An unexpected access to a new sphingoid base containing a vinyl sulfide unit

Article abstract of DOI:10.1055/s-0030-1259047

An unexpected access to a new sphingoid base containing a vinyl sulfide unit is described. The process involves the one-pot regioselective opening of an epoxide with a thiolate, followed by intramolecular acyl transfer, base-promoted elimination, and final hydrolysis. Excess sodium hydride and high dilution conditions are required for optimal yields. The process is amenable to a variety of thiolates. The resulting compounds can be regarded as new hybrid sphingoid bases that combine some structural motifs present in other reported sphingolipid analogues. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259047

LETTER
2950
An Unexpected Access to a New Sphingoid Base Containing a Vinyl Sulfide
Unit
U
nexpec
n
ted
A
ccess to
g
a
N
ew
S
ph
r
i
ase d Nieves,a María Garrido,a José Luis Abad,a Antonio Delgado*a,b
a
Spanish National Research Council (CSIC); Institute for Advanced Chemistry of Catalonia (IQAC), Department of Biomedicinal
Chemistry; Research Unit on BioActive Molecules (RUBAM), Jordi Girona 18–26, 08034 Barcelona, Spain
Fax +34(93)2045904; E-mail: adelgado@cid.csic.es
University of Barcelona, Faculty of Pharmacy, Medicinal Chemistry Unit (Associated to CSIC), Avgda. Juan XXIII, s/n,
08028 Barcelona, Spain
b
Received 24 June 2010
Dedicated to Prof. Pelayo Camps on the occasion of his 65th birthday
O
O
Abstract: An unexpected access to a new sphingoid base contain-
ing a vinyl sulfide unit is described. The process involves the ‘one-
pot’ regioselective opening of an epoxide with a thiolate, followed
by intramolecular acyl transfer, base-promoted elimination, and fi-
nal hydrolysis. Excess sodium hydride and high dilution conditions
are required for optimal yields. The process is amenable to a variety
of thiolates. The resulting compounds can be regarded as new
hybrid sphingoid bases that combine some structural motifs present
in other reported sphingolipid analogues.
this work
this work
S(CH2)12Me
O
HO
N
NH2
O
1
3A
ref. 1
Key words: amino alcohol, epoxide, thiolate, elimination, olefin,
sphingolipids
OH
OH
O
S(CH2)12Me
S(CH2)12Me
HO
(steps)
ref. 1
O
N
O
HN
In the course of our current research on new modulators
of sphingolipid metabolism, we required the preparation
of several batches of the novel dihydroceramide desatu-
rase inhibitor XM462.1 The synthesis relies on the regio-
controlled nucleophilic opening of epoxide 1, in DMF,
with n-tridecylthiolate (A) to afford the required b-alkyl-
thio alcohol 2A for its subsequent transformation into
XM462 (Scheme 1). Compound 2A was obtained in ac-
ceptable yields in all cases. However, a careful TLC anal-
ysis of the crude reaction mixtures revealed the presence
of a hitherto unnoticed, more polar compound in variable
yields, which could be isolated and characterized as the
vinyl sulfide 3A (around a 40:1 E/Z mixture, based on
NMR data; Scheme 1 and Table 1, entry 1).2 Although, at
first glance, formation of 3A seemed detrimental for our
purposes, we recognized it as an interesting new hybrid
sphingoid base that combines the presence of a sulfur
atom at C5 position (as in XM462) with the C3 unsatura-
tion present in a series of related ceramidase inhibitors
containing a 2-aminoethanol amide framework.3
O
2A
XM462
Scheme 1 Formation of vinylsulfide 3a and alcohol 2a from epoxide
1. For reaction conditions, see text and Table 1.
Scheme 2 Proposed mechanism leading to 3a from 1 and 2A. Ar-
rows indicate the anti relationship among the atoms involved in the
elimination step from 5A. In the ball and stick model, the hydrogen
atoms leading ultimately to the major E-olefin are also shown.
A plausible mechanism to account for the formation of 3A
from epoxide 1 is depicted in Scheme 2.
chemistry observed for the major isomer is in agreement
with the anti disposition between the acidic OC(H)SR
proton and the carbamate leaving group in the most stable
conformation, as illustrated in the ball and stick represen-
tation shown in Scheme 2.5 The stereochemistry of the
starting epoxide seems crucial for the outcome of the pro-
cess, since no elimination products were observed from
the corresponding epoxide epimeric at the C–O carbon.6
Although the base-promoted formation of oxazolidinones
structurally related to 5A has been reported in the litera-
Thus, intramolecular acyl transfer4 of the initially formed
alkoxide 4A leads to the bicyclic oxazolidinone 5A. Sub-
sequent E2 elimination (with loss of CO2) and final hy-
drolysis of the intermediate hemiaminal 6A during the
aqueous workup affords vinyl sulfide 3A. The E stereo-
SYNLETT 2010, No. 19, pp 2950–2952
x
x
.x
x
.2
0
1
0
Advanced online publication: 11.11.2010
DOI: 10.1055/s-0030-1259047; Art ID: D16210ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Unexpected Access to a New Sphingoid Base
2951
ture,7 no ensuing elimination products are usually found, olefin 3B were found. Thus, an excess base (NaH/1 molar
as illustrated in our previous work involving a similar pro- ratio 15:1) and high dilution conditions (0.02 M relative to
cess from an aryloxy derivative structurally related to 1) turned out to be crucial for this unprecedented addi-
2A.8 We rationalize the unexpected reaction outcome tion–elimination reaction (Table 2, entry 7).11 These opti-
from 2A as a result of the higher acidity of the vicinal me- mized conditions led also to 3A in a slightly higher yield
thylene protons a to the sulfur atom in intermediate 5A, (entry 6) than that reported above and, most importantly,
thus triggering the observed elimination process.
they also proved successful for the remaining thiols C–F
used in this study (entries 8–11), although formation of
minor amounts of epoxide-opening adducts 2E and 2F
was still observed in some cases (entries 10 and 11).12
In an attempt to exploit the synthetic usefulness of this un-
expected process, we carried out a systematic survey of
the optimal reaction conditions leading to 3A, as shown in
Table 1. Interestingly, the stoichiometry of NaH seemed
crucial, since an, at first sight irrelevant, slight increase in
the excess NaH (2.0 equiv/mol epoxide vs. our previously
reported1 1.6 equiv/mol) led to a roughly 1:1 mixture of
2A and 3A (entry 1). Furthermore, by increasing the NaH/
1 molar ratio to 5:1, no trace of 2A was observed in the
crude reaction mixture and compound 3A (E/Z isomeric
ratio around 40:1) was obtained in 49% yield (entry 2). In
agreement with these observations and the above mecha-
nistic proposal, the independent treatment of 2A under the
same conditions cleanly afforded 3A in comparable yields
(entry 5). In all cases, the use of THF as solvent led to
slow conversion rates (entries 4 and 6). Moreover, since
the process leading to 2A is formally catalytic in base,9 the
use of substoichiometric NaH led exclusively to 2A in ex-
cellent yield (Table 1, entry 3).10
Table 2 Optimized Reaction of Epoxide 1 with Thiols A–F
OH
SR
SR
RSH (A–F)
HO
1
O
NaH, DMF
N
O
NH2
O
2A–F
3A–F
Entrya Thiol R
Baseb Concnc Product,
yield (%)
Other,
yield
(%)
1
2
B
C
D
E
F
cyclohexyl
t-Bu
5
0.09
0.09
0.09
0.08
0.08
0.02
0.02
0.02
0.02
0.02
0.02
2B 58d
2C 61d
2D 74d
2E 47d
5
3C 6d
3
Bn
5
4
Ph
5
Table 1 Synthesis of 3a from Reaction of 1 with n-Tridecylthiolate
or 2a with NaH
5
2-naphthyl
n-tridecyl
cyclohexyl
t-Bu
5
3F 42d (9:1)e 2F 18d
3A 61f (40:1)e
Entrya Starting Baseb Solvent Time (h) Products (%)c
material
6
A
B
C
D
E
F
15
15
15
15
15
15
7
3B 79f (10:1)e
1
2
3
4
5
6
1
2.0
5.0
0.5
1.5
5.0
5.0
DMF
DMF
DMF
THF
DMF
THF
4
2A/3A (1:1)
3A 49 (40:1)d
2A 91
8
3C 78f (6:1)e
1
4
9
Bn
3D 76f (13:1)e
1
4
10
11
Ph
3E 67f (9:1)e 2E 9f
3F 59f (9:1)e 2F 18f
1
48
4
1/2A (1:3)
2-naphthyl
2a
3A 50 (40:1)d
3A 72 (40:1)d
a Reactions were carried out in DMF at 40 °C for 4 h (see ref. 12 for
details).
2a
18e
b Molar ratio of NaH relative to starting epoxide 1.
c Molar concentration of epoxide 1 in DMF.
d Calculated by NMR with dimethyl terephthalate as external stan-
dard.
a Reactions were carried out at 0.1 M concentration (based on epoxide
1) at 40 °C, unless otherwise noted.
b Molar ratio of NaH relative to starting epoxide 1.
c Relative ratio or isolated yield.
e Aprox E/Z ratio (based on 1H NMR).
f Isolated yield.
d Approximate E/Z ratio (based on 1H NMR).
e Reaction at 25 °C
The vinyl sulfides herein reported were obtained as mix-
tures of E/Z isomers in ratios ranging from 6:1 (for the
bulky tert-butyl derivative 3C, entry 8) to 40:1 (for 3A).
In general, the acceptable overall yields obtained with the
selected thiols (entries 6–11), together with their straight-
forward chromatographic separation from the correspond-
ing adducts 2, whenever formed, and the possibility to
carry out the separation of the minor Z olefin stereoisomer
at a later synthetic stage,13 makes this process synthetical-
ly useful. As far as vinyl sulfide 3A is concerned, accept-
able yields are also obtained using the more practical
In an attempt to widen the scope of this process, thiols B–
F were also evaluated as reaction partners for epoxide 1
(Table 2). However, the reaction conditions shown above
for 3A (Table 1, entry 2) failed to give the expected vinyl
sulfides 3, since epoxide-opening adducts 2B–E were ob-
tained as the major reaction products (Table 2, entries 1–
4). The only exception was 2-naphthylthiol F (entry 5),
which afforded olefin 3F (9:1 E/Z mixture) together with
the opening adduct 2F. After much experimentation with
cyclohexanethiol B, which was chosen as model, opti-
mized reaction conditions for the exclusive formation of
Synlett 2010, No. 19, 2950–2952 © Thieme Stuttgart · New York

2952
I. Nieves et al.
LETTER
(4) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835.
(5) Minimizations were carried out with the MM2 package
found in Chem3D ultra (version 9.0) from Cambridge Soft.
(6) Koviach, J. L.; Chappell, M. D.; Halcomb, R. L. J. Org.
Chem. 2001, 66, 2318.
(7) Triola, G.; Fabrias, G.; Casas, J.; Llebaria, A. J. Org. Chem.
2003, 68, 9924.
(8) Grijalvo, S.; Matabosch, X.; Llebaria, A.; Delgado, A. Eur.
reaction conditions shown in Table 1 (entry 2), in which
the use of high dilution conditions and a large excess NaH
can be avoided.
In summary, a new protocol for the synthesis of b-amino
alcohols containing a vinyl sulfide unit is reported. This
represents an addition to other methods based on radical
chemistry,14 as well a potential new entry into the vinyl
sulfone framework, a well-established motif found in sev-
eral families of Cys-protesase inhibitors.15 In addition, our
interest in vinyl sulfides 3 as a new, hybrid sphingoid
backbone opens new possibilities for the design of sphin-
golipid analogues with potential biological properties. Ef-
forts along this line are currently in progress in our group,
and results will be reported in due course.
J. Org. Chem. 2008, 150.
(9) The nucleophilic thiolate required for the opening of epoxide
1 can arise from deprotonation of the starting thiol by the
transient alkoxide 4A (see Scheme 2).
(10) In light of these results, we cannot rule out at this point the
possibility that the excess NaH reported in our previous
work (ref. 1) was lower than assumed, probably due to
adventitious reagent hydrolysis over prolonged storage.
(11) Reactions carried out at higher concentration (0.05 M
relative to epoxide 1) failed to give 3B, even in the presence
of excess base (NaH/1 molar ratio 15:1). Concentrations
between 0.05 and 0.02 M afforded variable mixtures of 2B
and 3B.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(12) Typical Procedure
A solution of 0.60 mmol of the required thiol in DMF (5 mL)
was added dropwise over an ice-cooled suspension of NaH
(250 mg of a 60% dispersion in mineral oil, 6.0 mmol) in
DMF (10 mL) under Ar. Once the addition was complete,
the reaction mixture was allowed to warm to r.t. and stirred
for an additional 30 min until a suspension formed. A
solution of epoxide 1 (100 mg, 0.4 mmol) in DMF (5 mL)
was next added dropwise to the above suspension, and the
reaction mixture was heated to 40 °C. After stirring for 4 h,
the reaction was cooled to r.t. and quenched with H2O (2.5
mL), dried with anhyd MgSO4, and filtered. The solids were
washed with Et2O (3 × 5 mL) and the combined filtrates
were evaporated to dryness to afford a crude residue, which
was purified by flash chromatography. Data for compounds
reported in Table 2 are collected in the Supporting
Information.
Acknowledgment
Partial financial support from the ‘Ministerio de Ciencia e Innova-
ción’, Spain (Project SAF2008-00706), CSIC (PIE 200880I034)
and ‘Generalitat de Catalunya’ (Grant 2009SGR-1072) is acknowl-
edged. MG is grateful to CSIC for predoctoral research training sup-
port within the JAE-Predoc program. The authors are grateful to
Mrs. Eva Dalmau for technical assistance with HRMS.
References and Notes
(1) Munoz-Olaya, J. M.; Matabosch, X.; Bedia, C.; Egido-
Gabas, M.; Casas, J.; Llebaria, A.; Delgado, A.; Fabrias, G.
ChemMedChem 2008, 3, 946.
(2) The higher 3J value found for C4–H in the major isomer was
indicative of the E-stereochemistry. Compound 3A (major
isomer): d = 6.32, (d, J = 14.9 Hz, 1 H), minor isomer:
d = 6.11, (d, J = 9.5 Hz, 1 H).
(13) For example, the major E-isomers of a series of amides of
3A could be easily purified by conventional chromatog-
raphic methods. Unpublished results.
(14) Friestad, G. K.; Jiang, T.; Fioroni, G. M. Tetrahedron 2008,
64, 11549.
(3) Bedia, C.; Canals, D.; Matabosch, X.; Harrak, Y.; Casas, J.;
Llebaria, A.; Delgado, A.; Fabrias, G. Chem. Phys. Lipids
2008, 156, 33.
(15) Santos, M. A.; Moreira, R. Mini-Rev. Med. Chem. 2007, 7,
1040.
Synlett 2010, No. 19, 2950–2952 © Thieme Stuttgart · New York