Highly enantioselective organocatalytic formation of functionalized cyclopentane derivatives via tandem conjugate addition/α-alkylation of enals

Article abstract of DOI:10.1002/ejoc.201200334

An enantioselective tandem reaction between dialkyl 2-haloethylmalonates and aromatic enals catalyzed by secondary amine catalysts is described. The reaction proceeds through a Michael/α-alkylation reaction sequence to afford the final 1,1,2,3-tetrasubstituted cyclopentanes in good yields (up to 75%) with high diastereoselectivity and enantioselectivity (up to 20:1dr and 93%ee). Moreover, the Michael/α-alkylation reaction also proceeds with a low catalyst loading (5 mol-%) with only a slight influence on selectivity and O- and N-alkylation products were not observed. Chiral 1,1,2,3-tetrasubstituted cyclopentanes were easily synthesized under mild and simple conditions from α,β-unsaturated aldehydes and dialkyl 2-haloethylmalonates in good yields with high diastereoselectivities and enantioselectivities. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Full text of DOI:10.1002/ejoc.201200334

Job/Unit: O20334
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200334
Highly Enantioselective Organocatalytic Formation of Functionalized
Cyclopentane Derivatives via Tandem Conjugate Addition/α-Alkylation of
Enals
[a]
ˇ[a]
Marek Remes and Jan Veselý*
Keywords: Organocatalysis / Domino reactions / Cyclopentanes / Amines / Michael addition
An enantioselective tandem reaction between dialkyl 2-halo-
ethylmalonates and aromatic enals catalyzed by secondary
amine catalysts is described. The reaction proceeds through
a Michael/α-alkylation reaction sequence to afford the final
1,1,2,3-tetrasubstituted cyclopentanes in good yields (up to
75%) with high diastereoselectivity and enantioselectivity
(up to 20:1dr and 93%ee). Moreover, the Michael/α-alkyl-
ation reaction also proceeds with a low catalyst loading
(5 mol-%) with only a slight influence on selectivity and O-
and N-alkylation products were not observed.
al. developed the formation of 1,1,2-trisubstituted cyclo-
pentanes by a domino reaction between aliphatic aldehydes
and (E)-5-iodo-1-nitropent-1-ene.[8] Recently, Ma reported
an elegant and highly efficient secondary amine catalyzed
cascade double Michael addition process to assemble poly-
substituted cyclopentanones with four contiguous stereo-
centers,[9] and more recently, Rovis et al.[10] and Enders et
al.[11] described multicatalytic[12] secondary amine/NHC-
catalyzed cascade sequences for the preparation of func-
tionalized cyclopentanones. To the best of our knowledge,
up to now, secondary amine catalysis by using nonstabilized
alkyl halides for inter- or intramolecular α-alkylation reac-
tions of aldehydes has remained unexplored.[13]
Introduction
The development of new organic transformations that al-
low the rapid construction of densely functionalized mole-
cules from simple and readily available starting materials is
still highly pursued in the chemical community. Although a
number of approaches can be used for this purpose, signifi-
cant achievements were obtained by expanding catalytic
cascade reactions.[1] Taking into account the increased de-
mand for the development of powerful and environmentally
friendly methodologies, organocatalysis nowadays repre-
sents a prospective field and general tool for the synthesis
of various complex molecules.[2]
Over the last decade, many organocatalytic cascade or
tandem reactions have emerged for the synthesis of cyclic
compounds.[3] In comparison to other heterocyclic deriva-
tives, only limited attention has been paid to the organocat-
alytic synthesis of functionalized cyclopentanes. However,
cyclopentane and cyclopentanone moieties frequently occur
in biologically active natural products.[4] In the realm of or-
ganocatalysis, the construction of the cyclopentane skeleton
has been accomplished mainly by secondary amine cataly-
sis; for example, List et al. reported an intramolecular α-
alkylation that renders cyclopentanes in excellent yields and
enantioselectivities.[5] Córdova’s group reported the con-
struction of 2,3,4-trisubstituted cyclopentanones through a
Michael/α-alkylation domino reaction,[6] Wang et al. de-
scribed the formation of highly functionalized cyclopen-
tanes through a double Michael addition,[7] and Enders et
Herein we wish to report the results of an investigation
that has led to a novel organocatalytic highly diastereo- and
enantioselective cascade Michael/α-alkylation reaction with
nonstabilized alkyl halide malonate derivatives that leads to
the formation of 1,1,2,3-tetrasubstituted cyclopentanes.
Results and Discussion
At the outset of our studies, we considered the use of
diethyl 2-bromoethylmalonate (1b)[14] as a Michael donor
together with (2E)-3-phenylprop-2-enal (2a) activated by a
secondary amine catalyst. On the basis of our previous ex-
perience in organocatalysis,[15] we selected the O-TMS-pro-
tected diphenylprolinol I[16] as the catalyst in our initial ex-
periments, and we screened different solvents and additives
to achieve corresponding tetrasubstituted cyclopentanes 3
in good yields with high diastereo- and enantioselectivity
(Tables 1 and 2). As we supposed, the presence of an ad-
ditional base was required to afford high yields, and the
model reaction in the absence of base yielded only a trace
amount of the desired product (Table 1, Entry 6); however,
the Michael adduct intermediate was observed by analysis
[a] Department of Organic and Nuclear Chemistry,
Faculty of Science, Charles University in Prague,
Hlavova 2030, 12843 Praha 2, Czech Republic
Fax: +420-221-951-305
E-mail: jxvesely@natur.cuni.cz
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200334.
Eur. J. Org. Chem. 0000, 0–0
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M. Remesˇ, J. Veselý
SHORT COMMUNICATION
of the crude product by 1H NMR spectroscopy. From a Table 2. Effect of solvent and temperature on the asymmetric cycli-
zation reaction.[a]
brief screening of the reaction conditions with the presence
of various bases (Table 1), NaOAc was selected for further
optimization. Screening of reaction solvents revealed that
the cascade reaction performed well in ether and chlori-
nated solvents, and the best results with respect to efficiency
and stereoselectivity were obtained in toluene (Table 2, En-
try 1). In contrast, no reaction was observed when polar
and protic solvents were used (Table 2, Entries 6 and 7). It
should also be noted that the efficiency of the reaction is
highly temperature dependent. At low reaction tempera-
tures, a significant increase in enantiocontrol and a signifi-
cant decrease in reaction efficiency were observed (Table 2,
Entries 8 and 9).
Table 1. Effect of base on the asymmetric cyclization reaction.[a]
[a] Performed
with
diethyl-2-(2-bromoethyl)malonate
(1b,
0.38 mmol), (2E)-3-phenylprop-2-enal (2a, 0.31 mmol), O-TMS
protected diphenylprolinol I (0.06 mmol), NaOAc (0.41 mmol) in
solvent (0.8 mL). [b] Determined by analysis of the crude reaction
mixture by NMR spectroscopy. [c] Isolated yield. [d] The ee values
were determined by chiral HPLC analysis of the corresponding
alcohol obtained after reduction performed with NaBH4
(5.0 equiv.) in methanol. [e] Reaction was performed at 0 °C. [f] Re-
action was performed at –20 °C.
tion with diethyl 2-bromoethylmalonate (1b, Table 4). Com-
pared to β-alkyl enals, for which no cyclopentane products
were obtained, cinnamic-type aldehydes provided highly
functionalized cyclopentanes in good yields with high enan-
tiomeric excess (up to 93%ee) and excellent diastereoselec-
tivity (up to 20:1dr).
For example, catalyst I in toluene catalyzed the asymmet-
ric reaction between (2E)-3-(4-chlorophenyl)enal (2c) and
diethyl 2-bromoethylmalonate (1b) with high stereoselecti-
vity and the corresponding cyclopentane derivative 3c was
[a] Performed
with
diethyl-2-(2-bromoethyl)malonate
(1b,
0.38 mmol), (2E)-3-phenylprop-2-enal (2a, 0.31 mmol), O-TMS
protected diphenylprolinol I (0.06 mmol), base (0.41 mmol) in tolu-
ene (0.8 mL). [b] Determined by analysis of the crude reaction mix-
ture by NMR spectroscopy. [c] Isolated yield. [d] The ee values were
determined by chiral HPLC analysis of the corresponding alcohol
obtained after reduction performed with NaBH4 (5.0 equiv.) in
methanol.
Other catalysts, such as (S)-diphenylprolinol and Mac- isolated in 67% yield as a single diastereomer with 90%ee
Millan’s imidazolidinone catalysts IV and V did not afford (Table 4, Entry 3). Also, other functional groups such as ni-
the corresponding cyclic product, and no Michael adducts tro, cyano, and other halogen atoms were tolerated under
were detected by 1H NMR spectroscopy. Interestingly, the same reaction conditions. Sterically larger groups have
when more bulky Jørgensen catalyst VI[17] was employed, a limited effect on the efficiency and diastereo- and enantio-
the rate of the reaction sequence significantly decreased as selectivity of the reaction (Table 4, Entry 6).
did the enantioselectivity (Table 3, Entry 6). Next, we
Next, we examined malonate derivatives 1 under the op-
studied the dependence of the reaction efficiency on catalyst timized conditions (Table 5). The alkyl group of the ester
loading. Interestingly, only a slight drop in enantio- moiety was found only partially to influence the reaction
selectivity was observed when 10 mol-% of O-TMS-pro- efficiency but significantly influenced the enantioselectivity
tected diphenylprolinol I was used (Table 3, Entry 8), and of the reaction. For example, the cascade reaction between
in contrast, the use of 5 mol-% of catalyst led to a lower (2E)-3-phenylprop-2-enal (2a) and dimethyl 2-bromoethyl-
conversion of the starting materials into the corresponding malonate (1a) under the optimized conditions afforded the
cyclic product (Table 3, Entry 9).
corresponding cyclopentane derivative 3g in 68% yield
Next, the scope of the asymmetric tandem Michael/α- (20:1dr) but with lower enantioselectivity (71%ee; Table 5,
alkylation reaction catalyzed by I was investigated under Entry 1). In contrast, when a substrate with a sterically
the optimized conditions. A series of α,β-unsaturated alde- larger ester moiety, such as isopropyl, was employed, cyclo-
hydes with varying substitution was subjected to the reac- pentane derivative 3h was obtained in lower yield (53%),
2
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Functionalized Cyclopentane Derivatives via Conjugate Addition/α-Alkylation
Table 3. Catalysts screened in the asymmetric cyclization.[a] Table 4. Scope of the asymmetric cyclization reaction.[a]
[a] Performed
with
diethyl-2-(2-bromoethyl)malonate
(1b,
0.38 mmol), enal 2a–f (0.31 mmol), O-TMS protected diphenyl-
prolinol I (0.06 mmol), NaOAc (0.41 mmol) in toluene (0.8 mL).
[b] Isolated yield. [c] The ee values were determined by chiral
HPLC analysis of corresponding alcohol obtained after reduction
performed with NaBH4 (5.0 equiv.) in methanol.
Table 5. Effect of different nucleophilic derivatives on the asymmet-
ric cyclization reaction.[a]
[a] Performed
with
diethyl-2-(2-bromoethyl)malonate
(1b,
0.38 mmol), (2E)-3-phenylprop-2-enal (2a, 0.31 mmol), catalyst I–
VI (0.06 mmol), NaOAc (0.41 mmol) in toluene (0.8 mL). [b] De-
termined by analysis of the crude reaction mixture by NMR spec-
troscopy. [c] Isolated yield. [d] The ee values were determined by
chiral HPLC analysis of the corresponding alcohol obtained after
reduction performed with NaBH4 (5.0 equiv.) in methanol.
[e] 10 mol-% of catalyst I was used. [f] 5 mol-% of catalyst I was
used.
but the high selectivity was maintained (20:1dr, 92%ee;
Table 5, Entry 3). We also examined other nucleophilic de-
rivatives with a bromoethyl moiety such as dicarbonyl com-
pounds to use for the asymmetric tandem Michael/α-alkyl-
ation reaction catalyzed by I. Bulky dicarbonyl compounds
did not react under the optimized reaction conditions
(Table 5, Entry 7); in contrast, 3-(2-bromoethyl)acetoacet-
one (1e) reacted with β-alkyl enal 2 to give 3j in good yield
and high diastereoselectivity (Table 5, Entry 6).
To ascertain the absolute configuration of cyclic products
3, we performed single-crystal X-ray diffraction analysis of
compound 7a,[18] which was obtained from 3a by oxidation
and subsequent amidation with enantiomerically pure (S)-
1-phenylethylamine (6, Scheme 1). As shown in Figure 1,
both stereogenic centers C2 and C3 have the (S) absolute
configuration. This configuration corresponds to the
gNOSY spectra, which suggest a relative trans configura-
tion of the aryl and formyl moieties at the cyclopentane
ring.
[a] Performed with haloethyl derivative 1a–f (0.38 mmol), enal 2a,
2e, or 2g (0.31 mmol), O-TMS protected diphenylprolinol
I
(0.06 mmol), NaOAc (0.41 mmol) in toluene (0.8 mL). [b] Isolated
yield. [c] The ee values were determined by chiral HPLC analysis
of the corresponding alcohol obtained after reduction performed
with NaBH4 (5.0 equiv.) in methanol. [d] The ee values could not
be determined (see the Supporting Information).
On the basis of the determined absolute configuration of
3
and previous reports on chiral pyrrolidine-catal- Scheme 1. Preparation of monocrystalline solid compound 7a.
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M. Remesˇ, J. Veselý
SHORT COMMUNICATION
Michael/α-alkylation reaction also proceeds with a low cat-
alyst loading (5 mol-%) and no O- or N-alkylation products
were observed. Mechanistic studies and synthetic applica-
tions of this new methodology, as well as the discovery of
new reactions based on this concept, are currently un-
derway in our laboratories.
Experimental Section
General: Chemicals and solvents were either purchased puriss p.A.
from commercial suppliers or purified by standard techniques. For
thin-layer chromatography (TLC), silica gel plates Merck 60F254
were used and compounds were visualized by irradiation with UV
light and/or by treatment with a solution of phosphomolybdic acid
(25 g), Ce(SO4)2·H2O (10 g), followed by heating. Flash chromatog-
raphy was performed by using silica gel Merck 60 (particle size
Figure 1. X-ray diffraction analysis of compound 7a.
1
0.063–0.200 mm). H NMR and 13C NMR spectra were recorded
yzed addition of malonates and β-keto esters to
enals,[6,19,20,15e–15g] we propose a mechanism for the studied
cascade Michael/α-alkylation reaction. The reaction starts
with iminium activation of the α,β-unsaturated aldehyde by
chiral pyrrolidine catalyst I (Scheme 2). Next, formed an
with a Varian Unity Inova-300 or Bruker Avance III 600. Chemical
shifts for protons are given in δ relative to tetramethylsilane (TMS)
and are referenced to residual protium in the NMR solvent
(CDCl3: δ = 7.26 ppm). Chemical shifts for carbon are given in δ
relative to tetramethylsilane (TMS) and are referenced to the car-
bon resonances in the solvent (CDCl3: δ = 77.0 ppm). Chiral HPLC
was carried out by using a LCP 5020 Ignos liquid chromatography
pump with LCD 5000 spectrophotometric detector. High-resolu-
tion mass spectroscopic data were obtained at Institute of Organic
Chemistry and Biochemistry AS CR, v.v.i.
iminium ion intermediate
8 undergoes stereoselective
nucleophilic conjugate attack on the β-carbon atom by 2-
bromoethyl malonate (1) to afford chiral enamine interme-
diate 9. In the next step, intramolecular 5-exo-tet cyclization
from the same face as incoming 1 followed by hydrolysis of
the resulting iminium intermediate gives cyclopentane prod-
uct 3.
General Procedure A – Asymmetric Cyclization Reactions: To a
stirred solution of enal 2 (0.31 mmol) in solvent (0.8 mL) was con-
secutively added catalyst I (0.06 mmol), nucleophilic derivative 1
containing
a haloethyl moiety (0.38 mmol), and the base
(0.41 mmol). The reaction mixture was vigorously stirred at room
temperature for the reported time. Then, the reaction mixture was
directly loaded and purified by silica gel chromatography (n-hex-
ane/EtOAc, 10:1–7:1) to give final product 3.
(2S,3S)-Diethyl 3-Formyl-2-phenylcyclopentane-1,1-dicarboxylate
1
(3a): Yield: 74%, colorless oil. [α]D = –15.4 (c = 0.39, CHCl3). H
NMR (300 MHz, CDCl3): δ = 9.65 (d, J = 2.1 Hz, 1 H), 7.29–7.18
(m, 5 H), 4.20 (d, J = 8.7 Hz, 1 H), 4.30–4.08 (m, 2 H), 3.78 (dq,
J = 7.2, 10.8 Hz, 1 H), 3.49 (dq, J = 7.2, 10.8 Hz, 1 H), 3.25 (dq,
J = 9.0, 2.1 Hz, 1 H), 2.82–2.71 (m, 1 H), 2.29–2.16 (m, 2 H), 2.04–
1.87 (m, 1 H), 1.23 (t, J = 7.2 Hz, 3 H), 0.80 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 201.6, 171.8, 169.8,
138.9, 128.8 (2 C), 128.2 (2 C), 127.4, 65.8, 61.7, 61.2, 57.6, 51.2,
34.0, 24.9, 14.0, 13.4 ppm. IR (KBr): ν = 3107, 3086, 3061, 3031,
˜
2981, 2936, 2903, 2876, 1726, 1602, 1584, 1453, 1368, 1258, 1157,
1096, 1018, 867, 752, 700 cm–1. HRMS (ESI): calcd. for C18H22O5
[M + Na]+ 341.1359; found 341.1359.
General Procedure B – Reduction of Cyclic Aldehydes: To a mixture
of cyclic aldehyde (1 equiv.) prepared by procedure A and methanol
(1–2 mL) was added NaBH4 (5 equiv.) at 0 °C. The reaction mix-
ture was stirred for 30 min at 0 °C, then poured into a mixture of
1 m HCl (aq., 5 mL) and EtOAc (10 mL) at 0 °C, and allowed to
stir for 30 min. Then, the crude mixture was diluted with EtOAc
(10 mL), extracted with H2O (3ϫ20 mL), dried with MgSO4, fil-
tered, and concentrated. The crude product was purified by column
chromatography (gradient n-hexane/EtOAc = 10:1 to 5:1) on silica
gel.
Scheme 2. Proposed mechanism for the cyclization reaction of α,β-
unsaturated aldehydes with nucleophilic derivatives.
Conclusions
In summary, we have developed an enantioselective tan-
dem reaction between dialkyl 2-haloethylmalonates and
aromatic enals catalyzed by secondary amine catalysts. The
reaction proceeds through a Michael/α-alkylation reaction
sequence to afford the final cyclopentanes in good yields
(2S,3S)-Diethyl-3-(Hydroxymethyl)-2-phenylcyclopentane-1,1-di-
carboxylate (4a): Yield: 55%, colorless oil. [α]D = –51.3 (c = 0.60,
with high diastereo- and enantioselectivity. Moreover, the CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.28–7.18 (m, 5 H),
4
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Functionalized Cyclopentane Derivatives via Conjugate Addition/α-Alkylation
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4.27–4.11 (m, 2 H), 3.80 (d, J = 10.2 Hz, 1 H), 3.74 (dq, J = 6.9,
10.5 Hz, 1 H), 3.64 (dd, J = 6.0, 10.8 Hz, 1 H), 3.53 (dd, J = 6.3,
10.8 Hz, 1 H), 3.42 (dq, J = 6.9, 10.5 Hz, 1 H), 2.79–2.68 (m, 1 H),
2.65–2.52 (m, 2 H), 2.24–2.09 (m, 2 H), 1.59–1.45 (m, 1 H), 1.23
(t, J = 7.2 Hz, 3 H), 0.75 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.6, 170.5, 140.1, 129.0 (2 C), 128.0 (2 C),
126.9, 65.9, 64.7, 61.4, 60.8, 52.8, 48.4, 34.2, 27.7, 13.9, 13.3 ppm.
IR (KBr): ν = 3542, 3371, 3106, 3085, 3059, 3028, 2979, 2936, 2870,
˜
1745, 1724, 1602, 1583, 1496, 1454, 1366, 1260, 1200, 1095, 1052,
869, 751, 702 cm–1. HRMS (ESI): calcd. for C18H24O5 [M + Na]+
343.1516, found 343.1516. HPLC (IC column, n-heptane/iPrOH =
95:5, λ = 210 nm, flow rate = 1.0 mLmin–1): tR = 31.3 (major),
26.1 (minor) min; 93%ee.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20334
/KAP1
Date: 31-05-12 17:26:10
Pages: 7
M. Remesˇ, J. Veselý
SHORT COMMUNICATION
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Received: March 16, 2012
[18] CCDC-870730 (for 7a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20334
/KAP1
Date: 31-05-12 17:26:10
Pages: 7
Functionalized Cyclopentane Derivatives via Conjugate Addition/α-Alkylation
Enantioselective Domino Reactions
ˇ
M. Remes, J. Veselý* ........................ 1–7
Highly Enantioselective Organocatalytic
Formation of Functionalized Cyclopen-
tane Derivatives via Tandem Conjugate
Addition/α-Alkylation of Enals
Chiral 1,1,2,3-tetrasubstituted cyclopent-
anes were easily synthesized under mild
and simple conditions from α,β-unsatu-
rated aldehydes and dialkyl 2-haloethyl-
malonates in good yields with high dia-
stereoselectivities and enantioselectivities.
Keywords: Organocatalysis / Domino reac-
tions / Cyclopentanes / Amines / Michael
addition
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