Gold-catalyzed intermolecular oxidation of chiral homopropargyl sulfonamides: A reliable access to enantioenriched pyrrolidin-3-ones

Article abstract of DOI:10.1039/c3cc49238a

A gold-catalyzed intermolecular oxidation of chiral homopropargyl sulfonamides has been developed, which provides a reliable access to synthetically useful chiral pyrrolidin-3-ones with excellent ee, by combining the chiral tert-butylsulfinimine chemistry and gold catalysis. This methodology has also been used in the facile synthesis of natural product (-)-irniine. The use of readily available starting materials, a broad substrate scope, a simple procedure and the mild nature of this reaction render it a viable alternative for the synthesis of enantioenriched pyrrolidin-3-ones.

Full text of DOI:10.1039/c3cc49238a

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Gold-catalyzed intermolecular oxidation of chiral
homopropargyl sulfonamides: a reliable access to
enantioenriched pyrrolidin-3-ones†
Cite this: Chem. Commun., 2014,
50, 2522
Received 5th December 2013,
Accepted 4th January 2014
Chao Shu, Long Li, Yong-Fei Yu, Shuang Jiang and Long-Wu Ye*
DOI: 10.1039/c3cc49238a
www.rsc.org/chemcomm
A gold-catalyzed intermolecular oxidation of chiral homopropargyl building blocks for the construction of complex molecules due to
sulfonamides has been developed, which provides a reliable access their latent reactivity and the large panel of highly selective transfor-
to synthetically useful chiral pyrrolidin-3-ones with excellent ee, by mations they can undergo.2 However, despite numerous preparative
combining the chiral tert-butylsulfinimine chemistry and gold cat- methods developed during the past decade,3 there are very few
alysis. This methodology has also been used in the facile synthesis examples of enantioselective synthesis of pyrrolidin-3-ones, especially
of natural product (ꢀ)-irniine. The use of readily available starting those with high enantioselectivity, flexibility and good modularity.4
materials, a broad substrate scope, a simple procedure and the mild
Recent rapid development in gold-catalyzed oxygen-atom transfer
nature of this reaction render it a viable alternative for the synthesis reactions offers easy access to an incredible variety of functionalized
of enantioenriched pyrrolidin-3-ones.
carbo- and heterocycles.5–8 In this regard, Shin and co-workers reported
an elegant protocol for the synthesis of functionalized pyrrolidin-3-
The pyrrolidin-3-one moiety has received considerable interest ones involving a gold-catalyzed intramolecular oxygen-transfer
because of its frequent occurrence in a large number of bioactive
Table 1 Optimization of reaction conditionsa
natural and non-natural molecules and has therefore been used as a
privileged structural subunit for the design of several pharmaceutical
agents.1 In addition, pyrrolidin-3-ones also served as valuable
Yieldb
(%)
Entry
L
Oxidant (R) Acid
2a 3a
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
PPh3
4a (2-Br)
4b (3,5-Cl2) 1.1 equiv. MsOH
4c (2,6-Br2) 1.1 equiv. MsOH
1.1 equiv. MsOH
37 o2
28
32
39
8
15
12
4d (3-Cl)
1.1 equiv. MsOH
1.1 equiv. MsOH
1.1 equiv. MsOH
1.1 equiv. MsOH
1.1 equiv. MsOH
1.1 equiv. MsOH
1.1 equiv. MsOH
1.1 equiv. MsOH
1.1 equiv. MsOH
1.1 equiv. MsOH
0.5 equiv. MsOH
/
PPh3
5d
35 o5
50 o2
34 o2
43 o2
26 o2
72 o2
42 o2
65 o2
20 o2
48 o2
43 o2
55 o2
XPhos
Cy-JohnPhos
BrettPhos
(4-CF3C6H4)3P 4a (2-Br)
Et3P
4a (2-Br)
4a (2-Br)
4a (2-Br)
9
10
11
12
13
14
15
16
17
18
4a (2-Br)
4a (2-Br)
4a (2-Br)
4a (2-Br)
4a (2-Br)
4a (2-Br)
4a (2-Br)
4a (2-Br)
4a (2-Br)
IPr
Mor-DalPhos
Au(III)c
Et3P
Et3P
Et3P
Et3P
Et3P
Scheme 1 Formation of pyrrolidin-3-ones through gold-catalyzed oxygen-
atom transfer to alkynes.
1.8 equiv. MsOH
State Key Laboratory for Physical Chemistry of Solid Surfaces, The Key Laboratory
for Chemical Biology of Fujian Province and Department of Chemistry, College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, Fujian,
PR China. E-mail: longwuye@xmu.edu.cn; Fax: +86-592-218-5833
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc49238a
1.1 equiv. CF3CO2H 69 o2
1.1 equiv. HNTf2
36 o2
a
b
Reaction conditions: [1a] = 0.05 M; DCE: 1,2-dichloroethane. Esti-
mated by 1H NMR using diethyl phthalate as an internal reference.
c
d
Dichloro(2-picolinato)gold(III). 8-methylquinoline 1-oxide.
2522 | Chem. Commun., 2014, 50, 2522--2525
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redox cyclization (Scheme 1).9 In our recent study toward gold- chiral pyrrolidin-3-ones in moderate to good yields and excellent
catalyzed 5-endo-dig cyclization of terminal alkynes, we reported enantioselectivities by successful combination of the chiral tert-
gold-catalyzed tandem cycloisomerization–oxidation and tandem butylsulfinimine chemistry with gold catalysis. The synthetic utility
cycloisomerization–dimerization from readily available chiral of this protocol was demonstrated by the enantioselective total
homopropargyl sulfonamides, leading to the efficient formation of synthesis of natural product (ꢀ)-irniine.
enantioenriched g-lactams and pyrrolidines, respectively.10 Inspired
Our initial investigation focused on the reaction of homo-
by these results, we envisioned that enantioenriched pyrrolidin-3- propargyl sulfonamide substrate 1a with pyridine N-oxide 4 in
ones might be accessed directly from chiral homopropargyl sulfon- DCE at room temperature in the presence of a gold(I) complex
amides through a gold-catalyzed intermolecular oxygen-transfer (5 mol%). To our delight, the desired pyrrolidin-3-one 2a was
redox cyclization, providing a flexible and alternative way for the indeed formed under the optimal conditions established by
preparation of versatile pyrrolidin-3-one derivatives (Scheme 1). Zhang for propargylic alcohol substrates (Table 1, entry 1).6h
In this communication, we describe herein the realization of However, the yield of this reaction was only 37%, indicating
such a gold-catalyzed intermolecular alkyne oxidation, affording that the sulfonamide here behaved very differently from its
Table 2 Reaction scope for the formation of enantioenriched pyrrolidin-3-onesa
Entry
1
Product
2
Yield ee (%)
Entry
10
Product
2
Yield ee (%)
69
99
61
99
2a
2j
57
99
52
99
2
3
4
5
6
2b
2c
2d
2e
2f
11
12
13
14
15b
2k
2l
62
99
63
98
61
99
67
99
2m
2n
2a0
60
99
70
99
63
99
60
99
2o
2p
70
55
60
99
7
8
2g
16
70
99
63
99
2h
2i
17
18
2q
2r
65
99
62
99
9
a
b
Reactions run in vials; [1] = 0.05 M; isolated yields are reported; ees are determined using HPLC on a chiral stationary phase. Using (S)-(+)-tert-
butylsulfinamide-derived homopropargyl amide 1a0 as the substrate.
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alcohol counterpart. Varying the oxidants did not improve the
reaction (Table 1, entries 2–5). Here, it should be mentioned
that a significant amount of dimer 3a was formed through
gold-catalyzed tandem cycloisomerization–dimerization in
some cases.10a Correlated with our previously reported gold-
catalyzed tandem cycloisomerization–oxidation reaction,10b we
speculate that the differential reactivity of the starting materials
mainly depends on the nucleophilicity of the oxidants. More
nucleophilic oxidants such as pyridine N-oxides here would
attack the gold-activated alkynes directly to deliver the a-oxo
gold carbenoids, which finally led to the formation of
3-pyrrolidones. However, in the presence of less nucleophilic
oxidants such as m-CPBA, the reaction would proceed through a
gold-catalyzed cycloisomerization and subsequent oxidation,
while a tandem cycloisomerization–dimerization occurred in
the absence of the oxidant. Screening of different gold catalysts
(Table 1, entries 6–13) revealed that Et3PAuNTf2 was best
suited for this reaction (Table 1, entry 10), followed by
Mor-DalPhosAuNTf2 (Table 1, entry 12).6a,b In addition, the
effect of acid was also investigated and it was found that the
use of other acids failed to improve the yield (Table 1, entries
14–18). Notably, no pyrrolidin-3-one was observed under acidic
conditions in the absence of the gold catalyst, and PtCl2 was not
effective in promoting this reaction.
Scheme 2 Enantioselective total synthesis of (ꢀ)-irniine.
no migration of the sulfonyl group was observed in this case, as
previously described in Shin’s Chemistry.9
(1)
The significance of this methodology is additionally demon-
strated by its application to the enantioselective total synthesis
The chiral homopropargyl sulfonamide substrates were then of (ꢀ)-irniine (Scheme 2).12 Chiral homopropargyl sulfonamide
prepared with excellent enantiomeric excesses according to substrate 1s was prepared from 10-phenyldecanal in a four-step
Ellman’s tert-butylsulfinimine chemistry.11 With these sub- process according to our well-established sequence. Then, the
strates in hand, we then probed the generality of the current treatment of substrate 1s under the previously optimized reac-
reaction. As shown in Table 2, homopropargyl sulfonamides 1 tion conditions allowed the formation of pyrrolidin-3-one 2s in
could undergo smooth cyclization to produce the corres- 63% yield with excellent enantioselectivity. The removal of the
ponding pyrrolidin-3-ones 2 in moderate to good yields. Of carbonyl group, followed by replacement of the tosyl group with
note, a range of functional groups were well tolerated during the methyl group, furnished the final (ꢀ)-irniine 6. Thus, the
the cyclization reaction, including phenyl (Table 2, entry 3), preparation of (ꢀ)-irniine was accomplished in 9 steps from
azido (Table 2, entry 4), protected amino (Table 2, entry 5), and readily available 10-phenyldecanal in 12.2% overall yield.
hydroxy (Table 2, entry 6). Importantly, excellent enantio- Importantly, this protocol represents a new access to versatile
selectivities could be achieved in all cases and essentially no optically active N-methyl pyrrolidine derivatives,13 and nicely
epimerization was observed, constituting a good combination complements the method we have developed very recently.10b
of chiral tert-butylsulfinimine chemistry with gold catalysis.
In summary, we have developed a gold-catalyzed intermolecular
In addition, the use of (S)-(+)-tert-butylsulfinamide-derived oxidation of chiral homopropargyl sulfonamides, allowing the
homopropargyl sulfonamide 1a0 also furnished the corres- convenient synthesis of optically active pyrrolidin-3-ones in combi-
ponding pyrrolidin-3-one 2a0 with the opposite enantio- nation with chiral tert-butylsulfinimine chemistry. With this newly
selectivity (Table 2, entry 15). Thus, this protocol allows a rapid established methodology, the enantioselective total synthesis of
and practical access to both enantiomers of pyrrolidin-3-one 2 natural product (ꢀ)-irniine could be easily achieved in a highly
just by the choice of the starting chiral source. This chemistry efficient and concise manner. Further investigations into the
can also be extended to the preparation of parent pyrrolidin-3- synthetic applications of the current protocol are in progress in
one 2o and 5,5-disubstituted pyrrolidin-3-one 2p in fairly good our laboratory.
yields (70% and 55% isolated yields, Table 2, entry 16). Besides
We are grateful for the financial support from the National
the tosyl group, it was found that the reaction could proceed Natural Science Foundation of China (No. 21102119 and
well for Bs and Ns protected substrates 1q–1r, resulting in good 21272191), NFFTBS (No. J1310024) and PCSIRT.
yields of the desired products 2q–2r (70% and 65% isolated
Notes and references
1 (a) T. Kawakami, T. Ishizawa and H. Murakami, J. Am. Chem. Soc.,
yields, Table 2, entries 17 and 18) with excellent ees, providing
an easier way for its later removal.
As shown in eqn (1), attempts to expand this chemistry to
internal alkynes were not successful presumably due to the
competing gold-catalyzed hydration reaction and 1,2-C–H
insertion via an a-oxo gold carbene intermediate.6f,8k Notably,
2013, 135, 12297; (b) D. Siegel, S. Merkel, W. Bremser, M. Koch and
I. Nehls, Anal. Bioanal. Chem., 2010, 397, 453; (c) X. Liu and
C. T. Walsh, Biochemistry, 2009, 48, 11032; (d) S. Collina, D. Rossi,
G. Loddo, A. Barbieri, E. Lanza, L. Linati, S. Alcaro, A. Gallelli and
O. Azzolinaa, Bioorg. Med. Chem., 2005, 13, 3117; (e) H. Poschenrieder,
2524 | Chem. Commun., 2014, 50, 2522--2525
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
H.-D. Stachel, G. Hofner and P. Mayer, Eur. J. Med. Chem., 2005,
ChemComm
¨
7 For selected work done by the Liu research group, see:
(a) S. K. Pawar, C.-D. Wang, S. Bhunia, A. M. Jadhav and R.-S. Liu,
Angew. Chem., Int. Ed., 2013, 52, 7559; (b) S. Ghorpade, M.-D. Su and
R.-S. Liu, Angew. Chem., Int. Ed., 2013, 52, 4229; (c) R. K. Kawade and
R.-S. Liu, Org. Lett., 2013, 15, 4094; (d) S. Bhunia, S. Ghorpade,
D. B. Huple and R.-S. Liu, Angew. Chem., Int. Ed., 2012, 51, 2939;
(e) R. B. Dateer, K. Pati and R.-S. Liu, Chem. Commun., 2012, 7200;
( f ) D. Vasu, H.-H. Hung, S. hunia, S. A. Gawade, A. Das and R.-S. Liu,
Angew. Chem., Int. Ed., 2011, 50, 6911.
´ ´
40, 391; ( f ) M. Bouygues, M. Medou, G. Quelever, J. C. Chermann,
M. Camplo and J. L. Kraus, Bioorg. Med. Chem. Lett., 1998, 8, 277.
2 (a) D. J. Rawson, D. Brugier, A. Harrison, J. Hough, J. Newman,
J. Otterburn, G. N. Maw, J. Price, L. R. Thompson, P. Turnpenny and
A. N. Warren, Bioorg. Med. Chem. Lett., 2011, 21, 3771; (b) F. A. Davis,
J. Zhang and Y. Wu, Tetrahedron Lett., 2011, 52, 2054;
´
´
(c) K. C. Nicolaou, A. Krasovskiy, U. Majumder, V. E. Trepanier
and D. Y.-K. Chen, J. Am. Chem. Soc., 2009, 131, 3690; (d) S. Gupta
and C. E. Schafmeister, J. Org. Chem., 2009, 74, 3652; (e) P.-Q.
Huang, T.-J. Wu and Y.-P. Ruan, Org. Lett., 2003, 5, 4341;
( f ) T. Gallagher, M. Giles, R. S. Subramanian and M. S. Hadley,
J. Chem. Soc., Chem. Commun., 1992, 166.
¨
8 For other examples, see: (a) P. Nosel, L. N. dos Santos Comprido,
T. Lauterbach, M. Rudolph, F. Rominger and A. S. K. Hashmi, J. Am.
Chem. Soc., 2013, 135, 15662; (b) L. Wang, X. Xie and Y. Liu, Angew.
Chem., Int. Ed., 2013, 52, 13302; (c) G. Henrion, T. E. J. Chava, X. Le
Goff and F. Gagosz, Angew. Chem., Int. Ed., 2013, 52, 6277; (d) J. Fu,
H. Shang, Z. Wang, L. Chang, W. Shao, Z. Yang and Y. Tang, Angew.
Chem., Int. Ed., 2013, 52, 4198; (e) S. Shi, T. Wang, W. Yang,
M. Rudolph and A. S. K. Hashmi, Chem.–Eur. J., 2013, 19, 6576;
( f ) K.-B. Wang, R.-Q. Ran, S.-D. Xiu and C.-Y. Li, Org. Lett., 2013,
15, 2374; (g) M. Xu, T.-T. Ren and C.-Y. Li, Org. Lett., 2012, 14, 4902;
(h) A. S. K. Hashmi, T. Wang, S. Shi and M. Rudolph, J. Org. Chem.,
2012, 77, 7761; (i) D. Qian and J. Zhang, Chem. Commun., 2012,
48, 7082; ( j) D. Qian and J. Zhang, Chem. Commun., 2011, 47, 11152;
(k) P. W. Davies, A. Cremonesi and N. Martin, Chem. Commun., 2011,
47, 379.
3 For recent examples, see: (a) G. Frey, H.-T. Luu, P. Bichovski,
M. Feurer and J. Streuff, Angew. Chem., Int. Ed., 2013, 52, 7131;
(b) O. K. Karjalainen, M. Nieger and A. M. P. Koskinen, Angew.
Chem., Int. Ed., 2013, 52, 2551; (c) T. Maegawa, K. Otake,
K. Hirosawa, A. Goto and H. Fujioka, Org. Lett., 2012, 14, 4798;
(d) J.-M. Yang, Z. Zhang, Y. Wei and M. Shi, Tetrahedron Lett., 2012,
53, 6173; (e) V. D. Pinho and A. C. B. Burtoloso, J. Org. Chem., 2011,
76, 289; ( f ) J. Robertson, A. J. Tyrrell, P. T. Chovatia and S. Skerratt,
Tetrahedron Lett., 2009, 50, 7141; (g) A. Alex, B. Larmanjat, J. Marrot,
F. Couty and O. David, Chem. Commun., 2007, 2500; (h) W. Van
Brabandt, R. Van Landeghem and N. De Kimpe, Org. Lett., 2006,
8, 1105; (i) F. A. Davis, Y. Wu, H. Xu and J. Zhang, Org. Lett., 2004,
9 H.-S. Yeom, E. So and S. Shin, Chem.–Eur. J., 2011, 17, 1764.
6, 4523; ( j) S. Berlin, C. Ericsson and L. Engman, J. Org. Chem., 10 (a) Y.-F. Yu, C. Shu, C.-H. Shen, T.-Y. Li and L.-W. Ye, Chem.–Asian J.,
2003, 68, 8386.
2013, 8, 2920; (b) C. Shu, M.-Q. Liu, S.-S. Wang, L. Li and L.-W. Ye,
J. Org. Chem., 2013, 78, 3292; (c) C. Shu, M.-Q. Liu, Y.-Z. Sun and
L.-W. Ye, Org. Lett., 2012, 14, 4958.
4 (a) S. Cai, B. K. Gorityala, J. Ma, M. L. Leow and X.-W. Liu, Org. Lett.,
2011, 13, 1072; (b) S. Kaden, M. Brockmann and H.-U. Reissig, Helv.
Chim. Acta, 2005, 88, 1826; (c) J. Courcambeck, F. Bihel, C. De 11 (a) M. T. Robak, M. A. Herbage and J. A. Ellman, Chem. Rev., 2010,
´ ´
Michelis, G. Quelever and J. L. Kraus, J. Chem. Soc., Perkin Trans. 1,
2001, 1421.
110, 3600; (b) J. A. Ellman, T. D. Owens and T. P. Tang, Acc. Chem.
Res., 2002, 35, 984.
5 For a review, see: J. Xiao and X. Li, Angew. Chem., Int. Ed., 2011, 12 For enantioselective synthesis of (ꢀ)-irniine, see: (a) H. Takahata,
50, 7226.
K. Ihara, M. Kubota and T. Momose, Heterocycles, 1997, 46, 349;
(b) A. Jossang, A. Melhaoui and B. Bodo, Heterocycles, 1996, 43, 755.
6 For selected work done by the Zhang research group, see: (a) K. Ji,
Y. Zhao and L. Zhang, Angew. Chem., Int. Ed., 2013, 52, 6508; 13 For recent selected natural products of the optically active N-methyl
(b) Y. Luo, K. Ji, Y. Li and L. Zhang, J. Am. Chem. Soc., 2012,
134, 17412; (c) Y. Wang, K. Ji, S. Lan and L. Zhang, Angew. Chem.,
Int. Ed., 2012, 51, 1915; (d) W. He, C. Li and L. Zhang, J. Am. Chem.
Soc., 2011, 133, 8482; (e) L. Ye, W. He and L. Zhang, Angew. Chem.,
Int. Ed., 2011, 50, 3236; ( f ) B. Lu, C. Li and L. Zhang, J. Am. Chem.
Soc., 2010, 132, 14070; (g) L. Ye, W. He and L. Zhang, J. Am. Chem.
Soc., 2010, 132, 8550; (h) L. Ye, L. Cui, G. Zhang and L. Zhang, J. Am.
Chem. Soc., 2010, 132, 3258.
2-alkylpyrrolidine alkaloids, see: (a) K.-J. Xiao, Y. Wang, K.-Y. Ye and
P.-Q. Huang, Chem.–Eur. J., 2010, 16, 12792; (b) M. Jordan,
˜
M. Humam, S. Bieri, P. Christen, E. Poblete and O. Munoz, Phyto-
chemistry, 2006, 67, 570; (c) C. J. Dunsmore, R. Carr, T. Fleming and
N. J. Turner, J. Am. Chem. Soc., 2006, 128, 2224; (d) G. Ferretti,
M. Dukat, M. Giannella, A. Piergentili, M. Pigini, W. Quaglia,
M. I. Damaj, B. R. Martin and R. A. Glennon, Bioorg. Med. Chem.
Lett., 2003, 13, 733; (e) D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435.
This journal is ©The Royal Society of Chemistry 2014
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