Total synthesis of maoecrystal v

Article abstract of DOI:10.1002/asia.201403228

Maoecrystal V (1) is a novel diterpenoid, which was originally isolated from the leaves of the Chinese medicinal herb Isodon eriocalyx in 2004 by Sun etal.1 It has been found to be selectively cytotoxic towards HeLa cells, with an IC₅₀ value of 20ng mL^-1. Significant research efforts have been devoted to the synthesis of maoecrystal V because of its intriguing biological properties, rarity in nature, and complex structural features. Herein, we describe our recent investigations, which have culminated in the total synthesis of (±)-maoecrystal V. The current strategy involved three key steps for the successful construction of the key tetrahydrofuran oxa-bridge skeleton, including a Wessely oxidative dearomatization, a novel intramolecular Diels-Alder reaction, and a Rh^II-catalyzed O-H insertion reaction.

Full text of DOI:10.1002/asia.201403228

DOI: 10.1002/asia.201403228
Full Paper
Total Synthesis
Total Synthesis of Maoecrystal V
Wei-Bin Zhang,[a] Guang Lin,[a] Wen-Bin Shao,[a] Jian-Xian Gong,*[a] and Zhen Yang*[a, b, c]
Abstract: Maoecrystal V (1) is a novel diterpenoid, which
was originally isolated from the leaves of the Chinese medic-
inal herb Isodon eriocalyx in 2004 by Sun et al.[1] It has been
found to be selectively cytotoxic towards HeLa cells, with an
IC50 value of 20 ngmLÀ1. Significant research efforts have
been devoted to the synthesis of maoecrystal V because of
its intriguing biological properties, rarity in nature, and com-
plex structural features. Herein, we describe our recent in-
vestigations, which have culminated in the total synthesis of
(Æ)-maoecrystal V. The current strategy involved three key
steps for the successful construction of the key tetrahydro-
furan oxa-bridge skeleton, including a Wessely oxidative
dearomatization, a novel intramolecular Diels–Alder reaction,
and a RhII-catalyzed OÀH insertion reaction.
Introduction
In 2004, Sun et al.[1] reported the isolation of maoe-
crystal V (1, Figure 1) from the leaves of the Chinese
medicinal herb Isodon eriocalyx, which has been used
for centuries in folk medicine for the treatment of
sore throats, inflammation, influenza, hypertension,
and dermatophytosis.[2] More than 600 diterpenoids
have been isolated from Isodon species to date,[3] and
a large number of these compounds have been re-
ported to exhibit potent antitumor activities.[4]
The cytotoxicity of maoecrystal V was evaluated
Figure 1. Naturally occurring ent-kaurane type maoecrystal compounds.
against five human tumor cell lines, including K562,
A549, BGC-823, CNE, and HeLa cells, and found to be selective-
ly cytotoxic towards HeLa cells with an impressive IC50 value of
approximately 20 ngmLÀ1.[1] In light of the potent and selective
cytotoxicity of this compound against gynecological cancer
cells there is an urgent need for further investigation. However,
the development of this lead compound has been severely
limited by the fact that it can only be isolated in small
amounts from natural sources (e.g., 5 mg/12 kg of dried leaves
of the plant[1]).
Structurally, maoecrystal V (1) differs from other members of
the ent-kauranoid maoecrystal family[3] such as 2–7 (Figure 1)
because it contains a [2.2.2]-bicyclic ring system rather than
a [3.2.1]-bicyclic ring system. Based on this difference in its mo-
lecular architecture, maoecrystal V (1) stands out as an atypical
member of this class of natural products.
[a] W.-B. Zhang, Dr. G. Lin, W.-B. Shao, Dr. J.-X. Gong, Prof. Dr. Z. Yang
Laboratory of Chemical Genomics, School of Chemical Biology and Biotech-
nology
From a synthetic perspective, maoecrystal V (1) is a compact
and highly functionalized cage-like molecule, which is regard-
ed by many researchers to be one of the most challenging nat-
ural products in organic synthesis.[5] The biggest challenge
posed by the total synthesis of maoecrystal V (1) arises from
its pentacyclic framework, which contains six interlocking vici-
nal stereogenic centers; three of which are contiguous quater-
nary stereocenters[6] with two all-carbon centers at C9 and C10.
Maoecrystal V (1) also contains a bicyclo[2.2.2]octan-2-one sub-
unit (D/E-ring) and a strained and highly substituted central
tetrahydrofuran ring (B-ring), which is flanked by a trans-fused
six-membered ring (A-ring), and these structural features could
also present a formidable challenge to its total synthesis.
In view of the intriguing structural features of maoecrystal V
(1) and its potential applications as a biological probe and
Peking University Shenzhen Graduate School
Shenzhen 518055 (China)
E-mail: zyang@pku.edu.cn
gongjx@pku.edu.cn
[b] Prof. Dr. Z. Yang
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Min-
istry of Education
and Beijing National Laboratory for Molecular Science (BNLMS)
Peking-Tsinghua Center for Life Sciences
Peking University
Beijing 100871 (China)
[c] Prof. Dr. Z. Yang
Key Laboratory of Marine Drugs, Chinese Ministry of Education
School of Medicine and Pharmacy, Ocean University of China
5 Yushan Road, Qingdao (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403228.
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drug-discovery lead, numerous research efforts have been di-
rected towards the synthesis of compounds belonging to this
novel class of natural products,[7] culminating in the total syn-
thesis of maoecrystal V (1) by the laboratories of Yang in
2010,[8] Danishefsky in 2012,[9] and Zakarian in 2013.[10a] The
enantiosynthesis of (À)-maoecrystal V has been completed by
Zakarian and co-workers.[10b]
In 2009, we reported our model study for the total synthesis
of maoecrystal V (1).[7a] One of the key steps in this study was
a lead-mediated Pinhey arylation reaction[11] involving the cou-
pling of the aryl-lead tricarboxylate 8 to b-ketoester 9. The
product of this reaction was subjected to an oxidative Wessely
dearomatization to give intermediate 10, which underwent an
intramolecular Diels–Alder (IMDA) reaction[12] to afford the tet-
racyclic compound 11. The acetate group in 11 was subse-
quently removed by a SmI2-mediated reductive deacetoxyla-
tion reaction[13] to yield 12, which mimicked the carbon core of
maoecrystal V (1) (Figure 2).
Figure 3. First generation retrosynthetic analysis.
sults of our previously reported model study (Figure 3). It was
envisioned that maoecrystal V could be assembled from 13
through a late stage allylic oxidation and the SmI2-mediated
reductive cleavage of the oxygenated substituent at C16. It
was anticipated that the tetrahydrofuran moiety of 13 could
be constructed by a remote oxidative CÀO bond forming reac-
tion from the Diels–Alder product 14, which could itself be
formed through the IMDA reaction of 15. Compound 15 could
be synthesized in turn from the cis-diol 16, which could be ac-
cessed by the stereoselective reduction of b-keto ester 17.
Our total synthesis began with the preparation of bicyclic
compound 14. Commercially available compound 18[14] was
treated with dimethyl carbonate in the presence of NaH to
give the b-keto ester 19 in 92% yield, which was subjected to
an oxidative arylation reaction with the aryl-lead reagent 20 to
afford the key intermediate 17 in 88% yield (Scheme 1).
The b-keto ester 17 was initially reduced with LiAlH4. Howev-
er, this reaction did not proceed in a diastereoselective manner
with both the trans-diol 21 and cis-diol 16 products being iso-
lated in a combined yield of 84% in favor of the undesired
product 21. The failure of this reaction was attributed to the
direction of the resulting primary alcohol, which would have
allowed the reducing agent to access the ketone from the
same side as the already reduced ester group (see the X-ray
Figure 2. Model study of maoecrystal V (1).
The biggest difference between the model compound 12
and the natural product can be found in the tetrahydrofuran
ring (B-ring), and the biggest challenge associated with the de-
velopment of an efficient strategy for the total synthesis of
maoecrystal V (1) must therefore focus on the con-
struction of this key tetrahydrofuran oxa-bridge skel-
eton. With this in mind, we developed three strat-
egies for the construction of this core scaffold, in-
cluding an IMDA/oxidative CÀO bond-forming ap-
proach; an intramolecular oxa-Michael reaction ap-
proach and a RhII-catalyzed OÀH insertion approach
and embarked on a study towards the total synthesis
of maoecrystal V (1). Herein, we report the details of
our total synthesis.
Results and Discussion
First Generation Approach: Oxidative CÀO Bond
Formation
The retrosynthetic strategy for our first generation
Scheme 1. Synthesis of key intermediate 16. Thermal ellipsoids are scaled to the 50%
total synthesis of maoecrystal V was based on the re- probability level.
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ylcarbodiimide/4-dimethylaminopyridine (DCC/DMAP) to give
the corresponding a,b-unsaturated ester 24 in 58% yield.
Compound 24 was then treated with trimethylsilyl bromide
(TMSBr) to remove its methoxymethyl (MOM) group, and the
resulting phenol was subjected to a Wessely oxidative dearo-
matization reaction to give 15 as a mixture of diastereoisomers
at C16 in a ratio of 3:1. To accelerate the IMDA reaction, com-
pound 15 was dissolved in toluene and the resulting mixture
was heated in a sealed tube at 1208C to give the cyclized
product 14 in a total yield of 62% for the last three steps. The
relative stereochemistry of 14 was confirmed by X-ray crystal-
lography. Thus, we achieved the diastereoselective formation
of the tetracyclic core of maoecrystal V.
Table 1. Screening of reducing agents for the selective reduction of 17.
Entry Solvent
Reagent
Temperature Yield
Ratio of 22/23
[a]
1
2
3
4
5
6
7
THF
THF
CH2Cl2
MeOH
MeOH
l-selectride
CBS/BH3
DIBAL-H
NaBH4
À788C to rt
–
–
–
–
5:1
3:2
[a]
rt
À788C to rt 85%
rt
90%
95%
CaCl2, NaBH4 rt
>30 :1
MeOH/THF nBu4NBH4
MeOH/THF Me4NBH4
408C
rt
65%[b] 23 only
81%[c] 23 only
We then moved on to investigate the installation of the
highly strained tetrahydrofuran ring system. Synthetically, it
was envisaged that the tetrahydrofuran ring could be con-
structed through a direct CÀH functionalization reaction, be-
cause several similar strategies have been reported in the liter-
ature.[18] With this in mind, compound 14 was subjected to
a variety of different oxidative coupling conditions, including
PhI(OAc)2/I2/hn[18c] and Pd(OAC)4/I2/hn,[18e] as well as the nitrite
ester photolysis conditions developed by Barton et al.[19] How-
ever, none of these conditions provided access to the expected
product 13 (Scheme 3), and it was therefore necessary to
[a] No reaction, recovered starting material. [b] 89% BRSM (based on re-
covered starting material). [c] 95% BRSM.
structure of 21). To achieve the desired product 16, it was
therefore necessary to use a stepwise reduction process and
a variety of reducing agents were screened against the reac-
tion, as illustrated in Table 1. Sterically hindered reducing
agents such as l-selectride or the Corey–Bakshi–Shibata (CBS)
catalyst were unsuccessful and resulted in the recovery of
starting material (Table 1, entries 1 and 2). This result indicated
that the ketone moiety of 17, which is adjacent to two quater-
nary carbon centers, is difficult to access because of the steric
hindrance imposed by the surrounding environment. When dii-
sobutylaluminum hydride (DIBAL-H) was used as a reducing
agent, compound 17 was selectively reduced to give com-
pounds 22 and 23 in a combined yield of 85% and a ratio of
5:1 in favor of product 22 (Table 1, entry 3). NaBH4 was also
evaluated as a reducing agent, and gave compounds 22 and
23 in a combined yield of 90% and a ratio of 3:2 in favor of 22
[15]
(Table 1, entry 4). However, NaBH4/CaCl2
as the reducing
agent led to a significant increase in the selectivity with com-
pounds 22 and 23 being formed in a ratio of >30:1 in favor of
22 (Table 1, entry 5). Pleasingly, the treatment of 17 with
(nBu4)NBH4 or Me4NBH4 in a mixed solvent of MeOH/
THF at 408C or room temperature afforded the de-
sired product 23 as the sole isomer in 65 and 81%
yields, respectively.[16]
Scheme 2. Diastereoselective synthesis of diol 16.
The diastereoselectivity of this process was attrib-
uted to the directing and accelerating effects of the
cationic-p interaction[17] between the ammonium salt
[(n-R)4NBH4] and the phenyl ring in substrate 17,
which would have ensured that the hydride was de-
livered to the Si face of the ketone in 17 to yield
compound 23. Pleasingly, the treatment of ester 23
with LiAlH4 afforded the corresponding cis-configured
diol 16 in 88% yield (Scheme 2).
With the desired cis-diol 16 in hand, we proceeded
to investigate the formation of the tetracyclic core of
maoecrystal V (1) using an IMDA reaction (Scheme 3).
Thus, cis-diol 16 was condensed with acrylic acid at
Scheme 3. Construction of the core structure of Maoecrystal V through an IMDA. Ther-
room temperature in the presence of 1,3-dicyclohex- mal ellipsoids are scaled to the 50% probability level.
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devise an alternative pathway for the construction of
this challenging fragment of maoecrystal V.
Second Generation Approach: Oxa-Michael Addi-
tion
A second approach was developed to solve the
issues associated with the late stage formation of the
tetrahydrofuran ring. In this approach, it was envis-
aged that an IMDA reaction could be used to build
up the [2.2.2]-bicyclic ring system together with the
in-situ generation of the tetrahydrofuran ring in com-
pound 25 (Figure 4), which could then be converted
into maoecrystal V (1) through a series of standard
synthetic transformations. The key step in our second
generation approach for the synthesis of maoecrystal
V (1) would therefore involve the intramolecular oxa-
Michael reaction[20] of 27 for the formation of the key
intermediate 26, as shown in Figure 4.
Scheme 4. Synthesis of compound 27.
to be developed for the construction of this challenging bond.
The Rh-catalyzed intramolecular OH insertion reaction[22] has
emerged as an effective method for the formation of
CÀO bonds. In this context, a-diazo carbonyl com-
pounds can be converted into carbene species in the
presence of a RhII catalyst. The resulting carbene spe-
cies can then undergo an intramolecular OÀH bond
insertion reaction to form CÀO bonds, and strategies
of this type have been successfully applied to the
construction of medium-sized ring systems.[23]
With this chemistry in mind, we began to explore
a third generation strategy for the construction of
the pentacyclic core of maoecrystal V using the RhII-
catalyzed CÀO insertion and IMDA reactions as key steps in
the process, as shown in Figure 5. It was envisioned that diol
16 could be converted into its corresponding phosphate de-
Figure 4. Retrosynthetic analysis of 25.
Scheme 4 shows the synthesis of intermediate 27, which is
an important precursor for the proposed oxa-Michael reaction.
For the synthesis of compound 27, diol 16 was initially treated
with triphosgene in the presence of pyridine to give the corre-
sponding carbonate 28 in 88% yield.[21] The subsequent treat-
ment of carbonate 28 with lithium acetylide afford esters 29
and 27 in 34 and 58% yields, respectively. Notably, ester 29
could be converted back into the starting diol 16 by treatment
with KOH in MeOH.
With precursor 27 in hand, we then began to explore the
feasibility of the proposed tandem oxa-Michael addition and
IMDA reactions for the synthesis of compound 25. Thus, the
MOM ether group in ester 27 was removed with H2SO4 (3n) to
give the corresponding phenol 30 in 93% yield, which was
subjected to a Wessely oxidation to afford 31 in 86% yield as
a mixture of diastereoisomers at C16 in a ratio of 3:1. The pro-
posed tandem oxa-Michael addition/IMDA reaction of com-
pound 31 was investigated under a wide variety of reaction
conditions but failed to provide any of the desired product 25.
The direct IMDA reaction of 33 also failed to provide the de-
sired product (Scheme 5).
Third Generation Approach: RhII-catalyzed OÀH Insertion
Given that strategies based on conventional synthetic methods
failed to allow for the formation of the sterically hindered CÀO
bond, it was clear that a novel synthetic strategy would have
Scheme 5. The attempt of intramolecular oxa-Michael addition.
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yield, together with its regioisomers 39 (exo-selective product)
and 40 (exo-selective product) in 28 and 12% yields, respec-
tively (Scheme 7). The structures of 13 and 40 were confirmed
by X-ray crystallography.
We then proceeded to the final stage in the completion of
this total synthesis, where we attempted to achieve the direct
conversion of 13 to enone 41 (Scheme 8). Unfortunately, how-
ever, we were unable to form enone 41, despite testing vari-
ous allylic oxidation conditions, and the failure of this ap-
proach was attributed to steric hindrance at the C1 position of
13 from the adjacent quaternary carbon atom.
In our final attempt to achieve the total synthesis of maoe-
crystal V (1), we explored the possibility of using a stepwise
strategy for the formation of product 41. It was envisaged that
Figure 5. Retrosynthetic analysis of the third generation approach.
rived a-diazo carbonyl compound 36, which would
undergo the proposed RhII-catalyzed intramolecular
OÀH bond insertion reaction to allow for the forma-
tion of the CÀO bond. The Horner–Wadsworth–
Emmons reaction of resulting phosphate 35 would
give 34, which would undergo the expected Wessely
oxidative dearomatization followed by an IMDA reac-
tion to afford the product 13 with the desired penta-
cyclic core of maoecrystal V (1). Thus, the total syn-
thesis of 1 could be accomplished by sequential
SmI2-mediated deacetylation and allylic oxidation[25]
reactions, with the installation of the carbonyl group
at C1 being a key step.
In practice, cis-diol 16 was coupled with diethyl-
phosphono-acetic acid in the presence of 1-ethyl-3-
(3-dimethylaminopropyl) carbodiimide hydrochlori-
de(EDCI) and DMAP in CH2Cl2 to give ester 37, which
was subsequently treated with toluenesulfonyl
azide[25] in the presence of 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) in CH2Cl2 at 08C to give the a-diazo
carbonyl compound 36 in 66% yield over the two
steps. Treatment of 36 with the Rh2(OAc)4 catalyst at
808C in anhydrous benzene gave lactone 35 in 60%
yield, which was then subjected to a Horner–Wads-
worth–Emmons reaction[26] with paraformaldehyde
to afford 34 in 95% yield. The MOM group in 34 was
subsequently removed by the treatment of this com-
pound with trifluoroacetic acid (TFA) in CH2Cl2 at 08C
over 30 min to afford phenol 38 in 90% yield
(Scheme 6).
Scheme 6. Synthesis of key intermediate 35.
With phenol 38 in hand, we proceeded to evalu-
ate its performance in the annulation reaction for
the formation of product 13 with the pentacyclic
core of maoecrystal V. In practice, the treatment of
phenol 38 with Pb(OAc)4 in acetic acid allowed for
the Wessely oxidation reaction to proceed smoothly
to give the corresponding dienes as a pair of re-
gioisomers. This regioisomeric mixture was then pro-
gressed into the next stage without separation and
was heated in a sealed tube for 24 h in toluene at
Scheme 7. The Wessely dearomatization/IMDA sequence. Thermal ellipsoids are scaled to
1458C to give the endo-selective product 13 in 36% the 50% probability level.
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This result revealed that we were close to achiev-
ing our goal of the total synthesis of maoecrystal V
(1). In an attempt to overcome the problems caused
by this unexpected SN2’-type reaction mechanism,
we became interested in the possibility of using a rad-
ical fragmentation process to achieve the proposed
SN2-type cleavage of the bromine motif. It was envis-
aged that the carbon–bromine bond in 44 could be
homolytically cleaved using a tin hydride reagent,
and that the resulting carbon radical could be
trapped by an oxygen atom source such as O2 or
2,2,6,6-tetramethylpiperidin-1-oxyl radical (TEMPO) in
a similar manner to those reported by the research
groups of Boger and Leighton.[29a,b] To test this strat-
egy, we initially treated 44 with Bu3SnH in the pres-
ence of TEMPO in refluxing benzene. Pleasingly, prod-
uct 49 was obtained in 75% yield. Encouraged by
this result, we treated 49 with zinc in a mixture of
acetic acid and THF, and this led to the formation of
50 bearing a hydroxy group at C1 in 85% yield. The
acetoxy group in 51 was removed by a SmI2-mediat-
ed reductive cleavage reaction,[13d] and a subsequent
regioselective hydrogenation using Lindlar catalyst
afforded 51 in 81% yield over the two steps. To com-
plete the total synthesis, alcohol 51 was oxidized
with Dess–Martin periodinane (DMP) in CH2Cl2 at
room temperature to give 52 as C16-epi-maoecrystal
V, which was isomerized with DBU at 1008C to give
maoecrystal V (1) in 48% yield (90% brsm) as a race-
mic mixture. The identity of the synthesized maoecrystal V (1)
was confirmed through a comparison of its NMR spectral data
with those of natural maoecrystal V (1) (Scheme 9).
Scheme 8. The attempt to install the carbonyl group at C1.
the C1 position could be brominated using an N-bromosuccini-
mide (NBS)-mediated radical reaction, and that the resulting
bromide could be converted into the corresponding ketone
using a 4-methoxypyridine-N-oxide-mediated SN2 re-
action.[27] In practice, compound 13 was initially treat-
ed with SmI2 to remove its acetyl group, and subse-
quently brominated with NBS in the presence of
benzoyl peroxide.[28] Unfortunately, however, these
reaction conditions led to the formation of the dibro-
minated product 43. To avoid bromination at C16,
13 was used as the substrate in the bromination re-
action, where it was treated with NBS in the pres-
ence of benzoyl peroxide to give the mono-bromi-
nated 44 in 90% yield. With the brominated precur-
sor in hand, we proceeded to explore the proposed
SN2 reaction for the installation of the C1 oxygen. In-
terestingly, treatment of 44 with 4-methoxypyridine-
N-oxide under the standard conditions did not give
Scheme 9. Total synthesis of maoecrystal V (1).
the expected product 45 through the proposed SN2-
type reaction, but instead gave 46 in 85% yield by
an SN2’-type mechanism through intermediates A
and B (Scheme 8). Furthermore, 46 was converted into 47 in
good yields under standard hydrogenation conditions. Al-
though compound 47 is an isomer of the desired product 41,
it could still be used as a model to reinstall the C1ÀC3 enone
system. With this in mind, 47 was treated with o-iodoxybenzo-
ic acid (IBX) in dimethyl sulfoxide (DMSO) at 858C to give 48 in
70% yield.
Conclusions
Following a series of systematic synthetic investigations, the
concise total synthesis of maoecrystal V (1) has been achieved
using a Wessely oxidative dearomatization, IMDA reaction, and
an Rh-catalyzed OÀH bond insertion as key steps in the strat-
egy. Notably, this strategy allowed for the total synthesis of
(Æ)-maoecrystal V (1) in 18 steps in a total yield of 1.3% from
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Lim, G. Y. C. Leugn, D. Y. K. Chen, Chem. Eur. J. 2011, 17, 5778; i) F. Peng,
S. J. Danishefsky, Tetrahedron Lett. 2011, 52, 2104; j) Z. H. Gu, A. Zakari-
an, Org. Lett. 2011, 13, 1080; k) K. E. Lazarski, B. Akpinar, R. J. Thomson,
Tetrahedron Lett. 2013, 54, 635; l) P. Carberry, D. R. Viernes, L. B. Choi,
M. W. Fegley, J. D. Chisholm, Tetrahedron Lett. 2013, 54, 1734; m) Total
synthesis of (À)-maoecrystal Z: J. Y. Cha, J. T. S. Yeoman, S. E. Reisman, J.
Am. Chem. Soc. 2011, 133, 14964. Recent total synthesis of related ent-
kauranoids: n) J. T. S. Yeoman, V. W. Mak, S. E. Reisman, J. Am. Chem.
Soc. 2013, 135, 11764; o) Z. Q. Pan, C. Y. Zheng, H. Y. Wang, Y. H. Chen, Y.
Li, B. Cheng, H. B. Zhai, Org. Lett. 2014, 16, 216.
the commercially available compound 18, and this chemistry
could be used to achieve the synthesis of several analogues of
maoecrystal V.
Experimental Section
The synthetic procedures and characterization of the compounds
studied herein can be found in the Supporting Information.
CCDC 864996 (13), CCDC 1038436 (14), CCDC 1038437 (21), and
CCDC 1038435 (40) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/data_request/cif.
[8] J. Gong, G. Lin, W. Sun, C. C. Li, Z. Yang, J. Am. Chem. Soc. 2010, 132,
16745.
[9] F. Peng, S. J. Danishefsky, J. Am. Chem. Soc. 2012, 134, 18860.
[10] a) P. Lu, Z. H. Gu, A. Zakarian, J. Am. Chem. Soc. 2013, 135, 14552; b) P.
Lu, A. Mailyan, Z. Gu, D. Guptill, H. Wang, H. M. L. Davies, A. Zakarian, J.
Am. Chem. Soc. 2014, DOI: 10.1021/ja510573v.
[11] a) J. T. Pinhey, Aust. J. Chem. 1991, 44, 1353; b) G. I. Elliot, J. P. Konopel-
ski, M. M. Olmstead, Org. Lett. 1999, 1, 1867.
Acknowledgements
[12] a) D. Magdziak, S. J. Meek, T. R. R. Pettus, Chem. Rev. 2004, 104, 1383;
b) R. M. Wilson, S. J. Danishefsky, Acc. Chem. Res. 2006, 39, 539.
[13] a) R. S. Rosenfeld, T. F. Gallagher, J. Am. Chem. Soc. 1955, 77, 4367;
b) R. S. Rosenfeld, J. Am. Chem. Soc. 1957, 79, 5540; c) L. A. Paquette,
J. S. Ward, R. A. Boggs, W. B. Farnham, J. Am. Chem. Soc. 1975, 97, 1101;
d) G. A. Molander, G. Hahn, J. Org. Chem. 1986, 51, 1135.
The authors thank the National Basic Research 973 Program of
China (Grant Nos. 2010CB833201, 2012CB722602), the National
863 Program (Grant No. 2013AA092903), Natural Science
Foundation of China (Grant Nos. 21372016 and 21402002),
[14] A more practicable synthetic route to obtain ketone 18 was carried out
in the lab, please see the Supporting Information for details.
Shenzhen
Basic
Research
Program
(Grant
Nos.
[15] a) P. V. Ramachandran, G. M. Chen, H. C. Brown, J. Org. Chem. 1996, 61,
88; b) E. G. Neeland, J. P. Ounsworth, R. J. Sims, L. Weiler, J. Org. Chem.
1994, 59, 7383; c) H. Urabe, Y. Aoyama, F. Sato, J. Org. Chem. 1992, 57,
5056; d) M. Fujita, T. Hiyama, J. Am. Chem. Soc. 1984, 106, 4629.
[16] a) M. Periasamy, M. Thirumalaikumar, J. Organomet. Chem. 2000, 609,
137; b) C. A. M. Fraga, L. H. P. Teixeira, C. M. d. S. Menezes, C. M. R. San-
t’Anna, M. d. C. K. V. Ramos, F. R. d. A. Neto, E. J. Barreiro, Tetrahedron
2004, 60, 2745; c) Q. Zhou, B. B. Snider, J. Org. Chem. 2008, 73, 8049.
[17] For a review, see: a) J. C. Ma, D. A. Dougherty, Chem. Rev. 1997, 97,
1303; b) S. Yamada, C. Morita, J. Am. Chem. Soc. 2002, 124, 8184.
[18] For the synthesis of tetrahydrofuran products through a radical proto-
JCYJ20130329180217059,
GJHS20120628101219325,
ZYC201105170335A, ZYC201105170358A), NSFC-Shandong
Joint Fund for Marine Science Research Centers (U1406402)
and China Postdoctoral Science Foundation for financial sup-
ports.
Keywords: Diels–Alder reaction · natural products · rhodium ·
total synthesis · oxidative dearomatization
ˇ
ˇ
´
´
col, see: a) M. L. Mihailovic, Z. Cekovic, Synthesis 1970, 209; b) J. Kalvo-
da, K. Heusler, Synthesis 1971, 501; c) J. I. Concepciꢁn, C. G. Francisco, R.
Hernꢂndez, J. A. Salazar, E. Suꢂrez, Tetrahedron Lett. 1984, 25, 1953;
d) R. L. Dorta, C. G. Francisco, R. Freire, E. Suꢂrez, Tetrahedron Lett. 1988,
29, 5429; e) P. Ceccherelli, M. Curini, M. C. Marcotullio, B. L. Mlari, E.
Wenkert, J. Org. Chem. 1986, 51, 1505.
[1] S. H. Li, J. Wang, X. M. Niu, Y. H. Shen, H. J. Zhang, H. D. Sun, M. L. Li,
Q. E. Tian, Y. Lu, P. Cao, Q. T. Zheng, Org. Lett. 2004, 6, 4327.
[2] a) E. Fujita, M. Node in Progress in the Chemistry of Organic Natural Prod-
ucts, Vol. 46 (Eds.: W. Herz, H. Grisebach, G. W. Kirby, G. W. Tamm),
Springer-Verlag, Vienna, 1984, pp. 77–157; b) H. D. Sun, Y.-L. Xu, B.
Jiang, Diterpenoids from Isodon Species, Science Press, Beijing, 2001.
[3] a) H. D. Sun, S. X. Qiu, L. Z. Lin, R. P. Zhang, Y. Zhou, Q. T. Zheng, M. E.
Johnson, H. H. S. Fong, N. R. Farnsworth, G. A. Cordell, J. Nat. Prod.
1997, 60, 203; b) H. D. Sun, S. X. Huang, Q. B. Han, Nat. Prod. Rep. 2006,
23, 673.
[4] a) X. Li, J. X. Pu, Z. Y. Weng, Y. Zhao, Y. Zhao, W. L. Xiao, H. D. Sun, Chem.
Biodiversity 2010, 7, 2888; b) X. N. Li, J. X. Pu, X. Du, L.-G. Lou, L.-M. Li,
S. X. Huang, B. Zhao, M. Zhang, F. He, X. Luo, W.-L. Xiao, H. D. Sun, J.
Nat. Prod. 2010, 73, 1803; c) H. Y. Wu, R. Zhan, W. G. Wang, H. Y. Jiang,
X. Du, X. N. Li, Y. Li, J. X. Pu, H. D. Sun, J. Nat. Prod. 2014, 77, 931.
[5] http://www.rsc.org/chemistryworld/Issues/2010/December/ColumnTo-
tallySynthetic.asp.
[19] D. H. R. Barton, J. M. Beaton, L. E. Geller, M. M. Pechet, J. Am. Chem. Soc.
1960, 82, 2640.
[20] For a review, see: C. F. Nising, S. Brꢃse, Chem. Soc. Rev. 2008, 37, 1218.
[21] F. Bracher, T. Litz, J. Prakt. Chem. 1995, 337, 516.
[22] a) D. J. Miller, C. J. Moody, Tetrahedron 1995, 51, 10811; b) T. Ye, A.
McKervey, Chem. Rev. 1994, 94, 1091; c) A. Padwa, L. Precedo, M. A.
Semones, J. Org. Chem. 1999, 64, 4079; d) A. Padwa, Z. J. Zhang, L. Zhi,
J. Org. Chem. 2000, 65, 5223.
[23] For a review, see: L. Yet, Chem. Rev. 2000, 100, 2963.
[24] For a review, see: V. Weidmann, W. Maison, Synthesis 2013, 45, 2201.
[25] E. F. V. Scriven, K. Turnbull, Chem. Rev. 1988, 88, 297.
[26] a) X. Homer, H. Hofiann, H. G. Wippel, Chem. Ber. 1968, 91, 61; b) W. S.
Wadsworth, W. D. Emmons, J. Am. Chem. Soc. 1961, 83, 1733.
[27] P. Duan, M. K. Fu, T. A. Gillespie, B. E. Winger, H. I. Kenttꢃmaa, J. Org.
Chem. 2009, 74, 1114.
[6] Recent reviews: a) E. J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed.
1998, 37, 388; Angew. Chem. 1998, 110, 2092; b) C. J. Douglas, L. E.
Overman, Proc. Natl. Acad. Sci. USA 2004, 101, 5363.
[7] Synthetic studies toward maocrystal V: a) J. Gong, G. Lin, C. C. Li, Z.
Yang, Org. Lett. 2009, 11, 4770; b) P. J. Krawczuk, N. Schone, P. S. Baran,
Org. Lett. 2009, 11, 4774; c) F. Peng, M. Yu, S. J. Danishefsky, Tetrahedron
Lett. 2009, 50, 6586–6587; d) K. C. Nicolaou, L. Dong, L. J. Deng, A. C.
Talbot, D. Y. K. Chen, Chem. Commun. 2010, 46, 70; e) K. E. Lazarski, D. X.
Hu, C. L. Sterm, R. J. Thomson, Org. Lett. 2010, 12, 3010; f) V. Singh, P.
Bhalerao, S. M. Mobin, Tetrahedron Lett. 2010, 51, 3337; g) I. Baitinger, P.
Mayer, D. Trauner, Org. Lett. 2010, 12, 5656; h) L. Dong, L. Deng, Y. H.
[28] S. Limura, L. E. Overman, R. Paulini, A. Zakarian, J. Am. Chem. Soc. 2006,
128, 13095.
[29] a) D. L. Boger, J. A. Mckie, J. Org. Chem. 1995, 60, 1271; b) B. Castagner,
J. L. Leighton, Tetrahedron 2007, 63, 5895.
Received: October 28, 2014
Published online on && &&, 0000
Chem. Asian J. 2014, 00, 0 – 0
www.chemasianj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
Total Synthesis
The total synthesis of maoecrystal V (1)
has been achieved by employing
Wei-Bin Zhang, Guang Lin, Wen-Bin Shao,
Jian-Xian Gong,* Zhen Yang*
a Wessely oxidative dearomatization, an
intramolecular Diels–Alder (IMDA) reac-
tion, and a Rh-catalyzed OÀH bond in-
sertion as key steps; this total synthesis
of (Æ)-maoecrystal V was completed in
18 steps in a total yield 1.3%.
&& – &&
Total Synthesis of Maoecrystal V
&
&
Chem. Asian J. 2014, 00, 0 – 0
www.chemasianj.org
8
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!