Enantioselective catalytic addition of nitroesters to N-carboalkyloxy imines: a route to quaternary stereocenters

Article abstract of DOI:10.1016/j.tetlet.2009.05.036

A readily available, low cost bifunctional organic catalyst promoted the addition of nitroesters to imines; in the reaction between 2-nitropropionates and N-Boc protected aldehyde-imines the product bearing a new quaternary stereocenter was obtained in up

Full text of DOI:10.1016/j.tetlet.2009.05.036

Tetrahedron Letters 50 (2009) 4340–4342
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective catalytic addition of nitroesters to N-carboalkyloxy imines:
a route to quaternary stereocenters
*
*
Alessandra Puglisi , Laura Raimondi, Maurizio Benaglia , Martina Bonsignore, Sergio Rossi
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A readily available, low cost bifunctional organic catalyst promoted the addition of nitroesters to imines;
in the reaction between 2-nitropropionates and N-Boc protected aldehyde-imines the product bearing a
new quaternary stereocenter was obtained in up to 81% ee. The positively charged catalyst was postu-
lated to control the attack of the enolic form of nitroester to imine through a hydrogen bonding network.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 April 2009
Revised 6 May 2009
Accepted 12 May 2009
Available online 18 May 2009
Keywords:
Synthetic methods
Bifuctional catalyst
Nitroesters
Catalysis
Quaternary stereocenter
The stereoselective carbon-carbon bond formation promoted by
a chiral catalyst is an area of major interest in asymmetric cataly-
sis.1 In this field, the stereoselective construction of quaternary ste-
reocenters is one of the most challenging topics of the modern
organic chemistry.2 The concurrent synthesis of adjacent quater-
nary and tertiary stereogenic centers is even more appealing since
it allows the assembly of highly functionalized molecules; such
possibility is specially intriguing in the case of chiral 1,2-diamino
acids, which are structures of extreme value for their relevance
in biological active compounds.3
organocatalyst was described11 we wish to report our preliminary
results in the field.
In our previous work a chiral bifunctional thiourea catalyst de-
rived from t-leucine was developed and successfully employed in
the stereoselective addition of activated nucleophiles to imines.12
Compound 1 ( Fig. 1) was easily prepared in five steps using a
straightforward general procedure: the condensation of N-methyl
benzylamine with N-protected Boc (S)-t-leucine afforded in quan-
titative yield N-benzyl, N-methyl amide of (S)-t-leucine, that was
converted in the corresponding isothiocyanate and immediately
reacted with (1R,2R)-1,2-diamino cyclohexane to afford the bifunc-
tional amino thiourea in 65% yield. Finally reductive amination
with formaldehyde and sodium borohydride, followed by treat-
ment with acetic acid allowed to isolate N,N-dimethyl amino deriv-
ative 1 in 61% yield after chromatographic purification.
Among the possible methods for the preparation of a,b-diamino
acids the Mannich addition to imines4 represents a viable approach
that has been recently explored.5 An alternative approach is repre-
sented by the addition to imines of nitroester, pioneered a few
years ago by Johnston.6 However, the synthesis of
a-tetrasubstitut-
ed diamino acids, that requires the use of
a
-substituted nitroesters,
On the basis of our work12 and with the aim of mimicking John-
ston’s proton complex10 we decided to protonate compound 1 with
acetic acid to afford catalyst 1/H+, which was fully characterized by
mass spectrometry and NMR spectroscopy. The addition of ethyl 2-
nitro propionate to N-Boc benzaldehyde imine was used as model
reaction to test the catalytic activity of 1 and 1/H+; the results are
collected in Table 1. In a typical experimental procedure, to a 1-mL
dichloromethane solution of the catalyst (0.02 mmol), cooled to
0 °C, under nitrogen atmosphere, 1 mL dichloromethane solution
of N-Boc benzaldehyde imine (0.2 mmol) was added, followed by
injection of ethyl 2-nitro propionate (0.21 mmol). The reaction
mixture was allowed to stir for 18 h at 0 °C, then it was concen-
trated under vacuum and purified by flash chromatography (hex-
ane–ethyl acetate 85:15) (Scheme 1).
remained an elusive goal7 that only very recently has been posi-
tively addressed by three different groups, either by employing
an organometallic catalyst8 or organocatalysts, namely, a chiral
ammonium betaine9 or a sterically hindered bifunctional proton
complex10 in reactions with very bulky nitroesters.
We thought that the use of a new and easily prepared bifunc-
tional catalyst in this very challenging reaction would have been
amenable. Prompted by a recent report where the use of chiral
1,2-diphenylethylenediamine, a commercially available, although
expensive diamine, as scaffold in a bifunctional thiourea/amine
* Corresponding author. Tel.: +39 0250314171; fax: +39 0250314159.
E-mail address: Maurizio.Benaglia@unimi.it (M. Benaglia).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.036

A. Puglisi et al. / Tetrahedron Letters 50 (2009) 4340–4342
4341
R1
N
S
R2
N
H
N
H
O
N
R3
R4
Me
N
S
Me
S
AcOH
N
N
H
N
H
N
H
N
H
OAc
H
O
N
O
N
Me
Me
Me
Me
1
1/H+
Figure 1. Bifunctional organic catalysts employed in the enantioselective addition of nitroesters to imines.
Table 1
The scope of the reaction was extended to differently substi-
tuted imines, as illustrated in Table 2. A coordinating protective
group on the imine nitrogen (R00 = Cbz, COOMe) is necessary to
achieve a good level of stereocontrol (entries 1 and 2). N-Acyl imi-
nes reacted in slightly lower yield and enantioselectivity. Having
established t-butyloxycarbonyl as the nitrogen protecting group
of choice15 a variation of the aldehydic substrates was studied. It
was found that electron-withdrawing group on the aldehyde ring
is better tolerated than electron-donating group (entry 5 vs entry
6).
Enantioselective addition of ethyl nitropropionate to N-Boc benzaldehyde imine
catalyzed by catalyst 1/H+ Scheme 1
Entry
Solvent
Temperature (°C)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7c
DCM
DCM
Et2O
25
0
25
0
71
81
72
41
88
47
89
70
81
73
81
60
77
59
Et2O
Toluene
DCM
DCM
0
ꢀ20
0
It is worth mentioning that an imine bearing a coordinating
group on the aldehydic part, such as the N-4-methoxyphenyl imine
of ethyl glyoxylate leads to the product in high yield but low
enantioselectivity (entry 7), as further indication of the decisive
role played by the Boc group of the imine in controlling the stereo-
selection of the process (Scheme 2).
Substitution at the nitroester was also tested: the addition of
ethyl-2-nitrobutanoate to N-Boc benzaldehyde imine promoted
by 1/H+ afforded the expected product in 60% yield and 72% ee in
DCM at 0 °C (Scheme 3).16
a
Yields determined after chromatographic purification.
Enantiomeric excess of anti isomer determined by HPLC (Chiracel OD).
Reaction run with neutral catalyst 1.
b
c
NHBoc
Ph
NO2
cat 10% mol
COOEt
+
Ph
18 h
N
COOEt
Me
Boc
O2N
The stereochemical outcome of the reaction finds a nice theo-
retical rationale in a very preliminary semiempirical (AM1) evalu-
ation of the complexes between 1/H+ with the two reactants. Due
to acidic reaction conditions, calculations were performed on the
(E)-enolic form of ethyl 2-NO2 propionate, that coordinates at
1/H+ via a hydrogen-bonding network involving NO2 (with the
Me
N
S
cat
N
H
N
H
Me
OAc
H
Me
O
N
Scheme 1. Addition of 2-nitropropionate to N-Boc imine.
Table 2
Enantioselective addition of ethyl 2-nitro propionate to different imines Scheme 2
Catalyst 1/H+ worked well both in dichloromethane and diethyl
Entrya
R0
R00
Yieldb (%)
eec (%)
ether at room temperature, affording the (S, S)-anti-product in
good yield and 70–73% enantiomeric excess (entries 1 and 3)
although with no diastereoselectivity (syn/anti ratio was about 1/
1).13 The (S,S)-anti configuration was determined on the basis of lit-
erature data. Lowering the reaction temperature was beneficial
both in terms of yield and enantiomeric excess in DCM (entry 2):
the product was obtained in 81% yield and 81% ee.
In diethyl ether the ee was improved while the yield was not
completely satisfactory (entry 4). The use of toluene as solvent al-
lowed isolating the product in 88% yield and 60% ee (entry 5). A
further lowering of the reaction temperature did not bring any in-
crease in the enantioselectivity. As expected, the use of protonated
catalyst14 proved to be necessary to obtain a good level of enanti-
oselectivity: compound 1 afforded the desired product in 89% yield
and 59% ee in DCM at 0 °C (entry 7). We believe that the proton on
the amine moiety allows the coordination of the imine to the cat-
alyst, thus playing a crucial role in determining the stereochemical
outcome of the reaction, as it will be discussed later.
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Cbz
48
66
55
81
74
73
77
65
58
54
81
27
67
37
COOMe
COPh
Boc
Boc
Boc
4-OMe-Ph
4-Cl-Ph
COOEt
4-OMe-Ph
a
Reaction run in DCM at 0 °C.
Yields determined after chromatographic purification.
Enantiomeric excess determined by HPLC.
b
c
NHR"
cat 1/H+ (10% mol)
R'
NO2
COOEt
COOEt
Me
+
R'
N
DCM, 18 h, 0°C
O2N
R''
Scheme 2. Addition of nitropropionate to different imines.

4342
A. Puglisi et al. / Tetrahedron Letters 50 (2009) 4340–4342
NHBoc
Supplementary data
cat 1/H+ (10% mol)
Ph
NO2
COOEt
COOEt
+
Ph
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.036.
DCM, 18 h, 0°C
Boc
O2N
Yield: 60%, ee: 72%
References and notes
Scheme 3. Addition of 2-nitrobutanoate to N-Boc imine.
1. Review: Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vols. I–IV,.
2. For a review on quaternary stereocenters see: Steven, A.; Overman, L. A. Angew.
Chem., Int. Ed. 2007, 46, 5488–5508 and references cited there.
3. Review: Viso, A.; de la Pradilla, R. F.; Garcia, A.; Flores, A. Chem. Rev. 2005, 105,
3167–3189.
4. Review on organocatalytic asymmetric Mannich reactions: Ting, A.; Schaus, S.
E. Eur. J. Org. Chem. 2007, 5797–5801.
5. For Mannich-type reactions of glycine Schiff base see: Shibuguchi, T.; Mihara,
H.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794–807
and references cited there.
6. Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418–
3419; Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007, 129,
3466–3467.
7. Knudsen, K. R.; Jorgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362–1365.
8. Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130,
2170–2171.
9. Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 10878–10879.
10. Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 5866–5867.
11. Han, B.; Liu, Q.-P.; Li, R.; Tian, X.; Xiong, X.-F.; Deng, J.-G.; Chen, Y.-C. Chem. Eur.
J. 2008, 14, 8094–8097.
S
N
N
H
O
N
H
+
N
H
O
2.189A
2.159A
2.236A
O
H
O
t
O -Bu
N
O
N
EtO
Ph
12. Puglisi, A.; Benaglia, M.; Annunziata, R.; Rossi, D. Tetrahedron: Asymmetry 2008,
19, 2258–2264.
13. Enantiomeric excess of syn diastereoisomer was lower than 50% under any
reaction conditions.
14. The use of different protic acids (trifluoroacetic acid, trifluoromethane sulfonic
acid, and methane sulfonic acid) resulted in high enantiomeric excess but low
reproducibility. According to a referee’s suggestion the reaction promoted by
the pivalate salt of catalyst 1 was studied, in order to explore the use of a more
basic carboxylate anion; by running the reaction in DCM at 0 °C for 18 h, the
product was obtained in 71% yield, 55/45 dr and 57% ee for the major
diastereoisomer.
Figure 2. Minimum energy complex between 1/H+ and reactants. Non-acidic
hydrogens are removed for sake of clarity. Distances between hydrogen-bonded
atoms are reported.
thioureic NH hydrogens) and enolic OH (with the amidic C@O). The
insertion of the imine slightly modifies this pattern: the nitroeno-
late is still hydrogen-bounded to the two NH of the thiourea, while
N-Boc benzaldehyde imine is held in place via an hydrogen bond
between the amidic C@O and the protonated amine of the ligand.17
All the possible four complexes were fully optimized and charac-
terized as minima,18 the structure of the lowest energy one—lead-
ing to the major, (S,S) diastereoisomer—is shown in Figure 2. The
calculated ee (88% at 0 °C) is in nice agreement with the experi-
mental results.
We believe that the extremely simple catalyst synthesis, as well
as the possibility of a modular approach for developing new and
more efficient metal-free promoters for a relatively unexplored
field like the nitroester reactions makes the present methodology
very attractive.19
15. It must be noted that Boc residue maybe the easier protecting group to
remove; for synthetic transformations of
a
-nitro, b-amino ester see Refs.6,10,11
16. Attempts at improving the diastereoselectivity of the reaction, for example, by
using bulkier esters (see Ref. 10) gave no satisfactory results.
17. The coordination of t-butyloxy carbonyl of imine to the thiourea and of the
nitro ester to the RMe2NH+ group of diaminocyclohexane is also possible;
however, from our preliminary calculations such arrangement does not allow
to establish a favorite mode of reaction of the two reagents.
18. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, V.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, A.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
GAUSSIAN 03, Revision D.01; Gaussian: Wallingford, CT, 2004.
Acknowledgment
This work was supported by MIUR (Rome) within the national
project ‘Nuovi metodi catalitici stereoselettivi e sintesi stereoselet-
tiva di molecole funzionali’.
19. For a recent contribution in the use of chiral Bronsted acids see: Wilt, J. C.; Pink,
M.; Johnston, J. N. Chem. Commun 2008, 4177–4179.