One-Pot asymmetric nitro-mannich/hydroamination cascades for the synthesis of pyrrolidine derivatives: Combining organocatalysis and gold catalysis

Article abstract of DOI:10.1021/cs401008v

The highly enantioselective preparation of trisubstituted pyrrolidine derivatives employing a one-pot nitro-Mannich/hydroamination cascade is reported. This cascade approach utilizes an asymmetric bifunctional organocatalytic nitro-Mannich reaction followed by a gold-catalyzed allene hydroamination reaction. The products are afforded in good yields and excellent diastereo- and enantioselectivities.

Full text of DOI:10.1021/cs401008v

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Letter
One-Pot Asymmetric Nitro-Mannich/Hydroamination
Cascades for the Synthesis of Pyrrolidine Derivatives:
Combining Organocatalysis and Gold Catalysis
David Barber, Andrej #uriš, Amber L. Thompson, Hitesh Sanganee, and Darren J. Dixon
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One-Pot Asymmetric Nitro-Mannich/Hydroamination Cascades
for the Synthesis of Pyrrolidine Derivatives: Combining Organo-
catalysis and Gold Catalysis.
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David M. Barber,† Andrej Ďuriš,†§ Amber L. Thompson,† Hitesh J. Sanganee‡ and Darren J.
§
Dixon†*
† Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA,
U.K.
‡ AstraZeneca R&D, Emerging Innovations, Alderley Park, Cheshire, SK10 4GT, U.K.
§ These authors contributed equally to this work.
KEYWORDS: organocatalysis, gold catalysis, cascade reactions, nitro-Mannich, hydroamination, pyrrolidine.
ABSTRACT: The highly enantioselective preparation of trisubstituted pyrrolidine derivatives employing a one-pot nitro-
Mannich/hydroamination cascade is reported. This cascade approach utilizes an asymmetric bifunctional organocatalytic
nitro-Mannich reaction followed by a gold-catalyzed allene hydroamination reaction. The products are afforded in good
yields and excellent diastereo- and enantioselectivities.
Pyrrolidine heterocycles are prevalent structures found in
a myriad of biologically active molecules and natural
products (Figure 1).1 Due to the abundance of the pyr-
rolidine motif, research into the synthesis of such an im-
portant structural unit continues to be an attractive chal-
lenge for the reaction designer.2
conducted in an asymmetric fashion, resulting in a new
methodology to produce enantioenriched pyrrolidine
heterocycles. Herein we report our findings.
In our proposed concept (Scheme 1), nitroallene II would
react with a protected imine I using an appropriate or-
ganocatalyst.7 The resulting enantioenriched β-
OH
nitroamine III would then be poised to cyclise via a di-
astereoselective gold catalysed 5-exo-trig allene hy-
droamination reaction.8 Protodemetallation would then
afford the desired enantioenriched pyrrolidine V and al-
low the catalytic cycle to continue.
Me
OAc
H
OH
N
N
N
H2N
H
HO
(!)-lepadiformine
Me OH
(+)-pumilotoxin B
(!)-slaframine
PG
organocatalysis
gold catalysis
PG
R1
N
N
Figure 1. Selection of biologically active natural products
.
O2N
R2
+
R2
R1
containing pyrrolidine motifs.
enantioocontrol?
O2N
R2
R2
I
II
V
Recently, cascade reactions have emerged as a power-
ful tool for the preparation of single and polycyclic sys-
tems.3 Cascade reactions are typically resource efficient
and can rapidly build up molecular complexity without
the need for isolation of the intermediate compounds. As
part of our ongoing research program into cascade reac-
tions using nitro-Mannich4 and hydroamination5 reac-
tions, we envisaged that a nitro-Mannich/hydroamination
cascade6 could provide an efficient method to access
trisubstituted pyrrolidine derivatives in an enantioselec-
tive fashion. Building on our previous diastereoselective
-[Au]
+H
organo-
catalysis
R2
PG
R1
.
[Au]
PG
R2
+[Au]
[Au]
R2
N
NH
-
H
R1
O2N
R2
NO2
III
IV
Scheme 1. Concept of an enantioselective pyrrolidine
synthesis using a nitro-Mannich/hydroamination cas-
cade.
Our previous investigation6c had utilised N-p-
toluenesulfonyl protected imines for the nitro-
Mannich/hydroamination cascade reaction. However,
this protecting group is known to give low enantioselec-
tivities in organocatalysed nitro-Mannich reactions,4a
pyrrolidine
synthesis
employing
a
nitro-
Mannich/hydroamination cascade in conjunction with N-
p-toluenesulfonyl protected imines,6c we postulated that
an effective combination of imine protecting group and
organocatalyst would allow this cascade reaction to be
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making it unsuitable for this study. In addition, N-Boc and nor increases in the diastereoselectivity of the hydroami-
1
2
3
4
N-phosphinoyl protected substrates did not undergo the
allene hydroamination reaction in our previous study.6c
Therefore, we decided to investigate N-Cbz protected
imines as a possible solution to our reactivity and
stereoselectivity issues.
nation reaction whilst maintaining good yields of pyrroli-
dine 4a (Table 2, entries 2 and 3).
Table 2. Cyclisation optimisation of β-nitroamines 3 and
3′.
5
6
7
8
9
.
Cbz
Ph
Cbz
Cbz
NH
DPP (20 mol%)
Au complex (10 mol%)
Ph
Ph
N
N
N
N
CF3
+
O
HN
NH
Ag salt (20 mol%)
PhMe, 70 °C, time
NO2
3:3!
O2N
O2N
N
N
F3C
N
H
N
H
4a
4a!
HN
O
O
NH
10
11
12
13
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dr 87:13; 91% ee for 3
N
A
B
C
entrya
Au complex
(10 mol%)
Ag salt
time yield drc
ee
CF3
F3C
F3C
CF3
(20 mol%) (h) (%)b 4a:4aʹ (%)d
Figure 2. Organocatalysts used in preliminary enantioin-
duction screen in the nitro-Mannich reaction of N-Cbz
imine 1a and nitroallene 2.
1
2
3
4
5
Au(PPh3)Cl
Au(PPh3)Cl
Au(PPh3)Cl
Au(PPh3)Cl
AgSbF6
AgOTf
AgNTf2
AgBF4
2
2
2
2
4
3
61
58
65
69
54
50
81:19 91
83:17 91
82:12 91
89:11 91
80:20 91
Table 1. Optimisation of the diastereo- and enantioselec-
tivity in the organocatalytic nitro-Mannich reaction of N-
Cbz imine 1a and nitroallene 2.
Au[(PhO)3P]Cl AgBF4
Au(PtBu3)Cl AgBF4
cat. (5 mol%)
PhMe, [1a] 0.5 M
temp, time
6
83:17 91
.
.
Cbz
Ph
Cbz
Ph
Cbz
+
NH
NH
N
a
b
.
O2N
+
All reactions were conducted on a 0.10 mmol scale. Iso-
lated yield of single diastereomer 3 after purification by flash
column chromatography on silica gel. c Determined by 1H NMR
Ph
NO2
NO2
3!
1a
2
(1.5 equiv)
3
d
analysis of the crude reaction mixture. Determined by HPLC
analysis of the purified product; ee of the major diastereomer
4a is shown, ee of the minor diastereomer 4aʹ was not deter-
mined. DPP = Diphenylphosphate
entrya cat.
temp
(ºC)
time
(h)
yield
(%)b
drc 3:3ʹ
ee (%)d
3/3ʹ
1
2
3
4
A
C
A
B
C
RT
20
15
72
72
44
59
77
57
59
77
65:35
75:25
79:21
82:18
87:13
55/33c
86/75
51/37c
58/55
RT
Employment of AgBF4 not only gave an improved yield
of pyrrolidine 4a (69%), but the diastereoselectivity of the
crude reaction mixture was also improved (dr 89:11;
Table 2, entry 4). Changing the ligand of the gold com-
plex to a phosphite, led to a reduced yield of pyrrolidine
4a and erosion of the diastereoselectivity (Table 2, entry
5).12
–15
–15
–15
5
91/77
a
b
All reactions were conducted on a 0.10 mmol scale. Iso-
lated yield after purification by flash column chromatography. c
Determined by HPLC analysis of the purified product. d Oppo-
site enantiomers obtained.
With both the nitro-Mannich and hydroamination reac-
tions independently optimised, we were confident that
combining these two reactions in a sequential cascade
procedure would allow for a highly enantioselective pyr-
rolidine synthesis.13 Pleasingly, the sequential procedure
was successful, affording pyrrolidine 4a in 60% yield and
91% ee as a single diastereomer after separation of the
minor diastereomer by column chromatography.
(Scheme 2).14
Accordingly, we investigated the level of enantioinduc-
tion obtained in the nitro-Mannich reaction between N-
Cbz imine 1a and nitroallene 2 using organocatalysts A,
B, and C (Figure 2).9 After a concise optimisation study
(Table 1), we found that the use of catalyst C (5 mol%)
at −15 °C and a concentration of 0.5 M resulted in the
best diastereo- and enantioselectivity in the formation of
β-nitroamine 3 (dr 87:13, 91% ee for the major isomer 3)
as well as the best isolated yield (77%; Table 1, entry 5).
i) cat. C (5 mol%), PhMe
!15 °C, 40 h, [1] 0.5 M
ii) DPP (20 mol%)
diluted to 0.1 M with PhMe
Cbz
Cbz
Ph
N
N
.
+
O2N
Au(PPh3)Cl (10 mol%)
AgBF4 (20 mol%), 70 °C, 3 h
Ph
With these results in hand, studies into the hydroamina-
tion reaction of the enantioenriched β-nitroamines 3 and
3′ were then conducted (Table 2). Pleasingly, β-
nitroamines 3 and 3′ (dr 87:13, 91% ee for the major
diastereomer 3) were successfully cyclised using a cata-
lyst combination of Au(PPh3)Cl (10 mol%) and AgSbF6
(20 mol%),10 affording pyrrolidine 4a in 61% yield and
81:19 crude dr without erosion of the enantioselectivity
observed in β-nitroamine 3 (91% ee; Table 2, entry 1).11
O2N
1a
4a
2
crude dr 84:16
60% yield, 91% ee
purified dr >98:2
(1.5 equiv)
Scheme
2.
One-pot
asymmetric
nitro-
Mannich/hydroamination cascade reaction to pyrrolidine
4a. DPP = Diphenylphosphate
To examine the scope of the developed reaction cas-
cade, a series of substituted N-Cbz imines 1 were sub-
Changing the silver salt to AgOTf and AgNTf2 gave mi-
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jected to our optimised nitro-Mannich/hydroamination antioenrichment (39% yield, 85% ee), but all of the other
1
2
3
4
5
6
7
8
conditions (Table 3). Pleasingly, the cascade reaction
was shown to tolerate variations in the substituents
present on the aromatic ring of the N-Cbz imines. The
electron-poor halogen (fluoro, chloro and bromo) substi-
tuted imines all afforded the desired enantioenriched
pyrrolidines 4b-4f in moderate to good yields (36-58%).
The diastereoselectivity observed in the crude reaction
mixtures were generally good (dr 78:22-85:15) with the
major isomer being isolated as a single diastereomer
after purification with excellent enantioselectivities in all
cases (90-96% ee).
pyrrolidines bearing methoxy groups were afforded with
good yields (64-67%) and enantioselectivities (91-92%
ee). The minor diastereomers 4j′ and 4l′ were also iso-
lated from these reactions. The electron-rich 2-thienyl
substituted pyrrolidine 4m was pleasingly furnished by
the cascade reaction, although it was obtained in only
32% yield and 85% ee.
To prove the absolute configuration of the prepared pyr-
rolidines 4, we obtained a single crystal of pyrrolidine 4k
for X-ray diffraction analysis by crystallisation from
CH2Cl2. The X-ray diffraction data showed that pyrroli-
dine 4k contained a (2S,3R,5R) configuration (Figure
3).15 All other major pyrrolidine diastereomers 4 were
assigned by analogy.
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Table 3. Scope of the enantioselective nitro-
Mannich/hydroamination cascade for the enantioselec-
tive synthesis of pyrrolidines 4 and 4ʹ.
i) cat. C (5 mol%), PhMe
!15 °C, time, [1] 0.5 M
ii) DPP (20 mol%)
Cbz
Cbz
Cbz
+
R1
R1
N
N
N
MeO
.
+
O2N
R1
diluted to 0.1 M with PhMe
Au(PPh3)Cl (10 mol%)
AgBF4 (20 mol%), 70 °C, time
Cbz
O2N
O2N
C2
MeO
N
1
2
4
C5
4"
(1.5 equiv)
O2N
4k
entrya R1
i)
ii)
crude yield drd
ee
(%)c 4:4ʹ (%)e
time time drb
(4:4ʹ)
Figure 3. X-Ray crystal structure representation of pyr-
rolidine 4k.
(h) (h) 4:4ʹ
1 (a) Ph
40
48
24
48
40
40
40
40
54
40
3
3
2
4
2
3
2
3
3
2
2
2
84:16 60
92:8 90
>98:2 90
>98:2 93
>98:2 95
>98:2 94
>98:2 96
>98:2 91
>98:2 91
>98:2 85
>98:2 92
93:7h 92
96:4 91
2 (b) o-ClC6H4
3f (c) p-ClC6H4
4(d) m-FC6H4
5f (e) p-FC6H4
6f (f) m-BrC6H4
7 (g) o-MeC6H4
8f (h) p-MeC6H4
9 (i) o-MeOC6H4
10f (j) m-MeOC6H4
85:15 52
79:21 36
78:22 58
84:16 50
84:16 54
82:18 66
81:19 53
76:24 39
84:16 64
85:15g 67
86:14 67
The relative configuration of the minor pyrrolidines 4ʹ
was determined using NOESY analysis of pyrrolidine
4hʹ.16 In this experiment the cis configuration of the pro-
tons in the C2-C5 positions was confirmed, see ESI for
details. All other minor pyrrolidine diastereomers 4ʹ were
assigned by analogy.
To demonstrate that the enantioenrichment of the syn-
thesised products was retained in subsequent reactions,
pyrrolidine 4f was transformed into the sulfonamide con-
taining pyrrolidine
5
using
a
two-step procedure
(Scheme 3). Firstly, reduction of the nitro group using
zinc powder and acetic acid in THF at RT proceeded
smoothly to furnish the amine which was then reacted
with p-TsCl in the presence of Et3N to afford pyrrolidine 5
in excellent enantioselectivity (dr 98:2, 95% ee).
11 (k) m,p-(MeO)2C6H3 40
12f (l)
40
m,p-
(OCH2O)C6H3
13 (m) 2-thienyl
48 14 87:13 32
88:12 85
i) Zn, AcOH, THF, RT, 40 h
ii) p-TsCl, Et3N, CH2Cl2
0 °C, 3 h then RT 3 h
a
b
All reactions were conducted on a 0.20 mmol scale. De-
Cbz
Cbz
1
c
termined by H NMR analysis of the crude reaction mixture.
Yield after purification by flash column chromatography on
silica gel. Determined by H NMR analysis of the purified
Br
Br
N
N
64%
dr 98:2, 95% ee
d
1
Ts
O2N
N
H
1
product; dr >98:2 minor isomer was 4ʹ not visible by H NMR
4f
dr >98:2, 96% ee
5
analysis. e Determined by HPLC analysis of the purified prod-
f
uct. Minor diastereomer 4ʹ isolated in this example; see ESI
for details. Approximately 8% of a third diastereomer of un-
Scheme 3. Nitro group reduction of pyrrolidine 4f.
g
1
known configuration was visible in the crude H NMR spec-
In summary, we have developed an enantioselective
synthesis of substituted pyrrolidines using a nitro-
Mannich/hydroamination cascade methodology. The
combination of bifunctional organocatalysis and gold
catalysis used in conjunction with N-Cbz imines afforded
pyrrolidines 4 in moderate to good yields (32-67%) with
excellent enantioselectivities (85-96% ee). This method-
ology will allow new highly substituted pyrrolidine based
architectures to be prepared for library generation and
target synthesis.
trum. h The minor diastereomer refers to that of unknown con-
figuration, see footnote g. DPP = Diphenylphosphate
In the preparation of compounds 4c, 4e and 4f, the mi-
nor isomers were also isolated after purification by col-
umn chromatography on silica gel with excellent enanti-
oselectivities (93-94% ee). Methoxy substituted aryl
groups were also found to be suitable substrates for the
cascade reaction. The ortho-methoxy substituted aryl
pyrrolidine 4i did suffer from a diminished yield and en-
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H. J.; Dixon, D. J. Org. Lett. 2012, 14, 5290–5293. (c) Ďuriš, A.;
Barber, D. M; Sanganee, H. J.; Dixon, D. J. Chem. Commun.
2013, 49, 2777–2779.
ASSOCIATED CONTENT
1
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3
4
5
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Supporting Information. Experimental procedures and
characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418–3419.
(f) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng,
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AUTHOR INFORMATION
Corresponding Author
*E-mail: darren.dixon@chem.ox.ac.uk
9
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the EPSRC (studentship to D.M.B.
and Leadership Fellowship to D.J.D.) and AstraZeneca (stu-
dentship to D.M.B.).
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(2) For reviews of synthetic approaches to pyrrolidine het-
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(11) Additional control experiments confirmed that neither
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hydroamination reaction.
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(15) Single-crystal X-ray diffraction data were collected at
150K with an Oxford Diffraction SuperNova diffractometer and
processed with CrysAlisPro as per the Supporting Information
(CIF). The structure was solved with SIR9217 and refined with
CRYSTALS18 including the Flack χ parameter19 which refined
to 0.04(11). Full crystallographic data (in CIF format) are avail-
able as Supporting Information and have been deposited with
the Cambridge Crystallographic Data Centre (reference code
975402).
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(16) The configuration of 4hʹ at the C2-C3 positions was as-
signed as trans because the proton in the C2 position showed
such a small coupling constant with the proton in the C3 (3JH,H
≈
90°), see: (a) Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870–
2871. (b) Minch, M. J. Concept Magnetic Res. 1994, 6, 41–56.
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The highly enantioselective preparation of trisubstituted pyrrolidine derivatives employing a one-pot nitro-
Mannich/hydroamination cascade is reported. This cascade approach utilizes an asymmetric bifunctional organo-
catalytic nitro-Mannich reaction followed by a gold-catalyzed allene hydroamination reaction. The products are af-
forded in good yields and excellent diastereo- and enantioselectivities.
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R1
N
Cbz
Cbz
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R1
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Organo-
catalysis
Gold
catalysis
One-Pot
O2N
.
O2N
13 examples
up to 67% yield, 87:13 dr and 96% ee
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