Readily available unprotected amino aldehydes

Article abstract of DOI:10.1021/ja065898s

We report a new class of bench-stable compounds that contain seemingly incompatible functional groups: an aldehyde and an unprotected secondary amine. The thermodynamic driving force to undergo condensation between these two functionalities is offset by a

Full text of DOI:10.1021/ja065898s

Published on Web 10/27/2006
Readily Available Unprotected Amino Aldehydes
Ryan Hili and Andrei K. Yudin*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, Canada, M5S 3H6
Received August 14, 2006; E-mail: ayudin@chem.utoronto.ca
Table 1. Aziridine Aldehyde Dimers Obtained through DIBAL
Continuing interest in stereochemically complex natural products
and natural product-inspired synthetic molecules requires processes
that minimize protection/deprotection sequences on incompatible
functional groups. Identification of such reactions, especially in
complex heterocycle synthesis, would facilitate discovery of
bioactive molecules. Herein we report a new class of bench-stable
compounds that contain seemingly incompatible functional
groups: an aldehyde and an unprotected secondary amine.
Reduction of Aziridine Estersa
Unveiling the secondary amine functionality in the presence of
an aldehyde is typically done when an instant condensation resulting
in an iminium/enamine system is desired.1 It is difficult to see how
an unprotected secondary amine could coexist with an aldehyde in
the same molecule for a prolonged period of time.2,3 Autoprotection
of the amine by protic acid has been employed in order to stabilize
labile primary amino aldehydes, although they were found to be
susceptible to self-condensation above pH 5.4 The possibility of
self-condensation can be suppressed, but it requires incorporation
of a quaternary R-carbon.5 Using an unprotected aziridine as a
secondary amine we considered the possibility that a thermodynamic
driving force to undergo condensation could be offset by a high
barrier imposed on this process by the aziridine ring strain (Figure
1).6 As a result, a previously unknown class of molecules,
unprotected aziridine aldehydes, has been identified. We highlight
the application of these valuable intermediates by generating
complex pentacyclic frameworks in one simple operation.
a Reactions were carried out using 1 equiv of ester and 2 equiv of DIBAL
in toluene at -78 °C. b Isolated yields.
Figure 2. X-ray structure of aziridine aldehyde dimer 2a.
Figure 1. Effect of ring strain on reversible formation of iminium ions
from secondary amines and aldehydes.
Scheme 1. Equilibrium between Homodimer 2a and Free
Aziridine Aldehyde with Subsequent Reductive Transformations
The aziridine aldehydes were prepared from aziridine esters,7
which were in turn made from readily available epoxy esters by
treatment with sodium azide followed by triphenylphosphine.8 The
reduction of the aziridine ester 1a with DIBAL furnished a bench-
stable white solid in 83% yield (Table 1, entry 1). Gratifyingly, its
X-ray crystallographic analysis (Figure 2) revealed that the aziridine
aldehyde was formed and had undergone a diastereoselective
homodimerization, rather than giving products of premature
condensation via iminium ion formation, confirming our hypothesis
that the aziridine and aldehyde functionalities can coexist.
Several aziridine aldehydes with different substitution patterns
were prepared using this method (Table 1). The products are off-
white solids that can be purified by recrystallization with the
exception of 2e and the parent aziridine aldehyde 2d, which is a
water-soluble, colorless liquid. In order to establish the synthetic
utility of aziridine aldehydes, we evaluated the nature of equilibrium
between their dimer and monomer states (Scheme 1).
The monomeric aldehydes can be obtained in MeOH/THF and
can be cleanly reduced with sodium borohydride to give the
aziridine alcohols (e.g., 3). Furthermore, reductive amination of 2a
with aniline furnished the diamine 4 in quantitative yield. This result
demonstrates that the aziridine functional group is orthogonal to
the aldehyde in the course of the reaction, allowing selective
reactivity with an external secondary amine at the aldehyde carbon.
Motivated by ongoing interest in efficient construction of
complex alkaloid scaffolds9 and encouraged by the chemoselective
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J. AM. CHEM. SOC. 2006, 128, 14772-14773
10.1021/ja065898s CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Preparation of Pentacycles from Aziridine Aldehydes
Scheme 3. Regioselective Ring Opening of 5b with Benzenethiol
and N-Benzyl Tryptamine
°C for 3 h, selective formation of the pentacyclic adduct 5a took
place in 97% yield. Gratifyingly, when the reaction temperature
was decreased to -20 °C, a >20:1 ratio of 5a/5b was obtained.
The heteroaromatic aziridine aldehyde 2c exhibited poor reactivity
as it was only moderately soluble in trifluoroethanol at room
temperature. Importantly, the parent aziridine aldehyde 2d, which
along with 2e is the most synthetically versatile compound of this
series, gave high yield of the pentacyclic product.
Table 2. Pentacycles Derived from Aziridine Aldehydes and
N-Benzyl Tryptaminea
In summary, an efficient synthesis of bench-stable amino
aldehydes has been developed and their synthetic utility has been
demonstrated. These novel molecules exist as dimers and contain
two orthogonal reaction centers, namely an amine/aziridine and an
aldehyde, over the span of only three atoms.11 Their ability to act
as linchpins has been evaluated in complex heterocycle synthesis.
The amphoteric nature of aziridine aldehydes should facilitate
invention of new transformations as well as efficient generation of
complex molecular skeletons with minimal use of protecting group
manipulations.
Acknowledgment. We thank NSERC and Amgen for financial
support. We also thank Dr. A. Lough for X-ray structure analyses
of 2a and 5b and Dr. Tim Burrow for 2D NMR analysis.
Supporting Information Available: Compound characterization
and experimental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Unless stated otherwise, the reactions were carried out using 1 mmol
of the dimer (2 mmol of aldehyde) and 2 mmol of N-benzyl tryptamine in
2 mL of TFE at 0 °C for 3 h. b Major diastereoisomer shown. c Isolated
yield. d Based on crude 1H NMR. e Reaction was run at -20 °C. f Elevated
temperature was required for reaction to occur.
References
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(2) For reviews on N-protected amino aldehydes see (a) Jurczak, J.;
Golebiowski, A. Chem. ReV. 1989, 89, 149. (b) Reetz, M. T. Angew.
Chem., Int Ed. 1991, 30, 1531. (c) Sardina, F. J.; Rapoport, H. Chem.
ReV. 1996, 1825.
(3) (a) D-Glucosamine, a naturally occurring amino aldehyde, is stable as a
cyclic aminal salt: Fischer, E.; Leuchs, H. Ber. Dtsch. Chem. Ges. 1902,
36, 24. (b) Glycinal was characterized through degradation studies:
Fischer, E. Ber. 1908, 41, 956. Fischer, E. Ber. 1908, 41, 1019. (c) For a
preparation of histidinal dihydrochloride, see Adams, E. J. Biol. Chem.
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iminium ion chemistry in the presence of an unprotected NH
aziridine moiety (Scheme 1), we further probed the orthogonal
relationship between the aziridine and aldehyde groups by reacting
2a with N-benzyltryptamine (6), a bifunctional nucleophile capable
of iminium ion formation.10 When aziridine aldehyde 2a was reacted
with 6 in toluene at 80 °C for 16 h, a 2:1 diastereomeric mixture
of pentacycles 5a and 5b was isolated in 74% yield as an off-
yellow solid (Scheme 2 and Table 2). The diastereomeric structures
were assigned using 2D-NMR and verified using X-ray analysis
of 5b. The aziridine ring of 5b can be readily opened by
benzenethiol in the presence of 5 mol % Zn(OTf)2 resulting in a
stable aminal product (Scheme 3). The reaction is completed within
1 h with >99% regioselectivity.
The diastereoselectivity of polycyclization was explored using
a variety of protic and aprotic solvents. When 5a was heated in
toluene with a catalytic (5 mol %) amount of water, a 10:1 mixture
of 5b and 5a was obtained. Since the thermodynamic product was
accessible under thermal conditions, a diastereoselective route to
5a was pursued. Polyfluorinated alcohols proved to be the optimal
media. When 2a and 6 were reacted in trifluoroethanol (TFE) at 0
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3236.
(5) Ooi, T.; Saito, A.; Maruoka, J. J. Am. Chem. Soc. 2003, 125, 3220.
(6) Strained iminium ions derived from aziridines can be formed under forcing
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(7) See Davis, F. A. In Aziridines and Epoxides in Organic Synthesis; Yudin,
A. K., Ed.; John Wiley & Sons: New York, 2006.
(8) (a) Legters, J.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1989, 30,
4881. (b) Serafin, S. V.; Zhang, K.; Aurelio, L.; Hughes, A. B.; Morton,
T. H. Org. Lett. 2004, 6, 1561.
(9) Hesse, M. Alkaloids: Nature’s Curse or Blessing?; John Wiley & Sons:
New York, 2002.
(10) For application of tryptamine derivatives in the Pictet-Spengler reaction,
see Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797.
(11) We have observed no evidence for epimerization of the amino aldehyde
R-stereocenter under basic or acidic conditions.
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