Facile and efficient synthesis of chiral sulfoxide esters: Versatile tool in asymmetric synthesis

Article abstract of DOI:10.1080/00397911.2018.1554145

Facile and efficient synthesis of sulfoxide esters using menthols as chiral auxiliary is described. Phenylthio/benzylthio/naphthylthioacetic esters act as an efficient substrate for chiral sulfoxides via oxidation in one step. The structural and stereochemical aspects of target product were established on the basis of various spectroscopic studies, namely FT-IR, NMR (¹H NMR and ¹³C NMR) and elemental analysis. This method is simple, fast, convenient and very efficient.

Full text of DOI:10.1080/00397911.2018.1554145

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Facile and efficient synthesis of chiral sulfoxide
esters: Versatile tool in asymmetric synthesis
Reshma Nagpal, Aman Bhalla, Jitender Bhalla, Shamsher S. Bari & Renu
Thapar
To cite this article: Reshma Nagpal, Aman Bhalla, Jitender Bhalla, Shamsher S. Bari & Renu
Thapar (2019): Facile and efficient synthesis of chiral sulfoxide esters: Versatile tool in asymmetric
synthesis, Synthetic Communications, DOI: 10.1080/00397911.2018.1554145
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https://doi.org/10.1080/00397911.2018.1554145
Facile and efficient synthesis of chiral sulfoxide esters:
Versatile tool in asymmetric synthesis
Reshma Nagpala, Aman Bhallab , Jitender Bhallac, Shamsher S. Barib, and
Renu Thapard
b
aDepartment of Chemistry, DAV College, Chandigarh, India; Department of Chemistry and Centre of
c
Advanced Studies in Chemistry, Panjab University, Chandigarh, India; Department of Chemistry,
d
Dev Samaj College for women, Chandigarh, India; University Institute of Engineering and Technology,
Panjab University, Chandigarh, India
ABSTRACT
ARTICLE HISTORY
Received 30 June 2018
Accepted 24 November 2018
Facile and efficient synthesis of sulfoxide esters using menthols as
chiral auxiliary is described. Phenylthio/benzylthio/naphthylthioacetic
esters act as an efficient substrate for chiral sulfoxides via oxidation
in one step. The structural and stereochemical aspects of target
product were established on the basis of various spectroscopic stud-
ies, namely FT-IR, NMR (1H NMR and 13C NMR) and elemental ana-
lysis. This method is simple, fast, convenient and very efficient.
KEYWORDS
b-Lactams; chiral sulfoxide
ester; menthol; oxidation
GRAPHICAL ABSTRACT
Introduction
The asymmetric synthesis of novel substrates for the synthesis of chiral molecules con-
stitutes an important field in synthetic organic chemistry. The use of chiral auxiliaries
in asymmetric synthesis has gained much attention of the scientific community in the
past few decades. With continuous efforts to explore the field of asymmetric synthesis
has led to the discovery of numerous groups as effective and efficient chirality control-
ler. The sulfinyl group is widely used as an important tool to bring about numerous
asymmetric transformations due to its high optical stability and better accessibility of
enantiomeric forms. Presently, the synthesis of chiral nonracemic sulfoxides with high
enantiomeric purity has been a subject of constant interest.[1–5]
CONTACT Aman Bhalla
amanbhalla@pu.ac.in; bhalla.jitender1@gmail.com
Department of Chemistry and Centre
of Advanced Studies in Chemistry, Panjab University, Chandigarh, 160 014, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

2
R. NAGPAL ET AL.
Figure 1. Biologically important sulfoxides.
The presence of stereogenic sulfinyl sulfur atom in many biologically active com-
pounds has increased the importance of sulfinyl derivatives. Omeprazole and its optic-
ally pure (S)-form A are well known antiulcer agents.[6,7] In addition to this,
sulforaphane B (anticancer drug), RP 73163 C (ACAT inhibitor) and many other sul-
finyl containing drugs are presently available in the market (Fig. 1).[8,9] Further, the
sulfoxide derivatives of b-lactams constitute a major class of mechanism-based b-lacta-
mase inhibitors such as sulbactam D.[10]
Our research group has been continuously working to explore novel b-lactam precur-
sors, various methodologies for the synthesis of monocyclic/spirocyclic/heteroaryl substi-
tuted b-lactams and their functionalization.[11,12] Recently, we have successfully utilized
b-lactam sulfoxides/selenoxide for the synthesis of (Z)- and (E)-3-allylidene-b-lac-
tams[13] and C-3 functionalized 3-sulfonyl-b-lactams.[14] Keeping in view of our interest
in b-lactam sulfoxides and their transformation into novel heterocycles triggered us to
carry out the synthesis of novel chiral sulfoxide esters which acts as versatile precursors
for chiral b-lactams and other valuable heterocycles.
Results and discussion
In continuation to above reports, it was envisaged to prepare esters 4 and 5 by the reac-
tion of methylthio/phenylthio/benzylthio/naphthylthioacetic acid 1 with chiral auxiliaries
such as (1R,2S,5R)-(ꢀ)-menthol/(1R,2S,5R)-(ꢀ)-8-phenylmenthol 2 in the presence of a
condensing agent, DCC and catalytic amount of DMAP. These esters were further oxi-
dized to give the corresponding pair of diastereomers 4–5.
Starting substrates, i.e. methylthio/phenylthio/benzylthio/naphthylthioacetic acid 1a–d
were prepared from chloroacetic acid and appropriate thiols using reported method-
ology.[15] In order to prepare chiral esters 3a–g, methylthio/phenylthio/benzylthio/naph-
thylthioacetic acid 1a–d were treated with cyclohexyl-based chiral alcohols, namely
(1R,2S,5R)-(ꢀ)-menthol 2a and (1R,2S,5R)-(ꢀ)-8-phenylmenthol 2b in the presence of a
condensing agent, N,N-dicyclohexylcarbodiimide (DCC) and catalytic amount of 4-(dime-
thylamino)pyridine (DMAP) in dry dichloromethane under nitrogen atmosphere, at room
temperature. The products 3a–g were purified by silica gel column chromatography (ethyl
1
acetate: hexane) and their structures were characterized on the basis of IR, H NMR, 13C
NMR and elemental analysis. The results are summarized in Table 1 and Scheme 1.

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3
Table 1. Chiral ester 3a–g.
Entry
R1
R2
Chiral ester 3
Yielda %
1
2
3
4
5
6
7
Me
Ph
Bz
Naphthyl
Me
Ph
Naphthyl
H
H
H
H
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
87
59
50
38
57
51
59
3g
aIsolated yields after chromatographic purification.
Scheme 1. Synthesis of chiral esters 3a–g.
Table 2. Chiral sulfoxide esters 4–5.
Chiral sulfoxide
esters 4–5
Entry
Chiral ester 3
Time (h)
Yielda %
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
117
23
114
15
95
17
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
94
85
82
85
83
66
71
3g
48
4g
5g
Reaction conditions: Chiral ester 3 (1 mmol), NaIO4 (1.1 mmol), MeOH:H2O (10:1), 0 ꢁC to rt, stirring.
aIsolated yields after chromatographic purification.
Scheme 2. Synthesis of chiral sulfoxide esters 4–5.
After the successful introduction of chiral auxiliary, various chiral esters 3a–g were oxi-
dized by using different oxidizing agents to give a pair of diastereomers 4–5. Initially, 3a
was oxidized with NaIO4 using MeOH:H2O as solvent system (H2O is used to enhance
the solubility of NaIO4). The progress of the reaction was monitored by TLC. The TLC
profile showed the appearance of a spot having Rf lower than the starting substrate. As
soon as starting substrate completely disappeared, reaction was stopped and worked up.
The crude product was purified by silica gel column chromatography eluting with 2%
EtOAc/hexane. The product was identified as a mixture of two diastereomeric chiral sulf-
oxide esters 4a and 5a (Table 2, and Scheme 2 entry 1). In addition to this, no sulfone for-
mation was observed in the reaction under controlled conditions.
The identification of the characteristic peaks in NMR spectra of 4f and 5f confirmed
the formation of products, namely in the 1H and 13C NMR spectrum, the most
desheilded aliphatic peak corresponds to methine proton directly attached to O of ester

4
R. NAGPAL ET AL.
Table 3. Utility of other oxidizing agents.
Reagent Time (4 þ 5, Yielda)
30% H2O2
in CH3COOH
30% H2O2/ClCOOEt
30% H2O2/C5H5N
in CH2Cl2
Entry
Chiral ester 3
in CH2Cl2
m-CPBA in CH2Cl2
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
22 h (84%)
51 h (76%)
30 min (93%)b
17 h (36%)
1.5 h (52%)
1 h (75%)b
–
46 h (79%)
10 h (75%)
1.5 h (76%)
4 h (53%)
2.5 h (70%)
45 min (86%)
–
1.5 h (96%)
40 min (58%)
4 h (80%)
15 min (82%)
–
–
–
–
45 h (36%)
–
–
–
–
3g
10 min (76%)
aIsolated yields of chiral sulfoxide esters (4 þ 5) after chromatographic purification.
bTemperature 60 ꢁC.
group (i.e. 4.82, 75.6 in 4f and 4.80, 75.9 in 5f). Further, two sets of doublets having
1
same coupling constant (J) values (2.73, 3.15 in 4f and 2.95, 3.06 in 5f) in H NMR and
desheilded peak (61.2 in 4f and 60.8 in 5f) due to the presence of C ¼ O group in the
neighborhood corresponds to CH2CO group.
The diastereomeric ratio (dr) of chiral sulfoxide esters 4a and 5a was calculated from
1H NMR. Since the signal for methine proton of the chiral auxiliary did not give much
information about the ratio of the two isomers due to its complex nature, therefore the
signal for the methyl (C50–Me) of both the isomers were analyzed for dr calculations.
1
The dr of 4a and 5a was found to be 1:1 as evident from H NMR analysis.
Further, the scope of the reaction was analyzed by treating various chiral esters 3b–d
[R2 = H; (1R,2S,5R)-(–)-menthol as chiral auxiliary] with varying R1 groups under simi-
lar reaction conditions which resulted in the formation of products in excellent yields
(Table 2, entries 2–4). However, products were obtained as non-separable mixture.
Therefore, in order to increase the utility of sulfoxide esters, oxidation of chiral esters
3e–g having bulky aryl group (R2 = Ph) was carried out and separable mixture of chiral
sulfoxide esters was obtained in case of chiral esters 3f–g (Table 2, entries 6–7). In case
of chiral ester 3f–g, the chiral sulfoxide esters 4f, 4g and 5f, 5g were easily separated by
column chromatography and assigned (S)- and (R)- configuration, respectively.[16] The
reaction was found to be general in all the cases and results are summarized in Table 2.
The structure of chiral sulfoxide esters 4–5(b–g) was confirmed on the basis of FT-IR,
1H NMR, 13C NMR and elemental analysis.
The chiral esters 3a–g were successfully oxidized using NaIO4 in MeOH:H2O solvent
system and the products were obtained excellent yields. However, the time required for
the completion of reaction was very high. Therefore, the oxidation of chiral esters 3a–g
was tried with different oxidizing agents and reaction conditions were optimized. For
this purpose, chiral esters 3a-g were oxidized using different oxidizing systems, namely
30% H2O2 in CH3COOH, 30% H2O2/ClCOOEt in CH2Cl2 and m-CPBA in CH2Cl2 and
the results are summarized in Table 3. The oxidation of chiral esters 3a–g with various
oxidizing agents afforded the products in very good to excellent yields as shown in
Table 3. Furthermore, m-CPBA in CH2Cl2 was found to be the best system for oxida-
tion of chiral esters 3a–g as time required for the completion of reaction was greatly
reduced in addition to excellent yields.
This is further supported by the kinetic study reported in the literature that oxidation
of sulfides using peracetic acids occurred very fast.[17] In general, both NaIO4 and m-

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SYNTHETIC COMMUNICATIONSV
5
Figure 2. Synthetic applications of chiral sulfoxide esters.
CPBA are very good reagents for oxidation of sulfides.[18] The actual mechanisms are
unknown, but more polar transition state formed during electrophilic transfer of oxygen
to sulfur using m-CPBA might be the primary cause of fast oxidation. Further, lack of
diastereoselectivity might be attributed to the presence of chiral auxiliary at the opposite
side of sulfoxide group and diastereoselectivity can be improved by increasing the prox-
imity of chiral auxiliary to the sulfide group.
Further, transformation of chiral sulfoxide esters 4–5 into various synthetically useful
molecules, namely chiral acids, esters, amides and b-lactams is currently being pursued
in our laboratory (Fig. 2).
Conclusion
To summarize, novel chiral sulfoxide esters were prepared using a simple, efficient and
fast methodology using cyclohexyl based chiral auxiliaries. Further, improving diastereo-
selectivity and transformation of these chiral synthons into corresponding chiral b-lac-
tams/other valuable heterocycles has been pursued in our laboratory. Further, a detailed
report elaborating synthesis and biological evaluation of chiral b-lactams will be pub-
lished in near future.
Experimental
Melting points were determined in an open capillary on melting point apparatus (Perfit
GSI-MP-3) and are uncorrected. Fourier transform infrared spectra were recorded on a
Thermo Scientific Nicolet iS50 (FT-IR) spectrophotometer (ꢀmax in cmꢀ1). 1H
(300 MHz) and 13C (75 MHz) NMR spectra were recorded on JEOL AL 300 (300 MHz)
spectrometer. Chemical shifts are given in ppm relative to Me4Si as an internal standard
1
(d ¼ 0 ppm) for H NMR, CDCl3 (d ¼ 77.0 ppm) for 13C NMR. The elemental analysis
(C, H) were recorded on Flash 2000 Organic elemental analyzer. Column chromatog-
raphy was performed using Merck Silica Gel (60–120 mesh) using EtOAc:hexane

6
R. NAGPAL ET AL.
(10:90) as an eluant system. Analytical thin-layer chromatography (TLC) was performed
on precoated silica gel F254 aluminum plates with visualization under UV light.
General procedure for the synthesis of chiral sulfoxide esters (4–5, a–g)
To a stirred solution of ester 3f (0.078 mmol) in 5 mL methanol, sodium metaperiodate
(0.079 mmol) dissolved in minimum amount of water at 0 ꢁC was added. The progress
of the reaction was monitored by TLC. After the completion of reaction, the solvent
was evaporated under reduced pressure and product was extracted with methylene
chloride (3 ꢂ 10 mL) and the contents were washed with water (2 ꢂ 10 mL). The com-
bined organic extracts were dried over anhydrous Na2SO4 and filtered. The residue after
solvent evaporation in vacuum, was purified by silica gel column chromatography using
10% EtOAc/hexane as eluent to furnish chiral sulfoxide esters 4 and 5. Their structures
were confirmed on the basis of following spectral data.
Benzenesulfinyl-acetic acid 50-methyl-20-(100-methyl-100-phenyl-ethyl)-cyclohexyl ester (4f)
Pale white solid; Yield 37%; mp 123–124 ꢁC; FT-IR (CHCl3) ꢀ: 1045 (S¼ O), 1721 (C ¼ O)
1
cmꢀ1; H NMR spectrum (300 MHz, CDCl3), d, ppm (J, Hz): 0.82–2.17 (17H, m), 2.73
(1H, d, J¼ 13.7 Hz, CH2), 3.15 (1H, d, J¼ 13.7 Hz, CH2), 4.82 (1H, dt, J¼ 4.5, 10.8 Hz,
CH), 7.11–7.58 (10H, m, ArH); 13C NMR spectrum (75MHz, CDCl3), d, ppm: 21.7 (CH3),
22.2 (CH3), 26.1 (CH2), 30.1 (CH3), 31.3 (CH), 34.4 (CH2), 39.4 (CMe2Ph), 41.3 (CH2),
50.0 (CH), 61.2 (CH2CO), 75.6 (CH–O), 124.4 (Ar-C), 125.1 (Ar-C), 125.5 (Ar-C), 128.1
(Ar-C), 129.3 (Ar-C), 131.6 (Ar-C), 143.4 (Ar-C), 152.0 (Ar-C), 164.0 (C=O); Elemental
analysis: found (%): C, 72.23; H, 7.51. C24H30O3S calculated (%): C, 72.32; H, 7.59.
Benzenesulfinyl-acetic
ester (5f)
acid
50-methyl-20-(100-methyl-100-phenyl-ethyl)-cyclohexyl
Crystalline solid; Yield 29%; mp 110–111 ꢁC; FT-IR (CHCl3) ꢀ: 1041 (S¼ O), 1721
1
(C ¼ O) cmꢀ1; H NMR spectrum (300 MHz, CDCl3), d, ppm (J, Hz): 0.82–2.02 (17H, m),
2.95 (1H, d, J¼ 14.2 Hz, CH2), 3.06 (1H, d, J¼ 14.1 Hz, CH2), 4.80 (1H, dt, J¼ 4.5, 10.8 Hz,
CH), 7.20–7.61 (10H, m, ArH); 13C NMR spectrum (75MHz, CDCl3), d, ppm: 21.8 (CH3),
22.8 (CH3), 26.2 (CH2), 29.7 (CH3), 31.3 (CH), 34.4 (CH2), 39.4 (CMe2Ph), 41.5 (CH2),
50.0 (CH), 60.8 (CH2CO), 75.9 (CH-O), 124.5 (Ar-C), 125.1 (Ar-C), 125.4 (Ar-C), 128.0
(Ar-C), 129.2 (Ar-C), 131.6 (Ar-C), 143.2 (Ar-C), 151.8 (Ar-C), 164.2 (C=O); Elemental
analysis: found (%): C, 72.11; H, 7.06. C24H30O3S calculated (%): C, 72.32; H, 7.59.
Funding
Reshma acknowledges the financial support from Council of Scientific and Industrial Research
(CSIR), New Delhi. AB gratefully acknowledges the financial support for this work from
Department of Science and Technology (DST), New Delhi, Government of India. Project No. SR/
FT/CS-037/2010 dated 28-10-2010. JB acknowledge the financial support from University Grants
Commission (UGC) vide sanction No. F.17-7(J)/2004 (SA-I) dated 03-10-2011.
ORCID
Aman Bhalla
http://orcid.org/0000-0003-4081-4116

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