Highly flexible synthesis of chiral azacycles via iridium-catalyzed hydrogenation

Article abstract of DOI:10.1021/ja103901e

A range of saturated chiral azacycles has been prepared in high yield and with high selectivity from simple starting materials. A modular approach with ring-closing metathesis as a key step was used to produce a number of five-, six-, and seven-membered c

Full text of DOI:10.1021/ja103901e

Published on Web 06/17/2010
Highly Flexible Synthesis of Chiral Azacycles via Iridium-Catalyzed
Hydrogenation
J. Johan Verendel, Taigang Zhou, Jia-Qi Li, Alexander Paptchikhine, Oleg Lebedev,† and
Pher G. Andersson*
Department of Biochemistry and Organic Chemistry, Uppsala UniVersity, Box 576, S-75123 Uppsala, Sweden
Received May 13, 2010; E-mail: Pher.Andersson@biorg.uu.se
Scheme 1. Synthesis of Precursors 2
Saturated, chiral nitrogen-containing heterocycles are common
motifs in medicinal compounds and natural products such as
alkaloids, and their preparation by asymmetric catalysis has seen
intensive study over the past 20 years.1 Transition-metal-catalyzed
hydrogenation, one of the most powerful, efficient and well-
established methods for preparing enantiomerically enriched com-
pounds, has been used.2 In fact, the most common strategy to access
chiral nitrogen heterocycles is via the hydrogenation of heteroaro-
matic compounds such as quinolines, isoquinolines, quinoxalines,
pyridines, and pyrroles.3
substituted olefin. Ligand D (Table 1, entry 4) produced a less
reactive catalyst.
Table 1. Screening of Catalysts for Asymmetric Hydrogenation of 2a
The metal-catalyzed asymmetric hydrogenation of cyclic imines
has also been achieved,4 most often in the presence of an aromatic
substituent. Naturally, this reaction can give chirality R to the
nitrogen atom only.
Enamide hydrogenation has been used but is usually dependent
on functionalization at nitrogen.5 Since Buchwald’s first report,6
several groups have hydrogenated unfunctionalized enamines,2b,7
though few have yielded high selectivity. Zhou and co-workers8
reported the direct hydrogenation of cyclic N,N-dialkyl enamines.
Two successful asymmetric hydrogenations of cyclic alkenes in
which the double bond is distant from nitrogen and in the same
ring have been reported. Szo¨llo¨si and co-workers9 used a cinchona-
modified Pd/Al2O3 catalyst to reduce an R,ꢀ-unsaturated carboxylic
acid with moderate selectivity. Zhang and co-workers10 hydroge-
nated a protected N-acyl-functionalized 2,5-dihydropyrrole with high
selectivity.
Since iridium-based hydrogenation catalysts [(L)Ir(COD)]+[BArF]-
(COD ) 1,4-cyclooctadiene, [BArF]- ) [(3,5-(F3C)2-C6H3)4B]-) do
not require coordinating groups to direct the stereoselectivity,11 we
imagined that they may be well-suited for the hydrogenation of
heterocyclic olefins in which the heteroatom is remote from the olefin,
such as substrate 2. Additionally, as iridium catalysts are not
coordinated by the N group, any protecting group can be chosen and
later removed, thus leaving room for further synthetic modifications.
Herein we report the use of iridium-catalyzed asymmetric
hydrogenations that produce five-, six-, and seven-membered
azacycles with good to excellent enantioselectivities. We synthe-
sized a range of tosyl-protected aminodienes 1 from the corre-
sponding amidoalkenes and allyl bromides (Scheme 1). Ring-closing
metathesis using Grubbs’ second-generation catalyst12 produced
1,2,3,6-tetrahydropyridines 2 in good yields.
a Reaction conditions: 0.5 mol % catalyst, 50 bar H2, 15 h, room
temperature. b Determined by 1H NMR spectroscopy. c Determined by
chiral HPLC.
These results encouraged us to evaluate a range of substrates
bearing different aliphatic or aromatic substituents using catalysts
based on ligands A and E (Table 2). We found that the catalyst
derived from ligand E tolerated several CH2X derivatives while
retaining selectivity (Table 2, entries 1-4). Excellent selectivity
and high activity were obtained for substrates with electron-
rich substituents (entries 5-9) using [(A)Ir(COD)]+[BArF]-,
whereas lower selectivity was obtained for those with electron-
poor aryl groups (entries 10, 12, and 14). However, these
substrates could be reduced faster and more enantioselectively
using [(B)Ir(COD)]+[BArF]-.
We screened six-membered, N-tosyl-protected azacyclic alkenes
bearing methyl or phenyl substituents against our catalyst library
(Table 1).13 Catalysts with the structurally similar ligands A-D
gave high selectivity for the phenyl-substituted olefin, whereas the
ligand with a bicyclic backbone, E, performed better for the methyl-
† Present address: Institute of Chemistry, University of Tartu, Ravila 14a, 50411
Tartu, Estonia.
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8880 J. AM. CHEM. SOC. 2010, 132, 8880–8881
10.1021/ja103901e  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Hydrogenation of Six-Membered
Scheme 2. Synthesis of the 3-PPP Precursor 5 via Asymmetric
Hydrogenation of Heterocyclic Olefin 3
N-Heterocyclic Olefinsa
Entry
R
Ligand
convb (%)
eec (%)
1
2
3
4
5
6
7
8
Me
Bu
Bn
CH2OH
C6H5
4-MeC6H4
3-MeC6H4
4-MeOC6H4
3-MeOC6H4
4-F3CC6H4
4-F3CC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
E
E
E
E
>99
>99
97
>99
>99
>99
97
>99
60
19
74
97 (-)
81 (-)
92 (-)
97 (-)
>99 (+)
>99 (+)
97 (+)
99 (+)
98 (+)
87 (+)
96 (-)
87 (+)
98 (-)
94 (+)
98 (-)
The ease of substrate preparation, high yield, and selectivity of this
reaction make it useful for the synthesis of medicinal compounds
and natural products, as demonstrated for 5, the precursor to 3-PPP.
We are currently investigating asymmetric hydrogenation of other
heterocyclic alkenes.
A
A
A
A
A
A
B
A
B
A
B
9
Acknowledgment. The Swedish Research Council (VR), the
Knut and Alice Wallenberg Foundation, and VR/SIDA supported
this work. We thank Prof. T. Govender and Mr. B. Peters for help
with HRMS and Dr. T. L. Church for useful discussions. Dedicated
to Professor Carmen Najera on the occasion of her 60th anniversary.
10
11
12
13
14
15
57
94
68
92
Supporting Information Available: Experimental details, separation
methods, and spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
a-cSee the corresponding footnotes in Table 1.
The method was also applicable to five- and seven-membered
heterocyclic alkenes (Table 3). The best catalyst for these hydro-
genations was [(C)Ir(COD)]+[BArF]-. Changing the protecting
group from Ts to Cbz slightly improved the selectivity for the five-
membered cyclic alkene (entry 1).
References
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a-cSee the corresponding footnotes in Table 1.
To demonstrate the utility of this type of hydrogenation, we
applied it to the synthesis of 3-PPP (Preclamol, 6; Scheme 2). 3-PPP
is the first selective D2-like dopamine autoreceptor agonist and has
been known since the 1980s.14 Several related 3-phenylpiperidines
show dopaminergic activity15 and have proven useful in the
treatment of various central nervous system disorders.16 We started
with compound 3 bearing an electron-rich aryl substituent. Thus,
catalyst [(A)Ir(COD)]+[BArF]- (1 mol %, 20 h) was used and gave
compound 4 in 93% yield and >99% ee after recrystallization from
Et2O. The ee before recrystallization was 98% (Table 2, entry 9).
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compound 5 in 85% yield. Compound 5 can be elaborated to 3-PPP
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In conclusion, we have developed a method for the synthesis of
chiral pyrrolidines, piperidines, and azepanes using N,P-ligated
iridium catalysts. The selectivity ranged from good to excellent.
JA103901E
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