Organocatalytic Desymmetrization of Meso-Aziridines Via Asymmetric Intramolecular Rearrangement

Article abstract of DOI:10.1002/ejoc.202100502

Herein we report the first organocatalytic method for the desymmetrization of meso-aziridines that does not require the use of an external nucleophilic reagent. The process was designed upon a base promoted rearrangement of bicyclic meso-cyclopentanone aziridines, that progresses in intramolecular fashion to provide densely functionalized cyclic ketones, key intermediates for the preparation of Active Pharmaceutical Ingredients. The key enantio-determining step proceeded under the catalysis of a bifunctional thiourea organocatalyst. The process provides an entry to a class of highly functionalized chiral amines, 4-aminocyclopentenones, not accessible with previous desymmetrization methods. The ambiphilic nature of the products makes them versatile synthetic intermediates in the preparation of natural products and popular antiviral nucleoside inhibitors, for example abacavir.

Full text of DOI:10.1002/ejoc.202100502

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Organocatalytic Desymmetrization of Meso-Aziridines Via
Asymmetric Intramolecular Rearrangement
Authors: Mauro F A Adamo, Martina Costanzo, Mauro Cortigiani,
Malachi W. Gillick-Healy, Brian G. Kelly, and Claudio
Monasterolo
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100502
Link to VoR: https://doi.org/10.1002/ejoc.202100502
01/2020

10.1002/ejoc.202100502
European Journal of Organic Chemistry
FULL PAPER
Organocatalytic Desymmetrization of Meso-Aziridines Via
Asymmetric Intramolecular Rearrangement
Martina Costanzo,[a] Mauro Cortigiani,[a] Malachi W. Gillick-Healy, [b] Brian G. Kelly,[b] Claudio
Monasterolo*[c] and Mauro F. A. Adamo* [a]
[a]
Dr. M. Costanzo, Dr. M. Cortigiani and Prof. M. F. A. Adamo, Centre for Synthesis and Chemical Biology, Department of Chemistry, Royal College of
Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland.
E-mail: madamo@rcsi.ie
[b]
[c]
Dr. M. W. Gillick-Healy, Dr. B. G. Kelly, Kelada Pharmachem. Ltd, A1.01, Science Centre South, Belfield, Dublin 4, Ireland.
Dr. C. Monasterolo, Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland.
E-mail: claudio.monasterolo@ucd.ie
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein we report the first organocatalytic method for the
desymmetrization of meso-aziridines that does not require the use of
an external nucleophilic reagent. The process was designed upon a
base promoted rearrangement of bicyclic meso-cyclopentanone
aziridines, that progresses in intramolecular fashion to provide
densely functionalized cyclic ketones, key intermediates for the
preparation of Active Pharmaceutical Ingredients. The key enantio-
determining step proceeded under the catalysis of a bifunctional
thiourea organocatalyst. The process provides an entry to a class of
highly functionalized chiral amines, 4-aminocyclopentenones, not
accessible with previous desymmetrization methods. The ambiphilic
nature of the products makes them versatile synthetic intermediates
in the preparation of natural products and popular antiviral nucleoside
inhibitors, for example abacavir.
Scheme 1. Meso-aziridines desymmetrization strategies: a) established
intermolecular ring-opening strategy via addition of nucleophiles; b) novel
Introduction
The stereoselective ring-opening of structurally strained N-
heterocycles has emerged as a powerful tool for the rapid
construction of highly functionalized N-species bearing multiple
stereocenters.1 In this context, the desymmetrization of meso-
aziridines has occupied a central role in the synthesis of chiral
amines, in consideration of their synthetic versatility and in virtue
of the plethora of methods developed for their desymmetrization,
proceeding either via metal-catalysis2 and organocatalysis.3 The
latter, in particular, has seen a steady advancement and the
proliferation of new reports, in the last decades.4
The examples reported (Scheme 1) to date all share a common
synthetic strategy, that relied on an intermolecular nucleophilic
ring-opening of the highly reactive aziridine three membered ring.
For example, the reaction of aziridines 1 (Scheme 1, line a) and a
wide range of nucleophiles proceeded to give amines 2 in high
yields and enantioselectivities. In this reaction, the
desymmetrization originated from the addition of a nucleophilic
species to the aziridine ring. However, because of the common
intramolecular desymmetrization via base-promoted rearrangement.
As part of our studies on the desymmetrization of cyclic ketones
for the manufacture of Active Pharmaceutical Ingredients (API),5
we became interested in the development of a new methodology
for the desymmetrization of meso-aziridines via ring-opening,
complementary to the available state of the art and amenable to
provide polyfunctional scaffolds, precursors to bioactive
compounds. With this in mind, we envisaged that meso-aziridines
3 could be taken through desymmetrization via an unprecedented
asymmetric rearrangement (Scheme 1, line b) involving basic
catalysis. Significantly, the intramolecular nature of the ring-
opening planned does not require additional nucleophilic species
and provides a new entry to chiral 4-amino-2-cyclopentenones 4,6
a scaffold containing five atoms of carbon, four of which holding a
functionality. The ambiphilic nature of products 4, containing two
electrophiles and one nucleophile, makes them versatile synthetic
intermediates in the preparation of natural products7 and APIs,
such as antiviral nucleoside inhibitors.8
mechanism underlying the desymmetrization of
1 by any
nucleophile, compounds 2 tend to be structurally similar, all α-
functionalised amines, resulting in a limited chemical diversity that
is achievable via this reaction.
1
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10.1002/ejoc.202100502
European Journal of Organic Chemistry
FULL PAPER
oxidants were screened, among which pyridinium chlorochromate
(PCC) showed the best preliminary results. After optimization
(Table 1), keto aziridine 3 was obtained without any β-elimination
side-product rac-4. We first performed oxidation of aziridine 3 with
PCC in the presence of 4Å molecular sieves at room temperature
for 12 hours obtaining 14% of side-product (Table 1, entry 2). We
then reduced the reaction time to 2 hours, which decreased the
amount of rac-4 (Table 1, entry 3). Molecular sieves were used as
additive in order to simplify the work-up as the reduced chromium
salts, as well as other reagent-derived side-products, deposit onto
their surface and can be readily removed by filtration. For this
purpose, next we tested Celite as additive in place of molecular
sieves, but this modification did not bring a better result when
performing the reaction for 12 hours (Table 1, entry 4). However,
when the reaction time was reduced from 12 to 2 hours no side-
product 4 was formed (Table 1, entry 5) and desired 3 was
isolated in 82% yields and high purity after work-up.
Results and Discussion
In order to explore the new meso-aziridines desymmetrization
strategy, we set out to prepare compound 3 (Scheme 2). Hence
cyclopentadiene 5 was converted to epoxide 6 in 83% yield by
reaction with peracetic acid9 which, in turn, was reacted with
lithium aluminium hydride (LiAlH4) to generate cyclopentenol 7
that was isolated in 91% yield.10 Aziridination of alkene 7 to
hydroxy aziridines 911 was performed with the method reported by
Sharpless and co-workers,12 by reacting N-chloro para-
toluenesulfonylamide sodium salt
8
in the presence of
phenyltrimethylammonium tribromide (PTAB) catalyst.13 This
reaction provided 9 as a mixture of cis and trans isomers and in
95% yields. The oxidation of hydroxy aziridine 9 to correspondent
3 has been reported by O’Brien and coworkers, who made use of
Dess-Martin periodinane (DMP) as the oxidant.14 This reaction
has been reported to provide quantitative crude yields of 3.
Table 1. Oxidation of hydroxy aziridine 9 to ketone, preparation of target meso-
aziridine 3.
Entry
Oxidant
(equiv.)
Additive
T (oC)
t (h)
3
rac-4
yield %
yield %
1
2
3
4
5
6
7
DMP (2.0)
PCC (3.1)
PCC (3.1)
PCC (3.1)
PCC (3.1)
PCC (3.1)
PCC (1.5)
-
r.t.
r.t.
r.t.
r.t.
r.t.
0
0.5
12
2
50-70[a]
42[a]
61[a]
68[a]
82[b]
55[a]
-
20-40[a]
14[a]
6[a]
4A MS
-
Celite
Celite
Celite
Celite
12
2
5[a]
Scheme 2. Preparation of meso-aziridine 3.
-
12
2
10[a]
-
Although described as sufficiently stable, prescriptions were
made to use 3 immediately as crude and to avoid purification via
chromatography on silica gel, because potential b-elimination
could occur in the presence of acids. We have therefore carried
out the oxidation of 9 to 3 by using Dess-Martin periodinane and
in line with previous reports14 we observed a fast and complete
oxidation to the keto-derivative 3 (Table 1, entry 1) that was
0
[a] Isolated yields after chromatography. [b] isolated yields without
chromatography.
With meso-aziridine 3 in hands, we moved ahead with the
development
of
the
organocatalytic
desymmetrization
isolated in ca 50-70% yield. The desired product
3 was
methodology. At the onset of the study, we aimed at gaining
general insights into the suitability and compatibility of the
proposed transformation with major classes of organocatalytic
processes (Figure 1) that included iminium/enamine covalent
catalysis,15 Phase-Transfer Catalysis16 and bifunctional
organocatalysis.17 It was reasoned that covalent catalysis may
provide an efficient tool for the desymmetrization of 3 via the
formation of a transient iminium species 10 (Figure 1, (A)) that
would then undergo base promoted rearrangement to 4. In
analogy with previous work reported regarding desymmetrization
of ketones5 we envisaged the possibility of using a Cinchona
based quaternary ammonium salt 11 (Figure 1, (B)) and an
inorganic base to promote the formation of 4. Finally, the adoption
of a bifunctional catalyst 12-13 (Figure 1, (C)) capable of
significantly contaminated by various amounts of rac-4, hence
unsuitable for a subsequent asymmetric desymmetrization study.
In addition, this reaction was scarcely reproducible in our hands
leading to reaction mixtures containing variable amounts of 3 and
rac-4 It was reasoned that the liberation of acetic acid from Dess-
Martin periodinane during the oxidation may be the reason behind
the degradation of 3, hampering its isolation in pure form. In order
to resolve this issue, we screened several conditions and work-
up methods, including: (i) carrying out the oxidation in the
presence of NaHCO3; (ii) quenching the crude mixture with 1
equivalent of NaHCO3; (iii) azeotropic distillation using toluene.
However, in no case a significant improvement was noted. An
alternative oxidation protocol, suitable for acid-sensitive
compound 3, was thus explored, for which reason a number of
2
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10.1002/ejoc.202100502
European Journal of Organic Chemistry
FULL PAPER
coordinating the ketone and possessing a basic functionality
could also be a potentially fruitful catalytic design, leading to
formation of desired 4 in high enantioselectivity.
Table 2. Organocatalytic desymmetrization of meso-aziridine 3: screening of
conditions and of catalysts 12-16.
The reaction of 3 under the catalysis of (S)-proline, (S)-3-
hydroxyproline and other related prolinols, privileged chiral
scaffolds widely used as catalysts in covalent iminium/enamine
processes,18 provided only negative results. Generally, the
reactions involving iminium/enamine catalysis gave very low
conversions of 3 (15-20%) and compound 4 as a racemate, even
when stochiometric amounts of amine were employed.
Entry
1
Catalyst
12
Additive
T (oC)
r.t.
r.t.
r.t.
r.t.
r.t.
0
t (h)
12
12
5
4 Yield %[a]
4 ee %[b]
27
74
0
-
98
98
44
78
-
Figure 1. Potential mechanisms of reaction for the desymmetrization of 3 via
iminium/enamine (A), phase-transfer catalysis (B) or bifunctional
organocatalysis (C).
2
13
-
3
14
-
4
15
-
2
16
-
Similarly, phase-transfer catalysis, conducted in the presence of
quaternary ammonium salt 11, was disappointingly, providing no
conversion of substrate 3, which was fully recovered. As in
previously reported procedures,19 we conducted a screening of
differently benzyl substituted ammonium salts, different bases
and solvents. However, in no instance these experiments met with
success. On the other hand, 10 mol% of diaminocyclohexane-
derived organocatalyst 12,20 capable of bifunctional activation,
exhibited a substantial catalytic activity providing complete
conversion of 3 and formation of desired 4 in an encouraging 27%
ee (Table 2, entry 1). This finding demonstrated the viability of the
strategy we planned for the preparation 4 via an intramolecular
desymmetrization approach and allowed us to narrow the
investigation to bifunctional organocatalysts. Therefore, catalysts
12-16 were selected as representative examples containing each
an H-bond donor structural motif and a basic site (Table 2).
Quinidine-derived catalyst 1421 furnished 4 in good conversion,
although with poor 16% ee, (Table 2, entry 4). The use of its 9-
NH2-precursor 1522 resulted in decreased efficiency, providing 4
in 40% conversion and as a racemate (Table 2, entry 3). Despite
the disappointing results, cinchona-derived chiral scaffolds
provided evidence of the influence of the catalyst’s functionalities
over the reaction outcome. Specifically, comparison of 14 and 15
5
16
-
48
12
24
2
6
13
-
97
66
98
53
35
31
45
88
62
98
97
25
78
28
56
41
72
70
55
56
30
16
0
7
13
-
-20
45
r.t.
0
8
13
-
9
13
-
-
24
36
36
24
12
6
10[c]
11[c]
12[d]
13[e]
14[f]
15[g]
16[f]
17[f]
18[g]
19[g]
20[h]
21[i]
13
13
-
-20
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
13
-
13
-
22
62
74
70
31
62
64
43
5
13
MeOH
MeOH
PNP
PhCO2H
MeOH
MeOH
MeOH
MeOH
13
4
13
6
13
18
12
18
12
12
13
suggested the thiourea moiety played
a key role in the
13
-20
r.t.
r.t.
desymmetrization process. The importance of the thiourea motif
was also supported by the finding that thiourea catalyst 12,
derived from diaminocyclohexane (DACH) chiral scaffold, not only
converted quantitatively compound 3 but also provided 4 in a
higher 27% ee (Table 2, entry 1). Interestingly, when the
demethylated analogue 1320 was used, a significant increase of
enantioselectivity was observed, from 27% to 74% ee (Table 2,
entry 2). Comparison of the specific rotation of the product with
previous reports allowed to determine the configuration of the 4-
aminocyclopentenone, i.e. (R)-4.6c The positive effect exerted by
the primary amine resulted strictly tied to the concomitant
13
13
[a] Reactions carried out with 10 mol% of 12-16; yields calculated by 1H-NMR
analysis of the reaction mixture vs an internal standard; [b] enantiomeric
excesses calculated by HPLC analysis on chiral stationary phase: AD column,
n-hexane/i-PrOH 90:10, 0.75 mL/min, 210 nm; [c] in toluene; [d] in THF; [e] in
dry CHCl3; [f] Additive (0.1 equiv.); [g] Additive (1.0 equiv.); [h] N-para-
chlorophenylsulfonyl meso-aziridine 3b used as substrate; [i] N-phenylsulfonyl
meso-aziridine 3c used as substrate. PNP = para-nitrophenol.
3
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10.1002/ejoc.202100502
European Journal of Organic Chemistry
FULL PAPER
presence of the thiourea moiety, as demonstrated by the
complete lack of catalytic activity showed by non-functionalized
diaminocyclohexane catalyst 16 (Table 2, entry 5). The analysis
of this small set of experiment let therefore concluding that for the
desymmetrization of 3 to 4 to occur in high enantioselectivity, the
catalyst must embed two structural motifs, namely a thiourea
required for the interaction with the ketone and an amino group of
moderate basicity to effect the deprotonation only after a tight pair
between catalyst and substrate has taken place. This latter would
explain the observation that more basic tertiary amine 12 provided
a significant lower ee compared to primary amine 13 (Table 2
entries 1 and 2).
of 13 with the ketone 3, leading to the imine/enamine equilibrium
between intermediates 18 and 19. Rearrangement of enamine 19
to conjugated imine 20 and hydrolysis deliver the product neutral
(R)-4 and regenerate 13 (Scheme 3, b).
Once identified thiourea 13 as the best organocatalyst, we
proceeded with the optimization the following parameters: (i)
solvent; (ii) temperature (iii) effect of water; (iv) effect of protic
additives. Changing solvent from chloroform to toluene or
tetrahydrofuran led to lower levels of enantioselectivity compared
to chloroform (Table 2, entries 9-12). Reducing the temperature
resulted in lower conversion and only a small variation in the
enantioselectivity (Table 2, entries 6 and 7). On the contrary, a
temperature increase had a negative effect on the ee (Table 2,
entry 8), although still a significant 55% ee was obtained at 45 oC.
When the reaction was performed under dry conditions, by using
dry chloroform as solvent, compound 4 was obtained with lower
conversion and in reduced ee (Table 2, entry 13). Addition of
methanol shortened the reaction time, without affecting the
enantioselectivity (Table 2, entries 14 and 15). Para-nitrophenol
similarly increased the reaction rate, while slightly decreasing the
ee (Table 2, entry 16). On the other hand, benzoic acid had a
negative effect on the reaction, leading to lower conversion and
ee (Table 2, entry 17), presumably by facilitating an acid-
catalyzed racemic rearrangement.
To conclude the screening, we studied the role of the substrate in
the rearrangement, specifically the effect of the electronics of the
N-substituted aziridine ring, by replacing the electron rich N-para-
tosyl group with the electron withdrawing N-para-chlorophenyl
sulfonyl analogue 3b, and the unsubstituted N-phenylsulfonyl 3c.
Unfortunately, in both cases we observed a detrimental impact on
the stability of the aziridines, which readily underwent non-
controlled ring-opening to rac-4b-4c and other side-products,
impeding their isolation in pure form.23 Eventually, the inferior ees
obtained from the desymmetrization of 3b and 3c (Table 1, entries
20 and 21), confirmed N-para-tosyl aziridine 3 as the substrate of
choice for the transformation.
On the basis of the results collected via the screening of
catalysts and reaction conditions (Table 2), two mechanisms can
be proposed, which differ according to the catalytic role played by
the primary amine of 13, i.e. basic or amine catalysis, in synergy
with the thiourea H-bonding activity shared by both potential
pathways (Scheme 3). The basic catalysis mechanism involves
the thiourea 13 engaging in H-bonding with the ketone 3, hence
promoting α-deprotonation by the amino group and triggering the
aziridine ring-opening (Scheme 3, a). The resulting amide 17
undergoes reprotonation to neutral (R)-4. It is possible that water
and methanol may facilitate this latter step which would explain
the faster turnover observed in the presence of protic additives. A
faster catalyzed process will therefore minimize the occurrence of
the undesired uncatalyzed racemic rearrangement which would
inevitably lead to erosion of ees of compound 4. Alternatively, a
second potential mechanism An alternative amine catalysis
mechanism would involve the condensation of the primary amine
Scheme 3. Proposed mechanisms for the organocatalytic desymmetrization of
meso-aziridine
3
via asymmetric intramolecular rearrangement. Two
bifunctional activation modes: a) basic catalysis and b) amine catalysis.
Conclusion
In conclusion, we have developed a new organocatalytic method
for the desymmetrization of meso-aziridines to produce highly
functionalized chiral amine 4. The process operates via an
unprecedented intramolecular mechanism featuring the
asymmetric rearrangement of bicyclic cyclopentanone meso-
aziridines 3 into enantioenriched 4-aminocyclopentenones (R)-4,
which was obtained in high yield and good enantioselectivity (up
to 74% ee; 87:13 er). To the best of our knowledge, this is the
first example of intramolecular desymmetrization of meso-
aziridines reported to date. The methodology herein described is
complemented by an alternative and more robust methodology for
the generation of highly reactive compounds 3, which has been
obtained
and
characterized
via
chromatography-free
methodology. Compounds alike 4 are synthetic intermediates in
the preparation of valuable natural products and antiviral
nucleoside inhibitor abacavir.6 Therefore this study will be of
interest to those involved in the preparation of bioactive
nucleoside analogues, especially via green organocatalytic
methodologies. Further studies are underway to improve the
4
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10.1002/ejoc.202100502
European Journal of Organic Chemistry
FULL PAPER
wise at 20 °C. The suspension was stirred for 2 hours at 20 °C and then
diluted with cold diethyl ether (10 mL). The solids were removed from the
crude mixture by filtration on Celite, washing with cold diethyl ether (2 x 10
mL). The filtrate was concentrated under reduced pressure to obtain pure
3, without the need for further purification. Rf = 0.3 (petroleum ether/ethyl
acetate 5:5). Orange solid, 28 mg, 82% yield, Rf = 0.3 (PeEt/EtOAc 5:5).
1H-NMR (400 MHz, CDCl3) δ 7.83 - 7.81 (m, 2H), 7.36 - 7.34 (m, 2H), 3.64
- 3.63 (m, 2H), 2.53 - 2.41 (m, 4H), 2.46 (s, 3H). 13C-NMR (101 MHz,
CDCl3) δ 210.9, 145.1, 135.1, 129.9, 127.9, 42.1, 39.7 , 21.8. HRMS (ESI):
C12H13NNaO3S requires 274.0514; found [M+Na]+ 274.0520. IR (KBr)
3650, 3599, 3066, 1753, 1604, 1272, 763 cm-1.
enantioselectivity of this reaction and to expand the methodology
to include additional classes of structurally strained heterocycles.
Experimental Section
General experimental: NMR experiments were performed on a Bruker
Avance 400 instrument and samples were obtained in CDCl3 referenced
to 7.26 ppm for 1H and 77.16 for 13C. Coupling constants (J) are in Hz.
Multiplicities are reported as follows: s, singlet, d, doublet, dd, doublets of
doublets, t, triplet, q, quartet, m, multiplet, c, complex, and br, broad. Mass
spectra were recorded on
a Micro mass LCT spectrometer using
Organocatalytic desymmetrization of meso-aziridine 3: To a solution
of cyclopentanone aziridine 3 (50.2 mg, 0.2 mmol) in CHCl3 (2.0 mL) were
added catalyst 13 (7.7 mg, 0.02 mmol) and MeOH (8.0 μL, 0.2 mmol). The
mixture was stirred for 4 hours at 20 °C. The volatiles were removed under
reduced pressure and the crude residue was purified by column
chromatography on silica gel eluting with petroleum ether/ethyl acetate 6:4,
to obtain (R)-4. Yellow oil, Rf = 0.4 (PetEt/EtOAc 4:6). [a]D 20 + 4.1 (c 0.4
CHCl3); Lit. (for (R)-4) [α]ꢀꢁꢂ: + 7.0 (c 0.4, CHCl3).6c HPLC analysis on chiral
stationary phase: column Chiralpak AD, n-hexane/isopropanol 90:10, 0.75
mL/min, 210 nm, 25 °C, tM= 43.9 min, tm= 48.9 min. 1H-NMR (400 MHz,
CDCl3) δ = 7.78 - 7.76 (m, 2H), 7.37 - 7.32 (m, 3H), 6.20 - 6.18 (m, 1H),
5.21 - 5.18 (m, 1H), 4.61 - 4.58 (m, 1H), 2.58 - 2.44 (m, 1H), 2.44 (s, 3H),
2.00 - 1.95 (m, 1H). 13C-NMR (101 MHz, CDCl3) δ 205.6, 161.1, 144.4,
137.3, 136.0, 130.2, 127.2, 53.7, 42.1, 21.7. HRMS (ESI): C12H13NNaO3S
requires 274.0514, found [M+Na]+ 274.0515. IR (KBr) 3498, 3066, 1650,
1604 cm-1.
electrospray (ES) ionisation techniques. All reagents and solvents were
used as purchased from Aldrich unless otherwise stated. Reactions were
monitored for completion by TLC (EM Science, silica gel 60 F254). Flash
chromatography was performed using silica gel 60 (0.040-0.063 mm, 230-
400 mesh) or alumina (activated, neutral, Brockmann activity I). The
enantiomeric excess (ee) of the products was determined by chiral
stationary phase HPLC (Daicel Chiralpak AD), using a UV detector
operating at 217 nm and 227 nm. Infrared (IR) spectra were recorded as
thin films between NaCl plates using a Bruker Tensor27 FT-IR instrument.
Absorption maximum (Vmax) was reported in wave numbers (cm-1) and only
selected peaks were reported
Preparation of 6-oxabicyclo[3.1.0]hex-3-ene 69 To an ice-cold stirred
mixture of freshly distilled cyclopentadiene (84.14 g, 1.24 mol) in DCM
(1.37 L) was added freshly grounded anhydrous sodium carbonate (530.0
g, 5.0 mol). To the suspension was added, over 2 hours, at 0 °C peracetic
acid (38-40%, 1.16 L, 3.0 mol), previously treated with sodium acetate (6.0
g). The reaction mixture was then warmed to room temperature and stirred
for 3 hours. The crude mixture was filtered on Celite, and the solid washed
with DCM. The filtrate was transferred in a separatory funnel and washed
with saturated sodium thiosulfate solution, followed by brine. The organic
phase was dried over sodium sulfate, filtered and the solvent removed
under reduced pressure to obtain pure epoxide 6. Yellow oil, 68.95 g, 83%
yield. Analytical data were in accordance with previously reported results.9
Acknowledgements
We like to acknowledge The Irish Research Council MC, IRC MC,
IRC MWGH
Keywords: Aziridine desymmetrization • organocatalysis • 4-
amino-2-cyclopentenones • amino thioureas
Preparation of cyclopent-3-enol 710 In a 50 mL flame-dried Schlenk flask
under nitrogen was prepared a solution of the epoxide 6 (1.0 g, 12.2 mmol)
in dry THF (20.0 mL) and the flask was cooled to 0 °C with an ice bath.
Lithium aluminium hydride solution 1.0 M in THF (18.3 mL, 18.3 mmol)
was added over 20 minutes at 0 °C. The reaction mixture was then warmed
to room temperature and stirred for 18 hours. The reaction mixture was
cooled to 0 °C, carefully quenched with methanol (10 mL) and then stirred
for 1 hour. The volatiles were removed under reduced pressure. The
residue was filtered on Celite, washed with DCM and the solution
evaporated. The crude residue was purified by column chromatography on
silica gel eluting with DCM/methanol 9:1 to obtain pure cyclopentenol 7.
Yellow oil, 934 mg, 91% yield, Rf = 0.3 (DCM/MeOH 9:1). Analytical data
were in accordance with previously reported results.10
[1]
a) C. Wang, Synthesis 2017, 49, 5307-5319; S. Stankovic, M. D’hooghe,
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Preparation of 6-tosyl-6-azabicyclo[3.1.0]hexan-3-ol 912 In a 50 mL
flame-dried Schlenk flask under nitrogen was prepared a solution of the
cyclopentenol 7 (334.0 mg, 3.9 mmol) in dry acetonitrile (20.0 mL). To the
solution, at 20 °C and under vigorous stirring, was added chloramine-T
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trihydrate
8
(1.21 g, 4.3 mmol) portion wise, followed by
phenyltrimethylammonium tribromide (146.6 mg, 0.39 mmol). The reaction
was stirred overnight at 20 °C. The mixture was filtered on a silica plug,
washed with diethyl ether, and the filtrate was concentrated under reduced
pressure. The crude residue was purified by column chromatography on
silica gel eluting with diethyl ether to obtain hydroxy aziridine 9. Analytical
data were in accordance with previously reported results.12 Green solid,
943 mg, diastereomeric ratio 73:27, 95% yield, Rf = 0.2 (Et2O).
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PCC oxidation of hydroxy aziridine 9 to cyclopentanone aziridine 3:
To a suspension of 9 (32.7 mg, 0.13 mmol) and Celite (50 mg) in DCM (8.0
mL), pyridinium chlorochromate (86.9 mg, 0.40 mmol) was added portion
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5
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10.1002/ejoc.202100502
European Journal of Organic Chemistry
FULL PAPER
F.
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Adamo,
Chem.
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optimized for 3, starting from the common precursor cyclopentenol 7,
involving aziridination with aromatic N-chlorosulfonylamides (Ar = p-
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contaminated by variable amounts of side-products. This resulted in poor
6
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10.1002/ejoc.202100502
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
O
O
Amine-thiourea (10 mol%)
MeOH (0.1 equiv.)
O
O
S
CHCl3, 4h, r.t.
N
N
up to 98% yield
74% ee (87:13 er)
Tol
H
SO2Tol
Enantioenriched N-tosyl-4-aminocyclopentenone, a key synthon for the preparation of natural products and many nucleoside
inhibitors, was obtained via a new ring-opening of a strained aziridine in high yields and in moderate (up to 74% ee, 87:13 er)
enantioselectivity.
7
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