Synthesis and biological evaluation of aziridine-containing analogs of phytosphingosine

Article abstract of DOI:10.1016/j.tet.2011.02.019

Six new aziridine-containing analogs of phytosphingosine designed as constrained anhydrophytosphingosine were synthesized. The synthetic route developed also afforded an access to an original bicyclic analog of the natural anhydrophytosphingosine jaspine B. All these new compounds were evaluated for their capacities to affect melanoma cell viability.

Full text of DOI:10.1016/j.tet.2011.02.019

Tetrahedron 67 (2011) 2570e2578
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and biological evaluation of aziridine-containing analogs
of phytosphingosine
a
,
b
c
a,
*
*
ꢀ
ꢀ
Stephanie Ballereau , Nathalie Andrieu-Abadie , Nathalie Saffon , Yves Genisson
a
ꢀ
SPCMIB, UMR CNRS 5068, Universite Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9, France
INSERM UMR-1037, Universite de Toulouse III, Centre de Recherche en Cancerologie de Toulouse, CHU Rangueil, 31432 Toulouse Cedex 4, France
SFTCM, FR2599, Universite Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9, France
b
ꢀ
ꢀ
c
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 January 2011
Received in revised form 4 February 2011
Accepted 7 February 2011
Available online 15 February 2011
Six new aziridine-containing analogs of phytosphingosine designed as constrained anhydrophyto-
sphingosine were synthesized. The synthetic route developed also afforded an access to an original bi-
cyclic analog of the natural anhydrophytosphingosine jaspine B. All these new compounds were
evaluated for their capacities to affect melanoma cell viability.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Phytosphingosine
Sphingosine
Aziridine
Jaspine B
Ceramide
1. Introduction
Sphingolipids (SLs) are ubiquitous membrane constituents that
have emerged as essential lipid mediators involved in signal
transduction1 and cancer development.2 Due to their implication in
the regulation of cell proliferation, cell death, adhesion, and mi-
gration, their metabolism has emerged as a potential target for
novel anti-cancer therapeutic approaches.
Naturally occurring SLs are based on a C18 skeleton named
D-erythro-sphingosine, which can be acylated with a fatty acid to
give ceramide. On the other hand, -ribo-phytosphingosine was
D
also described in keratinocytes and constitute the main long-chain
base of ceramide in the epidermis (Fig. 1).3
Fig. 1. D-erythro-sphingosine and D-ribo-phytosphingosine.
Among the structural modulations of the basic sphingosine
backbone of SLs, cyclization into diverse types of conformationally
restricted derivatives provided many biologically active com-
pounds interfering with the SLs metabolism.4 For instance, nitro-
genated heterocycles of various ring size have been reported. Lately,
the six-membered ring analog 1 (Fig. 2) synthesized by Cho et al.5
was shown to be cytotoxic against human lung carcinoma cells. Our
group described a series of five-membered ring iminosugar-based
SL analogs.6 The structure 2 was selected on the basis of its
potential mimic of the sphingosine backbone of ceramide. Grati-
fyingly, this C-alkyl derivative revealed to be a cytotoxic inhibitor of
glucosylceramide synthase in murine melanoma cells. Recently, the
Kobayashi’s group, who isolated and first described the structure of
penaresidin A and B,7 reported the synthesis of a series of simplified
diastereoisomeric penaresidin analogs bearing an unsubstituted
C14 alkyl chain.8 These compounds, as does the parent natural
penaresidins, embed an azetidine ring and can also be formally
considered as anhydrophytosphingosines (vide infra). The com-
pound 3 was described to be highly cytotoxic against human lung
epithelial cells and human colon cancer cells.
*
Corresponding authors. Tel.: þ33 5 61 55 62 99; fax: þ33 5 61 55 60 11; e-mail
addresses: ballereau@chimie.ups-tlse.fr (S. Ballereau), genisson@chimie.ups-tlse.fr
ꢀ
(Y. Genisson).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.019

S. Ballereau et al. / Tetrahedron 67 (2011) 2570e2578
2571
carboxylates as building blocks for the synthesis of sphingosine
analogs.12 More recently, a regio- and stereospecific aziridination
method of diene was used by Perez et al. to synthesize (ꢀ)-sphin-
gosine.13 The aziridine functionality is encountered in several im-
portant natural alkaloids.14 Because of its rigidity and its potential
reactivity, the aziridine ring is also a relevant structural fragment in
bioactive compounds. In this context, we wish to describe here the
synthesis of the targeted aziridine-containing analogs of phytos-
phingosine as well as their preliminary biological evaluations.
2. Results and discussion
2.1. Synthesis
Fig. 2. Chemical structures of constrained analogs of (phyto)sphingosine possessing
a nitrogenated heterocycle.
Our synthetic approach relied on the use of the aziridine/ynone
5 (Scheme 1) as a building block to obtain the targeted aziridine-
containing analogs of phytosphingosine. This cis-aziridine was
As a part of our ongoing research on the synthesis of SL analogs
and following the idea that constrained structures could bring
modulation in the biological properties of these lipids, we targeted
aziridine-containing analogs of phytosphingosine of general
structure 4. As shown in Fig. 3, this aziridine diol can also be con-
sidered as an anhydrophytosphingosine where the nitrogen-con-
taining heterocycle arise from a formal cyclodehydration involving
the primary amine and the 3-OH group.
prepared as described in Scheme 1. The racemic 2,3-aziridino-
g-
lactone 6 was obtained in two steps from -erythronic -lactone (7)
D
g
via the triflate derivative 8 according to the method of Dodd and
coll.15 The lactone 7 was then readily converted into the Weinreb
amide 9 by treatment with N,O-dimethylhydroxylamine in the
presence of trimethylaluminum.16 The hydroxyl group resulting
from the opening of the lactone was directly protected as a TBS-
ether to give compound 10. The Weinreb amide 10 was then
allowed to react with the lithium acetylide of tetradec-1-yne,
yielding the cis-aziridine ketone 5 possessing the C18 skeleton of
the parent phytosphingosine.
The following step of the synthesis was the diastereoselective
reduction of the ketone in 5 to obtain the corresponding protected
aziridine diol (Scheme 2). The group of Lee and Ha has studied the
synthetic potential of Weinreb amide derived from aziridine-2-
carboxylates17e21 and described the diastereoselective reduction of
2-acylaziridines.17,18 Very recently, this group also described the
Fig. 3. Targeted aziridine-containing analogs of phytosphingosine.
Although several azirine derivatives bearing an oxidized C-1
position were isolated from the marine sponge Dysidea fragilis,9,10
analogs of sphingosine possessing an aziridine ring were, to the
best of our knowledge, hitherto unprecedented. The aziridine
moiety is considered as an important scaffold in organic synthesis11
due to its capacity to undergo highly regio- and stereoselective
ring-opening reactions. In particular, Lee and Ha used aziridine-2-
Scheme 2. Reagents and conditions: see Table 1.
Scheme 1. Reagents and conditions: (a) Tf2O, pyridine, CH2Cl2, ꢁ78 ꢂC to ꢁ25 ꢂC, 3.5 h., 92%; (b) p-methoxybenzylamine, DMF, ꢁ30 ꢂC, 1 h, 45%; (c) HNMe(OMe).HCl, Me3Al, CH2Cl2,
ꢁ10 ꢂC to rt, 2 h, 92%; (d) TBSOTf, 2,6-lutidine, CH2Cl2, 0 ꢂC to rt, 4 h, 84%; (e) tetradec-1-yne, n-BuLi, THF, ꢁ78 ꢂC, 2 h, 95%.

2572
S. Ballereau et al. / Tetrahedron 67 (2011) 2570e2578
diastereoselective reduction of aziridine-2-yl propynyl ketone in
the synthesis of deoxyazasugars.21 Reduction with the non-che-
lating and bulky L-SelectrideÒ selectively delivered the syn isomer
according to the FelkineAnh model. On the other hand, treatment
of the same ketone with NaBH4 in the presence of ZnCl2 yielded the
chelation-controlled anti isomer in high selectivity.
Similar diastereocontrol was effectively observed using NaBH4
and ZnCl2 for the reduction of ynone 5. In these conditions, the anti
alcohol 11a was obtained as the only detectable product in a 92%
isolated yield (Table 1, entry 1) as a result of a chelation-controlled
process. However, with our substrate, the reduction with
L-SelectrideÒ gave a 60:40 mixture of the two alcohols 11a and 11b
still favoring the anti product 11a (Table 1, entry 2). The slightly
lower yield of this transformation (71% global) could be attributed
to the formation of over-reduced products arising from 1,4-re-
duction of the ynone, as already observed in the course of the re-
duction of aziridinyl vinyl ketone.22
a general trend for anti-diastereoselectivity was already observed
by Rapoport and coll. in the reduction of
a a,b-ynones as
0-amino-
part of a synthesis of sphingosine.26
The two diastereoisomeric alcohols 11a,b were readily sepa-
rated by chromatography on silica gel. The X-ray diffraction analysis
of a crystalline sample of the minor isomer 11b allowed confir-
mation of the syn relative configuration between the nitrogen atom
of the aziridine ring and the secondary hydroxyl group (Fig. 4). The
two enantiomers of the racemate crystallized in the unit cell.
Table 1
Reduction conditions
Reducing agent
Solvent, temperature
dr (11a/11b)
Yield
1
2
3
4
5
6
7
NaBH4, ZnCl2
L-SelectrideÒ
DIBAL
NaBH4, CeCl3
NaBH4
MeOH, ꢁ78 ꢂ
C
100:0
60:40
65:35a
100:0a
70:30
75:25a
55:45
92%
71%
ndb
ndb
96%
ndb
94%
THF, ꢁ78 ꢂ
C
Et2O, ꢁ78 ꢂ
C
MeOH, ꢁ78 ꢂ
MeOH, ꢁ78 ꢂ
C
C
NaBH4, NH4Cl
NMe4BH4
EtOH/H2O, ꢁ78 ꢂ
C
MeOH, ꢁ78 ꢂC to rt
a
Determined by 1H NMR of the crude reaction mixture.
Yields was quantitative and the purity of the crude product >95% according to
b
1H NMR.
Since we were interested in the two diastereoisomers, we ex-
plored other reducing agents so as to reverse the diaster-
eoselectivity in favor of the syn aziridine alcohol. The results of this
study are collected in Table 1. The reduction with DIBAL gave a se-
lectivity similar to the reaction with L-SelectrideÒ (entry 3). At-
tention was thus paid to the additive used along with the reducing
agent NaBH4. We attempted switching the Lewis acid from ZnCl2 to
CeCl3, as described by Lee and Ha who reported under these con-
ditions a syn diastereoselectivity for the reduction of an aziridinyl
methyl ketone.18 In our case, the anti product was again the only
detectable product of the reaction (entry 4). In order to favor the
FelkineAnh attack, we ran the reduction in the absence of any
chelating agent. When NaBH4 was used alone (entry 5), the anti/syn
ratio dropped to 70:30. In order to prevent any coordination of the
nitrogen atom of the aziridine ring, we tried to protonate the ter-
tiary amine by adding NH4Cl to the reaction mixture as described
by Guanti et al. for the synthesis of
a-amino-b
-hydroxyacids.23
Fig. 4. Molecular view of compound 11b syn. Thermal ellipsoids are drawn at the 50%
probability level. All hydrogen atoms are omitted for clarity.27
These conditions gave results very close to those obtained with
NaBH4 alone (entry 6). The best results were finally obtained with
Me4NBH4 as a reducing agent (entry 7). This borohydride with
a non-chelating bulky counter-cation was already described to fa-
vor the FelkineAnh transition state leading to the syn product.24,25
Treatment of 5 with Me4NBH4 gave an anti/syn ratio of 55:45 and
a 94% isolated yield.
Despite many trials, the major reduction product of 5 remained
the anti aziridine alcohol 11a. Lee, Ha and coll.21 reported a good
diastereocontrol in the reduction of aziridine-2-yl propynyl ketone
embedding an unsubstituted methylene on C-3. The intrinsic ste-
reochemical bias of our substrate favoring the anti-selective
reduction seems to be associated to the presence of the cis-sub-
stituent on the C-3 position of the aziridine ring. The silylated
hydroxymethyl group may develop interactions influencing the
reactive conformation of the ketone and hence disfavoring the
hydride attack resulting in the FelkineAnh-type syn product. Such
In the rest of the synthetic sequence, the alkyne chain was
partially or totally reduced and the protecting groups were elimi-
nated to give the targeted aziridine-containing phytosphingosine
analogs. In the anti series, the triple bond of the propargylic alcohol
11a was partially reduced with lithium aluminum hydride to give,
with concomitant deprotection of the primary hydroxyl group the
diol 12a (Scheme 3). The PMB group was then cleaved by action of
cerium ammonium nitrate in the presence of water to afford the
fully deprotected alkene 13a. In order to prepare the alkyne analog
14a and the saturated analog 15, the deprotection of the hydroxyl
group as well as that of the aziridine was studied. The order of these
two steps revealed important, the best overall yields being obtained
when the TBS-ether was cleaved first by action of tetrabuty-
lammonium fluoride to give the diol 16a. The PMB protecting group

S. Ballereau et al. / Tetrahedron 67 (2011) 2570e2578
2573
Fig. 5. Jaspine B and targeted aziridine-containing bicyclic analog 18.
With the alcohol 11a in hand, it seemed attractive to target the
aziridine-containing analog of jaspine B 18.
This synthesis could be achieved in four steps starting from al-
cohol 11a (Scheme 5) according to a cyclization process described
for the preparation of jaspine’s epimers.32
Scheme 3. Reagents and conditions: (a) LAH, THF, reflux, overnight, 94%; (b) CAN,
CH3CN/H2O, rt, overnight, 76% for 13a, 64% for 14a; (c) TBAF, THF, 0 ꢂC to rt, 2 h, 84%;
(d) H2, Pd/C, CH2Cl2, 0 ꢂC, 1 h, quant.
of the aziridine ring was then cleaved to give the alkyne analog 14a.
Hydrogenation of the triple bond furnished quantitatively the sat-
urated analog 15.
On the other hand, the syn propargylic alcohol 11b was also
subjected to the same reaction sequence (Scheme 4). The alkyne
bond was partially reduced to give the diol 12b, which after
cleavage of the PMB group, gave the alkene analog 13b. The alkyne
analog 14b was also synthesized by successive deprotection steps
via the diol 16b. When compound 14b was submitted to hydroge-
nation under the same reaction conditions used in the anti series,
the Z-alkene analog 17 could be isolated quantitatively.
Scheme 5. Reagents and conditions: (a) MsCl, NEt3, CH2Cl2, 0 ꢂC then rt, quant.; (b)
TBAF, THF, rt, overnight, 53%; (c) H2, Pd/C, MeOH, 0 ꢂC, rt, quant.; (d) CAN, CH3CN/H2O,
overnight, 42%.
The secondary alcohol was firstly activated to give mesylate 19.
The bicyclic tetrahydrofuran 20 was obtained by TBAF-promoted
desilylation of 19 and subsequent intramolecular cyclization via an
SN2-type displacement of the mesylate by the primary hydroxyl.
Hydrogenation of the alkyne 20 afforded the saturated compound
21 in a quantitative yield and subsequent PMB cleavage furnished
in a moderate yield the desired aziridine-containing jaspine B an-
alog 18.
The structure of compound 20 was confirmed by X-ray diffrac-
tion analysis (Fig. 6). The all-cis relative configuration of the tet-
rahydrofuran ring also indirectly confirmed the anti configuration
of the major reduction product 11a.
Scheme 4. Reagents and conditions: (a) LAH, THF, reflux, overnight, 84%; (b) CAN,
CH3CN/H2O, rt, overnight, 21% for 13b, 50% for 14b; (c) TBAF, THF, 0 ꢂC to rt, 2 h, 86%;
(d) H2, Pd/C, CH2Cl2, 0 ꢂC, 1 h, quant.
As a part of our research on the synthesis of molecules in-
terfering with the SL metabolism, we recently reported synthetic
and biological studies of jaspine B, another natural anhy-
drophytosphingosine.28,29 The all-cis tetrahydrofuran framework of
this highly cytotoxic compound revealed to be a relevant phar-
macophore. In particular, we identified jaspine B as a new structural
archetype for the development of sphingomyelin synthase in-
hibitors (Fig. 5).30 We also developed a synthetic strategy allowing
flexible introduction of various lipophilic fragments in the jaspine’s
skeleton.31
Fig. 6. Molecular view of compound 20. Thermal ellipsoids are drawn at the 50%
probability level. All hydrogen atoms are omitted for clarity.27

2574
S. Ballereau et al. / Tetrahedron 67 (2011) 2570e2578
2.2. Biological evaluation
DMEM, trypsineEDTA, and fetal calf serum (FCS) were from
Invitrogen (Cergy-Pontoise, France). 3-(4,5-Dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide (MTT) was supplied from Euro-
medex (Mundolsheim, France). Murine B16 melanoma cell line was
purchased from American Type Culture Collection (LGC, Molsheim,
France).
The ability of aziridine-containing analogs of phytosphingosine
and jaspine B to inhibit tumor cell growth was evaluated in murine
B16 melanoma cells by MTT assay. None of the tested compounds
affected the cell viability at low concentration (<10
mM). At a con-
centration of 25 M, the cytotoxicity of the saturated compound 15
m
was ꢃ20% and no effect on the cell viability was observed for the
aziridine jaspine analog 18. On the other hand, a significant effect
was observed for the compounds presenting an insaturation in the
alkyl chain: for diastereoisomers 13a and 13b the cytotoxicity at
4.2. General procedure for the PMB cleavage
The PMB-protected aziridine (1.0 equiv) was dissolved in
a mixture of CH3CN/H2O (3:1, 0.05 M) and cerium ammonium ni-
25
m
M was ꢄ60% and for alkynes 14a and 14b and for Z-alkene 17 it
trate (CAN) was added (6.0 equiv). The reaction mixture was stirred
overnight and water and CH2Cl2 were added. The organic phase
was separated and the aqueous phase was extracted twice with
CH2Cl2. The organic extracts were combined, dried over magne-
sium sulfate, and evaporated to dryness. A flash chromatography on
silica gel of the residue gives the expected free aziridine.
was ꢄ80%.
3. Conclusions
Six new aziridine-containing analogs of phytosphingosine
designed as constrained anhydrophytosphingosine were synthe-
sized. The synthetic route relied on the opening reaction of a bi-
cyclic lactone aziridine, the alkylation of the resulting Weinreb
amide, and the diastereoselective reduction of an ynone. The long
C14 chain of these aziridines was also reduced, partially or fully to
give the different targeted analogs. The synthetic plan developed
also afforded an access to an original bicyclic analog of the natural
anhydrophytosphingosine jaspine B. For all these new compounds
the cytotoxicity against B16 melanoma cells was evaluated. Com-
4.3. Specific chemical procedures and characterization data
4.3.1. 6-(4-Methoxybenzyl)-3-oxa-6-azabicyclo[3.1.0]hexan-2-one
(6). To a solution of
D-erythronolactone (2.00 g, 16.9 mmol) in
dichloromethane (80 ml) held at ꢁ78 ꢂC under argon were suc-
cessively added pyridine (6.85 ml, 84.7 mmol, 5.0 equiv) and a so-
lution of trifluoromethanesulfonic anhydride (7.60 ml, 45.7 mmol,
2.7 equiv) in dichloromethane (20 ml). After 15 min of stirring at
ꢁ78 ꢂC, the reaction mixture was slowly warmed to ꢁ25 ꢂC over
a period of 3.5 h. The reaction solution was then poured into cold
diethyl ether (200 ml). The precipitate was filtered, and the filtrate
was evaporated under reduced pressure at 0 ꢂC. The resulting res-
idue was rapidly purified by filtration on silica gel (Et2O) to afford
compound 8 (3.62 g, 92%) as a yellow oil, which was directly used in
the next step. To a solution of compound 8 (3.62 g, 15.6 mmol) in
DMF (70 ml) at ꢁ30 ꢂC under argon was added dropwise p-
methoxybenzylamine (3.06 ml, 23.4 mmol, 1.5 equiv). The reaction
mixture was stirred for 1 h at ꢁ30 ꢂC before being diluted with
ethyl acetate (60 ml) and water (60 ml). The layers were separated,
and the aqueous phase was extracted with ethyl acetate (2ꢅ60 ml).
The combined organic extracts were dried over magnesium sulfate
and evaporated to dryness. The resulting residue was purified by
flash chromatography on silica gel (Et2O/petroleum ether 2:1) to
pounds 14a, 14b, and 17 strongly altered cell viability at 25 mM.
4. Experimental section
4.1. General
The following solvents and reagents were dried prior to use:
CH2Cl2, MeOH (from calcium hydride), Et2O, petroleum ether, THF
(freshly distilled from sodium/benzophenone). Analytical thin
layer chromatography (TLC) was performed using Merck silica gel
60 F254 precoated plates. Chromatograms were observed under UV
light and/or were visualized by heating plates that were dipped in
10% phosphomolybdic acid in ethanol. Column chromatographies
were carried out with SDS 35e70 mM flash silica gel. NMR spec-
troscopic data were obtained with Bruker Advance 300. Chemical
shifts are quoted in parts per million (ppm) relative to residual
solvent peak. J values are given in hertz. For matter of homoge-
neity, sphingolipid numbering is used for NMR assignment
throughout the experimental section. Mass spectrometry (MS)
data were obtained on a ThermoQuest TSQ 7000 spectrometer,
high-resolution mass spectra (HRMS) were performed on a Ther-
moFinnigan MAT 95 XL spectrometer using electrospray ionization
(ESI) methods.
give the p-methoxybenzylaziridine-
g
-lactone 6 (1.53 g, 45%) as an
(ppm): 7.30e7.20 (m,
amorphous solid. 1H NMR (CDCl3, 300 MHz)
d
2H, Har); 6.95e6.85 (m, 2H, Har); 4.31 (d, 1H, H-1a, J1ae1b¼9.9); 4.19
(dd, 1H, H-1b, J1be1a¼9.9, J1be2¼3.0); 3.80 (s, 3H, OMe); 3.66 (d, 1H,
CH2N, 2J¼13.2); 3.39 (d, 1H, CH2N, 2J¼13.2); 2.93 (dd, 1H, H-2,
J2e3¼4.5, J2e1b¼3.0); 2.69 (d, 1H, H-3, J3e2¼4.5). 13C NMR (CDCl3,
75 MHz)
d (ppm): 172.4 (C-4); 159.1 (CeOMe); 129.1 (Car); 129.0
(Cqar); 113.9 (Car); 69.5 (C-1); 60.5 (CH2N); 55.2 (OMe); 41.9 and
39.4 (C-2 and C-3). MS (CI/NH3): m/z¼237.4 ([MþNH4]þ). HRMS m/
z: calcd for C12H14NO3 [MþH]þ: 220.0974; found: 220.0969.
For crystallographic analysis, the selected crystals were mounted
on a glass fiber using perfluoropolyether oil and cooled rapidly in
a stream of cold N2. X-ray intensity data of 11b were collected with
4.3.2. 3-(Hydroxymethyl)-N-methoxy-1-(4-methoxybenzyl)-N-
methylaziridine-2-carboxamide (9). To a solution of N,O-dime-
thylhydroxylamine hydrochloride (800 mg, 8.21 mmol, 3.0 equiv)
in CH2Cl2 (20 ml) under nitrogen at ꢁ10 ꢂC was added trimethy-
ꢁ
graphite-monochromated Mo K
by using phi- and omega-scans on a Bruker-AXS kappa APEX II
Quazar diffractometer using a 30 W air-cooled microfocus source
a
radiation (wavelength¼0.71073 A)
(ImS) with focusing multilayer optics at a temperature of 193 (2)K. X-
laluminum (2.0 M in toluene, 4.11 ml, 8.21 mmol, 3 equiv). The
ray intensity data of 20 were collected on a Bruker-AXS SMART APEX
II diffractometer equipped with the Bruker Kryo-Flex cooler device
mixture was stirred at rt for 30 min before to be cooled again to
ꢁ10 ꢂC.
A solution of p-methoxybenzylaziridine-g-lactone 6
and using a graphite-monochromated Mo K
a
radiation at a temper-
(600 mg, 2.74 mmol) in CH2Cl2 (7 ml) was added dropwise and the
reaction mixture was stirred at rt for 2 h. The reaction was carefully
quenched with a NH4Cl saturated solution (50 ml) and the mixture
was extracted with CH2Cl2 (3ꢅ50 ml). The combined organic ex-
tracts were dried over magnesium sulfate and evaporated to dry-
ness giving the expected Weinreb amide 9 (710 mg, 92%), which
was used without further purification. 1H NMR (CDCl3, 300 MHz)
ature of 193 (2)K.
The data were integrated with SAINT, and an empirical ab-
sorption correction with SADABS was applied.33,34 The structures
were solved by direct methods (SHELXS-97),35 and all non-hydro-
gen atoms were refined anisotropically using the least-squares
method on F2 (SHELXL-97).36

S. Ballereau et al. / Tetrahedron 67 (2011) 2570e2578
2575
d
(ppm): 7.30e7.25 (m, 2H, Har); 6.90e6.80 (m, 2H, Har); 3.81 (dd,
2 equiv) was slowly added and the mixture was stirred for 2 h at
ꢁ78 ꢂC. A saturated solution of NH4Cl (10 ml) was then added and
the reaction mixture was extracted with CH2Cl2 (3ꢅ15 ml). The
organic extracts were combined, dried over magnesium sulfate,
and evaporated to dryness. A flash chromatography on silica gel
(Et2O/petroleum ether 4:1 to 1:0) of the residue gives the two
diastereoisomeric alcohols 11a (323 mg, 63%) as a yellow oil and
11b (166 mg, 33%) as an amorphous solid.
1H, H-1a, J1ae1b¼11.7, J1ae2¼5.6); 3.80 (s, 3H, CeOMe); 3.75e3.65
(m, 5H, NeOMe, and CH2N); 3.65e3.55 (m, 1H, H-1b); 3.42 (d, 1H,
CH2N, 2J¼13.2); 3.21 (s, 3H, NMe); 3.10e2.90 (m,1H, OH); 2.70 (br d,
1H, H-3, J¼4.6); 2.22 (q, 1H, H-2, J¼6.3). 13C NMR (CDCl3, 75 MHz)
d
(ppm): 169.4 (C-4); 158.8 (CeOMe); 129.8 (Cqar); 129.3 (Car);
113.4 (Car); 62.8 (C-1); 61.4 (NeOMe); 60.8 (CH2N); 55.1 (CeOMe);
45.7 (C-2); 41.0 (C-3); 32.3 (NMe). MS (CI/NH3): m/z¼281.2
([MþH]þ).
Data of 11a. 1H NMR (CDCl3, 300 MHz)
d (ppm): 7.30e7.25 (m,
2H, Har); 6.90e6.80 (m, 2H, Har); 4.20 (dt, 1H, H-4, J4e3¼8.1,
J4e7¼1.7); 4.03 (dd, 1H, H-1a, J1ae1b¼11.3, J1ae2¼6.0); 3.78 (s, 3H,
OMe); 3.55 (dd, 1H, H-1b, J1be1a¼11.3, J1be2¼7.9); 3.55 (AB, 2H,
CH2N, Dd¼0.03, JAB¼13.3); 3.32 (br s, 1H, OH); 2.14 (td, 2H, H-7,
J7e8¼7.1, J7e4¼1.9); 2.06 (dd, 1H, H-3, J3e4¼8.1, J3e2¼6.6); 1.92 (dt,
1H, H-2, J2e1b¼7.8, J2e1a¼J2e3¼6.2); 1.55e1.35 (m, 2H, H-8);
1.35e1.15 (m, 18H, H-9 to H-17); 1.00e0.80 (m, 12H, H-18, and
SitBu); 0.07 and 00.6 (2s, 6H, Si(Me)2). 13C NMR (CDCl3, 75 MHz)
4.3.3. 3-((tert-Butyldimethylsilyloxy)methyl)-N-methoxy-1-(4-me-
thoxybenzyl)-N-methylaziridine-2-carboxamide (10). To a solution
of the crude Weinreb amide 9 (507 mg, 1.81 mmol) in CH2Cl2
(18 ml) at 0 ꢂC under nitrogen were added successively 2,6-lutidine
(295
m
L, 2.53 mmol, 1.4 equiv) and tert-butyldimethylsilyl tri-
L, 2.17 mmol,1.2 equiv). The reaction
fluoromethanesulfonate (416
m
mixture was stirred at rt for 4 h and water was added (20 ml). After
extraction with CH2Cl2 (3ꢅ20 ml), the combined organic extracts
were dried over magnesium sulfate, and evaporated to dryness. The
resulting residue was purified by flash chromatography on silica gel
(Et2O/petroleum ether 3:1) to give the p-methoxybenzylaziridine
d
(ppm): 158.8 (CeOMe); 130.7 (Cqar); 129.3 (Car); 113.7 (Car); 86.2
(C-5); 78.7 (C-6); 62.9 and 62.8 (CH2N and C-1); 61.9 (C-4); 55.2
(OMe); 48.4 (C-3); 43.7 (C-2); 31.9 (C-16); 29.7, 29.7, 29.7, 29.6, 29.4,
29.2, 28.9, and 28.6 (C-8 to C-15); 25.8 (C(CH3)3); 22.7 (C-17); 18.8
(C-7); 18.2 (C(CH3)3); 14.1 (C-18); ꢁ5.3 and ꢁ5.5 (SiCH3). MS (CI/
NH3): m/z¼530.3 ([MþH]þ). HRMS m/z: calcd for C32H56NO3Si
[MþH]þ: 530.4029; found: 530.4044.
10 (600 mg, 84%) as a yellow oil. 1H NMR (CDCl3, 300 MHz)
d (ppm):
7.30e7.25 (m, 2H, Har); 6.90e6.80 (m, 2H, Har); 3.88 (dd, 1H, H-1a,
J1ae1b¼10.9, J1ae2¼4.8); 3.78 (s, 3H, CeOMe); 3.71 (s, 3H, NeOMe);
3.60 (dd, 1H, H-1b, J1be1a¼11.0, J1be2¼7.4); 3.59 (s, 2H, CH2N); 3.19
(s, 3H, NMe); 2.77 (br d, 1H, H-3, J3e2¼5.6); 2.19 (td, 1H, H-2,
J2e1a¼J2e1b¼6.9, J2e3¼4.9); 0.84 (s, 9H, SitBu); 0.00 and 0.01 (2s,
Data of 11b. 1H NMR (CDCl3, 300 MHz)
d (ppm): 7.30e7.25 (m,
2H, Har); 6.90e6.80 (m, 2H, Har); 4.12 (br d, 1H, H-4, J4e3¼6.2); 3.75
(s, 3H, OMe); 3.72 (dd, 1H, H-1a, J1ae1b¼11.4, J1ae2¼5.3); 3.66 (dd,
1H, H-1b, J1be1a¼11.4, J1be2¼6.4); 3.46 (s, 2H, CH2N); 2.88 (br s, 1H,
OH); 2.18 (td, 2H, H-7, J7e8¼7.1, J7e4¼1.9); 2.03 (t, 1H, H-3,
J3e4¼J3e2¼6.7); 1.97 (td, 1H, H-2, J2e1b¼J2e3¼6.7, J2e1a¼5.3);
1.55e1.35 (m, 2H, H-8); 1.35e1.15 (m, 18H, H-9 to H-17); 1.00e0.80
(m, 12H, H-18, and SitBu); 0.03 (s, 6H, Si(Me)2). 13C NMR (CDCl3,
2ꢅ3H, Si(Me)2). 13C NMR (CDCl3, 75 MHz)
d (ppm): 171.4 (C-
4); 158.7 (CeOMe); 130.2 (Cqar); 129.3 (Car); 113.7 (Car); 63.0 (C-1);
61.6 (NeOMe); 61.2 (CH2N); 55.2 (CeOMe); 47.0 (C-2); 40.6 (C-3);
32.5 (NMe); 25.9 (C(CH3)3); 18.2 (C(CH3)3); ꢁ5.4 (SiCH3). HRMS
m/z: calcd for C20H35N2O4Si [MþH]þ: 395.2366; found: 395.2367.
75 MHz)
d (ppm): 158.9 (CeOMe); 130.6 (Cqar); 129.6 (Car); 113.9
4.3.4. 1-(3-((tert-Butyldimethylsilyloxy)methyl)-1-(4-methox-
ybenzyl)aziridin-2-yl)pentadec-2-yn-1-one (5). To a solution of tet-
(Car); 86.2 (C-5); 79.1 (C-6); 63.2 (CH2N); 62.1 (C-1); 60.3(C-4); 55.2
(OMe); 48.2 (C-3); 45.6 (C-2); 31.9 (C-16); 29.7, 29.7, 29.7, 29.6, 29.4,
29.2, 28.9, and 28.6 (C-8 to C-15); 25.9 (C(CH3)3); 22.7 (C-17); 18.8
(C-7); 18.2 (C(CH3)3); 14.1 (C-18); ꢁ5.3 and ꢁ5.4 (SiCH3). MS (DCI/
NH3): m/z¼530.3 ([MþH]þ). HRMS m/z: calcd for C32H56NO3Si
[MþH]þ: 530.4029; found: 530.4014. Crystal data for 11b:
radec-1-yne (393 mL, 1.60 mmol, 2 equiv) in anhydrous THF (10 ml)
at ꢁ78 ꢂC under nitrogen was added n-butyllithium (1.6
M solution
in hexanes, 1.1 ml, 1.76 mmol, 2.2 equiv). After 30 min of stirring,
a solution of the aziridine 10 (315 mg, 0.80 mmol) in THF (6 ml) was
added dropwise to the reaction mixture, which was stirred at
ꢁ78 ꢂC for further 2 h. A saturated solution of NH4Cl (30 ml) was
then added and the reaction mixture was extracted with CH2Cl2
(3ꢅ30 ml). The organic extracts were combined, dried over mag-
nesium sulfate, and evaporated to dryness. A flash chromatography
on silica gel (Et2O/petroleum ether 3:1) of the residue gives the
ketoaziridine 5 (400 mg, 95%) as a yellow oil. 1H NMR (CDCl3,
ꢁ
C64H110N2O6Si2, M¼1059.72, triclinic P1, a¼12.7209 (15) A,
ꢁ
ꢁ
3
ꢁ
b¼17.312 (2) ꢂA, c¼18.282 (2) A,
a
¼62.783 (6)ꢂ,
b
¼86.043 (6)ꢂ,
g
¼70.290 (6) , V¼3353.2 (7) A , Z¼2, 68,764 reflections (14,619
independent, Rint¼0.0342) were collected. Largest diff. peak and
ꢁꢁ3
hole: 0.344 and ꢁ0.196 e A , R1 (for I>2
data)¼0.1353.
s
(I))¼0.0456 and wR2 (all
*
*
*
300 MHz)
d
(ppm): 7.30e7.25 (m, 2H, Har); 6.90e6.80 (m, 2H, Har);
4.3.6. (R )-1-((2S ,3R )-3-((tert-Butyldimethylsilyloxy)methyl)-1-(4-
methoxybenzyl)aziridin-2-yl)pentadec-2-yn-1-ol (11a). To the solu-
tion of ketone 5 (400 mg, 0.78 mmol) in of MeOH (9 ml) at ꢁ78 ꢂC
was added ZnCl2 (156 mg, 1.18 mmol, 1.5 equiv). The solution was
stirred for 30 min, and NaBH4 (60 mg, 1.57 mmol, 2.0 equiv) was
added at ꢁ78 ꢂC. The mixture was stirred for 1 h and water was
added (6 ml). The organic layer was separated. The aqueous layer
was extracted with CH2Cl2 (3ꢅ10 ml), and the combined organic
extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Filtration over FloresilÒ provided 11a as an oil (368 mg, 92%).
3.89 (dd, 1H, H-1a, J1ae1b¼11.1, J1ae2¼5.6); 3.82 (s, 3H, OMe); 3.63
(dd, 1H, H-1b, J1be1a¼11.1, J1be2¼6.5); 3.58 (AB, 2H, CH2N, Dd¼0.07,
JAB¼13.4); 2.61 (d, 1H, H-3, J3e2¼6.8); 2.39 (t, 2H, H-7, J7e8¼7.4);
2.30 (q, 1H, H-2, J2e1a¼J2e1b¼J2e3¼6.6); 1.65e1.15 (m, 20H, H-8 to
H-17); 0.95e0.80 (m,12H, H-18, and SitBu); 0.04 (s, 6H, Si(Me)2). 13
C
NMR (CDCl3, 75 MHz)
d (ppm): 183.2 (C-4); 158.9 (CeOMe); 129.8
(Cqar); 129.2 (Car); 113.8 (Car); 96.7 (C-5); 81.3 (C-6); 62.9 (C-1); 60.8
(CH2N); 55.3 (OMe); 50.1 and 50.0 (C-3 and C-2); 31.9 (C-16); 29.7,
29.6, 29.6, 29.5, 29.4, 29.1, 28.9, and 27.7 (C-8 to C-15); 25.9 (C
(CH3)3); 22.7 (C-17); 19.1 (C-7); 18.2 (C(CH3)3); 14.1 (C-18); ꢁ5.3
and ꢁ5.4 (SiCH3). HRMS m/z: calcd for C32H54NO3Si [MþH]þ:
528.3873; found: 528.3890.
*
*
*
4.3.7. (R ,E)-1-((2S ,3R )-3-(Hydroxymethyl)-1-(4-methoxybenzyl)
aziridin-2-yl)pentadec-2-en-1-ol (12a). To a solution of propargylic
alcohol 11a (50 mg, 0.095 mmol) in THF (5 ml) at 0 ꢂC was added
lithium aluminum hydride (LAH) (14 mg, 0.38 mmol, 4 equiv). The
reaction mixture was heated to reflux overnight and after cooling at
rt. MeOH (5 ml) and a saturated aqueous solution of potassium
sodium tartrate tetrahydrate (10 ml) were added. This mixture was
stirred for 1 h and Et2O (15 ml) and NaHCO3 satd (25 ml) were
added. The organic phase was separated and the aqueous phase
*
*
*
4.3.5. (R )-1-((2S ,3R )-3-((tert-Butyldimethylsilyloxy)methyl)-1-
(4-methoxybenzyl)aziridin-2-yl)pentadec-2-yn-1-ol (11a) and
*
*
*
(S )-1-((2S ,3R )-3-((tert-butyldimethylsilyloxy)methyl)-1-(4-me-
thoxybenzyl)aziridin-2-yl)pentadec-2-yn-1-ol (11b). The ketone 5
(509 mg, 0.97 mmol) was dissolved in MeOH (12 ml) and the re-
action mixture was cooled to ꢁ78 ꢂC. NaBH4 (73 mg, 1.93 mmol,

2576
S. Ballereau et al. / Tetrahedron 67 (2011) 2570e2578
was extracted with Et2O (3ꢅ15 ml). The organic extracts were
combined, dried over magnesium sulfate, and evaporated to dry-
ness. A flash chromatography on silica gel (CH2Cl2/MeOH 96:4) of
the residue gives the expected aziridine diol 12a (37.2 mg, 94%). 1H
2.35e2.05 (m, 5H, containing at 2.16 (td, 2H, H-7, J7e8¼7.1, J7e4¼1.7),
2ꢅOH and NH); 1.55e1.35 (m, 2H, H-8); 1.35e1.15 (m, 18H, H-9 to
H-17); 0.85e0.75 (m, 3H, H-18). 13C NMR (CDCl3, 75 MHz)
d (ppm):
86.9 (C-5); 79.3 (C-6); 62.1 (C-4); 61.9 (C-1); 39.2 (C-3); 35.2 (C-2);
31.9 (C-16); 29.7, 29.7, 29.7, 29.6, 29.4, 29.2, 28.9, and 28.6 (C-8 to C-
15); 22.7 (C-17); 18.8 (C-7); 14.1 (C-18). HRMS m/z: calcd for
C18H34NO2 [MþH]þ: 296.2590; found: 296.2596.
NMR (CDCl3, 300 MHz)
d (ppm): 7.30e7.10 (m, 2H, Har); 7.00e6.80
(m, 2H, Har); 5.71 (dtd, 1H, H-6, J6e5¼15.1, J6e7¼6.6, J6e4¼0.8,); 5.44
(ddt, 1H, H-5, J5e6¼15.4, J5e4¼6.5, J5e7¼1.3,); 4.01 (t, 1H, H-4,
J4e5¼J4e3¼7.2); 3.96 (dd, 1H, H-1a, J1ae1b¼11.6, J1ae2¼6.0); 3.81 (s,
3H, OMe); 3.63 (dd, 1H, H-1b, J1be1a¼11.6, J1be2¼7.5); 3.49 (AB, 2H,
CH2N, Dd¼0.11, JAB¼12.9); 2.20e2.05 (m,1H, OH); 2.05e1.90 (m, 3H,
H-2, and H-7); 1.82 (t, 1H, H-3, J3e4¼J3e2¼7.1); 1.80e1.40 (m, 1H,
OH); 1.40e1.20 (m, 20H, H-8 to H-17); 1.00e0.80 (m, 3H, H-18). 13C
*
*
*
4.3.11. (R )-1-((2S ,3R )-3-(Hydroxymethyl)aziridin-2-yl)pentade-
can-1-ol (15). A solution of compound 14a (10 mg, 0.03 mmol) in
CH2Cl2 (2 ml) was hydrogenated at atmospheric pressure for 1 h at
0 ꢂC in the presence of 10% Pd/C (5 mg). The reaction was then
filtered over Celite, and the filtrate was evaporated to dryness un-
der reduced pressure to furnish compound 15 (10 mg, quant.). 1H
NMR (CDCl3, 75 MHz)
d (ppm): 158.9 (CeOMe); 133.5 (C-6); 130.7
(Cqar); 129.8 (C-5); 129.5 (Car); 113.8 (Car); 71.4 (C-4); 63.2 (CH2N);
61.6 (C-1); 55.2 (OMe); 47.4 (C-3); 44.2 (C-2); 32.3 (C-7); 31.9 (C-
16); 29.7, 29.7, 29.7, 29.7, 29.5, 29.4, 29.3, and 29.0 (C-8 to C-15);
22.7 (C-17); 14.1 (C-18). HRMS m/z: calcd for C26H44NO3 [MþH]þ:
418.3321; found: 418.3332.
NMR (CDCl3, 300 MHz)
d
(ppm): 3.97 (dd, 1H, H-1a, J1ae1b¼11.6,
J1ae2¼5.7); 3.43 (dd, 1H, H-1b, J1be1a¼11.6, J1be2¼8.3); 3.35 (td, 1H,
H-4, J4e3¼8.0, J4e5¼6.0); 2.70e2.30 (m, 2H, OH); 2.37 (dt, 1H, H-2,
J2e1b¼8.2, J2e3¼J2e1a¼6.0); 2.11 (dd, 1H, H-3, J3e4¼8.2, J3e2¼6.7);
1.80e1.05 (m, 27H, H-5 to H-17 and NH); 0.85e0.75 (m, 3H, H-18).
4.3.8. (R ,E)-1-((2S ,3R )-3-(Hydroxymethyl)aziridin-2-yl)pentadec-
2-en-1-ol (13a). According the general procedure for PMB cleavage,
the free aziridine 13a (20 mg, 76%) was obtained after flash chro-
matography on silica gel (CH2Cl2/EtOH/MeOH/NH4OH 29:2:1:1). 1H
13C NMR (CDCl3, 75 MHz)
d (ppm): 71.9 (C-4); 62.6 (C-1); 38.8 (C-3);
*
*
*
36.5 (C-5); 34.3 (C-2); 31.9 (C-16); 29.7, 29.7, 29.7, 29.6, 29.4, 25.5
(C-6 to C-15); 22.7 (C-17); 14.1 (C-18). HRMS m/z: calcd for
C18H38NO2 [MþH]þ: 300.2903; found: 300.2901.
NMR (CDCl3, 300 MHz)
d
(ppm): 5.81 (dtd, 1H, H-6, J6e5¼15.2,
*
*
*
J6e7¼6.6, J6e4¼0.6); 5.62 (ddt, 1H, H-5, J5e6¼15.4, J5e4¼6.7,
J5e7¼1.2); 4.01 (dd, 1H, H-1a, J1ae1b¼11.7, J1ae2¼5.8); 3.91 (t, 1H, H-
4, J4e5¼J4e3¼7.3); 3.53 (dd, 1H, H-1b, J1be1a¼11.7, J1be2¼8.2); 2.50
(dt, 1H, H-2, J2e3¼J2e1b¼8.1, J2e1a¼6.1); 2.27 (dd, 1H, H-3, J3e2¼8.0,
J3e4¼6.5); 2.07 (q, 2H, H-7, J¼6.7); 1.80e1.50 (m, 3H, OH, NH);
1.50e1.10 (m, 20H, H-8 to H-17); 1.00e0.80 (m, 3H, H-18). 13C NMR
4.3.12. (S ,E)-1-((2S ,3R )-3-(Hydroxymethyl)-1-(4-methoxybenzyl)
aziridin-2-yl)pentadec-2-en-1-ol (12b). The protocol described for
the synthesis of compound 12a was applied to the propargylic al-
cohol 11b (80 mg, 0.151 mmol) with LAH (23 mg, 0.605 mmol,
4 equiv) to give after purification the expected aziridine diol 12b
(53 mg, 84%). 1H NMR (CDCl3, 300 MHz)
d (ppm): 7.30e7.10 (m, 2H,
(CDCl3, 75 MHz)
d
(ppm): 133.9 (C-6); 130.0 (C-5); 72.7 (C-4); 62.5
Har); 6.90e6.80 (m, 2H, Har); 5.68 (dtd, 1H, H-6, J6e5¼15.2, J6e7¼6.6,
J6e4¼0.8,); 5.43 (ddt, 1H, H-5, J5e6¼15.4, J5e4¼6.8, J5e7¼1.3); 3.90 (t,
1H, H-4, J4e5¼J4e3¼7.0); 3.80 (s, 3H, OMe); 3.71 (dd, 1H, H-1a,
J1ae1b¼11.7, J1ae2¼5.0); 3.59 (dd, 1H, H-1b, J1be1a¼11.7, J1be2¼6.6);
3.55e3.45 (m, 2H, CH2N); 2.05e1.95 (m, 3H, H-2, and H-7); 1.85 (t,
1H, H-3, J3e4¼J3e2¼7.0); 1.80e1.50 (m, 2H, OH); 1.40e1.20 (m, 20H,
H-8 to H-17); 1.00e0.80 (m, 3H, H-18). 13C NMR (CDCl3, 75 MHz)
(C-1); 38.4 (C-3); 34.9 (C-2); 32.3 (C-7); 31.9 (C-16); 29.7, 29.7, 29.6,
29.6, 29.5, 29.4, 29.3, and 29.0 (C-8 to C-15); 22.7 (C-17); 14.1 (C-18).
HRMS m/z: calcd for C18H36NO2 [MþH]þ: 298.2746; found:
298.2758.
*
*
*
4.3.9. (R )-1-((2S ,3R )-3-(Hydroxymethyl)-1-(4-methoxybenzyl)
aziridin-2-yl)pentadec-2-yn-1-ol (16a). To a solution of tert-butyl-
dimethylsilylether 11a (130 mg, 0.25 mmol) in THF (3 ml) at 0 ꢂC
d
(ppm): 159.1 (CeOMe); 133.2 (C-6); 130.7 (Cqar); 129.7 (Car);
129.6 (C-5); 114.1 (Car); 70.5 (C-4); 63.5 (CH2N); 60.5 (C-1); 55.2
(OMe); 48.9 (C-3); 44.9 (C-2); 32.3 (C-7); 31.9 (C-16); 29.7, 29.7,
29.7, 29.7, 29.5, 29.4, 29.3, and 29.0 (C-8 to C-15); 22.7 (C-17); 14.1
(C-18). MS (DCI/NH3): m/z¼418.1 ([MþH]þ). HRMS m/z: calcd for
C26H44NO3 [MþH]þ: 418.3321; found: 418.3335.
was added TBAF (1.0
M in THF, 0.26 mmol, 260 mL, 1.05 equiv). The
reaction mixture was stirred at rt for 2 h. Water (5 ml) was then
added and the reaction mixture was extracted with CH2Cl2
(3ꢅ10 ml). The organic extracts were combined, dried over mag-
nesium sulfate, and evaporated to dryness. A flash chromatography
on silica gel (CH2Cl2/MeOH 96:4) of the residue gives the expected
*
*
*
4.3.13. (S ,E)-1-((2S ,3R )-3-(Hydroxymethyl)aziridin-2-yl)penta-
dec-2-en-1-ol (13b). According the general procedure for PMB
cleavage, the free aziridine 13b (3 mg, 21%) was obtained after flash
chromatography on silica gel (CH2Cl2/EtOH/MeOH/NH4OH
aziridine diol 16a (85 mg, 84%). 1H NMR (CDCl3, 300 MHz)
d (ppm):
7.24 (d, 2H, Har, J¼8.4); 6.86 (d, 2H, Har, J¼8.4); 4.31 (d, 1H, H-4,
J4e3¼8.1); 3.90 (dd, 1H, H-1a, J1ae1b¼11.8, J1ae2¼5.4); 3.79 (s, 3H,
OMe); 3.61 (dd, 1H, H-1b, J1be1a¼11.9, J1be2¼7.0); 3.52 (s, 2H,
CH2N); 2.16 (td, 2H, H-7, J7e8¼7.2, J7e4¼1.4); 2.07 (t, 1H, H-3,
J3e4¼J3e2¼6.8); 2.02 (q, 1H, H-2, J2e1b¼J2e1a¼J2e3¼6.4); 1.55e1.35
(m, 2H, H-8); 1.35e1.15 (m, 18H, H-9 to H-17); 1.00e0.80 (m, 3H, H-
20:2:1:1). 1H NMR (CDCl3, 300 MHz)
d (ppm): 5.75 (dtd, 1H, H-6,
J6e5¼15.2, J6e7¼6.5, J6e4¼0.5); 5.55 (ddt, 1H, H-5, J5e6¼15.8,
J5e4¼6.7, J5e7¼1.2); 3.91 (t, 1H, H-4, J4e5¼J4e3¼6.9); 3.68 (AB of an
ABX, 2H, 2ꢅH-1, Dd¼0.11, JAB¼13.4, JAX¼6.8, JBX¼5.2); 2.49 (q, 1H,
H-2, J2e3¼J2e1b¼J2e1a¼6.5); 2.32 (t,1H, H-3, J3e2¼J3e4¼7.2); 2.05 (q,
2H, H-7, J¼6.8); 1.95e1.55 (m, 3H, OH, NH); 1.50e1.10 (m, 20H, H-8
to H-17); 0.95e0.75 (m, 3H, H-18). 13C NMR (CDCl3, 75 MHz)
18). 13C NMR (CDCl3, 75 MHz)
d (ppm): 158.9 (CeOMe); 130.4
(Cqar); 129.5 (Car); 113.8 (Car); 86.7 (C-5); 79.3 (C-6); 62.8 (CH2N);
61.1 (C-4); 61.0 (C-1); 55.2 (OMe); 48.0 (C-3); 44.0 (C-2); 31.9 (C-
16); 29.7, 29.7, 29.7, 29.6, 29.4, 29.2, 28.9, and 28.6 (C-8 to C-15);
22.7 (C-17); 18.7 (C-7); 14.1 (C-18). HRMS m/z: calcd for C26H42NO3
[MþH]þ: 416.3165; found: 416.3179.
d
(ppm): 133.6 (C-6); 129.5 (C-5); 71.2 (C-4); 61.1 (C-1); 40.1 (C-3);
36.1 (C-2); 32.3 (C-7); 31.9 (C-16); 29.7, 29.7, 29.7, 29.6, 29.5, 29.4,
29.2, and 29.1 (C-8 to C-15); 22.7 (C-17); 14.1 (C-18). HRMS m/z:
calcd for C18H36NO2 [MþH]þ: 298.2746; found: 298.2758.
*
*
*
4.3.10. (R )-1-((2S ,3R )-3-(Hydroxymethyl)aziridin-2-yl)pentadec-
2-yn-1-ol (14a). According the general procedure for PMB cleavage,
the free aziridine 14a (41 mg, 64%) was obtained after flash chro-
matography on silica gel (CH2Cl2/EtOH/MeOH/NH4OH 29:2:1:1). 1H
*
*
*
4.3.14. (S )-1-((2S ,3R )-3-(Hydroxymethyl)-1-(4-methoxybenzyl)
aziridin-2-yl)pentadec-2-yn-1-ol (16b). The protocol described for
compound 16a was applied to the tert-butyldimethylsilylether 11b
NMR (CDCl3, 300 MHz)
J4e7¼1.8); 3.91 (dd, 1H, H-1a, J1ae1b¼11.9, J1ae2¼5.3); 3.48 (dd, 1H,
H-1b, J1be1a¼11.9, J1be2¼7.4); 2.50e2.35 (m, 2H, H-2, H-3);
d
(ppm): 4.16 (dt, 1H, H-4, J4e3¼7.3,
(84 mg, 0.16 mmol) with TBAF (1.0
1.05 equiv) to give after purification the expected aziridine diol 16b
(57 mg, 86%). 1H NMR (CDCl3, 300 MHz)
(ppm): 7.27 (d, 2H, Har,
M in THF, 0.167 mmol, 167 mL,
d

S. Ballereau et al. / Tetrahedron 67 (2011) 2570e2578
2577
J¼8.4); 6.87 (d, 2H, Har, J¼8.4); 4.19 (dt, 1H, H-4, J4e3¼6.8, J4e7¼1.8);
3.79 (s, 3H, OMe); 3.65 (AB of an ABX, 2H, 2ꢅH-1, Dd¼0.09,
JAB¼13.4, JAX¼5.2, JBX¼6.2); 3.49 (AB, 2H, CH2N, Dd¼0.11, JAB¼12.6);
2.19 (td, 2H, H-7, J7e8¼7.1, J7e4¼1.7); 2.09 (t, 1H, H-3,
J3e4¼J3e2¼6.9); 2.03 (q, 1H, H-2, J2e1b¼J2e1a¼J2e3¼6.5); 1.55e1.35
(m, 2H, H-8); 1.35e1.15 (m, 18H, H-9 to H-17); 1.00e0.80 (m, 3H, H-
(Cqar); 129.7 (Car); 113.6 (Car); 90.8 (C-5); 74.9 (C-6); 71.6 (C-4); 63.4
(CH2N); 61.9 (C-1); 55.2 (OMe); 45.8 and 45.5 (C-3 and C-2); 39.3
(CH3SO3); 31.9 (C-16); 29.7, 29.7, 29.7, 29.6, 29.4, 29.2, 28.9, and 28.6
(C-8 to C-15); 25.8 (C(CH3)3); 22.7 (C-17); 18.8 (C-7); 18.2 (C(CH3)3);
14.1 (C-18); ꢁ5.3 and ꢁ5.4 (SiCH3).
18). 13C NMR (CDCl3, 75 MHz)
d
(ppm): 159.1 (CeOMe); 130.5
4.3.18. (1S ,2S ,5R )-6-(4-Methoxybenzyl)-2-(tetradec-1-ynyl)-3-
oxa-6-azabicyclo[3.1.0]hexane (20). To a solution of the crude
mesylate 19 (455 mg, 0.70 mmol) in anhydrous THF (6 ml) at rt under
*
*
*
(Cqar); 129.7 (Car); 114.0 (Car); 86.9 (C-5); 78.7 (C-6); 63.2 (CH2N);
61.1 (C-4); 60.6 (C-1); 55.3 (OMe); 49.2 (C-3); 44.4 (C-2); 31.9 (C-
16); 29.7, 29.7, 29.7, 29.6, 29.4, 29.1, 28.9, and 28.6 (C-8 to C-15);
22.7 (C-17); 18.7 (C-7); 14.1 (C-18). HRMS m/z: calcd for C26H42NO3
[MþH]þ: 416.3165; found: 416.3186.
nitrogen atmosphere was added TBAF (1.0
M in THF, 0.70 mmol,
700 L, 1.0 equiv). The reaction mixture was stirred at rt overnight
m
thenwaterwasaddedandthemixturewasextractedthreetimeswith
Et2O. The combined extracts were washed with brine, dried over
MgSO4, and concentrated in vacuum. A flash chromatography on
silica gel (CH2Cl2/EtOAc/petroleum ether 40:10:50) of the residue
gives the expected furan 20 (148 mg, 53%).1H NMR (CDCl3, 300 MHz)
*
*
*
4.3.15. (S )-1-((2S ,3R )-3-(Hydroxymethyl)aziridin-2-yl)pentadec-
2-yn-1-ol (14b). According the general procedure for PMB cleavage,
the free aziridine 14b (17 mg, 50%) was obtained after flash chro-
matography on silica gel (CH2Cl2/EtOH/MeOH/NH4OH 29:2:1:1). 1H
d
(ppm): 7.38 (d, 2H, Har, J¼8.7); 6.84 (d, 2H, Har, J¼8.7); 4.42 (q,1H, H-
NMR (CDCl3, 300 MHz)
d
(ppm): 4.16 (dt, 1H, H-4, J4e3¼6.8,
4, J4e3¼J4e7¼1.8); 4.08 (d, 1H, H-1a, J1ae1b¼9.3); 3.79 (s, 3H, OMe);
3.72 (d, 1H, CH2N, J¼13.7); 3.61 (dd, 1H, H-1b, J1be1a¼9.3, J1be2¼1.8);
3.27 (d,1H, CH2N, J¼13.7); 2.50 (dd,1H, H-3, J3e2¼5.0, J3e4¼1.9); 2.45
(dd, 1H, H-2, J2e3¼5.0, J2e1b¼1.7); 2.24 (td, 2H, H-7, J7e8¼7.4,
J7e4¼1.7); 1.60e1.45 (m, 2H, H-8); 1.40e1.20 (m, 18H, H-9 to H-17);
J4e7¼1.8); 3.66 (AB of an ABX, 2H, 2ꢅH-1, Dd¼0.03, JAB¼11.7,
JAX¼5.7, JBX¼6.0); 2.55e2.35 (m, 2H, H-2, H-3); 2.15 (td, 2H, H-7,
J7e8¼7.1, J7e4¼1.7); 1.80e1.35 (m, 5H, H-8, 2ꢅOH, and NH);
1.35e1.15 (m, 18H, H-9 to H-17); 0.85e0.75 (m, 3H, H-18). 13C NMR
(CDCl3, 75 MHz)
d
(ppm): 85.8 (C-5); 78.6 (C-6); 61.8 (C-4); 61.2 (C-
1.00e0.80 (m, 3H, H-18). 13C NMR (CDCl3, 75 MHz)
d (ppm): 158.6
1); 40.3 (C-3); 35.4 (C-2); 31.9 (C-16); 29.7, 29.7, 29.7, 29.6, 29.4,
29.2, 28.9, and 28.6 (C-8 to C-15); 22.7 (C-17); 18.8 (C-7); 14.1 (C-
18). HRMS m/z: calcd for C18H34NO2 [MþH]þ: 296.2590; found:
296.2599.
(CeOMe); 130.7 (Cqar); 129.0 (Car); 113.5 (Car); 86.7 (C-5); 75.7 (C-6);
68.8 (C-4); 68.5 (C-1); 60.0 (CH2N); 55.2 (OMe); 47.0 (C-3); 43.7 (C-2);
31.9 (C-16); 29.7, 29.7, 29.7, 29.6, 29.4, 29.2, 28.9, and 28.6 (C-8 to C-
15);22.7(C-17);19.0(C-7);14.1(C-18). Crystaldatafor20:C26H39NO2,
ꢁ
ꢁ
M¼397.58, monoclinic P 21/c, a¼21.7664 (14) A, b¼5.4045 (4) A,
3
ꢁ
ꢂ
ꢁ
*
*
*
4.3.16. (S ,Z)-1-((2S ,3R )-3-(Hydroxymethyl)aziridin-2-yl)penta-
dec-2-en-1-ol (17). A solution of compound 14b (10 mg,
0.03 mmol) in CH2Cl2 (2 ml) was hydrogenated at atmospheric
pressure for 1 h at 0 ꢂC in the presence of 10% Pd/C (5 mg). The
reaction was then filtered on Celite, and the filtrate was evaporated
to dryness under reduced pressure to furnish compound 17 (10 mg,
c¼21.7426 (15) A, ¼111.439 (4) , V¼2380.7 (3) A , Z¼4, 21,418 re-
b
flections(3882 independent, Rint¼0.1884)were collected. Largestdiff.
ꢁꢁ3
peak and hole: 0.153 and ꢁ0.166 e A , R1 (for I>2
s
(I))¼0.0568 and
wR2 (all data)¼0.1235.
*
*
*
4.3.19. (1S ,2S ,5R )-6-(4-Methoxybenzyl)-2-tetradecyl-3-oxa-6-
azabicyclo[3.1.0]hexane (21). A solution of alkyne 20 (47 mg,
0.03 mmol) in MeOH (4 ml) was hydrogenated at atmospheric
pressure for 12 h in the presence of 10% Pd/C (10 mg). The reaction
was then filtered over Celite, and the filtrate was evaporated to
dryness under reduced pressure to furnish compound 21 (47 mg,
quant.). 1H NMR (CDCl3, 300 MHz)
d (ppm): 5.51 (dt, 1H, H-6,
J6e5¼11.0, J6e7¼6.8); 5.49 (dd, 1H, H-5, J5e6¼11.0, J5e4¼8.0); 4.26 (t,
1H, H-4, J4e5¼J4e3¼8.0); 3.75 (dd, 1H, H-1a, J1ae1b¼11.8, J1ae2¼7.6);
3.58 (dd, 1H, H-1b, J1be1a¼11.9, J1be2¼7.1); 3.10e2.70 (m, 3H, OH,
NH); 2.60e2.45 (m, 1H, H-2); 2.37 (t, 1H, H-3, J3e2¼J3e4¼6.8);
2.15e1.95 (m, 2H, H-7); 1.65e1.15 (m, 20H, H-8 to H-17); 0.95e0.75
quant.). 1H NMR (CDCl3,300 MHz)
d (ppm): 7.30e7.20 (m, 2H, Har);
(m, 3H, H-18). 13C NMR (CDCl3, 75 MHz)
d
(ppm): 134.0 (C-6); 128.6
6.90e6.80 (m, 2H, Har); 4.00 (d, 1H, H-1a, J1ae1b¼9.4); 3.79 (s, 3H,
OMe); 3.75 (d, 1H, CH2N, J¼13.0); 3.67 (ddd, 1H, H-4, J4e5a¼7.5,
J4e5b¼6.3, J4e3¼1.7); 3.60 (dd, 1H, H-1b, J1be1a¼9.4, J1be2¼1.8); 3.01
(d, 1H, CH2N, J¼13.0); 2.42 (dd, 1H, H-3, J3e2¼5.2, J3e4¼1.7); 2.30
(dd, 1H, H-2, J2e3¼5.2, J2e1b¼1.7); 1.70e1.10 (m, 26H, H-5 to H-17);
0.95e0.80 (m, 3H, H-18).
(C-5); 65.9 (C-4); 61.0 (C-1); 40.6 (C-3); 36.8 (C-2); 32.0 (C-7 and C-
16); 29.7, 29.7, 29.7, 29.7, 29.5, 29.4, 29.3, and 29.0 (C-8 to C-15);
22.7 (C-17); 14.1 (C-18). HRMS m/z: calcd for C18H36NO2 [MþH]þ:
298.2746; found: 298.2764.
*
*
*
4.3.17. (R )-1-((2S ,3R )-3-((tert-Butyldimethylsilyloxy)methyl)-1-
(4-methoxybenzyl)aziridin-2-yl)pentadec-2-ynyl methanesulfonate
(19). To a solution of alcohol 11a (368 mg, 0.70 mmol) in anhy-
drous CH2Cl2 (11 ml) at 0 ꢂC under nitrogen atmosphere was added
*
*
*
4.3.20. (1S ,2S ,5R )-2-Tetradecyl-3-oxa-6-azabicyclo[3.1.0]hexane
(18). According the general procedure for PMB cleavage, the free
aziridine 18 (14 mg, 42%) was obtained after flash chromatography
on silica gel (CH2Cl2/EtOAc/MeOH 70:30:1). 1H NMR
Et3N (1.05 mmol, 146
mL, 1.5 equiv). After 15 min of stirring at the
same temperature mesyl chloride (0.98 mmol, 76
m
L, 1.4 equiv) was
(CDCl3,300 MHz)
d
(ppm): 3.88 (d, 1H, H-1a, J1ae1b¼9.6); 3.67 (td,
added and the solution was stirred at 0 ꢂC for 30 min then at rt for
1 h. The reaction was quenched by addition of water and the mix-
ture was extracted three times with CH2Cl2. The combined extracts
were washed with brine, dried over MgSO4, and concentrated in
vacuum. The crude mesylate 19 (455 mg, quant.) was used without
1H, H-4, J4e5¼6.6, J4e3¼1.0); 3.67 (dd, 1H, H-1b, J1be1a¼9.6,
J1be2¼1.0); 2.60 (d, 1H, H-2, J2e3¼3.6); 2.56 (d, 1H, H-3, J3e2¼3.6);
1.70e1.10 (m, 26H, H-5 to H-17); 1.00e0.80 (m, 3H, H-18). 13C NMR
(CDCl3, 75 MHz) d (ppm): 78.5 (C-1); 68.4 (C-4); 37.2 (C-3); 34.6 (C-
2); 31.9 (C-16); 31.0, 29.7, 29.7, 29.7, 29.6, 29.4, 26.2 (C-5 to C-15);
22.7 (C-17); 14.1 (C-18). HRMS m/z: calcd for C18H36NO [MþH]þ:
282.2797; found: 282.2808.
further purification. 1H NMR (CDCl3,300 MHz)
d (ppm): 7.30e7.25
(m, 2H, Har); 6.90e6.80 (m, 2H, Har); 4.78 (dt, 1H, H-4, J4e3¼8.4,
J4e7¼1.9); 3.85 (dd, 1H, H-1a, J1ae1b¼11.4, J1ae2¼4.2); 3.77 (s, 3H,
OMe); 3.60 (dd, 1H, H-1b, J1be1a¼11.4, J1be2¼7.2); 3.50 (AB, 2H,
CH2N, Dd¼0.15, JAB¼13.0); 3.06 (s, 3H, CH3SO3); 2.10 (td, 2H, H-7,
J7e8¼6.9, J7e4¼1.8); 2.05 (dd, 1H, H-3, J3e4¼8.4, J3e2¼6.2); 1.93 (td,
1H, H-2, J2e1b¼6.7, J2e1a¼J2e3¼4.3); 1.55e1.15 (m, 20H, H-8 to H-
17); 1.00e0.80 (m, 12H, H-18, and SitBu); 0.07 and 0.06 (2s, 6H, Si
4.4. Biological evaluations
Murine B16 melanoma cells were grown in a humidified 5% CO2
atmosphere at 37 ꢂC in DMEM medium containing Glutamax
(2 mM), and heat-inactivated FCS (10%). Compounds were added to
the cells as ethanolic solution. For compounds 13a, 13b, 14a, 14b, 15,
(Me)2). 13C NMR (CDCl3, 75 MHz)
d (ppm): 158.8 (CeOMe); 130.4

2578
S. Ballereau et al. / Tetrahedron 67 (2011) 2570e2578
and 17, (2S,3S,4S)-4-amino-2-tetradecylpyrrolidin-3-ol,37 cytotoxic
aza analog of jaspine B, was used as a positive control whereas the
natural jaspine B was used for compound 18. Control cells were
treated with the same concentration of solvent (which did not
exceed 0.5%).
After treatment with aziridine-containing analogs, cell viability
of murine B16 melanoma cells was evaluated by using the MTT
assay based on the cleavage of the tetrazolium salt MTT to formazan
crystals by metabolically active cells as described earlier.38 The
formazan crystals formed were solubilized by adding dime-
thylsulfoxide for 1 h at 37 ꢂC and quantified spectrophotometrically
using an ELISA reader (the absorbance was measured at
ꢀ
ꢀ
ꢀ
ꢀ
13. Llaveria, J.; Beltran, A; Díaz-Requejo, M. M.; Matheu, M. I.; Castillon, S.; Perez, P.
J. Angew. Chem., Int. Ed. 2010, 49, 7092e7095.
14. Ismail, F. M. D.; Levitsky, D. O.; Dembitsky, V. M. Eur. J. Med. Chem. 2009, 44,
3373e3387.
15. de Saint-Fuscien, C.; Tarrade, A.; Dauban, P.; Dodd, R. H. Tetrahedron Lett. 2000,
41, 6393e6397.
16. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 18, 4171e4172.
17. Kim, B. C.; Lee, W. K. Tetrahedron 1996, 52, 12117e12124.
18. Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H. J. J. Org. Chem. 2003, 68,
7675e7680.
19. Kim, J.-W.; Kim, Y.-W.; Inagaki, Y.; Hwang, Y.-A.; Mitsutake, S.; Ryu, Y.-W.; Lee,
W. K.; Ha, H.-J.; Park, C.-S.; Igarashi, Y. Bioorg. Med. Chem. 2005, 13, 3475e3485.
20. Ha, H.-J.; Hong, M. C.; Ko, S. W.; Kim, Y. W.; Lee, W. K.; Park, J. Bioorg. Med.
Chem. Lett. 2006, 16, 1880e1883.
21. Ha, H.-J.; Singh, A.; Kim, B.; Lee, W. K. Org. Biomol. Chem. 2011, 9, 1372e1380.
22. Lee, H. K.; Im, J. H.; Jung, S. H. Tetrahedron 2007, 63, 3321e3327.
23. Guanti, G.; Banfi, L.; Narisano, E.; Scolastico, C. Tetrahedron 1988, 44,
3671e3684.
l¼560 nm).
24. Fraga, C. A. M.; Teixeira, L. H. P.; Menezes, C. M. d. S; Sant’Anna, C. M. R.; Ramos,
M. d. C. K. V.; Neto, F. R. d. A.; Barreiro, E. J. Tetrahedron 2004, 60, 2745e2755.
25. Zhou, Q.; Snider, B. B. J. Org. Chem. 2008, 73, 8049e8056.
26. Boutin, R. H.; Rapoport, H. J. Org. Chem. 1986, 51, 5320e5327.
27. CCDC 807146 (11b) and CCDC 807147 (20) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
28. Ledroit, V.; Debitus, C.; Lavaud, C.; Massiot, G. Tetrahedron Lett. 2003, 44,
225e228.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.02.019.
References and notes
1. Hannun, Y. A.; Obeid, L. M. Nat. Rev. Mol. Cell Biol. 2008, 9, 139e150.
2. Ogretmen, B.; Hannun, Y. A. Nat. Rev. Cancer 2004, 4, 604e616.
3. Hirabayashi, Y.; Igarashi, Y.; Merrill, A. H. J. Sphingolipid Biology; Springer:
Tokyo, 2006.
29. Kuroda, I.; Musman, M.; Ohtani, I. I.; Ichiba, T.; Tanaka, J.; Gravalos, D. G.; Higa,
T. J. Nat. Prod. 2002, 65, 1505e1506.
30. Salma, Y.; Lafont, E.; Therville, N.; Carpentier, S.; Bonnafe, M. J.; Levade, T.;
ꢀ
ꢀ
Genisson, Y.; Andrieu-Abadie, N. Biochem. Pharmacol. 2009, 78, 477e485.
4. Ballereau, S.; Baltas, M.; Genisson, Y. Curr. Org. Chem., in press.
ꢀ
31. Salma, Y.; Ballereau, S.; Maaliki, C.; Ladeira, S.; Andrieu-Abadie, N.; Genisson, Y.
5. Cho, J.; Lee, Y. M.; Kim, D.; Kim, S. J. Org. Chem. 2009, 74, 3900e3904.
ꢀ
Org. Biomol. Chem. 2010, 8, 3227e3243.
6. Faugeroux, V.; Genisson, Y.; Andrieu-Abadie, N.; Colie, S.; Levade, T.; Baltas, M.
32. Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.;
Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J.
E. Tetrahedron: Asymmetry 2007, 18, 2510e2513.
Org. Biomol. Chem. 2006, 4, 4437e4439.
7. Kobayashi, J.; Cheng, J.; Ishibashi, M.; Walchli, M. R.; Yamamura, S.; Ohizumi, Y.
J. Chem. Soc., Perkin Trans. 1 1991, 1135e1137.
33. Saint-Nt; Bruker AXS: Madison, WI, 2000.
8. Ohshita, K.; Ishiyama, H.; Takahashi, Y.; Ito, J.; Mikami, Y.; Kobayashi, J. Bioorg.
Med. Chem. 2007, 15, 4910e4916.
9. Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1988, 53, 2103e2105.
10. Skepper, C. K.; Dalisay, D. S.; Molinski, T. F. Org. Lett. 2008, 10, 5269e5271.
11. Yudin, A. K. Aziridines and Epoxides in Organic Synthesis; Wiley-VCH GmbH &
and Co. KGaA: Weinheim, 2006.
34. Sadabs; Program for data correction; BrukerꢁAXS.
35. Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46, 467e473.
36. Sheldrick, G. Acta Crystallogr., Sect. A 2008, 64, 112e122.
ꢀ
37. Rives, A.; Ladeira, S.; Levade, T.; Andrieu-Abadie, N.; Genisson, Y. J. Org. Chem.
2010, 75, 7920e7923.
38. Denizot, F.; Lang, R. J. Immunol. Methods 1986, 89, 271e277.
12. Lee, W. K.; Ha, H.-J. Aldrichimica Acta 2003, 36, 57e63.