Enantioselective Synthesis of Aminodiols by Sequential Rhodium-Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine-Based Catalysis

Article abstract of DOI:10.1002/chem.201705670

Regio- and stereoselective oxyamination of dienes through a tandem rhodium-catalysed aziridination–nucleophilic opening affords racemic oxazolidinone derivatives, which undergo a kinetic resolution acylation process with amidine-based catalysts (ABCs) to achieve s values of up to 117. This protocol was applied to the enantioselective synthesis of sphingosine.

Full text of DOI:10.1002/chem.201705670

A Journal of
Accepted Article
Title: Enantioselective Synthesis of Aminodiols by Sequential Rh-
Catalysed Oxyamination/Kinetic Resolution. Expanding the
Substrate Scope of Amidine-Based Catalysis
Authors: Joan Guasch, Irene Giménez, Ignacio Funes-Ardoiz, Isabel
Matheu, Feliu Maseras, Sergio Castillón, Yolanda Díaz, and
Miguel Bernús
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To be cited as: Chem. Eur. J. 10.1002/chem.201705670
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Enantioselective Synthesis of Aminodiols by Sequential
Rh-Catalysed Oxyamination/Kinetic Resolution. Expanding
the Substrate Scope of Amidine-Based Catalysis
Joan Guasch,[a],§ Irene Giménez-Nueno,[a],§ Ignacio Funes-Ardoiz,[b] Miguel Bernús,[a]
M. Isabel Matheu,[a] Feliu Maseras,[b,c] Sergio Castillón*[a] and Yolanda Díaz*[a]
Abstract: Regio- and stereoselective oxyamination of dienes
through
a tandem rhodium catalysed aziridination-nucleophilic
opening affords racemic oxazolidinone derivatives, which undergo a
kinetic resolution acylation process using ABCs (amidine-based
catalysts) achieving s values up to 117. This protocol was applied to
the enantioselective synthesis of sphingosine.
Introduction
Vicinal amino alcohol and 2-amino-1,3-diol derivatives (I,
Scheme 1) are common structural motifs present in nature.
Relevant members of this family are sphingoid bases,[1]
sphinganines and clavaminol derivatives,[2] which play important
roles in physiological processes. In particular, sphingolipids,
components of the cell membrane in living organisms, have been
reported to be involved in cell recognition and signal
transduction,[3] and show antitumor,[4] immune-modulatory,[5] and
immunosuppressive activities.[6] Their syntheses commonly
involve chiral pool approaches.[7]
An alternative strategy for the syntheses of vicinal amino
alcohol-containing compounds relies on the transition metal-
catalysed (osmiun, rhodium, palladium, copper or platinum)
oxyamination of allyl carbamates.[8] However, the oxyamination of
dienols to afford vinyl-aminodiols, which are interesting
intermediates in the synthesis of sphingoid bases, as well as
aminopolyols and amino- and iminosugars, has drawn much less
attention.[9] In 2001, Donohoe and coworkers reported the
oxyamination of 2,4-dien-1-yl carbamates with osmiun reagents
to afford 2-amino-pent-4-en-1,3-diol derivatives (Scheme 1a).[10]
Recently,
we
demonstrated
that
rhodium-catalysed
intramolecular aziridination of dienyl carbamates[11] in the
presence of PhI(OR)2 affords vinylaziridines,[12,13] which are in situ
opened by the OR group released after the nitrene transfer
reagent formation. The regioselectivity of this process (SN2 versus
SN2’) was controlled by properly selecting the catalyst and the
PhI(OR)2 reagent (Scheme 1b).[11] Thus oxazolidinone derivatives
with opposite
§
[a]
These authors contributed equally to this work.
Dr. J. Guasch, I. Giménez-Nueno, M. Bernús, Prof. M.I. Matheu,
Prof. S. Castillón, Dr. Y. Díaz
Scheme 1. Reported processes for the metal-catalysed oxyamination of
dienyl carbamates (a, b) and strategies for the enantioselective synthesis of
oxazolidinones (c).
Departament de Química Analítica i Química Orgànica
Universitat Rovira i Virgili
C/ Marcelino Domingo n.1, 43007, Tarragona, Spain
E-mail: sergio.castillon@urv.cat; yolanda.diaz@urv.cat
Prof. F. Maseras, Dr. I. Funes-Ardoiz
Intitut Català de Investigació Química (ICIQ), The Barcelona
Institute of Science and Technology
C/ Països Catalans 16, 43007, Tarragona, Spain
Prof. F. Maseras
relative configuration can be obtained from the same carbamate
depending on whether an osmium or rhodium catalysts is used
(Scheme 1), or modifying the configuration of the proximal
double bond at the dienyl carbamate under a given catalytic
system. Final hydrolysis of the oxazolidinone intermediate gave
access to desired 2-amino-1,3-diol compounds. Overall, a
variety of alkenyl aminodiols was accessible with high chemo-,
regio-, and stereoselectivity using these procedures. The
possibility of double bond functionalization or chain elongation
[b]
[c]
Departament de Química,
Universitat Autònoma de Barcelona
08193, Bellaterra, Spain
Supporting information for this article is given via a link at the end of
the document.
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very low ee or a total lack of reactivity would be expected in the
enantioselective ABC-catalysed acylation of the racemic
oxazolidinones obtained in the rhodium-catalysed oxyamination
process (Scheme 2b). Moreover, the additional stereocenter
present in these compounds could also influence the final
outcome of the kinetic resolution.
Despite the distant double bond present at the oxyamination
products, we hypothesised that the asymmetric process could be
controlled by selecting the protecting group in the hydroxyl
function (Scheme 2b). Thus, we undertook a systematic study of
different hydroxyl-protecting groups along with other variables
affecting the process, such as the catalyst, the acylating agent,
the concentration and the temperature.
Additionally, previous computational studies by Birman and
coworkers[18a] had proved that cation-π interactions were
determinant for the control of the enantioselectivity of the process
(Scheme 2a), and therefore we also applied them to analyse the
results obtained from our alkenyl oxazolidinones. Computational
chemistry has indeed demonstrated to be very convenient to
construct useful models to understand the factors that affect
organocatalytic reactions in terms of the chemo-, regio- or
enantioselectivity.[22] Specifically, density functional theory has
been a widely used method in organocatalytic processes such as
in cycloadditions,[23] in iodine(III)-mediated reactions[24] and in
photoorgano-catalysis.[25]
Scheme 2. Organocatalysed kinetic resolution (KR) acylation of oxazolidinones
via acylation: a) reported results,[18] b) this work.
with different R1 groups through metathesis reactions expand the
synthetic application of the present methodology.
However, to the best of our knowledge, the asymmetric
synthesis of vicinal amino alcohols via an enantioselective
catalytic oxyamination of dienyl carbamates or via a kinetic
resolution of the intermediate racemic oxazolidinones is still
unexplored (Scheme 1c).[14] Here we report a tandem regio- and
stereocontrolled rhodium-catalysed intramolecular aziridination/
ring-opening of 2,4-dien-1-yl carbamates with oxygen
nucleophiles, followed by an organocatalysed kinetic resolution
of the resulting oxazolidinones to obtain enantioenriched 4-ene-
2-amino-1,3-diol derivatives (Scheme 2). The usefulness of the
present methodology is illustrated by its application to the
synthesis of enantioenriched sphingosine (see Scheme 5).
Results and Discussion
Chiral Rh(II) catalysts bearing carboxyamidate or carboxylate
ligands have been widely used in asymmetric processes,
providing excellent results in terms of selectivity.[15] Aiming to
develop the enantioselective version of the oxyamination
procedure, we initially explored the reaction of carbamate 1 (See
Scheme 3) with PhI(OPiv)2 in the presence of chiral dirhodium
carboxyamidate catalysts Rh2(4S-MEOX)4(CH3CN)2, Rh2(4R-
Scheme 3. Preparation of the oxyamination products.
To confirm the previous hypothesis, compounds bearing
protecting groups with aromatic rings ((±)-2a and (±)-5), carbonyl
groups ((±)-2a-5), or a simple methyl moiety ((±)-6) were prepared
(Scheme 3). Derivatives (±)-2a-4a bearing Bz, Ac, Piv protecting
groups were synthesised from carbamate 1, Rh2(OAc)4 catalyst
and the appropriate PhI(OR)2 reagent under the optimised
reaction conditions for a SN2 aziridine opening. In this case,
catalyst and base play a determining role in the efficiency and
.16]
IPOX)4(CH3CN)2 and Rh2(4S-PHOX)4(CH3CN)2 However, all
three catalysts afforded a complex mixture of compounds under
different reaction conditions. We speculate that steric congestion
at the axial reactive sites of rhodium complexes containing
carboxymidate ligands could be the reason for the low catalyst
activity observed. Alternatively, other rhodium(II) complexes
bearing carboxylate ligands such as Rh2(DOSP)4 and
Rh2(PTAD)4 were tested in the reaction of 1 using PhI(OAc)2.
Under optimized conditions, only moderate yields (50%) of
oxazolidinone (±)-3a and low enantioselectivities (<20%) were
achieved with both catalysts.[17]
Due to the difficulty in finding a compromise between activity
and selectivity, we then considered kinetic resolution as an
alternative strategy for accessing the desired enantioenriched
compounds. In 2006, Birman reported the kinetic resolution of
oxazolidinones[18] through an efficient organocatalysed acylation
reaction using nucleophilic chiral amidine-based catalysts
(ABCs).[19,20] This protocol provided a new approach to the
synthesis of enantioenriched oxazolidinones (Scheme 2a).
However, the presence of an aryl, alkenyl or ester moiety directly
linked to the carbon atom adjacent to the NH group in the
oxazolidinone ring was apparently critical for the reaction
selectivity (Scheme 2a), driven by cation-π interactions between
the thiazolium ring at the acylated catalyst and the π-systems of
theses substrates.[18a,21] Based on these structural constraints,
[11]
selectivity (SN2 versus SN2’) of the oxyamination reaction.
Alternatively, PhIO mediated intramolecular aziridination of
carbamate 1 was applied for the preparation of compounds (±)-5
and (±)-6, using respectively a mixture of water in acetonitrile or
methanol as nucleophiles for the ring opening step. Final
esterification of the hydroxyl substituted intermediate with p-
MeOBzCl rendered oxazolidinone (±)-5 in good yields.
The role of the acylating agent on the kinetic resolution was
initially studied. For this purpose, oxazolidinone (±)-2a was
selected as model substrate since its benzoate group was
anticipated to favour cation-π interactions. Therefore, this
substrate was submitted to kinetic resolution conditions, in the
presence of 2 mol% of (R)-BTM catalyst, 75 mol% of acylating
agent, 75 mol% of DIPEA, Na2SO4 and using chloroform as
solvent (0.2 M respect to the substrate).[26] The addition of DIPEA
was found to be crucial to scavenge the acid generated that could
reduce catalyst activity. Along these lines, a desiccating agent
(Na2SO4) was necessary since water could react with the highly
electrophilic N-acyliminium intermediate.
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that the efficiency of the kinetic resolution was controlled by the
acyl protecting group at the additional stereocentre.[27]
[a]
Table 1. Kinetic resolution of (±)-2a. Optimisation of the acylating agent
.
Moreover, the use of different catalysts was studied. Apart
from BTM, two other catalysts with a related chemical structure,
tetramisole and HBTM, were tested. HBTM is the ring-expanded
version of BTM and has been reported to provide an inverse
pattern of selectivities in the kinetic resolution of alcohols.[28] Thus,
whereas BTM gives high selectivities when the π-system is
located α to a nucleophilic atom, HBTM presents better results for
substrates bearing the π system at β position. Disappointingly,
tetramisole only provided 10% of conversion after 21 hours (Table
1, entry 10), whereas HBTM did not show any improvement in
comparison with BTM but actually resulted less effective than
expected with a selectivity factor of 18 (Table 1, entry 11).
Entry
Acyl
donor
T
(ºC)
Conversion
(%)[b]
ee
(P/SM)[c]
Selectivity
(s)
Table 2. Kinetic resolution of (±)-2a-6. Optimisation of the reaction conditions,
1[d]
2
(Boc)2O
BzCl
20
20
0
0
--
--
--
protecting group and catalyst.[a]
<5
47
28
--
3
(iPrCO) 2O
(tBuCO)2O
92/80
90/35
59
27
4
0
[a] Na2SO4 (100 mg per 0.1 mmol of substrate). [b] Determined by 1H NMR
spectroscopy. [c] ee (P/SM): product/starting material ee ratio. Enantiomeric
excess was determined by chiral HPLC (See SI). [d] 4 mol% of (R)-BTM was
used.
The use of (Boc)2O did not produce any conversion (Table 1,
entry 1).[18b] Likewise, benzoyl chloride failed to give any
conversion (Table 1, entry 2), probably due to the nucleophilicity
of the chloride released which can interact with the chiral acylating
intermediate. As expected, acid anhydrides demonstrated to be
active acylating agents for our system. In particular, isobutyric
anhydride resulted the best option, providing compound (R,S)-7
in good yield and high selectivity, being even superior to the larger
pivalic anhydride (Table 1, entries 3 vs. 4). Interestingly, despite
the presence of a sp3 carbon neighbouring the oxazolidinone ring,
reaction conversions and enantioselectivities for the acylated
product were good.
The influence of the catalyst loading, reaction concentration,
temperature, protecting group and catalyst type were then
analysed (Table 2). At first sight, it appears that catalyst loading,
temperature and concentration do not have a strong influence on
the reaction outcome. Looking into more detail, dilution from 0.2
M to 0.1 M produced a considerable decrease in both the activity
and enantioselectivity when the reaction was carried out at room
temperature (Table 2, entries 1 vs. 2). Temperature did not show
a clear tendency, the best proving to be 0ºC although with only a
very slight improvement comparing with the results obtained at
room temperature (Table 2, entry 3). Contrary to what is normally
expected in asymmetric processes, further decrease in the
temperature to -40ºC resulted in slightly eroded selectivity (Table
2, entries 3 vs. 4) which significantly deteriorated when using
higher 6 mol% catalyst loading at low temperature (Table 2,
entries 4 vs. 5).
Entry
SM
Cat (mol%)
Time
(h)
Temp
(ºC)
Conv
(%)[b]
ee[c]
(P/SM)
(s)
1
2[d]
3
2a
2a
2a
2a
2a
3a
4a
5
BTM (4)
BTM (4)
4
10
4
20
20
0
43
37
48
45
55
46
42
46
--
94/72
93/55
93/85
92/76
80/97
92/79
89/65
91/79
--
70
48
75
55
37
60
35
50
--
BTM (4)
4
BTM (4)
21
21
5
-40
-40
20
20
20
20
20
20
20
5
BTM (6)
6
BTM (4)
7
BTM (4)
5.5
4
8
BTM (4)
9
6
BTM (4)
24
21
32
4
10
11
12[e]
2a
2a
2a
Tetramisole (4)
HBTM (4)
BTM (4)
10
26
43
--
--
86/31
96/73
18
108
We next explored the influence of the protecting group and
the catalyst type. Interestingly, acetyl derivative (±)-3a afforded a
similar enantioselectivity than that from the p-OMeBz derivative
(±)-5 and close to the previously obtained for the benzoyl
derivative (±)-2a (Table 2, entries 1, 6 and 8). On the other hand,
pivaloyl derivative (±)-4a provided lower selectivity (Table 2, entry
7). However, when the hydroxyl moiety was protected as a methyl
ether, no reaction was observed after 24h stirring under the
standard conditions (Table 2, entry 9). These results confirmed
[a] Na2SO4 (100 mg per 0.1 mmol of substrate). [b] Determined by 1H NMR
spectroscopy. [c] ee (P/SM): product/starting material ee ratio. Enantiomeric
excess was determined by chiral HPLC (See SI). [d] Concentration 0.1 M. [e]
BTM catalyst was recrystallised three times before being used.
The use of a catalyst batch with recrystallised material
rendered the acylated oxazolidinone (R,S)-7 in a slightly improved
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enantioselectivity (96% ee) achieving a selectivity factor of 108
(Table 2, entry 12 vs. entry 1). Absolute configuration of compound
(R,S)-7 was assigned by analogy with the acylated oxazolidinone
(R,S)-18 (See Scheme 7).
We next explored the sequential oxyamination/kinetic
resolution protocol for carbamate 12, with a Z configuration at the
reactive double bond adjacent to the carbamate moiety. Thus,
compound 12 was treated under the optimized aziridination/ring-
opening conditions, using PhI(OBz)2 to afford compound (±)-13 in
50% yield, which in turn was submitted to (R)-BTM catalysed
kinetic resolution (Scheme 4). The reaction rendered the acylated
product (R,R)-14 in 39% yield and 85% ee, while the starting
material was recovered in 40% yield and 61% ee, with an s-factor
of 23. The absolute configuration of compound (S,S)-13 was
assigned by comparison of its HPLC traces with the same product
prepared from Garner’s aldehyde applying a stereospecific
synthetic route (See supporting information).[29,30] These results
confirmed that the configuration of the carbon atom bearing the
amino function determines the enantiomer being acylated, for a
specific catalysts enantiomer, whereas the adjacent stereocenter
has little influence on the final outcome of the kinetic resolution
process.
Figure 1. 3D structures of the diasteromeric transition state of N-acylation of
compound (±)-2a by (R)-BTM-Ac catalyst. Free energies in kcal/mol.
Several structural factors in the systems shown in Figure 1
deserve comment. Hydrogen bond interactions between the
catalyst, hydroxyl group of the lactim and the acetate play an
important role in the transition state. The acetate group in
particular is assisting the C-N bond formation by the concerted
deprotonation of the O-H moiety in the lactim. These hydrogen
bonds are nevertheless quite similar in both transition sates. The
main difference between TS-(R,S)-2a and TS-(S,R)-2a is in the
interactions of the chain attached to the oxazolidinone ring. In TS-
(R,S)-2a, the favoured conformation has the carbonyl group of the
benzoate group pointing directly to the cationic BTM ring. The
cation-carbonyl distance is between 2.75 and 2.90 Å, stabilizing
this transition state respect to TS-(S,R)-2a, where those
interactions cannot take place due to the orientation of the side
chain away from the catalyst.
We repeated the same calculations for the transition states
associated to the syn reactant (±)-13. The corresponding
structures are shown in the Supporting Information (Figure S2).
The favoured structure is TS-(R,R)-13, 2.1 kcal/mol below TS-
(S,S)-13, again in agreement with the experimental information.
In this case, the energy is in better quantitative agreement with
the experimental s value of 23, associated to ΔΔG of 1.9 kcal/mol.
Again, the key interaction is the cation-carbonyl interaction,
demonstrating that the stereogenic center of the side chain plays
a minor effect in the enantiodifferentiation. Both of the substrates
we have considered, (R,S)-2a and (R,R)-13, can reach a stable
conformation with the C=O-cation interaction mentioned above.
Finally, in order to illustrate the usefulness of the developed
oxyamination/kinetic resolution protocol, we applied it to the
enantioselective synthesis of sphingolipid analogues. Two
different strategies were envisioned for this purpose: a) sequential
oxyamination/kinetic resolution of long-chain dienyl carbamate 16
and b) cross metathesis using enantioenriched product (R,S)-7
arising from kinetic resolution as starting material. Thus,
carbamate 16, which was prepared from dienol 15,[13a] was
treated with PhI(OBz)2 using Cs2CO3 as base and Rh2(OAc)4 as
catalyst to render oxazolidinone (±)-17 as a single regioisomer in
62% yield (Scheme 5a). Compound (±)-17 was then submitted to
kinetic resolution conditions furnishing acylated oxazolidinone
Scheme 4. Synthesis and KR of syn-oxazolidinone (±)-13.
We next analysed computationally through DFT calculations
with the M06-2X functional the origin of the efficient performance
of alkenyl oxazolidinones (±)-2a-5 in kinetic resolution. We used
a similar treatment to that previously applied by Houk and co-
workers for the identification of the important role of cation-π
interactions in the efficiency of related systems (Scheme 2a). We
evaluated the corresponding diasteromeric transition states
starting from substrate (±)-2a (in anti configuration) and substrate
(±)-13 (in syn configuration). Experimentally, substrate (±)-2a is
more efficient for kinetic resolution than substrate (±)-13 (sexp
108 in (±)-2a vs sexp = 23 in (±)-13), and both favour the same
isomer.
=
We report here the key transition states for C-N bond
formation from the lactim isomers of our systems (an extended
discussion on the lactim-lactam tautomerism is supplied in the
Supporting Information). We explored a variety of conformers for
the diastereomeric transition states associated to compound (±)-
2a and the most stable ones are depicted in Figure 1. The energy
difference between the TS-(R,S)-2a and TS-(S,R)-2a structures
is 4.7 kcal/mol. Despite the computed value overestimates the
experimental result (the reported sexp= 108 corresponds to a ΔΔG
of 2.8 kcal/mol) the trend is clearly reproduced.
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(R,S)-18 in 44% yield and 95% ee along with enantioenriched
starting material (S,R)-17 in 35% yield and 87% ee (s-factor of
117).[31] Final deprotection of intermediate (R,S)-18 gave access
to L-erythro-sphingosine (R,S)-19.
are in general suitable due to their stabilization of the favoured
transition state by C=O-cation interactions. Among them, benzoyl
group is the one providing higher selectivities. Moreover, in the
presence of (R)-BTM catalyst, compounds with E configuration
afforded better s values that the related Z analogues. Combining
regio- and steroeselective intramolecular rhodium-catalysed
aziridination of dienyl carbamates with organocatalysed kinetic
resolution of intermediate oxazolidinones, it was possible to
obtaining aminodiols in high enantioselectivities. The usefulness
of this methodology was demonstrated by preparing
enantioenriched L-erythro-sphingosine (R,S)-19 from dienol 15 in
five steps and clavaminol H derivative (R,S)-21 from commercially
available (2E,4E)-hexa-2,4-dien-1-ol in six steps. These results
constitute
a new strategy for accessing enantioenriched
aminoalcohols derived from oxyamination processes and expand
the applicability of ABC’s organocatalysts.
Experimental Section
General procedure for the conversion of allylic dienols to carbamates
(carbamoylation).[33] A solution of trichloroacetyl isocyanate (TAI) (1.05
mmol) in dry benzene (1 mL / mmol dienol) was added to a solution of
dienol (1.00 mmol) in dry dichloromethane (2 mL / mmol dienol). The
mixture was left at room temperature until TLC showed complete
consumption of the starting dienol. Then a 20 mol% solution of K2CO3 in
methanol (3 mL / mmol dienol) was added and the mixture was stirred at
room temperature for 3 hours. After solvent evaporation, the residue was
dissolved in a 1:1 mixture of dichloromethane and brine. The aqueous
phase was extracted with dichloromethane and the combined organic
extracts were dried over MgSO4 and concentrated under reduced pressure.
Scheme 5. a) Enantioselective synthesis of (R,S)-19 (L-erythro-sphingosine)
via sequential oxyamination/kinetic resolution. b) Enantioselective synthesis of
(R,S)-18 (L-erythro-sphingosine precursor) and (R,S)-21 (clavaminol
derivative) via cross metathesis.
H
General procedure for the tandem intramolecular aziridination-ring
opening of allyl carbamates.[11] The corresponding carbamate (0.10
mmol), oxidizing agent PhI(OR)2 (0.20 mmol), oven-dried MgO (0.33
mmol) and rhodium (II) dimer Rh2(OAc)4 (0.01 mmol) were placed in a 10
mL flame dried Schlenk flask. Then CH2Cl2 (2 mL) was added and the
mixture was stirred at room temperature until TLC showed complete
consumption of the starting material. The reaction crude was initially
purified through a short silicagel column (2-3 cm), washing with hexanes
to 50:50 AcOEt/hexanes to afford an essentially pure mixture of
regioisomers. Separation of isomers was achieved by column
chromatography, although yields dropped significantly after prolonged
contact with silicagel.
Alternatively, double bond functionalisation of acylated
oxazolidinone (R,S)-7 under optimised cross metathesis
conditions with commercially available 1-pentadecene and 1-
nonene rendered intermediates (R,S)-18 and (R,S)-20 in high
yields and good E:Z ratios (Scheme 5b. See supporting
information for the optimisation study).[32] Compound (R,S)-20
was finally deprotected by reaction with NaBH4 and
Ba(OH)2·8H2O to obtain clavaminol H derivative (R,S)-21.
The absolute configuration of compound (R,S)-19 was
assigned by comparison of the HPLC traces recorded under
identical conditions of derivatives (R,S)-22 and (S,R)-22, obtained
from (R,S)-19 and natural commercially available (S,R)-
sphingosine, respectively (Scheme 6). The results confirmed that
the (R)-BTM catalysed kinetic resolution of oxazolidinone (±)-17
afforded the synthetic sphingosine (R,S)-19 with opposite
configuration than that of the natural occurring product (See
supporting information).
General procedure for one-pot PhIO mediated Aziridination/Ring-
Opening. A flame dried Schlenk flask 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 (1.0
mmol) and PhIO (2.0 mmol) were added and the heterogeneous mixture
was stirred at 35ºC 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 reaction crude
was purified through a short column chromatography (2-3 cm) in order to
avoid product decomposition under prolonged contact with silicagel.
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 (R)-BTM (10.1 mg, 0.04 mmol) and DIPEA (131 µL, 0.75 mmol)
in CHCl3 (4.9 mL). One dram vial 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.
Scheme 6. Assignment of the absolute configuration of the synthetic
sphingosine (R,S)-19.
In conclusion, oxazolidinones resulting from the oxyamination
of dienyl carbamates, such as compounds (±)-2a-5, are good
substrates for the acylation-kinetic resolution process using the
amidine-based Birman’s catalyst. The efficiency of this kinetic
resolution is determined by the presence of an appropriate
protecting group in the hydroxyl moiety. Acyl protecting groups
General procedure for the N-acylation of racemic oxazolidinones with
isobutyric anhydride.[34] Oxazolidinone (0.10 mmol) was dissolved in
CH2Cl2 (0.1 M) at room temperature under argon atmosphere. Et3N (0.10
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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Acknowledgements
Financial support by the Ministerio de Economia y Competividad
(Mineco), Spain (CTQ2014-58664-R) and the European Regional
Development Fund are gratefully acknowledged. J.G. thanks
Generalitat de Catalunya for a FI fellowship and I.G-N. Mineco for
a predoctoral FPI fellowship (Ref: BES-2015-074435). F.M. and
I.F-A. thank the financial support from the CERCA
Programme/Generalitat de Catalunya and MINECO (Project
CTQ2014-57661-R and Severo Ochoa Excellence Accreditation
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Conflict of interest
The authors declare no conflict of interest
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Table of contents
Tandem regio- and steroeselective
intramolecular rhodium-catalysed
aziridination of dienyl carbamates/
opening followed by kinetic
ABC KR of oxazalidinones
J. Guasch, I. Giménez, I. Funes-
Ardoiz, M. Bernús, M.I. Matheu,
resolution via ABC-catalysed acylation F. Maseras, S. Castillón,* Y. Díaz*
of the oxazolidinones obtained, and
deprotection, allows obtaining
aminodiols with high
enantioselectivity. This kinetic
resolution process overcomes
reported structural limitations. The
efficiency of this methodology was
demonstrated by preparing
Enantioselective Synthesis of
Aminodiols by Sequential
Rh-Catalysed Oxyamination/
Kinetic Resolution. Expanding
the Substrate Scope of
Amidine- Based Catalysis
enantioenriched (R,S)-sphingosine
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