An inexpensive carbohydrate derivative used as a chiral auxiliary in the synthesis of α-hydroxy carboxylic acids

Article abstract of DOI:10.1016/S0040-4020(02)00871-2

Protected α-hydroxy carboxylic acids were synthesized in moderate yield and high diastereoselectivity by alkylation of glycolate (α-hydroxy acetate) enolates using a D-fructose-derived chiral auxiliary. The new chiral center was assigned the R configuration based on comparisons of optical rotations and on one crystal structure analysis. This alkylation methodology is compatible with several hydroxyl protecting groups. The free hydroxy acids were obtained upon removal of the protecting group from the hydroxyl functionality followed by saponification.

Full text of DOI:10.1016/S0040-4020(02)00871-2

Tetrahedron 58 (2002) 7663–7679
An inexpensive carbohydrate derivative used as a chiral auxiliary
in the synthesis of a-hydroxy carboxylic acids
*
Hongwu Yu, C. Eric Ballard, Paul D. Boyle and Binghe Wang
Department of Chemistry, North Carolina State University, Box 8204, Raleigh, NC 27695-8204, USA
Received 4 April 2002; accepted 16 July 2002
Abstract—Protected a-hydroxy carboxylic acids were synthesized in moderate yield and high diastereoselectivity by alkylation of glycolate
(a-hydroxy acetate) enolates using a D-fructose-derived chiral auxiliary. The new chiral center was assigned the R configuration based on
comparisons of optical rotations and on one crystal structure analysis. This alkylation methodology is compatible with several hydroxyl
protecting groups. The free hydroxy acids were obtained upon removal of the protecting group from the hydroxyl functionality followed by
saponification. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
camphorsulfonamide,57 or Evans’s oxazolidinone58 as
chiral auxiliaries. The first three strategies provided
excellent yield and good to excellent diastereomeric excess
(de) for the alkylation even with less reactive electrophiles
(e.g. butyl iodide), but they suffer the limitation of being
cleaved under harshly acidic conditions. The oxazolidinone
auxiliary gave excellent yields and diastereoselectivities,
but it was only studied with reactive electrophiles, mainly
allylic or propargylic iodides. However, no auxiliary that
can be removed by basic hydrolysis has been reported to
efficiently alkylate glycolates with a wide variety of
electrophiles.
a-Hydroxy carboxylic acids are important building blocks
for the synthesis of depsides and depsipeptides, natural
products that often exhibit significant biological
activity.1–16 Depsipeptides such as the potent antibiotic
vancomycin have been developed into therapeutic agents.
One way to make progress in this area is to make analogs of
these natural products containing unnatural hydroxy acids.
Development of synthetic routes to hydroxy acids will be
key to these efforts.
Reported enantioselective routes to a-hydroxy acids17,18
include hydroxylation of enolates,19,20 reduction of a-keto-
acid derivatives or their precursors,21–26 Horner–Wittig
reaction of aldehydes with a dialkoxymethyl phosphine
oxide followed by Sharpless dihydroxylation,27 carbonyl-
ene reactions of glyoxylates,28,29 addition of cyanide to
aldehydes and ketones,30,31 nucleophilic alkylation of
aldehydes32 or a-oxo acid derivatives,33–35 Friedel–Crafts
reactions of aromatic compounds with glyoxylates,36 O–H
insertions of diazoacetates,37 condensation of trans-1,3-
dithiane-1,3-dioxide with aldehydes,38 reduction of chiral
hemiacetals,39,40 osmium-catalyzed dihydroxylation fol-
lowed by a second oxidation,41 nucleophilic alkylation of
oxazin-4-ones,42 [2,3] Wittig rearrangement of propargyl-
oxy acetates,43 dynamic kinetic resolution,44 and enzymatic
resolution.45,46 Another straightforward method is the
stereoselective alkylation of glycolates (a-hydroxy
acetates).47–54 The most notable of these reports used a
trans-2,5-disubstituted pyrrolidine,55 menthone56 or
One readily available source of inexpensive chiral
auxiliaries is carbohydrates. Enolate alkylations using
carbohydrate auxiliaries have met with mixed results.59,60
Costa,61,62 Mulzer,63 and Koll64 achieved moderate yields
and selectivities with their systems. We investigated
1,2:4,5-di-O-isopropylidene-b-D-fructopyranose (D-fruc-
tose diacetonide)65 because it has proven valuable in
asymmetric synthesis. It has been used as an auxiliary in
Diels–Alder cycloadditions,66 and it is the precursor to an
epoxidation catalyst developed by Shi and co-workers.65
Earlier we outlined our preliminary results using D-fructose
diacetonide as an auxiliary in glycolate alkylation.67 Herein
we report our complete studies of asymmetric glycolate
alkylation.
2. Results and discussion
The auxiliary 1 was obtained from D-fructose in one step.65
Its free 3-hydroxyl group was esterified with benzyloxy-
acetic acid 2a using 1,3-dicyclohexylcarbodiimide (DCC)
and 4-(dimethylamino)pyridine (DMAP) to give glycolate
Keywords: chiral auxiliary; carbohydrate; asymmetric synthesis; hydroxy
carboxylic acid; enolate alkylation; glycolate alkylation.
*
Corresponding author. Tel.: þ1-919-515-2948; fax: þ1-919-515-3757;
e-mail: binghe_wang@ncsu.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00871-2

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H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
Scheme 1. General route for the synthesis and alkylation of glycolates 3.
3a (Scheme 1). Initial alkylations were conducted with two
reactive halides (allyl bromide and allyl iodide) to
determine the feasibility of using D-fructose diacetonide
as a chiral auxiliary (Scheme 1). Tetrahydrofuran (THF)
was used as the solvent for these reactions. Table 1
summarizes the findings of these experiments. Comparison
of entry 4 with entries 1–3 shows that lithium bis(tri-
methylsilyl)amide (LiHMDS) (2 equiv.) was the optimal
base in combination with the more reactive allyl iodide. In
an effort to maximize the de by performing the alkylation at
lower temperature, entry 5 shows that a higher yield was
obtained, but that the diastereoselectivity was slightly
lower.
Since these initial results were encouraging, we tried to
optimize the reaction with respect to a variety of factors,
including solvent, additives, base, cation, and hydroxyl
protecting group. The next studies examined the reaction as
a function of solvent polarity and coordination power. The
more Lewis basic solvents were expected to coordinate the
cation of the enolate more strongly, giving a more reactive
intermediate.68 The coordination of the enolate with solvent
and additives greatly affects the degree of aggregation of the
enolate in solution, which can significantly influence its
reactivity and selectivity.69 Some reports have shown that
aprotic polar additives such as hexamethylphosphoric
Table 1. Influences of base and temperature on the alkylation of 3a to 4b in
THF
Entry
RX
Base
Temp. Yield
(8C)
de
(%)
(%)
1
2
3
4
5
Allyl bromide LDA (1.5 equiv.)
278
278
59
51
41
54
78
66
92
81
92
86
Allyl iodide
Allyl iodide
Allyl iodide
Allyl iodide
LiHMDS (1.5 equiv.)
NaHMDS (1.5 equiv.) 278
LiHMDS (2 equiv.)
LiHMDS (2 equiv.)
278
292

H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
7665
Table 2. Reaction conditions, yields, and de’s for the optimization of the methylation of 3a to 4a (PG¼Bn, R¼Me)
Entry
Solvent
Additive
Base
Reaction temp. (8C)
Yield (%)
de (%)
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
THF
THF
PhMe
DME
THF
THF
THF
None
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
KHMDS
278
278
295
295
295
295
295
295
295
278
295
295
295
61
64
73
72
51
73
43
36
21
52
51
40
40
83
79
86
73
86
78
69
91
87
83
92
91
93
HMPA
HMPA
DMPU
TMEDA
HMPA
HMPA
HMPA
HMPA
HMPA
HMPAþMgBr2 (2.4 equiv.)
HMPAþLiBr (2.0 equiv.)
HMPAþLiCl (2.2 equiv.)
LiHMDS (1 equiv.)þn-BuLi (1 equiv.)
LiTMP
9
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
10
11
12
13
triamide (HMPA) can erode52,70 or even reverse62,71
stereoselectivity.
entries 6–8 shows that only KHMDS (2 equiv.) gave a
comparable yield, but with a slight sacrifice of de. The bulky
base lithium 2,2,6,6-tetramethylpiperidide (LiTMP) gave a
very low yield but a quite high de for the methylation.
Comparison of THF with the other solvents listed in entries
9 and 10, toluene and 1,2-dimethoxyethane (DME), show
that THF is superior. These solvents vary widely in their
ability to coordinate cations, and various reports have
shown each has been tested in certain examples of enolate
chemistry.52 The addition of various metal additives69,72 in
entries 11–13 gave much lower yields but good de’s. With
the lithium halide salts, about half of the starting material
was recovered unreacted.
These factors were optimized using glycolate 3a with MeI
as the alkylating agent (Scheme 1 and Table 2). The
initial conditions (entry 1) were the same as those used for
Table 1, entry 4: 2 equiv. of LiHMDS at 2788C. The
moderate yield and de for this reaction indicate that this is
an ideal reaction for optimization studies. If one of the
reaction conditions makes an important positive or
negative impact on the alkylation, the yield and/or
selectivity data should be significantly different from the
data in this baseline experiment. In addition, this product
1
offers the advantage that its de can be determined by H
NMR.
After these optimization studies had been completed, the
compatibility of other hydroxyl protecting groups (PG’s)
besides benzyl with these methylation conditions were
studied (Scheme 1 and Table 3). The alkylation conditions
used were LiHMDS (2 equiv.) in THF/5% HMPA at
2958C. Substrates in entries 2–11 were prepared by
DCC/DMAP coupling of the appropriately protected
glycolic acid with the auxiliary 1, except for glycolate 3j,
which was prepared by hydrogenolysis of 3a followed by
reprotection with the triethylsilyl group. These protecting
groups cover a large range of electronic and steric
characteristics. The overall impression from this table is
that the choice of protecting group had relatively little effect
on the stereoselectivity of the alkylation, but that it
significantly affected the yield. This was expected because
the directing influence of the reaction was assumed to arise
almost entirely from the chiral auxiliary. The differences in
yield probably arise from differences in stability of the
enolates.
The data in Table 2 indicate that the baseline conditions
were close to optimal, besides the use of HMPA as an
additive and lowering the reaction temperature. Comparison
of entries 1 and 2 shows that adding HMPA did not
significantly affect the reaction. However, with electrophiles
besides MeI, a large increase in yield was seen with the
addition of HMPA. For example, the addition of HMPA
increased the yield of the alkylation from 54% (92% de) to
76% (92% de) when allyl iodide was the electrophile.67
Comparison of entries 2 and 3 shows that lowering the
reaction temperature improved both the yield and de.
Comparison of HMPA with the other aprotic polar solvents
1,3-dimethylpropyleneurea (DMPU) and N,N,N0,N0-tetra-
methylethylenediamine (TMEDA) in entries 4 and 5 shows
that DMPU gives a comparable yield with slightly lower de
while TMEDA gives a much lower yield with comparable
stereoselectivity. Comparison of the different bases in
Table 3. Compatibility of different protecting groups with the optimal methylation conditions
Entry
Substrate
PG
Product (R¼Me)
Reaction temp. (8C)
Yield (%)
de (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
Bn
CH2C6H4NO2 ( p)
CH2C6H4OMe (p )
CH2C6H4F ( p)
Me
MOM
BOM
TBS
TBDPS
TES
TIPS
4a
5a
6a
7a
8a
9a
10a
11a
12a
13a
14a
295
295
295
295
295
295
295
278
278
278
295
73
19
66
75
66
65
68
76
83
77
70
86
89
91
93
92
91
87
84
89
88
84
9
10
11
3j
3k

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H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
Table 4. Yields and de’s for the conversion of esters 3a, h–j to 4, 11–13 in
the presence of HMPA at 2788C
the solution of substrate 3b turned dark red in color, unlike
those of the other substrates, which were pale yellow. Based
on the low pKa of p-nitrotoluene (20.4),75 competitive
deprotonation at the benzylic position may be occurring.
Comparison of entries 3 and 4 with entry 1 indicates that
the p-substituent had only a small effect on the yield of
the alkylation. The compound with the electron-with-
drawing fluorine (entry 4) gave a slightly greater yield
than that for the electron-donating methoxy (entry 3). A
possible explanation is that the electron-donating group
destabilizes the enolate, so that it undergoes more side
reactions.
Entry Substrate
Electrophile
(RX)
Product Yield de
(%) (%)
1
2
3
4
5
6
7
8
3a
3a
3a
3h
3h
3i
BnBr
CH3CH2I
PhCH2CH2I
CH2vCHCH2I
BnBr
CH2vCHCH2I
BnBr
CH2vCHCH2I
BnBr
CH3CH2I
4c
4d
4e
58
74
52
88
88
78
89
71
75
83
61
58
71
98
76
79
85
86
89
94
91
96
88
60
83
91
11b
11c
12b
12c
13b
13c
13d
13e
13f
3i
3j
3j
3j
3j
3j
3j
9
10
11
12
13
Entries 5–7 include more alkyl hydroxyl protecting groups:
methyl, methoxymethyl (MOM), and benxyloxymethyl
(BOM). The yields for these alkylations were slightly lower.
PhCH2CH2I
CH3(CH2)4I
2-(Bromomethyl)naphthalene 13g
The most successful reactions were carried out with silyl
protecting groups (entries 8–11). The groups tested
included the t-butyldimethylsilyl (TBS), t-butyldiphenyl-
silyl (TBDPS), triethylsilyl (TES), and triisopropylsilyl
(TIPS) groups. The less bulky groups (TBS, TBDPS, and
TES) provided the best yields and selectivities of any
protecting group, allowing for the different reaction
temperatures. The TIPS group gave a slightly lower yield,
with slightly lower selectivity. TIPS must be too large to
allow for efficient approach of the electrophile to the
enolate.
Scheme 2. Methylation of the glycolate 15 bearing larger protecting groups
on the auxiliary.
To confirm the conclusions from these studies, additional
electrophiles were tested with substrates 3a, h–j (PG¼Bn,
TBS, TBDPS, and TES, respectively, Scheme 1 and Table
4). Generally substrate 3a showed lower yield than the other
substrates. The TBDPS- and TES-protected substrates (3i
and 3j, respectively) gave comparably high yields and
selectivity. The TES glycolate 3j was chosen for further
studies with a wide range of electrophiles, including many
less reactive iodides (entries 10–12). Moderate yields and
good de values were also obtained with these substrates.
Scheme 3. Deprotection and hydrolysis of the esters 13 to give the free
acids 18.
Entry 1 of Table 3 is the same as entry 3 of Table 2 and
served as a baseline for this study. Entries 2–4 include
substituted benzyl groups and were included for comparison
with entry 1. The literature indicates that the protons of an
a-oxy carbonyl compound is more acidic than those of an
a-unsubstituted carbonyl compound.73,74 We hypothesized
that altering the electronics of the protecting group would
affect the yield of the reaction.
To test the importance of the bulkiness of the fructose diol
protecting groups, substrate 15 was prepared (Scheme 2).
Methylation of 15 proceeded in comparable yield and
selectivity at 2958C (71% yield, 85% de) compared with 3a
(73% yield, 86% de). The similarity of the results indicates
that the alkyl substituents of the ketals have little effect on
the selectivity. A possible explanation is that the dioxolane
rings of the ketals favor a particular conformation of the
auxiliary that leads to high asymmetric induction. There-
fore, the steric hindrance provided by the alkyl groups on
the ketal is less important than the conformational bias
provided by the ketals.
To test if this hypothesis were true for the subtly different
cases of unsubstituted and p-substituted benzyl groups, we
prepared substrates 3b–d. The reaction in entry 2 seems to
represent an odd case because during the addition of base,
Table 5. Specific optical rotations of the a-hydroxy carboxylic acids 16
a-Hydroxy carboxylic acid
[a ]D (8)
Absolute configuration
2-Hydroxypropionic acid (18a)
2-Hydroxy-3-phenylpropionic acid (18b)
2-Hydroxybutanoic acid (18c)
2-Hydroxy-4-phenylbutanoic acid (18d)
2-Hydroxyheptanoic acid (18e)
2-Hydroxy-3-naphthalen-2-yl-propionic acid (18f)
212.7 (c 0.33, EtOH)
þ12.7 (c 0.43, EtOH)
210.4 (c 0.12, EtOH)
213.3 (c 0.45, EtOH)
212.3 (c 0.41, CHCl3)
218.0 (c 0.74, EtOH)
Ra
Ra
R79
a
Comparison with data from the Aldrich Chemical catalog.

H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
7667
Scheme 4. The modified Cavelier’s method for determining if racemization
had occurred during the deprotection or hydrolysis of 13.
Figure 2. Stereoview of alkylated ester 4c.
The configuration of the newly generated stereocenter was
determined by the optical rotation of the free acids.
Compounds 4a,c were hydrolyzed in LiOH/THF/H2O to
give the hydroxyl-protected acid. Upon comparing their
specific rotations with the literature,76,77 they were con-
cluded to have the R configuration. In addition, the absolute
configurations of the enolate alkylation products 13 were
assigned by comparisons of the specific rotations of the
a-hydroxy carboxylic acids 18 obtained upon cleavage of
the protecting group with HF/pyridine followed by
saponification (Scheme 3) to those in the literature. The
results are listed in Table 5. These results indicated that the
newly formed chiral center had the R configuration.
boat-like conformation. More importantly, it is seen that the
new stereocenter has the R configuration.
In both structures the side closer to the 4,5-acetonide
appears to be more open. This is confirmed by analysis of
the crystal structures. In the starting material 3a the distance
of closest approach of a hydrogen atom on the a-carbon to
˚
the 1,2-acetonide is 3.37 A, while its distance of closest
˚
approach to the 4,5-acetonide is greater than 5.0 A. In the
product 4c the distance of closest approach of a hydrogen
atom on the a-carbon to the carbons of the 1,2-acetonide is
˚
3.49 A, while its distance of closest approach to the 4,5-
˚
acetonide is greater than 5.0 A.
To determine if racemization had occurred during the
deprotection or the saponification, Cavelier’s method
(Scheme 4) was followed.78 Alkylated products 13c,e
were deprotected with hydrogen fluoride-pyridine. 1H
NMR of the crude compounds 17 indicated that they had
the same de (within experimental error, 5%) as compounds
13. These crude compounds 17 were saponified as above to
give the free acids 18b,d, respectively. These acids were
coupled to H-Ala-OMe to give the amides 19 (Scheme 4).
1H NMR of the crude amides indicated they had the same de
(within experimental error, 5%) as compounds 13 and 17,
respectively. The deprotection, saponification, and amida-
tion steps were all high yielding (.86%), minimizing any
effects of kinetic resolution.
It is understood that these structures of the starting material
and the product do not provide information about the
conformation of the reactive intermediate, the enolate. The
factors responsible for the high de of the alkylations are
stereoselective formation of the enolate and selective
approach of the electrophile to one face of the enolate.
Literature precedent indicates that the enolate should have
the Z geometry.80,81 If the general conformation of the
enolate is similar to that of the starting material and the
product, the Z enolate is consistent with the R configuration
of the new chiral center.
3. Conclusion
To probe the factors responsible for the high stereo-
selectivity of these alkylations and to confirm the assign-
ment of the R configuration at the a-center, two of the
compounds were submitted for X-ray crystallography.
Glycolate 3a and product 4c were selected for analysis.
The stereoview of 3a (Fig. 1) shows the pyranose ring in a
boat conformation. The acyl group lies in a chain. The
stereoview of 4c (Fig. 2) shows that the alkylated acyl chain
lies roughly perpendicular to the acetonide protecting
groups on the carbohydrate. The pyranose ring is still in a
The synthesis of a-hydroxy carboxylic acids using auxiliary
1 has been successfully executed. The following features
were notable: (1) the crystalline auxiliary 1,2:4,5-di-O-
isopropylidene-b-D-fructopyranose 1 was easily obtained
on a large scale from an inexpensive starting material,
D-fructose; (2) the enolate alkylation proceeded in high de;
(3) the addition of HMPA increased the yield without
sacrificing diastereoselectivity; (4) the alkylation was
compatible with several hydroxyl protecting groups; and
(5) the other enantiomer of the auxiliary is readily
available.65,82 It is difficult to compare this auxiliary with
the others that have been reported in the literature, partly
because different electrophiles were used in each study.
However, on the whole, it seems that D-fructose diacetonide
is comparable with or better than most other auxiliaries that
have been used for glycolate alkylation. The fructose
auxiliary gave slightly lower yields and stereoselectivity
than Katsuki’s pyrrolidine55 and Uang’s57 and Pearson’s56
dioxolanone auxiliaries. It is not quite as selective as the
Evans auxiliary,58 but it gave good yields with a variety of
electrophiles. However, none of these other systems were
tested with the range of alkylating agents that were used in
this study. With the Evans auxiliary only especially reactive
electrophiles were examined. D-fructose diacetonide offers
Figure 1. Stereoview of glycolate 3a.

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H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
competitive selectivity and reactivity compared to these
proven auxiliaries. Furthermore, the D-fructose auxiliary
offers the advantage of low cost. Further development of
chiral auxiliaries available from inexpensive carbohydrates
will broaden the arsenal of tools available for the
preparation of a-hydroxy acids in a variety of situations.
(30 mL, 5 mL rinse) was cannulated over 10 min. The
reaction flask was insulated with aluminum foil and heated
to reflux. After 12 h, heating was discontinued. After the
mixture had cooled at rt for 3 h, it was poured onto crushed
ice and washed with EtOAc (4£40 mL). The aqueous layer
was cooled with crushed ice and acidified with concentrated
HCl until white material oiled out. The aqueous layer was
extracted with EtOAc (5£40 mL). (The aqueous layer was
reacidified after each extraction.) These combined organic
layers were washed with saturated NaCl (10 mL), dried
(MgSO4), filtered, rotovapped, and dried on the oil pump to
give an orange liquid (12.7 g). It was purified on a flash
silica column (2–10% MeOH/DCM). Fractions were
combined, rotovapped, and dried on the oil pump to give
4. Experimental
4.1. General
All reactions were performed in flame-dried or oven-dried
glassware (.1208C, .4 h) that was cooled under vacuum.
Some reagents were purified according to standard pro-
cedures83 as noted below. Dichloromethane (DCM) was
distilled from CaH2. THF was distilled from sodium and
benzophenone. HMPA and DMPU were distilled under
vacuum from CaH2 before use. TMEDA was used as
received (redistilled, Aldrich Sure-Seale bottle). LiHMDS
was purchased as a solution in THF (Aldrich Sure-Seale
bottle) and was titrated.84 NaHMDS was used as a 1.0 M
solution in THF (Aldrich Sure-Seale bottle). KHMDS was
used as a 0.5 M solution in toluene (Aldrich Sure-Seale
bottle). Reaction temperatures are the temperatures of
heating or cooling baths. Analytical thin-layer chromato-
graphy (TLC) was performed with Scientific Adsorbents
plastic-backed TLC silica gel 60F hard layer plates. TLC
plates were visualized with a 5% (w/v) solution of
phosphomolybdic acid in ethanol. Flash chromatography
was performed with Scientific Adsorbents silica gel (flash,
32–63 mm). Column chromatography was followed by
combining appropriate fractions, rotovapping, and drying
under oil pump vacuum. Mass spectrometry (MS) analyses
were performed by the Mass Spectrometry Laboratories of
North Carolina State University and the University of
1
2a as a pale yellow liquid (11.4 g, 89% yield). H NMR
(CDCl3, 300 MHz): d 7.37 (m, 5H), 4.66 (s, 2H), 4.14 (s,
2H).
4.1.2. Representative esterification procedure for the
preparation of the chiral glycolates. 1,2:4,5-Di-O-iso-
propylidene-b-D-fructopyranos-3-yl benzyloxyacetate
(3a). To a solution of benzyloxyacetic acid (2a, 2.7 g,
14.5 mmol) in dry DCM (25 mL) were added DCC (3.18 g,
14.5 mmol), 1,2:4,5-O-diisopropylidene-b-D-fructopyra-
nose 1 (2.0 g, 7.68 mmol) and DMAP (0.4 g, 3.08 mmol)
at 08C. The reaction mixture was stirred at 08C for 1 h and at
rt for 45 h. DCM was removed on the rotovap. The residue
was resuspended in EtOAc and kept in the freezer for
30 min before the solid was filtered off. The organic solution
was washed with saturated NaHCO3, 10% citric acid, and
saturated NaCl and dried (MgSO4). Upon filtration and
rotovapping, the residue was purified by flash chromato-
graphy on silica gel (hexanes/EtOAc 5:1 to 4:1) to afford 3a
as
a
white solid (4.9 g, 78%). Mp 103–1048C.
[a ]D¼2128.78 (c 0.46, CHCl3). 1H NMR (300 MHz,
CDCl3): d 7.30–7.37 (m, 5H), 5.22 (d, J¼8.1 Hz, 1H),
4.31–4.10 (m, 6H), 4.65 (d, J¼1.5 Hz, 2H), 3.98 (d,
J¼9.2 Hz, 1H), 3.86 (d, J¼9.2 Hz, 1H), 1.57 (s, 3H), 1.48
(s, 3H), 1.36 (s, 6H). 13C NMR (75.5 MHz, CDCl3): d 170.3,
137.2, 128.7, 128.3, 128.2, 112.3, 109.9, 103.7, 74.9, 73.9,
73.5, 72.1, 71.1, 67.2, 60.8, 28.0, 26.5, 26.4, 26.3. IR: n
2990, 2931, 2884, 1760, 1737, 1454, 1384, 1372, 1221,
1195, 1127, 1085, 1028, 976, 914, 886, 851, 824, 809, 744,
698 cm21. EIMS: 408 (Mþ). Anal. Calcd for C21H28O8: C,
61.75; H, 6.91. Found: C, 61.48; H, 6.80.
1
Kansas. H and 13C NMR spectra were recorded with a
Varian Gemini 300, GE Omega 300, Varian Mercury 300,
or Varian Mercury 400 NMR spectrometer. Chemical shifts
1
(d ) were given in ppm relative to TMS for H spectra and
relative to residual solvent for 13C spectra. IR spectra were
recorded of thin films of each compound cast from DCM or
chloroform on NaCl plates. Combustion analyses were
performed by Atlantic Microlabs, Inc., Norcross, Georgia.
All melting points were determined with a Thomas Hoover
capillary melting point apparatus and are uncorrected.
Specific rotations were determined on an AUTOPOL III
automatic polarimeter.
4.2. General procedure for the alkylation
To a solution of LiHMDS (2 mmol) in dry THF (6 mL)
(Method A) or in dry THF (6 mL) and HMPA (5 or 10%
v/v) (Method B) was added dropwise a solution of substrate
(1 mmol) in dry THF (4 mL) in 5 min at 2788C. The
resulting mixture was stirred at 2788C for 30 min, neat
alkyl iodide (5 mmol) was added. The reaction mixture was
stirred at 2788C until starting material had disappeared by
TLC (hexanes/EtOAc 3:2 or hexanes/Et2O 4:1). The
reaction was quenched at 2788C with saturated NH4Cl.
After the temperature of the mixture had reached about 08C,
the mixture was transferred to a separatory funnel and the
aqueous phase was extracted with EtOAc three times. The
combined organic layers were washed with saturated NaCl
and dried (MgSO4). Upon removing solvent on the rotovap,
the residue was purified by flash chromatography on silica
4.1.1. Benzyloxyacetic acid (2a).85 In a 2-neck 250 mL
round bottom flask sodium hydride (7.08 g, 177 mmol, 60%
dispersion in mineral oil) was washed with hexanes
(3£20 mL) and the remaining solvent was removed under
oil pump vacuum for 15 min. Into a rapidly stirred
suspension of this solid in dry THF (60 mL) at rt was
cannulated a solution of benzyl alcohol (15 mL, 145 mmol,
freshly distilled) in 50 mL dry THF (5 mL rinse) over
25 min. Additional benzyl alcohol (2 mL, 19 mmol, freshly
distilled) was added neat. After the mixture had stirred at rt
for 5 min, 15-crown-5 (0.10 mL, 0.50 mmol) and sodium
iodide (600 mg, 4 mmol, oven-dried) were added. Into this
white suspension, a solution of chloroacetic acid (7.30 g,
77.2 mmol, freshly recrystallized from CHCl3) in dry THF

H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
7669
gel (hexanes/Et2O) to afford the product. Method C was the
same as Method B except that the reaction was stirred at
2958C.
1.85 (m. 2H), 1.55 (s, 3H), 1.49 (s, 3H), 1.38 (s, 3H), 1.35 (s,
3H), 1.01 (t, J¼7.6 Hz, 3H). 13C NMR (75.5 MHz, CDCl3):
d 172.7, 137.6, 128.5, 128.2, 128.1, 127.9, 127.8, 112.2,
109.7, 103.7, 79.2, 74.8, 73.8, 72.2, 72.0, 71.0, 70.9, 60.7,
27.9, 26.5, 26.4, 26.3, 26.3, 26.2, 9.7. IR: n 2990, 2931,
2884, 1754, 1649, 1455, 1372, 1337, 1296, 1220, 1190,
4.2.1. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-3-
yl 2-(benzyloxy)propionate (4a). The product was
obtained in 73% yield using alkylation Method C. 1H
NMR (300 MHz, CDCl3): d 7.40–7.29 (m, 5H), 5.19 (d,
J¼8.1 Hz, 1H), 4.73 (d, J¼11.7 Hz, 1H), 4.44 (d,
J¼11.7 Hz, 1H), 4.31 (dd, J¼5.1, 7.8 Hz, 1H), 4.23 (dd,
J¼1.5, 5.1 Hz, 1H), 4.18–4.08 (m, 3H), 3.99 (d, J¼9.6 Hz,
1H), 3.86 (d, J¼9.6 Hz, 1H), 1.55 (s, 3H), 1.49 (s, 3H), 1.48
(d, J¼7.5 Hz, 3H), 1.38 (s, 3H), 1.35 (s, 3H). 13C NMR
(75.5 MHz, CDCl3): d 173.3, 137.7, 128.6, 128.3, 128.0,
112.3, 109.9, 103.8, 74.9, 74.2, 73.9, 72.2, 72.1, 71.1, 60.8,
28.0, 26.6, 26.5, 26.4, 19.0. IR: n 3031, 2987, 2936, 2885,
1755, 1496, 1454, 1372, 1326, 1296, 1240, 1220, 1194,
1140, 1085, 1066, 1028, 976, 912, 888, 862, 851, 836, 810,
741, 699 cm21. EIMS: 421 (M2Hþ). Anal. Calcd for
C22H30O8: C, 62.55; H, 7.16. Found: C, 62.69; H, 7.11.
1114, 1085, 1026, 976, 908, 888, 852, 817, 738, 668 cm21
.
FABMS: 443 (MþLi)þ.
4.2.5. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-3-
yl 2-(benzyloxy)-4-phenylbutanoate (4e). The product was
obtained in 52% yield using alkylation Method B. 1H NMR
(400 MHz, CDCl3): d 7.41–7.15 (m, 5H), 5.22 (d, J¼8 Hz,
1H), 4.76 (d, J¼11.6 Hz, 1H), 4.39 (d, J¼11.6 Hz, 1H), 4.30
(dd, J¼5.2, 7.6 Hz, 1H), 4.23 (dd, J¼1.6, 5.2 Hz, 1H), 4.15
(dd, J¼2.8, 13.6 Hz, 1H), 4.10 (d, J¼13.6 Hz, 1H), 3.99 (d,
J¼9.6 Hz, 1H), 3.98 (d, J¼6.8 Hz, 1H), 3.87 (d, J¼9.6 Hz,
1H), 2.82–2.69 (m, 2H), 2.12 (m, 2H), 1.55 (s, 3H), 1.48 (s,
3H), 1.35 (s, 3H), 1.34 (s, 3H). 13C NMR (75.5 MHz,
CDCl3): d 172.8, 141.4, 137.6, 128.8, 128.7, 128.6, 128.5,
128.4, 128.3, 128.2, 128.1, 128.0, 126.2, 112.4, 112.2,
110.0, 109.9, 103.8, 103.8, 74.9, 74.0, 72.5, 72.4, 72.3, 72.3,
72.1, 71.2, 71.1, 71.0, 60.9, 60.9, 35.0, 34.8, 32.9, 32.8,
31.5, 31.4, 29.9, 28.1, 27.5, 27.4, 26.7, 26.5, 26.4, 26.3,
26.2, 25.6, 14.1. IR: n 2987, 2933, 2873, 1754, 1604, 1496,
1454, 1383, 1372, 1296, 1220, 1191, 1168, 1113, 1086,
4.2.2. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-3-
yl 2-(benzyloxy)-4-pentenoate (4b). The product was
obtained in 76% yield using alkylation Method B. 1H
NMR (300 MHz, CDCl3): d 7.38–7.29 (m, 5H), 5.92–5.78
(m, 1H), 5.21–5.09 (m, 3H), 4.75 (d, J¼11.7 Hz, 1H), 4.43
(d, J¼11.7 Hz, 1H), 4.30 (dd, J¼5.1, 8.1 Hz, 1H), 4.23 (dd,
J¼1.5, 5.1 Hz, 1H), 4.15 (dd, J¼2.4, 14.1 Hz, 1H), 4.12 (m,
1H), 4.05 (d, J¼6.6 Hz, 1H), 3.98 (d, J¼9.6 Hz, 1H), 3.87
(d, J¼8.7 Hz, 1H), 2.58 (t, J¼7.5 Hz, 2H), 1.55 (s, 3H), 1.49
(s, 3H), 1.38 (s, 3H), 1.35 (s, 3H). 13C NMR (75.5 MHz,
CDCl3): d 172.2, 137.6, 133.0, 128.5, 128.3, 128.0, 112.3,
109.8, 103.8, 77.9, 74.8, 73.9, 72.3, 72.2, 72.1, 71.2, 60.8,
37.5, 28.0, 26.6, 26.4. IR: n 2990, 2931, 2884, 1755, 1643,
1454, 1372, 1337, 1220, 1190, 1112, 1085, 1026, 976, 913,
888, 851, 837, 810, 738, 698 cm21. FABMS: 447 (M2Hþ).
Anal. Calcd for C24H32O8: C, 64.27; H, 7.19. Found: C,
64.24; H, 7.16.
1066, 1028, 976, 912, 888, 850, 837, 810, 739, 699 cm21
FABMS: 519.2 (MþLi)þ.
.
4.2.6. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-3-
yl ( p-nitrobenzyloxy)acetate (3b). This was prepared by
the general esterification procedure using the alcohol 1 and
p-nitrobenzyloxyacetic acid86 2b to give 3b as a greenish
white solid (39%) and recovered alcohol 1 (33% recovery).
1
Mp 84–868C (dec.). H NMR (CDCl3, 400 MHz): d 8.22
(apparent d, J¼8.8 Hz, 2H), 7.56 (apparent d, J¼8.8 Hz,
2H), 5.22 (d, J¼8.0 Hz, 1H), 4.75 (s, 2H), 4.31 (d,
J¼16.4 Hz, 1H), 4.29 (d, J¼13.2 Hz, 1H), 4.25 (dd,
J¼8.4, 2.4 Hz, 1H), 4.23 (d, J¼16.4 Hz, 1H), 4.15 (dd,
J¼13.2, 2.4 Hz, 1H), 4.11 (d, J¼13.2 Hz, 1H), 3.99 (d,
J¼9.2 Hz, 1H), 3.88 (d, J¼9.6 Hz, 1H), 1.57 (s, 3H), 1.48
(s, 3H), 1.37 (s, 6H). 13C NMR (CDCl3, 75.5 MHz): d 169.7,
147.5, 144.8, 128.0, 123.6, 112.1, 109.7, 103.4, 74.6, 73.6,
72.0, 71.8, 71.2, 67.6, 60.5, 27.8, 26.3, 26.1, 26.0. IR: n
2987, 2931, 1761, 1607, 1523, 1384, 1347, 1243, 1220,
1196, 1135, 1085, 1026, 976, 914, 885, 851, 818, 805,
740 cm21. FABMS m/z (% of base peak): 454.1 (MþHþ,
28), 438.0, (MþH–Oþ, 88), 396.0 (MþH–CH3COCHþ3 ,
82), 243.1 (M2OCOCH2ORþ, 48), 136.0 (CH2Arþ, 100).
Anal. Calcd for C21H27NO10: C, 55.62; H, 6.00; N, 3.09.
Found: C, 55.80; H, 6.04; N, 3.09.
4.2.3. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-3-
yl 2-(benzyloxy)-3-phenylpropionate (4c). The product
1
was obtained in 58% yield using alkylation Method A. H
NMR (300 MHz, CDCl3): d 5.19 (d, J¼7.7 Hz, 1H), 4.71 (d,
J¼11.7 Hz, 1H), 4.36 (d, J¼11.7 Hz, 1H), 4.27–4.15 (m,
3H), 4.14 (dd, J¼2.4, 13.2 Hz, 1H), 4.07 (d, J¼13.4 Hz,
1H), 3.94 (d, J¼9.4 Hz, 1H), 3.77 (d, J¼9.4 Hz, 1H), 3.11
(m, 2H), 1.55 (s, 3H), 1.48 (s, 3H), 1.36 (s, 6H). 13C NMR
(75.5 MHz, CDCl3): d 172.1, 137.5, 137.1, 129.8, 128.5,
128.1, 127.9, 126.9, 112.3, 109.9, 103.7, 79.2, 74.8, 73.9,
72.5, 72.2, 71.3, 60.9, 39.5, 28.0, 26.6, 26.4. IR: n 2990,
2931, 1747, 1649, 1455, 1449, 1384, 1372, 1337, 1237,
1220, 1190, 1161, 1114, 1084, 973, 914, 864, 817 cm21
.
CIMS: 497 (M2Hþ). Anal. Calcd for C28H34O8: C, 67.45;
H, 6.87. Found: C, 67.38; H, 6.89.
4.2.7. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-3-
yl 2-( p-nitrobenzyloxy)propionate (5a). The product was
obtained as an oil in 19% yield using alkylation Method C.
1H NMR (CDCl3, 400 MHz): d 8.21 (apparent d, J¼8.8 Hz,
2H), 7.56 (apparent d, J¼8.8 Hz, 2H), 5.22–5.19 (d,
J¼8.0 Hz, 1H), 4.79 (d, J¼12.4 Hz, 1H), 4.57–4.56 (d,
J¼12.4 Hz, 1H), 4.34–4.07 (m, 5H), 3.99–3.97 (d,
J¼9.6 Hz, 1H), 3.87–3.84 (d, J¼9.2 Hz, 1H), 1.55 (s,
3H), 1.54 (d, J¼6.8 Hz, 3H), 1.49 (s, 3H), 1.39 (s, 3H), 1.35
(s, 3H). 13C NMR (CDCl3, 75.5 MHz): d 172.9, 147.7,
145.3, 128.3, 123.8, 112.3, 110.0, 103.8, 75.2, 74.9, 73.9,
4.2.4. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-3-
yl 2-(benzyloxy)butanoate (4d). The product was obtained
in 74% yield using alkylation Method B. 1H NMR
(400 MHz, CDCl3): d 5.20 (d, J¼7.6 Hz, 1H), 4.74 (d,
J¼11.6 Hz, 1H), 4.41 (d, J¼12.0 Hz, 1H), 4.29 (dd, J¼5.2,
7.6 Hz, 1H), 4.23 (dd, J¼1.6, 5.2 Hz, 1H), 4.15 (dd, J¼2.4,
13.2 Hz, 1H), 4.10 (d, J¼13.2 Hz, 1H), 4.00 (d, J¼9.2 Hz,
1H), 3.94 (dd, J¼5.6, 6.8 Hz, 1H), 3.88 (d, J¼9.2 Hz, 1H),

7670
H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
72.2, 71.6, 70.9, 60.9, 28.0, 26.6, 26.5, 26.3, 18.9. IR: n
2987, 2935, 2884, 1753, 1606, 1523, 1454, 1373, 1348,
1296, 1240, 1220, 1196, 1140, 1112, 1085, 1067, 1030, 976,
912, 888, 858, 821, 806, 739 cm21. FABMS m/z (% of base
peak): 474.2 (MþLiþ, 53), 452.2 (M2Meþ, 15), 410.2
(MþH–CH3COCHþ3 , 68), 243.2 (M2OCOCH(Me)ORþ,
36), 136.0 (CH2Arþ, 100). Anal. Calcd for C22H29NO10: C,
56.53; H, 6.25; N, 3.00. Found: C, 56.81; H, 6.32; N, 3.02.
(85 mL), washed with saturated NaHCO3 (5 mL), dried
(MgSO4), filtered, rotovapped, and dried on the oil pump to
give a pale green liquid (8.55 g, 59%). The material was
pure by 1H NMR and was used in subsequent reactions. 1H
NMR (CDCl3, 300 MHz): d 4.18 (d, J¼5.4 Hz, 2H), 3.81 (s,
3H), 2.34 (t, J¼5.5 Hz, 1H, exchanges with D2O).
p-Fluorobenzyloxyacetic acid (2d). In a two-neck flask a
suspension of sodium hydride (60% in mineral oil, 590 mg,
14.8 mmol) was washed with hexanes (3£10 mL) and then
dried under oil pump vacuum for 10 min. A solution of
methyl glycolate (1.04 g, 11.6 mmol) in dry THF (10 mL)
was added to the suspension of sodium hydride in dry THF
(50 mL) over about 3 min. After 5 min p-fluorobenzyl
bromide (2.17 mL, 17.3 mmol) was added dropwise over
about 3 min. Tetrabutylammonium iodide (110 mg,
0.30 mmol) and DMPU (0.30 mL, 2.5 mmol) were added.
The flask was insulated from light with aluminum foil and
the mixture was stirred overnight. The reaction was
followed by 1H NMR. After stirring at rt for 14 h, the
reaction mixture was heated in an oil bath to about 708C.
After stirring at this temperature for an additional 6 h, the
reaction mixture was allowed to cool to rt. After 30 min the
reaction was quenched by slow addition of saturated NH4Cl
(10 mL). The layers were separated, and the solvent was
removed from the organic layer. To the residue was added
1 M NaOH (50 mL) and the aqueous quench. After stirring
at rt for 1 h, the aqueous layer was washed with Et2O
(3£20 mL) and then cooled with crushed ice. Concentrated
HCl was added until the pH was 1–2. The aqueous layer
was extracted with DCM (3£20 mL). These combined
organic extracts were dried (MgSO4), filtered, and roto-
4.2.8. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-3-
yl ( p-methoxybenzyloxy)acetate (3c). This was prepared
by the general esterification procedure using the alcohol 1
and p-methoxybenzyloxyacetic acid86 2c to give 3c as a
greenish white solid (92%). Mp 868C (dec.). 1H NMR
(CDCl3, 400 MHz): d 7.30 (apparent d, J¼8.4 Hz, 2H), 6.88
(apparent d, J¼8.8 Hz, 2H), 5.21 (d, J¼7.6 Hz, 1H), 4.60 (d,
J¼11.2 Hz, 1H), 4.56 (d, J¼11.2 Hz, 1H), 4.28 (dd, J¼7.8,
5.0 Hz, 1H), 4.23 (dd, J¼5.2, 1.2 Hz, 1H), 4.19 (d,
J¼16.8 Hz, 1H), 4.14 (dd, J¼13.2, 2.4 Hz, 1H), 4.10 (d,
J¼16.4 Hz, 1H), 4.09 (d, J¼13.2 Hz, 1H), 3.97 (d,
J¼9.2 Hz, 1H), 3.86 (d, J¼9.2 Hz, 1H), 3.81 (s, 3H), 1.57
(s, 3H), 1.48 (s, 3H), 1.36 (s, 6H). 13C NMR (CDCl3,
75.5 MHz): d 170.3, 159.6, 129.9, 129.1, 113.9, 112.2,
109.8, 103.6, 74.7, 73.7, 73.0, 71.9, 70.8, 66.6, 60.6, 55.3,
27.9, 26.4, 26.3, 26.2. IR: n 2988, 1931, 1761, 1613, 1514,
1455, 1384, 1302, 1250, 1221, 1195, 1114, 1085, 1032, 976,
914, 886, 851, 818, 805, 714 cm21. FABMS m/z (% of base
peak): 437.2 (M2Hþ, 64), 438 (Mþ, 20), 423.0 (M2Meþ,
46), 381.0 (MþH–CH3COCHþ3 , 19), 244.0 (MþH–
OCOCH2ORþ, 80), 121.0 (CH2Arþ, 100). Anal. Calcd for
C22H30O9: C, 60.26; H, 6.90. Found: C, 60.15; H, 6.82.
1
4.2.9. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-3-
yl 2-(p-methoxybenzyloxy)propionate (6a). The product
was obtained as white crystals in 66% yield using alkylation
Method C. Mp 121.5–1238C. 1H NMR (CDCl3, 400 MHz):
d 7.30 (apparent d, J¼8.4 Hz, 2H), 6.87 (apparent d,
J¼8.8 Hz, 1H), 5.22–5.19 (d, J¼7.6 Hz, 1H), 4.70–4.65 (d,
J¼11.2 Hz, 1H), 4.39–4.38 (d, J¼11.2 Hz, 1H), 4.31 (dd,
J¼7.8, 5.4 Hz, 1H), 4.23 (dd, J¼5.2, 2.0 Hz, 1H), 4.15 (dd,
J¼13.4, 2.2 Hz, 1H), 4.11 (q, J¼6.8 Hz, 1H), 4.10 (dd,
J¼13.2, 2.4 Hz, 1H), 3.99 (d, J¼9.2 Hz, 1H), 3.86 (d,
J¼9.2 Hz, 1H), 3.79 (s, 3H), 1.55 (s, 3H), 1.49 (s, 3H), 1.46
(d, J¼7.2 Hz, 3H), 1.39 (s, 3H), 1.35 (s, 3H). 13C NMR
(CDCl3, 75.5 MHz): d 173.3, 159.5, 129.9, 129.7, 113.9,
112.2, 109.8, 103.7, 74.8, 73.8, 73.7, 73.4, 72.0, 71.7, 71.0,
70.9, 60.7, 55.3, 27.9, 26.5, 26.4, 18.9. IR: n 2987, 2937,
2825 (sh), 2050, 2003, 1901, 1748, 1612, 1587, 1514, 1489,
1467, 1449, 1375, 1344, 1316, 1300, 1251, 1221, 1179,
1137, 1112, 1085, 1063, 1028, 978, 914, 887, 865, 846, 824,
804, 767, 733, 686, 577 cm21. FABMS m/z (% of base
peak): 459.3 (MþLiþ, 36), 437.2 (M2Meþ, 10), 243.2
(M2OCOCH(Me)ORþ, 36), 121.0 (CH2Arþ, 100). Anal.
Calcd for C23H32O9: C, 61.05; H, 7.13. Found: C, 60.96; H,
6.94.
vapped to give a yellow liquid (1.0 g). H NMR indicated
that the liquid still contained some ester. To the liquid was
added 4 M NaOH (40 mL). This suspension was heated to
60–708C for 1 h, during which time it became a solution.
After cooling at rt for 20 min, the aqueous layer was washed
with DCM (3£20 mL) and then cooled with crushed ice.
Concentrated HCl (16 mL) was added until the pH was 1–2.
The aqueous layer was extracted with DCM (3£20 mL).
These combined organic extracts were dried (MgSO4),
filtered, rotovapped, and dried on the oil pump to give 2d as
a yellow liquid which froze into white needles in the freezer
(379 mg, 18%). Mp 44–458C. 1H NMR (CDCl3, 300 MHz):
d 7.37–7.32 (m, 2H), 7.09–7.03 (m, 2H), 4.62 (s, 2H), 4.14
(s, 2H). 13C NMR (CDCl3, 75.5 MHz): d 175.3, 162.7
(1JC – F¼246 Hz), 132.7, 130.0 (3JC – F¼8 Hz), 115.5
(2JC–F¼21 Hz), 72.7, 66.7. 19F NMR (CDCl3, 282 MHz):
d 2114.7. IR: n 3472–2919, 1731, 1604, 1511, 1433, 1223,
1155, 1116, 1016, 854, 821, 772, 660 cm21. FABMS m/z (%
of base peak): 183.1 (M2Hþ, 28).
The glycolate was prepared by the general esterification
procedure using the alcohol 1 and p-fluorobenzyloxyacetic
acid 2d to give 3d as a greenish white solid (84%). Mp
1058C. 1H NMR (CDCl3, 300 MHz): d 7.37–7.32 (m, 2H),
7.06–7.00 (m, 2H), 5.22 (d, J¼7.8 Hz, 1H), 4.60 (s, 2H),
4.29 (dd, J¼7.8, 5.3 Hz, 1H), 4.22 (d, J¼12.0 Hz, 1H), 4.22
(ddd, J¼11.1, 4.5, 1.2 Hz, 1H), 4.15 (d, J¼12.8 Hz, 1H),
4.12 (d, J¼2.4 Hz, 1H), 4.07 (d, J¼5.1 Hz, 1H), 3.97 (d,
J¼9.3 Hz, 1H), 3.87 (d, J¼9.3 Hz, 1H), 1.57 (s, 3H), 1.48
(s, 3H), 1.36 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): d 170.1,
162.6 (1JC–F¼246 Hz), 133.0, 129.9 (3JC–F¼8 Hz), 115.4
4.2.10. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl ( p-fluorobenzyloxy)acetate (3d). Methyl glycolate.
Glycolic acid (12.35 g, 163 mmol) and p-toluenesulfonic
acid monohydrate (102 mg, 0.537 mmol) were dissolved in
100 mL dry MeOH. The mixture was heated to reflux in a
heating mantle. After 2.5 h, the mixture was rotovapped to
give a colorless liquid. The liquid was dissolved in Et2O

H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
7671
(2JC–F¼22 Hz), 112.2, 109.8, 103.6, 74.7, 73.8, 72.6, 72.0,
71.1, 67.1, 60.7, 27.8, 26.4, 26.2. 19F NMR (CDCl3,
282 MHz): d 2115.1. IR: n 2990, 2931, 2884, 1759,
1602, 1509, 1455, 1373, 1222, 1196, 1127, 1084, 1026, 976,
914, 886, 855, 824, 818, 773, 738, 720, 668 cm21. FABMS
m/z (% of base peak): 433.2 (MþLiþ, 44), 369.1 (MþH–
CH3COCHþ3 , 62), 243.1 (M2OCOCH2ORþ, 20). Anal.
Calcd for C21H27FO8: C, 59.15; H, 6.38. Found: C, 59.44;
H, 6.44.
1451, 1373, 1264, 1237, 1220, 1189, 1127, 1113, 1084,
1066, 1041, 976, 914, 886, 854, 845, 820, 806, 800 cm21
FABMS m/z (% of base peak): 353.2 (MþLiþ, 62), 331.2
(M2Meþ, 72), 289.1 (MþH–CH3COCHþ3 , 100), 243.2
(M2OCOCH(Me)ORþ, 33). Anal. Calcd for C16H26O8: C,
55.48; H, 7.57. Found: C, 55.73; H, 7.66.
.
4.2.14. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl (methoxymethoxy)acetate (3f). Benzyl (methoxy-
methoxy)acetate. Benzyl glycolate87 (2.77 g, 16.7 mmol)
was dissolved in 20 mL dry THF at rt. i-Pr2NEt (4.7 mL,
27 mmol) and iodomethyl methyl ether (2.1 mL, 25 mmol)
were added. The mixture fumed and formed white
precipitate upon the addition of the iodide. After stirring
at rt for 3.5 h, the mixture was heated to reflux. After 22 h,
25 mL ice-cold saturated K2CO3 was added to the reaction
mixture. The mixture was extracted with EtOAc
(3£25 mL). The combined DCM extracts were washed
with saturated NaCl (10 mL), dried (MgSO4), and roto-
vapped to give a brown semi-solid. The liquid was separated
on a flash silica column (1:10 EtOAc/hexanes to 1:8
EtOAc/hexanes). Fractions were combined, rotovapped,
and dried on the oil pump to give the product as a yellow
liquid (2.97 g, 85%). 1H NMR (CDCl3, 300 MHz): d7.37 (s,
5H), 5.21 (s, 2H), 4.72 (s, 2H), 4.21 (s, 2H), 3.39 (s, 2H). 13C
NMR (CDCl3, 75.5 MHz): d 169.8, 135.4, 128.4, 128.3,
96.2, 66.3, 64.1, 55.5. IR: n 3033, 2952, 2896, 2825, 1758,
1498, 1456, 1404, 1364, 1279, 1194, 1152, 1121, 1062,
1015, 920, 841, 818, 804, 753, 698 cm21. FABMS m/z (%
of base peak): 211.1 (MþHþ, 100).
4.2.11. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-( p-fluorobenzyloxy)propionate (7a). The product
was obtained as a colorless oil in 75% yield using alkylation
1
Method C. H NMR (CDCl3, 400 MHz): d 7.37–7.34 (m,
2H), 7.05–7.00 (m, 2H), 5.22–5.19 (d, J¼8.0 Hz, 1H), 4.67
(d, J¼11.2 Hz, 1H), 4.40 (d, J¼11.2 Hz, 1H), 4.30 (dd,
J¼8.0, 5.2 Hz, 1H), 4.23 (dd, J¼5.4, 1.8 Hz, 1H), 4.16 (dd,
J¼13.6, 2.4 Hz, 1H), 4.11 (dd, J¼13.2, 1.8 Hz, 1H), 4.10 (q,
J¼7.2 Hz, 1H), 3.99 (d, J¼9.6 Hz, 1H), 3.87 (d, J¼9.2 Hz,
1H), 1.55 (s, 3H), 1.49 (s, 3H), 1.48 (d, J¼6.4 Hz, 3H), 1.39
(s, 3H), 1.36 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): d 173.2,
162.8 (1JC–F¼247 Hz), 133.6, 130.1 (3JC–F¼8 Hz), 115.5
(2JC–F¼22 Hz), 112.4, 110.0, 103.8, 75.0, 74.4, 74.0, 72.2,
71.5, 71.3, 60.9, 28.0, 26.6, 26.4, 19.0. 19F NMR (CDCl3,
282 MHz): d 2115.4. IR: n 3424, 2987, 2931, 1754, 1602,
1510, 1454, 1372, 1326, 1296, 1221, 1190, 1138, 1112,
1084, 1067, 1032, 975, 908, 885, 820 cm21. FABMS
m/z (% of base peak): 447.2 (MþLiþ, 27), 425.2
(M2Meþ, 15), 383.2 (MþH–CH3COCHþ3 , 84), 243.1
(M2OCOCH(Me)ORþ, 24). Anal. Calcd for C22H29FO8:
C, 59.99; H, 6.64. Found: C, 59.95; H, 6.61.
(Methoxymethoxy)acetic acid (2f). The ester (204 mg,
0.971 mmol) from above was dissolved in ,5 mL EtOAc.
The flask was evacuated and flushed with N2 three times.
Pd(OH)2 (23 mg) was added to the solution. The flask was
evacuated and flushed with H2 (balloon pressure) three
times. The mixture was stirred at rt for 2 h. The mixture was
filtered through a pad of packed Celite. The Celite was
washed with ,40 mL EtOAc. The filtrate was rotovapped
and dried on the oil pump to give 2f as a yellow liquid
(96 mg, 82%). 1H NMR (CDCl3, 300 MHz): d 10.52 (s, 1H),
4.74 (s, 2H), 4.24 (s, 2H), 3.43 (s, 3H). 13C NMR (CDCl3,
75.5 MHz): d 175.7, 96.5, 64.0, 56.0. IR: n 3449, 1734,
1605, 1428, 1215, 1151, 1114, 1055 cm21. FABMS m/z (%
of base peak): 120.0 (Mþ, 13). Anal. Calcd for C4H8O4: C,
40.00; H, 6.71. Found: C, 39.86; H, 6.85.
4.2.12. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl methoxyacetate (3e). This was prepared by the general
esterification procedure using the alcohol 1 and methoxy-
acetic acid (Acros) to give 3e as a yellowish green oil (74%)
and recovered alcohol 1 (25% recovery). 1H NMR (CDCl3,
400 MHz): d 5.21 (d, J¼8.0 Hz, 1H), 4.29 (dd, J¼7.8,
5.4 Hz, 1H), 4.24 (ddd, J¼5.4, 2.4, 1.2 Hz, 1H), 4.16 (d,
J¼16.4 Hz, 1H), 4.15 (dd, J¼13.4, 2.6 Hz, 1H), 4.09 (d,
J¼13.2 Hz, 1H), 4.08 (d, J¼16.8 Hz, 1H), 3.97 (d,
J¼9.6 Hz, 1H), 3.86 (d, J¼9.6 Hz, 1H), 3.47 (s, 3H), 1.56
(s, 3H), 1.48 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H). 13C NMR
(CDCl3, 75.5 MHz): d 170.1, 112.2, 109.8, 103.6, 74.5,
73.8, 72.0, 71.0, 69.7, 60.7, 59.5, 27.9, 26.5, 26.3, 26.2. IR:
n 2988, 2936, 2825, 1764, 1454, 1373, 1221, 1192, 1129,
1085, 976, 913, 885, 850, 839, 804, 714, 668 cm21
.
FABMS m/z (% of base peak): 331.2 (M2Hþ, 68), 317.2
(M2Meþ, 54), 275.2 (MþH–CH3COCHþ3 , 100), 243.2
(M2OCOCH2ORþ, 27). Anal. Calcd for C15H24O8: C,
54.21; H, 7.28. Found: C, 54.14; H, 7.11.
The glycolate was prepared by the general esterification
procedure using the alcohol 1 and methoxymethoxyacetic
acid 2f to give 3f as a yellow oil (771 mg, 31%). H NMR
1
(CDCl3, 400 MHz): d 5.20 (d, J¼7.6 Hz, 1H), 4.72 (s, 2H),
4.30 (d, J¼16.8 Hz, 1H), 4.29 (dd, J¼8.0, 5.6 Hz, 1H), 4.24
(ddd, J¼6.8, 1.2, 1 Hz, 1H), 4.20 (d, J¼16.8 Hz, 1H), 4.14
(dd, J¼13.4, 2.2 Hz, 1H), 4.09 (d, J¼13.6 Hz, 1H), 3.97 (d,
J¼9.3 Hz, 1H), 3.85 (d, J¼9.3 Hz, 1H), 3.40 (s, 3H), 1.56
(s, 3H), 1.48 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H). 13C NMR
(CDCl3, 75.5 MHz): d 170.0, 112.3, 109.9, 103.6, 96.6,
74.8, 73.8, 71.9, 71.0, 64.3, 60.7, 55.9, 27.9, 26.5, 26.4,
26.2. IR: n 3624, 3530, 2990, 2931, 2884, 2825, 1764,
1737, 1455, 1384, 1373, 1243, 1220, 1196, 1149, 1120,
4.2.13. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-methoxypropionate (8a). The product was obtained
as white crystals in 75% yield using alkylation Method
C. Mp 81–858C. 1H NMR (CDCl3, 400 MHz): d 5.20–5.17
(d, J¼7.8 Hz, 1H), 4.31 (dd, J¼8.0, 5.2 Hz, 1H), 4.23 (dd,
J¼5.2, 1.6 Hz, 1H), 4.15 (dd, J¼13.6, 2.4 Hz, 1H), 4.10 (d,
J¼13.6 Hz, 1H), 4.0–3.9 (m, 1H), 3.95 (dd, J¼6.6 Hz, 1H),
3.85–3.82 (d, J¼9.2 Hz, 1H), 3.41 (s, 3H), 1.60–1.34 (m,
15H). 13C NMR (CDCl3, 75.5 MHz): d 173.1, 112.3, 109.9,
103.8, 74.9, 73.9, 72.1, 71.1, 60.8, 57.9, 28.0, 26.6, 26.5,
26.4, 18.7. IR: n 2988, 2939, 2889, 2825, 1755, 1737, 1454,
1085, 1061, 979, 920, 885, 850, 808, 720 cm21
.
FABMS m/z (% of base peak): 369.3 (MþLiþ, 44), 347.2
(M2Meþ, 43), 305.2 (MþH–CH3COCHþ3 , 100), 243.2

7672
H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
(M2OCOCH2ORþ, 52). Anal. Calcd for C16H26O9: C,
53.03; H, 7.23. Found: C, 53.25; H, 7.32.
base peak): 197.0 (MþHþ, 56). Anal. Calcd for C10H12O4:
C, 61.22; H, 6.16. Found: C, 60.93; H, 5.99.
4.2.15. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(methoxymethoxy)propionate (9a). The product
was obtained in 65% yield using alkylation Method C. H
The glycolate was obtained by the general esterification
procedure using the alcohol 1 and benzyloxymethoxyacetic
acid 2g to give 3g as a green oil (85%). H NMR (CDCl3,
1
1
NMR (CDCl3, 400 MHz): d 5.18–5.14 (d, J¼8.4 Hz, 1H),
4.70 (q, J¼7.1 Hz, 2H), 4.29 (dd, J¼7.8, 5.0 Hz, 1H), 4.23
(dd, J¼5.6, 1.8 Hz, 1H), 4.14 (dd, J¼13.6, 2.4 Hz, 1H), 4.09
(d, J¼13.6 Hz, 1H), 3.96 (d, J¼9.2 Hz, 1H), 3.85 (d,
J¼9.2 Hz, 1H), 3.39 (s, 3H), 1.54 (s, 3H), 1.49 (s, 3H), 1.48
(d, J¼7.2 Hz, 3H), 1.40 (s, 3H), 1.35 (s, 3H). 13C NMR
(CDCl3, 75.5 MHz): d 173.0, 112.3, 109.8, 103.8, 96.3,
75.0, 74.0, 71.9, 71.8, 70.9, 60.7, 56.0, 27.9, 26.6, 26.2,
18.7. IR: n 2987, 2937, 2891, 2826, 1758, 1454, 1373, 1326,
1296, 1221, 1190, 1156, 1126, 1085, 1026, 976, 915, 886,
852, 810, 765, 750, 654, 626 cm21. FABMS m/z (% of base
peak): 383.2 (MþLiþ, 72), 361.2 (M2Meþ, 20), 319.2
(MþH–CH3COCHþ3 , 69), 243.2 (M2OCOCH(Me)ORþ,
34). Anal. Calcd for C17H28O9: C, 54.25; H, 7.50. Found: C,
54.38; H, 7.51.
400 MHz): d 7.35 (s, 5H), 5.20 (d, J¼7.6 Hz, 1H), 4.86 (s,
2H), 4.66 (s, 2H), 4.35 (d, J¼16.8 Hz, 1H), 4.28 (dd, J¼7.6,
5.2 Hz, 1H), 4.25 (d, J¼16.4 Hz, 1H), 4.23 (dd, J¼2.8,
1.2 Hz, 1H), 4.14 (dd, J¼13.6, 2.4 Hz, 1H), 4.09 (d,
J¼13.2 Hz, 1H), 3.94 (d, J¼9.6 Hz, 1H), 3.83 (d,
J¼9.6 Hz, 1H), 1.56 (s, 3H), 1.48 (s, 3H), 1.38 (s, 3H),
1.36 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): d 170.1, 137.6,
128.6, 128.1, 128.0, 112.3, 109.9, 103.7, 94.8, 74.7, 73.9,
72.0, 71.1, 70.2, 64.5, 60.7, 27.9, 26.5, 26.5, 26.3. IR:
n 2986, 2934, 2889, 1763, 1496, 1455, 1373, 1220,
1198, 1167, 1114, 1085, 1063, 1028, 976, 913, 884,
849, 805, 739, 699 cm21. FABMS m/z (% of base
peak): 445.3 (MþLiþ, 52), 423.3 (M2Meþ, 26), 381.3
(MþH–CH3COCHþ3 , 72), 351.2 (MþH–CH3COCH32
CH2Oþ, 47), 243.2 (M2OCOCH2ORþ, 100). Anal. Calcd
for C22H30O9: C, 60.26; H, 6.90. Found: C, 60.53; H, 6.91.
4.2.16. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl (benzyloxymethoxy)acetate (3g). Methyl (benzyl-
oxymethoxy)acetate. NaI (84 mg, 0.56 mmol) was dis-
solved in 25 mL dry THF at 08C. Methyl glycolate
(2.50 g, 27.8 mmol), i-Pr2NEt (10 mL, 57.5 mmol), and
benzyl chloromethyl ether88 (8.65 g, 55.3 mmol) were
added. The mixture was left to stir, with warming to rt.
After 45 h, the reaction mixture was poured into 30 mL ice-
cold saturated NaHCO3. The layers were separated, and the
aqueous layer was extracted with 4£25 mL EtOAc. The
combined organic layers were washed with 10 mL saturated
NaCl, dried (MgSO4), and rotovapped to give a yellow
liquid. It was separated on a flash silica column (1:10
EtOAc/hexanes to 1:4 EtOAc/hexanes). Fractions were
combined, rotovapped, and dried on the oil pump to give the
ester as a pale yellow liquid (4.524 g, 77%). 1H NMR
(CDCl3, 300 MHz): d 7.34 (s, 5H), 4.85 (s, 2H), 4.65 (s,
2H), 4.23 (s, 2H), 3.76 (s, 3H). 13C NMR (CDCl3,
75.5 MHz): d 170.3, 137.4, 128.2, 127.7, 127.6, 94.4,
69.6, 64.2, 51.6. IR: n 3037, 2953, 2896, 1758, 1737, 1498,
1454, 1437, 1383, 1285, 1215, 1170, 1122, 1063, 1028, 931,
844, 824, 814, 742, 699 cm21. FABMS m/z (% of base
peak): 211.0 (MþHþ, 60). Anal. Calcd for C11H14O4: C,
62.85; H, 6.71. Found: C, 62.57; H, 6.69.
4.2.17. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(benzyloxymethoxy)propionate (10a). The product
was obtained in 68% yield using alkylation Method C. Mp
1
82–83.58C. H NMR (CDCl3, 400 MHz): d 7.37–7.35 (m,
5H), 5.19–5.13 (d, J¼8.0 Hz, 1H), 4.85–4.81 (m, 2H),
4.68–4.61 (m, 2H), 4.34 (q, J¼6.8 Hz, 1H), 4.27 (dd,
J¼7.8, 5.4 Hz, 1H), 4.22–4.20 (m, 1H), 4.13 (dd, J¼13.2,
2.6 Hz, 1H), 4.07 (d, J¼13.6 Hz, 1H), 3.84 (d, J¼9.6 Hz,
1H), 3.77 (d, J¼9.6 Hz, 1H), 1.54 (s, 3H), 1.48 (d,
J¼7.6 Hz, 3H), 1.47 (s, 3H), 1.38 (s, 3H), 1.34 (s, 3H).
13C NMR (CDCl3, 75.5 MHz): d 173.0, 137.8, 128.6, 128.2,
128.0, 112.3, 109.9, 130.8, 96.4, 94.4, 75.0, 74.0, 72.0, 71.8,
70.9, 70.2, 60.7, 28.0, 26.6, 26.2, 18.8. IR: n 2987, 2937,
2890, 1760, 1454, 1373, 1221, 1167, 1123, 1114, 1084,
1026, 976, 912, 886, 852, 805, 738, 699 cm21. FABMS
m/z (% of base peak): 459.3 (MþLiþ, 53), 437.2 (M2Meþ,
38), 395.2 (MþH–CH3COCHþ3 , 48), 365.2 (MþH–CH3-
COCH32CH2Oþ, 24), 243.2 (M2OCOCH(Me)ORþ, 100).
Anal. Calcd for C23H32O9: C, 61.05; H, 7.13. Found: C,
61.30; H, 7.00.
4.2.18. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl (t-butyldimethylsilyloxy)acetate (3h). The glycolate
was obtained by the general esterification procedure using
alcohol 1 and (t-butyldimethylsilyloxy)acetic acid89 2h to
(Benzyloxymethoxy)acetic acid (2g). The ester (1.01 g,
4.80 mmol) from above was dissolved in 5 mL THF, 5 mL
deionized H2O, and 3 mL 4 M NaOH. After stirring
vigorously at rt for 30 min, the mixture was extracted with
2£15 mL Et2O. The aqueous layer was cooled with ice and
then acidified with 10% citric acid and ,0.5 mL concen-
trated HCl (pH ,2 by pH paper). The aqueous layer was
extracted with 4£25 mL Et2O. These combined Et2O layers
were washed with 10 mL saturated NaCl, dried (MgSO4),
filtered, rotovapped, and dried on the oil pump to give 2g as
a colorless oil (914 mg, 97% yield). 1H NMR (CDCl3,
300 MHz): d 7.35 (s, 5H), 4.87 (s, 2H), 4.67 (s, 2H), 4.27 (s,
2H). 13C NMR (CDCl3, 75.5 MHz): d 175.8, 137.3, 128.6,
128.0, 94.6, 70.1, 64.1. IR: n 3436, 3032, 2897, 1760, 1732,
1497, 1454, 1433, 1384, 1249, 1209, 1170, 1120, 1062,
1028, 938, 908, 824, 742, 698 cm21. FABMS m/z (% of
1
give 3h (49%). H NMR (300 MHz, CDCl3): d 5.17 (d,
J¼7.5 Hz, 1H), 4.39–4.21 (m, 4H), 4.14 (dd, J¼2.4,
13.8 Hz, 1H), 4.08 (d, J¼13.2 Hz, 1H), 3.96 (d, J¼9.6 Hz,
1H), 3.85 (d, J¼8.7 Hz, 1H), 1.54 (s, 3H), 1.48 (s, 3H), 1.38
(s, 3H), 1.35 (s, 3H), 0.92 (s, 9H), 0.11 (s, 6H). 13C NMR
(75.5 MHz, CDCl3): d 171.7, 112.3, 109.9, 103.8, 74.9,
74.0, 72.0, 70.9, 61.8, 60.7, 28.0, 26.6, 26.5, 26.4, 26.0,
25.9, 25.3. IR: n 2990, 2931, 2860, 1768, 1461, 1378, 1369,
1255, 1220, 1142, 1086, 973, 914, 885, 853, 836, 779 cm21
.
FABMS: 439.1 (MþLiþ). Anal. Calcd for C20H36O8Si: C,
55.53; H, 8.39. Found: C, 55.35; H, 8.39.
4.2.19. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(t-butyldimethylsilyloxy)propionate (11a). The
product was obtained in 76% yield using alkylation Method

H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
7673
1
B. H NMR (300 MHz, CDCl3): d 5.13 (d, J¼7.2 Hz, 1H),
n 3071, 2987, 2932, 2857, 1770, 1740, 1472, 1428, 1383,
1372, 1297, 1221, 1197, 1140, 1113, 1085, 1067, 1028, 976,
914, 881, 849, 822, 800, 741, 702, 609 cm21. FABMS:
563.4 (MþLiþ).
4.39 (dd, J¼7.5, 14.1 Hz, 1H), 4.28 (m, 1H), 4.21 (m, 1H),
4.14 (dd, J¼2.1, 13.2 Hz, 1H), 4.08 (d, J¼14.1 Hz, 1H),
3.96 (d, J¼9.6 Hz, 1H), 3.83 (d, J¼9.6 Hz, 1H), 1.52 (s,
3H), 1.48 (s, 3H), 1.45 (d, J¼6.6 Hz, 3H), 1.40 (s, 3H), 1.34
(s, 3H), 0.91 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H). 13C NMR
(75.5 MHz, CDCl3): d 174.3, 112.3, 109.8, 103.9, 74.9,
73.9, 72.1, 70.9, 68.6, 60.8, 28.0, 26.7, 26.6, 26.4, 26.0,
21.9, 18.5, 24.7, 25.2. IR: n 2987, 2933, 2888, 2857, 1768,
1740, 1472, 1383, 1372, 1254, 1220, 1143, 1086, 1068,
1030, 976, 914, 887, 837, 810, 780, 668 cm21. FABMS:
445.1 (M2Hþ). Anal. Calcd for C21H38O8Si: C, 56.48; H,
8.58. Found: C, 56.61; H, 8.63.
4.2.23. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(t-butyldiphenylsilyloxy)propionate (12a). The
product was obtained in 83% yield using alkylation Method
B. 1H NMR (300 MHz, CDCl3): d 7.70–7.66 (m, 4H),
7.47–7.33 (m, 6H), 5.08 (d, J¼7.2 Hz, 1H), 4.33 (dd,
J¼6.6, 13.8 Hz, 1H), 4.24–4.18 (m, 2H), 4.11 (dd, J¼2.1,
13.8 Hz, 1H), 4.05 (d, J¼14.1 Hz, 1H), 3.85 (d, J¼9.6 Hz,
1H), 3.49 (d, J¼9.6 Hz, 1H), 1.54 (s, 3H), 1.45 (s, 3H), 1.43
(d, J¼6.6 Hz, 3H), 1.35 (s, 3H), 1.23 (s, 3H), 1.10 (s, 9H).
13C NMR (75.5 MHz, CDCl3): d 173.7, 136.1, 135.9, 133.8,
133.1, 130.0, 127.9, 112.2, 109.8, 103.7, 74.9, 73.9, 71.7,
70.6, 69.0, 60.6, 28.0, 27.0, 26.8, 26.7, 26.2, 21.9, 19.4. IR:
n 3071, 2987, 2932, 2857, 1764, 1740, 1472, 1428, 1372,
1221, 1189, 1135, 1112, 1085, 1066, 1026, 975, 911, 887,
866, 823, 785, 740, 702, 608 cm21. FABMS: 577.5
(MþLiþ).
4.2.20. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(t-butyldimethylsilyloxy)-4-pentenoate (11b). The
product was obtained in 78% yield using alkylation Method
B. 1H NMR (400 MHz, CDCl3): d 5.90–5.80 (m, 1H),
5.17–5.08 (m, 3H), 4.33–4.26 (m, 2H), 4.21 (dd, J¼1.6,
5.2 Hz, 1H), 4.13 (dd, J¼2.4, 13.2 Hz, 1H), 4.08 (d,
J¼9.9 Hz, 1H), 3.95 (d, J¼9.2 Hz, 1H), 3.84 (d,
J¼9.2 Hz, 1H), 2.51 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H),
1.40 (s, 3H), 1.33 (s, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.06 (s,
3H). 13C NMR (75.5 MHz, CDCl3): d 173.2, 133.5, 118.5,
112.3, 109.8, 103.9, 74.8, 73.9, 72.3, 72.0, 71.0, 60.8, 40.2,
28.0, 26.7, 26.5, 26.4, 25.9, 18.5, 24.7, 25.2. IR: n 3080,
3987, 2932, 2887, 2838, 1765, 1738, 1643, 1472, 1462,
1434, 1384, 1372, 1296, 1220, 1140, 1086, 1044, 976, 913,
888, 836, 810, 779, 737, 668, 626 cm21. FABMS: 471.0
(M2Hþ). Anal. Calcd for C23H40O8Si (472.64); C, 58.45;
H, 8.57. Found: C, 58.47; H, 8.57.
4.2.24. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(t-butyldiphenylsilyloxy)-4-pentenoate (12b). The
product was obtained in 88% yield using alkylation Method
B. 1H NMR (300 MHz, CDCl3): d 7.69–7.66 (m, 4H),
7.45–7.33 (m, 6H), 5.90–5.77 (m, 1H), 5.18–5.03 (m, 3H),
4.38 (t, J¼5.1 Hz, 1H), 4.27 (dd, J¼2.1, 13.8 Hz, 1H),
4.22–4.16 (m, 2H), 4.04 (d, J¼13.8 Hz, 1H), 3.82 (d,
J¼9.3 Hz, 1H), 3.49 (d, J¼9.3 Hz, 1H), 2.46 (t, J¼6.6,
5.8 Hz, 2H), 1.52 (s, 3H), 1.46 (s, 3H), 1.34 (s, 3H), 1.25 (s,
3H), 1.10 (s, 9H). 13C NMR (75.5 MHz, CDCl3): d 172.4,
136.2, 136.1, 133.6, 133.1, 132.8, 130.0, 127.9, 118.7,
112.2, 109.7, 103.7, 74.9, 74.0, 72.4, 71.7, 70.7, 60.6, 40.0,
28.1, 27.1, 26.9, 26.8, 26.7, 19.6. IR: n 3072, 2990, 2931,
2861, 1766, 1738, 1472, 1372, 1243, 1220, 1136, 1113,
4.2.21. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(t-butyldimethylsilyloxy)-3-phenylpropionate
(11c). The product was obtained in 89% yield using
1
alkylation Method B. H NMR (300 MHz, CDCl3): d 7.25
(m, 5H), 5.16 (d, J¼8.1 Hz, 1H), 4.41 (dd, J¼3.6, 8.7 Hz,
1H), 4.28 (dd, J¼5.1, 7.2 Hz, 1H), 4.21 (dd, J¼1.5, 5.1 Hz,
1H), 4.15 (dd, J¼2.1, 13.8 Hz, 1H), 4.08 (d, J¼13.2 Hz,
1H), 3.92 (d, J¼9.3 Hz, 1H), 3.73 (d, J¼9.6 Hz, 1H), 3.12
(dd, J¼3.6, 13.8 Hz, 1H), 2.93 (dd, J¼8.7, 14.1 Hz, 1H),
1.54 (s, 3H), 1.48 (s, 3H), 1.40 (s, 3H), 1.35 (s, 3H), 0.80 (s,
6H), 20.09 (s, 3H), 20.23 (s, 3H). 13C NMR (75.5 MHz,
CDCl3): d 173.2, 137.5, 130.2, 128.3, 126.8, 112.2, 109.8,
103.8, 74.8, 73.9, 73.8, 72.0, 71.1, 60.8, 42.0, 28.0, 26.6,
26.5, 26.4, 25.8, 18.4, 25.2, 25.6. IR: n 2990, 2931, 2860,
1764, 1736, 1490, 1456, 1372, 1251, 1220, 1128, 1086, 976,
938, 903, 888, 845, 810, 779, 699 cm21. FABMS: 529.1
(MþLiþ).
1086, 1030, 996, 976, 912, 887, 862, 824, 740, 702 cm21
.
FABMS: 603.5 (MþLiþ).
4.2.25. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(t-butyldiphenylsilyloxy)-3-phenylpropionate
(12c). The product was obtained in 88% yield using
alkylation Method B. 1H NMR (300 MHz, CDCl3): d
7.61–7.53 (m, 2H), 7.43–7.17 (m, 13H), 5.00 (d, J¼7.2 Hz,
1H), 4.54 (t, J¼5.9 Hz, 1H), 4.14–4.03 (m, 3H), 3.99 (d,
J¼13.2 Hz, 1H), 3.66 (d, J¼9.3 Hz, 1H), 3.07 (d, J¼9.6 Hz,
1H), 3.02 (s, 1H), 3.00 (d, J¼1.5 Hz, 1H), 1.51 (s, 3H), 1.43
(s, 3H), 1.34 (s, 3H), 1.18 (s, 3H), 1.04 (s, 9H). 13C NMR
(75.5 MHz, CDCl3): d 172.2, 136.8, 136.3, 136.0, 133.4,
133.0, 130.3, 130.0, 129.9, 128.3, 127.8, 126.8, 112.1,
109.7, 103.5, 74.7, 73.9, 73.7, 71.5, 70.5, 60.6, 41.8, 27.9,
27.0, 26.9, 26.6, 26.2. IR: n 2990, 2931, 2860, 1766, 1731,
1455, 1384, 1372, 1214, 1113, 1085, 1032, 973, 886, 853,
818, 773, 738, 701, 668 cm21. FABMS: 653.3 (MþLiþ).
4.2.22. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl (t-butyldiphenylsilyloxy)acetate (3i). The glycolate
was obtained by the general esterification procedure using
the alcohol 1 and (t-butyldiphenylsilyloxy)acetic acid90 to
1
give 3i (79%). H NMR (300 MHz, CDCl3): d 7.72–7.67
(m, 4H), 7.44–7.37 (m, 6H), 5.15 (d, J¼7.2 Hz, 1H), 4.40
(d, J¼16.8 Hz, 1H), 4.24 (d, J¼16.8 Hz, 1H), 4.24–4.18
(m, 2H), 4.10 (dd, J¼1.5, 13.8 Hz, 1H), 4.05 (d, J¼13.2 Hz,
1H), 3.92 (d, J¼9.6 Hz, 1H), 3.68 (d, J¼9 Hz, 1H), 1.55 (s,
3H), 1.44 (s, 3H), 1.35 (s, 3H), 1.21 (s, 3H), 1.09 (s, 9H). 13C
NMR (75.5 MHz, CDCl3): d 171.0, 135.8, 135.7, 133.0,
132.8, 130.1, 130.1, 128.0, 112.2, 109.8, 103.7, 74.9, 73.9,
71.9, 70.7, 62.2, 60.6, 28.0, 26.9, 26.7, 26.6, 26.2, 19.5. IR:
4.2.26. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl (triethylsilyloxy)acetate (3j). A solution of 3a in
EtOAc was stirred in the presence of H2 (balloon pressure)
and 20% Pd(OH)2/C overnight. Pd(OH)2 was removed by
filtration through Celite. The crude product (1.52 g,
5.84 mmol) was dissolved in anhydrous pyridine (15 mL),
and triethylsilyl chloride (1.1 mL, 6.5 mmol) was added
dropwise at 08C. The reaction mixture was stirred at rt

7674
H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
overnight. Pyridine was removed on the rotovap. The
residue was dissolved in EtOAc and washed with saturated
NaHCO3 and brine and dried over MgSO4. Upon removing
solvent, the residue was purified by flash chromatography
on a silica gel column (hexanes/ethyl acetate) to afford 3j as
an oil (2.08 g, 82%). 1H NMR (300 MHz, CDCl3): d 5.18 (d,
J¼7.7 Hz, 1H), 4.35 (d, J¼16.8 Hz, 1H), 4.30–4.22 (m,
3H), 4.14 (dd, J¼2.1, 13.6 Hz, 1H), 4.08 (d, J¼13.2 Hz,
1H), 3.96 (d, J¼9.3 Hz, 1H), 3.85 (d, J¼9.5 Hz, 1H), 1.55
(s, 3H), 1.48 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H), 0.98 (t,
J¼7.8 Hz, 9H), 0.65 (dd, J¼7.6, 15.6 Hz, 6H). 13C NMR
(75.5 MHz, CDCl3): d 171.6, 112.3, 109.9, 103.8, 74.9,
74.0, 72.0, 70.8, 61.4, 60.7, 28.0, 26.6, 26.3, 6.8, 4.5. IR: n
2990, 2954, 2884, 1768, 1737, 1455, 1384, 1372, 1221,
J¼8.3, 13.5 Hz, 1H), 1.53 (s, 3H), 1.48 (s, 3H), 1.40 (s, 3H),
1.35 (s, 3H), 0.83 (t, J¼7.83 Hz, 9H), 0.46 (m, 6H). 13C
NMR (100 MHz, CDCl3): d 173.3, 137.4, 130.1, 128.3,
126.8, 112.2, 109.8, 103.8, 74.8, 73.9, 73.3, 71.9, 71.0, 60.7,
41.9, 28.0, 26.6, 26.6, 26.3, 6.8, 4.5. IR: n 3064, 3030, 2987,
2955, 2877, 1764, 1737, 1605, 1496, 1455, 1415, 1383,
1372, 1296, 1240, 1220, 1191, 1128, 1086, 1067, 1043,
1030, 976, 910, 888, 852, 811, 774, 743, 699, 668,
626 cm21. FABMS: 529.0 (MþLiþ). Anal. Calcd for
C27H42O8Si: C, 62.04; H, 8.10. Found: C, 62.01; H, 8.05.
4.2.30. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(triethylsilyloxy)butanoate (13d). The product was
obtained in 83% yield using alkylation Method B. 1H NMR
(300 MHz, CDCl3): d 5.14 (d, J¼7.8 Hz, 1H), 4.29–4.20
(m, 3H), 4.14 (dd, J¼1.8, 13.5 Hz, 1H), 4.08 (d, J¼13.4 Hz,
1H), 3.97 (d, J¼9.3 Hz, 1H), 3.84 (d, J¼9.3 Hz, 1H), 1.79
(m, 2H), 1.52 (s, 3H), 1.48 (s, 3H), 1.40 (s, 3H), 1.34 (s, 3H),
0.99 (t, J¼4.2 Hz, 3H), 0.97 (t, J¼8.0 Hz, 9H), 0.63 (dd,
J¼7.8, 15.6 Hz, 6H). 13C NMR (75.5 MHz, CDCl3): d
173.8, 112.2, 109.7, 103.9, 74.9, 73.9, 72.9, 72.0, 70.8, 60.7,
28.9, 28.0, 26.6, 26.5, 26.3, 9.4, 6.9, 4.8. IR: n 2986, 2956,
2878, 1760, 1736, 1460, 1415, 1383, 1372, 1326, 1296,
1240, 1221, 1190, 1140, 1114, 1086, 1069, 1028, 976, 910,
888, 848, 810, 743, 669, 626 cm21. FABMS: 466.9
(MþLiþ). Anal. Calcd for C22H40O8Si: C, 57.36; H, 8.75.
Found: C, 57.22; H, 8.74.
1196, 1142, 1086, 1067, 976, 887, 852, 816, 794, 745 cm21
.
FABMS: 439.1 (MþLiþ). Anal. Calcd for C20H36O8Si: C,
55.53; H, 8.39. Found: C, 55.69; H, 8.39.
4.2.27. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(triethylsilyloxy)propionate (13a). The product
1
was obtained in 77% yield using alkylation Method B. H
NMR (400 MHz, CDCl3): d 5.14 (d, J¼5.7 Hz, 1H), 4.39
(dd, J¼4.8, 9.9 Hz, 1H), 4.27 (dd, J¼3.9, 6.0 Hz, 1H), 4.22
(dd, J¼1.5, 3.9 Hz, 1H), 4.14 (dd, J¼1.8, 10.2 Hz, 1H), 4.08
(d, J¼10.2 Hz, 1H), 3.97 (d, J¼6.9 Hz, 1H), 3.83 (d,
J¼6.9 Hz, 1H), 1.52 (s, 3H), 1.49 (s, 3H), 1.46 (d,
J¼5.4 Hz, 3H), 1.40 (s, 3H), 1.34 (s, 3H), 0.97 (t,
J¼6.6 Hz, 9H), 0.63 (dd, J¼5.7, 11.7 Hz, 6H). 13C NMR
(100 MHz, CDCl3): d 174.2, 112.2, 109.8, 103.8, 74.8, 73.9,
71.9, 70.8, 68.0, 60.7, 27.9, 26.6, 26.5, 26.3, 21.9, 6.8, 4.7.
IR: n 2990, 2943, 2884, 2731, 1764, 1624, 1459, 1414,
1372, 1325, 1296, 1221, 1190, 1140, 1086, 1018, 977, 912,
4.2.31. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 4-phenyl-2-(triethylsilyloxy)butanoate (13e). The
product was obtained in 61% yield using alkylation Method
B. 1H NMR (400 MHz, CDCl3): d 7.30–7.18 (m, 5H), 5.18
(d, J¼7.6 Hz, 1H), 4.36 (t, J¼5.2 Hz, 1H), 4.29 (dd, J¼5.2,
8.0 Hz, 1H), 4.22 (dd, J¼1.6, 5.2 Hz, 1H), 4.15 (dd, J¼2.0,
13.6 Hz, 1H), 4.09 (d, J¼13.2 Hz, 1H), 3.98 (d, J¼9.2 Hz,
1H), 3.85 (d, J¼9.2 Hz, 1H), 2.74 (m, 2H), 2.07 (m, 2H),
1.52 (s, 3H), 1.48 (s, 3H), 1.38 (s, 3H), 1.34 (s, 3H), 0.97 (t,
J¼8 Hz, 9H), 0.64 (dd, J¼10.4, 18.4 Hz, 6H). 13C NMR
(75.5 MHz, CDCl3): d 173.6, 141.9, 128.7, 128.5, 126.0,
112.2, 109.8, 103.9, 74.9, 73.9, 72.0, 71.4, 71.1, 60.8, 37.6,
31.0, 28.0, 26.6, 26.5, 26.4, 6.9, 4.8. IR: n 3063, 3029, 2987,
2955, 2877, 1760, 1737, 1604, 1497, 1455, 1415, 1383,
1372, 1326, 1296, 1240, 1220, 1187, 1155, 1129, 1086,
1066, 1029, 976, 911, 888, 850, 931, 804, 744, 700, 669,
626 cm21. FABMS: 542.9 (MþLiþ). Anal. Calcd for
C28H44O8Si: C, 62.66; H, 8.26. Found: C, 62.68; H, 8.12.
889, 865, 850, 836, 812, 786, 746, 674, 626, 514 cm21
.
FABMS: 453.1 (MþLiþ). Anal. Calcd for C21H38O8Si
(446.61); C, 56.48; H, 8.58. Found: C, 56.24; H, 8.50.
4.2.28. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(triethylsilyloxy)-4-pentenoate (13b). The product
1
was obtained in 71% yield using alkylation Method B. H
NMR (400 MHz, CDCl3): d 5.91–5.81 (m, 1H), 5.18–5.09
(m, 3H), 4.33 (dd, J¼5.2, 6.8 Hz, 1H), 4.28 (dd, J¼6.6,
8.4 Hz, 1H), 4.21 (dd, J¼2.0, 5.6 Hz, 1H), 4.14 (dd, J¼2.8,
13.6 Hz, 1H), 4.08 (d, J¼13.2 Hz, 1H), 3.96 (d, J¼9.6 Hz,
1H), 3.84 (d, J¼9.2 Hz, 1H), 2.52 (m, 2H), 1.51 (s, 3H),
1.49 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H), 0.96 (t, J¼7.6 Hz,
9H), 0.62 (dd, J¼7.6, 15.6 Hz, 6H). 13C NMR (75.5 MHz,
CDCl3): d 173.2, 133.4, 118.4, 112.2, 109.8, 103.9, 74.9,
74.0, 72.0, 72.0, 71.0, 60.8, 40.2, 28.0, 26.7, 26.6, 26.4, 6.9,
4.8. IR: n 3079, 2987, 2954, 2878, 1763, 1738, 1642, 1457,
1415, 1383, 1372, 1296, 1240, 1220, 1190, 1139, 1114,
1086, 1067, 1043, 1030, 1004, 976, 912, 888, 850, 832, 810,
745, 676, 626, 514 cm21. FABMS: 471.0 (M2Hþ). Anal.
Calcd for C23H40O8Si (472.64); C, 58.45; H, 8.53. Found:
C, 58.70; H, 8.58.
4.2.32. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(triethylsilyloxy)heptanoate (13f). The product
1
was obtained in 58% yield using alkylation Method B. H
NMR (300 MHz, CDCl3): d 5.14 (d, J¼7.8 Hz, 1H), 4.29–
4.20 (m, 3H), 4.14 (dd, J¼2.0, 13.5 Hz, 1H), 4.05 (d,
J¼13.4 Hz, 1H), 3.97 (d, J¼9.3 Hz, 1H), 3.84 (d, J¼9.2 Hz,
1H), 1.73 (m, 2H), 1.51 (s, 3H), 1.48 (s, 3H), 1.43–1.30 (m,
6H), 1.40 (s, 3H), 1.33 (s, 3H), 0.96 (t, J¼8.0 Hz, 9H), 0.89
(t, J¼6.5 Hz, 3H), 0.62 (dd, J¼7.6, 15.6 Hz, 6H). 13C NMR
(75.5 MHz, CDCl3): d174.0, 112.2, 109.8, 103.9, 74.9, 74.0,
72.0, 70.8, 60.8, 35.7, 31.8, 28.0, 26.7, 26.6, 26.4, 24.6,
22.7, 14.2, 6.9, 4.8. IR: n 2987, 2955, 2876, 1761, 1736,
1458, 1416, 1382, 1372, 1296, 1240, 1220, 1190, 1140,
4.2.29. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 3-phenyl-2-(triethylsilyloxy)propionate (13c). The
product was obtained in 75% yield using alkylation Method
1
B. H NMR (300 MHz, CDCl3): d 7.25 (m, 5H), 5.15 (d,
J¼7.8 Hz, 1H), 4.44 (dd, J¼3.9, 8.3 Hz, 1H), 4.27 (dd,
J¼5.2, 7.6 Hz, 1H), 4.21 (m, 1H), 4.14 (dd, J¼2.2, 13.4 Hz,
1H), 4.07 (d, J¼13.4 Hz, 1H), 3.92 (d, J¼9.4 Hz, 1H), 3.72
(d, J¼8.7 Hz, 1H), 3.11 (dd, J¼3.7, 13.4 Hz, 1H), 2.95 (dd,
1114, 1030, 976, 912, 888, 851, 838, 810, 744, 668 cm21
.
FABMS: 500.9 (M2Hþ). Anal. Calcd for C25H46O8Si: C,
59.73; H, 9.22. Found: C, 59.95; H, 9.31.

H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
7675
4.2.33. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 3-naphthalen-2-yl-2-(triethylsilyloxy)propionate
(13g). The product was obtained in 71% yield using
alkylation Method B. 1H NMR (400 MHz, CDCl3): d
7.82–7.70 (m, 4H), 7.45–7.39 (m, 3H), 5.15 (d, J¼7.8 Hz,
1H), 4.54 (dd, J¼3.9, 7.8 Hz, 1H), 4.24 (dd, J¼5.2, 7.6 Hz,
1H), 4.18 (s, 1H), 4.10 (d, J¼1.5 Hz, 1H), 4.06 (d,
J¼13.2 Hz, 1H), 3.90 (d, J¼9.3 Hz, 1H), 3.74 (d,
J¼9.3 Hz, 1H), 3.27 (dd, J¼4.1, 13.6 Hz, 1H), 3.13 (dd,
J¼8.0, 13.4 Hz, 1H), 1.51 (s, 3H), 1.48 (s, 3H), 1.39 (s, 3H),
1.33 (s, 3H), 0.80 (t, J¼7.8 Hz, 9H), 0.45 (m, 6H). 13C NMR
(75.5 MHz, CDCl3): d 173.2, 134.9, 133.6, 132.6, 128.8,
128.3, 127.8, 126.0, 125.5, 112.2, 109.8, 103.8, 74.8, 73.9,
73.3, 72.0, 71.1, 60.8, 42.2, 27.9, 26.6, 26.5, 26.4, 6.8, 4.6.
IR: n 2990, 2954, 2872, 1760, 1731, 1455, 1372, 1220,
1190, 1124, 1085, 973, 888, 853, 817, 740 cm21. FABMS:
579.0 (MþLiþ). Anal. Calcd for C31H44O8Si: C, 65.01; H,
7.74. Found: C, 65.13; H, 7.81.
28.0, 26.5, 26.3, 18.0, 12.1. IR: n 2986, 2942, 2892, 2867,
2120, 1770, 1738, 1463, 1383, 1372, 1326, 1297, 1241,
1221, 1198, 1146, 1114, 1086, 1068, 1030, 977, 916, 883,
855, 816, 798, 748, 682, 668 cm21. FABMS m/z (% of base
peak): 481.4 (MþLiþ, 60), 473.4 (M2Hþ, 31), 459.4
(M2Meþ, 34), 417.3 (MþH–CH3COCHþ3 , 78), 243.2
(M2OCOCH2ORþ, 100). HRFABMS: Calcd for C23H42-
O8SiLi (MþLi)þ: 481.2809. Found: 481.2810.
4.2.35. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl 2-(triisopropylsilyloxy)propionate (14a). The product
was obtained as white needles in 70% yield using alkylation
Method C. Mp 77–798C (dec). 1H NMR (CDCl3,
400 MHz): d 5.14 (d, J¼8.0 Hz, 1H), 4.50 (q, J¼6.8 Hz,
1H), 4.27 (dd, J¼7.8, 5.4 Hz, 1H), 4.21 (dd, J¼5.4, 1.0 Hz,
1H), 4.14 (dd, J¼13.4, 2.6 Hz, 1H), 4.08 (d, J¼13.2 Hz,
1H), 3.96 (d, J¼9.2 Hz, 1H), 3.83 (d, J¼9.2 Hz, 1H), 1.55
(s, 3H), 1.52 (s, 3H), 1.49 (d, J¼5.6 Hz, 3H), 1.39 (s, 3H),
1.34 (s, 3H), 1.18–1.05 (m, 21H). 13C NMR (CDCl3,
75.5 MHz): d 174.3, 112.2, 109.8, 103.9, 74.9, 73.9, 72.1,
70.8, 68.7, 60.8, 28.0, 26.6, 26.5, 26.4, 22.4, 18.1, 12.3. IR:
n 2990, 2942, 2867, 1765, 1736, 1455, 1372, 1220, 1190,
1141, 1086, 1067, 976, 885, 820 cm21. FABMS m/z (% of
base peak): 495.4 (MþLiþ, 34), 487.4 (M2Hþ, 24), 473.4
(M2Meþ, 46), 431.4 (MþH–CH3COCHþ3 , 67), 243.2
4.2.34. 1,2:4,5-Di-O-isopropylidene-b-D-fructopyranos-
3-yl (triisopropylsilyloxy)acetate (3k). Benzyl (triisopro-
pylsilyloxy)acetate. Benzyl glycolate87 (1.66 g, 10.0 mmol)
and triethylamine (3.0 mL, 21.3 mmol) were dissolved in
dry DCM (15 mL) at rt. After 15 min triisopropyl
trifluoromethanesulfonate (3.6 mL, 13.4 mmol) was added
quickly. The mixture bubbled and became warm. The pale
green solution was stirred at rt overnight. After 22 h the
reaction mixture (red in color) was washed with 10 mL ice-
cold saturated NaHCO3 and 10 mL saturated NaCl, dried
(MgSO4), filtered, and rotovapped to give red liquid
(4.21 g). The liquid was dissolved in DCM and separated
on a flash silica column (1:6 EtOAc/hexanes, ,0.5% Et3N).
Fractions were combined, rotovapped, and dried on the oil
pump to give the ester as a yellow liquid (3.088 g, 96%). 1H
NMR (CDCl3, 300 MHz): d 7.35 (s, 5H), 5.18 (s, 2H), 4.36
(s, 2H), 1.15–1.03 (m, 21H). 13C NMR (CDCl3, 75.5 MHz):
d 171.3, 135.7, 128.5, 128.4, 128.3, 66.4, 62.1, 17.8, 12.0.
IR: n 3034, 2943, 2865, 1765, 1735, 1498, 1464, 1443,
1385, 1366, 1281, 1267, 1208, 1194, 1147, 1071, 1044, 996,
(M2OCOCH(Me)ORþ,
100).
Anal.
Calcd
for
C24H44O8Si: C, 58.99; H, 9.08. Found: C, 58.85; H, 9.10.
4.2.36. 1,2:4,5-Di-O-isopentylidene-b-D-fructopyranos-
3-yl (benzyloxy)acetate (15). 1,2:4,5-Di-O-isopentyl-
idene-b-D-fructopyranose. This compound was prepared
by a procedure modified from the literature.91 A solution of
3-pentanone (84 mL, 790 mmol), trimethyl orthoformate
(42 mL, 329 mmol), and p-toluenesulfonic acid mono-
hydrate (280 mg, 1.5 mmol) in 100 mL MeOH was heated
in an oil bath to ,768C. After 3 h, the bath temperature was
increased to ,958C, and the head temperature rose to 628C.
After 2.5 h at this bath temperature, the head temperature
started to fall. The mixture was allowed to cool at rt for
20 min. More 3-pentanone (200 mL, 1880 mmol) was
added, and the mixture was cooled in an ice bath. After
10 min D-fructose (ground to a powder, 26.9 g, 149 mmol)
and HClO4 (70%, 0.1 mL) were added. After stirring in the
ice bath for 4.5 h, the reaction was quenched with Et3N
(5 mL). After 15 min deionized water (25 mL) was added,
and the mixture was stirred vigorously. After 10 min stirring
at rt, the layers were separated. The organic layer was dried
(MgSO4), filtered, and rotovapped to give a clear pale green
liquid (45.4 g). After overnight storage in the freezer, the
crude product was dissolved in EtOAc and rotovapped again
(42.2 g). The mixture was separated on a flash silica column
(1:6 to 1:2 Et2O/hexanes). Fractions were combined,
rotovapped, and dried on the oil pump to give the product
967, 919, 882, 834, 823, 809, 796, 748, 694, 661, 644 cm21
.
FABMS m/z (% of base peak): 323.1 (MþHþ, 13). Anal.
Calcd for C18H30O3Si: C, 67.03; H, 9.38. Found: C, 66.90;
H, 9.51.
(Triisopropylsilyloxy)acetic acid (2k). Hydrogenolysis of
the ester above according to the procedure for 2f gave the
acid 2k in quantitative yield. 1H NMR (CDCl3, 300 MHz): d
9.3 (br s, 1H), 4.28 (s, 2H), 1.19–1.00 (m, 21H). 13C NMR
(CDCl3, 75.5 MHz): d 175.3, 61.6, 17.7, 12.3. FABMS m/z
(% of base peak): 233.2 (MþHþ, 21). Anal. Calcd for
C11H24O3Si: C, 56.85; H, 10.41. Found: C, 56.90; H, 10.57.
The glycolate was prepared by the general esterification
procedure using the alcohol 1and triisopropylsilyloxyacetic
acid 2k to give 3k as a green oil (87% yield) and recovered
1
as a light pale yellow oil (25.1 g, 53%). H (400 MHz,
CDCl3) and 13C NMR (75 MHz, CDCl3) spectra agreed
with those in the literature.91
1
alcohol 1 (9% recovery). H NMR (CDCl3, 400 MHz): d
5.18 (d, J¼7.6 Hz, 1H), 4.43 (d, J¼16.4 Hz, 1H), 4.36 (d,
J¼16.8 Hz, 1H), 4.27 (dd, J¼7.8, 5.4 Hz, 1H), 4.22 (dd,
J¼5.6, 1.8 Hz, 1H), 4.13 (dd, J¼13.8, 2.2 Hz, 1H), 4.08 (d,
J¼13.6 Hz, 1H), 3.96 (d, J¼9.2 Hz, 1H), 3.85 (d, J¼9.6 Hz,
1H), 1.54 (s, 3H), 1.48 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H),
1.13–1.05 (m, 21H). 13C NMR (CDCl3, 75.5 MHz): d
171.4, 112.2, 109.8, 103.8, 74.8, 73.9, 72.0, 70.7, 62.0, 60.7,
The glycolate was prepared by the general esterification
procedure using the alcohol above and benzyloxyacetic acid
2a to give 15 as a pale yellow oil (4.45 g, 70%). H NMR
(CDCl3, 400 MHz): d 7.38–7.30 (m, 5H), 5.23 (d,
J¼7.6 Hz, 1H), 4.64 (s, 2H), 4.32 (dd, J¼7.4, 5.4 Hz, 1H),
4.24 (dd, J¼6.4, ,1 Hz, 1H), 4.22 (d, J¼16.8 Hz, 1H), 4.11
1

7676
H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
(d, J¼16.8 Hz, 1H), 4.10 (d, J¼15.4 Hz, 1H), 4.07 (m, 1H),
3.95 (d, J¼9.2 Hz, 1H), 3.84 (d, J¼8.8 Hz, 1H), 1.84–1.59
(m, 8H), 0.98–0.83 (m, 12H). 13C NMR (CD3OD,
75.5 MHz): d 171.7, 138.5, 129.4, 129.2, 129.0, 117.5,
114.8, 104.7, 75.8, 74.9, 74.2, 73.1, 72.7, 67.9, 61.9, 31.0,
30.7, 29.7, 8.8, 8.7, 8.1. IR: n 2966, 2919, 2872, 1760, 1455,
1378, 1349, 1273, 1185, 1128, 1088, 1044, 972, 918, 855,
824, 739, 697 cm21. FABMS m/z (% of base peak): 466.2
(MþHþ, 36). Anal. Calcd for C25H36O8: C, 64.64; H, 7.81.
Found: C, 64.65; H, 7.78.
their 1H NMR spectra to those of the pseudo-racemic
standards.
Representative procedure for preparation of the standards
that were racemic at the a-center. Pseudo-racemic 1,2:4,5-
di-O-isopropylidene-b-D-fructopyranos-3-yl 2-(benzyloxy)
propionate (4a). Racemic (2-benzyloxy)propionic acid was
prepared by alkylating benzyloxyacetic acid 2a with MeI in
the presence of LDA according to a literature procedure92
(11%). The pseudo-racemic standard was prepared by the
general esterification procedure using the alcohol 1 and
racemic 2-(benzyloxy)propionic acid to give pseudo-
racemic standard 4a (84%).
4.2.37. 1,2:4,5-Di-O-isopentylidene-b-D-fructopyranos-
3-yl 2-(benzyloxy)propionate (16). The product was
obtained as an oil in 71% yield using alkylation Method
C. 1H NMR (CDCl3, 400 MHz): d 7.38–7.27 (m, 5H),
5.25–5.20 (d, J¼8.4 Hz, 1H), 4.72 (d, J¼11.6 Hz, 1H), 4.42
(d, J¼11.6 Hz, 1H), 4.34 (dd, J¼7.8, 5.8 Hz, 1H), 4.25 (dd,
J¼5.6, 1 Hz, 1H), 4.16–4.07 (m, 3H), 3.97 (d, J¼9.2 Hz,
1H), 3.84 (d, J¼9.2 Hz, 1H), 1.87–1.58 (m, 8H), 1.48 (d,
J¼6.4 Hz, 3H), 0.98–0.86 (m, 12H). 13C NMR (CDCl3,
75.5 MHz): d 173.3, 137.7, 128.6, 128.2, 128.0, 116.4,
113.9, 103.7, 74.7, 74.2, 73.9, 72.4, 72.1, 71.7, 61.1, 30.4,
29.9, 29.0, 28.9, 19.0, 8.7, 7.9. IR: n 2978, 2884, 1758,
1462, 1373, 1349, 1260, 1174, 1130, 1114, 1090, 1044, 975,
922, 848, 835, 822, 748, 698 cm21. FABMS m/z (% of base
peak): 485.3 (MþLiþ, 42), 449.3 (M2Etþ, 63), 393.3
(M2Et2COþ, 100), 299.2 (M2OCOCH(Me)ORþ, 58).
Anal. Calcd for C26H38O8: C, 65.25; H, 8.00. Found: C,
65.52; H, 8.15.
4.5. The modified Cevalier’s method for checking
racemization during deprotection or hydrolysis
The method was carried out as described in the literature78
with the following modifications: 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (EDC)/Et3N
were substituted for DCC and the hydrochloride salt of
H-Ala-OMe was used directly in the coupling. To verify the
identification of diastereomers by 1H NMR, pseudo-racemic
standards of 19a,b were prepared using the racemic
benzyloxy acids,92 followed by hydrogenolysis with
Pd(OH)2.
4.6. Crystal structure of 3a
Data Collection. The sample was mounted on the end of a
glass fiber using a small amount of silicon grease and
transferred to the diffractometer. The sample was main-
tained at a temperature of 21258C using a nitrogen cold
stream. All X-ray measurements were made on an Enraf–
Nonius CAD4-MACH diffractometer. The unit cell dimen-
sions were determined by a fit of 24 well centered reflections
and their Friedel pairs with 338,2u,368. A quadrant of
unique data and their Bijvoet pairs were collected using the
v scan mode in a non-bisecting geometry. The adoption of a
non-bisecting scan mode was accomplished by offsetting c
by 208 for each data point collected. This was done to
minimize the interaction of the goniometer head with the
cold stream. The Bijvoet pairs were collected using the
negative u position for the 2h 2k 2l reflection. This was
done so that the X-ray pathlength through the crystal was
identical for each pair. Three standard reflections were
measured every 4800 s of X-ray exposure time. Scaling the
data was accomplished using a 5 point smoothed curved
routine fit to the intensity check reflections. The intensity
data was corrected for Lorentz and polarization effects. No
absorption correction was applied to the data.
4.3. General procedure for the removal of the
O-protecting group and cleavage of the auxiliary
To a solution of ester 13 (PG¼TES) in THF/pyridine (1:1)
was added several drops of HF–pyridine. This mixture was
stirred at room temperature for 10 min. Distilled water then
was added. The mixture was extracted with DCM (4£). The
combined organic layers were washed with brine and dried
(MgSO4). Upon removing solvent, the residue was purified
by flash chromatography (elution with hexanes/EtOAc) or
used directly for the next step.
The residue obtained above (17) was dissolved in
THF/MeOH/H2O (2:2:1, v/v). To this was added LiOH
(2 equiv.). The reaction was monitored by TLC. When the
reaction was complete, THF and methanol were removed on
the rotovap. The aqueous solution was extracted with Et2O
to remove the auxiliary. After the aqueous phase had been
acidified with 10% HCl, it was extracted with DCM (3£)
and the combined organic layers were dried (MgSO4).
Solvent was removed to afford the pure free acid 18.
Structure solution and refinement. The data were reduced
using routines from the NRCVAX93 set of programs. The
structure was solved using SIR92.94 All of the non-H atom
positions were recovered from the initial E-map. All
hydrogen atom positions were derived from difference
Fourier maps. Hydrogen atom positional and isotropic
displacement parameters were allowed to refine in the least
squares refinement. The structure was refined using full
matrix least-squares based on F. All non-H atoms were
allowed to refine with anisotropic displacement
parameters (ADPs). The calculated structure factors
4.4. Determination of the de values
All reported yields and de values were based on isolated
product. Determinations of de values were made by
1
comparing the HPLC trace or the H NMR spectrum of
the product to a standard that was racemic at the a-position.
These pseudo-racemic standards were prepared by a
different synthetic route (see below). Pseudo-racemic
standards were prepared for alkylated compounds 4a–e,
11b, 12b, 13a, and 16; the de’s for the remainder of the
alkylated compounds were determined by analogies in

H. Yu et al. / Tetrahedron 58 (2002) 7663–7679
7677
included corrections for anomalous dispersion from the
usual tabulation.95 A secondary extinction correction was
included in the final refinements. The anomalous scattering
signal for 3a was weak which prevented the direct
determination of the absolute structure. Therefore, the
absolute structure for the sample was set using the absolute
configuration around atom C4 which was known to be S.
A secondary extinction correction was included in the final
refinements. The anomalous scattering signal for 4c was
weak which prevented the direct determination of the
absolute structure. Therefore, the absolute structure for the
sample was set using the absolute configuration around
atom C4 which was known to be S.
Results. Crystal system: monoclinic. Space group: P21. Unit
˚
˚
˚
Results. Crystal system: monoclinic. Space group: P21. Unit
cell: a¼8.0120(5) A, b¼14.1477(8) A, c¼11.7213(8) A.
Z¼2. A total of 4678 reflections were collected, of which
4479 were unique (Rmerge¼0.013). R¼0.035, Rw¼0.046,
GOF¼1.39 for 3975 reflections greater than 1.0s(I ).
˚
˚
˚
cell: a¼12.8625(10) A, b¼5.5705(3) A, c¼4.5033(7) A.
Z¼2. A total of 4452 reflections were collected of which
4015 were unique (Rmerge¼0.010). R¼0.027, Rw¼0.033,
GOF¼1.47 for 3791 reflections above 1.0s(I ).
Crystallographic data (excluding structure factors) for this
structure have been deposited with the Cambridge Crystal-
lographic Data Centre (CCDC 182698). Copies of the data
can be obtained, free of charge, on the Internet at
www.ccdc.cam.ac.uk/conts/retrieving.html or on appli-
cation to CCDC, 12 Union Road, Cambridge, CB2 1EZ,
UK [fax: þ44(0)-1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk].
Crystallographic data (excluding structure factors) for this
structure have been deposited with the Cambridge Crystal-
lographic Data Centre (CCDC 182697). Copies of the data
can be obtained, free of charge, on the Internet at www.
ccdc.cam.ac.uk/conts/retrieving.html or on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax:
þ44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.7. Crystal structure of 4c
Acknowledgments
Data Collection. The sample was mounted on the end of a
glass fiber using a small amount of silicon grease and
transferred to the diffractometer. The sample was main-
tained at a temperature of 21258C using a nitrogen cold
stream. All X-ray measurements were made on an Enraf–
Nonius CAD4-MACH diffractometer. The unit cell dimen-
sions were determined by a fit of 25 well centered reflections
and their Friedel pairs with 318,2u,368. A quadrant of
unique data and their Bijvoet pairs were collected using the
v scan mode in a non-bisecting geometry. The adoption of a
non-bisecting scan mode was accomplished by offsetting c
by 208 for each data point collected. This was done to
minimize the interaction of the goniometer head with the
cold stream. The Bijvoet pairs were collected using the
negative u position for the 2h 2k 2l reflection. This was
done so that the X-ray pathlength through the crystal was
identical for each pair. Three standard reflections were
measured every 4800 s of X-ray exposure time. Scaling the
data was accomplished using a 5 point smoothed curved
routine fit to the intensity check reflections. The intensity
data was corrected for Lorentz and polarization effects. No
absorption correction was applied to the data. During the
data collection, the low temperature device developed a
problem of excessive ice build up. This may have affected
the quality of the data slightly.
The authors thank the American Heart Association (Grant
9740117 N) for funding. The authors also wish to thank the
National Science Foundation for the funding (Grant
9509532) used to purchase the X-ray diffractometer.
C. E. B. gratefully acknowledges a graduate fellowship
from the Burroughs Wellcome Fund.
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