Organocatalytic enantioselective aziridination of α-substituted α,β-unsaturated aldehydes: Asymmetric synthesis of terminal aziridines

Article abstract of DOI:10.1002/adsc.201000650

The first example of a highly enantioselective organocatalytic aziridination of α-substituted α,β-unsaturated aldehydes is presented. The reaction is catalyzed by simple chiral amines and gives access to highly functional terminal azirdines containing an

Full text of DOI:10.1002/adsc.201000650

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DOI: 10.1002/adsc.201000650
Organocatalytic Enantioselective Aziridination of a-Substituted
a,b-Unsaturated Aldehydes: Asymmetric Synthesis of Terminal
Aziridines
Luca Deiana,a,b Gui-Ling Zhao,a,b,* Shuangzheng Lin,a Pawel Dziedzic,a,b
Qiong Zhang,d Hans Leijonmarck,a,b and Armando Cꢀrdovaa,b,c,
*
a
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax : +(46)-8-154-908; e-mail: acordova@organ.su.se, armando.cordova@miun.se
Berzelii Center EXSELENT on Porous Materials, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm,
Sweden
b
E-mail: zhaogl@organ.su.se
c
Department of Natural Sciences, Engineering and Mathematics, Mid Sweden University, 851 70 Sundsvall, Sweden
Department of Theoretical Chemistry, School of Biotechnology, Royal Institute of Technology, Roslagstullsbacken 15,
106 91 Stockholm, Sweden
d
Received: August 19, 2010; Revised: October 18, 2010; Published online: December 8, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000650.
Abstract: The first example of a highly enantiose-
lective organocatalytic aziridination of a-substituted
a,b-unsaturated aldehydes is presented. The reac-
tion is catalyzed by simple chiral amines and gives
access to highly functional terminal azirdines con-
taining an a-tertiary amine stereocenter in high
yields and enantiomeric ratios (95.5:4.5–98:2).
regioselective ring-opening with various nucleo-
AHCTUNGTRENNUNG
philes.[1a] In addition, there is no general method for
the synthesis of highly enantioenriched 2-substituted
(particularly 2-alkyl-substituted) terminal aziridines in
an efficient manner.[13,14] There are a few direct atom
economic catalytic enantioselective methods for the
direct enantioselective synthesis of terminal azirdines
as described above.[15] However, they are not yet ap-
plicable to the synthesis of 2-alkyl-substituted aziri-
dines. Moreover, terminal 2-alkyl-substituted aziri-
dines containing an a-tertiary amine stereocenter are
also important as precursors for the synthesis of a,a-
amino acid derivatives.[16]
Keywords: asymmetric catalysis; domino reactions;
organocatalysis; a-substituted a,b-unsaturated alde-
hydes; terminal aziridines
In 2006, we disclosed the chiral amine-catalyzed
asymmetric aziridination of simple linear enals.[17]
Aziridines are valuable compounds, which can be This has led to the development of aziridinations of
used as versatile chiral building blocks, ligands and a,b-unsaturated aldehydes and ketones.[18,19] However,
auxiliaries for organic synthesis.[1] They are also pres- the aziridination of a-substituted acryl aldehydes 1 is
ent in several natural products and can exhibit impor- still lacking in spite of the fact that this reaction
tant biologically activities.[1,2] It is therefore highly de- would give a direct access to highly functional termi-
sirable to develop catalytic asymmetric methods for nal aziridines 3, which are valuable precursors for the
the stereoselective synthesis of chiral aziridines. To synthesis of optically active nitrogen containing com-
date, a number of catalytic protocols have been devel- pounds.[16,19c,d] Thus, we envisioned a novel direct
oped for the enantioselective synthesis of aziri-
dines.[3–12] This includes the pioneering works by
Evans,[5a–c] Jacobsen,[5d–f] Wulf[10] and Aggarwal,[11]
among others.
In particular, terminal aziridines are, arguably, the
most useful aziridines and represent a particular chal-
lenging target. For example, they can be considered
as a potential two carbon atoms and one nitrogen
atom source due to the fact that they readily undergo
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Luca Deiana et al.
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Table 1. Catalyst screen for the reaction between 1a and 2a.[a]
[a]
Experimental conditions: A mixture of 2a (0.30 mmol), aldehyde 1a (0.25 mmol), ad-
ditive (0.75 mmol) and catalyst (20 mol%) in 1.0 mL solvent was stirred at the tem-
perature and conditions displayed in the Table.
Conversion of 1a as determined by NMR analysis.
Determined by chiral phase HPLC analysis.
Reaction run in 0.5 mL solvent. Isolated yield in parenthesis.
An excess of 1a (0.3 mmol) to 2a (0.25 mmol) was used.
Catalyst 7 (10 mol%).
[b]
[c]
[d]
[e]
[f]
[g]
[h]
2b was used instead of 2a.
Reaction run at 48C and 1.5 equiv. NaOAc were used. Bn=benzyl, Ts=p-toluenesul-
fonyl.
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Organocatalytic Enantioselective Aziridination of a-Substituted a,b-Unsaturated Aldehydes
Table 2. Scope of the organocatalytic terminal enantioselective aziridine synthesis.[a]
[a]
Experimental conditions: A mixture of aldehyde 1 (0.25 mmol), 2 (0.30 mmol),
NaOAc (0.375 mmol) and catalyst 4 (20 mol%) in toluene (0.5 mL) was stirred at
room temperature for the time shown in the Table. The crude product 3 was puri-
fied by column chromatography.
Isolated yield of pure product 3 after silica gel column chromatography.
Determined by chiral phase HPLC analysis.
[b]
[c]
[d]
Reaction run at room temperature. Bzl=benzoyl, Ts=p-toluenesulfonyl.
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Luca Deiana et al.
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route to highly functional terminal aziridines 3 con- 2-alkyl-2-formylaziridines in high yields and er
taining an a-tertiary amine stereocenter via a chiral (95.5:4.5–98:2).
amine-catalyzed reaction between a-substituted acryl
The key results from an initial catalyst and solvent
aldehydes 1 and a suitable nitrogen source 2, which screen are summarized in Table 1. We found to our
could first act as a nucleophile and at a later stage delight that protected diarylprolinols 4–7[20] catalyzed
become an electrophile [Eq. (1)].
the asymmetric aziridination reaction between alde-
Here we report the first example of a highly enan- hyde 1a and 2a to give terminal aziridine 3a in high
tioselective catalytic asymmetric aziridination of a- enantiomeric ratios. This is noteworthy since the de-
substituted a,b-unsaturated aldehydes 1, which gives velopment of aminocatalytic enantioselective reac-
tions using a-substituted a,b-unsaturated aldehydes is
challenging.[21,22]
Several bases were screened as additives and we
found that the employment of NaOAc is preferred
(entries 1–4). The highest enantiomeric ratio of 3a
was accomplished in toluene using chiral amines 4 or
5 as the catalysts. The reaction does not give product
3a if the amine catalyst is not present (entries 13 and
14). Our present conditions differ from our first pub-
Figure 1. Top left: ECD spectra calculated for the (2R)-2a and the optimized geometry. Top right: ECD spectra calculated
for the (2S)-2a and the optimized geometry. Lower picture: Experimental (full trace) ECD spectra of compound 2a.
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Organocatalytic Enantioselective Aziridination of a-Substituted a,b-Unsaturated Aldehydes
lished aziridination protocol where no base was
added and heating was used instead to accelerate the
reaction.[17] With these results in hand, we decided to
probe the scope of the catalytic aziridination of a-sub-
stituted aldehydes 1 with “nitrene” equivalent 2 using
4 as the amine catalyst and NaOAc as the additive in
the optimal solvent toluene (Table 2).
The reactions were efficient and proceeded with
high enantioselectivity to give the corresponding ter-
minal aziridine products 3a–3j in good to high yields
and high enantiomeric ratios (entries 1–10). The reac-
tion tolerated several enals 1 with different functional
groups at their a-alkyl substituent.[23] For example,
highly stereoselective aziridination of aldehyde 1e at
its less electron-rich olefin can be accomplished using
our methodology to give the corresponding Boc-pro-
tected terminal azirdine 3e in 73% yield and a 96:4 er
(entry 9). It is noteworthy that the scope of the reac-
tion can be broadened to a,b-disubstituted enals 1
[Eq. (2)]. As exemplified in the highly diastereo- and
enantioselective aziridination of disubstituted enal 1k
to give the corresponding product 3k in 61% yield
Scheme 1. The proposed reaction pathway for
amine-catalyzed enantioselective aziridination of a-substi-
tuted enals 1.
a chiral
with 89:11 dr and 99.5:05 er.
The absolute stereochemistry of terminal aziridines
3 was assigned by means of TD-DFT calculations of
the electronic dichroism (ECD) spectra of 3a
(Figure 1).[24] The density functional theory (DFT) Experimental Section
calculations of the S-enantiomer of 3a matched with
the experimental CD spectra of 3a (Figure 1). Thus, Representative Procedure for the Aziridination
the absolute configuration of 3a at C-2 is assigned as between Benzyl N-tosyloxycarbamate 2a or tert-butyl
S. The mechanistic proposal for our aminocatalytic N-tosyloxycarbamates 2b and a-Substituted a,b-
enantioselective synthesis of terminal aziridines 3 is Unsaturated Aldehyde 1
shown in Scheme 1. The efficient shielding of the
chiral iminium intermediate I by the bulky aryl
To a stirred solution of catalyst 4 (20 mol%) in toluene
(0.5 mL) were added a-substituted-a,b-unsaturated alde-
groups of catalysts 4–7 leads to stereoselective nucleo-
philic Re-facial conjugate attack on the b-carbon by
the amino group of 2 (Scheme 1). Next, the generated
chiral enamine intermediate II performs a stereose-
lective 3-exo-tet nucleophilic attack from its less steri-
cally hindered Si-face on the now electrophilic nitro-
gen and leaving group X is released (Scheme 1). The
intramolecular ring closure pushes the equilibrium
forward and makes this step irreversible. Subsequent
hydrolysis of the iminium intermediate III gives the
corresponding terminal azirdine 3 and releases the
amine catalyst.
hyde 1 (1.0 equiv., 0.25 mmol), benzyl N-tosyloxycarbamate
2a or tert-butyl N-tosyloxycarbamate 2b (1.2 equiv.,
0.30 mmol) and NaOAc (0.375 mmol, 1.5 equiv.) at 08C and
the resulting reaction mixture was vigorously stirred for the
reported time at 48C. Next, the reaction mixture was direct-
ly loaded upon a silica gel column and immediate chroma-
tography (pentane:EtOAc-mixtures) furnished the aziridine
product 3.
Acknowledgements
In summary, we report the first example of a highly
enantioselective organocatalytic aziridination of a-
substituted a,b-unsaturated aldehydes. The reaction is
We gratefully acknowledge the Swedish National Research
Council and Wenner-Gren-Foundation for financial support.
The Berzelii Center EXSELENT is financially supported by
efficiently catalyzed by simple chiral pyrrolidine de- VR and the Swedish Governmental Agency for Innovation
Systems (VINNOVA).
rivatives and gives the corresponding 2-alkyl substi-
tuted terminal aziridines containing an a-tertiary
amine stereocenter in high yields and er (95.5:4.5–
97.5:2.5). We are currently performing mechanistic
studies and synthetic applications of this transforma-
tion as well as development of other enantioselective
aziridinations based on this concept.
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