Organocatalyzed cyclopropanation of α-substituted α,β-unsaturated aldehydes: Enantioselective synthesis of cyclopropanes bearing a chiral quaternary center

Article abstract of DOI:10.1002/chem.201000334

An enantioselective cyclopropanation of α-substituted α,β-unsaturated aldehydes with bromomalonate has been successfully developed through a domino Michael/a-alkylation strategy. The method allows the efficient formation of cyclopropanes bearing a quaternary carbon stereocenter at the a-position of the aldehydes by using iminium/enamine catalysis and gives a nice extension on the organocatalytic cyclopropanation of bromomalonate and α β-unsaturated aldehydes previously reported by other groups. Very good yields (up to 81%) and enantioselectivities (up to 97% ee) have been obtained. The optically active cyclopropane derivatives are of high synthetic interest as useful targets for further elaboration into more complex structures. 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim aldehydes, cyclopropanes, domino reactions, organocatalysis, quaternary stereocenters.

Full text of DOI:10.1002/chem.201000334

FULL PAPER
DOI: 10.1002/chem.201000334
Organocatalyzed Cyclopropanation of a-Substituted a,b-Unsaturated
Aldehydes: Enantioselective Synthesis of Cyclopropanes Bearing a Chiral
Quaternary Center
Vincent Terrasson,[a] Arie van der Lee,[b] Renata Marcia de Figueiredo,*[a] and
Jean Marc Campagne*[a]
Abstract: An enantioselective cyclo-
propanation of a-substituted a,b-unsa-
turated aldehydes with bromomalonate
has been successfully developed
through a domino Michael/a-alkylation
strategy. The method allows the effi-
cient formation of cyclopropanes bear-
ing a quaternary carbon stereocenter at
the a-position of the aldehydes by
using iminium/enamine catalysis and
gives a nice extension on the organoca-
talytic cyclopropanation of bromomalo-
nate and a,b-unsaturated aldehydes
previously reported by other groups.
Very good yields (up to 81%) and
enantioselectivities (up to 97% ee)
have been obtained. The optically
active cyclopropane derivatives are of
high synthetic interest as useful targets
for further elaboration into more com-
plex structures.
Keywords: aldehydes
·
cyclopro-
panes · domino reactions · organo-
catalysis · quaternary stereocenters
Introduction
thetic groupsꢀ interest and inspired new asymmetric routes
allowing to their stereocontrolled construction.[3] Neverthe-
less, in the field of organocatalysis,[4,5] none of such studies
have yet been able to establish the synthesis of cyclopro-
panes in which the stereogenic carbon at the a-position of
the aldehydes involves a chiral quaternary center.[6] Al-
though syntheses of these unique strained rings which are
useful targets for further elaboration into more complex
structures are well documented,[7] the a,b-difunctionalization
of a-substituted a,b-unsaturated enals by chiral aminocatal-
ysis is still unexplored. Indeed, in this special case, very slug-
gish enamine activation rates or even inert capacities are
generally observed for secondary aminocatalysts which usu-
ally results in a complete absence of enantiocontrol at the
a-position.[8] Breakthrough findings on this goal were re-
cently reported by Melchiorre and co-workers in which pri-
mary amines derived from cinchona alkaloids were em-
ployed as catalysts for the organocascade intermolecular
aryl-amination and thio-amination of a-substituted a,b-unsa-
turated aldehydes.[9]
ꢀ
Amongst the most relevant transformations for carbon
carbon bond-formation, asymmetric construction of quater-
nary stereocenters represents a real challenging and exciting
area for which new procedures are particularly demand-
ing.[1,2] As part of our ongoing work on total synthesis of
complex natural products and organocatalysis, we were
looking to combine organocatalysis with a-substituted a,b-
unsaturated aldehydes for the synthesis of cyclopropanes
bearing a carbon center with four different carbon substitu-
ents. Over the years, cyclopropanes have gained many syn-
[a] Dr. V. Terrasson, Dr. R. Marcia de Figueiredo,
Prof. Dr. J. M. Campagne
Institut Charles Gerhardt Montpellier, UMR 5253 CNRS-UM2-
UM1-ENSCM
Ecole Nationale Supꢁrieure de Chimie, 8 Rue de lꢀEcole Normale
34296 Montpellier Cedex 5 (France)
Fax : (+33)4-6714-4322
E-mail: renata.marcia_de_figueiredo@enscm.fr
In this paper, we report the potential of commercially
available Jørgensen–Hayashi catalyst I[10] to guide enantiose-
lective cyclopropanations with a-substituted a,b-unsaturated
aldehydes and bromomalonate 2 that has an ambiphilic
function (Scheme 1). Before starting our studies, we specu-
lated whether the ability of I to generate iminium/enamine
intermediates could control first, a Michael-type conjugated
jean-marc.campagne@enscm.fr
[b] Dr. A. van der Lee+
Institut Europꢁen des Membranes, UMR 5635 CNRS-UM2
Place Eugꢂne Bataillon, 34095 Montpellier Cedex 5 (France)
[+] X-ray structure analysis
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000334.
Chem. Eur. J. 2010, 16, 7875 – 7880
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7875

Table 1. Optimization of the reaction conditions for the cyclopropanation
addition of bromomalonate 2 to the b-position of the unsa-
turated aldehyde (iminium catalysis) and then, an intramo-
lecular enamine-based a-alkylation reaction in an enantio-
controlled way to construct the quaternary carbon.
of aldehyde 1a with bromomalonate 2.[a]
Entry Cat. I
[mol%]
Additive
[equiv]
Solvent
t
Yield[b]
ee[c]
[%]
[h] [%]
1
2
10
–
EtOH
CHCl3
EtOH
EtOH
21 <20
67
rac
22
rac
79
10
10
–
Et3N (1)
Et3N (1)
Et3N (1)
propylene oxide EtOH
(5)
15
12
7
65
75
78
50
3[d]
4
5
10
48
Scheme 1. Targeted chiral cyclopropanes from a-substituted a,b-unsatu-
rated enals.
6
7
10
10
2,6-lutidine (5)
N-Me-imidazole EtOH
EtOH
36
5
38[e]
55
94
91
(5)
8
9
10
10
20
10
10
10
20
20
2,6-lutidine (3)
2,6-lutidine (1)
pyridine (5)
2,6-lutidine (5)
2,6-lutidine (5)
2,6-lutidine (5)
2,6-lutidine (3)
EtOH
EtOH
EtOH
CH2Cl2
THF
120
120
48
72
48 <20
60
91
70
91
–
Results and Discussion
24[e]
45
10[f]
11
12
13
14
15
Based on these assumptions, our investigations started by
using aldehyde 1a as a model compound in order to explore
the viability of an enantioselective cyclopropanation. In a
first experiment, the reaction of aldehyde 1a with bromo-
malonate 2, in the presence of 10 mol% of organocatalyst I
in ethanol,[11] lead to the desired cyclopropane 3a in a grati-
fying 67% ee, albeit in low yield (<20%) (Table 1, entry 1).
It is noteworthy that longer reaction times block the catalyt-
ic cycle due to the alkylation of the organocatalyst.[12]
Moving to the Et3N/I catalytic system, previously reported
for the cyclopropanation of a,b-unsaturated aldehydes,
proved to be poorly effective in our case.[5] This combination
dramatically decreases the enantioselection of the reaction
even under slow addition techniques (syringe pump)
(Table 1, entries 2–3). These observations prompted us to
surmise that, under the presence of this base, the cyclopro-
panation might occur via another mechanism which is not
driven by the organocatalyst (Scheme 2). Indeed, in the ab-
sence of organocatalyst I, Et3N is able to promote a racemic
cyclopropanation (Table 1, entry 4).
n.r.
–
CH3CN 48
EtOH
15
72
75
92
92
91
144
3
N-Me-imidazole EtOH
(5)
[a] Experimental conditions: To a solution of aldehyde 1a (0.68 mmol)
and cat. I (0.07 mmol or 0.14 mmol) in solvent (2.5 mL) at room tempera-
ture were added bromomalonate 2 (0.57 mmol) and additive. The mix-
ture was stirred over the time (t) and the cyclopropane 3a was purified
via column chromatography. [b] Yield of isolated product. [c] Determined
by chiral HPLC. [d] Syringe pump addition over 8 h of a pre-mixed mix-
ture of 2 and Et3N. [e] Low conversion of starting materials. [f] Pyridine
in CH2Cl2 or THF allows to unidentified side products.
Based on these preliminary results, we hypothesized
whether a base is crucial or only an acid scavenger could
allow the transformation without loss in enantioselectivity.
To validate this proposal, the potential of simple or sterical-
ly hindered mild bases was investigated. Moreover, such ad-
ditives might prevent alkylation of the catalyst and thus
allow our cyclopropanation in an enantioselective manner.
Propylene oxide proved to be a
good additive promoter and cy-
clopropane 3a was isolated in
50% yield and 79% ee
(Table 1, entry 5).[13] Moving to
2,6-lutidine or N-methyl imida-
zole, we were delighted to ob-
serve that high levels of enan-
tioselection (up to 94% ee)
could be reached in satisfactory
yields (Table 1, entries 6–7).
Reducing lutidineꢀs loading re-
sulted in a deleterious effect on
the enantioselectivity and reac-
tion rate (Table 1, entries 8–9).
We have also evaluated the ca-
pacity of pyridine to participate
to the transformation. With this
Scheme 2. Rational about the mechanism of the cyclopropanation via organocatalysis and via Et3N.
latter as additive, compound 3a
7876
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7875 – 7880

Organocatalyzed Cyclopropanation
FULL PAPER
Table 2. Substrate scope of organocatalytic cyclopropanation.
was isolated in an excellent 91% ee, nevertheless, the yield
was modest and unidentified side products were also formed
(Table 1, entry 10). At this point, a brief examination of the
solvent has been undertaken. CH2Cl2, THF or CH3CN gave
no reaction or only traces of the desired cyclopropanes,
however, high enantioselectivity could be observed in
CH3CN (Table 1, entries 11–13).
Upon these observations, we have established that in our
enantioselective cyclopropanation the best compromise be-
tween enantioselectivity and yield was reached with 20
mol% I[14] in ethanol[11] at room temperature. Either with
2,6-lutidine or N-methyl imidazole, cyclopropane 3a was iso-
lated in 72% yield, 92% ee and 75% yield, 91% ee, respec-
tively (Table 1, entries 14 and 15).[15] It should be empha-
sized that the rate acceleration for the cyclopropanation ob-
served with N-methyl imidazole was impressive (144 vs. 3 h,
Table 1, entries 14 and 15).
The experiments that explored the scope of this organoca-
talytic cyclopropanation are summarized in Table 2. Alde-
hydes 1 were synthesized by using the Pihko methylena-
tion.[16] In general, all reactions were very clean, especially
when 2,6-lutidine has been used as additive, and the cyclo-
propanes were obtained in high yields and enantioselectivi-
ties (up to 97% ee) under the previously optimized condi-
tions.[17] Different alkyl groups at the a-position of the alde-
hyde (R=Me, Et, Bu, Bn and iPr) were well tolerated
(Table 2, entries 1–5).[18,19] The more sterically encumbered
iPr substituent allowed to a slight decrease in the ee
(Table 2, entry 4). An ester-substituted side chain at the a-
position can also participate to the transformation with an
excellent 97% ee and 66% yield (Table 2, entry 6). The
same was observed when the alkyl side chain was replaced
by a hydrogen (Table 2, entry 7).
Entry Product
Conditions[a]
t
Yield[b]
ee[c]
[%]
[h] [%]
A
B
144 72
92
91
3
75
1
A
B
144 78
72
>95
3
96[e]
2
3
4
5
6
7
A
B
144 77
72
82
91
4
A
B
144 35[d]
43
79
86
7
A
B
144 65
58
94
97
6
A
B
144 66
52
97
7
91[e]
A
144 81
85[e]
[a] Experimental conditions: A: 2,6-Lutidine (3 equiv) and catalyst I
(20 mol%); B: N-Methylimidazole (5 equiv) and catalyst I (20 mol%).
[b] Isolated yields after column chromatography. [c] Determined by
chiral HPLC. [d] By NMR, only 40% conversion of starting material was
detected. [e] The ee value could be determined after conversion of 3b, 3 f
and 3g to the corresponding a,b-unsaturated ester (see Supporting Infor-
mation).
Conclusion
In summary, we have developed an efficient diphenylproli-
nol trimethylsilyl ether I mediated enantioselective cyclo-
propanation of a-substituted a,b-unsaturated aldehydes,
which involves easily prepared aldehydes 1a–g and commer-
cially available bromomalonate 2. To the best of our knowl-
edge, in the field of secondary-amine organocatalysts, this is
the first example in which a quaternary stereocenter in the
a-position of the aldehyde moiety is created in an enantio-
controlled pathway affording cyclopropanes. The lower en-
amine activation or even inert capacity which is commonly
observed with a,b-disubstituted a,b-unsaturated aldehydes is
a longstanding problem related to secondary amino cata-
lysts.[9] Nevertheless, by iminium/enamine catalysis with I,
the rapid access of cyclopropanes has been attained via a
domino Michael/a-alkylation reaction in high yields and
enantioselectivities (up to 97% ee). At the present stage,
the success of the protocol relies on the use of a-substituted
a,b-unsaturated aldehydes in which the a-substituents are
an alkyl or hydrogen group.[19] As illustrated in Scheme 3,
synthetically attractive applications can arise from products
Scheme 3. a) NaBH3CN, AcOH, THF, 08C!RT, overnight, 99%; b) (S)-
1-phenylethanamine, NaBH3CN, AcOH, THF, 08C!RT, overnight,
85%; c) NaClO2, NaH2PO4, tBuOH/H2O, 2-methyl-2-butene; RT, over-
night, 96%.
Chem. Eur. J. 2010, 16, 7875 – 7880
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7877

R. M. de Figueiredo, J. M. Campagne et al.
m/z (%): 306 (20), 305 (100) [M+H]+; HRMS: m/z: calcd for C17H21O5:
305.1389; found: 305.1377 [M+H]+.
3. In order to determine the stereochemical outcome of the
domino cyclopropanation, single crystals were obtained
from lactone 5a, and the absolute configuration was deter-
mined by X-ray analysis to be 2S,3R, thus confirming the R
stereochemistry for compounds 3 (Figure 1).[20] Future work
within the group is aimed at expanding this concept to other
asymmetric reactions (e.g., a,b-disubstituted unsaturated al-
dehydes) as well as to use the isolated cyclopropanes in
order to prepare more elaborated scaffolds.
Cyclopropane 3b: 2,6-Lutidine: 78% yield, N-methylimidazole: 72%
yield; colorless oil; Rf =0.20 (pentane/Et2O 9:1); [a]2D5 =ꢀ9.7 (c=1.13,
CHCl3); HPLC (after derivatization to 8b (see Supporting Information):
CHIRALCEL OD-H (250ꢅ4.6 mm ID) n-hexane/iPrOH 99:1; flow rate:
1.0 mLminꢀ1, 258C, l=254 nm, tmajor =8.81, tminor =12.17 min); 1H NMR
(400 MHz, CDCl3): d=9.26 (s, 1H), 4.29–4.19 (m, 4H), 2.09 (d, J=
5.6 Hz, 1H), 1.89 (d, J=5.6 Hz, 1H), 1.35 (s, 3H), 1.29 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=198.2, 167.2, 166.2, 62.2, 62.1, 42.2, 38.2,
24.2, 14.0, 13.9, 12.5 ppm; IR (film): n˜ =2983, 2940, 1731, 1448, 1370,
1333, 1231, 1110, 1020, 960, 862 cmꢀ1; MS (ESI): m/z (%): 301 (40), 275
(10), 230 (15), 229 (100) [M+H]+; HRMS: m/z: calcd for C11H17O5:
229.1076; found: 229.1075 [M+H]+.
Cyclopropane 3c: 2,6-Lutidine: 77% yield, N-methylimidazole: 72%
yield; colorless oil; Rf =0.30 (pentane/Et2O 9:1); [a]2D5 =ꢀ5.4 (c=1.115,
CHCl3); HPLC (CHIRALCEL OJ (250ꢅ4.6 mm ID) n-hexane/iPrOH
99.5:0.5; flow rate: 1.0 mLminꢀ1, 258C, l=200 nm, tmajor =10.26, tminor
=
12.65 min); 1H NMR (400 MHz, CDCl3): d=9.18 (s, 1H), 4.24–4.13 (m,
4H), 1.96 (m, 2H), 1.81 (d, J=5.6 Hz, 1H), 1.56 (m, 1H), 1.24 (m, 6H),
0.92 ppm (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=197.9,
167.0, 166.6, 62.2, 62.1, 43.7, 42.3, 23.0, 19.9, 14.0, 13.9, 11.5 ppm; IR
(film): n˜ =2981, 2870, 1793, 1730, 1469, 1369, 1277, 1251, 1218, 1111,
1026 cmꢀ1; MS (ESI): m/z (%): 470 (10), 244 (15), 243 (100) [M+H]+,
197 (10); HRMS: m/z: calcd for C12H19O5: 243.1232; found: 243.1228
[M+H]+.
Figure 1. X-ray crystal structure of lactone 5a.[20]
Experimental Section
Cyclopropane 3d: 2,6-lutidine: 35% yield (conversion of the starting ma-
terial: 40%), N-methyl imidazole: 43% yield; colorless oil; Rf =0.35
(pentane/Et2O 9:1); [a]2D5 =ꢀ25.6 (c=0.975, CHCl3); HPLC (CHIRAL-
CEL OJ (250ꢅ4.6 mm ID) n-hexane/iPrOH 99.5:0.5; flow rate:
1.0 mLminꢀ1, 258C, l=200 nm, tmajor =8.11, tminor =9.15 min); 1H NMR
(400 MHz, CDCl3): d=9.54 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.12 (q, J=
7.2 Hz, 2H), 1.94 (d, J=5.2 Hz, 1H), 1.77 (h, J=7.0 Hz, 1H), 1.66 (d, J=
5.2 Hz, 1H), 1.25 (t, J=7.2 Hz, 3H), 1.22–1.18 (m, 6H), 1.08 ppm (d, J=
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 198.1, 167.0, 166.8, 62.2,
61.9, 46.5, 43.2, 28.2, 23.2, 19.7, 19.1, 14.0, 13.9 ppm; IR (film): n˜ =2979,
General methods: Commercial reagents were used without purification.
Reactions were carried out in round-bottom flasks equipped with a mag-
netic stirring bar. TLC analysis of all reactions was performed on silica
gel 60 F254 TLC plates (using 2,4-dinitrophenylhydrazine stain for alde-
hydes and phosphomolybdic acid for the other compounds). Flash chro-
matography was carried out on silica gel 60 A (35–70 mm). Melting points
were determined with a Bꢄchi Melting Point B-540 unit. FT-IR spectra
were recorded with a Perkin–Elmer Spectrum 1000. 1H and 13C NMR
spectra were recorded with a Bruker Ultra shield 400 plus. 1H chemical
shifts are reported in delta (d) units in parts per million (ppm) relative to
the singlet at 7.26 ppm for CDCl3 (residual CHCl3). 13C chemical shifts
are reported in ppm relative to the central line of the triplet at 77.0 ppm
for CDCl3. Splitting patterns are designated as s, singlet; d, doublet; t,
triplet; q, quartet; h, heptet; m, multiplet; and br, broad and combina-
tions thereof. Optical rotations were measured with a Perkin–Elmer 341
polarometer. Low resolutions mass spectra were recorded on a Waters
QTof-I spectrometer using electrospray ionization. High resolution mass
spectra were obtained using the mass spectrometers operated by the Lab-
oratoire de Mesure Physique of University Montpellier 2.
2877, 1793, 1731, 1466, 1370, 1310, 1223, 1130, 1106, 1021, 926, 859 cmꢀ1
;
MS (ESI): m/z (%): 625 (20), 624 (40), 403 (20), 402 (100), 257 (40)
[M+H]+; HRMS: m/z: calcd for C13H21O5: 257.1389; found: 257.1382
[M+H]+.
Cyclopropane 3e: 2,6-Lutidine: 65% yield, N-methylimidazole: 58%
yield; colorless oil; Rf =0.40 (pentane/Et2O 9:1); [a]2D5 =+6.5 (c=1.075,
CHCl3); HPLC (CHIRALCEL OJ (250ꢅ4.6 mm ID) n-hexane/iPrOH
99.5:0.5; flow rate: 1.0 mLminꢀ1, 258C, l=200 nm, tmajor =7.24, tminor
=
8.87 min); 1H NMR (400 MHz, CDCl3): d=9.23 (s, 1H), 4.25–4.16 (m,
4H), 1.94–2.01 (m, 2H), 1.84 (d, J=5.6 Hz, 1H), 1.56–1.49 (m, 1H),
1.41–1.23 (m, 10H), 0.87 ppm (t, J=7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=198.1, 167.0, 166.6, 62.1, 62.0, 42.8, 42.3, 29.3, 26.3, 23.1, 22.7,
14.0, 13.9, 13.8 ppm; IR (film): n˜ =2961, 2873, 1731, 1466, 1370, 1301,
1240, 1201, 1107, 1020, 908, 862 cmꢀ1; MS (ESI): m/z (%): 640 (20), 639
(50), 272 (15), 271 (100) [M+H]+; HRMS: m/z: calcd for C14H23O5:
271.1545; found: 271.1537 [M+H]+.
General procedure for the organocatalyzed asymmetric cyclopropana-
tion: The a-methylene aldehydes (1a–f) were prepared according to the
procedure described by Pihko.[16] To a solution of the a-substituted a,b-
unsaturated aldehydes (1a–g; 0.684 mmol, 1.2 equiv) and organocatalyst
(I; 37.0 mg, 0.114 mmol, 20 mol%) in EtOH (2.5 mL) were successively
added the additive (2,6-lutidine: 199 mL, 1.71 mmol, 3.0 equiv or N-meth-
ylimidazole: 227 mL, 2.85 mmol, 5.0 equiv) and diethyl bromomalonate
(2; 97.0 mL, 0.57 mmol, 1.0 equiv). The reaction mixture was stirred at
room temperature for the indicated time (see Table 2) and the solvent
was removed. The residue was purified by flash chromatography on silica
gel (pentane/Et2O) to afford the desired cyclopropane 3a–g.
Cyclopropane 3 f: 2,6-Lutidine: 66% yield, N-methylimidazole: 52%
yield; colorless oil; Rf =0.20 (pentane/Et2O 4:1); [a]2D5 =+16.6 (c=1.205,
CHCl3); HPLC (after derivatization to 8 f (see Supporting Information):
CHIRALCEL OJ (250ꢅ4.6 mm ID) n-hexane/iPrOH 99.5:0.5; flow rate:
1.0 mLminꢀ1, 258C, l=200 nm, tminor =33.39, tmajor =62.76 min); 1H NMR
(400 MHz, CDCl3): d=9.11 (s, 1H), 4.27–4.16 (m, 4H), 3.64 (s, 3H),
2.53–2.45 (m, 1H), 2.38–2.30 (m, 1H), 2.27–2.19 (m, 1H), 2.03 (d, J=
5.6 Hz, 1H), 1.97–1.89 (m, 2H), 1.26 ppm (m, 6H); 13C NMR (100 MHz,
CDCl3): d=197.2, 172.8, 166.7, 166.1, 62.4, 62.3, 51.6, 42.1, 41.7, 31.3,
23.0, 22.0, 13.9, 13.8 ppm; IR (film): n˜ =2985, 1731, 1440, 1370, 1235,
1108, 1019, 913, 861, 838 cmꢀ1; MS (ESI): m/z (%): 302 (20), 301 (100)
[M+H]+; HRMS: m/z: calcd for C14H21O7: 301.1287; found: 301.1284
[M+H]+.
Cyclopropane 3a: 2,6-Lutidine: 72% yield, N-methylimidazole: 75%
yield; colorless oil; Rf =0.25 (pentane/Et2O 9:1); [a]2D5 =+21.6 (c=1.205,
CHCl3); HPLC (CHIRALCEL OD-H (250ꢅ4.6 mm ID) n-hexane/
iPrOH 99:1; flow rate: 1.0 mLminꢀ1
t
,
258C, l=254 nm,
tmajor =10.92,
minor =13.85 min); 1H NMR (400 MHz, CDCl3): d=9.26 (s, 1H), 7.29–
7.16 (m, 5H), 4.25–4.06 (m, 4H), 3.44 (d, J=15.4 Hz, 1H), 3.01 (d, J=
15.4 Hz, 1H), 2.09 (d, J=5.4 Hz, 1H), 2.05 (d, J=5.4 Hz, 1H), 1.29 (t,
J=7.2 Hz, 3H), 1.19 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=197.6, 166.7, 166.4, 137.7, 128.7 (2C), 128.4 (2C), 126.4, 62.3,
62.2, 42.8, 42.4, 31.5, 23.5, 13.9, 13.8 ppm; IR (film): n˜ =3030, 2983, 2938,
1731, 1497, 1454, 1370, 1252, 1183, 1108, 1017, 863, 699 cmꢀ1; MS (ESI):
Cyclopropane 3g: 2,6-Lutidine: 81% yield; colorless oil; Rf =0.30 (pen-
tane/Et2O 4:1); [a]2D5 =ꢀ83.3 (c=1.14, CHCl3); HPLC (after derivatiza-
tion to 8g (see Supporting Information): CHIRALCEL OD-H (250ꢅ
7878
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7875 – 7880

Organocatalyzed Cyclopropanation
FULL PAPER
4.6 mm ID) n-hexane/iPrOH 99:1; flow rate: 1.0 mLminꢀ1, 258C, l=
254 nm, tmajor =8.68, tminor =10.12 min); 1H NMR (400 MHz, CDCl3): d=
9.30 (d, J=4.4 Hz, 1H), 4.27–4.16 (m, 4H), 2.73 (ddd, J=4.4, 6.9, 8.8 Hz,
1H), 2.06 (dd, J=5.0, 6.9 Hz, 1H), 1.80 ppm (dd, J=5.0, 8.8 Hz, 1H),
1.27 (t, J=7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=196.3, 167.8,
165.8, 62.4, 62.1, 37.7, 34.7, 19.2, 13.9 ppm (2C); IR (film): n˜ =2984, 1731,
1447, 1371, 1316, 1267, 1202, 1134, 1065, 1023, 862 cmꢀ1; MS (ESI): m/z
(%): 301 (10), 215 (100) [M+H]+; HRMS: m/z: calcd for C10H15O5:
215.0919; found: 215.0919 [M+H]+. Data are in accordance with previ-
ously reported analysis.[12a]
1:1); m.p. 70–728C; [a]2D5 =+5.8 (c=0.685, CHCl3); 1H NMR (400 MHz,
CDCl3): d=10.12 (brs, 1H), 7.28–7.25 (m, 4H), 7.24–7.18 (m, 1H), 4.23–
4.08 (m, 4H), 3.41 (d, J=15.2 Hz, 1H), 2.94 (d, J=15.2 Hz, 1H), 2.18 (d,
J=5.2 Hz, 1H), 1.92 (d, J=5.2 Hz, 1H), 1.25–1.18 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=176.4, 166.8, 166.7, 137.9, 128.6 (2C),
128.3 (2C), 126.4, 62.4, 61.9, 41.8, 37.6, 33.2, 23.7, 13.9, 13.7 ppm; IR
(KBr): n˜ =3227, 1721, 1499, 1434, 1397, 1371, 1263, 1233, 1132, 1015, 856,
734, 699 cmꢀ1; MS (ESI): m/z (%): 640 (50), 639 (100) [2MꢀH]ꢀ, 433
(20), 320 (30), 319 (95) [MꢀH]ꢀ; HRMS: m/z: calcd for C17H19O6:
319.1182; found: 319.1186 [MꢀH]ꢀ.
Procedure for the sequential reduction/lactonization
Synthesis of lactone 5a: To a solution of the cyclopropane 3a (100 mg,
0.329 mmol, 1.0 equiv) in THF (2.0 mL) at 08C were added AcOH
(0.4 mL) and NaBH3CN (37.0 mg, 0.494 mmol, 1.5 equiv). The mixture
was slowly warmed to room temperature and stirred overnight. The reac-
tion was quenched by addition of a saturated aqueous NaHCO3 solution
(10 mL). The aqueous phase was extracted with Et2O (3ꢅ10 mL) and the
organic layers were combined, dried (MgSO4), and evaporated. The resi-
due was purified by flash chromatography on silica gel (pentane/EtOAc
4:1) to afford the desired lactone 5a (85 mg, 0.327 mmol, 99%). White
solid; Rf =0.50 (pentane/EtOAc 4:1); m.p. 50–528C; [a]2D5 =ꢀ120.4 (c=
1.37, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.36–7.26 (m, 3H), 7.19–
7.16 (m, 2H), 4.37–4.29 (m, 2H), 4.17 (d, J=9.2 Hz, 1H), 4.05 (d, J=
9.2 Hz, 1H), 3.08 (d, JAB =15.0 Hz, 1H), 3.03 (d, JAB =15.0 Hz, 1H), 2.24
(d, J=4.8 Hz, 1H), 1.51 (d, J=4.8 Hz, 1H), 1.35 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=171.2, 166.0, 136.4, 128.9 (2C), 128.5
(2C), 127.2, 70.4, 62.2, 39.9, 34.7, 34.1, 24.7, 14.2 ppm; IR (KBr): n˜ =2980,
1782, 1713, 1451, 1402, 1376, 1343, 1293, 1271, 1208, 1199, 1096, 1023,
712 cmꢀ1; MS (ESI): m/z (%): 522 (10), 521 (25) [2M+H]+, 320 (10), 262
(20), 261 (100) [M+H]+; HRMS: m/z: calcd for C15H17O4: 261.1127;
found: 261.1120 [M+H]+.
Acknowledgements
This work was made possible by financial support from the Agence Na-
tionale de la Recherche (ANR) Program “Chimie et Procꢁdꢁs pour le
Dꢁveloppement Durable (CP2D)”.
[1] For reviews on the creation of quaternary carbon stereocenters, see:
a) E. J. Corey, A. Guzman-Perez, Angew. Chem. 1998, 110, 402–
415; Angew. Chem. Int. Ed. 1998, 37, 388–401; b) J. Christoffers, A.
Mann, Angew. Chem. 2001, 113, 4725–4732; Angew. Chem. Int. Ed.
2001, 40, 4591–4597; c) I. Denissova, L. Barriault, Tetrahedron 2003,
59, 10105–10146; d) D. J. Ramon, M. Yus, Curr. Org. Chem. 2004, 8,
149–183; e) J. Christoffers, A. Baro, Quaternary Stereocenters—
Challenges and Solutions for Organic Synthesis, Wiley-VCH, Wein-
heim, 2005; f) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347,
1473–1482; g) B. M. Trost, C. Jiang, Synthesis 2006, 369–396;
h) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2007,
5969–5994.
Procedure for the sequential reductive amination/lactamization
Synthesis of lactame 6a: To a solution of the cyclopropane 3a (100 mg,
0.329 mmol, 1.0 equiv) in THF (2.0 mL) at room temperature were
added (S)-(a)-methylbenzylamine (64.0 mL, 60.0 mg, 0.494 mmol,
1.5 equiv) and AcOH (28.0 mL, 30.0 mg, 0.494 mmol, 1.5 equiv). The mix-
ture was stirred for 15 min, then cooled to 08C and NaBH3CN (27.0 mg,
0.428 mmol, 1.3 equiv) was added. The solution was slowly warmed to
room temperature and stirred overnight. The reaction was quenched by
addition of a saturated aqueous NaHCO3 solution (10 mL). The aqueous
phase was extracted with Et2O (3ꢅ10 mL) and the organic layers were
combined, dried (MgSO4), and evaporated. The residue was purified by
flash chromatography on silica gel (pentane/EtOAc 4:1) to afford the de-
sired lactame 6a (102 mg, 0.281 mmol, 85%). Colorless oil; Rf =0.20
(pentane/EtOAc 4:1); [a]2D5 =ꢀ99.1 (c=1.15, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.30–7.19 (m, 6H), 7.16–7.13 (m, 4H), 5.46 (q, J=
7.2 Hz, 1H), 4.31 (dq, J=1.3 and 7.0 Hz, 2H), 3.32 (d, J=10.4 Hz, 1H),
2.97 (d, JAB =14.8 Hz, 1H), 2.91 (d, JAB =14.8 Hz, 1H), 2.77 (d, J=
10.4 Hz, 1H), 1.96 (d, J=4.8 Hz, 1H), 1.48 (d, J=7.2 Hz, 3H), 1.33 (t,
J=7.0 Hz, 3H), 0.97 ppm (d, J=4.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 169.5, 167.6, 140.2, 137.5, 128.7 (2C), 128.5 (2C), 128.4 (2C),
127.5, 126.8 (3C), 61.6, 48.4, 46.5, 36.8, 35.8, 33.7, 23.8, 15.6, 14.3 ppm; IR
(film): n˜ =2976, 2931, 2873, 1682, 1603, 1495, 1453, 1417, 1377, 1350,
1271, 1223, 1177, 1099, 1049, 1024, 699 cmꢀ1; MS (ESI): m/z (%): 728
(10), 727 (30) [2M+H]+, 365 (30), 364 (100) [M+H]+; HRMS: m/z: calcd
for C23H26NO3: 364.1913; found: 364.1909 [M+H]+.
Procedure for the Pinnick oxidation[21] of the aldehyde 3a: To a solution
of the aldehyde 3a (100 mg, 0.329 mmol) in tBuOH (6.0 mL) and 2-
methyl-2-butene (1.6 mL) at room temperature was added dropwise a so-
lution of sodium chlorite (275 mg, 3.04 mmol) and sodium dihydrogen-
phosphate (275 mg, 2.29 mmol) in water (2.75 mL). The reaction mixture
was stirred overnight, and then volatile solvents were evaporated. The
residue was dissolved in water (10 mL) and the aqueous phase was ex-
tracted with pentane (2ꢅ10 mL). The aqueous solution was acidified to
pH 1 with concentrated HCl and extracted with Et2O (3ꢅ20 mL). The or-
ganic layers were combined, washed with a saturated aqueous NaCl solu-
tion (5 mL), dried (MgSO4), and evaporated to afford the desired acid 7a
(101 mg, 0.316 mmol, 96%) as a white solid. Rf =0.35 (pentane/EtOAc
[2] Review on organocatalytic approaches for creation of quaternary
carbon stereocenters, see: M. Bella, T. Gasperi, Synthesis 2009,
1583–1614.
[3] For excellent reviews on stereoselective cyclopropanation, see: a) H.
Pellissier, Tetrahedron 2008, 64, 7041–7095; b) H. Lebel, J. F. Mar-
coux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103, 977–1050
and references therein. For a recent highlight, see: R. S. Goudreau,
A. B. Charette, Angew. Chem. 2010, 122, 496–498; Angew. Chem.
Int. Ed. 2010, 49, 486–488.
[4] For asymmetric organocatalyzed cyclopropanation by catalyst-
bound ylides, see: a) V. K. Aggarwal, E. Alonso, G. Fang, M. Fer-
rara, G. Hynd, M. Porcelloni, Angew. Chem. 2001, 113, 1482–1485;
Angew. Chem. Int. Ed. 2001, 40, 1433–1436; b) C. D. Papageorgiou,
M. A. Cubillo de Dios, S. V. Ley, M. J. Gaunt, Angew. Chem. 2004,
116, 4741–4744; Angew. Chem. Int. Ed. 2004, 43, 4641–4644. For
enantioselective cyclopropanation upon olefin activation by indo-
line-2-carboxylic acid catalysts, see: c) R. K. Kunz, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 2005, 127, 3240–3241; d) A. Hartikka, P. I.
Arvidsson, J. Org. Chem. 2007, 72, 5874–5877; e) A. Hartikka, A. T.
´
Slꢆsarczyk, P. I. Arvidsson, Tetrahedron: Asymmetry 2007, 18, 1403–
1409. For cinchona alkaloids as catalysts, see: f) S. H. McCooey, T.
McCabe, S. J. Connon, J. Org. Chem. 2006, 71, 7494–7497; g) S.
Kojima, M. Suzuki, A. Watanabe, K. Ohkata, Tetrahedron Lett.
2006, 47, 9061–9065; h) C. C. C. Johansson, N. Bremeyer, S. V. Ley,
D. R. Owen, S. C. Smith, M. J. Gaunt, Angew. Chem. 2006, 118,
6170–6175; Angew. Chem. Int. Ed. 2006, 45, 6024–6028; i) J. Lv, J.
Zhang, Z. Lin, Y. Wang, Chem. Eur. J. 2009, 15, 972–979. For (ꢁ)-
proline as catalyst with bromonitroalkanes, see: J.-M. Zhang, Z.-P.
Hu, S.-Q. Zhao, M. Yan, Tetrahedron 2009, 65, 802–806.
[5] For the first organocatalytic enantioselective cyclopropanations of
a,b-unsaturated aldehydes with diphenylprolinol derivatives as cata-
lyst, see: a) R. Rios, H. Sundꢁn, J. Vesely, G.-L. Zhao, P. Dziedzic,
A. Cꢆrdova, Adv. Synth. Catal. 2007, 349, 1028–1032; b) H. Xie, L.
Zu, H. Li, J. Wang, W. Wang, J. Am. Chem. Soc. 2007, 129, 10886–
10894; c) I. Ibrahem, G.-L. Zhao, R. Rios, J. Vesely, H. Sundꢁn, P.
Dziedzic, A. Cꢆrdova, Chem. Eur. J. 2008, 14, 7867–7879; d) X.
Chem. Eur. J. 2010, 16, 7875 – 7880
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7879

R. M. de Figueiredo, J. M. Campagne et al.
Companyꢆ, A.-N. Alba, F. Cꢇrdenas, A. Moyano, R. Rios, Eur. J.
Org. Chem. 2009, 3075–3080. For a recent iminium/enamine cyclo-
propanation in aqueous medium, see: e) U. Uria, J. L. Vicario, D.
Badꢈa, L. Carrillo, E. Reyes, A. Pesquera, Synthesis 2010, 701–713.
[6] For an example of enantioselective nitrocyclopropanation of a,b-un-
saturated aldehydes a-cyanoimides by bifunctional thiourea as cata-
lyst, see: T. Inokuma, S. Sakamoto, Y. Takemoto, Synthesis 2009,
1627–1630.
[7] For selected reviews, see: a) J. Salaun, Chem. Rev. 1989, 89, 1247–
1270; b) A.-H. Li, L.-X. Dai, V. K. Aggarwal, Chem. Rev. 1997, 97,
2341–2372; c) A. Pfaltz in Comprehensive Asymmetric Catalysis
(Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidel-
berg, 1999, pp. 513–538; d) R. Faust, Angew. Chem. 2001, 113,
2312–2314; Angew. Chem. Int. Ed. 2001, 40, 2251–2253; e) H.-U.
Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151–1196; f) C. A.
Carson, M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051–3060.
[14] Diphenylprolinol tert-butyldimethylsilyl ether was also able to pro-
mote the reaction with good catalytic efficiency albeit at the expense
of reactivity.
[15] Contrary to 2,6-lutidine, in which longer reaction time is required
for reaching good yield without any decomposition or side reactions,
the cyclopropanation is much faster with N-methyl imidazole (5 h
vs. 5 d, respectively). Nevertheless, care has to be taken with this
latter as an additive since the transformation of 3a into compound
4a (15% yield), together with
other byproducts, can be ob-
served after several hours of reac-
tion. Intriguingly, 4a showed to
be relatively robust and could be
isolated after column chromatog-
raphy.
[16] a) A. Erkkilꢉ, P. M. Pihko, J. Org. Chem. 2006, 71, 2538–2541; b) A.
Erkkilꢉ, P. M. Pihko, Eur. J. Org. Chem. 2007, 4205–4216.
[17] With 10 mol% catalyst I loading and N-methyl imidazole (5 equiv),
high ee values are obtained, however, yields are slightly lower.
[18] In the case of R=Bu, we have observed, after 18 h of reaction with
N-methyl imidazole, the transformation of cyclopropane 3e into
products 4e as two diastereoisomers (see Supporting Information).
These compounds are easily separated by column chromatography
and, surprisingly, are relatively stable for few days at ꢀ188C.
[8] For an example where diarylprolinol trimethylsilyl ether [Ar=3,5-
(CF3)2Ph] was used to forge a quaternary stereocenter under en-
ACHTUNGTRENNUNGamine catalysis to the synthesis of a,a-chlorofluoro carbonyl com-
pounds, see: K. Shibatomi, H. Yamamoto, Angew. Chem. 2008, 120,
5880–5882; Angew. Chem. Int. Ed. 2008, 47, 5796–5798.
[9] P. Galzerano, F. Pesciaioli, A. Mazzanti, G. Bartoli, P. Melchiorre,
Angew. Chem. 2009, 121, 8032–8034; Angew. Chem. Int. Ed. 2009,
48, 7892–7894.
[10] a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen,
Angew. Chem. 2005, 117, 804–807; Angew. Chem. Int. Ed. 2005, 44,
794–797; b) M. Marigo, D. Fielenbach, A. Braunton, A. Kjasgærd,
K. A. Jørgensen, Angew. Chem. 2005, 117, 3769–3772; Angew.
Chem. Int. Ed. 2005, 44, 3703–3706; c) Y. Hayashi, H. Gotoh, T.
Hayashi, M. Shoji, Angew. Chem. 2005, 117, 4284–4287; Angew.
Chem. Int. Ed. 2005, 44, 4212–4215.
[11] Our screening of the reaction solvent has been started with EtOH
based on Jørgensen and co-workers studies on the first organocata-
lytic enantioselective addition of malonates to aromatic a,b-unsatu-
rated aldehydes: S. Brandau, A. Landa, J. Franzꢁn, M. Marigo,
K. A. Jørgensen, Angew. Chem. 2006, 118, 4411–4415; Angew.
Chem. Int. Ed. 2006, 45, 4305–4309.
[12] This is particularly problematic using amine-promoted a-alkylation
of aldehydes in the presence of alkylhalides. For an intramolecular
a-alkylation of halo-aldehydes, see: a) N. Vignola, B. List, J. Am.
Chem. Soc. 2004, 126, 450–451. For combination of organocatalysis
and metal-catalysis by SOMO activation of aldehydes radical, see:
b) D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77–80.
For excellent highlights on the a-alkylation of aldehydes, see: c) P.
Melchiorre, Angew. Chem. 2009, 121, 1386–1389; Angew. Chem. Int.
Ed. 2009, 48, 1360–1363; d) A.-N. Alba, M. Viciano, R. Rios, Chem-
CatChem 2009, 1, 437–439.
[19] Diels–Alder reaction of a-branched acroleins by primary amine cat-
alysis has been described previously. In this case, only alkylated
ones have also been used: a) K. Ishihara, K. Nakano, J. Am. Chem.
Soc. 2005, 127, 10504–10505; b) T. Kano, Y. Tanaka, K. Osawa, T.
Yurino, K. Maruoka, Chem. Commun. 2009, 1956–1958. Concerning
a-aryl substituents, we observed that a-phenyl acrolein was very un-
stable under our conditions. For similar observation, see: c) H. M. L.
Davies, X. Dai, J. Org. Chem. 2005, 70, 6680–6684.
[20] CCDC-758189 (5a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[21] B. S. Bal, W. E. Childers, Jr., H. W. Pinnick, Tetrahedron 1981, 37,
2091–2096.
[13] a) X. Moreau, J. M. Campagne, J. Organomet. Chem. 2003, 687,
322–326; b) Z. L. Tong, P. Gao, H. B. Deng, L. Zhang, P.-F. Xu,
H. B. Zhai, Synlett 2008, 3239–3241.
Received: February 8, 2010
Published online: May 28, 2010
7880
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7875 – 7880