Synthesis and photoinitiated radical cyclization of allyl- and propynyloxymethyl substituted cyclopentanones to tetrahydrocyclopenta[c]furanols

Article abstract of DOI:10.1016/j.tetlet.2005.09.040

Bicyclic cyclopentafuranols were formed by photoinitiated radical cyclization of allyl- and propinyloxymethyl substituted cyclopentanones with high regioselectivity. The irradiations were carried out at a wavelength of 300 nm in aprotic solvents such as benzene and acetonitrile. We could also show that reductive photoinduced electron transfer (PET) of the propynyloxymethyl substituted cyclopentanone 5 does not lead to any cyclization. The starting materials were synthesized in good yields following known procedures.

Full text of DOI:10.1016/j.tetlet.2005.09.040

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7751–7755
Synthesis and photoinitiated radical cyclization of allyl- and
propynyloxymethyl substituted cyclopentanones to
tetrahydrocyclopenta[c]furanols
a
a,
*
Nikolay T. Tzvetkov and Jochen Mattay
a
Organische Chemie I, Fakult a¨ t f u¨ r Chemie, Universit a¨ t Bielefeld, Postfach 100131, 33501 Bielefeld, Germany
Received 21 July 2005; revised 7 September 2005; accepted 7 September 2005
Available online 26 September 2005
Abstract—Bicyclic cyclopentafuranols were formed by photoinitiated radical cyclization of allyl- and propinyloxymethyl substituted
cyclopentanones with high regioselectivity. The irradiations were carried out at a wavelength of 300 nm in aprotic solvents such as
benzene and acetonitrile. We could also show that reductive photoinduced electron transfer (PET) of the propynyloxymethyl substi-
tuted cyclopentanone 5 does not lead to any cyclization. The starting materials were synthesized in good yields following known
procedures.
Ó 2005 Elsevier Ltd. All rights reserved.
Bicyclic cyclopentanols and cyclopentafuranols are
important structural units in a wide range of unusual
and biologically interesting natural products such as
cyclopentanoid monoterpenes (diquinane) and sesqui-
compounds can be prepared from d,e-unsaturated
ketones in good yields, initiated by photoinduced electron
transfer (PET) from triethylamine (TEA) in acetonitrile
or by photoionization in pure hexamethylphosphoric
1
10
terpenes. Furthermore, the cyclopentafuranols can be
triamide (HMPA). This methodology has also been
used as key intermediates for the synthesis of promising
building blocks for artificial oligonucleotides and other
complex molecules (e.g., hybrids with different pharma-
cophoric units).2
successfully applied for the synthesis of natural prod-
1
1
ucts and biologically active N-heterocyclics such as
1
2
(± )-isooxyskyanthine. The aim of this paper is to
report simple photochemical cyclization reaction of
a-allyl- and a-propynyloxymethyl substituted cyclopen-
1
3
Intramolecular radical reactions have been proven to be
synthetically useful for the construction of five-mem-
tanones leading to bicyclic tertiary cyclopentafuranols.
3
bered fused carbocyclic and heterocyclic structures. In
The general concept is illustrated in Scheme 1 showing
that a d-hydrogen atom abstraction by an electronically
excited carbonyl function is the key step. Here this
hydrogen abstraction from a d-position rather than
from the generally more favored c-position (cf. Nor-
rish-Type II reaction) is the exclusive process due to
the special features of the reactants: the c-position is
4
5
agreement with BaldwinÕs rules and the literature data,
formation of the cyclopentane ring via 5-exo cyclization
mode is highly favored. Accordingly, substituted bi-
cyclooctanols and a-hydroxy bicyclooctanones have
been synthesized using various methods such as electro-
6
chemistry or chemical reduction, for example, naphtha-
7
8
lene sodium and samarium(II)iodide (SmI ). An
2
alternative procedure which combines fragmentation
with intramolecular 1,5-hydrogen atom abstraction is
initiated by tributyltin hydride and led to the formation
9
O
OH
HO
of bicyclic tertiary cycloalkanols. Similarly, the same
O
O
O
hυ
3
00 nm
Keywords: Cyclopentanones; Cyclopentafuranols; Photochemistry;
H-abstraction; Radical cyclization.
I
II
III
*
Corresponding author. Tel.: +49 521 106 2072; fax: +49 521 106
417; e-mail: mattay@uni-bielefeld.de
Scheme 1. Possible pathway for the synthesis of bicyclic
cyclopentafuranols.
6
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.040

7752
N. T. Tzvetkov, J. Mattay / Tetrahedron Letters 46 (2005) 7751–7755
O
ethylene glycol/
CO Et p-TSA/benzene
O
O
O
O
CO Et LAH/THF
CH OH
2
2
2
90%
95%
1
2
3
A 1) NaH/HMPA/Et2O
/reflux
O
O
O
2
)
Br
5% H2SO4/THF
32%
O
O
B 1) NaH/THF/0 ˚C
2
)
4
5
Br
A: 77%
B: 95%
3
O
1
2
) NaH/THF/0 ˚C
Br
O
O
)
5% H2SO4/THF
92%
O
O
98%
6
7
Scheme 2. Synthesis of a-monosubstituted cyclopentanones 5 and 7.
blocked by O-substitution and the d-position is highly
O
O
O
reactive because of its allylic character. Other groups
1
4
have also made use of these special features.
hυ
O
HO
H
HO
H
3
00 nm
Accordingly, by irradiation at an appropriate wave-
length the alkyloxymethyl substituted cyclopentanone I
gives the 1,5-biradical II, which cyclizes to the tertiary
bicyclic cyclopentafuranol III (Scheme 1).
+
5
8a
8b
O
H
O
The propynyl- and allyloxymethyl substituted cyclopen-
tanones 5 and 7 were synthesized starting from the ethyl
1
5
9
2
-oxocyclopentanecarboxylate 1 in a four-step reac-
tion. The details for the synthesis of the starting materi-
als are shown in Scheme 2.
During ketalization,16 2 was formed in high yield and
further used without additional purification. The subse-
quent reduction of the ester group of 2 with LAH fur-
nished 3. Synthesis of 4 and 6 was carried out by
alkylation of 3 with propargyl and allyl bromides, gen-
erally by using sodium hydride in dry THF (see method
O
O
O
hυ
O
HO
H
HO
H
3
00 nm
+
7
10a
10b
1
7a
B in Scheme 2). To transform 3 into 4, we also used
H
sodium hydride in pure HMPA as an alternative method
see method A in Scheme 2).17b However, this procedure
O
O
(
gives lower yield of 4 compared to the method B.
Cleavage of the ketal group of 4 and 6 afforded the cor-
responding propynyl- and allyloxymethyl cyclopenta-
nones 5 and 7 in good yields.
H
H
1
1
Scheme 3. Photoinduced reactions of 5 and 7.
Irradiations of 5 and 7 were carried out at a wavelength
of 300 nm in dry benzene as well as in a polar solvent
ture of the isomers 10a/10b in 1:3 ratio and the oxetane
11 were obtained. Although the yields are not very high
(Table 1). Analysis of the reaction mixtures could not
reveal any reduction products such as alkyloxymethyl
cyclopentanols. Interestingly, both cyclization reactions
show diverse stereoselectivity. Whereas the alkynyl
derivative 5 preferentially leads to the all-cis configured
tetrahydrocyclopenta[c]furanol 8a, 7 forms 10b with the
vinylsubstituent in the trans position as the major
1
8
such as acetonitrile (Scheme 3). In all cases, we
observed the same regioselectivity for the formation of
the bicyclic cyclopentafuranols. At the same time the
unsaturated ethynyl and vinyl function remain
unchanged. The photoinduced reaction of 5 led to the
formation of the diastereomeric bicyclic products 8a/
8
9
b in 3:1 ratio and the one noncyclized minor product
. Starting from allyloxymethyl cyclopentanone 7, mix-

N. T. Tzvetkov, J. Mattay / Tetrahedron Letters 46 (2005) 7751–7755
7753
Table 1. Product yields of photoinduced reactions of 5 and 7 depending on reaction conditions
Entry
Conditions
hm (nm)
Time (h)
20
Conversion (%)
100
Product
Yield (%)
5
PhH (0.12 M)
300
8a
13
5
8
9
b
a
3
5
MeCN (0.12 M)
300
24
100
8a
14
4
5
8
9
b
5
7
MeCN/5 equiv Et
PhH (0.12 M)
3
N/1 equiv LiClO
4
300
300
24
53
––
100
––
10a
––
3
a
1
1
0b
1
16
8
4
a
a
7
MeCN (0.12 M)
300
28
89
10a
1
1
0b
1
12
5
a
The product yields were detected by GC from the combined isolated product fractions after purification by column chromatography.
product (substituent effect). To check the potential of an
alternative PET-cyclization, we irradiated 5 at 300 nm in
acetonitrile in presence of five equivalents of TEA and
ether side chain and/or photodimerization,19 was not
detected. The results of the photoinduced reactions of
5 and 7 as well as the reaction conditions are shown
in Scheme 3 and Table 1.
one equivalent of lithium perchlorate (LiClO ). How-
4
ever, conversion of the starting material under these
conditions was not detected. After purification 5 was
recovered almost completely. Reduction of the carbonyl
group or other side reactions, such as cleavage of the
The products 8–11 were purified by column chromato-
graphy on silica gel and the resulting isomeric mixtures
8a/8b and 10a/10b were separated additionally by
*
R
R
R
H
C
H
H
C
H
H
C
H
O
O
O
O
O
O
H
CH2
hυ
CH2
α-cleavage
CH2
H
R= -C CH, 5
R= -CH CH2, 7
H
δ,H-abstraction
(
Yang-reaction)
R
R
C
H
CH2
O
HO
O
O
CH2
CH2
H
12
R= -C CH, 9
I
II
R
H
H
R
R
C
O
C
CH2
O
O
H
HO
HO
H
O
CH2
CH2
CH2
H
H
H
R= -CH CH2, 11
H
R
R
H
HO
O
H
HO
O
H
R= -C CH, 8a
R= -CH CH2, 10a
R= -C CH, 8b
R= -CH CH2, 10b
Scheme 4. Mechanism of the product formation for the photoreactions of 5 and 7.

7754
N. T. Tzvetkov, J. Mattay / Tetrahedron Letters 46 (2005) 7751–7755
HPLC. The structural analysis was carried out by one-
and two-dimensional NMR (COSY and HMQC: 8a/
3. (a) Curran, D. P. Synthesis 1988, 417–439, and 489–513;
b) Curran, D. P. Synlett 1991, 63–72; (c) Giese, B. Angew.
(
Chem. 1985, 97, 555–566; Giese, B. Angew. Chem., Int. Ed.
Engl. 1985, 24, 553–565; (d) Giese, B. Radicals in Organic
Synthesis: Formation of Carbon–Carbon Bond; Pergamon
Press: Oxford, 1986; (e) Cossy, J.; Leblanc, C. Tetrahedron
Lett. 1989, 30, 4531–4534; (f) Pattenden, G.; Clough, J.
M.; Wight, P. G. Tetrahedron Lett. 1989, 30, 7469–7472;
8
b, 10b, and 11) as well as mass spectroscopy, including
HRMS. The stereochemistry of 8a/8b, 10a/10b, and 11
was assigned by qualitative NOESY in combination
with H NMR coupling constants. Additionally, the ste-
reochemistry of 11 was detected by supported calcula-
tions using MMFF94 force field conformational
analysis.
1
(
g) Sha, C.-K.; Jean, T.-S.; Wang, D.-C. Tetrahedron Lett.
2
0
1990, 31, 3745–3748; (h) Tzvetkov, N.; Schmidtmann, M.;
M u¨ ller, A.; Mattay, J. Tetrahedron Lett. 2003, 44, 5979–
5982.
Mechanistic details of the photoreaction of 5 and 7 are
shown in Scheme 4.
4
5
. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–
7
36.
. (a) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073–3100;
b) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985,
1, 3925–3941; (c) Surzur, J. M. In Reactive Intermediates;
Abramovitch, R. A., Ed.; Plenum: New York, 1983; Vol.
, p 164.
The initial step is a n,p*-excitation of the carbonyl
group followed either by an intramolecular d-hydrogen
atom abstraction to provide a 1,5-biradical 12 or by
a-cleavage to form the acyclic product 9 and the oxetane
(
4
2
1
1, which is probably formed via an intramolecular
6
. (a) Shono, T.; Nishigushi, I.; Ohmizu, H. Chem. Lett.
1976, 1233–1236; (b) Pattenden, G.; Robertson, G. M.
Tetrahedron Lett. 1983, 24, 4617–4620; (c) Pattenden, G.;
Robertson, G. M. Tetrahedron 1985, 41, 4001–4011; (d)
Little, R. D.; Fox, D. P.; Hijfte, L. V.; Dannecker, R.;
Sowell, G.; Wolin, R. L.; Mo e¨ ns, L.; Baizer, M. M. J. Org.
Chem. 1988, 53, 2287–2294; (e) Shono, T.; Kise, N.
Tetrahedron Lett. 1990, 31, 1303–1306.
1
4,21
Patern o´ –B u¨ chi reaction.
The intermediate 12 leads
to the formation of the corresponding bicyclic cyclopen-
tafuranols with the respective cis (pathway I: cyclization
to 8a and 10a) and trans conformation (pathway II:
cyclization to 8b and 10b). This 5-exo cyclization has
to be considered as Yang type reaction, also favorable
according to BaldwinÕs rules.
1
4
4
7
. (a) Hintz, S.; Heidbreder, A.; Mattay, J. Top. Curr. Chem.
1
996, 177, 77–124; (b) Pradhan, S. K.; Radhakrishnan, T.
V.; Subramanian, R. J. Org. Chem. 1976, 41, 1943–1952;
c) Pradhan, S. K.; Kadam, S. R.; Kolhe, J. N.; Radha-
In summary, we have shown that the photoinitiated
cyclization via 1,5-biradicals of propynyl- and allyl-
oxymethyl substituted cyclopentanones 5 and 7 can be
successfully used for the synthesis of ethynyl and vinyl
substituted tertiary cyclopentafuranols.
(
krishnan, T. V.; Sohani, S. V.; Thaker, V. B. J. Org. Chem.
1981, 46, 2622–2633; (d) Pradhan, S. K.; Kadam, S. R.;
Kolhe, J. N. J. Org. Chem. 1981, 46, 2633–2638.
8
. (a) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54,
3
321–3354; (b) Kakiuchi, K.; Fujioka, Y.; Yamamura, H.;
Tsutsumi, K.; Morimoto, T.; Kurosowa, H. Tetrahedron
Lett. 2001, 42, 7595–7598.
Supplementary material
9
. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091–
All synthetic procedures and analytical data of com-
pounds 2, 3, 5, and 7–11 are available from the authors
on request.
2
115.
1
0. (a) Belotti, D.; Cossy, J.; Pete, J.-P.; Portella, C. Tetra-
hedron Lett. 1985, 26, 4591–4594; (b) Belotti, D.; Cossy, J.;
Pete, J.-P.; Portella, C. J. Org. Chem. 1986, 51, 4196–4200;
(
c) Cossy, J. Bull. Soc. Chim. Fr. 1994, 131, 344–356.
1. Cossy, J.; Belotti, D.; Pete, J.-P. Tetrahedron 1990, 46,
859–1870.
2. (a) Cossy, J.; Leblanc, C. Tetrahedron Lett. 1991, 32,
051–3052; (b) Cossy, J.; Belotti, D.; Leblanc, C. J. Org.
Acknowledgements
1
1
1
Financial support by the Ministerium f u¨ r Schule,
Wissenschaft und Forschung des Landes Nordrhein–
Westfalen (MSWF-NRW), the Deutsche Forschungs-
gemeinschaft (DFG), the Fonds der Chemischen Indust-
rie and the Innovationsfonds der Universit a¨ t Bielefeld is
gratefully acknowledged.
3
Chem. 1993, 58, 2351–2354; (c) Cossy, J.; Belotti, D.;
Cuong, N. K.; Chassagnard, C. Tetrahedron 1993, 49,
7691–7700; (d) Cossy, J.; Madaci, A.; Pete, J.-P. Tetra-
hedron Lett. 1994, 35, 1541–1544.
1
3. Tzvetkov, N. T. Preliminary report: Ph.D. Dissertation,
University of Bielefeld, 2005.
References and notes
14. Organic Photochemistry and Photobiology, 2nd ed.; Hors-
pool, W., Lenci, F., Eds.; CRC Press: New York, 2004,
Chapters 52, 57, and 58.
15. Ethyl 2-oxocyclopentanecarboxylate 1 is commercially
available (Fluka Ltd) or can be synthesized following
known three-step procedure, see also (a) Sch a¨ fer, J. P.;
Bloomfield, J. J. Org. React. 1967, 15, 1; (b) Sisido, K.;
Utimoto, K.; Isida, T. J. Am. Chem. Soc. 1964, 29, 2781–
2782.
1
2
. (a) Velcicky, J.; Lex, J.; Schmalz, H.-G. Org. Lett. 2002, 4,
65–568; (b) Velcicky, J.; Lanver, A.; Lex, J.; Prokop, A.;
Wieder, T.; Schmalz, H.-G. Chem. Eur. J. 2004, 10, 5087–
110.
. (a) Paquette, L. A. Top. Curr. Chem. 1984, 119, 1–163; (b)
Paquette, L. A.; Doherty, A. M. Polyquinane Chemistry;
Springer: Berlin, Heidelberg, 1987; (c) Begley, M. J.;
Ladlow, M.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1
5
5
16. Kumar, P.; Saravanan, K. Tetrahedron 1998, 54, 2161–
2168.
1
998, 1095–1106; (d) Ladlow, M.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1988, 1107–1118; (e) Parkes, K. E.
B.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1988,
17. (a) Daniel, D.; Middleton, R.; Henry, H. L.; Okamura, W.
H. J. Org. Chem. 1996, 61, 5617–5625; (b) Harvey, D. F.;
Lund, K. P.; Neil, D. A. J. Am. Chem. Soc. 1992, 114,
8424–8434.
1119–1134; (f) Mehta, C.; Srikrishna, A. Chem. Rev. 1997,
97, 671–719.

N. T. Tzvetkov, J. Mattay / Tetrahedron Letters 46 (2005) 7751–7755
7755
1
8. Photochemical reactions were performed in a Rayonet
RPR-100 photochemical chamber reactor (Southern New
England Ultraviolet Company, Brandford) fitted with 16
19. (a) Smith, M. B.; March, J. MarchÕs Advanced Organic
Chemistry; John Wiley & Sons: New York, 2001, Chapter
7; (b) Schuster, D. I. In The Chemistry of Enones; Patai,
Rappoport, Eds.; John Wiley & Sons: New York, 1989;
Part 2, p 623.
20. The calculations were carried out using Titan V1.05,
Schr o¨ dinger Inc., Wavefunction Inc., 2000.
21. (a) B u¨ chi, G.; Inman, C. G.; Lipinsky, E. S. J. Am.
Chem. Soc. 1954, 76, 4327–4331; (b) Nonomija, I.;
Naito, T. Photochemical Synthesis; Academic Press:
New York, 1989; pp 138–151.
˚
lamps RPR-3000 A (emission maximum at 300 nm half
band width, each lamp 21 W) and merry-go-round inset
using duran tubes (12 mL vol, 1 cm diameter). Deoxygen-
ated with argon solutions (0.12 M) of the respective
propynyl- and allyloxymethyl cyclopentanones, 5 and 7,
were dissolved in dry benzene or acetonitrile and irradi-
ated. The conversion of the starting material was moni-
tored by GC and/or GC–MS.