A six-step synthetic approach to marine natural product (+)-aureol

Article abstract of DOI:10.1016/j.tetlet.2018.01.091

A concise synthetic approach to the marine natural product (+)-aureol has been achieved from readily available starting materials using obviously fewer steps in comparison to the related report in literature (6 steps versus 12 steps from (+)-sclareolide). Key steps of this protocol include a boron trifluoride-catalyzed domino 1,2-H and 1,2-methyl shifts and a nickel(II)-catalyzed cross-coupling reaction between an alkyl iodide and an aryl Grignard reagent.

Full text of DOI:10.1016/j.tetlet.2018.01.091

Accepted Manuscript
A six-step synthetic approach to marine natural product (+)-aureol
Jun-Li Wang, Hui-Jing Li, Meirong Wang, Jun-Hu Wang, Yan-Chao Wu
PII:
S0040-4039(18)30136-9
https://doi.org/10.1016/j.tetlet.2018.01.091
TETL 49678
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
21 December 2017
26 January 2018
29 January 2018
Please cite this article as: Wang, J-L., Li, H-J., Wang, M., Wang, J-H., Wu, Y-C., A six-step synthetic approach to
marine natural product (+)-aureol, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.091
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Tetrahedron Letters
A six-step synthetic approach to marine natural product (+)-aureol
Jun-Li Wanga, Hui-Jing Lia, Meirong Wangb, Jun-Hu Wanga and Yan-Chao Wua,c,
a
School of Marine Science and Technology, Harbin Institute of Technology, Weihai 264209, P. R. China
b School of Materials Science and Engineering, Harbin Institute of Technology, Weihai 264209, P. R. China
c
Beijing National Laboratory for Molecular Sciences (BNLMS), Institute of Chemistry Chinese Academy of Sciences, Beijing 100190, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise synthetic approach to the marine natural product (+)-aureol has been achieved from
readily available starting materials using obviously fewer steps in comparison to the related
report in literature (6 steps versus 12 steps from (+)-sclareolide). Key steps of this protocol
include a boron trifluoride-catalyzed domino 1,2-H and 1,2-methyl shifts and a nickel(II)-
catalyzed cross-coupling reaction between an alkyl iodide and an aryl Grignard reagent.
Available online
2009 Elsevier Ltd. All rights reserved.
kwords:
Aureol
Rearrangement
Coupling reaction
Marine natural products
In recent decades, more and more natural products, owing to
their special chemical structures and interesting biological
activities, have been isolated from marine organisms. (+)-Aureol
(1, Figure 1) was isolated from the marine sponge Smenospongia
aurea in 1980 by Faulkner,1 and subsequently isolated from
sponge Verongula gigantean2 and Smenospongia sp.3 The
structure of this marine natural product has been revealed by
means of extensive spectroscopic studies as well as X-ray
crystallographic analysis to have a novel tetracyclic skeleton with
four asymmetric carbon stereocenters. (+)-Aureol shows
selective cytotoxicity against human tumor cells, including
nonsmall cell lung cancer A549 and colon adenocarcinoma HT-
29 cells.4 The derivatives of (+)-aureol have shown promising
activity against Hepa59t/VGH, KB and Hela tumor cell lines.3
Besides, the structurally related (+)-strangylin A5 (2, Figure 1)
and (+)-stachyflin6 (3, Figure 1) were reported to display similar
antiviral and antitumor activities.
The unique structural features and important biological profile
of aureol-type natural products have attracted significant
attention from the synthetic community.7–11 The pioneering work
on the synthesis of the marine natural product (+)-aureol (1) was
carried out by the group of Katoh using various Wieland-
Miescher ketone derivatives as the starting materials,8 such as
(+)-Wieland-Miescher ketone analogue 4 (Scheme 1a).8a George
reported an elegant twelve-step synthesis of (+)-aureol (1) via the
key aldehyde intermediate 7, which was prepared from the cheap,
enantiopure terpenoid starting material (+)-sclareolide (6) in 8
steps (Scheme 1b).9 Marcos described a seminal synthesis of the
enantiomer of the natural (+)-aureol (1) in 15 steps with the use
of ent-halimic acid (8) as a chiral pool starting material (Scheme
1c).10 Recently, Rosales and Oltra reported an impressive eight-
step synthesis of (±)-aureol (1) via the key tetrasubstituted olefin
intermediate 11, which was prepared from epoxy-farnesol in 6
steps (Scheme 1d).11 Various skeletal rearrangement reactions
were involved in these synthetic protocols owing to their
unrivalled power to form multiple bonds in a single operation.
However, it is still a challenge to develop a facile and efficient
skeletal rearrangement reaction for a step-economical synthesis
of (+)-aureol (1) from commercially available starting materials.
In connection with our consistent interest towards the
development of concise strategies for the synthesis of bioactive
compounds,12 herein we report a six-step synthetic approach to
the marine natural product (+)-aureol (1) from readily available
and inexpensive starting material (+)-sclareolide (6) via the key
intermediate 12 (Scheme 1e). The concise synthetic approach
could be used for the preparation of sufficient quantity of this
marine natural product for biological and medical studies.
Figure 1. Structures of (+)-aureol and related natural products.
———
 Corresponding author. Tel.: +86-631-568-7230; fax: +86-631-568-7230; e-mail: ycwu@iccas.ac.cn

2
Tetrahedron Letters
a) Katoh's work:8
OH
As shown in Scheme 3, the synthesis of (+)-aureol (1)
commenced with commercially available sclareolide (6).
Reduction of (+)-sclareolide (6) using diisobutylaluminium
hydride (DIBAL-H) gave the sclaral 15, which upon exposure to
the hypoiodite-mediated C−C bond leava e onditions o
u re (PIDA/I2/hν) delivered drimanal iodoformate 14 in 76%
overall yield.14 We envisaged then to achieve the skeletal
rearrangement reaction of drimanal iodoformate 14 mentioned in
Scheme 2. After much experimentation (Table 1), this tandem
reaction was realized by treatment of drimanal iodoformate 14
with 200 mol % of BF3·Et2O in dichloromethane at –40 °C for 30
minutes to afford the desired alkyl iodide 12 and by-product 16
in 63% and 20% yields, respectively (Scheme 3). Subsequently,
the potential skeletal rearrangement reaction of by-product 16 to
alkyl iodide 12 has been extensively studied but failed
nevertheless.15 With alkyl iodide 12 in hand, the cross-coupling
reaction between alkyl iodide 12 and aryl Grignard reagent 13
was subsequently investigated. The optimization of reaction
HO
OH
4 steps
O
H
O
5 steps
O
O
H
4
5
(+)-aureol (1)
b) George's work:9
O
CHO
O
4 steps
8 steps
(+)-aureol (1)
H
(+)-sclareolide (6)
c) Marcos' work:10
OH
7
parameters
by
varying
the
catalysts
[(dppf)NiCl2,
CO2H
(dppf)NiCl2/ZnCl2, Pd2(dba)3, Pd(PPh3)4], the temperature (r.t.,
40 °C, 60 °C, 68 °C) and the solvents (THF, dioxane, toluene)
allowed us to identify the optimum reaction conditions. Thus, the
cross-coupling reaction of alkyl iodide 12 and aryl Grignard
reagent 13 was realized in the presence of (dppf)NiCl2 (10 mol
%) in THF under reflux for 36 hours to afford the key
tetrasubstituted olefin intermediate 11 in 56% yield (Scheme 3).
As olefin 11 is an advanced intermediate in the Rosales and
Oltra’s total synthesis o aureol,11 our work described herein
constitutes a formal synthesis of (+)-aureol (1, Scheme 3).
11 steps
4 steps
()-aureol (1)
H
CO2H
ent-halimic acid (8)
9
d) Rosales and Oltra's work:11
OH
MeO
OMe
2 steps
6 steps
(±)-aureol (1)
(+)-aureol (1)
O
10
11
I
e) This work:
3 steps
3 steps
(+)-sclareolide (6)
12
Scheme 1. Synthesis of aureol (1).
Our retrosynthesis of (+)-aureol (1) is outlined in Scheme 2.
(+)-Aureol (1) could be synthesized from olefin 11 in two known
steps.11 Olefin 11 was thought to be prepared by the cross-
coupling reaction between alkyl iodide 12 and aryl Grignard
reagent 13.13 The key intermediate 12 was planned to be
constructed by the skeletal rearrangement reaction of drimanal
iodoformate 14 via regioselective and stereoselective 1,2-H and
1,2-methyl shifts. Drimanal iodoformate 14 would be prepared
from readily available (+)-sclareolide (6) in two known steps.14
We report herein the realization of this strategy by developing a
six-step synthetic approach to (+)-aureol (1).
Scheme 3. Synthesis of (+)-aureol (1) from (+)-sclareolide (6).
OMe
MeO
BrMg
The BF3·Et2O-promoted stereospecific skeletal rearrangement
reaction of drimanal iodoformate 14 to alkyl iodide 12 as well as
the formation of by-products 16 and 21 could be understood by
the possible reaction mechanisms shown in Scheme 4.
Intermediate 17 was likely to be formed when drimanal
iodoformate 14 was treated with 200 mol % of BF3·Et2O. The
HCOO group of drimanal iodoformate 14 was activated by the
Lewis acid BF3·Et2O, and thereby left to form carbocation
intermediate 18. Since the cleavage of a C-H bond is usually
easier than that of a C-C bond, the 9-hydrogen, in this case, had a
higher migratory aptitude than the 9-alkyl group. The
configuration of C9 facilitated a 1,2-H shift on the α-face of the
carbocation intermediate 18 to form carbocation intermediate 19
(rout a, Scheme 4). Subsequently, the configuration of C10
I
OMe
10
2
2 steps
ref 11
OMe
9
6
13
1
4
8
7
(+)-aureol (1)
3
cross-coupling
reaction
5
11
12
I
skeletal
rearrangement
reaction
OCHO
2 steps
(+)-sclareolide (6)
H
14
Scheme 2. Retrosynthesis of (+)-aureol (1).

Table 1 Conditions of rearangement of compound 14
Yied (%)a
Entry
14
Conditions
12
16
21
1.0 equiv
1
2
--
--
--
13
20
7
85
73
--
BF3•Et2O (2.0 equiv), DCM, -78 C, 2 h
BF3•Et2O (2.0 equiv), DCM, -60 C, 2 h
BF3•Et2O (2.0 equiv), DCM, -40 C, 0.5 h
BF3•Et2O (2.0 equiv), DCM, -20 C, 0.5 h
BF3•Et2O (2.0 equiv), DCM, 0 C, 0.5 h
SnCl4 (2.0 equiv), DCM, -40 C, 0.5 h
AlCl3 (2.0 equiv), DCM, -40 C, 0.5 h
TiCl4 (2.0 equiv), DCM, -40 C, 0.5 h
FeCl3 (2.0 equiv), DCM, -40 C, 0.5 h
HCl (2.0 equiv), DCM, -40 C, 0.5 h
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
3
4b
63
18
9
--
5
4
--
6
--
--
57
15
--
7
8c
21
--
--
--
9
--
78
72
--
10
--
--
a Isolation yeild. b Most of the reagent degraded. c The reagent degraded.
facilitated a 1,2-methyl shift on the β-face of the carbocation
intermediate 19 to form carbocation intermediate 20, which
underwent a dehydrogenation process to afford the desirable
alkyl iodide 12 (Scheme 4). On the other hand, the carbocation
intermediates 18 and 19 underwent a dehydrogenation process to
generate by-products 16 and 21, respectively (routs b and c,
Scheme 4).
comparison to the related report in literature (6 steps versus 12
steps from (+)-sclareolide). This highly regioselective and
stereoselective skeletal rearrangement reaction, as well as a
nickel(II)-catalyzed cross-coupling reaction between an alkyl
iodide and an aryl Grignard reagent could facilitate the
preparation of sufficient quantity of this marine natural product
for biological and medical studies. Further applications of these
strategies for the synthesis of other bioactive natural products
with related skeletons are under investigation, and will be
reported in due course.
I
I
I
BF3
1
4
9
9
OCHO
OCHO
2
3
BF3•Et2O
8
10
8
a
H
H
5
b
7
H
Acknowledgments
6
H
H
H
14
17
18
This project was supported by the National Science
Foundation of China (21672046, 21272046), and the
Fundamental Research Funds for the Central Universities (HIT.
NSRIF.201701).
I
I
9
1,2-H shift
9
8
10
a
H
H
face α
H
19
18
Supplementary data
dehydrogenation
b
H
I
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.xxx.
These data include experimental procedures, characterization
data, and copies of NMR spectra (1H NMR and 13C NMR) of the
most important compounds described in this article.
face β
I
10
I
H
c
9
c
dehydrogenation
H
H
H 19
21
H
1,2-methyl shift
I
16
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Graphical Abstract
A six-step synthetic approach to marine natural product (+)-aureol
Jun-Li Wang, Hui-Jing Li, Meirong Wang, Jun-Hu Wang, Yan-Chao Wu
OH
O
I
I
OCHO
BF3•Et2O
3 steps
H
H
CH2Cl2, -40 °C
83%
H
 Domino 1,2-H and 1,2-methyl shifts
 High regioselectivity
H
(+)-aureol
 High stereoselectivity

6
Tetrahedron Letters
1. Highly regioselective and stereoselective skeletal rearrangement reaction;
2. Readily available and inexpensive starting material;
3. Step-economical synthetic approach to the marine natural product (+)-aureol.