Photoinduced radical reactions of α-alkylated ethyl 2-oxo-1-cyclopentanecarboxylate derivatives: α-cleavage and cyclization to the skeleton of linear cyclohexano diquinanes

Article abstract of DOI:10.1016/j.tetlet.2007.12.089

The tricyclic core of linear cyclohexano diquinanes was synthesized using photoinduced electron transfer (PET) as a key step. The reaction proceeded in high regioselective manner via ketyl radical anions leading to distonic δ-keto radical anion as reactive intermediates. The irradiation was carried out at a wavelength of 254 nm with triethylamine (TEA) as a strong reducing reagent in acetonitrile. We also showed that the photolysis of the α-alkylated 2-oxocyclopentanecarboxylate derivatives does not lead to any cyclization products via a δ-hydrogen abstraction process. In this case α-C-C bond cleavage as a predominant process was observed.

Full text of DOI:10.1016/j.tetlet.2007.12.089

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1710–1713
Photoinduced radical reactions of a-alkylated ethyl
2-oxo-1-cyclopentanecarboxylate derivatives: a-cleavage and
cyclization to the skeleton of linear cyclohexano diquinanes
Nikolay T. Tzvetkov a, Prashant A. Waske b, Beate Neumann c,
Hans-Georg Stammler c, Jochen Mattay d,*
a Pharmazeutisches Institut, Universita¨t Bonn, An der Immenburg 4, 53121 Bonn, Germany
b 23 College Road, Parsons Hall, Department of Chemistry, University of New Hampshire, Durham, NH 03824, USA
c Abteilung fu¨r Ro¨ntgenstrukturanalyse AC III, Fakulta¨t fu¨r Chemie, Universita¨t Bielefeld, Universita¨tsstr. 25, 36615 Bielefeld, Germany
d Organische Chemie I, Fakulta¨t fu¨r Chemie, Universita¨t Bielefeld, Postfach 100131, 33501 Bielefeld, Germany
Received 27 July 2007; revised 13 December 2007; accepted 18 December 2007
Available online 23 December 2007
Abstract
The tricyclic core of linear cyclohexano diquinanes was synthesized using photoinduced electron transfer (PET) as a key step. The
reaction proceeded in high regioselective manner via ketyl radical anions leading to distonic d-keto radical anion as reactive intermedi-
ates. The irradiation was carried out at a wavelength of 254 nm with triethylamine (TEA) as a strong reducing reagent in acetonitrile. We
also showed that the photolysis of the a-alkylated 2-oxocyclopentanecarboxylate derivatives does not lead to any cyclization products via
a d-hydrogen abstraction process. In this case a-C–C bond cleavage as a predominant process was observed.
Ó 2007 Elsevier Ltd. All rights reserved.
Among the natural products bearing a tricyclic cyclo-
15
H
H
H
pentane framework, the linearly fused triquinanes are most
versatile and abundant, mostly in microbial sources.1 The
class of linear triquinanes is further divided in four different
skeletal types, depending on the location of the four carbon
substituents. However, only the thermodynamically
favored cis,anti,cis-tricyclo[6.3.0.02,6]undecane skeleton 1
has been encountered as the basic carbocyclic framework
of a large number of naturally occurring triquinanes
(Fig. 1).
1
11
1
3
A
C
7
B
3
9
6
14
H
H
H
H
1
2
H
H
OH
H
O
HO2C
HO2C
5
11
3
9
The hirsutanes2,3 represent a group of fungal metabo-
lites, whose basic hydrocarbon skeleton biogenetically
arises from the connection of the C1–C11, C2–C9, and
C3–C7 carbon atoms as well as movement of the methyl
groups C14 and C15 in the farnesane sesquiterpene 2
(Fig. 1).2 The sesquiterpene ( )-hirsutene 3, isolated3 from
O
O
H
H
4
5
Fig. 1. Linear triquinane frameworks.
Basidomycetes Coriolus consors, is the simplest member of
the hirsutane group of linear triquinanes.1b,3 The epoxide
derivatives ( )-hirsutic acid-C 4, was the first triquinane
natural product isolated from Basidomycetes Stereum
hirsutum4 and its structure was later confirmed through
*
Corresponding author. Tel.: +49 521 106 2072; fax: +49 521 106 6417.
E-mail address: oc1jm@uni-bielefeld.de (J. Mattay).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.089

N. T. Tzvetkov et al. / Tetrahedron Letters 49 (2008) 1710–1713
1711
spectroscopic and X-ray analysis.5 The biogenetic precur-
Table 1
Monoalkylation of ethyl 2-oxo-1-cyclopentanecarboxylate 6
sor of the ( )-hirsutic acid-C 4, the sesquiterpene ( )-com-
plicatic acid 5, isolated from the fungus Stereum
complicatum6 consist a carbonyl group at position 5.1d
As a result of the promising biological properties of
compounds 4 and 5,7 several strategies for their synthesis
have been employed.3,8 In recent years, the photoinduced
radical/radical anionic cyclization was applied in the syn-
thesis of linear triquinanes.9 For example, rac-hirsutene 4
was synthesized by using of PET process as key step
reaction.9a
O
O
R
R
Br
CO2Et
*
base
CO2Et
6
7 a-d
R
Conditions
Product Yield
(%)
K2CO3 (2.5 equiv)
DMF, microwave
900 W, 4 min
1.2 equiv
7a
97
To demonstrate the potential of the PET method, the
syntheses of the skeleton of linearly fused cyclopentanoids
by PET will be presented in this Letter. Our synthetic con-
cept is illustrated in Scheme 1. We used a two-step conver-
gent strategy9a including a-alkylation of differently
substituted (R1 = R2 = H or Me) b-keto ester derivatives
(ring A) with 1-bromomethyl-1-cycloalkenyl reagents (ring
C) followed by an intramolecular ring fusion for the con-
struction of ring B. In general, this key step is achieved
by a photoinduced electron transfer from TEA (electron
donor) to the a-alkylated b-keto ester (electron acceptor)
in dry acetonitrile.
The main challenge in the synthesis of linear triquinanes
is the construction of five-membered rings, while the con-
trol of the stereochemistry during ring fusion is not a seri-
ous problem since cis,anti,cis is the preferred
stereochemistry.1
The a-substituted b-keto ester derivatives 7a–d were syn-
thesized using ethyl 2-oxocyclopentanecarboxylate 6 as a
starting material.10 The details of a-alkylation reactions
with various alkyl bromides are shown in Table 1. The
alkylation of the thermodynamically preferred a-position
was realized following a modified literature procedure.11
In general, 1 equiv of the corresponding alkylation reagent
and of potassium-tert-butylate as base were used under
reflux. The best yield (92%) was achieved with propargyl
bromide (ꢀ80% in toluene). In the case of 7a, alkylation
with benzyl bromide was carried out by using microwave
tBuOK (1.0 equiv)
tBuOH, 24 h reflux
1.0 equiv
1.0 equiv
7b
7c
25
92
tBuOK (1.0 equiv)
tBuOH, 2 h reflux
tBuOK (1.0 equiv)
tBuOH, 1 h reflux
1.0 equiv
7d
74
Me3Si
irradiation in the presence of potassium carbonate in
DMF.12
The synthesis of 2,3-disubstituted cyclopenta-indanes
9a and 9b via a photoinduced cyclization failed due to
preferred a-C–C-bond cleavage of 7a and subsequently
d-hydrogen atom abstraction in analogy to earlier results
published by us.13
The photolysis of 7a was carried out in accordance to
the literature data at a wavelength of 300 nm in dry benzene
(Scheme 2).14 Irradiation for 21 h led to the formation of
two isomers: the (E)-isomer 8a and the (Z)-isomer 8b in
26 and 30% yields, respectively, after chromatographic sep-
aration. The product ratio was determined by GC as 47:53
(8a/8b). The stereochemistry of 8a and 8b was accom-
plished by NMR analysis including NOESY experiments.
On the other hand, formation of the assumed tricyclic com-
pounds 9a and 9b under PET irradiation conditions was
not observed by means of GC and GC–MS analysis.
O
Br
C
( )m
O
O
α-alkylation
R1
R2
A
( )n*
O
H
300nm
*
+
C
( )m
R1
R2
CO2Et
O
PhH
α-C-C cleavage
A
CO2Et
CO2Et
( )n*
H
+
H
7a
8a
26%
(E)-isomer
CO2Et
CO2Et
H
PET
H
n
= 1,2
m = 1,2
R1 = R2 = H or CH3
δ-H abstraction
or PET
HO
A*
8b
30%
(Z)-isomer
*C
B
R1
R2
HO
HO
*
*
+
( )n
( )m
CO2Et
CO2Et
CO2Et
9a
9b
Scheme 1. Retrosynthesis of linear triquinanes using a two-step conver-
gent synthetic concept.
Scheme 2. Photoinitiated a-C–C cleavage of 7a.

1712
N. T. Tzvetkov et al. / Tetrahedron Letters 49 (2008) 1710–1713
The starting material of this PET reaction was completely
reisolated.
The mechanistic details of the reductive PET reaction of
7b are illustrated in Scheme 4. The initially formed ketyl
radical anions 12a/12b, resulting from the corresponding
conformers of 7b, cyclize to form the new distonic c-radical
anions 13a/13b giving 10a and 10b in a 5-endo fashion after
protonation and hydrogen saturation (Scheme 4). In this
case, the formation of 5-endo fused ring is highly favored
according to Baldwin’s rules and literature data.19
The calculated geometry of the lowest-energy conform-
ers of 10a (cis,anti,cis) and 10b (cis,syn,cis) is presented in
Scheme 4. The results of the calculates geometry of 10a
were confirmed by analysis of the X-ray data.16 In general,
the photolysis of 7b shows the same features compared to
7a, that is, a-C–C-bond cleavage followed by a d-hydrogen
atom abstraction. Consequently, irradiation in dry n-hex-
ane without TEA as electron donor led to a mixture of
In our previous communications, we reported that the
basic framework of linear triquinanes is easily accessible
by photoreduction of ring-expanded tricyclic alkanone
derivatives.15 Here this concept was applied to 2-oxocyclo-
hexenyl substituted b-keto ester 7b as starting material. The
details of the reductive PET reaction of 7b are shown in
Scheme 3 and Table 2.
A deoxygenated solution (0.05 M) of 7b in dry acetoni-
trile was irradiated in the presence of 10 equiv of TEA in a
Rayonet photochemical reactor at 254 nm (quartz tubes).
The degree of conversion of the starting material was mon-
itored by GC and GC/MS. The intramolecular radical
anion cyclization proceeded highly regioselective and led
to a mixture of two diastereoisomers: cis,anti,cis isomer
10a and cis,syn,cis isomer 10b.16 The mixture was purified
by column chromatography followed by preparative
HPLC separation. The product ratio was determined by
GC of the isolated mixture as 59:41 (10a/10b). The struc-
ture determination of 10a and 10b16 was accomplished by
spectroscopic analysis using one- and two-dimensional
NMR spectroscopy. Additionally, 10a was confirmed by
X-ray crystal structure analysis17 and shows the thermody-
namically preferred cis,anti,cis configuration (Scheme
3).1b,c The stereochemistry of 10b was assigned using qual-
itative NOESY spectroscopy in combination with 1H
NMR analysis supported by molecular modeling of the
respective geometries using MMFF94 force field
calculations.18
O
*
CO2Et
7b
-
-
-
+e
+e
-
O
O
12a
12b
-
-
H
H
O
O
O
HO
H
HO
H
hυ
*
+
EtO2C
EtO2C
CO2Et
EtO2C
H
EtO2C
H
13a
13b
+H+/+H
7b
10a
10b
+H+/+H
h
υ
O
H
CO2Et
H
mixture of two isomers
10a
cis,anti,cis
10b
cis,syn,cis
11a-b
10a
Scheme 4. Proposed reaction mechanism of reductive PET cyclization of
Scheme 3. Photoinitiated reactions of 7b.
a-substituted ethyl cyclopentanone carboxylate 7b.
Table 2
Irradiation reactions of ethyl 1-benzyl-2-oxocyclopentanecarboxylate 7b
Process
Conditions
Product
Yield (%)
PET cyclization
254 nm, TEA (10.0 equiv), MeCN (0.05 M), 1.5 h
10a
10b
12
9
58a
a-C–C cleavage
150 W Hg-lamp, n-hexane (0.02 M), 7 h
11a,b
a
Combined isolated yield of mixture of two isomers.

N. T. Tzvetkov et al. / Tetrahedron Letters 49 (2008) 1710–1713
1713
13. Tzvetkov, N. T.; Mattay, J. Tetrahedron Lett. 2005, 46, 7751–7755.
14. (a) Bischof, E. W. Ph.D. Dissertation, Reinisch-westfa¨lische Techni-
sche Hochschule, Aaachen, Germany, 1991. For diastereoselective
synthesis of functionalized 1,2,3-trisubstituted benzocyclopentenes:
(b) Adam, W.; Gogonas, E. P.; Hadjiarapoglon, L. P. J. Org. Chem.
2003, 68, 9155–9158.
15. (a) Mattay, J.; Banning, A.; Bischof, E. W.; Heidbreder, A.; Runsink,
J. Chem. Ber. 1992, 125, 2119–2127; (b) Bischof, E. W.; Mattay, J. J.
Photochem. Photobiol. A: Chem. 1992, 63, 249–251.
two E-/Z-isomer 11a/b in 58% combined yield after chro-
matographic purification (Scheme 3/Table 2).
In summary, we have shown that linear cyclohexano
diquinane frameworks 10a/10b are accessible using a two-
step convergent synthetic concept, starting from commer-
cially available b-keto ester 6. Furthermore, the reaction
sequence involving a reductive PET cyclization as a key
step should be capable for the preparation of other linearly
fused tricyclic systems possessing different ring-members
and substituents.
16. (a) Selected spectral data for compound 10a: 1H NMR (500 MHz,
C6D6) d 0.91 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.02–1.10 (m, 1H), 1.18
(dd, J = 6.5 and 12.9 Hz, 1H), 1.23 (dd, J = 6.0 and 11.1 Hz, 1H),
1.32–1.40 (m, 2H), 1.43 (dd, J = 4.9 and 15.5 Hz, 1H), 1.48–1.72 (m,
7H), 1.87 (dd, J = 6.1 and 11.0 Hz, 1H), 1.92 (dd, J = 6.5 and
11.3 Hz, 1H), 1.98–2.04 (m, 1H), 2.60 (t, J = 12.8 Hz, 2H), 2.98 (s,
1H, OH), 3.93 (q, J = 7.1 Hz, 2H, OCH2CH3) ppm; 13C NMR
(125 MHz, C6D6) d 14.4 (OCH2CH3), 21.8 (CH2), 22.4 (CH2), 25.7
(CH2), 26.2 (CH2), 27.0 (CH2), 35.1 (CH), 38.9 (CH2), 40.5 (CH2),
44.2 (CH2), 49.2 (CH), 60.9 (OCH2CH3), 62.5 (C), 94.4 (C), 176.8
(CO2Et) ppm; IR mmax (KBr)/cmÀ1 3511, 2925, 2875, 2854, 1724,
1704, 1448, 1367, 1255, 1130, 973; GC–MS (EI) m/z (%) 252 (6) [M+],
210 (8), 206 (17), 191 (20), 179 (23), 178 (33), 162 (77), 161 (63), 160
(18), 156 (100), 150 (32), 133 (30), 121 (17), 119 (29), 117 (18), 111
(26), 110 (67), 109 (74), 105 (27); HRMS (EI) calcd for C15H24O3 m/z
252.1725, m/z found 252.1714; (b) Selected spectral data for compound
Supplementary data
All synthetic procedures and analytical data of com-
pounds 7a–d and 8a,b are available from the authors on
request, or via http://bieson.ub.uni-bielefeld.de/opus/
frontdoor.php?source_opus=639.20
Acknowledgments
Financial support by the Volkswagen-Stiftung, the
Deutsche Forschungsgemeinschaft (DFG), and the Inno-
vationsfonds of the University of Bielefeld is gratefully
acknowledged.
10b: 1H NMR (500 MHz, C6D6)
d 0.92 (t, J = 7.0 Hz, 3H,
OCH2CH3), 1.01–1.10 (m, 1H), 1.11–1.15 (m, 1H), 1.16–1.24 (m,
1H), 1.25–1.31 (m, 1H), 1.38 (d, J = 12.4 Hz, 1H), 1.44–1.54 (m, 5H),
1.63 (dd, J = 7.8 and 13.6 Hz, 1H), 1.70–1.80 (m, 1H), 1.81–1.88 (m,
1H), 2.02 (dd, J = 5.6 and 18.7 Hz, 1H), 2.05 (d, J = 5.4 Hz, 1H),
2.33–2.42 (m, 1H), 2.46 (dd, J = 8.6 and 11.5 Hz, 1H), 2.67 (dtdd,
J = 2.2, 12.2, 12.0 and 23.9 Hz, 1H), 2.85 (s, 1H, OH), 3.95 (dq,
J = 2.7 and 9.7 Hz, 2H, OCH2CH3) ppm; 13C NMR (125 MHz,
C6D6) d 14.2 (OCH2CH3), 21.7 (CH2), 23.8 (CH2), 25.2 (CH2), 26.8
(CH2), 27.3 (CH2), 37.5 (CH2), 37.5 (CH2), 38.3 (CH), 40.0 (CH2),
49.9 (CH), 60.6 (OCH2CH3), 63.7 (C), 96.0 (C), 176.44 (CO2Et) ppm;
IR mmax (neat)/cmÀ1 3480, 2935, 2856, 1708, 1446, 1367, 1288, 1130,
1029, 977; GC–MS (EI) m/z (%) 253 (1) [M++1H], 252 (4) [M+], 210
(7), 206 (14), 191 (19), 189 (15), 179 (16), 178 (25), 162 (78), 161 (61),
160 (24), 157 (12), 156 (100), 150 (28), 149 (16), 133 (31), 127 (20), 119
(29), 117 (20), 111 (26), 110 (88), 109 (75), 105 (26); HRMS (EI) calcd
for C15H24O3 m/z 252.1725, m/z found 252.1712.
References and notes
1. (a) Paquette, L. A.; Doherty, A. M. In Polyquinane Chemistry;
Springer: New York, 1987; Vol. 26; (b) Mehta, G.; Srikrishna, A.
Chem. Rev. 1997, 97, 671–719; (c) Singh, V.; Thomas, B. Tetrahedron
1998, 54, 3647–3692; (d) Austin, K. A. B.; Banwell, M. G.; Harfoot,
G. J.; Willis, A. C. Tetrahedron Lett. 2006, 47, 7381–7384; (e) Mehta,
G.; Pallavi, K. Tetrahedron Lett. 2006, 47, 8355–8360.
2. (a) Nuhn, P. In Natrurstoffe, 2nd ed.; S. Hirzel: Stuttgart, 1990.
Chapter 8; (b) Breitmaier, E. In Terpene; Wiley-VCH: Weinheim,
2005; p 48.
3. Nozoe, S.; Furukawa, J.; Sankawa, U.; Shabata, S. Tetrahedron Lett.
1976, 195–198.
17. X-ray crystallographic data for compound 10a: C15H24O3, M = 252.34,
T = 100(2) K, monoclinic, space group P21/c, Z = 4, a = 11.7381(3),
4. Heatley, N. G.; Jennings, M. A.; Florey, H. W. Br. J. Exp. Pathol.
1947, 28, 35–46.
5. Comer, F. W.; Trotter, J. J. Chem. Soc. B 1966, 11–18.
6. Mellows, G.; Mantle, P. G.; Feline, T. C.; Williams, D. J.
Phytochemistry 1973, 12, 2717–2720.
7. Kupka, J.; Anke, T.; Giannetti, B.-M.; Steglich, W. Arch. Microbiol.
1981, 130, 223–227.
8. (a) Little, R. D.; Muller, G. W. J. Am. Chem. Soc. 1981, 103, 2744–
2749; (b) Curran, D. P.; Rakiewicz, D. M. J. Am. Chem. Soc. 1985,
107, 1448–1449; (c) Curran, D. P.; Rakiewicz, D. M. Tetrahedron
1985, 41, 3943–3958.
3
˚
˚
b = 9.2061(2), c = 12.4965(3) A, ß = 93.4107(15)°, V = 1348.03(6) A ,
Dx = 1.243 g/cm3, 3923 unique data (hmax = 30°), 2895 with I > 2r(I);
R = 0.0450, RW = 0.1107.
Atomic coordinates, bond lengths and angles, and displacement
parameters have been deposited at the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 656838.
These data can be obtained free-of-charge via www.ccdc.cam.ac.uk/
data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by
contacting the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
18. All calculations were carried out with Titan V1.05, Schro¨dinger Inc.,
Wavefunction Inc. (18 August 2000). The conformational analysis
was accomplished at a semiempirical level (AM1).
9. (a) Cossy, J.; Belotti, D.; Pete, J.-P. Tetrahedron 1990, 46, 1859–1870;
(b) Cossy, J.; Belotti, D. Tetrahedron 2006, 62, 6459–6470.
10. Ethyl 2-oxocyclopentanecarboxylate
6 is commercially available
19. (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736; (b)
Beckwith, A. L. J. Tetrahedron 1981, 37, 3073–3100; (c) Beckwith, A.
L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925–3941; (d) Surzur, J.
M. In Reactive Intermediates; Abramovitch, R. A., Ed.; Plenum Press:
New York, 1983; Vol. 2, p 164.
(Fluka Ltd) or can be synthesized following the known three-step
procedure, see also (a) Sisido, K.; Utimoto, K.; Isida, T. J. Am. Chem.
Soc. 1964, 29, 2781–2782; (b) Scha¨fer, J. P.; Bloomfield, I. J. Org.
React. 1967, 15, 1.
11. Klipa, D. H.; Hart, H. J. Org. Chem. 1981, 46, 2815–2816.
12. Nayyak, S.; Trehan, J.; Kaur, J. Ind. J. Chem. 2002, 41B, 2342–2345.
20. Tzvetkov, N. T. Ph.D. Dissertation, University of Bielefeld, 2005.