Base promoted isomerization of aziridinyl ethers: a new access to alpha- and beta-amino acids.

Article abstract of DOI:10.1039/b200708h

Aziridinyl ethers are selectively and easily converted to either amino vinyl ethers or alkoxy allylamines by treatment with mixed metal bases (superbases).

Full text of DOI:10.1039/b200708h

Base promoted isomerization of aziridinyl ethers: a new access to a- and
b-amino acids†
Alessandro Mordini,* Laura Sbaragli, Michela Valacchi, Francesco Russo and Gianna Reginato
Istituto di Chimica dei Composti Organometallici (ICCOM), Dipartimento di Chimica Organica “U. Schiff”,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy. E-mail: alessandro.mordini@unifi.it;
Fax: +39 055 4573531; Tel: +39 055 4573555
Received (in Cambridge, UK) 22nd January 2002, Accepted 12th February 2002
First published as an Advance Article on the web 12th March 2002
Aziridinyl ethers are selectively and easily converted to
either amino vinyl ethers or alkoxy allylamines by treatment
with mixed metal bases (superbases).
Enantiomerically enriched aziridinyl ethers 7–9a,b can be
prepared in a number of ways,14,15 among which we have
selected the sequences starting from epoxy ethers 10a,b,
through ring opening with sodium azide and subsequent ring
closure to aziridine either via mesylation followed by reduction
with lithium aluminum hydride or in a single step with triphenyl
phosphine (Scheme 2).16 The hydrogen atom on nitrogen of
aziridinyl ethers 12a,b has then been replaced by some different
protecting/activating groups. Thus benzyl- (7), tert-butoxy-
carbonyl- (Boc, 8) and para-toluenesulfonyl- (Ts, 9) aziridines
have been easily prepared following standard procedures.
In the last few years we have extensively studied the base-
promoted isomerization of oxiranyl ethers showing that they
can be stereoselectively converted into a number of synthet-
ically useful products by treatment with mixed metal reagents
(superbases).1–3 We have indeed found that depending on the
substrate and the base used, oxiranyl ethers 1 can be
transformed into hydroxy enethers 2 (RA = H) via a syn-
periplanar b-elimination process,4,5 di- and tri-substituted
oxetanes 3 via a 4-endo ring-closure (RA = H or alkyl),6–8
1,4-diols 4 probably through a carbene rearrangement,9,10
tetrahydrooxepines 5 (RB = CHNCH2)11 by means of a 7-endo
process and terminal allylic alcohols 6 (RB = SPh) via a
fragmentation reaction when radical anions are used (Scheme
1). The use of superbasic mixtures has found to be essential in
most cases in order to have highly regio- and stereoselective
reactions and high yields of converted products.
Scheme 2 Reagents and conditions: i, NaN3–NH4Cl, CH3OCH2CH2OH–
H2O 8+1 80 °C; ii, PPh3, PhCH3 reflux; iii, NaH, BnBr, THF or DMAP,
Boc2O, CH2Cl2 or pyridine, TsCl.
Compounds 7a, 8a and 9a have then been submitted to
treatment with various superbasic mixtures in order to first test
the influence of the group on nitrogen on the isomerization
process. We have found that only the tosyl aziridine 9a can be
isomerized with the superbase LIDAKOR (lithium diisopropy-
lamide–potassium tert-butoxide)17 to the corresponding amino
vinyl ether 13a, while the benzyl derivative 7a doesn’t react and
the Boc-aziridine 8a is surprisingly simply deprotected to the
starting aziridine 12a under the same reaction conditions. None
of the tested substrates is isomerized by treatment with
unactivated lithium diisopropylamide. The aziridine to amino
vinyl ether conversion is highly regio- and stereoselective,
Scheme 1
In order to further extend the scope of our studies, we have
recently undertaken an investigation of the reactivity of the
nitrogen analogues, the aziridinyl ethers, with superbasic
reagents, aiming at the synthesis of hydroxy amines and a- or b-
amino acids. Even if aziridines are known12 to be transformed
into allylic amines by treatment with Vitamin B12, their base-
promoted isomerization is practically unknown except for a
recent single report in which treatment of the N-tosyl aziridine
of cyclohexene with sec-butyllithium in the presence of
(2)-sparteine has been shown to afford the expected allylic
amine albeit in low yield and selectivity.13
† Electronic supplementary information (ESI) available: experimental
procedures and NMR data. See http://www.rsc.org/suppdata/cc/b2/
b200708h/.
Scheme 3 Reagents and conditions: i, LIDAKOR, pentane, 25 °C; ii,
Bu4NI, Me3SiCl, CH2Cl2, 220 °C; iii, H5IO6, cat. CrO3, MeCN–H2O 3+1,
0 °C.
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CHEM. COMMUN., 2002, 778–779
This journal is © The Royal Society of Chemistry 2002

compound 13a being the unique isomerized product detected.
The amino vinyl ether 13a is a very useful building block for
further transformations: as an example it has been easily
deprotected to the amino aldehyde 14 and the latter oxidized18
to the b-amino acid 15 (Scheme 3). Both processes occur under
mild reaction conditions and without epimerization thus leading
to amino aldehydes and amino acids having the same optical
purity as the starting oxirane.
ology to other similar substrates could lead to a new approach to
a large variety of unsaturated a-amino acids.
Therefore, depending on the nature of the substituents on the
aziridine ring, the base-promoted rearrangement may disclose
new pathways to unnatural a- and b-amino acid precursors.
Investigation of the reactivity of a variety of aziridines with
superbases is in progress in our laboratory.
This work was supported by the Consiglio Nazionale delle
Ricerche, Rome.
As an additional example the symmetrical aziridine 9c,
obtained from diethyl tartrate in seven steps, has been also
converted to the amino vinyl ether 13c with good yield and high
Notes and references
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Press, Greenwich, CT, 1992, vol. 1, p. 1.
3 M. Schlosser, J. Organomet. Chem., 1967, 8, 9.
4 A. Mordini, S. Pecchi, G. Capozzi, A. Capperucci, A. Degl’Innocenti,
G. Reginato and A. Ricci, J. Org. Chem., 1994, 59, 4784.
5 A. Mordini, M. Valacchi, S. Pecchi, A. Degl’Innocenti and G. Reginato,
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8 A. Mordini, M. Valacchi, C. Nardi, S. Bindi, G. Poli and G. Reginato,
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Scheme 4 Reagents and conditions: i, LIDAKOR, pentane, 20% HMPA,
25 °C.
selectivity (Scheme 4). Compound 13c is a very useful building
block due to the large number of conveniently elaborable
functional groups.
The formation of vinyl ethers 13a and 13c is obviously due to
selective deprotonation of the methylene group adjacent to the
OMOM group and the aziridinyl ring. When we have applied
the same reaction conditions to the aziridine 9b, having an
additional acidic position (the benzylic methylene group), we
have found a different reaction pathway, leading this time to the
9 A. Thurner, F. Faigl, A. Mordini, A. Bigi, G. Reginato and L. Toke,
Tetrahedron, 1998, 54, 11597.
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11 A. Mordini, S. Bindi, A. Capperucci, D. Nistri, G. Reginato and M.
Valacchi, J. Org. Chem., 2001, 66, 3201.
12 Z. da Zhang and R. Scheffold, Helv. Chim. Acta, 1993, 76, 2602.
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Scheme 5 Reagents and conditions: i, LIDAKOR, pentane, 25 °C.
16 D. Tanner and P. Somfai, Tetrahedron Lett., 1987, 28, 1693.
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18 M. Zhao, J. Li, Z. Song, R. Desmond, D. M. Tschaen, E. J. J. Grabowski
and P. J. Reider, Tetrahedron Lett., 1998, 39, 5323.
cinnamyl amino alcohol 16 in a very selective manner (Scheme
5). Compound 16 is the precursor of the b,g-unsaturated a-
amino acid, phenylglycine and the extension of this method-
CHEM. COMMUN., 2002, 778–779
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