DOI: 10.1002/anie.201105778
Asymmetric Catalysis
Asymmetric Synthesis of Chiral 1,3-Diaminopropanols:
À
Bisoxazolidine-Catalyzed C C Bond Formation with a-Keto Amides**
Hanhui Xu and Christian Wolf*
The ever-increasing demand for enantiopure drugs and
agrochemicals, and the use of chiral building blocks in
polymers, liquid crystals, and other materials has generated
a strong stimulus for the development of asymmetric methods
that utilize previously unexplored starting materials to gen-
erate efficient access to new and emerging target com-
pounds.[1] New drug candidates that bear a chiral 1,3-
diaminopropanol moiety or a corresponding oxazolidinone
derivative have recently been introduced for the treatment of
tuberculosis, Alzheimerꢀs disease, and nosocomial infections
caused by bacteria that are resistant to common antibiotics.[2]
The formation of these challenging structures relies on
multistep syntheses from chiral epoxy alcohols or esters and
typically involves laborious protection/deprotection proto-
cols. We envisioned that the enantioselective synthesis of N-
substituted 1,3-diaminopropanols could be accomplished in
three steps by nitroaldol reaction of a-keto amides, which are
unexplored starting materials in asymmetric catalysis, and
subsequent reduction of the nitro and amide groups
(Scheme 1). The first catalytic asymmetric nitroaldol reaction
been elusive.[6] We expected that careful reduction of the nitro
group in a-hydroxy b-nitro propanamides would avoid
problems with the facile retro-aldol reaction[7] and thus lead
to a practical route to a series of chiral 1,3-diaminopropa-
nols.[8]
In recent years, chiral 1,3-oxazolidines have found
increasing use as ligands and auxiliaries in asymmetric
synthesis, which may be attributed to the intriguing ring
topology and the possibility of modular synthesis from amino
alcohols.[9] We have previously introduced bisoxazolidine L1
and showed several applications of this C2-symmetric N,O-
diketal in asymmetric catalysis (Scheme 2).[10] Despite the
ease of preparation of L1, which can be obtained in a single
step from inexpensive cis-1-amino-2-indanol and 1,2-cyclo-
Scheme 1. Retrosynthetic analysis of N-monosubstituted 1,3-diamino-
propanols.
was developed in 1992 by Shibasaki and coworkers, who used
a BINOL-derived rare-earth-metal complex.[3] This reaction
has since received considerable attention and its value for the
synthesis of important chiral building blocks and complex
target compounds has been demonstrated by many research
groups.[4] Relatively few examples of asymmetric nitroaldol
reactions with ketones[5] are known compared to the wealth of
reactions with aldehydes. The use of a-keto amides has not
been reported to date, in fact, catalytic asymmetric intermo-
Scheme 2. Structures of bisoxazolidines L1–L7.
hexanedione, the synthesis of other diketone-derived bis-
oxazolidines is not straightforward and requires careful
selection of starting materials and reaction conditions.[11]
Accordingly, we chose to prepare a series of new ligands
L2–L7 derived from (1R,2S)-aminoindanol analogues and
several diketones to vary the rigidity of the N,O-diketal
backbone and to explore the catalytic performance of
fluxional bisoxazolidines in the nitroaldol reaction with keto
amides.
À
lecular C C bond formations with a-keto amides have so far
[*] H. Xu, Prof. Dr. C. Wolf
Department of Chemistry, Georgetown University
37th and O Streets, Washington, DC 20057 (USA)
E-mail: cw27@georgetown.edu
The synthesis of L2 started with the bromination of 1,2-
dihydronaphthalene (1) and mild hydrolysis of dibromide 2 to
give racemic trans-2-bromo-1-hydroxytetrahydronaphthalene
(3) in a high yield (Scheme 3).[12] The Ritter reaction of 3 then
produced racemic cis-1-amino-2-hydroxytetrahydronaphtha-
lene (4) in 79% yield. Resolution of the enantiomers of 4 by
crystallization with mandelic acid furnished (1R,2S)-4 in more
than 99.5% ee according to HPLC analysis of the tert-
butoxycarbonyl (tBoc) protected analogue (see the Support-
[**] Funding from the National Science Foundation (CHE-0848301) is
gratefully acknowledged.
Supporting information (containing general experimental proce-
dures, details on method development, and product character-
ization, including spectroscopic and chromatographic data) for this
Angew. Chem. Int. Ed. 2011, 50, 12249 –12252
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12249