Efficient synthesis of the functional central core lactides, a constituent of antibiotic fattiviracins

Article abstract of DOI:10.1016/j.tet.2010.04.007

An efficient convergent synthetic method has been developed for preparation of various stereoisomers and derivatives of fattiviracins via a common lactide. The synthetic route comprises seco acids prepared by the β-selective glycosylation of chiral 3-hydroxy-4-pentanoate obtained by enzymatic kinetic resolution. The regioselective protection of four individual hydroxy groups was achieved via the 4,6-O-benzylidenation of the glucose moiety from its TMS ethers. The dimeric cyclization of the seco acids under control of reaction concentration afforded the desired lactide without using KH. Our convergent synthetic method was successfully applied to direct installation of side chains to the lactide by cross metathesis to synthesize fattiviracin derivatives. We achieved improvements to the reported method with respect to: (1) synthesis of a convergent synthetic intermediate; (2) stereoselectivity in glycosylation; and (3) establishment of a low cost route suitable for large scale synthesis.

Full text of DOI:10.1016/j.tet.2010.04.007

Tetrahedron 66 (2010) 4089–4100
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of the functional central core lactides, a constituent
of antibiotic fattiviracins
*
Eisuke Kaji , Teruaki Komori, Masaki Yokoyama, Tomomi Kato, Takashi Nishino, Tatsuya Shirahata
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient convergent synthetic method has been developed for preparation of various stereoisomers and
derivatives of fattiviracins via a common lactide. The synthetic route comprises seco acids prepared by the
Received 23 February 2010
Received in revised form 1 April 2010
Accepted 1 April 2010
b-selective glycosylation of chiral 3-hydroxy-4-pentanoate obtained by enzymatic kinetic resolution. The
regioselective protection of four individual hydroxy groups was achieved via the 4,6-O-benzylidenation of
the glucose moiety from its TMS ethers. The dimeric cyclization of the seco acids under control of reaction
concentration afforded the desired lactide without using KH. Our convergent synthetic method was suc-
cessfully applied to direct installation of side chains to the lactide by cross metathesis to synthesize fat-
tiviracin derivatives. We achieved improvements to the reported method with respect to: (1) synthesis of
a convergent synthetic intermediate; (2) stereoselectivity in glycosylation; and (3) establishment of a low
cost route suitable for large scale synthesis.
Available online 7 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
An antiherpetic agent was discovered from a Streptomyces spe-
cies, and found to be identical to Streptomyces microflavus No.
2445.1 The antiherpetic agent was named fattiviracin (FV) and has
a lactide as a C2 symmetric core. S. microflavus No. 2445 produces 13
types of FVs (Fig. 1), and determination of each absolute structure
has been hampered by the difficult isolation.1 The fattiviracins,
especially FV-8, have been reported to exhibit activity against
enveloped DNA viruses such as in the herpes family, HSV-1 and
VZV, and enveloped RNA viruses such as influenza A and B, and
three strains of HIV-1.2 FV-8 acts on HIV-1 particles directly without
lysis of the particles, inhibiting viral entry into the host cell.2a This
mode of action is different from other antiviral agents that inhibit
reverse transcriptase or protease in the HIV-1 particles. Therefore,
FV has potential to be a new type of antiviral agent.
The cycloviracins, structurally related to FV, were isolated from
Kibdelosporangium albatum so. nov. (R761-7). Cycloviracin B1 ex-
hibits activity against the herpes simplex and HIV viruses.3 In ad-
dition, a similar glycolipid, glucolipsin A, was reported to be an
inhibitor against Cdc25 phosphatase and protein tyrosine phos-
phatase 1B (PTP1B), which are regulatory enzymes in the cell cycle3
(Fig. 2).
Figure 1. Structure of fattiviracins.
These glycolipids have been attractive targets for synthetic or-
ganic chemists, since glycolipids possess unique biological activi-
ties and structures. For example, since these lactides are C2
symmetric compounds, Fu¨rstner et al.4,5 adopted a strategy to
* Corresponding author. E-mail address: kajie@pharm.kitasato-u.ac.jp (E. Kaji).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.007

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E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
Scheme 1. Late stage of synthetic plan.
Figure 2.
cyclize two seco acid molecules directly. The cyclization was per-
formed in the presence of KH to construct the lactide in good yield.
It was determined that the glycolipids uptake KH to aid in the ring
4
closure. In this manner, the total syntheses of cycloviracin B1 and
glucolipsin A were completed.5
Cleophax et al. have undertaken a convergent strategy to syn-
thesize derivatives of these glycolipids.6 They prepared the mac-
rocyclic core of cycloviracin and glucolipsin by exploiting the same
type of cyclization as Fu¨rstner’s. However, the syntheses of de-
rivatives employing the macrocyclic core lactides have not been
reported to date.
While these synthetic strategies are fascinating, they do have
some drawbacks: (1) b-stereoselectivity in the glycosylations is not
perfect; (2) the starting material, levoglucosan, is expensive; and
(3) it is difficult to prepare derivatives, including many kinds of side
chains, in order to study structure–activity relationships. Thus,
a novel synthetic route to prepare many kinds of diastereomers
should be developed in order to determine the absolute stereo-
chemistry of six stereocenters, with the exception of the sugar
moiety in FV.
Scheme 2. Retrosynthetic analysis.
The key intermediate 2 could be directly constructed by cycli-
zation of two molecules of seco acid 4, which could be derived
from
construction of the anomeric position would be required to avoid
having to separate anomeric isomers. The -glycoside 5 was seg-
b-glycoside 5. For efficient synthesis of 5, stereoselective
b
Our goal to design a synthetic route for FV includes the
mented into an easily preparable glycosyl donor 6,8 which has acyl
group to take advantage of neighboring group participation, and
a chiral glycosyl acceptor 7. The chiral induction of glycosyl ac-
ceptor 7 would be envisioned to come from kinetic resolution by
lipase.
following: (1) achievement of perfect
sylation; (2) utilization of low cost starting materials; and (3)
development of convergent synthetic route to generate
b-selectivity in glyco-
a
many kinds of stereoisomers and derivatives via a common
lactide.
2. Results and discussion
2.1. Retrosynthesis
2.2. Syntheses of glycosyl acceptor and glycosyl donor
A racemic mixture of 7 was prepared by aldol reaction between
tert-butyl acetate and acrolein. According to the previous reports,9
kinetic resolution of the racemic alcohol 7 was carried out with
lipase PS-D Amano I, immobilized on diatomaceous earth, in pen-
tane with excess vinyl acetate at ambient temperature for 60 h to
provide enantioenriched alcohol (þ)-7 (45%, 99% ee) and acetate
derivative 8 (42%, 70% ee) (Scheme 3). In order to prevent the over-
esterification, arose from longer reaction times, we decided to re-
vise the reaction conditions being followed with chiral HPLC.
A convergent synthetic method is required to achieve the syn-
thesis of various FV derivatives. Our strategy includes the design of
the common intermediate 2 and the connection of various side
chains to this common intermediate (Scheme 1).
The retrosynthesis of FV is shown in Scheme 2. Each derivative
of FV could be synthesized through a cross metathesis reaction7
between the cyclic intermediate 2 and side chains 3.

E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
4091
Scheme 3. Enzymatic kinetic resolution and methanolysis.
Monitoring by chiral HPLC (DAICEL Chiral Pack IC, hexane/2-
propanol¼98:2) during kinetic resolution provides the enantio-
purities of all compounds in the reaction, and the enantiopurity of
(þ)-7 reached 99% ee in 5 h. The antipode (ꢀ)-7 was obtained by
removal of the acetyl group of 8 with K2CO3 in MeOH in 99% ee.10
Once both highly optically pure glycosyl acceptors were in hand,
we turned our attention to the preparation of the glycosyl donor.
The 2,3,4,6-tetra-O-acetyl-
lected and synthesized from commercially available penta-O-ace-
tyl- -glucose.
a-D-glucopyranosyl imidate (6) was se-
b-D
2.3. Glycosylation
For the synthesis of the desired seco acid, 3R-(þ)-7 as a glycosyl
acceptor was chosen for glycosylation with glycosyl donor 6 be-
cause (þ)-7 was available directly after kinetic resolution. As shown
in Scheme 4, these reactions were carried out in the presence of 4 Å
molecular sieves in dichloromethane. The use of 1.2 equiv of
BF3$OEt2 as a Lewis acid and 2.0 equiv of the acceptor (þ)-7, gave
Scheme 5. Benzylation of sugar hydroxy groups.
selective acetylation of the C-6 alcohol at ꢀ78 ꢁC under dilute
conditions afforded 14 in moderate yield. Unfortunately, benzyla-
tion with benzyl-2,2,2-trichloroacetimidate in the presence of
TMSOTf did not proceed at low temperature (ꢀ40 ꢁC), but resulted
in a complex mixture inseparable by flash column chromatography.
We believe that mono-O-Bn or di-O-Bn products were generated,
the best results (69% yield).11 The stereochemistry of the
b
-glyco-
3
0
0
sides was determined from the coupling constant, JH1 ,H2 , of ap-
proximately 8.1 Hz, as would be expected for glycosides with the
-glucopyranosyl (1,2-trans) stereochemistry. Removal of the Ac
group in glycoside 9 by methanolysis gave 10 in quantitative yield.
We thus achieved the preparation of the desired -glycoside in
b-
D
and TMSOTf caused decomposition of the b-oxyester moiety.
b
Then, focused on benzylation using PhCHO and a corresponding
reductive reagent via TMS ether as reported by Fukase and Izumi.12
Attempts to protect the alcohols using benzaldehyde, excess TMSCl
and triethyl silane as a reductive reagent afforded 30-benzyloxy
product 16 in 58% yield and 20,30-di-O-benzyloxy product 17 in 7%
yield, though the desired 20,30,40-tri-O-benzyloxy product was not
detected. A downfield shift in the 1H NMR spectrum after acetyla-
tion of 16 and 17 led to plausible structures for each compound as
shown in Scheme 5. These results indicate that the reactivity of the
C3-hydroxy group is even higher under mild acidic conditions, but
the C-2 hydroxy group has less activity and the C-4 hydroxy group
has no reactivity under these benzylation conditions (Fig. 3).
fewer steps using an inexpensive glucose derivative as the starting
material.
Scheme 4. Glycosylation of (þ)-7 with 6.
2.4. First generation synthesis
2.4.1. Mono Bn approach. For thesynthesis of seco acid4, benzyl (Bn)
groupwas chosen to protect theC-2, 3, 4 positions in the sugar moiety.
First, the selective protection of the 6-OH with a trityl group gave 11.
Subsequent benzylation (BnBr, NaH) of the hydroxy groups at C-2, 3, 4
afforded 1-benzyloxycompound 12 asan anomeric mixtureinstead of
the desired 13. This result suggests that unexpected E1cB elimination
occurred after deprotonation by a strong base, followed by benzyla-
tion at the C-1 position. Thus, we took another approach (Scheme 5).
The next approach using benzyl-2,2,2-trichloroacetimidate in
the presence of Lewis acid for the benzylation was attempted. First,
Figure 3. Reactivity of hydroxy groups.
2.4.2. Dimeric cyclization of mono Bn compound. With the mono-O-
Bn compound 16 in hand, we attempted cyclization according to the
reaction shown in Scheme 6. Deprotection of the tert-butyl ester
under acidic conditions with TFA provided the carboxylic acid, and
the Ac group was removed by methanolysis to afford the desired

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E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
seco acid 18 in excellent yield. We predicted that the most reactive C-
6 hydroxy group would smoothly cyclize to the product 19 even in
the presence of free hydroxy groups at C-2 and C-4, whose re-
activities were proved to be lower in the previous benzylation.
Scheme 6. Cyclization with monobenzyl compound.
The cyclization of 18 with DMC reported by Fu¨ rstner et al.4,5
provided the desired cyclic product 19. NMR studies on the
product 19 confirmed the proposed structure, evidenced by
Scheme 7. One-pot 4,6-O-benzylidene, 2,3-di-O-benzylation.
a
cross peak between C60-H and C-1 observed in HMBC
Applying Hung’s method to protect the hydroxy groups at C-2,
C-3 and especially C-4 effectively solved the issue of benzylating
the hindered hydroxy groups. The reaction using TMS ether as the
substrate is different from Fukase’s method,12 which generates
water during the reaction. Our method does not generate water,
thus avoiding decomposition of the delicate side chain bearing the
experiments.
Based on these results, even the substrate with only partial pro-
tection of the hydroxy groups is applicable to the cyclization. How-
ever, this synthetic route has some low yielding reactions such as
6-OH selective protection and benzylation, and is not suitable for
obtaining significant quantities of material. Moreover, low solubility
of 18 and 19 in organic solvents due to the free hydroxy groups
causes low yields in the coupling reaction. These results suggest that
complete protection of the C-2, 3, 4 hydroxy groups is required to
afford an efficient synthetic route.
b
-oxoester moiety.
2.5.2. Synthesis of the seco acid 25. With protected compound 22
plausibly in hand, regioselective opening of the 4,6-O-benzylidene
acetal was attempted to give 4-benzyloxy and 6-free hydroxy com-
pound. Although BH3 is usually used for reductive-opening of acetals,
chemoselective reductionwasrequired for the glycoside 24 possesses
the ester and the double bond. Several reducing agents were
screened to reveal that the yield of reduction with BH3$Me2NH14 at
ꢀ20 ꢁC was much higher.15
2.5. Second generation synthesis
2.5.1. Approach from 4,6-benzylidene intermediate. Faced with
these problems, we evaluated another approach to the desired seco
acid. In the previous study,9 protection of the C-2 and C-3 hydroxy
groups with benzyl groups was achieved using the combination of
benzaldehyde and a reductive reagent under mild acidic conditions.
The remaining protection of C-4 might be solved by formation of
a 4,6-benzylidene acetal followed by ring opening to give the 4-
benzyloxy group. Hung et al. has reported a combinatorial and
highly regioselective method13 that can be used to protect in-
dividual hydroxy groups of a monosaccharide such as glucose. This
approach can be used to install an orthogonal protecting group
pattern in a one-pot manner. In particular, it was reported that 4,6-
O-benzylidenation and 3-O-benzylation from 2,3,4,6-tetra-O-TMS
glucose derivatives could be carried out as a one-pot reaction.
To apply Hung’s methodology, delicate tetra-O-TMS compound
20 was prepared from the glycoside 10, by treating, with TMSCl in
pyridine. For large scale synthesis, the reaction temperature was set
to ꢀ78 ꢁC for the one-pot reaction. The details of the procedure in-
clude formation of the 4,6-O-benzylidene acetal by treatment of 20
with PhCHO and a catalytic amount of TMSOTf in the first step and
then addition of PhCHO and Et3SiH gave the benzyl ether in the
second step. Our first attempt at this one-pot reaction at ꢀ78 ꢁC gave
23 having a 3-benzyl ether as well as a small amount of the desired
22 having the 2,3-O-benzyl ether. Addition of excess PhCHO and
Et3SiH and warming the reaction mixture up to ꢀ40 ꢁC from ꢀ78 ꢁC
in the second step provided 22 in 86% yield. Since this reaction is
reproducible, it is suitable for large scale synthesis (Scheme 7).
Attempts to remove the tert-butyl group with TFA in CH2Cl2
furnished a 6-O-trifluoroacetylated product as well as the desired
25. Based on these results, we altered the procedure to remove the
tert-butyl group first, followed by methanolysis in the second step to
give 25 in high yield (Scheme 8).
Scheme 8. Deprotection of tert-butyl group.
This reaction sequence via the benzylidene acetal enabled us to
prepare the desired seco acid 25.
As described above, we have established a low cost synthetic
route to prepare the seco acid. This route also revised the efficiency
comparing with the current synthesis with respect to the protect-
ing group manipulation after the glycosylation.

E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
4093
Table 1
2.5.3. Synthesis of seco acid from (3S)-acceptor. Having optimized
Cyclization of (3R)-seco acid 25
the synthesis of seco acid 25 from (3R)-acceptor (þ)-7, we applied
this reaction sequence to (3S)-acceptor (ꢀ)-7 (Scheme 9) to furnish
seco acid 31. This result suggests that no difference is observed in
reactivity between the diastereomers.
BnO
OBn
OBn
Reagent (2.5 eq.)
Base (2.0 eq.)
MS4Å
CH2Cl2 (Conc.)
r.t.
O
(R)
HO
O
COOH
O
(R)
BnO
O
O
O
BnO
O
O
OBn
O
(R)
BnO
BnO
HMBC
O
25
OBn
32
Entry
Reagent
Base
Concn (M)
Yield (%)
1
2
3
4
5
6
7
EDCI
MNBA
DMC
DMC
DMC
DMC
DMC
DMAP
DMAP
DMAP
DMAP
DMAP
d
0.1
0.1
0.01
0.1
0.2
0.1
0.1
15
Trace
9
52
41
61
41
KHa
a
Excess amount of KH was employed.
cyclization with KH, which resulted in a lower yield than under non-
KH conditions (entry 7).
In addition, we confirmed that cyclized compound 32 had the
correct C2 symmetry by the perfectly overlapping peaks at sym-
metric positions in the 1H NMR spectrum. The observation of
a cross peak between C60–H and C1 in the HMBC experiments also
supported the cyclized structure.
We next turned to the cyclization of seco acid 31 (Table 2).
Under conditions similar to those described for 25, the cyclization
of 31 occurred in moderate yield to give not only desired product
33 but also self-cyclized product 34 (Table 2, entry 1), the con-
formation of which is shown in Figure 4, based on the 1H NMR
coupling constants. In the reactions at lower concentrations in
CH2Cl2, the yields of 33 decreased while those of 34 increased
(Table 2, entries 2 and 5). This phenomenon is explained by an
intramolecular lactonization, which occurred more easily in dilute
conditions, rather than an intermolecular cyclization. The dimeric
cyclization product 33 was not obtained in higher yields, despite
lowering the temperature (0 ꢁC, entry 3), adding DMAP (entries
4–6), and KH (entry 7).
Scheme 9. Synthesis of (3S)-seco acid 31.
2.5.4. Cyclization of the seco acids. With both seco acids 25 and 31
in hand, we optimized the reaction conditions for cyclization to
obtain the desired lactides. Fu¨rstner et al.4,5 and Cleophax et al.6
reported the same type of cyclization for synthesis of cycloviracin
B1 and glucolipsin A. Both of them used DMC16 and KH in the
presence of DMAP to synthesize the corresponding lactides. Re-
activity of the cyclization depended upon the structure of the
substrates, which resulted in various yields.
Our preliminary research showed that DMC was more suitable
than other reagents17 (Table 1, entries 1 and 2). Surprisingly, changing
the concentrations of DMC and DMAP in CH2Cl2 dramatically im-
proved yields of the cyclized product (entries 3–5). Contrary to our
expectations, the reactionwithout DMAP proceeded smoothly in 61%
yield (entry 6). Based on the report by Fu¨rstner, we attempted
It seems that seco acids 25, 31, and the compounds reported by
Fu¨rstner would form appropriate conformations that facilitated the
formation of cyclic dimers in CH2Cl2. In addition, DMC is the most
suitable condensation reagent in all cases. The differences in the
seco acids between ours and Furstner’s reflect their reactivities in
¨
Table 2
Cyclization of (3S)-seco acid 31
BnO
O
OBn
OBn
O
(S)
DMC (2.5 eq.)
Base (2.0 eq.)
MS4Å
CH2Cl2 (Conc.)
Temp.
HO
O
COOH
O
O
(S)
BnO
O
O
O
O
BnO
O
(S)
BnO
BnO
O
OBn
H
O
BnO
BnO
O
31
OBn
OBn
33
34
Entry
Base
Concn (M)
Temp
33 (%)
34 (%)
1
2
3
4
5
6
7
d
0.1
0.01
0.1
0.1
0.01
0.1
rt
rt
0
rt
rt
0
42
23
39
36
33
27
29
28
37
9
14
19
5
d
d
ꢁC
ꢁC
DMAP
DMAP
DMAP
KHa
0.1
rt
21
a
Excess amount of KH was employed.

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E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
Figure 4. Conformation of intramolecular cyclization product 34.
Scheme 11. C–C bond formation by cross metathesis.
3. Conclusion
terms of molecular size and existence of olefin. In Fu¨rstner’s case,
although the compounds are too large to be close to one other, they
succeeded in forming highly interfacial complexes with the aid of
KH, which should be expected to assist orientation of the hydroxy
group and carboxy group in the ring closure to achieve the desired
cyclization. In our case, the smaller substrate has a better chance to
ring close without KH, and increasing the concentration of the
substrate improved the cyclization.
In conclusion, we have described the first example of a conver-
gent synthetic route to fattiviracin and its derivatives. Key features
of the synthetic scheme to provide seco acids are: (1) the b-selec-
tive glycosylation of chiral acceptors (þ)-7 or (ꢀ)-7 prepared by
enzymatic kinetic resolution and (2) the regioselective protection
of four hydroxy groups via 4,6-benzylidenation from TMS ethers.
The dimeric cyclization of the seco acid by controlling the reaction
concentrations afforded the desired lactides without using KH. Our
convergent synthetic route was successfully applied to direct in-
stallation of side chains to lactide by cross metathesis aiming at
synthesizing fattiviracin derivatives. We achieved improvements in
(1) synthesis of a convergent synthetic intermediate, (2) stereo-
selectivity in glycosylation, and (3) establishment of a route suit-
able for large scale synthesis at a significantly lower cost compared
to previous reports.4–6 Further syntheses of other derivatives of FV
are in progress in our laboratory.
Thus, we achieved cyclization to generate the desired lactide in
reasonable yield without KH.
2.5.5. C–C bond formation after the cyclization. With the desired
lactide in hand, we attempted C–C bond formation followed by
deprotection for the synthesis of FV and its derivatives. To deprotect
the benzyl group and reduce the double bond at the same time, we
performed hydrogenation before the C–C bond formation. The hy-
drogenation of 32 and 33 in EtOAc and EtOH caused the simultaneous
deprotection of Bn and reduction of the double bond to furnish de-
sired 35 and 36, respectively, in quantitative yields (Scheme 10).
4. Experimental section
4.1. General remarks
Dry THF, toluene, ethyl ether, and CH2Cl2 were purchased from
Kanto Chemical Co. Precoated silica gel plates with a fluorescent
indicator (Merck 60 F254) were used for analytical and preparative
thin layer chromatography. Flash column chromatography was car-
ried out with Kanto Chemical silica gel (Kanto Chemical, silica gel
60N, spherical neutral, 0.040–0.050 mm, Cat. No. 37 563-84). 1H
NMR spectra were recorded at 300 or 400 MHz and 13C NMR spectra
were recorded at 75 or 100 MHz on Varian VXR-300 (300 MHz),
Varian XL-400 (400 MHz), or Varian UNITY-400 (400 MHz) spec-
trometers. The chemical shifts are expressed in parts per million
downfield from the internal solvent peaks for CDCl3 (7.26 ppm, 1H
NMR), CD3OD (3.31, 4.84 ppm, 1H NMR), CDCl3 (77.0 ppm, 13C NMR),
CD3OD (49.0 ppm, 13C NMR), or D2O (the end of both fields; 0,
200 ppm, 13C NMR) and J values are given in hertz. The coupling
patterns are denoted s (singlet), d (doublet), dd (double doublet),
ddd (double double doublet), t (triplet), dt (double triplet), q (quar-
tet), m (multiplet), or br (broad). High-performance liquid chroma-
tography (HPLC) was carried out using a Senshu UV–vis Detector
(SSC-5410) and Senshu HPLC-pump (SSC-3461) with DAICEL Chiral
Pack IC (hexane/2-propanol¼98:2, UV; 210 nm). All infrared spectra
were measured on a JASCO FT/IR-460 spectrometer. High- and low-
resolution mass spectra were measured on a JEOL JMS-T100 LP and
JEOL JMS-AX505 HA spectrometers. Optical rotations were measured
by using JASCO DIP-370 polarimeter. Melting points were measured
on a Yanagimoto Micro Apparatus.
Scheme 10. Hydrogenation of the lactides 32 and 33.
We then turned our focus on the C–C bond formation (Scheme 11)
to demonstrate the syntheses of new derivatives of FV.
The crossmetathesis of 32 with trans-3-hexene in the presence of
Grubbs second generation catalyst according to Basu’s report18 fur-
nished a mixture of 37 whose structure was difficult to determine.19
According to the established deprotection procedure described
above, hydrogenation and deprotection of 37 proceeded in high
yield to give 38. Thus, we have achieved a convergent synthesis of 38
from the core lactide. This strategy has never been utilized to syn-
thesize derivatives of FV and similar compounds so far.

E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
4095
4.2. Procedure
2-H), 2.05 (s, 3H, –OCOCH3), 2.04 (s, 3H, –OCOCH3), 2.00 (s, 3H,
–OCOCH3), 1.97 (s, 3H, –OCOCH3), 1.42 (s, 9H, –t-Bu); 13C NMR
4.2.1. Synthesis of glycosyl acceptor and glycosyl donor. 4.2.1.1. (3R)-
3-Hydroxy-4-pentenoic acid tert-butyl ester ((þ)-7) and (3S)-3-ace-
toxy-4-pentenoic acid tert-butyl ester (8). To a solution of 7 (16.4 g,
94.9 mmol), vinyl acetate (26.3 mL, 285 mmol), and MS4 Å (15 g)
in n-pentane (200 mL) at ambient temperature was added Lipase
PS-D amano I (immobilized on diatomaceous earth, Wako Pure
Chemical Industries, Ltd.) (10.4 g) in one portion. The reaction
mixture was stirred for 5 h at ambient temperature. The het-
erogeneous mixture was filtered through Celite, rinsed with Et2O
(50 mL). The resulting solution was washed with H2O
(2ꢂ200 mL) and brine (200 mL). The organic layers were dried
with sodium sulfate, filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (silica gel,
pentane/Et2O¼6:1/3:1) afforded (þ)-7 (7.28 g, 42.3 mmol, 45%)
as colorless liquid and 8 (9.60 g, 44.8 mmol, 47%) as colorless
liquid.
(75 MHz, CDCl3) d: 170.6 (–OCOCH3), 170.2 (–OCOCH3), 169.5 (C-1),
169.4 (–OCOCH3), 169.4 (–OCOCH3), 137.4 (C-4), 116.8 (C-5), 100.0
(C-10), 80.9 (–OC(CH3)3), 78.7 (C-3), 73.0 (C-30), 71.7 (C-50),
71.3 (C-20), 68.5 (C-40), 62.0 (C-60), 41.3 (C-2), 28.1 (–C(CH3)3),
20.7 (–OCOCH3), 20.6 (–OCOCH3), 20.6 (–OCOCH3); IR (KBr, cmꢀ1
) n:
2979,1756,1369,1223,1040; HRMS (FAB-pos, NBA matrix) m/z
525.1950 [MþNa]þ, calcd for C23H34O12Na: 525.1948 [MþNa].
4.2.2.2. (3R)-3-(b-D-Glucopyranosyloxy)-4-pentenoic acid tert-
butyl ester (10). To a solution of 9 (32.8 mg, 0.0653 mmol) in MeOH
(2 mL) at ambient temperature was added NaH (0.1 mg,
0.00327 mmol, 60% disp.) in one portion. The reaction mixture was
stirred for 1.5 h at ambient temperature before it was quenched by
addition of Duolite to neutralize the mixture. This mixture was fil-
tered, rinsed with MeOH (10 mL). The resulting solution was con-
centrated under reduced pressure to afford 10 (23.2 mg,
0.0694 mmol, quant.) as yellow oil. The resulting oil of 10 was used in
Compound (þ)-7: Rf¼0.28 (hexane/AcOEt¼3:1); 1H NMR
(300 MHz, CDCl3)
d
: 5.86 (ddd, J¼17.4, 10.4, 5.3 Hz, 1H, 4-H), 5.29 (dt,
the next step without further purification. Rf¼0.53 (CHCl3/
ꢀ6.13 (c 1.13, MeOH); 1H NMR (300 MHz, CD3OD)
21
J¼17.4, 1.3 Hz, 1H, 5-H (trans)), 5.12 (ddd, J¼10.4, 1.5, 1.3 Hz, 1H, 5-H
(cis)), 4.47 (ddddd, J¼8.1, 5.3, 4.4, 1.5, 1.3 Hz, 1H, 3-H), 2.49
(dd, J¼16.2, 4.4 Hz, 1H, 2-H), 2.41 (dd, J¼16.2, 8.1 Hz, 1H, 2-H), 1.44
(s, 9H, –t-Bu).
MeOH¼3:1); [
a
]
D
d
: 5.90 (ddd, J¼17.3, 10.6, 6.4 Hz, 1H, 4-H), 5.24 (dt, J¼17.3, 1.3 Hz, 1H,
5-H (trans)), 5.10 (dt, J¼10.6,1.3 Hz,1H, 5-H (cis)), 4.52 (br dddt, J¼7.0,
6.4, 6.3, 1.3 Hz, 1H, 3-H), 4.34 (d, J¼7.8 Hz, 1H, 10-H), 3.79 (dd, J¼11.9,
2.2 Hz,1H, 60-H), 3.62 (dd, J¼11.9, 5.3 Hz,1H, 60-H), 3.40–3.21 (m, 3H,
30-H, 40-H, 50-H), 3.17 (dd, J¼9.0, 7.8 Hz, 1H, 20-H), 2.63 (dd, J¼15.4,
7.0 Hz, 1H, 2-H), 2.45 (dd, J¼15.4, 6.3 Hz, 1H, 2-H), 1.42 (s, 9H, –t-Bu);
Compound 8: Rf¼0.46 (hexane/AcOEt¼3:1); 1H NMR (300 MHz,
CDCl3)
d
: 5.81 (ddd, J¼17.0, 10.6, 6.3 Hz, 1H, 4-H), 5.58 (dddt, J¼8.1,
6.3, 5.9, 1.3 Hz, 1H, 3-H), 5.28 (dt, J¼17.0, 1.3 Hz, 1H, 5-H (trans)),
5.18 (dt, J¼10.6, 1.3 Hz, 1H, 5-H (cis)), 2.58 (dd, J¼15.4, 8.1 Hz, 1H, 2-
H), 2.49 (dd, J¼15.4, 5.9 Hz, 1H, 2-H), 2.03 (s, 3H, –COCH3), 1.44 (s,
9H, –t-Bu).
13C NMR (75 MHz, CD3OD)
d: 172.2 (C-1), 139.2 (C-4), 116.8 (C-5),
103.3 (C-10), 82.3 (–OC(CH3)3), 78.6 (C-3), 78.0 (C-30), 77.9 (C-50), 75.3
(C-20), 71.5 (C-40), 62.7 (C-60), 42.1 (C-2), 28.4 (–C(CH3)3); IR (KBr,
cmꢀ1
) n: 3391, 2979, 2928, 1726, 1368, 1158, 1077; HRMS (FAB-pos,
4.2.1.2. (3S)-3-Hydroxy-4-pentenoic acid tert-butyl ester ((–)-7). To
a solution of 8 (9.60 g, 44.8 mmol) in MeOH (200 mL) at ambient
temperature was added K2CO3 (1.24 g, 8.96 mmol) in one por-
tion. The reaction mixture was stirred for 1 h at ambient tem-
perature before it was quenched by slow addition of AcOH. To
the mixture wad added saturated aqueous solution of NaHCO3
(100 mL) and H2O (30 mL). The resulting mixture was extracted
with Et2O (3ꢂ100 mL) The combined organic layer was washed
with H2O (2ꢂ200 mL) and brine (200 mL) and dried with sodium
sulfate, filtered, and concentrated under reduced pressure. Puri-
fication by flash column chromatography (silica gel, pentane/
Et2O¼3:1) afforded (ꢀ)-7 (6.13 g, 35.6 mmol, 80%) as colorless
liquid.
NBA matrix); m/z 357.1527 [MþNa]þ, calcd for C15H26O8Na: 357.1525
[MþNa].
4.2.3. First generation synthesis. 4.2.3.1. (3R)-3-(6-O-Trityl-b-D-glu-
copyranosyloxy)-4-pentenoic acid tert-butyl ester (11). To a solution
of 10 (79.2 mg, 0.237 mmol) in DMF (0.2 mL) at ambient temper-
ature were added TrCl (72.7 mg, 0.261 mmol), Et3N (75 mL), DMAP
(1.5 mg, 0.0123 mmol). The reaction mixture was stirred at ambient
temperature for 42 h before it was concentrated in vacuo. Purifi-
cation by flash column chromatography (silica gel, hexane/
AcOEt¼2:1/1:2) afforded 11 (70.2 mg, 0.122 mmol, 51%) as white
solid. Rf¼0.16 (hexane/AcOEt¼1:2); 1H NMR (300 MHz, CDCl3)
d:
7.46–7.16 (m, 15H, Ph–H), 5.85 (ddd, J¼17.1, 10.6, 6.6 Hz, 1H, 4-H),
5.35 (dt, J¼17.1, 1.2 Hz, 1H, 5-H (trans)), 5.15 (dt, J¼10.6, 1.2 Hz, 1H,
5-H (cis)), 4.49 (br dddt, J¼9.7, 6.6, 3.6, 1.2 Hz, 1H, 3-H), 4.31 (d,
J¼7.8 Hz, 1H, 10-H), 3.57–3.28 (m, 6H, 20-H, 30-H, 40-H, 50-H, 60-H2),
2.59 (dd, J¼16.6, 9.7 Hz, 1H, 2-H), 2.45 (dd, J¼16.6, 3.6 Hz, 1H, 2-H),
1.42 (s, 9H, –t-Bu).
4.2.2. Glycosylation. 4.2.2.1. (3R)-3-(2,3,4,6-Tetra-O-acetyl-b-D-glu-
copyranosyloxy)-4-pentenoic acid tert-butyl ester (9). To a solution
of 6 (39.2 mg, 0.0796 mmol), (þ)-7 (27.4 mg, 0.159 mmol), and
MS4 Å (200 mg) in CH2Cl2 (0.8 mL) at ꢀ20 ꢁC was added BF3$OEt2
(12 mL, 3.59 mmol) dropwise. The reaction mixture was stirred for
1.5 h at ꢀ20 ꢁC before it was quenched by addition of saturated
aqueous solution of NaHCO3 (2 mL). This mixture was filtered
through Celite, rinsed with AcOEt (10 mL). The resulting solution
was washed with H2O (2ꢂ10 mL) and brine (10 mL). The organic
layer was dried with sodium sulfate, filtered, and concentrated
under reduced pressure. Purification by flash column chromatog-
raphy (silica gel, hexane/AcOEt¼4:1/3:1) afforded 9 (27.7 mg,
4.2.3.2. Tetra-O-benzyl-6-O-trityl-a (and/or b)-D-glucopyranose
(12). A solution of 11 (70.2 mg, 0.122 mmol) in DMF (1 mL) at am-
bient temperature was treated with NaH (29.2 mg, 0.730 mmol, 60%
disp.) followed by cooling the flask to 0 ꢁC and adding BnBr (72
mL,
0.609 mmol) dropwise to this mixture. After warming to ambient
temperature, the reaction mixture was stirred at ambient temper-
ature for 1 h. The reaction was quenched with H2O (1 mL). The
resulting mixture was extracted with AcOEt (3 mLꢂ3). The organic
layer was washed with H2O (10 mLꢂ5), brine (10 mL), and dried
with sodium sulfate, filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (silica
gel, hexane/AcOEt¼9:1) to afford 12 (29.6 mg, 0.0378 mmol, 31%,
0.0551 mmol, 69%,
b
only) as colorless oil. Rf¼0.32 (benzene/
21
AcOEt¼3:1); [
a
]
D
þ0.76 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3)
d
: 5.85 (ddd, J¼17.3, 10.4, 7.2 Hz, 1H, 4-H), 5.24 (dt, J¼17.3, 1.2 Hz,
1H, 5-H (trans)), 5.17 (dd, J¼9.5, 9.4 Hz, 1H, 30-H), 5.13 (dt, J¼10.4,
1.2 Hz, 1H, 5-H (cis)), 5.03 (dd, J¼9.8, 9.4 Hz, 1H, 40-H), 4.95 (dd,
J¼9.5, 8.1 Hz, 1H, 20-H), 4.60 (d, J¼8.1 Hz, 1H, 10-H), 4.46 (br dddt,
J¼8.4, 7.2, 4.8, 1.2 Hz, 1H, 3-H), 4.20 (dd, J¼12.2, 5.1 Hz, 1H, 60-H),
4.07 (dd, J¼12.2, 2.5 Hz, 1H, 60-H), 3.64 (ddd, J¼9.8, 5.1, 2.5 Hz, 1H,
50-H), 2.55 (dd, J¼16.0, 8.4 Hz, 1H, 2-H), 2.36 (dd, J¼16.0, 4.8 Hz, 1H,
a/
b
¼39:61) as white solid. Rf¼0.43 (hexane/AcOEt¼3:1); 1H NMR
(300 MHz, CDCl3)
d
: 7.70–6.80 (m, 70H, Ph–H), 5.09 (d, J¼11.7 Hz,
1H, –CH2Ph), 5.03 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.99 (d, J¼11.0 Hz, 1H,
–CH2Ph), 4.96 (d, J¼3.8 Hz, 1H, 1 -H), 4.91 (d, J¼11.0 Hz, 1H,
a

4096
E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
–CH2Ph), 4.82 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.80 (d, J¼11.0 Hz, 2H,
–CH2Ph), 4.80 (d, J¼12.0 Hz, 1H, –CH2Ph), 4.78 (d, J¼11.7 Hz, 1H,
–CH2Ph), 4.73 (d, J¼12.0 Hz, 1H, –CH2Ph), 4.71 (d, J¼10.3 Hz, 2H,
–CH2Ph), 4.64 (d, J¼12.0 Hz, 1H, –CH2Ph), 4.63 (d, J¼12.0 Hz, 1H,
–CH2Ph), 4.68 (d, J¼11.3 Hz, 2H, –CH2Ph), 4.58 (br dddt, J¼7.0, 6.9, 6.6,
1.2 Hz, 1H, 3-H), 4.53 (d, J¼7.5 Hz, 1H, 10-H), 4.34 (dd, J¼11.9, 4.7 Hz,
1H, 60-H), 4.26 (dd, J¼11.9,1.9 Hz,1H, 60-H), 3.50–3.30 (m, 4H, 20-H, 30-
H, 40-H, 50-H), 2.70 (dd, J¼15.4, 6.9 Hz, 1H, 2-H), 2.49 (dd, J¼15.4,
6.6 Hz, 1H, 2-H), 2.07 (s, 3H, –OCOCH3), 1.42 (s, 9H, –t-Bu).
–CH2Ph), 4.57 (d, J¼7.3 Hz, 1H, 1 -H), 4.38 (d, J¼10.3 Hz, 1H,
b
–CH2Ph), 4.31 (d, J¼10.3 Hz, 1H, –CH2Ph), 4.03 (t, J¼9.2 Hz, 1H, 3
H), 3.92–3.80 (m, 1H, 5 -H), 3.72–3.57
-H), 3.84 (t, J¼9.2 Hz, 1H, 3
(m, 5H, 2 -H, 4 -H, 2 -H, 4 -H, 5
-H), 3.47 (dd, J¼10.0, 1.6 Hz, 1H,
-H), 3.46–3.40 (m, 1H, 6 -H),
-H), 3.28 (dd, J¼10.0, 4.0 Hz, 1H, 6
a
-
13C NMR (75 MHz, CDCl3)
d: 171.4 (–COOR), 169.7 (–COOR),
a
b
138.4, 138.3, 137.8 (C-4), 128.6, 128.3, 128.2, 128.0, 127.9, 127.7, 116.7
(C-5), 102.6 (C-10), 83.8 (C-30), 81.6 (C-20), 80.9 (–OC(CH3)3), 78.2
(C-3), 75.3 (–CH2Ph), 74.7 (–CH2Ph), 73.3 (C-50), 69.9 (C-40), 63.4
(C-60), 41.5 (C-2), 28.1 (–C(CH3)3), 20.1 (–OCOCH3); HRMS (FAB-pos,
NBA matrix) m/z 579.2575 [MþNa]þ, calcd for C31H40O9Na:
579.2570 [MþNa].
a
a
b
b
b
6
b
a
b
3.20 (dd, J¼10.3, 4.5 Hz, 1H, 6
a-H); LR-MS (FAB-pos, NBA matrix)
m/z 805 [MþNa]þ, calcd for C53H50O6Na: 805.35 [MþNa].
4.2.3.3. (3R)-3-(6-O-Acetyl-b-D-glucopyranosyloxy)-4-pentenoic
acid tert-butyl ester (14). To a solution of 10 (154 mg, 0.460 mmol)
4.2.3.5. (3R)-3-(4,6-Di-O-acetyl-2,3-di-O-benzyl-b-D-glucopyr-
anosyloxy)-4-pentenoic acid tert-butyl ester (17-Ac). To a solution of
17 (20 mg, 0.0359 mmol) in CH2Cl2 (0.2 mL), and pyridine (0.2 mL)
in CH2Cl2 (60 mL) and pyridine (56
was added a solution of AcCl (36
m
L, 0.689 mmol) at ꢀ78 ꢁC
m
L, 0.505 mmol) in CH2Cl2
(1.4 mL) dropwise. The reaction mixture was stirred at ꢀ78 ꢁC for
1 h before it was quenched with MeOH (5 mL). After warming the
resulting mixture to ambient temperature, the reaction mixture
was concentrated in vacuo. Purification by flash column chro-
matography (silica gel, CHCl3/MeOH¼50:1/40:1/30:1/10:1)
afforded 14 (104 mg, 0.276 mmol, 60%, conversion yield 72%) as
colorless oil while 10 (26.9 mg, 0.0805 mmol, 17%) was recovered.
at ambient temperature were added Ac2O (10
mL, 0.108 mmol) and
DMAP (0.5 mg, 3.59 mol). The reaction mixture was stirred at
m
ambient temperature for 1 h before it was quenched with H2O
(3 mL). The resulting mixture was extracted with AcOEt (3 mLꢂ3).
The combined organic layer was washed with saturated aqueous
solution of CuSO4 (10 mL), H2O (10 mLꢂ3), and brine (10 mL), dried
with sodium sulfate, filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (silica gel,
hexane/AcOEt¼2:1) afforded 17-Ac (19.3 mg, 0.0322 mmol, 90%) as
colorless oil. Rf¼0.44 (hexane/AcOEt¼3:2); 1H NMR (300 MHz,
Rf¼0.33 (CHCl3/MeOH¼10:1); 1H NMR (300 MHz, CDCl3)
d: 5.85
(ddd, J¼17.3, 10.4, 6.7 Hz, 1H, 4-H), 5.33 (dt, J¼17.3, 1.0 Hz, 1H, 5-H
(trans)), 5.17 (dt, J¼10.4, 1.0 Hz, 1H, 5-H (cis)), 4.48 (br dddt, J¼9.7,
6.7, 3.7, 1.0 Hz, 1H, 3-H), 4.37 (dd, J¼12.0, 4.5 Hz, 1H, 60-H), 4.31
(d, J¼7.8 Hz, 1H, 10-H), 4.27 (dd, J¼12.0, 1.8 Hz, 1H, 60-H), 3.57
(t, J¼8.8 Hz, 1H, 30-H), 3.50–3.36 (m, 2H, 40-H, 50-H), 3.36 (dd,
J¼9.1, 7.8 Hz, 1H, 20-H), 2.62 (dd, J¼16.7, 9.7 Hz, 1H, 2-H), 2.45 (dd,
J¼16.7, 3.7 Hz, 1H, 2-H), 2.07 (s, 3H, –OCOCH3), 1.42 (s, 9H, –t-Bu);
CDCl3)
d
: 7.40–7.17 (m, 10H, Ph–H), 5.94 (ddd, J¼17.2, 10.4, 7.0 Hz,
1H, 4-H), 5.27 (dt, J¼17.2, 1.2 Hz, 1H, 5-H (trans)), 5.16 (dt, J¼10.4,
1.2 Hz, 1H, 5-H (cis)), 4.98 (dd, J¼10.0, 9.1 Hz, 1H, 40-H), 4.91
(d, J¼11.0 Hz, 1H, –CH2Ph), 4.79 (d, J¼11.3 Hz, 1H, –CH2Ph), 4.66
(d, J¼11.0 Hz, 1H, –CH2Ph), 4.62–4.50 (m, 1H, 3-H), 4.58 (d,
J¼11.0 Hz, 1H, –CH2Ph), 4.53 (d, J¼7.6 Hz, 1H, 10-H), 4.17 (dd, J¼12.2,
5.7 Hz,1H, 60-H), 4.04 (dd, J¼12.2, 2.5 Hz,1H, 60-H), 3.57 (t, J¼9.1 Hz,
1H, 30-H), 3.54–3.45 (m, 2H, 20-H, 50-H), 2.70 (dd, J¼15.5, 7.0 Hz, 1H,
2-H), 2.49 (dd, J¼15.5, 6.4 Hz, 1H, 2-H), 2.05 (s, 3H, –OCOCH3), 1.89
(s, 3H, –OCOCH3), 1.42 (s, 9H, –t-Bu).
13C NMR (75 MHz, CDCl3)
d: 171.6 (–COOR), 171.4 (–COOR), 136.7
(C-4), 117.1 (C-5), 102.6 (C-10), 81.9 (–OC(CH3)3), 78.8 (C-3), 75.9
(C-30), 84.4 (C-20), 74.1 (C-50), 69.7 (C-40), 63.4 (C-60), 40.7 (C-2),
28.0 (–C(CH3)3), 20.8 (–OCOCH3) HRMS (FAB-pos, NBA matrix)
m/z 399.1631 [MþNa]þ, calcd for C17H28O9Na: 399.1631 [MþNa].
4.2.3.4. (3R)-3-(6-O-Acetyl-3-O-benzyl-
4-pentenoic acid tert-butyl ester (16) and (3R)-3-(6-O-acetyl-2, 3-di-
O-benzyl- -glucopyranosyloxy)-4-pentenoic acid tert-butyl ester
(17). To a solution of 14 (155 mg, 0.412 mmol) in CH2Cl2 (4 mL) at
ambient temperature were added TMSCl (1.64 mL, 13.0 mmol),
b
-
D
-glucopyranosyloxy)-
4.2.3.6. (3R)-3-(3-O-Benzyl-b-D-glucopyranosyloxy)-4-pentenoic
acid (18). To a solution of 16 (19.0 mg, 0.0407 mmol) in CH2Cl2
(1 mL) at ambient temperature was added TFA (0.2 mL) in one
portion. The reaction mixture was stirred for 1 h at ambient tem-
perature, before it was concentrated under reduced pressure to
remove TFA.
b-D
PhCHO (132 mL, 1.30 mmol), and Et3SiH (415 mL, 2.60 mmol). The
reaction mixture was stirred at ambient temperature for 20 h be-
fore it was concentrated. The residue was purified by flash column
chromatography (hexane/AcOEt¼6:1/5:1/4:1/3:1/2:1) to
afford 16 (112 mg, 0.240 mmol, 58%) as colorless oil and 17
(14.9 mg, 0.0268 mmol, 7%) as colorless oil.
To a solution of the residue in MeOH (1 mL) at ambient temper-
ature was added NaH (0.6 mg, 0.0145 mmol, 60% disp.) in one por-
tion. The reaction mixture was stirred for 1 h at ambient temperature
before it was quenched by addition of Duolite to neutralize the
mixture. This mixture was filtered, rinsed with MeOH (5 mL). The
resulting solution was concentrated under reduced pressure. Purifi-
cation of the residue by flash column chromatography (silica gel,
CHCl3/MeOH/AcOH¼5:1:0.1) afforded 18 (13.3 mg, 0.0362 mmol,
89%) as colorless oil. Rf¼0.25 (CHCl3/MeOH/AcOH¼100:10:1); 1H
Compound 16: Rf¼0.22 (hexane/AcOEt¼3:2); 1H NMR (300 MHz,
CDCl3)
d
: 7.44–7.24 (m, 5H, Ph–H), 5.85 (ddd, J¼17.3, 10.6, 6.9 Hz, 1H,
4-H), 5.35 (dt, J¼17.3, 1.0 Hz, 1H, 5-H (trans)), 5.19 (dt, J¼10.6, 1.0 Hz,
1H, 5-H (cis)), 5.09 (d, J¼11.7 Hz, 1H, –CH2Ph), 4.75 (d, J¼11.7 Hz, 1H,
–CH2Ph), 4.50 (br dddt, J¼10.0, 6.9, 3.2, 1.0 Hz, 1H, 3-H), 4.40–4.20
(m, 3H, 10-H, 60-H2), 3.54 (t, J¼8.1 Hz, 1H, 20-H), 3.51–3.38 (m, 3H, 30-
H, 40-H, 50-H), 2.63 (dd, J¼16.9, 10.0 Hz, 1H, 2-H), 2.47 (dd, J¼16.9,
3.2 Hz, 1H, 2-H), 2.06 (s, 3H, –OCOCH3), 1.47 (s, 9H, –t-Bu); 13C NMR
NMR (300 MHz, CDCl3)
d: 7.42–7.22 (m, 5H, Ph–H), 5.87 (ddd, J¼17.2,
10.3, 6.9 Hz, 1H, 4-H), 5.30(d, J¼17.2 Hz, 1H, 5-H (trans)), 5.18
(d, J¼10.3 Hz, 1H, 5-H (cis)), 4.98 (d, J¼11.6 Hz, 1H, –CH2Ph), 4.73
(d, J¼11.6 Hz, 1H, –CH2Ph), 4.59–4.47 (m, 1H, 3-H), 4.40 (d, J¼7.6 Hz,
1H, 10-H), 3.86–3.63 (m, 2H, 60-H2), 3.59–3.37 (m, 3H, 20-H, 30-H, 40-
H), 3.35–3.26 (m, 1H, 50-H), 2.70 (dd, J¼15.9, 9.5 Hz, 1H, 2-H), 2.54
(dd, J¼15.9, 2.5 Hz, 1H, 2-H).
(75 MHz, CDCl3) d: 171.4 (–COOR), 171.3 (–COOR), 138.6, 136.7 (C-4),
128.6, 128.1, 127.9, 117.1 (C-5), 103.1 (C-10), 83.3 (C-30), 81.8
(–OC(CH3)3), 79.2 (C-3), 75.3 (C-20), 74.7 (–CH2Ph), 73.8 (C-50), 69.3
(C-40), 63.4 (C-60), 40.6 (C-2), 28.0 (–C(CH3)3), 20.8 (–OCOCH3); HRMS
(FAB-pos, NBA matrix) m/z 489.2107 [MþNa]þ, calcd for C24H34O9Na:
489.2101 [MþNa].
4.2.3.7. (3R,30R)-3-(3-O-Benzyl-2,4-dihydroxy-
b-D-glucopyr-
anosyloxy)-4-pentenoic acid bimol. cyclic ester (19). To a solution of
18 (46 mg, 0.125 mmol) in CH2Cl2 (7 mL) at ambient temperature
were added DMC (52.9 mg, 0.313 mmol), K2CO3 (34.6 mg,
0.250 mmol) in one portion. The mixture was stirred at 0 ꢁC for 2 h
followed by addition of DMAP (30.5 mg, 0.250 mmol) to this mixture.
Compound 17: Rf¼0.35 (hexane/AcOEt¼3:2); 1H NMR (300 MHz,
CDCl3)
d
: 7.42–7.24 (m,10H, Ph–H), 5.94 (ddd, J¼17.3, 10.4, 7.0 Hz,1H,
4-H), 5.28 (dt, J¼17.3, 1.2 Hz, 1H, 5-H (trans)), 5.16 (dt, J¼10.4, 1.2 Hz,
1H, 5-H (cis)), 4.93 (d, J¼11.3 Hz, 1H, –CH2Ph), 4.91 (d, J¼11.3 Hz, 1H,

E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
4097
After it was warmed to rt, the reaction mixture was stirred at ambient
temperature for 17 h. The resulting mixture was filtered through
Celite, rinsed with CHCl3 (10 mL), and concentrated in vacuo. Purifi-
cation of the residue by flash column chromatography (silica gel,
CHCl3) afforded 19 (12.0 mg, 0.0171 mmol, 28%) as colorless oil.
Rf¼0.52 (CHCl3/MeOH/AcOH¼100:10:1); 1H NMR (300 MHz, CDCl3)
–CH2Ph), 4.73 (d, J¼11.0 Hz,1H, –CH2Ph), 4.63 (d, J¼7.8 Hz,1H,10-H),
4.59 (br dtt, J¼7.0, 6.6, 1.0 Hz, 1H, 3-H), 4.31 (dd, J¼10.4, 5.0 Hz, 1H,
60-H), 3.77 (dd, J¼10.4, 9.9 Hz, 1H, 60-H), 3.73 (dd, J¼9.1, 8.2 Hz, 1H,
30-H), 3.67 (t, J¼9.1 Hz, 1H, 40-H), 3.46 (dd, J¼8.2, 7.8 Hz, 1H, 20-H),
3.38 (br ddd, J¼9.9, 9.1, 5.0 Hz,1H, 50-H), 2.70 (dd, J¼15.4, 6.6 Hz,1H,
2-H), 2.47 (dd, J¼15.4, 7.0 Hz, 1H, 2-H), 1.41 (s, 9H, –t-Bu); 13C NMR
d
: 7.46–7.18 (m, 10H, Ph–H), 5.83 (ddd, J¼17.3, 10.7, 6.3 Hz, 2H, 4-H),
(75 MHz, CDCl3) d: 169.6 (C-1), 138.5, 138.4, 137.5, 137.3 (C-4), 128.9,
5.30 (d, J¼17.3 Hz, 2H, 5-H (trans)), 5.18 (d, J¼10.7 Hz, 2H, 5-H (cis)),
5.02 (d, J¼11.0 Hz, 2H, –CH2Ph), 4.77–4.63 (m, 2H, 3-H), 4.73
(d, J¼11.0 Hz, 2H, –CH2Ph), 4.48 (dd, J¼11.4, 1.3 Hz, 2H, 60-H), 4.44
(d, J¼7.8 Hz, 2H, 10-H), 3.95 (dd, J¼11.4, 9.8 Hz, 2H, 60-H), 3.69–3.55
(m, 2H, 50-H), 3.59 (br dd, J¼8.5, 7.8 Hz, 2H, 20-H), 3.42 (t, J¼8.5 Hz, 2H,
30-H), 3.36 (t, J¼8.5 Hz, 2H, 40-H), 2.96 (dd, J¼13.9, 4.5 Hz, 2H, 2-H),
128.3, 128.3, 128.2, 128.0, 127.6, 127.6, 126.0, 117.0 (C-5), 102.6 (C-10),
101.1 (–O2CHPh), 82.1 (C-20), 81.4 (C-40), 81.1 (C-30), 81.0
(–OC(CH3)3), 77.9 (C-3), 75.3 (–CH2Ph), 75.1 (–CH2Ph), 68.8 (C-60),
66.0 (C-50), 41.5 (C-2), 28.1 (–C(CH3)3); IR (KBr, cmꢀ1
) n: 2978, 2872,
1728, 1454, 1367, 1088; HRMS (FAB-pos, NBA matrix); m/z 625.2778
[MþNa]þ, calcd for C36H42O8Na: 625.2777 [MþNa].
2.47 (dd, J¼13.9, 11.0 Hz, 2H, 2-H); 13C NMR (75 MHz, CDCl3)
d: 169.2
(C-1),138.2,135.6 (C-4),128.7,128.1,128.1,117.9 (C-5), 99.6 (C-10), 83.6
(C-30), 74.8 (–CH2Ph), 74.4 (C-3), 74.2 (C-20), 73.4 (C-50), 70.1 (C-40),
65.0 (C-60), 39.8 (C-2); LR-MS (FAB-pos, NBA matrix) m/z 723
[MþNa]þ, calcd for C36H44O14Na: 723.26 [MþNa].
4.2.4.3. (3R)-3-(2,3,4-Tri-O-benzyl-b-D-glucopyranosyloxy)-4-
pentenoic acid tert-butyl ester (24). To a solution of 22 (15 mg,
0.0249 mmol) in CH2Cl2 (1.5 mL) at ꢀ20 ꢁC was added BH3$Me2NH
(7.4 mg, 0.125 mmol) dropwise. The mixture was stirred at ꢀ20 ꢁC for
30 min. To this mixture was added BF3$OEt2 (15.7 mL, 0.125 mmol)
4.2.4. Second generation synthesis. 4.2.4.1. (3R)-3-(2,3,4,6-Tetra-O-
trimethylsilyl-b-D-glucopyranosyloxy)-4-pentenoic acid tert-butyl
dropwise. The reaction mixture was stirred at ꢀ20 ꢁC for 2 h before it
was quenched with saturated NaHCO3 (1 mL). The resulting mixture
was extracted with AcOEt (3ꢂ3 mL). The organic layer was washed
with saturated aqueous solution of NaHCO3 (10 mL) and brine
(10 mL), dried over sodium sulfate, filtered, and concentrated under
reduced pressure. Purification of the residue by flash column chro-
matography (hexane/AcOEt¼8:1/6:1/4:1/3:1) afforded 24
ester (20). To a solution of 10 (1.31 g, 3.92 mmol) in CH2Cl2 (20 mL)
and pyridine (20 mL) at ambient temperature was added TMSCl
(5.0 mL, 39.2 mmol) dropwise. The reaction mixture was stirred for
3 h at ambient temperature before it was quenched by addition of
H2O (20 mL). The resulting mixture was extracted with hexane
(3ꢂ20 mL). The organic layer was washed with H2O (3ꢂ60 mL) and
brine (60 mL), dried over sodium sulfate, filtered, and concentrated
under reduced pressure. Purification of the residue by flash column
chromatography (silica gel, hexane/AcOEt¼5:1) to remove a little
(10.1 mg, 0.0167 mmol, 67%, conversion yield 74%) as colorless oil.
25
Rf¼0.24 (hexane/AcOEt¼2:1); [
a
]
þ16.8 (c 1.00, CHCl3); 1H NMR
D
(300 MHz, CDCl3)
d
: 7.40–7.20 (m, 15H, Ph-H), 5.94 (ddd, J¼17.3, 10.4,
7.0 Hz, 1H, 4-H), 5.28 (dt, J¼17.3, 1.2 Hz, 1H, 5-H (trans)), 5.17
(dt, J¼10.4,1.2 Hz,1H, 5-H (cis)), 4.92 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.91
(d, J¼11.0 Hz, 1H, –CH2Ph), 4.83 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.78
(d, J¼11.0 Hz,1H, –CH2Ph), 4.68 (d, J¼11.0 Hz,1H, –CH2Ph), 4.64–4.56
(m,1H, 3-H), 4.59 (d, J¼11.0 Hz,1H, –CH2Ph), 4.56 (d, J¼7.8 Hz,1H,10-
H), 3.82 (dd, J¼11.6, 2.6 Hz,1H, 60-H), 3.65 (t, J¼8.9 Hz,1H, 30-H), 3.60
(dd, J¼11.6, 5.7 Hz, 1H, 60-H), 3.46 (dd, J¼9.7, 8.9 Hz, 1H, 40-H), 3.42
(dd, J¼8.9, 7.8 Hz, 1H, 20-H), 3.34 (br ddd, J¼9.7, 5.7, 2.6 Hz, 1H, 50-H),
2.68 (dd, J¼15.4, 7.3 Hz, 1H, 2-H), 2.48 (dd, J¼15.4, 6.3 Hz, 1H, 2-H),
amount of pyridine, afforded 20 (2.18 g, 3.50 mmol, 89%) as color-
22
less oil. Rf¼0.56 (hexane/AcOEt¼6:1); [
a]
ꢀ4.11 (c 1.78, CHCl3); 1H
D
NMR (300 MHz, CDCl3)
d
: 5.89 (ddd, J¼17.2, 10.4, 6.6 Hz, 1H, 4-H),
5.24 (dt, J¼17.2, 1.4 Hz, 1H, 5-H (trans)), 5.10 (dt, J¼10.4, 1.4 Hz, 1H,
5-H (cis)), 4.54 (dddt, J¼7.9, 6.6, 6.0, 1.4 Hz, 1H, 3-H), 4.31
(d, J¼7.5 Hz, 1H, 10-H), 3.76 (dd, J¼11.3, 2.1 Hz, 1H, 60-H), 3.64 (dd,
J¼11.3, 5.1 Hz, 1H, 60-H), 3.43 (t, J¼8.4 Hz, 1H, 40-H), 3.36
(t, J¼8.4 Hz, 1H, 30-H), 3.24 (dd, J¼8.4, 7.5 Hz, 1H, 20-H), 3.15 (ddd,
J¼8.4, 5.1, 2.1 Hz, 1H, 50-H), 2.68 (dd, J¼15.1, 6.0 Hz, 1H, 2-H), 2.43
(dd, J¼15.1, 7.9 Hz, 1H, 2-H), 1.44 (s, 9H, –t-Bu), 0.15 (s, 9H,
–Si(CH3)3), 0.15 (s, 9H, –Si(CH3)3), 0.14 (s, 9H, –Si(CH3)3), 0.10 (s, 9H,
1.42 (s, 9H, –t-Bu); 13C NMR (75 MHz, CDCl3)
d: 169.7 (C-1), 138.5,
138.4, 138.3 (C-4), 137.9, 128.5, 128.3, 128.3, 128.1, 128.0, 127.9, 127.8,
127.6, 127.6, 116.5 (C-5), 102.4 (C-10), 84.6 (C-30), 82.2 (C-20), 81.1
(–OC(CH3)3), 78.0 (C-3), 77.9 (C-40), 75.7 (–CH2Ph), 75.0 (C-50), 75.0
(–CH2Ph), 74.8 (–CH2Ph), 62.3 (C-60), 41.7 (C-2), 28.1 (–C(CH3)3); IR
–Si(CH3)3); 13C NMR (75 MHz, CDCl3)
d: 170.0 (C-1), 137.9 (C-4),
116.1 (C-5), 101.5 (C-10), 80.7 (–OC(CH3)3), 78.1 (C-30), 76.7 (C-50),
76.2 (C-3), 75.2 (C-20), 71.5 (C-40), 62.1 (C-60), 41.3 (C-2), 28.1
(–C(CH3)3), 1.3 (–Si(CH3)3), 1.2 (–Si(CH3)3), 0.9 (–Si(CH3)3), ꢀ0.3
(KBr, cmꢀ1
) n: 3460, 2977, 2875, 1730, 1366, 1071; HRMS (FAB-pos,
NBA matrix) m/z 627.2947 [MþNa]þ, calcd for C36H44O8Na: 627.2934
[MþNa].
(–Si(CH3)3); IR (KBr, cmꢀ1
) n: 2957, 2902, 1733, 1251, 1091, 843.
4.2.4.2. (3R)-3-(2,3-Di-O-benzyl-4,6-O-benzylidene-
b
-
D
-gluco-
4.2.4.4. (3R)-3-(2,3,4-Tri-O-benzyl-b-D-glucopyranosyloxy)-4-
pyranosyloxy)-4-pentenoic acid tert-butyl ester (22). To a suspen-
sion of 20 (2.16 g, 3.47 mmol) and MS4 Å (3 g) in CH2Cl2 (30 mL) at
pentenoic acid (25). To a solution of 24 (500 mg, 0.827 mmol) in
CH2Cl2 (13 mL) at ambient temperature was added TFA (2 mL) in one
portion. The reaction mixture was stirred for 2 h at ambient tem-
perature, before it was concentrated under reduced pressure to
remove TFA. The resulting residue was used in the next step without
further purification.
ꢀ78 ꢁC were added PhCHO (386
mL, 3.82 mmol) and TMSOTf
(127 mL, 0.700 mmol) dropwise. The reaction mixturewas stirred for
2.5 h at ꢀ78 ꢁC. To this mixture were added Et3SiH (1.66 mL,
10.4 mmol), PhCHO (1.05 mL, 10.4 mmol), and TMSOTf (127 mL,
0.700 mmol) dropwise. The reaction mixture was stirred for 1 h at
ꢀ78 ꢁC and for 2 h at ꢀ40 ꢁC before it was quenched with Et3N. After
warmed up to ambient temperature, the resulting mixture was fil-
tered through Celite, rinsed with CH2Cl2 (30 mL), and concentrated
in vacuo. Purification of the residue by flash column chromatogra-
phy (silica gel, hexane/AcOEt¼20:1/15:1/10:1/8:1/6:1)
To a mixture of the previous reaction residue in MeOH (7 mL) at
ambient temperature was added NaH (60% disp.) in one portion.
The reaction mixture was stirred at ambient temperature before it
was quenched by addition of Duolite to neutralize the mixture. This
mixture was filtered, rinsed with MeOH. The resulting solution was
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (hexane/AcOEt:AcOH¼50:10:1/
afforded 22 (1.80 g, 2.99 mmol, 86%) as white solid. Rf¼0.24 (hex-
24
ane/AcOEt¼4:1); [
a
]
D
ꢀ16.9 (c 1.00, CHCl3); 1H NMR (300 MHz,
30:10:1/10:10:1) afforded 25 (400 mg, 0.729 mmol, 88%) as white
25
CDCl3)
d
: 7.56–7.20 (m, 15H, Ph–H), 5.91 (ddd, J¼17.2, 10.4, 7.0 Hz,
solid. Rf¼0.24 (hexane/AcOEt/AcOH¼10:10:1); [
a
]
þ16.8 (c 1.00,
D
1H, 4-H), 5.55 (s, 1H, –O2CHPh), 5.30 (dt, J¼17.2, 1.0 Hz, 1H, 5-H
(trans)), 5.18 (dt, J¼10.4, 1.0 Hz, 1H, 5-H (cis)), 4.89 (d, J¼11.0 Hz, 1H,
–CH2Ph), 4.88 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.77 (d, J¼11.0 Hz, 1H,
CHCl3); 1H NMR (300 MHz, CDCl3);
d: 7.36–7.21 (m, 15H, Ph–H),
5.95 (ddd, J¼17.3, 10.4, 6.9 Hz, 1H, 4-H), 5.23 (br dt, J¼17.3, 1.0 Hz,
1H, 5-H (trans)), 5.19 (br dt, J¼10.4, 1.0 Hz, 1H, 5-H (cis)), 4.89

4098
E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
(d, J¼11.0 Hz, 1H, –CH2Ph), 4.87 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.82
(d, J¼11.0 Hz, 1H, –CH2Ph), 4.78 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.70–
4.50 (m,1H, 3-H), 4.68 (d, J¼11.0 Hz,1H, –CH2Ph), 4.58 (d, J¼11.0 Hz,
1H, –CH2Ph), 4.56 (d, J¼7.8 Hz,1H,10-H), 3.81 (dd, J¼11.9, 2.6 Hz,1H,
60-H), 3.65 (t, J¼8.9 Hz, 1H, 30-H), 3.59 (dd, J¼11.9, 5.7 Hz, 1H, 60-H),
3.46 (dd, J¼9.7, 8.9 Hz, 1H, 40-H), 3.42 (dd, J¼8.9, 7.8 Hz, 1H, 20-H),
3.35 (br ddd, J¼9.7, 5.7, 2.5 Hz, 1H, 50-H), 2.72 (dd, J¼15.8, 8.4 Hz,
1H, 2-H), 2.55 (dd, J¼15.8, 4.8 Hz, 1H, 2-H); 13C NMR (75 MHz,
H), 3.79 (dd, J¼11.3, 2.1 Hz, 1H, 60-H), 3.64 (dd, J¼11.3, 5.4 Hz, 1H,
60-H), 3.45–3.34 (m, 2H, 30-H, 40-H), 3.26 (dd, J¼8.6, 7.5 Hz, 1H, 20-
H), 3.34 (br ddd, J¼8.9, 5.4, 2.1 Hz,1H, 50-H), 2.69 (dd, J¼14.5, 6.2 Hz,
1H, 2-H), 2.39 (dd, J¼14.5, 8.5 Hz, 1H, 2-H), 1.42 (s, 9H, –t-Bu), 0.15
(s, 9H, –Si(CH3)3), 0.14 (s, 9H, –Si(CH3)3), 0.14 (s, 9H, –Si(CH3)3), 0.12
(s, 9H, –Si(CH3)3); 13C NMR (75 MHz, CDCl3)
d: 169.5 (C-1), 136.0
(C-4), 119.7 (C-5), 98.7 (C-10), 80.5 (–OC(CH3)3), 78.5 (C-30), 76.6
(C-50), 75.6 (C-20), 74.5 (C-3), 71.8 (C-40), 62.2 (C-60), 42.2 (C-2), 28.1
(–C(CH3)3), 1.4 (–Si(CH3)3), 1.3 (–Si(CH3)3), 0.9 (–Si(CH3)3), ꢀ0.3
CDCl3) d: 174.8 (C-1), 138.3, 137.9, 137.8 (C-4), 128.5, 128.5, 128.4,
128.4, 128.1, 128.0, 128.0, 127.9, 127.9, 127.8, 127.7, 127.6, 116.9 (C-5),
102.3 (C-10), 84.6 (C-30), 82.1 (C-20), 77.9 (C-3), 77.8 (C-40), 75.7
(–CH2Ph), 75.1 (C-50), 75.0 (–CH2Ph), 74.9 (–CH2Ph), 62.2 (C-60), 40.2
(–Si(CH3)3); IR (KBr, cmꢀ1
) n: 2957, 2901, 1737, 1251, 1092, 843;
HRMS (FAB-pos, NBA matrix) m/z 645.3112 [MþNa]þ, calcd for
C15H26O8Na: 645.3107 [MþNa].
(C-2); IR (KBr, cmꢀ1
) n: 3439, 3063, 3031, 2915, 1714, 1070; HRMS
(FAB-pos, NBA matrix) m/z 571.2326 [MþNa]þ, calcd for
C32H36O8Na: 571.2308 [MþNa].
4.2.4.8. (3S)-3-(2,3-Di-O-benzyl-4,6-O-benzylidene-b-D-gluco-
pyranosyloxy)-4-pentenoic acid tert-butyl ester (29). According to
the synthesis of 22, protection of 28 (295 mg, 0.474 mmol) gave 29
(259 mg, 0.430 mmol, 91%) as white solid from the crude product
4.2.4.5. (3S)-3-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyloxy)-4-
pentenoic acid tert-butyl ester (26). The glycosylation was per-
formed according to the procedure (3.0 mL of CH2Cl2, 0 ꢁC, 4 h)
employing imidate donor 6 (423 mg, 0.859 mmol), acceptor (ꢀ)-7
after flash column chromatography (hexane/AcOEt¼12:1/8:1/
25
4:1). Rf¼0.29 (hexane/AcOEt¼4:1); [
a
]
ꢀ23.0 (c 1.00, CHCl3); 1H
D
NMR (300 MHz, CDCl3) d: 7.52–7.22 (m, 15H, Ph–H), 5.73 (ddd,
(296 mg, 1.72 mmol), and BF3$OEt2 (130
mL, 1.03 mmol) to give 26
J¼17.1, 10.3, 7.9 Hz, 1H, 4-H), 5.56 (s, 1H, –O2CHPh), 5.34 (ddd,
J¼17.1, 1.5, 0.7 Hz, 1H, 5-H (trans)), 5.27 (ddd, J¼10.3, 1.5, 0.7 Hz, 1H,
5-H (cis)), 4.89 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.88 (d, J¼11.0 Hz, 1H,
–CH2Ph), 4.78 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.74 (d, J¼11.0 Hz, 1H,
–CH2Ph), 4.61 (br ddd, J¼7.9, 7.2, 6.9 Hz, 1H, 3-H), 4.60 (d, J¼7.8 Hz,
1H, 10-H), 4.35 (dd, J¼10.4, 4.8 Hz, 1H, 60-H), 3.77 (dd, J¼10.4,
10.0 Hz, 1H, 60-H), 3.72 (dd, J¼9.1, 8.2 Hz, 1H, 30-H), 3.66 (t, J¼9.1 Hz,
1H, 40-H), 3.45 (dd, J¼8.2, 7.8 Hz, 1H, 20-H), 3.37 (br ddd, J¼10.0, 9.1,
4.8 Hz, 1H, 50-H), 2.66 (dd, J¼14.8, 6.9 Hz, 1H, 2-H), 2.47 (dd, J¼14.8,
(334 mg, 0.665 mmol, 77%,
b only) as colorless oil from the crude
product after flash column chromatography (hexane/AcOEt¼3:1/
22
2:1). Rf¼0.38 (benzene/AcOEt¼3:1); [
a
]
ꢀ12.8 (c 1.00, CHCl3); 1H
D
NMR (300 MHz, CDCl3)
d
: 5.66 (ddd, J¼17.2, 10.3, 7.5 Hz, 1H, 4-H),
5.28 (br d, J¼17.2 Hz, 1H, 5-H (trans)), 5.27 (br d, J¼10.3 Hz, 1H, 5-H
(cis)), 5.17 (t, J¼9.4 Hz, 1H, 30-H), 5.07 (dd, J¼9.6, 9.4 Hz, 1H, 40-H),
4.97 (dd, J¼9.4, 8.1 Hz, 1H, 20-H), 4.57 (d, J¼8.1 Hz, 1H, 10-H), 4.53
(br ddd, J¼7.5, 7.2, 6.6 Hz,1H, 3-H), 4.26 (dd, J¼12.2, 4.8 Hz,1H, 60-H),
4.10 (dd, J¼12.2, 2.5 Hz, 1H, 60-H), 3.64 (ddd, J¼9.7, 4.8, 2.5 Hz,1H, 50-
H), 2.62 (dd, J¼15.0, 6.6 Hz, 1H, 2-H), 2.40 (dd, J¼15.0, 7.2 Hz, 1H,
2-H), 2.08 (s, 3H, –OCOCH3), 2.02 (s, 3H, –OCOCH3), 2.01 (s, 3H,
–OCOCH3), 1.99 (s, 3H, –OCOCH3), 1.42 (s, 9H, –t-Bu); 13C NMR
7.2 Hz, 1H, 2-H), 1.44 (s, 9H, –t-Bu); 13C NMR (75 MHz, CDCl3)
d:
169.4 (C-1), 138.5, 138.3, 137.3, 136.1 (C-4), 128.9, 128.3, 128.2, 128.2,
128.0, 127.7, 127.6, 126.0, 119.3 (C-5), 101.1 (–O2CHPh), 100.2 (C-10),
81.9 (C-20), 81.5 (C-40), 80.9 (C-30), 80.7 (–OC(CH3)3), 75.8 (C-3), 75.3
(–CH2Ph), 75.1 (–CH2Ph), 68.8 (C-60), 65.9 (C-50), 42.4 (C-2), 28.1
(75 MHz, CDCl3) d: 170.6 (–OCOCH3), 170.3 (–OCOCH3), 169.4 (C-1),
169.2 (–OCOCH3), 169.2 (–OCOCH3), 135.9 (C-4), 118.8 (C-5), 97.6
(C-10), 80.8 (–OC(CH3)3), 76.1 (C-3), 72.9 (C-30), 71.6 (C-50), 71.3 (C-20),
68.4 (C-40), 61.9 (C-60), 42.0 (C-2), 28.0 (–C(CH3)3), 20.7 (–OCOCH3),
(–C(CH3)3); IR (KBr, cmꢀ1
) n: 2978, 2871, 1730, 1454, 1367, 1089;
HRMS (FAB-pos, NBA matrix) m/z 625.2781 [MþNa]þ, calcd for
C36H42O8Na: 625.2777 [MþNa].
20.6 (–OCOCH3), 20.6 (–OCOCH3), 20.5 (–OCOCH3); IR (KBr, cmꢀ1
) n:
2979,1757,1368,1225,1041; HRMS (FAB-pos, NBA matrix); m/z
4.2.4.9. (3S)-3-(2,3,4-Tri-O-benzyl-b-D-glucopyranosyloxy)-4-
525.1948 [MþNa]þ, calcd for C23H34O12Na: 525.1948 [MþNa].
pentenoic acid tert-butyl ester (30). According to the synthesis of
24, reaction of 29 (1.60 g, 2.65 mmol) gave 30 (1.09 g, 1.80 mmol,
68%) as colorless oil from the crude product after flash column
4.2.4.6. (3S)-3-(b-D-Glucopyranosyloxy)-4-pentenoic acid tert-
butyl ester (27). According to the synthesis of 10, deacetylation of 26
(310 mg, 0.623 mmol) gave 27 (212 mg, 0.634 mmol, quant.) as yel-
chromatography (hexane/AcOEt¼8:1/6:1/4:1/3:1). Rf¼0.32
25
(hexane/AcOEt¼2:1);
[
a]
þ3.39 (c 1.00, CHCl3); 1H NMR
D
23
low oil. Rf¼0.33 (CHCl3/MeOH¼4:1); [
a
]
ꢀ23.4 (c 1.62, MeOH); 1H
(300 MHz, CDCl3)
d: 7.20–7.10 (m, 15H, Ph–H), 5.60 (ddd, J¼17.4,
D
NMR (300 MHz, CD3OD)
d
: 5.76 (ddd, J¼17.3, 10.0, 7.6 Hz, 1H, 4-H),
10.1, 7.3 Hz, 1H, 4-H), 5.18 (dt, J¼17.4, 1.0 Hz, 1H, 5-H (trans)), 5.18
(dt, J¼10.1, 1.0 Hz, 1H, 5-H (cis)), 4.78 (d, J¼11.0 Hz, 1H, –CH2Ph),
4.77 (d, J¼11.0 Hz,1H, –CH2Ph), 4.69 (d, J¼11.0 Hz,1H, –CH2Ph), 4.63
(d, J¼11.0 Hz, 1H, –CH2Ph), 4.55 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.50–
4.41 (m, 1H, 3-H), 4.46 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.35 (d, J¼7.8 Hz,
1H, 10-H), 3.70 (dd, J¼11.7, 2.6 Hz, 1H, 60-H), 3.53–3.45 (m, 1H, 30-H),
3.50 (dd, J¼11.7, 5.2 Hz, 1H, 60-H), 3.37–3.24 (m, 2H, 20-H, 40-H), 3.19
(br ddd, J¼7.1, 5.2, 2.6 Hz, 1H, 50-H), 2.47 (dd, J¼14.8, 7.5 Hz, 1H,
2-H), 2.30 (dd, J¼14.8, 6.2 Hz, 1H, 2-H), 1.29 (s, 9H, –t-Bu); 13C NMR
5.39 (dt, J¼17.3, 1.0 Hz, 1H, 5-H (trans)), 5.28 (dt, J¼10.0, 1.0 Hz, 1H,
5-H (cis)), 4.70–4.61 (m, 1H, 3-H), 4.31 (d, J¼7.8 Hz, 1H, 10-H), 3.87
(dd, J¼11.7, 1.9 Hz, 1H, 60-H), 3.65 (dd, J¼11.7, 5.7 Hz, 1H, 60-H), 3.45–
3.15 (m, 4H, 20-H, 30-H, 40-H, 50-H), 2.62 (dd, J¼14.7, 7.5 Hz, 1H, 2-H),
2.46 (dd, J¼14.7, 7.5 Hz, 1H, 2-H), 1.45 (s, 9H, –t-Bu); 13C NMR
(75 MHz, CD3OD) d
: 172.1 (C-1), 137.8 (C-4), 119.5 (C-5), 100.6 (C-10),
82.2 (–OC(CH3)3), 78.0 (C-30), 77.9 (C-50), 76.1 (C-3), 75.0 (C-20), 71.8
(C-40), 62.9 (C-60), 43.2 (C-2), 28.3 (–C(CH3)3); IR (KBr, cmꢀ1
)
n: 3388,
2979, 2930, 1727, 1368, 1160, 1076; HRMS (FAB-pos, NBA matrix) m/z
357.1521 [MþNa]þ, calcd for C15H26O8Na: 357.1525 [MþNa].
(75 MHz, CDCl3) d: 169.8 (C-1), 138.5, 138.3, 137.9, 136.2 (C-4), 128.4,
128.4, 128.3, 128.2, 128.0, 127.8, 118.6 (C-5), 100.1 (C-10), 84.6 (C-30),
82.2 (C-20), 80.9 (–OC(CH3)3), 78.0 (C-40), 75.9 (C-3), 75.7 (–CH2Ph),
75.0 (C-50), 74.9 (–CH2Ph), 74.8 (–CH2Ph), 62.3 (C-60), 42.4 (C-2),
4.2.4.7. (3S)-3-(2,3,4,6-Tetra-O-trimethylsilyl-b-D-glucopyr-
anosyloxy)-4-pentenoic acid tert-butyl ester (28). According to the
synthesis of 20, protection of 27 (200 mg, 0.610 mmol) gave 28
(310 mg, 0.498 mmol, 83%) as colorless oil from the crude product
28.1 (–C(CH3)3); IR (KBr, cmꢀ1
) n: 3439, 2873, 1729, 1365, 1070;
HRMS (FAB-pos, NBA matrix) m/z 627.2935 [MþNa]þ, calcd for
C36H44O8Na: 627.2934 [MþNa].
after flash column chromatography (hexane/AcOEt¼12:1). Rf¼0.53
21
(hexane/AcOEt¼4:1);
[
a]
ꢀ11.7 (c 2.43, CHCl3); 1H NMR
4.2.4.10. (3S)-3-(2,3,4-Tri-O-benzyl-b-D-glucopyranosyloxy)-4-
D
(300 MHz, CDCl3)
d
: 5.66 (ddd, J¼17.2, 10.1, 8.5 Hz, 1H, 4-H), 5.30
pentenoic acid (31). According to the synthesis of 25, reaction of 30
(1.75 g, 2.89 mmol) gave 31 (1.36 g, 2.48 mmol, 86%) as colorless oil
from the crude product after flash column chromatography
(br dd, J¼17.2, 1.6 Hz, 1H, 5-H (trans)), 5.27 (br dd, J¼10.1, 1.6 Hz, 1H,
5-H (cis)), 4.63 (dt, J¼8.5, 6.2 Hz, 1H, 3-H), 4.24 (d, J¼7.5 Hz, 1H, 10-

E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
4099
(hexane/AcOEt/AcOH¼40:10:1/30:10:1/20:10:1). Rf¼0.13 (hex-
9.1 Hz, 2H, 2-H); 13C NMR (75 MHz, CDCl3)
d
: 169.2 (C-1),138.4,138.2,
25
ane/AcOEt/AcOH¼15:10: 1); [
(300 MHz, CDCl3)
a
]
þ15.7 (c 1.00, CHCl3); 1H NMR
137.5, 136.2 (C-4), 128.5, 128.4, 128.4, 128.2, 128.2, 128.0, 127.8, 127.8,
127.7, 119.5 (C-5), 99.9 (C-10), 84.6 (C-30), 82.0 (C-20), 78.1 (C-40), 75.7
(C-3), 75.1 (–CH2Ph), 75.1 (–CH2Ph), 75.0 (–CH2Ph), 72.9 (C-50), 63.9
D
d: 7.40–7.17 (m, 15H, Ph–H), 5.80 (ddd, J¼17.3,
10.4, 7.0 Hz, 1H, 4-H), 5.37 (dt, J¼17.3, 1.0 Hz, 1H, 5-H (trans)), 5.24
(dt, J¼10.4, 1.0 Hz, 1H, 5-H (cis)), 4.91 (d, J¼11.0 Hz, 1H, –CH2Ph),
4.91 (d, J¼11.0 Hz,1H, –CH2Ph), 4.83 (d, J¼11.0 Hz,1H, –CH2Ph), 4.79
(d, J¼11.0 Hz, 1H, –CH2Ph), 4.74–4.56 (m, 1H, 3-H), 4.70
(d, J¼11.0 Hz, 1H, –CH2Ph), 4.60 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.52
(d, J¼7.8 Hz, 1H, 10-H), 3.87 (dd, J¼11.9, 2.3 Hz, 1H, 60-H), 3.66
(dd, J¼11.9, 5.8 Hz, 1H, 60-H), 3.65 (t, J¼9.1 Hz, 1H, 30-H), 3.49
(t, J¼9.1 Hz, 1H, 40-H), 3.43 (dd, J¼9.7, 7.8 Hz, 1H, 20-H), 3.35 (br ddd,
J¼9.1, 5.8, 2.3 Hz, 1H, 50-H), 2.71 (dd, J¼15.5, 8.5 Hz, 1H, 2-H), 2.58
(C-60), 41.6 (C-2); IR (KBr, cmꢀ1
) n: 3031, 2919,1734,1068; HRMS (FAB-
pos, NBA matrix); m/z 1083.4513 [MþNa]þ, calcd for C64H68O14Na:
1083.4507 [MþNa].
Compound 34: Rf¼0.47 (hexane/AcOEt/AcOH¼15:10:1); 1H
NMR (300 MHz, CDCl3) d: 7.37–7.25 (m, 15H, Ph–H), 5.84 (ddd,
J¼17.2, 10.4, 5.1 Hz, 1H, 4-H), 5.28 (dt, J¼17.2, 1.5 Hz, 1H, 5-H
(trans)), 5.17 (dt, J¼10.4, 1.5 Hz, 1H, 5-H (cis)), 4.94 (d, J¼11.0 Hz, 1H,
–CH2Ph), 4.92 (dd, J¼11.9, 3.2 Hz, 1H, 60-H), 4.83 (s, 1H, 10-H), 4.74–
4.70 (m, 2H, –CH2Ph), 4.67 (d, J¼11.0 Hz, 1H, –CH2Ph), 4.60 (d,
J¼11.7 Hz, 1H, –CH2Ph), 4.51 (d, J¼11.7 Hz, 1H, –CH2Ph), 4.33–4.23
(m, 1H, 3-H), 4.27 (t, J¼10.1 Hz, 1H, 40-H), 4.00 (d, J¼11.9 Hz, 1H, 60-
H), 3.84 (d, J¼4.3 Hz, 1H, 20-H), 3.79 (dd, J¼10.1, 3.2 Hz, 1H, 50-H),
3.73 (dd, J¼10.1, 4.3 Hz, 1H, 30-H), 2.57 (dd, J¼11.6, 10.8 Hz, 1H, 2-H),
(dd, J¼15.5, 4.3 Hz, 1H, 2-H); 13C NMR (75 MHz, CDCl3)
d: 174.9
(C-1), 138.5, 138.2, 137.9, 136.2 (C-4), 128.4, 128.3, 128.1, 128.1, 128.0,
127.9, 127.8, 127.7, 127.6, 118.2 (C-5), 101.2 (C-10), 84.6 (C-30), 82.0
(C-20), 77.6 (C-40), 76.6 (C-3), 75.6 (–CH2Ph), 75.0 (–CH2Ph), 75.0
(–CH2Ph), 75.0 (C-50), 62.0 (C-60), 41.2 (C-2); IR (KBr, cmꢀ1
) n: 3429,
3063, 3031, 2911, 1719, 1070; HRMS (FAB-pos, NBA matrix); m/z
2.49 (dd, J¼11.6, 2.9 Hz, 1H, 2-H); 13C NMR (75 MHz, CDCl3)
d: 173.7
571.2307 [MþNa]þ, calcd for C32H36O8Na: 571.2308 [MþNa].
(C-1), 138.2, 138.1, 137.4 (C-4), 137.3, 128.5, 128.4, 128.3, 128.1, 128.0,
127.9, 127.8, 127.8, 127.6, 115.3 (C-5), 101.8 (C-10), 84.4 (C-20), 83.6
(C-30), 80.3 (C-3), 76.3 (C-50), 75.2 (–CH2Ph), 73.5 (C-40), 73.3
(–CH2Ph), 71.7 (–CH2Ph), 63.3 (C-60), 43.3 (C-2); HRMS (FAB-pos,
NBA matrix); m/z 553.2203 [MþNa]þ, calcd for C32H34O7Na:
553.2202 [MþNa].
4.2.4.11. (3R,30R)-3-(2,3,4-Tri-O-benzyl-
b-D-glucopyranosyloxy)-
4-pentenoic acid bimol. cyclic ester (32). To a suspension of 25
(50 mg, 0.0911 mmol) and MS4 Å (200 mg) in CH2Cl2 (1 mL) at
ambient temperature was added DMC (39 mg, 0.228 mmol) in one
portion. The reaction mixture was stirred for 20 h at ambient
temperature. The resulting mixture was filtered through Celite,
rinsed with CH2Cl2 (5 mL), and concentrated in vacuo. Purification
of the residue by flash column chromatography (silica gel, hexane/
4.2.5. After the cyclization. 4.2.5.1. (3S,30S)-3-(
b-D-Glucopyr-
anosyloxy)-4-pentanoic acid bimol. cyclic ester (35). A solution
of 32 (14.0 mg, 0.0132 mmol) in AcOEt (2 mL) and EtOH (4 mL)
was treated with 10 wt % palladium on activated carbon
(18.0 mg). The reaction flask was flushed with air and hydro-
gen atmospheres sequentially. The reaction mixture was then
placed under an atmosphere of hydrogen and stirred for 24 h.
The heterogeneous mixture was filtered through Celite, rinsed
with MeOH (10 mL), and concentrated in vacuo. Purification of
the residue by flash column chromatography (silica gel, CHCl3/
AcOEt¼6:1) afforded 32 (29.3 mg, 0.0276 mmol, 61%) as white
24
solid. Rf¼0.24 (hexane/AcOEt/AcOH¼10:10:1); [
a]
þ10.6 (c 0.30,
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d: 7.34–7.08 (m, 30H, Ph-H),
5.76 (ddd, J¼17.3, 10.4, 6.9 Hz, 2H, 4-H), 5.23 (d, J¼17.3 Hz, 2H, 5-H
(trans)), 5.10 (d, J¼10.4 Hz, 2H, 5-H (cis)), 4.87 (d, J¼11.0 Hz, 2H,
–CH2Ph), 4.80 (d, J¼11.0 Hz, 2H, –CH2Ph), 4.78 (d, J¼11.0 Hz, 2H,
–CH2Ph), 4.71 (d, J¼11.0 Hz, 2H, –CH2Ph), 4.66–4.54 (m, 2H, 3-H),
4.62 (d, J¼11.0 Hz, 2H, –CH2Ph), 4.48 (d, J¼11.0 Hz, 2H, –CH2Ph),
4.48 (d, J¼8.5 Hz, 2H, 10-H), 4.29 (d, J¼10.8 Hz, 2H, 60-H), 3.76
(t, J¼10.8 Hz, 2H, 60-H), 3.66–3.52 (m, 4H, 30-H, 50-H), 3.41
(t, J¼8.5 Hz, 2H, 20-H), 3.24 (t, J¼9.2 Hz, 2H, 40-H), 2.92 (dd, J¼13.3,
4.1 Hz, 2H, 2-H), 2.34 (dd, J¼13.3, 11.6 Hz, 2H, 2-H); 13C NMR
MeOH¼7:1) afforded 35 (9.6 mg, 0.0183 mmol, quant.) as
26
white solid. Rf¼0.17 (CHCl3/MeOH¼3:1); [
a
]
þ3.56 (c 0.33,
D
MeOH); 1H NMR (300 MHz, CD3OD)
d
: 4.43 (dd, J¼11.4, 1.6 Hz,
2H, 60-H), 4.36 (d, J¼7.8 Hz, 1H, 10-H), 4.15 (br ddd, J¼11.0, 7.6,
3.8 Hz, 2H, 3-H), 3.95 (dd, J¼11.4, 10.0 Hz, 2H, 60-H), 3.55 (dt,
J¼10.0, 1.6 Hz, 2H, 50-H), 3.38 (t, J¼9.1 Hz, 2H, 30-H), 3.19 (dd,
J¼9.1, 7.8 Hz, 2H, 20-H), 3.16 (dd, J¼10.0, 9.1 Hz, 2H, 40-H), 2.93
(dd, J¼13.9, 3.8 Hz, 2H, 2-H), 2.34 (dd, J¼13.9, 11.0 Hz, 2H, 2-
H), 1.67–1.43 (m, 4H, 4-H), 0.93 (t, J¼7.3 Hz, 6H, 5-H); 13C NMR
(75 MHz, CDCl3) d: 169.3 (C-1), 138.3, 138.0, 137.4, 135.8 (C-4),
128.5, 128.5, 128.4, 128.2, 128.1, 128.1, 127.9, 127.8, 127.7, 117.6 (C-
5), 102.2 (C-10), 84.7 (C-30), 81.9 (C-20), 78.2 (C-40), 75.8 (–CH2Ph),
75.1 (–CH2Ph), 74.7 (C-3), 72.8 (C-50), 64.9 (C-60), 40.1 (C-2); IR
(KBr, cmꢀ1
)
n
: 3031, 2901, 1739, 1068; HRMS (FAB-pos, NBA ma-
(75 MHz, CD3OD)
(C-3), 75.1 (C-50), 74.9 (C-20), 72.4 (C-40), 66.5 (C-60), 40.6 (C-2),
d
: 172.3 (C-1), 101.0 (C-10), 78.1 (C-30), 75.5
trix) m/z 1083.4528 [MþNa]þ, calcd for C64H68O14Na: 1083.4507
[MþNa].
29.0 (C-4), 9.8 (C-5); IR (KBr, cmꢀ1
) n: 3401,2925,1727;HRMS
(FAB-pos, NBAþDTT matrix) m/z 547.2017 [MþNa]þ, calcd for
C22H36O14Na: 547.2003 [MþNa].
4.2.4.12. (3S,30S)-3-(2,3,4-Tri-O-benzyl-
4-pentenoic acid bimol. cyclic ester (33) and (3S)-3-(2,3,4-tri-O-
benzyl- -glucopyranosyloxy)-4-pentenolactone (34). According to
b-D-glucopyranosyloxy)-
b
-D
4.2.5.2. (3R,30R)-3-(
b
-D-Glucopyranosyloxy)-4-pentanoic
acid
the synthesis of 25, reaction of 31 (50 mg, 0.0911 mmol) gave 33
(20.4 mg, 0.0192 mmol, 42%) as white solid and 34 (13.4 mg,
0.0250 mmol, 28%) as colorless oil from the crude product after
bimol. cyclic ester (36). According to the synthesis of 32, deprotection
of 33 (19.0 mg, 0.0179 mmol) gave 36 (10.8 mg, 0.0206 mmol,
quant.) as white solid from the crude product after flash column
flash column chromatography (hexane/AcOEt¼4:1).
chromatography (CHCl3/MeOH¼7:1). Rf¼0.50 (CHCl3/MeOH¼3:1);
þ9.39 (c 0.50, MeOH); 1H NMR (300 MHz, CD3OD)
d: 4.44
25
23
Compound 33: Rf¼0.38 (hexane/AcOEt/AcOH¼15:10:1); [
a
]
[a
]
D
D
þ13.0 (c 0.30, CHCl3); 1H NMR (300 MHz, CDCl3)
d: 7.37–7.22 (m, 30H,
(dd, J¼11.7, 2.1 Hz, 2H, 60-H), 4.35 (d, J¼7.8 Hz, 1H, 10-H), 4.01 (dd,
J¼11.7, 7.4 Hz, 2H, 60-H), 3.99–3.89 (m, 2H, 3-H), 3.47 (ddd, J¼9.5,
7.4, 2.1 Hz, 2H, 50-H), 3.36 (t, J¼8.9 Hz, 2H, 30-H), 3.24 (dd, J¼9.5,
8.9 Hz, 2H, 40-H), 3.18 (dd, J¼8.9, 7.8 Hz, 2H, 20-H), 2.96 (dd, J¼15.5,
5.3 Hz, 2H, 2-H), 2.46 (dd, J¼15.5, 7.5 Hz, 2H, 2-H), 1.67–1.53 (m, 4H,
Ph–H), 5.70 (ddd, J¼17.6, 9.8, 7.8 Hz, 2H, 4-H), 5.29 (br d, J¼9.8, 2H,
5-H (cis)), 5.28 (br d, J¼17.6 Hz, 2H, 5-H (trans)), 4.94 (d, J¼11.0 Hz,
2H, –CH2Ph), 4.92 (d, J¼11.0 Hz, 2H, –CH2Ph), 4.84 (d, J¼11.0 Hz, 2H,
–CH2Ph), 4.78–4.66 (m, 2H, 3-H), 4.77 (d, J¼11.0 Hz, 2H, –CH2Ph), 4.71
(d, J¼11.0 Hz, 2H, –CH2Ph), 4.67 (dd, J¼11.4, 1.9 Hz, 2H, 60-H), 4.56 (d,
J¼11.0 Hz, 2H, –CH2Ph), 4.48 (d, J¼9.8 Hz, 2H, 10-H), 3.76 (dd, J¼11.4,
8.4 Hz, 2H, 60-H), 3.65 (t, J¼8.9 Hz, 2H, 30-H), 3.46 (dd, J¼8.9, 7.8 Hz,
2H, 20-H), 3.43 (ddd, J¼9.8, 8.4, 1.9 Hz, 2H, 50-H), 3.34 (dd, J¼9.8,
8.9 Hz, 2H, 40-H), 2.90 (dd, J¼15.0, 5.6 Hz, 2H, 2-H), 2.56 (dd, J¼15.0,
4-H), 1.01 (t, J¼7.5 Hz, 6H, 5-H); 13C NMR (75 MHz, CD3OD)
d: 173.2
(C-1),105.7 (C-10), 80.7 (C-3), 77.8 (C-30), 75.1 (C-20), 74.6 (C-50)ꢀ, 711.9
(C-40), 65.4 (C-60), 42.3 (C-2), 29.1 (C-4), 10.1 (C-5); IR (KBr, cm
) n:
3422,2925,1736; HRMS (FAB-pos, NBAþDTT matrix) m/z 547.1995
[MþNa]þ, calcd for C22H36O14Na: 547.2003 [MþNa].

4100
E. Kaji et al. / Tetrahedron 66 (2010) 4089–4100
4.2.5.3. (3S,30S)-3-(
mol. cyclic ester (38). To a solution of 32 (10.4 mg, 9.80
CH2Cl2 (1.6 mL) were added trans-3-hexene (12.2 L, 0.0980 mmol)
and Grubbs second generation catalyst (1.7 mg, 0.196 mol). The
reaction mixture was stirred at 40 ꢁC for 4 days, while trans-3-
hexene (12.2 L, 0.0980 mmol) and Grubbs second generation
catalyst (1.7 mg, 0.196 mol) were added each 24 h. The resulting
b
-
D
-Glucopyranosyloxy)-4-heptanoic acid bi-
Supplementary data
mmol) in
m
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.04.007. This data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
m
m
m
mixture was concentrated in vacuo. Purification of the residue by
flash column chromatography (silica gel, hexane/AcOEt¼8:1/6:1)
afforded 37 (9.7 mg, 0.00868 mmol, 89%) as white solid.
References and notes
1. (a) Uyeda, M.; Yokomizo, K.; Miyamoto, Y.; Habib, E. E. J. Antibiot. 1998, 51,
823–828; (b) Uyeda, M. Yakugaku Zasshi 2004, 124, 469–479.
2. (a) Habib, E. E.; Yokomizo, K.; Nagao, K.; Harada, S.; Uyeda, M. Biosci. Biotechnol.
Biochem. 2001, 65, 683–685; (b) Habib, E. E.; Yokomizo, K.; Suzuki, K.; Uyeda, M.
Biosci. Biotechnol. Biochem. 2001, 65, 861–864.
3. (a) Tsunakawa, M.; Komiyama, N.; Tenmyo, O.; Tomita, K.; Kawano, K.; Kotake,
C.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45, 1467–1471; (b) Tsunakawa, M.;
Kotake, C.; Yamasaki, T.; Moriyama, T.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45,
1472–1480.
4. Fu¨rstner, A.; Albert, M.; Mlynarski, J.; Matheu, M.; DeClercq, E. J. Am. Chem. Soc.
2003, 125, 13132–13142.
5. Fu¨rstner, A.; Ruiz-Caro, J.; Prinz, H.; Waldmann, H. J. Org. Chem. 2004, 69,
459–467.
6. Bailliez, V.; de Figueiredo, R. M.; Olesker, A.; Cleophax, J. Tetrahedron Lett. 2003,
44, 9151–9153.
7. Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–1923.
8. (a) Chang, C.-W. T.; Hui, Y.; Elchert, B.; Wang, J.; Li, J.; Rai, R. Org. Lett. 2002,
4, 4603–4606; (b) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983,
1249–1256.
9. (a) Zibuck, R.; Streiber, J. M. J. Org. Chem. 1989, 54, 4717–4719; (b) Tan, C.-H.;
Holmes, A. B. Chem. Eur. J. 2001, 7, 1845–1854; (c) Seiser, T.; Kamena, F.; Cramer,
N. Angew. Chem., Int. Ed. 2008, 47, 6483–6485.
10. Chiral HPLC pattern resulted from the enzymatic kinetic resolution is shown in
Supplementary data.
A solution of 37 (9.5 mg, 8.50 mmol) in AcOEt (1 mL) and EtOH
(2 mL) was treated with 10 wt % palladium on activated carbon
(10.0 mg). The reaction flask was flushed with air and hydrogen at-
mospheres sequentially. The reaction mixture was then placed under
an atmosphere of hydrogen and stirred for 24 h. The heterogeneous
mixture was filtered through Celite, rinsed with MeOH (10 mL), and
concentrated in vacuo. Purification of the residue by flash column
chromatography (silica gel, CHCl3/MeOH¼7:1) afforded 38 (4.5 mg,
26
7.75
m
mol, 91%) as yellow solid. Rf¼0.29 (CHCl3/MeOH¼3:1); [
a]
D
þ2.47 (c 0.23, MeOH); 1H NMR (300 MHz, CD3OD)
: 4.48 (dd, J¼11.6,
d
1.6 Hz, 2H, 60-H), 4.37 (d, J¼7.8 Hz, 1H, 10-H), 4.28–4.16 (m, 2H, 3-H),
3.93 (dd, J¼11.6, 9.8 Hz, 2H, 60-H), 3.53 (dt, J¼9.8, 1.6 Hz, 2H, 50-H),
3.38 (t, J¼8.9 Hz, 2H, 30-H), 3.18 (dd, J¼8.9, 7.8 Hz, 2H, 20-H), 3.16 (dd,
J¼9.8, 8.9 Hz, 2H, 40-H), 2.93 (dd, J¼13.8, 4.0 Hz, 2H, 2-H), 2.34
(dd, J¼13.8, 10.7 Hz, 2H, 2-H), 1.59–1.43 (m, 4H, 4-H), 1.40–1.18 (m,
8H, 5-H, 6-H), 0.96–0.82 (m, 6H, 7-H); 13C NMR (75 MHz, CD3OD)
d:
172.3 (C-1),100.8 (C-10), 78.2 (C-30), 75.3 (C-50), 75.0 (C-20), 74.1 (C-3),
72.3 (C-40), 66.5 (C-60), 40.7 (C-2), 36.2 (C-4), 30.8 (C-5), 30.8 (C-6),
14.4 (C-7); IR (KBr, cmꢀ1
) n: 3423,2958,2925,2855,1737,1082; HRMS
11. Detail of the glycosylation conditions is shown in Supplementary data.
12. Izumi, M.; Fukase, K. Chem. Lett. 2005, 34, 594–595.
13. Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni, S. S.; Huang, Y.-W.; Lee, C.-C.; Chang,
K.-L.; Hung, S.-C. Nature 2007, 446, 896–899.
14. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
(FAB-pos, NBA matrix) m/z 603.2636 [MþNa]þ, calcd for
C26H44O14Na: 603.2629 [MþNa].
Acknowledgements
15. Detail of the ring opening reaction for the synthesis of 24 is shown in
Supplementary data.
16. Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984–6988.
17. Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.Chem. 2004, 69,1822–1830.
18. Rai, A. N.; Basu, A. J. Org. Chem. 2005, 70, 8228–8230.
19. The process of this cross metathesis reaction is shown in Supplementary
data.
This work was supported by Ministry of Education Culture,
Sports, Science and Technology (17590011). We also thank
A. Nakagawa, C. Sakabe, N. Sato, and Y. Kawauchi at Kitasato Uni-
versity for various instrumental analyses.