Highly efficient stereoselective synthesis of d-erythro-sphingosine and d-lyxo-phytosphingosine

Article abstract of DOI:10.1016/j.tet.2006.08.049

Starting from a single suitable functionalised epoxide, a highly efficient stereoselective synthesis of d-erythro-sphingosine and d-lyxo-phytosphingosine is described. The approach allows the formal preparation of all stereoisomers of these sphingoid stru

Full text of DOI:10.1016/j.tet.2006.08.049

Tetrahedron 62 (2006) 11821–11826
Highly efficient stereoselective synthesis of D-erythro-sphingosine
and D-lyxo-phytosphingosine
a
a
a
b,
Giuliana Righi,a, Simona Ciambrone, Claudia D’Achille, Andrea Leonelli and Carlo Bonini
*
*
aIstituto di Chimica Biomolecolare-Roma, c/o Dipartimento di Chimica, Universitaꢀ ‘La Sapienza’, P.le A. Moro 5, 00185 Roma, Italy
bDipartimento di Chimica, Universitaꢀ della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
Received 6 March 2006; revised 28 July 2006; accepted 11 August 2006
Available online 24 October 2006
Abstract—Starting from a single suitable functionalised epoxide, a highly efficient stereoselective synthesis of D-erythro-sphingosine and
D-lyxo-phytosphingosine is described. The approach allows the formal preparation of all stereoisomers of these sphingoid structures.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
The wide spectrum of the biological activity of these mole-
cules justifies the efforts towards the synthesis of them as
well as of their stereoisomers and various analogues. Al-
though the most commonly employed strategies are those
which make use of carbohydrates4 and serine5 as source of
chirality, many approaches are also based on asymmetric
reactions, such as aldol condensation6 as well as Sharpless
asymmetric dihydroxylation7 and asymmetric epoxidation
(using Shi’s catalyst8 or Sharpless protocol9).
Sphingolipids such as ceramides, cerebrosides and ganglio-
sides are ubiquitous components of cell membranes, where
they are involved in various processes based on recognition
phenomena.1 Common to this diverse group of natural prod-
ucts is a sphingoid base scaffold with a polar 2-amino alco-
hol head and a long aliphatic chain with a 4,5-trans double
bond as in sphingosines (Fig. 1) or an 2-amino-1,3,4 triol
head group without unsaturation as in phytosphingosines
(Fig. 2).2 The hydrophilic moiety, located on the external
surface of the membrane, determines the specificity of inter-
actions, whereas the lipophilic portion, anchored on the
outer-leaflet, contributes primarily to the structural rigidity
of the membrane.3
However, using the above-mentioned asymmetric reactions,
the required introduction of the amino group often suffered
from low regio- and stereoselectivity and therefore these ap-
proaches were scarcely utilised compared to those of natural
products from the chiral pool. Furthermore, rarely a single
OH
OH
OH
OH
HO
C13H27 HO
C13H27
HO
C13H27 HO
C13H27
NH2
NH2
NH2
NH2
L-threo-Sphingosine
D-threo-Sphingosine
A
D-erythro-Sphingosine
L-erythro-Sphingosine
Figure 1.
NH2 OH
HO
NH2 OH
NH2 OH
NH2 OH
HO
HO
HO
C14H29
C14H29
C14H29
C14H29
OH
B
OH
D-ribo-Phytosphingosine
OH
OH
D-xylo-Phytosphingosine
D-arabino-Phytosphingosine
D-lyxo-Phytosphingosine
Figure 2.
Keywords: Functionalised epoxides; Amino alcohols; Sphingosines; Phytosphingosines.
* Corresponding authors. Tel.: +39 6490422; fax: +39 649913628 (G.R.); e-mail: giuliana.righi@uniromal.it
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.08.049

11822
G. Righi et al. / Tetrahedron 62 (2006) 11821–11826
COOCH3
O
A, B
BnO
BnO
NBoc
BnO
OH
COOCH3
O
2
1
11
Scheme 1.
strategic approach has been designed to both sphingosines
and phytosphingosines classes, due to the differences in their
structure.
oxazolidine 6 was obtained from 1 with an overall yield of
82% without any purification of the previous intermediates.
Successively, 6 was converted into 11, a suitable common
precursor for the synthesis of sphingosine and phytosphingo-
sine, through a few high-yielding steps. As shown in Scheme
3, the transformation of 6 into the alcohol 8 was performed
by first reducing 6 with DIBAL to the aldehyde 7 and then
with NaBH4 to 8.12 After protection of the hydroxyl function
of 8 as silyl ether, 9 was debenzylated and then the free
alcohol group of 10 was oxidised to the aldehyde with the
Py/SO3 complex in a high-yielding sequence.
2. Results and discussion
In this regard, our approach to both classes of sphingoid
structures is based on a stereoselective route from an easily
prepared chiral epoxide 1, obtained by the Sharpless AE of
commercial allylic alcohol 2 (Scheme 1).
The introduction of the amino group to the common key
oxazolidine 11 could be easily achieved based on the results
obtained in the regio- and stereoselective opening of bifunc-
tionalised epoxides with metal halides,10 a route which can
be considered very attractive for its generality.
Multifunctional aldehyde 11 represents the key intermediate
for the final transformation into different sphingoid struc-
tures, such as the D-erythro-sphingosine A and D-lyxo-phytos-
phingosine B. Although its preparation was already known
starting from isoascorbic acid, our route is shorter (11 steps)
and with higher overall yield. Furthermore, starting from ent-
epoxy ester 2 the opposite enantiomer of 11 can be prepared.
Our synthesis started with known a,b-epoxy ester 1, derived
from the commercially available Z-4-benzyloxy-2-buten-1-
ol 2. Treatment with the NaBr/Amberlyst 15 system, already
utilised for the regioselective opening of differently sub-
stituted a,b-epoxy esters,11 furnished, with excellent
stereoselectivity and chemical yield, the bromohydrin 3
(Scheme 2).
Finally, aldehyde 11 was transformed into the D-erythro-
sphingosine A following the already reported synthetic
sequence13 (Scheme 4). On the other hand, the D-lyxo-phy-
tosphingosine B was finally prepared through the stereo-
selective addition of the required lithium cuprate, obtained
from tetradecyl bromide, as clearly demonstrated by the
value of the coupling constant of the diol system of 12
(Jw4 Hz), which confirms its syn stereochemistry.14 Subse-
quent deprotection afforded the phytosphingosine B, with
its tetraacetate derivative resulting identical to the data
reported in literature.5a,c,7b
Br
O
NaBr, Amb15
BnO
BnO
COOCH3
COOCH3
acetone, -20 °C
OH
3
>98%
1
Scheme 2.
The polar 2-amino alcohol head was then easily obtained by
subsequent transformation of the halide into an amino group:
thus stereoselective azide nucleophilic substitution fur-
nished the corresponding azido alcohol 4 in nearly quantita-
tive yield (Scheme 3). The subsequent hydrogenation of 4
afforded the vicinal anti amino alcohol 5, which was easily
transformed into 6. Worthy of note is that the key
In summary, through stereocontrolled, facile and high-yield
reactions, we have developed a general highly efficient
route, starting from the easily accessible Z-4-benzyloxy-2-
buten-1-ol, to the preparation of both enantiomers D- and
L-erythro-sphingosines. Starting from the known E-4-benz-
yloxy-2-buten-1-ol and following the same synthetic
scheme it would be possible to have access to the D- and
CHO
NBoc
COOCH3
NBoc
NHBoc
COOCH3
OH
5
N3
c
d
a
b
BnO
BnO
COOCH3
BnO
BnO
3
O
O
OH
4
6
7
yield 82% from 1
OTBDPS
NBoc
e, f
OP
OTBDPS
NBoc
g
h
OHC
BnO
NBoc
HO
O
O
O
8 P = H
9 P = TBDPS
10
11
Scheme 3. (a) NaN3, DMF, rt; (b) H2/Pd, Boc2O, EtOAc, rt; (c) 2,2-DMP, p-TsOH, CH2Cl2, rt; (d) DIBAL, toluene, ꢀ78 ꢁC, >95%; (e) NaBH4, i-PrOH/THF, rt,
>95%; (f) TBDPSCl, Et3N, DMAP, rt, 93%; (g) H2/Pd, MeOH, rt, 93%; (h) Py/SO3, DMSO, 0 ꢁC, 85%.

G. Righi et al. / Tetrahedron 62 (2006) 11821–11826
11823
NH2
C13H27
OH
OH
A
a, b, c
OTBDPS
NBoc
OTBDPS
NBoc
OH NH2
OH
OH
OHC
d
e
H29C14
H29C14
OH
B
O
O
12
11
Scheme 4. (a) nC14H29PPh3Br, nBuLi, THF, ꢀ78 ꢁC to rt, 95%; (b) hn, PhSSPh cat., c-hexane, 91% (Z/E, 30/70); (c) TFA/H2O 1:1, rt, 75%; (d) (nC14H29)2CuLi,
Et2O, ꢀ20 ꢁC, 65%; (e) TFA/H2O 1:1, rt, 75%.
L-threo-diastereoisomers of sphingosine. Preliminary stud-
ies have shown in fact for this substrate the same aptitude
for the formation of the corresponding oxazolidine
(Scheme 5).
in EtOH). Flash column chromatography on silica gel was
normally used for purification of the reaction mixtures.
All solvents were purified before use with standard drying
procedures, unless otherwise specified. Elemental analyses
for C and H were performed by the Servizio Micro-
ꢀ
analisi of the Dip. Chimica of the Universita of Roma
‘La Sapienza’.
On the other hand, we have also prepared the D-lyxo phytos-
phingosine as well as, formally, the L-lyxo-phytosphingo-
sine, throughout the syn diastereoselective addition of
tetradecyl lithium cuprate to the aldehyde 11.14 Starting
from the E-4-benzyloxy-2-buten-1-ol, the same diastereo-
selective reaction would give access to the D- or L-xylo-phy-
tosphingosine. Moreover, the use of a diastereoselective
organometallic anti addition to the aldehyde 1114 could be,
in principle, adaptable even for the synthesis of D-ribo-phy-
tosphingosine starting from the Z-4-benzyloxy-2-buten-1-ol
and of D-arabino-phytosphingosine starting from the E-4-
benzyloxy-2-buten-1-ol (Scheme 6).
Compounds A and B and its tetraacetyl derivative are
known.5a,c,13
3.1.1. (2R,3R)-Z-4-Benzyloxy-2,3-epoxybutanoic acid
methyl ester 1. To 2 mL of a 0.5 M solution of the (2R,3R)-
Z-4-benzyloxy-2,3-epoxybutanal15(192 mg, 1 mmol) in alco-
hol/water (9:1) buffered with NaHCO3 (1682 mg, 20 mmol)
was added 2 M solution of bromine (3 mmol) in MeOH/water
(9:1byvolume). Afterstirringfor 5 h,solidsodiumthiosulfate
was added to quench excess bromine and dilution with water
(2 mL) was followed by extraction with 8 mL of diethylether
(three times). Combined organic layers were dried (Na2SO4),
filtered and the solvent was evaporated in vacuo, giving 1 as
yellow pale oil (210 mg, 95%). No chromatographic purifica-
tion was necessary. Rf (20% EtOAc/petroleum ether) 0.82.
[a]2D0 ꢀ12.7 (c 5.0, CHCl3); nmax (liquid film) 3010, 1735,
1060, 830 cmꢀ1; dH (200 MHz, CDCl3) 7.39–7.27 (5H, m,
Ph), 4.85 (1H, d, J 11.5 Hz, CHaPh), 4.74 (1H, d, J 11.5 Hz,
CHbPh), 3.73 (3H, s, OMe), 3.82–3.65 (2H, m, OCH2), 3.56
3. Experimental
3.1. General
1H and 13C NMR spectra were recorded at 200 and
50.3 MHz, respectively. Reactions were monitored by TLC
using Merck silica gel 60 F254 plates with UV indicator or/
and visualised with phosphomolybdic acid (10% solution
COOCH3
OH
threo
O
BnO
COOCH3
BnO
COOCH3
diastereoisomers
NBoc
BnO
O
Br
Scheme 5.
Ring opening
Organometallic addition
Z-4-benzyloxy-2-buten-1ol: erythro
E-4-benzyloxy-2-buten-1ol: threo
syn (R2CuLi): lyxo from Z-4-benzyloxy-2-buten-1ol
xylo from E-4-benzyloxy-2-buten-1ol
anti (RLi/TiCl4): ribo from Z-4-benzyloxy-2-buten-1ol
arabino from E-4-benzyloxy-2-buten-1ol
NH2
C13H27
OH
OH NH2
OH
A
C13H27
OH
Sharpless AE
OH
B
L tartrate: D
D tartrate: L
Sharpless AE
L tartrate: D
D tartrate: L
Scheme 6.

11824
G. Righi et al. / Tetrahedron 62 (2006) 11821–11826
(1H, d, J 4.4 Hz, OCH), 3.43 (1H, dd, J 4.4, 9.9 Hz, OCH);
dC (50 MHz, CDCl3) 167.9, 137.5, 128.3, 127.6, 73.2, 66.9,
55.5, 52.2, 51.2. Anal. Calcd for C12H14O4 (222.09): C
64.85; H 6.35. Found: C 65.1; H 6.5.
was stirred at room temperature; after 3 h (TLC monitoring)
the mixture was diluted with CH2Cl2 (10 mL) and washed
with NaHCO3 (15 mL, satd aq). The organic extract was
dried over Na2SO4 and concentrated in vacuo. The residue
was chromatographed on silica gel (hexane/Et2OAc, 8:2)
affording 6 (348 mg, 0.91 mmol) (yield 82% from 1). nmax
(liquid film) 3010, 2950, 1730, 1310 (br), 1200,
1060 cmꢀ1; dH [(CD3)2SO, 80 ꢁC] 7.39–7.23 (5H, m, Ph),
4.58–4.34 (3H, m, CHOH+CH2Ph), 3.75–3.47 (3H, m,
CHN+CH2OBn), 3.65 (3H, s, OMe), 1.72 (3H, s, CH3),
1.55 (3H, s, CH3), 1.43 (9H, s, C(CH3)3); dC [(CD3)2SO,
80 ꢁC] 169.3, 150.9, 137.4, 127.5, 126.9, 126.8, 93.4, 78.9,
74.3, 72.3, 67.5, 60.1, 51.1, 27.5, 25.0, 23.8. Anal. Calcd
for C20H29NO6 (379.20): C 63.31; H 7.70; N 3.69. Found:
C 63.7; H 7.9; N 3.9.
3.1.2. (2S,3R)-4-Benzyloxy-2-bromo-3-hydroxybutanoic
acid methyl ester 3. To a solution of 1 (222 mg, 1 mmol)
in acetone (10 mL) was added NaBr (416 mg, 4 mmol)
and Amberlyst 15 (240 mg). The solution was stirred at
ꢀ20 ꢁC for 6 h (TLC monitoring), then was filtered through
a Celite pad and the solvent evaporated in vacuo affording 3
as yellow oil in almost quantitative yield (300 mg, >98%).
Rf (20% EtOAc/petroleum ether) 0.23. [a]2D0 ꢀ23.7 (c 3.5,
CHCl3); nmax (liquid film) 3200, 3010, 1740, 1260, 1060,
550 cmꢀ1; dH (200 MHz, CDCl3) 7.43–7.27 (5H, m, Ph),
4.59 (1H, d, J 3.7 Hz, CHBr), 4.55 (2H, s, CH2Bn), 4.21–
4.09 (1H, m, CHOH), 3.71 (3H, s, OMe), 3.70–3.49 (2H,
m, CH2OBn), 2.89 (1H, br s, OH); dC (50 MHz, CDCl3)
169.1, 137.2, 128.2, 127.6, 73.3, 70.2, 69.7, 53.2, 48.8.
Anal. Calcd for C12H15BrO4 (303.02): C 47.54; H 4.99.
Found: C 47.8; H 5.1.
3.1.6. (4R,5S)-5-Benzyloxymethyl-3-N-tert-butoxycar-
bonyl-4-formyl-2,2-dimethyl-1,3-oxazolidine 7. To
a
stirred solution of 6 (379 mg, 1 mmol) in toluene (2 mL)
at ꢀ78 ꢁC was added DIBAL (0.8 mL of a solution of
1.5 M in toluene, 1.2 mmol) dropwise. The reaction mixture
was stirred for 2 h (TLC monitoring) and then was quenched
by slowly adding, at ꢀ78 ꢁC, cold MeOH (0.38 mL). The
resulting white emulsion was slowly poured into 6.5 mL of
HCl 1 N with stirring over 15 min and the aqueous mixture
was then extracted with EtOAc (3ꢂ15 mL). The combined
organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo without further purifica-
tion, affording 7 (340 mg, 97%) as colourless oil. nmax
(liquid film) 3010, 2950, 1720, 1390, 1200, 1060 cmꢀ1; dH
[(CD3)2SO, 80 ꢁC] 9.60 (1H, d, J 2.9 Hz, CHO), 7.51–7.29
(5H, m, Ph), 4.73–4.49 (1H, m, CHOCH2OBn), 4.59 (2H,
s, CH2Ph), 4.46 (1H, dd, J 7.3, 2.9 Hz, CHN), 3.78 (1H,
dd, J 10.9, 4.4 Hz, CHaOBn), 3.66 (1H, dd, J 10.9, 3.6 Hz,
CHbOBn), 1.8 (3H, s, CH3), 1.6 (3H, s, CH3), 1.5 (9H, s,
C(CH3)3); dC [(CD3)2SO, 80 ꢁC] 198.7, 151.3, 137.3,
128.4, 128.3, 127.7, 94.9, 80.8, 75.7, 73.5, 67.0, 66.2,
28.1, 26.3, 23.8. Anal. Calcd for C19H27NO5 (349.19): C
65.31; H 7.79; N 4.01. Found: C 65.7; H 7.9; N 4.3.
3.1.3. (2R,3S)-2-Azido-4-benzyloxy-3-hydroxybutanoic
acid methyl ester 4. To a solution of 3 (303 mg, 1 mmol)
in 4 mL of DMF (or DMSO, 4 mL), NaN3 (260 mg,
4 mmol) was added and the mixture was stirred at room tem-
perature for 24 h. Then the reaction was diluted with EtOAc
(8 mL) and washed several times with water and brine. The
combined organic extracts were dried over Na2SO4 and con-
centrated in vacuo affording quantitatively 4 as yellow pale
oil (265 mg, >98%). Rf (20% EtOAc/petroleum ether)
0.20. [a]2D0 +10.7 (c 3.5, CHCl3); nmax (liquid film) 3200,
3010, 2235, 1740, 1250, 1050 cmꢀ1; dH (200 MHz, CDCl3)
7.41–7.26 (5H, m, Ph), 4.53 (2H, s, CH2Ph), 4.20–4.02
(1H, m, CHOH), 3.85–3.65 (2H, m, CH2OBn), 3.74 (3H, s,
OMe), 3.61 (1H, d, J 4.4 Hz, CHN3), 3.13 (1H, br s, OH);
dC (50 MHz, CDCl3) 168.9, 137.3, 128.2, 127.6, 73.3, 70.6,
69.8, 63.2, 52.4. Anal. Calcd for C12H15N3O4 (265.11): C
54.33; H 5.70; N 15.84. Found: C 54.7; H 5.3; N 16.1.
3.1.4. (2R,3S)-4-Benzyloxy-2-tert-butoxycarbonylamino-
3-hydroxybutanoic acid methyl ester 5. A solution of 4
(281 mg, 1 mmol) in EtOAc (2 mL) was hydrogenated at
atmospheric pressure over 10% Pd/C (51 mg) in the presence
of Boc2O (231 mg, 1.2 mmol) for 1.5 h at room temperature.
The solution was then filtered on a Celite pad and concen-
trated in vacuo affording 5 in almost quantitative yield as
yellow pale oil (335 mg, >98%). Rf (30% EtOAc/petroleum
ether) 0.25. [a]D20 ꢀ14.3 (c 2.5, CHCl3); nmax (liquid film)
3250, 3010, 2950, 1740, 1630, 1200, 1060 cmꢀ1; dH
(200 MHz, CDCl3) 7.44–7.27 (5H, m, Ph), 5.5 (1H, br d,
J 7.3 Hz, CHNH), 4.69–4.41 (1H, m, CHOH), 4.50 (2H,
s, CH2Ph), 4.17 (1H, dd, J 7.3, 4.5 Hz, CHNH), 3.67 (3H,
s, OMe), 3.55 (1H, d, J 5.9 Hz, CH2OBn), 3.24 (1H, br s,
OH), 1.44 (s, 9H, C(CH3)3); dC (50 MHz, CDCl3) 170.5,
146.6, 137.5, 128.2, 127.6, 80.2, 73.4, 71.0, 70.5, 56.5,
52.2, 24.2. Anal. Calcd for C17H25NO6 (339.17): C 60.16;
H 7.42; N 4.13. Found: C 60.5; H 7.6; N 4.3.
3.1.7. (4S,5S)-5-Benzyloxymethyl-3-N-tert-butoxycar-
bonyl-2,2-dimethyl-4-hydroxymethyl-1,3-oxazolidine 8.
To an ice-cold solution of 7 (336 mg, 1 mmol) in 12 mL of
isopropyl alcohol/THF (1:1) was added NaBH4 (110 mg,
3 mmol). After the mixture was stirred for 2 h (TLC moni-
toring) and then was portioned between HCl 1 N and EtOAc
until neutrality. The combined organic layers were washed
with brine, dried over Na2SO4, filtered and concentrated
in vacuo without further purification, affording 8 (446 mg,
96%) as colourless oil. nmax (liquid film) 3200, 3010,
2950, 1260, 1200, 1060 cmꢀ1; dH [(CD3)2SO, 80 ꢁC]
7.49–7.28 (5H, m, Ph), 4.59 (2H, s, CH2Ph), 4.34 (1H, ddd,
J 5.8, 5.1 Hz, CHOCH2OBn), 4.15–4.02 (1H, m, CHN),
3.89–3.05 (5H, m, CH2OBn+CH2OH+OH), 1.59 (3H, s,
CH3), 1.53 (3H, s, CH3), 1.47 (9H, s, C(CH3)3); dC
[(CD3)2SO, 80 ꢁC] 151.5, 137.3, 128.4, 127.9, 127.6, 93.2,
80.8, 74.4, 73.8, 67.4, 61.6, 60.4, 28.3, 27.4, 24.6. Anal.
Calcd for C19H29NO5 (351.2): C 64.93; H 8.32; N 3.99.
Found: C 65.2; H 8.5; N 3.6.
3.1.5. (4R,5S)-5-Benzyloxymethyl-3-N-tert-butoxycar-
bonyl-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid
methyl ester 6. A solution of 5 (338 mg, 1 mmol), DMP
(1.3 mL, 10 mmol) and p-TsOH (cat.) in CH2Cl2 (1 mL)
3.1.8. (4S,5S)-5-Benzyloxymethyl-3-N-tert-butoxycar-
bonyl-4-(tert-butyl-diphenyl-silyloxyl-methyl)-2,2-di-
methyl-1,3-oxazolidine 9. To a solution of 8 (338 mg,

G. Righi et al. / Tetrahedron 62 (2006) 11821–11826
11825
1 mmol)dissolvedin5 mLofCH2Cl2 at0 ꢁC, Et3N(0.27 mL,
1.1 mmol) and cat. DMAP were added. After 5 min
TBDPSCl (180 mg, 1.5 mmol) was added; the mixture was
stirred at room temperature for 24 h. After TLC monitoring,
the mixture was quenched with NaHCO3 (10 mL, satd aq).
Aqueous layer was extracted with CH2Cl2 and organic layer
was dried over Na2SO4 and concentrated in vacuo. The crude
mixture was purified by flash chromatography (petroleum
ether/EtOAc, 9:1) affording 9 (547 mg, yield 93%). nmax
(liquid film) 3010, 2950, 1200, 1090, 1060, 970 cmꢀ1; dH
[(CD3)2SO, 80 ꢁC] 7.85–7.55 (5H, m, Ph), 7.51–7.24 (10H,
m, 2Ph), 4.71–4.33 (3H, m, CHOCH2OBn+CH2Ph), 4.11–
3.49 (5H, m, CHN+CH2OBn+CH2OTBDPS), 1.52 (6H, s,
C(CH3)2), 1.11 (9H, s, OC(CH3)3), 1.03 (9H, s, SiC(CH3)3);
dC [(CD3)2SO, 80 ꢁC] 150.8, 137.4, 135.0, 134.9, 134.7,
134.1, 129.1, 128.9, 127.7, 92.8, 79.1, 75.2, 72.8, 68.2,
60.8, 58.8, 26.0, 24.5, 22.8, 18.4. Anal. Calcd for
C35H47NO5Si (589.32): C 71.27; H 8.03; N 2.37. Found: C
71.4; H 8.2; N 2.4.
3.1.11. (4S,5S,10S)-3-N-tert-Butoxycarbonyl-4-(tert-
butyl-diphenyl-silyloxyl-methyl)-5-(10-hydroxypenta-
decyl)-2,2-dimethyl-1,3-oxazolidine 12. To a solution of
(nC14H29)2CuLi freshly prepared in Et2O (10 mL) at
ꢀ20 ꢁC, 11 (497 mg, 1 mmol) was added. The resulting
solution was stirred for 5 h and after TLC monitoring, the
reaction was quenched with saturated NH4Cl solution and
extracted with Et2O; the combined organic extracts were
dried over Na2SO4 and then evaporated to dryness in vacuo.
The crude mixture was purified by flash chromatography
(hexane/EtOAc, 6:4) affording 12 (323 mg, yield 63%).
nmax (liquid film) 3200, 3010, 2950, 1260, 1090, 1060,
990 cmꢀ1; dH [(CD3)2SO, 80 ꢁC] 7.84–7.58 (5H, m, Ph),
7.53–7.32 (5H, m, Ph), 4.26–4.07 (1H, m, CHOH), 3.83
(1H, dd,
J 4.8, 4 Hz, CHO), 3.87–3.41 (3H, m,
CHN+CH2OTBDPS), 2.73 (1H, br d, J 7.3 Hz, OH), 1.52
(3H, s, CH3), 1.45 (3H, s, CH3), 1.48–1.19 (m, 26H), 1.25
(9H, s, OC(CH3)3), 1.06 (9H, s, SiC(CH3)3), 0.88 (3H, t, J
6.0 Hz); dC (50 MHz, CDCl3) 147.3, 135.2, 134.6, 129.2,
127.7, 126.7, 93.7, 79.5, 76.3, 72.4, 61.3, 60.9, 32.5, 32.0,
30.6, 30.3, 30.1, 28.5, 26.5, 24.7, 24.2, 23.5, 22.5, 19.0,
13.5. Anal. Calcd for C42H69NO5Si (695.49): C 72.47; H
9.99; N 2.01. Found: C 72.7; H 10.1; N 3.3.
3.1.9. (4S,5S)-3-N-tert-Butoxycarbonyl-4-(tert-butyl-di-
phenyl-silyloxyl-methyl)-2,2-dimethyl-5-hydroxy-
methyl-1,3-oxazolidine 10. A solution of 9 (589 mg,
1 mmol) in MeOH (2 mL) was hydrogenated at atmospheric
pressure over 10% Pd/C (51 mg) for 3 h at room tempera-
ture; then the solution was filtered on a Celite pad and con-
centrated in vacuo affording 10 (474 mg, 95%) as colourless
oil. nmax (liquid film) 3200, 3010, 2950, 1260, 1090, 1060,
970 cmꢀ1; dH [(CD3)2SO, 80 ꢁC] 7.81–7.61 (5H, m, Ph),
7.55–7.31 (5H, m, Ph), 4.42–4.21 (1H, m, CHOCH2OH),
4.19–3.82 (3H, m, CHN+CH2OH), 3.80–3.51 (2H, m,
CH2OTBDPS), 2.97 (1H, br t, OH), 1.53 (3H, s, CH3), 1.47
(3H, s, CH3), 1.25 (9H, s, OC(CH3)3), 1.07 (9H, s,
SiC(CH3)3); dC [(CD3)2SO, 80 ꢁC] 151.4, 135.6, 135.3,
134.8, 127.8, 127.6, 93.4, 80.0, 75.8, 61.5, 60.8, 59.4, 26.9,
24.6, 23.3, 19.1. Anal. Calcd for C28H41NO5Si (499.28): C
67.30; H 8.27; N 2.80. Found: C 67.7; H 8.4; N 3.0.
Acknowledgements
The authors thank MIUR for partial financial support (Pro-
ject FIRB RBNE017F8N).
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.08.049.
References and notes
3.1.10. (4S,5S)-3-N-tert-Butoxycarbonyl-4-(tert-butyl-di-
phenyl-silyloxyl-methyl)-5-formyl-2,2-dimethyl-1,3-oxa-
zolidine 11. To a solution of 10 (499 mg, 1 mmol) in 7.5 mL
of CH2Cl2, Et3N (0.56 mL, 4 mmol) was added and then the
mixture was stirred at 0 ꢁC. After 10 min, a solution of pyr-
idine/SO3 (477 mg, 3 mmol) in 3 mL of DMSO was poured
into the reaction mixture. After 2 h TLC monitoring, the
mixture was diluted with 20 mL of Et2O and 41 mL of hex-
ane and washed with 19 mL of aq NaHCO3. The combined
organic layers were washed with 39 mL of NaH2PO4 1 M
and then with brine, dried over Na2SO4, filtered and concen-
trated in vacuo. Flash chromatography (petroleum ether/
Et2O, 8:2) afforded 11 as colourless oil (462 mg, yield
93%). nmax (liquid film) 3010, 2950, 1720, 1090, 1060,
980 cmꢀ1; dH [(CD3)2SO, 80 ꢁC] 9.93 (1H, d, J 2.1 Hz,
CHO), 7.79–7.54 (5H, m, Ph), 7.52–7.30 (5H, m, Ph),
4.64–4.51 (1H, m, CHO), 4.49–4.25 (1H, m, CHN), 3.76
(1H, dd, J 10.4, 7.4 Hz, CHaOTBDPS), 3.64 (1H, dd,
J 10.4, 3.7 Hz, CHbOTBDPS), 1.81 (3H, s, CH3), 1.72
(3H, s, CH3), 1.32 (9H, s, OC(CH3)3), 1.12 (9H, s,
SiC(CH3)3); dC [(CD3)2SO, 80 ꢁC] 197.1, 149.3, 136.2,
134.8, 129.4, 127.7, 127.6, 94.8, 79.7, 79.1, 60.8, 60.3,
28.2, 26.5, 24.7, 23.5, 19.0. Anal. Calcd for C28H39NO5Si
(497.26): C 67.57; H 7.90; N 2.81. Found: C 67.8; H 8.1;
N 3.1.
1. For reviews, see: (a) Liao, J.; Tao, J.; Lin, G.; Liu, D.
Tetrahedron 2005, 61, 4715; (b) Koshinen, P. M.; Koshinen,
A. M. P. Synthesis 1998, 1075.
2. Karlsson, K. A. Lipids 1970, 5, 878.
3. Herold, P. Helv. Chim. Acta 1988, 71, 354.
4. (a) Kiso, M.; Nakamura, A.; Tomita, Y.; Hasegawa, A.
Carbohydr. Res. 1986, 158, 101; (b) Zimmermann, P.;
Schmidt, R. R. Liebigs Ann. Chem. 1988, 663; (c) Hirata, N.;
Yamagiwa, Y.; Kamikawa, T. J. Chem. Soc., Perkin Trans 1
1991, 2279; (d) Bettelli, E.; Chinzari, P.; D’Andrea, P.;
Passacantilli, P.; Piancatelli, G.; Topai, A. Korean J. Med.
Chem. 1996, 6, 339; (e) Lu, X.; Byun, H.-S.; Bittman, R.
J. Org. Chem. 2004, 69, 5433; (f) Chaudhari, V. D.; Kumar,
K. S. A.; Dhavale, D. D. Org. Lett. 2005, 7, 5805.
5. (a) Shirota, O.; Nakanishi, K.; Berova, N. Tetrahedron 1999, 55,
13643; (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P.
J.Org.Chem.1990,55, 1439 and referencetherein;(c)Sugiyama,
S.; Honda, M.; Komora, T. Liebigs Ann. Chem. 1990, 1069.
6. Enders, D.; Whitehouse, D. L.; Runsink, J. Chem.—Eur. J.
1995, 1, 382.
7. (a) Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2000, 41,
10309; (b) Martin, C.; Prunk, W.; Bortolussi, M.; Bloch, R.
Tetrahedron: Asymmetry 2000, 11, 1585.
8. Olofsson, B.; Somfai, P. J. Org. Chem. 2003, 68, 2514.

11826
G. Righi et al. / Tetrahedron 62 (2006) 11821–11826
9. (a) Li, S.; Pang, J.; Wilson, W. K.; Schroepfer, G. J., Jr.
Tetrahedron: Asymmetry 1999, 10, 1697; (b) Lin, G.; Shi, Z.
Tetrahedron 2001, 57, 5649; (c) Julina, R.; Herzig, T.;
Bernet, B.; Vasella, A. Helv. Chim. Acta 1986, 69, 368.
10. Righi, G.; Pescatore, G.; Bonadies, F.; Bonini, C. Tetrahedron
2001, 57, 5649.
12. The overall yield of these two steps (>95%) is better than the
yield of the direct reduction with NaBH4/THF or diossane.
(Bianco, A.; Passacantilli, P.; Righi, G. Synth. Commun.
1988, 18, 1765).
13. Tuch, A.; Saniere, M.; Le Merrer, Y.; Depezay, J. C.
Tetrahedron: Asymmetry 1996, 7, 897.
ꢀ
14. Ginesta, X.; Pasto, M.; Pericas, M. A.; Riera, A. Org. Lett.
ꢀ
11. (a) Bonini, C.; Righi, G.; Rumboldt, G. Tetrahedron 1995, 51,
13401; (b) Bonini, C.; Righi, G.; Rumboldt, G. J. Org. Chem.
1996, 61, 3557; (c) Righi, G.; D’Achille, C.; Pescatore, G.;
Bonini, C. Tetrahedron Lett. 2003, 44, 6999.
2003, 5, 3001.
15. Escudier, J.-M.; Baltas, M.; Gorrichon, L. Tetrahedron Lett.
1991, 39, 5345.