A highly efficient and versatile synthesis of D- and L-erythro-sphinganine

Article abstract of DOI:10.1055/s-2001-18784

An expedient convergent synthesis of naturally occurring C₁₈-erythro-sphinganine (dihydrosphingosine, 1) is presented. Chiral protected 2-amino-1,3,4-butanetriol 6 is readily transformed into oxazolinyl oxirane building block 9, which is alkylated by a copper mediated S_N2 type nucleophilic substitution with tetradecylmagnesium chloride. This method promises to be suited for largescale syntheses and for rapid access to sphinganine analogues modified in the backbone.

Full text of DOI:10.1055/s-2001-18784

LETTER
1965
A Highly Efficient and Versatile Synthesis of D- and L-erythro-Sphinganine
c
A
Highly
E
fficien
h
t
and
V
ersa
r
i
esis of
s
D
-
and
L
-
t
e
r ythr o
i
-Sphin
a
ganine n Hertweck,*a Pavel Šebek,b Aleš Svato
a
Hans-Knöll-Institute for Natural Products Research, Beutenbergstrasse 11a, 07745 Jena, Germany
Fax +49(3641)656699; E-mail: hertweck@pmail.hki-jena.de
b
c
BASF spol. s r.o., Šafránkova 3, 155 00 Prague 5, Czech Republic
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic
Received 1 August 2001
bases from natural and synthetic sources are known that
are often endowed with miscellaneous biological proper-
ties.7 Many methods have thus been developed for sphin-
ganine synthesis, which involve e.g. addition of
Abstract: An expedient convergent synthesis of naturally occur-
ring C18-erythro-sphinganine (dihydrosphingosine, 1) is presented.
Chiral protected 2-amino-1,3,4-butanetriol 6 is readily transformed
into oxazolinyl oxirane building block 9, which is alkylated by a
copper mediated SN2 type nucleophilic substitution with tetradecyl- nucleophilic reagents to amino aldehydes or amino es-
ters,8–13 hydrogenation of sphingosine derivatives,14 chain
magnesium chloride. This method promises to be suited for large-
elongation of carbohydrate precursors,15 or substitution of
scale syntheses and for rapid access to sphinganine analogues mod-
ified in the backbone.
a reactive oxygen species with azide on a preformed sph-
inganine skeleton.16–18
Key words: amino alcohols, coupling, natural products, sphin-
golipids, stereoselective synthesis
In the course of our synthetic studies towards sphingolipid
metabolites,14,19,20 we were motivated to establish a prac-
tical synthesis of sphinganine making use of the chiral
Sphingolipids, such as ceramides, cerebrosides and gan-
building blocks21 6 and ent-6 that are inexpensive indus-
gliosides, are essential components of the cell membrane
trial intermediates. The enantiopure protected 2-aminobu-
and play unique and critical roles in physiological pro-
tane-1,3,4-triols 6 and ent-6 are available in bulk
cesses like cell recognition, signal transduction and apop-
quantities by a (large scale) binaphthol titanium-catalyzed
tosis.1–3 Common to this diverse group of natural products
asymmetric aminolysis of the corresponding meso-ep-
is a sphingoid base scaffold with a long aliphatic chain
oxide.21 Compound 6 has been used in the synthesis of
and a polar 2-aminoalkanol head group. The most abun-
nelfinavir22,23 and is now commercially available in both
dant sphingoid bases in nature are sphingosine (2),
enantiomeric forms.24
phytosphingosine (3), and their shared biosynthetic pre-
Since the biological activity of sphingoid bases can vary
substantially with structural modifications of the alkyl
side chain, the protocol should allow for the synthesis of
both sphinganine and sphinganine analogs modified in the
tail. For this purpose, a highly convergent route is desir-
able, setting the configuration of the polar head group at
an early stage. Attachment of functionally diverse tail
groups by means of a compatible method would then
allow the synthesis of a wide array of derivatives and an-
alogues. Ultimately, no further manipulation of the side
chain would be required. These prerequisites are ideally
matched by nucleophilic ring opening of an appropriate
oxirane building block 4 with a carbanion equivalent
(Scheme 1). The versatile building blocks 6 and ent-6
could be readily transformed into functionalized oxiranes
9 or ent-9, which would be well suitable for the synthesis
of D- and L-erythro-sphinganine 1 and their analogs.
cursor C18-D-erythro-sphinganine (dihydrosphingosine,
1) (Figure).4
OH
HO
NH2
1
OH
HO
NH2
2
OH
HO
NH2 OH
3
Figure
OH
O
1. Nu (SN2)
Nu
Members of the sphinganine family have been found to be
inhibitors of protein kinase C, hence mediating a variety
of cellular responses.5,6 To date more than 60 sphingoid
R1O
HO
N
2. Deprotection
NH2
R2
R3
4 or ent-4
Scheme 1
5 or ent-5
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1965,1967,ftx,en;G16901ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1966
C. Hertweck et al.
LETTER
OMes
O
O
O
O
i)
OH
ii)
iii)
O
O
N
OMes
NH
OH
H2N
Ph
Ph
6 or ent-6
7 or ent-7
8 or ent-8
OH
O
O
N
O
N
Ph
Ph
10 or ent-10
1 or ent-1
iv)
9 or ent-9
Scheme 2 Reactions and conditions: i) a: 1 equiv PhCOCl, 2.5 equiv 10 % aq. NaHCO3–DCM, r.t., 2 h; b: 1.2 equiv MesCl, 1.5 equiv TEA,
DCM, 8 °C, 1 h, 92 %; ii) 3 equiv BF3 OEt2, DCM, 20 °C, 1 d, 63 %; iii) a: 1 equiv t-BuOK, THF, 0 °C, 4 h; b: 2 equiv ClMgC14H29, 10 mol%
CuCN, THF, –78 °C to 0 °C, 2 h, 85 % (over two steps); iv) 2 M HCl, THF, 0 °C to r.t., 5 h, then aq. NaOH, MeOH, 80 °C, 1 h, 88 %.
The synthesis of the desired oxazolinyl oxirane 9 is the known triacetyl sphinganine.13,17 In analogy, the enan-
straightforward (Scheme 2). Amino alcohol 6 was ben- tiomeric L-erythro-sphinganine is readily accessible from
zoylated using benzoyl chloride in biphasic dichlo- ent-6.
romethane (DCM)/aqueous NaHCO3. The dried amide
solution was carried on without purification to the mesy-
late 7 by treatment with triethylamine and mesyl chloride
in DCM (88% yield from 6). Subsequent boron trifluoride
mediated diol deprotection of 7 with concomitant in-
tramolecular cyclization gave oxazoline 8. A full differen-
tiation of the two primary hydroxyl groups was achieved
In conclusion, optically pure D- and L-erythro-sphinga-
nine can be prepared from precursors 6 and ent-6, which
are industrial intermediates. The efficient synthetic route
was accomplished without any expensive reagents or
complex procedures. In addition, no chromatographic pu-
rification is required for any of the intermediates. Accord-
ing to its convergent nature, this approach is ideally suited
by the condensation of the amide and its vicinal hydroxyl
for accessing sphinganine analogs modified in the back-
group, yielding the favored five-membered heterocycle.22
bone. Syntheses of novel sphinganine derivatives using
this protocol are in progress and will be reported in due
course.
-Hydroxymesylate 8 was then converted into the corre-
sponding epoxide 9 by means of potassium tert-butoxide
in THF at 0 °C. SN2 displacement proceeded with com-
plete inversion of the asymmetric center at C-3 and pro-
Acknowledgement
vided the desired erythro configuration. The rather
unstable epoxide 9 was then directly subjected to a nu-
cleophilic ring-opening with a Gilman cuprate, in situ
formed from commercially available tetradecylmagne-
sium chloride and CuCN (10 mol%) at –78 °C in THF.20
Copper(I) assisted ring openings of functionalized ox-
iranes have previously been reported to proceed highly re-
giospecifically.20,25,26 In fact, the protected C18-D-erythro-
sphinganine 10 was obtained in high yield (85% from 8)
and without any side reactions.27 The regioisomer could
not be detected by means of LC/MS and NMR spectros-
copy.
This work was partially supported from IOCB (research project Z4
055 905).
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75–76 °C; Lit: 74–76 °C (petroleum ether);31 22: +5.2 (c
D
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D
CHCl3–ethanol = 9:1)9}, as well as conversion of 1 into
Synlett 2001, No. 12, 1965–1967 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Highly Efficient and Versatile Synthesis of D- and L-erythro-Sphinganine
1967
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hexane gave 8 as colorless crystals (0.76 g, 63%).22 Mesylate
8 (0.76 g, 2,2 mmol) was dissolved in THF
(10 mL) and treated with t-BuOK (245 mg, 2.4 mmol) in
THF (10 mL) at 0 °C. After the solution was stirred at 0 °C
for 4 h, it was washed with 10% sodium phosphate buffer
(pH 7.0) and extracted with DCM. The organic phase was
dried over Na2SO4 and concentrated under reduced pressure.
To a cooled (–78 °C) solution of the crude epoxide 9 in THF
(10 mL) were added CuCN (20 mg, 10 mol%) and
ClMgC14H29 (4.5 mL, 1.0 M solution in THF) at –78 °C. The
solution was stirred for 15 min at –78 °C and was then
slowly warmed to 0 °C over the period of 2 h. After
quenching with sat. NH4Cl, the solution was extracted with
DCM, dried over Na2SO4 and concentrated under reduced
pressure. Crystallization of the residue from DCM–hexane
gave protected sphinganine 10 (725 mg, 85%, over two
steps) as colorless solid. mp 95–97 °C, Anal. calcd. for
C25H41NO2: C, 77.47; H, 10.66; N, 3.61. Found: C, 77.51; H,
2.3 (c = 1.2, CHCl3); 1H NMR (300
25
(24) Interpharma Praha a.s., Komo anská 955, 140 00 Praha 4 -
Kom any, Czech Republic.
10.62; N, 3.59.
:
D
MHz, CDCl3) 0.88 (3H, t, J = 6.7 Hz), 1.25 (18 H, m), 1.49
(2 H, m), 1.68 (1 H, m), 3.92 (1 H, m), 4.15–4.24 (1 H, dd, J
= 8.8, 9.9 Hz), 4.28 (1 H, dd, J = 8.6, 4.6 Hz), 4.46 (2 H, d,
J = 8.6 Hz), 7.29–7.47 (3 H, m), 7.81–7.92 (2 H, m); IR
(KBr): 3153, 1648, 1192 cm–1. MS/MS (ESI, 100 eV): m/z =
388, 370, 266, 164, 122.
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at r.t. until TLC analysis showed complete consumption of 7
(ca. 1 d). After quenching the reaction with 4-methyl-
morpholine (2 mL, 1.5 M aqueous solution) at 0 °C and
diluting the mixture with DCM (50 mL), the organic phase
was separated, washed with brine, dried over Na2SO4 and
concentrated. Crystallization of the residue from ethanol–
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Synlett 2001, No. 12, 1965–1967 ISSN 0936-5214 © Thieme Stuttgart · New York