Asymmetric Organocatalytic Michael Addition-Cyclization Cascade of Cyclopentane-1,2-dione with Substituted α,β-Unsaturated Aldehydes

Article abstract of DOI:10.1055/s-0036-1588787

An asymmetric organocatalytic Michael addition-cyclization cascade reaction has been developed using cyclopentane-1,2-dione as a Michael donor and α,β-unsaturated aldehydes as Michael acceptors. Bicyclic hemiacetals were obtained in excellent yields and enantioselectivities. On the basis of the results, a one-pot reaction has been developed to obtain chiral 3-substituted cyclopentane-1,2-diones and substituted dihydropyrans in good yields and excellent enantioselectivity.

Full text of DOI:10.1055/s-0036-1588787

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
de
G. Preegel et al.
Paper
Synthesis
Asymmetric Organocatalytic Michael Addition–Cyclization Cascade
of Cyclopentane-1,2-dione with Substituted α,β-Unsaturated
Aldehydes
Gert Preegela
R
O
1.
Estelle Silma
Sandra Kaabela,b
Ivar Järvinga
Kari Rissanenb
Margus Lopp*a
R
10 mol% aminocatalyst
CH2Cl2, rt
OH
O
2.
2 equiv NaBH4
MeOH, CH2Cl2
0 °C to rt
OH
OH
O
9 examples
up to 73% yield
up to 94% ee
a Department of Chemistry and Biotechnology, Tallinn University
of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia
margus.lopp@ttu.ee
b University of Jyvaskyla, Department of Chemistry,
Nanoscience Center, P.O. Box 35, 40014 Jyvaskyla, Finland
Received: 07.02.2017
Accepted after revision: 17.03.2017
Published online: 18.04.2017
We have previously shown that a Mukaiyama–Michael
addition reaction of cyclopentane-1,2-dione dienol silyl
ethers proceeds in an organocatalytic way with α,β-unsatu-
rated aldehydes.9 The preparation of the intermediate cy-
clopentane-1,2-dione dienol silyl ethers, however, is a labo-
rious and complicated procedure, making the overall yield
of the substituted chiral product low, although the addition
reaction proceeds in excellent enantioselectivity (Scheme 1,
path C).9 We have also shown previously that α-alkylation
of cyclopentane-1,2-diones in an organocatalytic manner
can be carried out with β,γ-unsaturated-α-keto esters and
with nitroolefins (Scheme 1, paths A and B).10,11 Several
other organocatalytic reactions of cyclic diketones with ex-
cellent stereoselectivity have also been investigated:
Rueping carried out two cascade reactions with cyclohex-
ane-1,2-dione and cyclohexane-1,3-dione, giving bicyclic
product in up to excellent yields and enantioselectivity
(Scheme 1, paths D and E);12 Jørgensen’s group has also
shown that cyclopentane-1,3-diones undergo a cascade re-
action with α,β-unsaturated aldehydes, giving bicyclic
product in excellent yields and stereoselectivity (Scheme 1,
path F).13 Here we present the results of using α,β-unsatu-
rated aldehydes as electrophiles in a direct reaction with
cyclopentane-1,2-dione.
We started with cyclopentane-1,2-dione (1) and trans-
cinnamaldehyde (2a) with L-proline (4a) as the aminocata-
lyst in ethanol and obtained hemiacetal 3a in very low yield
(6.5%) and with low enantioselectivity (16%; Table 1, entry
1). By using bulkier aminocatalysts, better yields and enan-
tioselectivities were obtained (Table 1, entries 2–5). The
best result was achieved with the bulkiest catalyst, 4e, giv-
ing 83% yield and 85% ee (Table 1, entry 5). The opposite en-
antiomer was also obtained with a catalyst derived from D-
proline (Table 1, entry 4).
DOI: 10.1055/s-0036-1588787; Art ID: ss-2017-z0079-op
Abstract An asymmetric organocatalytic Michael addition–cyclization
cascade reaction has been developed using cyclopentane-1,2-dione as
a Michael donor and α,β-unsaturated aldehydes as Michael acceptors.
Bicyclic hemiacetals were obtained in excellent yields and enantioselec-
tivities. On the basis of the results, a one-pot reaction has been devel-
oped to obtain chiral 3-substituted cyclopentane-1,2-diones and sub-
stituted dihydropyrans in good yields and excellent enantioselectivity.
Key words organocatalysis, asymmetry, diketones, dihydropyran,
Michael addition
At the present time, chemical synthesis is directed at
sustainability, looking for cleaner and more effective reac-
tions to get compounds of interest. In the biomass conver-
sion discipline, one of the conversions that has been some-
how neglected is selective conversion of biomass via 5-HMF
to cyclopentanone and cyclopent-2-en-1-one.1 Both of
these compounds can be easily converted into cyclopen-
tane-1,2-diones (1).2 These are compounds of many uses,
including as precursors with the means to increase the
heating value of conventional bio-jet fuels.3 Also derivatives
of cyclopentane-1,2-dione can be used as flavoring agents.4
We have used these molecules as starting materials/plat-
form molecules for making new high value-added fine
chemicals, such as nucleoside analogues5 and several bioac-
tive natural compounds6 and their analogues.7 On the other
hand, aminocatalysis has been an important research topic
for 10 years, providing the most widely used organocata-
lysts in the field.8
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
G. Preegel et al.
Paper
Synthesis
In a search for an optimal solvent for the reaction, dif-
ferent polar and non-polar solvents were screened. The re-
sults are presented in Table 2. We found that the halogen-
containing solvents gave the best stereoselectivity. In chlo-
roform, the reaction was complete in 2 hours, giving a good
yield (76%) and with excellent enantioselectivity (98% ee;
Table 2, entry 5). In 1,2-dichloroethane, similar results were
obtained after 6 hours of reaction (72% yield and 96% ee;
Table 2, entry 6). The best result was obtained with di-
chloromethane, affording an excellent yield (93%) and en-
antioselectivity (95% ee; Table 2, entry 7) in a fast reaction
(after 2 h).
Using these optimal conditions the scope of the reaction
with different aldehydes was investigated. As seen in
Scheme 2, the reaction tolerates different α,β-unsaturated
aldehydes with various electronic densities. Electron-
donating and -withdrawing groups at the aromatic ring
both gave good to excellent yields and enantioselectivities
(3b and 3e). Also, a heteroaromatic ring was tolerated, giv-
ing product 3g in 68% yield and 81% ee. Furthermore, an al-
kyl α,β-unsaturated aldehyde can also be used in the reac-
tion, affording 3h with good enantioselectivity (86% ee), al-
though with low yield (33% only). Finally, hexa-2,4-dienal
(2i) resulted in a 1,4-addition reaction only, giving 3i in an
average yield 65% and enantioselectivity 51% ee. As the
used starting material 2i was a 1:7 mixture of cis- and
trans-isomers, the product obtained was also a 1:7 mixture
of cis/trans isomers.
The absolute configuration of compound 3c was deter-
mined by a single-crystal X-ray diffraction to be (2S,4S)
(Figure 1) and the absolute configurations of compounds 3
were assigned by analogy.
As excellent yields were obtained only in some cases
with trans-cinnamaldehydes, additional screening of possi-
ble basic additives, with the usual co-catalyst enhancing
Previous work:
N
H
H
N
N
CF3
A)
D)
Ph
MeO
S
O
Ph
OTMS
O
O
R
N
H
CF3
O
N
R
+
OH
CHO
+
NO2
NO2
O
CH2Cl2, rt
O
EtOH
OH
OH
R
R
11 examples
Up to 91% yield
Up to 76% ee
10 examples
Up to 81% yield
Up to 98% ee
N
H
N
H
CF3
N
Ar
B)
E)
S
R'
Ar
OTMS
O
O
O
R
O
N
H
O
CF3
O
+
+
OH
R'
R''
O
O
CH2Cl2, rt
CH2Cl2, 0 °C
O
R''
OH
O
O
R
OH
O
O
Ar = Ph, 3,5-(CF3)C6H3
11 examples
8 examples
Up to 93% yield
Up to 98% ee
dr > 20:1
Up to 95% yield
Up to 98% ee
Ar
1.
C)
F)
Ar
OTMS
Ph
Ph
OTBS
N
OH
R
O
H
O
O
N
R
O
O
H
PhCO2H
+
O
+
EtOH
2. Ac2O, Et3N, DMAP
CH2Cl2
OTBS
TBSO
OH
R
O
TBSO
R
O
R
O
OAc
OH
O
Ar = Ph, 3,5-(CF3)C6H3
5 examples
13 examples
Up to 66% yield
Up to 94% ee
Up to 95% yield
Up to 96% ee
Up to 20:1 dr
This work:
R
R
O
O
OH
aminocatalysis
+
O
OH
OH
OH
O
R
O
Scheme 1 Previous and proposed work on cyclic diketones
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
G. Preegel et al.
Paper
Synthesis
Table 1 Screening of Organocatalystsa
Table 2 Screening of Solventsa
Ph
Ph
O
catalyst
EtOH
catalyst 4e
O
O
Ph
Ph
OTBS
O
O
N
solvent
Ph
H
Ph
H
H
O
OH
OH
OH
O
OH
O
O
1
2a
3a
4e
1
2a
3a
Entry
Solvent
Time (h)
Yield (%)b
ee (%)c
Ar
Ar
OH
Ar
Ar
OTMS
Ar
Ar
OTMS
Ar
Ar
OTBS
N
H
N
N
N
N
1
2
3
4
5
6
7
EtOH
18
24
24
5
83
74
72
83
76
72
93
85
88
96
97
98
96
95
H
H
H
H
OH
MeOH
THF
4a
4b
4c
4d
4e
4b, 4c, 4e: Ar = Ph
4d: Ar = 3,5-diCF3-Ph
toluene
CHCl3
C2H4Cl2
CH2Cl2
2
Entry
Catalyst (10 mol%) Time (h)
Yield (%)b
ee (%)c
6
1
2
3
4
5
4a
4b
4c
4d
4e
18
24
1.5
24
18
6.5
61
59
20
83
16
21
79
70d
85
2
a Reaction conditions: 1 (0.24 mmol), 2a (0.2 mmol), catalyst 4e (0.02
mmol), solvent (0.7 mL), r.t.
b Isolated yield after column chromatography.
c Determined by chiral HPLC.
a Reaction conditions: 1 (0.24 mmol), 2a (0.2 mmol), catalyst 4 (0.02
mmol), EtOH (0.7 mL), r.t.
the condensation of aminocatalyst to aldehyde, was per-
formed. It was found (see Table 3) that the best additive was
NaHCO3, leading to perfect yield (98%) and outstanding en-
antioselectivity (>99% ee) of the reaction (Table 3, entry 6).
b Isolated yield after column chromatography.
c Determined by chiral HPLC.
d Opposite enantiomer formed.
R
catalyst 4e
O
Ph
O
N
Ph
OTBS
CH2Cl2
R
H
O
H
O
OH
OH
O
1
2
3
4e
Cl
Br
NO2
O
OH
O
OH
O
O
OH
O
OH
O
OH
O
O
O
O
3a
3b
3c
3d
3e
93%, 95% ee
70%, 90% ee
62%, 83% ee
82%, 92% ee
86%, 95% ee
O
NO2
O
OH
O
OH
O
OH
O
OH
O
O
O
O
3f
87%, 91% ee
3g
68%, 81% ee
3h
3i
33%, 86% ee
65%, 51% ee (trans)/
71% ee (cis) 7:1
Scheme 2 Scope of the reaction. Reagents and conditions: 1 (0.24 mmol), 2 (0.2 mmol), catalyst 4e (0.02 mmol), CH2Cl2 (0.7 mL), r.t.; isolated yields
after column chromatography, the major diastereomer is presented; ee determined by chiral HPLC.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
G. Preegel et al.
Paper
Synthesis
R
R
O
NaHCO3, cat. 4e
2 equiv NaBH4, MeOH
OH
+
O
CH2Cl2
40 °C
CH2Cl2
0 °C to rt
R
H
OH
O
OH
OH
O
O
5
3
2
1
O
Cl
Br
NO2
OH
OH
OH
OH
OH
OH
OH
OH
OH
O
OH
O
O
O
O
5a
5b
5c
63%, 90% ee
5d
5e
74%, 92% ee
72%, 90% ee
60%, 92% ee
82%, 94% ee
O
NO2
OH
OH
OH
OH
OH
OH
OH
OH
O
O
O
O
5f
5g
60%, 83% ee
5h
29%, 75% ee
5i
35%, 94% ee
55%, 7:1 46% ee (trans)/73% ee (cis)
Scheme 3 One-pot reaction in the synthesis of chiral 3-substituted cyclopentane-1,2-diones 5. Reagents and conditions: 1 (0.24 mmol); 2 (0.2 mmol),
NaHCO3 (0.02 mmol), catalyst 4e (0.02 mmol), CH2Cl2 (0.7 mL), r.t.; isolated yields after column chromatography, ee determined by chiral HPLC.
2M H2SO4
56%
Et3SiH, TMSOTf
CH2Cl2
OH
O
OTMS
O
OH
O
O
O
5a
6
7
Figure 1 X-ray crystal structure (see Supporting Information for de-
tails) and the absolute configuration of 3c
Scheme 4 Transformation to dihydropyran
With these optimum conditions (solvent CH2Cl2, cata-
lyst 4e, and additive NaHCO3), we developed a one-pot pro-
cedure for the reaction sequence: Michael addition, cycliza-
tion reaction and reduction of the formed aldehyde with
NaBH4. This cascade of reactions resulted in a single prod-
uct 5 (Scheme 3).
In conclusion, a novel efficient method of making bicy-
clic hemiacetals 3a–i and 3-substituted cyclopentane-1,2-
diones 5a–i has been developed, giving good yields and ex-
cellent enantioselectivities. The method may be used for
the synthesis of a wide variety of substituted dihydropy-
rans 6.
All of the used substrates gave excellent enantioselec-
tivities, with good to satisfactory overall yields. We made
an attempt to reduce acetal 7 directly to the dihydropyran
according to Oshima et al.14 but without success. Instead,
the cyclization of enol 5 proceeded easily in the presence of
a strong acid, yielding dihydropyran 6 in 56% yield (not op-
timized) (Scheme 4).
1
Full assignment of H and 13C chemical shifts is based on the 1D and
2D FT NMR spectra measured on a Bruker Avance III 400 MHz instru-
ment. Residual solvent peaks (CHCl3/CDCl3, δ = 7.26/77.2) or TMS (δ =
0.00) were used as chemical shift references. Chiral HPLC was per-
formed using Phenomenex Lux® 3μm amylose-2, Chiralcel OD-H, and
Chiralpak AS-H and OJ-H columns. Mass spectra were recorded by us-
ing Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
G. Preegel et al.
Paper
Synthesis
Table 3 Screening of Additivesa
IR (KBr): 3377, 2929, 1701, 1645, 1494, 1454, 1408, 1394, 1283, 1121,
1090, 910, 733, 705 cm–1
.
Ph
1H NMR (400 MHz, CDCl3): δ = 7.40–7.33 (m, 2 H), 7.32–7.27 (m, 1 H),
7.24–7.19 (m, 2 H), 5.82 (d, J = 2.8 Hz, 1 H), 5.09 (s, 1 H), 4.00 (dd, J =
11.5, 6.1 Hz, 1 H), 2.40–2.31 (m, 3 H), 2.28–2.24 (m, 2 H), 1.99 (dd, J =
13.5, 11.8 Hz, 1 H).
additive, catalyst 4e
CH2Cl2
H
O
Ph
Ph
OTBS
O
N
Ph
H
O
OH
OH
O
13C NMR (101 MHz, CDCl3): δ = 202.8, 148.6, 148.5, 140.7, 129.1 (2 C),
1
2a
3a
4e
128.3 (2 C), 127.4, 92.9, 37.6, 35.7, 32.7, 23.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H15O3: 231.1016; found:
Entry
Additive (10 mol%)
Time (h)
Yield (%)b
ee (%)c
231.1016.
1
2
–
2
93
93
95
93
84
98
98
94
93
99
82
99
95
94
94
94
94
>99
95
94
94
95
95
93
NaOAc
pyridine
DMAP
K2CO3
NaHCO3
Na2CO3
Et3N
1.5
3
(2S,4S)-2-Hydroxy-4-(4-methoxyphenyl)-3,4,5,6-tetrahydrocyclo-
penta[b]pyran-7(2H)-one (3b)
3
4
1
Following GPA gave 3b after purification as a yellow oil; yield: 36 mg
(70%); 90% ee [HPLC (Chiralpak AS-H, hexane/i-PrOH 8:2, 1 mL/min,
254 nm): tR = 18.6 (major), 29.5 min (minor)]; [α]D +133.9 (c 0.05,
5
4
25
6
3.5
2.5
2.5
1.5
2
CHCl3).
7
IR (KBr): 3379, 2932, 1703, 1644, 1611, 1583, 1513, 1442, 1394, 1347,
1250, 1087, 1034, 794 cm–1
.
8
1H NMR (400 MHz, CDCl3): δ = 7.15–7.09 (m, 2 H), 6.93–6.86 (m, 2 H),
5.77 (br s, 1 H), 4.53 (br s, 1 H), 3.93 (dd, J = 11.4, 6.1 Hz, 1 H), 3.82 (s,
3 H), 2.40–2.36 (m, 2 H), 2.31 (ddd, J = 13.8, 6.2, 2.5 Hz, 1 H), 2.27–
2.23 (m, 2 H), 2.01–1.91 (m, 1 H).
9
DIPEA
DABCO
DBU
10
11
12
2.5
1
imidazole
13C NMR (101 MHz, CDCl3): δ = 202.3, 158.9, 148.7, 148.4, 132.5,
a Reaction conditions: 1 (0.24 mmol), 2a (0.2 mmol), additive (0.02 mmol),
catalyst 4e (0.02 mmol), CH2Cl2 (0.7 mL), r.t.
b Isolated yield after column chromatography.
c Determined by chiral HPLC.
129.3 (2 C), 114.5 (2 C), 92.9, 55.5, 36.7, 35.7, 32.8, 23.7.
HRMS (ESI): m/z [M + H]+ calcd for C15H17O4: 261.1121; found:
261.1103.
(2S,4S)-4-(4-Chlorophenyl)-2-hydroxy-3,4,5,6-tetrahydrocyclo-
penta[b]pyran-7(2H)-one (3c)
spectrometer by using AJ-ESI ionization. Optical rotations were ob-
tained using an Anton Paar GWB Polarimeter MCP 500. IR spectra
were recorded on a Bruker Tensor 27 Fourier transform infrared spec-
trophotometer. Absolute structure of the single crystal with Bruker-
Nonius Kappa CCD diffractometer. TLC: Merck precoated silica gel 60
F254 plates; column chromatography: Merck 60 (0.040–0.063 mm)
mesh silica gel. Commercial reagents and solvents were generally
used as received. Racemic samples of all compounds were prepared
following the general procedure using pyrrolidine as catalyst.
Following GPA gave 3c after purification as a white solid; yield: 33 mg
(62%); mp 168 °C; 83% ee [HPLC (Chiralpak AS-H, hexane/i-PrOH 8:2,
1
mL/min, 254 nm): tR
[α]D25 +233.2 (c 0.04, CHCl3).
IR (KBr) 3356, 2947, 1699, 1649, 1492, 1435, 1230, 1088, 844 cm–1
= 13.9 (major), 18.8 min (minor)];
.
1H NMR (400 MHz, CDCl3): δ = 7.34 (d, J = 8.3 Hz, 2 H), 7.15 (d, J = 8.4
Hz, 2 H), 5.79 (s, 1 H), 4.68 (s, 1 H), 3.97 (dd, J = 11.3, 6.0 Hz, 1 H),
2.41–2.36 (m, 2 H), 2.36–2.29 (m, 1 H), 2.27–2.20 (m, 2 H), 1.94 (t, J =
12.6 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 202.4, 148.7, 147.4, 139.1, 133.3,
129.7 (2 C), 129.3 (2 C), 92.8, 37.0, 35.6, 32.7, 23.6.
Cyclopentane-1,2-dione (1) was prepared according to a literature
procedure2a from commercially available cyclopentanone. Aldehydes
2a–i and catalysts 4a–e are commercially available and were used
without further purification.
HRMS (ESI): m/z [M + H]+ calcd for C14H14O3Cl: 265.0626; found:
265.0626.
4-Substituted 2-Hydroxy-3,4,5,6-tetrahydrocyclopenta[b]pyran-
7(2H)-one 3a–i; General Procedure A
(2S,4S)-4-(4-Bromophenyl)-2-hydroxy-3,4,5,6-tetrahydrocyclo-
penta[b]pyran-7(2H)-one (3d)
2-Hydroxycyclopent-2-en-1-one (1, 23.5 mg, 0.24 mmol), aldehyde 2
(25.2 μL, 0.2 mmol), and aminocatalyst 4e (7.3 mg, 0.02 mmol) were
dissolved in CH2Cl2 (0.7 mL). The mixture was stirred at r.t. until com-
pletion of the reaction (TLC monitoring). The mixture was purified by
column chromatography (CH2Cl2/EtOAc 25:1) to yield the product.
Following GPA gave 3d after purification as a white solid; yield: 50
mg (82%); mp 173 °C; 92% ee [HPLC (Chiralpak AS-H, hexane/i-PrOH
8:2, 1 mL/min, 254 nm): tR = 16.0 (major), 27.7 min (minor)];
[α]D25 +190.1 (c 0.04, CHCl3).
IR (KBr): 3354, 2947, 1699, 1649, 1489, 1127, 870, 843, 531 cm–1
.
(2S,4S)-2-Hydroxy-4-phenyl-3,4,5,6-tetrahydrocyclopen-
ta[b]pyran-7(2H)-one (3a)
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 8.3 Hz, 2 H), 7.10 (d, J = 8.3
Hz, 2 H), 5.80 (d, J = 1.9 Hz, 1 H), 5.11 (s, 1 H), 3.97 (dd, J = 11.3, 5.9 Hz,
1 H), 2.41–2.36 (m, 2 H), 2.36–2.28 (m, 1 H), 2.28–2.21 (m, 2 H), 1.94
(t, J = 12.7 Hz, 1 H).
Following GPA gave 3a after purification as a white solid; yield: 43 mg
(93%); mp 149 °C; 95% ee [HPLC (Chiralcel OD-H, hexane/i-PrOH 8:2,
1 mL/min, 254 nm): tR = 8.2 (major), 6.8 min (minor)]; [α]D25 +186.8 (c
0.04, CHCl3).
13C NMR (101 MHz, CDCl3): δ = 202.3, 148.7, 147.2, 139.6, 132.3 (2 C),
130.1 (2 C), 121.3, 92.7, 37.1, 35.5, 32.7, 23.6.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
G. Preegel et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C14H14O3Br: 309.0121; found:
309.0130.
(2S,4R)-4-Butyl-2-hydroxy-3,4,5,6-tetrahydrocyclopenta[b]pyran-
7(2H)-one (3h)
Following GPA gave 3h after purification as a yellow oil; yield: 14 mg
(33%); 86% ee [HPLC (Chiralcel OJ-H, hexane/i-PrOH 9:1, 1 mL/min,
254 nm): tR = 10.7 (major), 8.6 min (minor)]; [α]D25 +36.7 (c 0.04,
CHCl3).
(2S,4S)-2-Hydroxy-4-(4-nitrophenyl)-3,4,5,6-tetrahydrocyclopen-
ta[b]pyran-7(2H)-one (3e)
Following GPA gave 3e after purification as a white solid; yield: 47 mg
(86%); mp 160 °C; 95% ee [HPLC (Chiralpak AS-H, hexane/i-PrOH 8:2,
IR (KBr): 3316, 2926, 1691, 1634, 1461, 1395, 1098, 948, 846, 715 cm–1
.
1
mL/min, 254 nm): tR
[α]D25 +184.7 (c 0.03, CHCl3).
IR (KBr): 3305, 2931, 1693, 1646, 1607, 1516, 1345, 862, 754, 715 cm–1
= 27.8 (major), 41.5 min (minor)];
1H NMR (400 MHz, CDCl3): δ = 5.70 (s, 1 H), 4.79 (s, 1 H), 2.81–2.70
(m, 1 H), 2.61–2.52 (m, 1 H), 2.49–2.36 (m, 3 H), 2.18–2.09 (m, 1 H),
1.81–1.70 (m, 1 H), 1.58–1.47 (m, 1 H), 1.42–1.28 (m, 5 H), 0.97–0.88
(m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 202.4, 150.6, 147.8, 92.9, 32.8, 32.3,
31.5, 30.1, 29.0, 23.5, 22.9, 14.1.
.
1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 8.6 Hz, 2 H), 7.42 (d, J = 8.7
Hz, 2 H), 5.85 (d, J = 2.0 Hz, 1 H), 5.27 (s, 1 H), 4.16 (dd, J = 12.4, 6.5 Hz,
1 H), 2.45–2.40 (m, 2 H), 2.40–2.34 (m, 1 H), 2.33–2.21 (m, 2 H), 1.98
(t, J = 12.7 Hz, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C12H18O3Na: 233.1148; found:
233.1151.
13C NMR (101 MHz, CDCl3): δ = 202.5, 149.0, 148.3, 147.4, 145.9,
129.3 (2 C), 124.4 (2 C), 92.5, 37.5, 35.5, 32.7, 23.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H14O5N: 276.0866; found:
276.0875.
(2S,4S)-2-Hydroxy-4-[(E)-prop-1-en-1-yl]-3,4,5,6-tetrahydrocyclo-
penta[b]pyran-7(2H)-one (3i)
Following GPA from 2i (trans/cis 7:1) gave 3i after purification as an
orange oil; yield: 25 mg (65%); ratio trans/cis 7:1; cis-isomer 71% ee
(2S,4R)-2-Hydroxy-4-(2-nitrophenyl)-3,4,5,6-tetrahydrocyclopen-
ta[b]pyran-7(2H)-one (3f)
[HPLC (Chiralcel OJ-H, hexane/i-PrOH 9:1, 1 mL/min, 254 nm): tR
=
16.9 (major), 13.8 min (minor)]; trans-isomer 51% ee [HPLC (Chiralcel
OJ-H, hexane/i-PrOH 9:1, 1 mL/min, 254 nm): tR = 24.4 (major), 11.3
min (minor)]; [α]D25 +99.7 (c 0.05, CHCl3).
Following GPA gave 3f after purification as a white solid; yield: 48 mg
(87%); mp 160 °C; 91% ee [HPLC (Chiralpak AS-H, hexane/i-PrOH 8:2,
1
mL/min, 254 nm): tR
[α]D25 +234.3 (c 0.05, CHCl3).
IR (KBr): 3356, 2925, 1700, 1648, 1607, 1524, 1351, 789, 750, 719 cm–1
= 28.5 (major), 43.9 min (minor)];
IR (KBr): 3382, 2925, 1698, 1643, 1440, 1395, 1102, 914, 733 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.75–5.59 (m, 2 H), 5.38–5.29 (m, 1 H),
4.82 (br s, 1 H), 3.36 (dd, J = 15.5, 8.6 Hz, 1 H), 2.57–2.33 (m, 4 H),
2.14–2.05 (m, 1 H), 1.77–1.67 (m, 4 H).
13C NMR (101 MHz, CDCl3): δ = 202.4, 149.2, 147.6, 129.5, 128.7, 92.7,
34.6, 33.3, 32.8, 23.9, 18.1.
.
1H NMR (400 MHz, CDCl3): δ = 7.90 (dd, J = 8.2, 1.2 Hz, 1 H), 7.62 (td,
J = 7.6, 1.1 Hz, 1 H), 7.49–7.43 (m, 1 H), 7.30 (dd, J = 7.8, 1.0 Hz, 1 H),
5.80 (d, J = 1.8 Hz, 1 H), 4.71 (br s, 1 H), 4.57 (dd, J = 10.7, 6.2 Hz, 1 H),
2.56 (ddd, J = 13.6, 6.1, 2.5 Hz, 1 H), 2.45–2.39 (m, 2 H), 2.35–2.28 (m,
1 H), 2.27–2.18 (m, 1 H), 1.99 (t, J = 11.8 Hz, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C11H14O3Na: 217.0835; found:
217.0837.
13C NMR (101 MHz, CDCl3): δ = 202.4, 150.4, 149.5, 146.2, 135.2,
133.3, 130.4, 128.3, 124.9, 92.7, 35.4, 33.2, 32.7, 23.5.
HRMS (ESI): m/z [M + H]+ calcd for C14H14O5N: 276.0866; found:
276.0872.
2-Hydroxy-3-(1-substituted 3-hydroxypropyl)cyclopent-2-en-1-
ones 5a–i; General Procedure B
2-Hydroxycyclopent-2-en-1-one (1, 23.5 mg, 0.24 mmol), aldehyde 2
(25.2 μL, 0.2 mmol), aminocatalyst 4e (7.3 mg, 0.02 mmol), and
NaHCO3 (0.02 mmol) were dissolved in CH2Cl2 (0.7 mL). The mixture
was stirred at 40 °C until completion of the reaction (TLC and NMR
monitoring). The mixture was cooled to 0 °C and dry MeOH (0.5 mL)
and NaBH4 (12.6 mg, 0.33 mmol) were added. The mixture was
stirred at 0 °C for 30 min and was warmed to r.t. When the reaction
was completed CH2Cl2 (0.5 mL) and sat. aq NH4Cl solution (0.5 mL)
were added to the mixture. The mixture was extracted with CH2Cl2 (3
× 1 mL) and organic phase was dried with phase separator and con-
centrated. Mixture was purified by column chromatography (CH2Cl2/
MeOH, 50:1) to yield the product.
(2S,4R)-4-(Furan-2-yl)-2-hydroxy-3,4,5,6-tetrahydrocyclopen-
ta[b]pyran-7(2H)-one (3g)
Following GPA gave 3g after purification as a white solid; yield: 30 mg
(68%); mp 160 °C; 81% ee [HPLC (Chiralcel OD-H, hexane/i-PrOH 95:5,
1
mL/min, 254 nm): tR
[α]D25 +162.1 (c 0.04, CHCl3).
IR (KBr): 3375, 2926, 1702, 1647, 1505, 1120, 1088, 745 cm–1
= 19.6 (major), 15.8 min (minor)];
.
1H NMR (400 MHz, CDCl3): δ = 7.38 (dd, J = 1.8, 0.7 Hz, 1 H), 6.35 (dd,
J = 3.1, 1.9 Hz, 1 H), 6.19 (d, J = 3.1 Hz, 1 H), 5.80 (d, J = 2.7 Hz, 1 H),
5.05 (s, 1 H), 4.13 (dd, J = 11.1, 5.9 Hz, 1 H), 2.44–2.36 (m, 3 H), 2.33–
2.21 (m, 2 H), 2.15 (t, J = 12.4 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 202.6, 153.3, 148.1, 146.4, 142.3,
(S)-2-Hydroxy-3-(3-hydroxy-1-phenylpropyl)cyclopent-2-en-1-
110.4, 106.9, 92.7, 32.8, 31.8, 31.1, 23.9.
one (5a)
HRMS (ESI): m/z [M + H]+ calcd for C12H13O4: 221.0808; found:
221.0815.
Following GPB gave 5a after purification as a white solid; yield: 28 mg
(74%); mp 117 °C; 92% ee [HPLC (Phenomenex Lux® 3μm amylose-2,
hexane/EtOH 8:2, 1 mL/min, 254 nm): tR = 9.1 (major), 13.8 min (mi-
nor)].
1H NMR (400 MHz, CDCl3): δ = 7.35–7.21 (m, 5 H), 6.52 (br s, 1 H),
4.20 (t, J = 7.9 Hz, 1 H), 3.71–3.61 (m, 2 H), 2.45–2.17 (m, 6 H), 2.09 (br
s, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
G. Preegel et al.
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Synthesis
13C NMR (101 MHz, CDCl3): δ = 203.6, 148.5, 148.3, 141.3, 128.8 (2 C),
13C NMR (101 MHz, CDCl3): δ = 202.9, 149.0, 148.9, 147.0, 145.0,
128.0 (2 C), 127.0, 60.8, 41.4, 34.5, 31.8, 23.0.
128.8 (2 C), 124.0 (2 C), 60.3, 41.4, 34.5, 31.7, 23.3.
The spectral properties of the compound coincided with literature
data.9
The spectral properties of the compound coincided with literature
data.9
(S)-2-Hydroxy-3-(3-hydroxy-1-(4-methoxyphenyl)propyl)cyclo-
(S)-2-Hydroxy-3-[3-hydroxy-1-(2-nitrophenyl)propyl]cyclopent-
pent-2-en-1-one (5b)
2-en-1-one (5f)
Following GPB gave 5b after purification as a white solid; yield: 32
mg (72%); mp 106 °C; 90% ee [HPLC (Chiralpak AS-H, hexane/EtOH
9:1, 1 mL/min, 254 nm): tR = 29.6 (major), 26.4 min (minor)].
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.7
Hz, 2 H), 6.10 (s, 1 H), 4.13 (t, J = 8.0 Hz, 1 H), 3.79 (s, 3 H), 3.71–3.60
(m, 2 H), 2.44–2.18 (m, 6 H), 1.86 (br s, 1 H).
Following GPB gave 5f after purification as a yellow oil; yield: 16 mg
(35%); 94% ee [HPLC (Phenomenex Lux® 3μm amylose-2, hex-
ane/EtOH 8:2, 1 mL/min, 254 nm): tR = 20.6 (major), 36.4 min (mi-
nor)]; [α]D25 +100.3 (c 0.11, CHCl3).
IR (KBr): 3332, 2922, 1697, 1653, 1526, 1355, 1108, 755 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.77 (dd, J = 8.1, 1.1 Hz, 1 H), 7.60 (dtd,
J = 9.1, 8.0, 1.4 Hz, 2 H), 7.40 (ddd, J = 8.4, 7.2, 1.7 Hz, 1 H), 6.42 (s, 1
H), 4.56 (t, J = 7.7 Hz, 1 H), 3.71–3.61 (m, 2 H), 2.52–2.22 (m, 6 H), 2.16
(br s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 203.3, 158.6, 148.3, 148.1, 133.3,
128.9 (2 C), 114.1 (2 C), 60.8, 55.3, 40.6, 34.9, 31.7, 23.0.
The spectral properties of the compound coincided with literature
data.9
13C NMR (101 MHz, CDCl3): δ = 203.0, 149.7, 148.6, 144.6, 135.3,
132.3, 129.3, 127.3, 123.7, 59.9, 36.4, 35.0, 31.2, 24.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H16NO5: 278.1023; found:
(S)-3-[1-(4-Chlorophenyl)-3-hydroxypropyl]-2-hydroxycyclopent-
2-en-1-one (5c)
278.1027.
Following GPB gave 5c after purification as a white amorphous solid;
yield: 28 mg (63%); 90% ee [HPLC (Chiralpak AS-H, hexane/EtOH 8:2,
1 mL/min, 254 nm): tR = 8.9 (major), 11.2 min (minor)]; [α]D25 –55.1 (c
0.11, CHCl3).
(R)-3-[1-(Furan-2-yl)-3-hydroxypropyl]-2-hydroxycyclopent-2-
en-1-one (5g)
Following GPB gave 5g after purification as a white solid; yield: 22 mg
(60%); mp 120 °C (dec.); 83% ee [HPLC (Phenomenex Lux® 3μm amy-
lose-2, hexane/EtOH 8:2, 1 mL/min, 254 nm): tR = 9.9 (major), 14.4
min (minor)]; [α]D25 –86.0 (c 0.11, CHCl3).
IR (KBr): 3317, 2919, 1691, 1646, 1490, 1031, 822 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.27 (m, 2 H), 7.26–7.21 (m, 2 H),
6.24 (s, 1 H), 4.21–4.13 (m, 1 H), 3.71–3.60 (m, 2 H), 2.43–2.15 (m, 6
H), 1.92 (br s, 1 H).
IR (KBr): 3427, 3124, 2939, 1697, 1651, 1506, 1447, 739 cm–1
.
13C NMR (101 MHz, CDCl3): δ = 203.3, 148.5, 147.1, 139.8, 132.8,
129.3 (2 C), 128.9 (2 C), 60.6, 40.8, 34.7, 31.7, 23.0.
HRMS (ESI): m/z [M + H]+ calcd for C14H16ClO3: 267.0782; found:
267.0785.
1H NMR (400 MHz, CDCl3): δ = 7.36 (dd, J = 1.8, 0.7 Hz, 1 H), 6.33 (dd,
J = 3.2, 1.9 Hz, 1 H), 6.17 (d, J = 3.2 Hz, 1 H), 5.73 (s, 1 H), 4.39 (dd, J =
8.8, 7.0 Hz, 1 H), 3.74–3.59 (m, 2 H), 2.49–2.38 (m, 3 H), 2.33–2.21 (m,
2 H), 2.09 (m, 1 H), 1.79 (br s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 202.7, 154.2, 148.6, 144.9, 141.9,
110.2, 106.3, 60.3, 34.4, 33.5, 31.7, 22.7.
(S)-3-[1-(4-Bromophenyl)-3-hydroxypropyl]-2-hydroxycyclopent-
HRMS (ESI): m/z [M + H]+ calcd for C12H15O4: 223.0965; found:
2-en-1-one (5d)
223.0967.
Following GPB gave 5d after purification as a white solid; yield: 31
mg (60%); mp 105 °C; 92% ee [HPLC (Phenomenex Lux® 3μm amy-
lose-2, hexane/EtOH 8:2, 1 mL/min, 254 nm): tR = 8.9 (major), 10.6
min (minor)].
(R)-2-Hydroxy-3-(1-hydroxyheptan-3-yl)cyclopent-2-en-1-one
(5h)
1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 8.4 Hz, 2 H), 7.17 (d, J = 8.4
Hz, 2 H), 6.16 (s, 1 H), 4.18–4.12 (m, 1 H), 3.69–3.61 (m, 2 H), 2.44–
2.15 (m, 6 H), 1.71 (br s, 1 H).
Following GPB gave 5h after purification as a white solid; yield: 11
mg (29%); mp 97 °C; 75% ee [HPLC (Phenomenex Lux® 3μm amylose-
2, hexane/EtOH 8:2, 1 mL/min, 254 nm): tR = 6.7 (major), 21.0 min
(minor)].
13C NMR (101 MHz, CDCl3): δ = 203.2, 148.4, 146.9, 140.3, 131.8 (2 C),
129.7 (2 C), 120.9, 60.5, 40.9, 34.6, 31.7, 23.1.
1H NMR (400 MHz, CDCl3): δ = 6.38 (s, 1 H), 3.63 (ddd, J = 11.0, 6.2, 4.7
Hz, 1 H), 3.52 (ddd, J = 11.1, 8.9, 5.4 Hz, 1 H), 3.05–2.94 (m, 1 H), 2.46–
2.35 (m, 4 H), 1.95–1.81 (m, 1 H), 1.70–1.60 (m, 1 H), 1.58–1.50 (m, 2
H), 1.39–1.15 (m, 4 H), 0.88 (t, J = 7.1 Hz, 3 H).
The spectral properties of the compound coincided with literature
data.9
13C NMR (101 MHz, CDCl3): δ = 203.2, 150.4, 149.6, 60.8, 35.9, 34.6,
32.8, 31.9, 29.9, 22.7, 21.7, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C12H21O3: 213.1485; found:
213.1487.
(S)-2-Hydroxy-3-[3-hydroxy-1-(4-nitrophenyl)propyl]cyclopent-
2-en-1-one (5e)
Following GPB gave 5e after purification as a white solid; yield: 49 mg
(82%); mp 109 °C; 94% ee [HPLC (Phenomenex Lux® 3μm amylose-2,
hexane/EtOH 8:2, 1 mL/min, 254 nm): tR = 16.8 (major), 19.5 min (mi-
nor)].
The spectral properties of the compound coincided with literature
data.9
1H NMR (400 MHz, CDCl3): δ = 8.19 (dd, J = 9.0, 1.2 Hz, 2 H), 7.49 (d, J =
8.7 Hz, 2 H), 6.09 (s, 1 H), 4.34–4.27 (m, 1 H), 3.68 (t, J = 6.1 Hz, 2 H),
2.46–2.21 (m, 6 H), 1.77 (br s, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
G. Preegel et al.
Paper
Synthesis
(S,E)-2-Hydroxy-3-(1-hydroxyhex-4-en-3-yl)cyclopent-2-en-1-one
(5i)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588787.
Following GPB from 2i (trans/cis 7:1) gave 5i after purification as a
white amorphous solid; yield: 18 mg (55%); ratio trans/cis 7:1; trans-
isomer 46% ee; cis-isomer 73% ee [HPLC (Phenomenex Lux® 3μm am-
ylose-2, hexane/EtOH 8:2, 1 mL/min, 254 nm): tR = 7.8 (major trans),
20.0 (minor trans), 7.3 (major cis), 10.8 min (minor cis)]; [α]D25 –14.2
(c 0.09, CHCl3).
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References
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13C NMR (101 MHz, CDCl3): δ = 203.2, 148.7, 148.1, 130.0, 127.3, 60.7,
38.9, 35.3, 31.8, 22.7, 17.9.
HRMS (ESI): m/z [M + H]+ calcd for C11H17O3: 197.1172; found:
197.1173.
4-Phenyl-3,4,5,6-tetrahydrocyclopenta[b]pyran-7(2H)-one (6)
Compound 6 was synthesized using the following modified procedure
of Rueping et al.12b Precursor 5a (27 mg, 0.1 mmol) was dissolved in 2
M H2SO4 solution (0.6 mL). The mixture was stirred at r.t. for 1 h. The
solution was quenched with aq NaHCO3 and extracted with CH2Cl2 (3
× 1 mL). The combined organic phases were dried and the residue was
purified by column chromatography (CH2Cl2/EtOAc 5:1) to give a col-
orless oil; yield: 14 mg (56%).
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IR (KBr): 3491, 2916, 1701, 1650, 1408, 1234, 1126, 1015, 773, 707
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cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.22 (m, 5 H), 4.2 (dd, J = 8.6, 7.3
Hz, 1 H), 3.72–3.60 (m, 2 H), 2.46–2.16 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 203.5, 148.4, 148.2, 141.3, 128.7 (2 C),
128.0 (2 C), 127.0, 60.8, 41.4, 34.7, 31.8, 23.0.
(10) Preegel, G.; Noole, A.; Ilmarinen, K.; Järving, I.; Kanger, T.; Pehk,
T.; Lopp, M. Synthesis 2014, 46, 2595.
(11) Preegel, G.; Ilmarinen, K.; Järving, I.; Kanger, T.; Pehk, T.; Lopp,
M. Synthesis 2015, 47, 3805.
HRMS (ESI): m/z [M + H]+ calcd for C14H14O2: 215.1067; found:
215.1076.
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6329. (b) Rueping, M.; Kuenkel, A.; Tato, F.; Bats, J. W. Angew.
Chem. Int. Ed. 2009, 48, 3699.
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6317.
Funding Information
The authors thank the following agencies for financial support:
Estonian Ministry of Education and Research (IUT 19-32) (IUT 19-9)
(IUT 23-7) (PUT 692)
Tallinn University of Technology (B25)
European Social Fund (DoRa)
(14) Maeda, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1997, 62,
6429.
EU European Regional Development Fund (3.2.0101.08-0017)
Centre of Excellence in Molecular Cell Engineering (2014-
2020.4.01.15-0013)
Academy of Finland (263256) (265328) (292746)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H