Organocatalytic asymmetric remote aziridination of 2,4-dienals

Article abstract of DOI:10.1039/c3cc43506g

Highly regio- and stereoselective remote aziridination of 2,4-dienals has been developed, based on a vinylogous iminium-ion-dienamine catalytic cascade reaction. Transformations of the aziridine products into enantioenriched motifs are also demonstrated. Furthermore, the reaction concept is extended to include enantioselective 1,6-addition of thiols.

Full text of DOI:10.1039/c3cc43506g

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Organocatalytic asymmetric remote aziridination of
2,4-dienals†
Cite this: DOI: 10.1039/c3cc43506g
Kim Søholm Halskov, Tricia Naicker, Magnus E. Jensen and Karl Anker Jørgensen*
Received 10th May 2013,
Accepted 29th May 2013
DOI: 10.1039/c3cc43506g
www.rsc.org/chemcomm
Highly regio- and stereoselective remote aziridination of 2,4-dienals has
been developed, based on a vinylogous iminium-ion–dienamine catalytic
cascade reaction. Transformations of the aziridine products into enantio-
enriched motifs are also demonstrated. Furthermore, the reaction concept
is extended to include enantioselective 1,6-addition of thiols.
The ability to perform selective transformations is an important task in
organic synthesis. In this regard, chiral amines have been reported as
excellent catalysts for stereoselective transformations of carbonyl com-
pounds.1 Recently, dienamine2 and trienamine3 catalysis reactions have
emerged as new HOMO-raising strategies for the enantioselective
functionalization of enals and 2,4-dienals by the principle of vinylogy.4
Since the dienamine and trienamine intermediates contain several
reactive olefinic sites, the control of the regioselectivity of reactions
involving such intermediates remains a challenge.5
Although the HOMO-raising strategy has been applied to
extended vinylogous systems (di- and trienamine intermediates),2,3
the LUMO-lowering strategy of vinylogous iminium-ion activation
has not achieved the same progress.6,7 Enantioselective reactions
Scheme 1 (a) Previous 1,6- and 1,4-additions to cyclic 2,4-dienones and acyclic
2,4-dienals applying primary and secondary aminocatalyst, respectively. (b)
Proposed novel aminocatalytic remote aziridination of 2,4-dienals.
Aziridines are important scaffolds due to their presence in
which are based on vinylogous iminium-ion activation remain biologically active compounds11 and as valuable building blocks in
relatively unexplored. For cyclic 2,4-dienones, Melchiorre et al. organic synthesis.12 Their role in synthesis is highlighted by their
have demonstrated the 1,6-addition of thiols,8 while Hayashi application as chiral synthons, which can selectively e.g. be converted
et al. showed that exclusive b-functionalization via 1,4-addition into amine derivatives. As a consequence of their importance,
was observed when the same concept was applied to acyclic development of methods for the asymmetric aziridination of olefins
2,4-dienals (Scheme 1a).9
represents an ongoing challenge.13 In recent years, several organo-
We envisioned that a novel regio- and stereoselective remote catalytic procedures for the enantioselective aziridination on enals
functionalization could be achieved by the employment of and enones have emerged.14 Aziridine aldehydes are very useful
2,4-dienals, which could potentially participate in tandem vinylogous reagents, since they exhibit interesting reactivities due to their
iminium-ion–dienamine catalysis, resulting in functionalization of amphoteric nature.15 Furthermore, organocatalytically formed
the remote g- and d-positions.10 This reaction concept thus merges aziridines have found application in one-pot reactions providing
the LUMO-lowering strategy of the vinylogous iminium-ion and the facile entries into a broad range of useful compounds.16
HOMO-raising strategy of the dienamine intermediate in one
In the following we present the first remote enantioselective
combined process for the remote enantioselective aziridination of aziridination of 2,4-dienals (Scheme 1b). Our initial studies revealed
2,4-dienals (Scheme 1b).
that remote regio- and stereoselective aziridination of 2,4-dienals
was possible. However, a key feature of the reaction was the
employment of g-substituted cyclic dienals. A series of experiments
were performed to develop the optimal reaction conditions (see
ESI†). We found that the employment of 0.1 mmol of a mixture of
(E)- and (Z)-2-(2-methylcyclohex-2-en-1-ylidene)acetaldehyde 1a, 2 eq.
Center for Catalysis, Aarhus University,, Langelandsgade 140, DK-8000 Aarhus C,
Denmark. E-mail: kaj@chem.au.dk; Tel: +45 8715 5956
† Electronic supplementary information (ESI) available: Experimental proce-
dures, analytical data and NMR spectra. See DOI: 10.1039/c3cc43506g
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newly formed chiral hydrogen indicating an anti-relationship
between these atoms. In contrast, a correlation of the corres-
ponding hydrogens was observed for compound 4i indicating a
syn-relationship. This reveals that the 1,6-addition occurs by a
nucleophilic attack of 2 at the Re-face of a vinylogous iminium-ion
intermediate. The absolute stereochemistry of the remaining
products was assigned by analogy.
The products of the remote aziridination reaction were utilized in
transformations which apply other organocatalytic principles. N-
Heterocyclic carbenes (NHC) are organocatalysts, which are typically
employed in transformations initiated by inducing umpolung reac-
tivity of aldehydes.17 We were pleased to find that by adding the
NHC-catalyst precursor 5, along with an appropriate base, the
optically active aziridine products 4c,g underwent an allylic aziridine
opening to form N-protected allylic d-amino esters 6a,b (Scheme 3).18
The transformation was observed to proceed in high yields
with no deterioration of the stereocenters established in the
preceding reaction.
To further illustrate an advantage of the remotely substituted
aziridine, the intramolecular reactivity of the N-Boc-protecting
group was utilized to form a remote oxazolidinone moiety.19
Oxazolidinones represent a source of protected vicinal amino
alcohols, hence the transformation of N-Boc-protected aziridines
into oxazolidinones can be viewed as a formal syn-amino hydro-
xylation.20 Furthermore, oxazolidinones are also interesting in their
own right, since optically active oxazolidinones have been found to
exhibit e.g. biological activity.21 The N-Boc-aziridines can undergo
Lewis-acid catalyzed transformation into oxazolidinones.22 We have
Scheme 2 Scope of the organocatalyzed asymmetric remote aziridination of
2,4-dienals 1.
of TsONHBoc 2, 10 mol% of the TMS protected prolinol catalyst found that reduction of aziridine aldehyde 4 followed by treatment
3 and 4 eq. of NaOAc in CH2Cl2 (0.3 mL) provided aziridine with HCl in dioxane furnished oxazolidinone products 7a,b
product 4a in 77% yield and 95% ee.
(Scheme 4). These reactions proceeded in good overall yield and
These results encouraged us to investigate the generality of the enantiomeric excess was maintained with a single regioisomer
the organocatalytic asymmetric remote aziridination reaction being observed.
as presented in Scheme 2. The reaction proceeded with high
Upon further exploration of the concept of vinylogous iminium-
yields and an excellent enantioselectivity of 95% ee for cyclic ion activation, an expansion of the scope was targeted by the
2,4-dienals containing simple aliphatic substituents at the evaluation of other nucleophiles. To our delight, thiols were found
g-position (4a,b). Aromatic functionalities in the side chain were also to add regio- and enantioselectively in a 1,6-fashion to 2,4-dienals 1
tolerated (4c,d) as well as heteroatoms (4e) which all provided similar to yield the non-conjugated adducts 9 (Scheme 5).23,24
results. The ring-system is not restricted to 6-membered rings, as the
Benzyl mercaptan 8 adds to 2,4-dienals 1a–c in decent yields
5-membered cyclic 2,4-dienals performed equally well in the reaction, and good stereoselectivities up to 87% ee.
although a slightly lower enantioselectivity was observed (4f), how-
In conclusion, we have presented a novel tandem vinylogous
ever, a decrease to 40% ee was observed for the 7-membered aziridine iminium-ion–dienamine cascade reaction and demonstrated its
aldehyde 4g. Next, we decided to test the ability of the catalyst potential by the development of a regio- and enantioselective protocol
to override the steric bias from substituents on the cyclic moiety. for remote aziridination of cyclic 2,4-dienals. The aziridinations
2,4-dienals 1h and 1i were obtained from enantiopure R- and
S-carvones, respectively. In both cases, the catalyst demonstrated a
high degree of facial selectivity for the remote aziridination, yielding
the epimers 4h and 4i. Compound 4h is formed exclusively as one
epimer, whereas 4i is formed in a 92 : 8 ratio. As a result, there is a
matched (4h) and a mis-matched (4i) situation, respectively, between
the catalyst and the chiral substituent. It must be noted that the
employment of unsubstituted or acyclic analogues of substrate 1
provided no aziridination products.
The absolute configuration of the optically active aziridines
was determined by detailed NOESY NMR analysis of products
4h and 4i (see ESI†). Compound 4h showed no correlation of
the hydrogen signal at the already known stereocenter to the
Scheme 3 NHC-catalyzed allylic aziridine opening to form the optically active
allylic d-amino esters 6.
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Scheme 4 Formation of optically active oxazolidinone products 7.
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1,6-addition of thiols to cyclic 2,4-dienals.
This work was financially supported by the Aarhus Univer-
sity, OChem School, FNU and the Carlsberg Foundation.
South African National Research Foundation and Oppenheimer
Memorial Trust are thanked for financial support to TN.
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