A Synthesis of D-erythro- And L-threo-Sphingosine and Sphinganine Diastereomers via the Biomimetic Precursor 3-Ketosphinganine

Article abstract of DOI:10.1021/jo980003i

The four stereoisomers of sphingosine and sphinganine can be produced in protected form by a short, convergent, biomimetic synthesis from serine. Yields are good (26-38% overall from commercially available serine derivatives), and the stereoselectivities are excellent (>92% de, >95% ee). Several sphingosine L-threo-sphingosine analogues with modified, functionalized tails were prepared to demonstrate the versatility of the method.

Full text of DOI:10.1021/jo980003i

J . Org. Chem. 1998, 63, 3979-3985
3979
A Syn th esis of D-er yth r o- a n d L-th r eo-Sp h in gosin e a n d
Sp h in ga n in e Dia ster eom er s via th e Biom im etic P r ecu r sor
3-Ketosp h in ga n in e
Robert V. Hoffman* and J unhua Tao
Department of Chemistry and Biochemistry, New Mexico State University,
Las Cruces, New Mexico 88003-001
Received J anuary 5, 1998
The four stereoisomers of sphingosine and sphinganine can be produced in protected form by a
short, convergent, biomimetic synthesis from serine. Yields are good (26-38% overall from
commercially available serine derivatives), and the stereoselectivities are excellent (>92% de, >95%
ee). Several sphingosine L-threo-sphingosine analogues with modified, functionalized tails were
prepared to demonstrate the versatility of the method.
In tr od u ction
Although known for more than 100 years, the finding
that defects in sphingolipid metabolism lead to several
inherited human diseases and the finding that sphin-
golipids are involved in “essentially all aspects of cell
regulation”1 have led to an explosion of interest in
F igu r e 1.
sphingolipids.1-4 Sphingosine 1 is the core structure of
most sphingolipids 2, which can vary in the nature of
sets the stereochemistry of the C-3 hydroxyl group in one
step (Scheme 1a).8 The second major strategy uses
carbohydrate precursors as the source of stereochemistry
at C-2 and C-3. The tail is then attached by an anionic
addition of some type (Scheme 1b).7,9 The third major
category uses a variety of other chiral precursors to build
up the structure by nucleophilic addition processes.7a,10
A common theme in all these approaches is to set the
stereochemistry of the headgroups early and then attach
and/or manipulate the tail. Moreover, the tail is usually
attached as a nucleophilic species (organometallic, Wittig
reagent, etc.).
the headgroup R1 and the structure of the N-acyl group
R2 (if one is present) (Figure 1).5 Sphingosine analogues
which differ in the nature of the sphingosine tail R3 are
also common, one being the saturated analogue sphin-
ganine 3. Two problems make the utilization of sphin-
golipids from natural sources problematic. First there
are a large number of known sphingolipids which vary
in the headgroups (R1), N-acyl groups (R2), and/or tail
groups (R3) thus making the isolation of homogeneous
material from natural sources difficult.6 Second the
allylic alcohol function undergoes epimerization readily
during isolation or manipulation to produce partially
epimerized mixtures.6 For these reasons synthetic access
to individual sphingosine stereoisomers is an attractive
alternative.
Any sphingosine synthesis must address two key
issues. First, the D-erythro stereochemistry is most
common, but all four possible diastereomers of the 2,3-
Quite a number of syntheses of sphingosine and its
derivatives have been reported. In general these syn-
theses can be grouped into three main categories.7 The
first uses stereoselective addition of an organometallic
reagent (often a lithium acetylide) to a protected serinal.
This approach forms the 3,4 carbon-carbon bond and
(7) (a) For an excellent review of the sphingosine literature, see:
Nugent, T. C.; Hudlicky, T. J . Org. Chem. 1998, 63, 510. (b) For an
excellent discussion of synthetic approaches, see: Schmidt, R. R.; Bar,
T.; Wild, R. Synthesis 1995, 868. (c) Schmidt, R. R. In Synthesis in
Lipid Chemistry; Tyman, J . H. P., Ed.; Royal Society of Chemistry:
Cambridge, U.K., 1996; pp 93-118 and references therein.
(8) For example: (a) Nimkar, S.; Menaldino, D.; Merrill, A. H.;
Liotta, D. Tetrahedron Lett. 1988, 29, 3037. (b) Garner, P.; Park, J .
M.; Malecki, E. J . Org. Chem. 1988, 53, 4395. (c) Herold, P. Helv.
Chim. Acta 1988, 71, 354. (d) Polt, R.; Peterson, M. A.; DeYoung, L.
J . Org. Chem. 1992, 57, 5469 and references therein. (e) Soai, K.;
Takahashi, K. J . Chem. Soc., Perkins Trans. 1 1994, 1258. (f) Dondoni,
A.; Perrone, D.; Turturici, E. J . Chem. Soc., Perkins Trans. 1 1997,
2389.
(9) For example: (a) Hirata, N.; Yamagiwa, Y.; Kamikawa, T. J .
Chem. Soc., Perkin Trans. 1 1991, 2279. (b) Li, Y.-L.; Wu, Y.-L. Liebigs
Ann. 1996, 2079. (c) Murakami, T.; Hato, M. J . Chem. Soc., Perkin
Trans. 1 1996, 823.
(10) See, for example: (a) Katsumura, S.; Yamamoto, N.; Fukuda,
E.; Iwama, S. Chem. Lett. 1995, 393 and references therein. (b) Davis,
F. A.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 4349. (c) Hudlicky, T.;
Nugent, T.; Griffith, W. J . Org. Chem. 1994, 59, 7944. (d) Garigipati,
R. S.; Weinreb, S. M. J . Am. Chem. Soc. 1983, 105, 4499. (e) Spanu,
P.; Rassu, G.; Pinna, L.; Battistini, L.; Casiraghi, G. Tetrahedron:
Assymmetry 1997, 8, 3237. (f) Solladie´-Cavallo, A.; Koessler, J . L. J .
Org. Chem. 1994, 59, 3240. (g) Nicolaou, K. C.; Caulfield, T.; Kataoka,
H.; Kumazawa, T. J . Am. Chem. Soc. 1988, 110, 7910.
(1) For an excellent overview of sphingolipid functions, see: Merrill,
A. H., J r.; Sweeley, C. C. In Biochemistry of Lipids, Lipoproteins and
Membranes; Vance, D. E., Vance, J . E., Eds.; Elsevier Science B. V.:
Amsterdam, 1996; Chapter 12, pp 309-339.
(2) Hannun, Y. A.; Loomis, C. R.; Merrill, A. H., J r.; Bell, R. M. J .
Biol. Chem. 1986, 261, 12604.
(3) Hannun, Y. A.; Bell, R. M. Science 1989, 243, 500.
(4) (a) Merrill, A. H., J r.; Hannun, Y. A.; Bell, R. M. In Advances in
Lipid Research, Vol. 25, Sphingolipids Part A: Functions and Break-
down Products; Bell, R. M., Hannun, Y. A., Merrill, A. H., J r., Eds.;
Academic Press: San Diego, CA; 1993; pp 1-23. (b) Bell, R. M.;
Hannun, Y. A.; Merrill, A. H., J r., Eds. Advances in Lipid Research,
Vol. 25, Sphingolipids Part A: Functions and Breakdown Products;
Academic Press: San Diego, CA; 1993. (c) Cevc, G, Ed. Phospholipids
Handbook; Marcel Dekker: New York, 1993.
(5) Karlsson, K.-A. Lipids 1970, 5, 878.
(6) Kisic, A.; Tsuda, M.; Kulmacz, R. J .; Wilson, W. K.; Schroepfer,
G. J ., J r. J . Lipid Res. 1994, 35, 2305.
S0022-3263(98)00003-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/21/1998

3980 J . Org. Chem., Vol. 63, No. 12, 1998
Hoffman and Tao
Sch em e 1
Sch em e 3
Sch em e 2
Sch em e 4
amino alcohol unit are known and are all bioactive to
different degrees.11 Thus stereochemical control at C-2
and C-3 is crucial. Second, the attachment of functionally
diverse tail groups (other than the C13H27 tail of sphin-
gosine itself) by a trans double bond is required to access
many different sphingosine derivatives that have been
identified. The trans geometry is required for activity
so control of the double-bond geometry is critical. High
levels of stereocontrol are also desirable from a practical
point of view. Because separation of the various sphin-
gosine stereoisomers is difficult, only syntheses which
have high levels of stereocontrol have practical value in
making significant quantities of pure material.
Our interest in the synthesis of densely functionalized
molecules12 led to the retrosynthetic scheme for protected
sphingosine 1 shown in Scheme 2. This strategy is
fundamentally different from other syntheses in both
sequence and polarity. The tail is attached as an
electrophile to â-ketoester 6 and converted to its final
form in ketosphinganine 5. After introduction of the
double bond, stereoselective reduction of the ketone group
of 3-ketosphingosine 4 sets the stereochemistry of the C-3
hydroxyl group in the last stage of the synthesis. We
further envisioned that diastereoselectivity in the amino
ketone reduction might be achieved by tuning the nitro-
gen protecting group P2 for either open or chelated
transition states and thus syn or anti products.
open Felkin-Ahn transition state.12a,b,14 We envisioned
that a trityl protecting group might be superior since its
bulk could enforce an open Felkin-Ahn transition state,
but it is very easily added and removed. Although the
trityl group has been incorporated in a chiral auxiliary,15
to our knowledge, it has never been used by itself as a
stereochemical control element.
Resu lts a n d Discu ssion
To validate this approach, statine was synthesized by
a three-step sequence (Scheme 3). Leucine was trity-
lated16 and carried on without purification to the â-ke-
toester.12 Reduction with NaBH4 gave the tritylated
statine ester in 58% overall yield with an improved
diastereoselectivity of 93% de (cf. 88% for the N,N-
dibenzyl group) and no significant epimerization at C-2
(ee > 95% by an LIS study)! The reduction stereochem-
istry is syn resulting from an open Felkin-Ahn transition
The advantage of this approach is that the ketone
group can serve as the focal point for structural modifica-
tions in 5, and diverse tails can be attached as triflate
electrophiles derived from alcohols. This approach mim-
ics to a degree the biological route to sphingosines which
also passes through 3-ketosphinganine 5 (P1 ) P2 ) H)
as a key intermediate.4a,13
The N,N-dibenzyl protecting group has been used very
successfully to generate high syn diastereoselectivity in
the reduction of R-(N,N-dibenzylamino)ketones via an
state.14
This is by far the shortest and most efficient
synthesis of statine to date.12a
Adaptation of this methodology to the synthesis of
sphingosine is shown in Scheme 4. Commercially avail-
able L-(O-benzyl) serine 7 was tritylated and converted
to â-ketoester 8 with the lithium enolate of allyl acetate.
Ketoester 8 is a white solid which can be obtained in 70%
overall yield (5-10 g scale) after recrystallization from
hexane. Alkylation of 8 with 1-tetradecyl triflate17 gave
(11) Sachs, C. W.; Ballas, L. M.; Mascarella, S. W.; Safa, A. R.;
Lewin, A. H.; Loomis, C.; Carroll, F. I.; Bell, R. M.; Fine, R. L. Biochem.
Pharmacol. 1996, 52, 603.
(12) (a) Hoffman, R. V.; Tao, J .-H. J . Org. Chem. 1997, 62, 2292.
(b) Tao, J .-H.; Hoffman, R. V. J . Org. Chem. 1997, 62, 6240. (c)
Hoffman, R. V.; Tao, J . H. Tetrahedron Lett. In press.
(13) Geeraert, L.; Mannaerts, G. P.; Van Veldhoven, P. P. Biochem.
J . 1997, 327, 125.
(14) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531.
(15) Tomioka, K.; Hamada, N.; Suenaga, T.; Koga, K. J . Chem. Soc.,
Perkin Trans. 1 1990, 426.
(16) Barlos, K.; Papaioannou, P.; Theodoropoulos, D. J . Org. Chem.
1982, 47, 1324.
(17) 1-Bromotetradecane can also be used to alkylate the enolate
by refluxing in THF-HMPA (5:1) with 10% NaI.

Biomimetic Synthesis of Sphingosine
J . Org. Chem., Vol. 63, No. 12, 1998 3981
1e.8b The diastereoselectivity of the reduction was excel-
lent (92% de), and the anti stereochemistry results from
the expected chelation-controlled reduction. Again an
LIS study of 1e showed the sequence was highly enan-
tioselective (>95% ee). Deprotection of 1e to D-erythro-
sphingosine is straightforward.8b
Sch em e 5
Use of L-serine derivatives 7 and 11 as starting
materials gave L-threo-1t and D-erythro-1e diastereomers,
respectively. Using the D-serine enantiomers of 7 and
11 would lead to the D-threo-1t and L-erythro-1e stere-
oisomers, respectively. Thus any one of the four sphin-
gosine stereoisomers can be prepared in pure form simply
by choosing the chirality of the starting serine and the
appropriate protecting group.
As expected, reduction of 3-ketosphinganine 5 with
sodium borohydride gave L-threo-sphinganine derivative
3t in good yield (89%) and high diastereoselectivity (91%
de) without the need for CeCl3 because conjugate reduc-
tion is not an issue (eq 1). Reduction of 3-ketosphinga-
nine 13 under the same conditions gave D-erythro-
sphinganine derivative 3e (90% yield, 91% de) (eq 2). As
before, the use of D-serine derivatives as starting materi-
als would lead to D-threo 3t and L-erythro 3e stereoiso-
mers. Again by choice of the serine starting material and
the nitrogen protecting group, any one of the four
sphinganine stereoisomers can be produced.
9 in 78% yield. Without purification, 9 was treated with
Pd(PPh3)4 at room temperature which effected both
deallylation and decarboxylation to give 3-ketosphinga-
nine 5 in 92% yield.
18
Attempts to introduce the 4,5-double bond into the
alkylated â-ketoester intermediate 9 were not successful.
Neither the Knoevenagle reaction of 8,19a bromination-
elimination of 9,19b or Tsuji oxidation of 919c gave satisfac-
tory results. However conversion of 5 to the TMS-enol
ether using NaHMDS-TMS followed by treatment of the
crude product with Pd(OAc)2 produced the trans-3-
ketosphingosine 4 in excellent yield (90%).20 The trans
isomer was indicated by a vinyl coupling constant J )
15.7 Hz. Within the limits of NMR detection, no cis
isomer was produced.
The reduction of 4 by sodium borohydride with cerium
trichloride present to suppress conjugate reduction pro-
duced L-threo-sphingosine derivative 1t in 85% yield with
excellent diastereoselectivity (93% de).21 The syn stere-
ochemistry of the reduction, expected on the basis of the
statine model study, was confirmed by conversion of 1t
to sphingosine derivative 10 whose threo stereochemistry
was confirmed with comparison to literature data.9b The
optical purity of 1t was determined to be >95% ee by a
lanthanide-induced shift (LIS) study which demonstrates
that no epimerization at C-2 occurred throughout the
entire sequence. Deprotection of 1t to sphingosine can
This methodology lends itself well to the preparation
of radiolabeled sphingosine and sphinganine stereoiso-
mers which are needed to follow their distribution and
metabolism.23,24 For proof of concept, 3-ketosphingosine
4 and 3-ketosphinganine 5 (Scheme 4) were reduced with
NaBD4 to give 1t and 3t, respectively, which were
completely deuterated at C-3. By analogy, the use of
commercially available NaBT4 would provide a very easy
way to incorporate tritium at C-3. Alternatively the use
of allyl acetate-14C2 would yield products with a 14C label
at the C-4 carbon of sphingosine, e.g., 1t.
9b
be carried out by benzyl group removal with Na/NH3
and trityl removal with 50% acetic acid.
Access to the erythro diastereomer of the protected
sphingosine 1 requires that the reduction proceed by a
chelated transition state. Chelation control by an N-Boc-
protected oxazolidine provided the means to reverse the
stereochemical outcome of the sequence.8a,12c
Commercially available L-(N-Boc) serine methyl ester
11 was cyclized to a 2,2-oxazolidine22 and converted to
the â-ketoester 12 in 56% yield (Scheme 5). Alkylation
of 12 with 1-tetradecyl triflate followed by decarboxyla-
tion gave 3-ketosphinganine derivative 13 in 60% yield.
Installation of a double bond gave protected 3-ketosph-
ingosine 14 (90%), and reduction with NaBH4/CeCl3
(87%) gave the known D-erythro-sphingosine derivative
These results have provided a biomimetic synthesis of
the four stereoisomers of sphingosine in protected form
from serine. The sequence is short and convergent,
(18) Friedrich-Bochnitschek, S.; Waldmann, H.; Kunz, H. J . Org.
Chem. 1989, 54, 751.
(19) These transformations were successfully executed on similar
â-ketoesters: (a) Tietze, L.; Steinmetz, A. Angew. Chem., Int. Ed. Engl.
1996, 35, 651. (b) Mignani, G.; Morel, D.; Grass, F. Tetrahedron Lett.
1987, 28, 5505. (c) Shimizu, I.; Tsuji, J . J . Am. Chem. Soc. 1982, 104,
5844.
(20) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011.
(21) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454.
(22) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361.
(23) Smith, E. R.; Merrill, A. H., J r. J . Biol. Chem. 1995, 270, 18749.
(24) (a) Review: Maeda, H.; Seymour, L. W.; Miyamoto, Y. Biocon-
jugate Chem. 1992, 3, 351. (b) Kozikowski, A. P.; Ding, Q.; Spiegel, S.
Tetrahedron Lett. 1996, 37, 279. (c) Yatomi, Y.; Ruan, F.; Ohta, H.;
Welch, R. J .; Hakomori, S.-I.; Igarashi, Y. Anal. Biochem. 1995, 230,
315.

3982 J . Org. Chem., Vol. 63, No. 12, 1998
Hoffman and Tao
Sch em e 6
proceeds in good overall yields (≈30% for six steps from
commercially available materials), and requires little
chromatographic purification. Of the many syntheses
that have been reported for sphingosine, many are as
short and proceed in reasonable yields. For example Polt
reported a four step synthesis from serine (60%),8d
Nicolaou described a seven-step synthesis from a chiral
R-bromoketone (43%),10g and Solladie-Cavallo developed
a seven-step synthesis from a chiral aldehyde (27%).10f
These syntheses are notable for their stereocontrol.
Earlier syntheses (e.g., those of Herold,8c Garner,8b and
Liotta8a) are comparable in length but do not have quite
the same level of stereocontrol.
One reason for the large number of synthetic ventures
is that the majority are problematic in overall stereocon-
trol and convergency. Often when good levels of stereo-
control are possible, the method cannot be modified to
produce a different stereoisomer. For example the Polt
synthesis gives the L-threo isomer but the D-erythro
isomer is not accessible by this chemistry.8d The latter
is available via the routes of Nicolaou10g and Solladie-
Cavallo,10f but these routes cannot produce the L-threo
isomer. These comparisons illustrate a general problem
often encountered in the synthesis of sphingosinessthat
different chemistries are needed to produce the different
stereoisomers.
A second difficulty concerns controlling the cis-trans
geometry of the double bond. The most successful
routes8d,10g,f all have the trans geometry established in
the tail fragment prior to its attachment. Most other
routes to sphingosines require generation of the trans
double bond during attachment of the tail (Wittig) or
after its attachment (alkyne reduction).7a,8-10,25 Invari-
ably a cis-trans mixture is produced which is often
inseparable and which must be photoisomerized to the
all trans geometry. These factors contribute to lowered
yields and/or difficult processing and make the production
of pure compounds impractical on a large scale.
The present method does not have these difficulties.
The choice of the erythro or threo isomers is controlled
by the nitrogen protecting group, but the same synthetic
sequence is used to access either isomer. Moreover, the
Saegusa method used to introduce the double bond20 in
the tail has given only the trans isomer thus far; no traces
of the cis isomer have been detected.
Because this methodology uses attachment of the tail
as an electrophile, it lends itself readily to the prepara-
tion of sphingosine analogues which are modified in the
tail portion. To demonstrate this point, â-ketoester 8 was
alkylated with triflate electrophiles 15a -c which are
derived from commercially available alcohols and decar-
boxylated with Pd[0] to give 16a -c. Saegusa oxidation
gave unsaturated ketones 17a -c which were character-
ized spectrally but normally carried on without extensive
purification. Reduction gave the L-threo sphingosine
analogues 18a -c in satisfactory overall yields (45-50%)
(Scheme 6). The stereocontrol was very good (90-95%
de), and the double bond was exclusively trans within
the limits of NMR detection. While 18a -c have trun-
cated tails, these results demonstrate that functionality
in the sphingosine tail can be introduced easily by choice
of the triflate alkylating agent.
Exp er im en ta l Section
Infrared spectra were taken on as neat liquids or as KBr
pellets. 1H NMR and 13C NMR spectra were recorded at 200
and 50 MHz, respectively, and CDCl3 as NMR solvent. Thin-
layer chromatography was performed on silica gel 60 F254
plates from EM reagents and visualized by UV irridiation and/
or iodine. Analytical HPLC was performed with the indicated
solvent systems and flow rates on 8 mm × 25 mm cm silica
gel columns using UV detection. Preparative thin-layer chro-
matography was performed on silica gel 60 F254 plates from
EM reagents and visualized by UV irradiation. Flash chro-
matography was performed using silica gel 60 (230-400 mesh).
Optical rotations were determined on a Perkin-Elmer 241
polarimeter. Tetrahydrofuran was distilled from benzophe-
none ketyl. Other solvents were HPLC grade and were used
without further purification. Starting materials were pur-
chased from Aldrich, Sigma, or Novabiochem and used as
received. Elemental analyses were carried out by M-H-W
Laboratories, Phoenix, AZ. Lanthanide-induced shift (LIS)
studies were carried out with Eu(hfc)3.
Allyl 4-Tr ityla m in o-3-oxo-5-ben zyloxyp en ta n oa te, 8.
To a stirred solution of N-trityl O-benzyl serine (4.28 g, 9.78
mmol), which was prepared from L-(O-benzyl) serine 7 by a
known procedure,16 in THF (20 mL) was added carbonyl
diimidazole (CDI) (1.57 g, 9.78 mmol) at room temperature
under an N2 atmosphere. The resulting solution was stirred
for 5 h at the same temperature and used for the next reaction
without further purification. Meanwhile, a solution of lithium
enolate was made from BuLi (2.50 M, 12.8 mL, 32.0 mmol),
diisopropylamine (5.90 mL, 32.0 mmol), and allyl acetate (2.10
mL, 19.6 mmol). The above imidazole solution was added
dropwise to this pale yellow solution of lithium enloate at -78
°C under an N2 atmosphere. After 30 min, the resulting
mixture was warmed to room temperature for 60 min, and
then quenched with H2O (50 mL), and extracted with ether (3
× 50 mL). The organic extracts were combined, washed with
brine (100 mL), dried (MgSO4), and passed through a short
pad of silica gel. After concentration, the yellow residue was
triturated with hexane (100 mL) to give a white solid (8) which
was washed with cold Et2O (50 mL × 2): yield 70%, 3.55 g,
6.83 mmol; mp 106-108 °C; [R]25 +45.0 (c 1.29, CHCl3); H
1
D
NMR (CDCl3) δ 2.75 (d, 1H, J ) 16.6 Hz), 3.11 (m, 2H), 3.43
(d, 1H, J ) 16.6 Hz), 3.69 (m, 2H), 4.38 (s, 2H), 4.51 (d, 2H, J
) 5.6 Hz), 5.22 (m, 2H), 5.82 (m, 1H), 7.21-7.41 (m, 20H); 13
C
NMR (CDCl3) δ 47.9, 61.8, 65.5, 72.5, 73.0, 73.4, 118.2, 126.7,
128.0, 128.8, 132.0, 146.0, 166.6, 206.4; FTIR (neat) 3027, 1750,
1720, 1452, 1098, 749, 709 cm-1. Anal. Calcd for C34H33O4N:
H, 6.40; C, 78.59; N, 2.70. Found: H, 6.36; C, 78.70; N, 2.86.
(2S)-2-[N-(Tr ip h en ylm et h yl)a m in o]-3-oxo-1-O-b en zy-
locta d eca n -1-ol, 5. A solution of 8 (754 mg, 1.45 mmol) in
THF (10 mL) was added dropwise to a stirred suspension of
NaH (70 mg of 60% in oil, 1.75 mmol) in dry THF (10 mL) at
0 °C under nitrogen. The mixture was stirred for 10 min. To
this mixture was then added CH3(CH2)13OTf (552 mg, 1.60
mmol), which was prepared from a known procedure.12 The
resulting solution was stirred for 6 h, washed by H2O (50 mL),
and extracted by ether (75 mL × 2). The organic extracts were
(25) (a) Ohashi, K.; Yamigawa, Y.; Kamikawa, T.; Kates, M.
Tetrahedron Lett. 1988, 29, 1185. (b) Bernet, B.; Vasella, A. Tetrahe-
dron Lett. 1983, 24, 5491.

Biomimetic Synthesis of Sphingosine
J . Org. Chem., Vol. 63, No. 12, 1998 3983
combined, washed by brine (50 mL), dried (MgSO4), passed
through a short pad of silica gel, and concentrated to provide
a pale yellow oil. Without further purification, this oil was
dissolved in THF (10 mL). To this stirred solution under
nitrogen was then added Pd(PPh3)4 (169 mg, 0.15 mmol)
followed by morpholine (1.30 mL, 14.8 mmol). After 3 h, the
solvent was evaporated and the residue was taken up in ether
(100 mL) and filtered. The filtrate was washed with 5% cold
citric acid (20 mL × 2) and H2O (20 mL), dried (MgSO4), passed
through a short pad of silica gel, and concentrated to afford
colorless oil 5 (669 mg, 1.06 mmol, 73%) after purification by
N HCl (10 mL). The reaction was monitored by TLC. After 1
h of stirring, the mixture was extracted with ethyl acetate (50
mL × 3), dried (MgSO4), and concentrated to provide 10 as a
colorless gel (39 mg, 0.083 mmol, 73%) after flash chromatog-
raphy (ethyl acetate:methanol ) 50:2): [R]25 +4.72 (c 0.53,
D
CHCl3); 1H NMR δ 0.88 (t, 3H, J ) 6.6 Hz), 1.21-1.36 (m,
22H), 2.10 (m, 2H), 3.04 (m, 1H), 3.42-3.59 (m, 2H), 3.74 (dd,
1H, J ) 7.0, 8.1 Hz), 4.32 (d, 1H, J ) 11.4 Hz), 4.48 (d, 2H, J
) 4.0 z), 4.58 (d, 1H, J ) 11.4 Hz), 5.32 (dd, 1H, J ) 7.3, 15.3
Hz), 5.69 (dt, 1H, J ) 6.9, 15.3 Hz), 7.26-7.31 (m, 10H); FTIR
(neat) 3390, 1645 cm-1. Anal. Calcd for C32H49O2N‚HCl: C,
74.46; H, 9.76; N, 2.71. Found: C, 74.84; H, 9.51; N, 2.72.
These data are consistent with a structure assignment for 10
as the L-threo isomer by comparison with the literature data
for the D-erythro diastereosomer.9b
flash chromatography (hexane:ether ) 85:5 to 85:10): [R]25
D
+5.55 (c 2.1, CHCl3); 1H NMR δ 0.88 (t, 3H, J ) 6.6 Hz), 1.26
(br s, 26H), 2.11-2.20 (m, 2H), 3.29 (m, 2H), 3.57 (br, 1H),
3.75 (dd, 1H, J ) 4.7, 4.8 Hz), 4.43 (s, 2H), 7.23-7.43 (wo set
of m, 20H); 13C NMR δ 14.1, 22.7, 28.8, 29., 29.7, 31.9, 41.9,
61.2, 71.0, 73.2, 126.4, 127.5, 127.9, 128.3, 128.9, 137.9, 146.4,
213.6; FTIR (neat) 2927, 1720, 1461, 709 cm-1. Anal. Calcd
for C44H57O2N: C, 83.63; H, 9.09; N, 2.22. Found: C, 83.72;
H, 9.25; N, 1.95.
(4S)Allyl 3-Oxo-3-(2,2-d im eth yl-3-ter t-bu toxyca r bon yl)-
4-oxa zolid in ylp r op a n oa te, 12. (4S)-Methyl 3-(tert-butoxy-
carbonyl)-2,2-dimethyl-3,4-oxazolidine-4-carboxylate (1.30 g,
5.00 mmol), which was prepared by a known procedure from
N-Boc serine methyl ester,22 was dissolved in THF-H2O (10
mL:5 mL) with stirring. To this mixture was then added LiOH
(200 mg, 5.00 mmol). After 1.5 h, the mixture was neutralized
and THF was removed under vacuum. The aqueous residue
was then extracted with ethyl acetate (50 mL × 4), dried
(MgSO4), filtered, and concentrated to provide the correspond-
1-Bromotetradecane can also be used to alkylate the enolate
by refluxing in THF-HMPA (5:1) with 10% (in mol) NaI.
(2S,3S,4E)-2-[N-(Tr ip h en ylm eth yl)a m in o]-1-O-ben zyl-
4-octa d ecen e-1, 3-d iol, 1t. NaHMDS (2.0 M in THF, 0.15
mL, 0.30 mmol) was added to a -78 °C solution of 5 (150 mg,
0.24 mmol) in THF (20 mL). After 3.5 h at the same
tempreture, a solution of TMSCl (41 mg, 0.38 mmol) in THF
(10 mL) was added. The resulting solution was stirred at rt
for 1 h, diluted with hexane (100 mL), washed with ice-cold
saturated aqueous sodium bicarbonate (20 mL × 2), dried
(MgSO4), filtered and concentrated to provide a residue. The
residue was dissolved in CH3CN (3 mL) under nitrogen and
treated with Pd(OAc)2, (32 mg, 0.15 mmol) followed by p-
benzoquinone (16 mg, 0.15 mmol). The resulting mixture was
stirred at rt for 8 h, filtered, and concentrated to provide pale
yellow oil 4. Without further purification, 4 was dissolved in
dry methanol (6.0 mL) and cooled to -20 °C. To this solution
was then added CeCl3‚7H2O (29 mg, 0.08 mmol), followed by
NaBH4 (10.0 mg, 0.26 mmol). The reaction was monitored by
TLC. After 3 h at -20 °C, the solution was quenched with
H2O (20 mL), extracted by ether (2 × 50 mL), washed with
brine (50 mL), dried (MgSO4), and concentrated to provide 1t
as a colorless oil (101 mg, 0.16 mmol, 77% from 5, de 93% based
on 1H NMR) after purification by flash chromatography
(hexane:ether ) 85:10). The major diastereomer had ee > 95%
by a chiral LIS study using Eu(hfc)3 in comparison with a
1
ing carboxylic acid in quantative yield by H NMR. Without
further purification, the acid was dissolved in THF (20 mL).
To this stirred solution was added CDI (895 mg, 5.00 mmol)
at room temperature under an N2 atmosphere. The resulting
solution was stirred for 2 h at the same temperature and used
for the next reaction without further purification. Meanwhile,
a solution of lithium enolate was made from BuLi (2.50 M,
4.56 mL, 11.4 mmol), diisopropylamine (2.10 mL, 11.4 mmol),
and allyl acetate (1.22 mL, 11.4 mmol). The above imidazole
solution was added dropwise to this pale yellow solution of
lithium enloate at -78 °C under an N2 atmosphere. After 1 h
at the same temperature, the resulting mixture was warmed
to room temperature for 30 min, then quenched with H2O (50
mL), and extracted with ethyl acetate (3 × 50 mL). The
organic extracts were combined, washed with brine 100 mL),
dried (MgSO4), passed through a short pad of silica gel, and
concentrated to provide 12 as a colorless oil (56% based on
N-Boc serine methyl ester) after purification by flash chroma-
tography (hexane:ethyl acetate ) 4:1 to 4:2): [R]25 -58.0 (c
D
5.84, CHCl3); 1H NMR (CDCl3) (mixture of rotamers) δ 1.43-
1.09 (m, 15H), 3.59 (m, 2H), 4.03-4.10 (m, 2H), 4.38-4.60 (m,
1H), 4.65 (d, 2H, J ) 5.5 Hz), 5.29 (m, 2H), 5.90 (m, 1H); 13C
NMR (CDCl3) (mixture of rotamers) δ 23.6, 24.9, 25.5, 26.1,
28.3, 44.8, 45.4, 46.4, 59.6, 65.0, 65.4, 66.1, 81.4, 88.4, 95.4,
119.0, 131.6, 151.2, 166.6, 201.1; FTIR (neat) 2986, 1750, 1714,
1696, 1374, 1166, 1093 cm-1. Anal. Calcd for C16H25O6N: C,
58.70; H, 7.70; N, 4.28. Found: C, 58.90; H, 7.72; N, 4.10.
(4R)-1,1-Dim eth yleth yl 2,2-Dim eth yl-4-(1-oxo-2-h exa -
d eca n yl)-3-oxa zolid in eca r boxyla te, 13. The procedure
used to prepare 5 was used to convert 12 to 13 in 60% yield
after purification by flash chromatography (hexane:ethyl
racemic sample: [R]25 -13.4 (c 1.43, CHCl3); 1H NMR δ 0.88
D
(t, 3H, J ) 6.7 Hz), 1.23-1.26 (br s, 22H), 1.95 (m, 2H), 2.27
(m, 1H), 2.87-2.93 (m, 1H), 3.94 (dd, 1H, J ) 6.7, 7.0 Hz),
4.00 (d, 1H, J ) 11.8 Hz), 4.17 (d, 1H, J ) 11.8 Hz), 5.33 (dd,
1H, J ) 7.3, 15.3 Hz), 5.52 (dt, 1H, J ) 6.4, 15.3 Hz)), 7.19-
7.56 (two sets of m, 20H); 13C NMR δ 14.1, 22.6, 29.1, 29.6,
31.9, 32.3, 55.9, 68.1, 70.8, 72.8, 73.7, 126.4, 127.9, 128.3, 128.8,
129.7, 134.7, 137.9, 146.7; FTIR (neat) 3426, 2907, 1462, 709
cm-1. Anal. Calcd for C44H57O2N: C, 83.63; H, 9.09; N, 2.22.
Found: C, 83.74; H, 8.83; N, 2.19.
Intermediate 4 could be isolated as a pale yellow oil in 90%
yield and characterized completely: 1H NMR δ 0.88 (t, 3H, J
) 6.2 Hz), 1.23-1.26 (br s, 22H), 2.02 (m, 2H), 3.33 (dd, 1H, J
) 6.7, 8.9 Hz), 3.72 (m, 2H), 4.44 (s, 2H), 5.81 (d, 1H, J ) 15.7
Hz), 6.37 (dt, 1H, J ) 7.2, 15.7 Hz), 7.23-7.45 (m, 20H); 13C
NMR d 14.0, 22.6, 27.9, 29.6, 31.9, 32.2, 59.7, 71.0, 73.2, 126.3,
127.4, 127.8, 128.9, 138.0, 146.4, 201.8; FTIR (neat) 2917, 1696,
1631 cm-1. Anal. Calcd for C44H55O2N: C, 83.90; H, 8.80; N,
2.22. Found: C, 83.69; H, 8.76; N, 2.09. In practice 4 was
normally quite pure and carried on as the crude product to
1t.
(2S,3S,4E)-2-Am in o-1,3-d i-O-b en zyloct a d ec-4-en e-1,3-
d iol, 10. Alcohol 1t (70 mg, 0.11 mmol) was dissolved in DMF
(5 mL) and treated with NaH (5 mg, 0.12 mmol) at 0 °C. After
10 min BnBr (23 mg, 0.13 mmol) was added. The resulting
solution was stirred for 2 h at room temperature, extracted
with ether (50 mL × 3), and concentrated in a vacuum to
provide a pale yellow residue. Without further purification,
the residue was dissolved in THF (5 mL) and treated with 1
acetate ) 4:0.25): [R]25 -24.3 (c 1.59, CHCl3); 1H NMR
D
(CDCl3) (mixture of rotamers) δ 0.88 (t, 3H, J ) 6.1 Hz), 1.26
(s, 9H), 1.12-1.71 (set of m, 32H), 2.47-2.51 (two sets of m,
1H); 13C NMR (CDCL3) (mixture of rotamers) δ 14.43, 23.0,
23.4, 24.0, 25.2, 25.7, 26.5, 28.2, 28.7, 29.7, 30.0, 32.3, 38.8,
39.4, 65.7, 66.1, 80.8, 94.8, 95.5, 151.8, 152.8, 208.6, 209.0;
FTIR (neat) 2927, 1716 (br), 1367, 1173 cm-1. Anal. Calcd
for C26H49O4N: C, 71.03; H, 11.23; N, 3.19. Found: C, 71.24;
H, 11.02; N, 2.97.
1,1-Dim eth yl [R-[R*,S*-(E)]]-2,2-Dim eth yl-4-(1-h ydr oxy-
2-h exa d ecen yl)-3-oxa zolid in eca r boxyla te, 1e. The pro-
cedure used to prepare 1t was used with an overall yield of
78% from 13 after purification by flash chromatography
(hexane:ethyl acetate ) 4:0.5): [R]25 -27.3 (c 0.54, CHCL3)
D
(lit.8b [R]25 -28 (c 0.65, CHCl3)); de 92%. The major diaste-
D
reomer had ee > 95% by a chiral LIS study using Eu(hfc)3 in
comparison with a racemic sample: 1H NMR (CDCl3) (mixture
of rotamers) δ 0.88 (t, 3H, J ) 6.6 Hz), 1.25 (br s, 22H), 1.49
(br s, 9H), 1.43-1.59 (m, 6H), 2.17 (m, 2H), 3.64-4.24 (two

3984 J . Org. Chem., Vol. 63, No. 12, 1998
Hoffman and Tao
sets of m, 4H), 5.46 (dd, J ) 5.3, 15.3 Hz), 5.74 (dt, J ) 6.5,
15.3 Hz, 1H); FTIR (neat) 3436, 1700 cm-1. Anal. Calcd for
C26H49O4N: C, 71.03; H, 11.23; N, 3.19. Found: C, 71.10; H,
11.00; N, 2.88.
2H, J ) 8.7 Hz), 7.04 (d, 2H, J ) 8.7 Hz), 7.18-7.46 (two sets
of m, 20H); 13C NMR δ 23.0, 28.9, 31.8, 35.2, 42.2, 55.6, 61.6,
71.5, 73.7, 112.7, 114.2, 126.9, 128.3, 129.3, 135.2, 138.4, 146.8,
158.2, 213.8; FTIR (neat) 2937, 1716, 739 cm-1. Anal. Calcd
for C41H43O3N: C, 82.38; H, 7.25; N, 2.34. Found: C, 82.24;
H, 7.14; N, 2.23.
Intermediate 14 could be isolated as a pale yellow oil in 90%
yield and characterized completely: 1H NMR (CDCl3) (mixture
of rotamers) δ 0.88 (t, 3H, J ) 7.0 Hz), 1.26-1.70 (set of m,
37H), 2.22 (m, 2H), 3.94-4.17 (two sets of m, 2H), 4.50-4.70
(two sets of m, 1H), 6.22-6.34 (two sets of d, 1H, both J )
15.7 Hz), 7.01 (dt, 1H, J ) 6.9, 15.7 Hz); 13C NMR (CDCl3)
(mixture of rotamers) δ 14.0, 22.6, 24.1, 25.1, 26.0, 28.3, 29.3,
29.6, 31.9, 32.7, 63.8, 64.1, 65.4, 65.8, 80.4, 94.4, 95.1, 125.2,
(2S,7R)-2-[N-(Tr ip h en ylm eth yl)a m in o]-7,11-d im eth yl-
3-oxo-1-O-ben zyl-10-d od ecen e-1-ol, 16c, was prepared by
the alkylation of 8 with 15c by the same procedure used to
convert 8 to 5 in 71% yield after purification by flash chro-
matography (hexane:ether ) 85:5 to 85:10): [R]25 +53.7 (c
D
1
0.69, CHCl3); H NMR δ 0.79 (d, 3H, J ) 6.3 Hz), 0.88-1.41
149.6, 196.6; FTIR (neat) 2921, 1710 (br), 1627 cm-1
.
In
(set of m, 7H), 1.59 (s 3H), 1.68 (s, 3H), 1.91 (m, 2H), 2.04-
2.30 (m, 2H), 3.30 (m, 2H), 3.54 (br, 1H), 3.77 (dd, 1H, J )
4.4, 4.5 Hz), 4.43 (s, 2H), 5.08 (m, 1H), 7.19-7.41 (two sets of
m, 20H); 13C NMR δ 17.6, 19.4, 25.5, 32.0.2, 36.1, 36.8, 42.2,
61.2, 70.9, 73.2, 124.9, 126.4, 127.9, 128.3, 128.9, 130.9, 137.9,
146.4, 213.6; FTIR (neat) 2917, 1716, 1451, 709 cm-1. Anal.
Calcd for C40H47O2N: C, 83.73; H, 8.26; N, 2.44. Found: C,
83.79; H, 8.35; N, 2.39.
practice 14 was quite pure and was carried on as the crude
product to 1e.
(2S,3S)-2-[N-(Tr ip h en ylm eth yl)a m in o]-1-O-ben zylocta -
d eca n -1,3-d iol, 3t. Gen er a l P r oced u r e. A solution of 5 (90
mg, 0.142 mmol) in dry methanol (5.0 mL) (a minimum
amount of THF was added to increase the solubility) was
cooled to -20 °C and treated with NaBH4 (11.0 mg, 0.28
mmol). The reaction was monitored by TLC. After 8 h, the
solution was quenched with H2O (100 mL), extracted by ether
(2 × 75 mL), washed by brine (50 mL), dried (MgSO4), and
concentrated to provide 3t as a colorless oil (80 mg, 0.13 mmol,
89%, de 91% based on 1H NMR) after purification by flash
(2S ,4E )-2-[N -(T r ip h e n y lm e t h y l)a m in o ]-3-o x o -1-O -
ben zyl-9-O-ter t-bu tyldim eth ylsilyl-4-n on en e-1,9-diol, 17a,
was prepared from 16a by the same procedure used to convert
5 to 4 in 67% yield after purification by flash chromatography
(hexane:ethyl acetate ) 85:5): 1H NMR δ 0.04 (s, 6H), 0.89
(s, 9H), 1.43 (m, 4H), 2.00 (m, 2H), 3.33 (m, 2H), 3.57 (t, 2H,
J ) 6.0 Hz), 3.75 (m, 2H), 4.44 (s, 2H), 5.76 (d, 1H, J ) 15.7
Hz), 6.39 (dt, 1H, J ) 5.8, 15.7 Hz), 7.28-7.49 (two set of m,
20H); 13C NMR δ 18.4, 24.4, 26.1, 32.0, 60.0, 62.8, 71.2, 73.4,
112.4, 126.4, 127.6, 127.9, 129.0, 138.2, 146.5, 202.0; FTIR
(neat) 2867, 1691, 1626, 704 cm-1. This material was normally
not purified but carried on directly to the next step.
chromatography (hexane:ether ) 85:10): [R]25 -8.07 (c 1.3,
D
1
CHCl3); H NMR (CDCl3) δ 0.90 (t, 3H, J ) 4.8 Hz), 1.26 (br
s, 28H), 2.72-2.88 (set of m, 3H), 3.51 (m, 1H), 4.00 (d, 1H, J
) 12.0 Hz), 4.14 (d, 1H, J ) 12.0 Hz), 7.21-7.55 (two sets of
m, 20H); 13C NMR δ 14.1, 22.7, 26.2, 29.7, 31.9, 33.8, 34.8,
55.9, 68.9, 70.9, 72.4, 72.8, 74.4, 126.4, 127.6, 127.9, 128.3,
128.9, 137.9, 146.6; FTIR (neat) 3495, 2937, 1457, 704 cm-1
.
Anal. Calcd for C44H57O2N: C, 83.36; H, 9.38; N, 2.21.
Found: C, 83.09; H, 9.43; N, 2.07.
(2S ,4E )-2-[N -(T r ip h e n y lm e t h y l)a m in o ]-3-o x o -1-O -
ben zyl-8-(4-m eth oxy)p h en yl-4-octen e-1- ol, 17b, was pre-
pared from 16b by the same procedure used to convert 5 to 4
in 70% yield after purification by flash chromatography
(hexane:ethyl acetate ) 85:5): 1H NMR δ 1.62 (m, 2H), 2.00-
2.43 (two sets of m, 2H), 2.50 (m, 2H), 3.32 (dd, 1H, J ) 5.4,
9.0 Hz), 3.60 (m, 1H), 3.72 (m, 1H), 3.78 (s, 3H), 4.43 (s, 2H),
5.83 (d, 1H, J ) 15.7 Hz), 6.38 (dt, 1H, J ) 5.4, 15.7 Hz), 6.82
(d, 2H, J ) 8.7 Hz), 7.13 (d, 2H, J ) 8.7 Hz), 7.25-7.48 (two
sets of m, 20H); 13C NMR δ 21.7, 29.8, 31.6, 34.4, 43.8, 55.3,
60.0, 73.4, 113.9, 126.5, 127.6, 127.9, 129.,0 138.2, 146.1, 146.5,
158.0, 202.0; FTIR (neat) 2937, 1691, 704 cm-1. This material
was normally not purified but carried on directly to the next
step.
1,1-Dim eth yl [R-[R*,S*]]-2,2-Dim eth yl-4-(1-h yd r oxy-2-
h exa d eca n yl)-3-oxa zolid in eca r boxyla te, 3e. The proce-
dure used to prepare 3t was used with overall yield 90% and
91% de from 13 after purification by flash chromatography
(hexane:ethyl acetate ) 4:0.5): [R]25 -26.9 (c 2.54, CHCl3);
D
1H NMR (CDCl3) (mixture of rotamers) δ 0.88 (t, 3H, J ) 6.2
Hz), 1.26 (br s, 26H), 1.49 (s, 9H), 1.59 (s, 6H), 3.72 (br, 1H),
3.70-3.96 (m, 4H); FTIR (neat) 3450, 1700 cm-1. Anal. Calcd
for C26H51O4N: C, 70.70; H, 11.64; N, 3.17. Found: C, 70.59;
H, 11.62; N, 3.27.
(2S ,3S ,3-D )-2-[N -(T r i p h e n y lm e t h y l)a m i n o ]-1-O -
ben zylocta d eca n -1,3-d iol, 3-Deu ter o-1t: 1H NMR (CDCl3)
δ 0.90 (t, 3H, J ) 4.8 Hz), 1.26 (br s, 28H), 2.72-2.88 (set of
m, 3H), 4.00 (d, 1H, J ) 12.0 Hz), 4.14 (d, 1H, J ) 12.0 Hz),
7.21-7.55 (two sets of m, 20H).
(2S ,7R ,4E )-2-[N -(Tr ip h e n ylm e t h yl)a m in o]-7,11-d i-
m eth yl-3-oxo-1-O-ben zyl-4,10-d od eca d ien e-1-ol, 17c, was
prepared from 16c by the same procedure used to convert 5
to 4 in 70% yield after purification by flash chromatography
(hexane: ether ) 85:10): 1H NMR δ 0.82 (d, 3H, J ) 6.6 Hz),
0.90-1.55 (set of m, 4H), 1.59 (s 3H), 1.68 (s, 3H), 1.98 (m,
3H), 3.32 (dd, 1H, J ) 6.0, 9.9), 3.72 (dd, 1H, J ) 4.4, 9.9 Hz),
3.78 (m, 1H), 4.45 (s, 2H), 5.06 (t, 1H, J ) 6.7 Hz), 5.84 (d,
1H, J ) 15.7 Hz), 6.38 (dt, 1H, J ) 5.4, 15.7 Hz), 7.10-7.46
(two sets of m, 20H); 13C NMR δ 17.6, 19.5, 25.6, 32.0, 36.7,
39.8, 60.0, 71.1, 73.2, 124.4, 126.4, 127.4, 127.8, 128.9, 131.4,
(2S ,3S ,4E ,3-D)-2-[N -(Tr ip h e n ylm e t h yl)a m in o]-1-O-
ben zyl-4-octa d ecen e-1,3-d iol, 3-Deu ter o-3t: 1H NMR δ
0.88 (t, 3H, J ) 6.7 Hz), 1.23-1.26 (br s, 22H), 1.95 (m, 2H),
2.27 (m, 1H), 2.87-2.93 (m, 1H), 4.00 (d, 1H, J ) 11.8 Hz),
4.17 (d, 1H, J ) 11.8 Hz), 5.33 (d, 1H, J ) 15.3 Hz), 5.52 (dt,
1H, J ) 6.4, 15.3 Hz), 7.19-7.56 (two sets of m, 20H).
(2S)-2-[N-(Tr ip h en ylm eth yl)a m in o]-3-oxo-1-O-ben zyl-
9-O-ter t-bu tyld im eth ylsilyln on a n e-1,9-d iol, 16a , was pre-
pared by the alkylation of 8 with 15a by the same procedure
used to convert 8 to 5 in 68% yield after purification by flash
138.1, 145.3, 146.4, 201.4; FTIR (neat) 2907, 1691, 709 cm-1
.
This material was normally not purified but carried on directly
to the next step.
chromatography (hexane:ethyl acetate ) 85:5): [R]25 +70.6
D
(c 0.70, CHCl3); 1H NMR δ 0.05 (s, 6H), 0.90 (s, 9H), 1.18-
2.17 (set of m, 10H), 3.30 (dd, 1H, J ) 3.6, 6.0 Hz), 3.32 (1H),
3.56 (t, 2H, J ) 6.5 Hz), 3.58 (m, 2H), 3.79 (dd, 1H, J ) 4.6,
6.7 Hz), 4.44 (s, 1H), 7.20-7.44 (two sets of m, 20H); 13C NMR
δ 16.8, 23.2, 25.9, 26.4, 29.1, 33.1, 42.2, 61.6, 63.6, 71.4, 73.7,
126.9, 128.2, 129.3, 138.3, 146.8, 213.8; FTIR (neat) 2937, 1715,
1092, 704 cm-1. Anal. Calcd for C41H53O3NSi: C, 77.43; H,
8.40; N, 2.20. Found: C, 77.48; H, 8.42; N, 2.18.
(2S,3S,4E)-2-[N-(Tr ip h en ylm eth yl)a m in o]-1-O-ben zyl-
9-O-ter t-bu tyld im eth ylsilyl-4-n on en e-1,3,9-tr iol, 18a , was
prepared by the reduction of 17a by the same procedure used
to reduce 4 to 1t in a yield of 95% (92% de based on 1H NMR)
after purification by flash chromatography (hexane:ethyl
1
acetate ) 85:5): [R]25 -12.7 (c 0.84, CHCl3); H NMR δ 0.02
D
(s, 6H), 0.88 (s, 9H), 1.25-1.46 (set of m, 4H), 1.99 (m, 2H),
2.22 (m, 1H), 2.85 (two sets of m, 2H), 3.55 (t, 2H, J ) 6.3
Hz), 3.91 (dd, 1H, J ) 6.9, 8.0 Hz), 3.98 (d, 1H, J ) 12.0 hz),
4.16 (d, 1H, J ) 12.0 Hz), 5.36 (dd, 1H, J ) 7.3, 13.5 Hz), 5.51
(2S)-2-[N-(Tr ip h en ylm eth yl)a m in o]-3-oxo-1-O-ben zyl-
8-(4-m eth oxy)p h en yl-octa n -1-ol, 16b, was prepared by the
alkylation of 8 with 15b by the same procedure used to convert
8 to 5 in 70% yield after purification by flash chromatography
(dd, 1H, J ) 5.3, 13.5 Hz), 7.25-7.52 (two sets of m, 20H); 13
C
NMR δ 25.5, 26.1, 32.2, 32.5, 56.1, 63.1, 68.4, 70.9, 73.0, 73.7,
(hexane:ethyl acetate ) 85:5): [R]25 +9.79 (c 4.54, CHCl3);
112.4, 126.6, 128.0, 128.9, 130.2, 134.4, 138.0, 146.7; FTIR
D
1H NMR δ 1.08-2.22 (set of m, 8H), 2.48 (t, 2H, J ) 8.0 Hz),
(neat) 3475, 2927, 1098, 704 cm-1
.
Anal. Calcd for
3.28 (m, 2H), 3.55 (m, 1H), 3.77 (s, 3H), 4.41 (s, 2H), 6.80 (d,
C41H53O3NSi: C, 77.43; H, 8.40; N, 2.20. Found: C, 77.21; H,

Biomimetic Synthesis of Sphingosine
J . Org. Chem., Vol. 63, No. 12, 1998 3985
8.47; N, 2.11. The diastereomers were inseparable by flash
chromatography.
(2S,3S,4E)-2-[N-(Tr ip h en ylm eth yl)a m in o]-1-O-ben zyl-
8-(4-m eth oxy)p h en yl-4-octen e-1,3-d iol, 18b, was prepared
by the reduction of 17b by the same procedure used to reduce
4 to 1t in a yield of 90% (95% de based on 1H NMR) after
prepared by the reduction of 17c by the same procedure used
to reduce 4 to 1t in a yield of 90% (90% de based on 1H NMR)
after purification by flash chromatography (hexane:ether )
85:10): [R]25 -10.2 (c 1.92, CHCl3); 1H NMR δ 0.77 (d, 3H, J
D
) 6.6 Hz), 0.85-1.43 (set of m, 3H), 1.58 (s, 3H), 1.67 (s, 3H),
1.89-1.91 (m, 4H), 2.27(m, 1H), 2.80-2.89 (m, 2H), 3.90 (dd,
1H, J ) 6.3, 6.9 Hz), 4.08 (d, 1H, J ) 12.0 Hz), 4.17 (d, 1H, J
) 12.0 Hz), 5.05 (t, 1H, J ) 7.3 Hz), 5.34 (dd, 1H, J ) 7.5,
15.0 Hz), 5.49 (dt, 1H, J ) 6.5, 15.0 Hz) 7.23-7.53 (two sets
of m, 20H); 13C NMR δ 17.6, 19.4, 25.5, 30.3, 32.5, 36.7, 39.8,
55.8, 68.1, 70.8, 72.8, 73.7, 124.8, 126.5, 127.8, 128.3, 128.8,
purification by flash chromatography (hexane:ethyl acetate )
1
85:5): [R]25 -18.8 (c 0.88, CHCl3); H NMR δ 1.59 (m, 2H),
D
1.98 (m, 2H), 2.49 (t, 2H, J ) 7.32 Hz), 2.79-2.88 (m, 2H),
3.78 (s, 3H), 3.92 (dd, 1H, J ) 6.7, 9.2 Hz), 4.00 (d, 1H, J )
12.2 Hz), 4.17 (d, 1H, J ) 12.2 Hz), 5.37 (dd, 1H, J ) 6.7, 13.4
Hz), 5.54 (dt, 1H, J ) 5.4, 13.4 Hz), 6.80 (d, 2H, J ) 8.6 Hz),
7.07 (d, 2H, J ) 8.6 Hz), 7.25-7.56 (two sets of m, 20H); 13C
NMR δ 31.2, 31.9, 34.5, 55.3, 56.1, 68.4, 73.0, 73.5, 73.8, 112.4,
113.8, 126.6, 128.0, 129.9, 130.5, 134.1, 134.6, 137.9, 146.7,
157.9; FTIR (neat) 3460, 2937, 1247, 704 cm-1. Anal. Calcd
for C41H43O3N: C, 82.38; H, 7.25; N, 2.34. Found: C, 82.10;
H, 7.21; N, 2.18. The diastereomers were inseparable by flash
chromatography.
131.1, 133.3, 146.5; FTIR (neat) 3445, 2927, 1452, 709 cm-1
.
Anal. Calcd for C40H47O2N: C, 83.73; H, 8.26; N, 2.44.
Found: C, 83.62; H, 8.38; N, 2.30. The diastereomers were
inseparable by flash chromatography.
Ack n ow led gm en t. This work was supported by a
grant from the National Science Foundation (9520431).
(2S,3S,7R,4E)-2-[N-(Tr ip h en ylm et h yl)a m in o]-7,11-d i-
m et h yl-1-O-ben zyl-4,10-d od eca d ien e-1,3-d iol, 18c, was
J O980003I