Silver-Catalyzed Decarboxylative Radical Azidation of Aliphatic Carboxylic Acids in Aqueous Solution

Article abstract of DOI:10.1021/jacs.5b06821

We report herein an efficient and general method for the decarboxylative azidation of aliphatic carboxylic acids. Thus, with AgNO₃ as the catalyst and K₂S₂O₈ as the oxidant, the reactions of various aliphatic carboxylic acids with tosyl azide or pyridine-3-sulfonyl azide in aqueous CH₃CN solution afforded the corresponding alkyl azides under mild conditions. A broad substrate scope and wide functional group compatibility were observed. A radical mechanism is proposed for this site-specific azidation.

Full text of DOI:10.1021/jacs.5b06821

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Silver-Catalyzed Decarboxylative Radical Azidation of Aliphatic
Carboxylic Acids in Aqueous Solution
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Chao Liu,a Xiaoqing Wang,a Zhaodong Li,a Lei Cui,a and Chaozhong Li*, a, b
a Key Laboratory of Organofluorine Chemistry and Collaborative Innovation Center of Chemistry for Life Sciences,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P.
R. China, and b School of Chemical Engineering, Ningbo University of Technology, No. 89 Cuibai Road, Ningbo
315016, P. R. China
Supporting Information Placeholder
especially in a catalytic manner, is thus highly desirable.
ABSTRACT: We report herein an efficient and general
method for the decarboxylative azidation of aliphatic
Driven by our interest in silver-catalyzed decarboxylation
reactions,7 we set out to explore this possibility.
carboxylic acids. Thus with AgNO3 as the catalyst and
K2S2O8 as the oxidant, the reactions of various aliphatic
carboxylic acids with tosyl azide or pyridine-3-sulfonyl
azide in aqueous CH3CN solution afforded the
corresponding alkyl azides under mild conditions. A
broad substrate scope and wide functional group
compatibility were observed. A radical mechanism is
proposed for this site-specific azidation.
Organic azides perform irreplaceable roles in chemical
biology and drug discovery owing to the broad
application of azide–alkyne Huisgen cycloaddition and
Staudinger ligation in “click” chemistry.1 They are also
versatile intermediates in organic chemistry and
materials science.2 The access to this important class of
compounds has attracted a considerable attention, and a
number of new methods such as C–H azidation3 and
carboazidation4 of alkenes, have recently been developed.
Nevertheless, the discovery of general, efficient and site-
specific methods under mild conditions remains a
formidable challenge. Herein we report the silver-
catalyzed decarboxylative azidation of aliphatic
Figure 1. Decarboxylative azidation of aliphatic carboxylic
acids.
Thus, 2-ethyltetradecanoic acid (A-1) was initially
used as the model substrate for the optimization of
reaction conditions (see Table S1 in the Supporting
Information for details). We were pleased to find that,
with AgNO3 (20 mol %) as the catalyst and K2S2O8 (2
equiv) as the oxidant, the reaction of A-1 with pyridine-
3-sulfonyl azide (3 equiv) proceeded smoothly in
CH3CN/H2O (1:1) at 50 oC leading to the expected
decarboxylative azidation product
1 in essentially
quantitative yield. Among various azide reagents
screened, pyridine-3-sulfonyl azide was proved to be the
best, as shown in Scheme 1. Tosyl azide also afforded
alkyl azide 1 in an excellent yield. Benzenesulfonyl azide,
ethanesulfonyl azide and pyridine-2-sulfonyl azide were
less effective, and variable amounts of acid A-1 were
recovered at the end of reactions. On the other hand, no
product could be observed with the use of
azidobenziodoxolones presumably because of their
instability in aqueous solution. To check the consistency
of the above reactivity trend, two more substrates were
then tested, adamantane-1-caroboxylic acid (A-2) and
carboxylic acids in aqueous solution, providing
a
convenient and site-specific entry to organic azides with
high efficiency and broad substrate scope.
The ready availability, high stability, and low cost of
aliphatic carboxylic acids make them extremely
promising raw materials for chemical synthesis.5 In
particular, the decarboxylative reactions involving the
cleavage of C(sp3)–COOH bonds allow the site-specific
introduction of functional groups.6–8 The conversion of a
carboxylic acid into an azide is unique and very attractive
due to the versatility of the azide function. This
transformation was realized9 by converting carboxylic
acids to thiohydroxamate esters such as PTOC (pyridine-
2,2-di(acetoxymethyl)propionic
acid
(A-3).
The
azidodecarboxylation of A-2 with 3-PySO2N3 gave azide
2 in 17% yield only, while di- and tri-azidation side-
products could be detected by GC-MS analysis
presumably via C–H azidation. As a comparison, the use
of TsN3 afforded product 2 cleanly in 84% yield.
However in the case of A-3, alkyl azide 3 was obtained in
a good yield (68%) with 3-PySO2N3 but in a poor yield
(30%) with TsN3. In the latter case over 40% yield of A-3
was recovered. The above results indicate that 3-
2-thione-N-oxycarbonyl)
dimethyldithiocarbamoyl-N-oxy-carbonyl)
or
MMDOC
(N,S-
esters,
followed by reaction with a sulfonyl azide10 under radical
initiation conditions (hv or AIBN) (Figure 1).11 However,
this two-step method is of relatively low overall efficiency
and also suffers from the low stability of
thiohydroxamate esters. The efficient, operationally
simple, one-step and direct decarboxylative azidation,
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PySO2N3 is generally more reactive and also more prone
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Ag(I) (cat)/K2S2O8
TsN3 or 3-PySO2N3
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to side reactions than TsN3. Although the reasons for the
difference between the two reagents remain unclear, we
suspect that the basicity might play a role, as 3-PySO2N3
is more basic. Indeed, when the reaction of A-3 with
TsN3 was carried out in the presence of pyridine (3 equiv)
under otherwise identical conditions, the yield of 3
increased from 30% to 50%.12
R
CO2H
R
N3
CH3CN/H2O, 50 o
C
(yield)a,b
Me Me
n-C10H21
N3
4 (92%)c
n-C4H9 Et
n-C4H9
N3
5 (92%)c
C8H17-n
C8H17-n
N3
N3
6 (90%)c
7 (91%)c
Scheme 1. Effects of Different Azides in
Azidodecarboxylation
Me Me
N3
c-C6H11
c-C6H11
Et
Et
O
9
Tol
Ph
N3
11 (75%)d
N3
N3
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OC6H11-c
8 (81%)c
azide source (3 equiv)
AgNO3 (20 mol %)/K2S2O8 (2 equiv)
10 (80%)d
9 (82%)c
R
CO2H
R N3
CH3CN/H2O (1:1), 50 oC, 10 h
Et
Ar
Me
Et
Ar
Ar
Ar
14 (89%)c
N3
N3
n-C12H25
N3
N3
AcO
AcO
12 (78%)d
13 (60%)c, e
azide
source
N3
15 (61%)d, e
N3
(Ar = p-tBu-C6H4) (Ar = p-NO2-C6H4) (Ar = p-Cl-C6H4)
n-C12H25
N3
2
3
1
Ts
Me
N3
16 (76%)d
Et
O
Me
N3
N
3-PySO2N3
TsN3
98
17
84
82
68
30
68
30
20
24
14
Ph
Bz
Br
N3
17 (77%)d
Ph
4
N3
d, e
91
74
70
50
18 (64%)d
19
(72%)
PhSO2N3
EtSO2N3
2-PySO2N3
Ph
O
N
PhthN
N
O
O
N3
20 (74%)d
N3
N3
Ph
N3
23 (64%)c
21 (80%)d, f
22 (71%)c, f
O
I
N3
(X, X = O)
(X = Me)
0
0
0
0
0
0
X
O
Cl
X
N3
O
N3
O
N3
H
We then moved on to examine the scope and limitation
24 (68%)d
25 (73%)d
of this new decarboxylative azidation method with either
3-PySO2N3 or TsN3 as the azide reagent, and the results
are summarized in Scheme 2. Tertiary alkyl carboxylic
acids underwent efficient decarboxylative azidation to
afford the corresponding products 4–8 in excellent
yields. The reactions of secondary alkyl carboxylic acids
also proceeded smoothly, furnishing the alkyl azides 9–
22 in high yields. The azidodecarboxylation was also
applicable to α-oxy acids or α-amino acids, as
exemplified by the synthesis of azides 23–25. A variety
of functional groups including ether, ester, ketone, amide,
tosylate, sulfonamide, alkene, nitro, and aryl or alkyl
halides, were well tolerated. This excellent functional
group compatibility allowed the late-stage azidation of
complex molecules. For example, the decarboxylative
azidation of dehydrolithocholic acid led to the
corresponding product 26 in 74% yield.
H
H
26
(74%)d, g
O
n-C17H35 N3
28 (45%)h
n-C13H27 N3
27 (52%)h
a
Reaction conditions: carboxylic acid (0.2 mmol), 3-
PySO2N3 or TsN3 (0.6 mmol), AgNO3 (0.04 mmol), K2S2O8
(0.4 mmol), CH3CN (1 mL), H2O (1 mL), 50 oC, 10 h.
b
c
Isolated yield based on carboxylic acid. 3-PySO2N3 was
d
e
used. TsN3 was used. Four equivalents of azide reagent
were used. f trans/cis = 74:26. g d.r. = 50:50. h AgNO3 (0.06
mmol), 3-PySO2N3 (0.8 mmol) and K2S2O8 (0.6 mmol),
reflux, 12 h.
It can be concluded from Scheme 2 that the reactivity
of carboxylic acids decreased in the order tertiary >
secondary > primary >> aromatic. This reactivity pattern
thus allows the implementation of chemoselective
azidodecarboxylation. For example, the alkylic carboxyl
group in diacid A-29 was selectively removed while the
benzoic carboxyl group remained intact, providing alkyl
azide 29 in 92% yield (Eq 1). Similarly, 2,2-
Compared to secondary and tertiary alkyl acids,
primary alkyl carboxylic acids such as tetradecanoic acid
and stearic acid underwent decarboxylation sluggishly
under the above conditions. Nevertheless, when we
dimethylpentanedioic
chemoselective decarboxylation to give exclusively the
tertiary alkyl azide 30 (Eq 2).
acid
(A-30)
underwent
o
increased the reaction temperature to 80 C, the desired
products 27 and 28 could be achieved in moderate yields.
On the other hand, aromatic acids such as 4-
chlorobenzoic acid and 4-methoxybenzoic acid failed to
give any desired azidodecarboxylation products under
the above experimental conditions, while all of the
starting acids were recovered.
Scheme 2. Silver-Catalyzed Decarboxylative
Azidation
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treatment of ketone 36a with KHMDS/PhNTf2 gave
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3
4
5
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7
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vinyl triflate 37a, which underwent Pd-catalyzed
coupling reaction with an organozinc reagent to provide
ester 38a. The subsequent olefin hydrogenation with
simultaneous debenzylation afforded acid 39a in a
stereospecific manner owing to the directing effect of the
adjacent carboxyl group. Acid 39a then underwent
AgNO3-catalyzed azidodecarboxylation with 3-PySO2N3
to generate azide 40a as a 1:1 mixture of two
diastereoisomers. The reduction of 40a by LiBH4 yielded
alcohol 41a. Finally, the intramolecular Schmidt
reaction17 of azidoalcohol 41a according to Renaud’s
procedure15c led to the stereoselective synthesis of (-)-
indolizidine 209D with 83% ee.18 In a similar fashion, (-
)-indolizidine 167B was also synthesized from 34 in 26%
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14
15
overall
azidodecarboxylation
yield
with
86%
enables
ee.
the
Thus,
general
the
and
The above relative reactivities of carboxylic acids also
suggest that the reaction proceeds by an oxidative radical
decarboxylation mechanism. A more direct evidence was
the reaction of acid A-31 in with the azidation product
31 (50%) was accompanied by the cyclization product 32
(25%), as shown in Eq 3. To provide solid evidence on
the radical mechanism, cyclopropylacetic acid A-33 was
designed as the radical probe. The reaction of A-33 with
TsN3 under the above optimized conditions gave the
ring-opening product 33 in 42% yield as a 82:18 mixture
straightforward design towards these indolizidines.
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Scheme 3. Total Synthesis of (-)-Indolizidine
209D and 167B
t
CO2 Bu
NH
O
O
iPr
L-Val-OtBu
LDA
R-I
CO2Bn
R
CO2Bn
34
.
BF3 Et2O
36a (R = n-Hex)
78% (83% ee)
36b
(R = n-Pr)
77% (88% ee)
CO2Bn
(97%)
35
1
of two stereoisomers determined by H NMR (Eq 4).
These two experiments strongly support the involvement
of free radical mechanism in the azidodecarboxylation.
CO2Et
OTf
Pd(OAc)2, dppf
IZn(CH2)2CO2Et
KHMDS
PhNTf2
Pd/C
H2
CO2Bn
R
CO2Bn
R
37a
37b (92%)
(91%)
38a (73%)
38b (73%)
CO2Et
OH
CO2Et
AgNO3
K2S2O8
Figure 2. Proposed mechanism of decarboxylative
azidation.
LiBH4
N3
R
N3
R
CO2H
R
3-PySO2N3
A plausible mechanism was thus proposed as shown in
Figure 2. The oxidation of Ag(I) by persulfate generates
the Ag(II) intermediate,13 which undergoes single
electron transfer with a carboxylate to produce the
carboxyl radical. Fast decarboxylation of the carboxyl
radical gives the corresponding alkyl radical. The
subsequent attack of the alkyl radical at a sulfonyl azide
affords the alkyl azide along with the generation of a
sulfonyl radical. Further oxidation of the sulfonyl radical
leads to the formation of arenesulfonic acid.
39a (99%)
39b (99%)
40a (94%)
40b (97%)
41a (84%)
41b (85%)
H
NaH, Tf2O
NaBH4
(-)-indolizidine 209D (R = n-Hex) (65%)
(-)-indolizidine 167B (R = n-Pr) (63%)
N
R
In conclusion, we have successfully developed the first
silver-catalyzed decarboxylative azidation of aliphatic
carboxylic acids in aqueous solution. This method is
easily operational, mild, efficient, and chemoselective. In
view of its generality and excellent functional group
compatibility, this catalytic transformation should find
more applications in organic synthesis.
The above results provide a unique and efficient entry
to organic azides directly from aliphatic carboxylic acids.
To further demonstrate the synthetic utility of this new
method, we carried out the asymmetric synthesis of (-)-
indolizidine 209D and 167B with azidodecarboxylation
as the key step. These two natural molecules are
representatives of the rich indolizidine alkaloid family14
and their syntheses15 have attracted much interest from
the synthetic community, both to prepare them in
greater quantities and as a tool to validate new
methodologies. Our synthesis started from the simple
and commercially available β-keto ester 34 (Scheme 3).
The asymmetric alkylation16 of 34 (via enamine 35) with
hexyl iodide produced product 36a with 83% ee. The
ASSOCIATED CONTENT
Supporting Information
Full experimental details, characterizations of new
1
compounds, copies of H and 13C NMR spectra (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
3
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Page 4 of 5
Wang, Z.; Cheng, X.; Li, C. J. Am. Chem. Soc. 2012, 134,
14330.
Corresponding Author
1
(8) (a) Hu, F.; Shao, X.; Zhu, D.; Lu, L.; Shen, Q. Angew.
Chem., Int. Ed. 2014, 53, 6105. (b) Wang, P.-F.; Wang, X.-
Q.; Dai, J.-J.; Feng, Y.-S.; Xu, H.-J. Org. Lett. 2014, 16,
4586. (c) Feng, Y.-S.; Xu, Z. Q.; Mao, L.; Zhang, F.-F.; Xu,
H.-J. Org. Lett. 2013, 15, 1472.
clig@mail.sioc.ac.cn
2
3
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Notes
The authors declare no competing financial interest.
(9) (a) Nyfeler, E.; Renaud, P. Org. Lett. 2008, 10, 985. (b)
Masterson, D. S.; Porter, N. A. Org. Lett. 2002, 4, 4253.
(10) (a) Panchaud, P.; Chabaud, L.; Landais, Y.; Ollivier, C.;
Renaud, P.; Zigmantas, S. Chem. –Eur. J. 2004, 10, 3606.
(b) Panchaud, P.; Renaud, P. J. Org. Chem. 2004, 69,
3205. (c) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001,
123, 4717. (d) Ollivier, C.; Renaud, P. J. Am. Chem. Soc.
2000, 122, 6496.
(11) Radical azidation can also be achieved by using azidyl
radicals. For the latest selected examples, see: (a) Zhang,
B.; Studer, A. Org. Lett. 2013, 15, 4548. (b) Matcha, K.;
Narayan, R.; Antonchick, A. P. Angew. Chem., Int. Ed.
2013, 52, 7985. (c) Li, Z.; Zhang, C.; Zhu, L.; Liu, C.; Li, C.
Org. Chem. Front. 2014, 1, 100. (d) Xu, L.; Mou, X.-Q. ;
Chen, Z.-M.; Wang, S.-H. Chem. Commun. 2014, 50,
10676. (e) Sun, X.; Li, X.; Song, S.; Zhu, Y.; Liang, Y.-F.;
Jiao, N. J. Am. Chem. Soc. 2015, 137, 6059.
(12) The coordination of pyridine to Ag(I) might also play a role.
See: (a) Patel, N. R.; Flower, R. A., II. J. Am. Chem. Soc.
2014, 135, 4672. (b) Chiba, S.; Cao, Z.; Bialy, S. A. A. E.;
Narasaka, K. Chem. Lett. 2006, 35, 18.
(13) (a) Anderson, J. M.; Kochi, J. K. J. Am. Chem. Soc. 1970,
92, 1651. (b) Anderson, J. M.; Kochi, J. K. J. Org. Chem.
1970, 35, 986. (c) Patel, N. R.; Flowers, R. A. II J. Org.
Chem. 2015, 80, 5834.
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ACKNOWLEDGMENT
This project was supported by the National Natural Science
Foundation of China (Grants 21290180, 21472220 and
21361140377) and by the National Basic Research Program
of China (973 Program) (Grant 2011CB710805).
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REFERENCES
(1) (a) Grammel, M.; Hang, H. C. Nat. Chem. Biol. 2013, 9,
475. (b) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K.
Chem. Rev. 2013, 113, 4905.
(2) (a) Organic Azides: Syntheses and Applications; John
Wiley & Sons, Ltd: Chichester, U.K., 2010. (b) Brase, S.;
Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int.
Ed. 2005, 44, 5188.
(3) (a) Huang, X.; Bergsten, T. M.; Groves, J. T. J. Am. Chem.
Soc. 2015, 137, 5300. (b) Sharma, A.; Hartwig, J. F.
Nature 2015, 517, 600. (c) Matthews, M. L.; Chang, W.-c.;
Layne, A. P.; Miles, L. A.; Krebs, C.; Bollinger, J. M. Jr. Nat.
Chem. Biol. 2014, 10, 209. (d) Chen, H.; Yang, W.; Wu, W.;
Jiang, H. Org. Biomol. Chem. 2014, 12, 3340. (e) Deng,
Q.-H.; Bleith, T.; Wadepohl, H.; Gade, L. H. J. Am. Chem.
Soc. 2013, 135, 5356. (f) Viuf, C.; Bols, M. Angew. Chem.,
Int. Ed. 2001, 40, 623. (g) Zhdankin, V. V.; Krasutsky, A.
P.; Kuehl, C. J.; Simonsen, A. J.; Woodward, J. K.;
Mismash, B.; Bolz, J. T. J. Am. Chem. Soc. 1996, 118, 5192.
(4) (a) Renaud, P.; Ollivier, C.; Panchaud, P. Angew. Chem.,
Int. Ed. 2002, 41, 3460. (b) Panchaud, P.; Renaud, P. Adv.
Synth. Catal. 2004, 346, 925. (c) Chabaud, L.; Landais, Y.;
Renaud, P. Org. Lett. 2005, 7, 2587. (d) Schar, P.; Renaud,
P. Org. Lett. 2006, 8, 1569. (e) Weidner, K.; Giroult, A.;
Panchaud, P.; Renaud, P. J. Am. Chem. Soc. 2010, 132,
17511. (f) Lapointe, G.; Schenk, K.; Renaud, P. Chem. –Eur.
J. 2011, 17, 3207. (g) Lapointe, G.; Schenk, K.; Renaud, P.
Org. Lett. 2011, 13, 4774.
(14) For a review, see: Edwards, M. W.; Daly, J. W. J. Nat. Prod.
1988, 51, 1188–1197.
(15) (a) Jakel, M.; Qu, J.; Schnitzer, T.; Helmchen, G. Chem. –
Eur. J. 2013, 19, 16746. (b) Coia, N.; Mokhtari, N.; Vasse,
J.-L.; Szymoniak, J. Org. Lett. 2011, 13, 6292. (c) Kapat,
A.; Nyfeler, E.; Giuffredi, G. T.; Renaud, P. J. Am. Chem.
Soc. 2009, 131, 17746. (d) Yu, R. T.; Lee, E. E.; Malik, G.;
Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2379. (e) Patil,
N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett.
2005, 46, 2101. (f) Reddy, P. G.; Baskaran, S. J. Org.
Chem. 2004, 69, 3093. (g) Kim, G.; Jung, S.-d.; Kim, W.-j.
Org. Lett. 2001, 3, 2985. (h) Kim, G.; Lee, E.-j.
Tetrahedron: Asymmetry 2001, 12, 2073. (i) Back, T. G.;
Nakajima, K. J. Org. Chem. 2000, 65, 4543. (j) Yamazaki,
N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2, 465. (k)
Takahata, H.; Kubota, M.; Ihara, K.; Okamoto, N.;
Momose, T.; Azer, N.; Eldefrawi, A. T.; Eldefrawi, M. E.
Tetrahedron: Asymmetry 1998, 9, 3289. (l) Lee, E.; Li, K.
S.; Lim, J. Tetrahedron Lett. 1996, 37, 1445. (m) Ahman,
J.; Somfai, P. Tetrahedron 1995, 51, 9747. (n) Nukui, S.;
Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1995,
60, 398. (o) Jefford, C. W.; Wang, J. B. Tetrahedron Lett.
1993, 34, 3119. (p) Polniaszek, R. P.; Belmont, S. E. J. Org.
Chem. 1990, 55, 4688.
(5) For reviews, see: (a) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.;
Hor, T. S. A.; Liu, X. Chem. Soc. Rev. 2015, 44, 291. (b)
Parka, K.; Lee, S. RSC Adv. 2013, 3, 14165. (c) Shang, R.;
Liu, L. Sci. China Chem. 2011, 54, 1670. (d) Gooßen, L. J.;
Rodriguez, N,; Gooßen, K. Angew. Chem., Int. Ed. 2008,
47, 3100.
(6) For recent examples, see: (a) Ventre, S.; Petronijevic, F. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 5654. (b)
Rueda-Becerril, M.; Mahe, O.; Drouin, M.; Majewski, M. B.;
West, J. G.; Wolf, M. O.; Sammis, G. M.; Paquin, J.-F. J.
Am. Chem. Soc. 2014, 136, 2637. (c) Leung, J. C. T.;
Chatalova-Sazepin, C.; West, J.; Rueda-Becerril, M.;
Paquin, J.-F.; Sammis, G. M. Angew. Chem., Int. Ed. 2012,
51, 10804. (d) Shang, R.; Huang, Z.; Xiao, X.; Lu, X.; Fu, Y.;
Liu, L. Adv. Synth. Catal. 2012, 354, 2465. (e) Zuo, J.;
Liao, Y.-H.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem.
2012, 77, 11325. (f) Shang, R.; Huang, Z.; Chu, L.; Fu, Y.;
Liu, L. Org. Lett. 2011, 13, 4240. (g) Shang, R.; Ji, D.-S.;
Chu, L.; Fu, Y.; Liu, L. Angew. Chem., Int. Ed. 2011, 50,
4470. (h) Das, D.; Richers, M. T.; Ma, L.; Seidel, D. Org.
Lett. 2011, 13, 6584. (i) Shang, R.; Yang, Z.-W.; Wang, Y.;
Zhang, S.-L.; Liu, L. J. Am. Chem. Soc. 2010, 132, 14391. (j)
Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 1798. (k)
Bi, H.-P.; Zhao, L.; Liang, Y.-M.; Li, C.-J. Angew. Chem.,
Int. Ed. 2009, 48, 792.
(16) Fukuyama, Y.; Matsumoto, K.; Tonoi, Y.; Yokoyama, R.;
Takahashi, H.; Minami, H.; Okazaki, H.; Mitsumoto, Y.
Tetrahedron 2001, 57, 7127.
(17) (a) Aubé, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113,
8965. (b) Pearson, W. H.; Schkeryantz, J. M. Tetrahedron
Lett. 1992, 33, 5291. (c) Pearson, W. H.; Walavalkar, R.;
Schkeryantz, J. M.; Fang, W.; Blickensdorf, J. D. J. Am.
Chem. Soc. 1993, 115, 10183. (d) Milligan, G. L.; Mossman,
C. J.; Aubé, J. J. Am. Chem. Soc. 1995, 117, 10449. (e)
Lang, S.; Murphy, J. A. Chem. Soc. Rev. 2006, 35, 146. (f)
Nyfeler, E.; Renaud, P. Chimia 2006, 60, 276.
(18) The optically pure acid 39a could be easily obtained by
recrystallization of its salt with (S)-2-amino-2-
phenylethanol, which should lead to the synthesis of
optically pure (-)-indolizidine 209D. See SI for details.
(7) (a) Wang, Z.; Zhu, L.; Yin, F.; Su, Z.; Li, Z.; Li, C. J. Am.
Chem. Soc. 2012, 134, 4258. (b) Yin, F.; Wang, Z.; Li, Z.;
Li, C. J. Am. Chem. Soc. 2012, 134, 10401. (c) Liu, X.;
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