Straightforward Synthesis of Sphinganines via a Serine-derived Weinreb Amide

Article abstract of DOI:10.1021/jo030355b

Sphinganines can be synthesized in just three steps from easily prepared serine-derived Weinreb amide 4. Pre-deprotonation of the acidic (N-H and O-H) protons of 4 allows for its efficient conversion to amino ketones 5. Such ketones can be selectively reduced to either erythro- or threo-sphinganines. Partially protected sphinganines 11 are also readily accessible in five steps from 4. Thus, Weinreb amide 4 represents one of the most versatile templates described to date for sphinganine synthesis.

Full text of DOI:10.1021/jo030355b

SCHEME 1
Str a igh tfor w a r d Syn th esis of Sp h in ga n in es
via a Ser in e-d er ived Wein r eb Am id e
Regina C. So, Rachel Ndonye, Douglas P. Izmirian,
Stewart K. Richardson, Robyn L. Guerrera, and
Amy R. Howell*
Department of Chemistry, University of Connecticut,
Storrs, Connecticut 06269-3060
amy.howell@uconn.edu
Received November 18, 2003
at C4 of the sphingoid base),9 although it is obvious that
sphinganines are available in only one step from the
corresponding sphingosines by reduction. Sphinganines
have been synthesized from sugars,10,11 from the amino
acid, serine,12-17 and from racemic precursors by a variety
of asymmetric strategies.18-22 In general, the most com-
mon and straightforward syntheses exploit serine deriva-
tives, with routes from serine to the sphinganines
generally being six or more steps. By contrast, our
current approach to sphinganines 7 is a four-step, three-
purification procedure from commercially available Boc-
serine (Scheme 1).
Our initial plan for enhancing the efficiency of sphin-
ganine synthesis was to circumvent the modest meth-
ylenation yield in our previous approach (i.e., conversion
of 1 to 2) by directly reacting lactone 1, available in one
step from Boc-serine,23 with a Grignard or lithium
reagent. Not unexpectedly, even with sub-stoichiometric
amounts of the organometallic reagent, yields were low,
and the product ketones were contaminated with difficult
to separate tertiary alcohols. However, lactone 1 could
be converted in high yield to Weinreb amide 4. A
literature search revealed that 4 could be prepared
directly from Boc-serine.24 In fact, using the method
described, no purification of 4 was required. When 4 was
treated with excess n-BuLi (3.5 equiv) at -78 °C, ketone
5a was isolated in 67% yield. Reaction with excess,
commercially available tetradecylmagnesium chloride
Abstr a ct: Sphinganines can be synthesized in just three
steps from easily prepared serine-derived Weinreb amide 4.
Pre-deprotonation of the acidic (N-H and O-H) protons of
4 allows for its efficient conversion to amino ketones 5. Such
ketones can be selectively reduced to either erythro- or threo-
sphinganines. Partially protected sphinganines 11 are also
readily accessible in five steps from 4. Thus, Weinreb amide
4 represents one of the most versatile templates described
to date for sphinganine synthesis.
We are interested in glycosphingolipids because of their
ability to modulate immune responses.1-3 For example,
the â-galactosyl ceramide, plakoside A, isolated from the
marine sponge Plakortis simplex, was found to be a
noncytotoxic immunosuppressant.4,5 On the other hand,
KRN7000, an R-galactosyl ceramide identified from SAR
studies at Kirin Brewery, has been shown to be a potent
activator of the immune system.6,7 The preparation of the
sphingoid base represents one of the major challenges
in the synthesis of glycosphingolipids. We recently de-
scribed the exploitation of serine-derived 1,5-dioxaspiro-
[3.2]hexane 3 as a template for the construction of both
aminodiol and aminotriol sphingoid bases, illustrated by
the conversion of 3 to D-erythro-dihydrosphingosine and
D-xylo-phytosphingosine (Figure 1).8 In this paper, we
describe a more direct route to dihydrosphingosines
(sphinganines) from serine-derived Weinreb amide 4.
This approach (Scheme 1) represents one of the most
versatile, convenient, and direct methods reported to date
for the preparation of sphinganines.
(9) Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998, 1075-1091.
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R. J . K. J . Org. Chem. 2002, 67, 1802-1815.
Literature syntheses of sphinganines are not as abun-
dant as those for sphingosines (which have a double bond
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10.1021/jo030355b CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/08/2004
J . Org. Chem. 2004, 69, 3233-3235
3233

F IGURE 1. Sphingoid bases from serine-derived 1,5-dioxaspiro[3.2]hexane 3.
TABLE 1. Rea ction s of Ser in e-Der ived Wein r eb Am id e
4 w ith Sa cr ificia l Ba ses a n d Or ga n om eta llic Rea gen ts
SCHEME 2
entry sacrificial base
RM (equiv)
product % yield
1
2
3
4
5
6
7
8
9
n-BuMgCl
s-BuMgCl
s-BuMgCl
s-BuMgCl
n-BuLi
n-BuMgCl
s-BuMgCl
s-BuMgCl
n-BuLi
n-BuMgCl (1.2)
n-BuMgCl (1.2)
n-BuMgCl (1.9)
n-BuLi (1.2)
5a
5a
5a
5a
5a
5b
5b
5b
5b
5c
5c
5c
69
71
82
80
70
63
70
78
66
n-BuLi (1.2)
n-C14H29MgCl (1.2)
n-C14H29MgCl (1.2)
n-C14H29MgCl (1.9)
n-C14H29MgCl (1.2)
n-C15H31MgBr (1.2)
n-C15H31Li (1.2)
n-C15H31Li (1.2)
10
11
12
s-BuMgCl
s-BuMgCl
n-BuLi
73
<10a
12a
a
See text.
provided 5b in 53% yield. However, the use of multiple
equivalents of expensive or difficult to prepare organo-
metallic reagents would be unacceptable. For our pro-
gram of synthesizing glycosphingolipids, we had exam-
ined the use of a sacrificial lithium base (t-BuLi, 1.2
equiv) with partially protected Weinreb amide 13 (see
Scheme 2). Subsequent addition of tetradecyllithium at
-78 °C, followed by warming to rt, provided 8 in 44%
yield. A recent report of the use of sacrificial Grignard
reagents with Weinreb amides possessing Boc-amide
substituents25 prompted us to examine similar conditions
with 4, and herein, we report our straightforward ap-
proach to free and partially protected sphinganines 7 and
11.
or s-BuMgCl as the sacrificial base provided similar
yields of product (entries 1 vs 2 and 6 vs 7). Unlike the
outcomes observed in the studies of Liu et al.,25 use of
an organolithium agent as a sacrificial base did not give
substantially lower yields (entries 4 vs 5 and 7 vs 9).
Extended reaction times did not improve the yields.
Higher yields were achieved with more nucleophile.
Because of obvious concerns about alternative ketone
products, we chose not to employ more than 2 equiv of
the sacrificial base. Mass balance could be accounted for
by recovered Weinreb amide 4. When the deprotonation
and nucleophilic addition were conducted at 0 °C, no
product was isolated.
Unsatisfactory results were obtained with pentadecyl-
lithium (entries 11 and 12), prepared from pentadecyl-
iodide and excess t-BuLi, as desribed by Bailey and
Punzalan.26 Long-chain lithium reagents generated by
the Bailey procedure can be used with compound 13 when
the reaction is run at a lower temperature (-50 °C).
Weinreb amide 4 was treated with 2.0 equiv of either
n-BuMgCl or s-BuMgCl at -15 °C, followed by the
addition of the nucleophile. The solutions were then
warmed to room temperature and stirred for 4 h. The
results are shown in Table 1. The use of either n-BuMgCl
(25) Liu, J .; Ikemoto, N.; Petrillo, D.; Armstrong, J . D., III. Tetra-
hedron Lett. 2002, 43, 8223-8226.
(26) Bailey, W. F.; Punzalan, R. E. J . Org. Chem. 1990, 55, 5404-
5406.
3234 J . Org. Chem., Vol. 69, No. 9, 2004

The results shown in Table 1 demonstrate that pre-
deprotonation of Weinreb amide 4 with an inexpensive
sacrificial base provides efficient access to aminoketone
precursors of sphinganines. The protocol is simple and
avoids the use of large excesses of Grignard or lithium
reagents that might be costly or difficult to prepare. As
previously shown by Hoffman,27 diastereoselective reduc-
tion of the protected aminoketones 5 is readily achieved,
and deprotection completes the synthesis of the sphin-
ganines 7.
yield (94%), could be converted to ketone 8 with the use
of only 1 equiv of a sacrificial base. However, we found
that 8 (and the corresponding C-18 homolog) prepared
by this procedure was contaminated with a small amount
of an inseparable (and as yet unidentified) impurity.
In conclusion, sphinganines are found in an increasing
variety of biologically important molecules. Weinreb
amide 4, readily accessible from serine, represents a
versatile template for the efficient preparation of either
unprotected or partially protected sphinganines. The use
of a sacrifical Grignard or lithium reagent circumvents
the need for full protection.
In glycosylations of ceramides it is common for the OH
groups, other than the OH donor at C1 of the sphingoid
base, to be protected. Differential protection of C1 and
C3 of the sphingoid base can be achieved conveniently
by protecting ketones 5. For example, ketone 5b was
protected as the corresponding silyl ether 8 (Scheme 2).
The reduction of 8 was highly stereoselective (only one
Ack n ow led gm en t. We thank Marisa DiDonato for
preliminary studies. We thank Dr. Martha Morton for
assistance with NMR experiments and Professor Wil-
liam Bailey for helpful discussions. This manuscript is
based upon work supported by the National Science
Foundation (NSF) under Grant No. CHE-0111522. A
Bristol-Myers Squibb Summer Undergraduate Fellow-
ship to R.L.G. is gratefully acknowledged.
1
diastereomer was observed in H NMR’s of crude reaction
mixtures), and the hydroxyl group at C3 of 9 was
benzylated. Both the silyl protecting group and the Boc-
amide were cleaved upon treatment of 10 with aqueous
TFA, providing the monoprotected sphinganine 11 ef-
ficiently.
In theory, the use of a sacrificial base would be
unnecessary if 4 were converted to ketal 12. Our results
with 12 were consistent with those reported by Guanti
and co-workers28 in that, surprisingly, 12 did not react
with long-chain organometallic reagents. It was also
noteworthy that the silyl ether 13, derived from 4 in high
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data, as well as copies of high-
resolution 1H and 13C NMR spectra for those new compounds
for which elemental analyses are not reported. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O030355B
(27) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J . Org. Chem.
2002, 67, 1045-1056.
(28) Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Riva,
R.; Rocca, V. Tetrahedron 1995, 51, 8121-8134.
J . Org. Chem, Vol. 69, No. 9, 2004 3235