Disulfonimide-Catalyzed Asymmetric Synthesis of δ-Amino-β-Keto Esters

Article abstract of DOI:10.1055/s-0034-1379999

A chiral disulfonimide-catalyzed asymmetric synthesis of δ-amino-β-keto esters via a vinylogous Mukaiyama-Mannich reaction of the Chan diene with N-Boc imines has been developed. The desired products were obtained in good to excellent yields and enantioselectivities.

Full text of DOI:10.1055/s-0034-1379999

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 807–809
letter
807
Q. Wang, B. List
Letter
Synlett
Disulfonimide-Catalyzed Asymmetric Synthesis of δ-Amino-
β-Keto Esters
Qinggang Wang
Benjamin List*
Ar
SO2
Max-Planck-Institut für Kohlenforschung, Kaiser-
Wilhelm-Platz 1, 45470 Mülheim an der Ruhr,
Germany
BocHN
R
O
O
NBoc
H
TMSO
OTMS
OMe
DSI (2 mol%)
NH
+
OMe
R
11 examples
up to 95% yield
up to 96.5:3.5 er
SO2
list@mpi-muelheim.mpg.de
Ar
DSI
Ar = 3,5-[3,5-(CF3)2C6H3]2C6H3
Received: 02.12.2014
Accepted after revision: 12.01.2015
Published online: 10.02.2015
DOI: 10.1055/s-0034-1379999; Art ID: st-2014-d0994-l
BocHN
O
O
MeOH
∗
ref. 10c
R
O
Abstract A chiral disulfonimide-catalyzed asymmetric synthesis of
δ-amino-β-keto esters via a vinylogous Mukaiyama–Mannich reaction
of the Chan diene with N-Boc imines has been developed. The desired
products were obtained in good to excellent yields and enantioselectiv-
ities.
NBoc
TMSO
OTMS
OMe
BocHN
O
O
DSI 1
∗
+
R
H
R
OMe
4
2
3
this work
Scheme 1 Direct synthesis of enantioenriched δ-amino-β-keto esters
Key words chiral disulfonimides, δ-amino-β-keto esters, Chan diene,
N-Boc imines, vinylogous Mukaiyama–Mannich reaction
acyclic Chan diene (3) with N-Boc imines 2, thus offering a
direct catalytic asymmetric approach to enantioenriched δ-
amino-β-keto esters.
δ-Amino-β-keto esters are important building blocks1–3
that are frequently accessed via chain extension of enantio-
pure β-amino esters4 or using chiral auxiliaries.5 To the best
of our knowledge, direct catalytic asymmetric approaches
to enantioenriched δ-amino-β-keto esters are unknown.
Herein, we report an asymmetric synthesis of δ-amino-
β-keto esters via a disulfonimide-catalyzed vinylogous
Mukaiyama–Mannich reaction6 of the Chan diene 37 with
N-Boc imines 2 (Scheme 1).
Disulfonimides (DSI), of the general structure 1 (Table
1), are strong Brønsted acids,8 as well as precatalysts which
are converted into highly active Lewis acid catalysts by in
situ silylation. These Lewis acids readily activate aldehydes
and ketones in various transformations,9 and we recently
reported that they are equally suited for the activation of al-
kyloxycarbonyl imines. In this context we have developed
disulfonimide-catalyzed asymmetric aminoallylations,
Mukaiyama–Mannich reactions, and vinylogous Mukaiyama–
Mannich reactions.10 In our previous study,10c we reported a
two-step sequence for the asymmetric synthesis of δ-ami-
no-β-keto esters via a reaction between a cyclic silyloxy-
diene and N-Boc imines followed by thermal esterification.
We envisaged that our DSIs might also enable the enantio-
selective vinylogous Mukaiyama–Mannich reaction of the
Utilizing similar conditions as in our previous report,
we could indeed realize the target reaction. The substrate
scope of the DSI-catalyzed vinylogous Mukaiyama–Man-
nich reaction of Chan’s diene is shown in Table 1. From phe-
nyl N-Boc imine (2a), product 4a was obtained in 91% yield
and with 93.5:6.5 enantiomeric ratio (Table 1, entry 1).
With the corresponding 1-naphthyl N-Boc imine (2b), 85%
yield and 96.5:3.5 enantiomeric ratio were obtained (Table
1, entry 2). In this case, a single recrystallization improved
the enantiomeric ratio to 99.6:0.4. For the 2-naphthyl and
substituted 2-naphthyl N-Boc imines, comparably good
yields and enantioselectivities were observed (Table 1, en-
tries 3 and 4). The meta-methyl-substituted substrate gave
79% yield and 92.5:7.5 enantiomeric ratio (Table 1, entry 5).
For the meta-methoxy-substituted N-Boc imine product 4f
was isolated in 81% yield and with 94:6 enantiomeric ratio
(Table 1, entry 6). With the meta-vinyl-substituted sub-
strate, 95% yield and 95:5 enantiomeric ratio were obtained
(Table 1, entry 7). From halogen-substituted substrates,
products 4h and 4i were obtained with similarly good
yields and enantioselectivities (Table 1, entry 8 and 9). For
the 3,5-dimethyl-substituted N-Boc imine 2j, 94% yield and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 807–809

808
Q. Wang, B. List
Letter
Synlett
Table 1 (continued)
90:10 enantiomeric ratio were observed (Table 1, entry 10).
Finally, using 3,5-dimethoxy-substituted N-Boc imine,
product 4k was isolated in 83% yield and 93.5:6.5 enantio-
meric ratio (Table 1, entry 11). In all cases, the enantiose-
lectivity of the reaction was determined by derivatization
as the corresponding ketone, which was obtained via decar-
boxylation under basic conditions. We have already shown
that this procedure does not lead to any loss of enantiopuri-
ty.10c The absolute configuration was determined by com-
paring the [α]D of 4a with the reported data.3a
In summary, a direct organocatalytic asymmetric syn-
thesis of δ-amino-β-keto esters has been developed.11 Di-
sulfonimide 1 serves as a highly efficient precatalyst of the
asymmetric vinylogous Mukaiyama–Mannich reaction of
the Chan diene with N-Boc imines, giving the δ-amino-β-
keto esters with good to excellent yields and enantioselec-
tivities. These results represent a further application of our
asymmetric counteranion-directed catalysis (ACDC) strate-
gy applied to Lewis acid catalysis.12 Further explorations of
disulfonimide-catalyzed reactions are currently in progress
in our laboratories.
Entry
R
Product
Yield (%) erb,c
Me
5
4e
79
81
95
88
89
92.5:7.5
94:6
MeO
6
7
8
9
4f
4g
4h
4i
95:5
F
91.5:8.5
92:8
Cl
Me
10
11
4j
94
83
90:10
Table 1 DSI-Catalyzed Vinylogous Mannich Reactiona
Me
NBoc
BocHN
O
O
TMSO
OTMS
OMe
1 (2 mol%)
MeO
+
R
H
toluene, –30 °C R
F3C
OMe
4k
93.5:6.5
2
4
3
CF3
OMe
Ar
a Reactions were carried out with 2 (0.1 mmol) and 3 (0.15 mmol) in tolu-
ene (1 mL) for 3 d.
b The er was determined by HPLC analysis on a chiral stationary phase using
the corresponding ketone.
SO2
NH
Ar =
c The absolute configuration was determined by comparing the [α]D with
the reported data.
CF3
SO2
d After a single crystallization from hexane–MTBE (1:1).
Ar
1
CF3
Yield (%) erb,c
Entry
1
R
Product
Acknowledgment
4a
91
85
93.5:6.5
Generous support by the Max-Planck-Society and the European Re-
search Council (Advanced Grant ‘High Performance Lewis Acid Or-
ganocatalysis, HIPOCAT’) is gratefully acknowledged. We thank our
technicians, and the members of our NMR, HPLC, and MS depart-
ments.
96.5:3.5
2
4b
(99.6:0.4)d
Supporting Information
Supporting information for this article is available online at
3
4
4c
84
79
94:6
http://dx.doi.org/10.1055/s-0034-1379999.
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p
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ortiInfogrmoaitn
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References and Notes
4d
92.5:7.5
MeO
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1041.
(2) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 807–809

809
Q. Wang, B. List
Letter
Synlett
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tions from other groups after our seminal report, see: (b) Chen,
L.-Y.; He, H.; Chan, W.-H.; Lee, A. W. M. J. Org. Chem. 2011, 76,
7141. (c) Treskow, M.; Neudörfl, J.; Giernoth, R. Eur. J. Org. Chem.
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Lee, A. W. M. Eur. J. Org. Chem. 2010, 4181.
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(11) A septum-capped vial with a stirring bar was charged with the
corresponding N-Boc imine 2 (0.1 mmol), catalyst 1 (2.8 mg, 2
mol%), and dry toluene (1 mL). The resulting mixture was
cooled to –30 °C, before the Chan diene 3 (0.15 mmol) was
added via syringe. The resulting reaction mixture was stirred
for 3 d. The reaction mixture was quenched by addition of 10%
TFA in CH2Cl2 (0.3 mL) at the reaction temperature and diluted
with CH2Cl2 (20 mL). The organic phase was washed with sat.
NaHCO3 (20 mL) and brine (20 mL). After removing the solvent,
the residue was adsorbed onto silica gel and purified by column
chromatography (isohexanes–EtOAc, 3:1 to 0:1).
(12) For current reviews on asymmetric counteranion directed
catalysis (ACDC), see: (a) Mahlau, M.; List, B. Angew. Chem. Int.
Ed. 2013, 52, 518. (b) Brak, K.; Jacobsen, E. N. Angew. Chem. Int.
Ed. 2013, 52, 534. (c) Phipps, R. J.; Hamilton, G. L.; Toste, F. D.
Nat. Chem. 2012, 4, 603.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 807–809