Heterochiral Diastereomer-Discriminative Diphanes That Form Hierarchical Superstructures with Nonlinear Optical Properties.

In order to study the emergence of homochirality during complex molecular systems, most works mainly concentrated on the resolution of a pair of enantiomers. However, the preference of homochiral over heterochiral isomers has been overlooked, with very limited examples focusing only on noncovalent interactions. We herein report on diastereomeric discrimination of twin-cavity cages (denoted as diphanes) against heterochiral tris-(2-aminopropyl)amine (TRPN) bearing triple stereocenters. This diastereomeric selectivity results from distinct spatial orientation of reactive secondary amines on TRPN. Homochiral TRPNs with all reactive moieties rotating in the same way facilitate the formation of homochiral and achiral meso diphanes with low strain energy, while heterochiral TRPNs with uneven orientation of secondary amines preclude the formation of cage-like entity, since the virtual diphanes exhibit considerably high strain. Moreover, homochiral diphanes self-assemble into an acentric superstructure composed of single-handed helices, which exhibits interesting nonlinear optical behavior. Such a property is a unique occurrence for organic cages, which thus showcases their potential to spawn novel materials with interesting properties and functions.

Introduction

Life employs chirality as a pervasive tool from molecular to macroscopic scales to realize self-reproduction and physiological functions,[1] and yet the selection of homochirality remains mysterious.[2] Since Pasteur’s seminal work on chiral resolution of enantiomers from tartrate racemates during crystallization,[3] numerous artificial systems have been developed for a mechanistic interpretation of emergence of homochirality in molecular[4] and supramolecular[5] levels. The majority of these works focused on deracemization and/or chiral resolution from a pair of enantiomers. On the other hand, how homochiral isomers are favored over their heterochiral counterparts in multiple diastereomer-containing systems has been rarely studied,[6] and the insofar limited examples exclusively exploited noncovalent interactions.

In the present work, we have devised a model study to investigate if nonchiral molecules can distinguish homochiral isomers from their heterochiral analogues. To this end, a nonchiral hourglass-like hexa-aldehyde precursor is chosen to react with tris-(2-aminopropyl)amine (TRPN) bearing three chiral centers, which might form a twin-cavity cage denoted as diphane (Figure ).[7] An organic cage[8] is deemed as an ideal model for such a purpose: (i) the reversible nature of dynamic covalent chemistry (DCC) involved in its synthesis favors the formation of the thermodynamic product; (ii) its formation results from a delicate interplay between its three-dimensional framework and the spatial orientation of the multiple stereocenters within TRPN. By using experimental and theoretical approaches, we will elucidate the rationale behind the selective formation of homochiral diphanes and their achiral meso counterpart.

Figure 1

Selective formation of three diphanes, their self-assembly behavior in the crystalline phase, and different second-harmonic generation (SHG) responses. Nonchiral hexa-aldehyde compound 1 only reacts with racemic triamine rac-2 ((3R)-TRPN: (3S)-TRPN = 1:1), rather than hetero-2 ((2R1S)-TRPN : (1R2S)-TRPN = 1:1), to yield (3R,3R)-3, (3S,3S)-3 and (3R,3S)-3. Chiral diphanes (3R,3R)-3 and (3S,3S)-3 crystallize into noncentrosymmetric trigonal space group P3221 and P3121 with active SHG response, whereas achiral meso diphane (3R,3S)-3 crystallizes into centrosymmetric triclinic space group P1̅ that is SHG-silent.

We also investigate the self-assembly of homochiral and achiral diphanes, which serve as supramolecular building blocks for the construction of hierarchical superstructures. With the aids of single-crystal X-ray diffraction (SC-XRD) and circular dichroism (CD), we reveal that this configurational change of the cages yields superstructures with dramatically different molecular packing.[9] It in turn results in distinct emergent functions, as demonstrated by their second-order nonlinear optical (NLO) properties as a proof of concept (Figure ).

Results and Discussion

Diastereomeric Discrimination of Heterochiral TRPN during Diphane Formation

We first attempted the cycloimination reaction between nonchiral hexa-aldehyde precursor 1 and racemic mixture rac-2 composed of a pair of (R,R,R)- and (S,S,S)-TRPN (denoted (3R)- and (3S)-TRPN, Figure a). The matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) of the crude reaction mixture showed a major ion peak at m/z 1456.587, which corresponds to the expected diphane with the formula C104H95N8+ ([M + H]+ calcd for 1456.771, Figure S16) for rac-3′ in the imine form. Diphane rac-3′ was further reduced with NaBH(AcO)3, which yielded rac-3 in the amine form so as to facilitate the product purification. The careful characterization of rac-3 will be discussed in the next session (Figure ). On the other hand, the reaction between precursor 1 and heterochiral TRPN was unable to yield any cage entity. This scenario was exemplified with hetero-2 containing equal amount of epimers (2R1S)- and (1R2S)-TRPN (Figure S4). Out of 21 possible isomeric diphanes (Figure S7), none was formed with hetero-2, as they were even undetectable by MALDI-TOF MS (Figures S18 and S19).

Figure 2

(a) Cycloimination of nonchiral hexa-aldehyde 1 with racemic triamine rac-2 containing equal amount of (3R)- and (3S)-TRPN, followed by the reduction with NaBH(AcO)3, yielding rac-3 containing three diphanes (3R,3R)-3 (25%), (3R,3S)-3 (50%), and (3S,3S)-3 (25%) in an overall yield of 12%. (b) Chiral HPLC chromatograms of (3S,3S)-3 (magenta curve), (3R,3R)-3 (cyan curve), (3R,3S)-3 (blue curve), and rac-3 (black curve). (c) 1H NMR spectra (CD2Cl2, 400 MHz, 298 K) of (3R,3R)- or (3S,3S)-3 (magenta curve), (3R,3S)-3 (blue curve), and rac-3 (black curve). (d) Electronic circular dichroism (top) and UV–vis absorption spectra (bottom) of (3S,3S)-3 (magenta curve), (3R,3R)-3 (cyan curve) and (3R,3S)-3 (blue curve).

This striking difference is that during the formation of a cage-like entity with a three-dimensional skeleton, nonchiral hexa-aldehyde 1 obviously prefers the homochiral to heterochiral isomers, although the reaction with the latter cannot be excluded in the resulting oligomers with an ill-defined structure. Taking (3R)-TRPN (one enantiomer in rac-2) and (2R1S)-TRPN (one epimer in hetero-2) for comparison, their different spatial orientation can be revealed by density functional theory (DFT with geometry optimization, M06-2X/6-31G*, Figure a). The three aliphatic chains of (3R)-TRPN all rotate anticlockwise, with three secondary amines being positioned in the same way; while the three aliphatic chains of (2R1S)-2 are arranged in an uneven fashion, as one secondary amine rotates to the opposite direction of the other two.

Figure 3

DFT calculations and inspection of structural effect of rac-2 and hetero-2 on the formation of diphanes in the imine form (denoted (3R,3R)-3′ for example). (a) DFT calculations reveal that homochiral enantiomers (3R)- and (3S)-TRPN adopt regular orientations, whereas heterochiral (2R1S)- and (1R2S)-TRPN prefer disordered orientations. (b) Comparison of strain energy (SE) of homochiral diphane (3R,3R)-3′, achiral mesomer (3R,3S)-3′, and two virtual products, namely, heterochiral (2R1S,2R1S)-3′ and (2R1S,1R2S)-3′. The spatial orientations of the TRPN-derived moieties dissected from the corresponding (virtual) diphanes are given on the right side for comparison. Amines are in blue color. Hydrogen atoms are omitted for clarity.

We reasoned that the spatial orientation of these reactive amines might dramatically alter the formation possibility of diphanes. This hypothesis was probed by the comparison of SE of the diphanes (or virtual products) in the imine form (Figure b).[7b] DFT calculations show that (3R,3R)-3′ exhibits a similar strain to that of mesomer (3R,3S)-3′ (122.6 vs 119.9 kJ mol–1). This strain is lower than those of virtual diphanes formed with heterochiral precursors, with the representative examples of (2R1S,2R1S)-3′ with SE = 127.6 kJ mol–1 and (2R1S,1R2S)-3′ with SE = 127.2 kJ mol–1. Together with the experimental evidence, this significantly different SE therefore precludes the reaction with heterochiral TRPN during the formation of diphanes.

Formation of Homochiral and Achiral Meso Diphanes

As mentioned above, the condensation between precursor 1 with rac-2 successfully yielded diphane in the imine form, which was then converted to the corresponding rac-3 in the amine form to facilitate product purification (Figure a). We successfully resolved rac-3 by chiral HPLC, which consists of three isomeric fractions in a 1:1:2 ratio (Figure b), respectively assigned to a pair of homochiral (3R,3R)-3 and (3S,3S)-3, and an achiral mesomer (3R,3S)-3 with reference compounds synthesized beforehand (Figures S5 and S6). In the 1H NMR spectrum of rac-3, the sharp singlet at δ = 7.03 ppm and the doublet at δ = 4.06 ppm refer to homochiral diphane (3R,3R)-3 or (3S,3S)-3, while the broad peak at δ = 7.06 ppm and the doublet at δ = 3.95 ppm correspond to the mesomer (3R,3S)-3 (lower panel in Figure c, see assignment in Figure S64). This product distribution in rac-3 is in accordance with DFT calculations, which showed little SE difference between the diphanes in the imine form (Figure , vide supra).

Electronic CD spectra of the three diphanes in tetrahydrofuran (THF) solutions were recorded (Figure d). Owing to similar structures, they share almost identical UV–vis absorption spectra. They all display a featureless absorption peak at ca. 250 nm, which is assigned to the π → π* transitions of the twisted arenes in the cage skeleton. Obviously, meso diphane (3R,3S)-3 is CD-silent due to the presence of the inversion center, while the two homochiral diphanes exhibit a mirror-image profile over the range between 220 and 300 nm, as expected for the enantiomeric pair.

Diphane (3R,3R)-3 displays a positive cotton effect at 263 nm, followed by a negative one at 250 nm. This bisignate CD curve from longer to shorter wavelength (300–245 nm) is assigned to the P-configuration of three biphenyl arms of each propeller-like cavity. Similarly, the negative-to-positive bisignate curve is attributed to the M-configuration of diphane (3S,3S)-3. As compared to the previously reported single-cavity cages,[10,11] the value for the anisotropy factor of two chiral diphanes is relatively low (gabs = 0.0004 at 240 nm). This low value probably results from the relatively higher symmetry of the upper and lower halves of the diphanes (Figure a, vide infra).

Figure 4

Hierarchical self-assembly of homochiral (3R,3R)-3 molecules into the 3D acentric crystalline phase (trigonal space group P3221). (a) Stick model of the primary structure (3R,3R)-3 (left) and its top view (right) with three cyan arrows indicating the clockwise rotation of three aliphatic chains of TRPN-derived moiety. (b) Supramolecular dimer (secondary structure) self-assembled by (3R,3R)-3 molecules via C–H···π interactions, simplified with a cuboid model. (c) Top view (top) and side view (bottom) of 32-helix (tertiary structure) with a helical pitch of 41.9 Å, self-organized by the cuboids (secondary structure) rotating by 120o via C–H···π interactions. (d) Latitudinal packing of the helices yields the trigonal crystalline phase (quaternary structure). Three helical columns are interconnected via C–H···π interactions.

3D Hierarchical Structures Self-Assembled by Homochiral and Meso Diphanes

We[9b,12b,12c] and other groups[8b,10b,12a,12d,12e] have demonstrated that cage-like compounds could serve as promising self-assembling tectons for the search of novel supramolecular materials. As part of our continuous endeavor, we investigated the self-assembly behavior of homochiral and achiral meso diphanes in their crystalline phases. We were particularly interested in the effect of configurational change on the resulting hierarchical superstructures.

Single crystals of two homochiral diphanes suitable for XRD were obtained by gradual evaporation of the solvent from their solutions in THF/CH3CN = 1:4 (v/v) at a concentration of 15 mg/mL. Diphanes (3R,3R)-3 and (3S,3S)-3 crystallized into chiral superstructures of trigonal space group P3221 and P3121, respectively. We use (3R,3R)-3 to represent homochiral diphane in the following discussion, and the structural analysis of (3S,3S)-3 is given in Figures S12 and S13.

Its crystallographic analysis confirms the proposed structure of (3R,3R)-3 with two identical cavities (Figures a and S9). Each cavity exhibits a diameter of 10.6 Å and a height of 6.4 Å. From the top view of a diphane, three aliphatic chains of each cavity adopt a clockwise rotation (cyan arrows, Figure a), which also holds true for the three methyl groups at the R-stereogenic centers. This clockwise rotation also induces the P-configuration of three biphenyl arms surrounding each cavity, in line with its CD spectrum (Figure d, vide supra).

Careful inspection of molecular packing of the homochiral diphanes reveals that each crystalline phase is a hierarchical superstructure, which share the similarity with those formed by biomacromolecules, block copolymers, and dendimers.[13] Serving as the primary structure, two (3R,3R)-3 molecules self-assemble into a supramolecular dimer (secondary structure), simplified with a cuboid model, where the two adjacent diphanes are packed via quadruple C–H···π interactions (with d1 = 2.9 Å and d2 = 3.1 Å, Figures b and S10).

These dimers are arranged off crystallographic c-axis, around which a dimer rotates by 120° with respect to another, forming a single-handed 32-helix (tertiary structure) with a pitch of 41.9 Å (Figure c). Besides, along the helix, each diphane in the dimer below is packed with another diphane in the dimer above via C–H···π interaction with a distance of 2.8 Å (Figure c and S10). One helix is consequently packed in parallel with six neighboring helices via a network of C–H···π interactions (d4 = 2.8 Å), as presented with the simplified spring-like model (Figures d and S11). This hierarchical self-assembly thus yields an acentric trigonal crystalline phase (quaternary structure), which is composed of an array of left-handed helices.[6c,6,14]

The superstructure of achiral (3R,3S)-3 was also examined by XRD analysis of the single crystals obtained via slow evaporation of its solution in CHCl3/CH3OH = 1:4 (v/v) at a concentration of 15 mg/mL. (3R,3S)-3 molecules instead crystallized into centrosymmetric crystalline phase of triclinic space group P1̅. The detailed structural analysis of this superstructure is illustrated in Figure S14.

NLO Properties of Hierarchical Superstructures Self-Assembled by Homochiral and Achiral Meso Diphanes

As mentioned above, diphanes (3S,3S)-/(3R,3R)-3 and (3R,3S)-3 respectively self-assemble into acentric and centrosymmetric superstructures, which may endow them with different properties and functions. As a proof of concept, we explored their quadratic NLO effect, namely, SHG activity. In a typical SHG process, as mediated by the transition through a virtual energy state, two incident photons with frequency ω interact within an acentric medium, which subsequently are converted into an emitted photon with a doubled frequency 2ω (inset in Figure c). Compared to conventional inorganic dielectrics and semiconductors, organic NLO counterparts exhibit advantages such as light weight, large nonlinear coefficient, and flexibility,[15] which thus hold promise for the application in soft photo-electronics and photonics.

Figure 5

Different second-order nonlinear optical properties of three diphane crystals. (a) Optical and (b) SHG mapping images (λex = 1064 nm) of (3R,3R)-3 crystal within an 80 × 80 μm region. (c) SHG signal (532 nm) of (3R,3R)-3, (3R,3S)-3, and (3S,3S)-3 single crystals under excitation with a 1064 nm laser (Inset: illustration of fundamental principle of SHG). (d) SHG intensities of (3R,3R)-3 excited at various wavelengths from 840 to 1080 nm, represented with different colors. (e) Excitation power dependence of the SHG intensity at 480 nm (λex = 960 nm) for (3R,3R)-3 single crystals, with both axes shown on a logarithmic (log) scale. The fitted linear line satisfies the function y = 1.87x + 0.24, where y = lg[SHG intensity] and x = lg[excitation power]), and the fitted slope of ca. 2 confirms a typical second-order NLO process.

We first irradiated the single crystals of diphanes (3S,3S)-3, (3R,3R)-3, and (3R,3S)-3 with a Nd-yttrium-aluminum-garnet (Nd:YAG) laser beam (1064 nm, 20 Hz, 8 ns) at an angle of 45°. As shown with partial optical (Figure a) and SHG mapping (Figure b) images of a (3R,3R)-3 single crystal, for example, it exhibits a clear SHG response at 532 nm (right side of the dashed line), which is only active for the noncentrosymmetric crystalline phase. This is evident when compared with the substrate on which the crystal is deposited (left side of the dashed line, Figure b), where negligible output was observed. On the other hand, no SHG signal was detected for the centrosymmetric crystalline phase of achiral (3R,3S)-3 (Figure S15c). When the SHG response of the three diphanes was recorded in the transmission direction, the difference is unambiguous, as both homochiral (3S,3S)-3 and (3R,3R)-3 display strong and sharp peaks, while that of (3R,3S)-3 is near zero (Figure b). It is worth noting that we intentionally selected different sizes of single crystals of the two diphanes, so as to avoid the overlap of their SHG intensity.[16]

To further explore the NLO property of the superstructures formed by homochiral diphanes, at a fixed pumping power, the wavelength-dependent SHG behavior[15b,16] of a (3R,3R)-3 single crystal was investigated with different wavelengths (λex = 840–1080 nm, Figure d). It shows that the intensity of optical signals indeed varies with wavelength, with the highest photoluminescence intensity under excitation at λex = 960 nm. Moreover, both the fitted linear relationship between SHG intensity (λem = 480 nm) and excitation power (W, λex = 960 nm) on a logarithmic scale also reveals a typical second-order NLO behavior (Figure e).

Conclusions

In summary, we showed that among heterochiral and homochiral TRPN diastereomers, only the enantiomeric pair of homochiral isomers were selected by nonchiral hexa-aldehyde precursor 1 via cycloimination, forming the corresponding homochiral cages with twin-cavity (denoted (3R,3R)-/(3S,3S)-diphane) and their mesomer (3R,3S)-diphane. As revealed by DFT calculations, this discrimination of heterochiral isomers results from the different spatial orientation of reactive amines of TRPN. This example is distinct from the previous findings showing a similar reactivity of diastereomeric synthons under DCC conditions.[17]

We also showed that the self-assembly of homo- and achiral diphanes is dramatically different. The former forms an array of single-handed supramolecular helices with interesting second-order NLO properties, while the latter self-assembles into the centrosymmetric supramolecular columnar phase. Different from the current research focus of organic cages on their design, synthesis, and host–guest utility of their porosity,[8] our study showcases their promise with a tailored shape and structure for the search of a novel hierarchical superstructure with emergent properties and functions, which include but are not limited to nonlinear optics, bulk photovoltaics, and organic ferroelectrics. These topics are currently ongoing in our laboratories, which will be reported in due course.

Methods

Materials

Dimethyl terephthalate, phenyl lithium, aniline, tetrakis(triphenylphosphine)palladium, scandium(III) trifluorometha-nesulfonate, and phenol were purchased from Beijing J&K Chemical Co. Ltd. 2-Formylbenzeneboronic acid, (rac)-alaninol, (S)-alaninol, (R)-alaninol, and p-toluene sulfonyl chloride were purchased from Beijing InnoChem Co. Ltd. Sodium triacetoxyborohydride was purchased from Shanghai Adamas-Beta Co. Ltd. Inorganic salts including sodium nitrite, potassium carbonate, and potassium hydroxide were purchased from Greagent, China. THF was dried over sodium/benzophenone and distilled under a nitrogen atmosphere before use.

General Instrumentation

Nuclear magnetic resonance (NMR) spectra were performed on a Bruker Avance III HD 400 spectrometer at room temperature. MALDI-TOF MS was performed on a solariX XR 7.0 T hybrid quadrupole–FT ICR mass spectrometer (Bruker Daltonics, Bremen, Germany), using an ESI/APCI/MALDI ion source and external ion accumulation in positive ion mode. SC-XRD data were collected on a Bruker D8 Venture diffractometer. CD spectra were recorded on a Jasco J-1500 spectrometer at 25 °C. Analytical HPLC was conducted on a Shimadzu LC-20 AD system at 30 °C. The SHG measurement was conducted using a titanium–sapphire pulsed laser (Coherent, 140 fs pulse width, 80 MHz repetition rate).

Synthesis of Diphane Rac-3, (3S,3S)-3, (3R,3R)-3, and (3R,3S)-3

Rac-3

A 0.005 mol/L solution of hexa-aldehyde molecule 1 (200.0 mg, 0.168 mmol, 1 equiv) in 33.7 mL CHCl3 was charged into a 250 mL flask. Then a 0.005 mol/L solution of rac-2 (63.5 mg, 0.336 mmol, 2.0 equiv) in 67.5 mL CHCl3 was added dropwise, followed by addition of Sc(OTf)3 (50 mg, 0.10 mmol, 0.6 equiv) directly. The reaction mixture was stirred at 25 °C for 24 h. Then, the product was reduced by NaBH(OAc)3 (0.54 g, 2.53 mmol, 15.0 equiv) overnight, the excess reductant NaBH(OAc)3 was filtered off under vacuum, and the solution was quenched with NaOH solution (2.0 M, 120 mL), extracted with CHCl3 (3 × 50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product. Purification by flash column chromatography (DCM/MeOH/NH3(aq) = 150:2:3, v/v/v) afforded the diphane rac-3 (30 mg, 12%) as a white solid. HR-MS (MALDI): before reduction: C104H95N8+ [M + H]+, calcd: 1456.771; Found: 1456.587; after reduction: C104H107N8+ [M + H]+, calcd: 1468.865; Found: 1468.714.

(3S,3S)-3

A 0.005 mol/L solution of hexa-aldehyde molecule 1 (500.0 mg, 0.42 mmol, 1 equiv) in 84.3 mL CHCl3 was charged into a 500 mL flask. Then a 0.005 mol/L solution of (3S)-TRPN (158.7 mg, 0.84 mmol, 2.0 equiv) in 168.6 mL CHCl3 was added dropwise, followed by addition of Sc(OTf)3 (124.4 mg, 0.25 mmol, 0.6 equiv). The reaction mixture was stirred at 25 °C for 24 h. Then, the product was reduced by NaBH(OAc)3 (1.34 g, 6.32 mmol, 15.0 equiv) overnight, the excess reductant NaBH(OAc)3 was filtered off under vacuum, and the solution was quenched with NaOH solution (2.0 M, 300 mL), extracted with CHCl3 (3 × 150 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product. Purification by flash column chromatography (DCM/MeOH/NH3(aq) = 150:2:3, v/v/v) afforded the diphane (3S,3S)-3 (68 mg, 11%) as a white solid. 1H NMR (400 MHz, CD2Cl2, 298 K), δ = 7.05–7.57 (m, 52H), 4.07 (d, J = 12.0 Hz, 2H), 3.74 (d, J = 12.0 Hz, 2H), 3.62 (dd, J = 12.0 Hz, 12.0 Hz, 4H), 3.51 (d, J = 12.0 Hz, 2H), 3.37 (d, J = 12.0 Hz, 2H), 2.71–2.80 (m, 2H), 2.61–2.71 (m, 2H), 2.42–2.52 (m, 2H), 2.07–2.14 (m, 6H), 1.88–1.95 (m, 4H), 1.76 (d, J = 12.0 Hz, 2H), 1.13–1.19 (m, 18H). 13C NMR (101 MHz, CD2Cl2, 298 K), δ = 145.97, 145.82, 145.41, 144.53, 142.47, 142.20, 141.27, 139.64, 139.49, 139.03, 138.96, 138.26, 131.36, 130.84, 130.10,130.00, 129.79, 129.07, 128.44, 128.36, 127.89, 127.81, 127.68, 127.62, 127.41, 64.13, 63.68, 62.40, 61.58, 52.63, 52.20, 51.80, 50.26, 49.09, 20.85, 20.44, 19.69. HR-MS (MALDI): C104H107N8+ [M + H]+, calcd: 1468.865; Found: 1468.749.

(3 was obtained from hexa-aldehyde molecule 1 and (3R)-TRPN as starting materials, which was synthesized according the same procedure of (3.

(3R,3S)-3

A 0.005 mol/L solution of intermediate compound 4 (57.5 mg, 0.043 mmol, 1 equiv) in 8.7 mL CHCl3 was charged into a 25 mL flask. Then a 0.005 mol/L solution of (3R)-TRPN (8.2 mg, 0.043 mmol, 1.0 equiv) in 8.7 mL CHCl3 was added dropwise, followed by addition of Sc(OTf)3 (6.4 mg, 0.013 mmol, 0.3 equiv). The reaction mixture was stirred at 25 °C for 24 h. Then, the product was reduced by NaBH(OAc)3 (68.8 mg, 0.32 mmol, 7.5 equiv) overnight, the excess reductant NaBH(OAc)3 was filtered off under vacuum, and the solution was quenched with NaOH solution (2.0 M, 15 mL), extracted with CHCl3 (3 × 20 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product. Purification by flash column chromatography (DCM/MeOH/NH3(aq) = 150:2:3, v/v/v) afforded the (3R,3S)-3 (40 mg, 63%) as a white solid. 1H NMR (400 MHz, CD2Cl2, 298 K), δ = 7.06–7.50 (m, 52H), 3.95 (d, J = 12.0 Hz, 2H), 3.75 (d, J = 12.0 Hz, 2H), 3.65 (d, J = 12.0 Hz, 2H), 3.57 (d, J = 12.0 Hz, 2H), 3.52 (d, J = 12.0 Hz, 2H), 3.41 (d, J = 12.0 Hz, 2H), 2.62–2.78 (m, 4H), 2.43–2.52 (m, 2H), 1.87–2.07 (m, 10H), 1.57 (d, J = 12.0 Hz, 2H), 1.10–1.13 (m, 18H). 13C NMR (101 MHz, CD2Cl2, 298 K), δ = 146.10, 145.90, 145.51, 144.67, 142.51, 141.98, 139.96, 139.51, 139.46, 137.26, 131.80, 131.00, 130.45, 130.28, 130.04, 129.92, 129.48, 128.98, 128.51, 128.24, 128.11, 127.97, 127.89, 127.80, 127.39, 64.33, 62.75, 61.92, 61.17, 52.98, 52.13, 52.05, 51.65, 20.25, 19.57, 18.73. HR-MS (MALDI): C104H107N8+ [M + H]+, calcd: 1468.865; Found: 1468.863.