Formation of functionalized cyclopentenes via catalytic asymmetric [3+2] cycloaddition of acrylamides with an allenoate promoted by dipeptide-derived phosphines

Article abstract of DOI:10.1055/s-0030-1260460

Acrylamides derived from 3,5-dimethyl-1H-pyrazole are employed in the asymmetric [3+2] cycloaddition with the allenoate, tert-butyl buta-2,3-dienoate, for the first time. d-Threonine-l-tert-leucine-based bifucntional phosphines are effective catalysts for

Full text of DOI:10.1055/s-0030-1260460

PAPER
1859
Formation of Functionalized Cyclopentenes via Catalytic Asymmetric [3+2]
Cycloaddition of Acrylamides with an Allenoate Promoted by Dipeptide-
Derived Phosphines
F
ormation of Func
i
tionaliz
a
ed Cyclope
o
ntenes yu Han, Su-Xi Wang, Fangrui Zhong, Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute, National University of Singapore, Science Drive 3,
Singapore 117543, Republic of Singapore
Fax +6567791691; E-mail: chmlyx@nus.edu.sg
Received 18 March 2011
donors in the bifunctional phosphine catalysts, reinforcing
Abstract: Acrylamides derived from 3,5-dimethyl-1H-pyrazole are
the hydrogen bonding interactions between the carbonyl
group and the amide N–H moiety. Moreover, the presence
of the two methyl groups on the pyrazole ring was antici-
employed in the asymmetric [3+2] cycloaddition with the allenoate,
tert-butyl buta-2,3-dienoate, for the first time. D-Threonine-L-tert-
leucine-based bifucntional phosphines are effective catalysts for the
above reactions, affording regiospecific [3+2]-annulation products pated to introduce steric hindrance, thus facilitating the
in excellent yields and with moderate enantioselectivities.
formation of sterically less demanding regioisomers
(Figure 1). Herein, we describe the first asymmetric acryl-
amide–allene [3+2] cycloaddition mediated by dipeptide-
derived bifunctional phosphines; the reactions proceed ef-
ficiently at room temperature, and functionalized cyclo-
pentenes with a quaternary stereogenic center5 were
obtained in high yields and with moderate enantioselec-
tivities.
Key words: [3+2] cycloaddition, chiral phosphines, amino acids,
bifunctional phosphine catalysts
Phosphine-mediated [3+2] cycloaddition between elec-
tron-deficient alkenes and allenes or alkynes is a powerful
approach for the construction of functionalized cyclo-
pentenes;1 these structural motifs are often found in natu-
ral products and medicinally important agents.2
Significant progress has been made in phosphine-cata-
lyzed enantioselective [3+2] cycloadditions.3 The C2 syn-
thons employed for such annulations were mainly enones,
and occasionally acrylates and imines. To the best of our
knowledge, the direct application of acrylamides in the
phosphine-catalyzed asymmetric [3+2] cycloaddition has
not been reported. Thus, it is highly desirable to develop a
synthetic variant in which acrylamides can be used direct-
ly in such a cyclization.
amino acid
backbone
Ph
Ph
+P
O–
O
N
H
H
Ot-Bu
*
O
N
R1
N
R2
regioselectivity
control
R
N
potential hydrogen
bonding interactions
induce steric
hindrance
Figure 1 Working hypothesis
We have previously reported novel types of chiral phos-
phines based on simple dipeptides, and demonstrated that
such catalysts could promote effectively the enantioselec-
tive [3+2] cycloaddition of allenoates with acrylates, af-
fording functionalized cyclopentenes in high yields and
with excellent enantioselectivities.3i Given the high effi-
ciency and reactivity of our catalysts, we reasoned that
their application in the catalytic asymmetric [3+2] cy-
cloaddition between acrylamides and allenes may be fea-
sible. For the design of an efficient [3+2]-annulation
reaction, the allenoate, tert-butyl buta-2,3-dienoate (2) ap-
peared to be an excellent reaction component, since its ef-
fectiveness in inducing the formation of a-regioisomers
was demonstrated in our earlier studies.3i For the acryl-
amide substrates, we focused on 3,5-dimethyl-1H-pyra-
zole-derived acrylamides.4 The pyrazole nitrogen atoms
are expected to form hydrogen bonds with hydrogen bond
We chose the [3+2] cycloaddition between a-phenyl-sub-
stituted acrylamide 1a and allenoate 2 as a model reaction,
and investigated the catalytic effects of various phos-
phines derived from amino acids. The results are summa-
rized in Table 1. Given the success we achieved with
threonine-based catalytic systems,3i,5e,6 the threonine core
was incorporated into our catalytic systems. In all the ex-
amples examined, the corresponding a-regioisomers were
formed exclusively. L-Threonine-derived phosphine 4
promoted the reaction, but the enantioselectivity was very
poor (Table 1, entry 1). Combining L-threonine and D-va-
line led to a more effective catalytic system than that
based on L-threonine and L-valine (Table 1, entries 2 and
3). The thiourea–phosphine catalyst 7, however, was
found to be an extremely poor catalyst (Table 1, entry 4).
Introduction of a tert-leucine residue rendered further
improvement; when D-threonine-L-tert-leucine-derived
phosphine 8 or 9 was employed, the enantioselectivity
was improved to 49% (Table 1, entries 5 and 6). The pres-
ence of a carbamate moiety at the terminus of the dipep-
tide was found to be important, since catalyst 10
SYNTHESIS 2011, No. 12, pp 1859–1864
x
x.
x
x
.
2
0
1
1
Advanced online publication: 05.05.2011
DOI: 10.1055/s-0030-1260460; Art ID: C30611SS
© Georg Thieme Verlag Stuttgart · New York

1860
X. Han et al.
PAPER
containing the more hindered carbamate group proved to The scope of the reaction was next investigated (Table 2).
be superior, affording the desired cycloaddition product in Different a-aryl-substituted acrylamides were examined
86% yield and with 66% ee (Table 1, entry 7). Carrying in this cyclization, and a-regioisomeric products were ob-
out the reaction in different solvents and lowering the re- tained exclusively in good to excellent yields in each case.
action temperature did not result in any further improve- Satisfactory enantioselectivities were obtained for the
ments (Table 1, entries 8–16). It is noteworthy that the pyrazole-derived acrylamides with para-substituted aryl
dipeptide-based phosphine catalysts described here are groups at their a-positions (Table 2, entries 2–4). The
easily tunable, allowing specific interactions with differ- acrylamides containing meta- or ortho-substituted aro-
ent substrates. Hence, their application in a wide array of matic rings turned out to be less suitable substrates
asymmetric organic reactions is well anticipated.
(Table 2, entries 5 and 6), and moderate enantioselectivity
Table 1 [3+2] Cycloaddition of Acrylamide 1a with Allenoate 2 Catalyzed by Amino Acid Derived Phosphinesa
O
O
N
N
N
catalyst (10 mol%)
solvent, 24 h
N
+
Ph
CO2t-Bu
Ph
3a
CO2t-Bu
OTBDPS
NH
1a
2
OTBS
OTBDPS
OTBS
NH
OTBS
NH
OTBS
PPh2
O
NH
NH
PPh2
PPh2
OTBS
PPh2
PPh2
PPh2
O
NH
NH
O
O
O
NH
O
PPh2
NHBoc
NHBoc
NHBoc
NHBoc
S
NH
NHBoc
Cl
Cl
O
O
4
5
6
8
9
10
Cl
F3C
CF3
7
Entry
1
Catalyst
Solvent
Yield (%)b
ee (%)c
7
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
xylene
71
76
81
41
78
80
86
79
82
75
73
77
80
75
31
80
2
5
19
3
6
–39
–17
47
4d
5
7
8
6
9
49
7
10
10
10
10
10
10
10
10
10
10
66
8
41
9
43
10
11
12
13
14
15
16e
4-fluorotoluene
CH2Cl2
CHCl3
11
47
40
Et2O
58
THF
26
DMF
4
toluene
61
a Reaction conditions: 1a (0.05 mmol), 2 (0.075 mmol), catalyst (10 mol%), solvent (0.25 mL), r.t.
b Yield of isolated product.
c Determined by HPLC analysis on a chiral stationary phase.
d The reaction time was 48 h.
e The reaction was performed at –20 °C over 60 h.
Synthesis 2011, No. 12, 1859–1864 © Thieme Stuttgart · New York

PAPER
Formation of Functionalized Cyclopentenes
1861
was obtained when a naphthyl-substituted acrylamide was tions with different nucleophiles, such as alcohols,7
employed (Table 2, entry 7). Moreover, acrylamides with amines,8 and organometallic reagents.9 When cyclopen-
a-alkyl substituents could also be used, and up to 61% ee tene 3a was treated with sodium methoxide, the corre-
was attained (Table 2, entries 8 and 9). To account for the sponding methyl ester 11 was obtained in excellent yield
observed regiospecific formation of the a-isomer, we pro- (Scheme 1). The absolute configuration of 3a was deter-
pose that steric hindrance due to the presence of the bulky mined to be S by comparing the optical rotation value of
tert-butyl group on the allenoate and the 3,5-dimeth- 11 with literature data.3i
ylpyrazole moiety make formation of the g-isomer highly
O
O
N
unfavorable (Figure 2).
MeO
N
NaOMe
MeOH
(91%)
‡
Ph
11
Ph
3a
CO2t-Bu
CO2t-Bu
Ph
Si
Ph
O
O
Scheme 1 Derivatization of N-acylpyrazole-containing cyclopent-
ene 3a
H
O
Ph
N
H
Ph
O
In summary, we have utilized 3,5-dimethyl-1H-pyrazole-
derived acrylamides in asymmetric [3+2] cycloadditions
with an allenoate for the first time. The annulation reac-
tion was promoted effectively by dipeptide-derived phos-
phines, affording only the a-regioisomers in excellent
yields and moderate enantioselectivities. This is the first
example in which acrylamides are used directly in phos-
phine-catalyzed asymmetric [3+2]-cycloaddition reac-
tions. We are currently investigating the mechanistic
aspects of this novel reaction and are developing new cat-
alytic systems to further improve the enantioselectivities
of the reported reactions.
P
NH
Cl
Cl
Cl
O
O
O
N
N
steric interactions disfavor
formation of the γ-isomer
Figure 2 Suppression of formation of the g-isomer
The optically enriched functionalized cyclopentenes re-
All starting materials were obtained from commercial sources and
sulting from the [3+2] cycloadditions are useful synthetic were used without further purification unless otherwise stated. Tol-
uene, THF and Et2O were dried and distilled from sodium ben-
zophenone prior to use. CHCl3 and CH2Cl2 were distilled from
intermediates. In particular, the N-acylpyrazoles can be
converted readily into various acyl derivatives via reac-
Table 2 Asymmetric Allene–Acrylamide [3+2] Cycloadditions Catalyzed by Dipeptide-Derived Phosphine 10a
O
O
N
N
N
10 (10 mol%)
N
+
toluene, r.t., 20–48 h
R
CO2t-Bu
R
CO2t-Bu
1a–i
2
3a–i
Time (h)
24
Entry
Product (R)
Yield (%)b
ee (%)c
66
1
2
3
4
5
6
7
8
9
3a (Ph)
86
84
88
93
88
91
91
71
81
3b (4-BrC6H4)
3c (4-ClC6H4)
3d (4-PhC6H4)
3e (3-ClC6H4)
3f (2-FC6H4)
3g (2-naphthyl)
3h (Me)
24
60
24
60
20
62
24
44
20
36
24
56
48
47
3i (Bn)
48
61
a Reaction conditions: 1a–i (0.05 mmol), 2 (0.075 mmol), catalyst 10 (10 mol%), toluene (0.25 mL), r.t.
b Yield of isolated product.
c Determined by HPLC analysis on a chiral stationary phase.
Synthesis 2011, No. 12, 1859–1864 © Thieme Stuttgart · New York

1862
X. Han et al.
PAPER
CaH2 prior to use. All solvents used in reactions involving phospho-
rus-containing compounds were degassed using N2. Melting points
were determined using a Büchi B-540 melting point apparatus. Op-
tical rotations were measured using a Jasco DIP-1000 polarimeter.
1H and 13C NMR spectra were recorded on a Bruker ACF300 or
AMX500 (500 MHz) spectrometer. Chemical shifts are reported in
parts per million (ppm), and the residual solvent peak was used as
an internal reference: proton (CHCl3, d 7.26), carbon (CHCl3, d
77.0). Multiplicities are indicated as follows: s (singlet), d (doublet),
t (triplet), m (multiplet). Coupling constants are reported in hertz
(Hz). High-resolution mass spectra were obtained on a Finnigan/
MAT 95XL-T spectrometer. TLC was accomplished using Merck
pre-coated TLC plates (Merck 60 F254), and compounds were
made visual with UV light at 254 nm. Flash chromatographic sepa-
rations were performed on Merck 60 (0.040–0.063 mm) mesh silica
gel. Enantiomeric excesses were determined by HPLC analysis on
a chiral stationary phase. All the a-substituted acrylic acids were
prepared according to our previous reported method.3i Acrylamides
1a–g were prepared by reaction of the corresponding acids with ox-
alyl chloride and 3,5-dimethyl-1H-pyrazole in the presence of pyri-
dine in CH2Cl2;10 acrylamides 1h and 1i were prepared using
EDC·HCl, HOBt and 3,5-dimethyl-1H-pyrazole following the pro-
cedures reported in the literature.11
HPLC: 60% ee (Chiralcel IC-H, i-PrOH–hexane, 3:97, flow
rate = 0.5 mL/min, l = 254 nm): tR (major) = 11.2 min, tR (minor) =
12.5 min.
tert-Butyl (4S)-4-(4-Chlorophenyl)-4-[(3,5-dimethyl-1H-pyra-
zol-1-yl)carbonyl]cyclopent-1-ene-1-carboxylate (3c)
Yield: 17.6 mg (88%); white solid; mp 114.1–114.5 °C; [a]D
–49.0 (c 1.0, CHCl3).
26
=
1H NMR (300 MHz, CDCl3): d = 7.23–7.15 (m, 4 H), 6.60 (t, J = 2.0
Hz, 1 H), 5.78 (s, 1 H), 3.66–3.33 (m, 2 H), 3.27 (d, J = 16.5 Hz, 1
H), 3.06 (d, J = 19.4 Hz, 1 H), 2.52 (s, 3 H), 1.99 (s, 3 H), 1.48 (s, 9
H).
13C NMR (75 MHz, CDCl3): d = 174.0, 163.9, 151.3, 144.7, 143.4,
138.8, 135.4, 131.9, 128.3, 126.8, 80.5, 59.8, 44.8, 42.7, 28.1, 14.7,
13.8.
HRMS (ESI): m/z [M + Na]+ calcd for C22H25ClN2O3Na: 423.1446;
found: 423.1448.
HPLC: 60% ee (Chiralcel IC-H, i-PrOH–hexane, 5:95, flow
rate = 0.5 mL/min, l = 254 nm): tR (major) = 9.8 min, tR (minor) =
10.8 min.
tert-Butyl (4S)-4-(Biphenyl-4-yl)-4-[(3,5-dimethyl-1H-pyrazol-
1-yl)carbonyl]cyclopent-1-ene-1-carboxylate (3d)
Yield: 20.7 mg (93%); white solid; mp 135.6–136.0 °C; [a]D
–50.0 (c 0.9, CHCl3).
[3+2] Cycloaddition; General Procedure
26
=
To a flame-dried, round bottom flask were added catalyst 10 (4.2
mg, 0.005 mmol) and acrylamide 1 (0.05 mmol) under N2, followed
by the addition of anhyd toluene (0.25 mL). Allenoate 2 (11 mL,
0.075 mmol) was then added, and the mixture stirred at r.t. for a giv-
en period as specified in Table 2. Following completion of the reac-
tion the mixture was subjected directly to flash column
chromatographic separation using a mixture of hexane–EtOAc as
the eluent to afford cycloaddition products 3a–i.
1H NMR (500 MHz, CDCl3): d = 7.57 (t, J = 8.2 Hz, 2 H), 7.50 (t,
J = 14.5 Hz, 2 H), 7.42 (t, J = 19.5 Hz, 2 H), 7.39–7.31 (m, 3 H),
6.64 (t, J = 1.9 Hz, 1 H), 5.79 (s, 1 H), 3.71–3.61 (m, 2 H), 3.42 (d,
J = 17.6 Hz, 1 H), 3.21 (d, J = 19.0 Hz, 1 H), 2.56 (s, 3 H), 2.00 (s,
3 H), 1.50 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 174.5, 164.2, 151.1, 144.7, 144.0,
140.7, 139.1, 138.8, 135.6, 128.7, 127.1, 126.9, 126.8, 125.9, 110.4,
80.4, 60.1, 45.0, 42.8, 28.2, 14.8, 13.8.
tert-Butyl (4S)-4-[(3,5-Dimethyl-1H-pyrazol-1-yl)carbonyl]-4-
phenylcyclopent-1-ene-1-carboxylate (3a)
Yield: 15.7 mg (86%); white solid; mp 94.0–95.0 °C; [a]D26 = –47.2
(c 0.65, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C28H30N2O3Na: 465.2149;
found: 465.2149.
1H NMR (500 MHz, CDCl3): d = 7.26–7.17 (m, 4 H), 7.16–7.13 (m,
1 H), 6.61 (t, J = 1.9 Hz, 1 H), 5.77 (s, 1 H), 3.66–3.58 (m, 2 H),
3.37 (d, J = 16.4 Hz, 1 H), 3.14 (d, J = 19.0 Hz, 1 H), 2.54 (s, 3 H),
1.98 (s, 3 H), 1.49 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 174.6, 164.1, 150.9, 144.9, 144.6,
139.0, 135.5, 128.2, 126.1, 125.3, 110.2, 80.3, 60.3, 44.9, 42.7,
28.2, 14.7, 13.7.
HPLC: 62% ee (Chiralcel IC-H, i-PrOH–hexane, 5:95, flow
rate = 0.5 mL/min, l = 254 nm): tR (major) = 12.3 min, tR (minor) =
14.5 min.
tert-Butyl (4S)-4-(3-Chlorophenyl)-4-[(3,5-dimethyl-1H-pyra-
zol-1-yl)carbonyl]cyclopent-1-ene-1-carboxylate (3e)
Yield: 17.6 mg (88%); white solid; mp 98.8–99.5 °C; [a]D26 = –13.7
(c 0.9, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.26–7.25 (m, 1 H), 7.18–7.09 (m,
3 H), 6.60 (s, 1 H), 5.79 (s, 1 H), 3.64–3.57 (m, 2 H), 3.29 (d,
J = 17.7 Hz, 1 H), 3.11 (d, J = 19.6 Hz, 1 H), 2.54 (s, 3 H), 1.99 (s,
3 H), 1.49 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 173.8, 163.9, 151.3, 146.9, 144.7,
138.8, 135.4, 134.1, 129.4, 126.3, 125.7, 123.6, 110.4, 80.5, 60.1,
44.8, 42.7, 28.1, 14.7, 13.7.
HRMS (ESI): m/z [M + Na]+ calcd for C22H25ClN2O3Na: 423.1446;
found: 423.1450.
HRMS (ESI): m/z [M + Na]+ calcd for C22H26N2O3Na: 389.1836;
found: 389.1848.
HPLC: 66% ee (Chiralcel IC-H, i-PrOH–hexane, 5:95, flow
rate = 0.5 mL/min, l = 254 nm): tR (major) = 14.2 min, tR (minor) =
16.4 min.
tert-Butyl (4S)-4-(4-Bromophenyl)-4-[(3,5-dimethyl-1H-pyra-
zol-1-yl)carbonyl]cyclopent-1-ene-1-carboxylate (3b)
Yield: 18.7 mg (84%); white solid; mp 114.5–115.0 °C; [a]D
–54.7 (c 0.70, CHCl3).
26
=
1H NMR (500 MHz, CDCl3): d = 7.36 (d, J = 8.9 Hz, 2 H), 7.12 (d,
J = 8.8 Hz, 2 H), 6.59 (d, J = 2.6 Hz, 1 H), 5.78 (s, 1 H), 3.64–3.56
(m, 2 H), 3.30 (d, J = 17.1 Hz, 1 H), 3.08 (d, J = 18.9 Hz, 1 H), 2.52
(s, 3 H), 1.99 (s, 3 H), 1.48 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 173.9, 163.9, 151.3, 144.7, 144.0,
138.8, 135.5, 131.3, 127.2, 119.9, 110.4, 80.5, 59.9, 44.8, 42.7,
28.1, 14.7, 13.7.
HPLC: 44% ee (Chiralcel IC-H, i-PrOH–hexane, 5:95, flow
rate = 0.5 mL/min, l = 254 nm): tR (major) = 10.3 min, tR (minor) =
12.1 min.
tert-Butyl (4S)-4-[(3,5-Dimethyl-1H-pyrazol-1-yl)carbonyl]-4-
(2-fluorophenyl)cyclopent-1-ene-1-carboxylate (3f)
Yield: 17.5 mg (91%); yellow oil; [a]D26 = –37.2 (c 1.2, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.39–7.35 (m, 1 H), 7.16–7.07 (m,
2 H), 6.89–6.84 (m, 1 H), 6.63 (t, J = 1.9 Hz, 1 H), 5.77 (s, 1 H),
HRMS (ESI): m/z [M + Na]+ calcd for C22H25BrN2O3Na: 467.0941;
found: 467.0922.
Synthesis 2011, No. 12, 1859–1864 © Thieme Stuttgart · New York

PAPER
Formation of Functionalized Cyclopentenes
1863
3.72–3.57 (m, 2 H), 3.34 (d, J = 17.7 Hz, 1 H), 3.06 (d, J = 18.9 Hz,
1 H), 2.54 (s, 3 H), 1.91 (s, 3 H), 1.49 (s, 9 H).
3-tert-Butyl 1-Methyl (1S)-1-Phenylcyclopent-3-ene-1,3-dicar-
boxylate (11)
To a soln of 3a (73 mg, 0.2 mmol) in MeOH (2 mL) at 0 °C was add-
ed NaOMe (22 mg, 0.4 mmol) and the mixture stirred at r.t. for 1 h.
Next, the reaction was quenched by the addition of H2O (4 mL), and
the resulting mixture was extracted with Et2O (2 × 8 mL). The com-
bined organic extracts were washed with brine (6 mL) and dried
over Na2SO4. Purification by column chromatography (eluent: hex-
ane–EtOAc, 15:1) afforded diester 11.
13C NMR (125 MHz, CDCl3): d = 173.6, 164.0, 160.6, 158.8, 150.6,
144.4, 138.9, 133.0 (d, J = 13.7 Hz), 126.8 (d, J = 4.6 Hz), 123.7 (d,
J = 2.7 Hz), 115.2 (d, J = 22.8 Hz), 110.1, 80.5, 56.4, 44.0, 42.1,
28.2, 14.4, 13.6.
HRMS (ESI): m/z [M + Na]+ calcd for C22H25FN2O3Na: 407.1741;
found: 407.1747.
Yield: 55 mg (91%); white solid; mp 71.0–72.0 °C; [a]D26 = –24.0
HPLC: 36% ee (Chiralcel IC-H, i-PrOH–hexane, 5:95, flow
rate = 0.5 mL/min, l = 254 nm): tR (major) = 10.9 min, tR (minor) =
21.9 min.
(c 0.8, CHCl3) {Lit.3i [a]D26 = –35.2 (c 1.0, CHCl3)}.
1H NMR (500 MHz, CDCl3): d = 7.32–7.29 (m, 4 H), 7.26–7.23 (m,
1 H), 6.65 (s, 1 H), 3.66 (s, 3 H), 3.65–3.59 (m, 2 H), 3.03 (d,
J = 14.5 Hz, 1 H), 2.90 (d, J = 14.1 Hz, 1 H), 1.49 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 175.8, 163.9, 142.9, 139.7, 136.4,
128.5, 126.9, 126.4, 80.5, 58.2, 52.6, 43.4, 41.6, 28.1.
tert-Butyl (4S)-4-[(3,5-Dimethyl-1H-pyrazol-1-yl)carbonyl]-4-
(naphthalen-2-yl)cyclopent-1-ene-1-carboxylate (3g)
Yield: 18.9 mg (91%); white solid; mp 153.0–153.8 °C; [a]D
–45.9 (c 1.0, CHCl3).
26
=
1H NMR (500 MHz, CDCl3): d = 7.79–7.71 (m, 4 H), 7.45–7.39 (m,
3 H), 6.65 (t, J = 1.9 Hz, 1 H), 5.75 (s, 1 H), 3.73–3.45 (m, 2 H),
3.47 (d, J = 17.7 Hz, 1 H), 3.27 (d, J = 19.0 Hz, 1 H), 2.56 (s, 3 H),
1.92 (s, 3 H), 1.49 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 174.5, 164.1, 151.1, 144.6, 142.2,
139.0, 135.6, 133.4, 132.0, 128.0, 127.9, 127.4, 125.9, 125.5, 124.2,
123.8, 110.3, 80.4, 60.5, 44.9, 42.8, 28.2, 14.7, 13.7.
HRMS (ESI): m/z [M + Na]+ calcd for C18H22O4Na: 325.1410;
found: 325.1417.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
HRMS (ESI): m/z [M + Na]+ calcd for C26H28N2O3Na: 439.1992;
found: 439.2003.
Acknowledgment
We thank the National University of Singapore and the Ministry of
Education of Singapore (R-143-000-362-112) for generous finan-
cial support.
HPLC: 56% ee (Chiralcel IC-H, i-PrOH–hexane, 5:95, flow
rate = 0.5 mL/min, l = 254 nm): tR (major) = 12.3 min, tR (minor) =
14.0 min.
References
tert-Butyl (4S)-4-[(3,5-Dimethyl-1H-pyrazol-1-yl)carbonyl]-4-
methylcyclopent-1-ene-1-carboxylate (3h)
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Yield: 10.8 mg (71%); yellow oil; [a]D26 = +26.0 (c 0.3, CHCl3).
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HPLC: 47% ee (Chiralcel IC-H, i-PrOH–hexane, 5:95, flow
rate = 0.5 mL/min, l = 254 nm): tR (major) = 10.8 min, tR (minor) =
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tert-Butyl (4R)-4-Benzyl-4-[(3,5-dimethyl-1H-pyrazol-1-yl)car-
bonyl]cyclopent-1-ene-1-carboxylate (3i)
Yield: 15.4 mg (81%); yellow oil; [a]D26 = –2.2 (c 0.93, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.21–7.16 (m, 3 H), 6.80–6.78 (m,
2 H), 6.57 (d, J = 2.5 Hz, 1 H), 5.97 (s, 1 H), 3.52 (d, J = 13.3 Hz, 1
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13C NMR (125 MHz, CDCl3): d = 175.2, 164.4, 151.3, 144.9, 139.2,
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HRMS (ESI): m/z [M + Na]+ calcd for C23H28N2O3Na: 403.1992;
found: 403.1995.
HPLC: 61% ee (Chiralcel IC-H, i-PrOH–hexane, 5:95, flow
rate = 0.5 mL/min, l = 254 nm): tR (major) = 11.0 min, tR (minor) =
13.6 min.
Synthesis 2011, No. 12, 1859–1864 © Thieme Stuttgart · New York

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Synthesis 2011, No. 12, 1859–1864 © Thieme Stuttgart · New York