6-Methylenebicyclo[3.2.1]oct-1-en-3-one: A Twisted Olefin as Diels–Alder Dienophile for Expedited Syntheses of Four Kaurane Diterpenoids

Article abstract of DOI:10.1002/anie.201909349

6-Methylenebicyclo[3.2.1]oct-1-en-3-one, a twisted and highly reactive enone, was prepared for the first time by elimination of its bromide precursor. Its reactions as a dienophile with several dienes in Diels–Alder reactions proceeded smoothly to provide

Full text of DOI:10.1002/anie.201909349

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Accepted Article
Title: 6-Methylenebicyclo[3.2.1]oct-1-en-3-one: A twisted olefin as
Diels-Alder dienophile for expedite syntheses of four kaurane
diterpenoids
Authors: Dawei Ma and Junjie Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201909349
Angew. Chem. 10.1002/ange.201909349
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10.1002/anie.201909349
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
0
((Catch Phrase))
6
-Methylenebicyclo[3.2.1]oct-1-en-3-one: A Twisted Olefin as Diels-Alder
Dienophile for Expedite Syntheses of Four Kaurane Diterpenoids
Junjie Wang and Dawei Ma*
Abstract: 6-Methylenebicyclo[3.2.1]oct-1-en-3-one, a twisted and
highly reactive enone, was prepared for the first time via elimination
of its bromide precursor. Reactions with several dienes as a Diels-
Alder dienophile proceeded smoothly to provide tricyclic and
tetracyclic adducts, which allowed short syntheses (10-11 steps) of
four kurane diterpenoids including 11β-hydroxy-16-kaurene, 11α-
hydroxy-16-kaurene, liangshanin G, and gesneroidin B.
inherent electrophilicity of the enone subunit and allows a facile
addition with alcohols and amines at ambient temperature to
[
14a-e]
occur.
Although the [3.3.1]-bridgehead enones have been
[
14]
systematically investigated,
the synthetic studies of the [3.2.1]-bridgehead enones. The only
little attention has been directed to
[
15]
two reports described the formation of [3.2.1]-bridgehead enone 11
[
15]
through intramolecular Wittig reaction,
and reaction with some
Michael addition donors. Recently, we found a reliable method to
prepare the [3.2.1]-bridgehead enone 1, which enabled us to study
its Diels-Alder reaction. The resulting adducts allowed us to achieve
short syntheses of several kaurane diterpenoids. Herein we wish to
report our results.
The bicyclo[3.2.l]octane system is a common subunit that exists
[
1]
in a number of sesquiterpene and diterpene families including
[
2]
[3]
[4]
platensimycin 2, liangshanin G 3 and gesneroidin B 4 (ent-
[
5]
[6]
kaurane family), leucothol A 5
grayanane family), and GA73 methyl ester 7 (gibberellane family)
and pierisformaside C 6
[
7]
(
(
Figure 1). As a consequence, great attention has been directed to
O
Me
O
the method development in constructing the bicyclo[3.2.l]octane
system required for the assembly of related natural products during
HO
HO
OH
H
[
1,8]
OH
O
the past decades.
formed in the middle or the late stage of the synthetic pathway.
We envisioned that the initial formation of a bridged bicyclic system
such as [3.2.1]-bridgehead enone 1) followed by appendage of the
requisite rings could be an attractive alternative. This strategy was
Generally, this particular bicyclic system was
O
H
[
9-11]
HN
Me Me Liangshanin G (3)
Me
H
O
Me
H
O
(
O
H
Me Me OAc
Gesneroidin B 4
O
[
12]
Me
(
)
proposed by two groups about 30 years ago, and is yet to become
a reality mainly because a mild synthetic approach to the required
[
Platensimycin (2)
H
H
[
3.2.1]-bridgehead HO
O
3.2.1]-bridgehead enone 1 is unknown.
Similar to other bridgehead intermediates such as bridgehead
enone 1
(
)
Me
Me
OC
OH
H
anions, carbocations, and radicals, the bridgehead enones are
extremely unstable.
enone 9 could be easily prepared by elimination of bromide 8
H
O
H
CO
Me
2
Me
Leucothol
A (5)
[
13]
Me
methyl ester (7) GlcO
For example, although [3.3.1]-bridgehead
Me
OH
GA73
[
14]
(Figure 2), its isolation even at low temperatures is not feasible.
Me Me Pierisformaside C 6
( )
The only direct determination of the enone 9 was disclosed by
House and Trahanovsky, who utilized a retro-Diels-Alder reaction
for preparation using flash vacuum pyrolysis and detected 9 in
Figure 1. Representative natural products incorporating
a
bicyclo[3.2.1]octane moiety.
o
[14f]
solution at -78 C.
Calculations using Allinger's MM2 program
indicates that the geometry of [3.3.1]-bridgehead enone 9 is twisted
o [13c]
Previous
work
from planarity by approximately 25 ,
which greatly enhances the
O
O
O
O
base
base
O
Br
O
[
∗]
Mr. J. Wang and Prof. Dr. D. Ma
10
P
State Key Laboratory of Bioorganic & Natural Products
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of
Sciences
8
enone
9
MeO OMe
[
3.3.1]-bridgehead
( )
[3.2.1]-bridgehead
unknown for Diels-Alder reaction
enone
(11)
known for Diels-Alder reaction
R3
R4
This work
O
R1
2
O
R
O
R1
R5
R3
R2 R6
base
345 Lingling Lu, Shanghai 200032, China
R4
E-mail: madw@sioc.ac.cn
Br
R6
R5
HO
H
12
[3.2.1]-bridgehead
enone
Me
[
∗∗] The authors are grateful to Chinese Academy of Sciences
supported by the Strategic Priority Research Program,
1
)
(
(
Me Me
O
grant XDB20020200 & QYZDJ-SSW-SLH029) and the
National Natural Science Foundation of China (grant
O
α
-OH: 11β-hydroxy-
Me
Me
O
OH
1
6-kaurene (13)
Me Me
Me Me
OAc
Gesneroidin B (4)
α
21621002 & 21831009) for their financial support.
β-OH: 11 -hydroxy-
16-kaurene (14)
Liangshanin G (3)
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.
Figure 2. Formation and reaction of some bridgehead enones.
1
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Angewandte Chemie International Edition
10.1002/anie.201909349
As shown in Scheme 1, we started our investigation by
when the suspension of 12, Cs CO and 18 in THF was heated at 80
C, the desired [4+2]-cycloadduct 19 was isolated in 10% yield as a
1:1 diasteromeric mixture, together with [2+2]-cycloadduct 20 in
2
3
o
preparing [3.2.1]-bridgehead bromide 12. According to a known
[
16]
procedure,
methyl 3-methoxybenzoate 15 was transformed to
bicyclic acid 16 through 3 steps and in 75% overall yield. Inspired
8% yield. It is interesting to observe the formation of 20 because the
[
17]
[21]
by the similar transformations, halothane was used as the bromine
donor for Barton halodecarboxylation of 16, leading to the
formation of 12 in 78% yield. Noteworthy is that 12 is stable enough
to be stored at -20 ˚C for several weeks or in solution for several
months. The next task is base-mediated elimination of 12. After
many screenings, we found that inorganic bases such as Cs CO and
thermodynamic [2+2]-cycloaddition is relatively rare.
The high
reactivity of the [3.2.1]-bridgehead enone 1 could be used to
rationalize the present results in forming both [4+2] and [2+2]
cycloadditions. In order to improve the yields, we performed the
o
reaction under neat conditions and found reaction occurred at 45 C
to give an improved yield (entry 3). Further improvements were
possible by either increasing reaction temperature (entry 4) or
switching the base to K PO (entry 5). When the mixture of 12,
2
3
K PO gave satisfactory results, while organic bases did not induce
3
4
the elimination efficiently, although organic bases performed well in
3
4
[
14]
o
the formation of the [3.3.1]-bridgehead enone 9 from 8. To our
delight, in situ formed enone 1 reacted rapidly with 2,3-dimethyl-
K PO , and 18 was gradually heated to 80 C, yield of 19 was
3 4
increased to 26% (entry 6). Considering that another major side
product is diketone 29, a dimer of the [3.2.1]-bridgehead enone 1,
and that its formation is favored under lower temperatures, we
decided to place the reaction tube to a preheated oil bath, and a
better result was obtained (entry 7). Finally, the best result was
observed by slow addition of 12 to a mixture of the diene 18 and
1
,3-butadiene to afford adduct 17a in 68% yield. The result
indicated that 1 was a very reactive dienophile because it was
known that 2,3-dimethyl-1,3-butadiene could not easily react with 2-
[
18]
cyclohexen-1-one without the assistance of a Lewis acid.
Reaction with Danishefsky’s diene also led to a single adduct 17b in
a satisfactory yield with high regioselectivity. Moreover, the
cycloaddition with furan afforded adduct 17d and its diastereomer in
a ratio of 2:1. The relative configuration of 17d was established by a
NOESY experiment and therefore we concluded that the exo-
adducts might be major products, which suggested that the Diels-
Alder reaction preferred an exo-addition due to the inherent steric
hindrance of the enone 1. Additionally, the formation of tetracyclic
products 17c was also possible as demonstrated by the Diels-Alder
reaction of 1 with a diene derived from 1-(cyclohex-1-en-1-yl)ethan-
o
K PO at 100 C over 2 h. In this case, 19 was isolated in 48% yield,
3
4
which was subjected to DIBAL-H reduction to afford separable
alcohol 21 in 47% yield, together with its C10 epimer in 45% yield.
[
a]
Table 1. Condition screening for reaction of 12 and 18.
O
Me
0
HO
Me
O
DIBAL-H
toluene
78 oC, 47%
1
10
H
H
1
-one.
Br
-
Me Me
conditions
19
Me Me
1
2
21
O
+
+
O
,
DMF
2
OMe
(COCl)
CF CHBrCl, 0 oC to rt
Me
Me
reference [12b,16]
3
O
HO
H
7
3
5% for
steps
then
S
DMAP
Br
Me
HO C
o
2
120
C
MeO C
Me Me
Me Me
Me Me
2
N
78%
15
16
12
1
8
20
21
ONa
+
diene
O
O
H
H
Cs CO , THF
2
3
Me
Me
O
o
O
50 C, 8 h
furan
O
H
H
Me
Me
O
6
8%
71% (dr = 2:1)
29
1
7a
1
17d
Yield of
Yield of
OMe
Entry
Conditions
[
b]
[b]
19 (%)
20 (%)
TBSO
o
OTBS
O
70%
1
2
3
4
5
6
Cs
Cs
Cs
Cs
2
2
2
2
CO
CO
CO
CO
3
3
3
3
, THF, 45 C
0
0
8
76%
o
, THF, 80 C
10
14
20
17
26
37
48
MeO
O
H
H
o
, neat, 45 C
7
H
o
, neat, 80 C
12
8
TBSO
o
K
K
K
3
PO
4
4
4
, neat, 45 C
OTBS
17c
o
17b
3
PO
PO
, neat, 80 C
16
23
32
[
c]
o
7
3
, neat, 80 C
[
d]
o
8
K
3
4
PO , neat, 100 C
Scheme 1. Preparation of [3.2.1]-bridgehead enone 1 and its Diels-
Alder reaction.
[a] Reaction conditions: 12 (0.5 mmol), 18 (5 mmol), base (2.5 mmol),
solvent (2.5 mL), 8 h. [b] Isolated yield. [c] Sealed tube was directly
put in a preheated oil bath. [d] Slow addition of 12 to the mixture of
diene 18/K PO at 100 ˚C over 2 h; gram scale.
To synthesize the kaurane diterpenoids using the present
3
4
strategy, we carried out the Diels-Alder reaction between 1 and
[
19]
diene 18 (Table 1) or its derivatives, which was quite challenging
because it is well-known that the formation of two all-carbon
quaternary stereocenters through an intermolecular Diels-Alder
Having achieved the rapid assembly of the core structure 21 in a
highly efficient manner, we were positioned to test its feasibility for
divergent synthesis of some kaurane diterpenoids. Considering the
structural relevance to 21, total syntheses of 11β-hydroxy-16-
kaurene (13) that was isolated from Vellozia caput-ardeae, 11α-
hydroxy-16-kaurene (14) that was isolated from the Japanese
[
19d,20]
reaction is difficult even under the assistance of Lewis acids.
Initially, we tried the conditions illustrated in Scheme 1, and found
no trace of cycloadducts were detected (Table 1, entry 1). Pleasingly,
[
22]
2
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Angewandte Chemie International Edition
10.1002/anie.201909349
[
23]
[28]
liverwort Jungermannia truncata Nees,
and liangshanin G (3)
Li/ethylenediamine,
the epoxide ring opened at the quaternary
[
3]
that was isolated from Rabdosia liangshanica, were first pursued.
As outlined in Scheme 2, oxidation of the alcohol 21 with PCC
provided ketone 19a. Since we needed to hydrogenate the C5-C6
double bond of 19a to achieve the total synthesis, the more reactive
C16-C17 double bond was first functionalized. Initially, we tried a
temporary alkene protection with 9-BBN to achieve regioselective
semihydrogenation of dienes. Unfortunately, after the successful
attachment of 9-BBN to the C16-C17 double bond and subsequent
hydrogenation of the C5-C6 double bond, we failed to cleave the
corresponding trialkylborane under various conditions such as
addition of MNP, PhCHO as the electrophile, and heating at
00 C in the presence of 1 mol% BF ·Et O.
decided to reach our goal via oxidative cleavage of the
trialkylborane intermediate. Accordingly, after regioselective
hydroboration of 19a with 9-BBN and hydrogenation of the
remained C-C double bond, NaOH and H O were added to produce
carbon center to produce alcohol 26 in 43% yield. The structure of
26 was confirmed by X-ray analysis of its derivative 27. Finally,
esterification of 26 with NaH/AcCl followed by TBS deprotection
[
29]
with TBAF provided alcohol 28. The SeO -mediated oxidation of
2
the C15 methylene of 28 accompanying with oxidation of the
resultant allyl alcohol and the C11 alcohol units proceeded smoothly
to deliver gesneroidin B (4) in 76% yield.
[
24]
HO
TBSO
TBSOTf
Me
Me
Me
11
Me
11
o
5
m
CPBA, -60
C
5
Et N, DCM
3
[
24]
[25]
16
16
Me
6
Me
Me
6
Me
24
42% (89% brsm)
17
86%
o
[26]
17
1
Alternatively, we
21
3
2
TBSO
TBSO
Li/ethylenediamine
Me
AcCl, NaH
DMAP
then TBAF
THF, 50 o
43%
5
5
6
C
Me 6 Me
OH
MeO Me
63%
25
26
2
2
HO
SeO
2
O
alcohol 22 in 73% yield. Dehydration of the alcohol 22 according to
Grieco’s procedure provided olefin 23 in 82% yield.
of the ketone 23 with LiAlH in THF at 50 C led to the formation
of two isomers, which were proven to be 11β-hydroxy-16-kaurene
O
TBHP Me
then DMP
76%
[
27]
Reduction
Me Me
OAc
Me Me
OAc
Gesneroidin B (4)
o
4
28
TBSO
(
13, 51% yield) and 11α-hydroxy-16-kaurene (14, 25% yield).
9-BBN, THF
then NaOH, 30% H O2
Me
5
2
6
OTs
Finally, epoxidation of 14 with mCPBA, accompanying with an
intramolecular ether formation, furnished liangshanin G (3) in 86%
yield.
26
Me Me
then TsCl, Et N, DMAP
OH
3
64%
27
Scheme 3. Total synthesis of gesneroidin B: TBSOTf = tert-
butyldimethylsilyl trifluoromethanesulfonate, DMAP = N,N’-dimethyl-
aminopyridine, TBAF = tetrabutylammonium fluoride, TBHP = tert-
butyl hydroperoxide, DMP = Dess-Martin periodinane, 9-BBN = 9-
borabicyclo[3.3.1]nonane, TsCl = tosyl chloride.
HO
PCC
DCM
96%
O
11
9-BBN, THF
Me
Me
Me
11
Me
then H , Pd/C
5
5
2
16
6
16 17
then NaOH, 30% H O
Me
6
Me
Me Me
2
2
1
7
73%
21
19a
O
O
2
- NO PhSeCN
11
2
Me
n-Bu)
benzene
LiAlH4
(
3
P,
Me Me
Me Me
then H O , THF
OH
THF
In conclusion, we have developed an unprecedented method to
generate the [3.2.1]-bridgehead enone 1 in situ, which relied on an
elimination of its bromide precursor with inorganic bases. This
intermediate was proven to be a highly reactive dienophile for Diels-
Alder reaction particularly with difficult dienes such as 18. This
advantage allowed the development of a convergent and concise
approach for assembling the core structure of some kaurane
diterpenoids. Based on this study, we have accomplished the first
total syntheses of 11β-hydroxy-16-kaurene (13), 11α-hydroxy-16-
kaurene (14), liangshanin G (3), and gesneroidin B (4). Only 10 or
2
2
22
82%
23
HO
H
H
OH
11
Me
Me
O
11
mCPBA
86%
+
OH
Me Me
Me Me
Me Me
Liangshanin G (3)
α
ent-11β-
hydroxy-
6-kaurene (13)
1% yield
ent-11
16-kaurene (14)
-hydroxy-
1
5
25% yield
Scheme 2. Total syntheses of ent-11β-hydroxy-16-kaurene (13), ent-
1α-hydroxy-16-kaurene (14) and liangshanin (3): PCC
pyridinium chlorochromate, DCM = dichloromethane, 9-BBN = 9-
1
G
=
1
1 steps were required to finish the total syntheses of these complex
borabicyclo[3.3.1]nonane, THF
chloroperoxybenzoic acid
= tetrahydrofuran, mCPBA = 3-
natural products from commercially available methyl 3-
methoxybenzoate. The present strategy should be applicable for
assembling more complex kaurane diterpenoids by finely tuning the
diene partners. Moreover, it is also possible to construct more
natural products containing the bicyclo[3.2.l]octane system through
other C-C bond formation reactions with highly reactive enone 1.
These investigations are actively pursued in our laboratory and will
be disclosed in due course.
The intermediate 21 could also be used for the total synthesis of
gesneroidin B (Scheme 3), an ent-kaurane diterpenoid that was
isolated from lsodon gesneroides and showed potent cytotoxic
[
4]
activity to LNCap and ZR-75-1 cell lines. Obviously, the most
challenging problem in this transformation was how to introduce a
hydroxyl group at the C6 position of 21 in a regioselective and
stereoselective manner. We envisioned that the more electron-rich
C5-C6 double bond could be regioselectively epoxidized with
mCPBA, and thus the direct epoxidation of the alcohol 21 was
pursued. It was found that the mCPBA-mediated epoxidation
occurred, but no regioselectivity could be achieved between the two
C-C double bonds. Fortunately, after TBS protection of the hydroxyl
group with TBSCl, the resulting silyl ether could undergo a
regioselective epoxidation with mCPBA at low temperature to
afford the desired epoxide 25, although the yield was moderate
owing to incomplete conversion. Upon reduction of 25 with
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Angewandte Chemie International Edition
10.1002/anie.201909349
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[
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4
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Angewandte Chemie International Edition
10.1002/anie.201909349
((Catch Phrase))
O
A highly reactive twist leads
to short and divergent total
syntheses of kaurane
diterpenoids.
Junjie Wang and Dawei Ma*
______ Page – Page
_
O
Me
Me
O
OH
6
-Methylenebicyclo[3.2.1]oct-1-
H
H
O
en-3-one: A Twisted Olefin as
Diels-Alder Dienophile for
Expedite Syntheses of Four
Kaurane Diterpenoids
H
H
Me Me
Liangshanin G
Me Me
OAc
Gesneroidin B
5
This article is protected by copyright. All rights reserved.