Synthesis of nojirimycin C-glycosides

Article abstract of DOI:10.1039/b206623h

Nojirimycin α-C-glycosides, which have 1-α-allyl-1-deoxy-N-benzyl-2,3,4,6-tetra-O-benzylnojirimycin (9) as a key intermediate for further derivatisation, have been synthesized from commercially available 2,3,4,6-tetra-O-benzyl-D-glucopyranose (3) through a highly stereoselective procedure which involves treatment of 3 with benzylamine, reaction of the obtained glucosylamine 4 with allylmagnesium bromide and cyclization of the elongated open-chain aminosugar 5 by Fmoc-protection, oxidation of the free hydroxy group, and intramolecular reductive-amination, affording 9 in 59% overall yield. The efficient manipulation of the allylic appendage of 9 has required N-debenzylation and Fmoc-protection of the ring-nitrogen.

Full text of DOI:10.1039/b206623h

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Synthesis of nojirimycin C-glycosides
Laura Cipolla,* Amalia Palma, Barbara La Ferla and Francesco Nicotra*
Department of Biotechnology and Biosciences, University of Milano-Bicocca,
P.za della Scienza 2, 20126 Milano, Italy. E-mail: francesco.nicotra@unimib.it;
Fax: ϩ(39) 02 64483565; Tel: ϩ(39) 02 64483457
1
Received (in Cambridge, UK) 8th July 2002, Accepted 30th July 2002
First published as an Advance Article on the web 29th August 2002
Nojirimycin α-C-glycosides, which have 1-α-allyl-1-deoxy-N-benzyl-2,3,4,6-tetra-O-benzylnojirimycin (9) as a key
intermediate for further derivatisation, have been synthesized from commercially available 2,3,4,6-tetra-O-benzyl-
-glucopyranose (3) through a highly stereoselective procedure which involves treatment of 3 with benzylamine,
reaction of the obtained glucosylamine 4 with allylmagnesium bromide and cyclization of the elongated open-chain
aminosugar 5 by Fmoc-protection, oxidation of the free hydroxy group, and intramolecular reductive-amination,
affording 9 in 59% overall yield. The efficient manipulation of the allylic appendage of 9 has required N-debenzyl-
ation and Fmoc-protection of the ring-nitrogen.
synthesized in both the α11 and β12 anomeric configurations,
Introduction
but the development of new efficient and flexible procedures
The relevant role played by the glycosidic part of cell-wall glyco-
for the synthesis of these compounds is still an area of great
conjugates in cell–cell and cell–pathogen recognition phen-
interest.
omena1 has stimulated interest in compounds which are able to
inhibit carbohydrates processing enzymes, such as glycosidases
and glycosyltransferases. With reference to glycosidase inhibi-
tors, attention has been focused mainly on analogues of the
oxonium ion intermediate which participates in the hydrolysis
of the glycosidic bond. In order to mimic the oxonium ion
intermediate, two main strategies have been adopted: the intro-
duction of a stable positive charge at the ring-oxygen site,
and/or constraint to flatness of the sugar-like structure in order
to reproduce the conformation of the reactive intermediate.
The best and probably easiest way to generate a positive charge
in a sugar-like structure at the ring-oxygen position is to replace
the oxygen with a basic nitrogen which will assume the stable
protonated form in the active site of the enzyme, generating
compounds mimicking the structure of monosaccharides,
usually referred to as aza-sugars or iminosugars.2
Results and discussion
We describe herein an efficient approach for the synthesis of
nojirimycin C-glycosides from commercially available 2,3,4,6-
tetra-O-benzyl--glucopyranose (3) through an efficient and
stereoselective procedure exploiting, as a key intermediate for
further derivatisation, 1-α-allyl-1-deoxy-N-benzyl-2,3,4,6-tetra-
O-benzylnojirimycin (9).
The crucial steps for the synthesis of 9 (Scheme 1), previously
Nojirimycin (1) (Fig. 1) was discovered as the first natural
Fig. 1 Structures of nojirimycin (1) and 1-deoxynojirimycin (2).
glucose mimic in 1966,3 and since then iminosugars have been
found to be widespread in plants and microorganisms. The
lability of the hemiaminal function of iminosugars has shifted
the interest of chemists to the stable 1-deoxy derivatives, such
as 1-deoxynojirymicin (2). Deoxynojirimycin derivatives are
powerful inhibitors of the N-linked glycosylation pathway,
where they prevent the endoplasmic reticulum processing of
immature glycoproteins.4 The observation that iminosugars
have promising therapeutic potential in many diseases,5 such as
cancer, diabetes, and viral infections, has led to increased inter-
est and demand. Homologues,6 deoxygenated,7 N-alkylated,8
C-glycosylated,9 amino acids conjugates,10 and a number of
other deoxynojirimycin derivatives2 have been synthesized
during the last few years, both by chemical and enzymatic
methods. Some C-glycosides of nojirimycin have already been
Scheme 1 Reagents and conditions: a) BnNH2, pTsOH, CH2Cl2; b)
allylmagnesium bromide, Et2O; c) FmocCl, N,N-diisopropylethylamine
(DIPEA), CH3CN; d) PCC, CH2Cl2; e) Et2NH, CH3CN; f )
NaBH(OAc)3, Na2SO4, DCE, AcOH.
reported in a note,13 involve the introduction of the amino func-
tion and the allylic appendage, and then cyclisation to the
piperidine ring, with particular attention to the stereochemical
outcome of the allylation and cyclisation reactions. In more
detail, the reaction of 2,3,4,6-tetra-O-benzyl--glucopyranose
(3) with benzylamine, in the presence of toluene-p-sulfonic acid
and 4 Å molecular sieves, afforded the corresponding gluco-
sylamine 4 in quantitative yield. Stereoselective allylation of 4
by allylmagnesium bromide in dry diethyl ether gave the open
DOI: 10.1039/b206623h
J. Chem. Soc., Perkin Trans. 1, 2002, 2161–2165
This journal is © The Royal Society of Chemistry 2002
2161

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chain amino alcohol 5 in 90% de and 92% yield. The high stereo-
selection of this reaction can be ascribed to the formation of a
Cram-chelate intermediate, in which the magnesium coordin-
ates to the nitrogen of the imine, in equilibrium with the glyco-
syl amine, and the oxygen belonging to the benzyloxy group at
C-2, allowing the attack of the nucleophilic carbon preferen-
tially from the less hindered Si face. Cyclisation of compound 5
to the desired piperidine derivative was accomplished by reduc-
tive amination,14 after oxidation of the unprotected hydroxy
group. This oxidation was somewhat troublesome, as any
attempt to oxidise the hydroxy group of 5 failed under a wide
variety of experimental conditions. In conclusion, the oxidation
was possible only after protection of the amino function as a
carbamate. Two different carbamates were prepared from 5:
first, a tert-butoxycarbonyl derivative was synthesized by per-
forming a one-pot deprotection and reductive amination under
acidic conditions. However, the acidic conditions required for
the reductive amination by means of Na(OAc)3BH were not
effective in the tert-butoxycarbonyl hydrolysis, while stronger
acidity decomposed the product.15 Finally, fluorenylmethoxy-
carbonyl derivative 6 (Fmoc-Cl, 91% yield) turned out to be the
carbamate of choice. Oxidation of compound 6 with pyridin-
ium chlorochromate afforded ketone 7 (90% yield); subsequent
cleavage of the Fmoc protecting group with diethylamine, then
reductive amination of crude amino ketone 8 with Na(OAc)3-
BH, afforded the iminosugar 9 in 78% yield over two steps, and
90% de. It is worthy of note that, following this four-step pro-
cedure, the nojirimycin C-glycoside 9 was obtained in 59%
overall yield from a commercially available starting material.
The 1H NMR data at room temperature showed broad signals
in deuterobenzene, due to the conformational equilibrium
between the 3C6 and 6C3 conformations. When the temperature
was raised to 30 ЊC, the signals became sharper and the coup-
Fig. 2 Structure of the by-product obtained in the iodocyclisation
reaction.
9 during work-up with sodium thiosulfate. This result can be
ascribed, once more, to the presence of the nucleophilic
nitrogen, which competes in the iodocyclisation/debenzylation
reaction,17 toward derivative 13. It is noteworthy that bicyclic
compound 13 was obtained stereospecifically (only one
stereoisomer was detected by NMR analysis), the new stereo-
centre having an R configuration, as determined by NOESY
experiments (NOE effect between H-2 and H-3, correlated in
turn with H-3a).
In order to functionalise more efficiently the double bond of
the allylic appendage, it was clear that the nitrogen lone pair
reactivity had to be quenched by the introduction of a suitable
electron-withdrawing protecting group.18
We performed the synthetic sequence using p-methoxy-
benzylamine, instead of benzylamine, in order to achieve the
orthogonal deprotection of the nitrogen. Unfortunately,
the selective deprotection under both oxidative19 and acidic
conditions20 was unsuccessful.
We were forced to go back to the fully benzylated nojirimycin
derivative 9, basing our strategy on the possibility of selectively
hydrolysing an N-benzyl group, without affecting the other
benzyl groups present in the molecule. A number of methods
have been reported for the cleavage of tertiary to secondary
amines (the cleaved group being that with the best leaving
group tendency in an SN2-type mechanism) and for one-pot
conversion of tertiary amines into a carbamate21 or amide.22
Unfortunately, compound 9 did not react under any of these
experimental conditions (benzoyl chloride, acetyl chloride,
or benzyl, fluorenylmethyl, p-nitrophenyl, trichloroethyl and
1-chloroethyl chloroformate). We were able to effect efficiently
selective N-debenzylation by modifying a recently reported
procedure23 which exploits oxidative cleavage with ammonium
ceric nitrate (Scheme 3).
3
ling constants showed that the C6 was the only conformation
present [as supported by the H(4)–H(5) coupling constant value
of 9.5 Hz].
Compound 9 is a multifunctional key intermediate for
further derivatisation, since it possesses an allylic substituent
which can be properly derivatised. However, it became immedi-
ately clear that oxidative conditions were not fully compatible
with the presence of the tertiary nitrogen atom of the ring.
The formation of methyl ketone 10 (Scheme 2), by treatment
Scheme 2 Functionalisation of the allylic appendage.
of 9 with Na2PdCl4 and water, proceeded in low yield (50%); 1H
3
NMR of methyl ketone 10 showed a preference for the C6
Scheme 3 Reagents and conditions: a) CAN, THF–H2O, 5 : 1; b)
FmocCl, DIPEA, CH3CN; c) OsO4, NaIO4; d) NaClO2, NaH2PO4.
conformation in deuteroacetone as solvent at room temperature
(see Experimental section). The stereochemical integrity of the
C-6 stereocentre was not altered by possible epimerisation due
to elimination/addition reactions, as confirmed by the value of
In detail, the reported reaction conditions were found to be
unsuitable, when applied to our substrate 9; but just by chang-
ing the solvent system from the reported acetonitrile–water to
THF–water,† we were able to obtain efficiently the debenzylated
compound 15. The secondary amino group of compound 15
was protected as the fluorenylmethoxycarbonyl derivative,
affording compound 16 (Fmoc-Cl, MeCN, in 85% yield over
two steps), which was then subjected to oxidative cleavage in a
5.4 Hz for the H(1)–H(2) coupling constant.
16
Furthermore, oxidation (NaClO2–NaH2PO4
or CrO3–
H2SO4) of the crude aldehyde 11, obtained by cleavage of
the allylic double bond (OsO4–NaIO4), did not afford the
expected carboxylic acid 12. In addition, attempts to convert
nojirimycin derivative 9 to the bicyclic structure 13 gave poor
yields. The desired product 13, in fact, was obtained in 42%
yield by the competitive formation of the quaternary ammon-
ium salt 14 (Fig. 2) (identified by mass spectrometry of the
reaction mixture), which decomposed to the starting material
† Many different solvent mixtures were tested in order to optimise the
reaction yield: toluene–H2O, 1,4-dioxane–H2O, benzene–H2O, dichloro-
methane–H2O, pyridine–H2O, DMSO–H2O, diethyl ether–H2O.
2162
J. Chem. Soc., Perkin Trans. 1, 2002, 2161–2165

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two-step procedure (OsO4–NaIO4, then NaClO2–NaH2PO4),
affording the amino acid derivative 18 in 94% yield.
60.11 (2t), 47.74 (d), 35.40 (t); MALDI-MS: calcd for
C59H57NO7, 892.09; found [M ϩ Na]ϩ 915, [M ϩ K]ϩ 931. Anal.
calcd. for C59H57NO7: C, 79.44; H, 6.44; N, 1.57; found: C,
79.48; H, 6.41; N, 1.55%.
In conclusion, starting from commercially available tetra-
benzylglucose, by treatment with benzylamine, allylation with
allylmagnesium bromide, oxidation with pyridinium chloro-
chromate and subsequent reductive amination, it is possible to
obtain stereoselectively and in very good yield a nojirimycin
C-glycoside, which can undergo further functionalisation both
at the C-1 substituent and at the nitrogen atom,24 thus opening
the way to the synthesis of a large variety of new nojirimycin
derivatives.
(2R,3R,4R,5S,6R)-N-Benzyl-3,4,5-tris(benzyloxy)-2-benzyl-
oxymethyl-6-(prop-2-enyl)piperidine (9)
Compound 7 (0.050 g, 0.056 mmol) was dissolved in dry
CH3CN (400 µl) and diethylamine (100 µl) was added. After
2 h the solvent was evaporated under reduced pressure, avoid-
ing heating, and the unstable deprotected derivative 8 was
submitted to subsequent reaction without any further purifi-
cation. Hence, amine 8 was dissolved in dry 1,2-dichloro-
ethane (2 mL), the reaction mixture cooled to Ϫ35 ЊC, and
anhydrous sodium sulfate (0.199 g, 1.4 mmol), glacial acetic
acid (19 µl, 0.336 mmol) and sodium triacetoxyborohydride
(0.047 g, 0.224 mmol) were added. After 24 h, the suspension
was filtered, the solvent evaporated and the residue purified by
flash chromatography (toluene, 0.2% Et3N), affording pure 9
and its epimer at C-1 in 78% overall yield, and 90% de. Com-
Experimental
All solvents were dried over molecular sieves, for at least 24 h
prior to use. Thin-layer chromatography (TLC) was performed
on silica gel 60 F254 plates (Merck) with detection with UV light
when possible, or charring with a solution containing conc.
H2SO4–EtOH–H2O in a ratio of 5 : 45 : 45 or a solution con-
taining (NH4)6Mo7O24 (21 g), Ce(SO4)2 (1 g), conc. H2SO4
(31 mL) in 500 mL of water. Flash column chromatography
1
pound 9: [α]D ϩ21.4 (c 1, CHCl3); H NMR (500 MHz, C6D6)
was performed on silica gel 230–400 mesh (Merck). 1H and 13
C
δ 7.41–7.00 (m, 25 H), 5.92–5.78 (m, 1 H, H-2Љ), 5.13–4.98 (m, 2
H, H-3Љ), 5.03, 4.84 (ABq, 2 H, J = 11.2 Hz, PhCH2O), 5.04,
4.65 (ABq, 2 H, J = 11.4 Hz, PhCH2O), 4.34 (s, 2 H, PhCH2O),
4.20, 4.14 (ABq, 2 H, J = 11.9 Hz, PhCH2O), 4.04 (d, 1 H,
J = 14.0 Hz, PhCHN), 3.90–3.84 (m, 3 H, H-3, H-4, PhCHN),
3.83–3.75 (m, 2 H, H-1Јa, H-5), 3.63 (dd, 1 H, J = 10.3, 2.1 Hz,
H-1Јb), 3.16 (dt, 1 H, J = 8.6, 5.4 Hz, H-6), 3.11 (ddd, 1 H,
J = 9.5, 4.9, 2.1 Hz, H-2), 2.53 (dt, 1 H, J = 14.0, 5.4 Hz, H-1Љa),
2.39 (dt, 1 H, J = 14.0, 8.6 Hz, H-1Љb); 13C NMR (100.57 MHz,
C6D6) δ 141.19, 139.74, 139.58, 138.79, 138.51 (5s), 138.08
(d), 115.30 (t), 84.12, 79.44, 78.80 (3d), 75.27, 74.98, 73.02,
72.14 (4t), 68.70 (t), 57.97, 57.50 (2d), 53.22 (t), 30.24 (t).
MALDI-MS: calcd for C44H47NO4, 653.85; found [M ϩ H]ϩ
655. Anal. calcd. for C44H47NO4: C, 80.82; H, 7.25; N 2.14;
found: C, 80.77; H, 7.28; N, 2.11%.
NMR spectra were recorded on a Varian Mercury 400 MHz
instrument using CDCl3 as solvent unless otherwise stated.
Chemical shift assignments, reported in ppm, are referenced to
the corresponding solvent peaks. Due to conformational equi-
libria,11f 1H NMR for compounds 6, 7, and 18 showed unclear
resolution, and are not reported, whereas 13C NMR refers to
the major conformer at equilibrium. Mass spectra were
recorded on a MALDI2 Kompakt Kratos instrument, using
gentisic acid (DHB) as the matrix. IR spectra were recorded on
a Biorad FT/IR Spectrometer FTS-40A coupled to an IR
microscope Biorad UMA-40A. Optical rotations were meas-
ured at room temperature with a Perkin-Elmer 241 polarimeter
and are reported in units of 10Ϫ1 deg cm2 gϪ1
.
(2R,3R,4R,5S,6R)-6-[N-Benzyl-N-(fluoren-9-ylmethoxy-
carbonyl)amino]-1,3,4,5-tetrakis(benzyloxy)non-8-en-2-ol (6)
(2R,3R,4R,5S,6R)-N-Benzyl-3,4,5-tris(benzyloxy)-2-benzyl-
Amino alcohol 525 (1.16 g, 1.73 mmol) was dissolved in dry
CH3CN (30 mL), and N-ethyldiisopropylamine (355 µl, 2.07
mmol) and Fmoc-Cl (0.895 g, 3.46 mmol) were added. After
5 h, the reaction mixture was neutralized with AcOH, then the
solvent was evaporated under reduced pressure. The crude
residue was purified by flash chromatography (toluene–EtOAc
9 : 1), affording compound 6 (1.54 g) as colourless oil
in 97% yield. [α]D ϩ15.6 (c 1, CHCl3); 13C NMR (100.57
MHz) δ 157.49 (s), 144.27, 144.18, 141.72, 141.60 (4s), 140.03,
138.74, 138.74, 138.36, 137.97 (5s), 135.26 (d), 130.24–128.89
(m), 125.51 (d), 120.31 (d),118.06 (t), 81.14, 79.97, 78.40 (3d),
76.29, 75.42, 74.06, 73.81, 71.75 (5t), 70.25 (d), 66.78, 65.18 (2t),
57.10 (d), 47.72 (d), 35.62 (t); MALDI-MS: calcd for
C59H59NO7, 894.10; found [M ϩ H]ϩ 895. Anal. calcd. for
C59H59NO7: C, 79.26; H, 6.65; N, 1.57; found: C, 79.24; H, 6.68;
N, 1.59%.
oxymethyl-6-(2-oxopropyl)piperidine (10)
To a solution of compound 9 (0.027 g, 0.041 mmol) in DMF–
THF–H2O (0.8 mL : 0.5 mL : 0.1 mL) was added Na2PdCl4
(0.016 g, 0.054 mmol). The solution was concentrated in vacuo
and, after purification by flash chromatography (petroleum
ether–EtOAc 85 : 15), methyl ketone 10 was obtained in 50%
yield. [α]D ϩ9.6 (c 1, CHCl3); 1H NMR (400 MHz, acetone-d6)
δ 7.24–7.05 (m, 25 H), 4.81, 4.64 (ABq, 2 H, J = 11.2 Hz,
PhCH2O), 4.75, 4.45 (ABq, 2 H, J = 11.0 Hz, PhCH2O), 4.30,
4.24 (ABq, 2 H, J = 11.4 Hz, PhCH2O), 4.23 (br s, 2 H,
PhCH2O), 3.88 (d, 1 H, J = 14.3 Hz, PhCHN), 3.66–3.62
(m, 3 H, H-6, H-1Ј), 3.61 (t, 1 H, J = 8.8 Hz, H-4), 3.58 (d, 1 H,
J = 14.3 Hz, PhCHN), 3.54 (dd, 1 H, J = 8.8, 5.4 Hz, H-5), 3.48
(t, 1 H, J = 8.8 Hz, H-3), 2.80–2.74 (m, 2 H, H-2, H-1Љa), 2.47
(dd, 1 H, J = 15.1, 5.4 Hz, H-1Љb), 1.90 (s, 3 H, H-3Љ); 13C NMR
(100.57 MHz, C6D6) δ 207.35 (s), 128.60–126.63 (m), 83.88,
79.77, 79.13 (3d), 74.94, 74.92, 72.91, 72.33 (4t), 68.22 (t), 59.39,
54.85 (2d), 53.04 (t), 37.61 (t), 30.21 (q). MALDI-MS: calcd for
C44H47NO5, 669.85; found [M ϩ H]ϩ 671. Anal. calcd. for
C44H47NO5: C, 78.89; H, 7.07; N, 2.09; found: C, 78.92; H, 7.08;
N, 2.06%.
(3R,4R,5S,6R)-6-[N-Benzyl-N-(fluoren-9-ylmethoxycarbonyl)-
amino]-1,3,4,5-tetrakis(benzyloxy)non-8-en-2-one (7)
To a solution of alcohol 6 (0.160 g, 0.179 mmol) in dry dichloro-
methane (39 mL) were added 4 Å powdered molecular sieves
(0.180 g), and pyridinium chlorochromate (0.116 g, 0.537
mmol). After 24 h stirring the suspension was filtered and the
solvent evaporated under reduced pressure. The crude residue
was purified by flash chromatography (petroleum ether–EtOAc
9 : 1) giving ketone 7 (0.145 g) as yellowish oil (90% yield).
[α]D ϩ11.3 (c 1, CHCl3); 13C NMR (C6D6, 100.57 MHz)
δ 206.20 (s), 169.80 (s), 144.26, 144.25, 141.61, 141.56 (4s),
138.73, 138.49, 138.43, 138.29, 137.82 (5s), 135.12 (d),
129.03–127.91 (m), 125.14, 120.07 (2d), 117.57 (t, C-3Ј), 84.28,
82.88, 81.84 (3d), 75.88, 75.39, 75.05, 74.45, 73.21 (5t), 65.89,
(2R,3aR,5R,6R,7R,7aS )-N-Benzyl-6,7-bis(benzyloxy)-5-
benzyloxymethyl-2-iodomethyloctahydrofuro[3,2-b]pyridine (13)
Nojirimycin derivative 9 (0.100 g, 0.15 mmol) was dissolved in
dry THF (10 mL), and N-iodosuccinimide (0.338 g, 1.5 mmol)
was added; the reaction was quenched with aq. sodium thiosul-
fate until a colorless solution was obtained, and then the mix-
ture was extracted with dichloromethane. The organic layer was
dried over Na2SO4, filtered and concentrated to dryness. The
J. Chem. Soc., Perkin Trans. 1, 2002, 2161–2165
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residue was purified by flash chromatography (petroleum ether–
EtOAc 95 : 5), affording a yellowish oil (43 mg, 42% yield) as
the only detected isomer. [α]D ϩ11.0 (c 0.65, CHCl3); 1H
NMR (400 MHz) δ 7.48–7.13 (m, 20 H), 4.97, 4.78 (ABq, 2 H,
J = 11.4 Hz, PhCH2O), 4.61, 4.43 (ABq, 2 H, J = 11.0 Hz,
PhCH2O), 4.41 (s, 2 H, PhCH2O), 4.15 (t, 1 H, J = 8.3 Hz,
H-7a), 3.97–3.90 (m, 2 H, H-2, PhCHN), 3.86 (t, 1 H,
J = 8.3 Hz, H-7), 3.72–3.60 (m, 4 H, H-3a, H-1Љ, PhCHN),
3.55 (dd, 1 H, J = 8.1, 5.1 Hz, H-6), 3.30 (dd, 1 H, J = 9.9,
4.8 Hz, H-1Јa), 3.21 (dd, 1 H, J = 9.9, 6.8 Hz, H-1Јb),
3.03–2.98 (m, 1 H, H-5), 2.24 (dt, 1 H, J = 11.0, 5.7 Hz, H-3),
1.66 (br q, 1 H, J = 11.0 Hz, H-3); 13C NMR (100.57 MHz)
δ 128.60–126.63 (m), 84.16, 80.75, 80.00, 77.56 (4d) 74.06,
73.26, 72.84 (3t), 67.02 (t), 54.76 (t), 60.83, 59.34, (2d), 36.20 (t),
9.92 (t). MALDI-MS: calcd for C37H40INO4, 689.62; found
[M ϩ H]ϩ 691. Anal. calcd. for C37H40INO4: C, 64.44; H,
5.85; I, 18.40; N, 2.03; found: C, 64.60; H, 5.70; I, 18.55; N,
1.99%.
137.58 (4s), 129.50–120.14 (m), 80.59, 79.56, 75.65 (3d),
73.16, 72.53, 72.19, 71.14, 69.77, 67.58 (6t), 54.41, 49.61 (2d),
47.76 (d), 36.14 (t). MALDI-MS: calcd for C51H49NO8,
803.94; found [M ϩ Na]ϩ 828, [M ϩ K]ϩ 844. Anal. calcd.
for C51H49NO8: C, 76.19; H, 6.14; N, 1.74; found: C, 76.23;
H, 6.11; N, 1.75%.
Acknowledgements
This work was financially supported by MURST, project
COFIN MM03155477.
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231; (d ) C.-H. Wong, L. Provencher, J. A. Porco Jr, S.-H. Jung,
Y.-F. Wang, L. Chen, R. Wang and D. H. Steensma, J. Org. Chem.,
1995, 60, 1492; (e) N. Asano, M. Nishida, A. Kato, H. Kizu,
K. Matsui, Y. Shimada, A. A. Watson, R. J. Nash, P. M. de Q. Lilley,
T. Itoh, M. Baba and G. W. J. Fleet, J. Med. Chem., 1998, 41,
2565.
7 (a) Selected references: A. Arnone, P. Bravo, A. Donadelli and
G. Resnati, Tetrahedron, 1996, 52, 131; (b) J. Fitremann, A. Duréault
and J.-C. Depezay, Tetrahedron Lett., 1994, 35, 1201; (c) A.
Kilonmda, F. Compernolle, K. Peeterers, G. J. Joly, S. Toppet and
G. J. Hoornaert, Tetrahedron, 2000, 56, 1005; (d ) D. D. Dhavale,
N. N. Saha and V. N. Desai, J. Org. Chem., 1997, 62, 7482.
8 (a) Selected references: K. K.-C. Liu, T. Kajimoto, L. Chen,
Z. Zhong, Y. Ichikawa and C.-H. Wong, J. Org. Chem., 1991, 56,
6280; (b) T. Kajimoto, K. K.-C. Liu, R. L. Pederson, Z. Zhong,
Y. Ichikawa, J. A. Porco Jr and C.-H. Wong, J. Am. Chem. Soc.,
1991, 113, 6187.
(2R,3R,4R,5S,6R)-3,4,5-Tris(benzyloxy)-2-benzyloxymethyl-
N-(fluoren-9-ylmethoxycarbonyl)-6-(prop-2-enyl)piperidine (16)
To compound 9 (1.193 g, 1.825 mmol), dissolved in a 5 : 1
mixture of THF–H2O (120 mL), ammonium cerium() nitrate
(4.0 g, 7.30 mmol) was added in portions. When the reaction
was complete, the mixture was treated with an aq. satd. solution
of NaHCO3, until basic pH was reached, and extracted with
Et2O. The organic phase was dried (Na2SO4), filtered and con-
centrated, then crude 15 was dissolved in dry CH3CN (15 mL)
and directly subjected to the subsequent reaction by treatment
with DIPEA (375 µl, 2.19 mmol) and FmocCl (0.944 g, 3.65
mmol, dissolved in 15 mL of dry CH3CN). After 2 hours the
pH was adjusted to neutrality with AcOH and then the solution
was concentrated under reduced pressure. Purification by flash
chromatography (petroleum ether–EtOAc 9 : 1) afforded com-
pound 16 (1.035 g) in 73% yield (over two steps). [α]D ϩ8.8
(c 2.3, CHCl3); 1H NMR (400 MHz, C6D6, T = 60 ЊC) δ 7.60–
6.95 (m, 23 H), 5.98–5.82 (m, 1 H), 5.25 (d, 1 H, J = 16.9 Hz),
4.90 (d, 1 H, J = 10.0 Hz), 4.80 (dd, 1 H, J = 10.9, 5.4 Hz), 4.47–
4.20 (m, 11 H), 3.95 (br dd, 1 H, J = 3.3, 2.1 Hz), 3.92–3.87 (m,
2 H), 3.66 (dd, 1 H, J = 7.4, 5.9 Hz), 3.56 (br s, 1 H), 3.47 (t, 1 H,
J = 8.9 Hz), 2.74 (dt, 1 H, J = 14.5, 7.6 Hz), 2.62 (dt, 1 H,
J = 14.5, 6.9 Hz); 13C NMR (100.57 MHz) δ 156.07 (s), 144.24,
144.08, 141.61, 141.56 (4s), 138.54, 138.50, 138.36, 138.06 (4s),
136.47 (d), 130.00–120.00 (m), 116.25 (t), 81.75, 80.69, 77.49
(3d), 73.15, 73.01, 72.39, 72.12, 70.20, 66.97 (6t), 54.75, 53.10
(2d), 47.83 (d), 34.05 (t). MALDI-MS: calcd. for C52H51NO6,
785.96; found [M ϩ Na]ϩ 810, [M ϩ K]ϩ 826. Anal. calcd. for
C52H51NO6: C, 79.46; H, 6.54; N, 1.78; found: C, 79.41; H, 6.56;
N, 1.77%.
9 (a) B. A. Johns, Y. T. Pan, A. D. Elbein and C. R. Johnson,
J. Am. Chem. Soc., 1997, 119, 4856; (b) F. D’Andrea, G. Catelani,
M. Mariani and B. Vecchi, Tetrahedron Lett., 2001, 42, 1139 and
references cited therein.
10 T. Fuchss and R. R. Schmidt, Synthesis, 2000, 2, 259.
11 (a) H. Boshagen, W. Geiger and B. Unge, Angew. Chem., Int. Ed.
Engl., 1981, 20, 806; (b) P. S. Liu, J. Org. Chem., 1987, 52, 4717;
(c) S. Aoyagi, S. Fujimaki and C. Kibayashi, J. Chem. Soc.,
Chem. Commun., 1990, 1457; (d ) O. R. Martin, L. Liu and F. Yang,
Tetrahedron Lett., 1996, 75, 1991; (e) T. K. Chakraborty and
S. Jayaprakash, Tetrahedron Lett., 1997, 38, 8899; ( f ) T. Fuchss,
H. Streicher and R. R. Schmidt, Liebigs Ann./Recl., 1997, 1315.
12 (a) O. M. Saavedra and O. R. Martin, J. Org. Chem., 1996, 61, 6987;
(b) M. A. Leeuwenburgh, S. Picasso, H. O. Overkleeft, G. A. van der
Marel, P. Vogel and J. H. van Boom, Eur. J. Org. Chem., 1999, 1185.
13 L. Cipolla, B. La Ferla, F. Peri and F. Nicotra, Chem. Commun.,
2000, 1289.
(2R,3R,4R,5S,6R)-3,4,5-Tris(benzyloxy)-2-benzyloxymethyl-
N-(fluoren-9-ylmethoxycarbonyl)-6-carboxymethylpiperidine
(18)
Compound 16 (0.070 g, 0.089 mmol), dissolved in a 1 : 1 : 1
mixture of H2O–acetone–tBuOH (600 µL), was treated with
OsO4 (900 µL of a 5 mg mLϪ1 solution in tBuOH) and NaIO4
(0.057 g, 0.267 mmol). After 3 hours, the mixture was diluted
with EtOAc, the precipitate was filtered off, the organic phase
washed with water, then concentrated in vacuo after drying over
Na2SO4 and filtration. The crude aldehyde 17 was dissolved
in CH3CN (1 mL), and NaH2PO4ؒ2H2O (1.25 M solution in
H2O, 700 µl) and NaClO2 (0.080 g) were added; after 1 hour and
30 min the reaction mixture was concentrated and the residue
extracted with CHCl3. The organic phase was dried over
Na2SO4, filtered and evaporated. Purification by flash chrom-
atography (CHCl3 and 0.05% AcOH) afforded protected amino
acid 21 (0.068 g) in 94% yield over 2 steps. [α]D ϩ6.2 (c 0.93,
CHCl3); 13C NMR (100.57 MHz) δ 176.38 (s), 155.95 (s),
144.02, 143.74, 141.52, 141.49 (4s), 138.29, 138.07, 137.93,
14 (a) H. S. Overkleeft, J. Van Wiltenburg and U. K. Pandit,
Tetrahedron, 1994, 50, 4215; (b) R. Hoos, A. B. Naughton and
A. Vasella, Helv. Chim. Acta, 1993, 76, 2666.
15 Unpublished results.
16 G. W. J. Fleet and J. C. Son, Tetrahedron, 1988, 44, 2637.
17 L. Cipolla, L. Lay and F. Nicotra, J. Org. Chem., 1997, 62, 6678.
18 (a) Similar observations have been reported for N-benzyl-
pyrrolidine derivatives: C. Herdeis, A. Aschenbrenner, A. Kirfel
and F. Schwabenländer, Tetrahedron: Asymmetry, 1997, 8, 2421;
(b) C. A. Weir and C. M. Taylor, J. Org. Chem., 1999, 64, 1554.
19 I. T. Forbes, C. N. Johnson and M. Thompson, J. Chem. Soc.,
Perkin Trans. 1, 1992, 275.
2164
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20 L. Yan and D. Kahne, Synlett, 1995, 523.
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