Total Synthesis of Atisane-Type Diterpenoids: Application of Diels-Alder Cycloadditions of Podocarpane-Type Unmasked ortho-Benzoquinones

Article abstract of DOI:10.1021/jacs.5b08958

Few examples of [4 + 2] cycloaddition with unmasked ortho-benzoquinones (UMOBs) as carbodiene have been reported in complex molecule synthesis. Herein we report that this cycloaddition with podocarpane-type UMOB was developed and applied to construct fully functionalized bicyclo[2.2.2]octanes. Based on this methodology, divergent total syntheses of atisane-type diterpenoids, including (±)-crotobarin, crotogoudin, atisane-3β,16α-diol, and 16S,17-dihydroxy-atisan-3-one, were accomplished in 14, 14, 12, and 16 steps, respectively. Key elements in these total syntheses include: (1) FeCl₃-catalyzed cationic cascade cyclization to construct podocarpane-type skeleton; (2) Mn(III)/Co(II)-catalyzed radical hydroxylation of alkene with high regio-, diastereo-, and chemoselectivities; (3) and a ketal-deprotection/lactone-opening/deprotonation/lactonization cascade. Additionally, the synthetic utility of the fully functionalized bicyclo[2.2.2]octane framework was further elucidated by applying ring distortion strategy to afford different skeleton-rearranged natural product-like compounds.

Full text of DOI:10.1021/jacs.5b08958

Subscriber access provided by UNIVERSITY OF LEEDS
Article
Total Synthesis of Atisane-type Diterpenoids: Application of Diels-Alder
Cycloadditions of Podocarpane-type Unmasked ortho-Benzoquinones
Liqiang Song, Guili Zhu, Yongjiang Liu, Bo Liu, and Song Qin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b08958 • Publication Date (Web): 04 Oct 2015
Downloaded from http://pubs.acs.org on October 5, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Total Synthesis of Atisane-type Diterpenoids: Application of
Diels-Alder Cycloadditions of Podocarpane-type Unmasked
ortho-Benzoquinones
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
† ‡
Liqiang Song,†,§ Guili Zhu,†,§ Yongjiang Liu,† Bo Liu*, , , and Song Qin†
†Key Laboratory of Green Chemistry & Technology of the Ministry of Education, College of Chemistry, Sichuan
University, Chengdu, Sichuan 610064, China
‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
Supporting Information Placeholder
ABSTRACT: Few examples of [4+2] cycloaddition with unmasked orthoꢀbenzoquinones (UMOBs) as carbodiene have been reported in
complex molecule synthesis. Herein we report that this cycloaddition with podocarpaneꢀtype UMOB was developed and applied to
construct fully functionalized bicyclo[2.2.2]octanes. Based on this methodology, divergent total syntheses of atisaneꢀtype diterpenoids,
including (±)ꢀcrotobarin, crotogoudin, atisaneꢀ3β,16αꢀdiol and 16S,17ꢀdihydroxyꢀatisanꢀ3ꢀone, were accomplished in 14, 14, 12 and 16
steps respectively. Key elements in these total syntheses include: (1) FeCl3ꢀcatalyzed cationic cascade cyclization to construct
podocarpaneꢀtype skeleton; (2) Mn(III)/Co(II)ꢀcatalyzed radical hydroxylation of alkene with high regioꢀ, diastereoꢀ and chemoꢀ
selectivities; (3) and a ketalꢀdeprotection/lactoneꢀopening/ deprotonation/lactonization cascade. Additionally, the synthetic utility of the
fully functionalized bicyclo[2.2.2]octane framework was further elucidated by applying ring distortion strategy to afford different
skeletonꢀrearranged natural productꢀlike compounds.
However, to the best of our knowledge, no one has reported
attempts to use unmasked orthoꢀbenzoquinone as carbodiene in
DielsꢀAlder cycloaddition to construct bicyclo[2.2.2]octane
architecture in natural product synthesis.
INTRODUCTION
Inspired by the biogenetic connection between tricyclic and
tetracyclic diterpenoids via a carbocation intermediate, synthetic
chemists speculate that a podocarpaneꢀtype intermediate could
chemically provide a generalizable synthetic pathway to both
tricyclic and tetracyclic diterpenoids, through dearomatization of
podocarpane and subsequent appropriate functionalization.
Although the feasibility of this tactic toward tricyclic diterpenoids
has already been demonstrated,1 the transformation from the
podocarpaneꢀtype diterpenoids to tetracyclic diterpenoids is
underdeveloped and we believe it merits additional exploration
(Scheme 1).
Besides these developed synthetic strategies, Wiesner’s group
and Baran’s group installed this bicyclo[2.2.2]octane architecture
from
a podocarpaneꢀtype intermediate, using a sequential
dearomatization/allene [2+2] cycloaddition/ ozonolysis/ acidic
rearrangement strategy.8a,f Here we describe an alternative
strategy involving
a
dearomatization/[4+2] cycloaddition
sequence, in which unmasked orthoꢀbenzoquinone is used as
carbodiene in [4+2] cycloaddition. To further demonstrate
synthetic significance of this DielsꢀAlder cycloaddition of
Notably, the atisaneꢀtype diterpenoid or its enantiomeric natural
counterpart is a special member among the tetracyclic diterpenoid
family. It is biosynthetically related to abietane, beyerane, kaurane
and other types of diterpenoids, all of which are generated in a
carbocationꢀbased mechanism catalyzed by diterpene cyclase.2
Architectures including atisane occur frequently in the
podocarpaneꢀtype unmasked orthoꢀbenzoquinone,
a
[4+2]
cycloadduct in our strategy was converted to the counterparts of
several representative ent-atisaneꢀtype and ent-3,4ꢀsecoꢀatisane
natural products, as well as other skeletonꢀrearranged
diterpenoids.
C20ꢀditerpenoid
alkaloid
family.3
And
the
unique
In 2010, crotobarin (1) and crotogoudin (2) were isolated from
Croton barorum. and Croton goudotii (Figure 1).12 They are
cytotoxic to several human cancer cell lines (IC50 0.49ꢀ2.5 ꢀM)
and effectively induce apoptosis. Both molecules belong to the
rare ent-3,4ꢀsecoꢀatisane family of diterpenoids,13 and possess a
unique tetracyclic framework with five stereocenters. The
interesting bioactivity and challenging molecular architecture of
crotobarin and crotogoudin make them attractive targets for
synthetic chemists, and these efforts have culminated in total
synthesis of ent-crotogoudin by Carreira’s group,14 as well as
several synthetic studies.15 Carreira’s total synthesis includes a
baker’s yeastꢀcatalyzed desymmetrization of meso-[2.2.2]
bicyclo[2.2.2]octane skeleton within C20ꢀditerpenoid alkaloids can
be transformed to the bicyclo[3.2.1]octane skeleton in C18ꢀ and
C19ꢀ diterpenoid alkaloids,4,5 based on Overton’s conversion of
atisane to aconane.6
Due to their structural diversity and biogenetic importance,
atisaneꢀrelated diterpenoids and diterpenoid alkaloids, as well as
their entꢀfamily members, have been the focus of numerous
synthetic studies and total syntheses.7 Four principal approaches
have been explored to construct the bicyclo[2.2.2]octane
substructure in atisaneꢀtype natural products: (1) intramolecular
nucleophilic cyclization, including aldol, double Michael or SN2
reactions;8 (2) intramolecular radical cyclization of alkyne;9 (3)
rearrangement from a kauraneꢀ or trachylobaneꢀtype skeleton;10
and (4) intraꢀ or intermolecular DielsꢀAlder cycloaddition.11
diketone,
a
rhodiumꢀcatalyzed cyclopropanation and
a
SmI2ꢀpromoted radical cyclopropaneꢀopening/annulation/
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
Scheme 1. Biosynthetic and chemically synthetic connections among tricyclic and tetracyclic diterpenoids (applicable to
entꢀfamily diterpenoids as well)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
elimination cascade to access the tetracyclic skeleton. As a result
of this total synthesis, the absolute configuration of natural
crotogoudin was determined and the compound was classified
into the entꢀatisane family. Compounds 3 and 4 were isolated and
characterized more than twenty years ago.16 They embrace typical
atisaneꢀtype skeleton with multiple stereocenters and thus were
selected as our synthetic targets to illustrate the diversity of our
synthetic strategy.
podocarpaneꢀtype diterpenoid analogue, could be prepared from
compound F via cationic cascade cyclization.
Scheme 2. Hypothesis for biogenesis of ent-3,4ꢀsecoꢀatisane
and retrosynthetic analysis.
possible
biogenetic
pathway
12
17
16
13
11
9
1
15
lactone
opening
HO
O
2
O
O
10
C3 BꢀV [O]
5 OH 8
7
O
OH
OH
3
O
O
O
HO
H
H
A
B
C
dehydration
&
lactonization
OR
O
OH
OH
OR
O
O
O
O
PGO
PGO
D
E
O
2
crotogoudin,
F
RESULTS AND DISCUSSION
Synthesis of the unmasked benzoquinone 10. Since
siteꢀselective epoxidation at the terminal trisubstituted alkene in
the polyene 5 was unsuccessful,22 we initiated the total synthesis
by coupling epoxy geranyl bromide (6)23 with functionalized
benzyl anion, generated in situ from the commercially available
compound 7 (Scheme 3). This coupling approach to compound 8
Figure 1. Structures of representative atisaneꢀtype diterpenoids.
Considering the inherent relationship between ent-atisane and
entꢀ3,4ꢀsecoꢀatisane, we formulated a hypothesis for biogenesis of
ent-3,4ꢀsecoꢀatisane by taking crotogoudin as an example
(Scheme 2). The C3 carbonyl in compound A can undergo
BaeyerꢀVilliger oxidation to give B, a possible biosynthetic
process catalyzed by BaeyerꢀVilliger monooxygenase (BVMO) in
Nature.17,18 This oxidation can be followed by lactoneꢀopening in
the presence of lactone hydrolase to afford compound C.19
Subsequent dehydration and lactonization catalyzed by enzyme
afford crotogoudin in a streamlined fashion.20 The proposed
biohypothesis can be partly evidenced by coꢀoccurrence of
compound 3 and its natural siblings, 3a and 3b, in Excoecaria
agallocha,13c and coꢀoccurrence of compounds 4 and 4a in
Euphorbia acaulis.21
was exploited as
podocarpaneꢀtype diterpenoids. Then
a
straightforward entry to precursor of
biomimetic, Lewis
a
acidꢀcatalyzed cascade polycyclization of epoxy substrate 8 was
developed.23b,24 Extensive screening identified cheap and
environmentꢀfriendly iron (III) chloride as the optimal catalyst,
affording compound 9 as the sole isolable diastereomer in 55%
yield.8a This cascade reaction generated two new stereogenic
centers in a substrateꢀcontrolled fashion and formed two CꢀC
bonds simultaneously. While oxidation of 9 with CAN gave 10 in
only 43% yield, using Ce(SO4)2•4H2O increased the yield to 81%.
DielsꢀAlder cycloaddition of the unmasked benzoquinone 10.
Masked ortho-benzoquinone (MOB) is widely used in
intermolecular and intramolecular DielsꢀAlder reaction in organic
synthesis including natural product synthesis.25 Recently,
Fukuyama and Yokoshima’s group successfully realized
intermolecular DielsꢀAlder cycloaddition between a complex
MOB and ethylene in total synthesis of lepenine, a diterpenoid
alkaloid containing bicyclo[2.2.2]octane architecture.11e To our
surprise, reacting traditional MOB surrogates (10ꢀA and 10ꢀB) of
Retrosynthetic analysis suggested that we could obtain
compound A from compound D via multiꢀstep functional group
transformations. Oxidative dearomatization of compound E would
give orthoꢀbenzoquinone, which could undergo [4+2]
cycloaddition to yield compound D. Compound E,
a
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
compound 10 in an atmosphere of ethylene (7 MPa) did not
10 to the corresponding 1,2ꢀphenꢀdiol. When functionalized
1
2
3
4
5
6
7
8
terminal alkynes were used, the cycloadducts formed in
satisfactory selectivities and yields (Table 1, entries 1ꢀ3). In all
three major products, the bulky substituents (TMS, CH2OR) were
positioned outside the polycyclic skeleton. However, while no
selectivity was observed in the cycloaddition between structurally
simple reactants, i.e. 3,5ꢀdiꢀtertꢀbutylꢀoꢀbenzoquinone and
phenylacetylene,27a aromatic rings were directed inward to ring B
in the major cycloadduct when phenylacetylene and its derivatives
were reacted as dienophile with 10 (entries 4ꢀ6).
deliver any detectable [4+2] cycloadduct even at 70 ℃ for 48
hours. Application of trimethylsilylacetylene (20 eq.) instead of
ethylene in thermal conditions did not afford the desired
cycloadducts either. We then resorted to DielsꢀAlder
cycloaddition of 10ꢀA and 10ꢀB with trimethylsilylacetylene (20
eq.) in the presence of different Lewis acids, including AlCl3,
MeAlCl2, Et2AlCl, ZnCl2, Bi(OTf)3 and Fe(OTf)3. However, no
cycloadducts could be detected while decomposition of 10ꢀA and
10ꢀB was observed. Actually, the reactivity discrepancy between
our MOBs (10ꢀA and 10ꢀB) and Fukuyama and Yokoshima’s
MOB could be ascribed to the difference among their molecular
conformation, since the polycyclic skeleton of Fukuyama and
Yokoshima’s MOB substrate is distinctly distorted by an
additional nitrogenꢀcontaining heterocycle, compared to those of
our MOBs.11e
9
Scheme 3. Synthesis of 10.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Our failure in MOB cycloaddition prompted us to fall back on
an unmasked orthoꢀbenzoquinone (UMOB) DielsꢀAlder
methodology. Theoretically and experimentally, UMOB shows
versatile reactivity, acting as
a carbodiene, heterodiene,
dienophile and heteroꢀdienophile.26 Moreover, the cycloadducts
from UMOB are labile to lightꢀdriven decarbonylation and
aromatization.27a,b Thus there are only sporadic reports on
DielsꢀAlder cycloaddition involving UMOB and alkyne or
alkene.27 It may help explain why, to the best of our knowledge,
DielsꢀAlder cycloaddition with UMOB has not been reported in
natural product synthesis yet. Accordingly, applying such an
UMOB as compound 10 solely as carbodiene presents a challenge
for fulfilling requirements for chemoꢀ, regioꢀ, diastereoꢀ and
exo/endo selectivities. Herein we endeavor to demonstrate the
realizability and synthetic applicability of such type of
intermolecular DielsꢀAlder reactions.
Scrupulous screening of reaction conditions led us to
intermolecular DielsꢀAlder cycloaddition involving 10 and
different alkynes and alkenes (Table 1). Notably, these reactions
were performed in the presence of MnO2 to prevent reduction of
Table 1: Substrate scope of the DielsꢀAlder cyclization.[a]
entry
dienophile
major product
M:
yield[c]
entry
dienophile
major product
M:
Σisom
yield
79%
96%
Σisom.[b]
1
7:1
5:1
78%
3:1
3:1
7
2[d]
97%
8[d]
3
3:1
3:1
>99%
9[e]
6:1
3:1
>99%
99%
4
96%
10
Ar = Ph
Ar = Ph
Ar = Ph, 11d
Ar = Ph, 11j
5
6
Ar = 4ꢀMeOC6H4
Ar = 4ꢀFC6H4
Ar = 4ꢀMeOC6H4, 11e
Ar = 4ꢀFC6H4, 11f
3:1
3:1
96%
98%
11
12
Ar = 4ꢀMeOC6H4
Ar = 4ꢀFC6H4
Ar = 4ꢀMeOC6H4, 11k
Ar = 4ꢀFC6H4, 11l
3:1
2:1
94%
99%
[a] Unless otherwise stated, reactions were performed in dichloromethane in sealed tubes wrapped in aluminum foil at 140 ℃ for 2ꢀ6 hours with 10 (1 eq.),
dienophile (20 eq.) and freshly activated MnO2 (4 eq.). [b] M: Σisom. = major isomer : sum of minor isomers. These ratios were determined by 1H NMR analysis. [c]
Isolated yield combining all isomers. [d] These reactions were performed at 150 ℃. [e] KF (2.5 eq.), 18ꢀcrownꢀ6 (2.5 eq.) and 10 (1 eq.) were dissolved in THF at
0 ℃; then dienophile (1.2 eq.) was added dropwise at 0 ℃, and the reaction was stirred for 3h before quenching.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
Reacting 10 with 4ꢀtrimethylsilylꢀ3ꢀbutynꢀ2ꢀone, an
βꢀantiꢀTS. This makes αꢀfacial selectivity favorable with alkyne as
the dienophile.28a Moreover, theoretical calculation reveals the
different regioselectivities between entry 1 and entry 4 could be
ascribed to different HOMOꢀLUMO interactions between diene
and dienophile in different transition states. Greater
HOMOꢀLUMO interaction usually leads to lower Gibbs free
energy in transition state and thus benefits formation of the major
cycloadduct. For the cycloadditions in both entry 1 and entry 4,
NBO analysis implies the migration of electron from the HOMOs
of alkynes to the LUMO of 10 in transition states (Figure 2A).
The more chargeꢀtransfer in antiꢀTSs than that in synꢀTSs (0.07 e
vs. 0.06 e) suggests that antiꢀTSs possess greater HOMOꢀLUMO
interaction, which satisfactorily accounts for the regioselectivity in
entry 1. However, for the cycloaddition in entry 4, the synꢀTSs
possess greater HOMOꢀLUMO interaction than the antiꢀTSs
(chargeꢀtransfer: 0.07 e vs. 0.06 e), which affords the opposite
regioselectivity to that in entry 1 (Figure 2B).28a
1
2
3
4
5
6
7
8
electronꢀdeficient internal alkyne, afforded the corresponding
diastereomers in the ratio of 3:1 in 79% combined yield (entry 7).
Steric hindrance from the TMS group might cause it to project
outward in the major cycloadduct (entry 1 vs entry 7). Using a
symmetric internal alkyne showed excellent reactivity and
medium diastereoselectivity (entry 8). The highly reactive
benzyne, generated in situ, delivered the desired cycloadduct at
0 ℃ (entry 9). Interestingly, αꢀfacial selectivity predominated in
cycloaddition reactions with alkyne as dienophile (entries 1ꢀ9).
However, βꢀfacial selectivity was observed with aromatically
substituted terminal alkene as dienophile, and the corresponding
endoꢀtype cycloadducts were found to be predominant (entries
10ꢀ12).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A. Four typical transition states for entry 1
As for the cycloaddition in entry 10, the most energyꢀfavored
βꢀsyn-endoꢀTS is featured by the unique geometry that CꢀH bond
at C5 of compound 10 is vertical to the phenyl ring of styrene with
the distance of ca 2.5 Å (Figure 2C), suggesting a strong σꢀπ
interaction between two reactants in this transition state. This
CꢀHꢁꢁꢁπ interaction therefore stabilizes βꢀsyn-endoꢀTS and leads to
11j as the major product.28bꢀ28e
ꢀsynꢀTS (11.4 kJ/mol)
ꢀantiꢀTS (0.0 kJ/mol)
Attempts to react 10 with alkenes other than styrene derivatives,
including ethylene even under high pressure, failed to afford
significant amounts of DielsꢀAlder cycloadducts,11e which is
different from the reactivity with structurally simple UMOB as
diene.27e,f The relative stereochemistry of major cycloadducts in
Table 1 was confirmed by Xꢀray crystallography or NOESY
experiments after purifying them from isomeric mixtures by
recrystallization and/or chemical derivation. Although the
products decompose upon standing in sunlight, they are stable
under thermal reaction condition in the dark and in the purification
process. Undoubtedly, our developed cycloaddition with
podocarpaneꢀtype UMOB will further extend applicable scope of
DielsꢀAlder chemistry in natural product synthesis.29
ꢀsynꢀTS (18.7 kJ/mol)
ꢀantiꢀTS (10.8 kJ/mol)
B. Selected transition states for entry 4
Synthesis of rac-crotobarin. With mixture of 11a and its
inseparable diastereomers in hand, we selectively protected the
less hindered ketone moiety in 11a as a ketal to enhance its
stability and thereby to facilitate subsequent transformations.
Gramꢀscale synthesis of the ketal of 11a from compound 9 was
carried out over three steps in 42% overall yield, with just one
purification operation (Scheme 4). Desilylation with TBAF
afforded compound 13 in 90% yield. Diastereoselective reduction
of the carbonyl group in 13 with LiAlH4 afforded compound 14
with a βꢀoriented hydroxyl group. This diastereoselectivity was
achieved by reducing 13 at ꢀ78 ℃ firstly and then increasing
reaction temperature. Reduction of the ketone in 13 is necessary
because otherwise the skeleton rearrangement in the subsequent
Mn (III)ꢀmediated Mukaiyama hydroxylation would be
unavoidable in the presence of C15 carbonyl (see also scheme 7A).
Then C3ꢀhydroxyl was selectively oxidized to the ketone 15 at
low temperature with DessꢀMartin periodinane.
ꢀantiꢀTS (9.3 kJ/mol)
ꢀsynꢀTS (0.0 kJ/mol)
C. Optimal transition state for entry 10
ꢀsynꢀendoꢀTS (0.0 kJ/mol)
Figure 2. Selected transition states (optimized by DFT calculation)
for cycloadditions in entries 1, 4 and 10. Bond lengths are in
angstroms, and relative energies are in parentheses. Syn/anti
denotes different position of the substituent on dienophiles with
respect to ring B of 10.
In the condition developed by Mukaiyama’s group with
Mn(dpm)3,30 silane and oxygen, 15 was firstly converted into the
intermediate 16 at 0 ℃ by introducing a tertiary alcohol at the
To probe insightful information on the unexpected
regioselectivities in entries 4ꢀ6 and facialꢀselectivities in entries
10ꢀ12, DFT calculation on three typical DielsꢀAlder reactions
(entries 1, 4 and 10) was executed by employing M06ꢀ2X method
combined with the 6ꢀ31G(d,p) basis set. Calculation showes that
the major cycloadducts in these three entries are the most
energyꢀfavored among all four (entries 1 and 4) or eight (entry 10)
possible isomers.28a
trisubstituted alkene from the less hindered
β face. Increasing the
temperature from 0 ℃ to room temperature resulted in formation
of compound 17 in regioꢀ and diastereoꢀ selective style, through
the second radical hydroxylation on the disubstituted alkene (red
color in 16). The relative configuration of 17 was confirmed by
Xꢀray crystallography. The reactive priority of the trisubstituted
alkene over the disubstituted alkene in 15 can be ascribed to the
kinetic priority of formation of the more stable tertiary radical
For entry 1, compared to the stable conformation of 10 in
ground state, singleꢀpoint energy calculation indicates less
geometric distortion of the diene motif in αꢀantiꢀTS than that in
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
Scheme 4. Total synthesis of rac-crotobarin.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
leading to 16. Application of Co(acac)2 delivered lower yield than
Scheme 5. Total synthesis of rac-crotogoudin.
that of Mn(dpm)3 (28% vs. 43%), while using Fe(acac)3 afforded
neither 16 nor 17. Chemoselective protection with acetic
anhydride yielded compound 18 in the presence of pyridine,
although employing triethylamine as the base afforded inferior
result with only 22% yield of 18. The ketone in 18 was
subsequently transformed into a lactone through BaeyerꢀVilliger
rearrangement. To our delight, treating 19 under acidic condition
cat. Co(acac)2
PhSiH3, O2
1. N2H4 H2O, H2O2
MeOH, rt
OMe
OMe
OH
H
OMe
OMe
HO
HO
O
iꢀPrOH, 0 oC to rt
2. LiAlH4, THF, ꢀ78 o
99% (2 steps)
C
21
13
65%
OH
3
OH
H
OMe
OMe
HO
triggered
a cascade reaction, involving ketal deprotection,
lactoneꢀopening, isopropene formation and final lactonization, to
afford 20. The feasibility of transformations from 18 to 20
indicates the possibility of the biohypothesis for formation of
ent-3,4ꢀsecoꢀatisane (Scheme 2). Finally, subjection of compound
20 to DessꢀMartin periodinane, followed by selective Wittig
olefination on the less hindered C16 carbonyl in the resultant
22
ORTEP for 22 with interꢀ
molecular H bond
DessꢀMartin [O], NaHCO3
DCM, ꢀ30 oC, 77% (brsm)
O
1. DessꢀMartin [O]
NaHCO3
O
OH
DCM, ꢀ20 o
C
O
1. mꢀCPBA, NaHCO3
OH
OH
H
OMe
OMe
DCM, rt, 94%
O
2. Ph3PCH3Br, nꢀBuLi
ꢀ78 to ꢀ60 o
68% (2 steps)
2. pꢀTsOH H2O, PhH, rt
75%
diketone
intermediate,
afforded
racemic
crotobarin.
C
23
24
Characterization data of our synthetic racꢀ1 were in good
agreement with those of natural 112. Thus we accomplished the
first total synthesis of crotobarin in racemic form.
O
O
O
O
O
Synthesis of rac-crotogoudin. Enlightened by the above
successful total synthesis of racꢀcrotobarin, we turned our
attention to total synthesis of racꢀcrotogoudin. Thus the less
hindered disubstituted alkene of compound 13 was selectively
saturated under diimide reduction condition, and the following
diastereoselective reduction of ketone afforded compound 21
(Scheme 5). Regioselective radical hydration in the presence of
cobalt (II) catalyst, phenyl silane and oxygen, gave compound 22
as the sole isolable diastereomer (Scheme 5),31 while employing
Mn(dpm)3 or Fe(acac)3 as the catalyst just resulted in complex
mixture. The relative stereochemistry of 22 was confirmed by
Xꢀray crystallography. Chemoselective DessꢀMartin oxidation of
the C3ꢀhydroxyl in 22 afforded compound 23 in 77% yield based
on the recovery of starting material. The same biomimetic
strategy in the conversion from 18 to 20, involving
BaeyerꢀVilliger rearrangement and acidꢀcatalyzed cascade,
delivered compound 24. It was smoothly converted to
racꢀcrotogoudin through oxidation of secondary alcohol and final
selective Wittig reaction. Characterization data of our synthetic
racꢀ2 were in good agreement with those of natural 2 and
Carreira’s entꢀ2.12,14
O
2)
racꢀcrotogoudin (
Synthesis of rac- atisaneꢀ3β, 16αꢀdiol and 16S,
17ꢀdihydroxyꢀatisanꢀ3ꢀone. On the basis of total syntheses of
these two 3,4ꢀseco atisane diterpenoids, we turned our attention to
total syntheses of representative atisaneꢀtype diterpenoids, i.e. 3
and 4. Deprotection of the ketal moiety of 21 and SmI2ꢀmediated
dehydroxylation delivered the ketone 25. Nucleophilic addition
with methyl lithium produced two inseparable diastereomers, 26
and 27. Then diastereoselective hydrogenation of the double bond
with palladium on activated carbon afforded racemic
atisaneꢀ3β,16αꢀdiol (3) in 53% yield and compound 28 in 46%
yield over two steps. At this stage, racꢀ3 and 28 were separable on
silica column. The molecular structure of racꢀ3 was confirmed by
Xꢀray crystallography. Characterization data of our synthetic
sample were in agreement with those of natural 3 except one of
13C NMR signals, indicating that it be inadvertently misreported
in the isolation literature.16a,b
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
Alternatively, compound 25 was subjected to diastereoselective
collective synthesis of atisaneꢀtype diterpenoids for screening
bioactive lead compounds.32 In addition, we show here that these
atisaneꢀtype intermediates can also undergo rearrangement to
produce other types of diterpenoids with potentially useful
skeleton by applying a ringꢀdistortion strategy (Scheme 7).33
1
2
3
4
5
6
7
8
hydrogenation and Wittig olefination to afford compound 29 in
64% yield over two steps. Oxidation of the secondary hydroxyl to
ketone and dihydroxylation of the gemꢀdisubstituted alkene
afforded our desired target molecule 4, accompanied with the
inseparable diastereomer 4′ at nearly 1:1 ratio. Acetylation of the
primary alcohols in the diastereomeric mixture facilitated column
separation of these two resultant acetates. Hydrolysis of the
desired acetate resulted in smooth formation of racemic 16S,
17ꢀdihydroxyꢀatisanꢀ3ꢀone (4), whose characterization data were
in good accordance with those of natural 4.13f,16c
For example, under Yamada’s condition,31 a tertiary radical
was generated from compound 30, which was prepared from
compound 13 through diimide reduction of the disubstituted
alkene.34 It then induced transfer of the adjacent carbonyl to form
a radical bicyclo[3.2.1]octane through a cyclopropyl intermediate.
Trapping the radical in the presence of oxygen and silane afforded
racemic compound 31 in 67% yield, which embraces the
substructure of scopadulaneꢀtype diterpenoids (Scheme 7A).
Scopadulaneꢀtype diterpenoids feature complex tetracyclic
architecture and interesting bioactivities. Scopadulciol and
thyrsiflorin A are representative molecules in this family.35
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Syntheses of rac- atisaneꢀ3β,16αꢀdiol and 16S,
17ꢀdihydroxyꢀatisanꢀ3ꢀone.
Treating compound 11a with boron trifluoride activated either
carbonyl group and thus initiated transfer of the alkene attached to
trimethylsilyl in two reaction pathways, i.e. path a and path b.
These two concomitant rearrangements led to compounds 32 and
33 in 57% and 38% yield respectively, with functionalized
bicyclo[3.2.1]octane skeletons different from that of compound 31
(Scheme 7B). Notably, architecture of compounds 32 and 33
matchs the highlighted substructure with red color in andilesin A,
and thus can be regarded as potential synthetic precursors to
andilesin A and its natural siblings. These natural products belong
to fungal meroterpenoids isolated from Aspergillus sp.36
Alternatively, treating alcohol 34 with Tf2O initiated
WagnerꢀMeerweinꢀtype 1,2ꢀshift of the double bond with TMS to
generate a tertiary allylic carbocation (Scheme 7C). Compound 34
could be facilely prepared from compound 11a through selective
ketal protection of the C16 ketone, silyl protection of the C3
hydroxyl and diastereoselective DIBALꢀH reduction of the C15
ketone.34 Its deprotonation afforded compound 35 with
functionalized bicyclo[3.2.1]octane skeleton,
a
molecular
structure different from those of compounds 31ꢀ33.
Ring distortion strategy. Based on the resultant fully
functionalized bicyclo[2.2.2]octane scaffold from complex
UMOB, our DielsꢀAlder methodology facilitates divergent and
Scheme 7. Ring distortion strategy to convert functionalized bicyclo[2.2.2]octenes to natural productꢀlike compounds
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
(3) (a) Wang, F.ꢀP.; Liang X.ꢀT. in The Alkaloids: Chemistry and
CONCLUSION
Biology, Vol. 59 (Ed.: G. A. Cordell), Elservier Science, New York,
2002, pp. 1ꢀ280. (b) Wang, F.ꢀP.; Chen, Q.ꢀH.; Liu, X.ꢀY. Nat. Prod.
Rep. 2010, 27, 529.
(4) Wang, F.ꢀP.; Chen, Q.ꢀH.; Liang X.ꢀT. in The Alkaloids:
Chemistry and Biology, Vol. 67 (Ed.: G. A. Cordell), Elservier
Science, New York, 2009, pp. 1ꢀ78.
(5) Wang, F.ꢀP.; Chen Q.ꢀH. in The Alkaloids: Chemistry and
Biology, Vol. 69 (Ed.: G. A. Cordell), Elservier Science, New York,
2010, pp. 1ꢀ577.
(6) (a) Johnston, J. P.; Overton, K. H. J. Chem. Soc. Perkin Trans.
1, 1972, 1490. (b) Johnston, J. P.; Overton, K. H. J. Chem. Soc.
Chem. Commun., 1969, 329.
1
2
3
4
5
6
7
8
In conclusion, we have developed an intermolecular DielsꢀAlder
reaction involving unmasked orthoꢀbenzoquinone containing a
complex tricycle to efficiently construct fully functionalized
bicyclo[2.2.2]octanes. The use of this methodology was
demonstrated by converting the bicyclo[2.2.2]octane
intermediate to different complex molecules, such as
atisaneꢀtype diterpenoids (1ꢀ4), scopadulaneꢀtype diterpenoid
core (31), and other natural productꢀlike compounds (32, 33 and
35). Besides the DielsꢀAlder cycloaddition with UMOB, key
elements in these total syntheses include: (1) FeCl3ꢀcatalyzed
cationic cascade cyclization to construct podocarpaneꢀtype
skeleton; (2) Mn(III)/Co(II)ꢀcatalyzed radical hydroxylation of
alkene with high chemoꢀ, regioꢀ, and diastereoꢀ selectivities; (3)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) For seminal reviews, see: (a) Zhu, G.; Liu, R.; Liu, B.
Synthesis 2015, 47, 2691. (b) Hamlin, A. M.; Kisunzu, J. K.;
Sarpong, R. Org. Biomol. Chem. 2014, 12, 1846. (c) Cherney, C. C.;
Baran, P. S. Isr. J. Chem. 2011, 51, 391.
and
a
ketalꢀdeprotection/lactoneꢀopenning/deprotonation/
(8) (a) Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem.
Int. Ed. 2013, 52, 9019. (b) Hamin, A. M.; Cortez, F. J.; Lapointe, D.;
Sarpong, R. Angew. Chem. Int. Ed. 2013, 52, 4854. (c) Hamlin, A.
M.; Lapointe, D.; Owens, K.; Sarpong, R. J. Org. Chem. 2014, 79,
6783. (d) Ihara, M.; Suzuki, M.; Fukumoto, K.; Kametani, T.;
Kabuto, C. J. Am. Chem. Soc. 1988, 110, 1963. (e) Ihara, M.; Suzuki,
M.; Fukumoto, K.; Kametani, T.; Kabuto, C. J. Am. Chem. Soc. 1990,
112, 1164. (f) Guthrie, R. W.; Valenta, Z.; Wiesner, K. Tetrahedron
Lett. 1966, 7, 4645. (g) Nagata, W.; Sugasawa, T.; Narisada, M.;
Wakabayashi, T.; Hayase, Y. J. Am. Chem. Soc. 1963, 85, 2342.
(9) (a) Muratake, H.; Natsume, M.; Nakai, H. Tetrahedron 2006,
62, 7093. (b) Toyota, M.; Wada, T.; Ihara, M. Org. Lett. 1999, 1,
1627.
(10) (a) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am.
Chem. Soc. 1998, 120, 4916. (b) Toyota, M.; Wada, T.; Ihara, M. J.
Org. Chem. 2000, 65, 4565. (c) Toyota, M.; Asano, T.; Ihara, M. Org.
Lett. 2005, 7, 3929. (d) Abad, A.; Agulló, C.; Cuñat, A. C.; Navarro,
I. Tetrahedron Lett. 2001, 42, 8965. (e) Abad, A.; Agulló, C.; Cuñat,
A. C.; Navarro, I.; de Arellano, M. C. R. Synlett 2001, 349. (f) Abad,
A.; Agulló, C.; Cuñat, A. C.; de Alfonso Marzal, I.; Navarro, I.; Gris,
A. Tetrahedron 2006, 62, 3266. (g) Abad, A.; Agulló, C.; Cuñat, A.
C.; de Alfonso Marzal, I.; Gris, A.; Navarro, I.; de Arellano, C. R.
Tetrahedron 2007, 63, 1664. (h) Ungur, N.; Kulciţki, V.; Chetraru,
O.; Grinco, M.; Vlad, P. F. Helv. Chim. Acta 2013, 96, 864. (i)
Cherney, E. C.; Lopchuk, J. M.; Green, J. C.; Baran, P. S. J. Am.
Chem. Soc. 2014, 136, 12592.
(11) (a) Peese, K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128,
8734. (b) Peese, K. M.; Gin, D. Y. Chem. Eur. J. 2008, 14, 1654. (c)
Liu, X.ꢀY.; Cheng, H.; Li, X.ꢀH.; Chen, Q.ꢀH.; Xu, L.; Wang, F.ꢀP.
Org. Biomol. Chem. 2012, 10, 1411. (d) Singh, V.; Bhalerao, P.;
Sahu, B. C.; Mobin, S. M. Tetrahedron 2013, 69, 137. (e) Nishiyama,
Y.; Hanꢀya, Y.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc.
2014, 136, 6598.
(12) Rakotonandrasana, O. L.; Raharinjato, F. H.; Rajaonarivelo,
M.; Dumontet, V.; Martin, M.ꢀT.; Bignon, J.; Rasoanaivo, P. J. Nat.
Prod. 2010, 73, 1730.
(13) (a) Liu, J.ꢀH.; Latif, A.; Ali, M.; Zhang, G.ꢀP.; Xiang, W.ꢀJ.;
Ma, L.; Arfan, M.; Hu, L.ꢀH. Phytochemistry 2012, 75, 153. (b) Li
Y.; Liu J.; Yu S.; Proksch P.; Gu J.; Lin W. Phytochemistry 2010, 71,
2124. (c)Wang, Z. C.; Lin, Y. M.; Feng, D. Q.; Ke, C. H.; Lin, P.;
Yan, C. L.; Chen, J. D. Molecules 2009, 14, 414. (d) Wang, J.ꢀD.; Li,
Z.ꢀY.; Xiang, W.ꢀS.; Guo, Y.ꢀW. Helv. Chim. Acta 2006, 89, 1367.
(e) Wang, J.ꢀD.; Li, Z.ꢀY.; Guo, Y.ꢀW. Helv. Chim. Acta 2005, 88,
979. (f) Lal, A. R.; Cambie, R. C.; Rutledge, P. S.; Woodgate, P. D.
Phytochemistry 1990, 29, 1925.
lactonization cascade in total syntheses of racꢀcrotobarin and
crotogoudin. In principle, a general synthetic pathway can be
constructed from podocarpaneꢀtype diterpenoids (such as 9) to
different tricyclic and tetracyclic diterpenoids, and potentially to
diterpenoid alkaloids. In this regard, our work shows that after
generating the first stereogenic center in compound 6, the
remaining centers can be generated in a substrateꢀcontrolled
fashion. As a result, both atisaneꢀtype and entꢀatisaneꢀtype
diterpenoids can be synthesized smoothly when either antipode
of enantiopure 6 is used.23 Moreover, application of ring
distortion strategy (Scheme 7) into the total synthesis of other
terpenoids is under development in our laboratory.
ASSOCIATED CONTENT
Supporting Information
Experimental details, characterization data, 1H NMR and 13C
NMR spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*chembliu@scu.edu.cn
Author Contributions
§L. Song and G. Zhu contributed equally to this paper.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We acknowledge financial support from the NSFC (21290180,
21322205, 21321061). We also thank the comprehensive
training platform of the Specialized Laboratory in the College of
Chemistry at Sichuan University for compound testing.
REFERENCES
(1) For examples, see: (a) Zhou, B.; Li, X.; Tang, H.; Miao, Z.;
Feng, H.; Li, Y. Org. Biomol. Chem. 2011, 9, 3176. (b) Cambie, R.
C.; Rutledge, P. S.; Stevenson, R. J.; Woodgate, P. D. J. Organomet.
Chem. 1995, 486, 199. (c) Matsumoto, T.; Imai, S.; Mimura, K.;
Aiba, K. Chem. Lett. 1988, 17, 1399.
(2) For cyclaseꢀcatalyzed diterpenoid biosynthesis, see: (a)
Dickschat, J. S. Nat. Prod. Rep. 2011, 28, 1917. (b) Dewick, P. M.
Nat. Prod. Rep. 2002, 19, 181. (c) Gao, W.; Hillwig, M. L.; Huang,
L.; Cui, G.; Wang, X.; Kong, J.; Yang, B.; Peters, R. J. Org. Lett.
2009, 11, 5170. for computational chemistry of carbocation
intermediates, see: (d) Tantillo, D. J. Nat. Prod. Rep. 2011, 28, 1035.
(e) Tantillo, D. J. Chem. Soc. Rev. 2010, 39, 2847. (f) Hong, Y. J.;
Tantillo, D. J. Nat. Chem. 2014, 6, 104. (g) Hong, Y. J.; Tantillo, D.
J. Chem. Sci., 2013, 4, 2512; (h) Hong, Y. J.; Tantillo, D. J. J. Am.
Chem. Soc. 2010, 132, 5375.
(14) Breitler, S.; Carreira, E. M. Angew. Chem. Int. Ed. 2013, 52,
11168.
(15) (a) Guo, Y.; Liu, Q.; Jia, Y. Chem. Commun. 2015, 51, 889.
(b) Behera, T. K.; Singh, V. Tetrahedron 2014, 70, 7983. (c)
Ushakov, D. B.; Maier, M. E. Synlett 2013, 24, 705.
(16) For isolation and characterization of 3, see: (a) Schmitz, F. J.;
Vanderah, D. J.; Hollenbeak, K. H.; Enwall, C. E. L.; Gopichand, Y.
J. Org. Chem. 1983, 48, 3941. (b) Cafieri, F.; Fattorusso, E.;
Mahajnah, Y.; Mangoni, A. Magn. Reson. Chem. 1995, 33, 286. For
isolation and characterization of 4, see: (c) Satti, N. K.; Suri, O. P.;
Dhar, K. L. J. Nat. Prod. 1987, 50, 790.
(17) For elegant reviews on BVMO, see: (a) Leisch, H.; Morley,
K.; Lau, P. C. K. Chem. Rev. 2011, 111, 4165. (b) Alphand, V.;
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
Wohlgemuth, R. Curr. Org. Chem. 2010, 14, 1928. For
V.; Kumar, S. Synlett 1996, 1143. (g) Liao, C. C.; Lin, H. S. J. Chin.
BaeyerꢀVilliger oxidation of monoterpenoid in the presence of
BVMO, see: (c) Wang, Y.; Lim, L.; Madilao, L.; Lah, L.; Bohlmann,
J.; Breuil, C. Appl. Environ. Microbiol. 2014, 80, 4566. (d)
Cernuchova, P.; Mihovilovic, M. D. Org. Biomol. Chem. 2007, 5,
1715. (e) Van der Werf, M. J. Biochem. J. 2000, 347, 693. For
BaeyerꢀVilliger oxidation of meroterpenoid in the presence of
BVMOs, see: (f) Matsuda, Y.; Wakimoto, T.; Mori, T.; Awakawa, T.;
Abe, I. J. Am. Chem. Soc. 2014, 136, 15326. (g) Matsuda, Y.;
Awakawa, T.; Wakimoto, T.; Abe, I. J. Am. Chem. Soc. 2013, 135,
10962.
(18) For insightful study on catalytic mechanism of BVMO, see:
Yachnin, B. J.; Sprules, T.; McEvoy, M. B.; Lau, P. C. K.; Berghuis,
A. M. J. Am. Chem. Soc. 2012, 134, 7788.
(19) (a) Van der VlugtꢀBergmans, C. J. B.; Van der Werf, M. J.
Appl. Environ. Microbiol. 2001, 67, 733. (b) Van der Werf, M. J.;
Boot, A. M. Microbiology 2000, 146, 1129.
(20) (a) Liu, C.; Tagami, K.; Minami, A.; Matsumoto, T.; Frisvad,
J. C.; Suzuki, H.; Ishikawa, J.; Gomi, K.; Oikawa, H. Angew. Chem.
Int. Ed. 2015, 54, 5748. (b) Citron, C. A.; Brock, N. L.; Tudzynsk,
B.; Dickschat, J. S. Chem. Commun. 2014, 50, 5224.
(21) Suri, O. P.; Satti, N. K.; Suri, K. A.; Dhar, K. L.; Kachroo, P.
L.; Kawasaki, T.; Miyahara, K.; Tsunehiro, T.; Fumiko, Y. J. Nat.
Prod. 1990, 53, 470.
(22) Lichter, P. A.; Milller, S. J. Nat. Chem. 2012, 4, 990.
(23) (a) Racemic 6 was prepared in two steps from geraniol and
used as a crude compound without purification; see Supporting
Information for details. For recent accounts of preparing enantiopure
6, see: (b) Xu, S.; Gu, J.; Li, H.; Ma, D.; Xie, X.; She, X. Org. Lett.
2014, 16, 1996. c) Topczewski, J. J.; Kodet, J. G. J. Org. Chem.
2011, 76, 909.
(24) (a) Yu, L.ꢀG.; Ni, T.ꢀF.; Gao, W.; He, Y.; Wang, Y.ꢀY.; Cui,
H.ꢀW.; Yang, C.ꢀG.; Qiu, W.ꢀW. Eur. J. Med. Chem. 2015, 90, 10.
(b) Onyango, E. O.; Fu, L.; Gribble, G. W. Org. Lett. 2014, 16, 322.
(c) Kim, M. B.; Shaw, J. T. Org. Lett. 2010, 12, 3324. (d) Zhao, J.ꢀF.;
Zhao, Y.ꢀJ.; Loh, T.ꢀP. Chem. Commun. 2008, 1353.
Chem. Soc. 1986, 33, 73.
1
2
3
4
5
6
7
8
(28) (a) See Supporting Information for details on DFT
calculation. (b) Hong, Y. J.; Tantillo, D. J. Chem. Sci. 2013, 4, 2512.
(c) Shibasaki, K.; Fujii, A.; Mikami, N.; Tsuzuki, S. J. Phys. Chem.
A 2006, 110, 4397. (d) Ugozzoli, F.; Arduini, A.; Massera, C.;
Pochini, A.; Secchi, A. New J. Chem. 2002, 26, 1718. (e) Mo, Y.;
Subramanian, G.; Gao, J.; Ferguson, D. M. J. Am. Chem. Soc. 2002,
124, 4832.
(29) For recent reviews on the DielsꢀAlder reaction in natural
product synthesis, see: (a) Nawrat, C. C.; Moody, C. J. Angew. Chem.
Int. Ed. 2014, 53, 2056. (b) Parvatkar, P. T.; Kadam, H. K.; Tilve, S.
G. Tetrahedron 2014, 70, 2857. (c) Wan, C. Y.; Deng, J.; Liu, H.;
Bian, M.; Li, A. Sci. China Chem. 2014, 57, 926. for recent
application of DielsꢀAlder reaction in natural product synthesis in
our group, see: (d) Yuan, C.; Du, B.; Yang, L.; Liu, B. J. Am. Chem.
Soc. 2013, 135, 9291. (e) Du, B.; Yuan, C.; Yu, T.; Yang, L.; Liu, B.;
Qin, S. Chem. Eur. J. 2014, 20, 2613. f) Yang, L.; Yue, G.; Yuan, C.;
Du, B.; Deng, H.; Liu, B. Synlett 2014, 25, 2471.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(30) Inoki, S.; Kato, K.; Isayama, S.; Mukaiyama, T. Chem. Lett.
1990, 1869.
(31) (a) Kato, K.; Yamada, T.; Takai, T.; Inoki, S.; Isayama, S.
Bull. Chem. Soc. Jpn. 1990, 63, 179. (b) Inoki, S.; Kato, K.; Takai, T.;
Isayama, S.; Yamada, T.; Mukaiyama, T. Chem. Lett. 1989, 515.
(32) (a) Hao, X. Huaxue Jinzhan 2009, 21, 84. (b) Kume, T.;
Katuski, H.; Akaike, A. Biol. Pharm. Bull. 2004, 27, 964. (c) Hao,
X.; Shen, Y.; Li, L.; He, H. Curr. Med. Chem. 2003, 10, 2253. (d)
Kume, T. Asai, N.; Nishikawa, H.; Mano, N.; Terauchi, T.; Taguchi,
R.; Shirakawa, H.; Osakada, F.; Mori, H.; Asakawa, N.; Yonaga, M.;
Nishizawa, Y.; Sugimoto, H.; Shimohama, S.; Katsuki, H.; Kaneko,
S.; Akaike, A. Proc. Natl. Acad. Sci. USA 2002, 99, 3288.
(33) (a) Rafferty, R. J.; Hicklin, R. W.; Maloof, K. A.;
Hergenrother, P. J. Angew. Chem. Int. Ed. 2014, 53, 220. (b)
Huigens III, R. W.; Morrison, K. C.; Hicklin, R. W.; Flood Jr, T. A.;
Richter, M. F.; Hergenrother, P. J. Nat. Chem. 2013, 5, 195.
(34) For the related synthesis, see Supporting Information.
(35) For recent isolation and characterization of scopadulaneꢀtype
diterpenoids, see: (a) Fuentes, R. G.; Toume, K.; Arai, M. A.; Sadhu,
S. K.; Ahmed, F.; Ishibashi, M. J. Nat. Prod. 2015, 78, 864. (b)
Munoz, M. A.; Chamy, C.; Bucio, M. A.; HernandezꢀBaragan, A.;
JosephꢀNathan, P. Tetrahedron Lett. 2014, 55, 4274. (c) Liu, Q.;
Yang, Q.ꢀM.; Hu, H.ꢀJ.; Yang, L.; Yang, Y.ꢀB.; Chou, G.ꢀX.; Wang,
Z.ꢀT. J. Nat. Prod. 2014, 77, 1594. (d) Ahsan, M.; Islam, SK. N.;
Gray, A. I.; Stimson, W. H.; J. Nat. Prod. 2003, 66, 958.
(25) For selected reviews, see: (a) Roche, S. P.; Porco Jr., J. A.
Angew. Chem. Int. Ed. 2011, 50, 4068. b) Liao, C.ꢀC. Pure Appl.
Chem. 2005, 77, 1221.
(26) (a) Nair, V.; Menon, R. S.; Biju, A. T.; Abhilash, K. G.
Chem. Soc. Rev. 2012, 41, 1050. (b) Kumar, V.; Ramanathan, S.;
Sang, D.; Chen, X.; Lemal, D. M. J. Org. Chem. 2012, 77, 966.
(27) (a) Thomas, A.; Anilkumar, G.; Nair, V. Tetrahedron 1996,
52, 2481. (b) Nair, V.; Maliakal, D. Res Chem. Intermed. 2002, 28,
337. (c) Kaicharia, T.; Bhojgude, S. S.; Biju, A. Org. Lett. 2012, 14,
6238. (d) Nair, V.; Maliakal, D.; Treesa, P. M.; Rath, N. P.;
Eigendorf, G. K. Synthesis 2000, 850. (e) Müller, G. H.; Lang, A.;
Seithel, D. R.; Waldmann, H. Chem. Eur. J. 1998, 4, 2513. (f) Nair,
(36) (a) Matsuda, Y.; Wakimoto, T.; Mori, T.; Awakawa, T.; Abe,
I. J. Am. Chem. Soc. 2014, 136, 15326. (b) Dunn, A. W.; Johnstone,
R. A. W.; Sklarz, B. J. Chem. Soc. Chem. Commun. 1978, 533.
TOC
ACS Paragon Plus Environment