Total synthesis of mycalisine B

Article abstract of DOI:10.3390/md17040226

The first total synthesis of the marine nucleoside Mycalisine B-a naturally occurring and structurally distinct 4,5-unsaturated 7-deazapurine nucleoside-has been accomplished in 10 linear steps with 27.5% overall yield from commercially available 1,2,3,5-tetra-O-acetyl-ribose and tetracyanoethylene. Key steps of the approach include: (1) I₂ catalyzed acetonide formation from 1,2,3,5-tetra-O-acetylribose and acetone at large scale; (2) Vorbrüggen glycosylation using N⁴-benzoyl-5-cyano-6-bromo-7H-pyrrolo[2,3-d]pyrimidine as a nucleobase to avoid formation of N-3 isomer; (3) mild and scalable reaction conditions.

Full text of DOI:10.3390/md17040226

marine drugs
Communication
Total Synthesis of Mycalisine B
Haixin Ding, Zhizhong Ruan, Peihao Kou, Xiangyou Dong, Jiang Bai and Qiang Xiao *
Jiangxi Key Laboratory of Organic Chemistry, Institute of Organic Chemistry,
Jiangxi Science & Technology Normal University, Nanchang 330013, China; dinghaixin_2010@163.com (H.D.);
ruanzhizhong0404@yeah.net (Z.R.); koupeihao92@yeah.net (P.K.); dongxiangyou93@yeah.net (X.D.);
mtbaijiang@yeah.net (J.B.)
* Correspondence: xiaoqiang@tsinghua.org.cn; Tel.: +86-791-8642-2903
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 18 March 2019; Accepted: 10 April 2019; Published: 14 April 2019
Abstract: The first total synthesis of the marine nucleoside Mycalisine B—a naturally occurring
and structurally distinct 4,5-unsaturated 7-deazapurine nucleoside—has been accomplished in
10 linear steps with 27.5% overall yield from commercially available 1,2,3,5-tetra-O-acetyl-ribose
and tetracyanoethylene. Key steps of the approach include: (1) I2 catalyzed acetonide formation
from 1,2,3,5-tetra-O-acetylribose and acetone at large scale; (2) Vorbrüggen glycosylation using
N4-benzoyl-5-cyano-6-bromo-7H-pyrrolo[2,3–d]pyrimidine as a nucleobase to avoid formation of N-3
isomer; (3) mild and scalable reaction conditions.
Keywords: marine nucleoside; total synthesis; vorbrüggen glycosylation; mycalisine B
1. Introduction
Naturally occurring compounds, isolated from marine invertebrates, are a valuable and promising
resource for the identification of novel drug leads with unprecedented and novel mechanisms of
action [
simplest multicellular animal—exist worldwide. These marine sponges have produced a wide range of
secondary metabolites with diverse structural features and distinct biological activities [ ]. Among
1–3]. Until now, about 15,000 species of marine sponges—which are the most primitive and
4–6
these, mycalisines A and B (Figure 1) were isolated from a Japanese sponge Mycale sp. in 1985.
Biological activities evaluation showed that mycalisines A and B possess cell division inhibition of
fertilized starfish eggs at IC50 0.5 and 200 µg/mL, respectively [7]. Mycalisines A and B represent
structurally distinct 40,50-unsaturated 7-deazapurine nucleosides possessing pyrrolo[2,3-d]pyrimidine.
Figure 1. Structures of tubercidin (1), toyocamycin (2), mycalisine A (3) and mycalisine B (4).
It is noteworthy that a series of naturally occurring 7-deazapurine nucleosides—such as tubercidin
1
[
8
] and toyocamycin
2
[
9] (Figure 1) from Streptomyces sp—have been found to display interesting
biological activities [10
–
12]. In the structure of 7-deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides,
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N-7 of the purine base is replaced by a carbon atom. Thus, the resulting pyrrole moiety is more
electron-rich than the imidazole moiety of the corresponding purine and is thus likely to be more prone
to cation–π or π–π interactions with DNA/RNA or proteins [13–15]. In the past decade, a number
of 7-deazapurine nucleosides have been synthesized and proved to be a privileged scaffold in the
design of antitumor and antiviral nucleosides [16]. Moreover, 4’,5’-unsaturated nucleosides possess
an exocyclic double bond next to the ring oxygen of ribose. These nucleosides display powerful
biopotency and could interfere with some specific metabolic pathways [17,18]. Because of the rich
reactivity of the enol ether functional group, they offered many possibilities for further chemical
transformations [19].
Due to the above-mentioned reasons and our continuing effort to synthesize bioactive marine
nucleosides [20–27], we are interested in the total synthesis and structure-activity relationship studies
of 40,50-unsaturated 7-deazapurine nucleosides as antibiotics. A literature search revealed that the first
total synthesis of mycalisine A was accomplished using toyocamycin as a starting material shortly
after it was reported [28]. During this synthesis, methylation of toyocamycin with diazomethane
was first conducted using SnCl2 as a catalyst (Figure 2a) [29]. It afforded a mixture of 20-O-methyl
and 30-O-methyl isomers of toyocamycin with the ratio of 3:2 (yield not given). Separation of the
obtained regiomers was not achieved even though various purification methods, including silica
chromatography, reversed phase HPLC, and recrystallization, were tried. Therefore, the mixture was
directly acetylated with acetic anhydride. The acetate of 30-O-methyl isomers can be enriched to
give 90% purity by recrystallization. After removing the acetate group with methanolic ammonia,
30-O-methyl toyocamycin was obtained by recrystallization. Subsequent unsaturation of 50-hydroxyl
afforded mycalisine A. However, this approach is not only impractical, but the starting material
toyocamycin is also costly.
Figure 2. Retrosynthetic analysis of Mycalisine B (a) using toyocamycin as the starting material;
(b) using Vorbrüggen glycosylation as the key synthetic step.
Afterwards, our group reported an improved total synthesis of mycalisine A using a
commercially available d-xylose as a starting material in eleven linear steps with 15% overall
yield [27]. Our strategy used the late-stage Vorbrüggen glycosylation as the key step to
synthesize the nucleoside. The corresponding ribose glycosylation donor
5-O-benzoyl-1,2-O-isopropylidene- -d-xylofuranose by Dess-Martin oxidation, stereoselective NaBH4
reduction, and methylation. In the following scale-up of the total synthesis, some obstacles arose. First,
7 was obtained from
α

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the synthesis of 1,2-O-isopropylidene-
α
-d-xylofuranose from d-xylose needs two steps and involved
a tedious silica chromatography purification to provide crystalline substance. Second, Dess-Martin
oxidation was troublesome at a large scale. Third, the yield of the Vorbrüggen glycosylation was
moderate and the N-3 isomer was formed as a by-product.
Therefore, it is necessary to further develop an improved approach for the total synthesis of
mycalisines. In the present paper, an expeditious and first total synthesis of mycalisine B was
accomplished (Scheme 1) which addressed the corresponding obstacles we have encountered in the
synthesis mycalisine A.
Scheme 1. Synthesis of ribose glycosylation donor 7. Reagents and conditions
:
(
a
) i. I2, acetone; ii.
) CH3I,
K2CO3, MeOH, r.t., 87%; ( ) BzCl, E3N, CH2Cl2, 10 35%, 11 62%;( ) NaOMe, MeOH, r.t. 99%; (d
b
c
Ag2O, DMF, r.t., 95%; (e) Ac2O, H2SO4, HOAc, r.t., 91%.
2. Results and Discussion
According to our retrosynthetic analysis of mycalisine B (Figure 2b), the ribose glycosylation donor
can be obtained from 1,2,3,5-tetra-O-acetylribose ( ), which will obviate the oxidation and reduction
reactions for using d-xylose as a starting material. 1,2-O-acetonide ribose ( ) was initially synthesized
from 1,2,3,5-tetra-O-acetylribose ( ) utilizing AlMe3 as catalysis in acetone [30]. The disadvantage of this
7
8
9
8
method is that AlMe3 is explosive and difficult to handle. Later, a much-improved protocol was reported
which used I2 as a catalysis and acetone as solvent to facilitate acetonide-formation [31]. This protocol
is exceptionally mild and can be scaled-up smoothly. During our synthesis, 1,2-O-acetonide ribose
(9) was obtained at 100 g scale in two steps and 87% overall yield without purification by a column
chromatography (Scheme 1). We also found that the commercially available acetone without drying is
qualified for the reaction, which further◦simplified this protocol.
After careful benzoylation at 10 C, the 5-O-benzoyl ribose (11) was prepared in 62% yield.
−
Moreover, a single crystal of (11), suitable for X-ray crystallography, was obtained and its structure
is shown in Figure 3 [32]. Meanwhile, 3,5-O-dibenzoyl ribose (10) was obtained in 35% yield, which
can be deprotected with Zemplén transesterification (catalytic sodium methoxide in methanol) [33
]
to give 1,2-O-acetonide ribose (
9
) in almost quantitative yield. Therefore, the yield increased to
84% following two rounds of this procedure. Subsequently, methylation of 3-OH to synthesize
3-O-methyl ribose (12) was facilitated with freshly prepared silver oxide (Ag2O) [34] and methyl iodide
in N,N-dimethylformamide (DMF) with 95% yield, which is much milder than our former method
(sodium hydride and methyl iodide in DMF with 88% yield). Next, the cleavage of the acetonide with
acetic acid/acetic anhydride/H2SO4 afforded the key glycosylation donor (
7) in 91% yield as a mixture
of anomers (α:β = 2:3), which was used directly without further purification.

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Figure 3. X-ray crystal structure of 11.
Then we started to investigate the crucial late-stage Vorbrüggen glycosylation [35
–
37] with
nucleobase
6, which was synthesized by our improved procedure from tetracyanoethylene in two
steps [38]. In our previous total synthesis of mycalisine A, the yield of Vorbrüggen glycosylation was
moderate (58% yield) [27]. Although the reaction proceeded smoothly to give only one spot of product
in thin-layer chromatography (TLC), it was found that the N-9 glycosylation product 13 and the N-3
glycosylation product 14 were formed concurrently after purification (Scheme 2). The formation of
regioisomers was also previously reported by us and several other groups [35
total synthesis of naturally occurring 50-deoxytoyocamycin and 50-deoxysangivamycin, this dilemma
was successfully solved by introducing a benzoyl group at N-6 of nucleobase , which improved its
solubility and reduced the pyrimidine ring’s electron density and nucleophilicity [38].
,38–40]. During our
6
Scheme 2. Vorbrüggen glycosylation of ribose (7) and nucleobase (6). Reagents and conditions: (a) BSA,
TMSOTf, CH3CN, 80 ◦C, 4 h, 58%.
For this reason, we chose our newly developed nucleobase (15) to carry out the following synthesis
(Scheme 3). Effective silylation of nucleobase with 3 equiv. of N,O-bis(trimethylsilyl)acetamide (BSA)
in acetonitrile was first conducted. After the addition of ribose glycosylation donor (7), and followed
by the addition of trimethylsilyl trifluoromethanesulfonate (TMSOTf), the reaction mixture was heated
at 80 ◦C for 4 h. The corresponding nucleoside (16) was obtained in 89% yield without formation of the
N-3 regioisomer. This reaction further demonstrated that 7-deazapurine nucleobase (15) could be used
as a universal nucleobase for the synthesis of toyocamycin derivatives with the capacity to avoid the
formation of N-3 nucleoside isomer. Next, global deprotection with saturated ammonia in methanol
gave nucleoside (17) in 87% yield. Deamination with NaNO2 in acetic acid afforded 7-deazainosine (18
in 80% yields [41]. Then, debromination was performed by hydrogenation using 5% Pd/C as catalyst
to give (19) in 92% yield [27]. It is noteworthy that we chose the synthetic sequence of debromination
and subsequent deprotection during our total synthesis of mycalisine A. For purification reason, this
change made the whole synthesis more convenient during our present work.
)

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Scheme 3. Total synthesis of mycalisine B. Reagents and conditions
4h, 89%; (
) NH3/MeOH, 40 ◦C, 12 h, 87%; ( ) NaNO2, HOAc, 60 ◦C, 8 h, 80% (
r.t., 4 h, 92%; ( ) O-nitrophenylselenocyanate, Bu3P, Py, r.t., 4 h, 88%; ( ) i. H2O2, THF, r.t., 2 h; ii. Et3N,
Py, 50 ◦C, 5 h, 87%.
:
(
a
) BSA, TMSOTf, CH3CN, 80 ◦C,
) Pd/C, H2, THF/MeOH,
b
c
d
e
f
Subsequently, treatment nucleoside (19) with O-nitrophenylselenocyanate and tributyl phosphine
in pyridine smoothly gave intermediate (20) in 88% yield [42]. Selenide (20) was then oxidized to the
selenoxide intermediate with an excess of H2O2 in THF. Without further purification, the reaction
mixture was directly treated with Et3N at 50 ◦C for 5 h. After removal of the solvent, purification of
the residue afforded crystalline mycalisine B in 87% yield in two steps. It is noteworthy that mycalisine
B was originally reported as an oil [7]. All its spectroscopic data are in accordance with those reported
for mycalisine B [7] (See Supplementary Materials).
3. Conclusions
In summary, we have developed an expeditious and scalable approach for the total synthesis
of mycalisine B in ten linear steps with 27.5% overall yield (based on the quantitative converting
side product (10) to ribose (9)). The crucial ribose glycosylation donor (7) was synthesized from
1,2,3,5-tetra-O-acetylribose, which avoided oxidation and reduction reactions. Using N4-benzoyl-
5-cyano-6-bromo-7H-pyrrolo[2,3-d]pyrimidine (15) as a nucleobase, the N-9 glycosylation product
was obtained without the formation of N-3 isomer in Vorbrüggen glycosylation. We expected that
the current total synthetic strategy can be widely used in the syntheses of mycalisine derivatives.
However, this reported sequence continues to have some flaws, especially the double-bond formation

Mar. Drugs 2019, 17, 226
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reaction, which used the combination of O-nitrophenylselenocyanate and tributyl phosphine, which
is expensive and will be further addressed in the future. Investigation of the biological activities of
mycalisine B as potential antibiotics is ongoing, which will be reported in due course.
4. Materials and Methods
Unless otherwise specified, all the reagents were acquired from commercial sources and used
directly. Acetonitrile, dichloromethane, dimethylformamide (DMF), and pyridine were all distilled from
calcium hydride. NMR spectra (400 MHz/100 MHz) were recorded on an Advance DPX spectrometer
1
(Bruker, Billerica, MA, USA) at room temperature with DMSO-d6 or CDCl3 as solvent. H NMR data
are reported as the following format: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
br = broad, m = multiplet), coupling constant and integration. Specific rotations were acquired on
an Autopol IV polarimeter (Rudolph, Hackettstown, NJ, USA). High resolution mass spectrometry
(HRMS) data were measured with an AB Sciex TOF 4600 instrument (AB Sciex, Singapore). Melting
points were measured on an X-4 digital melting point apparatus (Beijing Taike Corparation, Beijing,
China). X-ray diffraction analysis was performed on a Bruker Smart Apex II system (Bruker, Billerica,
MA, USA).
4.1. Synthesis of 1,2-O-isopropylidene-α-d-ribofuranose (9)
To a solution of 1,2,3,5-O-tetraacetyl-β-d-ribose (8) (200.0 g, 628 mmol) in acetone (1.5 L) iodine
(9.6 g, 38 mmol) was added in portions at 0 ◦C under argon atmosphere. The obtained reaction mixture
was stirred for 4 h at room temperature and then quenched with 500 mL saturated NaS2O3. The solvent
was evaporated under reduced pressure and the residue was dissolved in CH2Cl2 (3 L). The solution
was washed with distilled water (500 mL
×
3), sat. NaHCO3 (500 mL
×
3), brine (500 mL
×
3), and
dried with anhydrous Na2SO4. After filtration, the filtrate was evaporated under reduced pressure.
Then the residue was dissolved in MeOH (1.5 L) and K2CO3 (10.0g, 72 mmol) was added. The mixture
was stirred for 3 h at room temperature. After filtrated and evaporated to dryness under reduced
pressure, the residue was recrystallized with PE (Petroleum ether)/EtOAc to give (
9
) as a white solid
91 ◦C; [α]2D5 + 62.30 (c = 0.10,
5.64 (d, J = 3.7 Hz, 1H), 4.97 (d, J = 6.7 Hz, 1H), 4.64 (t,
3.57 (m, 3H), 3.43–3.36 (m, 1H), 1.43 (s, 3H), 1.26 (s, 3H);
(104.1 g, 547 mmol, 87%). Rf = 0.2 (CH2Cl2:MeOH = 15:1, V:V); m.p. 89
−
CH3OH); 1H NMR (400 MHz, DMSO-d6)
J = 5.7 Hz, 1H), 4.43 (t, J = 3.9 Hz, 1H), 3.77
δ
−
13C NMR (100 MHz, DMSO-d6)
δ
111.7, 103.8, 80.8, 79.6, 71.0, 60.7, 27.1, 26.9; HRESIMS m/z: [M + Na]+
calcd. for C8H14O5, 213.0733; found, 213.0736.
4.2. Synthesis of 1,2-O-isopropylidene-5-O-benzoyl-α-d-ribofuranose (11)
To a solution of (9) (10.0 g, 52.57 mmol) in anhydrous CH2Cl2 (100 mL), pyridine (11.22 g, 141.96
mmol) ◦was added. Then benzoyl chloride (11.09 g, 78.85 mmol) was slowly added to the solution
at
−
10 C. After addition, the reaction mixture was stirred for 8 h and quenched with ice water.
The mixture was diluted with CH2Cl2 (500 mL) and washed with 5% HCl (150 mL
(150 mL 2), and brine (150 mL 2). After drying over anhydrous MgSO4, the filtrate was evaporated
to dryness under reduced pressure and purified by silica gel column to give a white solid (11) (9.58 g,
32.55 mmol, 62%) and (10) (7.34 g, 18.42 mmol, 35%).
×
2), sat. NaHCO3
×
×
Compound (11), Rf = 0.15 (PE/EtOAc = 4:1, V/V); m.p. 86
−
87 ◦C; [α]2D5 + 30.36 (c = 0.112, CH2Cl2);
1H NMR (400 MHz, CDCl3)
δ
8.05 (d, J = 7.4 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 5.84
(d, J = 3.8 Hz, 1H), 4.69 (dd, J = 12.3, 2.2 Hz, 1H), 4.60 (t, J = 4.4 Hz, 1H), 4.44 (dd, J = 12.3, 5.3 Hz, 1H),
4.08 (ddd, J = 7.9, 5.2, 2.4 Hz, 1H), 3.94 (td, J = 9.7, 5.2 Hz, 1H), 2.61 (d, J = 10.3 Hz, 1H), 1.58 (s, 3H), 1.37
(s, 3H); 13C NMR (100 MHz, CDCl3)
δ
166.6, 133.2, 129.9 (C
×
3), 128.5 (C
×
2), 112.9, 104.2, 78.6, 78.4,
72.3, 63.5, 26.6 (C × 2); HRESIMS m/z: [M + Na]+ calcd. for C15H18O6Na 317.0996, found 317.1102.
102 C; [α]2D5 + 123.01 (c = 0.113,
◦
Compound (10), Rf = 0.50 (PE/EtOAc = 4:1, V/V); m.p. 100
CH2Cl2); 1H NMR (400 MHz, CDCl3)
J = 21.0, 7.7 Hz, 4H), 5.96 (d, J = 3.0 Hz, 1H), 5.09
−
δ
8.05 (dd, J = 15.1, 7.7 Hz, 4H), 7.64
−
7.51 (m, 2H), 7.42 (dt,
−
4.99 (m, 2H), 4.71 (dd, J = 12.0, 3.3 Hz, 1H),

Mar. Drugs 2019, 17, 226
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4.68
−
4.62 (m, 1H), 4.50 (dd, J = 12.0, 4.7 Hz, 1H), 1.60 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3)
2), 129.8 (C 2), 129.7, 129.2, 128.5 (C 2), 128.4 (C 2), 113.4,
2); HRESIMS m/z: [M + Na]+ calcd. for C22H22O7Na 421.1258,
δ
166.3, 165.8, 133.5, 133.2, 130.0 (C
×
×
×
×
104.6, 77.6, 75.8, 73.5, 63.3, 26.8 (C
found 421.1262.
×
4.3. Synthesis of 1,2-O-isopropylidene-3-O-methyl-5-O-benzoyl-α-d-ribofuranose (12)
To a solution of (11) (5.0 g, 16.98 mmol) in DMF (50 mL) Ag2O (9.84 g, 42.47 mmol) and CH3I
(12.06 g, 84.94 mmol) were added at 0 ◦C under argon atmosphere. After addition, the reaction mixture
was stirred for 5 h at room temperature and then filtered with celite. The filtrated was diluted with
EtOAc (300 mL) and washed with distilled water (200 mL
(200 mL 2), and dried with anhydrous Na2SO4. After filtration, the filtrate was evaporated under
reduced pressure and purified by silica gel column to give a white solid (12) (4.98 g, 16.15 mmol, 95%).
Rf = 0.3 (PE/ EtOAc = 4:1, V/V); m.p. 74
75 ◦C; [α]D25 + 72.82 (c = 0.103, CH2Cl2); 1H NMR (400 MHz,
CDCl3) 8.05 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 5.81 (d, J = 3.5 Hz, 1H),
4.71 (t, J = 3.9 Hz, 1H), 4.65 (dd, J = 12.2, 2.2 Hz, 1H), 4.41 (dd, J = 12.2, 5.0 Hz, 1H), 4.33 4.27 (m, 1H),
3.63 (dd, J = 9.1, 4.2 Hz, 1H), 3.49 (s, 3H), 1.61 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3)
166.5,
×
2), sat. NaHCO3 (200 mL
×
2), brine
×
−
δ
−
δ
133.3, 130.2, 130.0 (C
×
2), 128.6 (C
×
2), 113.4, 104.4, 81.3, 77.6, 76.7, 63.6, 58.7, 27.0, 26.7; HRESIMS m/z:
[M + Na]+ calcd. for C16H20O6Na 331.1152, found 331.1136.
4.4. Synthesis of 1,2-O-diacetyl-3-O-methyl-5-O-benzoyl-d-ribofuranose (7)
To a solution of (12) (3.0 g, 9.73 mmol) in CH3CO2H (30 mL) and Ac2O (5.96 g, 58.38 mmol)
concentrated H2SO4 (900 mg) was added dropwise in ice-bath conditions. After addition, the reaction
mixture was stirred for 3h at room temperature. TLC detection showed the reaction was finished.
The mixture was poured into H2O (100 mL) and extracted with CH2Cl2 (100 mL
organic layer was washed with distilled water (150 mL 2), sat. NaHCO3 (150 mL
(150 mL 2), and dried with anhydrous Na2SO4. After filtration, the resulting solution was evaporated
×
3). The combined
×
×
2), brine
×
under reduced pressure and purified by silica gel column to give a viscous mass of monomers of (7)
(3.12 g, 8.86 mmol, 91%, α:β = 2:3).
7β:Rf = 0.25 (PE/EtOAc = 4:1, V/V); [α]D25
−
11.96 (c = 0.092, CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ
8.07 (d, J = 7.4 Hz, 2H), 7.57 (t, J = 7.1 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 6.15 (s, 1H), 5.33 (d, J = 3.9 Hz,
1H), 4.65 (dd, J = 12.0, 2.8 Hz, 1H), 4.40 (dd, J = 12.1, 4.1 Hz, 1H), 4.35 4.28 (m, 1H), 4.07 (dd, J = 7.9,
4.2 Hz, 1H), 3.40 (s, 3H), 2.16 (s, 3H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3)
169.8, 169.0, 166.2,
−
δ
133.4, 130.0, 129.8 (C × 2), 128.5 (C × 2), 98.6, 79.9, 79.2, 73.2, 63.8, 59.4, 21.0, 20.8, HRESIMS m/z: [M +
Na]+ calcd. for C17H20O8Na 375.1050, found 375.1047.
7α:Rf = 0.20 (PE/ EtOAc = 4:1, V/V); [α]2D5 + 59.02 (c = 0.122, CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ
8.03 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 6.41 (d, J = 4.6 Hz, 1H), 5.20
(dd, J = 6.3, 4.9 Hz, 1H), 4.51 (dd, J = 7.3, 4.9 Hz, 2H), 4.42 (dd, J = 12.8, 5.3 Hz, 1H), 3.96 (dd, J = 6.4,
3.9 Hz, 1H), 3.41 (s, 3H), 2.15 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3)
170.0 (C 2), 166.2,
δ
×
133.4, 129.8 (C × 2), 129.6, 128.6 (C × 2), 94.5, 81.6, 78.2, 71.1, 64.3, 59.2, 21.2, 20.6; HRESIMS m/z: [M +
Na]+ calcd. for C17H20O8Na 375.1050, found 375.1050.
4.5. Synthesis of N4-benzoyl-5-cyano-6-bromo-7-(20-O-acetyl -30-O-methyl-50-O-benzoyl-β-d- ribofuranosyl)
-7H-pyrrolo[2,3-d] pyrimidine (16)
To a suspended solution of N4-benzoyl-5-cyano-6-bromo-7H-pyrrolo[2,3-d] pyrimidine (15) (1.0 g,
2.92 mmol) in dry MeCN (15 mL), BSA (2.37 g, 11.68 mmol) was added and stirred for 20 min at 50 ◦C
under argon atmosphere. After cooling to room temperature, the solution of (7) (2.06 g, 5.84 mmol)
in dry MeCN (10 mL) along with TMSOTf (2.59 g, 11.68 mmol) w◦ere added to the reaction mixture
◦
at 0 C. The mixture was stirred for 15 min before heating to 80 C for 4h. Then the solution was
poured into cold sat. NaHCO3 solution (30 mL) and extracted with EtOAc (100 mL
×
2). The combined
organic layer was washed with sat. NaHCO3 (30 mL 3), brine (30 mL 2), and dried with anhydrous
×
×

Mar. Drugs 2019, 17, 226
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Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by a silica gel
column (CH2Cl2: MeOH, V/V = 100:1) to afford (16) (1.65 g, 2.60 mmol, 89%) as white solid. Rf= 0.40
(CH2Cl2/EtOAc = 5:1, V/V); m.p. 183
DMSO-d6) : 11.55 (s, 1H), 8.65 (s, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 7.7 Hz, 2H), 7.65 (t, J = 7.2 Hz,
2H), 7.57 (t, J = 7.5 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 6.40~6.29 (m, 1H), 6.20 (d, J = 3.1 Hz, 1H), 4.80 (t,
J = 6.4 Hz, 1H), 4.71 (dd, J = 12.3, 2.3 Hz, 1H), 4.56 4.45 (m, 1H), 4.44 4.34 (m, 1H), 3.46 (s, 3H),
2.13 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 170.2, 167.4, 165.8 152.9, 151.8, 151.4, 133.9, 133.1, 129.6
−
186 ◦C; [α]2D5
−
38.00 (c = 0.1, CH3OH); 1H NMR (400 MHz,
δ
−
−
(C
×
2), 129.4 (C
×
2), 129.1 (C
×
2), 129.0 (C
×
2), 128.9 (C
×
2), 127.2, 114.2, 111.7, 91.3, 89.7, 80.1, 78.0,
72.6, 63.2, 59.1, 21.0; HRESIMS m/z: [M + Na]+ calcd. for C29H24BrN5O7Na 656.0751, found 656.0758.
4.6. Synthesis of 5-cyano-6-bromo-7-(30-O-methyl-β-d-ribofuranosyl)-7H-pyrrolo[2,3-d] pyrimidine (17)
A solution of (16) (2.0 g, 3.15 mmol) in methanolic ammonia (saturated with NH3 at 0 ◦C for
◦
2h, 20 mL) was placed in an autoclave and stirred at 40 C for 12 h. Then the reaction mixture
was concentrated to dryness and the residue was purified by a silica gel column (CH2Cl2: MeOH,
V/V = 30:1) to afford (17) (1.05 g, 2.73 mmol, 87%) as white solid. Rf = 0.45 (CH2Cl2:CH3OH = 20:1,
V/V); m.p. 204
−
206 ◦C; [α]2D5
−
41.50 (c = 0.10, CH3OH); 1H NMR (400 MHz, DMSO-d6)
δ 8.21 (s, 1H),
7.11 (s, 2H), 5.91 (d, J = 6.9 Hz, 1H), 5.76 (s, 1H), 5.55 (d, J = 6.6 Hz, 1H), 5.39 (dd, J = 7.8, 4.2 Hz, 1H),
5.25 (d, J = 6.0 Hz, 1H), 4.07 (d, J = 2.0 Hz, 1H), 3.92 (d, J = 3.0 Hz, 1H), 3.68 (dd, J = 10.2, 5.9 Hz, 1H),
3.63
−
3.50 (m, 1H), 3.44 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
δ: 156.1, 153.2, 150.0, 121.6, 114.1, 102.1,
90.9, 87.5, 84.1, 80.0, 70.7, 61.9, 57.7; HRESIMS m/z: [M + Na]+ calcd. for C13H14BrN5O4Na 406.0121,
found 406.0126.
4.7. 4-carbonyl-5-cyano-6-bromo-7-(30-O-methyl-β-d-ribofuranosyl)-7H-pyrrolo[2,3-d] pyrimidine (18)
To a solution of (17) (1.0 g, 2.6 mmol) in CH3CO2H (20 mL), an aqueous solution (NaNO2/H2O,
1.79 g/9.0 mL) was added slowly. After addition, the reaction mixture was heated to 60 ◦C for 8 h.
After the reaction was finished (by TLC monitoring), the reaction mixture was concentrated to dryness.
The residue was dissolved with CH2Cl2 (20 mL). After filtration, the resulting solution was evaporated
under reduced pressure and the residue was purified by silica gel column to afford a white solid of
(
18) (0.795 g, 2.06 mmol, 80%). Rf = 0.32 (CH2Cl2:CH3OH = 20:1, V/V); m.p. 219
(c = 0.08, CH3OH); 1H NMR (400 MHz, DMSO-d6)
: 12.76 (brs, 1H), 8.14 (d, J = 3.6 Hz, 1H), 5.92 (d,
J = 6.6 Hz, 1H), 5.58 (brs, 1H), 5.14 (s, 1H), 4.99 (brs, 1H), 4.02 3.99 (m, 1H), 3.91 (dd, J = 5.2, 3.3 Hz,
1H), 3.65 (dd, J = 11.7, 5.2 Hz, 1H), 3.54 (dd, J = 11.5, 5.0 Hz, 1H), 3.42 (s, 3H); 13C NMR (100 MHz,
−
220 ◦C; [α]2D5
−
67.50
δ
−
DMSO-d6) δ: 156.0, 148.6, 147.0, 119.4, 114.0, 109.5, 91.4, 91.2, 84.3, 80.1, 71.4, 62.1, 58.2; HRESIMS m/z:
[M + Na]+ calcd. for C13H13BrN4O5Na 406.9962, found 406.9967.
4.8. Synthesis of 4-carbonyl-5-cyano-7-(30-O-methyl-β-d-ribofuranosyl)-7H-pyrrolo[2,3-d] pyrimidine (19)
To a solution of (18) (1.0 g, 2.6 mmol) in THF (10 mL) and MeOH (10 mL) was added 10% Pd/C
(100 mg) and Et3N (0.1 mL). After stirring at room temperature for 5 h under H2 atmosphere, the
mixture was filtered with celite and the filtrated was concentrated to dryness under reduced pressure
and purified by a silica gel column to afford a white solid of (19) (0.74 g, 2.42 mmol, 92%). Rf = 0.15
(CH2Cl2:CH3OH = 20:1, V/V); m.p. 94
DMSO-d6) 12.55 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 6.01 (d, J = 5.3 Hz, 1H), 5.60 (d, J = 6.2 Hz, 1H), 5.22
(t, J = 5.1 Hz, 1H), 4.47 (dd, J = 10.7, 5.4 Hz, 1H), 4.02 (d, J = 3.7 Hz, 1H), 3.83 (t, J = 4.3 Hz, 1H), 3.66 (m,
−
96 ◦C; [α]2D5
−
38.0 (c = 0.10, CH3OH); 1H NMR (400 MHz,
δ
1H), 3.56 (m, 1H), 3.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
δ 156.9, 148.0, 146.6, 130.5, 114.8, 107.6,
88.1, 86.7, 83.2, 79.3, 73.8, 61.1, 57.7; HRESIMS m/z: [M + Na]+ calcd. for C13H14N4O5Na 329.0856,
found 329.0848.

Mar. Drugs 2019, 17, 226
9 of 11
4.9. Synthesis of 4-carbonyl-5-cyano-7-(30-O-methyl-50-O-(2-nitrophenyl) selanyl -β-d-ribofuranosyl)-7H-
pyrrolo [2,3-d] pyrimidine (20)
To a solution of (11) (91.5 mg, 0.3 mmol) in anhydrous pyridine (2 mL), o-nitrophenyl selenocyanate
(204 mg, 0.9 mmol) and tributyl phosphine (0.225 mL, 0.9 mmol) were added under argon atmosphere.
The reaction mixture was stirred for 4 h at room temperature and concentrated to dryness under
reduced pressure. The residue was purified by a silica gel column to afford a yellow solid of (12
(129.1 mg, 0.26 mmol, 88%). Rf = 0.48 (CH2Cl2:CH3OH = 20:1, V/V); m.p. 187 40.0
191 ◦C; [α]2D5
(c = 0.10, CH3OH); 1H NMR (400 MHz, DMSO-d6)
12.55 (d, J = 3.1 Hz, 1H), 8.35 (s, 1H), 8.25 (dd,
J = 8.3, 1.2 Hz, 1H), 8.09 (d, J = 3.8 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.70 7.57 (m, 1H), 7.45 (t, J = 7.3 Hz,
)
−
−
δ
−
1H), 6.01 (d, J = 5.5 Hz, 1H), 5.70 (d, J = 6.1 Hz, 1H), 4.67 (dd, J = 10.6, 5.3 Hz, 1H), 4.22 (dd, J = 10.5,
6.6 Hz, 1H), 3.89 (t, J = 4.4 Hz, 1H), 3.44 (d, J = 6.7 Hz, 2H), 3.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
δ
156.7, 148.0, 146.5 (C
×
2), 134.2, 131.3, 130.7, 130.0, 126.3, 126.2, 114.4, 107.5, 88.1, 87.0, 82.3, 80.5, 72.8,
57.6, 28.5; HRESIMS m/z: [M + H]+ calcd. for C19H18N5O6Se 492.0417, found 492.0428.
4.10. Synthesis of mycalisine B (4)
To a solution of (20) (100 mg, 0.20 mmol) in THF (2 mL), 30% H2O2 (0.172 mL, 2 mmol) was
added at ice-bath. After addition, the reaction mixture was stirred for 2 h at room temperature and
concentrated to dryness under reduced pressure. The residue was dissolved in anhydrous pyridine
(4 mL) and Et3N (0.4 mL, 0.3 mmol). Then the mixture was heated to 50 ◦C for 5 h. After cooling, the
reaction mixture was concentrated under reduced pressure. The obtained residue was purified by
a silica gel column to afford a white solid of mycalisine B (
(CH2Cl2/CH3OH = 20:1, V/V); m.p. 85
88 ◦C; [α]2D5 70.0 (c = 0.10, CH3OH); 1H NMR (400 MHz,
DMSO-d6) 12.26 (brs, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 6.25 (d, J = 7.0 Hz, 1H), 5.83 (s, 1H), 4.83 (m, 1H),
4.45 (d, J = 1.5 Hz, 1H), 4.32 (d, J = 1.6 Hz, 1H), 4.21 (d, J = 4.7 Hz, 1H), 3.39 (s, 3H); 13C NMR (100 MHz,
4) (49.7 mg, 0.17 mmol, 87%). Rf = 0.32
−
−
δ
DMSO-d6)
δ 157.4, 156.6, 148.5, 146.8, 130.9, 114.2, 107.8, 87.8, 87.6, 87.4, 78.4, 72.4, 56.2; HRESIMS m/z:
[M + H]+ calcd. for C13H13N4O4 289.0931, found 289.0937.
Supplementary Materials: The NMR spectra of compound Mycalisine
4, 7–12, 16–20 and crystallographic data
of compound 11 are available online at http://www.mdpi.com/1660-3397/17/4/226/s1.
Author Contributions: Q.X. and H.D. conceived and designed the experiments; H.D., Z.R., P.K. and X.D.
performed the experiments; H.D. and J.B. analyzed the data; Q.X. and H.D. wrote the paper.
Funding: This research was funded by the National Natural Science Foundation of China (no. 21676131 and
no. 21462019), the Science Foundation of Jiangxi Province (20143ACB20012), and Jiangxi Science & Technology
Normal University (Doctor Startup Fund for Dr. H.D. 2018BSQD022) for financial support.
Conflicts of Interest: The authors declare no conflict of interest.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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