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Abstract

Monoterpene thiols are one of the classes of natural flavors that impart the smell of citrus fruits, grape must and wine, black currants, and guava and are used as flavoring agents in the food and perfume industries. Synthetic monoterpene thiols have found an application in asymmetric synthesis as chiral auxiliaries, derivatizing agents, and ligands for metal complex catalysis and organocatalysts. Since monoterpenes and monoterpenoids are a renewable source, there are emerging trends to use monoterpene thiols as monomers for producing new types of green polymers. Monoterpene thioderivatives are also known to possess antioxidant, anticoagulant, antifungal, and antibacterial activity. The current review covers methods for the synthesis of acyclic, mono-, and bicyclic monoterpene thiols, as well as some investigations related to their usage for the preparation of the compounds with antimicrobial properties.
Citation: Sudarikov, D.V.; Nikitina,
L.E.; Rollin, P.; Izmest’ev, E.S.;
Rubtsova, S.A. Monoterpene Thiols:
Synthesis and Modifications for
Obtaining Biologically Active
Substances. Int. J. Mol. Sci. 2023,24,
15884. https://doi.org/10.3390/
ijms242115884
Academic Editor: Antonella Piozzi
Received: 10 October 2023
Revised: 26 October 2023
Accepted: 30 October 2023
Published: 1 November 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
International Journal of
Molecular Sciences
Review
Monoterpene Thiols: Synthesis and Modifications for
Obtaining Biologically Active Substances
Denis V. Sudarikov 1,* , Liliya E. Nikitina 2, Patrick Rollin 3, Evgeniy S. Izmest’ev 1
and Svetlana A. Rubtsova 1
1Institute of Chemistry, Federal Research Center “Komi Scientific Center”, Ural Branch, Russian Academy of
Sciences, 167000 Syktyvkar, Russia; evgeniyizmestev@rambler.ru (E.S.I.);
rubtsova-sa@chemi.komisc.ru (S.A.R.)
2General and Organic Chemistry Department, Kazan State Medical University, 49 Butlerov St.,
420012 Kazan, Russia; nikitl@mail.ru
3
Institute of Organic and Analytical Chemistry (ICOA), Universitéd’Orléans et the French National Center for
Scientific Research (CNRS), UMR 7311, BP 6759, F-45067 Orléans, France; patrick.rollin@univ-orleans.fr
*Correspondence: sudarikov_dv@yahoo.com; Tel.: +7-8212-241-045
Abstract:
Monoterpene thiols are one of the classes of natural flavors that impart the smell of
citrus fruits, grape must and wine, black currants, and guava and are used as flavoring agents
in the food and perfume industries. Synthetic monoterpene thiols have found an application in
asymmetric synthesis as chiral auxiliaries, derivatizing agents, and ligands for metal complex catalysis
and organocatalysts. Since monoterpenes and monoterpenoids are a renewable source, there are
emerging trends to use monoterpene thiols as monomers for producing new types of green polymers.
Monoterpene thioderivatives are also known to possess antioxidant, anticoagulant, antifungal, and
antibacterial activity. The current review covers methods for the synthesis of acyclic, mono-, and
bicyclic monoterpene thiols, as well as some investigations related to their usage for the preparation
of the compounds with antimicrobial properties.
Keywords:
monoterpenoids; thiols; asymmetric synthesis; disulfides; thiosulfonates; sulfenimines;
sulfinamides; antimicrobial activity
1. Introduction
Sulfur-containing monoterpenoids, and especially thiols, being natural flavoring
agents that impart the pleasant aroma to citrus fruits, wine, and black currants, are of inter-
est in the exploration of flavors and fragrances [
1
4
]. Synthetic monoterpene thiols, known
for their natural enantiomeric purity, have found applications in asymmetric synthesis.
For example, pinane, menthane, and bornane thiols are used as chiral auxiliaries [
5
10
],
chiral ligands for metal complex catalysis [
11
14
], organocatalysts [
15
], and chiral resolving
agents [
16
]. Recently, there has been a tendency to exploit monoterpenes—in particular,
monoterpene thiols—as monomers for producing green polymers [17,18].
The spread of multidrug-resistant pathogenic microorganisms poses the challenge of
searching for new antimicrobials with novel modes of action to which microorganisms
have not yet developed resistance [
19
]. The acquisition of genes encoding efflux systems or
enzymes able to hydrolyze antimicrobials, the increased biofilm formation, and the struc-
tural changes in target molecules and the cell wall reduce the effectiveness of traditional
antibiotics [20].
Among the various classes of molecules which can keep down the growth of pathogenic
bacteria and fungi, monoterpene derivatives stand out for their broad spectrum of antimi-
crobial activity [
21
23
]. The ability of monoterpenoids to inhibit the growth of diverse
bacteria and fungi has been reported [21,2429].
Int. J. Mol. Sci. 2023,24, 15884. https://doi.org/10.3390/ijms242115884 https://www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2023,24, 15884 2 of 22
The combination of terpenes with known antimicrobials increases the activity of the
latter [
30
32
]. The introduction of sulfur functional groups into the structure of biologically
active terpenes often enhances the antibacterial and antifungal activity of the resulting
thio-modified monoterpenoids compared to the original terpenes [
21
,
29
,
33
36
]. Pinane and
menthane sulfides containing a fragment of 2-mercaptoacetic acid methyl ester showed
a wide range of antifungal activity against pathogenic strains of Candida albicans and a
number of mycelial fungi [21,29].
The reason for these synergistic effects may be explained by the increased affinity of
terpenes for the membrane or membrane-associated proteins. The binding site for cyclic
hydrocarbons, including terpenes, is known to be in the cell membrane of pathogenic
microorganisms [
37
]. Some terpenes, such as limonene,
α
- and
β
-pinenes, and
γ
-terpinene,
can suppress respiration and other energy-dependent processes localized in the cell mem-
branes of fungi and bacteria [
22
,
38
41
]. Furthermore, some terpene derivatives interact
with eukaryotic cell membranes [29,42].
Only a few reviews have been devoted to the synthesis and biological activity of thio-
modified monoterpenoids [
21
,
29
,
43
]. The current review covers methods for the synthesis
of acyclic, mono-, and bicyclic monoterpene thiols, as well as some investigations related to
their usage for preparing new compounds with antimicrobial properties.
2. Synthesis of Monoterpene Thiols
Thiols are one of the most convenient synthons in the synthesis of organosulfur
compounds. The typical methods to prepare monoterpene thiols include the electrophilic
addition of H
2
S or dithiols to the double bond of monoterpenes; nucleophilic substitution
of halides; tosylates/mesylates obtained from corresponding monoterpene alcohols; thia-
Michael addition of S-nucleophiles to α,β-unsaturated ketones; nucleophilic epoxide ring
opening; nucleophilic substitution of the activated methylene protons; and reduction of
sulfochlorides, dithiolanes, thiiranes, and sultones.
2.1. Synthesis from Alkenes
The synthesis of terpene thiols from limonene,
α
-pinene,
α
-,
γ
-terpinenes, terpinolene,
and 3-carene via a reaction of them with H
2
S in the presence of Lewis acids such as AlCl
3
or AlBr
3
is described in [
44
]. The addition of H
2
S usually occurs without selectivity and
is accompanied by numerous side reactions, including the rearrangement of the terpene
skeleton, especially in cases with bicyclic systems. The addition of H
2
S to limonene
1
catalyzed by AlCl
3
proceeds with no regioselectivity and gives thiols
2
5
in low yields,
with the intramolecular cyclization of thiols
4
and
5
at the double bond affording sulfides
6
and 7as the main products (Scheme 1) [4547].
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 2 of 23
spectrum of antimicrobial activity [2123]. The ability of monoterpenoids to inhibit the
growth of diverse bacteria and fungi has been reported [21,2429].
The combination of terpenes with known antimicrobials increases the activity of the
laer [3032]. The introduction of sulfur functional groups into the structure of
biologically active terpenes often enhances the antibacterial and antifungal activity of the
resulting thio-modified monoterpenoids compared to the original terpenes [21,29,3336].
Pinane and menthane sulfides containing a fragment of 2-mercaptoacetic acid methyl
ester showed a wide range of antifungal activity against pathogenic strains of Candida
albicans and a number of mycelial fungi [21,29].
The reason for these synergistic effects may be explained by the increased affinity of
terpenes for the membrane or membrane-associated proteins. The binding site for cyclic
hydrocarbons, including terpenes, is known to be in the cell membrane of pathogenic
microorganisms [37]. Some terpenes, such as limonene, α- and β-pinenes, and γ-
terpinene, can suppress respiration and other energy-dependent processes localized in the
cell membranes of fungi and bacteria [22,3841]. Furthermore, some terpene derivatives
interact with eukaryotic cell membranes [29,42].
Only a few reviews have been devoted to the synthesis and biological activity of thio-
modified monoterpenoids [21,29,43]. The current review covers methods for the synthesis
of acyclic, mono-, and bicyclic monoterpene thiols, as well as some investigations related
to their usage for preparing new compounds with antimicrobial properties.
2. Synthesis of Monoterpene Thiols
Thiols are one of the most convenient synthons in the synthesis of organosulfur
compounds. The typical methods to prepare monoterpene thiols include the electrophilic
addition of H2S or dithiols to the double bond of monoterpenes; nucleophilic substitution
of halides; tosylates/mesylates obtained from corresponding monoterpene alcohols; thia-
Michael addition of S-nucleophiles to α-unsaturated ketones; nucleophilic epoxide ring
opening; nucleophilic substitution of the activated methylene protons; and reduction of
sulfochlorides, dithiolanes, thiiranes, and sultones.
2.1. Synthesis from Alkenes
The synthesis of terpene thiols from limonene, α-pinene, α-, γ-terpinenes,
terpinolene, and 3-carene via a reaction of them with H2S in the presence of Lewis acids
such as AlCl3 or AlBr3 is described in [44]. The addition of H2S usually occurs without
selectivity and is accompanied by numerous side reactions, including the rearrangement
of the terpene skeleton, especially in cases with bicyclic systems. The addition of H2S to
limonene 1 catalyzed by AlCl3 proceeds with no regioselectivity and gives thiols 25 in
low yields, with the intramolecular cyclization of thiols 4 and 5 at the double bond
affording sulfides 6 and 7 as the main products (Scheme 1) [4547].
Scheme 1. The addition of H2S to limonene 1 catalyzed by AlCl3.
The interaction of α-pinene 8 with H2S under the same conditions leads to products
27, as well as cyclic sulfide 9 [44].
Scheme 1. The addition of H2S to limonene 1catalyzed by AlCl3.
The interaction of
α
-pinene
8
with H
2
S under the same conditions leads to products
27, as well as cyclic sulfide 9[44].
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 3 of 23
Electrophilic thiylation of α-pinene 8 with H2S in the presence of AlBr3 (A) is followed
by the pinenementhane rearrangement, providing carbocation 10, which, when reacting
with H2S, gives thiol 4. The softer Lewis acid EtAlCl2 (B) stereoselectively catalyzes the
anti-addition of H2S via the formation of intermediate 11 and leads to trans-pinane-2-thiol
12 (Scheme 2) [4]. With a strong Lewis acid (BF3·Et2O) used as a catalyst, the Wagner
Meerwein rearrangement occurs to yield isobornanethiol 13 [4,46].
Scheme 2. The addition of H2S to α-pinene 8.
The addition of hydrogen sulfide to 3-carene 14 in the presence of AlCl3 proceeds
nonselectively to give the products in low yields. The detected products included a
mixture of cis- and trans-thiols 15; episulfides 16, 6, and 7; and para-menthane thiols 17, 18,
2, and 3 (Scheme 3) [44].
Scheme 3. The addition of H2S to 3-carene 14 catalyzed by AlCl3.
Reactions of racemic camphene 19 with thioacetic acid under various conditions were
investigated in [48] (Scheme 4). It was established that, under catalyst-free conditions and
with a long reaction time (12 h), the anti-Markovnikov product 20 was predominantly
formed. The use of p-toluenesulfonic acid as a catalyst also leads to thioester 20, but in a
15% yield. Catalysis with trifluoromethanesulfonic acid (TfOH) and InCl3 at different
temperatures gives different ratios of products. The optimal yield of thioacetate 21 (75%),
a product of the WagnerMeerwein rearrangement, was achieved using a catalyst TfOH
at 40 °C for 20 min. The yield of a by-product, thioacetate 20, from this procedure does not
exceed 25%. The best method to obtain Markovnikov product 22 (82%) with a preserving
camphane structure was catalysis via In(OTf)3 at ≤0 °C. The deacylation of thioacetate 22
with LiAlH4 leads to racemic camphane thiol 23 at an 86% yield.
Electrophilic thiylation of
α
-pinene
8
with H
2
S in the presence of AlBr
3
(A) is followed
by the pinene–menthane rearrangement, providing carbocation
10
, which, when reacting
Int. J. Mol. Sci. 2023,24, 15884 3 of 22
with H
2
S, gives thiol
4
. The softer Lewis acid EtAlCl
2
(B) stereoselectively catalyzes the
anti-addition of H
2
S via the formation of intermediate
11
and leads to trans-pinane-2-thiol
12
(Scheme 2) [
4
]. With a strong Lewis acid (BF
3·
Et
2
O) used as a catalyst, the Wagner–
Meerwein rearrangement occurs to yield isobornanethiol 13 [4,46].
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 3 of 23
Electrophilic thiylation of α-pinene 8 with H2S in the presence of AlBr3 (A) is followed
by the pinenementhane rearrangement, providing carbocation 10, which, when reacting
with H2S, gives thiol 4. The softer Lewis acid EtAlCl2 (B) stereoselectively catalyzes the
anti-addition of H2S via the formation of intermediate 11 and leads to trans-pinane-2-thiol
12 (Scheme 2) [4]. With a strong Lewis acid (BF3·Et2O) used as a catalyst, the Wagner
Meerwein rearrangement occurs to yield isobornanethiol 13 [4,46].
Scheme 2. The addition of H2S to α-pinene 8.
The addition of hydrogen sulfide to 3-carene 14 in the presence of AlCl3 proceeds
nonselectively to give the products in low yields. The detected products included a
mixture of cis- and trans-thiols 15; episulfides 16, 6, and 7; and para-menthane thiols 17, 18,
2, and 3 (Scheme 3) [44].
Scheme 3. The addition of H2S to 3-carene 14 catalyzed by AlCl3.
Reactions of racemic camphene 19 with thioacetic acid under various conditions were
investigated in [48] (Scheme 4). It was established that, under catalyst-free conditions and
with a long reaction time (12 h), the anti-Markovnikov product 20 was predominantly
formed. The use of p-toluenesulfonic acid as a catalyst also leads to thioester 20, but in a
15% yield. Catalysis with trifluoromethanesulfonic acid (TfOH) and InCl3 at different
temperatures gives different ratios of products. The optimal yield of thioacetate 21 (75%),
a product of the WagnerMeerwein rearrangement, was achieved using a catalyst TfOH
at 40 °C for 20 min. The yield of a by-product, thioacetate 20, from this procedure does not
exceed 25%. The best method to obtain Markovnikov product 22 (82%) with a preserving
camphane structure was catalysis via In(OTf)3 at ≤0 °C. The deacylation of thioacetate 22
with LiAlH4 leads to racemic camphane thiol 23 at an 86% yield.
Scheme 2. The addition of H2S to α-pinene 8.
The addition of hydrogen sulfide to 3-carene
14
in the presence of AlCl
3
proceeds
nonselectively to give the products in low yields. The detected products included a mixture
of cis- and trans-thiols
15
; episulfides
16
,
6
, and
7
; and para-menthane thiols
17
,
18
,
2
, and
3
(Scheme 3) [44].
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 3 of 23
Electrophilic thiylation of α-pinene 8 with H2S in the presence of AlBr3 (A) is followed
by the pinenementhane rearrangement, providing carbocation 10, which, when reacting
with H2S, gives thiol 4. The softer Lewis acid EtAlCl2 (B) stereoselectively catalyzes the
anti-addition of H2S via the formation of intermediate 11 and leads to trans-pinane-2-thiol
12 (Scheme 2) [4]. With a strong Lewis acid (BF3·Et2O) used as a catalyst, the Wagner
Meerwein rearrangement occurs to yield isobornanethiol 13 [4,46].
Scheme 2. The addition of H2S to α-pinene 8.
The addition of hydrogen sulfide to 3-carene 14 in the presence of AlCl3 proceeds
nonselectively to give the products in low yields. The detected products included a
mixture of cis- and trans-thiols 15; episulfides 16, 6, and 7; and para-menthane thiols 17, 18,
2, and 3 (Scheme 3) [44].
Scheme 3. The addition of H2S to 3-carene 14 catalyzed by AlCl3.
Reactions of racemic camphene 19 with thioacetic acid under various conditions were
investigated in [48] (Scheme 4). It was established that, under catalyst-free conditions and
with a long reaction time (12 h), the anti-Markovnikov product 20 was predominantly
formed. The use of p-toluenesulfonic acid as a catalyst also leads to thioester 20, but in a
15% yield. Catalysis with trifluoromethanesulfonic acid (TfOH) and InCl3 at different
temperatures gives different ratios of products. The optimal yield of thioacetate 21 (75%),
a product of the WagnerMeerwein rearrangement, was achieved using a catalyst TfOH
at 40 °C for 20 min. The yield of a by-product, thioacetate 20, from this procedure does not
exceed 25%. The best method to obtain Markovnikov product 22 (82%) with a preserving
camphane structure was catalysis via In(OTf)3 at ≤0 °C. The deacylation of thioacetate 22
with LiAlH4 leads to racemic camphane thiol 23 at an 86% yield.
Scheme 3. The addition of H2S to 3-carene 14 catalyzed by AlCl3.
Reactions of racemic camphene
19
with thioacetic acid under various conditions were
investigated in [
48
] (Scheme 4). It was established that, under catalyst-free conditions and
with a long reaction time (12 h), the anti-Markovnikov product
20
was predominantly
formed. The use of p-toluenesulfonic acid as a catalyst also leads to thioester
20
, but in
a 15% yield. Catalysis with trifluoromethanesulfonic acid (TfOH) and InCl
3
at different
temperatures gives different ratios of products. The optimal yield of thioacetate
21
(75%), a
product of the Wagner–Meerwein rearrangement, was achieved using a catalyst TfOH at
40
C for 20 min. The yield of a by-product, thioacetate
20
, from this procedure does not
exceed 25%. The best method to obtain Markovnikov product
22
(82%) with a preserving
camphane structure was catalysis via In(OTf)
3
at
0
C. The deacylation of thioacetate
22
with LiAlH4leads to racemic camphane thiol 23 at an 86% yield.
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 4 of 23
Scheme 4. Synthesis of camphane thiol 23.
Photochemical addition of thioacetic acid to ()-sabinene 24 gives a mixture of anti-
Markovnikov bicyclic thioacetate 25 and unsaturated thioacetate 26 in an overall yield of
24% and a 3:1 ratio, respectively [49]. The unexpected formation of thioacetate 26 results
from cyclopropane ring cleavage. The mixture of thioacetates 25 and 26 was treated with
LiAlH4 to produce thiols 27 and 28 in an overall yield of 95% (Scheme 5). The obtained
thiols were isolated by preparative capillary GC.
Scheme 5. Synthesis of thiols from sabinene 24.
2.2. Ene Reaction of Monoterpenes with N-sulfinylbenzenesulfonamide
An efficient method for the synthesis of monoterpene allyl thiols using N-
sulfinylbenzenesulfonamide 29 as an enophile in ene reaction was proposed in the paper
[50] (Scheme 6). The interaction of terpenes (α- and β-pinenes 8 and 30; 2- and 3-carenes
31 and 14; and α-thujene 32) with N-sulfinylbenzenesulfonamide 29 proceeds at a double
bond with the formation of adducts 3337 with a migration of the double bond to an α-
position. It should be noted that these reactions occur stereo- and regioselectively. The
adducts 3337, when reduced with LiAlH4, provide the corresponding allyl thiols, 3842.
Scheme 6. Synthesis of allylic terpene thiols 3842.
Scheme 4. Synthesis of camphane thiol 23.
Int. J. Mol. Sci. 2023,24, 15884 4 of 22
Photochemical addition of thioacetic acid to (
)-sabinene
24
gives a mixture of anti-
Markovnikov bicyclic thioacetate
25
and unsaturated thioacetate
26
in an overall yield of
24% and a 3:1 ratio, respectively [
49
]. The unexpected formation of thioacetate
26
results
from cyclopropane ring cleavage. The mixture of thioacetates
25
and
26
was treated with
LiAlH
4
to produce thiols
27
and
28
in an overall yield of 95% (Scheme 5). The obtained
thiols were isolated by preparative capillary GC.
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 4 of 23
Scheme 4. Synthesis of camphane thiol 23.
Photochemical addition of thioacetic acid to ()-sabinene 24 gives a mixture of anti-
Markovnikov bicyclic thioacetate 25 and unsaturated thioacetate 26 in an overall yield of
24% and a 3:1 ratio, respectively [49]. The unexpected formation of thioacetate 26 results
from cyclopropane ring cleavage. The mixture of thioacetates 25 and 26 was treated with
LiAlH4 to produce thiols 27 and 28 in an overall yield of 95% (Scheme 5). The obtained
thiols were isolated by preparative capillary GC.
Scheme 5. Synthesis of thiols from sabinene 24.
2.2. Ene Reaction of Monoterpenes with N-sulfinylbenzenesulfonamide
An efficient method for the synthesis of monoterpene allyl thiols using N-
sulfinylbenzenesulfonamide 29 as an enophile in ene reaction was proposed in the paper
[50] (Scheme 6). The interaction of terpenes (α- and β-pinenes 8 and 30; 2- and 3-carenes
31 and 14; and α-thujene 32) with N-sulfinylbenzenesulfonamide 29 proceeds at a double
bond with the formation of adducts 3337 with a migration of the double bond to an α-
position. It should be noted that these reactions occur stereo- and regioselectively. The
adducts 3337, when reduced with LiAlH4, provide the corresponding allyl thiols, 3842.
Scheme 6. Synthesis of allylic terpene thiols 3842.
Scheme 5. Synthesis of thiols from sabinene 24.
2.2. Ene Reaction of Monoterpenes with N-sulfinylbenzenesulfonamide
An efficient method for the synthesis of monoterpene allyl thiols using N-sulfinyl
benzenesulfonamide
29
as an enophile in ene reaction was proposed in the paper [
50
]
(Scheme 6). The interaction of terpenes (
α
- and
β
-pinenes
8
and
30
; 2- and 3-carenes
31
and
14
; and
α
-thujene
32
) with N-sulfinylbenzenesulfonamide
29
proceeds at a double bond
with the formation of adducts
33
37
with a migration of the double bond to an
α
-position.
It should be noted that these reactions occur stereo- and regioselectively. The adducts
33
37
,
when reduced with LiAlH4, provide the corresponding allyl thiols, 3842.
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 4 of 23
Scheme 4. Synthesis of camphane thiol 23.
Photochemical addition of thioacetic acid to ()-sabinene 24 gives a mixture of anti-
Markovnikov bicyclic thioacetate 25 and unsaturated thioacetate 26 in an overall yield of
24% and a 3:1 ratio, respectively [49]. The unexpected formation of thioacetate 26 results
from cyclopropane ring cleavage. The mixture of thioacetates 25 and 26 was treated with
LiAlH4 to produce thiols 27 and 28 in an overall yield of 95% (Scheme 5). The obtained
thiols were isolated by preparative capillary GC.
Scheme 5. Synthesis of thiols from sabinene 24.
2.2. Ene Reaction of Monoterpenes with N-sulfinylbenzenesulfonamide
An efficient method for the synthesis of monoterpene allyl thiols using N-
sulfinylbenzenesulfonamide 29 as an enophile in ene reaction was proposed in the paper
[50] (Scheme 6). The interaction of terpenes (α- and β-pinenes 8 and 30; 2- and 3-carenes
31 and 14; and α-thujene 32) with N-sulfinylbenzenesulfonamide 29 proceeds at a double
bond with the formation of adducts 3337 with a migration of the double bond to an α-
position. It should be noted that these reactions occur stereo- and regioselectively. The
adducts 3337, when reduced with LiAlH4, provide the corresponding allyl thiols, 3842.
Scheme 6. Synthesis of allylic terpene thiols 3842.
Scheme 6. Synthesis of allylic terpene thiols 3842.
2.3. Synthesis from α,β-Unsaturated Carbonyl Compounds
Thiols are good nucleophiles for thia-Michael addition to
α
,
β
-unsaturated carbonyl
compounds [
51
]. However, harsh reaction conditions are required to convert the newly
formed sulfide group into a synthetically more versatile SH group. Thioacids (RCOSH) are
more attractive as nucleophiles for the Michael addition reaction, since the resulting thioesters
can be easily transformed into corresponding thiols under mild conditions [5,52,53].
Myrtenal-based hydroxythiol
43
was synthesized by two methods with a high yield
and stereoselectivity [
5
]. The treatment of (
)-myrtenal
44
with benzylthiol and 10% aque-
ous NaOH in THF at room temperature for 18 h led to sulfide
45
(yield 92%, de 96%).
Compound
45
was reduced to the corresponding alcohol
46
(yield 96%) with LiAlH
4
in
Et
2
O, which was then hydrogenolyzed to hydroxythiol
43
under Birch reduction conditions
(Scheme 7). The hydrogenolysis did not provide satisfactory results because small differ-
ences in reaction conditions altered the reaction course dramatically, sometimes producing
Int. J. Mol. Sci. 2023,24, 15884 5 of 22
a complex mixture of unidentified compounds. The same reaction conditions become
reproducible in switching to thioacetic acid as a nucleophilic reagent, which demonstrated
a high selectivity when added to (
)-myrtenal
44
to give thioacetate
47
(1,4-addition) in
yield of 98% and de > 99%. Thioester
47
was reduced by LiAlH
4
to obtain hydroxythiol
43
in a 95% yield. This one-pot method allowed us to simultaneously convert thioether and
aldehyde group to the corresponding thiol and primary alcohol (Scheme 7).
Scheme 7. Synthesis of pinane hydroxythiols based on myrtenal 44.
Trifluoromethylation of 2-formylisopinocampheyl-3-thioacetate
47
by Ruppert–Prakash
reagent in the presence of tetra-n-butylammonium fluoride (TBAF) was carried out at
30
C for 3 days. Diastereomers
48
and
49
are formed in a 52% total yield and de 42% with
the predominance of thioacetate
48
. Deacylation of thioacetates
48
and
49
with LiAlH
4
in
dry Et
2
O under an argon atmosphere gives the corresponding thiols
50
and
51
with 84 and
90% yields, respectively (Scheme 7) [54].
Thioacetate
52
was obtained from (1S)-(
)-verbenone
53
by using a procedure similar
to the synthesis of 2-formylisopinocampheyl-3-thioacetate
47
. The reaction produces one of
two theoretically possible diastereomers with the R-configuration of C-2 with a 71% yield
(Scheme 8). Thioacetate
52
does not react with the Rupert–Prakash reagent under the above
conditions, possibly because of the bulky TBAF use.
Int. J. Mol. Sci. 2023,24, 15884 6 of 22
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 6 of 23
LiAlH4 in dry Et2O under an argon atmosphere gives the corresponding thiols 50 and 51
with 84 and 90% yields, respectively (Scheme 7) [54].
Thioacetate 52 was obtained from (1S)-()-verbenone 53 by using a procedure similar
to the synthesis of 2-formylisopinocampheyl-3-thioacetate 47. The reaction produces one
of two theoretically possible diastereomers with the R-configuration of C-2 with a 71%
yield (Scheme 8). Thioacetate 52 does not react with the RupertPrakash reagent under
the above conditions, possibly because of the bulky TBAF use.
The addition of fluorine-containing initiator CsF made it possible to obtain the only
(4S)-diastereomer 54 in a 37% yield together with triuoromethyl alcohol 55 (31%) that is
a by-product of desulfurization (Scheme 8). Deacylation of thioacetate 54 gave
hydroxythiol 56 in 73% yield [54].
Scheme 8. Synthesis of pinane hydroxythiols based on verbenone 53.
The synthesis of isomeric hydroxythiols 5759 was carried out on the basis of β-
pinene 30 (Scheme 9) [55]. Trans-pinocarveol 60 was synthesized via the oxidation of β-
pinene 30 with the SeO2/TBHP system, and its further oxidation with MnO2 led to
pinocarvone 61. An inseparable mixture of two isomeric ketothioacetates (2S)-62 and (2R)-
63 in a 2:1 ratio in 95% yield is formed during the thia-Michael reaction of pinocarvone 61
with AcSH in the presence of catalytic amount of pyridine at 5 °C. The reduction of
thioacetates with LiAlH4 leads to three isomeric hydroxythiols, 5759.
Scheme 9. Synthesis of pinane hydroxythiols based on β-pinene 30.
The synthesis of pinane ketothiols 64 and 65 was implemented from α,β-unsaturated
pinane ketones 61 and 66 [56]. To obtain thioacetate 62 from enone 61, the synthetical
protocol proposed in [5] was used. However, the diastereoselectivity of this reaction under
the described conditions did not exceed 33%, as mentioned in [55]. The de value of
thioacetate 62 can be increased from 33 up to 92% if the reaction between pinocarvone 61
and AcSH is carried out in THF in a temperature range from 60 to 65 °C, with pyridine
as a co-solvent. The same conditions are applicable for the addition of BzSH to ketone 61,
with thioacetate 67 being formed in this case with a comparable de of 93% (Scheme 10).
Reducing thioacetate 62 via NH2NH2·H2O affords thiol 64 within 4-5 h in up to a 90% yield,
while deacylation of thiobenzoate 67 by the same reagent gives the thiol in only a 38-50%
yield due to incomplete conversion. Thus, at comparable maximum de values of thioesters
62 and 67, the preparation of thiol 64 from compound 62 is more optimal, taking into
account the higher total yield of thiol and the diacylation time.
Scheme 8. Synthesis of pinane hydroxythiols based on verbenone 53.
The addition of fluorine-containing initiator CsF made it possible to obtain the only
(4S)-diastereomer
54
in a 37% yield together with trifluoromethyl alcohol
55
(31%) that is a
by-product of desulfurization (Scheme 8). Deacylation of thioacetate
54
gave hydroxythiol
56 in 73% yield [54].
The synthesis of isomeric hydroxythiols
57
59
was carried out on the basis of
β
-pinene
30
(Scheme 9) [
55
]. Trans-pinocarveol
60
was synthesized via the oxidation of
β
-pinene
30
with the SeO
2
/TBHP system, and its further oxidation with MnO
2
led to pinocarvone
61
.
An inseparable mixture of two isomeric ketothioacetates (2S)-
62
and (2R)-
63
in a 2:1 ratio
in 95% yield is formed during the thia-Michael reaction of pinocarvone
61
with AcSH in
the presence of catalytic amount of pyridine at
5
C. The reduction of thioacetates with
LiAlH4leads to three isomeric hydroxythiols, 5759.
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 6 of 23
LiAlH4 in dry Et2O under an argon atmosphere gives the corresponding thiols 50 and 51
with 84 and 90% yields, respectively (Scheme 7) [54].
Thioacetate 52 was obtained from (1S)-()-verbenone 53 by using a procedure similar
to the synthesis of 2-formylisopinocampheyl-3-thioacetate 47. The reaction produces one
of two theoretically possible diastereomers with the R-configuration of C-2 with a 71%
yield (Scheme 8). Thioacetate 52 does not react with the RupertPrakash reagent under
the above conditions, possibly because of the bulky TBAF use.
The addition of fluorine-containing initiator CsF made it possible to obtain the only
(4S)-diastereomer 54 in a 37% yield together with triuoromethyl alcohol 55 (31%) that is
a by-product of desulfurization (Scheme 8). Deacylation of thioacetate 54 gave
hydroxythiol 56 in 73% yield [54].
Scheme 8. Synthesis of pinane hydroxythiols based on verbenone 53.
The synthesis of isomeric hydroxythiols 5759 was carried out on the basis of β-
pinene 30 (Scheme 9) [55]. Trans-pinocarveol 60 was synthesized via the oxidation of β-
pinene 30 with the SeO2/TBHP system, and its further oxidation with MnO2 led to
pinocarvone 61. An inseparable mixture of two isomeric ketothioacetates (2S)-62 and (2R)-
63 in a 2:1 ratio in 95% yield is formed during the thia-Michael reaction of pinocarvone 61
with AcSH in the presence of catalytic amount of pyridine at 5 °C. The reduction of
thioacetates with LiAlH4 leads to three isomeric hydroxythiols, 5759.
Scheme 9. Synthesis of pinane hydroxythiols based on β-pinene 30.
The synthesis of pinane ketothiols 64 and 65 was implemented from α,β-unsaturated
pinane ketones 61 and 66 [56]. To obtain thioacetate 62 from enone 61, the synthetical
protocol proposed in [5] was used. However, the diastereoselectivity of this reaction under
the described conditions did not exceed 33%, as mentioned in [55]. The de value of
thioacetate 62 can be increased from 33 up to 92% if the reaction between pinocarvone 61
and AcSH is carried out in THF in a temperature range from 60 to 65 °C, with pyridine
as a co-solvent. The same conditions are applicable for the addition of BzSH to ketone 61,
with thioacetate 67 being formed in this case with a comparable de of 93% (Scheme 10).
Reducing thioacetate 62 via NH2NH2·H2O affords thiol 64 within 4-5 h in up to a 90% yield,
while deacylation of thiobenzoate 67 by the same reagent gives the thiol in only a 38-50%
yield due to incomplete conversion. Thus, at comparable maximum de values of thioesters
62 and 67, the preparation of thiol 64 from compound 62 is more optimal, taking into
account the higher total yield of thiol and the diacylation time.
Scheme 9. Synthesis of pinane hydroxythiols based on β-pinene 30.
The synthesis of pinane ketothiols
64
and
65
was implemented from
α
,
β
-unsaturated
pinane ketones
61
and
66
[
56
]. To obtain thioacetate
62
from enone
61
, the synthetical
protocol proposed in [
5
] was used. However, the diastereoselectivity of this reaction
under the described conditions did not exceed 33%, as mentioned in [
55
]. The de value of
thioacetate
62
can be increased from 33 up to 92% if the reaction between pinocarvone
61
and AcSH is carried out in THF in a temperature range from
60 to
65
C, with pyridine
as a co-solvent. The same conditions are applicable for the addition of BzSH to ketone
61
,
with thioacetate
67
being formed in this case with a comparable de of 93% (Scheme 10).
Reducing thioacetate
62
via NH
2
NH
2·
H
2
O affords thiol
64
within 4-5 h in up to a 90%
yield, while deacylation of thiobenzoate
67
by the same reagent gives the thiol in only a
38-50% yield due to incomplete conversion. Thus, at comparable maximum de values of
thioesters
62
and
67
, the preparation of thiol
64
from compound
62
is more optimal, taking
into account the higher total yield of thiol and the diacylation time.
Int. J. Mol. Sci. 2023,24, 15884 7 of 22
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 7 of 23
Scheme 10. Synthesis of β-ketothiol from pinocarvone 61.
A multistep synthesis of 2-norpinanone 66 from (−)-β-pinene 30 was provided in [57]
(Scheme 11). This compound was obtained via nopinone 69 and then ketoenol 68
formation. Ketoenol 68 was produced in a 96% yield from ketone 69 by its reaction with
isoamyl formate and t-BuOK in THF at 0 °C for 6 h [56]. The following dihydroxylation of
ketoalcohol 68 by formaldehyde in sodium carbonate solution afforded 2-norpinanone 66
[56]. An addition of thioacetic acid to 2-norpinanone 66 was, for the first time,
implemented according to the procedure [5] and then by using pyridine as a catalyst [51]
in THF at room temperature [56]. The main product of this reaction was the isomer (3R)-
70 (de 98%) (Scheme 11). Its deacylation by hydrazine hydrate (NH2NH2·H2O) led to 2-
ketothiol 65 and disulfide 71 in a 3:1 ratio, respectively. Because of the mild reducing
properties of NH2NH2·H2O and its inability to donate protons, the diacylation proceeds
chemoselectively with the preservation of the carbonyl group [58], a behavior that is not
typical for LiAlH4 when used [55].
Scheme 11. Synthesis of β-ketothiol based on 2-norpinanone 66.
Pulegone 73 was used to synthesize para-menthane-derived β-hydroxythiol 72
(Scheme 12) [5962]. The 1,4-addition of sodium benzyl thiolate to pulegone led to a
diastereomeric mixture of ketosuldes 74 in a 4:1 ratio. Then, the mixture 74 was reduced
under Birch conditions by Na in liquid NH3 to give a mixture of hydroxythiols 72.
Condensation of 72 with benzaldehyde and subsequent crystallization from acetone
afforded diastereomerically pure oxathiane 75 in a 50% yield. When oxidized by AgNO3
in the presence of NCS, oxathiane 75 is transformed into sultines 76, the reduction of
which with LiAlH4 gives pure β-hydroxythiol 72.
Scheme 12. Synthesis of β-hydroxythiol based on pulegone 73.
Isomeric α-hydroxythiols 77 and 78 were obtained from natural 3-carene 14
(Scheme 13) [63]. 3-Carene, when oxidized by m-CPBA, selectively forms trans-epoxide
79, which is isomerized in the presence of diethylaluminum 2,2,6-tetramethylpiperidide
(DATMP) to enol 80 [64]. The oxidation of alcohol 80 to enone 81 is successfully
implemented by the bis(acetoxy)iodobenzene (BAIB)2,2,6,6-tetramethylpiperidine 1-
oxyl (TEMPO) system. Enone 81, being an unstable compound, cannot be isolated in its
Scheme 10. Synthesis of β-ketothiol from pinocarvone 61.
A multistep synthesis of 2-norpinanone
66
from (
)-
β
-pinene
30
was provided in [
57
]
(Scheme 11). This compound was obtained via nopinone
69
and then ketoenol
68
formation.
Ketoenol
68
was produced in a 96% yield from ketone
69
by its reaction with isoamyl
formate and t-BuOK in THF at 0
C for 6 h [
56
]. The following dihydroxylation of ketoal-
cohol
68
by formaldehyde in sodium carbonate solution afforded 2-norpinanone
66 [56]
.
An addition of thioacetic acid to 2-norpinanone
66
was, for the first time, implemented
according to the procedure [
5
] and then by using pyridine as a catalyst [
51
] in THF at
room temperature [
56
]. The main product of this reaction was the isomer (3R)-
70
(de 98%)
(Scheme 11). Its deacylation by hydrazine hydrate (NH
2
NH
2·
H
2
O) led to 2-ketothiol
65
and disulfide
71
in a 3:1 ratio, respectively. Because of the mild reducing properties of
NH
2
NH
2·
H
2
O and its inability to donate protons, the diacylation proceeds chemoselec-
tively with the preservation of the carbonyl group [
58
], a behavior that is not typical for
LiAlH4when used [55].
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 7 of 23
Scheme 10. Synthesis of β-ketothiol from pinocarvone 61.
A multistep synthesis of 2-norpinanone 66 from (−)-β-pinene 30 was provided in [57]
(Scheme 11). This compound was obtained via nopinone 69 and then ketoenol 68
formation. Ketoenol 68 was produced in a 96% yield from ketone 69 by its reaction with
isoamyl formate and t-BuOK in THF at 0 °C for 6 h [56]. The following dihydroxylation of
ketoalcohol 68 by formaldehyde in sodium carbonate solution afforded 2-norpinanone 66
[56]. An addition of thioacetic acid to 2-norpinanone 66 was, for the first time,
implemented according to the procedure [5] and then by using pyridine as a catalyst [51]
in THF at room temperature [56]. The main product of this reaction was the isomer (3R)-
70 (de 98%) (Scheme 11). Its deacylation by hydrazine hydrate (NH2NH2·H2O) led to 2-
ketothiol 65 and disulfide 71 in a 3:1 ratio, respectively. Because of the mild reducing
properties of NH2NH2·H2O and its inability to donate protons, the diacylation proceeds
chemoselectively with the preservation of the carbonyl group [58], a behavior that is not
typical for LiAlH4 when used [55].
Scheme 11. Synthesis of β-ketothiol based on 2-norpinanone 66.
Pulegone 73 was used to synthesize para-menthane-derived β-hydroxythiol 72
(Scheme 12) [5962]. The 1,4-addition of sodium benzyl thiolate to pulegone led to a
diastereomeric mixture of ketosuldes 74 in a 4:1 ratio. Then, the mixture 74 was reduced
under Birch conditions by Na in liquid NH3 to give a mixture of hydroxythiols 72.
Condensation of 72 with benzaldehyde and subsequent crystallization from acetone
afforded diastereomerically pure oxathiane 75 in a 50% yield. When oxidized by AgNO3
in the presence of NCS, oxathiane 75 is transformed into sultines 76, the reduction of
which with LiAlH4 gives pure β-hydroxythiol 72.
Scheme 12. Synthesis of β-hydroxythiol based on pulegone 73.
Isomeric α-hydroxythiols 77 and 78 were obtained from natural 3-carene 14
(Scheme 13) [63]. 3-Carene, when oxidized by m-CPBA, selectively forms trans-epoxide
79, which is isomerized in the presence of diethylaluminum 2,2,6-tetramethylpiperidide
(DATMP) to enol 80 [64]. The oxidation of alcohol 80 to enone 81 is successfully
implemented by the bis(acetoxy)iodobenzene (BAIB)2,2,6,6-tetramethylpiperidine 1-
oxyl (TEMPO) system. Enone 81, being an unstable compound, cannot be isolated in its
Scheme 11. Synthesis of β-ketothiol based on 2-norpinanone 66.
Pulegone
73
was used to synthesize para-menthane-derived
β
-hydroxythiol
72
(Scheme 12) [
59
62
]. The 1,4-addition of sodium benzyl thiolate to pulegone led to a
diastereomeric mixture of ketosulfides 74 in a 4:1 ratio. Then, the mixture 74 was reduced
under Birch conditions by Na in liquid NH
3
to give a mixture of hydroxythiols
72
. Con-
densation of
72
with benzaldehyde and subsequent crystallization from acetone afforded
diastereomerically pure oxathiane
75
in a 50% yield. When oxidized by AgNO
3
in the
presence of NCS, oxathiane
75
is transformed into sultines
76
, the reduction of which with
LiAlH4gives pure β-hydroxythiol 72.
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 7 of 23
Scheme 10. Synthesis of β-ketothiol from pinocarvone 61.
A multistep synthesis of 2-norpinanone 66 from (−)-β-pinene 30 was provided in [57]
(Scheme 11). This compound was obtained via nopinone 69 and then ketoenol 68
formation. Ketoenol 68 was produced in a 96% yield from ketone 69 by its reaction with
isoamyl formate and t-BuOK in THF at 0 °C for 6 h [56]. The following dihydroxylation of
ketoalcohol 68 by formaldehyde in sodium carbonate solution afforded 2-norpinanone 66
[56]. An addition of thioacetic acid to 2-norpinanone 66 was, for the first time,
implemented according to the procedure [5] and then by using pyridine as a catalyst [51]
in THF at room temperature [56]. The main product of this reaction was the isomer (3R)-
70 (de 98%) (Scheme 11). Its deacylation by hydrazine hydrate (NH2NH2·H2O) led to 2-
ketothiol 65 and disulfide 71 in a 3:1 ratio, respectively. Because of the mild reducing
properties of NH2NH2·H2O and its inability to donate protons, the diacylation proceeds
chemoselectively with the preservation of the carbonyl group [58], a behavior that is not
typical for LiAlH4 when used [55].
Scheme 11. Synthesis of β-ketothiol based on 2-norpinanone 66.
Pulegone 73 was used to synthesize para-menthane-derived β-hydroxythiol 72
(Scheme 12) [5962]. The 1,4-addition of sodium benzyl thiolate to pulegone led to a
diastereomeric mixture of ketosuldes 74 in a 4:1 ratio. Then, the mixture 74 was reduced
under Birch conditions by Na in liquid NH3 to give a mixture of hydroxythiols 72.
Condensation of 72 with benzaldehyde and subsequent crystallization from acetone
afforded diastereomerically pure oxathiane 75 in a 50% yield. When oxidized by AgNO3
in the presence of NCS, oxathiane 75 is transformed into sultines 76, the reduction of
which with LiAlH4 gives pure β-hydroxythiol 72.
Scheme 12. Synthesis of β-hydroxythiol based on pulegone 73.
Isomeric α-hydroxythiols 77 and 78 were obtained from natural 3-carene 14
(Scheme 13) [63]. 3-Carene, when oxidized by m-CPBA, selectively forms trans-epoxide
79, which is isomerized in the presence of diethylaluminum 2,2,6-tetramethylpiperidide
(DATMP) to enol 80 [64]. The oxidation of alcohol 80 to enone 81 is successfully
implemented by the bis(acetoxy)iodobenzene (BAIB)2,2,6,6-tetramethylpiperidine 1-
oxyl (TEMPO) system. Enone 81, being an unstable compound, cannot be isolated in its
Scheme 12. Synthesis of β-hydroxythiol based on pulegone 73.
Isomeric
α
,
β
-hydroxythiols
77
and
78
were obtained from natural 3-carene
14
(Scheme 13) [
63
]. 3-Carene, when oxidized by m-CPBA, selectively forms trans-epoxide
79
, which is isomerized in the presence of diethylaluminum 2,2,6-tetramethylpiperidide
(DATMP) to enol
80
[
64
]. The oxidation of alcohol
80
to enone
81
is successfully im-
plemented by the bis(acetoxy)iodobenzene (BAIB)–2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) system. Enone
81
, being an unstable compound, cannot be isolated in its pure