Synthesis of D-erythro-sphingosine and D-erythro-ceramide.

Article abstract of DOI:10.1039/b111071n

A 1,2-metallate rearrangment of a higher order cuprate derived from an alpha-lithiated xylal derivative and tridecyllithium is the key step in a synthesis of D-erythro-sphingosine and ceramide. A convenient method for preparing alpha-lithiated glycals from alpha-phenylsulfinyl glycals is also described.

Full text of DOI:10.1039/b111071n

Synthesis of
D
-erythro-sphingosine and -erythro-ceramide
D
Jacqueline E. Milne,a Krzysztof Jarowicki,a Philip J. Kocienski*a and Jorge Alonsob
a Department of Chemistry, Leeds University, Leeds, UK LS2 9JT
b Instituto Universitario de Química Organometállica ‘Enrique Moles’, Universidad de Oviedo, Julián
Clavería 8 33071-. Oviedo, Spain
Received (in Cambridge, UK) 4th December 2001, Accepted 11th January 2002
First published as an Advance Article on the web 1st February 2002
A 1,2-metallate rearrangment of a higher order cuprate
derived from an a-lithiated xylal derivative and tridecylli-
thium is the key step in a synthesis of -erythro-sphingosine
D
and ceramide. A convenient method for preparing a-
lithiated glycals from a-phenylsulfinyl glycals is also de-
scribed.
Sphingolipids anchor carbohydrates to cell surfaces. Enzymatic
cleavage of sphingolipids releases ceramide (1), which plays a
central role in signal transduction; it inhibits cell growth and
induces apoptosis. Strip ceramide of its N-acyl group and the
residual
D
-erythro-sphingosine (2) is itself an inhibitor of
protein kinase C.1,2 We now add a fresh brick to the pyramid of
sphingosine syntheses3–5 that is noteworthy for three reasons.
We report (a) two efficient methods for the synthesis of a-
lithiated glycals; (b) the first example of a 1,2-metallate
rearrangement of glycal derivatives; and (c) a rare O–C–O
silicon shuttle that imparts strategic benefit to our approach.
Scheme 1 Reagents and conditions: (i) mCPBA (2.1 equiv.), NaHCO3 (7.5
equiv.), CH2Cl2, 0 °C to rt, 12 h (80%); (ii) MeLi (1.5 equiv.), THF, 278
°C, 20 min (89%); (iii) Bu3SnMgBr·LiBr (2 equiv.), Ni(0) (0.1 equiv.), PPh3
(0.2 equiv.), THF–Et2O, 278 to 20 °C, 12 h (82%); (iv) BuLi (1 equiv.),
THF–Et2O, 278 °C, 15 min; (v) H2O2 (3 equiv.), (NH4)2MoO4 (6 mol%),
EtOH, 0 °C, 12 h; (vi) LDA (2.5 equiv.), THF, 278 °C, 2 h (97%); (vii) t-
BuLi (1 equiv.), THF–Et2O, 278 °C, 5 min.
tridecyllithium (4.4 equiv.) generated the alkenylsilane 10 in
60–68% overall yield after aqueous workup. The product can be
explained by a 1,2-metallate rearrangement of the higher order
cuprate 8 with inversion of configuration to give the alkenyl
cuprate 9 which undergoes a selective intramolecular O?C
silyl transfer of the C3O–silyl group. Crucial to the success of
the reaction were conditions that favoured the stability of the
putative higher order cuprate intermediate 8: (a) low initial
reaction temperature; (b) use of Et2O rather than THF as
solvent; (c) the presence of a large excess of SMe210 and (d) the
use of CuBr·SMe2 freshly prepared11 by reduction of CuBr2
The synthesis of the crucial a-lithiated glycal intermediate 6
is summarised in Scheme 1. 1-Thio-b- -xylopyranoside, pro-
D
tected as its tris(tert-butyldimethylsilyl) ether 3, was oxidised to
the corresponding sulfone. Subsequent b-elimination using
MeLi as base afforded the a-phenylsulfonyl glycal derivative 4
in 72% yield. A new Ni(0)-catalysed coupling of tributyl-
stannylmagnesium bromide converted the sulfone 4 to the
corresponding stannane 5 in 82% yield on a 20 mmol scale.6
Transmetallaton with BuLi then gave the desired lithium
derivative 6. A shorter synthesis of 6 from the thioglycoside 3
that avoided tin intermediates began with oxidation of the
thioether to the corresponding sulfoxide with hydrogen per-
oxide catalysed by ammonium molybdate and subsequent b-
elimination of t-BuMe2SiOLi with LDA to give the stable,
storable a-phenylsulfinyl glycal 7 in 69% yield from 3.
Reaction of sulfoxide 7 with t-BuLi at 278 °C resulted in
phenylsulfinyl-lithium exchange and generation of a-lithiated
glycal 6 in less than 5 min. The latter process is an adaptation of
a recent synthesis of glycosyllithiums from glycosyl sulfoxides
based on phenylsulfinyl–lithium exchange and solves a long-
standing problem in metallated glycal chemistry.7
The key step in our synthesis is a Cu( )-mediated 1,2-metal-
I
late rearrangement shown in Scheme 2.8,9 Reaction of the a-
lithiated glycal 6 with CuBr·SMe2 (1.1 equiv.) and n-
Scheme 2
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CHEM. COMMUN., 2002, 426–427
This journal is © The Royal Society of Chemistry 2002

with sodium sulfite.12 A further factor that contributed to good
yields in the transformation depicted in Scheme 2 was the use of
4.4 equiv. of tridecyllithium.
ysis of the benzylidene acetal 14,15 using standard literature
procedures (Ph3P, H2S)15,17 was either slow or gave several
products and modest yields at best but reduction with Zn and
To complete the synthesis (Scheme 3), the 1,3-diol 10 was
protected as its benzylidene acetal derivative 11 and the
remaining O-TBS ether cleaved with tetrabutylammonium
fluoride. The C-TBS group was then transferred back to oxygen
(Brook rearrangement)13,14 by treating alcohol 12 with sodium
hydride and 15-crown-5 in refluxing THF to give a mixture of
alcohol 13 and its O-TBS ether derivative. The mixture was
treated with tetrabutylammonium fluoride to give the known
alcohol 1315 in 93% yield whence a Mitsunobu reaction using
diphenylphosphoryl azide16 afforded the inverted azide 1415 in
59% yield. Reduction of the azide 15, derived from methanol-
ammonium chloride (40 equiv. each) in methanol afforded -
D
erythro-sphingosine (2) as a white waxy solid. Owing to the
instability of 2 towards recrystallisation and column chromatog-
raphy, it was characterised as the ceramide 1, prepared by
reaction of crude 2 with p-nitrophenyl stearate.18 Synthetic 1
gave mp 96–97 °C (lit mp 97–98 °C),19 [a]D 23.0 (lit [a]D
1
23.1),19 500 MHz H and 125 MHz 13C NMR spectroscopic
data were consistent with data reported for the natural
product.19
In conclusion, we have devised a 9-step synthesis of the
known
D
-erythro-sphingosine intermediate 13 (9–12% overall)
from cheap
D
-xylose using a 1,2-metallate rearrangement as the
key step. We have also described a method for making a-
lithiated glycals from a-phenylsulfinyl glycals that is fast,
efficient and devoid of tin.
We thank the EPSRC, Pfizer Central Research, Merck Sharp
& Dohme, and AstraZeneca Pharmaceuticals for support; the
Carnegie Foundation and Syngenta for scholarships to J. E. M.
and FICYT for a grant to J. A. We also thank Rebecca Davie and
Nynke Barkhuÿsen for additional experiments.
Notes and references
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Scheme 3 Reagents and conditions: (i) PhCH(OMe)2 (5 equiv.), p-TsOH
(12 mol%), CH2Cl2, rt, 2 h (82%); (ii) Bu4NF (1.2 equiv), THF, rt, 12 h
(90%); (iii) NaH (60 mol%), 15-crown-5 (60 mol%), THF, reflux, 14 h; (iv)
Bu4NF (1.2 equiv.) (93%): (v) PPh3 (2 equiv.), diphenylphosporyl azide (2
equiv.), diisopropyl azodicarboxylate (3 equiv.), PhMe, rt, 12 h, (59%); (vi)
p-TsOH (42 mol%), MeOH, rt, 12 h (82%); (vii) Zn powder (40 equiv.),
NH4Cl (40 equiv.), MeOH, rt, 12 h.
19 R. Julina, T. Herzig, B. Bernet and A. Vasella, Helv. Chim. Acta, 1986,
69, 368.
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