Synthesis and Antimicrobial Activity of Racemic 1,5-Diols: 2-(1,3-Diaryl-3-hydroxypropyl)cyclohexan-1-ol Derivatives

Article abstract of DOI:10.1002/hlca.201600048

A series of novel racemic 2-(1,3-diaryl-3-hydroxypropyl)cyclohexan-1-ol derivatives were synthesized from 1,5-diketones. All the synthesized compounds were characterized by spectroscopic methods. The antibacterial activities of obtained chiral 1,5-diols were investigated against four Gram-positive and three Gram-negative bacteria by determining of minimum inhibitory concentrations (MICs) in vitro. Compounds 3b, 3c, and 3d were found to be active against Enterococcus faecalis and Escherichia coli. In addition, compound 3j were found to be moderately active against all tested bacterial strains.

Full text of DOI:10.1002/hlca.201600048

Article Type: Full Paper
Synthesis and Antimicrobial Activity of Racemic 1,5-Diols: 2-(1,3-Diaryl-3-
hydroxypropyl)cyclohexan-1-ol Derivatives
by Hayreddin Gezegen*a), Uğur Tutara), and Mustafa Ceylanb)
a) Department of Nutrition and Dietetics, Faculty of Health Sciences, Cumhuriyet University,
58140, Sivas, Turkey
b) Department of Chemistry, Faculty of Arts and Sciences, Gaziosmanpasa University, 60250
Tokat, Turkey (phone: +90-346-2191010; fax: +90-346-2191261; e-mail:
gezegenh@cumhuriyet.edu.tr)
A series of novel racemic 2-(1,3-diaryl-3-hydroxypropyl)cyclohexan-1-ol derivatives
were synthesized from 1,5-diketones. All the synthesized compounds were characterized by
spectroscopic methods. The antibacterial activities of obtained chiral 1,5-diols were
investigated against four Gram-positive and three Gram-negative bacteria by determining of
minimum inhibitory concentrations (MICs) in vitro. Compounds 3b, 3c, and 3d were found to
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be active against E. faecalis and E. coli. In addition, compound 3j were found to be
moderately active against all tested bacterial strains.
Keywords: Chalcones, 1,5-Diketone compounds, 1,5-Diols, Michael addition,
Antimicrobial activity.
Introduction. - Chalcones are an important class of compounds that can be prepared
synthetically or isolated from natural sources. The chalcones have attracted a great deal of
attention due to their synthetic applications and wide range of biological activity [1-7]. The
presence of α,β-unsaturated carbonyl system on chalcone skeleton makes them polyfunctional
synthetic building block. Thus, they are used as starting material in synthesis of natural
heterocyclic compounds [2,8,9] and synthetically valuable intermediates [5,6]. For instance,
1,5-diketones are a valuable intermediates and they can be used different type reactions
including synthesis of pharmacologically active heterocyclic compounds [10], fused-ring
systems [11,12], cyclohexenones [7,13], bicyclic compounds [14] and oxathianes [15]. 1,5-
Diketones can be obtained from 1,4-Michael addition of ketones to chalcones. Various
synthetic methods for conjugated addition of cyclic ketones to chalcones have been presented
in the literature, including the following; tandem retro-Aldol [16], di-enamine mechanism
[17] and barium isopropoxide [18], chiral benzoylthiourea–pyrrolidine [19],
hydroxyphthalimide [20], pyrrolidine-based imides [21], pyrrolidine-pyridine [22], amino
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acid ionic liquid [23], pyrrolidine-sulfonamide catalyzed [24] 1,5-diketone syntheses. In
many of these methods [18-24], a chiral catalyst was used, and (S)-2-((R)-1,3-diaryl-3-
oxopropyl)cyclohexanone derivatives were synthesized in high enantioselectivities. On the
other hand, synthesis and application areas of 1,5-diols are importance in the organic
chemistry. 1,5-Diols are useful intermediates in synthesis of heterocycle located in natural
and bioactive products such as dihydropyrans [25], tetrahydropyrans [26], δ-lactones [27,28],
morpholine [29], and anabasine [30]. Also, chiral 1,5-diols are used in the synthesis of
enantiomerically pure 2,6-disubstituted and 3,5-disubstituted six-membered heterocycles
[31].
In our previous studies, we have reported the syntheses of 1,5-diketones from the
Michael addition of cyclohexanone to chalcone derivatives [2,32]. We thought that 1,5-
diketone derivatives could be transformed to the 1,5-diols. Therefore, in present study, we
have synthesized racemic 2-(1,3-diaryl-3-hydroxypropyl)cyclohexan-1-ol derivatives 3a – 3j
over of racemic 1,5-diketones 2a – 2j.
Results and Discussion. – Herein, we report the synthesis of racemic 2-(1,3-diaryl-3-
hydroxypropyl)cyclohexan-1-ol derivatives 3a – 3j that have four stereogenic centers. The
chalcone derivatives 1a – 1j were prepared by treatment of related aromatic ketones and
aromatic aldehydes with NaOH in EtOH at room temperature [33,34]. 1,5-Diketones 2a – 2j
were synthesized by modifying our reference method [2,32] via Michael addition in yields
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ranging from 80 to 90% (Table 1). In the syntheses of 1,5-diketones, no chiral catalyst was
used, therefore the products are racemic mixture. Obtained racemic 1,5-diketones 2a – 2j
were characterized by spectroscopic studies and literature data [2,32].
1,5-Diols 3a – 3j were obtained by reaction of 2a – 2j with NaBH4 in THF/MeOH
(5:1) solvent mixture at room temperature (Scheme). The TLC studies and 1H- and 13C-NMR
analyses indicated that at least four diastereoisomeric products were occurred during the
reaction. But diastereoisomeric composition of the reaction mixture could not be determined
because the 1H- and 13C-NMR spectra were very complex. The mixture was subjected to
crystallization in Et2O/hexane (3:1) [35]. Only one pure diastereoisomer was obtained by
crystallization of 3a – 3j in high yields (65-78%) (Table 2). Viscous oily product that
remaining after the crystallisation was subjected to column chromatography on silica gel
eluting with AcOEt/hexane (2:8) and different eluent systems (AcOEt/toluene,
CHCl3/hexane, etc.), but other diastereoisomers cannot be isolated.
The structures of synthesized 1,5-diols 3a – 3j were determined by spectroscopic
studies (1H-, 13C-, 2D-NMR, IR, GC/MS, and elemental analysis). The full analysis of HSQC
and HMBC spectra of 3a confirmed the presence of 1,5-diol structure (Table 3). In the
HMBC spectrum of 3a, the location of benzylic OH group was confirmed with correlations
of between OH–C(3) to C(3), C(2) and C(1''). Also the location of aliphatic OH group was
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confirmed by HMBCs of between OH–C(1') to C(1'), C(2') and C(6') (Table 3, Fig. 1). In the
1H-NMR spectrum of 3a, the OH H-atoms of benzyl alcohol and cyclohexanol gave a doublet
at δ(H) 4.79 (d, J = 4.7 Hz) and 4.18 (d, J = 4.2 Hz), respectively. The benzylic H-atom H–
C(3) adjacent to the OH group gave a multiplet at δ(H) 3.89-3.86 and methine H-atom H–
C(1') adjacent to the OH group of cyclohexanol gave a broad singlet at δ(H) 4.01. Other
benzylic H-atom H–C(1) on structure gave a triplet of doublet at δ(H) 2.90 (J = 11.1, 3.2 Hz)
and methine H-atom H–C(2') on cyclohexanol ring gave a triplet δ(H) 1.35 (J = 11.2 Hz).
While one of the CH2(2) H-atoms on propane chain gave a multiplet at δ(H) 2.17-2.09, the
other gave a triplet at δ(H) 1.56 (J = 12.5 Hz). All the aliphatic and aromatic signals in the
spectrum were consistent with the structure of 3a (Table 3).
The relative configuration of the compound 3c was established by X-ray diffraction
analysis [35]. The X-ray diffraction analysis confirmed that the proposed structure is rel-
(1R,2R)-2-[(1S,3S)-1-(4-Bromophenyl)-3-hydroxy-3-(4-methoxyphenyl)propyl]cyclohexanol
(3c; Fig. 2).
All the newly synthesized 1,5-diols 3a – 3j were investigated for their in vitro
antibacterial activity against four Gram-positive bacteria (Bacillus cereus ATCC 10987,
Bacillus subtilis ATCC 6633, Enterococcus faecalis ATCC 29212 and Staphylococcus aureus
ATCC 25923) and three Gram-negative bacteria (Escherichia coli ATCC 11229,
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Pseudomonas aeruginosa ATCC 27853 and Shigella boydii ATCC 9905). The antibacterial
activity tests were carried out by the microdilution method using 96-well microplates.
Minimal inhibitory concentrations (MICs) of the synthesized 1,5-diols were determined and
the results are given in Table 4. Piperacillin/tazobactam (8:1) was employed as a reference
antibacterial agent.
As seen in Table 4, the most active compound was 3c against E. faecalis and E. coli
with an MIC value of 15.6 µg/ml. Compound 3d (MIC 15.6 µg/ml) had the same effect as 3c
against E. coli, and also 3b and 3j have exhibited lower activity from them with the MIC
values of 31.3 and 250 µg/ml, respectively. While compounds 3d and 3j showed moderate
activity (MIC 125 µg/ml) against E. faecalis, 3b showed about one-quarter of the activity of
them (MIC 500 µg/ml). Besides, compound 3j exhibited moderate activity against other
tested bacterial strains with the MIC values of 125 µg/ml (P. aeruginosa) and 250 µg/ml (B.
cereus, B. subtilis, and S. aureus), respectively. The rest of the tested compounds were found
to be inactive against the selected bacteria at the tested concentrations.
In conclusion, a series of novel racemic (1RS,2RS)-2-((1SR,3SR)-1,3-diaryl-3-
hydroxypropyl)cyclohexan-1-ol derivatives 3a – 3j have been synthesized by reduction of 2a
– 2j with NaBH4 in good yields. The structures of new compounds were established on the
basis of spectroscopic methods. The antimicrobial activities of synthesized 1,5-diols 3a – 3j
were screened against four Gram-positive and three Gram-negative bacteria. While
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compounds 3b, 3c, and 3d were found to be active against E. faecalis and E. coli, compound
3j were found to be moderately active against all tested bacterial strains. These obtained 1,5-
diols 3a – 3j have potential applications in the synthesis of biologically and naturally
valuable compounds.
The authors are indebted to the Gaziosmanpaşa University (Grant BAP-2011/94) for
financial support of this work.
Experimental Part
General
Na2SO4 was used as a drying agent for the organic phase. Column chromatography
(CC): silica gel (60 – 230 mesh, Merck). M.p.: Electrothermal 9100 apparatus. IR Spectra:
JASCO FT/IR-430 spectrometer in KBr disc; ෤ in cm–1. 1H- and 13C-NMR spectra: Bruker
Avance DPX-400 NMR instrument in CDCl3 (for 2b – 2j) and (D6)DMSO (for 3a – 3j); δ in
ppm rel. to Me4Si (δ 0.00) for 1H-NMR, CDCl3 (δ 77.0) and (D6)DMSO (δ 39.5) for 13C-
NMR spectra as internal standards, J in Hz. 2D-NMR spectra of 2a and 3a: Agilent 600 MHz
Premium COMPACT NMR instrument in (D6)DMSO. GC/MS: PerkinElmer Clarus 500.
Elemental analyses: LECO CHNS 932 elemental analyzer; in %.
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General procedure for the synthesis of 1,5-diketones 2a – 2j. To a soln. of chalcone 1a
– 1j (3 mmol), cyclohexanone (6 mmol), and benzyltriethylammonium chloride (10 mol-%)
in CH2Cl2 (5 ml) was added 5M KOH (0.2 ml). The mixture was stirred at r.t. for 3 h. Then,
the mixture was neutralized with diluted HCl and extracted with CH2Cl2 (3 × 10 ml). Extract
was dried (Na2SO4), and the solvent was removed in vacuum. The crude product was
crystallized from EtOH/Et2O 3:1.
2-[1-(4-Chlorophenyl)-3-(4-methoxyphenyl)-3-oxopropyl]cyclohexanone (2a) [2].
1H-NMR: 7.87 (d, J = 8.9, H–C(2'',6'')); 7.25 (d, J = 8.7, H–C(3''',5''')); 7.23 (d, J = 8.6, H–
C(2''',6''')); 6.97 (d, J = 8.8, H–C(3'',5'')); 3.80 (s, MeO); 3.60 (td, J = 8.3, 6.4, H–C(1)); 3.31
(m, CH2(2)); 2.81 – 2.74 (m, H–C(2')); 2.38 (td, J = 12.2, 5.8, 1 H of CH2(6')); 2.31 – 2.25
(m, 1 H of CH2(6')); 1.90 (m, 1 H of CH2(5')); 1.65 (dd, J = 10.2, 4.5, 1 H of CH2(4')); 1.51
(m, 1 H of CH2(4'), 1 H of CH2(3'), 1 H of CH2(5')); 1.10 – 0.97 (m, 1 H of CH2(3')). 13C-
NMR: 212.62 (C(1')); 197.09 (C(3)); 163.45 (C(4'')); 141.93 (C(1''')); 131.09 (C(4''')); 130.82
(C(2''',6''')); 130.58 (C(2'',6'')); 130.09 (C(1'')); 128.37 (C(3''',5''')); 114.22 (C(3'',5'')); 55.91
(MeO); 54.82 (C(2')); 43.23 (C(2)); 42.48 (C(6')); 40.16 (C(1)); 32.35 (C(3')); 28.37 (C(5'));
24.54 (C(4')).
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2-[3-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-oxopropyl]cyclohexanone (2b).
Yield 84%. White solid. M.p. 128 – 131°. IR: 3027m, 2935s, 1702s (C=O), 1685s (C=O),
1590s, 817s. 1H-NMR: 7.84 (d, J = 8.4, H–C(2'',6'')); 7.31 (d, J = 8.4, H–C(3'',5'')); 7.03 (d, J
= 8.6, H–C(2''',6''')); 6.75 (d, J = 8.6, H–C(3''',5''')); 3.67 (s, MeO); 3.63 – 3.56 (m, H–C(1));
3.45 (dd, J = 15.8, 3.8, 1 H of CH2(2)); 3.08 (dd, J = 15.8, 9.6, 1 H of CH2(2)); 2.66 (td, J =
10.0, 4.8, H–C(2')); 2.46 – 2.43 (m, 1 H of CH2(6')); 2.38 – 2.30 (m, 1 H of CH2(6')); 1.93 (br.
s, 1 H of CH2(5')); 1.72 – 1.62 (m, 1 H of CH2(4'), 1 H of CH2(4'), 1 H of CH2(3')); 1.54 –
1.48 (m, 1 H of CH2(5')); 1.22 – 1.15 (m, 1 H of CH2(3')). 13C-NMR: 213.6 (C(1')); 197.7
(C(3)); 158.1 (C(4''')); 139.0 (C(4'')); 135.3 (C(1'')); 133.5 (C(1''')); 129.6 (C(2'',6'')); 129.1
(C(3'',5'')); 128.7 (C(2'',6'')); 113.8 (C(3''',5''')); 55.8 (MeO); 55.0 (C(2')); 44.5 (C(2)); 42.4
(C(6')); 40.5 (C(1)); 32.6 (C(3')); 28.6 (C(5')); 24.3 (C(4')). Anal. calc. for C22H23ClO3
(370.13): C 71.25, H 6.25; found: C 71.16, H 6.32.
2-[1-(4-Bromophenyl)-3-(4-methoxyphenyl)-3-oxopropyl]cyclohexanone (2c).
Yield 86%. White solid. M.p. 102 – 105°. IR: 3021m, 2931s, 1704s (C=O), 1668s (C=O),
1600s, 815s. 1H-NMR: 7.92 (d, J = 9.0, H–C(2'',6'')); 7.38 (d, J = 8.4, H–C(3''',5''')); 7.08 (d, J
= 8.4, H–C(2''',6''')); 6.90 (d, J = 9.0, H–C(3'',5'')); 3.84 (s, MeO); 3.69 (td, J = 9.8, 5.6, H–
C(1)); 3.45 (dd, J = 16.1, 3.6, 1 H of CH2(2)); 3.14 (dd, J = 16.1, 9.8, 1 H of CH2(2)); 2.70
(td, J = 10.0, 4.8, H–C(2')); 2.52 – 2.47 (m, 1 H of CH2(6')); 2.43 – 2.38 (m, 1 H of CH2(6'));
2.02 – 1.99 (m, 1 H of CH2(5')); 1.80 – 1.65 (m, 1 H of CH2(4'), 1 H of CH2(4'), 1 H of
CH2(3')); 1.58 – 1.54 (m, 1 H of CH2(5')); 1.29 – 1.11 (m, 1 H of CH2(3')). 13C-NMR: 213.1
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(C(1')); 196.9 (C(3)); 163.3 (C(4'')); 141.1 (C(1''')); 131.5 (C(3''',5''')); 130.4 (C(2'',6'')); 130.1
(C(2''',6''')); 129.9 (C(1'')); 120.3 (C(4''')); 113.6 (C(3'',5'')); 55.5 (MeO); 55.4 (C(2')); 43.5
(C(2)); 42.4 (C(6')); 40.7 (C(1)); 32.5 (C(3')); 28.5 (C(5')); 24.3 (C(4')). Anal. calc. for
C22H23BrO3 (414.08): C 63.62, H 5.58; found: C 63.49, H 5.65.
2-[3-(4-Bromophenyl)-1-(4-methoxyphenyl)-3-oxopropyl]cyclohexanone (2d).
Yield 82%. White solid. M.p. 130 – 133°. IR: 3058m, 2933s, 1704s (C=O), 1683s (C=O),
1585s, 825s. 1H-NMR: 7.80 (d, J = 8.6, H–C(2'',6'')); 7.55 (d, J = 8.6, H–C(3'',5'')); 7.05 (d, J
= 8.8, H–C(2''',6''')); 6.79 (d, J = 8.8, H–C(3''',5''')); 3.74 (s, MeO); 3.61 (td, J = 10.0, 4.0, H–
C(1)); 3.48 (dd, J = 15.8, 3.8, 1 H of CH2(2)); 3.09 (dd, J = 15.8, 9.8, 1 H of CH2(2)); 2.68
(td, J = 10.0, 5.0, H–C(2')); 2.51 – 2.46 (m, 1 H of CH2(6')); 2.43 – 2.38 (m, 1 H of CH2(6'));
2.01 – 1.97 (m, 1 H of CH2(5')); 1.78 – 1.64 (m, 1 H of CH2(4'), 1 H of CH2(4'), 1 H of
CH2(3')); 1.57 – 1.53 (m, 1 H of CH2(5')); 1.24 – 1.20 (m, 1 H of CH2(3')). 13C-NMR: 213.7
(C(1')); 198.0 (C(3)); 158.1 (C(4''')); 135.7 (C(1'')); 133.5 (C(1''')); 131.7 (C(3'',5'')); 129.8
(C(2'',6'')); 129.1 (C(2''',6''')); 127.9 (C(4'')); 113.8 (C(3''',5''')); 55.9 (MeO); 55.1 (C(2')); 44.5
(C(2)); 42.5 (C(6')); 40.6 (C(1)); 32.6 (C(3')); 28.6 (C(5')); 24.3 (C(4')). Anal. calc. for
C22H23BrO3 (414.08): C 63.62, H 5.58; found: C 63.53, H 5.67.
2-[1,3-Bis(4-methoxyphenyl)-3-oxopropyl]cyclohexanone (2e). Yield 80%. White
solid. M.p. 104 – 106°. IR: 3014m, 2933s, 1702s (C=O), 1600s (C=O), 1573s, 823s. 1H-
NMR: 7.92 (d, J = 8.4, H–C(2'',6''))); 7.08 (d, J = 8.8, H–C(2''',6''')); 6.88 (d, J = 8.8, H–
C(3''',5''')); 6.78 (d, J = 8.4, H–C(3'',5'')); 3.81 (s, MeO); 3.73 (s, MeO); 3.67 (td, J = 10.2,
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3.8, H–C(1)); 3.41 (dd, J = 15.6, 4.0, 1 H of CH2(2)); 3.11 (dd, J = 15.6, 9.6, 1 H of CH2(2));
2.68 (td, J = 9.8, 5.2, H–C(2')); 2.52 – 2.47 (m, 1 H of CH2(6')); 2.40 – 2.37 (m, 1 H of
CH2(6')); 1.97 (br. s, 1 H of CH2(5')); 1.79 – 1.65 (m, 1 H of CH2(4'), 1 H of CH2(4'), 1 H of
CH2(3')); 1.56 – 1.52 (m, 1 H of CH2(5')); 1.27 – 1.22 (m, 1 H of CH2(3')). 13C-NMR: 213.9
(C(1')); 197.5 (C(3)); 163.2 (C(4'')); 158.0 (C(4''')); 133.8 (C(1''')); 130.5 (C(2'',6'')); 130.0
(C(1'')); 129.2 (C(2''',6''')); 113.7 (C(3''',5''')); 113.5 (C(3'',5'')); 56.0 (MeO); 55.3 (MeO); 55.0
(C(2')); 44.0 (C(2)); 42.3 (C(6')); 40.5 (C(1)); 32.4 (C(3')); 28.5 (C(5')); 24.0 (C(4')). Anal.
calc. for C23H26O4 (366.18): C 75.38, H 7.15; found: C 75.26, H 7.23.
2-[1,3-Bis(4-methylphenyl)-3-oxopropyl]cyclohexanone (2f). Yield 81%. White
solid. M.p. 108 – 110°. IR: 3025m, 2938s, 1702s (C=O), 1677s (C=O), 1606s, 817s. 1H-
NMR: 7.85 (d, J = 8.2, H–C(2'',6''))); 7.23 (d, J = 8.2, H–C(3'',5''))); 7.08 (s, H–C(2''',6'''), H–
C(3''',5''')); 3.72 (td, J = 10.2, 3.8, H–C(1)); 3.46 (dd, J = 16.0, 5.2, 1 H of CH2(2)); 3.20 (dd,
J = 16.0, 9.6, 1 H of CH2(2)); 2.72 (td, J = 9.8, 5.2, H–C(2')); 2.55 – 2.52 (m, 1 H of CH2(6'));
2.44 – 2.40 (m, 1 H of CH2(6')); 2.40 (s, Me); 2.30 (s, Me); 2.00 – 1.97 (m, 1 H of CH2(5'));
1.83 – 1.67 (m, 1 H of CH2(4'), 1 H of CH2(4'), 1 H of CH2(3')); 1.59 – 1.55 (m, 1 H of
CH2(5')); 1.31 – 1.26 (m, 1 H of CH2(3')). 13C-NMR: 213.8 (C(1')); 198.5 (C(3)); 143.5
(C(4'')); 138.9 (C(1''')); 136.0 (C(4''')); 134.5 (C(1'')); 129.2 (C(3'',5'')); 129.1 (C(2''',6'''));
128.3 (C(3''',5''')); 128.2 (C(2'',6'')); 55.9 (C(2')); 44.1 (C(2)); 42.2 (C(6')); 40.7 (C(1)); 32.3
(C(3')); 28.5 (C(5')); 24.0 (C(4')); 21.6 (Me); 21.0 (Me). Anal. calc. for C23H26O2 (334.19): C
82.60, H 7.84; found: C 82.52, H 7.89.
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2-[1-(4-Methoxyphenyl)-3-(4-methylphenyl)-3-oxopropyl]cyclohexanone (2g).
Yield 82%. White solid. M.p. 117 – 120°. IR: 3058m, 2927s, 1704s (C=O), 1679s (C=O),
1608s, 825s. 1H-NMR: 7.84 (d, J = 8.0, H–C(2'',6'')); 7.22 (d, J = 8.0, H–C(3'',5'')); 7.10 (d, J
= 8.6, H–C(2''',6''')); 6.80 (d, J = 8.6, H–C(3''',5''')); 3.76 (s, MeO); 3.69 (td, J = 9.8, 4.4, H–
C(1)); 3.44 (dd, J = 16.0, 4.0, 1 H of CH2(2)); 3.17 (dd, J = 16.0, 9.6, 1 H of CH2(2)); 2.69
(td, J = 9.8, 5.0, H–C(2')); 2.54 – 2.49 (m, 1 H of CH2(6')); 2.42 – 2.40 (m, 1 H of CH2(6'));
2.39 (s, Me); 2.00 – 1.97 (m, 1 H of CH2(5')); 1.82 – 1.75 (m, 1 H of CH2(4'), 1 H of
CH2(4')); 1.72 – 1.54 (m, 1 H of CH2(3'), 1 H of CH2(5')); 1.29 – 1.25 (m, 1 H of CH2(3')).
13C-NMR: 213.8 (C(1')); 198.6 (C(3)); 158.0 (C(4''')); 143.5 (C(4'')); 134.5 (C(1'')); 133.9
(C(1''')); 129.2 (C(3'',5'')); 129.1 (C(2'',6'')); 128.3 (C(2''',6''')); 113.8 (C(3''',5''')); 56.0 (MeO);
55.1 (C(2')); 44.2 (C(2)); 42.2 (C(6')); 40.3 (C(1)); 32.3 (C(3')); 28.5 (C(5')); 24.0 (C(4'));
21.6 (Me). Anal. calc. for C23H26O3 (350.19): C 78.83, H 7.48; found: C 78.72, H 7.55.
2-[3-(4-Methoxyphenyl)-1-(4-methylphenyl)-3-oxopropyl]cyclohexanone (2h).
Yield 87%. White solid. M.p. 131 – 134°. IR: 3027m, 2933s, 1698s (C=O), 1662s (C=O),
1602s, 819s. 1H-NMR: 7.94 (d, J = 8.8, H–C(2'',6'')); 7.07 (s, H–C(2''',6'''), H–C(3''',5''')); 6.89
(d, J = 8.8, H–C(3'',5'')); 3.83 (s, MeO); 3.70 (td, J = 9.6, 4.0, H–C(1)); 3.44 (dd, J = 15.6,
4.0, 1 H of CH2(2)); 3.15 (dd, J = 15.6, 9.6, 1 H of CH2(2)); 2.72 (td, J = 9.8, 5.2, H–C(2'));
2.54 – 2.49 (m, 1 H of CH2(6')); 2.43 – 2.37 (m, 1 H of CH2(6')); 2.28 (s, Me); 2.00 – 1.96 (m,
1 H of CH2(5')); 1.81 – 1.75 (m, 1 H of CH2(4'), 1 H of CH2(4')); 1.71 – 1.66 (m, 1 H of
CH2(3')); 1.57 – 1.53 (m, 1 H of CH2(5')); 1.29 – 1.27 (m, 1 H of CH2(3')). 13C-NMR: 213.8
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(C(1')); 197.6 (C(3)); 163.2 (C(4'')); 138.9 (C(1''')); 135.9 (C(4''')); 130.5 C(2'',6'')); 130.1
(C(1'')); 129.1 (C(2''',6''')); 128.2 (C(3''',5''')); 113.5 (C(3'',5'')); 55.9 (MeO); 55.4 (C(2')); 43.9
(C(2)); 42.3 (C(6')); 40.9 (C(1)); 32.4 (C(3')); 28.6 (C(5')); 24.0 (C(4')); 21.0 (Me). Anal.
calc. for C23H26O3 (350.19): C 78.83, H 7.48; found: C 78.70, H 7.57.
2-[3-(4-Methylphenyl)-3-oxo-1-(thiophen-2-yl)propyl]cyclohexanone (2i). Yield
84%. White solid. M.p. 103 – 106°. IR: 3068m, 2935s, 1700s (C=O), 1677s (C=O), 1606s,
809s, 688s. 1H-NMR: 7.86 (d, J = 8.0, H–C(2'',6'')); 7.24 (d, J = 8.0, H–C(3'',5'')); 7.12 (d, J =
4.8, H–C(4''')); 6.90 – 6.87 (m, H–C(3''')); 6.84 (d, J = 2.8, H–C(2''')); 4.18 – 4.13 (m, H–
C(1)); 3.38 (dd, J = 16.3, 4.8, 1 H of CH2(2)); 3.33 (dd, J = 16.3, 8.7, 1 H of CH2(2)); 2.76 –
2.69 (m, H–C(2')); 2.51 – 2.46 (m, 1 H of CH2(6')); 2.42 – 2.37 (m, 1 H of CH2(6')); 2.40 (s,
Me); 2.03 – 2.00 (m, 1 H of CH2(5')); 1.89 – 1.82 (m, CH2(4')); 1.75 – 1.59 (m, 1 H of
CH2(3'), 1 H of CH2(5')); 1.39 – 1.33 (m, 1 H of CH2(3')). 13C-NMR: 212.6 (C(1')); 197.9
(C(3)); 145.7 (C(1''')); 143.7 (C(4'')); 134.4 (C(1'')); 129.2 (C(3'',5'')); 128.3 (C(2'',6'')); 126.4
(C(4''')); 125.5 (C(3''')); 123.6 (C(2''')); 56.2 (C(2')); 44.4 (C(2)); 42.3 (C(6')); 36.2 (C(1));
31.9 (C(3')); 28.2 (C(5')); 24.4 (C(4')); 21.6 (Me). Anal. calc. for C20H22O2S (326.13): C
73.58, H 6.79, S 9.82; found: C 73.45, H 6.84, S 9.87.
2-[3-Oxo-1,3-di(thiophen-2-yl)propyl]cyclohexanone (2j). Yield 81% (95% [19],
67% [21], 65% [24]). White solid. M.p. 121 – 124°. IR: 3068m, 2940s, 1695s (C=O), 1660s
(C=O), 1517m, 1415s, 742s, 688s. 1H-NMR: 7.80 (dd, J = 4.0, 0.8, H–C(4'')); 7.59 (dd, J =
4.0, 0.8, H–C(2'')); 7.13 – 7.09 (m, H–C(3''), H–C(4''')); 6.89 – 6.84 (m, H–C(2'''), H–C(3'''));
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4.12 (td, J = 8.8, 4.4, H–C(1)); 3.38 (dd, J = 15.9, 4.8, 1 H of CH2(2)); 3.27 (dd, J = 15.9, 9.0,
1 H of CH2(2)); 2.77 – 2.72 (m, H–C(2')); 2.50 – 2.45 (m, 1 H of CH2(6')); 2.41 – 2.37 (m, 1
H of CH2(6')); 2.04 – 2.00 (m, 1 H of CH2(5')); 1.89 – 1.81 (m, CH2(4')); 1.72 – 1.59 (m,
CH2(3'), 1 H of CH2(5')). 13C-NMR: 212.6 (C(1')); 191.1 (C(3)); 145.2 (C(1''')); 144.2
(C(1'')); 133.6 (C(2'')); 132.2 (C(4'')); 128.1 (C(3'')); 126.5 (C(4''')); 125.6 (C(3''')); 123.7
(C(2''')); 56.0 (C(2')); 45.1 (C(2)); 42.4 (C(6')); 36.6 (C(1)); 32.0 (C(3')); 28.3 (C(5')); 24.5
(C(4')). Anal. calc. for C17H18O2S2 (318.07): C 64.12, H 5.70, S 20.14; found: C 64.09, H
5.76, S 20.19.
General procedure for the synthesis of chiral 1,5-diols 3a – 3j. The synthesis of 3a –
3j were carried out according to our previous paper [20]. To a soln. of 2a – 2j (1 mmol) in
THF/MeOH 5:1 (12 ml) was added NaBH4 (3 mmol) and stirred for 16 h at r.t. 10% HCl (10
ml) was added to the mixture, and the mixture was extracted with Et2O (3 × 20 ml). The org.
layer was (Na2SO4) and evaporated. The crude product was crystallized from Et2O/hexane
3:1.
rel-(1R,2R)-2-[(1S,3S)-1-(4-Chlorophenyl)-3-hydroxy-3-(4-
methoxyphenyl)propyl]cyclohexanol (3a). Yield 71%. Colorless crystals. M.p. 198 – 200°.
IR: 3357s (br., OH), 3289s (br., OH), 3064m, 2938s, 1612m, 1513s, 1249s, 819s. 1H-NMR:
7.31 (d, J = 8.3, H–C(3''',5''')); 7.18 (d, J = 8.3, H–C(2''',6''')); 7.05 (d, J = 8.5, H–C(2'',6''));
6.78 (d, J = 8.6, H–C(3'',5'')); 4.79 (d, J = 4.7, HO–C(3)); 4.18 (d, J = 4.2, HO–C(1')); 4.01 (s,
H–C(1')); 3.89 – 3.86 (m, H–C(3)); 3.68 (s, MeO); 2.90 (td, J = 11.1, 3.2, H–C(1)); 2.17 –
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2.09 (m, 1 H of CH2(2)); 1.71 (d, J = 12.3, 1 H of CH2(6')); 1.56 (t, J = 12.5, 1 H of CH2(2));
1.52 – 1.49 (m, 1 H of CH2(5')); 1.47 – 1.42 (m, 1 H of CH2(4')); 1.35 (t, J = 11.2, H–C(2'));
1.30 – 1.23 (m, 1 H of CH2(5'), 1 H of CH2(6')); 1.15 (ddd, J = 25.2, 12.8, 3.0, 1 H of
CH2(3')); 0.98 – 0.88 (m, 1 H of CH2(4')); 0.76 (d, J = 11.0, 1 H of CH2(3')). 13C-NMR: 158.3
(C(4'')); 144.6 (C(1''')); 139.7 (C(1'')); 130.7 (C(4''')); 130.4 (C(2''',6''')); 128.4 (C(3''',5'''));
126.9 (C(2'',6'')); 113.7 (C(3'',5'')); 69.9 (C(3)); 64.5 (C(1')); 55.4 (MeO); 47.1 (C(2')); 43.9
(C(1)); 43.0 (C(2)); 34.2 (C(6')); 26.3 (C(4')); 25.6 (C(3')); 20.0 (C(5')). GC/MS: 358 ([M –
H2O]+, 0.6), 273 (2.0), 222 (2.4), 191 (0.6), 137 (100.0), 109 (15.2), 77 (13.6). Anal. calc. for
C22H27ClO3 (374.16): C 70.48, H 7.26; found: C 70.36, H 7.32.
rel-(1R,2R)-2-[(1S,3S)-3-(4-Chlorophenyl)-3-hydroxy-1-(4-
methoxyphenyl)propyl]cyclohexanol (3b). Yield 73%. Colorless crystals. M.p. 142 – 144°.
IR: 3336s (br., OH), 3035m, 2927s, 1608m, 1509s, 1245s, 836s. 1H-NMR: 7.34 (d, J = 8.2,
H–C(3'',5'')); 7.17 (d, J = 8.2, H–C(2'',6'')); 6.94 (d, J = 8.6, H–C(2''',6''')); 6.86 (d, J = 8.6, H–
C(3''',5''')); 5.03 (d, J = 4.4, HO–C(3)); 4.06 (s, HO–C(1'), H–C(1')); 4.04 – 4.01 (m, H–C(3));
3.74 (s, MeO); 2.31 (t, J = 10.0, H–C(1)); 2.09 (t, J = 10.8, 1 H of CH2(2)); 1.97 (td, J = 12.0,
4.0, 1 H of CH2(2)); 1.73 (br. d, J = 12.2, 1 H of CH2(6')); 1.48 – 1.40 (m, 1 H of CH2(5'), 1 H
of CH2(4')); 1.35 – 1.23 (m, H–C(2'), 1 H of CH2(5'), 1 H of CH2(6')); 1.00 – 0.88 (m, 1 H of
CH2(3'), 1 H of CH2(4')); 0.74 (br. d, J = 12.2, 1 H of CH2(3')). 13C-NMR: 157.7 (C(4'''));
144.5 (C(1'')); 137.0 (C(1''')); 131.7 (C(4'')); 129.5 (C(3'',5'')); 129.1 (C(2''',6''')); 128.2
(C(2'',6'')); 113.9 (C(3''',5''')); 71.4 (C(3)); 64.7 (C(1')); 55.3 (MeO); 47.5 (C(2')); 43.3 (C(1));
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41.4 (C(2)); 34.3 (C(6')); 26.3 (C(4')); 25.3 (C(3')); 20.0 (C(5')). GC/MS: 376 (M+, 0.9), 356
(1.0), 338 (1.8), 257 (12.1), 202 (11.8), 141 (69.6), 135 (100.0), 77 (44.0). Anal. calc. for
C22H27ClO3 (374.16): C 70.48, H 7.26; found: C 70.41, H 7.33.
rel-(1R,2R)-2-[(1S,3S)-1-(4-Bromophenyl)-3-hydroxy-3-(4-
methoxyphenyl)propyl]cyclohexanol (3c). Yield 75%. Colorless crystals. M.p. 197 – 199°
[20]. IR: 3361s (br., OH), 3311s (br., OH), 3064m, 2940s, 1614m, 1513s, 1247s, 819m. 1H-
NMR: 7.48 (d, J = 8.4, H–C(3''',5''')); 7.16 (d, J = 8.4, H–C(2''',6''')); 7.07 (d, J = 8.8, H–
C(2'',6'')); 6.81 (d, J = 8.4, H–C(3'',5'')); 4.83 (d, J = 4.4, HO–C(3)); 4.24 (d, J = 4.0, HO–
C(1')); 4.02 (br. s, H–C(1')); 3.89 – 3.86 (m, H–C(3)); 3.70 (s, MeO); 2.91 (td, J = 10.7, 3.4,
H–C(1)); 2.14 (td, J = 12.1, 3.4, 1 H of CH2(2)); 1.73 (br. d, J = 11.6, 1 H of CH2(6')); 1.61 –
1.45 (m, 1 H of CH2(2), 1 H of CH2(5'), 1 H of CH2(4')); 1.40 – 1.20 (m, H–C(2'), 1 H of
CH2(5'), 1 H of CH2(6')); 1.19 – 1.12 (m, 1 H of CH2(3')); 1.00 – 0.91 (m, 1 H of CH2(4'));
0.78 (br. d, J = 11.6, 1 H of CH2(3')). 13C-NMR: 158.3 (C(4'')); 145.1 (C(1''')); 139.7 (C(1''));
131.3 (C(3''',5''')); 131.2 (C(2''',6''')); 126.8 (C(2'',6'')); 118.9 (C(4''')); 113.7 (C(3'',5'')); 69.9
(C(3)); 64.5 (C(1')); 55.4 (MeO); 47.0 (C(2')); 43.9 (C(1)); 42.8 (C(2)); 34.1 (C(6')); 26.3
(C(4')); 25.6 (C(3')); 20.0 (C(5')). GC/MS: 400 ([M – H2O]+, 10.3), 302 (3.9), 244 (17.9), 182
(40.2), 134 (100.0), 108 (51.0), 91 (30.8), 77 (33.8). Anal. calc. for C22H27BrO3 (418.11): C
63.01, H 6.49; found: C 62.96, H 6.53.
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rel-(1R,2R)-2-[(1S,3S)-3-(4-Bromophenyl)-3-hydroxy-1-(4-
methoxyphenyl)propyl]cyclohexanol (3d). Yield 75%. Colorless crystals. M.p. 162 – 164°.
IR: 3334 (br. s, OH), 3033m, 2925s, 1608m, 1508s, 1245s, 835s. 1H-NMR: 7.48 (d, J = 8.4,
H–C(3'',5'')); 7.08 (d, J = 8.4, H–C(2'',6'')); 6.92 (d, J = 8.4, H–C(2''',6''')); 6.86 (d, J = 8.4, H–
C(3''',5''')); 5.03 (d, J = 4.4, HO–C(3)); 4.07 – 4.05 (m, HO–C(1'), H–C(1')); 4.00 – 3.94 (m,
H–C(3)); 3.74 (s, MeO); 2.27 (t, J = 10.0, H–C(1)); 2.07 – 2.01 (m, 1 H of CH2(2)); 1.93 (td,
J = 12.2, 4.0, 1 H of CH2(2)); 1.71 (br. d, J = 12.4, 1 H of CH2(6')); 1.46 – 1.39 (m, 1 H of
CH2(5') ; 1 H of CH2(4')); 1.34 – 1.22 (m, H–C(2'), 1 H of CH2(5'), 1 H of CH2(6')); 0.98 –
0.87 (m, 1 H of CH2(3'), 1 H of CH2(4')); 0.71 (br. d, J = 12.4, 1 H of CH2(3')). 13C-NMR:
157.6 (C(4''')); 144.9 (C(1'')); 136.9 (C(1''')); 131.1 (C(3'',5'')); 129.5 (C(2'',6''), C(2''',6''')),
120.2 (C(4'')); 113.9 (C(3''',5''')); 71.4 (C(3)); 64.6 (C(1')); 55.3 (MeO); 47.4 (C(2')); 43.3
(C(1)); 41.3 (C(2)); 34.3 (C(6')); 26.2 (C(4')); 25.3 (C(3')); 20.0 (C(5')). GC/MS: 420 (M+,
1.0), 384 (0.8), 303 (5.00), 185 (29.6), 135 (100.0), 121 (34.8), 77 (28.3). Anal. calc. for
C22H27BrO3 (418.11): C 63.01, H 6.49; found: C 62.93, H 6.55.
rel-(1R,2R)-2-[(1S,3S)-3-Hydroxy-1,3-bis(4-methoxyphenyl)propyl]cyclohexanol
(3e). Yield 70%. Colorless crystals. M.p. 160 – 163°. IR: 3451 (br. s, OH), 3066m, 2923s,
1610m, 1509s, 1247s, 831s. 1H-NMR: 7.06 (d, J = 8.8, H–C(2''',6''')); 6.91 (d, J = 8.4, H–
C(2'',6'')); 6.87 – 6.83 (m, H–C(3'',5''), H–C(3''',5''')); 4.76 (d, J = 4.4, HO–C(3)); 4.07 (br. s,
H–C(1')); 4.03 (d, J = 4.0, HO–C(1')); 3.96 – 3.90 (m, H–C(3)); 3.74 (s, 2 MeO); 2.31 (t, J =
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9.6, H–C(1)); 2.11 – 2.04 (m, H–C(2)) 1.92 (td, J = 12.2, 4.0, 1 H of CH2(2)); 1.72 (br. d, J =
12.4, 1 H of CH2(6')); 1.48 – 1.22 (m, 1 H of CH2(4'), H–C(2'), CH2(5'), 1 H of CH2(6')); 0.98
– 0.88 (m, 1 H of CH2(3'), 1 H of CH2(4')); 0.73 (br. d, J = 12.4, 1 H of CH2(3')). 13C-NMR:
158.6 (C(4'')); 157.6 (C(4''')); 137.4 (C(1''')); 137.2 (C(1'')); 129.5 (C(2'',6'')); 128.4
(C(2''',6''')); 113.9 (C(3''',5''')); 113.6 (C(3'',5'')); 71.6 (C(3)); 64.7 (C(1')); 55.4 (MeO); 55.3
(MeO); 47.5 (C(2')); 43.5 (C(1)); 41.3 (C(2)); 34.4 (C(6')); 26.3 (C(4')); 25.3 (C(3')); 20.0
(C(5')). GC/MS: 371 (M+, 0.6), 334 (0.7), 253 (21.0), 202 (12.6), 137 (100.0), 135 (74.4), 121
(67.3), 77 (22.2). Anal. calc. for C23H30O4 (370.21): C 74.56, H 8.16; found: C 74.44, H 8.19.
rel-(1R,2R)-2-[(1S,3S)-3-Hydroxy-1,3-bis(4-methylphenyl)propyl]cyclohexanol
(3f). Yield 76%. Colorless crystals. M.p. 134 – 136°. IR: 3399s (br., OH), 3332s (br., OH),
3019m, 2933s, 1511s, 1249s, 971s, 819s. 1H-NMR: 7.12 – 7.04 (m, C(2'',6''), C(3'',5''),
C(2''',6''')); 6.91 (d, J = 7.2, C(3''',5''')); 4.83 (d, J = 3.2, HO–C(3)); 4.11 (s, H–C(1')); 4.05 (s,
HO–C(3)); 4.00 (br. s, H–C(3)); 2.30 (s, 2 Me); 2.14 (t, J = 9.6, H–C(1)); 1.98 (m, 1 H of
CH2(2)); 1.75 (br. d, J = 12.0, 1 H of CH2(6')); 1.50 – 1.27 (m, 1 H of CH2(2), 1 H of CH2(4'),
H–C(2'), CH2(5'), 1 H of CH2(6')); 1.03 – 0.89 (m, 1 H of CH2(3'), 1 H of CH2(4')); 0.78 (br.
d, J = 12.4, 1 H of CH2(3')). 13C-NMR: 142.5 (C(1'')); 142.4 (C(1''')); 136.1 (C(4'')); 134.8
(C(4''')); 129.1 (C(3'',5'')); 128.8 (C(3''',5''')); 128.6 (C(2''',6''')); 127.3 (C(2'',6'')); 71.9 (C(3));
64.7 (C(1')); 47.5 (C(2')); 43.9 (C(1)); 41.4 (C(2)); 34.4 (C(6')); 26.4 (C(4')); 25.4 (C(3'));
21.2 (Me); 21.1 (Me); 20.1 (C(5')). GC/MS: 339 (M+, 0.6), 320 (1.8), 302 (3.7), 246 (1.4),
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221 (24.6), 186 (43.0), 121 (100.0), 105 (71.5), 91 (58.1), 77(32.5). Anal. calc. for C23H30O2
(338.22): C 81.61, H 8.93; found: C 81.52, H 8.97.
rel-(1R,2R)-2-[(1S,3S)-3-Hydroxy-1-(4-methoxyphenyl)-3-(4-
methylphenyl)propyl]cyclohexanol (3g). Yield 76%. Colorless crystals. M.p. 166 – 168°.
IR: 3442s (br., OH), 3031m, 2919s, 1608m, 1509s, 1236s, 829s. 1H-NMR: 7.10 (d, J = 8.0,
H–C(2'',6'')); 7.04 (d, J = 8.0, H–C(3'',5'')); 6.92 (d, J = 8.4, H–C(2''',6''')); 6.86 (d, J = 8.4, H–
C(3''',5''')); 4.83 (d, J = 4.0, HO–C(3)); 4.08 (br. s, H–C(1')); 4.04 (d, J = 4.0, HO–C(1')); 4.00
– 3.95 (m, H–C(3)); 3.75 (s, MeO); 2.36 – 2.30 (m, H–C(1)); 2.29 (s, Me); 2.12 – 2.06 (m, 1
H of CH2(2)); 1.93 (td, J = 12.2, 4.2, 1 H of CH2(2)); 1.73 (br. d, J = 12.4, 1 H of CH2(6'));
1.48 – 1.42 (m, 1 H of CH2(5'), 1 H of CH2(4')); 1.34 – 1.23 (m, H–C(2'), 1 H of CH2(5'), 1 H
of CH2(6')); 1.00 – 0.88 (m, 1 H of CH2(3'), 1 H of CH2(4')); 0.73 (br. d, J = 11.6, 1 H of
CH2(3')).13C-NMR: 157.7 (C(4''')); 142.5 (C(1'')); 137.2 (C(4'')); 136.1 (C(1''')); 129.5
(C(3'',5'')); 128.8 (C(2''',6''')); 127.3 (C(2'',6'')); 113.9 (C(3''',5''')); 71.9 (C(3)); 64.7 (C(1'));
55.3 (MeO); 47.6 (C(2')); 43.5 (C(1)); 34.4 (C(6')); 26.3 (C(4')); 25.4 (C(3')); 21.2 (Me); 20.0
(C(5')). GC/MS: 354 (M+, 1.6), 318 (1.1), 237 (14.8), 202 (9.0), 135 (60.8), 121 (100.0), 91
(27.5), 77 (16.1). Anal. calc. for C23H30O3 (354.22): C 77.93, H 8.53; found: C 77.87, H 8.55.
rel-(1R,2R)-2-[(1S,3S)-3-Hydroxy-3-(4-methoxyphenyl)-1-(4-
methylphenyl)propyl]cyclohexanol (3h). Yield 78%. Colorless crystals. M.p. 172 – 174°.
IR: 3353s (br., OH), 3288s (br., OH), 3052m, 2927s, 1614m, 1511s, 1247s, 819s. 1H-NMR:
7.11 – 7.05 (m, H–C(2'',6''), H–C(2''',6'''), H–C(3''',5''')); 6.81 (d, J = 8.8, H–C(3'',5'')); 4.77 (d,
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J = 4.8, HO–C(3)); 4.18 (d, J = 4.0, HO–C(1')); 4.04 (br. s, H–C(1')); 3.95 – 3.92 (m, H–
C(3)); 3.70 (s, MeO); 2.89 – 2.84 (m, H–C(1)); 2.28 (s, Me); 2.14 (t, J = 10.2, 1 H of
CH2(2)); 1.73 (br. d, J = 11.6, 1 H of CH2(6')); 1.60 – 1.44 (m, 1 H of CH2(2), 1 H of CH2(5'),
1 H of CH2(4')); 1.37 – 1.29 (m, H–C(2'), 1 H of CH2(5'), 1 H of CH2(6')); 1.21 – 1.09 (m, 1
H of CH2(3')); 1.00 – 0.90 (m, 1 H of CH2(4')); 0.83 (br. d, J = 11.6, 1 H of CH2(3')). 13C-
NMR: 158.3 (C(4'')); 142.5 (C(1''')); 140.0 (C(4''')); 134.7 (C(1'')); 129.1 (C(3''',5''')); 128.7
(C(2''',6''')); 126.8 (C(2'',6'')); 113.7 (C(3'',5'')); 69.9 (C(3)); 64.6 (C(1')); 55.4 (MeO); 47.3
(C(2')); 43.9 (C(1)); 43.2 (C(2)); 34.2 (C(6')); 26.4 (C(4')); 25.7 (C(3')); 21.1 (Me); 20.1
(C(5')). GC/MS: 354 (M+, 0.9), 318 (0.9), 237 (18.3), 186 (17.8), 137 (100.0), 118 (56.2), 105
(34.4), 77 (20.6). Anal. calc. for C23H30O3 (354.22): C 77.93, H 8.53; found: C 77.89, H 8.57.
rel-(1R,2R)-2-[(1S,3S)-3-Hydroxy-3-(4-methylphenyl)-1-(thiophen-2-
yl)propyl]cyclohexanol (3i). Yield 70%. Colorless crystals. M.p. 152 – 155°. IR: 3399s (br.,
OH), 3033m, 2927s, 1444s, 1000s, 823s, 700s. 1H-NMR: 7.34 (d, J = 4.8, H–C(4''')); 7.16 –
7.12 (m, H–C(2'',6''), H–C(3'',5'')); 6.97 – 6.94 (m, H–C(3''')); 6.65 (d, J = 3.2, H–C(2''')); 4.98
(d, J = 4.0, HO–C(3)); 4.19 – 4.12 (m, H–C(3)); 4.12 (s, HO–C(1'), H–C(1')); 2.57 – 2.51 (m,
H–C(1)); 2.48 – 2.41 (m, 1 H of CH2(2)); 2.32 (s, Me); 1.97 – 1.90 (m, 1 H of CH2(2)); 1.77
(br. d, J = 12.4, 1 H of CH2(6')); 1.49 (br. s, 1 H of CH2(5'), 1 H of CH2(4')); 1.38 – 1.28 (m,
H–C(2'), 1 H of CH2(5'), 1 H of CH2(6')); 1.13 – 0.94 (m, CH2(3'), 1 H of CH2(4')). 13C-
NMR: 149.7 (C(1''')); 142.2 (C(1'')); 136.2 (C(4'')); 128.9 (C(3'',5'')); 127.4 (C(2'',6'')); 126.8
(C(4''')); 124.9 (C(3''')); 123.6 (C(2''')); 71.8 (C(3)); 64.6 (C(1')); 48.8 (C(2')); 42.8 (C(1);
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C(2)); 34.3 (C(6')); 26.4 (C(4')); 25.4 (C(3')); 21.3 (Me); 20.0 (C(5')). GC/MS: 313 (M+, 0.6),
294 (7.5), 213 (31.2), 196 (46.6), 178 (59.3), 121 (100), 110 (77.2), 97 (55.5), 77 (43.2).
Anal. calc. for C20H26O2S (330.17): C 72.69, H 7.93, S 9.70; found: C 72.61, H 7.95, S 9.72.
rel-(1R,2R)-2-[(1S,3S)-3-Hydroxy-1,3-di(thiophen-2-yl)propyl]cyclohexanol (3j).
Yield 65%. Colorless crystals. M.p. 122 – 125°. IR: 3378s (br., OH), 3106m, 2927s, 1442m,
968m, 696s. 1H-NMR: 7.41 (dd, J = 5.0, 1.4, H–C(4'')); 7.35 (d, J = 5.2, H–C(4''')); 6.96 –
6.93 (m, H–C(2''), H–C(3'')); 6.87 (br. d, J = 3.2, H–C(2''')); 6.69 – 6.67 (m, H–C(3''')); 5.38
(d, J = 4.4, HO–C(3)); 4.39 – 4.34 (m, H–C(3)); 4.17 (d, J = 4.0, HO–C(1')); 4.03 (br. s, H–
C(1')); 2.69 – 2.63 (m, H–C(1)); 2.41 – 2.34 (m, 1 H of CH2(2)); 1.90 (dd, J = 12.2, 4.0, 1 H
of CH2(2)); 1.73 (br. d, J = 12.4, 1 H of CH2(6')); 1.50 – 1.42 (m, 1 H of CH2(5'), 1 H of
CH2(4')); 1.36 – 1.25 (m, H–C(2'), 1 H of CH2(5'), 1 H of CH2(6')); 1.09 – 0.95 (m, 1 H of
CH2(3'), 1 H of CH2(4')); 0.90 (br. d, J = 12.4, 1 H of CH2(3')). 13C-NMR: 149.7 (C(1'''));
149.3 (C(1'')); 126.9 (C(4'')); 126.6 (C(4''')); 125.1 (C(2'')); 124.9 (C(2''')); 124.0 (C(3''));
123.8 (C(3''')); 67.5 (C(3)); 64.6 (C(1')); 48.6 (C(2')); 43.6 (C(1), C(2)); 34.1 (C(6')); 26.2
(C(4')); 25.4 (C(3')); 19.9 (C(5')). GC/MS: 322 (M+, 0.9), 286 (3.3), 220 (9.2), 196 (31.3), 178
(47.7), 113 (100), 110 (69.8), 97 (67.2), 85 (44.3). Anal. calc. for C17H22O2S2 (322.11): C
63.32, H 6.88, S 19.88; found: C 63.27, H 6.94, S 19.91.
Antimicrobial activity, determination of MICs. The broth microdilution method was
employed for the determination of antimicrobial activities of the compounds according to the
recommendations of the CLSI [36]. The minimal inhibitory concentration (MIC) values of
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the compounds were studied using the micro-well dilution method for the bacterial strains.
Overnight broth cultures were used to prepare the inocula of the microorganisms and
suspensions were adjusted to 0.5 McFarland standard turbidity. After the dissolution of the 3a
– 3j for the purpose of testing in Mueller Hinton Broth (MHB) which has 10% (v/v) DMSO,
serial twofold dilutions were prepared in 96-well plates with MHB at a concentration varying
between 7.8-500 µg/ml. A Bio Tek microplate reader (Bio Tek Instruments, Inc., Winooski,
VT, USA) was used to measure the optical density (OD) at 620 nm and it was measured again
following the incubation for 24 h at 37°. MIC was determined as the lowest concentration of
3a – 3j that inhibits the growth of test bacteria.
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[36] Clinical and Laboratory Standards Institute (CLSI), Performance Standards for
Antimicrobial Susceptibility Testing, Twenty-Fourth Informational Supplement, CLSI
document M100-S24, Wayne, PA 2014.
Received February 26, 2016
Accepted June 1, 2016
Table 1. Synthesized 1,5-diketones 2a – 2j.
tab001-formula.tif
Entry
Ar1
Ar2
Product
2a
Yield [%]
1
2
4-MeOC6H4
4-ClC6H4
4-ClC6H4
90
84
86
82
80
81
82
87
84
81
4-MeOC6H4
4-BrC6H4
2b
2c
3
4-MeOC6H4
4-BrC6H4
4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
Thiophen-2-yl
Thiophen-2-yl
2d
2e
5
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
Thiophen-2-yl
6
2f
7
2g
8
2h
2i
9
10
2j
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Table 2. Synthesized 1,5-diols 3a – 3j.
tab002-formula.tif
Entry
Ar1
Ar2
Product
Yield [%]
1
2
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-BrC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
71
73
75
75
70
76
76
78
70
65
3a
4-MeOC6H4
4-BrC6H4
3b
3c
3d
3e
3f
3
4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
5
6
7
4-MeOC6H4
4-MeC6H4
3g
3h
3i
8
9
Thiophen-2-yl
10
Thiophen-2-yl Thiophen-2-yl
3j
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Table 3. 1H- (600 MHz) and 13C-NMR (150 MHz) data of 3a in (D6)DMSO. δ in ppm, J in
Hz.
Position HSQC (H → C)
δ(H)
HMBC (H → C)
2J
δ(C)
3J
1
2.90 (td, J = 11.1, 3.2)
43.9
C(2), C(2'),
C(1''')
C(3), C(1'), C(3'), C(2'''),
C(6''')
2
2.17 – 2.09 (m),
1.56 (t, J = 12.5)
43.0
C(1), C(3)
C(1), C(3)
C(1''), C(1''')
C(1''), C(1'''), C(2')
3
3.89 – 3.86 (m)
4.01 (br. s)
69.9
64.5
47.1
C(2), C(1'')
C(2''), C(6'')
C(3'), C(5')
C(1''')
1'
2'
3'
1.35 (t, J = 11.2)
C(1), C(3')
C(2'), C(4')
C(2'), C(4')
1.15 (ddd, J = 25.2, 12.8, 3.0), 25.6
0.76 (d, J = 11.0)
C(1'), C(5')
C(1'), C(5')
4'
5'
6'
1.47 – 1.42 (m),
0.98 – 0.88 (m)
26.3
20.0
34.2
C(2'), C(6')
C(3')
C(4')
1.52 – 1.49 (m),
1.30 – 1.23 (m)
C(3')
C(1')
1.71 (d, J = 12.3),
1.30 – 1.23 (m)
C(1'), C(5')
C(1'), C(5')
C(2'), C(4')
C(4')
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1''
–
139.7
126.9
113.7
158.3
113.7
126.9
144.6
130.4
128.4
130.7
128.4
130.4
–
2''
7.05 (d, J = 8.5)
6.78 (d, J = 8.6)
–
C(4''), C(6'')
C(1''), C(5'')
3''
4''
5''
6.78 (d, J = 8.6)
7.05 (d, J = 8.5)
–
C(1''), C(3'')
C(4''), C(2'')
6''
1'''
2'''
3'''
4'''
5'''
6'''
7.18 (d, J = 8.3)
7.31 (d, J = 8.3)
–
C(3''')
C(4''')
C(6''')
C(1'''), C(5''')
7.31 (d, J = 8.3)
7.18 (d, J = 8.3)
C(4''')
C(3''')
C(3)
C(1'''), C(3''')
C(3''')
HO–C(3) 4.79 (d, J = 4.7)
C(2), C(1'')
C(2'), C(6')
HO–
C(1')
MeO
4.18 (d, J = 4.2)
–
C(1')
3.68 (s)
55.4
C(4'')
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Table 4. Minimum-inhibitory concentrations of 1,5-diols 3a – j.
Microorganism Compound and MIC [µg/ml]
P/Ta)
3a
3b
3c
3d
3e 3f
3g 3h 3i
3j
Gram-positive
B. cereus
–b)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
250
250
250
125
125
B. subtilis
S. aureus
–
–
–
62.5
62.5
62.5
–
–
E. faecalis
Gram-negative
E. coli
–
500
15.6
125
–
–
–
31.3 15.6
15.6
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
250
125
250
7.8
62.5
62.5
P. aeruginosa
S. boydii
–
–
–
–
–
–
a) P/T, piperacillin/tazobactam (8:1). b) Inactive (MIC > 500 µg/ml).
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Captions:
Scheme. Syntheses of 1,5-diols 3a – 3j starting from chalcones 1a – 1j.
i) NaOH, EtOH, r.t., 3 h. ii) KOH, ■Benzyltriethylammonium?■ chloride, CH2Cl2, r.t., 3 h.
iii) NaBH4, THF/MeOH, r.t., 16 h.
Fig. 1. Selected HMBCs of 3a.
Fig. 2. Structure of 3c.
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