Synthesis of Central Chirality-containing Triarylmethanols and

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Synthesis of Central Chirality-containing Triarylmethanols and Triarylmethyl Radicals with Extraordinarily Stable Configurations Yingchun Li, Weixiang Zhai, Yongfang Liao, Jiangping Nie, Guifang Han, Yuguang Song, Shao-Yong Li, Jingli Hou, and Yangping Liu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01675 • Publication Date (Web): 27 Aug 2019 Downloaded from pubs.acs.org on August 30, 2019

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The Journal of Organic Chemistry

Synthesis of Central Chirality-containing Triarylmethanols and Triarylmethyl Radicals with Extraordinarily Stable Configurations Yingchun Li,# Weixiang Zhai,# Yongfang Liao, Jiangping Nie, Guifang Han, Yuguang Song, Shaoyong Li, Jingli Hou*, Yangping Liu*

Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, P. R. China. #

These authors contributed equally to this work.

E-mail: [email protected]; [email protected]

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract: Triarylmethanol adopts a propeller-shaped conformation with either right-handed (P) or left-handed (M) configuration. Herein, new triarylmethanols with two chiral centers were obtained via introduction of two cis-hydroxyl groups on the side chains, affording four stereoisomers. These four stereoisomers were easily separated by silica gel column chromatography into two pairs of propeller–shaped enantiomers as shown by NMR and X-ray crystallographic studies. HPLC studies showed that the configuration of the hydroxyl-bearing triarylmethanols is much more stable than the bulky tert-butyldimethylsilyl (TBS) protected precursors, inconsistent with the general strategy in which the steric repulsion is largely responsible for the configurational stability. Similarly, two hydroxyl-bearing TAM radicals also exhibit excellent configurational stability and are thus separable by CS-HPLC into four stereoisomers. Interestingly, both helical chirality from tri-aryl group (M or P) and central chirality (R and S) on the side chain have little effect on their electron paramagnetic resonance (EPR) properties. Our present study provides a new strategy to construct configurationally stable tri-aryl compounds and demonstrates that the side chain on TAM radicals is a new site for their structural modifications.


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Introduction Molecules with three aryl rings attached to a central atom (eg. tris-aryl methanes, tris-aryl amines and tri-aryl phosphine oxides) adopt chiral conformations in which all rings are twisted in the same sense with regard to a reference plane. These tri-aryl compounds are usually dubbed “molecular propellers”1-3. The stereoisomerism of these propeller-shaped molecules has attracted a lot of attention in the last four decades.4-6 In most case, such molecules are configurationally instable because of the easily reversed helicity at room temperature. Attempts were made to obtain configurationally stable molecular propellers by introduction of bulky substituents on the aryl ring(s) to restrict the rotation of the aryl rings around C-Z bonds (Z: the central atom such as P, B or C; C: the carbon atom on the aryl ring which is directly connected to the central atom Z) and thus generate residual stereoisomerism.7,8 Tetrathiatriarylmethyl radicals (TAM, trityl) are a new class of tri-aryl molecules and have single and narrow electron paramagnetic resonance (EPR) line9,10. These TAM radicals have attracted much attention due to their biomedical and biophysical applications as spin probes for EPR spectroscopy and imaging9,11-17, as spin labels for distance measurements in biomacromolecules18-24, and as polarizing agents for dynamic nuclear polarization (DNP)25-29. Similar to other tri-aryl molecules, TAM radicals also have the propeller-shaped structures which was firstly predicted by DFT calculation30 and then confirmed by X-ray crystallographic results9. The three aryl rings in TAM radical are nearly mutually orthogonally twisted out of plane, thus affording left-handed (M) and right-handed (P) helices (Fig. 1a). Due to the large steric hindrance of three aryl rings, the interconversion between the M and P helices is so slow that the two enantiomers are separable. The half-life of racemization for the two enantiomers of the ethyl ester derivative of TAM radical CT-03 was determined to be 343 h in ethyl acetate at room temperature which was much longer than the value (16.9 h) of the corresponding tetrathiatriarylmethanol under the same condition30,31. The introduction of 12 bulky tert-butyl ether groups on the methylene bridges tremendously lengthens its racemization half-life (1.36 years) relative to its analogue with 12 methyl groups (8.4 h)32. However, the para-substituent on the aryl ring plays a very minor role in the racemisation rate31. Interestingly, the para-substituents on the aryl rings change the molecular symmetry of TAM radicals. X-ray crystallographic results showed that the methyl ester derivative of CT-03 exhibits a strict C3 symmetry9, while the C3 symmetry is broken in the nitro derivative.31 Taken together, both the substituents on the para-position of the aryl ring and on the methylene bridge can have important effects on their molecular structures. These structural modifications could affect the spin density distribution of the unpaired electrons and change their EPR properties and electron relaxations. Therefore, understanding the factors affecting molecular structure is very helpful for the development of new TAM radicals.



(a)

S

S

-

S

OOC

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S COO-

S

S

-

S

OOC

COO-

S

enantiomerization S

S

C

S

S

S

S

S

S

S

S

S

S COO-

CT-03

CT-03 Left handed ( M)

S

Right handed ( P )

S S

S S

COO-

(b)

S

C

S

S

S

S

S

S

introduction of OH group S

C

S

S OH

S

S

S

S

S

S

C

S

S OH

S

S

S

S

HO

S OH

6

1

32 Figure 1. (a) Enantiomerization between the M and P helices of CT-03 ; (b) Design of configurationally stable triarymethanol 6 in which two

cis-hydroxyl groups are introduced into methylene bridges.

The great demand for TAM radicals has stimulated efforts towards development of new TAM analogues with the focus on the derivatization at the para-position of the three aryl rings33,34. Due to the synthetic difficulty, the TAM derivatives with the substituents on the methylene bridges are almost unexplored in the research community35,36, although these structural modifications provide new strategies to improve the physicochemical properties of TAM radicals. It is worth noting that the different substitution on the methylene bridge leads to the generation of an additional chiral center. As such, there is a need to investigate effects of the chiral center on the interconversion between the M and P helices as well as physicochemical properties of TAM radicals. To this end, in the present work, we synthesized a new class of central chirality-containing triarymethanols and their radicals via introduction of two cis-hydroxylmethyl group on methylene bridges (Fig. 1b). Four diastereoisomers of the triarymethanols were separated and their propeller-shaped conformations were verified by NMR spectroscopy and X-ray crystallography. The high configuration stability of the triarymethanols was studied by CS-HPLC. In addition, the electronic circular dichroism (ECD) and EPR spectra of the corresponding TAM radicals were also investigated. Our results show that introduction of hydroxylmethyl groups on the methylene bridge is a much simpler approach to construct configurationally stable triarylmethanol and triarylmethyl radical than the previous strategy using the very bulky substituents. The presence of the chiral center on the methylene bridge does not lead to any difference in EPR properties of TAM radicals, providing new strategy for their structural modification.

Results and Discussion Synthesis


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The asymmetric TAM radical 7 was synthesized through six steps from tetra-tert-butylthiobenzene 1 according to the previous methods with some modifications.36 As shown in Scheme 1, the diester 2 was firstly obtained in 80% yield by condensation of 1 with ethyl pyruvate in the presence of boron triflouride etherate (BF3-Et2O) and p-toluenesulfonic acid (TsOH). The two ester groups in 2 can be located either at the same or opposite sides relative to the plane consisting of the aryl ring and two five-membered rings. As such, the diester 2 has both cis- and trans- isomers which, unfortunately, are inseparable by silica gel column chromatography. Subsequent reduction of the diester 2 using LiAlH4 in THF afforded a mixture of cis and trans diols, which can be easily separated using silica gel column chromatography in the yields of 42% and 42% respectively. Note that only the cis isomer of the diol (i.e.,compound 3) is used in the present study in order to minimize the isomer numbers of the corresponding triarylmethanols and TAM radicals. X-ray crystal structure of the compound 3 (CCDC 1909525) confirmed its absolute configuration where two OH groups are located at the same side of the plane (Fig. S1). Then, two hydroxy groups of the compound 3 were protected using tert-butyldimethylsilyl chloride (TBSCl) in the presence of imidazole to afford the compound 4 in 85% yield. Thereafter,the compound 4 was lithiated with n-BuLi and tetramethylethylenediamine (TMEDA) in Et2O to produce the corresponding aryl anion which then reacted with the ketone34,36, which was obtained in an overall 48% yield over two steps from compound 1, to give the triarylmethanol 5 in 46% yield. At this step, separation of 5 was easily achieved on silica gel column chromatograpy to afford two pairs of enantiomers (i.e., 5-I and 5-II, see Fig. 2 below) with the ratio of 1:1. Finally, deprotection of 5-I and 5-II with tetrabutylammonium fluoride (TBAF) afforded the compounds 6-I and 6-II, which were further converted into the corresponding TAM radicals 7-I and 7-II, respectively, by treatment with trifluoroacetic acid (TFA) and Tin (II) chloride (SnCl2)37.

tBuS

StBu

tBuS

StBu

acetone p-toluenesulfonic acid BF3.Et2O

O

S

CHCl3,reflux

S

S

S

S

S

n-BuLi,(MeO)2CO S

ether

S

S

S

intermediate (88%)

1

ketone (55%)

S

S HO tBuS

ethyl pyruvate, BF3.Et2O, p-toluenesulfonic acid

StBu

EtOOC

CHCl3, reflux, 24h

StBu

tBuS

S

S

S

S

1

S

S

OH S S byproduct (42%)

LiAlH4 COOEt

THF, 0°C, 4h

S

S

S

S

TBSCl, Imidazole

HO

OH

2 (80%)

DMF, rt,12h

3 (42%)

S

S S S

S

S

S

TBSO

OTBS 4 (85%)

2)

1) n-BuLi, TMEDA ether, 0°C, 3-4h S S

OH

S

S

S

rt, 24h

S

S

S

S

TBSO

S

OTBS

S

S S

THF

S

S

S

S

TBAF S

S S

O

S

S

OH S

S

S

S

HO

S

Scheme 1. Synthetic route of asymmetric triarylmethanol 6 and its radical 7


6 (70%)

TFA, SnCl2

S S

S S

S

DCM OH

5(46%)

S

S

S

S

S

S

S

S

S

HO

OH 7(96%)


NMR studies on Propeller-Shaped Configuration of Triarylmethanols Two chiral elements exist in the triarylmethanol 5: axial chirality (M and P) from the three aryl rings and central chirality (R and S) from the two quaternary carbons which are linked to the CH2OTBS group. As mentioned above, the two CH2OTBS groups in the triarylmethanol 5 locate at the same side. Hence, it can be predicted that four chiral stereoisomers exist in 5, with the configurations as (M,S,R), (P,R,S), (P,S,R) and (M,R,S) (see Fig. 2a). During the purification process, the four isomers were easily separated into two pairs (named as 5-I and 5-II) by silica gel column chromatography. 1H and 13C{H} NMR spectra were recorded to characterize the structures of 5-I and 5-II. Two protons in each methylene group of 5-I are diastereotopic due to the central chirality of the bridge carbon as well as the axial chirality of the triarylmethanol. Accordingly, 1H NMR signals of the two methylene groups in 5-I consist of an AB system at 3.86 and 3.83 ppm (J = 9.6 Hz) for one methylene group along with two doublets at 3.93 and 3.76 ppm (J = 10.0 Hz) for the other methylene group (See Fig. 2b). H-H COSEY experiment of 5-I further confirmed correct assignment of the methylene protons (see Fig. S2). Due to the asymmetry of three aryl rings, three singlets at 7.10, 7.12 and 7.16 ppm were observed for three aromatic protons (see Fig. 2b). Based on the above results, it can be concluded that there is only one set of 1H NMR signals

in 5-I. Thus, the two isomers of 5-I are indistinguishable by 1H-NMR spectroscopy. Similar

results were also observed for 5-II except that two doublets was only observed for each methylene group in its 1H NMR spectrum. Of note is that the 1H-NMR signals from two of the four methylene protons in 5-II are overlapping, thus affording three groups of doublets (Fig. S3). The indistinguishable 1H NMR signals imply that the two isomers in either 5-I or 5-II are most likely a pair of enantiomers. (a) C

S OH S

S TBSO

M1

S

C

S

S

S

TBSO

OTBS

S A

S

S M, R, S

P, R, S M1

M1 S

S

C

S

R

M1

S

S

C

S

S A

S

B

C

OH S

S TBSO

S

S B

S

S

S

S

C S

OTBS

R

S

S

S

S OH S

S

S A

R

B

C

B C

S

S

S

S

S S

S

S

S

S

S OH S

S OTBS

TBSO

S M, S, R

5-I

S

S A

S

R

OTBS

S P, S, R

5-II

Fig 2. (a) Predicted stereoisomers of 5-I/5-II and their interconversion; M1 represents two-ring flip mechanism which involves one edge interchange 1 and two rings flips. (b) Partial H NMR spectrum of compound 5-I showing the peaks from protons on the methylene and aryl ring.

X-ray crystallographic study on 6-II X-ray crystallographic study is a reliable method to further conform if two enantiomers exist in both 5-I and 5-II, and


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what configurations they have. However, attempts to crystallize 5-I or 5-II were unsuccessful. Fortunately, crystals of 6-II, whose stereoisomers have the same absolute configurations with those of 5-II, were obtained from the mixed solvents consisting of DCM and n-hexane (1:4) in the refrigerator (4 ºC). As shown in Fig. 3, two mirror-image stereoisomers with the configurations as (M, R, S) and (P, S, R) were found in unit cell of 6-II (CCDC1881226). The presence of two enantiomers in 6-II is consistent with the NMR results from 5-I and 5-II. Similar to the X-ray structure of the previously reported triarylmethanol, the three aromatic rings in the two enantiomers of 6-II are twisted in the same direction; however their molecular structures lack an exact three-fold symmetry. For example, the bond lengths between the central carbon and three aromatic-carbons are slightly different with the values of 1.537, 1.545 and 1.542 (Ǻ) for the enantiomer (M, R, S). For the same enantiomer, the dihedral angles (73.84°, 72.77° and 73.87°) formed between the two nearest Cipso-Cortho bonds at two adjacent rings are also different (Table 1). In addition, the two five-membered rings fused to the aryl ring are twisted in the opposite direction on the two blades, whereas they are twisted in the same direction on another hydroxymethyl-containing blade. The same is true for the other enantiomer (P, S, R) of 6-II. Since the conversion from 5-I/5-II to 6-I/6-II does not change their molecular configurations, the two enantiomers in 5-I and 5-II have the same configurations as those in 6-I and 6-II, respectively. According to the proposed configurations for 5-I and 5-II, it can be deduced that 6-I also contains two enantiomers which have the configurations as (P, R, S) and (M, S, R).

Figure 3 The structures of the two enantiomers in the crystal of 6-II are shown in stick model using the Pymol software. Hydrogen atoms are omitted for clarity. Color code: green for carbon, orange for sulfur and red for oxygen. Table 1. Crystallographic data of two enantiomers in 6-II S

S S

S

Compound

B

C 1

S S

S OH

S 4 HO

2

3 S

S

6-II

d (C1-C2A)

θ2(CB3-CB2-CC2-CC4)

d (C1-C2B)

θ3(CC3-CC2-CA2-CA4)

d (C1-C2C)

73.84°/-72.24°

1.537 (3) Å/1.538 (3) Å

72.77°/-73.15°

1.545 (3) Å/1.548 (3) Å

73.87°/-71.21°

1.542 (3) Å/1.540 (3) Å

OH

A S

S

θ1(CA3-CA2-CB2-CB4)

6-II



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Configurational Stability of triarylmethanols It has been shown that the enantiomers of tri-aryl compounds can be interconverted with various half-life times, depending on the substituents on the aryl rings31,32. It is interesting to know if the substituents on the side chains affect this interconversion of the asymmetric tri-aryl compounds 5-I/5-II, 6-I/6-II and 7-I/7-II. To do so, the kinetics of racemization of their enantiomers were followed by HPLC. As shown in Fig. 4a, 5-II was gradually converted into 5-I upon heating at 64 °C in chloroform. The racemization rate constant (Krac) which is equal to two fold of Kenant (the rate of the enantiomerization) was determined by a first-order reversible kinetic equation (see SI). Gibbs activation energy of ΔG‡(25ºC), the activation enthalphy (ΔH≠) and entropy (ΔS≠) were derived by fitting Kenant at various temperatures to the Eyring equation (1)： ln(kenanth/kBT)= -ΔG/ kBT = ΔS≠/R-ΔH≠/RT

(1)

As shown in Table 2, the half-life time of the racemization (t1/2 = ln2/Krac) for the conversion of 5-I into 5-II was calculated to be 2.5 days at 25°C in CDCl3, which is much longer than that of the symmetric tris(tetrathioaryl)methanol 1 (Fig. 1, 8.4 h in DMSO)32. Similar ΔG‡(25ºC) and the half life of the racemization were also observed for the opposite conversion of 5-II into 5-I (See SI). The relatively stable configuration of the two residual enantiomers 5-I and 5-II is most likely due to the steric hindrance of the bulky group “TBS“ on the side chain, consistent with the previously reported results1,7.

Figure 4. (a) Racemization of 5-II monitored by HPLC. The solution of 5-II in CDCl3 was kept at 64 °C and aliquots of the sample were taken for HPLC analysis at different time (0h, 1h, 3h, 5h); (b) HPLC analysis 6-II after incubation in CDCl3 at 54 °C for 13 h or in toluene at 100 °C for 5h.

Table 2. Experimental parameters for the interconversion between 5-I and 5-II in CDCl3. Compound

∆H≠ [kJ/mol]

∆S≠ [J/mol ]

∆G≠[kcal/mol] (25ºC)

t1/2(25ºC)

5-I

73.3

-104.5

25.0

2.6 d

5-II

52.7

-173.3

24.9

2.5 d


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The interconversion between 6-I and 6-II was also studied by HPLC. Surprisingly, no conversion from 6-II to 6-I was observed upon heating at 54 °C for 13 h in CDCl3 or at 100 °C for 5 h in toluence (Fig. 4b). Similar result was also observed for the inverse conversion (Fig. S6). In contrast to 5-I/5-II, the high configuration stability of 6-I/6-II is not due to the steric hindrance of the substituents since the hydroxyl group in 6-I/6-II has much smaller size than the –OTBS group in 5-I/5-II. Considering that the hydroxyl group is both a good H-bonding donor and acceptor, the H-bonding interaction may be invloved in this configurational stabilization. However, examination of the X-ray crystal structure of 6-II found that no H-bonding interactions exist between the hydroxyl groups and the approximate hydrogen or sulfur atoms (Fig. 3). This result was further confirmed by the NMR method, evidenced by the value of hydrogen bond acidity (ANMR> 0.3)38 (see experimental section). Since in the two-ring flip pathway of 6-I/6-II39, the side chains of the two adjacent aryl rings in a“gear-clashing”counterrotation are encountered, the H-bonding interaction of the hydroxyl group with the approximate atom(s) in another aryl ring may be formed in the transiton state during the flip process. Configurational determination and EPR studies of the two enantiomers in 7-I/7-II Based on the above results, each TAM radical 7-I or 7-II should contain an enantiomeric pair. To further investigate the configurations of these tri-aryl compounds and explore the configurational effect on their EPR spectra, the racemate of 7-I and 7-II were separated by chiral HPLC (CHIRALPAKIG) to give the corresponding two enantiomers (assigned as 7-Ia/7-Ib and 7-IIa/7-IIb, Fig.5a and Fig. S7). As shown in Fig. 5b, the ECD spectrum of the first eluted enantiomer 7-Ia is characteristic of TAM radical with positive Cotton effects at 209 nm, 236 nm, 278 nm, 359 nm and 445 nm, and negative Cotton effects at 263 nm, 317 nm and 404 nm. Clearly, the ECD spectra of 7-Ia and 7-Ib are almost mirror images, further confirming their nature of an enantiomeric pair. Of note is that the ECD signals of the central chirality on the two quaternary carbons are very weak and negligible as compared to the signals of the trityl part. Our recent work showed that the trityl radical with the M configuration has two positive cotton effects from 350 to 500 nm29. Assuming that the configuration was unchanged from 6-I to 7-I, the absolute configurations of 7-Ia and 7-Ib can be deduced to be (M, S, R) and (P, R, S), respectively (Fig. S8). Likewise, the absolute configurations of 7-IIa and 7-IIb are (M, R, S) and (P, S, R), respectively.



Fig 5. (a) Chiral HPLC resolution of the enantiomeric pair of 7-II (CHIRALPAKIG column,hexane/ethyl acetate 3:1); b) Experimental ECD spectra of the first eluted fraction 7-IIa (red trace) and the second eluted fraction 7-IIb (green trace) measured in methanol

With 7-Ia, 7-Ib, 7-IIa and 7-IIb in hand, we studied their configurational stability by CSP-HPLC (see Experimental Section for details). As expected, no interconversion occurred between these stereoisomers at 58 ºC in CDCl3 for 5 h or at 100 ºC in toluene for 5 h (Fig. S9), further confirming that the hydroxyl groups play a crucial role in stabilizing the configurations of these tri-aryl compounds. Owing to the paramagnetic nature of 7-Ia, 7-Ib, 7-IIa and 7-IIb, EPR spectrscopy can be used to further investigate their configurations. Fig. 6 shows EPR spectra of 7-Ia and 7-Ib in DMSO under anaerobic conditions. Both spectra consist of an intense quartet (1:3:3:1) due to almost identical hyperfine splittings (αH ~ 2.3 G) from three aromatic protons. The same EPR profiles were also observed for 7-IIa and 7-IIb (Figure S10) with the almost same αH values (~ 2.3 G, Table S4). These four TAM radicals also have the same EPR line widths (84 mG, Table S4) under anaerobic conditions. In addition to the main quartet lines, there were also a plenty of weak EPR signals from 13C on the aryl rings. Interestingly, these TAM radicals also have the very similar

13

C hyperfine splittings, which are well consistent with the corresponding

values of the other TAM radical, an unsubstituted form of CT-03 (CT00, Table S4). The substitutions at para position of the aromatic rings exert slight effects on the 13C hyperfine splitting, especially for the values at the sites of C3 and C4, as compared to the fully substituted TAM radicals (Table S4)40. Taken together, the helical chirality (M and P) and central chirality (R and S) on the side chains almost have no significant effect on EPR spectra of these TAM radicals. Thus, the side chain may be a potential position for structural modification or spin labeling whereby EPR properties of TAM radicals are not changed.


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Fig 6. Experimental (solid, black) and simulated (red, dotted) EPR spectra of 7-Ia (Left) and 7-Ib (Right) in DMSO under anaerobic conditions.

Conclusions Novel triarylmethanols with central chirality were synthesized by introducing two cis-hydroxyl groups on the side chain. Due to the presence of the axial chirality (M and P) from the three aryl rings and central chirality (R and S) from the two quaternary carbons on the side chains, these triarylmethanols have four stereoisomers which were separated on silica gel column chromatography into two pairs of enantiomers. NMR and X-ray results demonstrated that both pairs contain two propeller-shaped enantiomeric isomers with the configurations as (M, S, R) and (P, S, R), or (P, R, S) and (M, R, S). Interestingly, the introduction of two hydroxyl groups leads to extraordinarily stable configurations of the triarylmethanols and TAM radicals possibly due to the formation of the H-bonding interaction of the hydroxyl groups with proton or sulfur atoms on another aryl rings during the two-ring flip process. Importantly, both the helical (M and P) and central chiralities (R or S) have little influence on the EPR properties of TAM radicals. Therefore, our present study provides a new strategy to construct configurationally stable tri-aryl compounds and develop new TAM radicals which retain excellent EPR properties but have improved physicochemical properties.

Experimental Section General synthetic conditions: All air/moisture sensitive reactions were carried out under argon, in dried glassware. All chemicals were purchased as reagent grade and used without further purification. Dichloromethane (CH2Cl2, DCM) was distilled over CaH. Ethyl ether (Et2O) and tetrahydrofuran (THF) was distilled over sodium/benzophenone. TLC was performed on silica gel 60 F254 glass plates and visualized under UV light (254 nm). Column chromatography was performed with Qingdao silica gel (200-300 mesh). Chiral resolution of radicals was performed on HPLC using CHIRALPAKIG Column (4.6 mm × 250 mm) at 1.0 mL min-1. 1H and 13C{1H} NMR spectra were recorded at room temperature on a Bruker AVANCE III 400 instrument. The chemical shifts are reported in ppm relative to chemical shifts for the deuterated solvents. The coupling constants (J) are given in Hertz (Hz). The NMR signals were designated as follows: s (singlet), d (doublet), t (triplet) or m (multiplet). Synthesis Synthesis of the ketone: To a stirred suspension of 1 (10.00 g, 23 mmol) in chloroform (30 mL) were added acetone (16.2 mL, 223 mmol), p-toluenesulfonic acid (0.8 g, 4.6 mmol), and BF3•Et2O (10.36 mL, 69.7 mmol) sequentially. The reaction mixture was stirred under an argon atmosphere in an oil bath at 75-80 °C for 24 h. After completion, as indicated by TLC, the reaction was quenched carefully by saturated aqueous NaHCO3 solution (20 mL). The organic layer was separated and the aqueous layer was extracted with



dichloromethane (DCM,3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was recrystallized from anhydrous ethanol to afford the intermediate (5.85 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3, δ) 7.02 (s, 2H), 1.88 (s, 12H); 13C{1H} NMR (100 MHz, CDCl3, δ) 135.9, 127.3, 117.0, 65.9, 31.5

To a solution of the intermediate (10 g, 35 mmol) in dry ether (300 mL) at room temperature was added n-BuLi (2.4 M in hexane, 16 mL, 38.5 mmol) dropwise for about 30 minutes. The resulting mixture was stirred at room temperature for 3.5 h, followed by the addition of distilled dimethyl carbonate solution (1.98 g, 16.8 mmol). The reaction mixture was stirred for 24 h and monitored by TLC analysis. Upon completion, the reaction was quenched with sat.aq. NaHCO3 (20 mL). The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (EA, 3 x 20 mL). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a red crude product. Purification of the crude product by column chromatography using petroleum ether (PE) as eluent afforded the desirable ketone (5.75 g, 55%) as an orange-red solid. 1H NMR (400 MHz, CDCl3, δ) 7.16 (s, 2H), 1.83 (s, 24H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 137.7, 127.3, 119.3, 65.4, 31.2.

diethyl 2,6-dimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-2,6-dicarboxylate (2):To a solution of compound 1 (43.2 g, 100 mmol) in CHCl3 (170 mL), were added ethyl pyruvate (90 mL, 800 mmol), p-toluenesulfonic acid (3.45 g, 20.03 mmol) and BF3•Et2O solution (44.8 mL, 300 mmol). The resulting mixture was stirred in an oil bath at 80°C for 24 h under argon and the reaction was monitored by TLC. Upon completion, the reation was quenched carefully with saturated aqueous solution of NaHCO3 (30 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE/DCM 8:1 to 2:1) to afford the compound 2 (32 g, 80%) as a white solid. 1H NMR (400 MHz, CDCl3, δ) 6.96 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 2.05 (s, 6H), 1.28 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3, δ) 170.3, 134.9, 115.8, 67.7, 63.0, 27.5, 14.0.

((2s,6s)-2,6-dimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)-2,6-diyl)dimethanol (3): To a solution of LiAlH4 (2.86 g, 75.4 mmol) in dry THF (30 mL) at 0 °C (ice bath) was added dropwise a soultion of compound 2 (10 g, 29 mmol) in dry THF (40 mL) over about 15 min. Then, the ice bath was removed and the resulting mixture was continously stirred at room temperature for 2 h. The reaction was monitored by TLC. Upon completion, the reaction was carefully quenched with concentrated HCl (12 M, 10 mL) and the resulting mixture was diluted with EtOAc (30 mL).The organic phase was separated and the aqueous phase was extracted with EA (3 x 50 mL).The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (PE/DCM 3:1 to DCM) to afford compound 3 (6.7 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6, δ) 7.15 (s, 2H), 5.65 (t, J = 6.0 Hz, 2H), 3.63 (d, J = 6.0 Hz, 4H), 1.75 (s, 6H); 13C{1H} NMR (100 MHz, DMSO-d6, δ) 134.8, 116.3, 70.1, 68.7, 24.9.


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(2s,6s)-2,6-bis(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylbenzo[1,2-d:4,5-d']bis([1,3]dithiole)

(4):

To

a

solution

of

compound 3 (10 g, 31 mmol) in dimethylformide (DMF, 35 mL) were added tert-butyldimethylsilyl chloride (TBSCl, 13.96 g, 92.4 mmol) and imidazole (12.6 g, 184.8 mmol). The reaction was stirred at room temperature for 10 h and the reaction was monitored by TLC. Once the starting material was disappeared, water (150 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EA (3 x 80 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using PE as eluent to afford compound 4 (14.5 g, 85%) as a white solid.1H NMR (400 MHz, CDCl3, δ) 6.85 (s,2H), 3.76 (s, 4H), 1.77 (s, 6H), 0.84 (s, 18H), 0.00 (s, 12H); 13C{1H} NMR (100 MHz, CDCl3, δ) 135.5, 116.3, 71.0, 69.8, 26.0, 24.9, 18.5, -5.2.

Compound 5 (5-I and 5-II): To a solution of compound 4 (2.09 g, 3.8 mmol) in dry diethyl ether (10 mL) in ice-bath (∼0°C) under argon were sequentially added TMEDA (1.14 mL, 7.6 mmol) and n-BuLi (2.4 M in hexane, 1.56 mL, 4.2 mmol). The resulting mixture was then stirred at room temperature for 3.5 h, followed by addition of the ketone (0.76 g, 1.27 mmol). The reaction mixture was stirred for 24 h and then quenched by adding saturated aqueous solution of NaHCO3 (10 mL). The organic layer was separated and the aqueous layer was further extracted with EA (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (PE/DCM, 10:1 to 5:1) to afford equal amount of 5-I (1.04 g, 23%) and 5-II (1.04 g, 23%). 5-I: Rf = 0.26 (PE/DCM 2:1).1H NMR (400 MHz, CDCl3, δ) 7.16 (s, 1H), 7.12 (s, 1H), 7.10 (s, 1H), 6.39 (s, 1H), 3.93 (d, J = 10.0 Hz, 1H), 3.86 (d, J = 9.6 Hz, 1H), 3.83 (d, J = 9.6 Hz, 1H), 3.76 (d, J = 10.0 Hz, 1H), 1.82-1.66 (m, 30H), 0.89 (s, 9H), 0.87 (s, 9H), 0.05 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 139.7, 139.0, 139.0, 138. 9, 138.0, 137.8, 137.8, 137.3, 137.3, 136.3, 136.2, 132. 3, 132. 2, 131. 2, 118.4, 117.8, 83.6, 70.7, 69.9, 69.7, 68.6, 63.9, 63.5, 63.5, 63.4, 35. 4, 34. 8, 33. 4, 32.9, 29.8, 29.6, 28.8, 28.5, 28.0, 27.6, 26.1, 26.0, 25.1, 18.6, 18.5, -5.2, -5.2, -5.2, two carbons are less than expected due to overlapping; 5-II Rf = 0.24 (PE/DCM 2:1).1H NMR (400 MHz, CDCl3, δ) 7.18 (s, 1H), 7.16 (s, 1H), 7.01 (s, 1H), 6.12 (s, 1H), 4.09 (d, J = 10.4 Hz, 1H), 3.87 (d, J = 10.4 Hz, 1H), 3.39 (d, J = 10.4 Hz, 2H), 1.85-1.60 (m, 30H), 0.89 (s, 9H), 0.88 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, δ) 139.3, 139.2, 139.1, 139.0, 138.3, 138.2, 138.2, 137.7, 137.6, 137.2, 132.1, 132.1, 131.5, 118.4, 118.4, 117.7, 83.7, 71.1 70.5, 67.2, 67.2, 64.6, 64.5, 63.8, 63.4, 35.2, 34.8, 32.0, 31.7, 29.9, 29.7, 27.9, 27.2, 26.1, 26.0, 22.8, 22.4, 18.4, 18.4, -4.7, -4.8, -4.8, three carbons are less than expected due to overlapping.

Compound6 (6-I and 6-II): To a solution of 5-I or 5-II (2 g, 1.7 mmol, 1.0 eq.) in anhydrous THF (15 mL) under argon was added TBAF (1 M in THF, 10 mL, 17 mmol, 10 eq.) dropwise. The resulting mixture was stirred in an oil bath at 40 ºC for 6 h.Then, saturated brine (15 mL) was added to quench the reaction. The organic phase was separated and the aqueous phase was extracted with EA (3 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude brown oil, which was purified by column chromatography (PE/EA 6:1 to 1:1) to afford 1.12 g (70%) of compound 6-I or 6-II as a yellow solid. Compound 6-I



was obtained from complound 5-I as starting materials: 1H NMR (400 MHz, CDCl3, δ) 7.21 (s, 1H), 7.18 (s, 1H), 7.13 (s, 1H), 6.20 (s, 1H), 3.98 (dd, J = 11.2, 3.2 Hz, 1H), 3.66 (dd, J = 11.2, 3.2 Hz, 1H), 3.52 (dd, J = 11.2, 6.8 Hz, 1H), 3.41 (t, J = 10.4 Hz, 1H), 2.68 (dd, J = 9.6, 4.4 Hz, 1H), 2.33 (t, J = 6.4 Hz, 1H), 1.84-1.62 (m, 30H); 13C{1H} NMR (100 MHz, CDCl3, δ) 140.0, 139.2, 139.2, 138.5, 138.3, 138.1, 137.9, 137.8, 137.6, 137.3, 137.0, 132.2, 132.1, 131.9, 118.9, 118.4, 118.4, 83.5, 69.9, 69.7, 68.0, 66.9, 65.4, 64.5, 64.3, 63.1, 34.4, 33.1, 32.0, 31.3, 29.9, 29.7, 29.1, 26.9, 21.0, 20.8, one carbon is less than expected due to overlapping; HRMS (MALDI, m/z) for 6-I: [M + Na]+ Calcd for C37H40NaO3S12 938.9518; found 938.9519; Compound 6-II was obtained from complound 5-I as starting materials: 1H NMR (400 MHz, CDCl3, δ) 7.21 (s, 1H), 7.18 (s, 1H), 7.13 (s, 1H), 6.20 (s, 1H), 3.98 (dd, J = 11.2, 3.2 Hz, 1H), 3.66 (dd, J = 11.2, 3.2 Hz, 1H), 3.52 (dd, J = 11.2, 7.2 Hz, 1H), 3.41 (t, J = 10.4 Hz, 1H), 2.68 (dd, J = 9.6, 4.4 Hz, 1H), 2.33 (t, J = 6.8 Hz, 1H), 1.84-1.62 (m, 30H); 13C{1H} NMR (100 MHz, CDCl3, δ) 140.0, 139.2, 139.2, 138.5, 138.3, 138.1, 137.9, 137.8, 137.6, 137.3, 137.0, 132.2, 132.1, 131.9, 118.9, 118.4, 118.4, 83.5, 69.9, 69.7, 68.0, 66.9, 65.4, 64.5, 64.3, 63.1, 34.4, 33.1, 32.0, 31.3, 29.9, 29.7, 29.1, 26.9, 21.0, 20.8, one carbon is less than expected due to overlapping; HRMS (MALDI, m/z) for 6-II: [M + Na]+ Calcd for C37H40NaO3S12 938.9518; found 938.9520. Radicals 7-I and 7-II: Radicals 7-I and 7-II were synthesized according to the previous method22,37. To a solution of compound 6-I or 6-II (20 mg, 0.02 mmol, 1.0 eq.) in DCM (0.3 mL) was added TFA (0.3 ml, 4.03 mmol). The resulting solution turned bright green immediately. After stirring for 30 min at room temperature, the resulting dark green-blue solution was treated with SnCl2 (1.8 mg, 0.01 mmol, 0.5 eq.) in THF (1 mL). After 10 min, saturated aqueous solution of NaH2PO4 (2 mL) was added. The organic phase was separated and the aqueous phase was extracted with DCM (2 × 3 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated on vacuum to give 18.8 mg (96%) of compound 7-I or 7-II as a green solid. HRMS (ESI, m/z) for 7-I and 7-II: [M + NH4]+ Calcd for C37H43NO2S12 916.9937; found 916.9885 and 916.9881 for 7-I and 7-II, respectively.

Assessment of intramolecular hydrogen bonding by NMR: According to the previous report38, intramolecular hydrogen bonding can be assessed by 1H NMR chemical shifts and value for the hydrogen bond acidity (A). The NMR A value (named as ANMR) can be calculated by the difference (∆δ) of the chemical shifts of the OH group in CDCl3 and DMSO-d6 using an equation ANMR = 0.0065 + 0.133∆δ. For aliphatic OH, If ANMR > 0.3, the OH does not take part in intramolecular hydrogen bonding. However, if ANMR < 0.1, the OH group forms intramolecular hydrogen bonding. For compound 8-I, the 1H NMR signals for the two OH groups were shifted from 2.68 and 2.33 in CDCl3 to 5.32 in DMSO-d6 (see SI). The calculated ANMR values for the two OH groups of 6-I are 0.358 and 0.408, suggesting that no intramolecular hydrogen bonding is formed in 6-I.

Measurement of Racemization Rates: Chloroform or toluene was used as a solvent due to their high volatility. The sample solution was transferred to the screw cap test tube which was kept in the oil bath maintained at designed temperature. The temperature was precisely controlled (± 0.2 °C). Subsequently, small aliquots of sample were taken out with pipette at the time point as indicated. After removal of


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the solvent by blowing with air, the sample was re-dissolved with eluent and analyzed by HPLC. HPLC conditions for 5-I and 5-II are as follows: Unitary Silica column (5 µm, 4.6 mm x 250 mm); n-hexane/ethyl acetate (99.2/0.8 v/v) as the mobile phase; flow rate at 1 mL min-1; UV detection at 254 nm; column temperature at 25 °C. The same HPLC conditions were used for 6-I and 6-II except for n-hexane/ethyl acetate (67/33 v/v) as the mobile phase. HPLC conditions for TAM radicals 7-I or 7-II were the same as the conditions used for their chiral resolutions (see the section of “Chiral resolution” above).

Chiral resolution: Chiral resolution of 7-I and 7-II was carried out on a chiral HPLC CHIRALPAKIG column (5 µm, 4.6 mm × 250 mm); mobile phase: ethyl acetate/n-hexane 1:3; flow rate: 1 mL min-1; detector: UV detection at 254 nm; column temperature: 25 °C.

CD Spectra CD spectra were recorded on a Jasco J715 spectropolarimeter (Jasco Corporation, Tokyo, Japan) at 25 °C in HPLC-grade methanol solutions; cell length: 1 mm; bandwidth: 2 nm; scan range: 200 - 800 nm.

X-ray Structure Determination Single-crystal X-ray diffraction was performed on a Bruker APEX-II CCD equipped with a Cu-Kα source (λ = 1.54184 Å) at 120 K and a XtaLAB AFC12 (RINC): Kappa single. Crystal data for 6-II are as follow: 2(C37H38O3S12), 3(CH2Cl2), Mr = 2085.56 g mol−1, triclinic, space group P-1, a = 14.03840(8), b = 18.16861(8), c = 19.83360(7) Å, α= 91.8589 (3), β = 110.3299(4), γ = 98.7848 (4)°, V =4667.96(4) Å3 , Z = 2, T = 120 K, reflections: 18656, collected: 18656 unique, Rint = 0.0340, R1(|F|>2sigma(F)) = 0.1176, wR2(|F|>2sigma(F)) = 0.0461.

EPR spectra determination EPR measurements were carried out on a Bruker EMX-plus X-band spectrometer at room temperature (298 K) under anaerobic conditions. General instrumental settings were as follows: modulation frequency, 100 KHz; microwave power, 0.08 mW; modulation amplitude, 0.03 G; scan time, 30s. Briefly, the sample was dissolved in dimethylsulfoxide and transferred to the gas-permeable Teflon tube (i.d. = 0.8 mm) which was then sealed at both ends. After placing the tube inside a quartz EPR tube, argon gas was allowed to bleed into the EPR tube and then the EPR spectrum was recorded.

Associated Content Supporting Information The supporting information is available free of charge on the ACS publications website at DOI: Copies of H-H COSY spectra, 1H NMR spectra, 13C NMR spectra and HRMS spectra; EPR spectra and hyperfine splitting constants; CD spectra; crystal structure and X-ray data; HPLC analysis for configuration stability (PDF); X-ray data of compound 3 and 6-II (CIF).



Acknowledgements This work was financially supported by the National Natural Science Foundation of China (No. 81603064, 21871210, 21572161, 31500684 and 21603163), Science & Technology Projects of Tianjin (18JCYBJC95300 and 18JCQNJC76100), The Open Project Program of Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics) and Tianjin Municipal 13th five year plan (Tianjin Medical University Talent Project).

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Nucleophilic

Quenching

of

Tris(2,3,5,6-tetrathiaaryl)methyl

Cations

and

Practical

and

Tris(4-carboxy-2,3,5,6-tetrathiaaryl)methyl Radical. Eur. J. Org. Chem. 2013, 2013, 3347-3355.


Convenient

Large-Scale

Synthesis

of

Persistent


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Triarylmethyl Radicals: An EPR Study of 13C Hyperfine Coupling Constants. Z. Phys. Chem. 2017, 231, 777-794.

TOC graphic:

S

S S

S

S Enantiomerization

OH

S

S S

S S

HO

X

*

OH S S

S

S S S

S

*

S

OH

S S

Enantiomerization S S

S

X

S

S

S

S

S

*

S

TFA SnCl2

S

HO

OH

*

S

TFA SnCl2

S

S

*

HO

S

S

S

S

OH

*

S

S

S

S

S

S

S

S

HO

S

*

*

S

S M and P

M and P


OH

Synthesis of Central Chirality-containing Triarylmethanols and

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