Synergistic Kinetic Resolution and Asymmetric Propargyl Claisen Rearrangement for the Synthesis of Chiral Allenes

Article abstract of DOI:10.1002/anie.201511776

The asymmetric propargyl Claisen rearrangement provides a convenient entry to chiral allene motifs. Herein, we describe the development of a kinetic resolution and asymmetric rearrangement of racemic propargyl vinyl ethers. This transformation afforded chiral allene products along with the enantiomerically enriched substrate in good yields with excellent diastereo- and enantioselectivity. The complete chirality transfer and facially selective rearrangement enabled the simultaneous construction of an axially chiral allenic unit and a quaternary carbon stereocenter.

Full text of DOI:10.1002/anie.201511776

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201511776
German Edition: DOI: 10.1002/ange.201511776
Chirality Transfer
Synergistic Kinetic Resolution and Asymmetric Propargyl Claisen
Rearrangement for the Synthesis of Chiral Allenes
Yangbin Liu, Xiaohua Liu,* Haipeng Hu, Jing Guo, Yong Xia, Lili Lin, and Xiaoming Feng*
Abstract: The asymmetric propargyl Claisen rearrangement
provides a convenient entry to chiral allene motifs. Herein, we
describe the development of a kinetic resolution and asym-
metric rearrangement of racemic propargyl vinyl ethers. This
transformation afforded chiral allene products along with the
enantiomerically enriched substrate in good yields with
excellent diastereo- and enantioselectivity. The complete chir-
ality transfer and facially selective rearrangement enabled the
simultaneous construction of an axially chiral allenic unit and
a quaternary carbon stereocenter.
A
llenes are commonly encountered in natural products with
biological activity, and also serve as versatile intermediates in
[
1]
organic synthesis. Among various synthetic approaches, the
[
2]
[3]
Claisen rearrangement of propargyl vinyl ethers (PVEs) is
a simple and effective protocol for the preparation of
elaborated functionalized allenes. The direct catalytic asym-
metric rearrangement of achiral PVEs to generate achiral
allenyl-substituted quaternary carbon stereocenters has been
[
4]
reported previously (Scheme 1a). Moreover, when chiral
PVEs are used for the rearrangement, the central chirality can
be transferred into axial chirality through a concerted sigma-
tropic process, as successfully illustrated by Sherry and
[
5]
I
Toste, who used an achiral Au complex to transform
enantiomerically enriched PVEs into axially chiral allenic
alcohols (Scheme 1b). Although this discovery enabled
access to chiral allenes, it depended on high stereochemical
fidelity of the transformation of optically active alcohols into
chiral PVEs. Thus, we sought to explore a more valuable
enantioselective variant that would enable the use of racemic
substrates instead of enantiomerically enriched starting
materials.
Scheme 1. Access to axially chiral allenes through Claisen rearrange-
ment.
[6]
rangement (Scheme 1c). It should recognize one enantiomer
of a racemic PVE, which would then undergo a catalytic
asymmetric Claisen rearrangement. Thus, the axially chiral
allene unit and the neighboring quaternary carbon stereo-
center could be constructed simultaneously by chiral recog-
nition and chirality transfer. Herein, we demonstrate the
We envisioned the possibility of an enantioselective
Claisen rearrangement that took advantage of chirality
[
7]
transfer by kinetic resolution. The chiral catalyst used
should achieve two objectives: kinetic resolution of racemic
PVEs and ligand-controlled enantioselective Claisen rear-
[
8]
application of a chiral N,N’-dioxide–nickel(II) catalyst in the
development of a synergistic kinetic resolution and catalytic
asymmetric propargyl Claisen rearrangement. A series of
chiral allene derivatives and enantiomerically enriched PVEs
were obtained in good yields with excellent diastereo- and
enantioselectivity.
[
*] Y. B. Liu, Prof. Dr. X. H. Liu, H. P. Hu, J. Guo, Y. Xia, Dr. L. L. Lin,
Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry and Technology
Ministry of Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
We began our investigation with the kinetic resolution of
E-mail: liuxh@scu.edu.cn
[9]
a racemic phosphonate-substituted propargyl vinyl ether by
xmfeng@scu.edu.cn
Claisen rearrangement (Table 1). Racemic propargyl alcohols
can be readily prepared by a Sonogashira cross-coupling
reaction or the 1,2-addition of an alkyne and an aldehyde.
In view of the excellent performance of chiral N,N’-dioxide–
Prof. Dr. X. M. Feng
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin)
[
10]
Tianjin 300071 (China)
[4b]
metal complexes in the asymmetric Claisen rearrangement,
we treated rac-1a with l-PiMe /Ni(OTf) in CH Cl at 358C.
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201511776.
2
2
2
2
4
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Table 1: Influence of reaction time on kinetic resolution.
entries 3–6). This deterioration of the yield mainly resulted
from the generation of unidentified by-products from the
allene (as monitored by TLC). The continued consumption
[12]
of the unreacted enantiomer 1a was sluggish, thus indicating
excellent discrimination of the enantiomers of 1a by the
II
l-PiMe /Ni complex.
2
Having optimized the reaction protocol, we investigated
the kinetic resolution of different phosphonate-substituted
propargyl vinyl ethers by Claisen rearrangement (Table 2). As
expected, the inverse-configuration allene ent-2a and ether
ent-1a were provided enantioselectively by the ligand enan-
[
a]
Entry
t [h]
2a
1a
[
b]
[c]
[b]
[c]
Yield [%]
ee [%]
Yield [%]
ee [%]
1
2
3
4
5
6
1.5
3
5
8
10
12
31
43
44
42
39.5
37.5
95.5
97.5
96.5
95.3
93.4
90.5
60
48
46.5
46
45.5
45
51
99
99
99
99
99
[13]
tiomer (Table 2, entry 2). Gratifyingly, the kinetic resolu-
tion of PVEs with diethyl, cyclopentyl, or cyclohexyl sub-
stituents at the terminal vinyl unit proceeded with very high
selectivity (Table 2, entries 3–5). When a chloro, bromo, ester,
or methyl substituent was present at the para (or meta)
position of the aryl group on the alkyne unit (Table 2,
entries 6–10), high enantioselectivity was observed for the
formation of the rearrangement product 2 (2e–i, 90–95% ee),
and 1e–i were recovered with 98–99% ee. The resolution time
was shorter for reactant 1h with an electron-donating
substituent than for those bearing electron-withdrawing
substituents (Table 2, entry 9 versus entries 6–8 and 10). The
1-naphthyl-substituted PVE rac-1j underwent excellent
kinetic resolution to give enantiomerically enriched 2j with
97% ee, while PVE 1j was recovered with 98% ee (Table 2,
entry 11). Encouraged by these results, we further investi-
gated the tolerance of the catalytic system toward various
alkyl substituents at the stereogenic center of the PVE.
Variation of the length of the alkyl chain (substrates rac-
1k,l,n,o) or the degree of steric hindrance (substrate rac-1m)
[
a] All reactions were carried out with rac-1a (0.10 mmol), l-PiMe2/
Ni(OTf) (1:1, 5 mol%), and H O (5.0 mL) in CH Cl (1.0 mL) at 358C.
b] Determined by H NMR analysis. [c] Determined by HPLC analysis on
a chiral stationary phase. Tf =trifluoromethanesulfonyl.
2
2
2
2
1
[
To our delight, the desired kinetic resolution through [3,3]
[
11]
rearrangement occurred smoothly (Table 1, entry 1). The
efficiency of the kinetic resolution was highly sensitive to the
conversion. The best outcome was observed after 3 h, when
the allene 2a had formed in 43% yield with 97% ee and PVE
a was recovered in 48% yield with 99% ee (Table 1,
entry 2). As the reaction time increased, both the yield and
1
the ee value of product 2a decreased slightly (Table 1,
Table 2: Kinetic resolution of racemic propargyl enol phosphonates.
Entry
1
rac-1
t [h]
2
1
1
2
3
[a]
[b]
[a]
[b]
R
R
R
Yield [%]
ee [%]
Yield [%]
ee [%]
rac-1a
rac-1a
rac-1b
rac-1c
rac-1d
rac-1e
rac-1 f
rac-1g
rac-1h
rac-1i
rac-1j
rac-1k
rac-1l
rac-1m
rac-1n
rac-1o
rac-1p
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
nPr
iPr
nBu
CH CH Ph
Me
Me
Et
-(CH ) -
Ph
Ph
Ph
Ph
Ph
3
3
42 (2a)
97
À97
98
95
92
90
90
93
95
90
97
97
95
92
95
93
92
45 (1a)
99
À99
99
99
98
99
98
99
98
99
98
98
99
98
99
99
99
[
c]
[d]
[d]
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
44 (ent-2a)
46 (2b)
45 (2c)
40 (2d)
43 (2e)
48 (2 f)
45 (2g)
41 (2h)
44 (2i)
48 (ent-1a)
47 (1b)
48 (1c)
42 (1d)
46 (1e)
46 (1 f)
40 (1g)
47 (1h)
47 (1i)
16
24
10
20
20
16
2
16
11
9
10
18
10
14
12
2
4
-(CH ) -
2 5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-ClC H
4-BrC H
6 4
4-MeO CC H
4-MeC H
3-BrC H
1-naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
6
4
2
6
4
6
4
1
1
1
1
1
1
1
1
6
4
36 (2j)
46 (2k)
44 (2l)
38 (2m)
47 (2n)
46 (2o)
36 (2p)
47 (1j)
48 (1k)
46 (1l)
40 (1m)
45 (1n)
47 (1o)
33 (1p)
2
2
2
2
CH
CH
SCH
3
[
a] Yield of the isolated product. [b] Determined by HPLC analysis on a chiral stationary phase. [c] The opposite enantiomer of the N,N’-dioxide ligand
1
was used. [d] Determined by H NMR analysis. Phth=phthaloyl.
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had no adverse effect on the efficiency of kinetic resolution
Table 2, entries 12–16). Furthermore, the kinetic resolution
was used, the allenic cyclohexanone derivative 4d was
isolated in 37% yield with 99% ee and d.r. 50:1, and PVE
3d was recovered in 45% yield with 92% ee (Table 3,
entry 4). When a hydrogen or an alkyl substituent was present
at the alkyne terminus, the reaction proceeded with good
chiral recognition and facial selectivity for the rearrangement
(Table 3, entries 5 and 6). Further exploration of the impact of
substitution on the alkyne unit showed that increased steric
congestion at the stereogenic carbon center of n-butyl-
substituted 3g resulted in lower diastereo- and enantioselec-
tivity (Table 3, entry 7).
(
through Claisen rearrangement took place efficiently when
a sulfur-containing group was present (substrate rac-1p),
although the allene product 2p and resolved PVE 1p were
isolated in only moderate yield (Table 2, entry 17). These
results show that central chirality can be efficiently trans-
ferred to axial chirality in this Claisen rearrangement in the
[
14]
presence of the chiral l-PiMe /Ni(OTf) catalyst. Further-
2
2
more, these resolved chiral allenes bearing ketophosphonate
functional groups were confirmed to be useful in a variety of
[15]
transformations (see the Supporting Information).
Enantiomerically enriched chiral PVEs were also
Further investigations were carried out with substrates
bearing two different alkyl substituents at the vinyl terminal
unit. The resolution efficiency was less affected by the Z/E
configuration of double-bond isomers, as shown by the
recovery of 1q with excellent ee values of the two isomers
employed as precursors in the Ni(OTf) -catalyzed Claisen
2
rearrangement (Scheme 3). Treatment of the recovered sub-
strate (S)-1h afforded (aS)-2h in 86% yield with complete
chirality transfer; this product is the opposite enantiomer of
the product obtained with the kinetic-resolution system
(Scheme 3a). A high reaction temperature was required in
(
Scheme 2a). The allenic ketophosphonate 2q was also
formed in satisfying yield with good ee values. Notably, the
this case, thus indicating that the l-PiMe ligand could lower
2
Scheme 2. Claisen rearrangement of unsymmetrical vinyl propargyl
ethers.
Scheme 3. Claisen rearrangement of enantiomerically enriched sub-
strates. DCE=1,2-dichloroethane.
same chiral catalyst also promoted the enantioselective
transformation of the achiral single isomer (Z)-1r into 2r
with a quaternary carbon stereocenter in 87% yield with
the activation energy. Moreover, in the absence of the chiral
ligand, the reaction of (S)-3g proceeded with low diastereo-
selectivity in favor of the enantiomer of the product formed
[16]
[
17]
9
5% ee (Scheme 2b). This example indicated that the catalyst
with the kinetic-resolution system
(Scheme 3b). These
was also suitable for the enantiocontrol of the vinyl unit. On
the basis of the above results, we thus envisioned that
synergistic cooperation of the kinetic resolution and asym-
metric propargyl Claisen rearrangement of racemic PVEs
would enable the rapid construction of allene derivatives with
vicinal axial chirality and quaternary centers.
Next, we expanded the present resolution system to the
reaction of a variety of cyclic propargyl vinyl ether deriva-
tives, which would afford chiral allene-substituted cyclic b-
ketoesters (Table 3). It was found that carbocyclic substrates
with diverse ring sizes were tolerated (Table 3, entries 1–3).
The corresponding rearrangement products 4a–c were
obtained with high enantioselectivity (92–96% ee) and dia-
stereoselectivity (9:1–24:1), and PVEs 3a–c were recovered
with 96–99% ee. The efficiency of the kinetic resolution
generally improved as the size of the ring increased; mean-
while, a slight increase in temperature was required to ensure
a high reaction rate. When cyclohexyl-based substrate rac-3d
results indicate that complete central-to-axial chirality trans-
fer occurs in this propargyl Claisen rearrangement and that
the effect of ligand control is predominant over the substrate-
induction effect for the formation of the new stereogenic
carbon center.
In conclusion, we have developed an enantioselective
Claisen rearrangement of racemic propargyl vinyl ethers. The
synergistic kinetic resolution and asymmetric rearrangement
were efficiently promoted by the nickel(II)–N,N’-dioxide
catalytic system. Various racemic linear and cyclic propargyl
vinyl ether derivatives successfully underwent the rearrange-
ment to furnish diverse allene derivatives with high diastereo-
and enantioselectivity, and the other enantiomer of the
substrate was recovered with good optical purity. Vicinal
axially chiral allenic and quaternary stereocenters could be
constructed simultaneously. Both enantiomers of the allenes
could be obtained through either the kinetic-resolution
protocol or the central-to-axial chirality transfer method.
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Table 3: Kinetic resolution and asymmetric Claisen rearrangement of racemic propargyl enol esters.
[a]
[b]
[c]
[a]
[b]
Entry
T [8C]
t [h]
4
Yield [%]
ee [%]
d.r.
3
Yield [%]
ee [%]
1
2
3
À20
0
35
1
5
23
n=1 (4a)
n=2 (4b)
n=3 (4c)
51
45
48
92
95
96
9:1
24:1
15:1
n=1 (3a)
n=2 (3b)
n=3 (3c)
43
40
48
96
99
96
4
0
25
37
99
50:1
45
92
5
6
0
0
20
11
R=H (4e)
R=Et (4 f)
47
43
98
98
49:1
24:1
R=H (3e)
R=Et (3 f)
50
47
95
92
7
0
20
45
92
9:1
48
93
1
[
a] Yield of the isolated product. [b] Determined by HPLC analysis on a chiral stationary phase. [c] The diastereomeric ratio was determined by H NMR
or HPLC analysis. NaBArF =NaB[3,5-(CF ) C H ] .
4
3
2
6
3 4
Further studies on the asymmetric Claisen rearrangement are
ongoing.
C. E. Stivala, A. Zakarian, Chem. Soc. Rev. 2009, 38, 3133; c) J.
Rehbein, M. Hiersemann, Synthesis 2013, 1121.
3] For a review on the propargyl Claisen rearrangement, see: D.
Tejedor, G. MØndez-Abt, L. Cotos, F. García-Tellado, Chem.
Soc. Rev. 2013, 42, 458.
4] a) T. Cao, J. Deitch, E. C. Linton, M. C. Kozlowski, Angew.
Chem. Int. Ed. 2012, 51, 2448; Angew. Chem. 2012, 124, 2498;
b) Y. B. Liu, H. P. Hu, H. F. Zheng, Y. Xia, X. H. Liu, L. L. Lin,
X. M. Feng, Angew. Chem. Int. Ed. 2014, 53, 11579; Angew.
Chem. 2014, 126, 11763.
[
[
Acknowledgements
We acknowledge the National Natural Science Foundation of
China (Nos. 21432006, 21321061) and the Fok Ying Tung
Education Foundation (141115) for financial support.
[
[
[
5] B. D. Sherry, F. D. Toste, J. Am. Chem. Soc. 2004, 126, 15978.
6] For details, please see the Supporting Information.
7] For reviews on kinetic resolution, see: a) H. B. Kagan, J. C.
Fiaud, Top. Stereochem. 1988, 18, 249; b) C. E. Müller, M. Jure,
P. R. Schreiner, Angew. Chem. Int. Ed. 2011, 50, 6012; Angew.
Chem. 2011, 123, 6136; c) H. Pellissier, Adv. Synth. Catal. 2011,
Keywords: allenes · asymmetric catalysis · chirality transfer ·
Claisen rearrangement · kinetic resolution
How to cite: Angew. Chem. Int. Ed. 2016, 55, 4054–4058
Angew. Chem. 2016, 128, 4122–4126
3
53, 1613; for recent examples, see: d) X.-H. Yang, K. Wang, S.-
F. Zhu, J.-H. Xie, Q.-L. Zhou, J. Am. Chem. Soc. 2014, 136,
7426; e) T. Yamanaka, A. Kondoh, M. Terada, J. Am. Chem.
1
[
1] For reviews on allenes in natural compounds and organic
synthesis, see: a) A. Hoffmann-Rçder, N. Krause, Angew. Chem.
Int. Ed. 2004, 43, 1196; Angew. Chem. 2004, 116, 1216; b) C.
Aubert, L. Fensterbank, P. Garcia, M. Malacria, A. Simonneau,
Chem. Rev. 2011, 111, 1954; c) S. Yu, S. Ma, Angew. Chem. Int.
Ed. 2012, 51, 3074; Angew. Chem. 2012, 124, 3128; d) J. Ye, S.
Ma, Acc. Chem. Res. 2014, 47, 989.
ˇ
Soc. 2015, 137, 1048; f) J. H. Kim, I. Cori c´ , C. Palumbo, B. List, J.
Am. Chem. Soc. 2015, 137, 1778; g) B. Wanner, I. Kreituss, O.
Gutierrez, M. C. Kozlowski, J. W. Bode, J. Am. Chem. Soc. 2015,
137, 11491.
[8] For kinetic resolution catalyzed by N,N’-dioxide/metal com-
plexes, see: a) L. Zhou, X. H. Liu, J. Ji, Y. H. Zhang, X. L. Hu,
L. L. Lin, X. M. Feng, J. Am. Chem. Soc. 2012, 134, 17023;
b) Y. H. Zhang, X. H. Liu, L. Zhou, W. B. Wu, T. Y. Huang, Y. T.
[
2] For reviews on the Claisen rearrangement, see: a) A. M.
Martín Castro, Chem. Rev. 2004, 104, 2939; b) E. A. Ilardi,
Angew. Chem. Int. Ed. 2016, 55, 4054 –4058
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Liao, L. L. Lin, X. M. Feng, Chem. Eur. J. 2014, 20, 15884;
c) T. Y. Huang, L. L. Lin, X. L. Hu, J. F. Zheng, X. H. Liu, X. M.
Feng, Chem. Commun. 2015, 51, 11374.
[13] Ligand ent-l-PiMe was initially synthesized from (R)-2-piper-
2
idinecarboxylic acid.
[14] The absolute configuration of derivative 9h (Ar= 4-MeC H )
6 4
[
9] J. Tan, C.-H. Cheon, H. Yamamoto, Angew. Chem. Int. Ed. 2012,
was characterized to be aR by X-ray crystal-structure analysis,
thus indicating that the corresponding allene 2h had the aR
configuration. Please see the Supporting Information.
[15] a) E. Breuer, The Chemistry of Organophosphorus Compounds,
Vol 4, Wiley, New York, 1996; b) B. Iorga, F. Eymery, V. Mouries,
P. Savignac, Tetrahedron 1998, 54, 14637; c) C. E. McKenna,
B. A. Kashemirov, Top. Curr. Chem. 2002, 220, 201.
[16] The single isomer (Z)-1r was separated smoothly from the
E isomer by subjecting the E/Z mixture of 1r to column
chromatography twice.
5
1, 8264; Angew. Chem. 2012, 124, 8389.
10] a) J. Panteleev, R. Y. Huang, E. K. J. Lui, M. Lautens, Org. Lett.
011, 13, 5314; b) H. Yamabe, A. Mizuno, H. Kusama, N.
[
[
2
Iwasawa, J. Am. Chem. Soc. 2005, 127, 3248.
11] A trace amount of H O adsorbed by Ni(OTf) was confirmed to
2
2
influence the reaction greatly. Thus, water was used to ensure the
reproducibility of the observed catalyst performance. To simplify
the operation procedure, the amount of water added was
adjusted to 5 mL. For the acceleration of the Claisen rearrange-
ment by H O, see: a) L. Abraham, M. Kçrner, P. Schwab, M.
Hiersemann, Adv. Synth. Catal. 2004, 346, 1281; b) M. Kçrner,
M. Hiersemann, Org. Lett. 2007, 9, 4979.
[17] This outcome showed that the chirality transfer was not efficient
at inducing the enantioselective construction of the quaternary
carbon center in this case.
2
[
12] We tried to isolate and characterization the by-product(s)
formed by the deterioration of allene 2a; however, the
Received: December 20, 2015
Published online: February 17, 2016
1
H NMR spectrum was quite complex.
4
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