Peptide-catalyzed conjugate addition reactions of aldehydes to nitroolefins

Article abstract of DOI:10.1055/s-0029-1218651

The tripeptide H-D-Pro-Pro-Glu-NH₂ is an efficient catalyst for conjugate addition reactions of aldehydes to nitroolefins. Chiral γ-nitroaldehydes are obtained in excellent yields and stereoselectivities in the presence of as little as 1 mol% o

Full text of DOI:10.1055/s-0029-1218651

1568
PRACTICAL SYNTHETIC PROCEDURES
Peptide-Catalyzed Conjugate Addition Reactions of Aldehydes to Nitroolefins
A
symmetric Conjugate
a
A
ddition
R
r
eactionskus Wiesner, Helma Wennemers*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2670976; E-mail: Helma.Wennemers@unibas.ch
Received 21 December 2009
PSP
No183
Abstract: The tripeptide H-D-Pro-Pro-Glu-NH2 is an efficient catalyst for conjugate addition reactions of aldehydes to nitroolefins. Chiral
g-nitroaldehydes are obtained in excellent yields and stereoselectivities in the presence of as little as 1 mol% of the tripeptide catalyst. Under
further optimized reaction conditions the product was obtained in essentially perfect stereoselectivity (syn/anti, >99:1, 99% ee).
Key words: asymmetric catalysis, conjugate addition reactions, organocatalysis, peptides, proline
O
H
N
NH2
N
O
O
O
R2
O
CO2H
NH⋅TFA
chiral γ-amino acids,
(1 mol%)
NO2
NO2
pyrrolidines, γ-butyrolactones,
γ-butyrolactams, etc.
R2
H
+
H
NMM (1 mol%)
R1
R1
CHCl3–i-PrOH (9:1)
r.t., 12–24 h
(1.5 equiv)
(1 equiv)
syn/anti 6:1 to >99:1
90–99% ee
Scheme 1
Introduction
lenges outlined above. Herein, we highlight the catalytic
efficiency of the peptidic catalyst 1 and describe an opti-
mized synthetic protocol that allows the preparation of the
target molecules in close to perfect stereoselectivities.
Asymmetric conjugate addition reactions of aldehydes to
nitroolefins are highly versatile and valuable transforma-
tions.1,2 The resulting g-nitroaldehydes are useful building
blocks for the synthesis of diverse compounds such as
chiral pyrrolidines, g-butyrolactones, b-amino acids, g- Scope and Limitations
amino acids, and homoproline derivatives, as well as tet-
Tripeptide 1 is not only a highly stereoselective asymmet-
rahydropyrans and cyclohexenes; many of them are inter-
esting for medicinal chemistry (Scheme 1).1–3 As a result,
conjugate addition reactions between aldehydes and ni-
troolefins have attracted a lot of attention over recent
years and a variety of chiral primary and secondary
amine-based organocatalysts have been developed for this
asymmetric reaction.1–8 Typical challenges encountered
are: a) the need for high catalyst loadings and a large ex-
cess of the aldehyde to obtain good product yields; b) lim-
ited substrate scope, and c) long reaction times.
Furthermore, the addition of acids and/or bases is often re-
quired. Our contribution to the field are tripeptides of the
general type Pro-Pro-Xaa, where Xaa is an amino acid
bearing a carboxylic acid.5–8
ric catalyst but also distinguishes itself by its high activity
and broad substrate scope. As little as 1 mol% of 1 is suf-
ficient to form g-nitroaldehydes in high to excellent yields
and stereoselectivities for a broad range of different alde-
hyde and nitroolefin combinations (Scheme 2).6–8 Diaste-
reoselectivities in favor of the syn- over the anti-
diastereoisomer of ≥20:1 are observed for most substrate
combinations. Enantioselectivities of the syn-diastereo-
isomers are typically ≥95% ee. The substrate scope in-
cludes aldehydes with aromatic, linear and b-branched
aliphatic substituents, as well as functional groups such as
O
H
N
NH2
N
O
In particular, the peptide H-D-Pro-Pro-Glu-NH2 (1;
Figure 1) is a highly effective catalyst for asymmetric
conjugate addition reactions of aldehydes to trans-b-sub-
stituted nitroolefins, which provides solutions to the chal-
O
CO2H
NH
Figure 1 Tripeptidic catalyst H-D-Pro-Pro-Glu-NH2 (1)
SYNTHESIS 2010, No. 9, pp 1568–1571
x
x
.
x
x
.2
0
1
0
Advanced online publication: 25.01.2010
DOI: 10.1055/s-0029-1218651; Art ID: Z27709SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Asymmetric Conjugate Addition Reactions
1569
O
R2
O
1⋅TFA (1 mol%)
NO2
(1 equiv)
NO2
Ph
+
R2
NMM (1 mol%)
CHCl3–i-PrOH (9:1)
r.t., 12–24 h
H
H
R1
R1
(1.5 equiv)
O
Ph
O
Ph
O
Ph
O
O
Ph
NO2
NO2
NO2
NO2
NO2
H
H
H
H
H
Me
98% yield
Et
96% yield
n-Bu
98% yield
Ph
93% yield[a]
syn/anti 61:1, 96% ee
94% yield
syn/anti 7:1, 95% ee
syn/anti 42:1, 97% ee
syn/anti 27:1, 96% ee
syn/anti 25:1, 97% ee
Cl
OMe
O
O
O
O
O
Cl
CF3
NO2
NO2
NO2
NO2
NO2
H
H
H
H
H
Et
Et
Et
Et
Me
97% yield
syn/anti 36:1, 96% ee
95% yield
syn/anti >99:1, 98% ee
quant. yield[a]
syn/anti 21:1, 95% ee
90% yield
syn/anti 24:1, 97% ee
84% yield[a]
syn/anti 6:1, 98% ee
MeO
O
OMe
NO2
MeO
O
OMe
NO2
MeO
O
OMe
NO2
H
H
H
Et
CO2Me
95% yield
syn/anti 16:1, 90% ee
quant. yield
syn/anti 68:1, 92% ee
95% yield[a]
syn/anti >99:1, 95% ee
a Amount of catalyst used: 2 mol%
Scheme 2 Substrate scope of conjugate addition reactions between aldehydes and b-substituted nitroolefins catalyzed by peptide 17
esters and olefins. Sluggish reactions have thus far only removed from the acid-labile resin by using TFA. Purifi-
been observed with a,a-disubstituted aldehydes. Like- cation of the resulting TFA-salt of 1 is straightforward, in-
wise, aliphatic as well as electron-poor and electron-rich volving only precipitation from diethyl ether and
aromatic b-substituted nitroolefins and nitroolefins bear- filtration. The tripeptide performs equally well when the
ing functional groups all react readily. Amongst them, al- TFA is removed from the peptide-TFA salt by ion-
dehydes with bulky substituents in the b-position, as well exchange chromatography and the ‘desalted peptide’ is
as electron-rich aromatic nitroolefins, are slightly less re- utilized (without addition of base).7
active compared to the other substrates and therefore re-
The reaction proceeds readily in a range of solvents. High-
quire 2 mol% instead of 1 mol% of the tripeptidic catalyst
est reactivities are observed in alcohols such as isopro-
to provide the products in excellent yields within 24
panol, whereas the highest stereoselectivities are obtained
hours. Hardly any side products, such as homoaldol con-
in chloroform. Often, a mixture of these two solvents is an
densation products, form in the course of the reaction. As
ideal compromise for obtaining both high reactivity and
a result, only a small excess of the aldehyde (1.5 equiv)
stereoselectivity. In addition, this solvent mixture allows
with respect to the nitroolefin is sufficient to obtain the g-
nitroaldehydes in yields of typically ≥95% (Scheme 2).7
good solubility of all the reaction components.5
The substrate scope is not limited to b-substituted ni-
troolefins; nitroethylene, the simplest of all nitroolefins, is
also an excellent electrophile for reactions of functional-
ized and non-functionalized aldehydes in the presence of
1 (Scheme 3).6 The resulting monosubstituted g-nitroal-
dehydes offer a facile route to the synthesis of chiral
monosubstituted g2-amino acids that were previously only
accessible using chiral auxiliaries. Despite the intrinsic
polymerization tendency of nitroethylene, products are
typically obtained in yields of 80–90%.
An additional benefit of the peptidic catalyst is the fact
that no additives are necessary for its excellent catalytic
performance.7 Both the catalytic activity and stereoselec-
tivity are equally as good when the peptide is used by it-
self or in the presence of trifluoroacetic acid (TFA) and an
equivalent amount of a tertiary amine base such as N-
methylmorpholine (NMM). However, it is generally more
practical to perform the asymmetric catalysis using the
TFA-salt of the tripeptide together with NMM, which lib-
erates the secondary amine and allows catalysis. This pro-
cedure is convenient since 1 is easily prepared on
multigram scales by solid-phase peptide synthesis on
Rink Amide resin following the Fmoc/t-Bu protocol and
To evaluate the scope of the peptide-catalyzed conjugate
addition reactions in more detail, we sought to further op-
timize the reaction conditions. In particular, we aimed to
use an even smaller excess of the aldehyde with respect to
Synthesis 2010, No. 9, 1568–1571 © Thieme Stuttgart · New York

1570
M. Wiesner, H. Wennemers
PRACTICAL SYNTHETIC PROCEDURES
O
O
1. 1⋅TFA (1 mol%), NMM (1 mol%)
CHCl3, r.t., 12–24 h
NO2
NO2
NH2
+
H
HO
HO
2. BH3⋅THF, –15 °C
R
R
R
(1.5 equiv) (1 equiv)
NO2
NO2
NO2
NO2
NO2
HO
HO
HO
HO
HO
Me
84% yield, 95% ee
Et
82% yield, 98% ee
n-Pr
n-Bu
Ph
90% yield, 99% ee
84% yield, 99% ee
82% yield, 98% ee
O
O
O
NO2
NO2
NO2
NO2
NO2
HO
HO
H
H
H
Et
CO2Me
CO2Me
4
67% yield, 98% ee[a]
85% yield, 97% ee
a Amount of catalyst used: 3 mol%.
86% yield, 97% ee
87% yield, 95% ee
80% yield, 96% ee
Scheme 3 Conjugate addition reactions of aldehydes to nitroethylene catalyzed by peptide 16
the nitroolefin and obtain the product in even higher ste- Materials and reagents were of the highest commercially available
grade and were used without further purification. Reactions were
monitored by TLC using Merck silica gel 60 F254 plates; com-
pounds were visualized under UV irradiation and with KMnO4.
reoselectivities. Towards this goal, the reaction between
butanal and trans-b-nitrostyrene was chosen as a model
reaction. A series of experiments demonstrated that reduc-
Flash chromatography was performed using Merck silica gel 60,
tion of the temperature to 0 °C improved the stereoselec-
1
particle size 40–63 mm. H and 13C NMR spectra were recorded
tivity significantly but also slowed down the reaction rate.
An increase in the reaction rate was, however, achieved
by utilizing dried solvents (crown cap quality).9 To obtain
full conversion within 24 hours under these conditions
(dried solvents, 0 °C), utilizing only 1.1 equivalents of the
aldehyde, an only slightly higher catalyst loading of 2
mol% was still sufficient. Because g-nitroaldehydes are
prone to epimerize at the a-carbon, the aldehyde was re-
duced by addition of BH3·THF upon completion of the
conjugate addition reaction. The resulting nitroalcohol
was isolated in a yield of 93% and near perfect diastereo-
and enantioselectivities (syn/anti >99:1, 99% ee;
Scheme 4).
with a Bruker DPX 400 spectrometer. Chemical shifts (d) are re-
ported in ppm using the residual solvent peak as a reference. HPLC
analyses were performed on an analytical instrument with a diode
array detector from Shimadzu.
Synthesis of TFA·H-D-Pro-Pro-Glu-NH2 (1)7
i-Pr2NEt (3 M in NMP, 9 equiv) was added to a solution of Fmoc-
Glu(OtBu)-OH (3 equiv) and O-(6-chlorobenzotriazol-1-yl)-
N,N,N´,N´-tetramethyluronium hexafluorophosphate (HCTU; 3
equiv) in DMF. The activated amino acid was added to amino-func-
tionalized Rink Amide AM resin (0.62 mmol·g–1, 5 g, 3.1 mmol)
and the mixture was agitated for 1.5 h before washing with DMF
and CH2Cl2 (5 × each). Piperidine in DMF (20% v/v) was added to
the resin (pre-swollen in DMF) and the reaction mixture was agitat-
ed for 5 min, drained and the piperidine treatment was repeated for
10 min. The resin was then washed with DMF and CH2Cl2
(5 × each). The coupling and Fmoc deprotection cycles were repeat-
ed with Fmoc-Pro-OH (3 equiv) and then with Boc-D-Pro-OH (3
equiv). All coupling and deprotection steps were monitored by
TNBS, qualitative Kaiser, and chloranil tests (secondary amines).
The immobilized peptide was cleaved into solution by agitating the
resin in a mixture of TFA–CH2Cl2 (2:1 v/v) for 1 h, filtration and
then repeating the acid treatment for a further 30 min. Pooling of fil-
trates and removal of volatiles under vacuum followed by precipi-
tation and thorough washing with Et2O afforded the peptide as its
trifluoroacetate salt, which was dried under high vacuum and used
without further purification.
O
1. 1⋅TFA (2 mol%)
NMM (2 mol%)
(1.1 equiv)
Ph
CHCl3–i-PrOH (9:1)
0 °C, 24 h, "dry"
H
+
NO2
Et
HO
2. BH3⋅THF (1.3 equiv)
NO2
(1 equiv)
Et
Ph
–15 °C, 1 h
93% yield
syn/anti >99:1
99% ee
Scheme 4 Conjugate addition reactions of butanal to trans-b-nitro-
styrene catalyzed by peptide 1 under optimized conditions
These results further underline the versatility of peptide 1
as an asymmetric catalyst for conjugate addition reactions
of aldehydes to nitroolefins. Most recently, kinetic studies
1H NMR (400 MHz, D2O, 25 °C): d = 4.51 (dd, J = 7.1, 8.8 Hz,
1 H), 4.34 (dd, J = 3.6, 9.0 Hz, 1 H), 4.23 (dd, J = 5.2, 9.5 Hz, 1 H),
3.60 (m, 1 H), 3.49 (m, 1 H), 3.29 (m, 2 H), 2.40 (m, 3 H), 2.19 (m,
provided insight into the rate-determining step of these re- 1 H), 2.08–1.80 (m, 8 H).
actions.8 This allowed further optimization of the reaction
conditions and a reduction of the catalyst loading by a fac-
tor of ten to as little as 0.1 mol%.8 Thus, the high catalytic
efficiency, paired with the ease of peptide synthesis, ren-
ders H-D-Pro-Pro-Glu-NH2 very attractive for asymmetric
conjugate addition reactions of aldehydes to nitroolefins.
13C NMR (100 MHz, D2O, 25 °C): d = 177.4, 176.2, 174.5, 168.6,
61.2, 59.6, 53.2, 48.0, 47.0, 30.3, 29.8, 28.5, 26.4, 24.7, 24.3.
HRMS (ESI): m/z [M + H]+ calcd for C15H25N4O5: 341.1824; found:
341.1821.
Synthesis 2010, No. 9, 1568–1571 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Asymmetric Conjugate Addition Reactions
1571
Conjugate Addition Followed by Reduction of the Aldehyde;
Typical Procedure for (2S,3R)-2-Ethyl-4-nitro-3-phenylbutan-
1-ol (2)
(2) For early examples, see: (a) Betancort, J. M.; Barbas, C. F.
III Org. Lett. 2001, 3, 3737. (b) Alexakis, A.; Andrey, O.
Org. Lett. 2002, 4, 3611.
TFA·H-D-Pro-Pro-Glu-NH2 (1·TFA; 62.0 mg, 0.136 mmol, 0.02
equiv) was suspended in i-PrOH (1 mL) and NMM (15 mL, 0.136
mmol, 0.02 equiv) followed by addition of butyraldehyde (675 mL,
7.5 mmol, 1.1 equiv) and CHCl3 (9 mL). The colorless solution was
then cooled to 0 °C, b-nitrostyrene (1.01 g, 6.80 mmol, 1.0 equiv)
was added and the resulting yellow solution was stirred for 48 h at
0 °C (or 24 h when using dried solvents and reagents). After this
time, TLC analysis (pentane–EtOAc, 10:1) showed complete con-
version. The reaction mixture was then cooled to –15 °C and a
solution of borane in THF (1 M, 8.0 mL, 8.2 mmol, 1.2 equiv) was
added dropwise. After stirring for 1 h at –15 °C, the mixture was
quenched with an excess of concd. AcOH (2.0 mL, 31.7 mmol, 4.7
equiv) and concentrated under reduced pressure. The crude product
was dissolved in CH2Cl2–pentane (1:2 v/v) and purified by flash
chromatography over silica gel (pentane–EtOAc, 5:1) to obtain ni-
troalcohol 2 (1.34 g, 93%) as a colorless oil.
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.36 (m, 2 H, PhH), 7.30
(m, 1 H, PhH), 7.25 (m, 2 H, PhH), 4.94 (dd, J = 12.7, 5.5 Hz, 1 H,
CH2NO2), 4.84 (dd, J = 12.7, 10.1 Hz, 1 H, CH2NO2), 3.79 (dd,
J = 11.1, 3.4 Hz, 1 H, CHHOH), 3.73 (ddd, J = 10.1, 7.7, 5.6 Hz,
1 H, CHPh), 3.63 (dd, J = 11.1, 6.0 Hz, 1 H, CHHOH), 1.79 (m,
2 H, CHCH2OH and CH2OH), 1.40 (dqd, J = 15.0, 7.5, 4.0 Hz, 1 H,
CH2CH3), 1.23 (qdd, J = 14.3, 9.0, 7.3 Hz, 1 H, CH2CH3), 0.92 (t,
J = 7.4 Hz, 3 H, CH3).
(3) For recent reviews on 1,4-addition reactions using
organocatalysts, see: (a) Tsogoeva, S. B. Eur. J. Org. Chem.
2007, 1701. (b) Sulzer-Mossé, S.; Alexakis, A. Chem.
Commun. 2007, 3123. (c) Vicario, J. L.; Badía, D.; Carrillo,
L. Synthesis 2007, 2065. (d) Almasi, D.; Alonso, D. A.;
Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299.
(e) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471.
(4) For selected examples of conjugate additions between
aldehydes and nitroolefins catalyzed by organocatalysts,
see: (a) Zheng, Z.; Perkins, B. L.; Ni, B. J. Am. Chem. Soc.
2010, 132, 50. (b) Alza, E.; Pericàs, M. A. Adv. Synth. Catal.
2010, 352, in press; DOI 10.1002/adsc.200900817.
(c) Lombardo, M.; Chiarucci, M.; Quintavalla, A.;
Trombini, C. Adv. Synth. Catal. 2009, 351, 2801. (d) Luo,
R.-S.; Weng, J.; Ai, H.-B.; Chan, A. S. C. Adv. Synth. Catal.
2009, 351, 2449. (e) Chang, C.; Li, S.-H.; Reddy, R. J.;
Chen, K. Adv. Synth. Catal. 2009, 351, 1273. (f) Ruiz, N.;
Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L.; Uria, U.
Chem. Eur. J. 2008, 14, 9357. (g) Belot, S.; Massaro, A.;
Tenti, A.; Mordini, A.; Alexakis, A. Org. Lett. 2008, 10,
4557. (h) Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H.
J. Am. Chem. Soc. 2008, 130, 5608. (i) García-García, P.;
Ladépeche, A.; Halder, R.; List, B. Angew. Chem. Int. Ed.
2008, 47, 4719. (j) Hayashi, Y.; Itoh, T.; Ohkubo, M.;
Ishikawa, H. Angew. Chem. Int. Ed. 2008, 47, 4722.
(k) Zhu, S.; Yu, S.; Ma, D. Angew. Chem. Int. Ed. 2008, 47,
545. (l) McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9,
599. (m) Palomo, C.; Vera, S.; Mielgo, A.; Gómez-Bengoa,
E. Angew. Chem. Int. Ed. 2006, 45, 5984. (n) Lalonde, M.
P.; Chen, Y.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006,
45, 6366. (o) Wang, J.; Li, J.; Lou, B.; Zu, L.; Guo, H.;
Wang, W. Chem. Eur. J. 2006, 12, 4321. (p) Mossé, S.;
Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett.
2006, 8, 2559. (q) Mase, N.; Watanabe, K.; Yoda, H.;
Takabe, K.; Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc.
2006, 128, 4966. (r) Hayashi, Y.; Gotoh, H.; Hayashi, T.;
Shoji, M. Angew. Chem. Int. Ed. 2005, 44, 4212.
(5) Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem.
Int. Ed. 2008, 47, 1871.
13C NMR (100 MHz, CDCl3, 25 °C): d = 139.1, 129.2, 128.6, 127.9,
79.2, 62.5, 46.3, 45.8, 21.9, 12.1.
Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found: C,
64.30; H, 7.66; N, 6.21.
The diastereomeric ratio (syn:anti) and the enantiomeric excess
were determined by HPLC using a Chiracel AD-H column (n-hex-
ane–i-PrOH, 99.4:0.6; 25 °C) at a flow rate of 1.2 mL/min, UV de-
tection at 210 nm: tR (anti, minor) = 101.7, tR (anti, major) = 107.4,
tR (syn, minor) = 115.5 min, tR (syn, major) = 119.4 min.
Acknowledgment
This work was supported by BACHEM and the Swiss National
Science Foundation. We thank the EU for support through the
Research Training Network REVCAT. H.W. is grateful to
BACHEM for an endowed professorship.
(6) Wiesner, M.; Revell, J. D.; Tonazzi, S.; Wennemers, H.
J. Am. Chem. Soc. 2008, 130, 5610.
(7) Wiesner, M.; Neuburger, M.; Wennemers, H. Chem. Eur. J.
2009, 15, 10103.
(8) Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J. Am.
Chem. Soc. 2010, 132, 6.
(9) For the role of water and its effect on the reaction rate see ref.
8.
References
(1) For reviews, see: (a) Berner, O. M.; Tedeschi, L.; Enders, D.
Eur. J. Org. Chem. 2002, 1877. (b) Krause, N.; Hoffmann-
Röder, A. Synthesis 2001, 171.
Synthesis 2010, No. 9, 1568–1571 © Thieme Stuttgart · New York