Phosphine-catalyzed addition/cycloaddition domino reactions of β′-Acetoxy allenoate: Highly stereoselective access to 2-oxabicyclo[3.3.1]nonane and Cyclopenta[a]pyrrolizine

Article abstract of DOI:10.1021/jacs.5b03273

Two classes of phosphine-catalyzed addition/cycloaddition domino reactions of β′-acetoxy allenoate 1 have been developed. The reaction of 1 with 2-acyl-3-methyl-acrylonitrile 2 readily occurs to give 2-oxabicyclo[3.3.1]nonane 3, furnishing the β′-addition

Full text of DOI:10.1021/jacs.5b03273

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Article
Phosphine-Catalyzed Addition/Cycloaddition Domino Reactions
of #’-Acetoxy Allenoate: Highly Stereoselective Access to
2-Oxabicyclo[3.3.1]nonane and Cyclopenta[a]pyrrolizine
Yiting Gu, Pengfei Hu, Chunjie Ni, and Xiaofeng Tong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b03273 • Publication Date (Web): 23 Apr 2015
Downloaded from http://pubs.acs.org on May 3, 2015
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Phosphine-Catalyzed Addition/Cycloaddition Domino Reac-
tions of β’-Acetoxy Allenoate: Highly Stereoselective Access
to 2-Oxabicyclo[3.3.1]nonane and Cyclopenta[a]pyrrolizine
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Yiting Gu,⊥ Pengfei Hu,⊥ Chunjie Ni and Xiaofeng Tong*
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology,
Shanghai, 200237, China.
ABSTRACT: Two classes of phosphine-catalyzed addition/cycloaddition domino reactions of β’-acetoxy allenoate 1 have
been developed. The reaction of 1 with 2-acyl-3-methyl-acrylonitrile 2 readily occurs to give 2-oxabicyclo[3.3.1]nonane 3,
furnishing the β’-addition/[4+4] cycloaddition domino sequence. In this sequence, β’C of allenoate 1 is an electrophilic
center and its β’C and γC serve as a 1,4-dipole. When the other reaction partner is switched to 2-acyl-3-(2-pyrrole)-
acrylonitrile 8, γ-addition/[3+2] cycloaddition domino reaction is instead observed, in which allenoate 1 exhibits dual elec-
trophilic reactivity of γC and 1,3-dipole chemical behavior of βC and β’C. Furthermore, both of these two asymmetric vari-
ants have also been achieved with up to 93% ee. The domino reactions presented in this report are valuable for highly
stereoselective construction of complex structures under mild reaction conditions.
INTRODUCTION
Since the pioneering report of Lu’s [3+2] cycloaddition,1
the research paradigm of the phosphine-catalyzed cy-
cloadditions of activated allenes has been well estab-
lished.2 From a mechanistic point of view, this chemistry
strongly depends on the zwitterionic intermediates,
which are generated via 1,4-addition of phosphine catalyst
to activated allenes and exhibit excellent dipolar-type
cycloaddition reactivity toward various electrophiles. In
addition to zwitterionic intermediate A for Lu’s [3+2] cy-
cloaddition (Scheme 1a), zwitterionic intermediate B,
which is reported by Kwon’s group on the basis of α-
substituted activated allene, is prone to undergo [4+2]
cycloadditions with activated alkenes and imines (Scheme
1b).3 Interestingly, Lu’s group has also demonstrated that
intermediate B is capable of reacting with β,γ-unsaturated
α-keto ester, providing an alternative [4+2] cycloaddition
(Scheme 1c).4 Moreover, Huang and Marinetti inde-
pendently developed the phosphine-catalyzed [4+2] cy-
cloadditions of γ-substituted allenoates and activated
alkenes, in which zwitterionic intermediate C has been
proposed to be involved (Scheme 1d).5
Despite these contributions, the major limitation of this
chemistry is the requirement of an electrophile as the
other cycloaddition partner. The main issue is considered
to be the preferential nucleophilic carbanion reactivity of
the involved zwitterionic intermediates A-C. In contrast,
we have developed the phosphine-catalyzed [4+1]
cycloaddition of β’-acetoxy allenoate 1, which features the
utilization of a bisnucleophile as the other reaction
partner (Scheme 1e).6
Scheme 1. Variants of the Phosphine-Catalyzed Cy-
cloadditions of Activated Allenes
The installation of an acetoxy group at β’C of allenoate 1
is essential for the generation of the key double activated
buta-1,3-diene intermediate D via the process of 1,4-
addition of phosphine followed by 1,2-elimination of the
acetate group.7 The electrophilicity of intermediate D
eventually allows the attack of the bisnucleophile, leading
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i
to the formation of intermediate E.8 Then, the carbanion
of intermediate E is implemented as a base to promote
intramolecular addition of the second nucleophilic center,
thus furnishing this [4+1] cycloaddition (Scheme 1e).9
entries 2 and 3). Organic bases, such as Et3N and Pr2NEt,
gave similar results (Table 1, entries 4 and 5). Fortunately,
the use of Cs2CO3 afforded a promising result with 78%
isolated yield of 3a (Table 1, entry 6). Furthermore, the
examination of phosphine catalysts showed that neither
electron-deficient nor electron-rich phosphines exhibited
any superior performance over PPh3 (Table 1, entries 7-10).
Surprisingly, reducing the catalyst loading to 10 mol%
provided a much cleaner reaction and the yield of 3a was
further improved to 87% (Table 1, entry 11). These results
suggested that keeping relatively lower concentration of
catalyst might be beneficial for the reaction performance.
Indeed, the yield of 3a dropped to 56% when 50 mol%
PPh3 was used (Table 1, entry 12). Notably, the optimal
conditions were found to be reliable for the gram-scale
reaction of 1a (6.0 mmol) and 2a (5.0 mmol) without
affecting the reaction outcome (Table 1, entry 13).
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Scheme
2.
Design
Plan
for
the
Addi-
Table 1. Condition Optimization for the Phosphine-
Catalyzed Reaction of 1a and 2aa
tion/Cycloaddition Domino Reaction
The [4+1] cycloaddition via electrophilic intermediate D
provides a complement to the aforementioned zwitterion-
involved reaction mode. Accordingly, we are encouraged
to further design novel phosphine-catalyzed reactions on
the basis of D. Our design plan is illustrated in Scheme 2.
In conjunction with compound
2
bearing both
a
entry
cat.
base
yield (%)b
pronucleophile (NuH) and an electrophilic C=X group
(activated alkene or imine), we envisioned that
intermediate D would also be reliable for the Michael-
type addition of 2 to its β’C and/or γC. Such addition(s)
might lead to the formation of zwitterionic intermediate(s)
F and/or G. As a result, an intramolecular dipolar-type
cycloaddition10 between the newly formed zwitterion
moiety and the prearranged C=X group was anticipated
(Scheme 2). Herein, we report the phosphine-catalyzed
addition/cycloaddition domino reaction of allenoate 1 and
compound 2 with the hope to having access to complex
structures, which not only exploits potential of allenoate 1
but also extends the existing phosphine-catalyzed cy-
cloaddition scope.
1
PPh3
Na2CO3
K2CO3
KOtBu
Et3N
iPr2NEt
Cs2CO3
Cs2CO3
25
2
PPh3
34
3
PPh3
complex
18
4
PPh3
5
PPh3
34
6
PPh3
78
7
P(2-furyl)3
28
8
P(4-F-C6H4)3 Cs2CO3
72
9
PBu3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
56
10
11c
12d
13c, e
MePPh2
PPh3
75
87
PPh3
56
PPh3
81
RESULTS AND DISCUSSION
a Reaction conditions: to the solution of 2a (0.2 mmol), phos-
phine (0.04 mmol) and base (0.24 mmol) in PhMe (2 mL),
was slowly added a solution of 1a (0.24 mmol) in PhMe (2 mL)
1. PPh3-Catalyzed β’-Addition/[4+4] Cycloaddition
Domino Reaction. To challenge our hypothesis shown
in Scheme 2, we commenced our study with the screening
of appropriate compounds 2. After extensive screening,11
we were delighted to find that, with the help of 20 mol%
PPh3 and 1.2 equiv Na2CO3, compound 2a12 indeed reacted
with allenoate 1a in toluene at room temperature to give
the bridged cycle 3a in 25% yield after 12 hours (Table 1,
entry 1). The structural assignment of 3a was corroborated
by the X-ray crystallography of compound 3o (Figure 1).13
Apparently, the methyl group and oxo-diene moiety of 2a
serve as our desired nucleophilic and electrophilic
functions, respectively, providing a nice opportunity for
the realization of β’-addition/[4+4] cycloaddition domino
reaction with allenoate 1a. Then, the base additive was
evaluated. The use of K2CO3 slightly improved the yield of
3a to 34% while KOtBu led to a complex mixture (Table 1,
over 30 minutes. b Isolated yield. c 10 mol% PPh3 was used.
d
e
50 mol% PPh3 was used. The reaction was run in the 5.0
mmol scale.
Figure 1. X-ray Structure of 3o
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thyl group, either primary or secondary alkyl R1 group was
Table 2. Reaction Scope of Substrates 2 with Aromatic
Substituentsa
tolerated, affording the corresponding products 3s-3u in
somewhat lower yields (Table 3, entries 4-6). More inter-
estingly, the PPh3-catalyzed domino reaction could be
used to prepare more complex molecular architecture in
addition to bridged rings 3a-3v. Indeed, the reaction of
substrate 2w under the optimal conditions gave product
3w in 63% yield (Eq 2).
1
2
3
4
5
Ar1
Ar1
CN
Ar2
AcO
10 mol% PPh3
CN
Ar2
O
O
+
1.2 equiv Cs2CO3
toluene, rt, 12 h
BnO2C
E
6
1a (1.2 equiv)
2 (1.0 equiv)
3 (E = CO2Bn)
7
8
entry 2 (Ar1, Ar2)
3/yield (%)b
3a/87
3b/76
3c/74
3d/80
3e/81
Table 3. Reaction Scope of Substrates 2 with Alkyl
Substituent(s)a
9
1
2a (Ar1 = Ph, Ar2 = Ph)
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2
2b (Ar1 = 4-MeOC6H4, Ar2 = Ph)
2c (Ar1 = 4-BrC6H4, Ar2 = Ph)
2d (Ar1 = 2-BrC6H4, Ar2 = Ph)
2e (Ar1 = 2-furyl, Ar2 = Ph)
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4
5
6
2f (Ar1 = Ph, Ar2 = 4-MeOC6H4)
2g (Ar1 = Ph, Ar2 = 4-MeC6H4)
2h (Ar1 = Ph, Ar2 = 4-FC6H4)
2i (Ar1 = Ph, Ar2 = 4-ClC6H4)
2j (Ar1 = Ph, Ar2 = 4-BrC6H4)
2k (Ar1 = Ph, Ar2 = 2-furan)
2l (Ar1 = Ph, Ar2 = 2-thiophene)
3f/65
entry 2 (R1, R2)
3/yield (%)b
3p/88
3q/86
3r/83
7
3g/75
3h/72
3i/75
1
2p (R1 = Ph, R2 = Me)
8
2
3
4
5
6
2q (R1 = Ph, R2 = iPr)
2r (R1 = Ph, R2 = cyclopropyl)
2s (R1 = C5H11, R2 = Me)
2t (R1 = cyclohexyl, R2 = Me)
2u (R1 = cyclopropyl, R2 = Me)
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3j/73
3s/45
3k/80
3l/85
3t/61
2m (Ar1 = Ph, Ar2 = naphthalen-2-yl) 3m/63
3u/63
2n (Ar1 = Ph, Ar2 = 3-BrC6H4)
3n/54
3o/55
a Reaction conditions: to the solution of 2 (0.2 mmol), PPh3
(0.02 mmol) and Cs2CO3 (0.24 mmol) in PhMe (2 mL), was
slowly added a solution of 1a (0.24 mmol) in PhMe (2 mL)
over 30 minutes. b Isolated yield.
2o (Ar1 = 4-BrC6H4, Ar2 = 4-BrC6H4)
a Reaction conditions: to the solution of 2 (0.2 mmol), PPh3
(0.02 mmol) and Cs2CO3 (0.24 mmol) in PhMe (2 mL), was
slowly added a solution of 1a (0.24 mmol) in PhMe (2 mL)
over 30 minutes. b Isolated yield.
Having established the optimal reaction conditions, we
explored various substitution partners on compounds 2 to
examine the substrate scope. The results are summarized
in Table 2. When Ar2 was a phenyl group, the Ar1 groups
with different electronic properties (e.g., electron-neutral,
-rich, or -deficient) were well tolerated and the corre-
sponding products 3a-3d were obtained in high yields
(Table 2, entries 1-4). Even 2-furyl group could be intro-
duced, giving 3e in 81% yield (Table 2, entry 5). On the
other hand, when Ar1 was a phenyl group, the electronic
properties of the Ar2 groups also had little influence on
the yields of the corresponding products 3f-3l (Table 2,
entries 6-12). However, the steric properties of the Ar2
groups strongly affected the reaction yield. For instance,
substrate 2m with a naphthalen-2-yl substituent gave the
product 3m in 63% yield (Table 2, entry 13). Moreover, the
yield of 3n with a meta-BrC6H4 substituent significantly
dropped to 54% (Table 2, entry 14).
Unfortunately, β’-phenyl allenoate 1b was found to be
inert to 2a under the catalytic systems (Eq 3), notably
because of the steric hindrance of β’-phenyl group
preventing the β’-addition event on the related
intermediate D. When 1,3-dicarbonyl derivative 2x was
subjected to the standard conditions, no reaction was
observed (Eq 4). This result clearly demonstrated the im-
portant role of the nitrile group of 2a on the activation of
the pronucleophile methyl group.
As shown in Table 3, the reaction scope was also
successfully extended to substrates
2
with alkyl
substituent(s). When R1 was a phenyl group, various alkyl
R2 groups were tolerated, including methyl, isopropyl as
well as cyclopropyl, and the products 3p-3r were obtained
in high yields (Table 3, entries 1-3). However, for the case
of 2v with an ethyl R2 substituent, a regioselectivity issue
appeared, leading to the isolation of two isomers 3v and
3v’ with the former as majority (Eq 1). When R2 was a me-
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After having investigated the reaction scope, we turned
our attention to the reaction mechanism. Two deuterium-
labeled control experiments were conducted. When D2O
(0.5 mL) was introduced into the standard catalytic sys-
tems, product 3a-d4, containing 18% D1, 31% D2, 21% D3
and 52% D4, was isolated in 65% yield (Eq 5). The results
implied that intermediates with a carbanion at these four
carbon centers should be involved.14 The somewhat higher
deuterium content of D4 led us to speculate that the for-
mation of intermediate H via the deprotonation of 2a
might be a slow step. Indeed, the reaction of 2a-d3 (58% D)
under the standard conditions gave 3a-d1 (69% D) with
enriched deuterium content, showing a slight isotopic
effect (Eq 6).
Scheme 4. The Reactions of 1a with Substrates 2h-2j
It was worth mentioning that, for the cases of 2h-2j
with an electron-deficient phenyl group, side products
4h-4j were isolated in ca. 10% yield along with the major
products 3h-3j (Scheme 4). These observations fit well
with the proposed reaction mechanism shown in Scheme
3. Indeed, the formation of side products 4 might arise
from an alternative pathway starting from intermediate J
which has two different activated H atoms, β’H and γH
(Scheme 4). For most cases of substrates 2, the impedi-
ment to γH abstraction might be due to the steric conges-
tion imposed by the neighboring quaternary carbon cen-
ter and phosphonium. However, in the cases of 2h-2j, a
small percentage of the corresponding γH atom was ab-
stracted along with the major β’H abstraction, enabling
the formation of intermediates K2 and L2. Then, follow-
ing a similar reaction pathway to that of phosphine-
catalyzed umpolung γ-addition,15 the side product 4 is
formed instead (Scheme 4).
Scheme 3. Plausible Mechanism of the Reaction of 1a
and 2
On the basis of the above observations, a proposed
mechanism of the β’-addition/[4+4] cycloaddition dom-
ino reaction of 1a and 2 is depicted in Scheme 3. Addition
of PPh3 to 1a followed by 1,2-elimination of acetate group
generates the electrophilic intermediate D, which is at-
tacked by the carbanion of H at the β’C position to form
the zwitterionic intermediate I. Likely due to the slow
step of carbanion H formation and high activity of inter-
mediate D, relatively lower concentration of D was sup-
posed to be beneficial for the reaction performance. Then,
the γ-carbanion of I undergoes an intramolecular addition
to yield the enolate intermediate J. The resulting enolate
serves as a base to abstract a β’H to produce intermediate
K1 which co-exists with its resonance form L1. After an H-
shift process, intermediate L1 is converted to M1, which is
followed by a SN2’-type process to release product 3 and
regenerate PPh3 catalyst (Scheme 3).
Scheme 5. The Reaction of 1a and 5
In line with the observation of side products 4, the re-
action of 1a and 5 afforded products 6 and 7 in 37% and 41%
yields, respectively (Scheme 5). We surmised that, for the
related intermediate N, a γH would be selectively ab-
stracted to afford intermediate O. Then, a 1,2-elimination
process seemed to occur,16 giving dicyanomethanide and
intermediate P. The former underwent [4+1] cycloaddi-
tion with D to afford product 6.6 Although the exact
mechanism cannot be entirely concluded at this stage, a
reasonable route to the benzannulation product 7 via in-
termediate P was illustrated in Scheme 5.
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2. PPh3-Catalyzed γ-Addition/[3+2] Cycloaddition allenoate 1a to give products 9a−9e in high yields. We
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5
6
7
8
were also delighted to find that substrates 8f-8i with an
aliphatic ketone moiety exhibited better reaction perfor-
mance, affording the corresponding products 9f-9i in
almost quantitative yields. Moreover, the reaction could
be applicable to substrate 8j, which was derived from the
condensation of 2-pyrrolaldehyde and malononitrile, alt-
hough product 9j was obtained in a lower yield (32%) due
to some decomposition of 8j under the conditions. 3-
Bromo-pyrrole substrate 8k gave product 9k in 75% yield.
However, no reaction was observed for 2,3-dibromo-
pyrrole substrate 8l, likely due to the steric hindrance. It
should be mentioned that all of these products 9a-9k
were isolated as a single isomer. The relative stereochem-
istry of 9h was determined by X-ray crystallography (Fig-
ure 2).13 The stereochemistry of other products 9 was as-
signed by analogy with 9h.
Domino Reaction. The success of the β’-addition/[4+4]
cycloaddition domino reaction between 1a and 2 clearly
pointed out that the β’C position of intermediate D was
liable to be attacked by a C-nucleophile. On the other
hand, the γC is a potential reactive β-position of the vi-
nylphosphonium moiety. Vinylphosphonium salts are
important organophosphorus compounds and one of the
most attractive transformations is aza-Michael addition.17
Thus, to access the anticipated γ-addition/cycloaddition
domino reaction of 1a, several amphiphilic compounds
bearing both N-nucleophiles and activated alkenes were
examined.11 Finally, we found that 2-benzoyl-3-(2-
pyrrole)-acrylonitrile 8a was a suitable reaction partner
for 1a with the help of 10 mol% PPh3 and 1.2 equiv Cs2CO3,
giving tetrahydrocyclopenta[a]pyrrolizine product 9a in
47% yield. Further optimization of reaction conditions
disclosed that the combination of 20 mol% PPh3 and 1.2
equiv Na2CO3 ensured product 9a being obtained in 90%
yield and as one single isomer, thus furnishing γ-
addition/[3+2] cycloaddition domino reaction with excel-
lent diastereoselectivity.
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Figure 2. X-ray Structure of 9h
Scheme 7. Reactions of Allenoates 1b and 1c
In sharp contrast to its inert reaction with substrate 2a,
β’-phenyl allenoate 1b reacted smoothly with 8f to afford
product 9fb in 57% yield (Scheme 7). Again, only one
isomer of 9fb was isolated, demonstrating the excellent
diastereoselectivity of this reaction. However, relatively
lower diastereoselectivity (10:3) was observed for the reac-
tion of β’-ethyl allenoate 1c with 8f. These results clearly
implied that the stereochemistry might be mainly deter-
mined by the β’C substituent of allenoate and be fairly
insensitive to the steric factor of the ketone moiety of 8.
Indeed, the reaction of 1c and 8a gave 9ac with the same
diastereoselectivity as that of 9fc (Scheme 7).
Scheme 6. Substrate scope of the γ-addition/[3+2] cy-
cloaddition domino reaction. Reaction conditions: to the
solution of 8 (0.24 mmol), PPh3 (0.04 mmol) and Na2CO3
(0.24 mmol) in PhMe (2 mL), was slowly added a solution
of 1a (0.2 mmol) in PhMe (2 mL) over 30 minutes. Isolat-
ed yields were presented.
Under the optimal reaction conditions, the substrate
scope of the γ-addition/[3+2] cycloaddition domino reac-
tion was further explored and the results are summarized
in Scheme 6. A range of substrates 8 with an aryl ketone
moiety, including electron-neutral, electron-donating as
well as electron-withdrawing arenes, reacted well with
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Scheme 9. Kwon’s Phosphine-Catalyzed Asymmetric
Reaction of 1a and 2
Scheme 8. Plausible Mechanism of the Reaction of 1a
and 8
In a preliminary attempt, the asymmetric reaction of 1a
and 2a was evaluated with several chiral phosphine cata-
lysts. Fortunately, commercially available Kwon’s phos-
phine21 10 was found to work well, enabling the isolation
of product 3a in 74% yield and with 93% ee (Scheme 9).
Moreover, the reaction of 1a and 2p afforded 3p in 86%
yield and with 82% ee. The smaller methyl substituent
might impose negative effect on the asymmetric induc-
tion. Indeed, substrate 2r with a larger cyclopropyl sub-
stituent afforded product 3r with slightly higher enanti-
oselectivity (86% ee).
A plausible mechanism of the γ-addition/[3+2] cycload-
dition domino reaction was illustrated in Scheme 8. With
the assistance of Na2CO3, substrate 8 undergoes aza-
Michael addition to γC of intermediate D, resulting in the
formation of Q. Surprisingly, no deuterium incorporation
into product 9a was observed when additional D2O (0.5
mL) was introduced into the reaction of 1a and 8a under
the otherwise identical conditions (Eq 7). This result im-
plied that intermediate Q might not coexist with its reso-
nance structure R.6 This might be attributed to the stable
ylide characteristic of intermediate Q. Another reason
might stem from the concerted intramolecular [3+2] cy-
cloaddition between dipole moiety and highly activated
alkene in intermediate Q, affording product 9 directly.
The stepwise pathway via intermediate S was proposed to
be an alternative route to product 9. However, the ob-
served excellent diastereoselectivity of the reaction indi-
cated that the concerted pathway would be more possible
(Scheme 8).18
We also examined the feasibility of phosphine 10 as
catalyst for the asymmetric γ-addition/[3+2] cycloaddition
domino reaction. It was found that, using 20 mol% 10 as
the catalyst under the otherwise identical conditions,
products 9a and 9f were obtained with 83% ee and 87%
ee, respectively (Eq 8).
CONCLUSIONS
In summary, we have developed two new classes of the
phosphine-catalyzed addition/cycloaddition domino reac-
tions of allenoates 1, which strongly relied on the electro-
philic intermediate D. With the help of a base, 2-acyl-3-
methyl-acrylonitriles 2 well matched the reactivity of D to
achieve the β’-addition/[4+4] cycloaddition domino se-
Figure 3. the Corresponding Intermediates D Derived
from 1b and 1c
As shown in Figure 3, the cases of allenoates 1b and 1c
would bring about an additional stereochemical issue
quence, which provided
a
facile access to 2-
oxabicyclo[3.3.1]nonane derivatives 3 under mild reaction
conditions. In this sequence, allenoate 1 exhibits both
electrophilic reactivity at the β’C position and 1,4-dipole
chemical behavior of the β’C and γC. On the other hand,
when 2-acyl-3-(2-pyrrole)-acrylonitriles 8 were instead
employed as the reaction partner for allenoate 1, the γ-
addition/[3+2] cycloaddition domino reaction smoothly
occurred, giving cyclopenta[a]pyrrolizine products 9 with
excellent diastereoselectivity, wherein allenoate 1 exhibits
high electrophilic reactivity at the γC and 1,3-dipole
chemical behavior of the β’C and βC. These results are
believed to represent a new reaction mode of the phos-
related to the alkene configuration in the corresponding
19
intermediates D.9,
This issue might be an important
element to account for the observed stereochemical out-
come in products 9fb, 9fc and 9ac.
3. The Development of Asymmetric Variants. The 2-
oxabicyclo[3.3.1]nonane and cyclopenta[a]pyrrolizine are
two classes of ubiquitous frameworks in natural products
and biologically active compounds.20 Thus, the develop-
ment of an efficient asymmetric catalysis for their enanti-
oselective synthesis would be very attractive.
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(8) Intermediate E arises from the attack of the nucleophile at
phine catalysis. Furthermore, the asymmetric variants of
1
2
3
4
5
6
7
8
β’C of D. Actually, the attack of the nucleophile at γC of D is also
a workable pathway to this [4+1] cycloaddition (not shown in
Scheme 1). For the detailed discussion, see Ref 6.
(9) (a) Han, X.; Yao, W.; Wang, T.; Tan, Y. R.; Yan, Z.; Kwiat-
kowski, J.; Lu, Y. Angew. Chem. Int. Ed. 2014, 53, 5643. (b) Ziegler,
D. T.; Riesgo, L.; Ikeda, T.; Fujiwara, Y.; Fu, G. C. Angew. Chem.
Int. Ed. 2014, 53, 13183.
(10) (a) Wang, J.-C.; Ng, S.-S.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 3682. (b) Henry, C. E.; Kwon, O. Org. Lett. 2007, 9,
3069. (c) Ye, L.-W.; Sun, X.-L.; Wang, Q.-G.; Tang, Y. Angew.
Chem. Int. Ed. 2007, 46, 5951. (d) Wang, Q.-G.; Zhu, S.-F.; Ye, L.-
W.; Zhou, C.-Y.; Sun, X.-L.; Tang, Y.; Zhou, Q.-L. Adv. Synth.
Catal. 2010, 352, 1914.
these two reactions have also been realized with up to 93%
ee using Kwon’s phosphine 10 as catalyst. Further investi-
gations on the asymmetric catalysis and synthetic applica-
tions are ongoing in our laboratories and will be reported
in due course.
ASSOCIATED CONTENT
Detailed experimental procedures and characterization of
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
(11) For the details, see the Supporting Information.
(12) In this work, substrates 2 were used with (E)- and (Z)-
form mixtures while only (E)-8 were used.
tongxf@ecust.edu.cn
(13) The crystallographic coordinates of 3o and 9h have been
deposited with the deposition numbers CCDC 1008712 and
CCDC 1054938, respectively. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre, at
deposit@ccdc.cam.ac.uk.
(14) (a) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang,
F.; Liu, S.; Li, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470. (b)
Mercier, E.; Fonovic, B.; Henry, C.; Kwon, O.; Dudding, T. Tetra-
hedron Lett. 2007, 48, 3617.
(15) (a) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819.
(b) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167. (c)
Trost, B. M.; Dake, G. R. J. Org. Chem. 1997, 62, 5670. (d) Smith,
S. W.; Fu, G. C. J. Am. Chem. Soc. 2009, 131, 14231. (e) Sun, J.; Fu,
G. C. J. Am. Chem. Soc. 2010, 132, 4568. (f) Lundgren, R. J.; Wilsi-
ly, A.; Marion, N.; Ma, C.; Chung, Y. K.; Fu, G. C. Angew. Chem.
Int. Ed. 2013, 52, 2525.
(16) For representative examples, see: (a) Bernasconi, C. F.;
Kanavarioti, A.; Killion, R. B. Jr. J. Am. Chem. Soc. 1985, 107, 3612.
(b) Yang, G.; Luo, C.; Mu, X.; Wang, T.; Liu, X.-Y. Chem. Com-
mun. 2012, 48, 5880.
(17) For representative examples, see: (a) Maryanoff, B. E.;
Reitz, A. B. Chem. Rev. 1989, 89, 863. (b) Schweizer, E. E.; Light,
K. K. J. Am. Chem. Soc. 1964, 86, 2963. (c) Schweizer, E. E.;
Smucker, L. D. J. Org. Chem. 1966, 31, 3146. (d) Kumarn, S.; Shaw,
D. M.; Ley, S. V. Chem. Commun. 2006, 3211. (d) Kumarn, S.;
Shaw, D. M.; Longbottom, D. A.; Ley, S. V. Org. Lett. 2005, 7,
4189.
(18) (a) Wang, J.-C.; Krische, M. J. Angew. Chem. Int. Ed. 2003,
42, 5855. (b) Lee, S. Y.; Fujiwara, Y.; Nishiguchi, A.; Kalek, M.; Fu,
G. C. J. Am. Chem. Soc. 2015, 137, 4587.
(19) Li, C.; Zhang, Q.; Tong, X. Chem. Commun. 2010, 46, 7828.
(20) For 2-oxabicyclo[3.3.1]nonane frameworks, see: (a) Yoko-
yama, R.; Huang, J.-M.; Hosoda, A.; Kino, K.; Yang, C.-S.; Fuku-
yama, Y. J. Nat. Prod. 2003, 66, 799. (b) Zhu, Q.; Tang, C.-P.; Ke,
C.-Q.; Wang, W.; Zhang, H.-Y.; Ye, Y. J. Nat. Prod. 2009, 72, 238.
For cyclopenta[a]pyrrolizine frameworks, see: (c) Hartmann, T.;
Witte, L. In Alkaloids: Chemical and Biological Perspectives, Vol.
9; Pelletier, S. W., Ed.; Elsevier Science, Ltd.: Oxford, 1995; Chap-
ter 4. (d) Liddel, J. R. Nat. Prod. Rep. 2002, 19, 773. (e) Schröder,
F.; Sinnwell, V.; Baumann, H.; Kaib, K.; Francke, W. Angew.
Chem. Int. Ed. Engl. 1997, 36, 77.
Author Contribution
⊥ Y. G. and P. H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work is supported by NSFC (No. 21272066 and
21472042), the Fundamental Research Funds for the Central
Universities, and the Program for New Century Excellent
Talents in University (NCET-12-0851).
REFERENCES
(1) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.;
Lu, X. J. Org. Chem. 1998, 63, 5031.
(2) For selected reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc.
Chem. Res. 2001, 34, 535. (b) Methot, J. L.; Roush, W. R. Adv.
Synth. Catal. 2004, 346, 1035. (c) Lu, X.; Du, Y.; Lu, C. Pure Appl.
Chem. 2005, 77, 1985. (d) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev.
2009, 38, 3102. (e) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev.
2008, 37, 1140. (f) Denmark, S. E.; Beutner, G. L. Angew. Chem.
Int. Ed. 2008, 47, 1560. (g) Fan, Y. C.; Kwon, O. Chem. Commun.
2013, 49, 11588. (h) Xiao, Y.; Sun, Z.; Guo, H.; Kwon, O. Beilstein J.
Org. Chem. 2014, 10, 2089. (i) Wei, Y.; Shi, M. Acc. Chem. Res.
2010, 43, 1005. (j) Wang, S.-X.; Han, X. Y.; Zhong, F. R.; Wang, Y.
Q.; Lu, Y. Synlett 2011, 2766. (k) Zhao, Q.-Y.; Lian, Z.; Wei, Y.; Shi,
M. Chem. Commun. 2012, 48, 1724. (l) Wang, Z.; Xu, X.; Kwon, O.
Chem. Soc. Rev. 2014, 43, 2927.
(3) (a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125,
4716. (b) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632.
(c) Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318.
(d) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. (e)
Xiao, H.; Chai, Z.; Wang, H.-F.; Wang, X.-W.; Cao, D.-D.; Liu, W.;
Lu, Y.-P.; Yang, Y.-Q.; Zhao, G. Chem. – Eur. J. 2011, 17, 10562. (f)
Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Chem. Sci. 2012, 3, 1231. (g)
Xiao, H.; Chai, Z.; Cao, D.; Wang, H.; Chen, J.; Zhao, G. Org.
Biomol. Chem. 2012, 10, 3195.
(4) Yao, W.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2015, 137, 54.
(5) (a) Meng, X.; Huang, Y.; Zhao, H.; Xie, P.; Ma, J.; Chen, R.
Org. Lett. 2009, 11, 991. (b) Zheng, J.; Huang, Y.; Li, Z. Org. Lett.
2013, 15, 5064. (c) Li, E.; Huang, Y.; Liang, L.; Xie, P. Org. Lett.
2013, 15, 3138. (d) Li, E.; Jia, P.; Liang, L.; Huang, Y. ACS Catal.
2014, 4, 600. (e) Gicquel, M.; Gomez, C.; Retailleau, P.; Voituriez,
A.; Marinetti, A. Org. Lett. 2013, 15, 4002.
(6) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc. 2010, 132,
2550.
(7) A related buta-1,3-diene intermediate has been detected by
the ESI-MS analysis: Kramer, S.; Fu, G. C. J. Am. Chem. Soc. 2015,
137, 3803.
(21) (a) Henry, C. E.; Xu, Q.; Fan, Y. C.; Martin, T. J.; Belding,
L.; Dudding, T.; Kwon, O. J. Am. Chem. Soc. 2014, 136, 11890. (b)
Andrews, I. P.; Kwon, O. Chem. Sci. 2012, 3, 2510.
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