Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 2235−2243
Design and Synthesis of Open-Chain Hosts Having a Partial Structure of p-tert-Butylthiacalixarene Naoya Morohashi,* Kazuki Nanbu, Hayato Sonehara, Jun Ogihara, Takanori Shimazaki, and Tetsutaro Hattori* Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, 6-6-11 Aramaki-Aoba, Aoba-ku, Sendai 980-8579, Japan S Supporting Information *
ABSTRACT: The development of separation materials for hardto-separate molecular mixtures is highly desired from environmental and economic perspectives. Although the crystal of p-tertbutylthiacalix[4]arene exhibits high guest selectivity in inclusion from a mixture of molecules with similar sizes and shapes, it cannot include molecules larger than its calix cavity. To extend its guest inclusivity, we designed and synthesized an open-chain host, [3,3′-thiobis(5-tert-butyl-2-hydroxybenzene)-1,1′-diyl]diacetic acid (4). The competitive inclusion among toluidine isomers using compound 4 gave inclusion crystals containing the p-isomer in 1:1 (host/guest) ratio, with lesser amounts of other isomers and/or solvent molecules. The isomer selectivity varied between 66% and 97% depending on the solvent employed. X-ray analysis of inclusion crystals 4·p-toluidine·MeCN and 4·p-toluidine·(o-toluidine)0.5 revealed that compound 4 includes p-toluidine by forming macrocyclic 2:2 inclusion complex(es) and that its higher-order structure has vacant spaces, in which molecules other than p-toluidine are included. Compound 4 was then transformed into monopropyl ester 5 to fill the vacant spaces with propyl moieties. Compound 5 included p-toluidine with high selectivity (∼96%) without the coinclusion of other molecules, regardless of the solvent employed.
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INTRODUCTION The development of separation materials for molecular mixtures that are difficult to separate by simple crystallization and distillation is highly desired from environmental and economic perspectives. Nanoporous materials such as zeolites,1 metal− organic frameworks (MOFs),2 and covalent organic network polymers (COFs)3 have been extensively studied for the capture, separation, and storage of inorganic gases and organic compounds. Nanoporous molecular crystals (NMCs) consisting of discrete molecules with only weak noncovalent interactions have also been studied for these purposes.4 Unlike other nanoporous materials, a considerable number of NMCs have no empty-channel structures.5 These NMCs have been classified as NMCs with “porosity without pores”,6 and they include guest molecules, accompanied by a structural change in the crystal packing. Because of differences in the activation energies (kinetic factor) for the formation of respective clathrates and in the lattice energies (thermodynamic factor) of the resulting crystals, they have potential to precisely discriminate molecules similar in size and shape. Calixarenes (e.g., compounds 1 and 2) are used as host molecules to construct this type of NMCs.7−11 We recently found that a crystal of p-tert-butylthiacalix[4]arene (2) selectively includes ethanol from an equimolar mixture of methanol and ethanol, because of its kinetic and thermodynamic favorability.11a In competitive inclusion between dimethylamine and trimethyl© 2018 American Chemical Society
amine, the crystal included the individual amines with high selectivities (97−98%) in solutions of different polarities under kinetic and thermodynamic control.11d Switching of guest selectivity was also observed in the competitive inclusion between formic acid and propionic acid using a metastable crystal polymorph of compound 2;11e complete selectivity toward individual acids was achieved by changing the temperature under kinetic and thermodynamic controls. Although compound 2 exhibits high performance in discriminating molecules similar in size and shape, as shown in these examples, the inclusion with the crystal of compound 2 has a low upper limit on the guest size because of its narrow calix cavity and the packing structure of the resulting inclusion crystals.11c It is difficult to increase this limit by simple expansion of the ring size while maintaining the guest selectivity, as suggested by the fact that p-tert-butylthiacalix[6]arene includes some guest molecules inside and/or outside the calix cavity, therefore locating the guest molecules in heterogeneous environments.12 With the aim of developing NMCs with both high guest selectivity and applicability, we have designed and synthesized open-chain hosts that have a partial structure of compound 2. Received: December 13, 2017 Published: January 31, 2018 2235
DOI: 10.1021/acs.joc.7b03137 J. Org. Chem. 2018, 83, 2235−2243
Article
The Journal of Organic Chemistry Scheme 1. Synthesis of Compounds 4 and 5a
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RESULTS AND DISCUSSION Design and Synthesis of Open-Chain Hosts 4 and 5. We previously studied on the chemical modification of a sulfurbridged phenol tetramer that has a structure formally derived from p-tert-butylthiacalix[4]arene by removing a sulfur atom from the macrocycle and capping the termini of the resulting open chain with hydrogen atoms.13 Dicarboxylic acid 3 derived from the phenol tetramer formed a macrocyclic dimer through a couple of intermolecular hydrogen bonds between the carboxy groups.13a With the aim of constructing a similar cyclic structure through intermolecular hydrogen bonds, we designed a sulfurbridged phenol dimer that has carboxy groups at the ortho positions to the hydroxy groups through methylene linkers (4). This compound was further modified to half ester 5 on the basis of crystallographic considerations of its inclusion crystals (vide infra).
Reagents and conditions: (a) Br2, CH2Cl2, 0 °C to rt, 95%; (b) MeI, K2CO3, acetone, reflux, 97%; (c) BuLi, hexane, −78 °C to rt; then DMF, THF, −78 °C to rt, 65%; (d) PPh3, CBr4, CH2Cl2, 0 °C, 99%; (e) pyrrolidine, H2O, rt, 98%; (f) NaH, C8H17SH, DMF, 100 °C, 97%; (g) KOH, EtOH, H2O, reflux, 85%; (h) PrOH, HCl, rt, 38%. a
stirred for 24 h, and then the crystals were separated from the solution and analyzed by 1H NMR spectroscopy to determine the inclusion ratio (n̅i), which is defined as the mean number of guest molecules (i) included in the crystals per host molecule. As compound 4 mainly included p-toluidine, the selectivity toward p-toluidine (Sp) was calculated according to eq 1. Sp = np̅ /(no̅ + nm̅ + np̅ ) × 100
(1)
The results are listed in Table 1. Compound 4 included ptoluidine with an np̅ value of ∼1, and o-toluidine, m-toluidine, and Table 1. Competitive Inclusion among Toluidine Isomers with Compound 4a n̅
Compounds 4 and 5 were readily prepared from bisphenol 614 according to Scheme 1. Thus, bisphenol 6 was brominated with bromine in dichloromethane to give dibromide 7. After protecting the hydroxy groups with iodomethane (8), the dibromide was lithiated with butyllithium and then formylated with DMF to give dialdehyde 9. The dialdehyde was subjected to Wittig reaction with a phosphonium ylide derived from tetrabromomethane and triphenylphosphine.15 This led to the formation of bis(dibromoethylene) 10, which was treated with pyrrolidine by a literature procedure16 to give diamide 11. Removal of the methyl groups from 11 using sodium octanethioate, followed by alkaline hydrolysis of the amide moieties, furnished the desired diacid 4 in an overall yield (based on the starting bisphenol 6) of 48%. Further, acid-catalyzed esterification of diacid 4 with propan-1-ol under mild conditions delivered half ester 5 in 38% yield. Competitive Inclusion among Toluidine Isomers with Compound 4. The molecular recognition ability of compound 4 was evaluated based on the competitive inclusion of toluidine isomers. To a solution containing equimolar amounts of three regioisomers of toluidine were added powdery crystals of compound 4 at room temperature. The crystals once dissolved in the solution and inclusion crystals precipitated immediately or gradually, depending on the solvent employed. The mixture was
entry
solvent
o
m
p
solvent
Sp (%)
1 2 3 4 5 6 7
hexane toluene cyclohexane xylenesb mesitylene acetonitrile benzene
0.30 0.25 0.23 0.24 0.27 −c 0.02
0.18 0.14 0.16 0.16 0.20 0.03 0.04
0.94 0.92 0.96 0.95 0.99 0.97 0.96
−c 0.11 0.14 0.09 0.02 0.37 0.75
66 70 71 70 68 97 94
Conditions: 4 (11−22 μmol), toluidine isomers (220 μmol each), solvent (0.5−1.0 mL), 24 h, rt. bA mixture of o-, m-, and p-xylene and ethylbenzene in a molar ratio of 12:66:14:8. cInclusion was not observed. a
solvent molecules with the sum of n̅ values of ∼0.5 for most of the solvents employed (entries 1−5). For acetonitrile and benzene, however, it mainly coincluded solvent molecules, thus giving high isomer selectivities (Sp = ∼ 97%) (entries 6 and 7). It should be noted that thiacalixarene 2 does not form inclusion crystals with any of the regioisomers.17 X-ray Crystallographic Analysis of Compound 4 and Its Inclusion Crystals with Toluidine Isomers. To gain insight into the inclusion behavior of compound 4, X-ray crystallographic analysis was carried out. A prerequisite single crystal of 2236
DOI: 10.1021/acs.joc.7b03137 J. Org. Chem. 2018, 83, 2235−2243
Article
The Journal of Organic Chemistry compound 4 was prepared by slow diffusion of hexane vapor into a solution of compound 4 in ethyl acetate, while single crystals of inclusion complexes formulated as 4·p-toluidine·MeCN and 4·ptoluidine·(o-toluidine)0.5 were obtained by crystallizing compound 4 from an acetonitrile solution of p-toluidine and from a toluene solution containing equimolar amounts of o- and ptoluidine, respectively. The crystal of compound 4 belongs to the orthorhombic system with the Pccn space group (Z = 4). The two benzene rings of compound 4 adopt an antiperiplanar conformation with a dihedral angle of 165° (Figure 1a). A hydrogen bond is observed
Figure 1. X-ray structure of compound 4: (a) molecular structure, (b) interactions between adjacent layers, and (c) a parallel cross-section to the a−b plane. Selected distances: H1···S1 (2.506 Å), H11B···A′′′ (2.753 Å), H11A···O2′′′ (2.634 Å), S1′′···A (3.500 Å), H3A···O2′′ (1.789 Å).
between each hydroxy group and the epithio linkage. Two host molecules related by an inversion center are connected through an intermolecular hydrogen bond between each one of carboxy groups; repetition of this connection results in a zigzag chain along the [1 1 0] direction (Figure 1c). The zigzag chains are arranged parallel to the a−b plane, and the resulting layer and another layer, having the structure in which the mirror images of the molecules in the former layer in regard to the a−b plane are rotated 180° around the [1 1 0] direction, pile up alternately along the c-axis. Each molecule is connected to two neighboring molecules in the upper and lower layers along the c-axis through S−π interactions and CH−π interactions (Figure 1b), thereby leading to tight packing. As a result, there are no voids that are capable of accommodating guest molecules in the crystal. Inclusion crystal 4·p-toluidine·MeCN belongs to the triclinic system with the P1̅ space group (Z = 2). The two benzene rings of compound 4 adopt a periplanar conformation with a dihedral angle of 19.5°, with the aid of consecutive hydrogen bonds from one hydroxy group to the distal carboxy group through the other hydroxy group (Figure 2a). This carboxy group is converted into a carboxylato group through salt formation with the amino group of a toluidine molecule. The other carboxy terminus of the host molecule is connected to the resulting ammonio group through a
Figure 2. X-ray structure of 4·p-toluidine·MeCN: (a) 4·p-toluidine salt, (b) a dimer of the salt (dimer complex) and acetonitrile molecules interacting with it, (c) a column constructed by the dimer complexes along the a-axis, (d) a parallel cross-section to the b−c plane, and (e) a parallel cross-section to a−b plane. Interactions between unitary components in (a−c), as well as intramolecular hydrogen bonds in (a), are shown as dotted lines. In (e), pore channels between columns, which accommodate acetonitrile molecules, are shown as solventaccessible surfaces calculated after removing the coordinates of the acetonitrile molecules. Selected interatomic distances: H1···O3 (1.791 Å), H2···O1 (2.276 Å), H1B···O6A (1.917 Å), H1C···O3 (1.865 Å), H21···C1 (2.899 Å), H21···C18 (2.976 Å), H25···O3′ (2.608 Å), H1A··· O4′ (1.885 Å), C27···O5A (3.215 Å), H5A···O4″ (1.753 Å). 2237
DOI: 10.1021/acs.joc.7b03137 J. Org. Chem. 2018, 83, 2235−2243
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The Journal of Organic Chemistry hydrogen bond in such a way that the host molecule surrounds the toluidine molecule, forming a pseudomacrocyclic 1:1 (host/ guest) inclusion complex. CH−π interactions are observed between a hydrogen atom of the toluidine molecule at the ortho position to the ammonio group and the two benzene rings of the host molecule. Furthermore, two salts related by an inversion center are gathered to form a 2:2 complex by virtue of a couple of hydrogen bonds between ammonio hydrogens and carboxylato oxygens, and those between hydrogen atoms at the ortho positions to the ammonio groups and the other oxygen atoms of the carboxylato groups (Figure 2b). The dimer complex has such a geometry that thiacalixarene 2 with a 1,2-alternate conformation includes two p-toluidine molecules. However, the ring size of the dimer complex expands to a greater extent than that of thiacalix[6]arene; the distance between the sulfur atoms of the dimer complex is 15.046 Å, while the longest distance between facing sulfur atoms of thiacalix[6]arene with a 1,2,3-alternate conformation is 11.903 Å.12b Two adjacent dimer complexes are connected through a couple of hydrogen bonds between carboxy and carboxylato groups, thereby forming an infinite columnar structure along the a-axis (Figure 2c). Interconnected voids of 218 Å3 per unit cell are observed between two adjacent columns along the a-axis (Figure 2e). Each void accommodates two acetonitrile molecules (Figure 2d). A hydrogen bond is observed between the methyl group of each acetonitrile molecule and a carboxy group of an adjacent dimer complex (Figure 2b). Inclusion crystal 4·p-toluidine·(o-toluidine)0.5 belongs to the triclinic system with the P1̅ space group (Z = 4). There are two independent salts between compound 4 and p-toluidine. One of them forms a dimer complex (A) by the same intramolecular and intermolecular interactions as seen in the dimer complex in 4·ptoluidine·MeCN (Figure 3a and b), except that a hydrogen atom of the toluidine molecule at the ortho position to the ammonio group forms a CH−π interaction only with a benzene ring of the host molecule including the toluidine molecule (Figure 3a compared with Figure 2a) and that a couple of hydrogen bonds between hydrogen atoms at the ortho positions to the ammonio groups and oxygen atoms of the carboxylato groups are not observed (Figure 3b compared with Figure 2b). Two adjacent dimer complexes A are connected through a couple of hydrogen bonds between their benzyl hydrogens and carboxylato oxygens, resulting in an infinite columnar structure along the a-axis (Figure 3c). The other independent salt forms another dimer complex (B) having a similar structure to that of complex A, and intermolecular hydrogen bonds between dimer complexes B construct an infinite columnar structure along the a-axis (Figure S1 in the Supporting Information). The two different columns constructed by dimer complexes A and B pile up alternately along the b-axis (Figure 3d) with disconnected voids [226 Å3 or 243 Å3, depending on the disordered structures of complex B (see the Supporting Information)] between them (Figure 3e). In each void, an o-toluidine molecule is included with the aid of intermolecular hydrogen bonds with two adjacent dimer complexes A; they are N···HO and NH···O bonds with a carboxy and a carboxylato group of one complex, respectively (Figure 3b) and an NH···O bond with a hydroxy group of the other complex (Figure 3c). As mentioned above, although the crystal of compound 4 shows tight packing with no vacant space to accommodate guest molecules, it includes p-toluidine by forming macrocyclic 2:2 inclusion complexes, which are connected through intermolecular hydrogen bonds to form infinite columnar structures.
Figure 3. X-ray structure of 4·p-toluidine·(o-toluidine)0.5: (a) 4·ptoluidine salt, (b) a dimer of the salt (dimer complex A) and o-toluidine molecules interacting with it, (c) a column constructed by complex A along the a-axis, (d) a parallel cross-section to the b−c plane, and (e) a parallel cross-section to the a−b plane. Interactions between unitary components in (a−c), as well as intramolecular hydrogen bonds in (a), are shown as dotted lines. In (e), disconnected voids between columns, 2238
DOI: 10.1021/acs.joc.7b03137 J. Org. Chem. 2018, 83, 2235−2243
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The Journal of Organic Chemistry
shows TGA desorption curves of these inclusion crystals. The inclusion crystal of m-toluidine desorbed acetonitrile gradually from room temperature to ∼110 °C and m-toluidine rapidly at ∼130 °C, and then decomposed at ∼200 °C. The weight of the sample decreased by 3.6% from room temperature to ∼110 °C and by 18.4% at ∼130 °C, consistent with the respective theoretical weight losses of 1.5% and 18.4% as calculated from the sample composition. On the other hand, the inclusion crystal of p-toluidine gradually lost weight in a temperature range of 30− 290 °C; the weight loss was only ∼10% even at 180 °C, before which all the m-toluidine was desorbed from its inclusion crystal. Therefore, it may be concluded that the selective inclusion of ptoluidine in the competitive experiments (Table 1) is attributed to the stability of the resulting inclusion crystals, originating from not only the highly symmetric structure of the para isomer but also its high basicity. Improvement of Guest Selectivity by Chemical Modification of Compound 4. The inclusion crystals of ptoluidine with compound 4 have pore channels or disconnected voids, in which undesired molecules are included. Therefore, it is desired to create a host molecule that forms inclusion crystals with no vacant space. In 4·p-toluidine·(o-toluidine)0.5, one carboxy hydrogen of compound 4 is necessary to form a salt with p-toluidine. However, as shown in Figure 3b, the other carboxy hydrogen not only does not contribute to the construction of the dimer complex and its higher-order structure, but also assists the inclusion of o-toluidine in the vacant space by forming a hydrogen bond. We reasoned that the inclusion of otoluidine could be avoided by derivatizing the carboxy group into an ester group. With the aim of filling the vacant space, we chose a propyl group as the ester alkyl moiety because it has the same number of heavy atoms as that of acetonitrile. Competitive inclusion of toluidine isomers was then carried out using monopropyl ester 5. As the half ester was more soluble in nonpolar solvents, especially aromatic solvents, than diacid 4, the experiment was conducted at a lower temperature (0 °C) and hexane was used as a cosolvent when needed. We found that compound 5 included p-toluidine with essentially the same selectivity as compound 4 in acetonitrile and benzene (Sp = ∼ 96%), without including solvent molecules (Table 2). The
Figure 3. continued which accommodate o-toluidine molecules, are shown as solventaccessible surfaces calculated after removing the coordinates of otoluidine molecules. Selected interatomic distances: H1···O2 (2.486 Å), H2···O5 (1.778 Å), H1A···O5 (1.906 Å), H1B···O3 (1.870 Å), H23··· C8 (2.937 Å), H4···N3 (1.912 Å), H1C···O6′ (1.856 Å), H3B···O6′ (2.399 Å), H3A···O1″ (2.402 Å), H18A···O6‴ (2.593 Å).
Stacking of the columns leaves pore channels or disconnected voids, in which molecules other than p-toluidine (i.e., acetonitrile or o-toluidine) are included. From these observations, we reasoned that the high inclusion selectivity toward p-toluidine in the competitive experiment using benzene (entry 7 in Table 1) as well as acetonitrile is attributed to the inclusion of the solvent in the vacant space. Conversely, the inferior selectivity toward the other solvents is attributed to the inclusion of o- and m-toluidine in the vacant space, instead of the solvents. The interaction of the macrocyclic 2:2 inclusion complex with o-toluidine in 4·p-toluidine·(o-toluidine)0.5 is apparently stronger than that with acetonitrile in 4·p-toluidine·MeCN (Figure 3b compared with Figure 2b). However, the vacant space left between columns constructed by the dimer complexes was filled not with o-toluidine but with acetonitrile in the competitive inclusion conducted in acetonitrile (entry 6 in Table 1). This is attributed to the difference in the concentrations of acetonitrile and o-toluidine used as a solvent and guest, respectively. In order to confirm this notion, a competitive inclusion was conducted from a solution containing equimolar amounts of p-toluidine, otoluidine, and acetonitrile in mesitylene, which is not included in the vacant space. The experiment actually gave inclusion crystals containing p-toluidine (n̅ = 1.01, Sp = 69%) and o-toluidine (n̅ = 0.45) with a similar composition ratio to that of 4·p-toluidine·(otoluidine)0.5. Thermogravimetric Analysis (TGA) of Inclusion Crystals of Compound 4 with Toluidine Isomers. When compound 4 was immersed in acetonitrile solutions of mtoluidine and p-toluidine, inclusion crystals with composition ratios of 1:0.96:0.21 (4/m-toluidine/MeCN) and 1:0.99:0.41 (4/p-toluidine/MeCN) were obtained, respectively. On the other hand, no inclusion crystals were obtained from an acetonitrile solution of o-toluidine. Powder X-ray diffraction analysis revealed that the inclusion crystal of p-toluidine has the same crystal lattice as that of 4·p-toluidine·MeCN, whereas the inclusion crystal of m-toluidine dose not (Figure S6). Figure 4
Table 2. Competitive Inclusion among Toluidine Isomers with Compound 5a n̅ entry
solvent
o
m
p
solvent
Sp (%)
1b 2 3 4
hexane toluene/hexane acetonitrile benzene/hexane
−c −c −c −c
0.04 0.06 0.06 0.07
0.90 0.90 0.90 0.89
−c −c −c −c
96 94 94 93
Conditions: 5 (20.5 μmol), toluidine isomers (205 μmol each), solvent (0.5−1.0 mL), 24 h, 0 °C. bConducted at rt. cInclusion was not observed.
a
presence of the m-isomer in the resulting crystals is attributed to the separate formation of its inclusion crystals besides those of the p-isomer, as shown in the following X-ray analysis. A single crystal formulated as 5·p-toluidine was obtained by diffusion of hexane vapor into a toluene solution containing compound 5 and p-toluidine in a molar ratio of 1:30. An X-ray analysis was then carried out as shown in Figure 5. The crystal belongs to the triclinic system with the P1̅ space group (Z = 2). Compound 5 forms a dimer (2:2) complex with p-toluidine
Figure 4. TGA desorption curves for the inclusion crystals of m- and ptoluidine with compound 4 prepared in acetonitrile. The composition ratios of the crystals are 1:0.96:0.21 (4/m-toluidine/MeCN) and 1:0.99:0.41 (4/p-toluidine/MeCN), respectively. 2239
DOI: 10.1021/acs.joc.7b03137 J. Org. Chem. 2018, 83, 2235−2243
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The Journal of Organic Chemistry
(Figure 5d). The volumes of an acetonitrile, o-toluidine, and propyl group in the crystals are 41.87 Å3, 100.09 Å3 on average, and 49.80 Å3, respectively, indicating that two propyl moieties are sufficient to fill the vacant space. Competitive Inclusion among Toluidine Isomers with Compound 5 under Practical Conditions for Isomer Separation. We have shown that compound 5 exhibited high selectivity in the competitive inclusion in solutions containing a large excess of toluidine isomers (10 molar equiv each) regardless of the solvent used (Table 2). Going a step further, we tested its inclusivity in solutions containing equimolar amounts of toluidine isomers to compound 5, aiming for the practical use of this compound for isomer separation. The experiments were carried out by decreasing the amounts of toluidine isomers (21.0 μmol each) under conditions similar to those listed in Table 2. Although inclusion crystals were not obtained from acetonitrile and toluene, hexane gave crystals mainly including the p-isomer with a small amount of the m-isomer (Sp = 87%) at room temperature. A similar inclusion experiment was conducted on a large scale, and the resulting crystals were dissolved in chloroform and passed thorough an alumina column to dissociate inclusion complexes using chloroform as the eluent, which gave p-enriched toluidine (87% purity) in 70% yield based on compound 5 (see the Experimental Section).
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CONCLUSION We have prepared novel open-chain host compounds 4 and 5 that have a partial structure of p-tert-butylthiacalixarene. They selectively included p-toluidine from solutions containing three regioisomers of toluidine. This illustrates that ring opening is an efficient way to extend the guest applicability of thiacalix[4]arene. However, the crystals of compounds 4 and 5 are not solid absorbents as they dissolved during the inclusion. To prevent dissolution, further modification, i.e., increasing the molecular weights and/or introducing less soluble functional groups, is necessary. The application of compounds 4 and 5 to otherwise difficult separation of amines, including aliphatic ones, is underway. The results will be reported in the near future.
Figure 5. X-ray structure of 5·p-toluidine: (a) 5·p-toluidine salt, (b) a dimer of the salt (dimer complex), (c) a column constructed by the dimer complexes along the a-axis, and (d) a parallel cross-section to the b−c plane. Interactions between unitary components in (a−c), as well as intramolecular hydrogen bonds in (a) are shown as dotted lines. Selected interatomic distances: H3A···O1 (1.737 Å), H4···O3 (2.407 Å), H1A···O6 (1.896 Å), H1B···O1 (1.868 Å), H33···C1 (2.879 Å), H29···O1′ (2.549 Å), H1C···O2′ (1.807 Å), H23A···C30′′ (2.880 Å), H23B···O2′′ (2.520 Å), H25B···O1′′′ (2.650 Å).
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EXPERIMENTAL SECTION
General Methods. Melting points were taken using a micro melting point apparatus and are uncorrected. 1H NMR and 13C NMR spectra were measured using tetramethylsilane as an internal standard and CDCl3 as a solvent, unless otherwise noted. High resolution mass spectra (HRMS) were measured using a double focusing mass spectrometer. Silica gel 60 (63−200 μm) was used for column chromatography. Water- and air-sensitive reactions were routinely carried out under nitrogen. DMF (CaSO4), acetone (CaSO4), dichloromethane (CaH2), and hexane (Na) were distilled from dehydrating agents indicated in the parentheses and stored under nitrogen. Dry THF (water content
