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Highly sensitive, simple, and cost/time-effective method to determine the absolute configuration of a secondary alcohol using competing enantioselective acylation coupled with LC/MS Seoung Rak Lee, Hyun Bong Park, and Ki Hyun Kim Anal. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Oct 2018 Downloaded from http://pubs.acs.org on October 24, 2018

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Analytical Chemistry

Highly sensitive, simple, and cost/time-effective method to determine the absolute configuration of a secondary alcohol using competing enantioselective acylation coupled with LC/MS Seoung Rak Lee,† Hyun Bong Park,‡,§ and Ki Hyun Kim*,† †School

of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea of Chemistry, Yale University, New Haven, Connecticut 06520, United States §Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, United States ‡Department

*Corresponding author: [email protected]

ABSTRACT: The absolute configuration determination of natural products and synthetic compounds with stereogenic centers is very important because stereoisomers dramatically and differentially affect many crucial properties such as physical behaviors and biological functions. Despite several established methods for determining the absolute configuration, significant unmet needs for new methods still exist owing to the specific limitations of established methodologies. Here, we present a simple optimized new chemical derivative method that utilizes competing enantioselective acylation followed by LC/MS analysis and demonstrate its successful application to determine the absolute configuration of a secondary alcohol in natural products with multiple reactive functional groups. This new development relies on the enantiomeric pair of the HBTM (homobenzotetramisole) catalysts exhibiting adequate kinetic resolution for acylation of secondary alcohol and then fast reaction was quantitatively confirmed via LC/MS as the characterization technique for the enantioselective transformations. Our new approach was successfully applied to determine the absolute configuration of one secondary alcohol in compound 1, which has other hydroxyl groups to be reacted. The identified stereocenter of 1 was verified by previously established methods including quantum chemical electronic circular dichroism (ECD) calculations, computational NMR chemical shift calculations followed by DP4+ calculations and modified Mosher’s method. In addition, our method was applied to five known naturally-occurring compounds, which led to the successful verification of their absolute configurations. Our newly developed method using HBTM catalyst provides a highly sensitive, simple, and cost/time effective approach and an applicable and convenient analytical method for determining the absolute configuration of one secondary alcohol in natural products.

The unambiguous determination of absolute configuration in natural products and synthetic compounds with stereogenic centers is thought to be very important because it has been reported that stereoisomers dramatically and differentially affect many crucial properties such as physical behaviors and biological functions.1 Alcohols are common in natural products and have been useful functionalities for absolute structure determination. Several reliable methods to determine the absolute configuration of secondary alcohols include Mosher’s method, X-ray crystallographic analysis, electronic and vibrational circular dichroism, and total synthesis.1 The method used for the assignment of absolute configuration is dependent on a number of key factors including the functionality surrounding the stereogenic center, and availability and properties of substance as well as access to instrumentation. Recently, a new implementation of the competing enantioselective conversion (CEC) method has been developed for qualitative determination of the absolute conﬁguration of secondary alcohols using thin-layer chromatography (TLC).2 The method depends on rate differences in parallel reactions of an optically enriched substrate with each enantiomer of an enantioselective catalyst. The CEC method has advantages in that the entire process requires approximately only 60 min and utilizes micromole quantities of the secondary alcohol being

tested. Currently, the CEC method has been applied to assign the absolute configuration of cyclic secondary amines,3 lactams,4 oxazolidinones,4 and β-chiral primary alcohols5 as well as secondary alcohols.6,7 Characterization techniques used to determine the reaction conversion rate include 1H NMR spectroscopy and TLC. However, the CEC method could not be applied for organic compounds with multiple hydroxyl groups, which are abundant in natural products. Particularly, the method uses TLC and 1H NMR spectroscopic analysis for verifying resultant products, which is inappropriate for determining the reaction rate and selectivity when the synthetic selectivity is unexpected in the practical enantioselective acylation and several reacted products are detected without a control. Thus, despite several established methods for determining the absolute configuration of secondary alcohols, a significant unmet need for new methods exists. Here, we report a simple and optimized new chemical derivative method that utilizes competing enantioselective acylation (CEA) coupled with LC/MS analysis. Its successful application determines the absolute configuration of a secondary alcohol in natural products with multiple reactive functional groups together with one secondary hydroxyl group. Our method was also applied to several known naturally-

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occurring compounds, demonstrating its utility for natural products. (1)

EXPERIMENTAL SECTION Chemicals and Reagents. All reactions were conducted capped under dimethylformamide (DMF) as an organic solvent with air at room temperature. All solvents and reagents, including DMF, N,N-diisopropylethylamine, and propionic anhydride, were freshly dried and distilled. S- and Rhomobenzotetramisole (HBTM) as organic catalysts were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). Experimental Procedure to Determine Absolute Configuration. (1) CEA reaction - Parallel reactions were performed using S- and R-HBTM stock solutions; other procedures and conditions were identical for both reactions. Compound 1 (0.5 mg, 1.37 µmol) was transferred to two labeled 5 mL transparent capped vials at room temperature, and dimethylformamide (90 µL) was added as organic solvent for CEA reaction. Stock solutions of both S- and R-HBTM (10 µL, 0.38 µmol) were added, and the stock solution of N,Ndiisopropylethylamine (2.9 µL, 16.4 µmol) was successively transferred. Propionic anhydride (2.1 µL, 16.4 µmol) was added to start the CEA reaction. During the reactions, a 2 µL aliquot from both reactions was acquired at different time intervals for LC/MS analysis and quenched with 98 µL of MeOH to give a total volume of 100 µL. After 40 min, MeOH was added to stop the reaction. (2) LC/MS analysis - An aliquot (5 µL) of sample (100 µL) acquired from parallel reactions at different time intervals was directly injected onto the LC/MS (Phenomenex Luna C18, 4.6 × 100 mm, 3.5 μm, flow rate: 0.3 mL/min, Torrance, CA, USA), and the full scan in positive and negative ion modes (scan range m/z 100 to 1000) was applied to identify the desired acylated derivatives. The mobile phase consisting of formic acid in distilled water [0.1% (v/v)] (A) and MeOH (B) was carried with a gradient solvent system as follows: 10-100% (B) for 10 min, 100% (B) isocratic for 5 min, and then 10% (B) isocratic for 5 min, to conduct a post-run washing procedure for the column. The reaction rate catalyzed by both S- and RHBTM was determined by measuring the peak area of fully acylated derivatives. Electronic circular dichroism (ECD) Calculation. To obtain the conformational differences between 1a (7S,8R) and 1b (7R,8S), computational density functional theory (DFT) calculations were carried out. The first structural energy minimizations of 1a and 1b were performed by utilizing Avogadro 1.2.0 with the UFF force field. Then, the ground-state geometries of 1a and 1b were established by Tmolex 4.3.1 with the DFT settings (B3-LYP functional/M3 grid size), geometry optimization options (energy 10-6 hartree, gradient norm |dE/dxyz| = 10-3 hartree/bohr), and the basis set def-SV(P) for all atoms. The calculated ECD spectra of optimized structures of 1a and 1b were acquired at the B3LYP/DFT functional settings with the basis set def-TZVPP for all atoms. The obtained CD spectra were simulated by overlying each transition, where σ is the width of the band at 1/e height. ΔEi and Ri are the excitation energies and rotatory strengths for transition i, respectively. In the present study, the value of σ was 0.10 eV (eq 1):

Computational NMR Chemical Shift Calculations for DP4+ Analysis. Conformational searches were performed using the Tmolex 4.3.1 with the DFT settings (B3-LYP functional/M3 grid size), geometry optimization settings (energy 10-6 hartree, gradient norm |dE/dxyz| = 10-3 hartree/bohr), and the basis set def-SV(P) for all atoms. NMR shielding constants calculations were performed on the optimized ground state geometries at the DFT B3LYP/def-SV(P) level of theory. The NMR chemical shifts of the diastereomers 1 (7S,8R) and 2 (7R,8R) were obtained by Boltzmann averaging the 1H and 13C NMR chemical shift of the stable conformers at 298.15 K. Chemical shift values were calculated using the equation below where 𝛿𝑥𝑐𝑎𝑙𝑐 is the calculated NMR chemical shift for nucleus x, and σ𝑜 is the shielding tensor for the proton and carbon nuclei in tetra methylsilane calculated at the DFT B3LYP/def-SV(P) basis set (eq 2):8 𝛿𝑥𝑐𝑎𝑙𝑐 =

σ𝑜 ― 𝜎𝑥 1 ― σ𝑜/106

(2)

The calculated NMR properties of diastereomers 1 and 2 were averaged based upon their respective Boltzmann populations and DP4+ probability analysis was facilitated by the Excel sheet (DP4+) provided by Grimblat et al.9 Preparation of Mosher Ester Derivatives from 1. Compound 1 (0.3 mg) dissolved in deuterated pyridine (0.25 mL) was transferred into a clean NMR tube and then a small quantity of 4-(dimethylamino)pyridine was added. (S)-(+)-α-Methoxy-α(trifluoromethyl) phenylacetyl (MTPA) chloride (5 µL) was transferred into the NMR tube under a N2 gas stream and the NMR tube was shaken carefully to mix the sample with added reagents. The NMR tube was stored at room temperature overnight, which afforded the (R)-MTPA ester derivative of 1. The (S)-MTPA ester derivative of 1 was also acquired using (R)-MTPA chloride according to the procedure described above. The 1H NMR and TOCSY spectra were directly obtained from the Mosher ester derivatives of 1 in NMR tubes.

RESULTS AND DISCUSSION As part of our continuing studies to explore structurally new natural products from natural resources, we isolated one chemical constituent (1) from the MeOH extract of bark of Acer tegmentosum Maxim (Aceraceae) (Figure 1), followed by column chromatographic separation and HPLC purification (see Supporting Information). Compound 1 was isolated as an amorphous powder with a negative specific rotation value ([α] -3.26, in MeOH). The molecular formula of 1 was assigned to be C18H22O8 from the [M - H]- peak at m/z 365.1238 (calcd for C18H21O8, 365.1236) in the HR-ESIMS data. Detailed analysis of the 1H and 13C NMR data (Table S1) revealed that compound 1 possessed a guaiacylglycerol moiety and a 3',5'-dimethoxy1',4'-dioxyphenyl group, and the NMR data of 1 were nearly identical to those of (+)-(7S,8S)-1',4-dihydroxy-3,3',5'trimethoxy-7',8',9'-trinor-8,4'-oxyneoligna-7,9-diol.10 Based on the comparison of NMR data and HR-ESIMS data analysis, the planar structure of 1 was determined to be 1',4-dihydroxy3,3',5'-trimethoxy-7',8',9'-trinor-8,4'-oxyneoligna-7,9-diol,


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Analytical Chemistry which was unambiguously confirmed by analysis of the 2D NMR data (1H-1H COSY, HSQC, and HMBC) (Figure 1). However, compound 1 was speculated to be a new phenylpropanoid derivative since reported spectroscopic data values were not in agreement with that of compound 1 for coupling constant value for H-7/H-8.10 The main difference was the smaller coupling constant (5.0 Hz) between H-7 and H-8 of 1, compared with 7.5 Hz reported previously.10 The smaller coupling constant value (5.0 Hz) for H-7/H-8 suggested that compound 1 has a 7,8-erythro-configuration rather than the 7,8threo-configuration of the one reported in CD3OD.11,12 To the best of our knowledge, 1',4-dihydroxy-3,3',5'-trimethoxy7',8',9'-trinor-8,4'-oxyneoligna-7,9-diol with 7,8-erythroconfiguration has not been reported in the literature. H3CO 5'

(a) 9

5

6 1 2 3

OCH3

3'

OH

(b)

H3CO

2'

HO

OCH3

7

4

HO

O 4'

8

HO

6' 1'

OH

OH

O OCH3 OH

HO OCH3

Figure 1. (a) Chemical structure of compound 1. (b) The 1H-1H COSY correlations (blue bond) and key HMBC correlations (H→C) of compound 1.

Determination of Absolute Configuration of a Secondary Alcohol using Competing Enantioselective Acylation Coupled with LC/MS. To determine the absolute configuration of compound 1, we tried to develop a simple optimized new chemical derivative method since compound 1 has multiple reactive hydroxyl moieties besides one secondary hydroxyl group. The recently developed CEC method uses Birman’s homobenzotetramisole (HBTM)-kinetic resolution catalyst, which appears to be quite versatile, with kinetic resolution reported for a variety of substrates. In previous reports, HBTM catalyst exhibited adequate kinetic resolution in different enantiomeric environments and was effectively applied to secondary benzylic alcohols.13 In addition, absolute configurations of amines, alcohols, lactams, and oxazolidinones were simply identified by acylating optically pure compounds in both enantiomers of the HBTM kinetic resolution catalysts.3-7 The HBTM catalyst was utilized in this study, and the reaction rate between parallel reactions was compared by LC/MS analysis instead of TLC and 1H NMR spectroscopic analysis as well as MS analysis, which cannot determine the reaction rate clearly if the selectivity of the catalyst with the secondary alcohol of each substrate was not identified and/or a number of reacted products are detected without a control. The crucial strategy of our newly developed method was that each enantiomeric pair of the HBTM catalysts for acylation of secondary alcohol at stereogenic center was applied as the acylation of the stereogenic alcohol is the slow step, which led to discrepancy of acylation rate, and then the fast reaction was sensitively and quantitatively confirmed by LC/MS analysis as LC/MS is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography (or HPLC) with the mass analysis capabilities, which led to the identification of the targeted reaction product with high sensitivity even though recent literatures regarding chiral recognition by MS-based methods were reported.14

The parallel acylation reactions required two sets of 1 (each 0.5 mg) and S- and R-HBTM catalysts (each 0.1 mg). Conveniently, the acylation reactions of compound 1 with S- and R-HBTM catalysts were simply performed at room temperature. A 2 µL aliquot from each reaction was acquired and quenched with 98 µL of MeOH to afford a total volume of 100 µL at different time intervals. Samples acquired from each reaction at different time intervals were quantitatively analyzed by LC/MS equipment to measure the reaction rate catalyzed by S- and R-HBTM. Although we could not fully anticipate the regioselectivity of the esterification of 1, the production of fully acylated derivative (1A; [M + Na]+ peak at m/z 613), which was esterified by propionic anhydride in all four hydroxyl groups, was expected as a result of nucleophilic elimination (Figure 2). In fact, compound 1 has four hydroxyl groups to be reacted; however, among the hydroxyl groups, only hydroxylated methine (C-7) was a chiral carbon, which allowed us to anticipate that the chiral environment of C-7 would affect the parallel acylation rate of 1 in the enantiomeric pair of HBTM kinetic resolution catalysts. Based on the analysis of LC/MS data, we easily confirmed that the esterification reaction with SHBTM was faster by comparison of the peak areas of fully acylated derivatives identified in parallel reactions with S- and R-HBTM (Figure 3, Figure S8, see Supporting Information). According to reported literature, the absolute configuration of C-7 was assigned as S because faster esterification with SHBTM is attributable to the hydroxyl group forward the plane of compound 1 in the transition state when the distinctive aromatic ring (π-system) is located to the left and the alkyl group is placed to the right in transition state (Figure 4).6,15 The remaining stereogenic center of 1 was deduced to be 8R based on the coupling constant value (5.0 Hz) for H-7/H-8, indicating a 7,8-erythro-configuration.11,12 S H3CO HO

OH

O *

*

OCH3 OH

HO OCH3 1

N

N

H3CO

O

*

0.1 mg of HBTM (EtCO)2O (12.0 equiv) i-Pr2NEt (12.0 equiv) DMF

O

O

O

O (R) (S)

OCH3 O

O O

O OCH3 1A

Figure 2. CEA reaction for determination of absolute configuration of compound 1.

Figure 3. Optically active compound 1 was reacted with propionic anhydride (16.4 µmol) and 0.38 µmol of both R-HBTM and SHBTM catalysts. The reaction rate was examined by measuring the peak area of the fully acylated derivative (1A; [M + Na]+ peak at m/z 613) from LC/MS.



(a)

(b)

H O H

EtO2C OCH3 O S N N

OH

S N

N

CO2Et R-HBTM

R1

R2

R-HBTM f ast reation

R1 = , R2 = alkyl H

S N

N

S-HBTM

OH R2 R1 S-HBTM f ast reation

Figure 4. (a) Proposed favorable transition state of 1 in CEA reaction. (b) Mnemonic to predict the configuration of secondary alcohols in CEA reaction.

Therefore, the structure of 1 was established as (7S,8R)-1',4dihydroxy-3,3',5'-trimethoxy-7',8',9'-trinor-8,4'-oxyneoligna7,9-diol, which has not been previously reported in the literature. Determination of Absolute Configuration of Compound 1 using Previously Established Methods. To verify the 7S,8Rconfiguration of 1, we performed quantum chemical ECD calculations for comparison of the experimental ECD spectrum of 1 with the calculated ECD data of two possible enantiomers 1a (7S,8R) and 1b (7R,8S) (Figure 5) since compound 1 has a 7,8-erythro-configuration. The two isomers (1a and 1b) were introduced to perform ECD calculation utilizing TD-DFT at the B3LYP/def-TZVPP//B3LYP/def-SV(P) level for all atoms. Notably, the experimental ECD spectrum of 1 revealed a good agreement with the predicted ECD curve of 1a. Next, we employed a gauge-including atomic orbital (GIAO) NMR chemical shift calculation, which was followed by DP4+ probability analysis.9 The computed 1H and 13C NMR chemical shifts of two possible diastereomers 1 (7S,8R) and 2 (7R,8R) were compared with the experimental values of 1 by utilizing DP4+ probability analysis, which indicated the structural equivalence of 1 to diastereomer 1 (7S,8R) with 99.98% probability (Figure S23, see Supporting Information). Finally, the modified Mosher’s method was performed on compound 1 to verify the absolute configuration at C-7. Detailed interpretation of 1H NMR and TOCSY spectra of the (R)- and (S)-MTPA ester derivatives of 1 suggested that the absolute configuration of C-7 was S (Figure S28, see Supporting Information). These results supported the absolute configurations of 1 as 7S,8R, as established by the newly developed method.

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Verification of the Newly Developed Method for Determining Absolute Configurations of Natural Products Containing a Secondary Alcohol. To verify the application of our newly developed method, we applied this method to five known natural products (2-6) in the natural product library of our laboratory, where natural products containing various functional groups were tested for examination of utility of this method (Figure 6). (+)-Epicatechin (2), isolated from the bark of Tilia amurensis, was employed to verify its stereochemistry by the developed method because the compound has a β-aryl secondary alcohol, but also has other hydroxyl groups to be reacted; compound 2 has a total of five hydroxyl groups to be reacted, however only one hydroxyl group at a chiral center is able to react, which can affect the parallel acylation rate (Figure S16, see the Supporting Information). Based on the abovedescribed experimental procedure, we unambiguously confirmed that the esterification reaction with R-HBTM was faster by comparison of the peak areas of fully acylated derivatives in parallel reactions, which successfully suggested that the absolute configuration of 2 at C-3 was S (Figure 6). A hypothetical transition state for the fast-reacting catalystalcohol combination is presented in Figure S29 (see the Supporting Information). To extend the applicable candidates for verification of our developed method, the known furofuran lignan analogue, (1S,2R,5S,6R)-6-(4-hydroxy-3methoxyphenyl)-3,7-dioxabicyclo[3.3.0]octan-2-ol (3) that has a lactol moiety, was subjected to the developed method for verifying the absolute configuration, which demonstrated its absolute configuration of C-1 as S by utilizing CEA followed by LC/MS analysis (Figures S17 and S29, see the Supporting Information). We also carried out parallel acylation reactions with S- and R-HBTM catalysts using the relatively complicated natural product roridin E (4), well-known as a potent cytotoxic macrocyclic trichothecene from a poisonous mushroom Podostroma cornudamae,16 which provided clear evidence to confirm the absolute configuration of 4 at C-13' as R (Figures S18 and S29, see Supporting Information). Finally, we applied the developed method to (R)-1-mono-laurin (5) and (2R,7R,11R)-phyten-3(20)-1,2-diol (6) for confirming their absolute configurations, which led to the verification of the stereochemistry (Figure 6). The hypothetical favorable transition states for their fast-reacting catalyst-alcohol combination are proposed (Figure S29, see the Supporting Information) where the selectivity of HBTM for secondary alcohols can be rationalized by π−π interactions, rather than interaction with non-π group of heteroatoms. (a) OH OH

O

O

3 S-HBTM

R-HBTM

O

f ast reation

O

O

H

2 f ast reation

O

H

OH OH

R-HBTM

H O

O

O

HO

H

OCH3

HO

OH O

OH

S-HBTM

4 O O

5 R-HBTM

f ast reation

R-HBTM

OH OH (b)

S-HBTM

(polar group) ( -system) R1 R-HBTM

OH

Figure 5. Experimental ECD spectrum of 1 and calculated ECD data of 1a and 1b.

6 R-HBTM


f ast reation

f ast reation

OH S-HBTM

R-HBTM

OH R2 (alkyl)

f ast reation

(polar group) ( -system) R1

S-HBTM

S-HBTM

OH R2 (alkyl)

f ast reation

S-HBTM

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Analytical Chemistry Figure 6. (a) Chemical structure of natural products 2-6 and indication of the fast-reacting catalyst for their fully acylated derivatives by S- and R-HBTM catalysts. (b) Mnemonic to predict the configuration of secondary alcohols in CEA reaction.

CONCLUSIONS We have presented a new approach using HBTM chiral acylating catalyst coupled with LC/MS analysis to determine the absolute configuration of secondary alcohol in natural products with other functional groups to be reacted, besides one secondary alcohol. This method is very practical and operationally simple to perform, time-effective to analyze the experimental results, highly sensitive by LC/MS analysis, and required only small quantities of substrates, which can be a simple and effective method applicable to natural products.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental section, HR-ESIMS, 1D and 2D NMR data of 1, the LC/MS data of acylated derivatives from CEA reactions, 1H NMR data of 2-6, DP4+ analysis of compound 1 with diastereomers 1 and 2, analysis of modified Mosher’s method for 1, and proposed favorable transition states of compounds 1-6 in CEA reaction.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Author Contributions S. R. L. performed all experiments. H. B. P. conducted computational NMR chemical shift calculations. S. R. L., H. B. P., and K. H. K. analyzed the data. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2018R1A2B2006879).

REFERENCES (1) Seco, J. M.; Quinoa, E.; Risuera, R. The assignment of absolute configuration by NMR. Chem. Rev. 2004, 104, 17-117. (2) Wagner, A. J.; Rychnovsky, S. D. Determination of absolute configuration of secondary alcohols using thin-layer chromatography. J. Org. Chem. 2013, 78, 4594-4598. (3) Burtea, A.; Rychnovsky, S. D. Determination of the Absolute Configuration of Cyclic Amines with Bode’s Chiral Hydroxamic Esters Using the Competing Enantioselective Conversion Method. Org. Lett. 2017, 19, 4195-4198. (4) Perry, M. A.; Trinidad, J. V.; Rychnovsky, S. D. Absolute Configuration of Lactams and Oxazolidinones Using Kinetic Resolution Catalysts. Org. Lett. 2013, 15, 472-475. (5) Burns, A. S.; Wagner, A. J.; Fulton, J. L.; Young, K.; Zakarian, A.; Rychnovsky, S. D. Determination of the Absolute Configuration of βChiral Primary Alcohols Using the Competing Enantioselective Conversion Method. Org. Lett. 2017, 19, 2953-2956. (6) Wagner, A. J.; Miller, S. M.; King, R. P.; Rychnovsky, S. D. Nanomole-Scale Assignment and One-Use Kits for Determining the Absolute Configuration of Secondary Alcohols. J. Org. Chem. 2016, 81, 6253-6265. (7) Burns, A. S.; Ross, C. C.; Rychnovsky, S. D. Heteroatom-Directed Acylation of Secondary Alcohols To Assign Absolute Configuration. J. Org. Chem. 2018, 83, 2504-2515. (8) Smith, S. G.; Goodman, J. M. Assigning stereochemistry to single diastereoisomers by GIAO NMR calculation: The DP4 probability. J. Am. Chem. Soc. 2010, 132, 12946-12959. (9) Grimblat, N.; Zanardi, M. M.; Sarotti, A. M. Beyond DP4: an improved probability for the stereochemical assignment of isomeric compounds using quantum chemical calculations of NMR shifts. J. Org. Chem. 2015, 80, 12526-12534. (10) Xiong, L.; Xhu, C.; Li, Y.; Tian, Y.; Lin, S.; Yuan, S.; Hu, J.; Hou, Q.; Chen, N.; Yang, Y.; Shi, J. Lignans and neolignans from Sinocalamus affinis and their absolute configurations. J. Nat. Prod. 2011, 74, 1188-1200. (11) Liao, S. G.; Wu, Y.; Yue, J. M. Lignans from Wikstroemia hainanensis. Helv. Chim. Acta. 2006, 89, 73. (12) Jutiviboonsuk, A.; Zhang, H.; Tan, G. T.; Ma, C.; Hung, N. V.; Cuong, N. M.; Bunyapraphatsara, N.; Soejarto, D. D.; Fong, H. H. S. Bioactive constituents from roots of Bursera tonkinensis. Phytochemistry 2005, 66, 2745-2751. (13) Birman, V. B.; Li, X. Homobenzotetramisole: an effective catalyst for kinetic resolution of aryl-cycloalkanols. Org. Lett. 2008, 10, 11151118. (14) Yu, X.; Yao, Z. P. Chiral recognition and determination of enantiomeric excess by mass spectrometry: A review. Anal. Chim. Acta 2017, 968, 1-20. (15) Wagner, A. J.; David, J. G.; Rychnovsky, S. D. Determination of absolute configuration using kinetic resolution catalysts. Org. Lett. 2011, 13, 4470-4473. (16) Saikawa, Y.; Okamoto, H.; Inui, T.; Makabe, M.; Okuno, T.; Suda, T.; Hashimoto, K.; Nakata, M. Toxic principles of a poisonous mushroom Podostroma cornu-damae. Tetrahedron 2001, 57, 82778281.

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