Synthesis of novel spiro-isoxazoline and spiro-isoxazolidine derivatives of tomentosin

Article abstract of DOI:10.1039/c6ra25869g

A series of novel enantiomerically pure spiro-isoxazolidines and spiro-isoxazolines were synthesized regioselectively by 1,3-dipolar cycloaddition using respectively two dipoles, nitrones and nitrile oxides, on the exocyclic double bond of the B ring of t

Full text of DOI:10.1039/c6ra25869g

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Synthesis of novel spiro-isoxazoline and spiro-
isoxazolidine derivatives of tomentosin†
Cite this: RSC Adv., 2017, 7, 6523
Mohamed Zaki,ab Abdelouahd Oukhrib,c Mohamed Akssirab and Sabine Berteina-
a
*
Raboin
Received 26th October 2016
Accepted 5th January 2017
A series of novel enantiomerically pure spiro-isoxazolidines and spiro-isoxazolines were synthesized
regioselectively by 1,3-dipolar cycloaddition using respectively two dipoles, nitrones and nitrile oxides, on
the exocyclic double bond of the B ring of tomentosin (a-methylene-g-butyrolactone), a sesquiterpene
lactone extracted from Dittrichia viscosa.
DOI: 10.1039/c6ra25869g
www.rsc.org/advances
frameworks has aroused particular interest among medicinal
chemists.16,17 For example, the Ding and Kumar groups18–20
Introduction
recently synthesized spiro-isoxazoline and spiro-isoxazolidine
derivatives of parthenin, a-santonin and artemisinin and
promising anti-cancer activities were obtained. As part of
the Moroccan plant development program,21–25 Dittrichia
viscosa L. Greuter, an invasive perennial weed, was particularly
examined.26,27 This plant is used either as extracts or essential
oil in traditional Moroccan medicine for its antipyretic, anti-
septic and anti-inammatory properties.28,29 Easily accessible, it
is a renewable source of sesquiterpene lactones such as
tomentosin (1),30,31 also known as xanthalongin. This molecule
is straightforwardly isolated in respectively 1.5% with respect to
the dry weight of the aerial part of the plant (Fig. 1).32,33
Tomentosin was already reported to act as a cytotoxic and anti-
inammatory agent34–36 but despite this biological potential, it
has received little pharmacological attention so far. Therefore,
we propose herein the introduction of an isoxazoline and an
isoxazolidine functionality to form libraries of structurally
original spiro-bicyclic analogues of tomentosin by 1,3-dipolar
cycloaddition with two dipoles, nitrones and nitrile oxides on
the exocyclic double bond of the B ring of tomentosin (Fig. 2).
Plants have a long history as therapeutics in the treatment of
human diseases and have been a continuous source of inspi-
ration for the development of new medicines. Among them, the
genus Inula (Asteraceae) comprises more than 100 species, many
of which are widely used in traditional medicine for a variety of
biological purposes including anti-inammatory, anti-cancer
and antibacterial activities.1–3 Numerous compounds of
interest have been isolated and identied from these plants
such as avonoids, monoterpenes, triterpenoids, and poly-
phenols. This genus is also a rich source of sesquiterpene acids
and lactones. Many studies have focused on sesquiterpene
lactones since they exhibit a wide range of biological proper-
ties4–6 and have candidates in different phases of clinical trials
such as parthenolide, costunolide, helenalin, and artemisinin
(Fig. 1). The cytotoxicity of sesquiterpene lactones was partly
attributed to the presence of potential alkylating agents such as
the a-methylene-g-lactone moiety, which are prone to covalently
react with biological nucleophiles, e.g., L-cysteine, in a Michael-
type addition.7–12 This highly electrophilic structure may also be
the origin of a major contact allergen effect and plants that
contain sesquiterpene lactones are held responsible for an
increasing number of cases of contact dermatitis.13–15
Using this reactive site, various structural modications have
been carried out to obtain less toxic and more reactive candi-
dates and lately the introduction of spiro-heterocyclic molecular
a
´
´
Institut de Chimie Organique et Analytique, Universite d'Orleans, UMR CNRS 7311,
´
B.P. 6759, 45067 Orleans Cedex 2, France. E-mail: sabine.berteina-raboin@
univ-orleans.fr
b
´
Laboratoire de Chimie Physique & Chimie Bioorganique, Departement de Chimie,
ˆ
´
´
URA C 22, Pole RePAM, F. S. T. Universite Hassan II de Casablanca, B.P. 146
Yasmina, 28800, Mohammedia, Morocco
c
´
´
´
Laboratoire de Chimie Biomoleculaire Substances Naturelles et Reactivite (URAC 16),
´
´
Faculte des Sciences Semlalia, Universite Cadi Ayyad, B.P. 2390 Marrakech, Morocco
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra25869g
Fig. 1 Examples of biologically active sesquiterpene lactones.
RSC Adv., 2017, 7, 6523–6529 | 6523
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Fig. 2 Sesquiterpene lactones, ring B of tomentosin.
Results and discussion
The spiroisoxazoline derivatives of tomentosin were synthe-
sized through a 1,3-dipolar cycloaddition of various aldoximes 2
with the exocyclic ring B double bond (Scheme 1).
Nitrile oxides 2 were prepared by converting various
aromatic aldehydes to the corresponding oximes via the reac-
tion with hypochlorite anion present in bleach. The bleach was
used in two steps: initially to produce chlorooxime and then
thanks to its basicity to induce dehydrohalogenation, leading to
the nitrile oxide. Experimentally, aldoxime was mixed with the
tomentosin in THF, and then a bleach solution (14.5% of
chlorine) was added dropwise during 12 hours. Only one dia-
stereoisomer was isolated and characterized by NMR spectro-
scopic analysis and mass spectrometry. The 1H NMR spectra of
the spiroisoxazoline derivatives of tomentosin 3a showed the
disappearance of the alkene protons along with the appearance
of two doublets at respectively 3.42 and 3.58 ppm that conrm
the selectivity of the nitrile oxide cycloaddition. The reaction
took place whatever the substituent in the para position of the
aryl entity, whether electron donating (CH3, OCH3) or electron-
attracting (F). When a poor or electron-rich heteroaryl was used,
the reaction did not take place and only the starting material
was recovered.
Scheme 2 Synthesis of spiro-isoxazolidine derivatives of tomentosin.
in reuxing dry benzene (Scheme 2).37–39 Nitrones 4 were
straightforwardly obtained according to the literature proce-
dure in which nitroaryls were rst reduced in the presence of
zinc and acetic acid to obtain the corresponding aryl hydroxyl-
amines that were condensed with various aromatic aldehydes.40
The spiro-isoxazolidines 5 were obtained as one diaste-
reomer aer purication by ash chromatography. The oper-
ating conditions are compatible with the introduction of
nitrones with aryl entities bearing electron-donating (CH3,
OCH3) or electron-attracting (CF3, F) substituents. The use of
nitrones with heteroaryl entities was carried out successfully. It
should be noted that the use of toluene instead of benzene, for
environmental reasons, did not unfortunately allow us to obtain
the products. The structures of the spiroisoxazolidines were
The spiroisoxazolidine derivatives of tomentosin were ob-
tained through 1,3-dipolar cycloaddition of various nitrones 4
1
conrmed by their H, 13C and 2 D NMR spectroscopic data as
described for 5q (Fig. 3). The 1H and 1H-COSY data showed the
correlation of H-7 with H-8 and H-8 with H-16. Further, the
HMBC experiment showed the correlation of H-7 and H-8 with
C-17 and H-7 with C-16 (Fig. 3).
1
In the H NMR comparison with the literature data, Reddy
et al.18 obtained two diastereomers. Each diastereomer was
isolated and the clear chemical shi deviation of the benzylic
proton adjacent to the nitrogen atom in the isoxazolidine ring
Scheme 1 Synthesis of spiro-isoxazoline derivatives of tomentosin.
6524 | RSC Adv., 2017, 7, 6523–6529
Fig. 3 Selected 1H, 1H–COSY and HMBC correlations of 5q.
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between two diastereomers was observed in 1H NMR. In the 30.8 (CH2), 30.1 (CH3), 22.7 (CH2), 21.2 (CH3); HRMS (ESI+): calc.
major isomer this proton appeared at 5 ppm, but in the minor For C22H25NO4 [M + H]+ 368.1856; found 368.1856.
isomer this signal shied toward a more shielding region and
appeared approximately at 4 ppm.
13-[Amino, (p-tolyl)-methyl]-11, N-epoxy-tomentosin (3b).
Following the general procedure, using tomotensin (80 mg, 0.32
mmol), column chromatography on silica gel (petroleum ether/
ethyl acetate 6/4) provided 3b (89 mg, 0.23 mmol, 72%) as
1
a colorless oil; [a]2D0 +46.0 (c 1.0, CH2Cl2); H NMR (400 MHz,
Experimental section
General information
CDCl3) d 7.55 (d, J ¼ 8.0 Hz, 2H), 7.21 (d, J ¼ 7.9 Hz, 2H), 5.43
(dd, J ¼ 9.4, 3.5 Hz, 1H), 4.90 (ddd, J ¼ 11.4, 6.5, 4.6 Hz, 1H), 3.56
(d, J ¼ 16.8 Hz, 1H), 3.40 (d, J ¼ 17.0 Hz, 1H), 2.84 (ddd, J ¼ 13.0,
6.6, 3.0 Hz, 1H), 2.59–2.39 (m, 3H), 2.38 (s, 3H), 2.36–2.15 (m,
All reagents were purchased from commercial suppliers and
were used without further purication. The reactions were
monitored by thin-layer chromatography (TLC) analysis using
silica gel (60 F254) plates. Compounds were visualized by UV
irradiation. Flash column chromatography was performed on
silica gel 60 (230–400 mesh, 0.040–0.063 mm). 1H and 13C NMR
spectra were recorded on a Bruker AVANCE II spectrometer at
250 MHz (13C, 62.9 MHz) and on a Bruker AVANCE III HD
nanobay at 400 MHz (13C 101 MHz). Chemical shis are given in
parts per million from tetramethylsilane (TMS) or deuterated
solvents (MeOH-d4, CDCl3) as internal standard. The following
abbreviations were used for the proton spectra multiplicities: b:
broad, s: singlet, d: doublet, t: triplet, q: quartet, p: pentuplet,
m: multiplet. Coupling constants (J) are reported in hertz (Hz).
High-resolution mass spectra (HRMS (ESI)) were performed on
a Maxis Bruker 4G.
4H), 2.13 (s, 3H), 2.02–1.86 (m, 2H), 1.16 (d, J ¼ 7.0 Hz, 3H); 13
C
NMR (101 MHz, CDCl3) d 208.0 (C), 173.8 (C), 156.1 (C), 145.1
(C), 141.1 (C), 129.6 (2 CH), 127.0 (2 CH), 125.7 (C), 120.7 (CH),
88.8 (C), 80.1 (C), 46.2 (CH), 42.6 (CH2), 37.7 (CH2), 36.6 (CH2),
33.1 (CH), 30.8 (CH2), 30.1 (CH3), 22.7 (CH2), 21.6 (CH3), 21.2
(CH3); HRMS (ESI+): calc. For C23H27NO4 [M + H]+ 382.2012;
found 382.2012.
13-[Amino,
(4-methoxyphenyl)-methyl]-11,
N-epoxy-
tomentosin (3c). Following the general procedure, using
tomotensin (80 mg, 0.32 mmol), column chromatography on
silica gel (petroleum ether/ethyl acetate 5/5) provided 3c
(87 mg, 0.22 mmol, 68%) as a colorless oil; [a]2D0 +41.9 (c 1.0,
CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.63–7.57 (m, 2H), 6.95–
6.90 (m, 2H), 5.43 (d, J ¼ 3.7 Hz, 1H), 4.92 (ddd, J ¼ 11.3, 6.6,
4.4 Hz, 1H), 3.85 (s, 3H), 3.56 (d, J ¼ 16.8 Hz, 1H), 3.39 (d, J ¼
16.8 Hz, 1H), 2.84 (ddd, J ¼ 13.0, 6.6, 3.1 Hz, 1H), 2.61–2.15 (m,
General procedure for the synthesis of spiro-isoxazolines
7H), 2.14 (s, 3H), 2.03–1.87 (m, 2H), 1.17 (d, J ¼ 7.0 Hz, 3H); 13
C
The appropriate aldehyde (1 equiv.) was diluted in CH2Cl2 NMR (101 MHz, CDCl3) d 208.0 (C), 173.9 (C), 161.6 (C), 155.7
(10 mL) and stirred at room temperature. Hydroxylamine (C), 145.2 (C), 128.6 (2 CH), 121.1 (C), 120.8 (CH), 114.4 (2 CH),
(2 equiv.) and NaOH (2 equiv.) were added and the mixture was 88.7 (C), 80.1 (CH), 55.5 (CH3), 46.3 (CH), 42.6 (CH2), 37.9
heated to reux for 4 h. Ethanol was evaporated under reduced (CH2), 36.6 (CH2), 33.1 (CH), 30.8 (CH2), 30.1 (CH3), 22.8 (CH2),
pressure then the crude mixture was diluted with water (10 mL) 21.3 (CH3); HRMS (ESI+): calc. For C23H27NO5 [M + H]+
and AcOEt (10 mL) then extracted with AcOEt (3 ꢀ 10 mL). The 398.1962; found 398.1961.
combined organic layers were dried with MgSO4, ltered and
13-[Amino, (4-uorophenyl)-methyl]-11, N-epoxy-tomentosin
concentrated under reduced pressure to lead to the aldoxime (3d). Following the general procedure, using tomotensin
intermediate. The aldoxime was diluted in THF (10 mL) then (80 mg, 0.32 mmol), column chromatography on silica gel
tomentosin (0.2 equiv.) and bleach (5 mL) were added dropwise. (petroleum ether/ethyl acetate 6/4) provided 3d (86 mg,
The reaction mixture was stirred at room temperature for 12 h. 0.22 mmol, 69%) as a colorless oil; [a]2D0 +76.0 (c 1.0, CH2Cl2); 1H
The mixture was diluted with water (10 mL) and extracted with NMR (400 MHz, CDCl3) d 7.66 (dd, J ¼ 8.6, 5.3 Hz, 2H), 7.10 (t, J
CH2Cl2 (3 ꢀ 10 mL). The combined organic layers were dried ¼ 8.5 Hz, 2H), 5.43 (dd, J ¼ 9.4, 3.5 Hz, 1H), 4.91 (ddd, J ¼ 11.3,
with MgSO4, ltered and concentrated under reduced pressure 6.6, 4.5 Hz, 1H), 3.54 (d, J ¼ 16.8 Hz, 1H), 3.40 (d, J ¼ 16.9 Hz,
providing a crude product, which was puried by ash chro- 1H), 2.84 (ddd, J ¼ 13.0, 6.6, 3.0 Hz, 1H), 2.60–2.14 (m, 7H), 2.13
matography on silica gel.
(s, 3H), 2.01–1.87 (m, 2H), 1.16 (d, J ¼ 7.0 Hz, 3H); 13C NMR (101
13-[Amino, phenyl-methyl]-11, N-epoxy-tomentosin (3a). MHz, CDCl3) d 207.9 (C), 173.6 (C), 164.1 (d, J ¼ 251.7 Hz, C),
Following the general procedure, using tomotensin (80 mg, 0.32 155.2 (C), 145.2 (C), 129.0 (d, J ¼ 8.5 Hz, 2 CH), 124.9 (d, J ¼
mmol), column chromatography on silica gel (petroleum ether/ 3.5 Hz, CH), 120.6 (CH), 116.1 (d, J ¼ 22.0 Hz, 2 CH), 89.1 (C),
ethyl acetate 6/4) provided 3a (88 mg, 0.24 mmol, 75%) as 80.14 (CH), 46.1 (CH), 42.6 (CH2), 37.6 (CH2), 36.6 (CH2), 33.1
a yellow oil; [a]2D0 ꢁ38.8 (c 1.0, CH2Cl2); 1H NMR (400 MHz, (CH), 30.8 (CH2), 30.1 (CH3), 22.7 (CH2), 21.2 (CH3); HRMS
CDCl3) d 7.66 (dt, J ¼ 7.6, 1.4 Hz, 2H), 7.46–7.36 (m, 3H), 5.43 (ESI+): calc. For C22H24FNO4 [M + H]+ 386.1762; found 386.1762.
(dd, J ¼ 9.4, 3.5 Hz, 1H), 4.91 (ddd, J ¼ 11.3, 6.5, 4.5 Hz, 1H), 3.58
(d, J ¼ 16.8 Hz, 1H), 3.42 (d, J ¼ 16.9 Hz, 1H), 2.84 (ddd, J ¼ 13.1,
General procedure for the synthesis of spiro-isoxazolidines
6.7, 3.1 Hz, 1H), 2.59–2.15 (m, 7H), 2.13 (s, 3H), 1.94 (ddd, J ¼
23.2, 11.4, 7.4 Hz, 2H), 1.16 (d, J ¼ 7.0 Hz, 3H); 13C NMR (101 The appropriate nitrone (1.1 equiv.) was added to a solution of
MHz, CDCl3) d 208.0 (C), 173.7 (C), 156.1 (C), 145.1 (C), 130.8 (C), tomentosin (1 equiv.) in benzene (2 mL). The resulting
128.9 (2 CH), 128.5 (CH), 127.0 (2 CH), 120.7 (CH), 89.0 (C), 80.1 suspension was heated to reux for 12 h. Then the reaction
(CH), 46.1 (CH), 42.6 (CH2), 37.6 (CH2), 36.6 (CH2), 33.1 (CH), mixture was concentrated under reduced pressure and the
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crude material was puried by ash chromatography on silica tomotensin (80 mg, 0.32 mmol) and corresponding nitrone
gel to provide the expected spiro-isoxasolidine. (76 mg, 0.35 mmol) column chromatography on silica gel
13-[(Phenylamine), phenyl-methyl]-11, N-epoxy-tomentosin (petroleum ether/ethyl acetate 6/4) provided 5d (103 mg,
(5a). Following the general procedure, using tomotensin 0.22 mmol, 69%) as a yellow oil; [a]2D0 ꢁ78.6 (c 1.0, CH2Cl2); 1H
(80 mg, 0.32 mmol) and corresponding nitrone (70 mg, 0.35 NMR (400 MHz, CDCl3) d 7.47 (dd, J ¼ 8.3, 5.3 Hz, 2H), 7.24–7.17
mmol), column chromatography on silica gel (petroleum ether/ (m, 2H), 7.09 (t, J ¼ 8.4 Hz, 2H), 6.99–6.89 (m, 3H), 5.44 (dd, J ¼
ethyl acetate 6/4) provided 5a (104 mg, 0.23 mmol, 72%) as 9.4, 3.4 Hz, 1H), 5.11 (dd, J ¼ 9.4, 6.7 Hz, 1H), 4.94 (ddd, J ¼ 11.4,
1
a yellowish oil; [a]2D0 +45.6 (c 1.0, CH2Cl2); H NMR (400 MHz, 6.6, 4.5 Hz, 1H), 2.86 (ddd, J ¼ 19.2, 9.8, 4.8 Hz, 2H), 2.62–2.20
CDCl3) d 7.49 (d, J ¼ 7.8 Hz, 2H), 7.41–7.35 (m, 2H), 7.34–7.28 (m, 7H), 2.17 (s, 3H), 2.11 (t, J ¼ 4.2 Hz, 1H), 2.01–1.86 (m, 2H),
(m, 1H), 7.21–7.12 (m, 2H), 6.96–6.86 (m, 3H), 5.44–5.37 (m, 1.17 (d, J ¼ 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 208.0 (C),
1H), 5.14–5.07 (m, 1H), 4.96–4.89 (m, 1H), 2.85 (td, J ¼ 12.3, 174.7 (C), 162.5 (d, J ¼ 246.4 Hz, C), 151.0 (C), 144.8 (C), 136.1 (d,
11.0, 5.4 Hz, 2H), 2.60–2.17 (m, 7H), 2.15 (s, 3H), 2.13–2.07 (m, J ¼ 3.2 Hz, C), 128.8 (2 CH), 128.4 (d, J ¼ 8.0 Hz, 2 CH), 122.9
1H), 1.92 (ddd, J ¼ 19.2, 12.8, 7.4 Hz, 2H), 1.14 (d, J ¼ 6.9 Hz, (CH), 121.1 (CH), 116.0 (d, J ¼ 21.6 Hz, 2 CH), 115.8 (2 CH), 85.4
3H); 13C NMR (101 MHz, CDCl3) d 208.2 (C), 174.9 (C), 151.4 (C), (C), 79.8 (CH), 69.6 (CH), 45.8 (CH), 43.6 (CH2), 42.6 (CH2), 36.7
145.0 (C), 140.7 (C), 129.3 (2 CH), 128.9 (2 CH), 128.2 (CH), 126.9 (CH2), 33.2 (CH), 30.8 (CH2), 30.0 (CH3), 22.9 (CH2), 21.2 (CH3);
(2 CH), 122.8 (CH), 121.4 (CH), 115.8 (2 CH), 85.6 (C), 80.0 (CH), HRMS (ESI+): calc. For C28H30FNO4 [M + H]+ 464.2228; found
70.4 (CH), 46.0 (CH), 43.9 (CH2), 42.9 (CH2), 36.9 (CH2), 33.4 464.2231.
(CH), 31.0 (CH2), 30.3 (CH3), 23.1 (CH2), 21.4 (CH3); HRMS
13-[(Phenylamine), (4-triuoromethylphenyl)-methyl]-11, N-
(ESI+): calc. For C28H31NO4 [M + H]+ 446.2325; found 446.2325. epoxy-tomentosin (5e). Following the general procedure, using
13-[(Phenylamine), (p-tolyl)-methyl]-11, N-epoxy-tomentosin tomotensin (80 mg, 0.32 mmol) and corresponding nitrone
(5b). Following the general procedure, using tomotensin (94 mg, 0.35 mmol) column chromatography on silica gel
(80 mg, 0.32 mmol) and corresponding nitrone (74 mg, 0.35 (petroleum ether/ethyl acetate 5/5) provided 5e (102 mg,
mmol) column chromatography on silica gel (petroleum ether/ 0.20 mmol, 62%) as a colorless oil; [a]2D0 +85.6 (c 1.0, CH2Cl2); 1H
ethyl acetate 6/4) provided 5b (104 mg, 0.22 mmol, 69%) as NMR (400 MHz, CDCl3) d 7.68–7.59 (m, 4H), 7.24–7.15 (m, 2H),
1
a yellowish oil; [a]D20 +59.7 (c 1.0, CH2Cl2); H NMR (400 MHz, 6.98–6.92 (m, 1H), 6.88 (d, J ¼ 7.9 Hz, 2H), 5.40 (dd, J ¼ 9.4,
CDCl3) d 7.37 (d, J ¼ 7.7 Hz, 2H), 7.17 (ddd, J ¼ 13.8, 6.8, 2.7 Hz, 3.4 Hz, 1H), 5.23–5.16 (m, 1H), 4.94 (ddd, J ¼ 11.4, 6.3, 4.6 Hz,
4H), 6.96–6.87 (m, 3H), 5.42 (dd, J ¼ 9.4, 3.5 Hz, 1H), 5.06 (dd, J 1H), 2.91–2.80 (m, 2H), 2.59–2.17 (m, 7H), 2.15 (s, 3H), 2.10 (q, J
¼ 9.5, 6.7 Hz, 1H), 4.91 (ddd, J ¼ 11.4, 6.5, 4.4 Hz, 1H), 2.91–2.76 ¼ 4.7, 4.1 Hz, 1H), 2.00–1.82 (m, 2H), 1.15 (d, J ¼ 6.9 Hz, 3H); 13
C
(m, 2H), 2.60–2.37 (m, 4H), 2.36 (s, 3H), 2.34–2.17 (m, 3H), 2.15 NMR (101 MHz, CDCl3) d 208.0 (C), 174.5 (C), 151.0 (C), 144.9
(s, 3H), 2.13–2.06 (m, 1H), 1.93 (dt, J ¼ 14.5, 11.5 Hz, 2H), 1.14 (C), 145.0 (C), 130.4 (d, J ¼ 32.4 Hz, C), 128.9 (2 CH), 127.1 (2
(d, J ¼ 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 208.0 (C), 174.8 CH), 126.1 (q, J ¼ 3.8 Hz, C), 124.1 (d, J ¼ 273.2 Hz, 2 CH), 122.9
(C), 151.3 (C), 144.7 (C), 137.8 (C), 137.4 (C), 129.8 (2 CH), 128.7 (CH), 121.0 (CH), 115.4 (2 CH), 85.6 (C), 79.9 (CH), 69.6 (CH),
(2 CH), 126.7 (2 CH), 122.6 (CH), 121.1 (CH), 115.7 (2 CH), 85.3 45.8 (CH), 43.4 (CH2), 42.6 (CH2), 36.7 (CH2), 33.1 (CH), 30.8
(C), 79.7 (CH), 70.1 (CH), 45.8 (CH), 43.8 (CH2), 42.7 (CH2), 36.7 (CH2), 30.1 (CH3), 23.0 (CH2), 21.3 (CH3); HRMS (ESI+): calc. For
(CH2), 33.2 (CH), 30.8 (CH2), 30.1 (CH3), 22.9 (CH2), 21.2 (CH3),
21.2 (CH3); HRMS (ESI+): calc. For C29H33NO4 [M + H]+ 460.2480;
found 460.2482.
C
29H30F3NO4 [M + H]+ 514.2197; found 514.2199.
13-[(Phenylamine), (4-dimethylaminophenyl)-methyl]-11, N-
epoxy-tomentosin (5f). Following the general procedure, using
13-[(Phenylamine), (4-methoxyphenyl)-methyl]-11, N-epoxy- tomotensin (80 mg, 0.32 mmol) and corresponding nitrone
tomentosin (5c). Following the general procedure, using (85 mg, 0.35 mmol) column chromatography on silica gel
tomotensin (80 mg, 0.32 mmol) and corresponding nitrone (petroleum ether/ethyl acetate 3/7) provided 5f (93 mg,
1
(80 mg, 0.35 mmol) column chromatography on silica gel 0.19 mmol, 59%) as a brown oil; [a]2D0 +48.9 (c 1.0, CH2Cl2); H
(petroleum ether/ethyl acetate 5/5) provided 5c (103 mg, NMR (400 MHz, CDCl3) d 7.32 (d, J ¼ 8.4 Hz, 2H), 7.16 (t, J ¼
1
0.22 mmol, 68%) as a yellow oil; [a]2D0 +38.0 (c 1.0, CH2Cl2); H 7.7 Hz, 2H), 6.98–6.89 (m, 3H), 6.73 (d, J ¼ 8.4 Hz, 2H), 5.43 (dd,
NMR (400 MHz, CDCl3) d 7.43–7.35 (m, 2H), 7.16 (t, J ¼ 7.4 Hz, J ¼ 9.3, 3.5 Hz, 1H), 4.98 (dd, J ¼ 9.7, 6.5 Hz, 1H), 4.89 (ddd, J ¼
2H), 6.97–6.87 (m, 5H), 5.42 (dd, J ¼ 9.3, 3.5 Hz, 1H), 5.03 (dd, J 11.4, 6.9, 4.3 Hz, 1H), 2.96 (s, 6H), 2.89–2.75 (m, 2H), 2.60–2.18
¼ 9.5, 6.7 Hz, 1H), 4.90 (ddd, J ¼ 11.4, 6.7, 4.5 Hz, 1H), 3.81 (s, (m, 7H), 2.15 (s, 3H), 2.10 (dd, J ¼ 10.5, 3.4 Hz, 1H), 1.95 (ddd, J
3H), 2.87–2.78 (m, 2H), 2.60–2.17 (m, 7H), 2.15 (s, 3H), 2.10 (dt, J ¼ 21.0, 9.5, 2.7 Hz, 2H), 1.14 (d, J ¼ 6.9 Hz, 3H); 13C NMR (101
¼ 13.9, 4.2 Hz, 1H), 1.99–1.84 (m, 2H), 1.14 (d, J ¼ 6.8 Hz, 3H); MHz, CDCl3) d 208.0 (C), 175.0 (C), 151.3 (C), 150.4 (C), 144.7 (C),
13C NMR (101 MHz, CDCl3) d 208.0 (C), 174.9 (C), 159.4 (C), 128.6 (2 CH), 127.7 (2 CH), 127.3 (C), 122.7 (CH), 121.2 (CH),
151.2 (C), 144.7 (C), 132.1 (C), 128.7 (2 CH), 128.0 (2 CH), 122.8 116.2 (2 CH), 112.9 (2 CH), 85.1 (C), 79.6 (CH), 70.2 (CH), 45.8
(CH), 121.1 (CH), 116.0 (2 CH), 114.5 (2 CH), 85.2 (C), 79.7 (CH), (C), 43.8 (CH2), 42.7 (CH2), 40.7 (2 CH3), 36.7 (CH2), 33.3 (CH),
70.0 (CH), 55.4 (CH3), 45.8 (CH), 43.7 (CH2), 42.7 (CH2), 36.7 30.8 (CH2), 30.1 (CH3), 22.8 (CH2), 21.2 (CH3); HRMS (ESI+): calc.
(CH2), 33.2 (CH), 30.8 (CH2), 30.1 (CH3), 22.9 (CH2), 21.2 (CH3); For C30H36N2O4 [M + H]+ 489.2744; found 489.2747.
HRMS (ESI+): calc. For C29H33NO5 [M + H]+ 476.2429; found
476.2431.
13-[(Phenylamine), ((4-hydroxy-3-methoxy)phenyl)-methyl]-
11, N-epoxy-tomentosin (5g). Following the general procedure,
13-[(Phenylamine), (4-uorophenyl)-methyl]-11, N-epoxy- using tomotensin (80 mg, 0.32 mmol) and corresponding
tomentosin (5d). Following the general procedure, using nitrone (86 mg, 0.35 mmol) column chromatography on silica
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gel (petroleum ether/ethyl acetate 3/7) provided 5g (78 mg, 6.98 (d, J ¼ 8.2 Hz, 2H), 6.84 (d, J ¼ 8.2 Hz, 2H), 5.42 (dd, J ¼ 9.4,
0.16 mmol, 50%) as an orange oil; [a]2D0 ꢁ68.0 (c 1.0, CH2Cl2); 1H 3.5 Hz, 1H), 5.02 (dd, J ¼ 9.6, 6.4 Hz, 1H), 4.89 (ddd, J ¼ 11.4, 6.8,
NMR (400 MHz, CDCl3) d 7.21–7.14 (m, 2H), 7.01 (d, J ¼ 1.9 Hz, 4.4 Hz, 1H), 2.85–2.78 (m, 2H), 2.60–2.25 (m, 7H), 2.23 (s, 3H),
1H), 6.98–6.89 (m, 5H), 5.67 (s, 1H), 5.45–5.39 (m, 1H), 5.03 (dd, 2.15 (s, 3H), 2.10 (dt, J ¼ 13.7, 4.1 Hz, 1H), 1.98–1.86 (m, 2H),
J ¼ 9.6, 6.5 Hz, 1H), 4.91 (ddd, J ¼ 11.3, 6.7, 4.3 Hz, 1H), 3.88 (s, 1.14 (d, J ¼ 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 208.0 (C),
3H), 2.87–2.77 (m, 2H), 2.60–2.17 (m, 7H), 2.14 (s, 3H), 2.10 (dt, J 174.9 (C), 162.5 (d, J ¼ 246.4 Hz, C), 148.3 (C), 144.8 (C), 135.7 (d,
¼ 13.7, 4.1 Hz, 1H), 1.99–1.88 (m, 2H), 1.14 (d, J ¼ 7.0 Hz, 3H); J ¼ 3.2 Hz, C), 133.0 (C), 129.4 (2 CH), 128.6 (d, J ¼ 8.1 Hz, 2 CH),
13C NMR (101 MHz, CDCl3) d 208.1 (C), 174.8 (C), 151.3 (C), 121.1 (CH), 116.9 (2 CH), 115.9 (d, J ¼ 21.5 Hz, 2 CH), 85.2 (C),
147.1 (C), 145.4 (C), 144.8 (C), 132.1 (C), 128.7 (2 CH), 122.7 79.8 (CH), 70.0 (CH), 46.0 (CH), 43.6 (CH2), 42.7 (CH2), 36.7
(CH), 121.2 (CH), 119.7 (CH), 115.8 (2 CH), 114.8 (CH), 108.9 (CH2), 33.2 (CH), 30.8 (CH2), 30.0 (CH3), 22.9 (CH2), 21.2 (CH3),
(CH), 85.3 (C), 79.7 (CH), 70.3 (CH), 56.2 (CH3), 45.8 (CH), 43.8 20.8 (CH3); HRMS (ESI+): calc. For C29H32FNO4 [M + H]+
(CH2), 42.6 (CH2), 36.7 (CH2), 33.2 (CH), 30.8 (CH2), 30.1 (CH3), 478.2387; found 478.2388.
22.9 (CH2), 21.2 (CH3); HRMS (ESI+): calc. For C29H33NO6 [M +
H]+ 492.2381; found 492.2380.
13-[(p-Tolylamine), (4-triuoromethylphenyl)-methyl]-11, N-
epoxy-tomentosin (5k). Following the general procedure, using
13-[(p-Tolylamine), phenyl-methyl]-11, N-epoxy-tomentosin tomotensin (80 mg, 0.32 mmol) and corresponding nitrone
(5h). Following the general procedure, using tomotensin (98 mg, 0.35 mmol) column chromatography on silica gel
(80 mg, 0.32 mmol) and corresponding nitrone (74 mg, 0.35 (petroleum ether/ethyl acetate 5/5) provided 5k (104 mg,
mmol) column chromatography on silica gel (petroleum ether/ 0.20 mmol, 62%) as a yellowish oil; [a]2D0 +98.7 (c 1.0, CH2Cl2);
ethyl acetate 6/4) provided 5h (105 mg, 0.23 mmol, 72%) as 1H NMR (400 MHz, CDCl3) d 7.63 (t, J ¼ 6.1 Hz, 4H), 7.00 (d, J ¼
1
a yellowish oil; [a]D20 ꢁ34.8 (c 1.0, CH2Cl2); H NMR (400 MHz, 8.1 Hz, 2H), 6.83 (d, J ¼ 8.1 Hz, 2H), 5.40 (dd, J ¼ 9.5, 3.4 Hz,
CDCl3) d 7.47 (d, J ¼ 7.4 Hz, 2H), 7.40–7.33 (m, 2H), 7.33–7.27 1H), 5.13 (dd, J ¼ 9.4, 6.7 Hz, 1H), 4.91 (ddd, J ¼ 11.3, 6.7, 4.5 Hz,
(m, 1H), 6.98 (d, J ¼ 8.1 Hz, 2H), 6.86 (d, J ¼ 8.2 Hz, 2H), 5.41 1H), 2.84 (dd, J ¼ 12.6, 6.6 Hz, 2H), 2.59–2.25 (m, 7H), 2.24 (s,
(dd, J ¼ 9.4, 3.5 Hz, 1H), 5.04 (dd, J ¼ 9.5, 6.6 Hz, 1H), 4.90 (ddd, 3H), 2.15 (s, 3H), 2.13–2.06 (m, 1H), 1.91 (dd, J ¼ 13.7, 11.3 Hz,
J ¼ 11.3, 6.8, 4.4 Hz, 1H), 2.89–2.78 (m, 2H), 2.60–2.25 (m, 7H), 2H), 1.14 (d, J ¼ 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 208.0
2.23 (s, 3H), 2.15 (s, 3H), 2.10 (dt, J ¼ 13.8, 4.1 Hz, 1H), 1.99–1.87 (C), 174.7 (C), 148.3 (C), 144.9 (C), 144.5 (C), 133.0 (C), 130.3 (d, J
(m, 2H), 1.14 (d, J ¼ 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) ¼ 32.5 Hz, C), 129.5 (2 CH), 127.2 (2 CH), 126.0 (q, J ¼ 3.7 Hz, 2
d 208.0 (C), 174.9 (C), 148.6 (C), 144.7 (C), 140.1 (C), 132.6 (C), CH), 124.1 (d, J ¼ 272.1 Hz, C), 121.0 (CH), 116.5 (2 CH), 85.4 (C),
129.3 (2 CH), 129.0 (2 CH), 128.0 (CH), 126.9 (2 CH), 121.1 (CH), 79.9 (CH), 69.9 (CH), 45.9 (CH), 43.5 (CH), 42.6 (CH), 36.7 (CH2),
116.6 (2 CH), 85.2 (C), 79.7 (CH), 70.5 (CH), 45.9 (CH), 43.7 33.2 (CH), 30.8 (CH2), 30.0 (CH3), 22.9 (CH2), 21.2 (CH3), 20.8
(CH2), 42.7 (CH2), 36.7 (CH2), 33.2 (CH), 30.8 (CH2), 30.0 (CH3), (CH3); HRMS (ESI+): calc. For C30H32F3NO4 [M + H]+ 528.2355;
22.8 (CH2), 21.2 (CH3), 20.8 (CH3); HRMS (ESI+): calc. For found 528.2356.
C
29H33NO4 [M + H]+ 460.2481; found 460.2482.
13-[(p-Tolylamine), (4-methoxyphenyl)-methyl]-11, N-epoxy- tomentosin (5l). Following the general procedure, using tomo-
13-[(4-Fluorophenylamine), phenyl-methyl]-11, N-epoxy-
tomentosin (5i). Following the general procedure, using tomo- tensin (80 mg, 0.32 mmol) and corresponding nitrone (76 mg,
tensin (80 mg, 0.32 mmol) and corresponding nitrone (85 mg, 0.35 mmol) column chromatography on silica gel (petroleum
0.35 mmol) column chromatography on silica gel (petroleum ether/ethyl acetate 6/4) provided 5l (102 mg, 0.22 mmol, 68%) as
1
ether/ethyl acetate 5/5) provided 5i (108 mg, 0.22 mmol, 69%) as a yellowish oil; [a]2D0 +57.9 (c 1.0, CH2Cl2); H NMR (400 MHz,
a brown oil; [a]D20 +94.3 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.48–7.43 (m, 2H), 7.40–7.28 (m, 3H), 6.96–6.83 (m,
CDCl3) d 7.37 (d, J ¼ 8.4 Hz, 2H), 6.97 (d, J ¼ 8.2 Hz, 2H), 6.88 4H), 5.45–5.37 (m, 1H), 4.99 (dd, J ¼ 9.8, 6.4 Hz, 1H), 4.87 (ddd, J
(dd, J ¼ 10.0, 8.3 Hz, 4H), 5.42 (dd, J ¼ 9.4, 3.5 Hz, 1H), 4.96 (dd, ¼ 11.4, 7.0, 4.1 Hz, 1H), 2.89–2.78 (m, 2H), 2.62–2.18 (m, 7H),
J ¼ 9.7, 6.4 Hz, 1H), 4.88 (ddd, J ¼ 11.4, 6.8, 4.3 Hz, 1H), 3.80 (d, J 2.15 (s, 3H), 2.10 (dt, J ¼ 13.8, 4.2 Hz, 1H), 2.00–1.83 (m, 2H),
¼ 1.1 Hz, 3H), 2.86–2.75 (m, 2H), 2.60–2.25 (m, 7H), 2.23 (s, 3H), 1.14 (d, J ¼ 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 208.0 (C),
2.15 (s, 3H), 2.09 (dt, J ¼ 13.7, 4.3 Hz, 1H), 1.99–1.86 (m, 2H), 175.1 (C), 159.3 (d, J ¼ 241.6 Hz, C), 147.0 (d, J ¼ 2.5 Hz, C),
1.14 (d, J ¼ 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 208.0 (C), 144.8 (C), 139.5 (C), 129.1 (2 CH), 128.3 (CH), 127.0 (2 CH), 120.9
175.1 (C), 159.4 (C), 148.4 (C), 144.7 (C), 132.8 (C), 131.6 (C), (CH), 118.6 (d, J ¼ 8.0 Hz, 2 CH), 115.4 (d, J ¼ 22.6 Hz, 2 CH),
129.3 (2 CH), 128.2 (2 CH), 121.1 (CH), 117.1 (2 CH), 114.4 (2 85.1 (C), 79.7 (CH), 71.1 (CH), 45.7 (CH), 43.9 (CH2), 42.7 (CH2),
CH), 85.0 (C), 79.7 (CH), 70.3 (CH), 55.4 (CH3), 46.0 (CH), 43.7 36.7 (CH2), 33.5 (CH), 30.8 (CH2), 30.1 (CH3), 22.8 (CH2), 21.2
(CH2), 42.7 (CH2), 36.7 (CH2), 33.3 (CH), 30.8 (CH2), 30.0 (CH3), (CH3); HRMS (ESI+): calc. For C28H30FNO4 [M + H]+ 464.2231;
22.8 (CH2), 21.2 (CH3), 20.8 (CH3); HRMS (ESI+): calc. For found 464.2231.
C30H35NO5 [M + H]+ 490.2586; found 490.2588.
13-[(4-Fluorophenylamine), (p-tolyl)-methyl]-11, N-epoxy-
13-[(p-Tolylamine), (4-uorophenyl)-methyl]-11, N-epoxy- tomentosin (5m). Following the general procedure, using
tomentosin (5j). Following the general procedure, using tomo- tomotensin (80 mg, 0.32 mmol) and corresponding nitrone
tensin (80 mg, 0.32 mmol) and corresponding nitrone (81 mg, (81 mg, 0.35 mmol) column chromatography on silica gel
0.35 mmol) column chromatography on silica gel (petroleum (petroleum ether/ethyl acetate 6/4) provided 5m (95 mg,
ether/ethyl acetate 6/4) provided 5j (96 mg, 0.20 mmol, 63%) as 0.20 mmol, 62%) as a yellowish oil; [a]2D0 +66.4 (c 1.0, CH2Cl2);
1
a yellowish oil; [a]2D0 +55.8 (c 1.0, CH2Cl2); H NMR (400 MHz, 1H NMR (400 MHz, CDCl3) d 7.36–7.30 (m, 2H), 7.17 (d, J ¼
CDCl3) d 7.43 (dd, J ¼ 8.4, 5.3 Hz, 2H), 7.05 (t, J ¼ 8.5 Hz, 2H), 7.8 Hz, 2H), 6.97–6.82 (m, 4H), 5.42 (dd, J ¼ 9.2, 3.7 Hz, 1H), 4.94
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(dd, J ¼ 9.9, 6.3 Hz, 1H), 4.85 (ddd, J ¼ 11.4, 7.0, 4.1 Hz, 1H), 13C NMR (101 MHz, CDCl3) d 208.0 (C), 174.6 (C), 151.6 (C),
2.90–2.75 (m, 2H), 2.60–2.40 (m, 5H), 2.35 (s, 3H), 2.32–2.19 (m, 150.5 (C), 144.7 (C), 142.9 (CH), 128.8 (2 CH), 123.4 (CH), 121.4
2H), 2.15 (s, 3H), 2.10 (dt, J ¼ 13.7, 4.2 Hz, 1H), 2.02–1.85 (m, (CH), 116.5 (2 CH), 110.7 (CH), 108.5 (CH), 85.7 (C), 80.1 (CH),
2H), 1.14 (d, J ¼ 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 208.0 64.7 (CH), 46.3 (CH), 42.7 (CH2), 38.5 (CH2), 36.7 (CH2), 33.0
(C), 175.2 (C), 159.3 (d, J ¼ 241.5 Hz, C), 147.0 (d, J ¼ 2.5 Hz, C) (CH), 30.9 (CH2), 30.1 (CH3), 23.0 (CH2), 21.3 (CH3); HRMS
144.8 (C), 138.1 (C), 136.3 (C), 129.8 (2 CH), 127.0 (2 CH), 120.9 (ESI+): calc. For C26H29NO5 [M + H]+ 436.2118; found 436.2118.
(CH), 118.8 (d, J ¼ 7.9 Hz, 2 CH), 115.3 (d, J ¼ 22.5 Hz, 2 CH),
13-[(Phenylamine), (thiophen-3-yl)-methyl]-11, N-epoxy-
85.0 (C), 79.7 (CH), 70.9 (CH), 45.7 (CH), 44.0 (CH2), 42.7 (CH2), tomentosin (5q). Following the general procedure, using
36.7 (CH2), 33.5 (CH), 30.8 (CH2), 30.1 (CH3), 22.7 (CH2), 21.3 tomotensin (80 mg, 0.32 mmol) and corresponding nitrone
(CH3), 21.1 (CH3); HRMS (ESI+): calc. For C29H32FNO4 [M + H]+ (72 mg, 0.35 mmol) column chromatography on silica gel
478.2386; found 478.2388.
(petroleum ether/ethyl acetate 6/4) provided 5q (99 mg,
13-[(4-Fluorophenylamine), (4-methoxyphenyl)-methyl]-11, 0.22 mmol, 68%) as a yellowish oil; [a]2D0 ꢁ17.0 (c 1.0, CH2Cl2);
N-epoxy-tomentosin (5n). Following the general procedure, 1H NMR (400 MHz, CDCl3) d 7.36 (dd, J ¼ 5.0, 3.0 Hz, 1H), 7.28
using tomotensin (80 mg, 0.32 mmol) and corresponding (dt, J ¼ 3.0, 1.0 Hz, 1H), 7.22–7.14 (m, 3H), 6.96 (ddt, J ¼ 8.3, 3.3,
nitrone (86 mg, 0.35 mmol) column chromatography on silica 1.7 Hz, 3H), 5.41 (dt, J ¼ 7.8, 2.4 Hz, 1H), 5.16 (dd, J ¼ 9.0,
gel (petroleum ether/ethyl acetate 5/5) provided 5n (94 mg, 6.6 Hz, 1H), 4.91 (ddd, J ¼ 11.3, 6.7, 4.4 Hz, 1H), 2.82 (ddd, J ¼
0.19 mmol, 59%) as a yellowish oil; [a]2D0 +71.0 (c 1.0, CH2Cl2); 19.3, 11.2, 4.9 Hz, 2H), 2.60–2.17 (m, 7H), 2.15 (s, 3H), 2.10 (dt, J
1H NMR (400 MHz, CDCl3) d 7.38–7.32 (m, 2H), 6.98–6.82 (m, ¼ 13.8, 4.1 Hz, 1H), 2.00–1.85 (m, 2H), 1.14 (d, J ¼ 7.0 Hz, 3H);
6H), 5.46–5.40 (m, 1H), 4.93–4.80 (m, 2H), 3.81 (s, 3H), 2.89–2.72 13C NMR (101 MHz, CDCl3) d 208.2 (C), 175.0 (C), 151.2 (C),
(m, 2H), 2.61–2.18 (m, 7H), 2.15 (s, 3H), 2.10 (dt, J ¼ 13.7, 4.2 Hz, 145.0 (C), 141.3 (C), 129.0 (2 CH), 127.2 (CH), 126.2 (CH), 123.3
1H), 2.03–1.85 (m, 2H), 1.14 (d, J ¼ 7.0 Hz, 3H); 13C NMR (101 (CH), 122.4 (CH), 121.4 (CH), 116.5 (2 CH), 85.6 (C), 80.1 (CH),
MHz, CDCl3) d 208.0 (C), 175.3 (C), 159.6 (C), 159.4 (d, J ¼ 67.0 (CH), 46.3 (CH), 42.9 (CH2), 42.4 (CH2), 36.9 (CH2), 33.4
241.7 Hz, C), 146.9 (d, J ¼ 2.5 Hz, C), 144.8 (C), 130.9 (C), 128.3 (2 (CH), 31.0 (CH2), 30.3 (CH3), 23.2 (CH2), 21.4 (CH3); HRMS
CH), 120.9 (CH), 119.2 (d, J ¼ 8.0 Hz, 2 CH), 115.3 (d, J ¼ 22.5 Hz, (ESI+): calc. For C26H29NO4S [M + H]+ 452.1887; found 452.1890.
2 CH), 114.5 (2 CH), 84.9 (C), 79.6 (CH), 70.9 (CH), 55.4 (CH3),
45.7 (CH), 43.9 (CH2), 42.7 (CH2), 36.7 (CH2), 33.6 (CH), 30.8
Conclusions
(CH2), 30.1 (CH3), 22.7 (CH2), 21.1 (CH3); HRMS (ESI+): calc. For
C
29H32FNO5 [M + H]+ 494.2336; found 494.2337.
In summary, we described here the synthesis of interesting
13-[(Phenylamine),
(pyridin-4-yl)-methyl]-11,
N-epoxy- spiro-isoxazolidine and isoxazoline derivatives of tomentosin by
tomentosin (5o). Following the general procedure, using a 1,3-dipolar cycloaddition of respectively nitrones and nitrile
tomotensin (80 mg, 0.32 mmol) and corresponding nitrone oxides to the natural compound. We used an enantiomerically
(70 mg, 0.35 mmol) column chromatography on silica gel pure and natural starting material, thereby limiting the chem-
(petroleum ether/ethyl acetate 2/8) provided 5o (76 mg, ical impact on the environment. This procedure allowed us to
0.17 mmol, 53%) as a yellowish oil; [a]2D0 +15.1 (c 1.0, CH2Cl2); generate enantiomerically pure spiro compounds in one dia-
1H NMR (400 MHz, CDCl3) d 8.66–8.58 (m, 2H), 7.52–7.39 (m, stereoisomer form with a limited number of steps.
2H), 7.23–7.15 (m, 2H), 7.01–6.82 (m, 3H), 5.40 (dd, J ¼ 9.2,
3.4 Hz, 1H), 5.14 (dd, J ¼ 9.1, 7.0 Hz, 1H), 4.95 (ddd, J ¼ 11.3, 6.6,
Acknowledgements
4.5 Hz, 1H), 2.89–2.82 (m, 2H), 2.66–2.17 (m, 7H), 2.14 (s, 3H),
2.13–2.07 (m, 1H), 2.00–1.80 (m, 2H), 1.14 (d, J ¼ 7.0 Hz, 3H); This work was supported by the Region Centre, France in the
13C NMR (101 MHz, CDCl3) d 207.9 (C), 174.3 (C), 150.8 (C), ValPAMMeT Program and was carried out in collaboration with
150.6 (2 CH), 150.0 (C), 145.0 (C), 129.0 (2 CH), 122.9 (CH), 121.6 the Meknes-Talalet area in Morocco.
(2 CH), 121.0 (CH), 115.1 (2 CH), 85.8 (C), 80.0 (CH), 68.9 (CH),
45.7 (CH), 42.8 (CH2), 42.6 (CH2), 36.7 (CH2), 33.1 (CH), 30.8
Notes and references
(CH2), 30.1 (CH3), 23.0 (CH2), 21.3 (CH3); HRMS (ESI+): calc. For
C
27H30N2O4 [M + H]+ 447.2277; found 447.2278.
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13-[(Phenylamine),
(furan-2-yl)-methyl]-11,
N-epoxy-
tomentosin (5p). Following the general procedure, using
tomotensin (80 mg, 0.32 mmol) and corresponding nitrone
(66 mg, 0.35 mmol) column chromatography on silica gel
(petroleum ether/ethyl acetate 6/4) provided 5p (87 mg,
0.20 mmol, 63%) as a yellowish oil; [a]2D0 +71.3 (c 1.0, CH2Cl2);
1H NMR (400 MHz, CDCl3) d 7.44 (dd, J ¼ 1.8, 0.9 Hz, 1H), 7.25–
7.18 (m, 2H), 6.99 (dd, J ¼ 8.4, 7.1 Hz, 3H), 6.35 (dd, J ¼ 3.3,
1.8 Hz, 1H), 6.31 (dt, J ¼ 3.3, 0.7 Hz, 1H), 5.45 (ddd, J ¼ 7.9, 2.5,
1.2 Hz, 1H), 5.10 (dd, J ¼ 8.2, 7.0 Hz, 1H), 4.93 (ddd, J ¼ 11.3, 6.6,
4.6 Hz, 1H), 2.88–2.72 (m, 2H), 2.60–2.18 (m, 7H), 2.15 (s, 3H),
2.14–2.07 (m, 1H), 2.03–1.90 (m, 2H), 1.15 (d, J ¼ 7.0 Hz, 3H);
6 J. R. Woods, H. Mo, A. A. Bieberich, T. Alavanja and
D. A. Colby, J. Med. Chem., 2011, 54, 7934.
6528 | RSC Adv., 2017, 7, 6523–6529
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RSC Advances
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