Direct catalytic asymmetric synthesis of cyclic aminals from aldehydes

Article abstract of DOI:10.1021/ja8071034

A highly enantioselective Bronsted acid catalyzed direct synthesis of cyclic aminals from aldehydes has been developed. The methodology has been applied to the first asymmetric synthesis of several antihypertensive aminal drugs including (R)-Thiabutazide. Copyright

Full text of DOI:10.1021/ja8071034

Published on Web 11/01/2008
Direct Catalytic Asymmetric Synthesis of Cyclic Aminals from Aldehydes
Xu Cheng, Sreekumar Vellalath, Richard Goddard, and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470, Mu¨lheim an der Ruhr, Germany
Received September 8, 2008; E-mail: list@mpi-muelheim.mpg.de
Despite the enormous advancements of asymmetric catalysis, the
catalytic enantioselective generation of acetals and related com-
pounds only recently became a possibility. Inspired by the advent
of asymmetric Brønsted acid catalysis,1,2 Antilla et al. developed
phosphoric acid catalyzed syntheses of acyclic aminals and hemi-
aminals via additions of amides and alcohols to preformed imines.3
Realizing the ubiquitous occurrence of stereogenic cyclic aminals
and similar structures in drugs and other compounds of use, and
the lack of available enantioselective routes toward their preparation,
we became interested in this fascinating problem. Here we report
a highly enantioselective direct synthesis of aminals from aldehydes,
catalyzed by a new chiral phosphoric acid catalyst.
Although possibly considered metabolically unstable, cyclic
aminals and acetals are relatively common structural elements of
diverse commercial pharmaceuticals. A small collection is shown
in Figure 1 and includes Aquamox and Thiabutazide, two members
of the benzo(thia)diazine class of cyclic aminals used for the
treatment of high blood pressure.4 Other examples include Cevime-
line,5 which contains an S,O-acetal and is used in the treatment of
dry mouth associated with Sjo¨gren’s syndrome, the O,O-acetal
Pipoxolan,6 an antispasmodic drug, the parasympathomimetic N,N-
acetal Physostigmine,7 as well as the Seebach imidazolidinone chrial
auxiliary,8 more recently used as an organocatalyst.9
complete reaction occurred at room temperature within 12 h furnishing
product 3a in 4 er (56% ee) and in 86% yield. After optimizing the
conditions (see Supporting Information, SI), a benchmark screening
of different chiral phosphoric acids was carried out (Table 1). At -45
°C, (S)-TRIP gave up to 8 er with full conversion after 24 h (entry 1).
Anthrancenyl substituted phosphoric acid 4b gave product 3a with an
er of only 4 (entry 2). Both catalyst 4c previously used by Akiyama
et al. and VAPOL-derived phosphoric acid 4f, which Antilla et al.
utilized to catalyze the corresponding intermolecular reaction, did not
improve the enantioselectivity of our reaction (entries 3 and 6).
Remarkably, anthracenyl-modified TRIP catalyst 4d, which we have
previously used to catalyze the direct asymmetric Kabachnik-Fields
reaction, dramatically increased the enantioselectivity to 99 er (98%
ee).14 In addition, catalyst 4e bearing the adamantyl backbone gave
high enantioselectivity.
Table 1. Catalyst Investigation
Figure 1. Important compounds that contain a stereogenic cyclic acetal,
thioacetal, or aminal.
We felt that especially the benzo(thia)diazine pharmaceuticals, which
have been used as effective diuretic drugs since 1957 and are
commonly used to treat high blood pressure, would be attractive
targets.4 The widely used protocol for their synthesis involves the
condensation of substituted 2-aminobenzamide or 2-aminobenzene-
sulfonamide with an aldehyde in the presence of a Brønsted acid
catalyst or reagent.10 So far only achiral acids have been used in the
preparation of racemic diazines. While it has been established that their
enantiomers have different bioacitivtiy,11 to the best of our knowledge,
the only method to access enantiomerically enriched species has been
HPLC separation.12 A catalytic asymmetric route would be highly
attractive for a possible second generation enantiomerically pure drug.
A model reaction between 2-aminobenzamide (1a) and isovaleral-
dehyde (2a) to furnish dihydroquinazolinone 3a was initially estab-
lished. In the presence of 10 mol% of (S)-TRIP (4a)13 a clean and
a From HPLC analysis using an OD-H column. b Opposite enantiomer.
Having identified acid 4d as a suitable catalyst, we reacted different
aldehydes (2b-g) and ketone 5 under the same conditions with amide
1a to furnish cyclic aminals 3 (Table 2). Aliphatic, R-unbranched
aldehydes all gave high yields and enantioselectivities in the conversion
to aminal 3 (entries 1-5). Isobutyraldehyde (2a) and benzaldehyde
(2g) as representatives of R-branched and aromatic aldehydes gave
somewhat lower enantioselectivities. As a highly reactive ketone, we
also investigated isatin (5) under the standard conditions and found it
to give spirocyclic product 6 in moderate enantioselectivity (12 er).
In this case, (S)-TRIP 4a turned out to be a superior catalyst giving
product 6 in good enantioselectivity (entry 8).
We also explored various substituted 2-aminobenzamides (1b-l)
in their reaction with isovaleraldehyde (2a) (Table 3). The reaction
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15786 J. AM. CHEM. SOC. 2008, 130, 15786–15787
10.1021/ja8071034 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Aldehyde Scope
and (R)-Penflutizide could be synthesized in high enantioselectivity
using our methodology. (S)-Aquamox could also be prepared. In
this case, somewhat lower enantioselectivity was achieved.16
Figure 2. Antihypertensive pharmaceuticals made using our new
methodology.
In summary, we have developed a direct synthesis of chiral
aminals from aldehydes using a phosphoric acid as catalyst. This
methodology has been applied to pharmaceutically relevant com-
pounds. Current studies in our laboratories aim at further expanding
the scope of this chemistry.
a From chiral stationary phase HPLC analysis. b Reaction at -15 °C.
c (S)-TRIP 4a (10 mol%) was used as catalyst (70 °C, 4 h).
turned out to be highly tolerant to arene substitution, and essentially
all investigated amides gave excellent enantioselectivities (entries
1-11). Aminal 3k was crystallized from CH2Cl2, and its structure,
including its absolute configuration, was determined from Ro¨ntgen
diffraction studies. Furthermore, sulfonamide 7 gave the corre-
sponding cyclic product 8 in excellent enantioselectivity. Aminal
8 has previously been shown to racemize at room temperature,
which we confirmed.15
Acknowledgment. We thank the Alexander von Humboldt
Foundation (fellowship for S.V.), the Max-Planck-Society, the DFG
(Priority Program Organocatalysis SPP1179), AstraZeneca (Award
in Organic Chemistry to B.L.), Merck KGaA, and the Fond der
Chemischen Industrie (Award to B.L.).
Supporting Information Available: Experimental procedures,
compound characterization, NMR-spectra, and HPLC traces and
Rontgen data (PDF). This material is available free of charge via the
Table 3. 2-Aminobenzamide Scope
¨
Internet at http://pubs.acs.org.
References
(1) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed.
2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356. For a review, see: (c) Akiyama, T. Chem. ReV. 2007, 107, 5744.
(2) (a) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005,
44, 7424. (b) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2006, 128, 84. (c) Rueping, M.; Sugiono, E.; Azap, C.
Angew. Chem., Int. Ed. 2006, 45, 2617. (d) Guo, Q.-X.; Liu, H.; Guo, C.;
Luo, S.-W.; Gu, Y.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 3790. (e)
Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew. Chem.,
Int. Ed. 2007, 46, 5565. (f) Jiao, P.; Nakashima, D.; Yamamoto, H. Angew.
Chem., Int. Ed. 2008, 47, 2411.
(3) (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.;
Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696. (b) Liang,
Y.; Rowland, E. B.; Rowland, G. B.; Perman, J. A.; Antilla, J. C. Chem.
Commun. 2007, 4477. (c) Li, G.-L.; Fronczek, F. R.; Antilla, J. C. J. Am.
Chem. Soc. 2008, 130, 12216.
(4) Verdel, B. M.; Souverein, P. C.; Egberts, A. C. G.; Leufkens, H. G. M.
Ann. Pharm. 2006, 40, 1040, and references therein.
(5) Mavragani, C. P.; Moutsopoulos, H. M. Clinic ReV. Allerg. Immunol. 2007,
32, 287.
(6) Felix, W.; Rimbach, G.; Wengenroth, H. Arzneim.-Forsch. 1969, 19, 1860.
(7) Militante, J; Ma, B.-W.; Akk, G.; Steinbach, H. Mol. Pharmacol. 2008,
74, 764.
(8) Naef, R.; Seebach, D. HelV. Chim. Acta 1985, 68, 135.
(9) (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, W. C. J. Am. Chem. Soc. 2005,
127, 32. (b) Yang, J. W.; Fonseca, M. T. H.; List, B. J. Am. Chem. Soc.
2005, 127, 15036.
(10) (a) Sharma, S. D.; Kaur, V. Synthesis 1989, 677. (b) Braghiroli, D.; Puia,
G.; Cannazza, G.; Tait, A.; Parenti, C.; Losi, G.; Baraldi, M. J. Med. Chem.
2002, 45, 2355.
(11) Uzunov, D. P.; Zivkovich, I.; Pirkle, W. H.; Costa, E.; Guidotti, A. J. Pharm.
Sci. 1995, 84, 937.
a From HPLC analysis using an OD-H column. b Er measured from
crude product; compound 8 racemizes upon storage at room temperature.
Finally, our methodology can also be applied to systems of
practical relevance. While Thiabutazide could not be prepared using
our standard conditions because of a lack of solubility of the
required reagent, clean conversion occurred if the reaction was
conducted in CH2Cl2 using catalyst 4e providing (R)-Thiabutazide
in 81% yield and 21 er (91% ee) (Figure 2). Thiabutazide proved
to be configurationally stable during the reaction conditions and
isolation. Similarly, (R)-Cyclopenthiazide, (R)-Bendroflumethiazide,
(12) Hyun, M. H.; Pirkle, W. H. J. Chromatogr., A 2000, 876, 221.
(13) For a review on TRIP, see: Adair, G.; Mukherjee, S.; List, B. Aldrichimica
Acta 2008, 41, 31.
(14) Cheng, X.; Goddard, R.; List, B. Angew. Chem., Int. Ed. 2008, 47, 5079.
(15) Cannazza, G.; Braghiroli, D.; Iuliani, P.; Parenti, C. Tetrahedron: Asymmetry
2006, 17, 3158.
(16) Catalyst (R)-4f was used in this case. For details, see SI.
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