4-Formylazetidin-2-one as a useful building block for the formal synthesis of xylo-(2S,3R,4R)-phytosphingosine and threo-(2S,3S)-sphingosine

Article abstract of DOI:10.1055/s-2007-983815

Stereoselective formal synthesis of xylo-(2S,3R,4R)-phytosphingosine and threo-(25,35)-sphingosine is described starting from an enantiopure formyl-substituted β-lactam. Grignard reaction of the N-Boc-protected- β-lactam carbonyl group, followed by furthe

Full text of DOI:10.1055/s-2007-983815

PAPER
2631
4-Formylazetidin-2-one as a Useful Building Block for the Formal Synthesis of
xylo-(2S,3R,4R)-Phytosphingosine and threo-(2S,3S)-Sphingosine
Formal Synthesis
of
xylo-
a
(2
S
,3
R
,4
R
)
y
-Phytosphing
k
osine and th
u
reo-(
2
S
,3
S
)-
m
S
phingosine ar S. Kale,a Prathmesh S. Sakle,a Vikas K. Gumaste,a Abdul Rakeeb A. S. Deshmukh*b
a
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, Maharashtra, India
Emcure Pharmaceuticals Limited, ARC-H, P-2, I.T.-B.T. Park, Phase-II, M.I.D.C., Hinjwadi, Pune 411057, Maharashtra, India
E-mail: Abdulrakeeb.Deshmukh@emcure.co.in
b
Received 28 March 2007; revised 23 May 2007
transformations. Various natural products and intermedi-
ates have thus been synthesized using the b-lactam syn-
thon method.4d,5,6 It has been applied successfully to
asymmetric synthesis of a variety of protein and nonpro-
Abstract: Stereoselective formal synthesis of xylo-(2S,3R,4R)-
phytosphingosine and threo-(2S,3S)-sphingosine is described start-
ing from an enantiopure formyl-substituted b-lactam. Grignard re-
action of the N-Boc-protected-b-lactam carbonyl group, followed
by further transformations, provides a common intermediate for tein amino acids, peptides and peptidomimetics.4d,6 Syn-
xylo-(2S,3R,4R)-phytosphingosine and threo-(2S,3S)-sphingosine.
thesis of the phenylisoserine side chain of taxol from
enantiopure 3-hydroxy-b-lactams7 has provided one of
Keywords: b-lactam, Grignard reaction, sphingosine, phytosphin-
gosine, azetidin-2-one
the most practical semisynthetic routes to taxol. The sub-
ject has been extensively reviewed8c and remains a field of
constant activity. We have been engaged in the use of
enantiopure b-lactams as synthons for biologically useful
compounds and intermediates.8,9 As a part of this research
program, we now present our work on the synthesis of
sphingolipids, xylo-(2S,3R,4R)-phytosphingosine (2) and
threo-(2S,3S)-sphingosine (5) (Figure 1), from an optical-
ly pure formyl-substituted b-lactam.
b-Lactams have a prominent position in medicinal chem-
istry as the most widely used antibiotics and continue to
exhibit utility in newer applications.1–3 Over the last few
decades the scope and applications of the b-lactams has
widened appreciably opening new avenues of research.4
Amongst these applications the most important one,
which has shown a staggering growth, has been their use
as synthons for other biologically important products.5
The ease of cleavage of the b-lactam bond, ascribable
largely to ring strain, makes it amenable to various trans-
formations. All four bonds of the b-lactam ring can be
cleaved selectively, which renders it flexible for different
Sphingolipids are membrane components of all eukaryot-
ic cells, plasma membranes and some intramolecular cell
organelles.10 It is known that sphingosines and ceramides
play an important role in intracellular signaling, along
with secondary messenger molecules.11 Sphingosines are
lipophilic components of glycosphingolipids and ceram-
OH NH2
OH NH2
OH
OH
C14H29
C14H29
OH
OH
xylo-(2R,3R,4R)-phytosphingosine (1)
xylo-(2S,3R,4R)-phytosphingosine (2)
OH NH2
OH
OH NH2
OH
C
14H29
C14H29
OH
OH
ribo-(2S,3S,4R)-phytosphingosine (3)
arabino-(2S,3R,4S)-phytosphingosine (4)
NH2
NH2
C13H27
OH
C13H27
OH
OH
OH
threo-(2S,3S)-sphingosine (5)
erythro-(2S,3R)-sphingosine (6)
Figure 1
SYNTHESIS 2007, No. 17, pp 2631–2636
x
x.
x
x
.
2
0
0
7
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-983815; Art ID: Z08107SS
© Georg Thieme Verlag Stuttgart · New York

2632
A. S. Kale et al.
PAPER
ides.11b,12 Phytosphingosines (e.g., 1–4) constitute the ma- ly furnishing the required keto compound 11 in good
jor base component of higher plants, protozoa, yeast and yield. Attempts to deprotect the N-Boc and O-Boc groups
fungi.13 They have also been found in human kidney cere- using various conditions led to a complex mixture of
brosides and in some cancer cell types.14 D-erythro-Sphin- products. Alternatively, it was decided to reduce the keto
gosine (6) shows promising protein kinase inhibitory group first and then carry out the deprotection; however,
activity.11c,15 Moreover, it has been shown that diastereo- to our dismay, the reduction reaction also gave a very
mers of ceramides, sphingosines and dihydrosphingosines complex reaction mixture. Therefore, the hydroxymethyl-
exhibit different activities and metabolisms.16 Thus, ow- ene group at the C-4 position of azetidin-2-one 9 was pro-
ing to the number of applications, this area has attracted a tected as the O-tert-butyldimethylsilyl ether 12
large number of synthetic chemists.17 The subtle varia- (Scheme 2). This was followed by protection of the lac-
tions in biological activities over the range of diastereo- tam nitrogen as the tert-butoxycarbonyl derivative 13.
mers have inevitably led to synthesis of all diastereomers Compound 13 was then subjected to Grignard reaction
of sphingosines. This fact is reflected in a steep rise in the with n-tetradecylmagnesium bromide in tetrahydrofuran
number of publications dealing with the synthesis of to obtain compound 14. The benzyloxy group was suc-
sphingosines.13,14,17
cessfully deprotected by transfer hydrogenation with am-
monium formate and 10% Pd/C to give 15. Compound 15
on treatment with tert-butyldimethylsilyl chloride yielded
the protected (2S,3R)-2-(tert-butoxycarbonylamino)-1,3-
bis(tert-butyldimethylsilyloxy)octadecan-4-one (16) in
good yield. The transformation of 16 to xylo-(2S,3R,4R)-
phytosphingosine (2) is a well-documented three-step
synthetic protocol.17i,j Compound 16 is also an important
intermediate in the synthesis of threo-(2S,3S)-sphingosine
(5), via a well-established three-step synthetic se-
quence.17i,j Thus, (2S,3R)-2-(tert-butoxycarbonylamino)-
1,3-bis(tert-butyldimethylsilyloxy)octadecan-4-one (16)
is a common intermediate in the synthesis of xylo-
(2S,3R,4R)-phytosphingosine (2) and threo-(2S,3S)-
sphingosine (5).
Since sphingosines are popular synthetic targets, many
synthetic routes have been reported; however, a literature
survey brought forth only two examples using b-lactams
as synthons. In one of the reports the starting b-lactam was
subjected to ring opening by a phosphonate-stabilized
carbanion, followed by a Horner–Wadsworth–Emmons
reaction to obtain unsaturated ketone, which on further
elaboration yielded sphingosines.17i In another approach
n-tetradecyl p-toluenesulfonate and n-butyllithium were
used to open the b-lactam ring. Subsequent desulfonyla-
tion using lithium naphthalenide, and further synthetic
manipulations, led to the corresponding sphingosines.12g
While both reports present beautiful approaches to sphin-
gosines, the installation of the tetradecyl chain essentially
happens in a two-step process in both cases. In view of the In conclusion, we have established a stereoselective syn-
above-mentioned facts, we envisaged that an attack of thesis of a common intermediate 16 for xylo-(2S,3R,4R)-
Grignard reagent would open the b-lactam ring and simul- phytosphingosine (2) and threo-(2S,3S)-sphingosine (5)
taneously bring into place the side chain in one step starting from an enantiopure formyl-substituted b-lactam.
(Scheme 1).
A Grignard reaction on the b-lactam carbonyl, followed
by further transformations, provided this crucial common
precursor in good yield.
The optically pure formyl-substituted b-lactam 7 can be
easily prepared from commercially available D-glyceral-
dehyde acetonide via a Staudinger ketene–imine cycload-
dition reaction, in excellent yield and high enantiopurity,
by following a reported procedure.6a The aldehyde 7 was
reduced in good yield to the corresponding alcohol 8 with
sodium borohydride. Oxidative removal of the p-meth-
oxyphenyl group was then carried out using cerium(IV)
ammonium nitrate to provide N-deprotected b-lactam 9.
Subsequently, the b-lactam nitrogen and the hydroxy
1H and 13C NMR spectra were recorded in CDCl3 solution on a
Bruker AV200 or DRX500 spectrometer and the chemical shifts are
1
reported in ppm downfield from TMS (for H NMR spectra). IR
spectra were recorded on a Shimadzu FTIR-8400 instrument using
NaCl optics. Mass spectrometric measurements were carried out
with electrospray ionization on an API QSTAR Pulsar mass spec-
trometer. Melting points were recorded on a Buchi Melting Point B
540 apparatus and are uncorrected. Optical rotations were recorded
were protected as the N-Boc and O-Boc derivatives, re- on a JASCO-181 digital polarimeter under standard conditions. The
spectively, giving compound 10. Grignard reaction of 10
with n-tetradecylmagnesium bromide proceeded smooth-
microanalyses were performed on a Carlo–Erba CHNS-O EA 1108
elemental analyzer. Petroleum ether refers to the fraction boiling at
60–80 °C.
H
H
N
H
H
N
H
H
N
H
H
N
O
NHBoc
OBoc
CHO
PMP
BnO
BnO
BnO
BnO
OH
PMP
OH
OBoc
b
c
d
a
C14H29
O
O
O
H
O
Boc
OBn
11, 62%
7
8, 82%
9, 68%
10, 70%
Scheme 1 Synthesis of keto compound 11. Reagents and conditions: a) NaBH4, MeOH, 8 h; b) CAN, MeCN–H2O, 45 min; c) (Boc)2O,
DMAP, CH2Cl2, 12 h; d) C14H29MgBr, THF, –78 °C to –40 °C, 1 h.
Synthesis 2007, No. 17, 2631–2636 © Thieme Stuttgart · New York

PAPER
Formal Synthesis of xylo-(2S,3R,4R)-Phytosphingosine and threo-(2S,3S)-Sphingosine
2633
H
H
N
H
H
N
H
H
N
O
NHBoc
OTBDMS
BnO
BnO
BnO
OH
OTBDMS
OTBDMS
Boc
13, 83%
a
b
c
C14H29
O
H
O
H
O
OBn
14, 65%
9
12, 90%
O
NHBoc
OTBDMS
O
NHBoc
OTBDMS
d
e
C14H29
2 and 5
C14H29
OH
15, 85%
OTBDMS
16, 73%
Scheme 2 Synthesis of common intermediate 16. Reagents and conditions: a) TBDMSCl, imidazole, DMF, 3 h; b) (Boc)2O, DMAP, CH2Cl2,
5 h; c) C14H29MgBr, THF, –78 °C to –40 °C, 1 h; d) HCOONH4, 10% Pd/C, MeOH, reflux, 1 h; e) TBDMSCl, imidazole, DMF, 35 °C, 12 h.
(3R,4S)-3-(Benzyloxy)-4-(hydroxymethyl)-1-(4-methoxyphe-
nyl)azetidin-2-one (8)
13C NMR (50 MHz, CDCl3): d = 54.8, 61.5, 73.4, 82.1, 128, 128.2,
128.5, 136.5, 169.1.
To a cooled soln of the 4-formylazetidin-2-one6a 7 (3.11 g, 10
mmol) in MeOH (50 mL) at 0 °C was added NaBH4 (1.85 g, 50
mmol) portionwise under an argon atmosphere. The mixture was al-
lowed to warm to r.t. and stirred for 8 h. After completion of the re-
action (TLC), H2O (20 mL) was added carefully and the mixture
was further stirred for 1 h. MeOH was removed under reduced pres-
sure and the residue was extracted with EtOAc (2 × 80 mL). The
combined organic layer was washed with brine (15 mL) and dried
(anhyd Na2SO4). Removal of the solvent under reduced pressure
gave the crude product, which was purified by column chromatog-
raphy (acetone–petroleum ether, 25:75) to afford alcohol 8 (2.56 g,
82%) as a white crystalline solid; mp 119–120 °C; [a]D +160 (c
1.0, CHCl3).
IR (CHCl3): 3337, 1743 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.38 (dd, J = 5.6 Hz, 1 H), 3.79 (s,
3 H), 3.99–4.08 (m, 2 H), 4.08–4.26 (m, 1 H), 4.78 (d, J = 11.6 Hz,
1 H), 4.87 (d, J = 5.1 Hz, 1 H), 5.03 (d, J = 11.6 Hz, 1 H), 6.87 (d,
J = 9.1 Hz, 2 H), 7.36–7.42 (m, 7 H).
13C NMR (50 MHz, CDCl3): d = 55.3, 57.9, 59.2, 73.5, 80.7, 114.3,
118.7, 128, 128.2, 128.5, 130.4, 136.4, 156.7, 164.1.
MS: m/z = 208 [M + 1].
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.62; H, 6.28; N, 6.68.
(3R,4S)-3-(Benzyloxy)-1-(tert-butoxycarbonyl)-4-[(tert-butoxy-
carbonyloxy)methyl]azetidin-2-one (10)
Boc2O (3.8 mL, 16.9 mmol) and DMAP (0.77 g, 6.3 mmol) were
added to a soln of azetidin-2-one 9 (1 g, 4.8 mmol) in CH2Cl2 (20
mL) at 0 °C, and the reaction mixture was stirred for 12 h. Then,
CH2Cl2 (25 mL) was added, and the mixture was washed with sat.
aq NaHCO3 (20 mL) and brine (10 mL). The organic layer was
dried (anhyd Na2SO4) and the solvent was removed under reduced
pressure to give crude product, which was purified by column chro-
matography (acetone–petroleum ether, 5:95) to furnish the title
b-lactam 10 (1.38 g, 70%) as a white solid; mp 98–99 °C; [a]D25 +77
(c 1.0, CHCl3).
30
IR (CHCl3): 1812, 1741 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.44 (s, 9 H), 1.46 (s, 9 H), 4.26–
4.33 (m, 2 H), 4.36–4.44 (m, 1 H), 4.63 (d, J = 5.1 Hz, 1 H), 4.72
(d, J = 11.7 Hz, 1 H), 4.79 (d, J = 11.7 Hz, 1 H), 7.27–7.37 (m, 5 H).
MS: m/z = 314 [M + 1].
13C NMR (50 MHz, CDCl3): d = 27.6, 27.8, 55.5, 62.5, 73.4, 80.5,
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
68.93; H, 6.09; N, 4.38.
82.2, 83.7, 127.8, 128.0, 128.3, 136.4, 147.5, 152.8, 164.1.
MS: m/z = 408 [M + 1].
Anal. Calcd for C21H29NO7: C, 61.90; H, 7.17; N, 3.44. Found: C,
61.77; H, 7.12; N, 3.31.
(3R,4S)-3-(Benzyloxy)-4-(hydroxymethyl)azetidin-2-one (9)
A soln of CAN (10.5 g, 19.2 mmol) in H2O (65 mL) was added
dropwise to a soln of (3R,4S)-3-(benzyloxy)-4-(hydroxymethyl)-1-
(4-methoxyphenyl)azetidin-2-one (8) (2 g, 6.4 mmol) in MeCN (67
mL) at 0 °C. The mixture was stirred at 0 °C for 45 min. H2O (50
mL) was added, and the mixture was extracted with EtOAc (3 × 125
mL) and washed with sat. aq NaHCO3 (2 × 50 mL). The aqueous
NaHCO3 layer was extracted with EtOAc (1 × 25 mL), and the com-
bined organic extracts were washed with 40% NaHSO3 (3 × 60 mL)
and brine (10 mL), and then dried (anhyd Na2SO4). The solvent was
removed under reduced pressure to give crude product, which was
purified by flash column chromatography (acetone–petroleum
ether, 40:60) to furnish 9 (0.9 g, 68%) as a white solid; mp 80 °C;
[a]D25 –36 (c 1.0, CHCl3).
(2S,3R)-3-(Benzyloxy)-2-(tert-butoxycarbonylamino)-1-(tert-
butoxycarbonyloxy)octadecan-4-one (11)
n-Tetradecylmagnesium bromide (1 M in THF; 3.2 mL, 3.2 mmol)
was added to a soln of the starting b-lactam 10 (1.2 g, 2.9 mmol) in
THF (15 mL) at –78 °C (acetone–CO2 bath). The reaction mixture
was stirred at –40 °C (MeCN–CO2 bath) for 1 h. After completion
of the reaction (TLC), sat. NH4Cl soln (4 mL) was poured into the
mixture, which was then extracted with EtOAc (3 × 40 mL). The
combined organic extracts were washed with brine (10 mL) and
dried (anhyd Na2SO4). The solvent was removed under reduced
pressure to yield the product. Purification by flash column chroma-
tography (acetone–petroleum ether, 3:97) gave b-amino ketone 11
(1.1 g, 62%) as an oil; [a]D25 +56 (c 0.8, CHCl3).
IR (CHCl3): 3373, 1753 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.51–3.9 (m, 5 H), 4.62 (d, J =
11.6 Hz, 1 H), 4.66 (d, J = 5.5 Hz, 1 H), 4.78 (d, J = 11.6 Hz, 1 H),
7.34–7.42 (m, 5 H).
IR (CHCl3): 3438, 1739, 1722 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.86–0.92 (m, 3 H), 1.17–1.26 (m,
21 H), 1.35–1.43 (m, 3 H), 1.40 (s, 9 H), 1.49 (s, 9 H), 2.42–2.53
Synthesis 2007, No. 17, 2631–2636 © Thieme Stuttgart · New York

2634
A. S. Kale et al.
PAPER
(m, 2 H), 3.56 (br s, 1 H), 4.07 (d, J = 6.3 Hz, 2 H), 4.41 (d, J = 11.4
Hz, 1 H), 4.67–4.73 (m, 2 H), 4.95 (d, J = 11.4 Hz, 1 H), 7.33–7.36
(m, 5 H).
13C NMR (50 MHz, CDCl3): d = 13.9, 22.5, 23.0, 27.6, 28.1, 28.2,
29.0, 29.2, 29.3, 29.4, 30.2, 31.7, 39.0, 50.3, 64.9, 72.8, 75.9, 81.3,
81.5, 81.9, 127.8, 128.1, 128.3, 136.9, 152.9, 154.9, 208.9.
(TLC), sat. NH4Cl soln (4 mL) was poured into the mixture, which
was then extracted with EtOAc (3 × 30 mL). The combined organic
layer was washed with brine (10 mL) and dried (anhyd Na2SO4).
The solvent was removed under reduced pressure to yield the prod-
uct. Purification by flash column chromatography (EtOAc–petro-
leum ether, 1:99) gave b-amino ketone 14 (0.804 g, 65%) as an oil;
[a]D25 –4 (c 1.0, CHCl3).
MS: m/z = 606 [M + 1].
IR (CHCl3): 3436, 1718, 1706 cm–1.
Anal. Calcd for C35H59NO7: C, 69.39; H, 9.82; N, 2.31. Found: C,
69.28; H, 9.78; N, 2.24.
1H NMR (200 MHz, CDCl3): d = 0.05 (s, 3 H), 0.07 (s, 3 H), 0.85–
0.89 (m, 12 H), 1.20–1.30 (m, 22 H), 1.39 (s, 9 H), 1.55 (t, J = 6.8
Hz, 2 H), 2.48 (dd, J = 6.8, 14.4 Hz, 2 H), 3.51–3.69 (m, 2 H), 4.05–
4.18 (m, 1 H), 4.26 (d, J = 2.9 Hz, 1 H), 4.40 (d, J = 11.2 Hz, 1 H),
4.68 (d, J = 11.2 Hz, 1 H), 4.91 (d, J = 9.6 Hz, 1 H), 7.29–7.39 (m,
5 H).
13C NMR (50 MHz, CDCl3): d = –5.5, –5.4, 14.1, 18.1, 22.6, 23.4,
25.8, 28.2, 29.2, 29.3, 29.4, 29.6, 31.9, 39.1, 53.1, 61.4, 73.0, 81.3,
127.9, 128.1, 128.4, 137.4, 155.2, 210.3.
(3R,4S)-3-(Benzyloxy)-4-[(tert-butyldimethylsilyloxy)meth-
yl]azetidin-2-one (12)
To a mixture of azetidin-2-one 9 (0.73 g, 3.5 mmol) and imidazole
(0.6 g, 8.8 mmol) in anhyd DMF (1.2 mL) was added TBDMSCl
(0.63 g, 4.2 mmol) at r.t. The reaction mixture was stirred at r.t. for
3 h. After completion of the reaction (TLC), the mixture was poured
onto H2O (5 mL) and extracted with EtOAc (3 × 15 mL). The com-
bined organic extracts were successively washed with H2O (3 × 5
mL) and brine (10 mL), then dried (anhyd Na2SO4). The solvent
was removed under reduced pressure to afford crude product, which
was purified by column chromatography (EtOAc–petroleum ether,
20:80) to furnish 12 (1.02 g, 90%) as a colorless oil; [a]D25 +0.51 (c
1.0, CHCl3).
MS: m/z = 620 [M + 1].
Anal. Calcd for C36H65NO5Si: C, 69.74; H, 10.57; N, 2.26. Found:
C, 69.61; H, 10.48; N, 2.12.
(2S,3R)-2-(tert-Butoxycarbonylamino)-1-(tert-butyldimethyl-
silyloxy)-3-hydroxyoctadecan-4-one (15)
IR (neat): 3259, 1762 cm–1.
A mixture of b-amino ketone 14 (0.62 g, 1 mmol), ammonium for-
mate (0.189 g, 3 mmol) and 10% Pd/C (0.07 g) in MeOH (10 mL)
was refluxed for 1 h. The reaction mixture was filtered through a
small pad of Celite® and washed with EtOAc (2 × 10 mL). The sol-
vent was removed under reduced pressure. The residue was diluted
with EtOAc (50 mL), and washed with H2O (2 × 5 mL) and brine (5
mL). The organic layer was dried (anhyd Na2SO4) and concentrated
to give crude product, which was purified by flash column chroma-
tography (EtOAc–petroleum ether, 2:98) to afford 15 (0.45 g, 85%)
as an oil; [a]D25 –24 (c 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 0.05 (s, 3 H), 0.06 (s, 3 H), 0.88
(s, 9 H), 3.70–3.82 (m, 3 H), 4.67 (d, J = 11.9 Hz, 1 H), 4.71–4.74
(m, 1 H), 4.81 (d, J = 11.9 Hz, 1 H), 6.12 (br s, 1 H), 7.26–7.35 (m,
5 H).
13C NMR (50 MHz, CDCl3): d = –5.4, 18.2, 25.8, 55.7, 62.8, 73.1,
82, 127.9, 128.3, 128.4, 137, 168.7.
MS: m/z = 322 [M + 1].
Anal. Calcd for C17H27NO3Si: C, 63.51; H, 8.47; N, 4.36. Found: C,
63.40; H, 8.41; N, 4.22.
IR (CHCl3): 3442, 1712 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.09 (s, 3 H), 0.10 (s, 3 H), 0.79–
0.97 (m, 13 H), 1.20–1.35 (m, 23 H), 1.39 (s, 9 H), 2.41–2.62 (m, 2
H), 3.61–3.73 (m, 3 H), 4.10–4.25 (m, 1 H), 4.30–4.50 (m, 1 H),
4.56–4.65 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = –5.5, –5.4, 14.1, 18.2, 22.7, 23.6,
25.8, 28.2, 29.1, 29.3, 29.4, 29.5, 29.6, 31.9, 37.7, 53.1, 62.3, 74.7,
79.7, 155.2, 211.5.
(3R,4S)-3-(Benzyloxy)-1-(tert-butoxycarbonyl)-4-[(tert-butyl-
dimethylsilyloxy)methyl]azetidin-2-one (13)
Boc2O (1.35 mL, 5.9 mmol) and DMAP (0.04 g, 0.3 mmol) were
added to a soln of azetidin-2-one 12 (0.950 g, 2.9 mmol) in anhyd
CH2Cl2 (10 mL) at 0 °C, and the mixture was stirred for 5 h. Then,
CH2Cl2 (20 mL) was added, and the mixture was washed with sat.
NaHCO3 soln (20 mL) and sat. brine (10 mL). The organic layer
was dried (anhyd Na2SO4) and the solvent was removed under re-
duced pressure to give crude product, which was purified by column
chromatography (EtOAc–petroleum ether, 12:88) to furnish the title
MS: m/z = 530 [M + 1].
Anal. Calcd for C29H59NO5Si: C, 65.74; H, 11.22; N, 2.64. Found:
C, 65.61; H, 11.18; N, 2.52.
25
b-lactam 13 (1.03 g, 83%) as a colorless oil; [a]D +51 (c 1.5,
CHCl3).
IR (neat): 1811, 1718 cm–1.
(2S,3R)-2-(tert-Butoxycarbonylamino)-1,3-bis(tert-butyldi-
methylsilyloxy)octadecan-4-one (16)
1H NMR (200 MHz, CDCl3): d = 0.05 (s, 3 H), 0.06 (s, 3 H), 0.89
(s, 9 H), 1.51 (s, 9 H), 3.97–4.03 (m, 2 H), 4.04–4.09 (m, 1 H), 4.69
(d, J = 5.2 Hz, 1 H), 4.77 (s, 2 H), 7.31–7.36 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = –5.6, –5.5, 18.2, 25.7, 28, 58.2,
63.1, 73.3, 80.3, 83.3, 127.9, 128.2, 128.4, 136.8, 148, 164.9.
To a mixture of hydroxy compound 15 (0.3 g, 0.56 mmol) and imi-
dazole (0.096 g, 1.4 mmol) in anhyd DMF (1 mL) was added
TBDMSCl (0.102 g, 0.68 mmol) at 35 °C. The reaction mixture was
stirred at 35 °C for 12 h. After completion of the reaction (TLC), the
mixture was poured onto H2O (3 mL) and extracted with EtOAc
(3 × 15 mL). The combined organic extracts were successively
washed with H2O (3 × 5 mL) and sat. brine (8 mL), then dried (an-
hyd Na2SO4). The solvent was removed under reduced pressure to
give crude product, which was purified by column chromatography
(EtOAc–petroleum ether, 1:99) to furnish 16 (0.26 g, 73%) as a col-
orless oil; [a]D25 –9 (c 1.0, CHCl3).
MS: m/z = 422 [M + 1].
Anal. Calcd for C22H35NO5Si: C, 62.67; H, 8.37; N, 3.32. Found: C,
62.49; H, 8.29; N, 3.24.
(2S,3R)-3-(Benzyloxy)-2-(tert-butoxycarbonylamino)-1-(tert-
butyldimethylsilyloxy)octadecan-4-one (14)
n-Tetradecylmagnesium bromide (1 M in THF; 2.2 mL, 2.2 mmol)
was added to a soln of b-lactam 13 (0.84 g, 2 mmol) in THF (5 mL)
at –78 °C (acetone–CO2 bath). The reaction mixture was stirred at
–40 °C (MeCN–CO2 bath) for 1 h. After completion of the reaction
IR (CHCl3): 3436, 1715 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.01 (s, 3 H), 0.04 (s, 3 H), 0.07
(s, 3 H), 0.10 (s, 3 H), 0.90 (s, 9 H), 0.94 (s, 9 H), 1.20–1.27 (m, 22
H), 1.41 (s, 9 H), 1.45–1.61 (m, 5 H), 2.42–2.53 (m, 2 H), 3.51 (t,
Synthesis 2007, No. 17, 2631–2636 © Thieme Stuttgart · New York

PAPER
Formal Synthesis of xylo-(2S,3R,4R)-Phytosphingosine and threo-(2S,3S)-Sphingosine
2635
J = 8.5 Hz, 1 H), 3.62–3.67 (m, 1 H), 3.70 (br s, 1 H), 4.42–4.44 (m,
1 H), 4.90 (d, J = 9.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = –5.4, –5.3, –4.7, 14.1, 18.2, 18.3,
22.7, 23.5, 25.8, 28.3, 29.2, 29.4, 29.5, 29.6, 31.9, 38.6, 54.2, 61.0,
75.7, 77.2, 79.5, 155.2, 211.3.
(5) (a) Nagahara, T.; Kametani, T. Heterocycles 1987, 25, 729.
(b) Thomas, R. C. In Recent Progress in the Chemical
Synthesis of Antibiotics; Lukacs, G.; Ohno, M., Eds.;
Springer-Verlag: Berlin, 1990, 553. (c) Palomo, C. In
Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G.; Ohno, M., Eds.; Springer-Verlag: Berlin, 1990,
565. (d) Palomo, C.; Arrieta, A.; Cossío, F. P.; Aizpurua, J.
M.; Mielgo, A.; Aurrekoetxea, N. Tetrahedron Lett. 1990,
31, 6429. (e) Palomo, C.; Cabre, F.; Ontoria, J. M.
Tetrahedron Lett. 1992, 33, 4819. (f) Annunziata, R.;
Benaglia, M.; Cinquini, M.; Cozzi, F.; Ponzini, F. J. Org.
Chem. 1993, 58, 4746.
MS: m/z = 645 [M + 1].
Anal. Calcd for C35H73NO5Si2: C, 65.26; H, 11.42; N, 2.17. Found:
C, 65.14; H, 11.28; N, 2.10.
Acknowledgment
(6) (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M. J.
Org. Chem. 1994, 59, 932. (b) Jayaraman, M.; Nandi, M.;
Sathe, K. M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron: Asymmetry 1993, 4, 609. (c) Jayaraman, M.
J.; Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron 1996,
52, 8989. (d) Banik, B. K.; Mathur, C.; Wagle, D. R.;
Manhas, M. S.; Bose, A. K. Tetrahedron 2000, 56, 5603.
(7) (a) Denis, J.-N.; Greene, A. E.; Guénard, D.; Guéritte-
Voegelein, F.; Mangatal, L.; Potier, P. J. Am. Chem. Soc.
1988, 110, 5917. (b) Holton, R. A.; Liu, J. H. Bioorg. Med.
Chem. Lett. 1993, 3, 2475. (c) Georg, G. I.; Cheruvallath, Z.
S.; Harriman, G. C. B.; Hepperle, M.; Park, H. Bioorg. Med.
Chem. Lett. 1993, 3, 2467.
(8) (a) Jayaraman, M.; Puranik, V. G.; Bhawal, B. M.
Tetrahedron 1996, 52, 9005. (b) Srirajan, V.; Deshmukh, A.
R. A. S.; Puranik, V. G.; Bhawal, B. M. Tetrahedron:
Asymmetry 1996, 7, 2733. (c) Deshmukh, A. R. A. S.;
Bhawal, B. M.; Krishnaswamy, D.; Govande, V. V.;
Shinkre, B. A.; Jayanthi, A. Curr. Med. Chem. 2004, 11,
1889. (d) Shirode, N. M.; Kulkarni, K. C.; Gumaste, V. K.;
Deshmukh, A. R. A. S. ARKIVOC 2005, (i), 53. (e) Tiwari,
D. K.; Gumaste, V. K.; Deshmukh, A. R. A. S. Synthesis
2006, 115.
(9) (a) Krishnaswamy, D.; Govande, V. V.; Deshmukh, A. R. A.
S. Synthesis 2003, 1903. (b) Kale, A. S.; Deshmukh, A. R.
A. S. Synlett 2005, 2370.
(10) (a) Thudichum, J. L. W. A Treatise on the Chemical
Constitution of the Brain; Archon Books: Hamden, CT,
1962. (b) Hakomori, S. J. Biol. Chem. 1990, 265, 18713.
(c) van Meer, G.; Burger, K. N. J. Trends Cell Biol. 1992, 2,
338.
(11) (a) Merrill, A. H. Jr.; Sweeley, C. C. In Biochemistry of
Lipids, Lipoproteins and Membranes; Vance, D. E.; Vance,
J. E., Eds.; Elsevier: Amsterdam, 1996, Chap. 12, 309.
(b) Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998,
1075. (c) Kolter, T.; Sandhoff, K. Angew. Chem. Int. Ed.
1999, 38, 1532.
(12) For recent studies of D-erythro-sphingosine synthesis, see:
(a) Nugent, T. C.; Hudlicky, T. J. Org. Chem. 1998, 63, 510.
(b) Hoffman, R. V.; Tao, J. Tetrahedron Lett. 1998, 39,
3953. (c) Hoffman, R. V.; Tao, J. J. Org. Chem. 1998, 63,
3979. (d) Yin, J.; Liu, H.; Pidgeon, C. Bioorg. Med. Chem.
Lett. 1998, 8, 179. (e) Khiar, N.; Singh, K.; Garcia, M.;
Martin-Lomas, M. Tetrahedron Lett. 1999, 40, 5779.
(f) Hertweck, C.; Boland, W. J. Org. Chem. 1999, 64, 4426.
(g) Nakamura, T.; Shiozaki, M. Tetrahedron Lett. 1999, 40,
9063. (h) Azuma, H.; Tamagaki, S.; Ogino, K. J. Org. Chem.
2000, 65, 3538.
The authors thank the Department of Science and Technology New
Delhi for financial support and CSIR New Delhi for a research fel-
lowship to A.S.K.
References
(1) For reviews on b-lactam antibiotics, see: (a) Dürkheimer,
W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 180. (b) Chemistry and
Biology of b-Lactam Antibiotics, Vol. 1-3; Morin, R. B.;
Gorman, M., Eds.; Academic: New York, 1982.
(c) Coulton, S.; Hunt, E. In Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products,
Vol. 2; Lukacs, G., Ed.; Springer-Verlag: Berlin, 1993, 621.
(d) Southgate, R. Contemp. Org. Synth. 1994, 1, 417.
(e) Rothstein, J. D.; Patel, S.; Regan, M. R.; Haenggelli, C.;
Huang, Y. H.; Bergles, D. E.; Jin, L.; Hoberg, M. D.;
Vidensky, S.; Chung, D. S.; Toan, S. V.; Bruijn, L. I.; Su, Z.-
z.; Gupta, P.; Fisher, P. B. Nature (London) 2005, 433, 73.
(f) Burnett, D. A.; Caplen, M. A.; Davis, H. R. Jr.; Burrie, R.
E.; Clader, J. W. J. Med. Chem. 1994, 37, 1733. (g) Dugar,
S.; Yumibe, N.; Clader, J. W.; Vizziano, M.; Huie, K.; van
Heek, M.; Compton, D. S.; Davis, H. R. Jr. Bioorg. Med.
Chem. Lett. 1996, 6, 1271.
(2) The Chemistry of b-Lactams; Page, M. I., Ed.; Chapman &
Hall: London, 1992.
(3) For comprehensive general reviews, see: (a) Koppel, G. A.
In Small Ring Heterocycles, Vol. 42; Hasner, A., Ed.; Wiley
& Sons: New York, 1983, 219. (b) Backes, J. In Houben–
Weyl Methoden der organischen Chemie, Vol. E 16b;
Klamann, D., Ed.; Georg Thieme: Stuttgart, 1991, 31.
(c) De Kimpe, N. In Comprehensive Heterocyclic Chemistry
II, Vol. 1B; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.;
Padwa, A., Eds.; Pergamon: Oxford, 1996, 507. (d) Wu, G.
G. Org. Process Res. Dev. 2000, 4, 298. (e) Han, W. T.;
Trehan, A. K.; Wright, J. J. K.; Federici, M. E.; Seiler, S. M.;
Meanwell, N. A. Bioorg. Med. Chem. 1995, 3, 1123.
(f) Zhou, N. E.; Guo, D.; Thomas, G.; Reddy, A. V. N.;
Kaleta, J.; Purisima, E.; Menard, R.; Micetich, R. G.; Singh,
R. Bioorg. Med. Chem. Lett. 2003, 13, 139.
(4) (a) Ojima, I.; Georg, G. I. The Organic Chemistry of b-
Lactams; VCH: New York, 1993, 197; and references cited
therein. (b) Palomo, C.; Aizpurua, J.; Ganboa, I. In
Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: New York, 1997, 279–357; and references
cited therein. (c) For a review on this subject, see: Ojima, I.;
Delaloge, F. Chem. Soc. Rev. 1997, 26, 377. (d) Alcaide,
B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226.
(e) Alcaide, B.; Almendros, P. Synlett 2002, 381.
Synthesis 2007, No. 17, 2631–2636 © Thieme Stuttgart · New York

2636
A. S. Kale et al.
PAPER
(13) For studies on the synthesis of phytosphingosine and its
derivatives, see: (a) Sugiyama, S.; Honda, M.; Komori, T.
Liebigs Ann. Chem. 1990, 1069. (b) Dondoni, A.; Fantin,
G.; Fogagnolo, M.; Pedrini, P. J. Org. Chem. 1990, 55, 439.
(c) Wild, R.; Schmidt, R. R. Tetrahedron: Asymmetry 1994,
5, 2195. (d) Murakami, T.; Minamikawa, H.; Hato, M.
Tetrahedron Lett. 1994, 35, 745. (e) Nakashima, H.; Hirata,
N.; Iwamura, T.; Yamagiwa, Y.; Kamikawa, T. J. Chem.
Soc., Perkin Trans. 1 1994, 2849. (f) Kobayashi, S.;
Hayashi, T.; Kawasuji, T. Tetrahedron Lett. 1994, 35, 9573.
(g) Matsumoto, K.; Ebatu, T.; Matsushita, H. Carbohydr.
Res. 1995, 279, 93. (h) Wild, R.; Schmidt, R. R. Liebigs
Ann. 1995, 755. (i) Li, Y. L.; Mao, X. H.; Wu, Y. L. J.
Chem. Soc., Perkin Trans. 1 1995, 1559. (j) Kemp, S. J.;
Bao, J.; Pedersen, S. F. J. Org. Chem. 1996, 61, 7162.
(k) Lin, G. Q.; Shi, Z. C. Tetrahedron 1996, 52, 2187.
(l) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron:
Asymmetry 1996, 7, 2113. (m) Murakami, M.; Ito, H.; Ito,
Y. Chem. Lett. 1996, 185. (n) Wee, A. G. H.; Tang, F.
Tetrahedron Lett. 1996, 37, 677. (o) Shimizu, M.; Wakioka,
I.; Fujisawa, T. Tetrahedron Lett. 1997, 38, 6027.
(p) Imashiro, R.; Sakurai, O.; Yamashita, T.; Horikawa, H.
Tetrahedron 1998, 54, 10657. (q) Takikawa, H.; Muto, S.;
Mori, K. Tetrahedron 1998, 54, 3141. (r) Li, S.; Pang, J.;
Wilson, W. K.; Schroepfer, J. Jr. Tetrahedron: Asymmetry
1999, 10, 1697. (s) Murakami, T.; Toguchi, K. Tetrahedron
1999, 55, 989. (t) Shirota, O.; Nakanishi, K.; Berova, N.
Tetrahedron 1999, 55, 13643. (u) Martin, C.; Prunck, W.;
Bortolussi, M.; Bloch, R. Tetrahedron: Asymmetry 2000, 11,
1585.
(15) (a) Karlsson, K.-A. Trends Pharmacol. Sci. 1991, 12, 265.
(b) Hannun, Y.; Bell, R. M. Science (Washington, D. C.)
1989, 243, 500. (c) Hannun, Y. Science (Washington, D. C.)
1996, 274, 1855. (d) Vankar, Y. D.; Schmidt, R. R. Chem.
Soc. Rev. 2000, 29, 201. (e) Brodesser, S.; Sawatzki, P.;
Kolter, T. Eur. J. Org. Chem. 2003, 2021.
(16) (a) Motoki, K.; Kobayashi, E.; Uchida, T.; Fukushima, H.;
Koezuka, Y. Bioorg. Med. Chem. Lett. 1995, 5, 705.
(b) Pushkareva, M.; Chao, R.; Bielawska, A.; Merrill, A. H.;
Crane, H. M.; Lagu, B.; Liotta, D.; Hannun, Y. A.
Biochemistry 1995, 34, 1885. (c) Inokuchi, J.-i.; Usuki, S.;
Jimbo, M. J. Biochem. (Tokyo) 1995, 117, 766.
(17) (a) Olofsson, B.; Somfai, P. J. Org. Chem. 2003, 68, 2514.
(b) Jeong, I.-Y.; Lee, J. H.; Lee, B. W.; Kim, J. H.; Park, K.
H. Bull. Korean Chem. Soc. 2003, 24, 617. (c) Milne, J. E.;
Jarowicki, K.; Kocienski, P. J.; Alonso, J. Chem. Commun.
2002, 426. (d) Lees, W. J.; Gargano, J. M. Tetrahedron Lett.
2001, 42, 5845. (e) Duclos, R. I. Chem. Phys. Lipids 2001,
111, 111. (f) Lee, J.-M.; Lim, H.-S.; Chung, S.-K.
Tetrahedron: Asymmetry 2002, 13, 343. (g) Bittman, R.;
Chun, J.; Li, G.; Byun, H.-S. Tetrahedron Lett. 2002, 43,
375. (h) Chaudhari, V. D.; Ajish Kumar, K. S.; Dhavale, D.
D. Org. Lett. 2005, 7, 5805. (i) Lee, K. H.; Kim, E.-K.; Pak,
C. S. Tetrahedron Lett. 2002, 43, 9641. (j) Nakamura, T.;
Shiozaki, M. Tetrahedron 2001, 57, 9087. (k) Raghavan,
S.; Rajandar, A.; Yadav, J. S. Tetrahedron: Asymmetry
2003, 14, 2093. (l) 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. (m) Lombardo, M.;
Capdevila, M. G.; Pasi, F.; Trombini, C. Org. Lett. 2006, 8,
3303.
(14) For recent reviews on sphingosines/ceramides, see:
(a) Liao, J.; Tao, J.; Lin, G.; Liu, D. Tetrahedron 2005, 61,
4715. (b) Curfman, C.; Liotta, D. Methods Enzymol. 1999,
311, 391.
Synthesis 2007, No. 17, 2631–2636 © Thieme Stuttgart · New York