C-(4-methoxybenzyloxymethyl)-N-methylnitrone cycloaddition to highly functionalized pyrrolinone: A regio- and stereoselective approach to new omuralide-salinosporamide a hybrids

Article abstract of DOI:10.1002/ejoc.200800607

An advanced intermediate in the synthesis of new omuralide-salinosporamide A hybrids as potential proteasome 20S inhibitors was prepared in a few steps from methyl pyroglutamate. For this purpose, an O-protected hydroxyethyl chain has been successfully in

Full text of DOI:10.1002/ejoc.200800607

FULL PAPER
DOI: 10.1002/ejoc.200800607
C-(4-Methoxybenzyloxymethyl)-N-methylnitrone Cycloaddition to Highly
Functionalized Pyrrolinone: A Regio- and Stereoselective Approach to New
Omuralide–Salinosporamide A Hybrids
Nicole Langlois,*[a] Jean-Christophe Legeay,[a] and Pascal Retailleau[a]
Keywords: Cycloaddition / Nitrone / γ-Lactams / Proteasome inhibitors / Salinosporamide
An advanced intermediate in the synthesis of new omural- pyrrolinone by a regio- and stereoselective C-(4-methoxy-
ide–salinosporamide A hybrids as potential proteasome 20S
inhibitors was prepared in a few steps from methyl pyroglut-
amate. For this purpose, an O-protected hydroxyethyl chain
has been successfully introduced to a highly functionalized
benzyloxymethyl)-N-methylnitrone 1,3-dipolar cycload-
dition.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
weakly interacts with the target protein and that a hydrogen
is also convenient in this position.[7] Therefore, we designed
compound 4 as the synthetic goal suitable for potential fur-
ther syntheses of new omuralide–salinosporamide hybrids.
Introduction
The remarkable biological activity of omuralide (1), a β-
lactone derived from lactacystin (2),[1] has generated great
interest in the synthesis of proteasome 20S inhibitors, par-
ticularly in the synthesis of the more potent salinosporam-
ide A (3).[2–4]
Results and Discussion
Taking account of our previous work in this field,[8] we
investigated the simultaneous introduction of a C-3 hydroxy
and vicinal, protected, hydroxyethyl chain involving a suit-
able regio- and stereoselective C-alkoxymethylnitrone cyclo-
addition to pyrrolinone (Ϯ)-5, which was obtained in a few
steps from methyl pyroglutamate. For this purpose, C-(4-
methoxybenzyloxymethyl)-N-methylnitrone 7 (which has
not been reported before, to the best of our knowledge)
appeared to suit our needs and was particularly attractive
for subsequent selective hydroxy deprotection. Thus,
nitrone 7 was efficiently prepared (95%), according to
Scheme 1, from the corresponding aldehyde 6, derived from
solketal.[9]
Salinosporamides[5] and other closely related natural cin-
nabaramides, which have been recently isolated from terres-
trial Streptomyces strain JS360,[6] are distinguished by the
substitution pattern on the bicyclic γ-lactam-β-lactone core.
In these compounds, the isopropyl moiety present in 1 is
replaced by a cyclohexenyl group, and various substituents
can also be present α to the lactam carbonyl such as ethyl,
chloro- or bromoethyl, hexyl, or hydroxyhexyl. In addition,
these compounds are substituted at C-3 by a methyl or an
ethyl group which is not present in omuralide (1). However,
structure–activity relationship studies have shown that this
C-3 methyl group in salinosporamide A and its analogues
Scheme 1.
The protection of the solketal free hydroxy group with
PMBBr (NaH, THF, 96%) was followed, as described, by
the carefully controlled hydrolysis of the acetonide moiety
[a] Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
E-mail: nicole.langlois@icsn.cnrs-gif.fr
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Eur. J. Org. Chem. 2008, 5810–5814

Stereoselective Approach to Omuralide–Salinosporamide A Hybrids
and subsequent oxidation of the vicinal diol with sodium 76% yield (Scheme 2), together with isomer 8b (≈ 8%). It is
periodate to give aldehyde 6 (92% over 2 steps).[9b] In the important to note that using a higher temperature led to
presence of triethylamine, N-methylhydroxylamine hydro- some dimeric by-products of nitrone 7.[11]
chloride and aldehyde 6 in toluene were converted at room
The configurational assignments at the 3a and 6a posi-
temp. to nitrone 7 as a single isomer, isolated in high yield. tions were established by NMR spectroscopy. These data
The (Z) configuration of 7 was postulated by analogy with show that the regioselectivity is the same for both com-
other C-alkoxy- and C-(silyloxymethyl)nitrones,[10] and this pounds and that the additions occurred on the same face
attribution was confirmed by a NOESY experiment, which of the dipolarophile. The close chemical shifts of H-6a (8a:
showed a correlation between the N-methyl and azomethine 4.54 and 8b: 4.63 ppm), and the nOe observed between
protons.
these protons and the methylene 6-CH2O agree with struc-
The cycloaddition of 7 to unsaturated γ-lactam 5 was tures 8. In addition to these high regio- and diastereofacial
carried out in toluene at 60 °C to give cycloadduct 8a in selectivities, a further indication of the relative configura-
tion at C-3 in major diastereomer 8a was given by the steric
course of the subsequent elimination step leading to 10. Af-
ter reductive cleavage of the isoxazolidine N–O bond and
N-dimethylation of the resulting crude product 9 with ex-
cess iodomethane, treatment with NaHCO3 gave rise mainly
to unsaturated compound 10. The (E) configuration of 10
was confirmed by the high chemical shift of the ethylenic
proton (δ = 6.85 ppm).[12] The formation of 10 by an anti
elimination (72% yield for the three-step procedure) is com-
patible with the relative configurations indicated for 8a in
Scheme 2. The structure of cycloadduct 8a was ascertained
by X-ray analysis (Figure 1).[13] The postulated transition
state leading to this highly endo-selective cycloaddition is
depicted in Figure 2.
Scheme 2.
Figure 2. Postulated transition state in the formation of 8a.
Figure 1. ORTEP diagram from the X-ray crystallographic analysis of cycloadduct 8a.
Eur. J. Org. Chem. 2008, 5810–5814
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N. Langlois, J.-C. Legeay, P. Retailleau
FULL PAPER
JЈ = 6.4 Hz, 1 H, Hb-5), 3.81 (s, 3 H, OMe), 3.54 (dd, J = 9.8, JЈ
= 5.6 Hz, 1 H, PMBOCHa), 3.44 (dd, J = 9.8, JЈ = 5.6 Hz, 1 H,
PMBOCHb), 1.43 (s, 3 H, Me), 1.37 (s, 3 H, Me) ppm (in full
agreement with literature data).[9c]
A deprotection of the lactam nitrogen in 10 was first at-
tempted with ZnBr2 in dichloromethane,[14] but the O-pro-
tecting p-methoxybenzyl group was also partially removed
with this mild reagent. A more chemoselective result was
obtained with MgCl2 in acetonitrile,[15,16] as 11 was readily
formed in good yield (97%). The corresponding TBS ether
(TBSOTf, 2,6-lutidine, room temp., 86%) was slowly hydro-
genated over PtO2 (100% yield, 80% de) leading to 4 by
simple recrystallisation (79% yield, Ͼ95% pure according
3-(4-Methoxybenzyloxy)propane-1,2-diol: To a solution of O-PMB
solketal (969.1 mg, 3.84 mmol) in THF (8.4 mL) was added 1 
HCl (8.3 mL). The mixture was stirred at room temp. until conver-
sion was complete (6 h). NaHCO3 was then added at 0 °C until the
pH reached 8 and, after concentration of the mixture under re-
duced pressure, the resulting mixture was extracted with EtOAc.
The organic layers were dried with MgSO4, and the solvents were
evaporated. Purification of the residue by silica gel chromatography
(eluent: Et2O) afforded the diol (749.9 mg, 92%) as a colourless oil.
1H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 8.5 Hz, 2 H, MeOAr-
H), 6.88 (d, J = 8.5 Hz, 2 H, MeOAr-H), 4.49 (s, 2 H, Ar-CH2O),
3.88 (m, 1 H, H-2), 3.82 (s, 3 H, OMe), 3.69 (dd, J = 11.4, JЈ =
3.9 Hz, 1 H, OCHa), 3.62 (dd, J = 11.4, JЈ = 5.5 Hz, 1 H, OCHb),
3.54 (m, 2 H, OCH2), 2.55 (br., OH) ppm. 13C NMR (75 MHz,
1
to H NMR). Thus, these results match those obtained in
the unsubstituted N-methylnitrone series,[8b] affording the
required diastereomer in an efficient manner.
Conclusions
In conclusion, this short synthetic route to polysubsti-
tuted pyrrolidinone 4 was conducted by two diastereoselec- CDCl3): δ = 159.51, 129.87, 129.57, 114.02, 73.36, 71.61, 70.73,
64.20, 55.40 ppm.[9b,9c]
tive steps, namely the regio-, facial-, and endo-selective 1,3-
dipolar cycloaddition of C-(4-methoxybenzyloxymethyl)-N-
methylnitrone 7 to unsaturated γ-lactam (Ϯ)-5 and the hy-
drogenation of its derivative 12. Thus, this work demon-
strated that our previously developed synthetic scheme to
omuralide (1) could be extended to the cycloaddition of
more complex nitrones and could offer access to advanced
precursors of new omuralide–salinosporamide A hybrids as
well as several natural cinnabaramides.
2-(4-Methoxybenzyloxy)ethanal (6): To a solution of 3-(4-methoxy-
benzyloxy)propane-1,2-diol (636 mg, 3.0 mmol) in CH2Cl2
(6.4 mL) were added H2O (0.35 mL) and NaIO4 (770 mg,
3.6 mmol), and the biphasic mixture was stirred at room temp. for
22 h. After the addition of CH2Cl2 (35 mL), the mixture was dried
over MgSO4, the solvent was removed by evaporation, and the al-
dehyde (542 mg, 100%) obtained was pure enough for the next step.
1H NMR (500 MHz, CDCl3): δ = 9.71 (s, 1 H, CHO), 7.29 (d, J =
8.7 Hz, 2 H, MeOAr-H), 6.90 (d, J = 8.7 Hz, 2 H, MeOAr-H), 4.57
(s, 2 H, ArCH2O), 4.07 (s, 2 H, PMBOCH2), 3.82 (s, 3 H, OMe)
ppm. 13C NMR (75 MHz, CDCl3): δ = 200.76, 159.76, 129.88,
128.98, 114.11, 75.12, 73.45, 55.40 ppm.
Experimental Section
General: Melting points were uncorrected. NMR spectra were re-
corded with a Bruker spectrometer at 500 or 300 MHz for 1H
NMR and 125 or 75 MHz for 13C NMR; chemical shifts are given
[2-(4-Methoxybenzyloxy)ethylidene]methanamine Oxide (7): To a
solution of aldehyde
6 (540 mg, 3.0 mmol) in dry toluene
(15.6 mL), were added at room temp. MeNHOH hydrochloride
(524 mg, 6.27 mmol) and NEt3 (1.57 mL, 11.3 mmol). The mixture
was stirred for 1.5 h. The insoluble salts were then filtered and
washed with toluene. The solution was evaporated at 22 °C. The
crude residue was purified by chromatography on silica gel (eluent:
CH2Cl2/MeOH, 97:3) to give the pure nitrone (595 mg, 95%) as
1
in ppm relative to residual CHCl3 (δ = 7.27 ppm for H NMR and
77.14 ppm for the middle line in 13C NMR); s, d, t, dd and m
indicate singlet, doublet, triplet, doublet of doublets, and multiplet,
respectively. Mass spectra and high-resolution mass spectra (m/z)
were measured with ESI. All moisture-sensitive reactions were per-
formed under argon. THF was freshly distilled from the sodium
complex of benzophenone before use. Dichloromethane was freshly
distilled from CaH2. Toluene was distilled from sodium. Column
chromatography was performed with silica gel (SDS 230–
400 mesh), and preparative thin-layer chromatography (TLC) was
performed with silica gel (Merck HF 254 + 366).
1
colourless crystals; m.p. 56 °C. H NMR (500 MHz, CDCl3): δ =
7.27 (d, J = 8.6 Hz, 2 H, MeOAr-H), 6.90 (d, J = 8.6 Hz, 2 H,
MeOAr-H), 6.86 (m, 1 H, NCH), 4.51 (s, 2 H, MeOArCH2O), 4.44
(m, 2 H, PMBOCH2), 3.82 (s, 3 H, OMe), 3.68 (br. s, 3 H, NMe)
ppm. 13C (125 MHz, CDCl3): δ = 159.63, 138.44, 129.72, 129.46,
114.04, 73.50, 65.57, 55.39, 52.25 ppm. HRMS (ESI, CH2Cl2/
MeOH): calcd. for C11H15NNaO3 [M + Na]+ 232.0950; found
232.0946.
4-(4-Methoxybenzyloxymethyl)-2,2-dimethyl-1,3-dioxolane: Solketal
(500 µL, 4.02 mmol) was added dropwise under Ar to a stirred sus-
pension of NaH (60%, 206 mg, 5.37 mmol) in dry THF (8.0 mL)
at 0 °C. The mixture was stirred for 10 min at 0 °C and then at
room temp. for 1.5 h and cooled again to 0 °C. PMBBr (596 µL,
4.07 mmol) was then added, and the solution was stirred for 10 min
at room temp. and then at reflux for 22 h. The solvent was evapo-
rated, and heptane was added. The insoluble salts were filtered,
and the solution was washed with water and dried with MgSO4.
After the usual workup, the product was purified by chromatog-
raphy on silica gel (eluent: heptane/Et2O, 1:1), giving rise to O-
PMB solketal as a colourless liquid (975 mg, 96%). 1H NMR
(3aR*,6R*,6aS*)-5-tert-Butyl 6-Methyl 6-(Benzyloxymethyl)-3-[(4-
methoxybenzyloxy)methyl]-2-methyl-4-oxotetrahydro-2H-pyrrolo-
[3,4-d]isoxazole-5,6(3H)-dicarboxylates (8): A solution of (Ϯ)-5
(330 mg, 0.91 mmol) in toluene (6.0 mL) was added to nitrone 7
(260 mg, 1.24 mmol), and the mixture was stirred at 60 °C for 27 h.
The crude product obtained after evaporation of the solvent was
purified by chromatography on silica gel (eluent: CH2Cl2/MeOH,
99:1) to give (3S*,3aR*,6R*,6aS*)-8a (398.0 mg, 76%) as a colour-
less oil and a mixture of starting material and 8b. Diastereomer 8b
was formed in about 8% yield (established by NMR) and purified
(500 MHz, CDCl3): δ = 7.27 (d, J = 8.5 Hz, 2 H, MeOAr-H), 6.88 by preparative TLC (slow elution with CH2 Cl2) to give
(d, J = 8.5 Hz, 2 H, MeOAr-H), 4.54 (d, J = 11.3 Hz, 1 H, MeOAr-
CHaO), 4.49 (d, J = 11.3 Hz, 1 H, MeOArCHbO), 4.29 (m, 1 H,
(3R*,3aR*,6R*,6aS*)-8b (38 mg, 7%) as a colourless gum. Major
cycloadduct (3S*,3aR*,6R*,6aS*)-8a: 1H NMR (300 MHz,
H-4), 4.05 (dd, J = 8.2, JЈ = 6.4 Hz, 1 H, Ha-5), 3.73 (dd, J = 8.2, CDCl3): δ = 7.36–7.20 (m, 5 H, Ph-H), 7.24 (masked d, J = 8.7 Hz,
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Stereoselective Approach to Omuralide–Salinosporamide A Hybrids
2 H, MeOAr-H), 6.86 (d, J = 8.7, 2 H, MeOAr-H), 4.60–4.42 (m,
5 H, 2ϫArCH2O, H-6a), 4.13 (d, J = 9.6 Hz, 1 H, BnOCHa), 3.98
(d, J = 9.6 Hz, 1 H, BnOCHb), 3.80 (s, 3 H, OMe), 3.74 (s, 3 H,
OMe), 3.58 (m, 2 H, PMBOCH2), 3.47 (dd, J = 6.9, JЈ = 4.5 Hz,
1 H, H-3a), 3.32 (br. m, 1 H, NCH), 2.71 (br. s, 3 H, NMe), 1.44
(s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.60, 167.08,
159.35, 149.16, 137.32, 129.99, 129.38, 128.69, 128.08, 127.71,
113.93, 83.92, 79.51, 73.65, 73.05, 72.09, 70.30, 70.0 (br.), 55.37,
52.42, 45.4 (br.), 27.93 ppm. HRMS (ESI, CH2Cl2/MeOH): calcd.
for C30H38N2NaO9 [M + Na]+ 593.2475; found 593.2478. For X-
ray analysis, 8a was crystallised from EtOAc/pentane; m.p. 87–
89 °C. Minor cycloadduct 8b: 1H NMR (500 MHz, CDCl3): δ =
7.36–7.23 (m, 7 H, 5 Ph-H, 2ϫMeOAr-H), 6.87 (d, J = 8.7 Hz, 2
H, MeOAr-H), 4.63 (d, J = 7.4 Hz, 1 H, H-6a), 4.49 (2 H, Ar-
CH2O), 4.47 (2 H, ArCH2O), 4.19 (dd, J = 10.7, JЈ = 2.5 Hz, 1 H,
PMBOCHa), 4.10 (d, J = 9.6 Hz, 1 H, BnOCHa), 4.01 (d, J =
9.6 Hz, 1 H, BnOCHb), 3.81 (s, 3 H, OMe), 3.76 (s, 3 H, OMe),
3.64 (dd, J = 10.7, JЈ = 8.0 Hz, 1 H, PMBOCHb), 3.50 (1 H, H-
3a), 2.93 (m, 1 H, H-3), 2.69 (s, 3 H, NMe), 1.42 (s, 9 H, tBu) ppm.
13C NMR (125 MHz, CDCl3): δ = 171.55, 167.46, 159.34, 148.67,
137.39, 130.32, 129.53, 128.72, 128.11, 127.76, 113.94, 83.73, 77.87,
73.71, 73.20, 70.86, 69.76, 67.48, 55.41, 53.97, 52.39, 44.84, 28.00
ppm. HRMS (ESI, CH2Cl2/MeOH): calcd. for C30H38N2NaO9
[M + Na]+ 593.2475; found 593.2448.
159.86, 149.73, 137.74, 136.47, 134.00, 129.87, 128.56, 128.34,
127.89, 127.68, 114.25, 83.83, 73.57, 73.52, 70.97, 69.32, 68.92,
68.07, 55.41, 52.40, 28.03 ppm. HRMS (ESI, CH2Cl2/MeOH):
calcd. for C29H35NNaO9 [M + Na]+ 564.2210; found 564.2211.
(2R*,3S*,E)-Methyl 2-(Benzyloxymethyl)-3-hydroxy-4-[2-(4-meth-
oxybenzyloxy)ethylidene]-5-oxopyrrolidine-2-carboxylate (11):
Dried MgCl2 (13.1 mg, 0.137 mmol) was added to a solution of 10
(82.0 mg, 0.151 mmol) in MeCN (1.1 mL), and the mixture was
stirred at 40 °C for 2.5 h. After dilution with CH2Cl2 and filtration
of the resulting mixture, the salt was washed with CH2Cl2. The
solution was evaporated to dryness giving rise to deprotected 11 as
colourless crystals (64.7 mg, 97 %); m.p. 104 °C. 1H NMR
(500 MHz, CDCl3/D2O): δ = 7.37–7.25 (5 H, Ph-H), 7.23 (d, J =
8.5 Hz, 2 H, MeOAr-H), 6.89 (d, J = 8.5 Hz, 2 H, MeOAr-H), 6.69
(m, 1 H, CH-4), 4.70 (m, 1 H, H-3), 4.54 (apparent s, 2 H, Ar-
CH2O), 4.52 (masked 2 d, 2 H, ArCH2O), 4.31 (m, 2 H,
PMBOCH2), 4.08 (d, J = 8.8 Hz, 1 H, BnOCHa), 3.82 (s, 3 H,
OMe), 3.79 (s, 3 H, OMe), 3.35 (d, J = 8.8 Hz, 1 H, BnOCHb)
ppm. 13C NMR (125 MHz, CDCl3): δ = 170.09, 168.13, 159.85,
137.36, 134.37, 134.17, 129.84, 128.62, 128.08, 127.80, 114.26,
73.79, 73.69, 73.42, 69.87, 69.04, 67.74, 55.42, 52.90 ppm. HRMS
(ESI, CH2Cl2/MeOH): calcd. for C24H27NNaO7 [M + Na]+
464.1685; found 464.1675.
(2R*,3S*,E)-Methyl 2-(Benzyloxymethyl)-3-(tert-butyldimethylsilyl-
oxy)-4-[2-(4-methoxybenzyloxy)ethylidene]-5-oxopyrrolidine-2-
carboxylate (12): To a solution of 11 (63.1 mg, 0.143 mmol) in dry
CH2Cl2 (0.86 mL) at 15 °C were successively added, under argon,
2,6 lutidine (117 µL, 1.0 mmol) and TBSOTf (117 µL, 0.51 mmol).
The mixture was stirred for 6 h at the same temperature and then
cooled to 0 °C before the addition of CH2Cl2 and NaHCO3 (5%
w/v). After extraction of the aqueous phase with CH2Cl2 and the
usual workup, the product was purified by preparative TLC (elu-
ent: heptane/Et2O, 1:9) to afford 12 (68.3 mg, 86%) as colourless
(2R*,3S*,4R*)-1-tert-Butyl 2-Methyl 2-(Benzyloxymethyl)-3-hy-
droxy-4-[2-(4-methoxybenzyloxy)-1-(methylamino)ethyl]-5-oxo-
pyrrolidine-1,2-dicarboxylate (9): A solution of cycloadduct 8a
(199.5 mg, 0.35 mmol) in EtOAc (3.4 mL) was stirred under H2 in
the presence of Pd(OH)2 (38 mg) at room temp. for 16 h. The cata-
lyst was filtered through celite and washed with EtOAc. Evapora-
tion of the solvent under reduced pressure afforded the crude hy-
drogenolysis product as a colourless gum (198 mg, 99%). 1H NMR
(500 MHz, CDCl3/D2O): δ = 7.36–7.18 (7 H, Ph-H, MeOAr-H),
6.87 (d, J = 8.5 Hz, 2 H, MeOAr-H), 4.59 (d, J = 6.8 Hz, 1 H, H-
3), 4.50–4.46 (4 d, J ≈ 11.7 Hz, 4 H, 2ϫArCH2O), 4.13 (d, J =
9.8 Hz, 1 H, BnOCHa), 4.03 (d, J = 9.8 Hz, 1 H, BnOCHb), 3.80
(s, 3 H, OMe), 3.73 (s, 3 H, OMe), 3.73 (masked m, 1 H,
PMBOCHa), 3.63 (masked m, 1 H, PMBOCHb), 3.60 (1 H, CH-
4), 2.97 (dd, J = 6.8, JЈ = 3.5 Hz, 1 H, H-4), 2.36 (s, 3 H, NMe),
1.44 (s, 9 H, tBu) ppm. 13C NMR (125 MHz, CDCl3): δ = 174.33,
168.43, 159.48, 149.62, 137.55, 129.94, 129.78, 129.48, 128.64,
128.00, 127.70, 114.03, 83.58, 74.87, 73.69, 73.06, 70.64, 69.17,
57.92, 55.39, 52.23, 45.41, 34.07, 27.98 ppm. HRMS (ESI, CH2Cl2/
MeOH): calcd. for C30H41N2O9 [M + H]+ 573.2812; found
573.2803.
1
crystals; m.p. 115–116 °C. H NMR (300 MHz, CDCl3): δ = 7.4–
7.2 (m, 5 H, Ph-H), 7.22 (masked d, J = 8.7 Hz, 2 H, MeOAr-H),
6.88 (d, J = 8.7 Hz, 2 H, MeOAr-H), 6.65 (ddd, J ≈ JЈ ≈ 5.6, JЈЈ =
1 Hz, 1 H, CH-4), 6.32 (br. s, 1 H, NH), 4.84 (m, apparent br. s, 1
H, H-3), 4.56–4.40 (4 d, 4 H, PhCH2O, MeOArCH2O), 4.20–4.19
(m, 2 H, PMBOCH2), 3.90 (d, J = 8.8 Hz, 1 H, BnOCHa), 3.82 (s,
3 H, OMe), 3.76 (s, 3 H, OMe), 3.23 (d, J = 8.8 Hz, 1 H, BnOCHb),
0.79 (s, 9 H, SitBu), 0.00 (s, 3 H, SiMe), –0.01 (s, 3 H, SiMe) ppm.
13C NMR (75 MHz, CDCl3): δ = 169.30, 168.26, 159.59, 137.39,
134.54, 133.56, 129.57, 128.61, 128.05, 127.67, 114.06, 73.73, 73.26,
72.70, 71.25, 70.95, 66.83, 55.44, 52.67, 25.72, 18.01, –4.16, –4.46
ppm. HRMS (ESI, CH2Cl2/MeOH): calcd. for C30H41NNaO7Si
[M + Na]+ 578.2550; found 578.2535.
(2R*,3S*,E)-1-tert-Butyl 2-Methyl 2-(Benzyloxymethyl)-3-hydroxy-
4-[2-(4-methoxybenzyloxy)ethylidene]-5-oxopyrrolidine-1,2-dicarb-
oxylate (10): Iodomethane (0.41 mL, 6.6 mmol) was added under
argon to a solution of 9 (126.2 mg, 0.22 mmol) in dry THF
(1.6 mL), and the mixture was stirred at room temp. for 24 h. MeI
(2R*,3S*,4R*)-Methyl 2-(Benzyloxymethyl)-3-(tert-butyldimethyl-
silyloxy)-4-[2-(4-methoxybenzyloxy)ethyl]-5-oxopyrrolidine-2-carb-
oxylate (4): Compound 12 (55.0 mg, 1.0 mmol), dissolved in EtOAc
(0.41 mL, 6.6 mmol) and NaHCO3 (25 mg, 0.3 mmol) were then (2.6 mL), was stirred under H2 in the presence of PtO2 (9 mg) for
added, and stirring was maintained for an additional 40 h before
the solvent and reagent in excess were evaporated. The residue was
filtered through silica gel (eluent: Et2O) to give the crude product,
which was purified by preparative TLC (eluent: CH2Cl2/MeOH,
98:2) affording 10 as a colourless gum (87.3 mg, 73% over 2 steps).
1H NMR (300 MHz, CDCl3): δ = 7.35–7.15 (m, 7 H, Ph-H,
MeOAr-H), 6.89 (d, J = 8.7 Hz, 2 H, MeOAr-H), 6.85 (m, 1 H,
60 h. The catalyst was filtered through celite and washed with
EtOAc, and the solvent was evaporated under reduced pressure.
The crude product (55.2 mg, de = 80%, as deduced from 1H NMR)
was recrystallized from Et2O/pentane to afford 4 (43.5 mg, 79%,
Ͼ95 % pure according to 1H NMR); m.p. 72–73 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.40–7.20 (m, 5 H, Ph-H), 7.26 (masked d,
J = 8.7 Hz, MeOAr-H), 6.86 (d, J = 8.7 Hz, 2 H, MeOAr-H), 6.04
CH-4), 5.03 (m, 1 H, H-3), 4.57–4.48 (4 d, J = 11.5 Hz, 4 H, 2ϫAr- (br. s, 1 H, NH), 4.52 (apparent s, 2 H, PhCH2O), 4.47 (d, J =
CH2O), 4.37 (centre of m, 2 H, PMBOCH2), 4.17 (d, J = 9.8 Hz, 11.7 Hz, 1 H, MeOArCHaO), 4.42 (d, J = 11.7 Hz, 1 H,
1 H, BnOCHa), 4.03 (d, J = 9.8 Hz, 1 H, BnOCHb), 3.99 (d, 1 H
MeOArCHbO), 4.31 (d, J = 6.7 Hz, 1 H, H-3), 3.96 (d, J = 8.8 Hz,
1 H, BnOCHa), 3.80 (s, 3 H, OMe), 3.73 (s, 3 H, OMe), 3.70 (m,
exchanged, OH), 3.82 (s, 3 H, OMe), 3.73 (s, 3 H, OMe), 1.46 (s,
9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.84, 165.72, 1 H, PMBOCHa), 3.65 (m, 1 H, PMBOCHb), 3.43 (d, J = 8.8 Hz,
Eur. J. Org. Chem. 2008, 5810–5814
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5813

N. Langlois, J.-C. Legeay, P. Retailleau
FULL PAPER
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1 H, BnOCHb), 2.64 (m, 1 H, H-4), 1.91 (m, 2 H, CH2-4), 0.86 (s,
9 H, SitBu), 0.05 (s, 3 H, SiMe), 0.03 (s, 3 H, SiMe) ppm. 13C
(125 MHz, CDCl3): δ = 176.81, 170.17, 159.22, 137.39, 130.92,
129.39, 128.62, 128.06, 127.78, 113.85, 73.83 (CH and CH2), 73.29,
72.65, 71.06, 67.96, 55.39, 52.58, 43.25, 25.87, 25.24, 18.13, –3.96,
– 4. 74 ppm. HRMS (ESI, CH 2 Cl 2 /M eO H ) : c a l c d . fo r
C30H43NNaO7Si [M + Na]+, 100%): 580.2707; found 580.2700. A
small amount of minor diastereomer 13 (ca 2.4 mg, 4%) was ob-
tained from the mother liquor after preparative TLC (eluent: hep-
1
tane/Et2O/MeOH, 4:2:0.1). 13: H NMR (500 MHz, CDCl3): δ =
7.40–7.25 (m, 5 H, Ph-H), 7.22 (d, J = 8.6 Hz, 2 H, MeOAr-H),
6.85 (d, J = 8.6 Hz, 2 H, MeOAr-H), 5.98 (br. s, NH), 4.52 (d, J =
12.0 Hz, 1 H, PhCHaO or MeOArCHaO), 4.49 (d, J = 12.0 Hz, 1
H, PhCHbO or MeOArCHbO), 4.38 (apparent s, 2 H, PhCH2O or
MeOArCH2O), 4.21 (d, J = 6.9 Hz, 1 H, H-3), 4.03 (d, J = 8.8 Hz,
BnOCHa), 3.80 (s, 3 H, OMe), 3.72 (s, 3 H, OMe), 3.66 (m, 1 H,
PMBOCHa), 3.62 (m, 1 H, PMBOCHb), 3.31 (d, J = 8.8 Hz, 1 H,
BnOCHb), 2.63 (m, 1 H, H-4), 1.93 (m, 2 H, CH2-4), 0.84 (s, 9 H,
SitBu), 0.04 (s, 3 H, SiMe), –0.01 (s, 3 H, SiMe) ppm. 13C NMR
(125 MHz, CDCl3): δ = 176.20, 170.24, 159.26, 137.49, 130.69,
129.40, 128.60, 128.05, 127.83, 113.84, 76.48, 73.76, 72.81, 72.67,
69.53, 67.67, 55.39, 52.51, 47.00, 27.95, 25.66, 17.84, –4.24, –4.66
ppm. HRMS (ESI, CH2Cl2/MeOH): calcd. for C30H43NNaO7Si
[M + Na]+ 580.2707; found 580.2707.
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[12] Some amount of the (Z) isomer was also obtained (ethylenic
proton: δ = 6.50 ppm, CDCl3). In general, and particularly in
N-Boc-4-alkylidene pyroglutamates, it is well known that the
ethylenic proton of the (E) isomer is more deshielded than the
corresponding proton in the (Z) isomer. For examples, see: a)
J. Ezquerra, C. Pedregal, B. Yruretagoyena, A. Rubio, M. C.
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[13] CCDC-692590 (for 8a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. The crystal structure de-
termination was performed by P. Retailleau.
[14] S. C. Nigam, A. Mann, M. Taddei, C.-G. Wermuth, Synth.
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We are grateful to Institut de Chimie des Substances Naturelles
(Centre National de la Recherche Scientifique, Gif-sur-Yvette) for
a grant to J.-C. L.
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Received: June 21, 2008
Published Online: October 16, 2008
5814
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5810–5814