Organocatalytic Enantioselective Michael-Addition of Malonic Acid Half-Thioesters to β-Nitroolefins: From Mimicry of Polyketide Synthases to Scalable Synthesis of γ-Amino Acids

Article abstract of DOI:10.1002/adsc.201100458

Highly enantioselective biomimetic Michael addition reactions of malonic acid half thioesters (MAHTs) to a variety of nitroolefins, affording the optically active γ-amino acid precursors, were developed by employing the Cinchona-based squaramides (up to >

Full text of DOI:10.1002/adsc.201100458

FULL PAPERS
DOI: 10.1002/adsc.201100458
Organocatalytic Enantioselective Michael-Addition of Malonic
Acid Half-Thioesters to b-Nitroolefins: From Mimicry of
Polyketide Synthases to Scalable Synthesis of g-Amino Acids
Han Yong Bae,a Surajit Some,a Jae Heon Lee,a Ju-Young Kim,b
Myoung Jong Song,b Sungyul Lee,b,* Yong Jian Zhang,c,* and Choong Eui Songa,*
a
Department of Chemistry, Department of Energy Science, Sungkyunkwan University, 300 Cheoncheon, Suwon, Gyeonggi
440-746, Korea
Fax : (+82)-31-290-7075; e-mail: s1673@skku.edu
Department of Applied Chemistry, Kyunghee University, Yongin, Gyeoggi 446-701, Korea
b
E-mail: sylee@khu.ac.kr
c
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
Peopleꢀs Republic of China
E-mail: yjian@sjtu.edu.cn
Received: June 6, 2011; Published online: November 17, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100458.
Abstract: Highly enantioselective biomimetic Mi- formal synthesis of pharmaceutically important g-
chael addition reactions of malonic acid half thioest- amino acids such as baclofen. Moreover, a quantum
ers (MAHTs) to a variety of nitroolefins, affording chemical analysis of the catalyst-substrate complexes
the optically active g-amino acid precursors, were de- is shown to give a detailed and instrumental insight
veloped by employing the Cinchona-based squar- into the origin of the observed catalytic activity.
ACHTUNGTRENNUNGamides (up to >99% ee). Remarkably, this biomim-
etic process is enantioconvergent, a highly desirable
feature of a catalytic asymmetric reaction, whereby Keywords: g-amino acids; biomimetic catalysis; Cin-
E/Z-isomers of the nitroolefins afford the same prod- chona-based squaramide catalysts; malonic acid half
uct enantiomer. The synthetic utility of this organo- thioesters (MAHTs); Michael addition; organocatal-
catalytic protocol was also demonstrated in the ysis
Introduction
tive Claisen condensation.[3] Inspired by these biocata-
lytic processes, the groups of Shair[4] and Cozzi[5] re-
The direct generation of enolates or their equivalents ported independently on a Cu-catalyzed enantioselec-
for catalytic and stereoselective carbon-carbon bond tive thioester aldol reaction with MAHTs as direct
formation reactions has been intensively investigated thioester enolate donors. However, polyketide syn-
over the past decade. Both for metal-catalyzed and thases do not possess metal ions, but only organic res-
organocatalytic processes, however, the donor sub- idues [cysteine, histidine and asparagines (or another
strates are mostly limited to specific ketones or alde- histidine)] in their active sites. Shortly thereafter,
hydes. Use of donor substrates with the oxidation Ricci[6] and Wennemers[7] independently demonstrat-
state of carboxylic acid derivatives remains a chal- ed in their pioneering works that organocatalytic
lenging task with very few successful reports[1] since asymmetric transformations can also be accomplished
the pKa of the a-proton in carboxylic acid derivatives with MAHTs via hydrogen bond catalysis using Cin-
is much larger than that in ketones or aldehydes.[2] In chona-based organocatalysts such as b-isocupreidine
contrast, in the biosynthesis of polyketides and fatty and Cinchona-based (thio)ureas, respectively. Un-
acids, nature freely uses the enzymatic activation of fortunately, the catalytic activity and enantioselectivi-
malonic acid half thioesters (MAHTs) to generate ty achieved in their work were insufficient for syn-
ester enolates or their equivalents that undergo the thetic use.
chain elongation step smoothly by the decarboxyla-
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Organocatalytic Enantioselective Michael-Addition of Malonic Acid Half-Thioesters to b-Nitroolefins
Figure 1. Squaramide-based bifunctional organocatalysts.
Quite recently, chiral squaramides[8] have been Results and Discussion
shown to serve as a more effective hydrogen bond
donor than their thiourea analogues for a variety of To assess the efficiency of different types of squar-
enantioselective organocatalytic reactions, benefitting
ACHTUNGTRENaNUNG mide-based catalysts for the MAHT-associated
from the squaramideꢀs characteristic dual hydrogen- asymmetric transformations, we initially examined the
bonding catalysis, due to the more accessible reaction asymmetric Michael addition[15] of the MAHT 2 to
site[8a,9] and fixed anti/anti-orientation[10–12] of the NH trans-b-nitrostyrene (1a) as a model substrate in
protons relative to the carbonyl groups. Moreover, methyl tert-butyl ether (MTBE) at ambient tempera-
the apparently higher Brønsted acidity of the NH pro- ture with the squaramide catalysts I (20 mol%).[16,17]
tons of the squaramide with respect to those of thio- Gratifyingly, as shown in Table 1, regardless of the
urea allows the squaramide to activate the electro- substituent at the C-3 and C-6’ positions of alkaloids
phile more efficiently.[13] Thus, we anticipated that Ia–c, the Michael additions afforded the Michael
squaramide-based bifunctional catalysts, such as I–III adduct (S)-3a[18] in excellent yields with unprecedent-
(Figure 1), would be more compatible for MAHT-as- edly high enantioselectivities (93% ee, entries 1–3).[19]
sociated asymmetric transformations.
However, a relatively long reaction time (72 h) was
We report herein the highly enantioselective and required for the completion of the reaction. A dra-
scalable organocatalytic Michael addition of MAHTs matic increase in the reactivity, without any erosion
to nitroolefins using bifunctional squaramide-based of the enantioselectivity, was achieved simply by in-
organocatalysts, which allows a rapid access to opti- creasing the reaction temperature. Thus, at 458C, the
cally pure g-amino acids.[14] Remarkably, this biomim- reaction was completed within 8 h to afford the prod-
etic process was shown to be stereoconvergent, where uct (S)-3a (93% ee, entry 4). At this temperature, a
E/Z-isomers of nitroolefins afford the same product lower catalyst loading of up to 2 mol% still results in
enantiomer.
excellent catalytic activity and enantioselectivity
Table 1. Catalytic enantioselective Michael addition of MAHT 2 to trans-b-nitrostyrene (1a).[a]
Entry
Catalyst (mol%)
Temperature [oC]
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ia (20)
Ib (20)
Ic (20)
Ia (20)
Ia (5)
Ia (2)
II (20)
III (20)
20
20
20
45
45
45
20
20
72
72
72
8
30
72
72
72
96
94
89
84
80
78
48
38
93
93
93
93
93
93
77
18
[a]
Reactions were carried out with 1a (0.2 mmol), 1.5 equiv. of MAHT 2 and catalysts (2–20 mol%) in MTBE (2 mL) at
208C or 458C.
Isolated yields after chromatographic purification.
[b]
[c]
Determined by chiral HPLC (see Supporting Information).
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Scheme 1. Organocatalytic enantioselective Michael addition of MAHT 2 to trans-b-nitrostyrene.
(93% ee, entries 5 and 6). In contrast to these results,
Having established that the squaramide catalyst I
other types of squaramide catalysts II and III showed acts as a highly active and enantioselective catalyst,
much inferior catalytic activity and enantioselectivity we undertook to explore the scope of the substrate
(entries 7 and 8), which might be due to the relatively under the optimized reaction conditions. All of the re-
lower acidity of the squaramide moiety than that of I. actions were carried out in the presence of 5 mol% of
The results described in Scheme 1 highlight the su- the squaramide catalyst Ia at 458C in methyl tert-
perior catalytic efficiency of the squaramide catalyst butyl ether (MTBE). As shown in Table 2, a variety
Ia relative to other H-bond donors, such as the thio- of nitroolefins 1a–1j bearing aryl, heteroaryl and alkyl
ACHTUNGTRENNUNG
urea analogue (QN-TU)[20] or the sulfonamide ana- groups at the b-position were smoothly converted
logue (QN-SA).[21] Under the same reaction condi- into the desired Michael adducts 3a–3j with excellent
tions [1a (1 mmol), 2 (1.5 equiv.), MTBE (10 mL), cat- ee values (up to >99% ee).[25] To the best of our
alyst (5 mol%)], much better results were obtained knowledge, this level of enantioselectivity is unprece-
with the squaramide catalyst Ia (93% ee and 80% dentedly high in biomimetic organocatalytic reactions
yield) than with the thiourea catalyst QN-TU (63% in which MAHTs are utilized as the enolate precur-
ee, 36% yield) and the sulfonamide catalyst (24% ee, sors. Moreover, in most cases, a single recrystalliza-
15% yield).
tion provides the enantiomerically pure form (>
The observed differences of catalytic activity of the 99.5% ee) (from Et2O). However, poor conversions
sulfonamide QN-SA, the thiourea QN-TU and the were observed in the case of alkyl-substituted nitroo-
squaramide Ia were in agreement with our quantum lefins, perhaps due to their weak electrophilicity.
chemical analysis carried out by employing the densi-
We also investigated the influence of the stereo-
ty functional theory method (MPW1B95)[22] with the chemistry at the double bond of the nitroolefin. Re-
6-311+ +G** basis set as implemented in the Gaussi- markably, when we subjected both the isolated pure
an 03 suite of programs.[23] Structures of the com- E or Z[26] isomers of b-nitrostyrene 1a to our reaction
plexes IV, V and VI of trans-nitrostyrene 1a with the conditions, the same (S)-enantiomer of the Michael
sulfonamide, thiourea and squaramide catalysts, re- adduct 3a was obtained with the same ee value (en-
spectively, (modeled by substituting the NH-epi-alka- tries 1 and 2 in Table 2, 93% ee). Similarly, E/Z-1a
À
loid moiety by an NH CH3 to reduce computational mixtures always gave the same result, and independ-
efforts) were optimized using default criteria. The ent of their exact ratio, all of them furnished (S)-3a
natural bond orbital (NBO) analyses[24] were then car- with 93% ee (Table 2, entry 3). Thus, this process is
ried out to understand the nature of the activation of enantioconvergent, a highly desirable feature for a
the b-carbon of 1a. As shown in Figure 2, the hydro- catalytic asymmetric reaction, where a mixture of ste-
gen bonds in VI are shorter than those in IV and V reoisomers affords only one product enantiomer.[27]
À
À
(lengths: H-2 O-5=2.38 ꢂ, H-2 O-3=2.32 ꢂ for IV, Mechanistically, the Z-isomers of the b-nitroalkene
À
À
À
H-4 O-7=2.20 ꢂ, H-3 O-5=2.05 ꢂ for V, H-4 O- are rapidly isomerized into the E-isomer in the pres-
7=2.26 ꢂ, H-3 O-5=1.99 ꢂ for VI). Moreover, the ence of the squaramide catalysts 1.[28]
À
NBO charge at C-9 in VI (À0.086 e) was less negative
The stereoconvergency of the reaction, the ob-
than those of C-7 in IV (À0.105 e) and C-9 in V served superior catalytic activity of the squaramide
(À0.092 e), implying that the C-9 site in VI is more catalyst relative to that of the other H-donors exam-
electrophilic than those of IV and V, which is consis- ined in this study, and the retention of ee values at
tent with the experimental observations in Scheme 1. higher temperature strongly indicate that the strong
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Organocatalytic Enantioselective Michael-Addition of Malonic Acid Half-Thioesters to b-Nitroolefins
(Scheme 2). The Michael addition of MAHT 2 to the
nitroolefin 1e proceeded smoothly on a 5-g scale of
the substrate to afford the corresponding Michael
adduct 3e in high yield and excellent enantioselecitivi-
ty (82% yield and 91% ee). The reduction of the nitro
group of 3e, followed by intramolecular cyclization
and recrystallization from Et2O/hexane, affords enan-
tiomerically pure g-butyrolactam 4 (see the Support-
ing Information for details). Lactam 4 has already
been transformed by hydrolysis[32] to (S)-(+)-baclo-
fen·HCl salt[32,33]
Conclusions
In summary, the Cinchona-based squaramides I were
shown to act as remarkably effective catalysts for the
biomimetic enantioselective Michael addition reac-
tions of MAHTs to a variety of nitroolefins, affording
optically active g-amino acid precursors with up to
>99% ee. Remarkably, this process was shown to pro-
ceed enantioconvergently. We also demonstrated the
synthetic utility of our catalytic protocol in the formal
synthesis of pharmaceutically important g-amino
acids, such as baclofen. Moreover, a quantum chemi-
cal analysis of the catalyst-substrate complexes is
shown to give a detailed and instrumental insight into
the origin of the observed catalytic activity. The more
detailed mechanism of the reaction and the basis for
enantioselectivity are currently under investigation
and will be reported in due course.
Experimental Section
General Remarks
The organocatalysts examined in this study (Ia,[8g] Ic,[8g] II,[8a]
III,[34] QN-TU[35] and QN-SA[21a]) were prepared starting
from the corresponding 9-epi-amino-Cinchona alkaloids ac-
cording to the literature procedures. MAHT was prepared
according to the literature procedure reported by Shair
et al.[36] (Z)-Nitrostyrene was prepared according to the lit-
erature procedure.[26] The chromatographic purification of
the products was carried out by flash chromatography using
Merck silica gel 60 (230–400 mesh). Thin-layer chromatogra-
phy was carried out on Merck silica gel 60F plates. HPLC
analyses were performed on a Varian Pro Star Series instru-
ment equipped with an isostatic pump using a CHIRAL-
1
CEL OD-H Column (250ꢃ4.6 mm). The H and 13C NMR
Figure 2. Calculated structures of IV, V and VI.
spectra were recorded on Varian 300 spectrometers. The IR
spectra were obtained using a Bruker Vertex 70 spectrome-
ter with MIRacle Micro ATR accessory. The HR-mass spec-
tra were recorded on a Jeol JMS-700M station. The melting
points (mp) were determined on a Buchi B-540 melting
point apparatus and are uncorrected. The optical rotation
was measured on a Perkin–Elmer Polarimeter 343 plus. All
chemicals used in this study were obtained from commercial
coordination of the nitroalkene to the squaramide
moiety is crucial for catalysis.[29,30]
To illustrate the synthetic utility of our methodolo-
gy, a short formal synthesis of pharmaceutically im-
portant g-amino acids such as baclofen[31] was devel-
oped starting from trans-b-nitro-4-chlorostyrene (1e) sources and used without further purification.
Adv. Synth. Catal. 2011, 353, 3196 – 3202
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Table 2. Enantioselective Michael addition of MAHT 2 to various nitrostyrenes 1a-1j.[a]
Entry
R
Time [h]
Yield [%][b]
ee [%][c]
1
(E)-Ph (1a)
(Z)-Ph (1a)
30
8
8
80 (96)[d]
78
77
93 (93)[d]
93
93
2[e]
3[e]
4
(E)/(Z)-Ph (1a)
4-Me-C6H4 (1b)
4-MeO-C6H4 (1c)
4-F-C6H4 (1d)
4-Cl-C6H4 (1e)
4-Br-C6H4 (1f)
2-furyl (1g)
2-thienyl (1h)
i-Bu (1i)
cyclohexyl (1j)
34
34
25
22
22
33
24
60
60
81 (96)[d]
80 (94)[d]
82 (86)[d]
80 (88)[d]
83 (86)[d]
78 (88)[d]
79 (91)[d]
22
96 (96)[d]
92 (92)[d]
91 (91)[d]
90 (90)[d]
91 (91)[d]
88 (88)[d]
91 (91)[d]
92
5
6
7
8
9
10
11
12
15
>99
[a]
Unless otherwise indicated, the reactions were carried out with 1 (0.2 mmol), 1.5 equiv. of MAHT 2 and catalyst Ia
(5 mol%) in MTBE (2 mL) at 458C.
Isolated yields after chromatographic purification.
Determined by chiral HPLC (see Supporting Information).
The values in parentheses were obtained from the reactions carried out using 20 mol% of Ia at room temperature for 3
days.
[b]
[c]
[d]
[e]
For the Z- or E/Z- mixture, the reactions were performed at 458C using 20 mol% of Ia.
were determined by chiral HPLC using a Daicel CHIRAL-
CEL OD-H column.
Acknowledgements
This work was supported by grants from Basic Science Re-
search Program (MEST) (NRF-20090085824), Priority Re-
search Centers Program, (MEST) (NRF-2010-0029698), SRC
program, (MEST) (2011-0001334), WCU program (MEST)
(R31-2008-10029), Cooperative R&D Program, Korea Re-
search Council Industrial Science and Technology (B551179-
10-03-00), Converging Research Program (MEST)
(2010K001203), and by Sungkyunkwan University (Postdoc-
toral Research Program, 2010).
Scheme 2. Synthesis of (S)-baclofen.
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[16] Other solvents were also screened for the reaction
using the catalyst Ia, but the yield and enantioselectivi-
ty were found to be slightly inferior in comparison to
those of MTBE: THF (66% yield, 92% ee), EtOAc
(48% yield, 88% ee), Et2O (75% yield, 84% ee), EVE
(67% yield, 74% ee), CH3CN (44% yield, 71% ee), ace-
tone (62% yield, 84% ee), CH2Cl2 (56% yield, 80% ee),
toluene (41% yield, 72% ee). For more experimental
results, see the Supporting Information.
[17] MAHTs with phenyl and benzyl substituents gave simi-
lar results (93% ee and 91% ee, respectively) to those
obtained with MAHT 2.
[9] The distance between the two hydrogens of the squar-
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Adv. Synth. Catal. 2011, 353, 3196 – 3202