Stereospecific total syntheses of sphingosine and its analogues from L- serine

Full text of DOI:10.1021/jo991447x

3538
J . Org. Chem. 2000, 65, 3538-3541
Notes
Sch em e 1
Ster eosp ecific Tota l Syn th eses of
Sp h in gosin e a n d Its An a logu es fr om
L-Ser in e
Hideki Azuma,* Seizo Tamagaki, and Kenji Ogino*
Department of Bioapplied Chemistry, Faculty of
Engineering, Osaka City University, Sugimoto 3-3-138,
Sumiyoshi-ku, Osaka 558-8585, J apan
Received September 14, 1999
In tr od u ction
Glycosphingolipids and sphingomyelins that are biomem-
brane components serve physiologically important roles
in bioorganisms.1 The lipophilic ceramide tail, a long
chain acid amide derivative of the sphingosine amino
alcohol moiety, acts as a membrane anchor, while the
hydrophilic headgroup such as saccharide or phosphate,
which is predominantly located on the external surface
of the membrane, is associated with the molecular
recognition process. Physiologically, sphingosines have
been reported to function as a positive regulator of cell
growth in Swiss 3T3 fibroblast2 and a potent inhibitor of
protein kinase C in vitro.3 Recently, it has been suggested
that sphingosines or their related lipids were used as a
potent precursor for the biosynthesis of a sleep-inducing
substance.4 Until now, however, sphingosines,5 dihy-
drosphingosines,6 and phytosphingosines7 have been
independently synthesized by many workers from L-
serine or various sugars by different methods. We present
here a sophisticated method for synthesizing three dif-
ferent types of sphingosines with 18 carbon atoms
passing through the (Z)-olefin 2 as the common inter-
mediate.
a
b
C15H31PPh3Br, LHMDS, -78 °C. m-CPBA, room tempera-
ture. c Excess LiAlH4, 0 °C. CF3CO2H, room temperature, then
Ac2O, DMAP, room temperature.
d
protected serine aldehyde 1 is the starting material of
the present synthesis.8 First, we have attempted to
prepare geometrically pure (Z)-2 olefin from this aldehyde
under the Wittig reaction conditions. However, the
ordinary Wittig olefination of 1 employing n-BuLi as a
base with pentadecyltriphenylphosphonium bromide
(C15H31PPh3Br) resulted in only a low yield of the desired
olefin. Previously, Dondoni and co-workers reported the
Wittig olefination of a sterically hindered serine-derived
aldehyde with tetradecyltriphenylphosphonium bromide
(3.2 equiv);5a the use of 2.8 equiv of lithium hexameth-
yldisilazide (LHMDS freshly prepared from n-BuLi and
NH(SiMe3)2) as the base produced a mixture of (Z)- and
(E)-isomers in 80-84% isolated yield. Similarly, by using
the C15H31PPh3Br/LHMDS/1 (mole ratio ) 2.3:2.1:1)
combination system, we have obtained a 90:10 mixture
of (Z)- and (E)-isomers in 83% total yield based on 1H
NMR analysis after purification by column chromatog-
raphy. Use of sodium hexamethyldisilazide (NaHMDS)
as a base did not increase the population of the Z form;13
Resu lts a n d Discu ssion
(i) Dih yd r osp h in gosin es. The synthetic approach to
dihydrosphingosines is outlined in Scheme 1. Garner’s
(1) (a) Hakamori, S. In Handbook of Lipid Research: Sphingolipid
Biochemistry; Kanfer, J . N., Hakomori, S., Ed.; Plenum Press: New
York, 1983; Vol. 3, pp 1-150. (b) Kolter, T.; Sandhoff, K. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 1532.
(2) Zhang, H.; Buckley, N. E.; Gibson K.; Spiegel, S. J . Biol. Chem.
1990, 265, 76.
(3) Merrill, A. H., J r.; Nimkar, S.; Menaldino, D.; Hannun, Y. A.;
Loomis, C.; Bell, R. M.; Tyagi, S. R.; Lambeth, J . D.; Stevens, V. L.;
Hunter, R.; Liotta, D. C. Biochemistry 1989, 28, 3138.
(4) Kolter, T.; Sandlhoff, K. Angew. Chem., Int. Ed. Engl. 1995, 34,
2363.
(5) (a) Dondoni, A.; Perrone, D.; Turturici, E. J . Chem. Soc., Perkin
Trans. 1 1997, 2389. (b) Zimmermann, P.; Schmidt, R. R. Liebigs Ann.
Chem. 1988, 663. (c) Herold, P. Helv. Chim. Acta 1988, 71, 354. (d)
Garner, P.; Park, J . M.; Malecki, E. J . Org. Chem. 1988, 53, 4395. (e)
Nimkar, S.; Menaldino, D.; Merrill, A. H.; Liotta, D. Tetrahedron Lett.
1988, 29, 3037.
(6) (a) Mori, K.; Uenishi, K. Liebigs Ann. Chem. 1994, 41. (b)
Yoshida, J .; Nakagawa, M.; Seki, H.; Hino, T. J . Chem. Soc., Perkin
Trans. 1 1992, 343. (c) Roush, W. R.; Adam, M. A. J . Org. Chem. 1985,
50, 3752. (d) Reist, E. J .; Christie, P. H. J . Org. Chem. 1970, 10, 3521.
(7) (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J . Org.
Chem. 1990, 55, 1439. (b) Sugiyama, S.; Honda, M.; Komori, T. Liebigs
Ann. Chem. 1988, 619. (c) Mulzer, J .; Brand, C. Tetrahedron 1986,
42, 5961. (d) Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann. Chem.
1990, 1069.
(8) (a) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361. (b)
Dondoni, A.; Perrone, D. Synthesis 1997, 527.
(9) Roush, W. R.; Straub, J . A.; Brown, R. J . J . Org. Chem. 1987,
52, 5127.
(10) Eliel, E. L.; Rerick, M. N. J . Am. Chem. Soc. 1960, 82, 1362.
(11) Kobayashi, J .; Ishibashi, M.; Nakamura, H.; Hirata, Y.; Ya-
masu, T.; Sasaki, T.; Ohizumi, Y. Experientia 1988, 44, 800.
(12) Sharpless, K. B.; Lauer, R. F. J . Am. Chem. Soc. 1973, 95, 2697.
(13) (a) Viala, J .; Santelli, M. Synthesis 1988, 395. (b) Bestmann,
H. J .; Stransky, W.; Vostrowsky, O. Chem. Ber. 1976, 109, 1694.
10.1021/jo991447x CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/04/2000

Notes
J . Org. Chem., Vol. 65, No. 11, 2000 3539
Ta ble 1. Solven t Effect for th e Oxid a tion a of (Z)-2 w ith
m -CP BA
Sch em e 2
solvent
reaction time
total yieldb (%)
A:B ratioc
benzene
CH2Cl2
tert-BuOH
THF
4 hours
1 day
2 days
2 days
87.2
91.5
86.7
89.3
82:18
70:30
89:11
92:8
a
Method: m-CPBA (2.5 equiv), Na2HPO4 (2.5 equiv), room
temperature. Obtained by column chromatography. c Analyzed
b
by 1H NMR.
no significant improvement in selectivity was observed
(Z/E ) 91:9) with slightly decreased yield to 74%.
Nevertheless, column chromatographic purification and
isolation with n-hexane-EtOAc (20:1) as an eluent, gave
pure (Z)-2 in 66% yield. The (Z)-olefin 2 thus formed may
be synthetically more valuable than the corresponding
(E)-olefin, as will be substantiated below, because the
former is more susceptible to steric hindrance toward
attacking reagents due to its bulky N-Boc group than the
latter.
Next, the epoxidation of each olefin using 2 equiv of
m-CPBA was examined in various solvents in the pres-
ence of 2 equiv of Na2HPO4 as the base. Addition of the
phosphate was effective in avoiding the unfavorable acid-
catalyzed ring-opening of the epoxide once formed. Little
or no diastereoselectivity was observed for (E)-2 in a wide
range of solvents tested, while remarkably high diaste-
reoselectivity was observed for (Z)-2. Table 1 indicates
that THF is the best of choice among the solvents, in
which 3 and 4 were formed with a 92:8 ratio. The epoxide
3 and 4 were readily separated by column chromatogra-
phy with n-hexane-diethyl ether (4:1) and obtained in
84% and 4% yields, respectively. Incidentally, the epoxi-
dation of (Z)-2 employing the Mo(CO)6-TBHP system
failed due probably to the bulkiness of the oxidant.9
The epoxide 3 thus formed was reduced with LiAlH4
in diethyl ether at 0 °C to give rise to the desired
3-hydroxy compound 5 with an excellent regioselectivity,
demonstrating that the less hindered carbon atom of the
epoxide is vulnerable to the preferred attack of the
relatively small hydride anion.10 The removal of the
protective N-Boc group of 5 with trifluoroacetic acid,
followed by acetylation, a technique for easy purification
and characterization of the product, afforded N,O,O-
triacetyl-D-erythro-dihydrosphingosine 7 in 83% yield.
The overall yield based on 1 was 39%. The free form of
the triacetyl compound 7 is an amino component of
symbioramide, an activator of a sarcoplasmic reticulum
Ca2+-ATPase.11 The threo-isomer 8 could also be prepared
from 4 in the same manner (see the Experimental Section
for the detail).
a
b
PhSeSePh, NaBH4, reflux. 30% H2O2, room temperature.
c CF3CO2H, room temperature, then Ac2O, DMAP, room temper-
ature. 30% H2O2, NaHCO3, room temperature.
d
Sch em e 3
a
N-methylmorpholine N-oxide hydrate, OsO4, room tempera-
b
ture. CF3CO2H, room temperature, then Ac2O, DMAP, room
temperature.
N-Boc group around the selenoxide moiety. Therefore, the
smaller N-Ac derivative 11 was substituted for the N-Boc
derivative 9 for the sake of selective elimination of the
selenoxide group; actually, when the N-Ac derivative 11
was oxidized with 30% hydrogen peroxide, followed by
facile PhSeOH-elimination, N,O,O-triacetyl-D-erythro-
sphingosine 13 was obtained in 31% isolated yield, as
expected. Attempts to prepare the threo-isomer 14 from
4 entirely failed because no target molecule 10 could be
detected in the reaction mixture.
(ii) Sp h in gosin es. The epoxide 3 was converted to the
allylic alcohol 9′ according to the method described by
Sharpless12 (Scheme 2); treatment of 3 with diphenyl
diselenide (PhSeSePh) and sodium tetrahydroborate gave
the hydroxy selenide 9, which was the sole product
1
detected by H NMR spectroscopy after purification of
the reaction mixture by column chromatography. The
subsequent oxidation of the crude hydroxyselenide 9 with
30% hydrogen peroxide resulted in a comparatively low
selectivity of a 9:1 mixture of (E)- and (Z)-allylic alcohols,
irrespective of Sharpless' rule that the alkyl selenoxide
will exclusively decompose to the (E)-allylic alcohol.12
Probably, such a low observed selectivity appears to be
attributed to too large a steric hindrance by the large
(iii) P h ytosp h in gosin es. To obtain the 3,4-diol 15,
we have examined the osmylation of the olefin (Z)-2
(Scheme 3); OsO4/N-methylmorpholine N-oxide7c con-
verted (Z)-2 into a mixture of diols 15 and 16, which were
readily separated by column chromatography using
n-hexane-EtOAc (3:1) in 55% and 19% yields, respec-
tively. The isolated 15 and 16 were deprotected and then
acetylated to provide N,O,O,O-tetraacetyl-D-ribo-phyto-

3540 J . Org. Chem., Vol. 65, No. 11, 2000
Notes
Com p ou n d 3: mp 43 °C; [R]25 ) +33.4° (c 2.0, CHCl3); IR
sphingosine 17 and arabino-isomer 18, respectively. The
overall yield of 17 from 1 was 27%.
D
(KBr) 2920, 2851, 1699, 1472, 1387, 1366, 1167, 1103, 1059, 868
cm-1 1H NMR (400 MHz, C6D6, 75 °C) δ 0.91 (t, 3 H, J ) 6.8
;
Hz), 1.33 (s, 24 H), 1.41 (s, 9 H), 1.49 (s, 3 H), 1.50-1.60 (m, 2
H), 1.65 (s, 3 H), 2.89-2.93 (m, 1 H), 3.0 (dd, 1 H, J ) 3.9, 7.8
Hz), 3.72-3.77 (m, 1 H), 3.76 (t, 1 H, J ) 6.3 Hz), 4.13 (dd, 1 H,
J ) 8.3, 2.0 Hz). HRMS (FAB, direct) Calcd for C26H49NO4: [M
+ H]+ 440.3740. Found: 440.3736 (9%). Anal. Calcd: C, 71.03;
H, 11.23; N, 3.19. Found: C, 70.9; H, 11.25; N, 3.16.
Con clu sion s
Three different types of sphingosine derivatives, 7, 13,
and 17, were prepared from L-serine through the common
intermediate (Z)-2. It is found for the first time that both
the oxidation of (Z)-2 with m-CPBA or OsO4/N-methyl-
morpholine N-oxide and the epoxy-ring opening reaction
with LiAlH4 or PhSe- take place stereoselectively; these
high selectivities appear to arise from the presence of a
sterically encumbered N-Boc group near the reacting
centers.
Com p ou n d 4: mp 39 °C; [R]25 ) +10.5° (c 2.0, CHCl3); IR
D
(KBr) 2920, 2855, 1699, 1474, 1391, 1366, 1252, 1092, 1057, 845
cm-1 1H NMR (400 MHz, C6D6, 75 °C) δ 0.89 (t, 3 H, J ) 6.8
;
Hz), 1.29 (s, 26 H), 1.54 (s, 9 H), 1.58 (s, 3 H), 1.73 (s, 3 H),
2.54-2.58 (m, 1 H), 2.87 (dd, 1 H, J ) 4.4, 7.6 Hz), 3.57 (dd, 1
H, J ) 7.8, 1.6 Hz), 3.69-3.76 (m, 2 H). HRMS (FAB, direct)
Calcd for C26H49NO4: [M + H]+ 440.3740. Found: 440.3725
(12%). Anal. Calcd: C, 71.03; H, 11.23; N, 3.19. Found: C, 71.04;
H, 11.22; N, 3.07.
Exp er im en ta l Section
(2S,3R)-2-[(ter t-Bu toxyca r bon yl)a m in o]-1,2-O,N-isop r o-
p ylid en eocta d eca n e-1,3-d iol (5). To a solution of the epoxide
3 (400 mg, 0.9 mmol) in dry diethyl ether (50 mL) was added
LiAlH4 (140 mg, 3.6 mmol) at 0 °C. The mixture was stirred for
1 h at 0 °C under N2. The reaction mixture was cooled at -78
°C, and EtOAc was added to quench. The resulting white
emulsion was poured into an ice-cooled 1 M HCl solution and
extracted with EtOAc; the organic layer was dried with Na2SO4
and concentrated. Purification by column chromatography with
All the materials were obtained commercially (guaranteed
reagent grade) and used without further purification. All
solvents were freshly distilled under nitrogen before use; THF
and diethyl ether were distilled from LiAlH4; CH2Cl2 was
distilled from P2O5; EtOH was distilled from CaO. 1H and 13C
NMR spectra were recorded in CDCl3, C6D6 or DMSO-d6 solution
with TMS as an internal standard. Column chromatography was
performed on silica gel (Wakogel C-200).
n-hexane-EtOAc (5:1) gave 5 (340 mg, 85.5%) as an oil: [R]25
(R,Z)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-1,2-O,N-isop r o-
p ylid en eocta d ec-3-en -1-ol ((Z)-2). To a solution of 1,1,1,3,3,3-
hexamethyldisilazane (8.13 g, 50.4 mmol) in dry THF (100 mL)
was added n-BuLi (1.6 M in n-hexane, 31.5 mL) at room
temperature (LHMDS solution). The LHMDS solution was
treated dropwise with pentadecyltriphenylphosphonium bromide
(30.6 g, 55.3 mmol) in dry THF (100 mL). The resulting dark
red solution was added dropwise to a solution of Garner’s
aldehyde8 1 (5.52 g, 24 mmol) in dry THF (50 mL) at -78 °C.
After stirring overnight at room temperature, the mixture was
poured into an ice-cooled 1 M HCl solution and extracted with
EtOAc. After drying with Na2SO4, the solvent was concentrated
and the residue was purified by column chromatography with
chloroform to give a mixture of (Z)- and (E)-isomers in a 9:1 ratio
D
) -12.6° (c 2.51, CHCl3) {lit.6d [R]20D ) -12.7° (c 1.09, CHCl3)};
1H NMR (400 MHz, C6D6, 75 °C) δ 0.90 (t, 3 H, J ) 6.8 Hz),
1.33 (s, 28 H), 1.42 (s, 9 H), 1.46 (s, 3 H), 1.63 (s, 3 H), 3.67 (dd,
1 H, J ) 6.8, 8.8 Hz), 3.79-3.90 (m, 3 H); 13C NMR (100 MHz,
C6D6, 75 °C) δ 14.0, 22.9, 24.1, 26.4, 26.8, 28.4, 29.6, 29.9, 30.0,
32.2, 33.9, 62.7, 64.5, 72.6, 80.0, 94.3. MS (FAB, direct) Calcd
for C26H51NO4: [M + H]+ 442.4. Found: 442.5 (11%).
(2S,3S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-1,2-O,N-isop r o-
p ylid en eocta d eca n e-1,3-d iol (6). The reaction was carried out
as described above starting from 4 (300 mg, 0.68 mmol), although
the amount of adding LiAlH4 was 2-fold equimolar. Purification
by column chromatography with n-hexane-EtOAc (5:1) gave 6
(240 mg, 79.9%) as an oil: [R]25 ) -36.9° (c 1.7, CHCl3); IR
D
1
(by H NMR analysis). Further purification by column chroma-
(CHCl3) 3450, 2924, 2855, 1701, 1670, 1394, 1366, 1258, 1175,
1
tography with n-hexane-EtOAc (20:1) gave the major isomer
1109, 1061 cm-1; H NMR (400 MHz, C6D6, 75 °C) δ 0.91 (t, 3
(Z)-2 as a colorless oil (6.78 g, 66.4%).
H, J ) 6.8 Hz), 1.33 (s, 28 H), 1.40 (s, 9 H), 1.47 (s, 3 H), 1.65 (s,
3 H), 3.65-3.73 (m, 2 H), 3.80-3.90 (m, 2 H); 13C NMR (100
MHz, C6D6, 75 °C) δ 14.0, 22.9, 24.2, 25.9, 27.1, 28.3, 29.6, 30.0,
30.1, 32.2, 34.3, 62.7, 65.0, 75.5, 80.3, 94.3. HRMS (FAB, direct)
Calcd for C26H51NO4: [M + H]+ 441.3818. Found: 442.3896
(11%). Anal. Calcd: C, 70.70; H, 11.64; N, 3.17. Found: C, 70.39;
H, 11.63; N, 3.17.
Com p ou n d (Z)-2: [R]25D ) +55.9° (c 1.72, CHCl3); IR (CHCl3)
2975, 2855, 1701, 1460, 1385, 1366, 1252, 1176, 1096, 1037, 851
cm-1 1H NMR (400 MHz, C6D6, 75 °C) δ 0.91 (t, 3 H, J ) 6.8
;
Hz), 1.34 (s, 24 H), 1.44 (s, 9 H), 1.60 (s, 3 H), 1.70 (s, 3 H), 2.12
(brs, 2 H), 3.55 (dd, 1 H, J ) 3.4, 8.8 Hz), 3. 85 (dd, 1 H, J ) 6.3,
8.8 Hz), 4.61 (brs, 1 H), 5.37-5.52 (m, 2 H); 13C NMR (100 MHz,
C6D6, 75 °C) δ 14.0, 22.9, 24.8, 27.1, 27.7, 28.5, 29.6, 29.8, 29.9,
30.0, 30.1, 32.2, 55.0, 69.1, 77.5, 79.2, 130.9, 152.0. HRMS (FAB,
direct) Calcd for C26H49NO3: [M + H]+ 424.3791. Found:
424.3779 (13%). Anal. Calcd: C, 73.71; H, 11.66; N, 3.31.
Found: C, 73.71; H, 11.68; N, 3.27.
N,O,O-Tr ia cetyl-D-er yth r o-d ih yd r osp h in gosin e (7). To
the protected sphingosine 5 (200 mg, 0.45 mmol) was added a
solution of trifluoroacetic acid (1 mL) and water (0.3 mL). After
1 h, the solvent was evaporated in vacuo and a saturated
aqueous NaHCO3 was added. The mixture was extracted with
EtOAc, dried with Na2SO4, and concentrated. To the residue
dissolved in pyridine (10 mL) were added DMAP (170 mg, 1.35
mmol) and acetic anhydride (230 mg, 2.25 mmol). After 1 day of
stirring, the solvent was removed in vacuo. Saturated aqueous
NaHCO3 was added to the residue, and the mixture was
extracted with diethyl ether. The organic layer was dried with
Na2SO4 and concentrated. Purification by column chromatog-
raphy with n-hexane-EtOAc (5:1) gave 7 (160 mg, 83.1%) as a
solid: mp 97-98 °C (lit.6d mp 90-93 °C and lit.6c mp 93-94 °C);
[R]25D ) +17.4° (c 1.0, CHCl3) {lit.6d [R]19D ) +16.0° (c 0.5, CHCl3)
Com p ou n d (E)-2: [R]25D ) -4.63° (c 2.1, CHCl3); IR (CHCl3)
2926, 2855, 1701, 1460, 1385, 1366, 1254, 1178, 1099, 1057, 964,
1
851 cm-1; H NMR (400 MHz, C6D6, 75 °C) δ 0.91 (t, 3 H, J )
6.8 Hz), 1.33 (s, 24 H), 1.46 (s, 9 H), 1.57 (s, 3 H), 1.72 (s, 3 H),
2.0 (dt, 2 H, J ) 6.8, 6.3 Hz), 3.56 (dd, 1 H, J ) 3.4, 8.8 Hz),
3.78 (dd, 1 H, J ) 6.0, 8.8 Hz), 4.20 (brs, 1 H), 5.49 (dd, 1 H, J
) 7.2, 15.4 Hz), 5.62 (dt, 1 H, J ) 15.4, 6.3 Hz). HRMS (FAB,
direct) Calcd: [M + H]+ 424.3791. Found: 424.3787 (11%). Anal.
Calcd for C26H49NO3: C, 73.71; H, 11.66; N, 3.31. Found: C,
73.64; H, 11.7; N, 3.25.
(2S,3S,4R)-2-[(ter t-Bu toxyca r bon yl)a m in o]-1,2-O,N-iso-
p r op ylid en e-3,4-ep oxyocta d eca n -1-ol (3). To a solution of
(Z)-2 (4.24 g, 10 mmol) and Na2HPO4 (3.55 g, 25 mmol) in dry
THF (100 mL) was added m-CPBA (4.31 g, 25 mmol) at 0 °C.
The mixture was stirred for 1 h and then 2 days at room
temperature. The solution was treated with saturated aqueous
NaHCO3 and Na2S2O3 and extracted with CH2Cl2. The organic
layer was dried with Na2SO4 and concentrated to give a residue
containing the epoxide 3 and the (2S,3R,4S)-isomer 4 in a 92:8
ratio (by 1H NMR analysis), which was purified by column
chromatography with n-hexane-diethyl ether (4:1), affording 3
(3.67 g, 83.5%) and 4 (170 mg, 3.9%) as solids, respectively.
and lit.6c [R]23 ) +17.5° (c 1.0, CHCl3)}; 1H NMR (400 MHz,
D
CDCl3) δ 0.87 (t, 3 H, J ) 7.0 Hz), 1.24 (s, 26 H), 1.59 (brs, 2 H),
2.00 (s, 3 H), 2.06 (s, 3 H), 2.07 (s, 3 H), 4.05 (dd, 1 H, J ) 3.9,
11.2 Hz), 4.35-4.41 (m, 1H), 4.90 (dt, 1 H, J ) 7.3, 5.4 Hz), 5.96
(d, 1 H, J ) 9.3 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 20.8,
21.0, 22.6, 23.3, 25.3, 29.3, 29.4, 29.5, 29.6, 31.4, 31.9, 50.4, 62.6,
73.9, 169.7, 170.9, 171.1. MS (FAB, direct) Calcd for C24H45
-
NO5: [M + H]+ 428.3. Found: 428.4 (83%).
N,O,O-Tr ia cetyl-L-th r eo-d ih yd r osp h in gosin e (8). The re-
action was carried out as described above for 7, starting from 6
(160 mg, 0.32 mmol). Purification by column chromatography
with n-hexane-EtOAc (5:1) gave 8 (160 mg, 83.1%) as a solid:

Notes
J . Org. Chem., Vol. 65, No. 11, 2000 3541
mp 43-44 °C; [R]25 ) -6.86° (c 2.0, CHCl3); IR (KBr) 3304,
dropwise to the solution. After stirring the mixture for 1 day at
room temperature, the solution was treated with saturated
aqueous Na2S2O3 and was stirred for 30 min. The mixture was
extracted with EtOAc. After drying with Na2SO4, the solvent
was concentrated and the residue was purified by column
chromatography with n-hexane-EtOAc (3:1) to give 15 (300 mg,
55.4%) and the (2S,3R,4S)-isomer 16 (100 mg, 18.5%) as solids,
respectively.
D
2920, 2851, 1746, 1653, 1558, 1541, 1369, 1244, 1047 cm-1; H
1
NMR (400 MHz, CDCl3) δ 0.85 (t, 3 H, J ) 6.8 Hz), 1.22 (s, 26
H), 1.50-1.57 (m, 2 H), 2.00 (s, 3 H), 2.03 (s, 3 H), 2.05 (s, 3 H),
4.00 (d, 2 H, J ) 5.7 Hz), 4.37 (ddt, 1 H, J ) 9.3, 3.4, 6.4 Hz),
5.04 (ddd, 1 H, J ) 3.9, 7.3, 5.9 Hz), 5.74 (d, 1 H, J ) 9.3 Hz);
13C NMR (100 MHz, CDCl3) δ 14.0, 20.7, 20.9, 22.6, 23.1, 25.1,
29.2, 29.3, 29.3, 29.4, 29.6, 29.6, 31.2, 31.8, 49.9, 63.2, 72.3, 170.0,
170.3, 170.7. HRMS (FAB, direct) Calcd for C24H45NO5: [M +
H]+ 428.3376. Found: 428.3369 (72%). Anal. Calcd: C, 67.41;
H, 10.61; N, 3.28. Found: C, 67.38; H, 11.61; N, 3.24.
Com p ou n d 15: mp 55 °C; [R]25 ) -5.36° (c 2.0, CHCl3); IR
D
(KBr) 3412, 2957, 2851, 1688, 1472, 1402, 1366, 1261, 1186,
1111, 1069, 1042, 853 cm-1; 1H NMR (400 MHz, DMSO-d6, 130
°C) δ 0.88 (t, 3 H, J ) 6.8 Hz), 1.28 (s, 24 H), 1.45 (s, 12 H), 1.51
(s, 3 H), 1.41-1.58 (m, 2 H), 3.34-3.38 (m, 1 H), 3.74 (m, 1 H),
3.80 (d, 1 H, J ) 5.9 Hz, exchanged with D2O), 3.84 (dd, 1 H, J
) 6.8, 3.4, 8.8 Hz), 3.88 (d, 1 H, J ) 6.3 Hz, exchanged with
D2O), 4.04 (dt, 1 H, J ) 6.8, 3.4 Hz), 4.10 (dd, J ) 3.4, 8.3 Hz).
HRMS (FAB, direct) Calcd for C26H51NO5: [M + H]+ 458.3845.
Found: 458.3841 (17%). Anal. Calcd: C, 68.23; H, 11.23; N, 3.06.
Found: C, 67.94; H, 11.25; N, 3.02.
(2S,3S,4S)-2-[(ter t-Bu t oxyca r b on yl)a m in o]-1,2-O,N-iso-
p r op ylid en e-4-p h en ylselen ylocta d eca n e-1,3-d iol (9). To a
solution of diphenyl diselenide (160 mg, 0.51 mmol) in absolute
ethanol (3 mL) was added sodium tetrahydroborate (42 mg, 1.11
mmol, evolution of H2) at room temperature. The mixture was
stirred under N2; the yellow solution turned colorless. Then a
solution of 3 (400 mg, 0.91 mmol) in absolute ethanol (3 mL)
was added dropwise and the mixture was heated under reflux
for 2 h. After cooling to room temperature, the mixture was
poured into an ice-cooled 1 M HCl solution and extracted with
diethyl ether. After drying with Na2SO4, the solvent was
removed in vacuo. Purification by column chromatography with
n-hexane-diethyl ether (3:1) gave 9 (470 mg, 86.5%) as an oil:
Com p ou n d 16: mp 38-39 °C; [R]25D ) -30.3° (c 2.0, CHCl3);
IR (KBr) 3464, 2920, 2853, 1678, 1472, 1396, 1366, 1248, 1171,
1
1105, 1074, 1059, 1043, 890 cm-1; H NMR (400 MHz, DMSO-
d6, 130 °C) δ 0.88 (t, 3 H, J ) 6.8 Hz), 1.28 (s, 24 H), 1.46 (s, 12
H), 1.53 (s, 3 H), 1.45-1.65 (m, 2 H), 3.33-3.37 (m, 2 H), 3.76
(d, 1 H, J ) 6.3 Hz, exchanged with D2O), 3.89-3.96 (m, 3 H,
exchanged with D2O), 4.04-4.07 (m, 1 H). HRMS (FAB, direct)
Calcd for C26H51NO5: [M + H]+ 458.3845. Found: 458.3835
(11%). Anal. Calcd: C, 68.23; H, 11.23; N, 3.06. Found: C, 68.16;
H, 11.23; N, 3.16.
[R]25 ) -16.9 ° (c 1.92, CHCl3); IR (CHCl3) 3470, 2926, 2855,
D
1699, 1477, 1366, 1258, 1173, 1094, 847 cm-1
;
1H NMR (400
MHz, DMSO, 100 °C) δ 0.86 (t, 3 H, J ) 6.8 Hz), 1.17-1.35 (m,
24 H), 1.43 (s, 9 H), 1.45 (s, 3 H), 1.50 (s, 3 H), 1.62-1.71 (m, 1
H), 1.78-1.87 (m, 1 H), 3.27-3.33 (m, 1 H), 3.82-3.87 (m, 1 H),
3.85 (dd, 2 H, J ) 6.3, 8.8 Hz), 4.02-4.07 (m, 1 H), 4.22 (dd, 1
H, J ) 2.0, 8.8 Hz), 5.03 (d, 1 H, J ) 5.4 Hz, exchanged with
D2O), 7.2-7.24 (m, 3 H), 7.55-7.59 (m, 2 H). HRMS (FAB, direct)
Calcd for C32H55NO4Se: [M]+ 597.3296. Found: 597.3317 (11%).
Anal. Calcd: C, 64.41; H, 9.29; N, 2.35. Found: C, 64.46; H, 9.31;
N, 2.31.
N,O,O,O-Tetr a a cetyl-D-r ibo-p h ytosp h in gosin e (17). The
reaction was carried out as described above for 7, starting from
15 (140 mg, 0.31 mmol). Purification by column chromatography
with n-hexane-EtOAc (5:1) gave 17 (110 mg, 73.1%) as a solid;
mp 46 °C (lit.7c mp 48 °C); [R]25 ) +26.2° (c 2.0, CHCl3) {lit.7c
D
[R]20 ) +26.3° (c 2.0, CHCl3)}; 1H NMR (400 MHz, CDCl3) δ
D
N,O,O-Tr ia cetyl-D-er yth r o-sh in gosin e (13) via (2S,3S,4S)-
N,O,O-Tr ia cetyl-2-a m in o-4-p h en ylselen ylocta d eca n e-1,3-
d iol (11). The reaction was carried out as described above for 7
starting from 9 (400 mg, 0.67 mmol) without purification. The
obtained crude product 11 was dissolved in a mixture of EtOAc-
THF (2:1, 5 mL), and NaHCO3 (160 mg, 1.9 mmol) was added
to the mixture. To the solution was added slowly 30% hydrogen
peroxide (0.3 mL) at 0 °C. The mixture was stirred for 30 min
at 0 °C and then for 1 h at room temperature. The solution was
treated with saturated aqueous Na2S2O3 and was stirred for 30
min. The mixture was extracted with EtOAc. After drying with
Na2SO4, the solvent was concentrated to give 13 (190 mg, 66.6%)
as a colorless solid after recrystallization from n-hexane-
0.86 (t, 3 H, J ) 7.2 Hz), 1.23 (s, 24 H), 1.63 (brs, 2 H), 2.01 (s,
3 H), 2.03 (s, 6 H), 2.06 (s, 3 H), 3.98 (dd, 1 H, J ) 11.7, 2.9 Hz),
4.26 (dd, 1 H, J ) 11.2, 5.9 Hz), 4.42-4.48 (m, 1 H), 4.91 (dt, 1
H, J ) 9.6, 2.9 Hz), 5.09 (dd, 1 H, J ) 8.3, 2.9 Hz), 6.16 (d, 1 H,
J ) 9.3 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 20.7, 21.0, 22.6,
23.2, 25.4, 28.0, 29.2, 29.3, 29.4, 29.5, 29.6, 31.9, 47.5, 62.8, 71.8,
72.9, 169.8, 170.1, 170.8, 171.1; MS (FAB, direct) Calcd for
C26H47NO7: [M + H]+ 486.3. Found: 486.4 (75%).
N,O,O,O-Tetr a a cetyl-L-a r a bin o-p h ytosp h in gosin e (18).
The reaction was carried out as described above for 7, starting
from 16 (90 mg, 0.20 mmol). Purification by column chromatog-
raphy with n-hexane-EtOAc (5:1) gave 18 (50 mg, 52.3%) as a
solid; mp 47-48 °C; [R]25 ) -25.1° (c 1.5, CHCl3); IR (KBr)
EtOAc: mp 106 °C (lit.5a mp 105-106 °C); [R]25 ) -13.0° (c
D
D
3933, 2918, 2851, 1749, 1684, 1518, 1373, 1232, 1209, 1047 cm-1
;
1
1.0, CHCl3) {lit.5a [R]D ) -12.9° (c 1.0, CHCl3)}; H NMR (400
1H NMR (400 MHz, CDCl3) δ 0.88 (t, 3 H, J ) 6.83 Hz), 1.24 (s,
24 H), 1.54 (brs, 2 H), 1.99 (s, 3 H), 2.05 (s, 3 H), 2.06 (s, 3 H),
2.11 (s, 3 H), 4.00 (d, 2 H, J ) 6.4 Hz), 4.57-4.63 (m, 1 H), 5.00
(dt, 1 H, J ) 4.4, 7.3 Hz), 5.19 (dd, 1 H, J ) 3.2, 6.3 Hz), 5.63 (d,
1 H, J ) 9.8 Hz); HRMS (FAB, direct) Calcd for C26H47NO7: [M
+ H]+ 486.3431. Found: 486.3449 (53%). Anal. Calcd: C, 64.3;
H, 9.75; N, 2.88. Found: C, 64.21; H, 9.71; N, 2.8.
MHz, CDCl3) δ 0.88 (t, 3 H, J ) 6.8 Hz), 1.25 (brs, 22 H), 1.99
(s, 3 H), 2.07 (s, 3 H), 2.08 (s, 3 H), 2.01-2.07 (m, 2 H), 4.04 (dd,
1 H, J ) 11.7, 3.9 Hz), 4.29 (dd, 1 H, J ) 11.7, 6.1 Hz), 4.42 (m,
1 H), 5.28 (dd, 1 H, J ) 6.4, 6.8 Hz), 5.39 (dd, 1 H, J ) 7.3, 15.1
Hz), 5.64 (d, 1 H, J ) 8.8 Hz), 5.79 (dt, 1 H, J ) 15.1, 7.3 Hz);
13C NMR (100 MHz, CDCl3) δ 14.1, 20.8, 21.1, 22.7, 23.3, 28.9,
29.2, 29.3, 29.4, 29.6, 29.6, 31.9, 32.3, 50.6, 62.6, 73.8, 124.1,
137.5, 169.7, 170.0, 171.0. MS (FAB, direct) Calcd for C24H43
-
NO5: [M + H]+ 426.3. Found: 426.4 (38%).
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for all new compounds (Z)- or (E)-2, 3, 4, 6, 8, 9, 15, 16,
and 18. This material is available free of charge via the
Internet at http://pubs.acs.org.
(2S,3S,4R)-2-[(ter t-Bu toxyca r bon yl)a m in o]-1,2-O,N-iso-
p r op ylid en eocta d eca n e-1,3,4-tr iol (15). A solution of N-
methylmorpholine N-oxide hydrate (50% in water, 320 mg) and
acetone (3 mL) was treated with osmium tetroxide (12.7 mg, 0.05
mmol) in tert-butyl alcohol (3 mL). After 15 min at room
temperature, 2 (500 mg, 1.22 mmol) in acetone (2 mL) was added
J O991447X