Efficient total synthesis of lissodendrin b, 2-aminoimidazole marine alkaloids isolated from lissodendoryx (acanthodoryx) fibrosa

Article abstract of DOI:10.3390/md18010036

Lissodendrin B is a 2-aminoimidazole alkaloid bearing a (p-hydroxyphenyl) glyoxal moiety that was isolated from the Indonesian sponge Lissodendoryx (Acanthodoryx) fibrosa. We reported the first efficient total synthesis of Lissodendrin B. The precursor 4,5-disubstituted imidazole was obtained through Suzuki coupling and Sonogashira coupling reactions from 4-iodoimidazole. C2-azidation and reduction of the azide then provided the core structures of Lissodendrin B. Subsequent triple-bond oxidation, demethylation, and deacetylation gave the final product. The synthesis approach consists of ten steps with an overall yield of 1.1% under mild reaction conditions, and it can be applied for future analog synthesis and biological studies.

Full text of DOI:10.3390/md18010036

Article
Efficient Total Synthesis of Lissodendrin B, 2-
Aminoimidazole Marine Alkaloids Isolated
from Lissodendoryx (Acanthodoryx) Fibrosa
1
1
1,2
1,2
1,2
Xianfeng Wei , Xuelong Hu , Rilei Yu , Shengbiao Wan and Tao Jiang
*
1
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy,
Ocean University of China, Yushan Road 5, Qingdao 266003, China; weixfeng427@163.com (X.W.);
1146701884@qq.com (X.H.); ryu@ouc.edu.cn (R.Y.); biaowan@ouc.edu.cn (S.W.)
Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and
Technology, Qingdao 266003, China
2
* Correspondence: jiangtao@ouc.edu.cn; Tel: +86-532-82033054
Received: 30 November 2019.; Accepted: 20 December 2019.; Published: 31 December 2019
Abstract: Lissodendrin B is a 2-aminoimidazole alkaloid bearing a (p-hydroxyphenyl) glyoxal
moiety that was isolated from the Indonesian sponge Lissodendoryx (Acanthodoryx) fibrosa. We
reported the first efficient total synthesis of Lissodendrin B. The precursor 4,5-disubstituted
imidazole was obtained through Suzuki coupling and Sonogashira coupling reactions from 4-
iodoimidazole. C2-azidation and reduction of the azide then provided the core structures of
Lissodendrin B. Subsequent triple-bond oxidation, demethylation, and deacetylation gave the final
product. The synthesis approach consists of ten steps with an overall yield of 1.1% under mild
reaction conditions, and it can be applied for future analog synthesis and biological studies.
Keywords: total synthesis; Lissodendrin B; 2-aminoimidazole; marine alkaloids
1. Introduction
Marine alkaloids offer significant advantages for the discovery of leading compounds because
of their unique, complex structures and diverse bioactivities [1]. Unfortunately, most marine
alkaloids are isolated in very small quantities, which limits further studies to generate combinatorial
libraries for drug discovery and compound leads optimization. Therefore, efficient chemical
synthesis of marine alkaloids in greater quantities is necessary for their usage in bioactivity studies.
2-aminoimidazole alkaloids, the most commonly investigated representative marine alkaloid, are
found primarily in calcareous sponges, especially in the genera Leucetta and Clathrina [2–5]. These
compounds have been extensively studied because of their various biological activities, including
anticancer [3–5], antimicrobial [2,6], antivirus properties [7,8], P-gp-mediated MDR reversal activity
[9] as well as leukotriene B4 receptor [10] and epidermal growth factor (EGF) receptor antagonist
activities [11]. Therefore, efficient synthesis of 2-aminoimidazole compound is subject to increasing
demand. There are two major approaches for preparation of 2-aminoimidazole compound: (1) the
condensation of α-haloketone with an acetylated guanidine [12] or condensation of an α-
aminoketone with cyanamide [13] and (2) functionalization of imidazole scaffold via protection, C2-
amination, and deprotection [14,15].
The secondary metabolites, Lissodendrin A and Lissodendrin B (Figure 1) were isolated from
the ethyl acetate fraction of the sponge Lissodendoryx (Acanthodoryx) fibrosa in 2016 and structural
elucidation of these compounds was achieved using spectroscopic techniques. Lissodendrin A and
Lissodendrin B possess unprecedented 2-aminoimidazole skeletons with the latter compound
Mar. Drugs 2020, 18, 36; doi:10.3390/md18010036
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bearing a (p-hydroxyphenyl) glyoxal moiety, which is rarely encountered in natural products. The
new natural alkaloid 11 is devoid of cytotoxicity to the L5178Y mouse lymphoma cell line at a dose
of 10 μg/mL [16]. The precedent of diverse biological activity of 2-aminoimidazole alkaloids, coupled
with the lack of synthetic methods available to date, argues well for its synthesis to support further
biological evaluation. Herein, we reported the first successful and efficient total synthesis of
Lissodendrin B involving Suzuki coupling and Sonogashira coupling reactions and we constructed
the precursor 4,5-disubstituted imidazole. C2-azidation and reduction of the azide then provided the
core structures of Lissodendrin B, and subsequent triple-bond oxidation, demethylation, and
deacetylation led to the completion of the synthesis. All the compounds thus synthesized were fully
1
13
characterized by H, C, and HRMS.
Figure 1. Structures of Lissodendrin A and Lissodendrin B.
2. Results and Discussion
2.1. Retrosynthetic Analysis of Lissodendrin B
Scheme 1 illustrates the retrosynthetic pathway of Lissodendrin B. From the retrosynthetic
analysis, we envisioned that the natural product could be produced by deacetylation [17] from
acetamide 10, which was obtained from triple-bond oxidation [18,19] and demethylation [20] of the
key intermediate 8. We initially anticipated that compound 8 could be produced through Sonogashira
coupling reaction[21] from compound 12, whose core moiety, 2-aminoimidazole skeletons, could be
prepared by the condensation of α-haloketone 13 with an acetylated guanidine (Route 1) [12].
However, when we applied this strategy to our compound synthesis, the formation of compound 8
proceeded unsuccessfully via Sonogashira coupling reaction. We speculated that the electron-
donating effect of acetamino group generated increasing electron clouds at the imidazole ring,
leading to the reaction not occurring. Then, we attempted another approach (Route 2), in which the
2-amineimidazolone skeleton of intermediate 8 was constructed from the C2-azidation [14,15]and
reduction [22] from intermediate 5, which could be prepared by Sonogashira coupling reaction and
Suzuki coupling reaction [23] from easily accessible starting material 1.

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Scheme 1. Retrosynthetic analysis of Lissodendrin B.
2.2. Synthesis of Lissodendrin B
Scheme 2 shows a successful synthetic approach developed for production of Lissodendrin B.
The synthesis commenced with the preparation of 4-(4-methoxyphenyl)-1H-imidazole 2, using
Pd(PPh3)4 as the catalyst and CsF as the base. The 4-iodoimidazole was treated with 4-methoxyphenyl
boronic acid via Suzuki−Miyaura cross-coupling reaction in combined solution of toluene and water
(V/V = 5/1) afforded the desired cross-coupling product 2 at a yield of 82% [23]. To introduce the 4-
methoxyphenylacetylene by Sonogashira coupling reaction, iodization of arylimidazole 2 with NIS
provided iodoimidazole 3 as a white solid at a yield of 79% [24]. The optimal conditions entailed the
slow addition of 1.2 equiv. of NIS to avoid the formation of diiodide side-product. Sonogashira
reactions of compound 3 with 4-methoxyphenylacetylene proceeded smoothly in the presence of
Pd(PPh3)4 andCuI as catalysts and triethylamine as the base, affording coupling products 4 at a yield
of 70% as a light-yellow liquid [21]. Using triethylamine as a catalyst, protection of the imidazole
nitrogen with triphenylmethyl chloride at 45 °C in CH2Cl2 gave the known N-trityl imidazole 5 at
77% yield as a white solid [25]. Deprotonation of the imidazole 5 at C2 positions with n-BuLi in THF
at –78 °C and trapping with TsN3 provided the azide 6 at 46% yield as a white solid [14,15].
Subsequent treatment with Na2S⸱9H2O in methanol at room temperature led to the reduction of the
azide to amine 7 at good yield as a brown-yellow solid [22]. Acetylation of amine 7 with acetic
anhydride in CH2Cl2 in the presence of triethylamine at reflux gave the corresponding acetamide,
which was treated with concentrated hydrochloric acid causing removal of the trityl group, resulting
in the expected compound 8 forming at a yield of 62% (in two steps).

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Scheme 2. Synthesis of Lissodendrin B. Reagent and conditions: (a) 4-methoxyphenylboronic acid,
Pd(PPh3)4, CsF, toluene, H2O, 100 °C, 24 h, 82% (b) NIS, CH2Cl2, r.t., 4 h, 79%; (c) 4-
methoxyphenylacetylene, Pd(PPh3)4, CuI, TEA, DMF, 80 °C, 8 h, 70%; (d) Ph3CCl, TEA, CH2Cl2, reflux,
4 h, 77%; (e) n-C4H9Li, TsN3, THF, - 78 °C, 6 h, 46%; (f) Na2S⸱9H2O, CH3OH; r.t., 4 h, 69%; (g) 1) Ac2O,
TEA, CH2Cl2, reflux, 4 h; 2) HCl, CH3OH, r.t., 4 h, 62%; (h) Hg(NO3)2, DMF, r.t., 4 h, 51%; (i) BBr3,
CH2Cl2, r.t., 4 h, 66%; (j) concentrated H2SO4, CH3OH, H2O, reflux, 4 h, 51%.
With amide 8 in hand, oxidation of the triple-bond was performed to construct the
corresponding α-diketone structure. At the outset, KMnO4 and NaHCO3 were used to convert
compound 8 to α-diketone 9 [18]. The desired compound 9 was formed, but the yield thereof was
poor (17%). Numerous attempts to optimize the reaction conditions through varying KMnO4 and
NaHCO3 equivalents, solvent or order of addition were unsuccessful (Table 1). Subsequently,
mercuric nitrate hydrate was used for this transformation [19]. It was encouraging that the triple-
bond of amide 9 was successfully converted into α-diketone 9 at a yield of 51% as a yellow solid using
mercuric nitrate hydrate (2 equiv.) in DMF at room temperature.
Table 1. Optimization of oxidation of the triple-bond.
Catalyst (equiv.)
KMnO4 (2 equiv.)
KMnO4 (2 equiv.)
KMnO4(4 equiv.)
Hg(NO3)2(2equiv.)
Base
NaHCO3 (1 equiv.) Acetone
NaHCO3(1 equiv.) THF
NaHCO3(2 equiv.) Acetone
DMF
solvent Temperature Time (h) Yield (%)
0 °C -r.t.
0 °C -r.t.
0 °C -r.t.
0 °C -r.t.
4
8
8
2
17
10
20
51
—
At this juncture, with core structure 9 in hand, we further performed functional modification,
including demethylation and deacetylation: to our surprise, demethylation of α-diketone 9 was
accomplished using BBr3 (5 equiv.) in CH2Cl2 at ambient temperature giving the corresponding
diphenol 10 at a yield of 66% as a yellow solid [20]. Finally, the acetyl moiety of diphenol 10 was
removed by using concentrated sulfuric acid in combined solution of methanol and water (V/V = 2/1)
at 80 °C to give Lissodendrin B at a yield of 51% as a yellow solid [17]. It is noteworthy that the α-
diketone moiety of Lissodendrin B is stable below 80 °C.

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Thus, we completed the first total synthesis of Lissodendrin B in ten steps with an overall yield
of 1.1%. Spectra of the synthesized Lissodendrin B were in excellent agreement with that of the
natural product [16].
3. Materials and Methods
3.1. General Information
Dichloromethane and tetrahydrofuran were dried by distillation. All reagents used in the
experiments were obtained from commercial sources without further purification. Reactions were
monitored by thin layer chromatography (TLC). Visualization was achieved under a UV lamp (254
nm and 365 nm), and developed the plates with potassium permanganate. Flash column
1
13
chromatography was performed on a silica gel (200-300 mesh,). H NMR and C NMR spectra were
1
13
taken on Jnm-Ecp-600 spectrometer, respectively, H NMR and C NMR spectra were referenced to
tetramethylsilane (Me4Si). High resolution (ESI) MS spectra were recorded using a QTOF-2
Micromass spectrometer.
3.2. Methods
3.2.1. Synthesis of 4-(4-methoxyphenyl)-1H-imidazole (2)
To a solution of 4-iodoimidazole 1 (15 g, 77.3 mmol ) in toluene (300 mL) and H2O (100 mL) was
sequentially added 4-methoxyphenylboronic acid (23.5 g, 155 mmol), Pd(PPh3)4 (8.9 g, 7.7 mmol), CsF
(23.5 g, 155 mmol) and N2 was bubbled it for 3-5min. The heterogeneous mixture was stirred at 100 °C
for 24 h under N2 atmosphere. The reaction mixture was cooled to room temperature and water was
added, layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 200 mL). The
combined organic extracts were washed with brine, dried (anhydrous Na2SO4)and concentrated. The
crude residue was purified by flash chromatography (CH2Cl2/CH3OH, 30:1) to give product 2 (11 g,
1
82%) as a white solid. H NMR (500 MHz, DMSO-d6) δ 12.13 (s, 1H), 7.66 (d, J = 8.9 Hz, 3H), 7.41 (s,
13
1H), 6.92 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H). C NMR (101 MHz, DMSO-d6) δ 159.13, 138.80, 128.71, 114.41,
+
55.66. HRMS calcd for C10H11ON2 [M+ H] 175.0866, found 175.0864. Spectroscopic data agrees with
those previously reported [23].
3.2.2. Synthesis of 5-iodo-4-(4-methoxyphenyl)-1H-imidazole (3)
To a stirring solution of Compound 2 (11 g, 63.1 mmol) in anhydrous CH2Cl2 (300 mL) was added
NIS (17.0 g, 75.7 mmol) in several portions. After stirring for 4 h at room temperature. The solvent
was removed under vacuum, the residue was poured into saturated NaHCO3 solution and extracted
with ethyl acetate (2 × 300 mL). The combined organic layers were washed with water brine, dried
(anhydrous Na2SO4) and concentrated. The crude residue was purified by silica gel column
1
chromatography (CH2Cl2/CH3OH, 50:1) to give compound 3 (15 g, 79%) as a white solid. H NMR
13
(500 MHz, DMSO-d6) δ 12.65 (s, 1H), 7.62 (m, 3H), 7.03 (d, J = 8.2 Hz, 2H), 3.79 (s, 3H). C NMR (101
MHz, DMSO-d6) δ 158.30, 136.32, 136.06, 125.98, 114.43, 113.40, 55.52. HRMS calcd for C10H10ON2I[M+
+
H] 300.9832, found 300.9826.
3.2.3. Synthesis of 5-(4-methoxyphenyl)-4-((4-methoxyphenyl)ethynyl)-1H-imidazole (4)
To a solution of Compound 3 (15 g, 50 mmol) in DMF (200 mL) was added 4-
methoxyphenylacetylene (9.9 g, 75 mmol), Pd(PPh3)4 (5.8 g, 5 mmol), CuI (950 mg , 5 mmol),
triethylamine (208 mL, 150 mmol) and N2 was bubbled it for 3-5 min. The reaction mixture was stirred
at 100 °C for 8h under N2 atmosphere. The reaction mixture was cooled to room temperature and the
solvent was removed under vacuum. The residue was poured into water and extracted with ethyl
acetate (2 × 300 mL). The combined organic layers were washed with water, brine, dried (anhydrous
Na2SO4) and concentrated. The crude residue was purified by silica gel column chromatography
1
(CH2Cl2/CH3OH, 50:1) to give compound 4 (10.6 g, 70%) as a yellow oil. H NMR (400 MHz,

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Chloroform-d) δ 8.04 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H),
13
6.87 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H). 3.83(s, 3H). C NMR (101 MHz, Chloroform-d) δ 159.77, 159.17,
135.03, 132.84, 127.34, 124.81, 115.08, 114.13, 114.08, 94.17, 80.25, 55.35, 55.32.HRMS calcd for
+
C19H17O2N2 [M+ H] 305.1285, found 305.1276.
3.2.4. Synthesis of 5-(4-methoxyphenyl)-4-((4-methoxyphenyl)ethynyl)-1-trityl-1H-imidazole (5)
To a stirring solution of Compound 4 (10 g, 32.9 mmol) in anhydrous CH2Cl2 (200 mL) was added
triphenylmethyl chloride (13.8 g, 49.4 mmol) and trimethylamine (22.8 mL,164.5 mmol). After stirring
for 4 h at reflux, the solvent was removed under vacuum, the residue was poured into saturated
NaHCO3 solution and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were
washed with water, brine, dried (anhydrous Na2SO4) and concentrated. The crude residue was
purified by silica gel column chromatography (petroleum ether/ethyl acetate, 4:1) to give compound
1
5 (13.8 g, 77%) as a white solid. H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 8.9 Hz, 2H), 7.48 (d, J
= 0.9 Hz, 1H), 7.34 – 7.28 (m, 15H), 6.95 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.9 Hz,
13
2H), 3.85 (s, 3H), 3.78 (s, 3H). C NMR (101 MHz, Chloroform-d) δ 159.39, 159.07, 145.40, 141.73,
139.11, 132.23, 130.24, 128.16, 127.94, 127.81, 127.73, 127.55, 126.85, 115.22, 113.70, 112.98, 100.30, 80.45,
+
76.07, 55.33, 55.25.HRMS calcd for C38H31O2N2 [M+ H] 547.2380, found 547.2378.
3.2.5. Synthesis of 2-azido-5-(4-methoxyphenyl)-4-((4-methoxyphenyl)ethynyl)-1-trityl-1H-
imidazole (6)
Compound 5(3.0 g, 5.5 mmol) in anhydrous THF (200 mL) was cooled to -78 °C and n-BuLi (11
mL, 27.5 mmol, 2.5 M in solution in THF) was added dropwise. After complete addition of the n-
BuLi, the reaction was stirred for 2 h at -78 °C, then TsN3(4.4 g, 22.0 mmol) dissolved in anhydrous
THF (15 mL) was added. The reaction mixture was allowed to room temperature and stirred for 4 h.
The reaction was quenched carefully with saturated aqueous NH4Cl and extracted with ethyl acetate
(2 × 200 mL). The combined organic layers were washed with water, brine, dried (anhydrous Na2SO4)
and concentrated. The residue was purified by silica gel column chromatography (petroleum
1
ether/ethyl acetate, 15:1) to give compound 6 (1.5 g, 46%) as a white solid. H NMR (400 MHz,
Chloroform-d) δ 8.10 (d, J = 8.8 Hz, 2H), 7.54–7.47 (m, 6H), 7.33 – 7.28 (m, 6H), 7.27–7.22 (m, 3H), 6.93
13
(d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H). C NMR
(101 MHz, Chloroform-d) δ 159.33, 159.17, 145.33, 143.69, 142.28, 142.03, 134.67, 133.00, 132.40, 129.87,
129.74, 127.97, 127.87, 127.63, 127.22, 126.98, 126.25, 115.35, 113.73, 113.60, 111.11, 101.86, 81.30, 76.52,
+
55.32, 55.28. HRMS calcd for C38H30O2N5 [M+ H] 588.2325, found 588.2328.
3.2.6. Synthesis of 5-(4-methoxyphenyl)-4-((4-methoxyphenyl)ethynyl)-1-trityl-1H-imidazol-2-
amine (7)
To a stirring solution of Compound 6 (1.5 g, 2.6 mmol) in CH3OH (100 mL) was addedNa2S⸱9H2O
(5.3 g, 26 mmol). After stirring for 4 h at room temperature, the solvent was removed under vacuum.
The residue was poured into water and extracted with ethyl acetate (2 × 100 mL). The combined
organic layers were washed with water, brine, dried (anhydrous Na2SO4) and concentrated to give
compound 7 (1 g, 69%) as a yellow solid. (Compound 7 was used in the next step without further
1
purification.) H NMR (500 MHz, Chloroform-d) δ 8.00 (d, J = 8.5 Hz, 2H), 7.52 (m, 6H), 7.31 (m, 6H),
7.27 (dd, J = 7.4, 1.2 Hz, 3H), 6.87 (d, J = 8.5 Hz, 2H), 6.72 (m, 4H), 4.04 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H).
13
C NMR (101 MHz, Chloroform-d) δ 158.98, 158.91, 149.86, 142.62, 142.43, 132.08, 130.34, 128.04,
127.81, 127.66, 126.97, 116.26, 113.76, 113.60, 108.06, 100.37, 83.02, 75.82, 55.41, 55.37. HRMS calcd for
+
C38H32O2N3 [M+ H] 562.2489, found 562.2481.
3.2.7. Synthesis of N-(5-(4-methoxyphenyl)-4-((4-methoxyphenyl)ethynyl)-1H-imidazol-2-yl)
acetamide (8)
To a stirring solution of Compound 7 (1.0 g, 1.8 mmol) in anhydrous CH2Cl2 (50 mL) was added
triethylamine (2.5 mL, 18.0 mmol) and acetic anhydride (0.9 mL, 9.0 mmol). After stirring for 4 h at

Mar. Drugs 2020, 18, 36
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reflux, the solvent was removed under vacuum, the residue was dissolved in CH3OH (50 mL) and
concentrated hydrochloric acid (5 mL) was added at 0°C. After stirring for 4 h at room temperature,
the solvent was removed under vacuum. The residue was poured into saturated NaHCO3 solution
and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water,
brine, dried (anhydrous Na2SO4) and concentrated. The crude residue was purified by silica gel
column chromatography (petroleum ether/ethyl acetate, 2:1) to give compound 8 (400 mg,62%) as a
1
pale yellow solid. H NMR (500 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.31 (s, 1H), 7.98 (s, 2H), 7.48 (d, J =
13
8.2 Hz, 2H), 7.00 (m, 4H), 3.79 (s, 3H), 3.78 (s, 3H), 2.08 (s, 3H). C NMR (126 MHz, DMSO-d6) δ 169.09,
159.79, 158.83, 141.39, 140.22, 132.76, 129.12, 127.07, 126.94, 115.15, 114.94, 114.37, 103.97, 95.27, 80.60,
+
55.76, 55.57, 23.28. HRMS calcd for C21H20O3N3[M + H] 362.1499, found 362.1496.
3.2.8. Synthesis of N-(5-(4-methoxyphenyl)-4-(2-(4-methoxyphenyl)-2-oxoacetyl)-1H-imidazol-2-yl)
acetamide (9)
To a stirring solution of Compound 8 (360 mg, 1.0 mmol) in DMF (30 mL) was added
Hg(NO3)2⸱1/2H2O (667.2 mg, 2.0 mmol). After stirring for 4 h at room temperature, the solvent was
removed under vacuum. The residue was poured into water and extracted with ethyl acetate (2 × 50
mL). The combined organic layers were washed with water brine, dried (anhydrous Na2SO4) and
concentrated. The crude residue was purified by silica gel column chromatography (petroleum
ether/ethyl acetate, 2:1) to give compound 9 (200 mg, 51%) as a yellow solid. [Caution: Mercury salts
1
are highly toxic. Handling of all mercury compounds should be done carefully.] H NMR (500
MHz, DMSO-d6) δ 12.50 (s, 1H), 11.21 (s, 1H), 7.92 (m, 2H), 7.80 (m, 2H), 7.07 (m, 4H), 3.84 (s, 3H),
13
3.83 (s, 3H), 2.01 (s, 3H). C NMR (101 MHz, DMSO-d6) δ 194.48, 190.76, 169.87, 164.56, 160.71, 145.96,
141.69, 136.84, 132.16, 130.89, 129.05, 126.31, 120.63, 115.01, 114.13, 56.20, 55.82, 23.15. HRMS calcd for
+
C21H20O5N3[M + H] 394.1397, found 394.1392.
3.2.9. Synthesis of N-(5-(4-hydroxyphenyl)-4-(2-(4-hydroxyphenyl)-2-oxoacetyl)-1H-imidazol-2-yl)
acetamide (10)
To a stirring solution of Compound 9 (200 mg, 0.5 mmol) in anhydrous CH2Cl2 (25 mL) was
added BBr3 (48 µL, 2.5 mmol) at 0 °C. The mixture was allowed to room temperature and stirred for
4 h. The mixture was neutralized carefully with saturated aqueous NaHCO3 at 0 °C and extracted
with CH2Cl2 (2 × 50 mL). The combined organic layers were washed with water, brine, dried
(anhydrous Na2SO4) and concentrated. The crude residue was purified by silica gel column
1
chromatography (CH2Cl2/CH3OH, 30:1) to give compound 10 (120 mg, 66%) as a yellow solid. H
NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 11.20 (s, 1H), 10.63 (s, 1H), 9.93 (s, 1H), 7.80 (d, J = 8.3 Hz,
13
2H), 7.68 (d, J = 8.5 Hz, 2H), 6.88 (t, J = 9.0 Hz, 4H), 2.01 (s, 3H). C NMR (125 MHz, DMSO-d6) δ
194.34, 190.93, 169.94, 163.59, 159.18, 142.52, 141.48, 132.43, 130.87, 128.77, 125.02, 119.08, 116.27,
+
115.48, 110.74, 107.32, 23.13. HRMS calcd for C19H16O5N3[M + H] 366.1084, found 366.1076.
3.2.10. Synthesis of Lissodendrin B (11)
To a stirring solution of Compound 10 (100 mg, 0.27 mmol) in CH3OH (30 mL) and water (5 mL)
was added concentrated H2SO4 (1 mL) at 0 °C. After stirring for 4 h at 80 °C, the reaction mixture was
neutralized carefully with saturated aqueous NaHCO3 at 0 °Cand extracted with ethyl acetate (2 × 50
mL). The combined organic layers were washed with water, brine, dried (anhydrous Na2SO4) and
concentrated. The crude residue was purified by silica gel column chromatography (CH2Cl2/CH3OH,
1
30:1) to give Lissodendrin B (45 mg, 51%) as a yellow solid. H NMR (500 MHz, CH3OH-d4) δ 7.60 (d,
13
J = 8.7 Hz, 2H), 7.14 (m, 2H), 6.78 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 8.5 Hz, 2H). C NMR (125 MHz,
CH3OH-d4) δ 194.32, 184.00, 164.90, 159.74, 155.32, 154.43,133.39, 132.07, 126.79, 124.69, 123.36, 116.47,
+
115.57. HRMS calcd for C17H14O4N3[M + H] 324.0979, found 324.0974.
4. Conclusions

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In summary, a concise total synthesis of marine alkaloids Lissodendrin B was accomplished in
ten steps giving an overall yield of 1.1%. Highlights of the synthesis included: (1) the precursor 4,5-
disubstituted imidazole construction based on Suzuki coupling and Sonogashira coupling reactions,
(2) 2-aminoimidazole skeleton synthesis using C2-azidation and reduction of the azide, and (3) the
α-diketone structure preparation based on the oxidation of the triple-bond. Cost-effective reagents
and mild reaction conditions were used in each step of our route. Results from this study are useful
for design and synthesis of novel bioactive 2-aminoimidazole alkaloids. Further biological activity
studies are underway and will be reported in due course.
Supplementary Materials: Supplementary materials can be found at www.mdpi.com/xxx/s1.
Author Contributions: X.W. and X.H. performed the experimental studies; X.W., R.Y., S.W. and T.J. wrote the
manuscript; This manuscript describes original work and is not under consideration by any other journals. All
authors approved the manuscript and this submission.
Funding: The authors are grateful for the financial support granted by the National Science and Technology
Major Project Fund of China (2018ZX09735-004), the NSFC-Shandong Joint Fund (U1706213 and U1406403),
Innovation Project funding from Qingdao National Laboratory for Marine Science and Technology (No
2015ASKJ02) and the Marine S&T Fund of Shandong Province for Pilot National Laboratory for Marine Science
and Technology (Qingdao) (No. 2018SDKJ0403).
Acknowledgments: We are deeply indebted to the entire research team for their valuable effort during the
period of this research work.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviation
P-gp P-glycoprotein
MDR multidrug resistance
DMF N,N-Dimethylformamide
TEA Triethylamine
Ac2O Acetic anhydride
DMSO Dimethyl sulfoxide
THF Tetrahydrofuran
TsN3 p-toluenesulfonyl azide
CsF cesium fluoride
NIS N-iodosuccinimide
CuI copper(I) iodide
THF Tetrahydrofuran
UV ultraviolet
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