Phthalimidomethylation of O-nucleophiles with O-phthalimidomethyl trichloroacetimidate: A powerful imidomethylating agent for O-protection

Article abstract of DOI:10.1055/s-2003-39164

Phthalimidomethylation of oxygen nucleophiles by using O-phthalimidomethyl (Pim) trichloroacetimidate in the presence of TMSOTf has been achieved in high yields. Hydrazinolysis of the phthalimido group from the O-derivatives leads to the hydroxy precursor

Full text of DOI:10.1055/s-2003-39164

PAPER
1065
Phthalimidomethylation of O-Nucleophiles with O-Phthalimidomethyl
Trichloroacetimidate: A Powerful Imidomethylating Agent for O-Protection
O
-Phthal
b
imidomethyl
r
Trichlo
a
roacetimida
h
te: APowe
r
i
m
for
OA
-Protection . I. Ali,a Adel A.-H. Abdel-Rahman,a El Sayed H. El Ashry,b Richard R. Schmidt*a
a
Department of Chemistry, University of Konstanz, Fach M 725, 78457 Konstanz, Germany
E-mail: Richard.Schmidt@uni-konstanz.de
b
Department of Chemistry, Faculty of Science, University of Alexandria, Alexandria, Egypt
E-mail: eelashry@link.net or eelashry60@hotmail.com
Received 22 January 2003
Abstract: Phthalimidomethylation of oxygen nucleophiles by us-
ing O-phthalimidomethyl (Pim) trichloroacetimidate in the pres-
ence of TMSOTf has been achieved in high yields. Hydrazinolysis
of the phthalimido group from the O-derivatives leads to the hy-
droxy precursors. Thus a convenient method for the protection of
oxygen nucleophiles is provided, which complements the repertoire
of available hydroxy protecting groups.
Key words: imides, alcohols, aminomethylations, phthalimide, nu-
cleophiles, protecting groups
A study on the hypolipidemic activity of phthalimidome-
thyl (Pim) tetra-O-acyl-α-D-mannopyranosides in mice
showed significant reduction of plasma cholesterol and Scheme 1 Synthesis of the trichloroacetimidate 2 and reaction with
triglyceride levels.1 Moreover, some phthalimidomethyl
O-nucleophiles
and phthalimide derivatives possess analgesic,2 hypolipi-
demic,3,4 anticonvulsant,5 and antitumor6 activities. They
such as 3–5, in the presence of TMSOTf as catalyst gave
are also useful as synthetic intermediates,7–16 for instance
the respective phthalimidomethyl derivatives 13–15
in polymer chemistry.17 The phthalimidomethyl deriva-
(Scheme 2; entries 1–3, Table 1) in 77–94% yields. The
tives have been used for the identification18–22 of amines
reaction was then extended to benzyl alcohols 6 and 7, to
and alcohols via nucleophilic substitution23 of a leaving
cholesterol 8 as well as to carbohydrate derivatives 9–12
group on the Pim moiety. The biological activities as well
to give the corresponding imidomethyl derivatives 16–22
as our interest in the reactivity of trichloroacetimi-
(entries 4–10, Table 1). None of the O-protecting groups
dates24–27 attracted our attention to develop a method for
of the starting materials was affected under the reaction
introducing the phthalimidomethyl group on nucleophiles
conditions. The spectral analysis of the products agreed
to form, for instance, CO bonds under acid catalysis. O-
1
with the assigned structures. They showed in their H
Phthalimidomethyl trichloroacetimidate (2) (Scheme 1)
NMR spectra a singlet at δ = 5.1 confirming the introduc-
was expected to serve as an imidomethylating agent; en-
tion of the NCH2 group.
suing removal of the phthaloyl residue in the products will
Reaction of 2 can be rationalized by acid catalyzed gener-
ation of a carbocation intermediate, which reacts with the
nucleophiles to give the products; thus, a method for the
imidomethylation of nucleophiles under mild acid condi-
tions is provided. The amido and imidomethylation of nu-
cleophiles under more drastic conditions has been known
for many years.28,29 The trichloroacetamide leaving group
offers a particularly convenient method for the synthesis
of such compounds.
readily provide the corresponding aminomethyl deriva-
tives. In the case of O-nucleophiles, the O-aminomethyl
intermediate will liberate the hydroxy group, thus exhibit-
ing that Pim is also a useful protecting group.
The synthesis of 2 was achieved by reaction of N-hy-
droxymethylphthalimide (1) with trichloroacetonitrile in
dichloromethane as solvent and in the presence of DBU as
a base which promotes the addition to the nitrile group
(Scheme 1). The product 2 was isolated in 87% yield after
column chromatography; its structure was readily as-
signed from the 1H NMR spectrum (δ = 5.9 for CH2, 8.59
for NH). Reaction of the trichloroacetimidate 2 with com-
pounds having primary and secondary hydroxy groups,
Attempted cleavage of the phthalimido group with hydra-
zine hydrate or methylamine in methanol gave from 19
the respective alcohol 9 whose formation is the result of
hydrolysis of intermediate 23 (Scheme 2). Treatment of
21 with aqueous acetic acid (80%) at 80 °C led to selec-
tive removal of the 5,6-O-isopropylidene group without
affecting the Pim O-protection. Also hydrogenolysis of 19
in methanol with palladium on carbon as catalyst cleanly
Synthesis 2003, No. 7, Print: 20 05 2003.
Art Id.1437-210X,E;2003,0,07,1065,1070,ftx,en;T00503SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1066
I. A. I. Ali et al.
PAPER
Table 1 Phthalimidomethylation of Oxygen Nucleophiles 3–12 by 2
Entry
1
ROH
Reaction time (min)
180
RO-Pim
Yield (%)a
81
2
3
45
60
94
77
4
5
60
90
87
90
6
60
89
7
20
75
8
9
30
30
80
69
10
90
80
a Isolated yield after column chromatography.
furnished the 2,3,4-O-unprotected intermediate; subse- in the presence of DBU as a base led to trichloroacetimi-
quent transformation into the 2,3,4-tri-O-acetyl derivative date 25; only the α-anomer was obtained (1H NMR:
with pyridine–acetic anhydride and de-O-acetylation with δ = 6.54; J1,2 = 3.3 Hz).
sodium methoxide in methanol afforded the 2,3,4-O-un-
Glycosylation of methanol, octanol and 6-O-unprotected
protected compound again without affecting the Pim O-
glucopyranoside 9 with 25 as glycosyl donor in the pres-
protection. Hence, the Pim group is compatible with and
ence of TMSOTf as a catalyst afforded glucosides 26–28
in high yields; the β-anomers were the main products (α/
β, 1:1.5–6.0). The preference for the β-product may be
due to a steric effect and/or neighboring group participa-
orthogonal to all important hydroxy protecting groups; it
offers selective removal with strong nucleophiles, thus
complementing the repertoire of the available hydroxy
protecting groups which are generally sensitive to acid,
tion via a seven-membered intermediate. Thus, in terms of
base, or hydrogenolysis, respectively.30
glycosyl donor properties and anomeric control there is a
Also the effect of a neighboring Pim group on glycoside big difference between a 2-O-acyl group and a 2-O-Pim
bond formation has been investigated. To this end, 2-O- group. The Pim group rather resembles the 2-O-benzyl
Pim protected glucopyranoside 22 was de-O-allylated group which offers high glycosyl donor properties with
with Wilkinson’s catalyst to afford glucose derivative 24 little interference in anomeric stereocontrol.24–26
(α/β, 2:3) (Scheme 3). Reaction with trichloroacetonitrile
Synthesis 2003, No. 7, 1065–1070 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
O-Phthalimidomethyl Trichloroacetimidate: A Powerful Imidomethylating Agent for O-Protection
1067
Scheme 2 Phthaloyl group removal and deprotection
QC). MS spectra were recorded with MALDI-Kompakt (Kratos)
and FAB with Finningen Mat 312/AMD instruments. Microanaly-
ses were performed in the unit of Microanalysis at the Department
of Chemistry, Universität Konstanz. Petroleum ether refers to the
fraction with bp 35–65 ºC.
In conclusion, a general method has been developed for
introducing the Pim group on different oxygen nucleo-
philes. The O-Pim trichloroacetimidate, which can be
stored without decomposition, can be considered as the
reagent of choice for forming CO bonds with O-nucleo-
philes under mild acid conditions. It is characterized by a
high reactivity in the electrophilic displacement reactions.
The respective Pim products can be easily isolated and
identified. The Pim group can be used for the protection
of hydroxy groups; with good nucleophiles it can be
smoothly removed in a one-pot reaction via two cleavage
steps. The Pim group is stable in the presence of weak nu-
cleophiles and under acidic, basic, and hydrogenolytic
conditions.
O-Phthalimidomethyl Trichloroacetimidate (2)
A stirred solution of N-hydroxymethylphthalimide (0.58 g, 5 mmol)
in anhyd CH2Cl2 (30 mL) and trichloroacetonitrile (5 mL, 50 mmol)
was treated with DBU (71 µL) at r.t. and then left for 2 h. The sol-
vent was evaporated and the product was purified by column chro-
matography (5% Et3N in toluene– EtOAc, 25:1) to give 2.
Yield: 1.3 g (87%); white powder; mp 145–147 °C.
1H NMR (250 MHz, CDCl3): δ = 8.59 (s, 1 H, NH), 7.79–7.99 (m,
4 H, HAr), 5.90 (s, 2 H, CH2).
13C NMR (150.8 MHz, CDCl3): δ = 64.9 (CH2), 90.6 (CCl3), 124.0,
131.8, 134.7 (ArC), 161.2 (CNH), 166.5 (CO).
Mps are uncorrected. TLC was performed on plastic plates (Silica
Gel 60 F254; E. Merck, layer thickness 0.2 mm). The detection was
achieved by treatment with a solution of ammonium molybdate (20
g) and cerium(IV) sulfate (0.4 g) in H2SO4 (400 mL of 10%), or with
H2SO4 (15%), and heating at 150 °C. Flash chromatography was
carried out on silica gel (Baker, 30–60 µm). Optical rotations were
determined at 20 °C with a Perkin–Elmer 241 MC polarimeter (1
dm cell). NMR spectra were recorded with Bruker AC 250 and 600
DRX instruments, using tetramethylsilane as an internal standard.
The assignment of 13C NMR spectra were based on carbon–proton
shift-correlation heteronuclear multiple quantum coherence (HM-
EI-MS: m/z = 321.
Reaction of Trichloroacetimidate 2 with Alcohols; General Pro-
cedure
A solution of 2 (0.45 g, 1.4 mmol) and alcohol (1.4 mmol) in anhyd
CH2Cl2 (40 mL) was stirred under nitrogen at r.t. and then TMSOTf
(13 µL, 0.06 mmol) was added. After 20 min–3 h, the reaction mix-
ture was neutralized with solid NaHCO3, filtered and concentrated
in vacuo. The residue was purified by flash chromatography.
Isopropyl Phthalimidomethyl Ether (13)
Yield: 0.25 g (81%); white powder; Rf 0.54 (petroleum ether–
EtOAc, 5:1); mp 92 °C (lit.30 92–93 °C).
Cyclohexyl Phthalimidomethyl Ether (14)
Yield: 0.45 g (90%); white powder; Rf 0.81; petroleum ether–
EtOAc, 5:1); mp 83 °C (lit.22 81–83 °C).
The analytical data 14 are identical with the published values.22
5-Methyl-2-phenyl-5-(phthalimidomethyloxy)methyl-1,3-diox-
ane (15)
Yield: 0.4 g (77%); white powder; Rf 0.65 (petroleum ether–EtOAc,
5:1); mp 76 °C.
1H NMR (250 MHz, CDCl3): δ = 0.76 (s, 3 H, CH3), 3.50 (d,
Jgem = 11.8 Hz, 2 H, CH2), 3.84 (s, 2 H, CH2), 4.00 (d, Jgem = 11.8
Hz, 2 H, CH2), 5.20 (s, 2 H, CH2), 5.32 (s, 1 H, CH), 7.87–7.26 (m,
9 H, ArH).
13C NMR (62.8 MHz, CDCl3): δ = 17.2 (CH3), 34.4, 67.8, 71.6,
73.1 (4 CH2), 101.8 (CH), 123.5, 123.6, 126.0, 128.1, 128.7, 131.8,
134.2, 138.1 (ArC), 163.7 (C), 168.0 (CO).
Scheme 3 Pim as neighbouring group in glycosylation reaction: (a)
Wilkinson’s catalyst, toluene, EtOAc; (b) CCl3CN, DBU; (c) HOR,
TMSOTf
EI-MS: m/z = 367.
Anal. Calcd for C21H21NO5 (367.4): C, 68.65; H, 5.76; N, 3.81.
Found: C, 68.82, H, 5.94; N, 4.01
Synthesis 2003, No. 7, 1065–1070 ISSN 0039-7881 © Thieme Stuttgart · New York

1068
I. A. I. Ali et al.
PAPER
Benzyl Phthalimidomethyl Ether (16)
EI-MS: m/z = 623.
Yield: 0.32 g (87%); white powder; Rf 0.82 (petroleum ether–
Anal. Calcd for C37H37NO8 (623.7): C, 71.25; H, 5.97; N, 2.24.
Found: C, 70.79; H, 6.03; N, 1.80.
EtOAc, 5:1); mp 80 °C (lit.31 81 °C).
(3,5-Dinitrobenzyl) Phthalimidomethyl Ether (17)
Yield: 0.45 g (90%); yellow powder; Rf 0.53 (petroleum ether–
EtOAc, 4:1); mp 115 °C.
1H NMR (250 MHz, CDCl3): δ = 4.80 (s, 2 H, CH2), 5.30 (s, 2 H,
1:2,5:6-Di-O-isopropylidene-3-O-phthalimidomethyl- -D-glu-
cofuranose (21)
Yield: 0.4 g (69%); colourless oil; Rf 0.65 (petroleum ether–EtOAc,
4:1); [α]D20 –12.5 (c 4.0, CH2Cl 2).
CH2), 8.55–7.70 (m, 7 H, HAr).
13C NMR (62.8 MHz, CDCl3): δ = 67.2, 69.4 (2 CH2), 117.9, 123.9,
134.7 (ArC), 167.7 (CO).
1H NMR (600 MHz, CDCl3): δ = 1.10, 1.20, 1.35, 1.40 (4 CH3),
3.94 (m, 3 H, H-4, H-6, H-6′), 4.30 (d, J = 2.7 Hz, 1 H, H-3), 4.16
(m, 1 H, H-5), 4.58 (d, J2,1 = 3.5 Hz, 1 H, H-2), 5.23 (s, 2 H, CH2),
5.85 (d, J1,2 = 3.5 Hz, 1 H, H-1), 7.70–8.00 (m, 4 H, HAr).
13C NMR (150.8 MHz, CDCl3): δ = 23.8, 24.2, 26.2, 26.8 (4 CH3),
67.1 (C-6), 67.9 (CH2), 72.1 (C-5), 80.8 (C-4), 81.0 (C-3), 83.7 (C-
2), 105.2 (C-1), 108.8, 112.1, 123.6, 123.7, 131.9, 123.7, 131.9,
132.2, 134.2, 134.3 (CAr), 167.9 (CO).
EI-MS: m/z = 357.
Anal. Calcd for C16H11N3O7 (357.3): C, 53.78; H, 3.10; N, 11.76.
Found: C, 53.51, H, 3.05; N, 11.43
Cholesteryl Phthalimidomethyl Ether (18)
Yield: 0.7 g (89%); white powder; Rf 0.74 (petroleum ether–EtOAc,
25:1); mp 132 °C.
1H NMR (250 MHz, CDCl3): δ = 0.64–2.28, (m, 43 H, cholesteryl),
3.55 (m, 1 H, CH), 5.36 (m, 1 H, CH), 5.60 (m, 2 H, CH2), 7.90–
7.20 (m, 4 H, ArH).
EI-MS: m/z = 419.0.
Anal. Calcd for C21H25NO8 (419.4): C, 60.13; H, 6.00; N, 3.34.
Found: C, 60.43; H, 5.90; N, 3.31.
Allyl 3,4,6-Tri-O-benzyl-2-O-phthalimidomethyl- -D-glucopyr-
anoside (22)
Anal. Calcd for C36H51NO3 (545.8): C, 79.22; H, 9.41; N, 2.56.
Found: C, 79.07; H, 9.49; N, 2.55.
Yield: 0.7 g (80%); colourless oil; Rf 0.43 (petroleum ether–EtOAc,
5:1); [α]D20 –2.4 (c 5.0, CH2Cl 2).
Methyl 2,3,4-Tri-O-benzyl-6-O-phthalimidomethyl- -D-gluco-
pyranoside (19)
1H NMR (250 MHz, CDCl3): δ = 3.45 (dd, J6,5 = 3.6, Jgem = 10.3
Hz, 1 H, H-6), 3.68 (dd, J6,5 = 3.4, Jgem = 10.4 Hz, 1 H, H-6′), 3.60
(m, 2 H, H-2, H-4), 3.70 (m, 1 H, H-5), 4.02 (dd, J3,2 = 3.8, J3,4 = 9.7
Hz, 1 H, H-3), 4.22 (m, 2 H, CH2CH=CH2), 4.42 (d, Jgem = 10.5 Hz,
1 H, CHPh), 4.45 (d, Jgem = 10.5 Hz, 1 H, CHPh), 4.60 (d,
Jgem = 10.4 Hz, 1 H, CHPh), 4.64 (d, Jgem = 10.4 Hz, 1 H, CHPh),
4.70 (m, 2 H, CH2=CH), 4.91 (d, Jgem = 10.5 Hz, 1 H, CHPh), 5.02
(d, J1,2 = 3.1 Hz, 1 H, H-1), 5.17 (d, Jgem = 10.5 Hz, 1 H, CHPh),
5.23 (s, 2 H, CH2), 5.80 (m, 1 H, CH2=CH), 7.07–7.40 (m, 15 H,
HAr), 7.75 (m, 4 H, HAr).
Yield: 0.65 g (75%); white powder; Rf 0.38 (petroleum ether–
EtOAc, 4:1); [α]D20 + 51.53 (c 1.5, CH2Cl 2); mp 89 °C.
1H NMR (600 MHz, CDCl3): δ = 3.30 (s, 3 H, OCH3), 3.45 (dd,
J1,2 = 3.5 Hz, J2,3 = 9.6 Hz, 1 H, H-2), 3.55 (dd, J4,3 = 9.3, J4,5 = 9.6
Hz, 1 H, H-4), 3.67 (m, 1 H, H-5), 3.78 (dd, J6′,5 = 1.3, Jgem = 9.6
Hz, 1 H, H-6′), 3.87 (dd, J6,5 = 3.6, Jgem = 9.6 Hz, 1 H, H-6), 3.92
(dd, J3,4 = 9.3, J3,2 = 9.6 Hz, 1 H, H-3), 4.35 (d, J1,2 = 3.4 Hz, 1 H,
H-1), 4.60 (d, Jgem = 12.1 Hz, 1 H, CHPh), 4.74 (d, Jgem = 12.0 Hz,
1 H, CHPh), 4.78 (d, Jgem = 11.0 Hz, 1 H, CHPh), 4.80 (d,
Jgem = 11.0 Hz, 1 H, CHPh), 4.83 (d, Jgem = 12.1 Hz, 1 H, CHPh),
4.94 (d, Jgem = 10.9 Hz, 1 H, CHPh), 5.18 (q, Jgem = 10.9 Hz, 2 H,
CH2Phth), 7.79–7.11 (m, 19 H, ArH).
13C NMR (150.8 MHz, CDCl3): δ = 55.1 (OCH3), 68.6 (C-6), 69.9
(C-5), 77.5 (C-4), 79.8 (C-2), 82.0 (C-3), 89.2 (C-1), 67.8, 73.4,
74.9, 75.6 (4 CH2), 123.6, 127.5, 127.8, 127.9, 128.1, 128.2, 128.3,
128.4, 131.8, 134.2, 138.2, 138.3, 138.8 (C-Ar), 167.8 (CO).
MS (MALDI, positive mode, matrix: DHB): m/z = 672 (M + Na)+,
688 (M + K)+.
Anal. Calcd for C39H39NO8 (649.74): C, 72.09; H, 6.05; N, 2.15.
Found: C, 72.31, H, 6.23; N, 1.92.
3,4,6-Tri-O-benzyl-2-O-phthalimidomethyl- , -D-glucopyra-
nose (24)
To a solution of 22 (1.2 g, 1.85 mmol) in a mixture of toluene–
EtOH–H2O (40:40:2 mL) was added Wilkinson’s catalyst (342 mg,
0.36 mmol) and the reaction mixture was refluxed at 110 °C. After
stirring for 8 h, the solvent was evaporated in vacuo and the residue
was purified by flash chromatography (petroleum ether–EtOAc,
8:1) to give α/β mixture of 24.
EI-MS: m/z = 623.
Anal. Calcd for C37H37O8 (623.7): C, 71.25; H, 5.97; N, 2.24.
Found: C, 70.94; H, 5.82; N, 1.89.
Methyl 2,3,6-Tri-O-benzyl-4-O-phthalimidomethyl- -D-gluco-
pyranoside (20)
Yield: 0.77 g (68%); colourless oil; Rf 0.35 (petroleum ether–
EtOAc, 5:1); [α]D20 + 50.6 (c 2.0, CH2Cl 2).
Yield: 0.7 g (80%); white powder; Rf 0.35 (petroleum ether–EtOAc,
5:1); [α]D20+3.5 (c 10, CH2Cl 2); mp 62 °C.
1H NMR (600 MHz, CDCl3): δ = 1.50 (br, 1 H, OH), 3.47 (m, 1 H,
βH-5), 3.54 (m, 3 H, βH-2, βH-3, βH-4), 3.60 (m, 3 H, αH-4, H-6′),
3.80 (dd, J2,1 = 3.5, J2,3 = 9.4 Hz, 1 H, αH-2), 3.90 (dd, Jgem = 9.3
Hz, 1 H, H-3), 4.02 (m, 1 H, H-5), 4.44 (3 d, J = 10.4 Hz, 3 H, 3
CHPh), 4.60 (d, J1,2 = 9.8 Hz, 1 H, βH-1), 4.70 (m, 3 H, 3 CHPh),
5.25 (d, Jgem = 10.9 Hz, 2 H, βCH2), 5.37 (d, J1,2 = 3.4 Hz, 1 H, αH-
1), 5.45 (d, Jgem = 11.2 Hz, 2 H, αCH2), 7.00–7.20 (m, 15 H, HAr),
7.25–7.40 (m, 4 H, HAr).
13C NMR (150.8 MHz, CDCl3): δ = 67.3 (CH2), 67.9 (CH2), 68.6
(C-6), 70.3 (C-5), 73.4, 74.8 (2 CH2), 77.8 (C-4), 79.7 (C-2), 80.9
(C-3), 96.8 (C-1), 123.6, 123.7, 127.4, 127.6, 127.8, 127.9, 128.2,
128.4, 131.7, 134.2, 134.4, 137.8, 138.3, 138.5 (CAr), 167.6, 168.1
(2 CO).
1H NMR (600 MHz, CDCl3): δ = 3.25 (s, 3 H, OCH3), 3.44 (dd,
J1,2 = 3.3, J2,3 = 9.2 Hz, 1 H, H-2), 3.52 (m, 2 H, H-4, H-5), 3.72 (m,
1 H, H-3), 3.84 (m, 2 H, H-6), 4.40 (d, J1,2 = 3.3 Hz, 1 H, H-1), 4.5
(m, 2 H, 2 CHPh), 4.54 (d, Jgem = 12.1 Hz, 1 H, CHPh), 4.58 (d,
Jgem = 12.1 Hz, 1 H, CHPh), 4.96 (d, Jgem = 11.6 Hz, 1 H, CHPh),
5.04 (d, Jgem = 11.2 Hz, 1 H, CHPh), 5.30 (d, Jgem = 7.5 Hz, 2 H,
CH2), 7.70–7.30 (m, 19 H, HAr).
13C NMR (150.8 MHz, CDCl3): δ = 55.0 (OCH3), 67.8 (C-6), 69.4
(C-4), 69.8 (C-5) 73.3, 79.4, 79.7 (3 CH2), 79.2 (C-2), 80.9 (C-3),
81.3 (CH2), 123.3, 123.4, 123.5, 127.2, 127.6, 127.8, 127.9, 128.1,
128.3, 128.4, 131.7, 131.8, 132.0, 133.9, 134., 134.1, 137.9, 138.0,
138.6, 138.7 (CAr), 167.3, 167.8 (CO).
Synthesis 2003, No. 7, 1065–1070 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
O-Phthalimidomethyl Trichloroacetimidate: A Powerful Imidomethylating Agent for O-Protection
1069
MS (MALDI, positive mode, matrix: DHB): m/z = 632.5 (M +
Compound 27
Na)+.
1H NMR (600 MHz, CDCl3): δ = 0.84–1.50 [m, 13 H, CH3(CH2)5],
1.57–1.60 (m, 2 H, CH2), 3.43 (m, 2 H, CH2), 3.61 (m, 2 H, H-4, H-
6), 3.71 (m, 1 H, H-6), 3.78 (m, 1 H, H-5), 3.79 (m, 1 H, H-2), 3.90
(dd, J3,2 = 9.2, J3,4 = 9.3 Hz, 1 H, H-3), 4.52 (d, Jgem = 12.2 Hz, 1 H,
CHPh), 4.64 (d, Jgem = 11.2 Hz, 1 H, CHPh), 4.72 (m, 2 H, 2 CHPh),
4.75 (d, Jgem = 11.2 Hz, 1 H, CHPh), 4.81 (d, Jgem = 11.1 Hz, 1 H,
CHPh), 4.98 (d, J1,2 = 3.4 Hz, 1 H, H-1), 5.32 (s, 2 H, CH2), 7.09–
7.32 (m, 15 H, ArH), 7.44–7.60 (m, 4 H, ArH).
Anal. Calcd for C36H35NO8 (609.67): C, 70.92; H, 5.78; N, 2.29.
Found: C, 70.48; H, 6.20; N, 2.33.
O-3,4,6-Tri-O-benzyl-2-O-phthalimidomethyl- -D-glucopyra-
nosyl Trichloroacetimidate (25)
A stirred solution of glucose derivative 24 (0.61 g, 1.0 mmol) in an-
hyd CH2Cl2 (30 mL) and trichloroacetonitrile (1 mL, 10 mmol) was
treated with DBU (10 µL) at r.t. and then left for 1.5 h. The solvent
was evaporated and the product was purified by column chromatog-
raphy (5% Et3N in toluene–EtOAc, 25:1) to give 25.
Yield: 0.65 g (86%); oil; Rf 0.43 (2% Et3N in toluene); [α]D20 + 34.5
(c 1.0, CH2Cl 2).
13C NMR (150.8 MHz, CDCl3): δ = 14.1, 22.6, 25.8, 26.0, 29.1,
31.8, 32.7 [CH3(CH2)5], 67.3, 68.4 (2 CH2), 68.7 (C-6), 70.2 (C-5),
73.5, 75.3, 75.4 (3 CH2), 78.0 (C-4), 79.7 (C-2), 81.3 (C-3), 96.7 (C-
1), 123.5, 127.1, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.1,
128.3,133.9, 134.3 (ArC), 167.6, 167.8 (2 CO).
MS (MALDI, positive mode, matrix: DHB): m/z = 744.4 (M +
1H NMR (250 MHz, CDCl3): δ = 3.88 (m, 2 H, H-6, H-6′), 4.05 (m,
2 H, H-4, H-5), 4.60 (m, 3 H, 2 CHPh, H-3), 4.80 (d, Jgem = 9.7 Hz,
1 H, CHPh), 4.83 (d, Jgem = 11.1 Hz, 1 H, CHPh), 4.85 (d,
Jgem = 11.1 Hz, 1 H, CHPh), 5.20 (d, Jgem = 9.7 Hz, 1 H, CHPh),
5.30 (d, Jgem = 12.7 Hz, 2 H, CH2), 6.54 (d, J1,2 = 3.3 Hz, 1 H, H-1),
7.00–7.28 (m, 15 H, ArH), 7.61–7.77 (m, 4 H, HAr), 8.36 (s, 1 H,
NH).
Na)+, 760 (M + K)+.
Anal. Calcd for C44H51NO8 (721.9): C, 73.21; H, 7.12; N, 1.94.
Found: C, 73.04; H, 7.32; N, 1.83.
Compound 27
1H NMR (600 MHz, CDCl3): δ = 0.84–1.50 [m, 13 H, CH3(CH2)5],
1.57–1.60 (m, 2 H, CH2), 3.39 (m, 3 H, CH2, H-5), 3.53 (m, 2 H, H-
3, H-4), 3.64 (m, 2 H, H-2, H-6), 3.71 (m, 1 H, H-6′), 4.27 (d,
J1,2 = 7.8 Hz, 1 H, H-1), 4.52 (d, Jgem = 12.2 Hz, 1 H, CHPh), 4.64
(d, Jgem = 11.2 Hz, 1 H, CHPh), 4.72 (m, 2 H, 2 CHPh), 4.75 (d,
Methyl 3,4,6-Tri-O-benzyl-2-O-phthalimidomethyl- -D-glu-
copyranoside (26)
A solution of the trichloroacetimidate 25 (0.53 g, 0.7 mmol) and an-
hyd MeOH (0.28 mL, 7.0 mmol) in anhyd CH2Cl2 (10 mL) was
treated with TMSOTf (13 µL, 0.07 mmol), and then stirred for 1 h.
The reaction was quenched by the addition of solid NaHCO3, fil-
tered and concentrated. The crude residue was purified by column
chromatography (silica gel; petroleum ether–EtOAc, 15:1) to afford
26.
Jgem = 11.2 Hz, 1 H, CHPh), 4.81 (d, Jgem = 11.1 Hz, 1 H, CHPh),
5.26 (q, Jgem = 10.8 Hz, 2 H, CH2), 7.09–7.32 (m, 15 H, ArH), 7.44–
7.60 (m, 4 H, ArH).
13C NMR (150.8 MHz, CDCl3): δ = 14.1, 22.6, 25.8, 26.0, 29.1,
31.8, 32.7 [CH3(CH2)5], 67.3, 68.4 (2 CH2), 68.7 (C-6), 73.5 (CH2),
74.9 (C-5), 75.3, 75.4 (2 CH2), 78.0 (C-3), 81.7 (C-2), 84.3 (C-4),
102.6 (C-1), 123.5, 127.1, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9,
128.1, 128.3,133.9, 134.3 (ArC), 167.6, 167.8 (2 CO).
Yield: 0.34 g (78%); colourless oil; Rf 0.68 (petroleum ether–
EtOAc 5:1); [α]D20 + 10.7 (c 0.5, CH2Cl 2).
1H NMR (600 MHz, CDCl3): δ = 3.28 (s, 3 H, OCH3), 3.39 (m, 1 H,
H-5), 3.54 (dd, J3,2 = 7.4, J3,4 = 14.4 Hz, 1 H, H-3), 3.55 (dd,
J4,3 = 7.8, J4,5 = 14.6 Hz, 1 H, H-4), 3.59 (dd, J2,1 = 7.7, J2,3 = 7.4
Hz, 1 H, H-2), 3.64 (dd, J6,5 = 4.8, Jgem = 10.7 Hz, 1 H, H-6′), 3.72
(m, 1 H, H-6), 4.17 (d, J1,2 = 7.7 Hz, 1 H, H-1), 4.48 (d, Jgem = 11.0
Hz, 1 H, CHPh), 4.53 (d, Jgem = 12.1 Hz, 1 H, CHPh), 4.59 (d,
Jgem = 12.1 Hz, 1 H, CHPh), 4.70 (d, Jgem = 11.0 Hz, 1 H, CHPh),
4.76 (d, Jgem = 11.0 Hz, 1 H, CHPh), 4.82 (d, Jgem = 11.0 Hz, 1 H,
CHPh), 5.33 (q, Jgem = 11.1 Hz, 2 H, CH2), 7.08–7.31 (m, 15 H,
HAr), 7.66–7.79 (m, 4 H, H-Ar).
13C NMR (150.8 MHz, CDCl3): δ = 57.1 (CH3), 68.2 (CH2), 68.8
(C-6), 73.5 (CH2), 74.8 (C-5), 74.9, 75.5 (2 CH2), 77.8 (C-4), 81.7
(C-2), 84.1 (C-3), 103.7 (C-1), 123.5, 127.2, 127.3, 127.6, 127.7,
127.8, 127.9, 128.2, 128.3,132.0, 134.0, 137.9, 138.1, 138.4 (ArC),
167.9 (CO).
MS (MALDI, positive mode, matrix: DHB): m/z = 744.4 (M +
Na)+, 760 (M + K)+.
Anal. Calcd for C44H51NO8 (721.9): C, 73.21; H, 7.12; N, 1.94.
Found: C, 73.04; H, 7.32; N, 1.83.
Methyl O-(3,4,6-Tri-O-benzyl-2-O-phthalimidomethyl- / -D-
glucopyranosyl)-(1-6)-2,3,4-tri-O-benzyl- -D-glucopyranoside
(28)
A solution of the trichloroacetimidate 25 (0.53 g, 0.7 mmol) and
methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (0.325 g, 0.7
mmol) in anhyd CH2Cl2 (30 mL) was treated with TMSOTf (13 µL,
0.07 mmol), and then stirred for 1.5 h. The reaction proceeded as
above. The crude residue was purified by column chromatography
(silica gel; petroleum ether–EtOAc, 20:1) affording 28.
Yield: 0.42 g (56%); colourless oil; Rf 0.68 (petroleum ether–
MS (MALDI, positive mode, matrix: DHB): m/z = 646.2 (M +
EtOAc, 5:1); [α]D20 + 13.7 (c 1.0, CH2Cl 2).
Na)+, 662.2 (M + K)+.
Compound 28
Anal. Calcd for C37H37NO8 (623.70): C, 71.25; H, 5.97; N, 2.24.
Found: C, 71.41, H, 6.05; N, 2.18.
1H NMR (600 MHz, CDCl3): δ = 3.41 (s, 3 H, OCH3), 3.43 (m, 2 H,
H-4a, H-5b), 3.51 (m, 2 H, H-2a, H-3b), 3.57 (dd, J4,3 = 9.2, J4,5 = 9.4
Hz, 1 H, H-4b), 3.66 (m, 2 H, H-6b, H-6′b), 3.70 (m, 1 H, H-6a), 3.74
(dd, J2,1 = 7.8, J2,3 = 8.6 Hz, 1 H, H-2b), 3.84 (m, 1 H, H-5a), 3.99
(dd, J3,2 = 9.2, J3,4 = 9.3 Hz, 1 H, H-3a), 4.11 (m, 1 H, H-6′a), 4.36
(d, J1,2 = 7.8 Hz, H-1b), 4.48 (d, Jgem = 10.7 Hz, 1 H, CHPh), 4.54
(d, Jgem = 12.1 Hz, 1 H, CHPh), 4.61(d, J1,2 = 3.3 Hz, 1 H, H-1a),
4.62 (m, 2 H, 2 CHPh), 4.66 (d, Jgem = 12.1 Hz, 1 H, CHPh), 4.72
(d, Jgem = 10.7 Hz, 1 H, CHPh), 4.75 (d, Jgem = 12.1 Hz, 1 H,
CHPh), 4.78 (d, Jgem = 12.1 Hz, 1 H, CHPh), 4.80 (d, Jgem = 10.7
Hz, 1 H, CHPh), 4.83 (d, Jgem = 10.7 Hz, 1 H, CHPh), 4.88 (d,
n-Octyl 3,4,6-Tri-O-benzyl-2-O-phthalimidomethyl- / -D-glu-
copyranoside (27)
A solution of the trichloroacetimidate 25 (0.53 g, 0.7 mmol) and oc-
tanol (1.10 mL, 7.0 mmol) in anhyd CH2Cl2 (10 mL) was treated
with TMSOTf (13 µL 0.07 mmol), and then stirred for 1.5 h. The
reaction was processed as above and the product was purified by
column chromatography (silica gel; petroleum ether–EtOAc, 20:1)
to afford 27.
Yield: 0.36 g (71%); colourless oil; Rf 0.43 (petroleum ether–
J
gem = 10.7 Hz, 1 H, CHPh), 4.97 (d, Jgem = 10.7 Hz, 1 H, CHPh),
EtOAc, 10:1); [α]D20 + 2.6 (c 2.0, CH2Cl 2).
5.37 (q, J gem = 11.1 Hz, 2 H, CH2Phth), 7.06–7.55 (m, 34 H, HAr).
Synthesis 2003, No. 7, 1065–1070 ISSN 0039-7881 © Thieme Stuttgart · New York

1070
I. A. I. Ali et al.
PAPER
13C NMR (150.8 MHz, CDCl3): δ = 55.2 (OCH3), 68.1 (CH2), 68.5
(C-6b), 68.8 (C-6a), 70.0 (C-5a), 73.3, 73.4, 73.8 (3 CH2), 74.9 (C-
5b), 75.0, 75.1, 75.7 (3 CH2), 77.8 (C-4b), 78.1 (C-4a), 79.8 (C-2a),
81.2 (C-2b), 81.9 (C-3a), 83.8 (C-3b), 97.8 (C-1a), 103.1 (C-1b),
123.5, 126.7, 126.9, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.2,
128.3, 128.4, 131.7, 134.0, 137.8, 138.1, 138.2, 138.3 (CAr), 167.6,
167.8 (2 CO).
References
(1) Srivastava, R. M.; Oliveira, F. J. S.; da Silva, L. P.; Filho, J.
R. D. F.; Oliveira, S. P.; Lima, V. L. M. Carbohydr. Res.
2001, 332, 335.
(2) Antunes, R.; Batista, H.; Srivastava, R. M.; Thomas, G.;
Araujo, C. C. Bioorg. Med. Chem. Lett. 1998, 8, 3071.
(3) Murthy, A. R. K.; Wong, O. T.; Reynolds, D. J.; Hall, I. H.
Pharm. Res. 1987, 4, 21.
(4) Chapman, J. M.; Wyrick, S. D.; Voorstad, P. J.; Magnire, J.
H.; Cocolas, G. H.; Hall, I. H. J. Pharm. Sci. 1984, 73, 1482.
(5) Bailleux, V.; Vallee, L.; Nuyts, J. P.; Vameeq, J. Biomed.
Pharmacother. 1994, 48, 95.
MS (MALDI, positive mode, matrix: DHB): m/z = 1080 (M + Na)+,
1096 (M + K)+.
Anal. Calcd for C64H65NO13 (1056.2): C, 72.77; H, 6.20; N, 1.32.
Found: C, 72.3, H, 6.32; N, 1.32.
(6) Chan, C. L.; Lien, E. J.; Tokes, Z. A. J. Med. Chem. 1987,
30, 509.
(7) Kundu, N. G.; Khan, M. W. Tetrahedron Lett. 1997, 38,
6937.
(8) Hammen, P. D.; Braisted, A. C.; Northrup, D. L. Synth.
Commun. 1991, 21, 2157.
(9) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C. J.
Org. Chem. 1998, 63, 3128.
(10) Decroix, B.; Pigeon, P. Tetrahedron Lett. 1997, 38, 1041.
(11) Othman, M.; Pigeon, P.; Decroix, B. Tetrahedron 1997, 53,
2495.
(12) Pigeon, P.; Decroix, B. Tetrahedron Lett. 1997, 38, 2985.
(13) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z.
Tetrahedron Lett. 1997, 38, 3627.
(14) Pigeon, P.; Decroix, B. Tetrahedron Lett. 1996, 37, 7707.
(15) Othman, M.; Decroix, B. Synth. Commun. 1996, 26, 2803.
(16) Ohkubo, M.; Nishimura, T.; Jona, H.; Honma, T.;
Morishima, H. Tetrahedron 1996, 52, 8099.
(17) Iijima, T.; Suzuki, N.; Fukuda, W.; Tomoi, M. Eur. J. Polym.
1995, 31, 775.
Compound 28
Colourless oil; Rf 0.72 (petroleum ether–EtOAc, 5:1); [α]D20 + 9.1
(c 0.5, CH2Cl 2).
1H NMR (600 MHz, CDCl3): δ = 3.33 (s, 3 H, OCH3), 3.51 (dd,
J2,1 = 3.3, J2,3 = 9.6 Hz, 1 H, H-2a), 3.58 (m, 3 H, H-4a, H-4b, H-6b),
3.63 (dd, J6′,5 = 3.8, Jgem = 10.8 Hz, 1 H, H-6′b), 3.71 (m, 2 H, H-5a,
H-6a), 3.73 (m, 2 H, H-2b, H-5b), 3.79 (m, 1 H, H-6′a), 3.85 (dd,
J3,2 = 9.1, J3,4 = 9.2 Hz, 1 H, H-3b), 3.96 (dd, J3,2 = 9.2, J3,4 = 9.3 Hz,
1 H, H-3a), 4.41 (d, Jgem = 10.7 Hz, 1 H, CHPh), 4.44 (d, Jgem = 10.7
Hz, 1 H, CHPh), 4.52 (d, J1,2 = 3.3 Hz, 1 H, H-1a), 4.58 (d,
Jgem = 12.1 Hz, 1 H, CHPh), 4.61 (d, Jgem = 10.7 Hz, 1 H, CHPh),
4.69 (d, Jgem = 12.1 Hz, 1 H, CHPh), 4.71 (d, Jgem = 12.1 Hz, 1 H,
CHPh), 4.74 (d, Jgem = 10.7 Hz, 1 H, CHPh), 4.77 (d, Jgem = 12.1 Hz,
1 H, CHPh), 4.79 (m, 1 H, CHPh), 4.85 (d, Jgem = 10.7 Hz, 1 H,
CHPh), 4.89 (d, Jgem = 10.7 Hz, 1 H, CHPh), 4.94 (d, Jgem = 10.7 Hz,
1 H, CHPh), 5.13 (d, J1,2 = 3.3 Hz, 1 H, H-1b), 5.16 (q, Jgem = 11.0
Hz, 2 H, CH2Phth), 7.36–7.08 (m, 34 H, HAr).
13C NMR (150.8 MHz, CDCl3): δ = 55.1 (OCH3), 65.9 (C-6a), 66.6
(CH2), 68.6 (C-6b), 70.1 (C-5b), 70.2 (C-5a), 73.3, 73.4, 74.8, 74.9,
75.3, 75.7 (6 CH2), 77.8 (C-4a), 77.9 (C-4b), 79.1 (C-2b), 79.8 (C-
2a), 81.1 (C-3b), 82.0 (C-3a), 97.0 (C-1b), 97.9 (C-1a), 123.6, 127.2,
127.5, 127.6, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.6, 131.8,
134.2, 138.0, 138.2, 138.4, 138.6, 138.7 (CAr), 167.6 (CO).
(18) Winstead, M. B.; Heine, H. W. J. Am. Chem. Soc. 1955, 77,
1913.
(19) Moore, M. B.; Rapala, R. T. J. Am. Chem. Soc. 1946, 68,
1657.
MS (MALDI, positive mode, matrix: DHB): m/z = 1080 (M + Na)+,
(20) Sachs, F. Ber. Dtsch. Chem. Ges. 1898, 31, 3233.
(21) Weaver, W. I.; Simons, J. K.; Baldwin, W. E. J. Am. Chem.
Soc. 1944, 66, 222.
(22) Mancera, O.; Lemberger, O. J. Org. Chem. 1950, 15, 1253.
(23) Uchino, M.; Suzuki, K.; Sekiya, M. Chem. Pharm. Bull.
1978, 26, 1837.
(24) Schmidt, R. R.; Jung, K.-H. Carbohydrs Eur. 1999, 27, 12.
(25) Schmidt, R. R.; Jung, K.-H. In Chemistry of Saccharides,
Vol. 1; Ernst, B.; Hart, G. W.; Sinay, P., Eds.; Wiley-VCH:
Weinheim, 2000, 5–59.
(26) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem.
1994, 50, 21.
(27) Abdel-Rahman, A. A.-H.; Takhi, M.; El Ashry, El S. H.;
Schmidt, R. R. J. Carbohydr. Chem. 2002, 21, 113.
(28) (a) Zaugg, H. E.; Martin, W. B. Organic Reactions 1965, 14,
52. (b) Takamizawa, A.; Matsumoto, S. Chem. Pharm. Bull.
1978, 26, 790.
1096 (M + K)+.
Anal. Calcd for C64H65NO13 (1056.2): C, 72.77; H, 6.20; N, 1.32.
Found: C, 72.3, H, 6.32; N, 1.32.
Removal of the Phthaloyl Group
Methyl 2,3,4-tri-O-benzyl-6-O-phthalimidomethyl-α-D-glucopyra-
noside 19 (0.2 g, 0.32 mmol) was dissolved in MeOH (10 mL) and
hydrazine (1 mL) and the reaction mixture refluxed for 1 h, the sol-
vent was evaporated in vacuo and the residue was purified by flash
chromatography (petroleum ether–EtOAc, 2:1) to give 9. Methyl-
amine can be used instead of hydrazine.
Yield: (76%); white powder.
Acknowledgements
(29) Schmidt, R. R. Angew. Chem. Int. Ed. Engl. 1973, 12, 212;
Angew. Chem. 1973, 85, 235.
(30) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991, 10–118.
(31) Tingle, J. B.; Brenton, B. F. P. J. Am. Chem. Soc. 1910, 32,
113.
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. I. A. I. Ali is grateful for
a stipend within the fellowship program from the Egyptian govern-
ment. A. A.-H. A. R. is grateful for an Alexander von Humboldt-
Fellowship. The continued support from the Alexander von Hum-
boldt Stiftung for El S. H. El Ashry is highly appreciated.
Synthesis 2003, No. 7, 1065–1070 ISSN 0039-7881 © Thieme Stuttgart · New York