Efficient and selective synthesis of D-arabino-, D-lyxo-, and D-xylo-phytosphingosine from D-ribo-phytosphingosine

Article abstract of DOI:10.1021/jo702147y

(Chemical Equation Presented) A new high-yield approach to the regio- and stereoselective synthesis of D-arabino-, D-lyxo-, and D-xylo-phytosphingosines from inexpensive D-ribo-phytosphingosine is described. The synthetic methodologies mainly rely on the

Full text of DOI:10.1021/jo702147y

Efficient and Selective Synthesis of D-arabino-, D-lyxo-, and
D-xylo-Phytosphingosine from D-ribo-Phytosphingosine†
Sanghee Kim,* Nakyong Lee, Sukjin Lee, Taeho Lee, and Yun Mi Lee
College of Pharmacy, Seoul National UniVersity, San 56-1, Shilim, Kwanak, Seoul 151-742, Korea
pennkim@snu.ac.kr
ReceiVed October 3, 2007
A new high-yield approach to the regio- and stereoselective synthesis of D-arabino-, D-lyxo-, and D-xylo-
phytosphingosines from inexpensive D-ribo-phytosphingosine is described. The synthetic methodologies
mainly rely on the selective configurational inversion of the stereocenter through a neighboring group
participation mechanism.
Introduction
Sphingoid bases are long-chain aliphatic compounds typically
possessing a 2-amino-1,3-diol functionality. They are the
principal structural backbone of sphingolipids which play critical
roles in many physiological processes.1 Among the naturally
occurring sphingoid bases, phytosphingosines are one of the
most important and common species.2 They are widely distrib-
uted in plants, yeasts, fungi, and even mammalian tissues. They
consist mainly of an 18-carbon chain and possess a 2-amino-
1,3,4-triol head group. In nature, the most predominant stere-
oisomer of phytosphingosines is D-ribo-phytosphingosine (1,
Figure 1). Although it had been costly to isolate 1 from natural
sources, it is now readily obtainable on an industrial scale from
a yeast fermentation process.3
FIGURE 1. 1. D-ribo-Phytosphingosine (1) and its stereoisomers 2-4.
a great deal of effort has been devoted toward the synthesis of
1 as well as other stereoisomers, such as D-lyxo- (2), D-arabino-
(3), and D-xylo- (4) phytosphingosines, shown in Figure 1.2,5,6
To establish the desired stereochemistry, most syntheses rely
on chiral pools such as carbohydrates and amino acids, or
Because of the interesting biological properties of phytosph-
ingosine itself and phytosphingosine-containing sphingolipids,4
(4) (a) Kester, M.; Kolesnick, R. Pharmacol. Res. 2003, 47, 365-371.
(b) Rosen, H.; Liao, J. Curr. Opin. Chem. Biol. 2003, 7, 461-468.
(5) For selected publications for recent syntheses of phytosphingosines,
see: (a) Jeon, J.; Shin, M.; Yoo, J. W.; Oh, J. S.; Bae, J. G.; Jung, S. H.;
Kim, Y. G. Tetrahedron Lett. 2007, 48, 1105-1108. (b) Yoon, H. J.; Kim,
Y.-W.; Lee, B. K.; Lee, W. K.; Kim, Y.; Ha, H.-J. Chem. Commun. 2007,
79-81. (c) Lombardo, M.; Capdevila, M. G.; Pasi, F.; Trombini, C. Org.
Lett. 2006, 8, 3303-3305. (d) Righi, G.; Ciambrone, S.; Achille, C. D.;
Leonelli, A.; Bonini, C. Tetrahedron 2006, 62, 11821-11826. (e) Lu, X.;
Byun, H.-S.; Bittman, R. J. Org. Chem. 2004, 65, 5433-5438. (f) Raghavan,
S.; Rajender, A. J. Org. Chem. 2003, 68, 7094-7097. (g) Ndakala, A. J.;
Hashemzadeh, M.; So, R. C.; Howell, A. R. Org. Lett. 2002, 4, 1719-
1722.
* To whom correspondence should be addressed. Phone: 82-2-740-8913.
Fax: 82-2-762-8322.
† Dedicated to Prof. Moon Woo Chun on the occasion of his retirement.
(1) Merrill, A. H., Jr.; Sandhoff, K. Sphingolipids: Metabolism and Cell
Signaling. In Biochemistry of Lipids, Lipoprotein, and Membranes; Vance,
D. E., Vance, J. E., Eds.; Elsevier: New York, 2002; pp 373-407.
(2) For recent reviews, see: (a) Liao, J.; Tao, J.; Lin, G.; Liu, D.
Tetrahedron 2005, 61, 4715-4733. (b) Howell, A. R.; Ndakala, A. J. Curr.
Org. Chem. 2002, 6, 365-391. (c) Curfman, C.; Liotta, D. Methods
Enzymol. 1999, 311, 391-440. (d) Koskinen, P. M.; Koskinen, A. M. P.
Synthesis 1998, 1075-1091.
(3) Bae, J.-H.; Sohn, J.-H.; Park, C.-S.; Rhee, J.-S.; Choi, E.-S. Appl.
EnViron. Microbiol. 2003, 69, 812-819 and references cited therein.
10.1021/jo702147y CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/16/2008
J. Org. Chem. 2008, 73, 1379-1385
1379

Kim et al.
asymmetric transformations such as Sharpless asymmetric
dihydroxylation. The reported methodologies each have their
own advantages and disadvantages, and many of them were not
satisfactory in view of the stereoselective synthesis of all four
possible stereoisomers of D-phytosphingosine.6
Our strategy relied mainly on the selective configurational
inversion of the stereocenter through a neighboring group
participation mechanism.
Results and Discussion
In the course of our ongoing sphingolipid research, all four
stereoisomers of D-phytosphingosines 1-4 were needed as
starting materials for the synthesis of certain sphingolipids. It
would be medicinal-chemically interesting to examine and
compare the biological activities of each of four phytosphin-
gosine-derived sphingolipids. This is because the different
configurations of one or two hydroxyl groups of phytosphin-
gosines could elicit different biological effects of sphingolipids
as a result of the different conformations and hydrogen-bonding
patterns of a molecule.7 We considered the cheap and com-
mercially available ribo isomer 1 as possibly an ideal starting
material8 for the preparation of other stereoisomers 2-4 since
they are identical except for the stereochemistries at either or
both C-3 and C-4.
The selective configurational inversion of the given hydroxyl
group of the diol or polyol is one of the important transforma-
tions in synthetic organic chemistry, especially in the area of
carbohydrate chemistry. A number of useful methods have been
developed, including protocols based on the anchimeric assis-
tance, the Mitsunobu reaction, and sequential oxidation/reduction
route as well as triflation/nitrite addition.9 Although this type
of inversion has been extensively studied in the context of cyclic
systems, the regioselective inversion of the distal or proximal
hydroxyl groups in an acyclic system has been less widely
explored.10
At the commencement of the synthesis, it occurred to us that
the proper choice of protecting groups for 1,2-â-amino-alcohol
functionality in D-ribo-phytosphingosine (1) was important to
avoid the complication caused by the multiple anchimeric
assistance during the inversion of activated hydroxyl groups.
Thus, the non-nucleophilic azide was chosen as an amino
protecting group, and the bulky silyl protecting group was
introduced at the primary hydroxyl group. The suitably protected
phytosphingosine 5 (Scheme 1) was easily prepared from 1 by
a two-step sequence as described in our previous work.12
With multigram quantities of 5 in hand, we first examined
whether the 3,4-vicinal diol of 5 would be selectively mono-
functionalized with a moderately reactive leaving group such
as tosylate or mesylate. We felt that the difference in the steric
and electronic environment surrounding each secondary hy-
droxyl group of 5 would enable us to differentiate the two
hydroxyl groups and introduce sulfonyl groups in a regioselec-
tive fashion.13 After some trials, it was found that treatment of
5 with a slight excess of TsCl in pyridine provided predomi-
nantly 4-O-tosylate 6 (75%; 81% yield based on the recovered
starting material), along with a minor amount of its regioisomer
3-O-tosylate (4%). The corresponding ditosylate was not
detected in the crude 1H NMR spectra. The minor regioisomer,
3-O-tosylate, could be removed by rather tedious column
chromatography, although for practical reasons it is preferred
to separate the isomeric mixture in the subsequent steps. The
regiochemistry of 6 was determined by the 1H NMR chemical
shifts and splitting patterns of the protons at C-3 and C-4. To
utilize the Winstein’s neighboring group participation14,15 in
inverting the configuration at C-4 within 6, the C-3 hydroxyl
group was converted to its acetate 7 in 95% yield with Ac2O/
pyridine.
Herein, we wish to report a concise and efficient stereose-
lective synthetic route to the above-mentioned three stereoiso-
mers of phytosphingosine 2-4 from inexpensive ribo isomer 1
via a selective inversion of either of the two hydroxyl groups
at C-3 and C-4. The route also provides access to the corres-
ponding 2-azido intermediates which might be synthetically
useful especially in the preparation of 1-glycosyl sphingolipids.11
Heating the obtained 7 in refluxing wet ethanol (5% v/v) in
the presence of 1 equiv of CaCO3 for 4 days afforded a 4.3:1
mixture of inseparable acetates 8a and 8b in 91% combined
yield. No other isomers were detected by careful H NMR
analysis of the reaction mixture. In this process, the presence
(6) For the synthesis of more than one stereoisomer of phytosphingosine,
see: (a) Enders, D.; Palecˇek, J.; Grondal, C. Chem. Commun. 2006, 655-
657. (b) Cai, Y.; Ling, C. C.; Bundle, D. R. Org. Biomol. Chem. 2006, 4,
1140-1146. (c) Lu, X.; Bittman, R. Tetrahedron Lett. 2005, 46, 3165-
3168. (d) He, L.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2000, 65, 7618-
7626. (e) Imashiro, R.; Sakurai, O.; Yamashita, T.; Horikawa, H. Tetra-
hedron 1998, 54, 10657-10670. (f) Li, Y.-L.; Mao, X.-H.; Wu, Y.-L. J.
Chem. Soc., Perkin Trans. 1 1995, 1559-1564. (g) Mulzer, J.; Brand, C.
Tetrahedron 1986, 42, 5961-5968.
(7) For a recent paper that discusses this topic, see; (a) Kok, J. W.;
Nikolava-Karakashian, M.; Klappe, K.; Alexander, C.; Merrill, A. H. J.
Biol. Chem. 1997, 272, 21128-21136. (b) Puskareva, M.; Chao, R.;
Bielavska, A.; Merrill, A. H.; Crane, H. M.; Lagu, B.; Liotta, D.; Hannun,
Y. A. Biochemistry 1995, 34, 1885-1892. (c) Motoki, K.; Kobayashi, E.;
Uchida, T.; Fukushima, H.; Koezuka, Y. Bioorg. Med. Chem. Lett. 1995,
5, 705-710.
(8) Our group and van Boom’s group have previously utilized 1 as a
starting material in the synthesis of another sphingoid base, sphingosine,
see: (a) van den Berg, R. J. B. H. N.; Korevaar, C. G. N.; van der Marel,
G. A.; Overkleeft, H. S.; van Boom, J. H. Tetrahedron Lett. 2002, 43, 8409-
8412. (b) van den Berg, R. J. B. H. N.; Korevaar, C. G. N.; Overkleeft, H.
S.; van der Marel, G. A.; van Boom, J. H. J. Org. Chem. 2004, 69, 5699-
5704. See also ref 12.
1
(11) For reviews and selected examples, see: (a) Morales-Serna, J. A.;
Boutureira, O.; D`ıaz, Y.; Matheu, M. I.; Castillo´n, S. Carbohydr. Res. 2007,
342, 1595-1612. (b) Vankar, Y. D.; Schmidt, R. R. Chem. Soc. ReV. 2007,
29, 201-216. (c) Du, W.; Gervay-Hague, Org. Lett. 2005, 7, 2063-2065.
(d) Fan, G.-T.; Pan, Y.-S.; Lu, K.-C.; Cheng, Y.-P.; Lin, W.-C.; Lin, S.;
Lin, C.-H.; Wong, C.-H.; Fang, J.-M.; Lin, C.-C. Tetrahedron. 2005, 61,
1855-1862. (e) Lu, X.; Bittman, R. Tetrahedron Lett. 2005, 46, 3165-
3168. (f) Barbieri, L.; Costantino, V.; Fattorusso, E.; Mangoni, A.; Aru,
B.; Parapini, S.; Taramelli, D. Eur. J. Org. Chem. 2004, 468-473. (g)
Costantino, V.; Fattorusso, E.; Imperatore, C.; Mangoni, A. Tetrahedron
2002, 58, 369-375.
(12) Kim, S.; Lee, S.; Lee, T.; Ko, H.; Kim, D. J. Org. Chem. 2006, 71,
8661-8664.
(13) (a) O’Donnell, C. J.; Burke, S. D. J. Org. Chem. 1998, 63, 8614-
8616. (b) Fleming, P. R.; Sharpless, K. B. J. Org. Chem. 1991, 56, 2869-
2875.
(9) For selected examples, see: (a) Dong, H.; Pei, Z.; Ramstro¨m, O. J.
Org. Chem. 2006, 71, 3306-3309. (b) Chang, C.-W. T.; Hui, Y.; Elchert,
B. Tetrahedron Lett. 2001, 42, 7019-7023. (c) Weinges, K.; Haremsa, S.;
Maurer, W. Carbohydr. Res. 1987, 164, 453-458. (d) Lattrell, R.; Lohaus,
G. Justus Liebigs Ann. Chem. 1974, 901-920.
(10) (a) Curti, C.; Zanardi, F.; Battistini, L.; Sartori, A.; Rassu, G.; Pinna,
L.; Casiraghi, G. J. Org. Chem. 2006, 71, 8552-8558. (b) Kemp, S. J;
Bao, J.; Pedersen, S. F. J. Org. Chem. 1996, 61, 7162-7167.
(14) (a) Winstein, S.; Buckles, R. E. J. Am. Chem. Soc. 1942, 64, 2780-
2786. (b) Winstein, S.; Buckles, R. E. J. Am. Chem. Soc. 1942, 64, 2787-
2790. (c) Winstein, S.; Buckles, R. E. J. Am. Chem. Soc. 1942, 64, 2796-
2801.
(15) For a recent application of the Winstein procedure in inverting the
configuration, see: (a) Davies, S. G.; Long, M. J. C.; Smith, A. D. Chem.
Commun. 2005, 4536-4538. (b) Pei, Z.; Dong, H.; Ramstro¨m, O. J. Org.
Chem. 2005, 70, 6952-6955.
1380 J. Org. Chem., Vol. 73, No. 4, 2008

Synthesis of D-arabino-, D-lyxo-, and D-xylo-Phytosphingosines
SCHEME 1. Synthesis of D-lyxo-Diol 10
SCHEME 2. Synthesis of D-arabino-Diol 13
of CaCO3 was essential because its absence led to very complex
mixtures of unidentified products. The use of other carbonate
salts such as K2CO3 did not afford the desired products, 8a and
8b, but instead gave the corresponding C3-C4 epoxide as a
major product. The stereochemistry of 8a and 8b was deter-
mined by their conversion to the final product 2 as discussed
later.
The formations of both acetates 8a and 8b as well as the
configurational inversion of C-4 denoted the Winstein’s anchi-
meric assistance mechanism during the process of inversion and
strongly suggested this reaction proceeds via an oxonium ion
intermediate 9. From the previous observations14,16 and the
present results, it is apparent that the C-4 inverted intermediate
9 collapses via path a to produce 8a and 8b. Attack on 9 at C-3
(path b) or C-4 (path c) by oxygen nucleophiles (H2O or EtOH)
would produce the arabino- or ribo-derviatives, respectively,
which were not produced during the reaction. It was seen that
the formation of 8a and 8b would also result from the direct
SN2 displacement of the C-4 tosylate 7 with nucleophile (water)
and subsequent acyl migration. However, this is quite unlikely
based on literature precedents14,16 and our result that no trace
described in our previous work. We found that the treatment of
cyclic sulfate 11 with cesium benzoate17 in DMF followed by
acidic hydrolysis of the intermediate O-sulfate provided the 4-O-
benzoate 12 as the only identifiable regioisomer in 92% yield,
giving inversion of C-4 configuration in the product. The
excellent regioselectivity could be attributed to the steric and
electronic interactions between the neighboring substituents and
nucleophile. Cleavage of the benzoate ester in 12 with NaOMe/
MeOH furnished the 1,2-protected lyxo isomer 10 in 99% yield,
which was identical with 10 prepared from 6 (Scheme 1).
With compound 12 in hand, we sought to apply it to the
synthesis of arabino isomer 13 (Scheme 2). To invert the
configuration at C-3 within 12, the Winstein’s neighboring group
participation was again utilized. At first, we attempted to convert
the C-3 hydroxyl group of 12 to the corresponding tosylate.
The formation of the tosylate by the reaction with TsCl did not
occur even at elevated temperatures, probably due to the steric
crowding at C-3. On the other hand, mesylation with MsCl at
room temperature proceeded effectively in 95% yield to give
14. The resulting mesylate 14 was subjected to the same reaction
conditions as described for 7 (CaCO3 in refluxing wet ethanol).
In this case, however, the reaction was very sluggish and did
not reach completion even after one week (67% conversion).
The low conversion rate might be attributed to the fact that the
benzoyl group is less reactive than the acetyl counterpart to
1
of C-4 ethyl ether was detected in the crude H NMR spectra.
Acetate hydrolysis of a mixture of 8a and 8b with K2CO3 in
methanol provided the 1,2-amino-alcohol protected D-lyxo-
phytosphingosine 10 in 95% yield. Alternatively and more
conveniently, 10 could be obtained in one-pot fashion from 7
without the isolation and purification of a mixture of 8a and
8b. After the displacement reaction was completed to give 8a
and 8b as judged by TLC analysis, K2CO3 (3 equiv) and excess
methanol were added to the reaction mixture at room temper-
ature for the acetate hydrolysis to provide 10 in higher overall
yield (94%).
The protected lyxo isomer 10 could be also prepared via
another route. In our previous study, it was found that the
nucleophilic ring opening of cyclic sulfate 11 (Scheme 1) with
iodide occurred exclusively at C-4 with clean inversion.12 This
result prompted us to investigate the reaction of 11 with oxygen
nucleophiles to develop a new route to lyxo isomer 10. Cyclic
sulfate 11 was easily prepared from 5 in high overall yield as
(17) (a) Pettit, G. R.; Melody, N.; Herald, D. L. J. Org. Chem. 2001,
66, 2583-2587. (b) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995,
117, 10143-10144. (c) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988,
110, 7538-7539.
(16) Ryan, K.; Arzoumanian, H.; Acton, E. M.; Goodman, L. J. Am.
Chem. Soc. 1964, 86, 2497-2503.
J. Org. Chem, Vol. 73, No. 4, 2008 1381

Kim et al.
SCHEME 4. Synthesis of D-lyxo- (2), D-arabino- (3), and
SCHEME 3. Synthesis of D-xylo-Diol 19
D-xylo- (4) Phytosphingosine
neighboring group participation.18 Therefore, the reaction solvent
was changed to a higher boiling point solvent, 1-propanol, and
the reaction temperature was raised to reflux. This modification
successfully led to the formation of the desired C-3 inverted
product 15 as the only detectable isomer in 90% yield after 4
days refluxing. In this process, unlike the inversion reaction
for the lyxo isomer (7 to 8), only a single ester was formed.
Saponification of the benzoyl ester in 15 with NaOMe/MeOH
produced the targeted 1,2-protected arabino isomer 13 in 88%
yield.
For the synthesis of the xylo-isomer from the ribo-isomer
using the Winstein’s neighboring group participation, regiose-
lective acylation of the hydroxyl group at C-4 was required.
This was accomplished by treating diol 5 with 1 equiv of
benzoyl chloride in a mixture of pyridine and CH2Cl2 in the
presence of a catalytic amount of DMAP to furnish 4-O-
benzoate 16 with very high yield (92%) and regioselectivity
(Scheme 3). Only a trace amount (<5%) of 3-O-benzoate was
detected in the crude mixture, and it was removed by column
chromatography. Mesylation of the resulting secondary alcohol
16 gave 17 in 95% yield and set the stage for the inversion of
the stereocenter at C-3. When the inversion reaction of 17 was
conducted under the same reaction conditions as those for 7, a
2.8:1 mixture of the separable benzoates 18a and 18b was
obtained in 97% combined yield. No other isomers were
detected in the crude 1H NMR spectra. The ester product
distribution of this inversion reaction was different from those
obtained from 7 and 14. Although the factors that determine
which products are formed depend on many variables, these
results could be a reflection of the relative thermodynamic
preference of each system.19 Removal of the benzoate group in
18a and 18b with NaOMe/MeOH afforded the 1,2-protected
xylo isomer 19 in 94% yield.
and 19 with Bu4NF in THF furnished the corresponding
2-azidophytosphingosine 20, 21, and 22 in 99%, 93%, and 94%
yields, respectively (Scheme 4). Finally, reduction of the azide
groups of 2-azidophytosphingosines 20, 21, and 22 was achieved
by hydrogenation with Pd/C in MeOH to give the desired target
compounds D-lyxo- (2), D-arabino- (3), and D-xylo- (4) phytosph-
ingosines in 86%, 85%, and 91% yields, respectively. For
analytical reasons, the obtained phytosphingosines 2-4 were
peracetylated with Ac2O/pyridine to provide the corresponding
tetraacetate derivatives in high yields. The analytical and
spectroscopic data of both the synthetic phytosphingosine
isomers 2-4 and their tetraacetate derivatives were identical
with those reported in the literature.5e-g,6d-g,20
In conclusion, these studies provide a practical preparative
route to D-lyxo- (2), D-arabino- (3), and D-xylo- (4) phytosph-
ingosines from the low-cost D-ribo-phytosphingosine (1) in high
overall yield. An important feature of this synthesis is the
selective configurational inversion of the stereocenter through
a neighboring group participation mechanism as well as a
nucleophilic substitution of cyclic sulfate. The process is highly
selective and seems to be readily amenable to multigram-scale
synthesis. In addition, the synthetic methodology also provided
the protected isomers of phytosphingosines which could be
synthetically useful in the preparation of various sphingolipid
derivatives.
Experimental Section
(2S,3S,4R)-2-Azido-1-(tert-butyldiphenylsilyloxy)-3-hydroxy-
octadecan-4-yl 4-Methylbenzenesulfonate (6). To a solution of
diol 5 (610 mg, 1.05 mmol) in pyridine (5 mL) was added TsCl
(240 mg, 1.26 mmol) at room temperature. After being stirred at
room temperature for 20 h, this reaction mixture was diluted with
CH2Cl2 then washed with H2O. The aqueous phase was extracted
with CH2Cl2 twice. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo. The crude
All the obtained 1,2-protected isomers, 10, 13, and 19, were
completely free from any other isomers. With these compounds
in hand, efforts were next directed toward the deprotection steps.
Removal of the silyl protecting groups in compounds 10, 13,
(20) (a) Nakamura, T.; Shiozaki, M. Tetrahedron 2001, 44, 9087-9092.
(b) Azuma, H.; Tamagaki, S.; Ogino, K, J. Org. Chem. 2000, 65, 3538-
3541. (c) Shirota, O.; Nakanishi, K.; Berova, N. Tetrahedron 1999, 55,
13643-13658. (d) Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann. Chem.
1990, 11, 1069-1078. (e) Schmidt, R.; Maier, T. Carbohydr. Res. 1988,
174, 169-180.
(18) Dong, H.; Pei, Z.; Angelin, M.; Bystro¨m, S.; Ramstro¨m, O. J. Org.
Chem. 2007, 72, 3694-3701.
(19) Exposure of the purified minor products 18b to the same reaction
conditions as those for starting 17 (CaCO3 in refluxing wet ethanol) for 2
days led to a 2.4:1 mixture of 18a and 18b.
1382 J. Org. Chem., Vol. 73, No. 4, 2008

Synthesis of D-arabino-, D-lyxo-, and D-xylo-Phytosphingosines
product was purified by silica gel column chromatography (hexane/
EtOAc, 40:1) to give tosylate 6 (580 mg, 75%; 81% yield based
on the recovered starting material) as a colorless oil as well as its
regioisomer 3-O-tosylate (30 mg, 4% yield based on the recovered
starting material), along with recovered starting material 5 (45
mg): [R]25D +36.7 (c 0.8, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
0.89 (t, J ) 6.6 Hz, 3H), 1.09 (s, 9H), 1.14-1.28 (m, 20H), 1.40-
1.49 (m, 2H), 1.67-1.79 (m, 2H), 2.43 (s, 3H), 3.26-3.32 (m,
1H), 3.89 (dd, J ) 5.4, 11.1 Hz, 1H), 3.95-3.98 (m, 1H), 4.03
(dd, J ) 3.0, 10.8 Hz, 1H), 4.70 (td, J ) 3.0, 9.3 Hz, 1H), 7.32 (d,
J ) 8.1 Hz, 1H), 7.38-7.50 (m, 6H), 7.67-7.72 (m, 4H), 7.80 (d,
J ) 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 19.1, 21.6,
22.6, 24.9, 26,7, 28.0, 29.1, 29.30, 29.32, 29.4, 29.60, 29.62, 29.64,
31.9, 62.7, 64.4, 71.2, 84.4, 127.79, 127.82, 127.9, 129.8, 129.87,
129.91, 132.58, 132.63, 133.6, 135.55, 135.58, 144.9; IR (CH3Cl)
υmax 3493, 3073, 2926, 2855, 2101, 1177, 1113, 918 (cm-1); MS
(FAB) m/z 736 ([M + 1]+, 6), 135 (100), 199 (55), 240 (23), 458
(10); HRMS (FAB) calcd for C41H62N3O5SSi 736.4179 ([M + H]+),
found 736.4152.
(FAB) calcd for C36H58N3O4Si 624.4197 ([M + H]+), found
624.4196.
1
8b: colorless oil; H NMR (CDCl3, 300 MHz) δ 0.88 (t, J )
6.6 Hz, 3H), 1.08 (s, 9H), 1.25 (s, 24H), 1.54-1.64 (m, 2H), 1.93
(s, 1H), 2.66 (d, J ) 9.3 Hz, 1H), 3.44-3.48 (m, 1H), 3.66-3.80
(m, 3H), 4.83 (dd, J ) 1.8, 7.8 Hz, 1H), 7.36-7.49 (m, 6H), 7.64-
7.72 (m, 6H); MS (FAB) m/z 646 ([M + 23]+, 6), 135 (100), 199
(70), 240 (40), 606 (23); HRMS (FAB) calcd for C36H57N3O4SiNa
646.4016 ([M + Na]+), found 646.3986.
(2S,3S,4S)-2-Azido-1-(tert-butyldiphenylsilyloxy)-3-hydroxy-
octadecan-4-yl Benzoate (12). To a solution of cyclic sulfate 11
(4.25 g, 6.60 mmol) in DMF (33 mL) were added BzOH (1.37 g,
11.2 mmol) and CsCO3 (3.23 g, 9.91 mmol). This reaction mixture
was stirred at room temperature for 6 h, and to it were added
concentrated H2SO4 (5 mL), H2O (6 mL), and THF (11.5 mL).
The mixture was stirred for 2 h at room temperature, and then
diluted with EtOAc. It was then washed with saturated aqueous
NaHCO3 solution and brine. The organic layer was dried over Na2-
SO4 and concentrated in vacuo. The crude product was purified by
silica gel column chromatography (hexane/EtOAc, 10:1) to give
(2S,3S,4R)-2-Azido-1-(tert-butyldiphenylsilyloxy)-4-(tosyloxy)-
octadecan-3-yl Acetate (7). To a solution of tosylate 6 (314 mg,
0.426 mmol) in pyridine (4 mL) were added Ac2O (120 µL, 1.29
mmol) and DMAP (3 mg, 0.02 mmol) at 0 °C. After being stirred
at room temperature for 3 h, this reaction mixture was poured into
saturated NaHCO3 solution and extracted with CH2Cl2 twice. The
combined 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, 15:1) to give
benzoate 12 (4.17 g, 92%) as a colorless oil: [R]27 +7.4 (c 1.2,
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.6 Hz, 3H),
1.08 (s, 9H), 1.20-1.40 (m, 24H), 1.64-1.94 (m, 2H), 2.30 (d, J
) 8.1 Hz, 1H), 3.33-3.39 (m, 1H), 3.71 (td, J ) 2.1, 8.4 Hz, 1H),
3.92 (dd, J ) 6.3, 11.1 Hz, 1H), 4.04 (dd, J ) 3.9, 10.8 Hz, 1H),
5.35 (ddd, J ) 2.1, 6.3, 8.1 Hz, 1H), 7.32-7.50 (m, 9H), 7.56-
7.72 (m, 4H), 8.02-8.08 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ
14.1, 19.0, 22.6, 25.4, 26.7, 29.28, 29.34, 29.38, 29.44, 29.54, 29.58,
29.60, 29.62, 30.7, 31.8, 63.9, 64.6, 71.4, 74.2, 127.73, 127.75,
128.3, 129.7, 129.8, 129.9, 132.6, 132.7, 133.0, 135.5, 135.51,
165.9; IR (CHCl3) υmax 3493, 2926, 2863, 2100, 1711, 1271, 1111
(cm-1); MS (FAB) m/z 708 ([M + 23]+, 3), 105 (100), 135 (45),
199 (23), 240 (15); HRMS (FAB) calcd for C41H59N3O4SiNa
708.4173 ([M + Na]+), found 708.4181.
acetate 7 (315 mg, 95%) as a colorless oil: [R]25 +15.0 (c 1.2,
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 0.89 (t, J ) 6.6 Hz, 3H),
1.06 (s, 9H), 1.18-1.31 (m, 20H), 1.55-1.64 (m, 2H), 1.86 (s,
3H), 2.41 (s, 3H), 3.53-3.59 (m, 1H), 3.67 (dd, J ) 6.6, 10.8 Hz,
1H), 3.79 (dd, J ) 2.7, 10.8 Hz, 1H), 4.75 (ddd, J ) 2.4, 5.7, 7.8
Hz, 1H), 4.95 (dd, J ) 2.1, 8.1 Hz, 1H), 7.25-7.30 (m, 1H), 7.37-
7.48 (m, 6H), 7.60-7.76 (m, 4H), 7.70-7.75 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 19.00, 19.03, 20.6. 21.6, 22.7, 25.2, 26.5,
26.6, 26.7, 29.1, 29.2, 29.4, 29.5, 29.65, 29.66, 29.67, 29.7, 29.9,
31.9, 61.9, 63.9, 71.3, 81.8, 127.7, 127.8, 127.9, 129.6, 129.7, 129.9,
132.6, 132.7, 134.0, 134.8, 135.2, 135.5, 135.55, 135.61, 135.63,
144.7, 169.3; IR (CH3Cl) υmax 3468, 3073, 2930, 2855, 2103, 1754,
1177, 1113, 910 (cm-1); MS (FAB) m/z 800 ([M + 23]+, 9), 135
(100), 197 (70), 353 (18); HRMS (FAB) calcd for C43H63N3O6-
SSiNa 800.4105 ([M + Na]+), found 800.4136.
(2S,3S,4S)-2-Azido-1-(tert-butyldiphenylsilyloxy)octadecane-
3,4-diol (10). Method A: To a solution of the crude acetate 8 (174
mg, 0.279 mmol) in MeOH (3 mL) was added K2CO3 (58 mg,
0.42 mmol) at room temperature. After being stirred at room
temperature for 1 h, this reaction mixture was poured into saturated
NH4Cl solution and extracted with EtOAc twice. The combined
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, 8:1) to give lyxo-diol
10 (154 mg, 95%) as a colorless oil.
(2S,3S,4S)-2-Azido-1-(tert-butyldiphenylsilyloxy)-3-hydroxy-
octadecan-4-yl Acetate (8a) and (2S,3S,4S)-2-Azido-1-(tert-
butyldiphenylsilyloxy)-4-hydroxyoctadecan-3-yl Acetate (8b). To
a solution of acetate 7 (246 mg, 0.316 mmol) in wet EtOH (4 mL,
5% v/v) was added CaCO3 (32 mg, 0.32 mmol). This reaction
mixture was heated under reflex for 4 days. The reaction was
filtered, and then concentrated to dryness under reduced pressure.
The residue was dissolved in EtOAc and washed with water and
brine, dried over MgSO4, and concentrated in vacuo to give acetate
8 (200 mg, 91%) as a mixture of acetates 8a and 8b in a ratio of
4.3:1. The crude mixture was used in the next step without further
purification. Acetates 8a and 8b were separated by repeated
preparative TLC on silica gel (hexane/EtOAc, 25:1) for analytical
purposes.
8a: colorless oil; [R]24D +8.4 (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 0.88 (t, J ) 6.6 Hz, 3H), 1.08 (s, 9H), 1.25 (s, 24H),
1.57-1.74 (m, 2H), 2.08 (s, 3H), 2.13 (d, J ) 8.1 Hz, 1H), 3.27-
3.33 (m, 1H), 3.59 (dt, J ) 2.1, 8.4 Hz, 1H), 3.89 (dd, J ) 6.0,
11.1 Hz, 1H), 4.01 (dd, J ) 3.9, 11.1 Hz, 1H), 5.08 (ddd, J ) 2.1,
7.5, 8.7 Hz, 1H), 7.36-7.49 (m, 6H), 7.64-7.72 (m, 6H); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 19.1, 21.1, 22.7, 25.3, 26.8, 29.35, 29.39,
29.47, 29.52, 29.65, 29.68, 30.7, 32.0, 63.9, 64.7, 71.2, 73.4, 83.2,
127.85, 127.87, 130.0, 135.6, 170.3; IR (CH3Cl) υmax 3468, 3073,
2928, 2854, 2361, 2102, 1717, 1262, 1113 (cm-1); MS (FAB) m/z
624 ([M + 1]+, 6), 135 (100), 199 (48), 240 (29), 606 (10); HRMS
Method B: To a solution of benzoate 12 (1.03 g, 1.50 mmol) in
MeOH (15 mL) was added NaOMe (1.5 equiv, 25 wt % solution
in MeOH) at 0 °C. After being stirred at room temperature for 1 h,
this reaction mixture was poured into saturated NH4Cl solution and
MeOH was evaporated under reduced pressure. The residue was
extracted with EtOAc and washed with brine, dried over MgSO4,
and concentrated in vacuo. The crude product was purified by silica
gel column chromatography (hexane/EtOAc, 8:1) to give lyxo-diol
10 (865 mg, 99%) as a colorless oil: [R]27 +1.8 (c 0.6, CHCl3);
D
1H NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.6 Hz, 3H), 1.08 (s,
9H), 1.26 (s, 24H), 1.40-1.52 (m, 2H), 2.08 (d, J ) 5.7 Hz, 1H),
2.60 (d, J ) 7.2 Hz, 1H), 3.48 (dt, J ) 1.8, 7.2 Hz, 1H), 3.55-
3.63 (m, 1H), 3.70-3.78 (m, 1H), 3.88 (dd, J ) 5.7, 10.5 Hz, 1H),
3.97 (dd, J ) 4.5, 10.8 Hz, 1H), 7.37-7.50 (m, 6H), 7.66-7.72
(m, 6H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 19.1, 22.7, 25.7, 26.7,
29.3, 29.5, 29.6, 29.63, 29.7, 31.9, 33.8, 64.3, 64.5, 70.4, 72.5,
127.8, 129.9, 132.6, 135.5; IR (CH3Cl) υmax 3418, 2926, 2849, 2361,
2098, 1113 (cm-1); MS (FAB) m/z 604 ([M + 23]+, 13), 135 (100),
199 (65); HRMS (FAB) calcd for C34H55N3O3SiNa 604.3910 ([M
+ Na]+), found 604.3907.
(2S,3S,4S)-2-Azido-1-(tert-butyldiphenylsilyloxy)-3-(methyl-
sulfonyloxy)octadecan-4-yl Benzoate (14). To a solution of
benzoate 12 (1.56 g, 2.27 mmol) in CH2Cl2 (22 mL) were added
TEA (1.60 mL) and MsCl (350 µL, 4.54 mmol) at 0 °C. After
being stirred at room temperature for 30 min, this reaction mixture
J. Org. Chem, Vol. 73, No. 4, 2008 1383

Kim et al.
was diluted with CH2Cl2 then washed with H2O. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated. The crude product was purified by silica gel column
chromatography (hexane/EtOAc, 10:1) to give benzoate 14 (1.65
1H NMR (CDCl3, 300 MHz) δ 0.89 (t, J ) 6.6 Hz, 3H), 1.08 (s,
9H), 1.16-1.48 (m, 24H), 1.68-1.94 (m, 2H), 2.78 (br s, 1H),
3.47 (dt, J ) 3.3, 6.3 Hz, 1H), 3.88-4.08 (m, 3H), 5.25 (dt, J )
4.2, 8.7 Hz, 1H), 7.33-7.48 (m, 9H), 7.54-7.72 (m, 4H), 7.98-
8.04 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 19.1, 22.7, 25.4,
26.5, 26.6, 26.7, 29.31, 29.38, 29.40, 29.51, 29.53, 29.57, 29.61,
29.64, 31.9, 63.4, 64.6, 72.5, 76.0, 127.6, 127.77, 127.80, 128.4,
129.5, 129.66, 129.8, 129.9, 132.5, 133.2, 134.8, 135.6, 166.3; IR
(CHCl3) υmax 3486, 3073, 2928, 2855, 2101, 1721, 1273, 1113,
708 (cm-1); MS (FAB) m/z 708 ([M + 23]+, 2), 105 (100), 135
(50), 199 (25), 240 (17); HRMS (FAB) calcd for C41H59N3O4SiNa
708.4173 ([M + Na]+), found 708.4181.
1
g, 95%) as a colorless oil: [R]27 -3.4 (c 0.4, CHCl3); H NMR
(CDCl3, 300 MHz) δ 0.88 (t, J )D6.3 Hz, 3H), 1.07 (s, 9H), 1.18-
1.37 (m, 24H), 1.62-1.78 (m, 2H), 2.93 (s, 3H), 3.77-3.93 (m,
3H), 4.90 (t, J ) 4.2 Hz, 1H), 5.37-5.45 (m, 1H), 7.32-7.49 (m,
9H), 7.54-7.70 (m, 4H), 8.01-8.08 (m, 2H); 13C NMR (CDCl3,
75 MHz) δ 14.1, 19.0, 22.7, 24.9, 26.5, 26.7, 29.3, 29.32, 29.34,
29.5, 29.54, 29.6, 29.63, 29.64, 31.2, 31.9, 38.8, 63.4, 63.44, 71.4,
80.3, 127.7, 127.8, 128.4, 129.5, 129.6, 129.8, 130.0, 132.4, 132.5,
133.2, 134.8, 135.5, 135.6, 165.6; IR (CHCl3) υmax 3430, 3073,
2928, 2855, 2110, 1725, 1369, 1267, 1179, 708 (cm-1); MS (FAB)
m/z 786 ([M + 23]+, 1), 105 (100), 135 (33), 197 (15), 303 (12);
HRMS (FAB) calcd for C42H61N3O6SSiNa 786.3948 ([M + Na]+),
found 786.3943.
(2S,3S,4R)-2-Azido-1-(tert-butyldiphenylsilyloxy)-3-(methyl-
sulfonyloxy)octadecan-4-yl Benzoate (17). To a solution of
benzoate 16 (1.69 g, 2.42 mmol) in CH2Cl2 (24 mL) were added
TEA (1.69 mL) and MsCl (380 µL, 4.84 mmol) at 0 °C. After
being stirred at room temperature for 30 min, this reaction mixture
was diluted with CH2Cl2 then washed with H2O. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated. The crude product was purified by silica gel column
chromatography (hexane/EtOAc, 10:1) to give benzoate 17 (1.76
(2S,3R,4S)-2-Azido-1-(tert-butyldiphenylsilyloxy)-3-hydroxy-
octadecan-4-yl Benzoate (15). To a solution of benzoate 14 (1.31
g, 1.71 mmol) in wet 1-PrOH (17 mL, 5% v/v) was added CaCO3
(171 mg, 1.71 mmol). This reaction mixture was heated under reflex
for 4 days. The reaction was filtered, and then concentrated to
dryness under reduced pressure. The residue was dissolved in
EtOAc and washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The crude product was purified by silica
gel column chromatography (hexane/EtOAc, 10:1) to give benzoate
1
g, 95%) as a colorless oil: [R]26 +7.8 (c 0.3, CHCl3); H NMR
(CDCl3, 300 MHz) δ 0.88 (t, J )D6.3 Hz, 3H), 1.09 (s, 9H), 1.20-
1.38 (m, 24H), 1.66-1.82 (m, 2H), 2.92 (s, 3H), 3.80-3.90 (m,
2H), 4.0-4.09 (m, 1H), 4.91 (dd, J ) 3.9, 5.4 Hz, 1H), 5.40 (ddd,
J ) 3.9, 7.8, 9.0 Hz, 1H), 7.35-7.48 (m, 9H), 7.52-7.72 (m, 4H),
7.94-8.00 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 19.0, 22.7,
25.3, 26.7, 29.18, 29.2, 29.3, 29.35, 29.47, 29.54, 29.61, 29.62,
29.64, 31.9, 38.9, 63.1, 63.8, 72.6, 80.1, 127.8, 128.5, 129.5, 129.7,
129.92, 129.94, 132.4, 132.6, 133.2, 135.6, 165.6; IR (CHCl3) υmax
3410, 3073, 2928, 2855, 2359, 2110, 1725, 1366, 1179, 1109, 708
(cm-1); MS (FAB) m/z 786 ([M + 23]+, 2), 105 (100), 135 (33),
197 (16), 277 (11), 303 (11); HRMS (FAB) calcd for C42H61N3O6-
SSiNa 786.3948 ([M + Na]+), found 786.3943.
15 (1.06 g, 90%) as a colorless oil: [R]27 +5.1 (c 1.6, CHCl3);
D
1H NMR (CDCl3, 300 MHz) δ 0.89 (t, J ) 6.6 Hz, 3H), 1.08 (s,
9H), 1.20-1.45 (m, 24H), 1.68-1.92 (m, 2H), 2.46 (d, J ) 8.1
Hz, 1H), 3.52-3.58 (m, 1H), 3.80-3.88 (m, 1H), 3.88-4.00 (m,
2H), 5.22 (dt, J ) 3.6, 7.5 Hz, 1H), 7.31-7.51(m, 9H), 7.56-7.72
(m, 4H), 8.02-8.08 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.1,
19.0, 22.7, 24.9, 26.7, 29.3, 29.4, 29.5, 29.6, 30.6, 31.9, 63.1, 64.9,
71.8, 74.6, 127.8, 128.4, 129.7, 129.9, 129.94, 132.5, 133.1, 135.5,
166.0; IR (CHCl3) υmax 3480, 3073, 2926, 2855, 2110, 1723, 1271,
1113, 708 (cm-1); MS (FAB) m/z 708 ([M + 23]+, 3), 105 (100),
135 (49), 199 (22), 240 (19); HRMS (FAB) calcd for C41H59N3O4-
SiNa 708.4173 ([M + Na]+), found 708.4181.
(2S,3R,4R)-2-Azido-1-(tert-butyldiphenylsilyloxy)-3-hydroxy-
octadecan-4-yl Benzoate (18a) and (2S,3R,4R)-2-Azido-1-(tert-
butyldiphenylsilyloxy)-4-hydroxyoctadecan-3-yl Benzoate (18b).
To a solution of benzoate 17 (1.53 g, 2.00 mmol) in wet EtOH (20
mL, 5% v/v) was added CaCO3 (20 mg, 2.0 mmol). This reaction
mixture was heated under reflex for 4 days. The reaction was
filtered, and then concentrated to dryness under reduced pressure.
The residue was dissolved in EtOAc and washed with water and
brine, dried over MgSO4, and concentrated in vacuo to give
benzoate 18 (1.33 g, 97%) as a mixture of benzoates 18a and 18b
in a ratio of 2.8:1. The crude mixture was used in the next step
without further purification. Benzoates 18a and 18b were isolated
by column chromatography on silica gel (hexane/EtOAc, 15:1) for
analytical purposes.
18a: colorless oil; [R]26D +17.3 (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 0.88 (t, J ) 6.3 Hz, 3H), 1.07 (s, 9H), 1.20-1.40 (m,
24H), 1.69-1.80 (m, 2H), 2.32 (br s, 1H), 3.52-3.62 (m, 1H),
3.79 (t, J ) 3.9 Hz, 1H), 3.91 (dd, J ) 5.7, 5.7 Hz, 2H), 5.23 (m,
1H), 7.34-7.49 (m, 9H), 7.53-7.71 (m, 4H), 8.00-8.07 (m, 2H);
13C NMR (CDCl3, 75 MHz) δ 14.1, 19.1, 22.7, 25.3, 26.7, 29.3,
29.4, 29.50, 29.59, 29.63, 30.7, 31.9, 64.5, 64.9, 71.4, 75.3, 127.81,
127.84, 128.4, 129.7, 129.9, 129.94, 132.67, 132.70, 133.1, 135.5,
135.6, 166.5; IR (CH3Cl) υmax 3474, 3073, 2932, 2855, 2106, 1719,
1271, 1111, 708 (cm-1); MS (FAB) m/z 708 ([M + 23]+, 4), 105
(100), 135 (49), 197 (23), 240 (15); HRMS (FAB) calcd for
C41H59N3O4SiNa 708.4173 ([M + Na]+), found 708.4181.
18b: colorless oil; [R]26D +25.6 (c 0.3, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 0.88 (t, J ) 6.6 Hz, 3H), 1.08 (s, 9H), 1.20-1.32 (m,
24H), 1.39-1.51 (m, 2H), 1.93 (d, J ) 7.8 Hz, 1H), 3.77-3.87
(m, 2H), 3.91 (dd, J ) 1.2, 5.1 Hz, 2H), 5.30 (dd, J ) 3.3, 5.7 Hz,
1H), 7.30-7.50 (m, 9H), 7.56-7.70 (m, 4H), 8.02-8.08 (m, 2H);
13C NMR (CDCl3, 75 MHz) δ 14.1, 19.1, 22.6, 25.4, 26.7, 29.3,
29.4, 29.47, 29.51, 29.61, 29.64, 31.9, 33.7, 63.4, 63.6, 70.9, 74.9,
127.77, 127.81, 128.4, 129.4, 129.9, 132.5, 132.6, 133.3, 135.50,
135.54, 165.9; IR (CH3Cl) υmax 3437, 3073, 2928, 2855, 2101, 1726,
(2S,3R,4S)-2-Azido-1-(tert-butyldiphenylsilyloxy)octadecane-
3,4-diol (13). To a solution of benzoate 15 (1.03 g, 1.50 mmol) in
MeOH (15 mL) was added NaOMe (1.5 equiv, 25 wt % solution
in MeOH) at 0 °C. After being stirred at room temperature for 1 h,
this reaction mixture was poured into saturated NH4Cl solution and
MeOH was evaporated under reduced pressure. The residue was
extracted with EtOAc and washed with brine, dried over MgSO4,
and concentrated in vacuo. The crude product was purified by silica
gel column chromatography (hexane/EtOAc, 8:1) to give arabino-
diol 13 (769 mg, 88%) as a colorless oil: [R]27 +10.7 (c 2.1,
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.6 Hz, 3H),
1.08 (s, 9H), 1.26 (s, 24H), 1.48-1.86 (m, 2H), 2.48 (br s, 1H),
3.44-3.52 (m, 1H), 3.56-3.66 (m, 1H), 3.74-3.82 (m, 1H), 3.90
(dd, J ) 4.5, 10.5 Hz, 1H), 3.96 (dd, J) 6.9, 10.8 Hz, 1H), 7.36-
7.50 (m, 6H), 7.64-7.73 (m, 6H); 13C NMR (CDCl3, 75 MHz) δ
14.1, 19.0, 22.7, 25.5, 26.7, 29.3, 29.6, 29.63, 29.7, 31.9, 33.3, 63.0,
65.6, 72.5, 73.7, 127.9, 129.9, 130.0, 132.5, 132.6, 135.5, 135.6;
IR (CH3Cl) υmax 3424, 3073, 2920, 2855, 2361, 2110, 1111 (cm-1);
MS (FAB) m/z 604 ([M + 23]+, 20), 135 (100), 199 (65), 240
(30); HRMS (FAB) calcd for C34H55N3O3SiNa 604.3910 ([M +
Na]+), found 604.3907.
(2S,3S,4R)-2-Azido-1-(tert-butyldiphenylsilyloxy)-3-hydroxy-
octadecan-4-yl Benzoate (16). To a solution of diol 5 (1.69 g,
2.90 mmol) in pyridine/CH2Cl2 (1:1, 29 mL) were added BzCl (0.34
mL, 2.9 mmol) and DMAP (18 mg, 0.15 mmol) at 0 °C. After
being stirred at room temperature for 30 min, this reaction mixture
was diluted with CH2Cl2 then washed with H2O. The combined
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, 40:1) to give benzoate
16 (1.93 g, 97%) as a colorless oil: [R]26 +19.5 (c 0.9, CHCl3);
D
1384 J. Org. Chem., Vol. 73, No. 4, 2008

Synthesis of D-arabino-, D-lyxo-, and D-xylo-Phytosphingosines
1267, 1113, 708 (cm-1); MS (FAB) m/z 708 ([M + 23]+, 4), 105
(100), 135 (49), 197 (23), 240 (15); HRMS (FAB) calcd for
C41H59N3O4SiNa 708.4173 ([M + Na]+), found 708.4181.
(2S,3R,4R)-2-Azido-1-(tert-butyldiphenylsilyloxy)octadecane-
3,4-diol (19). To a solution of benzoate 18 (1.32 g, 1.92 mmol) in
MeOH (22 mL) was added NaOMe (1.5 equiv, 25 wt % solution
in MeOH) at 0 °C. After being stirred at room temperature for 1 h,
this reaction mixture was poured into saturated NH4Cl solution and
MeOH was evaporated under reduced pressure. The residue was
extracted with EtOAc and washed with brine, dried over MgSO4,
and concentrated in vacuo. The crude product was purified by silica
m/z 366 ([M + 23]+, 25), 414 (18), 717 (17), 739 (34); HRMS
(FAB) calcd for C18H37N3O3Na 366.2733 ([M + Na]+), found
366.2744.
General Procedure for Azide Reduction. A solution of azide
20, 21, or 22 (100 mg, 0.290 mmol) in MeOH (0.1 M) was added
to 10% Pd/C (50 wt %) and the mixture was hydrogenated for 3 h
at room temperature. The suspension was diluted with MeOH and
filtered through a pad of Celite. The solvent was removed, and the
residue was purified by silica gel column chromatography (CH2-
Cl2/MeOH/NH4OH, 40:10:1) to give D-phytosphingosine 2, 3, or
4.
gel column chromatography (hexane/EtOAc, 8:1) to give xylo-diol
(2S,3S,4S)-2-Aminooctadecane-1,3,4-triol (D-lyxo-phytosphin-
gosine, 2) (79.1 mg, 86%) was obtained as a white solid: mp 104-
105 °C (lit.6d mp 104.8-106.0 °C, lit.20a mp 92-95 °C, lit.20e mp
95 °C); [R]25 -6.7 (c 0.9, pyridine) {lit.5e [R]25 -7.5 (c 1.0,
1
19 (1.05 g, 94%) as a waxy oil: [R]25 +19.9 (c 3.8, CHCl3); H
D
NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.3 Hz, 3H), 1.08 (s, 9H),
1.26 (s, 24H), 1.48-1.51 (m, 2H), 2.32 (d, J ) 4.8 Hz, 1H), 2.48
(d, J ) 6.0 Hz, 1H), 3.49-3.52 (m, 2H), 3.52-3.54 (m, 1H), 3.89
(dd, J ) 4.2, 10.8 Hz, 1H), 3.95 (dd, J) 6.0, 10.8 Hz, 1H), 7.36-
7.50 (m, 6H), 7.62-7.72 (m, 6H); 13C NMR (CDCl3, 75 MHz) δ
14.1, 19.1, 22.7, 25.5, 26.7, 29.3, 29.56, 29.58, 29.65, 29.7, 31.9,
33.5, 64.5, 65.1, 71.8, 72.8, 127.9, 130.0, 132.6, 135.5, 135.6; IR
(CH3Cl) υmax 3395, 3073, 2926, 2855, 2106, 1265, 1113, 702
(cm-1); MS (FAB) m/z 604 ([M + 23]+, 43), 73 (98), 199 (49);
HRMS (FAB) calcd for C34H55N3O3SiNa 604.3910 ([M + Na]+),
found 604.3904.
General Procedure for Removal of the Silyl Protecting
Groups in Compounds 10, 13, and 19. To a solution of 10, 13,
or 19 (300 mg, 0.520 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 Na2SO4 and concentrated. The crude product was purified by
silica gel column chromatography (hexane/EtOAc, 2:1) to give 20,
21, or 22.
D
D
pyridine), lit.6d [R]25 -7.4 (c 0.9, pyridine), lit.20a [R]24 -2.6 (c
D
D
0.2, pyridine), lit.6f [R]20 -7.1 (c 0.4, pyridine)}; 1H NMR
D
(pyridine-d5, 300 MHz) δ 0.85 (t, J ) 6.6 Hz, 3H), 1.12-1.45 (m,
22H), 1.49-1.66 (m, 1H), 1.69-1.84 (m, 1H), 1.85-2.08 (m, 2H),
3.67 (ddd, J ) 4.8, 6.6, 11.4 Hz, 1H), 4.00 (dd, J ) 2.7, 6.9 Hz,
1H), 4.19 (dd, J ) 6.6, 10.5 Hz, 1H), 4.26-4.36 (m, 2H); 13C NMR
(pyridine-d5, 75 MHz) δ 14.3, 22.9, 26.8, 29.6, 29.9, 30.1, 30.3,
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 + 1]+,
25), 43 (100), 60 (97), 81 (22), 282 (17); HRMS (FAB) calcd for
C18H40NO3 318.3008 ([M + H]+), found 318.3011.
(2S,3R,4S)-2-Aminooctadecane-1,3,4-triol (D-arabino-phytosph-
ingosine, 3) (78.2 mg, 85%) was obtained as a white solid: mp
86-88 °C (lit.6e mp 86 °C, lit.6g mp 75 °C); [R]23 -2.76 (c 1.0,
D
pyridine) {lit.6e [R]26D -3.7 (c 1.0, pyridine), lit.6g [R]20D -12.3 (c
0.6, pyridine), lit.20c [R]23 -4.5 (c 0.6, pyridine)}; 1H NMR
D
(pyridine-d5, 300 MHz) δ 0.84 (t, J ) 6.3 Hz, 3H), 1.14-1.48 (m,
22H), 1.54-1.70 (m, 1H), 1.74-1.94 (m, 2H), 1.98-2.12 (m, 1H),
3.84 (t, J ) 5.4 Hz, 1H), 4.06 (dd, J ) 1.8, 6.6 Hz, 1H), 4.10-
4.16 (m, 1H), 4.16-4.29 (m, 2H); 13C NMR (pyridine-d5, 75 MHz)
δ 14.3, 22.9, 26.5, 29.6, 29.9, 30.0, 30.1, 30.3, 32.1, 35.2, 54.4,
65.8, 73.8, 74.0; IR (KBr) υmax 3353, 2922, 2853, 1591, 1468, 1053,
760 (cm-1); MS (FAB) m/z 318 ([M + 1]+, 54), 60 (100), 154
(97), 643 (48); HRMS (FAB) calcd for C18H40NO3 318.3008 ([M
+ H]+), found 318.3007.
(2S,3S,4S)-2-Azidooctadecane-1,3,4-triol (20) (175 mg, 99%)
was obtained as a white solid: mp 77-78 °C; [R]26D +9.6 (c 1.3,
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.3 Hz, 3H),
1.16-1.36 (m, 22H), 1.38-1.50 (m, 2H), 1.50-1.66 (m, 2H), 2.48
(br d, J ) 6.9 Hz, 3H), 3.50-3.64 (m, 2H), 3.77 (t, J ) 6.0 Hz,
1H), 3.88 (dd, J ) 4.5, 11.7 Hz, 1H), 3.97 (dd, J ) 4.2, 11.1 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.7, 25.7, 29.3, 29.52,
29.55, 29.64, 29.66, 29.68, 31.9, 34.1, 62.6, 64.2, 70.7, 73.2; IR
(KBr) υmax 3329, 2917, 2847, 2357, 2091, 1472 (cm-1); MS (FAB)
m/z 366 ([M + 23]+, 38), 176 (64), 413 (28), 717 (29), 739 (58);
HRMS (FAB) calcd for C18H37N3O3Na 366.2733 ([M + Na]+),
found 366.2733.
(2S,3R,4R)-2-Aminooctadecane-1,3,4-triol (D-xylo-phytosph-
ingosine, 4) (83.7 mg, 91%) was obtained as a white solid: mp
99-100 °C (lit.5g mp 98-99 °C); [R]25 +14.2 (c 1.0, pyridine)
D
{lit.5g [R]27D +11.8 (c 0.45, pyridine)}; 1H NMR (pyridine-d5, 300
MHz) δ 0.85 (t, J ) 6.6 Hz, 3H), 1.24 (s, 22H), 1.47-1.62 (m,
1H), 1.64-1.78 (m, 1H), 1.78-1.90 (m, 1H), 1.90-2.04 (m, 1H),
3.46 (dt, J ) 3.0, 6.3 Hz, 1H), 4.0-4.07 (m, 2H), 4.08-4.18 (m,
2H); 13C NMR (pyridine-d5, 75 MHz) δ 14.3, 22.9, 26.5, 29.6, 29.9,
30.0, 30.1, 30.3, 32.1, 34.8, 57.3, 65.6, 72.8, 74.6; IR (KBr) υmax
3372, 2920, 2851, 2361, 1734, 1470, 1057 (cm-1); MS (FAB) m/z
318 ([M + 1]+, 25), 60 (93), 154 (38), 643 (53); HRMS (FAB)
calcd for C18H40NO3 318.3008 ([M + H]+), found 318.3007.
(2S,3R,4S)-2-Azidooctadecane-1,3,4-triol (21) (165 mg, 93%)
was obtained as a white solid: mp 77.0-78.2 °C; [R]27D +16.5 (c
1
0.4, CHCl3); H NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.9 Hz,
3H), 1.20-1.40 (m, 22H), 1.40-1.75 (m, 4H), 3.60 (dd, J ) 2.4,
6.3 Hz, 1H), 3.63-3.70 (m, 2H), 3.81 (dt, J ) 2.7, 5.4 Hz, 1H),
3.96 (dd, J ) 5.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.1,
22.7, 25.5, 29.3, 29.6, 29.7, 31.9, 33.4, 62.9, 63.9, 72.7, 74.3; IR
(KBr) υmax 3405, 3291, 2917, 2851, 2128, 1267, 1086 (cm-1); MS
(FAB) m/z 366 ([M + 23]+, 18), 136 (80), 154 (100), 717 (15),
739 (8); HRMS (FAB) calcd for C18H37N3O3Na 366.2733 ([M +
Na]+), found 366.2734.
Acknowledgment. This work was supported by the Korea
Science and Engineering Foundation (KOSEF) through the
National Research Laboratory Program funded by the Ministry
of Science and Technology (M10500000055-06J0000-05510).
(2S,3R,4R)-2-Azidooctadecane-1,3,4-triol (22) (166 mg, 94%)
was obtained as a white solid: mp 76.0-76.6 °C; [R]25D +16.2 (c
1
1.2, CHCl3); H NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.3 Hz,
Supporting Information Available: Experimental procedures
for peracetylation of phytosphingosines 2-4 and copies of NMR
spectra for compounds 2-4, 6-8, 10, and 12-25. This material is
available free of charge via the Internet at http://pubs.acs.org.
3H), 1.26 (s, 22H), 1.08-1.52 (m, 4H), 2.44 (br s, 1H), 2.50 (br s,
1H), 2.78 (d, J ) 5.4, Hz, 1H), 3.50-3.53 (m, 2H), 3.74 (br s,
1H), 4.09 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.7,
25.6, 29.3, 29.6, 29.7, 31.9, 33.5, 62.3, 64.4, 71.5, 73.7; IR (KBr)
υ
max 3372, 2919, 2851, 2103, 1717, 1466, 1265 (cm-1); MS (FAB)
JO702147Y
J. Org. Chem, Vol. 73, No. 4, 2008 1385