A convenient synthesis of iminosugar-C-glycosides via organometallic addition to N-benzyl-N-glycosylhydroxylamines

Article abstract of DOI:10.1016/S0040-4020(03)00631-8

N-Benzyl-N-glycosylhydroxylamines were prepared in very good yield via condensation of furanoses and pyranoses with N-benzylhydroxylamine at 110°C for 30 min under solvent-free conditions. These anomeric sugar-hydroxylamines exist in equilibrium with the

Full text of DOI:10.1016/S0040-4020(03)00631-8

Tetrahedron 59 (2003) 4261–4273
A convenient synthesis of iminosugar-C-glycosides via
organometallic addition to N-benzyl-N-glycosylhydroxylamines
*
Alessandro Dondoni and Daniela Perrone
`
Laboratorio di Chimica Organica, Dipartimento di Chimica, Universita di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
Received 14 February 2003; revised 11 April 2003; accepted 16 April 2003
Abstract—N-Benzyl-N-glycosylhydroxylamines were prepared in very good yield via condensation of furanoses and pyranoses with
N-benzylhydroxylamine at 1108C for 30 min under solvent-free conditions. These anomeric sugar-hydroxylamines exist in equilibrium with
the open-chain nitrone form. In fact upon treatment with various organometallic reagents, the corresponding adducts were obtained with good
to high diastereoselectivity. These adducts were converted into iminosugar-C-glycosides by reductive dehydroxylation and intramolecular
cyclization. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
based on the nucleophilic addition to chiral nitrones.6
Subsequently we have found that N-benzyl-N-glycosyl-
hydroxylamines (hidden N-benzylnitrones) derived from
sugars are suitable substrates for the synthesis of imino-
sugars.7 In fact, in recent papers we have demonstrated the
ability of several N-benzyl-N-furanosylhydroxylamines, to
act as versatile synthetic precursors of pyrrolidine homo-
azasugars 1 (Fig. 1) by their reaction with 2-lithiothiazole
followed by suitable transformations of resulting adducts.
The formyl aza-C-glycosides 2, the precursor of 1, were
employed for the synthesis of more complex derivatives,
namely, aza-C-disaccharides.7b,8
Interest in polyhydroxylated pyrrolidines and piperidines
(iminosugars) for their biological properties as glycosidase
and glycosyltransferase inhibitors has been extensively
documented.1 Glycosidases and glycosyltransferases act on
the glycosidic linkage of oligosaccharides and glyco-
peptides by stabilizing an intermediate oxonium ion, thus
facilitating the lysis and modification of the anomeric
center.2 The ability of these iminosugars to function as
glycosidase and glycosyltransferase inhibitors is generally
attributed to their potency in mimicking the oxonium ion
intermediate which participates in both enzymatic reactions.
Glycosidases are involved in a wide range of important
biological processes, such as intestinal digestion, post-
translational processing of glycoproteins and lysosomal
catabolism of glycoconjugates. Glycosidase inhibitors have
potential application in the treatment of viral infections,3
cancer,4 and diabetes and other metabolic disorders.5
As an extension of our previous work, we would like to
report here, a convenient synthesis of various fully protected
C1 substituted iminosugars via the stereoselective addition
of organometallic reagents to N-benzyl-N-glycosylhydroxyl-
amines derived from furanoses and pyranoses. To this aim,
startingfrom different sugars and changing the organometallic
reagents, avarietyofpyrrolidinesandpiperidinesoftype3and
4 were obtained with different saturated and unsaturated
appendages R at the carbon adjacent to the nitrogen atom.
In earlier studies of our group we developed a stereo-
selective chemical synthesis of amino and iminosugars
Figure 1.
Keywords: nitrones; N-benzyl-N-glycosylhydroxylamines; iminosugars; glycosidase inhibitors; organometallic addition.
*
Corresponding author. Tel.: þ39-532291176; fax: þ39-532291167; e-mail: adn@dns.unife.it
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00631-8

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A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
Biological evaluations have suggested that the presence of
short N- or C-alkyl appendages often leads to an increase in
either potency and/or specificity of the iminosugar,9 as in the
case of some a-L-fucosidase inhibitors.10 The above sugges-
tions provided growing interest in the synthesis of C1
substituted iminosugars.11
7b in approximately 15%. The presence of the nitrone 7b
was substantiated by its 1H NMR spectrum showing a
doublet at d 6.74 ppm corresponding to the CH proton of the
nitrone group. This spectroscopic evidence confirmed the
assumption that N-glycosylhydroxylamines exist as
anomeric mixtures in equilibrium through the nitrone
form, as already observed.7,12 Nevertheless, in the other
cases the open-chain tautomer was not detectable by NMR
spectroscopy, whereas the thermodynamically most stable
glycosylhydroxylamine was present as a single compound.
2. Results and discussion
As a first objective of this work, we applied our improved
synthesis of sugar hydroxylamines7b to prepare various
derivatives on a multigram scale starting from the readily
available sugars 5a-d (Table 1). Heating these compounds
with 1.5 equiv. of N-benzylhydroxylamine for 30 min at
1108C in the absence of solvent, the corresponding
N-benzyl-N-glycosylhydroxylamines 6a-d were obtained.
Pure products were isolated at the end of the reaction by
crystallization or flash chromatography. The yields (75–
82%) were well comparable with those reported by others,12
employing more complex reaction conditions, such as
highly boiling solvents or Lewis acids and long reaction
time. The configuration at the anomeric center of 6a-d was
assigned on the base of their spectroscopic properties. The
anomeric signals for 6a (J1,2¼0 Hz), 6c (J1,2¼9.0 Hz) and
6d (J1,2¼8.5 Hz) were consistent with the presence of
b-anomers, according to the known spectral properties of
b-glycosyl derivatives.13 Only compound 6b afforded a
mixture of a and b anomers with the open-chain tautomer
With the desired glycosylhydroxylamines 6a-d in hand, in
order to synthesize iminosugar-C-glycosides, we decided to
investigate their reactivity toward various types of organo-
metallic nucleophiles,14 particularly 2-lithiothiazole, 1-tri-
methylsilylethynyllithium and allylmagnesium bromide.
The results of the addition reactions are summarized in
Table 2. In all experiments 3.5 equiv. of organometallic
reagent in diethyl ether or THF were added dropwise to a
cooled solution (275 or 2308C) of the glycosylhydroxyl-
amines 6 in THF. The resulting mixtures were stirred for a
few hours to provide, after the usual aqueous work-up,
mixtures of syn and anti hydroxylamines 8-17 in good yields
(65–95%). On the contrary, if a stoichiometric amount of
organometallic reagent was used, the reactions did not go to
completion. The diastereomeric ratios of the products were
determined by 1H NMR analysis of the crude mixtures. The
configuration of the newly created stereocenters was
assigned on the base of NOE experiments, after the
Table 1. Synthesis of N-benzyl-N-glycosylhydroxylamines from the corresponding sugars
Sugar
Product
Yielda (%)
81
a/bb
0/100
82
75
Not determinedc
0/100
75
0/100
a
Isolated chemical yield after crystallization or flash chromatography.
The ratio was determined by 1H NMR analysis of the crude product.
See text and Section 4.
b
c

A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
Table 2. Addition of organometallic reagents (RM) to N-benzyl-N-glycosylhydroxylamines
4263
Entry
1
Glycosyl-hydroxylamine
RM
Yielda (%)
65
Products
anti/synb
6a
98/2
2
6a
6a
6b
6b
6b
6c
6c
6d
6d
72
95
72
82
80
85
85
85
90
syn-9
syn-10
syn-11
syn-12
syn-13
syn-14
syn-15
syn-16
syn-17
70/30
96/4
3
4
80/20
90/10
85/15
85/15
50/50
75/25
50/50
5
6
7
8
9
10
a
Isolated chemical yield of the mixture after flash chromatography.
The diastereomeric ratio was determined by 1H NMR on the crude mixture. Th¼2-thiazolyl; TMS¼trimethylsilyl.
b

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A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
Scheme 1. Reagents and conditions: (a) (AcO)2Cu, Zn, AcOH, H2O, 708C; (b) MsCl, pyridine, rt.
conversion of the hydroxylamines 8-17 into the final cyclic
compounds. The reactions of 6a and 6b showed good levels
of diastereoselectivity with organolithium (entries 1, 2, 4
and 5) as well as organomagnesium (entries 3 and 6)
reagents. Also, the reactions of the pyranosylhydroxyl-
amines 6c and 6d with 1-trimethylsilylethynyllithium
proceeded with good diastereofacial selectivity (entries 7
and 9). In contrast, both 6c and 6d were found to be
unreactive toward 2-lithiothiazole and afforded a 1:1
mixture of diastereomeric adducts with allylmagnesium
bromide (entries 8 and 10). The stereoselectivity degree was
not improved by lowering the reaction temperature to
2508C, while at this temperature the yields dramatically
decreased (40–45%). The same poor diastereoselectivity
has been previously observed for additions of allylmag-
nesium reagents to aldimine or a-alkoxy ketones.11h,15
protons and the methylenic protons of the CH2OBn
confirmed the cis-relationship in the epimer 20. Conse-
quently, the stereochemistry at C5 was opposite to that in
the starting sugar 5b, as a result of the stereoselective
intramolecular cyclization process occurring via an SN2-like
mechanism. Moreover, from this result it can be inferred
that the major isomer (85%) in the mixture of hydrox-
ylamines 13 is the anti adduct.18 The same stereochemical
outcomes were reported for the addition of 2-lithiothiazole
to N-benzyl-N-furanosylhydroxylamines.7 However, it is
worth mentioning that the addition of nucleophiles to
nitrones affords preferentially syn adducts, while anti
adducts are obtained when the nitrones are precomplexed
with Lewis acids.6 Hence, also in this case the anti
selectivity can be rationalized by a preferential confor-
mation adopted by the open-chain nitrone form 7b due to
the magnesium coordination involving the nitrone oxygen
and the free hydroxyl group (Fig. 2). Consequently the
addition occurs to the less hindered side of this complex to
give the anti-product.
The next step of this work, was the conversion of
hydroxylamines 8-17 into iminosugar-C-glycosides. As an
example, this transformation is illustrated for compound 13
(Scheme 1). The syn and anti mixture of hydroxylamines 13
was subjected to reductive dehydroxylation using zinc-
copper (II) acetate as we have described in earlier work.16
Because of the difficulty in separation, the resulting mixture
It is worth noting that the pyrrolidines 19 and 20 have been
recently employed for the synthesis of two natural
iminosugars with specific glycosidase inhibitory properties:
6-deoxy-homo DMDP and the gulo-epimer.19
1
of crude benzylamines 18 (85% yield, 95% pure by H
NMR) was converted into pyrrolidines 19 and 20 by treating
at room temperature with 2.5 equiv. of methansulfonyl
chloride17 in pyridine and in presence of activated powdered
molecular sieves. The cyclization products 19 and 20 were
easily separated by flash chromatography (CH2Cl2) in 90%
overall yield.
Examination of nuclear Overhauser effects (NOE) on 19 and
20 allowed the assignment of the configuration at the newly
formed stereocenter C2, and at C5. The trans-relationship
between the allyl and the CH2OBn groups in 19 was
assigned on the basis of a NOE of H2 with H4 and of H5
with H3, while the presence of a NOE between the allylic
Figure 2.

A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
4265
Table 3. Conversion of hydroxylamines 8-12 and 14-16 into iminosugar-C-glycosides 22, 25, 27, 29, 32, 35, 37, 40 and 42
Hydroxylamine
Benzylamine
Ethynyl derivative
Iminosugar-C-glycoside
Yielda (%)
63
anti-8
anti-syn-9
58
anti-10
80
67b
54
anti-11
anti-syn-12
anti-syn-14
48
anti-syn-15
anti-syn-16
anti-syn-17
57
58
72
The minor syn isomers (not shown) of 24, 31, 33 and 38 were separated by flash chromatography (see Section 4).
Overall yield of conversion.
a
b
See Ref. 7b. Th¼2-thiazolyl; TMS¼trimethylsilyl.
By the same reaction sequence shown in Scheme 1, the anti-
benzylhydroxylamines 8, 10 and 11 were transformed into
the protected iminosugar-C-glycosides 22 (63% yield), 27
(80% yield) and 29 (67% yield) (Table 3). The structure of
these compounds was established on the basis of NOE
experiments. On the contrary, the cyclic products 37 and 42,
(Table 3) were isolated as diastereomeric mixtures, since
these compounds and their precursors 15, 17, 36, and 41,
were inseparable by flash chromatography. Finally the
conversionofthemixturesofanti–syn-benzylhydroxylamines

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A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
9, 12, 14 and 16 into the iminosugar-C-glycosides 25, 32, 35
and 40, required an additional step to remove the
trimethylsilyl group (Table 3). Briefly, compounds 9, 12,
14 and 16 were reduced into the benzylamines 23, 30, 33,
and 38 which were treated with an aqueous solution of
NaOH to afford the ethynyl derivatives 24, 31, 34 and 39 as
pure major diastereomers. Finally, all these compounds
were subjected to intramolecular cyclization with methane-
sulfonyl chloride to give the C1 substituted iminosugars 25,
32, 35 and 40 with good yields (65–91%), the structure of
which was assigned by the aid of NOE experiments. In all
cases the structure of these final cyclic products confirmed
the anti selectivity of the addition of 1-trimethylsilyl-
ethynyllithium to the glycosylhydroxylamines 6a-d.
4.2. General procedure for the synthesis of N-benzyl-N-
glycosylhydroxylamines 6
A mixture of sugar 5 (20.0–30.0 mmol) and N-benzyl-
hydroxylamine (1.2 equiv. ) was stirred at 1108C for 45 min.
The resulting residue was cooled to rt and purified by
crystallization or by flash chromatography (h: 10 cm).
4.2.1. 1-(N-Benzylhydroxylamino)-2,3-O-isopropyl-
idene-1-deoxy-b-D-erythrose (6a). Purification by flash
chromatography afforded pure 6a (81%) as a white solid:
mp 93–948C (cyclohexane); [a]2D0¼270.0 (c 1.1, CHCl3).
IR nO–H 3540 cm21. 1H NMR (400 MHz) d 7.40–7.25 (m,
5H, Ph), 4.92 (d, 1H, J2,3¼6.0 Hz, H-2), 4.87 (ddd, 1H,
J3,2¼6.0 Hz, J3,4a¼4.0 Hz, J3,4b¼1.0 Hz, H-3), 4.73 (s, 1H,
H-1), 4.65 (s, 1H, OH), 4.27 (dd, 1H, J4a,3¼4.0 Hz,
J4a,4b¼9.5 Hz, H-4a), 4.08 and 3.88 (2d, 2H, J¼13.5 Hz,
PhCH2N), 4.07 (dd, 1H, J4b,3¼1.0 Hz, J4b,4a¼9.5 Hz,
H-4b), 1.50 and 1.35 (2 s, 6H, 2CH3). 13C NMR
(75 MHz) d 136.8, 129.5, 128.3, 127.4, 111.9, 99.4, 83.6,
81.0, 76.2, 59.2, 26.4, 24.7. MALDI-TOF MS (265.31):
266.5 (MþH), 288.4 (MþNa), 304.3 (MþK). Anal. calcd
for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.13;
H, 7.37; N, 5.12.
3. Conclusion
In summary, our synthetic strategy based on the stereo-
selective addition of organometallic reagents onto
N-benzyl-N-glycolsylhydroxylamines followed by intra-
molecular cyclization, provides an efficient and practical
access to various fully protected iminosugar-C-glycosides.
These compounds can be regarded as multifunctional key
intermediates for further derivatizations, since they possess
as substituents, allyl, ethynyl and thiazolyl groups, which
are easily convertible in other functional groups. Finally, the
stereochemistry at the newly created stereocenter appears to
be reproducible, so that employing different N-alkyl-N-
glycosylhydroxylamines and other types of functionalized
nucleophiles a larger collection of iminosugar-C-glycosides
of predictable configuration could be obtained starting from
simple precursors.
4.2.2. 1-(N-Benzylhydroxylamino)-2,3,4,6-O-tetra-
benzyl-1-deoxy-b-D-glucose (6c). Purification by crystal-
lization from cyclohexane afforded pure 6c (75%) as a white
solid: mp 135–1368C; [a]2D0¼þ21.1 (c 0.8, CHCl3). IR
1
nO–H 3530 cm21. H NMR (400 MHz) d 7.40–7.15 (m,
25H, 5Ph), 5.02 and 4.77 (2d, 2H, J¼11.0 Hz, PhCH2), 4.94
and 4.82 (2d, 2H, J¼11.5 Hz, PhCH2), 4.83 and 4.57 (2d,
2H, J¼11.0 Hz, PhCH2), 4.60 (s, 2H, PhCH2), 4.34 (s, 1H,
OH), 4.24 and 4.07 (2d, 2H, J¼13.0 Hz, PhCH2N), 4.05 (d,
1H, J1,2¼9.0 Hz, H-1), 3.89 (dd, 1H, J2,1¼J2,3¼9.0 Hz,
H-2), 3.78 (dd, 1H, J6a,5¼2.0 Hz, J6a,6b¼10.5 Hz, H-6a),
3.72 (dd, 1H, J6b,5¼5.0 Hz, J6b,6a¼10.5 Hz, H-6b), 3.66 (dd,
4. Experimental
4.1. General
1H, J3,2¼J3,4¼9.0 Hz, H-3), 3.56 (dd, 1H, J4,3¼J4,5
¼
9.0 Hz, H-4), 3.46 (ddd, 1H, J5,4¼9.0 Hz, J5,6a¼2.0 Hz,
J5,6b¼5.0 Hz, H-5). 13C NMR (75 MHz) d 138.6, 138.5,
138.1, 138.0, 137.1, 129.0–127.3 (Ph), 92.5, 85.7, 78.0,
77.8, 76.3, 75.6, 74.9, 74.3, 73.3, 69.1, 60.2. MALDI-TOF
MS (645.78): 646.2 (MþH), 668.1 (MþNa), 684.3 (MþK).
Anal. calcd for C41H43NO6: C, 76.25; H, 6.71; N, 2.17.
Found: C, 76.35; H, 6.63; N, 2.29.
All moisture-sensitive reactions were performed under a
nitrogen atmosphere using oven-dried glassware. Solvents
were dried over standard drying agent20 and freshly distilled
˚
prior to use. Commercially available powdered 4 A
molecular sieves (5 mm average particle size) were used
without further activation. Reactions were monitored by
TLC on silica gel 60 F254 with detection by charring with
sulfuric acid, or alcoholic solutions of ninhydrin. Flash
column chromatography21 was performed on silica gel 60
(230–400 mesh). Melting points were determined with a
capillary apparatus. Optical rotations were measured at
20^28C in the stated solvent; [a]D values are given in
1021 deg cm2 g21. Infrared spectra were recorded in KBr
4.2.3. 1-(N-Benzylhydroxylamino)-2,3,4,6-O-tetra-
benzyl-1-deoxy-b-D-galactose (6d). Purification by crys-
tallization from cyclohexane afforded pure 6d (75%) as a
white solid: mp 92–938C; [a]2D0¼þ7.8 (c 1.0, CHCl3). IR
1
nO–H 3530 cm21. H NMR (400 MHz) d 7.42–7.20 (m,
25H, 5Ph), 5.01 and 4.62 (2d, 2H, J¼11.0 Hz, PhCH2), 4.97
and 4.81 (2d, 2H, J¼11.5 Hz, PhCH2), 4.77 and 4.72 (2d,
2H, J¼12.0 Hz, PhCH2), 4.55 (s, 1H, OH), 4.51 and 4.46
(2d, 2H, J¼12.0 Hz, PhCH2), 4.25 (dd, 1H,
J2,1¼J2,3¼8.5 Hz, H-2), 4.22 and 4.04 (2d, 2H,
J¼13.5 Hz, PhCH2N), 4.06 (d, 1H, J1,2¼8.5 Hz, H-1),
3.92–3.89 (m, 1H, H-4), 3.65 (dd, 1H, J6a,5¼6.0 Hz,
J6a,6b¼9.0 Hz, H-6a), 3.62 (dd, 1H, J6b,5¼6.0 Hz,
J6b,6a¼9.0 Hz, H-6b), 3.59–3.52 (m, 2H, H-3, H-5). 13C
NMR (75 MHz) d 138.8, 138.7, 138.5, 137.8, 137.3, 129.0–
127.2 (Ph), 93.0, 83.2, 75.4, 74.7, 74.6, 74.3, 73.5, 73.4,
72.8, 68.8, 60.0. MALDI-TOF MS (645.78): 646.8 (MþH),
1
pellets on a Nicolet 510 P FT-IR instrument. H (300 or
400 MHz) and 13C (75 MHz) NMR spectra were recorded in
CDCl3 solutions at room temperature. Assignments were
aided by homo-two-dimensional experiments. MALDI-
TOF mass spectra were acquired using a-cyano-4-hydrox-
ycinnamic acid as the matrix. Glucopyranose 5c was
commercially available. Erythrofuranose 5a,22 galacto-
pyranose 5d,23 benzylxylosylhydroxylamine 6b,7b benzyl-
hydroxylamine anti-11,7b benzylamine 287b and pyrrolidine
297b were synthesized as described.

A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
4267
668.4 (MþNa), 684.7 (MþK). Anal. calcd for C41H43NO6:
C, 76.25; H, 6.71; N, 2.17. Found: C, 76.38; H, 6.92; N,
2.05.
H-2, OH), 4.46 (d, 1H, J4,3¼9.5 Hz, H-4), 3.90 and 3.76 (2d,
2H, J¼12.5 Hz, PhCH2N), 3.75 (dd, 1H, J1a,1b¼12.0 Hz,
J1a,2¼5.0 Hz, H-1a), 3.64 (dd, 1H, J1b,1a¼12.0 Hz,
J1b,2¼8.5 Hz, H-1b), 1.18 and 1.15 (2 s, 6H, 2CH3). 13C
NMR (75 MHz) d 165.1, 141.7, 135.1, 129.7, 128.5, 128.0,
120.0, 108.5, 77.6, 76.9, 64.7, 62.0, 60.1, 27.6, 25.0.
MALDI-TOF MS (350.43): 351.3 (MþH), 373.1 (MþNa),
389.3 (MþK). Anal. calcd for C17H22N2O4S: C, 58.27; H,
6.33; N, 7.99. Found: C, 58.09; H, 6.41; N, 7.85.
4.3. General procedure for the addition of 2-lithio-
thiazole to N-benzyl-N-glycosylhydroxylamines 6
To a cooled (2788C) and stirred solution of n-BuLi
(3.5 equiv. of a 1.6 M solution in hexane) in dry Et2O
(0.25 M) was added dropwise a solution of freshly distilled
2-bromothiazole (3.5 equiv.) in dry Et2O (0.8 M). The rate
of addition was adjusted so as to keep the temperature of the
reaction mixture below 2708C. After the pale yellow
solution of 2-lithiothiazole had been stirred at this
temperature for 20 min, a solution of N-benzyl-N-glycosyl-
hydroxylamine 6 (1.00 mmol) in dry THF (0.2 M) was
added slowly while the temperature of the mixture was
maintained below 2658C. The reaction mixture was stirred
at 2708C for 5 h, then aqueous phosphate buffer (20 mL, pH
7) was added, and the mixture was allowed to warm to rt.
The layers were separated, and the aqueous layer was
extracted with AcOEt (3£20 mL). The combined organic
extracts were dried (Na2SO4) and concentrated.
4.5.2. (2R,3S,4S) and (2R,3S,4R)-4-N-Benzylhydroxyl-
amino-2,3-O-isopropylidene-4-(1-trimethylsilylethynyl)-
1,2,3-butanetriol (anti-9 and syn-9). Crude 9 was a 70/30
1
mixture of 4S/4R epimers (by H NMR). Purification by
flash chromatography (3:1 cyclohexane–AcOEt) afforded
the not separable syrup anti-syn-9 in 72% yield. IR nO–H
1
3500–3200 cm21; nCuC 2235 cm21. H NMR (300 MHz,
selected data) d 7.42–7.30 (m, 5H, Ph), 6.05–5.80 (m,
0.7H, OH), 5.60 (s, 0.3H, OH), 4.55 (dd, 0.3H, J3,2¼6.0 Hz,
J3,4¼7.5 Hz, H-3), 4.42 (dd, 0.7H, J3,2¼6.0 Hz,
J3,4¼9.0 Hz, H-3), 4.05 and 3.93 (2d, 1.4H, J¼12.5 Hz,
PhCH2N), 3.68 (dd, 0.3H, J1a,1b¼12.0 Hz, J1a,2¼7.0 Hz,
H-1a), 3.51 (dd, 0.7H, J1a,1b¼12.0 Hz, J1a,2¼6.0 Hz, H-1a),
3.30 (dd, 0.7H, J1b,1a¼12.0 Hz, J1b,2¼8.5 Hz, H-1b), 1.50
and 1.40 (2 s, 3H, CH3), 1.39 and 1.38 (2 s, 3H, CH3), 0.30
and 0.25 (2 s, 9H, 3CH3). MALDI-TOF MS (363.52): 364.5
(MþH), 386.2 (MþNa), 402.4 (MþK).
4.4. General procedure for the addition of 1-trimethyl-
silylethynyllithium to N-benzyl-N-glycosylhydroxyl-
amines 6
To a cooled (2308C) and stirred solution of ethynyl-
trimethylsilane (3.5 equiv.) in THF (0.25 M) was added
n-BuLi (3.5 equiv. of a 1.6 M solution in hexane). After
30 min a solution of N-benzyl-N-glycosylhydroxylamine 6
(1.00 mmol) in dry THF (0.3 M) was added. The resulting
mixture was stirred at this temperature for 3.5 h, then treated
with aqueous phosphate buffer (20 mL, pH 7) and allowed
to warm to rt. The layers were separated, and the aqueous
layer was extracted with AcOEt (3£20 mL). The combined
organic extracts were dried (Na2SO4) and concentrated.
4.5.3. (2R,3S,4S) and (2R,3S,4R)-4-N-Benzylhydroxyl-
amino-2,3-O-isopropylidene-5-vinyl-1,2,3-pentanetriol
(anti-10 and syn-10). Crude 10 was a 96/4 mixture of 4S/4R
1
epimers (by H NMR). Purification by crystallization from
cyclohexane afforded pure anti-10 (88% yield) as a white
solid: mp 128–1298C; [a]2D0¼28.1 (c 0.9, CHCl3). IR nO–H
3500–3200 cm21; nCvC 1634 cm21. 1H NMR (400 MHz) d
7.40–7.23 (m, 5H, Ph), 6.15–6.00 (m, 2H, H-20, OH),
5.26–5.17 (m, 2H, H-10a, OH), 5.11–5.06 (m, 1H, H-10b),
4.31 (dd, 1H, J3,2¼5.5 Hz, J3,4¼9.5 Hz, H-3), 4.14 (ddd,
1H, J2,1a¼9.0 Hz, J2,1b¼4.5 Hz, J2,3¼5.5 Hz, H-2), 3.98
and 3.81 (2d, 2H, J¼13.0 Hz, PhCH2N), 3.45 (dd, 1H,
J1a,1b¼11.5 Hz, J1a,2¼9.0 Hz, H-1a), 3.32 (dd, 1H,
J1b,1a¼11.5 Hz, J1b,2¼4.5 Hz, H-1b), 3.18–3.12 (m, 1H,
H-4), 2.82–2.74 (m, 1H, H-5a), 2.65–2.57 (m, 1H, H-5b),
1.38 and 1.32 (2s, 6H, 2CH3). 13C NMR (75 MHz) d 137.2,
136.1, 129.9, 128.4, 127.8, 116.0, 107.6, 77.8, 77.3, 76.9,
76.5, 64.6, 60.6, 60.2, 30.5, 27.8, 25.2. MALDI-TOF MS
(307.38): 308.2 (MþH), 330.4 (MþNa), 346.6 (MþK).
Anal. calcd for C17H25NO4: C, 66.43; H, 8.20; N, 4.56.
Found: C, 66.38; H, 8.35; N, 4.54.
4.5. General procedure for the addition of allyl-
magnesium bromide to N-benzyl-N-glycosylhydroxyl-
amines 6
To a cooled (2308C) and stirred solution of N-benzyl-N-
glycosylhydroxylamine 6 (1.00 mmol) in dry THF (0.3 M)
was added a solution of freshly prepared allylmagnesium
bromide (3.5 equiv. of a 1.0 M solution in Et2O). The
resulting mixture was stirred at this temperature for 3.5 h,
then treated with aqueous phosphate buffer (20 mL, pH 7)
and allowed to warm to rt. The layers were separated, and
the aqueous layer was extracted with AcOEt (3£20 mL).
The combined organic extracts were dried (Na2SO4) and
concentrated.
4.5.4. (2S,3R,4R,5R) and (2S,3R,4R,5S)-5-N-Benzyl-
hydroxylamino-1,3,4-O-tribenzyl-5-(1-trimethylsilyl-
ethynyl)-1,2,3,4-pentanetetrol (anti-12 and syn-12).
1
Crude 12 was a 90/10 mixture of 5R/5S epimers (by H
4.5.1. (2R,3S,4R) and (2R,3S,4S)-4-N-Benzylhydroxyl-
amino-2,3-O-isopropylidene-4-(2-thiazolyl)-1,2,3-buta-
netriol (anti-8 and syn-8). Crude 8 was a 98/2 mixture of
4S/4R epimers (by 1H NMR). Purification by crystallization
from cyclohexane afforded pure anti-8 (60% yield) as a
white solid: mp 179–1808C; [a]2D0¼210.3 (c 0.4, CHCl3).
IR nO–H 3500–3200 cm21. 1H NMR (300 MHz) d 7.94 and
7.49 (2d, 2H, J¼3.2 Hz, Th), 7.43–7.25 (m, 5H, Ph), 4.94
(dd, 1H, J3,2¼5.5 Hz, J3,4¼9.5 Hz, H-3), 4.52–4.42 (m, 2H,
NMR). Purification by flash chromatography (3:1 cyclo-
hexane–AcOEt) afforded the not separable syrup anti-syn-
12 in 82% yield. IR nO–H 3500–3200 cm21; nCuC
2245 cm21 1H NMR (300 MHz, selected data for the
.
major compound anti-12) d 7.45–7.20 (m, 20H, 4Ph), 5.73
(s, 1H, OH), 4.77 and 4.62 (2d, 2H, J¼11.0 Hz, PhCH2),
4.53 (s, 2H, PhCH2), 4.51 and 4.45 (2d, 2H, J¼11.5 Hz,
PhCH2), 4.13 and 3.88 (2d, 2H, J¼13.0 Hz, PhCH2N), 4.07
(ddd, 1H, J2,1a¼5.0 Hz, J2,1b¼7.0 Hz, J2,3¼3.5 Hz, H-2),

4268
A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
4.00 (dd, 1H, J3,2¼3.5 Hz, J3,4¼8.0 Hz, H-3), 3.90 (dd, 1H,
J4,3¼J4,5¼8.0 Hz, H-4), 3.86 (d, 1H, J5,4¼8.0 Hz, H-5),
3.56 (dd, 1H, J1a,1b¼9.5 Hz, J1a,2¼5.0 Hz, H-1a), 3.48 (dd,
1H, J1b,1a¼9.5 Hz, J1b,2¼7.0 Hz, H-1b), 0.26 (s, 9H, 3CH3).
MALDI-TOF MS (623.85): 624.9 (MþH).
0.25 (s, 6.75H, 3CH3). MALDI-TOF MS (744.00): 745.2
(MþH).
4.5.9. (2R,3S,4R,5S,6S) and (2R,3S,4R,5S,6R)-6-N-Ben-
zylhydroxylamino-1,3,4,5-O-tetrabenzyl-7-vinyl-
1,2,3,4,5-heptanepentol (anti-17 and syn-17). Crude 17
was a 50/50 mixture of 6S/6R epimers (by 1H NMR).
Purification by flash chromatography (5:1 cyclohexane–
AcOEt) afforded the not separable syrup anti-syn-17 in 90%
4.5.5. (2S,3R,4R,5R) and (2S,3R,4R,5S)-5-N-Benzyl-
hydroxylamino-1,3,4-O-tribenzyl-6-vinyl-1,2,3,4-hexa-
netetrol (anti-13 and syn-13). Crude 13 was an 85/15
1
mixture of 5R/5S epimers (by H NMR). Purification by
yield. IR nO–H 3500–3200 cm21; nCvC 1635 cm21 1H
.
flash chromatography (3:1 cyclohexane–AcOEt) afforded
the not separable syrup anti-syn-13 in 80% yield. IR nO–H
3500–3200 cm21; nCvC 1637 cm21.1H NMR (300 MHz,
selected data) d 7.45–7.20 (m, 20H, 4Ph), 6.14–6.98 (m,
0.85H, H-20), 5.89 (s, 0.85H, OH), 5.78–5.62 (m, 0.15H,
H-200), 5.55 (s, 0.15H, OH), 5.18–5.00 (m, 2H, H-10a,
H-1 b), 3.26–3.20 (m, 0.15H, H-5), 3.20–3.12 (m, 0.85H,
H-5), 2.87–2.46 (m, 2H, H-6a, H-6b). MALDI-TOF MS
(567.71): 568.8 (MþH).
NMR (300 MHz, selected data) d 7.40–7.15 (m, 25H, 5Ph),
6.09–5.96 (m, 0.5H, H-20), 5.74–5.61 (m, 0.5H, H-20), 5.29
(s, 1H, OH) 3.06–2.98 (m, 0.5H, H-6), 2.88–2.95 (m, 0.5H,
H-6), 2.80–2.45 (3 m, 2H, H-7a, H-7b). MALDI-TOF MS
(687.86): 688.9 (MþH).
4.6. General procedure for the reduction of N-benzyl-
hydroxylamines 8-17 into N-benzylamines 18, 21, 23, 26,
28, 30, 33, 36, 38 and 41
4.5.6. (2R,3R,4R,5S,6S) and (2R,3R,4R,5S,6R)-6-N-Ben-
zylhydroxylamino-1,3,4,5-O-tetrabenzyl-6-(1-trimethyl-
silylethynyl)-1,2,3,4,5-hexanepentol (anti-14 and syn-14).
To a solution of (AcO)2Cu·H2O (20%) in AcOH (0.1 M)
was added Zn dust (10 equiv.). The resulting suspension
was vigorously stirred at rt for 10 min, then a solution of
N-benzylhydroxylamine (8-17) in 3:1 AcOH–H2O (0.2 M)
was added and the mixture was warmed to 708C for 1 h.
After this time, the resulting suspension was filtered through
Celite and the collected solution was neutralized with an
aqueous solution of NaOH (3 M), extracted with AcOEt
(3£10 mL) and washed with a saturated aqueous solution of
EDTA (30 mL). The organic phase was dried (Na2SO4) and
concentrated.
1
Crude 14 was an 85/15 mixture of 6S/6R epimers (by H
NMR). Purification by flash chromatography (3:1 cyclo-
hexane–AcOEt) afforded the not separable syrup anti-syn-
14 in 85% yield. IR nO–H 3500–3200 cm21; nCuC
1
2245 cm21. H NMR (300 MHz, selected data) d 7.42–
7.15 (m, 25H, 5Ph), 5.06 (d, 0.15H, J¼11.0 Hz, PhCH2),
5.04 (d, 0.85H, J¼11.0 Hz, PhCH2), 3.66 (dd, 0.85H,
J1a,1b¼9.5 Hz, J1a,2¼3.5 Hz, H-1a), 3.55 (dd, 0.85H,
J1b,1a¼9.5 Hz, J1b,2¼5.0 Hz, H-1b), 0.25 (s, 9H, 3CH3).
MALDI-TOF MS (744.00): 745.5 (MþH).
4.7. General procedure for the hydrolysis of trimethyl-
silyl group of compounds: 23, 30, 33 and 38. Synthesis of
the ethynyl derivative: 24, 31, 34 and 39
4.5.7. (2R,3R,4R,5S,6S) and (2R,3R,4R,5S,6R)-6-N-Ben-
zylhydroxylamino-1,3,4,5-O-tetrabenzyl-7-vinyl-
1,2,3,4,5-heptanepentol (anti-15 and syn-15). Crude 15
was a 50/50 mixture of 6S/6R epimers (by 1H NMR).
Purification by flash chromatography (5:1 cyclohexane–
AcOEt) afforded the not separable syrup anti-syn-15 in 85%
To a stirred solution of trimethylsilyl ethynylbenzylamine
(23, 30, 33 and 38) in 5:1 CH3OH–Et2O (0.05 M) was
added a solution of NaOH (2 equiv. of a 1.0 M aqueous
solution). The resulting mixture was stirred at rt for 1 h, then
diluted with aqueous phosphate buffer and concentrated to
remove CH3OH. The residue was extracted with AcOEt,
dried (Na2SO4) and concentrated.
yield. IR nO–H 3500–3200 cm21; nCvC 1633 cm21 1H
.
NMR (300 MHz, selected data) d 7.40–7.10 (m, 25H, 5Ph),
6.06–5.95 (m, 0.5H, H-20), 5.68–5.56 (m, 0.5H, H-20), 5.39
(s, 1H, OH), 3.19–3.13 (m, 0.5H, H-6), 2.88–2.83 (m,
0.5H, H-6), 2.74–2.44 (m, 2H, H-7a, H-7b). MALDI-TOF
MS (687.86): 688.8 (MþH).
4.8. General procedure for the cyclization reaction with
methanesulfonyl chloride. Synthesis of iminosugar-C-
glycosides: 19, 20, 22, 25, 27, 29, 32, 35, 37, 40 and 42
4.5.8. (2R,3S,4R,5S,6S) and (2R,3S,4R,5S,6R)-6-N-Ben-
zylhydroxylamino-1,3,4,5-O-tetrabenzyl-6-(1-trimethyl-
silylethynyl)-1,2,3,4,5-hexanepentol (anti-16 and syn-16).
A mixture of N-benzylamine (18, 21, 24, 26, 28, 31, 34, 36,
˚
39 and 41) in dry pyridine (0.1 M) and activated 4 A
1
Crude 16 was a 75/25 mixture of 6S/6R epimers (by H
powdered molecular sieves (200 mg/0.1 mmol) was stirred
ar rt for 10 min and then treated with MsCl. The resulting
suspension was stirred at rt (1–3 h) for the synthesis of
pyrrolidines, and at 1008C (1–3 h) for the synthesis of
piperidines, then filtered through Celite and concentrated.
NMR). Purification by flash chromatography (4:1 cyclo-
hexane–AcOEt) afforded the not separable syrup anti-syn-
16 in 85% yield. IR nO–H 3500–3200 cm21; nCuC
1
2247 cm21. H NMR (300 MHz, selected data) d 7.45–
7.15 (m, 25H, 5Ph), 5.20–5.38 (m, 1H, OH), 4.98 and 4.71
(2d, 1.5H, J¼11.5 Hz, PhCH2), 4.86 and 4.81 (2d, 0.5H,
J¼11.5 Hz, PhCH2), 4.65 and 4.57 (2d, 1.5H, J¼11.5 Hz,
PhCH2), 4.52 and 4.45 (2d, 1.5H, J¼12.0 Hz, PhCH2), 4.46
and 4.38 (2d, 1.5H, J¼12.0 Hz, PhCH2), 4.26 and 3.82 (2d,
1.5H, J¼13.0 Hz, PhCH2N), 3.54 (dd, 0.75H,
J1a,1b¼9.0 Hz, J1a,2¼5.5 Hz, H-1a), 3.38 (dd, 0.25H,
J1a,1b¼9.5 Hz, J1a,2¼7.0 Hz, H-1a), 0.28 (s, 2.25H, 3CH3),
4.8.1. (2S,3R,4R,5R) and (2S,3R,4R,5S)-5-N-Benzyl-
amino-1,3,4-O-tribenzyl-6-vinyl-1,2,3,4-hexanetetrol
(18). Compound 18 was an 85/15 mixture of 5R/5S epimers
(by 1H NMR), not separable by flash chromatography.
Crude 18 (85% yield; ca. 95% pure by 1H NMR) was used
1
for the next reaction without further purification. H NMR
(300 MHz, selected data) d 7.50–7.20 (m, 20H, 4Ph),

A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
4269
5.80–5.48 (m, 1H, H-20), 5.20–5.05 (m, 2H, H-10a, H-10b),
3.10–3.20 (m, 0.15H, H-5), 3.08–2.96 (m, 0.85H, H-5),
2.62–2.20 (m, 2H, H-6a, H-6b). MALDI-TOF MS (551.72):
552.9 (MþH).
H-4), 4.31 (d, 1H, J2,3¼2.5 Hz, H-2), 3.95 and 3.60 (2d, 2H,
J¼13.0 Hz, PhCH2N), 3.32 (dd, 1H, J5a,4¼5.0 Hz,
J5a,5b¼11.0 Hz, H-5a), 2.79 (dd, 1H, J5b,4¼2.5 Hz,
J5b,5a¼11.0 Hz, H-5b), 1.65 and 1.35 (2s, 6H, 2CH3). 13C
NMR (75 MHz) d 175.1, 142.6, 138.0, 128.9, 128.8, 127.8,
119.2, 110.1, 79.6, 77.8, 59.9, 58.9, 51.6, 27.9, 25.1.
MALDI-TOF MS (316.42): 317.3 (MþH). Anal. calcd for
C17H20N2O2S: C, 64.53; H, 6.37; N, 8.85. Found: C, 64.51;
H, 6.48; N, 8.71.
4.8.2. (2R,3R,4R,5R) and (2S,3R,4R,5R)-N-Benzyl-3,4-
dibenzyloxy-5-benzyloxymethyl-2-(2-propenyl)pyrroli-
dine (19) and (20). Chromatography on silica gel (CH2Cl2)
of the crude mixture afforded as first eluate the pyrrolidine
19 (80% yield) as a syrup: [a]2D0¼224.0 (c 0.6, CHCl3). IR
1
nCvC 1634 cm21. H NMR (300 MHz) d 7.42–7.20 (m,
4.8.5. (2R,3S,4S) and (2R,3S,4R)-4-N-Benzylamino-2,3-
O-isopropylidene-4-(1-trimethylsilylethynyl)-1,2,3-buta-
netriol (23). Compound 23 was a 70/30 mixture of 4S/4R
20H, 4Ph), 5.84–5.69 (m, 1H, H-20), 5.06–4.96 (m, 2H,
H-10a, H-10b) 4.54 and 4.47 (2d, 2H, J¼12.0 Hz, PhCH2),
4.49 and 4.45 (2d, 2H, J¼11.5 Hz, PhCH2), 4.48 (s, 2H,
PhCH2), 4.06 and 3.73 (2d, 2H, J¼14.0 Hz, PhCH2N), 3.98
(dd, 1H, J4,3¼2.5 Hz, J4,5¼3.0 Hz, H-4), 3.86 (dd, 1H,
J3,2¼4.0 Hz, J3,4¼2.5 Hz, H-3), 3.60 (dd, 1H, J6a,5¼5.0 Hz,
J6a,6b¼9.5 Hz, H-6a), 3.56 (dd, 1H, J6b,5¼6.5 Hz,
J6b,6a¼9.5 Hz, H-6b), 3.30–3.24 (ddd, 1H, J5,4¼3.0 Hz,
J5,6a¼5.0 Hz, J5,6b¼6.5 Hz, H-5), 3.21–3.14 (m, 1H, H-2),
2.52–2.41 (m, 1H, H-30a), 2.36–2.23 (m, 1H, H-30b). 13C
NMR (75 MHz) d 139.4, 138.4, 138.3, 135.2, 128.2–127.4
(Ph), 126.6, 117.0, 85.9, 87.7, 73.1, 71.3, 71.2, 69.4, 64.5,
64.2, 51.0, 32.4. MALDI-TOF MS (533.70): 534.5 (MþH).
Anal. calcd for C36H39NO3: C, 81.02; H, 7.37; N, 2.62.
Found: C, 81.11; H, 7.45; N, 2.60.
1
epimers (by H NMR), not separable by flash chromato-
1
graphy. Crude 23 (90% yield; ca. 95% pure by H NMR)
was used for the next reaction without further purification.
1H NMR (300 MHz, selected data) d 7.40–7.30 (m, 5H,
Ph), 4.21 (dd, 0.7H, J3,2¼6.0 Hz, J3,4¼8.0 Hz, H-3), 4.10
and 3.85 (2d, 1.4H, J¼12.0 Hz, PhCH2N), 4.08 and 3.86
(2d, 0.6H, J¼12.0 Hz, PhCH2N), 3.78 (d, 0.7H,
J4,3¼8.0 Hz, H-4), 1.50 and 1.48 (2s, 3H, CH3), 1.40 and
1.38 (2s, 3H, CH3), 0.24 (s, 9H, 3CH3). MALDI-TOF MS
(347.52): 348.7 (MþH).
4.8.6. (2R,3S,4S)-4-N-Benzylamino-2,3-O-isopropyli-
dene-4-ethynyl-1,2,3-butanetriol (24). Chromatography
on silica gel (1:1 cyclohexane–AcOEt) of the crude mixture
afforded as first eluate the ethynyl derivative 24 (71% yield)
as a syrup contaminated by a small amount of the 4R-epimer
Eluted next was the pyrrolidine 20 (10% yield) as a syrup:
[a]2D0¼þ32.0 (c 0.7, CHCl3). IR nCvC 1634 cm21. 1H NMR
(400 MHz) d 7.38–7.15 (m, 20H, 4Ph), 5.77–5.65 (m, 1H,
H-20), 5.07–5.01 (m, 1H, H-10a), 4.97–4.93 (m, 1H, H-10b),
4.54 and 4.47 (2d, 2H, J¼12.0 Hz, PhCH2), 4.43 and 4.25
(2d, 2H, J¼12.0 Hz, PhCH2), 4.37 and 4.30 (2d, 2H,
J¼12.0 Hz, PhCH2), 3.99 and 3.70 (2d, 2H, J¼14.0 Hz,
PhCH2N), 3.88–3.87 (m, 1H, H-4), 3.77 (d, 1H,
J3,2¼4.5 Hz, H-3), 3.31 (dd, 1H, J6a,5¼J6a,6b¼10.5 Hz,
H-6a), 3.12–3.03 (m, 3H, H-2, H-5, H-6b), 2.52–2.43 (m,
1H, H-30a), 2.35–2.27 (m, 1H, H-30b). 13C NMR (75 MHz)
d 139.2, 138.4, 138.1, 136.0, 129.2–127.3 (Ph), 126.8,
116.2, 82.3, 82.1, 72.7, 71.8, 71.5, 70.5, 68.9, 66.4, 58.2,
32.8. MALDI-TOF MS (533.70): 534.7 (MþH). Anal. calcd
for C36H39NO3: C, 81.02; H, 7.37; N, 2.62. Found: C, 81.20;
H, 7.48; N, 2.53.
1
1
(by H NMR analysis). H NMR (400 MHz) d 7.40–7.25
(m, 5H, Ph), 4.38 (ddd, 1H, J2,1a¼4.5 Hz, J2,1b¼9.0 Hz,
J2,3¼5.5 Hz, H-2), 4.17 (dd, 1H, J3,2¼5.5 Hz, J3,4¼9.0 Hz,
H-3), 4.09 and 3.82 (2d, 2H, J¼12.0 Hz, PhCH2N), 3.79
(dd, 1H, J1a,1b¼12.0 Hz, J1a,2¼4.5 Hz, H-1a), 3.70 (dd, 1H,
0
J4,1 ¼2.0 Hz, J4,3¼9.0 Hz, H-4), 3.57 (dd, 1H, J1b,1a
¼
0
12.0 Hz, J1b,2¼9.0 Hz, H-1b), 2.50 (d, 1H, J1 ,4¼2.0 Hz,
H-10), 1.46 and 1.36 (2s, 6H, 2CH3). MALDI-TOF MS
(275.34): 276.4 (MþH), 298.2 (MþNa), 315.3 (MþK).
Anal. calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.83; H, 7.55; N, 4.91.
Eluted next was the 4R-epimer of 24 (10% yield) as a syrup:
[a]2D0¼273.5 (c 0.8, CHCl3): 1H NMR (300 MHz) d 7.42–
7.30 (m, 5H, Ph), 4.45 (dd, 1H, J3,2¼2.5 Hz, J3,4¼7.0 Hz,
H-3), 4.27 (ddd, 1H, J2,1a¼4.5 Hz, J2,1b¼7.0 Hz,
J2,3¼2.5 Hz, H-2), 4.12 and 3.86 (2d, 2H, J¼12.5 Hz,
PhCH2N), 3.89 (dd, 1H, J1a,1b¼12.5 Hz, J1a,2¼4.5 Hz,
H-1a), 3.68–3.62 0 (m, 2H, H-1b, H-4), 2.52 (d, 1H,
4.8.3. (2R,3S,4R)-4-N-Benzylamino-2,3-O-isopropyli-
dene-4-(2-thiazolyl)-1,2,3-butanetriol (21). Crude 21
1
(syrup; 78% yield; ca. 95% pure by H NMR) was used
1
for the next reaction without further purification. H NMR
0
(300 MHz) d 7.90 and 7.40 (2d, 2H, J¼3.2 Hz, Th), 7.40–
7.22 (m, 5H, Ph), 4.53 (ddd, 1H, J2,1a¼4.5 Hz,
J2,1b¼9.5 Hz, J2,3¼5.5 Hz, H-2), 4.38 (dd, 1H,
J3,2¼5.5 Hz, J3,4¼9.5 Hz, H-3), 4.22 (d, 1H, J4,3¼9.5 Hz,
H-4), 3.84 (dd, 1H, J1a,1b¼11.5 Hz, J1a,2¼4.5 Hz, H-1a),
3.71 (dd, 1H, J1b,1a¼11.5 Hz, J1b,2¼9.5 Hz, H-1b), 3.72 and
3.64 (2d, 2H, J¼12.0 Hz, PhCH2N), 1.43 and 1.30 (2 s, 6H,
2CH3). MALDI-TOF MS (334.43): 335.6 (MþH).
J1 ,4¼2.5 Hz, H-1 ), 1.50 and 1.40 (2s, 6H, 2CH3).
MALDI-TOF MS (275.34): 276.5 (MþH), 298.2
(MþNa), 315.5 (MþK). Anal. calcd for C16H21NO3: C,
69.79; H, 7.69; N, 5.09. Found: C, 70.08; H, 7.81; N, 5.04.
4.8.7. (2S,3S,4R)-N-Benzyl-3,4-O-2-ethynylpyrrolidine
(25). Chromatography on silica gel (3:1 cyclohexane–
AcOEt) afforded pure 25 (91% yield) as a white solid: mp
76–778C (cyclohexane); [a]2D0¼þ76.0 (c 0.5, CHCl3). IR
4.8.4. (2R,3S,4R)-N-Benzyl-3,4-O-isopropylidenoxy-2-(2-
thiazolyl)pyrrolidine (22). Chromatography on silica gel
(4:1 cyclohexane–AcOEt) afforded pure 22 (80% yield) as
a white solid: mp 78–798C (cyclohexane); [a]2D0¼þ12.6 (c
0.8, CHCl3).1H NMR (300 MHz) d 7.80 (d, 1H, J¼3.2 Hz,
Th), 7.40–7.22 (m, 6H, Ph and Th), 4.85–4.76 (m, 2H, H-3,
nCuC–H 3288 cm21
;
nCuC 2100 cm21
.
1H NMR
(400 MHz) d 7.40–7.20 (m, 5H, Ph), 4.72 (dd, 1H,
J4,3¼6.0 Hz, J4,5b¼4.5 Hz, H-4), 4.67 (d, 1H, J3,4¼6.0 Hz,
0
H-3), 3.77 (d, 1H, J2,1 ¼2.0 Hz, H-2), 3.76 and 3.72 (2d, 2H,
J¼13.0 Hz, PhCH2N), 2.94 (d, 1H, J5a,5b¼11.0 Hz, H-5a),
2.64 (dd, 1H, J5b,4¼4.5 Hz, J5b,5a¼11.0 Hz, H-5b), 2.35 (d,

4270
A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
0
1H, J1 ,2¼2.0 Hz, H-1 ) 1.55 and 1.30 (2s, 6H, 2CH3). 13C
NMR (75 MHz) d 138.4, 128.5, 128.1, 126.9, 111.9, 84.7,
79.1, 78.0, 75.2, 58.8, 56.7, 54.6, 26.4, 25.3. MALDI-TOF
MS (257.33): 258.0 (MþH). Anal. calcd for C16H19NO2:
C, 74.68; H, 7.44; N, 5.44. Found: C, 74.51; H, 7.53; N,
5.15.
(2d, 2H, J¼12.0 Hz, PhCH2), 4.10 and 3.78 (2d, 2H,
0
J¼12.0 Hz, PhCH2N), 4.09 (ddd, 1H, J2,1a¼5.5 Hz,
0
J2,1b¼9.0 Hz, J2,3¼1.0 Hz, H-2), 3.93 (dd, 1H, J5,1
¼
2.5 Hz, J5,4¼1.0 Hz, H-5), 3.89 (dd, 1H, J4,3¼6.0 Hz,
J4,5¼1.0 Hz, H-4), 3.76 (dd, 1H, J3,2¼1.0 Hz, J3,4
¼
6.0 Hz, H-3), 3.62 (dd, 1H, J1a,1b¼9.0 Hz, J1a,2¼5.5 Hz,
H-1a), 3.53 (dd, 1H, J1b,1a¼J1b,2¼9.0 Hz, H-1b), 2.42 (d,
1H, J1 ,5¼2.5 Hz, H-10). MALDI-TOF MS (535.67): 536.8
0
4.8.8. (2R,3S,4S)-4-N-Benzylamino-2,3-O-isopropyli-
dene-5-vinyl-1,2,3-pentanetriol (26). Crude 26 (syrup;
90% yield; ca. 95% pure by H NMR) was used for the
(MþH). Anal. calcd for C35H37NO4: C, 78.48; H, 6.96; N,
1
2.61. Found: C, 78.58; H, 7.15; N, 2.55.
next reaction without further purification. 1H NMR
(300 MHz) d 7.40–7.25 (m, 05H, Ph), 5.94–5.79 (m, 1H,
H-20), 5.31–5.22 (m, 2H, H-1 a, H-10b), 4.42–4.35 (m, 1H,
H-2), 4.03 (dd, 1H, J3,2¼5.5 Hz, J3,4¼9.5 Hz, H-3), 3.90
and 3.71 (2d, 2H, J¼12.0 Hz, PhCH2N), 3.76–3.70 (m, 2H,
H-1a, H-1b), 3.17–3.09 (m, 1H, H-4), 2.64–2.58 (m, 2H, H-
5a, H-5b), 1.45 and 1.36 (2s, 6H, 2CH3). MALDI-TOF MS
(291.39): 292.8 (MþH).
Eluted next was 31 (80% yield) as a syrup: [a]2D0¼213.9 (c
1
1.4, CHCl3). H NMR (300 MHz) d 7.40–7.20 (m, 20H,
4Ph), 4.78 and 4.58 (2d, 2H, J¼11.5 Hz, PhCH2), 4.77 and
4.74 (2d, 2H, J¼11.0 Hz, PhCH2), 4.52 and 4.45 (2d, 2H,
J¼11.5 Hz, PhCH2), 4.05 and 3.78 (2d, 2H, J¼13.0 Hz,
PhCH2N), 4.00–3.90 (m, 3H, H-2, H-3, H-4), 3.70 (dd, 1H,
0
J5,1 ¼2.5 Hz, J5,4¼5.0 Hz, H-5), 3.57 (dd, 1H, J1a,1b
¼
9.5 Hz, J1a,2¼6.0 Hz, H-1a), 3.49 (dd, 1H, J1b,1a¼9.5 Hz,
J1b,2¼6.0 Hz, H-1b), 2.43 (d, 1H, J1 ,5¼2.5 Hz, H-10). 13C
0
4.8.9. (2S,3S,4R)-N-Benzyl-3,4-O-isopropylidenoxy-2-(2-
propenyl)pyrrolidine (27). Chromatography on silica gel
(6:1 cyclohexane–AcOEt) afforded pure 27 (89% yield) as
NMR (75 MHz) d 139.1, 138.0, 128.3–127.0 (Ph), 82.3,
81.1, 79.5, 74.5, 73.4, 73.1, 71.1, 69.2, 50.9, 50.8. MALDI-
TOF MS (535.67): 536.5 (MþH). Anal. calcd for
C35H37NO4: C, 78.48; H, 6.96; N, 2.61. Found: C, 78.51;
H, 7.17; N, 2.48.
an oil: [a]2D0¼þ68.1 (c 0.6, CHCl3). IR nCvC 1643 cm21
.
1H NMR (300 MHz) d 7.40–7.20 (m, 5H, Ph), 5.98–5.82
(m, 1H, H-20), 5.22–5.11 (m, 2H, H-10a, H-10b), 4.61 (ddd,
1H, J4,3¼7.0 Hz, J4,5a¼6.0 Hz, J4,5b¼4.5 Hz, H-4), 4.43
(dd, 1H, J3,2¼3.5 Hz, J3,4¼7.0 Hz, H-3), 4.00 and 3.46 (2d,
2H, J¼13.0 Hz, PhCH2N), 3.08 (dd, 1H, J5a,4¼6.0 Hz,
J5a,5b¼10.0 Hz, H-5a), 2.86–2.79 (m, 1H, H-2), 2.51 (dd,
1H, J5b,4¼4.5 Hz, J5b,5a¼10.0 Hz, H-5b), 2.51–2.43 (m,
1H, H-30a), 2.31–2.19 (m, 1H, H-30b), 1.55 and 1.34 (2 s,
6H, 2CH3). 13C NMR (75 MHz) d 138.6, 134.5, 128.6,
128.1, 126.9, 117.2, 112.5, 83.6, 77.9, 67.7, 58.0, 56.8, 33.7,
27.1, 25.1. MALDI-TOF MS (273.37): 274.6 (MþH). Anal.
calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C,
74.78; H, 8.63; N, 5.04.
4.8.12. (2R,3R,4R,5R)-N-Benzyl-5-benzyloxymethyl-3,4-
dibenzyloxy-2-ethynylpyrrolidine (32). Chromatography
on silica gel (10:1 cyclohexane–AcOEt) afforded pure 32
(75% yield) as a syrup: [a]2D0¼257.7 (c 1.1, CHCl3). IR
1H NMR
nCuC–H 3290 cm21
;
nCuC 2100 cm21
.
(400 MHz) d 7.45–7.22 (m, 20H, 4Ph), 4.52 and 4.44 (2d,
2H, J¼12.0 Hz, PhCH2), 4.52 and 4.39 (2d, 2H, J¼12.0 Hz,
PhCH2), 4.51 and 4.49 (2d, 2H, J¼12.0 Hz, PhCH2), 4.19
and 3.71 (2d, 2H, J¼13.5 Hz, PhCH2N), 4.05 (dd, 1H,
J3,2¼1.5 Hz, J3,4¼2.5 Hz, H-3), 3.83 (ddd, 1H, J4,2¼1.0 Hz,
J4,3¼2.5 Hz, J4,5¼6.0 Hz, H-4), 3.75–3.73 (m, 1H, H-2),
3.66 (dd, 1H, J6a,5¼4.5 Hz, J6a,6b¼9.0 Hz, H-6a), 3.64 (dd,
1H, J6b,5¼5.0 Hz, J6a,6b¼9.0 Hz, H-6b), 3.13 (ddd, 1H,
J5,4¼6.0 Hz, J5,6a¼4.5 Hz, J5,6b¼5.0 Hz, H-5), 2.45 (d, 1H,
4.8.10. (2S,3R,4R,5R) and (2S,3R,4R,5S)-5-N-Benzyl-
amino-1,3,4-O-tribenzyl-5-(1-trimethylsilylethynyl)-
1,2,3,4-pentanetetrol (30). Compound 30 was a 90/10
mixture of 5R/5S-epimers (by H NMR), not separable by
J1 ,2¼2.5 Hz, H-10). 13C NMR (75 MHz) d 138.8, 138.2,
1
0
flash chromatography. Crude 30 (90% yield; ca. 95% pure
by 1H NMR) was used for the next reaction without further
purification. 1H NMR (300 MHz, selected data for the major
5R-epimer) d 7.50–7.20 (m, 20H, 4Ph), 4.79 and 4.73 (2d,
2H, J¼10.0 Hz, PhCH2), 4.75 and 4.56 (2d, 2H, J¼10.5 Hz,
PhCH2), 4.51 and 4.44 (2d, 2H, J¼11.5 Hz, PhCH2), 4.04
and 3.78 (2d, 2H, J¼13.0 Hz, PhCH2N), 3.98 (ddd, 1H,
138.1, 137.6, 128.8–126.8 (Ph), 87.1, 85.6, 79.6, 75.6, 73.1,
71.6, 70.5, 65.6, 56.4, 52.8. MALDI-TOF MS (517.66):
518.5 (4MþH). Anal. calcd for C35H35NO3: C, 81.21; H,
6.81; N, 2.71. Found: C, 81.45; H, 7.02; N, 2.53.
4.8.13. (2R,3R,4R,5S,6S)-6-N-Benzylamino-1,3,4,5-O-tet-
rabenzyl-6-(1-trimethylsilylethynyl)-1,2,3,4,5-hexane-
pentol (33). Chromatography on silica gel (5:1
cyclohexane–AcOEt) of the crude mixture afforded as
first eluate the 6R-epimer of 33 (10% yield) as a syrup:
[a]2D0¼253.2 (c 1.5, CHCl3).1H NMR (400 MHz) d 7.40–
7.15 (m, 25H, 5Ph), 4.98 and 4.81 (2d, 2H, J¼11.0 Hz,
PhCH2), 4.83 and 4.64 (2d, 2H, J¼11.0 Hz, PhCH2), 4.56
and 4.53 (2d, 2H, J¼11.0 Hz, PhCH2), 4.46 and 4.22 (2d,
J2,1a¼J2,1b¼6.0 Hz, J2,3¼2.5 Hz, H-2), 3.93 (dd, 1H, J3,2
¼
2.5 Hz, J3,4¼6.0 Hz, H-3), 3.87 (dd, 1H, J4,3¼J4,5¼6.0 Hz,
H-4), 3.72 (d, 1H, J5,4¼6.0 Hz, H-5), 3.56 (dd, 1H, J1a,1b
¼
9.5 Hz, J1a,2¼6.0 Hz, H-1a), 3.47 (dd, 1H, J1b,1a¼9.5 Hz,
J1b,2¼6.0 Hz, H-1b), 0.22 (s, 9H, 3CH3). MALDI-TOF MS
(607.85): 609.0 (MþH).
4.8.11. (2S,3R,4R,5R)-5-N-Benzylamino-1,3,4-O-tri-
benzyl-5-ethinyl-1,2,3,4-pentanetetrol (31). Chromato-
graphy on silica gel (3:1 cyclohexane–AcOEt) of the
crude mixture afforded as first eluate the 5S-epimer of 31
(9% yield) as a syrup contaminated by a small amount of 31
2H, J¼11.5 Hz, PhCH2), 4.22 (dd, 1H, J4,3¼3.0 Hz, J4,5¼
7.5 Hz, H-4), 4.08 (ddd, 1H, J2,1a¼3.5 Hz, J2,1b¼6.0 Hz,
J2,3¼6.5 Hz, H-2), 4.04 (dd, 1H, J5,4¼7.5 Hz, J5,6¼3.0 Hz,
H-5), 4.02 and 3.70 (2d, 2H, J¼13.0 Hz, PhCH2N), 3.64
(dd, 1H, J1a,1b¼10.0 Hz, J1a,2¼3.5 Hz, H-1a), 3.58 (dd, 1H,
J1b,1a¼10.0 Hz, J1b,2¼6.0 Hz, H-1b), 3.44 (dd, 1H,
J3,2¼6.5 Hz, J3,4¼3.0 Hz, H-3), 3.31 (d, 1H, J6,5¼3.0 Hz,
H-6). MALDI-TOF MS (728.00): 729.3 (MþH). Anal.
1
1
(by H NMR analysis). H NMR (300 MHz) d 7.45–7.15
(m, 20H, 4Ph), 4.71 and 4.64 (2d, 2H, J¼11.0 Hz, PhCH2),
4.53 and 4.48 (2d, 2H, J¼12.0 Hz, PhCH2), 4.53 and 4.43

A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
4271
calcd for C46H53NO5Si: C, 75.89; H, 7.34; N, 1.92. Found:
C, 76.01; H, 7.53; N, 1.78.
4.8.17. (2S,3S,4R,5R,6S) and (2R,3S,4R,5R,6S)-N-
Benzyl-6-benzyloxymethyl-3,4,5-tribenzyloxy-2-(2-pro-
penyl)piperidine (37). Compound 37 (65% yield) was a 50/
50 mixture of 2S/2R epimers (by 1H NMR), not separable by
chromatography. A small amount of the 2R-epimer
(contaminated by ca. 10% of the 2S-epimer) was isolated
after flash chromatography (12:1 cyclohexane–AcOEt). IR
Eluted next was 33 (78% yield) as a syrup: [a]2D0¼þ40.3 (c
0.9, CHCl3).1H NMR (300 MHz) d 7.40–7.10 (m, 25H,
5Ph), 4.83 and 4.79 (2d, 2H, J¼11.0 Hz, PhCH2), 4.74 and
4.70 (2d, 2H, J¼11.0 Hz, PhCH2), 4.56 and 4.46 (2d, 2H,
J¼12.0 Hz, PhCH2), 4.51 (s, 2H, PhCH2), 4.23 (dd, 1H,
J4,3¼4.0 Hz, J4,5¼5.5 Hz, H-4), 4.02–3.95 (m, 1H, H-2),
3.95 and 3.67 (2d, 2H, J¼13.0 Hz, PhCH2N), 3.92 (dd, 1H,
J5,4¼J5,6¼5.5 Hz, H-5), 3.73 (dd, 1H, J3,2¼7.0 Hz,
J3,4¼4.0 Hz, H-3), 3.68–3.56 (m, 3H, H-1a, H-1b, H-6),
3.10–2.90 (m, 1H, OH), 0.21 (s, 9H, 3CH3). 13C NMR
(75 MHz) d 139.8, 138.5, 138.3, 138.1, 137.9, 129.0–126.8
(Ph), 105.3, 89.9, 80.0, 78.8, 77.1, 74.3, 74.0, 73.2, 73.0,
71.1, 71.0, 51.6, 50.1, 0.0. MALDI-TOF MS (728.00):
729.4 (MþH). Anal. calcd for C46H53NO5Si: C, 75.89; H,
7.34; N, 1.92. Found: C, 75.78; H, 7.48; N, 1.83.
1
nCvC 1640 cm21. H NMR (400 MHz) d 7.40–7.20 (m,
25H, 5Ph), 5.93–5.81 (m, 1H, H-20), 5.01–4.91 (m, 2H,
H-10a, H-10b), 4.83 and 4.80 (2d, 2H, J¼10.5 Hz, PhCH2),
4.62 and 4.56 (2d, 2H, J¼11.5 Hz, PhCH2), 4.57 and 4.54
(2d, 2H, J¼11.5 Hz, PhCH2), 4.49 (s, 2H, PhCH2), 4.13 and
4.07 (2d, 2H, J¼15.0 Hz, PhCH2N), 3.83 (dd, 1H,
J7a,6¼5.5 Hz, J7a,7b¼10.0 Hz, H-7a), 3.78–3.70 (m, 3H,
H-4, H-5, H-7b), 3.64 (dd, 1H, J3,2¼5.5 Hz, J3,4¼9.0 Hz,
H-3), 3.54–3.49 (m, 1H, H-6), 3.23–3.17 (m, 1H, H-2),
2.54–2.45 (m, 1H, H-30a), 2.39–2.31 (m, 1H, H-30b).
MALDI-TOF MS (653.85): 654.5 (MþH). Anal. calcd for
C44H47NO4: C, 80.82; H, 7.25; N, 2.14. Found: C, 80.75; H,
7.41; N, 2.03.
4.8.14. (2R,3R,4R,5S,6S)-6-N-Benzylamino-6-ethynyl-
1,3,4,5-O-tetrabenzyl-1,2,3,4,5-hexanepentol (34). Crude
34 (syrup; 95% yield; ca. 95% pure by 1H NMR) was used
for the next reaction without further purification.1H NMR
(300 MHz) d 7.40–7.15 (m, 25H, 5Ph), 4.85 and 4.79 (2d,
2H, J¼11.0 Hz, PhCH2), 4.80 and 4.71 (2d, 2H, J¼11.0 Hz,
PhCH2), 4.56 and 4.50 (2d, 2H, J¼12.0 Hz, PhCH2), 4.47 (s,
2H, PhCH2), 4.21 (dd, 1H, J4,3¼3.5 Hz, J4,5¼7.0 Hz, H-4),
4.00 (dd, 1H, J5,4¼7.0 Hz, J5,6¼4.5 Hz, H-5), 4.05–3.98
(m, 1H, H-2), 3.94 and 3.63 (2d, 2H, J¼13.0 Hz, PhCH2N),
3.70–3.56 (m, 3H, H-1a, H-1b, H-3), 3.54 (dd, 1H,
4.8.18. (2R,3S,4R,5S,6S)-6-N-Benzylamino-1,3,4,5-O-
tetrabenzyl-6-(1-trimethylsilylethynyl)-1,2,3,4,5-hexane-
pentol (38). Chromatography on silica gel (4:1 cyclo-
hexane–AcOEt) of the crude mixture afforded as first eluate
the 6R-epimer of 38 (15% yield) as a syrup: [a]2D0¼255.5 (c
1
1.0, CHCl3). H NMR (300 MHz) d 7.50–7.20 (m, 25H,
5Ph), 4.96 and 4.80 (2d, 2H, J¼11.0 Hz, PhCH2), 4.82 and
4.78 (2d, 2H, J¼11.5 Hz, PhCH2), 4.68 and 4.42 (2d, 2H,
J¼11.5 Hz, PhCH2), 4.48 and 4.41 (2d, 2H, J¼12.0 Hz,
PhCH2), 4.34 (dd, 1H, J4,3¼3.0 Hz, J4,5¼7.0 Hz, H-4), 4.07
and 3.73 (2d, 2H, J¼13.0 Hz, PhCH2N), 4.02 (ddd, 1H,
J2,1a¼6.0 Hz, J2,1b¼7.0 Hz, J2,3¼2.0 Hz, H-2), 3.92 (dd,
1H, J5,4¼7.0 Hz, J5,6¼3.0 Hz, H-5), 3.66 (dd, 1H,
J3,2¼2.0 Hz, J3,4¼3.0 Hz, H-3), 3.60 (d, 1H, J6,5¼3.0 Hz,
H-6), 3.56 (dd, 1H, J1a,1b¼9.0 Hz, J1a,2¼6.0 Hz, H-1a), 3.48
(dd, 1H, J1b,1a¼9.0 Hz, J1b,2¼7.0 Hz, H-1b), 0.25 (s, 9H,
3CH3). MALDI-TOF MS (728.00): 729.5 (MþH). Anal.
calcd for C46H53NO5Si: C, 75.89; H, 7.34; N, 1.92. Found:
C, 75.71; H, 7.42; N, 2.13.
0
0
J6,1 ¼2.0 Hz, J6,5¼4.5 Hz, H-6), 2.39 (d, 1H, J1 ,6¼2.0 Hz,
H-10). MALDI-TOF MS (655.82): 656.9 (MþH).
4.8.15. (2S,3S,4R,5R,6S)-N-Benzyl-6-benzyloxymethyl-2-
ethynyl-3,4,5-tribenzyloxypiperidine (35). Chromato-
graphy on silica gel (10:1 cyclohexane–AcOEt) afforded
pure 35 (65% yield) as a syrup: [a]2D0¼þ1.9 (c 0.5, CHCl3).
IR nCuC–H 3280 cm21; nCuC 2100 cm21
.
1H NMR
(400 MHz) d 7.40–7.15 (m, 25H, 5Ph), 4.96 and 4.85 (2d,
2H, J¼10.5 Hz, PhCH2), 4.87 and 4.77 (2d, 2H, J¼11.0 Hz,
PhCH2), 4.52 and 4.49 (2d, 2H, J¼11.0 Hz, PhCH2), 4.49
and 4.47 (2d, 2H, J¼12.0 Hz, PhCH2), 4.37 and 3.96 (2d,
Eluted next was 38 (70% yield) as a syrup: [a]2D0¼þ8.9 (c
1
0
2H, J¼14.0 Hz, PhCH2N), 4.05 (dd, 1H, J2,1 ¼2.5 Hz,
1.0, CHCl3). H NMR (300 MHz) d 7.40–7.20 (m, 25H,
5Ph), 4.81 (s, 2H, PhCH2), 4.89 (s, 2H, PhCH2), 4.63 and
4.45 (2d, 2H, J¼11.5 Hz, PhCH2), 4.45 and 4.38 (2d, 2H,
J2,3¼9.5 Hz, H-2), 3.82–3.65 (m, 5H, H-3, H-4, H-5, H-7a,
0
H-7b), 3.20–3.15 (m, 1H, H-6), 2.40 (d, 1H, J1 ,2¼2.5 Hz,
H-10). 13C NMR (75 MHz) d 139.6, 138.4, 138.3, 138.2,
128.3–126.7 (Ph), 82.9, 82.7, 78.8, 75.5, 75.3, 73.6, 73.1,
72.4, 65.4, 55.4, 54.7, 53.8, 53.4, 29.6. MALDI-TOF MS
(637.81): 638.8 (MþH). Anal. calcd for C43H43NO4: C,
80.97; H, 6.80; N, 2.20. Found: C, 81.13; H, 6.91; N,
2.21.
J¼12.0 Hz, PhCH2), 4.33 (dd, 1H, J4,3¼4.5 Hz, J4,5¼
6.0 Hz, H-4), 4.01 (ddd, 1H, J2,1a¼5.0 Hz, J2,1b¼6.5 Hz,
J2,3¼2.0 Hz, H-2), 4.00 and 3.67 (2d, 2H, J¼13.0 Hz,
PhCH2N), 3.78 (dd, 1H, J3,2¼2.0 Hz, J3,4¼4.5 Hz, H-3),
3.75 (dd, 1H, J5,4¼6.0 Hz, J5,6¼5.0 Hz, H-5), 3.66 (d, 1H,
J6,5¼5.0 Hz, H-6), 3.55 (dd, 1H, J1a,1b¼9.0 Hz, J1a,2
¼
5.0 Hz, H-1a), 3.48 (dd, 1H, J1b,1a¼9.0 Hz, J1b,2¼6.5 Hz,
H-1b), 3.28–3.20 (m, 1H, OH), 0.22 (s, 9H, 3CH3). 13C
NMR (75 MHz) d 139.8, 138.6, 138.1, 138.0, 128.3–127.0
(Ph), 105.0, 90.5, 81.0, 80.7, 75.1, 74.2, 73.2, 72.7, 70.9,
70.0, 51.9, 51.1, 29.7, 0.1. MALDI-TOF MS (728.00):
729.3 (MþH). Anal. calcd for C46H53NO5Si: C, 75.89; H,
7.34; N, 1.92. Found: C, 75.92; H, 7.48; N, 1.80.
4.8.16. (2R,3R,4R,5S,6S) and (2R,3R,4R,5S,6R)-6-N-
Benzylamino-1,3,4,5-O-tetrabenzyl-7-vinyl-1,2,3,4,5-
heptanepentol (36). Compound 36 was a 50/50 mixture of
6S/6R-epimers (by 1H NMR), not separable by flash
chromatography. Crude 36 (88% yield; ca. 95% pure by
1H NMR) was used for the next reaction without further
1
purification. H NMR (300 MHz, selected data) d 7.40–
7.15 (m, 25H,05Ph), 5.84–5.72 (m, 0.5H, H-20), 5.65–5.53
(m, 0.5H, H-2 ), 2.90–2.84 (m, 0.5H, H-6), 2.63–2.56 (m,
0.5H, H-6), 2.48–2.20 (m, 2H, H-7a, H-7b). MALDI-TOF
MS (671.86): 672.8 (MþH).
4.8.19. (2R,3S,4R,5S,6S)-6-N-Benzylamino-6-ethynyl-
1,3,4,5-O-tetrabenzyl-1,2,3,4,5-hexanepentol (39). Crude
39 (syrup; 95% yield; ca. 95% pure by 1H NMR) was used
for the next reaction without further purification.1H NMR

4272
A. Dondoni, D. Perrone / Tetrahedron 59 (2003) 4261–4273
(300 MHz) d 7.40–7.20 (m, 25H, 5Ph), 4.85 and 4.82 (2d,
2H, J¼11.0 Hz, PhCH2), 4.84 and 4.76 (2d, 2H, J¼11.5 Hz,
PhCH2), 4.65 and 4.49 (2d, 2H, J¼11.5 Hz, PhCH2), 4.45
and 4.38 (2d, 2H, J¼12.0 Hz, PhCH2), 4.32 (dd, 1H,
J7b,6¼7.0 Hz, J7b,7a¼10.0 Hz, H-7b), 3.30 (ddd, 1H,
J6,5¼3.5 Hz, J6,7a¼5.0 Hz, J6,7b¼7.0 Hz, H-6), 2.98–2.91
(m, 01H, H-2), 2.76–2.68 (m, 1H, H-30a), 2.54–2.45 (m, 1H,
H-3 b). 13C NMR (75 MHz) d 140.2, 138.7, 138.5, 138.1,
136.4, 128.6–127.3 (Ph), 126.5, 115.7, 79.9, 77.2, 74.5,
74.1, 72.8, 71.6, 71.2, 67.8, 59.1, 55.0, 51.2, 32.0. MALDI-
TOF MS (653.85): 654.7 (MþH). Anal. calcd for
C44H47NO4: C, 80.82; H, 7.25; N, 2.14. Found: C, 80.71;
H, 7.23; N, 2.43.
J4,3¼4.0 Hz, J4,5¼6.5 Hz, H-4), 4.08 (ddd, 1H, J2,1a
¼
5.5 Hz, J2,1b¼6.5 Hz, J2,3¼2.0 Hz, H-2), 4.00 and 3.64
(2d, 2H, J¼13.0 Hz, PhCH2N), 3.85 (dd, 1H, J5,4¼6.5 Hz,
J5,6¼4.5 Hz, H-5), 3.78 (dd, 1H, J3,2¼2.0 Hz, J3,4¼4.0 Hz,
0
H-3), 3.63 (dd, 1H, J6,1 ¼2.5 Hz, J6,5¼4.5 Hz, H-6), 3.56
(dd, 1H, J1a,1b¼9.0 Hz, J1a,2¼5.5 Hz, H-1a), 3.49 (dd, 1H,
J1b,1a¼9.0 Hz, J1b,2¼6.5 Hz, H-1b), 2.42 (d, 1H,
J1 ,6¼2.5 Hz, H-10), 1.65–1.50 (m, 1H, OH). MALDI-TOF
0
Acknowledgements
MS (655.82): 656.7 (MþH).
We gratefully acknowledge MIUR-COFIN 2002 (Italy) for
financial support. Thanks are due to Mr P. Formaglio for
technical assistance in NMR spectroscopy.
4.8.20. (2S,3S,4R,5S,6S)-N-Benzyl-6-benzyloxymethyl-2-
ethynyl-3,4,5-tribenzyloxypiperidine (40). Chromato-
graphy on silica gel (9:1 cyclohexane–AcOEt) afforded
pure 40 (88% yield) as a syrup: [a]2D0¼þ17.9 (c 0.5,
CHCl3). IR nCuC–H 3280 cm21; nCuC 2100 cm21 1H
.
NMR (300 MHz) d 7.50–7.20 (m, 25H, 5Ph), 4.62 and 4.54
(2d, 2H, J¼12.0 Hz, PhCH2), 4.52 and 4.48 (2d, 2H,
J¼12.0 Hz, PhCH2), 4.51 (s, 2H, PhCH2), 4.45 and 4.38 (2d,
2H, J¼12.0 Hz, PhCH2), 4.38 and 3.79 (2d, 2H, J¼13.5 Hz,
PhCH2N), 3.97 (dd, 1H, J3,2¼J3,4¼6.0 Hz, H-3), 3.92 (dd,
0
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1
purification. H NMR (300 MHz, selected data) d 7.40–
7.18 (m, 25H,05Ph), 5.83–5.70 (m, 0.5H, H-20), 5.69–5.61
(m, 0.5H, H-2 ), 2.86–2.80 (m, 0.5H, H-6), 2.70–2.62 (m,
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´
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