Organocatalytic michael addition of nitro esters to a,β-unsaturated aldehydes: Towards the enantioselective synthesis of trans-3-substituted proline derivatives

Article abstract of DOI:10.1002/adsc.201200538

A facile five-step strategy has been developed for the enantioselective synthesis of trans-3- substituted proline derivatives with high diasteroselectivity (dr>20:1) and enantioselectivity (up to 97% ee). The key step is the asymmetric organocatalytic Michael addition of nitro esters to a,β-unsaturated aldehydes, which affords the chiral Michael adducts in high yields (up to 96%) and excellent enantioselectivity (up to 99% ee) by using diaryl- ACHTUNGTRENUNGprolinol silyl ether as the organocatalyst.

Full text of DOI:10.1002/adsc.201200538

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DOI: 10.1002/adsc.201200538
Organocatalytic Michael Addition of Nitro Esters to
a,b-Unsaturated Aldehydes: Towards the Enantioselective
Synthesis of trans-3-Substituted Proline Derivatives
Man-Yi Han,a Yong Zhang,b Huai-Zhen Wang,a Wan-Kai An,a Bao-Chun Ma,a
Yuan Zhang,a and Wei Wanga,*
a
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou, Gansu 730000, Peopleꢀs Republic of China
Fax : (+ 86)-931-891-5557; e-mail: wang_wei@lzu.edu.cn
College of Chemistry and Chemical Engineering, Gannan Normal University, Ganzhou, Jiangxi 341000, Peopleꢀs
b
Republic of China
Received: June 19, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200538.
Abstract: A facile five-step strategy has been devel-
oped for the enantioselective synthesis of trans-3-
substituted proline derivatives with high diasterose-
lectivity (dr>20:1) and enantioselectivity (up to
97% ee). The key step is the asymmetric organoca-
talytic Michael addition of nitro esters to a,b-unsa-
turated aldehydes, which affords the chiral Michael
adducts in high yields (up to 96%) and excellent
enantioselectivity (up to 99% ee) by using diaryl-
tion products after the Michael addition of aminomal-
onates to a,b-unsaturated aldehydes.
On the other hand, asymmetric organocatalysis[5]
has emerged as an attractive tool for the synthesis of
optically active compounds. In this regard, Hayashi[6]
as well as Rios and Cꢁrdova[7] have applied organoca-
talytic Michael reactions for the enantioselective syn-
thesis of 3-aryl-substituted prolines. Hayashi and co-
workers[6] synthesized substituted tetrahydropyrans
via a Michael/isomerization reaction of nitroethanol
and a,b-unsaturated aldehydes. The phenyl-substitut-
ed tetrahydropyran intermediate could be further
transformed to the trans-3-phenylproline derivative.[6]
Rios, Cꢁrdova and co-workers[7] realized the organo-
catalytic tandem reaction of 2-acylaminomalonates
and a,b-unsaturated aldehydes to synthesize a series
of 5-hydroxypyrrolidines. The reductive deoxygena-
ACHTUNGTRENNUNGprolinol silyl ether as the organocatalyst.
Keywords: asymmetric organocatalysis; Michael ad-
dition; trans-3-substituted proline derivatives
Due to their structural uniqueness, trans-3-substituted
proline derivatives[1] are widely used as building
blocks for the synthesis of conformationally-constrain-
ed peptides[2] with high biological activities. More-
over, trans-3-substituted proline scaffolds are impor-
tant structural motifs existing in many natural prod-
ucts and pharmaceuticals[3] (Figure 1). Over the past
decades, progress has been made in synthesizing
chiral 3-substituted proline derivatives[4] by using an
organometallic reagent or a chiral precursor/auxiliary.
For example, Schmalz and co-workers[4a] recently de-
veloped a Cu-catalyzed 1,4-addition strategy to syn-
thesize the racemic trans-3-substituted proline deriva-
tives in four steps. The chiral trans-3-vinylproline
could, accordingly, be obtained with 74% ee in six
steps via the Evans auxiliary approach. Another strat-
egy to synthesize the chiral 3-substituted prolines is
the optical resolution[4k] of the reduction/decarboxyla-
Figure 1. Representative natural products and pharmaceuti-
cals containing trans-3-substituted proline moieties.
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tion of phenyl-substituted 5-hydroxypyrrolidine and derivatives from the Michael adducts in four steps.
the sequential processes of decarboxylation/epimeri- Via this approach, trans-3-substituted proline deriva-
zation/ester hydrolysis afforded the trans-3-phenylpro- tives could be successfully obtained with excellent
line derivative.[7]
diastereoselectivity (up to dr>30:1) and enantioselec-
The organocatalytic synthesis of trans-3-alkyl-sub- tivity (up to 97% ee).
stituted proline derivatives was first attempted by Be-
Aiming at the enantioselective synthesis of trans-3-
lokon and co-workers[8] in 1993. However, the reac- substituted proline derivatives, we first studied the or-
tion products were obtained as mixtures with poor ganocatalytic asymmetric Michael addition reaction
diastereoselectivity (1:1.1) and low enantioselectivity of nitro esters to a, b-unsaturated aldehydes. We
(42% ee). In 2007, Hamada and co-workers[9] succeed- chose initially the conjugate addition of ethyl nitroa-
ed in synthesizing 3-hydroxy-3-substituted proline de- cetate 1a to crotonaldehyde 2a as the model reaction
rivatives with low to moderate enantioselectivity (30– to examine the yield and the stereoselectivity of the
88% ee) by intramolecular asymmetric aldol reaction. products 3a. As shown in Table 1, the screening
Due to the use of ketoaldehyde substrates, however, (Table 1, entries 1–4) of chiral secondary amine cata-
the synthesis of 3-alkyl-substituted prolines (without lysts[13] I–IV in toluene revealed that, in the presence
3-hydroxy substitution) could not be realized via this of benzoic acid (10 mol%), catalysts II and IV are
strategy.
both effective in the enantioselectivity control at
Accordingly, there is still in urgent need to develop room temperature. With II (entry 2) or IV (entry 4)
a facile and general method for the enantioselective
synthesis of trans-3-substituted, especially trana-3-
alkyl-substituted prolines. Herein, we report an orga-
Table 1. Optimization of the reaction conditions.[a]
nocatalytic asymmetric Michael reaction of nitro
esters to a,b-unsaturated aldehydes (Table 2 and
Table 3) with high yields (up to 96%) and excellent
enantioselectivities (up to 99% ee) via iminium catal-
ysis.[10] It is worthy of mention that although the enan-
tioselective Michael addition of nitro esters to a,b-un-
saturated ketones has recently been developed,[11] that
of nitro esters to a,b-unsaturated aldehydes has not
been investigated. The only relevant work is that of
Jørgensen and co-workers[12] who reported one exam-
ple of the double addition of a nitro ester to an a,b-
unsaturated aldehyde via organocatalysis. Further-
more, we demonstrate a facile approach (Scheme 1)
to provide optically pure trans-3-substituted proline
Entry Catalyst Solvent
Yield [%][b] dr[c]
ee [%][d]
1:1.1 27/32
1[e]
2[e]
3[e]
4[e]
5
I
II
III
IV
II
IV
IV
IV
IV
IV
IV
IV
IV
toluene
toluene
toluene
toluene
toluene
toluene
DCM
30
66
78
87
61
95
94
1:1.2 77/78
1:1.0 59/62
1:1.0 79/76
1:1.3 81/83
1:1.0 90/89
1:1.3 89/89
1:1.2 88/89
1:1.0 88/88
1:1.0 86/86
1:1.3 81/84
1:1.0 86/87
1:1.0 89/89
6
7
8
9
p-xylene 91
n-hexane 76
10
11
12[f]
13[g]
Et2O
THF
toluene
toluene
78
84
85
84
[a]
Unless otherwise noted, the experimental conditions are:
mixture of 1a (0.158 mmol), crotonaldehyde 2a
a
(0.158 mmol), catalyst (10 mol%), and PhCO2H
(10 mol%) in 0.32 mL of solvent was stirred at 08C for
4 h.
Scheme 1. Synthesis of chiral trans-3-substituted proline de-
rivatives. Experimental conditions: (a) MeOH, PTSA·H2O,
[b]
[c]
[d]
CH
N
Isolated yield after purification by flash chromatography.
1
for 5l. (b) Raney Ni, H2, 708C; 74% yield for 6a;
NiCl2·6H2O, NaBH4, MeOH, 47% yield for 6h; 50% yield
for 6lL. (c) One-pot operation: HCl, MeOH, 708C; Pd/C,
H2, MeOH; Et3N, CbzCl, THF, 21% yield for 7a; 28% yield
for 7h; 24% yield and 80%/86% ee for 7l. (d) LiOH, H2O/
MeOH/THF (1:1:3), 0–108C, 65% yield and 88% ee for 8a;
55% yield and 97% ee for 8h; 69% yield and 66% ee for 8l.
Determined by H NMR analysis of the crude mixture.
Determined by chiral HPLC analysis after the aldehydes
were converted into the corresponding a,b-unsaturated
esters.
Reaction was performed at room temperature.
Reaction was performed at a 0.25M concentration.
5 mol% of IV was used.
[e]
[f]
[g]
2
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Organocatalytic Michael Addition of Nitro Esters to a,b-Unsaturated Aldehydes
Table 2. Substrate scope of the asymmetric Michael addition
as the catalyst, the obtained enantioselectivities of the
products 3a are 77%/78% and 79%/76% ee, respec-
tively; while the reaction yields are 66% and 87%, re-
spectively. When the reaction temperature was low-
ered to 08C, catalyst IV (entry 6) proved to be superi-
or to catalyst II (entry 5), which was evidenced by the
increased yield of 95% and the increased enantiose-
lectivity of 90%/89% ee. We also tested the catalytic
activity of catalyst IV in other solvents, such as DCM,
p-xylene, n-hexane, Et2O, and THF, but no improve-
ment in the yield or enantioselectivity could be ob-
served (entries 7–11). Addition of other acidic addi-
tives, such as (+)-CSA, p-nitrobenzoic acid, 3,5-dini-
trobenzoic acid, or PTSA, could not further improve
the results either (see the Supporting Information for
details). When the substrates 1a and 2a were diluted
in toluene at a 0.25M concentration (entry 12) or
5 mol% of catalyst IV was used (entry 13), the prod-
ucts 3a were obtained in slightly lowered yields and
enantioselectivities. It should be noted that, in all
cases, the low diastereoselectivity (dr from 1:1.0 to
1:1.3) was attributable to the high CH acidity[8] of the
a-proton in 3a. Fortunately, the diastereoselectivity of
the synthesized 3-substituted proline derivatives could
be significantly improved to dr>20:1 by efficient ki-
netic discrimination. Accordingly, the optimal condi-
tions for the organocatalytic asymmetric Michael ad-
dition of nitro esters to a, b-unsaturated aldehydes
were selected as: 10 mol% of catalyst IV, 10 mol% of
benzoic acid, toluene as the solvent, and reaction at
08C.
with aliphatic a,b-unsaturated aldehydes as the Michael ac-
ceptor.[a]
With the optimal reaction conditions in hand, we
next investigated the substrate scope for the asym-
metric Michael reaction. The addition reaction of cro-
tonaldehyde 2a with different nitro esters was firstly
examined. As summarized in Table 2, excellent yields
(93–96%) and high enantioselectivities (79%/88% to
90%/89% ee) were successfully obtained by using an
array of nitro esters with different ester moieties
(Table 2, entries 1–4). Remarkably, the trisubstituted
substrate, ethyl 2-nitropropanoate, also gave the de-
sired product 3e in good ee value (82%/88% ee), but
the diastereoslectivity did not show an appreciable
improvement (dr of 1:1.3) and the yield dropped to
44% (entry 5). To further expand the scope of this re-
action, a number of aliphatic a,b-unsaturated alde-
hydes was employed as the Michael acceptor with
structural diversity. To our delight, aliphatic a,b-unsa-
turated aldehydes were identified as suitable sub-
strates (Table 2, entries 6–10), affording the desired
adducts in high yields (78–94%) and excellent enan-
tioselectivities (94%/92% to 97%/98% ee). Notably,
when the oxygen heteroatom was introduced to the
substrate, the reaction also gave the desired product
in good yield (89%) and high enantioselectivity (91%/
92% ee, entry 11).
[a]
Experimental conditions: a mixture of 1 (0.158 mmol), 2
(0.158 mmol), catalyst IV (10 mol%), and PhCO2H
(10 mol%) in 0.32 mL of toluene was stirred at 08C.
[b]
Isolated yield after purification by flash chromatography.
[c]
[d]
1
Determined by H NMR analysis of the crude mixture.
Determined by chiral HPLC analysis after the aldehydes
were converted into the corresponding a,b-unsaturated
esters.
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Table 3. Substrate scope of the asymmetric Michael addition
with a,b-unsaturated aromatic aldehydes as the Michael ac-
ceptor.[a]
tained with low yield (52%) and low enantioselectivi-
ty (43%/45% ee) (Table 3, entry 4).
Having developed the asymmetric organocatalytic
methodology to obtain the key intermediates 3, we
next embarked on the enantioselective synthesis of
trans-3-substituted proline derivatives. Initially, we
conducted the direct intramolecular reductive alkyla-
tion of 3a to construct the trans-3-methyl-substituted
pyrrolidine 7a. Unfortunately, all attempts to use the
literature protocols, such as metal/acid[14] or H2/Raney
Ni,[15] were in vain. The direct reductive alkylation
conditions[15] led to complicated side reactions, which
suggests the necessity to protect the aldehyde group
of 3a. Accordingly, the synthetic strategy via the pro-
tection of the aldehyde group was chosen (Scheme 1).
Firstly, we were able to obtain directly the key in-
termediate acetal 5a[16] by using the one-pot operation
without separating the Michael adduct 3a (see the
Supporting Information for details). This method was
also scalable to at least 4.5 mmol without any loss of
the ee value. Subsequently, the reduction of nitro
group of 5a with Raney Ni afforded the product 6a in
the yield of 74%. Remarkably, we succeeded next in
constructing the N-Cbz-protected pyrrolidine 7a
through the one-pot operation, including intramolecu-
lar cyclization,[17] hydrogenation,[18] and N-Cbz protec-
tion.[19] Finally, in order to further improve the low di-
astereoselectivity,[4a] the product 7a was treated with
0.98 equiv. of LiOH in H2O/MeOH/THF. The effi-
cient kinetic discrimination and hydrolysis resulted in
the trans-diastereomer 8a with high enantioselectivity
(88% ee) and excellent diastereoselectivity (dr>
30:1). The product 8a was easily converted into the
corresponding 3-methylproline, the absolute configu-
ration of which was determined by comparing the op-
tical rotation value with that reported in the litera-
[a]
Experimental conditions: a mixture of 1a (0.158 mmol), 2
(0.158 mmol), catalyst IV (10 mol%), and PhCO2H
(10 mol%) in 0.32 mL of Et2O was stirred at 08C.
[b]
Isolated yield after purification by flash chromatography.
[c]
[d]
1
Determined by H NMR analysis of the crude mixture.
Determined by chiral HPLC analysis after the aldehydes
were converted into the corresponding a,b-unsaturated
esters.
ture[4l] (see the Supporting Information for details).
To further demonstrate the utility of this methodol-
[e]
Toluene as the solvent.
ogy, another two typical trans-3-substituted proline
derivatives, trans-3-isopropyl- and trans-3-phenylpro-
We also tested the possibility of applying a,b-unsa- line derivatives were synthesized from the corre-
turated aromatic aldehydes as the Michael acceptor in sponding Michael products via the same synthetic
this reaction (Table 3). Considering the different reac- strategy, respectively. As shown in Scheme 1, trans-3-
tivity between aromatic and aliphatic a,b-unsaturated isopropyl proline derivative 8h could be obtained
aldehydes, we first examined the solvent effect with with excellent enantioselectivity (97% ee) and diaste-
cinnamaldehyde as the Michael acceptor. Compared reoselectivity (dr>20:1). trans-3-Phenylproline deriv-
with toluene as the solvent (60% yield, 76%/78% ee), ative 8l could also be obtained with high diastereose-
Et2O proved more suitable for this reaction, giving lectivity (dr>20:1) by isomerization of mixture of 7l
the desired product with higher yield (80%) and with 0.98 equiv. of LiOH. However, a decrease in
higher enantioselectivity (81%/88% ee) (Table 3, enantioselectivity (66% ee) from that of 7l (80/86%
entry 1, see the Supporting Information for details). ee) was observed, probably due to the partial racemi-
With Et2O as the sovlent, the halogen-substituted (2- zation of the benzyl carbon at the 3-position in the
Cl or 4-Br) aromatic aldehydes gave the desired prod- presence of basic LiOH.
ucts in moderate yields and enantioselectivities as
In summary, we have developed a simple and gen-
well (Table 3, entries 2 and 3). However, when an eral procedure for the enantioselective synthesis of
electron-donating group (4-OMe) was employed on trans-3-substituted proline derivatives, the key step of
the aromatic moiety, the reaction product 3o was ob- which is the organocatalytic asymmetric Michael addi-
4
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Organocatalytic Michael Addition of Nitro Esters to a,b-Unsaturated Aldehydes
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hydes. The Michael addition reaction is applicable to
a variety of aliphatic and aromatic a,b-unsaturated al-
dehydes, affording the desired Michael adducts in
high yields (up to 96%) and excellent enantioselectiv-
ities (up to 99% ee). The Michael adducts with low
diastereoselectivity (dr from 1:1.0 to 1:1.3) could be
transformed to the corresponding trans-3-substituted
prolines with excellent diastereoselectivity (dr>20:1)
via the efficient kinetic discrimination. The enantiose-
lective route we developed for the facile synthesis of
trans-3-substituted, especially trans-3-alkyl-substitut-
ed, proline derivatives may, therefore, find further ap-
plications towards the construction of conformational-
ly constrained peptides and structurally complicated
natural products.
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Experimental Section
Representative Procedure for Asymmetric Michael
Addition of Nitro Esters to a,b-Unsaturated Alde-
hydes
To a solution of crotonaldehyde 2a (11.1 mg, 0.158 mmol),
catalyst IV (9.4 mg, 0.0158 mmol) and benzoic acid (1.9 mg,
0.0158 mmol) in toluene (0.32 mL), was added ethyl nitroa-
cetate 1a (21.0 mg, 0.158 mmol) at 08C. After stirring for 4 h
at this temperature, the reaction mixture was directly sub-
jected to flash column chromatography (petroleum ether/
EtOAc=4/1 as eluent) to afford the desired product 3a as
a light yellow liquid; yield: 30.5 mg (95%).
The product 3a was converted to the corresponding a,b-
unsaturated ester, which was subjected to chiral HPLC anal-
ysis to determine the enantiomeric excess.
[7] a) R. Rios, I. Ibrahem, J. Vesely, H. Sundꢄn, A. Cꢁrdo-
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Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (No. 20972064) and the 111 project is gratefully
acknowledged.
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Organocatalytic Michael Addition of Nitro Esters to a,b-
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