Angewandte
Chemie
DOI: 10.1002/anie.200801173
Multicomponent Reactions
Direct Catalytic Asymmetric Three-Component Kabachnik–Fields
Reaction**
Xu Cheng, Richard Goddard, Gernot Buth, and Benjamin List*
The reaction of a carbonyl compound, an amine, and a
phosphite by in situ imine hydrophosphonylation [Eq. (1)],
often called the Kabachnik–Fields reaction, is an attractive
approach to a-amino phosphonates.
kinetic resolution (DKR) that is catalyzed by TRIP, a chiral
phosphoric acid we have developed previously.[13c,14,15] We
envisioned that an extension of these strategies to the
Kabachnik–Fields reaction may be possible, leading directly
to b-branched a-amino phosphonates 4 [Eq. (2)]. The anal-
ogous b-branched a-amino carboxylic acids have attracted
attention in peptidomimetic chemistry as they uniquely
restrict the conformational flexibility within a peptide.[16]
Our design, however, seemed to be particularly challenging
as it combines a dynamic kinetic resolution with the parallel
creation of an additional stereogenic center.
As mimics of a-amino acids,[1] a-amino phosphonates
have great promise as antibacterial[2] and anti-HIV[3] agents as
well as protease inhibitors.[4,5] Consequently, their enantiose-
lective synthesis, in particular by catalytic enantioselective
hydrophosphonylation of preformed imines, has attracted
considerable interest.[6,7] Both chiral metal complexes[8] as
well as organic catalysts such as Jacobsenꢀs chiral thiourea
derivatives,[9] chiral phosphoric acid derivatives,[10] and qui-
nine have been used with success.[11] Despite these achieve-
ments however, a direct catalytic asymmetric Kabachnik–
Fields reaction, has to our knowledge not been described
before.[12] Here we show that racemic a-branched aldehydes,
in the presence a new chiral phosphoric acid catalyst,[13]
directly react with p-anisidine and a phosphite to furnish b-
branched a-amino phosphonates highly diastereoselectively
and enantioselectively by a dynamic kinetic resolution.
Akiyama et al.[10] recently developed an enantioselective
hydrophosphonylation of preformed aromatic and unsatu-
rated imines that is catalyzed by chiral binol-derived phos-
phoric acids pioneered in their laboratories as well as by
Terada et al.[13b] Our group reported a highly enantioselective
reductive amination of a-branched aldehydes by dynamic
Indeed, the direct asymmetric three-component Kaba-
chnik–Fields reaction of one equivalent each of aldehyde 1a,
p-anisidine (2a), and di(3-pentyl)phosphite (3a),[17] catalyzed
by TRIP (5, 10 mol%) furnished the desired product 4a
highly diastereoselectively (d.r. 16:1) and with moderate
enantioselectivity (e.r. 83:17; 66% ee) [Eq. (3)]. We also
tested the anthrancenyl-substituted catalyst 6, which has
previously been used with success in imine activation
reactions.[18] However, no improvement in enantioselectivity
was obtained. We then started investigating new phosphoric
acids and found that the p-anthracenyl-substituted TRIP
analogue 7[19] was indeed both highly effective and stereose-
[*] Dr. X. Cheng, Dr. R. Goddard, Prof. Dr. B. List
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2999
E-mail: list@mpi-muelheim.mpg.de
Dr. G. Buth
ISS, Forschungszentrum Karlsruhe
Postfach 3640, 76021 Karlsruhe (Germany)
[**] We thank Alfred Deege and Heike Hinrichs for HPLC measure-
ments. This work was funded in part by the DFG (priority program
“Organocatalysis” SPP1179). Generous support by the Max Planck
Society, Novartis (Young Investigator Award to B.L.), the Fonds der
Chemischen Industrie (Silver Award to B.L.), and AstraZeneca
(Research Award in Organic Chemistry to B.L.) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2008, 47, 5079 –5081
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5079