Traceless solid-phase synthesis of hydroxylated cyclopentenones

Article abstract of DOI:10.1016/j.tetlet.2008.09.080

Intramolecular nitrone-alkene cycloadditions on solid phase can be performed using polymer-bound hydroxylamine. Condensation of this reagent with sugar derived 4-pentenals followed by N-O cleavage, quaternization of the amine thus produced, and finally oxidative elimination of the amino group detaches the chiral hydroxylated cyclopentenones from the polymer. The natural antibiotic pentenomycin I was prepared in this way.

Full text of DOI:10.1016/j.tetlet.2008.09.080

Tetrahedron Letters 49 (2008) 6804–6806
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Tetrahedron Letters
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Traceless solid-phase synthesis of hydroxylated cyclopentenones
*
Christos I. Stathakis, John K. Gallos
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki GR 541 24, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2008
Revised 1 September 2008
Accepted 12 September 2008
Available online 18 September 2008
Intramolecular nitrone–alkene cycloadditions on solid phase can be performed using polymer-bound
hydroxylamine. Condensation of this reagent with sugar derived 4-pentenals followed by N–O cleavage,
quaternization of the amine thus produced, and finally oxidative elimination of the amino group detaches
the chiral hydroxylated cyclopentenones from the polymer. The natural antibiotic pentenomycin I was
prepared in this way.
Ó 2008 Elsevier Ltd. All rights reserved.
O
O
Cyclopentenone (+)-1 and its enantiomer (Fig. 1) are important
chiral building blocks,1 widely used in organic synthesis.2 A num-
ber of publications describing their enantioselective syntheses
have been reported in the literature, including both asymmetric
synthesis3 and chiral pool.4 In addition, the antibiotic pentenomy-
cin I (2),5 a hydroxymethylated derivative of (+)-1, isolated from
culture broths of Streptomyces eurythermus, is active against both
Gram-positive and Gram-negative bacteria. It has attracted consid-
erable attention and a number of racemic and chiral syntheses
have been reported.6
HO
HO
OH
O
O
(+)-1
2
Figure 1. Target cyclopentenones.
Me
O
N
O
We have recently reported7 a methodology for the synthesis of
such compounds (Scheme 1). Starting from the appropriate carbo-
O
Sugar
R
R
O
O
O
hydrate, a
c,d-unsaturated aldehyde or ketone can be prepared,
which upon intramolecular nitrone cycloaddition is converted to
aminocyclitols. Quaternization of the latter, followed by oxidative
elimination of the amino group, leads to the formation of the
desired cyclopentenone.
3
4
+
NMe3X-
O
HO
HO
NHMe
R
It was considered at this point that cyclopentenone synthesis
would be simplified significantly by transfer of the above method-
ology from solution to solid phase. Despite the fact that inter- and
intramolecular 1,3-dipolar nitrone-olefin cycloadditions have been
extensively studied and have found wide application in the synthe-
sis of various natural products and synthetic materials,8 their
application in solid-phase synthesis is limited,9 particularly when
compared to other 1,3-dipoles.10 To realize this aim, we firstly
had to solve two problems: (i) find an efficient linker in order to at-
tach the substrates on the polymer and (ii) to use reagents compat-
ible with the solid-phase synthesis.
R
R
O
O
O
O
O
O
7
6
5
Scheme 1. General synthetic scheme towards cyclopentenones.
these two linkers, which in fact has the hydroxylamine attached
to the Wang resin has already been used for intermolecular nitrone
cycloaddition to alkenes,9c catalyzed by Yb(OTf).3
We, however, attached hydroxylamine to the solid phase using
a different approach to that mentioned in the literature. Starting
from the Merrifield resin, the 4-hydroxybenzyl alcohol or 1,4-
butanediol linkers were introduced by standard procedures, and
then the protected hydroxylamine was attached via a Mitsunobu
reaction. All modifications were followed by infrared spectroscopy
and after removal of the protecting groups, the weight increase of
the polymer corresponded to 80% and 95% overall yields for 13a
and 13b, respectively. In addition, 12a,b were subjected to a
We decided to bind the hydroxylamine to the polymer using
two similar linkers 13a,b (Scheme 2). This technique has the
advantage of being traceless, since in the last step the formation
of an enone detaches the product from the polymer. The first of
* Corresponding author. Tel.: +30 2310 997714; fax: +30 2310 997679.
E-mail address: igallos@chem.auth.gr (J. K. Gallos).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.080

C. I. Stathakis, J. K. Gallos / Tetrahedron Letters 49 (2008) 6804–6806
6805
i or ii
iii, iv
v
O
O
X
11
vi
OH
Cl
R
O
NHOH
i-v
O
+
8
TrO
TrO
O
O
O
O
13b
HO
HO
CHO
OH
21
22
Boc
NOBoc
9
X
Scheme 4. Reagents and conditions: (i) MeOH, 20 °C, 12 h; (ii) PhCl, reflux, 1–2 h;
(iii) SmI2, THF; (iv) MeI, K2CO3, THF, 20 °C, 20 h; (v) (COCl)2, DMSO, Et3N, DCM,
À65 °C (see text also).
R
O
12
vii
10
a, R = polystyrene, X = p-C6H4
polystyrene,
b, R =
c, R =
X = (CH2)3
X = -C H
Ph,
p
X
NHOH
6
d, R = Ph, X = (CH2) 4
cyclopentenone (+)-1 in a 3:1 ratio and 37% combined yield from
18d. Moffatt oxidation (DCC, DMSO, pyridine, TFA, benzene,
20 °C) of 18d again gave the same products but in an improved
yield and ratio (68%, 1:1). Swern oxidation [(COCl)2, DMSO, Et3N,
CH2Cl2, À40 °C] converted the same substrate exclusively to the
thiomethyl product 20. This compound apparently derives from
the desired cyclopentenone formed by 1,4-addition of a ‘methyl-
thiol’ equivalent intermediately generated by reduction of DMSO.
Thus, the Swern oxidation at lower temperature (À65 °C) pre-
vented ‘methylthiol’ addition and afforded the cyclopentenone
(+)-1 as the sole product from both the ammonium salts 18c,d in
very good yields (76% and 79%, respectively).11,13
Having established the optimized conditions, the solid-phase
synthesis was then performed easily by following the sequence
discussed above. Finally, the cyclopentenone (+)-1 was detached
from the polymer by Swern oxidation at À65 °C in 18% and 15%
yields based on the loading of the starting resin, respectively,
contaminated by a 2% yield of 20. The overall yields are considered
satisfactory, although somewhat lower than that of the solution-
phase synthesis (24%).7a It is noteworthy that both (+)-1 and (À)-
1, which are widely used key intermediates in organic synthesis,
can be prepared in this way, since both enantiomers of 14 are read-
ily available, thus increasing the utility of the present method.
The scope of this methodology was further shown by condens-
ing aldehyde 217 with the polymer-bound hydroxylamine 13b
(Scheme 4). Following the five-step sequence described in Scheme
3, protected pentenomycin I 22 was prepared in 16% overall yield,
based on the loading of the starting resin.11,13
R
O
3
13
Scheme 2. Reagents and conditions: (i) 4-hydroxybenzaldehyde, NaOH, DMSO,
then NaBH4, MeOH, reflux; (ii) 1,4-butanediol, NaH, DMF, 2 h at 0 °C, then 8,
n-Bu4NI, 20 °C, 12 h; (iii) BnCl, NaOH, DMF, 85%; (iv) NaBH4, MeOH, 98%; (v) Ag2O,
BnCl, DCM, 20 °C, 2 h, 98%; (vi) BocNHOBoc, DIAD, Ph3P, THF, 0?20 °C, 24 h; (vii)
TFA, DCM, 1–3 h, then Na2CO3.
second reaction cycle with BocNHOBoc, but the weight of the poly-
mer remained practically unchanged.
In order to address the problem of checking reaction progress
and completion, we prepared N-substituted hydroxylamines
13c,d (Scheme 2) as models that mimic the monomeric units of
the polymer and the linkers used. Their synthesis was achieved
easily by preparing the corresponding benzyloxybenzyl alcohol
11c and O-benzyl-1,4-butanediol 11d, followed by Mitsunobu
reaction with BocNHOBoc and subsequent deprotection.11
With the model compounds 13c,d in hand, we were ready to
apply the protocol depicted in Scheme 1 for the synthesis of enan-
tiomerically pure hydroxylated cyclopentenones. Condensation of
13c,d with pentenal 14 led to the formation of nitrones 15c
(69%) and 15d (77%), which upon heating in refluxing chloroben-
zene gave adducts 16c and 16d in 74% and 65% yields, respectively
(Scheme 3).
The problem we had to face at this point was to use a new
reagent in order to cleave the N–O bond, since the heterogenous
catalysis used hitherto was not compatible with the solid-phase
synthesis. Samarium iodide12 proved to be an excellent reducing
agent and compounds 17c,d were prepared from 16c,d in 93%
and 94% yields, which were quaternized using MeI and K2CO3.
In the final step, a number of conditions were investigated in
order to eliminate oxidatively the ammonium group and to detach
the products from the polymer. PDC oxidation in CH2Cl2 led to the
formation of the iodinated product 197 together with the desired
In conclusion, polymer-bound hydroxylamine proved to be a
very useful material for intramolecular nitrone–alkene cycloaddi-
tions. The methodology in solution phase recently reported by us
was transferred successfully to the solid phase and a traceless syn-
thesis of enantiomerically pure cyclopentenones was achieved.
Acknowledgement
A fellowship to Christos I. Stathakis from the Hellenic Ministry
of Education is gratefully acknowledged.
O
O
N
X
X
NHOH
O
R
i
Supplementary data
R
O
ii
+
O
O
O
13
O
O
15
Supplementary data (1H NMR spectra of compounds 12c,d,
15c,d, 16c,d and 17c,d, and 13C NMR spectra of compounds
12c,d, 15d, 16d) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2008.09.080.
14
O
R
H
Me Me
N
O
O
N
O
X
HO
N
X
HO
X
O
R
O
R
iii
iv
I
O
O
O
References and notes
17
16
18
I
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a, R = polystyrene, X = p-C
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Scheme 3. Reagents and conditions: (i) MeOH, 20 °C, 12 h; (ii) PhCl, reflux, 1–2 h;
(iii) SmI2, THF; (iv) MeI, K2CO3, THF, 20 °C, 20 h; (v) (COCl)2, DMSO, Et3N, DCM,
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known compounds (+)-1, 19 and 22 were characterized from their [
a] values
D
and NMR data, which were identical to those reported in the literature. Selected
data for compound 20: 1H NMR (500 MHz, CDCl3) d 4.73 (d, J = 5.3 Hz, 1H),
4.37 (d, J = 5.3 Hz, 1H), 3.42 (d, J = 7.6 Hz, 1H), 3.04 (dd, J = 18.5, 7.6 Hz, 1H),
2.26 (d, J = 18.5 Hz, 1H), 2.19 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H). 13C NMR
(125 MHz, CDCl3) d 211.2, 113.0, 80.9, 78.0, 41.9, 39.9, 26.7, 24.9, 14.6. HRMS
m/z: calcd for C9H14O3SNa [(M+Na)+]: 225.0556; found 225.0553.
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13. The products released from the support were of satisfactory purity (P95%) as
determined by 1H NMR.