Stereoselective ring-opening of N-tert-butanesulfinylaziridines: Access to acetylenic α-amino alcohols

Article abstract of DOI:10.1055/s-2006-939063

Ring-opening of enantiopure trans and cis 2,3-disubstituted ethynyl N-tert-butanesulfinylaziridines by water under acidic conditions proved to be highly regio- and diastereoselective, leading to the corresponding enantiopure anti and syn acetylenic α-amin

Full text of DOI:10.1055/s-2006-939063

LETTER
1039
Stereoselective Ring-Opening of N-tert-Butanesulfinylaziridines: Access to
Acetylenic a-Amino Alcohols
Stereoselective
a
R
ing-Open
ë
ingof
N
-
te
t
i
t
ylaziri
i
dine
s
a Palais, Fabrice Chemla, Franck Ferreira*
Université Pierre et Marie Curie (Paris 6), Laboratoire de Chimie Organique (UMR CNRS 7611), Institut de Chimie Moléculaire (FR 2769),
case 183, 4 place Jussieu, 75252 Paris Cedex 05, France
Fax +33(1)44277567; E-mail: franck.ferreira@upmc.fr
Received 13 February 2006
In the course of our study, we reasoned that these sulfinyl-
Abstract: Ring-opening of enantiopure trans and cis 2,3-disubsti-
aziridines could be regarded as good precursors of enan-
tiopure acetylenic a-amino alcohols through the ring-
opening by oxygen-containing nucleophiles. However,
tuted ethynyl N-tert-butanesulfinylaziridines by water under acidic
conditions proved to be highly regio- and diastereoselective, lead-
ing to the corresponding enantiopure anti and syn acetylenic a-ami-
no alcohols. The regio- and stereochemistries were unambiguously despite their great synthetic potential, to the best of our
determined by NOE experiments through the formation of oxazol-
idinone derivatives.
knowledge, such ring-opening of ethynyl aziridines has
not been described to date. Thus, we report herein our re-
Key words: amino alcohols, asymmetric synthesis, aziridines, dia-
stereoselectivity, regioselectivity
sults on the regio- and stereoselective ring-opening reac-
tion of ethynyl N-tert-butanesulfinylaziridines 3 by water
under acidic conditions, which affords enantiopure acetyl-
enic a-amino alcohols 4.
Ring-opening of aziridines has been thoroughly
investigated1 and applied to numerous synthetic schemes
over the past years.2 For instance, ring-opening reactions
of aziridines by various nucleophiles have been applied to
the asymmetric syntheses of a- or b-amino acids,3 chiral
amines and diamines,4,3g a-chloro amines,5,3g a-azido and
cyano amines,6,3g b-lactams,7 oxazolidinones,4c,8 and aza-
sugars.9 In particular, aziridines were proven to be good
precursors of a- or b-amino alcohols,2g,l,10 which con-
stitute interesting building blocks for the synthesis of bio-
logically active compounds such as sphingosines and
sphinganines,11 the shingoid bases of shingolipids.
We first envisioned the ring-opening of N-tert-butane-
sulfinylaziridines 3 following Davis’ procedure, which in-
volves treatment with a mixture of TFA and H2O in
acetone at 0 °C, and which had previously been success-
fully applied to vinylic N-p-toluenesulfinylaziridines.14
However, under these conditions, no reaction occurred at
0 °C while only unidentified by-products were formed at
higher temperatures. This result has been attributed to the
much lower electrophilicity of the propargylic carbon in
aziridines 3 compared with the vinylic carbon in Davis’
10b
substrates. Other procedures using BF3·OEt2 or HClO4
as activators also failed, no reaction was observed. Final-
Recently, we disclosed a straightforward access to enan- ly, performing the reaction under acidic conditions de-
tiopure trans-N-tert-butanesulfinylaziridines 3 through scribed by Concellón and co-workers for non-activated
the condensation of the racemic allenylzinc ( )-1, derived aziridines4d was successful. These conditions allowed
from 1-chloro-3-trimethysilylpropyne, with enantiopure aziridine ring-opening and deprotection of the nitrogen to
Ellman’s N-tert-butanesulfinimines 2.12 Moreover, carry- occur at the same time, furnishing the corresponding fully
ing out the reaction in the presence of an excess of HMPA deprotected acetylenic a-amino alcohols 4 in high regio-
allowed the diastereo- and enantioselective synthesis of and diastereoselectivity. In a typical procedure,15 N-tert-
cis-N-tert-butanesulfinylaziridines 3 (Scheme 1).13
butanesulfinylaziridines 3 were refluxed (20 h) in MeCN–
H2O (7:1) in the presence of one equivalent of PTSA
(Scheme 2).
TMS
TMS
O
S
R
•
ZnBr
Cl
OH
R2
R'
(±)-1
N
S
N
R1
Et2O
R
R'
TMS
NH2
O
TMS
4
2
R1
trans-3 or cis-3
MeCN, H2O
+
R2
N
Scheme 1 Stereoselective synthesis of enantiopure trans- and cis-
N-tert-butanesulfinylaziridines 3.12,13
PTSA, reflux
NH2
R1
R2
S
O
TMS
OH
3, >99% ee
5
SYNLETT 2006, No. 7, pp 1039–1042
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939063; Art ID: G05306ST
© Georg Thieme Verlag Stuttgart · New York
0
3.
0
5.
2
0
0
6
Scheme 2 Regio- and stereoselective ring-opening of enantiopure
N-tert-butanesulfinylaziridines 3.

1040
L. Palais et al.
LETTER
After basic work-up with a saturated aqueous solution of The 2,3,3-trisubstituted aziridine 3g (with a quaternary
NaHCO3, 2,3-disubstituted aziridines 3a–f (Table 1, en- center at the homopropargylic position) gave the corre-
tries 1–9) led predominantly to acetylenic a-amino alco- sponding acetylenic a-amino alcohol 4g with a poor 1.3:1
hols 4a–f with high regio- and diastereoselectivities. regioselectivity (Table 1, entry 10). Moreover, the latter
Indeed, as seen by 1H NMR spectroscopy (400 MHz), the could not be isolated in pure form by flash chromato-
latter, formed as single diastereomers (>20:1 dr), were ac- graphy over silica gel as it is not satisfactorily separable
companied by small amounts (less than 5%) of the corre- from its regiosomer 5g. This low regioselectivity can be
sponding regioisomers 5a–f. Acetylenic a-amino alcohols explained by the enhanced electrophilicity of the quater-
4a–e were isolated in good yields (60–73%) after flash nary homopropargylic carbon of the aziridine ring under
chromatography over silica gel (Table 1, entries 1–8).
acidic conditions, which makes nucleophilic attack of
water at the homopropargylic carbon (leading to 5g) more
competitive than that at the propargylic center (leading
to 4g).
On the other hand, a-amino alcohol anti-4f was obtained
in low yield (albeit in excellent regio- and stereoselectiv-
ity) as the minor product of the reaction (Table 1, entry 9).
The major compound 6, also formed as a single stereomer In the case of unsaturated trans-aziridines 3h and 3i, only
(>20:1 dr), was isolated in good yield (70%) resulting unidentified by-products were observed, even when the
from the preferred intramolecular 6-endo-cyclization of reaction was run at –10 °C (Table 1, entries 11 and 12).
the arene moiety as previously reported by others in the Although the basis of this result still remains unclear to us,
reactions of aziridines with p-nucleophiles (Scheme 3).16
the higher reactivity of these aziridines with a vinylic and
a benzylic center could certainly be invoked: under acidic
conditions, aziridines 3h and 3i could lead to the corre-
sponding stabilized carbocations, which could undergo
subsequent side reactions.
TMS
NH2
Due to the presence of the ethynyl moiety, the structure of
compounds 4 and 5 could not be unambiguously deter-
mined from their 1H NMR data. Indeed, in regioisomers 5,
because of the electron-withdrawing nature of the carbon–
carbon triple bond, the chemical shift of the propargylic
hydrogen (i.e. CHN) could be higher than that of the
homopropargylic hydrogen (i.e. CHO).
TMS
O
6, 70%, >20:1 dr
S
N
MeCN, H2O
PTSA, reflux
+
anti-4f, 21%
(see Table 1)
trans-3f
Scheme 3 Intramolecular cyclization of aziridine trans-3f.
Table 1 Preparation of Acetylenic a-Amino Alcohols 415
Entry
1
Imine
R1
R2
a-Amino alcohol 4
anti-4a
syn-4a
4/5a
dr of 4a
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
–
Yield of 4 (%)b
trans-3a
cis-3a
Me
H
>20:1
20:1
20:1
>20:1
>20:1
>20:1
20:1
20:1
>20:1
1.3:1
–
64
66
66
71
60
66
70
73
21c
n.d.d
0e
2
H
Me
H
3
trans-3b
cis-3b
n-Pr
anti-4b
syn-4b
4
H
n-Pr
Heptyl
H
5
trans-3c
cis-3c
H
anti-4c
syn-4c
6
Heptyl
i-Pr
7
trans-3d
trans-3e
trans-3f
3g
H
anti-4d
anti-4e
anti-4f
8
c-Hexyl
PhCH2CH2
Pentyl
(E)-Cinnamyl
Ph
H
9
H
10
11
12
Pentyl
H
4g
trans-3h
trans-3i
anti-4h
anti-4i
–
H
–
–
0e
a Regio- and diastereoselectivities were measured by 1H NMR spectroscopy (400 MHz) of the crude reaction mixtures.
b Yields of purified major isomers. All new compounds were fully characterized by 1H, 13C NMR, and IR spectroscopy and optical rotation.
c a-Amino alcohol anti-4f was obtained as the minor product, the major product was formed via intramolecular addition of the arene (see
Scheme 3).
d Aziridine 4g and its regioisomer 5g were not satisfactorily separable.
e Only unidentified by-products were observed.
Synlett 2006, No. 7, 1039–1042 © Thieme Stuttgart · New York

LETTER
Stereoselective Ring-Opening of N-tert-Butanesulfinylaziridines
1041
The regiochemistry of the major products 4a–g was as- and syn-4b. A reasonable assumption is that all N-tert-
1
signed from the H NMR spectrum of oxazolidinone 8. butanesulfinylaziridines 3a–g behaved in the same man-
The latter was readily obtained in a three-step synthesis: i) ner when reacted with water in the presence of PTSA in
reaction with diphosgene (2 equiv) on activated charcoal refluxing MeCN–H2O, therefore we were able to assign
gave compound 7,17 ii) desilylation of the acetylenic moi- the stereochemistry of all acetylenic a-amino alcohols
ety, and iii) complete hydrogenation of the carbon–carbon 4a–g. The stereochemistry of the minor regioisomers
triple bond, in 41% overall yield from a-amino alcohol 5a–g could not be determined but was reasonably deduced
anti-4e (Scheme 4). The cis stereochemistry of oxazolidi- from that of acetylenic a-amino alcohols 4a–g.
none 7 was first confirmed by a strong NOE (15%) be-
tween H1 and H2. The structure of cis-oxazolidinone 8 has
further been determined unambiguously from the 1H
NMR data of H1 and H2. Indeed, their chemical shifts (i.e.
4.46 and 3.59 ppm, respectively) along with the multiplic-
ities of their signals (i.e. ddd and t, respectively) allowed
the structure of 8 to be assigned on the basis that the two
substituents of the oxazolidinone ring (i.e. the ethyl and
cyclohexyl groups) could reasonably be considered to
have comparable electronic effects. The data were fully in
accordance with the presence of a hydroxyl group at the
propargylic position in anti-4e. We could then conclude
that, as expected, all acetylenic a-amino alcohols 4a–g re-
sulted from nucleophilic attack of water at the propargylic
carbon (which is the more electrophilic center) of aziri-
dines 3a–g. On the other hand, regioisomers 5a–g were
formed in very low yields through nucleophilic attack of
water at the less electrophilic homopropargylic center.
O
diphosgene (2 equiv)
charcoal
OH
O
NH
H2
THF, 20 °C
H1
TMS
NH2
anti-4b
NOE 13%
TMS
cis-9, 62%
O
diphosgene (2 equiv)
charcoal
OH
O
NH
H2
THF, 20 °C
H1
TMS
NH2
syn-4b
TMS
NOE 3%
trans-9, 100%
Scheme 5 NOE experiments on cis- and trans-oxazolidinones 9.
It is noteworthy that under the same conditions, acetylenic
NH aziridines12 led to the analogous acetylenic a-amino
alcohols but with lower regio- and diastereoselectivities.
For instance, a poor regioselectivity of 3:1 and dr of 4:1
were attained for a-amino alcohol anti-3e from the NH
aziridine derived from N-tert-butanesulfinylaziridine
trans-3e. This result strongly suggests that aziridine ring-
opening first occurred in a SN2-like process (presumably
through the protonation of the nitrogen atom) followed by
subsequent removal of the N-tert-butanesulfinyl group on
the nitrogen under acidic conditions (Scheme 6).
O
diphosgene (2 equiv)
charcoal
OH
O
NH
H2
H1
THF, 20 °C
TMS
NH2
anti-4e
TMS
cis-7
O
O
NH
H2
1) TBAF, THF, 20 °C
H1
2) H2, Pd/C, MeOH, 20 °C
TMS
OH
R2
R1
cis-8, 41% yield (3 steps)
R1
R2
H2O
H
Scheme 4 Determination of the regiochemistry of acetylenic
a-amino alcohol anti-4e.
3a–g
TMS
NH
S
(SN2)
NH
S
O
O
The stereochemistry of acetylenic a-amino alcohols 4a–g
was determined through NOE experiments on oxazolidi-
nones cis-9 and trans-9. The latter were readily available
in good yields by the reaction with diphosgene,17 as de-
scribed above, from anti-4b and syn-4b, respectively
(Scheme 5). The cis and trans stereochemistries of ox-
azolidinones 9 were first deduced from the coupling con-
stants between H1 and H2 on the oxazolidinone ring. As
expected, the coupling constant is smaller in the cis-ox-
azolidinone (6.4 Hz) than in the trans-oxazolidinone (8.1
Hz). These stereochemistries were further confirmed by a
NOE between H1 and H2 which was found to be strong
(13%) in the cis-oxazolidinone and very small (only 3%)
in the trans-oxazolidinone. These results allowed the
trans and the cis sterochemistries to be assigned for
oxazolidinones 9 derived from a-amino alcohols anti-4b
OH
R2
H
R1
TMS
NH2
4a–g, major
Scheme 6 Postulated pathway for the formation of acetylenic
a-amino alcohols 4a–g.
In summary, we have developed a straightforward one-
step synthesis of acetylenic a-amino alcohols by
treatment of the corresponding 2,3-disubstituted ethynyl
N-tert-butanesulfinylaziridines with PTSA in refluxing
MeCN–H2O (7:1). This preparation was shown to be
highly regio- (>20:1) and diastereoselective (>20:1),
trans and cis aziridines furnished the parent anti and syn
Synlett 2006, No. 7, 1039–1042 © Thieme Stuttgart · New York

1042
L. Palais et al.
LETTER
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method to carbon- and nitrogen-containing nucleophiles,
in order to obtain the corresponding homopropargylic
amines and acetylenic a,b-diamines, and the synthetic use
of enantiopure acetylenic a-amino alcohols, are currently
under investigation in our group and will be reported in
due course.
Acknowledgment
Thanks are due to Nadia Colliot for the preparation of some N-tert-
butanesulfinylaziridines 3.
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(15) Acetylenic a-Amino Alcohols 4a–g; Typical Procedure. A
stirred solution ofN-tert-butanesulfinylaziridines 3a–g(1.00
mmol) and PTSA monohydrate (190 mg, 1.00 mmol) in
MeCN (40 mL) and H2O (5.7 mL) was refluxed for 20 h.
After cooling to r.t., a sat. aq solution of NaHCO3 (40 mL)
and CH2Cl2 (40 mL) were added and the resulting mixture
was stirred for 15 min at r.t. The layers were then separated
and the aqueous layer was extracted with CH2Cl2 (3 ꢀ 40
mL). The combined organic layers were washed with a sat.
aq solution of NaHCO3 (40 mL), dried over anhyd Na2SO4,
and concentrated in vacuo. The residual oil was purified by
flash chromatography over silica gel (CH2Cl2 → MeOH–
CH2Cl2, 1:9) to first give regioisomers 5a–g and then the
corresponding diastereo- and enantiomerically pure
acetylenic a-amino alcohols 4a–g.
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Synlett 2006, No. 7, 1039–1042 © Thieme Stuttgart · New York