Synthesis of N-tosylhomosphinganine and N-tosylsedridine

Article abstract of DOI:10.1002/jccs.200800063

A straightforward synthesis of N-tosylhomosphinganine and N-tosylsedridine has been achieved from trans-4-hydroxyproline by Grignard addition, regioselective Baeyer-Villiger reaction, cross or ring-closing metathesis and hydrogenation as the key steps.

Full text of DOI:10.1002/jccs.200800063

Journal of the Chinese Chemical Society, 2008, 55, 421-430
421
Synthesis of N-Tosylhomosphinganine and N-Tosylsedridine
Meng-Yang Changa* (
Tsun-Cheng Wua (
), Chun-Yu Linb (
) and Pei-Pei Sunc (
),
)
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan, R.O.C.
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C.
cCenter of General Studies, National Kaohsiung Marine University, Kaohsiung 811, Taiwan, R.O.C.
A straightforward synthesis of N-tosylhomosphinganine and N-tosylsedridine has been achieved
from trans-4-hydroxyproline by Grignard addition, regioselective Baeyer-Villiger reaction, cross or
ring-closing metathesis and hydrogenation as the key steps.
Keywords: trans-4-Hydroxyproline; N-Tosylhomosphinganine; Sedridine; Allosedridine; Grig-
nard addition; Regioselective Baeyer-Villiger reaction; Cross metathesis; Ring-clos-
ing metathesis.
INTRODUCTION
Based on the structural framework of trans-4-hy-
tutent (sugar, phosphate or sulfate residue) which is at-
tached to a 1-primary hydroxyl group, (2) a fatty acyl chain
which is linked to a 2-amino group by an amide bond, and
(3) a sphingoid base with an 2-amino-1,3-diol. In general,
this family possesses identical structural features of a
sphingoid base except for C4-C5 trans-olefin. Basically,
some novel synthetic methods for this family and related
analogs can be summarized mainly based on asymmetric
methodologies (Sharpless dihydroxylation or expoxida-
tion, Henry reaction, or chiral auxiliaries), chiral-pool
(serine, galactal, glucose, mannose, lyxose, tartartic acid or
aziridine) approaches, and enzymatic resolution.4 Among
this family, the structural characteristics of sphinganine
(1a) provides the simplest skeleton. Compound 1 and the
related analogs 1a~1g are shown in Fig. 2. Here, synthetic
studies toward homosphinganine (1) with an extra methy-
lene group (-CH2-) between the C1-C2 position of sphin-
ganine is described. To date, there are only a few reports for
synthesizing the homo-analogs.5 They have also been dem-
onstrated to possess potential apoptotic activities in HL-60
human leukemia cells.5c Sedum alkaloids with potential bi-
ological activities are a large family of 2-substituted and
2,6-discubstituted piperidines having various hydroxyl
functionalities in the side chain, many of which feature the
1,3-aminoalcohol moiety, for example, sedridine (2) and
allosedridine (2a).6-7 Diverse and elegant synthetic ap-
proaches exist toward sedridine (2) and allosedridine (2a).8
Sedridine (2) and allosedridine (2a) have a common struc-
tural framework of a piperidine ring and their only differ-
ence is the hydroxyl group configuration of the 2-substi-
droxyproline, it possesses three functional groups that can
be easily modified.1 The skeleton represents a significant
feature for producing a series of different carbon frame-
works using an efficient modification technique. Recently
we have introduced a straightforward approach to epiba-
tidine,2a pancracine,2b streptorubin B core,2c 4-aryl-3-hy-
droxyprolinols,2d and statine2e employing trans-4-hydroxy-
proline as the starting material. In connection with our
studies on trans-4-hydroxyproline as the chiral material,
we are interested in developing a new synthetic route to-
ward homosphinganine (homodihydrosphingosine) and
sedridine via Grignard addition, regioselective Baeyer-
Villiger reaction, cross or ring-closing metathesis and hy-
drogenation as the key steps (Fig. 1).
Various sphingolipids with different biological activ-
ities are found widely in nature, having been identified and
isolated from different organisms.3 Structurally, this family
is composed of three distinct subunits: (1) a polar substi-
Fig. 1. Structural characteristics of homosphinganine,
sedridine, and trans-4-hydroxyproline.

422 J. Chin. Chem. Soc., Vol. 55, No. 2, 2008
Chang et al.
Fig. 2. Structural characteristics of the sphinganine family, sedridine and allosedridine.
tuted side chain.
Synthesis of N-tosylhomosphinganine (3)
The synthesis of N-tosylhomosphinganine (3) began
from compound 7 as illustrated in Scheme II. According to
our preliminary reports,2a the four-step preparation of pro-
linol 7 with 90% overall yield was provided from trans-
4-hydroxyproline. Initially, prolinol 7 was treated with
Swern oxidation and followed by diastereoselective Grig-
nard addition to give compounds 12 and 12a as a mixture of
epimers at -78 °C.6 The epimeric ratio was nearly 6:1 as de-
termined by the isolated yield. The diastereoselective addi-
tion occurred in favor of the anti isomer through a chelated
intermediate.9a-b The structural skeleton of compound 12
was determined by single-crystal X-ray analysis.10 Then,
ketone 6 was provided via O-benzylation of allylic alcohol
12 with benzyl bromide and sodium hydride and followed
by desilylation of compound 13 with tetra-n-butylammo-
RESULTS AND DISCUSSION
Retrosynthetic analysis of N-tosylhomosphinganine
and N-tosylsedridine
We now wish to describe a novel synthesis of N-tosyl-
homosphinganine (3) and N-tosylsedridine (8) by the re-
markable key steps as shown in Scheme I. One is the access
to produce the structural framework of tetrahydro-1,3-ox-
azin-6-ones 4 and 10 by the regioselective Baeyer-Villiger
reaction of pyrrolidin-4-ones 5 and 11. The other is a cross
metathesis between ketone 6 and 1-pentadecene and a
ring-closing metathesis of diene 9. Thus, ketones 6 and 11
could be easily synthesized by a series of functional group
transformations of prolinol 7.
Scheme I Retrosynthetic analysis of N-tosylhomosphinganine and N-tosylsedridine

Synthesis of N-Tosylhomosphinganine and N-Tosylsedridine
Scheme II Synthesis of N-tosylhomosphinganine (3)
J. Chin. Chem. Soc., Vol. 55, No. 2, 2008 423
nium fluoride and subsequent oxidation of the correspond-
ing secondary alcohol with pyridinium chlorochromate and
Celite. To elongate the side arm, ketone 6 was subjected to
cross metathesis reaction. Intermolecular olefin cross me-
tathesis reaction has been established as a powerful method
for the synthesis of carbohydrates, heterocycles, and alka-
loids.11 While pondering over the related literature re-
ports,12 we investigated the olefin cross metathesis reac-
tion between ketone 6 and 1-pentadecene. When ketone 6
was subjected to cross metathesis reaction with 1-pen-
tadecene employing first generation Grubbs’ catalyst
[Cl2(PCy3)2Ru=CHPh], the expected compound 5 was only
generated in nearly 20~26% yields under a number of con-
ditions (prolonged reaction time, elevated temperature, and
different solvents). Therefore, we next turned our attention
to examine the second generation Grubbs’ catalyst, which
has higher thermal stability and lower sensitivity to double
bond migration. Using similar reaction conditions, ketone
5 was obtained in 82% yield.
Synthesis of N-tosylsedridine (8)
As shown in Scheme III, we studied the approach to
sedridine (2) from ketone 11, which was prepared from
prolinol 7 as in our preliminary report.2a Regioselective
Baeyer-Villiger lactonization13 of ketone 11 was carried
out by treating with m-chloroperoxybenzoic acid and so-
dium carbonate to afford sole tetrahydro-1,3-oxazin-6-one
10. During the lactonization process, the other ring-ex-
panded framework was not observed. Reduction of the
regioisomer 10 with lithium aluminum hydride provided
1,3-aminoalcohol 14. Compound 9 was synthesized in 74%
yield over two steps via silylation of compound 14 with
t-butyldimethylsilyl chloride and imidazole and followed
by N-alkylation of the resultant product with 4-bromo-1-
butene and sodium hydride at room temperature. The key
ring-closing metathesis was examined in the following
step.14 To build up the piperidine skeleton, diene 9 was sub-
jected to a ring-closing metathesis employing Grubbs’ 2nd
catalyst; the expected 2-substituted piperidine ring 15 was
generated in 88% yield. Compound 15 was further trans-
formed to aldehyde 16 in 82% yield over two steps by
desilylation with tetra-n-butylammonium fluoride and sub-
sequent pyridinium chlorochromate-mediated oxidation
under the standard conditions. When olefinic compound 15
was hydrogenated to yield saturated compound 15a, we
found that Singh and co-workers8m had developed the key
intermediate 15a toward the synthetic applications of
various analogs of sedamine and tetraponerine.
With compound 5 in hand, regioselective Baeyer-
Villiger reaction of compound 5 was next examined. Ac-
cording to the our preliminary experiences and Young’s
group reports,13 compound 5 was successfully treated with
sodium carbonate and m-chloroperoxybenzoic acid to af-
ford the tetrahydro-1,3-oxazin-6-one 4 in 63% yield via the
regiospecific ring expansion by the nitrogen lone pair of
ketone 5. Finally, synthesis of N-tosylhomosphinganine (3)
was accomplished via reduction with lithium aluminum hy-
dride and hydrogenation with hydrogen in the presence of a
catalytic amount of 10% palladium on activated carbon.
Next, Grignard addition of aldehyde 16 with methyl
magnesium bromide yielded a mixture of alcohols 17 and

424 J. Chin. Chem. Soc., Vol. 55, No. 2, 2008
Scheme III Synthesis of N-tosylsedridine (8)
Chang et al.
17a with a nearly 1:1 ratio. Finally, known compounds 8
and 8a were afforded via hydrogenation of compounds 17
and 17a with hydrogen in the presence of a catalytic
amount of 10% palladium on activated carbon. The NMR
spectral data of N-tosylsedridine (8) and N-tosylallosedri-
dine (8a) were in accordance with those reported in the lit-
erature.8h
nitrogen with magnetic stirring. Products in organic sol-
vents were dried with anhydrous magnesium sulfate before
concentration in vacuo. All reported melting temperatures
are uncorrected.
2-(1-Hydroxy-2-propenyl)-4-(t-butyldimethylsilanyloxy)-
1-(4-methylphenylsulfonyl)-pyrrolidine (12)
A stirred solution of oxalyl chloride (400 mg, 3.15
mmol) in CH2Cl2 (20 mL) was mixed with dimethyl sulf-
oxide (400 mg, 5.1 mmol) at –78 °C. The solution was
warmed to –40 °C for 15 min and recooled to –78 °C, and
then a solution of compound 7 (385 mg, 1.0 mmol) in
CH2Cl2 (10 mL) was added dropwise for 90 min followed
by excess triethylamine (4 mL, 28.5 mmol) for 30 min.
The reaction mixture was warmed to rt and poured into
NH4Cl(aq) solution (15%, 2 mL) and concentrated. The resi-
due was diluted with water (15 mL) and extracted with
EtOAc (3 ´ 30 mL). The organic layer was washed with
brine and water, dried, filtered and evaporated to produce
crude product. Without further purification, a solution of
vinylmagnesium bromide (1.0 M in THF, 1.5 mmol, 1.5
mL) was added to a stirred solution of resulting product in
THF (20 mL) at -78 °C. The reaction mixture was stirred at
CONCLUSION
In summary, we succeeded in accomplishing the syn-
thesis of N-tosylhomosphinganine (3) and N-tosylsedridine
(8) and N-tosylallosedridine (8a) from trans-4-hydroxy-
proline via the Grignard addition, regioselective Baeyer-
Villiger reaction, cross or ring-closing metathesis and hy-
drogenation as the key steps.
EXPERIMENTAL
General
Tetrahydrofuran (THF) was distilled prior to use. All
other reagents and solvents were obtained from commer-
cial sources and used without further purification. Reac-
tions were routinely carried out under an atmosphere of dry

Synthesis of N-Tosylhomosphinganine and N-Tosylsedridine
J. Chin. Chem. Soc., Vol. 55, No. 2, 2008 425
rt for 2 h. Saturated NaHCO3(aq) (1 mL) was added to the re-
action mixture and the solvent was concentrated. Water (3
mL) and EtOAc (10 mL) was added to the residue and the
mixture was filtered through a short plug of Celite. The fil-
trate was evaporated to afford the residue. The residue was
extracted with EtOAc (3 ´ 20 mL). The combined organic
layers were washed with brine, dried, filtered and evapo-
rated to afford crude product. Purification on silica gel
(hexane/EtOAc = 4/1) afforded compound 12 (230 mg,
56% of two steps) and compound 12a (37 mg, 9% of two
steps). Compound 12: [a] 2D8 -64.2° (c 0.01, CHCl3); IR
(CHCl3) 3482, 1923, 1341, 1159, 836 cm-1; HRMS (ESI,
M++1) calcd for C20H34NO4SSi 412.1978, found 412.1980;
1H NMR (300 MHz, CDCl3) d 7.73 (d, J = 8.4 Hz, 2H), 7.30
(d, J = 8.4 Hz, 2H), 5.81 (ddd, J = 5.4, 10.5, 17.1 Hz, 1H),
5.35 (dt, J = 2.5, 17.1 Hz, 1H), 5.21 (dt, J = 2.5, 10.5 Hz,
1H), 4.64 (br s, 1H), 4.28-4.23 (m, 1H), 3.71 (dt, J = 2.1,
7.8 Hz, 1H), 3.58 (dd, J = 4.2, 11.1 Hz, 1H), 3.24 (ddd, J =
1.8, 2.4, 11.1 Hz, 1H), 2.99 (br s, 1H), 2.41 (s, 3H), 2.00
(ddd, J = 4.8, 8.1, 12.9 Hz, 1H), 1.64-1.56 (m, 1H), 0.71 (s,
9H), -0.10 (s, 3H), -0.13 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 143.90, 136.33, 134.11, 129.95 (2x), 128.09 (2x),
116.93, 73.37, 69.96, 63.78, 58.80, 36.21, 25.90 (3x),
21.74, 18.20, -4.71, -4.84. Compound 12a: mp 172-173 °C;
[a] 2D9 +81.6° (c 0.01, CHCl3); IR (CHCl3) 3434, 2954,
1636, 1347, 1159 cm-1; HRMS (ESI, M++1) calcd for
C20H34NO4SSi 412.1978, found 412.1978; 1H NMR (300
MHz, CDCl3) d 7.75 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz,
2H), 5.81 (ddd, J = 4.8, 10.8, 17.1 Hz, 1H), 5.40 (dt, J = 1.2,
17.1 Hz, 1H), 5.19 (d, J = 10.8 Hz, 1H), 4.60 (br s, 1H),
4.02-3.96 (m, 1H), 3.88-3.83 (m, 1H), 3.71 (d, J = 5.4 Hz,
1H), 3.38 (dd, J = 5.1, 10.8 Hz, 1H), 3.24 (dd, J = 3.3, 10.8
Hz, 1H), 2.42 (s, 3H), 1.87-1.81 (m, 2H), 0.84 (s, 9H), 0.02
(s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) d 144.04,
137.91, 134.85, 130.02 (2x), 127.76 (2x), 116.18, 73.37,
70.31, 63.55, 57.20, 34.49, 25.83 (3x), 21.76, 18.19, -4.78,
-4.91; Anal. Calcd for C20H33NO4SSi: C, 58.36; H, 8.08; N,
3.40. Found: C, 58.62; H, 8.29; N, 3.56.
afford the residue. The residue was extracted with EtOAc
(3 ´ 20 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated to afford crude
product. Purification on silica gel (hexane/EtOAc = 10/1)
afforded compound 13 (380 mg, 76%) as a viscous oil.
[a]2D9 -20.3° (c 0.01, CHCl3); HRMS (ESI, M++1) calcd for
C27H40NO4SSi 502.2447, found 502.2449; 1H NMR (300
MHz, CDCl3) d 7.72 (d, J = 8.1 Hz, 2H), 7.37-7.23 (m, 7H),
5.70 (ddd, J = 6.0, 10.5, 17.1 Hz, 1H), 5.39 (d, J = 17.1 Hz,
1H), 5.26 (d, J = 10.5 Hz, 1H), 4.63-4.42 (m, 4H),
3.75-3.70 (m, 1H), 3.60 (dd, J = 5.4, 9.9 Hz, 1H), 3.04 (dd,
J = 4.8, 9.9 Hz, 1H), 2.41 (s, 3H), 2.19 (dt, J = 5.4, 12.6 Hz,
1H), 1.50-1.41 (m, 1H), 0.74 (s, 9H), -0.10 (s, 3H), -0.12 (s,
3H); 13C NMR (75 MHz, CDCl3) d 143.48, 139.05, 136.03,
135.07, 129.85 (2x), 128.47 (2x), 127.85 (2x), 127.73 (2x),
127.60, 117.96, 82.28, 72.16, 70.63, 62.94, 56.71, 34.92,
25.96 (3x), 21.73, 18.29, -4.78, -4.85; Anal. Calcd for
C27H39NO4SSi: C, 64.63; H, 7.83; N, 2.79. Found: C,
64.46; H, 8.01; N, 2.51. A solution of tetra-n-butylammo-
nium fluoride (1.0 M in THF, 1.2 mL, 1.2 mmol) in THF (2
mL) was added to a solution of compound 13 (350 mg, 0.7
mmol) in THF (5 mL) at rt. The reaction mixture was
stirred at rt for 2 h, poured into NH4Cl(aq) (15%, 2 mL), and
evaporated to afford the residue. The residue was extracted
with EtOAc (3 ´ 20 mL). The combined organic layers
were washed with brine, dried, filtered and evaporated to
afford crude product. Without further purification, a solu-
tion of the resultant product in CH2Cl2 (5 mL) was added to
a mixture of pyridinium chlorochromate (431 mg, 2.0
mmol) and Celite (1.0 g) in CH2Cl2 (20 mL). After being
stirred at rt for 20 h, the mixture was filtered through a short
silica gel column. The filtrate was dried, filtered and evap-
orated to yield crude product. Purification on silica gel
(hexane/EtOAc = 5/1) afforded compound 6 (215 mg, 80%
of two steps). mp 83-84 °C; [a] 2D8 +123.2° (c 0.01, CHCl3);
IR (CHCl3) 2953, 1759, 1625, 1152 cm-1; HRMS (ESI,
M++1) calcd for C21H24NO4S 386.1426, found 386.1423;
1H NMR (300 MHz, CDCl3) d 7.71 (d, J = 8.1 Hz, 2H),
7.34-7.26 (m, 5H), 7.15 (d, J = 8.1 Hz, 2H), 5.67 (ddd, J =
6.0, 10.5, 17.1 Hz, 1H), 5.39 (dt, J = 2.0, 17.1 Hz, 1H), 5.29
(dt, J = 2.0, 10.5 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.36-
4.27 (m, 2H), 4.22 (d, J = 11.7 Hz, 1H), 3.76 (d, J = 17.7
Hz, 1H), 3.69 (d, J = 17.7 Hz, 1H), 2.50 (d, J = 18.0 Hz,
1H), 2.42 (s, 3H), 2.10 (dd, J = 9.6, 18.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 209.30, 144.36, 137.94, 135.86,
134.24, 130.33 (2x), 128.63 (2x), 127.82, 127.28 (2x),
127.24 (2x), 119.71, 83.36, 71.42, 60.84, 53.95, 37.29,
2-(1-Benzyloxy-2-propenyl)-1-(4-methylphenylsulfonyl)-
pyrrolidin-4-one (6)
A solution of compound 12 (410 mg, 1.0 mmol) in
THF (5 mL) was added to a rapidly stirred suspension of
sodium hydride (60%, 100 mg, 2.5 mmol) in THF (10 mL).
After the reaction mixture was stirred at rt for 10 min, a so-
lution of benzyl bromide (200 mg, 1.16 mmol) in THF (2
mL) was added. The reaction mixture was stirred at rt for
20 h, poured into NH4Cl(aq) (15%, 2 mL), and evaporated to

426 J. Chin. Chem. Soc., Vol. 55, No. 2, 2008
Chang et al.
21.77; Anal. Calcd for C21H23NO4S: C, 65.43; H, 6.01; N,
3.63. Found: C, 65.27; H, 6.33; N, 3.96.
2.47-2.39 (m, 1H), 2.41 (s, 3H), 2.06 (q, J = 6.9 Hz, 2H),
1.26 (br s, 22H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) d 169.28, 145.06, 138.17, 137.48, 135.15,
130.34 (2x), 128.73 (2x), 128.08 (3x), 127.90 (2x), 124.92,
82.56, 76.17, 71.48, 55.42, 32.56, 32.16, 29.92 (5x), 29.69,
29.59, 29.44, 29.19, 28.51, 22.92, 21.87, 14.36; Anal.
Calcd for C34H49NO5S: C, 69.95; H, 8.46; N, 2.40. Found:
C, 70.28; H, 8.32; N, 2.68.
2-(1-Benzyloxy-2-pentadecenyl)-1-(4-methylphenylsul-
fonyl)-pyrrolidin-4-one (5)
Grubbs’ 2nd generation catalyst (30 mg) was added to
a solution of compound 6 (200 mg, 0.52 mmol) in CH2Cl2
(50 mL) at rt. The reaction mixture was refluxed under ni-
trogen atmosphere for 2 h. The mixture was evaporated and
purified by flash column chromatography (hexane/EtOAc
= 4/1) to yield compound 5 (242 mg, 82%). mp 50-51 °C;
[a] 2D8 +2.3° (c 0.01, CHCl3); IR (CHCl3) 2924, 2853, 1766,
1455, 1351, 1159, 1093 cm-1; HRMS (ESI, M++1) calcd for
3-(4-Methylphenylsulfonylamino)-nonadecan-1,4-diol
(3)
A solution of the compound 4 (115 mg, 0.2 mmol) in
THF (10 mL) was added to a rapidly stirred suspension of
lithium aluminum hydride (76 mg, 2.0 mmol) at 0 °C. The
reaction mixture was stirred at rt for 2 h. NH4Cl(aq) (15%, 2
mL) was added to the reaction mixture. The residue was fil-
tered through a short plug of Celite and washed with
EtOAc (2 ´ 10 mL). The combined organic layers were
evaporated to yield the crude product. Without further puri-
fication, the resultant compound was dissolved in MeOH
(20 mL) and 10% palladium on activated carbon (10 mg) as
catalyst was added. Then hydrogen was bubbled into the
mixture for 10 min, and stirring occurred at rt for 10 h. The
catalyst was filtered through a short plug of Celite and
washed with MeOH (2 ´ 10 mL). The combined organic
layers were evaporated under reduced pressure to yield the
crude product. Purification on silica gel (hexane/EtOAc =
5/1) afforded compound 3 (43 mg, 46%). mp 76-77 °C;
HRMS (ESI, M++1) calcd for C26H48NO4S 470.3304,
found 470.3306; 1H NMR (300 MHz, CDCl3) d 7.77 (d, J =
8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 5.32 (br d, J = 7.5 Hz,
1H), 3.85-3.78 (m, 1H), 3.70-3.63 (m, 1H), 3.41-3.33 (m,
1H), 3.31-3.26 (m, 1H), 2.43 (s, 3H), 1.95 (br s, 2H), 1.73-
1
C34H50NO4S 568.3461, found 568.3464; H NMR (300
MHz, CDCl3) d 7.70 (d, J = 8.1 Hz, 2H), 7.31-7.22 (m, 5H),
7.12 (d, J = 8.1 Hz, 2H), 5.79 (dt, J = 6.6, 15.3 Hz, 1H),
5.22 (dd, J = 7.2, 15.3 Hz, 1H), 4.50 (d, J = 12.0 Hz, 1H),
4.27 (br s, 1H), 4.25 (br s, 1H), 4.17 (d, J = 12.0 Hz, 1H),
3.76 (d, J = 17.7 Hz, 1H), 3.69 (d, J = 17.7 Hz, 1H), 2.51 (d,
J = 17.7 Hz, 1H), 2.42 (s, 3H), 2.11 (dd, J = 9.6, 17.7 Hz,
1H), 2.05 (q, J = 7.2 Hz, 2H), 1.26 (br s, 22H), 0.88 (t, J =
6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 209.59, 144.23,
138.22, 137.22, 136.01, 130.27 (2x), 128.57 (2x), 127.68,
127.26 (2x), 127.18 (2x), 125.63, 83.17, 70.83, 61.36,
53.99, 37.51, 32.59, 32.15, 29.92 (3x), 29.85 (2x), 29.67,
29.59, 29.42, 29.19, 22.92, 21.76, 14.35; Anal. Calcd for
C34H49NO4S: C, 71.92; H, 8.70; N, 2.47. Found: C, 72.30;
H, 8.41; N, 2.78.
4-(1-Benzyloxy-2-pentadecenyl)-3-(4-methylphenylsul-
fonyl)-[1,3]oxazinan-6-one (4)
A solution of m-chloroperoxybenzoic acid (138 mg,
75%, 0.6 mmol) in CH2Cl2 (10 mL) was added to a solution
of ketone 5 (210 mg, 0.37 mmol) and Na2CO3 (106 mg, 1.0
mmol) in CH2Cl2 (20 mL) at 0 °C. The reaction mixture
was stirred at rt for 20 h. Saturated Na2CO3(aq) (10 mL) was
added to the reaction mixture and the solvent was evapo-
rated to afford the residue. The residue was extracted with
EtOAc (3 ´ 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product. Purification on silica gel (hexane/EtOAc =
4/1~2/1) afforded compound 4 (136 mg, 63%) as a viscous
oil. [a] 2D6 -3.8° (c 0.01, CHCl3); HRMS (ESI, M++1) calcd
for C34H50NO5S 584.3410, found 584.3410; 1H NMR (300
MHz, CDCl3) d 7.73 (d, J = 8.1 Hz, 2H), 7.39-7.24 (m, 7H),
5.90-5.80 (m, 1H), 5.80 (d, J = 12.0 Hz, 1H), 5.29 (d, J =
12.0 Hz, 1H), 5.24 (dd, J = 7.5, 15.6 Hz, 1H), 4.62 (d, J =
11.7 Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H), 4.36 (d, J = 7.5 Hz,
1H), 3.72-3.66 (m, 1H), 3.00 (dd, J = 10.5, 16.2 Hz, 1H),
1.58 (m, 2H), 1.25 (br s, 28H), 0.88 (t, J = 6.9 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) d 143.84, 137.80, 130.03 (2x),
127.18 (2x), 73.32, 58.54, 55.06, 33.92, 32.16, 30.46,
29.94 (5x), 29.82 (2x), 29.70, 29.60, 29.53, 25.94, 22.93,
21.80, 14.37.
3-(4-Methylphenylsulfonyl)-4-vinyl-[1,3]oxazinan-6-one
(10)
To a solution of m-chloroperoxybenzoic acid (600
mg, 75%, 2.6 mmol) in CH2Cl2 (10 mL) was added a solu-
tion of ketone 11 (265 mg, 1.0 mmol) and Na2CO3 (420 mg,
4.0 mmol) in CH2Cl2 (20 mL) at 0 °C. The reaction mixture
was stirred at rt for 40 h. Saturated aqueous Na2CO3 (10
mL) was added to the reaction mixture and the solvent was
concentrated under reduced pressure. The residue was ex-
tracted with EtOAc (3 ´ 20 mL). The combined organic

Synthesis of N-Tosylhomosphinganine and N-Tosylsedridine
J. Chin. Chem. Soc., Vol. 55, No. 2, 2008 427
layers were washed with brine, dried, filtered and evapo-
rated to afford crude product. Purification on silica gel
(hexane/EtOAc = 4/1~2/1) afforded compound 10 (242
mg, 86%). [a] 3D1.4 -174.31° (c 0.025, CHCl3); HRMS (ESI,
M++1) calcd for C13H16NO4S 282.0800, found 282.0803;
1H NMR (500 MHz, CDCl3) d 7.71 (d, J = 8.0 Hz, 2H), 7.29
(d, J = 8.0 Hz, 2H), 5.83 (ddd, J = 5.0, 10.5, 17.0 Hz, 1H),
5.77 (dd, J = 1.0, 11.5 Hz, 1H), 5.29 (dd, J = 1.5, 17.0 Hz,
1H), 5.25 (dd, J = 1.5, 10.5 Hz, 1H), 5.12 (d, J = 11.5 Hz,
1H), 4.35-4.31 (m, 1H), 2.58 (dd, J = 7.5, 16.5 Hz, 1H),
2.50 (dd, J = 9.0, 16.5 Hz, 1H), 2.37 (s, 3H); 13C NMR (125
MHz, CDCl3) d 167.57, 144.72, 135.07, 134.79, 129.91
(2x), 127.58 (2x), 117.18, 74.00, 52.50, 33.72, 21.36;
Anal. Calcd for C13H15NO4S: C, 55.50; H, 5.37; N, 4.98.
Found: C, 55.69; H, 5.60; N, 5.12.
washed with brine, dried, filtered and evaporated to yield
crude product. Without further purification, a solution of
the resultant product in DMF (2 mL) was added to a rapidly
stirred suspension of sodium hydride (60%, 100 mg, 2.5
mmol) in DMF (3 mL). After the reaction mixture was
stirred at 0 °C for 5 min, 4-bromo-1-butene (110 mg, 0.82
mmol) was added at 0 °C. The resultant mixture was stirred
at rt for 3 h. The reaction was quenched with NH4Cl(aq)
(15%, 2 mL) and the mixture was concentrated. The resi-
due was diluted with water (10 mL) and the mixture was
extracted with EtOAc (3 ´ 20 mL). The combined organic
layers were washed with brine, dried, filtered and evapo-
rated to yield crude product. Purification on silica gel (hex-
ane/EtOAc = 10/1) afforded compound 9 (185 mg, 74%
yield of two steps). [a] 3D0 +40.2° (c 0.005, CHCl3); HRMS
(ESI) m/z calcd for C22H38NO3SSi (M++1) 424.2342, found
424.2344; 1H NMR (500 MHz, CDCl3) d 7.72 (d, J = 9.0
Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H), 5.75-5.57 (m, 2H),
5.12-5.01 (m, 4H), 4.46-4.41 (m, 1H), 3.62-3.53 (m, 2H),
3.17 (ddd, J = 5.0, 10.5, 15.0 Hz, 1H), 3.06 (ddd, J = 5.5,
10.5, 16.0 Hz, 1H), 2.48-2.41 (m, 1H), 2.42 (s, 3H), 2.36-
2.28 (m, 1H), 1.84-1.76 (m, 2H), 0.89 (s, 9H), 0.04 (s, 3H),
0.03 (s, 3H); 13C NMR (125 MHz, CDCl3) d 142.96,
138.10, 136.14, 134.95, 129.49 (2x), 127.33, 127.30 (2x),
117.72, 116.77, 59.83, 56.89, 44.33, 35.53, 25.91 (3x),
21.49, 18.24, -5.38 (2x); Anal. Calcd for C22H37NO3SSi: C,
62.37; H, 8.80; N, 3.31. Found: C, 62.67; H, 8.59; N, 3.66.
2-(1-t-Butyldimethylsilyloxyethyl)-1-(4-methylphenyl-
sulfonyl)-1,2,3,6-tetrahydropyridine (15)
N-[1-(2-Hydroxyethyl)allyl]-4-methylbenzenesulfon-
amide (14)
A solution of compound 10 (200 mg, 0.71 mmol) in
THF (10 mL) was added to a rapidly stirred suspension of
lithium aluminum hydride (76 mg, 2.0 mmol) in THF (20
mL) at 0 °C. The reaction mixture was stirred at rt for 2 h.
NH4Cl(aq) (15%, 2 mL) was added to the reaction mixture
and filtered through a short silica gel column. The filtrate
was dried, filtered and evaporated to yield crude com-
pound. Purification on silica gel (hexane/EtOAc = 2/1) af-
forded aminoalcohol 14 (162 mg, 89%). [a] 3D1. 2 +22.94° (c
0.017, CHCl3); HRMS (ESI) m/z calcd for C12H18NO3S
1
(M++1) 256.1007 found 256.1010; H NMR (500 MHz,
CDCl3) d 7.75 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H),
5.57 (ddd, J = 6.0, 9.5, 16.5 Hz, 1H), 5.24 (d, J = 8.0 Hz,
1H), 4.97 (d, J = 16.5 Hz, 1H), 4.95 (d, J = 9.5 Hz, 1H),
3.99 (br s, 1H), 3.86 (dt, J = 3.5, 12.5 Hz, 1H), 3.69-3.65
(m, 1H), 2.42 (s, 3H), 2.37 (br s, 1H), 1.84-1.78 (m, 1H),
1.61-1.55 (m, 1H); 13C NMR (125 MHz, CDCl3) d 143.39,
137.61, 137.22, 129.58 (2x), 127.12 (2x), 115.78, 58.82,
53.48, 37.22, 21.50; Anal. Calcd for C12H17NO3S: C,
56.45; H, 6.71; N, 5.49. Found: C, 56.59; H, 6.54.; N, 5.85.
N-1-Butenyl-N-[1-(2-t-butyldimethylsilyloxyethyl)allyl]-
4-methylbenzenesulfonamide (9)
Grubbs’2nd catalyst (17 mg, 0.02 mmol) was added to
a solution of compound 9 (150 mg, 0.35 mmol) in CH2Cl2
(10 mL) and the reaction mixture was refluxed under nitro-
gen atmosphere for 2 h. The mixture was concentrated to
yield crude product. Purification on silica gel (hexane/
EtOAc = 8/1) afforded compound 15 (123 mg, 88%). [a] D25
+26.3° (c 0.005, CHCl3); HRMS (ESI) m/z calcd for
1
C20H34NO3SSi (M++1) 396.2029, found 396.2032; H
NMR (500 MHz, CDCl3) d 7.70 (d, J = 8.0 Hz, 2H), 7.24
(d, J = 8.0 Hz, 2H), 5.66-5.58 (m, 2H), 4.41 (br s, 1H), 3.88
(dd, J = 6.0, 14.5 Hz, 1H), 3.74-3.67 (m, 2H), 3.14 (ddd, J =
4.5, 11.5, 14.5 Hz, 1H), 2.41 (s, 3H), 1.87-1.81 (m, 2H),
1.79-1.70 (m, 2H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H);
13C NMR (125 MHz, CDCl3) d 142.93, 138.50, 129.47
(2x), 128.00, 127.01 (2x), 124.77, 60.14, 50.93, 38.31,
37.94, 25.92 (3x), 23.03, 21.49, 18.24, -5.29, -5.41; Anal.
Calcd for C20H33NO3SSi: C, 60.72; H, 8.41; N, 3.54.
t-Butyldimethylsilyl chloride (150 mg, 1.0 mmol)
and imidazole (136 mg, 2.0 mmol) were added to a stirred
solution of compound 14 (150 mg, 0.59 mmol) in DMF (3
mL) at rt. The reaction mixture was stirred at rt for 2 h. The
reaction mixture was concentrated. The residue was diluted
with water (10 mL) and the mixture was extracted with
EtOAc (3 ´ 20 mL). The combined organic layers were

428 J. Chin. Chem. Soc., Vol. 55, No. 2, 2008
Chang et al.
Found: C, 60.59; H, 8.16; N, 3.92.
THF, 0.5 mL, 0.5 mmol) was added to a stirred solution of
compound 16 (50 mg, 0.18 mmol) in THF (5 mL) at -78 °C.
The reaction mixture was stirred at 0 °C for 2 h. The reac-
tion was quenched with NH4Cl(aq) (15%, 1 mL) and the
mixture was concentrated. The residue was diluted with
water (5 mL) and the mixture was extracted with EtOAc (3
´ 20 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated to yield crude product.
Purification on silica gel (hexane/EtOAc = 4/1) afforded
two compounds 17 (21 mg, 40%) and 17a (24 mg, 45%).
For compound 17: [a] D26 +16.8° (c 0.005, CHCl3); HRMS
(ESI) m/z calcd for C15H22NO3S (M++1) 296.1320, found
296.1322; 1H NMR (500 MHz, CDCl3) d 7.72 (d, J = 8.5
Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 5.64-5.56 (m, 2H), 4.40-
4.15 (m, 1H), 4.06-4.01 (m, 1H), 3.90 (dd, J = 6.0, 15.0 Hz,
1H), 3.20 (ddd, J = 5.0, 11.5, 19.5 Hz, 1H), 2.41 (s, 3H),
2.20 (br s, 1H), 1.85-1.61 (m, 4H), 1.26 (d, J = 6.0 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 143.30, 137.94, 129.57
(2x), 127.71, 127.07 (2x), 125.00, 66.30, 52.05, 43.64,
38.28, 23.72, 22.60, 21.52. For compound 17a: [a] D28
-12.8° (c 0.005, CHCl3); HRMS (ESI) m/z calcd for
C15H22NO3S (M++1) 296.1320, found 296.1325; 1H NMR
(500 MHz, CDCl3) d 7.71 (d, J = 8.5 Hz, 2H), 7.26 (d, J =
8.5 Hz, 2H), 5.58-5.51 (m, 2H), 4.51 (dd, J = 2.5, 11.5 Hz,
1H), 4.16-4.10 (m, 1H), 3.90 (dt, J = 3.0, 15.0 Hz, 1H),
3.57 (br s, 1H), 3.11 (ddd, J = 7.0, 9.0, 14.5 Hz, 1H), 2.42
2-(1-t-Butyldimethylsilyloxyethyl)-1-(4-methylphenyl-
sulfonyl)-piperidine (15a)8m
10% Palladium on activated carbon (10 mg) was
added to the solution of compounds 15 (20 mg, 0.05 mmol)
in MeOH (10 mL). Then hydrogen was bubbled into the
mixture for 10 min, and the reaction mixture was stirred for
3 h at rt. The catalyst was filtered through a short plug of
Celite and washed with MeOH (2 ´ 10 mL). The combined
organic layers were evaporated to yield crude compound.
Purification on silica gel (hexane/EtOAc = 10/1) afforded
compound 15a (19 mg, 95%). HRMS (ESI) m/z calcd for
C20H36NO3SSi (M++1) 398.2185, found 398.2184; H
1
NMR (500 MHz, CDCl3) d 7.72 (d, J = 8.0 Hz, 2H), 7.27
(d, J = 8.0 Hz, 2H), 4.16-4.12 (m, 1H), 3.80 (dd, J = 4.0,
14.0 Hz, 1H), 3.57 (t, J = 7.0 Hz, 2H), 2.98 (dt, J = 2.5, 14.0
Hz, 1H), 2.42 (s, 3H), 1.84-1.77 (m, 1H), 1.71-1.64 (m,
1H), 1.57-1.46 (m, 2H), 1.30-1.22 (m, 4H), 0.89 (s, 9H),
0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz, CDCl3) d
142.71, 138.85, 129.56 (2x), 126.99 (2x), 60.62, 50.20,
40.73, 32.59, 29.69, 27.73, 25.91 (3x), 24.68, 21.48, 18.54,
-5.36, -5.43.
2-[1-(4-Methylphenylsulfonyl)-3,4-dihydro-1H-pyridin-
2-yl]-acetaldehyde (16)
A solution of tetra-n-butylammonium fluoride (0.5
mL, 1.0 M in THF, 0.5 mmol) in THF (1 mL) was added to a
solution of compound 15 (100 mg, 0.25 mmol) in THF (3
mL) at rt for 1 h. A mixture of pyridinium chlorochromate
(216 g, 1.0 mmol), Celite (0.5 g) and CH2Cl2 (10 mL) was
added to the stirred reaction. After being stirred at rt for 10
h, the mixture was filtered through a short silica gel col-
umn. The filtrate was dried, filtered and evaporated to yield
crude product. Purification on silica gel (hexane/EtOAc =
8/1) afforded compound 16 (58 mg, 82% yield of two
steps). [a] 2D8 -18.2° (c 0.005, CHCl3); HRMS (ESI) m/z
calcd for C14H18NO3S (M++1) 280.1007, found 280.1008;
1H NMR (500 MHz, CDCl3) d 9.81 (t, J = 2.0 Hz, 1H), 7.71
(d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 5.72-5.66 (m,
2H), 4.84 (br s, 1H), 3.87 (dd, J = 5.5, 14.5 Hz, 1H), 3.11
(ddd, J = 5.0, 11.0, 19.0 Hz, 1H), 2.81 (ddd, J = 2.5, 6.5,
17.0 Hz, 1H), 2.74 (ddd, J = 2.0, 7.5, 17.0 Hz, 1H), 2.42 (s,
3H), 1.87-1.78 (m, 2H); 13C NMR (125 MHz, CDCl3) d
200.08, 143.48, 137.69, 129.71 (2x), 127.01 (2x), 126.59,
126.10, 48.96, 38.57, 29.69, 22.93, 21.53.
(s, 3H), 1.66-1.49 (m, 4H), 1.24 (d, J = 6.5 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) d 143.43, 137.94, 129.67 (2x),
128.10, 126.83 (2x), 124.72, 62.87, 50.99, 43.20, 38.06,
22.46, 22.21, 21.52.
1-[1-(4-Methylphenylsulfonyl)-piperidin-2-yl]-propan-
2-ol (8) and (8a)8h,8m
10% Palladium on activated carbon (10 mg) was
added to the solution of compounds 17a (15 mg, 0.05
mmol) or 17b (15 mg, 0.05 mmol) in MeOH (10 mL). Then
hydrogen was bubbled into the mixture for 10 min, and the
reaction mixture continued to be stirred for 3 h at rt. The
catalyst was filtered through a short plug of Celite and
washed with MeOH (2 ´ 10 mL). The combined organic
layers were evaporated to yield crude compound. Purifica-
tion on silica gel (hexane/EtOAc = 4/1) afforded compound
8 (14.3 mg, 95%) or 8a (14.5 mg, 96%). For compound 8:
[a] 2D6 +21.3° (c 0.005, CHCl3); HRMS (ESI) m/z calcd for
C15H24NO3S (M++1) 298.1477, found 298.1478; 1H NMR
(500 MHz, CDCl3) d 7.75 (d, J = 8.5 Hz, 2H), 7.31 (d, J =
8.5 Hz, 2H), 4.25-4.21 (m, 1H), 4.03-3.97 (m, 1H), 3.91
(dd, J = 4.0, 15.0 Hz, 1H), 3.49 (br s, 1H), 3.02 (dt, J = 2.5,
1-[1-(4-Methylphenylsulfonyl)-3,4-dihydro-1H-pyridin-
2-yl]-propan-2-ol (17) and (17a)
A solution of methylmagnesium bromide (1.0 M in

Synthesis of N-Tosylhomosphinganine and N-Tosylsedridine
J. Chin. Chem. Soc., Vol. 55, No. 2, 2008 429
Lin, G.; Liu, D. Tetrahedron 2005, 61, 4715.
15.0 Hz, 1H), 2.44 (s, 3H), 2.02 (ddd, J = 2.5, 12.5, 14.5
Hz, 1H), 1.48-1.38 (m, 3H), 1.33-1.16 (m, 4H), 1.24 (d, J =
6.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 143.16,
138.67, 129.85 (2x), 126.70 (2x), 63.12, 49.64, 40.81,
39.31, 27.76, 23.87, 22.66, 21.52, 18.67. For compound
8a: [a] 2D8 +36.5° (c 0.005, CHCl3); HRMS (ESI) m/z calcd
5. (a) Shikata, K.; Niiro, H.; Azuma, H.; Tachibana, T.; Ogino,
K. Bioorg. Med. Chem. Lett. 2003, 13, 613. (b) Shikata, K.;
Niiro, H.; Azuma, H.; Ogino, K.; Tachibana, T. Bioorg. Med.
Chem. Lett. 2003, 13, 2723. (c) de Jonge, S.; Lamote, I.;
Venkataraman, K.; Boldin, S. A.; Hillaert, U.; Rozenski, J.;
Hendrix, C.; Busson, R.; de Keukeleire, D.; van Calenbergh,
S.; Futerman, A. H.; Herdewijn, P. J. Org. Chem. 2002, 67,
988.
1
for C15H24NO3S (M++1) 298.1477, found 298.1479; H
NMR (500 MHz, CDCl3) d 7.75 (d, J = 8.5 Hz, 2H), 7.29
(d, J = 8.5 Hz, 2H), 4.23-4.19 (m, 1H), 3.93-3.87 (m, 1H),
3.81 (dd, J = 4.5, 14.5 Hz, 1H), 3.08 (dt, J = 3.0, 14.0 Hz,
1H), 2.43 (s, 3H), 1.90 (dt, J = 8.0, 14.0 Hz, 1H), 1.55-1.32
6. For a review, see: (a) Bates, R. W.; Sa-Ei, K. Tetrahedron
2002, 58, 5957. (b) Buffat, M. P. G. Tetrahedron 2004, 60,
1701. (c) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem.
Commun. 1998, 633.
(m, 6H), 1.26-1.17 (m, 2H), 1.23 (d, J = 6.5 Hz, 3H); 13
C
7. (a) Kim, J. H.; Hart, H. T.; Stevens, J. F. Phytochemistry
1996, 41, 1319. (b) Fodor, G.; Butruille, D.; Huber, S. C.;
Letourneau, F. Tetrahedron 1971, 27, 2025. (c) Weiland, H.;
Koschara, K.; Dane, E.; Renz, J.; Schwarze, W.; Linde, W.
Liebigs Ann. Chem. 1939, 540, 103.
NMR (125 MHz, CDCl3) d 143.07, 138.41, 129.69 (2x),
126.08 (2x), 66.38, 50.95, 40.87, 39.15, 27.79, 24.15,
23.75, 21.50, 18.47. The desulfonated procedure from
compounds 8 and 8a to sedridine (2) and allosedridine (2a)
is shown in references 8h and 8m.
8. For synthesis of sedridine and allosedridine, see: (a) Uyehara,
T.; Chiba, N.; Suzuki, I.; Yamamoto, Y. Tetrahedron Lett.
1991, 32, 4371. (b) Murahashi, S.; Imada, Y.; Kohno, M.;
Kawakami, T. Synlett 1993, 395. (c) Louis, C.; Hootele, C.
Tetrahedron: Asymmetry 1995, 6, 2149. (d) Louis, C.;
Hootele, C. Tetrahedron: Asymmetry 1997, 8, 109. (e) Lit-
tler, B. J.; Gallagher, T.; Boddy, I. K.; Riordan, P. D. Synlett
1997, 22. (f) Takahata, H.; Kubota, M.; Ikota N. J. Org.
Chem. 1999, 64, 8594. (g) Felpin, F.-X.; Lebreton, J. Tetra-
hedron Lett. 2002, 43, 225. (h) Davis, F. A.; Prasad, K. R.;
Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5, 925. (i) Raghavan, S.;
Rajender, A. Tetrahedron 2004, 60, 5059. (j) Kang, B.;
Chang, S. Tetrahedron 2004, 60, 7353. (k) Passarella, D.;
Barilli, A.; Belinghieri, F.; Fassi, P.; Riva, S.; Sacchetti, A.;
Silvani, A.; Danieli, B. Tetrahedron: Asymmetry 2005, 16,
2225. (l) Szakonyi, Z.; D’hooghe, M.; Kanizsai, I.; Fülöp, F.;
De Kimpe, N. Tetrahedron 2005, 61, 1595. (m) Bisai, A.;
Singh, V. K. Tetrahedron Lett. 2007, 48, 1907.
ACKNOWLEDGEMENT
The authors would like to thank the National Science
Council (NSC-95-2113-M-390-003-MY2) of the Republic
of China for financial support.
Received July 17, 2007.
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