Total Synthesis of (?)-Pepluanol B: Conformational Control of the Eight-Membered-Ring System

Article abstract of DOI:10.1002/anie.201915876

The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo-epoxidation to control the eight-membered-ring conform

Full text of DOI:10.1002/anie.201915876

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Accepted Article
Title: Total Synthesis of (-)-Pepluanol B: Conformational Control of the
Eight-Membered Ring System
Authors: Jing Zhang, Meng Liu, Chuanhua Wu, Gaoyuan Zhao, Peiqi
Chen, Lin Zhou, Xingang Xie, Ran Fang, Huilin Li, and
Xuegong She
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915876
Angew. Chem. 10.1002/ange.201915876
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10.1002/anie.201915876
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis of ()-Pepluanol B: Conformational Control of the
Eight-Membered Ring System
Jing Zhang, Meng Liu, Chuanhua Wu, Gaoyuan Zhao, Peiqi Chen, Lin Zhou, Xingang Xie, Ran Fang,
Huilin Li* and Xuegong She*
[*]
J. Zhang, M. Liu, C. Wu, G. Zhao, P. Chen, L. Zhou, Prof. Dr. X. Xie, Prof. Dr. R. Fang, Prof. Dr. H. Li, Prof. Dr. X. She
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering
Lanzhou University
222 South Tianshui Road, Lanzhou 730000, Gansu, P. R. China
E-mail: lihuilin@lzu.edu.cn; shexg@lzu.edu.cn
Abstract: The first total synthesis of the Euphorbia diterpenoid
pepluanol B is described in 20 steps from a known bicyclic diol in
both racemic and asymmetric manners. This synthesis highlights an
unprecedented bromo-epoxidation maneuver to control the eight-
membered ring conformation. In addition, salient features for
construction of the tetracyclic backbone include a sterically hindered
aldol reaction to establish the quaternary center, a ring-closing
metathesis (RCM) to forge the eight-membered ring and
a
diastereoselective cyclopropanation to assemble the embedded
cyclopropane motif.
Owing to their wide distribution and medicinal value, many
species of the Euphorbia genus have been used in traditional
herbal medicines to treat a range of diseases with long history.[1]
The plants of this genus have provided a large number of
significant diterpenoids that have attracted widespread attention
from both chemical and biological communities.[2] The Euphorbia
diterpenoids generally possess diverse intricate polycyclic
molecular archetectures,[2] and moreover, display a broad
spectrum of bioactivities[3] closely associated with human health,
such as antitumor, multidrug-resistance reversing (MDR),
antiviral and anti-inflammatory properties, which render them
intriguing and challenging targets for total synthesis, culminating
in numerous elegant synthetic achievements.[4]
In 2016 and 2018, five novel biogenetically related
diterpenoids have been successively discovered and named as
pepluacetal (1) and pepluanols A-D (2-5) respectively by Qiu
and co-workers from the plant of E. peplus (Figure 1).[5]
Significantly, all the five compounds showed effectively inhibitory
actions on the kv1.3 potassium channel which is responsible for
autoimmune disorders, making them applicable for treatment of
intractable diseases such as asthma, type-1 diabetes, multiple
sclerosis, and psoriasis. Among them, pepluanol B (3) offered
the best IC50 value of 9.50 μM. The unique fused polycyclic
skeletons with a high oxidation pattern, incorporating 6-8
stereogenic centers, renders these natural products formidable
synthetic targets. So far, only the total synthesis of ()-pepluanol
A (2) has been accomplished by Ding and coworkers via
exploiting an elegant Ti(III)-catalyzed reductive annulation.[4o]
Herein, we report the first total synthesis of pepluanol B in both
racemic and asymmetric manners in 20 steps.
Figure 1. Structures and synthetic progress of Euphorbia diterpenoids 1-5.
one bridge-head all-carbon quaternary center (Scheme 1).
Notably, the C14 carbonyl adopts a downward orientation based
on the single X-ray diffraction analysis. Furthermore, the
situation that the C14 carbonyl locates between the C13 and
C15 stereocenters is quite similar with the famous challenging
“in-out” substructure in bridged cyclic systems like ingenol.[6]
Thus, it was envisaged that the stereoselective construction of
the eight-membered ring system with proper control of the
cyclooctanone conformation and installation of the stereocenters
would be the critical and formidable task of the synthesis. As for
Structurally, pepluanol B (3) comprises a rare fused [5-5-8-
3] tetracyclic framework and six stereogenic centers including
Scheme 1. Retrosynthetic analysis of pepluanol B.
1
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10.1002/anie.201915876
Angewandte Chemie International Edition
COMMUNICATION
could be derived from cyclooctadiene in 2 steps according to the
literature protocol.[7]
We commenced our synthesis with the decagram-scale
preparation of bicyclic diol 10 in 2 steps from commercially
available cyclooctadiene according to the modified literature
procedures (Scheme 2).[7] To quickly examine our designed
strategy, racemic 10 was initially utilized for route exploration.
Mono-protection of 10 with PMB and subsequent oxidation of
the other alcohol smoothly delivered ketone 11, followed by
Eschenmoser methylenation[9] giving enone 12. Then, the exo-
methylene was effectively converted to the more stable endo
form enabled by Rh-catalyzed double bond isomerization,[10]
which afforded the -methylcyclopentenone product 13. To
construct the eight-membered ring, it next calls for two terminal
olefin arms with different length. Therefore, aldol reaction of 13
with aldehyde 9 by using LDA as base formed the desired C15
all-carbon quaternary center along with 3:2 dr for the secondary
alcohol, furnishing compound 14 after the ensuing TMS
protection. Then, 1,2-nucleophilic addition of the enone moiety
with allylmagnesium bromide in the presence of anhydrous
[11]
CeCl3
delivered 8 with exclusive facial selectivity. For the
critical RCM reaction to forge the eight-membered ring, after
several trials, Grubbs catalyst 2nd generation was gratifyingly
found capable for this transformation with high efficiency to
deliver cyclic Z-alkene intermediate 7. Furthermore,
dibromocyclopropanation of the Z-alkene 7 proceeded with
exclusive regio- and diastereoselectivity followed by nucleophillic
bismethylation with Me3CuLi2/MeI which successfully assembled
the requisite gem-dimethyl cyclopropane subunit.[12] The
stereospecificity of this cyclopropanation reaction is presumably
because the alkene in 7 provided the less hindered convex face
for dibromocarbene attacking. Subsequent desilylation with
Scheme 2. Construction of tetracyclic scaffold 15. Reagents and conditions: a)
NaH (1.0 equiv.), PMBCl (1.0 equiv.), TBAI (0.1 equiv.), THF, 0 oC → reflux, 3
h; b) (COCl)2 (2.0 equiv.), DMSO (4.0 equiv.), Et3N (6.0 equiv.), CH2Cl2, 78
oC → 25 oC, 1 h, 80% (2 steps); c) LDA (1.2 equiv.), TMSCl (2.0 equiv.), THF,
78 oC → 0 oC, 3 h; d) [(CH3)2NCH2]I- (3.0 equiv.), CH2Cl2, 25 oC, 16 h; e) MeI
(12.0 equiv.), Al2O3 (basic), CH2Cl2, 25 oC, overnight, 65% (3 steps); f)
RhCl3•H2O (5 mol%), EtOH/pH 7 buffer (19:1), sealed tube, 110 oC, 25 min,
86%; g) LDA (1.3 equiv.), aldehyde 9 (1.5 equiv.), THF, 78 oC, 3 h; h) Et3N
(4.0 equiv.), TMSOTf (2.0 equiv.), CH2Cl2,  oC, 30 min, 78% (2 steps); i)
CeCl3 (3.0 equiv.), allylmagnesium bromide (3.0 equiv.), THF, 78 oC → 25 oC,
4 h, 72%; j) Grubbs catalyst 2nd generation (5 mol%), CH2Cl2, reflux, 3 h, 88%;
k) TEBAC (0.1 equiv.), CHBr3 (5.0 equiv.), NaOH (aq., 50 wt%), CH2Cl2,  oC
→ 25 oC, 1 h, 78%; l) CuI (4.0 equiv.), MeLi (12.0 equiv.), MeI (28.0 equiv.),
Et2O, 45 oC → 25 oC, 12 h; m) TBAF (1.5 equiv.), THF, 25 oC, 30 min; n)
TPAP (10 mol%), NMO (1.5 equiv.), 4 Å MS (0.5 g/mmol), CH2Cl2, 25 oC, 30
min, 75% (3 steps). PMB = p-methoxybenzyl, TBAI = tetrabutylammonium
iodide, DMSO = dimethylsulfoxide, LDA = lithium diisopropylamide, TMS =
trimethylsilyl, Tf = trifluoromethanesulfonyl, TEBAC = benzyltriethylammonium
chloride, TBAF = tetrabutylammonium fluoride, TPAP = tetrapropylammonium
perruthenate, NMO = N-methylmorpholine oxide.
TBAF gave the diol intermediate 6 and Ley-Griffith oxidation of 6
Me
O
O
Me
Me
S
14
14
13
HO
TMSO
Me
a. pyridine,TMSOTf
b. LDA, MeI, -78 o
Me
15
15
H
H
H
Me
H
Me
H
C
78% over 2 steps
H
H
PMBO
PMBO
backward addittion
MeI
16
15
O
Me
TMSO
Me
15
H
H
H
Int-I
Me
O
Me
Me
TMSO
c. DDQ, CH2Cl2
H
H
Me
H
d. TPAP, NMO
68% over 2 steps
H
O
17
CCDC 1939170
e. TMMN, Ac2O, DMF
the [5-5] bicyclic system, we recognized that it exhibits a hidden
C2-symmetric character and could be arisen from the known
bicyclic diol 10[7] just by elaborating it to -methylcyclopentenone.
Thus, with the point in mind that the key solution for its synthesis
lies in the stereoselective construction of the fused [8-3]-bicyclic
framework containing a cyclooctanone and a gem-dimethyl
cyclopropane motif, a general disconnection was devised as
shown in Scheme 1. First, the target molecule 3 could be
obtained via an array of late-stage transformations from its
precursor 6 which could be traced back to a tricyclic alkene 7
through diastereoselective cyclopropanation. Next, an RCM
reaction was chosen to forge the eight-membered ring from
intermediate 8,[8] and the two terminal olefin arms in 8 could be
installed through elaboration of bicyclic diol 10 with aldehyde 9
and allylmagnesium bromide. Ultimately, the bicyclic diol 10
96 oC, 75%
Me
O
Me
O
Me
Me
Me
Me
S
14
13
HO
TMSO
15
H
H
f. 20 mol% RhCl3 3H2O
H
Me
H
Me
H
H
Me
52%
H
H
O
O
18
19
Scheme 3. Synthesis of compound 19. Reagents and conditions: a) pyridine
(4.0 equiv.), TMSOTf (2.0 equiv.), CH2Cl2, 0 oC, 30 min; b) LDA (10.0 equiv.),
MeI (10.0 equiv.), THF, 78 oC, 30 min, 78% (2 steps); c) DDQ (3.0 equiv),
CH2Cl2/pH 7 buffer (9:1), 25 oC, 1 h; d) TPAP (10 mol%), NMO (1.5 equiv.), 4Å
MS (0.5 g/mmol), CH2Cl2, 25 oC, 30 min, 68% (2 steps); e) TMMN, Ac2O, DMF,
96 oC, 1 h, 75%; f) RhCl3•3H2O (20 mol%), EtOH/CH2Cl2 (6:1), sealed tube,
100 oC, 2 h, 52%. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TMMN
= tetramethylmethylenediamine.
2
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10.1002/anie.201915876
Angewandte Chemie International Edition
COMMUNICATION
H
HO
Me
Me
Me
with TPAP produced the crucial compound 15 that contains the
tetracyclic framework of pepluanol B.
14
14
15
HO
b. LDA, MeI, 72%
a. NBS, pyridine
Me
15
H
O
H
Me
H
then DMP
95%
O
backward addition
H
After comparing the 13C NMR spectra of 15 with natural
pepluanol B, a considerable discrepancy of the chemical shifts
for the C14 carbonyl signal (223.1 ppm and 209.2 ppm for 15
and 3 respectively) was observed. To further secure the specific
structure of 15, subsequent X-ray analysis of 15 (CCDC
1939171) was then carried out, and we surprisingly found that
the C14 carbonyl in 15 adopted an upward orientation nearly
parallel to the C7-OH group, which is opposite with natural
pepluanol B (vide supra) although they share the similar cyclic
backbones. To invert the cyclooctanone to the desired twist-boat
conformation, 15 was subjected to thermally basic conditions.
However, neither DBU in refluxing toluene nor NaOMe in
refluxing MeOH was effective for this transformation. We initially
anticipated that this conformational issue[13] might be in situ
diminished in the following synthetic steps with basic conditions.
Thus, compound 15 was directly utilized in the following
synthetic attempts aiming for the target pepluanol B (Scheme 3).
When 15 was treated with NaHMDS and methylation reagent
(MeI or MeOTf), the free tertiary alcohol was methylated
preferably. Therefore, TMS protection was performed prior to the
C13 methylation, which successfully delivered intermediate 16
with excellent diastereoselectivity. X-Ray crystallographic
analysis of 16 (CCDC 1939170) suggested that the expected
inversion of the cyclooctanone conformation didn’t occur while
the newly formed C13 configuration was determined to be the
Me
PMBO
Br
H
MeI
H
H
H
PMBO
Me
13
6
20
15
Me
O
H
Int-II
H
R
H
Me
Me
H
H
Me
Me
Me
Me
13
13
14
d. DDQ, CH2Cl2
e. TPAP, NMO
15
15
O
O
H
H
O
O
Me
Me
48% for 2 steps
PMBO
O
Br
Br
H
H
H
H
23
21
f. Zn-Cu, EtOH
sat. aq. NH4Cl
93%
c. Zn-Cu, EtOH
reflux, 61%
H
H
Me
Me
HO
R
H
H
Me
Me
Me
13
13
14
HO
15
15
Me
O
O
H
Me
H
Me
H
H
PMBO
O
22
24
CCDC 1969369
g. TMMN, Ac2O, DMF
95 oC, 96%
H
R
H
Me
Me
HO
H
H
Me
Me
Me
Me
13
13
HO 14
h. 20 mol% RhCl3 3H2O
15
15
O
O
H
H
Me
Me
60% brsm.
Me
H
H
O
O
Pepluanol B (3)
25
undesired
S
rather than R. We speculated that the
Scheme 4. Total synthesis of ()-pepluanol B. Reagents and conditions: a)
NBS (6.0 equiv.), pyridine (6.0 equiv.), CH2Cl2, 25 oC, 1 h, then DMP (3.0
equiv.), 0 oC → 25 oC, 2h, 95%; b) LDA (10.0 equiv.), MeI (10.0 equiv.), THF,
78 oC, 30 min, 72%; c) Zn-Cu couple (1-3% Cu, 45 equiv.), EtOH, reflux, 3 h,
61%; d) DDQ (3.0 equiv.), CH2Cl2/pH 7 buffer (9:1), 25 oC, 1 h; e) TPAP (10
mol%), NMO (1.5 equiv), 4 Å MS (0.5 g/mmol), CH2Cl2, 25 oC, 30 min, 48% (2
steps); f) Zn-Cu couple (1-3% Cu, 15 equiv.), EtOH/sat. aq. NH4Cl (10 : 1), 25
oC, 15 min, 93%; g) TMMN, Ac2O, DMF, 95 oC, 1 h, 96%; h) RhCl3•3H2O (20
mol%), EtOH/pH 7 buffer (4:1), sealed tube, 95 oC, 40 min, 48%, 60% brsm.
NBS = N-bromosuccinimide, DMP = Dess-Martin periodinane, brsm = based
on recovered starting material.
stereochemical outcome for the C13 methylation was because it
might generate a stereospecific Z-enolate intermediate (Int-I)
that only provides the backward direction for MeI approaching.
To invert the C13 configuration, compound 16 was exposed to a
series of basic conditions, but all failed even the strong base
tBuLi was used. Further removal of the PMB protection with
DDQ and oxidation of the corresponding secondary alcohol
resulted in ketone 17, which underwent similar process with 11
including -methylenation with the in situ generated dimethyl
iminium cation[14] to afford 18 and Rh-catalyzed double bond
isomerization[10] with simultaneous TMS deprotection to
introduce the left -methylcyclopentenone moiety to furnish
compound 19. Even up to this stage, the NMR spectra of 19
were not identical with natural pepluanol B, signifying that the
expected in situ inversion event of the cyclooctanone
conformation as well as the C13 configuration still didn’t happen.
Disappointingly, DBU in refluxing DCE also failed to convert the
stereoisomer 19 to pepluanol B.
Faced with the failure on inversion of the C14 carbonyl
orientation and the configuration at C13 stereogenic center, we
supposed that the C13 methylation selectivity was dominated by
the cyclooctanone conformation because it determines the
spatial direction of the Z-enolate double bond. Thus, the key
point to tackle the problem lies in the conformational control of
the cyclooctanone, which drove us back to reinvestigate the
TPAP oxidation step from 6 to 15 (Scheme 2). It was presumed
that the C7 tertiary alcohol with an upward orientation might drag
the C14 oxygen atom through intramolecular hydrogen bonding
in the oxidation process, leading the C14 carbonyl to adopt a
favored upward direction. Thereby, the allylic alcohol motif in
intermediate 6 was supposed to be temporarily hidden prior to
the oxidation of the C14 hydroxyl group. Hence, a bromo-
epoxide[15] was chosen to unravel this task because it could
release allylic alcohol at proper time and moreover, the strained
epoxide could enhance the rigidity of the molecular backbone for
better stereocontrol. Therefore, intermediate 6 was exposed to
NBS/pyridine to convert the allylic alcohol into the bromo-
epoxide and subsequently treated with Dess-Martin periodinane
in one-pot to oxidize the secondary alcohol to ketone 20 as a
sole isomer (Scheme 4). Then, the LDA-promoted methylation
occurred smoothly to give compound 21 with the R configuration
at the C13 stereocenter established exclusively, suggesting that,
in one hand, the Z-enolate configuration provided the backward
direction for MeI approaching, and on the other hand, the Z-
enolate double bond was dominated by the cyclooctanone to
adopt
a
vertical spatial orientation (Int-II). Gratifyingly,
subsequent release of the tertiary allylic alcohol with Zn-Cu
couple in refluxing EtOH[15a] yielded compound 22 as a white
solid for single crystallographic X-ray analysis (CCDC 1969369)
which unambitiously revealed that the C14 carbonyl adopted a
downward orientation as expected, and the C13 methyl
configuration was well-established as desired. Up to this stage,
the obtained eight-membered ring conformation in compounds
20 and 21 could also be elucidated as the desired one.
3
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10.1002/anie.201915876
Angewandte Chemie International Edition
COMMUNICATION
With the conformational issue addressed successfully, and
in order to further introduce the left -methylcylcopentenone
moiety for finishing the total synthesis, we initially tried to
remove the PMB protecting group in 22. However, a series of
conditions failed to achieve this transformation, probably due to
the instability of the allylic alcohol moiety. Pleasingly, it was
found that the bromo-epoxide intermediate 21 could tolerate the
oxidative condition with DDQ to cleave the PMB protecting
group and the corresponding secondary alcohol was then
oxidized to cylcopentanone 23 with TPAP. Subsequently, the
bromo-epoxide mask in 23 was taken off to unveil the allylic
alcohol 24 in excellent yield with Zn-Cu couple in the presence
of saturated aqueous NH4Cl.[15b] As the endgame, following
similar protocol shown in Scheme 3, compound 24 underwent-
methylenation[14] to furnish enone 25 and Rh-catalyzed double
bond isomerization[10] of 25 completed the first total synthesis of
()-pepluanol B. Accordingly, the NMR data of the obtained
sample were in good agreement with the isolated pepluanol B.
cyclopropanation reaction. Notably, the C14 carbonyl orientation
was found to be critical to the C13 methylation stereochemical
outcome, making the conformational control of the eight-
membered ring a formidable problem for the synthesis. Finally,
when a bromo-epoxide was significantly designed and exploited
as the tertiary allylic alcohol mask, the challenging goal was
successfully achieved with the C14 carbonyl to adopt a desired
downward orientation and the C13 methylation stereochemistry
to be solved accordingly. The enantioselective synthesis of
pepluanol B was accomplished starting from chiral bicyclic diol
()-10 that was obtained with high optical purity by enzyme-
promoted kinetic resolution. This described route allows
sufficient supply of ()-pepluanol B (7.7 mg) for further biological
investigations. Synthetic efforts towards other members of this
family is currently ongoing in our laboratory.
Acknowledgements
We acknowledge the generous financial support by NSFC
(21732001, 21871118 and 21572088) and PCSIRT
(IRT_15R28).
Keywords: Euphorbia diterpenoid • pepluanol B• total synthesis
• conformational control • bromo-epoxide
[1]
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Bresinsky, C. Körner, Strasburger – Lehrbuch der Botanik, Spektrum
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[2]
[3]
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19151921; d) G. M. Keating, Drugs 2012, 72, 23972405.
Scheme 5. Enantioselective synthesis of ()-pepluanol B. Reagents and
conditions for lipase resolution: lipase from Pseudomonas cepacia (15.0
g/50.0 g starting material), vinyl acetate/TBME = 1/2 (v/v), c = 0.70 M, 25 oC,
15 days, 44%. TBME = tert-butyl methyl ether.
Having established the stereoselective route toward ()-
pepluanol B, its enantioselective version was implemented
starting from the chiral diol ()-10 (Scheme 5). Thus, efficient
kinetic resolution of racemic 10 was carried out to supply chiral
diol ()-10 in 99.6% ee when lipase from pseudomonas cepecia
served as an acetylation enzyme.[7] Following the developed
synthetic route, the first enantioselective total synthesis of ()-
pepluanol B was finally realized with 94% ee. Based on the X-
ray crystallographic analysis of the chiral intermediate ()-24
[4]
For representative examples for total syntheses of Euphorbia
diterpenoids, see: a) P. A. Wender, K. D. Rice, M. E. Schnute, J. Am.
Chem. Soc. 1997, 119, 78977898; b) J. D. Winkler, M. B. Rouse, M. F.
Greaney, S. J. Harrison, Y. T. Jeon, J. Am. Chem. Soc. 2002, 124,
97269728; c) K. Tanino, K. Onuki, K. Asano, M. Miyashita, T.
Nakamura, Y. Takahashi, I. Kuwajima, J. Am. Chem. Soc. 2003, 125,
14981500; d) A. Nickel, T. Maruyama, H. Tang, P. D. Murphy, B.
Greene, N. Yusuff, J. L. Wood, J. Am. Chem. Soc. 2004, 126,
1630016301; e) C. Schnabel, M. Hiersemann, Org. Lett. 2009, 11,
25552558; f) C. Lentsch, U. Rinner, Org. Lett. 2009, 11, 53265328;
g) T. Ohyoshi, S. Funakubo, Y. Miyazawa, K. Niida, I. Hayakawa, H.
Kigoshi, Angew. Chem. Int. Ed. 2012, 51, 49724975; Angew. Chem.
2012, 124, 50565059; h) L. Jørgensen, S. J. McKerrall, C. A. Kuttruff,
F. Ungeheuer, J. Felding, P. S. Baran, Science 2013, 341, 878882; i)
S. J. McKerrall, L. Jørgensen, C. A. Kuttruff, F. Ungeheuer, P. S. Baran,
J. Am. Chem. Soc. 2014, 136, 57995810; j) Y. Jin, C.-H. Yeh, C. A.
Kuttruff, L. Jørgensen, G. Dunstl, J. Felding, S. R. Natarajan, P. S.
Baran, Angew. Chem. Int. Ed. 2015, 54, 14044–14048; Angew. Chem.
2015, 127, 14250–14254; k) S. Pan, J. Xuan, B. Gao, A. Zhu, H. Ding,
Angew. Chem. Int. Ed. 2015, 54, 69056908; Angew. Chem. 2015, 127,
70097012; l) T. Asaba, Y. Katoh, D. Urabe, M. Inoue, Angew. Chem.
Int. Ed. 2015, 54, 1445714461; Angew. Chem. 2015, 127, 14665–
14669; m) S. Kawamura, H. Chu, J. Felding, P. S. Baran, Nature 2016,
532, 9093; n) S. Hashimoto, S.-I. Katoh, T. Kato, D. Urabe, M. Inoue,
(CCDC 1965417), and in association with the optical rotation
25
data comparison of the synthetic and authentic samples ([α]D
=
25
90.0, c 0.10 MeOH; lit. [α]D = 29.8, c 0.10 MeOH), the
absolute configuration of naturally-occurring pepluanol B was
unambitiously confirmed.
In conclusion, the first total synthesis of bioactive Euphorbia
diterpenoid pepluanol
B
in both racemic and highly
enantioselective manners was accomplished in 20 steps from
the known bicyclic diol 10 (23 steps from commercially available
feedstock) in 3.0% overall yield. The tetracyclic carbon
backbone of the target molecule was constructed through a
series of highly stereoselective C-C bond formation reactions
including a sterically hindered aldol reaction, a nucleophilic
Grignard reagent addition, an RCM reaction and
a
4
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5
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Entry for the Table of Contents
Me
O
Me
Me
S
14
13
HO
7 steps
Me
15
H
H
Me
H
Me
H
O
HO
HO
OH
H
H
19
14
13 steps
Me
15
H
Me
H
H
Me
R
H
HO
Me
Me
H
13
PMBO
HO 14
15
7 steps
O
H
bromo-epoxidation
maneuver
Me
Me
H
O
Pepluanol B
Make it downward. The first total synthesis of the Euphorbia diterpenoid pepluanol B is described in both racemic and asymmetric
manners. This synthesis features an unprecedented bromo-epoxidation maneuver to dominate the C14 carbonyl to a downward
orientation as naturally-occurred, with which the stereochemistry of C13 methylation can be established properly. In addition, an array
of other stereocontrolled chemical transformations are exploited to construct the tetracyclic backbone, including a sterically hindered
aldol reaction to establish the C15 quaternary center, a ring-closing metathesis (RCM) to forge the eight-membered ring and a
diastereoselective cyclopropanation to assemble the embedded cyclopropane motif.
6
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