Enantioselective Assembly of Spirolactones through NHC-Catalyzed Remote β-Carbon Addition of Enals with Isatins

Article abstract of DOI:10.1021/acscombsci.5b00197

A chiral N-heterocyclic carbene (NHC)-catalyzed formal [4 + 2] annulation of β-methyl substituted enals with isatins was developed to construct six-membered spirolactones bearing highly congested quaternary carbon stereocentersin good yields and high enan

Full text of DOI:10.1021/acscombsci.5b00197

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Letter
Enantioselective Assembly of Spirolactones through NHC-
Catalyzed Remote #-Carbon Addition of Enals with Isatins
Xianfeng Rong, Hong Yao, Wenjing Xia, Yonglei Du, Yu Zhou, and Hong Liu
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.5b00197 • Publication Date (Web): 30 Mar 2016
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Enantioselective Assembly of Spirolactones through
NHC-Catalyzed Remote γ-Carbon Addition of Enals
with Isatins
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Xianfeng Ronga, b, Hong Yaob, Wenjing Xiab, Yonglei Dua, b, Yu Zhoub, *, and Hong Liub, *
a Nano Science and Technology Institute, University of Science and Technology of China, 166
Ren Ai Road, Suzhou 215123. b CAS Key Laboratory of Receptor Research, Shanghai Institute
of Materia Medica, Chinese Academy of Sciences 555 Zuchongzhi Road, Shanghai 201203, P.
R. China.
KEYWORDS: isatins; γ-carbon; spirolactones.
ABSTRACT: A chiral N-heterocyclic carbene (NHC)-catalyzed formal [4+2] annulation of
β-methyl substituted enals with isatins was developed to construct six-membered spirolactones
bearing highly congested quaternary carbon stereocentersin good yields and high
enantioselectivities. The strategy realized a challenging remote γ-carbon addition of enals and
chiral control of β-methyl substituted enals in the presence of the NHC catalyst only.
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Introduction
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Spiroheterocycles have become attractive targets in organic synthesis because of their
widespread distribution in biologically active pharmaceuticals and natural products, and their
increasing use in a range of vital chemical and technological processes, such as asymmetric
synthesis and organic optoelectronics.1 Therefore, the development of novel methods to
construct spirocyclic frameworks is of great importance, particularly when these methods lead to
the enantioselective formation of a quaternary stereocenter, which itself is considered a
meaningful transformation.2,3 Spirolactone is an intriguing spiroheterocyclic compound
involving a tetra substituted quaternary stereocenters. Several methods, including alkylation,4
transition-metal-based approaches,5 rearrangement-based approaches,6 ring-expansion method,7
ring-contraction methods,8 photochemical approaches,9 ring closure of geminally disubstituted
compounds,10 the Diels-Alder [4+2] approach,11 ring-closing-metathesis12 and other methods,
have been employed successfully to construct these pharmacologically intriguing scaffolds.
However, the construction of their quaternary stereocenters,13,14,15 especially the single-step
assembly of compounds with congested tetra substituted carbon stereocenters, still remains a
serious challenge. The obstacle to forming such centers is rooted in the inherent huge space
imposed by the four non-hydrogen substituents. Recently, N-heterocyclic carbene (NHC)
organocatalysis16 has been studied widely because of its special ability to deteriorate the natural
reactivity of a functional group, which offers unconventional access to a set of umpolung
reactions.17 However, the activation of the γ-carbon of enals18 still remains a significant
challenge: it is very difficult to obtain good chemoselectivity and enantioselectivity because of
the occurrence of competitive homoenolate, enolate or acyl anion intermediates and the fact that
chiral auxiliaries are more remote from the γ-carbon than α- or β-carbons of carbonyl
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compounds.19 In our previous work, we successfully developed three highly efficient
organocatalyzed methods for the asymmetric synthesis of spiro-oxindoles as part of the
construction of a natural product-like library for further bioactivity screening,20,21 and we also
successfully achieved γ-carbon activation of carbonyl compounds to enantioselectively assemble
δ-lactams with NHC/Brønsted acids cooperative catalysis.22
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Scheme 1. Activation of γ-disubstituted enals by NHC catalysis.
Recently, Glorius et al. developed an elegant a3-d3 umpolung reactivity of the β,
β-disubstituted enals to aid construction of five-membered spirolactones bearing two highly
contiguous quaternary stereocenters through a β-carbon activation of enals.23 To continue our
exploration of γ-carbon activation of carbonyl compounds and the intriguing spiroheterocycles,
we herein attempted to employ β-methyl substituted enals as substrates to achieve their γ-carbon
activation via NHC catalysis, and to construct novel intriguing six-membered spirolactone
compounds (Scheme 1).
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Results and Discussion
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Initially, we explored the reaction of isatin derivative 1a and β-methyl-saturated
cinnamaldehyde 2a in the presence of four different triazolium NHC pre-catalysts in THF
solvent using Cs2CO3 as the base. The key results of our experiments are summarized in Table 1.
Surprisingly, the process could deliver the desired six-membered spirolactone with a moderate
yield of 80% and a high enantioselectivity of 81% ee in the presence of the NHC pre-catalyst B
(Table 1, entries 1-4). This proof-of-principle result clearly indicated that activation of the
γ-carbon of enal as a nucleophile using the NHC organocatalyst is feasible. Accordingly, a
variety of alternative solvents were investigated. Although desirable products could be observed
when MTBE, toluene, Et2O, CH2Cl2, EA, DMF and DMSO were used as the solvent, better
results were not obtained (Table 1, entries 5-11). We further explored the influences of different
bases, including inorganic and organic bases, and good yields could be obtained; however, only
moderate enantioselectivity are detected (Table 1, entries 12-16).
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Table 1. Optimization of the reaction conditions.a
Entry
Cat
A
Solvent
THF
Base
ee (%)
32
Yield (%)
1
2
3
4
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
42
80
32
26
63
B
THF
THF
81
C
60
D
THF
/
B
MTBE
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B
B
B
B
B
B
B
B
B
B
B
Toluene
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOH
62
83
40
75
64
47
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53
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42
69
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7
Et2O
CH2Cl2
EA
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DMF
DMSO
THF
THF
THF
tBuOK
DBU
THF
THF
Et3N
a 1a (0.125 mmol) and catalyst (0.1 eq) in the specified solvent (2 mL) were reacted in a sealed
vial under argon atmosphere at rt for 12 h. The Oxidant is 3,3',5,5'-tetra-tert-butyl-[1,1'-
bi(cyclohexylidene)]-2,2',5,5'-tetraen-4-one.
With the optimized catalysis conditions identified (Table 1, entry 2), we further investigated
the substrate scope of the annulation process. As shown in Table 2, a variety of β-substituted
butenals were investigated as potential substrates (Table 2, entries 3a-3i), and the results
demonstrated that different substituents, including electron-donating, electron-withdrawing and
halogen groups substituted phenyls, heterocyclic aryl, and alkyl groups at β-position of butenals
were well tolerated, affording the desired annulation products in good yields (56-82%) with good
enantioselectivities (66-86%). Simultaneously, we introduced Cl, Br and OCH3 into the
6-position of isatin to explore the reactivities of the strategy (Table 2, entries 3j-3q), which give
good results, especially when treating of 4-Cl, 6-Cl and 6-Br substituted isatins with β-(4-
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Table 2. Enantioselective synthesis of target compounds.a
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a 1 (0.125 mmol) and catalyst (0.1 eq) in the specified solvent (2 mL) were reacted in a sealed vial under argon
atmosphere
at
rt
for
12
h.
The
Oxidant
is
3,3',5,5'-tetra-tert-butyl-[1,1'-bi(cyclohexylidene)]-2,2',5,5'-tetraen-4-one.
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methoxylphenyl)-butenal, producing excellent enantioselectivities at 97%, 98%, >99% ee, (Table
2, entries 3k, 3p and 3t). We further investigated the tolerance of the process by varying the R1
group at other positions (Table 2, entries 3q-3v). The diversified substrates also produced
annulation products with good yields (46%-62%) and high enantioselectivities (58%-86%). We
further explored the reactivity of the N-phenyl isatin and obtained both a good yield and
enantioselectivity (compound 3w). The absolute configuration of compound 3f (Tables 2, entry
3f) was determined by X-ray analysis (see Figure S1 in the Supporting Information).
H
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Ph
O
3a
2a
NHC
(C)
Mes
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N
N
O
N Mes
O
O
N
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O
HO
Ph
HO
Ph
Ph
Ph
V
[O]
Ph
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O
N Mes
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Mes
Ph
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IV
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O
N Mes
N
O
base
HO
Ph
O
III
Ph
N
1a
Scheme 2. The plausible mechanism.
A plausible mechanism for the reaction is illustrated in Scheme 2. Addition of the NHC
catalyst to the enal delivers the intermediate I, which is further oxidized and deprotonated to
form the vinyl enolate intermediate III.24 Vinyl enolate III then undergoes nucleophilic addition
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to isatins 1a to give the adduct V, after which intra molecular alkoxide attacks at the carbonyl
group, leading to the production of the desired spirolactone 3a.
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Conclusion
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In summary, we developed a chiral NHC-catalyzed formal [4+2] annulation of β-methyl
substituted enals with isatins to prepare six-membered spirolactones with good yields and high
enantioselectivities. The biggest challenge was to realize remote activation and chiral control of
γ-carbon of enals using only an NHC catalyst. The mild reaction conditions, good
enantioselectivities and wide reaction scope make this γ-carbon activation strategy potentially
useful for the synthesis of biologically active molecules or natural product analogs. The
mechanistic details, the further activation and chiral control of remote carbons of enals for the
asymmetric synthesis of diversified spirohetercylcles are under study in our laboratory.
1
Supporting Information. General experimental methods, H- and 13C-NMR spectrum of all
products, optical data, X-ray, as well as chiral HPLC spectrum. The supporting information is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Email: zhouyu@simm.ac.cn; hliu@mail.shcnc.ac.cn
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the National Natural Science Foundation of
China Grant (81220108025 and 21372235), Major Project of Chinese National Programs for
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Fundamental Research and Development (2015CB910304), National S&T Major Project
(2014ZX09507002-001).
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Enantioselective Assembly of Spirolactones through NHC-Catalyzed
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Remote γ-Carbon Addition of Enals with Isatins
Xianfeng Rong, Hong Yao, Wenjing Xia, Yonglei Dua, Yu Zhoub and Hong Liu
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