Synthesis of D-erythro-dihydrosphingosine and D-xylo-phytosphingosine from a serine-derived 1,5-dioxaspiro[3.2]hexane template

Article abstract of DOI:10.1021/ol0200448

Matrix presented A serine-derived 1,5-dioxaspiro[3.2]hexane template is shown to be a useful precursor for both aminodiol and aminotriol sphingoid bases by its conversion to D-erythro-dihydrosphingosine and D-xylo-phytoshingosine.

Full text of DOI:10.1021/ol0200448

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1719-1722
Synthesis of
D-erythro-Dihydrosphingosine and
D-xylo-Phytosphingosine from a
Serine-Derived 1,5-Dioxaspiro[3.2]hexane
Template
Albert J. Ndakala, Mehrnoosh Hashemzadeh, Regina C. So, and Amy R. Howell*
Department of Chemistry, UniVersity of Connecticut, Storrs, Connecticut 06269-3060
amy.howell@uconn.edu
Received February 26, 2002
ABSTRACT
A serine-derived 1,5-dioxaspiro[3.2]hexane template is shown to be a useful precursor for both aminodiol and aminotriol sphingoid bases by
its conversion to D-erythro-dihydrosphingosine and D-xylo-phytoshingosine.
Interest in glycosphingolipids has increased in recent years,
in part due to the recognition that they modulate immune
responses.1-3 For example, the â-galactosyl ceramide, plako-
side A, isolated from the marine sponge Plakortis simplex,
was found to be a noncytotoxic immunosuppressant.4,5 On
be a potent activator of the immune system.6,7 One of the
most challenging aspects of synthesizing glycosphingolipids
is the construction of the sphingoid base, the aminodiol or
aminotriol, portion of the molecules. We have been interested
in exploiting the reactivity and level of functionality housed
in 1,5-dioxaspiro[3.2]hexanes,8 a class of compounds whose
preparation we pioneered.9 We felt that serine-derived
(1) Merrill, A. H.; Sweeley, C. C. In Biochemistry of Lipids, Lipoproteins
and Membranes; Vance, D. E., Vance, J., Eds.; Elsevier: Amersterdam,
1996; Vol. 31, pp 309-339.
(2) Hannum, Y. A. Sphingolipid-Mediated Signal Transduction; R. G.
Landes Company: Austin, 1997.
(3) Porcelli, S. A.; Modlin, R. L. Annu. ReV. Immunol. 1999, 17, 297-
329.
(4) Nicolaou, K. C.; Li, J.; Zenke, G. HelV. Chim. Acta 2000, 83, 1977-
2006.
(5) Costantino, V.; Fattorusso, E.; Mangoni, A.; Di Rosa, M.; Ianaro,
A. J. Am. Chem. Soc. 1997, 119, 12465-12470.
(6) Kawano, T.; Cui, J.; Koezuka, Y.; Toura, I.; Kaneko, Y.; Motoki,
K.; Ueno, H.; Nakagawa, R.; Sato, H.; Kondo, E.; Koseki, H.; Taniguchi,
M. Science 1997, 278, 1626-1629.
(7) Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.; Sakai, T.; Sawa,
E.; Yamaji, K.; Koezuka, Y.; Kobayashi, E.; Fukushima, H. J. Med. Chem.
1995, 38, 2176-2187.
the other hand, KRN7000, an R-galactosyl ceramide identi-
fied from SAR studies at Kirin Brewery, has been shown to
(8) Howell, A. R.; Ndakala, A. J. Org. Lett. 1999, 1, 825-827.
10.1021/ol0200448 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/18/2002

dioxaspirohexane 1 represented a versatile and novel template
for the construction of diverse sphingoid bases, as illustrated
in Figure 1.10 In this Letter, the utility of 1 is demonstrated
Scheme 1
entry to aminodiol sphingoid bases (see Figure 1, path a).
The ketones 2 produced by such reactions would need only
stereoselective reduction and deprotection to provide dihydro-
sphingosines. To illustrate this, we prepared D-erythro-
dihydrosphingosine, as shown in Scheme 1. Our first goal
was to ascertain the appropriate organometallic reagent to
effect the conversion of 1 to 7. Not surprisingly, reaction of
1 with either organolithium or Grignard reagents led to
complex mixtures, since the initial ketonic products appeared
to be at least as reactive as 1. Organocuprates are reported
to be more effective than organomagnesium or organolithium
reagents in opening oxiranes.13,14 Reaction of 1 with the
mixed higher order thienylcuprate 1015 gave 11 in 24% yield.
When the mixed higher order alkyl cuprate 12 was used,16
11 was isolated in 43% yield. Gratifyingly, when mixed alkyl
Figure 1. General strategy for sphingoid base synthesis from 1.
by its conversion to D-erythro-dihydrosphingosine and D-
xylo-phytosphingosine.
Our route to dioxaspirohexane 1 is shown in Scheme 1.
We have previously described the preparation of this
compound.9 Thus, â-lactone 4 was secured from the protected
serine under Mitsunobu conditions, as described by Ved-
eras.11 Methylenation provided 5. Oxidation with dimethyl-
dioxirane (DMDO) was quantitative and clean, and 112 was
used without further purification.
cuprate 6 was employed, ketone 7 was isolated in 65% yield
(Scheme 1). Stereoselective reduction of 7 with lithium tris-
(tert-butoxy)aluminum hydride17 provided solely the erythro-
diastereomer 8 in excellent yield, and treatment with TFA
gave D-erythro-dihydrosphingosine. This was converted to
the corresponding known triacetate 9 to confirm its identity.
We envisaged that both sphingosines and phytosphingo-
sines could be procured from a protected aldehyde, such as
We felt that ring-opening of 1 by an appropriate organo-
metallic reagent represented a particularly straightforward
(9) Ndakala, A. J.; Howell, A. R. J. Org. Chem. 1998, 63, 6098-6099.
(10) Approaches to sphingosines (Koskinen, P. M.; Koskinen, A. M. P.
Synthesis 1998, 1075-1091. Curfman, D.; Liotta, D. Methods Enzymol.
2000, 311, 391-440) and phytosphingosines (Howell, A. R.; Ndakala, A.
J. Curr. Org. Chem., in press) have been recently reviewed. For recent
syntheses of dihydrosphingosines, see: (a) Hertweck, C.; Sebek, P.; Svatos,
A. Synlett 2001, 1965-1967. (b) Fernandes, R. A.; Kumar, P. Eur. J. Org.
Chem. 2000, 3447-3449. (c) Azuma, H.; Tamagaki, S.; Ogino, K. J. Org.
Chem. 2000, 65, 3538-3541. (d) Fernandes, R. A.; Kumar, P. Tetrahe-
dron: Asymmetry 1999, 10, 4797-4802. (e) Villard, R.; Fotiadu, F.; Buono,
G. Tetrahedron: Asymmetry 1998, 9, 607-611. (f) Hoffman, R. V.; Tao,
J. J. Org. Chem. 1998, 63, 3979-3985.
(12) Compound 1 was isolated as a mixture of diastereomers (95/5). The
identity of the major diastereomer is not known. Evidence (see ref 9)
suggests that diastereoselectivity is largely sterically controlled. It is
noteworthy that the diastereomeric ratio is inconsequential for the subsequent
transformations of 1 in the applications described in this Letter.
(13) Lipshutz, B. H. Synthesis 1987, 325-341.
(14) Posner, G. H. Org. React. 1975, 22, 253-400.
(15) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987,
28, 945-948.
(16) Lipshutz, B. H.; Kozlowski, J. A.; Wilhelm, R. S. J. Org. Chem.
1984, 49, 3943-3949.
(17) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem. 2002,
67, 1045-1056.
(11) Pansare, S. V.; Arnold, L. D.; Vederas, J. C. Org. Synth. 1992, 70,
10-17.
1720
Org. Lett., Vol. 4, No. 10, 2002

3 (see Figure 1, path b). Such a species could undergo either
olefination to yield sphingosines or provide phytosphingo-
sines by reaction with an appropriate nucleophile. Obviously,
in either case, diastereoselective control of reactions of 3 is
crucial for the versatility of the template. Because of our
interest in KRN7000, we decided to examine the utility of 1
as a precursor for phytosphingosines.
Scheme 3
We had previously found that a variety of heteroatom
nucleophiles opened 1,5-dioxaspirohexanes at the unhindered
epoxide carbon to give R-functionalized-â′-hydroxyketones.8
Acetic acid was employed to cleave 1 to ketol 13 (Scheme
2), because we had found the acetate functionality to be labile
Scheme 2
for discussion of determination of relative stereochemistry)
in 71% yield. Due to conformational complications caused
by restricted inversion at the nitrogen, the diastereomeric ratio
1
could not be determined by H NMR. However, global
deprotection of the mixture with TFA/H2O, followed by
tetraacetylation, allowed us to ascertain the diastereomeric
ratio (7:2) by 1H NMR. An attempt to improve the diastereo-
selectivity by running the reaction at a lower temperature
(-78 °C) was hampered by the reduced solubility of the
Grignard reagent at temperatures below -20 °C. Neverthe-
less, when the Grignard reagent was added slowly to a
solution of the aldehyde in THF at -78 °C and the resulting
mixture was left to warm slowly to rt, the diastereoselectivity
improved to 15:2. However, the yield was lower (61%).
under the reductive conditions employed in converting 14
to 15. Acetonide protection of 13 provided 14. Initially,
sodium borohydride was used to reduce 14 in very good yield
(88%). The conversion of 2-methyleneoxetane 5 to diol 15
could be conducted without purification of the intermediates
in an overall yield of 64%.
The reduction of 14 with sodium borohydride was ste-
reoselective (diastereomeric ratio 9:1), and the diastereomers
could be separated by careful chromatography. The C-2
epimer could be procured stereoselectively (2:1) with
DIBAL. To unambiguously assign the absolute stereochem-
istry, compounds 15a and 15b were converted to known
protected aldehydes 17a and 17b.18 The sequence for the
transformation of 15a to 17a is shown in Scheme 3. The
optical rotation and the correlation of NMR spectroscopic
data established that 15a had the absolute stereochemistry
shown at C-2. This was confirmed by the synthesis and
characterization of 17b.
Deprotection of 20 with TFA/H2O, followed by treatment
with KOH and recrystallization, provided xylo-phytosphin-
gosine in 79% yield. Tetraacetylation gave 21. The stereo-
chemical outcome of the nucleophilic addition to aldehyde
19 was determined by comparison of the specific rotation
and other physical data of tetraacetate 21 with the literature
values of the four diastereomeric tetraacetates of 2S-
phytosphingosine.20 This assignment also confirmed our
previous assignment of a syn stereochemistry to diol 15a.
Scheme 4
Diastereomer 15a was used to examine conditions for the
preparation of a sphingoid base (see Scheme 4). Conversion
to aldehyde 19 was based on literature precedent for selective
oxidation of primary silyl (TMS or TES) protected alcohols
in the presence of secondary silyl alcohols.19 Thus, bis-TES
protection provided 18, which was oxidized under Swern
conditions to aldehyde 19. A nucleophilic addition of
tetradecylmagnesium chloride to 19 at -10 °C provided a
mixture of diastereomeric diols (major isomer 20a: vide infra
(18) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J. Org. Chem.
1990, 55, 1439-1446.
(19) Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron
Lett. 1999, 40, 5161-5164.
Org. Lett., Vol. 4, No. 10, 2002
1721

The stereochemical outcome of the nucleophilic addition
to aldehyde 19 can be ascribed to a significant level of chelate
controlled addition of the Grignard reagent.21 These results
suggest that the C2 epimer of aldehyde 19 (19b) should
provide predominantly the lyxo-diastereomer 20b. Thus,
alternative strategies will be required to access ribo- and
arabino-phytosphingosine, and approaches to these com-
pounds via 1 are under investigation.
and further studies are underway to exploit this building
block and expand its utility.
Acknowledgment. Helpful discussions with Nina Berova,
Robert V. Hoffman, Bruce Lipshutz, and Robin Polt are
gratefully acknowledged. A.R.H. thanks the NSF for a
CAREER Award.
Supporting Information Available: Experimental pro-
cedures and characterization data, as well as copies of high-
resolution 1H and C 13NMR 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.
OL0200448
(21) Eliel and Frye and co-workers have shown (see: Chen, X.;
Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc. 1992, 114,
1778-1784) that the addition of Grignard reagents to R-siloxy ketones
proceeds via chelated transition states to varying degrees. However, there
is evidence that TES ethers can participate in chelatation to a significant
extent. Due to competing steric effects of the bulky BOC-protected
oxazolidine and the TES ether, it would be anticipated that an open transition
state would afford low levels of diastereoselectivity. The lower diastereo-
selectivity at -10 °C in comparison to that at -78 °C can be attributed to
the reaction proceeding through a mixture of chelated and open transition
states with reaction through the chelated intermediate predominating to a
greater extent at the lower temperature.
In summary, we have shown that serine-derived dioxa-
spirohexane 1 can be readily converted to dihydrosphingosine
and xylo-phytosphingosine. We believe that these preliminary
results demonstrate that 1 represents a template of consider-
able potential for the preparation of biologically important
dihydrosphingosines, phytosphingosines, and sphingosines,
(20) Shirota, O.; Nakanishi, K.; Berova, N. Tetrahedron 1999, 55,
13643-13658.
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Org. Lett., Vol. 4, No. 10, 2002