Base-Induced Heterochiral Dimerization of an Oxiranyl Carbaldimine: Stereoselective Synthesis of a Highly Functionalized Aziridine

Article abstract of DOI:10.1021/ol0158314

matrix presented Treatment of the oxiranyl carbaldimine with base (LDA or LDA/KOtBu) leads in an one-step procedure to the polyfunctionalized aziridine. This highly diastereoselective reaction is explained by a new type of an Aza-Darzens reaction, in which one enantiomer of the starting material is deprotonated to form an oxiranyl anion, which attacks the imine carbon atom of the other enantiomer (mutual kinetic resolution by double diastereofacial selection).

Full text of DOI:10.1021/ol0158314

ORGANIC
LETTERS
2
001
Vol. 3, No. 10
527-1530
Base-Induced Heterochiral Dimerization
of an Oxiranyl Carbaldimine:
1
Stereoselective Synthesis of a Highly
Functionalized Aziridine
Dirk Alickmann, Roland Fr o1 hlich, and Ernst-Ulrich W u1 rthwein*
Institut f u¨ r Organische Chemie, Corrensstrasse 40, D-48149 M u¨ nster, Germany
wurthwe@uni-muenster.de
Received March 13, 2001
ABSTRACT
Treatment of the oxiranyl carbaldimine with base (LDA or LDA/KOtBu) leads in an one-step procedure to the polyfunctionalized aziridine. This
highly diastereoselective reaction is explained by a new type of an Aza-Darzens reaction, in which one enantiomer of the starting material is
deprotonated to form an oxiranyl anion, which attacks the imine carbon atom of the other enantiomer (mutual kinetic resolution by double
diastereofacial selection).
Similar to oxiranes, aziridines are reactive, valuable building
blocks for selective organic transformations by ring-opening
processes. In recent years chiral aziridines have found many
interesting applications for the stereoselective synthesis of
In this report we present a new, unexpected example of a
highly diastereoselective Aza-Darzens reaction, where an
oxiranyl carbaldimine dimerizes to form an aziridine with
seven neighboring functionalized carbon centers and four
stereogenic centers in one step. This reaction was observed
while attempting to synthesize the imino allyl alcohol
3-hydroxy-1-azapenta-1,4-diene (5) from the (rac)-trans-
oxiranyl carbaldimine (rac)-3 by base-induced ring opening
using a lithium diisopropylamide (LDA) and potassium tert-
1
challenging molecules. Among several synthetic routes to
chiral aziridines, which start from amino alcohols, epoxides,
alkenes, azirines, and imines,2 the Aza-Darzens reaction
presents an attractive but as yet seldom used access to
substituted aziridines. This approach involves the nucleo-
philic attack of a leaving group containing carbanion species
on imine-type molecules.4
,3
11
butylate (KOtBu) mixture. The imine (rac)-3 was produced
in 65% yield as a trans/cis mixture (92:8) from the
corresponding epoxy aldehyde (rac)-2. Compound 2 (trans/
cis ratio 92:8) was obtained in 18% yield from croton-
-10
(
1) McCoull, W.; Davis, F. A. Synthesis 2000, 1347.
(2) Tanner, D. Angew. Chem. 1994, 106, 625; Angew. Chem., Int. Ed.
12
Engl. 1994, 33, 599.
3) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8,
693.
aldehyde 1, using hydroperoxide (30%) in buffered aqueous
solution (pH ) 8) as oxidant (Scheme 1).
(
1
For the intended base-induced oxirane opening process of
(
(
(
4) Coutrot, P.; El Gadi, A. J. Organomet. Chem. 1985, 280, C11.
5) Cainelli, G.; Panunzio, M. Tetrahedron Lett. 1991, 32, 121.
6) Cantrill, A. A.; Jarvis, A. N.; Osborn, H. M. I.; Ouadi, A.; Sweeney,
1
1
(rac)-3 a superbase consisting of LDA/KOtBu was used.
However, treatment of (rac)-3 with an equimolar amount of
this base at -78 °C, warming to room temperature, and
subsequent aqueous workup does not give the expected
J. B. Synlett 1996, 847.
7) Cantrill, A. A.; Hall, L. D.; Jarvis, A. N.; Osborn, H. M. I.; Raphy,
J.; Sweeney, J. B. J. Chem. Soc., Chem. Commun. 1996, 2631.
8) Fujisawa, T.; Hayakawa, R.; Shimizu, M. Tetrahedron Lett. 1992,
3, 7903.
(
(
3-hydroxy-1-azapenta-1,4-diene 5 but yields the functional-
3
1
1
(9) Li, A.-H.; Dai, L.-X.; Hou, X.-L. J. Chem. Soc., Chem. Commun.
996, 491.
(
999, 71, 1033.
(11) Mordini, A.;. Rayana, E. B.; Margot, C.; Schlosser, M. Tetrahedron
1990, 46, 2401.
(12) Ceroni, M.; S e´ quin, U. HelV. Chim. Acta 1982, 65, 302.
10) Dai, L.-X.; Lin, Y.-R.; Hou, X.-L.; Zhou, Y.-G. Pure Appl. Chem.
1
0.1021/ol0158314 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/20/2001

tion; notice the reversal of the stereochemical descriptor at
C1 of the 1-hydroxy-2-propenyl substituent upon oxirane
opening!). The substitution pattern of the aziridine ring is
cis, with the two hydroxy functions on the same side. The
isopropyl substituent at the aziridine nitrogen atom N2 points
to the less substituted face of the three-membered ring. The
imino group shows (E)-configuration. The C-N-C bond
angle of the aziridine is slightly larger than 60° (61.48°).
An intramolecular hydrogen bridge from O14 to N1 (2.086
Å) and an intermolecular hydrogen bridge from O5 to N2′
Scheme 1a
(2.147 Å) are present in the solid state.
The unexpected formation of (rac)-4 may be explained
by a new type of Aza-Darzens reaction that is induced by
deprotonation of the starting imine (rac)-3 at the R-carbon
atom (Scheme 2). This position is obviously more acidic
Scheme 2
a
2 2 2
(i) 30% H O . (ii) iPr NH /molecular sieves.
ized aziridine (rac)-4 in 53.4% yield as colorless crystals.
NMR spectra of the crude mixture indicate the formation of
6
5-70% of (rac)-4 without other products with comparable
1
13
signals. H and C NMR spectra show the presence of a
single diastereomer, indicating a highly stereoselective
reaction pathway. Later experiments showed that LDA also
leads to (rac)-4 in similar yield and selectivity.
1
The unexpected structure of (rac)-4 was elucidated by H
NMR NOE experiments and by X-ray crystallography
(Figure 1). Figure 1 clearly shows the constitution and the
compared to the terminal methyl group, which is usually
attacked by strong bases in ring-opening processes of
oxiranes to form allyl alkoxides. The structural and electronic
properties of the resulting anion, which might be regarded
1
3-15
as an unusual aza-enolate type anion (6)
involving an
1
6
oxirane ring, have been investigated by use of quantum
chemical calculations. According to DFT calculations on the
1
7
B3LYP/6-31+G** level the preferred structure of the
isolated anion is characterized by a pyramidal carbanionic
center (sum of angles, 311.5°), despite the possible delocal-
ization of charge toward the imine group (aza-enolate), which
would however increase the angle (Baeyer) strain in the
three-membered ring (Figure 2).
Figure 1. Molecular structure of (rac)-4.
However, the calculated barrier toward inversion at the
carbanionic center involving a planar three-coordinate center
is very low (4.4 kcal/mol), indicating the possibility of
reactions as nucleophile either by retention or inversion at
this center. The calculated structure (B3LYP/6-31+G**) of
substitution pattern of (rac)-4 in the crystalline state. (rac)-4
crystallizes in the triclinic space group P1 (No. 2) with two
enantiomeric molecules in the unit cell. The most interesting
fact concerns the relative stereochemistry of the newly
formed stereogenic aziridine carbon centers; as Figure 1
shows the “dimer” (rac)-4 is formed from each one of the
two possible enantiomers of (rac)-3 (heterochiral combina-
(13) Wittig, G.; Reif, H. Angew. Chem. 1968, 80, 8.
(
14) Mukaiyama, T. Org. React. 1982, 28, 203.
(15) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517.
(16) Satoh, T. Chem. ReV. 1996, 96, 3303.
1528
Org. Lett., Vol. 3, No. 10, 2001

ion keeping the two reacting enantiomers together in a well-
defined six-membered transition complex (Scheme 2; see also
below). Now regioselective nucleophilic ring opening of the
oxirane ring originating from the carbanion leads to the
indicated aziridine intermediate 8. Finally, base-induced ring
opening of the other oxirane ring and aqueous work up
produces the aziridine (rac)-4.
The exclusive formation of the cis configurated aziridine
ring may shed some light on the stereochemical pathway of
the reaction. According to semiempirical PM318 and DFT
calculations (B3LYP/6-31G*), the stereochemistry of the
product observed is in agreement with a six-membered
transition state of the Zimmerman-Traxler type involving a
bridging lithium cation between the two nitrogen atoms.
However, because of the special substitution pattern, a clear
prediction of the resulting stereochemistry after bond forma-
tion on the basis of the distinction of steric demands for
equatorial and axial positions is difficult. To explain the high
heterochiral diastereoselectivity of the reaction, we postulate
an additional chelating by a second lithium cation between
the two oxirane rings, keeping them on the same side of the
developing aziridine ring (Figures 4 and 5). The DFT
Figure 2. DFT optimized structure of anion 6. Selected bond
lengths [Å]: N-C1 1.313, C1-C2 1.411, C2-O 1.476, C2-C3
1
.456, C3-O 1.446; selected bond angles [deg]: N-C1-C2 129.5,
C1-C2-O 123.4, C3-C2-O 59.1 (B3LYP/6-31+G**//B3LYP/
-31+G**).
6
the corresponding lithium compound 6-Li (Figure 3) is quite
similar to that of 6; in monomeric 6-Li lithium is four-
coordinate, bridging carbon, oxygen, and nitrogen. The bond
lengths indicate a little more aza-enolate character (lengthen-
ing of N-C1 and shortening of the C1-C2 bond). The
C2-O bond is considerably longer in comparison to that of
6, as a result of the very strong Li-O interaction. Again,
the most interesting feature of this structure is the highly
pyramidalized four-coordinate carbanionic center (sum of
angles, 309.2°). The product of an inversion at C2 is
calculated to be 0.99 kcal/mol higher in energy than 6-Li.
With regard to the low inversion barrier its concentration in
the reaction mixture is expected to be low.
We assume that this species 6-Li (or aggregates of it)
attacks as a nucleophile a second, enantiomeric molecule of
3
at the imino carbon atom in a highly stereoselective
manner, forming intermediate 7 (Scheme 2) (heterochiral
combination). We describe this type of diastereoselectivity
as mutual kinetic resolution by double diastereofacial selec-
tion, which may well be supported by a bridging lithium
Figure 4. DFT optimized transition structure of the heterochiral
combination, assuming retention of configuration and a second
lithium ion chelating the oxirane rings. Length of the developing
C-C bond: 2.116 Å. (B3LYP/6-31G*//B3LYP/6-31G*).
calculations of such cationic bislithium transition complexes,
starting from the energetically more favorable oxiranyllithium
compound with retention of configuration, reveal an energy
(17) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.6; Gaussian,
Inc.: Pittsburgh, PA, 1998.
Figure 3. DFT optimized structure of lithium compound 6-Li.
Selected bond lengths [Å]: Li-N 1.884, Li-C1 2.456, Li-C2
2
.504, Li-O 1.811, N-C1 1.331, C1-C2 1.397, C2-O 1.529,
C2-C3 1.452, C3-O 1.467 (B3LYP/6-31+G**//B3LYP/6-
1+G**).
3
Org. Lett., Vol. 3, No. 10, 2001
1529

difference of 6.8 kcal/mol in favor of the heterochiral
combination (Figure 4), despite the manifold lithium chela-
tion of the homochiral combination (Figure 5).
enantioselectively starting from (2S-trans)-3 (86% ee) as
obtained from Sharpless epoxidation of crotyl alcohol. H
1
NMR spectra and GC indicate the formation of about 10
products, among them one (<10%) with the NMR signals
of 4. Obviously, the lack of the corresponding enantiomer
precludes this reaction from taking place and side reactions
dominate. The formation of the small amount of 4 may be
explained by the presence of the minor enantiomer in the
starting material.
This Aza-Darzens-type reaction is to our knowledge
noteworthy because of three new features: (a) For the first
time, a 1-aza allylanion bearing an oxirane moiety at the
â-carbon atom acts as nucleophile. (b) The leaving group
for the formation of the aziridine ring is the oxirane oxygen
atom, thus making no use of halogenide-type leaving groups
as in conventional Darzens reactions. (c) Both nucleophile
and electrophile originate from enantiomers of the same
precursor molecule, allowing a highly diastereoselective
formal dimerization accompanied by substantial molecular
reorganization. All these features provide new, interesting
synthetic potential for further synthetic applications in small
ring heterocyclic chemistry.
Figure 5. DFT optimized transition structure of the homochiral
combination, assuming retention of configuration and a second
lithium ion chelating the oxirane rings. Length of the developing
C-C bond: 2.069 Å (B3LYP/6-31G*//B3LYP/6-31G*).
Acknowledgment. We thank Prof. D. Hoppe for helpful
stereochemical discussions and Mrs. Antje Kauert for careful
technical assistance. Financial support by the Deutsche
Forschungsgemeinschaft (Graduiertenkolleg “Hochreaktive
Mehrfachbindungssysteme” and SFB 424) and by the Fonds
der Chemischen Industrie (Frankfurt) is gratefully acknowl-
edged.
On the basis of this postulated mechanism the reaction
may be classified as a new type of Aza-Darzens reaction, in
which the three-membered heterocyclic ring (here aziridine)
is set up by formal addition of an oxiranyl anion to a CdN
double bond.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data of the new compounds obtained,
and computational details (GAUSSIAN 98 archive entries).
This material is available free of charge via the Internet at
http://pubs.acs.org.
The surprisingly high diastereoselectivity is further sup-
ported by unsuccessful experiments to run the same reaction
(18) MOPAC93; Stewart, J. J. P. Fujitsu Limited, 1993; Stewart, J. J. P.
J. Comput. Chem. 1989, 10, 209, 221. Anders, E.; Koch, R.; Freunscht, P.
J. Comput. Chem. 1993, 14, 1301.
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