Total synthesis of sphingofungin E from D-glucose derivative

Article abstract of DOI:10.1016/S0040-4020(02)01058-X

Total synthesis of sphingofungin E (1) from an already known D-glucose derivative 9 in a stereocontrolled manner is described.

Full text of DOI:10.1016/S0040-4020(02)01058-X

Tetrahedron 58 (2002) 8779–8791
Total synthesis of sphingofungin E from D-glucose derivative
*
Tsuyoshi Nakamura and Masao Shiozaki
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-Chome, Shinagawa-ku, Tokyo 140-8710, Japan
Received 25 May 2002; accepted 22 August 2002
Abstract—Total synthesis of sphingofungin E (1) from an already known D-glucose derivative 9 in a stereocontrolled manner is
described. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
potent immunosuppressive agent.2 In conse-quence of many
organic chemists having been interested in the structure of
myriocin and its characteristic biological activity, myriocin
and its related compounds have been successfully syn-
thesized.3 Concurrently with the synthetic studies of myriocin,
several reports on total syntheses of sphingofungins have
been published.4–6 Especially, four groups including us
have recently reported the total synthesis of sphingofungin
E in a row.5 Here we would like to describe in detail the total
synthesis of sphingofungin E from an already known
D-glucose derivative 9.
The sphingofungins have been isolated by the Merck group
as new antifungal natural products (Fig. 1).1 These
compounds have a unique mechanism for expression of
their biological activities. Namely, they act as fungicides by
inhibiting serine palmitoyl transferase, an enzyme essential in
the biosynthesis of sphingolipids.1a,c The sphingofungins have
four consecutive chiral centers and a trans olefinic group in
their polar head moiety. In particular, sphingofungin E (1) and
F (2) contain a quaternary center at the C-2 position. Their
structures, especially the structure of sphingofungin E, are
strikingly similar to myriocin (3), which has been reported as a
Based on the retrosynthetic analysis depicted in Fig. 2,
the molecule of 1 was divided into two fragments, the
hydrophilic polar head group 5 and the lipophilic chain part
4. We adopted the B-alkyl Suzuki–Miyaura cross-coupling
reaction7 for coupling these two fragments in a similar way
to Trost’s synthesis of sphingofungins E and F.5c,6a We
thought that this method was the most suitable for conjoining
a protected derivative of amino-polyol carboxylic acid 5 and
a protected ketone derivative of 4 under moderate
conditions to regulate the E-geometry of the alkenyl part.
In further analysis, we envisioned that this protected
derivative of 5 might be derived from a protected derivative
of amino-polyol 6 having a C-2 tetra-substituted carbon and
four contiguous chiral centers. Regarding this amino-polyol
6, we focused particularly on the stereochemistry of the C-5
carbon, which has S-configuration. However, it should be
understood that the C-5 diastereomeric isomer 7 of 6, easily
obtainable from lactone 8, showed R-configuration on the
C-5 carbon atom. Therefore, we had to convert the
configuration on the C-5 carbon atom from R to S. A
derivative of the lactone 8, possessing C-2 branched
mannosamine-like functional groups in its stereochemistry,
had already been synthesized from D-glucose using a
procedure via a spiro a-chloroepoxide8 by Olesker et al.9
A notable feature of this approach is that all of the functional
groups of D-glucose are utilized for the synthesis, and
the stereochemistry of the final product and synthetic
intermediates are quite unambiguous.
Figure 1. Structures of sphingofungins and myriocin.
Keywords: antifungals; D-glucose; sphingofungin E; Suzuki–Miyaura
reaction; total synthesis.
*
Corresponding author. Tel.: þ81-3-3492-3131; fax: þ81-3-5436-8570;
e-mail: shioza@shina.sankyo.co.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01058-X

8780
T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
Figure 2. Retrosynthetic analysis of sphingofungin E.
2. Results and discussion
To determine the stereochemistry of the quaternary C-2
position, an NOE experiment of aldehyde 13 was con-
ducted. Irradiation of the aldehyde proton (Ha) at d 9.28
(singlet) induced enhancement of the C-3 proton (Hb) signal
at d 4.58 (d, J¼9.8 Hz) by 13%. Additionally, irradiation of
the Hb signal induced enhancement of the Ha signal and the
C-5 proton (Hc) signal at d 3.97 (dt, J¼9.8, 3.9 Hz) by 16
and 9%, respectively. Based on these observations, the
stereochemistry of the C-2 position was reasonably
established.
The first stage of the synthesis was stereoselective
construction of the C-2 tetra-substituted carbon by using
a spiro a-chloroepoxide method8 (Scheme 1).
The protected D-glucose derivative 9, which was easily
prepared by a modification of the procedure reported by
Fukase et al.,10 could be converted to ketone 10 in 76%
yield by Swern oxidation. Addition of dichloromethyl-
lithium to the ketone moiety of 10 afforded C-2 dichloro-
methylated tertiary alcohol 11, exclusively, in 70% yield
without detection of the C-2 epimer, due to the steric
hindrance of the anomeric axial allyloxy group. Treatment
of a solution of 11 in dimethyl sulfoxide (DMSO) with
1,8-diazabicyclo[5.4.0]undec-7-en (DBU) gave a spiro
a-chloroepoxide 12,11 which was then treated with NaN3
in the presence of 15-crown-5 using hexamethylphosphor-
amide (HMPA) as a solvent to give azide-aldehyde 13
without yielding diastereo- or regioisomers. The aldehyde
was immediately reduced with NaBH4 to afford primary
alcohol 14 in 84% yield in 3 steps.
The following steps from the primary alcohol 14 to acyclic
amide 20 are depicted in Scheme 2.
Protection of the primary hydroxy group of 14 with tert-
butyldiphenylsilyl chloride (TBDPS-Cl) and imidazole
using N,N-dimethylformamide (DMF) as a solvent, and
successive deprotection of the 4,6-O-benzylidene group
with camphorsulfonic acid (CSA) in MeOH afforded diol
15 in 86% yield. The regioselective silylation at the
C-6 hydroxy group of 15 with tert-butyldimethylsilyl
chloride (TBDMS-Cl) and imidazole followed by the
Scheme 1. Construction of the C-2 tetra-substituted carbon and determination of its stereochemistry by NOE experiment. Reagents and conditions: (a) Swern
oxidation, 2788C, 1 h; (b) LiCHCl2, THF, 2788C, 30 min; (c) DBU, DMSO, 08C, 3 h; (d) NaN3, cat. 15-crown-5, HMPA, 708C, 17 h; (e) NaBH4, MeOH, 08C,
1.5 h.

T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
8781
Scheme 2. Reagents and conditions: (a) TBDPS-Cl, imidazole, DMF, 608C, 3 h; (b) cat. CSA, MeOH, rt, 26 h; (c) TBDMS-Cl, imidazole, DMF, 08C, 2 h;
(d) PMB-Cl, NaH, DMF, 2238C, 5 h; (e) [Ir(C8H12)(PMePh2)2]PF6, THF, rt, 2.5 h; (f) NBS, H2O, THF, 08C, 2 h; (g) Dess–Martin periodinane, CH2Cl2, rt,
2 h; (h) H2NMe, MeOH, rt, 1.5 h; (i) Swern oxidation, 2788C, 1 h; (j) L-Selectride, THF, 2788C, 30 min; (k) SEM-Cl, EtN(i-Pr)2, 1,2-dichloroethane, 608C,
4 h.
p-methoxybenzyl (PMB) ether formation of the C-4
hydroxy group with PMB-Cl and NaH in DMF at 2238C
for 5 h afforded 16 in 64% yield. The C-1 anomeric O-allyl
group was deprotected by treatment with an Ir complex12
and successive hydrolysis with N-bromosuccinimide (NBS)
to give pyranose 17 in 82% yield. Compound 17 was
oxidized to a lactone using Dess–Martin periodinane, and
successively treated with methylamine in MeOH to afford
stable amide 18 in 94% yield. In this lactone opening
reaction, only mono-alkylamines as nucleophiles afforded
stable amides. When ammonia or several di-alkylamines
were used as nucleophiles, the corresponding acyclic
amides could not be obtained as stable compounds.
Next, we carried out the cleavage of the amide bond via the
formation of a five-membered lactone by the removal of the
C-4 O-PMB group (Scheme 3).
The deprotection of the C-4 O-PMB group by treatment of
mono methyl amide 20 with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) in CH2Cl2–H2O proceeded smoothly
to give 21, which did not lactonize even in the presence of
pyridinium p-toluenesulfonate (PPTS) at 608C for 14 h.
However, compound 21 lactonized by treatment with
1 equiv. of CSA in toluene to give both C-5 O-SEM and
C-6 O-TBDMS deprotected compound 22 in low yield.
This lactone formation was achieved by activation of the
amide bond by methylation to N,N-dimethyl amide from
N-methylamide. Treatment of 20 with MeI in the
presence of NaH as a base in DMF afforded N,N-
dimethylamide 23 in 97% yield. After cleaving the PMB
group, the reaction of 23 with PPTS in toluene at 808C
afforded desired lactone 24 in 62% yield without the
undesired deprotection.
Since the configuration of the C-5 hydroxy group of 18 was
opposite to that of natural sphingofungin E, we had to
inverse the configuration from R to S. Therefore, compound
18 was oxidized by Swern oxidation to give a ketone, which
was then reduced to alcohol 19 with lithium tri-sec-
butylborohydride (L-Selectride). This hydride reduction
was achieved in a 96:4 ratio diastereo-selectively. After
purification by silica gel column chromatography, an
inverted alcohol 19 was obtained in 82% yield in two
steps. The C-5 hydroxy group of 19 was protected by
treatment with 2-(trimethylsilyl)ethoxymethyl chloride
(SEM-Cl) and diisopropylethylamine in dichloroethane to
give SEM ether 20 in 85% yield.
The next stage of the synthesis was installation of the
lipophilic chain possessing an E-geometrical alkenyl part
(Scheme 4).
After the reduction of the azide group of 24 under hydrogen
atmosphere using Pd on carbon as a catalyst in ethyl acetate,
Scheme 3. Lactone formation from amide 20.

8782
T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
Scheme 4. Reagents and conditions: (a) Pd/C, H2, AcOEt, rt, 14 h; (b) PhCOCl, Et3N, CH2Cl2, rt, 2 h; (c) 5% aq. H2SO4, acetone, rt, 13 h; (d) Dess–Martin
periodinane, CH2Cl2, rt, 1.5 h; (e) CrCl2, CHI3, THF, rt, 2 h; (f) 28, PdCl2(dppf), Ph3As, Cs2CO3, THF–DMF, rt, 2 h.
Scheme 5. Deprotection of the C-3 O-benzyl group.
treatment of the resulting amine with benzoyl chloride and
triethylamine afforded the benzoylamide 25 in 87% yield.
Selective cleavage of the C-6 O-TBDMS group of 25 with
5% aqueous H2SO4 in acetone was accomplished to give
alcohol 26 in 82% yield. Dess–Martin oxidation of the C-6
hydroxy group of 26 to an aldehyde, followed by iodo
olefination13 of the resulting aldehyde afforded iodoolefin
27 in 52% yield as a single geometrical isomer. B-alkyl
Suzuki–Miyaura reaction5c,6a,7 of vinyl iodide 27 and
organoborane 285c,6a provided the desired alkene 29 in
94% yield. The coupling constant (J¼15.6 Hz) between the
two olefinic protons (d 5.28 and 5.78) of compound 29
revealed the olefin geometry to be E-configuration.
removed in good yield by using BCl3 in CH2Cl2. This
difference in reactivity between the C-3 and C-4 O-benzyl
groups may be caused by the steric hindrance of the C-2
quaternary carbon. Additionally, oxidative deprotection of
the C-3 O-benzyl group of 32 also did not work well. For
instance, treatment of NaBrO3 and Na2S2O4 toward 32 in
1
AcOEt–H2O afforded a complex mixture. The H NMR
spectrum of this crude product showed no sign of the
olefinic protons of 32. Therefore, it was obvious that the
double bond moiety of 32 could not be preserved under
these reaction conditions.
To avoid the difficulty of removing the C-3 O-benzyl group
after introducing the lipophilic chain, we investigated
Deprotection reactions of the benzyl group in the final stage
of synthesis are shown in Scheme 5.
Table 1. Oxidative cleavage of C-3 O-benzyl group
The C-14 ethylene acetal moiety of 29 was removed by
hydrolysis with 5% aqueous H2SO4 in acetone. Treatment
of the obtained ketone with an HF–pyridine complex in
tetrahydrofuran (THF) cleaved both TBDPS and SEM ether
to give keto diol 30 in 67% yield. Cleavage of the C-3
O-benzyl group proved to be very difficult in this stage.
Treatment of lactone 30 with BCl3 in CH2Cl2 to remove the
benzyl group afforded desired triol 31 in only 16% yield.
Furthermore, deprotection of the C-3 O-benzyl group of 32
with BCl3 in CH2Cl2 after saponification of the lactone ring
only afforded a 0trace amount of allyl chloride 33, which was
caused by SN2 -type substitution reaction of the chloride
anion. In contrast, it was stated by Kobayashi et al. in their
report4c of the total synthesis of sphingofungin F that the
C-4 O-benzyl group of a similar compound to 32 could be
Entry
Conditions
Results (% yielda)
1
2
3
RuCl3, NaIO4 CH2Cl2, rt, 7 h
NaBrO3, Na2S2O4 AcOEt, rt, 2 h
NaBrO3, NaHSO3 AcOEt, rt, 1 h
34 (trace)
34 (45%), 35 (35%)
34 (69%), 35 (trace)
a
Isolated yields.

T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
8783
Scheme 6. Reagents and conditions: (a) Pd/C, H2, AcOEt, rt, 14 h; (b) PhCOCl, Et3N, CH2Cl2, rt, 2 h; (c) 5% aq. H2SO4, acetone, rt, 13 h; (d) Dess–Martin
periodinane, CH2Cl2, rt, 1.5 h; (e) CrCl2, CHI3, THF, rt, 2 h; (f) 28, PdCl2(dppf), Ph3As, Cs2CO3, THF–DMF, rt, 2 h; (g) 5% aq. H2SO4, acetone, rt, 5 h;
(h) HF–pyridine complex, THF, rt, 5.5 h; (i) NaOH, H2O, dioxane, 708C, 7.5 h, then neutralized with Amberlite IR-120.
oxidative cleavage14 of the C-3 O-benzyl group using
lactone 24 as a substrate (Table 1).
accomplished from the known D-glucose derivative 9 in 29
steps in 1.1% overall yield. In our synthesis, it is noteworthy
that all of the functional groups of D-glucose were utilized
effectively for the synthesis. Moreover, the target product
was solely obtained in fairly good yield in each step.
Treatment of 24 with a catalytic amount of RuCl3 and
excess NaIO4 in CH2Cl2 afforded a trace amount of
debenzylated product 34 (entry 1). The debenzylation
proceeded smoothly by treatment of 24 with NaBrO3 and
Na2S2O4 in AcOEt–H2O, but undesired desilylation of the
C-6 O-TBDMS group occured to give diol 35 (entry 2).
Finally, treatment of 24 with NaBrO3 and NaHSO3 gave the
desired debenzylated product 34 in 69% yield15 (entry 3).
4. Experimental
4.1. General procedures
Infrared spectra were recorded on a Jasco FT-IR610
spectrophotometer. High-resolution mass (HRMS) spectro-
scopy was carried out with a JEOL JMS-700V mass
The synthesis of sphingofungin E was achieved by applying
the above mentioned procedure (Scheme 6).
1
spectrometer. H NMR spectra were recorded on a Varian
Namely, reduction of the azide group of 34 under hydrogen
using Pd on carbon in ethyl acetate, followed by treatment
with 3 equiv. of benzoyl chloride and excess triethylamine,
afforded the O-benzoylated benzoylamide 36 in 80% yield.
Selective cleavage of the C-6 O-TBDMS group of 36 by
treatment with 5% aqueous H2SO4 in acetone was
accomplished to give alcohol 37 in 87% yield. Dess–
Martin periodinane oxidation of the C-6 hydroxy group of
37 to an aldehyde, followed by iodo olefination of the
resulting aldehyde afforded E-iodoolefin 38 exclusively in
69% yield. Suzuki–Miyaura cross-coupling reaction of
vinyl iodide 38 and organoborane 28 provided the desired
E-alkene 39 in 81% yield. Deprotection reaction to convert
39 to 1 was carried out as follows. The C-14 ethylene acetal
of 39 was removed by hydrolysis with 5% aqueous H2SO4
in acetone. Treatment of the obtained ketone with an
HF–pyridine complex in THF cleaved both TBDPS and
SEM ether to give keto diol 40 in 58% yield. Finally, the
lactone ring, benzamide and benzoyl ester groups of 40 were
saponified in the presence of NaOH in dioxane–H2O, then
neutralization with Amberlite IR-120 ion-exchange resin
afforded sphingofungin E (1) in 88% yield. The spectral data
of the obtained synthetic sample closely agreed with those
of both natural sphingofungin E reported by the Merck
group1c and synthetic sphingofungin E reported by Trost,5c
Lin5a and Chida.5d
(500 MHz) instrument with tetramethylsilane as an internal
reference. 13C NMR spectra were recorded on a Varian
(500 MHz) at 125 MHz or a JEOL JNM-GSX400 at
100 MHz. Separation of the compounds by column
chromatography was carried out with Silica Gel 60
(Merck, 230–400 mesh ASTM) or Silica Gel 60 N
(Kanto, spherical, neutral). All reactions were carried out
under positive pressure of N2 unless otherwise noted.
Tetrahydrofuran was distilled immediately before use from
sodium benzophenone ketyl.
4.1.1. Allyl 3-O-benzyl-4,6-O-benzylidene-a-D-arabino-
hexopyranosid-2-ulose (10). To a solution of oxalyl
chloride (13.1 ml, 151 mmol) in CH2Cl2 (100 ml) was
slowly added a solution of DMSO (21.4 ml, 301 mmol) in
CH2Cl2 (50 ml) at 2788C. After stirring for 10 min, to the
mixture was added a solution of 9 (30.0 g, 75.3 mmol) in
CH2Cl2 (100 ml), and the mixture was stirred for 1 h at
2788C. To the resulting solution was slowly added Et3N
(83.4 ml, 602 mmol), and the mixture was stirred for 1 h at
08C. After the addition of water (200 ml), the reaction
mixture was poured into water and extracted with ether. The
organic layer was washed with brine, dried over anhydrous
MgSO4 and filtered. The filtrate was evaporated in vacuo to
give 39.7 g of a crude product. Recrystallization from
hexane–AcOEt gave ketone 10 (22.6 g, 76%) as a white
crystalline solid, mp 77–798C. [a]2D4¼þ28.7 (c 1.2, CHCl3).
IR (KBr) 1753 cm21 1H NMR (CDCl3) d 3.80 (t, 1H,
.
3. Conclusion
J¼6.8 Hz), 3.88 (t, 1H, J¼9.8 Hz), 4.09 (dd, 1H, J¼4.9,
12.7 Hz), 4.20–4.27 (m, 2H), 4.37 (dd, 1H, J¼4.9, 9.8 Hz),
4.56 (d, 1H, J¼10.7 Hz), 4.72 (d, 1H, J¼12.7 Hz), 4.91 (d,
In summary, total synthesis of sphingofungin E has been

8784
T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
1H, J¼12.7 Hz), 4.93 (d, 1H, J¼12.7 Hz), 5.26 (d, 1H, J¼
11.7 Hz), 5.31 (d, 1H, J¼15.6 Hz), 5.56 (s, 1H), 5.89 (ddt,
1H, J¼15.6, 11.7, 5.9 Hz), 7.27–7.34 (m, 3H), 7.36–7.45
(m, 5H), 7.48–7.53 (m, 2H). 13C NMR (100 MHz, CDCl3) d
63.40, 68.68, 69.17, 73.51, 80.74, 82.41, 99.98, 101.13,
118.86, 126.13 (2C), 127.82 (2C), 128.24 (2C), 128.36 (2C),
129.12, 132.67, 136.89, 137.49, 197.34. HRMS (FAB,
positive-ion), calcd for C23H25O6: (MþH)þ 397.1651;
found: 397.1646.
The residual crude product of aldehyde 13 was dissolved in
MeOH (100 ml). To this solution was added NaBH4 (3.1 g,
80.9 mmol) at 08C. After stirring for 1.5 h at 08C, to the
reaction mixture was quenched with water (20 ml). The
resulting mixture was evaporated in vacuo to remove
MeOH, and diluted with ether, which was washed with
water and brine, dried over MgSO4 and filtered. The filtrate
was evaporated in vacuo to give 35.9 g of a crude product,
which was purified by silica gel column chromatography.
Elution with EtOAc–hexane (1:9 then 2:8) afforded 14
(30.7 g, 84%) as a colorless oil. Physical data of 13:
[a]D24¼þ74.0 (c 1.4, CHCl3). IR (neat) 2136, 1735 cm21. 1H
NMR (CDCl3) d 3.88 (t, 1H, J¼9.8 Hz), 3.93 (dd, 1H,
J¼6.8, 13.6 Hz), 3.97 (dt, 1H, J¼9.8, 3.9 Hz), 4.15 (dd, 1H,
J¼5.9, 13.6 Hz),4.24 (t, 1H, J¼9.8 Hz), 4.58 (d, 1H, J¼
9.8 Hz), 4.66 (s, 1H), 4.72 (d, 1H, J¼11.7 Hz), 4.96 (d, 1H,
J¼12.7 Hz), 5.19–5.24 (m, 2H), 5.66 (s, 1H), 5.73–5.82
(m, 1H), 7.23–7.35 (m, 5H), 7.36–7.43 (m, 3H), 7.51 (dd,
2H, J¼2.0, 7.8 Hz), 9.28 (s, 1H). 13C NMR (100 MHz,
CDCl3) d 64.05, 68.51, 68.64, 73.92, 74.68, 74.95, 80.47,
99.02, 101.79, 118.86, 125.99, 127.99 (2C), 128.09 (2C),
128.35 (2C), 128.50 (2C), 129.13, 132.30, 137.18, 137.40,
195.93. HRMS (FAB, positive-ion), calcd for C24H26N3O6:
(MþH)þ 452.1821; found: 452.1814. Physical data of 14:
[a]D24¼þ50.6 (c 1.0, CHCl3). IR (neat) 3515, 2125 cm21. 1H
NMR (CDCl3) d 2.50 (t, 1H, J¼ 6.8 Hz), 3.84–3.90 (m,
2H), 3.92 (d, 2H, J¼6.8 Hz), 4.03 (dd, 1H, J¼5.9, 12.7 Hz),
3.98–4.31 (m, 4H), 4.72 (s, 1H), 4.73 (d, 1H, J¼12.7 Hz),
4.98 (d, 1H, J¼11.7 Hz), 5.28 (d, 1H, J¼11.7 Hz), 5.32 (d,
1H, J¼15.6 Hz), 5.65 (s, 1H), 5.89 (ddt, 1H, J¼15.6, 11.7,
6.8 Hz), 7.27–7.41 (m, 8H), 7.45–7.50 (m, 2H). 13C NMR
(100 MHz, CDCl3) d 62.83, 63.94, 68.03, 68.61, 68.70,
75.29, 76.53, 80.50, 100.12, 101.62, 119.06, 126.00, 127.76
(2C), 127.99 (2C), 128.26 (2C), 128.37 (2C), 128.99,
132.63, 137.34, 138.01. HRMS (FAB, positive-ion), calcd
for C24H28N3O6: (MþH)þ 454.1978; found: 454.1956.
4.1.2. Allyl 3-O-benzyl-4,6-O-benzylidene-2-C-dichloro-
methyl-a-D-glucopyranoside (11). To a solution of
CH2Cl2 (4.1 ml, 63.8 mmol) in THF (50 ml) was slowly
added a 1.54 M solution of n-BuLi in hexane (37.6 ml,
57.9 mmol) at 2788C. After stirring for 10 min, to the
reaction mixture was slowly added a solution of 10 (7.70 g,
19.3 mmol) in THF (20 ml) via cannula at 2788C. After
stirring for 30 min, to the reaction mixture were slowly
added MeOH (3 ml) and sat. NH4Cl (10 ml). The resulting
mixture was poured into water and extracted with ether. The
organic layer was washed with brine, dried over anhydrous
MgSO4 and filtered. The filtrate was evaporated in vacuo to
give a crude mixture, which was purified by silica gel
column chromatography. Elution with EtOAc–hexane (1:9)
afforded 11 (7.5 g, 80%) as a colorless oil. [a]2D4¼þ42.7
1
(c 1.1, CHCl3). IR (neat) 3528 cm21. H NMR (CDCl3) d
3.52 (s, 1H), 3.82 (t, 1H, J¼10.3 Hz), 3.94 (dt, 1H, J¼9.8,
4.9 Hz), 4.08 (d, 1H, J¼9.8 Hz), 4.13 (dd, 1H, J¼4.9,
10.7 Hz), 4.25–4.32 (m, 2H), 4.34 (d, 1H, J¼9.8 Hz), 4.85
(d, 1H, J¼11.7 Hz), 4.92 (d, 1H, J¼11.7 Hz), 5.28 (s, 1H),
5.29 (d, 1H, J¼12.7 Hz), 5.35 (d, 1H, J¼16.6 Hz), 5.61
(s, 1H), 5.94 (ddt, 1H, J¼4.9, 12.7, 16.6 Hz), 6.25 (s, 1H),
7.28–7.33 (m, 4H), 7.37–7.40 (m, 4H), 7.46–7.48 (m, 2H).
13C NMR (100 MHz, CDCl3) d 63.05, 68.76, 69.10, 73.14,
75.77, 78.00, 79.50, 82.45, 97.06, 101.30, 119.01, 126.02
(2C), 127.69, 127.83 (2C), 128.19 (2C), 128.26 (2C),
128.93, 132.64, 137.28, 138.04. HRMS (FAB, positive-ion),
calcd for C24H27Cl2O6: (MþH)þ 481.1185; found:
481.1188.
4.1.4. Allyl 2-azido-3-O-benzyl-2-C-(tert-butyldiphenyl-
silyloxymethyl)-2-deoxy-a-D-mannopyranoside (15). To
a solution of alcohol 14 (13.5 g, 29.8 mmol) and imidazole
(6.1 g, 89.3 mmol) in DMF (30 ml) was added TBDPS-Cl
(8.5 ml, 32.8 mmol), and this solution was stirred for 14 h at
room temperature. After further stirring for 3 h at 608C, to
this reaction mixture was added sat. NaHCO3 (10 ml). The
resulting mixture was diluted with ether, which was washed
with water and brine, dried over MgSO4 and filtered. The
filtrate was evaporated in vacuo to give a residue. This
residue was dissolved in MeOH (40 ml) and THF (25 ml),
and to this solution was added CSA (1.0 g). After stirring for
26 h at room temperature, to this reaction mixture was
added Et3N (10 ml). After evaporation of this mixture in
vacuo, the reaction mixture was diluted with ether, which
was washed with water and brine, dried over MgSO4 and
filtered. The filtrate was evaporated in vacuo to give 25.0 g
of a crude product, which was purified by silica gel column
chromatography. Elution with EtOAc–hexane (3:7 then
4:6) afforded 15 (15.8 g, 86%) as a white crystalline solid,
mp 107–1098C. [a]2D4¼þ23.8 (c 1.6, CHCl3). IR (KBr)
4.1.3. Allyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-
deoxy-2-C-formyl-a-D-mannopyranoside (13) and allyl
2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-C-
hydroxymethyl-a-D-mannopyranoside (14). To a solution
of alcohol 11 8.9 g (80.8 mmol) in DMSO (100 ml) was
added DBU (13.3 ml, 88.9 mmol) at 08C. After stirring for
3 h at room temperature, to this reaction mixture was added
water (10 ml). The resulting mixture was poured into water
and extracted with ether. The combined organic layer was
washed with brine, dried over MgSO4 and filtered. The
filtrate was evaporated in vacuo to give 34.3 g of residue.
This residue was dissolved in HMPA (150 ml) to which
were added NaN3 (52.5 g, 808 mmol) and 15-crown-5
(3.2 ml, 16.2 mmol), and the mixture was stirred for 17 h
at 708C. The resulting mixture was poured into water
(200 ml) and extracted with ether. The combined
organic layer was washed with brine, dried over MgSO4
and filtered. The filtrate was evaporated in vacuo to give
37.3 g of a crude product. A small amount of this crude
product of the aldehyde 13 was purified by silica gel column
chromatography for an NOE experiment. Elution with
EtOAc–hexane (1:9) afforded aldehyde 13 as a colorless
oil.
1
3411, 2128 cm21. H NMR (CDCl3) d 1.06 (s, 9H), 2.58
(brs, 1H), 3.13 (d, 1H, J¼3.9 Hz), 3.56 (d, 1H, J¼8.8 Hz),
3.63 (dt, 1H, J¼9.8, 3.9 Hz), 3.80–3.88 (m, 3H), 3.93–4.00
(m, 2H), 4.04 (dt, 1H, J¼4.9, 9.8 Hz), 4.22 (dd, 1H, J¼5.9,
12.7 Hz), 4.41 (d, 1H, J¼11.7 Hz), 4.65 (d, 1H, J¼11.7 Hz),

T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
8785
5.07 (s, 1H), 5.19 (d, 1H, J¼10.7 Hz), 5.26 (d, 1H, J¼
18.6 Hz), 5.86 (ddt, 1H, J¼10.7, 18.6, 4.9 Hz), 7.03–7.08
(m, 2H), 7.10–7.14 (m, 3H), 7.35–7.41 (m, 4H), 7.41–7.47
(m, 2H), 7.62 (d, 2H, J¼6.8 Hz), 7.69 (d, 2H, J¼6.8 Hz).
13C NMR (125 MHz, CDCl3) d 19.11, 26.65 (3C), 62.25,
64.28, 68.56, 69.00, 69.63, 72.00, 75.75, 80.13, 97.13,
117.47, 127.66 (2C), 127.74 (2C), 127.78, 127.85 (2C),
128.30 (2C), 129.66, 129.84, 132.25, 132.77, 133.29,
135.47 (2C), 135.68 (2C), 137.38. HRMS (FAB, positive-
ion), calcd for C33H41N3O6SiNa: (MþNa)þ 626.2662;
found: 626.2664.
(10 ml) was placed in a two-necked flask and the air was
replaced with a hydrogen atmosphere. After stirring for
5 min, the color of the solution turned to colorless from red,
then the hydrogen was replaced with nitrogen. To the
reaction mixture was added a solution of 16 (10.6 g,
12.6 mmol) in THF (12 ml) via cannula, and this solution
was stirred for 2.5 h at room temperature. Evaporation of the
reaction mixture in vacuo afforded a residue, which was
dissolved in THF (15 ml) and H2O (5 ml). To this solution
was added NBS (2.7 g, 15.1 mmol) at 08C, and the mixture
was stirred for 2 h. The reaction mixture was quenched with
sat. NaHCO3 (5 ml) and sat. Na2S2O3 (5 ml). The resulting
mixture was diluted with ether, which was washed with
water and brine, dried over MgSO4 and filtered. The filtrate
was evaporated in vacuo to give a crude product, which was
purified by silica gel column chromatography. Elution with
AcOEt–hexane (7:93 then 1:9) afforded 17 (8.26 g, 82%) as
a colorless oil. [a]2D4¼þ12.6 (c 1.2, CHCl3). IR (neat) 3428,
2120 cm21. 1H NMR (CDCl3) d 0.08 (s, 3H), 0.11 (s, 3H),
0.92 (s, 9H), 1.04 (s, 9H), 2.72 (d, 1H, J¼2.9 Hz), 3.69 (d,
1H, J¼8.8 Hz), 3.71 (d, 1H, J¼9.8 Hz), 3.76–3.82 (m, 4H,
involving a singlet at d 3.78), 3.82–3.94 (m, 3H), 4.00
(t, 1H, J¼8.8 Hz), 5.40 (d, 1H, J¼3.9 Hz), 6.85 (d, 2H,
J¼8.8 Hz), 7.03–7.08 (m, 2H), 7.09–7.14 (m, 3H), 7.19–
7.24 (m, 2H), 7.34–7.48 (m, 6H), 7.63 (d, 2H, J¼6.8 Hz),
7.67 (d, 2H, J¼7.8 Hz). 13C NMR (125 MHz, CDCl3) d
25.34, 25.17, 18.36, 19.15, 25.91 (3C), 26.71 (3C), 55.22,
62.46, 65.09, 69.55, 72.94, 74.79, 75.59, 76.36, 78.76,
92.23, 113.86 (2C), 127.69 (2C), 127.71, 127.75 (2C),
128.05 (2C), 128.23 (2C), 129.60 (2C), 129.72,
129.79, 130.44, 132.49, 132.75, 135.58 (2C), 135.63 (2C),
137.41, 159.25. HRMS (FAB, positive-ion), calcd for
C44H58N3O7Si2: (M2H)þ 796.3813; found: 796.3824.
4.1.5. Allyl 2-azido-3-O-benzyl-6-O-(tert-butyldimethyl-
silyl)-2-C-(tert-butyldiphenylsilyloxymethyl)-2-deoxy-4-
O-(p-methoxybenzyl)-a-D-mannopyranoside (16). To a
solution of diol 15 (15.6 g, 25.8 mmol) and imidazole
(5.3 g, 77.5 mmol) in DMF (30 ml) was added TBDMS-Cl
(4.1 g, 27.1 mmol). After stirring for 2 h at 08C, to this
reaction mixture was added sat. NaHCO3 (10 ml). The
resulting mixture was diluted with ether, which was washed
with water and brine, dried over MgSO4 and filtered. The
filtrate was evaporated in vacuo to give 18.5 g of a residue.
This residue was dissolved in DMF (30 ml). PMB-Cl
(7.0 ml, 51.6 mmol) was added to this solution. After
cooling the solution to 2238C, to this mixture was slowly
added 55 wt% NaH (1.2 g, 28.4 mmol). After stirring for
5 h, the reaction mixture was quenched with 1 M aq. NaOH
(10 ml). The resulting mixture was diluted with ether, which
was washed with water and brine, dried over MgSO4 and
filtered. The filtrate was evaporated in vacuo to give 26.2 g
of a crude product, which was dissolved in THF (25 ml).
To this solution were added 1 M aq. NaOH (20 ml)
and 15-crown-5 (0.5 ml) to convert excess PMB-Cl to
PMB-OH. After observance of the disappearance of
PMB-Cl by TLC monitoring, the reaction mixture was
diluted with ether, which was washed with water and brine,
dried over MgSO4 and filtered. The filtrate was evaporated
in vacuo to give a crude product, which was purified by
silica gel column chromatography. Elution with EtOAc–
hexane (3:97 then 1:19) afforded 16 (13.9 g, 64%) as a
colorless oil. [a]2D4¼þ34.5 (c 0.64, CHCl3). IR (neat)
2124 cm21. 1H NMR (CDCl3) d 0.09 (s, 3H), 0.11 (s, 3H),
0.93 (s, 9H), 1.03 (s, 9H), 3.59–3.66 (m, 2H), 3.69 (d, 1H,
J¼10.3 Hz), 3.76–3.90 (m, 6H, involving a singlet at d
3.79), 4.23 (dd, 1H, J¼5.1, 12.4 Hz), 4.31 (d, 1H, J¼
11.0 Hz), 4.59 (d, 1H, J¼12.4 Hz), 4.73 (d, 2H, J¼11.0 Hz),
5.14 (s, 1H), 5.18 (dd, 1H, J¼1.5, 10.3 Hz), 5.23 (dd, 1H,
J¼1.5, 16.8 Hz), 5.86 (ddt, 1H, J¼10.3, 16.8, 5.1 Hz), 6.86
(d, 2H, J¼8.8 Hz), 6.98–7.10 (m, 5H), 7.22 (d, 2H, J¼
8.1 Hz), 7.33–7.50 (m, 6H), 7.58–7.63 (m, 2H), 7.66–7.72
(m, 2H). 13C NMR (125 MHz, CDCl3) d 25.35, 25.22,
18.23, 19.05, 25.83 (3C), 26.60 (3C), 55.20, 62.09,
65.11, 68.18, 69.77, 72.91, 74.88, 75.66, 76.33, 79.31,
96.35, 113.87 (2C), 117.07, 127.64 (2C), 127.73, 127.75
(2C), 128.18 (2C), 129.58 (2C), 129.63 (2C), 129.75,
130.40, 132.35, 132.76, 133.50, 135.49 (2C), 135.66 (2C),
137.29, 159.30. HRMS (FAB, positive-ion), calcd for
C47H63N3O7Si2Na: (MþNa)þ 860.4102; found: 860.4108.
4.1.7. (2S,3R,4S,5R)-N-Methyl-2-azido-3-benzyloxy-6-
(tert-butyldimethylsilyloxy)-2-(tert-butyldiphenylsilyloxy-
methyl)-4-(p-methoxybenzyloxy)hexanoamide (18). To a
solution of 17 (1.87 g, 2.3 mmol) in CH2Cl2 (5 ml) was
added Dess–Martin periodinane (1.50 g, 3.5 mmol) at 08C
and this solution was stirred for 5 min. After further stirring
for 2 h at room temperature, to this reaction mixture were
slowly added sat. NaHCO3 (5 ml) and sat. Na2S2O3 (5 ml).
The resulting mixture was diluted with ether, which was
washed with water and brine, dried over MgSO4 and
filtered. The filtrate was evaporated in vacuo to give 1.80 g
of a residue, which was dissolved in MeOH (5 ml). To this
solution was added 40% solution of MeNH2 in MeOH
(5 ml). After stirring for 1.5 h at room temperature, the
solvent of the reaction mixture was removed in vacuo to
give a crude product, which was purified by silica gel
column chromatography. Elution with AcOEt–hexane (1:9
then 3:17) afforded 18 (1.85 g, 94%) as a white solid, mp
85–878C. [a]2D4¼þ35.3 (c 1.0, CHCl3). IR (KBr) 3317,
2130, 1650 cm21. 1H NMR (CDCl3) d 0.06 (s, 3H), 0.07 (s,
3H), 0.90 (s, 9H), 1.03 (s, 9H), 2.68 (d, 1H, J¼6.6 Hz), 2.79
(d, 3H, J¼5.1 Hz), 3.57 (dd, 1H, J¼2.2, 8.1 Hz), 3.66–3.75
(m, 3H), 3.79 (s, 3H), 4.09 (s, 2H), 4.37–4.45 (m, 3H), 4.63
(d, 1H, J¼10.3 Hz), 4.78 (d, 1H, J¼11.0 Hz), 6.81–6.89
(m, 3H), 7.09–7.26 (m, 7H), 7.34–7.47 (m, 6H), 7.61 (dd,
2H, J¼1.5, 7.3 Hz), 7.66 (dd, 2H, J¼1.5, 8.1 Hz). 13C NMR
(125 MHz, CDCl3) d 25.37, 25.35, 18.22, 19.16, 25.87
(3C), 26.59 (3C), 55.18, 63.39, 65.73, 71.56, 73.57, 74.28,
75.33, 77.91, 79.69, 113.64 (2C), 127.53, 127.63 (2C),
4.1.6. 2-Azido 3-O-benzyl-6-O-(tert-butyldimethylsilyl)-
2-C-(tert-butyldiphenylsilyloxymethyl)-2-deoxy-4-O-(p-
methoxybenzyl)-a-D-mannopyranoside (17). A solution
of [Ir(C8H12)(MePPh2)2]PF6 (0.2 g, 0.24 mmol) in THF

8786
T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
127.74 (4C), 128.07, 128.19 (2C), 129.42 (2C), 129.75,
129.84, 130.53, 132.46, 132.59, 135.51 (2C), 135.56
(2C), 137.59, 159.10, 169.26. HRMS (FAB, positive-ion),
calcd for C45H63N4O7Si2: (MþH)þ 827.4235; found:
827.4232.
AcOEt–hexane (1:9) afforded 20 (1.31 g, 85%) as a
colorless oil. [a]2D4¼21.5 (c 0.6, CHCl3). IR (neat) 3438,
1
2127, 1681, 1515, 1250 cm21. H NMR (CDCl3) d 0.00 (s,
9H), 0.06 (s, 3H), 0.07 (s, 3H), 0.87 (m, 11H, involving a
singlet at d 0.93), 0.17 (s, 9H), 2.86 (d, 3H, J¼4.8 Hz), 3.42
(br, t, 1H, J¼7.8 Hz), 3.54 (dt, 1H, J¼5.9, 10.3 Hz), 3.70–
3.79 (m, 4H), 3.81 (s, 3H), 3.90 (dd, 1H, J¼1.8, 6.6 Hz), 4.15
(d, 1H, J¼10.5 Hz), 4.18 (d, 1H, J¼6.6 Hz), 4.25 (d, 1H, J¼
10.5 Hz), 4.37 (d, 1H, J¼11.7 Hz), 4.50 (d, 1H, J¼10.5 Hz),
4.75–4.84 (m, 3H), 4.88 (d, 1H, J¼11.7 Hz), 6.81 (d, 2H,
J¼8.5 Hz), 6.84 (q, 1H, J¼4.8 Hz), 7.05–7.11 (m, 2H),
7.17–7.26 (m, 5H), 7.41–7.52 (m, 6H), 7.65 (d, 2H, J¼
7.1 Hz), 7.72 (d, 2H, J¼7.8 Hz). 13C NMR (125 MHz,
CDCl3) d 25.49, 25.46, 21.44 (3C), 18.11 (2C), 19.19,
25.86 (3C), 26.41, 26.59 (3C), 55.17, 61.94, 65.40, 65.72,
74.25, 74.72, 75.00, 76.10, 79.49, 79.70, 96.39, 113.49 (2C),
127.23, 127.46 (2C), 127.73 (2C), 127.75 (2C), 128.07 (2C),
129.71, 129.85, 130.07 (2C), 130.82, 132.51, 132.69, 135.55
(2C), 135.60 (2C), 138.14, 159.05, 168.58. HRMS (FAB,
positive-ion), calcd for C51H76N4O8Si3Na: (MþNa)þ
979.4869; found: 979.4861.
4.1.8. (2S,3R,4S,5S)-N-Methyl-2-azido-3-benzyloxy-6-
(tert-butyldimethylsilyloxy)-2-(tert-butyldiphenylsilyloxy-
methyl)-5-hydroxy-4-(p-methoxybenzyloxy)hexano-
amide (19). To a solution of oxalyl chloride (0.36 ml,
4.1 mmol) in CH2Cl2 (5 ml) was slowly added DMSO
(0.58 ml, 8.2 mmol) at 2788C. After stirring for 10 min, to
this mixture was added a solution of 18 (1.68 g, 2.03 mmol)
in CH2Cl2 (5 ml) via cannula and the mixture was stirred for
1 h at 2788C. To this resulting mixture was slowly added
Et3N (2.3 ml, 16.4 mmol), and this mixture was stirred for
30 min at 08C. The resulting mixture was diluted with ether,
which was washed with water and brine, dried over MgSO4
and filtered. The filtrate was evaporated in vacuo to give
1.83 g of residue, which was dissolved in THF (5 ml) and
slowly transferred into a 1.0 M solution of L-Selectride in
THF (6.0 ml, 6.0 mmol) via cannula at 2788C. After
stirring for 30 min, to this reaction mixture were added
1 M aq. NaOH (2 ml) and 40% aq. H2O2 (2 ml). After
stirring for 30 min at room temperature, the resulting
mixture was quenched with sat. Na2S2O3 (1 ml). The
resulting mixture was diluted with ether, which was washed
with water and brine, dried over MgSO4 and filtered. The
filtrate was evaporated in vacuo to give a crude product,
which was purified by silica gel column chromatography.
Elution with AcOEt–hexane (1:9 then 3:17) afforded 19
(1.38 g, 82%) as a colorless oil. [a]2D4¼þ12.8 (c 0.50,
4.1.10. Physical data of (2S,3R,4S,5S)-N-methyl-2-azido-
3-benzyloxy-6-(tert-butyldimethylsilyloxy)-2-(tert-butyl-
diphenylsilyloxymethyl)-4-hydroxy-5-[2-(trimethylsilyl)-
ethoxymethoxy]hexanoamide (21). [a]2D4¼211.2 (c 1.1,
1
CHCl3). IR (neat) 3539, 3435, 3370, 2127, 1681 cm21. H
NMR (CDCl3) d 0.00 (s, 3H), 0.02 (s, 3H), 0.89 (s, 9H), 1.04
(s, 9H), 2.84 (d, 3H, J¼5.1 Hz), 3.02 (d, 1H, J¼5.9 Hz),
3.44–3.49 (m, 1H), 3.55 (ddd, 1H, J¼6.6, 9.5, 10.3 Hz),
3.69 (ddd, 1H, J¼6.6, 9.5, 10.3 Hz), 3.72–3.83 (m, 3H),
4.08 (d, 1H, J¼10.3 Hz), 4.12 (d, 1H, J¼3.7 Hz), 4.17 (d,
1H, J¼10.3 Hz), 4.37 (d, 1H, J¼11.0 Hz), 4.74 (d, 1H, J¼
11.0 Hz), 4.80 (s, 2H), 6.86 (q, 1H, J¼5.1 Hz), 7.08–7.12
(m, 2H), 7.20–7.24 (m, 3H), 7.37–7.48 (m, 6H), 7.63
(d, 2H, J¼6.8 Hz), 7.67 (d, 2H, J¼6.8 Hz). 13C NMR
(125 MHz, CDCl3) d 25.44 (2C), 21.46 (3C), 15.24, 18.11,
18.23, 19.19, 25.88 (3C), 26.34, 26.62 (3C), 63.45, 65.08,
65.81, 70.09, 75.33, 75.66, 78.63, 79.55, 95.19, 127.57 (2C),
127.78 (2C), 127.80 (2C), 128.35 (2C), 129.80, 129.91,
132.41, 132.53, 135.59 (2C), 135.61 (2C), 137.53, 169.00.
HRMS (FAB, positive-ion), calcd for C43H69N4O7Si3:
(MþH)þ 837.4474; found: 837.4476.
4.1.11. Physical data of (10S,3S,4R,5S)-3-azido-4-benzyl-
oxy-3-(tert-butyldiphenylsilyloxymethyl)-5-(10,20-di-
hydroxyethyl)-2-oxo-tetrahydrofuran (22). 1H NMR
(CDCl3) d 1.12 (s, 9H), 1.96 (br, 1H), 2.88 (br, 1H), 3.67
(t, 2H, J¼5.4 Hz), 3.84 (d, 1H, J¼10.3 Hz), 4.00 (d, 1H,
J¼10.3 Hz), 4.08–4.13 (m, 1H), 4.40 (d, 1H, J¼5.6 Hz),
4.47 (d, 1H, J¼11.0 Hz), 4.60 (t, 1H, J¼4.7 Hz), 4.93 (d,
1H, J¼11.0 Hz), 7.28–7.34 (m, 5H), 7.38–7.55 (m, 6H),
7.63–7.70 (m, 4H). MS (FAB, positive-ion) m/z, 584
(MþNa)þ; 600 (MþK)þ.
1
CHCl3). IR (neat) 3433, 2128, 1737, 1677 cm21. H NMR
(CDCl3) d 0.04 (s, 6H), 0.89 (s, 9H), 1.03 (s, 9H), 2.54 (br, d,
1H, J¼5.9 Hz), 2.82 (d, 3H, J¼4.9 Hz), 3.41–3.47 (m, 1H),
3.49 (t, 1H, J¼7.8 Hz), 3.59 (dd, 1H, J¼5.9, 9.8 Hz), 3.76–
3.85 (m, 4H, involving a singlet at d 3.78), 4.06 (d, 1H,
J¼9.8 Hz), 4.17 (d, 1H, J¼10.7 Hz), 4.27 (d, 1H, J¼
6.8 Hz), 4.34 (d, 1H, J¼11.7 Hz), 4.48 (d, 1H, J¼10.7 Hz),
4.74 (d, 1H, J¼10.7 Hz), 4.79 (d, 1H, J¼11.7 Hz), 6.77–
6.85 (m, 3H), 7.01–7.07 (m, 2H), 7.14–7.22 (m, 3H), 7.35–
7.48 (m, 6H), 7.59 (d, 2H, J¼6.8 Hz), 7.66 (d, 2H,
J¼6.8 Hz). 13C NMR (125 MHz, CDCl3) d 25.48, 25.42,
18.08, 19.08, 25.80 (3C), 26.33, 26.52 (3C), 55.08 (2C),
63.57, 65.56, 71.58, 74.37, 74.56, 76.90, 80.57, 113.53 (2C),
127.36, 127.42 (2C), 127.70 (2C), 127.71 (2C), 128.11 (2C),
129.72, 129.78 (2C), 129.84, 130.45, 132.26, 132.41,
135.42 (2C), 135.51 (2C), 137.58, 159.09, 169.24. HRMS
(FAB, positive-ion), calcd for C45H63N4O7Si2: (MþH)þ
827.4235; found: 827.4239.
4.1.9. (2S,3R,4S,5S)-N-Methyl-2-azido-3-benzyloxy-6-
(tert-butyldimethylsilyloxy)-2-(tert-butyldiphenylsilyloxy-
methyl)-4-(p-methoxybenzyloxy)-5-[2-(trimethylsilyl)-
ethoxymethoxy]hexanoamide (20). To a solution of 19
(1.33 g, 1.61 mmol) in dichloroethane (5 ml) were added
EtN(i-Pr)2 (1.3 ml, 8.0 mmol) and SEM-Cl (0.85 ml,
4.8 mmol). After stirring for 4 h at 608C, the reaction
mixture was quenched with sat. NaHCO3 (2 ml). This
mixture was diluted with ether, which was washed with
water and brine, dried over MgSO4 and filtered. The filtrate
was evaporated in vacuo to give a crude product, which was
purified by silica gel column chromatography. Elution with
4.1.12. (2S,3R,4S,5S)-N,N-Dimethyl-2-azido-3-benzyl-
oxy-6-(tert-butyldimethylsilyloxy)-2-(tert-butyldiphenyl-
silyloxymethyl)-4-(p-methoxybenzyloxy)-5-[2-(tri-
methylsilyl)ethoxymethoxy]hexanoamide (23). To
a
solution of 20 (1.56 g, 1.63 mmol) in DMF (3 ml) were
added MeI (0.30 ml, 4.8 mmol) and 55 wt% of NaH (87 mg,
2.0 mmol) at 08C. After stirring for 1.5 h, the reaction
mixture was quenched with sat. NH4Cl (2 ml). The resulting

T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
8787
mixture was diluted with ether, which was washed with
water and brine, dried over MgSO4 and filtered. The filtrate
was evaporated in vacuo to give 1.62 g of a crude product,
which was purified by silica gel column chromatography.
Elution with AcOEt–hexane (1:19) afforded 23 (1.50 g,
97%) as a colorless oil. [a]2D4¼210.2 (c 0.5, CHCl3). IR
(neat) 2111, 1633, 1616 cm21. 1H NMR (CDCl3) d 0.00 (s,
9H), 0.05 (s, 6H), 0.91 (s, 9H), 1.10 (s, 9H), 2.93 (brs, 3H),
3.36 (brs, 3H), 3.55 (dt, 1H, J¼6.0, 9.8 Hz), 3.64 (dt, 1H,
J¼2.6, 9.8 Hz), 3.69–3.83 (m, 6H, involving a singlet at d
3.79), 3.90 (dd, 1H, J¼2.5, 5.5 Hz), 4.21 (d, 1H, J¼
10.6 Hz), 4.28 (d, 1H, J¼10.6 Hz), 4.33 (d, 1H, J¼5.5 Hz),
4.48 (d, 1H, J¼11.6 Hz), 4.51 (d, 1H, J¼10.6 Hz), 4.75
(d, 1H, J¼10.6 Hz), 4.82 (s, 2H), 4.86 (d, 1H, J¼11.6 Hz),
6.81 (d, 2H, J¼8.6 Hz), 7.13–7.18 (m, 2H), 7.19–7.28 (m,
5H), 7.36–7.50 (m, 6H), 7.67 (d, 2H, J¼6.5 Hz), 7.73 (d,
2H, J¼6.7 Hz). 13C NMR (125 MHz, CDCl3) d 25.51,
25.47, 21.46 (3C), 18.08, 18.09, 19.11, 25.84 (3C), 26.71
(3C), 38.78, 55.10 (2C), 62.42, 65.36, 67.46, 74.03, 75.03,
76.45, 79.55, 80.18, 96.14, 113.42 (2C), 127.14, 127.55
(2C), 127.71 (2C), 127.74 (2C), 128.02 (2C), 129.70, 129.79
(2C), 129.84, 131.01, 132.48, 132.58, 135.55 (2C), 135.61
(2C), 138.33, 158.92, 168.40. HRMS (FAB, positive-ion),
calcd for C52H78N4O8Si3K: (MþK)þ 1009.4765; found:
1009.4763.
(tert-butyldimethylsilyloxy)-10-[2-(trimethylsilyl)ethoxy-
methoxy]ethyl]-3-(tert-butyldiphenylsilyloxymethyl)-2-
oxo-tetrahydrofuran (25). To a solution of 24 (0.22 g,
0.27 mmol) in AcOEt (1 ml) was added 10% Pd–C (0.22 g)
and the air was replaced with hydrogen. After stirring for 3 h
at room temperature, the reaction mixture was filtered
through Celite. The filtrate was evaporated in vacuo to give
a crude amine, which was dissolved in CH2Cl2 (1 ml). To
this solution were added DMAP (10 mg), Et3N (0.11 ml,
0.82 mmol) and PhCOCl (63 ml, 0.55 mol). After stirring
for 1 h at room temperature, the reaction mixture was
quenched with sat. NaHCO3 (0.5 ml). The resulting mixture
was diluted with ether, which was washed with water and
brine, dried over MgSO4 and filtered. The filtrate was
evaporated in vacuo to give a crude product, which was
purified by silica gel column chromatography. Elution with
AcOEt–hexane (1:19) afforded 25 (0.21 g, 87%) as a
colorless oil. [a]2D4¼þ32.5 (c 0.5, CHCl3). IR (neat) 3422,
1
3352, 1783, 1668 cm21. H NMR (CDCl3) d 0.00 (s, 6H),
0.01 (s, 3H), 0.83–0.98 (m, 11H, involving a singlet at d
0.84), 1.01 (s, 9H), 3.65 (t, 2H, J¼8.3 Hz), 3.69 (dd, 1H,
J¼3.9, 11.1 Hz), 3.75 (dd, 1H, J¼3.1, 11.1 Hz), 4.06–4.09
(m, 1H), 4.29 (d, 1H, J¼10.0 Hz), 4.34 (d, 1H, J¼10.0 Hz),
4.49 (d, 1H, J¼11.3 Hz), 4.62 (d, 1H, J¼4.3 Hz), 4.66 (d,
1H, J¼11.3 Hz), 4.73 (d, 1H, J¼6.9 Hz), 4.77 (d, 1H,
J¼6.9 Hz), 4.93 (dd, 1H, J¼4.3, 7.5 Hz), 6.77 (broad s, 1H),
7.06–7.12 (m, 2H), 7.12–7.18 (m, 3H), 7.27–7.49 (m, 9H),
7.56–7.60 (m, 2H), 7.61 (d, 2H, J¼6.7 Hz), 7.66 (d, 2H,
J¼7.2 Hz). 13C NMR (125 MHz, CDCl3) d 25.49, 25.41,
21.42 (3C), 17.95, 18.20, 19.16, 25.86 (3C), 26.66 (3C),
62.87, 64.07, 65.35, 66.59, 74.40, 76.07, 79.74, 82.43,
94.97, 127.01 (2C), 127.52 (2C), 127.70, 127.74 (2C),
127.85 (2C), 128.24 (2C), 128.51 (2C), 129.88, 129.92,
131.87, 132.02, 132.02, 132.43, 133.56, 135.49 (2C),
135.61 (2C), 137.23, 167.61, 174.20. HRMS (FAB,
positive-ion), calcd for C49H70NO8Si3: (MþH)þ
884.4409; found: 884.4398.
4.1.13. (10S,3S,4R,5S)-3-Azido-4-benzyloxy-5-[20-(tert-
butyldimethylsilyloxy)-10-[2-(trimethylsilyl)ethoxy-
methoxy]ethyl]-3-(tert-butyldiphenylsilyloxymethyl)-2-
oxo-tetrahydrofuran (24). To a solution of 23 (1.49 g,
1.53 mmol) in CH2Cl2 (3 ml) was added H2O (0.5 ml) and
DDQ (0.42 g, 1.84 mmol) at 08C. After stirring for 3 h at
room temperature, to this reaction mixture was added 1 M
aq. NaOH (5 ml). This mixture was diluted with ether,
which was washed with water and brine, dried over MgSO4
and filtered. The filtrate was evaporated in vacuo to give
1.44 g of a crude alcohol, which was dissolved in toluene
(5 ml), and PPTS (0.78 g, 3.1 mmol) was added to this
solution. After stirring for 24 h at 708C, the reaction mixture
was quenched with sat. NaHCO3 (2 ml). The resulting
mixture was diluted with ether, which was washed with
water and brine, dried over MgSO4 and filtered. The filtrate
was evaporated in vacuo to give a crude product, which was
purified by silica gel column chromatography. Elution with
AcOEt–hexane (1:19) afforded 24 (0.83 g, 62%) as a
colorless oil. [a]2D4¼26.4 (c 0.6, CHCl3). IR (neat) 2120,
1785 cm21. 1H NMR (CDCl3) d 0.01 (s, 12H), 0.04 (s, 3H),
0.84–1.00 (m, 11H, involving a singlet at d 0.87), 1.07 (s,
9H), 3.57 (dt, 1H, J¼15.6, 5.9 Hz), 3.64–3.77 (m, 4H), 3.88
(d, 1H, J¼8.8 Hz), 3.96 (dd, 1H, J¼4.9, 10.7 Hz), 4.41 (d,
1H, J¼10.7 Hz), 4.45 (d, 1H, J¼5.9 Hz), 4.70 (d, 1H,
J¼6.8 Hz), 4.75 (d, 1H, J¼6.8 Hz), 4.85 (d, 1H, J¼4.9 Hz),
4.86 (d, 1H, J¼5.9 Hz), 7.28–7.38 (m, 5H), 7.38–7.50 (m,
6H), 7.60–7.70 (m, 4H). 13C NMR (125 MHz, CDCl3) d
25.49, 25.40, 21.46, 17.99, 18.26, 19.18, 25.89 (3C),
26.70 (3C), 55.51, 62.31, 65.33, 65.58, 69.82, 74.33,
75.65, 77.82, 80.14, 95.03, 114.27, 127.93 (2C), 127.94
(2C), 128.00 (2C), 128.22, 128.55 (2C), 130.14, 131.75,
131.92, 131.97, 135.56 (2C), 135.57 (2C), 136.54, 171.69.
HRMS (FAB, positive-ion), calcd for C42H63N3O7Si3Na:
(MþNa)þ 828.3872; found: 828.3859.
4.1.15. (10S,3S,4R,5S)-3-Benzamido-4-benzyloxy-3-(tert-
butyldiphenylsilyloxymethyl)-5-[20-hydroxy-10-[2-(tri-
methylsilyl)ethoxymethoxy]ethyl]-2-oxo-tetrahydro-
furan (26). To a solution of 25 (0.21 g, 0.24 mmol) in
acetone (1.2 ml) was added 5% aq. H2SO4 (0.2 ml). After
stirring for 3 h at room temperature, the reaction mixture
was quenched with sat. NaHCO3 (0.5 ml). The resulting
mixture was evaporated in vacuo, and diluted with ether,
which was washed with water and brine, dried over MgSO4
and filtered. The filtrate was evaporated in vacuo to give a
crude product, which was purified by silica gel column
chromatography. Elution with AcOEt–hexane (3:17)
afforded 26 (0.15 g, 82%) as a colorless oil. [a]2D4¼þ30.3
(c 0.6, CHCl3). IR (neat) 3426, 1784, 1667 cm21. 1H NMR
(CDCl3) d 0.01 (s, 9H), 0.86–1.00 (m, 2H), 1.02 (s, 9H),
2.78 (broad s, 1H), 3.46–3.52 (m, 1H), 3.58–3.70 (m, 2H),
3.74 (dt, 1H, J¼11.0, 6.0 Hz), 4.08–4.11 (m, 1H), 4.26
(d, 1H, J¼10.3 Hz), 4.29 (d, 1H, J¼10.3 Hz), 4.48 (d, 1H,
J¼11.1 Hz), 4.58 (d, 1H, J¼4.1 Hz), 4.63 (d, 1H, J¼
11.1 Hz), 4.77 (d, 1H, J¼7.0 Hz), 4.81 (d, 1H, J¼7.0 Hz),
4.83 (dd, 1H, J¼4.1, 8.5 Hz), 6.72 (brs, 1H), 7.05–7.09 (m,
2H), 7.12–7.18 (m, 3H), 7.30–7.50 (m, 9H), 7.58 (d, 2H,
J¼7.9 Hz), 7.62 (d, 2H, J¼7.9 Hz), 7.67 (d, 2H, J¼7.1 Hz).
13C NMR (125 MHz, CDCl3) d 21.47 (3C), 18.05, 19.15,
26.66 (3C), 62.04, 64.29, 65.92, 66.56, 74.64, 78.53, 79.55,
4.1.14. (10S,3S,4R,5S)-3-Benzamido-4-benzyloxy-5-[20-

8788
T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
81.89, 95.57, 127.00 (2C), 127.77 (2C), 127.82 (2C),
128.87, 127.93 (2C), 128.29 (2C), 128.55 (2C), 123.00,
130.04, 131.89, 131.96, 132.24, 133.37, 135.52 (2C),
135.59 (2C), 136.87, 167.53, 174.14. HRMS (FAB,
positive-ion), calcd for C43H56NO8Si2: (MþH)þ
770.3544; found: 770.3542.
further stirring for 1 h at room temperature, to the reaction
mixture was added H2O (0.5 ml). The resulting mixture was
diluted with ether, which was washed with water and brine,
dried over MgSO4 and filtered. The filtrate was evaporated
in vacuo to give a crude product, which was purified by
silica gel column chromatography. Elution with AcOEt–
hexane (0:10 then 1:9) afforded 29 (60 mg, 94%) as a
colorless oil. [a]2D4¼þ50.9 (c 0.3, CHCl3). IR (neat) 3423,
1787, 1668 cm21. 1H NMR (CDCl3) d 0.02 (s, 9H), 0.88 (t,
3H, J¼6.8 Hz), 0.88–0.96 (m, 2H), 1.02 (s, 9H), 1.20–1.38
(m, 16H), 1.53–1.62 (m, 4H), 2.00 (q, 2H, J¼7.8 Hz), 3.54
(dt, 1H, J¼5.9, 9.8 Hz), 3.79 (dt, 1H, J¼6.8, 9.8 Hz), 3.92
(s, 4H), 4.26 (d, 1H, J¼9.8 Hz), 4.36 (d, 1H, J¼10.7 Hz),
4.44 (d, 1H, J¼10.7 Hz), 4.48 (d, 1H, J¼2.9 Hz), 4.52 (t,
1H, J¼8.3 Hz), 4.60 (d, 1H, J¼11.7 Hz), 4.66 (dd, 1H, J¼
2.9, 7.8 Hz), 4.69 (d, 1H, J¼6.8 Hz), 4.73 (d, 1H, J¼
6.8 Hz), 5.28 (dd, 1H, J¼7.8, 15.6 Hz), 5.78 (dt, 1H, J¼6.8,
15.6 Hz), 6.80 (s, 1H), 7.04–7.10 (m, 2H), 7.13–7.18
(m, 3H), 7.30–7.51 (m, 9H), 7.58 (d, 2H, J¼7.8 Hz), 7.63
(d, 2H, J¼7.8 Hz), 7.66 (d, 2H, J¼7.8 Hz). 13C NMR
(125 MHz, CDCl3) d 21.38 (3C), 14.09, 17.92, 19.19,
22.61, 23.78, 23.81, 26.67 (3C), 28.96, 29.33, 29.61,
29.76, 31.84, 32.54, 37.14, 37.17, 63.73, 64.88 (2C),
65.15, 66.88, 74.18, 74.38, 79.73, 84.65, 92.00, 111.81,
123.80, 127.06 (2C), 127.18 (2C), 127.50, 127.78 (2C),
127.91 (2C), 128.16 (2C), 128.53 (2C),129.91, 129.99,
131.90, 132.12, 132.43, 133.52, 135.58 (2C), 135.64 (2C),
137.50, 138.62, 167.63, 174.32. HRMS (FAB, positive-ion),
calcd for C59H83NO9Si2Na: (MþNa)þ 1028.5504; found:
1028.5482.
4.1.16. (20E,10S,3S,4R,5R)-3-Benzamido-4-benzyloxy-3-
(tert-butyldiphenylsilyloxymethyl)-5-[30-iodo-10-[2-(tri-
methylsilyl)ethoxymethoxy]prop-20-en-10-yl]-2-oxo-
tetrahydrofuran (27). To a solution of 26 (80 mg,
0.10 mmol) in CH2Cl2 was added Dess–Martin periodinane
(89 mg, 0.21 mmol) at 08C. After stirring for 1.5 h at room
temperature, the reaction mixture was quenched with sat.
NaHCO3 (0.2 ml) and sat. Na2S2O3 (0.2 ml). The resulting
mixture was diluted with ether, which was washed with
water and brine, dried over MgSO4 and filtered. The filtrate
was evaporated in vacuo to give a residue, which was
dissolved in THF (1 ml). To this solution was added CHI3
(0.12 g, 0.31 mmol). To a suspension of CrCl2 (77 mg,
0.63 mmol) in THF (0.6 ml) was added this solution via
cannula at 08C. After stirring for 1 h, the reaction mixture
was further stirred for 2 h at room temperature and
quenched with H2O (1 ml). The resulting mixture was
diluted with ether, which was washed with water and brine,
dried over MgSO4 and filtered. The filtrate was evaporated
in vacuo to give a crude product, which was purified by
silica gel column chromatography. Elution with AcOEt–
hexane (0:10 then 1:9) afforded 27 (48 mg, 52%) as a
colorless oil. [a]2D4¼þ29.6 (c 0.7, CHCl3). IR (neat) 3420,
1
3318, 1783, 1667 cm21. H NMR (CDCl3) d 0.02 (s, 9H),
0.83–0.96 (m, 2H), 1.02 (s, 9H), 3.54 (dt, 1H, J¼10.7,
6.8 Hz), 3.70 (dt, 1H, J¼10.7, 5.9 Hz), 4.27 (s, 2H), 4.34 (d,
1H, J¼10.7 Hz), 4.45–4.47 (m, 2H), 4.60–4.65 (m, 2H),
4.67 (d, 1H, J¼6.8 Hz), 4.69 (d, 1H, J¼6.8 Hz), 6.31–6.40
(m, 2H, involving a doublet at d 6.37, J¼13.6 Hz), 6.75 (s,
1H), 7.04–7.10 (m, 2H), 7.14–7.19 (m, 3H), 7.29–7.50 (m,
9H), 7.56 (d, 2H, J¼6.8 Hz), 7.61 (d, 2H, J¼6.8 Hz), 7.66
(d, 2H, J¼7.8 Hz). 13C NMR (125 MHz, CDCl3) d 21.39
(3C), 17.89, 19.16, 26.70 (3C), 64.19, 65.43, 66.64, 74.69,
76.18, 79.50, 83.35, 83.38, 93.08, 127.04 (2C), 127.41
(2C), 127.79, 127.85 (2C), 127.99, 128.11 (2C), 128.33
(2C), 128.58 (2C), 130.04, 130.11, 131.94, 132.02,
132.27, 133.28, 135.55 (2C), 135.62 (2C), 137.07, 140.37,
167.56, 174.00. HRMS (FAB, positive-ion), calcd for
C44H55INO7Si2: (MþH)þ 892.2562; found: 892.2568.
4.1.17. (20E,10S,3S,4R,5R)-3-Benzamido-4-benzyloxy-3-
(tert-butyldiphenylsilyloxymethyl)-5-[100,100-ethylene-
dioxy-10-[2-(trimethylsilyl)ethoxymethoxy]hexadec-20-
en-10-yl]-2-oxo-tetrahydrofuran (29). To a solution of
7,7-ethylenedioxy-1-tridecene (91 mg, 0.38 mmol) in THF
(0.1 ml) was added 0.5 M solution of 9-borabicyclo[3.3.1]-
nonane (9-BBN) in THF (0.38 ml, 0.19 mmol). After
stirring for 2 h at room temperature, the reaction mixture
was treated with distilled water (22 ml) and stirred for
10 min. This reaction mixture was added to a solution of 27
(56 mg, 0.06 mmol), Ph3As (1.8 mg, 0.006 mmol) and
Cs2CO3 (0.20 g, 0.63 mmol) in DMF (0.1 ml) via cannula,
which was washed with DMF (0.40ml). After cooling to 08C,
to this mixture was added [1,1 -bis(diphenylphosphino)-
4.1.18. (20E,10S,3S,4R,5R)-3-Benzamido-4-benzyloxy-3-
hydroxymethyl-5-(10-hydroxy-100-oxo-hexadec-20-en-10-
yl)-2-oxo-tetrahydrofuran (30). To a solution of 29
(16 mg, 0.016 mmol) in acetone (0.3 ml) was added 5%
aq. H2SO4 (40 ml). After stirring for 5 h at room
temperature, the reaction mixture was quenched with sat.
NaHCO3 (0.1 ml). The resulting mixture was diluted with
ether, which was washed with water and brine, dried over
MgSO4 and filtered. The filtrate was evaporated in vacuo to
give a residue, which was dissolved in THF (0.2 ml). To this
solution was added HF–Py complex (0.1 ml). The mixture
was stirred for 5 h at room temperature and quenched with
sat. NaHCO3 (0.5 ml). The resulting mixture was diluted
with ether, which was washed with water and brine, dried
over MgSO4 and filtered. The filtrate was evaporated in
vacuo to give a crude product, which was purified by silica
gel column chromatography. Elution with MeOH–CHCl3
(0:10 then 1:19) afforded 30 (6.3 mg, 67%) as a colorless
oil. [a]2D4¼þ34.5 (c 0.2, CHCl3). IR (neat) 3364, 1777,
1
1710, 1656 cm21. H NMR (CDCl3) d 0.89 (t, 3H, J¼
6.8 Hz), 1.22–1.42 (m, 12H), 1.49–1.62 (m, 4H), 2.01–
2.06 (m, 2H), 2.38 (t, 4H, J¼7.8 Hz), 2.69 (brs, 1H), 3.87 (t,
1H, J¼11.7 Hz), 4.19 (d, 1H, J¼12.7 Hz), 4.46–4.62 (m,
4H), 4.85 (d, 1H, J¼3.8 Hz), 5.23 (d, 1H, J¼9.8 Hz), 5.50
(dd, 1H, J¼15.6, 6.8 Hz), 5.85 (dt, 1H, J¼15.6, 6.8 Hz),
7.07 (s, 1H), 7.08–7.14 (m, 2H), 7.18–7.25 (m, 3H), 7.43
(t, 2H, J¼7.8 Hz), 7.56 (t, 1H, J¼6.8 Hz), 7.75 (d, 2H, J¼
6.8 Hz). 13C NMR (125 MHz, CDCl3) d 14.02, 22.49,
23.76, 23.85, 28.62, 28.91, 28.93, 28.99, 31.60, 32.28,
42.70, 42.83, 65.74, 68.20, 70.64, 74.74, 78.00, 84.15,
126.07, 127.25 (2C), 127.81 (2C), 128.21, 128.51 (2C),
128.84 (2C), 132.61, 132.78, 136.50, 136.52, 169.75,
ferrocene]dichloropalladium
(PdCl2(dppf))
(5.0 mg,
0.006 mmol) and the mixture was stirred for 1 h. After

T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
8789
173.73, 211.66. HRMS (FAB, positive-ion), calcd for
C35H47NO7Na: (MþNa)þ 616.3250; found: 616.3238.
4.1.21. (10S,3S,4R,5S)-3-Benzamido-4-benzoyloxy-5-[20-
(tert-butyldimethylsilyloxy)-10-[2-(trimethylsilyl)ethoxy-
methoxy]ethyl]-3-(tert-butyldiphenylsilyloxymethyl)-2-
oxo-tetrahydrofuran (36). To a solution of 34 (0.24 g,
0.34 mmol) in AcOEt (1 ml) was added 10% Pd–C (0.20 g)
and air was replaced with a hydrogen. After stirring for 14 h
at room temperature, the reaction mixture was filtered
through Celite. The filtrate was evaporated in vacuo to give
a residue, which was dissolved in CH2Cl2 (1 ml). To this
solution were added DMAP (10 mg), Et3N (0.19 ml,
1.36 mmol) and PhCOCl (0.11 ml, 1.02 mmol). After
stirring for 2 h at room temperature, the reaction mixture
was quenched with sat. NaHCO3 (0.5 ml). The resulting
mixture was diluted with ether, which was washed with
water and brine, dried over MgSO4 and filtered. The filtrate
was evaporated in vacuo to give a crude product, which was
purified by silica gel column chromatography. Elution with
AcOEt–hexane (1:19 then 3:17) afforded 36 (0.24 g, 80%)
as a colorless oil. [a]D24¼þ28.8 (c 1.5, CHCl3). IR (neat)
4.1.19. (20E,10S,3S,4R,5R)-3-Benzamido-4-hydroxy-3-
hydroxymethyl-5-(10-hydroxy-100-oxo-hexadec-20-en-10-
yl)-2-oxo-tetrahydrofuran (31). To a solution of 30
(5.8 mg, 0.01 mmol) in CH2Cl2 (0.1 ml) was slowly added
1.0 M BCl3 solution in CH2Cl2 (20 ml, 0.02 mmol) at
2788C. After stirring for 1 h, the reaction mixture was
quenched with sat. NaHCO3 (0.1 ml). The resulting mixture
was diluted with ether, which was washed with water and
brine, dried over MgSO4 and filtered. The filtrate was
evaporated in vacuo to give a crude product, which was
purified by thin layer chromatography on silica gel (Silica
gel 60 F254, 0.5 mm, Merck). Development with MeOH–
CHCl3 (1:9) (Rf¼0.223) afforded 31 (0.8 mg, 16%) as a
white powder. [a]2D4¼þ24.5 (c 0.5, CHCl3). IR (KBr) 3604,
3418, 1782, 1705, 1652 cm21. 1H NMR (CDCl3) d 0.87 (t,
3H, J¼6.8 Hz), 1.20–1.36 (m, 6H), 1.37–1.66 (m, 8H),
2.05–2.15 (m, 2H), 2.35 (dt, 2H, J¼2.0, 6.8 Hz), 2.39 (t,
2H, J¼7.8 Hz), 2.69 (brs, 1H), 3.93–4.12 (m, 3H, involving
a doublet at d 4.06, J¼10.7 Hz), 4.57 (dd, 1H, J¼5.9,
3.9 Hz), 4.66 (t, 1H, J¼5.9 Hz), 4.92 (brs, 1H), 5.61 (dd,
1H, J¼6.8, 15.6 Hz), 5.93 (dt, 1H, J¼15.6, 6.8 Hz), 7.00 (s,
1H), 7.47 (t, 2H, J¼7.8 Hz), 7.57 (t, 1H, J¼6.8 Hz), 7.82 (d,
2H, J¼8.8 Hz). 13C NMR (125 MHz, CDCl3) d 14.02,
22.47, 23.76, 23.78, 25.97, 28.20, 28.37, 28.68, 28.88,
31.56, 31.91, 42.65, 42.77, 64.44, 67.77, 70.96, 72.34,
84.67, 126.34, 127.35 (2C), 128.80 (2C), 132.44, 132.67,
135.60, 169.52, 173.93, 212.92. HRMS (FAB, positive-
ion), calcd for C28H42NO7: (MþH)þ 504.2961; found:
504.2962.
1
3432, 3347, 1788, 1726, 1673 cm21. H NMR (CDCl3) d
0.00 (s, 6H), 0.04 (s, 9H), 0.85 (s, 9H), 0.88–1.06 (m, 2H),
1.12 (s, 9H), 3.69 (dt, 1H, J¼5.9, 9.8 Hz), 3.77 (dt, 1H,
J¼5.9, 9.8 Hz), 3.80–3.88 (m, 2H), 4.11 (d, 1H, J¼9.8 Hz),
4.21–4.26 (m, 1H), 4.27 (d, 1H, J¼9.8 Hz), 4.86 (d, 1H, J¼
6.8 Hz), 4.93 (d, 1H, J¼6.8 Hz), 5.14 (dd, 1H, J¼5.9,
8.8 Hz), 6.25 (d, 1H, J¼5.9 Hz), 6.32 (s, 1H), 7.18 (t, 2H,
J¼7.8 Hz), 7.27–7.51 (m, 12H), 7.67 (d, 2H, J¼6.8 Hz),
7.71–7.72 (m, 2H), 7.90 (d, 2H, J¼7.8 Hz). 13C NMR
(125 MHz, CDCl3) 25.63, 25.59, 21.44 (3C), 17.95,
18.24, 19.19, 25.85 (3C), 26.71 (3C), 63.60, 64.35, 65.40,
65.51, 72.49, 76.35, 80.21, 95.49, 126.77 (2C), 127.92 (2C),
127.99 (2C), 128.14 (2C), 128.29 (2C), 128.57, 129.78 (2C),
130.09, 130.11, 131.43, 131.60, 131.96, 132.72, 133.38,
135.48 (2C), 135.65 (2C), 165.18, 166.48, 172.73. HRMS
(FAB, positive-ion), calcd for C49H68NO9Si3Na: (MþH)þ
920.4021; found: 920.4019.
4.1.20. (10S,3S,4R,5S)-3-Azido-5-[20-(tert-butyldimethyl-
silyloxy)-10-[2-(trimethylsilyl)ethoxymethoxy]ethyl]-3-
(tert-butyldiphenylsilyloxymethyl)-4-hydroxy-2-oxo-
tetrahydrofuran (34). To a solution of 24 (0.44 g,
0.55 mmol) and NaBrO3 (0.25 g, 1.64 mmol) in AcOEt
(2 ml) and H2O (1 ml) was slowly added 1.64 M NaHSO3
solution in H2O (1.0 ml, 1.64 mmol) at 08C and the mixture
was stirred for 10 min. After further stirring for 1 h at room
temperature, the reaction mixture was quenched with sat.
Na2S2O3 (0.5 ml). The resulting mixture was diluted with
ether, which was washed with water and brine, dried over
MgSO4 and filtered. The filtrate was evaporated in vacuo to
give a crude product, which was purified by silica gel
column chromatography. Elution with AcOEt–hexane
(1:19) afforded 34 (0.83 g, 61%) as a colorless oil. [a]2D4¼
þ14.3 (c 1.5, CHCl3). IR (neat) 3426, 2126, 1786 cm21. 1H
NMR (CDCl3) d 0.03 (s, 9H), 0.12 (s, 6H), 0.88–1.03 (m,
11H, involving a singlet at d 0.91), 1.06 (s, 9H), 3.03–3.72
(m, 3H), 3.80 (d, 1H, J¼10.7 Hz), 3.85–3.92 (m, 3H,
involving a doublet at d 3.87, J¼10.7 Hz), 4.09 (dt, 1H,
J¼3.9, 7.8 Hz), 4.48 (dd, 1H, J¼3.9, 6.8 Hz), 4.54 (t, 1H,
J¼4.9 Hz), 4.77 (d, 1H, J¼6.8 Hz), 4.81 (d, 1H, J¼6.8 Hz),
7.38–7.49 (m, 3H), 7.61–7.66 (m, 2H). 13C NMR
(125 MHz, CDCl3) d 25.64, 25.62, 21.46 (3C), 18.07,
18.23, 19.18, 25.80 (3C), 26.66 (3C), 62.91, 65.12,
65.84, 69.75, 71.73, 75.31, 83.23, 95.23, 127.98 (2C),
127.99 (2C), 130.18, 130.19, 131.75, 131.91, 135.50 (2C),
135.55 (2C), 171.72. HRMS (FAB, positive-ion), calcd
for C35H57N3O7Si3Na: (MþNa)þ 738.3402; found:
738.3400.
4.1.22. (10S,3S,4R,5S)-3-Benzamido-4-benzoyloxy-3-
(tert-butyldiphenylsilyloxymethyl)-5-[20-hydroxy-10-[2-
(trimethylsilyl)ethoxymethoxy]ethyl]-2-oxo-tetrahydro-
furan (37). To a solution of 36 (0.22 g, 0.24 mmol) in
acetone (1 ml) was added 5% aq. H2SO4 (0.2 ml). After
stirring for 13 h at room temperature, the reaction mixture
was quenched with sat. NaHCO3 (0.5 ml). The resulting
mixture was evaporated in vacuo and diluted with ether,
which was washed with water and brine, dried over MgSO4
and filtered. The filtrate was evaporated in vacuo to give a
crude product, which was purified by silica gel column
chromatography. Elution with AcOEt–hexane (2:8 then
1:3) afforded 37 (0.16 g, 87%) as a colorless oil. [a]2D4¼
þ31.0 (c 0.8, CHCl3). IR (neat) 3430, 1789, 1726,
1
1672 cm21. H NMR (CDCl3) d 0.02 (s, 9H), 0.86–1.13
(m, 2H), 1.11 (s, 9H), 2.87 (br, 1H), 3.64 (dt, 1H, J¼10.7,
5.9 Hz), 3.80 (dt, 1H, J¼10.7, 5.9 Hz), 4.07 (d, 1H, J¼
9.8 Hz), 4.20–4.26 (m, 1H), 4.28 (d, 1H, J¼9.8 Hz), 4.87
(d, 1H, J¼6.8 Hz), 4.90 (d, 1H, J¼6.8 Hz), 4.99 (dd, 1H,
J¼8.8, 5.9 Hz), 6.18 (d, 1H, J¼5.9 Hz), 6.27 (s, 1H), 7.18 (t,
2H, J¼7.8 Hz), 7.28 (t, 3H, J¼7.3 Hz), 7.31–7.50 (m, 9H),
7.66 (d, 2H, J¼6.8 Hz), 7.70 (d, 2H, J¼6.8 Hz), 7.88 (d, 2H,
J¼7.8 Hz). 13C NMR (125 MHz, CDCl3) 21.50 (3C),
18.03, 19.18, 26.69 (3C), 62.61, 64.14, 65.66, 65.99, 72.40,
78.43, 79.48, 95.90, 126.75 (2C), 127.98 (2C), 128.05 (2C),
128.21 (2C), 128.29, 128.36 (2C), 129.78 (2C), 130.19,

8790
T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
130.20, 131.38, 131.72, 131.83, 132.57, 133.54, 135.50
(2C), 135.66 (2C), 165.30, 166.60, 172.85. HRMS
(FAB, positive-ion), calcd for C43H53NO9Si2K: (MþK)þ
822.2896; found: 822.2893.
purified by silica gel column chromatography. Elution with
AcOEt–hexane (0:10 then 1:9) afforded 39 (58 mg, 81%) as
a colorless oil. [a]2D4¼þ43.5 (c 0.7, CHCl3). IR (neat) 3433,
3348, 1790, 1726, 1676 cm21. 1H NMR (CDCl3) d 0.04 (s,
9H), 0.88 (t, 3H, J¼6.8 Hz), 0.90–1.05 (m, 2H), 1.06–1.20
(m, 12H), 1.52–1.62 (m, 4H), 1.79–1.90 (m, 2H), 3.60 (dt,
J¼9.8, 5.9 Hz), 3.83 (dt, 1H, J¼10.7, 5.9 Hz), 3.91 (s, 4H),
4.06 (d, 1H, J¼10.7 Hz), 4.23 (d, 1H, J¼10.7 Hz), 4.53 (t,
1H, J¼8.8 Hz), 4.70 (dd, 1H, J¼4.9, 8.8 Hz), 4.74 (d, 1H,
J¼7.8 Hz), 4.76 (d, 1H, J¼2.8 Hz), 5.18 (dd, 1H, J¼8.8,
15.6 Hz), 5.56 (dt, 1H, J¼6.8, 15.6 Hz), 6.08 (d, 1H, J¼
5.9 Hz), 6.38 (s, 1H), 7.19 (t, 2H, J¼7.8 Hz), 7.27–7.35 (m,
3H), 7.38–7.50 (m, 9H), 7.69 (t, 4H, J¼6.8 Hz), 7.89 (d, 2H,
J¼7.8 Hz). 13C NMR (125 MHz, CDCl3) d 21.38 (3C),
14.07, 17.92, 19.21, 22.58, 23.72, 23.79, 26.79 (3C), 28.59,
29.21, 29.59, 29.72, 31.82, 32.34, 37.14, 37.15, 40.10, 40.13,
64.43, 64.85 (2C), 65.21, 74.72, 82.24, 92.08, 111.81, 123.23,
126.80 (2C), 128.00 (2C), 128.07 (2C), 128.26 (2C), 128.30
(2C), 128.82, 129.83 (2C), 130.21, 130.25, 131.56, 131.61,
131.94, 133.04, 133.30, 135.57 (2C), 135.77 (2C), 138.88,
164.54, 166.34, 172.58. HRMS (FAB, positive-ion), calcd for
C59H81NO10Si2K: (MþK)þ 1058.5036; found: 1058.5015.
4.1.23. (20E,10S,3S,4R,5R)-3-Benzamido-4-benzoyloxy-3-
(tert-butyldiphenylsilyloxymethyl)-5-[30-iodo-10-[2-(tri-
methylsilyl)ethoxymethoxy]prop-20-en-10-yl]-2-oxo-
tetrahydrofuran (38). To a solution of 37 (0.157 g,
0.20 mmol) in CH2Cl2 (0.5 ml) was added Dess–Martin
periodinane (0.21 g, 0.50 mmol) at 08C. After stirring for
1.5 h at room temperature, the reaction mixture was
quenched with sat. NaHCO3 (0.5 ml) and sat. Na2S2O3
(0.5 ml). The resulting mixture was diluted with ether,
which was washed with water and brine, dried over MgSO4
and filtered. The filtrate was evaporated in vacuo to give a
residue, which was dissolved in THF (1 ml). To this solution
was added CHI3 (0.24 g, 0.60 mmol). To a suspension of
CrCl2 (0.15 g, 1.2 mmol) in THF (1.2 ml) was added this
solution via cannula at 0 8C. After stirring for 1 h, the
reaction mixture was further stirred for 2 h at room
temperature, and quenched with H2O (1 ml). The resulting
mixture was diluted with ether, which was washed with
water and brine, dried over MgSO4 and filtered. The filtrate
was evaporated in vacuo to give a crude product, which was
purified by silica gel column chromatography. Elution with
AcOEt–hexane (0:10 then 3:17) afforded 38 (0.12 g, 80%)
as a colorless oil. [a]D24¼þ17.8 (c 0.7, CHCl3). IR (neat)
4.1.25. (20E,10S,3S,4R,5R)-3-Benzamido-4-benzoyloxy-3-
hydroxymethyl-5-(10-hydroxy-100-oxo-hexadec-20-en-10-
yl)-2-oxo-tetrahydrofuran (40). To a solution of 39
(34.1 mg, 0.033 mmol) in acetone (0.5 ml) was added 5%
aq. H2SO4 (0.1 ml). After stirring for 5 h at room
temperature, the reaction mixture was quenched with sat.
NaHCO3 (0.1 ml) and diluted with ether, which was washed
with water and brine, dried over MgSO4 and filtered. The
filtrate was evaporated in vacuo to give a residue, which
was dissolved in THF (0.2 ml). To this solution was added
HF–pyridine complex (60 ml) and the mixture was stirred
for 5.5 h at room temperature. The reaction mixture was
quenched with sat. NaHCO3 (0.5 ml) and diluted with ether,
which was washed with water and brine, dried over MgSO4
and filtered. The filtrate was evaporated in vacuo to give a
crude product, which was purified by silica gel column
chromatography. Elution with MeOH–CHCl3 (0:10 then
1:19) afforded 40 (11.5 mg, 58%) as a colorless oil.
[a]2D4¼þ27.7 (c 0.4, CHCl3). IR (neat) 3961, 3605, 3423,
1
3431, 3386, 1792, 1729, 1675 cm21. H NMR (CDCl3) d
0.00 (s, 9H), 0.84–1.00 (m, 2H), 1.09 (s, 9H), 3.58 (dt, 1H,
J¼9.8, 5.9 Hz), 3.72 (dt, 1H, J¼9.8, 5.9 Hz), 4.00 (d, 1H,
J¼9.8 Hz), 4.21 (d, 1H, J¼9.8 Hz), 4.56 (dd, 1H, J¼5.9,
8.8 Hz), 4.62 (dd, 1H, J¼5.9, 8.8 Hz), 4.70 (d, 1H, J¼
6.8 Hz), 4.78 (d, 1H, J¼6.8 Hz), 6.02 (d, 1H, J¼4.9 Hz),
6.29–6.38 (m, 3H), 7.17 (t, 2H, J¼7.8 Hz), 7.20–7.34 (m,
4H), 7.34–7.48 (m, 8H), 7.66 (d, 4H, J¼6.8 Hz), 7.85 (d,
2H, J¼7.8 Hz). 13C NMR (125 MHz, CDCl3) 21.40 (3C),
17.89, 19.18, 26.79 (3C), 63.96, 65.43, 65.52, 71.31, 76.29,
80.89, 83.18, 93.34, 126.81 (2C), 128.07 (2C), 128.11 (2C),
128.29 (2C), 128.39 (2C), 128.44, 129.85 (2C), 130.27,
130.34, 131.39, 131.75, 131.81, 132.70, 133.50, 135.52
(2C), 135.79 (2C), 140.01, 164.83, 166.41, 172.21. HRMS
(FAB, positive-ion), calcd for C44H52INO8Si2 K: (MþK)þ
944.1913; found: 944.1901.
1
1787, 1737, 1711, 1667 cm21. H NMR (CDCl3) d 0.88
(t, 3H, J¼6.8 Hz), 1.12–1.22 (m, 12H), 1.24–1.34 (m, 4H),
1.45–1.59 (m, 4H), 1.88–1.94 (m, 2H), 2.36 (t, 2H, J¼
7.8 Hz), 2.38 (t, 2H, J¼7.8 Hz), 4.09 (d, 1H, J¼11.7 Hz),
4.18 (d, 1H, J¼11.7 Hz), 4.68 (t, 1H, J¼6.2 Hz), 4.84 (t, 1H,
J¼5.9 Hz), 5.49 (dd, 1H, J¼6.8, 15.6 Hz), 5.72 (dt, 1H, J¼
6.8, 15.6 Hz), 6.11 (d, 1H, J¼5.9 Hz), 6.81 (s, 1H), 7.24 (t,
2H, J¼7.8 Hz), 7.33 (t, 2H, J¼7.8 Hz), 7.38 (t, 1H, J¼
7.8 Hz), 7.50 (t, 1H, J¼7.8 Hz), 7.51 (d, 2H, J¼7.8 Hz),
7.89 (d, 2H, J¼7.8 Hz). 13C NMR (125 MHz, CDCl3)
14.02, 22.48, 23.71, 23.83, 28.29, 28.67, 28.87, 28.91,
31.58, 32.05, 42.70, 42.82, 64.88, 65.13, 70.68, 71.54,
82.69, 125.94, 127.04 (2C), 128.25, 128.45 (2C), 128.55
(2C), 129.80 (2C), 132.17, 132.35, 133.82, 136.45, 165.22,
168.29, 172.82, 212.16. HRMS (FAB, positive-ion), calcd
for C35H46NO8: (MþH)þ 608.3223; found: 608.3240.
4.1.24. (20E,10S,3S,4R,5R)-3-Benzamido-4-benzoyloxy-3-
(tert-butyldiphenylsilyloxymethyl)-5-[100,100-ethylene-
dioxy-10-[2-(trimethylsilyl)ethoxymethoxy]hexadec-20-
en-10-yl]-2-oxo-tetrahydrofuran (39). To a solution of
7,7-ethylenedioxo-1-tridecene (0.10 g, 0.42 mmol) in THF
(0.1 ml) was added 0.5 M 9-BBN solution in THF (0.42 ml,
0.21 mmol). After stirring for 2 h at room temperature, the
reaction mixture was treated with distilled water (25 ml) and
stirred for 10 min. This solution was added to a solution of
38 (64 mg, 0.07 mmol), Ph3As (2.1 mg, 0.007 mmol) and
Cs2CO3 (0.23 g, 0.70 mmol) in DMF (0.5 ml) via cannula.
After cooling at 0 8C, to the mixture was added PdCl2(dppf)
(5.7 mg, 0.007 mmol) and this mixture was stirred for 1 h.
After further stirring for 1 h at room temperature, to the
reaction mixture was added H2O (0.5 ml). The resulting
mixture was diluted with ether, which was washed with
water and brine, dried over MgSO4 and filtered. The filtrate
was evaporated in vacuo to give a crude product, which was
4.1.26. (6E,2S,3R,4R,5S)-2-Amino-2-hydroxymethyl-14-
oxo-3,4,5-trihydroxyeicos-6-enoic acid (1) (sphingofungin
E). To a solution of diol 40 (11.0 mg, 0.018 mmol) in
dioxane (0.2 ml) and H2O (0.2 ml) was added NaOH

T. Nakamura, M. Shiozaki / Tetrahedron 58 (2002) 8779–8791
8791
4. For total synthesis of sphingofungin D, see: (a) Chida, N.;
Ikemoto, H.; Noguchi, A.; Amano, S.; Ogawa, S. Nat. Prod.
Lett. 1995, 6, 295. (b) Mori, K.; Otaka, K. Tetrahedron Lett.
1994, 35, 9207. For total synthesis of sphingofungin B and F,
see: (c) Otaka, K.; Mori, K. Eur. J. Org. Chem. 1999,
1795–1802. (d) Kobayashi, S.; Matsumura, M.; Furuta, T.;
Hayashi, T.; Iwamoto, S. Synlett 1997, 301. (e) Kobayashi, S.;
Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada, K. J. Am.
Chem. Soc. 1998, 120, 908–919, see also 4256. (f) Kobayashi,
S.; Furuta, T. Tetrahedron 1998, 54, 10275–10294.
5. For total synthesis of sphingofungin E, see: (a) Wang, B.; Yu,
X.-M.; Lin, G.-Q. Synlett 2001, 904–906. (b) Nakamura, T.;
Shiozaki, M. Tetrahedron Lett. 2001, 42, 2701–2704.
(c) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123,
12191–12201. (d) Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.;
Iida, M.; Chida, N. Org. Lett. 2002, 4, 151–154.
(2.2 mg, 0.055 mmol). After stirring for 7.5 h at 708C, the
reaction mixture was cooled to room temperature and acidic
resin (IR-120) was added to neutralize the pH of the
solution. The resulting mixture was filtered through Celite
and the filtrate was concentrated in vacuo to give a crude
product, which was purified by silica gel column chroma-
tography. Elution with CHCl3–MeOH–H2O (9:1:0 then
8:2:1) afforded 1 (6.7 mg, 88%) as a white powder, mp
145–1478C. [a]2D4¼25.43 (c 0.5, CH3OH). IR (KBr) 3532,
1
3198, 2928, 2855, 1711, 1637 cm21. H NMR (CD3OD) d
0.90 (t, 3H, J¼6.8 Hz), 1.26–1.44 (m, 12H), 1.49–1.58 (m,
4H), 2.05 (q, 2H, J¼6.8 Hz), 2.44 (t, 2H, J¼7.3 Hz), 2.45 (t,
2H, J¼7.3 Hz), 3.64 (d, 1H, J¼6.9 Hz), 3.85 (d, 1H, J¼
11.7 Hz), 3.94–4.00 (m, 2H, involving a doublet at d 3.97
J¼11.7 Hz), 4.11 (t, 1H, J¼7.3 Hz), 5.45 (dd, 1H, J¼7.8,
15.6 Hz), 5.77 (dt, 1H, J¼15.6, 6.8 Hz). 13C NMR
(125 MHz, CD3OD) 14.37, 23.58, 24.84, 24.86, 29.99,
30.01, 30.14, 30.16, 32.81, 33.42, 43.45, 43.48, 64.95,
70.03, 71.11, 75.52, 76.27, 130.14, 135.70, 173.42, 214.34.
HRMS (FAB, positive-ion), calcd for C21H40NO7: (MþH)þ
418.2805; found: 418.2806.
6. For total synthesis of sphingofungin F, see: Ref. 2c, (a) Trost,
B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818–6819.
(b) Liu, D.-G.; Wang, B.; Lin, G.-Q. J. Org. Chem. 2000, 65,
9114.
7. (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314–321. For a
recent review on the B-alkyl Suzuki–Miyaura cross-coupling
reaction, see: (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457. (c) Chemler, S. R.; Trauner, D.; Danishefsky, S. J.
Angew. Chem. Int. Ed. 2001, 40, 4544–4568.
References
1. Isolation of sphingofungins A–D: (a) VanMiddlesworth, F.;
Giacobbe, R. A.; Lopez, M.; Garrity, G.; Bland, J. A.; Bartizal,
K.; Fromtling, R. A.; Polishook, J.; Zweerink, M.; Edison,
A. M.; Rozdilsky, W.; Wilson, K. E.; Monaghan, R. A.
J. Antibiot. 1992, 45, 861–867. Structure elucidation:
(b) VanMiddlesworth, F.; Dufresne, C.; Wincott, F. E.;
Mosley, R. T.; Wilson, K. E. Tetrahedron Lett. 1992, 33,
297–300. Isolation of sphingofungins E and F: (c) Horn, W. S.;
Smith, T. L.; Bills, G. F.; Raghoobar, S. L.; Helms, G. L.;
Kurts, M. B.; Marrinan, J. A.; Frommer, B. R.; Thornton, R. A.;
Mandara, S. M. J. Antibiot. 1992, 45, 1692–1696.
8. (a) Sato, K.; Suzuki, K.; Ueda, M.; Katayama, M.; Kajihara, Y.
Chem. Lett. 1991, 1469–1472. (b) Sato, K.; Kajihara, Y.;
Nakamura, Y.; Yoshimura, J. Chem. Lett. 1991, 1559–1562.
9. (a) Deloisy, S.; Thang, T.; Olesker, A.; Lukacs, G.
Tetrahedron Lett. 1994, 35, 4783–4786. For a review on the
synthesis of branched-chain sugars, see: (b). In Preparative
Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker:
New York, 1997; pp 207–262.
10. Fukase, K.; Matsumoto, T.; Ito, N.; Yoshimura, T. Bull. Chem.
Soc. Jpn 1992, 65, 2643–2654.
2. (a) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki,
S.; Toyama, R.; Yoneta, M.; Hoshino, Y.; Okumoto, T.
J. Antibiot. 1994, 47, 208. (b) Miyake, Y.; Kozutsumi, Y.;
Nakamura, S.; Fujita, T.; Kawasaki, T. Biochem. Biophys. Res.
Commun. 1995, 211, 396.
11. a-Chloroepoxide 12 was obtained as a single diastereomer.
The stereochemistry of the newly formed chiral center
(a-position of the chloride) was not determined.
12. Preactivated [Ir(C8H12)(PMePh2)2]PF6 by hydrogen was used
as a catalyst. (a) Haines, L. M.; Singleton, E. J. Chem. Soc.,
Dalton Trans. 1972, 1891–1896. (b) Oltvoort, J. J.; van
Boeckel, C. A. A.; de Koning, J. H.; van Boom, J. H. Synthesis
1981, 305–308.
3. For total syntheses of myriocin, see: (a) Banfi, L.; Bretta,
M. G.; Colombo, L.; Gennari, C.; Scolastico, C. J. Chem. Soc.,
Chem. Commun. 1982, 488. (b) Banfi, L.; Bretta, M. G.;
Colombo, L.; Gennari, C.; Scolastico, C. J. Chem. Soc., Perkin
Trans. 1 1983, 1613. (c) Yoshikawa, M.; Yokokawa, Y.;
Okuno, Y.; Murakami, N. Chem. Pharm. Bull. 1994, 42, 994.
(d) Yoshikawa, M.; Yokokawa, Y.; Okuno, Y.; Murakami, N.
Tetrahedron 1995, 51, 6209. (e) Sano, S.; Kobayashi, Y.;
Kondo, T.; Takebayashi, M.; Maruyama, S.; Fujita, T.;
Nagano, Y. Tetrahedron Lett. 1995, 36, 2097. (f) Hatakeyama,
S.; Yoshida, M.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Kawamoto,
T.; Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1997, 45,
7887.
13. Takai, T.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
14. Other methods for cleavage of the benzyl group were
ineffective (e.g. Pd/C-H2, Li/NH3).
15. (a) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A.
Tetrahedron Lett. 1999, 40, 8439–8441. (b) Adinolfi, M.;
Guariniello, L.; Iadonisi, A.; Mangoni, L. Synlett 2000, 9,
1277–1278.