Alkynylation/dearomatizative cyclization to construct spiro[5.5]undecanes

Article abstract of DOI:10.1039/c6ra02463g

A new access to spiro[5.5]undecane frameworks was reported through the ZnMe₂-promoted alkynylation of salicylaldehyde and HCO₂H-mediated dearomatizative cyclization which can be used to construct an all-carbon quaternary spirocenter. This method can be applied to the rapid synthesis towards a series of useful motifs of natural products, such as the core of elatol and aphidicolin.

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Alkynylation/Dearomatizative Cyclization to Construct
Spiro[5.5]undecanes
Jidong Shao,a Liqi Li,*a Jie Zhang,b Jingping Hu,a Jijun Xue,a and Ying Li*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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A new access to spiro[5.5]undecane frameworks was reported One commonly exploited mechanistic approach to construct
through the ZnMe2-promoted alkynylation of salicylaldehyde and spirocycle skeleton is the dearomatizative spirocyclization of
HCO2H-mediated dearomatizative cyclization that can be used to functionalized phenols and naphthols. For example, chiral
construct an all-carbon quaternary spirocenter. This method can hypervalent iodine catalyst using m-CPBA as terminal oxidant
be applied to the rapid synthesis towards a series of useful motifs was developed for intramolecular spirolactonization.5,6
of natural products, such as the core of elatol and aphidicolin.
Palladium- or iridium-catalyzed intramolecular allylic
dearomatization of phenols was also described.7 Feringa et al.
developed one-pot spirocyclization involving asymmetric
conjugate addition and subsequent oxidative dearomatization
of 2-naphthols.8 Katsuki et al. reported iron-catalyzed
asymmetric tandem spirocyclization from 1-methyl-2-
naphthols and phenols.9 Luan et al. and You et al. described Ru
or Rh-catalyzed vinylative dearomatization of naphthols or
phenols via a C(sp2)−H bond activation approach.10 Gulías et al.
Spirocycles1 are a common structural pattern found at the core
of numerous natural products with broad structural diversities
and important bioactivities (Figure 1).2 For example, elatol
displays activity against bacteria (including human pathogenic
bacteria)3a-b and demonstrates cytotoxicity against HeLa and
Hep-2 human carcinoma cell lines.3c Aphidicolin also exhibits
significant antiviral and antitumor activity.4a-b
and Lam et al.
independently reported Rh-catalyzed
spiroannulation of ortho-vinylphenols triggered by terminal
C−H funcꢀonalizaꢀon of the alkenyl moiety.11 Luan et al.
developed a Pd-catalyzed [2+2+1] annulative dearomatization
between β-naphthols and two alkyne units,12 and Pd-catalyzed
alkyne insertion/β-naphthol dearomatization cascade to
construct spirocycles.13 Other methods were also described by
various groups.14-18 However, the reported approaches are
either transition-metal catalysis or their substrates are mostly
limited to structurally similar cyclic lactones or lactams. Thus,
new strategies for intermolecular spirocyclization using
different classes of starting materials in one-pot process are
highly desirable but challenging.
Cl
X
HO
O
Br
X=Cl, Laurencenone B
X=H, Laurencenone C
Elatol
OH
OH
O
OH
O
H
HO
H
H
HO
Aphidicolin
Martiusane
Figure 1. Selected natural products containing spiro[5.5]undecane cores.
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Our previous work:
R2
15
HCO2H
CH2Cl2
r.t.
46
R2
H
aUnless otherwise specified, all reactions were performed using Cu(OTf)2 (8
mol%), ZnMe2 (5 equiv), 1a (1 equiv), 2a (4 equiv), 3a (5 equiv), and acid (1.5
equiv). bFor all entries, dr is > 20:1, which was determined by 1H NMR
spectroscopy. In our experimental results, if diastereoisomers could not be
detected in 1H NMR spectra, we identified the dr as > 20:1. cYield of isolated
product. d(R)-(-)-1,1'-Binaphthyl-2,2'-diyl hydrogenphosphate. e2a (4 equiv), and
ZnMe2 (4 equiv). f2a (5 equiv), and ZnMe2 (4 equiv).
O
1)ZnMe2
H
one-pot
R1
R1
OH
O
R3
2)ZnCl2 Et2O
R3
This work:
On the basis of this initial observation, we used 5-
methoxysalicylaldehyde (1a), 3-methoxyprop-1-yne (2a), and
6,6-dimethyl-1-vinylcyclohex-1-ene (3a) as model substrates
for further optimization (Table 1). Various acids were initially
evaluated in toluene at 40 °C (entries 1-9). The experimental
results indicated that HCO2H is a beneficial acid. By using the
ideal acid, we discovered that the stoichiometric ratio of 2a
and ZnMe2 in alkynylation sequence effectively facilitated the
desired transformation (entries 9-11). We then screened
several organic solvents, including THF, hexane and CH2Cl2
(entries 12-15). As a result, CH2Cl2 was found to be the best
choice at room temperature, and the anticipated spirocycle
containing product 4a can be produced in 46% yield. We also
R2
H
O
1)ZnMe2
R1
R2
H
one-pot
R1
O
OH
2)HCO2H
R3
R3
Scheme 1. Alkynylation/cyclization in one-pot process.
In 2015, we reported an approach to synthesize 2,4-
difunctionalized benzopyrans in one-pot process (Scheme 1,
top).19 As a continuation of our focus on this research program,
the present paper describes
a
new access to
performed
a stepwise investigation under the optimal
spiro[5.5]undecane frameworks through the ZnMe2-promoted
alkynylation of salicylaldehyde and HCO2H-mediated
dearomatizative cyclization that can be applied to construct an
all-carbon quaternary spirocenter (Scheme 1, bottom).
The present investigation began by reacting different diene
substrate (3a) with 5-methoxysalicylaldehyde (1a) and 3-
methoxyprop-1-yne (2a) under standard reaction conditions,
which were developed in our previous research.19 We
unexpectedly obtained a spirocycle product (4a) in 7% yield
instead of benzopyran compound (Table 1, entry 2). The
structure of 4a was identified by X-ray crystallography (Figure
2).
conditions but leading to a lower yield (22%, for details see
ESI). So we proposed that the existence of ZnMe2 may play a
very significant role in the one-pot process.
Table 1 Optimization of reaction conditionsa
O
O
O
O
Cu(OTf)2
ZnMe2
MeO
3a
O
H
+
Solvent
4Å MS
Acid
OH
1a
2a
Acid
BiCl3
4a
temp
(°C)
Yield
(%)c
Figure 2. The X-ray structure of 4a.
Entryb
Solvent
1
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
40
40
40
40
40
40
40
40
40
40
40
40
40
40
trace
7
Having identified optimal reaction conditions (Table 1, entry
15), we first examined the substrate scope of this
ZnCl2·Et2O
CF3CO2H
MSA
(R)-(-)-BPAd
p-TsOH
CSA
3
trace
7
transformation
with
respect
to
the
substituted
4
salicylaldehydes partner. Table 2 shows that the electronic
effect of the substrates is very significant. Electron-donating
groups, such as dimethoxy (4g), methoxy (4a,h), and methyl
5
11
6
18
7
32
(
4b) are more favorable for the envisioned spirocycle products
8
CH3CO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
HCO2H
41
than the electron-withdrawing groups, such as bromo (4d),
chloro (4e), and ester (4f). The reaction is also restricted to the
terminal alkyne (4a, 4h-k). The steric effect of these electron-
rich alkynes exerts a great impact on the yields(23%-46%).
Functionalized 1,3-butadienes were also investigated. We
obtained both spirocycle products (4l-1, 4m-1, 4n-1) and
benzopyran compounds (4l-2, 4m-2, 4n-2) when the reaction
9
43
10e
11f
12
13
14
39
32
trace
30
Hexane
CH2Cl2
25
2 | J. Name., 2012, 00, 1-3
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was treated with isoprene or 2,3-dimethyl-1,3-butadiene. underwent intramolecular nucleophilic addition to form the
Benzopyran compounds were not observed when using 6,6- benzopyran compound 4-2 through path b.
R2
dimethyl-1-vinylcyclohex-1-ene (3a) as diene (Table 2, 4a-k).
We then speculated that the benzopyran products
R1
corresponding to 3a are unstable under acidic conditions.
O
R3
4-2
Table 2 Substrate scope of alkynylation/dearomatizative cyclization toward spirocycle
compoundsa
path b
R2
R2
R2
OH
OH
R3
+
R3
+
3
+
R3
Cu(OTf)2
ZnMe2
HCO2
H
1
2
R1
R1
R1
+
R1
R2
4Å MS
OH
O
OH
H
5
TS-C
TS-A
TS-B
path a
R1
R2
O
R3
4-1
Scheme 2. Plausible reaction mechanism.
Conclusions
We developed an approach to construct spiro[5.5]undecanes.
The ZnMe2-promoted alkynylation of salicylaldehyde and
HCO2H-mediated dearomatizative cyclization occurred in
sequence in a one-pot process, which not only involves readily
available starting materials but also demonstrates high
diastereoselectivities. Utilizing multicomponent synthesis and
one-pot process as the core strategies, a number of spirocycles
were prepared smoothly.
Notes and references
‡ The authors acknowledge the financial support provided by
the National Natural Science Foundation of China (21202069,
21272099, and 21472078). We thank Dr. Yuan Zhang and Prof.
Zhi-Xiang Xie (Lanzhou University) for helpful discussion.
1
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3
Scheme 2. The reaction of ZnMe2 with terminal alkyne (
generated an active alkynylzinc,20 which attacked the
substituted salicylaldehyde ( ) to form alcohol ( ). Under
acidic conditions, was converted into carbocation TS-A
2)
1
5
5
,
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acetylenyl group through conjugation effects. The formed
carbocation TS-A underwent electrophilic addition with diene
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Graphical abstract
One-pot process to construct spiro[5.5]undecanes.