Total Synthesis of Anmindenol A and Its Application to the Design, Synthesis, and Biological Evaluation of Derivatives Thereof

Article abstract of DOI:10.1021/acs.joc.9b01564

The first total synthesis of anmindenol A is described in four steps. A notable feature of the synthetic route includes the efficient construction of the 3,10-dialkylsubstituted benzofulvene core via a stereoselective vinylogous Stork enamine aldol condensation. The strategy provided a blueprint for the practical preparation of derivatives with modifications in the C-10 alkyl substituents. The novel derivatives inhibited nitric oxide production in stimulated RAW 264.7 macrophage cells.

Full text of DOI:10.1021/acs.joc.9b01564

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Article
Total Synthesis of Anmindenol A and Its Application to the Design,
Synthesis, and Biological Evaluation of Derivatives Thereof
Jeyun Jo, Myeonggyo Jeong, Ji-Su Ahn, Jinia Akter, Hyung-Sik Kim, Young-Ger Suh, and Hwayoung Yun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01564 • Publication Date (Web): 30 Jul 2019
Downloaded from pubs.acs.org on July 30, 2019
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Total Synthesis of Anmindenol A and Its Application to the Design, Synthesis, and
Biological Evaluation of Derivatives Thereof
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Jeyun Jo,†,‖ Myeonggyo Jeong,†,‖ Ji-Su Ahn, Jinia Akter, Hyung-Sik Kim, Young-Ger Suh and Hwayoung Yun
‡
†
‡
§
*,†
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†
College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
‡
Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of
Korea
§
College of Pharmacy, CHA University, 120 Haeryong-ro, Pocheon-si, Gyeonggi-do 11160, Republic of Korea
‖
These authors contributed equally to this work.
CORRESPONDING AUTHOR
*
E-mail: hyun@pusan.ac.kr (H. Yun)
TABLE OF CONTENTS
ABSTRACT
The first total synthesis of anmindenol A is described in four steps. A notable feature of the synthetic route includes the efficient
construction of the 3,10-dialkylsubstituted benzofulvene core via a stereoselective vinylogous Stork enamine aldol condensation. The
strategy provided a blueprint for the practical preparation of derivatives with modifications in the C-10 alkyl substituents. The novel
derivatives inhibited nitric oxide production in stimulated RAW 264.7 macrophage cells.
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INTRODUCTION
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Benzofulvenes and related indenes are known as the key privileged structures of biologically active compounds and are useful
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subunits in the field of materials science. These semiaromatic structures with a polarized exocyclic olefin are rarely encountered in
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naturally occurring sesquiterpenoids. Recently, a new class of benzofulvene sesquiterpenoids, which includes anmindenol A (1),
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nicotianasesterpenes A (2), B (3),3b and compounds 4-6, was isolated from natural sources (Figure. 1).
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Figure 1. Naturally occurring benzofulvene sesquiterpenoids.
Despite their structural similarity, these natural benzofulvene sesquiterpenoids showed diverse biological activities, such as anti-
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inflammatory, antiviral, and anticancer. Anmindenol A (1) was first identified from a marine-derived bacterium Streptomyces sp. in
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014.3a This target natural product consists of a unique indene skeleton, which is decorated by a synthetically formidable (E)-
trisubstituted exo-olefin. Anmindenol A effectively inhibits inducible nitric oxide synthase (iNOS) without displaying any significant
cytotoxicity.3a The structural uniqueness and biological properties of the benzofulvene sesquiterpenoid prompted us to attempt
substantial synthetic effort toward total synthesis of 1 and its derivatization.
From a synthetic point of view, the major challenges for anmindenol A (1) are the stereoselective generation of the (E)-trisubstituted
olefin at C-1/10 and the incorporation of the hydroxymethyl group at C-3. Several synthetic methods of structurally unique 3,10-
disubstituted benzofulvenes have been reported: (a) condensation of 3-substituted indenes;1,4 (b) acid-catalyzed cycloisomerization
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of 1,1,4-triphenylbutenyne; (c) transition metal-catalyzed cycloisomerization of aromatic enynes; and (d) Wolff rearrangement-
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induced cascade reaction of 1-diazonaphthalen-2(1H)-ones. Although these reactions are highly relevant and valuable, almost all of
them are probably inapplicable to the synthesis of 1 owing to harsh conditions, starting material incompatibility and poor synthetic
efficiency and stereoselectivity. Recently, Lash et al. reported highly remarkable vinylogous-type Claisen-Schmidt condensation of
indene-derived enamine, which successfully provides 10-aryl-3-formylbenzofulvenes under Lewis acid condition.2a,8 Considering the
reactive nucleophilicity of the enamine precursor and the mild conditions, the condensation would be feasible to form the uniquely
challenging 3,10-dialkylbenzofulvenes by replacing aromatic aldehyde to aliphatic aldehyde even if the latter is enolizable.
Accordingly, we sought to further expand the work of Lash et al. by exploiting vinylogous Stork enamine aldol condensation
(
VSEAC), thereby efficiently constructing the whole carbon framework of 1. Herein, we describe our efforts toward total synthesis
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of anmindenol A (1) through a stereoselective VSEAC, its application to the synthesis of a novel series of rationally designed 3,10-
dialkylbenzofulvene derivatives, and biological evaluation of the synthesized compounds.
RESULTS AND DISCUSSION
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Our retrosynthetic route for anmindenol A (1) and its regioisomer 7 is outlined in Scheme 1. The synthetic plan intended to utilize
vinylogous Stork enamine aldol condensations of the enamine precursors 10 and 11 to construct the highly functionalized (E,Z)-δ-
9
iPr-α,β,γ,δ-unsaturated aldehydes 8 and 9. The final benzofulvenes 1 and 7 could be readily obtained by Luche reduction of the
corresponding aldehydes 8 and 9 followed by Negishi cross-coupling with dimethylzinc.10 Both enamine 10 and 11 were expected to
be conveniently prepared as regioisomers from commercially available indanone 12.
Scheme 1. Retrosynthesis of anmindenol A (1) and its regioisomer 7.
In order to prepare enamine precursors for VSEAC, we initially commenced the synthesis using indanone 13, which had a methyl
group inserted at the C-6 (Scheme 2). Exposure of 13 to NaBH
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and the dehydration of the resulting alcohol 14 with p-toluenesulfonic
1
1
acid afforded indene 15. Subsequent solvent-free condensation of 15 with N,N-dimethylformamide dimethyl acetal (DMF-DMA)
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smoothly provided the enamine precursors 16 and 17 in a ratio of almost 1:1 in 81% combined yield. Unfortunately, these
regioisomers were inseparable by column chromatography. Thus, we circumvented the unexpected problem by employing 6-bromo-
1
-indanone (12) as a starting material, which was strategically advantageous not only to form stable enamines13 but also to introduce
a missing methyl group to the final benzofulvenes at the late stage. The same three-step sequence of 12 enabled to furnish the separable
1
enamines 10 and 11 in a high yield (1.15:1 ratio by H NMR analysis).
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Scheme 2. Preparation of enamine precursors 10 and 11.
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With the stable enamine 10 in hand, we have investigated to determine the optimal reaction conditions for VSEAC (Table 1).
Gratifyingly, an initial attempt with isobutyraldehyde stereoselectively resulted in the desired aldehyde 8 in a 7:1 E/Z ratio in a
8a
moderate yield under the relevant conditions (Table 1, entry 1). Encouraged by this result, further evaluation of different parameters,
such as reagent, temperatures, concentration, and solvent, was performed to improve the stereoselectivity and productivity. Previous
studies by Lash et al. showed that TiCl
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as a Lewis acid is also applicable to vinylogous-type Claisen-Schmidt condensation.2a
However, the use of TiCl gave very low yield of the desired product 8 with the lower stereoselectivity (Table 1, entry 2). Although
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higher temperature (reflux) accelerated the reaction rate, no significant changes were observed (Table 1, entry 3). In addition, cooling
the reaction temperature to −20 °C decreased the yield and stereoselectivity (Table 1, entry 4). Subsequently, we manipulated the
reaction by increasing the enamine concentration by 10 times to allow eco-friendly scale-up synthesis,14 however, the yield and
stereoselectivity of aldehyde 8 were slightly diminished (Table 1, entry 5). Notably, switching the reaction solvent to THF led to
greatly improved yield with the consistent stereoselectivity (Table 1, entry 6). Taken together, we concluded that the optimal reaction
conditions are those in entry 6.
Table 1. Optimization of VSEAC of enamine 10 with isobutyraldehyde.
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entry
Lewis acid
solvent
conc.(N)a
temp.
time
yieldb
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E/Z ratio)c
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Bu
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BOTf
DCM
DCM
DCM
DCM
DCM
THF
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0.005
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0.005
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rt
rt
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14 h
3 h
65% (7 : 1)
7% (4.5 : 1)
62% (6 : 1)
16% (4.5 : 1)
44% (5.5 : 1)
77% (7 : 1)
TiCl
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Concentration of the enamine 10. Isolated yield. The E/Z ratio of product was determined by H NMR.
Having successfully constructed the benzofulvene sesquiterpenoid skeleton, we then explored the total synthesis of anmindenol A
(1) and its regioisomer 7 (Scheme 3). α,β,γ,δ-Unsaturated aldehyde 8 was carefully reduced with NaBH
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and CeCl
3
ꞏ7H
2
O under the
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cooled condition, providing alcohol 20 in 80% yield. Subsequent Negishi cross-coupling of 6-bromobenzofulvene 20 with Me
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Zn
1
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in the presence of Pd(PPh
3
4
) finally rendered anmindenol A (1) in high yield. The structure of 1 was confirmed through comparison
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13
1
3a
of its spectra ( H NMR and C{ H} NMR) with those reported in the literature. Next, synthesis of 7 commenced from the enamine
11, which was previously prepared in Scheme 2. The precursor 11 was successfully converted into benzofulvene aldehyde 9 in an 8:1
E/Z ratio in 71% yield under the established procedure. Finally, Luche reduction of 9, followed by Negishi cross-coupling produced
the regioisomer 7 in an excellent yield.
Scheme 3. Total syntheses of anmindenol A (1) and its regioisomer 7.
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Our synthetic efforts of the benzofulvene sesquiterpenoids 1 and 7 simultaneously led us into such a journey of discovering novel
analogs with potent biological activities. A molecular modeling study revealed that the hydroxy group of anmindenol A tends to form
a hydrogen bond with a crucial residue of iNOS (Supporting Information).15 Therefore, our derivatization was focused on the
modification of the isopropyl group at C-10 to decipher the effect of alkyl substituents on iNOS inhibition.
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Initially, we explored the substrate scope of the VSEAC between enamines 10 and 11 and several alkyl aldehydes (Table 2).
Fortunately, all condensations proceeded smoothly and resulted in good to moderate yields. In the case of one- or two-carbon
truncated aldehydes, the E/Z ratios were slightly decreased to approximately 4:1, compared with those in the synthetic results of 8
and 9 (Table 2, entries 1-4). In particular, the condensation with pivalaldehyde, which was decorated with an additional one-carbon,
gave the desired E-isomer only (Table 2, entries 5 and 6). These results indicated that the stereoselectivity of our VSEAC was
presumably affected by the steric property of alkyl aldehydes.
Table 2. VSEAC of enamine substrates 10 and 11 with alkyl aldehydes.
a
b
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enamine
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aldehyde
product
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yield (E/Z ratio)
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acetaldehyde
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68% (4 : 1)
42% (4.5 : 1)
35% (4 : 1)
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acetaldehyde
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propionaldehyde
propionaldehyde
pivalaldehyde
pivalaldehyde
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10
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39% (E-isomer only)
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57% (E-isomer only)
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Isolated yield. The E/Z ratio of product was determined by H NMR.
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With the carefully purified E stereoisomers 22-27 in hand, we then executed syntheses of novel derivatives of natural benzofulvene
anmindenol A for the construction of a structurally unexplored chemical library. As depicted in Scheme 4, reductions of aldehydes
2-27 under Luche condition and Negishi cross-couplings of the resultant alcohols 28-33 with Me Zn successfully afforded the final
analogs 34-39 in high yields.
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Scheme 4. Syntheses of anmindenol A analogs 34-39.
In order to assess the iNOS inhibitory activities of newly synthesized anmindenol A and its analogs, all compounds including
structurally closely related intermediates 20 and 21 were tested against lipopolysaccharide (LPS)-activated macrophage RAW264.7
cells in a dose-dependent manner.16 The results of the biological evaluation are shown in Table 3. Anmindenol A (1) as a positive
control inhibited nitric oxide production with an IC50 value of 33.6 μM nearly equal to the previously reported value.3a In general,
most of the novel derivatives exhibited slightly improved activities (IC50 = 17.3−35.5 μM) compared to that of 1, which presumably
indicated that the benzofulvene moiety played a crucial role in the iNOS inhibitory activity of the compounds. Interestingly, one-
carbon-truncated analog 36 showed approximately 2-fold higher potency to the natural product 1. Moreover, among the regioisomers,
one-carbon-truncated analog 37 also displayed the highest activity against NO release.
Table 3. Inhibitory effects of the synthesized compounds on NO production.
comp.
1
IC50 (µM)
33.6
comp.
7
IC50 (µM)
22.7
20
18.4
21
33.0
3
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28.3
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CONCLUSION
In conclusion, we have accomplished the first total synthesis of rare benzofulvene sesquiterpenoid anmindenol A (1) (27% overall
yield) in only four steps from the known indene 19. The key feature of our synthesis includes the stereoselective construction of the
3
,10-dialkylsubstituted benzofulvene backbone utilizing a vinylogous Stork enamine aldol condensation. The developed synthetic
strategy was applied to synthesize unexplored derivatives of 1, which were rationally designed by using computational docking
analysis. The synthesized 3,10-dialkylbenzofulvenes were evaluated for their iNOS inhibitory activities in stimulated RAW 264.7
macrophage cells. The findings in this work suggested that benzofulvene-based compounds may have a chance to be developed as a
potential anti-inflammatory or anti-senescence agents. Employing this practical synthetic route, our further studies toward syntheses
of other natural benzofulvenes and evaluation of their biological activities are currently underway.
EXPERIMENTAL SECTION
General Experimental Procedure
Unless noted otherwise, all starting materials and reagents were obtained from commercial suppliers and were used without further
purification. Reaction flasks were dried at 100 ℃. Air- and moisture-sensitive reactions were performed under argon atmosphere. All solvents
used for routine isolation of products and chromatography were reagent grade. Flash column chromatography was performed using silica gel
6
0 (230-400 mesh, Merck) with the indicated solvents. Thin-layer chromatography was performed using 0.25 mm silica gel plates (Merck).
1H and 13C{ H} NMR spectra were recorded on Varian Unity 400, AVANCE NEO 500 and Unity-Inova 500 as solutions in the indicated
1
solvents. Chemical shifts were expressed in parts per million (ppm, δ) downfield from tetramethylsilane and were referenced to the deuterated
1
solvent. H NMR data were reported in the order of chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet and/or
multiple resonance), number of protons, and coupling constant in hertz (Hz). Infrared (IR) spectra were obtained by an FT/IR spectrometer
-
1
and are reported as absorption wavenumbers (cm ). High resolution mass spectra were obtained with an Agilent 6530 Accurate-Mass Q-
TOF and a JEOL JMS-AX 505WA instrument.
6
-Methyl-2,3-dihydro-1H-inden-1-ol (14).17 To a solution of 6-methyl-1-indanone (526 mg, 3.60 mmol) in EtOH (12.0 mL) was added
NaBH (136 mg, 3.60 mmol) at ambient temperature. After being stirred for 1 h at the same temperature, the reaction mixture was quenched
with saturated NH Cl and then concentrated in vacuo. The residue was extracted with EtOAc. The combined organic layers were dried over
4
4
MgSO
4
and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 5) to
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afford 522 mg (98%) of alcohol 14 as white solid: H NMR (CDCl
3
, 500 MHz) δ 7.23 (s, 1H), 7.15 (d, 1H, J = 7.7 Hz), 7.09 (d, 1H, J = 7.7
Hz), 5.20 (q, 1H, J = 6.2 Hz), 3.02 (m, 1H), 2.78 (m, 1H), 2.48 (m, 1H), 2.37 (s, 3H), 1.94 (m, 2H); 13C{ H} NMR (CDCl
1
, 125 MHz) δ
3
1
45.2, 140.4, 136.5, 129.3, 124.8, 124.7, 76.5, 36.2, 29.5, 21.4.
5-Methyl-1H-indene (15).11 To a solution of alcohol 14 (502 mg, 3.38 mmol) in benzene (14.0 mL) was added PTSAꞏH
O (64.4 mg, 0.338
and then
and concentrated in vacuo. The residue was purified by flash
2
mmol) at ambient temperature. After being stirred for 3 h at 65 ℃, the reaction mixture was quenched with saturated NaHCO
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
extracted with EtOAc. The combined organic layers were dried over MgSO
4
1
3
column chromatography on silica gel (n-hexane) to afford 279 mg (63%) of 15 as a colorless oil: H NMR (CDCl , 500 MHz) δ 7.36 (d, 1H,
J = 7.6 Hz), 7.23 (s, 1H), 7.02 (d, 1H, J = 7.5 Hz), 6.84 (m, 1H), 6.54 (m, 1H), 3.36 (s, 2H), 2.40 (s, 3H); 13C{ H} NMR (CDCl
1
, 125 MHz)
3
δ 145.2, 140.8, 135.9, 134.6, 132.1, 125.5, 123.5, 121.8, 38.8, 21.6.
(E)-N,N-Dimethyl-1-(5-methyl-1H-inden-1-ylidene)methanamine
ylidene)methanamine (17). To an indene 15 (81.0 mg, 0.622 mmol) was added DMF-DMA (83.0 µL, 0.622 mmol) at ambient temperature.
After being stirred for 17 h at 100 ℃, the reaction mixture was quenched with H O and then extracted with EtOAc. The combined organic
layers were dried over Na SO and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc /
n-hexane = 1 : 5, TEA 2%) to afford 93.6 mg (81% yield as a 1 : 1 regioisomeric enamine mixture) of 16 as brown solid: FT-IR (thin film,
(16)
and
(E)-N,N-dimethyl-1-(6-methyl-1H-inden-1-
2
2
4
-1 1
neat) νmax 3001, 2913, 2859, 1705, 1625, 1489, 1451, 1439, 1408, 1384, 1336 cm ; H NMR (CDCl
3
, 500 MHz) δ (mixture of regioisomer
1
7) 7.51 (d, 1H, J = 7.9 Hz), 7.43 (s, 1H), 7.39 (m, 2H), 7.37 (s, 1H), 7.31 (s, 1H), 7.05 (d, 1H, J = 5.1 Hz), 7.01 (d, 1H, J = 5.4 Hz), 7.00
(
m, 1H), 6.98 (m, 1H), 6.81 (m, 2H), 3.25 (s, 6H), 3.24 (s, 6H), 2.48 (s, 3H), 2.46 (s, 3H); 13C{ H} NMR (CDCl
1
3
, 125 MHz) δ (mixture of
regioisomer 17) 140.3, 140.2, 138.5, 138.4, 135.8, 135.7, 131.8, 131.4, 123.7, 123.3, 123.0, 122.1, 121.7, 121.7, 120.7, 120.0, 116.5, 115.7,
+
1
09.8, 109.7, 43.5, 22.0, 21.7; HRMS (ESI+) m/z: [M + H] Calcd for C13
-Bromo-2,3-dihydro-1H-inden-1-ol (18).11 To a solution of indanone 12 (5.00 g, 23.7 mmol) in EtOH (250 mL) was added NaBH
(806
4
H16N 186.1277; Found 186.1277.
6
mg, 21.3 mmol) at ambient temperature. After being stirred for 12 h at the same temperature, the reaction mixture was quenched with
saturated NH Cl and then concentrated in vacuo. The residue was extracted with EtOAc. The combined organic layers were dried over
MgSO
4
4
and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 4) to
1
afford 4.86 g (96%) of 18 as white solid: H NMR (CDCl
3
, 400 MHz) δ 7.52 (s, 1H), 7.36 (dd, 1H, J = 8.0, 1.7 Hz), 7.11 (d, 1H, J = 8.0 Hz),
1
5
.21 (q, 1H, J = 6.4 Hz), 2.98 (m, 1H), 2.75 (m, 1H), 2.49 (m, 1H), 1.94 (m, 2H); 13C{ H} NMR (CDCl
3
, 125 MHz) δ 147.4, 142.3, 131.4,
127.6, 126.6, 120.4, 76.2, 36.3, 29.5.
-Bromo-1H-indene (19).11 To a solution of alcohol 18 (4.47 g, 21.0 mmol) in benzene (150 mL) was added PTSAꞏH
5
2
O (399 mg, 2.10
and then
and concentrated in vacuo. The residue was purified by flash
mmol) at ambient temperature. After being stirred for 14 h at 65 ℃, the reaction mixture was quenched with saturated NaHCO
extracted with EtOAc. The combined organic layers were dried over MgSO
column chromatography on silica gel (n-hexane) to afford 3.58 g (88%) of 19 as a colorless oil: H NMR (CDCl
3
4
1
3
, 500 MHz) δ 7.54 (s, 1H),
1
7
.32 (m, 2H), 6.82 (m, 1H), 6.60 (m, 1H), 3.36 (m, 2H); 13C{ H} NMR (CDCl
3
, 125 MHz) δ 147.1, 142.5, 136.1, 131.4, 127.4, 125.1, 124.2,
120.4, 38.9.
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(E)-1-(5-Bromo-1H-inden-1-ylidene)-N,N-dimethylmethanamine
dimethylmethanamine (11). To an indene 19 (330 mg, 1.69 mmol) was added DMF-DMA (226 µL, 1.69 mmol) at ambient temperature.
After being stirred for 12 h at 100 ℃, the reaction mixture was quenched with H O and then extracted with EtOAc. The combined organic
layers were dried over Na SO and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc /
n-hexane = 1 : 3) to afford 417 mg (99%) of 10 and 11 as a 1.15 : 1 mixture.
Compound 10: Brown solid; FT-IR (thin film, neat) νmax 2917, 1623, 1587, 1447, 1383, 1327 cm ; H NMR (CDCl
(10)
and
(E)-1-(6-Bromo-1H-inden-1-ylidene)-N,N-
2
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
1 1
3
, 400 MHz) δ 7.58 (d,
1H, J = 1.7 Hz), 7.44 (d, 1H, J = 8.2 Hz), 7.41 (s, 1H), 7.20 (dd, 1H, J = 8.3, 1.8 Hz), 7.07 (d, 1H, J = 5.2 Hz), 6.75 (d, 1H, J = 5.2 Hz), 3.29
(
[
s, 6H); 13C{ H} NMR (CDCl
1
3
, 100 MHz) δ 141.6, 139.5, 136.5, 124.4, 124.0, 123.0, 120.4, 117.3, 115.7, 109.0, 43.7; HRMS (FAB+) m/z:
+
M] Calcd for C12
H12BrN 249.0153; Found 249.0151.
-1 1
3
Compound 11: Brown solid; FT-IR (thin film, neat) νmax 2919, 1628, 1450, 1421, 1410, 1384, 1337 cm ; H NMR (CDCl , 500 MHz) δ
7.69 (m, 1H), 7.38 (s, 1H), 7.32 (d, 1H, J = 8.1 Hz), 7.20 (dd, 1H, J = 8.1, 1.7 Hz), 7.04 (d, 1H, J = 5.2 Hz), 6.77 (d, 1H, J = 5.1 Hz), 3.28
(
[
s, 6H); 13C{ H} NMR (CDCl
1
3
, 100 MHz) δ 141.7, 139.8, 136.4, 124.8, 123.3, 121.6, 120.7, 119.0, 115.9, 108.8, 43.5; HRMS (FAB+) m/z:
12BrN 249.0153; Found 249.0146.
E)-6-Bromo-1-(2-methylpropylidene)-1H-indene-3-carbaldehyde (8). To a solution of isobutyraldehyde (24.9 µL, 0.273 mmol) in THF
4.10 mL) was added Bu BOTF (273 µL of a 1.0 M solution in CH Cl ) at ambient temperature. To a reaction mixture was immediately
+
M] Calcd for C12
H
(
(
2
2
2
added a solution of enamine 10 (68.3 mg, 0.273 mmol) in THF (1.36 mL) via cannula. After being stirred for 3 h, the reaction mixture was
quenched with H O and then extracted with EtOAc. The combined organic layers were dried over Na SO and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel (EtOAc / n-hexane = 1 : 7) to afford 58.5 mg (77% yield, E : Z = 7 : 1)
2
2
4
-1
1
3
of aldehyde 8 as yellow solid: FT-IR (thin film, neat) νmax 2966, 2921, 2852, 2352, 2307, 1718, 1679, 1466 cm ; H NMR (CDCl , 500 MHz)
δ 10.12 (s, 1H), 7.94 (d, 1H, J = 8.1 Hz), 7.75 (d, 1H, J = 1.7 Hz), 7.54 (s, 1H), 7.44 (dd, 1H, J = 8.1, 1.7 Hz), 6.84 (d, 1H, J = 10.3 Hz), 3.15
1
(
m, 1H), 1.23 (d, 6H, J = 6.6 Hz); 13C{ H} NMR (CDCl
3
, 100 MHz) δ 188.9, 149.5, 140.7, 138.8, 136.4, 130.5, 124.1, 124.0, 122.8, 122.7,
14BrO 277.0228; Found 277.0223.
(E)-(6-Bromo-1-(2-methylpropylidene)-1H-inden-3-yl)methanol (20). To a solution of aldehyde 8 (49.9 mg, 0.180 mmol) in EtOH (3.00
mL) was added a solution of CeCl ꞏ7H O (101 mg, 0.271 mmol), NaBH (7.49 mg, 0.198 mmol) in EtOH (2.00 mL) dropwise at 0 ℃. After
being stirred for 1 h at the same temperature, the reaction mixture was quenched with 1N HCl and then concentrated in vacuo. The residue
was extracted with EtOAc. The combined organic layers were dried over MgSO and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (EtOAc / n-hexane = 1 : 3) to afford 40.2 mg (80%) of alcohol 20 as yellow solid: FT-IR (thin
+
1
20.7, 30.8, 23.1; HRMS (FAB+) m/z: [M + H] Calcd for C14H
3
2
4
4
-1
1
3
film, neat) νmax 3361, 2960, 2927, 2868, 1712, 1647, 1595, 1448, 1416, 1316 cm ; H NMR (CDCl , 400 MHz) δ 7.69 (dd, 1H, J = 1.8, 0.5
Hz), 7.35 (dd, 1H, J = 8.0, 1.8 Hz), 7.17 (d, 1H, J = 7.9 Hz), 6.74 (m, 1H), 6.42 (dd, 1H, J = 10.0, 0.7 Hz), 4.73 (s, 2H), 3.02 (m, 1H), 1.96
(
s, 1H), 1.16 (d, 6H, J = 6.6 Hz); 13C{ H} NMR (CD
1
3
OD, 100 MHz) δ 145.5, 141.4, 141.2, 141.0, 137.8, 130.4, 123.2, 122.4, 121.5, 120.1,
15BrO 278.0306; Found 278.0299.
+
5
9.5, 30.8, 23.4; HRMS (FAB+) m/z: [M] Calcd for C14
H
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The Journal of Organic Chemistry
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3 4
Anmindenol A (1). To a solution of alcohol 20 (4.60 mg, 16.5µmol) in THF (300 µL) was added a solution of Pd(PPh ) (3.0 mg, 2.60
µmol) in THF (200 µL) and Me
2
Zn (41.3 µL of a 1.2 M solution in toluene) at ambient temperature. After being refluxed for 2 h, the reaction
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3 4
mixture was quenched with saturated NaHCO and then extracted with EtOAc. The combined organic layers were dried over MgSO and
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc / n-hexane = 1 : 4) to afford 3.4 mg
-1 1
(
96%) of anmindenol A (1) as a yellow oil: FT-IR (thin film, neat) νmax 3370, 2960, 2924, 2867, 1708, 1648, 1607, 1464, 1362 cm ; H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
NMR (CDCl , 400 MHz) δ 7.41 (m, 1H), 7.21 (d, 1H, J = 7.6 Hz), 7.06 (ddd, 1H, J = 7.6, 1.5, 0.7 Hz), 6.70 (d, 1H, J = 1.0 Hz), 6.40 (dd,
1H, J = 9.9, 0.6 Hz), 4.76 (dd, 2H, J = 5.8, 0.9 Hz), 3.04 (m, 1H), 2.40 (s, 3H), 1.16 (d, 6H, J = 6.7 Hz); 13C{ H} NMR (CDCl
1
, 100 MHz)
3
+
δ 144.3, 138.7, 138.5, 138.1, 137.1, 135.2, 127.7, 120.5, 120.0, 118.8, 60.1, 29.7, 23.4, 21.8; HRMS (FAB+) m/z: [M] Calcd for C15
H
18
O
2
14.1358; Found 214.1352.
(E)-5-Bromo-1-(2-methylpropylidene)-1H-indene-3-carbaldehyde (9). To a solution of isobutyraldehyde (22.2 µL, 0.243 mmol) in THF
3.65 mL) was added Bu BOTF (243 µL of a 1.0 M solution in CH Cl ) at ambient temperature. To a reaction mixture was immediately
added a solution of enamine 11 (60.9 mg, 0.243 mmol) in THF (1.21 mL) via cannula. After being stirred for 3 h, the reaction mixture was
quenched with H O and then extracted with EtOAc. The combined organic layers were dried over Na SO and concentrated in vacuo. The
(
2
2
2
2
2
4
residue was purified by flash column chromatography on silica gel (EtOAc / n-hexane = 1 : 7) to afford 48.9 mg (72% yield, E : Z = 8 : 1)
of aldehyde 9 as yellow solid: FT-IR (thin film, neat) νmax 2963, 2928, 2868, 2809, 2713, 1714, 1677, 1638, 1597, 1570, 1538, 1445, 1421,
-1
1
1
391, 1364, 1306 cm ; H NMR (CDCl
3
, 400 MHz) δ 10.12 (s, 1H), 8.25 (d, 1H, J = 1.7 Hz), 7.58 (s, 1H), 7.48 (d, 1H, J = 8.1 Hz), 7.42
(
dd, 1H, J = 8.1, 1.8 Hz), 6.84 (d, 1H, J = 10.3 Hz), 3.16 (m, 1H), 1.23 (d, 6H, J = 6.6 Hz); 13C{ H} NMR (CDCl
1
3
, 100 MHz) δ 188.8, 149.3,
14BrO 277.0223; Found
+
1
2
40.4, 139.6, 139.3, 136.6, 135.6, 129.4, 125.9, 121.8, 120.6, 30.8, 23.2; HRMS (ESI+) m/z: [M + H] Calcd for C14
H
77.0226.
E)-(5-Bromo-1-(2-methylpropylidene)-1H-inden-3-yl)methanol (21). To a solution of aldehyde 9 (98.2 mg, 0.354 mmol) in EtOH (6.00
mL) was added a solution of CeCl ꞏ7H O (186 mg, 0.499 mmol), NaBH (16.0 mg, 0.423 mmol) in EtOH (8.00 mL) dropwise at 0 ℃. After
being stirred for 1 h at the same temperature, the reaction mixture was quenched with 1N HCl and then concentrated in vacuo. The residue
was extracted with EtOAc. The combined organic layers were dried over MgSO and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (EtOAc / n-hexane = 1 : 6 to 1 : 4) to afford 92.7 mg (94%) of alcohol 21 as yellow solid: FT-IR
(
3
2
4
4
-1
1
(
3
thin film, neat) νmax 3348, 2960, 2927, 2868, 1712, 1648, 1596, 1558, 1446, 1416, 1385, 1362, 1323 cm ; H NMR (CDCl , 400 MHz) δ
7.46 (d, 1H, J = 1.7 Hz), 7.42 (d, 1H, J = 8.0 Hz), 7.32 (dd, 1H, J = 8.0, 1.7 Hz), 6.78 (m, 1H) 6.42 (dd, 1H, J = 10.0, 0.3 Hz), 4.72 (d, 2H,
J = 1.8 Hz), 3.02 (m, 1H), 1.96 (s, 1H), 1.16 (d, 6H, 6.6 Hz); 13C{ H} NMR (CDCl
1
3
, 100 MHz) δ 143.4, 142.8, 140.5, 136.4, 136.3, 128.0,
+
1
22.6, 122.4, 120.8, 120.4, 59.7, 29.9, 23.3; HRMS (FAB+) m/z: [M] Calcd for C14
H15BrO 278.0306; Found 278.0300.
3 4
Regioisomer of anmindenol A (7). To a solution of alcohol 21 (31.0 mg, 0.111 mmol) in THF (3.00 mL) was added a solution of Pd(PPh )
(
2
19.0 mg, 16.4 µmol) in THF (2.00 mL) and Me Zn (278 µL of a 1.2 M solution in toluene) at ambient temperature. After being refluxed for
2
3
h, the reaction mixture was quenched with saturated NaHCO and then extracted with EtOAc. The combined organic layers were dried
4
over MgSO and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc / n-hexane = 1 : 4)
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6
-
1 1
3
to afford 23.6 mg (99%) of 7 as a yellow oil: FT-IR (thin film, neat) νmax 3370, 2961, 2867, 1708, 1648, 1610, 1462 cm ; H NMR (CDCl ,
4
00 MHz) δ 7.47 (d, 1H, J = 7.6 Hz), 7.15 (m, 1H), 7.03 (d, 1H, J = 7.6 Hz), 6.74 (m, 1H), 6.36 (d, 1H, J = 9.8 Hz), 4.76 (dd, 2H, J = 5.8,
1
1
.0 Hz), 3.04 (m, 1H), 2.39 (s, 3H), 1.16 (d, 6H, J = 6.6 Hz); 13C{ H} NMR (CDCl
3
, 100 MHz) δ 144.1, 141.2, 138.5, 136.9, 136.9, 135.2,
18O 214.1358; Found 214.1346.
+
126.2, 121.6, 119.9, 118.9, 60.1, 29.8, 23.5, 21.8; HRMS (FAB+) m/z: [M] Calcd for C15
H
(
E)-6-Bromo-1-ethylidene-1H-indene-3-carbaldehyde (22). To a solution of the acetaldehyde (35.4 µL, 0.631 mmol) in THF (9.46 mL)
was added Bu BOTF (631 µL of a 1.0 M solution in CH Cl ) at ambient temperature. To a reaction mixture was immediately added a solution
of enamine 10 (158 mg, 0.631 mmol) in THF (3.16 mL) via cannula. After being stirred for 3 h at the same temperature, the reaction mixture
was quenched with H O and then extracted with EtOAc. The combined organic layers were dried over Na SO and concentrated in vacuo.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
2
2
4
The residue was purified by flash column chromatography on silica gel (EtOAc / n-hexane = 1 : 10) to afford 80.4 mg (57% yield, E : Z =
4.5 : 1) of 22 as yellow solid: FT-IR (thin film, neat) νmax 3402, 3063, 2965, 2927, 2817, 2718, 1714, 1678, 1641, 1597, 1559, 1538, 1452,
-1 1
1
416, 1389 cm ; H NMR (CDCl
3
, 400 MHz) δ 10.12 (s, 1H), 7.94 (d, 1H, J = 8.1 Hz), 7.70 (d, 1H, J = 1.7 Hz), 7.53 (s, 1H), 7.43 (dd, 1H,
J = 8.1, 1.8 Hz), 7.06 (q, 1H, J = 7.5 Hz), 2.31 (d, 3H, J = 7.5 Hz); 13C{ H} NMR (CDCl
1
, 100 MHz) δ 188.9, 140.7, 139.6, 138.6, 138.3,
3
+
1
38.0, 136.4, 130.6, 124.0, 122.6, 120.8, 17.0; HRMS (ESI-) m/z: [M – H] Calcd for C12
H
8
BrO 246.9764; Found 246.9766.
(
E)-5-Bromo-1-ethylidene-1H-indene-3-carbaldehyde (23). Enamine 11 (114 mg, 0.456 mmol) was reacted under the condition described
above for 22. The crude product was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 7) to afford 76.6 mg
(
68% yield, E : Z = 4 : 1) of 23 as yellow solid: FT-IR (thin film, neat) νmax 3401, 3061, 2963, 2929, 2872, 2825, 2718, 1881, 1716, 1679,
-1 1
1
7
641, 1596, 1568, 1541, 1450, 1419, 1379, 1305 cm ; H NMR (CDCl
3
, 500 MHz) δ 10.11 (s, 1H), 8.24 (d, 1H, J = 0.9 Hz), 7.57 (s, 1H),
.44 (d, 1H, J = 8.1 Hz), 7.40 (dd, 1H, J = 8.1, 1.3 Hz), 7.08 (q, 1H, J = 7.5 Hz), 2.31 (d, 3H, J = 7.5 Hz); 13C{ H} NMR (CDCl
1
3
, 125 MHz)
+
δ 188.8, 140.3, 139.8, 139.2, 139.2, 137.8, 135.4, 129.4, 125.9, 121.7, 120.5, 17.0; HRMS (ESI+) m/z: [M + H] Calcd for C12
48.9910; Found 248.9913.
E)-6-Bromo-1-propylidene-1H-indene-3-carbaldehyde (24). To a solution of the propionaldehyde (45.7 µL, 0.636 mmol) in THF (9.50
mL) was added Bu BOTF (636 µL of a 1.0 M solution in CH Cl ) at ambient temperature. To a reaction mixture was immediately added a
solution of enamine 10 (159 mg, 0.636 mmol) in THF (3.20 mL) via cannula. After being stirred for 3 h at the same temperature, the reaction
mixture was quenched with H O and then extracted with EtOAc. The combined organic layers were dried over Na SO and concentrated in
H10BrO
2
(
2
2
2
2
2
4
vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc / n-hexane = 1 : 7) to afford 69.9 mg (42% yield, E :
Z = 4.5 : 1) of 24 as yellow solid: FT-IR (thin film, neat) νmax 2967, 2932, 2873, 2814, 2716, 1715, 1678, 1638, 1595, 1538, 1450, 1415,
-
1 1
1
8
3
391 cm ; H NMR (CDCl , 500 MHz) δ 10.12 (s, 1H), 7.94 (d, 1H, J = 8.2 Hz), 7.74 (d, 1H, J = 1.6 Hz), 7.53 (s, 1H), 7.44 (dd, 1H, J =
.2, 1.7 Hz), 7.01 (t, 1H, J = 8.1 Hz), 2.69 (quintet, 2H, J = 7.6 Hz), 1.24 (t, 3H, J = 7.5 Hz); 13C{ H} NMR (CDCl
1
, 125 MHz) δ 189.0,
10BrO 260.9921;
3
+
144.6, 140.7, 138.7, 138.6, 138.1, 136.4, 130.6, 124.0, 122.7, 120.8, 24.6, 14.1; HRMS (ESI-) m/z: [M – H] Calcd for C13
H
Found 260.9927.
(
E)-5-Bromo-1-propylidene-1H-indene-3-carbaldehyde (25). Enamine 11 (103 mg, 0.412 mmol) was reacted under the condition
described above for 24. The crude product was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 4) to afford
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
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4
5
5
5
5
5
5
5
5
5
5
6
38.2 mg (35% yield, E : Z = 4 : 1) of 25 as yellow solid: FT-IR (thin film, neat) νmax 3062, 2964, 2930, 2873, 2716, 1716, 1678, 1636, 1596,
-
1 1
1
3
564, 1541, 1447, 1421, 1383, 1306 cm ; H NMR (CDCl , 500 MHz) δ 10.12 (s, 1H), 8.25 (d, 1H, J = 1.4 Hz), 7.57 (s, 1H), 7.47 (d, 1H,
J = 8.1 Hz), 7.41 (dd, 1H, J = 8.1, 1.5 Hz), 7.02 (t, 1H, J = 8.1 Hz), 2.70 (quintet, 2H, J = 7.7 Hz), 1.25 (t, 1H, J = 7.5 Hz); 13C{ H} NMR
1
(CDCl
Calcd for C13
E)-6-Bromo-1-(2,2-dimethylpropylidene)-1H-indene-3-carbaldehyde (26). To a solution of the pivalaldehyde (31.0 µL, 0.281 mmol) in
THF (4.22 mL) was added Bu BOTF (281 µL of a 1.0 M solution in CH Cl ) at ambient temperature. To a reaction mixture was immediately
added a solution of enamine 10 (70.3 mg, 0.281 mmol) in THF (1.40 mL) via cannula. After being stirred for 3 h at the same temperature,
the reaction mixture was quenched with H O and then extracted with EtOAc. The combined organic layers were dried over Na SO and
3
, 125 MHz) δ 188.8, 144.3, 140.4, 139.4, 139.3, 138.3, 135.5, 129.5, 125.9, 121.8, 120.6, 24.7, 14.1; HRMS (ESI+) m/z: [M + H]+
H
12BrO 263.0066; Found 263.0051.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
2
2
2
2
4
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc / n-hexane = 1 : 7) to afford 32.0 mg
1
(
39%) of 26 as a yellow oil: H NMR (CDCl
3
, 500 MHz) δ 10.13 (s, 1H), 7.95 (d, 1H, J = 8.1), 7.74 (s, 1H), 7.72 (s, 1H), 7.44 (d, 1H, J =
, 125 MHz) δ 190.4, 155.7, 140.7, 140.3, 140.0, 134.7, 134.1, 129.9, 123.1,
16BrO 291.0379; Found 291.0383.
E)-5-Bromo-1-(2,2-dimethylpropylidene)-1H-indene-3-carbaldehyde (27). Enamine 11 (107 mg, 0.428 mmol) was reacted under the
1
8
1
.1 Hz), 7.06 (s, 1H), 1.39 (s, 9H); 13C{ H} NMR (DMSO-d
6
+
23.0, 119.8, 36.5, 30.6; HRMS (ESI+) m/z: [M + H] Calcd for C15
H
(
condition described above for 26. The crude product was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 8)
1
to afford 71.1 mg (57%) of 27 as yellow solid: H NMR (CDCl
3
, 500 MHz) δ 10.12 (s, 1H), 8.25 (s, 1H), 7.77 (s, 1H), 7.47 (d, 1H, J = 8.1
Hz), 7.41 (d, 1H, J = 8.1 Hz), 7.07 (s, 1H), 1.40 (s, 9H); 13C{ H} NMR (DMSO-d
1
, 125 MHz) δ 190.2, 154.9, 141.3, 139.6, 137.6, 137.1,
16BrO 291.0379; Found 291.0391.
6
+
1
34.3, 128.7, 124.1, 121.5, 120.2, 36.3, 30.6; HRMS (ESI+) m/z: [M + H] Calcd for C15
H
General procedure for preparation of alcohols 28-33: To a solution of the starting aldehyde in EtOH was added a solution of
CeCl ꞏ7H O (1.0 equiv), NaBH (1.0 equiv) in EtOH dropwise at 0 ℃. After being stirred for 1 h at the same temperature, the reaction
mixture was quenched with 1N HCl and then concentrated in vacuo. The residue was extracted with EtOAc. The combined organic layers
were dried over MgSO and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel.
3
2
4
4
(E)-(6-Bromo-1-ethylidene-1H-inden-3-yl)methanol (28). Aldehyde 22 (90.7 mg, 0.364 mmol) afforded 76.2 mg (83%) of 28 as yellow
solid via the above general procedure. Compound 28 was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 3) :
-1
1
3
FT-IR (thin film, neat) νmax 3361, 2912, 2866, 1708, 1650, 1596, 1447, 1416, 1373, 1317 cm ; H NMR (CDCl , 500 MHz) δ 7.67 (d, 1H, J
= 1.1 Hz), 7.36 (dd, 1H, J = 8.0, 1.3 Hz), 7.20 (d, 1H, J = 8.0 Hz), 6.78 (s, 1H), 6.66 (q, 1H, J = 7.3 Hz), 4.75 (d, 2H, J = 2.4 Hz), 2.18 (d,
H, J = 7.3 Hz), 1.65 (t, 1H, J = 5.3 Hz); 13C{ H} NMR (CDCl
1
3
1
3
, 100 MHz) δ 143.8, 139.7, 139.5, 139.4, 129.6, 128.7, 122.4, 121.4, 120.5,
+
19.6, 59.9, 16.1; HRMS (ESI-) m/z: [M – H] Calcd for C12
H10BrO 248.9920; Found 248.9924.
(E)-(5-Bromo-1-ethylidene-1H-inden-3-yl)methanol (29). Aldehyde 23 (212 mg, 0.851 mmol) afforded 186 mg (87%) of 29 as yellow
solid via the above general procedure. Compound 29 was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 3) :
-1
1
3
FT-IR (thin film, neat) νmax 3315, 3070, 2913, 2863, 1871, 1711, 1650, 1596, 1558, 1445, 1417, 1368, 1315 cm ; H NMR (CDCl , 500
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
MHz) δ 7.48 (s, 1H), 7.42 (d, 1H, J = 8.0 Hz), 7.33 (d, 1H, J = 8.0 Hz), 6.82 (s, 1H), 6.67 (q, 1H, J = 7.3 Hz), 4.75 (s, 2H), 2.17 (d, 3H, J =
1
7
.3 Hz), 1.62 (s, 1H); 13C{ H} NMR (CDCl
3
, 100 MHz) δ 143.4, 142.8, 139.4, 136.2, 128.5, 128.1, 122.5, 122.3, 120.8, 120.3, 59.8, 16.1.
(E)-(6-Bromo-1-propylidene-1H-inden-3-yl)methanol (30). Aldehyde 24 (52.4 mg, 0.199 mmol) afforded 40.0 mg (76%) of 30 as yellow
solid via the above general procedure. Compound 30 was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 4) :
-1 1
3
FT-IR (thin film, neat) νmax 3350, 2966, 2931, 2871, 1707, 1648, 1596, 1557, 1449, 1415, 1376, 1341, 1316 cm ; H NMR (CDCl , 400
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz) δ 7.69 (d, 1H, J = 1.8 Hz), 7.37 (dd, 1H, J = 8.0, 1.7 Hz), 7.20 (d, 1H, J = 8.0 Hz), 6.76 (m, 1H), 6.60 (t, 1H, J = 7.9 Hz), 4.76 (d, 2H,
J = 4.0 Hz), 2.57 (quintet, 2H, J = 7.6 Hz), 1.62 (t, 1H, J = 5.9 Hz), 1.18 (t, 3H, J = 7.5 Hz); 13C{ H} NMR (CDCl
1
, 100 MHz) δ 143.9,
12BrO 263.0077;
3
+
1
39.8, 139.6, 138.0, 135.6, 129.7, 122.6, 121.6, 120.5, 119.6, 59.9, 23.8, 14.4; HRMS (ESI-) m/z: [M – H] Calcd for C13
H
Found 263.0076.
(E)-(5-Bromo-1-propylidene-1H-inden-3-yl)methanol (31). Aldehyde 25 (50.7 mg, 0.193 mmol) afforded 42.0 mg (82%) of 31 as yellow
solid via the above general procedure. Compound 31 was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 5) :
-1 1
3
FT-IR (thin film, neat) νmax 3347, 3327, 2966, 2931, 2872, 1711, 1648, 1596, 1559, 1446, 1416, 1378, 1324 cm ; H NMR (CDCl , 500
MHz) δ 7.48 (d, 1H, J = 1.5 Hz), 7.43 (d, 1H, J = 8.0 Hz), 7.34 (dd, 1H, J = 8.0, 1.6 Hz), 6.80 (s, 1H), 6.61 (t, 1H, J = 7.9 Hz), 4.75 (d, 2H,
J = 4.2 Hz), 2.57 (quintet, 2H, J = 7.6 Hz), 1.61 (t, 1H, J = 5.1 Hz), 1.18 (t, 3H, J = 7.5 Hz); 13C{ H} NMR (CDCl
1
, 125 MHz) δ 143.4,
3
1
42.8, 137.9, 136.3, 135.4, 128.1, 122.5, 122.5, 120.8, 120.4, 59.8, 23.8, 14.4.
E)-(6-Bromo-1-(2,2-dimethylpropylidene)-1H-inden-3-yl)methanol (32). Aldehyde 26 (18.1 mg, 0.062 mmol) afforded 15.6 mg (86%)
of 32 as yellow solid via the above general procedure. Compound 32 was purified by flash column chromatography on silica gel (EtOAc :
(
-
1
n-hexane = 1 : 5) : FT-IR (thin film, neat) νmax 3305, 2957, 2929, 2903, 2866, 1636, 1587, 1556, 1451, 1415, 1396, 1363, 1346, 1317 cm ;
1H NMR (CDCl
, 400 MHz) δ 7.69 (d, 1H, J = 1.7 Hz), 7.36 (dd, 1H, J = 8.0, 1.7 Hz), 7.19 (d, 1H, J = 8.0 Hz), 6.93(m, 1H), 6.66 (s, 1H),
3
4
1
.75 (s, 1H), 1.73 (s, 1H), 1.33 (s, 9H); 13C{ H} NMR (CDCl
1
3
, 100 MHz) δ 144.4, 144.2, 141.1, 138.3, 135.1, 129.6, 122.3, 122.3, 120.3,
19.6, 59.9, 35.4, 31.4.
E)-(5-Bromo-1-(2,2-dimethylpropylidene)-1H-inden-3-yl)methanol (33). Aldehyde 27 (32.5 mg, 0.111 mmol) afforded 26.4 mg (81%)
of 33 as yellow solid via the above general procedure. Compound 33 was purified by flash column chromatography on silica gel (EtOAc :
(
-
1
n-hexane = 1 : 4) : FT-IR (thin film, neat) νmax 3304, 2957, 2930, 2903, 2865, 1864, 1713, 1636, 1594, 1558, 1447, 1417, 1362, 1316 cm ;
1H NMR (CDCl
, 400 MHz) δ 7.47 (d, 1H, J = 1.7 Hz), 7.43 (d, 1H, J = 8.1 Hz), 7.33 (dd, 1H, J = 8.1, 1.7 Hz), 6.97 (m, 1H), 6.67 (s, 1H),
3
4.74 (s, 2H), 1.71 (s, 1H), 1.33 (s, 9H); 13C{ H} NMR (CDCl
1
3
, 100 MHz) δ 144.0, 144.0, 141.4, 137.8, 135.1, 128.0, 123.2, 122.3, 120.7,
1
20.1, 59.8, 35.4, 31.5.
General procedure for preparation of 34-39: To a solution of the starting alcohol in THF was added a solution of Pd(PPh
3
)
4
(0.3 equiv)
Zn (3.0 equiv) at ambient temperature. After being refluxed for 2 h, the reaction mixture was quenched with saturated
3 4
and then extracted with EtOAc. The combined organic layers were dried over MgSO and concentrated in vacuo. The residue was
in THF and Me
2
NaHCO
purified by flash column chromatography on silica gel.
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(E)-(1-Ethylidene-6-methyl-1H-inden-3-yl)methanol (34). Alcohol 28 (76.2 mg, 0.303 mmol) afforded 41.2 mg (73%) of 34 as yellow
solid via the above general procedure. Compound 34 was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 4) :
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
1
3
FT-IR (thin film, neat) νmax 3303, 3007, 2973, 2915, 2856, 1651, 1610, 1590, 1564, 1439, 1370, 1321 cm ; H NMR (CDCl , 500 MHz) δ
7.39 (s, 1H), 7.21 (d, 1H, J = 7.6 Hz), 7.06 (d, 1H, J = 7.5 Hz), 6.72 (s, 1H), 6.63 (q, 1H, J = 7.3 Hz), 4.76 (d, 2H, J = 3.9 Hz), 2.40 (s, 3H),
2
1
.16 (d, 3H, J = 7.3 Hz), 1.57 (m, 1H); 13C{ H} NMR (CDCl
1
3
, 100 MHz) δ 144.3, 140.3, 138.4, 137.9, 135.2, 127.7, 126.4, 120.2, 119.9,
15O 187.1117; Found 187.1111.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
18.8, 60.1, 21.8, 15.9; HRMS (ESI+) m/z: [M + H] Calcd for C13
H
(E)-(1-Ethylidene-5-methyl-1H-inden-3-yl)methanol (35). Alcohol 29 (186.2 mg, 0.741 mmol) afforded 118 mg (85%) of 35 as yellow
solid via the above general procedure. Compound 35 was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 4) :
-1 1
3
FT-IR (thin film, neat) νmax 3379, 3047, 2978, 2930, 2868, 1708, 1650, 1610, 1576, 1450, 1373, 1320 cm ; H NMR (CDCl , 500 MHz) δ
7.45 (d, 1H, J = 7.7 Hz), 7.16 (s, 1H), 7.03 (d, 1H, J = 7.6 Hz), 6.77 (s, 1H), 6.60 (q, 1H, J = 7.3 Hz), 4.76 (d, 2H, J = 2.8), 2.40 (s, 3H), 2.16
1
(
d, 3H, J = 7.4 Hz), 1.59 (t, 1H, J = 5.3 Hz); 13C{ H} NMR (CDCl
3
, 125 MHz) δ 144.0, 141.1, 139.9, 136.7, 134.9, 126.2, 126.1, 121.2,
15O 187.1117; Found 187.1112.
+
1
19.8, 118.7, 60.0, 21.7, 15.8; HRMS (ESI+) m/z: [M + H] Calcd for C13
H
(
E)-(6-Methyl-1-propylidene-1H-inden-3-yl)methanol (36). Alcohol 30 (65.5 mg, 0.247 mmol) afforded 43.2 mg (87%) of 36 as yellow
solid via the above general procedure. Compound 36 was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 5) :
-1 1
FT-IR (thin film, neat) νmax 3322, 2966, 2931, 2873, 1706, 1648, 1608, 1456, 1377, 1324 cm ; H NMR (CDCl
3
, 500 MHz) δ 7.41 (s, 1H),
7
3
1
.21 (d, 1H, J = 7.6 Hz), 7.06 (d, 1H, J = 7.6 Hz), 6.70 (s, 1H), 6.57 (t, 1H, J = 7.8 Hz), 4.76 (s, 2H), 2.56 (quintet, 2H, J = 7.6 Hz), 2.40 (s,
H), 1.58 (s, 1H), 1.17 (t, 3H, J = 7.5 Hz); 13C{ H} NMR (CDCl
1
, 125 MHz) δ 144.4, 138.7, 138.5, 138.0, 135.2, 133.4, 127.7, 120.4, 120.0,
17O 201.1274; Found 201.1266.
3
+
18.8, 60.1, 23.6, 21.8, 14.5; HRMS (ESI+) m/z: [M + H] Calcd for C14
H
(
E)-(5-Methyl-1-propylidene-1H-inden-3-yl)methanol (37). Alcohol 31 (48.0 mg, 0.181 mmol) afforded 34.0 mg (94%) of 37 as a yellow
oil via the above general procedure. Compound 37 was purified by flash column chromatography on silica gel (EtOAc : n-hexane = 1 : 5) :
-1 1
FT-IR (thin film, neat) νmax 3342, 2966, 2930, 2872, 2732, 1709, 1648, 1611, 1570, 1458, 1378, 1326 cm ; H NMR (CDCl
3
, 500 MHz) δ
7
.47 (d, 1H, J = 7.6 Hz), 7.16 (s, 1H), 7.03 (d, 1H, J = 7.6 Hz), 6.74 (s, 1H), 6.54 (t, 1H, J = 7.8 Hz), 4.76 (d, 2H, J = 5.0 Hz), 2.56 (quintet,
2H, J = 7.6 Hz), 2.40 (s, 3H), 1.58 (t, 1H, J = 5.6 Hz), 1.17 (t, 3H, J = 7.5 Hz); 13C{ H} NMR (CDCl
1
, 125 MHz) δ 144.2, 141.2, 138.6,
17O 201.1274; Found
3
+
1
2
36.9, 135.1, 133.3, 126.2, 121.5, 119.9, 118.9, 60.1, 23.6, 21.8, 14.6; HRMS (ESI+) m/z: [M + H] Calcd for C14
H
01.1265.
(E)-(1-(2,2-Dimethylpropylidene)-6-methyl-1H-inden-3-yl)methanol (38). Alcohol 32 (10.3 mg, 0.035 mmol) afforded 7.3 mg (96%) of
8 as yellow solid via the above general procedure. Compound 38 was purified by flash column chromatography on silica gel (EtOAc : n-
3
-1
1
hexane = 1 : 5) : FT-IR (thin film, neat) νmax 3313, 2956, 2926, 2864, 1715, 1634, 1561, 1461, 1394, 1376, 1363, 1345, 1322 cm ; H NMR
(CDCl
3
, 400 MHz) δ 7.40 (s, 1H), 7.21 (d, 1H, J = 7.6 Hz), 7.06 (d, 1H, J = 7.6 Hz), 6.87 (m, 1H), 6.64 (s, 1H), 4.76 (s, 2H), 2.41 (s, 3H),
1
1
.33 (s, 9H); 13C{ H} NMR (CDCl
3
, 100 MHz) δ 145.0, 142.1, 139.5, 137.1, 135.9, 135.2, 127.6, 121.2, 119.7, 118.7, 60.2, 35.1, 31.6, 21.8;
+
HRMS (ESI+) m/z: [M + H] Calcd for C16
H21O 229.1587; Found 229.1583.
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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5
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5
5
5
5
6
(E)-(1-(2,2-Dimethylpropylidene)-5-methyl-1H-inden-3-yl)methanol (39). Alcohol 33 (6.0 mg, 0.020 mmol) afforded 4.2 mg (97%) of 39
as a yellow oil via the above general procedure. Compound 39 was purified by flash column chromatography on silica gel (EtOAc : n-hexane
-1
1
=
1 : 5) : FT-IR (thin film, neat) νmax 3312, 2957, 2927, 2904, 2865, 1636, 1611, 1595, 1559, 1461, 1396, 1377, 1363, 1322 cm ; H NMR
(CDCl
3
, 400 MHz) δ 7.46 (d, 1H, J = 7.7 Hz), 7.16 (m, 1H), 7.04 (m, 1H), 6.92 (d, 1H, J = 1.0 Hz), 6.62 (s, 1H), 4.77 (s, 2H), 2.40 (s, 3H),
1
3
.65 (s, 1H), 1.33 (s, 9H); 13C{ H} NMR (CDCl
1
3
, 100 MHz) δ 144.8, 142.0, 139.8, 136.8, 136.6, 135.8, 126.2, 122.2, 119.7, 118.6, 60.1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
5.1, 31.6, 21.7; HRMS (ESI+) m/z: [M + H] Calcd for C16H21O 229.1587; Found 229.1581.
Molecular Docking Simulations
The 3D ligand structure was prepared and minimized by MM2 using Chem 3D Pro 12.0 software. The structure of iNOS was downloaded
from the RCSB protein data bank (PDB ID: 1M8D). Chain B and all non-standard residues of the protein were removed by using UCSF
1
8
1
9
C
h
i
m
e
r
a
1
.
1
1
.
R
e
s
u
l
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Molecular docking analysis were performed using AutoDock Tools 1.5.6. and AutoDock 4.2.620 and the visual investigation and hydrogen
bonding analysis were accomplished using UCSF Chimera 1.11.
Nitric Oxide Detection
5
2
RAW 264.7 cells (American Type Culture Collection, Manassas, VA, USA) were plated at a density of 1.5  10 cells/cm on 48 well
plates. Cells were stabilized for 24 h in Dulbecco's Modified Eagle Medium with high glucose (Gibco BRL, Grand Island, NY, USA)
2
containing 10% Fetal Bovine Serum (Gibco BRL) at 37 °C in a humidified incubator with 5% CO followed by media replacement. Cells
were treated with 1 μg/mL LPS (Invivogen, San Diego, California, USA) for 24 h in the presence or absence of chemical compounds in
concentrations ranging from 6.25 to 100 µM (2-fold serial dilution). NO was measured from culture supernatant using a Griess reagent
(Promega, Madison, Wisconsin, USA) according to the manufacturer’s instruction. Absorbance at 535 nm was measured using a microplate
reader (Bio-Tek, Winooski, VT, USA).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1
13
1
Copies of the H and C{ H} NMR spectra for all compounds, natural and synthetic compound comparison tables and computational docking
analysis. (PDF)
ACKNOWLEDGEMENTS
This research was supported by a grant from the Health Fellowship Foundation.
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