Total syntheses of the non-peptide bradykinin B1 receptor antagonist velutinol a and its analogs, seco-pregnanes with a cage-like moiety

Article abstract of DOI:10.1246/bcsj.20190048

We describe here the syntheses of velutinol A (1) and the structurally similar compounds 24 sharing a highly oxygenated seco-pregnane cage-like structure. The synthesis of velutinol A (1, 15,16-seco-pregnane) features the highly regioselective construction of |¹⁴ silyl enol ether from 15-keto-21,22-diol, followed by stereoselective introduction of a sterically hindered β-hydroxy group at the C14 position by Rubottom oxidation. Prolonged reaction time and the use of an excess amount of mCPBA at this step allowed double Rubottom oxidation, enabling us to introduce the requisite hydroxy groups at the C14 and C16 positions in one pot. Subsequent oxidative cleavage of the C1516 bond, deprotection, and intramolecular acetalization allowed the concise total synthesis of velutinol A (1). Utilization of α,α-dihydroxy-ketone, the double Rubottom oxidation product, for formation of the ether F-ring by 5-exo-cyclization, and subsequent C1421 oxidative cleavage, effectively achieved the synthesis of pentalinonside-aglycon (2). Construction of the 14,15-seco-structures of two other analogs, argeloside aglycon (3) and illustrol (4), was achieved by BaeyerVilliger oxidation of 15(21)-keto derivatives. Introduction of the 20-oxo group potentially embedded in argeloside aglycon was accomplished by Wacker oxidation of |²⁰, which was constructed by GriecoNishizawa syn-β-elimination of the C21-primary alcohol obtained by reduction of the BaeyerVilliger product. Intra-molecular double acetalization of the 15,16-dihydroxy-14,20-oxo derivative to form the cage-like structure of the DEF-rings required a moderately weak acid. This step was the key to accessing argeloside aglycon (3), as otherwise the easily aromatized β,γ-dihydroxyketone moiety was transformed to furan. Sharpless asymmetric dihydroxylation of |²⁰ to set the C20 stereocenter, followed by intramolecular double acetalization, achieved the stereoselective synthesis of illustrol With all synthesized compounds, structural requirements of steroidal bradykinine B1 receptor antagonist would be revealed.

Full text of DOI:10.1246/bcsj.20190048

Document type: Article
Total Syntheses of the Non-Peptide Bradykinin B1 Receptor Antagonist
Velutinol A and Its Analogs, seco-Pregnanes with a Cage-Like Moiety
Minoru Tamiya,* Nobuhisa Isaka, Takaaki Kitazawa, Atsushi Hasegawa, Kazuya Ishizawa,
Mayu Ikeda, Saki Kawada, and Masaji Ishiguro*
Department of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences,
265-1 Higashijima, Akiha-ku, Niigata 965-8603, Japan
E-mail: tamiya@nupals.ac.jp (M. Tamiya), ishiguro@nupals.ac.jp (M. Ishiguro)
Received: February 23, 2019; Accepted: May 19, 2019; Web Released: June 5, 2019
Minoru Tamiya
Minoru Tamiya studied chemistry at Tokyo Institute of Technology, finishing his Ph.D. in 2007 under the
supervision of Prof. Keisuke Suzuki. After a postdoctoral stay in the group of Prof. Alois Fürstner in Mülheim,
Germany, with a research fellowship for young scientist from JSPS, he became Assistant Professor in the
group of Prof. Ishiguro (2007.10–2015.10) at Niigata University of Pharmacy and Applied Life Sciences.
Since 2015.11, he has been with Chugai Pharmaceutical Co. Ltd. as a supervisor in the discovery chemistry
department.
Masaji Ishiguro
Masaji Ishiguro received his Ph.D. in 1977 from Tokyo Institute of Technology. He worked in the laboratory of
Professor E. J. Corey at Harvard University as a postdoctoral fellow from 1977 to 1979. After joining the
Suntory Institute for Biomedical Research in 1980, he directed a computer-aided molecular design and
medicinal chemistry group. In 1995, he moved to Suntory Institute of Bioorganic Research and engaged in
receptor-ligand research. In 2006, he was appointed as a professor at Niigata University of Pharmacy and
Applied Life Sciences. Currently, he is the president of Niigata Bioresearch Park Co. Ltd. after retiring from
the university.
Abstract
potentially embedded in argeloside aglycon was accomplished
by Wacker oxidation of ¦20, which was constructed by Grieco-
Nishizawa syn-β-elimination of the C21-primary alcohol
obtained by reduction of the Baeyer-Villiger product. Intra-
molecular double acetalization of the 15,16-dihydroxy-14,20-
oxo derivative to form the cage-like structure of the DEF-rings
required a moderately weak acid. This step was the key to
accessing argeloside aglycon (3), as otherwise the easily
aromatized β,γ-dihydroxyketone moiety was transformed to
furan. Sharpless asymmetric dihydroxylation of ¦20 to set the
C20 stereocenter, followed by intramolecular double acetaliza-
tion, achieved the stereoselective synthesis of illustrol With all
synthesized compounds, structural requirements of steroidal
bradykinine B1 receptor antagonist would be revealed.
We describe here the syntheses of velutinol A (1) and the
structurally similar compounds 2-4 sharing a highly oxy-
genated seco-pregnane cage-like structure. The synthesis of
velutinol A (1, 15,16-seco-pregnane) features the highly
regioselective construction of ¦14 silyl enol ether from 15-
keto-21,22-diol, followed by stereoselective introduction of a
sterically hindered β-hydroxy group at the C14 position by
Rubottom oxidation. Prolonged reaction time and the use of
an excess amount of mCPBA at this step allowed double
Rubottom oxidation, enabling us to introduce the requisite
hydroxy groups at the C14 and C16 positions in one pot.
Subsequent oxidative cleavage of the C15-16 bond, depro-
tection, and intramolecular acetalization allowed the concise
total synthesis of velutinol A (1). Utilization of α,α-dihydroxy-
ketone, the double Rubottom oxidation product, for formation
of the ether F-ring by 5-exo-cyclization, and subsequent C14-
21 oxidative cleavage, effectively achieved the synthesis of
pentalinonside-aglycon (2). Construction of the 14,15-seco-
structures of two other analogs, argeloside aglycon (3) and
illustrol (4), was achieved by Baeyer-Villiger oxidation of
15(21)-keto derivatives. Introduction of the 20-oxo group
Keywords: Bradykinin B1 receptor (B1R)
j
seco-Pregnane
j
Natural product syntheses
1. Introduction
G protein coupled receptors (GPCRs) are one of several
superfamilies of proteins, consisting of an extracellular N-
terminal domain, seven transmembrane helices domain, and
1474 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

intracellular domains. GPCRs interact with G-proteins at the
intracellular site and transduce a large number of signals across
the cell membrane by binding signaling molecules such as ions,
odorants, biogenic amines, lipids, peptides, and proteins at the
extracellular side of the membrane. GPCRs have been proven
to be promising drug targets, with more than 30% of drugs cur-
rently on the market being GPCR agonists or antagonists. The
bradykinin receptor is a pharmacologically important receptor
belonging to the GPCR family and plays important roles in the
pathophysiological process of pain and inflammation.1 The
bradykinin receptor has two subtypes, referred to as bradykinin
B1 receptor (B1R) and B2 receptor (B2R), and these subtypes
differ in their level of expression and their binding to ligands.
B2R is constitutively expressed in a number of tissues and
evokes the acute pain response after activation by the nona-
peptide bradykinin (H-Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-
Phe8-Arg9-OH), whereas a corresponding metabolite, des-
Arg9-bradykinin (DABK), serves as the agonist for B1R,2
which is inductively expressed at high levels in injured tis-
sues.3 Preclinical data accumulated to date suggest that B1R is
involved in the propagation, potentiation, and maintenance of
chronic pain.4 Therefore, the up-regulation of B1R in response
to inflammation would be an attractive target for drug develop-
ment. In this context, the development of B1R antagonists has
proceeded based on the structure-activity relationship (SAR)
with its agonist ligand, DABK. Consequently, B1R antagonists
identified to date have tended to be peptides,5 which com-
promises their in vivo application.
Velutinol A (1) was isolated from the rhizomes of
Mandevilla velutina (Apocynaceae), a plant native to the
Brazilian savanna. Infusions or alcoholic extracts of these
rhizomes are used as folk medicine for the treatment of
venomous snake bites.8
We previously reported our preliminary construction of a
complex structural model of velutinol A (1) and DABK bound
to human B1R (hB1R) for comparison of binding site and
mode of these antagonists. These models were generated with
the homology module (Insight II) using a model of a meta-
rhodopsin photointermediate in the bovine rhodopsin photo-
cascade as the template (Figure 2A-C).9
Figure 2A and B show the complex model of velutinol A (1)
bound to hB1R which suggested a characteristic receptor-
ligand interaction in which three oxygen atoms in the cage-like
structure of the DEF-rings of velutinol A (1) formed hydrogen
bonds with Lys118 in the third transmembrane helix. Another
hydrogen bond was observed between a hydrogen atom on the
hemiacetal hydroxy group in the DEF-rings and Tyr266. It
should be noted that electron density of the oxygen atom in the
phenol moiety of Tyr266 was increased by hydrogen bond
formation between the hydrogen atom of the phenolic hydroxy
group and the carboxylate oxygen of Asp183, which strength-
ened hydrogen bonding between the hydroxy group of the
hemiacetal moiety and Tyr266.
O
H
O16
H
H
O
O
Several non-peptide B1R selective antagonists have recently
been identified.6 Velutinol A (1, Figure 1), consisting of a
15,16-seco-14β,17α-pregn-5-ene core with a cage-like structure
in the steroidal DEF-rings, is the first and only known non-
peptide B1R antagonist natural product.7
15
O
H
OH
HO
O
HO
OH
velutinol A (1)
Figure 1. Structure of velutinol A.
Figure 2. Complex structural models of (A and B) velutinol A (blue), (C) DABK (yellow), (E) pentalinonside aglycon (orange),
(F) argeloside aglycon (magenta), and (G) illstrol (green) bound to hB1R. (D) Superposed structure of velutinol A and DABK
bound to hB1R.
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1475

Table 1. Site-Directed Mutagenesis Data of DABK.10b
pounds interacted with Lys118 as was observed in the case of
velutinol A. However, Tyr266 interacted with none of these
three molecules, whereas velutinol A formed a strong hydrogen
bond. To investigate the mechanism of molecular recognition
between the ligands and B1R, we developed a general synthetic
route for the construction of cage-like seco-pregane derivatives
1-4.14-17 Among the natural seco-preganes, pentalinonside and
argeloside form a glycosyl bond at C3-OH and the removal of
the sugar moieties is difficult due to the presence of the acid-
sensitive tricyclic acetals at the seco-D-ring. Thus, the synthesis
of these derivatives may not only contribute to the structure-
activity studies of the non-peptide steroid derivatives, but also
impact the field of drug design as a new approach of bioisoteric
replacement of carboxylate with drug likeness. In addition to
our previous results,14-17 this paper will detail our efforts and
investigations towards the syntheses of seco-pregnane deriva-
tives with the highly oxygenated cage-like structures. This syn-
thetic strategy may be applicable to the syntheses of structural
analogs of 1-4.
Entry
hB1R
Ki (nM)
1
2
3
4
5
WT
100 « 25
Lys118Ala
Lys118Ser
Phe302Ala
His267Gln
2600 « 1400
2800 « 1100
3000 « 610
4.3 « 0.3
H
O
O
H
H
O
O
O
H
HO
O
HO
pentalinonside aglycon (2)
H
O
H
H
O
O
O
H
O
H
H
HO
O
HO
HO
argeloside aglycon (3)
H
2. Results and Discussion
O
O
H
O
O
Synthetic Strategy. Scheme 2 outlines our retrosynthetic
blueprint for compounds 1-4. We expected that the DEF-rings
embedded in compounds 1, 3, and 4, and the DE-rings of
compound 2, could be constructed by intramolecular acetaliza-
tion, and thus we chose compounds I-IV as the precursors.
Dialdehyde I would also be derived from α,α-dihydroxyketone
VI by oxidative cleavage of the C15-C16 bond. Ketone I can
presumably be obtained from diol V via oxidative cleavage of
the C14-21 bond; 5-exo-cyclization for annulation of the F-ring
would be accomplished by intramolecular SN2 addition of a
C15 hydroxy group to the C20 position in α,α-dihydroketone
VI. The hydroxy group at C20 in VI could be stereoselectively
installed via Rubottom oxidation of α-hydroxyketone XI.18
Stereoselective introduction of a tert-alcohol group at C14 in X
could presumably be accomplished by two independent routes:
1) pinacol coupling19 of keto-aldehyde VII derived from lac-
tone XI, 2) Rubottom oxidation of α-hydroxyketone XI. The
20-oxo-group of III could be introduced by Wacker oxidation20
of olefin VIII, whose seco-structure was constructed by regio-
selective Baeyer-Villiger oxidation of XIV. The stereochem-
istry at the C20 position of IV could be controlled by Sharpless
asymmetric dihydroxylation,21 and thus olefin IX was chosen
as a precursor. As with compound VIII, Baeyer-Villiger oxida-
tion would achieve construction of the seco-structure, and thus
compound XIV was used as the precursor of IX. Both com-
pounds XIV and XIII would be prepared via Sharpless asym-
metric dihydroxylation or oxidative cleavage from olefin XV,
which can be synthesized through stereospecific Michael addi-
tion of a soft vinyl anion derivative at the C17 position of
enone XVI. Thus, olefin XV would be a common interme-
diate for compounds 1-4. Ito-Saegusa oxidation22 and Wharton
reaction23 would provide enone XVI from epi-andronsterone.
Despite these rather simple strategies, the primary challenge for
the synthesis of compounds 1, 3, and 4 was to escape the easy
aromatization of the β,γ-dihydroxycarbonyl moiety in as well
as the construction of the structurally equivalent F-ring moiety
in 1, 3, and 4. Specifically, since acids may promote the aro-
matization of 1, 3, 4, I, III, and IV (Scheme 1, eq 1 and 2),24
HO
O
O
illustrol (4)
Figure 3. Highly oxygenated seco-pregnanes with cage-
like structure.
Figure 2C shows a complex structural model of DABK
bound to hB1R. Our docking model is consistent with the
results of reported site-directed mutagenesis data (Table 1,
reported by Ha et al).10a Thus, Lys118, His267 and Phe302,
whose mutations considerably affected the affinity of hB1R for
DABK,10 interacted with DABK in our constructed hB1R-
DABK complex model. The C-term (Phe8) of DABK bonded
to Lys118 by charge-charge interaction in our model. A
mutation of Lys118 to Ala or Ser led to approximately 27-fold
decrease in affinity for DABK (Entries 2 and 3).10b
In addition, 30-fold loss of affinity for DABK in the case
of a Phe302Ala mutant (Entry 5) supported plausibility of our
model, since the mutation from Phe to Ala loses a hydrophobic
interaction between Phe302 and the ligand (Phe8).10b Further-
more, our model was consistent with the increase in the affinity
of DABK for a His267Gln mutant strengthening a hydrogen
bond with ligand (Ser6).
To compare the binding mode in the pocket, a superposed
structure of the complex models of DABK and velutinol A (1)
was constructed as shown in Figure 2D. A superposed structure
revealed that DABK and velutinol A (1) were positioned in the
same pocket and the cage-like structure in velutinol A plays a
role as a bioisostere of the carboxylate.
We therefore hypothesized that the seco-pregnane deriva-
tives pentalinonside aglycon (2),11 argeloside aglycon (3),12
and illustrol (4),13 which have similar cage-like structures,
might have similar biological activities (Figure 3). To evaluate
the binding mode of pentalinonside aglycon (2), argeloside
aglycon (3), and illustrol (4), we constructed complex structural
models of these three compounds bound to hB1R, respectively
(Figure 2E-G). The cage-like moieties of these three com-
1476 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

HO
appropriate acidic conditions are required for the conversion of
I, III, and IV into 1, 3, and 4.
OTHP
O
O
AcONa
(1)
(2)
Synthesis of Velutinol A.14 The major challenge in the
synthesis of velutinol A (1) was the selective introduction of
the hydroxy group at the C14β position. For installing the
hydroxy group stereoselectively, two methods were investigat-
ed: 1) pinacol coupling, and 2) Rubottom oxidation. There are
pros and cons of both methods in terms of stereoselectivity and
reaction steps. Figure 4 shows two plausible transition states of
metal mediated pinacol coupling. As shown in Figure 4, TS2,
leading to undesired cis-diol, would be energetically unfavor-
able compared to TS1 because of steric hinderance between
the C18-Me group and aldehyde in the case of metal medi-
ated pinacol coupling. Thus, stereochemistry at C14 seems to
be easy to control by the pinacol coupling route. However,
AcOH
100 °C
R
R
HO
OTHP
O
O
TsOH
THF/H2O
60 °C
Scheme 1. Furan formation reaction from β,γ-dihydroxy
ketone.
H16
O
F
H20
20
H
20O
O
H
17
O
F
F
17O
17
20H
O
O
H
H
H
H
H
O
O
O16
16 H
H
O 16
O
H
H
H
H
OH
HO
HO
HO
HO
illustrol (4)
Double-
argeloside aglycon (3)
velutinol A (1)
Pentalinonside aglycon (2)
Double-
Acetalization
Double-
Acetalization
Acetalization
Acetalization
HO
H
HO 20
HO 20
HO
16
16
OH
O
OH
O
OH
O
H
H
H
F
O
17
17
17
17
20
16
16
20
H
H
H
H
H
14
H
H
Oxidative
Cleavage
O
O
O
OH
O
H
O
IV
III
II
I
HO
16
H
Sharpless
Asymmetric
Dihydroxylation
17
H14 20
21
F
Oxidative
Cleavage
Wacker
Oxidation
O
H
OH
V
RO 16(20)
16
RO
16
RO
O
H
OH
16
OR
H
OR
H
OR
H
5-Exo
Cyclization
20
20
20
H14
OH
H
H
H
(15)
20(16)
O
O
O
O
OH
VI
H
VIII
O
H
IX
VII
Pinacol
Rubottom
Oxidation
Coupling
16
OR
16
RO
RO 16(20)
OR
H
20
H
20
OR
H
H
H
H
20(16)
(15)
14
O
O
O
O
H
H
OH
O
Aromatized
by Acids!
XI
X
XII
Baeyer–
Villiger
Oxidation
Baeyer–
Villiger
Oxidation
Rubottom
Oxidation
O
R
HO
OH
H
H
OH
H
O
H
H
14
H
H
XIII
R = H or Me
O
O
XIV
Sharpless
Asymmetric
Dihydroxylation
Oxidative
Cleavage
O
O
Michael
Addition
Wharton
Reaction
Ito–Saegusa
Oxidation
H
H
H
H
H
H
H
O
HO
dehydroepiandrosteron
H
H
H
XV
O
O
XVII
XVI
Scheme 2. Retrosynthetic Analysis.
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1477

Me
18Me
O
O
H
Me
H
O
H
H
H
O
O
or
a
H
b
H
O
H
H
H
H
H
+
Met
O
O
Met
MeO
H
H
O
Met
TS2
undesired
TS1
desired
OMe
5
5a
6
O
H
H
H
H
H
c
H
H
+
H
H
OH
OH
O
MeO
H
OH
OH
OH
OH
OMe
7
8a
8
Figure 4. Plausible transition states of pinacol coupling.
O
O
H
H
d, e
H
H
H
H
H
O
H
H
H
14
H
OH
H
O
14
14
H
OSiR3
9
OMe
H
H
OH
OMe
10
O
tautomerization
H
Scheme 4. Synthesis of 9. Reagents and conditions: a) LDA,
TMSCl, THF, ¹78 °C; then Pd(OAc)2, p-benzoquinone,
DMSO, 60 °C, 2 h, 86% from 5; b) NaClO, pyridine, EtOH,
¹10 °C, 20 min, 93%; c) NH2NH2¢H2O, Et3N, AcOH,
CH3CN, 30 min, rt, 74% (8: 63%, 8a: 10%); d) TPAP,
NMO, CH2Cl2, rt, 92%; e) vinylmagnesium bromide, CuI,
THF, ¹30 °C, 30 min, quant. LDA = lithium diisopropyl-
amide, TMS = trimethylsilyl, THF = tetrahydrofuran,
DMSO = dimethyl sulfoxide, rt = room temperature,
TPAP = tetrapropylammonium perruthenate, NMO =
N-methylmorpholine-N-oxide.
H
14
H
H
14
H
O
OH
H
O
H
14
Step 1
Enolization
H
H
OSiR3
H
H
OH
14
14
Step 2
Rubottom
Oxidation
OH
OH
O
O
Scheme 3. Synthetic issue for the introduction of 14β-OH.
Table 2. Dihydroxylation of olefin 9.
HO
synthesis of keto-aldehyde needs more reaction steps compared
to Rubottom methods as shown in Scheme 2 (XIII¼XI¼
VII¼X).
Chiral Ligand
20
cat. OsO4
K3[Fe(CN)6]
CH3SO2NH2
K2CO3
OH
H
H
H
H
On the other hand, the Rubottom oxidation route has poten-
tial stereo- and regio-selectivity problems, even though it has
an advantage in terms of reaction steps. To highlight the
essence of the problems of the Rubottom oxidation route,
Scheme 3 shows a hypothetical route based on silylenolization
(step 1) followed by Rubottom oxidation (step 2).18 In partic-
ular, step 1 would not be straightforward since enolization of
the 15-keto derivative under basic conditions might occur at the
undesired side to generate ¦15 due to steric hindrance, and the
16-α-hydroxy ketone derivative generated in the following
Rubottom oxidation step would easily tautomerize. Even if
Step 1 occurred with high regioselectivity, Step 2 must occur
with high diastereofacial selectivity. With these issues in mind,
we embarked on the synthesis of 1.
Scheme 4 shows the synthesis of the key intermediate
ketone 9 in five steps, starting from known compound 5.25,26
Ito-Saegusa oxidation of a mixture of 5 and 5a was accom-
plished by using a catalytic amount of palladium acetate with
2 equiv. of p-benzoquinone as a re-oxidant of palladium (0) to
afford enone 6 in 86% yield.22b When oxygen was used instead
of p-benzoquinone,22a,27 α,β-unsaturated lactone 10 was gen-
erated in 6% yield as a side product via Baeyer-Villiger-type
rearrangement triggered by the palladium peroxide generated in
the reaction.28 This side reaction led to a low yield of enone
6 (73%). After treatment of enone 6 with NaClO (93%), the
resulting epoxide 7 was converted to allyl alcohol 8 by hydra-
zine monohydrate in the presence of Et3N and AcOH in 74%
yield (8: 63%, 8a: 11%). It should be noted that 3-MeO
H
H
O
H
H
O
tBuOH/H2O
(1/1), 0 °C
OMe
11
OMe
9
Entry
Chiral Ligand
Time [h]
Yield [%] (20S:20R)
1
2
3
4
(DHQD)2PHAL
(DHQ)2PHAL
(DHQ)2AQN
(DHQ)2PYR
4
3
2.5
2.0
82 (1:1.7)
97 (5.5:1)
76 (2.5:1)
87 (7.7:1)
DHQ = dihydroquinoline,
DHQD = dihydroquinidine.
PHAL = phthalazine derivative. AQN = anthraquinone deriv-
ative. PYR = diphenylpyrimidine derivative.
derivative contaminated from compound 5 was separable at
this stage to give pure 8. Oxidation of the alcohol group in 8 by
tetrapropylammonium perruthenate (TPAP, 92%)29 followed by
substrate-controlled Michael addition of a vinyl copper reagent
to the resulting enone, provided olefin 9.
Sharpless asymmetric dihydroxylation was applied to olefin
9 for stereoselective introduction of the C20-hydroxy group
(Table 2).21 First, the use of (DHQD)2PHAL as a chiral ligand
gave the desired 20S-11 and its diastereomer 20R-11 in 30%
and 52% yield, respectively (Entry 1). It is worth noting that
20R-11 and 20S-11 were easily separable by silica-gel column
chromatography. As we expected, 20S-11 was obtained as the
major diastereomer (82%) concomitant with 20R-11 (15%)
when a catalytic amount of (DHQ)2PHAL was used instead of
its diastereomer (DHQD)2PHAL (Entries 1 and 2). To gain
1478 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

F3C
*
F3C
*
+0.02
CH3
OMe
O
OMe
O
–0.04
+0.16
–0.04
O
H
O
H
CH3
OH
C(CH3)3
C(CH3)3
O
O
HO
H
OSi
OSi
–0.05
O
O
+0.06
CH3
+0.06/0.00
CH3
–0.04
+0.06
H
–0.12/–0.03
a, b
c
d
H
H
–0.07
H
H
H
+0.03
–0.02
+0.03
H
H
H
H
OH OH
O
O
–0.05/–0.03
+0.04/+0.12
O
H
H
O
O
14a
15a
20S-11
OMe 12
OMe
13
O
H
O
O
O
O
O
Figure 5. ¦¤SR values for the MTPA esters of compound 12
and 13.
H
H
e
f
H
H
H
+
O
O
O
OH
O
OH
18
H
OH
16
17
higher diastereoselectivity, another chiral ligand, (DHQ)2AQN,
was also examined, but unfortunately it gave lower selectivity
compared to (DHQ)2PHAL (Entry 3). Although higher selec-
tivity was obtained when (DHQ)2PYR was employed (Entry 4),
the yield of 20R-11 (77%) was lower than that of Entry 2. We
also tested the diastereomers of the catalysts (Entries 3, 4) and
similarly observed lower selectivity.
CD spectra of 19a (λmax = 319 nm)
O
nm
H
H
14
OH
19a
O
The absolute stereochemistry at C20 was determined by the
Mosher method (Figure 5).30 Thus, after protection of each
primary alcohol at the C21 position in diol 20S-11 and 20R-11
as TBS, each secondary alcohol at C21 was derivatized with
the two enantiomers of (R)- and (S)-α-methoxy-α-trifluoro-
methyl-α-phenylacetic acid (MTPA), respectively, to afford
(R)- and (S)-MTPA-12 and (R)- and (S)-MTPA-13. The
1H NMR spectra of the four derivatives were recorded and
each ¦δSR value [= δ(S)-MTPA-12 ¹ δ(R)-MTPA-12 or δ(S)-
MTPA-13 ¹ δ(R)-MTPA-13] was calculated. As a result, the
absolute stereochemistry of C20 in 12 and 13 was determined
as shown in Figure 5, which indicates the stereochemistry of
C20 in 20S-11 and 20R-11.
With the requisite ketones 20S-11 in hand, we investigated
the pinacol route (Scheme 5). After protection of diol moiety
of 20S-11 as an acetonide (91%), the resulting ketone was
converted to lactone 14a by Beayer-Villiger reaction using
mCPBA (69%), whose lactone moiety was reduced by LiAlH4
to afford diol 15a in a quantitative yield. Contrary to our
expectation, subsequent Swern oxidation gave lactol 16 as a
major product in addition to keto-aldehyde 17 as a minor prod-
uct. The requisite keto-aldehyde 17 was then converted into
diol 18 by intramolecular pinacol coupling. Thus, SmI2 in THF
(1.0 M) was added to a solution of keto-aldehyde 17 in
degassed THF/MeOH at 0 °C until the reaction mixture turned
dark blue (³2.5 equiv. of SmI2). Stirring at 0 °C for 10 min
afforded diol 18 in 65% yield. Stereochemistry at C14 was
determined after conversion of diol 18 to α-ketal 19a by TPAP
oxidation. Thus, a negative Cotton effect at 319 nm observed
in the circular dichroism (CD) spectrum of 19a suggested that
19a would possess cis-fused CD rings according to the octant
rule.31
Scheme 5. Investigation of pinacol route. Reagents and
conditions: a) 2-methoxypropene, cat. TsOH¢H2O, DMF,
rt, 30 min, 91%; b) mCPBA, NaHCO3, CH2Cl2, 0 °C to rt,
1 d, 69%; c) LiAlH4, THF, 0 °C, 5 min, quant.; d) (COCl)2,
DMSO, Et3N, CH2Cl2, ¹78 °C (1 h) to rt, 46% for 16, 25%
for 17; e) SmI2, THF/MeOH (10/1), 0 °C, 10 min, 65%; f)
TPAP, NMO, CH2Cl2, rt, 2 h, 85%.
was obtained when 20S-11 was used as the starting material
(Entry 2). Furthermore, the reaction proceeded in a fully regio-
selective manner when Et3N was used instead of 2,6-lutidine
to produce 21 (92% yield, Entry 3). According to the results
shown in Entries 1 and 2, the sterically more hindered H14
reacted rather than H16. On the other hand, when compound 22
was treated under the same conditions, ketal 23 was obtained
in 30% yield concomitant with 15-keto-20,21-di-TBS ether in
54% yield (Entry 4). In other words, the first step was enoli-
zation to form ¦15 enol, which reacted with the carbonyl of the
C20 acetate group to afford cyclized compound 23. When the
epimer at C20,20R-11 was employed, lower regioselectivity
and a lower yield were obtained (Entry 5). These results indi-
cated the participation of the hydroxy group at C20, as shown
in Figure 6, to form the ¦14 enol in the case of 20 and 20S-11,
as otherwise nucleophilic attack on the less hindered H16 took
place to afford ¦15 enol. To conform this prediction, ketones
25a and 9 were treated under the same conditions as 20S-11,
resulting in the formation of ¦15 isomers as the sole products
(Entries 6 and 7).
Rubottom oxidation was applied to the silyl enol ether 21 to
introduce a hydroxy group at the 14-position (Scheme 6).18
Thus, 21 was treated with mCPBA (1.05 equiv.) in CH2Cl2 at
0 °C for 20 min to afford α-ketol 19b in 54% yield along with
hydroxy enol 29 in 26% yield. An extended reaction (10 h)
resulted in only enol 29 in 87% yield without α-ketol 19b. The
stereochemistry at the C14 position of α-ketol 19b was deter-
mined by CD spectroscopic analysis. Observation of a negative
Cotton effect at 318 nm in the CD spectrum suggested that 19b
possessed cis-fused CD rings, in accordance with the octant
rule.31 Enol 29 was then treated with mCPBA, followed by
For the other synthetic route, the Rubottom oxidation route
was conducted. First of all, we transformed ketones 20S-11 to
ketones 20, 22, and 25a and investigated the regio-selective
construction of ¦14 enol, one of the key reactions of this syn-
thesis (Table 3). We first applied the enolization reaction to
ketone 20 by treatment with 2,6-lutidine and TBSOTf in
CH2Cl2 at 0 °C and obtained ¦14-silyl enol ether 21, the desired
regio-isomer, as a major product (Entry 1). The same result
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1479

OTBS
OTBS
mCPBA
Table 3. Enolization of 15-keto derivatives
TBSO
TBSO
TBSOTf
(1.7 equiv.)
Base
H
H
H
(1 equiv.)
work-up
H
H
H
H
H
(1.75 equiv.)
CH2Cl2
0 °C
or
H
H
H
H
O
O
28
OTBS
CH2Cl2
0 °C to rt
OTBS
OTBS
21
H
OTBS
OTBS
OTBS
OMe
mCPBA
(1 equiv.)
then
OTBS
A
B
TBSO
TBSO
TBSO
H
H
H
Time Yield/%
/h (A:B[a])
2 M HCl
Entry
1[b]
Ketone
Major product
Base
+
H
H
H
OH
CH2Cl2
0 °C
OH
29
OH
19b
OH
30
OTBS
OTBS
TBSO
OTBS
O
O
HO
H
H
94%
54% (20 min)
0% (10 h)
26% (20 min)
87% (10 h)
73
(1:0)
H
H
2,6-lutidine
6
H
O
OTBS
Me
H
250 300 350 400
[nm]
12
20
21
0
H
9
OH
16
OH
OTBS
TBSO
HO
Hax
H
H
O
OH
H
H
87
(9:1)
2[c]
3[c]
4
2,6-lutidine 0.3
H
H
CD spectrum of 19b
(λmax = 318 nm)
NOE correlation of 30
H
O
OTBS
20S-11
21
Scheme 6. Synthesis of 30. mCPBA = m-chloroperbenzoic
acid.
OH
OTBS
TBSO
HO
H
H
92
(1:0)
H
H
OTBS
OTBS
Et3N
1.0
TBSO
TBSO
H
O
OTBS
mCPBA
H
H
21
H+
(3 equiv.)
20S-11
(3)
H
H
OH
OTBS
OTBS
CH2Cl2
AcO
rt, 2 h
OH
30
H
O
OTBS
O
H
87%
17[d]
(0:1)
21
OTBS
H
H
2,6-lutidine 48
2,6-lutidine 0.3
H
H
O
H
O
Scheme 7. Double Rubottom oxidation of enol 21.
22
23
exposure to 2 M HCl to give α,α-dihydroketone 30 in 94%
yield. The stereochemical assignment of ketone 30 was estab-
lished by nuclear Overhauser effect (NOE) experiments. The
NOE correlation between H-16 and Hax-12 revealed the stereo-
chemistry at C16 and C14 shown in Scheme 6.
OH
H
OTBS
HO
TBSO
H
30[e]
(3:1)
5[c]
H
H
H
O
OTBS
20R-11
24
According to these results, “double Rubottom oxidation”
was achieved by treatment of enol 21 with 3 equiv. of mCPBA
in CH2Cl2 at room temperature for 2 hours to provide keto-diol
30 with a yield of 87% (Scheme 7, eq 3).32 Thus, the Rubottom
oxidation route was highly stereoselective and has fewer steps
than the pinacol route.
The reduction of keto-diol 25 by NaBH4 in MeOH at 0 °C
completed within 10 min, giving the desired 15,16-cis-triol
32 and undesired 15,16-trans-triol 31 in yields of 74% and
23%, respectively (Scheme 8). On the other hand, LiAlH4 took
longer reaction time (20 min) to reduce 30 in a less selective
manner compared to NaBH4 to give 32 in 40% and 31 in 45%
yields.
To determine each stereochemistry at the C15 positions of
31 and 32, the hydroxy groups at the C16 position of 31 and
the C15/C16 positions of 32 were protected as MTPA and
acetonide, respectively. The NOE correlation between H-16
and Hax-12, H-15 and H-7/H-17 in 35 indicated the stereo-
chemistry of C15 as shown in Figure 7. The stereochemistry of
C15 in 36 was also determined by the NOE correlation between
H-16 and Hax-12, H-15 and Hax-7/H-9. Therefore, the stereo-
chemistry of C15 in triols 31 and 32 was confirmed as shown in
Scheme 8. Oxidative cleavage of the C15-16 bond of 32 for
construction of the 15,16-seco-structure was achieved by using
NaIO4 to afford a mixture of the dialdehyde 33 and the cyclic
compound 34 (81%).
O
O
O
O
H
H
81
(0:1)
6
7
2,6-lutidine 36
2,6-lutidine 0.3
H
H
H
H
H
OTBS
O
25a
26
H
H
H
95
(0:1)
H
H
OTBS
O
27
9
[a] The diastereomeric ratio was determined by 1H NMR.
[b] 3.4 equiv. of TBSOTf and 3.5 equiv. of 2,6-lutidine were
used. [c] 4.9 equiv. of TBSOTf and 5.2 equiv. of base were
used. [d] Recovery of starting material in 74% yield. [e] The
15-keto-20,21-di-TBS ether was obtained in 54% yield.
TBS = tert-butyldimethylsilyl, Tf = trifluoromethanesulfonyl.
OH
OTBS
HO
TBSO
H
Me
O
H
H
H
H
O
H
OR
H
O
OTBS
20S-11
21
R = H or TBS
Figure 6. Plausible mechanism of regio-selective enoliza-
tion of 20S-11.
1480 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

OTBS
OTBS
OTBS
Table 4. Investigation of final stage.
TBSO
TBSO
TBSO
OTBS
H
H
H
OTBS
TBSO
TBSO
b
a
H
OH
H
OH
H
OH
+
H
H
OH
OH
30
OH
31
OH
OH
O
OH
1) nBu4NF, THF
rt, 30 min
O
H
H
32
O
H
OH
H
OH
OH
2) acid
1,4-dioxane/H2O
(5:4), temp, time
OTBS
O
OTBS
TBSO
TBSO
H
OMe
OMe
34
33
H
H
OH
O
H
O
H
O
O
H
H
OH
H
OH
OH
H
O
O
H
OMe
OMe
34
OH
33
HO
velutinol A (1)
Scheme 8. Total synthesis of velutinol A. Reagents and
conditions: a) NaBH4, MeOH, 0 °C, 10 min, 32: 74%, 31:
23%; b) NaIO4, THF/H2O (1:1), 5 h, 81%.
Entry
acid
Temp.
Time
Yield/%
1
2
3
4[a]
AcOH
1 M HCl
TsOH
HClO4
rt
rt
1 d
1 d
2 h
2 h
No reaction
No reaction
7
88[b]
OTBS
OTBS
Reflux
rt
TBSO
TBSO
12
12
17
H
H
16
16
[a] HClO4 was directly added to the mixture of 33 and 34
without using nBu4NF. [b] conc. HCl aq. was needed to
observe velutinol A in NMR measurement, also see below.
H
OMTPA
Hax
H
O
9
Hax
15
H
OH
15
O
H 7
OH
Hax
H
7
OH
Hax
Heq
Heq
MeO
35
MeO
36
NOE
NOE
Me
Me
H
H
12
12
H
OH
Heq
H
OH
Heq
17
9
7
7
16
16
Hax
H
axH
H
H
OMTPA
O
15
15
HO
H
H
O
Hax
Hax
Figure 7. Stereochemical assignment of triol 35 and 36.
The final stage of synthesis required the deprotection of the
AB ring moiety and detachment of the TBS groups, followed
by an intramolecular double acetalization. To achieve total
synthesis of velutinol A, we carefully investigated appropriate
acids for the construction of the cage like moiety and conver-
sion of the AB ring moiety (Table 4), since the β,γ-dihydroxy-
carbonyl moiety and its structural equivalents would be
easily aromatized.24 Thus, after removal of the TBS groups
by nBu4NF, the resulting crude diol was treated with AcOH
(Entry 1) or 1 M HCl (Entry 2) at room temperature. However,
these treatments resulted in no reaction. The final desired prod-
uct was then obtained in 7% when TsOH was used at reflux
condition (Entry 3). These results suggested that conversion to
the AB ring moiety would need stronger acid, and the β,γ-
dihydroxycarbonyl moiety and its structural equivalents resist
aromatization in these strong acidic condition. After some
optimization of reaction conditions, the conversion of the AB
ring moiety, detachment of the TBS groups, and the intra-
molecular double acetalization were achieved using a strong
acid. Thus, exposure of the mixture of 33 and 34 to HClO4
in 1,4-dioxane/H2O provided velutinol A (1) in 88% yield
(Entry 4).
Figure 8. CDCl3, 500 MHz for 1H NMR spectra (9.5-3.8
ppm) of; a) reaction crude, b) products after the purification
of reaction crude by silica gel, and c) product after addition
of conc. HCl aq. to the purified products.
by silica gel, as shown in Figure 8. In the absence of this acid
treatment, peaks assignable to hemi-acetal protons (the red
peaks at ³5.25 ppm and ³5.45 ppm) and hydroxy proton of
hemi-acetal shifted to low magnetic field by hydrogen bond-
ing (³9.18 ppm, ³8.55 ppm, and ³7.98 ppm) were detected as
shown in Figure 8b.
Synthesis of the Pentalinonside Aglycon.15 Pentalinon
andrieuxii Mueller-Itrgoviensis, a native Mexican plant grow-
ing in the Yucatan Peninsula, has been used as a Mayan folk
medicine for the treatment of cutaneous leishmaniasis lesions.
As part of the discovery of naturally occurring anti-leishmania
agents, pentalinonside (37, Figure 9), a novel polyoxygenated
14,15-seco-pregnane with a β-diginosyl group at C3 and cage-
like DEF-rings, was isolated from the hexane-soluble extract of
the roots of P. andrieuxii in 2012.11 Although isolated from
The final product was identical to an authentic sample.8 It
should be noted that addition of conc. HCl aq. was essential for
obtaining the acetalized (cage-like) structure before purification
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1481

HMBC
TBSO
O
OTBS
OTBS
TBSO
TBSO
15
(21)
O
H
H
(16)
20
(16)
20
CH2
O
H
H
HO
MeO
H
a
O
b
H
H
O
OTs
H
O
OH
O
O
H
Table 5
H
H
OH
5.52 ppm
OH 20(16)
4.63 ppm
pentalinonside (37)
HO
42
HO
H
H
43
32
Figure 9. Structure of pentalinoside (37).
TBSO
H
TBSO
H
OTBS
OTBS
O
H
O
H
TBSO
HO
H
TBSO
c
d
H
H
H
H
O
O
O
OH
a
b
O
H
OH
H
OMs
H
44
H
OH
OH
OH
O
O
O
TBSO
H
H
30
38
39
H
O
O
H
OAc
OH
OAc
AcO
HO
AcO
O
O
H
H
e
H
H
H
O
O
H
H
H
H
H
20(16)
O
c
20
(15)
H14
H
H
HMBC
correlation
21
O
H14
HO
pentalinonside aglycon (2)
O
O
21
O
45
S
S
O
H
O
21' S
O
OMe
21'
(15')
O
O
O
OH
40
O
O
O
H
H
H
β H
α
H
H
Scheme 10. Synthesis of pentalinonside aglycon (2). Rea-
gents and conditions: a) TsCl, DMAP, CH2Cl2, rt, 2 h,
93%; b) nBu4NF/AcOH (1:2), THF, reflux, 2 h, 71%,
yields and conditions see Table 5; c) NaIO4, THF/H2O
(1:1), rt, 5 h, 81%; d) NaBH4, MeOH, 0 °C, 10 min, 71%;
e) HClO4, 1,4-dioxane/H2O (5:4), rt, 2 h, 95%. Ts =
toluenesulfonyl, DMAP = 4-dimethylaminopyridine.
MeO
41
LSMS (ESI+): m/z: calcd for:
C27H44NO10S [M+NH4]: 574.27,
found: 574.28
HMBC
correlations
Scheme 9. Unsuccessful route for F-ring formation. Rea-
gents and conditions: a) MsCl, pyridine, rt, 2.5 h, 88%;
b) nBu4NF, THF, rt, 12 h, 39: 0%, 40: 45%; c) pyridine,
Ac2O, rt, 10 min, 86%. Ms = methanesulfonyl.
Table 5. Optimization of the exo-cyclization for the con-
struction of F-ring.
bioactive extracts, pentalinonside (37) does not exhibit anti-
leishmania activity. However, due to its structural similarity
to velutinol A (1), our main goal was the synthesis of the
pentalinonside aglycon (2), even though the biological activ-
ities of pentalinonside (37) have not yet been specified.
OTBS
TBSO
H
TBSO
nBu4NF
(2.5 equiv.)
AcOH
H
O
H
H
OTs
THF, rt, 2 d
H
OH
OH
OH
OH
43
42
As shown in our retrosynthetic analysis (vide ante,
Scheme 2), the synthesis begins from α,α-dihydoxyketone 30
(Scheme 9). To construct the E-ring moiety via 5-exo-cycliza-
tion, the C20(16)-hydroxy group was mesylated. Unfortunate-
ly, removal of the TBS groups of ketone 38 by nBu4NF resulted
in the formation of an oxatholanedioxide ring to afford 40
instead of 39 in 45% yield.33 The structure of 40 was confirmed
by heteronuclear multiple bond correlation (HMBC) experi-
ments of diacetate 41, easily accessible from compound 40.
After protection of the 15(21), 16(20)-dihydroxy groups as
acetyl groups (86%), the HMBCs of 41 were measured. HMBC
from H21¤α to C20(16)/C21(15) and from H21¤(15¤)β to C14/
C21(15) indicated the formation of an oxatholanedioxide ring,
and this was further supported by mass spectrometry.
Yield/%
Entry
AcOH/equiv.
43
42 (recovery of s. m.)
1[a]
2
3
4[b]
®
2.5
5.0
5.0
®
32
46
71
®
35
35
®
[a] Triol 46 and tetrol 47 were obtained in 89% and 9%,
respectively. [b] The reaction was performed under reflux
conditions for 2 h.
Table 5 summarizes the optimization process of the key 5-
exo-cyclization reaction for construction of the F-ring. First,
nBu4NF was used not only for removal of the TBS groups but
also as a weak base for the intramolecular SN2-type reac-
tion (Entry 1). Despite quantitative conversion of 42, E2-
elimination was the major reaction instead of F-ring annulation,
affording triol 46 (89%) and tetrol 47 (9%, Figure 10). For triol
46, the hydroxide at C16(20) generated by fluoride attack on
the silyl-group assisted E2-elimination (path a.), and for tetrol
47, protonation of the hydroxide at C16(20) prevented E2-
elimination (path b.). These results suggested that selective de-
silylation at C15(21), and not at C16(20), would prevent E2-
elimination and activation of the tosylate to induce SN1 and
provide desired product 43. For this purpose, diol 11 was
treated with nBu4NF in the presence of AcOH (Entries 2-5).
To prevent annulation, triol 32 was used as the starting
material and the p-toluenesulfonyl (Ts) group was attached to
the C20(16) hydroxy group (Scheme 10). The first step was
regioselective installation of the tosyl group at C20(16). We
anticipated that the nucleophilicity of the hydroxy group at
C21(15) is weaker than that of C20(16) because of neighboring
group participation from the C14 hydroxy group. Therefore,
triol 32 was treated with TsCl in the presence of 4-dimethyl-
aminopyridine (DMAP) in CH2Cl2, which gave tosylate 42 as a
1
sole product in a 93% yield. The H NMR value assigned to
H20(16) was shifted from 4.63 ppm to 5.52 ppm after tosyla-
tion, confirming installation of the Ts group at the C20(16)
hydroxy group.
1482 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

Table 6. 13C- and 1H NMR spectroscopic data of the natural
pentalinonside and synthetic aglycon (2).
Me
Me
OTBS
TBSO
HO
H
HO
H
15
16
H+
b.
H
H
(21)
H
(20)
a.
H
natural pentalinonside[a]
[ppm]
synthetic aglycon[b]
[ppm]
Ts
O
O
O
O
SiR3
O
TsO
H
H
SiR3
OTs
H
H
+R
Position
¤
C
¤
H
¤
¤
H
C
SN1
H
16
HO
O
OH
42
(20)
F–
15
E2
[ppm]
37.5
(J [Hz])
[ppm]
37.7
(J [Hz])
OH
H(21)
a.
Activation
of TsO
b.
1
2
α 1.05 m
β 1.75 m
α 2.13 m
β 1.68 m
3.90 m
α 2.59 m
β 2.40 m
®
α 1.18-1.10 m
β 1.90-1.83 m
α 2.13-2.06 m
β 1.83-1.73 m
3.89-3.81 m
α and β
OH
OH
TBSO
H
HO
HO
H
H
30.4
32.5
O
H
H
OTs
H
H
3
4
77.3
39.4
71.2
43.4
OH
OH
OH
46
OH
OH
O
47
43
2.63-2.58 m
®
Figure 10. Reaction pathway to byproducts 46 and 47.
5
6
7
139.7
122.6
25.5
140.4
121.8 5.49-5.45 m
25.4
5.52 t (2.5)
2.40 m
2.50 m
1.85 m
1.42 m
®
2.52-2.44 m
2.66-2.60 m
1.89-1.84 m
1.45-1.40 m
®
8
9
10
11
36.2
46.1
41.4
20.6
36.2
46.0
41.3
20.5
α and β
1.43 m
α 1.38 m
β 1.67 m
®
1.34-1.28 m
1.52-1.46 m
α 1.38-1.32 m
β 1.49-1.43 m
®
12
34.9
34.8
13
14
15
37.1
108.2
74.3
36.8
108.1
74.2
®
®
α 4.02 dd
(10.0, 4.4)
β 4.23 d
(10.0)
α 4.03 dd
(10.1, 4.6)
β 4.23 d
(10.1)
16
17
80.9
54.6
4.56 t
(4.5)
2.60 dd
(7.6, 4.4)
1.08 s
80.7
54.5
4.57 t
(4.6)
2.61 dd
(8.0, 4.6)
1.10 s
18
19
20
17.3
19.6
76.3
17.2
19.6
76.2
0.97 s
1.02 s
4.49 ddd
(7.6, 6.0, 1.5)
α 4.05 dd
(12.4, 6.0)
β 3.79 dd
(12.4, 1.3)
1
4.49 ddd
(8.0, 5.8, 1.2)
α 4.06 dd
(12.6, 5.8)
β 3.80 dd
(12.6, 1.2)
Figure 11. 1H NMR and 13C NMR spectra of synthetic
aglycon (blue, 500 MHz for 1H- and 125 MHz for
13C NMR, pyridine-d5) and natural pentalinonside (red,
400 MHz for 1H- and 100 MHz for 13C NMR, pyridine-d5).
21
66.2
66.1
[a] pyridine-d5, 400 MHz for H- and 100 MHz for 13C NMR,
see ref 10. [b] pyridine-d5, 500 MHz for H- and 125 MHz for
13C NMR.
The desired product 43 was obtained in 32% yield, concom-
itant with the recovery of 42 in 35% yield when 2.5 equiv. of
AcOH were used (Entry 2). Addition of 5.0 equiv. of AcOH
raised the yield of 43 to 46% (Entry 3). Finally, refluxing for
2 h in the presence of 5.0 equiv. of AcOH gave 43 in 71% yield
(Entry 4). The structural elucidation of compound 43 was es-
tablished based on the HMBC between H15(21) and C20(16).
Oxidative cleavage of the C14-21(15) bond of compound 43
was achieved using NaIO4 to afford keto-aldehyde 44 (81%,
Scheme 10). The C20(16)-oxo group in 44 was selectively
reduced using NaBH4 at 0 °C to give hemi-ketal 45 [71%, con-
firmed by HMBC correlation between H21(15) and C14]. The
final conversion was achieved with HClO4 to give pentalinon-
side aglycon (2) in 95% yield. The structure of 2 was con-
firmed by comparing the 1H NMR and 13C NMR spectra of the
synthetic aglycon and authentic pentalinonside (Figure 11 and
Table 6).11 The NMR peaks of 2 were analogous to those of
pentalinonside (37), except for those assigned as H2-H4 and
C2-C4, which are the positions adjacent to the glycoside bond.
1
Synthesis of the Argeloside Aglycon.16 More than ten
14,15-seco-pregnane glycosides with a cage-like structure in
the DEF-rings, generally referred to as “argelosides”, were
recently isolated from the alcoholic extracts of the leaves and
hairy seeds of the Egyptian medicinal plant Solenostemma
argel Hayne (Asclepiadaceae, Figure 12).12,34
This plant grows in the eastern desert and along the Nile in
southern Egypt.35 Some argeloside congeners have potent anti-
inflammatory activities, as evaluated by their inhibition in LPS-
stimulated RAW 264.7 mouse cells of the release of TNF-α,
a potent pro-inflammatory cytokine capable of inducing an
inflammatory response.12b On the other hand, the aglycon of the
argeloside, which is structurally similar to velutinol A, has not
been isolated from natural sources.12,36 Thus, we focused our
attention on the aglycon of argeloside.
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1483

HMBC
H
OH
H
OH
H
O
HO
HO 16
HO
H
O
16
R2
(20)
16
R2
H
O
H
O
E
D
O
a
b
H
OF
O
H
H
14
H
H
O
R1O
O
O
O
R1O
OH
14
49
H
H
O
O
O
48
O
O
R4O
O
16S-11
(20S-11)
O
A
O
O
MeO
R3O
MeO
OR
15
HO
O
MeO
HO
TBSO
TBSO
H
O
O
O
R3O
HO
O
H
O
B
O
O
O
O
OH
HO
c
+
H
H
H
H
HO
MeO
21
MeO
OH
OH OH
OH
O
O
O
O
O
O
O
R3O
H
O
C
D
O
O
50
53
MeO
HO
51: R = TBS
52: R = H
MeO
MeO
O
R3O
MeO
O
O
O
Scheme 12. Investigation of the synthetic route to argeloside
aglycon (3). Reagents and conditions: a) mCPBA,
NaHCO3, CH2Cl2, 0 °C to rt, 1 d, 77%; b) TBSCl,
imidazole, DMF, 0 °C, 20 min, 97%; c) LiAlH4, THF,
0 °C, 1 min, 60% for 52, 28% for 53.
MeO
HO
MeO
MeO
O
O
HO
E
MeO
O
Argeloside A (3a) : R1=A, R2=CH2OAc, R3=H, R4=β-gulcose
B (3b) : R1=B, R2=CH2OAc, R3=β-gulcose
C (3c) : R1=A, R2=Me, R3=Me, R4=H
OTBS
OTBS
a
OTBS
D (3d) : R1=A, R2=CH2OH, R3=Me, R4=H
E (3e) : R1=A, R2=CH2OAc, R3=Me, R4=H
F (3f) : R1=A, R2=Me, R3=H, R4=β-gulcose
G (3g) : R1=A, R2=Me, R3=Me, R4=β-gulcose
H (3h) : R1=A, R2=CH2OAc, R3=Me, R4=β-gulcose
TBSO
TBSO
H
TBSO
H
H
H
b
c
H
H
O
O
H
47
OTBS
O
I
(3i) : R1=A, R2=Me, R3=H, R4=H
48
15
J (3j) : R1=A, R2=CH2OAc, R3=H, R4=H
K (3k) : R1=C, R2=Me, R3=β-gulcose
L (3l) : R1=C, R2=CH2OAc, R3=β-gulcose
M(3m): R1=A, R2=CH2OH, R3=Me, R4=β-gulcose
N (3n) : R1=D, R2=CH2OH, R3=β-gulcose
O (3o) : R1=E, R2=Me
OTBS
OTBS
H
TBSO
TBSO
H
H
H
Figure 12. Structure of argelosides.
O
OH
OH OH
49
50
OR
OR
15
RO
15
RO
Scheme 13. Unsuccessful synthetic route to the argeloside
aglycon (3). Reagents and conditions: a) 1 M HCl, THF,
0 °C, 2 h, 80%; b) mCPBA, NaHCO3, CH2Cl2, 0 °C to rt,
2 d, 55%; c) LiAlH4, THF, 0 °C to rt, 1 d, 96%.
16
16
H
H
4) Wacker
Oxidation
O
H
H
14
21
14
21
5) Oxidation
OH
O
H
XIV
H
XV
O
3) Nishizawa–
Grieco
Elimination
O
O
H
H
is considerably different from that of C16, allowing these
alcohols to be distinguished.
argeloside
aglycon (3)
OR
OH
15
RO
HO
1) Baeyer
With these points in mind, we started the synthesis with the
diol 16S-11 (Scheme 12). Treatment of diol 16S-11 with
mCPBA gave lactone 49 equipped with the distinguished
secondary alcohols at C14 and C16 in 77% yield via inter-
molecular lactone exchange of the Baeyer-Villiger oxidation
product 48. The structure of lactone 49 was established from
the 2D-NMR spectrum, with the HMBC between H15 and
C21 indicating the formation of γ-lactone, as illustrated in
Scheme 12. After selective protection of the primary alcohol
moiety at C15 as TBS, the resulting lactone 50 was reduced by
LiAlH4 to afford tetrol 52 in 60% yield and lactol 53 in 28%
yield, instead of the desired triol 51 (with the primary alcohols
at C15 and C21 distinguished). To obtain the triol 51, other
reducing agents were examined but resulted in the formation
of lactol 53 as the sole product (e.g., Dibal-H, 63%; Red-Al,
87%; LiBH4, 99%). Thus, we decided to abandon this synthetic
route.
16
16
(20)
H
–Villiger
H
Oxidation
H
H
14
21
2) Reduction
OH OH
H
H
O
XVIII
16S-11
(20S-11)
Scheme 11. Details of the synthetic strategy.
Scheme 11 details a synthetic strategy to the final structure
3 from diol 16S-11 (20S-11). The oxo groups in compound XV
at the C14 and 20 positions could respectively be constructed
by the oxidation of C14-OH and Wacker oxidation20 of ¦20 in
olefin XIV, easily accessible from diprotected-tetrol XVIII
through Nishizawa-Grieco elimination.37 From this retrosyn-
thetic analysis, it is obvious that the crucial point in accessing
compound XVIII is the discrimination of prim-alcohols C15-
OH, C21-OH/sec-alcohols C14-OH, and C16-OH before or
after Baeyer-Villiger oxidation of diol 16S-11. In particular,
the discrimination of C15-OH and C21-OH is more important
because steric hindrance around the secondary alcohol at C14
As an alternative synthetic route, we utilized the enol 21, the
intermediate in velutinol A (1) synthesis (Scheme 13). The
silyl enol ether moiety of 21 was selectively hydrolyzed with
1484 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

P
P
P
O
H
O
H
O
H
OH
HO
H
O
O
O
O
H
O
a, b
c
H
H
H
H
H
a
O
OH OH
O
O
O
H
H
O
20S-11
(16S-11)
HO
15a: P = C(Me)2
15b: P = Si(iPr)2OSi(iPr)2
14b: P = Si(iPr)2OSi(iPr)2
OMe
60a: P = C(Me)2
62
P
P
O
O
60b: P = Si(iPr)2OSi(iPr)2
O
O
H
H
b
f
g
d, e
H
OH
H
H
H
OH
O
O
O
58a: P = C(Me)2
58b: P = Si(iPr)2OSi(iPr)2
59a: P = C(Me)2
59b: P = Si(iPr)2OSi(iPr)2
H
H
O
O
acids
H
H
O
OH
+
decompose
H
H
P
O
O
15
16
OMe
63
OMe
H
64
O
H
iPr
iPr
O
AcOH
O
Si
Cl
Si
Cl
H
iPr
iPr
Scheme 15. Conversion of 60 towards the argeloside agly-
con (3). Reagents and conditions: a) HClO4, 1,4-dioxane/
H2O, rt, 2 h, 68%; b) nBu4NF, AcOH, THF, rt, 6 h, then
AcOH, 66%.
61
OMe
60a: P = C(Me)2
60b: P = Si(iPr)2OSi(iPr)2
Scheme 14. Investigation of the protecting group for 20,21-
diol moiety of 20S-11. Reagents and conditions: a) disilyl-
ether 61, imidazole, DMF, rt, 30 min, 82%; b) mCPBA,
NaHCO3, CH2Cl2, 0 °C to rt, 3 d, 56% (19% recovery);
c) LiAlH4, THF, 0 °C, 2 h, 99%; d) 2-nitrophenylselenyl
cyanide, nBu3P, THF, rt, a: 20 min, 96%; b: 3 h, quant.;
e) 30% H2O2 aq. THF, rt, a: 3.5 h, 98%; b: 3 h, quant.;
f) TPAP, NMO, CH2Cl2, rt, a: 1 d, 96%; b: 5 h, 90%;
g) cat. PdCl2, CuCl, O2, DMF/THF/H2O, rt, a: 20 min,
95%; b: 6 h, 55%.
The next stage was the selective dehydration of the primary
alcohol at C15 using the Nishizawa-Grieco method.34 Thus,
after treatment of the alcohols 15a and b with 2-nitrophenyl-
selenyl cyanide in the presence of nBu3P, the resulting sele-
nides were exposed to 30% hydrogen peroxide, providing
olefins 58a and 58b in 84% and 100% yield, respectively (two
steps). Ketones 59a and b, resulting from TPAP oxidation of
the C14-OH in olefins 58a and b, were treated with catalytic
amounts of PdCl2 and CuCl in an O2 atmosphere (Wacker
oxidation20 conditions) to introduce an oxo group at C20 to
yield diketones 60a (91%, two steps) and 60b (50%, two
steps). It should be noted that the reactivity of the reactants in
the Baeyer-Villiger reaction, reduction, and Wacker oxidation
were strongly influenced by the steric hindrance of the 15,16-
diol protecting groups.
To remove the acetonide and restore the hydroxy group at C3
and ¦5 from the 3,5-cyclo-6-methoxy protection, the diketone
60a was treated with HClO4 (Scheme 15). Unfortunately, this
treatment only resulted in the undesirable formation of furan 62
instead of argeloside aglycon (3). Other acids, such as TsOH,
HCl, pyridinium para-toluenesulfonate, and trifluoroacetic acid
(TFA) were also examined in an effort to obtain the desired
product 3; however, all the acidic conditions only induced the
decomposition of 60a. Therefore, although a strong acid was
needed for removal of the acetonide moiety, the β,γ-diol ketone
moiety appeared to be unstable under the strongly acidic
conditions.
1 M aq. HCl in THF to afford the 15-ketone 54 with cis-fused
CD-rings in 80% yield. Baeyer-Villiger oxidation of ketone 54
was examined by treatment with mCPBA in the presence of
NaHCO3 to give lactone 55 in 55% yield. Unfortunately, the
reduction of lactone 55 provided only lactol 56, the semi-
reduced product, which was resistant to further reduction to the
desired 14,21-diol 57.38 These results suggest that cis-fused
lactol moiety in compound 56 is extremely stable which might
prevent equilibration with hydroxy-aldehyde derivatives. We
therefore examined strategies for the preparation and reduc-
tion of the trans-fused lactone. For preparing the trans-fused
lactone, appropriate conditions and a protecting group for
15,16-diol moiety to prevent enolization of the 15-ketone were
required.
Actually, the acetonide was an option for protecting the diol
moiety as shown in Scheme 5 (vide ante), which led to diffi-
culty of deprotection in acidic conditions because of aroma-
tization. Thus, towards the accomplishment of the synthesis,
bis-silyl ether was also chosen for the protection of diol moiety
(Scheme 14).
In an alternative route, the bis-silyl ether moiety of com-
pound 60b was removed by using nBu4NF in the presence of
AcOH to afford two separable products, 63 and 64. Because
bishemiketal 63 was easily converted to 64 by exposure to
AcOH, 60b was directly converted to 64 in 66% yield by the
addition of excess AcOH after treatment of 60b with nBu4NF/
AcOH. However, against our expectations, final conversion
of the AB-ring moiety using acids such as TsOH, TFA, and
HClO4 led to a complex mixture, and furan 62 was the only
After the diol moiety of compound 20S-11 was protected as
bis-silyl ether (82%) by using 61, treatment with mCPBA of the
resulting ketones possessing trans-fused CD-rings afforded the
lactones 14b (56%). With the requisite lactones 14b with trans-
fused CD-rings in hand, reduction of 14b with LiAlH4 cleanly
gave diol 15b (99%).
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1485

O
H
O
H
O
H
OR
H
O
O
O
RO
H
Wacker
Oxidation
H
H
TPAP
NMO
H
b
d–f
O
OR
OH
OAc
H
H
H
H
HO
OMe
59a
OMe
58a: R = H
66: R = Ac
OMe
58a
deprotection
Path A
deprotection
Path B
67: R = H
68: R = TBS
a
c
OTBS
TBSO
Scheme 16. Remaining choices for the final approach to
argeloside aglycon.
H
H
O
O
H
H
H
O
O
g
O
O
O
H
H
HO
TBSO
69
H
H
argeloside aglycon (3)
Wacker
Oxidation
H
H
HClO4
O
Scheme 18. Successful route to aglycone (3, Path B).
Reagents and conditions: a) Ac2O, DMAP, pyridine, rt,
1 h, 89%; b) HClO4, 1,4-dioxane/H2O, rt, 2 h, 90%;
c) TBSOTf, Et3N, CH2Cl2, 0 °C to rt, 1 h, 80%; d) LiAlH4,
THF, 0 °C to rt, 8.5 h, 80%; e) TPAP, NMO, CH2Cl2, rt,
2 h, 81%; f) cat. PdCl2, CuCl, O2, DMA/H2O, rt, 5 h, 69%;
g) nBu4NF, THF, rt, 1 d then AcOH, 74%. DMA = N,N-
dimethylacetoamide.
O
O
1,4-dioxane
2 h, quant.
H
H
HO
65
59a OMe
Scheme 17. Deprotection of 59a in advance of Wacker
oxidation (Path A).
identifiable product. Further investigations revealed that the
DEF-ring moiety in 64 was as unstable as the β,γ-diol ketone
moiety in 60 under the acidic conditions required for recovery
of the hydroxy group at C3 and ¦5 from the 3,5-cyclo-6-
methoxy moiety. Our results suggest that the oxo group at C20
causes decomposition or aromatization. Therefore, we con-
cluded that reconsidering the synthetic route or another alter-
native deprotection process would be necessary to obtain the
argeloside aglycon.
As described above, the γ-dihydroxyketone moiety in the
seco-E ring did not tolerate the acidic conditions necessary for
the recovery of the 3β-hydroxy-5-ene moiety in the AB ring
from the 6β-methoxy-3,5-cyclopropane moiety, being convert-
ed to the furan moiety or a complex mixture. Thus, the AB ring
moiety was deprotected in a step prior to Wacker oxidation
(Path a) or TPAP oxidation (Path B) before the generation of
the acid-sensitive tricyclic cage-like moiety (Scheme 16).
We first investigated removal of the acetonide and conver-
sion of the AB-rings before constructing the oxo group at C20
(Scheme 17). Treatment of ketone 59a with HClO4 resulted in
the formation of internally ketalized product 65 in quantitative
yield. This result suggested that deprotection should be per-
formed in advance of Wacker oxidation. However, subsequent
Wacker oxidation led to decomposition of the product.
Figure 13. ¦δC value of authentic argeloside C aglycon
and synthetic aglycon.
The final stage of the synthesis required removal of the three
TBS groups and an intramolecular double ketalization. The
reaction conditions used for the conversion of 63 to 64 (vide
ante, Scheme 15) provided useful information for these present
conversions. Thus, after confirming removal of all the TBS
groups by nBu4NF treatment by NMR, intramolecular double
ketalization was achieved by treating the resulting polar
products with AcOH to afford compound 3 in 86% yield in
one pot.
After several fruitful and thorough investigations, we were
pleased to identify a successful synthetic route to access
argeloside aglycon (3, Scheme 18). Following protection of
the C14-hydroxy group of 58a as acetyl (89%), removal of the
diol protecting groups and restoration of the 3-hydroxy group
and ¦5 in the AB-ring moiety were achieved by using HClO4
(90%). The resulting triol 67 was then reprotected with the TBS
groups (80%), followed by removal of the acyl group using
LiAlH4 to give the corresponding alcohol (80%). The C14-
hydroxy group of this alcohol was oxidized via TPAP oxida-
tion29 to give the corresponding ketone in 81% yield. The
subsequent Wacker oxidation of ¦20,38 afforded diketone 69.
The structure of 3 was elucidated through comparison of the
1H and 13C NMR spectroscopic data with those of the aglycon
portion of argeloside C (3c, vide ante, Figure 13).12c As shown
in Figure 13, the ¦δC (= 13C NMR δ of authentic argeloside C
aglycon ¹ 13C NMR δ of synthetic aglycon) value of each
carbon indicated that the 13C NMR peaks of 3 were analogous
to those of argeloside C (3a), except for those assigned as C2-
C4, which are the positions adjacent to the glycoside bond.
Synthesis of Illustrol and Its Glycoside.17
In 1993,
illustrol (4) was isolated from hydroalcoholic extracts of the
rhizomes of Mandevilla illustris Vel. Woodson (Apocynaceae),
a native Brazilian plant used in folk medicine to treat inflam-
1486 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

H
OTBDPS
H
H
OH
H
O
H
H
O
O
O
H
a, b
c–f
H
H
H
H
H
H
HO
illustrol (4)
O
O
O
OH OH
HO
H
H
H
OH
H
OMe
H
72
9
71
O
H
O
O
OTBDPS
H
OTBDPS
OTBDPS
H
H
H
H
OH
OH
20
O
g–i
j
HO
O
S
R
H
+
OAc
OAc OH
OAc OH
MeO
2,6-dideoxy-3-O-methylpyranosylillustrol (70)
H
H
20S-74 (undesired)
73
20R-74 (desired)
Figure 14. Structures of illustrol (4) and its glycoside 70.
ΔδSR value = δ(S)-MTPA-75 – δ(R)-MTPA-75
k, l or m
Ph
mation and snake bites.39 Illustrol (4, Figure 14), consisting of
a 14,15-seco-15-nor-pregnane core with a cage-like framing of
DEF-rings, is structurally related to the selective B1R antag-
onist velutinol A. However, although illustrol was isolated
from extracts of the rhizomes of M. illustris and shows an
antagonistic effect to bradykinin-induced responses,40 and
despite its structural similarity to the B1R antagonist velutinol
A (1),13 illustrol does not exhibit significant biological activity.
On the other hand, 2,6-dideoxy-3-O-methylpyranosylillustrol
(70), isolated from ethyl acetate extracts of the rhizomes of
M. illustris, was found to inhibit rat paw edema induced by car-
rageenan, dextran, and the B1R agonist des-Arg-9-bradykinin,7
without affecting edema caused by bradykinin B2R agonists.41
From these results, we believe that compound 70 is a B1R-
selective non-peptide antagonist.
On the basis of our retrosynthetic analysis (vide ante,
Scheme 2), we first synthesized olefin 73 and investigated
the diastereoselectivity of its dihydroxylation (Scheme 19).
Following oxidative cleavage and construction of the 15-nor-
structure of olefin 9 by using OsO4-NaIO4 (71%), the resulting
keto-aldehyde was reduced to diol 71 with NaBH4 in 94%
yield. The primary alcohol of 71 at C16 was protected as
TBDPS (88%), and subsequent oxidation of the remaining
secondary alcohol at C21 via TPAP24 (92%) gave the corre-
sponding 21-keto-derivative (92%). Baeyer-Villiger oxidation
of the 21-keto-derivative using mCPBA achieved construction
of the seco-structure to afford the corresponding lactone in 87%
yield, followed by reduction to diol 72 using LiAlH4 (86%).
Diol 72 was easily converted to the olefin 73 via Nishizawa-
Grieco elimination37 (80% for 2 steps), followed by protection
of C14-OH as Ac (91%).
With the requisite olefin 73 in hand, we investigated its
dihydroxylation. Thus, olefin 73 was treated with a catalytic
amount of OsO4 in the presence of a stoichiometric amount
of NMO at room temperature for 10 h to give a mixture of
undesired diol 20S-74 and desired diol 20R-74 in 60% yield
with a diastereoselectivity of 5.9:1, along with 28% recovery of
the starting material. Structural determination of the major
diastereomer 20S-74 was established as follows. After protec-
tion of the C20-OH in compound 20S-74 as TBS, the resulting
alcohol was treated with (S)-MTPACl or (R)-MTPACl in the
presence of DMAP to give (S)- and (R)-MTPA-75 in 80% and
72% yield, respectively, and the ¦δSR value [= δ(S)-MTPA-
75 ¹ δ(R)-MTPA-75] was calculated.30 The ¦δSR value shown
in Scheme 19 determined the absolute configuration of C20 in
the major diastereomer 74 to be S.
Ph
Si
–0.004
tBu
–0.125
OTBDPS
O
–0.173
OMe
CF3
H
–0.044
Me
H
OMTPA
O
Ph
H
H
O
OAc OTBS
O
H
OAc
+0.068
Me
Me
Si
+0.141
/+0.097
(S)-MTPA-75
or (R)-MTPA-75
tBu
+0.025
+0.080
Scheme 19. Unsuccessful route toward illutsrol (4). Rea-
gents and conditions: a) OsO4, NaIO4, 1,4-dioxane, H2O,
rt, 6 h, 71%; b) NaBH4, MeOH, rt, 70 min, 94%;
c) TBDPSCl, imidazole, DMF, 0 °C, 3.3 h, 88%; d) cat.
TPAP, NMO, CH2Cl2, rt, 1 h, 92%; e) mCPBA, NaHCO3,
CH2Cl2, 0 °C to rt, 12 h, 87%; f) LiAlH4, THF, 0 °C, 2.5 h,
62%; g) 2-nitrophenylselenyl cyanide, nBu3P, THF, rt,
70 min, 86%; h) H2O2, THF, rt, 1.7 h, 93%; i) Ac2O,
DMAP, CH2Cl2, rt, 4.3 h, 91%; j) cat. OsO4, NMO,
acetone, rt, 10 h, 61% (20S-74:20R-74 = 5.9:1, recovery
28%); k) TBSCl, imidazole, DMF, rt, 1 h, 69%; l) (S)-
MTPACl, DMAP, CH2Cl2, rt, 12 h, 80%; m) (R)-MTPACl,
DMAP, CH2Cl2, rt, 12 h, 72%.
After the investigation of alternative promising routes,
illustrol (4) was finally synthesized starting from keto-
aldehyde 76 (Scheme 20). The formyl group of the ketoalde-
hyde was selectively reduced to alcohol with NaBH4 at low
temperature (¹40 °C) to afford alcohol 77 in 68% yield and
recovery of 76 (28%). After protection of the primary alcohol
of 77 as TBS (98%), Baeyer-Villiger oxidation using mCPBA
gave the corresponding lactone (88%), which was reduced with
LiAlH4 to afford diol 78 in 87% yield. Diol 78 was converted
to olefin 79 via the Nishizawa-Grieco protocol.37 Thus, diol 79
was treated with 2-nitrophenylselenyl cyanide and nBu3P to
give the corresponding selenide (95%); the selenium moiety
was then oxidized by using 30% H2O2 to afford olefin 79 with
concomitant syn-elimination of the resulting selenoxide (94%).
After detachment of the TBS protecting group with nBu4NF,
Swern oxidation of the resulting diol afforded the desired
ketoaldehyde 80 without epimerization of the C17 position.
Notably, careful and rapid silica-gel column chromatography
was critical for obtaining a good isolation yield of ketoalde-
hyde 80, since otherwise the isolation yield of ketoaldehyde 80
was decreased due to decomposition.
With the requisite olefin 80 in hand, we performed asym-
metric dihydroxylation (Table 7). First, olefin 80 was treated
with a catalytic amount of OsO4 in the presence of a stoichi-
ometric amount of NMO at 0 °C to afford the desired diol 83 and
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1487

O
H
HMBC
NOE
OTBS
H
correlation
correlation
OH
H
H
18
CH3
HO
H
O
H
16
b–d
a
H
H
H
H
H
O
16
O
OH
OH
20
H
H
H
OH OH
17
21
12
H
H
HO
14
H
H
H14
O
16
H
17
20
OMe
H
H
OH
78
21
O
76
77
O
H
O
OH
81
O
H
H
OTBS
H
O
H
83
H
H
NOE
correlation
HMBC
correlation
e, f
g, h
H
O
OH
H
HO
O
H
16
80
79
21
H
CH3
H
H
OH20
OH
20
16
OH
OH
20
17
O
Scheme 20. Synthesis of olefin 80. Reagents and conditions:
a) NaBH4, MeOH, ¹40 °C, 30 min, 68% (recovery 28%);
b) TBSCl, imidazole, DMF, 30 min, 95%; c) mCPBA,
NaHCO3, CH2Cl2, rt, 1 d, 88%; d) LiAlH4, THF, 0 °C,
30 min, 87%; e) 2-nitrophenylselenyl cyanide, nBu3P,
THF, 0 °C, 20 min, 95%; f) H2O2, THF, rt, 5 h, 94%;
g) nBu4NF, THF, rt, 10 min, quant.; h) DMSO, (COCl)2,
¹78 °C, 8 h, 97%.
H
H14
21
H
O
OH
82
21
O
O 16
O
84
Figure 15. Structural determination of 81 and 82.
HO
18
CH3
H
O
H
H
12
H
H
HO
14
16
O
OH
H
17
Table 7. Dihydroxylation of ¦20.
OH
H
O
H
20
O
H
H
Chiral Ligand
HO
HO
H
H
O
H
H
cat. OsO4
K3[Fe(CN)6]
K2CO3
16
OMe
H
81
H
H
21
20
O
16
20
a
20
17
16
O
+
H
H14
OH
21
H14
H
tBuOH/H2O
(1/1), 0 °C
21
H
H
O
O
OH
O
O
H
82
80
81
O
O
O
desired
undesired
H
HO
O
O
HO
illustrol (4)
Entry
Chiral Ligands
Time [h]
Yield [%] (81:82[b]
)
1[a]
2
3
4
®
14
22
22
22
18
quant. (59:41)
77 (62:38)
63 (65:35)
55 (73:27)
85 (81 only)
a
(DHQ)2PHAL
(DHQD)2PHAL
(DHQ)2PYR
(DHQD)2PYR
HO
H
CH3
O
H
OH
H
5
OH20
O
OH
H
21
H
[a] Solvent: acetone, reagents: cat. OsO4, NMO. [b] 5:1
mixture of 82 and 84 by H NMR analysis.
O 16
O
1
OMe
82
Scheme 21. Total Synthesis of illustrol. Reagents and
conditions: a) HClO4, 1,4-dioxane, H2O, rt, 2 h, quant.
the undesired diol 84 (vide infra, Figure 15), which were spon-
taneously converted into compound 81 (59%) and 82 (41%),
respectively, concomitant with double acetalization (Entry 1).
Sharpless asymmetric dihydroxylation was also applied to
olefin 80.21 Thus, treatment of olefin 80 with a stoichiometric
amount of K3[Fe(CN)6] and K2CO3 and a catalytic amount of
OsO4 in the presence of a catalytic amount of (DHQ)2PHAL at
0 °C afforded compound 81 and 82 in 48% and 29% yield,
respectively (Entry 2). Surprisingly, the same selectivity was
obtained even though (DHQD)2PHAL, the diastereomer of
(DHQD)2PHAL, was used as the chiral ligand (Entry 3). The
diastereomer ratio was raised to 73:27 when (DHQ)2PYR was
used (Entry 4). Finally, perfect selectivity and high yield were
achieved by using (DHQD)2PYR (Entry 5). Thus, treatment of
olefin 80 with typical Sharpless asymmetric dihydroxylation
conditions by using (DHQD)2PYR as the chiral ligand gave
compound 81 in 88% yield and no detectable 82.
determined by NOE correlation between H16 and H12α/H12β.
The structure of 81 was also supported with other evidence
(i.e., NOE correlations between H16 and H18). For compound
82, HMBC correlation between H16 and C14 and between
H16 and C21 indicated the formation of a hexahydrofuro-
[2,3-b]furan skeleton, and the NOE correlation between H18
and H20 established the stereochemistry at C20, as shown
Figure 15.
The final step for the synthesis of illustrol (4), the construc-
tion of the DEF cage-like rings and concomitant conversion of
the AB-rings, were achieved by the exposure of 81 to HClO4,
providing illustrol (4) in quantitative yield (Scheme 21). This
synthetic product was identical to an authentic specimen.13 It
should be noted that compound 82 is structurally more similar
to illustrol (4) than is 81 (see also Figure 15). Compound 82
was thus subjected to the same conditions as used for the con-
version of 81 to illustrol (4). However, contrary to our expecta-
tion, the reaction resulted in the production of a complex
mixture instead of illustrol (4).
The structures of 81 and 82 were confirmed by NOE and
HMBC experiments For compound 81, formation of a hexahy-
drofuro[3,4-b]furan skeleton was confirmed by HMBC corre-
lation between H16 and C21 (3JCH) and between H21 and C14
(4JCH), and the stereochemistry at C14, C16, C17, and C20 was
1488 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

Ph
O
Ph
O
Ph
O
a, b
c
O
O
O
O
O
O
3. Conclusion
HO
OMe
MeO
OMe
HO
OMe
Syntheses of the non-peptide bradykinin B1 receptor antag-
onist velutinol A and its derivatives, the seco-pregnanes with
cage-like moiety, have been accomplished. Construction of
highly oxygenated structures were established by the combi-
nation of three of five oxidative processes: 1) Sharpless asym-
metric dihydroxylation, 2) Rubottom oxidation, 3) Baeyer-
Villiger oxidation, 4) Wacker oxidation, 5) Oxidative cleavage
via NaIO5. The syntheses of these aglycon derivatives may be
useful for the structure-activity studies of non-peptide ligands
for the bradykinin B1 receptor (B1R). Now, construction of an
appropriate in vitro assay system for 1-4 is under investigation.
85
87
86
f, g
d, e
O
O
BzO
BzO
OAc
MeO
MeO
OMe
89
88
Scheme 22. Synthesis of Sugar Moiety 89. Reagents and
conditions: a) TPAP, NMO, rt, 16 h, 70%; b) NaBH4,
MeOH, 0 °C, 20 min, 87%; c) MeI, NaH, DMF, 0 °C, 1 h,
99%; d) BaCO3, NBS, CCl4, 60 °C, 2 h, 83%; e) nBu3SnH,
AIBN, benzene, reflux, 40 min, 93%; f) AcOH, H2O,
reflux, 2 h; g) Ac2O, pyridine, 30 min, 77% (β:α = 85:15,
2 steps). NBS = N-bromosuccinimide, AIBN = azobisiso-
butyronitrile.
4. Experimental
General Method. All the experiments involving air- and
moisture-sensitive compounds were conducted under an atmos-
phere of dry argon. Dichloromethane and N,N-dimethylforma-
mide were distilled from CaH2 and stored over 4 ¡ molecular
sieves. Anhydrous tetrahydrofuran from Kanto Chemicals
(water: 0.002%max) was directly used as solvent. For TLC
analysis, Marck precoated plates (silica gel 60 F254, art 5715,
0.25 mm) were used. For flash column chromatography, silica
gel 60N (Spherical, neutral, 23-210 ¯m) from Kanto Chemicals
was used. Melting point (M.p.) determinations were performed
using a Yanako P-J3 instrument. 1H and 13C NMR spectra were
recorded using a JEOL ECA-500 (500 MHz), or a Bruker
Avance-400 (400 MHz) spectrometer in the solvent indicated;
chemical shifts (¤) are given in ppm relative to tetramethyl-
silane and coupling constants (J) are reported in Hz. Multiplici-
ties are described by the following abbreviations; s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.
Attenuated total reflectance Fourier-transform infrared (ATR-
FTIR) spectra were recorded using a Shimadzu IRAffinity-1
equipped with a Shimadzu MIRacle single reflection ATR
accessory, wavenumbers (v~) in cm¹1. Optical rotations ([α]D)
were measured using a JASCO P-2300 polarimeter. High-
resolution mass spectra (HRMS) were obtained with a Bruker
micrOTOF II spectrometer (ESI+).
H
O
H
H
O
O
O
a
BzO
MeO
OAc
+
H
HO
H
4
89 (β/α = 85/15)
H
O
H
O
O
H
O
O
RO
MeO
90: R = Bz
70: R = H
b
Scheme 23. Total synthesis of glycoside of illustrol 70.
Reagents and conditions: a) BF3¢OEt2, CH2Cl2, 0 °C to rt,
20 min, 71%; b) MeONa, MeOH, rt, 12 h, quant.
Scheme 22 shows the synthesis of the sugar moiety of 70.
Inversion of the 3-OH moiety of the known compound 85
derived from 2-deoxy-D-glucose42 was established by a simple
oxidation and reduction method using TPAP and NaBH4 to
afford compound 86 (61% yield for 2 steps). After protection of
the 3-OH moiety as the methyl ether using MeI in the presence
of NaH (99%), the 1,3-dioxane ring was cleaved by treatment
with NBS (83%). The resulting bromobenzoate derivative was
reductively debrominated with nBu3SnH in the presence of
AIBN to afford 88 in 93% yield. Hydrolysis and acetylation of
the anomeric position gave compound 89 in a moderate yield
(77% for 2 steps).
Compound 42.
OTBS
TBSO
21
18
20
12
H
11
9
17
H13
OTs
H
16
19
1
14
15
2
3
H 8 OH
10
OH
7
6
5
4
OMe
With the requisite illustrol (4) and compound 89 in hand,
we synthesized 2,6-dideoxy-3-O-methylpyranosylillustrol
(Scheme 23). The β-selective glycosidation of illustrol (4)
was achieved by using 2,6-dideoxypyranoside 89 as the glyco-
syl donor. Thus, compounds 4 and 89 were treated with a
catalytic amount of BF3¢OEt2 at 0 °C for 20 min to give β-
glycoside 90 as a sole product in 71% yield. The high stereo-
selectivity obtained may have resulted from hindrance of α-side
attack at the C1¤ position by electronic repulsion between the
axially oriented α-OMe group at the C3¤ position and the
alcoholic oxygen. Removal of the benzoyl group of β-anomer
90 was accomplished with MeONa to afford 2,6-dideoxy-3-O-
methylpyranosylillustrol (70) in a quantitative yield, and 70
was shown to be identical to an authentic specimen.41,43
TsCl (315.1 mg, 1.65 mmol) and DMAP (403.2 mg, 3.30 mmol)
were added to a solution of compound 32 (103.3 mg, 0.165
mmol) in CH2Cl2 (3.0 mL) at room temperature. After stirring
for 2 h, the reaction was stopped by adding water, and the
mixture was extracted with EtOAc (©3). The combined organic
extract was washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash column
chromatography (silica gel hexane/EtOAc = 8:2) to afford
compound 42 (120.0 mg, 93%) as a colorless oil whose
1H NMR in CDCl3 showed the contamination of ³6 mol%
20
1
EtOAc. ½ꢀꢀD = +27.7 (c = 0.200, CHCl3); H NMR (400 Hz,
CDCl3): δ = 7.86 (d, J = 8.1 Hz, 2H, ArH), 7.31 (d, J = 8.1
Hz, 2H, ArH), 5.52 (t, J = 7.9 Hz, 1H, H-16), 3.68 (dd,
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1489

J = 5.6, 8,4 Hz, 1H, H-20), 3.30 (s, 3H, OCH3-6), 4.39 (dd,
J = 5.2, 7.9 Hz, 1H, H-15), 3.28 (dd, J = 5.6, 9.6 Hz, 1H, H-
21), 3.24 (d, J = 5.2 Hz, OH-15), 3.10 (dd, J = 8.4, 9.6 Hz, 1H,
H-21), 2.84 (t, J = 2.9 Hz, 1H, H-6), 2.81 (s, 1H, OH-14), 2.65
(d, J = 7.9 Hz, 1H, H-17), 2.43 (s, 3H, Ts), 2.17 (td, J = 2.9,
13.6 Hz, 1H, H-7), 1.98 (dt, J = 2.9, 12.3 Hz, 1H, H-8), 1.88-
1.78 (m, 1H, H-2), 1.57 (dd, J = 7.4, 12.5 Hz, 1H, H-2), 1.52-
1.44 (m, 2H, H-1 and H-7), 1.44-1.33 (m, 2H, H-11 and H-12),
1.32-0.99 (m, 3H, H-12, H-11 and H-9), 1.02 (s, 3H, H-18),
1.00 (s, 3H, H-19), 0.98-0.85 (m, 2H, H-3 and H-1), 0.89 (s,
9H, OSiC(CH3)3), 0.81 (s, 9H, OSiC(CH3)3), 0.62 (dd, J = 3.7,
5.0 Hz, 1H, H-4), 0.46 (dd, J = 5.0, 7.9 Hz, 1H, H-4), 0.05 (s,
3H, OSiCH3), 0.03 (s, 3H, OSiCH3), ¹0.07 (s, 3H, OSiCH3),
¹0.09 ppm (s, 3H, OSiCH3); 13C NMR (100 Hz, CDCl3): δ =
144.7 (Ar), 134.1 (Ar), 129.7 (2C, Ar), 127.9 (2C, Ar), 82.0 (C-
6), 81.5 (C-14), 78.6 (C-16), 69.6 (C-15), 69.5 (C-20), 65.8 (C-
21), 56.5 (OCH3-6), 52.5 (C-17), 43.9 (C-13), 43.7 (C-10), 43.4
(C-9), 35.8 (C-8), 35.3 (C-5), 33.7 (C-1), 32.7 (C-11), 29.6
(C-7), 26.2 (3C, OSiC(CH3)3), 25.9 (3C, OSiC(CH3)3), 25.0
(C-2), 21.9 (C-3), 21.6 (2C, OSO2Ph-4-CH3-16 and C-12), 19.4
(C-19), 18.3 (OSiC(CH3)3), 18.2 (OSiC(CH3)3), 18.1 (C-18),
13.2 (C-4), ¹3.2 (OSiCH3), ¹4.6 (OSiCH3), ¹5.4 ppm (2C,
20), 56.6 (OCH3-6), 54.3 (C-17), 47.6 (C-13), 43.7 (C-10), 43.6
(C-9), 36.2 (C-8), 34.6 (C-5), 33.7 (C-1), 30.8 (2C, C-7 and C-
12), 25.9 (3C, OSiC(CH3)3-20), 24.9 (C-2), 22.2 (C-11), 21.5
(C-3), 19.6 (C-18), 19.3 (C-19), 18.0 (OSiC(CH3)3-20), 13.4
(C-4), ¹5.0 (OSiCH3-20), ¹5.1 ppm (OSiCH3-20); IR (ATR):
v~ = 3510, 3392, 3004, 2953, 2927, 2876, 2815, 1472, 1461,
¹1
1375, 1253, 1139, 1100, 1037, 1017, 915, 859, 836, 776 cm
;
HRMS (ESI): m/z calcd for C28H52NO5Si [M + NH4]+:
510.3609, found: 510.3608.
Compound 44.
TBSO
15
16
18H
12
O
20
17
11
H13
H
O
19
1
4
9
21
14
2
3
O
10
8
H
7
6
5
OMe
Sodium periodate (558.6 mg, 2.61 mmol) was added to a
solution of compound 43 (128.7 mg, 0.261 mmol) in THF/H2O
(1:1) (3.0 mL) at room temperature. After stirring for 2 h, the
reaction was stopped by adding water, and the mixture was
extracted with EtOAc (©3). The combined organic extract was
washed with brine, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography
(silica gel, hexane/EtOAc = 8:2) to give compound 44
~
OSiCH3); IR (ATR): v = 3527, 3494, 3357, 2953, 2929, 2884,
2855, 1728, 1600, 1471, 1463, 1360, 1252, 1174, 1098, 1079,
1007, 899, 832, 813, 776, 757, 675 cm¹1; HRMS (ESI): m/z
calcd for C41H74NO8SSi2 [M + NH4]+: 796.4668, found:
796.4672.
20
(105.7 mg, 81%) as a colorless oil. ½ꢀꢀD = +19.0 (c = 0.270,
1
CHCl3); H NMR (400 Hz, CDCl3): δ = 9.74 (d, J = 4.2 Hz,
1H, H-21), 4.82 (t, J = 2.9 Hz, 1H, H-16), 4.39 (dd, J = 4.2,
8.8 Hz, 1H, H-20), 4.03 (dd, J = 2.9, 9.2 Hz, 1H, H-15), 3.94
(d, J = 9.2 Hz, 1H, H-15), 3.33 (s, 3H, OCH3-6), 2.94 (dt, J =
3.0, 12.3 Hz, 1H, H-8), 2.88 (t, J = 2.3 Hz, 1H, H-6), 2.64 (dd,
J = 2.9, 8.8 Hz, 1H, H-17), 2.27-2.15 (m, 2H, H-12 and H-7),
1.83-1.64 (m, 2H, H-2 and H-11), 1.61-1.42 (m, 5H, H-2, H-
11, H-12, H-1 and H-7), 1.33 (s, 3H, H-18), 1.31-1.18 (m, 1H,
H-9), 1.10 (s, 3H, H-19), 0.98-0.82 (m, 2H, H-3 and H-1), 0.88
(s, 9H, OSiC(CH3)3-16) 0.67 (dd, J = 3.9, 5.2 Hz, 1H, H-4),
0.49 (dd, J = 5.2, 8.2 Hz, 1H, H-4), 0.09 (s, 3H, OSiCH3-
16), 0.05 ppm (s, 3H, OSiCH3-16); 13C NMR (100 Hz, CDCl3):
δ = 216.4 (C-14), 204.8 (C-21), 82.6 (C-20), 81.7 (C-6), 77.8
(C-15), 72.6 (C-16), 56.7 (OCH3-6), 56.2 (C-17), 48.3 (C-13),
48.0 (C-9), 44.2 (C-10), 40.9 (C-8), 37.2 (C-12), 34.3 (C-5),
33.5 (C-1), 30.1 (C-7), 25.8 (3C, OSiC(CH3)3-16), 24.8 (C-2),
22.3 (C-18), 21.8 (C-11), 21.3 (C-3), 18.8 (C-19), 17.7
(OSiC(CH3)3-16), 13.2 (C-4), ¹4.3 (OSiCH3-16), ¹4.6 ppm
(OSiCH3-16); IR (ATR): v~ = 2953, 2928, 2859, 2821, 1723,
1698, 1460, 1378, 1255, 1092, 1019, 1002, 990, 938, 829, 811,
775, 754 cm¹1; HRMS (ESI): m/z calcd for C28H47O5Si
[M + H]+: 491.3187, found: 491.3216.
Compound 43.
TBSO
20
18
H
21
12
11
17
16
H13
19
O
1
9
14
H
15
2
3
10
8
H
OH
OH
7
6
5
4
OMe
Tetrabuthylammonium fluoride (1.0 mol/L in THF, 1.2 mL,
1.2 mmol) and AcOH (0.14 mL, 2.35 mmol) were added to a
solution of compound 42 (365.4 mg, 0.469 mmol) in THF
(5.0 mL) at room temperature. After stirring for 2 h at 60 °C, the
reaction was stopped by adding water, and the mixture was
extracted with EtOAc (©3). The combined organic extract was
washed with brine, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography
(silica gel, hexane/EtOAc = 9:1) to afford compound 43
20
(163.5 mg, 71%) as a colorless oil. ½ꢀꢀD = +26.1 (c = 0.340,
1
CHCl3); H NMR (400 Hz, CDCl3): δ = 4.74 (q, J = 8.3 Hz,
1H, H-20), 4.40 (brs, 1H, H-15), 4.21 (dd, J = 1.9, 7.2 Hz, 1H,
H-16), 3.96 (t, J = 8.3 Hz, 1H, H-21), 3.62 (t, J = 8.3 Hz, 1H,
H-21), 3.34 (s, 3H, OCH3-6), 2.85 (t, J = 2.9 Hz, 1H, H-6),
2.81 (br s, 1H, OH-15), 2.77 (dd, J = 7.2, 8.3 Hz, 1H, H-17),
2.25-2.20 (m, 1H, OH-14), 2.20 (td, J = 3.2, 13.6 Hz, 1H, H-
12), 2.11 (td, J = 2.9, 13.5 Hz, 1H, H-7), 1.96-1.87 (m, 1H, H-
8), 1.85-1.73 (m, 1H, H-2), 1.65 (dt, J = 4.0, 13.6 Hz, 1H, H-
12), 1.59-1.40 (m, 4H, H-1, H-2, H-7 and H-11), 1.39-1.27 (m,
1H, H-11), 1.27-1.16 (m, 1H, H-9), 1.19 (s, 3H, H-18), 1.02 (s,
3H, H-19), 0.96-0.84 (m, 2H, H-3 and H-1), 0.89 (s, 9H,
OSiC(CH3)3-20), 0.65 (dd, J = 3.7, 5.0 Hz, 1H, H-4), 0.48 (dd,
J = 5.0, 7.9 Hz, 1H, H-4), 0.07 (s, 3H, OSiCH3-20), 0.03 ppm
(s, 3H, OSiCH3-20); 13C NMR (100 Hz, CDCl3): δ = 92.6 (C-
16), 86.4 (C-14), 82.0 (C-6), 79.3 (C-15), 74.6 (C-21), 74.2 (C-
Compound 45.
TBSO
15
16
18H
12
O
20
17
11
H13
H
19
1
4
9
14
21
2
3
O
10
8
H
OH
7
6
5
OMe
NaBH4 (0.9 mg, 0.0240 mmol) was added to a solution of com-
pound 44 (9.8 mg, 0.0199 mmol) in MeOH (0.5 mL) at 0 °C.
After stirring for 10 min at 0 °C, the reaction was stopped by
adding 0.1 N AcOH, and the mixture was extracted with EtOAc
(©3). The combined organic extract was washed with brine,
1490 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

dried (Na2SO4), and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel, hexane/
EtOAc = 9:1) to afford compound 45 (7.0 mg, 71%) as a color-
(2R,4aR,6S,8aR)-6-Methoxy-2-phenyltetrahydropyrano-
[3,2-d][1,3]dioxin-8(4H)-one.
Ph
O
O
O
less oil whose 1H NMR in CDCl3 showed the contamination of
O
20
OMe
³5 mol% of minor isomer and ³10 mol% of EtOAc. ½ꢀꢀD
=
1
¹2.9 (c = 0.140, CHCl3); H NMR (400 Hz, CDCl3): δ = 4.76
(ddd, J = 7.2, 8.0, 8.9 Hz, 1H, H-16), 4.05 (dd, J = 3.1,
13.1 Hz, 1H, H-21), 3.93 (dd, J = 8.0, 8.9 Hz, 1H, H-15), 3.85
(d, J = 13.1 Hz, 1H, H-21), 3.71 (dd, J = 3.1, 4.3 Hz, 1H, H-
20), 3.56 (t, J = 8.0 Hz, 1H, H-15), 3.35 (s, 3H, OCH3-6), 2.90
(t, J = 3.0 Hz, 1H, H-6), 2.27 (dd, J = 4.3, 7.2 Hz, 1H, H-17),
2.19-2.16 (m, 1H, H-8), 2.16-2.01 (m, 2H, H-12), 1.88-1.75
(m, 2H, H-2 and H-7), 1.63 (ddd, J = 3.0, 12.1, 13.2 Hz, 1H,
H-7), 1.54-1.45 (m, 2H, H-2 and H-1), 1.43-1.32 (m, 3H,
H-9 and H-11), 1.23 (s, 3H, H-18), 1.01 (s, 3H, H-19), 0.95-
0.79 (m, 2H, H-3 and H-1), 0.91 (s, 9H, OSiC(CH3)3-16), 0.65
(dd, J = 4.0, 5.0 Hz, 1H, H-4), 0.46 (dd, J = 5.0, 8.1 Hz, 1H,
H-4), 0.08 (s, 3H, OSiCH3-16), 0.05 ppm (s, 3H, OSiCH3-16);
13C NMR (100 Hz, CDCl3): δ = 99.0 (C-14), 82.2 (C-6), 76.1
(C-16), 74.9 (C-20), 72.4 (C-15), 61.0 (C-21), 56.7 (OCH3-6),
45.3 (C-17), 43.5 (C-10), 41.7 (C-9), 38.5 (C-13), 36.0 (C-8),
34.5 (C-5), 33.5 (C-1), 30.0 (C-12), 28.3 (C-7), 25.9 (3C,
OSiC(CH3)3-16), 24.9 (C-2), 21.6 (C-11), 21.4 (C-3), 21.1
(C-18), 19.1 (C-19), 18.0 (OSiC(CH3)3-16), 13.3 (C-4), ¹4.9
Tetrapropylammonium perruthenate (420.3 mg, 1.20 mmol) and
4-methylmorpholine (18.2 g, 155.4 mmol) were added to a
solution of compound 85 (6.37 g, 23.9 mmol) in CH2Cl2 (150
mL) at room temperature. After 1 h at room temperature, the
reaction was stopped by adding water, and the mixture was
extracted with EtOAc (©3). The combined organic extract was
washed with brine, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography
(silica gel, hexane/EtOAc = 7:3) to afford (2R,4aR,6S,8aR)-6-
methoxy-2-phenyltetrahydropyrano [3,2-d][1,3]dioxin-8(4H)-
one (4.60 g, 73%) as a white solid. M.p. = 175.0-176.1 °C;
20
½ꢀꢀD = +122.3 (c = 0.575, CHCl3); 1H NMR (400 Hz,
CDCl3): δ = 7.53-7.47 (m, 2H), 7.39-7.33 (m, 3H), 5.58 (s,
1H), 5.14 (d, J = 4.7 Hz, 1H), 4.37 (dd, J = 4.7, 10.2 Hz, 1H),
4.30 (dd, J = 1.1, 10.2 Hz, 1H), 4.15 (dt, J = 4.7, 10.2 Hz, 1H),
3.91 (t, J = 10.2 Hz, 1H), 3.38 (s, 3H), 2.83 (ddd, J = 1.1, 4.7,
14.6 Hz, 1H), 2.66 ppm (d, J = 14.6 Hz, 1H); 13C NMR (100
Hz, CDCl3): δ = 197.4, 136.5, 129.3, 128.3, 126.4, 102.2,
~
100.6, 83.1, 69.5, 65.1, 55.0, 46.4 ppm; IR (ATR): v = 2940,
~
(OSiCH3-16), ¹5.0 ppm (OSiCH3-16); IR (ATR): v = 3526,
1730 (C=O), 1451, 1403, 1379, 1273, 1131, 1090, 1017, 978,
908, 748, 696, 655 cm¹1; HRMS (ESI): m/z calcd for C14H17O5
[M + H]+: 265.1071, found: 265.1097.
3473, 3342, 2955, 2929, 2859, 1728, 1471, 1463, 1442, 1388,
1377, 1259, 1252, 1131, 1088, 1059, 1037, 1013, 911, 870,
836, 776 cm¹1; HRMS (ESI): m/z calcd for C28H48NaO5Si
[M + Na]+: 515.3163, found: 515.3186.
Ph
O
Compound 86.
O
O
HO
OMe
Pentalinonside Aglycon (2). HClO4 (0.1 mL) was added to
a solution of 45 (2.4 mg, 4.87 ¯mol) in 1,4-dioxane/H2O (5:4)
(0.5 mL) at room temperature. After stirring for 2 h at room
temperature, the reaction was stopped by adding water, and the
mixture was extracted with EtOAc (©3). The combined organic
extract was washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (silica gel, hexane/Et2O/CH3CN = 4:5:1) to af-
ford pentalinonside aglycon (2, 1.6 mg, 95%) as a white solid.
NaBH4 (790.2 mg, 20.9 mmol) was added to a solution of
(2R,4aR,6S,8aR)-6-methoxy-2-phenyltetrahydropyrano[3,2-d]-
[1,3]dioxin-8(4H)-one (4.60 g, 17.4 mmol) in MeOH (100 mL)
at 0 °C. After stirring for 10 min at 0 °C, the reaction was
stopped by adding 0.1 M AcOH, and the mixture was extracted
with EtOAc (©3). The combined organic extract was washed
with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash column chromatography (silica
gel, hexane/EtOAc = 7:3) to afford compound 86 (4.60 g,
20
M.p. 206.2-206.4 °C; ½ꢀꢀD = ¹37.19 (c = 0.32, MeOH);
20
1H NMR (500 MHz, pyridine-d5): δ = 5.49-5.45 (m, 1H, H-
6), 4.57 (t, 1H, J = 4.6 Hz, H-16), 4.49 (ddd, 1H, J = 8.0, 5.8,
1.2 Hz, H-20), 4.23 (d, 1H, J = 10.1 Hz, H-15b), 4.06 (dd, 1H,
J = 12.6, 5.8 Hz, H-21a), 4.03 (dd, 1H, J = 10.1, 4.6 Hz, H-
15a), 3.89-3.81 (m, 1H, H-3), 3.80 (dd, 1H, J = 12.6, 1.2 Hz,
H-21b), 2.66-2.60 (m, 1H, H-7), 2.63-2.58 (m, 2H, H-4), 2.61
(dd, 1H, J = 8.0, 4.6 Hz, H-17), 2.52-2.44 (m, 1H, H-7), 2.13-
2.06 (m, 1H, H-2a), 1.90-1.83 (m, 1H, H-1b), 1.89-1.84 (m,
1H, H-8), 1.83-1.73 (m, 1H, H-2b), 1.52-1.46 (m, 1H, H-11),
1.49-1.43 (m, 1H, H-12b), 1.45-1.40 (m, 1H, H-9), 1.38-1.32
(m, 1H, H-12a), 1.34-1.28 (m, 1H, H-11), 1.18-1.10 (m, 1H,
H-1a), 1.1 (s, 3H, H-18), 1.02 (s, 3H, H-19) ppm; 13C NMR
(125 MHz, pyridine-d5): δ = 140.4 (C-5), 121.8 (C-6), 108.1
(C-14), 80.7 (C-16), 76.2 (C-20), 74.2 (C-15), 71.2 (C-3), 66.1
(C-21), 54.5 (C-17), 46.0 (C-9), 43.4 (C-4), 41.3 (C-10), 37.7
(C-1), 36.8 (C-13), 36.2 (C-8), 34.8 (C-12), 32.5 (C-2), 25.4
(C-7), 20.5 (C-11), 19.6 (C-19), 17.2 (C-18) ppm; IR (ATR):
quant.) as a colorless oil. ½ꢀꢀD = +108.29 (c = 0.525, CHCl3);
1H NMR (400 Hz, CDCl3): δ = 7.54-7.48 (m, 2H), 7.40-7.31
(m, 3H), 5.63 (s, 1H), 4.80 (dd, J = 0.8, 4.0 Hz, 1H), 4.33 (dd,
J = 5.1, 9.9 Hz, 1H), 4.24 (dt, J = 5.1, 9.9 Hz, 1H), 4.19 (qd,
J = 3.0, 6.2 Hz, 1H), 3.78 (t, J = 9.9 Hz, 1H), 3.61 (dd, J =
3.0, 9.9 Hz, 1H), 3.41 (s, 3H), 3.01 (d, J = 6.2 Hz, 1H, OH),
2.20 (ddd, J = 0.8, 3.0, 14.9 Hz, 1H), 2.01 ppm (ddd, J = 3.0,
4.0, 14.9 Hz, 1H); 13C NMR (100 Hz, CDCl3): δ = 137.3,
129.1, 128.3, 126.3, 102.1, 98.7, 79.7, 69.4, 65.0, 58.2, 55.5,
~
35.5 ppm; IR (ATR): v = 3503 (OH), 2933, 1459, 1410, 1389,
1184, 1134, 1112, 1095, 1042, 993, 964, 927, 862, 772,
710 cm¹1; HRMS (ESI): m/z calcd for C14H19O5 [M + H]+:
267.1227, found: 267.1234.
Ph
O
Compound 87.
O
O
MeO
OMe
Sodium hydride (319.2 mg, 7.98 mmol) was added to a solution
of compound 86 (1.76 g, 6.65 mmol) in DMF (30 mL) at 0 °C.
After 1 h at room temperature, the reaction mixture was cooled
to 0 °C. Iodomethane was added to the reaction mixture at 0 °C.
~
v = 3309, 2927, 1439, 1381, 1364, 1269, 1202, 1169, 1133,
1101, 1052, 1019, 986, 972, 954 cm¹1; HRMS (EI): m/z calcd
for C21H31O4 [M + H]+: 347.2217, found: 347.2223.
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1491

After stirring for 20 min at 0 °C, the reaction was stopped by
adding water, and the mixture was extracted with EtOAc (©3).
The combined organic extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, hexane/EtOAc =
7:3) to afford compound 87 (1.85 g, 99%) as a white solid.
CHCl3); 1H NMR (400 Hz, CDCl3): δ = 8.12-8.05 (m, 2H),
7.61-7.55 (m, 1H), 7.49-7.42 (m, 2H), 4.88 (dd, J = 3.2,
9.3 Hz, 1H), 4.72 (dd, J = 1.6, 4.5 Hz, 1H), 4.40 (qd, J = 6.3,
9.3 Hz, 1H), 3.86 (dt, J = 3.2, 3.8 Hz, 1H), 3.41 (s, 3H), 3.40
(s, 3H), 2.23 (ddd, J = 1.6, 3.8, 14.7 Hz, 1H), 1.96 (ddd, J =
3.8, 4.5, 14.7 Hz, 1H), 1.25 ppm (d, J = 6.3 Hz, 3H); 13C NMR
(100 Hz, CDCl3): δ = 165.9, 133.2, 129.9, 129.8, 128.4, 97.7,
75.0, 74.2, 62.2, 58.6, 55.6, 33.0, 17.6 ppm; IR (ATR):
20
M.p. = 81.5-82.6 °C; ½ꢀꢀD = +83.53 (c = 0.230, CHCl3);
1H NMR (400 Hz, CDCl3): δ = 7.53-7.46 (m, 2H), 7.40-7.30
(m, 3H), 5.53 (s, 1H), 4.69 (dd, J = 0.7, 4.6 Hz, 1H), 4.38-4.27
(m, 2H), 3.81-3.77 (m, 1H), 3.74-3.66 (m, 2H), 3.55 (s, 3H),
3.39 (s, 3H), 2.22 (ddd, J = 0.7, 2.8, 14.9 Hz, 1H), 1.93 ppm
(ddd, J = 3.6, 4.6, 14.9 Hz, 1H); 13C NMR (100 Hz, CDCl3):
δ = 137.7, 129.0, 128.3, 126.2, 102.3, 97.9, 80.7, 73.7, 69.6,
~
v = 2978, 2932, 2830, 1716 (C=O), 1451, 1344, 1263, 1200,
1106, 1053, 1018, 1026, 990, 711 cm¹1; HRMS (ESI): m/z
calcd for C15H24NO5 [M + NH4]+: 298.1649, found: 298.1645.
Compound 89.
O
BzO
OAc
MeO
59.6, 58.1, 55.6, 34.3 ppm; IR (ATR): v~ = 2932, 1716 (C=O),
¹1
1385, 1123, 1098, 1042, 1001, 984, 962, 907, 771, 704 cm
;
H2O (1.5 mL) were added to a solution of compound 88 (271.6
mg, 0.969 mmol) in acetic acid (5.0 mL) at room temperature.
After stirring for 2 h at 80 °C, the reaction was stopped by
adding water, and the mixture was extracted with EtOAc (©3).
The combined organic extract was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, hexane/Et2O/
CH3CN = 6:3:1) to afford crude containing with (2R,3R,4S)-6-
hydroxy-4-methoxy-2-methyltetrahydro-2H-pyran-3-ylbenzo-
ate (251.8 mg) as a colorless oil which was used for the next
reaction without further purification. Ac2O (0.25 mL) were add-
ed to a solution of crude material containing with (2R,3R,4S)-
6-hydroxy-4-methoxy-2-methyl tetrahydro-2H-pyran-3-yl ben-
zoate (13.1 mg) in pyridine (0.5 mL) at room temperature. After
stirring for 30 min at room temperature, the reaction was
stopped by adding water, and the mixture was extracted with
EtOAc (©3). The combined organic extract was washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash column chromatography (silica gel, hex-
ane/EtOAc = 7:3) to afford compound 89 (14.0 mg, 77% for 2
HRMS (ESI): m/z calcd for C15H21O5 [M + H]+: 281.1384,
found: 281.1393.
(2S,3S,4S,6S)-2-(Bromomethyl)-4,6-dimethoxytetrahydro-
2H-pyran-3-yl Benzoate.
Br
BzO
O
MeO
OMe
Barium carbonate (541.1 mg, 2.74 mmol) and N-bromosuccin-
imide (1.00 g, 5.94 mmol) were added to a solution of com-
pound 87 (1.28 g, 4.57 mmol) in CCl4 (50 mL) at room
temperature. After stirring for 2 h at 60 °C, the reaction was
stopped by adding water, and the mixture was extracted with
EtOAc (©3). The combined organic extract was washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by flash column chromatography (silica gel,
hexane/EtOAc = 8:2) to afford (2S,3S,4S,6S)-2-(iodometh-
yl)-4,6-dimethoxytetrahydro-2H-pyran-3-yl benzoate (1.46 g,
20
89%) as a colorless oil. ½ꢀꢀD = +119.49 (c = 1.13, CHCl3);
1H NMR (400 Hz, CDCl3): δ = 8.09-8.05 (m, 2H), 7.62-7.57
(m, 1H), 7.50-7.44 (m, 2H), 5.06 (dd, J = 3.2, 9.6 Hz, 1H),
4.83 (dd, J = 1.1, 4.7 Hz, 1H), 4.54 (ddd, J = 2.6, 6.6, 9.6
Hz, 1H), 3.95 (dt, J = 3.2, 3.5 Hz, 1H), 3.65 (dd, J = 2.6,
11.1 Hz, 1H), 3.55 (dd, J = 6.6, 11.1 Hz, 1H), 3.46 (s, 3H),
3.40 (s, 3H), 2.26 (ddd, J = 1.1, 3.5, 14.9 Hz, 1H), 2.00 ppm
(ddd, J = 3.5, 4.7, 14.9 Hz, 1H); 13C NMR (100 Hz, CDCl3):
δ = 165.5, 133.4, 129.8, 129.5, 128.5, 98.1, 73.9, 72.6, 65.1,
20
steps, β:α = 85:15) as a colorless oil. 89β: ½ꢀꢀD = +29.59
1
(c = 0.785, CHCl3); H NMR (400 Hz, CDCl3): δ = 8.09-8.05
(m, 2H), 7.62-7.56 (m, 1H), 7.49-7.43 (m, 2H), 6.10 (dd,
J = 2.4, 9.0 Hz, 1H), 4.85 (dd, J = 2.8, 8.9 Hz, 1H), 4.32 (qd,
J = 6.4, 8.9 Hz, 1H), 3.98 (td, J = 2.8, 4.8 Hz, 1H), 3.40 (s,
3H), 2.27 (ddd, J = 2.4, 4.8, 13.6 Hz, 1H), 2.12 (s, 3H), 1.86
(ddd, J = 2.8, 9.0, 13.6 Hz, 1H), 1.30 ppm (d, J = 6.4 Hz, 3H);
13C NMR (100 Hz, CDCl3): δ = 169.2, 165.9, 133.3, 129.8
(2C), 128.5, 91.1, 74.6, 74.1, 69.5, 58.1, 33.5, 21.2, 18.2 ppm;
IR (ATR): v~ = 2978, 2943, 2897, 2841, 1753 (C=O), 1713
(C=O), 1451, 1354, 1270, 1218, 1121, 1094, 1056, 1010, 726
cm¹1; HRMS (ESI): m/z calcd for C16H20NaO6 [M + Na]+:
~
58.6, 55.8, 33.4, 32.6 ppm; IR (ATR): v = 2932, 2897, 2825,
¹1
1717 (C=O), 1280, 1260, 1096, 1052, 1025, 983, 712 cm
HRMS (ESI): m/z calcd for C15H20BrO5 [M + H]+: 359.0489,
found: 359.0491.
;
O
BzO
1
331.1152, found: 331.1179; 89α: H NMR (400 Hz, CDCl3):
MeO
OMe
δ = 8.11-8.07 (m, 2H), 7.61-7.56 (m, 1H), 7.49-7.43 (m, 2H),
6.10 (dd, J = 1.6, 4.2 Hz, 1H), 4.88 (dd, J = 3.0, 9.5 Hz, 1H),
4.52 (qd, J = 6.3, 9.5 Hz, 1H), 3.93 (td, J = 3.0, 3.9 Hz, 1H),
3.38 (s, 3H), 2.36 (ddd, J = 1.6, 3.9, 15.2 Hz, 1H), 2.12 (s, 3H),
2.00 (ddd, J = 3.0, 4.2, 15.2 Hz, 1H), 1.27 ppm (d, J = 6.3 Hz,
3H); 13C NMR (100 Hz, CDCl3): δ = 170.0, 165.8, 133.3,
129.8 (2C), 128.5, 90.9, 74.5, 73.2, 64.7, 57.4, 30.8, 21.3,
17.6 ppm.
Tributyltin hydride (1.7 mL, 6.22mmol) and azobisisobutyro-
nitrile (510.4 mg, 3.11 mmol) were added to a solution of
(2S,3S,4S,6S)-2-(iodomethyl)-4,6-dimethoxy-tetrahydro-2H-
pyran-3-yl benzoate (1.86 g, 5.18 mmol) in benzene (50 mL) at
room temperature. After stirring for 40 min at 80 °C, the
reaction was stopped by adding water, and the mixture was
extracted with EtOAc (©3). The combined organic extract was
washed with brine, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by flash column chromatography
(silica gel, hexane/EtOAc = 8:2) to afford compound 88
This project was partially supported by The Science
Research Promotion Fund and a Grant-in-Aid for Scientific
Research (B: 25293029) to M. I. The Naito Foundation Natural
20
(1.35 g, 93%) as a colorless oil. ½ꢀꢀD = +120.39 (c = 0.905,
1492 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan

Tetrahedron Lett. 1974, 15, 4319. b) A. Hassner, R. H. Reuss,
H. W. Pinnick, J. Org. Chem. 1975, 40, 3427.
Science Scholarship and a Grant-in-Aid for Young Scientists
(B: 20710172) to M. T. is gratefully acknowledged.
19 For review, see: K. Suzuki, M. Tamiya, in Comprehensive
Organic Synthesis, 2nd ed., ed. by P. Knochel, G. A. Molander,
Elsevier, Amsterdam, 2014, Vol. 3, p. 580. doi:10.1016/B978-0-
08-097742-3.00316-5.
20 For leading references, see: a) C. Xu, E. Negishi, in
Handbook of Organopalladium Chemistry for Organic Synthesis,
ed. by E. Negishi, 2002, p. 2289. doi:10.1002/0471212466.ch100.
b) J. M. Takacs, X. Jiang, Curr. Org. Chem. 2003, 7, 369.
21 a) For leading references, see: H. C. Kolb, M. S.
VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483.
b) H. C. Kolb, K. B. Sharpless, in Transition Metals for Organic
Synthesis, 2nd ed., ed. by M. Beller, C. Bolm, Wiley-VCH, New
York, 2004, Vol. 2, p. 306.
Supporting Information
Experimental and copies of H and 13C NMR spectra of all
the compounds on successful route, copy of CD spectra of
compound 30. This material is available on https://doi.org/
10.1246/bcsj.20190048.
1
References
1
For review, see: a) L. M. F. Leeb-Lundberg, F. Marceau, W.
Müller-Esterl, D. J. Pettibone, B. L. Zuraw, Pharmacol. Rev. 2005,
57, 27. b) D. Regoli, J. Barabé, Pharmacol. Rev. 1980, 32, 1, and
the references cited therein.
2
For review, see: F. Marceau, J. F. Hess, D. R. Bachvarov,
22 a) Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43,
1011. b) R. C. Larock, N. H. Lee, Tetrahedron Lett. 1991, 32,
5911. c) R. C. Larock, T. R. Hightower, G. A. Kraus, P. Hahn, D.
Zheng, Tetrahedron Lett. 1995, 36, 2423.
Pharmacol. Rev. 1998, 50, 357, and the references cited therein.
3
4
F. Marceau, Immunopharmacology 1995, 30, 1.
A. Ahluwalia, M. Perretti, Trends Pharmacol. Sci. 1999,
20, 100.
23 a) P. S. Wharton, D. H. Bohlen, J. Org. Chem. 1961, 26,
3615. For review, see: b) A. R. Chamberlin, D. J. Sall, in
Comprehensive Organic Synthesis, ed. by B. M. Trost, I. Fleming,
Oxford, Pergamon, 1991, Vol. 8, p. 923, and the references cited
therein. doi:10.1016/b978-0-08-052349-1.00251-1.
24 a) A. P. Kozikowski, C.-S. Li, J. Org. Chem. 1985, 50, 778.
b) R. Antonioletti, F. Bonadies, A. Scettri, J. Org. Chem. 1988, 53,
5540. c) O. Tsuge, S. Kanemasa, H. Suga, Bull. Chem. Soc. Jpn.
1988, 61, 2133. d) H. Kashihara, H. Suemune, N. Tsunehiro, K.
Sakai, Chem. Pharm. Bull. 1990, 38, 2581. e) A. Fürstner,
M. D. B. Fenster, B. Fasching, C. Godbout, K. Radkowski, Angew.
Chem., Int. Ed. 2006, 45, 5510. f) C. Wang, C. J. Forsyth, Org.
Lett. 2006, 8, 2997. g) J. S. Yadav, B. V. S. Reddy, S. Meraj, P.
Vishnumurthy, K. Narsimulu, A. C. Kunwar, Synthesis 2006,
2923. h) A. Boto, D. Hernández, R. Hernández, Org. Lett. 2007, 9,
1721.
5
For a review of the discovery of peptide bradykinin
antagonists, see: J. M. Stewart, Peptides 2004, 25, 527, and
references therein.
6
M. M. Campos, P. C. Leal, R. A. Yunes, J. B. Calixto,
Trends Pharmacol. Sci. 2006, 27, 646.
a) W. M. Mattos, M. M. Campos, E. S. Fernandes, G. P.
7
Richetti, R. Niero, R. A. Yunes, J. B. Calixto, Regul. Pept. 2006,
136, 98. b) W. M. Mattos, J. Ferreira, G. P. Richetti, R. Niero,
R. A. Yunes, J. B. Calixto, Neuropeptides 2006, 40, 125.
8
a) R. A. Yunes, M. G. Pizzolatti, A. E. G. Sant’Ana, G. E.
Hawkes, J. B. Calixto, Phytochem. Anal. 1993, 4, 76. b) E. S.
Bento, J. B. Calixto, G. E. Hawkes, M. G. Pizzolatti, A. E. G.
Sant’Ana, R. A. Yunes, J. Chem. Soc., Perkin Trans. 2 1996, 1359.
9
a) M. Ishiguro, J. Am. Chem. Soc. 2000, 122, 444. b) M.
Ishiguro, ChemBioChem 2004, 5, 1210.
10 a) S. Bastian, S. Prunau, B. Loillier, C. Robert, J. C.
Bonnafous, J. L. Paquet, J. Biol. Chem. 2000, 275, 6107. b) S. N.
Ha, P. J. Hey, R. W. Ransom, M. G. Bock, D.-S. Su, K. L. Murphy,
R. Chang, T.-B. Chen, D. Pettibone, J. F. Hess, Biochemistry 2006,
45, 14355.
25 H. Suginome, Y. Nakayama, H. Senboku, J. Chem. Soc.,
Perkin Trans. 1 1992, 1837.
26 Compound 5-7 are all contaminated with ³10% of 3-OMe
derivatives. 3-MeO derivative was separable after the Wharton
reaction to generate compound 8.
11 L. Pan, C. M. Lezama-Dávila, A. P. Isaac-Márquez, E. P.
Calomeni, J. R. Fuchs, A. R. Satoskar, A. D. Kinghorn,
Phytochemistry 2012, 82, 128.
12 a) A. Plaza, G. Bifulco, A. I. Hamed, C. Pizza, S. Piacente,
Tetrahedron Lett. 2003, 44, 8553. b) A. Plaza, A. Perrone, C.
Balestrieri, M. L. Balestrieri, G. Bifulco, V. Carbone, A. Hamed,
C. Pizza, S. Piacente, Tetrahedron 2005, 61, 7470. c) A. Perrone,
A. Plaza, S. F. Ercolino, A. I. Hamed, L. Parente, C. Pizza, S.
Piacente, J. Nat. Prod. 2006, 69, 50.
13 a) R. A. Yunes, R. L. Brum, J. B. Calixto, H. Rimplert,
Phytochemistry 1993, 34, 787. b) I. Vencato, R. Niero, J. L.
Montanari, J. B. Calixto, A. E. G. Sant’Ana, R. A. Yunes, Acta
Crystallogr., Sect. C 1999, 55, 827.
14 N. Isaka, M. Tamiya, A. Hasegawa, M. Ishiguro, Eur. J.
Org. Chem. 2012, 665.
27 A. Nakamura, Y. Kaji, K. Saida, M. Ito, Y. Nagatoshi, N.
Hara, Y. Fujimoto, Tetrahedron Lett. 2005, 46, 6373.
28 M. Tamiya, F. Takada, N. Isaka, N. Iimura, M. Ishiguro,
Heterocycles 2011, 82, 1119.
29 For review, see: S. V. Ley, J. Norman, W. P. Griffith, S. P.
Marsden, Synthesis 1994, 639, and the references cited therein.
30 a) I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am.
Chem. Soc. 1991, 113, 4092. For review, see: b) J. M. Seco, E.
Quiñoá, R. Riguera, Chem. Rev. 2004, 104, 17, and the references
cited therein.
31 For octant rule, see: G. Snatzke, Angew. Chem., Int. Ed.
Engl. 1968, 7, 14.
32 a) H. Wang, Y. W. Andemichael, F. G. Vogt, J. Org. Chem.
2009, 74, 478. For an example of double oxidation under
Rubottom conditions, see: b) Y. Horiguchi, E. Nakamura, I.
Kuwajima, Tetrahedron Lett. 1989, 30, 3323.
15 N. Isaka, S. Kawada, M. Ishiguro, M. Tamiya, Heterocycles
2015, 91, 1715.
33 X. Creary, J. Org. Chem. 1980, 45, 2419.
16 M. Tamiya, N. Isaka, T. Kitazawa, M. Ishiguro, Asian J.
Org. Chem. 2014, 3, 264.
17 M. Tamiya, N. Isaka, K. Ishizawa, M. Ikeda, M. Ishiguro,
Chem. Lett. 2014, 43, 1704.
34 G. Hocking, in A Dictionary of Terms in Pharmacognosy
and Other Divisions of Economic Botany, Charles C Thomas
Publisher LTD, Springfield, IL, 1955, p. 212.
35 L. Boules, in Flora of Egypt, Al Hadara, Cairo, 2000,
Vol. 2, p. 212.
18 a) G. M. Rubottom, M. A. Vazquez, D. R. Pelegrina,
Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan | 1493

36 The degradation procedure used to determine the structure
of the sugar moiety is described in ref. 12c; however, structural
data for the aglycon were not provided. The same conditions were
also applied to the synthetic aglycone produced in the present
study; however, our procedure resulted in the formation of the
corresponding furan.
37 P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem.
1976, 41, 1485.
38 We examined Red-Al, DIBAL-H, LiBH4, and NaBH4/
BF3OEt2; however, these reducing agents only provided lactol 56.
39 a) J. B. Calixto, M. Nicolau, R. A. Yunes, Br. J. Pharmacol.
1985, 85, 729. b) J. B. Calixto, M. Nicolau, M. G. Pizzolatti, R. A.
Yunes, Br. J. Pharmacol. 1987, 91, 199.
40 J. B. Calixto, R. A. Yunes, Gen. Pharmacol. 1991, 22, 99.
41 R. Niero, R. V. Alves, V. C. Filho, J. B. Calixto, J. E.
Hawkes, A. E. G. Sant’Ana, R. A. Yunes, Planta Med. 2002, 68,
850.
42 M. K. Gurjar, P. K. Ghosh, J. Carbohydr. Chem. 1988, 7,
799.
43 The NMR data is provided by Prof. Dr. R. Niero.
1494 | Bull. Chem. Soc. Jpn. 2019, 92, 1474–1494 | doi:10.1246/bcsj.20190048
© 2019 The Chemical Society of Japan