A short and efficient total synthesis of ficuseptamines A and B

Article abstract of DOI:10.3390/molecules23081865

A rapid and efficient total synthesis of ficuseptamines A and B by a cross metathesis strategy is described.

Full text of DOI:10.3390/molecules23081865

molecules
Article
A Short and Efficient Total Synthesis of
Ficuseptamines A and B
Hani Mutlak A. Hassan
King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia;
hmahassan@kau.edu.sa
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 11 July 2018; Accepted: 23 July 2018; Published: 26 July 2018
Abstract: A rapid and efficient total synthesis of ficuseptamines A and B by a cross metathesis
strategy is described.
Keywords: ficuseptamines A and B; cross metathesis; total synthesis
1. Introduction
Ficuseptamines A, B, and C (1a
Shin-ya and co-workers in 2009 (Figure 1) [
–
c
) were isolated from the leaves of Ficus septica and reported by
]. Ficuseptamines A and B possess an aminocaprophenone
1
structure, while ficuseptamine C contains a pyrrolidine moiety in its structure. After their isolation,
these alkaloids were evaluated for cytotoxicity against HeLa (human cervical carcinoma) and
ACC-MESO-1 (malignant pleural mesothelioma) cancer cell lines. Ficuseptamine A displayed IC50
values of 57
showed better cytotoxicity against the same cell lines (IC50: 23
while ficuseptamine C showed no activity against either cell line. The aryl ketone motif, which is
present in ficuseptamines A and B, is frequently found in natural products [ ] and biologically active
molecules [ ]. We were interested in devising a novel strategy targeting ficuseptamines A and B for
µM and 160
µM against HeLa and ACC-MESO-1 cells lines, respectively. Ficuseptamine B
µ
M for HeLa; 72 M for ACC-MESO-1),
µ
2,3
4
their first total synthesis. We thought that designing an efficient and facile strategy for their rapid total
synthesis would offer the possibility of synthesizing ficuseptamine A and B analogues for biological
evaluation, given the commercial availability of a wide variety of functionalized terminal olefins, which
could be utilized in library design and synthesis. In addition, the incorporation of fluorine atom(s)
into ficuseptamines A and B to synthesize fluorinated analogues could also significantly improve their
biological activity [5,6].
Figure 1. Structures of ficuseptamine A, B, and C (1a–c).
Olefin metathesis is one of the most useful carbon–carbon bond-forming reactions, and it has
found tremendous use in organic chemistry for the construction of a myriad of organic molecules [7–10].
Molecules 2018, 23, 1865; doi:10.3390/molecules23081865
www.mdpi.com/journal/molecules

Molecules 2018, 23, 1865
2 of 9
This highly powerful transformation has also been elegantly utilized in the total synthesis of numerous
natural products [11 12]. Olefin metathesis catalysts that promote this transformation are displayed
,
in Figure 2. Cross metathesis (CM) is one of the most popular transformations for connecting two
independent olefins together to form a more complex olefinic product, which could require several
steps to synthesize if a different methodology was employed. Although ring-closing metathesis
(RCM) has found extensive use in the total synthesis of numerous natural products, CM has become
increasingly popular in the field of total synthesis [13–15], particularly after the discovery of Z-selective
olefin metathesis catalysts [16]. As part of our interest in the power of olefin metathesis to facilitate
useful transformations [17], we report herein a highly efficient methodology for the total synthesis of
ficuseptamines A and B, utilizing a cross metathesis approach.
Figure 2. Ruthenium-based olefin metathesis catalysts.
2. Results and Discussion
A retrosynthetic analysis of ficuseptamines A and B is depicted in Scheme 1. We commenced
the synthetic work by first targeting ficuseptamine A for total synthesis. Aryl ketone 9a was
prepared in two sequential steps from commercially available alcohol 11 via halogenation and
dehydrohalogenation reactions (Scheme 2).
Scheme 1. Retrosynthetic analysis of ficuseptamines A and B.
Thus, primary alcohol 11 was transformed into its bromo counterpart (i.e., 12), under the influence
of hydrobromic acid to furnish 12 in high yield (93%). Subsequent treatment of the brominated

Molecules 2018, 23, 1865
3 of 9
product 12 with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) delivered CM precursor 9a in 69% yield
through dehydrobromination.
Scheme 2. Bromination of 11 followed by dehydrobromination with DBU to give CM precursor 9a.
Next, we explored the key CM reaction between 9a and N,N-dimethyl-4-pentene-1-amine 10 to
afford the
catalyst (5 mol %) with CH2Cl2 as a solvent to afford CM product 8a in 22% yield (entry 1, Table 1).
Increasing the Grubbs I catalyst loading (10 mol %) provided 8a in a disappointing 15% yield (entry
2, Table 1). We then turned our attention to Grubbs II catalyst , which gave the CM product 8a in
α,β-unsaturated CM product 8a. We initially performed the CM reaction using Grubbs I
4
4
5
modest 37 and 41% yields using 5 mol % and 10 mol % catalyst loading in CH2Cl2, respectively (entries
3 and 4, Table 1). Switching the solvent from CH2Cl2 to toluene and performing the reaction with
Grubbs II catalyst 5 (10 mol %) at 80 ◦C improved the yield to 47% (entry 5, Table 1).
Table 1. Optimization of the CM reaction.
◦
E
Substrate 9a (equiv.) Substrate 10 (equiv.)
Catalyst (Loading)
Solvent
T ( C)
Yield % a
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
2
G I 4 (5 mol %)
G I 4 (10 mol %)
G II 5 (5 mol %)
G II 5 (10 mol %)
G II 5 (10 mol %)
H-G II 7 (5 mol %)
H-G II 7 (10 mol %)
H-G II 7 (10 mol %)
H-G II 7 (10 mol %)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
40
40
40
40
80
40
40
80
40
22
15
37
41
47
68
76
52
42
a
All reactions were performed using 9a (2 mmol), 10 (1 mmol), solvent, and temperature for 10 h, except entry 9, in
which the reaction was carried out using 9a (1 mmol) and 10 (2 mmol). E = entry.
A report by Grubbs and co-workers described how the presence of the phosphine ligand (PCy3)
in olefin metathesis catalysts can attack the carbine through its dissociation from the metal complex
via decomposition [18]. This fact turned our attention to Hoveyda-Grubbs II
7, which lacks the PCy3
ligand. Pleasingly, the use of Hoveyda-Grubbs II (5 mol %) increased the yield significantly, to afford
7

Molecules 2018, 23, 1865
4 of 9
8a in a 68% yield using CH2Cl2 as the solvent (entry 6, Table 1). Treating 9a and 10 with an increased
Hoveyda-Grubbs II loading (10 mol %) in CH2Cl2 provided 8a in an excellent 76% yield (entry 7,
7
Table 1). In contrast, increasing the temperature to 80 ◦C and changing the solvent from CH2Cl2 to
toluene diminished the yield to 52% (compare entry 7 vs. 8, Table 1). The double bond geometry of the
CM product 8a was identified as the (E)-configured isomer, indicating that CM proceeded selectively
to give the thermodynamically stable (E)-isomer exclusively. A change in molar ratio of the coupling
partners 9a and 10, and performing the reaction using 10 mol % of Hoveyda-Grubbs II 7 in CH2Cl2,
resulted in a reduction of the yield to 42%, with formation of the homodimer of 10 as a competing
side-product (entry 9, Table 1). Grubbs and co-workers categorized olefin metathesis substrates as
Type I, Type II, Type III, or Type IV [19]. According to Grubbs’ selectivity model, terminal olefin 10 is
a Type I olefin substrate, which usually undergoes fast homodimerization, while olefin 9a is a Type
II olefin, which undergoes slow homodimerization. Thus, such a change in the ratio of the coupling
partners 9a and 10 has promoted homodimerization of 10 to occur.
With synthesis of compound 8a accomplished through CM, saturation of the newly formed
double bond (Pd/C, H2, CH3OH, r.t., 16 h) proceeded smoothly to provide ficuseptamine A in 62%
isolated yield. We then envisioned performing one-pot CM/hydrogenation reactions for the synthesis
of ficuseptamine A without isolation of the unsaturated CM product 8a. In fact, a literature screen
revealed that such a CM/hydrogenation maneuver had been reported by Cossy and co-workers in
their total synthesis of (-)-centrolobine [20]. One-pot sequential reactions are increasingly being utilized
in organic synthesis to accelerate the synthesis of target molecules [21]. Motivated by Cossy’s work,
we subjected aryl ketone 9a and terminal olefin 10 to our optimized CM conditions, followed by
hydrogenation in a one-pot fashion, to afford ficuspetamine A in 65% yield directly from the starting
materials 9a and 10 (Scheme 3). This one-pot CM/hydrogenation sequence proved to be fruitful, thus
improving the efficiency of the synthesis of ficuseptamine A.
Scheme 3. Improving ficuseptamine A (1a) synthesis by a one-pot CM/hydrogentation sequence.
With ficuseptamine A (1a) synthesis accomplished, we moved forward to target ficuseptamine
B (1b). We imagined employing a dual ethenolysis [22] and CM approach for its total synthesis.
We envisaged that aryl ketone 9b, which is a different regioisomer to aryl ketone 9a, could be achieved
by ethenolysis of the Claisen-Schmidt product 17, using a suitable olefin metathesis catalyst to dissect
the internal alkene of 17 to give the desired terminal olefin 9b (Scheme 4). We also thought that this
method would allow access to styrene derivatives (e.g., compounds such as 18), which are important
building blocks in organic chemistry.

Molecules 2018, 23, 1865
5 of 9
Scheme 4. Synthetic plan for the synthesis of aryl ketone 9b via a Claisen-Schmidt reaction followed
by ethenolysis.
We began the synthesis towards ficuseptamine B by first preparing the Claisen-Schmidt product 17
.
We initially combined 3-hydroxy-4-methoxyacetophenone 15 and 3-hydroxy-4-methoxybenzaldehyde
16 under aqueous NaOH conditions in EtOH, which provided chalcone 17 in 46% yield (entry 1,
Table 2). The use of cesium carbonate (Cs2CO3) as the base in EtOH led to 17 in 41% yield (entry 2,
Table 2). However, efficient synthesis of 17 was achieved using SOCl2/EtOH as a catalyst system (acid
catalysis) [23] to afford 17 in 83% yield (entry 3, Table 2).
a
Table 2. Synthesis of Claisen-Schmidt product 17 under various catalysis conditions. All reactions
◦
were carried out using ketone 15 (1 equiv.), aldehyde 16 (1 equiv.), and catalyst in EtOH at 23 C.
b
NaOH (10% w/v).
Entry
Catalyst
Equivalent
Time (h)
Yield (%) a
NaOH b
Cs2CO3
SOCl2
1
2
3
2
2
1
16
16
4
46
41
83
With the Claisen-Schmidt product 17 in hand, we employed the conditions reported by Diver
and co-workers with slight modification for its ethenolysis [24]. Exposing 17 to ethylene gas (60 psi
◦
pressure) with Hoveyda-Grubbs II
7
and using 1,2-DCE (1,2-dichloroethane) as a solvent at 40 C
delivered aryl ketone 9b in 71% yield (Scheme 5).
Scheme 5. Ethenolysis of chalcone 17 to deliver aryl ketone 9b.

Molecules 2018, 23, 1865
6 of 9
To the best of our knowledge, this is the first time ethenolysis has been applied to cleave a chalcone
compound (i.e., structure such as 17). Importantly, no isomerization [25] of the double bond is possible,
given the structure of chalcone 17, which lacks any methylene groups adjacent to the double bond.
Having accomplished the synthesis of aryl ketone 9a through ethenolysis, we employed the one-pot,
two-step CM/hydrogenation protocol previously used in ficuseptamine A synthesis. Gratifyingly,
subjecting aryl ketone 9b and terminal olefin 10 to our optimized CM conditions (Hoveyda-Grubbs
II
yield (Scheme 6).
7
(10 mol %), CH2Cl2, 40 ◦C) followed by one-pot hydrogenation delivered ficuseptamine B in 69%
Scheme 6. Synthesis of ficuseptamine B (1b) by one-pot CM/hydrogenation sequence.
The spectroscopic data of the synthetic ficuseptamines A and B were identical to those reported by
Shin-ya and co-workers [ ]. The described chemistry for the synthesis of ficuseptamines A and B through
1
CM allows the generation of various analogues of these natural products in a straightforward manner,
which could have other biological activities, such as potential ligands for the 5-HT7 receptor [26].
3. Conclusions
In summary, we have reported a highly efficient methodology for the first total synthesis of
ficuseptamines A and B through a CM strategy. A sequential one-pot, two-step CM/hydrogenation
procedure was employed to expediently accomplish their total synthesis.
4. Materials and Methods
4.1. General Chemistry Experimental
Chemical reactions were performed in over-dried glassware under nitrogen and anhydrous
conditions, unless otherwise stated. Reactions were magnetically stirred using a Teflon-coated stir
bar and monitored by pre-coated silica gel aluminum plates (0.25 mm thickness) with a fluorescent
indicator (254 nm), using UV light as the visualizing agent. Alternatively, oxidative staining using
an aqueous basic solution of KMnO4 and heat was carried out for visualization. Silica gel (60 Å,
200–425 mesh) was used for flash column chromatography. Nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker 400 MHz spectrometer (Bruker, Billerica, MA, USA) in acetone-d6,
CDCl3, or DMSO-d6 as the solvent. Chemical shifts are reported in parts per million (ppm) with
reference to the hydrogenated residues of the deuterated solvent as the internal standard. Coupling
constants (J values) are recorded in Hertz (Hz), and signal patterns are expressed as follows: singlet (s),
doublet (d), dd (doublet of doublets), triplet (t), quintet (quint), and multiplet (m). Elemental analyses
were performed on a 2400 Perkin Elmer Series II analyzer (PerkinElmer, Inc., Waltham, MA, USA).

Molecules 2018, 23, 1865
7 of 9
High-resolution mass spectrometry was conducted using a Micromass Q-ToF mass spectrometer
(Waters Corporation, Milford, MA, USA).
4.2. Experimental Procedures for Chemical Synthesis and Characterization Data of Compounds
4.2.1. Synthesis of 1-(4-Hydroxy-3-methoxyphenyl)prop-2-en-1-one (9a)
A round-bottom flask equipped with a magnetic stir bar was charged with 3-hydroxy-1-(4-
hydroxy-3-methoxyphenyl)propan-1-one 11 (2.52 g, 12.8 mmol) and conc. HBr (30 mL) was then
◦
added. The reaction mixture was then stirred at 95 C for 2 h. The reaction mixture was cooled
to room temperature and the resulting precipitate was filtered, washed with ice-cold H2O, and
dried to afford 3-bromo-1-(4-hydroxy-3-methoxyphenyl)propan-1-one 12 (quantitative yield, 3.09 g,
93%) as a white solid, which was judged to be of good purity by TLC analysis and mass
spectrometry, and carried forward in crude form to the next step. To a stirred solution of
3-bromo-1-(4-hydroxy-3-methoxyphenyl)propan-1-one 12 (3 g, 11.6 mmol) in dry benzene (50 mL),
was added, dropwise, a solution of DBU (2.08 mL, 13.9 mmol) in dry benzene (5 mL). A condenser was
◦
attached, and the reaction mixture was stirred at 70 C for 3 h. The solvent was removed in vacuo, and
the crude product was extracted with EtOAc (three times). The combined organic layers were washed
with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then
1
purified by silica gel column chromatography to afford 9a (1.42 g, 69%) as a white solid. H-NMR
(400 MHz, acetone-d6):
δ 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 17.0, 10.4 Hz,
1H), 6.95 (d, J = 8.4 Hz, 1H), 6.36 (dd, J = 17.0, 2.0 Hz, 1H), 5.86 (dd, J = 10.4, 2.0 Hz, 1H), 3.93 (s, 3H);
HRMS calcd. for C10H11O3 [M + H]+ 179.0708, found 179.0713. Anal. calcd. for C10H10O3: C, 67.41; H,
5.66. Found: C, 67.31; H, 5.55.
4.2.2. Synthesis of Ficuseptamine A by a One-Pot Cross Metathesis/Hydrogenation Procedure (1a)
To a stirred solution of aryl ketone 9a (315 mg, 1.77 mmol) and N,N-dimethyl-4- pentene-1-amine 10
(100 mg, 0.885 mmol) in dry and degassed CH2Cl2 (5 mL), was added Hoveyda-Grubbs second
generation catalyst 7 (55 mg, 0.0885 mmol, 10 mol %). The reaction mixture was then deoxygentated
by performing vacuum/N2 cycles four times and stirred at 40 ◦C for 10 h. After the completion of the
reaction, Pd/C (10 wt %) was added, and the N2 atmosphere was substituted with H2 by performing
vacuum/H2 cycles four times. The reaction mixture was then stirred under a double layer H2 balloon
at 23 ◦C for 16 h. The Pd/C catalyst was removed by filtration through a pad of Celite®, followed by
washing of the filter cake with CH2Cl2 (10 mL), and the filtrate was evaporated in vacuo. The crude
product was purified directly by silica gel column chromatography to afford ficuseptamine A (1a
)
as a white solid (153 mg, 65%). Spectroscopic data for synthetic ficuseptamine A matched literature
1
data of natural ficuseptamine A [
1
]. H-NMR (400 MHz, acetone-d6):
δ
7.57 (dd, J = 8.4, 2.0 Hz, 1H),
7.54 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.93 (t, J = 7.2 Hz, 2H), 2.21 (t, J = 7.2 Hz,
2H), 2.13 (s, 2 3H), 1.68 (quint, J = 7.2 Hz, 2H), 1.47 (quint, J = 7.2 Hz, 2H), 1.37 (quint, J = 7.2 Hz,
2H); 13C-NMR (100 MHz, acetone-d6)
×
δ
: 198.6, 152.1, 148.3, 130.6, 123.8, 115.3, 111.5, 60.2, 56.2, 45.6,
38.4, 28.3, 27.8, 25.3; HRMS calcd. for C15H24NO3 [M + H]+ 266.1756, found 266.1767. Anal. calcd. for
C15H23NO3: C, 67.90; H, 8.74; N, 5.18. Found: C, 67.76; H, 8.70; N, 5.07.
4.2.3. Synthesis of (2E)-1,3-Bis(3-Hydroxy-4-methoxyphenyl)prop-2-en-1-one (17)
Compound 17 was synthesized using a previously reported method, except that it required
purification [23]. To a stirred solution of 3-hydroxy-4-methoxyacetophenone 15 (1.20 g, 7.89 mmol)
and 3-hydroxy-4-methoxybenzaldehyde 16 (1.31 g, 7.89 mmol) in absolute EtOH (5 mL), was added
thionyl chloride (0.58 mL, 7.89 mmol) dropwise and the reaction mixture was stirred at 23 ◦C for 4 h.
The reaction mixture was precipitated by the addition of H2O (~5 mL), and the resulting precipitate
was filtered, washed with ice-cold H2O, and ice-cold EtOH. After the crude product was allowed to air
dry, purification by recrystallization from EtOH afforded 17 (1.97 g, 83%) as a yellow solid. Analytical

Molecules 2018, 23, 1865
8 of 9
1
data were in accordance with literature data [27]. H-NMR (400 MHz, CDCl3):
δ
7.72 (d, J = 16.2 Hz,
1H), 7.63-7.60 (m, 2H), 7.40 (d, J = 16.2 Hz, 1H), 7.28-7.27 (m, 1H), 7.12 (dd, J = 10.4, 2.0 Hz, 1H), 6.93
(d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
δ
188.5, 152.7, 150.7, 147.0, 146.9, 144.3, 131.3, 128.1, 122.8, 122.4, 119.8, 115.2, 114.8, 112.5, 111.8, 56.3,
56.2; HRMS calcd. for C17H17O5 [M + H]+ 301.1076, found 301.1065. Anal. calcd. for C17H16O5: C,
67.99; H, 5.37. Found: C, 67.80; H, 5.41.
4.2.4. Synthesis of 1-(3-Hydroxy-4-methoxyphenyl)prop-2-en-1-one (9b)
Compound 9b was synthesized using the slightly modified reaction conditions of Diver et al. [24].
To an inert and oven-dried high-pressure flask, was added compound 17 (800 mg, 2.67 mmol), dry
and degassed 1,2-dichloroethane (35 mL), and Hoveyda-Grubbs second generation catalyst 7 (42 mg,
0.067 mmol). The flask was purged with ethylene for 5 min, pressurized to 60 psi, and stirred at 40 ◦C
for 12 h, after which time TLC analysis indicated consumption of the internal alkene 17. The pressure
was then slowly vented, and the solvent was evaporated in vacuo. The crude product was then purified
1
directly by silica gel column chromatography, to afford 9b (337 mg, 71%) as a white solid. H-NMR
(400 MHz, acetone-d6):
δ 7.59 (dd, J = 8.4, 2.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 17.0, 10.4 Hz,
1H), 7.07 (d, J = 8.4 Hz, 1H), 6.33 (dd, J = 17.0, 2.0 Hz, 1H), 5.84 (dd, J = 10.4, 2.0 Hz, 1H), 3.94 (s, 3H);
13C NMR (100 MHz, acetone-d6):
δ 188.9, 153.0, 147.7, 133.2, 131.8 128.9, 122.8, 115.7, 111.8, 56.5; HRMS
calcd. for C10H11O3 [M + H]+ 179.0708, found 179.0719. Anal. calcd. for C10H10O3: C, 67.41; H, 5.66.
Found: C, 67.35; H, 5.59.
4.2.5. Synthesis of Ficuseptamine B by a One-Pot Cross Metathesis/Hydrogenation Procedure (1b)
The experimental procedure for the synthesis of ficuseptamine A (1a) was followed, except that aryl
ketone 9b was used as the cross metathesis partner with N,N-dimethyl-4-pentene-1-amine 10 to afford
ficuspetamine B (1b) (162 mg, 69%) as a white solid. Spectroscopic data for synthetic ficuseptamine B
1
matched literature data of natural ficuseptamine B [
1
]. H-NMR (400 MHz, acetone-d6):
δ
7.52 (dd, J = 8.5,
2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H), 2.24
(t, J = 7.2 Hz, 2H), 2.15 (s, 2 3H), 1.66 (quint, J = 7.2 Hz, 2H), 1.48 (quint, J = 7.2 Hz, 2H), 1.37 (quint,
J = 7.2 Hz, 2H); 13C-NMR (100 MHz, acetone-d6):
×
δ
198.9, 152.4, 147.3, 131.7, 121.7, 115.2, 111.5, 60.1,
56.3, 45.5, 38.5, 28.1, 27.7, 25.2; HRMS calcd. for C15H24NO3 [M + H]+ 266.1756, found 266.1741. Anal.
calcd. for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C, 67.78; H, 8.66; N, 5.19.
Author Contributions: Conceived of and designed the experiments: H.M.A.H. Performed the experiments:
H.M.A.H. Analyzed the data: H.M.A.H. Wrote the paper: H.M.A.H.
Acknowledgments: This work was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University,
under grant number G-1436-141-202. The author, therefore, would like to thank DSR for financial support.
Conflicts of Interest: The author declares no conflict of interest.
References
1.
2.
3.
4.
Ueda, J.-Y.; Takagi, M.; Shin-ya, K. Aminocaprophenone- and pyrrolidine-type alkaloids from the leaves of
Ficus septica. J. Nat. Prod. 2009, 72, 2181–2183. [CrossRef] [PubMed]
Battaglia, U.; Moody, C.J. A short synthesis of the triazolopyrimidine antibiotic essramycin. J. Nat. Prod.
2010, 73, 1938–1939. [CrossRef] [PubMed]
Wang, W.; Zeng, Y.H.; Osman, K.; Shinde, K.; Rahman, M.; Gibbons, S.; Mu, Q. Norlignans, acylphloroglucinols,
and a dimeric xanthone from Hypericum chinense. J. Nat. Prod. 2010, 73, 1815–1820. [CrossRef] [PubMed]
Pais, G.C.G.; Zhang, X.; Marchand, C.; Neamati, N.; Cowansage, K.; Svarovskaia, E.S.; Pathak, V.K.; Tang, Y.;
Nicklaus, M.; Pommier, Y.; et al. Structure activity of 3-aryl-1,3-diketo-containing compounds as HIV-1
integrase inhibitors. J. Med. Chem. 2002, 45, 3184–3194. [CrossRef] [PubMed]
5.
Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37,
320–330. [CrossRef] [PubMed]

Molecules 2018, 23, 1865
9 of 9
6.
Han, C.; Salyer, A.E.; Kim, E.H.; Jiang, X.; Jarrad, R.E.; Powers, M.S.; Kirchhoff, A.M.; Salvador, T.K.;
Chester, J.A.; Hockerman, G.H.; et al. Evaluation of difluoromethyl ketones as agonists of the γ-aminobutyric
acid type B (GABAB) receptor. J. Med. Chem. 2013, 56, 2456–2465. [CrossRef] [PubMed]
7.
8.
9.
Vougioukalakis, G.C.; Grubbs, R.H. Ruthenium-based heterocyclic carbene-coordinated olefin metathesis
catalysts. Chem. Rev. 2010, 110, 1746–1787. [CrossRef] [PubMed]
Hassan, H.M.A. Recent applications of ring-closing metathesis in the synthesis of lactams and macrolactams.
Chem. Commun. 2010, 46, 9100–9106. [CrossRef] [PubMed]
Connon, S.J.; Blechert, S. Recent developments in olefin cross-metathesis. Angew. Chem. Int. Ed. 2003, 42,
1900–1923. [CrossRef] [PubMed]
10. Hoveyda, A.H.; Zhugralin, A.R. The remarkable metal-catalysed olefin metathesis reaction. Nature 2007, 450,
243–251. [CrossRef] [PubMed]
11. Nicolaou, K.C.; Bulger, P.G.; Sarlah, D. Metathesis reactions in total synthesis. Angew. Chem. Int. Ed. 2005, 44,
4490–4527. [CrossRef] [PubMed]
12. Fürstner, A. Metathesis in total synthesis. Chem. Commun. 2011, 47, 6505–6511. [CrossRef] [PubMed]
13. Chatare, V.K.; Andrade, R.B. Total synthesis of (
[CrossRef] [PubMed]
−
)-albocycline. Angew. Chem. Int. Ed. 2017, 56, 5909–5911.
14. Herbert, M.B.; Marx, V.M.; Pederson, R.L.; Grubbs, R.H. Concise syntheses of insect pheromones using
Z-selective cross metathesis. Angew. Chem. Int. Ed. 2013, 52, 310–314. [CrossRef] [PubMed]
15. Mann, T.J.; Speed, A.W.H.; Schrock, R.R.; Amir, H.; Hoveyda, A.H. Catalytic Z-selective cross-metathesis
with secondary silyl- and benzyl-protected allylic ethers: Mechanistic aspects and applications to natural
product synthesis. Angew. Chem. Int. Ed. 2013, 52, 8395–8400. [CrossRef] [PubMed]
16. Herbert, M.B.; Grubbs, R.H. Z-selective cross metathesis with ruthenium catalysts: Synthetic applications
and mechanistic implications. Angew. Chem. Int. Ed. 2015, 54, 5018–5024. [CrossRef] [PubMed]
17. Hassan, H.M.A.; Brown, F.K. A convenient approach to acyclic unsaturated amino acids via ring-closing
metathesis. Chem. Commun. 2010, 46, 3013–3015. [CrossRef] [PubMed]
18. Hong, S.H.; Wenzel, A.G.; Salguero, T.T.; Day, M.W.; Grubbs, R.H. Decomposition of ruthenium olefin
metathesis catalysts. J. Am. Chem. Soc. 2007, 129, 7961–7968. [CrossRef] [PubMed]
19. Chatterjee, A.K.; Choi, T.-L.; Sanders, D.P.; Grubbs, R.H. A general model for selectivity in olefin cross
metathesis. J. Am. Chem. Soc. 2003, 125, 11360–11370. [CrossRef] [PubMed]
20. Boulard, L.; BouzBouz, S.; Cossy, J.; Franck, X.; Figadère, B. Two successive one-pot reactions leading to the
expeditious synthesis of (−)-centrolobine. Tetrahedron Lett. 2004, 45, 6603–6605. [CrossRef]
21. Hayashi, Y. Pot economy and one-pot synthesis. Chem. Sci. 2016, 7, 866–880. [CrossRef] [PubMed]
22. Bidange, J.; Fischmeister, C.; Bruneau, C. Ethenolysis: A green catalytic tool to cleave carbon—Carbon double
bonds. Chem. Eur. J. 2016, 22, 12226–12244. [CrossRef] [PubMed]
23. Petrov, O.; Ivanova, Y.; Gerova, M. SOCl2/EtOH: Catalytic system for synthesis of chalcones. Catal. Commun.
2008, 9, 315–316. [CrossRef]
24. Clark, J.R.; French, J.M.; Diver, S.T. Alkene metathesis approach to β-unsubstituted anti-allylic alcohols and
their use in ene-yne metathesis. J. Org. Chem. 2012, 77, 1599–1604. [CrossRef] [PubMed]
25. Hong, S.H.; Sanders, D.P.; Lee, C.W.; Grubbs, R.H. Prevention of undesirable isomerization during olefin
metathesis. J. Am. Chem. Soc. 2005, 127, 17160–17161. [CrossRef] [PubMed]
26. Perrone, R.; Berardi, F.; Colabufo, N.A.; Lacivita, E.; Leopoldo, M.; Tortorella, V. Synthesis and
structure-affinity relationships of 1-[ω-(4-aryl-1-piperazinyl) alkyl]-1-aryl ketones as 5-HT7 receptor ligands.
J. Med. Chem. 2003, 46, 646–649. [CrossRef] [PubMed]
27. Leow, P.-C.; Bahety, P.; Boon, C.P.; Lee, C.Y.; Tan, K.L.; Yang, T.; Ee, P.-L.R. Functionalized curcumin analogs
as potent modulators of the Wnt/β-catenin signaling pathway. Eur. J. Med. Chem. 2014, 71, 67–80. [CrossRef]
[PubMed]
Sample Availability: Samples of the compounds are not available from the author.
©
2018 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).