Catalytic enantio- and diastereoselective Mannich reaction of α-substituted isocyanoacetates and ketimines

Article abstract of DOI:10.1039/c6cc04132a

The highly diastereo- and enantioselective Mannich addition/cyclisation reaction of α-substituted isocyanoacetate ester pronucleophiles and (hetero)aryl and alkyl methyl ketone-derived ketimines using a silver acetate and a cinchona-derived amino phosphine binary catalyst system is reported.

Full text of DOI:10.1039/c6cc04132a

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Fernandez, A. Gammack Yamagata, I. Ortín, A. Franchino, A. L. Thompson, B. Odell and D. Dixon, Chem.
Commun., 2016, DOI: 10.1039/C6CC04132A.
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DOI: 10.1039/C6CC04132A
The highly diastereo- and enantioselective Mannich reaction/cyclisation of α-substituted isocyanoacetates and ketimines
catalysed by silver acetate and a cinchona-derived amino phosphine is reported.

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ARTICLE
Catalytic Enantio- and Diastereoselective Mannich Reaction of α-
Substituted Isocyanoacetates and Ketimines
Received 00th January 20xx,
Accepted 00th January 20xx
R. De La Campa, A. D. Gammack Yamagata, I. Ortín, A. Franchino, A. L. Thompson, B. Odell and D.
*
J. Dixon
DOI: 10.1039/x0xx00000x
The highly diastereo- and enantioselective Mannich addition/cyclisation reaction of α-substituted
isocyanoacetate ester pronucleophiles and (hetero)aryl and alkyl methyl ketone-derived ketimines using a
www.rsc.org/
silver acetate and
a cinchona-derived amino phosphine binary catalyst system is reported.
The Mannich reaction is a powerful tool for the creation of
1
carbon-carbon bonds and since its discovery in the early 20th
century great progress in the development of catalytic
2
enantioselective variants has been made. To date, the
majority of studies have employed aldimines for the
enantioselective preparation of amine derivatives possessing
3
,4
tertiary stereogenic centres. However recent efforts have
focussed on the development of new catalytic Mannich
reactions with ketimines for the stereoselective production of Scheme 1 Enantioselective construction of chiral imidazolines with two contiguous
tetrasubstituted stereocentres.
amine derivatives possessing tetrasubstituted stereogenic
5
centres; the construction of which remains an important
6
challenge in the field. To this end, our group recently Initially
we
selected
acetophenone-derived
N-
developed a catalytic enantioselective Mannich reaction of diphenylphosphinoyl ketimine 3a as our model electrophile
isocyanoacetate esters and ketimines to generate and investigated range of 2-isocyanopropanoate ester
trisubstituted chiral imidazolines possessing vicinal quaternary pronucleophiles
a
7
a
2
using our previously optimised catalyst
and tertiary stereogenic carbon atoms. Under the control of a system comprising quinine-derived amino phosphine 1a (20
binary catalyst system comprising silver oxide and a cinchona mol%) and Ag O (5 mol%) in ethyl acetate at −20 °C (Table 1).
7
2
alkaloid-derived amino phosphine, impressive reactivity and Methyl 2-isocyanopropanoate 2a was first investigated as the
8
high enantio- and diastereocontrol were achieved. As well as pronucleophile. Very pleasingly after 60 hours, N-DPP
being important building blocks for the synthesis of α,
9
β
diamino acids, substituted imidazolines, such as those
-
protected trans-imidazoline 4a was afforded as a single
diastereomer. To allow full characterisation and determination
of enantiomeric excess (ee) via HPLC analysis, DPP group
removal using 1 M HCl was found to be necessary and
imidazoline 5a was afforded in 59% yield over the two steps, in
produced by this chemistry, can be identified as the core of
1
biologically active compounds.
0
We recognised that the catalytic enantioselective Mannich
reaction of α-substituted isocyanoacetate pronucleophiles
8
9% ee (entry 1). With reasonable reactivity and
stereoselectivity identified, the performance of more bulky 2-
with ketimines could provide
a synthetically powerful
isocyanopropanoate esters – specifically iso-propyl (2b), tert-
approach for the enantioselective synthesis of imidazolines
1
1
butyl
(
2c), benzyl
(
2d)
and benzhydryl
(
2e
)
2-
possessing two vicinal tetrasubstituted stereocentres. To this
end, and in a further development of our ongoing research
program, we wish to report our efforts leading to a catalytic
isocyanopropanoates – was studied (entries 2-5). With tert-
butyl ester 2c the high enantioselectivity (89% ee) was
maintained and the reaction yield was slightly improved to
enantioselective ketimine Mannich reaction of
α-substituted
6
3% (entry 3), therefore subsequent optimisation in terms of
isocyanoacetate esters affording chiral imidazolines with two
contiguous fully substituted carbon stereocentres, promoted
by a catalytic system made from a cinchona-derived amino
phosphine ligand and a silver (I) salt (Scheme 1).
catalyst loading, reactivity and enantiocontrol was done using
this pronucleophile. The loading with respect to amino
phosphine 1 was lowered to 10 mol% and that of the Ag(I) ions
to 5 mol% and the effect of the silver salt was investigated.
Interestingly, when the reaction was run using Ag O in the
2
presence of 1a the yield increased to 85% and
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a
Table 2 Reaction scope
enantioselectivity was maintained at 89% ee (entry 6). With
silver carbonate a marginal increase in enantioselectivity (to
9
0% ee) was seen but the yield was lower (75%, entry 7). With
both Ag and Ag CO the formation of translucent
precipitate was observed. Efforts to form a more soluble
2
O
2
3
a
1
2
complex were made by changing the silver source to AgOAc,
which pleasingly gave imidazoline 5c in high ee (89 %) with an
increased yield (90%) within a shorter reaction time (48 hours,
entry 8). Quinidine-derived ligand 1b and cinchonidine-derived
amino phosphine 1c with silver acetate afforded 5c in slightly
lower enantioselectivity (entries 9 and 10, 80% and 86% ee
respectively). Increasing the reaction temperature to 0 °C had
a negligible effect on both ee and yield, whereas decreasing it
to –30 °C completely suppressed reactivity (entries 11 and 12).
Control experiments, first omitting 1a and secondly AgOAc,
confirmed that the silver salt was critical for reactivity, whilst
the amino phosphine was essential for stereocontrol (entries
3
1
2
b
Entry
R
3
R
R
t
2
5
Yield
90
71
87
89
80
80
65
63
80
83
Ee
89
89
88
90
89
90
87
95
87
91
87
90
89
92
93
91
90
88
93
87
1
Ph
4-MeC
4-PhC H
3a Me
3b Me
3c Me
3d Me
3e Me
Bu 2c 5c
Bu 2c 5f
Bu 2c 5g
Bu 2c 5h
Bu 2c 5i
Bu 2c 5j
Bu 2c 5k
Bu 2c 5l
Bu 2c 5m
Bu 2c 5n
Bu 2c 5o
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
2
6 4
H
3
6
4
4
4-FC
4-ClC
4-MeOC
3-ClC
2-FC
6
H
4
5
6
H
4
6
6
H
4
3f
Me
7
6
H
4
3g Me
3h Me
8
6
H
4
13 and 14).
9
3-pyridyl
2-furyl
3i
3j
Me
Me
a
Table 1 Optimisation studies
10
c
1
1
PhCH
2
CH
2
3k Me
3a Et
3e Et
48
Me
O
1
:Ag (I)
1 M HCl
CH2Cl2
12
13
14
Ph
Bu 2f
Bu 2f
Bu 2f
Bu 2f
5p
5q
5r
62
81
79
84
85
83
80
83
28
Ph2P
CN
Ph
2
CO2R1
(2:1)
N
N
N
NH
Me
4-ClC6H4
4-MeOC
2-furyl
Ph
P(O)Ph2 AcOEt
20 °C
Ph
Me
Me
CO2R1 5-12 h
Ph
Me
6
H
4
3f
3j
Et
N
1
4
Å MS
20 °C
CO2R
1
5
Et
5s
5
–
4
n
Me
16
17
3a
3d
3e
3j
Bu
Bu 2g 5t
Bu 2g 5u
Bu 2g 5v
Bu 2g 5w
3
a
n
n
n
R
OMe
4-FC
6
H
4
Bu
Bu
Bu
N
N
1
8
4-ClC
6 4
H
R = MeO, 1a
R = H, 1c
NH PPh2
Ph2P HN
19
2-furyl
4-MeC
N
N
O
2
0
6
H
4
3b Me Me 2a 5y
O
1b
a
Performed under N
2
with 1 equiv. of 2, 1.1 equiv. of 3, 0.1 equiv. of 1a,
1
b
c
Entry
1
[Ag]
R
2
5
t
Yield
Ee
0.05 equiv. of AgOAc, 4 Å MS in AcOEt (0.09 M) at −20 °C for 48 h.
Imidazolines
(
mol%)
(h)
60
1
4 were obtained with dr > 98:2 (determined by H-NMR
b
analysis of the crude reaction mixture) unless otherwise stated. Yield over
1
2
3
4
5
6
7
8
9
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (10)
1a (10)
1a (10)
1b (10)
1c (10)
1a (10)
1a (10)
-
Ag
Ag
Ag
Ag
Ag
Ag
2
2
2
2
2
2
O
O
O
O
O
O
Me
2a 5a
2b 5b
59
77
63
77
62
85
75
90
81
89
82
0
89
79
89
83
84
89
90
89
i
c
two steps for isolated product 5 (single diastereomer) after FCC. N-DPP
Pr
60
60
60
60
60
70
48
48
48
48
120
72
120
72
48
t
imidazoline 4o was obtained with a 5:1 dr in favour of the trans isomer, as
1
determined by H-NMR analysis of the crude reaction mixture.
Bu
2c
5c
Bn
2d 5d
2e 5e
CHPh
2
It was possible to further reduce the ligand:AgOAc loading to
t
Bu
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
2
.5:1.25 mol% with no effect on the ee or yield albeit with
t
Ag
2
CO
3
Bu
slightly increased reaction time (entry 15). A 1:1 ratio of
ligand:AgOAc resulted in slightly lower yield (entry 16). For
convenience in weighing out the small amounts of silver
acetate, the scope of the reaction was assessed at 10:5 mol%
ligand:AgOAc ratio at –20 °C.
t
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
-
Bu
t
d
Bu
80
86
88
n/a
0
t
1
0
Bu
e
t
1
1
Bu
f
t
A
range of ketimines derived from aromatic and
1
2
Bu
13
t
heteroaromatic methyl ketones (3a-3j) were subjected to the
1
1
1
3
Bu
64
0
t
reaction conditions (Table 2). Electron-withdrawing and
electron-donating groups in the 4-position of the aromatic ring
4
5
1a (10)
1a(2.5)
1a (10)
Bu
n/a
90
90
t
AgOAc
AgOAc
Bu
89
75
were well tolerated, giving 5f
enantiomeric excess (88-90% ee, entries 2-6). Meta- and
aromatic ketimines afforded the
-5j in good yield (71-89%) and
g
t
1
6
Bu
a
Performed under N
2
with 1 equiv. of 2, 1.1 equiv. of 3a, 1:Ag(I) in 2:1 ratio, 4 Å ortho-substituted
b
MS in AcOEt (0.09 M) at −20 °C. Yield over two steps for isolated product 5
imidazolines 5k and 5l with lower yield (65% and 63%) and
good ee (87% and 95% respectively, entries 7 and 8).
Heteroaromatic N-DPP ketimines derived from methyl 3-
pyridyl ketone and methyl 2-furyl ketone gave products 5m
and 5n in high yield and ee (entries 9 and 10). Aliphatic
c
(
single diastereomer) after flash column chromatography (FCC). Enantiomeric
excess (ee) of compound 5 determined by HPLC analysis on a chiral stationary
d
e
f
g
phase. Enantiomeric (4R,5S)-5c obtained. At 0 °C. At −30 °C. With 10 mol%
AgOAc and 10 mol% 1a.
2
| J. Name., 2012, 00, 1-3
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ketimine 3k derived from 4-phenyl-2-butanone could be In order to better understand the results from the catalyst
converted to imidazoline 5o with moderate yield (48%) and modification studies and to determine how ligand 1a binds to
1
5
good enantioselectivity (87% ee, entry 11). Next, tert-butyl 2- AgOAc, a crystal of complex 1a•AgOAc was grown (Figure 1).
isocyanobutanoate 2f was assessed on a range of ketimines to Single crystal X-ray diffraction determined that 1a acts as a
afford exclusively the trans imidazolines 5p 5s with an ethyl P,N-bidentate ligand, binding silver through both the
substituent in the α-position in similarly high ee and yield phosphine and the quinuclidine N atom to create a 9-
entries 12-15). The tert-butyl 2-isocyanohexanoate 2g also membered macrocycle. The other groups coordinating to silver
performed well in the reaction to give products 5t 5w in are the acetate and a quinoline unit belonging to a symmetry
-
(
-
1
4
excellent yield and ee (entries 16-19). NOe NMR experiments related molecule of 1a leading to the formation of polymeric
established the relative trans stereochemical configuration of chains in the solid state. The four-coordinate silver adopts a
products 5f
, 5o, 5q and 5v. Absolute configuration was distorted tetrahedral geometry. An intramolecular hydrogen
determined by comparison of the specific rotation of bond between the acetate group on silver and the
5
c
imidazoline 5y with that reported in the literature.
transannular amide N-H at 1.896(3) Å is present with a N···O
distance of 2.752(4) Å. The π system of the amide group is
oriented towards the silver with a distance of 2.9571(18) Å
between the amide nitrogen and the silver centre suggesting a
possible interaction. Such an interaction would transfer charge
resulting in acidification of the amide NH thus enhancing its H-
bond donor ability.
1
) 1 M HCl 3 h, reflux
N
NH
H2N
NH2
2
) 50% aq KOH, 6 h, reflux
Ph
Me
Me
CO2tBu
Ph
Me
Me
CO H
69%
2
5c
6c
Scheme 2 Application to the synthesis of fully substituted α,β-diamino acids.
As a demonstration of the synthetic utility of this newly
established method, product 5c was hydrolysed to afford α,β-
diamino acid 6c (Scheme 2). Such compounds are difficult to
9
access in enantioenriched form by other methods.
To gain insight into the importance of the various functional
groups possessed by amino phosphines
1, a series of control
experiments using modified ligand structures (1d
-
1g) were
performed (Table 3). Diastereomeric ligand 1d gave
imidazoline 5c with a large decrease in enantioselectivity
(entry 2). Ligand 1e, lacking the phosphine moiety, was
significantly worse: product 5c was obtained in low yield with
poor enantioselectivity (entry 3). Ligand 1f with an ester linker Figure 1 Structure of 1a
•AgOAc from single crystal X-ray diffraction studies
showing the intramolecular H-bond (H···O = 1.896(3) Å; N···O = 2.752(4) Å).
gave imidazoline 5c in slightly decreased yield and Displacement ellipsoids drawn at 30% probability; solvent and selected hydrogen
atoms omitted for clarity.
enantioselectivity (entry 4). Finally ligand 1g with a N-methyl
group on the amide promoted the reaction with a similar yield
3
1
1
P and H NMR studies of a 1:1 ratio of amino phosphine 1a
and AgOAc at −20 °C were also performed (see SI for full NMR
to 1a but much lower levels of enantioselectivity (entry 5).
3
studies). The P NMR experiments showed a quantitative
1
binding of silver(I) in solution and H NMR analysis of the same
1
Table 3 Variation on ligand structure
mixture revealed a large downfield shift (approximately 3.4
ppm relative to that of the free ligand) of the amide N-H
consistent with presence of the same H-bonding interaction.
Additionally, the protons adjacent to the quinuclidine nitrogen
were also shifted downfield, consistent with coordination of
the quinuclidine nitrogen to silver. In the solution phase there
is no strong evidence that the quinoline N atom binds the Ag
centre; the change of chemical shift for the proton adjacent to
the quinoline nitrogen is only 0.07 ppm. When methyl
isocyanoacetate is added to the solution of 1a and AgOAc, the
a
Entry
1
Yield
Ee
89
20
5
2
CH group appears as a characteristic ABq system, providing
evidence for complexation of the isonitrile to silver.
1
2
3
4
5
1a
1d
1e
1f
1g
90
Building on the results of experiments using modified ligand
structures (Table 3) and the structural data obtained from
both the X-ray and NMR studies we propose a transition
structure that rationalises the enantio- and diastereoselectivity
observed in this Mannich reaction (Figure 2). The N atom of
the (E)-configurated ketimine is postulated to make a key
hydrogen bond to the amide N-H, which both orientates the
89
23
75
72
27
86
a
Yield over two steps for product 5c (single diastereomer) after FCC.
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electrophile and activates it towards nucleophilic addition. The
aromatic ring of the H-bonded ketimine is oriented away from
the quinuclidine and quinoline units on steric grounds and C-H
Hernández-Toribio, R. G. Arrayás, J. C. Carretero, J. Am.
Chem. Soc., 2008, 130, 16150. (h) D. Shang, Y. Liu, X. Zhou, X.
Liu, X. Feng, Chem. Eur. J., 2009, 15, 3678. (i) J. Hernández-
Toribio, R. G. Arrayás, J. C. Carretero, Chem. Eur. J., 2010, 16,
1153. (j) G. Liang, M.-C. Tong, H. Tao, C.-J. Wang, Adv. Synth.
16
/
π-interactions between it and the aromatic ring of the
carboxamide could provide additional binding/organisation,
accounting for the high enantiofacial selectivity observed using
Catal., 2010, 352, 1851. (k) E. Hernando, R. G. Arrayás, J. C.
Carretero, Chem. Comm., 2012, 48, 9622.
Enantioselective Mannich reactions of isocyanoacetate
esters and aldimines: (a) X.-T. Zhou, Y.-R. Lin, L.-X. Dai, J. Sun,
L.-J. Xia, M.-H. Tang, J. Org. Chem. 1999, 64, 1331. (b) X.-T.
7
a,8
4
this catalyst.
The ester group of the isocyanoacetate is
oriented away from the aromatic group on the ketimine on
steric grounds. Subsequent to the enantio- and
diastereodetermining C-C bond forming step, ring closure and
protonolysis would yield the N-DPP protected imidazoline with
the observed stereochemical configuration. Satisfyingly, this
transition state model, with its multipoint binding interactions,
would also rationalise the stereochemical outcomes of the
Zhou, Y.-R. Lin, L.-X. Dai, Tetrahedron: Asymmery, 1999, 10
,
855. (c) J. Aydin, A. Rydén, K. J. Szabó, Tetrahedron:
Asymmery, 2008, 19, 1867. (d) Z.-W. Zhang, G. Lu, M.-M.
Chen, N. Lin, Y.-B. Li, T. Hayashi, A. S. C. Chan, Tetrahedron:
Asymmery, 2010, 21, 1715. (e) S. Nakamura, Y. Maeno, M.
Ohara, A. Yamamura, Y. Funanashi, N. Shibata, Org. Lett.,
2012, 14, 2960. (f) P.-L. Shao, J.-Y. Liao, Y. A. Ho, Y. Zhao,
Angew. Chem. Int. Ed. 2014, 53, 5435.
8
a
8b
previously reported reactions with aldehydes and ketones.
5
Enantioselective Mannich reactions of ketimines: (a) Y. Du,
L.-W. Xu, Y. Shimizu, K. Oisaki, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc., 2008, 130, 16146. (b) L. C. Wieland, E. M. Vieira,
M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc., 2009, 131
5
,
70. (c) G. Lu, T. Yoshino, H. Morimoto, S. Matsunaga, M.
Shibasaki, Angew. Chem. Int. Ed., 2011, 50, 4382. (d) M.
Hayashi, M. Sano, Y. Funahashi, S. Nakamura, Angew. Chem.
Int. Ed., 2013, 52, 5557. (e) M. G. Núñez, A. J. M. Farley, D. J.
Dixon, J. Am. Chem. Soc., 2013, 135, 16348. (f) Y.-Q. Wang, Y.
Zhang, K. Pan, J. You, J. Zhao, Adv. Synth. Catal, 2013, 355,
3381. (g) M.-X. Zhao, H.-L. Bi, R.-H. Jiang, X.-W. Xu, M. Shi,
Figure 2 Proposed transition structure.
Org. Lett., 2014, 16, 4566. (h) S. Zhang, L. Li, Y. Hu, Z. Zha, Z.
Wang, T.-P. Loh, Org. Lett., 2015, 17, 1050. (i) S. Lin, Y.
Kawato, N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed.,
In conclusion, we have developed
a diastereo- and
enantioselective Mannich reaction/cyclisation of α-substituted
isocyanoacetates and ketimines catalysed by silver acetate and
a cinchona-derived amino phosphine. The reaction scope is
broad and includes substituted aryl, heteroaryl and alkyl
methyl ketimines as well as isocyanoacetates with linear alkyl
chains in the α-position. Hydrolysis of the product imidazolines
provides access to fully substituted α,β-diamino acids.
Information arising from X-ray and NMR studies, as well as
control studies on the ligand, have allowed a detailed
transition state model to be postulated.
2
015, 54, 5183. (j) S. Nakamura, R. Yamaji, M. Hayashi,
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411.
,
8
The authors thank the EPSRC for a leadership fellowship to
D.J.D., Merck, Sharp & Dohme (Hoddesdon, UK) for a CASE
award to A.D.G.Y., and the EC for IEF to R.C. (PIEF-GA-2012-
8
9
(a) F. Sladojevich, A. Trabocchi, A. Guarna, D. J. Dixon, J. Am.
Chem. Soc., 2011, 133, 1710. (b) R. de la Campa, I. Ortín, D. J.
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A. Viso, R. Fernández de la Pradilla, M. Tortosa, A. García, A.
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1 During the preparation of the present manuscript, the
following article was published online: S. Nakamura, R.
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2 Q.-A. Chen, D.-S. Wang, Y.-G. Zhou, Chem. Commun., 2010,
329689), IEF to I.O. (PIEF-GA-2010-275788) and PhD fellowship
to A.F. (FP7/2007-2013, REA grant agreement 316955).
1
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3 Reaction between 2c and 4’-bromopropiophenone-derived
ketimine, followed by removal of the DPP group, gave the
corresponding imidazoline in 62% overall yield and 70% ee.
4 Reaction between 3a and valine-derived tert-butyl
isocyanoacetate (isopropyl group at the α-position), followed
by DPP deprotection, gave the corresponding imidazoline in
1
1
1
3
Enantioselective Mannich reactions of aldimines: (a) K. Juhl,
N. Gathergood, K. A. Jørgensen, Angew. Chem. Int. Ed., 2001,
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2
9% overall yield (8 days reaction time) and 98% ee.
5 Full crystallographic data (in CIF format) is available as ESI
and can be obtained from The Cambridge Crystallographic
Data Centre at www.ccdc.cam.ac.uk/data_request/cif
(reference number CCDC 1493438).
6 S. Tsuzuki, A. Fujii, Phys. Chem. Chem. Phys., 2008, 10, 2584.
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