Total syntheses of drimane-type sesquiterpenoids enabled by a gold-catalyzed tandem reaction

Article abstract of DOI:10.1021/ja206837j

Development of a gold-catalyzed tandem reaction of 1,7-diynes with both internal and external nucleophiles was realized, which constructed five chemical bonds, two rings, and two stereogenic centers in a single step. Based on the novel cascade transformat

Full text of DOI:10.1021/ja206837j

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pubs.acs.org/JACS
Total Syntheses of Drimane-Type Sesquiterpenoids Enabled by a
Gold-Catalyzed Tandem Reaction
Hang Shi, Lichao Fang, Ceheng Tan, Lili Shi, Weibin Zhang, Chuang-chuang Li,* Tuoping Luo,*,‡ and
Zhen Yang*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School,
Shenzhen 518055, China, and Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and
Beijing National Laboratory for Molecular Science, College of Chemistry, Peking University, Beijing 100871, China
S Supporting Information
b
ABSTRACT: Development of a gold-catalyzed tandem
reaction of 1,7-diynes with both internal and external nucleo-
philes was realized, which constructed five chemical bonds,
two rings, and two stereogenic centers in a single step. Based
on the novel cascade transformation, we achieved a unified
strategy toward the stereoselective total syntheses of C-15
oxygenated drimane-type sesquiterpenoids and their analo-
gues, which provided the natural products kuehneromycin A,
antrocin, anhydromarasmone, and marasmene as a proof-of-
concept study.
Figure 1. Synthetic analysis of C-15 oxygenated drimane-type
sesquiterpenoids.
alternative synthetic strategy that could readily reach analogues
of these promising natural products, we recognized that the key
intermediate A would give rise to 1À4 straightforwardly with
minimum functional group manipulation. We further envisioned
that A could be accessed from 1,7-diyne C through a tandem
reaction involving the sequential nucleophilic addition of alkynes
(Figure 1). High alkynophilicity and good functional group
compatibility make gold catalysts a good choice for this cascade
transformation.11
It was reported that strategic placement of multiple alkynes
and nucleophiles could result in sequential alkyne activation to
accomplish various cascade reactions.12 In our scenario, 5-endo-
dig addition of oxygen to an alkyne leads to a polarized olefin
functionality, which functions as the nucleophile in the following
6-exo-dig cyclization (Figure 1, B). The reaction will be termi-
nated by an external nucleophile (e.g., alcohol), affording tricyclic
compound A as the final product.
As a model system for this envisioned tandem transformation,
racemic diyne acid 513 was subjected to the cationic gold catalyst
either in the absence or in the presence of p-nitrobenzylic alcohol
at room temperature. To our delight, 6 and 7 were isolated,
respectively (Table 1, entries 1 and 2). When 6 was again
subjected to the gold catalyst in the presence of p-nitrobenzylic
alcohol, it afforded tricyclic 7 (Table S1). It is notable that the
reaction leading to 6 was much faster than the formation of 7,
indicating that the 6-exo-dig cyclization14 is the rate-determin-
ing step in the tandem reaction. It was further observed that
tris(p-trifluoromethylphenyl)phosphine, a less-electron-donating
ligand than triethylphosphine, resulted in a decreased yield of 7,
n our continuous efforts toward the total syntheses of biologi-
cally active natural products, we attempt to prepare both
I
known compounds and their analogues more efficiently than
realized through existing approaches to enable an enhanced
exploitation of their structureÀactivity relationships.1 Special
attention has been paid to novel synthetic strategies and meth-
odologies that could lead to a modular and concise approach that
is predisposed for further medicinal chemistry optimization if
necessary.2 To showcase the intertwined nature of synthetic
strategies and methodologies, we describe herein a new cascade
reaction allowing the collective syntheses3 of several drimane-
type sesquiterpenoids.
Drimane-type sesquiterpenoids are a large group of natural
products possessing a variety of remarkable biological activities.4
Many members are oxygenated at C-15 and have a characteristic
[6-6-5] tricyclic system (Figure 1). For instance, kuehneromycin
A (1) and mniopetal F inhibit the reverse transcriptase of some
RNA viruses, including HIV-1.5 We are particularly interested in
antrocin (2), a metabolite originally reported by Chiang et al. in
1995,6 which has recently been identified as a selective and novel
inhibitor of Akt/mTOR signaling in metastatic breast cancer
MDA-MB-231 cells.7 The structural complexity of these sesqui-
terpenoids is increased by incorporating another ring system,
leading to anhydromarasmone (3) and marasmene (4), which
are metabolites isolated from Marasmius oreades featuring a [6-6-
5-5] tetracyclic skeleton.8 The molecular complexity also in-
creases rapidly by substituting the core skeleton, culminating in
the complicated left-wing fragment of azadirachtin.9
The conventional synthetic method toward these sesquiter-
penoids has focused on applying an intramolecular DielsÀAlder
reaction to construct the tricyclic core structure.10 Aiming at an
Received: July 21, 2011
Published: August 23, 2011
r
2011 American Chemical Society
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Table 1. Optimization of the Cascade Cyclization Conditions
for Synthesizing Tricyclic Lactone 7a
Table 2. Scope of Diynes in the Gold-Catalyzed Cascade
Reactiona
yield, %b
entry
catalyst
conditionsa
6
7
8
c
1
(Et3P)AuCl/AgSbF6
(Et3P)AuCl/AgSbF6
CH2Cl2, 10 min 70
0
0
2
CH2Cl2, 5 h
0
0
62
45
77
9
0
0
3
(p-CF3C6H4)3PAuCl AgSbF6 CH2Cl2, 1.5 h
4
(tBu3P)AuCl/AgSbF6
IMes)AuCl/AgSbF6
(IPr)AuCl/AgSbF6
(IPr)AuCl/AgBF4
(IPr)AuCl/AgNTf2
(IPr)AuCl/AgOTf
(IPr)AuCl/AgSbF6
(IPr)AuCl/AgSbF6
(IPr)AuCl/AgAgSbF6
CH2Cl2, 2 h
CH2Cl2, 12 hd
CH2Cl2, 0.8 h
CH2Cl2, 5 h
CH2Cl2, 10 h
CH2Cl2, 1 h
toluene, 0.8 h
MeCN, 12 h
THF, 6 h
0
0
5
72
0
0
6
86
43
62
10
60
0a
0
0
0
7
0
8
0
0
9
0
0
10
11
12
13
14
15
0
0
0
0
0
76
0
NaAuCl4 H2O
CH2Cl2, 6 hd
CH2Cl2, 12 h
CH2Cl2, 12 h
83
0
9
0e
0e
3
AgSbF6
0
a Conditions: diyne (0.1À0.2 mmol, 0.05 M), p-nitrobenzylic alcohol
(3 equiv), [(IPr)AuCl]/AgSbF6 (5 mol %), CH2Cl2, rt. Diynes and
products are racemic and isolated in >20:1 diastereomeric ratio, except
11 (dr = 10:1).
(Tf)2NHf
0
0
a [5] = 0.05 M (0.13 mmol), 3 equiv of p-nitrobenzylic alcohol. Products
are racemic. b Isolated yields after column chromatography. Without
c
alcohol. d Substrate 5 was consumed completely within 1 h. e Substrate 5
was recovered. f 10 mol % (Tf)2NH.
yield of 16 in 20 h, also sparing the second alkyne (entry 4).
Though diyne 17 provided the cascade cyclization product
18, the reaction yield was significantly lower than that of its
diastereomer 9 (entry 5). These results indicate that the cyclo-
alkane scaffold, as well as the trans relationship between two
alkynes, might be important for the second cyclization (6-exo-
dig). We envisioned that the challenging second cyclization
could be facilitated by increasing the nucleophilicity of the
polarized olefin resulting from the first cyclization (5-endo-dig),
which could be realized by reducing the carboxylic acid to a
primary alcohol. Consistent with this notion, diynes 19 and 21
respectively gave cascade cyclization products 20 and 22 in a
much higher yield compared to the carboxylic acid counterparts
13 and 17 (entries 6 and 7). However, when diynes 23 and 25
were subjected to the cascade reaction, 24 and 26 were formed
with similar efficiency compared to 7 and 10, respectively
(entries 8 and 9). Intriguingly, the [(IPr)AuCl]/AgSbF6 catalytic
system failed to effect any reaction of amide 27, simply resulting
in recovery of the starting material (entry 10).
To investigate the scope of external nucleophiles, we focused
on two diynes, 5 and 23, which are envisioned to deliver antrocin
analogues with a [6-6-5] tricyclic skeleton if successfully imple-
mented (Table 3). It turned out that phenol and sulfonamide
are suitable external nucleophiles for the reaction with substrate 5
(entries 1 and 2), but neither indole nor aniline provided the
desired tricyclic product. In comparison, diyne 23 reacted with
methanol and carbon-based nucleophiles (including allylsilane,
trimethoxybenzene, and indole) to give the corresponding cascade
cyclization products in synthetically useful yields (entries 3À6).
Similarly, diyne 21 afforded tricycle 34 in 81% yield with indole
while tri-tert-butylphosphine increased the yield to 77% (entries
3 and 4). Intriguingly, two carbene ligands provided 6 and 7 as
the major product respectively, with 1,3-bis(2,6-diisopropylphe-
nyl)imidazol-2-ylidene giving the best result (entries 5 and 6).15
Investigation of the counterion effect revealed that AgBF4,
AgOTf, and AgNTf2 led to a decreased yield compared to
AgSbF6 (entries 7À9). The use of different solvents also could
affect the reaction, as shown by the decreased yields of 7 in
toluene, THF, and acetonitrile (entries 10À12). Presumably, the
6-exo-dig cyclization (Figure 1, B) is not favorable in THF;
therefore, intermolecular addition of alcohol to the alkyne yields
8 as the major product. As a gold(III) catalyst, NaAuCl4 only
slightly promoted the second cyclization and afforded 6 as the
major product in 6 h (entry 13). Neither AgSbF6 nor the
Brønsted acid Tf2NH catalyzed any cyclization, both leading to
the recovery of starting material 5 (entries 14 and 15). Among
these reactions, 7 was obtained as a single diastereomer, the
structure of which has been determined unambiguously by X-ray
crystallography.
The scope of the cascade reaction was further explored with a
variety of substrates using the optimum conditions identified in
Table 1 (entry 6). Table 2 summarizes variations in 1,7-diyne
that affect the outcome of the reaction. Diynes 9 and 11 pro-
duced the corresponding [7-6-5] tricycle 10 and [5-6-5] tricycle
12, respectively, though 12 was obtained in a lower yield (entries
1 and 2). In contrast, linear diyne 13 did not give rise to any
identifiable cascade cyclization product but instead afforded 14
in 75% yield, even after a longer reaction time (entry 3). The
reaction of diyne 15, which is the diastereomer of 5, afforded 61%
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Table 3. Scope of External Nucleophiles in the
Gold-Catalyzed Cascade Reactiona
Scheme 2. Total Syntheses of Sesquiterpenoids 1À3a
a Reagent and conditions: (a) TEMPO (0.7 equiv), BAIB (1.2 equiv),
CH2Cl2, rt; (b) NaClO2 (8.0 equiv), 2-methylbutene, CH2Cl2, rt, 51%
over two steps; (c) BnOH (3.0 equiv), [(IPr)AuCl]/AgSbF6 (5 mol %),
CH2Cl2, rt, 54%; (d) DessÀMartin periodinane (1.5 equiv), NaHCO3
(3.0 equiv), CH2Cl2, rt, 95%; (e) mCPBA (3.0 equiv), CH2Cl2, rt, 96%;
(f) TfOH (2.0 equiv), CH2Cl2, À25 °C, 65%; (g) IBX (15.0 equiv),
a Conditions: diyne (0.1À0.2 mmol, 0.05 M), nucleophile (3 equiv),
[(IPr)AuCl]/AgSbF6 (5 mol %), CH2Cl2, rt, 1À20 h (see the Support-
ing Information). Diynes and products are racemic and isolated in >20:1
diastereomeric ratio.
Scheme 1. Total Synthesis of Marasmene (4)a
NMO (15.0 equiv), DMSO, 85 °C, 60%; (h) RhCl3 3H2O (0.5 equiv),
3
EtOH, reflux, 81%; (i) PhSeBr (2.0 equiv), THF/H2O, rt; (j) H2O2/
H2O, CH2Cl2, rt, 43% in two steps; (k) Na, NH3, THF, À78 °C; (l)
HCl, MeOH, 50 °C, 71% in two steps; (m) NaHMDS (1.5 equiv), CS2
(3.0 equiv), MeI (7.0 equiv), THF, rt; (n) nBu3SnH (2.0 equiv), AIBN
(0.1 equiv), toluene, 110 °C, 78% over two steps.
yield with >20:1 diastereoselectivity. The cyclization precursor,
diyne 39, was obtained by the reduction and desilylation of 38.
Gratifyingly, with benzylic alcohol as the external nucleophile,
the gold-catalyzed cascade reaction of 39 gave tricyclic com-
pound 40 in 96% yield as a single diastereomer,18 while the
presence of the secondary alcohol group did not interfere with
the reaction. The secondary alcohol then underwent Barton
reduction in 95% yield over a two-step sequence. Epoxidation of
the olefin in 41 with mCPBA followed by one-pot acid-catalyzed
epoxide-opening and intramolecular transacetalization gave maras-
mene (4) in 55% yield.
Encouraged by this result, we proceeded to make 1À3
(Scheme 2). Selective oxidation of the primary alcohol in diol
39 to an aldehyde, followed by further oxidation, afforded
carboxylic acid 42, which underwent the aforementioned gold-
catalyzed cascade cyclization to give the crucial intermediate
tricyclic 43 in 54% yield. Subsequent oxidations, epoxide-opening
and intramolecular transacetalization similar to those in synthe-
sizing 4, provided tetracyclic compound 44, which had been
achieved en route toward anhydromarasmone (3).10f Alter-
natively, introduction of a double bond conjugated to the ketone
could also be achieved by IBX oxidation, which gave 3 in 60%
yield. At this stage, we anticipated that kuehneromycin A (1)
could also be synthesized from 44. Olefin isomerization of 44
following conditions reported by Jauch and co-workers provided
45 in 81% yield.10f The vinyl ether moiety was set ready for
oxidation using PhSeBr,19 after which treatment with hydrogen
peroxide gave rise to 1 in moderate yield over two steps. Last, we
carried out the synthesis of antrocin (2) by executing a sequence
a Reagent and conditions: (a) 36 (2.5 equiv), CuBr Me2S (0.3 equiv),
3
THF, À78 °C; (b) 37 (1.4 equiv), TBAF/THF (1.4 equiv), À40 °C,
58% over two steps; (c) LiAlH4 (4.0 equiv), THF, rt, 87%; (d) KOH
(5.0 equiv), THF/MeOH/H2O, reflux, 95%; (e) BnOH (3 equiv),
[(IPr)AuCl]/AgSbF6 (5 mol %), CH2Cl2, rt, 96%; (f) NaHMDS (1.5
equiv), CS2 (3 equiv), MeI (7 equiv), THF, rt; (g) nBu3SnH (4.0 equiv),
AIBN (0.1 equiv), toluene, 110 °C, 95% over two steps; (h) mCPBA
(2.0 equiv), CH2Cl2, rt, 95%; (i) PTSA (1.2 equiv), CHCl3, 50 °C, 58%.
as the external nucleophile (entry 7; structures of 33 and 34 have
been confirmed by X-ray crystallography).
After establishing the gold-catalyzed tandem reaction, we
moved toward the total syntheses of various interested drimane-
type sesquiterpenoids (Scheme 1). Conjugated addition of
Grignard reagent 36 to known cyclohexenone 35,16 followed
by treatment with hypervalent iodine reagent 37,17 assembled
two alkynes on the cyclohexyl skeleton to give 38 in 58% overall
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of reductions of 43. Interestingly, we found that the ketal in 43
could be reduced under Birch reduction conditions, and sub-
sequent acid-catalyzed lactonization furnished 46 in 71% yield
over two steps. Eventually, straightforward Barton reduction of
46 led to 2 in 78% yield. The 1H NMR and 13C NMR spectra of
the synthesized sesquiterpenoids 1À4 (racemic) are identical to
the published data of naturally occurring compounds.5,6,8,10a
In summary, we have developed a unified strategy for the
syntheses of drimane-type sesquiterpenoids based on an enabling
gold-catalyzed tandem reaction under mild conditions. This
strategy has not only accomplished the first total syntheses of
antrocin (2) and marasmene (4) but also provided an efficient
approach to access analogues of biologically active drimane-type
sesquiterpenoids. The mechanism of the tandem reaction, espe-
cially the 6-exo-dig cyclization followed by external nucleophilic
attack, deserves further investigation. Preparation of enantiopure
38, which is contemplated to automatically lead to enantioselec-
tive syntheses of 1À4, is underway and will be reported in due
course.
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, compound characterization data, and CIFs for 7, 33, and
34. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
chuangli@pku.edu.cn; tuoping.luo@gmail.com; zyang@pku.edu.cn
Present Addresses
‡H3 Biomedicine Inc., 300 Technology Square, Cambridge,
MA 02139
’ ACKNOWLEDGMENT
We thank Prof. Yefeng Tang (Tsinghua University) and Prof.
Weiping Tang (University of WisconsinÀMadison) for helpful
discussions. This work has been supported by 973 Program
(Grants 2010CB833201, 2009CB940904), the National Science
and Technology Major Project (2009ZX10004-016), the NSFC
(21172009, 20832003, 20902007 and 91013004), and the Shenzhen
Basic Research Program (Nos. JC200903160352A, JC201005260097A,
and CXB201005260053A).
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