Synthesis of phytosphingosine using olefin cross-metathesis: a convenient access to chain-modified phytosphingosines from d-lyxose

Article abstract of DOI:10.1016/j.tet.2007.03.047

This work establishes a general protocol for synthesizing phytosphingosines with various lengths of lipid chains. The synthetic strategy included the Wittig reaction and olefin cross-metathesis as key steps. Combining these two C-C bond formation methods

Full text of DOI:10.1016/j.tet.2007.03.047

Tetrahedron 63 (2007) 4310–4318
Synthesis of phytosphingosine using olefin cross-metathesis:
a convenient access to chain-modified phytosphingosines
from D-lyxose
Chi-We Chang,a,b Yeng-Nan Chen,c Avijit Kumar Adak,c Kun-Hsien Lin,a,d
Der-Lii M. Tzoua and Chun-Cheng Linc,
*
aInstitute of Chemistry, Academia Sinica, Taipei 115, Taiwan
bDepartment of Chemistry, National Chun-Chen University, Chia-Yi 621, Taiwan
cDepartment of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
dDepartment of Chemistry, National Taiwan Normal University, Taipei 106, Taiwan
Received 6 December 2006; revised 16 February 2007; accepted 7 March 2007
Available online 12 March 2007
Abstract—This work establishes a general protocol for synthesizing phytosphingosines with various lengths of lipid chains. The synthetic
strategy included the Wittig reaction and olefin cross-metathesis as key steps. Combining these two C–C bond formation methods provide
rapid access to adequately protected phytosphingosine backbones.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
carbohydrates5 and amino acids5a as chiral starting mate-
rials; asymmetric syntheses are fewer.6 Recently, given the
availability of powerful ruthenium-based olefin cross-
metathesis (CM) reagents,7 sphingolipid and glycolipids
were synthesized by the CM of two terminal olefins.8 As
part of our program to develop glycolipid-based vaccines
and adjuvants, we have developed the synthesis of glyco-
sphingolipids, and evaluated their cell proliferation activities
of mouse splenocytes as well as the expression of cytokines
IFN-g and IL-4.4a Modifications of the lipid chain length in
a-galactosyl ceramides can influence an array of cytokines’
release and demonstrate a profound relationship between
structure and activity.3b,4c In this publication, we report an
efficient route for construction of a small phytosphingosine
library (2 in Fig. 1) based on the modification of lipid chain
from commercially available D-lyxose, with CM as a key
step.
Sphingolipids are highly diverse bioactive compounds as
both first and second messengers1 and backbones of glyco-
sphingolipids.2 Glycosphingolipids contain two basic struc-
tural motifs—carbohydrate (hydrophilic head) and ceramide
(lipophilic tail). The ceramide portion comprises sphingoid
bases (glycosyl acceptors), which are long-chain alkanes
or alkenes of around 14–20 carbons in length with an
amide-linked fatty acyl chain at position 2 and hydroxyl sub-
stituents at positions 1 and 3, as presented in Figure 1 for
phytosphingosine 1.
Phytosphingosines and their glycosylated derivatives3 are
biologically important and have attracted many attentions.
New methods for synthesizing them have been developed.4
Most methods for synthesizing phytosphingosines involve
O
site for chain
extension
O
NH2 OH
3
O
Wittig reaction, and
cross metathesis
O
P1O
HO
P1O
7
4 R
2
N3
R
OH CH=O
OH
8
2
SN2 displacement
by –N3
1
Figure 1. Retrosynthesis and steps involved in the synthesis of phytosphingosine analog 2 from D-lyxose.
Keywords: Phytosphingosine; Cross-metathesis; Wittig reaction; Lipid.
* Corresponding author. Tel.: +886 3 5753147; fax: +886 3 5711082; e-mail: cclin66@mx.nthu.edu.tw
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.047

C.-W. Chang et al. / Tetrahedron 63 (2007) 4310–4318
4311
Following in this vein, we demonstrated the advantage of
using D-lyxose as an excellent five-carbon building block
to generate the desired core structure, 2-amino-1,3,4-triol
moiety,5b with an appropriate stereochemical disposition,
corresponding to the phytosphingosine, while providing a
chemical handle for further synthesis. The lipid chains of
phytosphingosine analogs were extended by the Wittig reac-
tion with various ylides. However, such an approach for syn-
thesizing a phytosphingosine library is not straightforward
because various Wittig reagents must be prepared in each
case. In the present study, we employed Wittig reaction to
construct the core building block and elaborated CM reac-
tion to produce the lipid library, as presented in Figure 1.
unidentified compound. Although we got correct molecular
ion (MW 456.2287) and IR absorption of azide (2106 cmꢁ1
)
of the compound as the desired product, but one proton was
missed according to the 1H NMR spectrum. Notably, when
the reaction temperature was lowered to ꢁ60 ꢀC, only tri-
flate product was observed. These results are unexpected,
since in our earlier work,5b we observed that alcohol 8 under-
went smooth azidation to 9 by triflate activation followed by
treatment with TMGA in the presence of internal olefin. The
difficulty over the course of this azidation reaction in 6 is still
unknown to us.
We envisioned that perhaps the terminal double bond in 6
prohibited azidation during SN2 type reaction, and an azido
replacement could be achieved onto fully hydrogenated
alcohol 10 (Scheme 2). Thus, the double bond in 6 was
reduced to 10, which was treated with trifluoromethanesul-
fonic anhydride (Tf2O) followed by TMGA to afford the
azide 11 in 72% yield with inversion of configuration.
2. Results and discussion
In this context, the sequential application of the Wittig reac-
tion and olefin cross-metathesis to the syntheses of phyto-
sphingosine analogs 2 was investigated. In Scheme 1, the
core compounds 6–7 were synthesized from D-lyxose 3. In
brief, selective acetal formation at the 2,3-dihydroxyl groups
of 3 using 2-methoxypropene was followed by tritylation
(TrCl, Py, 50 ꢀC)9 or silylation (TBDMSCl, imidazole, DMF,
0 ꢀC) of the primary hydroxyl group to yield 45b and 5 (70%
over two steps). Wittig reaction of the acetals 4 and 5 with
phosphonium salt Ph3P+CH3Brꢁ in the presence of lithium
hexamethyldisilazide (LHMDS) at 0 ꢀC produced hy-
droxy-alkenes 6 and 7 in 82% and 78% yield, respectively.5a
Attempt to introduce an azide group by triflate activation of
the free hydroxyl group and substitution by azide using tetra-
methylguanidium azide (TMGA) at this stage in 6 gave an
An earlier report on intramolecular alkene–azide cycliza-
tion,10 the above results and the need for terminal olefin as
a cross-metathesis component motivated us to insert two
more carbons for extending the distance between reaction
carbon center and terminal olefin. Hopefully, this chain ex-
tension will block the unknown reaction that occurred during
our initial azido replacement studies. Therefore, a detailed
study was conducted to prepare a,b-unsaturated esters 12
and 13. Motivated by the recent development of the Wittig
reaction on sugar lactols,11 reactions of 4 with stabilized
ylide under various conditions were investigated, as shown
in Table 1.
RO
HO
OH
OH
LHMDS,
O
O
O
i. 2-methoxypropene,
CSA, DMF, 4 °C
ii. R-Cl
Ph3P+CH2Br-
O
RO
THF, 0 °C to rt
O
O
HO
OH
OH
3
6: R = Tr (82%)
7: R = TBDMS (78%)
D-Lyxose
4: R = Tr (70%)
5: R = TBDMS (71%)
2,6-lutidine,
O
Tf2O, TMGA,
O
O
unidentified
TrO
product
CH2Cl2, 0 °C to rt
OH
6
OH
C12H25
N3
C12H25
Tf2O, Py, - 60 °C
TrO
TrO
O
then TMGA, - 60 °C
84%
O
O
8
9
Scheme 1. Azido replacement studies.
2,6-lutidine,
O
O
O
O
H2, Pd/C
Tf2O, TMGA,
O
O
TrO
TrO
EtOAc, rt
99%
TrO
CH2Cl2, 0 °C to rt
72%
N3
OH
10
OH
11
6
Scheme 2. Azide substitution reaction onto saturated alcohol 10.

4312
Table 1. Effect of solvent and temperature on the Wittig reaction of 4 and 5
RO
C.-W. Chang et al. / Tetrahedron 63 (2007) 4310–4318
CO2Me
OH
O
TrO
O
O
O
Ph3P=CHCO2Me
RO
O
+
solvent, temperature
O
O
O
O
OH
OMe
4: R = Tr
5: R = TBDMS
Z-12: R = Tr
Z-13: R = TBDMS
14
Entry
Substrate
Solvent
Temperature (ꢀC)
Additives
Products
Yields (%)
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
5
5
5
5
5
CH3CN
CH3CN
Toluene
CH2Cl2
CH2Cl2
Toluene
CH3CN
CH3CN
Toluene
CH2Cl2
CH3CN
CH2Cl2
40
80
90
rt
40
90
40
rt
rt
rt
70
50
—
—
—
—
14
14
14
Z-12
—
—
—
Z-13
Z-13
Z-13
Z-13
Z-13
70
50
50
35
—
—
—
30
20
40
30
40
Benzoic acid
Benzoic acid
Benzoic acid
—
—
—
—
—
9
10
11
12
An initial attempt to react (EtO)2P(O)CH2CO2Et with 4
using DBU, NaH, and LHMDS as bases, respectively, in
various solvents (such as CH3CN, THF, and DMSO),
while using LiCl as a promoter, failed to give 12 in an
acceptable yield. Reaction of 4 with stabilized ylide
(Ph3P]CHCO2Me) in acetonitrile at 40 ꢀC gave the unde-
sired Michael adduct 14 as a mixture of a- and b-C-glyco-
sides (entry 1).11a An increase in temperature (entry 2) and
change in solvent (entry 3) had little effect on the product
yield. To our surprise, this Wittig reaction in the presence
of benzoic acid in refluxing dichloromethane12 (entry 5), tol-
uene (entry 6), and acetonitrile (entry 7), respectively, did
not led to product formation. We then examined TBDMS
ether protected lactol 5 for the Wittig reaction, and similar
results were obtained as expected. Compound 5 reacted
with the ylide in acetonitrile (entry 8) or toluene (entry 9)
at room temperature to provide Z-13 in 30% and 20% yield,
respectively, while the same Wittig reaction performed in
THF, DMF or 1,2-dichloroethane resulted no product forma-
tion. Furthermore, the yield was not significantly improved
by increasing reaction temperature (entries 11 and 12). After
extensive experimentations, it was found that the Wittig ole-
fination of 4 and 5 with stabilized ylide (Ph3P]CHCO2Me)
was best performed at room temperature in dichloromethane
(entries 4 and 10) with the isolated yield of 35% and 40% for
Z-12 and Z-13, respectively. The cis stereochemistries of the
products were determined by 1H NMR analysis as the cou-
pling constant of the two olefinic protons is 11.6 Hz.
toluene was used as solvent in the presence of 0.3 equiv of
Ti(OiPr)4 at 75 ꢀC, the CM product yield was improved over
that obtained using standard Grubbs’ catalyst reaction condi-
tions (entry 4 vs 7). Notably, a single geometrical trans
isomer was observed under these reaction conditions.14
More workable quantities of the key intermediate 12 enabled
the synthesis of tritylated azidophytosphingosine 16 in a rel-
atively straightforward and efficient manner, as shown in
Scheme 3. Catalytic hydrogenation (Pd/C, H2) of 12 readily
yielded saturated ester 17in 85% yield. The conversionof hy-
droxyl group in 17 to azide 18 with the inversion of configu-
ration was achieved by triflate activation with Tf2O, followed
by a reaction with TMGA at 30 ꢀC.5a,b Reduction of methyl
ester 18 by the slow addition of diisobutylaluminium hydride
(DIBAL) in toluene at ꢁ78 ꢀC gave the aldehyde 19 in a
reasonable 66% yield. Treatment of the phosphonium salt
Ph3P+CH3Brꢁ with lithium hexamethyldisilazide (LHMDS)
at 0 ꢀC generated the ylide, which was then reacted with 19
furnished the cross-metathesis precursor 16 in 71% yield.
Table 2. Cross-metathesis reaction onto model olefin 6 with methyl acrylate
O
O
O
O
O
15 (10 mol%)
TrO
+
TrO
OMe
OH
OH
E-12
MesN
Cl
Cl
NMes
6
O
Ru
OMe
Ph
PCy3
Alternatively, 12 can also be obtained by the cross-metathe-
sis of alkene 6 with methyl acrylate. Table 2 presents details
of the use of Grubbs’ second-generation catalyst 1513 for
hetero-CM reaction. Under the reaction conditions used
for CM (10.0 mol % catalyst 15, CH2Cl2, rt), the reaction
of alkene 6 in the presence of 2.0 equiv of methyl acrylate
led to the formation of the desired CM product E-12 in
20% yield (entry 1). The addition of 20.0 (entry 2) and
10.0 equiv (entry 4) of methyl acrylate at refluxing temper-
ature led to an increased yield of 31% and 37%, respectively.
Use of additives and changing solvents and reaction temper-
ature were not beneficial (entries 5 and 6). However, when
15
Entry Methyl Catalyst (equiv)
acrylate
(equiv)
Solvent Temperature Yields
(ꢀC)
(%)
1
2
3
4
5
6
7
2
20
2
10
2
0.05
0.05
0.1
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 Reflux
CH2Cl2 Reflux
20
31
23
37
25
15
43
0.1
0.1+0.3 Ti(OiPr)4 Toluene 80
0.1+0.3 Ti(OiPr)4 Toluene Reflux
0.1+0.3 Ti(OiPr)4 Toluene 75
10
10

C.-W. Chang et al. / Tetrahedron 63 (2007) 4310–4318
4313
O
O
2,6-lutidine,
Tf2O, TMGA
O
O
H2, Pd/C
TrO
O
O
TrO
O
CH2Cl2, 0 °C to rt,
18 h, 63%
EtOAc, rt, 3 h
85%
OH
12
OH
OMe
OMe
17
O
O
LHMDS,
O
DIBAL-H
Ph3P+CH3Br-
O
O
TrO
TrO
O
TrO
O
Toluene, - 78 °C
66%
N3
CH2Cl2, 0 °C to rt
71%
N3
18
N3
OMe
H
16
19
Scheme 3. Synthesis of olefin cross-metathesis building block 16.
O
O
Acryloyl chloride,
DMAP, Et3N
O
O
15
TBDMSO
TBDMSO
CH2Cl2, 0 °C, 1 h
83%
CH2Cl2, 55 °C, 16 h
75%
O
O
OH
7
21
O
O
O
O
O
H2, Pd(OH)2
O
NaOMe
MeOH, rt.,1 h
93%
TBDMSO
TBDMSO
OH
O
TBDMSO
EtOAc, rt., 1 h
99%
O
O
OMe
20
O
O
22
23
Scheme 4. Ring-closing metathesis reaction onto 7.
Alternatively, compound 20, TBDMS protected analog of
key intermediate 17, was synthesized by ring-closing me-
tathesis (RCM) approach, as illustrated in Scheme 4. The hy-
droxyl group of 7 reacted with acryloyl chloride generated
21 (83%) to set the stage for RCM reaction. Metathesis of
terminal olefins of 21 was achieved by using catalyst 15
in CH2Cl2 at 55 ꢀC to give a,b-unsaturated lactone 22 in
75% yield. The double bond was catalytically reduced
(Pd(OH)2, H2) to afford lactone 23, in quantitative yield,
which underwent basic ring opening (NaOMe in methanol)
to provide the methyl ester 20 in 93% yield.
reported that the presence of the azido functional group
caused the failure of cross-metathesis reactions.8b,15 In con-
trast, increasing the distance between azide and reaction ter-
minal olefin facilitated the building block 16 to undergo
cross-metathesis to afford the suitably protected phytosphin-
gosine analogs in moderate to good yields. Furthermore, al-
though excess lipid alkenes were used to obtain reasonable
yields of products in these experiments, no tractable homo-
dimers were found.
In summary, the core building block 16 was obtained
in seven-step manipulation from commercially available
With the successful outcome of the cross-metathesis reac-
tion onto alkene 6 and methyl acrylate, we subsequently ex-
amined the effectiveness of azide-containing building block
16 as a coupling partner. The results of our small phytosphin-
gosine library are summarized in Table 3. Initially, alkene
16 reacted with 1-heptadecene (entry 1) in the presence of
catalyst 15 (10 mol %) in dichloromethane (0.1 M, 16/
1-heptadecene¼1:10) at room temperature and the trans iso-
mer 2a was isolated in 59% yield. Then, selected terminal
olefins were further processed in the CM to test the general-
ity of our protocol. The results in Table 3 demonstrate that
our synthetic strategy is efficient for synthesizing phytophin-
gosine analogs with various lengths in the lipid chain. Cross-
metathesis reaction with other linear alkenes (entries 2 and
3) afforded 2b–c in isolated yields ranging between 57%
and 60%, whereas branched terminal olefin (entry 4) re-
sulted 2d in a low CM yield (25%). For alkenes with phenyl
and bromide substituents gave the corresponding substituted
CM products 2e–f (entries 5 and 6) in a reasonable 57% and
56% isolated yield, respectively. Notably, trans isomers were
observed as major products with very trace amount of cis
isomers based on the 1H NMR characterization. It has been
Table 3. Synthesis of phytosphingosine library (2a–f) by olefin cross-
metathesis reaction of 16 with various alkenes
O
O
alkenes,
O
O
15 (10 mol%)
TrO
TrO
CH2Cl2, rt, 18 h
(25-60%)
R
N3
N3
2a-f
16
Entry
Alkene
Product (2)
Yield
(%)
1
2
C15H31
C7H15
59
57
2a R =
14
2b R =
2c R =
6
9
C10H21
3
4
60
25
2d R =
2e R =
5
6
57
56
2f R =
Br
Br

4314
C.-W. Chang et al. / Tetrahedron 63 (2007) 4310–4318
D-lyxose. Compound 16 was further used to achieve the syn-
thesis of suitably protected phytosphingosines with various
lengths and substitutions in lipid chains. CM of 16 with al-
kenes catalyzed by Grubbs’ catalyst (II) gave heterodimers
in moderate yields. This procedure is flexible for synthesiz-
ing a phytosphingolipid library and provides a clear avenue
for elucidating structure–activity relationships16 for this
class of biomolecules.
J¼7.0 Hz, 3H), 1.18–1.40 (m, 16H), 1.45–1.69 (m, 2H
overlapped with H2O), 1.96–2.26 (m, 4H), 3.35 (dd,
J¼7.6, 9.6 Hz, 1H), 3.48 (ddd, J¼2.4, 7.6, 9.1 Hz, 1H),
3.53 (dd, J¼2.4, 9.6 Hz, 1H), 3.87 (dd, J¼5.5, 9.2 Hz,
1H), 4.11 (ddd, J¼3.6, 5.5, 9.4 Hz, 1H), 5.41 (ddd, J¼6.0,
6.0, 15.4 Hz, 1H), 5.46 (ddd, J¼6.1, 6.1, 15.4 Hz,
1H), 7.20–7.34 (m, 10H), 7.44–7.51 (m, 5H). 13C
NMR (100 MHz, CDCl3): d 14.1, 22.7, 25.7, 28.0, 29.2,
29.2, 29.3, 29.6, 31.9, 32.6, 60.7, 64.5, 75.8, 77.2, 87.3,
108.1, 127.1, 127.8, 128.7, 129.0, 131.5, 143.8. HRMS
(FAB) calcd for C37H48NO3 (Mꢁ2N+H+): 554.3624. Found:
554.3634.
3. Experimental
3.1. General
3.1.3. (2S,3S,4R)-2-Azido-3,4-di-O-isopropylidene-1-tri-
tyloxy-octadec-7-ene (2c). Yield 60%. Rf 0.20 (hexanes/
EtOAc¼20:1); 1H NMR (500 MHz, CDCl3): d 0.88 (t,
J¼7.1 Hz, 3H), 1.17–1.40 (m, 22H), 1.48–1.68 (m, 2H over-
lapped with H2O), 1.93–2.12 (m, 3H), 2.18–2.27 (m, 1H),
3.35 (dd, J¼7.7, 9.9 Hz, 1H), 3.48 (ddd, J¼2.4, 7.7,
9.3 Hz, 1H), 3.53 (dd, J¼2.4, 9.9 Hz, 1H), 3.87 (dd,
J¼5.5, 9.3 Hz, 1H), 4.11 (ddd, J¼3.7, 5.5, 10.1 Hz, 1H),
5.41 (ddd, J¼6.4, 6.4, 15.5 Hz, 1H), 5.46 (ddd, J¼6.4, 6.4,
15.5 Hz, 1H), 7.20–7.36 (m, 10H), 7.43–7.54 (m, 5H). 13C
NMR (100 MHz, CDCl3): d 14.1, 22.7, 25.7, 28.0, 29.2,
29.2, 29.3, 29.4, 29.6, 29.6, 29.7, 31.9, 32.6, 60.7, 64.5,
75.8, 87.3, 108.1, 127.1, 127.9, 128.7, 128.9, 131.5, 143.8.
HRMS (FAB) calcd for C40H53N3O3 (M+): 623.4087.
Found: 623.4087.
All commercial materials were used without further purifica-
tion unless otherwise noted. Dichloromethane (CH2Cl2) was
distilled from calcium hydride under N2. THF was distilled
from sodium/benzophenone ketyl radical under N2. Analyti-
cal thin layer chromatography was performed on E. Merck
silica gel 60 F254 plates (0.25 mm). Liquid column chromato-
graphy was performed using forced flow of the indicated sol-
vent on silica gel 60 (E. Merck Co.). NMR spectra were
recorded on either Bruker 400 or Bruker 500 MHz instru-
ments and are reported in parts per million (d) units. Coupling
1
constants (J) are reported in hertz (Hz). Assignment of H
NMR spectra was achieved using 2D methods (COSY).
High-resolution mass spectra were obtained by means of a
Micromass(Autospec)massspectrometer.Allreactionswere
carried out in oven-dried glasswares (120 ꢀC) under an atmo-
sphere of nitrogen unless otherwise indicated. The Grubb’s II
catalyst used in the metathesis reactions was purchased from
Aldrich.
3.1.4. (2S,3S,4R)-2-Azido-3,4-di-O-isopropylidene-9,13-
dimethyl-1-trityloxy-hexadec-7-ene (2d). Yield 25%. Rf
0.50 (hexanes/EtOAc¼20:1); 1H NMR (500 MHz,
CDCl3): d 0.78 (s, 3H), 0.79 (s, 3H), 0.81 (d, J¼7 Hz, 3H),
0.88 (d, J¼7 Hz, 3H), 1.05–1.18 (m, 9H), 1.40–1.62 (m,
4H overlapped with H2O), 1.97–2.07 (m, 3H), 2.12–2.25
(m, 2H), 3.40 (ddd, J¼4.4, 9.5, 14.2 Hz, 1H), 3.78–3.96
(m, 4H), 4.13 (ddd, J¼4.0, 5.6, 9.6 Hz, 1H), 5.26 (dd,
J¼1.2, 10 Hz, 1H), 5.31 (ddd, J¼5.3, 5.3, 10 Hz, 1H),
7.17–7.40 (m, 15H). 13C NMR (100 MHz, CDCl3): d 25.8,
28.1, 29.3, 29.4, 34.5, 36.2, 60.8, 64.6, 75.9, 77.5, 125.9,
127.2, 127.9, 128.0, 128.4, 128.6, 128.9, 129.8, 130.0,
130.5, 142.2, 143.9. HRMS (FAB) calcd for C40H53N3O3Na
(M++Na): 646.3997. Found: 646.3997.
3.1.1. (2S,3S,4R)-2-Azido-4,5-di-O-isopropylidene-1-tri-
tyloxy-tricos-7-ene (2a). To a solution of alkene 16
(19 mg, 39.3 mmol) in de-oxygenated CH2Cl2 (393 mL,
0.1 M for CM reaction) was added 1-heptadecene (119 mL,
393 mmol) under nitrogen. To the resulting mixture was
added catalyst 15 (4 mg, 3.93 mmol) and then stirred at
room temperature for 18 h. The solvent was evaporated to
give brown residues. The crude residues were subjected to
flash silica gel column chromatography to give 2a (16 mg,
59%) as a colorless oil. Rf 0.27 (hexanes/EtOAc¼20:1);
1H NMR (400 MHz, CDCl3): d 0.88 (t, J¼7.0 Hz, 3H),
1.18–1.41 (m, 28H), 1.25 (s, 6H), 1.47–1.70 (m, 2H overlap-
ped with H2O), 1.94–2.11 (m, 3H), 2.16–2.27 (m, 1H), 3.35
(dd, J¼7.6, 9.7 Hz, 1H), 3.48 (ddd, J¼2.4, 7.6, 9.1 Hz, 1H),
3.53 (dd, J¼2.4, 9.7 Hz, 1H), 3.87 (dd, J¼5.5, 9.1 Hz, 1H),
4.11 (ddd, J¼3.7, 5.5 10.0 Hz, 1H), 5.4 (ddd, J¼6.1, 6.1,
15.4 Hz, 1H), 5.46 (ddd, J¼6.1, 6.1, 15.4 Hz, 1H), 7.2–
7.35 (m, 10H), 7.45–7.51 (m, 5H). 13C NMR (100 MHz,
CDCl3): d 14.1, 22.7, 25.6, 28.0, 29.2, 29.2, 29.3, 29.4,
29.6, 29.6, 29.7, 29.7, 31.9, 32.6, 60.7, 64.5, 75.8, 77.2,
87.3, 108.1, 127.1, 128.8, 128.7, 128.9, 131.5, 143.8.
HRMS (FAB) calcd for C45H64NO3 (Mꢁ2N+H+):
666.4886. Found: 666.4886.
3.1.5. (2S,3S,4R)-2-Azido-3,4-di-O-isopropylidene-10-
phenyl-dec-7-ene (2e). Yield 57%. Rf 0.50 (hexanes/
EtOAc¼20:1); 1H NMR (500 MHz, CDCl3): d 1.15 (s,
3H), 1.17 (s, 3H), 1.36–1.58 (m, 2H), 1.94–2.19 (m, 2H),
2.26 (td, J¼6.0, 7.6 Hz, 2H), 2.61 (t, J¼7.6 Hz, 2H), 3.3
(dd, J¼7.6, 9.8 Hz, 1H), 3.4 (ddd, J¼2.4, 7.4, 9.4 Hz, 1H),
3.46 (dd, J¼2.4, 9.8 Hz, 1H), 3.79 (dd, J¼5.6, 9.3 Hz,
1H), 3.99 (ddd, J¼3.9, 5.6, 9.8 Hz, 1H), 5.37 (ddd, J¼6.0,
6.0, 15.4 Hz, 1H), 5.44 (ddd, J¼6.0, 6.0, 15.4 Hz, 1H),
7.09–7.25 (m, 15H), 7.37–7.43 (m, 5H). 13C NMR
(100 MHz, CDCl3): d 20.8, 22.4, 22.6, 22.6, 24.6, 25.0,
25.5, 27.9, 28.0, 29.2, 29.3, 36.7, 37.3, 39.0, 61.1, 61.8,
63.1, 63.9, 77.0, 82.0, 108.4, 126.8, 126.9, 127.0, 127.2,
127.7, 127.7, 127.9, 128.7, 129.6, 137.7, 146.8. HRMS
(FAB) calcd for C38H42NO3 (Mꢁ2N+H+): 560.3165. Found:
560.3162.
Compounds 2b–f were synthesized by following the method
described in the synthesis of 2a.
3.1.2. (2S,3S,4R)-2-Azido-3,4-di-O-isopropylidene-1-tri-
tyloxy-pentadec-7-ene (2b). Yield 57%. Rf 0.20 (hexanes/
EtOAc¼20:1); 1H NMR (400 MHz, CDCl3): d 0.88 (t,
3.1.6. (2S,3S,4R)-2-Azido-10-bromo-3,4-di-O-isopropyl-
idene-1-trityloxy-dec-7-ene (2f). Yield 56%. Rf 0.18

C.-W. Chang et al. / Tetrahedron 63 (2007) 4310–4318
4315
(hexanes/EtOAc¼20:1); 1H NMR (400 MHz, CDCl3):
d 1.23 (s, 3H), 1.25 (s, 3H), 1.49–1.71 (m, 2H overlapped
with H2O), 2.08–2.13 (m, 1H), 2.23–2.29 (m, 1H), 2.57
(td, J¼6.8, 7.2 Hz, 2H), 3.36 (dd, J¼7.6, 10.8 Hz, 1H),
3.38 (dd, J¼7.2, 9.8 Hz, 2H), 3.48 (ddd, J¼2.5, 7.1,
9.4 Hz, 1H), 3.53 (dd, J¼2.5, 9.8 Hz, 1H), 3.88 (dd,
J¼5.5, 9.4 Hz, 1H), 4.11 (ddd, J¼3.5, 5.5, 9.8 Hz, 1H),
5.46 (ddd, J¼6.6, 6.6, 15.3 Hz, 1H), 5.56 (ddd, J¼6.6, 6.6,
15.3 Hz, 1H), 7.21–7.34 (m, 10H), 7.45–7.51 (m, 5H). 13C
NMR (100 MHz, CDCl3): d 25.7, 28.0, 28.9, 29.2, 32.8,
36.0, 60.7, 64.5, 75.7, 77.2, 87.3, 108.2, 127.1, 127.5,
127.9, 128.7, 132.7, 143.7.
79.08, 86.73, 108.71, 119.43, 127.07, 127.85, 128.72,
134.04, 143.84. HRMS (FAB) calcd for C28H30O4 (M+):
430.2144. Found: 430.2144.
3.1.9. (2R,3R,4R)-1-O-(tert-Butyldimethylsilyl)-2-
hydroxyl-3,4-O-isopropylidene-hex-5-ene (7).17 This
compound was similarly prepared as that described for 6.
Starting from 5-tert-butyldimethylsilyloxy-2,3-O-isopro-
pylidene-D-lyxofuranose 5 (3.42 g, 11.2 mmol), pure com-
pound 7 (2.52 g) was isolated as a light oil in 78% yield.
1H NMR (500 MHz, CDCl3): d 0.048 (s, 3H), 0.051 (s,
3H), 0.88 (s, 9H), 1.38 (s, 3H), 1.51 (s, 3H), 3.60 (m over-
lapped with s at 3.59 ppm, J2,3¼3.3 Hz, H-1, H-2, 3H),
4.23 (dd, J3,4¼7.5 Hz, J3,2¼3.3 Hz, H-3, 1H), 4.58 (t,
J4,3¼7.5 Hz, J4,5¼7.5 Hz, H-4, 1H), 5.27 (d, J6a,6b¼10.2 Hz,
H-6a, 1H), 5.33 (d, J6b,5¼17.2 Hz, H-6b, 1H), 6.04 (ddd,
J5,6b¼17.2 Hz, J5,6a¼10.2 Hz, J5,4¼7.5 Hz, H-5, 1H). 13C
NMR (100 MHz, CDCl3): d ꢁ5.16ꢂ2, 18.54, 25.18,
26.10ꢂ3, 27.42, 64.39, 70.18, 79.35, 108.87, 119.57,
134.71. HRMS (FAB) calcd for C15H31O4Si (M+H+):
303.1996. Found: 303.1992.
3.1.7. 5-O-(tert-Butyldimethylsilyl)-2,3-O-isopropyl-
idene-a/b-D-lyxofuranose (5). To a magnetically stirred so-
lution of 2,3-O-isopropylidene-D-lyxofuranose4a (160 mg,
0.84 mmol) in DMF (1.6 mL) at 0 ꢀC were added imidazole
(114 mg, 1.68 mmol) and tert-butyldimethylsilyl chloride
((127 mg, 0.84 mmol) under argon. The reaction was then
slowly warmed to room temperature and stirred for 9 h at
ambient temperature. The solution was concentrated and
the residue was dissolved in EtOAc. The organic layer was
successively washed with water and brine, dried with
MgSO4, and filtered. The solution was concentrated and
the residue was purified by silica gel column chromato-
graphy to afford 5 (258 mg, 71%) as a yellowish oil (hex-
anes/EtOAc¼8:1–4:1). 1H NMR (400 MHz, CDCl3):
3.1.10. (2R,3R,4R)-3,4-O-Isopropylidene-1-trityloxy-hex-
ane-2-ol (10). Palladium on charcoal (Pd/C) (100 mg; 5%
Pd content) was suspended to a solution of 6 (150 mg,
0.35 mmol) in EtOAc (5.0 mL). The flask was purged with
H2, and a hydrogen balloon was attached. After 1 h, the cat-
alyst was filtered off through a pad of Celite, the solvent was
removed in vacuo, and the residue was purified by flash silica
gel column chromatography to give 10 (149 mg; quanti-
tative) as a yellow solid. Rf 0.32 (hexanes/EtOAc¼3:1);
mp¼115.4 ꢀC; 1H NMR (500 MHz, CDCl3): d 0.96 (t,
J¼7.4 Hz, 3H), 1.36 (s, 3H), 1.41–1.50 (m, 3H), 1.45 (s,
3H), 1.62–1.73 (m, 1H), 2.30 (d, J¼6.0 Hz, 1H), 3.19 (dd,
J¼5.7, 9.6 Hz, 1H), 3.22 (dd, J¼6.0, 9.6 Hz, 1H), 3.72
(ddd, J¼3.8, 5.7, 6.0 Hz, 1H), 4.00 (ddd, J¼4.2, 6.3,
10.0 Hz, 1H), 4.15 (dd, J¼3.8, 6.3 Hz, 1H), 7.20–7.36 (m,
10H), 7.40–7.51 (m, 5H). 13C NMR (125 MHz, CDCl3):
d 11.10, 22.87, 25.22, 27.39, 65.28, 68.90, 78.97, 86.87,
107.76, 127.06, 127.83, 128.73, 143.91. HRMS (FAB) calcd
for C28H32O4 (M+): 432.2309. Found: 432.2301.
t
d 0.08 (s, Me, 3H), 0.90 (s, Bu, 9H), 1.30 (s, Me, 3H),
1.43 (s, Me, 3H), 3.81 (dd, J5a,5b¼10.8 Hz, J5a,4¼7.2 Hz,
H-5a, 1H), 3.92 (dd, J5b,5a¼10.8 Hz, J5b,4¼4.6 Hz, H-5b,
1H), 4.23 (ddd, J4,5a¼7.2 Hz, J4,5b¼4.6 Hz, J4,3¼3.7 Hz,
H-4, 1H), 4.58 (d, J2,3¼5.9 Hz, H-2, 1H), 4.74 (dd,
J3,2¼5.9 Hz, J3,4¼3.7 Hz, H-3, 1H), 5.39 (s, H-1, 1H). 13C
NMR (100 MHz, CDCl3): d ꢁ5.12, ꢁ5.04, 18.69, 25.11,
26.14ꢂ3, 26.19, 26.30, 61.76, 80.02, 81.40, 85.72, 101.50.
HRMS (FAB) calcd for C14H29O5Si (M+H+): 305.1783.
Found: 305.1784.
3.1.8. (2R,3R,4R)-2-Hydroxyl-3,4-O-isopropylidene-1-
trityloxy-hex-5-ene (6). Lithium hexamethyldisilazane
(LHMDS) (22.7 mL of 1.0 M solution in THF) was added
to a solution of triphenyl-tridecyl-phosphonium bromide
(8.14 g, 22.7 mmol) in anhydrous THF (100 mL) at 0 ꢀC un-
der nitrogen. After being stirred at 0 ꢀC for 1 h, a solution
containing LHMDS (15.2 mL of 1.0 M in THF) and 5-tri-
tyloxy-2,3-O-isopropylidene-D-lyxofuranose 45b (6.57 g,
15.2 mmol) in THF (100 mL) was slowly added at 0 ꢀC un-
der nitrogen. The reaction mixture was allowed to warm to
room temperature and stirred for 9 h. After quenching the re-
action with methanol, the solvent was removed in vacuo. The
resulting residues were dissolved in EtOAc and washed with
H2O and brine. The organic layer was dried over Na2SO4 and
concentrated to dryness. The crude material was purified by
silica gel column chromatography to afford 6 (5.37 g; 82%)
as white solid. Rf 0.30 (hexanes/EtOAc¼3:1); mp¼79.4 ꢀC;
1H NMR (500 MHz, CDCl3): d 1.38 (s, 3H), 1.49 (s, 3H),
2.36 (d, J¼6.2 Hz, 1H), 3.14 (dd, J¼5.8, 9.6 Hz, 1H), 3.23
(dd, J¼4.9, 9.6 Hz, 1H), 3.71 (ddd, J¼4.7, 4.9, 5.8 Hz,
1H), 4.29 (dd, J¼4.7, 6.8 Hz, 1H), 4.45 (dd, J¼6.8,
8.3 Hz, 1H), 5.12 (dd, J¼18.5 Hz, 1H), 5.13 (dd,
J¼10.3 Hz, 1H), 5.87 (ddd, J¼8.3, 10.3, 18.5 Hz, 1H),
7.19–7.38 (m, 10H), 7.41–7.55 (m, 5H). 13C NMR
(125 MHz, CDCl3): d 25.09, 27.36, 64.68, 69.19, 77.73,
3.1.11. (2S,3S,4R)-2-Azido-4,5-di-O-isopropylidene-1-
trityloxy-hexane (11). To a stirred solution of 10 (66 mg,
0.15 mmol) in dry CH2Cl2 (1.0 mL) with freshly activated
˚
4 A MS (20 mg) was added 2,6-lutidine (35 mL,
8.81 mmol). The reaction mixture was cooled to ꢁ40 ꢀC
and TMSOTf (38 mL, 0.23 mmol) was added to it. After be-
ing stirred at ꢁ40 ꢀC for 30 min, tetramethylguanidinium
azide (72 mg, 0.46 mmol) was added and stirred at the
same temperature for an additional 30 min. The reaction
mixture was allowed to warm to room temperature for
over 18 h. The reaction mixture was diluted with EtOAc, fil-
tered, and washed with H2O and brine. Following drying
(MgSO4) and concentration, the crude product was purified
by flash silica gel chromatography to afford 11 (50 mg; 72%)
1
as a yellow oil. Rf 0.50 (hexanes/EtOAc¼3:1); H NMR
(500 MHz, CDCl3): d 1.03 (t, J¼7.4 Hz, 3H), 1.23 (s, 3H),
1.26 (s, 3H), 1.42–1.53 (m, 1H), 1.59–1.70 (m, 1H), 3.36
(dd, J¼7.9, 9.9 Hz, 1H), 3.47 (ddd, J¼2.2, 7.9, 9.3 Hz,
1H), 3.53 (dd, J¼2.2, 9.9 Hz, 1H), 3.89 (dd, J¼5.5,
9.3 Hz, 1H), 4.02 (ddd, J¼4.1, 5.5, 9.6 Hz, 1H), 7.19–
7.40 (m, 10H), 7.43–7.55 (m, 5H). 13C NMR (125 MHz,

4316
C.-W. Chang et al. / Tetrahedron 63 (2007) 4310–4318
CDCl3): d 10.93, 22.45, 25.66, 28.01, 60.74, 64.56, 75.80,
79.41, 87.28, 108.13, 127.07, 127.84, 128.73, 143.77.
HRMS (FAB) calcd for C28H31N3O3 (M+): 457.2361.
Found: 457.2365.
MgSO4 and concentrated to dryness. The crude residues
were purified by flash silica gel column chromatography to
afford pure compound 16 (85 mg; 57%) as a yellow oil.
Rf 0.21 (hexanes/EtOAc¼20:1); 1H NMR (500 MHz,
CDCl3): d 1.22 (s, 3H), 1.24 (s, 3H), 1.50–1.60 (m, 1H over-
lapped with H2O), 1.62–1.71 (m, 1H), 2.07–2.16 (m, 1H),
2.23–2.33 (m, 1H), 3.34 (dd, J¼7.7, 9.9 Hz, 1H), 3.46
(ddd, J¼2.5, 7.7, 9.4 Hz, 1H), 3.52 (dd, J¼2.5, 9.9 Hz,
1H), 3.87 (dd, J¼5.6, 9.4 Hz, 1H), 4.10 (ddd, J¼3.5, 5.6,
10.3 Hz, 1H), 4.98 (br dd, J¼1.7, 10.2 Hz, 1H), 5.04 (br
dd, J¼1.7, 16.9 Hz, 1H), 5.83 (dddd, J¼6.6, 6.6, 10.2,
16.9 Hz, 1H), 7.19–7.35 (m, 10H), 7.43–7.52 (m, 5H). 13C
NMR (125 MHz, CDCl3): d 25.7, 28.0, 28.6, 30.5, 60.7,
64.5, 75.8, 87.3, 108.2, 115.1, 127.1, 127.9, 128.7, 137.9,
143.8. HRMS (FAB) calcd for C30H34N3O3 (M+H+):
484.2588. Found: 484.2600.
3.1.12. (4R,5R,6R)-Methyl Z-2,3-dideoxy-4,5-O-isopro-
pylidene-7-O-trityl-D-lyxo-2-heptenonate (Z-12). A mix-
ture of 5-trityloxy-2,3-O-isopropylidene-D-lyxofuranose
4
5b (4.65 g, 10.70 mmol) and methyl(triphenylphosphoranyl-
idene)acetate (7.20 g, 21.50 mmol) in dry CH2Cl2 (50 mL)
was stirred for 13 h at room temperature under nitrogen. Vol-
atiles were removed under reduced pressure. The resulting
residues were dissolved in EtOAc and then washed with
water and brine, dried (MgSO4), filtered, and concentrated.
Flash silica gel column chromatography yielded Z-12
(1.92 g; 36%) as a white solid. Mp¼122 ꢀC; Rf 0.33 (hex-
1
anes/EtOAc¼3:1); H NMR (500 MHz, CDCl3): d 1.38 (s,
3H), 1.50 (s, 3H), 2.16 (d, J¼8.5 Hz, 1H), 3.14 (dd, J¼5.7,
9.4 Hz, 1H), 3.20 (dd, J¼6.7, 9.4 Hz, 1H), 3.51–3.61 (m,
1H), 3.71 (s, 3H), 4.59 (dd, J¼1.6, 7.7 Hz, 1H), 5.61 (ddd,
J¼1.5, 6.9, 7.7 Hz, 1H), 5.90 (dd, J¼1.5, 11.6 Hz, 1H),
6.50 (dd, J¼6.9, 11.6 Hz, 1H), 7.18–7.37 (m, 10H), 7.40–
7.50 (m, 5H). 13C NMR (125 MHz, CDCl3): d 24.3, 26.7,
51.5, 65.5, 68.6, 75.0, 78.2, 86.2, 108.9, 120.7, 127.0,
127.8, 128.7, 144.0, 148.0, 166.2. HRMS (FAB) calcd for
C30H32O6 (M+): 488.2202. Found: 488.2199.
3.1.15. (4R,5R,6R)-6-Hydroxy-4,5-di-O-isopropylidene-
7-trityloxy-heptanoic acid methyl ester (17). To a stirred
solution of 12 (236 mg, 0.48 mmol) in EtOAc (5.0 mL)
was added a catalytic amount of palladium (5 wt % on acti-
vated C). Then, the mixture was degassed by hydrogen and
then stirred at room temperature for 1 h under hydrogen.
The crude residues were purified by flash silica gel column
chromatography to afford pure compound 17 (222 mg,
94 %) as a yellow syrup. Rf 0.24 (hexanes/EtOAc¼3:1);
1H NMR (500 MHz, CDCl3): d 1.32 (s, 3H), 1.42 (s, 3H),
1.75 (dddd, J¼2.9, 8.7, 10.2, 13.9 Hz, 1H), 1.96 (dddd,
J ¼5.6, 8.5, 10.7, 13.9 Hz, 1H), 2.26 (d, J¼6.5 Hz, 1H),
2.34 (ddd, J¼8.5, 10.2, 16.2 Hz, 1H), 2.50 (ddd, J¼5.6,
8.7, 16.2 Hz, 1H), 3.18 (dd, J¼5.8, 9.5 Hz, 1H), 3.22 (dd,
J¼6.0, 9.5 Hz, 1H), 3.65 (s, 3H), 3.72 (dddd, J¼3.7, 5.8,
6.0, 6.5 Hz, 1H), 4.07 (ddd, J¼2.9, 6.4, 10.6 Hz, 1H),
4.17 (dd, J¼3.7, 6.4 Hz, 1H), 7.18–7.34 (m, 10H), 7.39–
7.47 (m, 5H). 13C NMR (125 MHz, CDCl3): d 25.2,
25.5, 27.4, 31.0, 51.6, 65.2, 68.8, 76.3, 76.9, 86.9,
108.1, 127.1, 127.9, 128.7, 143.8, 173.7. HRMS (FAB)
calcd for C30H34O6Na (M+Na+): 513.2254. Found:
513.2253.
3.1.13. (4R,5R,6R)-Methyl E-2,3-dideoxy-4,5-O-isopro-
pylidene-7-O-trityl-D-lyxo-2-heptenonate (E-12). This
compound was prepared by cross-metathesis reaction of al-
kene 6 and methyl acrylate in refluxing CH2Cl2. Typically, to
a solution of 5 (150 mg, 0.35 mmol) in dry CH2Cl2 (7.0 mL,
0.05 M for CM reaction) were added methyl acrylate
(314 mL, 3.84 mmol) and Grubb’s II catalyst 15 (30 mg,
35.0 mmol) at room temperature under nitrogen. After being
refluxed for 13 h, the reaction mixture was evaporated to
dryness. The crude material was purified by silica gel flash
column chromatography to afford pure compound E-12
(62 mg; 37%) as a white solid. Rf 0.33 (hexanes/
1
EtOAc¼3:1); H NMR (500 MHz, CDCl3): d 1.38 (s, 3H),
1.49 (s, 3H), 2.27 (d, J¼6.5 Hz, 1H), 3.12 (dd, J¼5.6,
9.6 Hz, 1H), 3.22 (dd, J¼5.3, 9.6 Hz, 1H), 3.64 (ddd,
J¼4.5, 5.3, 4.5 Hz, 1H), 3.71 (s, 3H), 4.38 (dd, J¼4.5,
6.9 Hz, 1H), 4.56 (dd, J¼6.9, 7.0 Hz, 1H), 5.85 (d,
J¼15.7 Hz, 1H), 6.85 (dd, J¼7.0, 15.7 Hz, 1H), 7.18–7.34
(m, 10H), 7.37–7.49 (m, 5H). 13C NMR (125 MHz,
CDCl3): d 25.14, 27.28, 51.67, 64.61, 68.84, 76.51, 78.09,
86.87, 109.46, 123.26, 127.15, 127.90, 128.66, 143.35,
143.70, 166.08. HRMS (FAB) calcd for C30H32O6Na
(M+Na+): 511.2087. Found: 511.2097.
3.1.16. (4R,5S,6S)-6-Azido-4,5-di-O-isopropylidene-7-
trityloxy-heptanoic acid methyl ester (18). To a stirred so-
˚
lution of 17 (1.44 g, 2.94 mmol) and freshly activated 4 A
MS (60 mg) in dry CH2Cl2 (30 mL) was added 2,6-lutidine
(1.03 mL, 8.81 mmol). The reaction mixture was cooled to
ꢁ40 ꢀC and TMSOTf (993 mL, 5.88 mmol) was added to
it. After being stirred at ꢁ40 ꢀC for 30 min, tetramethylgua-
nidinium azide (1.4 g, 8.81 mmol) was added and stirred at
the same temperature for an additional 30 min. The reaction
mixture was allowed to warm to room temperature for over
18 h. The reaction mixture was diluted with EtOAc, filtered,
and washed with H2O and brine. Following drying (MgSO4)
and concentration, the crude product was purified by flash
silica gel chromatography to afford 18 (1.39 g, 92%) as a
yellow oil. Rf 0.50 (hexanes/EtOAc¼3:1); 1H NMR
(500 MHz, CDCl3): d 1.25 (s, 6H), 1.70–1.79 (m, 1H),
1.91–2.01 (m, 1H), 2.42 (ddd, J¼7.0, 8.6, 16.2 Hz, 1H),
2.54 (ddd, J¼5.7, 9.0, 16.2 Hz, 1H), 3.39 (dd, J¼7.3,
9.9 Hz, 1H), 3.46 (ddd, J¼2.4, 7.3, 9.6 Hz, 1H), 3.55 (dd,
J¼2.4, 9.9 Hz, 1H), 3.69 (s, 3H), 3.96 (dd, J¼5.6, 9.6 Hz,
1H), 4.11 (ddd, J¼3.1, 5.6, 10.8 Hz, 1H), 7.21–7.35 (m,
10H), 7.45–7.52 (m, 5H). 13C NMR (100 MHz, CDCl3):
d 25.1, 25.7, 28.0, 30.8, 51.6, 60.2, 64.4, 75.5, 77.2, 87.3,
3.1.14. (2S,3S,4R)-2-Azido-3,4-di-O-isopropylidene-1-
trityloxy-oct-7-ene (16). LHMDS (372 mL of 1 M solution
in THF) was added to a solution of methyltriphenylphospho-
nium bromide (121 mg, 0.34 mmol) in dry THF (2.0 mL) at
0 ꢀC under nitrogen and the resulting mixture was stirred
for 1 h. A solution containing the aldehyde 19 (150 mg,
0.31 mmol) in dry THF (2.5 mL) was added slowly at 0 ꢀC
to the above mixture. The reaction mixture was warmed to
room temperature and stirred for 9 h, and then quenched
with MeOH. The solvents were removed in vacuo. The
resulting residues were diluted with EtOAc and washed
with H2O and brine. The crude residues were dried with

C.-W. Chang et al. / Tetrahedron 63 (2007) 4310–4318
4317
108.6, 127.1, 127.9, 128.7, 143.7, 173.7. HRMS (FAB)
calcd for C30H33N3O5Na (M+Na+): 538.2308. Found:
538.2318.
3.73 (d, J1,2¼5.9 Hz, H-1, 2H), 4.48 (dd, J3,4¼6.9 Hz,
J3,2¼3.9 Hz, H-3, 1H), 4.67 (dddd, J4,5¼7.5 Hz, J4,3
6.9 Hz, J4,6¼1.2 Hz, J4,7¼1.2 Hz, H-4, 1H), 4.92 (td,
¼
J2,1¼5.9 Hz, J2,3¼3.9 Hz, H-2, 1H), 5.24 (ddd, J6b,5
¼
3.1.17. (4R,5S,6S)-6-Azido-4,5-di-O-isopropylidene-7-
trityloxy-heptanal (19). DIBAL (1.25 mL of 1 M solution
in toluene) was added dropwise to a solution of compound
18 (429 mg, 0.83 mmol) in toluene (12 mL) at ꢁ78 ꢀC for
6 h. The reaction mixture was quenched with MeOH and
then warmed to room temperature. The resulting residues
were concentrated to dryness and purified by flash silica
gel column chromatography to afford pure compound 19
(291 mg, 70%) as a yellow oil. Rf 0.40 (hexanes/
10.3 Hz, J6b,6a¼1.3 Hz, J6b,4¼1.2 Hz, H-6b, 1H), 5.35
(ddd, J6a,5¼17.2 Hz, J6a,6b¼1.3 Hz, J6a,4¼1.2 Hz, H-6a,
1H), 5.80 (ddd, J5,6a¼17.2 Hz, J5,6b¼10.3 Hz, J5,4
¼
0
0
0
0
7.5 Hz, H-5, 1H), 5.85 (dd, J3 b,2 ¼10.4 Hz, J3 b,3 a¼1.5 Hz,
H-30b, 1H), 6.14 (dd, J2 ,3 a¼17.2 Hz, J2 ,3 b¼10.4 Hz, H-20,
0
0
0
0
1H), 6.44 (dd, J3 a,2 ¼17.2 Hz, J3 a,3 b¼1.5 Hz, H-30a, 1H).
13C NMR (125 MHz, CDCl3): d ꢁ5.26, ꢁ5.22, 18.44,
25.67, 26.02ꢂ3, 27.37, 61.49, 72.47, 75.99, 78.66, 109.13,
119.30, 128.82, 131.30, 133.51, 165.59. HRMS (FAB) calcd
for C18H33O5Si (M+H+): 357.2102. Found: 357.2097.
0
0
0
0
1
EtOAc¼3:1); H NMR (400 MHz, CDCl3): d 1.25 (s, 6H),
1.74 (dddd, J¼6.2, 7.9, 10.9, 14.0 Hz, 1H), 1.95 (dddd,
J¼3.1, 6.7, 8.1, 14.0 Hz, 1H), 2.52–2.72 (m, 2H), 3.40 (dd,
J¼7.2, 9.7 Hz, 1H), 3.47 (ddd, J¼2.2, 7.2, 9.4 Hz, 1H),
3.55 (dd, J¼2.2, 9.7 Hz, 1H), 3.97 (dd, J¼5.6, 9.4 Hz,
1H), 4.10 (ddd, J¼3.1, 5.6, 10.9 Hz, 1H), 7.21–7.35 (m,
10H), 7.45–7.51 (m, 5H), 9.81 (s, 1H). 13C NMR
(100 MHz, CDCl3): d 22.4, 25.6, 28.0, 40.8, 60.2, 64.4,
75.5, 76.8, 87.4, 108.6, 127.1, 127.9, 128.7, 143.7, 201.7.
HRMS (FAB) calcd for C29H32NO4 (Mꢁ2N+H+):
458.2324. Found: 458.2331.
3.1.20. (4R,5R,6R)-7-(tert-Butyldimethylsilyl)-5,6-di-
O-isopropylidene-6,7-dihydro-5H-oxepin-2-one (22). A
solution of 21 (1.16 g, 3.3 mmol) in degassed CH2Cl2
(113 mL) containing catalyst 15 (278 mg, 0.33 mmol) was
heated to reflux under nitrogen for 16 h. The reaction mix-
ture was cooled to room temperature and treated with acti-
vated charcoal for 16 h after passing through a short silica
gel bed. Charcoals were filtered off through Celite, and
then concentrated under reduced pressure. Column chroma-
tography on silica gel (hexanes/EtOAc¼8:1–6:1) afforded
1
3.1.18. (4R,5R,6R)-7-O-(tert-Butyldimethylsilyl)-4,5-di-
O-isopropylidene-6-hydroxy-heptanoic acid methyl ester
(20). To a solution of lactone 23 (205 mg, 0.62 mmol) in
MeOH (5.0 mL) was added catalytic amount of NaOMe
(3.3 mg, 0.062 mmol). After 10 min of stirring at 25 ꢀC,
the reaction mixture was neutralized with acidic resin. The
resin was filtered off and the filtrate was concentrated. The
residue after silica gel column chromatography afforded title
compound 20 (210 mg, 94%) as light oil (hexanes/
813 mg (75%) of 22 as a white solid. H NMR (500 MHz,
t
CDCl3): d 0.09 (s, Me, 3H), 0.10 (s, Me, 3H), 0.90 (s, Bu,
9H), 1.37 (s, Me, 3H), 1.50 (s, Me, 3H), 3.84 (dd, J7b,7a
¼
10.1 Hz, J7b,6¼6.3 Hz, H-7b, 1H), 3.90 (dd, J7a,7b¼10.1 Hz,
J7a,6¼7.3 Hz, H-7a, 1H), 4.18 (ddd, J6,7a¼7.3 Hz,
J6,7b¼6.3 Hz, J6,5¼0.6 Hz, H-6, 1H), 4.48 (dd, J5,4¼6.7 Hz,
J5,6¼0.6 Hz, H-5, 1H), 4.67 (dd, J4,3¼6.7 Hz, J4,5¼6.7 Hz,
H-4, 1H), 6.24 (d, J2,3¼11.1 Hz, H-2, 1H), 6.68
(dd, J3,2¼11.1 Hz, J3,4¼6.7 Hz, H-3, 1H). 13C NMR
(100 MHz, CDCl3): d ꢁ5.29, ꢁ5.15, 18.50, 25.26, 25.55,
26.05ꢂ3, 61.44, 71.88, 77.48, 78.95, 109.78, 137.27,
166.81. HRMS (FAB) calcd for C16H29O5Si (M+H+):
329.1783. Found: 329.1784.
1
EtOAc¼9:1–7:1). [a]2D6 ꢁ3.25 (c 1.04, CHCl3); H NMR
t
(500 MHz, CDCl3): d 0.08 (s, 6H), 0.91 (s, Bu, 9H), 1.36
(s, Me, 3H), 1.49 (s, Me, 3H), 1.89–1.96 (m, H-3a, 1H),
2.02–2.09 (m, H-3b, 1H), 2.40–2.47 (m, J2a,2b¼16.3 Hz,
H-2a, 1H), 2.54–2.61 (m, J2b,2a¼16.3 Hz, H-2b, 1H), 3.60
(dd, J7a,7b¼9.7 Hz, J7a,6¼6.5 Hz, H-7a, 1H), 3.66 (dd,
J7b,7a¼9.7 Hz, J7b,6¼5.9 Hz, H-7b, 1H), 3.67–3.73 (m over-
lapped with s at 3.69 ppm, J6,7a¼6.5 Hz, J6,7b¼5.9 Hz, H-6,
Me, 4H), 4.14–4.20 (m overlapped with d at 4.16 ppm, H-4,
H-5, 2H). 13C NMR (125 MHz, CDCl3): d ꢁ5.22ꢂ2, 18.49,
25.39, 25.81, 26.07ꢂ3, 27.58, 31.11, 51.78, 64.75, 76.45,
76.76, 108.23, 173.95. HRMS (FAB) calcd for C17H35O6Si
(M+H+): 363.2206. Found: 363.2203.
3.1.21. (4R,5R,6R)-7-(tert-Butyldimethylsilanyloxy-
methyl)-5,6-di-O-isopropylidene-oxepan-2-one (23). Cat-
alytic amount of Pd(OH)2 (20% on active carbon) was
suspended to a solution of 22 (321 mg, 0.98 mmol) in EtOAc
(3.0 mL). The flask was purged with H2, and a hydrogen bal-
loon was attached. After 1 h, the catalyst was filtered off
through a pad of Celite and the filtrate was concentrated
to give lactone 23 (321 mg; 99%) as a white solid.
1H NMR (500 MHz, CDCl3): d 0.09 (s, Me, 3H), 0.10 (s,
t
3.1.19. (4R,5R,6R)-1,2-Dideoxy-3,4-di-O-isopropylidene-
5-acryloxy-6-O-(tert-butyldimethylsilyl)-D-lyxohex-1-
enitol (21). Acryloyl chloride (150 mL, 1.85 mmol) was
added to a stirred solution of 7 (466 mg, 1.54 mmol),
DMAP (19 mg, 0.15 mmol), and Et3N (263 mL,
1.89 mmol) in CH2Cl2 (5.0 mL) under argon at 0 ꢀC. After
being stirred for 60 min, the reaction mixture was evaporated
to dryness. The resulting residues were diluted with EtOAc
and successively washed with H2O and brine. The organic
layer was dried (MgSO4), filtered, and concentrated to dry-
ness. The crude residues were purified by flash silica gel col-
umn chromatography to afford pure compound 21 (456 mg,
Me, 3H), 0.91 (s, Bu, 9H), 1.37 (s, Me, 3H), 1.50 (s, Me,
¼
3H), 2.03 (dddd, J3a,3b¼15.3 Hz, J3a,2b¼9.8 Hz, J3a,2a
5.4 Hz, J3a,4¼2.6 Hz, H-3a, 1H), 2.29 (dddd, J3b,3a
¼
15.3 Hz, J3b,2a¼9.3 Hz, J3b,2b¼5.9 Hz, J3b,4¼5.9 Hz, H-3b,
1H), 2.73 (dd, J2a,2b¼13.6 Hz, J2a,3b¼9.3 Hz, J2a,3a¼5.4 Hz,
H-2a, 1H), 2.76 (dd, J2b,2a¼13.6 Hz, J2b,3a¼9.8 Hz, J2b,3b
¼
5.9 Hz, H-2b, 1H), 3.81 (dd, J7a,7b¼10.0 Hz, J7a,6¼6.0 Hz,
H-7a, 1H), 3.85 (dd, J7b,7a¼10.0 Hz, J7b,6¼7.2 Hz, H-7b,
1H), 4.27 (d, J5,4¼6.5 Hz, H-5, 1H), 4.28 (dd, J6,7b
7.2 Hz, J6,7a¼6.0 Hz, H-6, 1H), 4.49–4.52 (m, J4,5
¼
¼
6.5 Hz, J4,3b¼5.9 Hz, J4,3a¼2.6 Hz, H-4, 1H). 13C NMR
(100 MHz, CDCl3): d ꢁ5.24, ꢁ5.15, 18.52, 20.63, 25.55,
25.99, 26.07ꢂ3, 28.23, 61.81, 74.15, 74.41, 77.43, 109.83,
171.76. HRMS (FAB) calcd for C16H31O5Si (M+H+):
331.1946. Found: 331.1941.
1
83%) as yellow oil (hexanes/EtOAc¼16:1–12:1). H NMR
(500 MHz, CDCl3): d 0.52 (s, Me, 3H), 0.59 (s, Me, 3H),
0.89 (s, Bu, 9H), 1.40 (s, Me, 3H), 1.54 (s, Me, 3H),
t

4318
C.-W. Chang et al. / Tetrahedron 63 (2007) 4310–4318
(d) Lu, X.; Bittman, R. Tetrahedron Lett. 2005, 46, 3165–
Acknowledgements
3168; (e) For review: Howell, A. R.; Ndakala, A. J. Curr.
Org. Chem. 2002, 6, 365–391.
This research was generously supported by the National
Tsing Hua University, Academia Sinica and National Sci-
ence Council (NSC 95-2752-B-007-002-PAE) in Taiwan.
6. (a) Enders, D.; Palecek, J.; Grondal, C. Chem. Commun. 2006,
655–657; (b) Jung, D. Y.; Kang, S.; Chang, S. B.; Kim, Y. H.
Synlett 2005, 2183–2186; (c) Song, B. G.; Son, B. S.; Seo,
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