Organocatalytic Activation of the Leaving Group in the Intramolecular Asymmetric SN2′ Reaction

Article abstract of DOI:10.1002/anie.201502831

A Bronsted-acid-catalyzed intramolecular enantioselective S_N2′ reaction was developed utilizing trichloroacetimidate as a leaving group. The findings indicated that dual activation of the substrates is operative. This metal-free allylic alkylat

Full text of DOI:10.1002/anie.201502831

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502831
German Edition: DOI: 10.1002/ange.201502831
Organocatalysis
Organocatalytic Activation of the Leaving Group in the Intramolecular
Asymmetric S 2’ Reaction**
N
Yusuke Kuroda, Shingo Harada, Akinori Oonishi, Yousuke Yamaoka, Ken-ichi Yamada,* and
Kiyosei Takasu*
Abstract: A Brønsted-acid-catalyzed intramolecular enantio-
to give a chiral p-allyl palladium complex, which is attacked
[
3]
selective S 2’ reaction was developed utilizing trichloroaceti-
by a nucleophile. Because the reaction is initiated by
nucleophilic attack of a palladium(0) species with expulsion
of the leaving group from the substrate, this type of allylic
substitution can be regarded as nucleophilic catalysis.
Allylic substitution is also an important process in
N
midate as a leaving group. The findings indicated that dual
activation of the substrates is operative. This metal-free allylic
alkylation allows highly enantioselective access to 2-vinyl-
pyrrolidines bearing various substituents.
[
4,5]
biological systems.
These processes are catalyzed by
N
ucleophilic allylic substitution is a fundamental and
enzymes with simultaneous activation of a nucleophile and
an electrophile. On the other hand, it is well known that
[
1]
[6]
important reaction in organic synthesis. Several catalytic
enantioselective allylic substitutions have been developed.
One major strategy is the activation of a nucleophile by a base
a chiral phosphoric acid realizes acid–base dual activation
[7]
through H-bonds. We also reported the kinetic resolution of
chiral secondary alcohols by a chiral phosphoric acid-cata-
(
Figure 1a). In this type of reaction, the enantiotopic face of
[
8]
the nucleophile, such as enol(ate)s, is discriminated by a chiral
catalyst. Consequently, the stereogenic center of the products
lyzed acylation with acid anhydride. In that reaction, the
acid anhydride and the alcohols are likely activated through
H-bonds with the PÀOH and the P=O moieties of the catalyst,
[2]
arises at the nucleophilic carbon atom of the nucleophiles.
An alternative major strategy is transition metal catalysis
Figure 1b). For example, in the Tsuji–Trost reaction, an
respectively. We envisioned that the chiral phosphoric acid
could activate a leaving group as well as a nucleophile, which
would accelerate the allylic substitution like the enzymatic
SN2’ process (Figure 1c). To the best of our knowledge,
catalytic activation of a leaving group in a catalytic asym-
(
allylic substrate is activated by a chiral palladium(0) catalyst
[9–12]
metric S 2’ reaction has rarely been reported.
Herein, we
N
describe the enantioselective intramolecular S 2’ reaction
N
catalyzed by a chiral phosphoric acid providing chiral
pyrrolidines.
Because the selection of a leaving group is a key for
achieving the reaction with high enantioselectivity, we first
searched for functional groups that could act as a leaving
group in the presence of a Brønsted acid (Scheme 1). Free
alcohol 1a was treated with a catalytic amount of diphenyl
phosphate in toluene at room temperature in the presence of
powdered molecular sieves but was unreactive. Next, a 3-
[
13]
nitro-2-pyridyl group was tested,
but 1b was also left
unchanged. When N-phenyltrifluoroacetimidate 1c was
used, however, a small amount of the desired pyrrolidine
Figure 1. Strategies for an asymmetric S 2’ reaction.
[14]
N
2
a was observed. To our delight, when trichloroacetimidate
[
*] Y. Kuroda, Dr. S. Harada, A. Oonishi, Dr. Y. Yamaoka,
Prof. Dr. K. Yamada, Prof. Dr. K. Takasu
Graduate School of Pharmaceutical Sciences
Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: yamak@pharm.kyoto-u.ac.jp
kay-t@pharm.kyoto-u.ac.jp
[
**] We thank MEXT (Japan) for financial support (a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts”, a Grants-in-Aid for Scientific
Research and Platform for Drug Design, Discovery, and Develop-
ment). Y.K. thanks JSPS for a research fellowship for young
scientists.
Scheme 1. Screening of leaving groups. The reactions were performed
with 1 (0.1 mmol), (PhO) PO H (0.01 mmol), and MS 4 Š (50 mg) in
toluene (0.4 mL). Yields of isolated compound 2a are shown.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502831.
2
2
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Angewandte
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[15]
[a]
1
da was used,
the substitution occurred efficiently with
Table 2: Substrate scope.
marked improvement in the yield of 2a. Trichloroacetate 1e,
an oxygen analogue of 1da, was totally unreactive. This result
indicates that protonation at the basic imino group was
operative in the reaction of 1da.
[b]
[c]
Entry
Product
t [h]
Yield [%]
ee [%]
1
(R)-2e
1
92
96
With the appropriate leaving group in hand, we screened
[16]
[d]
chiral phosphoric acids in toluene at room temperature in
2
2 f
1
1
89
94
94
96
[17]
the presence of powdered molecular sieves. Using catalyst
a substituted with 9-anthracenyl provided us with a promis-
3
ing start point (Table 1, entries 1–3). Subsequently, we turned
our attention to the substituent of the nitrogen nucleophile.
We reasoned that a substrate with a more acidic NH group
could interact more tightly with the Brønsted-basic phospho-
ryl oxygen of 3 to enhance the enantioselectivity of the
reaction. Consistent with this expectation, changing the
substituent of the amino group to a 4-nitrobenzensulfonyl
3
2g
[
d,e]
4
2h
2i
4
4
93
92
96
96
(
(
4-Ns) group remarkably increased the enantioselectivity
entry 4). The position of the nitro substituent was important,
[d,e]
5
as the enantioselectivity was increased when 2-nitrosulfonyl
amino substrate 1dc was used (entry 5). Further improvement
[
18]
6
7
2j
48
48
0
–
6
was realized with 2,4-dinitrobenzensulfonyl (DNs) amino
substrate 1dd, which provided pyrrolidine 2d in 69% yield
and 86% ee (entry 6).
[d,f]
2k
89
With the best substituent of the amino group, the catalyst
was further optimized by extending the 3,3’-substituents of
the BINOL backbone. We postulated that addition of a bulky
substituent at the 10-position of the anthracene moiety could
enhance the discrimination between the enantiotopic faces of
the C=C bond far away from the chiral scaffold. As expected,
[a] Reactions were performed with sulfonamide (0.1 mmol), (R)-3e
(
(
0.005 mmol), and 4 Š molecular sieves (50 mg) in fluorobenzene
0.4 mL). [b] Yield of isolated product. [c] Determined by HPLC on
a chiral stationary phase. [d] 7.5 mol% catalyst loading. [e] At 508C. [f] At
room temperature.
[19]
catalyst 3d, bearing 10-phenylanthracene,
remarkably
enhanced the enantioselectivity, furnishing 2d in 86% yield
and 91% ee (entry 7). Further investigation revealed that
catalyst 3e, bearing 10-mesitylanthracene, was the optimal
catalyst, giving the desired product in 93% yield and 96% ee
enabled us to reduce the catalyst loading to 5 mol% with the
same level of catalyst activity (entry 9).
The scope of the reaction was then explored (Table 2).
The reaction giving (R)-2e demonstrated that geminal
disubstitution is not necessary to
[20]
(
entry 8). Finally, the use of fluorobenzene as solvent at 08C
achieve high yield and enantioselec-
[a]
Table 1: Optimization of the phosphoric-acid-catalyzed S 2’ reaction of sulfonamide 1.
N
tivity (entry 1). The reaction giving
spiropyrrolidine 2 f also had excel-
lent enantioselectivity, but required
higher catalyst loading to achieve
a satisfactory yield (entry 2). The
reaction was also applied to sub-
strates with trisubstituted alkenes. 2-
Propylene-substituted pyrrolidine
2
9
g was obtained in 94% yield and
6% ee (entry 3). Halogen-substi-
[b]
[c]
Entry PG
1
Ar
Solvent
2
Yield [%]
ee [%]
tuted pyrrolidines such as 2h and 2i
were produced with excellent enan-
tiomeric excess, although these sub-
strates required a higher temper-
ature (508C) to achieve complete
conversion (entries 4 and 5). The
reaction failed to produce piperi-
dine 2j, probably due to the slower
rate of the 6-exo cyclization
1
2
3
4
5
6
7
8
9
Ts
Ts
Ts
1da
1da
1da
9-anthracenyl (3a)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
2a 55
2a 39
2a 96
2b 57
51
43
30
62
75
86
91
96
97
2,4,6-(iPr) C H (3b)
3
6
2
3,5-(CF ) C H (3c)
3
2
6
3
4-Ns 1 db 9-anthracenyl (3a)
2-Ns 1dc
DNs
DNs
DNs
DNs
9-anthracenyl (3a)
9-anthracenyl (3a)
10-phenylanthracen-9-yl (3d)
10-mesitylanthracen-9-yl (3e) toluene
2c
61
1dd
1dd
1dd
1dd
2d 69
2d 86
2d 93
[
d]
10-mesitylanthracen-9-yl (3e) fluorobenzene 2d 93
[
a] Unless otherwise noted, reactions were performed with sulfonamide 1 (0.1 mmol), catalyst (R)-3
[21]
(entry 6).
The cyclization pro-
(0.01 mmol) and 4 A molecular sieves (50 mg) in toluene (0.4 mL). [b] Isolated yields. [c] Determined by
ceeded with the substrate bearing
an arene tether to give tetrahydro-
HPLC on a chiral stationary phase. [d] 5 mol% catalyst at 08C. PG=protecting group, Ts =p-
toluenesulfonyl, 4-Ns=4-nitrobenzenesulfonyl, 2-Ns=2-nitrobenzenesulfonyl, DNs=2,4-dinitroben-
zenesulfonyl.
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isoquinoline 2k in 89% yield, but with poor selectivity under
[22]
the present conditions (entry 7).
The absolute configuration of (R)-2e was determined by
comparing the sign of the specific rotation with that of (S)-2e
derived from l-prolinol. For all the other compounds, the
absolute configuration was assigned by analogy.
To probe the reaction mechanism, the reaction was
conducted using (Z)-1dd. Under the optimized conditions,
only 9% of (Z)-1dd was converted to 2d with 50% ee, and the
rest was quantitatively recovered (Scheme 2A). The striking
Figure 2. Chem3D perspective view of transition state models. The H
atoms of CÀH are omitted for clarity.
nesulfonamide moiety and the 10-substituent on the anthra-
cenyl group increased enantioselectivity (Table 1, entries 4
versus 5 and 6 versus 8), probably as a result of the enhanced
steric repulsion in the minor TS. The plausibility of the
proposed TS is supported by the findings.
In summary, we demonstrated a novel mode of activation
for a substitution reaction, wherein a leaving group was
activated by a chiral Brønsted acid. The developed intra-
Scheme 2. Exclusion of an S 1 mechanism and nucleophilic catalysis.
N
difference in reactivity between E- and Z-isomers suggests
that the catalyst should interact with both the leaving group
and the sulfonamide moiety by H-bonding, and therefore, the
relative position of these functionalities is likely important.
This is consistent with the expected S 2’ mechanism rather
molecular S 2’ reaction provided a variety of pyrrolidines in
N
N
than the alternative S 1 pathway.
good yields with excellent enantioselectivities. The control
experiments ruled out the possibility that the nucleophilic
catalysis was operative. The reaction tolerated halogen
functionality, which is incompatible in a conventional
method such as a transition-metal-catalyzed reaction. Further
investigations into the mechanism and applications of this
methodology are under way.
N
Phosphonate 1 ff was prepared and subjected to the
reaction using diphenylphosphonate as a Brønsted-acidic
catalyst (Scheme 2B). Although this catalyst converted
imidate 1da into 2a (Scheme 1), no reaction occurred with
phosphonate 1 ff, which was quantitatively recovered. This
result clearly indicates that the developed asymmetric reac-
tion is not a nucleophilic catalysis in which phosphonates are
generated as intermediates from allylic imidates 1d and
Keywords: asymmetric catalysis · nucleophilic substitution ·
organocatalysis · pyrrolidines
[
9]
phosphoric acids 3.
The geometries of the transition state (TS) model were
calculated at the B3LYP/6-31G** level of theory (Figure 2).
In the major TS (Figure 2A), the bond lengths of the forming
CÀN and the breaking CÀO were 2.29 and 2.44 Š, respec-
tively. The distances of > N···H···OÀP and =N···H···O=P were
How to cite: Angew. Chem. Int. Ed. 2015, 54, 8263–8266
Angew. Chem. 2015, 127, 8381–8384
[1] a) B. M. Trost, C. Lee in Catalytic Asymmetric Synthesis, 2nd ed.
(Ed.: I. Ojima), Wiley-VCH, New York, 2000, pp. 593 – 649;
b) A. Pfaltz, M. Lautens, in Comprehensive Asymmetric Catal-
ysis I – III, (Ed.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, pp. 833 – 884.
1
.06 and 1.63, and 1.03 and 1.79 Š, respectively. These atomic
distances indicate that this substitution synchronously pro-
ceeds with spontaneous activation of the leaving group and
the sulfonamide by hydrogen bonding, as expected.
[
2] a) M. J. O’Donnell, Acc. Chem. Res. 2004, 37, 506; b) T.
Hashimoto, K. Maruoka, Chem. Rev. 2007, 107, 5656.
The free energy of the minor TS (Figure 2B) was higher
À1
by 1.7 kcalmol than that of the major TS. The phenyl
[
3] Recent reviews: a) B. M. Trost, T. Zhang, J. D. Sieber, Chem. Sci.
2010, 1, 427; b) Z. Lu, S. Ma, Angew. Chem. Int. Ed. 2008, 47,
258; Angew. Chem. 2008, 120, 264; c) B. M. Trost, J. Org. Chem.
substituent of the catalyst was laid over the sulfonyl oxygen
with a distance between the oxygen atom and the nearest
carbon atom of 3.53 Š. The steric and electronic repulsion
between these two electron-rich moieties could be the main
factor to elevate the energy of the minor TS. This model
accounts for the following results: The catalyst bearing more
electron-rich 3,3’-substituents produced higher enantioselec-
tivity (Table 1, entries 1–3). The 2-nitro group of the benze-
2
1
004, 69, 5813; d) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,
03, 2921.
[
4] a) F. L. Zhang, P. J. Casey, Annu. Rev. Biochem. 1996, 65, 241;
b) P. -H. Liang, T.-P. Ko, A. H.-J. Wang, Eur. J. Biochem. 2002,
2
69, 3339.
[
5] H. K. Lichtenthaler, Annu. Rev. Plant Physiol. Plant Mol. Biol.
1999, 50, 47.
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8265

.
Angewandte
Communications
[
[
6] U. Metzger, C. Schall, G. Zocher, I. Unsçld, E. Stec, S.-M. Li, L.
Heide, T. Stehle, Proc. Natl. Acad. Sci. USA 2009, 106, 14309.
7] a) D. Parmar, E. Sugiono, S. Raja, M. Rueping, Chem. Rev. 2014,
Lattanzi, Org. Lett. 2009, 11, 3330; i) M. Senatore, A. Lattanzi, S.
Santoro, C. Santi, G. D. Sala, Org. Biomol. Chem. 2011, 9, 6205;
j) S. Lin, E. N. Jacobsen, Nat. Chem. 2012, 4, 817; k) Z. Wang, Z.
Chen, J. Sun, Angew. Chem. Int. Ed. 2013, 52, 6685; Angew.
Chem. 2013, 125, 6817.
1
14, 9047; b) A. Zamfir, S. Schenker, M. Freund, S. B. Tsogoeva,
Org. Biomol. Chem. 2010, 8, 5262; c) M. Terada, Bull. Chem.
Soc. Jpn. 2010, 83, 101; d) M. Terada, Synthesis 2010, 1929; e) M.
Terada, Chem. Commun. 2008, 4097.
[13] M. Nakano, W. Kikuchi, J. Matsuo, T. Mukaiyama, Chem. Lett.
2001, 30, 424.
[
[
8] S. Harada, S. Kuwano, Y. Yamaoka, K. Yamada, K. Takasu,
Angew. Chem. Int. Ed. 2013, 52, 10227; Angew. Chem. 2013, 125,
[14] B. Yu, H. Tao, Tetrahedron Lett. 2001, 42, 2405.
[15] R. R. Schmidt, J. Michel, Angew. Chem. Int. Ed. Engl. 1980, 19,
731; Angew. Chem. 1980, 92, 763.
[16] For pioneering work in the field of chiral phosphoric acids, see:
a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. Int.
Ed. 2004, 43, 1566; Angew. Chem. 2004, 116, 1592; b) D.
Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356.
[17] In the absence of molecular sieves, hydrolysis of 1da to 1e
competed.
1
0417.
9] S 2’-type reactions through nucleophilic catalysis; a) N. D.
N
Shapiro, V. Rauniyar, G. L. Hamilton, J. Wu, F. D. Toste,
Nature 2011, 470, 245; b) Z. Sun, G. A. Winschel, P. M. Zimmer-
man, P. Nagorny, Angew. Chem. Int. Ed. 2014, 53, 11194; Angew.
Chem. 2014, 126, 11376.
[
[
[
10] A chiral Brønsted-acid-catalyzed S 1-type allylic substitution:
N
M. Rueping, U. Uria, M.-Y. Lin, I. Atodiresei, J. Am. Chem. Soc.
[18] T. Fukuyama, M. Cheung, C. K. Jow, Y. Hidai, T. Kan,
Tetrahedron Lett. 1997, 38, 5831.
[19] G. Lu, V. B. Birman, Org. Lett. 2011, 13, 356.
[20] Although fluorobenzene was the best solvent when 1e was used
in the reaction, no remarkable solvent effect was observed with
1d. See the Supporting Information for details.
2
011, 133, 3732.
ˇ
11] A chiral Brønsted-acid-catalyzed S
N
2-type reaction: I. Cori c´ ,
J. H. Kim, T. Vlaar, M. Patil, W. Thiel, B. List, Angew. Chem. Int.
Ed. 2013, 52, 3490; Angew. Chem. 2013, 125, 3574.
12] Ring opening reactions of epoxides, aziridines, episulfonium
ions, and oxetanes through an S 2 pathway: a) Z. Wang, W. K.
[21] The allylic compound 1dj alkylated the catalyst to give the
phosphoric acid triester, which has no catalytic activity. See
Scheme 2B.
[22] The N-Ts substrate was used because of the low solubility of the
N-DNs substrate.
N
Law, J. Sun, Org. Lett. 2013, 15, 5964; b) M. R. Monaco, S.
PrØvost, B. List, Angew. Chem. Int. Ed. 2014, 53, 8142; Angew.
Chem. 2014, 126, 8280; c) M. R. Monaco, B. Poladura, M. D.
de Los Bernardos, M. Leytzsch, R. Goddard, B. List, Angew.
Chem. Int. Ed. 2014, 53, 7063; Angew. Chem. 2014, 126, 7183;
d) E. B. Rowland, G. B. Rowland, E. Rivera-Otero, J. C. Antilla,
J. Am. Chem. Soc. 2007, 129, 12084; e) G. L. Hamilton, T. Kanai,
F. D. Toste, J. Am. Chem. Soc. 2008, 130, 14984; f) S. E. Larson,
J. C. Baso, G. Li, J. C. Antilla, Org. Lett. 2009, 11, 5186; g) T.
Mita, E. N. Jacobsen, Synlett 2009, 1680; h) G. D. Sala, A.
Received: March 27, 2015
Revised: April 12, 2015
Published online: May 28, 2015
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