Asymmetric total synthesis of mycoleptodiscin A

Article abstract of DOI:10.1002/anie.201501021

The first total synthesis of mycoleptodiscin A, a structurally unusual indolosesquiterpenoid possessing an ortho-benzoquinone motif, has been accomplished. A sulfone alkylation coupled two readily available fragments to give an aryl triene intermediate. The tetracyclic core of the molecule was assembled through a highly enantioselective iridium-catalyzed polyene cyclization. The benzylic homologation was achieved by a cationic cyanation. The indole motif was constructed via a copper-mediated intramolecular C-N bond formation at a late stage.

Full text of DOI:10.1002/anie.201501021

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501021
German Edition: DOI: 10.1002/ange.201501021
Natural Product Synthesis
Asymmetric Total Synthesis of Mycoleptodiscin A**
Shupeng Zhou, Hao Chen, Yijie Luo, Wenhao Zhang, and Ang Li*
Abstract: The first total synthesis of mycoleptodiscin A,
a structurally unusual indolosesquiterpenoid possessing an
ortho-benzoquinone motif, has been accomplished. A sulfone
alkylation coupled two readily available fragments to give an
aryl triene intermediate. The tetracyclic core of the molecule
was assembled through a highly enantioselective iridium-
catalyzed polyene cyclization. The benzylic homologation was
achieved by a cationic cyanation. The indole motif was
a structural perspective, 1 contains an indole motif linked to
the sesquiterpenoid framework at the C4 position, which is
relevant to indole terpenoids such as hapalindole H (3) and
petromindole (4).[5,6] Biosynthetically, a Friedel–Crafts reac-
tion may be responsible for the indole C4 alkylation.
However, this seemingly straightforward biomimetic trans-
formation proves to be problematic in chemical synthesis,
which is due to the lower nucleophilicity at C4 than that at C2.
A few elegant alternative strategies have been developed to
address the issue, such as reductive Heck annulation[7] and
indoline Friedel–Crafts cyclization.[8] In the particular case of
1, the unusual ortho-benzoquinone moiety brings extra
difficulties to the execution of these strategies; for instance,
for the reductive Heck approach, preparing the 4-Br indole
precursor is non-trivial. Thus, the synthesis of 1 could be
divided to two problems: 1) assembly of the multisubstituted
indole motif;[9] and 2) construction of the sesquiterpenoid
framework in an asymmetric fashion. Herein, we describe the
first total synthesis of 1 using a highly enantioselective Ir-
catalyzed polyene cyclization and a Cu-mediated aryl amina-
tion to solve the above problems.
ꢀ
constructed via a copper-mediated intramolecular C N bond
formation at a late stage.
I
ndolosesquiterpenoids have recently attracted much atten-
tion in the fields of chemical synthesis and biosynthesis .[1–3]
Mycoleptodiscins A and B (1 and 2, Figure 1) are a pair of
We undertook a retrosynthetic analysis of 1 (Scheme 1).
The ortho-benzoquinone moiety could be masked as a cat-
Figure 1. Mycoleptodiscins A and B and related C4-alkylated indole
terpenoids.
indolosesquiterpenoids isolated by Cubilla-Rios et al. from
endophytic fungus Mycoleptodiscus sp. in 2013.[4] Compound
2 displays significant cytotoxicity against cancer cell lines,
while the biological activity of 1 was not reported, which is
possibly due to its scarcity from the natural source. From
[*] S. Zhou,[+] H. Chen,[+] Y. Luo, W. Zhang, Prof. Dr. A. Li
State Key Laboratory of Bioorganic and Natural Products Chemistry
Collaborative Innovation Center of Chemistry for Life Sciences
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: ali@sioc.ac.cn
Scheme 1. Retrosynthetic analysis of mycoleptodiscin A.
Homepage: http://angligroup.sioc.ac.cn
[+] These authors contributed equally to this work.
echol dimethyl ether. The indole system was disassembled at
ꢀ
the C17 N bond to give an intermediate such as 5. A
[**] Financial Support was provided by the Ministry of Science &
Technology (2013CB836900) and the National Natural Science
Foundation of China (21290180, 21172235, and 21222202).
transition-metal-mediated aryl amination reaction was envi-
sioned for the ring closure. Compound 5 was further
simplified to a tetracycle such as 6, and a cationic cyanation
was anticipated to effect the homologation. The C17
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501021.
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methoxyl could serve as the precursor of a triflate. The
enantioselective synthesis of 6 would be a key step. The
Carreira cyclization,[10] namely the Ir-catalyzed asymmetric
polyene cyclization, has emerged as a powerful method in
organic synthesis.[11,12] We recently applied it to the total
synthesis of taiwaniadducts.[13] However, in most cases, the
reaction was used for assembling bi- and tricyclic systems.
Carreira described the only example of tetracycle forma-
tion;[10] it would be interesting to showcase such a tandem
cyclization in natural product synthesis. We considered aryl
triene 7 as a cyclization precursor, and the electron-rich arene
may facilitate the final Friedel–Crafts type trapping of the
cation intermediate. Compound 7 was traced back to sulfone
8 and bromide 9, the coupling of which may rely on alkylation
and reductive desulfonation.[14] Both 8 and 9 could be readily
prepared from commercially available materials.
The synthesis commenced with preparing the polyene 7
(Scheme 2). Farnesyl acetate (10) was subjected to a three-
step sequence (dihydroxylation, diol cleavage, and methyle-
nation) developed by Schulz et al. to reach terminal olefin
11.[15] Positional selective hydroboration followed by peroxide
cleavage afforded alcohol 12 (86%). Dess–Martin oxidation
formed the aldehyde, exposure of which to vinylMgBr gave
a secondary allylic alcohol. The alcohol underwent silyl
protection and deacetylation to afford primary alcohol 13
with good overall efficiency. Bromination gave compound 9,
which is unstable against moisture and thus needs to be
directly subjected to the next alkylation in a crude form.
Scheme 2. Total synthesis of mycoleptodiscin A. Reagents and conditions: a) 9-BBN (1.05 equiv), THF, 228C, 24 h, then aq. NaHCO3, aq. H2O2 (30 wt%),
08C, 2 h, 86%; b) DMP (1.2 equiv), CH2Cl2, 228C, 1 h, 90%; c) vinylmagnesium bromide (1.05 equiv), THF, ꢀ788C, 1 h, 87%; d) TBSCl (1.1 equiv),
imidazole (1.2 equiv), DMF, 228C, 1 h; K2CO3 (1.0 equiv), MeOH, 228C, 2 h, 98%; e) MsCl (3.0 equiv), Et3N (5.0 equiv), LiBr (10.0 equiv), THF, ꢀ208C, 1 h;
f) KHMDS (1.05 equiv), THF, ꢀ788C, 1 h, then 9, ꢀ788C, 1 h, 85% (2 steps); g) Na(Hg) (2.0 equiv), Na2HPO4 (4.5 equiv), MeOH, ꢀ208C, 1 h; h) HF·py/
THF (1:10), 228C, 4 h, 82% (2 steps); i) [{Ir(cod)Cl}2] (4 mol%), R-15 (16 mol%), Zn(OTf)2 (20 mol%), DCE, 228C, 16 h, 21% of 6 + 58% of cascade-
interruption products; j) BF3·OEt2 (2.5 equiv), CH2Cl2, 08C, 1 h, 87%; k) K2OsO2(OH)2 (10 mol%), 2,6-lutidine (1.0 equiv), NaIO4 (3.0 equiv), acetone/water
(3:1), 228C, 8 h, 84%; l) tBuOK (10 equiv, MeI (10 equiv), tBuOH, 3 h, 89%; m) N2H4·H2O (10.0 equiv), diethylene glycol, 1608C, 2 h, then KOH
(10.0 equiv), 1808C, 4 h, 81%; n) 3,5-dimethylpyrazole (20.0 equiv), CrO3 (20.0 equiv), 08C, 1 h, 85%; o) AlCl3 (1.1 equiv), CH2Cl2, 228C, 2 h, 87%;
p) NaBH4 (1.0 equiv), MeOH/CH2Cl2 (1:1), 08C, 30 min, 92%; q) TMSBr (20 mol%), InCl3 (10 mol%), TMSCN (1.2 equiv), MeCN, 228C, 1 h, 89%;
r) BH3·THF (2.1 equiv), THF, 508C, 3 h; s) Tf2O (2.1 equiv), Et3N (3.0 equiv), 4-DMAP (10 mol%), CH2Cl2, 08C, 30 min, 73% (2 steps); t) CuI (4.0 equiv),
CsOAc (10.0 equiv), NMP, 1608C, 4 h, 64%+27% of recovered 5; u) DDQ (5.0 equiv), toluene, 1108C, 4 h, 71%; v) BBr3 (10.0 equiv), CH2Cl2, ꢀ78!228C,
15 min, then 228C, 30 min; w) Mg (10.0 equiv), NH4Cl (2.0 equiv), MeOH, sonication, 5 min, then work up under an air atmosphere, 89% (2 steps).
cod=1,5-cyclooctadiene, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 4-DMAP=4-dimethylaminopyridine, DMP=Dess–Martin periodinane,
KHMDS=potassium hexamethyldisilazane, Ms=methanesulfonyl, OTf=triflate, TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl.
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Table 1: Investigation of conditions for benzylic cyanation.
Treatment of 9 with the carbanion of sulfone 8 provided the
alkylation product in 85% yield, and reductive desulfonation
(sodium amalgam) occurred smoothly to furnish compound
14.[14] In this case, the above route is more efficient and
flexible than the previous ones used by Carreira[10] and us[13]
for preparing similar polyene precursors (the Suzuki–Miyaura
coupling approach, see the Supporting Information for
comparison). Desilylation of 14 gave 7 in 82% yield for the
two steps.
Entry
Conditions[a]
Yield of 18 [%]
1
2
3
4
5
6
7
8
BF3·OEt2, CH2Cl2, 08C
FeCl3, CH2Cl2, 228C
Bi(OTf)3, CH2Cl2, 228C
Zn(OTf)2, CH2Cl2, 228C
InBr3, CH2Cl2, 228C
InCl3, CH2Cl2, 228C
InCl3, MeCN, 228C
InCl3, TMSBr (0.2 equiv), MeCN, 228C
44
57
46
52
68
66
71
89
We then investigated the enantioselective cascade cycli-
zation (Scheme 2). Under the standard conditions (namely
[{Ir(cod)Cl}2], ligand R-15, Zn(OTf)2), the desired product 6
was isolated in 21% yield. A large portion of cascade-
interruption products (presumably 6a and 6b)[16] were
obtained in 58% yield. Exposure of this mixture to
BF3·OEt2 gave another portion of 6 (87%), which increased
its overall yield to 71% (from 7). The relative stereochemistry
of 6 was determined by X-ray crystallographic analysis[17]
(Figure 2), and its enantiopurity was measured to be > 99%
ee by HPLC after further derivatization. The cyclization was
reliably performed on gram scale.
[a] 10 mol% of catalyst, 2.0 equiv of TMSCN.
structure was confirmed by X-ray crystallographic analysis[17]
(Figure 2). The cyano group possesses a pseudo-equatorial
conformation. Reduction of 18 with BH3·THF gave a primary
amine, which was directly subjected to triflating conditions to
give compound 5.[21]
ꢀ
The completion of the synthesis relied on a C N bond
forming reaction. We first examined the conditions of
Buchwald–Hartwig amination[22] on the basis of the inves-
tigations by Shekhar and co-workers with relevant substrates
(sulfonamides and sulfonates).[23] Under their optimized
conditions ([Pd2(dba)3], tBuXphos, K3PO4, tAmOH, 80–
1008C), the desired cyclization was not observed. Instead,
the release of the free phenol through triflate hydrolysis
occurred after prolonged reaction times. We tested ligands
(CyXphos, Sphos, BINAP, Xantphos, Josiphos-CyPFtBu), Pd
sources (Pd(OAc)2, [{Pd(allyl)Cl}2], PdCl2), solvents (1,4-
dioxane, toluene), and inorganic bases (Cs2CO3, K2CO3)
orthogonally, but failed to detect the cyclization product.
Although Cu-mediated amination reactions of aryl triflates
are rather rare compared with those of halides,[24,25] a proce-
dure (CuI, CsOAc, NMP) modified from that of Fukuyama et
al.[26] delivers the indoline in 64% yield along with 27% of
recovered 5. Notably, NMP was a superior solvent to
previously reported DMSO[26] (< 20% yield) in this case.
DDQ oxidation of the indoline gave indole derivative 19
(71%). A sequence of methyl deprotection, reductive desul-
fonation, and spontaneous aerobic oxidation provided myco-
leptodiscin A (1) with good overall efficiency. The spectra and
physical properties of the synthetic sample are identical with
those reported for the natural product, which verifies its
absolute configuration.
Figure 2. ORTEPs of tetracycle 6 and nitrile 18.
We functionalized the tetracyclic core (Scheme 2).
Although the conversion of the vinyl to the desired gem-
dimethyl consumes additional efforts, the intermediates along
the route provide opportunities for syntheses of analogues
with higher oxidation states. Compound 6 underwent a one-
pot dihydroxylation/cleavage, and the resultant aldehyde was
C-methylated by treatment with tBuOK and MeI to afford
compound 16 as a single diastereomer bearing an axial
aldehyde substituent. Wolff–Kishner–Huang reduction
(N2H4, then KOH, diethylene glycol)[18] followed by benzylic
oxidation[19] gave ketone 17 with good overall efficiency. The
carbonyl group served as a handle for the homologation
process. Demethylation of 17 with AlCl3 followed by NaBH4
reduction provided a mixture of diastereomeric alcohols (ca.
1:1, inconsequential), setting the stage for the homologation.
We examined a variety of conditions for benzylic cyana-
tion (Table 1). Exposure of the benzylic alcohol to BF3·OEt2
and TMSCN gave nitrile 18 in 44% yield (Entry 1), and
severe decomposition of the starting material was observed.
Lewis acids such as FeCl3, Bi(OTf)3, and Zn(OTf)2
(Entries 2–4) failed to improve the cyanation efficiency.
Inspired by the work of Baba and co-workers,[20] we found
that InBr3 and InCl3 are more effective promoters (Entries 5
and 6), and MeCN is a superior solvent (Entry 7). Finally, the
combination of InCl3 and TMSBr turned out to be optimal,[20b]
and 18 was obtained in 89% yield as a single diastereomer. Its
In summary, we have accomplished the total synthesis of
1. A scalable asymmetric Ir-catalyzed polyene cyclization was
exploited to assemble its core structure. A Cu-mediated aryl
amination using a triflate substrate was responsible for the
construction of the multisubstituted indole moiety. The
chemistry developed may facilitate the biological and bio-
synthetic studies of the mycoleptodiscin family and find more
applications in indole terpenoid synthesis.
ꢀ
Keywords: allylic substitution · C N bond formation ·
indole terpenoids · iridium catalysis · polyene cyclization
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
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next C N bond formation.
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Angewandte
Chemie
[22] Selected recent reviews: a) J. F. Hartwig, Acc. Chem. Res. 2008,
41, 1534; b) D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed.
2008, 47, 6338; Angew. Chem. 2008, 120, 6438.
[23] S. Shekhar, T. B. Dunn, B. J. Kotecki, D. K. Montavon, S. C.
Cullen, J. Org. Chem. 2011, 76, 4552.
[24] Selected examples of copper mediated amination of aryl halides:
a) D. Ma, Y. Zhang, J. Yao, S. Wu, F. Tao, J. Am. Chem. Soc. 1998,
120, 12459; b) A. Kiyomori, J. F. Marcoux, S. L. Buchwald,
Tetrahedron Lett. 1999, 40, 2657; c) A. Klapars, J. C. Antilla, X.
Huang, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727; d) D.
Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450.
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Am. Chem. Soc. 2006, 128, 7136; e) K. Okano, H. Tokuyama, T.
Fukuyama, Chem. Asian J. 2008, 3, 296; f) K. Okano, H.
Fujiwara, T. Noji, T. Fukuyama, H. Tokuyama, Angew. Chem.
Int. Ed. 2010, 49, 5925; Angew. Chem. 2010, 122, 6061; g) H.
Tokuyama, K. Okano, H. Fujiwara, T. Noji, T. Fukuyama, Chem.
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2002, 231; b) M. Pineschi, F. Bertolini, P. Crotti, F. Macchia, Org.
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[25] Selected applications in natural product synthesis: a) D. Ma, C.
Xia, J. Jiang, J. Zhang, Org. Lett. 2001, 3, 2189; b) A. Fꢂrstner, V.
Mamane, Chem. Commun. 2003, 2112; c) K. Yamada, T.
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Received: February 3, 2015
Revised: March 5, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
Natural Product Synthesis
The first and enantioselective total syn-
thesis of mycoleptodiscin A (see picture),
a structurally unusual indolosesquiterpe-
noid, is accomplished by using iridium-
catalyzed polyene cyclization and copper-
S. Zhou, H. Chen, Y. Luo, W. Zhang,
A. Li*
&&&& — &&&&
ꢀ
Asymmetric Total Synthesis of
Mycoleptodiscin A
mediated C N bond forming reactions as
key steps.
6
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!