Dihydroxylation of 2-vinylaziridine: Efficient synthesis of D-ribo-phytosphingosine

Article abstract of DOI:10.1039/b612740a

An efficient and highly stereoselective synthesis of D-ribo-(2S,3S,4R)- phytosphingosine was accomplished in 62% overall yield starting from commercially available (2S)-hydroxymethylaziridine via osmium-catalyzed asymmetric dihydroxylation as a key step. The Royal Society of Chemistry.

Full text of DOI:10.1039/b612740a

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Dihydroxylation of 2-vinylaziridine: efficient synthesis of D-ribo-
phytosphingosine{
Hyo Jae Yoon,a Yong-Woo Kim,a Baeck Kyoung Lee,a Won Koo Lee,*a Yongeun Kimb and Hyun-Joon Ha*b
Received (in Cambridge, UK) 4th September 2006, Accepted 30th October 2006
First published as an Advance Article on the web 17th November 2006
DOI: 10.1039/b612740a
yield D-ribo-phytosphingosine from commercially available (2S)-
hydroxymethylaziridine through a simple five-step transformations
including stereoselective dihydroxylation.
An efficient and highly stereoselective synthesis of D-ribo-
(2S,3S,4R)-phytosphingosine was accomplished in 62% overall
yield starting from commercially available (2S)-hydroxymethyl-
aziridine via osmium-catalyzed asymmetric dihydroxylation as
a key step.
Aziridine-2(S)-carbaldehyde was readily prepared via Swern
oxidation of the enantiomerically pure aziridine-2(S)-methanol
which is commercially available.7 The bromopentadecane was
converted to the corresponding phosphonium salt in 80% yield by
stirring with triphenylphosphine in acetonitrile at reflux for 30 h.8
Treatment of the phosphonium salt with LiHMDS at 278 uC
generated the ylide which was then reacted with aziridine-2(S)-
carbaldehyde to provide 2(S)-[(Z)-hexadec-1-enyl]aziridine 2a in
93% yield with the ratio of 99 : 1 (Z : E).
Sphingolipids along with glycerides are the main constituents of
cell membranes and their metabolism is closely related to many
inherited human diseases and to cell regulation. Sphingosine and
phytosphingosine are two most important long-chain backbones
of sphingolipids in the realm of nature (Fig. 1).1 Recently, it has
been revealed that phytosphingosine shows a great variety of
biological activities such as cell differentiation, signal transduction,
regulation, proliferation and induction of apoptosis.2
Furthermore, phytosphingosine was shown to be widely distrib-
uted as one of the molecular species of sphingolipids in
microorganisms, plants, and many mammalian tissues such as
brain, hair, kidney, skin, liver, uterus, intestine and in blood
plasma.3
We studied the stereoselective dihydroxylations of the (Z)-2-
alkenylaziridine (2a) under a variety of conditions (Scheme 1 and
Table 1). The Sharpless asymmetric dihydroxylation with AD-mix
a and AD-mix b was not completed after two days. Furthermore,
the ratio of the vicinal diols 3Aa and 3Ba was poor in terms of
stereoselectivity. We concluded that the reluctance of the
dihydroxylation of the 2-vinylaziridine using AD-mix reagents is
due to the steric congestion around the double bond of the
aziridine which hinders the approach of the bulky oxidation
catalyst to the double bond. This interaction between the catalyst
and bulkiness of the substrate in stereoselective dihydroxylation
has been reported in the literature.9 When the 2-vinylaziridine was
oxidized with 10 mol% of osmium tetraoxide in aqueous acetone
with N-methylmorpholine oxide (NMO) as re-oxidant, we
obtained the two vicinal diols 3Aa and 3Ba with high
stereoselectivity (93 : 7) and high yield. A better ratio (99 : 1)
was obtained by lowering the reaction temperature to 210 uC. The
diastereomeric mixture of the diols was easily separated by flash
column chromatography to remove trace amount of the other
isomer. The identity of each diastereoisomeric diol was confirmed
Among all eight possible stereoisomers of phytosphingosine,
(2S,3S,4R)-2-aminooctadecane-1,3,4-triol with D-ribo-stereochem-
istry, is the most common. Owing to interests in these vital
biological activities many synthetic approaches to enantiomerically
pure phytosphingosines have been reported in the literature.4
However, most of them suffer from long synthetic steps and low
overall yield. Recent success in the synthesis of sphingosine5 and
ceramide analogues6 prompted us to aim for the efficient
synthesis of phytosphingosine. In this communication we
would like to report a remarkably efficient synthetic route to
1
by H NMR spectra in the literature after regioselective aziridine
ring opening with AcOH and removing the benzyl group from the
nitrogen. Once we obtained 2-(1,2-dihydroxyhexadecanyl)aziridine
(3Aa) in high yield, we looked into the origin of the stereo-
selectivity and the scope of dihydroxylation reactions of the
2-vinylaziridine in general.
Fig. 1 Structure of sphingosine and D-ribo-phytosphingosine (1).
aDepartment of Chemistry and Program of Integrated Biotechnology,
Sogang University, Seoul, 121-742, Korea.
E-mail: wonkoo@sogang.ac.kr; Fax: +82 2-701-0967;
Tel: +82 2-705-8449
bDepartment of Chemistry, Hankuk University of Foreign Studies,
Yongin, 449-791, Korea. E-mail: hjha@hufs.ac.kr; Fax: +82 31-3304566;
Tel: +82 31-3304369
{ Electronic supplementary information (ESI) available: Experimental
details of all reactions and the calculated rotational energy barriers of 2a
and 2b. See DOI: 10.1039/b612740a
Scheme 1 Dihydroxylation reactions of 2a.
Chem. Commun., 2007, 79–81 | 79
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Table 1 Dihydroxylation conditions of the 2-vinylaziridine 2a
Entry
Reagents
Solvent
Temp
Time
3Aa : 3Bac
Yieldd (%)
1
2
3
4
5
6
7
a
AD-mix a (1.4 g/1 mmol)
AD-mix b (1.4 g/1 mmol)
t-BuOH–H2O (1 : 1)
t-BuOH–H2O (1 : 1)
Acetone–H2O (1 : 1)
Acetone
Acetone–H2O (9 : 1)
Acetone/H2O (9 : 1)
Acetone/H2O (9 : 1)
c
RT
RT
RT
RT
RT
0 uC
210 uC
2 days
2 days
2 days
2 days
2 h
2 : 3
3 : 2
ND
,40
,40
Trace
Trace
80
OsO4 (1.1 equiv.)–TMEDAb (1.1 equiv.)
a
a
OsO4 (1.1 equiv.)
ND
a
OsO4 (0.1 equiv.)–NMO (3 equiv.)
5 : 1
93 : 7
99 : 1
a
OsO4 (0.1 equiv.)–NMO (3 equiv.)
4 h
10 h
88
87
a
OsO4 (0.1 equiv.)–NMO (3 equiv.)
b
d
5 wt% in H2O. N,N,N9,N9-Tetramethylethylenediamine. Based on the integration of the crude 1H NMR (300 MHz) spectra. Total
isolated yields.
The origin of this high stereoselectivity was investigated by
changing the substrate structures to address the following
questions. Is there any steric influence of the vinyl substituents R
in 2a–h? Will stereoselectivity be changed by double bond
configuration? Is there any influence by the group X attached
on the aziridine ring nitrogen? Thereby various 2-vinylaziridines
(2b–h) were used to investigate the stereoselectivities of dihydroxyla-
tion reactions (Scheme 2) and the results were shown in Table 2.
The Z isomer of the olefins (2a, 2d and 2f) always showed better
selectivity than E (2b, 2e and 2g). When we compare the reactions
of Z isomeric substrates (2a, 2c, 2d and 2f) we find that a
longer alkyl chain gives better selectivity. Decrease of selectivity,
from 93 : 7 to 83 : 17, was also observed by changing the alkyl
group X attached on the nitrogen of the aziridine from phenylethyl
(2a) to benzyl (2h). These observations can be explained by the
conformational preference during the hydroxylation. In the
literature, it has been reported that some ligands, especially
tertiary amine group for asymmetric dihydroxylation, play an
important role in controlling enantioselectivity by coordinating
with OsO4.10 We assume that the two substituents on the nitrogen
and the vinyl group at C-2 have an anti relationship11 and OsO4
may coordinate to the aziridine ring nitrogen. Two conformations
(A and B, Fig. 2) from the Z-stereoisomer (2a, 2d and 2f) are
possible by rotating the s-bond for the double bond to get close to
the oxygen atoms of OsO4 for the dihydroxylation reactions. One
pathway ‘‘b’’ leading to the conformer B is unfavorable due to
nonbonding interaction between X and the bulky R groups while
the other pathway ‘‘a’’ toward the conformer A is easily accessible.
Therefore, the nitrogen bound OsO4 can readily deliver oxygen
atoms to the double bond with A conformer to result in the major
dihydroxylation product 3Aa. In the case of E-stereoisomers (2b,
2e and 2g) the rotation barrier difference to go to the possible
conformers A9 and B9 are not as large as for A and B of the
Z-isomers since the steric interaction between the bulky substituent
of the E-double bond and X group is less than that of the
Z-stereoisomer. Therefore, the E-stereoisomer shows decreased
diastereoselectivity in the asymmetric dihydroxylation reaction.
The decrease of the selectivity by changing the alkyl group X
attached on the nitrogen of the aziridine from phenylethyl (2a) to
the smaller benzyl (2h) also can be explained by the decrease of the
nonbonding interaction of the reactive conformation A or B.
Regioselective ring opening reaction of the aziridine diol 3Aa by
AcOH and hydrolysis of the acetate by KOH in ethanol provided
the aminotriol 4 (Scheme 3). AcOH was used for the activation of
Scheme 2 Dihydroxylation reactions and their stereoselectivities of 2.
Table 2 Selectivity of dihydroxylation of (2S)-vinylaziridinea
Yield
Subst.
X
R
Isomer 3A : 3Bb 3A9 : 3B9b (%)
2a
2b
2c
2d
2e
2f
2g
2h
a
(R)-Phenylethyl C14H29
(R)-Phenylethyl C14H29
(R)-Phenylethyl C5H11
(R)-Phenylethyl Phenyl
(R)-Phenylethyl Phenyl
(R)-Phenylethyl Benzyl
(R)-Phenylethyl Benzyl
Z
E
Z
Z
E
Z
E
Z
93 : 7
88
90
92
84
79
88
82
85
72 : 28
89 : 11
70 : 30
58 : 42
71 : 29
b
84 : 16
83 : 17
Benzyl
C14H29
Under the reaction conditions of entry 6 in Table 1. Based on the
integration of the crude 1H NMR (300 MHz) spectra.
Fig. 2 Dihydroxylations of (Z)- and (E)-2-alkenylaziridine (2).
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Notes and references
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Scheme 3 Conversion of dihydroxyaziridine (3Aa) to D-ribo-phyto-
sphingosine (1). Reagents and conditions: (i) (1) AcOH, CH2Cl2; (2)
KOH, EtOH, rt, 93%; (ii) Pd(OH)2, H2(g) 100 psi, EtOH, rt, 92%; (iii)
Pd(OH)2, H2(g) 100 psi, EtOH, rt, (Boc)2O, 95%; (iv) acetic anhydride,
pyridine, rt, 98%.
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the basic ring nitrogen of the aziridine and was also used as the
source of the acetate nucleophile to attack the less sterically
hindered C-3 position of the aziridine.5 Finally, enantiomerically
pure D-ribo-phytosphingosine 1 was obtained by palladium
catalyzed debenzylation reaction. We further synthesized and
characterized N-Boc derivative 5 and tetraacetate 6 to confirm
the absolute configuration of the C-3 and C-4 hydroxy group in
D-ribo-phytosphingosine.
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In summary, we efficiently synthesized enantiomerically pure
D-ribo-phytosphingosine through a five-step sequence in 62%
overall yield from commercially available (2S)-hydroxymethylazir-
idine using asymmetric dihydroxylation of the Z-vinylaziridine as
the key step. This methodology also provides an efficient way for
the preparation of structurally modified phytosphingosine analogs.
Additional study regarding the relation between the stereo-
selectivity in the dihydroxylation and the chain length of the
substituents will be reported in due course.
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This work was supported by the following institutions:
The Korea Science and Engineering Foundation (R01-2005-000-
10032-0 and the Center for Bioactive Molecular Hybrids to
HJH), Korea Research Foundation (KRF-2002-070-C00060 to
WKL) and Imagene for providing enantiomerically pure chiral
aziridines.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 79–81 | 81