Enantioselective Synthesis of 3-Heterosubstituted-2-amino-1-ols by Sequential Metal-Free Diene Aziridination/Kinetic Resolution

Article abstract of DOI:10.1002/chem.201902734

A general protocol for the enantioselective synthesis of 3-heterosubstituted-2-amino-1-ols was developed based on metal- free intramolecular regio- and stereoselective diene aziridination and regioselective opening. Kinetic resolution of the resulting (1′-NR¹R² and 1′-SR)-4-oxazolidinones was performed using ABCs organocatalysts, expanding the application of this methodology.

Full text of DOI:10.1002/chem.201902734

A Journal of
Accepted Article
Title: Enantioselective Synthesis of 3-Heterosubstituted-2-amino-1-ols
by Sequential Metal-free Diene Aziridination/Kinetic Resolution
Authors: Irene Gimenez-Nueno, Joan Guasch, Ignacio Funes-Ardoiz,
Feliu Maseras, Isabel Matheu, Sergio Castillón, and Yolanda
Díaz
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To be cited as: Chem. Eur. J. 10.1002/chem.201902734
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10.1002/chem.201902734
Chemistry - A European Journal
RESEARCH ARTICLE
Enantioselective Synthesis of 3-Heterosubstituted-2-amino-1-ols
by Sequential Metal-free Diene Aziridination/Kinetic Resolution
Irene Giménez-Nueno,[a] Joan Guasch, [a] Ignacio Funes-Ardoiz, [b] Feliu Maseras, [b,c]
M. Isabel Matheu, [a] Sergio Castillón*[a] and Yolanda Díaz*[a]
However, publications on this approach are scarce.7 In addition,
only few reports deal with the intermolecular metal-free
preparation of vinylaziridines based on the use of DppONH2/R3N8
and PhthNNH2 (Scheme 1Bi), whereas there are no reports
Abstract
9
A
general protocol for the enantioselective synthesis of 3-
heterosubstituted-2-amino-1-ols was developed based on metal-
free intramolecular regio- and stereoselective diene aziridination and
regioselective opening. Kinetic resolution of the resulting (1’-NR and
1’-SR)-4-oxazolidinones was performed using ABCs organocatalysts,
expanding the application of this methodology.
concerning the intramolecular version. Along these lines, metal-
free aziridination of simple alkenes can be effected in the
presence of PhthNNH2/PhI(OAc)2 system10 or via in situ formation
of intermediate iminoiodinane11 (Scheme 1Bii).The intramolecular
formation of aziridinium intermediates has also been described.12
The increased concern in developing greener processes for
already known chemical transformations13 has favoured the use
of hypervalent iodine reagents as interesting surrogates of
transition metal catalysts.14 Thus, most of the processes for metal-
free intramolecular aziridination are based on the use of I(III)
reagents, and particularly iodosobenzene (PhIO).11 Moreover,
despite the current interest in metal-free alkene functionalisation,
Introduction
Vinylaziridines have recently emerged as important intermediates
for the synthesis of pharmaceutical drugs and natural occurring
products.1 The thoroughly studied reactivity of the strained
aziridine ring along with the possibility of later double bond
functionalisation, make them versatile building blocks in organic
synthesis.2 General methods for the direct preparation of
vinylaziridines include the Darzens-type reaction, the addition of
allyl ylides or benzylsulfonium salts (Corey-Chaykvozky reaction)
to imines, the ring-opening/closing of vinyl epoxides and the ring
closing of 1,2-aminohalides (Scheme 1A).2a,b Moreover, the
addition of a nitrene moiety into a conjugated diene has drawn
much attention in the past few years (Scheme 1A).3 In particular,
remarkable examples on metal-catalysed intermolecular
aziridination of conjugated double bonds in the presence of
mechanistic
studies
regarding
PhIO-mediated
amination/aziridination reactions are still missing.
Within this context, our group became interested in the use of
vinylaziridines as intermediates for the synthesis of unsaturated
vicinal amino-alcohols related to relevant lipids occurring in
nature.6a,b We have previously reported a rhodium-catalysed
regio- and stereoselective oxyamination of dienes via tandem
intramolecular aziridination/ring-opening (Scheme 1C).7b
Despite the outstanding control of the regioselectivity obtained at
the ring opening step (SN2 vs. SN2’), based on the precise choice
of the Rh catalyst, the method suffered from a lack of flexibility:
the carboxylate ligands from hypervalent iodine reagent
(PhI(OR2)2), released to the reaction medium, produced the in situ
ring opening of the aziridine intermediate, thus preventing the
discretional use of an external nucleophile.
As part of our interest in building-up a general protocol for
synthesizing 3-heterosubstituted-2-amino-1-ol derivatives, we
envisioned an intramolecular metal-free aziridination strategy
amenable to be coupled with a sequential ring opening using an
external nucleophile of choice (Scheme 1D). The resulting
racemic oxazolidinones could be then subjected to an
organocatalysed kinetic resolution applying a reported procedure
by our group15 to obtain enantioenriched synthetic intermediates
bearing both the nucleophile and the amino moiety in a 1,2-array.
Here we report our results on the one-pot PhIO mediated
intramolecular aziridination/ring-opening of dienyl carbamates in
the presence of O-, N-, S-nucleophiles and the generalisation of
our BTM-catalysed kinetic resolution for substrates bearing
alternative heteroatoms and groups adjacent to the oxazolidinone
ring. A DFT mechanistic study on aziridine formation from PhIO
as well as the final synthesis of two sphingosine analogues have
also been performed.
sulfamates,4
sulfonamides,1a,b
aryl
azide5
or
[N-(p-
toluenesulfonyl)imino]phenyliodinane (PhI=NTs)1c,d,6 as nitrene
sources can be found at the literature. Common problems related
to this approach are the control of the regioselectivity as well as
the stereoselectivity, since cis/trans isomerization has been
observed for some metals. Metal-catalysed intramolecular diene
aziridination can overcome former regioselectivity issues.
[a]
I. Giménez-Nueno, Dr. Joan Guasch, Prof. M. Isabel Matheu, Prof.
Sergio Castillón, Dr. Yolanda Díaz
Department de Química Analítica i Química Orgànica
Universitat Rovira I Virgili C/ Marcel·lí Domingo nº 1.
430077, Tarragona (Spain)
E-mail: sergio.castillon@urv.cat and yolanda.diaz@urv.cat
Dr. I. Funes-Ardoiz, Prof. F. Maseras
Institut Català de Investigació Química (ICIQ)
The Barcelona Institut of Science and Technology
C/Paisos Catalans 16, 43007, Tarragona (Spain)
[b]
[c]
Prof. F. Maseras
Departament de Química, Universitat Autònoma de Barcelona
08913 Bellatera (Spain)
Supporting information and the ORCIS identification number(s) for
the authors of this article can be found xxxxxxxxxxxxx
1
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10.1002/chem.201902734
Chemistry - A European Journal
RESEARCH ARTICLE
3 resulted in an important decrease
of
yield
due
to
product
decomposition under prolonged
contact with silicagel.
At this point, thorough analysis of the
reaction crude NMR spectra
revealed the presence of two by-
products:
oxazolidinone (±)-4 (up to 20%
NMR-yield) and mixture of
chloro
substituted
a
epoxides (±)-5trans and (±)-5cis
(≤5% NMR-yield) (see Table S1 in
Supporting Information for
a
preliminary study on PhIO-mediated
diene epoxidation).
Whereas epoxide subproducts were
consistently obtained in all reactions,
the yield in the chloro derivative
proved erratic and significantly
varied depending of the substrate
batch. Hence, we sought the proper
conditions for optimal aziridination
reaction,
free
of
chlorinated
subproducts. Chlorinated solvents
have been reported to form either Cl
radicals or HCl that in situ opened
fused-ring intermediates with
a
similar chemical structure than
vinylaziridine (±)-2.17
Taking into account this piece of
information,
PhIO-mediated
aziridination was carried out in the
presence of dibutylhydroxytoluene
(butylated hydroxytoluene, BHT) as a radical scavenger. However,
the final yield on (±)-3 did not improve after overnight stirring while
a relevant percentage of chlorinated oxazolidinone (±)-4 was still
generated (Table 1, entry 14).
Optimisation of the reaction conditions showed that
recrystallisation of the apparently pure carbamate 1 resulted in a
dramatic improvement in methoxy oxazolidinone (±)-3 yield,
formed in a remarkable 95% NMR-yield (70% isolated yield)
(Table 1, entry 15).
Scheme 1. A. General protocols for diene aziridination. B. Metal-free strategies
for alkene aziridination. C. Consecutive metal-catalysed intramolecular
aziridination/opening from dienyl carbamates. D. This work: Synthesis of vinyl-
aziridines by metal-free intramolecular diene aziridination and in situ conversion
into 3-substituted derivatives.
Results and Discussion
We then became interested in testing alternative sources of
hypervalent iodine reagent as oxidants for the intramolecular
aziridination reaction. However, when carbamate 1 was reacted
with PhI(OAc)2 or PhI(OCOCF3)2 under the optimised conditions,
no reaction or starting material decomposition, respectively, was
observed (Table 1, entries 16 and 17).
Then, we carried out DFT calculations to clarify some of these
experimental aspects. We used the M06-2X functional18 and
included the solvent implicitly by the SMD method (see the
Supporting Information for full computational details).19,20 We first
analysed the difference between the I(III) sources. We computed
the thermodynamics for the nitrene formation from the
carbamate substrate 1 and each of the three precursors.21 We
used a trimeric structure of PhI=O as a model for the polymeric
structure of this precursor (see Scheme 2).22
At the outset of this project, model carbamate 1 was initially
treated with PhIO in the presence of 4Å molecular sieves to form
vinylaziridine intermediate (±)-2 which was directly opened in the
reaction medium using methanol as a nucleophile to finally furnish
the desired oxazolidinone (±)-3 in an overall 56% NMR-yield as a
single diastereomer with complete regiocontrol (Table 1, entry 1).
Initial optimisation proved that solvent was a crucial factor for the
final outcome of the reaction.16 Chlorinated solvents gave the
highest yields for the aziridination/ring-opening procedure (Table
1, entries 1 and 2) whereas oxazolidinone (±)-3 was only formed
up to 18% NMR-yield for all the other solvents tested (Table 1,
entries 3-8). Working at higher concentrations (0.10 M of CH2Cl2)
had a negative effect in conversion (Table 1, entry 9).
Disappointingly, alternative desiccant agents or different
temperatures did not improve the final reaction yields (Table 1,
entries 10-13). Therefore, only a moderate 61% NMR-yield over
two steps was obtained after initial screening, even though
We found the transformation to be slightly endergonic for PhI=O
(0.8 kcal/mol per nitrene unit). We consider that the use of
molecular sieves in the experimental setup can be sufficient to
displace the equilibrium towards the formation of the nitrene.
1
complete consumption of starting material was confirmed by H-
NMR. Moreover, preliminary attempts to isolate oxazolidinone (±)-
2
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10.1002/chem.201902734
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RESEARCH ARTICLE
In contrast, the analogous process for both PhI(OAc)2 and
PhI(COCF3)2 was found to be significantly more endergonic,
which agrees with the lack of experimental reactivity. We
attribute this behaviour to the low basicity of the corresponding
acetate or trifluoroacetate moieties in the PIDA and PIFA
reactants.
We also analysed computationally the detailed mechanism for
the intramolecular nitrene transfer from intermediate 1t (Figure
1). The first step is a conformational rearrangement from 1t to 2t
via rotation around the C-O bond. From 2t, we explored two
different mechanisms for the aziridine formation: concerted
(Figure 1, black) and bimolecular (Figure 1, grey). The
bimolecular path was discarded due to the high free energy of
the TS 5t-6t transition state (30.3 kcal/mol). A non-productive
stepwise mechanism was also considered and dismissed (see
Supporting Information for details).
Table 1. Intramolecular aziridination of dienyl carbamates
1
with PhIO.
Optimisation of reaction conditions.[a]
Figure 1. Free energy profile of the aziridine formation from the iminoiodinane
intermediate. Energies in kcal/mol.
Desiccant
agent
Temp
(ºC)
35
Yield
(%)[b]
56
Entry
Solvent (M)
1
2
CH2Cl2 (0.04)
1,2-DCE (0.04)
CH3CN (0.04)
Toluene (0.04)
Benzene (0.04)
CF3-Benzene (0.04)
THF (0.04)
4Å M.S.
4Å M.S.
4Å M.S.
4Å M.S.
4Å M.S.
4Å M.S.
4Å M.S.
4Å M.S.
4Å M.S.
MgSO4
Na2SO4
4Å M.S.
4Å M.S.
4Å M.S.
4Å M.S.
-
35
61
3
35
18
4
35
15
5
35
13
6
35
C.M.[c]
C.M.[c]
7
35
C.M.[c]
8
1,4-Dioxane (0.04)
CH2Cl2 (0.10)
CH2Cl2 (0.04)
CH2Cl2 (0.04)
CH2Cl2 (0.04)
CH2Cl2 (0.04)
CH2Cl2 (0.04)
CH2Cl2 (0.04)
CH2Cl2 (0.04)
CH2Cl2 (0.04)
35
9
35
18
18
10
11
12
13
14[d]
15[e]
16[e,f]
17[e,g]
35
35
14
r.t.
35
Figure 2. 3D Structures of the concerted transition states TS 2t-3t and the
conformer TS 2t-3t’. Relevant bond distances in Å.
Reflux
35
52
32
35
95(70)
-
35
-
35
C.M.[c]
[a] Carbamate 1 (1 equiv.), PhIO (2 equiv.), desiccant agent (100 mg per 0.1
mmol carbamate 1). MeOH as a quenching agent (2 mL). [b] Determined by
1H NMR spectroscopy using 1,3-dinitrobenzene as an internal standard
(isolated yield). [c] Complex mixture. [d] 10 mol% of radical inhibitor BHT. [e]
Recrystallised carbamate
PhI(OCOCF3)2 (2 equiv.).
1 (1 equiv.). [f] PhI(OAc)2 (2 equiv.). [g]
The concerted pathway has its highest free energy point (23.2
kcal/mol) at transition state TS 2t-3t. Interestingly, there are two
conformers of the transition state: the most stable one (Figure 2,
left) has a dispersion interaction between the phenyl group and
the distal double bond of the substrate, while the least stable
(Figure 2, right) has the phenyl group pointing out. We confirmed
the concerted character of the preferred transition state via IRC
calculation, although the aziridine formation is highly
asynchronous. The N-C2 bond (on the O side of the substrate
chain) is formed first. The asymmetry in the forming C-N bond
lengths is 0.64 Å in the transition state. More details are giving in
Figure S3 in the Supporting Information. The concerted
character of the transition state, together with the presence of
Scheme 2. Thermodynamics of the iminoiodinane formation from PhIO
trimeric structure, PhI(OAc)2 or PhI(OOCCF3)2. and substrate 1 (R-NH2 = 1).
Free energies in kcal/mol.
3
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10.1002/chem.201902734
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RESEARCH ARTICLE
dispersion interactions, are promising hints towards the
development of an enantioselective process using a chiral
hypervalent iodine reagent.
steps. Further improvement of the ring-opening yield was
achieved by switching to PhSNHEt3 as the nucleophile, furnishing
oxazolidinone (±)-15 in a 63% yield (40% isolated yield).
Aziridination scope and subsequent opening with methanol was
then studied for carbamates containing different side-chains 6-8
(Scheme 3). Reactions under the optimised conditions led to the
aziridine intermediates 9-11, as judged by TLC, which were
sequentially opened by addition of methanol to give compounds
12-14 in good yields, although the aziridination step required
longer reaction times or increased temperatures (Scheme 3).
As mentioned before, one of the main advantages of the present
metal-free aziridination strategy is the possibility to select external
nucleophiles to perform the ring-opening step, providing
differently substituted oxazolidinones. According to previous
strategies,6a,23 several oxygen, nitrogen, and sulphur nucleophiles
were chosen in order to explore the scope of the ring-opening step
(Scheme 3). Moderate to high yields were achieved after
optimisation of the reaction conditions for each nucleophile (see
Supporting Information for the complete optimisation study).
Initially, we tested the ring-opening step using water as a
nucleophile in order to directly introduce the alcohol moiety.
However, the molecular sieves present in the reaction medium
trapped the water added, leading to low reaction yields. Driving
the reaction in two different basic media (K2CO3, KOH), even in
the presence of DMSO for avoiding the formation of a two-phase
system, led to discouraging results (See SI, Table S2). Finally,
hydroxy oxazolidinone (±)-19 was generated along with a small
percentage of the SN2’ ring-opening product 20 in a promising
70% overall yield using a mixture of H2O in MeCN (See SI, Table
S2). Likewise, long-chain oxazolidinone (±)-21 was also prepared
in 32% overall yield applying the same ring-opening strategy
(Scheme 3). Moreover, another O-containing analogue, acetoxy
oxazolidinone (±)-16, was synthesised using an excess of NaOAc
salt in the presence of catalytic amounts of 15-crown-5 ether (See
SI, Table S3) (Scheme 3).
As part of our increased interest on the synthesis of sphingolipid
analogues as potential SK1 inhibitors for cancer treatment, we
envisioned the possibility of applying the PhIO-mediated
aziridination/ring-opening methodology to the preparation of new
sphingosine analogues bearing substituents in a syn-relative
configuration starting from (2Z,4E)-hexa-2,4-dien-1-yl carbamate
27 (Scheme 4). The synthesis of this starting material was
accomplished through a four-step procedure from commercially
available propargyl alcohol 22. Initial carbamoylation reaction
followed by a Sonogashira coupling with trans-1 bromo-1-
propene6b gave access to enyne carbamate 24. Subsequent
platinum-catalysed hydrosilylation reaction24 furnished a mixture
of E-silylenones 25 and 26, which were finally treated with TBAF
to afford 27 (Scheme 4a).
The recrystallised (2Z,4E)-dienyl carbamate 27 was then
submitted to the PhIO-mediated aziridination reaction under the
optimised conditions to give vinylaziridine (±)-28, which was
subsequently treated with the same set of nucleophiles used for
the ring-opening step of (±)-2 to afford compounds (±)-29-33
(Scheme 4b). In general, final oxazolidinone yields were lower
than those previously observed for 2E,4E dienyl carbamate 1.
For the introduction of N-nucleophiles, benzylamine and
potassium phthalimide were selected. The ring-opening reaction
proceeded smoothly when benzylamine was directly added to the
reaction mixture, providing full conversion to oxazolidinone (±)-18
which was isolated in a 48% yield over two steps, due to product
decomposition during column chromatography (Scheme 3).
Phthalimide, however, was a more challenging nucleophile that
required an intense optimisation work (See SI, Table S4). The
best results were obtained upon treatment of vinyl aziridine
intermediate (±)-2 with potassium phthalimide and catalytic
amounts of 18-crown-6 ether, to furnish oxazolidinone (±)-17 in a
40% overall yield (Scheme 3).
Scheme 3. Aziridination of carbamates 1,6-8 and opening of vinylaziridines (±)-
2, 9-11 to give 3-OR-, 3-NR1R2-, 3-SPh- and 2-amino-4-ene-1-ols.
Finally, thiophenol was selected to illustrate the ring-opening step
with S-containing nucleophiles. Preliminary results suggested that
the soft and slightly acid character of this nucleophile favoured
SN2’ ring-opening product over the SN2 oxazolidinone (±)-15 (See
SI, Table S5). In fact, slow addition of PhSH led to a substantial
increase in the formation of SN2 product (±)-15. Then, considering
previous ring-opening examples, NaSPh salt was tested as
nucleophile for the ring opening step (See SI, Table S5). However,
no nucleophile incorporation was observed when intermediate
vinyl aziridine (±)-2 was directly treated with the solid salt.
Attempts to solubilise NaSPh in different organic solvents were
unsuccessful. However, the addition of catalytic amounts of 15-
crown-5 ether triggered PhSNa solubilisation and nucleophilicity
providing the desired oxazolidinone (±)-15 in a 55% yield for two
Looking for an explanation for this fact, we also explored
computationally the mechanism of the 2Z,4E substrate 27. In this
case, the free energy barrier for the aziridine formation is 26.4
kcal/mol, 3.2 kcal/mol higher than that from the corresponding
2E,4E substrate (see Figure S4 in the Supporting Information),
which may be the reason for observed lower yields. This higher
barrier can be rationalized due to the lack of the dispersion
interaction between the PhI moiety and the second double bond.
Especially notorious was the case of phenyl sulfanyl
oxazolidinone (±)-33 (Scheme 4b). When the optimised
PhSNHEt3 salt was used as a nucleophile, oxazolidinone (±)-33
was not obtained. By switching the nucleophile to a mixture of
4
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10.1002/chem.201902734
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RESEARCH ARTICLE
NaSPh and catalytic amounts of 15-crown-5 ether, we were able
to form product (±)-33, although in low yields. Nevertheless, all
oxazolidinone products were isolated as single diastereomers.
Syn-configuration was assigned based on the different chemical
shifts and coupling constants of the oxazolidinone ring in this
series when compared to the NMR-spectra of related anti-
products. The formation of diastereomerically pure anti- or syn-
products from both the E,E- and the Z,E dienyl carbamates,
respectively, accounts for the stereospecificity of the whole
process, involving the alkene aziridination but also the ring
opening.
an enantioselective N-acylation of the corresponding lactame.15,25
The interaction between the carbonyl moiety present at the
protecting group and the heterocyclic thiazolium cation formed
after the initial acylation of the BTM catalyst favoured the
stabilisation of the reactive transition state. We hypothesised that
S- and N-containing oxazolidinones could also be used as starting
materials for the former kinetic resolution since the PhS group, or
the carbonyl moieties from phthalimide group, could favour the
stabilisation of the transition state in a similar way. Thus, S-
substituted oxazolidinones, (±)-15 and (±)-33, and N-substituted
oxazolidinones, (±)-17 and (±)-30, previously obtained from the
PhIO mediated aziridination/ring-opening methodology, were
submitted to kinetic resolution conditions using (S)-BTM
as catalyst (Scheme 5). To our delight, both anti-
oxazolidinones (±)-15 and (±)-17 underwent the kinetic
resolution
in
good
yields
and
remarkable
enantioselectivities, 94% ee and 98% ee for the acylated
products (S,R)-34 and (S,R)-35 and 90% ee and 85% ee
for the recovered starting material (R,S)-15 and (R,S)-17,
respectively. However, only moderate selectivities were
observed for the syn-S-substituted oxazolidinone (±)-33
whereas syn-N-substituted oxazolidinone (±)-30 proved
to be mainly unreactive under the kinetic resolution
conditions due to its low solubility in the reaction medium.
With the aim of exploiting this methodology in the
synthesis of biologically relevant molecules such as
sphingosine analogues, the enantioenriched acylated
oxazolidinones were further elaborated via a cross-
metathesis reaction to introduce the characteristic
aliphatic chain of these natural products. Only anti-
substituted oxazolidinones (S,R)-34 and (R,R)-35
rendered the desired elongated products (S,R)-38 and
(R,R)-39 when they were treated under optimised cross-
metathesis conditions (Scheme 5).14 The reason for this
lack of reactivity of syn isomers is not clear and has not
been addressed but could be due to steric clash between
the catalyst and the syn-heteroatomic substituted
oxazolidinone.
Deprotection of the terminal amino-alcohol moiety was
accomplished to finally obtain two enantioenriched
sphingosine analogues with the same configuration than that of
the natural occurring product bearing a thiophenol group (S,R)-40
and a primary amine (R,R)-41 at the 3-position respectively
(Scheme 5).
Scheme 4. a) Synthesis of cis-trans-dienylcarbamate 27. b) One-pot
aziridination/ring-opening of carbamate 27 with O-, N- and S-nucleophiles.
Conclusions
A general protocol for accessing (1’-OR, 1’-NR and 1’-SR)-4-
oxazolidinones in a regio- and stereoselective manner was
developed based on a metal-free intramolecular aziridination of
dienyl carbamates to give vinylaziridines and subsequent opening
with the corresponding nucleophiles. This method could be
expanded to the introduction of carbon nucleophiles.23 The
organocatalyzed kinetic resolution of the so obtained racemic
oxazolidinones gives access to enantioenriched 3-NHR- and 3-
SR-2-amino-4-ene-1-ols. This general protocol was applied to the
enantioenriched synthesis of (2S,3R)-3-deoxy-3-SPh- and
(2R,3R)-3-amino-3-deoxy-sphingosine derivatives via cross-
metathesis reaction and removal of protecting groups. A DFT
mechanistic study on PhIO promoted aziridination is also
Scheme 5. Kinetic resolution of intermediate anti-oxazolidinones (±)-15, (±)-17
and syn-oxazolidinones (±)-30, (±)-33 and final synthesis of sphingosine
analogues (S,R)-40 and (R,R)-41 via cross-metathesis and deprotection.
We have recently reported an efficient BTM-catalysed kinetic
resolution of several O-acyl protected hydroxy oxazolidinones via
5
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10.1002/chem.201902734
Chemistry - A European Journal
RESEARCH ARTICLE
set collection of computational results is available in IoChem-BD
repository.33
provided, including an explanation for the remarkable
performance of PhIO over other related I(III) reagents for this
transformation.
Acknowledgments
Experimental Section
Financial support by the Ministerio de Economia y Competividad
(Mineco), Spain (CTQ2017-89750-R) and the European Regional
Development Fund are gratefully acknowledged. I.G-N. thanks
Mineco for a predoctoral FPI fellowship (Ref: BES-2015-074435)
and J.G. thanks Generalitat de Catalunya for a FI fellowship. F.M.
and I.F-A. thank the financial support from the CERCA
Programme/Generalitat de Catalunya and MINECO (Project
CTQ2017-87792-R). I.F-A thanks the Severo Ochoa predoctoral
training fellowship (Ref: SVP-2014-068662).
General procedure for one-pot PhIO mediated Aziridination/Ring-
Opening. A flame dried Schlenk containing a magnetic stirring bar was
charged with activated 4Å M.S. (100 mg / 0.1 mmol carbamate) in distilled
CH2Cl2 (0.04M) under argon atmosphere. Dienyl carbamate (0.1 mmol)
and PhIO (0.2 mmol) were added and the heterogeneous mixture was
stirred at 35ºC unless stated in the specific procedure until TLC showed
complete consumption of the starting material. Nucleophile was then
added and the reaction mixture was stirred overnight. The crude solution
was filtered over celite, abundantly washed with CH2Cl2 and concentrated
under reduced pressure. The yield over the two steps was determined by
1H-NMR spectroscopy, using 1,3-dinitrobenzene as internal standard. The
reaction crude was initially purified through
chromatography (2-3 cm) in order to avoid product decomposition under
prolonged contact with silicagel.
a
short column
Conflict of interest
The authors declare no conflict of interest
General procedure for the BTM-catalysed kinetic resolution of
oxazolidinones with isobutyric anhydride. The reactions were set at the
globe box. The catalyst was used within a solution which was prepared by
dissolving (S)-BTM (10.1 mg, 0.04 mmol) and DIPEA (131 µL, 0.75 mmol)
in CHCl3 (4.9 mL). One dram vial
Keywords: vinylaziridines synthesis• metal-free aziridination •
carbamates kinetic resolution • organocatalysis • ABC catalysts •
enantioselectivity • sphingosine analogues
was charged with the oxazolidinone substrate (0.10 mmol) and 0.5 mL of
the catalyst solution. Then 100 mg of Na2SO4 were added and the reaction
mixture was magnetically stirred for 5 min before being treated with
isobutyric anhydride (0.075 mmol). The reaction mixture was kept under
stirring and followed by 1H NMR. Methanol was finally added to quench
the reaction.
1
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mmol) was then added and the solution was cooled to 0ºC. Stirring was
continued for approximately 20 min and DMAP (2.5 mol%) and (iPrCO2)O
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0ºC for one hour and then warmed to room temperature. After completion,
the crude was concentrated under reduced pressure.
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General procedure for the cross metathesis of alkenyl
oxazolidinones with terminal olefins.15 A two-neck round-bottom flask
fitted with a reflux condenser was charged with a solution of alkenyl
oxazolidinone (0.10 mmol) in dry dichloromethane (0.05 M). Terminal
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Computational Methods
All the calculations were performed using Gaussian09 program package
(Rev. D01).27 We chose the M06-2X method28
based on its well-
5
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recognized accuracy in iodine(III) chemistry.29 In addition, all the
structures were optimized in solution considering the experimental solvent
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method.30 We carried out the optimizations and frequency calculations
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further refined using the 6-311++G(d,p) basis set for C, H, N and O
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All the stationary points were characterized as minima or as transition
states by frequency analyses (zero imaginary frequencies for minima and
one for transition states). Transition states were connected towards
reactants and products using IRC calculation when needed. All the
energies shown along the manuscript are free energies in solution
calculated at standard conditions (298 K and 1 atm) and in kcal/mol. A data
6
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10.1002/chem.201902734
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RESEARCH ARTICLE
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RESEARCH ARTICLE
Table of contents
RESEACH ARTICLE
I. Giménez, J. Guasch, I. Funes-Ardoiz,
F. Maseras, M.I. Matheu, S. Castillón,*
Y. Díaz*
Page No. – Page No.
Enantioselective synthesis of 3-
Heterosubstituted-2-amino-1-ols by
sequential metal-free diene
Metal-free intramolecular aziridination of dienyl carbamates afforded vinylaziridines that
were opened with different nucleophiles. Kinetic resolution via ABC-catalysed acylation
of the so obtained racemic oxazolidinones allows to stablish a general protocol for
obtaining 3-heterosubstituted 2-aminoalcohols with high enantioselectivity. The efficiency
of this methodology was demonstrated by preparing enantioenriched (2S,3R)-3-deoxy-
3-SPh- and (2R,3R)-3-amino-3-deoxy-sphingosine derivatives.
aziridination/kinetic resolution
8
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