Postdoc journal Journal of Postdoctoral Research Vol. 6, No. 3, March 2018 www.postdocjournal.com

Assignment of Absolute Stereochemistry of Hydroxyl Centre Using Mandalate Ester: An Anisotropic Effect of Phenyl Group on Remote Protons

GanapathySubramanian Sankarana*†, Vasantha Rb†, Dandamudi V. Leninb, Sivaraman Balasubramaniamc

aUniversity of Massachusetts medical school, Worcester, MA-02464.

bSchool of Chemical Sciences, Central University of Gujarat, Gandhinagar, India-382030.

c High Value Chemicals group, Reliance Industries Limited, Ghansoli, Navi Mumbai, India- 400701.

*corresponding author:ganapathy.sankaran@umassmed.edu

† equal contribution

Abstract

An absolute configuration of a hydroxy center is assigned by using methoxy mandelic acid taking the advantage of anisotropic effect of phenyl group. The enantiomeric excess and absolute configuration of unknown compounds are determined using 1H NMR spectra. The influence of anisotropic effect of the phenyl ring on remote protons is revealed.

Key words: Absolute configuration, Optical purity, Anisotropic effect, Diastereoselectivity, Chiral alcohols.

Introduction

Stereochemistry plays very important role in our lives, particularly in the area of drug discovery and natural product synthesis. In particular stereo selective synthesis of organic molecules is imperative in drug discovery wherein a particular stereoisomer is responsible for its efficacy or the biological activity.1 In this context, absolute configuration of a stereogenic center plays a critical role in total synthesis of natural products2, bioluminescence imaging studies3a and pharmaceuticals3b. There are number of methods used to determine absolute configuration including the advanced NMR spectroscopy method,4−6 chiral derivatization reagents,7 vibrational circular dichroism,8 exciton chirality,9−11 NMR spectroscopic chiral shift reagents,12−15 lipase-catalyzed resolutions,16 and X-ray crystallographic analysis. In chiral solvating agent (CSA) no derivatization of substrate is required. Chiral solvating agent is added to the substrate dissolved in deuterated solvent and the chiral environment is produced. This method is convenient and user friendly but has some

limitations,as the difference of chemical shift values obtained from NMR spectra of both the isomers is negligible and both the enantiomers are essentially required. Also, Chiral Solvating agents are costly and difficult to recycle which makes them a less attractive choice for synthetic chemists. Most of the organic compounds are liquids which limits the application of X-Ray Diffraction (XRD) to determine the absolute configuration. On the other hand, Chiral derivatizing agents (CDA) in which the pure isomer is converted into the diastereomer by covalent bond formation. This method has some distinct advantages. Firstly, the difference in chemical shift values of both isomers is significant and secondly, one of the enantiomers is sufficient to determine the absolute configuration.

In 1980s Mosher6a came up with an idea that the absolute configuration of a compound can be assigned by comparing the 1H NMR data of the corresponding esters as depicted in Scheme 1. Subsequently, Trost6b reported a convenient methodology for assignment of absolute configuration. The chiral alcohol will be converted to the corresponding mandalate

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ester derivative without isomerization, the ester will adopt the configuration in which OMe, C=O, H will be in the plane and remaining

groups will occupy space depending on their configuration, Scheme 1.

Scheme 1 Mosher’s Method

Trost method

Scheme 1. Determination of absolute configuration

Herein we report the assignment of absolute configuration of a hydroxy center, determination of enantiomeric excess and the anisotropic effect of phenyl ring on remote protons in NMR spectra. 1H NMR requires less amount of compound, the difference in chemical shift values are higher than 13C NMR.

Result and Discussion

As part of our ongoing research toward stereo selective synthesis of natural products, various chiral substrates were prepared. The absolute configuration at the newly generated stereogenic center in 2 was assigned by preparation of mandelate esters of allylic

alcohol 1 (Scheme 2). Allylic alcohol 1 on reaction with (R)-methoxy mandelic acid and (S)-methoxy mandelic acid afforded the corresponding esters 2a and 2b. Comparison of 1H NMR data of 2a and 2b revealed that the olefinic protons of 2a appeared more down field compared to the olefinic protons of 2b, confirming as S configuration for the carbinol carbon. The anisotropic effect of phenyl ring is clearly seen in 2a as the methyl [Refer Table 1, a)]protons are shielded although these protons are located far away. In 2b the acetonide and benzylic protons are shielded. In both the isomers, the difference between chemical shift values are high and clearly distinguishable.

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Scheme 2

We are particularly interested to explore the anisotropic effect of phenyl ring on long chain protons. Similarly, the propargylic alcohol 3 was prepared by enantioselective reduction of corresponding ketone using (R,R)-Noyori catalyst (er = 98:2), (Scheme 3). The absolute configuration and enantiomeric purity of alcohol 3 was determined by conversion to its mandelate derivatives 3a, 3b by reacting with enantiomerically pure methoxy mandelic acid a, b. The 1H NMR spectrum of 3a showed resonances at δ 1.02 (t, J = 6.0 Hz, 3H) for -CH2-CH3, 0.30 (s, 9H) for –CC-Si(CH3)3 and the 1H NMR spectrum of 3b showed resonances at δ 0.99 (t, J = 6.9 Hz, 3H) for -CH2-CH3 and 0.26 (s, 9H) for –CC-Si(CH3)3. The anisotropic effect of phenyl ring is clearly observed at the methyl protons which is thirteen carbons away from

the phenyl group attached carbon. The optical purity and the absolute configuration of the diol 4 was determined as R by comparing the chemical shift values of its mandelate derivatives 6a, 6b. The diol 4 was protected as its mono benzoate 4a which was further converted to its mandelate derivative 6a by reacting with (R)-methoxy mandelic acid a, (Scheme 4). The 1H NMR spectrum of 6a showed resonances at δ 4.32-4.12 (m, 2H) for –O-CH2-O-C(O)Ph, 2.15 (dt, J = 6.9, 2.6 Hz, 2H) for –CH2-CCH and 1.84 (t, J = 2.6 Hz, 1H) for –CH2-CCH. The 1H NMR spectrum of 6b showed resonances at δ 4.33 (dd, J = 7.2, 5.1 Hz, 1H), 4.20 (dd, J = 7.2, 6.2 Hz, 1H) for –O-CH2-O-C(O)Ph, 2.07 (dt, J = 6.9, 2.6 Hz, 2H) for –CH2-CCH, 1.78 (t, J = 2.6 Hz, 1H) for –CH2-CCH protons

.

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Scheme 3 Determination of configuration for alkynol 3

Scheme 4 Synthesis of mandelate ester 6a, 6b

These observations and trend were observed in few other substrates we synthesized for the total synthesis of various bioactive targets in our laboratory consistently (Scheme 5). The list of various mandelate esters and the observed anisotropic effect of phenyl ring on the long

chain protons are summarized in the below table with the corresponding chemical shift values.

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Table 1

Conclusion

The above observation clearly demonstrates that the anisotropic effect of phenyl ring has an influence not only in the proximal protons but also in the long range protons. This will be helpful in assigning configuration of an unknown hydroxy group in a polyol system

with a long chain where the chemical shift difference of the corresponding mandelate derivative resonates in upfield region and exhibits clear shift which will be helpful for synthetic chemists in establishing the absolute configuraton.

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Experimental

Preparation of Mandelate ester 2a

To a solution of alcohol 1 (36 mg, 0.1 mmol) in DCM (0.4 mL) cooled at 0 º C was added DCC (30 mg, 0.15 mmol), DMAP (1.2 mg), and (R)-methoxymandelic acid (20 mg, 0.12 mmol). The reaction mixture was gradually allowed to attain rt and stirred at the same temperature overnight. The solvent was evaporated under reduced pressure to furnish the crude compound which was purified by column chromatography using 5% EtOAc/Hexanes

(v/v) as the eluent to afford the product 2a (40 mg, 0.08 mmol) in 80% yield as a liquid. TLC, Rf

0.32 (15% EtOAc/Hexanes); 1H NMR (CDCl3, 200 MHz) δ 7.40-7.20 (m, 10H), 5.59 (m, 1H), 5.19 (dd, J = 15.2, 5.1 Hz, 1H), 4.61 (s, 1H), 4.51 (d, J = 11.7 Hz, 1H), 4.49 (d, J = 15.3 Hz, 1H), 4.16 (td, J = 4.4, 2.2 Hz, 1H), 3.78-3.68 (m, 1H), 3.48-3.42 (m, 2H), 3.31 (s, 3H), 1.47-1.37 (m, 2H), 1.35 (s, 3H), 1.33 (s, 3H), 1.28-1.00 (m, 8H), 0.77 (t, J = 6.5 Hz, 3H).

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Preparation of mandelate ester 2b

The ester 2b was prepared following the procedure detailed for the preparation of 2a.

1H NMR (CDCl3, 300 MHz) δ 7.40-7.20 (m, 10H), 5.46 (dd, J = 15.1, 6.0 Hz, 1H), 5.23 (dd, J = 15.1, 6.0 Hz, 1H), 4.64 (s, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 19.6 Hz, 1H) 4.03 (dd, J = 8.3, 6.0 Hz, 1H), 3.32 (s, 3H), 3.60-3.55 (m, 1H), 3.40-3.24 (m, 2H), 1.54-1.44 (m, 2H), 1.32 (s, 3H), 1.28 (s, 3H), 1.22-1.12 (m, 8H), 0.81 (t, J = 6.7 Hz, 3H).

Preparation of Mandelate ester 3a

To the solution of propargylic alcohol 3 (26 mg, 0.1 mmol) in DCM (1 mL) cooled at 0 ºC was added DCC (30 mg, 0.15 mmol), DMAP (1.2 mg), and (R)-methoxymandelic acid a (20 mg, 0.12 mmol). The reaction mixture was stirred overnight while gradually allowing the temperature to rise to rt. The solvent was evaporated under reduced pressure to furnish the crude compound which was purified by

column chromatography using 5% EtOAc/Hexanes (v/v) as the eluent to afford the product 3a (40 mg, 0.08 mmol) in 80% yield as a liquid. TLC, Rf 0.32 (10% EtOAc/Hexanes); 1H NMR (CDCl3, 300 MHz) δ 7.49-7.27 (m, 5H), 5.50 (t, J = 6.5 Hz, 1H), 4.88 (s, 1H), 3.55 (s, 3H), 1.36-1.08 (m, 18H), 1.02 (t, J = 6.0 Hz, 3H), 0.30 (s, 9H).

Preparation of Mandelate ester 3b

Prepared following the procedure detailed above using (S)-methoxymandelic acid as the acid partner.

1H NMR (CDCl3, 300 MHz) δ 1H NMR (CDCl3, 300 MHz) δ 7.53-7.39 (m, 5H), 5.44 (dd, J = 8.6, 6.5 Hz, 1H), 4.84 (s, 1H), 3.52 (s, 3H), 1.49-1.23 (m, 18H), 0.99 (t, J = 6.9 Hz, 3H), 0.26 (s, 9H).

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Mandelate ester of compound 7b:

O

O

OMe

HPh

H

Ph(O)CO

5

R R

1H NMR (400 MHz, CDCl3) δ7.8-6.9 (m, 10H), 5.4-5.3 (m, 1H), 4.75 (s, 1H), 4.3 (dd, J = 11.8, 4.0 Hz, 1H), 4.17 (dd, J = 11.8, 7.0 Hz, 1H), 3.4 (s, 3H), 2.18 (td, J = 7.4, 2.3 Hz, 2H), 1.86 (t, J = 2.3 Hz, 1H), 1.7-0.8 (m, 10H). MS (EI) m/z 445 [M+Na]+.

Mandelate ester of the enantiomer 7a:

O

O

OMe

HPh

HS

R

5

OC(O)Ph

1H NMR (400 MHz, CDCl3) δ7.9-7.1 (m, 10H), 5.3-5.2 (m, 1H), 4.7 (s,1H), 4.4 (dd, J = 12.0, 3.8 Hz, 1H), 4.26 (dd, J = 12.0, 6.8 Hz, 1H), 3.36 (s, 3H), 2.10 (td, J = 7.5, 2.3 Hz, 2H), 1.85 (t, J = 2.3 Hz, 1H), 1.6-0.9 (m, 10H). MS (EI) m/z 445 [M+Na]+.

Mandelate ester 6a

1H NMR (CDCl3, 300 MHz) δ 7.75 (d, J = 8.0 Hz, 2H), 7.45-7.10 (m, 8H), 5.30-5.20 (m, 1H), 4.73 (s, 1H), 4.32-4.12 (m, 2H), 3.40 (s, 3H), 2.15 (dt, J = 6.9, 2.6 Hz, 2H), 1.84 (t, J = 2.6 Hz, 1H), 1.74-1.18 (m, 12H).

Mandelate ester 6b

1H NMR (CDCl3, 300 MHz) δ 7.92 (d, J = 7.1 Hz, 2H), 7.50 (d, J = 7.1 Hz, 1H), 7.40-7.20 (m, 7H), 5.25-5.20 (m, 1H), 4.70 (s, 1H), 4.33 (dd, J = 7.2, 5.1 Hz, 1H), 4.20 (dd, J = 7.2, 6.2 Hz, 1H), 3.30 (s, 3H), 2.07 (dt, J = 6.9, 2.6 Hz, 2H), 1.78 (t, J = 2.6 Hz, 1H), 1.53-1.10 (m, 12H).

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Spectras

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