Phosphine-catalyzed enantioselective [3 + 2] cycloadditions of γ-substituted allenoates with β-perfluoroalkyl enones

Article abstract of DOI:10.1039/c7sc01432e

The enantioselective construction of densely functionalized cyclopentene bearing contiguous three stereocenters has been a challenging task in organic synthesis. Herein, we present a phoshine-catalyzed highly regio-, diastereo-and enantioselective [3 + 2]

Full text of DOI:10.1039/c7sc01432e

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Phosphine-catalyzed Enantioselective [3+2] Cycloadditions of -
γ
Substituted Allenoates with β-Perfluoroalkyl Enones
Received 00th January 20xx,
Accepted 00th January 20xx
Wei Zhou, Huamin Wang, Mengna Tao, Chao-Ze Zhu, Tao-Yan Lin and Junliang Zhang*
DOI: 10.1039/x0xx00000x
The enantioselective construction of densely functionalized cyclopentene bearing contiguous three stereocenters has
been a long-standing challenging task in organic synthesis. Herein we present a phoshine-catalyzed highly regio-,
www.rsc.org/
diastereo- and enantioselective [3+2] cycloaddition of
γ-substituted allenoates with β-perfluoroalkyl enones, delivering a
wide range of densely functionalized perfluoroalkylated cyclopentenes with three contiguous chiral stereocenters.
NH
2
H
N
N
Me
N
Introduction
CH
2
OH
CHO
H
N
Me
Me
CHO
Cyclopentenes (or cyclopentanes) are valuable skeletons found
HO
HO
Me
[1]
in many natural products and pharmaceuticals (Figure 1).
Me
OH
(
-)-α-Necrodol
Me
HN
Chrysomelidial
Neplanocin A
Among existing methodologies for their preparation, the
phosphine-catalyzed [3+2] cycloaddition of allenoates with
electron-deficient olefins first reported by Lu in 1995 is a
powerful and straightforward strategy for the construction of
O
Me
Me
OH
O
2
CO H
H
N
H
3
F C
2
H N
O
[2,3]
functionalized cyclopentene rings.
As
a
result of
NH
N
H
N
H
2
CO H
Peramivir
huDGAT-1 IC50 9 nM
tremendous effort from many research groups, the
enantioselective Lu’s [3+2] cycloaddition reaction of terminal
Figure 1. Selected natural products and pharmaceuticals contain
allenoates with electron-deficient olefins have been well cyclopentene or cyclopentane rings.
[4]
established over the past years. However, the asymmetric
3+2] cycloaddition reaction of -substituted allenoates with
(
a) Stoichiometric process
[
γ
BnO
2
C
Ph
O
CO Bn
O
2
O
BocHN
electron-deficient olefins have been less explored, despite the
stereo chemical diversity of the cycloaddition products would
be dramatically increased. In 2007, the group of Miller first
100 mol% A
+
OMe
PPh2
Ar
89-94% yields
Ar
A
Ph Me
Me
8
7-93% ees
(
b) Catalytic process
Previous work: construction of two stereocenters
R3
realized
cycloaddition of chalcone with racemic
requisite the use of stoichiometric amount of chiral phosphine
a
unique “deracemization” reaction upon
γ
-methyl allenoates but
2
R2
2
R O C
2
O C
CO
2
R2
5 mol% B
EWG
CN
CN
10 mol% C
NC CN
[4c]
∗
A
catalyst
accomplished the cycloaddition reaction of racemic
substituted allenoates with heteroatom-bearing olefins with
the use of catalytic amount of chiral phosphine , furnishing a
facile access to functionalized cyclopentenes with two
A
(Scheme 1a). Subsequently, Fu and co-workers
∗
A
EWG
R1
R1
R1
γ
-
5
6-94% yields
R
3
68-98% yields
77-99% ees
82-97% ees
nPr
nPr
Ph
B
Ph
P
P
Ph
= Ipc*
[5]
Ipc*
adjacent stereo centers (Scheme 1b). Recently, the group of
Marinetti reported highly enantioselective [3+2]
cycloaddition of -substituted allenoates with
benzylidenemalononitrile by utilizing chiral phosphaheli-cenes
Ph
a
B
C
γ
This work: construction of three stereocenters
EtO C
[6]
R
f
2
EtO C
R
f
2
O
2
CO Et
catalyst
C
(Scheme 1b).
O
R2 = Alkyl R1
(S)-P3
R
2
= Aryl
O
+
Despite these elegant progress has been made, the scope of
-substituted allenoates and electron-deficient olefin partner
R1
R1
R
f
R2
(R,R)-DIPAMP
R2
R2
γ
up to 86% yield
Kinetic Resolution
''Deracemization" up to 88% yield
99% ee
96% ee
general substrate scope
good regio- and stereoselectivity
three contiguous stereocenters with a perfluoroalkylated one
readily or comercially avallable chiral phosphine catalysts used
Scheme 1. [3+2] cycloaddition reaction of γ-substituted allenoates
and olefins.
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for enantioselective Lu’s annulation is still very limited and the reaction conditions were identified: 10 mol% (R,R)-DIPAMP as
o
construction of cyclopentene derivatives with three the catalyst and toluene as the reaction medium at -20 C.
contiguous chiral stereo centers has been a long-standing
challenging but highly desirable task. Meanwhile, the
[
a]
introduction
of
perfluoroalkylated,
especially Table 1: Optimization of reaction conditions
trifluoromethylated stereo centers into chiral compounds have
aroused special attention in pharmaceutical and pesticide
industry since the polarity, bioavailability, metabolic stability
and other properties of the parent molecules could be
[7]
influenced greatly by these perfluoroalkyl groups. During the
course of our continuous interest in design, synthesis and
[8,9]
application of novel chiral β-aminephosphines
in
asymmetric catalysis and the synthesis of enantioenriched
[8d,8i]
trifluoromethylated building blocks,
we envisaged that the
challenging enantioselective [3+2] cycloadditions of
γ
-
substituted allenoates with β-perfluoralkyl α,β-enones might
be addressed by systematic screening of known phosphines or
rational design of new catalyst (Scheme 1b). In this article, we
wish to report our efforts to address this challenging reaction
by identifying two phosphine catalysts, commercially available
bisphosphine (R,R)-DIPAMP and novel multifunctional (S)-P3
which developed in our group. Further control experiments
showed that the reaction under the catalysis of (R,R)-DIPAMP
is a deracemization process, while the kinetic resolution
reaction was observed under the multifunc-tional phosphine
catalyst.
o
Entry
Cat.
T ( C)
t (h)
Yield
Ee
[b]
[c]
(%)
(%)
--
1
2
3
4
5
6
7
8
9
(S,S)-DIOP
(R,R)-Et-Duphos
(R,R)-Et-BPE
(R,R)-DIPAMP
(S)-P1
25
25
25
25
25
25
25
25
25
25
0
12
12
8
<10
<10
64
81
79
85
84
86
91
88
84
81
78
63
23
--
39
89
3
6
3
Results and discussion
(S)-P2
3
14
40
21
31
38
90
91
92
92
50
(S)-P3
3
In order to validate the feasibility of the asymmetric [3+2]
(S)-P4
3
cycloaddition of γ-substituted allenoates with β-perfluoralkyl
α,β-enones, allenoate 2a and enone 1a were exposed to a
(S)-P5
0.5
0.5
6
1
1
0
1
(S)-P6
range of commercially available chiral bisphosphine catalysts
(R,R)-DIPAMP
(R,R)-DIPAMP
(R,R)-DIPAMP
(R,R)-DIPAMP
(R,R)-DIPAMP
(
Table 1). A small amount of the desired 3aa was observed
when (S,S)-DIOP or (R,R)-Et DUPHOS were utilized as catalysts
Table 1, entries 1-2). To our delight, (R,R)-Et BPE delivered a
12
13
14
15
-10
-20
-25
-20
8
-
12
20
24
(
-
[d]
promising level of reactivity with 64% yield and stereo
induction with 39% ee (Table 1, entry 3). Fortunately, 86%
yield of 3aa with 89% ee was obtained by using the (R,R)-
DIPAMP as catalyst (Table 1, entry 4). Noteworthy,
multifunctional chiral phosphines (S)-P1-P6 bearing hydrogen
bond donors, such as amide and (thio) urea groups, could
deliver very high chemical yield but with unacceptable
enantioselectivity (Table 1, entries 5-10). Gratifyingly, the
enantioselectivity was improved to 92%, albeit with a slightly
lower yield when decreasing the reaction temperature from 25
[a] Unless otherwise specified, all reactions were carried out with
E)-1a (0.1 mmol), racemic 2a (0.15 mmol) in toluene (1 mL). [b]
(
Yield of isolated products; d.r. and r.r. > 20:1. [c] Determined by
HPLC analysis. [d] (Z)-1a was used.
With optimal reaction conditions in hand, we next
investigated the scope of this enantioselective [3+2]
cycloaddition reaction. Remarkably, a wide range of β-
trifluoromethyl substituted enones containing different
electron nature functional groups worked well with allenoate
o
o
C to -20 C (Table 1, entries 11–13). However, much lower
2
a
, delivering the highly regioselective α-addition products
reaction temperature was not beneficial for the
enantioselectivity and reactivity any more (Table 1, entry 14).
Additionally, much lower yield and enantioselectivity was
observed when (Z)-1a was utilized in the reaction, indicating
that the configuration of the enone also affected the reaction
significantly (Table 1, entry 15). Further screening of solvents
demonstrated that toluene was the best reaction medium for
this transformation (see SI for details). Then the optimized
3
ba-3ha in good yields with 88-94% ees. However, the
introduction of an ortho substituent such as Cl and Br to the
phenyl ring of enone led to dramatic decrease in the
enantioselectivity (3ia and 3ja). To our delight, naphthyl- and
heteroaryl-containing substrates 1k
efficiently furnishing set of trifluoromethylated
cyclopentenes containing naphthyl- and heteroaryl
frameworks 3ka 3oa. Additionally, the present protocol could
-1o are also compatible,
a
-
also be readily extended to the challenging cyclohexenyl and
2
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ARTICLE
cyclohexyl based trifluoromethyl enone 1p and 1q. It is
noteworthy that both β-pentafluoroethyl and β-
heptafluoropropyl enone were particularly effective in the
present transformation, delivering valuable perfluoroalkyl
substituted cyclopentene 3ra and 3sa in good yields with 94%
ee. Furthermore, γ-aryl allenoates 2b-2d with substituted aryl
and hetereoaryl groups are well applicable, delivering the
corresponding products 3ab-3ad with high regioselectivity and
enantioselectivity. The absolute configuration of product 3aa
was confirmed by the single-crystal X-ray diffraction
[10]
After further intensive screening of various chiral phosphine
catalysts again, we were pleased to find that multifunctional
analysis.
Scheme 2: Enantioselective [3+2] cycloadditions of
tuted allenoates with β-perfluoro substituted enone.
γ
a]
-aryl substi- phosphine (S)-P3 displayed good performance in the
[
substrates with ortho-substituent and the desired products 3ia
and 3ja could be isolated in 85-88% yields with 96 and 99% ee,
respectively (Scheme 3).
Unfortunately, the performance of (R,R)-DIPAMP in the
cycloaddition of
γ
as that in the cases of
-alkyl substituted allenoates was not as good
-aryl substituted allenoates. For
γ
3
3ba
aa, X = H, 12 h, 78%, 92% ee
X
example, the reaction of 2e with 1c delivered the desired 3ce
in 67% yield but with only 86% ee. After further screening of a
series of chiral phosphine catalysts, solvents and reaction
temperature, we again found (S)-P3 as a privileged catalyst for
,
X = F, 8 h, 82%, 94% ee
EtO2C
CF3
3ca, X = Cl, 8 h, 76%, 90% ee
3da, X = Br, 8 h, 75%, 90% ee
3ea, X = NO2, 6 h, 81%, 90% ee
b
O
3fa
, X = CN, 6 h, 70%, 88% ee
c
Ph
3
3
ga, X = Me,8 h, 68%, 92% ee
ha, X = Ph, 8 h, 71%, 92% ee
3
aa~3fa
cycloaddition of γ-alkyl allenoates. In general, allenoates 2e
with different alkyl substituents at the
-2g
CO2Et
CF3
Cl
γ
position participated
EtO2C
CF3
O
EtO C
CF3
2
Ph
in the annulation with good regio- and enantioselectivity.
Additionally, diverse alkyl substituents such as benzyl, halogen
and ester group were well tolerant, furnishing the
Cl
Br
O
Ph
Ph
O
3
ia
3ja
3ka
86%, 91% ee
,
12 h
corresponding cycloadducts 3ch-3cj in moderate to good yields
6
h, 76%, 67% ee
6 h,75%, 84% ee
with high enantioselectivity. Further-more, allenoates with
bulkyl substituents such as isopropyl, cyclopentyl and
EtO2C
CF3
EtO C
CF3
EtO C
CF3
2
2
O
S
S
cyclohexyl at the γ position worked also well, delivering the
desired 3ck 3cm in good yields with 92-94% ees. Good to
O
O
O
Ph
Ph
Ph
-
3
la, 12 h
3ma, 12 h
3na, 12 h
excellent regioselectivity and enantioselectivity were also
obtained in the cycloaddition reactions of allenoate 2g with a
wide range of β-trifluoromethyl substituted enones.
7
EtO2C
0%, 94% ee
68%, 95% ee
75%, 94% ee
EtO2C
CF3
CF3
EtO2C
CF3
N
O
O
Ph
Scheme 4: Enantioselective [3+2] cycloadditions of
substituted allenoates with β-perfluoro substituted enone.
γ-alkyl
[a]
O
Ph
Ph
3
qa, 14 h
4%, 91% ee
3
oa, 14 h
4%, 82% ee
3pa, 12 h
59%, 92% ee
6
6
EtO2C
CF3
Ph
EtO2C
Rf
EtO C
CF3
2
Ph
Ph
O
O
O
Ph
ra, 10 h Rf = C2F5
9%, 94% ee
Ar
S
3
3
ab, 10 h, Ar = 4-Cl-C6H4
76%, 94% ee
3ac, 10 h, Ar = 4-MeO-C H4
7
3ad, 8 h
68%, 95% ee
3
sa, 10 h R = n-C F
f
3
7
6
82%, 94% ee
73%, 93% ee
[
a] Unless otherwise specified, all reactions were carried out with
E)- (0.2 mmol), racemic (0.3 mmol), (R,R)-DIPAMP (10 mol%) in
(
1
2
o
toluene (2 mL) at -20 C; isolated yield; d.r. and r.r. > 20:1. [b] r.r. =
:1. [c] r.r. = 11:1.
8
Scheme 3: (S)-P3 catalysed enantioselective [3+2] cycloadditions
of 1i and 1j with 2a
.
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Based on the abovementioned results and previous reports
[11]
,
a plausible catalytic cycle for (R,R)-DIPAMP catalysed
asymmetric [3+2] cycloaddition reaction of -aryl allenoates
with trifluoromethyl enones is illustrated in Scheme 6. The
zwitterionic intermediate was formed through nucleophilic
addition of (R,R)-DIPAMP to racemic 2a. The deracemization
2
process results from the same nucleophilic attack rate (K = K )
γ
I
1
of (R,R)-DIPAMP to the two enantiomers of allenoates 2a. The
subsequent [3+2] cycloaddition favours α-addition to provide
intermediate II which then undergoes proton transfer to
provide intermediate III. Finally, (R,R)-DIPAMP and cyclopean-
[
(
(
[
a]Unless otherwise specified, all reactions were carried out with
E)-1 (0.2 mmol), racemic 2 (0.44 mmol) , (S)-P3 (10 mol%) in CHCl
o
3
o
2 mL) at -20 C. [b] toluene,-20 C, 10 h, (R,R)-DIPAMP (10 mol%).
c] the regioisomer of 3cl was isolated and its structure was
tene 3da were released from intermediate III
.
confirmed by 2D-NMR analysis.
Scheme 6: Possible catalytic cycle for (R,R)-DIPAMP catalysed
Next, we turned our attention to gain insight of the catalytic
process for this [3+2] cycloaddition reaction. In the case of
asymmetric [3+2] cycloaddition.
(
R,R)-DIPAMP catalysed cycloaddition of 1d and racemic 2a
the starting material 2a was recovered in 38% yield (based on
) with 0% ee (Eq 1). Furthermore, when optically active
allenoate (+)-2a (76% ee) was served as substrate, the ee of
da was not improved but the recovered (+)-2a has a higher ee
Eq 2). These results supported that a deracemization process
was followed in the (R,R)-DIPAMP catalysed cycloaddition of
and 2a
,
2
a
3
(
1
d
.
In contrast to (R,R)-DIPAMP, a clearly kinetic resolution
reaction takes place with the use of the multifunctional chiral
[13]
[12]
phosphine (S)-P3 as catalyst since the (+)-2a and (+)-2g
was recovered in 76% ee (in toluene, 77% ee in CHCl ) and 81%
3
ee respectively (Eqs 3 and 4). In order to confirm the possible
hydrogen-bonding interaction during the catalytic process, (S)-
P7 without hydrogen-bonding donor was synthesized and
subjected to the cycloaddition reaction (Scheme 7), the
conversion decreased dramatically even under higher catalyst
loading and higher reaction temperature. What’s more, the ee
value of recovered 2g was vanished (Scheme 7b). These results
clearly demonstrated that the hydrogen-bonding donor in (S)-
P3 is crucial for the enantioselectively formation of cycloadd-
ition product via a nice kinetic resolution process.
To examine the two phosphines in (R,R)-DIPAMP induce
enantioselectivity independently or cooperatedly, (R,R)-
SDIPAMP that containing only one nucleophilic phosphine was
synthesized and subjected to the reaction of 1d and racemic
2a (Scheme 5). Although the reaction became slower, the
enantio-selectivity of 3da was not changed, demonstrating
that the two phosphines in (R,R)-DIPAMP might induce
enantioselectivity independently (Scheme 5b).
Scheme 5: Synthesis of (R,R)-SDIPAMP and its application in the
asymmetric [3+2] cycloaddition of 2a and 1d
.
4
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Scheme 7: Synthesis of (S)-P7 and its application in the
asymmetric [3+2] cycloaddition of 2g and 1d
.
Conclusions
In conclusion, we have developed a highly regio-, diastereo-
and enantioselective [3+2] cycloaddition of -substituted
γ
allenoates with β-perfluoroalkyl enones with the use of (R,R)-
DIPAMP or (S)-P3 as catalyst, which provides a facile access to
a wide range of trifluoromethylated cyclopentenes with three
contiguous chiral centers (up to 88% yield with 99% ee). In the
case of
γ-aryl allenoate, commercially available chiral
phosphine (R,R)-DIPAMP was identified to be the most
efficient catalyst. In contrast, our developed multifunctional
phosphine (S)-P3 displayed high performance in the
asymmetric cycloaddition of
trifluoromethyl enones. Additionally, control experiments
demonstrated that under the catalysis of (R,R)-DIPAMP
On the basis of the above control experiments and recent racemic allenoate reacted with trifluoromethyl enone through
γ-alkyl allenoates with
,
[11]
excellent mechanistic studies
on the [3+2] cycloaddition
a “deracemization” process, whereas a clearly kinetic
allenoates with electron-deficient olefins, a tentative proposed resolution reaction takes place with the use of the
catalytic cycle for (S)-P3 catalysed asymmetric [3+2] multifunctional chiral phosphine (S)-P3 as catalyst due to the
cycloaddition reaction of racemic allenoate with hydrogen-bonding interaction between catalyst and the
trifluoromethyl enone is shown in Scheme 8. (-)-2 might has a allenoate. Efforts toward other transformations of allenoate
preferable configuration which facilitate the hydrogen-bonding under the catalysis of our developed catalysts P1
interactions of N-H and carbonyl group (Scheme 8, TS-1). On currently underway and will be reported in due course.
-P6 are
the other hand, the nucleophilic attack of (S)-P3 with (+)-
2
2
might be suppressed by the steric interactions of the bulky R
group with the phenyl moiety (Scheme 8, TS-2). Accordingly, Acknowledgements
the different nucleophilic attack rate (K
1 2
> K ) of (S)-P3 to the
We are grateful to 973 Programs (2015CB856600), National
Natural Science Foundation of China (21372084, 21425205,
two enantiomers of allenoates 2 contributes to the kinetic
resolution process. Noteworthy, further experimental and
theoretical studies are required to gain insight of this kinetic
resolution process.
2
1672067) and Changjiang Scholars and Innovative Research
Team in University (PCSIRT) for financial supports.
Scheme 8: Possible catalytic cycle for (S)-P3 catalysed asymmetric
Notes and references
[3+2] cycloaddition reaction of racemic allenoate with trifluoro-
methyl enone.
1
2
a) J. Meinwald, T. H. Jones, J. Am. Chem. Soc. 1978, 100,
1
883; b) B. Roach, T. Eisner, J. Meinwald, J. Org. Chem. 1990,
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3
Journal Name
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Plea sC eh de om ni oc ta al dS j uc si et nm c ae rgins
View Article Online
DOI: 10.1039/C7SC01432E
Journal Name
ARTICLE
The enantioselective construction of densely functionalized cyclopentene bearing contiguous three stereocenters has been a long-
standing challenging task in organic synthesis. Herein we present a phoshine-catalyzed highly regio-, diastereo- and enantioselective
[3+2] cycloaddition of γ-substituted allenoates with β-perfluoroalkyl enones, delivering a wide range of densely functionalized
perfluoroalkylated cyclopentenes with three contiguous chiral stereocenters.
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