Stereoselective synthesis of configurationally stable functionalized ethano-bridged Troeger bases

Article abstract of DOI:10.1039/b925065d

New functionalized ethano-bridged Troeger bases are readily prepared using a simple alkylation/rearrangement sequence which affords configurationally stable derivatives as single stereoisomers (de > 96%).

Full text of DOI:10.1039/b925065d

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Stereoselective synthesis of configurationally stable functionalized
¨
ethano-bridged Troger basesw
a
a
b
c
´
Christophe Michon, Ankit Sharma, Gerard Bernardinelli, Eric Francotte and
a
´
Jerome Lacour*
Received (in Cambridge, UK) 30th November 2009, Accepted 13th February 2010
First published as an Advance Article on the web 25th February 2010
DOI: 10.1039/b925065d
¨
New functionalized ethano-bridged Troger bases are readily
prepared using a simple alkylation/rearrangement sequence
which affords configurationally stable derivatives as single
stereoisomers (de > 96%).
properties.17 [1,2]-Stevens rearrangements, which are spontaneous
transformations of quaternary ammonium ions into tertiary
amines under basic conditions,18 have also been investigated
for their interesting mechanism and synthetic utility.19 In the
course of these studies, we noticed that a [1,2]-Stevens
rearrangement of Troger derivatives had never been reported.
¨
Troger bases of type 1, which are the classical products from
¨
condensation reactions of aromatic amines with formaldehyde,
This was somewhat surprising as several quaternary ammonium
salts of compounds 1 had been described14,15,20 and all the
more interesting as such a rearrangement had the potential to
create novel interesting framework(s).18
have been extensively studied for their properties and
reactivities.1–4 A large array of Troger bases has been prepared
¨
thanks to modular synthetic routes to the tricyclic core,5,6 and
this for a variety of applications such as molecular recognition,7
DNA-interacting probes,8 biomimetic systems,9 and self-
assembled structures.10,11 In the field of organic stereochemistry,
Troger bases hold a special place, being the first compounds
¨
(1)
with stereogenic nitrogen atoms to be resolved.12 Regrettably,
reactions using compounds 1 as enantiopure ligands, auxiliaries
or catalysts are rare.6 This situation is possibly due to the
relatively facile racemization of compounds 1 in acidic media
(barrier of inversion ca. 101 kJ molꢀ1).13,14 A few solutions to
this problem have been brought forward,3,11,13 including the
To test the feasibility of the transformation, salt [3a][Br] was
prepared following reported conditions (eqn (1), R = Ph).14
However, in line with previous reports,20,21 we observed only
starting material and/or demethylenated product 4a (up to
93%, Scheme 1) with no trace of rearrangement adduct(s) in
our many attempts.22 This exclusive formation of 4a was
explained by a preferred reactivity of the added bases with
the bridge-methylene carbon of 3a (Scheme 1, path a). To
upset the situation, we considered that the deprotonation of
the side-chain protons to form a necessary ylide should be
enforced (Scheme 1, path b). This should be achieved by the
introduction of more acidic hydrogen atoms and that of
ArCOCH2 side-chains in particular. A search of the literature
indicated that these protons should indeed be more acidic than
the previously-used benzylic ones (pKa 14.6 and 31.9 for
PhCOCH2N+Me3 and PhCH2N+Me3, respectively).23 Salt
interesting transformation of methano-Troger bases into
¨
ethano-derivatives (2).15,16 The presence of the ethano bridge
in 2 avoids the conventional racemization pathway via an
achiral iminium intermediate. Herein, we report a novel
two-step sequence for the preparation of ethano-Troger bases
¨
via the synthesis of quaternary ammonium salts and an
unprecedented ring-expansion Stevens-like rearrangement.
This simple-to-run protocol yields configurationally stable
functionalized derivatives as single stereoisomers.
[3b][Br] was then prepared by treatment of Troger base 1a
¨
with a-bromoacetophenone at reflux in benzene (87%, eqn (1)).
Experiments on the rearrangement of [3b][Br] were initially
disappointing using regular conditions for the Stevens
rearrangement (NaOH, KOH, t-BuOK as bases). Only
dihydrodibenzodiazocine adduct 4b was observed in the
1H NMR spectra of the crude reaction mixtures. However,
with other bases (CsOH, Cs2CO3, NaOMe, NaOAc), a trace
amount of a new compound was noticed. Using organic
amines (Table 1, entries 1–4), reactions were slow. After
10 h, starting material was still present but an isolable
amount of this novel species was afforded (5–18%) which
was characterized as novel rearrangement product 5b. Yet,
diazocine 4b was still a major component even in the reactions
Previously, our group has studied quaternary ammonium
salts for their conformational, configurational and host–guest
a Department of Organic Chemistry, Quai Ernest Ansermet 30,
Ch-1211 Geneva 4, Switzerland. E-mail: jerome.lacour@unige.ch;
Fax: +41 22 379 3215
b Laboratoire de Cristallographie, University of Geneva, Quai Ernest
Ansermet 24, CH-1211 Geneva 4, Switzerland
c Global Discovery Chemistry, Novartis Institutes for Biomedical
Research, WKL-122.P.25 Postfach, CH-4002 Basel, Switzerland
w Electronic supplementary information (ESI) available: Synthetic
procedures and spectral characterization of salts 3 and products 4–7.
CCDC 756194 (5b). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b925065d
ꢁc
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Scheme 1 Possible reactivity pathways of quaternary ammonium
salts of cations of type 3 in the presence of bases.
of hindered bases such as i-Pr2NEt (entry 4). Looking then for
essentially non-nucleophilic conditions, basic alumina
(Brockman activity I, pH 9.5 ꢂ 0.5, entries 5–6) was used.
Fig. 1 ORTEP view of the crystal structure of rac-5b. Only the
(5S,11S,14R) enantiomer is shown. Ellipsoids are represented at 30%.
To our delight, ethano-bridged Troger 5b was now isolated in
¨
much higher yields than before (up to 85%).
While it was clear by NMR spectroscopy that compound 5b
was a single stereoisomer (diastereomeric ratio, dr > 98 : 2),
the configuration of the new sp3 center relative to the stereogenic
N-atoms could not be determined with certainty. X-Ray
diffraction analysis of a monocrystal of racemic 5b, obtained
by slow evaporation of an Et2O solution, was performed and
revealed (5S,11S,14R)/(5R,11R,14S) configurations for the
tricyclic moiety (Fig. 1).24 Interestingly, the folded geometry
chromatographic resolution on chiral stationary phases is now
recognized as a very powerful and general method to separate
and isolate enantiomers of racemic compounds in good yield
and high optical purity.26 This approach was applied to rac-5b
and the two enantiomers were obtained on a preparative scale
using cellulose-based phase Chiralcel OJ and a mixture of
n-heptane : ethanol 90 : 10. From a batch of 190 mg of racemic
5b, two separated fractions were afforded, 53 mg (ee > 99%,
28%) and 60 mg (ee > 99%, 32%) for the first and second
eluted fractions.27 These fractions correspond to (+)-5b and
(ꢀ)-5b, respectively. Solutions in MeOH or CHCl3 of each
enantiomer were then stirred for 2 h at 25 and at 60 1C with no
visible loss of enantiomeric purity even in the presence of a
strong acid such as (+)-camphorsulfonic acid (2 equiv.). Only
under more forcing conditions (DMF, 100 1C, 2 h, 2 equiv. of
camphorsulfonic acid) was a drop of enantiomeric purity
observed (from >99% to 88%, HPLC monitoring).28
of classical Troger bases remains with the ethano bridge and
¨
the extra substituent. The planes of the tolyl rings are almost
perpendicular to each other (831 vs. ca. 901 for compounds 1).
With the optimized conditions in hand, the scope of the
rearrangement was studied (Table 2). Salts [3c][Br] to [3f][PF6]
bearing different substituents on the aromatic nucleus of the
side-chain were used. As expected, these compounds afforded
the rearranged products with excellent stereoselectivity, albeit
lower yields (34–65%, entries 1–5). Better yields seem to be
obtained with electron-poor rather than strongly electron-
donating substituents on the migrating group. From the
NMR spectra, one can conclude that the relative configuration
of the corresponding compounds 5 remains the same. Looking
Finally, ketone 5b was treated with NaBH4 (MeOH, 0 1C)
and the corresponding amino-alcohol 6 was afforded in good
yield (97%) and excellent diastereoselectivity (dr > 49 : 1,
Scheme 2). This excellent result prompted us to study the
reactivity of 5b with a few other nucleophiles (MeLi, p-Br-PhLi,
LiCH2CN, 2-LiPy) and, in all cases, the corresponding tertiary
for a possible influence of substituents on the Troger core itself,
¨
rac-2,3,8,9-tetramethoxy-Troger was prepared25 and reacted with
¨
a-bromoacetophenone to afford the ammonium salt [3g][Br]
(57% yield). Treatment of [3g][Br] with basic alumina led
to rearranged product 5g (35% yield); the lower yield being
probably due to a noticeable instability of the starting salt.
With rac-5b in hand, we turned our attention to its
enantiomeric resolution and configurational stability. Preparative
Table 2 Rearrangement of ammoniums 3c to 3g, side-chain influencea
Table 1 Rearrangement of [3b][Br], base influence
Entry Salt
Base
Equiv. 5b : 4ba Yieldb
1c
2c
3c
4c
5d
6d
[3b][Br] DABCO
[3b][Br] Et3N
[3b][Br] Proton sponge
5.0
5.0
5.0
5.0
34 : 64 10%
Entry Salt
X, Y
R0
Yieldb drc
51% >98 : 2
43 : 57
27 : 73
8%
5%
1
2
3
4
5
[3c][Br]
[3d][Br]
[3e][Br]
[3f][PF6] Me, H
[3g][Br]
Me, H
Me, H
Me, H
C6H4-p-Me
C6H4-p-OMe 34%
C6H4-p-F
C6H4-o-Br
[3b][Br] Hunig’s base
60 : 40 18%
94 : 6 45%
89 : 11 85%
¨
>98 : 2
>98 : 2
>98 : 2
>98 : 2
[3b][Br] Al2O3 (pH = 9.5 ꢂ 0.5) 20ꢃ
65%
40%
35%
[3b][Br] Al2O3 (pH = 9.5 ꢂ 0.5) 40ꢃ
OMe, OMe Ph
a
Determined by 1H NMR (400 MHz) spectroscopy on the crude
a
b
b
reaction mixture. Isolated yields. [3b][Br], Base, CHCl3, 10 h,
c
Ammonium salt, Al2O3 (pH 9.5 ꢂ 0.5), CHCl3, 2 h, 25 1C. Isolated
c
yields. Determined by H NMR (400 MHz) spectroscopy.
1
d
25 1C. [3b][Br], Al2O3, CHCl3, 2.5 h, 25 1C. Mass equivalents are used.
ꢁc
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We are grateful for financial support of this work from the
Swiss National Science Foundation and the State Secretariat
for Education and Science. We thank Mr Stephane Grass for
´
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24 Crystallographic data for rac-5b: (C25H24N2O); Mr = 368.5, tetra-
3
ꢀ
gonal, P421c, a = 23.9934(10), c = 6.8262(3) A, U = 3929.7(3) A ;
Z = 8, m = 0.076 mmꢀ1, dx = 1.246 g cmꢀ3, Mo-Ka radiation
(l = 0.71073 A); 22 803 reflections measured at 150 K on a STOE
IPDS diffractometer, 3854 unique reflections of which 2304 with
|Fo| > 2s(Fo). The structure was solved by direct methods
(SIR97). All calculations were performed with the XTAL system.
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1/(s2(Fo) + 0.0002(Fo2)) gave final values R = 0.034, wR = 0.023
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27 Retention times were 7.54 and 10.25 min for these two fractions
using an analytical Chiralcel OJ–H (0.46 ꢃ 25 cm) and a mixture of
n-heptane : ethanol 90 : 10 as eluent. Flow 1 ml minꢀ1. UV 210 nm.
The electronic circular dichroism (ECD) spectra of the separated
enantiomers are reported in the ESIw.
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28 The reason for this surprising loss is still under evaluation.
ꢁc
This journal is The Royal Society of Chemistry 2010
2208 | Chem. Commun., 2010, 46, 2206–2208