TCP- and phthalimide-protected n-pentenyl glucosaminide precursors for the synthesis of nodulation factors as illustrated by the total synthesis of nodRf-III (C18:1, MeFuc)

Article abstract of DOI:10.1021/jo962362o

TCP- and phthalimide-protected n-pentenyl glucosaminide (NPG) precursors have been utilized in a convergent stereocontrolled synthesis of the nodulation factor NodRf-III (C18:1, MeFuc) produced by Rhizobium fredii USDA257, 2. Nodulation factors are lipool

Full text of DOI:10.1021/jo962362o

J . Org. Chem. 1997, 62, 4591-4600
4591
TCP - a n d P h th a lim id e-P r otected n -P en ten yl Glu cosa m in id e
P r ecu r sor s for th e Syn th esis of Nod u la tion F a ctor s As Illu str a ted
by th e Tota l Syn th esis of Nod Rf-III (C18:1, MeF u c)
J ohn S. Debenham,,† Robert Rodebaugh,† and Bert Fraser-Reid*,‡
Paul M. Gross Chemical Laboratory, Department of Chemistry, Duke University,
Durham, North Carolina 27708, and Natural Products and Glycotechnology Research Institute,
4118 Swarthmore Road, Durham, North Carolina 27707
Received December 17, 1996X
TCP- and phthalimide-protected n-pentenyl glucosaminide (NPG) precursors have been utilized in
a convergent stereocontrolled synthesis of the nodulation factor NodRf-III (C18:1, MeFuc) produced
by Rhizobium fredii USDA257, 2. Nodulation factors are lipooligosaccharides that are secreted by
bacteria which trigger the early steps in the formation of root nodules in leguminous plants. This
symbiotic relationship between plant and bacteria plays a major role in the global nitrogen cycle.
Key to our synthetic approach was the use of the TCP (tetrachlorophthaloyl) group to provide for
N-differentiation of the linear glucosamine backbone and the use of FeCl3 for the removal of benzyl
protecting groups from the tetrasaccharide. The saccharide skeleton was assembled via the NPG-
based coupling of a linear â(1f4) glucosamine disaccharide to a 6-O-fucosylated glucosamine
acceptor. Significant yield enhancements for NPG couplings were observed at lower temperatures.
Subsequent exchange of benzyl to tert-butyldimethylsilyl protecting groups via FeCl3 mediation
and installation of the fatty chain on the nonreducing terminus via selective removal of TCP led to
a late intermediate which was deprotected in high yield to afford the natural product.
In tr od u ction
while ensuring that the assembly occurs with 1,2-trans-
glycosidic linkages, and both can be accomplished by the
use of a tetrachlorophthaloyl (TCP)4,7 protected glucos-
amine in the presence of other phthalimide-protected
amino sugars.
A symbiotic relationship exists between bacteria of the
genera Rhizobium, Bradyrhizobium, and Azorhizobium
and leguminous plants which fix atmospheric nitrogen
into a metabolizable form. So important is this relation-
ship that it is estimated that leguminous root nodules
account for the production of as much metabolizable
nitrogen per year as do industrial sources. Root nodules
can therefore be considered the largest source of organic
nitrogen in the global nitrogen cycle.1 In order for this
process to occur, the soil bacteria secrete a lipochitooli-
gosaccharide, called a nodulation factor, which initiates
the early steps in formation of a root nodule that
eventually provides a home for the nitrogen-fixing bac-
teria.
Nodulation factors, 1, are composed primarily of a
linear glucosamine (2-amino-2-deoxy-D-glucose) backbone
which is N-acylated with acetic and fatty acid residues
(Figure 1), the latter residing at the nonreducing termi-
nus.2 Their agricultural and ecological value have made
them important targets of laboratory synthesis.3 Key
requirements are (a) the need to differentiate between
the constituent glucosamines and (b) ready oligosaccha-
ride assembly. Both of these themes resonate with
current interests in our laboratory on amine protection4,5
and glycosyl donors.6 Requirements a and b must be met
n-Pentenyl glycosides (NPGs)6 are glycosyl donors that
are able to survive many protecting group and other
chemical manipulations, yet be ready for immediate
activation with N-iodosuccinimide/triethylsilyl trifluo-
romethanesulfonate (NIS/TESOTf) (Figure 2). An ad-
ditional advantage for larger nod factors, e.g., 1, n ) 2,
3, etc., is that the repeating glucosamine unit can be
prepared in bulk as 8b and divided into portions which
can be utilized directly as glycosyl donors or be “side-
tracked” by bromination,8 as in 5, to serve as glycosyl
acceptors. These unique properties of NPGs have facili-
tated the preparation of a diverse array of naturally
occurring oligosaccharides.9 Herein we give full details10
of our strategy for the construction of the N-differentiated
nodulation factor backbone through the synthesis of
NodRf-III (C18:1, MeFuc),11 2, produced by Rhizobium
fredii USDA257, which requires 11 synthetic operations,
(4) (a) Debenham, J . S.; Madsen, R.; Roberts, C.; Fraser-Reid, B. J .
Am. Chem. Soc. 1995, 117, 3302-3303. (b) Debenham, J . S.; Fraser-
Reid, B. J . Org. Chem. 1996, 61, 432-433.
(5) For applications of the N-pentenoyl group in amine protection,
see: Madsen, R.; Roberts, C.; Fraser-Reid, B. J . Org. Chem. 1995, 60,
7920-7926.
(6) (a) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.; Merritt,
J . R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927-942. (b)
Madsen, R.; Fraser-Reid, B. In Modern Methods in Carbohydrate
Synthesis; Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic
Publishers: Amsterdam, 1996; pp 155-170.
(7) Castro-Palomino, J . C.; Schmidt, R. R Tetrahedron Lett. 1995,
36, 5343-5346.
(8) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J . Org.
Chem. 1990, 55, 6068-6070.
(9) (a) Udodong, U. E.; Madsen, R.; Roberts, C.; Fraser-Reid, B. J .
Am. Chem. Soc. 1993, 115, 7886-7887. (b) Merritt, J . R.; Naisang, E.;
Fraser-Reid, B. J . Org. Chem. 1994, 59, 4443-4449.
(10) Debenham, J . S.; Rodebaugh, R.; Fraser-Reid, B. J . Org. Chem.
1996, 61, 6478-6479.
† Duke University.
‡ Natural Products and Glycotechnology Research Institute.
X Abstract published in Advance ACS Abstracts, J une 15, 1997.
(1) (a) Denarie, J .; Cullimore, J . Cell 1993, 74, 951-954. (b) Nap,
J . P.; Bisseling, T. Science 1990, 250, 948-954. (c) Long, S. R. Cell
1989, 56, 203-214.
(2) For a recent review, see: Lerouge, P. Glycobiology 1994, 4, 127-
134.
(3) For related synthetic efforts, see: (a) Nicolaou, K. C.; Bockovich,
N. J .; Carcanague, D. R.; Hummel, C. W.; Even, L. F. J . Am. Chem.
Soc. 1992, 114, 8701-8702. (b) Wang, L. X.; Li, C.; Wang, Q. W.; Hui,
Y. Z. J . Chem. Soc., Perkin Trans. 1 1994, 621-628. (c) Tailler, D.;
J acquinet, J . C.; Beau, J . M. J . Chem. Soc., Chem. Commun. 1994,
1827-1828. (d) Ikeshita, S.; Sakamoto, A.; Nakahara, Y.; Nakahara,
Y.; Ogawa, T. Tetrahedron Lett. 1994, 35, 3123-3126. (e) Ikeshita, S.;
Nakahara, Y.; Ogawa, T. Glycoconjugate J . 1994, 11, 257-261.
S0022-3263(96)02362-6 CCC: $14.00 © 1997 American Chemical Society

4592 J . Org. Chem., Vol. 62, No. 14, 1997
Debenham et al.
F igu r e 1.
Sch em e 1
F igu r e 2.
most of them being chemoselective, for obtaining the fully
deprotected nod factor from the constituent monosaccha-
rides.
Discu ssion
The logical disconnection of 3 (n ) 1) into two disac-
charides facilitated a strategy involving convergent cou-
pling to give a late stage key tetrasaccharide interme-
diate, installing the fatty acid residue thereon, and then
deprotecting to generate 2. With this aim the nonreduc-
ing end disaccharide was made of monosaccharides
prepared from D-glucosamine hydrochloride (Scheme 1),
while the reducing end disaccharide was prepared from
L-fucose and D-glucosamine hydrochloride (Scheme 2). In
the construction of the former, the procedure of Lemieux
and co-workers12 was adapted for preparing the phthal-
imides 16a and 16b, and a Koenigs-Knorr reaction was
used for converting them into the corresponding n-
pentenyl glycosides 17a and 17b. Benzylidination fol-
lowed by chemoselective Garegg13 reductive cleavage lead
to alcohols 8a and 8b. The TCP-containing donor was
generated through acetylation to afford 4. In the case of
the acceptor residue, standard bromination with Br2 and
Et4NBr would be undesirable, since our previous experi-
ence has shown that NPG glucosamine species dibromi-
nated poorly.14 Substantial hydrolysis of the pentenyl
glycosidic group turned out to be the major reaction
course, and efforts to counteract this trend were not
availing. That glucosamine derivatives should be so
reactive to hydrolysis during dibromination was unfor-
tunate, since the analogous glucose and mannose deriva-
tives could be consistently dibrominated in 80-90%
(11) (a) Bec-Ferte´, M. P.; Savagnac, A.; Pueppke, S. G.; Prome´, J .
C. In New Horizons in Nitrogen Fixation; Proceedings of the 9th
International Congress on Nitrogen Fixation Palacios, R., Mora, J .,
Newton, W. E., Eds.; Kluwer Academic Publishers: Dordrecht, 1992,
pp 157-158. (b) Bec-Ferte´, M. P.; Krishnan, H. B.; Prome´, D.;
Savagnac, A.; Pueppke, S. G.; Prome´, J . C. Biochemistry 1994, 33,
11782-11788.
(12) Lemieux, R.; Takeda, T.; Chung, B. In Synthetic Methods for
Carbohydrates, American Chemical Society: El Khadem, H. S., Ed.;
American Chemical Society: Washington, DC, 1976; ACS Symposium
Series 39, pp 90-115.
(13) (a) Garegg, P. J .; Hultberg, H. Carbohydr. Res. 1981, 93, c10-
c11. (b) Garegg, P. J .; Hultberg, H.; Wallen, S. Carbohydr. Res. 1982,
108, 97-101.
(14) (a) Fraser-Reid, B.; Merritt, J . R.; Handlon, A. L.; Andrews, C.
W. Pure Appl. Chem. 1993, 65, 779-786. (b) Debenham, J . S. Ph.D.
Dissertation, Duke University, 1997. (c) Rodebaugh, R. Ph.D. Dis-
sertation; Duke University, 1997.

TCP- and Phth-Protected n-Pentenyl Glucosaminide Precursors
J . Org. Chem., Vol. 62, No. 14, 1997 4593
Ta ble 1. Key Tetr a sa ch h a r id e Cou p lin g
Sch em e 2
reagents/conditions
temp, °C
yield, %
1.3 equiv of donor
1.3 equiv of NIS
0.35 equiv of TESOTf
CH2Cl2
25
10
0
45
56
65
}
The reducing end disaccharide was then prepared.
Installation of isopropylidene on 21 allowed for subse-
quent 2-O-methylation affording 22. Hydrolysis followed
by benzoylation gave the fucosyl donor 6. The glu-
cosamine acceptor 718 was prepared from 16b, via the
glycosyl bromide, and Koenigs-Knorr coupling to benzyl
alcohol. Hydrolysis then produced the benzyl glycoside
23. Benzylidination followed by benzylation at the
3-position then gave 24 which could be hydrolyzed to
afford the diol 7.
The acceptor disaccharide 25 was prepared by coupling
the n-pentenyl fucoside 6, used as an anomeric mixture,
to diol 7 using a 1:1 stoichiometric ratio of donor to
acceptor. Regioselectivity was readily achieved by relying
upon the increased reactivity of the primary hydroxyl
group19 of 7, while the R-anomeric stereoselectivity,
attributable to solvent control20 and the presence of the
benzoate esters of 6, was anticipated from literature
precedents.21 This afforded 25 in 85% yield based on
recovered acceptor (or 62% isolated) with only the R-ano-
mer being formed as was evident by the 1H NMR doublet
at δ 5.22 ppm (J H1-2 ) 3.7 Hz). Use of more than 1 equiv
of the pentenyl donor resulted in difucosylation even at
lower temperatures.
F igu r e 3.
Convergent coupling of disaccharides 20b and 25 then
afforded the tetrasaccharide intermediate 26 in 65%
yield, and it was again noted that the yield increased as
the temperature was lowered from room temperature to
0 °C (Table 1).
yields.6a,8 Clearly a more efficient method of dibromina-
tion would be required if glucosamine NPGs were going
to be sidetracked in a synthetically useful manner. As a
result of exhaustive model studies it was shown that the
use of 5 equiv of CuBr2 and 10 equiv LiBr in 3:1 MeCN:
THF could afford virtually quantitative recovery of the
dibromide 5.15
Typically NPG couplings promoted with NIS/TESOTf,
carried out at room temperature, are complete within 15
min. Under these conditions coupling of 4 and 5 afforded
a disappointing 40% yield of disaccharide 20a (Figure 3).
However, when the temperature was lowered to -20 °C,
20a was formed just as rapidly, but in a much improved
71% yield.16 As anticipated, the TCP group, as with
phthalimide, directed the glycosidation to give only the
â-linked disaccharide as was evident by the 1H NMR
doublet at δ 5.51 ppm (J H1-2 ) 8.3 Hz) for the newly
formed anomeric center. Debromination with NaI af-
forded the donor 20b in near quantitative yield. Notably
other methods of debromination such as Zn or SmI2
proved less reliable in the presence of the TCP group.17
With the oligosaccharide scaffolding in place, the
objective was to replace the TCP group with the fatty
acid chain to complete the carbon skeleton of the nod
factor. Successive deprotection events would then lead
to the desired product 2. Accordingly the TCP moiety of
26 was cleaved with 2 equiv of ethylenediamine affording
the free base; but the latter proved to be a modest
nucleophile in the condensation with the activated 11-
(Z)-octadecenoic acid. For example, activation with
2-chloro-1-methylpyridinium iodide22 did afford the lipi-
dated material, and the unpurified reaction mixture was
acetylated to facilitate isolation of product 27 in 19% yield
over three steps. Recovery of an additional 26% of the
N-acetylated 28 illustrates the poor nucleophilicity of the
amino sugar toward the fatty acid. Experience in other
laboratories has shown that many higher amino sugars
(18) Ogawa, T.; Nakabayashi, S. Carbohydr. Res. 1981, 97, 81-86.
(19) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 30, 155-
224.
(15) A complete description of the use of the CuBr2/LiBr brominating
reagent including mechanistic analysis will be published shortly.
(16) Further reductions in temperture did not improve the yield of
20a .
(17) Merritt, J . R.; Debenham, J . S.; Fraser-Reid, B. J . Carbohydr.
Chem. 1996, 15, 1, 65-72.
(20) Rodebaugh, R.; Patel, N. S.; Fraser-Reid, B. Unpublished
results.
(21) Zuurmond, H. M; van der Laan, S.; van der Marel, G. A., van
Boom, J . H. Carbohydr. Res. 1991, 215, c1-c3.
(22) Sutherland, J . K.; Widdowson, P. A. J . Chem. Soc. 1964, 4650.
See also, ref 3a.

4594 J . Org. Chem., Vol. 62, No. 14, 1997
Debenham et al.
a
Ta ble 2. Deben zyla tion w ith F eCl3
Sch em e 3
a
Products were completely debenzylated. The pent-4-enyl side
chain was left unharmed as a result of debenzylation.
tures larger than monosaccharides.25 Our support stud-
ies on model systems,26 Table 2, were most encouraging.
Note that in the debenzylation of the NPG 33 in 83%
yield, the terminal double bond is left untouched. Of
particular interest is the survival of the glycosidic link-
ages, including the very acid labile (1f6) fucosyl link-
ages27 of the tetrasaccharides 26 and 28. Amides and
esters were also unreactive to this process. Unfortu-
nately, when this debenzylation procedure was employed
for 29 containing the 11-(Z)-octadecenoyl chain, a com-
plex product resulted. It was evident that this outcome
was associated with the fatty acid moiety.
Sch em e 4
Thus it was necessary to revise our approach so that
the benzyl groups could be cleaved before installation of
the fatty chain. However, it would still be necessary to
protect the anomeric center during the amine-promoted
dephthaloylation step in order to avoid decomposition of
the tetrasaccharide. Their replacement would have to
be installed under nonbasic conditions, be stable to high
temperatures, excess amine, and NaOMe/MeOH, and yet
be cleaved without affecting unsaturation, amides, or
glycosidic linkages. Thus, tert-butyldimethylsilyl protec-
tion seemed the logical choice. To this end, tetrasaccha-
ride 26 was treated with FeCl3 at 0 °C, and the resultant
tetrol, 34a , was exposed to excess tert-butyldimethylsilyl
chloride affording the trisilylated material 34b (Scheme
are poor nucleophiles toward fatty acids activated by
2-chloro-1-methylpyridinium iodide,3a O-acyl-N-hydroxy-
succinimide,3d-e 3-acylthiazolidine-2-thione,3b and acyl
chlorides3c even when treated with excess activated acid
(3-10 equiv) over prolonged reaction times (up to 3 days).
Indeed in the DCC-mediated coupling of 30 to 11-(Z)-
octadecenoic acid (Scheme 4), only 35% of amide 32 was
formed while half of the activated acid was consumed
through the undesired formation of the N-acylurea 31
even in the presence of excess HOBt (1-hydroxybenzo-
triazole).
Treatment of 27 with 150 equiv of ethylenediamine at
60 °C for 10 h effected the removal of the phthalimides
and most of the esters. N-Acetylation followed by meth-
oxide treatment and then peracetylation23 gave 29 in 64%
yield over four steps.
1
5). This intermediate also allowed for H NMR resolution
of all of the anomeric protons, which had been partially
obscured on the benzylated intermediate. All of the
glucosamine â-glycosidic linkages were verified by the 1H
NMR doublets at δ 5.41 ppm (J H1-2 ) 8.5 Hz), 5.37 ppm
(J H1-2 ) 8.5 Hz), and 5.35 ppm (J H1-2 ) 8.2 Hz) along
with the R-fucosyl linkage at 4.91 ppm (J H1-2 ) 3.4 Hz).
At this point the tetrasaccharide was ready for fatty
acid installation. Treatment with ethylenediamine as
before yielded the amino sugar which was now subjected
to 5 equiv of 11-(Z)-octadecenoic acid activated with
2-chloro-1-methylpyridinium iodide (twice as much as the
previous time). Acetylation of the unpurified reaction
mixture afforded the desired lipooligosaccharide 34c in
25% yield over three steps. Treatment of 34c with
ethylenediamine (500 equiv) at 90 °C for 34 h removed
all of the phthalimides as expected, but surprisingly one
of the acetates was only cleaved partially. As a result
The presence of the unsaturation in the fatty chain
precluded debenzylation by hydrogenolysis, while metal/
ammonia reduction might have caused amide cleavage.24
We were therefore attracted to anhydrous Lewis acid
catalyzed debenzylation using FeCl3, a procedure that to
our knowledge had not previously been used on struc-
(25) For application of FeCl3 to debenzylation, see: (a) Park, M. H.;
Takeda, R.; Nakanishi, K. Tetrahedron Lett. 1987, 28, 3823-3824. (b)
Kartha, K. P. R.; Dasgupta, F.; Singh, P. P.; Srivastava, H. C. J .
Carbohydr. Chem. 1986, 5, 437. For application of FeCl3 to anomer-
ization, see: (c) Ikemoto, N.; Kim, O. K.; Lo, L. C.; Satyanarayana, V.;
Chang, M.; Nakanishi, K. Tetrahedron Lett. 1992, 33, 4295-4298.
(26) Rodebaugh, R.; Debenham, J . S.; Fraser-Reid, B. Tetrahedron
Lett. 1996, 37, 5477-5478.
(23) Peracetylation of the tetrasachharide was required for solubility
purposes since debenzylation with FeCl3 required the use of CH2Cl2.
These reactions end prematurely if the substrate precipitates as a
result of its increased polarity due to deprotection.
(24) Pearson, A. J .; Rees, D. C. J . Am. Chem. Soc. 1982, 104, 1118-
1119
(27) Kunz, H.; Unverzagt, C. Agnew. Chem., Int. Ed. Engl. 1988,
27, 1697-1699.

TCP- and Phth-Protected n-Pentenyl Glucosaminide Precursors
J . Org. Chem., Vol. 62, No. 14, 1997 4595
Sch em e 5
Further studies to extend the methodologies reported
herein are underway and will be reported in due course.
Exp er im en ta l Section
Gen er a l P r oced u r es. General methods have been fol-
lowed as previously reported.31 Experimental procedures and
analytical data for monosaccharides not described herein can
be found elsewhere.12,31
P en t -4-en yl 3-O-Acet yl-4,6-O-b en zylid en e-2-d eoxy-2-
tetr a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (18a ). To
pent-4-enyl 4,6-O-benzylidene-2-deoxy-2-tetrachlorophthalimido-
â-D-glucopyranoside31 (21.81 g, 34.88 mmol) in pyridine (75
mL) was added acetic anhydride (9.87 mL, 104.6 mmol). The
reaction was stirred for 2 h before the pyridine was removed
in vacuo. The residue was dissolved in CH2Cl2 (300 mL) and
washed with 5% aqueous HCl (1 × 100 mL). The aqueous
portion was back extracted with CH2Cl2 (1 × 70 mL). The
solution was then washed with a saturated aqueous NaHCO3
solution (1 × 100 mL) and back extracted with CH2Cl2 (1 ×
70 mL). The product was purified via flash chromatography
eluting with 12:88 EtOAc/petroleum ether to afford 18a as a
foam (21.85 g, 97%): Rf 0.40 (15:85 EtOAc/petroleum ether);
1H NMR (300 MHz, CDCl3) δ 7.36-7.47 (m, 5H), 5.78 (app t,
J ) 9.3 Hz, 1H), 5.62-5.71 (m, 1H), 5.54 (s, 1H), 5.42 (d, J )
8.4 Hz, 1H), 4.44-4.87 (m, 2H), 4.41 (dd, J ) 4.6, 6.3 Hz, 1H),
4.28 (dd, J ) 4.6, 6.3 Hz, 1H), 3.69-3.89 (m, 4H), 3.45-3.53
(m, 1H), 1.93 (s, 3H), 1.87-1.98 (m, 2H), 1.54-1.63 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 170.56, 163.29, 162.56, 140.42,
140.17, 137.38, 136.65, 129.79, 129.67, 129.03, 128.06, 126.91,
126.71, 126.05, 114.76, 101.48, 98.07, 78.72, 69.84, 69.23,
68.41, 65.99, 55.99, 29.62, 28.28, 20.47; [R]20 -5.8° (c 1.04,
D
CH2Cl2). Anal. Calcd for C28H25NO8Cl4: C, 51.12; H, 3.90.
Found: C, 52.10; H, 3.86.
Ta ble 3. Desilyla tion Con d ition s
P en t-4-en yl 3-O-Acetyl-6-O-ben zyl-2-d eoxy-2-tetr a ch lo-
r op h th a lim id o-â-D-glu cop yr a n osid e (8a ). To 18a (20.70
g, 32.09 mmol) in THF (175 mL) and ether (175 mL) were
added 4 Å molecular sieves (9.7 g) and NaCNBH3 (22.90 g,
364.6 mmol). HCl(g) was bubbled through the solution until
the foaming had stopped at which point it was diluted with
CHCl3 (350 mL) and washed vigorously with saturated aque-
ous NaHCO3 (1 × 150 mL) solution, back extracting with
CHCl3 (1 × 70 mL), and with 5% aqueous HCl (1 × 300 mL),
back extracting with CHCl3 (1 × 70 mL). The concentrated
solution was purified via flash chromatography, eluting with
5:95 EtOAc/CH2Cl2 to afford 8a as a white foam (16.98 g,
82%): Rf 0.33 (5:95 EtOAc/CH2Cl2); 1H NMR (300 MHz, CDCl3)
δ 7.27-7.36 (m, 5H), 5.58-5.70 (m, 1H), 5.55 (dd, J ) 8.8,
10.6 Hz, 1H), 5.35 (d, 1H), 4.81-4.87 (m, 2H), 4.62 (dd, J )
12, 19.4 Hz, 2H), 4.21 (dd, J ) 8.5, 10.7 Hz, 1H), 3.78-3.87
(m, 4H), 3.67-3.72 (m, 1H), 3.45-3.51 (m, 1H), 3.10 (d, J )
4.0 Hz, 1H), 1.96 (s, 3H), 1.80-1.96 (m, 2H), 1.53-1.59 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 171.39, 163.36, 162.79,
140.40, 137.64, 137.50, 129.82, 128.45, 127.87, 127.71, 126.96,
114.77, 97.59, 73.94, 73.73, 73.58, 71.15, 69.97, 69.02, 55.39,
the product mixture was N-acetylated and then treated
with NaOMe/MeOH to afford 35 in 80% yield over three
steps.
In order to obtain the natural product 2 desilylation
was necessary. While this is normally a trivial process,
the operation can be problematic for desilylation at the
anomeric position. In order to avoid Lobry de Bruyn-
Alberda van Ekenstein rearrangement and other base-
promoted degradations,28 we examined the desilylation
of 36 to afford the reducing sugar 3729 under a variety of
conditions to ensure that the final deprotection step
would be uneventful (Table 3). The mildly acidic methods
for TBDMS removal were fruitless even after extended
reaction times. However buffering the tetrabutylammo-
nium fluoride reaction with AcOH provided good conver-
sion to 37, as did treatment with HF in pyridine. In view
of these encouraging results, compound 35 was treated
with tetrabutylammonium fluoride and AcOH which
afforded NodRf-III (C18:1, MeFuc), 2, in 83% yield.30
29.81, 28.42, 20.70; MS (FAB) m/ e 647.04 M-; [R]20 -4.5° (c
D
1.00, CH2Cl2). Anal. Calcd for C28H27NO8Cl4: C, 51.95; H,
4.20. Found: C, 51.86; H, 4.24.
P en t-4-en yl 3,4-Di-O-Acetyl-6-O-ben zyl-2-d eoxy-2-tet-
r a ch lor op h th a lim id o-â-D-glu cop yr a n osid e (4). Acetyla-
tion procedure as per 18a . The title compound was purified
via flash chromatography, eluting with 18:82 EtOAc/petroleum
ether to afford a white foam (0.495 g, 93%): Rf 0.24 (15:85
1
EtOAc/petroleum ether); H NMR (300 MHz, CDCl3) δ 7.27-
7.33 (m, 5H), 5.65-5.71 (m, 2H), 5.34 (d, J ) 8.4 Hz, 1H), 5.18
(t, J ) 9.1 Hz, 1H), 4.82-4.88 (m, 2H), 4.56 (dd, J ) 12, 13.6
Hz, 2H), 4.30 (dd, J ) 8.4 Hz, 10.6H), 3.78-3.86 (m, 2H), 3.58-
3.62 (m, 2H), 3.47-3.50 (m, 1H), 1.92 (s, 3H), 1.89 (s, 3H),
1.89-1.95 (m, 2H), 1.55-1.66 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 170.64, 169.45 (bs), 14.49, 137.63, 129.95, 129.90,
128.35, 127.83, 127.72, 126.93, 114.81, 97.60, 73.58, 73.26,
(28) Collins, P.; Ferrier, R. In Monosaccharides Their Chemistry and
Their Roles in Natural Products; Wiley: Chichester, 1995; pp 139-
143.
(29) Glaudemans, C. O. J .; Fletcer, H. G. In Methods in Carbohy-
drate Chemistry, Vol. 2.; Whistler, R., BeMiller, T. N., Eds.; Academic
Press: New York; pp 373-375.
(30) 1H NMR, 13C NMR, and HRMS data were consistent with the
proposed structure for 2.
(31) Debenham, J . S.; Debenham, S. D.; Fraser-Reid, B. Bioorg. Med.
Chem. 1996, 4, 1909-1918.

4596 J . Org. Chem., Vol. 62, No. 14, 1997
Debenham et al.
71.12, 69.62, 69.12, 68.80, 55.49, 29.81, 28.41, 20.59, 20.50;
to afford 20a as a white foam (0.643 g, 71%): Rf ) 0.16 (25:75
EtOAc/petroleum ether); [R]20D 43.2° (c 1.14, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.71-7.85 (m, 4H), 7.09-7.36 (m, 10H),
5.76 (t, J ) 9.6 Hz, 1H), 5.61 (dd, J ) 9.3, 10.2 Hz, 1H), 5.51
(d, J ) 8.3 Hz, 1H), 5.19-5.29 (m, 2H), 4.34-4.53 (m, 4H),
4.09-4.23 (m, 3H), 3.88-3.90 (m, 1H), 3.72-3.85 (m, 1H),
3.28-3.64 (m, 9H), 1.89 (s, 3H), 1.85 (s, 3H), 1.81 (s, 3H), 1.51-
2.05 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 170.33, 169.62,
168.98, 167.74, 167.32, 163.51, 162.21, 140.01, 137.56, 137.22,
134.01, 131.31, 131.14, 129.35, 128.09, 127.95, 127.67, 127.47,
127.22, 126.71, 126.31, 123.30, 97.82, 97.75, 96.81, 74.56,
74.27, 73.16, 72.99, 72.57, 71.54, 70.63, 68.91, 68.27, 68.02,
67.73, 55.69, 54.81, 52.11, 35.92, 32.51, 32.46, 26.71, 26.65,
20.40, 20.35, 20.23; MS (FAB) m/ z 1272.0 M-. Anal. Calcd
for C53H50N2O16Br2Cl4: C, 50.02; H, 3.96; N, 2.20. Found: C,
49.91; H, 3.92; N, 2.16.
P en t-4-en yl (3,4-Di-O-a cetyl-6-O-ben zyl-2-d eoxy-2-tet-
r a ch lor op h t h a lim id o-â-D-glu cop yr a n osyl)-(1f4)-3-O-
a cet yl-6-d i-O-b en zyl-2-d eoxy-2-p h t h a lim id o-â-D-glu co-
p yr a n osid e (20b). To 20a (0.506 g, 0.398 mmol) in methyl
ethyl ketone (18 mL) was added NaI (0.894g, 5.964 mmol). The
reaction stirred 13 h at 80 °C and was then concentrated in
vacuo. The syrup was dissolved in EtOAc (20 mL) and washed
with 10% aqueous Na2S2O3 (15 mL), back extracting the
aqueous phase with EtOAc (2 × 15 mL). The concentrated
EtOAc solution was purified via flash chromatography, eluting
with 40:60 EtOAc/petroleum ether to afford 20b as a white
foam (0.442 g, 93%): Rf 0.16 (25:75 EtOAc/petroleum ether);
[R]20D 53.0° (c 1.13, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.71-
7.85 (m, 4H), 7.10-7.34 (m, 10H), 5.78 (dd, J ) 8.9, 10.6 Hz,
1H), 5.50-5.66 (m, 3H), 5.18-5.30 (m, 2H), 4.66-4.76 (m, 2H),
4.36-4.56 (m, 4H), 4.08-4.24 (m, 3H), 3.37-3.78 (m, 8H), 1.90
(s, 3H), 1.85 (s, 6H), 1.81-1.92 (m, 2H), 1.40-1.51 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 170.45, 169.74, 169.09, 167.79,
167.65, 163.64, 162.32, 140.11, 137.72, 137.47, 137.32, 134.08,
131.33 (bd), 129.46, 128.18, 128.01, 127.77, 127.55, 127.27,
126.83, 126.44, 123.28, 114.55, 97.85, 96.94, 74.74, 74.35,
73.27, 73.04, 72.65, 71.71, 70.77, 69.06, 68.71, 68.16, 67.78,
55.79, 54.98, 29.62, 28.28, 20.49, 20.41, 20.30; MS (FAB) m/ z
1112.1 M-. Anal. Calcd for C53H50N2O16Cl4‚H2O: C, 56.29;
H, 4.64; N, 2.48. Found: C, 56.48; H, 4.65; N, 2.42.
MS (FAB) m/ e 689.06 M-; [R]20 41.2° (c 1.02, CHCl3). Anal.
D
Calcd for C30H29NO9Cl4: C, 52.27; H, 4.24. Found: C, 52.24;
H, 4.29.
P en t -4-en yl 3-O-Acet yl-4,6-O-b en zylid en e-2-d eoxy-2-
p h th a lim id o-â-D-glu cop yr a n osid e (18b). Acetylation pro-
cedure as per 18a . The title compound was purified via flash
chromatography, eluting with 25:75 EtOAc/petroleum ether
to afford a white foam (16.64 g, 97%): Rf 0.34 (30:70 EtOAc/
petroleum ether); 1H NMR (300 MHz, CDCl3) δ 7.73-7.88 (m,
4H), 7.34-7.48 (m, 5H), 5.89 (dd, J ) 8.9, 10.4 Hz, 1H), 5.55
(s, 1H), 5.53-5.66 (m, 1H), 5.43 (d, J ) 8.4 Hz, 1H), 4.69-
4.79 (m, 2H), 4.42 (dd, J ) 4.2, 10.2 Hz, 1H), 4.30 (dd, J )
8.5, 10.4 Hz, 1H), 3.73-3.89 (m, 4H), 3.43-3.50 (m, 1H), 1.90
(s, 3H), 1.83-1.90 (m, 2H), 1.50-1.59 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 170.11, 168.01 (bs), 137.49, 136.87, 134.20,
131.4 (bs), 129.09, 128.18, 126.17, 123.49, 114.74, 101.56,
98.61, 79.29, 69.72, 69.34, 68.64, 66.15, 55.35, 29.68, 28.40,
20.54; MS (CI) m/ e 508 MH+, 525 (M+NH4)+; [R]20 -20.7° (c
D
1.07, CHCl3). Anal. Calcd for C28H29NO8: C, 66.26; H, 5.76.
Found: C, 66.36; H, 5.79.
P en t-4-en yl 3-O-Acetyl-6-O-ben zyl-2-d eoxy-2-p h th a l-
im id o-â-D-glu cop yr a n osid e (8b). Reductive benzylidene
cleavage as per 8a . The title compound was purified via flash
chromatography, eluting with a gradient of 30 f 45% EtOAc/
petroleum ether to afford 8 as a white foam (12.75 g, 79%):
Rf 0.28 (40:60 EtOAc/petroleum ether); 1H NMR (300 MHz,
CDCl3) δ 7.70-7.86 (m, 4H), 7.30-7.37 (m, 5H), 5.58-5.69 (m,
2H), 5.35 (d, J ) 8.4 Hz, 1H), 4.58-4.78 (m, 4H), 4.23 (dd, J
) 8.5, 10.8 Hz, 1H), 3.74-3.86 (m, 5H), 3.40-3.47 (m, 1H),
3.07 (d, J ) 3.7 Hz, 1H), 1.93 (s, 3H), 1.86-1.89 (m, 2H), 1.51-
1.56 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.05, 167.60 (bs),
137.77, 137.48, 134.04, 131.19, 128.20, 127.49, 127.43, 123.27,
114.49, 97.68, 74.59, 73.41, 70.63, 69.77, 68.74, 54.60, 29.60,
28.27, 20.44; MS (CI) m/ e 527 (M + NH4)+; [R]20 -19.7° (c
D
1.12, CH2Cl2). Anal. Calcd for C28H31NO8: C, 66.00; H, 6.13.
Found: C, 66.02; H, 6.15.
4,5-Dibr om op en ta n yl 3-O-Acetyl-6-O-ben zyl-2-d eoxy-
2-p h th a lim id o-â-D-glu cop yr a n osid e (5). To CuBr2 (3.134
g, 14.0 mmol) and LiBr (2.432 g, 28.0 mmol) in CH3CN (37.0
mL) and THF (16 mL) was cannulated 8b (1.430 g, 2.806
mmol) in CH3CN (16.0 mL) and THF (7 mL). The reaction
was stirred for 12 h in darkness at which point the solution
was concentrated to 20% of its original volume. The solution
was then diluted with EtOAc (140 mL) and washed with H2O
(1 × 70 mL) and brine (1 × 70 mL) before the aqueous portions
were combined and back extracted with EtOAc (1 × 70 mL).
The concentrated solution was purified via flash chromatog-
raphy, eluting with 40:60 EtOAc/petroleum ether affording a
white foam (1.852 g, 99%): Rf 0.36 (45:55 EtOAc/petroleum
ether); [R]20D 13.0° (c 1.36, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.71-7.87 (m, 4H), 7.31-7.37 (m, 5H), 5.64 (dd, J ) 8.6,
10.4 Hz, 1H), 5.37 (d, J ) 8.4 Hz, 1H), 4.63 (dd, J ) 12.1, 18.1
Hz, 2H), 4.23 (dd, J ) 8.5, 10.8 Hz, 1H), 3.72-4.00 (m, 6H),
3.59-3.65 (m, 1H), 3.45-3.58 (m, 1H), 3.29-3.38 (m, 1H), 3.01
(d, J ) 2.9 Hz, 1H), 1.93 (s, 3H), 1.92-1.22 (m, 1H), 1.56-
1.66 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 171.16, 168.88 (bs),
137.67, 134.18, 131.31, 128.37, 127.71, 127.60, 123.51, 97.91,
97.83, 74.38, 73.60, 73.43, 71.05, 69.94, 68.56, 68.51, 54.54,
52.36, 52.27, 36.10, 36.06, 32.71, 32.63, 26.94, 26.82, 20.60;
MS (FAB) m/ e 670.09 MH+.
4,5-Dib r om op en t a n yl (3,4-Di-O-a cet yl-6-O-b en zyl-2-
d eoxy-2-t et r a ch lor op h t h a lim id o-â-D-glu cop yr a n osyl)-
(1f4)-3-O-a cetyl-6-d i-O-ben zyl-2-d eoxy-2-p h th a lim id o-â-
D-glu cop yr a n osid e (20a ). To 5 (0.673 g, 0.924 mmol) and 4
(0.476 g, 0.711 mmol) (both dried by azeotroping together with
toluene) in CH2Cl2 (6.6 mL) were added N-iodosuccinimide
(0.291 g, 1.294 mmol) and triethylsilyl triflate (83.6 µL, 0.370
mmol). After the solution was stirred for 16 min at -20 °C,
the glycosyl donor had been consumed and the reaction was
quenched with 10% aqueous Na2S2O3 (4 mL) and a saturated
aqueous NaHCO3 (4 mL) solution. The mixture was stirred
for an additional 5 min before the layers were separated and
the aqueous phase was extracted with CH2Cl2 (3 × 15 mL).
The concentrated CH2Cl2 solution was purified via flash
chromatography, eluting with 25:75 EtOAc/petroleum ether
P en t-4-en yl
L-F u cop yr a n osid e (21). To a mixture of
L-fucose (21.4 g, 130.4 mmol) and pentenyl alcohol (115 mL)
was added a catalytic amount of camphorsulfonic acid (300
mg) and the mixture was heated at 90 °C for 48 h. The
reaction mixture was cooled, neutralized with triethylamine,
and then the excess pentenyl alcohol was removed under high
vacuum. The residue was purified by flash chromatography
eluting with 96:4 f 90:10 CH2
Cl2/MeOH to afford 21 as a clear
syrup (26.05 g, 86%): Rf 0.35 (90:10 CH2Cl2/MeOH); 1H NMR
(300 MHz) δ 5.74-5.89 (m, 1H), 4.81-5.05 (m, 3H), 4.21 (d,
1H), 3.89-4.00 (m, 1H), 3.65-3.79 (m, 3H), 3.41-3.63 (m, 3H),
3.21-3.41 (bs, 3H), 2.08-2.18 (m, 2H), 1.69-1.78 (m, 2H),
1.21-1.39 (m, 3H); 13
C NMR (75 MHz) 138.02, 114.96, 103.14,
98.67, 74.05, 72.11, 71.73, 71.19, 70.99, 70.59, 69.48, 68.91,
67.56, 66.04, 30.31, 30.02, 28.66, 16.35, 16.25; MS (FAB) m/ e
233.14 MH+. Anal. Calcd for C11H20O5: C, 56.88; H, 8.68.
Found: C, 56,62; H, 8.55.
P en t -4-en yl 3,4-O-Isop r op ylid en e-2-O-m et h yl-L-fu co-
p yr a n osid e (22). To a solution of pent-4-enyl L-fucopyrano-
side 21 (21.20 g, 91.3 mmol) in acetone previously dried over
3 Å molecular sieves (250 mL) was added p-toluenesulfonic
acid (1.042 g, 0.06 equiv). After 30 min, 2,2-dimethoxypropane
(21.3 mL, 173.5 mmol, 1.9 equiv) was added, and the mixture
was stirred for an additional 30 min before being quenched
with saturated aqueous NaHCO3 (10 mL). The concentrated
material was taken up in CHCl3 (300 mL) and washed
consecutively with H2O (2 × 125 mL) and brine (2 × 100 mL)
before concentration. The residue was purified via flash
chromatography eluting with 75:25 f 70:30 petroleum ether/
EtOAc to afford pent-4-enyl 3,4-O-isopropylidene-L-fucopyra-
noside as a yellow oil (20.14 g, 81%): Rf 0.60 (3:1 petroleum
ether/EtOAc); 1H NMR (300 MHz) δ 5.74-5.89 (m, 1H), 4.96-
5.05 (m, 2H), 4.80 (d, J ) 3.5 Hz, 1H), 4.21 (t, 1H), 4.01-4.16
(m, 2H), 3.71-3.79 (m, 2H), 3.48-3.55 (m, 2H), 2.42 (d, 1H),
2.08-2.18 (m, 2H), 1.69-1.78 (m, 2H), 1.52 (d, 3H), 1.31-1.46

TCP- and Phth-Protected n-Pentenyl Glucosaminide Precursors
J . Org. Chem., Vol. 62, No. 14, 1997 4597
(m, 6H); 13C NMR (75 MHz) 138.12, 137.90, 114.91, 114.78,
102.61, 96.41, 79.37, 76.07, 75.72, 74.11, 69.56, 67.52, 63.02,
30.22, 28.84, 28.38, 27.91, 26.38, 26.28, 16.53, 16.31; MS (FAB)
m/ e 273.18 MH+. Anal. Calcd for C14H24O5: C, 61.74; H, 8.88.
Found: C, 61.64; H, 8.82.
ether/EtOAc to give benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-
phthalimido-â-D-glucopyranoside as a white solid (34.95 g,
74%): Rf 0.42 (70:30 petroleum ether/EtOAc); mp 106 °C;
[R]21D -11.2° (c 1.32, CHCl3); 1H NMR (300 MHz) δ 7.71-7.86
(m, 4H), 7.07-7.12 (m, 5H), 5.79 (dd, J ) 9.2, 10.5 Hz, 1H),
5.37 (d, J ) 8.4 Hz, 1H), 5.19 (t, J ) 9.8 Hz, 1H), 4.85 (d, J )
12.3 Hz, 1H), 4.53 (d, J ) 12.2 Hz, 1H), 4.32-4.41 (m, 2H),
4.18-4.22 (m, 1H), 3.84-3.90 (m, 1H), 2.14 (s, 3H), 2.03 (s,
3H), 1.86 (s, 3H); 13C NMR (75 MHz) δ 170.76, 170.13, 169.51,
167.50, 136.61, 134.19, 131.37, 128.25, 127.84, 127.75, 127.61,
127.58, 123.55, 97.18, 71.32, 70.64, 68.97, 62.02, 54.62, 20.81,
20.65, 20.47; MS (FAB) m/ e 526.19 MH+. Anal. Calcd for
C27H27NO20: C, 61.70; H, 5.18; N, 2.67. Found: C, 61.54; H,
5.20; N, 2.68.
To benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-â-D-glu-
copyranoside (34.52 g, 65.69 mmol) in acetone (710 mL) were
added H2O (325 mL) and concentrated HCl (75 mL). The
mixture was heated at 80 °C for 16 h before the mixture was
concentrated and the residue was diluted in EtOAc (600 mL).
The EtOAc layer was washed with H2O (2 × 300 mL) and
saturated aqueous NaHCO3 (2 × 300 mL) before concentration
to give the triol 23 as a white solid (24.40 g, 93%). 23 was
then dissolved in acetonitrile (250 mL) before addition of
benzaldehyde dimethyl acetal (17.3 mL, 115.4 mmol, 2 equiv)
and p-toluenesulfonic acid (439 mg, 2.31 mmol). After the
A
solution of pent-4-enyl 3,4-O-isopropylidene-L-fuco-
pyranoside (16.7 g, 61.3 mmol) in THF was cooled to 0 °C, and
NaH (3.433 g of a 60% dispersion in mineral oil, 1.4 equiv)
was added. After the evolution of H2 subsided, MeI (5.7 mL,
1.5 equiv) was added dropwise. The solution was allowed to
slowly come to room temperature after 3 h at 0 °C, and it was
stirred overnight before being quenched with glacial acetic
acid. The mixture was diluted with ether (600 mL) and
consecutively washed with H2O (1 × 200 mL), saturated
aqueous NaHCO3 (2 × 250 mL), and brine (1 × 250 mL). The
concentrated solution was purified via flash chromatography
(90:10 f 85:15 petroleum ether/EtOAc) to give 22 as a yellow
oil (16.27 g, 93%). Rf 0.45 (90:10 petroleum ether/EtOAc); 1H
NMR (300 MHz) 5.74-5.86 (m, 1H), 4.94-5.06 (m, 2H), 4.88
(d, J ) 3.5 Hz, 1H), 4.15-4.25 (m, 1H), 3.91-4.11 (m, 2H),
3.61-3.69 (m, 1H), 3.54-3.59 (m, 1H), 3.51 (s, 3H), 3.33-3.37
(dd, J ) 3.5, 7.9 Hz, 1H), 2.08-2.15 (m, 2H), 1.68-1.78 (m,
2H), 1.61 (s, 1H), 1.31-1.42 (m, 5H); 13C NMR (75 MHz) δ
138.12, 137.99, 114.89, 114.79, 102.68, 96.47, 82.32, 79.27,
79.07, 76.39, 76.10, 75.72, 67.48, 63.00, 58.52, 30.23, 28.49,
28.38, 26.36, 26.28, 16.54, 16.31; MS (FAB) m/ e 287.2 MH+.
Anal. Calcd for C15H26O5: C, 62.91; H, 9.15. Found: C, 62.97;
H, 9.09.
P en t-4-en yl 3,4-Di-O-ben zoyl-2-O-m eth yl-L-fu cop yr a -
n osid e (6). A solution of 22 (16.06 g, 56.08 mmol) in 80%
glacial acetic acid (200 mL) was heated at 60 °C for 5 h. The
acetic acid was then azeotroped with toluene to give pent-4-
enyl 2-O-methyl-L-fucopyranoside as a clear oil (13.27 g,
96%): 1H NMR (300 MHz) δ 5.76-5.85 (m, 1H), 4.95 -5.05
(m, 3H), 4.21 (d, J ) 7.7 Hz, 1H), 3.82-3.99 (m, 2H), 3.67-
3.73 (m, 1H), 3.61 (s, 1H), 3.41-3.53 (m, 5H), 2.11-2.20 (m,
2H), 1.68-1.79 (m, 2H), 1.26-1.37 (m, 3H); MS (FAB) m/ e
247.2 MH+.
Pent-4-enyl 2-O-methyl-L-fucopyranoside (13.27 g, 53.9
mmol) was dissolved in pyridine (50 mL) at 0 °C, and benzoyl
chloride (19.8 mL, 3 equiv) was slowly added via a syringe.
The mixture was allowed to slowly warm to room temperature
and was stirred overnight before being quenched with satu-
rated aqueous NaHCO3 (50 mL). The reaction mixture was
diluted with ether (400 mL) and washed consecutively with
saturated aqueous NaHCO3 (2 × 150 mL), H2O (1 × 200 mL),
5% HCl (2 × 100 mL), and saturated aqueous NaHCO3 (2 ×
150 mL). The concentrated solution was purified via flash
chromatography (95:5 f 87:13 petroleum ether/EtOAc) to
afford 6 as a yellow syrup (20.58 g, 84%): Rf 0.47 (87:13
petroleum ether/EtOAc); 1H NMR (300 MHz) δ 7.84-8.12 (m,
4H), 7.47-7.63 (m, 4 H), 7.31-7.39 (m, 2H), 5.76-5.85 (m,
1H), 5.62-5.71 (m, 2 H), 4.95-5.19 (m, 3H), 4.30-4.42 (m,
1H), 3.90-3.99 (m, 1H), 3.52-3.65 (m, 2H), 3.49 (s, 3H), 2.15-
2.29 (m, 2H), 1.75-1.88 (m, 2H), 1.21-1.33 (m, 3H); 13C NMR
(75 MHz) δ 165.95, 165.87, 165.65, 165.61, 138.02, 133.35,
133.23, 133.01, 132.87, 129.94, 129.77, 129.60, 128.50, 128.21,
115.00, 103.70, 97.17, 78.72, 76.07, 73.53, 72.27, 71.42, 70.93,
69.67, 69.22, 67.75, 64.73, 60.98, 59.03, 30.29, 30.14, 28.88,
28.61, 16.34, 16.12; MS (FAB) m/ e 455.19 MH+. Anal. Calcd
for C26H30O7: C, 68.71; H, 6.65. Found: C, 68.61; H, 6.65.
solution was refluxed for 15 h, the reaction was quenched with
1
Et3
N (2 mL) and concentrated to
/ of its original volume
4
before being diluted with EtOAc (500 mL). The organic
solution was then washed with saturated aqueous NaHCO3
(1 × 250 mL) and H2O (1 × 250 mL), back extracting the
combined aqueous portions with EtOAc (3 × 150 mL). The
concentrated residue was recrystallized from EtOAc/petroleum
ether (2:1) to give benzyl 4,6-O-benzylidene-2-deoxy-2-phthal-
imido-â-D-glucopyranoside as a white solid (26.013 g, 93%): Rf
0.44 (70:30 petroleum ether/EtOAc); mp 189 °C; [R]21 -81.8°
D
(c 1.67, CHCl3); 1H NMR (300 MHz) δ 7.71-7.86 (m, 4H), 7.36-
7.51 (m, 5H), 7.03-7.10 (m, 5H), 5.58 (s, 1H), 5.26 (d, J ) 8.4
Hz, 1H), 4.84 (d, J ) 12.3 Hz, 1H), 4.61-4.68 (m, 1H), 4.52 (d,
J ) 12.4 Hz, 1H), 4.45 (m, 1H), 4.29 (dt, J ) 8.5, 10.5 Hz, 1H),
3.81-3.90 (m, 1H), 3.62-3.71 (m, 1H), 2.55 (bs, 1H); 13C NMR
(75 MHz) δ 167.66, 136.71, 136.53, 133.70, 131.28, 129.05,
128.09, 127.94, 127.43, 127.35, 126.04, 123.10, 101.61, 97.59,
81.82, 70.94, 68.38, 68.11, 65.79, 56.32; MS (FAB) m/ e 488.2
MH+. Anal. Calcd for C28H25NO7: C, 68.99; H, 5.17; N, 2.87.
Found: C, 68.76; H, 5.25; N, 2.83.
To benzyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-â-D-glu-
copyranoside (11.80 g, 24.2 mmol) in dimethylformamide (47
mL) were added NaH (1.452 g of a 60% dispersion in mineral
oil, 36.3 mmol, 1.5 equiv) and benzyl bromide (5.76 mL, 48.4
mmol, 2 equiv) at 0 °C. The reaction was allowed to come to
room temperature after 10 min and was quenched after an
additional 1 h of stirring with AcOH (3 mL). The DMF was
evaporated under high vacuum, and the residue was taken
up in CH2
Cl2 (250 mL). The organic solution was washed with
H2O (1 × 150 mL) and saturated aqueous NaHCO3 (1 × 150
mL). The combined aqueous layers were back extracted with
CH2
Cl2 (2 × 100 mL). The combined organic layers were
concentrated and purified via flash chromatography, eluting
with 12:88 f 20:80 EtOAc/petroleum ether to afford 24 as an
oil (13.36 g, 96%): Rf 0.76 (70:30 petroleum ether/EtOAc);
[R]21D -95.6° (c 1.55, CHCl3); 1H NMR (300 MHz) δ 7.71-7.86
(m, 4H), 7.36-7.51 (m, 5H), 6.84-7.10 (m, 10H), 5.64 (s, 1H),
5.20 (d, J ) 8.4 Hz, 1H), 4.76-4.83 (m, 2H), 4.38-4.46 (m,
4H), 4.23-4.29 (m, 1H), 3.80-3.92 (m, 2H), 3.62-3.68 (m, 1H);
13C NMR (75 MHz) δ 167.56, 137.94, 137.37, 136.87, 133.73,
131.57, 129.06, 128.34, 128.21, 128.09, 128.04, 127.67, 127.39,
126.10, 123.28, 101.35, 97.91, 83.04, 74.42, 74.08, 71.19, 68.82,
66.06, 55.84; MS (FAB) m/ e 578.2 MH+. Anal. Calcd for
C35H31NO7: C, 72.78; H, 5.41; N, 2.42. Found: C, 72.78; H,
5.42; N, 2.37.
Ben zyl
3-O-Ben zyl-4,6-O-b en zylid en e-2-d eoxy-2-
p h th a lim id o-â-D-glu cop yr a n osid e (24). To 16b12 (43.00 g,
90.0 mmol) was added HBr (577 mmol, 78 mL, 30 wt % in
acetic acid) in acetic anhydride (20 mL). After being stirred
in darkness for 24 h, the reaction mixture was diluted with
CHCl3 (500 mL) and poured onto ice-cold H2O (500 mL). The
layers were separated, and the organic portion was washed
with H2O (2 × 400 mL) and saturated aqueous NaHCO3 (2 ×
300 mL), dried, and concentrated to a syrup. To the crude
glycosyl bromide were added benzyl alcohol (18.6 mL, 180
mmol, 2 equiv) and Ag zeolite powder (72.1 g) in CH2Cl2 (300
mL). The reaction was stirred in darkness at 50 °C for 36 h
and was then filtered through Celite. After concentration of
the CH2Cl2 solution, the residue was flash chromatographed,
eluting with 70:30 petroleum ether/EtOAc f 60:40 petroleum
Ben zyl 3-O-Ben zyl-2-d eoxy-2-p h t h a lim id o-â-D-glu co-
p yr a n osid e (7). To 24 (14.13 g, 24.45 mmol) in CH2Cl2/MeOH
(2:1, 280 mL) was added p-toluenesulfonic acid (930 mg, 4.89
mmol, 0.2 equiv), and the reaction mixture was refluxed at 50
°C for 15 h. The reaction was then quenched with Et3N (0.5
mL) and concentrated, and the residue was purified via flash

4598 J . Org. Chem., Vol. 62, No. 14, 1997
Debenham et al.
chromatography (53:47 f 62:38 EtOAc/CH2Cl2) to afford 7 as
an oil (10.75 g, 90%): Rf 0.31 (1:1 EtOAc/CH2Cl2); [R]21D -2.65°
(c 1.77, CHCl3); 1H NMR (300 MHz) δ 7.55-7.84 (m, 4H), 6.96-
7.26 (m, 10H) 5.18 (d, J ) 8.0 Hz, 1H), 4.76 (d, J ) 12.3 Hz,
1H), 4.65 (d, J ) 12.2 Hz, 1H), 4.51 (d, J ) 12.3 Hz, 2H), 4.17-
4.31 (m, 2H), 3.75-3.98 (m, 3H), 3.51 (m, 1H), 2.53 (bs, 1H);
13C NMR (75 MHz) δ 167.95 (bs), 138.08, 137.09, 133.76 (bs),
131.56 (bs), 128.34, 128.22, 127.88, 127.69, 127.51, 123.32,
97.61, 78.97, 75.25, 74.46, 72.07, 71.24, 62.32, 55.62. Anal.
Calcd for C28H26NO7: C, 68.70; H, 5.56; N, 2.86. Found: C,
68.41; H, 5.67; N, 2.80.
132.81, 131.59, 131.41, 129.98, 129.87, 129.77, 129.65, 129.42,
128.49, 128.26, 128.08, 128.04, 127.91, 127.65, 127.63, 127.55,
127.45, 127.34, 127.21, 126.94, 126.76, 126.71, 126.63, 126.33,
123.74, 123.41, 97.76, 96.79, 96.54, 96.28, 76.48, 76.12, 75.52,
75.28, 74.28, 74.18, 73.52, 73.40, 73.25, 72.65, 72.59, 72.37,
70.77, 70.64, 69.95, 69.33, 68.49, 67.50, 64.74, 64.58, 59.44,
55.94, 55.84, 55.63, 20.63, 20.53, 20.41, 15.98; MS (FAB) m/ z
1883.34 M-. Anal. Calcd for C97H87N3O28Cl4‚2H2O: C, 60.66;
H, 4.78; N, 2.19. Found: C, 60.71; H, 4.60; N, 2.10.
Ben zyl (3,4-Di-O-a cet yl-6-O-b en zyl-2-d eoxy-2-{11(Z)-
octa d ecen a m id o}-â-D-glu cop yr a n osyl)-(1f4)-(3-O-a cetyl-
6-O-ben zyl-2-d eoxy-2-p h th a lim id o-â-D-glu cop yr a n osyl)-
(1f4)-[(3,4-d i-O-ben zoyl-2-O-m eth yl-r-L-fu cop yr a n osyl)-
(1f6)]-3-O-b e n zyl-2-d e o xy -2-p h t h a lim id o-â-D -g lu c o -
p yr a n osid e (27). To 26 (132.0 mg, 70.04 µmol) in 1.0 mL of
3:1 acetonitrile/ tetrahydrofuran was added ethylenediamine
(10.6 µL, 0.1582 mmol) before the solution was heated to 60
°C. The reaction mixture was stirred for 10.5 h, allowed to
cool to room temperature, concentrated and then filtered
through a short column of silica gel with 5:95 MeOH/CH2Cl2.
The amine in CH3CN (1.5 mL) was then added to cis-11-
octadecenoic acid (50.3 mg, 0.178 mmol) pretreated with both
triethylamine (37.2 µL, 0.267 mmol) for 15 min and then
2-chloro-N-methylpyridinium iodide (45.5 mg, 0.178 mmol) in
CH3CN (0.5 mL) for 15 min at 40 °C. The reaction was stirred
2 h at 45 °C and was then concentrated in vacuo. The residue
was dissolved in CH2Cl2 (30 mL) and washed with saturated
aqueous NaHCO3 (10 mL), back extracting the aqueous portion
with CH2Cl2 (2 × 5 mL). The solution was dried (Na2SO4) and
concentrated. To the residue were added acetic anhydride
(0.280 mL, 2.965 mmol), triethylamine (49.6 µL, 0.3558 mmol),
and DMAP (29.0 mg, 0.237 mmol) in pyridine (1 mL) for 10 h.
The reaction mixture was concentrated in vacuo before being
diluted with CH2Cl2 (25 mL) and washed with both 5%
aqueous HCl (1 × 8 mL), back extracting with CH2Cl2 (2 × 10
mL), and saturated aqueous NaHCO3 (8 mL), back extracting
the aqueous portion with CH2Cl2 (2 × 10 mL). The reaction
mixture was concentrated, and the residue was purified by
flash chromatography, eluting with a gradient of 3.5 f 5%
MeOH/CH2Cl2. Compound 27 was recovered as a film (24.2
Ben zyl (3,4-Di-O-b en zoyl-2-O-m et h yl-r-L-fu cop yr a n -
o s y l)-(1f6)-3-O -b e n zy l-2-d e o x y -2-p h t h a lim id o -â-D -
glu cop yr a n osid e (25). To 6 (887.0 mg, 1.95 mmol) and 7
(958.1, 1.95 mmol) (both dried by azeotroping together with
toluene) in Et2O:CH2Cl2 (5:1, 17 mL) were added N-iodosuc-
cinimide (677 mg, 3.01 mmol) and triethylsilyl triflate (146
µL, 0.645 mmol). After the solution was stirred for 25 min at
room temperature, the glycosyl donor had been consumed and
the reaction was quenched with 10% aqueous Na2S2O3 (5 mL)
and saturated aqueous NaHCO3 (5 mL). The mixture was
diluted with CHCl3 (150 mL) and washed with brine (2 × 50
mL). The aqueous layers were back extracted with CHCl3 (3
× 50 mL). The concentrated CHCl3 solution was purified via
flash chromatography, eluting with 65:35 f 45:55 petroleum
ether/EtOAc to afford 25 as a white foam (1.0373 g, 1.21 mmol)
and recovered 7 (259.5 mg, 0.53 mmol). The total yield of 25
was 85% on the basis of on recovered alcohol 7: Rf 0.39 (45:55
EtOAc/petroleum ether); [R]20 -128.0° (c 1.30, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ 8.06 (d, J ) 7.1 Hz, 2H), 7.89 (d, J
) 7.1 Hz, 2H), 7.49-7.86 (m, 8H), 7.30-7.35 (m, 3H), 6.92-
7.11 (m, 9H), 5.66-5.71 (m, 2H), 5.22 (d, J ) 3.7 Hz, 1H),
5.16-5.19 (m, 1H), 4.78 (dt, J ) 2.4 Hz, 12.5 Hz, 2H), 4.52 (t,
J ) 13.3 Hz, 2H), 4.43-4.46 (m, 1 H), 4.25 (dd, J ) 3.5, 4.5
Hz, 2H), 3.89-4.14 (m, 4H), 3.70-3.75 (m, 1H), 3.51 (s, 3H),
2.75 (m, 1H), 1.23 (d, J ) 6.57 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.92, 165.87, 165.50, 138.34, 137.11, 133.70, 133.32,
133.00, 131.67, 130.01, 129.81, 129.75, 129.65, 128.58, 128.29,
128.20, 128.10, 127.93, 127.59, 127.34, 123.27, 97.92, 97.28,
78.41, 76.34, 74.25, 73.69, 73.41, 72.19. 71.07, 70.64, 68.73,
65.25, 59.55, 55.55, 16.13; MS (FAB) m/ z 857.2 M-. Anal.
Calcd for C49H47NO13‚H2O: C, 66.98; H, 5.48; N, 1.58.
Found: C, 67.19; H, 5.64; N, 1.60.
1
mg, 19%): Rf 0.71 (5:95 MeOH/CH2Cl2); H NMR (400 MHz,
CDCl3) δ 6.78-8.12 (m, 38H), 5.62-5.74 (m, 4H), 5.31-5.38
(m, 3H), 4.67-5.20 (m, 6H), 4.22-4.61 (m, 10H), 4.12 (t, J )
8.5 Hz, 1H), 4.04 (t, J ) 8.9 Hz, 1H), 3.51 (s, 3H), 3.40-3.96
(m, 12H), 3.33 (bd, J ) 9.9 Hz, 1H), 1.98-2.08 (m, 6H), 1.88
(s, 3H), 1.85 (s, 3H), 1.79 (s, 3H), 1.16 (d, J ) 6.5 Hz, 3H),
1.04-1.38 (m, 20H), 0.82-0.92 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 172.17, 170.51, 170.22, 169.48, 168.20, 167.58, 165.92,
165.03, 163.83, 138.57, 137.83, 137.34, 136.95, 134.37, 134.18,
133.54, 133.47, 133.44, 133.41, 133.21, 132.86, 131.65, 131.54,
131.45, 129.93, 129.89, 129.78, 129.67, 129.60, 129.22, 128.80,
128.73, 128.67, 128.51, 128.34, 128.27, 128.10, 127.87, 127.77,
127.51, 127.39, 126.87, 123.66, 123.44, 100.40, 96.78, 96.14,
95.91, 77.54, 77.25, 77.16, 76.78, 75.57, 75.34, 74.81, 73.85,
73.71, 73.57, 73.45, 73.31, 72.82, 72.42, 72.30, 71.06, 70.26,
70.01, 69.63, 68.91, 64.54, 58.99, 55.68, 55.57, 53.39, 36.09,
31.76, 29.79, 29.71, 29.57, 29.49, 29.41, 29.35, 29.31, 28.97,
28.81, 27.20, 25.52, 25.28, 22.64, 20.65, 20.60, 20.38, 15.95,
14.12; MS (FAB) m/ e 1880.8 MH+.
Ben zyl (2-Acetam ido-3,4-di-O-acetyl-6-O-ben zyl-2-deoxy-
â-D-glu copyr an osyl)-(1f4)-(3-O-acetyl-6-O-ben zyl-2-deoxy-
2-p h th a lim id o-â-D-glu cop yr a n osyl)-(1f4)-[(3,4-d i-O-ben -
zoyl-2-O-m eth yl-r-L-fu cop yr a n osyl)-(1f6)]-3-O-ben zyl-2-
d eoxy-2-p h t h a lim id o-â-D-glu cop yr a n osid e (28). This
compound was isolated as a reaction byproduct of the above
reaction (30 mg, 26%): Rf 0.32 (5:95 MeOH/CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 6.78-8.10 (m, 38H), 5.71-5.78 (m, 2H),
5.62-5.68 (m, 2H), 5.35 (d, J ) 3.4 Hz, 1H), 4.99 (d, J ) 8.5
Hz, 1H), 4.67-4.98 (m, 5H), 4.53-4.62 (m, 2H), 4.20-4.48 (m,
6H), 4.12 (dd, J ) 8.5, 10.2 Hz, 1H), 3.54 (s, 3H), 3.38-4.44
(m, 14H), 3.33 (bd, J ) 9.6 Hz, 1H), 1.89 (s, 3H), 1.85 (s, 3H),
1.80 (bs, 3H), 1.77 (s, 3H), 1.16 (d, J ) 6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.66, 170.17, 169.41, 169.20, 168.19,
167.58, 165.94, 165.02, 138.56, 137.72, 137.34, 136.96, 134.32,
134.13, 133.42, 133.19, 132.91, 131.68, 131.59, 131.51, 129.91,
129.83, 129.76, 129.63, 129.34, 128.82, 128.63, 128.51, 128.43,
Ben zyl (3,4-Di-O-a cet yl-6-O-b en zyl-2-d eoxy-2-t et r a -
ch lor oph th alim ido-â-D-glu copyr an osyl)-(1f4)-(3-O-acetyl-
6-O-ben zyl-2-d eoxy-2-p h th a lim id o-â-D-glu cop yr a n osyl)-
(1f4)-[(3,4-d i-O-ben zoyl-2-O-m eth yl-r-L-fu cop yr a n osyl)-
( 1 f6 ) ] -3 -O -b e n z y l -2 -d e o x y -2 -p h t h a l i m i d o -â-D -
glu cop yr a n osid e (26). To 20b (0.413 g, 0.37 mmol) and 25
(0.245 g, 0.29 mmol) (both dried by azeotroping together with
toluene) in CH2Cl2 (2.9 mL) at 0 °C were added N-iodosuccin-
imide (0.110 g, 0.48 mmol) and triethylsilyl triflate (30 µL, 0.13
mmol). After the solution was stirred for 22 min at 0 °C, the
reaction was quenched with 10% aqueous Na2S2O3 (2 mL) and
saturated aqueous NaHCO3 (2 mL). The mixture was diluted
with CH2Cl2 (15 mL) before the layers were separated. The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
concentrated residue was purified via flash chromatography,
eluting with 2:3 EtOAc/petroleum ether to give 26 as a white
amorphous powder (0.349 g, 65%): Rf 0.39 (45:55 EtOAc/
petroleum ether); [R]20 -30.0° (c 1.06, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 8.09 (d, J ) 7.3 Hz, 2H), 7.90-7.92 (bs, 2H),
7.88 (d, J ) 7.3 Hz, 2H), 7.71-7.81 (m, 3H), 7.58-7.66 (m,
2H), 7.46-7.54 (m, 3H), 7.37 (t, J ) 7.8 Hz, 2H), 7.20-7.32
(m, 6H), 7.12-7.19 (m, 3H), 6.96-7.04 (m, 5H), 6.93 (d, J )
6.7 Hz, 2H), 6.77 (d, J ) 6.7 Hz, 2H), 6.61-6.70 (m, 4H), 5.80
(dt, J ) 1.6 Hz, 8.6 Hz, 1H), 5.58-5.66 (m, 4H), 5.49 (d, J )
8.3 Hz, 1H), 5.27 (d, J ) 3.5 Hz, 1H), 5.17 (t, 9.4 Hz, 1H), 4.94
(d, J ) 8.6 Hz, 1H), 4.67 (d, J ) 12.4 Hz, 1H), 4.59 (d, J )
12.9 Hz, 1H), 4.32-4.47 (m, 7H), 4.11-4.24 (m, 5H), 4.03-
4.08 (m, 1H), 3.91 (dd, J ) 6.5 Hz, 3.5 Hz, 2H), 3.85 (d, J )
11.0 Hz, 1H), 3.78 (d, J ) 12.1 Hz, 1H), 3.72 (d, J ) 9.6 Hz,
1H), 3.41-3.60 (m, 8H), 3.32 (bd, J ) 7.8 Hz, 1H), 1.89 (s,
3H), 1.80 (s, 6H), 1.14 (d, J ) 6.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.55, 169.77, 169.27, 168.26, 167.63, 165.87, 165.31,
140.06, 138.27, 137.92, 137.46, 137.02, 134.49, 134.25, 133.17,

TCP- and Phth-Protected n-Pentenyl Glucosaminide Precursors
J . Org. Chem., Vol. 62, No. 14, 1997 4599
128.32, 128.24, 128.10, 127.84, 127.78, 127.74, 127.52, 127.39,
126.89, 123.64, 123.42, 100.42, 96.84, 95.95, 95.71, 76.52,
75.63, 75.41, 74.44, 73.73, 73.67, 73.61, 73.37, 73.33, 72.96,
72.49, 72.32, 71.13, 70.11, 69.99, 69.61, 68.98, 64.61, 64.53,
58.83, 55.71, 55.54, 53.49, 22.22, 20.62, 20.58, 20.33, 15.94;
MS (FAB) m/ e 1658.4 MH+.
(d, J ) 12.3 Hz, 2H), 4.40 (d, J ) 11.7 Hz, 1H), 4.24 (dd, J )
8.8, 11.1 Hz, 1H), 4.44 (t, J ) 9.4 Hz, 1H), 3.80-3.86 (m, 1H),
3.40-3.66 (m, 8H), 1.97 (s, 3H), 1.89 (s, 3H), 1.82 (s, 3H), 1.82-
2.40 (m, 8H), 1.48-1.72 (m, 4H), 1.06-1.38 (m, 20H), 0.84-
0.92 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 172.75, 170.53,
170.30, 169.51, 167.86, 167.54, 137.83, 137.70, 137.43, 134.05,
131.41, 131.38, 129.91, 129.78, 128.76, 128.71, 128.46, 128.37,
127.85, 127.74, 123.43, 114.66, 99.72, 98.13, 77.21, 75.01,
74.26, 73.54, 73.31, 72.47, 70.80, 69.57, 69.02, 68.74, 67.32,
54.90, 54.75, 49.07, 36.62, 33.91, 31.74, 29.79, 29.76, 29.69,
29.54, 29.50, 29.36, 29.29, 28.95, 28.43, 27.18, 25.57, 25.50,
24.92, 22.62, 20.65, 20.48, 14.09; MS (FAB) m/ e 1109.57 MH+;
Ben zyl (3,4-Di-O-a cet yl-6-O-b en zyl-2-d eoxy-2-{11(Z)-
octadecen am ido}-â-D-glu copyr an osyl)-(1f4)-(2-acetam ido-
3-O-acetyl-6-O-ben zyl-2-deoxy-â-D-glu copyr an osyl)-(1f4)-
[(3,4-d i-O-a cet yl-2-O-m et h yl-r-L-fu cop yr a n osyl)-(1f6)]-
2-acetam ido-3-O-ben zyl-2-deoxy-â-D-glu copyr an oside (29).
To 27 (23.0 mg, 12.22 µmol) in EtOH (1 mL) was added
ethylenediamine (0.122 mL, 1.833 mmol). The reaction was
stirred for 10 h at 60 °C and then concentrated in vacuo. The
reaction mixture was filtered through a short column of silica
gel with 10:90 MeOH/CH2Cl2. The residue was then treated
with acetic anhydride (11.5 µL, 0.122 mmol) and NEt3 (17 µL,
0.122 mmol) in CH2Cl2 (1 mL) for 25 min before the reaction
mixture was concentrated in vacuo. To the residue were added
a NaOMe solution (0.125 mmol in 0.25 mL MeOH) in MeOH
(0.5 mL) and THF (0.5 mL). After being stirred for 4 h, the
reaction mixture was quenched with AcOH (7.0 µL, .125
mmol), concentrated, and then treated with acetic anhydride
(68.0 µL, 0.726 mmol), NEt3 (14.2 µL, 0.103 mmol) and DMAP
(7.3 mg, 0.060 mmol) in pyridine (0.75 mL) and CH2Cl2 (0.5
mL) for 12 h. The reaction mixture was concentrated in vacuo
before being diluted with CH2Cl2 (25 mL) and washed with
both 5% aqueous HCl (1 × 8 mL), back extracting with CH2-
Cl2 (2 × 10 mL), and saturated aqueous NaHCO3 (8 mL), back
extracting the aqueous portion with CH2Cl2 (2 × 10 mL). The
reaction mixture was concentrated, and the residue was
purified by flash chromatography, eluting with 5:95 MeOH/
CH2Cl2. Compound 29 was recovered as a film (12.3 mg,
64%): Rf 0.20 (5:95 MeOH/CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ 7.22-7.44 (m, 20H), 6.50 (d, J ) 9.6 Hz, 1H), 5.90 (bs, 1H),
5.18-5.38 (m, 4H), 4.32-5.20 (m, 15H), 3.53 (s, 3H), 3.42-
4.20 (m, 18H), 2.16 (s, 3H), 2.04 (s, 3H), 1.94 (s, 3H), 1.93 (s,
3H), 1.90 (s, 3H), 1.88 (s, 3H), 1.83 (s, 3H), 1.82-2.06 (m, 8H),
1.18-1.42 (m, 20H), 0.93 (d, J ) 6.2 Hz, 3H), 0.86-0.87 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 172.80, 170.99, 170.59,
170.39, 170.31, 170.23, 169.45, 139.17, 137.59, 137.46, 129.93,
129.80, 129.08, 128.90, 128.72, 128.39, 128.33, 128.26, 127.89,
127.77, 127.65, 127.57, 127.53, 127.24, 102.02, 99.90, 99.67,
97.29, 78.33, 77.20, 76.26, 73.92, 73.48, 73.43, 72.95, 72.49,
71.55, 70.26, 69.61, 68.88, 67.58, 67.48, 65.02, 60.29, 53.87,
53.65, 36.44, 31.76, 29.78, 29.71, 29.58, 29.39, 29.34, 28.96,
27.21, 25.52, 23.20, 22.63, 20.90, 20.69, 15.55, 14.10; HRMS
(FAB) calcd for MH+ C85H118N3O25 1580.8054, found 1580.8022.
P en t-4-en yl (3,4-Di-O-a cetyl-6-O-ben zyl-2-d eoxy-2-{11-
(Z)-oct a d e ce n a m id o}-â-D-glu cop yr a n osyl)-(1f4)-3-O-
a cetyl-6-O-ben zyl-2-d eoxy-2-p h th a lim id o-â-D-glu cop yr a -
n osid e (32). To 20b (136.0 mg, 0.1222 mmol) in 0.9 mL of
2:1:1 acetonitrile/tetrahydrofuran/ethanol was added ethyl-
enediamine (15.5 µL, 0.2322 mmol) before the solution was
heated to 60 °C. The reaction mixture was stirred for 16 h,
allowed to cool to room temperature, concentrated, and then
filtered through a short column of silica gel with 5:95 MeOH/
CH2Cl2. The amine residue was dissolved in CH2Cl2 (1 mL)
along with 11(Z)-octadecenoic acid (28.4 mg, 0.1005 mmol). To
this was added DCC (20.8 mg, 0.1008 mmol) in CH2Cl2 (1 mL).
The reaction was stirred for 2.5 h and then filtered through
Celite before being concentrated in vacuo. To the residue were
added acetic anhydride (0.280 mL, 2.965 mmol), triethylamine
(0.125 mL, 0.93 mmol), and DMAP (49.0 mg, 0.401 mmol) in
CH2Cl2 (3 mL) for 12 h. The reaction mixture was concen-
trated in vacuo before being diluted with CH2Cl2 (30 mL) and
washed with saturated aqueous NaHCO3 (8 mL), back extract-
ing the aqueous portion with CH2Cl2 (2 × 10 mL). The
reaction mixture was concentrated, and the residue was
purified by flash chromatography eluting with a gradient of 5
f 15% EtOAc/CH2Cl2. Compound 32 was recovered as a film
(47 mg, 35%): Rf 0.64 (5:95 EtOAc/CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 7.69-7.85 (m, 4H), 7.26-7.48 (m, 10H), 5.68
(app t, J ) 9.4 Hz, 1H), 5.54-5.64 (m, 1H), 5.32-5.38 (m, 2H),
5.29 (d, J ) 8.8 Hz, 1H), 5.09 (t, J ) 10 Hz, 1H), 5.00 (t, J )
8.8 Hz, 1H), 4.70-4.88 (m, 4H), 4.58 (d, J ) 8.2 Hz, 1H), 4.48
[R]20 5.8° (c 1.00, CHCl3). Reaction byproduct 31 (24 mg,
D
51%). MS (FAB) m/ e 489.4 MH+.
ter t-Bu t yld im et h ylsilyl (3,4-Di-O-a cet yl-2-d eoxy-6-O-
(ter t-bu tyld im eth ylsilyl)-2-tetr a ch lor op h th a lim id o-â-D-
glu copyr an osyl)-(1f4)-(3-O-acetyl-2-deoxy-2-ph th alim ido-
6-O-(ter t-bu tyld im eth ylsilyl)-â-D-glu cop yr a n osyl)-(1f4)-
[(3,4-d i-O-ben zoyl-2-O-m eth yl-r-L-fu cop yr a n osyl)-(1f6)]-
2-d eoxy-2-p h th a lim id o-â-D-glu cop yr a n osid e (34b). To 26
(73.2 mg, 0.0388 mmol) in CH2Cl2 (2.6 mL) at 0 ˚C under strict
anhydrous conditions was added FeCl3 (100.6 mg, 0.62 mmol).
The reaction was stirred at 0 °C for 2 h 20 min before being
quenched with H2O (1 mL). The mixture was diluted with
CHCl3 (25 mL) and extracted with brine (10 mL). The aqueous
phase was extracted with CHCl3 (2 × 10 mL), and the organic
layers were combined, filtered, and concentrated. The residue
was flash chromatographed, eluting with 45:55 CH2Cl2/EtOAc
to give the tetrol (48 mg, 81%) as a white solid (MS (FAB)
m/ z 1523 M-). To the tetrol 34a (196.4 mg, 0.129 mmol) in
dimethylformamide (6 mL) at 0 °C was added imidazole (98.3
mg, 1.44 mmol). After 10 min, TBDMSCl (282.2 mg, 1.87
mmol) was added at 0 °C. The reaction was allowed to slowly
come to room temperature and stirred for 12 h before being
quenched by addition of saturated aqueous NaHCO3. The
excess dimethylformamide was concentrated in vacuo, and the
residue was taken up in CHCl3 (100 mL) and washed succes-
sively with saturated aqueous NaHCO3 (25 mL) and brine (25
mL). The aqueous layers were extracted with CHCl3 (4 × 25
mL). The organic layers were combined, filtered, and concen-
trated. The residue was flash chromatographed eluting with
30:70 f 35:65 EtOAc/petroleum ether to afford 34b (192.3 mg,
80%) as a white amorphous powder: Rf ) 0.51 (35:65 EtOAc/
petroleum ether); [R]20 -35.7° (c 1.50, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 8.02 (d, J ) 6.9 Hz, 2H), 7.91-7.96 (m, 2H),
7.78-7.87 (m, 5H), 7.68-7.73 (m, 2H), 7.59-7.65 (m, 1 H),
7.46-7.53 (m, 3H), 7.28-7.35 (m, 3H), 5.74 (dd, J ) 8.9, 10.6
Hz, 1H), 5.64 (dd, J ) 9.2, 10.6 Hz, 1H), 5.55 (d, J ) 3.4 Hz,
1H), 5.40-5.42 (m, 1H), 5.41 (d, J ) 8.5 Hz, 1H), 5.37 (d, J )
8.5 Hz, 1H), 5.35 (d, J ) 8.2 Hz, 1H), 5.11 (t, J ) 9.4 Hz, 1H),
4.91 (d, 3.4 Hz, 1H), 4.32 (bdd, J ) 7.5, 10.9 Hz, 1H), 4.18 (dd,
J ) 8.2, 10.6 Hz, 1H), 4.12 (dd, J ) 8.2, 10.3 Hz, 1H), 3.96-
4.05 (m, 4H), 3.69-3.81 (m, 4H), 3.49-3.62 (m, 6H), 3.41 (s,
3H), 3.38 (m, 1H), 3.26 (bdd, J )4.5, 10.6 Hz, 1H), 1.99 (s,
3H), 1.94 (s, 3H), 1.84 (s, 3H), 1.12 (d, J ) 6.5 Hz, 3H), 0.92
(s, 9H), 0.77 (m, 9H), 0.66 (m, 9H), 0.08 (s, 3H), 0.07 (s, 3H),
0.03 (s, 3H), -0.04 (s, 3H), -0.08 (s, 3H), -0.10 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.57, 169.87, 169.16, 168.35,
167.80, 167.48, 167.09, 165.75, 165.31, 163.24, 162.44, 162.06,
140.62, 134.63, 134.42, 134.36, 134.13, 133.73, 133.14, 132.79,
131.81, 131.31, 131.17, 129.88, 129.72, 129.67, 129.49, 128.42,
128.17, 126.64, 123.91, 123.78, 123.45, 123.29, 122.75, 98.00,
97.00, 96.08, 93.17, 80.91, 75.99, 75.21, 74.42, 73.59, 73.57,
71.91, 71.04, 70.94, 70.15, 69.33, 69.20, 65.38, 64.27, 62.23,
61.48, 59.46, 57.95, 55.77, 54.86, 25.84, 25.69, 25.23, 20.75,
20.68, 20.40, 18.25, 18.01, 17.44, 16.03, -4.36, -5.54, -5.59,
-5.62; MS (FAB) m/ e 1865.1 M-.
ter t-Bu tyld im eth ylsilyl (3,4-Di-O-a cetyl-2-d eoxy-2-{11-
(Z)-oct a d ecen a m id o}-6-O-(ter t-b u t yld im et h ylsilyl)-â-D-
glu copyr an osyl)-(1f4)-(3-O-acetyl-2-deoxy-2-ph th alim ido-
6-O-(ter t-bu tyld im eth ylsilyl)-â-D-glu cop yr a n osyl)-(1f4)-
3-O -a c e t y l-[(3,4-D i-O -b e n zo y l-2-O -m e t h y l-r-L -fu c o -
p yr a n osyl)-(1f6)]-2-d eoxy-2-p h th a lim id o-â-D-glu cop yr a -
n osid e (34c). To 34b (194.6 mg, 0.108 mmol) in 1.3 mL of
3:1 acetonitrile/ tetrahydrofuran was added ethylenediamine
(15.2 µL, 0.227 mmol) before the solution was heated to 60

4600 J . Org. Chem., Vol. 62, No. 14, 1997
Debenham et al.
°C. The reaction mixture was stirred for 10 h, allowed to cool
to room temperature, concentrated, and then filtered through
a short column of silica gel with 10:90 MeOH/CH2Cl2. The
amine in CH3CN (1.5 mL) was then added to 11(Z)-octa-
decenoic acid (0.146 g, 0.517 mmol) pretreated with both
triethylamine (0.144 mL, 1.03 mmol) for 15 min and then
2-chloro-N-methylpyridinium iodide (0.132 g, 0.517 mmol) in
CH3CN (0.5 mL) for 15 min at 40 °C. The reaction was stirred
for 2.5 h at 40 °C and was then concentrated in vacuo. To the
residue were added acetic anhydride (0.256 mL, 2.71 mmol),
triethylamine (45 µL, 0.325 mmol), and DMAP (40.0 mg, 0.325
mmol) in CH2Cl2 (1 mL) for 12 h. The reaction mixture was
diluted with CH2Cl2 (15 mL) and washed with saturated
aqueous NaHCO3 (8 mL), back extracting the aqueous portion
with CH2Cl2 (4 × 15 mL). The reaction mixture was concen-
trated, and the residue was purified by flash chromatography
eluting with 40:60 EtOAc/petroleum ether. Compound 34b
was recovered as a film (49 mg, 25%): Rf 0.43 (40:60 EtOAc/
recovered as a film (8.0 mg, 80%): Rf 0.32 (10:90 MeOH/CH2-
Cl2); H NMR (400 MHz, 20% MeOD-d4/80% CDCl3) δ 5.19-
1
5.27 (m, 2H), 4.73 (d, J ) 3.1 Hz, 1H), 4.44-4.50 (m, 1H),
4.33-4.41 (m, 1H), 4.3 (d, J ) 8.6 Hz, 1H), 3.92-4.0 (m, 1H),
3.15-3.90 (m, 33H), 2.05-2.12 (m, 1H), 1.86-1.92 (m, 4H),
1.85 (s, 3H), 1.84 (s, 3H), 1.12-1.25 (m, 22H), 1.10 (d, J ) 6.5
Hz, 3H), 0.78-0.82 (m, 12H), 0.77 (s, 9H), 0.73 (s, 9H), -0.08
to -0.02 (m, 15H), -0.13 (s, 3H); 13C NMR (100 MHz, 20%
MeOD-d4/80% CDCl3) δ 175.67, 171.74 (bs), 129.71, 129.61,
101.49, 101.34, 95.54, 96.15, 79.67, 79.25, 78.62, 77.20, 76.29,
74.62, 72.96, 72.72, 72.36, 71.78, 70.53, 69.99, 65.96, 65.36,
63.26, 61.13, 59.86, 59.61, 57.32, 55.40, 54.65, 36.23, 31.55,
29.58, 29.47, 29.39, 29.25, 29.14, 28.75, 26.98, 25.64, 25.49,
25.34, 25.13, 22.63, 22.57, 22.42, 18.18, 17.76, 17.57, 15.75,
13.80, -0.34, -4.11, -4.61, -5.82, -6.10; HRMS (FAB) calcd
for MH+ C65H126N3O20Si3 1352.8243, found 1352.8263.
O- (2-Deoxy-2-{11(Z)-octa d ecen a m id o}-â-D-glu cop yr a -
n osyl)-(1f4)-(2-acetam ido-2-deoxy-2-â-D-glu copyr an osyl)-
(1f4)-[(2-O-m eth yl-r-L-fu copyr an osyl)-(1f6)]-2-acetam ido-
2-d eoxy-D-glu cop yr a n ose (2). To 35 (2.5 mg, 1.8 µmol) in
300 µL of THF:MeOH (3:1) was added glacial acetic acid (40
µL), and the mixture was cooled to 0 °C before dropwise
addition of a 1 M solution of TBAF (200 µL). The reaction
was allowed to slowly come to room temperature and was
stirred for 6 h before addition of an additional 100 µL of acetic
acid. The mixture was concentrated and purified by C18
chromatography, eluting with H2O f 3:1 H2O/MeOH f 1:1
H2O/MeOH f 1:3 H2O/MeOH f MeOH. Lyophilization of the
fractions containing the desired product gave compound 2 (1.5
mg, 83%) as a white powder and a monsilylated derivative of
petroleum ether); [R]20 -39.3° (c 1.00, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 8.09 (d, J ) 6.8 Hz, 2H), 7.78-7.87 (m, 5H),
7.62-7.75 (m, 5H), 7.44-7.54 (m, 3H), 7.26-7.32 (m, 3H),
5.54-5.76 (m, 5H), 5.46 (d, J ) 7.9 Hz, 1H), 5.32-5.37 (m,
2H), 5.29 (d, J ) 3.4 Hz, 1H), 5.14 (d, J ) 8.9 Hz, 1H), 5.07 (t,
J ) 10.3 Hz, 1H), 4.98 (t, J ) 9.2 Hz, 1H), 4.69 (d, J ) 8.5 Hz,
1H), 4.48 (m, 1H), 4.18-4.27 (m, 2H), 4.02-4.10 (m, 2H), 3.85-
3.96 (m, 3H), 3.63-3.75 (m, 5H), 3.57 (d, J ) 9.6 Hz, 2H), 3.47
(s, 3H), 3.36-3.42 (m, 1H), 1.97-2.05 (m, 6H,), 1.96 (s, 3H),
1.94 (s, 3H), 1.92 (s, 3H), 1.87 (s, 3H), 1.20-1.37 (m, 22H),
1.17 (d, J ) 6.8 Hz, 3H), 0.97 (s, 9H), 0.83-0.09 (m, 12H),
0.66 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H), -0.01 (s, 3H), -0.02 (s,
3H), -0.03 (s, 3H), -0.15 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 172.27, 170.93, 170.29, 169.28, 168.11 (bs), 167.39, 167.27,
165.92, 165.18, 134.23, 134.08, 133.93, 133.23, 132.85, 131.69,
131.48, 131.37, 129.93, 129.79, 129.75, 128.53, 128.24, 123.67,
123.26 (bs), 100.23, 96.19, 95.68, 93.24, 77.20, 76.47, 75.09,
74.88, 74.38, 73.64, 72.96, 72.37, 72.31, 71.23, 70.28, 70.21,
69.19, 64.98, 64.51, 62.33, 61.41, 59.02, 57.22, 55.29, 54.54,
36.44, 31.77, 29.78, 29.72, 29.55, 29.39, 29.34, 29.29, 28.98,
28.88, 27.21, 26.09, 25.82, 25.24, 22.65, 21.05, 20.78, 20.67,
18.20, 17.48, 16.20, 14.12, -0.02, -4.35, -4.94, -5.27, -5.59,
-5.62, -5.66; HRMS (FAB) calcd for MH+ C99H142N3O28Si3
1904.9088, found 1904.9178.
ter t-Bu tyld im eth ylsilyl (2-Deoxy-2-{11(Z)-octa d ecen a -
m id o}-6-O-(ter t-bu tyld im eth ylsilyl)-â-D-glu cop yr a n osyl)-
(1f4)-(2-a ceta m id o-2-d eoxy-6-O-(ter t-bu tyld im eth ylsilyl-
â-D -g lu c o p y r a n o s y l)-(1f4)-[(2-O -m e t h y l-r-L -fu c o -
p yr a n osyl)-(1f6)]-2-a ceta m id o-2-d eoxy-â-D-glu cop yr a n o-
sid e (35). To 34c (14.0 mg, 7.347 µmol) in EtOH (0.67 mL)
and MeOH (0.33 mL) was added ethylenediamine (0.45 mL,
6.74 mmol). The reaction was stirred for 34 h at 90 °C and
then concentrated in vacuo. The reaction mixture was filtered
through a short column of silica gel with 12:88 MeOH/CH2-
Cl2. The residue was then treated with acetic anhydride (17
µL, 0.184 mmol) and NEt3 (25 µL, 0.184 mmol) in CH2Cl2 for
45 min before the reaction mixture was concentrated in vacuo.
To the residue was added NaOMe solution (0.25 mmol in 0.5
mL MeOH) in MeOH (1 mL). The reaction mixture was
concentrated after 2 h and then purified by flash chromatog-
raphy eluting with 12:88 MeOH/CH2Cl2. Compound 35 was
1
35 (0.3 mg, 15%): 2: Rf 0.62 (2:1:1 n-BuOH/EtOH/H2O); H
NMR (400 MHz, DMSO-d6) δ 6.57 (bs, 1H), 5.32 (m, 2H), 5.10
(bs, 1H), 4.90-4.98 (m, 2H), 4.85 (bs, 1H), 4.78 (d, J ) 5.81
Hz, 1H), 4.67-4.76 (m, 2H), 4.42-4.53 (m, 1H), 4.34 (d, J )
8.2 Hz, 2H), 3.57-3.8 (m, 6H), 3.26-3.49 (m, 10H), 2.97-3.19
(m, 6H), 1.95-2.07 (m, 4H), 1.82 (s, 3H), 1.80 (s, 3H), 1.40-
1.54 (m, 4H), 1.21-1.3 (m, 24H), 1.52 (d, J ) 6.5 Hz, 3H), 0.95
(s, 3H), 0.92 (t, J ) 7.5 Hz, 2H), 0.81-0.87 (m, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 172.11, 172.00, 168.99, 129.66, 129.60,
101.96, 101.53, 96.47, 90.53, 81.09, 80.62, 78.04, 76.93, 74.71,
73.99, 72.14, 71.80, 70.72, 66.37, 65.63, 65.03, 61.04, 60.09,
58.38, 57.49, 55.24, 53.65,37.59, 35.75, 31.11, 29.15, 29.06,
29.02, 28.96, 28.66, 28.24, 27.57, 25.71, 25.65, 24.97, 23.04,
22.95, 22.06, 19.19, 16.33, 13.93; HRMS (FAB) calcd for MH+
C47H84N3O20 1010.5648, found 1010.5676.
Ack n ow led gm en t. This work was supported by
NIH Grant GM-40171. We gratefully acknowledge Dr.
George Dubay for mass spectrometry assistance.
Su p p or tin g In for m a tion Ava ila ble: Listings of experi-
mental procedures for the desilylation and debenzylation
studies with selected analytical data (2 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
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