Regioselective inversion of the hydroxyl group in d-ribo-phytosphingosine via a cyclic sulfate and bis-sulfonate intermediate

Article abstract of DOI:10.1021/jo101757k

The selective synthesis of d-xylo-and d-lyxo-phytosphingosines from commercially available d-ribo-phytosphingosine is described. Thermolysis of the N-carbonyl protected cyclic sulfate led to an inversion of configuration of the proximal hydroxyl group to

Full text of DOI:10.1021/jo101757k

pubs.acs.org/joc
Regioselective Inversion of the Hydroxyl Group
in D-ribo-Phytosphingosine via a Cyclic Sulfate and
Bis-Sulfonate Intermediate
Yun Mi Lee, Dong Jae Baek, Seokwoo Lee, Deukjoon Kim, and Sanghee Kim*
College of Pharmacy, Seoul National University, San 56-1, Shilim, Kwanak, Seoul 151-742, Korea
pennkim@snu.ac.kr
Received September 7, 2010
The selective synthesis of D-xylo- and D-lyxo-phytosphingosines from commercially available D-ribo-
phytosphingosine is described. Thermolysis of the N-carbonyl protected cyclic sulfate led to an
inversion of configuration of the proximal hydroxyl group to give the xylo-isomer, whereas the
corresponding bis-sulfonate resulted in an inversion of configuration of the distal hydroxyl group to
give the lyxo-isomer. This study allowed the comparison between a cyclic sulfate and a bis-sulfonate
in an intramolecular substitution reaction involving a carbonyl oxygen nucleophile.
Introduction
Depending on the target, substrate- or reagent-controlled
diastereo- and enantioselective reactions can be additionally
applied to install the remaining stereocenters of the vicinal
amino diol moiety. However, these strategies sometimes suffer
from low selectivity due to a mismatch in asymmetric induc-
tion between the substrate control and reagent control. Thus,
in some cases, the selective configurational inversion of a
hydroxyl group of the 1-amino-2,3-diol is necessary. The
selective configurational inversion of such a hydroxyl group
has been well studied in cyclic systems. However, it has been
less widely explored in acyclic systems.3
The 1-amino-2,3-diol subunit is found in many natural
and synthetic compounds with a wide range of interesting
bioactivities.1 Consequently, efficient routes for the stereose-
lective preparation of this subunit are of continuing interest
and significant value. To establish the desired stereochemistry
of consecutive stereocenters of vicinal amino diols, most
syntheses rely on chiral pools, such as carbohydrates and
amino acids, or asymmetric induction, such as Sharpless
asymmetric dihydroxylation and aminohydroxylation.2
Phytosphingosines are long-chain, aliphatic natural com-
pounds possessing a 1-amino-2,3-diol subunit. They are the
principal structural backbone of biologically important
sphingolipids and are widely distributed in plants, yeasts,
*To whom correspondence should be addressed. Tel: 82-2-880-2487. Fax:
82-2-888-0649.
(1) For selected examples, see: (a) Rosenberg, S. H.; et al. J. Med. Chem.
1993, 36, 449–459. (b) Ocain, T. D.; Abou-Gharbia, M. Drugs Future 1991,
16, 37–51. (c) Greenlee, W. J.; Siegl, P. K. S. Annu. Rep. Med. Chem. 1991, 26,
63–72. (d) Greenlee, W. J. Med. Res. Rev. 1990, 10, 173–236.
(2) For selected examples, see: (a) Enomoto, M.; Kuwahara, S. J. Org.
Chem. 2009, 74, 7566–7569. (b) Zhou, X.; Liu, W.-J.; Ye, J.-L.; Huang, P.-Q.
(3) For selected examples, see: (a) Curti, C.; Zanardi, F.; Battistini, L.;
Sartori, A.; Rassu, G.; Pinna, L.; Casiraghi, G. J. Org. Chem. 2006, 71, 8552–
ꢀ
€
J. Org. Chem. 2007, 72, 8904–8909. (c) Patel, S. K.; Murat, K.; Py, S.; Vallee,
8558. (b) Dong, H.; Pei, Z.; Ramstrom, O. J. Org. Chem. 2006, 71, 3306–
Y. Org. Lett. 2003, 5, 4081–4084. (d) Schwindt, M. A.; Belmont, D. T.;
Carlson, M.; Franklin, L. C.; Hendrickson, V. S.; Karrick, G. L.; Poe, R. W.;
Sobieray, D. M.; Vusse, J. V. D. J. Org. Chem. 1996, 61, 9564–9568. (e) Chan,
M. F.; Hsiao, C.-N. Tetrahedron Lett. 1992, 33, 3567–3570.
3309. (c) Chang, C.-W. T.; Hui, Y.; Elchert, B. Tetrahedron Lett. 2001, 42,
7019–7023. (d) Weinges, K.; Haremsa, S.; Maurer, W. Carbohydr. Res. 1987,
164, 453–458. (e) Lattrell, R.; Lohaus, G. Justus Liebigs Ann. Chem. 1974,
901–920.
408 J. Org. Chem. 2011, 76, 408–416
Published on Web 12/30/2010
DOI: 10.1021/jo101757k
r
2010 American Chemical Society

Lee et al.
JOCArticle
FIGURE 1. D-ribo-Phytosphingosine (1) and its stereoisomers 2-4.
fungi, and even mammalian tissues.4 In nature, the most
predominant stereoisomer of phytosphingosines is D-ribo-phy-
tosphingosine (1, Figure 1). The growing interest in the biolo-
gical functions of sphingolipids has generated a need to develop
efficient methods for the preparation of D-ribo-phytosphingo-
sine (1) and other stereoisomers, such as D-xylo- (2), D-arabino- (3),
and D-lyxo-phytosphingosines (4), which are shown in
Figure 1.5,6
FIGURE 2. Synthesis of stereoisomers of D-ribo-phytosphingosine
(1) via a cyclic sulfate or a bis-sulfonate.
In this regard, we have previously reported a high-yield
approach to the stereoselective synthesis of D-xylo-, D-arabino-,
and D-lyxo-phytosphingosines from inexpensive D-ribo-phyto-
sphingosine (1).7 Our synthetic strategy was not based on
stereochemical induction; it was rather based on a selective con-
figurational inversion of pre-existing stereocenters. The hydro-
xyl group of phytosphingosines was inverted via the regioselec-
tive activation/acylation of vicinal hydroxyl groups and a
neighboring-group participation. The amino group was pro-
tected as a non-nucleophilic azide to avoid complications caused
by multiple anchimeric assistances during the inversion of
activated hydroxyl groups.
FIGURE 3. Pedersen’s inversion of a hydroxyl group in xylo-
phytosphingosine via a cyclic sulfate.
activation of only one vicinal hydroxyl group is not required.
For the regioselective configurational inversion of activated
hydroxyl groups, we decided to utilize nucleophilic amino
protecting groups, such as carbamates, to allow a nucleophilic
intramolecular substitution at C-3 or C-4.
Results and Discussion
In the course of our ongoing sphingolipid research, we
have explored an alternative and efficient route for the trans-
formation of cheap, commercially available D-ribo-phytosphin-
gosine (1) into other stereoisomers. As shown in Figure 2, our
new strategy is based on the use of a cyclic sulfate 5 or bis-
sulfonate 6 for the activation of the vicinal hydroxyl groups of
1. One of the advantages of this approach is that a selective
In fact, Pedersen and co-workers have previously reported
a similar approach; a cyclic sulfate was used for the config-
urational inversion of hydroxyl groups in vicinal amino
diols.8 As shown in Figure 3, the Cbz-protected xylo-phyto-
sphingosine was converted into its stereoisomer via a cyclic
sulfate intermediate with the aid of a carbamate protecting
group. Thermolysis of the cyclic sulfate 7 in acetonitrile led to
an inversion of configuration of the distal hydroxyl group to
form a 1,3-oxazinan-2-one 8. As discussed by Pedersen, the
thermolytic formation of the oxazinanone 8 proceeded via an
initial nucleophilic substitution of the cyclic sulfate function
by the oxygen atom of the carbamate to give the intermediate
oxonium ion 9, followed by an irreversible fragmentation
step that led to the oxazinanone sulfate 10. Hydrolysis of the
sulfate ester group of 10 finally afforded 8.
Conceptually, the nucleophilic carbonyl of the carbamate
in the ribo-phytosphingosine-derived cyclic sulfate 5 could
attack either the C-3 or C-4 position to give the 5-membered
oxazolidinone 11 or the 6-membered oxazinanone 12, respec-
tively (Figure 4). On the basis of the literature demonstrating the
rearrangement of cyclic sulfate 13 into more stable isomeric
cyclic sulfate 15 via hemisulfate anion/oxonium intermediate 14
(Figure 5),9 we speculated that the first nucleophilic substitution
(4) (a) Liao, J.; Tao, J.; Lin, G.; Liu, D. Tetrahedron 2005, 61, 4715–4733.
(b) Muralidhar, P.; Radhika, P.; Krishna, N.; Rao, D. V.; Rao, Ch. B. Nat.
Prod. Sci. 2003, 9, 117–142. (c) Howell, A. R.; Ndakala, A. J. Curr. Org.
Chem. 2002, 6, 365–391.
(5) Selected publications for recent syntheses of phytosphingosines, see:
(a) Liu, Z.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2010, 75, 4356–4364.
(b) Pandey, G.; Tiwari, D. K. Tetrahedron Lett. 2009, 50, 3296–3298.
(c) Jiang, H.; Elsner, P.; Jensen, K. L.; Falcicchio, A.; Marcos, V.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2009, 48, 6844–6848. (d) Yoon, H. J.; Kim,
Y.-W.; Lee, B. K.; Lee, W. K.; Kim, Y.; Ha, H.-J. Chem. Commun. 2007,
79–81. (e) Righi, G.; Ciambrone, S.; Achille, C. D.; Leonelli, A.; Bonini, C.
Tetrahedron 2006, 62, 11821–11826. (f) Lombardo, M.; Capdevila, M. G.;
Pasi, F.; Trombini, C. Org. Lett. 2006, 8, 3303–3305. (g) Lu, X.; Byun, H.-S.;
Bittman, R. J. Org. Chem. 2004, 65, 5433–5438. (h) Raghavan, S.; Rajender,
A. J. Org. Chem. 2003, 68, 7094–7097. (i) Ndakala, A. J.; Hashemzadeh, M.;
So, R. C.; Howell, A. R. Org. Lett. 2002, 4, 1719–1722.
(6) For the synthesis of more than one stereoisomer of phytosphingosine,
see: (a) Dubey, A.; Kumar, P. Tetrahedron Lett. 2009, 50, 3425–3427.
ꢀ
(b) Llaveria, J.; Dıaz, Y.; Matheu, M. I.; Castillon, S. Org. Lett. 2009, 11,
205–208. (c) Enders, D.; Palecek, J.; Grondal, C. Chem. Commun. 2006, 655–
ꢁ
657. (d) Cai, Y.; Ling, C. C.; Bundle, D. R. Org. Biomol. Chem. 2006, 4, 1140–
1146. (e) Lu, X.; Bittman, R. Tetrahedron Lett. 2005, 46, 3165–3168. (f) He,
L.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2000, 65, 7618–7626.
(g) Imashiro, R.; Sakurai, O.; Yamashita, T.; Horikawa, H. Tetrahedron
1998, 54, 10657–10670.
(8) Kemp, S. J.; Bao, J.; Pedersen, S. F. J. Org. Chem. 1996, 61, 7162–
7167.
(7) Kim, S.; Lee, N.; Lee, S.; Lee, T.; Lee, Y. M. J. Org. Chem. 2008, 73,
1379–1385.
(9) Leurquin, F.; Ozturk, T.; Pilkington, M.; Wallis, J. D. J. Chem. Soc.,
Perkin Trans. 1 1997, 3173–3177.
J. Org. Chem. Vol. 76, No. 2, 2011 409

Lee et al.
JOCArticle
FIGURE 4. Plan for inversion of the hydroxyl groups in ribo-
phytosphingosine via a cyclic sulfate.
FIGURE 6. Density functional calculations at the PBE/DNP level
on the conformers of hemisulfate anion/oxonium intermediates.
(a) Truncated systems of the ribo-phytosphingosine-derived inter-
mediates 16 and 17. (b) Modified systems of the xylo-phytosphingosine-
derived intermediate 9 and its isomeric form.
FIGURE 5. Rearrangement of cyclic sulfate 13 to the six-mem-
bered isomeric cyclic sulfate 15.9
amounts of 5 could be detected after 12 h. The polar material
was deduced to be the sulfate esters 16 and/or 17. Thus, the
resulting solution was treated with aqueous H2SO4 for
hydrolysis of the sulfate ester group. This treatment provided
oxazolidinone 11 and oxazinanone 12 in a ratio of 5.1:1 and
in 65% yield. When the cyclic sulfate 5 was heated at 45 °C
(oil bath temperature) in acetonitrile for 2 h and treated with
acid, oxazolidinone 11 and oxazinanone 12 were obtained in
a 3.9:1 ratio with a combined yield of 66%. When the solvent
was changed to THF (45 °C, 2 h), oxazolidinone 11 was also
obtained as a major product along with the minor oxazina-
none 12 in a similar ratio (4.8:1) in combined 68% yield. As
expected, the observed regioselectivity of the cyclic sulfate 5
during the thermolysis reaction was opposite to that ob-
tained with the cyclic sulfate 7 that was derived from the
xylo-isomer. Although more systematic studies are needed,
these results led us to believe that the different regioselec-
tivities could be due to the stability of the intermediate
oxonium ions and a thermodynamic control. The obtained
major isomer 11 was deprotected to afford D-xylo-phyto-
sphingosine (2) in two steps. For analytical reasons, 2 was
peracetylated with Ac2O/pyridine to provide the tetraacetate
derivative 19. The analytical and spectroscopic data of both
the synthetic D-xylo-phytosphingosine (2) and its tetraace-
tate 19 were in agreement with those reported in the
literature.5b,h,11
step of 5 could be reversible leading to the thermodynamically
more stable oxonium intermediate.
Our computational studies suggested that the oxazolidi-
none yielding intermediate 16 is more stable than the
oxazinanone yielding intermediate 17. Density functional
calculations at the PBE/DNP level on the truncated system
of 16 and 17, shown in Figure 6 as A and B, respectively,
revealed that A is more stable than B by 0.9 kcal/mol. In the
case of the cyclic sulfate 7 derived from the xylo-isomer,
calculations on the modified systems C and D indicated that
the oxazolidinone yielding intermediate C is less stable than
the oxazinanone yielding intermediate D by 8.7 kcal/mol.
This energy difference correlated well with the result ob-
tained by Pedersen. Thus, we envisioned that the regiochem-
ical outcome of the ribo-phytosphingosine-derived cyclic
sulfate 5 would be different from that of the xylo-phyto-
sphingosine-derived cyclic sulfate 7; we expected that the
cyclic sulfate 5 would mainly be transformed into the
5-membered oxazolidinone 11.
The known N-Boc- and 1-O-silyl-protected phytosphin-
gosine 1810 was easily prepared from D-ribo-phytosphingo-
sine (1) with a high overall yield (Scheme 1). The 3,4-vicinal
diol 18 was converted into the cyclic sulfate 5 by treatment
with thionyl chloride followed by oxidation with RuCl3/
NaIO4. The obtained cyclic sulfate 5 was found to be rather
unstable and decomposed into a polar material on standing
in acetonitrile solution at room temperature; only trace
To examine the effect of other amino protecting groups on
the regioselectivity and product distribution, a N-acetyl-
protected cyclic sulfate was examined. For the synthesis of
(10) (a) Yoshimitsu, Y.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. J. Org.
Chem. 2010, 75, 3843–3846. (b) Veerapen, N.; Leadbetter, E. A.; Brenner,
M. B.; Cox, L. R.; Besra, G. S. Bioconjugate Chem. 2010, 21, 741–747.
(11) (a) Shirota, O.; Nakanishi, K.; Berova, N. Tetrahedron 1999, 55,
13643–13658. (b) Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann. Chem.
1990, 11, 1069–1078.
410 J. Org. Chem. Vol. 76, No. 2, 2011

Lee et al.
JOCArticle
SCHEME 1. Synthesis of D-xylo-Phytosphingosine (2) via
Cyclic Sulfate 5
SCHEME 3. Synthesis of Oxazinanone 26 and Oxazolidinone
27 via Bis-Mesylate 25
with the electron-rich amide group under the reaction con-
ditions. The only obtained product after acidic hydrolysis was
the 5-membered oxazoline 23 (66%). No 6-membered isomer
1
was detected in the crude H NMR spectra. The cyclization
followed a pattern similar to that of the N-Boc-protected cyclic
sulfate 5 in that the 5-membered isomer was preferentially
formed over the 6-membered isomer with the configurational
inversion occurring at C-3. The exposure of oxazoline 23 to
HCl/THF followed by treatment of the resulting compound
with Bu4NF provided the known N-acetyl D-xylo-phytosphin-
gosine 2412 in 87% overall yield. The identity of 24 was further
confirmed by its conversion to tetraacetate 19.
After obtaining the results with the cyclic sulfate, we
examined the use of a bis-sulfonate as a diol activating group.
Cyclic sulfates and bis-sulfonates could be regarded as
synthetic equivalents in that they both activate vicinal hy-
droxyl groups. However, they could display different chemi-
cal behaviors in the substitution reaction with the oxygen
atom of a carbonyl group since they could have different
transition state conformations and reactivities. We envi-
saged that the first substitution step of the bis-sulfonate 6
(Figure 2) might be irreversible, unlike that of the cyclic
sulfate 5. In the cyclic sulfate system (Figure 4), the hemisulfate
anions 16 and 17, generated from the cyclic sulfate 5, could have
a great chance to intramolecularly attack the nearby reactive
C-3 and C-4 positions to reform the starting compound and
thus lead to a thermodynamical equilibrium. On the other hand,
in the acyclic bis-sulfonate system, the nucleophilic substitution
generates the oxonium ion intermediate and the dissociated
sulfonate anion. The two separated species would have a low
chance to intermolecularly react with each other to give the
starting compound. Thus, its substitution step is less likely
reversible and the product would be formed under kinetic
control. With these considerations in mind, studies were made
to compare the chemistry of a bis-sulfonate with that of its
corresponding cyclic sulfate.
SCHEME 2. Synthesis of N-Acetyl D-xylo-Phytosphingosine 24
First, the vicinal bis-mesylate 25 was prepared from the
3,4-vicinal diol 18 and thermolyzed (Scheme 3). Bis-mesylate
25 was found to be stable during heating; it was even stable in
acetonitrile at reflux. Thus, thermolysis of 25 in acetonitrile
was conducted in a sealed tube at 110 °C for 12 h. In contrast
to the corresponding cyclic sulfate 5, the bis-mesylate 25 gave
the 6-membered oxazinanone 26 as the major product and
oxazolidinone 27 as the minor product (2:1 ratio; 74%
combined yield).
the N-acetyl-protected cyclic sulfate 20 (Scheme 2), the 3,4-
vicinal diol 21 was first converted into the cyclic sulfite 22 by
treatment with thionyl chloride. When the cyclic sulfite 22
was treated with RuCl3/NaIO4 at room temperature for its
oxidation into a cyclic sulfate, it was found that the generated
cyclic sulfate was reactive enough to undergo cyclization
(12) Sugiyama, S.; Honda, M.; Higuchi, R.; Komori, T. Liebigs Ann.
Chem. 1991, 4, 349–356.
J. Org. Chem. Vol. 76, No. 2, 2011 411

Lee et al.
JOCArticle
SCHEME 4. Synthesis of D-lyxo-Phytosphingosine (4) via
Bis-Triflate 28
SCHEME 5. Synthesis of N-Acetyl D-lyxo-Phytosphingosine 32
first example of such a comparison. The reasons for the
significant change in the position of the nucleophilic attack
depending on the structure of the leaving group (cyclic
sulfate vs bis-sulfonate) are not yet completely understood.
We suggested that the different outcomes might be the result
of a thermodynamic or kinetic control of the reaction path-
ways. However, more systematic experimental and compu-
tational studies are needed.
We next attempted to prepare the bis-triflate 28 (Scheme 4).
When the 3,4-vicinal diol 18 was treated with an excess (3 equiv)
of triflic anhydride in CH2Cl2/pyridine at low temperature
(-30 °C), the obtained product was not the anticipated bis-
triflate 28 but the 6-membered oxazinanone 12 (76%) after
column chromatography. No 5-membered oxazolidinone pro-
duct was detected in the crude 1H NMR spectra. Intermediate
29, the C-3 triflate derivative of 12, could be obtained after rapid
purification. However, it was too unstable to be fully character-
ized, and rapidly underwent hydrolysis to give 12 on standing at
room temperature. The presence of the C-3 triflate 29 implied
that the formation of 12 proceeded via the bis-triflate 28. These
experiments provided a facile route for the selective configura-
tional inversion of the C-4 hydroxyl group of ribo-phytosphin-
gosine. The selectively obtained 12 was deprotected to afford
D-lyxo-phytosphingosine (4) in two steps. For analytical reasons,
4 was also peracetylated to provide tetraacetate 30, of which
spectroscopic data were identical with those reported.5f,6f,11,13
The N-acetyl-protected 3,4-vicinal diol 21 was also treated
with an excess of triflic anhydride to examine the effect of the
acetyl protecting group on the regioselectivity (Scheme 5). The
reaction of 21 under the same conditions as for 18 provided the
6-membered oxazine 31 (64%) as the only identifiable regio-
isomer. No trace of the other possible regioisomer 23 was
Conclusion
In summary, we describe herein a synthesis of D-xylo- (2)
and D-lyxo-phytosphingosines (4) from the low-cost D-ribo-
phytosphingosine (1) based on the configurational inversion
of the stereocenter via a regioselective nucleophilic substitu-
tion of a cyclic sulfate and bis-sulfonate. The synthetic
methodology also provided protected isomers of phyto-
sphingosines that could be synthetically useful in the pre-
paration of various sphingolipid derivatives. We found that
the thermolysis of the cyclic sulfates 5 and 20 led to an
inversion of configuration of the proximal hydroxyl group,
whereas the bis-sulfonates 25 and 28 led to an inversion of
configuration of the distal hydroxyl group. This study
allowed us to compare a cyclic sulfate and a bis-sulfonate
in an intramolecular substitution reaction that involved an
oxonium ion intermediate. In addition, this study demon-
strated that the cyclic sulfate 5 that was obtained from ribo-
phytosphingosine exhibited a regiochemical behavior that
was substantially different from that observed for the xylo-
phytosphingosine-derived cyclic sulfate 7. Finally, we antici-
pate the regioselective inversion of a hydroxyl group of the
1-amino-2,3-diol with ribo configuration by the approach
presented in this paper is of practical interest since it allows
easy access to xylo- and lyxo-configured vicinal amino diols
that are less readily available than the ribo-type system.
1
observed in the crude H NMR spectra. The cyclization
followed the same pattern as that observed in the case of
N-Boc-protected 18. These results once again demonstrate
that cyclic sulfates and bis-sulfonates display different chemical
behaviors in the substitution reaction with the oxygen atom
of a carbonyl group. The exposure of oxazine 31 to HCl/
THF followed by treatment of the resulting compound with
Bu4NF provided the known N-acetyl D-lyxo-phytosphingo-
sine 3212 in 70% overall yield. The identity of 32 was further
confirmed by its conversion to tetraacetate 30.
To our knowledge, the direct comparison between a cyclic
sulfate and a bis-sulfonate in an intramolecular substitution
reaction with a carbonyl oxygen nucleophile has not yet been
reported in the literature. Our study could therefore be the
Experimental Section
(2S,3S,4R)-1-(tert-Butyldiphenylsilyloxy)-2-[N-(tert-butyloxy-
carbonyl)amino]octadecan-3,4-diol (18). To a solution of compound
1 (1.50 g, 4.72 mmol) in EtOH/H2O (1:1, 12 mL) was added 1 N
NaOH (6 mL) and di-tert-butyl dicarbonate (1.6 mL, 6.96 mmol) at
0 °C. After being stirred for 12 h at room temperature, the reaction
mixture was poured into water and extracted with CH2Cl2 twice.
The combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. Purification of the crude
product by column chromatography on silica gel (hexane/EtOAc,
1:1) afforded the N-Boc-protected compound (1.89 g, 96%).
Triethylamine (0.9 mL, 6.46 mmol), DMAP (45 mg, 0.37 mmol),
and TBDPS-Cl (1.5 mL, 5.86 mmol) were added at 0 °C to a
solution of the N-Boc-protected compound (1.80 g, 4.31 mmol) in
CH2Cl2/DMF (1:1, 10 mL). The reaction mixture was stirred at
(13) (a) Nakamura, T.; Shiozaki, M. Tetrahedron 2001, 57, 9087–9092.
(b) Schmidt, R.; Maier, T. Carbohydr. Res. 1988, 174, 169–180.
412 J. Org. Chem. Vol. 76, No. 2, 2011

Lee et al.
JOCArticle
room temperature for 24 h. It was then diluted with EtOAc. The
organic layer was washed with brine, dried over MgSO4, and
concentrated. Purification of the crude product by column chro-
to 45 °C until the disappearance of the starting material on TLC
(2 h). The reaction was cooled to room temperature, and concen-
trated H2SO4 (4 μL), H2O (5 μL), and THF (70 μL) were added.
The mixture was stirred for 1 h at room temperature. It was then
diluted with EtOAc and washed with a saturated aqueous NaH-
CO3 solution and brine. The organic layer was dried over MgSO4
and concentrated in vacuo to provide a crude mixture. The crude
isomer ratio of 3.9:1 was determined from the 1H NMR spectrum
in CDCl3. Purification of the crude material by column chroma-
tography on silica gel (hexane/EtOAc, 2:1) afforded oxazolidinone
11 (47 mg, 53%) and oxazinanone 12 (12 mg, 13%).
(4S,5R)-4-((tert-Butyldiphenylsilyloxy)methyl)-5-((R)-1-hydroxy-
pentadecyl)oxazolidin-2-one (11). As a colorless oil: Rf 0.45 (hexane/
EtOAc, 2:1); [R]25D -38.8 (c 0.2, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 0.88 (t, J = 6.6 Hz, 3H), 1.05 (s, 9H), 1.26 (s, 23H), 1.40-
1.60 (m, 3H), 2.38 (br s, 1-OH), 3.49-3.57 (m, 1H), 3.58-3.69 (m,
2H), 3.85 (dd, J = 4.8, 10.2 Hz, 1H), 4.22 (dd, J = 4.2, 5.1 Hz, 1H),
5.66 (s, 1-NH), 7.36-7.48 (m, 6H), 7.60-7.66 (m, 4H); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 19.1, 22.7, 25.5, 26.7 (3C), 29.3, 29.4, 29.5,
29.6, 29.63 (2C), 29.7 (3C), 31.9, 32.6, 55.4, 65.3, 72.3, 81.3, 127.9
(4C), 130.1 (2C), 132.5, 132.6, 135.46 (2C), 135.5 (2C), 158.8; IR
(CHCl3) υmax 3303, 2925, 2854, 1756, 2098, 1114 (cm-1);MS(FAB)
m/z582([Mþ H]þ,28),265(30),199(71),135(100);HRMS(FAB)
calcd for C35H56NO4Si 582.3979 ([M þ H]þ), found 582.3971.
(4S,5S,6S)-4-((tert-Butyldiphenylsilyloxy)methyl)-5-hydroxy-
matography on silica gel (hexane/EtOAc, 10:1) afforded the diol 18
1
(2.77 g, 98%) as a colorless oil: [R]25 þ13.6 (c 0.3, CHCl3); H
D
NMR (CDCl3, 300 MHz) δ 0.87 (t, J = 6.6 Hz, 3H), 1.06 (s, 9H),
1.25 (s, 23H), 1.41 (s, 9H), 1.46-1.56 (m, 2H), 1.62-1.74 (m, 1H),
2.62 (br s, 1-OH), 3.11 (d, J = 6.9 Hz, 1-OH), 3.58-3.68 (m, 2H),
3.76-3.89 (m, 2H), 3.92-4.02 (m, 1H), 5.17 (d, J = 8.4 Hz, 1-NH),
7.34-7.46 (m, 6H), 7.60-7.68 (m, 4H); 13C NMR (CDCl3, 75
MHz) δ 14.1, 19.1, 22.7, 25.9, 26.8 (3C), 28.3 (3C), 29.3, 29.5, 29.6
(3C), 29.7 (4C), 31.9, 33.1, 52.0, 64.0, 73.4, 75.6, 79.6, 127.9 (4C),
129.97, 127.98, 132.3, 132.5, 135.5 (2C), 135.5 (2C), 155.7; IR
(CHCl3) υmax 3443, 2925, 2854, 1693, 1112 (cm-1); MS (FAB)
m/z 656 ([M þ H]þ, 16), 556 (100), 199 (50); HRMS (FAB) calcd
for C39H66NO5Si 656.4710 ([M þ H]þ), found 656.4708.
(2S,3S,4R)-1-(tert-Butyldiphenylsilyloxy)-2-[N-(tert-butyloxy-
carbonyl)amino]octadecan-3,4-cyclic Sulfate (5). To a solution of
diol 18 (0.35 g, 0.53 mmol) in CH2Cl2 (6 mL) were added
triethylamine (0.20 mL, 1.43 mmol) and thionyl chloride (0.06
mL, 0.69 mmol) at 0 °C. After 30 min, the reaction mixture was
poured into brine and extracted with EtOAc twice. The organic
layers were dried over MgSO4 and concentrated. The crude product
was purified by column chromatography on silica gel (hexane/
EtOAc, 15:1) to give a diastereomeric mixture of cyclic sulfites (0.36 g,
1
6-tetradecyl-1,3-oxazinan-2-one (12). As a colorless oil: Rf 0.23
96%) as a colorless oil: H NMR (CDCl3, 300 MHz, mixture of
1
(hexane/EtOAc, 2:1); [R]25 -44.7 (c 0.1, CHCl3); H NMR
two diastereomers) δ 0.89 (t, J = 6.9 Hz, 6H, both diastereomers),
1.07 (s, 18H, both diastereomers), 1.26 (s, 48H, both diastereomers),
1.46 (s, 18H, both diastereomers), 1.50-1.58 (m, 2H, both diaster-
eomers), 1.60-1.76 (m, 2H, both diastereomers), 1.76-1.90 (m,
1H, diastereomer 1), 1.98-2.22 (m, 1H, diastereomer 2), 3.66-3.98
(m, 3H, both diastereomers), 3.85 (dd, J = 3.0, 10.2 Hz, 1H, dias-
tereomer 1), 4.10-4.26 (m, 1H, diastereomer 2), 4.54-4.70 (m, 2H,
both diastereomers), 4.86-5.60 (m, 3H, both diastereomers), 7.36-
7.49 (m, 12H, both diastereomers), 7.61-7.68 (m, 8H, both dias-
tereomers); 13C NMR (CDCl3, 75 MHz, mixture of two diastereo-
mers) δ 14.1 (2C, both diastereomers), 19.3 (diastereomer 1), 19.4
(diastereomer 2), 22.7 (2C, both diastereomers), 25.8 (diastereo-
mer 1), 25.9 (diastereomer 2), 26.8 (3C, diastereomer 1), 26.9 (3C,
diastereomer 2), 28.3 (6C, both diastereomers), 29.3 (2C, both dias-
tereomers), 29.5 (2C, both diastereomers), 29.56 (diastereomer 1),
29.6 (diastereomer 2), 29.63 (6C, both diastereomers), 29.7 (8C,
both diastereomers), 31.9 (2C, both diastereomers), 50.2 (diastereo-
mer 1), 50.8 (diastereomer 2), 63.4 (diastereomer 1), 63.9 (diastereo-
mer 2), 78.7 (diastereomer 1), 80.2 (diastereomer 2), 81.2 (diastereo-
mer 1), 83.5 (diastereomer 2), 85.2 (2C, both diastereomers), 127.8
(8C, both diastereomers), 129.9 (2C, diastereomer 1), 129.94 (2C,
diastereomer 1), 132.5 (diastereomer 1), 132.7 (diastereomer 2),
132.9 (diastereomer 1), 132.95 (diastereomer 2), 135.43 (2C, dia-
stereomer 1), 135.47 (2C, diastereomer 2), 135.5 (2C, diastereomer
1), 135.6 (2C, diastereomer 2), 154.7 (diastereomer 1), 154.9 (dias-
tereomer 2); MS (FAB) m/z 702 ([M þ H]þ, 5), 588 (47), 199 (66),
57 (100); HRMS (FAB) calcd for C39H64NO6SSi 702.4224
([M þ H]þ), found 702.4234.
D
(CDCl3, 400 MHz) δ 0.86 (t, J = 6.3 Hz, 3H), 1.02 (s, 9H), 1.25
(s, 22H), 1.37-1.47 (m, 1H), 1.55-1.66 (m, 1H), 1.70-1.84 (m,
2H), 3.45-3.58 (m, 2H), 3.63 (dd, J = 4.5, 9.6 Hz, 1H), 3.79 (br s,
1H), 3.88 (br s, 1-OH), 4.09 (t, J = 6.5 Hz, 1H), 6.71 (s, 1-NH),
7.30-7.45 (m, 6H), 7.55-7.62 (m, 4H); 13C NMR (CDCl3, 100
MHz) δ 14.1, 19.1, 22.7, 25.2, 26.8 (3C), 29.4, 29.5, 29.6 (2C), 29.65
(2C), 29.7 (3C), 30.3, 31.9, 58.3, 63.9, 65.3, 77.7, 127.9 (4C), 129.9,
130.0, 132.55, 132.6, 135.49 (2C), 135.5 (2C), 155.1; IR (CHCl3)
υ
max 3358, 2925, 2854, 1710, 1113 (cm-1);MS(FAB) m/z582([Mþ
H]þ, 64), 199 (65), 135 (100);HRMS(FAB) calcdfor C35H56NO4Si
582.3979 ([M þ H]þ), found 582.3976.
(2S,3S,4R)-1-(tert-Butyldiphenylsilyloxy)-2-[N-(acetyl)amino]-
octadecan-3,4-diol (21). To a solution of tetraacetyl-D-ribo-phyto-
sphingosine (3.00 g, 6.18 mmol) in anhydrous methanol (20 mL)
was added sodium methoxide (5 mL, 21.9 mmol, 25 wt % solution
in MeOH). After being stirred at room temperature for 30 min, the
reaction mixture was diluted with EtOAc, washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo. The crude
N-acetyl-phytosphingosine (2.20 g, 6.11 mmol) was dissolved in
CH2Cl2/DMF (15 mL, 1:1) and triethylamine (1.5 mL, 10.8 mmol),
DMAP (70.0 mg, 0.57 mmol), and TBDPS-Cl (2.5 mL, 9.61 mmol)
were added at 0 °C. The reaction mixture was stirred at room
temperature for 24 h. It was then diluted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and concentrated.
Purification of the crude product by column chromatography on
silica gel (hexane/EtOAc, 3:1) afforded the diol 21 (3.60 g, 99%) as a
colorless oil: [R]25 þ19.6 (c 0.1, CHCl3); 1H NMR (CDCl3, 300
D
MHz) δ 0.88 (t, J = 6.6 Hz, 3H), 1.08 (s, 9H), 1.26 (s, 23H),
1.40-1.58(m, 2H), 1.68-1.80(m, 1H), 1.90(s, 3H), 2.56(d, J=7.5
Hz, 1-OH), 3.32 (d, J = 8.1 Hz, 1-OH), 3.54-3.68 (m, 2H), 3.80
(dd, J = 5.1, 10.8 Hz, 1H), 4.02 (dd, J = 3.3, 10.5 Hz, 1H), 3.97 (dt,
J = 4.2, 8.4 Hz, 1H), 6.08 (d, J = 8.7 Hz, 1-NH), 7.36-7.50 (m,
6H), 7.60-7.68 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 19.1,
22.7, 23.3, 25.8, 26.9 (3C), 29.3 (3C), 29.6, 29.64 (2C), 29.7 (3C),
31.9, 33.4, 51.1, 63.7, 73.3, 75.7, 128.0 (4C), 130.2 (2C), 132.0, 132.4,
135.5 (2C), 135.53 (2C), 169.9; IR (CHCl3) υmax 3334, 2925, 2854,
1653, 1113 (cm-1); MS (FAB) m/z 598 ([M þ H]þ, 72), 342 (100),
199 (80), 135 (92); HRMS (FAB) calcd for C36H60NO4Si 598.4249
([M þ H]þ), found 598.4287.
To a solution of cyclic sulfite (0.25 g, 0.36 mmol) in CCl4/
CH3CN/H2O (6 mL, 1:1:1) were added RuCl3 3H2O (6 mg, 0.03
3
mmol) and NaIO4 (280 mg, 1.31 mmol). After the reaction
mixture was stirred at room temperature for 2 h, it was diluted
with EtOAc and washed with a saturated NaHSO3 solution. The
organic layer was dried over MgSO4, concentrated, and purified
by column chromatography on silica gel (hexane/EtOAc, 10:1)
to give the cyclic sulfate 5 (0.35 g, 92%) as a colorless oil.
The isolated cyclic sulfate 5 was unstable in NMR solvents
and underwent facile cyclization to give the sulfate esters 16 and
17, as described above. Thus, its full characterization was not
performed.
Procedure for the Thermolysis of the Cyclic Sulfate 5. A solution
of the cyclic sulfate 5(0.15 mmol) in dry CH3CN (5 mL) was heated
(2S,3S,4R)-1-(tert-Butyldiphenylsilyloxy)-2-[N-(acetyl)amino]-
octadecan-3,4-cyclic Sulfite (22). To a solution of diol 21 (1.00 g,
J. Org. Chem. Vol. 76, No. 2, 2011 413

Lee et al.
JOCArticle
1.67 mmol) in CH2Cl2 (10 mL) were added triethylamine (0.8 mL,
5.74 mmol) and thionyl chloride (0.2 mL, 2.31 mmol) at 0 °C. After
30 min, the reaction mixture was poured into brine and extracted
with EtOAc twice. The organic layers were dried over MgSO4 and
concentrated. It was purified by column chromatography on silica
gel (hexane/EtOAc, 10:1) to give a diastereomeric mixture of
cyclic sulfite 22 (1.05 g, 97%) as a colorless oil: 1H NMR (CDCl3,
300 MHz, mixture of two diastereomers) δ 0.88 (t, J = 6.9 Hz, 6H,
both diastereomers), 1.08 (s, 18H, both diastereomers), 1.26 (s,
44H, both diastereomers), 1.42-1.68 (m, 5H, both diastereomers),
1.68-1.82 (m, 3H, both diastereomers), 1.92 (s, 3H, diastereomer
1), 1.94 (s, 3H, diastereomer 2), 3.70 (dd, J = 3.0, 10.5 Hz, 1H,
diastereomer 1), 3.76 (dd, J = 2.7, 10.8 Hz, 1H, diastereomer 2),
3.87 (dd, J = 3.3, 10.5 Hz, 1H, diastereomer 1), 4.11 (dd, J = 2.4,
10.5 Hz, 1H, diastereomer 2), 4.24 (dt, J = 3.3, 8.7 Hz, 1H, dias-
tereomer 1), 4.44-4.54 (m, 1H, diastereomer 2), 4.54-4.60 (m, 1H
diastereomer 1), 4.60-4.66 (m, 1H diastereomer 2), 4.91 (ddd, J =
3.3, 5.1, 9.3 Hz, 1H, diastereomer 1), 5.05 (dd, J = 5.4, 8.1 Hz, 1H,
diastereomer 2), 5.78 (d, J = 9.3 Hz, 1-NH, diastereomer 1), 5.86
(d, J = 9.6 Hz, 1-NH, diastereomer 2), 7.36-7.49 (m, 12H, both
diastereomers), 7.60-7.67 (m, 8H, both diastereomers); 13C NMR
(CDCl3, 75 MHz, mixture of two diastereomers) δ 14.1 (2C, both
diastereomers), 19.3 (diastereomer 1), 19.4 (diastereomer 2), 22.7
(2C, both diastereomers), 23.3 (diastereomer 1), 23.33 (diastereo-
mer 2), 25.7 (diastereomer 1), 25.8 (diastereomer 2), 26.8 (3C,
diastereomer 1), 26.9 (3C, diastereomer 2), 28.2 (2C, both dias-
tereomers), 28.97(diastereomer1), 29.0(diastereomer 2), 29.3(4C,
both diastereomers), 29.4 (diastereomer 1), 29.41 (diastereomer 2),
29.47 (diastereomer 1), 29.5 (diastereomer 2), 29.6 (4C, both
diastereomers), 29.63 (4C, both diastereomers), 31.9 (2C, both
diastereomers), 48.7 (diastereomer 1), 49.2 (diastereomer 2), 63.1
(diastereomer 1), 63.9 (diastereomer 2), 79.1 (diastereomer 1), 81.3
(diastereomer 2), 83.1 (diastereomer 1), 84.8 (diastereomer 2),
127.87 (2C, both diastereomers), 127.89 (3C, both diastereomers),
127.9 (3C, both diastereomers), 130.0 (4C, both diastereomers),
132.4 (diastereomer 1), 132.6 (diastereomer 2), 132.8 (diastereomer
1), 132.9 (diastereomer 2), 135.4 (2C, diastereomer 1), 135.44 (2C,
diastereomer 2), 135.46 (2C, diastereomer 1), 135.5 (2C, diaster-
eomer 2), 169.3 (diastereomer 1), 169.5 (diastereomer 2); MS
(FAB) m/z 644 ([M þ H]þ, 22), 586 (65), 199 (77), 135 (100);
HRMS (FAB) calcd for C36H58NO5SSi 644.3805 ([M þ H]þ),
found 644.3807.
stirred for 12 h at room temperature, the reaction mixture was
poured into water and extracted with CH2Cl2. The organic layer
was dried over MgSO4 and concentrated in vacuo. Purification of
the crude product by silica gel column chromatography (hexane/
EtOAc, 15:1) afforded bis-mesylate 25 (118 mg, 97%) as a color-
less oil: [R]25D -5.7 (c 0.2, CHCl3); 1H NMR (300 MHz, CDCl3) δ
0.89 (t, J = 6.4 Hz, 3H), 1.11 (br s, 9H), 1.21-1.27 (m, 24H), 1.44
(br s, 9H), 1.70-1.77 (m, 2H), 3.03 (s, 3H), 3.09 (s, 3H), 3.66-3.74
(m, 1H), 3.81-3.93 (m, 2H), 4.90-4.97 (m, 2H), 5.25 (d, J = 9.4
Hz, 1-NH), 7.32-7.47 (m, 6H), 7.62-7.71 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 14.3, 19.5, 22.9, 25.6, 26.7 (2C), 27.0, 28.4, 29.5,
29.7 (2C), 29.8 (2C), 29.9 (2C), 31.4, 32.1, 38.6, 38.7, 38.9, 39.0,
39.2, 39.5, 51.8, 62.3, 80.5, 80.8, 81.3, 128.1 (2C), 128.2 (2C), 130.2,
130.4, 132.7 (2C), 135.8 (2C), 135.9 (2C), 155.3; IR (CHCl3) υmax
3418, 2926, 2855, 1712, 1467, 1361, 1176 (cm-1); MS (FAB) m/z
812 ([M þ H]þ, 35), 588 (55), 135 (25); HRMS (FAB) calcd for
C41H70NO9S2Si 812.4261 ([M þ H]þ), found 812.4258.
Procedure for the Themolysis of Bis-Mesylate 25. Bis-mesylate
25 (100 mg, 0.12 mmol) was dissolved in CH3CN (3 mL). The
resulting solution was transferred to a sealed tube, degassed with
N2 gas, and heated at 110 °C (oil bath) for 12 h. The reaction
mixture was cooled to room temperature and concentrated in
vacuo to provide a mixture of oxazinanone 26 and oxazolidi-
1
none 27 in a ratio of 2.0:1 according to H NMR in CDCl3.
Purification of the crude material by column chromatography
on silica gel (hexane/EtOAc, 2:1) gave oxazinanone 26 (39 mg,
49%) and oxazolidinone 27 (20 mg, 25%).
(4S,5S,6S)-4-((tert-Butyldiphenylsilyloxy)methyl)-2-oxo-6-tetra-
decyl-1,3-oxazinan-5-yl Methanesulfonate (26). As a colorless oil:
1
Rf 0.15 (hexane/EtOAc, 3:1); [R]25 -30.0 (c 0.2, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 0.81 (t, J = 6.3 Hz, 3H), 1.00 (s, 9H),
1.19 (s, 22H), 1.32-1.54 (m, 2H), 1.62-1.78 (m, 2H), 3.02 (s, 3H),
3.47-3.54 (dd, J = 6.8, 10.4 Hz, 1H), 3.62-3.68 (dd, J = 5.1, 10.6
Hz, 1H), 3.75-3.79 (m, 1H), 4.14-4.20 (m, 1H), 4.86 (br s, 1H),
5.29 (br s, 1-NH), 7.32-7.40 (m, 6H), 7.53-7.58 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 13.9, 14.0, 18.9, 20.8, 22.5, 24.6, 26.6
29.0, 29.1, 29.2, 29.3, 29.4 (2C), 29.5 (3C), 30.4, 31.7, 38.9, 56.3,
64.4, 71.6, 74.7, 127.0, 127.1, 127.8, 127.82, 129.9, 130.0, 132.0,
132.1, 135.3 (2C), 135.4 (2C), 153.4; IR (CH3Cl) υmax 3289, 2925,
2849, 2855, 1715, 1465, 1361, 1177, 1113 (cm-1); MS (FAB) m/z
660 ([M þ H]þ, 43), 243 (100), 154 (15); HRMS (FAB) calcd for
C36H58NO6SSi 660.3754 ([M þ H]þ), found 660.3750.
(R)-1-((4S,5R)-4-((tert-Butyldiphenylsilyloxy)methyl)-2-methyl-
4,5-dihydrooxazol-5-yl)pentadecan-1-ol (23). To a solution of cyclic
sulfite 22 (590 mg, 0.92 mmol) in CCl4/CH3CN/H2O (9 mL, 1:1:1)
(R)-1-((4S,5R)-4-((tert-Butyldiphenylsilyloxy)methyl)-2-oxo-
oxazolidin-5-yl)pentadecyl Methanesulfonate (27). As a colorless
oil: Rf 0.31 (hexane/EtOAc, 3:1); [R]25D -21.1 (c 0.2, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 0.81 (t, J = 6.6 Hz, 3H), 0.99 (s, 9H),
1.19 (s, 22H), 1.48-1.50 (m, 2H), 1.63-1.67 (m, 2H), 3.02 (s, 3H),
3.57 (d, J = 4.9 Hz, 2H), 3.70-3.76 (m, 1H), 4.38-4.40 (m, 1H),
4.58-4.62 (m, 1H), 4.92 (s, 1-NH), 7.40-7.37 (m, 6H), 7.50-7.58
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 14.3, 19.3, 22.8 (2C), 25.2,
26.9 (2C), 29.4, 29.5 (2C), 29.7 (2C), 29.8 (3C), 30.5, 32.0 (2C),
39.5, 55.4, 65.3, 78.1, 81.5, 128.2 (4C), 130.3, 130.34, 132.5, 135.66,
135.7 (4C), 163.8; IR (CHCl3) υmax 3289, 2925, 2854, 1762, 1464,
1354, 1174, 1113 (cm-1); MS (FAB) m/z 660 ([M þ H]þ, 37), 428
(100), 344 (45); HRMS (FAB) calcd for C36H58NO6SSi 660.3754
([M þ H]þ), found 660.3756.
were added RuCl3 3H2O (9.5 mg, 0.05 mmol) and NaIO4 (560mg,
3
2.62 mmol). After the reaction mixture was stirred at room
temperature for 2 h, concentrated H2SO4 (24 μL), H2O (30 μL),
and THF (430 μL) were added. The mixture was further stirred for
1 h at room temperature. It was then diluted with EtOAc and
washed with a saturated NaHSO3 solution. The organic layer was
dried over MgSO4, concentrated, and purified by column chro-
matography on silica gel (CH2Cl2/MeOH, 15:1) to give the oxazo-
line 23 (350 mg, 66%) as a colorless oil: [R]25D -0.9 (c 0.7, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 0.88 (t, J = 6.9 Hz, 3H), 1.05 (s,
9H), 1.25 (s, 26H), 1.58-1.75 (m, 1H), 2.03 (s, 3H), 3.50-3.61 (m,
1H), 3.64-3.87 (m, 2H), 4.40-4.58 (m, 1H), 5.34 (s, 1H), 7.24-
7.42 (m, 6H), 7.60-7.65 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ
14.1, 19.1, 20.5, 22.7, 25.0, 26.8 (3C), 29.4 (2C), 29.48, 29.6, 29.66
(2C), 29.7 (3C), 31.9, 32.5, 55.6, 61.1, 66.8, 80.3, 127.99 (2C), 128.0
(2C), 130.0, 130.2, 131.7 (2C), 135.5 (2C), 135.7 (2C), 170.1; IR
(CHCl3) υmax 3418, 2926, 2855, 1755, 1217, 1113 (cm-1); MS
(FAB) m/z 580 ([M þ H]þ, 13), 135 (100), 199 (65); HRMS (FAB)
calcd for C36H58NO3Si 580.4186 ([M þ H]þ), found 580.4194.
(2S,3S,4R)-2-(tert-Butoxycarbonylamino)-1-(tert-butyldiphenyl-
silyloxy)octadecane-3,4-diol Dimethanesulfonate (25). To a solu-
tion of diol 18 (100 mg, 0.15 mmol) in CH2Cl2 (3 mL) and pyridine
(0.3 mL) was added MsCl (36 μL, 0.46 mmol) at 0 °C. After being
Procedure for Cyclization via Bis-Triflate. To a solution of
diol 18 or 21 (0.20 mmol) in CH2Cl2 (3 mL) and pyridine (1 mL)
was added triflic anhydride (0.60 mmol) at -30 °C. After being
stirred for 12 h at -30 °C, the reaction mixture was poured into
water and extracted with CH2Cl2 twice. The organic layers were
dried over MgSO4 and concentrated in vacuo. Purification of
the obtained crude material by column chromatography on
silica gel (hexane/EtOAc, 2:1) gave oxazinanone 12 (109 mg,
76%) or oxazine 31 (74 mg, 64%), respectively.
The concentration of the reaction mixture followed by the
rapid purification of the obtained residue by column chroma-
tography on silica gel provided 29. Compound 29 was too
414 J. Org. Chem. Vol. 76, No. 2, 2011

Lee et al.
JOCArticle
unstable to be fully characterized, and rapidly underwent hy-
drolysis to give 12 on standing at room temperature. Thus, its
full characterization was not performed.
General Procedure for the Removal of the Protecting Groups of
Compounds 23 and 31. To a solution of oxazoline 23 or oxazine
31 (0.17 mmol) in THF (5 mL) was added 2% HCl solution
(5 mL). After being stirred for 12 h at room temperature, this
reaction mixture was poured into 10% aqueous NaHCO3
solution and extracted with EtOAc twice. The combined organic
layers were washed with brine, dried over MgSO4, and concen-
trated in vacuo. The crude compound was dissolved in THF
(5 mL) and TBAF (0.25 mmol, 1.0 M solution in THF) was
added at room temperature. After being stirred for 1 h at room
temperature, the reaction mixture was diluted with EtOAc and
washed with brine. The organic layer was dried over MgSO4 and
concentrated in vacuo. Purification of the residue by silica gel
column chromatography (CH2Cl2/MeOH, 15:1) afforded the
compounds 24 or 32, respectively.
(4S,5S,6S)-4-((tert-Butyldiphenylsilyloxy)methyl)-2-oxo-6-tetra-
decyl-1,3-oxazinan-5-yl Trifluoromethanesulfonate (29). As a col-
orless oil: 1H NMR (CDCl3, 300 MHz) δ 0.81 (t, J = 6.7 Hz, 3H),
0.99 (s, 9H), 1.20 (s, 22H), 1.27-1.50 (m, 2H), 1.69-1.75 (m, 2H),
3.44 (dd, J = 7.7, 10.4 Hz, 1H), 3.68-3.78 (m, 2H), 4.01-4.10 (m,
1H), 5.04 (s, 1H), 6.08 (s, 1-NH), 7.30-7.43 (m, 6H), 7.50-7.56
(m, 4H); MS (FAB) m/z 714 ([M þ H]þ, 40), 586 (40), 538 (100),
220 (57), 199 (43), 135 (78); HRMS (FAB) calcd for C36H55F3-
NO6SSi 714.3471 ([M þ H]þ), found 714.3459.
(4S,5S,6S)-4-((tert-Butyldiphenylsilyloxy)methyl)-2-methyl-6-
tetradecyl-5,6-dihydro-4H-1,3-oxazin-5-ol (31). As a colorless oil
(74 mg, 64%); [R]25D -4.6 (c 1.0, CHCl3); 1H NMR (CDCl3, 500
MHz) δ 0.86 (t, J = 6.8 Hz, 3H), 1.04 (s, 9H), 1.24 (s, 22H),
1.42-1.50 (m, 2H), 1.52-1.68 (m, 2H), 1.88 (s, 3H), 3.43-3.49
(m, 2H), 3.90-3.94 (m, 1H), 3.97 (d, 1H, J = 6.4 Hz), 3.99-4.02
(m, 1H), 7.35-7.42 (m, 6H), 7.62-7.66 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 14.1, 19.2, 21.4, 22.7, 25.4, 26.8 (2C), 26.9,
29.3 (2C), 29.5, 29.6 (3C), 29.7, 31.9, 32.7, 58.2, 62.8, 66.6, 74.6,
127.8 (2C), 127.9, 128.0, 129.9 (2C), 130.1, 130.2, 135.5 (2C),
135.6, 135.8, 171.6; IR (CHCl3) υmax 3347, 3071, 2925, 2854,
1667, 1466, 1240, 1112 (cm-1); MS (FAB) m/z 580 ([M þ H]þ,
22), 557 (12), 301 (89), 279 (100); HRMS (FAB) calcd for
C36H58NO3Si 580.4186 ([M þ H]þ), found 580.4142
N-((2S,3R,4R)-1,3,4-Trihydroxyoctadecan-2-yl)acetamide (24).
As a white solid (84 mg, 91%): mp 100-103 °C (lit.12 mp 104-
106 °C); [R]25 þ10.2 (c 0.7, pyridine) {lit.12 [R]27 þ3.4 (c 1.0,
D
D
MeOH)}; 1H NMR (pyridine-d5, 300 MHz) δ 0.85 (t, J = 6.0 Hz,
3H), 1.23 (s, 22H), 1.57-1.71 (m, 1H), 1.73-1.92 (m, 2H),
1.94-2.08 (m, 1H), 2.11 (s, 3H), 4.12-4.20 (m, 1H), 4.21-4.34
(m, 2H), 4.41(dd, J=2.7, 6.3 Hz, 1H), 4.84-4.92 (m, 1H), 8.25 (d,
J = 8.4 Hz, 1H); 13C NMR (pyridine-d5, 75 MHz) δ 14.3, 22.9,
23.2, 26.3, 29.6 (3C), 29.9 (3C), 30.1 (3C), 32.1, 34.2, 53.7, 62.7,
72.2, 73.5, 170.4; IR (KBr) υmax 3381, 2905, 2891, 1604, 1570, 1114
(cm-1); MS (FAB) m/z 360 ([M þ H]þ, 65), 282 (50), 60 (100);
HRMS (FAB) calcd for C20H42NO4 360.3114 ([M þ H]þ), found
360.3110.
General Procedure for the Removal of the Protecting Groups of
Compounds 11 and 12. To a solution of 11 or 12 (100 mg, 0.17
mmol) in THF (0.1 M) was added TBAF (2 equiv, 1.0 M solution in
THF) at room temperature. After being stirred for 1 h at room
temperature, the reaction mixture was diluted with EtOAc and
washed with brine. The organic layer was dried over MgSO4 and
concentrated. Purification of the crude product by silica gel column
chromatography (hexane/EtOAc, 2:1) led to the desilylated com-
pound. A solution of the desilylated compound (30.0 mg, 0.09
mmol) in 1 N KOH (EtOH/H2O 2:1) was refluxed for 2 h. The
reaction mixture was cooled to room temperature and a 10% HCl
solution (2 mL) was added. The reaction mixture was extracted with
EtOAc, dried over MgSO4, and concentrated in vacuo. Purification
of the residue by silica gel column chromatography (CH2Cl2/
MeOH/NH4OH, 40:10:1) gave the D-phytosphingosine 2 or 4.
(2S,3R,4R)-2-Aminooctadecane-1,3,4-triol (D-xylo-Phyto-
sphingosine, 2). As a white solid (43 mg, 80%): mp 99-100 °C
N-((2S,3S,4S)-1,3,4-Trihydroxyoctadecan-2-yl)acetamide (32).
As a white solid (43 mg, 70%): mp 114.6-115.0 °C (lit.12 mp
114-115 °C); [R]25 þ8.4 (c 1.0, pyridine) {lit.12 [R]27 þ1.02
D
D
(c 1.0, MeOH)}; 1H NMR (pyridine-d5, 300 MHz) δ 0.85 (t, J =
6.9 Hz, 3H), 1.23 (s, 20H), 1.49-1.53 (m, 1H), 1.65-1.70 (m, 1H),
1.79-1.96 (m, 1H), 2.05-2.12 (m, 2H), 2.14 (s, 3H), 4.06 (dd, J =
1.8, 8.4 Hz, 1H), 4.10-4.17 (m, 1H), 4.33 (dd, J = 4.2, 11.1 Hz,
1H), 4.53 (dd, J = 4.5, 11.1 Hz, 1H), 4.69-4.76 (m, 1H), 8.67 (d,
J = 8.7 Hz, 1H); 13C NMR (pyridine-d5, 75 MHz) δ 14.3, 22.9,
23.2, 26.8, 29.6 (3C), 29.9 (3C), 30.1 (3C), 32.1, 34.3, 54.8, 61.9,
71.1, 73.5, 171.6; IR (KBr) υmax 3381, 2905, 1605, 1565, 1114
(cm-1); MS (FAB) m/z 360 ([M þ H]þ, 40), 282 (50), 60 (100);
HRMS (FAB) calcd for C20H42NO4 360.3114 ([M þ H]þ), found
360.3110.
General Procedure for Acetylation of D-Phytosphingosine. To
a solution of 2, 4, 24, or 32 (0.06 mmol) in pyridine (1 mL) was
added Ac2O (1 mL). After being stirred at room temperature
overnight, this reaction mixture was poured into saturated
NaHCO3 solution and extracted with CH2Cl2 twice. The com-
bined organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo. The crude product was purified by
silica gel column chromatography (hexane/EtOAc, 1:1) to give
tetraacetate 19 or 30.
(lit.5h mp 98-99 °C); [R]25D þ12.9 (c 0.5, pyridine) {lit.5h [R]27
D
þ11.8 (c 0.45, pyridine)}; 1H NMR (pyridine-d5, 300 MHz) δ 0.85
(t, J = 6.0 Hz, 3H), 1.23 (s, 22H), 1.51-1.58 (m, 1H), 1.70-1.75
(m, 1H), 1.80-1.90 (m, 1H), 1.96-2.02 (m, 1H), 3.55 (dt, J = 3.3,
6.6 Hz, 1H), 4.06-4.09 (m, 2H), 4.08-4.22 (m, 2H); 13C NMR
(pyridine-d5, 75 MHz) δ 14.2, 22.8, 26.5, 29.5, 29.8 (2C), 29.9 (3C),
30.1 (3C), 32.0, 34.7, 57.9, 60.7, 70.8, 72.8; IR (KBr) υmax 3372,
2920, 2851, 2361, 1734, 1470, 1057 (cm-1); MS (FAB) m/z 318
([M þ H]þ, 25), 60 (93), 154 (38), 643 (53); HRMS (FAB) calcd
for C18H40NO3 318.3008 ([M þ H]þ), found 318.3007.
(2S,3R,4R)-2-Acetamidooctadecane-1,3,4-triol Triacetate (Tetra-
acetyl-D-xylo-phytosphingosine, 19). As a white solid (from 2: 25 mg,
86%; from 24: 19 mg, 88%): mp 45.5-46.5 °C(lit.5b mp 44-46 °C);
[R]25D þ10.5 (c0.75, CHCl3) {lit.5b [R]27D þ6.5 (c0.9, CHCl3),lit.11b
[R]27D þ6.1 (c 0.6, CHCl3)}; 1H NMR (CDCl3, 300 MHz) δ 0.88 (t,
J = 6.6 Hz, 3H), 1.20-1.34 (m, 24H), 1.53-1.64 (m, 2H), 2.02 (s,
3H), 2.06 (s, 3H), 2.09 (s, 3H), 2.11 (s, 3H), 4.00 (dd, J = 5.7, 11.4
Hz, 1H), 4.05 (dd, J= 6.3, 11.3 Hz, 1H), 4.52 (m, 1H), 5.05 (dd, J=
6.6, 12.9 Hz, 1H), 5.16 (dd, J= 4.2, 6.3 Hz, 1H), 5.72 (d, J=9.6Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 20.6, 20.7, 20.9, 22.7, 23.2,
24.8, 29.2, 29.3, 29.4 (2C), 29.5 (2C), 29.69 (3C), 30.5, 31.9, 47.9,
62.9, 71.9, 72.2, 169.8, 170.1, 170.5 (2C); IR (KBr) υmax 3295, 2926,
2855, 1746, 1663, 1541, 1227 (cm-1); MS (FAB) m/z 486 ([M þ
H]þ, 77), 426 (100), 508 (63); HRMS (FAB) calcd for C26H48NO7
486.3431([M þ H]þ), found 486.3445.
(2S,3S,4S)-2-Aminooctadecane-1,3,4-triol (D-lyxo-Phyto-
sphingosine, 4). As a white solid (41 mg, 76%): mp 104-105 °C
(lit.5f mp 104.2-105.5 °C, lit.6f mp 104.8-106.0 °C, lit.13a mp
92-95 °C, lit.13b mp 95 °C,); [R]25 -6.7 (c 0.9, pyridine) {lit.5f
D
[R]25D -7.5 (c 1.0, pyridine), lit.6f [R]25D -7.4 (c 0.9, pyridine), lit.13a
[R]24D -2.6 (c 0.2, pyridine), lit.13b [R]23D -6.2 (c 1.0, pyridine)}; 1H
NMR (pyridine-d5, 300 MHz) δ 0.85 (t, J = 6.3 Hz, 3H), 1.23 (s,
22H), 1.50-1.63 (m, 1H), 1.70-1.92 (m, 1H), 1.93-2.13 (m, 2H),
3.64 (ddd, J = 4.5, 6.6, 11.4 Hz, 1H), 3.96 (dd, J = 2.1, 6.6 Hz, 1H),
4.17 (dd, J = 6.6, 10.2 Hz, 1H), 4.22-4.39 (m, 2H); 13C NMR
(pyridine-d5, 75 MHz) δ 14.3, 22.9, 26.8, 29.6 (2C), 30.0 (3C), 30.3
(4C), 32.1, 34.6, 56.5, 65.2, 72.3, 75.1; IR (KBr) υmax 3358, 2924,
2853, 2361, 1645, 1468, 1119 (cm-1); MS (FAB) m/z 318 ([M þ
H]þ, 25), 43 (100), 60 (97), 81 (22), 282 (17); HRMS (FAB) calcd for
C18H40NO3 318.3008 ([M þ H]þ), found 318.3011.
(2S,3S,4S)-2-Acetamidooctadecane-1,3,4-triol Triacetate (Tetra-
acetyl-D-lyxo-phytosphingosine, 30). As a white solid (from 4: 24 mg,
J. Org. Chem. Vol. 76, No. 2, 2011 415

Lee et al.
JOCArticle
82%; from 32: 18 mg, 85%): mp 73.5-74.1 °C; [R]25D -8.5 (c 0.8,
CHCl3) {lit.11a [R]22D -3.1 (c 1.1, CHCl3), lit.11b [R]28D -3.3 (c 0.5,
CHCl3)}; 1H NMR (CDCl3, 300 MHz) δ 0.86 (t, J = 6.3 Hz, 3H),
1.16-1.36 (m, 24H), 1.36-1.59 (m, 2H), 1.96 (s, 3H), 2.05 (s, 3H),
2.08 (s, 3H), 2.11 (s, 3H), 4.21 (dd, J = 4.5, 11.4 Hz, 1H), 4.50-459
(m, 1H), 5.08 (m, 2H), 5.77 (d, J = 9.3 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 14.0, 20.57, 20.65, 20.9, 22.6, 23.1, 25.1, 29.25, 29.30,
29.38, 29.43, 29.51, 29.55 (2C), 29.58 (2C), 30.8, 31.8, 47.3, 63.1,
71.0, 71.7, 169.6, 170.2, 170.5, 170.6; IR (KBr) υmax 2924, 2845,
1746, 1655, 1559, 1223 (cm-1);MS(FAB) m/z486 ([M þ H]þ, 100),
426 (70), 508 (50); HRMS (FAB) calcd for C26H48NO7 486.3431
([M þ H]þ), found 486.3433.
density functional theory (DFT) method as implemented in the
DMol3 package,14 which is available as part of the Material Studio
5.0 package. In the DFT calculations, we employed the Perdew,
Burke, and Ernzerhof (PBE) function15 for the exchange-correla-
tion interaction within a generalized gradient approximation
(GGA) and a double numerical basis set including d-polarization
functions (DNP) as implemented in the DMol3.
Acknowledgment. This work was supported by the SRC/
ERC program (R11-2007-107-02001-0) and the WCU pro-
gram (R32-2008-000-10098-0) through KOSEF funded by
MEST.
Theoretical Calculations. Theoretical calculations of the trun-
cated conformers A, B, C, and D were performed by using the
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra of compounds 2, 4, 11, 12, 18-19, 21-27,
29-32, and cyclic sulfite derivative from diol 18. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) (a) Delley, B. J. Chem. Phys. 1990, 92, 508–517. (b) Delley, B. J.
Chem. Phys. 2000, 113, 7756–7764.
(15) Perdew, J. P.; Burke, K. Phys. Rev. Lett. 1996, 77, 3865–3868.
416 J. Org. Chem. Vol. 76, No. 2, 2011