311++G(d,p) level, (b) amplitude (A = Rlong – Rshort) of rotatory strengths corresponding to experimental exciton couplets of the 1Bb electronic transition as a function of angles α1 and α2.

The three-dimensional surface, connecting the predicted chiroptical properties, namely the amplitude of the exciton couplet, is shown in Figure b. The long-wavelength rotatory strengths and the amplitude of the exciton couplet have the same two-dimensional behavior, whereas the short-wavelength component is the opposite (see the Supporting Information). It is clearly seen that the long- and short-wavelength rotatory strengths remain in an approximate relation as an object to its mirror image, that is, the minimum at the first surface corresponds to the maximum on the other. This is apparently due to the exciton-type mechanism of optical activity generation.

The sign of the given rotational strength value is not directly associated with the respective α1 and α2 values, although it corresponds directly to the ω angle. As expected, for positive values of the ω angle, the positive values of long-wavelength rotatory strengths (and hence positive exciton couplets) were calculated and vice versa.

Noticeably, the low-energy conformers are characterized by high values of the calculated rotatory strengths. For example, amplitudes of rotatory strengths calculated for the lowest-energy conformers’ assume values ±1200 × 10–40 erg esu cm Gauss–1 (see Figure b). A large and rapid change in the calculated values of rotatory strengths along with the α1 and α2 angles change is also worth mentioning.

At the next stage, we investigated compounds characterized by the presence of the permanent stereogenic center to establish the mechanism of the chirality transmission. Because in-depth elaboration of each calculated structure may obscure the problem, we have limited the discussion to the lowest-energy structures of 1e and 3b–10b and their crystal counterparts (if applicable). As the compound 5b deserves special attention, it will be discussed separately. The remaining theoretical results are deposited as the Supporting Information.

The ethers under study are characterized by rather high conformational dynamics (Table and see the Supporting Information for details). Apart from compound 8b, in any of the derivatives studied, the population of the lowest-energy conformer did not exceed 50%.

Table 3

ΔΔG-Based Percentage Populations (Denoted Here as Pop.), Dihedral Angles α, β, γ, and ω (in Degrees), and the Helicity of the Di(naphthyl)methane Fragment Observed in the Crystal Structures of 1e, 4b, 6b, 7b, and 9b and Calculated on the B3LYP/6-311++G(d,p) Level for Individual Lowest-Energy Conformers of Ethers 1e and 3b–10b

compda	Pop.	α1b	α2c	β1d	β2e	γf	ωg	helicity
1e(1)	22	–71	11	43	41	–64	–55	M
1e(A)h,i		–14	98	48	45	–164	67	P
1e(B)h,i		–99	15	–50	–40	–173	–67	M
3b(19)	26	–23	104	41	178	63	69	P
4b(1)	44	–73	11	33	40	–56	–57	M
5b(2)j	17	–12	70	–48	–43	86	53	P
5b(8)j	17	–29	115	50	60	83	88	P
5b(16)k	36l	132	123	55	56	83	–115	M
6b(5)	44	–23	103	23	–44	–179	80	P
6bh		–14	99	43	44	–171	63	P
7b(2)	22	–88	20	–41	–51	–47	–63	M
7bh		–81	11	–31	–40	–47	–54	M
8b(1)	56	–97	19	–21	45	–172	–75	M
9b(3)	46	–13	70	–47	–48	35	52	P
9bh		–4	76	–42	–46	40	45	P
10b(5)	43	–111	31	–57	–57	21	–83	M
10b(A)h,i		–22	103	55	54	64	–23	M
10b(B)h,i		–99	14	–63	–50	71	–66	M

The number of the conformer is shown in parentheses; conformers are numbered according to their appearance during the conformational search.

α1 = C2Ar–C1Ar–C–O.

α1 = C2′Ar–C1′Ar–C–O.

β1 = H–C–O–C*.

β2 = C–O–C*–H.

γ = O–C*–C–C.

ω = the angle formed by the middle points of C2–C3, C9–C10, C9′–C10′, and C3′–C2′ bonds in the chromophore (see Chart for definition).

X-ray data.

Two independent molecules.

Conformer nos. 2 and 8 are equal in ΔΔG energy.

ΔE-based lowest-energy conformer.

ΔE-based percentage population.

A detailed look at the calculated low-energy structures of ethers and those present in crystals allowed us to determine the factors that affect the molecular conformation and therefore responsible for chirality transmission and optical activity of the chromophore (see Table ). The β1 and β2 angles describe the spatial orientation of C–H and C*–O and C–O and C*–H bonds, which might adopt either ±synclinal (sc) and/or ±synperiplanar (sp) orientation with the exception of 3b, where the β2 angle adopts antiperiplanar (ap) conformation in each low-energy structure. The change of γ angle, which describes the spatial relationships between C*-O and C–C aliphatic bonds, affects the energy of the molecule only in the cases of acyclic and flexible compounds, such as 1e and 3b.

In the ΔΔG-based lowest-energy conformers of 1e, 3b, and 6b–10b (shown in Figure ), the structure of the di(1-naphthyl)methane fragment is determined by the electrostatic interaction between a positively charged aromatic proton connected with a C2 carbon atom from one of the naphthyl groups and the oxygen atom. The calculated (CAr)H···O distances range from 2.249 to 2.473 Å, which is consistent with the sp conformation of one of the α angles. As in the case of 11, conformation of the second α2 angle is, among others, a function of the α1 angle. Because of the CH···π interactions between the hydrogen atom attached to the C2 carbon atom in the second naphthyl group and π clouds of the first naphthalene, the second naphthyl ring adjusted to the conformation of the first one.

Figure 4

ΔΔG-based lowest-energy conformers of 1e, 3b, 4b, and 6b–10b calculated on the B3LYP/6-311++G(d,p) level. Black dashed lines indicate possible attractive interactions. Green dashed lines indicate the sterical interactions responsible for the generation of optical activity in the given compound. Distances are in angstroms (Å).

Other attractive interactions can be found between the oxygen atom and one of the aliphatic hydrogen atoms from the inducer. These interactions are visible, for instance, in the lowest-energy conformers of 1e, 3b, 4b, and 7b between one of the hydrogen atoms from the terminal methyl group (1e), the protons from the methylene group (3b), the HC(CH3)2 methine proton (4b), and one of the protons from the methyl group at C13 of the testosterone skeleton (7b).

The presence of additional polar groups in the inducer skeleton may further stabilize the conformation of the given compound. In the case of 8b, weak C=O···HCAr interactions can be seen, which become even more important for the mandelic acid derivative 10b. The calculated distance between the carbonyl oxygen atom and the hydrogen atom attached to the C8 carbon atom of naphthalene is 2.237 Å. These interactions might be treated as the main factor that controls the structure of the lowest-energy conformer of 10b.

It can be concluded that the oxygen atom(s) organizes substituents in a specific order around itself. As a consequence, the weak sterical interactions between the given substituents from the inductor and one of the naphthyl groups, not involved in strong (CAr)H···O interactions, shifted the equilibrium into either P- or M-helical conformers. In the cases of 1e, 4b, 7b, 8b, and 10b, the dominant conformers are characterized by M-helicity of chromophoric systems, where the ω angles adopt values −55°, −57°, −63°, −75°, and −83°, respectively. For 3b, 6b, and 9b, the values of the ω angle are positive, 69°, 80°, and 77°, respectively, which correspond to the positive helicity of the chromophoric systems. The testosterone derivative is an exception. Because of the β (equatorial) position of the C*–O bond at C17 and the large distance, the angular methyl group at C13 has less impact on induced optical activity than the attractive CH···π interactions between the axial hydrogen atom at C17 and the Cipso carbon atom from the naphthalene ring. The steric and/or electrostatic CH···π interactions between naphthalene and the protons from the C12 and C16 methylene groups are less important.

The correctness of the conformational analyses discussed above has been confirmed by the direct comparison of the experimental ECD spectra with those calculated for ethers 1e, 3b, 4b, and 6b–10b. The examples of the ECD spectra measured and calculated for the arbitrarily chosen ethers 1e, 4b, and 7b are shown in Figure (the remaining results are deposited in the Supporting Information). The agreement between the shapes of experimental and theoretical data is good to excellent, even for conformationally flexible molecules, with the exception of 5b.

The calculated and ΔΔG-based and Boltzmann-averaged ECD spectrum of 5b did not reproduce well the experimental one. A more detailed look at the calculated low-energy conformers and their ECD spectra allows explaining this discrepancy. In the case of 5b, instead of one dominant conformer, there are two ΔΔG-based lowest-energy structures (conformer nos. 2 and 8), which account for 32% of the population of all thermally allowed conformers (see Figure a). The structure of conformer no. 2 is stabilized only by the (CAr)H···O(C*) and CH···π interactions. The same interactions characterize the structure of conformer no. 8 and the ΔE-based lowest-energy conformer no. 16. However, in both conformers (nos. 8 and 16), the (CAr)H···O interactions between the aromatic proton, attached to the C8 carbon atom of the <span class="Chemical">naphthalene skeleton, and the tetrahydrofurane oxygen atom are observed. These interactions involved those naphthyl groups whose conformations are not stabilized by (CAr)H···O(C*) interactions. Consequently, the role of the O1 oxygen atom for the induction of dynamic chirality is more significant than the results from the simplified empirical analysis presented above.

Figure 5

(a) Structures of the ΔΔG-based lowest-energy conformers (nos. 2 and 8) and the structure of the ΔE-based lowest-energy conformer no. 16 of 5b. Black dashed lines indicate possible attractive interactions. Distances are in angstroms (Å). (b) ECD spectra of 5b, experimental, measured in cyclohexane solution (solid black line) and calculated on the TD-CAM-B3LYP/6-311++G(d,p) level for conformer no. 2 (green line), no. 6 (blue line), no. 16 (red line), and ΔΔG-based Boltzmann-averaged (dashed black line). Wavelengths were corrected to match the experimental UV maxima. Values of Δε are in dm3·mol–1·cm–1. Rotatory strengths (in 10–40 erg esu cm Gauss–1) were calculated as dipole-velocity representation (Rvel).

The comparison of the experimental and calculated for individual conformer nos. 2, 8, and 16 and Boltzmann-averaged ECD spectra of 5b unambiguously shows that only for conformer no. 16, the agreement between the experiment and the theory is very good. ECD spectra, calculated for conformer nos. 2 and 8 as well as the Boltzmann-averaged theoretical ECD spectrum, remain in disagreement with the experimental one. This discrepancy is due to the underestimation of conformer no. 16 (and related structures) population.

Taking conformer no. 16 as the representative, we intend to explain the source of the unusual pattern of ECD spectrum of 5b. As expected, the CEs forming the exciton couplet originated from transitions involving π orbitals of the naphthalene fragments (see Figure ). The electronic transitions responsible for the lower energy CE involves mainly HOMO, HOMO–1, HOMO–3, and LUMO+3 orbitals, whereas electron transitions from HOMO and HOMO–2 to LUMO+7 are mainly responsible for the second ECE, which is higher in energy. The presence of two etheric oxygen atoms in the molecule skeleton caused appearance of the third CE in the experimental spectrum found at around 215 nm. This particular transition involves, among others, occupied orbitals HOMO–4 and HOMO–5 and virtual orbitals LUMO+1, LUMO+3, and LUMO+7.

Figure 6

Orbitals involved in main electronic transitions in conformer no. 16 of 5b.

It is worth noting that in the ECD spectrum of 5b measured in acetonitrile (see the Supporting Information), the CEs vanished, which confirms the importance of weak CH···O hydrogen bonds for the stabilization of the structure and therefore the generation of optical activity.

Interestingly, in the crystal phase, the conformation of the di(1-naphthyl)methane fragment, as well as the whole molecular system, depends rather on the way of crystal packing than on the subtle intramolecular interactions (see Figure ). This is especially evident in the case of a conformationally labile compound 1e. In the crystal of 1e, there are two independent molecules A and B (shown in Figure a). Both of them are characterized by the same ±sc conformations of β1 and β2 angles, which correspond well with theoretical data. Furthermore, in both molecules A and B, one α angle is ±anticlinal, whereas the other one remains ±sc. Additionally, both molecules A and B are characterized by the bent conformation of the carbon chain, which corresponds to the ap conformation of the γ angle. Noticeably, the structures of 1e found in the crystal and calculated in the gas phase are mutually incompatible with each other.

Figure 7

Molecular structure of (a) 1e (two independent molecules); (b) 6b; (c) 7b; (d) 9b; and (e) 10b (two independent molecules). Dashed lines indicate possible intramolecular interactions. Distances are in angstroms (Å). Note that because of the disorder observed in the crystal of 1e, the alkyl chain in molecule A adopts two bent conformations (A and A′).

Two independent molecules A and B have also been found in the crystal of 10b (see Figure e). The characteristic feature of both molecules is the sp arrangement of the C*–O and C=O bonds. Referring to the calculated structures, such conformation of the inductor skeleton is associated with an increase in energy, which for this particular conformer no. 74 is 1.59 kcal mol–1 above the minimum.

The comparison between the theoretically calculated and experimentally determined structures of 6b, 7b, and 8b (Figure b–d) is more consistent. Both the values of the respective angles and the general structure of the molecules remain in good agreement.

In the structures found in the crystal, the molecular conformation is stabilized by the intramolecular C–H···O hydrogen bonds and C–H···π interactions shown in Figure a–e (see Table S2 in the Supporting Information). The bulky substituents prevent the participation of an oxygen atom in the intermolecular interactions.

Conclusions

In a natural way, it seemed legitimate to raise a question about the advantage of di(1-naphthyl)methane probe over benzhydryl and other similar probes described so far. Among the compounds characterized by the presence of the sec-butyl inductor group attached to the bi- or trichromophoric probe, a comparison to benzhydryl-based probe sensitivity in chirogenesis was reported for an N-(1,8-naphthaloyl)-2-aminobenzoyl derivative (|A|/ε = 1.80 × 10–4).[57] Derivatives containing the trityl group, namely (R)-trityl-2-butyl ether and triphenylacetamide of (S)-2-butylamine, are characterized by different sensitivities. Whereas the sensitivity estimated for the O-trityl group is quite high (|A|/ε = 2.42 × 10–4) and comparable to 1e, the amide is less sensitive to small changes in the inductor structure because of the significantly larger inductor–receptor distance.[65,68] The latter structural factor is also the reason for the low sensitivity of the biphenyl-based probe reported by Kuwahara et al. (|A|/ε = 8.00 × 10–5).[85] Although for effective chirality transmission, the bent molecular structure is not a necessary condition, it significantly improves the sensitivity of the probe.

On the other hand, the shortcomings of the di(1-naphthyl)methyl probe should also be reported here. Similar to other probes, the correlation between the sign of induced ECEs and the structure is straightforward for inductors having aliphatic groups flanking the stereogenic center, which significantly differ in size. Therefore, for compounds of type 1e, 2b, and 4b, the plus or minus sign of the exciton couplet corresponds directly to S and R ACs of the stereogenic center. Compound 9b is a special case because the Me group is by volume larger than a phenyl group but less important in the determination of the AC according to the CIP rules. However, the calculations indicate that the decisive factors for the dynamic induction of chirality in compounds studied here can be attributed to weak CH···O or CH···π interactions. Therefore, the simply “mechanical” model, which takes into account only the bulkiness of substituents did not perform well in the cases where subtle interactions determine the structure. Thus, in such cases (5b, 8b, and 10b), the reverse correlation is visible, that is, the negative couplet corresponds to the S AC. Moreover, the larger the share of this type of interaction in the stabilization of the structure, the greater the solvent dependence of ECD output is visible. In the most demanding case of 5b, the change of the environment to highly polar caused diminishing of the respective CEs. Some chromophoric systems, especially aromatic, in the inductor structure might have an influence on the CE’s pattern in a way that cannot be a priori predicted. Thus, the extensive theoretical studies are compulsory in such cases, which in turn, make it difficult to define general “correlating” rules.

To sum up this paragraph, we feel empowered to state that the di(1-naphthyl)methyl probe is highly sensitive to even small structural differences in the inductor skeleton. The spectacular sensitivity of the di(1-naphthyl)methane probe to the remote molecular chirality is illustrated with 3-hydroxytetrahydrofurane derivative 5b. Although the sterical difference between an oxygen atom and the methylene group flanking the stereogenic center is negligible, the transfer of chirality is observed.

Finally, the awareness of the advantages and disadvantages of this and other similar probes can significantly help in the design and synthesis of new systems of this and other types.

Experimental Section

General Information

Unless otherwise noted, all reactions were carried out in air atmosphere. Tetrahydrofuran was dried by distillation over potassium. Deuterated chloroform (CDCl3), solvents, and other chemicals were purchased from commercial suppliers and used as received without further purification.

1H and 13C{H} NMR spectra were recorded on a Bruker Ascend 600 MHz spectrometer at room temperature. Chemical shifts are reported in parts per million (ppm). Spectra are referenced using an internal reference (trimethylsilane or CDCl3 residual solvent peak). Data is described as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad), coupling constants (Hz), and integration. Thin-layer chromatography (TLC) was carried out using Sigma-Aldrich precoated TLC plates (60 Å medium pore diameter with fluorescent indicator 254 nm). Melting points were measured on a BUCHI B-545 apparatus. High-resolution mass spectra (HRMS) were measured on a Bruker Impact HD spectrometer. Optical rotations were recorded on a Jasco P-2000 polarimeter at 20 °C. ECD and UV spectra were measured using a Jasco J-810 spectropolarimeter at room temperature in cyclohexane and acetonitrile solutions and with the use of a quartz cell of optical length 0.05 cm. The concentration of the ether solutions ranged from 1.2 to 2.5 × 10–4 mol L–1. Background spectra of the pure solvents were recorded from 400 to 185 nm with a scan speed of 100 nm min–1. The ECD spectra of ether samples were measured with 8 accumulations.

For the X-ray diffraction experiment details and calculation details, see the Supporting Information.

The general procedure for the synthesis of di(1-naphthyl)methanol, di(2-naphthyl)methanol, di(2-methoxyphenyl)methanol, and di(4-methoxyphenyl)methanol was based on the procedure described by Lin et al.[86] Compound 1b was obtained according to the procedure described by Ściebura and Gawroński.[71]

General Procedure for the Synthesis of Inductor–Reporter Systems

The general procedures for the synthesis of respective ethers were based on the modified procedures described by Sharma et al.[87]

General Procedure for the Synthesis of Inductor–Reporter Systems 1e, 1f, 2b–8b, and 10b

To a 10 mL round-bottom flask containing diarylmethanol (1 equiv, 1.06 mmol), chiral alcohol 1a–8a or 10a (1.1 equiv, 1.16 mmol), and FeCl3 (0.1 equiv, 0.11 mmol), CH2Cl2 (4 mL) was added. The flask was then sealed, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with CH2Cl2 (15 mL) and washed with water (2 × 25 mL) and brine (1 × 25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to afford a yellow-to-brown oil. The corresponding ethers were purified by column chromatography, crystallization, or both.

(R)-1,1′-(sec-Butoxymethylene)dinaphthalene (1e)

White crystals, mp 106–108 °C, 20% yield (71 mg). 1H NMR (600 MHz, CDCl3): δ 8.21–8.17 (m, 2H), 7.90–7.83 (m, 2H), 7.78 (dd, J = 7.8, 5.0 Hz, 2H), 7.54 (t, J = 6.8 Hz, 2H), 7.47–7.43 (m, 4H), 7.40 (q, J = 7.7 Hz, 2H), 7.05 (s, 1H), 3.71 (q, J = 6.0 Hz, 1H), 1.85–1.77 (m, 1H), 1.64–1.55 (m, 1H), 1.30 (d, J = 6.1 Hz, 3H), 0.87 (t, J = 7.5 Hz, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 137.6, 137.2, 134.0, 131.7, 131.6, 128.9, 128.9, 128.35, 128.3, 126.4, 126.21, 126.17, 126.1, 125.50, 125.47, 125.43, 125.39, 123.8, 123.7, 75.2, 74.3, 29.4, 19.3, 10.0. HRMS (ESI-Q-TOF), m/z: [M + Na]+ calcd for C25H24NaO, 363.1725; found, 363.1696. Optical rotation [α]D20 −22.5 (c = 1.00, CHCl3).

(R)-2,2′-(sec-Butoxymethylene)dinaphthalene (1f)

Colorless oil, 24% yield (29 mg). 1H NMR (600 MHz, CDCl3): δ 7.88 (d, J = 4.0 Hz, 2H), 7.82 (t, J = 6.5 Hz, 2H), 7.77 (m, 4H), 7.49 (d, J = 8.7 Hz, 2H), 7.47–7.40 (m, 4H), 5.80 (s, 1H), 3.55 (h, J = 6.1 Hz, 1H), 1.71 (m, 1H), 1.63–1.51 (m, 1H), 1.23 (d, J = 6.1 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 140.6, 140.1, 133.23, 133.18, 132.9, 132.8, 128.2, 128.04, 128.03, 128.0, 127.7, 127.6, 126.1, 126.00, 125.97, 125.8, 125.7, 125.59, 125.56, 125.4, 80.7, 74.2, 29.4, 19.4, 9.9. HRMS (ESI-Q-TOF), m/z: [M + Na]+ calcd for C25H24NaO, 363.1725; found, 363.1698. Optical rotation [α]D20 −69.2 (c = 1.00, CHCl3).

(S)-1,1′-((Octan-2-yloxy)methylene)dinaphthalene (2b)

Colorless oil, 12% yield (52 mg). 1H NMR (600 MHz, CDCl3): δ 8.20 (q, J = 4.3, 3.8 Hz, 2H), 7.89–7.81 (m, 2H), 7.77 (t, J = 7.7 Hz, 2H), 7.54 (dd, J = 7.4, 3.0 Hz, 2H), 7.46–7.41 (m, 4H), 7.40 (dt, J = 10.7, 7.8 Hz, 2H), 7.04 (s, 1H), 3.75 (h, J = 6.1 Hz, 1H), 1.82–1.70 (m, 1H), 1.61–1.49 (m, 1H), 1.30 (d, J = 6.2 Hz, 3H), 1.29–1.25 (m, 2H), 1.24–1.16 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 137.6, 137.1, 134.0, 131.6, 131.5, 128.9, 128.8, 128.3, 128.2, 126.4, 126.2, 126.06, 126.05, 125.42, 125.39, 125.34, 125.31, 123.7, 123.6, 74.2, 73.8, 36.8, 31.8, 29.4, 25.4, 22.6, 19.8, 14.1. HRMS (ESI-Q-TOF), m/z: [M + Na]+ calcd for C29H32NaO, 419.2351; found, 419.2336. Optical rotation [α]D20 +9.0 (c = 1.18, CHCl3).

(S)-1,1′-(((3,7-Dimethyloct-6-en-1-yl)oxy)methylene)dinaphthalene (3b)

White crystals, mp 75–78 °C, 11% yield (46 mg). 1H NMR (600 MHz, CDCl3): δ 8.07–8.01 (m, 2H), 7.92–7.86 (m, 2H), 7.84–7.77 (m, 2H), 7.53–7.43 (m, 4H), 7.42–7.33 (m, 4H), 6.80 (s, 1H), 5.05 (t, J = 7.1 Hz, 1H), 3.81–3.71 (m, 2H), 2.02–1.95 (m, 1H), 1.95–1.86 (m, 1H), 1.81–1.72 (m, 1H), 1.65 (s, 3H), 1.64–1.59 (m, 1H), 1.56 (s, 3H), 1.55–1.51 (m, 1H), 1.38–1.30 (m, 1H), 1.17–1.09 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 136.54, 136.51, 134.0, 131.86, 131.86, 131.1, 128.79, 128.78, 128.5, 126.18, 126.15, 125.83, 125.80, 125.5, 125.4, 124.8, 123.9, 123.8, 78.1, 68.7, 37.2, 37.1, 29.5, 25.7, 25.4, 19.5, 17.6. HRMS (ESI-Q-TOF), m/z: [M + Na]+ calcd for C31H34NaO, 445.2507; found, 445.2509. Optical rotation [α]D20 −1.7 (c = 0.96, CHCl3).

Menthyl-di(1-naphthyl)methyl Ether (4b)

White crystals, mp 82–85 °C, 10% yield (30 mg). 1H NMR (600 MHz, CDCl3): δ 8.31 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.87–7.85 (m, 1H), 7.81 (dd, J = 12.7, 7.5 Hz, 2H), 7.76 (t, J = 8.1 Hz, 2H), 7.62 (d, J = 7.0 Hz, 1H), 7.50–7.40 (m, 4H), 7.40–7.34 (m, 2H), 7.08 (s, 1H), 3.35 (td, J = 10.4, 4.1 Hz, 1H), 2.38–2.32 (m, 1H), 2.31–2.25 (m, 1H), 1.64–1.53 (m, 2H), 1.39–1.32 (m, 1H), 1.22 (br, 1H), 1.07 (q, J = 11.9 Hz, 1H), 0.88 (d, J = 6.5 Hz, 3H), 0.87–0.80 (m, 2H), 0.78 (d, J = 7.1 Hz, 3H), 0.27 (d, J = 6.9 Hz, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 138.8, 137.6, 133.82, 133.78, 131.8, 131.0, 128.9, 128.8, 128.1, 127.9, 127.1, 126.1, 125.9, 125.6, 125.4, 125.34, 125.28, 125.2, 123.7, 123.3, 76.4, 72.3, 48.7, 40.7, 34.5, 31.5, 24.9, 22.9, 22.5, 21.3, 15.8. HRMS (ESI-Q-TOF), m/z: [M + K]+ calcd for C31H34KO, 461.2247; found, 461.2240. Optical rotation [α]D20 −150.4 (c = 1.04, CHCl3).

(3S)-3-(Di(naphthalen-1-yl)methoxy)tetrahydrofuran (5b)

White solid, mp 147–148 °C, 11% yield (27 mg). 1H NMR (600 MHz, CDCl3): δ 8.20–8.11 (m, 2H), 7.91–7.86 (m, 2H), 7.81 (t, J = 7.6 Hz, 2H), 7.52 (d, J = 7.2 Hz, 1H), 7.50–7.37 (m, 7H), 6.94 (s, 1H), 4.43 (br, 1H), 4.06 (d, J = 9.4 Hz, 1H), 3.96 (q, J = 7.9 Hz, 1H), 3.85–3.77 (m, 2H), 2.26–2.19 (m, 1H), 2.07–2.00 (m, 1H). 13C{H} NMR (151 MHz, CDCl3): δ 136.4, 136.3, 134.0, 131.6, 131.5, 129.0, 128.9, 128.7, 126.39, 126.38, 126.4, 126.3, 125.61, 125.59, 125.4, 125.3, 123.54, 123.45, 78.3, 76.3, 72.4, 67.2, 33.0. HRMS (ESI-Q-TOF), m/z: [M + K]+ calcd for C25H22KO2, 393.1257; found, 393.1252. Optical rotation [α]D20 +9.4 (c = 1.00, CHCl3).

3-Di(naphthalen-1-yl)methoxy-Δ5-cholestene (6b)

White crystals, mp 209–211 °C, 28% yield (190 mg). 1H NMR (600 MHz, CDCl3): δ 8.21–8.13 (m, 2H), 7.90–7.86 (m, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.52–7.43 (m, 6H), 7.43–7.37 (m, 2H), 7.12 (s, 1H), 5.32 (dt, J = 5.9, 1.8 Hz, 1H), 3.55 (tt, J = 11.1, 4.5 Hz, 1H), 2.63–2.57 (m, 1H), 2.53–2.46 (m, 1H), 2.17–2.11 (m, 1H), 2.01–1.90 (m, 2H), 1.88–1.68 (m, 3H), 1.52–1.28 (m, 10H), 1.18–1.02 (m, 6H), 1.02–0.98 (m, 3H), 0.98–0.92 (m, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.85 (dd, J = 6.6, 2.6 Hz, 6H), 0.84–0.80 (m, 1H), 0.66 (s, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 140.9, 137.09, 137.05, 134.0, 131.6, 131.5, 128.9, 128.40, 128.37, 126.20, 126.17, 126.1, 125.5, 125.38, 125.37, 123.6, 123.5, 121.8, 78.1, 74.3, 56.7, 56.1, 50.1, 42.3, 39.8, 39.6, 39.5, 37.3, 36.9, 36.2, 35.8, 31.9, 31.9, 28.9, 28.2, 28.0, 24.3, 23.80, 22.81, 22.6, 21.0, 19.4, 18.7, 11.9. HRMS (ESI-Q-TOF), m/z: [M + K]+ calcd for C48H60KO, 691.4281; found, 691.4253. Optical rotation [α]D20 −1.7 (c = 0.98, CHCl3).

17β-Di(naphthalen-1-yl)methoxy-4-androsten-3-on (7b)

Off-white solid, mp 248–251 °C, 54% yield (250 mg). 1H NMR (600 MHz, CDCl3): δ 8.32 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.7 Hz, 2H), 7.78 (dd, J = 19.1, 8.2 Hz, 2H), 7.62 (d, J = 7.1 Hz, 1H), 7.51–7.39 (m, 6H), 7.36 (t, J = 7.7 Hz, 1H), 6.87 (s, 1H), 5.69 (s, 1H), 3.59 (t, J = 8.4 Hz, 1H), 2.43–2.27 (m, 3H), 2.21 (d, J = 14.4 Hz, 1H), 2.03–1.92 (m, 3H), 1.86–1.73 (m, 2H), 1.68–1.58 (m, 1H), 1.57–1.47 (m, 3H), 1.45–1.36 (m, 1H), 1.36–1.25 (m, 1H), 1.14 (s, 3H), 1.06–0.97 (m, 1H), 0.94–0.76 (m, 6H). 13C{H} NMR (151 MHz, CDCl3): δ 199.5, 171.2, 137.7, 136.9, 133.90, 133.89, 131.7, 131.6, 128.8, 128.31, 128.29, 126.44, 126.36, 126.0, 125.44, 125.38, 125.3, 125.2, 124.12, 124.05, 123.8, 86.9, 76.6, 53.9, 50.2, 43.1, 38.6, 37.1, 35.7, 35.4, 33.9, 32.7, 31.5, 27.5, 23.4, 20.6, 17.4, 11.9. HRMS (ESI-Q-TOF), m/z: [M + H]+ calcd for C40H43O2, 555.3263; found, 555.3245. Optical rotation [α]D20 +11.7 (c = 1.00, CHCl3).

(2S)-Di(naphthalen-1-yl)methoxy-succinic Acid (8b)

White oil, 3% yield (15 mg). 1H NMR (600 MHz, CDCl3): δ 8.40 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 7.1 Hz, 1H), 7.52–7.40 (m, 6H), 7.35 (t, J = 7.7 Hz, 1H), 7.27 (s, 1H), 4.52 (t, J = 6.4 Hz, 1H), 3.65 (s, 3H), 3.55 (s, 3H), 2.87 (d, J = 6.4 Hz, 2H). 13C{H} NMR (151 MHz, CDCl3): δ 171.7, 170.3, 136.1, 135.0, 134.0, 133.9, 131.7, 131.5, 129.0, 128.9, 128.74, 128.69, 126.7, 126.4, 126.3, 126.3, 125.7, 125.5, 125.4, 125.2, 124.0, 123.5, 73.0, 52.1, 51.8, 38.0. HRMS (ESI-Q-TOF), m/z: [M + K]+ calcd for C27H24KO5, 467.1261; found, 467.1245. Optical rotation [α]D20 −30.1 (c = 0.91, CHCl3).

Methyl (S)-2-(di(naphthalen-1-yl)methoxy)-2-phenylacetate (10b)

White crystals, mp 129–130 °C, 2% yield (10 mg). 1H NMR (600 MHz, CDCl3): δ 8.29 (dd, J = 7.6, 1.9 Hz, 1H), 7.89 (dd, J = 7.3, 2.1 Hz, 1H), 7.84 (dd, J = 12.4, 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.50–7.33 (m, 10H), 7.25 (s, 1H), 7.06 (s, 1H), 5.06 (s, 1H), 3.67 (s, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 171.3, 136.4, 135.8, 135.4, 134.0, 133.9, 131.8, 131.5, 128.9, 128.8, 128.7, 128.6, 128.1, 126.8, 126.4, 126.3, 126.2, 125.64, 125.56, 125.4, 125.3, 124.0, 123.6, 78.8, 75.8, 52.2. HRMS (ESI-Q-TOF), m/z: [M + Na]+ calcd for C30H24NaO3, 455.1623; found, 455.1620. Optical rotation [α]D20 −3.1 (c = 0.74, CHCl3).

General Procedure for the Synthesis of Inductor–Reporter Systems 1c, 1d and 9b

To a 10 mL round-bottom flask containing diarylmethanol (1 equiv, 1.23 mmol), chiral alcohol 1a or 9a (1.1 equiv, 1.35 mmol), and Yb(OTf)3 (0.1 equiv, 0.12 mmol), CH2Cl2 (4 mL) was added. The flask was then sealed, and resulting mixture was stirred at room temperature overnight. The white precipitate was filtered out, and the solution was concentrated in vacuo to afford a yellow oil. The corresponding ethers were purified by column chromatography and crystallization (9b).

(R)-2,2′-(sec-Butoxymethylene)bis(methoxybenzene) (1c)

White solid, mp 78–80 °C, 19% yield (71 mg). 1H NMR (600 MHz, CDCl3): δ 7.40 (dd, J = 7.6, 1.7 Hz, 1H), 7.31 (dd, J = 7.6, 1.7 Hz, 1H), 7.23–7.18 (m, 2H), 6.91 (dt, J = 15.0, 7.5 Hz, 2H), 6.86–6.80 (m, 2H), 6.29 (s, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.43 (h, J = 6.1 Hz, 1H), 1.72–1.62 (m, 1H), 1.52–1.42 (m, 1H), 1.17 (d, J = 6.1 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 157.3, 157.0, 131.3, 130.9, 128.5, 128.2, 128.1, 128.0, 120.3, 110.6, 110.5, 74.8, 68.4, 55.5, 29.3, 19.4, 10.0. HRMS (ESI-Q-TOF), m/z: [M + Na]+ calcd for C19H24NaO3, 323.1623; found, 323.1626. Optical rotation [α]D20 −27.8 (c = 1.01, CHCl3).

(R)-4,4′-(sec-Butoxymethylene)bis(methoxybenzene) (1d)

Colorless oil, 48% yield (237 mg). 1H NMR (600 MHz, CDCl3): δ 7.27–7.22 (m, 4H), 6.84 (d, J = 8.3 Hz, 4H), 5.40 (s, 1H), 3.77 (s, 6H), 3.41 (h, J = 5.8 Hz, 1H), 1.66–1.59 (m, 1H), 1.53–1.44 (m, 1H), 1.15 (d, J = 6.1 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 158.8, 158.7, 135.8, 135.3, 128.5, 128.1, 113.61, 113.60, 79.6, 73.7, 55.24, 55.22, 29.3, 19.3, 9.9. HRMS (ESI-Q-TOF), m/z: [M + Na]+ calcd for C19H24NaO3, 323.1623; found, 323.1620. Optical rotation [α]D20 −36.3 (c = 1.05, CHCl3).

(R)-1,1′-((1-Phenylethoxy)methylene)dinaphthalene (9b)

White crystals, mp 155–156 °C, 13% yield (30 mg). 1H NMR (600 MHz, CDCl3): δ 7.91 (d, J = 7.1 Hz, 1H), 7.88 (dd, J = 8.3, 4.4 Hz, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.44–7.38 (m, 5H), 7.37–7.32 (m, 2H), 7.29–7.20 (m, 4H), 6.79 (s, 1H), 4.61 (q, J = 6.5 Hz, 1H), 1.59 (d, J = 6.5 Hz, 3H). 13C{H} NMR (151 MHz, CDCl3): δ 142.7, 137.0, 136.6, 134.0, 133.9, 131.7, 131.2, 128.8, 128.6, 128.53, 128.46, 128.2, 128.1, 127.8, 126.6, 126.1, 125.9, 125.5, 125.42, 125.36, 125.3, 123.64, 123.61, 76.1, 73.7, 23.4. HRMS (ESI-Q-TOF), m/z: [M + K]+ calcd for C29H24KO, 427.1464; found, 427.1449. Optical rotation [α]D20 −123.9 (c = 1.16, CHCl3).