Total synthesis of sphingofungin E and 4,5-di-epi-sphingofungin E

Article abstract of DOI:10.1248/cpb.c17-00322

Total synthesis of sphingofungin E and 4,5-di-epi-sphingofungin E was achieved from an intermediate same as that of myriocin and mycestericin D via antipodal stereoselective dihydroxylations.

Full text of DOI:10.1248/cpb.c17-00322

Vol. 65, No. 7
Chem. Pharm. Bull. 65, 687–696 (2017)
687
Note
Total Synthesis of Sphingofungin E and 4,5-Di-epi-sphingofungin E
Narumi Noda, Hisanori Nambu, Tomoya Fujiwara, and Takayuki Yakura*
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama; Sugitani, Toyama 930–0194,
Japan.
Received April 18, 2017; accepted April 30, 2017
Total synthesis of sphingofungin E and 4,5-di-epi-sphingofungin E was achieved from an intermediate
same as that of myriocin and mycestericin D via antipodal stereoselective dihydroxylations.
Key words sphingofungin E; dihydroxylation; stereoselectivity; osmium tetroxide; total synthesis
Myriocin (1),1–4) mycestericin D (2),5,6) sphingofungins E moallylic functionality.55–62) Finally, cross metathesis reaction
(3),7) and F7) are classified as members of a unique family in with known alkene 663) would afford 3 and 4.
sphingosine-related natural products (Fig. 1). They have an ad-
The stereoselective dihydroxylation of 7 was investigated,
ditional carbon substituent at the C-2 position and contiguous as illustrated in Chart 3. First, we examined a reagent-
stereogenic centers. They act as antifungal and immunosup- controlled dihydroxylation method. The Wittig reaction of
pressive agents through the inhibitory activity of serine palmi- 545) afforded the α,β-unsaturated ester 7a46) (R=CO2Me). The
toyl transferase.8–12) Because of interesting structural features reactions of 7a with an AD-mix β under several conditions did
and potent biological activities, these natural products have not proceed at all, probably due to the steric hindrance of the
attracted considerable attention of synthetic organic chemists allylic and homoallylic substituents of 7a. Subsequently, we
and several total syntheses have already been reported.13–44) investigated dihydroxylation of 7a under usual reaction condi-
Recently, we reported total synthesis of 1 and 2 from the tions [using OsO4 and N-methylmorpholine N-oxide (NMO)].
same intermediate 5, which was derived from commercially The OsO4/NMO dihydroxylation usually results in diastere-
available diethyl D-tartrate using rhodium(II)-catalyzed C–H oselectivity under steric or stereoelectronic control.52–54) The
amination, following stereoselective vinylation45,46) (Chart 1). reaction of 7a with catalytic amounts of OsO4 in the presence
As part of our synthetic investigations of sphingosine natural of NMO proceeded with the complete facial selectivity to
products,47–51) herein, we report the total synthesis of 3 and produce diol 11 with 89% yield as a single diastereomer.64)
4,5-di-epi-sphingofungin E (4) from the intermediate 5 via Donohoe conditions [OsO4 and tetramethylethylenediamine
antipodal stereoselective dihydroxylations.
(TMEDA)]55–62) were tested with the expectation of antipodal
facial selectivity via a hydrogen-bonding mediated process.
The dihydroxylation of 7a under Donohoe conditions formed a
Results and Discussion
Our synthetic plan for 3 and 4 is illustrated in Chart 2. mixture of products; the major product was also diol 11. For-
By expanding the utility of our recently reported synthetic tunately, the mixture could be separated via chromatography
procedure45,46) for the synthesis of sphingosine natural prod- to afford 10 in 16% yield and 11 in 77% yield. The two-step
ucts having C-2 quaternary centers, we planned to investigate dedihydroxylation65) of 11 was achieved by thiocarbonation
the synthesis of the more structurally complicated analog 3 (93%) of diol and the following reduction of the resulting
and its 4,5-di-epimer 4 from the common intermediate 5. thiocarbonate 12 with P(OMe)3 (92%) to afford 7a which can
After conversion of aldehyde into alkene, the stereoselec- be used for reoxidation to 10 under Donohoe dihydroxylation
tive introduction of a diol group via dihydroxylation52–54) conditions.
of 7 would result in both vinyl intermediates 8 and 9. Such
Second, we investigated synthesis of 3 and 4 from 10 and
antipodal diastereoselectivity has already been demonstrated 11, respectively (Chart 4). The diol moiety of 10 was protected
in dihydroxylations of substrates having an allylic and/or ho- as an acetonide group by treatment with 2,2-dimethoxy-
Fig. 1. Structures of Sphingosine and Its Related Natural Products Having an Additional Carbon Substituent at the C-2 Position
*To whom correspondence should be addressed. e-mail: yakura@pha.u-toyama.ac.jp
© 2017 The Pharmaceutical Society of Japan

688
Chem. Pharm. Bull.
Vol. 65, No. 7 (2017)
Chart 1. Synthesis of Myriocin (1) and Mycestericin D (2) via Aldehyde 5
Chart 2. Synthetic Plan for 3 and 4
Chart 3. Dihydroxylation of 7a
propane in the presence of pyridinium p-toluenesulfonate the sequential oxidation of 15 (Swern oxidation, followed by
(PPTS) to produce 13. The ester group of 13 was reduced Pinnick oxidation) to carboxylic acid through 16, and the final
with diisobutylaluminum hydride (DIBAL-H), followed by deprotection of the amino and hydroxy groups with trifluoro-
the Wittig reaction to afford the terminal alkene 8a in 63% acetic acid (TFA) were achieved to synthesize sphingofungin
yield from 10. The resultant 8a required five equivalents of E (3), which was purified by the acetylation–deacetylation
663) in the presence of 30mol% of Grubbs second generation process via 17 (3: [α]D20 +49.8 (c=0.60, CHCl3); lit.33,34) [α]D23.2
catalyst to react with reflux methylene chloride due to its low +48.6 (c=0.27, CHCl3), 17: [α]D19 −6.17 (c=0.60, CH3OH);
reactivity against the cross-metathesis reaction. (E)-Alkene lit.31) [α]D24 −5.43 (c=0.48, CH3OH)). The diastereomeric diol
14 was selectively produced in 79% yield. The desilylation of 11 was also effectively converted into 4 in a similar manner.
14 with tetrabutylammonium fluoride (TBAF), followed by
The OsO4/TMEDA complex is known to function as a

Vol. 65, No. 7 (2017)
Chem. Pharm. Bull.
689
Reagents and conditions: (a) Me2C(OMe)2, PPTS, benzene; (b) DIBAL-H, CH2Cl2, −80°C; (c) Ph3PCH3Br, NaH, THF; (d) 6 (5eq), Grubbs 2nd (30mol%), CH2Cl2, re-
flux; (e) TBAF, THF, r.t.; (f) DMSO, (COCl)2, Et3N, CH2Cl2; (g) NaClO2, NaH2PO4·H2O, 2-methyl-2-butene, tert-BuOH–H2O; (h) TFA, THF–H2O; (i) Ac2O, pyridine, r.t.;
(j) 10% NaOH, MeOH; (k) Ph3PCH3Br, tert-BuOK, THF; (l) 6 (4eq), Grubbs 2nd (5mol%), CH2Cl2, reflux.
Chart 4. Synthesis of 3 and 4
Table 1. Dihydroxylation of Alkenes 18–24 under Donohoe Conditions
Entry
Alkene
R1
R2
Diol
Yield (%)
a:ba)
1
18
19
20
21
22
23
24
H
MOM
H
CO2Me
CO2Me
25b)
26b)
27
67
74
93
84
92
85
86
25b
2
26b
3
4c)
CH2OAc
CH2OAc
CH2OPiv
CH2OBz
CH2OBn
1:1.3
1:2.0
1:2.1
1:1.8
1:2.5
H
28
5
THP
H
29
6
7d)
30
H
31
a) Determined by the 1H-NMR spectrum of a mixture. b) Corresponding γ-lactone was obtained. c) OsO4 (2.2eq) and TMEDA (2.6eq) were used. d) OsO4 (3.3eq) and
TMEDA (3.9eq) were used.
hydrogen-bond acceptor to the dihydroxylate substrate directly Swern oxidation, followed by the Wittig reaction.
in the presence of potential hydrogen-bond donors, such as
In summary, we achieved total synthesis of 3 and 4 via the
allylic hydroxy groups.55–62) We investigated dihydroxylation same synthetic intermediate 5 by the antipodal stereoselec-
reactions of alcoholic compounds 18–24 under Donohoe con- tive dihydroxylation of alkene. The common dihydroxylation
ditions in order to achieve higher stereoselectivity. The results conditions resulted in complete stereoselectivity to afford diol
are summarized in Table 1. The oxidation of esters 18 and 19 11, which was converted into 4. Donohoe conditions exhibited
afforded lactones 25b and 26b with the same stereoselectivity the antipodal selectivity; the highest selectivity was obtained
as that in the reaction of 7a (Entries 1, 2). Additionally, the by the reaction of the dihydroxyallyl ether 20. Sphingofungin
similar reactions of allyl ethers 20–24 showed higher an- E (3) was synthesized from the antipodal diastereoisomers 10
tipodal stereoselectivity than those of 18 and 19, and formed and 27a.
1:1.3–1:2.5 mixtures of diastereofacial isomers 27–31 in high
yields (Entries 3–7). The resultant oxidized product was con-
verted into the sphingofungin E intermediate (Chart 5). The
Experimental
General Melting points are uncorrected. IR spectra were
acetonide protection of the 1:1.3 mixture of tetraols 27a and b recorded on a JASCO FT/IR-460 Plus spectrophotometer and
afforded chromatographically separable di-acetonide 32a and absorbance bands are reported in wavenumber (cm−1). All
b in 36 and 48% yields, respectively. The deacetylation of 32a NMR spectra were recorded using a JEOL JNM-ECX400P
with DIBAL-H reduction afforded alcohol 33, which was con- spectrometer. 1H-NMR spectra were recorded at 400MHz.
verted into the key intermediate of 3, terminal alkene 8a, via Chemical shifts are reported relative to internal standard

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Vol. 65, No. 7 (2017)
Reagents and conditions: (a) Me2C(OMe)2, PPTS, benzene; (b) DIBAL-H, CH2Cl2, −80°C; (c) DMSO, (COCl)2, Et3N, CH2Cl2; (d) Ph3PCH3Br, NaH, THF.
Chart 5. Conversion of 27 into 8a
(tetramethylsilane at δH 0.00, CDCl3 at δH 7.26, or CD3OD at (3×10mL). Filtrate was concentrated in vacuo, and the resi-
δH 3.31). Data are presented as follows: chemical shift (δ, ppm), due was purified by column chromatography (silica gel, 10%
multiplicity (s=singlet, d=doublet, t=triplet, m=multiplet, EtOAc in hexane) to provide 10 (40mg, 16%) as a colorless
br=broad), coupling constant and integration. 13C-NMR spec- oil and 11 (190mg, 77%) as a colorless oil. 10: 1H-NMR
tra were recorded on JEOL JNM-ECX400P (100MHz) spec- (400MHz, CDCl3) δ: 7.69–7.65 (4H, m), 7.45–7.36 (6H, m),
trometer. The following internal reference was used (CDCl3 6.41 (1H, s), 4.38 (3H, brs), 4.22 (1H, d, J=4.4Hz), 3.96 (1H, d,
at δ 77.0 or CD3OD at δ 49.0). All 13C-NMR spectra were J=10.4Hz), 3.83 (1H, m), 3.79 (3H, s), 3.28 (1H, d, J=10.8 Hz),
determined with complete proton decoupling. High-resolution 3.12 (1H, s), 1.42 (3H, s), 1.40 (3H, s), 1.37 (9H, s), 1.07 (9H,
(HR)-MS were determined with JEOL JMS-GCmate II and s). 13C-NMR (100MHz, CDCl3) δ: 173.4, 155.1, 135.7, 135.6,
JEOL JMS-AX505HAD instruments. Column chromatogra- 132.7, 132.6, 129.8, 127.8, 127.7, 99.3, 77.2, 71.4, 70.2, 68.5,
phy was performed on Silica Gel 60 PF254 (Nacalai Tesque, 63.4, 56.5, 52.6, 28.4, 27.9, 26.8, 19.6, 19.2. IR (film) cm−1:
Kyoto, Japan) and Kanto silica gel 60N (63–210 mesh) under 3506, 3388, 1740, 1713, 1511. FAB-MS m/z: 618.3123 (Calcd
pressure. Analytical TLC was carried out on Merck Kieselgel for C32H48NO9Si: 618.3098). [α]D26 −4.23 (c=0.5, CHCl3). 11:
60 F254 plates. Visualization was accomplished with UV light 1H-NMR (400MHz, CDCl3) δ: 7.65–7.63 (4H, m), 7.45–7.35
and phosphomolybdic acid stain solution followed by heating.
(6H, m), 5.32 (1H, s), 4.90 (1H, brs), 4.47 (1H, d, J=10.0 Hz),
All reagents are commercially available and were purchased 4.38 (1H, d, J=7.8Hz), 4.05 (1H, d, J=8.8Hz), 3.96–3.81 (4H,
from suppliers such as Sigma-Aldrich Co. (St. Louis, MO, m), 3.78 (3H, s), 2.86 (1H, d, J=7.8Hz), 1.43 (9H, s), 1.40 (6H,
U.S.A.); Wako Pure Chemical Industries, Ltd. (Osaka, Japan); s), 1.05 (9H, s). 13C-NMR (100MHz, CDCl3) δ: 174.2, 156.7,
Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan); Nacalai 135.61, 135.59, 132.8, 132.6, 129.84, 129.79, 127.8, 127.7, 99.2,
Tesque, Inc. Dehydrated CH2Cl2, THF, benzene, acetone, di- 80.1, 77.2, 71.9, 70.8, 66.7, 63.1, 56.6, 52.4, 28.2, 26.8, 19.3.
methyl sulfoxide (DMSO) and pyridine were purchased from IR (film) cm−1: 3540, 3431, 3381, 1747, 1692, 1511. FAB-MS
Wako Pure Chemical Industries, Ltd. and Kanto Chemical m/z: 618.3137 (Calcd for C32H48NO9Si: 618.3098). [α]D20 −6.70
Co., Inc. (Tokyo, Japan). Pentadec-1-en-9-one (6)63) was pre- (c=0.5, CHCl3).
pared according to literature procedures.
Methyl [2R,3S,3(4R,5R)]-3-[5-(tert-Butyldiphenylsilyl- oxy)methyl-2,2-dimethyl-5-(1,1-dimethylethoxycarbonyl)-
oxy)methyl-2,2-dimethyl-5-(1,1-dimethylethoxycarbonyl)- amino-1,3-dioxane-4-yl]-2,3-thiocarbonylbutanoate (12)
Methyl [2S,3SR,3(4R,5R)]-3-[5-(tert-Butyldiphenylsilyl-
amino-1,3-dioxane-4-yl]-2,3-dihydroxybutanoate (10) and 1,1′-Thiocarbonyldiimidazole (374mg, 2.1mmol) and N,N-
Methyl [2S,3R,3(4R,5R)]-3-[5-(tert-Butyldiphenylsilyloxy)- dimethyl-4-aminopyridine (DMAP) (64mg, 0.525mmol) were
methyl-2,2-dimethyl-5-(1,1-dimethylethoxycarbonyl)ami- added to a solution of diol 11 (650mg, 1.05mmol) in CH2Cl2
no-1,3-dioxane-4-yl]-2,3-dihydroxybutanoate (11) OsO4 (16mL). After stirring at reflux for 5h, the reaction mixture
(112mg, 0.44mmol) in CH2Cl2 (0.6mL) was added dropwise was quenched with saturated NH4Cl and the whole mixture
to a solution of α,β-unsaturated ester 7a46) (234mg, 0.40mmol) was extracted with EtOAc (3×10mL). The combined organic
and TMEDA (60mg, 0.52mmol) in CH2Cl2 (1.5mL) at −78°C. layers were washed with water (10mL) and brine (10mL),
After stirring for 1h, the solvent was removed in vacuo. and dried over anhydrous MgSO4. Filtrate was concentrated
NaHSO3 (230mg, 2.2mmol) was added to a solution of re- in vacuo, and the residue was purified by column chroma-
sulting residue in pyridine–H2O (1:1, 2.4mL). After stirring tography (silica gel, 10% EtOAc in hexane) to provide 12
1
at room temperature overnight, the reaction was quenched (646mg, 93%) as a colorless oil. H-NMR (400MHz, CDCl3)
with water and the whole mixture was extracted with EtOAc δ: 7.66–7.62 (4H, m), 7.46–7.40 (6H, m), 5.45 (1H, dd, J=4.4,

Vol. 65, No. 7 (2017)
Chem. Pharm. Bull.
691
2.8Hz), 5.38 (1H, d, J=4.4Hz), 5.05 (1H, s), 4.27 (1H, d, +8.30 (c=0.5, CHCl3).
J=2.8Hz), 4.00 (1H, d, J=10.8Hz), 3.94 (1H, d, J=10.8 Hz), [1R,1(4R,5R),2S,3E]-1-[5-(tert-Butyldiphenylsilyloxy)-
3.90 (1H, d, J=12.0Hz), 3.82 (3H, s), 3.80 (1H, d, J=12.0Hz), methyl-2,2-dimethyl-5-(1,1-dimethylethoxycarbonyl)-
1.43 (3H, s), 1.39 (3H, s), 1.38 (9H, s), 1.09 (9H, s). 13C-NMR amino-1,3-dioxane-4-yl]-1,2-isopropylidenedioxy-hep-
(100MHz, CDCl3) δ: 189.8, 166.5, 155.2, 135.64, 135.57, 132.3, tadec-3-en-11-one (14) Pentadec-1-en-9-one (6)63) (85mg,
132.1, 130.11, 130.10, 128.0, 100.7, 83.0, 80.4, 77.9, 72.4, 64.8, 0.405mmol) and second generation Grubbs catalyst (21mg,
63.6, 56.3, 53.3, 28.2, 27.1, 26.9, 20.2, 19.2. IR (film) cm−1: 0.0243mmol) were added to a solution of alkene 8a (51mg,
3430, 1759, 1712, 1504, 1163. FAB-MS m/z: 660.2645 (Calcd 0.081mmol) in CH2Cl2 (2.0mL). After stirring at reflux over-
for C33H46NO8SiS: 660.2662). [α]D20 +12.3 (c=0.5, CHCl3).
night, the solvent was removed in vacuo. The resulting residue
Conversion of 12 into 7a P(OMe)3 (6.0mL) was added to was purified by column chromatography (silica gel, 5% EtOAc
12 (646mg, 0.98mmol). After stirring at reflux for 5h, the sol- in hexane) to provide 14 (52mg, 79%) as a colorless oil.
vent was removed in vacuo. The resulting residue was purified 1H-NMR (400MHz, CDCl3) δ: 7.63–7.59 (4H, m), 7.45–7.36
by column chromatography (silica gel, 10% EtOAc in hexane) (6H, m), 6.34 (1H, s), 5.79 (1H, dt, J=14.7, 7.6Hz), 5.34 (1H,
to provide 7a (526mg, 92%) as a colorless oil.
dd, J=14.7, 8.4Hz), 4.45 (1H, dd, J=8.4, 8.0Hz), 4.37 (1H,
[1R,1(4R,5R),2S,3E]-1-[5-(tert-Butyldiphenylsilyloxy)- d, J=11.6Hz), 4.08–3.99 (3H, m), 3.95 (1H, d, J=11.6Hz),
methyl-2,2-dimethyl-5-(1,1-dimethylethoxycarbonyl)- 3.86 (1H, d, J=10.4Hz), 2.39–2.36 (4H, m), 1.98–1.94 (2H,
amino-1,3-dioxane-4-yl]-1,2-isopropylidenedioxy-3-butene m), 1.57–1.52 (4H, m), 1.44 (3H, s), 1.43 (3H, s), 1.42 (6H,
(8a) 2,2-Dimethoxypropane (64mg, 0.615mmol) and PPTS s), 1.32–1.23 (12H, m), 1.05 (9H, s), 0.88 (3H, t, J=6.8Hz).
(5mg, 0.0185mol) were added to a solution of 10 (38mg, 13C-NMR (100MHz, CDCl3) δ: 211.4, 155.1, 137.9, 135.6,
0.0615mmol) in benzene (1.4mL). After stirring at reflux 135.5, 132.8, 129.9, 127.73, 127.68, 126.2, 109.6, 99.5, 78.9,
for 2.5h, the reaction was quenched with 5% NaHCO3 and 78.5, 77.2, 67.2, 63.8, 63.3, 57.4, 42.8, 42.7, 32.3, 31.6, 29.0,
the whole mixture was extracted with EtOAc (3×5mL). The 28.9, 28.7, 28.4, 28.3, 27.5, 27.4, 27.1, 26.9, 26.2, 23.8, 23.7,
combined organic layers were washed with water (5mL) and 22.4, 20.5, 19.2, 14.0. IR (film) cm−1: 3402, 1722, 1713, 1516,
brine (5mL), and dried over anhydrous MgSO4. Filtrate was 971, 903. FAB-MS m/z: 822.5527 (Calcd for C48H76NO8Si:
concentrated in vacuo to provide crude product 13 (32mg), 822.5340). [α]D18 +0.97 (c=0.5, CHCl3).
which was used in the next step without further purification.
DIBAL-H (0.097mL, 0.097mmol) was added dropwise to ethoxycarbonyl)amino-5-hydroxylmethyl-1,3-dioxane-
a solution of crude 13 (32mg) in CH2Cl2 (1.0mL) at −78°C 4-yl]-1,2-isopropylidendioxy-heptadec-3-en-11-one (15)
[1R,1(4R,5S),2S,3E]-1-[2,2-Dimethyl-5-(1,1-dimethyl-
under nitrogen. After stirring for 1h, the reaction was Tetrabutylammonium fluoride (TBAF) (0.32mL, 1M in THF,
quenched with saturated potassium sodium tartrate and the 0.32mmol) was added to a solution of 14 (87mg, 0.106mmol)
whole mixture was extracted with EtOAc (3×5mL). The com- in THF (1.5mL) at 0°C. After stirring at room temperature
bined organic layers were washed with water (5mL) and brine for 24h, the reaction was quenched with water and the whole
(5mL), and dried over anhydrous MgSO4. Filtrate was concen- mixture was extracted with EtOAc (3×10mL). The combined
trated in vacuo, and the residue was filtered through a pad of organic layers were washed with water (10mL) and brine
Celite to provide crude aldehyde (29mg), which was used in (10mL), and dried over anhydrous MgSO4. Filtrate was con-
the next step without further purification.
centrated in vacuo, and the residue was purified by column
Ph3PCH3Br (191mg, 0.535mmol) was added slowly to a chromatography (silica gel, 10% EtOAc in hexane) to pro-
1
suspension of NaH (60% in mineral oil, 19mg, 0.486mmol) vide 15 (60mg, 97%) as a colorless oil. H-NMR (400MHz,
in THF (2.0mL) at 0°C. After stirring for 3h under nitro- CDCl3) δ: 6.07 (1H, s), 5.76 (1H, dt, J=15.5, 6.4Hz), 5.41
gen at room temperature, the reaction mixture was cooled (1H, dd, J=15.5, 8.5Hz), 4.45 (1H, brd, J=5.6Hz), 4.37 (1H,
to −80°C and crude aldehyde (29mg) in THF (1.0mL) was dd, J=8.8, 8.5Hz), 4.22 (1H, d, J=12.2Hz), 3.92 (1H, d,
added dropwise to the reaction mixture, and the resulting J=11.6Hz), 3.78 (1H, d, J=12.2Hz), 3.71 (1H, d, J=8.8Hz),
mixture was warmed to room temperature and stirred for 2h. 3.58 (2H, brs), 2.38 (4H, t, J=7.2Hz), 2.09–2.04 (2H, m),
The reaction mixture was quenched with saturated NH4Cl and 1.61–1.50 (4H, m), 1.49–1.34 (2H, m), 1.46 (9H, s), 1.44 (6H,
the whole mixture was extracted with EtOAc (3×5mL). The s), 1.40 (6H, s), 1.35–1.27 (10H, m), 0.88 (3H, t, J=6.8Hz,).
combined organic layers were washed with water (5mL) and 13C-NMR (100MHz, CDCl3) δ: 211.6, 157.1, 137.7, 126.4,
brine (5mL), and dried over anhydrous MgSO4. Filtrate was 109.8, 99.2, 79.8, 78.8, 78.4, 69.3, 66.0, 63.5, 56.3, 42.8, 42.7,
concentrated in vacuo, and the residue was purified by column 32.1, 31.6, 29.0, 28.9, 28.8, 28.7, 28.4, 28.3, 27.4, 26.0, 23.8,
chromatography (silica gel, 10% EtOAc in hexane) to pro- 23.7, 23.5, 22.5, 19.1. IR (film) cm−1: 3410, 1712, 970, 902.
1
vide 8a (24mg, 63% for 3 steps) as a colorless oil. H-NMR FAB-MS m/z: 583.4079 (Calcd for C32H57NO8: 583.4084). [α]D20
(400MHz, CDCl3) δ: 7.63–7.59 (4H, m), 7.45–7.35 (6H, m), +2.60 (c=0.5, CHCl3).
6.30 (1H, s), 5.71 (1H, ddd, J=16.8, 10.6, 8.0Hz), 5.35 (1H,
d, J=16.8Hz), 5.25 (1H, d, J=10.6Hz), 4.47 (1H, dd, J=8.4, ethoxycarbonyl)amino-5-formyl-1,3-dioxane-4-yl]-1,2-iso-
8.0Hz), 4.38 (1H, d, J=11.8Hz), 4.10–4.06 (2H, m), 3.99 (1H, propylidenedioxy-heptadec-3-en-11-one (16) solution
[1R,1(4R,5S),2S,3E]-1-[2,2-Dimethyl-5-(1,1-dimethyl-
A
d, J=10.6Hz), 3.95 (1H, d, J=11.8Hz), 3.87 (1H, d, J=10.6 Hz), of DMSO (48mg, 0.618mmol) in CH2Cl2 (0.3mL) was added
1.45 (6H, s), 1.42 (6H, s), 1.39 (9H, s), 1.05 (9H, s). 13C-NMR dropwise to a solution of oxalyl chloride (52mg, 0.412mmol)
(100MHz, CDCl3) δ: 155.1, 135.62, 135.55, 135.1, 132.84, in CH2Cl2 (0.6mL) at −78°C under nitrogen and stirred
132.79, 129.84, 129.80, 127.73, 127.70, 119.9, 110.1, 99.5, 78.9, for 5min. A solution of alcohol 15 (60mg, 0.103mmol) in
78.7, 78.4, 67.3, 63.8, 63.2, 57.3, 28.0, 27.3, 27.2, 26.9, 26.2, CH2Cl2 (0.7mL) was added dropwise to the reaction mix-
20.3. IR (film) cm−1: 3402, 3073, 1713, 1516, 990, 903. FAB- ture and stirred for 20min. A solution of Et3N (0.14mL,
MS m/z: 626.3543 (Calcd for C35H52NO7Si: 626.3513). [α]D21 1.03mmol) in CH2Cl2 (0.3mL) was added dropwise to the

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reaction mixture at −78°C. The reaction mixture was warmed (1.0mL) and stirring at 70°C for 2.5h. The reaction mixture
to −40°C and stirred for 1h. The reaction was quenched was cooled to 0°C, and then neutralized with Amberlite®
with saturated NH4Cl and the whole mixture was extracted IRC-86 (H+ type). The insoluble material was removed by fil-
with EtOAc (3×5mL). The combined organic layers were tration and the filtrate was concentrated in vacuo. The result-
washed with water (5mL) and brine (5mL), and dried over ing residue was purified by column chromatography (1:1:10
anhydrous MgSO4. Filtrate was concentrated in vacuo, and to 1:3:10 (gradient) H2O–MeOH–CHCl3 (lower phase)) to
the residue was purified by column chromatography (silica afford sphingofungin E (3) (12mg, 67%) as white crystals.
gel, 10% EtOAc in hexane) to provide 16 (44mg, 73%) as 1H-NMR (400MHz, CD3OD) δ: 5.77 (1H, dt, J=15.3, 6.8Hz),
1
a colorless oil. H-NMR (400MHz, CDCl3) δ: 9.69 (1H, s), 5.45 (1H, dd, J=15.3, 7.2Hz), 4.10 (1H, dd, J=7.2, 7.0Hz), 3.97
6.38 (1H, s), 5.74 (1H, m), 5.33 (1H, dd, J=15.0, 8.4Hz), 4.36 (1H, d, J=10.8Hz), 3.94 (1H, s), 3.85 (1H, d, J=10.8Hz), 3.64
(1H, t, J=8.4Hz), 4.18 (1H, s), 4.17 (1H, m), 3.81 (1H, s), 3.57 (1H, d, J=4.8Hz), 2.43 (4H, t, J=7.2Hz), 2.08–2.03 (2H, m),
(1H, d, J=8.4Hz), 2.39 (4H, t, J=7.2Hz), 2.06–2.01 (2H, m), 1.55–1.52 (4H, m), 1.42–1.28 (12H, m), 0.89 (3H, t, J=6.4Hz).
1.59–1.52 (4H, m), 1.48 (9H, s), 1.47 (3H, s), 1.46 (3H, s), 13C-NMR (100MHz, CD3OD) δ: 214.3, 173.3, 135.7, 130.3,
1.45 (3H, s), 1.44 (3H, s), 1.28–1.27 (12H, m), 0.88 (3H, t, 76.3, 75.5, 71.0, 64.9, 43.50, 43.47, 33.4, 32.8, 30.19, 30.16,
J=6.4Hz). 13C-NMR (100MHz, CDCl3) δ: 211.6, 201.8, 155.7, 30.04, 30.01, 24.9, 24.7, 23.6, 14.4. IR (KBr) cm−1: 3348, 3189,
138.1, 125.8, 110.2, 99.5, 80.4, 79.6, 78.3, 68.4, 63.7, 63.1, 42.8, 2928, 2855, 1714, 1636. mp 144–147°C (lit.31) mp 145–147°C).
42.7, 32.1, 31.6, 29.0, 28.9, 28.8, 28.6, 28.4, 28.2, 28.1, 27.4, [α]D25 −6.17 (c=0.60, CH3OH) {lit.31) [α]D24 −5.43 (c=0.48,
25.9, 23.8, 23.5, 22.5, 19.0, 14.0. IR (film) cm−1: 3419, 1726, CH3OH)}.
1713, 1704, 1495, 971, 903. FAB-MS m/z: 582.4003 (Calcd for
[1S,1(4R,5R),2R,3E]-1-[5-(tert-Butyldiphenylsilyloxy)-
methyl-2,2-dimethyl-5-(1,1-dimethylethoxycarbonyl)ami-
C32H56NO8: 582.4006). [α]D18 +10.0 (c=0.25, CHCl3).
(2S,3R,4R)-2-Acetamido-3-acetoxy-2-acetoxymethyl- no-1,3-dioxane-4-yl]-1,2-isopropylidenedioxy-3-butene
4-[(E,S)-1-acetoxy-10-oxohexadec-2-en-1-yl)-4-butanolide (4,5-Di-epi-8a) 2,2-Dimethoxypropane (0.46mL, 3.77mmol)
(17)
A solution of NaClO2 (55mg, 0.605mmol) and and PPTS (7mg, 0.038mmol) were added to a solution of
NaH2PO4·H2O (42mg, 0.302mmol) in water (0.42mL) was 11 (233mg, 0.38mmol) in benzene (11mL). After stirring at
added to a solution of 16 (44mg, 0.0756mmol) and 2-methyl- 50°C for 9h, the reaction was quenched with 5% NaHCO3
2-butene (0.21mL) in t-BuOH (1.3mL). After stirring at room and the whole mixture was extracted with EtOAc (3×10mL).
temperature for 1.5h, the reaction was quenched with H2O The combined organic layers were washed with water (10mL)
and the whole mixture was extracted with EtOAc (3×5mL). and brine (10mL), and dried over anhydrous MgSO4. Filtrate
The combined organic layers were washed with brine (5mL), was concentrated in vacuo to provide crude product (224mg),
and dried over anhydrous MgSO4. Filtrate was concentrated in which was used in the next step without further purification.
vacuo to provide the crude carboxylic acid (48mg), which was
used in the next step without further purification.
DIBAL-H (0.68mL, 1.0M in hexane, 0.68mmol) was added
dropwise to a solution of crude product (224mg) in CH2Cl2
TFA (0.63mL) was added to a solution of the crude alcohol (4.8mL) at −78°C under nitrogen. After stirring for 1h, the
in THF (1.0mL) at 0°C. After stirring at room temperature reaction was quenched with saturated potassium sodium
for 1h, H2O (1.0mL) was added to the solution. After stir- tartrate and the whole mixture was extracted with EtOAc
ring at 50°C for 5.5h, the reaction mixture was alkalified (3×10mL). The combined organic layers were washed with
with K2CO3. Insoluble materials were filtered off, and the water (10mL) and brine (10mL), and dried over anhydrous
filtrate was concentrated in vacuo to provide the crude prod- MgSO4. Filtrate was concentrated in vacuo, and the residue
uct (82mg), which was used in the next step without further was filtered through a pad of Celite to provide crude aldehyde
purification.
(216mg), which was used in the next step without further pu-
Ac2O (1.0mL) was added to a solution of the crude product rification.
in pyridine (1.0mL) at 0°C. After stirring at room temperature
t-BuOK (381mg, 3.4mmol) in THF (7.0mL) was added to a
overnight, the solvent was removed in vacuo. The resulting solution of Ph3PCH3Br (1.34g, 3.74mmol) in THF (5.0mL) at
residue was solved with EtOAc (10mL), and washed with −78°C. The reaction mixture was warmed to room tempera-
water (5mL) and brine (5mL), and dried over anhydrous ture and stirred for 1h. The reaction mixture was cooled to
MgSO4. Filtrate was concentrated in vacuo, and the residue −78°C, a solution of crude product (216mg) in THF (6.0mL)
was purified by column chromatography (silica gel, 50% was added dropwise to the reaction mixture, and the resulting
EtOAc in hexane) to provide 17 (24mg, 56% for 3 steps) as mixture was warmed to 0°C and stirred for 1h. The reac-
1
a colorless oil. H-NMR (400MHz, CDCl3) δ: 6.04 (1H, s), tion mixture was quenched with saturated NH4Cl and the
5.87 (1H, dt, J=15.4, 6.4Hz), 5.80 (1H, d, J=5.0Hz), 5.54 whole mixture was extracted with EtOAc (3×10mL). The
(1H, dd, J=8.4, 7.6Hz), 5.34 (1H, dd, J=15.4, 7.6Hz), 4.76 combined organic layers were washed with water (10mL)
(1H, dd, J=8.4, 5.0Hz), 4.56 (1H, d, J=11.6Hz), 4.49 (1H, and brine (10mL), and dried over anhydrous MgSO4. Filtrate
d, J=11.6Hz), 2.38 (4H, t, J=8.0Hz), 2.12 (3H, s), 2.09 (3H, was concentrated in vacuo, and the residue was purified by
s), 2.02 (6H, s), 1.96–2.05 (2H, m), 1.55 (4H, brs), 1.34–1.27 column chromatography (silica gel, 10% EtOAc in hexane)
(12H, m), 0.88 (3H, t, J=6.4Hz). 13C-NMR (100MHz, CDCl3) to provide 4,5-di-epi-8a (167mg, 71% for 3 steps) as a color-
δ: 211.6, 171.7, 170.2, 169.2, 168.2, 139.5, 122.0, 80.5, 77.2, less oil. 1H-NMR (400MHz, CDCl3) δ: 7.71–7.65 (4H, m),
71.6, 70.4, 62.8, 62.5, 42.8, 42.6, 32.2, 31.6, 28.93, 28.90, 28.2, 7.44–7.36 (6H, m), 5.88 (1H, ddt, J=16.8, 10.4, 4.8Hz), 5.37
23.8, 23.7, 22.6, 22.5, 21.1, 20.6, 20.5, 17.4, 14.0. [α]D20 +49.8 (1H, d, J=16.8Hz), 5.18 (1H, d, J=10.4Hz), 4.93 (1H, s), 4.32
(c=0.6, CHCl3) {lit33,34) [α]D23.2 +48.6 (c=0.27, CHCl3)}.
(1H, t, J=7.4Hz), 4.20 (1H, d, J=12.0Hz), 4.15–4.09 (2H, m),
Sphingofungin E (3) Aqueous NaOH solution (10%, 3.88 (1H, t, J=7.4Hz), 1.4 (3H, s), 1.39 (3H, s), 1.38 (3H, s),
1.0mL) was added to 17 (24mg, 0.0423mmol) in MeOH 1.32 (3H, s), 1.35 (9H, s), 1.08 (9H, s). 13C-NMR (100MHz,

Vol. 65, No. 7 (2017)
Chem. Pharm. Bull.
693
CDCl3) δ: 155.1, 136.5, 135.7, 135.6, 133.2, 133.1, 129.7, 129.6, 2.38 (4H, t, J=7.2Hz), 2.06–2.01 (2H, m), 1.58–1.52 (4H, m),
127.7, 127.6, 116.5, 109.4, 99.1, 80.9, 78.3, 77.2, 73.8, 63.3, 1.49 (9H, s), 1.41 (3H, s), 1.38 (6H, s), 1.34–1.26 (16H, m),
56.4, 28.3, 27.8, 26.9, 26.8, 19.9, 19.3. IR (film) cm−1: 3427, 0.88 (3H, t, J=6.8Hz). 13C-NMR (100MHz, CDCl3) δ: 211.5,
2073, 1726, 1499, 998, 925. FAB-MS m/z: 626.3466 (Calcd for 199.8, 156.1, 134.8, 127.4, 110.2, 99.0, 82.0, 81.0, 77.2, 76.7,
C35H52NO7Si: 626.3513). [α]D19 +17.6 (c=1.0, CHCl3).
63.0, 61.9, 42.8, 42.7, 32.2. 31.6, 29.7, 29.0, 28.93, 28.90, 28.80,
[1S,1(4R,5R),2R,3E]-1-[5-(tert-Butyldiphenylsilyloxy)- 28.79, 28.2, 27.2, 26.4, 23.8, 23.7, 22.5, 18.6, 14.0. IR (film)
methyl-2,2-dimethyl-5-(1,1-dimethylethoxycarbonyl)ami- cm−1: 3362, 1723, 1714, 965, 945. FAB-MS m/z: 582.3986
no-1,3-dioxane-4-yl]-1,2-isopropylidenedioxyheptadec-3- (Calcd for C32H56NO8: 582.4006). [α]D19 +20.2 (c=0.5, CHCl3).
en-11-one
(4,5-Di-epi-14) Pentadec-1-en-9-one
(6)63)
(2S,3R,4S)-2-Acetamido-3-acetoxy-2-acetoxymethyl-
(224mg, 1.07mmol) and second generation Grubbs catalyst 4-[(E,R)-1-acetoxy-10-oxohexadec-2-en-1-yl)-4-butanolide
(11mg, 0.0134mmol) were added to a solution of alkene (4,5-Di-epi-17) A solution of NaClO2 (167mg, 1.85mmol)
4,5-di-epi-8a (167mg, 0.267mmol) in CH2Cl2 (2.0mL). After and NaH2PO4⋅H2O (170mg, 1.24mmol) in water (1.6mL) was
stirring at reflux for 5h, the solvent was removed in vacuo. added to a solution of 4,5-di-epi-16 (60mg, 0.103mmol) and
The resulting residue was purified by column chromatogra- 2-methyl-2-butene (0.28mL) in t-BuOH (1.6mL). After stir-
phy (silica gel, 5% EtOAc in hexane) to provide 4,5-di-epi-14 ring at room temperature for 1.5h, the reaction was quenched
1
(212mg, 97%) as a colorless oil. H-NMR (400MHz, CDCl3) with H2O and the whole mixture was extracted with EtOAc
δ: 7.71–7.65 (4H, m), 7.43–7.36 (6H, m), 5.75 (1H, dt, J=15.3, (3×5mL). The combined organic layers were washed with
6.8Hz), 5.44 (1H, dd, J=15.3, 7.2Hz), 4.92 (1H, s), 4.29 (1H, brine (5mL), and dried over anhydrous MgSO4. Filtrate was
t, J=7.2Hz), 4.20–4.17 (2H, m), 4.05 (3H, brs), 3.85 (1H, t, concentrated in vacuo to provide the crude carboxylic acid
J=7.6Hz), 2.38 (4H, t, J=7.2Hz), 2.06–2.01 (2H, m), 1.59–1.52 (70mg), which was used in the next step without further pu-
(4H, m), 1.43 (3H, s), 1.37 (9H, s), 1.35–1.27 (21H, m), 1.08 rification.
(9H, s), 0.88 (3H, t, J=7.2Hz). 13C-NMR (100MHz, CDCl3)
TFA (1.3mL) was added to a solution of the crude alcohol
δ: 211.6, 155.1, 135.7, 135.6, 134.8, 133.23, 133.15, 129.7, 129.6, in THF (1.3mL) at 0°C. After stirring at room temperature for
127.77, 127.69, 127.57, 108.9, 99.0, 80.9, 78.2, 77.2, 76.7, 73.6, 1h, H2O (1.3mL) was added to the solution. After stirring at
63.5, 56.6, 42.8, 42.7, 32.3, 31.59, 31.58, 29.1, 29.0, 28.91, 50°C for 6h, the reaction mixture was alkalified with K2CO3.
28.87, 28.3, 27.7, 26.9, 26.8, 23.81, 23.77, 23.76, 22.5, 20.0, Insoluble materials were filtered off, and the filtrate was
19.3, 14.0. IR (film) cm−1: 3414, 1721, 1717, 1496, 972, 943. concentrated in vacuo to provide the crude product (152mg),
FAB-MS m/z: 822.5343 (Calcd for C48H76NO8Si: 822.5340). which was used in the next step without further purification.
[α]D18 +14.3 (c=0.5, CHCl3).
Ac2O (1.9mL) was added to a solution of the crude product
[1S,1(4R,5S),2R,3E]-1-[2,2-Dimethyl-5-(1,1-dimethyl- in pyridine (1.9mL) at 0°C. After stirring at room temperature
ethoxycarbonyl)amino-5-formyl-1,3-dioxane-4-yl]-1,2- overnight, the solvent was removed in vacuo. The resulting
isopropylidenedioxyheptadec-3-en-11-one
(4,5-Di-epi-16) residue was solved with EtOAc (10mL), and washed with
Tetrabutylammonium fluoride (TBAF) (0.26mL, 1.0M in THF, water (10mL) and brine (10mL), and dried over anhydrous
0.258mmol) was added to a solution of 4,5-di-epi-14 (71mg, MgSO4. Filtrate was concentrated in vacuo, and the residue
0.086mmol) in THF (1.4mL) at 0°C. After stirring at room was purified by column chromatography (silica gel, 50%
temperature for 4h, the reaction was quenched with water and EtOAc in hexane) to provide 4,5-di-epi-17 (28mg, 48% for 3
1
the whole mixture was extracted with EtOAc (3×10mL). The steps) as a colorless oil. H-NMR (400MHz, CDCl3) δ: 6.42
combined organic layers were washed with water (10mL) and (1H, brs), 5.92 (1H, dt, J=12.0, 5.2Hz), 5.47–5.35 (2H, m),
brine (10mL), and dried over anhydrous MgSO4. Filtrate was 4.98 (1H, s), 4.72 (1H, s), 4.55 (1H, d, J=6.8Hz), 4.30 (1H,
concentrated in vacuo to provide crude product 4,5-di-epi-15 s, J=6.8Hz), 2.39 (4H, t, J=5.6Hz), 2.17 (3H, s), 2.14–1.99
(66mg), which was used in the next step without further pu- (2H, m), 2.12 (3H, s), 2.07 (3H, s), 2.05 (3H, s), 1.55 (4H,
rification.
brs), 1.35–1.27 (12H, m), 0.88 (3H, t, J=5.6Hz). 13C-NMR
A solution of DMSO (40mg, 0.516mmol) in CH2Cl2 (100MHz, CDCl3) δ: 211.7, 171.0, 170.8, 170.2, 169.9, 169.8,
(0.3mL) was added dropwise to a solution of oxalyl chloride 139.1, 122.5, 82.2, 73.7, 70.7, 64.6, 61.0, 42.8, 42.7, 32.2,
(44mg, 0.344mmol) in CH2Cl2 (0.5mL) at −78°C under ni- 31.6, 29.0, 28.90, 28.87, 28.4, 23.8, 23.7, 22.5, 21.9, 21.1, 20.7,
trogen and stirred for 5min. A solution of crude 4,5-di-epi-15 20.4, 14.0. IR (film) cm−1: 3321, 3209, 1795, 1760, 1747, 1713,
(66mg) in CH2Cl2 (0.7mL) was added dropwise to the reac- 1688, 1668. FAB-MS m/z: 568.3123 (Calcd for C29H46NO10:
tion mixture and stirred for 20min. A solution of Et3N (88mg, 568.3121). [α]D20 −99.4 (c=0.5, CHCl3).
0.86mmol) in CH2Cl2 (0.3mL) was added dropwise to the
(E,2S,3R,4S,5R)-2-Amino-3,4,5-trihydroxy-2-hy-
reaction mixture at −78°C. The reaction mixture was warmed droxymethyl-14-oxoicos-6-enoic Acid [4,5-Di-epi-sphin-
to −40°C and stirred for 1h. The reaction was quenched gofungin E (4)] Aqueous NaOH solution (10%, 0.48mL)
with saturated NH4Cl and the whole mixture was extracted was added to 4,5-di-epi-17 (24mg, 0.042mmol) in MeOH
with EtOAc (3×5mL). The combined organic layers were (0.48mL) and stirring at 70°C for 2h. The reaction mixture
washed with water (5mL) and brine (5mL), and dried over was cooled to 0°C, and then neutralized with Amberlite®
anhydrous MgSO4. Filtrate was concentrated in vacuo, and the IRC-86 (H+ type). The insoluble material was removed by fil-
residue was purified by column chromatography (silica gel, tration and the filtrate was concentrated in vacuo. The result-
10% EtOAc in hexane) to provide 4,5-di-epi-16 (41mg, 82% ing residue was purified by column chromatography (1:1:10
1
for 2 steps) as a colorless oil. H-NMR (400MHz, CDCl3) to 1:3:10 (gradient) H2O–MeOH–CHCl3 (lower phase)) to
1
δ: 9.58 (1H, s), 5.71 (1H, dt, J=15.2, 6.8Hz), 5.45–5.40 (2H, afford 4 (12mg, 70%) as white crystals. H-NMR (400MHz,
m), 4.27 (1H, d, J=12.4Hz), 4.23 (1H, t, J=7.7Hz), 4.06 (1H, CD3OD) δ: 5.66 (1H, dt, J=15.6, 6.4Hz), 5.52 (1H, dd, J=15.6,
d, J=12.4Hz), 3.96 (1H, d, J=7.7Hz), 3.78 (1H, t, J=7.7Hz), 6.4Hz), 4.19 (1H, d, J=3.6Hz), 3.94–3.83 (2H, m), 3.58–3.55

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Chem. Pharm. Bull.
Vol. 65, No. 7 (2017)
(2H, m), 2.34 (1H, t, J=6.8Hz), 1.99–1.98 (2H, m), 1.50–1.43 quenched with water and the whole mixture was extracted
(4H, m), 1,31–1.19 (12H, m), 0.80 (3H, t, J=6.4Hz). 13C-NMR with EtOAc (3×10mL). The combined organic layers were
(100MHz, CD3OD) δ: 214.3, 137.8, 133.8, 131.3, 80.1, 76.9, washed with brine (10mL), and dried over anhydrous MgSO4.
72.9, 71.1, 64.2, 43.50, 43.47, 32.8, 30.8, 30.20, 30.18, 30.17, Filtrate was concentrated in vacuo to provide crude tetraol
30.1, 30.0, 24.8, 23.6, 14.4. IR (KBr) cm−1: 3472, 3266, 3205, (102mg), which was used in the next step without further
3123, 2928, 2851, 1705, 1639. FAB-MS m/z: 418.2802 (Calcd purification.
for C21H40NO7: 418.2805). mp 141–143°C. [α]D20 −1.77 (c=0.25,
DMSO).
2,2-Dimethoxypropane (0.61mL, 5.01mmol) and PPTS
(13mg, 0.0501mmol) were added to a solution of crude prod-
(4S,5S,2E)-5-(tert-Butyldiphenylsilyloxy)methyl-4,6-di- uct in benzene (5mL). After stirring at reflux for 2.5h, the re-
hydroxy-2,2-dimethyl-5-(1,1-dimethylethoxycarbonyl)ami- action was quenched with 5% NaHCO3 and the whole mixture
no-2-hexenyl Acetate (20) DIBAL-H (0.62mL, 0.62mmol) was extracted with EtOAc (3×10mL). The combined organic
was added dropwise to a solution of ester 7a46) (120mg, layers were washed with water (5mL) and brine (10mL), and
0.206mmol) in CH2Cl2 (2.0mL) at −78°C under nitrogen. dried over anhydrous MgSO4. Filtrate was concentrated in
After stirring for 1h, the reaction was quenched with satu- vacuo, and the residue was purified by column chromatogra-
rated potassium sodium tartrate and the whole mixture was phy (silica gel, 10% EtOAc in hexane) to provide 32a (40mg,
extracted with EtOAc (3×10mL). The combined organic lay- 36% for 2 steps) as a colorless oil and 32b (54mg, 48% for 2
1
ers were washed with water (10mL) and brine (10mL), and steps) as a colorless oil. 32a: H-NMR (400MHz, CDCl3) δ:
dried over anhydrous MgSO4. Filtrate was concentrated in 7.72–7.71 (4H, m), 7.46–7.36 (6H, m), 5.07 (1H, s), 4.67 (1H,
vacuo, and the residue was filtered through a pad of Celite to d, J=6.4Hz), 4.40 (1H, d, J=9.4Hz), 4.18 (1H, dd, J=9.6,
provide crude alcohol (101mg), which was used in the next 3.2Hz), 4.13 (1H, d, J=8.2Hz), 4.04 (1H, dd, J=9.6, 6.4Hz),
step without further purification.
3.95 (1H, m), 3.78 (1H, d, J=9.6Hz), 3.74 (1H, m), 3.69 (1H,
Ac2O (2.0mL) was added to a solution of the crude product d, J=8.2Hz), 2.03 (3H, s), 1.44 (9H, s), 1.36 (6H, s), 1.20 (6H,
in pyridine (2.0mL). After stirring at room temperature for s), 1.08 (9H, s). 13C-NMR (100MHz, CDCl3) δ: 170.9, 154.6,
1.5h, the solvent was removed in vacuo. The resulting residue 135.9, 135.7, 133.1, 132.7, 129.8, 129.8, 127.8, 127.6, 102.1,
was solved with EtOAc (10mL), and washed with water (5mL) 101.6, 77.2, 68.5, 68.0, 67.2, 63.1, 61.4, 60.2, 58.0, 28.42, 28.37,
and brine (5mL), and dried over anhydrous MgSO4. Filtrate 26.8, 25.6, 24.9, 24.3, 24.2, 23.4, 21.0, 19.3. IR (film) cm−1:
was concentrated in vacuo to provide crude acetate (121mg), 3447, 1734, 1719, 1491. FAB-MS m/z: 672.3541 (Calcd for
which was used in the next step without further purification.
C36H54NO9Si: 672.3568). [α]D20 +0.55 (c=0.47, CHCl3). 32b:
PPTS (14mg, 0.0546mmol) was added to a solution of 1H-NMR (400MHz, CDCl3) δ: 7.71–7.60 (4H, m), 7.44–7.36
crude product in MeOH (2.0mL). After stirring at reflux for (6H, m), 4.96 (1H, s), 4.51 (1H, dd, J=11.6, 1.6Hz), 4.19 (1H,
2.5h, the reaction was quenched with 5% NaHCO3 and the dd, J=11.6, 9.4Hz), 4.12 (1H, d, J=8.0Hz), 4.05 (1H, m),
whole mixture was extracted with EtOAc (3×10mL). The 3.98–3.90 (3H, m), 3.95 (1H, d, J=8.0Hz), 2.10 (3H, s), 1.44
combined organic layers were washed with water (10mL) (3H, s), 1.41 (3H, s), 1.38 (12H, s), 1.30 (3H, s), 1.08 (9H, s).
and brine (10mL), and dried over anhydrous MgSO4. Filtrate 13C-NMR (100MHz, CDCl3) δ: 170.7, 155.0, 135.6, 133.2,
was concentrated in vacuo, and the residue was purified by 133.1, 129.7, 129.6, 127.6, 127.5, 110.1, 99.1, 78.7, 77.2, 74.3,
column chromatography (silica gel, 20% EtOAc in hexane) to 73.9, 65.3, 63.1, 56.3, 28.4, 28.2, 27.9, 26.9, 26.7, 20.9, 19.6,
1
provide 20 (71mg, 61% for 3 steps) as a colorless oil. H-NMR 19.2. IR (film) cm−1: 3414, 1747, 1716, 1505. FAB-MS m/z:
(400MHz, CDCl3) δ: 7.65–7.62 (4H, m), 7.48–7.39 (6H, m), 672.3588 (Calcd for C36H54NO9Si: 672.3568). [α]D20 +18.4
5.48–5.72 (2H, m), 5.38 (1H, s), 4.93 (1H, d, J=8.0Hz), 4.50 (c=0.60, CHCl3).
(2H, d, J=4.8Hz), 4.13 (1H, dd, J=8.6, 5.2Hz), 3.94 (1H, dd,
Conversion of 32a into 8a DIBAL-H (0.076mL,
J=12.0, 5.2Hz), 3.84 (1H, d, J=10.2Hz), 3.70 (1H, dd, J=12.0, 0.076mmol) was added dropwise to a solution of ester 32a
8.8Hz), 3.61 (1H, d, J=10.2Hz), 3.18 (1H, brs), 2.03 (3H, s), (17mg, 0.0253mmol) in CH2Cl2 (0.8mL) at −78°C under ni-
1.44 (9H, s), 1.09 (9H, s). 13C-NMR (100MHz, CDCl3) δ: trogen. After stirring for 1h, the reaction was quenched with
170.6, 156.8, 135.5, 132.3, 132.1, 131.9, 130.13, 130.11, 127.9, saturated potassium sodium tartrate and the whole mixture
127.1, 80.4, 73.3, 64.2, 63.9, 62.5, 61.9, 28.2, 26.9, 20.9, 19.2. was extracted with EtOAc (3×5mL). The combined organic
IR (film) cm−1: 3416, 1740, 1689, 1499, 970, 910. FAB-MS layers were washed with water (5mL) and brine (5mL), and
m/z: 598.3202 (Calcd for C33H48NO7Si: 598.3200). [α]D19 −17.2 dried over anhydrous MgSO4. Filtrate was concentrated in
(c=0.5, CHCl3).
vacuo, and the residue was filtered through a pad of Celite to
[2S,3R,3(4R,5S)]-3-[5-(tert-Butyldiphenylsilyloxy)meth- provide crude alcohol (14mg), which was used in the next step
yl-4,6-dihydroxy-2,2-dimethyl-5-(1,1-dimethylethoxy- without further purification.
carbonyl)amino]-2,3-isopropylidenedioxy Propyl Acetate
A solution of DMSO (16mg, 0.20mmol) in CH2Cl2 (0.3mL)
(32a) and [2R,3S,3(4R,5S)]-3-[5-(tert-Butyldiphenylsilyl- was added dropwise to a solution of oxalyl chloride (17mg,
oxy)methyl-4,6-dihydroxy-2,2-dimethyl-5-(1,1-dimethyl- 0.133mmol) in CH2Cl2 (0.5mL) at −78°C and stirred for
ethoxycarbonyl)amino]-2,3-isopropylidenedioxy
Propyl 5min. A solution of crude product in CH2Cl2 (0.6mL) was
Acetate (32b) OsO4 (46mg, 0.184mmol) in CH2Cl2 (1.2mL) added dropwise to the reaction mixture and stirred for 20min.
was added dropwise to a solution of 27a and 27b (93mg, Et3N (34mg, 0.333mmol) in CH2Cl2 (0.3mL) was added drop-
0.167mmol) and TMEDA (25mg, 0.217mmol) in CH2Cl2 wise to the reaction mixture and stirred at −78°C for 2.5h,
(2.5mL) at −78°C. After stirring for 1h, the solvent was re- and the reaction mixture was allowed to warm to room tem-
moved in vacuo. NaHSO3 (98mg, 0.94mmol) was added to perature and stirred for 30min. The reaction was quenched
a solution of resulting residue in pyridine–H2O (1:1, 1mL). with saturated NH4Cl and the whole mixture was extracted
After stirring at room temperature overnigt, the reaction was with CH2Cl2 (3×5mL). The combined organic layers were

Vol. 65, No. 7 (2017)
Chem. Pharm. Bull.
695
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washed with water (5mL) and brine (5mL), and dried over
anhydrous MgSO4. Filtrate was concentrated in vacuo to pro-
vide crude aldehyde (12mg), which was used in the next step
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Acknowledgments This research was supported, in part,
by a Grant-in-Aid for Scientific Research (C) (Grant No.
JP16K08158) from the Japan Society for the Promotion of Sci-
ence (JSPS) and JSPS Core-to-Core Program, B. Asia-Africa
Science Platforms.
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Conflict of Interest The authors declare no conflict of
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