Highly stereocontrolled total synthesis of secodolastane diterpenoid isolinearol

Article abstract of DOI:10.1039/d0ob01430c

The first asymmetric total synthesis of isolinearol has been achieved with high stereoselectively. The synthetic method includes enatio-and diastereoselective reductive desymmetrization, stereocontrolled introduction of the methallyl group, regio-and stereocontrolled allylation and introduction of the side chain carbonyl group using olefin cross-metathesis with a pinacol vinyl boronic ester.

Full text of DOI:10.1039/d0ob01430c

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Highly stereocontrolled total synthesis of
secodolastane diterpenoid isolinearol†
Cite this: DOI: 10.1039/d0ob01430c
Toyoharu Kobayashi, * Yui Tomita, Yuichiro Kawamoto
and Hisanaka Ito*
Received 11th July 2020,
Accepted 29th July 2020
DOI: 10.1039/d0ob01430c
rsc.li/obc
The first asymmetric total synthesis of isolinearol has been 14-deoxyisoamijiol,10 and indicol (3)11 have been published its
achieved with high stereoselectively. The synthetic method asymmetric total synthesis. To the best of our knowledge, and
includes enatio- and diastereoselective reductive desymmetriza- the absolute configuration of indicol (3) was determined by its
tion, stereocontrolled introduction of the methallyl group, regio- asymmetric total synthesis. To the best of our knowledge,
and stereocontrolled allylation and introduction of the side chain there have been no reports on the total synthesis of isolinearol
carbonyl group using olefin cross-metathesis with a pinacol vinyl (1), and its absolute configuration, although presumably the
boronic ester.
same as indicol, has not yet been determined.
The structural features and biological activities of
1
Marine brown algae of the genus Dictyota, belonging to the
family Dictyotaceae, are a rich source of structurally diverse
secondary metabolites possessing defensive properties that
contribute to their successful survival in marine environments.
Several diterpenes from the Dictyota species exhibit potent
cytotoxic or antiviral activities which make them promising
drug candidates due to their remarkable pharmacological
activities.1
Isolinearol (1) was first isolated from the marine brown alga
Dictyota cervicornis in 1986 by Teixeira et al. along with known
related diterpenoids including linearol (2) and amijiol (4)
(Fig. 1).2 Compound 1 was subsequently isolated from Dictyota
indica in 1990 by Ahmad et al. along with indicol (3) and indi-
carol acetate.3 It was also isolated from the Brazilian brown
alga Canistrocarpus cervicornis.4 Isolinearol has a characteristic
bicyclo[5.4.0]undecane carbon framework with a hemiacetal
bridge and contains five stereocenters, including two all-
carbon quaternary centers. The biological activity of isolinearol
was not initially reported, however recently it was found that
mixtures of linearol and isolinearol inhibited hemolysis and
proteolysis caused by B. jararaca venom5 and anti-herbivory
activity.6
attracted our interest, and a synthetic study of isolinearol (1)
was initiated. Our goal was to develop a stereocontrolled syn-
thetic procedure to access isolinearol (1) and to extend the pro-
cedure to an asymmetric synthesis. Herein, we report the first
total synthesis of isolinearol with high stereocontrol in both
racemic and enantioenriched forms.
In this synthetic study, the key challenge is how to construct
three continuous chiral centers on the cyclohexane ring and
the all-carbon quaternary center on the cycloheptane ring with
high stereoselectivity. Our retrosynthetic analysis of the total
synthesis of 1 to address these issues is shown in Fig. 2. The
final compound would be synthesized from diketone 7 by the
removal of all protecting groups and the subsequent formation
of a hemiacetal bridge. Diketone 7 would be obtained from
ketone 8 by the regio- and stereocontrolled introduction of the
side chain moiety to construct the all-carbon quaternary
Some examples of the total synthesis of dolastane and seco-
dolastane diterpenoids isoamijiol (5),7,8 dolastatrienol (6),8,9
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail: itohisa@toyaku.ac.jp,
tkoba@toyaku.ac.jp
†Electronic supplementary information (ESI) available. CCDC 2003840 and
2003841. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d0ob01430c
Fig. 1 Structures of isolinearol (1) and related diterpenoids 2–6.
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Fig. 3 Stereoselectivity of the methallylation of silicon-bridged com-
pound 11.
The introduction of the butenyl group into the activated
methine of compound 14 gave the symmetric diketone 13 in
35% yield along with the O-butenyl compound in 30% yield.
The diastereoselective reductive desymmetrization12 of 13 was
achieved using NaBH4 in MeOH at −78 °C to provide the
desired 12 in 97% yield with high diastereoselectivity. The
silicon-bridged compound 11 was obtained according to
Nakada’s protocol.13 Thus, treatment of 12 with ClMe2SiCH2Br
afforded the corresponding silyl ether in quantitative yield,
then silicon bridge formation occurred by using LHMDS as a
base to give compound 11 in 87% yield for the 2 steps.
Methallyl group introduction into the silicon-bridged com-
pound 11 using 2-methylallylmagnesium chloride provided
the diene derivative 15 in 94% yield as a single diastereomer
having the desired stereochemistry, as expected. We con-
sidered that the high stereoselectivity of the methallylation
was due to the approach of the reagent from the opposite side
of the silicon bridge (Fig. 3). Tamao oxidation of 15 provided
the triol 10 in 91% yield and ring-closing metathesis of triol 10
using Grubbs second-generation catalyst provided the bicyclic
compound 16 in 94% yield.
Having bicyclic compound 16 with the contiguous chiral
centers in hand, we next focused on stereocontrolled construc-
tion of the all-carbon chiral center on the cycloheptane ring
(Scheme 2). The primary and secondary alcohols of triol 16
were protected by TBS groups and the tertiary alcohol was pro-
tected by a TMS group to give compound 9 in 95% yield for 2
steps. The hydroboration–oxidation of 9 using BH3·THF and
NaBO3·4H2O followed by oxidation of the resulting secondary
alcohol using AZADOL® 14 afforded the ketone 8 in 74% yield
for 2 steps. Then, in order to construct an all-carbon chiral
center on the cycloheptane ring, we attempted several reaction
conditions. As the results, we found out the allylation via silyl
enol ether 18 was the suitable condition for this object. Thus,
treatment of the ketone 8 with TMSOTf and Et3N in CH2Cl2
provided more highly substituted trimethylsilyl enol ether 19,
which was converted to the lithium enolate by adding MeLi at
0 °C in THF, and then the addition of allyl iodide and HMPA
at −30 °C afforded the desired compound 20 as the sole
product. The stereochemistry of compound 20 was determined
by X-ray crystallographic analysis of compound 21,15 which
was derived from 20 by deprotection of the silyl groups fol-
lowed by hemiacetal formation. The high stereoselectivity of
the allylation was assumed to be due to the approach of the
reagent to avoid the trimethylsilyl group present on the α-face.
Fig. 2 Retrosynthetic analysis for the total synthesis of isolinearol (1).
center and form the exo-methylene. Ketone 8 would be derived
from bicyclic compound 9, which would be prepared from
diene derivative 10 via ring-closing metathesis. Diene deriva-
tive 10 would be obtained by the stereocontrolled introduction
of a methallyl group into the silicon-bridged compound 11,
which would be prepared from alcohol 12. Alcohol 12 would
be synthesized by a diastereoselective reductive desymmetriza-
tion of the symmetric diketone 13. Symmetric diketone 13
could be derived from commercially available 2-methyl-1,3-
cyclohexanedione (14).
Stereocontrolled construction of the contiguous chiral
centers on the cyclohexane ring was the first aim of this syn-
thetic project. The synthesis began with the commercially
available 2-methyl-1,3-cyclohexanedione (14) as shown in
Scheme 1.
Scheme 1 Stereocontrolled synthesis of bicyclic compound 16.
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Scheme 3 Total synthesis of isolinearol (1).
Scheme 2 Stereocontrolled construction of the all-carbon quaternary
chiral center on the cycloheptane ring.
ceeded simultaneously, and the target molecule
1 was
obtained in 93% yield as the sole product. Both 1H and 13C
After the successful construction of the all-carbon chiral NMR spectra of the synthetic compound 1 were identical to
center on the cycloheptane ring, our interest turned to the those of the reported natural isolinearol.2 Additionally, the
completion of the total synthesis of target molecule
1
structure of compound 1 was unambiguously confirmed by
(Scheme 3). First, after several attempts, the construction of X-ray crystallographic analysis.19
the exo-methylene group was achieved by syn-elimination of a
Thus, we achieved the total synthesis of isolinearol (1) in
selenoxide using a four-step conversion as follows. Thus, the racemic form. The remaining challenges were the asymmetric
selective deprotection of the TBS ether using 0.5 M HCl fol- synthesis and verification of the absolute configuration of iso-
lowed by tosylation of the resulting primary alcohol provided linearol (1). According to our synthetic route, in order to syn-
compound 22 in 69% yield for 2 steps. The transformation of thesize optically active isolinearol (1), compound 12 must be
tosylate 22 to corresponding selenide was carried out under obtained in optically active form. After several attempts at the
heating conditions (100 °C) in a mixed solvent of EtOH and asymmetric reductive desymmetrization of 13, we found that
cyclopentyl methyl ether using NaSePh generated in situ by the the Corey–Bakshi–Shibata (CBS) reduction20 was suitable to
reaction of (PhSe)2 with NaBH4.16 Oxidation of the obtained obtain the optically active 12 with high enantiomeric excess
selenide using the Davis oxaziridine followed by syn-elimin- (Scheme 4). Thus, the CBS reduction of 13 using (S)-2-n-Bu-
ation of the resulting selenoxide provided the desired exo- CBS-oxazoborolidine and catecholborane afforded 12 in satis-
methylene compound 23 in 60% yield for 2 steps. Next, the factory yield (42%, brsm 95%) in 91% ee21 as a single diaster-
conversion of the terminal olefin to an aldehyde for construc- eomer. In order to determine the absolute configuration, com-
tion of the side chain was investigated. As a result, the syn- pound 12 was transformed to known compound 27 22 via
thesis of aldehyde 25 was achieved by the olefin cross-meta- acetylation of the secondary alcohol and Wacker oxidation of
thesis of 23 with pinacol vinyl boronic ester17 in the presence the terminal olefin. The optical rotation of synthetic 27 had
of Zhan catalyst-1B,18 followed by oxidation of the resulting the opposite rotation to that reported in the literature [syn-
vinyl boronic ester 24 using NaBO3·4H2O. Compound 7 posses- thetic 27: [α]2D5 −39.3 (c 0.24, CHCl3); reported (1S,2S)-27: [α]2D5
sing the side chain moiety was successfully obtained from 25 +42.9 (c 1.03, CHCl3) 22]. Therefore, the absolute configuration
via the aldehyde–selective introduction of an isopropyl group of (−)-12 was assigned as 1R,2R.
and oxidation of the resulting secondary alcohol with DMP in
With the optically active 12 in hand, the asymmetric syn-
85% yield. Finally, upon treatment of 7 with conc. HCl in thesis of isolinearol (1) through the established procedure was
1
MeOH for 10 h at room temperature, deprotection of the TBS attempted. Both H and 13C NMR spectra of synthetic 1 were
and TMS groups and formation of the hemiacetal bridge pro- identical with those of natural isolinearol (1) and the optical
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Acknowledgements
This work was supported by JSPS KAKENHI and the Platform
for Drug Discovery, Informatics, and Structural Life Science
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan (Grant No. 17K08223).
Notes and references
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Scheme 4 Asymmetric total synthesis of (−)-isolinearol (1).
rotation of synthetic 1 had the same rotation as that reported
for the natural product [synthetic 1: [α]2D5 −47.4 (c 0.12, CHCl3);
natural product 1: [α]2D5 −52.1 (c 1.00, CHCl3) 2]. Therefore, we
have determined the absolute configuration of natural isoli-
nearol as expected [4R,5R,8R,12R,14S].
Conclusions
In conclusion, the first total synthesis of racemic isolinearol
(1) was accomplished from the commercially available
2-methyl-1,3-cyclohexanedione in a total of 22 steps. The
overall yield was 1.7% from 2-methyl-1,3-cyclohexanedione
(14). This synthesis included the following features: (i) con-
struction of three contiguous chiral centers on the cyclo-
hexane ring utilizing diastereoselective reductive desymme-
trization of 2-butenyl-2-methyl-1,3-cyclohexanedione and
stereocontrolled introduction of a methallyl group into the
silicon-bridged compound; (ii) construction of the quatern-
ary carbon chiral center using regio- and stereocontrolled
allylation via a silyl enol ether derivative; and (iii) introduc-
tion of the side chain carbonyl group using olefin cross-
metathesis with pinacol vinyl boronic ester followed by oxi-
dation. In addition, we achieved the asymmetric total syn-
thesis of 1 using CBS reduction in the asymmetric reductive
desymmetrization of the 1,3-cyclohexanedione derivative and
determined its absolute configuration. Our methodology can
be extended to the synthesis of dolastane and secodolastane
diterpenoids. Further investigations are now in progress in
our laboratory.
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Conflicts of interest
There are no conflicts to declare.
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18 Z.-Y. J. Zhan, U. S. patent, US0043180A1, 2007.
19 CCDC 2003841 contains the supplemental crystallographic
data of compound 1.†
21 Enantiomeric excess was determined using chiral HPLC
after compound (−)-12 was transformed to the corres-
ponding benzoyl derivative; see ESI.†
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