Organic Letters
Letter
selective phenol addition is preferred on the Re-face for alkyl
aldimine addition using (S)-Ph-Box and the Si-face using (R)-Bn-
Box for aryl aldimine addition. A steric match between aryl
imine/alkyl-Box or alkyl imine/aryl-Box appeared optimal from
the ligand screening data (Table 1 and optimization table in SI).
The imine sulfonyl group was expected to be very sterically
demanding; thus, its placement on the same face as the closest
(cis) chiral ligand substituent was avoided. Hydrogen bonding
between the phenol hydrogen and the other sulfonyl oxygen as
drawn (Figure 1) could add additional activation and structure at
the transition state.
using a copper(II)-bis(oxazoline) catalyst. Good to excellent ee’s
were observed for alkyl aldimines and aryl aldimines. The
synthetic utility of the products was displayed by the
enantioselective synthesis of a known dual orexin receptor
antagonist, as well as a chiral 2-aryltetrahydroquinoline.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
Experimental procedures and chiral HPLC traces of all
NMR spectra of all new compounds (PDF)
The synthetic utility of the alkyl aldimine aza-Friedel−Crafts
reaction was demonstrated by synthesizing a dual orexin receptor
antagonist in its enantioenriched form for the first time (Scheme
5).3,4 Phenolic benzyl amine 3q1 was O-methylated, followed by
Accession Codes
graphic data for this paper. These data can be obtained free of
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
Scheme 5. Enantioselective Synthesis of an Orexin Receptor
Antagonist
AUTHOR INFORMATION
■
Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We gratefully acknowledge the National Institutes of Health
(GM078383) for financial support of this work. We acknowledge
Dr. William W. Brennessel and the Crystallography Facility at the
University of Rochester for obtaining the X-ray structures of 3i
(CCDC 1588079) and 5d (CCDC 1588080). We thank Dr.
Valerie Frerichs (UB instrument center) for help with the chiral
HPLC.
hydrogenation to both hydrodebrominate the aromatic ring and
cleave the benzyl ether, affording alcohol 7.23 Oxidative
cyclization utilizing pyridinium dichromate gave the 5-aryl-N-
tosyl amide 8.24 Tosyl deprotection using lithium-naphthale-
nide25 and N-alkylation provided the dual orexin receptor
antagonist (−)-11.
Additionally, benzylamine 3s was converted to 2-aryltetrahy-
droquinoline 13 (Scheme 6). O-Methylation of phenolic
benzylamine 3s provided 12. Palladium-catalyzed intramolecular
cyclization/coupling26 of the pendant amine to the aryl bromide
of 12 then efficiently formed the N-tosyl-2-aryl-tetrahydroquino-
line 13.
REFERENCES
■
(1) Frederich, M.; Tits, M.; Goffin, E.; Philippe, G.; Grellier, P.; De
Mol, P.; Hayette, M.-P.; Angenot, L. Planta Med. 2004, 70, 520.
(2) Frederich, M.; Bentires-Alj, M.; Tits, M.; Angenot, L.; Greimers, R.;
Gielen, J.; Bours, V.; Merville, M.-P. J. Pharmacol. Exp. Ther. 2003, 304,
1103.
(3) Sifferlen, T.; Boller, A.; Chardonneau, A.; Cottreel, E.; Hoecker, J.;
Aissaoui, H.; Williams, J. T.; Brotschi, C.; Heidmann, B.; Siegrist, R.;
Gatfield, J.; Treiber, A.; Brisbare-Roch, C.; Jenck, F.; Boss, C. Bioorg.
Med. Chem. Lett. 2014, 24, 1201.
In conclusion, we have developed a catalytic enantioselective
aza-Friedel−Crafts reaction between phenols and aldimines
(4) Sifferlen, T.; Boller, A.; Chardonneau, A.; Cottreel, E.; Gatfield, J.;
Treiber, A.; Roch, C.; Jenck, F.; Aissaoui, H.; Williams, J. T.; Brotschi,
C.; Heidmann, B.; Siegrist, R.; Boss, C. Bioorg. Med. Chem. Lett. 2015,
25, 1884.
Scheme 6. Synthesis of a Tetrahydroquinoline
(5) Lavecchia, A.; Di Giovanni, C.; Cerchia, C.; Russo, A.; Russo, G.;
Novellino, E. J. Med. Chem. 2013, 56, 2861.
(6) Montesinos-Magraner, M.; Vila, C.; Canto
Fernandez, I.; Munoz, M. C.; Pedro, J. R. Angew. Chem., Int. Ed. 2015,
54, 6320.
́
n, R.; Blay, G.;
́
̃
(7) Zhou, D.; Huang, Z.; Yu, X.; Wang, Y.; Li, J.; Wang, W.; Xie, H. Org.
Lett. 2015, 17, 5554.
(8) Kumari, P.; Barik, S.; Khan, N. H.; Ganguly, B.; Kureshy, R. I.; Abdi,
S. H. R.; Bajaj, H. C. RSC Adv. 2015, 5, 69493.
(9) Chauhan, P.; Chimni, S. S. Eur. J. Org. Chem. 2011, 2011, 1636.
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