N-heterocyclic carbene/Lewis acid strategy for the stereoselective synthesis of spirocyclic oxindole-dihydropyranones

Article abstract of DOI:10.1021/ol501224p

Under the cooperative catalysis of NHC/Lewis acid, the mild, straightforward [4 + 2] annulation of α-bromo-α,β-unsaturated aldehydes bearing γ-H with isatin derivatives gave spirocyclic oxindole-dihydropyranones stereoselectively. This approach is particu

Full text of DOI:10.1021/ol501224p

Letter
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene/Lewis Acid Strategy for the Stereoselective
Synthesis of Spirocyclic Oxindole−Dihydropyranones
Zhaoxin Xiao,† Chenxia Yu,† Tuanjie Li,† Xiang-Shan Wang,† and Changsheng Yao*,†
†School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. China
S
* Supporting Information
ABSTRACT: Under the cooperative catalysis of NHC/Lewis
acid, the mild, straightforward [4 + 2] annulation of α-bromo-
α,β-unsaturated aldehydes bearing γ-H with isatin derivatives
gave spirocyclic oxindole−dihydropyranones stereoselectively.
This approach is particularly attractive due to the concise
construction, avoidance of external oxidants, and the potential
utilization value of final products in molecular biology and
pharmacy.
Scheme 1. Formation of NHC-Bounded Vinyl Enolate from
Unsaturated Acyl Chlorides, Oxidation of Enal, or 2-Bromo-
2-enal
n recent decades, N-heterocyclic carbenes (NHCs) have
Ibeen proven to be excellent organocatalysts for various
organic reactions. In addition to the widely known benzoin
condensation and Stetter reaction, the utility of the NHCs as
organocatalysts has recently been extended to a host of other
reactions such as ring-opening polymerization, homoenolate
formations, and transesterification reactions.1 Asymmetric
reactions catalyzed by chiral NHCs have also achieved
noticeable progress in the past years.2,3 Furthermore,
cooperative catalysis, which was pioneered by Scheidt, by
combining Lewis acids with NHCs to provide new modes of
activating molecules, is emerging as a powerful strategy in
asymmetric synthesis.1g,3 Recently, Chi et al. demonstrated that
enantioselective control involving the relatively remote enal γ-
carbon could be nicely accomplished through the introduction
of Sc(OTf)3 or Sc(OTf)3/Mg(OTf)2 as a relatively strong
Lewis acid cocatalyst (Scheme 1, eq a).4 A literature survey
revealed that the use of a Lewis acid in conjunction with an
NHC could also enhance yield and enantioselectivity and
reverse diastereoselectivity.3,5,6
Indole and dihydropyranone are important structural motifs
prevalent in many biologically active natural products; thus,
they are important not only to synthetic but also to medicinal
chemists.7 So far, several strategies including oxidative
spirocyclization,8 metal-mediated multistep transformations,9
Prins-type cyclization10 and amino enyne catalysis11 have been
developed for the efficient assembly of a spirocyclic oxindole-
pyranone architecture, an attractive combination of pharmaco-
logically interesting pyran and oxindole units. Besides, Ye et al.
reported an enantioselective NHC-catalyzed annulation of
unsaturated acyl chlorides with isatin derivatives to prepare
spirocyclic oxindole−dihydropyranones via NHC-bonded vinyl
enolate A in 2011 (Scheme 1, eq b).12 Our previous work
showed that achiral NHCs are capable of activating 2-bromo-2-
enal bearing γ-H to react with isatin derivatives to give racemic
spirocyclic oxindole−dihydropyranones via a similar interme-
diate.13d To continue our work on NHC-catalyzed cascade
synthesis of heterocycles,13 in this paper, we report an
enantioselective assembly of a spirocyclic oxindole−pyranone
scaffold by the reaction of 2-bromo-2-enal with isatin
derivatives catalyzed by chiral N-heterocyclic carbene in
combination with La-based Lewis acid (Scheme 1, eq c).
Considering that the catalyst plays a key role in the whole
reaction process, we first explored the influence of catalysts by
taking the reaction of 2-bromo-3-methylbut-2-enal (1a) with N-
methylisatin (2a) as an initial platform. Catalyst 5 derived from
aminoindanol displayed promising catalytic activity during the
preliminary screening. However, in the absence of the Lewis
acid as cocatalyst, only 19−41% ee was observed in all cases
Received: April 29, 2014
© XXXX American Chemical Society
A
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Letter
(Table 1, entries 2−4). When this reaction was performed
under the relatively bulky triazolium compounds 4 and 6, trace
Al(OiPr)3] (Table 1, entries 10−14). Encouraging results
emerged that the product ee jumped from 45 to 75% when
La(OTf)3 was used as a Lewis acid cocatalyst (Table 1, entry 8
vs 12). The reaction in the presence of Y(OTf)3 or Sc(OTf)3
showed a slightly lower ee than La(OTf)3 (Table 1, entries 10
and 11). For Ti(OiPr)4 and Al(OiPr)3, product 3a was not
obtained (Table 1, entries 13 and 14). A catalyst loading test
indicated that 20 mol % of 5b would be better (Table 1, entries
15 and 16). Subsequently, the influences of different temper-
atures, solvents, bases, and the amount of base required on the
reaction of 1a and 2a were examined to optimize the reaction
conditions (Table 1, entries 17−30). Finally, we found that
THF was the best solvent among THF, toluene, ether, and
CH2Cl2, and K2CO3 was superior to Cs2CO3 in terms of both
reaction yield and enantioselectivity at 0 °C, the optimal
temperature, affording 3a with 94% ee in 82% yield (Table 1,
entry 24). The optimization studies revealed that decreasing or
increasing the loading of base was not beneficial.
Table 1. Optimization of the Reaction Conditions
Under the optimized reaction conditions, the generality of
the reaction was briefly explored (Table 2). It was found that
Table 2. Enantioselective Synthesis of Spirocyclic Oxindole−
Dihydropyranones
a
b
c
a
b
c
Yield of the isolated product. Determined by HPLC. Reaction time:
Yield of the isolated product. Determined by HPLC. The minus ee
45 h.
value indicate that (−)-3a was isolated as the major isomer.
or no formation of 3a was observed (Table 1, entries 1 and 5−
6). Recent success employing Lewis acids with NHC catalysis
prompted us to investigate this reaction using a NHC/Lewis
acid approach instead of modifying the NHC catalysts to
control the enantioselectivity outcome.3,4 Thus, we investigated
the precatalysts 5a−c in the presence of Yb(OTf)3 further, and
triazolium salt 5b was found to be the best (Table 1, entries 7−
9). With the optimal catalyst in hand, several other Lewis acids
were screened [Y(OTf)3, Sc(OTf)3, La(OTf)3, Ti(OiPr)4,
isatins with both electron-withdrawing groups (4-F, 4-Br) and
electron-donating groups (4-Me) were compatible with the
reaction conditions. Small substituents such as methyl on the N
atom or with electron-donating substituents on the aromatic
ring of isatins reacted well with 1a to give the products with
relatively high enantioselectivities (Table 2, entries 1, 5, 6, 11,
and 12). Others such as ethyl, allyl, or benzyl in place of methyl
on the N-atom were also tolerated. Gratifyingly, when the β-
methyl group of the enal was changed to a phenyl group or a
B
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para-substituted phenyl group, such as 4-MeC6H4, 4-BrC6H4,
or 4-MeOC6H4, the reaction went smoothly as well to give the
desired product in good yield and excellent enantioselectivity
exhibiting an outstanding adaptability (Table 2, entries 11−15).
These results highlighted the wide application scope of the
cooperative catalysis of NHC/Lewis acid.
The optical rotation data and HPLC analysis data of
spirocyclic oxindole−dihydropyranone 3k were found to be
in good agreement with those reported in the literature; thus,
the absolute configuration could be determined by compar-
ison.12 In addition, the configuration of compound 3a was
further confirmed by single-crystal X-ray analysis. Other
product configurations were deduced based on analogy (see
the Supporting Information for further details.)
A further transformation exemplified the synthetic utility of
the products of this NHC-catalyzed cascade reaction
successfully. Hydrazinolysis of spirocyclic oxindole 3n with
hydrazine hydrate afforded the ring-opened product 7, an
integration of 3-hydroxyoxindole, and cinnamohydrazide with
biological and synthetic potential, in excellent yield with high
enantiopurity (Scheme 2).14
intermediate F, eventually affording product 3a. Similar to
Chi’s report,4 the La(III) Lewis acid may, like the Sc(III) Lewis
acid, have good affinities for carbonyl oxygens and carboxylates
in multisite coordination to bring the ketone electrophile into
close proximity with intermediate D, as illustrated by E. To
some extent, this coordination enhances the chiral induction
exerted by the chiral NHC catalyst.
In conclusion, we have developed a chiral NHC/Lewis acid
catalyzed [4 + 2] annulation of α-bromo-α,β-unsaturated
aldehydes bearing γ-H with isatin derivatives to prepare
spirocyclic oxindole−dihydropyranones in good yield and
with high enantioselectivity. This approach is particularly
attractive due to the avoidance of external oxidants and the
potential utilization value of final products in molecular biology
and pharmaceuticals. This paper promotes the development of
the powerful strategy of combining umpolung catalysis of NHC
with Lewis acid activation. New applications related to this
strategy are underway in our laboratory and will be reported in
due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 2. Hydrazinolysis of Spirocyclic Oxindole 3n
Experimental procedures and characterization of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: csyao@jsnu.edu.cn.
Notes
The authors declare no competing financial interest.
The catalytic cycle of this NHC-catalyzed reaction is possibly
initiated by the addition of the NHC to the 2-bromo-2-enal 1a
to give the Breslow intermediate B, which is then transformed
into C through a3 → d3 umpolung and debromination (Scheme
3).13b,15 With the aid of base, the acylazoliumion C is
deprotonated at the γ-position to give the vinyl enolate D. It
then undergoes nucleophilic addition to isatin 2a via
ACKNOWLEDGMENTS
■
We are grateful for financial support by National Natural
Science Foundation of China (Nos. 21242014 and 21372101),
a Project Funded by the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions, Natural Science
Foundation of Xuzhou City (XM12B074).
Scheme 3. Possible Catalytic Cycle
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