Rh-Catalyzed [3 + 2] Cycloaddition of 1-Sulfonyl-1,2,3-triazoles: Access to the Framework of Aspidosperma and Kopsia Indole Alkaloids

Article abstract of DOI:10.1021/acs.orglett.6b01968

A Rh(II)-catalyzed dearomative intramolecular [3 + 2] dipolar cycloaddition involving the indolic C2-C3 carbon-carbon double bond has been developed. The reaction was launched from the triazole moiety within the substrate and proceeded efficiently under m

Full text of DOI:10.1021/acs.orglett.6b01968

Letter
pubs.acs.org/OrgLett
Rh-Catalyzed [3 + 2] Cycloaddition of 1‑Sulfonyl-1,2,3-triazoles:
Access to the Framework of Aspidosperma and Kopsia Indole
Alkaloids
Yun Li,*,†,‡ Qingyu Zhang,† Qiucheng Du,† and Hongbin Zhai*,†,⊥
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engeneering, Lanzhou University, Lanzhou
730000, China
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
⊥Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: A Rh(II)-catalyzed dearomative intramolecular [3 + 2] dipolar cycloaddition involving the indolic C2−C3
carbon−carbon double bond has been developed. The reaction was launched from the triazole moiety within the substrate and
proceeded efficiently under mild conditions. A wide range of functional groups could be tolerated. These features render the
current reaction a highly useful tool for the synthesis of polycyclic indole alkaloids, as showcased by a rapid assembly of the core
structure of Aspidosperma and the related alkaloids.
ndole alkaloids represent a plethora of small molecules with
unparalleled structural diversity.1 Because of their intriguing
1-Sulfonyl-1,2,3-triazoles are readily prepared from terminal
alkynes and N-sulfonyl azides by copper-catalyzed 1,3-dipolar
cycloaddition. These compounds could serve as convenient
precursors of α-imino metallocarbenes on treatment with
rhodium(II) salts which were originally reported by Fokin and
Gevorgyan.5 The resulting α-imino metallocarbenes are very
electrophilic and can undergo a variety of useful trans-
formations.6 In most cases, such species (A1) act as a formal
N,C 1,3-dipole equivalent7 (Scheme 1, route a) in the reactions
with nitriles,5 aldehydes,8 imines,8 alkynes,9 isocyanates,10
indoles,11 allenes,12 or aromatic rings7 to form a five-membered
ring system.
I
chemical structures and significant biological properties2
exemplified by strychnine, tubotaiwine, and vindoline (Figure
1), indole alkaloids are broadly considered to be attractive
It is conceivable that trapping of the electrophilic α-imino
carbene with a carbonyl group properly located within the same
molecule would lead to an oxonium ylide,13 which could serve
as a C,C 1,3-dipole (A2) capable of generating a substituted
tetrahydrofuran through a cycloaddition with an olefin (Scheme
1, route b). In contrast to the oxonium ylide generated from α-
diazo keto derivatives, reported previously by Padwa and co-
workers,4e,13a,c the current imido oxonium ylide-based reaction
could have two advantages. (1) The resulting imine motifs
would facilitate their further transformation into the corre-
Figure 1. Some bioactive indole alkaloids.
synthetic targets. Many effective approaches for the stereo-
selective construction of various annulated indoline arrays3
have thus been developed. In this regard, we were attracted to
the idea of using an intramolecular [3 + 2] cycloaddition
approach to access such structures in a single operation. Herein,
we report a novel 1-sulfonyl-1,2,3-triazole-triggered intra-
molecular dipolar cycloaddition of indole which provides a
rapid and practical entry to Aspidosperma and Kopsia alkaloid
core structures to represent a useful complement to existing
elegant studies.4
Received: July 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01968
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 1. Formal [3 + 2] Cycloaddition of Metallocarbenes
Table 1. [3 + 2] Cycloaddition of 1a
b
entry
catalyst
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(oct)4
DCM
25
90
NR
62
20
45
42
73
87
CHCl3
hexane
1,2-DCE
PhMe
90
90
120
90
CHCl3
CHCl3
c
7
Rh2(oct)4
140
a
All reactions were performed with 0.1 mmol of triazole 1a and 2 mol
b
c
% of the Rh catalyst. Isolated yield. Performed in a microwave
reactor.
of anhydrous solvent and high dilution (0.02 M) proved
essential for the reaction.
Facile formation of the tetracyclic moiety present in many
indole alkaloids from readily available triazole 1a prompted us
to further study the scope of the current rhodium-catalyzed
intramolecular [3 + 2] cycloaddition. As shown in Figure 2, this
sponding aldehydes or sulfonamides, which would greatly
expand the structural diversity of the products. (2) Without the
extra carbonyl present in ylide A2 in our case, the ylide would
be more reactive and prefer dipolar cycloaddition rather than
undergoing an intramolecular 1,3-hydrogen transfer to afford a
furanone, a product generated from ylide A3 (route c, the 3 + 2
cycloaddition does not occur if a hydrogen atom exists at C2 in
the α-diazoketo substrate).14
It is well-known that intramolecular cycloaddition reactions
can offer a quick assembly of structural complexities. We
envisioned that tryptamine-derived indolyl-1-tosyl-1,2,3-tria-
zoles might provide the tetracyclic scaffolds of aspidosperma
and kopsia alkaloids upon treatment with rhodium(II) salts if
the imido oxonium ylide could be successfully generated
(Scheme 2). These promising features promoted us to evaluate
the feasibility of this synthetic method in our lab.
Scheme 2. Rh-Catalyzed Intramolecular Dipolar
Cycloaddition
Figure 2. Rh-catalyzed cycloaddition of triazoles. Reactions performed
(in a sealed tube) with 1 (0.1 mmol) and Rh2(oct)4 (2 μmol) in
CHCl3 (5 mL) at 140 °C for 10 min in a microwave reactor unless
otherwise noted, with yields referring to isolated yields after
chromatography on silica gel.
Our investigations began with the reaction of 1a in the
presence of a rhodium catalyst. Although with Rh2(OAc)4 as
the catalyst no desired cyclization product was detected in
DCM at room temperature (Table 1, entry 1), the cyclo-
addition15 did proceed at a higher temperature (90 °C) in
CHCl3 to give the expected 2a as a single isomer in 62% yield
(entry 2). The structure of 2a was secured by both NMR data
and an X-ray crystallographic analysis of 3n.16 Further
examinations of the reaction conditions showed that CHCl3
was the best solvent, while Rh2(oct)4 was a more effective
catalyst, especially at higher temperatures (see Table 1).
Notably, the yield could be further improved to 87% under
microwave irradiation at 140 °C in a sealed tube (entry 7). Use
protocol tolerated a variety of functionalities on both the indole
moiety and the amido tether. Considering the commercial
availability, trypitamine and its C5-methoxyl derivative were
chosen as the starting material of the substrates, the reaction
results revealed the substituents on the indole N1 (Me, Bn)
and C5 positions (H, MeO) had little influence on the reaction.
The reactants with an N-tosyl group on the nitrogen atom
within the amide tether also gave good to excellent yields
(2c,d). The substrates with a cyclic imido tether (1e−g) were
B
DOI: 10.1021/acs.orglett.6b01968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
also transformed smoothly into the pentacyclic Aspidosperma
skeleton in good yields (2e−g).
substituent on the indole C5 position showed only a negligible
influence on the cyclization. However, an electronic-rich group
(such as methyl or benzyl) on the indolic nitrogen N1 position
was essential for the success of the cyclization, while
carbomethoxy derivatives did not form any desired products
at all. On the other hand, the substitution at the amido nitrogen
atom with an acyl or sulfonyl group (Boc, Bz, Ts, Ns) only had
a minor influence on the reaction. The substrates with different
groups at the amido tether reacted smoothly to deliver the
corresponding products (3a−h) in yields ranging from 52% to
85%. As expected, triazoles containing either a tosyl or a mesyl
behaved similarly (3i, 3j). The substrates with a cyclic 6-
membered tether (3k−n) generally gave the products in higher
yields, while their counterparts with a 5-membered imido tether
led only to a complex mixture, presumably due to the steric
strain.
It was found that the [3 + 2] cycloaddition products
(aldehydes after hydrolysis) were not so stable. Therefore,
direct reduction before reaction workup and product
purification appeared to be more appropriate. After several
sets of reaction conditions were screened,17 NaBH4 in THF
containing 1% MeOH was found to give the best results,
providing the more stable secondary sulfonamides as a single
isomer in reasonable to good yields. As shown in Figure 3, a
more extensive scope exploration was then conducted by
adopting the one-pot cyclization−reduction process. In general,
the reaction displayed good functional group tolerance, and in
all cases, the resulting indolines were obtained as a single
isomer. A variety of substituents on the indole, the amido
tether, and triazole moieties were extensively evaluated. The
To test the practicality of our protocol, a gram-scale
preparation of 3o was executed. Triazole 1o was prepared
(3.8 g for a single synthetic sequence) from tryptamine via a
four-step straightforward synthesis18 (Scheme 3). Compound
Scheme 3. Gram-Scale Synthesis of 3o
1o was heated in the presence of 2 mol % of Rh2(oct)4 in
CHCl3, and this was followed by reduction with NaBH4 to
afford 3o in 69% yield (1.2 g-scale). It is noteworthy that the
above-mentioned cycloaddition showed distinct diastereoselec-
tivitiy; the transition state TS1 (see the Supporting
Information) seemed to be more favored and therefore gave
the desired product.
In conclusion, we have developed a rhodium-catalyzed
intramolecular [3 + 2] cycloaddition with N-sulfonyl-1,2,3-
triazoles as the 1,3-dipole precursor, which showed excellent
stereoselectivity and allowed for a quick access to the scaffold of
Aspidosperma- and Kopsia-related alkaloids. In contrast to
previously reported N-sulfonyl-1,2,3-triazole-based [3 + 2]
cycloaddition reactions, the present protocol generates in situ a
C,C-1,3 dipole synthon for the subsequent cycloaddition and
thus provides a new entry to the polysubstituted tetrahydrofur-
ans. Based upon its operational simplicity and the mild reaction
conditions, the current approach may open up a new and
efficient access to an array of valuable indole alkaloid analogues.
Figure 3. Scope of the Rh-catalyzed cycloaddition. Reactions
performed (in a sealed tube) with 1 (0.1 mmol) and Rh2(oct)4 (2
μmol) in CHCl3 (5 mL) at 140 °C for 10 min in a microwave reactor.
The crude product after removal of the solvent was then treated with
NaBH4 (0.2 mmol) in THF (2 mL) and MeOH (20 μL) at rt for 5 h,
with yields referred to two-step isolated ones after chromatography on
silica gel.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01968.
C
DOI: 10.1021/acs.orglett.6b01968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
Synthetic procedures; H and 13C NMR spectra for all
241−251. (g) Choi, Y.; Ishikawa, H.; Velcicky, J.; Elliott, G. I.; Miller,
M. M.; Boger, D. L. Org. Lett. 2005, 7, 4539−4542.
(5) (a) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2007, 46, 4757−4759. (b) Horneff, T.; Chuprakov, S.;
Chernyak, N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130,
14972−14974.
organic products (PDF)
X-ray data of compound 3n (ZIP)
AUTHOR INFORMATION
■
(6) Davies, H. M. L.; Alford, J. S. Chem. Soc. Rev. 2014, 43, 5151−
5162. (b) Chattopadhyay, B.; Gevorgyan, V. Angew. Chem., Int. Ed.
2012, 51, 862−872. (c) Gulevich, A. V.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2013, 52, 1371−1373.
Corresponding Authors
*E-mail: liyun@lzu.edu.cn.
*E-mail: zhaihb@pkusz.edu.cn.
Notes
(7) Miura, T.; Funakoshi, Y.; Murakami, M. J. Am. Chem. Soc. 2014,
136, 2272−2275.
The authors declare no competing financial interest.
(8) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2013, 52, 1507−
1510.
ACKNOWLEDGMENTS
(9) (a) Chattopadhyay, B.; Gevorgyan, V. Org. Lett. 2011, 13, 3746−
3749. (b) Shi, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 5394−5396.
(10) Chuprakov, S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc.
2013, 135, 4652−4655.
■
This research was supported by the National Natural Science
Foundation of China (21302078, 21572089, 21290183),
Program for Changjiang Scholars and Innovative Research
Team in University (PCSIRT: IRT_15R28), FRFCU (lzujbky-
2016-ct02, lzujbky-2016-52), and SRFDP (20130211120020).
We thank Profs. Tse-Lok Ho and Yikang Wu of SIOC for
enlightening discussions as well as assistance in manuscript
revision.
(11) (a) Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135,
6802−6805. Bora, P. P.; Luo, Z.-L.; Chen, L.; Kang, Q. Tetrahedron
2016, 72, 1467−1471.
(12) (a) Schultz, E. E.; Sarpong, R. J. Am. Chem. Soc. 2013, 135,
4696−4699. (b) Miura, T.; Hiraga, K.; Biyajima, T.; Nakamuro, T.;
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(13) For the reactions of carbonyl ylide, see: (a) England, D. B.;
Padwa, A. J. Org. Chem. 2008, 73, 2792−2802. (b) Hirata, Y.;
Nakamura, S.; Watanabe, N.; Kataoka, O.; Kurosaki, T.; Anada, M.;
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(15) The innate generated sulfonyl imine product could be identified
by the 1H NMR spectrum (see the SI) using the directly concentrated
resulting reaction mixture. However, the sole product changed to
corrresponding aldehyde after the sillica gel chromatography with
elution containing 5% triethylamine.
(16) CCDC1463221 (3n) contains the supplementary crystallo-
graphic data for this paper. Data can be obtained free of charge from
the Cambridge Crystallographic Data Centre.
(17) Reduction of the resulting sulfonyl imines with NaBH4, NaBH
(OAc)3, or Na(CN)BH3 in classical protic solvents such as MeOH,
EtOH or i-PrOH led to total decomposition of product, while DABAL
or LiAl(OtBu)3H in THF gave low yields.
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Org. Lett. XXXX, XXX, XXX−XXX