Organocatalytic asymmetric cyanation of isatin derived N-Boc ketoimines

Article abstract of DOI:10.1039/c2cc36665g

We report the first catalytic asymmetric cyanation of N-Boc ketoimines, which enables highly enantioselective synthesis of oxindole based α-amino nitriles. An unprecedented tandem aza-Wittig/Strecker reaction is also developed, emerging as a promising strategy for the catalytic asymmetric cyanation of ketoimines formed in situ from achiral ketones.

Full text of DOI:10.1039/c2cc36665g

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Organocatalytic asymmetric cyanation of isatin derived N-Boc ketoimineswz
Yun-Lin Liu and Jian Zhou*
Received 13th September 2012, Accepted 9th October 2012
DOI: 10.1039/c2cc36665g
We report the first catalytic asymmetric cyanation of N-Boc
ketoimines, which enables highly enantioselective synthesis of oxindole
based a-amino nitriles. An unprecedented tandem aza-Wittig/
Strecker reaction is also developed, emerging as a promising
strategy for the catalytic asymmetric cyanation of ketoimines
formed in situ from achiral ketones.
In addition, the resulting imines 4 might be substantially reactive
due to the electron-withdrawing Boc group. To testify this idea,
isatin derived N-Boc ketoimines 87 were first prepared for the
Strecker reaction, as the highly enantioselective synthesis of
oxindole based a-amino nitriles is unprecedented, despite the need
for privileged scaffolds in drug discovery to promote the catalytic
asymmetric synthesis of 3-aminooxindoles, which widely occur in
natural products and drugs.8 Previously, we had pioneered the
catalytic asymmetric cyanation of p-methoxyaniline derived isatin
ketoimines, which were not reactive enough and afforded the
desired products in only moderate yield and ee.5c In addition, we
tried in vain to remove the p-methoxyphenyl group of products by
all the known methods, which greatly decreased the value of this
method. Here, we wish to report that the use of N-Boc ketoimines
8 is a good solution to the aforementioned problems.
Despite the great achievements in the catalytic asymmetric
Strecker reaction of aldimines,1 the corresponding processes
using ketoimine substrates proved to be more difficult.2 As
enantioenriched Ca-tetrasubstituted a-amino acid derivatives
and diamines are very useful,3 much effort has gone into
catalytic asymmetric cyanation of ketoimines. While Jacobsen,
Shibasaki, Feng and Yamamoto have made significant
contributions in this field,2 there is still much to be done to
improve synthetic efficiency and enlarge the scope of ketoimine
substrates. For example, the use of N-Boc protected ketoimines
for reaction development is unknown, despite the easy removal
of Boc group from products. In addition, the catalytic asymmetric
Strecker reaction of ketoimines formed in situ from achiral
ketones was unsuccessful,4 possibly due to two reasons. (1) To
improve the reactivity, activated N-tosyl2g or N-phosphinyl keto-
imines2e were mostly used, but their synthetic procedures made it
difficult to develop the one-pot three component process. (2) The
water produced in imine formation might have a negative effect
on the enantiofacial control.4c
The reaction of N-Boc ketoimine 8a and TMSCN was
undertaken for condition optimization (Table 1). The ketoimine
Table 1 Reaction optimization
Temp
(1C)
Time Yieldb eec
Entrya Cat.
Solvent
Additive
(h)
(%)
(%)
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C5
C2
C2
C2
C2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
—
—
—
—
—
—
—
—
36
77
97
94
86
91
92
67
56
93
32
92
91
92d
83d
92
90
98
98
36
36
36
36
36
36
96
96
With our efforts in the cyanation of ketoimines5a–c and Wittig
chemistry,6a we considered using N-Boc iminophosphorane 26b
as an amine source to react with ketone 1 to enable a catalyst-free
synthesis of N-Boc ketoimine 4 without water generation, which
might be used to develop one-pot three-component protocols.
Toluene ꢀ30
EtOAc
CH2Cl2
CH2Cl2
ꢀ30
ꢀ70
ꢀ70
HFIP
(1.0 equiv.)
HFIP
(2.0 equiv.)
HFIP
(1.0 equiv.)
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N. Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: jzhou@chem.ecnu.edu.cn; Tel: +8621-6223-4560
w This article is part of the ChemComm ‘Emerging Investigators 2013’
themed issue.
10
C2
C2
CH2Cl2
CH2Cl2
ꢀ70
ꢀ70
96
94
61
96
96
11e
144
a
b
Run on a 0.10 mmol scale. Isolated yield. Determined by chiral
c
d
HPLC analysis. Opposite enantiomer. 1.0 mol% of catalyst loading.
e
z Electronic supplementary information (ESI) available: Experimental
details and spectra data. See DOI: 10.1039/c2cc36665g
c
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8a was indeed very reactive, so the evaluation of catalysts was
carried out at ꢀ30 1C using CH2Cl2 as the solvent, in the presence
of 5.0 mol% of the catalyst. Based on our previous studies,5b,c
bifunctional tertiary amine–hydrogen bond donor catalysts were
tried.9,10 Phosphinamide C15c proved to be ineffective (entry 1).
To our delight, cinchonidine derived thiourea catalyst C29e–h
could promote the reaction to finish within 36 h, giving product
9a in 97% yield with 92% ee (entry 2). No improvement was
observed when using quinidine derived catalyst C3 (entry 3). The
cinchonine derived thiourea catalyst C4 afforded the opposite
enantiomer of 9a in 91% ee (entry 4). Takemoto’s catalyst C510e
provided 9a in 83% ee (entry 5). The toluene and ethyl acetate
were also good reaction media when using catalyst C2 (entries 6
and 7), but CH2Cl2 was the best. Further lowering the temperature
to ꢀ70 1C improved the ee to 98%, but the reaction was very slow
(entry 8). Helpfully, the addition of 1.0 equiv. of (CF3)2CHOH
(HFIP)5b could improve the reactivity without the erosion of ee
(entry 9 vs. 10). Even using only 1.0 mol% of catalyst C2, product
9a could be obtained in 61% yield and 96% ee (entry 11).
Table 2 Substrate scopea,b,c
Based on the above screenings, the substrate scope was
investigated under the optimal conditions to run the reaction
in CH2Cl2 at ꢀ70 1C, using 5 mol% of catalyst C2 and 1.0 equiv.
of HFIP. This protocol was able to tolerate a variety of different
substituted N-Boc ketoimines 8 (Table 2). The position of
substituents had no obvious effect on the enantiofacial control,
as evidenced by the excellent ee for all the products 9a–r.
It should be noted that both enantiomers of product 9 could
be readily obtained in excellent ee by using catalyst C2 or C4.
For instance, both (R)-9r and (S)-9r were obtained in excellent ee,
but catalyst C4 was not as reactive as C2, which gave (S)-9r in
obviously lower yield (also see entries 2 and 4 in Table 1).
The a-amino nitrile 9a could be readily converted to the
Ca-tetrasubstituted a-amino acid ester 10, without loss of ee.
Such conformationally constrained a-amino acid esters are
potentially useful in peptidomimetic chemistry.3
a
b
On a 0.25 mmol scale. Isolated yield. Determined by HPLC
c
d
e
analysis. ClCH2CH2Cl was used at ꢀ30 1C. 5.0 mol% of catalyst
C4 was used.
The synthetic utility of this method was further demonstrated
in the first catalytic asymmetric synthesis of spirohydantoin I,
which was developed by AstraZeneca for the potential use in
the treatment of pain. (Scheme 1).11 The N-Boc ketoimine 8c
was prepared in 84% yield from 14b via an aza-Wittig reaction.
To demonstrate the practicability of our method, the Strecker
reaction of 8c and TMSCN was carried out on a 2.5 mmol
scale. The use of 5.0 mol% of chiral catalyst C4 readily gave
(S)-9c in 82% yield and 94% ee. The removal of the Boc group
by HCl gave the corresponding nitrile 15, which was not stable
and was directly converted to the desired spirohydantoin I in
46% yield in two steps, with a diminished 79% ee. Fortunately, the
ee could be easily improved to 99% by a single recrystallization.
By studying control experiments, it was believed that bi-
functional catalysis played an important role in this reaction,
with the tertiary amine moiety of catalyst C2 activating
the in situ generated HCN12 and the activation of N-Boc
Scheme 1 Total synthesis of spirohydantoin I.
ketoimines 8 by the thiourea part through H-bonding inter-
action (for details and the stereochemical model, see ESIz).
To improve the synthetic efficiency, we further tried the
combination of the aza-Wittig and Strecker reaction in a one-pot
sequential protocol. The presence of Ph3PO and remaining
reagents had a negative effect on the reactivity, so the Strecker
reaction step of this one-pot procedure was run at ꢀ30 1C to
secure reasonable yield of product 9. By this novel sequence,
c
Chem. Commun.
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Table 3 One-pot tandem aza-Wittig/Strecker reactiona,b,c
H. Yamamoto, J. Am. Chem. Soc., 2009, 131, 15118;
(k) M. Rueping, E. Sugiono and S. A. Moreth, Adv. Synth. Catal.,
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Synth. Catal., 2010, 352, 3147.
3 H. Voget and S. Brase, Org. Biomol. Chem., 2007, 5, 406.
4 As far as we know, only one example with up to 40% ee obtained,
see: (a) G.-W. Zhang, D.-H. Zheng, J. Nie, T. Wang and J.-A. Ma,
Org. Biomol. Chem., 2010, 8, 1399; The successful examples based
on aldehydes were also limited: (b) H. Ishitani, S. Komiyama,
Y. Hasegawa and S. Kobayashi, J. Am. Chem. Soc., 2000, 122, 762;
(c) S. C. Pan and B. List, Org. Lett., 2007, 9, 1149; (d) Y. Wen,
B. Gao, Y. Fu, S. Dong, X. Liu and X. Feng, Chem.–Eur. J., 2008,
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5 (a) Y.-L. Liu, X.-P. Zeng and J. Zhou, Chem.–Asian. J., 2012,
7, 1759; (b) Y.-L. Liu, T.-D. Shi, F. Zhou, X.-L. Zhao, X. Wang
and J. Zhou, Org. Lett., 2011, 13, 3826; (c) Y.-L. Liu, F. Zhou,
J.-J. Cao, C.-B. Ji, M. Ding and J. Zhou, Org. Biomol. Chem.,
2010, 8, 3847; For our related work: (d) Y.-L. Liu, B.-L. Wang,
J.-J. Cao, L. Chen, Y.-X. Zhang, C. Wang and J. Zhou, J. Am.
Chem. Soc., 2010, 132, 15176; (e) M. Ding, F. Zhou, Y.-L. Liu,
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(g) Z.-Q. Qian, F. Zhou, T.-P. Du, B.-L. Wang, M. Ding,
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a
b
On a 0.25 mmol scale. Isolated yield. Determined by HPLC
c
analysis.
6 (a) J.-J. Cao, F. Zhou and J. Zhou, Angew. Chem., Int. Ed., 2010,
49, 4976; (b) F. Palacios, C. Alonso, D. Aparicio, G. Rubiales and
J. M. de los Santos, Tetrahedron, 2007, 63, 523.
7 During this work, Wang and Shibata reported the use of ketoimines
8 for new reactions, see: (a) W. Yan, D. Wang, J. Feng, P. Li,
D. Zhao and R. Wang, Org. Lett., 2012, 14, 2512; (b) J. Feng,
W. Yan, D. Wang, P. Li, Q. Sun and R. Wang, Chem. Commun.,
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Y. Funahashi and N. Shibata, Chem.–Eur. J., 2012, 18, 9276.
8 For reviews, see: (a) K. Shen, X. Liu, L. Lin and X. Feng, Chem.
Sci., 2012, 3, 327; (b) F. Zhou, Y.-L. Liu and J. Zhou, Adv. Synth.
Catal., 2010, 352, 1381; for selected examples, see: (c) Y.-X. Jia,
J. M. Hillgren, E. L. Watson, S. P. Marsden and E. P. Kundig,
Chem. Commun., 2008, 4040; (d) L. Cheng, L. Liu, D. Wang and
Y.-J. Chen, Org. Lett., 2009, 11, 3874; (e) S. Mouri, Z. Chen,
H. Mitsunuma, M. Furutachi, S. Matsunaga and M. Shibasaki,
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C. Milite and C. F. Barbas III, Org. Lett., 2010, 12, 5696;
(g) K. Shen, X. Liu, G. Wang, L. Lin and X. Feng, Angew. Chem.,
Int. Ed., 2011, 50, 4684; (h) Q.-X. Guo, Y.-W. Liu, X.-C. Li,
L.-Z. Zhong and Y.-G. Peng, J. Org. Chem., 2012, 77, 3589;
(i) H. Zhang, S.-J. Zhang, Q.-Q. Zhou, L. Dong and
Y.-C. Chen, Beilstein J. Org. Chem., 2012, 8, 1241.
9 For reviews on the cinchona alkaloid derivatives, see: (a) E. M.
O. Yeboah, S. O. Yeboah and G. S. Singh, Tetrahedron, 2011,
67, 1725; (b) T. Marcelli and H. Hiemstra, Synthesis, 2010, 1229;
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products 9 were obtained in good to excellent ee (Table 3).
Despite the ample room for improvement, these results clearly
demonstrated that the novel aza-Wittig/Strecker sequence is a
promising approach for the development of the catalytic
asymmetric Strecker reaction of ketoimines formed in situ
from achiral ketones.
In conclusion, we have developed a highly enantioselective
synthesis of oxindole based a-amino nitriles, and applied it to
the total synthesis of spirohydantoin I. This is the first time
that N-Boc ketoimines have been used for the catalytic asymmetric
Strecker reaction. A tandem aza-Wittig/Strecker reaction has also
been developed, which offers the premise to develop catalytic
asymmetric Strecker reaction of ketoimines generated in situ from
achiral ketones. The development of catalytic asymmetric Strecker
reactions of other types of N-Boc ketoimines is now in progress.
The financial support from the NSFC (21172075,
21222204), Innovation Program of SMEC (12ZZ046) and
the Fundamental Research Funds for the Central Universities
(East China Normal University 11043) is highly appreciated.
Notes and references
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12 The reaction of TMSCN and alcohol would produce HCN,
see: K. Mai and G. Patil, J. Org. Chem., 1986, 51, 3545.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.