Synthesis and application of 1,2-aminoalcohols with neoisopulegol-based octahydrobenzofuran core

Article abstract of DOI:10.3390/molecules25010021

A library of 1,2-aminoalcohol derivatives with a neoisopulegol-based octahydrobenzofuran core was developed and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The allylic chlorination of (+)-neoisopulegol, derived from natural (-)-isopulegol followed by cyclization, gave the key methyleneoctahydrobenzofuran intermediate. The stereoselective epoxidation of the key intermediate and subsequent oxirane ring opening with primary amines afforded the required 1,2-aminoalcohols. The ring closure of the secondary amine analogues with formaldehyde provided spiro-oxazolidine ring systems. The dihydroxylation of the methylenetetrahydrofuran moiety with OsO4/NMO (4-methylmorpholine N-oxide) resulted in the formation of a neoisopulegol-based diol in a highly stereoselective reaction. The antimicrobial activity of both the aminoalcohol derivatives and the diol was also explored.

Full text of DOI:10.3390/molecules25010021

molecules
Article
Synthesis and Application of 1,2-Aminoalcohols with
Neoisopulegol-Based Octahydrobenzofuran Core
1
1,2
, Bettina Volford , András Szekeres 3 and
3
Fatima Zahra Bamou , Tam Minh Le
Zsolt Szakonyi 1
,4,
*
1
Institute of Pharmaceutical Chemistry, University of Szeged, Interdisciplinary excellent center,
H-6720 Szeged, Eötvös utca 6, Hungary; fatima.z@pharm.u-szeged.hu (F.Z.B.);
leminhtam@pharm.u-szeged.hu (T.M.L.)
MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, H-6720 Szeged,
Eötvös utca 6, Hungary
Department of Microbiology, University of Szeged, 6726 Szeged, Közép fasor 52, Hungary;
bettina.volford86@gmail.com (B.V.); andras.j.szekeres@gmail.com (A.S.)
Interdisciplinary Centre of Natural Products, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary
Correspondence: szakonyi@pharm.u-szeged.hu; Tel.: +36-62-546809; Fax: +36-62-545705
2
3
4
*
Academic Editors: Antal Csámpai, Panayiotis A. Koutentis and Antonio Massa
Received: 22 November 2019; Accepted: 16 December 2019; Published: 19 December 2019
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: A library of 1,2-aminoalcohol derivatives with a neoisopulegol-based octahydrobenzofuran
core was developed and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde.
The allylic chlorination of (+)-neoisopulegol, derived from natural (–)-isopulegol followed by
cyclization, gave the key methyleneoctahydrobenzofuran intermediate. The stereoselective
epoxidation of the key intermediate and subsequent oxirane ring opening with primary amines
afforded the required 1,2-aminoalcohols. The ring closure of the secondary amine analogues
with formaldehyde provided spiro-oxazolidine ring systems. The dihydroxylation of the
methylenetetrahydrofuran moiety with OsO /NMO (4-methylmorpholine N-oxide) resulted in
4
the formation of a neoisopulegol-based diol in a highly stereoselective reaction. The antimicrobial
activity of both the aminoalcohol derivatives and the diol was also explored.
Keywords: neoisopulegol; octahydrobenzofuran; 1,2-aminoalcohol; chiral catalyst; antimicrobial activity
1
. Introduction
The benzofuran moiety is prevalent in a great number of biologically active compounds and natural
products [
in the preparation of natural products and clinical medicines [
these building blocks, numerous methods have been developed for the preparation of benzofuran
systems [ 11]. However, only a few examples of the synthesis of octahydrobenzofuran derivatives
have been reported including free-radical reactions [12 13], hydrogenation [14 15], tandem conjugate
1
,2]. Moreover, compounds bearing this ring system are also promising key intermediates
3–5]. Due to the availability of
6
–
,
,
addition [16], base- [17] or acid-catalyzed cyclization [18], and photochemical rearrangement [19].
Furthermore, octabenzohydrofuran derivatives are well-known versatile precursors for the construction
of a variety of therapeutic drugs [20]. For example, (
bear a hexahydrobenzofurane moiety have shown antibacterial effects toward Micrococcus luteus [21].
–)-Siccanin exhibits potent antifungal activity against several pathogenic fungi, and its clinical
±
)-adunctin B and its modified derivatives that
(
effectiveness against surface mycosis is also known [22].
The 1,2-aminoalcohol moiety is present in a wide range of compounds that exhibit pharmaceutically
and biologically interesting properties [23]. For example, compounds bearing the hydroxyethylamine
core have the capacity to inhibit aspartic protease enzymes and are widely used as anti-HIV [24,25],
Molecules 2020, 25, 21; doi:10.3390/molecules25010021
www.mdpi.com/journal/molecules

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antimalarial [26
–
28], and antileishmanial [29] agents. The 1,2-aminoalcohol function is found in a
broad range of
β
-adrenergic blockers that are used extensively in the management of cardiovascular
disorders [30], including hypertension, angina pectoris and cardiac arrhythmias, and other disorders
that are related to the sympathetic nervous system [31,32].
1
,2-aminoalcohols have also been demonstrated to be excellent chiral auxiliaries and chiral
catalysts in asymmetric synthesis [33]. To achieve new, efficient, and commercially available chiral
catalysts, natural chiral terpenes, such as -pinene [34 38], -pinene [34 39], (–)-3-carene [39 40],
–)-verbenone [41 42], (–)-fenchone [43 44], (+)-camphor [43 45 46], and (–)-menthone [47] have proven
α
–
β
,
,
(
,
,
,
,
to be excellent sources for the synthesis of bifunctional chiral compounds and heterocycles.
In the present work, we set out to create a compound library with a (+)-neoisopulegol-based
octahydrobenzofuran core and 1,2-aminoalcohol moieties. The synthesis started from commercially
available (–)-isopulegol and then utilizing the resulting 1,2-aminoalcohol derivatives as chiral catalysts
in the enantioselective addition of diethylzinc to benzaldehyde. Furthermore, the antimicrobial
activities of the synthesized compounds were also tested on multiple bacterial and fungal strains.
2
. Results
2
.1. Synthesis of Key Intermediate 3
Key intermediate (–)-3-methylenetetrahydrofuran 3 was prepared from commercially available
(
–)-isopulegol
resulting carbonyl group, thus providing (+)-neoisopulegol
+)-neoisopulegol was followed by the cyclization-produced (–)-methylenetetrahydrofuran
which was transformed into ( )-methylenetetrahydrofuran by allylic oxidation after applying the
literature method [55,56] (Figure 1).
1
by oxidizing its hydroxyl function, followed by the stereoselective reduction of the
48 51]. The allylic chlorination of
52 55],
2
[ –
(
2
3
[
–
−
4
Figure 1. Synthesis of (–)-isopulegol-based methylenetetrahydrofuran
3
: (
i
) PCC (2 equivalents), DCM
◦
◦
(
(
(
Dichloromethane), 25 C, 48 h, 80% than L-selectride (1.5 equivalents) dry THF,
−
78 C, 1 h, 90% [48
–
51];
◦
◦
ii) Ca(OCl) , DCM, rt 25 C, 3 h, 70% than NaH (2 equivalents), dry THF, 50 C, 6 h [52–55];
(iii) CrO3
2
3 equivalents), DCM/pyridine, reflux, 1.5 h, 84% [55,56].
2
.2. Synthesis of Ispulegol-Based 1,2-Aminoalcohols
Our previous work has shown that epoxidation with t-BuOOH in the presence of vanadyl
acetylacetonate (VO(acac) ) as a catalyst can be successfully applied to prepare a new family of
2
neoisopulegol-based chiral aminodiol libraries [57]. However, upon applying this condition with
3
, (–)-
explained by the allylic oxidation process shown in Figure 2 [58
was achieved by reacting with mCPBA (meta-Chloroperoxybenzoic acid) in a stereoselective reaction
Scheme 1) [60–63].
α
-methylene-
γ
-butyrolactone
4
was observed as the major product. The formation of
4 was
,
59]. Finally, the synthesis of epoxide
5
3
(

Molecules 2020, 25, 21
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Figure 2. Proposed reaction pathway of allylic oxidation of 3.
◦
(i) mCPBA (2 equivalents), Na HPO . 2H O (3 equivalents), 25 C, 2 h, 23%; (ii) RNH (2
2 4 2 2
Scheme 1.
equivalents), LiClO (1 equivalent), MeCN, 70–80 C, 6 h, 65–85%; (iii) 5% Pd/C, H (1 atm), MeOH,
◦
4
2
◦ ◦
5 C, 24 h, 70–75%; (iv) 35% HCHO, Et O, 25 C, 1 h, 50–90%; (v) 2% OsO /t-BuOH, 50% NMO/H O,
2 4 2
acetone, 25 C, 24 h, 50%.
2
◦
Given that we clearly demonstrated in previous works [64,65] that the substitution of the nitrogen
atom of aminoalcohols definitely influences the efficiency of their catalytic activity, aminoalcohol
library 10 was prepared through the aminolysis of epoxide with primary amines and lithium
perchlorate as a catalyst [66 67]. Since the ring closure of monoterpene-based aminoalcohols with rigid
structures has been shown to enhance their catalytic potential in our earlier experiments [64 65 68],
the treatment of aminoalcohols 10 with formaldehyde at room temperature resulted in the formation
7
–
5
,
,
,
7–

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of spiro-oxazolidines 12
–
15. The debenzylation by hydrogenolysis of compounds
7–
9
over Pd/C
in MeOH provided primary aminoalcohol 11 in moderate yields (Scheme 1). Since neither the
hydrogenolysis of N-benzyl analogues 10 nor the formation of an oxazolidine ring system by ring
7–
closure with formaldehyde had an effect on the absolute configuration of C-3, the relative configuration
of the chiral centers of 11–15 is known to be the same as that of 7–10 [64,65,68].
The syn-selective dihydroxylation of compound
3 with OsO in the presence of a stoichiometric
4
amount of the co-oxidant, NMO (4-methylmorpholine N-oxide) produced product
6 as a single
diastereomer in a moderate yield [68,69] (Scheme 1).
The relative stereochemistry of aminoalcohols
constant data and the NOESY (Nuclear Overhauser Effect SpecroscopY) spectral analysis. The large
coupling constant of H-9 (J4,9 = 11.2 Hz with and J4,9 = 12.2 Hz with 10) indicated that it should be
axially oriented, while the coupling constant values between H-3 and H-4 (J4,3 = J3,4 = 2.3 Hz with
and J4,3 = J3,4 = 2.2–3.0 Hz with 10) supported their equatorial orientation. Furthermore, NOESY
7–10 and diol 6 was established by coupling
6
7–
6
7–
correlations between OH-7 and H-3 as well as OH-7 and H-4 protons in DMSO-d6 (Dimethylsulfoxide-d6)
indicated that these groups were oriented in the same direction (see Supporting Information), Therefore,
the structures of 6–10 were concluded, as shown on Figure 3. The stereochemistry of 11 and 12–15 was
proven in a similar manner by 1D and 2D NMR measurements.
Figure 3. Determination of relative configuration of aminoalcohols 7–10 and diol 6.
2
.3. Application of Aminoalcohol Derivatives as Chiral Ligands for Catalytic Addition of Diethylzinc
to Benzaldehyde
Aminoalcohol derivatives 7–15 were applied as chiral catalysts in the enantioselective addition of
diethylzinc to benzaldehyde 16 to form (S)- and (R)-1-phenyl-1-propanol 17 (Scheme 2).
Scheme 2. Model reaction for enantioselective catalysis.
The enantiomeric purity of 1-phenyl-1-propanols (S)-17 and (R)-17 was determined by GC analysis
on a Chirasil-DEX CB column using literature methods [70
was observed. Aminoalcohols afforded the (S)-enantiomer (except
was observed), while the formation of the (R)-enantiomer was predominant when spiro-oxazolidines
were applied as catalysts (Table 1). Aminoalcohol showed the best catalytic activity (ee = 40%)
,
71]. A low-to-moderate enantioselectivity
7, where a weak (R) selectivity
8
with an (S)-selectivity (entry 2). The obtained results clearly indicate that the spiro-oxazolidine ring
had a poorer catalytic performance, probably due to the flexible spiro system. These results are in
good correlation with those observed with pinane- or sabinane-based spiro-oxazolidines in our earlier
studies [72,73].

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Table 1. Addition of diethylzinc to benzaldehyde catalyzed by aminoalcohol derivatives.
ee b (%)
Configuration of the Major Product c
Entry
Ligand
Yield a (%)
1
2
3
4
5
6
7
8
9
7
8
9
10
11
12
13
14
15
86
90
89
93
95
88
90
82
80
8
40
11
4
7
11
3
(R)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
6
7
a
After silica column chromatography. b Determined using the crude product by GC analysis (Chirasil-DEX CB
column). c Determined by comparing the tR of GC analysis and optical rotations with literature data.
2
.4. Antimicrobial Effects
Since several aminoalcohols have been shown to exert antimicrobial activities on various bacterial
and fungal strains [74
diol were tested against two yeasts, as well as two Gram-positive and two Gram-negative bacteria
Table 2). Compounds and 12 inhibited the studied Gram-positive bacteria with efficiencies over
0%, while other derivatives showed weak activities. In the case of Bacillus subtilis, showed more
,75], the antimicrobial activities of the prepared aminoalcohol analogues and
6
(
8
2
8
potential antimicrobial activity, while for Staphylococcus aureus, 12 proved to be the most effective agent.
Furthermore, only showed an inhibition activity over 30% for Pseudomonas aeruginosa, while it had
9
only a moderate effect against Escherichia coli. All compounds presented low-to-moderate inhibitions
against E. coli in the range of 5–30%.
Table 2. Antimicrobial activities of the synthesized compounds.
Inhibitory effect (%) ± RSD
(%)
Yeast
Gram-Negative
P.
Gram-Positive
B. subtilis S. aureus
Analogue
Conc. (µg/mL)
C. albicans
C. krusei
E. coli
aeruginosa
1
0
−
−
36.5 ± 8.43
−
−
−
−
−
6
7
8
9
1
1
1
1
1
1
1
1
1
1
00
58.4 ± 14.41
−
−
21.7 ± 6.05
1
0
00
−
−
8.7 ± 3.15
7.5 ± 1.54
−
−
−
−
20.0 ± 2.81
8.7 ± 0.49
−
7.1 ± 4.3
1
0
00
−
−
−
−
−
−
19.0 ± 2.61
31.9 ± 2.74
−
17.1 ± 4.94
5.3 ± 4.31
−
1
0
00
−
−
16.7 ± 6.68
9.9 ± 1.8
−
−
−
−
21.0 ± 5.05 31.6 ± 1.73
9.8 ± 11.2
13.8 ± 1.73
1
0
00
−
−
−
−
3.7 ± 1.68
−
−
−
10
11
12
13
14
15
4.3 ± 10.71
2.3 ± 5.93
10.5 ± 10.12
−
1
0
00
−
3.7 ± 0.04
−
−
−
−
−
−
16.0 ± 14.5
−
−
−
1
0
00
−
−
−
15.3 ± 4.35
26.2 ± 4.06
−
−
−
9.2 ± 7.75
−
1.8 ± 6.28
20.2 ± 8.92
1
0
00
−
−
−
17.1 ± 8.19
−
−
−
−
27.7 ± 8.54
7.0 ± 4.62
−
3.9 ± 3.39
1
0
00
−
−
−
14.6 ± 4.38
4.1 ± 7.10
−
−
12.6 ± 0.57
−
25.3 ± 2.99 16.8 ± 5.69
14.0 ± 3.68
1
0
00
−
−
−
5.1 ± 7.92
−
−
−
−
−
14.8 ± 4.87
−
1.5 ± 11.4
According to our results, N-substituted 1,2-aminoalcohols
7
–10 had a moderate activity against
both Gram-negative and Gram-positive bacteria. Most of the ring-closing oxazolidine products (12
–
14)

Molecules 2020, 25, 21
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showed a similar moderate antibacterial activity. The removal of the nitrogen substituent of the
aminoalcohols led to the loss of antibacterial activity (see amino diol ). None of the aminoalcohol
showed significant antifungal
6
derivatives exhibited any remarkable antifungal effect, while diol
activity against Candida krusei (Table 2).
6
3
. Materials and Methods
3
.1. Materials and General Methods
Commercially available compounds were used as-obtained from suppliers (Molar Chemicals
Ltd., Hal sztelek, Hungary; Merck Ltd., Budapest, Hungary and VWR International Ltd., Debrecen,
á
Hungary), while solvents were dried according to standard procedures. Optical rotations were
◦
measured in MeOH at 20 C with a PerkinElmer 341 polarimeter (PerkinElmer Inc., Shelton, CT, USA).
Chromatographic separations and monitoring of reactions were carried out on a Merck Kieselgel
60 (Merck Ltd., Budapest, Hungary). Elemental analyses of all compounds were performed on a
PerkinElmer 2400 Elemental Analyzer (PerkinElmer Inc., Waltham, MA, USA). GC measurements for
the direct separation of commercially available enantiomers of isopulegol to determine the enantiomeric
purity of starting material
1 and the separation of O-acetyl derivatives of enantiomers were performed
on a Chirasil-DEX CB column (2500 × 0.25 mm I.D.) on a PerkinElmer Autosystem XL GC consisting
of a flame ionization detector (PerkinElmer Corporation, Norwalk, CT, USA) and a Turbochrom
Workstation data system (PerkinElmer Corp., Norwalk, CT, USA). Melting points were determined on
1
13
a Kofler apparatus (Nagema, Dresden, Germany) and were uncorrected. H- and C-NMR spectra
1
13
were recorded on a Brucker Avance DRX 500 spectrometer [500 MHz ( H) and 125 MHz ( C),
TMS, Tetramethylsilane)]. Chemical shifts are expressed in ppm ( ) relative to TMS as the internal
reference. J values are given by Hz.
–)-Isopulegol is commercially available from Merck Co with ee = 95%. (+)-Neoisopulegol
and (–)-6-methyl-3-methylenetetrahydrofuran were prepared according to literature procedures. All
δ = 0
(
δ
(
1
2
3
1
13
spectroscopic data of the synthesized compounds were similar to those described therein [55]. H, C,
HSQC, HMBC and NOESY NMR spectra of new compounds are available in Supplementary Materials.
0
0
3
.2. (2 R,3aR,6R,7aS)-6-Methylhexahydro-2H-spiro[benzofuran-3,2 -oxirane] (5)
m-chloroperbenzoic acid (70% purity, 5.87 g, 23.8 mmol) was added at 0 C to a solution of 3
11.9 mmol) in CH Cl (50 mL) and Na HPO 12H O (6.35 g, 35.7 mmol) in water (130 mL), and the
◦
(
·
2
2
2
4
2
mixture was stirred at room temperature. When the reaction was complete, as indicated by TLC (Thin
layer chromatography) (2 h), the mixture was separated and the aqueous phase was extracted with
CH Cl (100 mL). The organic layer was washed with a 5% KOH solution (3
×
50 mL), then dried
2
2
(
Na SO ) and evaporated to provide 5 as the single product.
2 4
20
1
Yield: 23%, colorless oil. [α]D
=
−
26.0 (c 0.27, MeOH). H NMR (500 MHz, CDCl ): δ = 0.83–0.93
3
(
1H, m), 0.90 (3H, d, J = 6.5 Hz), 1.18–1.26 (1H, m), 1.32–1.42 (1H, m), 1.55–1.75 (4H, m), 2.03–2.10 (1H,
m), 2.83 (1H, d, J = 4.2 Hz), 2.96 (1H, d, J = 4.2 Hz), 3.63 (1H, d, J = 10.6 Hz), 4.21 (1H, d, J = 10.6 Hz),
4
7
.25 (1H, d, J = 2.4 Hz). 13C NMR (125 MHz, CDCl3):
7.9. Anal. Calculated for C H O : C, 71.39; H, 9.59. Found: C, 71.43; H, 9.52.
δ = 22.4, 24.7, 26.4, 33.0, 36.5, 42.7, 47.4, 68.0, 70.1,
10
16
2
3
.3. General Procedure for Ring-Opening of Epoxide with Primary Amines
A solution of the appropriate amine (5.88 mmol) in MeCN (10 mL) and LiClO (0.31 g, 2.94 mmol)
4
was added to a solution of epoxide
reflux temperature for 6 h. When the reaction was completed (indicated by TLC), the mixture was
evaporated to dryness, and the residue was dissolved in water (15 mL) then extracted with CH Cl
5 (0.50 g, 2.94 mmol) in MeCN (30 mL). The mixture was kept at
2
2
(
3 × 50 mL). The combined organic phase was dried (Na SO ), filtered, and concentrated. The crude
2
4
product was purified by column chromatography on silica gel with an appropriate solvent mixture

Molecules 2020, 25, 21
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(
CHCl :MeOH = 19:1). Further purification by recrystallization from a mixture of n-hexane:Et O
3
2
resulted in compounds 7–10.
3
.3.1. (3R,3aR,6R,7aS)-6-Methyl-3-((((R)-1-phenylethyl)amino)methyl)octahydrobenzofuran-3-ol (7)
◦
20
D
1
Yield: 65%, white crystals, m.p.: 77–81 C. [α] = +27.0 (c 0.25, MeOH). H NMR (500 MHz,
CDCl3):
δ = 0.78–0.87 (1H, m), 0.86 (3H, d, J = 6.5 Hz), 0.98–1.06 (1H, m), 1.12–1.18 (1H, m), 1.38 (3H,
d, J = 6.6 Hz), 1.45–1.50 (1H, m), 1.51–1.63 (3H, m), 1.66–1.72 (1H, m), 2.00–2.05 (1H, m), 2.42 (1H, d,
J = 12.1 Hz), 2.77 (1H, d, J = 12.1 Hz), 3.64 (1H, d, J = 9.5 Hz), 3.70 (1H, d, J = 9.6 Hz), 3.79 (1H, q,
J = 6.5 Hz), 4.37 (1H, q, J = 3.0 Hz), 7.25–7.35 (5H, m). 13C NMR (125 MHz, CDCl3):
δ
= 22.4, 24.4, 24.5,
2
7
6.5, 33.2, 37.0, 47.1, 49.5, 58.6, 76.3, 77.6, 82.4, 126.7, 127.4, 128.8. Anal. Calculated for C H NO : C,
4.70; H, 9.40; N, 4.84. Found: C, 74.73; H, 9.45; N, 4.80.
18
27
2
3
.3.2. (3R,3aR,6R,7aS)-6-Methyl-3-((((S)-1-phenylethyl)amino)methyl)octahydrobenzofuran-3-ol (8)
Yield: 75%, colorless oil. [α]20
=
−
23.0 (c 0.255, MeOH). H NMR (500 MHz, CDCl ):
1
δ
= 0.75–0.85
3
D
(
1H, m), 0.85 (3H, d, J = 6.3 Hz), 0.90–1.00 (1H, m), 1.10–1.16 (1H, m), 1.35–1.40 (1H, m), 1.39 (3H, d,
J = 6.6 Hz), 1.50–1.60 (2H, m), 1.63–1.67 (1H, m), 2.01 (1H, d, J = 14.5 Hz), 2.46 (1H, d, J = 12.2 Hz), 2.65
1H, d, J = 12.2 Hz), 3.73 (3H, dd, J = 9.5, 20.2 Hz), 4.37 (1H, s), 7.25–7.40 (5H, m). 13C NMR (125 MHz,
CDCl3): = 22.3, 24.2, 24.3, 26.5, 33.1, 37.0, 46.9, 49.6, 58.9, 76.2, 77.6, 82.3, 126.4, 127.4, 128.8, 144.9.
Anal. Calculated for C H NO : C, 74.70; H, 9.40; N, 4.84. Found: C, 74.68; H, 9.43; N, 4.85.
(
δ
18
27
2
3
.3.3. (3R,3aR,6R,7aS)-3-((Benzylamino)methyl)-6-methyloctahydrobenzofuran-3-ol (9)
◦
20
1
Yield: 78%, white crystals, m.p.: 55–56 C. [α]D
3
= 7.0 (c 0.255, MeOH). H NMR (500 MHz,
−
CDCl ): δ = 0.80–0.87 (1H, m), 0.87 (3H, d, J = 6.5 Hz), 1.03–1.06 (1H, m), 1.11–1.17 (1H, m), 1.45–1.49
(1H, m), 1.55–1.62 (2H, m), 2.01–2.05 (1H, m), 2.58 (1H, d, J = 12.1 Hz), 2.70 (1H, brs), 2.86 (1H, d,
J = 12.2 Hz), 3.70 (1H, d, J = 9.5 Hz), 3.79 (1H, d, J = 9.6 Hz), 3.80 (1H, s), 4.39 (1H, dd, J = 3.0, 6.0 Hz),
7
8
7
.25-7.35 (5H, m). 13C NMR (125 MHz, CDCl3):
2.4, 127.4, 128.1, 128.6, 139.7. Anal. Calculated for C H NO : C, 74.14; H, 9.15; N, 5.09. Found: C,
4.20; H, 9.10; N, 4.05.
δ = 22.3, 24.3, 26.4, 33.1, 36.9, 47.1, 51.1, 54.3, 76.3, 77.6,
17
25
2
3
.3.4. (3R,3aR,6R,7aS)-3-((Isopropylamino)methyl)-6-methyloctahydrobenzofuran-3-ol (10)
◦
20
1
Yield: 83%, white crystals, m.p.: 171–173 C. [α]D
DMSO-d6): = 0.75–1.00 (2H, m), 0.84 (3H, d, J = 3.5 Hz), 1.10–1.30 (2H, m), 1.22 (6H, s), 1.48 (1H,
brs), 1.57 (2H, d, J = 8.7 Hz), 1.75–1.95 (2H, m), 2.91 (1H, d, J = 12.2 Hz), 3.06 (1H, d, J = 12.3 Hz),
.28 (1H, brs), 3.60 (1H, d, J = 8.8 Hz), 3.81 (1H, d, J = 8.9 Hz), 4.30 (1H, brs). 13C NMR (125 MHz,
DMSO-d6): δ = 18.3, 18.6, 22.1, 23.2, 26.0, 32.4, 36.3, 46.1, 46.6, 50.5, 75.1., 76.4, 80.1. Anal. Calculated
for C H NO : C, 68.68; H, 11.08; N, 6.16. Found: C, 68.70; H, 11.03; N, 6.18.
=
−
7.0 (c 0.28, MeOH). H NMR (500 MHz,
δ
3
13
25
2
3
.4. General Procedure for Ring Closure of Aminoalcohols 7–10 with Formaldehyde
Thirty-five percent aqueous formaldehyde (20 mL) was added to a solution of aminoalcohols
7
–10 (1.8 mmol) in Et O (5 mL), and the mixture was stirred at room temperature. After 1 h, it was
2
made alkaline with 10% aqueous KOH (20 mL) and extracted with Et O (3
×
50 mL). After drying
2
(
(
Na SO ) and solvent evaporation, crude products 12
–15 were purified by column chromatography
2
4
CHCl :MeOH = 19:1).
3
0
0
3
.4.1. (3R,3aR,6R,7aS)-6-Methyl-3 -((R)-1-phenylethyl)hexahydro-2H-spiro[benzofuran-3,5
-
oxazolidine] (12)
2
0
1
Yield: 50%, colorless oil. [α] = +27.0 (c, 0.275 MeOH). H NMR (500 MHz, CDCl ):
δ = 0.84–0.95
3
D
(
2H, m), 0.87 (3H, d, J = 6.3 Hz), 1.10–1.17(1H, m), 1.34 (3H, d, J = 6.4 Hz), 1.50–1.65 (3H, m), 1.78–1.83
(1H, m), 2.02 (1H, d, J = 14.4 Hz), 2.57 (1H, d, J = 10.5 Hz), 2.94 (1H, d, J = 10.6 Hz), 3.35–3.40 (1H,

Molecules 2020, 25, 21
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m), 3.88 (2H, dd, J = 9.7, 19.1 Hz), 4.24–4.30 (3H, m), 7.22–7.33 (5H, m). 13C NMR (125 MHz, CDCl3):
δ = 22.3, 23.4, 24.6, 26.3, 33.2, 36.9, 45.7, 53.3, 62.5, 76.4, 78.3, 84.6, 91.5, 127.2, 127.4, 128.6, 144.8. Anal.
Calculated for C H NO : C, 75.71; H, 9.03; N, 4.65. Found: C, 75.73; H, 9.00; N, 4.68.
19
27
2
0
0
3
.4.2. (3R,3aR,6R,7aS)-6-Methyl-3 -((S)-1-phenylethyl)hexahydro-2H-spiro[benzofuran-3,5
-
oxazolidine] (13)
Yield: 95%, colorless oil. [α]20
=
−
27.0 (c, 0.25 MeOH). H NMR (500 MHz, CDCl ):
1
δ
= 0.82–0.96
3
D
(
3H, m), 0.87 (3H, d, J = 6.3 Hz), 1.12–1.20 (1H, m), 1.25 (1H, s), 1.36 (3H, d, J = 6.2 Hz), 1.54–1.65
(
3
3H, m), 1.80–1.85 (2H, m), 2.02 (1H, d, J = 14.4 Hz), 2.53 (1H, d, J = 10.6 Hz), 2.94 (1H, d, J = 10.7 Hz),
.35–3.45 (1H, m), 3.87 (2H, t, J = 10.7 Hz), 4.26 (2H, s), 4.36 (1H, s), 7.20–7.40 (5H, m). 13C NMR
(
125 MHz, CDCl3): δ = 22.3, 23.5, 24.5, 26.3, 33.2, 36.8, 45.7, 53.4, 62.5, 76.2, 78.2, 84.8, 127.2, 127.4, 128.7.
Anal. Calculated for C H NO : C, 75.71; H, 9.03; N, 4.65. Found: C, 75.70; H, 9.07; N, 4.63.
19
27
2
0
0
3
.4.3. (3R,3aR,6R,7aS)-3 -Benzyl-6-methylhexahydro-2H-spiro[benzofuran-3,5 -oxazolidine] (14)
◦
20
D
1
Yield: 90%, white crystals, m.p.: 76–77 C. [α] = -9.0 (c, 0.25 MeOH). H NMR (500 MHz, CDCl ):
3
δ
= 0.84–1.00 (2H, m), 0.88 (3H, d, J = 6.5 Hz), 1.14–1.21 (1H, m), 1.55–1.65 (3H, m), 1.80–1.84 (1H, m),
2
.04 (1H, d, J = 13.8 Hz), 2.70 (1H, d, J = 11.8 Hz), 3.09 (1H, d, J = 11.8 Hz), 3.68 (2H, dd, J = 13.0,
13
1
8.4 Hz), 3.91 (2H, dd, J = 9.8, 11.2 Hz), 4.31 (1H, d, J = 2.7 Hz), 4.35 (2H, s), 7.25–7.35 (5H, m). C NMR
125 MHz, CDCl3): = 22.3, 24.6, 26.3, 33.2, 36.8, 46.1, 54.5, 58.7, 76.7, 78.6, 86.0, 90.5, 127.5, 128.6, 128.8,
38.6. Anal. Calculated for C H NO : C, 75.22; H, 8.77; N, 4.87. Found: C, 75.25; H, 9.73; N, 4.90.
(
1
δ
18
25
2
0
0
3
.4.4. (3R,3aR,6R,7aS)-3 -Isopropyl-6-methylhexahydro-2H-spiro[benzofuran-3,5 -oxazolidine] (15)
Yield: 95%, colorless oil. [α]20
=
−
13.0 (c 0.25, MeOH). H NMR (500 MHz, DMSO-d ): δ = 0.79–0.86
1
6
D
(
1H, m), 0.83 (3H, d, J = 6.6 Hz), 0.89–1.01 (2H, m), 0.99 (6H, d, J = 6.2 Hz), 1.07–1.13 (1H, m), 1.45–1.55
(1H, m), 1.55–1.60 (2H, m), 1.68–1.73 (1H, m), 1.86 (1H, d, J = 14.2 Hz), 2.35–2.40 (1H, m), 2.60 (1H,
d, J = 10.1 Hz), 2.87 (1H, d, J = 10.2 Hz), 3.64 (1H, d, J = 9.6 Hz), 3.84 (1H, d, J = 9.6 Hz), 4.09 (1H, d,
J = 2.6 Hz), 4.18 (1H, d, J = 3.2 Hz), 4.20 (1H, d, J = 3.2 Hz). 13C NMR (125 MHz, DMSO-d6):
= 21.7,
1.8, 22.2, 23.7, 25.8, 32.5, 36.4, 44.9, 51.8, 51.9, 75.4, 77.1, 83.6, 91.1. Anal. Calculated for C H NO : C,
δ
2
7
14
25
2
0.25; H, 10.53; N, 5.85. Found: C, 70.28; H, 10.50; N, 5.83.
3
.5. (3R,3aR,6R,7aS)-3-(Aminomethyl)-6-methyloctahydrobenzofuran-3-ol (11)
Aminoalcohols
7–9 (14.0 mmol) in MeOH (100 mL) were added to a suspension of
palladium-on-carbon (5% Pd, 0.22 g) in MeOH (50 mL), and the mixture was stirred under an
H atmosphere (1 atm) at room temperature. After the completion of the reaction (as monitored by
2
TLC, 24 h), the mixture was filtered through a Celite pad, and the solution was evaporated to dryness.
The crude product was recrystallized in Et O, resulting in primary aminoalcohol 11.
2
◦
20
D
Yield: 73% (with
.25, MeOH). H NMR (500 MHz, DMSO-d ):
7
); 75% (with
8
); 70% (with
9
), white crystals, m.p.: 217–221 C. [α] = +7.0 (c
1
0
δ
= 0.74–0.89 (2H, m), 0.83 (3H, d, J = 5.7 Hz), 1.46 (1H,
6
brs), 1.53–1.65 (2H, m), 1.75–1.83 (1H, m), 1.87 (1H, d, J = 13.8 Hz), 2.83 (1H, d, J = 12.9 Hz), 2.95 (1H, d,
J = 12.9 Hz), 3.56 (1H, d, J = 9.2 Hz), 3.80 (1H, d, J = 9.2 Hz), 4.28 (1H, s), 5.45 (1H, s), 8.04 (3H, s). 13
NMR (125 MHz, DMSO-d6): = 22.2, 23.2, 25.9, 32.4, 36.4, 41.8, 45.7, 74.9, 76.5, 80.3. Anal. Calculated
for C H NO : C, 64.83; H, 10.34; N, 7.56. Found: C, 64.85; H, 10.32; N, 7.60.
C
δ
10
19
2
3
.6. (3R,3aR,6R,7aS)-3-(Hydroxymethyl)-6-methyloctahydrobenzofuran-3-ol (6)
An aqueous solution of NMO (12 mL, 50% aqueous solution) and a solution of OsO in t-BuOH
4
(
6 mL, 2% t-BuOH solution) were added in one portion to a solution of compound
acetone (60 mL). The reaction mixture was stirred at room temperature for 24 h, then quenched by the
addition of a saturated aqueous solution of Na SO (100 mL), and extracted with EtOAc (Ethyl acetate,
3 (2.13 g, 14 mmol) in
2
3
3
×
80 mL). The organic layer was dried (Na SO ) and evaporated. The crude product was purified
2 4

Molecules 2020, 25, 21
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by chromatography on silica gel by using n-hexane:EtOAc = 1:4. The product after purification was
recrystallized in Et O resulting in compound 6 as white crystals.
2
◦
20
D
1
Yield: 50%, white crystals, m.p.: 67–68 C. [α] = +3.0 (c 0.27, MeOH). H NMR (500 MHz,
DMSO-d6):
1H, m), 1.50–1.57 (2H, m), 1.62–1.67 (1H, m), 1.85 (1H, d, J = 14.3 Hz), 3.34–3.38 (1H, m), 3.42 (1H, d,
J = 9.2 Hz), 3.47 (1H, dd, J = 5.5, 11.1Hz), 3.68 (1H, d, J = 9.2 Hz), 4.23 (1H, d, J = 2.2 Hz), 4.49 (1H, s),
δ = 0.75–0.80 (1H, m), 0.82 (3H, d, J = 6.5 Hz), 0.94–1.03 (1H, m), 1.04–1.11 (1H, m), 1.40–1.50
(
4
7
.52 (1H, t, J = 5.4 Hz). 13C NMR (125 MHz, DMSO-d6):
6.5, 83.5. Anal. Calculated for C H O : C, 64.49; H, 9.74. Found: C, 64.55; H, 9.69.
δ = 22.3, 23.4, 26.2, 32.8, 36.7, 46.2, 63.2, 74.8,
10
18
3
3
.7. General Procedure for the Reaction of Benzaldehyde with Diethylzinc in the Presence of Chiral Catalysts
To the respective catalyst (0.1 mmol), 1 M Et Zn in an n-hexane solution (3 mL, 3 mmol) was
2
added under argon atmosphere at room temperature. The solution was stirred for 25 min at room
temperature, and then benzaldehyde (1 mmol) was added. After stirring at room temperature for a
further 20 h, the reaction was quenched with a saturated NH Cl solution (15 mL), and the mixture
4
was extracted with EtOAc (2
×
20 mL). The combined organic phase was washed with H O (10 mL),
2
dried (Na SO ) and evaporated under vacuum. The obtained crude secondary alcohols were purified
2
4
by flash column chromatography (n-hexane:EtOAc = 4:1). The ee and absolute configuration of the
resulting material were determined by chiral GC on a Chirasil-DEX CB column after O-acetylation in
Ac O/DMPA/pyridine.
2
3
.8. Antimicrobial Analyses
For the antimicrobial analyses, the pure synthesized compounds were dissolved in MeOH and
diluted with H O to reach concentration levels up to 400 and 40
µg/mL with a final MeOH content of
2
10%. Then, these test solutions were investigated in a microdilution assay with two Gram-positive
bacteria (Bacillus subtilis SZMC 0209 and Staphylococcus aureus SZMC 14611), two Gram-negative
bacteria (Escherichia coli SZMC 6271 and Pseudomonas aeruginosa SZMC 23290), and two yeast strains
(
Candida albicans SZMC 1533 and C. krusei SZMC 1352) according to the M07-A10 CLSI guideline [76
]
and our previous work [57 77]. For the assay, the suspensions of the microbes were prepared from
,
overnight cultures that were cultivated in a ferment broth (bacteria: 10 g/L peptone, 5 g/L NaCl,
◦
5
g/L yeast extract; yeast: 20 g/L peptone, 10 g/L yeast extract, and 20 g/L glucose) at 37 C, and their
5
concentrations were set to 2
by dispensing 100
×
10 cells/mL with sterile media. Then, 96-well plates were prepared
µ
L of suspension containing the bacterial or yeast cells, 50
µ
L of sterile broth, and
◦
50
µ
L of the test solutions into each well, which were then incubated for 24 h at 37 C. The mixture of
150
µL of broth and 50
µL of 10% MeOH was used as the blank sample for background correction,
while 100
µL of the microbial suspension supplemented with 50 µL of the sterile broth and 50 µL of
1
0% MeOH was applied as the negative control. The positive control contained ampicillin (Sigma)
or nystatin (Sigma) for bacteria or fungi, respectively, at two concentration levels (100 g/mL and
g/mL). The inhibitory effects of each derivative were spectrophotometrically determined at 620 nm
µ
10 µ
after incubation, and the inhibition rate was calculated as the percentage of the positive control after
blank correction.
4
. Conclusions
A new library of neoisopulegol-based chiral 1,2-aminoalcohols and a diol were developed from
+)-neoisopulegol, as derived from commercially available (–)-isopulegol. The obtained aminoalcohols
(
and diol may serve as useful building blocks for the synthesis of new heterocyclic ring systems and
biologically active compounds.
The in vitro antimicrobial studies have clearly shown that the resulting N-substituted
aminoalcohols possess moderate antibacterial action on different bacterial strains, while the diol
has a remarkable antifungal effect.

Molecules 2020, 25, 21
10 of 14
Aminoalcohol derivatives were also applied as chiral catalysts in the enantioselective addition of
diethylzinc to benzaldehyde with moderate but opposite enantioselectivity.
Supplementary Materials: The following are available online, Figures S3–S31: 1H, 13C, HSQC, HMBC and
NOESY NMR spectra of new compounds.
Author Contributions: The listed authors contributed to this work as described in the following. Z.S., T.M.L.
and A.S. designed, planned the research and interpreted the results. F.Z.B. and B.V. carried out the synthetic
work. F.Z.B. and T.M.L. discussed the results and contributed to the writing of the paper. All authors discussed
the results, and they also prepared and commented on the manuscript. All authors have read and agreed to the
published version of the manuscript.
Funding:
This research was funded by EU-funded Hungarian grant GINOP, grant number
GINOP-2.3.2-15-2016-00014. The APC was funded by University of Szeged Open Access Fund’ (FundRef,
Grant number 4479).
Acknowledgments: Z.S. is grateful for financial support from University of Szeged Open Access Fund’ (FundRef,
Grant number 4479) and the EU-funded Hungarian grant GINOP-2.3.2-15-2016-00014.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
.
Keay, B.A.; Hopkins, J.M.; Dibble, P.W. Furans and their benzo derivatives: Applications. In Comprehensive
Heterocyclic Chemistry III, 1st ed.; Katritzky, A.R., Ramsden, C.A., Scriven, E.F.V., Taylor, R.J.K., Eds.; Elsevier:
Amsterdam, The Netherlands, 2008; Volume 5, pp. 571–623.
2
.
Keay, B.A.; Dibble, P.W. Furans and their benzo derivatives: Applications. In Comprehensive Heterocyclic
Chemistry II, 2nd ed.; Katritzky, A.R., Rees, C.V., Scriven, E.F.V., Eds.; Elsevier: Amsterdam, The Netherlands,
1
996; Volume 2, pp. 395–436.
3
.
.
Leibeling, M.; Koester, D.C.; Pawliczek, M.; Schild, S.C.; Werz, D.B. Domino access to highly substituted
chromans and isochromans from carbohydrates. Nat. Chem. Biol. 2010, 6, 199–201. [CrossRef] [PubMed]
Zhang, Y.; Negishi, E. Metal-promoted cyclization. 25. Palladium-catalyzed cascade carbometalation of
4
alkynes and alkenes as an efficient route to cyclic and polycyclic structures. J. Am. Chem. Soc. 1989
11, 3454–3456. [CrossRef]
,
1
5
.
.
Huang, Q.; Larock, R.C. Synthesis of substituted Naphthalenes and Carbazoles by the Palladium-catalyzed
annulation of internal alkynes. J. Org. Chem. 2003, 68, 7342–7349. [CrossRef] [PubMed]
6
Manarin, F.; Roehrs, J.A.; Gay, R.M.; Brand
cyclization of 2-Chalcogenealkynylanisoles: Versatile access to 2-Chalcogen-benzo[b]furans. J. Org. Chem.
009, 74, 2153–2162. [CrossRef] [PubMed]
ão, R.; Menezes, P.H.; Nogueira, C.W.; Zeni, G. Electrophilic
2
7
.
.
Isono, N.; Lautens, M. Rhodium(I)-catalyzed cyclization reaction of o-alkynyl Phenols and Anilines. Domino
approach to 2,3-disubstituted Benzofurans and Indoles. Org. Lett. 2009, 11, 1329–1331. [CrossRef]
Zhao, D.; Wu, N.; Zhang, S.; Xi, P.; Su, X.; Lan, J.; You, J. Synthesis of phenol, aromatic ether, and Benzofuran
derivatives by Copper-catalyzed hydroxylation of aryl halides. Angew. Chem. Int. Ed. 2009, 48, 8729–8732.
8
[CrossRef]
9
.
Shen, Z.; Dong, V.M. Benzofurans prepared by C-H Bond functionalization with acylsilanes. Angew. Chem.
Int. Ed. 2009, 48, 784–786. [CrossRef]
1
0. Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Wang, F.; Li, J.-H. Cycloaddition of arynes with Iodonium
Ylides: A mild and general route for the synthesis of Benzofuran derivatives. Org. Lett. 2008, 10, 1525–1528.
[CrossRef]
1
1
1. Kokubo, K.; Harada, K.; Mochizuki, E.; Oshima, T. A new approach to benzofuran synthesis: Lewis acid
mediated cycloaddition of benzoquinones with stilbene oxides. Tetrahedron Lett. 2010, 51, 955–958. [CrossRef]
2. Baguley, P.A.; Jackson, L.V.; Walton, J.C. Preparation of 1-phenylcyclohexa-2,5-diene-1-carboxylates and their
use in free-radical mediated syntheses. J. Chem. Soc. Perkin 1 2002, 304–309. [CrossRef]

Molecules 2020, 25, 21
11 of 14
1
1
1
3. McCarroll, A.J.; Walton, J.C. Enhanced radical delivery from aldoxime esters for EPR and ring closure
applications. Chem. Commun. 2000, 351–352. [CrossRef]
4. Harvey, W.E.; Tarbell, D.S. The reaction of the magnesium salt of N-cyclohexylcyclohexylimine with epoxides.
J. Org. Chem. 1967, 32, 1679–1681. [CrossRef]
5. Coaviche-Yoval, A.; Andrade-Jorge, E.; P
Quantum reality in the selective reduction of a Benzofuran system. Molecules 2019, 24, 2061. [CrossRef]
PubMed]
6. Yakura, T.; Yamada, S.; Shima, M.; Iwamoto, M.; Ikeda, M. Synthesis of Octahydrobenzo[b]furans using
Tandem conjugate addition reactions initiated by oxygen nucleophile. Chem. Pharm. Bull. (Tokyo) 1998
6, 744–748. [CrossRef]
7. Ferraz, H.M.C.; Longo, L.S. Bicyclic β-hydroxytetrahydrofurans as precursors of medium ring keto-lactones.
érez-González, C.; Luna, H.; Tovar-Miranda, R.; Trujillo-Ferrara, J.G.
[
1
,
4
1
1
1
2
J. Org. Chem. 2007, 72, 2945–2950. [CrossRef]
8. Herrinton, P.H.; Hopkins, M.H.; Mishra, P.; Brown, M.J.; Overman, L.E. Ring-enlarging furan annulations.
J. Org. Chem. 1987, 52, 3711–3712. [CrossRef]
9. Groves, J.T. A stereochemical probe of the fate of carbon radicals oxidized by metals. Tetrahedron Lett. 1975
6, 3113–3116. [CrossRef]
0. Sohail, M.; Wang, Y.-F.; Wu, S.; Zeng, W.; Chen, F.-X. Asymmetric synthesis of octahydrobenzofuran
core structure with three contiguous stereogenic centers and development of the absolute configurations.
Synth. Commun. 2014, 44, 115–120. [CrossRef]
,
1
2
2
2
2
2
2
1. Arimitsu, K.; Nomura, S.; Iwasaki, H.; Ozeki, M.; Yamashita, M. First total synthesis of ( )-adunctin B.
Tetrahedron Lett. 2011, 52, 7046–7048. [CrossRef]
2. Trost, B.M.; Shen, H.C.; Surivet, J.-P. An enantioselective biomimetic total synthesis of (–)-Siccanin.
Angew. Chem. Int. Ed. 2003, 42, 3943–3947. [CrossRef]
3. Bhagavathula, D.; Boddeti, G.; Reddy, V. A brief review on synthesis of β-amino alcohols by ring opening of
±
epoxides. Res. Rev. J. Chem. 2017, 6, 27–46.
4. Brik, A.; Wong, C.-H. HIV-1 protease: Mechanism and drug discovery. Org. Biomol. Chem. 2003, 1, 5–14.
CrossRef] [PubMed]
5. Ghosh, A.K.; Bilcer, G.; Schiltz, G. Syntheses of FDA ppproved HIV protease inhibitors. Synthesis 2001
001, 2203–2229. [CrossRef] [PubMed]
[
,
2
6. Andrews, K.T.; Fairlie, D.P.; Madala, P.K.; Ray, J.; Wyatt, D.M.; Hilton, P.M.; Melville, L.A.; Beattie, L.;
Gardiner, D.L.; Reid, R.C.; et al. Potencies of human immunodeficiency virus protease inhibitors in vitro
against Plasmodium falciparum and in vivo against murine malaria. Antimicrob. Agents Chemother. 2006
0, 639–648. [CrossRef]
7. Nöteberg, D.; Hamelink, E.; Hultén, J.; Wahlgren, M.; Vrang, L.; Samuelsson, B.; Hallberg, A. Design and
synthesis of plasmepsin I and plasmepsin II inhibitors with activity in Plasmodium falciparum-infected
cultured human erythrocytes. J. Med. Chem. 2003, 46, 734–746. [CrossRef]
8. Parikh, S.; Gut, J.; Istvan, E.; Goldberg, D.E.; Havlir, D.V.; Rosenthal, P.J. Antimalarial cctivity of human
immunodeficiency virus type 1 protease inhibitors. Antimicrob. Agents Chemother. 2005, 49, 2983–2985.
,
5
2
2
[
CrossRef]
9. Savoia, D.; Allice, T.; Tovo, P.-A. Antileishmanial activity of HIV protease inhibitors. Int. J. Antimicrob. Agents
005, 26, 92–94. [CrossRef]
0. Conolly, M.E.; Kersting, F.; Dollery, C.T. The clinical pharmacology of beta-adrenoceptor-blocking drugs.
Prog. Cardiovasc. Dis. 1976, 19, 203–234. [CrossRef]
1. Shanks, R.G.; Wood, T.M.; Dornhorst, A.C.; Clark, M.L. Some pharmacological properties of a new adrenergic
β-receptor antagonist. Nature 1966, 212, 88–90. [CrossRef]
2. Zimmerman, T.J.; Boger, W.P. The beta-adrenergic blocking agents and the treatment of glaucoma.
Surv. Ophthalmol. 1979, 23, 347–362. [CrossRef]
3. Ager, D.J.; Prakash, I.; Schaad, D.R. 1,2-Amino alcohols and their heterocyclic derivatives as chiral auxiliaries
in asymmetric synthesis. Chem. Rev. 1996, 96, 835–876. [CrossRef] [PubMed]
4. Griesbeck, A.G.; Lex, J.; Saygin, K.M.; Steinwascher, J. Azidohydroperoxidation of pinenes: Stereoselectivity
pattern and the first X-ray structure of a 2-azidohydroperoxide. Chem. Commun. 2000, 2205–2206. [CrossRef]
2
3
3
3
3
3
2

Molecules 2020, 25, 21
12 of 14
3
5. Frensch, G.; Labes, R.; Wosch, C.L.; Munaretto, L.D.S.; Salom
é
, K.S.; Guerrero, P.G.; Marques, F.A. New chiral
ligands derived from (+) and (–)-
α
-pinene for the enantioselective addition of diethylzinc to aldehydes.
Tetrahedron Lett. 2016, 57, 420–422. [CrossRef]
3
3
3
6. Hobuß, D.; Baro, A.; Laschat, S.; Frey, W. Catalytic enantioselective borane reduction of arylketones with
pinene-derived amino alcohols. Tetrahedron 2008, 64, 1635–1640. [CrossRef]
7. Masui, M.; Shioiri, T. A practical method for preparation of optically pure oxazaborolidines from α-Pinene.
Tetrahedron 1995, 51, 8363–8370. [CrossRef]
8. Boobalan, R.; Chang, Y.-M.; Chen, C.; Lee, G.-H. Copper complex of Pinene based Schiff base [CuSBADBH]2:
Synthesis and its application in catalytic asymmetric nitroaldol (Henry) reaction. ChemistrySelect 2016
, 2028–2034. [CrossRef]
,
1
3
4
9. Ła˛czkowski, K.Z.; Kmieciak, A.; Kozakiewicz, A. Stereoselective synthesis of new monoterpene β-amino
alcohols. Tetrahedron Asymmetry 2009, 20, 1487–1492. [CrossRef]
0. Banina, O.A.; Sudarikov, D.V.; Nigmatov, A.G.; Frolova, L.L.; Slepukhin, P.A.; Zlotin, S.G.; Kutchin, A.V.
Carane amino alcohols as organocatalysts in asymmetric aldol reaction of isatin with acetone. Russ. Chem. Bull.
2
017, 66, 293–296. [CrossRef]
4
1. Rafi n´ ski, Z.; Krzemi n´ ski, M.P. Synthesis of (–)-Verbenone-derived triazolium salts and their application in
enantioselective intramolecular Stetter reaction. Catalysts 2019, 9, 117. [CrossRef]
4
2. Frolova, L.L.; Sudarikov, D.V.; Alekseev, I.N.; Banina, O.A.; Slepukhin, P.A.; Kutchin, A.V. Synthesis of
new enantiomerically pure
CrossRef]
3. Dimitrov, V.; Dobrikov, G.; Genov, M. Chiral
β-amino alcohols of the pinane series. Russ. J. Org. Chem. 2017, 53, 335–343.
[
4
β- and γ-aminoalcohols derived from (+)-camphor
and (–)-fenchone as catalysts for the enantioselective addition of diethylzinc to benzaldehyde.
Tetrahedron Asymmetry 2001, 12, 1323–1329. [CrossRef]
4
4
4. Rafi n´ ski, Z. Enantioselective benzoin condensation catalyzed by spirocyclic terpene-based N-heterocyclic
carbenes. Tetrahedron 2016, 72, 1860–1867. [CrossRef]
5. Rafi n´ ski, Z.; Kozakiewicz, A.; Rafi n´ ska, K. Highly efficient synthesis of spirocyclic (1R)-camphor-derived
triazolium salts: Application in the catalytic asymmetric benzoin condensation. Tetrahedron 2014
0, 5739–5745. [CrossRef]
,
7
4
4
6. Wilkinson, H.S.; Grover, P.T.; Vandenbossche, C.P.; Bakale, R.P.; Bhongle, N.N.; Wald, S.A.; Senanayake, C.H.
A new lithium alkoxide accelerated diastereoselective cyanation of ketones. Org. Lett. 2001, 3, 553–556.
[CrossRef] [PubMed]
7. Panev, S.; Linden, A.; Dimitrov, V. Chiral aminoalcohols with a menthane skeleton as catalysts for the
enantioselective addition of diethylzinc to benzaldehyde. Tetrahedron Asymmetry 2001, 12, 1313–1321.
[
CrossRef]
8. Friedrich, D.; Bohlmann, F. Total synthesis of various elemanolides. Tetrahedron 1988, 44, 1369–1392.
CrossRef]
4
4
5
[
9. Rigamonti, M.G.; Gatti, F.G. Stereoselective synthesis of hernandulcin, peroxylippidulcine A, lippidulcines
A, B and C and taste evaluation. Beilstein J. Org. Chem. 2015, 11, 2117–2124. [CrossRef]
0. Moreira, J.A.; Corr
sex pheromone component of Leucoptera coffeella, from (–)-isopulegol. Tetrahedron Asymmetry 2003
4, 3787–3795. [CrossRef]
êa, A.G. Enantioselective synthesis of three stereoisomers of 5,9-dimethylpentadecane,
,
1
5
5
1. Nazimova, E.; Pavlova, A.; Mikhalchenko, O.; Il’ina, I.; Korchagina, D.; Tolstikova, T.;
Volcho, K.; Salakhutdinov, N. Discovery of highly potent analgesic activity of isopulegol-derived
(2R,4aR,7R,8aR)-4,7-dimethyl-2-(thiophen-2-yl)octahydro-2H-chromen-4-ol. Med. Chem. Res. 2016
,
2
5, 1369–1383. [CrossRef]
2. Engel, W. In vivo studies on the metabolism of the monoterpene Pulegone in humans using the metabolism
of ingestion-correlated amounts (MICA) approach: Explanation for the toxicity differences between (S)-(–)-
and (R)-(+)-Pulegone. J. Agric. Food Chem. 2003, 51, 6589–6597. [CrossRef]
5
3. Bulliard, M.; Balme, G.; Gore, J. Fragmentation of isopulegol by a radical process. Tetrahedron Lett. 1989
0, 2213–2216. [CrossRef]
,
3
5
4. Hegde, S.G.; Beckwith, D.; Doti, R.; Wolinsky, J. Synthesis with hypochlorous acid. Conversion to pulegone
and isopulegol to menthofuran. Preparation of 3,6-dimethyl-2,6-cycloheptadien-1-one from phorone.
J. Org. Chem. 1985, 50, 894–896. [CrossRef]

Molecules 2020, 25, 21
13 of 14
5
5. Brocksom, T.J.; dos Santos, R.B.; Varanda, N.A.; Brocksom, U. An efficient synthesis of monoterpene
α-methylene-γ-butyrolactones. Synth. Commun. 1988, 18, 1403–1410. [CrossRef]
5
6. Schlosser, M.; Kotthaus, M. Isopulegol as a model compound: Metalation and substitution of an allylic
position in the presence of an unprotected hydroxy function. Eur. J. Org. Chem. 1999, 1999, 459–462.
[CrossRef]
5
5
7. Le, T.M.; Szilasi, T.; Volford, B.; Szekeres, A.; Fülöp, F.; Szakonyi, Z. Stereoselective synthesis and investigation
of isopulegol-based chiral ligands. Int. J. Mol. Sci. 2019, 20, 4050. [CrossRef] [PubMed]
8. Chen, J.; Chen, M.; Zhang, B.; Nie, R.; Huang, A.; Goh, T.W.; Volkov, A.; Zhang, Z.; Ren, Q.; Huang, W. Allylic
oxidation of olefins with a manganese-based metal–organic framework. Green Chem. 2019, 21, 3629–3636.
[CrossRef]
5
6
9. Islam, S.M.; Roy, A.S.; Mondal, P.; Salam, N. Efficient allylic oxidation of olefins catalyzed by polymer
supported metal Schiff base complexes with peroxides. J. Inorg. Organomet. Polym. Mater. 2012, 22, 717–730.
[
CrossRef]
0. Jia, Y.X.; Wu, B.; Li, X.; Ren, S.K.; Tu, Y.Q.; Chan, A.S.C.; Kitching, W. Synthetic studies of the HIV-1 protease
ihibitive didemnaketals: Stereocontrolled synthetic approach to the key mother spiroketals. Org. Lett. 2001
, 847–849. [CrossRef]
1. Waddell, T.G.; Ross, P.A. Chemistry of 3,4-epoxy alcohols. Fragmentation reactions. J. Org. Chem. 1987
2, 4802–4804. [CrossRef]
2. Kim, J.H.; Lim, H.J.; Cheon, S.H. A facile synthesis of (6S,1 S)-(+)-hernandulcin and (6S,1 R
-(+)-epihernandulcin. Tetrahedron 2003, 59, 7501–7507. [CrossRef]
3. Kim, J.H.; Lim, H.J.; Cheon, S.H. Synthesis of (+)-hernandulcin and (+)-epihernandulcin. Tetrahedron Lett.
002, 43, 4721–4722. [CrossRef]
,
3
6
6
6
6
6
,
5
0
0
)
2
4. Szakonyi, Z.; Csillag, K.; Fülöp, F. Stereoselective synthesis of carane-based aminodiols as chiral ligands for
the catalytic addition of diethylzinc to aldehydes. Tetrahedron Asymmetry 2011, 22, 1021–1027. [CrossRef]
5. Szakonyi, Z.; Cs o˝ r,
Á.; Csámpai, A.; Fülöp, F. Stereoselective synthesis and modelling-driven optimisation of
Carane-based aminodiols and 1,3-oxazines as catalysts for the enantioselective addition of diethylzinc to
benzaldehyde. Chem. - Eur. J. 2016, 22, 7163–7173. [CrossRef] [PubMed]
6
6. Shivani; Pujala, B.; Chakraborti, A.K. Zinc(II) perchlorate hexahydrate catalyzed opening of epoxide ring by
amines: Applications to synthesis of (RS)/(R)-Propranolols and (RS)/(R)/(S)-Naftopidils. J. Org. Chem. 2007
2, 3713–3722. [CrossRef] [PubMed]
7. Bergmeier, S.C. The synthesis of vicinal amino alcohols. Tetrahedron 2000, 56, 2561–2576. [CrossRef]
8. Gonda, T.; Szakonyi, Z.; Cs mpai, A.; Haukka, M.; Fülöp, F. Stereoselective synthesis and application of
,
7
6
6
á
tridentate aminodiols derived from (+)-pulegone. Tetrahedron Asymmetry 2016, 27, 480–486. [CrossRef]
9. Morikawa, H.; Yamaguchi, J.; Sugimura, S.; Minamoto, M.; Gorou, Y.; Morinaga, H.; Motokucho, S.
Systematic synthetic study of four diastereomerically distinct limonene-1,2-diols and their corresponding
cyclic carbonates. Beilstein J. Org. Chem. 2019, 15, 130–136. [CrossRef]
6
7
0. Tanaka, T.; Yasuda, Y.; Hayashi, M. New chiral Schiff base as a tridentate ligand for catalytic enantioselective
addition of diethylzinc to aldehydes. J. Org. Chem. 2006, 71, 7091–7093. [CrossRef]
7
1. Jimeno, C.; Past
as chiral controllers for Et2Zn addition to aldehydes: Illustration of a design principle. J. Org. Chem. 2003
8, 3130–3138. [CrossRef]
2. Tashenov, Y.; Daniels, M.; Robeyns, K.; Van Meervelt, L.; Dehaen, W.; Suleimen, Y.; Szakonyi, Z. Stereoselective
syntheses and application of chiral bi- and tridentate ligands derived from (+)-Sabinol. Molecules 2018
3, 771. [CrossRef]
3. Szakonyi, Z.; Hetényi, A.; Fülöp, F. Synthesis and application of monoterpene-based chiral aminodiols.
ó, M.; Riera, A.; Pericàs, M.A. Modular amino alcohol ligands containing bulky alkyl groups
,
6
7
,
2
7
7
7
Tetrahedron 2008, 64, 1034–1039. [CrossRef]
4. Yendapally, R.; Lee, R.E. Design, synthesis, and evaluation of novel ethambutol analogues. Bioorg. Med.
Chem. Lett. 2008, 18, 1607–1611. [CrossRef] [PubMed]
5. Cunico, W.; Gomes, C.R.B.; Ferreira, M.L.G.; Ferreira, T.G.; Cardinot, D.; de Souza, M.V.N.; Lourenço, M.C.S.
Synthesis and anti-mycobacterial activity of novel amino alcohol derivatives. Eur. J. Med. Chem. 2011
6, 974–978. [CrossRef] [PubMed]
,
4

Molecules 2020, 25, 21
14 of 14
7
7
6. Weinstein, M.P. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 11th ed.;
Clinical and Laboratory: Wayne, PA, USA, 2018.
ni, Z.; D ny, M.; Kov cs, B.; Csupor-Löffler, B.; Zomborszki, Z.; Kerekes, E.; Szekeres, A.; Urb
Hohmann, J.; V nyol s, A. Bioactivity-guided isolation of antimicrobial and antioxidant metabolites from
the mushroom Tapinella atrotomentosa. Molecules 2018, 23, 1082. [CrossRef]
7.
B
é
é
ká
á
án, E.;
á
ó
Sample Availability: Samples of the compounds 3–15 are available from the authors.
©
2019 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 (http://creativecommons.org/licenses/by/4.0/).