A new alkoxyallene-based [3+2] approach to the synthesis of highly substituted cyclopentenones

Article abstract of DOI:10.1055/s-2008-1042895

Lithiated methoxyallene 1 and aldehydes 2 provided after base- or gold-catalyzed cyclization dihydrofurans 3 which were oxidatively cleaved giving α,β-unsaturated γ-ketoaldehydes 4 as key intermediates. These smoothly underwent intramolecular aldol additi

Full text of DOI:10.1055/s-2008-1042895

CLUSTER
769
A New Alkoxyallene-Based [3+2] Approach to the Synthesis of Highly
Substituted Cyclopentenones
Synthesis of
H
igh
r
ly Subs
an
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 30 November 2007
1. Et2O, –78 °C
1–4 h
2. KOt-Bu or Au(I)
see Table 1
Abstract: Lithiated methoxyallene 1 and aldehydes 2 provided af-
OMe
Li
OMe
ter base- or gold-catalyzed cyclization dihydrofurans 3 which were
oxidatively cleaved giving a,b-unsaturated g-ketoaldehydes 4 as
key intermediates. These smoothly underwent intramolecular aldol
addition to furnish highly substituted cyclopentene derivatives 5 in
good yields. Due to their dense pattern of functional groups com-
pounds 5 are versatile intermediates, suitable for subsequent elabo-
rations. This was demonstrated by transformation of 5e into enol
phosphate 8 and of 5c into tetracyclic nitrone cycloadduct 13.
R1
R2
R1
R2
+
O
O
1
2
3
2 equiv DDQ
H2O, CH2Cl2
r.t., 30 min to 1 h
Key words: allenes, gold catalysis, aldol reactions, cyclopenten-
ones, cycloadditions
OMe
O
OMe
R1
base
O
see Table 1
Recently, we have demonstrated the versatility of a,b-un-
saturated g-ketoaldehydes 4 as useful building blocks for
the synthesis of different heterocycles1 as well as hetero-
cyclic natural products and their analogues.2 In this report
we expand this methodology to the synthesis of highly
functionalized carbocycles.3 The cyclopentenone ring
structure is present in a wide array of natural products and
interesting drug targets such as prostaglandins,4 penteno-
mycins,5 and methylenomycins.6 Methods to generate the
cyclopentenone core include intramolecular aldol and
Wittig-type reactions, Pauson–Khand reactions, Nazarov
cyclizations, and several other reactions.7 Here we would
like to report an efficient synthesis of densely substituted
cyclopentenone derivatives 5 starting from lithiated meth-
oxyallene 1 and aldehydes 2 bearing an a-C–H moiety
with dihydrofurans 3 and ketoaldehydes 4 as crucial inter-
mediates (Scheme 1).
HO
O
R2
R2 R1
5
4
Scheme 1 Synthesis of cyclopentenone derivatives 5
cently been developed in our group.11 The method utilizes
AuCl (5 mol%), pyridine (15 mol%) in CH2Cl2 (the cata-
lytic system originally reported by Krause for 6-endo cy-
clization of b-allenyl alcohols to dihydropyrans)12 and
proved to be superior to all aforementioned reagent sys-
tems. All reactions investigated were completed very rap-
idly and products were formed with high yields and
perfect selectivity even in the case of sensitive sub-
strates.11 The corresponding dihydrofurans 3a–e were ob-
tained in good to excellent yields using either KOt-Bu-
(method A) or AuCl-mediated (method B) cyclizations
(Table 1).
Addition of lithiated methoxyallene 1 towards aldehydes
2a–e quantitatively furnishes the expected allenyl alco-
hols (purity generally >95% by 1H NMR).1,8 These inter-
mediates are subjected to a 5-endo-trig cyclization to
dihydrofurans 3a–c without further purification in the
presence of KOt-Bu (1 equiv, 60 °C in DMSO). This
method, developed by Brandsma and Arens,9 utilizes rath-
er harsh reaction conditions and therefore sensitive sub-
strates may provide considerably lower yields.
Alternative Lewis acid promoted cyclizations are also
known. The efficacy of Ag(I)-catalyzed cyclizations of a-
allenyl alcohols or amines was also found to be substrate
sensitive.1,10,11 Fortunately, a strongly improved protocol
for 5-endo-trig cyclization of a-allenyl alcohols has re-
Oxidative ring-opening reaction of dihydrofurans 3 with
DDQ in wet CH2Cl2 selectively affords E-isomers of a,b-
unsaturated g-ketoaldehydes 4 in good yields.1,2 The ke-
toaldehydes 4a–e derived from aldehydes 2a–e with a-C–
H units (Table 1, entries 1–5) smoothly undergo intramo-
lecular aldol addition either in the presence of MeONa in
MeOH (method C) or of saturated aqueous Na2CO3 solu-
tion in THF (method D) to generate highly substituted cy-
clopentenones 5a–e in good yields (Table 1).13 In the case
of aldehydes 4a,d,e, the intramolecular aldol reaction pro-
ceeds with high diastereoselectivity, preferentially giving
in all cases the more stable 4,5-trans configured cyclopen-
tenones 5a,d,e. This is clearly the result of a thermody-
namically controlled reaction, since treatment of pure
trans-5e or cis-5e with saturated aqueous Na2CO3 solu-
tion in THF resulted in both cases in the formation of the
mixture of diastereomers.14
SYNLETT 2008, No. 5, pp 0769–0773
x
x.
x
x.
2
0
0
8
Advanced online publication: 10.03.2008
DOI: 10.1055/s-2008-1042895; Art ID: Y01907ST
© Georg Thieme Verlag Stuttgart · New York

770
B. Dugovič, H.-U. Reissig
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Table 1 Addition of Lithiated Methoxyallene 1 to Aldehydes 2 Followed by Cyclization to Dihydrofurans 3, Oxidative Ring Opening to 4
and Intramolecular Aldol Addition to Cyclopentenones 5
Entry
Aldehyde
Cyclization
conditionsa
Yield of 3
(%)
Yield of 4
Aldol
Yield of 5
(%)
Product
(%)b
conditionsa
OMe
O
HO
1
A
55
68
C
77
C10H21
O
C10H21
trans/cis = 94:6
2a
5a
OMe
2
3
A
A
47
91
76
93
C
C
83
76
HO
O
O
2b
5b
OMe
O
HO
O
2c
5c
OMe
O
O
HO
c
c
4
5
B
B
76
77
–
–
76
78
Ph
trans/cis = 94:6
2d
5d
OMe
O
HO
O
67
D
BnO
BnO
trans/cis = 92:8
2e
5e
a Conditions A: KOt-Bu (1 equiv), DMSO, 60 °C, 1–2 h. Conditions B: AuCl (0.05 equiv), pyridine (0.15 equiv), CH2Cl2, r.t., 0.5–5 h. Condi-
tions C: MeONa (0.1 equiv), MeOH, r.t., 2–15 h. Conditions D: sat. aq Na2CO3 solution, THF (1:3), r.t., 2 d.
b Conditions: DDQ (2 equiv), H2O, CH2Cl2 (1:20), r.t., 30 min to 1 h.
c Ketoaldehyde 4d spontaneously undergoes intramolecular aldol reaction during flash chromatography on silica gel.
It is worth to mention that the overall sequence does not attempts failed. After protection of the hydroxyl group of
require any purification of intermediates 3 and 4, which in 5e and chromatographic separation of diastereomers, we
fact tend to be rather unstable upon exposure to silica gel. finally succeeded to convert compound 6 into 3-bromo-2-
In the case of cyclopentenones 5c and 5e we were able to hydroxycyclopent-2-enone 7 using NBS in MeCN and
obtain comparable overall yields (65% vs. 64% in the case H2O (Scheme 2).16 This opened us access to enol phos-
of 5c) or even higher yields (55% vs. 40% in the case of phate 817 and bromo triflate 9 in moderate yields.18 These
5e) when no purification was performed. A further simpli- intermediates may be suitable for cross-coupling reac-
fication of our protocol represents a one-pot transforma- tions.
tion of crude primary allene adducts into ketoaldehydes 4.
Upon completion of the AuCl-catalyzed 5-endo-trig cy-
Next, we wanted to demonstrate the potential of our high-
ly substituted cyclopentenones as precursors of unusual
clization of a-allenyl alcohols, just H2O and DDQ were
amino acid derivatives. This goal should be achieved by
added to the reaction mixture and after usual workup15 the
1,3-dipolar cycloaddition19 of nitrone 12 (Scheme 3). The
resulting a,b-unsaturated g-ketoaldehydes 4 were isolat-
ed.
thermal intermolecular cycloaddition of cyclopentenone
5c and nitrone 12 did not yield any product, whereas the
We were then interested in selective transformations of more reactive nitrile oxide, generated in situ from the cor-
the enol ether moiety of the cyclopentenones prepared. responding chloroxime 10, provided at least 28% of the
This, however, proved to be an arduous task as different expected cycloadduct 11 (60:40 mixture of two diaste-
Synlett 2008, No. 5, 769–773 © Thieme Stuttgart · New York

CLUSTER
Synthesis of Highly Substituted Cyclopentenones
771
OMe
Br
OH
destine them as interesting substrates for diversity orient-
ed synthesis.
b
RO
O
TBDMSO
O
Acknowledgment
OBn
OBn
7
5e: R = H
6: R = TBDMS
The authors thank the Deutsche Forschungsgemeinschaft, the Alex-
ander von Humboldt Stiftung (research fellowship for B.D.), the
Fonds der Chemischen Industrie, and the Bayer Schering Pharma
AG for generous support. We are very grateful to Dr. Malte Bras-
holz for preliminary experiments on intramolecular aldol additions
and help during preparation of this manuscript.
a
c
d
OPO(OMe)2
Br
OTf
TBDMSO
O
TBDMSO
O
References and Notes
OBn
OBn
9
8
(1) Flögel, O.; Reissig, H.-U. Eur. J. Org. Chem. 2004, 2797.
(2) Brasholz, M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2007,
46, 1634; Angew. Chem. 2007, 119, 1659.
(3) Related ketoaldehydes have recently been utilized for the
total synthesis of the cyclopentenone core of
Scheme 2 Synthesis of enol phosphate 8 and of bromo triflate 9.
Reagents and conditions: a) TBDMSCl, imidazole, CH2Cl2, r.t., 12 h,
80%; b) NBS, MeCN, H2O, r.t., 18 h, 75%; c) 1. n-BuLi, Et2O,
–78 °C; 2. Tf2O, –78 °C, 1 h, 38%; d) P(OMe)3, CH2Cl2, r.t., 2 d,
42%.
Litseaverticillols: (a) Vassilikogiannakis, G.; Stratakis, M.
Angew. Chem. Int. Ed. 2003, 42, 5465; Angew. Chem. 2003,
115, 5623. (b) Vassilikogiannakis, G.; Margaros, I.;
Montagnon, T. Org. Lett. 2004, 6, 2039.
reomers). The low reactivity of cyclopentenone 5c is
probably due to the fact that electron-donating and elec-
tron-withdrawing substituents are geminally attached to
double bond.20 It is well known that nitrone cycloaddi-
tions can be strongly accelerated in the presence of Lewis
acids.21 Tamura et al. reported that treatment of a-meth-
oxycarbonyl-substituted nitrones with allyl alcohols in the
presence of Ti(Oi-Pr)4 resulted in tandem transesterifica-
tion, E/Z-isomerization and an intramolecular cycloaddi-
(4) Noyori, R.; Suzuki, M. Science 1994, 259, 44.
(5) (a) Umino, K.; Furumai, T.; Matsuzawa, N.; Awataguchi,
Y.; Ito, Y.; Okuda, T. J. Antibiot. 1973, 26, 506. (b)Umino,
K.; Takeda, N.; Ito, Y.; Okuda, T. Chem. Pharm. Bull. 1974,
22, 1233.
(6) (a) Haneishi, T.; Terahara, A.; Arai, M.; Hata, T.; Tamura,
C. J. Antibiot. 1974, 27, 386. (b) Haneishi, T.; Terahara, A.;
Arai, M.; Hata, T.; Tamura, C. J. Antibiot. 1974, 27, 393.
(7) For recent reviews on routes to cyclopentenones, see:
(a) Tius, M. A. Eur. J. Org. Chem. 2005, 2193. (b) Gibson,
S. E.; Mainolfi, N. Angew. Chem. Int. Ed. 2005, 44, 3022;
Angew. Chem. 2005, 117, 3082. (c) Gibson, S. E.; Lewis, S.
E.; Mainolfi, N. J. Organomet. Chem. 2004, 689, 3873.
(8) (a) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim.
Pays-Bas 1968, 87, 1179. (b) Magnus, P.; Albaugh-
Robertson, P. J. Chem. Soc., Chem. Commun. 1984, 804.
(c) Zimmer, R.; Reissig, H.-U. In Modern Allene Chemistry,
Vol. 1; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004, Chap. 8, 425–492. (d) Hormuth, S.;
Reissig, H.-U. Synlett 1991, 179. (e) Hormuth, S.; Reissig,
H.-U. J. Org. Chem. 1994, 59, 67.
tion to provide polycyclic compounds in
a
stereocontrolled manner.22 Gratifyingly, the Ti(Oi-Pr)4-
promoted cycloaddition of nitrone 12 to cyclopentenone
5c, gave a single tetracyclic product 13 in 75% yield.23
This interestingly functionalized cycloadduct offers many
options for further synthetic endeavors.
OMe
N
EtOOC
O
HO
a
N
H
OMe
O
+
HO
O
EtOOC
Cl
HO
(9) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim. Pays-
Bas 1969, 88, 609.
10
5c
(10) (a) Olsson, L.-I.; Claesson, A. Synthesis 1979, 743.
(b) Okala Amombo, M.; Hausherr, A.; Reissig, H.-U. Synlett
1999, 1871. (c) Flögel, O.; Okala Amombo, M.; Reissig, H.-
U.; Zahn, G.; Brüdgam, I.; Hartl, H. Chem. Eur. J. 2003, 9,
1405. (d) Kaden, S.; Brockmann, M.; Reissig, H.-U. Helv.
Chim. Acta 2005, 88, 1826. (e) Kaden, S.; Reissig, H.-U.
Org. Lett. 2006, 8, 4763. (f) Chowdhury, M. A.; Reissig, H.-
U. Synlett 2006, 2383.
11 (dr ≈ 60:40)
Bn
OMe
O
N
O
O
–
O
Bn
+
N
H
HO
OMe
b
O
+
O
EtOOC
5c
12
(11) Brasholz, M.; Reissig, H.-U. Synlett 2007, 1294.
(12) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
(13) Typical Procedure for the Intramolecular Aldol
Reaction: Preparation of Compound 5c
13
Scheme
3
1,3-Dipolar cycloadditions of cyclopentenone 5c.
Reagents and conditions: a) Et3N, Et2O, r.t., 17 h, 28%; b) Ti(Oi-Pr)4
The mixture of ketoaldehyde 4c (1.61 g, 8.20 mmol) and
MeONa (44 mg, 0.82 mmol) in dry MeOH (15 mL) was
stirred at r.t. overnight. The reaction was quenched with sat.
aq NH4Cl solution, extracted with Et2O, and dried (Na2SO4).
After evaporation of solvents the resulting crude product
was purified by flash chromatography [silica gel, EtOAc–
hexane (1:2)] yielding 1.23 g (76%) of a brownish syrup.
1H NMR (500 MHz, CDCl3): d = 1.32–1.80 (m, 10 H,
(1 equiv), CH2Cl2, r.t., 2 d, 75%.
In conclusion, we have reported a simple and efficient
synthesis of highly substituted cyclopentenones starting
from lithiated methoxyallene as C3 building block and al-
dehydes with a-C–H moiety as C2 unit.24 Easy access,
unique substitution pattern, and structural variability pre-
Synlett 2008, No. 5, 769–773 © Thieme Stuttgart · New York

772
B. Dugovič, H.-U. Reissig
CLUSTER
5 × CH2), 1.90 (sbr, 1 H, OH), 3.76 (s, 3 H, OCH3), 4.60 (dbr,
Si(CH3)2], 0.88 [s, 9 H, C(CH3)3], 2.41–2.43 (m, 1 H, 5-H),
3.71 (dd, J = 9.4, 3.5 Hz, 1 H, CH2O), 3.83 (d, JHP = 11.9 Hz,
3 H, OCH3), 3.85 (t, J = 9.4 Hz, 1 H, CH2O), 3.88 (d,
JHP = 11.4 Hz, 3 H, OCH3), 4.44, 4.52 (2 d, J = 12.0 Hz,
2 × 1 H, CH2Ph), 4.96 (sbr, 1 H, 4-H), 7.06 (dt, J = 2.5, 1.2
Hz, 1 H, 3-H), 7.27–7.36 (m, 5 H, Ph) ppm. 13C NMR (125
MHz, CDCl3): d = –4.7 [q, Si(CH3)2], 17.9 [s, C(CH3)3],
25.7 [q, C(CH3)3], 55.1 (d, C-5), 55.3 (2 qd, JCP = 6.3 Hz,
OCH3), 65.9 (t, CH2O), 68.9 (d, C-4), 73.3 (t, CH2Ph), 127.7,
127.8, 128.3, 137.7 (3 d, s, Ph), 141.2 (dd, JCP = 3.3 Hz, C-
3), 148.3 (s, C-2), 197.5 (s, C-1) ppm. IR (film): n = 2955–
2855 (=CH, CH), 1735 (C=O), 1630 (C=C) cm–1. HRMS
(ESI-TOF): m/z calcd for C21H33O7NaPSi+ [M + Na]+:
479.1631; found: 479.1631.
J = 3.2 Hz, 1 H, 4-H), 6.22 (d, J = 3.2 Hz, 1 H, 3-H) ppm. 13
C
NMR (125 MHz, CDCl3): d = 22.1, 22.7, 25.0, 27.7, 34.1 (5
t, 5 × CH2), 50.6 (s, C-5), 57.1 (q, OCH3), 74.1 (d, C-4),
123.6 (d, C-3), 156.5 (s, C-2), 205.1 (s, C-1) ppm. IR (film):
n = 3430 (OH), 3010–2855 (=CH, CH), 1710 (C=O), 1635
(C=C) cm–1. MS (EI, 80 eV): m/z (%) = 196 (64) [M+], 179
(7) [M+ – OH], 71 (100) [C5H11+]. HRMS (ESI-TOF): m/z
calcd for C11H17O3+ [M + H]+ 197.1178; found: 197.1157.
(14) The organocatalytic approach using L-proline as catalyst for
aldol reaction resulted only in moderate yields (12–34%) of
cyclopentenones 5a. Moreover, in most cases a significant
amount of starting ketoaldehyde 4a was recovered: Dugovič,
B.; Reissig, H.-U. unpublished results.
(15) Typical Procedure for the One-Pot Transformation:
Preparation of Compound 4c
(18) Preparation of Compound 9
Under an atmosphere of Ar a solution of 7 (200 mg, 0.47
mmol) in Et2O (5 mL) was successively treated at –78 °C
with n-BuLi (2.5 M in hexane, 0.19 mL, 0.47 mmol) and
Tf2O (0.10 mL, 0.17 g, 0.62 mmol). After 1 h, the reaction
was quenched by addition of sat. aq NaHCO3 solution, H2O
was added and the mixture was extracted with Et2O, the
combined extracts were dried (Na2SO4), and the solvent was
evaporated. The crude product was purified by
Methoxyallene (6.90 mL, 5.80 g, 82.6 mmol) was dissolved
in Et2O (150 mL) at –40 °C under an atmosphere of Ar. n-
BuLi (30.4 mL, 2.5 M in hexane, 75.9 mmol) was added, the
mixture was stirred for 1 h and then cooled to –78 °C. A
solution of cyclohexanecarbaldehyde (2c, 4.00 mL, 3.70 g,
33.0 mmol) in Et2O (50 mL) was slowly added and the
mixture was stirred at –78 °C for 1.5 h. Then, H2O (50 mL)
was added and the mixture was warmed up to r.t. The layers
were separated and the aqueous layer was extracted with
Et2O. The combined organic layers were dried (Na2SO4),
filtered, and after evaporation the allenyl alcohol was
obtained as a yellow oil (6.13 g, quant.). The crude product
was dissolved in dry CH2Cl2 (300 mL). Pyridine (0.40 mL,
0.39 g, 4.95 mmol) and AuCl (0.38 g, 1.65 mmol) were
added with vigorous stirring under an atmosphere of Ar at
r.t. After 1 h TLC showed complete consumption of allenyl
alcohol. Water (15.0 mL) and DDQ (15.0 g, 66.0 mmol)
were added and stirring was continued for 1 h. The mixture
was poured into sat. aq NaHCO3 solution, and the aqueous
phase was extracted with CH2Cl2. The combined organic
phases were washed with brine and dried (Na2SO4) and the
solvent was removed to provide 6.75 g of crude
chromatography on silica gel (3% EtOAc in hexane) to yield
100 mg (38%) of 9 as colorless oil.
1H NMR (500 MHz, CDCl3): d = 0.06, 0.19 [2 s, 2 × 3 H,
Si(CH3)2], 0.89 [s, 9 H, C(CH3)3], 2.64 (td, J = 3.3, 2.0 Hz, 1
H, 5-H), 3.69, 3.89 (2 dd, J = 9.6, 3.3 Hz, 2 × 1 H, CH2O),
4.43, 4.54 (2 d, J = 12.1 Hz, 2 × 1 H, CH2Ph), 4.96 (d,
J = 2.0 Hz, 1 H, 4-H), 7.25–7.36 (m, 5 H, Ph) ppm. 13C NMR
(125 MHz, CDCl3): d = –4.6, –4.5 [2 q, Si(CH3)2], 18.0 [s,
C(CH3)3], 25.6 [q, C(CH3)3], 56.4 (d, C-5), 65.2 (t, CH2O),
72.4 (d, C-4), 73.5 (t, CH2Ph), 127.9, 128.0, 128.5, 137.2 (3
d, s, Ph), 147.2, 150.9 (2 s, C-2, C-3), 191.3 (s, C-1) ppm,
signal of CF3 not detectable. IR (film): n = 3090–2860 (=CH,
CH), 1740 (C=O), 1635 (C=C) cm–1. HRMS (ESI-TOF):
m/z calcd for C20H27BrF3O6SSi+ [M + H]+: 559.0433; found:
559.0438.
ketoaldehyde 4c. Purification by flash chromatography on
silica gel (CH2Cl2) provided 5.51 g (85%) of pure 4c.
Mp 41–45 °C. 1H NMR (500 MHz, CDCl3): d = 1.19–1.27,
1.28–1.40, 1.68–1.71, 1.78–1.87 (4 m, 10 H, 5 × CH2), 2.90–
2.95 (m, 1 H, 1¢-H), 3.79 (s, 3 H, OCH3), 5.53 (d, J = 7.3 Hz,
1 H, 2-H), 9.76 (d, J = 7.3 Hz, 1 H, 1-H) ppm. 13C NMR (125
MHz, CDCl3): d = 25.4, 25.7, 27.7 (3 t, 3 × CH2), 46.7 (d, C-
1¢), 56.4 (q, OCH3), 108.4 (d, C-2), 169.5 (s, C-3), 191.0 (d,
C-1), 201.3 (s, C-4) ppm. IR (KBr): n = 3070–2850 (=CH,
CH), 1705, 1660 (C=O), 1595 (C=C) cm–1. MS (EI, 80 eV):
m/z (%) = 196 (35) [M+], 83 (72) [C6H11+], 55 (100)
[C3H3O+]. Anal. calcd for C11H16O3 (196.2): C, 67.32; H,
8.22. Found: C, 67.22; H, 8.11.
(19) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565;
Angew. Chem. 1963, 75, 604.
(20) (a) We also tried [2+1] and [4+2] cycloadditions of
cyclopentenone 5c or its tert-butyldimethylsilyl ether with
methyl diazoacetate and a-trifluoromethyl-a-nitrosoalkene,
respectively, but in all cases no cycloadducts were formed.
(b) For a recent study on 1,3-dipolar cycloadditions of
captodative olefins see: Herrera, R.; Mendoza, J. A.;
Morales, M. A.; Méndez, F.; Jiménez-Vázquez, H. A.;
Delgado, F.; Tamariz, J. Eur. J. Org. Chem. 2007, 2352.
(21) (a) Gothelf, K. V.; Kanemasa, S.; Jørgensen, K. A. In
Cycloaddition Reactions in Organic Synthesis; Kobayashi,
S.; Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim, 2001,
211–326. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev.
1998, 98, 863. (c) Dugovič, B.; Fišera, L.; Hametner, C.
Synlett 2004, 1569. (d) Dugovič, B.; Wiesenganger, T.;
Fišera, L.; Hametner, C.; Prónayová, N. Heterocycles 2005,
65, 591. (e) Dugovič, B.; Fišera, L.; Cyrański, M. K.;
Hametner, C.; Prónayová, N.; Obranec, M. Helv. Chim. Acta
2005, 88, 1432. (f) Dugovič, B.; Fišera, L.; Reissig, H.-U.
Eur. J. Org. Chem. 2007, 277.
(16) (a) Nowick, J. S.; Danheiser, R. L. Tetrahedron 1988, 44,
4113. (b) Flögel, O.; Reissig, H.-U. Synlett 2003, 405.
(17) Preparation of Compound 8
The solution of 6 (329 mg, 0.91 mmol) in MeCN (12 mL)
and H2O (1 mL) was treated with NBS (161 mg, 0.91 mmol)
at r.t. for 18 h. Water was added and the mixture was
extracted with hexane, the combined extracts were dried
(Na2SO4), and after evaporation the crude product was
filtered through silica gel and washed with 2.5% i-PrOH in
hexane to yield 292 mg (75%) of compound 7. A solution of
7 (68 mg, 0.16 mmol) and P(OMe)3 (56 mL, 59 mg, 0.48
mmol) in CH2Cl2 (1.5 mL) was stirred at r.t. for 2 d. The
volatile components were removed in vacuo and the residue
was purified by chromatography (silica gel, 1:3 EtOAc–
hexane) to yield 31 mg (42%) of 8 as colorless oil.
(22) Tamura, O.; Yamaguchi, T.; Noe, K.; Sakamoto, M.
Tetrahedron Lett. 1993, 34, 4009.
(23) Preparation of Compound 13
The reaction was carried out under an argon atmosphere. To
a stirred solution of cyclopentenone 5c (0.46 g, 2.35 mmol)
and nitrone 12 (0.96 g, 4.63 mmol) in CH2Cl2 (10 mL) was
added Ti(Oi-Pr)4 (0.70 mL, 0.87 g, 2.35 mmol) at r.t., and
stirring was continued at the same temperature until
1H NMR (500 MHz, CDCl3): d = 0.06, 0.10 [2 s, 2 × 3 H,
Synlett 2008, No. 5, 769–773 © Thieme Stuttgart · New York

CLUSTER
cyclopentenone 5c disappeared (monitored by TLC, 2 d).
Synthesis of Highly Substituted Cyclopentenones
773
54.1 (d, C-4), 57.4 [s, C(CH2)2], 67.3 (dbr, C-3), 79.7 [d,
CHOC(O)] 127.7, 128.5, 128.8, 135.9 (3 × d, s, Ph), 172.4
[sbr, OC(O)], 206.2 (s, C=O) ppm; signals of C-5 and
NCH2Ph are not visible, according to HMBC C-5, d ca.
110.2, NCH2Ph, d ca. 67.3 ppm. IR (KBr): n = 3110–2840
(=CH, CH), 1790, 1750 (C=O) cm–1. HRMS (ESI-TOF):
m/z calcd for C20H24NO5+ [M + H]+: 358.1655; found:
358.1687. Anal. calcd for C8H12O3 (357.4): C, 67.21, H,
6.49; N, 3.92. Found: C, 67.03; H, 6.46; N, 3.95.
The reaction mixture was poured onto silica gel, which was
then washed with EtOAc–hexane (1:3). After removal of
solvents the crude product was recrystallized (EtOAc–
hexane, 1:3) to provide 0.62 g (75%) of 13 as colorless solid.
Mp 148–152 °C. 1H NMR (500 MHz, CDCl3): d = 1.36–
1.54, 1.61–1.66, 1.73–1.81 (3 m, 4 H, 2 × 3 H, CH2), 3.49 (s,
3 H, OCH3), 4.00 (sbr, 1 H, 4-H), 4.25 (d, J = 13.3 Hz, 1 H,
CH2Ph), 4.30 (d, J = 7.7 Hz, 1 H, 3-H), 4.48 (dbr, J = 13.3
Hz, 1 H, CH2Ph), 4.84 [d, J = 6.9 Hz, 1 H, CHOC(O)], 7.29
(d, J = 7.2 Hz, 1 H, Ph), 7.34 (t, J = 7.2 Hz, 2 H, Ph), 7.44 (d,
J = 7.2 Hz, 2 H, Ph) ppm. 13C NMR (100 MHz, CDCl3):
d = 21.0, 21.5, 25.0, 26.5, 30.9 (5 × t, CH2), 52.8 (q, OCH3),
(24) For an interesting alternative approach to cyclopentene
derivatives employing lithiated allenyl MOM ethers, see:
Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398.
Synlett 2008, No. 5, 769–773 © Thieme Stuttgart · New York

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