Dimethyldioxirane oxidation of 2-silyloxypyrroles: An efficient regiocontrolled synthesis of 5-hydroxy-3-pyrrolin-2-ones

Article abstract of DOI:10.1055/s-2007-992376

A new method for the synthesis of 5-hydroxy-3-pyrrolin-2-ones is reported. Conversion of N-Boc-3-pyrrolin-2-ones into 2-triisopropylsilyloxypyrroles and ensuing oxidation with dimethyldioxirane provides the corresponding N-Boc-5-hydroxy-3-pyrrolin-2-ones in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992376

3198
LETTER
Dimethyldioxirane Oxidation of 2-Silyloxypyrroles:
An Efficient Regiocontrolled Synthesis of 5-Hydroxy-3-pyrrolin-2-ones
D
imethyld
o
ioxirane
O
xi
h
dation of 2-S
n
ilyloxypyrroles Boukouvalas,* Yufang Xiao, Yun-Xing Cheng, Richard P. Loach
Département de Chimie, Université Laval, Quebec City, QC, G1K 7P4, Canada
Fax +1(418)6567916; E-mail: john.boukouvalas@chm.ulaval.ca
Received 16 August 2007
methods have their own particular merits, few can be cat-
egorized as entirely flexible or efficient.
Abstract: A new method for the synthesis of 5-hydroxy-3-pyrrolin-
2-ones is reported. Conversion of N-Boc-3-pyrrolin-2-ones into 2-
triisopropylsilyloxypyrroles and ensuing oxidation with dimethyl-
dioxirane provides the corresponding N-Boc-5-hydroxy-3-pyrrolin-
2-ones in high yields.
In our quest for such a method, we sought to explore the
oxidation of 2-silyloxypyrroles as a means of installing
the hydroxyl substituent onto a preformed pyrrolinone
ring (Scheme 1). So far, the chemistry of 2-silyloxypyr-
roles has been confined to C–C bond-forming processes
such as vinylogous aldol and Michael addition reactions.10
In the present instance, oxyfunctionalization at C-5 was
envisioned through the use of dimethyldioxirane
(DMDO) as a masked equivalent of the hydroxyl cation.11
We now report the success of this strategy for preparing a
range of substituted 5-hydroxypyrrolinones.
Key words: alkaloids, lactams, oxyfunctionalization, regioselec-
tivity, Wittig reaction
The 5-hydroxy-3-pyrrolin-2-one moiety is a key structur-
al component of a growing number of naturally occurring
and biologically important compounds.1,2 Notable exam-
ples include axinellamide3 (1, Figure 1), the endothelin
ETB receptor antagonist oteromycin (2),4 and the synthetic
antitumor agent MT-21 (3) which causes apoptosis
through direct release of cytochrome c from mitochon-
dria.5 Apart from their intrinsic value, 5-hydroxypyrroli-
nones are being increasingly used as intermediates in
organic synthesis.6
O
O
HO
N
R
N
R
HO
O
SiR'3
O
O
N
R
O
N
H
HO
Scheme 1
axinellamide (1)
The ready availability of N-Boc-pyrrolinones12 prompted
their use as starting materials (cf. 4a–f, Table 1). Silyla-
tion with triisopropylsilyl trifluoromethanesulfonate
(TIPSOTf) and 2,6-lutidine in dichloromethane afforded
the desired 2-triisopropylsilyloxypyrroles 5a–f in excel-
lent yields.13 Treatment of 5a with DMDO14 in CH2Cl2/
acetone at –78 °C, followed by quenching with aqueous
acetone and Amberlyst-15 at room temperature, provided
5-hydroxypyrrolinone 6a in 94% yield after flash chroma-
tography (entry 1).15 Subsequent attempts to detect plau-
sible epoxide or acyclic intermediates,11a,16 by performing
NMR analysis of the crude DMDO-oxidation product at
ca. –50 °C, revealed that conversion into 6a had already
occurred.
H
O
O
Ph
N
OH
O
H
oteromycin (2)
O
N
HO
MT-21 (3)
Figure 1
Classical approaches to these heterocycles,2 such as those
involving photooxygenation of pyrroles7 or aminolysis of
5-alkoxy-2(5H)-furanones,8 lack generality and/or require
precursors that are not readily available. Recent
methodologies9 have included regioselective reduction of
maleimides,9a,e oxidative 5-endo cyclization of en-
amides,9b halolactamization–hydroxylation of allen-
amides9d and oxidation of oxazoles.9g Whilst these
Whatever the identity of intermediate(s), the foregoing
procedure worked equally well with 3-, 4- and 5-substitut-
ed 2-silyloxypyrroles to furnish the corresponding 5-hy-
droxypyrrolinones with complete regiocontrol (entries 2–
6). Furthermore, oxidation of the silyloxypyrrole moiety
proceeded with high chemoselectivity as evidenced by the
clean conversion of 5f into prenyl-substituted hydroxy-
pyrrolinone 6f (entry 6).17
SYNLETT 2007, No. 20, pp 3198–3200
Advanced online publication: 21.11.2007
x
x
.x
x
.2
0
0
7
DOI: 10.1055/s-2007-992376; Art ID: S05907ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Dimethyldioxirane Oxidation of 2-Silyloxypyrroles
3199
Table 1 Synthesis of N-Boc-5-Hydroxy-3-pyrrolin-2-ones
R2
R3
R2
R3
R2
R1
HO
R3
TIPSOTf
DMDO, –78 °C
R1
R1
then
O
2,6-lutidine
CH2Cl2
O
OTIPS
N
N
N
Amberlyst-15, H2O
Boc
Boc
Boc
4
5
6
Entry
Substrate
R1
R2
H
R3
Yield (%)a of 5
93 (5a)
Yield (%)a of 6
1
2
3
4
5
6
4ab
H
H
94 (6a)
95 (6b)
90 (6c)
94 (6d)
88 (6e)
83 (6f)
4b12b
4c12d
4d12a
4e12a
4f12c
H
H
Me
H
94 (5b)
H
Me
H
90 (5c)
Me
H
89 (5d)
PhCH2
Me2C=CHCH2
H
H
87 (5e)
H
H
92 (5f)
a Yields refer to chromatographically isolated products.
b This compound is commercially available.
Attention was next turned to the possibility of combining References and Notes
the oxidation step with subsequent transformations of
(1) (a) Suzuki, S.; Hosoe, T.; Nozawa, K.; Kawai, K.; Yaguchi,
T.; Udagawa, S. J. Nat. Prod. 2000, 63, 768. (b) Osterhage,
C.; Kaminsky, R.; König, G. M.; Wright, A. D. J. Org.
Chem. 2000, 65, 6412. (c) Agatsuma, T.; Akama, T.; Nara,
S.; Matsumiya, S.; Nakai, R.; Ogawa, H.; Otaki, S.; Ikeda,
S.; Saitoh, Y.; Kanda, Y. Org. Lett. 2002, 4, 4387.
(d) Grube, A.; Köck, M. J. Nat. Prod. 2006, 69, 1212.
(e) Yang, Y.-L.; Lu, C.-P.; Chen, M.-Y.; Chen, K.-Y.; Wu,
Y.-C.; Wu, S.-H. Chem. Eur. J. 2007, 13, 6985.
synthetic interest. Thus, sequential treatment of 5a with
DMDO and 10% trifluoroacetic acid18 in dichloromethane
provided the N-deprotected hydroxypyrrolinone 7 (74%,
Scheme 2), which is reportedly endowed with significant
growth inhibitory properties, comparable to those of com-
mercial plant growth retardants such as Cycocel and ma-
leic hydrazide.19
Alternatively, Wittig olefination6a of the crude oxidation
product (cf. 6a) with carboethoxy-1-ethylidene triphe-
nylphosphorane proceeded with high E/Z stereoselectivity
(>20:1) to afford the bisfunctionalized diene 820 in an un-
optimized yield of 69% (Scheme 2).
(2) Dittami, J. P.; Xu, F.; Qi, H.; Martin, M. W.; Bordner, J.;
Decosta, D. L.; Kiplinger, J.; Reiche, P.; Ware, R.
Tetrahedron Lett. 1995, 36, 4201; and references therein.
(3) Miller, S. L.; Tinto, W. F.; Yang, J.-P.; McLean, S.;
Reynolds, W. F. Tetrahedron Lett. 1995, 36, 5851.
(4) Singh, S. B.; Goetz, M. A.; Jones, T.; Bills, G. F.; Giacobbe,
R. A.; Herranz, L.; Stevens-Miles, S.; Williams, D. L. Jr.
J. Org. Chem. 1995, 60, 7040.
DMDO, Me2CO, –78 °C
(5) (a) Watabe, M.; Machida, K.; Osada, H. Cancer Res. 2000,
60, 5214. (b) Watabe, M.; Machida, K.; Osada, H. J. Biol.
Chem. 2002, 277, 31243.
O
OTIPS
HO
then TFA (10% in CH2Cl2)
0 °C, 1 h
N
N
H
Boc
5a
7 (74%)
(6) (a) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6, 577.
(b) Yamaguchi, J.; Kakeya, H.; Uno, T.; Shoji, M.; Osada,
H.; Hayashi, Y. Angew. Chem. Int. Ed. 2005, 44, 3110.
(c) Coleman, R. S.; Walczak, M. C.; Campbell, E. L. J. Am.
Chem. Soc. 2005, 127, 16038. (d) Lambert, T. H.;
Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 426.
(e) Hoye, T. R.; Dvornikovs, V. J. Am. Chem. Soc. 2006,
128, 2550. (f) Goh, W. K.; Iskander, G.; Black, D. S.;
Kumar, N. Tetrahedron Lett. 2007, 48, 2287.
(7) Iesce, M. R.; Cermola, F.; Temussi, F. Curr. Org. Chem.
2005, 9, 109.
(8) Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa, S. J. Org.
Chem. 1996, 61, 2845.
(9) (a) Mase, N.; Nishi, T.; Hiyoshi, M.; Ichihara, K.; Bessho, J.;
Yoda, H.; Takabe, K. J. Chem. Soc., Perkin Trans. 1 2002,
707. (b) Clark, A. J.; Dell, C. P.; McDonagh, J. M.; Geden,
J.; Mawdslay, P. Org. Lett. 2003, 5, 2063. (c) Snider, B. B.;
Neubert, B. J. J. Org. Chem. 2004, 69, 8952. (d) Ma, S.;
Xie, H. Tetrahedron 2005, 61, 251. (e) Issa, F.; Fischer, J.;
Turner, P.; Coster, M. J. J. Org. Chem. 2006, 71, 4703.
(f) Alizadeh, A.; Movahedi, F.; Masrouri, H.; Zhu, L.-G.
Synthesis 2006, 3431. (g) Evans, D. A.; Nagorny, P.; Xu, R.
Org. Lett. 2006, 8, 5669.
DMDO, Me2CO, –78 °C
NHBoc
then Ph3P=C(Me)CO2Et
CH2Cl2, 0 °C to r.t.
EtO
O
8 (69%)
O
Scheme 2
In conclusion, we have devised a new, concise and effi-
cient pathway to 5-hydroxy-3-pyrrolin-2-ones, based on
the DMDO oxidation of 2-silyloxypyrroles. The high re-
gio- and chemoselectivity of oxidation, along with the di-
verse substitution patterns accommodated by this
approach, set the stage for broad application in alkaloid
synthesis. Further work in this area is currently underway.
Acknowledgment
We thank NSERC (Canada), Merck Frosst Canada and Eisai Rese-
arch Institute (Andover, MA, USA) for financial support. We also
thank HydroQuébec for a postgraduate scholarship to R.P.L.
Synlett 2007, No. 20, 3198–3200 © Thieme Stuttgart · New York

3200
J. Boukouvalas et al.
LETTER
(10) (a) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem.
Soc. Rev. 2000, 29, 109. (b) Curti, C.; Zanardi, F.; Battistini,
L.; Sartori, A.; Rassu, G.; Auzzas, L.; Roggio, A.; Pinna, L.;
Casiraghi, G. J. Org. Chem. 2006, 71, 225. (c) Suga, H.;
Takemoto, H.; Kakehi, A. Heterocycles 2007, 71, 361; and
references cited therein.
(11) For the vinylogous oxyfunctionalization of 2-silyloxyfurans
with DMDO, see: (a) Boukouvalas, J.; Lachance, N. Synlett
1998, 31. (b) Boukouvalas, J.; Cheng, Y.-X.; Robichaud, J.
J. Org. Chem. 1998, 63, 228. (c) Boukouvalas, J.; Wang, J.-
X.; Marion, O.; Ndzi, B. J. Org. Chem. 2006, 71, 6670.
(d) Boukouvalas, J.; Robichaud, J.; Maltais, F. Synlett 2006,
2480. (e) See also: Marcos, I. S.; Pedrero, A. B.; Sexmero,
M. J.; Diez, D.; García, N.; Escola, M. A.; Basabe, P.;
Conde, A.; Moro, R. F.; Urones, J. G. Synthesis 2005, 3301.
(12) (a) Zanardi, F.; Battistini, L.; Rassu, G.; Cornia, M.;
Casiraghi, G. J. Chem. Soc., Perkin Trans. 1 1995, 2471.
(b) Bermejo, F. A.; Rico-Ferreira, R.; Bamidele-Sanni, S.;
García-Granda, S. J. Org. Chem. 2001, 66, 8287.
(15) Typical Procedure: To a solution of 5a (339 mg, 1.0 mmol)
in anhyd CH2Cl2 (5 mL) at –78 °C was added dropwise a
solution of DMDO (0.055 M in acetone, 20 mL, 1.1 equiv)
and the reaction mixture was stirred for 1 h at –78 °C. The
volatiles were evaporated and the residue was dissolved in
acetone (10 mL). After addition of H2O (7 mL) and
Amberlyst-15 (ca. 100 mg), the reaction mixture was stirred
for 1 h at r.t. The mixture was filtered, the filtrate was
extracted with Et2O (3 × 10 mL) and the combined organic
layers were dried over anhyd MgSO4. After evaporation of
the volatiles, the residue was purified by flash chromatog-
raphy on silica gel (hexanes–EtOAc, 7:3) to furnish 6a (187
mg, 94%) as a white solid (mp 100–101 °C). 1H NMR (300
MHz, CDCl3): d = 1.54 (s, 9 H), 4.32 (br d, J = 4.8 Hz, 1 H),
5.96 (br m, 1 H), 6.07 (d, J = 6.4 Hz, 1 H), 7.02 (dd, J = 4.8,
6.4 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 28.0, 82.0,
83.8, 128.3, 146.3, 149.9, 166.4. Anal. Calcd for C9H13NO4:
C, 54.26; H, 6.58; N, 7.03. Found: C, 54.62; H, 6.53; N, 7.00.
(16) Epoxides have been obtained from reactions of DMDO with
indoles: Zhang, X.; Foote, C. S. J. Am. Chem. Soc. 1993,
115, 8867.
(c) Wrobel, M. N.; Margaretha, P. Helv. Chim. Acta 2003,
86, 515. (d) Hermet, J.-P.; Caubert, V.; Langlois, N. Synth.
Commun. 2006, 36, 2253. (e) Yoon-Miller, S. J. P.; Opalka,
S. M.; Pelkey, E. T. Tetrahedron Lett. 2007, 48, 827.
(f) Albrecht, D.; Bach, T. Synlett 2007, 1557.
(17) Data for 6f: mp 62–64 °C. 1H NMR (300 MHz, CDCl3): d =
1.53 (s, 9 H), 1.54 (br s, 3 H), 1.63 (br s, 3 H), 2.74 (dd, J =
6.8, 14.5 Hz, 1 H), 2.90 (dd, J = 8.3, 14.5 Hz, 1 H), 4.42 (br
s, 1 H), 4.86 (dd, J = 6.8, 8.3 Hz, 1 H), 6.03 (d, J = 6.0 Hz, 1
H), 7.00 (d, J = 6.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
d = 17.8, 25.7, 27.8, 36.5, 83.7, 92.6, 116.2, 126.6, 136.4,
145.3, 150.3 (2 × C), 166.6. Anal. Calcd for C14H21NO4: C,
62.90; H, 7.92; N, 5.24. Found: C, 62.84; H, 7.87; N, 5.16.
(18) For the removal of the Boc group from compounds 6b,c
using neat TFA at 0 °C, see: Yakushijin, K.; Suzuki, R.;
Hattori, R.; Furukawa, H. Heterocycles 1981, 16, 1157.
(19) Masuko, M.; Miyamoto, K.; Sakurai, K.; Iino, M.; Takeuchi,
Y.; Hashimoto, T. Phytochemistry 1983, 22, 1278.
(13) Typical Procedure: To a solution of 4a (732 mg, 4.0 mmol)
in anhyd CH2Cl2 (5 mL) were added 2,6-lutidine (1.290 g,
12.0 mmol) and TIPSOTf (1.232 g, 4.54 mmol) under
nitrogen at r.t. After stirring for 30 min, the solvent was
evaporated and the residue was purified by flash chromatog-
raphy on silica gel (hexanes–EtOAc, 95:5) to give 5a
(1.263 g, 93%) as a colorless oil. For smaller-scale reactions,
purification was carried out by chromatography on basic
silica gel.11c
Data for 5a: 1H NMR (300 MHz, CDCl3): d = 1.10 (d, J = 7.2
Hz, 18 H), 1.25 (hept, J = 7.2 Hz, 3 H), 1.54 (s, 9 H), 5.21
(dd, J = 1.7, 3.6 Hz, 1 H), 5.86 (dd, J = 1.7, 3.6 Hz, 1 H), 6.67
(t, J = 3.6 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 12.4,
17.9, 27.8, 82.4, 91.7, 107.6, 112.5, 143.6, 148.1. HRMS:
m/z calcd for C18H33NO3Si: 339.2230; found: 339.2233.
(14) (a) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber.
1991, 124, 2377. (b) Murray, R. W.; Singh, M. Org. Synth.,
Coll. Vol. IX; Wiley: New York, 1998, 288.
(20) Data for 8: colorless oil. 1H NMR (300 MHz, CDCl3): d =
1.27 (t, J = 7.0 Hz, 3 H), 1.45 (s, 9 H), 2.00 (s, 3 H), 4.20 (q,
J = 7.0 Hz, 2 H), 6.78 (d, J = 11.7 Hz, 1 H), 6.91 (dd, J =
11.7, 11.7 Hz, 1 H), 7.69 (br s, 1 H), 8.11 (d, J = 11.7 Hz, 1
H). 13C NMR (75 MHz, CDCl3): d = 12.6, 14.1, 27.8, 60.8,
82.6, 123.6, 132.3, 135.3, 137.3, 150.3, 165.5, 167.8.
HRMS: m/z [M + H+] calcd for C14H22NO5: 284.1498;
found: 284.1502.
Synlett 2007, No. 20, 3198–3200 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.