with various neurodegenerative diseases.10 Their bioactivities
have recently rendered them potential drugs of the future.11
Both (S)-AIDA and (S)-APICA were found to be the active
isomers in various biological assays.12,13 Although the
asymmetric synthesis of these compounds has been reported
using chiral pool12 and chiral ligand-exchange chromatog-
raphy13 approaches, there is still a need for a more direct
asymmetric route that allows for the multigram preparation
of these compounds and their analogues.
Brase and co-workers demonstrated that (S)-proline can
catalyze the reaction of 2-phenylpropionaldehyde with di-
ethylazodicarboxylate to give the corresponding amino
aldehyde in 86% ee after 60 h in CH2Cl2.14c Although this
substrate gave good ee, the reaction was fairly substrate
dependent, and ees varied from 32 to 86% ee. One substrate
that was not tested that was of particular interest to us was
indane carboxyaldehyde 1. Previously, we had found 1 to
be a very reactive donor in the quaternary Mannich reaction,
where it gave excellent enantio- and diastereoselectivity.4
Because 1 contains the core structure of AIDA and APICA,
the amination of 1 would provide the precursor amino
aldehyde, which upon further elaboration would yield the
corresponding amino acid.
The (S)-proline-catalyzed amination of aldehydes has
recently been reported as an efficient way to prepare chiral
amino aldehydes.14 As outlined in Scheme 1, the correspond-
As indicated in Scheme 2, the coupling of 1 to dibenzyl-
Scheme 1. Organocatalysis in the Preparation of Amino Acids
Scheme 2. (S)-Proline Catalyzed Amination of Indane
Carboxaldehyde 1
azodicarboxylate (DBAD) is efficiently and selectively
catalyzed by (S)-proline giving only one enantiomer in
quantitative yield. Having demonstrated that high ees could
be obtained using indane 1 as the donor, we devised
syntheses of (S)-AIDA and (S)-APICA according to Schemes
3 and 4.
ing amino acids can be prepared by simple oxidation and
N-N bond cleavage of the amino aldehyde adducts. Thus,
utilizing this amination sequence, (S)-AIDA and (S)-APICA
could be prepared via organocatalysis. Herein we report a
practical and efficient organocatalytic enantioselective syn-
thesis of (S)-AIDA and (S)-APICA where the amination of
branched aldehyde donors is used as a key step.
The synthesis of (S)-AIDA began with cyanation of
commercially available 5-bromoindanone giving 3 in 78%.15
Wittig olefination afforded 4 as a mixture of E and Z isomers,
and upon hydrolysis of the cyano group and subsequent
esterification, 5 was obtained in excellent yield. Various
attempts to hydrolyze the enol ether 5 using mineral acids
or PTSA resulted in low yields. However, when boron
tribromide was used, the demethylation of 5 ensued without
affecting the ester functionality,16 thus providing indane
aldehyde 6 in good yield. The functionalized indane 6 proved
to be a good substrate for the amination reaction. When a
slight excess of aldehyde was reacted with DBAD with 20
mol % (R)-proline at ambient temperature, the amination
product was obtained in >99% ee and 96% yield in less
than 4 h. Subsequent oxidation and esterification gave
precursor 7.
(7) (a) Chowdari, N. S.; Ramachary, D. B.; Cordova, A.; Barbas, C. F.,
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D. W. C. Science 2004, 305, 1753-1755. (c) Suri, J. T.; Ramachary, D.
B.; Barbas, C. F., III. Org. Lett. 2005, 7, 1383-1385.
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Initially, high-pressure hydrogenation over Ra-Ni was
attempted in order to cleave the N-N bond.14 Because yields
were low (less than 10%), an alternative route was carried
out utilizing SmI2. We first applied a one-pot trifluoroacety-
lation-selective benzyloxycarbonyl deprotection protocol17
(15) Matveeva, E. D.; Podrugina, T. A.; Morozkina, N. Y.; Zefirova, O.
N.; Seregin, I. V.; Bachurin, S. O.; Pellicciari, R.; Zefirov, N. S. Russ. J.
Org. Chem. 2002, 38, 1769-1774.
(16) Dharanipragada, R.; Fodor, G. Org. Biol. Chem. 1986, 4, 545-50.
(17) Chowdari, N.; Barbas, C. F., III. Org. Lett. 2005, 7, 867-870.
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A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jorgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 1790-1793. (c) Vogt, H.; Vanderheiden, S.; Brase,
S. Chem. Commun. 2003, 2448-2449.
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