Oxazine formation by MsCl/Et3N as a convenient tool for the stereochemical interconversion of the hydroxyl group in N-acetyl 1,3-aminoalcohols. Asymmetric synthesis of N-acetyl L-xylo- and L-arabino-phytosphingosines

Article abstract of DOI:10.1016/j.tetlet.2004.08.030

Use of MsCl/Et₃N was proven to provide a convenient synthetic tool for the stereochemical intercoversion of the hydroxyl group in N-acetyl 1,3-aminoalcohols. Thus, under these conditions, the alcohols 4 and 6 smoothly converted to the oxazines

Full text of DOI:10.1016/j.tetlet.2004.08.030

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7239–7242
Oxazine formation by MsCl/Et3N as a convenient tool for the
stereochemical interconversion of the hydroxyl group in
N-acetyl 1,3-aminoalcohols. Asymmetric synthesis of N-acetyl
L-xylo- and L-arabino-phytosphingosines
Om V. Singh, Dorothy J. Kampf and Hyunsoo Han*
Department of Chemistry, The University of Texas at San Antonio, 6900 N. Loop 1604 West, San Antonio, TX78249, USA
Received 9 July 2004; accepted 5 August 2004
Available online 24 August 2004
Abstract—Use of MsCl/Et3N was proven to provide a convenient synthetic tool for the stereochemical intercoversion of the hydr-
oxyl group in N-acetyl 1,3-aminoalcohols. Thus, under these conditions, the alcohols 4 and 6 smoothly converted to the oxazines 5
and 7, respectively, which were hydrolyzed to generate the corresponding inverted alcohols 6 and 4 in one pot. Further elaboration
of 4 and 6 led to the efficient asymmetric synthesis of N-acetyl L-xylo- and L-arabino-phytosphingosines (11 and 15), respectively, via
olefin cross metathesis reactions.
ꢀ 2004 Published by Elsevier Ltd.
Along with sphingosines and sphinganines, phyto-
sphingosines (PS) constitute the three most abundant
core structures for the sphingolipids, which are ubiqui-
tous membrane components in eukaryotic cells and in
all plasma membranes. In addition to their passive struc-
tural roles as membrane constituents, sphingolipids are
also dynamically involved in essentially all aspects of cell
regulation covering cellular recognition, growth, and
development.1 Phytosphingosines are major membrane
components in plants and yeasts, and have also been dis-
covered in mammalian tissues and marine organisms.2
to be involved in the activation of natural killer T cells
and is currently under clinical trial for the treatment
of liver tumors.6 Phytosphingosines with other chain
lengths as well as different stereochemistries of the
amino and hydroxyl groups are also known and bio-
active to varying degrees.2
As a consequence of these diverse biological roles of
phytosphingosines, a considerable number of methodol-
ogies have been developed for the synthesis of phyto-
sphingosines, most of which rely upon use of chiral
starting materials such as a-amino acids and carbo-
hydrates.2,7 Asymmetric approaches have scarcely been
reported, and/or are quite lengthy.8
Among these, of particular interest is D-ribo-phyto-
sphingosine with 18-carbons, since it is the most fre-
quently occurring in nature and has been shown to play
an important role as a potential heat stress signal in
yeast cells,3 as a modulator for the activity of the Ca2+
release channel,4 and as an inhibitor for calf thymus
DNA primase as well as a cytotoxic agent against
human leukemic cell lines.5 Furthermore, D-ribo-phyto-
sphingosine is an essential part of more complex
bioactive molecules such as KRN7000, which is believed
Recently we became interested in the asymmetric syn-
thesis of phytosphingosines, since it was envisioned that
the reactions between the aldehyde 1 and various Grig-
nard reagents would provide the most direct and flexible
asymmetric route for their production (Eq. 1). Indeed,
this approach worked out well for the asymmetric syn-
thesis of phytosphingosines with syn-diol stereochemis-
try at C3 and C4. However, for the cases in which R
is longer than a five carbon chain, inversion of the C4
hydroxyl group of 2 using either Mitsunobu9 or
Burgess10 conditions was not possible, limiting the flex-
ibility and general applicability of this approach (Eq. 1
of Fig. 1).
Keywords: Phytosphingosine; Regioselective asymmetric aminohydr-
oxylation; Olefin cross metathesis; Oxazine.
*
Corresponding author. Tel./fax: +1 210 458 4958; e-mail: hhan@
utsa.edu
0040-4039/$ - see front matter ꢀ 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.08.030

7240
O. V. Singh et al. / Tetrahedron Letters 45 (2004) 7239–7242
Ac
Ac
O
Ac
NH
O
NH OH
4
NH
O
RMgX
a
O
PS
PMPO
PMPO
OEt
PMPO
OEt
R
H
2
1
OPMB
8
9
OH
MeO
OPMB
regioselectivity = >20:1
Mitsunobu
(Eq. 1)
enantioselectivity = >99%
Burgess
NH OH
Ac
PMPO
Ac
Ac
O
NH OH
NH
R
b
d
c
PMPO
PMPO
3
OPMB
(CH2)13CH3
OPMB
diastereoselectivity = >10:1
10
1
OPMB
Ac
NH OH
N
O
MsCl, Et3N
PMPO
PMPO
Ac
NH OH
(CH2)13CH3
4
5
OPMB
OPMB
O
HO
H+ then OH-
MsCl, Et3N
(Eq. 2)
Ac
OH
11
NH OH
N
PMPO
PMPO
Scheme 1. Asymmetric synthesis of N-acetyl L-xylo-(2R,3S,4S)-phyto-
sphingosine using Grignard reagents. Reagents and conditions: (a)
K2OsO4Æ2H2O, (DHQD)2PHAL, LiOH, AcNHBr, t-BuOH–H2O 2:1,
4ꢁC, 70%; (b) (i) NaH, PMBCl, DMF, 0ꢁC, 80%; (ii) DIBAL-H,
CH2Cl2, ꢀ78ꢁC, 60%; (c) C14H29MgBr, THF, ꢀ30ꢁC, 1h then 25ꢁC,
2h, 88%; (d) CAN, MeCN–H2O 4:1, 0ꢁC to room temperature, 75%.
7
6
OPMB
OPMB
Figure 1. Formation and hydrolysis of the oxazines 5 and 7.
During the course of other research projects in the
laboratory, it was observed that treating the N-acetyl
1,3-aminoalcohols 4 and 6 with MsCl and Et3N in
THF resulted in the formation of the oxazines 5 and
7, respectively, with the stereochemical inversion at the
allylic carbons, which were hydrolyzed to generate the
corresponding inverted N-acetyl 1,3-aminoalcohols 6
and 4 (Eq. 2of Fig. 1). Formation and subsequent
hydrolysis of the oxazines 5 and 7 could be done in
one pot, making it possible to interconvert between
the syn- and anti-diol stereochemistries at the C3 and
C4 of these phytosphingosines.
Scheme 1 describes the asymmetric synthesis of N-acetyl
L-xylo-(2R,3S,4S)-phytosphingosine (11) with the syn-
3,4-diol stereochemistry via the RAA reaction of the
achiral olefin 8 and the reaction of the aldehyde 1 with
Grignard reagents. The RAA reaction of 8 using the
(DHQD)2PHAL as a ligand and N-bromoacetamide as
a nitrogen source/oxidant afforded the syn-aminoalcohol
9 with excellent regio- (>20:1) and enantioselecivity
(>99% after one recrystallization from ethyl acetate).
Protection of the hydroxyl group of 9 by p-meth-
oxybenzyl (PMB) chloride and sodium hydride in
DMF13 and the partial reduction of the resulting ester
by slow addition of DIBAL at ꢀ78ꢁC14 generated the
aldehyde 1. Reactions of the aldehyde 1 with tetradecyl-
magnesium bromide were examined under various con-
ditions. Slow addition of the Grignard reagent to the
reaction mixture at ꢀ30ꢁC in THF followed by the slow
warm-up of the reaction mixture to room temperature
proved to provide optimal conditions in terms of both
diastereoselectivity and reaction yield, providing the
alcohol 10 as a major product in a ratio of >10:1 and
88% yield.7f Simultaneous deprotection of the PMP
and PMB groups of 10 by CAN15 gave N-acetyl
L-xylo-(2R,3S,4S)-phytosphingosine (11).
Then, as shown in Figure 2, it was envisioned that com-
bining the present oxazine chemistry with an olefin cross
metathesis (CM) reaction11 could lead to an extremely
efficient and flexible methodology for the asymmetric
synthesis of phytosphingosines. The C2and C3 stereo-
centers of phytosphingosines could be installed by the
regioselective asymmetric aminohydroxylation (RAA)
reaction12 of the readily available achiral olefin VI.
Ac
Ac
NH OH
NH OH
3
CM
PGO
HO
R
2
4
III
OPG
MsCl/Et3N
OH
I
N-Acetyl L-xylo-(2R,3S,4S)-phytosphingosine (11) was
also prepared using a nuclophilic addition reaction of
the aldehyde 1 with vinylmagnesium bromide and a
cross metathesis reaction of the resulting olefin 4 with
1-tetradecene (Scheme 2). The second generation
Grubbsꢀ catalyst {Tricyclohexylphosphine[1,3-bis(2,4,6-
trimethyl-phenyl)-4,5-dihydroimidazol-2-ylidene][benzyl-
idine]-ruthenium (IV) dichloride} was used for the
cross metathesis reaction. Hydrogenation of the olefin
12 and deprotection of the PMP group by CAN yielded
N-acetyl L-xylo-(2R,3S,4S)-phytosphingosine (11).17
Ac
N
O
NH OH
3
CM
PGO
HO
R
2
4
IV
OPG
OH
II
Ac
O
NH
O
RAA
PGO
PGO
OEt
OEt
VI
V
OH
To prepare N-acetyl L-arabino-(2R,3S,4R)-phytosphingo-
sine (15) with anti-3,4-diol stereochemistry, the allylic
Figure 2. Retrosynthetic analysis for phytosphingosines.

O. V. Singh et al. / Tetrahedron Letters 45 (2004) 7239–7242
7241
involving MsCl and Et3N. As with the olefin 4, a se-
quence of cross metathesis reaction of 6 with 1-tetrade-
cene in the presence of the second generation Grubbsꢀ
catalyst, the hydrogenation of 14, and final deprotection
of the PMP group by CAN finished the asymmetric syn-
thesis of N-acetyl L-arabino-(2R,3S,4R)-phytosphingo-
sine (15) (Scheme 3).17
Ac
Ac
Ac
O
NH
NH OH
b
a
PMPO
PMPO
H
1
OPMB
4 OPMB
diastereoselectivity = 6:1
Ac
NH OH
NH OH
c
CH3
13
CH3
11
HO
PMPO
In summary, we have shown that MsCl/Et3N can be
conveniently used for the stereochemical intercoversion
of the hydroxyl group in N-acetyl 1,3-aminoalcohols
through the formation of the corresponding oxazines.
Also demonstrated is that, combined with the regioselec-
tive asymmetric aminohydroxylation (RAA) and olefin
cross metathesis (CM) reactions, the developed oxazine
chemistry provides an extremely efficient and flexible
route for the asymmetric synthesis of phytosphingo-
sines. Asymmetric synthesis of other phytosphingosine
derivatives is currently in progress, and will be reported
in the full paper version of this letter.
11 OH
OPMB
12
Scheme 2. Asymmetric synthesis of 11 using olefin cross metathesis
reaction. Reagents and conditions: (a) vinylmagnesium bromide, THF,
ꢀ50ꢁC to room temp, 74%; (b) 1-tetradecene, second generation
Grubbsꢀ catalyst, CH2Cl2, 40ꢁC, 8h, 80%; (c) (i) H2, Pd/C, ethyl
acetate, quantitaive; (ii) CAN, MeCN–H2O 4:1, 0ꢁC, 80%.
hydroxyl group of the alcohol 4 was inverted to give the
alcohol 6 in a three-step, one-pot operation: treatment
of 4 with MsCl and Et3N followed by the sequential
additions of 0.5N HCl and K2CO3 after the complete
disappearance of 4 and 5, respectively.10,16 Use of MsCl
and Et3N (0ꢁC to ambient temperature) transformed the
alcohol 4 to the corresponding mesylate, under which
conditions the alcohol 4 underwent an SN2type intra-
molecular cyclization to give the oxazine 5. Acidic
hydrolysis of the oxazine 5 by 0.5N HCl at ambient tem-
perature generated the O-acetyl ester 13, which upon
treatment with K2CO3 at 60ꢁC underwent a 1,5-shift
of the acetyl group to provide the inverted alcohol 6.
Similarly the alcohol 6 with anti-diol stereochemistry
could be transformed back to the alcohol 4 with syn-diol
stereochemistry. The oxazine 5 could also be prepared
by using Mitsunobu reaction or Burgess reagent. How-
ever, the former method suffered from interference by
a triphenylphosphine oxide by-product during column
chromatography, and the latter reagent is commercially
available but expensive. Notably, a clean one-pot oper-
ation was possible only with the reaction conditions
Acknowledgements
Financial support from National Institute of Health
(GM 08194) and The Welch Foundation (AX-1534) is
gratefully recognized.
References and notes
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Ac
NH OH
N
O
a
b
PMPO
PMPO
PMPO
4
OPMB
5
OPMB
Cl-
Ac
Ac
NH3+ O
NH OH
c
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PMPO
6
13 OPMB
OPMB
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Ac
Ac
NH OH
NH OH
d
CH3
11
HO
PMPO
(CH2)13CH3
15 OH
14 OPMB
Scheme 3. Asymmetric synthesis of N-acetyl L-arabino-(2R,3S,4R)-
phytosphingosine (15) using olefin cross metathesis reaction and
oxazine chemistry. Reagents and conditions: (a) MsCl, TEA, 0ꢁC to
room temperature, 6h; (b) 0.5N HCl, THF, 30min then K2CO3, 60ꢁC,
8h, 70% in two steps; (c) 1-tetradecene, second generation Grubbsꢀ
catalyst, CH2Cl2, 40ꢁC, 8h, 80%; (d) (i) H2, Pd/C, ethyl acetate,
quantitaive; (ii) CAN, MeCN–H2O 4:1, 0ꢁC, 75%.
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7242
O. V. Singh et al. / Tetrahedron Letters 45 (2004) 7239–7242
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J = 1.5 and 17.0Hz), 5.22 (dt, 1H, J = 1.5 and 10.5Hz),
4.68 (d, 1H, J = 11.0Hz), 4.57 (d, 1H, J = 11.0Hz), 4.52–
4.46 (m, 1H), 4.22–4.18 (m, 1H), 3.93 (dd, 1H, J = 5.0 and
9.0Hz), 3.82–3.73 (m, 8H), 2.62 (br s, 1H), 1.94 (s, 3H);
13C NMR (125MHz, CDCl3) d 170.09, 159.58, 154.07,
152.32, 136.64, 130.02, 129.62,117.00, 115.44, 114.67,
113.96, 79.59, 74.87, 73.03, 67.01, 55.69, 55.22, 48.69,
23.31; HRMS m/z 415.1991 (calcd for C23H29NO6
415.1995). The oxazine intermediates 5 and 7 were isolated
and characterized. 5: [a]589 +38.33 (c 1.2, CH2Cl2); 1H
NMR (500MHz, CDCl3) d 7.15 (d, 2H, J = 8.4Hz), 6.82
(s, 4H), 6.76 (d, 2H, J = 8.4Hz), 5.83–5.72(ddd, 1H,
J = 4.5, 11.0, and 15.5Hz), 5.31–5.23 (m, 2H), 4.82–4.78
(m, 1H), 4.60 (d, 1H, J = 11.0Hz), 4.47 (d, 1H,
J = 11.0Hz), 4.11–4.00 (m, 2H), 3.77 (s, 3H), 3.76–3.75
(m, 4H), 3.71–3.63 (m, 1H), 2.03 (s, 3H); 13C NMR
(75MHz, CDCl3) d 159.16, 157.01, 153.65, 152.65, 134.11,
130.01, 129.66, 117.11, 115.11, 114.48, 113.62, 75.35,
71.19, 69.48, 67.65, 55.56, 55.04, 50.39, 21.39; HRMS
m/z 397.1880 (calcd for C23H27NO5 397.1889). 7: [a]589
7618–7626; (d) Torssell, S.; Somfai, P. Org. Biomol. Chem.
2004, 2, 1643–1646.
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1
15. Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetra-
hedron Lett. 1985, 26, 6291–6292.
ꢀ9.0 (c 1.0, CHCl3); H NMR (500MHz, CDCl3) d 7.12
(d, 2H, J = 8.5Hz), 6.84 (s, 4H), 6.75 (d, 2H, J = 8.5Hz),
5.95 (ddd, 1H, J = 6.5, 10.0, 15.6Hz), 5.42(dt, 1H, J = 1.5
and 16.0Hz), 5.29 (br d, 1H, J = 10.0Hz), 4.57 (d, 1H,
J = 6.5Hz), 4.54 (d, 1H, J = 12.0Hz), 4.47 (d, 1H,
J = 12.0Hz), 4.11 (dd, 1H, J = 5.0, 9.0Hz), 3.97–3.94 (m
2H), 3.85–3.80 (m, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 1.99 (s,
3H); 13C NMR (125MHz, CDCl3) d 159.16, 158.23,
153.73, 152.41, 134.13, 130.03, 129.88, 118.06, 114.98,
114.59, 113.45, 77.98, 74.39, 70.17, 67.86, 55.59, 55.49,
55.04, 21.34; HRMS m/z 397.1884 (calcd for C23H27NO5
397.1889). For other approaches for the formation of
oxazines and oxazolines, see: (a) Lee, S.-H.; Yoon, J.;
Nakamura, K.; Lee, Y.-S. Org. Lett. 2000, 2, 1243–1246;
(b) Aguilera, B.; Fernandez-Mayoralas, A. J. Org. Chem.
1998, 63, 2719–2723; (c) Ikemoto, N.; Schreiber, S. L. J.
Am. Chem. Soc. 1992, 114, 2524–2536; (d) Yoshimura, J.;
Iwakawa, M.; Ogura, Y. Bull. Chem. Soc. Jpn. 1976, 49,
2506–2510.
16. One pot procedure for the conversion of 4 to 6: MsCl
(172mg, 1.5mmol) was slowly added to a solution of the
alcohol 4 (415mg, 1mmol) and Et3N (350lL, 2.5mmol) in
THF (20mL) at 0ꢁC. After the addition, the reaction
mixture was brought to room temperature, and further
stirred until the alcohol 4 disappeared on TLC. At this
point, 0.5N HCl (5mL) was added, and the resulting
mixture was stirred for 30min. Then, solid potassium
carbonate was added in small portions until pH of the
reaction mixture became ꢁ9.5 (as measured by pH paper).
Temperature was raised to 60ꢁC, and the reaction mixture
was stirred at this temperature for 8h. After cooling to
room temperature, the reaction mixture was partitioned
between water and CH2Cl2. The aqueous phase was
further extracted with CH2Cl2 (2 · 50mL). The combined
organic layers were washed with brine, and dried over
anhydrous sodium sulfate. Evaporation of all volatile
solvents and recrystallization of the remaining residue
from ethyl acetate/hexane gave the inverted alcohol 6 as a
white crystalline compound (291mg, 70%): mp 118–19ꢁC;
[a]589 ꢀ11.67 (c 1.2, CHCl3); 1H NMR (500MHz, CDCl3)
d 7.18 (d, 2H, J = 8.5Hz), 6.88–6.76 (m, 6H), 6.02(ddd,
1H, J = 6.0, 10.5, and 16.5Hz), 5.89 (d, 1H, J = 8.5Hz),
5.44 (dt, 1H, J = 1.5 and 17.0Hz), 5.28 (dt, 1H, J = 1.5,
10.5Hz), 4.66–4.62(m, 1H), 4.59 (d, 1H, J = 11.0Hz), 4.41
(d, 1H, J = 11.0Hz), 4.02(br t, 1H), 3.92(dd, 1H, J = 5.0
and 9.5Hz), 3.84 (dd, 1H, J = 7.0 and 9.5Hz), 3.81–3.76
(br s, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.60 (dd, 1H, J = 1.5
and 7.0Hz), 2.04 (s, 3H); 13C NMR (125MHz, CDCl3) d
171.44, 159.58, 154.19, 152.33, 137.33, 130.10, 129.78,
116.82, 115.49, 114.71, 113.90, 80.70, 74.32, 71.93, 67.50,
55.72, 55.24, 49.08, 23.23; HRMS m/z 415.1993 (calcd for
C23H29NO6 415.1995). Similarly the alcohol 6 was con-
17. N-Acetyl L-xylo-(2R,3S,4S)-phytosphingosine (11): mp
106–07ꢁC; [a]589 ꢀ3.15 (c 0.67, MeOH–CH2Cl2); 1H
NMR (300MHz, MeOH-d4) d 4.07–3.99 (m, 1H), 3.66–
3.55 (m, 3H), 3.50–3.44 (m, 1H), 1.97 (s, 3H), 1.29 (s,
26H), 0.89 (t, J = 7.0Hz, 3H); 13C NMR (75MHz,
MeOH-d4) d 173.38, 73.59, 72.88, 62.68, 53.83, 34.19,
33.08, 30.79, 30.48, 26.73, 23.73, 22.68, 14.46; HRMS m/z
359.3034 (calcd for C20H41NO4 359.3036). N-Acetyl L-
arabino-(2R,3S,4R)-phytosphingosine (15): mp 129–30ꢁC;
[a]589 +34.2[ c, 0.7, CHCl3–MeOH (1:2)]; 1H NMR
(500MHz, CDCl3–MeOH-d4) d 4.11 (dt, 1H, J = 1.5 and
5.75Hz, H-2), 3.67 (dd, 1H, J = 5.5 and 11.0Hz, H-1),
3.63 (dd, 1H, J = 6.0 and 11.0Hz, H-10), 3.44 (dd, 1H,
J = 1.5 and 8.5Hz, H-3), 3.21–3.17 (m, 1H, H-4), 1.99 (s,
3H), 1.71–1.65 (m, 1H), 1.52–1.44 (m, 1H), 1.20 (s, 24H),
0.82(t, J = 7.0Hz, 3H); 13C NMR (75MHz, CDCl3) d
173.53, 75.42, 71.88, 63.84, 51.86, 33.53, 32.51, 30.29,
29.91, 26.36, 23.23, 23.08, 14.49; HRMS m/z 359.3039
(calcd for C20H41NO4 359.3036).
1
verted back to 4: [a]589 ꢀ37.4 (c, 5.0, CHCl3); H NMR
(500MHz, CDCl3) d 7.23 (d, 2H, J = 8.5Hz), 6.84 (d, 2H,
J = 8.5Hz). 6.81 (s, 4H), 5.98–5.89 (m, 2H), 5.36 (dt, 1H,