Communications
DOI: 10.1002/anie.200705776
Synthetic Methods
Amphoteric Amino Aldehydes Enable Rapid Assembly of
Unprotected Amino Alcohols**
Ryan Hili and Andrei K. Yudin*
A variety of molecules that contain functionally significant b-
amino alcohol motifs[1] are assembled by the addition of
carbon nucleophiles to N-protected a-amino aldehydes. This
chemistry has been used in numerous industrial processes,
including the production of marketed protease inhibitors
containing hydroxyethylene isosteres.[2] Owing to the inherent
incompatibility of the amine and aldehyde functionalities, the
protection of the nitrogen atom has been unavoidable in all of
these applications. Such protection disfavors undesired con-
densation reactions but increases the risk of racemization of
chiral amino aldehydes.[3] The recourse to protecting groups
has also produced complications in metal-mediated addition
reactions to chiral a-amino aldehydes, as delicate tuning of
the nitrogen substituent is required to selectively minimize
the competing governance of stereocontrol by either chela-
tion or nonchelation models.[4] Furthermore, the removal of
the protecting groups from the amino alcohol product is often
not trivial. This limitation is not restricted to the synthesis of
amino alcohols from amino aldehydes. Both olefin amino-
long-standing problems associated with the rapid formation
of complex nitrogen-containing molecules without protect-
ing-group manipulations. Undesired intermolecular iminium
ion formation from amphoteric aziridine aldehydes is disfa-
vored thermodynamically owing to the increase in ring strain
involved in such a process. Aziridine aldehydes can be
prepared from simple starting materials, such as a-amino
acids, and exist as stable dimers with the monomer/dimer
equilibrium lying towards the dimer in a variety of solvents
(Scheme 1). The addition of carbon nucleophiles to ampho-
Scheme 1. Monomer/dimer dynamics in amphoteric amino aldehydes.
hydroxylation[5] and more recent methods based on C H
teric aziridine aldehydes has been elusive until now. Herein
we describe how the curious structural preferences in the
course of aziridine aldehyde dimer dissociation enable the
protecting-group-free, stereoselective synthesis of complex
amino alcohols.
Initial investigations into the addition of carbon nucleo-
philes, such as Grignard and organolithium reagents, to
aziridine aldehyde dimers resulted in quantitative recovery of
the starting materials. We attribute this disappointing lack of
reactivity to unfavorable dimer dissociation under basic
conditions (Scheme 1). The deprotonated dimer is unreactive
towards nucleophiles. To access aldehyde reactivity, a means
for shifting the equilibrium to unveil the aldehyde function-
À
activation require subsequent deprotection steps.[6]
The rapid assembly of stereochemically complex b-amino
alcohol structures without recourse to the use of protecting
groups has been a long-standing challenge. We sought a
synthetic method that would not only deliver unprotected
amino alcohols but would also enable downstream diver-
gency. As direct progenitors of amino alcohols, unprotected
amino aldehydes can be viewed as key strategic building
blocks; however, there has been limited success with their
synthesis. One hundred years ago, Fischer attempted to
prepare glycinal, which was found to be unstable.[7] Many
years later, Myers et al. described autoprotection of the
amino functionality in a-amino aldehydes by treatment with
trifluoroacetic acid in methanol. The resulting hemiacetal
adducts are intriguing intermediates but are prone to self-
condensation above pH 5.[8]
ality in the presence of
a nucleophile was required
(Scheme 1). Our attention was directed to the use of protic
solvents and carbon–carbon bond-forming reactions medi-
ated by the water-tolerant indium reagents.[12] Gratifyingly,
the addition of allyl indium reagents to aziridine aldehyde
dimers was successful (Table 1). The scope of amino alcohol
formation was explored by using a variety of allyl bromides.
In all cases the chemical yields were high, with exclusive
production of the syn b-amino alcohols through g addition.
No undesired aziridine ring opening was observed in the
reaction, in contrast to the well-known scission of epoxides by
Our recent studies in the field of amphoteric mole-
cules[9–11] provided an opportunity to address some of the
[*] R. Hili, Prof. Dr. A. K. Yudin
Davenport Research Laboratories
Department of Chemistry, University of Toronto
80 St. George Street, Toronto, ON, M5S3H6 (Canada)
Fax: (+1)416-946-7676
allyl indium reagents under similar conditions.[13] A 1:1
E-mail: ayudin@chem.utoronto.ca
[12]
mixture of H2Oand THF
was optimal as the solvent in
[**] We thank the Natural Science and Engineering Research Council
(NSERC) and Canadian Institutes of Health Research (CIHR) for
financial support. R.H. is grateful to the NSERC for a postgraduate
fellowship.
terms of both the yield and the rate of the reaction, with the
syn diastereoisomers formed as the only detectable products.
No conversion was observed with other solvents, such as
trifluoroethanol, DMF, or anhydrous THF. The potential
utility of the 1,2-amino alcohol template is immediately
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4188
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Angew. Chem. Int. Ed. 2008, 47, 4188 –4191