A new stereoselective synthesis of cyclopropanes containing quaternary stereocentres via organocatalytic michael addition to vinyl selenones

Article abstract of DOI:10.1002/adsc.200900222

A novel organocatalytic method for the stereoselective synthesis of highly substituted cyclopropanes is reported. The Michael adducts, generated through the addition of α-substituted cyanoacetates to easily accessible vinyl selenones catalyzed by a bifunc

Full text of DOI:10.1002/adsc.200900222

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DOI: 10.1002/adsc.200900222
A New Stereoselective Synthesis of Cyclopropanes Containing
Quaternary Stereocentres via Organocatalytic Michael Addition
to Vinyl Selenones
Francesca Marini,a,* Silvia Sternativo,a Francesca Del Verme,a Lorenzo Testaferri,a
and Marcello Tieccoa
a
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Universitꢀ degli Studi di Perugia,
Via del Liceo 1, 06123 Perugia, Italy
Fax : (+39) 075-585-5116; e-mail: marini@unipg.it
Received: April 3, 2009; Revised: June 12, 2009; Published online: August 5, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900222.
Abstract: A novel organocatalytic method for the
stereoselective synthesis of highly substituted cyclo-
propanes is reported. The Michael adducts, generat-
ed through the addition of a-substituted cyanoace-
tates to easily accessible vinyl selenones catalyzed
by a bifunctional ureidic catalyst, smoothly cyclize
by intramolecular alkylation induced by a de-eth-
and chiral catalysts. Thus, asymmetric Simmons–
Smith reactions or cyclopropanations of olefins by
metal-catalyzed decomposition of diazo compounds
have been successfully explored.[3] Very recently sig-
nificant advances have also been made in the devel-
opment of organocatalytic cyclopropanations based
on Michael initiated ring closure reactions (MIRC).[3,4]
In these processes, the addition of an ylide or an eno-
late containing a good leaving group to an electrophil-
ic alkene generates an anionic intermediate, which
easily undergoes a ring closure reaction by intramo-
lecular alkylation. During our studies on the asym-
metric Michael addition of a-substituted cyanoace-
tates to vinyl selenones catalyzed by ureidic or thiour-
eidic bifunctional catalysts, we observed that the dia-
stereomeric mixture of Michael adducts 4aA and 5aA
affords the cyclopropane 6aA as a single isomer by
simple treatment with KCN in DMF (Scheme 1).[5]
We explained this process as a Krapcho-type de-
ethoxycarbonylation, followed by an intramolecular
ACHTUNGTRENNUNGoxycarbonylation process. The one-pot sequence
generates cyclopropanes bearing adjacent tertiary
and quaternary stereocentres as single Z-isomers in
moderate to high yields and good enantiomeric ex-
cesses.
Keywords: asymmetric organocatalysis; cyclopro-
panes; Michael addition; quaternary stereocenters;
selenones
The cyclopropane ring is the basic structural motif of nucleophilic substitution of the selenonyl moiety by
a wide range of natural products and biologically the enolate intermediate. The excellent leaving group
active compounds, such as conformationally restricted properties of this species have been already exploited
amino acids or peptides, enzyme inhibitors and thera- for other synthetically useful inter- or intramolecular
peutic agents with antipsychotic, antifungal, antibacte- substitutions.[5,6] This first result prompted us to study
rial, antitumoral or antiviral activities.[1] Furthermore, the sequence in detail and develop a novel one-pot
the three-membered ring, due to its strong angular
strain and great ring-opening ability, is a recognized
intermediate in the construction of complex molecu-
lar skeletons.[2] On these grounds, the development of
simple and efficient methods for the stereocontrolled
preparation of variously substituted cyclopropanes re-
mains an interesting task for synthetic chemists. In
the last years great attention has been focused on the
identification of new asymmetric methodologies
based on readily available achiral starting materials Scheme 1. Formation of the cyclopropane 6aA.
Adv. Synth. Catal. 2009, 351, 1801 – 1806
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Francesca Marini et al.
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the enantioselectivity of the sequence. The commer-
cial ethyl a-phenylcyanoacetate 2a and the (E)-vinyl
selenone 3A[6j] were used as the model substrates in
the presence of the commercial 1f or easily accessible
1a–e chiral urea or thiourea derivatives reported in
Figure 1, which have recently emerged as efficient
catalysts for a broad range of highly enantioselective
Michael additions.[10] These bifunctional catalysts,
bearing an hydrogen-bond donor group besides a
basic site on a chiral scaffold, accelerate the 1,4-addi-
tions and improve yields and stereoselectivities by si-
multaneous activation of both the Michael acceptor
and the carbon nucleophile. The results of the experi-
ments confirmed the efficiency of the ureidic catalyst
1a, which gave in toluene the best results in terms of
yield, diastereo- and enantioselectivity (Table 1).
Figure 1. Ureidic or thioureidic catalysts 1a–f.
The stereoinduction is slightly affected by the ester
size with a decrement of the enantioselectivity as the
procedure for the enantioselective preparation of sub- size of the ester increases (Table 1, entries 1, 5, 6).
stituted cyclopropanes containing adjacent all carbon When the temperature was raised at 508C the reac-
quaternary and tertiary stereocentres starting from tion time was shortened at 48 h, albeit with a loss of
readily available vinyl selenones.[7] Some catalytic ap- selectivity (Table 1, entry 4). It is interesting to point
proaches for the stereoselective construction of such out that an attempt to effect the addition of 2a on the
cyclopropanes are available in the literature[3,4f,k,8] in- phenyl (E)-2-phenylethenyl sulfone, structurally relat-
cluding methods for the preparation of nitrile-substi- ed to 3A, failed indicating a different behaviour be-
tuted cyclopropanes,[9] but only few of them employ tween the sulphur[11,12] and the selenium[5] containing
organocatalysts.
compounds.
Preliminary experiments were carried out in order
After the optimization of the addition step, the ring
to examine the addition step which is responsible of formation was examined. The crude mixture of 4aA
Table 1. Selected results for the Michael addition of 2a–c to vinyl selenone 3A.[a]
Entry
Catalyst
R
Solvent
Time [h]
Yield [%][b]
4:5[c]
ee [%][d]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2b
2c
2a
2a
2a
2a
2a
Et
Et
Et
Et
Bn
i-Pr
Et
Et
Et
Et
Et
toluene
CH2Cl2
THF
90
94
78
73
99
87
97
–
81
21
<20
40
85:15
78:22
74:26
82:18
79:21
77:23
–
78:22
68:32
68:32
42:58
80
56
54
64
64
66
–
144
144
48[e]
90
90
72
120
144
144
144
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
68[f]
58[f]
56[f]
50[f]
9
10
11
[a]
Catalysts 1a–f (0.02 mmol, 20 mol%) and 3A (0.1 mmol) were dissolved in the indicated solvent (0.4 mL), then 4 ꢂ MS
(20 mg) and 2a–c (0.15 mmol, 1.5 equiv.) were added at room temperature.
[b]
[c]
[d]
Yields refer to the mixture of diastereoisomers 4 and 5.
1
Determined by H NMR analysis after passing through a plug of silica gel.
The ee values, determined by chiral HPLC analysis, refer to the adducts 4. The minor diastereomers 5 have ee lower than
20%.
[e]
[f]
The reaction was carried out at 508C.
The opposite enantiomer was obtained.
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A New Stereoselective Synthesis of Cyclopropanes Containing Quaternary Stereocentres
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Table 2. Optimization of the cyclization step.
Entry Reaction Conditions[a]
Yield ee
[%][b] [%][c]
Scheme 2. Cyclization of adducts 4dA and 5dA.
1
2
3
4
5
6
7
8
LiCl, HMPA, 808C, 2 h
65
[37][e]
66
66
–
–
–
LiCl, toluene/HMPA 1:1, 1008C, 24 h 31[d]
propane 6aA with an enantiomeric excess which is
almost identical to that of the major adduct 4aA and
seems not affected by the presence of the poorly
enantioenriched minor adduct 5aA. This observation
suggests that under these conditions only 4aA is
quantitatively converted into the cyclic compound
6aA.
Additional experiments performed on the chroma-
tographically separated adducts, generated from cya-
noacetate 2d and the vinyl selenone 3A, confirmed
this hypothesis. In fact, the cyclization of the major
adduct 4dA proceeds smoothly, while the conversion
of the minor isomer 5dA generates 6dA in a very
poor yield (28% yield) together with unidentified by-
products (Scheme 2). As demonstrated by the
1H NMR analyses of the crude reaction mixtures in
both cases the E-cyclopropane was not present.
The one-pot process, in which the addition, de-
ethoxycarbonylation and cyclization steps are carried
out sequentially and without isolation of the inter-
mediates, was applied to a range of b-aryl-substituted
vinyl selenones containing electron-withdrawing or
LiCl, DMSO, 1608C, 2 h
LiCl, toluene, 12-crown-4, 808C, 24 h [48][e]
NaBr, DMSO, 1008C, 5 h
aq. NaOH, MeOH, r.t., 24 h
EtONa/EtOH, 08C!r.t., 2 h
EtONa/EtOH, 08C!r.t., 2 h
[51][e]
[f]
–
54
41
76
64 g]
[a]
1a (0.02 mmol, 20 mol%) and 3A (0.1 mmol) were dis-
solved in toluene (0.4 mL), then 4 ꢂ MS (20 mg) and 2a
(0.15 mmol, 1.5 equiv.) were added at room temperature.
After 90 h the toluene (if necessary) was removed under
reduced pressure and the indicated reagents and solvent
were added.
[b]
[c]
[d]
Determined on isolated 6aA.
The ee values were determined by chiral HPLC analysis.
Products of nucleophilic substitution of the selenonyl
group by chloride ion were also formed.
The alkene 7 was recovered as the main product with the
yield reported in parentheses.
A complex mixture of products was formed.
The opposite enantiomer was obtained by using catalyst
1c.
[e]
[f]
[g]
and 5aA, obtained by simple removal of the toluene electron-donating groups at different positions of the
under vacuum, was submitted to treatment with LiCl phenyl ring. Different a-aryl cyanoacetates were also
or NaBr in a polar aprotic solvent (Krapcho-type pro- used as the Michael donor. Methods A and B were
tocols)[13] or with an aqueous solution of NaOH in both used for the cyclization. The cyclopropanes 6
MeOH[14] (Table 2). An alternative treatment with were generated in moderate to good yields, complete
NaOEt in EtOH was also attempted. Only in the diastereoselectivity and good enantioselectivity
presence of LiCl in HMPA (method A) and NaOEt (Table 3 entries 1–8). The results obtained with
in EtOH (method B) was the cyclopropane 6aA EtONa in EtOH are particularly interesting. In fact,
formed in good yields.
this strategy provide higher enantiomeric excesses
The stereochemical assignment of 6aA[15] allows us and comparable yields than those with the Krapcho
to assign the 3S absolute configuration at the tertiary protocol which involves the hazardous HMPA. The b-
stereocenter of the major adduct 4aA. Reasonably, alkyl-substituted vinyl selenone 3G was also exam-
the LiCl or the NaOEt, respectively, attack the ethyl ined as the Michael acceptor in the presence of the a-
or the carbonyl group of the ester moiety forming a arylcyanoacetates 2a and 2f. The addition step pro-
nitrile enolate which promotes the 3-exo-tet ring clo- ceeded smoothly and at a faster rate than in the pres-
sure reaction. The process is completely diastereose- ence of the corresponding aryl compounds. Only the
lective, giving the sole Z-isomer with good enantio- treatment with LiCl in HMPA gave the Z-2-alkyl-sub-
meric excesses (Table 2, entries 1 and 7). In the other stituted cyclopropanes 6aG and 6fG[16] in high yields
conditions more complex reaction mixtures, contain- and moderate selectivity (Table 3, entries 9–11).
ing products generated by intermolecular nucleophilic
Further experiments demonstrated that the pres-
substitution of the selenonyl group or considerable ence of an a-aryl group on the starting cyanoacetate 2
amounts of the elimination product 7, were obtained. is essential for the de-ethoxycarbonylation of the ad-
The cyclization with method B generates the cyclo- ducts 4. In fact, the reactions between the a-allylcya-
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Table 3. Formation of the cyclopropanes 6.
Method A[a]
Yield [%][c] ee [%][d]
Method B[b]
Entry
Ar
R
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2d
2e
2a
2a
2f
Ph
Ph
Ph
Ph
Ph
Ph
p-Br-C6H4
p-F-C6H4
Ph
3A
3B
3C
3D
3E
3F
3A
3D
3G
3G
3G
Ph
(ꢀ)-6aA
(ꢀ)-6aB
(ꢀ)-6aC
(ꢀ)-6aD
(ꢀ)-6aE
(ꢀ)-6aF
(ꢀ)-6dA
(ꢀ)-6eD
(ꢀ)-6aG
(ꢀ)-6aG
(ꢀ)-6fG
65
64
51
40
55
56
52
42
81
90[e]
91
66
66
68
72
74
48
61
74
48
54
52
54
40
58
40
65
45
50
66
18
–
76
74
76
72
74
68
70
66
54
–
p-MeO-C6H4
p-Me-C6H4
p-Cl-C6H4
m-F-C6H4
o-Me-C6H4
Ph
p-Cl-C6H4
C6H13
C6H13
9
10
11
Ph
p-MeO-C6H4
C6H13
–
–
[a]
Method A: LiCl (2.5 equiv.) in HMPA.
[b]
[c]
[d]
[e]
Method B: EtONa (2.5 equiv.) in EtOH.
Determined on isolated compounds.
Determined by chiral HPLC analysis.
Reaction carried out at ꢀ208C for 144 h.
noacetate and 3A under the experimental conditions rhodium-catalyzed cyclopropanation of electron-rich
described in Table 3 did not afford any cyclopropana- olefins by 2-diazo-2-phenylacetonitrile, which selec-
tion product.
tively affords enantioenriched E-nitrile-substituted cy-
The stereochemical assignment of the cyclopro- clopropanes.[9a] Moreover, it expands the use of privi-
panes 6aA and 6fG[15,16] suggests that in the presence leged organocatalysts in the field of selenium chemis-
of 1a the Michael addition occurs preferentially on try and opens attractive prospects for up to now
the Re face of the b-substituted unsaturated selen- scarcely explored organocatalytic selenium-based
ACHTUNGTRENNUNGones. Thus, the facial selectivity is opposite to that ob- transformations.
served in similar reactions with Michael acceptors
containing nitro or carbonyl groups and urea and
thio
tives.[17]
The presence of the non-planar selenonyl group
should modify the spatial arrangement of the ternary
complex formed by the catalyst, the Michael acceptor
and the nucleophile. In conclusion, we have described
the first organocatalytic synthesis of enantioenriched
cyclopropanes starting from b-substituted vinyl selen-
ACHTUNGTRENNUNGurea-substituted 9-epi-dihydroquinine deriva-
Experimental Section
General Procedure for the One-Pot Synthesis of
Enantioenriched Z-Cyclopropanes 6
In an ordinary vial equipped with a Teflon-coated stir bar,
catalyst 1a (0.04 mmol, 20 mol%) and the selenones 3A–F[19]
or 3G[20] (0.2 mmol) were dissolved in undistilled toluene
(0.8 mL) with 20 mg of 4 ꢂ MS. The a-substituted cyanoace-
tate 2a, d–f (0.3 mmol, 1.5 equiv.) were added at room tem-
perature (15–188C) and the resulting mixtures were stirred
in air for 48–144 h. The solvent was removed under reduced
ACHTUNGTRENNUNGones. The key step of this procedure is the Michael
addition of a-aryl-substituted cyanoacetates to b-sub-
stituted vinyl selenones,[18] followed by a de-ethoxy-
carbonylation and a ring closure reaction. In most pressure and the crude reaction mixtures were submitted to
cyclization following method A or B.
cases, the reactions can be carried out with compara-
ble or even better results using EtONa in EtOH
which avoids the use of HMPA with advantages for
health and environment. The practical one-pot se-
quence, which occurs with complete diastereoselectiv-
ity and good enantioselectivity, is based on the pecu-
liar properties of the selenonyl moiety which acts
both as an electron-withdrawing group during the ad-
dition step and as a leaving group during the cycliza-
Method A: the crude reaction mixtures were dissolved in
HMPA (1.5 mL). Then LiCl (0.5 mmol) was added and the
mixtures were stirred at 808C for 2–4 h. The reactions were
quenched with water (20 mL) and extracted with diethyl
ether (3ꢃ10 mL). The organic layers were washed with
brine (10 mL), dried over Na2SO4, filtered and concentrated
under vacuum. The residues were purified by flash chroma-
tography to yield the cyclopropanes 6.
Method B: the crude residues were dissolved in EtOH
tion. Our procedure nicely complements the recent (1 mL) and a solution of EtONa (0.5 mmol) in EtOH
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A New Stereoselective Synthesis of Cyclopropanes Containing Quaternary Stereocentres
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(1 mL) was added at 08C. The resulting solutions were al-
lowed to warm to room temperature and stirred for 1–4 h.
The reaction mixtures were quenched with water (20 mL)
and extracted with diethyl ether (3ꢃ10 mL). The organic
layers were washed with brine (10 mL), dried over Na2SO4,
filtered and concentrated under vacuum. The residues were
purified by flash chromatography to yield the cyclopropanes
6.
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Acknowledgements
Financial support from MIUR, National Projects PRIN 2007,
University of Perugia and Consorzio CINMPIS, Bari is
gratefully acknowledged.
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[15] The relative configuration of 6aA was assigned by com-
1
parison of the H NMR spectrum with that reported in
boxylic esters through an alternative cascade process
which involves a Michael addition, a proton exchange
and a cyclization by displacement of the PhSeO2
group.[6j,l,m] The organocatalytic version of this process
merits investigations. These are currently under way in
our laboratory.
the literature (ref.[15a]). The absolute configuration was
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1
pound 6fG was assigned by comparison of its H NMR
spectrum and specific optical rotation, respectively,
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1806
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Adv. Synth. Catal. 2009, 351, 1801 – 1806