Synthesis of Enantioenriched Pyrrolidines via Gold-Catalyzed Tandem Cycloisomerization/Hydrogenation of Chiral Homopropargyl Sulfonamides

Article abstract of DOI:10.1021/acs.orglett.6b02736

A novel gold-catalyzed tandem cycloisomerization/hydrogenation of chiral homopropargyl sulfonamides has been developed. Various enantioenriched pyrrolidines can be obtained in excellent yields and excellent enantioselectivities by combination of chiral tert-butylsulfinimine chemistry with gold catalysis. Importantly, this represents the first example of a pyrrolidine synthesis from homopropargyl sulfonamide.

Full text of DOI:10.1021/acs.orglett.6b02736

Letter
pubs.acs.org/OrgLett
Synthesis of Enantioenriched Pyrrolidines via Gold-Catalyzed
Tandem Cycloisomerization/Hydrogenation of Chiral
Homopropargyl Sulfonamides
Yong-Fei Yu,† Chao Shu,† Tong-De Tan,† Long Li,† Shahid Rafique,† and Long-Wu Ye*,†,‡
†State Key Laboratory of Physical Chemistry of Solid Surfaces and Key Laboratory for Chemical Biology of Fujian Province, College
of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
‡State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A novel gold-catalyzed tandem cycloisomerization/
hydrogenation of chiral homopropargyl sulfonamides has been
developed. Various enantioenriched pyrrolidines can be obtained
in excellent yields and excellent enantioselectivities by combina-
tion of chiral tert-butylsulfinimine chemistry with gold catalysis.
Importantly, this represents the first example of a pyrrolidine
synthesis from homopropargyl sulfonamide.
hiral pyrrolidines are one of the prevalent frameworks
found in numerous biologically active natural products and
allowing the facile and efficient synthesis of various valuable
heterocycles from readily available homopropargyl sulfonamides
or alcohols. In addition, we also realized the direct gold-catalyzed
5-endo-dig anti-Markovnikov cycloisomerization of homopro-
pargyl sulfonamides, leading to synthetically useful 2,3-
dihydropyrroles (Scheme 1).8d Inspired by these results, we
C
drugs (Figure 1)1 and are also employed as important
Scheme 1. Initial Design: Gold-Catalyzed Tandem Anti-
Markovnikov Cycloisomerization/Hydrogenation of Chiral
Homopropargyl Sulfonamides
Figure 1. Selected examples of chiral pyrrolidines in biologically active
natural products and drugs.
organocatalysts2 and ligands3 in organic synthesis. Although
many impressive strategies have been established for the
construction of the pyrrolidine motif in the past decades,4
successful examples of enantioselective synthesis of the
pyrrolidine unit remain scarce.5 In particular, these method-
ologies generally suffer from drawbacks such as multistep
synthesis, limited substrate scope, and inaccessible starting
materials. Therefore, development of novel methods for
preparation of the chiral pyrrolidine skeleton is still highly
desirable, especially those with high enantioselectivity, efficiency,
and flexibility.
In past decades, homogeneous gold catalysis was proven to be
an extremely powerful tool for the straightforward synthesis of
cyclic compounds, especially the heterocycles.6,7 In our recent
study of gold-catalyzed cycloisomerization reactions,8 we
developed a variety of gold-catalyzed cycloisomerization-
initiated oxidation,8a,b dimerization,8c and halogenations,8e
envisioned that by adding suitable reductants the preparation of
chiral pyrrolidines 2 might be achieved through the direct gold-
catalyzed tandem cycloisomerization/hydrogenation of chiral
homopropargyl sulfonamides 1 (Scheme 1). Notably, pyrroli-
dine synthesis from 2,3-dihydropyrroles mainly relies on
hydrogenation under palladium or iridium catalysis.9 In this
communication, we report herein the realization of such a gold-
catalyzed tandem anti-Markovnikov cycloisomerization/hydro-
genation, leading to chiral pyrrolidines in excellent yields and
excellent enantioselectivities by successful combination of the
chiral tert-butylsulfinimine chemistry10 with gold catalysis. To the
best of our knowledge, this represents the first example of a
pyrrolidine synthesis from homopropargyl sulfonamide. In
Received: September 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02736
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Organic Letters
Letter
a
addition, the synthetic utility of this protocol was also described
by the formal synthesis of natural product (−)-irniine.
Table 2. Reaction Scope Study
At the outset, homopropargyl sulfonamide 1a was used as the
model substrate to react with various hydride sources. To our
delight, it was found that the use of organosilane11 as hydride
could deliver the desired product, while other hydrides such as
Hantzsch ester12 and NaBH4 failed. The treatment of substrate
1a with 3.0 equiv of Et3SiH in the presence of 5 mol % of
Ph3PAuNTf2 as gold catalyst at 45 °C in 10 h afforded the
expected pyrrolidine 2a in 50% yield, albeit together with dimer
3a as a significant byproduct (Table 1, entry 1).8c We then sought
a
Table 1. Optimization of Reaction Conditions
b
yield (%)
entry
metal catalyst
hydride
additive
2a
50
3a
c
1
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Me3PAuNTf2
Et3PAuNTf2
XPhosAuNTf2
BrettPhosAuNTf2
IPrAuNTf2
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Ph3SiH
Ph2SiH2
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
15
20
30
25
28
<5
<5
<1
<1
<1
<1
<1
<1
2
AcOH (0.3)
AcOH (1.0)
TFA (0.3)
60
52
3
4
51
5
MsOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
AcOH (0.3)
45
6
72
7
74
8
89
9
97
10
11
>99
95
d
12
<1
<1
d
13
a
Reaction conditions: [1a] = 0.05 M; DCE 1, 2-dichloroethane.
b
1
Estimated by H NMR using diethyl phthalate as internal reference.
c
d
Reaction time: 10 h. More than 95% of 1a remained unreacted.
to use different equivalents and types of acids as additives (entries
2−5) and found that the reaction yield could be improved to 60%
in the presence of 0.3 equiv of AcOH (entry 2). Of note, the use
of acid significantly shortens the reaction time. Gratifyingly, the
screening of different silanes (entries 6−8) revealed that use of
triisopropylsilane completely suppressed the dimer formation,
and the desired 2a was formed in 89% yield (entry 8).
Subsequently, the influence of various gold catalysts was
examined (entries 9−13), and almost quantitative yield was
achieved by employing Et3PAuNTf2 as gold catalyst (entry 10),
while bulky gold catalysts such as BrettPhosAuNTf2 and
IPrAuNTf2 could not catalyze this reaction (entries 12 and
13). In addition, in the absence of the gold catalyst, the desired
product was not formed under the acidic reaction conditions, and
PtCl2 and AgNTf2 also failed to catalyze such a tandem reaction.
With the optimized reaction conditions in hand, the scope of
this novel gold-catalyzed cycloisomerization/hydrogenation
reaction was then examined, as summarized in Table 2. All of
the chiral homopropargyl sulfonamides 1, readily prepared with
excellent enantiomeric excesses by using Ellman’s tert-
butylsulfinimine chemistry, underwent smooth cycloisomeriza-
tion-initiated hydrogenation, leading to the corresponding
pyrrolidines 2 in excellent yields (90−99%). In particular,
excellent enantioselectivities could be achieved in all cases, and
a
Reactions run in vials; [1] = 0.05 M; isolated yields are reported; ees
b
are determined using HPLC on a chiral stationary phase. Reaction
run at 10 °C, 24 h. With 5 mol % of Me3PAuNTf2, 12 h.
c
B
DOI: 10.1021/acs.orglett.6b02736
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Letter
essentially no epimerization was observed, highlighting the good
combination of chiral tert-butylsulfinimine chemistry with gold
catalysis. In addition, the functional groups, such as protected
hydroxy (entry 5) and N-phthaloyl (entry 6), were well tolerated
under this cyclization reaction. Besides the tosyl group, it was
found that the reaction could also proceed well for Bs (p-
bromobenzenesulfonyl) and benzenesulfonyl-protected sub-
strate 1n,o, resulting in the efficient formation of the desired
products 2n,o (entries 14 and 15). Moreover, (S)-(+)-tert-
butylsulfinamide-derived homopropargyl sulfonamide 1a′ also
delivered the corresponding pyrrolidine 2a′ with opposite
enantioselectivity (entry 16). Thus, this strategy provides a
highly efficient and practical strategy for the preparation of both
enantiomers of pyrrolidine derivatives just by a simple choice of
the starting chiral source.
deuterium loss was observed when deuterium-labeled 1a (91%
D) was treated under the optimal conditions (eq 4). These
results indicate the reaction is presumably initiated by a gold-
catalyzed 5-endo-dig cycloisomerization but does not go through
the gold vinylidene intermediate pathway.
On the basis of these experimental observations, a plausible
mechanism to rationalize the formation of 2a is proposed
(Scheme 3). The reaction may initially involve a gold-catalyzed
In addition, this chemistry could also be extended to the
synthesis of parent pyrrolidine 2p and spiropyrrolidine 2q in 99
and 88% yield, respectively (eq 1). Notably, attempts to extend
Scheme 3. Plausible Reaction Mechanism
direct 5-endo-dig cycloisomerization, followed by the in situ
generation of intermediate 4a, which is quickly converted into
iminium intermediate B catalyzed by gold and acid. In other
words, gold serves dual functions in this tandem reaction. Finally,
the iminium species undergoes facile reduction by hydride to
afford the target product 2a.
In summary, we have developed a practical and general
method for the enantioselective synthesis of various pyrrolidines
through gold-catalyzed tandem anti-Markovnikov cycloisomeri-
zation/hydrogenation of chiral homopropargyl sulfonamides,
which represents the first example of a pyrrolidine synthesis from
homopropargyl sulfonamide. Moreover, this chemistry combines
the homogeneous gold catalysis well with the organosilane
reduction, which has been rarely reported.15 Importantly, gold
serves dual catalytic roles in such a tandem sequence. In addition,
its synthetic application has also been demonstrated by a formal
synthesis of (−)-irniine in a highly efficient and concise manner.
the reaction to 4-pentyn-1-amides only resulted in the formation
of 2-methyl pyrrolidines 2r,s in excellent yields presumably via
gold-catalyzed 5-exo-dig Markovnikov cycloisomerization/hy-
drogenation (eq 2).
The utility of this methodology was further demonstrated in
the formal enantioselective synthesis of (−)-irniine (Scheme
2).13 Starting from chiral homopropargyl sulfonamide 1t, the
Scheme 2. Formal Enantioselective Synthesis of (−)-Irniine
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02736.
Experimental procedures and spectral data for all new
compounds (PDF)
tandem sequence mentioned above furnished the desired
pyrrolidine 2t in one step in 93% yield, which could be
transformed into the natural product (−)-irniine.14 It is worth
mentioning that starting from the same substrate 1t, the synthesis
of 2t demands three steps with low efficiency (47% overall yield)
according to our previously reported method based on oxidative
gold catalysis.14
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: longwuye@xmu.edu.cn.
Notes
The authors declare no competing financial interest.
To explore the reaction mechanism, several control experi-
ments were conducted. As shown in eq 3, the treatment of 2,3-
dihydropyrrole 4a8d with Pr3SiH could deliver the desired
i
ACKNOWLEDGMENTS
We are grateful for financial support from the NNSFC
(21272191 and 21572186), NSFFJ for Distinguished Young
■
pyrrolidine 2a in 90% yield only in the presence of gold catalyst.
In addition, a deuterium labeling study revealed that almost no
C
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Letter
(10) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984. For examples on its applications in chiral pyrrolidine
synthesis, see: (c) Redford, J. E.; McDonald, R. I.; Rigsby, M. L.;
Wiensch, J. D.; Stahl, S. S. Org. Lett. 2012, 14, 1242. (d) Leemans, E.;
Mangelinckx, S.; De Kimpe, N. Chem. Commun. 2010, 46, 3122.
(e) Reddy, L. R.; Prashad, M. Chem. Commun. 2010, 46, 222. (f) Brinner,
K. M.; Ellman, J. A. Org. Biomol. Chem. 2005, 3, 2109.
(11) For recent examples on the AuNP-catalyzed hydrogenations by
employing organosilane as hydride, see: (a) Takale, B. S.; Tao, S. M.; Yu,
X. Q.; Feng, X. J.; Jin, T.; Bao, M.; Yamamoto, Y. Tetrahedron 2015, 71,
7154. (b) Takale, B. S.; Tao, S. M.; Yu, X. Q.; Feng, X. J.; Jin, T.; Bao, M.;
Yamamoto, Y. Org. Lett. 2014, 16, 2558. (c) Takale, B. S.; Wang, S. Q.;
Zhang, X.; Feng, X. J.; Yu, X. Q.; Jin, T.; Bao, M.; Yamamoto, Y. Chem.
Commun. 2014, 50, 14401. (d) Yan, M.; Jin, T.; Chen, Q.; Ho, H. E.;
Fujita, T.; Chen, L.-Y.; Bao, M.; Chen, M.-W; Asao, N.; Yamamoto, Y.
Org. Lett. 2013, 15, 1484. (e) Yan, M.; Jin, T.; Ishikawa, Y.; Minato, T.;
Fujita, T.; Chen, L.; Bao, M.; Asao, N.; Chen, M.; Yamamoto, Y. J. Am.
Chem. Soc. 2012, 134, 17536.
Scholars (2015J06003), and the President Research Funds from
Xiamen University (20720150045).
REFERENCES
■
(1) (a) Bhat, C.; Tilve, S. G. RSC Adv. 2014, 4, 5405. (b) Galliford, C.
V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748. (c) Felpin, F.-X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 2003, 3693. (d) Lewis, J. R. Nat.
Prod. Rep. 2001, 18, 95. (e) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(f) Michael, J. P. Nat. Prod. Rep. 1999, 16, 675.
(2) (a) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2011, 50, 8492. (b) MacMillan, D. W. C. Nature 2008, 455, 304.
(c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007,
107, 5471. (d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138.
(3) (a) Caputo, C. A.; Jones, N. D. Dalton T. 2007, 4627. (b) Fache, F.;
Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159.
(4) (a) Han, M.-Y.; Jia, J.-Y.; Wang, W. Tetrahedron Lett. 2014, 55, 784.
(b) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156.
(c) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484.
(d) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311.
(e) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
(5) (a) Lin, T.-Y.; Zhu, C.-Z.; Zhang, P.; Wang, Y.; Wu, H.-H.; Feng, J.-
J.; Zhang, J. Angew. Chem., Int. Ed. 2016, 55, 10844. (b) Lin, J.-S.; Yu, P.;
Huang, L.; Zhang, P.; Tan, B.; Liu, X.-Y. Angew. Chem., Int. Ed. 2015, 54,
(12) For recent selected examples on Au-catalyzed hydrogenations by
employing Hantzsch ester as hydride, see: (a) Tomas-Mendivil, E.;
́
Starck, J.; Ortuno, J.-C.; Michelet, V. Org. Lett. 2015, 17, 6126. (b) Tu,
X.-F.; Gong, L.-Z. Angew. Chem., Int. Ed. 2012, 51, 11346. (c) Han, Z.-Y.;
Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 9182.
(13) For enantioselective synthesis of (−)-irniine, see: (a) Takahata,
H.; Ihara, K.; Kubota, M.; Momose, T. Heterocycles 1997, 46, 349.
(b) Jossang, A.; Melhaoui, A.; Bodo, B. Heterocycles 1996, 43, 755.
(14) Shu, C.; Li, L.; Yu, Y.-F.; Jiang, S.; Ye, L.-W. Chem. Commun. 2014,
50, 2522.
̌
7847. (c) Barber, D. M.; Duris,
Dixon, D. J. ACS Catal. 2014, 4, 634. (d) Pascual-Escudero, A.;
Gonzalez-Esguevillas, M.; Padilla, S.; Adrio, J.; Carretero, J. C. Org. Lett.
̌
A.; Thompson, A. L.; Sanganee, H. J.;
́
2014, 16, 2228. (e) Trost, B. M.; Lam, T. M.; Herbage, M. A. J. Am.
Chem. Soc. 2013, 135, 2459. (f) Guo, C.; Song, J.; Gong, L.-Z. Org. Lett.
2013, 15, 2676. (g) Jui, N. T.; Garber, J. A. O.; Finelli, F. G.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2012, 134, 11400. (h) Liwosz, T. W.;
(15) Ito, H.; Yajima, T.; Tateiwa, J.-i.; Hosomi, A. Chem. Commun.
2000, 981.
́
Chemler, S. R. J. Am. Chem. Soc. 2012, 134, 2020. (i) Hernandez-
Toribio, J.; Padilla, S.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed.
2012, 51, 8854. (j) Jana, R.; Pathak, T. P.; Jensen, K. H.; Sigman, M. S.
Org. Lett. 2012, 14, 4074. (k) McDonald, R. I.; White, P. B.; Weinstein,
A. B.; Tam, C. P.; Stahl, S. S. Org. Lett. 2011, 13, 2830. (l) Mai, D. N.;
Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157.
(6) (a) Asiri, A. M.; Hashmi, A. S. K. Chem. Soc. Rev. 2016, 45, 4471.
(b) Zheng, Z.; Wang, Z.; Wang, Y.; Zhang, L. Chem. Soc. Rev. 2016, 45,
4448. (c) Liu, L.; Zhang, J. Chem. Soc. Rev. 2016, 45, 506. (d) Huple, D.
B.; Ghorpade, S.; Liu, R.-S. Adv. Synth. Catal. 2016, 358, 1348. (e) Qian,
D.; Zhang, J. Chem. Soc. Rev. 2015, 44, 677. (f) Dorel, R.; Echavarren, A.
M. Chem. Rev. 2015, 115, 9028. (g) Wang, Y.; Muratore, M. E.;
Echavarren, A. M. Chem. - Eur. J. 2015, 21, 7332. (h) Yeom, H.-S.; Shin,
S. Acc. Chem. Res. 2014, 47, 966. (i) Fensterbank, L.; Malacria, M. Acc.
Chem. Res. 2014, 47, 953. (j) Obradors, C.; Echavarren, A. M. Acc. Chem.
Res. 2014, 47, 902. (k) Zhang, L. Acc. Chem. Res. 2014, 47, 877.
(l) Hashmi, A. S. K. Acc. Chem. Res. 2014, 47, 864.
(7) For reviews on gold catalysis in total synthesis, see: (a) Pflasterer,
̈
D.; Hashmi, A. S. K. Chem. Soc. Rev. 2016, 45, 1331. (b) Rudolph, M.;
Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41, 2448. (c) Hashmi, A. S. K.;
Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766.
(8) (a) Shu, C.; Liu, M.-Q.; Sun, Y.-Z.; Ye, L.-W. Org. Lett. 2012, 14,
4958. (b) Shu, C.; Liu, M.-Q.; Wang, S.-S.; Li, L.; Ye, L.-W. J. Org. Chem.
2013, 78, 3292. (c) Yu, Y.-F.; Shu, C.; Shen, C.-H.; Li, T.-Y.; Ye, L.-W.
Chem. - Asian J. 2013, 8, 2920. (d) Yu, Y.-F.; Shu, C.; Zhou, B.; Li, J.-Q.;
Zhou, J.-M.; Ye, L.-W. Chem. Commun. 2015, 51, 2126. (e) Shu, C.; Li,
L.; Shen, C.-H.; Ruan, P.-P.; Liu, C.-Y.; Ye, L.-W. Chem. - Eur. J. 2016,
22, 2282. (f) Shu, C.; Chen, C.-B.; Chen, W.-X.; Ye, L.-W. Org. Lett.
2013, 15, 5542. (g) Shu, C.; Li, L.; Chen, C.-B.; Shen, H.-C.; Ye, L.-W.
Chem. - Asian J. 2014, 9, 1525.
(9) (a) Yang, Z.-P.; Wu, Q.-F.; Shao, W.; You, S.-L. J. Am. Chem. Soc.
2015, 137, 15899. (b) Johnston, H. J.; McWhinnie, F. S.; Landi, F.;
Hulme, A. N. Org. Lett. 2014, 16, 4778. (c) Miura, T.; Tanaka, T.;
Hiraga, K.; Stewart, S. G.; Murakami, M. J. Am. Chem. Soc. 2013, 135,
13652. (d) Yang, L.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Am.
Chem. Soc. 2009, 131, 10390. (e) Hou, G.-H.; Xie, J.-H.; Yan, P.-C.;
Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 1366. (f) Del Valle, J. R.;
Goodman, M. Angew. Chem., Int. Ed. 2002, 41, 1600.
D
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