Highly enantioselective [3+2] cycloadditions of terminal allenoates with β-trifluoromethyl α,β-enones

Article abstract of DOI:10.1039/d0cc02876b

Highly enantio- and diastereoselective phosphine-catalyzed [3+2] cycloadditions of terminal allenoates with β-perfluoroalkyl α,β-enones leading to a range of trifluoromethylated cyclopentenes with two contiguous chiral centers (up to 99percent yield with 99percent ee) have been developed. Moreover, these reactions could be performed at the gram scale by using only 1 molpercent catalyst. The method developed here was also applied to the concise synthesis of trifluoromethylated DGAT-1 inhibitor. This journal is

Full text of DOI:10.1039/d0cc02876b

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DOI: 10.1039/D0CC02876B
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Highly Enantioselective [3+2] Cycloadditions of Terminal
Allenoates with - Trifluoromethyl ,-Enones
Maizhan Li and Wei Zhou*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly enantio- and diastereoselective phosphine catalyzed [3+2]
cycloadditions of terminal allenoates with -perfluoroalkyl -
enones leading to a range of trifluoromethylated cyclopentenes
with two contiguous chiral centers (up to 99% yield with 99% ee)
have been disclosed. What’s more, this reaction could be amenable
to gram scale by utilizing only 1 mol% catalyst and also applied in
the concise synthesis of trifluoromethylated DGAT-1 inhibitor.
Figure 1. Bioactive molecules featuring with trifluoromethylated
cyclopentene skeleton.
On the other hand, cyclopentene and its derivatives are key
structural motif in in many natural products and active
pharmaceuticals.5 Over the last few decades, enantioselective
construction of cyclopentene skeletons has garnered
considerable attention and a set of synthetic methodologies
have been well developed. Among the existing synthetic
methods, Lu’s [3+2] annulation of activated alkenes with
allenoates is a highly efficiency, yet straightfoward strategy for
the synthsis of functionalized cyclopentene rings.6,7 However, to
the best of our knowledge, reports concerning chiral phos-
phine catalysed Lu’s [3+2] annulations for the construction of
trifluoromethylated cyclopentene skeleton are relatively
limited. In 2017, Zhang and co-workers reported a phosphine
catalyzed enantioselective [3+2] annulation of -substituted
allenoates with -trifluoromethyl ,-enones afford to a set of
trifuoromethylated cyclopentenes.8 Inspired by Zhang’s work
and with regard to the significance of trifuoromethylated
cyclopentenes in bioactive molecules (Figure 1),9 we would like
to further explore the asymmetric [3+2] cycloaddition reaction
of terminal allenotes with -trifluoromethyl ,-enones and
expand its synthetic application (Scheme 1).
The enantioselective introduction of trifluoromethyl group into
organic molecules has become an important research field in
the agrochemical and pharmaceutical industries.1 The metabo-
lic stability, lipophilicity and solubility of some drug candidates
could be greatly influenced by the trifluoromethyl stereoce-
nters due to its special electronic and steric properties.2
Accordingly, tremendous efforts have been made for the
incorporation of these trifluoromethyl moiety in catalytic
asymmetric reactions during last few decades. Efforts in this
area could be generally divided into two aspects. The first
strategy involve entioselectively introducing trifluoromethyl
group into prochiral substrate.3 The second category involves
the asymmetric functionalization of trifluoromethyl-containing
building blocks.4 Notably, the second approach is well suited for
some readily available trifluoromethyl containing substrates,
such as trifluoromethylated carbonyls, imines and Michael
acceptors.
Zhang's work
O
Rf
Me
Me
O
10 mol% (R,R)-DIPAMP
CO2R3
O
R1
O
R3O
O
O
O
N
O
+
R1
S
F3C
H2N
Rf
Ph2
P
N
R2
or
F3C
OH
O
Cl
O
CF3
R2
COOH
N
H
N
H
A
N
-Substituted allenoates
R
CF3
-addition product
H
CF3
R = 3,5-tBu2C6H3
C
B
This work
O
O
R1
O
2.5 mol% P*
+
R1
Rf
R2O
CO2R2
F3
C
CF3
International Cooperative Laboratory of Traditional Chinese Medicine Moderniza-
tion and Innovative Drug Development of Chinese Ministry of Education, College of
Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632,
China. E-mail: weizhou88@jnu.edu.cn.
Electronic Supplementary Information (ESI) available: Experimental details,
analytical data, NMR spectra of products. See DOI: 10.1039/x0xx00000x
Rf
Terminal Allenoates
P* =
O
NH

-addition product
PPh2
up to 99% yield
99% ee
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Scheme 1. [3+2] cycloaddition reactions of allenes with diverse Moreover, the introduction of an ortho substituenVtieswucArhticalesOFn,liCnel
electron-deficient olefins.
and Br to the phenyl ring of enone was DwOeIl:l1t0o.1l0e3r9a/tDe0dCaCn0d28t7h6Be
corresponding 3ka-3ma were isolated in 96-98% yields with
excellent enantioselectivity (Table 2, entries 11-13). Notably,
the high performance of (S)-P1 was not impeded by the
naphthyl- and heteroaryl-containing substrates 1n-1q (Table 2,
entries 14-17). -Trifluoromethyl ,-enones contain
cyclohexyl (1r) and cyclohexenyl (1s) also proceeded smoothly
to furnish the desired cyclopentene, albeit with relatively lower
enantioselectivity (Table 1, Entry 18 and 19). Different terminal
allenoates such as methyl allenoate 2b and benzyl allenoate 2c
were also applicable, affording 3ab-3ac in high yields with 94-
96% ees (Table 2, entries 20-21). Finally, both -
pentafluoroethyl and -heptafluoropropyl enone were
particularly effective in the present asymmetric [3+2]
cycloaddition transformation, delivering valuable perfluoro
substituted cyclopentene 3ta-3ua in high ee (Table 2, entries
22-23). The absolute configuration of product 3pa was
confirmed by the single-crystal X-ray diffraction analysis.12
Absolute configuration of other trifluoromethylated cyclopen-
tene were assigned by analogy.
Our study was initiated by exploring the performance of
commercially available chiral phosphine catalyst (S,S)-P1 and
(R,R)-P2 in the cycloaddition of allenoate 2a and enone 1a.
Unfortunately, these two phosphine catalysts did not offer
satisfactory enantioselectivity (Table 1, entries 1-2). Inspired by
previous studies,10 the hydrogen-bonding interactions play vital
influence on the enantioselectivity and reactivity in chiral
phosphine catalysis, we then envisaged that multifunctional
phosphine which contains hydrogen-bonding donor might be
helpful for the improvement of enantioselectivity. To our
delight, the desired 3aa was obtained in excellent yield with
high regioselectivity and good enantioselectivity under the
catalysis of (S)-P4,11 (Table 1, entry 4). Further improvement in
ee was achieved by lowering the reaction temperature to -20 oC
(Table 1, entries 5-8). Gratifyingly, lowering the catalyst loading
of (S)-P4 to 2.5 mol% proved to be feasible and both the
efficiency and enantioselectivity were maintained (Table 1,
entries 9-10).
Table 1: Optimization of reaction conditions for the enantioselective
Table 2: Enantioselective [3+2] cycloadditions of allenoates with β-
perfluoro substituted enone catalysed by (S)-P4.[a]
[3+2] cycloaddition reaction.[a]
O
O
Ph
CF3
O
X
Cat.* ( mol%)
R1
Rf
O
P4
(S)-
(2.5 mol%)
EtO2C
R2O2C
+
CF3
Ph
+
toluene, T, t
R1
Rf
CO2Et
toluene, - 20 o
C
CO2R2
1a
3aa
2a
3
2
1
F3C
CF3
O
S
Entry
R1/Rf (1)
R2 (2)
3
Yield ee
OMe
(%)[b] (%)[c]
Ph
Ph2P
NH
PPh2
tBu
O
NH
PPh2
P
1
2
3
4
5
6
7
8
C6H5/CF3 (1a)
Et (2a)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
96
99
95
95
96
97
96
94
95
95
97
98
96
95
94
95
96
90
82
95
92
95
97
97
99
99
98
98
97
98
95
95
99
98
99
95
97
95
96
99
61
84
96
94
96
98
P
O
O
PPh2
Me
Me
Ph
4-NO2C6H4/CF3 (1b)
4-CNC6H4/CF3 (1c)
4-CF3C6H4/CF3 (1d)
4-FC6H4/CF3 (1e)
4-ClC6H4/CF3 (1f)
4-BrC6H4/CF3 (1g)
4-MeC6H4/CF3 (1h)
4-MeOC6H4/CF3 (1i)
4-PhC6H4/CF3 (1j)
2-FC6H4/CF3 (1k)
2,4-Cl2C6H3/CF3 (1l)
2-BrC6H4/CF3 (1m)
2-naphthyl/CF3 (1n)
2-furyl/CF3 (1o)
2-thienyl/CF3 (1p)
Benzothiophene/CF3(1q)
cyclohexyl/CF3(1r)
1-cyclohexenyl/CF3(1s)
1a
MeO
P1
P3
P4
(S)-
(S,S)-
(S,Rs)-
P2
(R,R)-
Entry
Cat.
X
T (oC)
t (h)
Yield (%)[b] ee (%)[c]
1
2
3
4
5
6
7
8
9
(S,S)-P1
(R,R)-P2
5
5
5
5
5
5
5
5
2.5
1
25
25
25
25
0
-15
-20
-25
-20
-20
0.5
0.5
0.5
0.5
0.5
1
1
1.5
1
76
83
90
96
96
96
96
96
96
41
23
76
34
90
93
94
97
97
97
96
(S,Rs)-P3
(S)-P4
(S)-P4
(S)-P4
(S)-P4
(S)-P4
(S)-P4
(S)-P4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ab
3ac
3ta
3ua
10
12
[a] Unless otherwise specified, all reactions were carried out with 1a (0.1
mmol), 2a (0.12 mmol) in solvent (1 mL). [b] Yield of isolated products;
both diastereo- and regioselectivity were >20:1. [c] Determined by HPLC
analysis using a chiral stationary phase.
With a set of optimal conditions (2.5 mol% (S)-P4, toluene as
the solvent) in hand, our efforts concentrated on investigating
the scope of this enantioselective [3+2] cycloaddition reaction.
Remarkably, a wide range of -trifluoromethyl substituted
enones containing electron-rich or electron-poor functional
groups were universally worked well with allenoate 2a,
delivering the highly selective -addition products 3aa-3ja in
excellent yields with 95-99% ees (Table 2, entries 1-10).
2a
2a
Me (2b)
Bn (2c)
2a
1a
C6H5/C2F5 (1t)
C6H5/C3F7 (1u)
2a
[a] Unless otherwise specified, all reactions were carried out with 1 (0.2
mmol), 2 (0.24 mmol) , (S)-P4 (2.5 mol%) in toluene (2 mL) at -20 oC for
1.5 h; [b] Isolated yield; diastereoselectivity and regioselectivity for all
2 | J. Name., 2012, 00, 1-3
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examples were more than 20:1; determined by 1H NMR analysis. [c]
Determined by chiral HPLC analysis.
could be easily prepared. The selective reduction of carbonyl
View Article Online
group provided an effective access to vaDluOaIb: 1le0.1c0h3i9r/aDl0aClcCo0h2o87l64B.
Transformations involving the C=C double bond of 3gb, such as
Michael addition with thiophenol, dipolar cycloaddition
reaction with 1,3-dipole and dihydroxylation were carried out
and the corressponding synthetic valuable frameworks 5, 6 and
7 were furnished without loss of enantiopurity.
Table 3: Enantioselective [3+2] cycloadditions of allenoates
with enone catalysed by (S)-P4.[a]
O
O
R1
Ph
R1
Ph
R1
EtO2C
+
O
P4
(S)-
(10 mol%) EtO2C
Most importantly, a creative and concise synthetic strategy
for trifluoromethylated DGAT-1 inhibitor 10 was successfully
developed (Scheme 3).[13] Starting from 3gb, the Suzuki coupling
reaction worked well and gave compound 8 in 81% yield. The
urea-based compound 9 was subsequently obtained in 69%
yield (overall yield for three steps) from 8 via sequential
hydrogenation, isocyanate coupling and PCC oxidation. Finally,
hydrolysis of the ester group gave the target molecule 10 in high
yield without loss of enantiopurity.
1v-1x
toluene, -20 o
C
+
Ph
3va-3xa
3va'-3xa'
CO2Et
2a
Entry
R1
3
3/3’ ratio Yield
ee
3+3‘ (%)[b] (%)[c]
1
2
3
Me (1v)
Ph (1w)
4-NO2C6H4 (1X)
3va
3wa
3xa
13:1
5:1
20:1
64
72
83
22
11
6
NO2
[a] Unless otherwise specified, all reactions were carried out with 1 (0.2
mmol), 2 (0.24 mmol) , (S)-P4 (10 mol%) in toluene (2 mL) at -20 oC for
8 h; [b] Isolated yield; [c] Determined by chiral HPLC analysis.
O
Br
O
MeO2C
MeO2C
a
CF3
CF3
8
3gb
99% ee
81% yield
99% ee
Following the above successful experiments, the [3+2]
cycloaddition reactions of enones (1v-1x) with allenoates 2a
were studied (Table 3). In the presence of a 10 mol % chiral
phosphine (S)-P4, enones 1v-1x were able to convert to the
desired cyclopentenes 3va-3xa through preferential γ-addition
in moderate yields with poor enantioselectivities (Table 3, Entry
1-3). These results demonstrated that the chiral phosphine (S)-
P4 was not a suitable catalyst for the [3+2] annulation reactions
of this type Michael acceptors.
b
c d
,
,
O
OH
O
DGAT-1 inhibitor
O
CO2Me
O
e
F3C
F3C
N
H
N
H
F3C
O
F3C
N
N
H
10
, 92% yield,
99% ee
H
9
, 69% yield for 3 steps
98% ee
Scheme 3. Concise synthetic strategy for trifluoromethylated DGAT-
inhibitor: (a) Pd(PPh3)4, 4-nitro-phenylboronic acid, KF,
O
MeO2C
1
Br
DME/toluene/EtOH/ H2O, 60 °C, 36 h; (b) Pd/C, MeOH, 25 °C, 24 h;
(c) 4-(trifluoromethyl)phenyl isocyanate, THF, 25 C, 1 h; (d) PCC,
DCM, 25 oC, 2 h; (e) LiOH, THF/H2O, 25 oC, 3 h.
S
CF3
o
5
, 69% yield
98% ee, 8:1 d.r.
Cl
In order to conform the possible hydrogen-bonding interac-
tions during the catalytic process, (S)-P5 without hydrogen-
bonding donor was synthesized and utilized in the [3+2]
cycloaddition reaction of 1a and 2a (Scheme 4). When (S)-P5
was employed as the catalyst, the enantioselective [3+2]
cycloaddition reaction proceeded much slower with dramaticlly
decreased enantioselectivity demonstrated that the hydrogen-
bonding donors in the chiral phosphine catalyst were vital for
both reactivity and enantioselectivity of this [3+2] cycloaddition
reaction.
b
Br
MeO2C O
Br
HO
Br
O

MeO2C


MeO2C
c
a
N
CF3

CF3
CF3
N
6
, 72% yield
98% ee, >20:1 d.r.
Ph
3gb
3.68 g of
4
, 96% yield
99% ee, 4:1 d.r.
O
98% yield, 99% ee
d
Br
O
MeO2C
HO
HO
CF3
F3C
CF3
7
, 55% yield
98% ee, 1:1 d.r.
O
O
Ph
CF3
O
2a
( 1.2 equiv)
EtO2C
CF3
Scheme 2. Synthetic transformations of 3gb: (a) NaBH4,
THF/H2O, 0 oC, 1h; (b) 4-chlorothiophenol, DABCO, DCM, 25 oC,
12 h; (c) benzoyl(3,4-dihydroisoquinolin-2-ium-2-yl)amide,
toluene, 100 C, 8 h; (d) RuCl3, NaIO4, CH3CN/H2O/EtOAc, 0 C,
0.5 h.
Ph
CF3
O
N
P5
(S)- (10 mol%)
toluene, 25 oC, 12 h
3aa
1a
CF3
PPh2
o
o
51%, 5% ee
P5
(S)-
Scheme 4. Performance of (S)-P5 in the enantioselective [3+2]
cycloaddition reaction of 1a and 2a.
A gram-scale [3+2] cycloaddition reaction of 1g and 2b was
then conducted, which proceeded smoothly with the use of
only 1 mol% catalyst and delivered 3.68 g of 3gb in 98% yield
with 99% ee (Scheme 2). Additionally, the synthetic utility of 3gb
was showcased and a wide range of other chiral building blocks
Based on the above control experiment and previous
mechanistic studies on the [3 + 2] annulation of allenoates with
electron-deficient alkenes,14 proposed catalytic cycle for (S)-P4
This journal is © The Royal Society of Chemistry 20xx
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4
5
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Morandi, B. Mariampillai, E. M. Carreira, AngeVwie.wCAhrteicmle O. nInlinte.
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catalyzed asymmetric [3 +2] cycloaddition of terminal allenoate
with trifluoromethyl enone is shown in Scheme 5. Nucleophilic
attack of chiral phosphine catalyst (S)-P4 on allenoate 2a
generates zwitterionic intermediate I which stabilized by
hydrogen-bonding interactions of N–H and carbonyl group.
Intermediate II was then created from the less hindered -
addition. The subsequent intramolecular Michael addition,
followed by proton transfer and release of catalyst, afford the
final [3+2] cycloaddition product 3aa.
6
7
a) C. Zhang, X. Lu, J. Org. Chem. 1995, 60, 2906; b) Y. Du, X. Lu,
Y. Yu, J. Org. Chem. 2002, 67, 8901; c) Y. Du, X. Lu, J. Org.
Chem. 2003, 68, 6463.
O
O
Ph
CF3
P4
(S)-
(2.5 mol%)
EtO2C
+
CF3
Ph
toluene, - 20 oC, 1.5 h
For selected reviews related to the cycloaddition of allenes
with olefins, see: a) X. Lu, C. Zhang, Z. Xu, Acc. Chem. Res.
2001, 34, 535; b) L.-W. Ye, J. Zhou, Y. Tang, Chem. Soc. Rev.
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CO2Et
2a
F3C
3aa
96%, 97% ee
1a
CF3
CO2Et
O
NH
3aa
2a
PPh2
P4
8
9
(S)-
Ph
P
H
O
Ph
CO2Et
PR3
Ph

Ph
F3C
H
R1
O
N

I
IV
OEt
10 a) Y. Wei, M. Shi, Acc. Chem. Res. 2010, 43, 1005; b) S.-X.
Wang, X. Han, F. Zhong, Y. Wang, Y. Lu, Synlett 2011, 2766; c)
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11 Phosphine catalyst (S)-P4 was prepared according to Zhang’s
reports: a) a) X. Su, W. Zhou, Y. Li, J. Zhang, Angew. Chem. Int.
Ed. 2015, 54, 6874; b) W. Zhou, X. Su, M. Tao, C. Zhu, Q. Zhao,
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12 CCDC 1503839 (3pa) contain the supplementary crystallogra-
phyic data for this paper.
13 G. Zhao, A. J. Souers, M. Voorbach, H. D. Falls, C. A. Collins, H.
Sham, R. M. Reilly, M. E. Brune, P. R. Kym, J. Med. Chem. 2008,
51, 380.
14 Y. Xia, Y. Liang, Y. Chen, M. Wang, L. Jiao, F. Huang, S. Liu, Y.
Li, Z.-X. Yu, J. Am. Chem. Soc. 2007, 129, 3470.
regionselective
addition
O
proton shift
Ph
CF3
1a
O
CO2Et
PR3
O
CO2Et
PR3
Ph
F3C
Ph
F3C
III
II
Scheme 5. Proposed mechanism.
In conclusion, we have developed a highly enantio- and
diastereoselective phosphine catalyzed [3+2] cycloadditions of
terminal allenoates with -perfluoroalkyl -enones. Diverse
trifluoromethylated cyclopentenes were delivered in good
yields with high regio-, diastereo-, and enantioselectivities. The
synthetic utilities of this methodology were further
demonstrated by the concise synthesis of trifluoromethylated
DGAT-1 inhibitor and other valuable building blocks. Efforts
toward the chiral phosphine catalyzed other asymmetric
transformations is currently underway in our group and will be
reported in due course.
We thank the financial support from the Fundamental
Research Funds for the Central Universities (21620354).
Notes and references
1
2
3
a) K. Muller, C. Faeh, F. Diederich, Science 2007, 317, 1881; b)
N. A. Meanwell, J. Med. Chem. 2011, 54, 2529; c) S. Purser, P.
R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008,
37, 320.
a) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359; b) D. Barnes-
Seeman, M. Jain, L. Bell, S. Ferreira, S. Cohen, X.-H. Chen, J.
Amin, B. Snodgrass, P. Hatsis, ACS Med. Chem. Lett. 2013, 4,
514.
a) X. Yang, T. Wu, R. J. Phipps, F. D. Toste, Chem. Rev. 2015,
115, 826; b) J.-A. Ma, D. Cahard, Chem. Rev. 2004, 104, 6119.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC02876B
O
OH
O
O
R1
O
DGAT-1 inhibitor
O
O
2.5 mol% P*
R2O
+
R1
Rf
CO2R2
Rf
F3C
F3C
CF3
5 steps
F3C
-addition product
Terminal Allenoates
N
N
P* =
H
H
O
NH
up to 99% yield
PPh2
99% ee
99% ee
A highly enantio- and diastereoselective phosphine catalyzed [3+2] cycloadditions of terminal allenoates with -
perfluoroalkyl -enones leading to a series of trifluoromethylated cyclopentenes with two contiguous chiral centers
(up to 99% yield with 99% ee) have been disclosed. This reaction could be amenable to gram scale by utilizing only 1
mol% catalyst and also applied in the concise synthesis of trifluoromethylated DGAT-1 inhibitor.