Synthetic studies towards the tunicamycins and analogues based on diazo chemistry. Total synthesis of tunicaminyl uracil.

Article abstract of DOI:10.1039/b307674a

A synthetic approach to the tunicamycins, a complex family of nucleosides with potent antibiotic and antiviral activities is reported based on diazo chemistry. The corresponding precursors for the synthesis of tunicaminyl uracil derivatives, the non-stabilized diazo derived from 13 and the aldehyde derivative of uridine, compound 4, were prepared efficiently from commercially available D-galactal and uridine, respectively. After a high yielding coupling reaction to obtain the ketone 14, a stereoselective reduction provided the corresponding tunicaminyl uracil derivative 17a and its C-7 epimer 17b. The interconversion of the diazo and aldehyde functional groups in the requisite building blocks was similarly achieved to obtain the ketone 32, which after reduction yielded the corresponding 7-deoxy-6-hydroxy tunicaminyl uracil analogs 33a and 33b.

Full text of DOI:10.1039/b307674a

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Synthetic studies towards the tunicamycins and analogues based on
diazo chemistry. Total synthesis of tunicaminyl uracil
Francisco Sarabia,* Laura Martín-Ortiz and F. Jorge López-Herrera†
Departamento de Bioquímica, Biología Molecular y Química Orgánica, Facultad de Ciencias,
Universidad de Málaga, 29071. Málaga, SPAIN
Received 8th July 2003, Accepted 8th September 2003
First published as an Advance Article on the web 1st October 2003
A synthetic approach to the tunicamycins, a complex family of nucleosides with potent antibiotic and antiviral
activities is reported based on diazo chemistry. The corresponding precursors for the synthesis of tunicaminyl uracil
derivatives, the non-stabilized diazo derived from 13 and the aldehyde derivative of uridine, compound 4, were
prepared efficiently from commercially available -galactal and uridine, respectively. After a high yielding coupling
reaction to obtain the ketone 14, a stereoselective reduction provided the corresponding tunicaminyl uracil derivative
17a and its C-7 epimer 17b. The interconversion of the diazo and aldehyde functional groups in the requisite building
blocks was similarly achieved to obtain the ketone 32, which after reduction yielded the corresponding 7-deoxy-6-
hydroxy tunicaminyl uracil analogs 33a and 33b.
represent suitable and useful tools for biochemical studies
Introduction
related to the biological role of N-glycans in recognition
The tunicamycins isolated from Streptomyces lysosuperficus1
phenomena.8,9 The structure is comprised of the undecose
represent an interesting and attractive family of natural complex
fragment tunicamine, which contains a C–C linkage between
nucleosides2 possessing fascinating molecular architectures
two sugar units, coupled with an N-acetylglucosamine unit
and intriguing antibiotic and antiviral activities.3 Particularly,
through an intriguing α,β-trehalose linkage.10 It is worthy of
the biological action of the tunicamycins relies on their
mention that other related complex nucleoside type antibiotics,
potent inhibition against the phospho-N-acetylmuramyl-penta-
such as streptovirudin11 and corynetoxins,12 contain the same
peptide translocase (translocase I) enzyme in bacteria4,5 and
undecose component.
UDP:GlcNAc:dolichyl phosphate N-acetylglucosaminyltrans-
So far, three total syntheses have been described13–15 and
ferase (IC50 = 7 nM), an essential enzyme involved in the bio-
synthesis of N-glycans in eukaryotic cells.6 Due to the latter
mechanism of action, the tunicamycins exhibit very high toxicity
in mammals, thus making them unsuitable for use as thera-
peutic agents in humans. Exploring the structure of one of
the most important members, tunicamycin V (1), it can be
concluded that tunicamycin mimics the transition state
of the substrate–enzyme intermediate 2 (Fig. 1) involved in
N-glycosylation.7 Despite their high toxicities, the tunicamycins
numerous synthetic approaches have been reported16 focusing
mainly on the construction of the undecose tunicamine through
the formation of the C–C bond between the 2-deoxy-2-galactos-
amine and uridine residues. As we reported in previous
publications,17,18 we have devised the use of non-stabilized
diazo sugars as suitable reagents for the construction of
C-disaccharides in a smooth and straightforward fashion
under very mild conditions. Thus, according to the brief
retrosynthetic analysis depicted in Scheme 1, the main two
Fig. 1 Structures of tunicamycin V (1) and the transition state of the
substrate–enzyme intermediate (2).
† With the utmost respect and consternation, we regret to inform the
scientific community of the passing of Professor López-Herrera.
Scheme 1 Retrosynthetic analysis of tunicamycin (1) based on diazo
chemistry (PMB = 4-methoxybenzyl).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
3716

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disconnections would be located at the glycosydic site of the
α,β-trehalose unit and the C–C linkage contained in the
undecose residue. Our initial synthetic studies directed towards
the synthesis of the tunicamycins have focused on this undecose
unit. According to the retrosynthetic analysis, we propose
non-stabilized diazo 3 and aldehyde 4 as the key precursors
required for the synthesis of the tunicaminyl uracil component
of the tunicamycins.
derivative 13 according to the procedure reported in earlier
communications.17
With the diazo precursor 13 and aldehyde 414 in hand, the
key condensation was accomplished under the same conditions
as previously reported.17,18 Thus, the ketone 14 was obtained in
61% yield, with no detection of epoxide formation. Ketone 14
was reduced to the corresponding alcohol by the action of
sodium borohydride in the presence of cerium trichloride24 to
obtain a 4 : 1 inseparable mixture of alcohols 15a/b, whose
major product was tentatively assigned the configuration, 7R
according to previous theoretical and synthetic studies carried
out in our laboratories with a model compound.17 When this
reduction was carried out with sodium borohydride alone,
a 1 : 1 mixture of alcohols was obtained. Other attempts to
improve the stereoselectivity of the reduction, through the use
of bulky reductive reagents were unsuccessful. The mixture of
alcohols was then submitted to a silylation reaction, and the
resulting silyl ethers (16a/b) were treated with DDQ25 in the
presence of water to furnish compounds 17a and 17b as pure
β-anomers in 85% combined yield, which were separated by
flash column chromatography on silica gel (Scheme 3).
Results and discussion
The synthesis of the key fragment, diazo 3, commenced from
the 2-deoxy-2-azidogalactosyl derivative 5, readily prepared
from -galactal according to the procedures described in the
literature.19–21 Thus, as it is outlined in Scheme 2, compound 5
was transformed into the corresponding trichloroacetimidate
derivative 6,22 which was subjected to a glycosylation reaction
with p-methoxybenzylalcohol mediated by a catalytic amount of
trimethylsilyl trifluoromethylsulfonate (TMSOTf ) to obtain 7
in 82.4% yield as a 4 : 1 mixture of α:β anomers. The p-methoxy-
benzyl glycoside 7 was then submitted to a sequential trans-
formation of the azide functional group to the corresponding
phthalimide 8 by treatment with PPh3–H2O23 followed by
reaction of the resulting amine with phthalic anhydride in
refluxing DMF. After these functional group transformations,
we proceeded with the installation of the diazo functional
group at the C-6 position. Thus, silyl ether 8 was treated with
TBAF, and the resulting alcohol 9 was transformed into the
tosyl derivative 10. Reaction of 10 with sodium azide in
refluxing DMF furnished the 6-azido derivative 11 in 78%
yield, which was then transformed to the N-nitroso-N-acetyl
Scheme 2 Synthesis of the diazo precursor, N-nitroso derivative (13).
Reagents and conditions: (a) 10.0 equiv. Cl3CCN, 5.0 equiv. K2CO3,
CH2Cl2, 0
25 ЊC, 12 h, 83% (4 : 1 mixture of β:α anomers). (b) 1.2
equiv. PMBOH, 0.5 equiv. TMSOTf, 4 Å mol. sieves, THF, Ϫ78 ЊC 1 h,
then 0 ЊC 1 h, 82.4% (4 : 1 mixture of α:β anomers). (c) (1) 1.5 equiv.
Scheme 3 Coupling of diazo (3) and aldehyde (4). Synthesis of
tunicaminyl uracil derivatives 17a:17b. Reagents and conditions: (a) 1.1
equiv. of 13, 40% KOH, Et2O/MeOH (10/1), 0 ЊC, 5 min.; then addition
of 1.0 equiv. of 4, Et2O, 0 ЊC, 1 h, 61%. (b) 5.0 equiv. CeCl3.7 × H2O, 5.0
equiv. NaBH4, MeOH, 0 ЊC, 0.5 h, 95%. (c) 1.5 equiv. TBDMSOTf, 2.0
equiv. 2,6-lutidine, CH2Cl2, 0 ЊC, 1 h, 94%. (d) 1.5 equiv. DDQ,
CH2Cl2–H2O (10 : 1), 25 ЊC, 8 h, 68% for 17a, 17% for 17b.
Ph3P, 0
48 h, 57% overall yield. (d) 1.5 equiv. TBAF, THF, 0Њ C, 1 h, 98%. (e) 3.0
equiv. TsCl, pyr., 0 25 ЊC, 8 h, 85%. (f ) 20.0 equiv. NaN3, DMF,
reflux, 12 h, 78%. (g) (1) 2.5 equiv. Ph3P, 0 25 ЊC, 1 h, then H2O, 5 h;
(2) 7.0 equiv. Ac2O, pyr., 0 25 ЊC, 1.5 h. (h) 52.0 equiv. NaNO2,
Ac2O:AcOH (5 : 1), Ϫ10 ЊC, 1 h, 85% overall yield.
25 ЊC, 8 h, then H2O, 2 h; (2) 2.0 equiv. PhthO, DMF, reflux,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
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Since the epoxide derivatives of these compounds represented
very interesting products from both synthetic and biological
points of view, we considered it of interest to explore other
diazo substrates with the objective of obtaining such com-
pounds. In this sense, the α,β anomeric mixture of azido deriv-
ative 7 was transformed into the tosylated compound 19 as the
pure α-anomer, through the alcohols α-18/β-18, which were
separated by flash column chromatography, in very good yields.
The reaction of tosyl derivative 19 with potassium phthalimide
led to the quantitative formation of the phthalimide derivative
20, which was reacted with hydrazine to provide amine 21.
Acetylation of this amine, followed by N-nitrosation of the
resulting acetamide 22 furnished the N-nitroso 23 as a new
diazo precursor for a reaction with the uridinyl aldehyde 4. The
in situ formation of diazo compound according to previous
protocols, followed by addition of aldehyde 4, afforded ketone
24 in excellent yield (80%). Unfortunately, once again, no
epoxide was detected in this reaction. Nevertheless, the interest
of this synthetic alternative relied on the high yielding process
of obtaining the undecose derivative 24. In addition, reduction
of 24 with sodium borohydride yielded alcohol 25 with a high
stereoselectivity degree (8 : 1), however assignment of the
configuration at C-7 has not been attempted (Scheme 4).
Scheme 5 Coupling of diazo derived from 30 with aldehyde (31).
Synthesis of tunicamynil uracil analogues 33a:33b. Reagents and
conditions: (a) 3.0 equiv. TsCl, pyr., 0 25 ЊC, 5 h, 88%. (b) 30.0 equiv.
NaN3, DMF, 50 ЊC, 3 days, 77%. (c) (1) 2.5 equiv. Ph3P, 0 25 ЊC, 1 h,
then H2O, 5 h; (2) 7.0 equiv. Ac2O, pyr., 0 25 ЊC, 1.5 h. (d) 52.0 equiv.
NaNO2, Ac2O:AcOH (5 : 1), Ϫ10 ЊC, 1 h, 76% overall yield. (e) 2.0
equiv. DMP, CH2Cl2, 25 ЊC, 1 h, 94%. (f ) 1.1 equiv. of 30, 40% KOH,
Et2O/MeOH (10/1), 0 ЊC, 5 min.; then addition of 1.0 equiv. of 31,
Et2O, 0 ЊC, 1 h, 60%. (g) 5.0 equiv. NaBH4, MeOH, 0 ЊC, 15 min., 98%.
30 through tosyl 27, azide 28 and the N-acetyl derivative 29 in
high yields. On the other hand, oxidation of alcohol β-18 with
DMP27 furnished aldehyde 31 in 94% yield. Thus, the coupling
reaction of the diazo derived from 30 with aldehyde 31 was
undertaken according to the general procedure described
previously, to give in a reasonable yield the ketone 32 (60%)
as the sole product. The corresponding 5-deoxy-6-hydroxy
analogue of tunicaminyl uracil was finally prepared by reduc-
tion of ketone 32 with sodium borohydride to obtain essentially
one alcohol, compound 33, whose configuration at C-6 remains
to be assigned.
In conclusion, synthetic efforts carried out in our laboratories
concerning the use of non-stabilized diazo sugars towards the
synthesis of biologically active carbohydrates led us to target
the tunicamycins as attractive synthetic targets. The present
work demonstrates that the synthetic methodology based on
diazo chemistry, established in earlier contributions, can be
extended to more complex products such as the synthesis
of tunicaminyl uracil and its epimer at C-7, as well as related
compounds. Our future work includes the formation of the β,α-
trehalose linkage present in the natural product, followed by the
eventual completion of the total synthesis of tunicamycin V (1).
Scheme 4 Coupling of diazo derived from 23 with aldehyde (4).
Synthesis of tunicaminyl uracil derivatives 25a:25b. Reagents and
conditions: (a) 1.2 equiv. TBAF, THF, 0 ЊC, 1.0 h, 45% for α-18, 30% for
β-18. (b) 3.0 equiv. TsCl, pyr., 0
25 ЊC, 8 h, 88%. (c) 2.5 equiv.
PhthNK, DMF, reflux, 48 h, 99%. (d) 1.5 equiv. NH2NH2, MeOH, 25
ЊC, 12 h. (e) 60.0 equiv. Ac2O, pyr., 0 25 ЊC, 1.5 h, 99%. (f ) 52.0 equiv.
NaNO2, Ac2O:AcOH (5 : 1), Ϫ10 ЊC, 1 h, 82%. (g) 1.1 equiv. of 23, 40%
KOH, Et2O/MeOH (10/1), 0 ЊC, 5 min.; then addition of 1.0 equiv. of 4,
Et2O, 0 ЊC, 1 h, 80%. (h) 5.0 equiv. NaBH4, MeOH, 0 ЊC, 15 min., 92%.
Finally, the feasibility of interchanging the functional groups
in order to produce related compounds of interesting biological
value, prompted us to prepare the non-stabilized diazo deriv-
ative of uridine, which would react with the corresponding
aldehyde derivative of -galactosamine. As is described in
Scheme 5, the synthesis was performed starting from alcohol
26,26 which was transformed into N-nitroso-N-acetyl derivative
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
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p-Methoxybenzyl 2-azido-2-deoxy-6-O-tert-butyldiphenylsilyl-
3,4-O-isopropylidene-ꢀ,ꢁ-D-galactopyranoside 7. Reaction of
trichloroacetimidate 6 with p-methoxybenzyl alcohol
Experimental
General techniques
All reactions were carried out under an argon atmosphere with
dry, freshly distilled solvents under anhydrous conditions,
unless otherwise noted. Tetrahydrofuran (THF) and ethyl
ether (ether) were distilled from sodium benzophenone, and
methylene chloride (CH2Cl2), benzene (PhH), and toluene
from calcium hydride. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless
otherwise stated. All solutions used in workup procedures
were saturated unless otherwise noted. All reagents were pur-
chased at highest commercial quality and used without further
purification unless otherwise stated.
All reactions were monitored by thin-layer chromatography
carried out on 0.25 mm E. Merck silica gel plates (60F-254)
using UV light as visualizing agent and 7% ethanolic phos-
phomolybdic acid or p-anisaldehyde solution and heat as
developing agents. E. Merck silica gel (60, particle size
0.040–0.063 mm) was used for flash column chromatography.
Preparative thin-layer chromatography (PTLC) separations
were carried out on 0.25, 0.50 or 1 mm E. Merck silica gel plates
(60F-254).
NMR spectra were recorded on a Bruker Advanced-400
instrument and calibrated using residual undeuterated solvent
as an internal reference. The following abbreviations were used
to explain the multiplicities: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; band, several overlapping signals;
b, broad. IR spectra were recorded on a Beckman Aculab IV
spectrometer. Optical rotations were recorded on a Perkin-
Elmer 241 polarimeter. High resolution mass spectra (HRMS)
were recorded on a Kratos MS 80 RFA mass spectrometer
under fast atom bombardment (FAB) conditions.
To a solution of trichloroacetimidate 6 (10.0 g, 16.00 mmol,
1.0 equiv.), p-methoxybenzyl alcohol (2.4 mL, 19.29 mmol,
1.2 equiv.) and 4 Å molecular sieves (30 g) in THF (500 mL)
were added dropwise TMSOTf (1.45 mL, 8.04 mmol,
0.5 equiv.) at Ϫ78ЊC. After being stirred for 1 h, the solution
was allowed to warm to 0 ЊC for an additional 1 h. After this
time, Et3N (1.12 mL, 8.04 mmol, 0.5 equiv.) was added and the
crude mixture was filtered through silica gel. After dilution with
EtOAc, the organic solution was washed with water, and the
aqueous phase was extracted with EtOAc (3 × 100 mL). The
combined organic solution was washed with brine, dried over
MgSO4 and concentrated under vacuum. The crude mixture
was purified by flash column chromatography (silica gel, 25%
EtOAc in hexanes) to provide glycoside 7 (8.0 g, 82.4%) as a
4 : 1 inseparable mixture of α:β anomers: Rf = 0.67 (silica gel,
25% EtOAc in hexanes); νmax/cmϪ1 (thin film) 3060 (w, CH),
2919 (m, CH), 2860 (m, CH), 2096 (s, N3), 1613 (w), 1507 (m),
1460 (m), 1425 (m), 1372 (m), 1243 (s) and 1108 (s); δH (400
MHz, CDCl3) (α anomer) 7.84–7.80 (5H, m, SiPh), 7.58–7.35
(5H, m, SiPh), 7.31 (2H, d, J = 8.6, p-CH2C6H4OCH3), 6.87
(2H, d, J = 8.6, p-CH2C6H4OCH3), 4.94 (1H, d, J = 3.3,
H–C(1)), 4.69 (1H, d, J = 11.7, p-CH2C6H4OCH3), 4.51 (1H, d,
J = 11.7, p-CH2C6H4OCH3), 4.44 (1H, dd, J = 8.6 and 5.2,
H–C(3)), 4.33 (1H, dd, J = 5.1 and 2.4, H–C(4)), 4.20 (1H, ddd,
J = 11.9, 5.2 and 2.4, H–C(5)), 4.02 (1H, dd, J = 12.0 and 6.2,
CH2OTPS), 3.93 (1H, dd, J = 9.8 and 6.4, CH2OTPS), 3.84 (3H,
s, –OCH3), 3.34 (1H, dd, J = 8.8 and 3.3, H–C(2)), 1.53 and 1.38
(6H, 2 s, C(CH3)2), 1.13 (9H, s, SiC(CH3)3); δC (100 MHz,
CDCl3) (α anomer) 159.4, 135.5, 135.4, 133.5, 133.3, 129.8,
129.6, 127.9, 127.8, 127.6, 113.8, 109.5 (C(CH3)2), 96.1 (C-1),
73.4, 72.7, 69.1 (C-3, C-4, C-5), 68.3 (C-6), 62.8 (C-2), 61.3
(–OCH2–), 55.1 (–OCH3), 28.3 (C(CH3)2), 26.7 (SiC(CH3)3),
26.1 (C(CH3)2), 19.1 (SiC(CH3)3); MALDI-FTMS (NBA) m/z
626.2658, M ϩ Naϩ calcd for C33H41N3O6Si: 626.2662.
2-Azido-2-deoxy-6-O-tert-butyldiphenylsilyl-3,4-O-
isopropylidene-ꢀ,ꢁ-D-galactopyranosyl trichloroacetimidate 6
A solution of hemiacetal 5 (9.3 g, 19.23 mmol, 1.0 equiv.)
in CH2Cl2 (300 mL) was treated with trichloroacetonitrile
(19.3 mL, 192.3 mmol, 10.0 equiv.) and K2CO3 (13.3 g, 96.15
mmol, 5.0 equiv.) at 0ЊC. Then, the reaction was allowed
to reach room temperature and after 12 h, the resulting
mixture was filtered, and the filtrate concentrated under
reduced pressure. Purification by flash column chromatography
(silica gel, 25% EtOAc in hexanes) provided pure trichloro-
acetimidate 6 (10.1 g, 83%) as a 4 : 1 mixture of β:α anomers
and as a foamed solid: Rf = 0.57 (silica gel, 25% EtOAc
in hexanes); νmax/cmϪ1 (thin film) 3448 (w, NH), 3342 (w, NH),
p-Methoxybenzyl 6-O-tert-butyldiphenylsilyl-2-deoxy-3,4-O-
isopropylidene-2-N-phthalimido-ꢀ,ꢁ-D-galactopyranoside 8
A solution of azido 7 (6.0 g, 9.94 mmol, 1.0 equiv., 4 : 1 mixture
of anomers) in THF (50 mL) was treated with triphenyl-
phosphine (3.91 g, 14.91 mmol, 1.5 equiv.) at 0 ЊC. The reaction
mixture was stirred at 25 ЊC for 8 h. After this time, H2O (50 mL)
was added and after vigorous stirring for 2 h, the organic layer
was separated. The aqueous phase was extracted with Et2O
(2 × 50 mL), and the combined organic solution was washed
with brine, dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude product was subjected to the next
step without further purification. Thus, the crude amine was
dissolved in DMF (200 mL) and treated with phthalic
anhydride (2.94 g, 19.88 mmol, 2.0 equiv.). After 48 h under
reflux conditions, the crude mixture was diluted with ether and
washed with water. The aqueous phase was extracted with Et2O
(2 × 50 mL), and the combined organic solution was washed
with brine, dried (MgSO4), filtered, and concentrated under
reduced pressure. Purification by flash column chromatography
(silica gel, 20% EtOAc in hexanes) provided N-phthalimide 8
(4.0 g, 57% overall yield) as a yellow oil: Rf = 0.37 (silica gel,
25% EtOAc in hexanes); νmax/cmϪ1 (thin film) 3060 (m, CH),
2931 (m, CH), 2860 (m, CH), 2108 (s, N ), 1725 (m, C᎐NH),
᎐
3
1672 (m), 1460 (w), 1425 (w), 1284 (m) and 1108 (s);
δH (400 MHz, CDCl ) 8.82 (1H, s, C᎐NH), 7.86–7.75 (5H, m,
᎐
3
SiPh), 7.57–7.30 (5H, m, SiPh), 6.35 (1H, d, J = 2.9, H–C(1),
α-anomer), 5.65 (1H, d, J = 8.9, H–C(1), β-anomer), 4.57–4.54
(1H, m), 4.48 (1H, dd, J = 5.4 and 2.4, α-anomer), 4.38 (1H,
J = 5.2 and 1.8 Hz, β-anomer), 4.19–4.12 (2H, m), 4.06–3.94
(2H, m), 3.76–3.69 (1H, m, CHN3), 1.63 and 1.43 (6H,
2 s, C(CH3)2, β-anomer), 1.59 and 1.45 (6H, 2 s, C(CH3)2,
α-anomer), 1.11 (9H, s, SiC(CH3)3, α-anomer), 1.10 (9H, s,
SiC(CH3)3, β-anomer); δC (100 MHz, CDCl3) (β anomer)‡
161.2 (C᎐NH), 135.8, 135.7, 133.5, 133.4, 130.0, 128.3,
᎐
128.2, 128.1, 127.9, 110.8 (C(CH3)2), 96.7 (C-1), 77.6, 74.6,
72.6 (C-3, C-4, C-5), 65.0 (C-6), 62.5 (C-2), 60.9 (CCl3),
28.5 (C(CH3)2), 27.1 (SiC(CH3)3), 26.4 (C(CH3)2), 19.5
(SiC(CH3)3).
2931 (s, CH), 2872 (s, CH), 1848 (m), 1772 (s, C᎐O), 1713 (s,
᎐
C᎐O), 1607 (m), 1507 (s), 1460 (s), 1378 (s), 1243 (s) and 1102
᎐
(s); δH (400 MHz, CDCl3) (α anomer) 7.87–7.79 (2H, m,
NPhth), 7.75–7.72 (5H, m, SiPh), 7.69–7.67 (2H, m, NPhth),
7.44–7.36 (5H, m, SiPh), 7.07 (2H, d, J = 8.7, p-CH2C6H4-
OCH3), 6.63 (2H, d, J = 8.7, p-CH2C6H4OCH3), 5.78 (1H, dd,
J = 9.5 and 5.2, H–C(3)), 4.86 (1H, d, J = 3.5, H–C(1)), 4.69
(1H, d, J = 12.3, p-CH2C6H4OCH3), 4.50 (1H, dd, J = 9.5 and
3.5, H–C(2)), 4.47 (1H, d, J = 12.3, p-CH2C6H4OCH3), 4.45
‡ The 13C-NMR spectra obtained for compound 6 corresponds to the
α,β-anomeric mixture and contains the signals of both anomers, but
only the signals corresponding to the major anomer have been reported.
Similarly, the same was done in the description of the 1H and 13C NMR
spectra for compounds 7–14.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
3719

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(1H, dd, J = 5.2 and 2.3, H–C(4)), 4.37–4.34 (1H, m), 4.10–4.03
(1H, m), 3.97 (1H, dd, J = 10.0 and 6.6, CH2OTPS), 3.67 (3H, s,
–OCH3), 1.50 and 1.33 (6H, 2 s, C(CH3)2), 1.08 (9H, s,
4.11 (1H, m), 3.67 (3H, s, –OCH3), 2.43 (3H, s, p-OSO2-
C6H4CH3), 1.42 and 1.25 (6H, 2 s, C(CH3)2); δC (100 MHz,
CDCl ) (α anomer) 168.2 (C᎐O), 159.1, 144.9, 133.9, 132.9,
᎐
3
SiC(CH3)3); δC (100 MHz, CDCl ) (α anomer) 168.3 (C᎐O),
131.7, 131.6, 129.9, 129.8, 129.5, 127.7, 123.2, 113.6, 109.8
(C(CH3)2), 96.0 (C-1), 72.5, 69.3, 69.2 (C-3, C-4, C-5), 68.7
(C-6), 66.0 (–OCH2–), 55.1 (–OCH3), 53.9 (C-2), 28.1 (C(CH3)2),
26.4 (C(CH3)2), 21.6 (–CH3); MALDI-FTMS (NBA) m/z
646.1710, M ϩ Naϩ calcd for C32H33NO10S: 646.1717.
᎐
3
158.9, 135.6, 133.7, 131.8, 129.7, 129.1, 127.7, 127.6, 123.5,
113.5, 109.5 (C(CH3)2), 96.3 (C-1), 72.8, 68.9, 68.7, 68.3
(C-3, C-4, C-5, C-6), 63.1 (–OCH2–), 55.1 (–OCH3), 54.6 (C-2),
28.3 (C(CH3)2), 26.7 (SiC(CH3)3), 26.4 (C(CH3)2), 19.2
(SiC(CH3)3); MALDI-FTMS (NBA) m/z 730.2885, M ϩ Naϩ
calcd for C41H45NO8Si: 730.2812.
p-Methoxybenzyl 6-azido-2,6-dideoxy-3,4-O-isopropylidene-2-
N-phthalimido-ꢀ,ꢁ-D-galactopyranoside 11. Reaction of tosylate
10 with sodium azide
p-Methoxybenzyl 2-deoxy-3,4-O-isopropylidene-2-N-
phthalimido-ꢀ,ꢁ-D-galactopyranoside 9. Treatment of
N-phthalimide 8 with tetrabutylammonium fluoride
To a solution of tosylate 10 (2.2 g, 3.53 mmol, 1.0 equiv.) in
DMF (30 mL) was added NaN3 (4.6 g, 70.6 mmol, 20.0 equiv.)
in one portion at 25 ЊC. The reaction mixture was heated at
reflux until the reaction was complete as judged by TLC (ca 12
h). The crude mixture was then poured into saturated aqueous
NH4Cl solution (30 mL), diluted with Et2O (50 mL) and the
layers separated. The aqueous solution was extracted with Et2O
(2 × 30 mL) and the combined organic extracts were washed
with brine (50 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (silica gel, 20%
EtOAc in hexanes) provided azide 11 (1.37 g, 78%) as a 4 : 1
mixture of anomers: Rf = 0.48 (silica gel, 25% EtOAc in
hexanes); νmax/cmϪ1 (thin film) 2987 (s, CH), 2871 (s, CH), 2097
(s, N ), 1773 (s, C᎐O), 1715 (s, C᎐O), 1608 (m), 1511 (m), 1458
A solution of silyl ether 8 (3.0 g, 4.24 mmol, 1.0 equiv.) in THF
(20 mL) at 0 ЊC was treated with TBAF (6.36 mL, 1 M solution
in THF, 6.36 mmol, 1.5 equiv.). After stirring for 1 h, the
reaction mixture was diluted with Et2O (50 mL) and washed
with saturated aqueous NH4Cl solution (50 mL). The aqueous
solution was extracted with Et2O (2 × 20 mL) and the combined
organic phase was washed with brine (50 mL), dried over
MgSO4 and concentrated under reduced pressure. The crude
mixture was purified by flash column chromatography (silica
gel, 50% EtOAc in hexanes) to provide alcohol 9 (1.95 g, 98%)
as a 4 : 1 mixture of anomers: Rf = 0.23 (silica gel, 50% EtOAc
in hexanes); νmax/cmϪ1 (thin film) 3497 (s, OH), 2971 (s, CH),
᎐
᎐
3
2916 (s, CH), 1771 (s, C᎐O), 1710 (s, C᎐O), 1609 (s), 1508 (s),
(m), 1385 (s), 1255 (s), 1153 (s) and 1028 (s); δH (400 MHz,
CDCl3) (α anomer) 7.79–7.77 (2H, m, NPhth), 7.71–7.63 (2H,
m, NPhth), 7.07 (2H, d, J = 8.5, p-CH2C6H4OCH3), 6.59 (2H, d,
J = 8.5, p-CH2C6H4OCH3), 5.72 (1H, dd, J = 9.4 and 5.2,
H–C(3)), 4.86 (1H, d, J = 3.6, H–C(1)), 4.65 (1H, d, J = 12.1,
p-CH2C6H4OCH3), 4.43 (1H, dd, J = 9.4 and 3.6, H–C(2)), 4.39
(1H, d, J = 12.1, p-CH2C6H4OCH3), 4.33–4.29 (1H, m,
H–C(5)), 4.24 (1H, dd, J = 5.2 and 2.4, H–C(4)), 3.67 (3H, s,
–OCH3), 3.64 (1H, dd, J = 13.0 and 8.3, CH2N3), 3.43 (1H, dd,
J = 13.0 and 4.6, CH2N3), 1.49 and 1.29 (6H, 2 s, C(CH3)2);
᎐
᎐
1458 (s), 1380 (s), 1240 (s) and 1061 (s); δH (400 MHz, CDCl3)
(α anomer) 7.80–7.77 (2H, m, NPhth), 7.70–7.67 (2H, m,
NPhth), 7.07 (2H, d, J = 8.6, p-CH2C6H4OCH3), 6.61 (2H, d,
J = 8.6, p-CH2C6H4OCH3), 5.76 (1H, dd, J = 9.7 and 5.3,
H–C(3)), 4.89 (1H, d, J = 3.5, H–C(1)), 4.63 (1H, d, J = 12.2,
p-CH2C6H4OCH3), 4.44 (1H, dd, J = 9.6 and 3.5, H–C(2)), 4.37
(1H, d, J = 12.2, p-CH2C6H4OCH3), 4.32 (1H, dd, J = 5.2 and
2.5, H–C(4)), 4.29 (1H, dd, J = 9.0 and 8.9, CH2OH), 4.25–4.23
(1H, m, H–C(5)), 4.04–3.98 (1H, m, CH2OH), 3.66 (3H,
s, –OCH3), 2.26 (1H, bs, OH), 1.49 and 1.32 (6H, 2 s, C(CH3)2);
δC (100 MHz, CDCl ) (α anomer) 168.2 (C᎐O), 159.1, 133.9,
᎐
3
δC (100 MHz, CDCl ) (α anomer) 168.3 (C᎐O), 159.1, 133.9,
131.7, 129.5, 129.1, 128.8, 123.2, 113.6, 109.8 (C(CH3)2), 96.2
(C-1), 73.3, 69.4, 68.7 (C-3, C-4, C-5), 67.3 (–OCH2–), 55.1
(–OCH3), 54.2 (C-2), 51.3 (C-6), 28.2 (C(CH3)2), 26.5
(C(CH3)2); MALDI-FTMS (NBA) m/z 517.1675, M ϩ Naϩ
calcd for C25H26N4O7: 517.1694.
᎐
3
131.7, 129.4, 129.0, 123.2, 113.6, 109.9 (C(CH3)2), 96.5 (C-1),
74.1, 69.4, 68.8 (C-3, C-4, C-5), 67.8 (C-6), 62.9 (–OCH2–),
55.1 (–OCH3), 54.4 (C-2), 28.3 (C(CH3)2), 26.5 (C(CH3)2);
MALDI-FTMS (NBA) m/e 492.1631, M ϩ Naϩ calcd for
C25H27NO8: 492.1629.
p-Methoxybenzyl 6-acetamido-2,6-dideoxy-3,4-O-
isopropylidene-2-N-phthalimido-ꢀ,ꢁ-D-galactopyranoside 12.
Reduction of Azide 11 and acetylation
p-Methoxybenzyl 2-deoxy-3,4-O-isopropylidene-2-N-
phthalimido-6-O-p-toluenesulfonyl-ꢀ,ꢁ-D-galactopyranoside 10.
Treatment of alcohol 9 with p-toluenesulfonylchloride
To a stirred solution of azide 11 (1.37 g, 2.77 mmol, 1.0 equiv.)
in THF (30 mL) was added Ph3P (1.81 g, 6.93 mmol, 2.5 equiv.).
After being stirred for 1 h at 25 ЊC, H2O (30 mL) was added and
the mixed system was vigorously stirred for an additional 5 h at
room temperature. After that time, the reaction mixture was
poured into brine (30 mL), the layers were separated and the
aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic phase was dried (MgSO4), filtered and
concentrated. The resulting residue was dissolved in pyridine
(10 mL), followed by addition of Ac2O (1.83 mL, 19.39 mmol,
7.0 equiv.) at 0 ЊC. After stirring for 30 min, the reaction
mixture was allowed to warm to 25 ЊC and was stirred for 1 h at
this temperature. The crude mixture was diluted with CH2Cl2
(30 mL) and the resulting solution was washed with aqueous
HCl (30 mL, 1 M solution). The aqueous phase was extracted
with CH2Cl2 (2 × 20 mL), and the combined organic extracts
were sequentially washed with saturated aqueous Na2CO3
solution (30 mL) and brine (30 mL), followed by drying over
MgSO4, filtration and concentration under reduced pressure.
The resulting crude mixture was used for the next step without
further purification: Rf = 0.13 (silica gel, 50% EtOAc in
hexanes); νmax/cmϪ1 (thin film) 3366 (s, NH), 3072 (s, CH), 2720
To a solution of alcohol 9 (1.95 g, 4.15 mmol, 1.0 equiv.) in
pyridine (50 mL) was added portionwise tosyl chloride (2.37 g,
12.46 mmol, 3.0 equiv.) at 0 ЊC. After stirring for 15 min, the
solution was allowed to warm to 25 ЊC, and after 8 h at room
temperature, the reaction mixture was diluted with Et2O (50
mL) and washed with aqueous HCl (20 mL, 1 M solution). The
aqueous phase was extracted with Et2O (2 × 20 mL), and the
combined organic solution was washed with brine (50 mL),
dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (silica
gel, 20%
50% EtOAc in hexanes) furnished tosylate 10 (2.2 g,
85%) as a 4 : 1 mixture of anomers: Rf = 0.34 (silica gel, 25%
EtOAc in hexanes); νmax/cmϪ1 (thin film) 2989 (m, CH), 2931 (m,
CH), 1772 (m, C᎐O), 1713 (s, C᎐O), 1607 (m), 1508 (m), 1455
᎐
᎐
(s), 1372 (s, SO2), 1249 (s), 1172 (s, SO2) and 1038 (s); δH (400
MHz, CDCl3) (α anomer) 7.81 (2H, d, J = 8.5, p-OSO2-
C6H4CH3), 7.78–7.76 (2H, m, NPhth), 7.70–7.67 (2H, m,
NPhth), 7.33 (2H, d, J = 8.5, p-OSO2C6H4CH3), 7.04 (2H, d,
J = 8.4, p-CH2C6H4OCH3), 6.61 (2H, d, J = 8.4, p-CH2C6H4-
OCH3), 5.66 (1H, dd, J = 9.2 and 5.2, H–C(3)), 4.77 (1H, d,
J = 3.7, H–C(1)), 4.56 (1H, d, J = 12.1, p-CH2C6H4OCH3),
4.40–4.36 (2H, m), 4.32–4.29 (2H, m), 4.23–4.21 (1H, m), 4.13–
(s, CH), 1760 (s, C᎐O), 1696 (s, C᎐O), 1549 (s), 1513 (s), 1384
᎐
᎐
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
3720

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(s) and 915 (s); δH (400 MHz, CDCl3) (α anomer) 7.83–7.78
(2H, m, NPhth), 7.49–7.40 (2H, m, NPhth), 7.09 (2H, d, J = 8.5,
p-CH2C6H4OCH3), 6.65 (2H, d, J = 8.5, p-CH2C6H4OCH3),
5.80 (1H, dd, J = 9.6 and 5.0, H–C(3)), 4.89 (1H, d, J = 3.5,
H–C(1)), 4.64 (1H, d, J = 12.1, p-CH2C6H4OCH3), 4.47 (1H,
dd, J = 9.6 and 3.5, H–C(2)), 4.39 (1H, d, J = 12.1, p-CH2C6H4-
OCH3), 4.36–4.31 (2H, m), 3.93–3.87 (1H, m), 3.71 (3H, s,
–OCH3), 3.50–3.47 (1H, m), 2.07 (3H, s, NHCOCH3), 1.55
and 1.37 (6H, 2 s, C(CH3)2); δC (100 MHz, CDCl3) (α anomer)
EtOAc in hexanes) to obtain ketone 14 (1.05 g, 61%) as a white
solid and a 4 : 1 mixture of anomers: Rf = 0.43 (silica gel, 60%
EtOAc in hexanes); δH (400 MHz, CDCl3) (α anomer) 7.79–7.77
(2H, m, NPhth), 7.69–7.67 (2H, m, NPhth), 7.32 (2H, d, J = 8.5,
p-CH C H OCH ), 7.23 (1H, d, J = 8.0, CH᎐CH), 7.11 (2H,
᎐
6
4
3
d, J =28.2, p-CH2C6H4OCH3), 6.77 (2H, d, J = 8.2, p-CH2C6H4-
OCH3), 6.60 (2H, d, J = 8.4, p-CH2C6H4OCH3), 5.80 (1H, d,
J = 8.0, CH᎐CH ), 5.72 (1H, dd, J = 9.6 and 5.3, H–C(3)), 5.52
᎐
(1H, s, C(O)H–N), 5.08 (1H, d, J = 5.9, H–C(11)), 5.03–4.96
(2H, m), 4.89 (1H, dd, J = 14.1 and 13.8, CH), 4.72 (1H, d,
J = 3.2, H–C(1)), 4.65 (1H, d, J = 11.8, p-CH2C6H4OCH3), 4.61
(1H, d, J = 11.8, p-CH2C6H4OCH3), 4.45–4.34 (3H, m), 4.24–
4.22 (1H, m), 3.71 (3H, s, –OCH3), 3.66 (3H, s, –OCH3), 3.01
(1H, dd, J = 17.1 and 9.0, H–C(6)), 2.66 (1H, dd, J = 17.1 and
4.4, HЈ–C(6)), 1.57, 1.55, 1.37 and 1.29 (12H, 4 s, 2 × C(CH3)2);
170.7 (CH C᎐O), 168.2 (C᎐O), 158.9, 133.8, 131.7, 129.7, 129.2,
᎐
᎐
3
128.9, 123.9, 113.5, 109.5 (C(CH3)2), 96.3 (C-1), 73.8, 69.3, 68.6
(C-3, C-4, C-5), 65.9 (–OCH2–), 54.9 (–OCH3), 54.2 (C-2), 40.5
(C-6), 28.2 (C(CH ) ), 26.3 (C(CH ) ), 22.9 (O᎐CCH );
᎐
3
2
3
2
3
MALDI-FTMS (NBA) m/z 533.1882, M ϩ Naϩ calcd for
C27H30N2O8: 533.1894.
δC (100 MHz, CDCl ) (α anomer) 203.2 (C-7), 168.3 (C᎐O),
᎐
3
p-Methoxybenzyl 6-(N-nitroso)-acetamido-2,6-dideoxy-3,4-O-
isopropylidene-2-N-phthalimido-ꢀ,ꢁ-D-galactopyranoside 13.
Treatment of acetamide 12 with sodium nitrite
162.4 (C᎐O), 159.1 (C᎐O), 159.0 (C᎐O), 151.2, 141.3, 133.9,
᎐ ᎐ ᎐
131.7, 130.5, 128.8, 128.4, 123.2, 113.7, 113.5, 109.4 (C(CH3)2),
102.6 (C(CH3)2), 98.5 (C-11), 96.1 (C-1), 94.5, 84.5, 82.7 (C-8,
C-9, C-10), 74.5, 69.1, 68.6 (C-3, C-4, C-5), 63.5 (–OCH2–),
55.2 (–OCH3), 55.1 (–OCH3), 54.3 (C-2), 43.6 (–NCH2–), 39.7
(C-6), 28.4 (C(CH3)2), 26.7 (C(CH3)2), 26.5 (C(CH3)2), 25.1
(C(CH3)2); MALDI-FTMS (NBA) m/z 876.2959, M ϩ Naϩ
calcd for C45H47N3O14: 876.2956.
To a stirred solution of acetamide 12 (ca 2.77 mmol, 1.0 equiv.)
in a mixed solvent system of Ac2O : AcOH (5 : 1, 36 mL) was
added in small portions NaNO2 (9.94 g, 144.04 mmol, 52.0
equiv.) at Ϫ10 ЊC. The reaction mixture was stirred for 1 h,
before being poured into an ice–water mixture and extracted
with Et2O (3 × 30 mL). The combined ethereal solution was
washed with a 5% sodium hydrogen carbonate several times
until removal of acetic acid was complete. Finally, the organic
solution was washed with brine (50 mL), dried (MgSO4),
filtered and concentrated under reduced pressure. Purification
3-(4-Methoxybenzyl)-1-[p-methoxybenzyl (11R)-2,6-dideoxy-
3,4:9,10-di-O-isopropylidene-2-N-phthalimido-L-allo-ꢀ,ꢁ-D-
galacto-undecodialdo-1,5-pyranoside-11,8-furanosyl]uracil 15a
and L-altro-ꢀ,ꢁ-D-galacto-undecodialdo-1,5-pyranoside-11,8-
furanosyl]uracil 15b. Reduction of ketone 14
by flash column chromatography (silica gel, 20%
50%
A solution of ketone 14 (0.5 g, 0.58 mmol, 1.0 equiv.) in MeOH
(10 mL) was sequentially treated with CeCl3. 7 × H2O (1.1 g,
2.93 mmol, 5.0 equiv.) and NaBH4 (110 mg, 2.93 mmol, 5.0
equiv.) at 0 ЊC. After stirring for 0.5 h at 0 ЊC, the reaction
mixture was diluted with EtOAc (10 mL) and washed with
saturated aqueous NH4Cl solution (20 mL). The aqueous
solution was extracted with EtOAc (3 × 10 mL) and the
combined organic phase was washed with brine (50 mL), dried
over MgSO4 and concentrated under reduced pressure.
Purification by flash column chromatography (silica gel, 66%
EtOAc in hexanes) provided alcohols 15a/b (0.47 g, 95%) as an
inseparable mixture of diastereoisomers.
EtOAc in hexanes) afforded N-nitroso derivative 13 (1.27 g,
85% overall yield from 11) as a 4 : 1 mixture of anomers: Rf =
0.57 (silica gel, 50% EtOAc in hexanes); νmax/cmϪ1 (thin film)
2989 (m, CH), 2919 (m, CH), 1772 (m, C᎐O), 1713 (s, C᎐O),
᎐
᎐
1607 (m), 1507 (s, N᎐O), 1378 (s), 1243 (s), 1126 (s), 1072 (s)
᎐
and 1032 (s); δH (400 MHz, CDCl3) (α anomer) 7.79–7.77 (2H,
m, NPhth), 7.68–7.65 (2H, m, NPhth), 6.97 (2H, d, J = 8.6,
p-CH2C6H4OCH3), 6.59 (2H, d, J = 8.6, p-CH2C6H4OCH3),
5.62 (1H, dd, J = 9.3 and 5.0, H–C(3)), 4.72 (1H, d, J = 3.7,
H–C(1)), 4.51 (1H, dd, J = 14.2 and 8.8, CH N(N᎐O)Ac), 4.39
᎐
2
(1H, dd, J = 9.2 and 3.7, H–C(2)), 4.38 (1H, d, J = 12.0,
p-CH2C6H4OCH3), 4.25 (1H, dd, J = 9.0 and 8.9, CH), 4.21–
4.19 (1H, m), 4.14 (1H, d, J = 12.0, p-CH2C6H4OCH3), 3.85
(1H, ddd, J = 13.8, 3.7 and 3.4, H–C(5)), 3.66 (3H, s, –OCH3),
3-(4-Methoxybenzyl)-1-[p-methoxybenzyl (11R)-7-O-tert-
butyldimethylsilyl-2,6-dideoxy-3,4:9,10-di-O-isopropylidene-2-
N-phthalimido-L-allo-ꢀ,ꢁ-D-galacto-undecodialdo-1,5-pyrano-
side-11,8-furanosyl]uracil 16a and L-altro-ꢀ,ꢁ-D-galacto-
undecodialdo-1,5-pyranoside-11,8-furanosyl]uracil 16b.
Silylation of alcohols 15a/b
2.78 (3H, s, N(N᎐O)COCH ), 1.48 and 1.27 (6H, 2 s, C(CH ) );
᎐
3
3 2
δC (100 MHz, CDCl ) (α anomer) 174.2 (O᎐CCH ), 168.2
᎐
3
3
(C᎐O), 159.1, 133.9, 131.7, 129.4, 129.0, 128.6, 123.2, 113.6,
᎐
109.8 (C(CH3)2), 96.3 (C-1), 73.2, 69.2, 68.7 (C-3, C-4, C-5),
64.6 (–OCH2–), 55.1 (–OCH3), 53.9 (C-2), 38.9 (C-6), 28.2
(C(CH3)2), 26.4 (C(CH3)2), 22.5 (OCCH3); MALDI-FTMS
(NBA) m/z 539.1898, Mϩ calcd for C27H29N3O9: 539.1904.
A solution of alcohols 15a/b (154 mg, 0.180 mmol, 1.0 equiv.) in
CH2Cl2 (5 mL) was treated, at 0 ЊC, with 2,6-lutidine (43 µL,
0.360 mmol, 2.0 equiv.) and tert-butyldimethylsilyl trifluoro-
methansulfonate (62 µL, 0.269 mmol, 1.5 equiv.). After stirring
for 1 h, saturated aqueous NH4Cl solution (10 mL) was added
and the resulting biphasic mixture was separated. The aqueous
phase was extracted with CH2Cl2 (3 × 10 mL) and the
combined organic solution was washed with brine (15 mL),
dried over MgSO4 and concentrated under reduced pressure.
Purification by flash column chromatography (silica gel, 10%
EtOAc in hexanes) provided silyl ethers 16a/b (165 mg, 94%) as
an inseparable mixture of diastereoisomers.
3-(4-Methoxybenzyl)-1-[p-methoxybenzyl (11R)-2,6-dideoxy-
3,4:9,10-di-O-isopropylidene-7-keto-2-N-phthalimido-L-ribo-
ꢀ,ꢁ-D-galacto-undecodialdo-1,5-pyranoside-11,8-furanosyl]-
uracil 14. Reaction of aldehyde 4 with diazo derived from 13
To a solution of N-nitroso acetamide 13 (1.20 g, 2.22 mmol,
1.1 equiv.) in Et2O (20 mL) was added MeOH (2 mL), cooled
to 0 ЊC and protected from the light. Under these conditions,
a 40% aqueous solution of KOH (4 mL) was added and
after stirring for 5 min, the crude mixture was diluted with H2O
(15 mL), the layers were separated and the aqueous phase was
extracted with Et2O (1 × 20 mL). The combined organic
extracts were washed with brine (20 mL) and the resulting
solution was immediately treated with a solution of aldehyde
4 (0.81 g, 2.02 mmol, 1.0 equiv.) in Et2O (5 mL) at 0 ЊC. After
stirring for 1 h, the solvent was removed by concentration under
reduced pressure and the resulting residue was subjected to
purification by flash column chromatography (silica gel, 50%
3-(4-Methoxybenzyl)-1-[(11R)-7-O-tert-butyldimethylsilyl-2,6-
dideoxy-3,4:9,10-di-O-isopropylidene-2-N-phthalimido-L-allo-ꢁ-
D-galacto-undecodialdo-1,5-pyranoside-11,8-furanosyl]uracil
17a and L-altro-ꢁ-D-galacto-undecodialdo-1,5-pyranoside-11,8-
furanosyl]uracil 17b. Reaction of silyl ethers 16a/b with DDQ
To a solution of silyl ethers 16a/b (141 mg, 0.145 mmol,
1.0 equiv.) in CH2Cl2 (5 mL) was added H2O (0.5 mL) and
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
3721

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DDQ (50 mg, 0.217 mmol, 1.5 equiv.) at 25 ЊC. After stirring for
8 h, the reaction mixture was diluted with CH2Cl2 (5 mL) and
the resulting organic solution was washed with H2O (10 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 5 mL) and
the combined organic solution was washed with brine (10 mL),
dried over MgSO4 and concentrated under reduced pressure.
Purification by preparative thin layer chromatography (silica
gel, 70% EtOAc in hexanes) provided pure hemiacetals 17a
(84 mg, 68%) and 17b (21 mg, 17%) as white solids and as pure
enantiomers. Hemiacetal 17a: Rf = 0.26 (silica gel, 60% EtOAc
column chromatography (silica gel, 50% EtOAc in hexanes) to
provide the corresponding alcohols in form of pure α and β
anomers α-18 (0.47 g, 45%) and β-18 (0.31 g, 30%) respectively,
as colorless oils. Alcohol α-18: Rf = 0.46 (silica gel, 50% EtOAc
in hexanes); [α]22 ϩ134.9 (c 0.6 in CH2Cl2); δH (400 MHz,
D
CDCl3) 7.29 (2H, d, J = 8.6, p-CH2C6H4OCH3), 6.88 (2H, d,
J = 8.6, p-CH2C6H4OCH3), 4.97 (1H, d, J = 3.3, H–C(1)), 4.66
(1H, d, J = 11.6, p-CH2C6H4OCH3), 4.51 (1H, d, J = 11.6,
p-CH2C6H4OCH3), 4.42 (1H, dd, J = 8.7 and 5.3, H–C(3)), 4.23
(1H, dd, J = 5.3 and 2.6, H–C(4)), 4.11–4.08 (1H, m, H–C(5)),
3.94 (1H, dd, J = 11.8 and 6.5, CH2OH), 3.83 (1H, dd, J = 11.8
and 4.4, CH2OH), 3.79 (3H, s, –OCH3), 3.33 (1H, dd, J = 8.7
and 3.3, H–C(2)), 2.45 (1H, bs, OH), 1.51 and 1.35 (6H, 2 s,
C(CH3)2); δC (100 MHz, CDCl3) 159.4, 129.6, 128.4, 113.8,
109.8 (C(CH3)2), 96.4 (C-1), 73.6, 73.5, 69.5 (C-3, C-4, C-5),
67.9 (C-6), 62.4 (C-2), 61.1 (–OCH2–), 55.1 (–OCH3), 28.2
(C(CH3)2), 26.2 (C(CH3)2); FAB (NBA) m/z 365.1597, Mϩ
calcd for C17H23N3O6: 365.1587. Alcohol β-18: Rf = 0.29 (silica
in hexanes); [α]22 ϩ34.2 (c 1.4 in CH2Cl2); δH (400 MHz,
D
CDCl3) 7.78–7.76 (2H, m, NPhth), 7.66–7.64 (2H, m, NPhth),
7.38 (2H, d, J = 8.7, p-CH2C6H4OCH3), 7.15 (1H, d, J = 8.1,
CH᎐CH), 6.76 (2H, d, J = 8.7, p-CH C H OCH ), 5.81 (1H, d,
᎐
2
6
4
3
J = 3.2, H–C(11)), 5.72 (1H, d, J = 8.1, CH᎐CH ), 5.16 (1H, d,
᎐
J = 8.5, H–C(1)), 5.02 (1H, d, J = 13.6, p-CH2C6H4OCH3), 4.93
(1H, d, J = 13.6, p-CH2C6H4OCH3), 4.81–4.76 (2H, m, H–C(3),
H–C(9)), 4.64 (1H, dd, J = 6.9 and 3.3, H–C(10)), 4.12 (1H, dd,
J = 8.9 and 8.5, H–C(2)), 4.01–3.98 (3H, m, H–C(5), H–C(7),
H–C(8)), 3.90 (1H, dd, J = 5.0 and 3.8, H–C(4)), 3.69 (3H, s,
–OCH3), 2.11 (1H, ddd, J = 14.5, 9.2 and 4.7, H–C(6)), 1.83
(1H, ddd, J = 14.5, 8.0 and 3.9, HЈ–C(6)), 1.56, 1.52, 1.28 and
1.25 (12H, 4 s, 2 × C(CH3)2), 0.86 (9H, s, SiC(CH3)3), 0.06 and
gel, 50% EtOAc in hexanes); [α]22 ϩ53.3 (c 0.3 in CH2Cl2);
D
δH (400 MHz, CDCl3) 7.26 (2H, d, J = 8.5, p-CH2C6H4OCH3),
6.84 (2H, d, J = 8.5, p-CH2C6H4OCH3), 4.82 (1H, d, J = 11.6,
p-CH2C6H4OCH3), 4.61 (1H, d, J = 11.6, p-CH2C6H4OCH3),
4.22 (1H, d, J = 8.4, H–C(1)), 4.02 (1H, dd, J = 5.3 and 1.6,
H–C(4)), 3.93 (1H, dd, J = 11.6 and 7.3, CH2OH), 3.84 (1H, dd,
J = 8.0 and 5.3, H–C(3)), 3.79 (1H, dd, J = 11.6 and 4.4,
CH2OH), 3.75 (3H, s, –OCH3), 3.75–3.72 (1H, m, H–C(5)), 3.39
(1H, dd, J = 8.4 and 8.2, H–C(2)), 2.47 (1H, bs, OH), 1.48 and
1.29 (6H, 2 s, C(CH3)2); δC (100 MHz, CDCl3) 159.4, 129.7,
128.4, 113.8, 110.6 (C(CH3)2), 99.7 (C-1), 77.2, 73.3, 72.9 (C-3,
C-4, C-5), 70.5 (C-6), 65.0 (C-2), 62.1 (–OCH2–), 55.1 (–OCH3),
28.0 (C(CH3)2), 26.1 (C(CH3)2); FAB (NBA) m/z 365.1590, Mϩ
calcd for C17H23N3O6: 365.1587.
0.01 (6H, 2 s, Si(CH3)2); δC (100 MHz, CDCl ) 168.4 (C᎐O),
᎐
3
162.4 (C᎐O), 159.1, 150.6, 138.7, 134.1, 131.8, 130.8, 128.8,
᎐
123.7, 123.4, 113.7, 110.2 (C(CH3)2), 102.4 (C(CH3)2), 92.4
(C-11), 91.1 (C-1), 87.6, 83.6, 78.9 (C-8, C-9, C-10), 75.4, 73.6,
69.2, 68.0 (C-3, C-4, C-5, C-7), 56.8 (–OCH3), 55.2 (C-2),
43.7 (–NCH2–), 35.5 (C-6), 28.0 (C(CH3)2), 27.3 (C(CH3)2),
26.4 (C(CH3)2), 25.9 (SiC(CH3)3), 25.4 (C(CH3)2), 18.1
(SiC(CH3)3), Ϫ4.1 (Si(CH3)2), Ϫ4.5 (Si(CH3)2); FAB (NBA)
m/z 872.3402, M ϩ Naϩ calcd for C43H55N3O13Si: 872.3402.
Hemiacetal 17b: Rf = 0.31 (silica gel, 60% EtOAc in hexanes);
[α]22D ϩ36.1 (c 0.4 in CH2Cl2); δH (400 MHz, CDCl3) 7.77–7.75
(3H, m), 7.65–7.63 (2H, m, NPhth), 7.39 (2H, d, J = 8.7,
p-CH2C6H4OCH3), 6.75 (2H, d, J = 8.7, p-CH2C6H4OCH3),
p-Methoxybenzyl 2-azido-2-deoxy-3,4-O-isopropylidene-6-p-
toluenesulfonyl-ꢀ-D-galactopyranoside 19. Tosylation of ꢀ-18
Tosylate 19 (585 mg, 88%) was prepared from alcohol α-18
(470 mg, 1.28 mmol) according to the procedure described
above for 10. 19: colorless oil; Rf = 0.28 (silica gel, 20% EtOAc
6.05 (1H, d, J = 3.6, H–C(11)), 5.69 (1H, d, J = 8.2, CH᎐CH ),
᎐
5.16 (1H, dd, J = 8.2 and 8.0, H–C(1)), 5.03 (1H, d, J = 13.5,
p-CH2C6H4OCH3), 4.92 (1H, d, J = 13.5, p-CH2C6H4OCH3),
4.74 (1H, dd, J = 9.1 and 5.0, H–C(3)), 4.68 (1H, dd, J = 6.2 and
1.9 Hz, H–C(9)), 4.56 (1H, dd, J = 6.0 and 3.6, H–C(10)), 4.34
(1H, d, J = 1.9, H–C(8)), 4.16 (1H, ddd, J = 9.8, 4.4 and 2.2,
H–C(5)), 4.11 (1H, dd, J = 9.0 and 8.2, H–C(2)), 3.99 (1H, dd,
J = 5.0 and 2.0, H–C(4)), 3.94 (1H, ddd, J = 10.3 and 1.9,
H–C(7)), 3.70 (3H, s, –OCH3), 3.34 (1H, d, J = 7.7, OH), 2.20
(1H, ddd, J = 14.6, 10.7 and 4.5, H–C(6)), 1.90 (1H, ddd,
J = 14.6, 9.5 and 2.5, HЈ–C(6)), 1.56, 1.55, 1.28 and 1.25 (12H, 4
s, 2 × C(CH3)2), 0.83 (9H, s, SiC(CH3)3), 0.09 and 0.06 (6H, 2 s,
in hexanes); [α]22 ϩ100.9 (c 1.3 in CH2Cl2); δH (400 MHz,
D
CDCl3) 7.76 (2H, d, J = 8.2, p-OSO2C6H4CH3), 7.29 (2H, d, J =
8.2, p-OSO2C6H4CH3), 7.21 (2H, d, J = 8.6, p-CH2C6H4OCH3),
6.83 (2H, d, J = 8.6, p-CH2C6H4OCH3), 4.81 (1H, d, J = 3.4,
H–C(1)), 4.54 (1H, d, J = 11.5, p-CH2C6H4OCH3), 4.38 (1H, d,
J = 11.5, p-CH2C6H4OCH3), 4.31 (1H, dd, J = 8.5 and 5.3,
H–C(3)), 4.23–4.17 (3H, m), 3.75 (3H, s, –OCH3), 3.20 (1H, dd,
J = 8.5 and 3.4, H–C(2)), 2.39 (3H, s, –CH3), 1.38 and 1.23 (6H,
2 s, C(CH3)2); δC (50.3 MHz, CDCl3) 159.5, 144.9, 129.8, 127.9,
113.9, 110.1 (C(CH3)2), 96.1 (C-1), 73.4, 72.4, 69.6 (C-3, C-4,
C-5), 68.8 (C-6), 66.1 (–OCH2–), 60.8 (C-2), 55.3 (–OCH3), 28.1
(C(CH3)2), 26.2 (C(CH3)2), 21.6 (–CH3); FAB (NBA) m/z
519.1679, M ϩ calcd for C24H29N3O8S: 519.1675.
Si(CH3)2); δC (100 MHz, CDCl ) 168.4 (C᎐O), 162.5 (C᎐O),
᎐
᎐
3
159.0, 150.9, 138.3, 134.0, 131.8, 130.8, 128.9, 123.4, 113.9,
113.6, 110.4 (C(CH3)2), 102.3 (C(CH3)2), 92.6 (C-11), 92.0
(C-1), 85.7, 84.8, 81.6 (C-8, C-9, C-10), 75.3, 73.5, 70.2, 69.9
(C-3, C-4, C-5, C-7), 56.8 (–OCH3), 55.2 (C-2), 43.6 (–NCH2–),
34.5 (C-6), 28.0 (C(CH3)2), 27.3 (C(CH3)2), 26.4 (C(CH3)2),
25.8 (SiC(CH3)3), 25.2 (C(CH3)2), 17.9 (SiC(CH3)3), Ϫ4.2
(Si(CH3)2), Ϫ4.8 (Si(CH3)2); FAB (NBA) m/z 872.3398,
M ϩ Naϩ calcd for C43H55N3O13Si: 872.3402.
p-Methoxybenzyl 2-azido-2,6-dideoxy-3,4-O-isopropylidene-N-
phthalimido-ꢀ-D-galactopyranoside 20. Treatment of tosylate 19
with potassium phthalimide
To a solution of tosylate 19 (90 mg, 0.173 mmol, 1.0 equiv.)
in DMF (5 mL) was added potassium phthalimide (80 mg,
0.433 mmol, 2.5 equiv.). The reaction mixture was then heated
at reflux for 48 h with complete depletion of starting material
according to TLC. The crude mixture was allowed to reach
25 ЊC and was diluted with Et2O (10 mL) and washed with
saturated aqueous NH4Cl solution (15 mL). The aqueous
solution was extracted with Et2O (2 × 10 mL) and the combined
organic phase was washed with brine (15 mL), dried over
MgSO4 and concentrated under reduced pressure. Purification
by flash column chromatography (silica gel, 20% EtOAc in
hexanes) furnished N-phthalimide 20 (85 mg, 99%) as a white
solid: Rf = 0.33 (silica gel, 50% EtOAc in hexanes); δH (400
MHz, CDCl3) 7.84–7.78 (2H, m, NPhth), 7.69–7.67 (2H, m,
p-Methoxybenzyl 2-azido-2-deoxy-3,4-O-isopropylidene-ꢀ,ꢁ-D-
galactopyranoside 18. Desilylation of 7
A solution of silyl ether 7 (1.7 g, 2.82 mmol, 1.0 equiv.), as a
4 : 1 mixture of anomers, in THF (15 mL) at 0 ЊC was treated
with TBAF (3.38 mL, 1 M solution in THF, 3.38 mmol, 1.2
equiv.). After stirring for 1 h, the reaction mixture was diluted
with Et2O (30 mL) and washed with saturated aqueous NH4Cl
solution (30 mL). The aqueous solution was extracted with
Et2O (2 × 15 mL) and the combined organic phase was washed
with brine (40 mL), dried over MgSO4 and concentrated under
reduced pressure. The crude mixture was purified by flash
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
3722

View Article Online
NPhth), 7.01 (2H, d, J = 8.5, p-CH2C6H4OCH3), 6.70 (2H, d,
J = 8.5, p-CH2C6H4OCH3), 4.80 (1H, d, J = 3.4, CH–OCH2-
C6H4OCH3), 4.42 (1H, ddd, J = 9.6, 2.8 and 2.7 Hz, CH),
4.33–4.29 (2H, m), 4.26–4.15 (3H, m), 3.77 (1H, dd, J = 14.2
and 3.1, CH2NPhth), 3.69 (3H, s, –OCH3), 3.29 (1H, dd, J = 8.5
and 3.4, CHN3), 1.47 and 1.29 (6H, 2 s, C(CH3)2); δC (100 MHz,
same procedure for the preparation of 14, to afford ketone 24
(27 mg, 80%) as a white solid: Rf = 0.45 (silica gel, 20% EtOAc
in hexanes); δH (400 MHz, CDCl3) 7.25 (2H, d, J = 8.6, p-CH2-
C6H4OCH3), 7.24 (2H, d, J = 8.7, p-CH2C6H4OCH3), 7.18 (1H,
d, J = 8.0, CH᎐CH), 6.81 (2H, d, J = 8.6, p-CH C H OCH ),
᎐
2
6
4
3
6.71 (2H, d, J = 8.7, p-CH2C6H4OCH3), 5.76 (1H, d, J = 8.0,
CDCl ) 168.1 (C᎐O), 159.4, 134.2, 134.1, 131.8, 129.8, 128.1,
CH᎐CH ), 5.45 (1H, s, H–C(11)), 5.33 (1H, dd, J = 6.1 and 2.2,
᎐
᎐
3
123.3, 113.8, 110.0 (C(CH3)2), 96.1 (C-1), 73.6, 73.1, 69.3 (C-3,
C-4, C-5), 65.1 (C-2), 60.9 (–OCH2–), 55.2 (–OCH3), 38.8 (C-6),
28.2 (C(CH3)2), 26.2 (C(CH3)2); FAB (NBA) m/z 494.1809, Mϩ
calcd for C25H26N4O7: 494.1802.
H–C(9)), 5.07 (1H, d, J = 6.1, H–C(10)), 4.93 (1H, d, J = 13.8,
p-CH2C6H4OCH3), 4.80 (1H, d, J = 13.8, p-CH2C6H4OCH3),
4.73 (1H, d, J = 3.3, H–C(1)), 4.63 (1H, d, J = 11.2, p-CH2C6-
H4OCH3), 4.55 (1H, d, J = 2.2, H–C(8)), 4.44 (1H, ddd, J = 8.9,
3.4 and 3.0, H–C(5)), 4.35 (1H, d, J = 11.2, p-CH2C6H4OCH3),
4.30 (1H, dd, J = 8.7 and 5.2, H–C(3)), 3.98 (1H, dd, J = 5.2 and
2.5, H–C(4)), 3.74 (3H, s, –OCH3), 3.62 (3H, s, –OCH3), 3.14
(1H, dd, J = 8.7 and 3.3, H–C(2)), 2.90 (1H, dd, J = 17.0 and
9.1, H–C(6)), 2.56 (1H, dd, J = 17.0 and 4.1, HЈ–C(6)), 1.50,
1.44, 1.33 and 1.27 (12H, 4 s, 2 × C(CH3)2); δC (100 MHz,
p-Methoxybenzyl 6-acetamido-2-azido-2,6-dideoxy-3,4-O-
isopropylidene-ꢀ-D-galactopyranoside 22. Hydrazinolysis of
N-phthalimide 20 and acetylation of amine 21
To a stirred solution of N-phthalimide 20 (85 mg, 0.172 mmol,
1.0 equiv.) in MeOH (3 mL) was added NH2NH2 (273 µL, 1.0
M solution in THF, 0.273 mmol, 1.5 equiv.). After being stirred
for 12 h at 25 ЊC, the reaction mixture was diluted with EtOAc
(5 mL) and H2O (5 mL). After separation of the layers, the
aqueous phase was extracted with EtOAc (3 × 5 mL), and
the combined organic phase was dried (MgSO4), filtered
and concentrated. The resulting amine 21, practically pure, was
dissolved in pyridine (5 mL), followed by addition of Ac2O (1.0
mL, 10.59 mmol, 60.0 equiv.) at 0 ЊC. After stirring for 30 min,
the reaction mixture was allowed to warm to 25 ЊC and was
stirred for 1 h at this temperature. The crude mixture
was diluted with CH2Cl2 (5 mL) and the resulting solution was
washed with aqueous HCl (5 mL, 1 M solution). The aqueous
phase was extracted with CH2Cl2 (2 × 5 mL), and the combined
organic extracts were sequentially washed with saturated
aqueous Na2CO3 solution (10 mL) and brine (10 mL). Finally,
the organic solution was dried (MgSO4), filtrated and con-
centrated under reduced pressure. The resulting acetamide 22
(74 mg, 99% for two steps) was practically pure according to its
NMR spectra and did not require further purification.
CDCl ) 202.9 (C-7), 162.2 (C᎐O), 158.9, 141.4, 129.9, 128.4,
᎐
3
113.8, 113.7, 109.5 (C(CH3)2), 102.5 (C(CH3)2), 98.7 (C-11),
95.8 (C-1), 94.6, 84.3, 82.6 (C-8, C-9, C-10), 74.3, 73.3, 69.2
(C-3, C-4, C-5), 63.1 (–OCH2–), 60.8 (C-2), 55.1 (–OCH3), 54.9
(–OCH3), 43.5 (–NCH2–), 39.3 (C-6), 28.2 (C(CH3)2), 26.5
(C(CH3)2), 25.5 (C(CH3)2), 24.8 (C(CH3)2); FAB (NBA) m/z
750.2990, M ϩ Hϩ calcd for C37H43N5O12: 750.2986.
3-(4-Methoxybenzyl)-1-[p-methoxybenzyl (11R)-2-azido-
2,6-dideoxy-3,4:9,10-di-O-isopropylidene-L-allo-ꢀ-D-galacto-
undecodialdo-1,5-pyranoside-11,8-furanosyl]uracil 25a and
–L-altro-ꢀ-D-galacto-undecodialdo-1,5-pyranoside-
11,8-furanosyl]uracil 25b. Reduction of ketone 24
A solution of ketone 24 (20 mg, 0.026 mmol, 1.0 equiv.) in
MeOH (2 mL) was treated with NaBH4 (4.8 mg, 0.13 mmol,
5.0 equiv.) at 0 ЊC for 15 min. The solution was diluted with
Et2O (5 mL) and then saturated aqueous NH4Cl solution
(5 mL) was carefully added. The aqueous solution was
extracted with Et2O (2 × 5 mL) and the combined organic
phase was washed with brine (5 mL), dried over MgSO4 and
concentrated under reduced pressure. Purification by flash
column chromatography (silica gel, 66% EtOAc in hexanes)
gave alcohols 25a/b (18 mg, 92%) as an inseparable mixture in
a 8 : 1 proportion: Rf = 0.30 (silica gel, 20% EtOAc in hexanes);
δH (400 MHz, CDCl3) (major isomer) 7.49 (2H, d, J = 8.7,
p-CH2C6H4OCH3), 7.38 (2H, d, J = 8.6, p-CH2C6H4OCH3),
p-Methoxybenzyl 6-(N-nitroso)-acetamido-2-azido-2,6-dideoxy-
3,4-O-isopropylidene-ꢀ-D-galactopyranoside 23. Treatment of
acetamide 22 with sodium nitrite
N-nitroso acetamide 23 was prepared from acetamide 22 (74 mg,
0.182 mmol, 1.0 equiv.) by treatment with sodium nitrite and
acetic acid according to the same procedure described above
for the preparation of 13, to obtain pure N-nitroso 23 (65 mg,
82%) as a pale yellow solid: Rf = 0.57 (silica gel, 50% EtOAc in
hexanes); δH (400 MHz, CDCl3) 7.11 (2H, d, J = 8.6, p-CH2C6-
H4OCH3), 6.81 (2H, d, J = 8.6, p-CH2C6H4OCH3), 4.75 (1H, d,
J = 3.4, H–C(1)), 4.44 (1H, dd, J = 13.9 and 9.2 Hz, CH2-
7.23 (1H, d, J = 8.0, CH᎐CH), 6.82 (2H, d, J = 8.6, p-CH -
᎐
2
C6H4OCH3), 6.76 (2H, d, J = 8.7, p-CH2C6H4OCH3), 5.77 (1H,
d, J = 3.3, H–C(11)), 5.72 (1H, d, J = 8.0, CH᎐CH ), 5.32 (1H, d,
᎐
J = 3.1, H–C(10)), 5.07 (1H, d, J = 13.7, p-CH2C6H4OCH3),
4.96 (1H, bs, CH), 4.93 (1H, d, J = 13.7, p-CH2C6H4OCH3),
4.88–4.84 (2H, m), 4.78 (1H, dd, J = 6.5 and 3.3, H–C(9)), 4.58
(1H, d, J = 11.7, p-CH2C6H4OCH3), 4.46 (1H, d, J = 11.7,
p-CH2C6H4OCH3), 4.33 (1H, dd, J = 8.7 and 5.2, H–C(3)),
4.08–4.04 (1H, m), 3.91–3.87 (1H, m), 3.75 (3H, s, –OCH3),
3.69 (3H, s, –OCH3), 3.26 (1H, dd, J = 8.8 and 3.3, H–C(2)),
1.89–1.95 (1H, m, CH2CH(OH)), 1.64 (1H, ddd, J = 12.8,
7.4 and 3.8, CH2CH(OH)), 1.53, 1.51, 1.31 and 1.29 (12H, 4 s,
2 × C(CH3)2); δC (100 MHz, CDCl3) (major isomer) 162.4
N(N᎐O)Ac), 4.32 (1H, d, J = 11.3, p-CH C H OCH ), 4.27
᎐
2
6
4
3
(1H, dd, J = 8.6 and 5.3, H–C(3)), 4.23 (1H, d, J = 11.3,
p-CH2C6H4OCH3), 4.06 (1H, dd, J = 5.3 and 2.5, H–C(4)), 4.01
(1H, ddd, J = 9.2, 3.3 and 2.8, H–C(5)), 3.75 (3H, s, –OCH3),
3.72 (1H, dd, J = 13.9 and 3.3, CH N(N᎐O)Ac), 3.25 (1H, dd,
᎐
2
J = 8.6 and 3.4, H–C(2)), 2.75 (3H, s, –N(N᎐O)COCH ), 1.46
᎐
3
and 1.29 (6H, 2 s, C(CH ) ); δ (100 MHz, CDCl ) 169.5 (C᎐O),
᎐
3
2
C
3
129.7, 113.8, 109.9 (C(CH3)2), 96.1 (C-1), 73.4, 72.9, 69.4 (C-3,
C-4, C-5), 64.4 (–OCH2–), 60.6 (C-2), 55.1 (–OCH3), 38.5 (C-6),
28.1 (C(CH3)2), 26.1 (C(CH3)2), 22.4 (C(O)CH3); FAB (NBA)
m/z 436.1840, M ϩ Hϩ calcd for C19H25N5O7: 436.1832.
(C᎐O), 159.5, 139.5, 130.9, 130.7, 129.6, 113.8, 113.7, 110.8
᎐
(C(CH3)2), 102.3 (C(CH3)2), 96.4 (C-11), 94.2 (C-1), 88.1, 83.7,
80.8 (C-8, C-9, C-10), 75.6, 74.3, 73.2, 70.1, 69.8 (C-3, C-4, C-5,
C-7), 66.9 (–OCH2–), 60.8 (C-2), 55.1 (–OCH3), 55.0 (–OCH3),
43.5 (–NCH2–), 33.7 (C-6), 28.2 (C(CH3)2), 27.2 (C(CH3)2),
25.4 (C(CH3)2), 24.8 (C(CH3)2); FAB (NBA) m/z 752.3139,
M ϩ Hϩ calcd for C37H45N5O12: 752.3143.
3-(4-Methoxybenzyl)-1-[p-methoxybenzyl (11R)-2-azido-
2,6-dideoxy-3,4:9,10-di-O-isopropylidene-7-keto-L-ribo-ꢀ-D-
galacto-undecodialdo-1,5-pyranoside-11,8-furanosyl]uracil 24.
Reaction of aldehyde 4 with diazo derived from 23
1-(2,3-O-Isopropylidene-5-O-p-toluenesulfonyl-ꢁ-D-
ribofuranosyl)-3-(4-methoxybenzyl)uracil 27. Tosylation of
alcohol 26
A solution of diazo derived from N-nitroso acetamide 23
(20 mg, 0.046 mmol, 1.1 equiv.), prepared in exactly the same
way as described above for 13, in Et2O (5 mL) was reacted with
aldehyde 4 (17 mg, 0.042 mmol, 1.0 equiv.) according to the
Tosylate 27 (0.86 g, 88%) was prepared from alcohol 26 (0.71 g,
1.75 mmol) according to the procedure described above for 10.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
3723

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19: white solid; Rf = 0.27 (silica gel, 25% EtOAc in hexanes);
νmax/cmϪ1 (thin film) 3060 (m, CH), 2978 (s, CH), 2884 (m, CH),
N-nitroso 30 (281 mg, 76%) as a pale yellow solid: Rf = 0.56
(silica gel, 25% EtOAc in hexanes); [α]22 ϩ76.3 (c 0.6 in
D
1719 (s, C᎐O), 1666 (s, C᎐O), 1507 (s), 1455 (s), 1367 (s),
CH2Cl2); δH (400 MHz, CDCl3) 7.41 (2H, d, J = 8.5,
᎐
᎐
1255 (s), 1108 (s) and 979 (s); δH (400 MHz, CDCl3) 7.71
(2H, d, J = 8.3, p-OSO2C6H4CH3), 7.40 (2H, d, J = 8.3,
p-OSO2C6H4CH3), 7.27 (2H, d, J = 8.7, p-CH2C6H4OCH3),
p-CH C H OCH ), 7.05 (1H, d, J = 8.0, CH᎐CH), 6.78 (2H, d,
᎐
2 6 4 3
J = 8.5, p-CH C H OCH ), 5.76 (1H, d, J = 8.0, CH᎐CH ), 5.36
᎐
2
6
4
3
(1H, bs, H–C(1)), 5.08 (1H, d, J = 13.5, p-CH2C6H4OCH3), 5.05
(1H, bs, H–C(2)), 5.02 (1H, d, J = 13.5, p-CH2C6H4OCH3), 4.77
(1H, dd, J = 6.3 and 3.5, H–C(3)), 4.21 (1H, dd, J = 13.4 and
7.11 (1H, d, J = 8.1, CH᎐CH), 6.79 (2H, d, J = 8.7,
᎐
p-CH C H OCH ), 5.70 (1H, d, J = 8.1, CH᎐CH ), 5.60 (1H,
᎐
2
6
4
3
bs, H–C(1)), 5.00 (1H, d, J = 13.6, p-CH2C6H4OCH3), 4.90
(1H, d, J = 13.6, p-CH2C6H4OCH3), 4.85 (1H, ddd, J = 6.4
and 1.8, H–C(4)), 4.78 (1H, dd, J = 6.4 and 3.5, H–C(3)),
4.33–4.30 (1H, m), 4.26–4.22 (2H, m), 3.76 (3H, s, –OCH3),
2.41 (3H, s, p-OSO2C6H4CH3), 1.51 and 1.31 (6H, 2 s,
8.2, CH N(N᎐O)Ac), 4.06 (1H, ddd, J = 8.4, 4.9 and 3.5,
᎐
2
H–C(4)), 3.95 (1H, dd, J = 13.4 and 4.9, CH N(N᎐O)Ac), 3.74
᎐
2
(3H, s, –OCH ), 2.71 (3H, s, N(N᎐O)COCH ), 1.46 and 1.29
᎐
3
3
(6H, 2 s, C(CH ) ); δ (100 MHz, CDCl ) 174.3 (C᎐O), 162.5
᎐
3
2
C
3
(C᎐O), 159.0, 150.8, 140.8, 130.5, 128.7, 114.2, 113.6, 102.5
᎐
C(CH3)2); δC (100 MHz, CDCl ) 162.3 (C᎐O), 159.2, 150.6,
(C(CH3)2), 96.8 (C-1), 84.6, 84.4, 82.7 (C-2, C-3, C-4), 55.2
(–OCH3), 43.6 (–NCH2–), 40.1 (C-5), 26.9 (C(CH3)2), 25.2
(C(CH3)2), 22.5 (–COCH3); FAB (NBA) m/z 497.1639,
M ϩ Naϩ calcd for C22H26N4O8: 497.1648.
᎐
3
145.2, 139.6, 132.6, 130.8, 129.9, 128.6, 127.9, 114.5,
113.7, 102.3 (C(CH3)2), 95.5 (C-1), 84.9, 84.5, 80.9 (C-2,
C-3, C-4), 69.2 (C-5), 55.2 (–OCH3), 43.5 (–NCH2–), 27.0
(C(CH3)2), 25.2 (C(CH3)2), 21.6 (–CH3); MALDI-FTMS
(NBA) m/z 581.1568, M ϩ Naϩ calcd for C27H30N2O9S:
581.1564.
p-Methoxybenzyl 2-azido-2-deoxy-3,4-O-isopropylidene-ꢁ-D-
galacto-hexonodialdo-1,5-pyranoside 31. Oxidation of alcohol
ꢁ-18
1-(5-Azido-5-deoxy-2,3-O-isopropylidene-ꢁ-D-ribofuranosyl)-3-
(4-methoxybenzyl)uracil 28. Reaction of tosylate 27 with sodium
azide
To a solution of alcohol β-18 (244 mg, 0.67 mmol, 1.0 equiv.)
in CH2Cl2 (5 mL) was added Dess–Martin periodinane
(566 mg, 1.33 mmol, 2.0 equiv.) in one portion at 25 ЊC.
After stirring at this temperature for 1 h, the crude mixture
was then poured into saturated aqueous NaHCO3 solution
(20 mL), diluted with Et2O (20 mL) and the layers were
separated. The aqueous solution was extracted with Et2O
(2 × 20 mL) and the combined organic extracts were washed
with brine (40 mL), dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (silica gel,
20% EtOAc in hexanes) provided aldehyde 31 (230 mg, 94%) as
a colorless oil.
To a solution of tosylate 27 (0.85 g, 1.53 mmol, 1.0 equiv.) in
DMF (5 mL) was added NaN3 (2.9 g, 45.81 mmol, 30.0 equiv.)
in one portion at 25 ЊC. The reaction mixture was heated at
50 ЊC for 3 days. There was no detection after this time of the
starting tosylate by TLC. The crude mixture was then poured
into saturated aqueous NH4Cl solution (20 mL), diluted with
Et2O (20 mL) and the layers separated. The aqueous solution
was extracted with Et2O (2 × 20 mL) and the combined organic
extracts were washed with brine (40 mL), dried (MgSO4) and
concentrated in vacuo. Purification by flash column chromato-
graphy (silica gel, 20% EtOAc in hexanes) provided azide 28
(0.51 g, 77%) as a colorless oil: Rf = 0.35 (silica gel, 25% EtOAc
in hexanes); νmax/cmϪ1 (thin film) 3084 (w, CH), 2955 (m, CH),
3-(4-Methoxybenzyl)-1-[p-methoxybenzyl (11R)-2-azido-
2,7-dideoxy-3,4:9,10-di-O-isopropylidene-6-keto-L-ribo-ꢁ-D-
galacto-undecodialdo-1,5-pyranoside-11,8-furanosyl]uracil 32.
Reaction of aldehyde 31 with diazo derived from 30
2096 (s, N ), 1707 (s, C᎐O), 1666 (s, C᎐O), 1507 (s), 1455 (s),
᎐
᎐
3
1384 (s), 1343 (s), 1255 (s), 1085 (s) and 908 (s); δH (400 MHz,
CDCl3) 7.38 (2H, d, J = 8.8, p-CH2C6H4OCH3), 7.20 (1H, d,
A solution of diazo derived from N-nitroso acetamide 30
(225 mg, 0.474 mmol, 1.01 equiv.), prepared under the same
conditions as the diazo derived from 13, in Et2O (5 mL) was
reacted with aldehyde 31 (170 mg, 0.468 mmol, 1.0 equiv.)
according to the same procedure as for the preparation of 14, to
afford ketone 32 (210 mg, 60%) as a white solid: Rf = 0.40 (silica
J = 8.0, CH᎐CH), 6.80 (2H, d, J = 8.8, p-CH C H OCH ), 5.75
᎐
2
6
4
3
(1H, d, J = 8.0, CH᎐CH ), 5.63 (1H, d, J = 1.8, H–C(1)), 5.00
᎐
(2H, s, p-CH2C6H4OCH3), 4.94 (1H, dd, J = 6.3 and 1.8,
H–C(2)), 4.78 (1H, dd, J = 6.6 and 4.0, H–C(3)), 4.20 (1H, q,
J = 4.0, H–C(4)), 3.77 (3H, s, –OCH3), 3.55 (2H, bs, CH2N3),
1.56 and 1.32 (6H, 2 s, C(CH3)2); δC (100 MHz, CDCl3) 162.3
gel, 20% EtOAc in hexanes); [α]22 ϩ3.5 (c 1.0 in CH2Cl2);
D
δH (400 MHz, CDCl3) 7.36 (2H, d, J = 8.6, p-CH2C6H4OCH3),
7.24 (2H, d, J = 8.7, p-CH2C6H4OCH3), 7.21 (1H, d, J = 8.0,
(C᎐O), 159.1, 150.6, 139.8, 130.5, 114.6, 113.7, 102.4 (C(CH ) ),
᎐
3
2
95.3 (C-1), 85.7, 84.5, 81.4 (C-2, C-3, C-4), 55.2 (–OCH3), 52.3
(C-5), 43.5 (–NCH2–), 27.1 (C(CH3)2), 25.2 (C(CH3)2);
MALDI-FTMS (NBA) m/z 452.1540, M ϩ Naϩ calcd for
C20H23N5O6: 452.1546.
CH᎐CH), 6.82 (2H, d, J = 8.6, p-CH C H OCH ), 6.75 (2H,
᎐
2
6
4
3
d, J = 8.7, p-CH C H OCH ), 5.72 (1H, d, J = 8.0, CH᎐CH ),
᎐
2
4
3
5.71 (1H, d, J =6 3.7, H–C(11)), 4.98 (1H, d, J = 13.7,
p-CH2C6H4OCH3), 4.93 (1H, d, J = 13.8, p-CH2C6H4OCH3),
4.90 (1H, dd, J = 6.8 and 3.2, H–C(9)), 4.81 (1H, d, J = 11.6,
p-CH2C6H4OCH3), 4.73 (1H, dd, J = 6.6 and 3.6, H–C(10)),
4.59 (1H, d, J = 11.6, p-CH2C6H4OCH3), 4.45 (1H, ddd,
J = 5.0, H–C(8)), 4.23 (1H, dd, J = 5.3 and 2.5, H–C(4)), 4.18
(1H, d, J = 8.4, H–C(1)), 3.99 (1H, d, J = 2.5, H–C(5)),
3.86 (1H, dd, J = 7.7 and 5.4, H–C(3)), 3.73 (3H, s, –OCH3),
3.68 (3H, s, –OCH3), 3.42 (1H, dd, J = 8.4 and 8.1, H–C(2)),
3.17 (1H, dd, J = 18.7 and 4.9, H–C(7)), 3.02 (1H, dd, J = 18.7
and 5.7, HЈ–C(7)), 1.53, 1.43, 1.29 and 1.23 (12H, 4 s,
2 × C(CH3)2); δC (100 MHz, CDCl3) 204.2 (C-6), 163.8
1-(5-Acetamido-5-deoxy-2,3-O-isopropylidene-ꢁ-D-
ribofuranosyl)-3-(4-methoxybenzyl)uracil 29. Reduction of azide
28 and acetylation
The treatment of azide 28 (505 mg, 1.17 mmol, 1.0 equiv.) with
Ph3P (460 mg, 1.75 mmol, 1.5 equiv.) and subsequent acetyl-
ation with acetic anhydride were carried out exactly as described
above for 12 and yielded acetamide 29 (440 mg, 84%) which was
used for the next step without purification.
(C᎐O), 159.6, 158.9, 150.7, 139.5, 130.6, 129.8, 129.7, 128.7,
᎐
1-(5-(N-Nitroso)-acetamido-5-deoxy-2,3-O-isopropylidene-ꢁ-D-
ribofuranosyl)-3-(4-methoxybenzyl)uracil 30. Treatment of
acetamide 29 with sodium nitrite
128.4, 113.9, 113.7, 110.8 (C(CH3)2), 102.4 (C(CH3)2), 99.6
(C-1), 93.8 (C-11), 84.4, 83.2, 81.8 (C-8, C-9, C-10), 77.9,
77.0, 73.1, (C-3, C-4, C-5), 70.8 (C-2), 64.5 (–OCH2–), 55.2
(–OCH3), 55.1 (–OCH3), 43.6 (–NCH2–), 42.3 (C-7), 28.1
(C(CH3)2), 27.2 (C(CH3)2), 25.9 (C(CH3)2), 25.1 (C(CH3)2);
FAB (NBA) m/z 772.2789, M ϩ Naϩ calcd for C37H43N5O12:
772.2806.
N-Nitroso acetamide 30 was prepared from acetamide 29
(350 mg, 0.78 mmol, 1.0 equiv.) by treatment with sodium
nitrite and acetic acid according to the same procedure as
described above for the preparation of 13, to obtain pure
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
3724

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Trends Biochem. Sci., 1980, 65; (c) M. J. Morin and R. Bernacki,
3-(4-Methoxybenzyl)-1-[p-methoxybenzyl (11R)-2-azido-2,7-
dideoxy-3,4:9,10-di-O-isopropylidene-L-ribo-D-glycero-ꢁ-D-
galacto-undecodialdo-1,5-pyranoside-11,8-furanosyl]uracil 33a
and L-ribo-L-glycero-ꢁ-D-galacto-undecodialdo-1,5-pyranoside-
11,8-furanosyl]uracil 33b. Reduction of ketone 32
J. Cancer Res., 1983, 43, 1669.
4 For an extensive review: K.-i. Kimura and T. D. H. Bugg, Nat. Prod.
Rep., 2003, 20, 252–273.
5 (a) G. Tamura, T. Sasaki, M. Matsuhashi, A. Takatsuki and
M. Yamasaki, Agric. Biol. Chem., 1976, 40, 447–449; (b) P. E.
Brandish, K.-I. Kimura, M. Inukai, R. Southgate, J. T. Lonsdale
and T. D. H. Bugg, Antimicrob. Agents Chemother., 1996, 40,
1640–1644.
6 (a) A. Heifetz, R. W. Keenan and A. D. Elbein, Biochemistry, 1979,
18, 2186–2192; (b) G. Tamura and A. Takatsuki, Proc. Jpn. Acad.,
1980, 56, 251.
7 P. Paul, T. M. Lutz, C. Osborn, S. Kyosseva, A. D. Elbein,
H. Towbin, A. Radominska and R. R. Drake, J. Biol. Chem., 1993,
268, 12933–12938.
8 (a) R. A. Dwek, Chem. Rev., 1996, 96, 683–720; (b) E. E. Simanek,
G. L. McGarvey, J. A. Jablonowski and C.-H. Wong, Chem. Rev.,
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Ed., 1999, 38, 2300–2324.
9 R. Wang, D. H. Steensma, Y. Takaoka, J. W. Yun, T. Kajimoto and
C.-H. Wong, Bioorg. Med. Chem., 1997, 5, 661–672.
10 (a) A. Takatsuki, K. Kawamura, Y. Kodama, T. Ito and G. Tamura,
Agric. Biol. Chem., 1979, 43, 761; (b) T. Ito, Y. Kodama,
K. Kawamura, K. Suzuki, A. Takatsuki and G. Tamura, Agric. Biol.
Chem., 1979, 43, 1187.
11 (a) K. Eckhardt, W. Ihn, D. Tresselt and D. Krebs, J. Antibiot., 1981,
34, 1631; (b) K. Eckhardt, J. Nat. Prod., 1983, 46, 544.
12 J. A. Edgar, J. L. Frahn, P. A. Cockrum, N. Anderton, M. V. Jago,
C. C. J. Culvenor, A. J. Jones, K. Murray and K. J. Shaw, J. Chem.
Soc., Chem. Commun., 1982, 222.
13 T. Suami, H. Sasai, K. Matsuno, N. Suzuki, Y. Fukuda and
O. Sakanaka, Tetrahedron Lett., 1984, 25, 4533–4536.
14 S. J. Danishefsky, S. L. DeNinno, S.-h. Chen, L. Boisvert and
M. Barbachyn, J. Am. Chem. Soc., 1989, 111, 5810–5818.
15 A. G. Myers, D. Y. Gin and D. H. Rogers, J. Am. Chem. Soc., 1993,
115, 2036.
Alcohol 33 was prepared from ketone 32 (80 mg, 0.107 mmol,
1.0 equiv.) by treatment with sodium borohydride according
to the same procedure as described above for the preparation
of 25, to obtain alcohol 33 (79 mg, 98%) as a white solid: Rf =
0.39 (silica gel, 50% EtOAc in hexanes); δH (400 MHz, CDCl3)
7.34 (2H, d, J = 8.7, p-CH2C6H4OCH3), 7.23 (2H, d, J = 8.5,
p-CH C H OCH ), 7.15 (1H, d, J = 8.0, CH᎐CH), 6.83 (2H, d,
᎐
2
6
4
3
J = 8.5, p-CH2C6H4OCH3), 6.75 (2H, d, J = 8.7, p-CH2C6H4-
OCH ), 5.71 (1H, d, J = 8.0, CH᎐CH ), 5.60 (1H, d, J = 2.5,
᎐
3
H–C(11)), 4.97 (1H, d, J = 13.6, p-CH2C6H4OCH3), 4.92 (1H, d,
J = 13.6, p-CH2C6H4OCH3), 4.86 (1H, dd, J = 6.6 and 2.5,
H–C(10)), 4.78 (1H, d, J = 11.7, p-CH2C6H4OCH3), 4.75 (1H,
dd, J = 6.8 and 4.6, H–C(9)), 4.59 (1H, d, J = 11.7, p-CH2C6H4-
OCH3), 4.27 (1H, ddd, J = 6.4 and 6.2, H–C(8)), 4.18 (1H, d,
J = 8.5, H–C(1)), 4.15–4.12 (1H, m, H–C(6)), 3.98 (1H, dd,
J = 5.3 and 2.1, H–C(4)), 3.81 (1H, dd, J = 8.0 and 5.4, H–C(3)),
3.74 (3H, s, –OCH3), 3.69 (3H, s, –OCH3), 3.45 (1H, dd, J = 5.9
and 2.0, H–C(5)), 3.37 (1H, dd, J = 8.5 and 8.2, H–C(2)), 2.90
(1H, s, OH), 1.98–1.94 (1H, m, H–C(7)), 1.83–1.76 (1H, m,
HЈ–C(7)), 1.52, 1.47, 1.29 and 1.26 (12H, 4 s, 2 × C(CH3)2);
δ (100 MHz, CDCl ) 162.4 (C᎐O), 159.5, 159.1, 150.6, 139.7,
᎐
C
3
130.5, 129.7, 128.7, 113.9, 113.7, 110.8 (C(CH3)2), 102.4
(C(CH3)2), 99.8 (C-1), 94.5 (C-11), 84.1, 84.0, 83.8 (C-8, C-9,
C-10), 77.5, 74.9, 73.2, 70.7 (C-3, C-4, C-5, C-6), 68.6 (C-2),
64.8 (–OCH2–), 55.2 (–OCH3), 55.1 (–OCH3), 43.5 (–NCH2–),
35.0 (C-7), 28.1 (C(CH3)2), 27.2 (C(CH3)2), 26.1 (C(CH3)2),
25.3 (C(CH3)2); FAB (NBA) m/z 774.2945, M ϩ Naϩ calcd for
C37H45N5O12: 774.2962.
16 (a) J. A. Secrist III and S.-R. Wu, J. Org. Chem., 1979, 44, 1434–
1438; (b) S. Danishefsky and M. Barbachyn, J. Am. Chem. Soc.,
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17 F. Sarabia-García, F. J. López-Herrera and M. S. Pino-González,
Tetrahedron, 1995, 51, 5491–5500.
18 F. Sarabia-García and F. J. López-Herrera, Tetrahedron, 1996, 52,
4757–4768.
Acknowledgements
This work was financially supported by Fundación Ramón
Areces and the Dirección General de Investigación (Ministerio
de Ciencia y Tecnología, ref. BQU2001-1576). L. M. O. thanks
the Dirección General de Universidades e Investigación (Junta de
Andalucía) for a scholarship. We thank Dr J. I. Trujillo from
Pharmacia (St. Louis, MI) for assistance in the preparation of
this manuscript. We thank Unidad de Espectroscopía de Masas
de la Universidad de Sevilla for exact mass spectroscopic
assistance.
19 R. U. Lemieux and R. M. Ratcliffe, Can. J. Chem., 1979, 57,
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25 K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa and O. Yonemitsu,
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References and notes
1 (a) A. Takatsuki, K. Arima and G. Tamura, J. Antibiot., 1971, 24,
215; (b) T. Ito, Y. Kodama, K. Kawamura, K. Suzuki, A. Takatsuki
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Chem., 1980, 44, 695.
2 (a) S. Knapp, Chem. Rev., 1995, 95, 1859–1876; (b) G. Tamura, in
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3 (a) T. Ito, A. Takatsuki, K. Kawamura, K. Saito and G. Tamura,
Agric. Biol. Chem., 1980, 44, 695; (b) R. T. Schwartz and R. Datema,
26 C. A. Gentle, S. A. Harrison, M. Inukai and T. D. H. Bugg, J. Chem.
Soc., Perkin Trans. 1, 1999, 1287–1294.
27 (a) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155;
(b) D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 1 6 – 3 7 2 5
3725