Application of a tandem seleno-michael/aldol reaction in the total syntheses of (+)-Pericosine B, (+)-Pericosine C, (+)-COTC and 7-chloro-analogue of (+)-Gabosine C

Article abstract of DOI:10.1016/j.tet.2020.131397

Synthesis of (+)-Pericosine B, (+)-Pericosine C, (+)-COTC and a 7-chloro-analogue of (+)-Gabosine C was achieved via tandem seleno-Michael/aldol reactions as key steps. The carbasugar linear precursor was obtained from cheap and readily available D-ribose in 7 steps which included resolution of the D-ribopyranose and the D-ribofuranose forms. Further transformation of the cyclic product involving a regioselective Steglich esterification or methylation of the secondary hydroxyl group gave rise to protected (+)-COTC, (+)-Pericosine B and (+)-Pericosine C. Deprotection of benzyl ethers at ?78 °C gave the titled compounds in satisfactory yields.

Full text of DOI:10.1016/j.tet.2020.131397

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Application of a tandem seleno-michael/aldol reaction in the total
syntheses of (þ)-Pericosine B, (þ)-Pericosine C, (þ)-COTC and 7-
chloro-analogue of (þ)-Gabosine C
*
ꢀ
Natalia Bidus, Piotr Banachowicz, Szymon Buda
Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Krakow, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of (þ)-Pericosine B, (þ)-Pericosine C, (þ)-COTC and a 7-chloro-analogue of (þ)-Gabosine C was
achieved via tandem seleno-Michael/aldol reactions as key steps. The carbasugar linear precursor was
Received 4 April 2020
Received in revised form
3 July 2020
Accepted 9 July 2020
Available online xxx
obtained from cheap and readily available
D-ribose in 7 steps which included resolution of the D-ribo-
pyranose and the -ribofuranose forms. Further transformation of the cyclic product involving a regio-
D
selective Steglich esterification or methylation of the secondary hydroxyl group gave rise to protected
(þ)-COTC, (þ)-Pericosine B and (þ)-Pericosine C. Deprotection of benzyl ethers at ꢀ78 ꢁC gave the titled
compounds in satisfactory yields.
Keywords:
Seleno-michael/aldol reaction
Carbasugars
© 2020 Elsevier Ltd. All rights reserved.
Pericosines
Cyclization
Gabosines
1. Introduction
topoisomerase II or protein kinase EGFR [10].
In 1974 (ꢀ)-Gabosine C was isolated from a culture broth of
Carbasugars [1] are important carbohydrate analogues in which
the ring oxygen is replaced with a methylene group. This structural
difference leads to the absence of a hemiacetal linkage which
makes them more stable than their parent true sugars.
Streptomyces filipensis and is identical to a known antibiotic KD16-
U1 [11]. The crotonic ester of (ꢀ)-Gabosine C known as a (ꢀ)-COTC
was isolated one year later and was reported to possess cytotoxic
and cancerostatic activity [12,13].
The first carbasugar, 5a-carba-
sized by prof. G.E McCasland’s group in 1966 [2]. A few years later
5a-carba- -galactopyranose was isolated from a natural source of
a fermentation broth of Streptomyces sp. MA-4145 [3]. Since then,
interest in these compounds has increased dramatically, mainly
because of their interesting and unique biological properties such
as antitumor, antibacterial, antiviral and enzyme inhibitory activity
[1,4e8].
Pericosines (A-E) are a subclass of carbasugars which have been
isolated from the fungus Perconia byssoides (OUPSeN133), origi-
nally separated from sea hare, Aplysia kurodai (Fig. 1) [9]. They have
been shown to display a wide range of interesting biological ac-
tivities such as significant cytotoxicity against P388 lymphocytic
human cancer cells, growth inhibition of tumor cell lines HBC-5 and
SNB-75 and inhibition of some enzymes including human
a
-
DL-talopyranose, was synthe-
The valuable biological activities of carbasugars attracts the
attention of both biologists and chemists. The majority of synthetic
approaches for the total synthesis of Pericosines start from shikimic
acid or quinic acids, which are relatively expensive and have limited
a-D
availability [14,15]. Other synthetic strategies involve multistep D-
ribose transformation and an RCM strategy of carbocylic ring con-
struction [16e20] or functionalization of the carbocyclic core from
commercially available enantiopure bromocyclohexadiene diol
[21,22].
Synthetic strategies for the preparation of carbasugars from the
Gabosine family have been more extensively studied, mainly due to
more diversification in that group of bioactive compounds. Total
syntheses of Gabosines were reviewed in 2012 by Mac and co-
workers [23]. From that time some novel interesting approaches
arose including transformation of
d-D-gluconolactone and aldol
type cyclization [24,25], demethylative construction of functional-
ized cyclohexenecarbaldehyde by vinylogous ketal cleavage pre-
pared from inositols [26] or tandem seleno-Michael/aldol type
* Corresponding author.
E-mail address: szym.buda@gmail.com (S. Buda).
https://doi.org/10.1016/j.tet.2020.131397
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
ꢀ
Please cite this article as: N. Bidus et al., Application of a tandem seleno-michael/aldol reaction in the total syntheses of (þ)-Pericosine B,
(þ)-Pericosine C, (þ)-COTC and 7-chloro-analogue of (þ)-Gabosine C, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131397

ꢀ
N. Bidus et al. / Tetrahedron xxx (xxxx) xxx
2
Scheme 2. Preparation of mixture of protected D-ribopyranose and D-ribofuranoses.
Fig. 1. Structures of naturally occurring Pericosines, (þ)-Gabosine C and (þ)-COTC.
products were not observed under refluxing. Attempts of chro-
matographic separation of desired 11 from 12 were unsuccessful.
In order to separate 11 from 12, we turned our attention to re-
agents selective towards primary hydroxyl groups. Initial attempts
were performed using the most typical approaches, being the re-
action with tert-butyldiphenylsilyl chloride (TBDPSCl) in the pres-
ence of imidazole or triphenylmethyl chloride (TrCl) in pyridine and
catalytic amounts of 4-dimethylaminopyridine (DMAP). However,
even those reactions carried out with an excess of TrCl or TBDPSCl
for 24 h, resulted in poor installation of the appropriate ether
(based on TLC plate, and NMR analysis of crude products). We
searched for alternative reagents and chose the less hindered and
more reactive tert-butyldimethylsilyl chloride which was initially
rejected in order to avoid additional installation on the secondary
group. Maintaining a low temperature and monitoring the reaction
by TLC allowed us to obtain a satisfactory yield of 13 (56%) and
recover a significant amount of unreacted 11 (27%) via chroma-
tography (Scheme 3). The removal of the TBS-ether with an excess
of Olah’s reagent was quantitative and allowed the desired 12 to be
carbocyclization of monosaccharide derived precursors [27,28].
In this work we present our recent studies of the application of
the tandem seleno-Michael/aldol process in carbasugar synthesis
involving D-ribose as a readily available and cheap starting material.
2. Results and discussion
Compounds 2, 3 and 7 were synthesized using the method
initially proposed by us in 2018 in the total synthesis of
(þ)-valienamine, where the carbasugar precursor was obtained in
5-steps from naturally occurring -xylose [28]. In our first approach
we planned to prepare linear precursor 12 in a similar way from
b-
D
D
-
ribose. After cyclization of 12 under optimized conditions we were
going to methylate the obtained carbasugar, yielding protected
(þ)-Pericosine B (2) and C (3) or perform a selective reduction of
the allylic methyl ester, conduct esterification on the crotonic acid
derivative and finally oxidize the remaining hydroxyl group,
resulting in protected (þ)-COTC (7) (Scheme 1).
obtained in 37% yield over 6 steps from D-ribose. Oxidation of the
Our initial studies focused on the preparation of precursor 12.
Starting from
D-ribose we prepared protected D-ribopyranose
(Scheme 2) [29].
Unfortunately, regardless of the great effort put into chro-
matographic purification of the pyranose form from the furanose
one, we were not able to separate them on a satisfactory scale. After
3 steps we obtained a complex mixture of 10 in 73% yield and we
decided to use it without further purification in the next step. The
Wittig reaction of 10 with the appropriate phosphonium ylide re-
sults in a mixture of E/Z-diastereoisomers derived from both py-
ranose and furanose forms with a total yield 91%. Oxo-Michael
Scheme 3. Synthesis and resolution of 12.
Scheme 1. Retrosynthetic analysis of (þ)-Pericosine B, (þ)-Pericosine C and (þ)-COTC from D-ribose.
ꢀ
Please cite this article as: N. Bidus et al., Application of a tandem seleno-michael/aldol reaction in the total syntheses of (þ)-Pericosine B,
(þ)-Pericosine C, (þ)-COTC and 7-chloro-analogue of (þ)-Gabosine C, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131397

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N. Bidus et al. / Tetrahedron xxx (xxxx) xxx
3
Table 1
Optimization of methylation reaction.
Entry
Solvent
T [ꢁC]
t [h]
16
17
syn-15
ꢂ1a
ꢂDCM
ꢂDCM
ꢂPhMe
ꢂPhMe
ꢂrt
ꢂ24
ꢂ24
ꢂ24
ꢂ48
ꢂtraces
ꢂ52%
ꢂtraces
ꢂtraces
ꢂ21%
ꢂ e
ꢂ2b
ꢂ40
ꢂ48%
ꢂ21%
ꢂtraces
ꢂ3b,c
ꢂ100
ꢂ100
ꢂ37%
ꢂ4b,c
ꢂ51%
ꢂ18%
Conditions: 100 mg scale, [a] 10 equiv. MeI, 1.1 equiv. Ag2O [b] 20 equiv. MeI, 5
equiv. Ag2O, [c] reaction was performed in a sealed tube.
obtain (þ)-Pericosine C (3) and (þ)-Pericosine B (2) in 85% and 54%
yield, respectively. 1H and 13C NMR spectra of obtained products are
comparable to literature values [17].
Scheme 4. Preparation of carbasugar precursor and cyclization step.
Finally, we turned our attention to the synthesis of (þ)-COTC (7)
from carbocyclic intermediate 15 (Scheme 7). In the first step a
mixture of diastereoisomers 15 was selectively reduced with
DIBAL-H resulting in a mixture of 18. In the next step different
conditions for esterification of the primary hydroxyl group with the
crotonyl fragment were examined. Initial attempts of conducting
the reaction with crotonic acid and BF3 or crotonyl chloride and a
base catalyst failed. The first method resulted in a complex mixture
of products mainly containing the product with two ester frag-
ments. Application of crotonyl chloride and an organic base (pyri-
dine or TEA) led to single esterification of the substrate in moderate
primary hydroxyl group with Dess-Martin periodinane gave car-
basugar precursor 14 as a mixture of diastereoisomers (E/Z 0.51:1)
in a very good yield. Further cyclization under tandem seleno/
Michael aldol reaction conditions and consecutive oxidation-
elimination steps allowed us to obtain the carbocyclic core 15 in
68% yield as a nearly equimolar mixture of syn and anti di-
astereoisomers (Scheme 4).
Initially we assumed that the major diastereoisomer would have
a relative configuration of C5 and C6 centers anti, which was
indicated by the relatively high JH5-H6 (7.8 Hz versus 4.4 Hz for syn-
15) in the 1H NMR spectrum. Our theory was confirmed in the total
syntheses of natural products derived from both diastereoisomers
and by comparison of the obtained 1H and 13C NMR spectra.
(þ)-Pericosine B (2) and (þ)-Pericosine C (3) were obtained from 15
by methylation with excess MeI/Ag2O in a sealed tube at 100 ꢁC
(Scheme 5). Initial attempts were conducted under much milder
conditions and are summarized in Table 1. Only long-term heating
in a sealed tube in toluene allowed both diastereoisomers to un-
dergo the reaction to give 16 and 17 in 69% yield.
We postulate that the difference in reactivity of said di-
astereoisomers could be caused by the fact that the secondary
hydroxyl group of 17 is in a pseudo-axial position is more sterically
hindered and less reactive than the pseudo-equatorial group in 16
(Scheme 6). The difference is significant to the extent that under
very mild conditions (DCM/40 ꢁC, excess of MeI/Ag2O) anti-15 was
completely consumed when syn-15 was fully recovered from the
reaction. Fortunately, after the methylation step, 16 and 17 were
easily separated by simple column chromatography, while the
mixture of anti/syn-15 was inseparable.
Scheme 6. Possible conformation of compound 15.
The final step of the synthesis of (þ)-Pericosine B (2) and C (3)
involved deprotection with BCl3. Due to the presence of an
a,b-
unsaturated ester fragment, we were limited solely to non-
hydrogenolysis methods of benzyl ether removal [30]. After a few
unsuccessful attempts, we found that it was crucial to quench the
reaction with NaHCO3 and MeOH at ꢀ78 ꢁC to avoid a side reaction
or decomposition of products. The deprotection step allowed us to
Scheme 5. Preparation of (þ)-Pericosine B and (þ)-Pericosine C.
Scheme 7. Final steps of synthesis of (þ)-COTC and 7-chloro-7-deoxy-(þ)-Gabosine C.
ꢀ
Please cite this article as: N. Bidus et al., Application of a tandem seleno-michael/aldol reaction in the total syntheses of (þ)-Pericosine B,
(þ)-Pericosine C, (þ)-COTC and 7-chloro-analogue of (þ)-Gabosine C, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131397

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4
yield (66%). However, the product was found to have an unexpected
structure and only the rearrangement product whit a terminal
alkene 21 was observed.
NMR spectra were measured at 150 and 75 MHz with complete
proton decoupling. Chemical shifts were reported in ppm from the
residual solvent as an internal standard: CDCl3
CD3OD (
resolution mass spectra were acquired using ESI-TOF method.
(
d
¼ 77.16 ppm);
After optimization of the conditions of both processes we
decided to focus on a different method of preparing the ester. We
turned our attention to the Steglich reaction, which is known as an
effective and mild method for ester synthesis. Initial attempts at
selective esterification with a stoichiometric amount of crotonic
acid and 1.5 equiv. of DCC resulted in very poor yields, even when
running the reaction for 24 h. After optimization of the conditions
we found a good balance between conversion of substrate and the
appearance of an over-esterified product. For effective preparation
of 19 a 1.5 M excess of crotonic acid and addition of 0.2 equiv. of
DMAP were crucial. This combination resulted in a 52% yield and
recovery of 9% of unreacted substrate. Tri-O-benzylated (þ)-COTC
20 was obtained by Swern oxidation of the remaining hydroxyl
group in quantitative yield. Other oxidation strategies, including
oxidation with Dess-Martin periodinane, even at increased tem-
perature resulted in selective oxidation of only one diastereoisomer
of 19, leaving the other untouched. This could be explained by the
same effect of an axial sterically hindered hydroxyl group, which
makes it much less reactive, as was the case in the methylation
process.
d
¼ 49.00 ppm); (CD3)2CO (
d
¼ 206.26 ppm). High-
4.1.1. Synthesis of methyl (4S,5R,6R)-4,5,7-tris(benzyloxy)-6-
hydroxyhept-2-enoate (11) and methyl (4S,5S,6R)-4,5,6-
tris(benzyloxy)-7-hydroxyhept-2-enoate (12)
To a methanolic solution of 0.8% HCl (prepared by dropwise
addition of SOCl2 (2 mL) to anhydrous methanol (125 mL)) D-ribose
(12.50 g, 83.26 mmol) was added in one portion, and the resulting
mixture was refluxed for 4 h under argon (reaction was monitored
by TLC DCM/MeOH v/v ¼ 10:1). The reaction mixture was allowed
to cool to room temperature, neutralized by addition of solid
NaHCO3 (8.50 g, 0.101 mol) and concentrated under reduced
pressure. The residue was dissolved in ethanol (100 mL) and
concentrated to half of the original volume, toluene (50 mL) was
added, and the mixture was concentrated to dryness. The residual
crude oil was used without further purification in the next step. The
viscous oil from the previous step was dissolved in anhydrous DMF
(125 mL) and anhydrous THF (125 mL) and in five portions was
added to a 60% NaH suspension in mineral oil (16.63 g, 0.416 mol)
cooled to 0 ꢁC. After hydrogen evolution was complete, the mixture
was treated with BnBr (39.56 mL, 0.333 mol) and stirred for 48 h in
room temperature (reaction was monitored by TLC Hex/EA v/
v ¼ 4:1). The reaction mixture was carefully quenched with 10%
cold, aqueous solution of NH4Cl (65 mL). The aqueous layer was
extracted with ethyl acetate (2 ꢃ 100 mL), and the combined
organic layers were washed with water (3 ꢃ 80 mL) and brine
(100 mL), dried over anhydrous MgSO4, and concentrated under
reduced pressure. Flash chromatography (Hex/EA v/v 3:1) allowed
to remove major impurities before the next step. The partially
purified mixture of ribosides from the previous step was heated
under reflux for 10 h with 1 M H2SO4 (105 mL), AcOH (120 mL), and
1,4-dioxane (110 mL). The mixture was cooled to room tempera-
ture. The aqueous layer was extracted with ethyl acetate
(2 ꢃ 125 mL), and the combined organic layers were washed with
water (3 ꢃ 100 mL) and brine (100 mL), dried over anhydrous
MgSO4, and concentrated under reduced pressure. Column chro-
matography (Hex/EA v/v ¼ 3:1) gave the complex mixture of py-
ranoses and furanoses 10 as a yellowish syrup (73%, 25.50 g,
60.64 mmol). 1H NMR spectrum is attached in SI.
The final deprotection step with boron trichloride turned out to
be extremely difficult due to the presence of the crotonic ester and
the other carbonyl group in the molecule. Treatment of 20 with
boron trichloride under previously optimized conditions led to a
mixture of unprotected (þ)-COTC (7) and the 7-chloro-analogue of
(þ)-Gabosine C (22) in 26% and 40% yield, respectively. We have not
further examined the deprotection step.
3. Conclusion
In summary, we have synthesized three known carbasugars:
(þ)-Pericosine B, (þ)-Pericosine C, (þ)-COTC (unnatural) and novel
derivative 7-chloro-7-deoxy-(þ)-Gabosine C using intramolecular
seleno-Michael/aldol reactions as key steps. The developed pro-
cedure seems to be a good method for synthesis of the carbasugar
core in general. The newly obtained 7-chloro-analogue of
(þ)-Gabosine C could be an interesting building block for the
preparation of more complex carbasugar structures.
4. Experimental section
To a solution of 10 (2.50 g, 5.95 mmol) in anhydrous benzene
(20 mL) methyl (triphenylphosphoranylidene)acetate (3.98 g,
11.89 mmol) was added in one portion, and the mixture was stirred
at reflux for 8 h (reaction was monitored by TLC Hex/EA v/v ¼ 3:1).
After the indicated time, the next portion of methyl (triphenyl-
phosphoranylidene) acetate (1.99 g, 5.95 mmol) was added and
heating at reflux was continued for the next 4 h. The reaction
mixture was cooled to room temperature and benzene was evap-
orated under reduced pressure. Triphenylphosphine oxide was
precipitated from the mixture of Hex/Ether v/v ¼ 1:1 and filtered by
suction. The solvent was removed under reduced pressure and the
crude product was purified by column chromatography (Hex/EA v/
v ¼ 2:1). The product as a mixture of primary and secondary al-
cohols 11 and 12 (12E/12Z/11E/11Z 1:0.54:0.51:0.30) was obtained
as a colorless oil (91%, 2.58 g, 5.41 mmol). 1H NMR (only key signals)
4.1. General information
All starting materials and reagents were purchased from com-
mercial sources and were used without purification. Reactions
were monitored using TLC on silica [alu-plates (0.2 mm)]. Plates
were visualized with UV light (254 nm) and by treatment with:
aqueous cerium (IV) sulfate solution with molybdic and sulfuric
acid followed by heating. All organic solutions were dried over
anhydrous magnesium sulfate. Reaction products were purified by
column chromatography using silica gel 60 (240e400 mesh). Op-
tical rotations were measured at room temperature with a digital
polarimeter. CDCl3, D2O, CD3OD, (CD3)2CO were used as NMR sol-
vents. 1H NMR spectra were recorded at 600 or 300 MHz, and
referenced relative to: CDCl3
¼ 7.26 ppm); D2O e solvent residual peak (
e solvent residual peak (
¼ 3.31 ppm); (CD3)2CO e solvent residual
peak (
e
solvent residual peak
(d
d
¼ 4.79 ppm); CD3OD
(300 MHz, CDCl3)
d
7.05 (dd, J ¼ 15.9, 6.8 Hz, 0.51H 11E), 6.95 (dd,
d
J ¼ 15.8, 6.5 Hz, 1H 12E), 6.45 (dd, J ¼ 11.8, 9.1 Hz, 0.30H 11Z), 6.32
(dd, J ¼ 11.8, 8.5 Hz, 0.54H 12Z), 6.14 (dd, J ¼ 15.9, 1.1 Hz, 0.51H 11E),
6.03 (dd, J ¼ 11.8, 1.1 Hz, 0.30H 11Z), 5.95 (dd, J ¼ 15.9, 1.2 Hz, 1H
12E), 5.92 (dd, J ¼ 11.8, 1.3 Hz, 0.54H 12Z).
d
¼ 2.05 ppm). Data are reported as follows: chemical shift in
parts per million (ppm), multiplicity (s ¼ singlet, d ¼ doublet,
t ¼ triplet, dd ¼ doublet of doublets, dd ¼ doublet of doublet of
doublets, ddd ¼ doublet of doublet of doublet of doublets,
m ¼ multiplet), coupling constants (in hertz) and integration. 13C
To a solution of 11 and 12 (2.58 g, 5.41 mmol) in anhydrous DMF
(35 mL) was added tert-butyldimethylsilyl chloride (0.82 g,
ꢀ
Please cite this article as: N. Bidus et al., Application of a tandem seleno-michael/aldol reaction in the total syntheses of (þ)-Pericosine B,
(þ)-Pericosine C, (þ)-COTC and 7-chloro-analogue of (þ)-Gabosine C, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131397

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5
5.41 mmol) and imidazole (0.73 g, 10.82 mmol) at ꢀ20 ꢁC. The
mixture was allowed to reach ꢀ10 ꢁC. After 1 h the reaction mixture
was carefully quenched with aqueous solution of NH4Cl (20 mL).
The aqueous layer was extracted with ethyl acetate (2 ꢃ 40 mL),
and the combined organic layers were washed with water
(2 ꢃ 50 mL) and brine (40 mL). The organic phase was dried over
anhydrous MgSO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography (Hex/EA v/
v ¼ 10:1) to give the titled compound 13 as a mixture of di-
(m, 0.53H), 3.67 (s, 1.59H), 3.56 (dt, J ¼ 6.8, 4.1 Hz, 1H); 13C NMR
(150 MHz, CDCl3)
d 166.2, 166.2, 148.1, 144.9, 138.2, 138.1, 137.8,
137.6, 128.5, 128.4, 128.4, 128.4, 128.3, 128.3, 128.3, 128.1, 128.0,
127.9, 127.9, 127.8, 127.7, 127.7, 127.6, 127.6, 123.4, 121.2, 81.5, 80.7,
78.6, 78.4, 78.1, 75.3, 74.1, 73.1, 71.8, 71.8, 71.5, 61.2, 60.8, 51.6, 51.4;
HRMS (ESI): calcd. for C29H32NaO6 [MþNa]þ 499.2091, found
499.2091.
4.1.3. Synthesis of methyl (4S,5S,6S,Z)-4,5,6-tris(benzyloxy)-7-
oxohept-2-enoate (14)
astereoisomers (E/Z 1:0.50) as
a colorless oil. (56%, 1.79 g,
3.03 mmol) and an unreacted mixture of secondary alcohols 11 (E/
Z: 1:0.71) as a colorless oil (27%, 0.705 g, 1.48 mmol). Methyl
(4S,5S,6R)-4,5,6-tris(benzyloxy)-7-((tert-butyldimethylsilyl)oxy)
hept-2-enoate (13): Yield after 5 steps ¼ 37.2%; 1H NMR (600 MHz,
A solution of 12 (1.36 g, 2.85 mmol) in anhydrous methylene
chloride (30 mL) was cooled to 0 ꢁC and DesseMartin periodinane
(1.82 g, 4.82 mmol) was added in one portion and stirred at 0 ꢁC for
15 min. Afterwards the ice bath was removed and reaction mixture
was stirred for 3 h at room temperature (reaction was monitored by
TLC Hex/EA v/v ¼ 2:1). The reaction was quenched with a saturated
aqueous solution of NaHCO3. The aqueous layer was extracted with
methylene chloride (3 ꢃ 30 mL), and the combined organic layers
were washed with water (2 ꢃ 100 mL) and brine (100 mL). The
organic phase was dried over anhydrous MgSO4, and concentrated
under reduced pressure. The crude product was purified by column
chromatography (Hex/EA v/v ¼ 6:1) to give the title compound as a
mixture of diastereoisomers (E/Z 1:0.51) as a colorless syrup (86%,
CDCl3)
d
7.36e7.26 (m, 22.5H), 6.97 (dd, J ¼ 15.8, 6.6 Hz, 1H E-iso-
mer), 6.32 (dd, J ¼ 11.8, 8.6 Hz, 0.5H Z-isomer), 5.96 (dd, J ¼ 15.9,
1.2 Hz, 1H E-isomer), 5.87 (dd, J ¼ 11.8, 1.3 Hz, 0.5H Z-isomer), 5.45
(dd, J ¼ 8.6, 3.0, 1.3 Hz, 0.5H Z-isomer), 4.83 (d, J ¼ 11.5 Hz, 0.5H),
4.77 (d, J ¼ 11.4 Hz, 1H), 4.75e4.71 (m, 1.5H), 4.65 (d, J ¼ 11.6 Hz,
0.5H), 4.63 (d, J ¼ 11.4 Hz, 1H), 4.60e4.54 (m, 1.5H), 4.52 (d,
J ¼ 11.6 Hz, 1H), 4.42 (d, J ¼ 11.7 Hz, 1H), 4.34 (dd, J ¼ 6.5, 3.9, 1.3 Hz,
1H), 3.95 (dd, J ¼ 10.9, 2.3 Hz, 0.5H), 3.90 (dd, J ¼ 11.0, 3.3 Hz, 1H),
3.86 (dd, J ¼ 6.4, 3.9 Hz, 1H), 3.82 (dd, J ¼ 7.1, 3.0 Hz, 0.5H),
3.78e3.73 (m, 1.5H), 3.72e3.69 (m, 2H), 3.73 (s, 3H CH3-E-isomer),
3.72e3.69 (m, 0.5H), 3.63 (s, 1.5H CH3-Z-isomer), 3.58 (dd, J ¼ 6.4,
5.4, 3.3 Hz, 1H), 0.89 (s, 9H), 0.88 (s, 4.5H), 0.03 (s, 6H), 0.01 (s, 3H);
1.17 g, 2.47 mmol); 1H NMR (600 MHz, CDCl3)
d
9.55 (d, J ¼ 1.5 Hz,
0.51H), 9.50 (d, J ¼ 1.0 Hz, 1H), 7.36e7.23 (m, 22.5H), 6.92 (dd,
J ¼ 15.8, 6.2 Hz, 1H), 6.10 (dd, J ¼ 11.7, 8.8 Hz, 0.51H), 6.05 (dd,
J ¼ 15.8, 1.2 Hz,1H), 5.96 (dd, J ¼ 11.7,1.1 Hz, 0.51H), 5.55 (dd, J ¼ 8.7,
5.9, 1.0 Hz, 0.51H), 4.73 (d, J ¼ 12.0 Hz, 1H), 4.70e4.65 (m, 2H), 4.62
(s, 1H), 4.59e4.54 (m, 3H), 4.53e4.49 (m, 1H), 4.44 (d, J ¼ 11.3 Hz,
1H), 4.32 (dd, J ¼ 7.7, 6.3, 1.1 Hz, 1H), 4.10 (dd, J ¼ 4.2, 1.5 Hz, 0.51H),
4.05e4.02 (m, 1H), 3.87 (dd, J ¼ 5.9, 4.2 Hz, 0.51H), 3.81 (dd, J ¼ 7.9,
2.7 Hz, 1H), 3.76 (s, 3H), 3.69 (s, 1.53H); 13C NMR (150 MHz, CDCl3)
13C NMR (150 MHz, CDCl3)
d 166.6, 166.4, 148.4, 145.7, 139.0, 138.8,
138.8, 138.5, 138.4, 138.1, 128.5, 128.4, 128.4, 128.3, 128.3, 128.2,
128.2, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.5, 127.3, 123.2, 120.9,
81.1, 80.3, 79.7, 79.5, 79.1, 75.5, 74.1, 73.1, 72.7, 72.5, 71.7, 71.5, 63.5,
62.8, 51.7, 51.4, 26.0, 18.4. HRMS (ESI): calcd. for C35H46NaO6Si
[MþNa]þ 613.2956, found 613.2956. Methyl (4S,5R,6R)-4,5,7-
tris(benzyloxy)-6-hydroxyhept-2-enoate (11): Yield after
5
d 201.3, 201.3, 166.4, 166.3, 146.8, 145.5, 138.0, 137.7, 137.5, 137.2,
steps ¼ 17.9%; 1H NMR (300 MHz, CDCl3)
d
7.37e7.21 (m, 25.5H),
137.2, 128.6, 128.5, 128.5, 128.4, 128.3, 128.2, 128.1, 128.1, 128.1,
128.0, 127.9, 127.8, 127.7, 123.6, 123.0, 83.0, 82.5, 82.2, 82.2, 76.7,
73.6, 73.3, 73.1, 73.0, 72.6, 72.0, 51.8, 51.5; HRMS (ESI): calcd. for
7.04 (dd, J ¼ 15.9, 6.8 Hz, 1H), 6.44 (dd, J ¼ 11.9, 9.0 Hz, 0.7H), 6.13
(dd, J ¼ 15.9, 1.2 Hz, 1H), 6.02 (dd, J ¼ 11.9, 1.2 Hz, 0.7H), 5.41 (dd,
J ¼ 9.1, 2.2, 1.1 Hz, 0.7H), 4.88 (d, J ¼ 11.3 Hz, 0.7H), 4.76 (d,
J ¼ 11.3 Hz, 1H), 4.66e4.57 (m, 2.7H), 4.57e4.47 (m, 4.4H), 4.42 (d,
J ¼ 11.8 Hz, 1H), 4.40e4.36 (m, 0.7H), 3.86 (dd, J ¼ 8.8, 2.3 Hz, 0.7H),
3.81e3.51 (m), 3.75 (s, 3H CH3-E-isomer), 3.72 (s, 2.1H CH3-Z-
isomer).
C
29H30NaO6 [MþNa]þ 497.1935, found 497.1936.
4.1.4. Synthesis of methyl (3S,4S,5R)-3,4,5-tris(benzyloxy)-6-
hydroxycyclohex-1-ene-1-carboxylate (15)
A suspension of elemental selenium (0.373 g, 4.73 mmol) in
anhydrous THF (75 mL) was cooled in an ice bath and n-BuLi (2.5 M
in hexanes, 1.89 mL, 4.73 mmol) was added dropwise (a clear so-
lution was produced) and the mixture was cooled to ꢀ78 ꢁC. The
solution of 14 (1.87 g, 3.94 mmol in 25 mL of anhydrous THF) was
added dropwise and stirring was continued for the next 20 min and
then the mixture was allowed to warm to room temperature and
was stirred for the next 1 h (reaction was monitored by TLC Hex/EA
v/v ¼ 3:1). After towards, the reaction was cooled to 0 ꢁC and a
hydrogen peroxide solution (35%, 3.48 mL, 39.4 mmol) and pyridine
(1.59 mL, 19.70 mmol) were added. The ice bath was removed and
the mixture was heated to 50 ꢁC for 1 h. After that time, water
(100 mL) was added and the mixture was extracted with ethyl
acetate (3 ꢃ 100 mL). The combined organic phases were washed
with water (2 ꢃ 150 mL) and brine (150 mL). The organic phase was
dried over anhydrous MgSO4. The solvent was evaporated under
reduced pressure and the crude product was purified by column
chromatography (Hex/EA v/v ¼ 3.5:1) to give the title product as
white solid (68%, 1.27 g, 2.68 mmol); 6 S (anti)/6R (syn) 1.1:1 (based
4.1.2. Synthesis of methyl (4S,5S,6R)-4,5,6-tris(benzyloxy)-7-
hydroxyhept-2-enoate (12)
A solution of 13 (1.74 g, 2.94 mmol) in anhydrous THF (20 mL)
was cooled in an ice bath and Olah’s reagent (0.79 mL, ~30 mmol)
was added. The resulting mixture was warmed to room tempera-
ture and was stirred for 20 h. The reaction mixture was neutralized
by addition of solid NaHCO3 and filtered on a thin pad of Celite
directly into a separatory funnel with water (30 mL). The aqueous
layer was extracted with ethyl acetate (3 ꢃ 20 mL), and the com-
bined organic layers were washed with water (2 ꢃ 30 mL) and brine
(30 mL). The organic phase was dried over anhydrous MgSO4 and
concentrated under reduced pressure. The crude product was pu-
rified by column chromatography (Hex/EA v/v ¼ 2:1) to give the
title compound as a mixture of diastereoisomers (E/Z 1:0.53) as a
colorless oil (99%, 1.39 g, 2.92 mmol); 1H NMR (600 MHz, CDCl3)
d
7.38e7.21 (m, 23H), 6.94 (dd, J ¼ 15.8, 6.6 Hz, 1H E-isomer), 6.31
(dd, J ¼ 11.8, 8.5 Hz, 0.53H Z-isomer), 5.96e5.89 (m, 1.53H E/Z-
isomers), 5.49 (dd, J ¼ 8.5, 3.0, 1.3 Hz, 1H), 4.84 (d, J ¼ 11.5 Hz,
0.53H), 4.77 (d, J ¼ 11.3 Hz, 1H), 4.70 (d, J ¼ 11.5 Hz, 0.53H), 4.67 (d,
J ¼ 11.3 Hz, 1H), 4.64e4.59 (m, 2H), 4.59e4.56 (m, 1.53H), 4.54 (d,
J ¼ 11.9 Hz, 0.53H), 4.49 (d, J ¼ 11.6 Hz, 1H), 4.43 (d, J ¼ 11.8 Hz, 1H),
4.26 (dd, J ¼ 6.5, 3.7, 1.1 Hz, 1H), 3.90e3.86 (m, 1.53H), 3.81 (dd,
J ¼ 11.8, 4.8 Hz, 0.53H), 3.78e3.74 (m, 2.5H), 3.74 (s, 3H), 3.72e3.68
on 1H NMR spectrum); 1H NMR (600 MHz, CDCl3)
d 7.34e7.17 (m,
31.5H), 6.85 (t, J ¼ 1.7 Hz, 1H 15-syn), 6.77 (d, J ¼ 1.3 Hz, 1.1H 15-
anti), 4.90e4.87 (m, 1.1H 15-anti), 4.82 (dd, J ¼ 11.7, 2.7 Hz, 2H),
4.80e4.70 (complex multiplet, 2H (15-syn) þ 4.4H (15-anti)), 4.60
(d, J ¼ 12.0 Hz, 1.1H), 4.54 (s, 2H), 4.50e4.44 (m, 1 (15-syn) þ2.2H
(15-anti)), 4.21 (dd, J ¼ 3.4, 1.4 Hz, 1H), 4.10 (dt, J ¼ 3.1, 1.6 Hz, 1.1H),
ꢀ
Please cite this article as: N. Bidus et al., Application of a tandem seleno-michael/aldol reaction in the total syntheses of (þ)-Pericosine B,
(þ)-Pericosine C, (þ)-COTC and 7-chloro-analogue of (þ)-Gabosine C, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131397

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N. Bidus et al. / Tetrahedron xxx (xxxx) xxx
6
4.08 (dd, J ¼ 4.9, 2.5 Hz, 1.1H), 3.98e3.94 (m, 1H), 3.73 (s, 3H), 3.70
(s, 3.3H), 3.50 (dd, J ¼ 7.8, 1.5 Hz, 1.1H), 3.30 (dd, J ¼ 4.4, 1.4 Hz, 1H);
DIBAL-H (1 M in methylene chloride, 3.79 mL, 3.79 mmol) was
added dropwise. When the addition was complete, the mixture was
stirred at ꢀ10 ꢁC for 2 h. Subsequently, the mixture was warmed to
13C NMR (150 MHz, CDCl3)
d 166.7, 166.1, 138.7, 138.6, 138.5, 138.0,
137.8, 137.6, 137.5, 137.5, 132.7, 131.7, 128.6, 128.6, 128.6, 128.5, 128.4,
128.4, 128.3, 128.2, 128.1, 127.9, 127.9, 127.7, 127.7, 127.7, 127.6, 81.8,
76.7, 76.1, 75.7, 75.1, 74.9, 74.9, 73.7, 73.0, 71.3, 71.0, 70.0, 69.7, 63.8,
52.2, 52.1; HRMS (ESI): calcd. for C29H30NaO6 [MþNa]þ 497.1935,
found 497.1935.
0
ꢁC and stirred for 1 h (reaction was monitored by TLC Hex/EA v/
v ¼ 1:1). The reaction was quenched with methanol (2 mL) and the
mixture was stirred at room temperature for 1 h. Afterwards, a few
drops of 1 M aqueous HCl were added (to dissolved solidified res-
idue in the flask), followed by addition of water (20 mL). The
aqueous phase was extracted with methylene chloride (3 ꢃ 10 mL)
and the combined organic phases were washed with water
(2 ꢃ 20 mL), brine (20 mL) and dried over anhydrous MgSO4. The
solvent was evaporated under reduced pressure. Crude oil was
purified by column chromatography (Hex/EA v/v ¼ 1 : 1) to give 18
as a white solid as a mixture of diastereoisomers (86%, 0.243 g,
4.1.5. Synthesis of 3,4,5-tri-O-benzyl-(þ)-pericosine B (17) and
3,4,5-tri-O-benzyl-(þ)-pericosine C (16)
Procedure I: To solution of 15 (0.20 g, 0.421 mmol) in anhydrous
methylene chloride (6 mL) was added silver oxide (0.488 g,
2.11 mmol) and methyl iodide (0.52 mL, 8.43 mmol). The mixture
was stirred at 40 ꢁC for 16 h (reaction was monitored by TLC Hex/EA
v/v ¼ 3:1). The reaction mixture was filtered through a thin pad of
Celite. The solvent was removed under reduced pressure and the
crude product was purified by column chromatography (Hex/EA v/
v ¼ 3:1) to give 16 as a white solid (52%, 0.107 g, 0.219 mmol) and
one diastereoisomer of substrate syn-15 (47%, 0.094 g, 0.198 mmol).
Procedure II: To solution of 15 (0.20 g, 0.421 mmol) in anhy-
drous toluene (6 mL) was added silver oxide (0.488 g, 2.11 mmol)
and methyl iodide (0.52 mL, 8.43 mmol). The mixture was stirred at
100 ꢁC for 24 h in a sealed tube. The reaction mixture was filtered
through a thin pad of Celite. The solvent was removed under
reduced pressure and the crude product was purified by column
chromatography (Hex/EA v/v ¼ 3:1) to give the titled compounds as
a white solids (16: 37%, 0.076 g, 0.155; 17: 21%, 0.044 g, 0.090 mmol)
and recovered substrate syn-15 (13%, 0.026 g, 0.055 mmol).
0.54 mmol); 1H NMR (600 MHz, CDCl3)
d 7.41e7.26 (m, 30H),
5.80e5.77 (m, 1H), 5.74e5.70 (m, 1H), 4.89 (dd, J ¼ 12.0, 8.3 Hz, 2H),
4.83 (dd, J ¼ 11.9, 4.7 Hz, 3H), 4.81e4.78 (m, 1H), 4.63 (d, J ¼ 11.7 Hz,
1H), 4.61e4.56 (m, 5H), 4.46 (d, J ¼ 11.7 Hz, 1H), 4.33 (d, J ¼ 4.6 Hz,
1H), 4.32e4.28 (m, 3H), 4.26 (dd, J ¼ 3.5,1.3 Hz,1H), 4.23 (dt, J ¼ 3.3,
1.6 Hz, 1H), 4.15 (d, J ¼ 13.0 Hz, 1H), 4.10 (dt, J ¼ 4.6, 1.6 Hz, 1H),
4.01e3.97 (m, 1H), 3.47 (dd, J ¼ 8.3, 1.6 Hz, 1H), 3.42 (dd, J ¼ 4.5,
1.4 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 139.9, 138.6, 138.1, 138.0,
137.9, 137.9, 137.8, 128.6, 128.4, 128.4, 128.3, 128.3, 128.2, 128.1,
128.0, 127.8, 127.7, 127.7, 127.7, 127.5, 127.5, 127.5, 124.3, 122.7, 83.1,
76.0, 75.9, 75.0, 74.5, 73.7, 73.5, 71.8, 71.3, 71.0, 70.7, 69.8, 65.9, 64.7,
64.5; HRMS (ESI): calcd. for C28H30NaO5 [MþNa]þ 469.1986, found
469.1983.
4.1.7. Synthesis of ((3S,4S,5R)-3,4,5-tris(benzyloxy)-6-
hydroxycyclohex-1-en-1-yl)methyl (2e)-but-2-enoate (19)
3,4,5-tri-O-benzyl-(þ)-Pericosine C (16) ½a D24
ꢄ
¼ þ75.5 (c 0.50,
A solution of 18 (0.145 g, 0.32 mmol) in anhydrous methylene
chloride (5 mL) was cooled to 0 ꢁC. DCC (dicyclohexylcarbodiimide)
(0.101 g, 0.49 mmol), DMAP (7.9 mg, 0.065 mmol) and crotonic acid
(30.8 mg, 0.36 mmol) were added and the mixture was stirred for
4 h at 0 ꢁC (reaction was monitored by TLC Hex/EA v/v ¼ 2:1). The
mixture was warmed to room temperature and stirred for 2 h. After
that time, the reaction was quenched with methanol (2 mL) and the
solvent was evaporated under reduced pressure. The crude product
was purified by column chromatography (Hex/EA v/v ¼ 4:1) to give
19 as a white solid as a mixture of diastereoisomers 6S/6R ¼ 1:1
CHCl3); mp: 87e89 ꢁC; 1H NMR (600 MHz, CDCl3)
d
7.34e7.11 (m,
15H), 6.69e6.64 (m,1H), 4.76e4.69 (m, 2H), 4.58 (d, J ¼ 11.8 Hz,1H),
4.54 (d, J ¼ 11.8 Hz, 1H), 4.52 (s, 2H), 4.39e4.35 (m, 1H), 4.06 (dt,
J ¼ 4.6, 2.3 Hz,1H), 4.04 (dt, J ¼ 3.2,1.5 Hz,1H), 3.68 (s, 3H), 3.57 (dd,
J ¼ 6.9, 1.6 Hz, 1H), 3.50 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 166.6,
138.7, 138.3, 137.9, 137.4, 132.5, 128.5, 128.5, 128.3, 128.0, 127.9,
127.7, 127.7, 127.6, 81.5, 78.2, 75.0, 75.0, 73.2, 72.3, 71.5, 60.7, 51.9;
HRMS (ESI): calcd. for C30H32NaO6 [MþNa]þ 511.2091, found
511.2091.3,4,5-tri-O-benzyl-(þ)-Pericosine B (17) ½a D24
¼ ꢀ19.2 (c
ꢄ
1.2, CHCl3); mp: 92.5e93.5 ꢁC; 1H NMR (600 MHz, CDCl3)
(36%, 0.060 g, 0.117 mmol).; 1H NMR (600 MHz, CDCl3)
d 7.41e7.24
d
7.34e7.29 (m, 2H), 7.27e7.10 (m, 13H), 6.79 (t, J ¼ 1.5 Hz, 1H), 4.85
(m, 30H), 7.04e6.95 (m, 2H), 5.89e5.84 (m, 2H), 5.79 (s, 1H), 5.76
(d, J ¼ 1.2 Hz, 1H), 4.94e4.82 (m, 6H), 4.75 (d, J ¼ 13.2 Hz, 1H),
4.67e4.60 (m, 3H), 4.60e4.52 (m, 6H), 4.25 (d, J ¼ 2.2 Hz, 1H),
4.23e4.20 (m, 1H), 4.08 (s, 1H), 3.99 (s, 1H), 3.47 (dd, J ¼ 8.1, 1.5 Hz,
1H), 3.42 (dd, J ¼ 4.3, 0.9 Hz, 1H), 1.91e1.85 (m, 6H); 13C NMR
(d, J ¼ 12.7 Hz, 1H), 4.79 (d, J ¼ 12.7 Hz, 1H), 4.57 (d, J ¼ 12.0 Hz, 1H),
4.53 (d, J ¼ 12.0 Hz, 1H), 4.49 (d, J ¼ 12.1 Hz, 1H), 4.37 (d, J ¼ 12.1 Hz,
1H), 4.30 (d, J ¼ 4.4 Hz, 1H), 4.15e4.07 (m, 1H), 3.82 (dt, J ¼ 3.7,
1.8 Hz,1H), 3.66 (s, 3H), 3.61 (s, 3H), 3.26 (dd, J ¼ 4.4,1.3 Hz,1H); 13C
NMR (150 MHz, CDCl3)
d 166.4, 139.5, 139.3, 138.1, 138.0, 130.6,
(150 MHz, CDCl3)
d 166.5, 166.1, 145.4, 145.1, 138.8, 138.0, 137.9,
128.6, 128.5, 128.3, 128.1, 127.8, 127.7, 127.6, 127.4, 127.3, 79.1, 75.6,
137.8, 136.2, 135.0, 128.5, 128.4, 128.4, 128.4, 128.3, 128.1, 128.0,
127.8, 127.8, 127.7, 127.7, 127.7, 127.5, 127.5, 127.4, 125.7, 124.8, 122.4,
122.3, 82.9, 76.6, 76.0, 75.8, 75.1, 74.5, 73.7, 73.4, 72.2, 71.1, 70.8,
69.9, 69.6, 65.3, 64.2, 63.7, 60.4, 18.0; HRMS (ESI): calcd. for
73.0, 72.3, 71.5, 71.3, 70.5, 61.7, 52.0; HRMS (ESI): calcd. for
C
30H32NaO6 [MþNa]þ 511.2091, found 511.2092. Methyl
(3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-hydroxycyclohex-1-ene-1-
a 2D4
ꢄ
¼
þ11.2 (c 0.96, CHCl3); mp:
C
32H34NaO6 [MþNa]þ 537.2248, found 537.2249.
carboxylate (syn-15)
½
108.5e110.5 ꢁC; 1H NMR (600 MHz, CDCl3)
d
7.35e7.17 (m, 15H),
Sample 19 was separated into two pure diastereoisomers by
column chromatography (Hex/EA 4:1) to collect pure 1H NMR and
6.85 (t, J ¼ 1.8 Hz, 1H), 4.83 (dd, J ¼ 11.7, 2.7 Hz, 2H), 4.77 (d,
J ¼ 11.5 Hz, 1H), 4.72 (s, 1H), 4.55 (s, 2H), 4.49 (d, J ¼ 11.8 Hz, 1H),
4.22 (dd, J ¼ 3.5, 1.5 Hz, 1H), 3.97e3.95 (m, 1H), 3.73 (s, 3H), 3.30
13C
hydroxycyclohex-1-en-1-yl)methyl (2E)-but-2-enoate (6S-19):
1H NMR (600 MHz, CDCl3)
NMR
spectra.
((3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-
(dd, J ¼ 4.4, 1.4 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 166.1, 138.0,
d
7.39 (d, J ¼ 7.4 Hz, 2H), 7.38e7.25 (m,
137.8, 137.5, 137.5, 132.7, 128.6, 128.5, 128.4, 128.4, 128.1, 127.9, 127.9,
13H), 7.00 (dq, J ¼ 13.9, 6.9 Hz, 1H), 5.87 (dd, J ¼ 15.5, 1.7 Hz, 1H),
5.77 (d, J ¼ 1.1 Hz, 1H), 4.95e4.84 (m, 3H), 4.65 (dt, J ¼ 13.3, 7.9 Hz,
3H), 4.60e4.53 (m, 3H), 4.25e4.20 (m, 1H), 4.09 (s, 1H), 3.48 (dd,
J ¼ 8.1, 1.4 Hz, 1H), 1.88 (dd, J ¼ 6.9, 1.6 Hz, 3H); 13C NMR (150 MHz,
127.7, 76.7, 76.1, 74.9, 71.3, 69.7, 63.8, 52.2; HRMS (ESI): calcd. for
C
29H30NaO6 [MþNa]þ 497.1935, found 497.1935.
4.1.6. Synthesis of (4S,5S,6R)-4,5,6-tris(benzyloxy)-2-
(hydroxymethyl)cyclohex-2-en-1-ol (18)
CDCl3) d 166.7, 145.5, 138.9, 138.2, 135.1, 128.6, 128.5, 128.3, 128.2,
127.9, 127.8, 127.8, 127.6, 127.5, 125.8, 122.5, 83.1, 76.1, 73.9, 73.6,
72.3, 70.9, 69.7, 63.8, 18.1; ((3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
hydroxycyclohex-1-en-1-yl)methyl (2E)-but-2-enoate (6R-19):
A solution of compound 15 (0.300 g, 0.63 mmol) in anhydrous
methylene chloride (10 mL) was cooled to ꢀ30 ꢁC and a solution of
ꢀ
Please cite this article as: N. Bidus et al., Application of a tandem seleno-michael/aldol reaction in the total syntheses of (þ)-Pericosine B,
(þ)-Pericosine C, (þ)-COTC and 7-chloro-analogue of (þ)-Gabosine C, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131397

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N. Bidus et al. / Tetrahedron xxx (xxxx) xxx
7
1H NMR (600 MHz, CDCl3)
d
7.41e7.26 (m, 15H), 6.99 (dq, J ¼ 15.4,
4.2.1. (þ)-COTC (7) and 7-chloro-7-deoxy-(þ)-gabosine C (22)
6.9 Hz, 1H), 5.86 (dq, J ¼ 15.4, 1.5 Hz, 1H), 5.79 (s, 1H), 4.89 (d,
J ¼ 11.7 Hz, 1H), 4.87e4.82 (m, 3H), 4.75 (d, J ¼ 13.2 Hz, 1H),
4.60e4.53 (m, 3H), 4.27 (dd, J ¼ 14.6, 3.2 Hz, 2H), 3.99 (s, 1H), 3.42
(dd, J ¼ 4.4, 1.0 Hz, 1H), 1.89 (dd, J ¼ 6.9, 1.7 Hz, 3H); 13C NMR
20 (40 mg, 0.078 mmol) was dissolved in anhydrous methylene
chloride (3 mL) and cooled to ꢀ78 ꢁC. Afterwards, a 1 M BCl3 so-
lution in methylene chloride was added dropwise (0.78 mL,
0.78 mmol) and mixture was stirred for 24 h at ꢀ78 ꢁC. After the
indicated time, the reaction was quenched with solid NaHCO3
(295 mg, 3.51 mmol) followed by the addition of anhydrous
methanol (0.8 mL). The reaction mixture was allowed to warm to
room temperature and filtered through a short pad of Celite. The
solvent was evaporated under reduced pressure and products were
purified by column chromatography (chloroform/MeOH 6:1).
(þ)-COTC (7) was obtained as a white solid (26%, 5.0 mg,
(150 MHz, CDCl3)
d 166.2, 145.3, 138.1, 138.0, 137.9, 136.4, 128.6,
128.5, 128.5, 127.9, 127.9, 127.9, 127.7, 124.9, 122.5, 76.7, 75.9, 75.2,
74.6, 71.2, 70.0, 65.4, 64.3, 18.1.
4.1.8. Synthesis of 3,4,5-tri-O-benzyl-(þ)-COTC (20)
A solution of oxalyl chloride (0.030 mL, 0.485 mmol) in anhy-
drous methylene chloride (5 mL) was cooled to ꢀ78 ꢁC. After, DMSO
(0.069 mL, 0.972 mmol) was added dropwise and the mixture
stirred was for 30 min. A solution of 19 (50.0 mg, 0.097 mmol) in
anhydrous methylene chloride (2 mL) was slowly added to the
oxidative mixture, and kept at ꢀ78 ꢁC for the next 1 h. Triethyl-
amine (0.203 mL, 1.46 mmol) was added, and stirring was
continued for 30 min. After the indicated time, the reaction mixture
was allowed to slowly warm to room temperature. The reaction
was quenched with the addition of saturated NH4Cl (5 mL), fol-
lowed by the addition of water (20 mL). The aqueous layer was
extracted with methylene chloride (3 ꢃ 5 mL) and the combined
organic phases were washed with water (2 ꢃ 10 mL) and brine
(10 mL). The organic phase was dried over anhydrous MgSO4. The
solvent was evaporated under reduced pressure (below 35 ꢁC). The
crude product was purified by column chromatography (Hex/EA v/
v ¼ 3:1) to give the titled compound as a white solid (95%, 47.5 mg,
0.021 mmol); ½a 1D9
ꢄ
¼ þ94.7 (c 0.42, MeOH); 1H NMR (600 MHz,
CD3OD)
d
7.02 (dq, J ¼ 15.5, 6.9 Hz, 1H), 6.70 (td, J ¼ 2.3, 1.2 Hz, 1H),
5.89 (dq, J ¼ 15.5, 1.7 Hz, 1H), 4.87 (dd, J ¼ 2.2, 1.4 Hz, 1H), 4.76 (dt,
J ¼ 13.7, 1.6 Hz, 1H), 4.64 (dq, J ¼ 3.9, 2.0 Hz, 1H), 4.37e4.35 (m, 1H),
4.29 (d, J ¼ 2.5 Hz, 1H), 1.89 (dd, J ¼ 6.9, 1.7 Hz, 3H); 13C NMR
(150 MHz, CD3OD) d 198.6,167.5,147.8,147.0,133.4, 123.0, 77.6, 76.8,
69.3, 61.2, 18.0. and 7-chloro-7-deoxy-(þ)-Gabosine C (22) was
obtained as a colorless oil (40%, 6.0 mg, 0.031 mmol); ½a D19
¼ þ88.6
ꢄ
(c 0.57, EtOH); 1H NMR (600 MHz, CD3OD)
d
6.85 (tt, J ¼ 2.3, 1.1 Hz,
1H), 4.68e4.65 (m, 1H), 4.39e4.35 (m, 2H), 4.29 (d, J ¼ 2.5 Hz, 1H),
4.18 (dt, J ¼ 12.3, 1.2 Hz, 1H); 13C NMR (150 MHz, CD3OD)
d 198.0,
149.1, 135.1, 77.7, 77.0, 69.3, 40.7; HRMS (ESI): calcd. for C7H9ClO4
[MþNa]þ 215.0082, found [Mþ2 þ Na]þ 217.0057 (32%).
Declaration of competing interest
0.093 mmol); ½a 2D4
ꢄ
¼ ꢀ10.4 (c 0.50, CHCl3); mp: 87e89 ꢁC; 1H NMR
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
(600 MHz, CDCl3)
d
7.39e7.26 (m, 15H), 6.99 (dq, J ¼ 15.5, 6.9 Hz,
1H), 6.72 (t, J ¼ 2.1 Hz, 1H), 5.86 (dq, J ¼ 15.5, 1.6 Hz, 1H), 5.03 (d,
J ¼ 12.1 Hz, 1H), 4.97 (dd, J ¼ 14.1, 2.3, 1.5 Hz, 1H), 4.88 (d,
J ¼ 12.3 Hz, 1H), 4.85e4.77 (m, 2H), 4.60 (d, J ¼ 12.1 Hz, 1H), 4.55 (d,
J ¼ 12.0 Hz, 1H), 4.47 (d, J ¼ 12.0 Hz, 1H), 4.44e4.41 (m, 1H),
4.32e4.29 (m, 1H), 3.99 (d, J ¼ 1.9 Hz, 1H), 1.88 (dd, J ¼ 6.9, 1.7 Hz,
Acknowledgements
3H); 13C NMR (150 MHz, CDCl3)
d 195.3, 166.2, 145.7, 142.9, 138.3,
Financial support from the Polish National Science Centre (Grant
No. 2015/17/D/ST5/01334) is gratefully acknowledged. The research
was carried out with the equipment purchased thanks to the
financial support of the European Regional Development Fund in
the framework of the Polish In-novation Economy Operational
Program (contract no. POIG.02.01.00-12-023/08).
137.9, 137.4,134.0,128.7, 128.7, 128.6,128.4,128.2,128.1,127.9,127.9,
127.8, 122.4, 82.8, 78.9, 75.8, 73.6, 73.1, 71.2, 60.4, 18.3; HRMS (ESI):
calcd. for C32H32NaO6 [MþNa]þ 535.2091, found 535.2091.
4.2. General procedure for removing benzyl ether with BCl3
Appendix A. Supplementary data
16, 17 or 20 (50 mg) was dissolved in anhydrous methylene
chloride (3 mL) and cooled to ꢀ78 ꢁC. Subsequently, a 1 M BCl3
solution in methylene chloride was added dropwise (10 equiv.) and
the mixture was stirred for 24 h at ꢀ78 ꢁC. After indicated time, the
reaction was quenched with solid NaHCO3 (45 equiv.) followed by
the addition of anhydrous methanol (1 mL). The reaction mixture
was allowed to warm to room temperature and was filtered
through a short pad of Celite. The solvent was evaporated under
reduced pressure and the products were purified by column
chromatography (chloroform/MeOH).
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131397.
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