One-step catalytic asymmetric synthesis of configurationally stable troeger bases

Article abstract of DOI:10.1002/anie.201100134

(Chemical Equation Presented) Bridging the gap: Configurationally stable ethano-bridged Troeger bases have been prepared in a single step by the direct rhodium(II)-catalyzed reaction of methano-bridged Troeger bases and diazo esters (see scheme). The proc

Full text of DOI:10.1002/anie.201100134

DOI: 10.1002/anie.201100134
Synthetic Methods
One-Step Catalytic Asymmetric Synthesis of Configurationally Stable
Trꢀger Bases**
Ankit Sharma, Laure Guꢀnꢀe, Jean-Valꢁre Naubron, and Jꢀrꢂme Lacour*
Trꢀger bases of type 1,[1] which are the readily made products
from condensation reactions of anilines with formaldehyde,
have been extensively studied for their interesting properties,
reactivity, and a host of applications (Scheme 1).[2] In
derivatives 2 with very high level of chirality transfer—a
remarkable result in both [1,2]-Stevens-like processes and
Trꢀger chemistry.[8]
As mentioned, the development of a general route to
enantiopure compounds 2 was desirable and a direct proce-
dure involving metal-catalyzed reactions of a-carbonyl diazo
moieties 3 and derivatives 1 was considered. In fact, the
metal-catalyzed decomposition of diazo compounds is a
powerful method for the generation of electrophilic metal
carbenes,[9] which are known to react with tertiary amines to
form nitrogen–ylide intermediates.[10] Subsequent [1,2]-Ste-
vens rearrangements can occur with often high diastereose-
lectivity.[11] However, of relevance to this study, when the
migrating carbon atom or the quaternized nitrogen atom are
the only stereocenters present on the substrate, important
losses in enantiomeric purity are normally observed as a result
of the mechanism involved.[12,13]
First, rac-1 was treated with diazo compounds 3a to 3 f at
1008C in toluene (Table 1). While the use of 3a was
unproductive, all other diazo compounds 3b to 3 f afforded
the corresponding ethano-bridged Trꢀger bases in good to
excellent yield (2b to 2 f, 50–85%). Low diastereomeric ratios
(2:1 and 5:1 d.r.) were achieved for the synthesis of 2c and
2d,[14] but products 2e and 2 f were obtained with a good
diastereoselectivity (> 49:1 and 10:1 d.r., respectively).[15]
The major diastereomer of rac-2 f was isolated by
chromatography and found to be a racemic conglomerate
that crystallizes as single enantiomers of which the relative
Scheme 1. Methano- (1) and ethano-bridged (2) Trꢀger bases.
stereochemistry, Trꢀger bases are unique, being the first
chiral compounds with stereogenic nitrogen atoms to be
resolved.[3] Compounds 1 are yet configurationally labile in
acidic media[4] and this has limited their use as ligands,
auxiliaries, or catalysts.[5] Transformation of methano-bridged
Trꢀger bases 1 into ethano-bridged derivatives 2 is an answer
to this problem,[6] but such a solution has been rarely used
owing to a lack of general routes to these compounds.[7]
Herein, we report a new development in the direct synthesis
of ethano-bridged Trꢀger bases 2 (up to 99% ee) from
methano-bridged Trꢀger 1 using rhodium(II)-catalyzed reac-
tions. In a single step, the ethano bridge is constructed, a new
carbon quaternary stereogenic center is introduced (up to
49:1 d.r.), and enantiopure bases 1 are transformed into
Table 1: Initial screening.[a]
[*] A. Sharma, Prof. J. Lacour
Department of Organic Chemistry
University of Geneva
quai Ernest Ansermet 30, 1211 Genꢁve 4 (Switzerland)
Fax: (+41)22-379-3215
E-mail: jerome.lacour@unige.ch
Homepage: http://www.unige.ch/sciences/chiorg/lacour/
Dr. L. Guꢂnꢂe
Laboratory of Crystallography, University of Geneva
quai Ernest Ansermet 24, 1211 Genꢁve 4 (Switzerland)
Entry
Diazo
R1
R2
Prod.
Yield [%][b]
d.r.[c]
1
2
3
4
5
6
3a
3b
3c
3d
3e
3 f
COMe
CO2Et
CO2Et
Ph
Ph
Ph
COMe
CO2Et
COMe
COMe
CO2Et
CO2Me
–
–
–
–
2:1
Dr. J.-V. Naubron
Spectropole—Campus Saint Jꢂrꢃme
13397 Marseille Cedex 20 (France)
2b
2c
2d
2e
2 f
85
80
70
50
75
5:1
[**] We thank Dr. D. Jeannerat and A. Pinto for NMR measurements, the
University of Geneva, and the Swiss National Science Foundation
for financial support. We also acknowledge the contributions of the
Sciences Mass Spectrometry (SMS) platform at the Faculty of
Sciences (University of Geneva), and the CRCMM and the
Spectropole at the University of Aix-Marseille for computer time and
use of the VCD facility, respectively.
>49:1
10:1
[a] Typical reaction conditions: rac-1 (0.4 mmol), [Rh2(OAc)4] (1 mol%),
toluene(1 mL), 1008C, 16 h; reported results are the average of at least
two experiments. Substituents indicated at positions R1 and R2
correspond to that of the major diastereomer of 2. [b] Yield of isolated
product (both diastereomers). [c] Determined by 1H NMR analysis
(400 MHz) of the crude reaction mixtures.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100134.
Angew. Chem. Int. Ed. 2011, 50, 3677 –3680
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3677

Communications
product than that of 2e (71% vs. 50%, Table 2) led us to use
methyl rather than ethyl ester diazo derivatives for the
remainder of the study.
The results are summarized in Table 2. Both electron-
donating and electron-withdrawing substituents are amenable
on the aryl group of the diazo reagent. These functional
groups can be introduced at para- or at meta-positions. Yields
of isolated products of the major diastereomer are usually
good (70–80%); diastereoselectivity ratios being the only
parameters fluctuating from moderate (4:1; Table 2, entry 11)
to high (20:1; Table 2, entry 12) values. A slight decrease in
enantiomeric purity can be noticed moving in the series from
products carrying donor substituents (2g–2j: OMe, Me) to
electron-poor functional groups (2k–2o: Cl, Br, CF3, F), this
effect was particularly noticeable in the reaction of (À)-(R,R)-
1 and 3p that yields (À)-2p in 64% enantiomeric purity only.
This outcome can be rationalized in terms of the
mechanism. It involves the catalytic generation of electro-
philic metal carbenoids and additions of Trꢀger bases 1 to
these intermediates (Scheme 3). Stabilized nitrogen ylides of
type 4 are generated. Then, radical pair 5 and/or zwitterionic
species 6 are formed;[21] these ring-opened intermediates
collapse to form ethano-bridged Trꢀger bases 2. In reactions
of 3b, 3c, 3d, and 3p, we can hypothesize that the loss of
enantiomeric purity results from a stronger stabilization of
intermediates 5 or 6 by the electron-withdrawing substituents
that surround the reactive carbon center. These intermediates
5 or 6 have then a longer life-time and the opportunity to
racemize through a complete planarization of the core.
For the reactions with substrates 3 f to 3o that proceed
with high enantiospecificity, care was taken to determine the
absolute configuration of products 2 with certainty.[19] The
configuration was established by vibrational circular dichro-
ism (VCD) in view of the rigidity of compounds 2.[22] Infrared
absorption and VCD spectra were measured for solutions
(CCl4) of the major diastereomer of both (+)- and (À)-2 f and
compared to the averaged spectrum calculated for
(5SN,11RN,14RC)-2 f (Figure 1).[19,23]
Scheme 2. Drawing of 2 f (major diastereomer) and ORTEP view of its
crystal structure; (5SN,11RN,14RC) enantiomer shown. Hydrogen atoms
are omitted for clarity and thermal ellipsoids are drawn at 50%
probability.
Table 2: Enantiospecific rearrangement.[a]
Entry
X
Diazo R1
Prod. Yield d.r.[c]
[%][b]
ee
[%][d]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
Ph
Ph
2e
2 f
2g
50
71
80
83
72
70
78
75
75
70
50
82
89
>49:1 93
10:1 99
9:1 98
2-naphthyl
p-MeOC6H4 2h
10:1 98
[e]
p-MeC6H4
m-MeC6H4
p-ClC6H4
m-ClC6H4
p-BrC6H4
p-CF3C6H4
p-FC6H4
2i
2j
2k
2l
2m
2n
2o
2p
7
–
98
8:1 98
7.5:1 97
6:1 97
8:1 97
12:1 97
4:1 96
9
10
11
12
13
p-NO2C6H4
Ph
20:1 64
16:1 97
OMe[f] 3 f
[a] Reaction conditions: (À)-(R,R)-1 (0.1 mmol), [Rh2(OAc)4] (1 mol%),
dry toluene (0.25 mL), 1008C, 6 h; major diastereomer of 2 and 7 shown.
Reported results are the average of at least two experiments [b] Yield of
isolated product (major diastereomer). [c] Determined by 1H NMR
analysis (400 MHz) of the crude reactions mixtures. [d] Determined by
CSP-HPLC analysis on a chiral stationary phase. [e] Could not be
determined. [f] 98% ee.
Conformational analysis showed only two possible con-
formations;[24] the most stable having a geometry close to that
determined by X-ray crystallographic analysis. The geometry
configuration could be determined by X-ray crystallographic
analysis (5SN,11RN,14RC or 5RN,11SN,14SC, Scheme 2, see the
Supporting Information). All data indicate that this relative
configuration is conserved for the major diastereomer within
the series of products 2e to 2p (Table 2).[16]
Then, the efficiency of the chirality transfer was tested.
Enantiopure (À)-(R,R)-1 was used as the substrate.[17–19]
Diazo 3b to 3d gave corresponding products 2b, 2c, and 2d
in low enantiomeric purity (5, 34 and 10% ee, respectively for
both diastereomers).[12] However, reactions with 3e and 3 f
generated products (À)-2e and (À)-2 f with high enantiomer-
ic excesses (93% and 99% ee, respectively).[20] The higher
enantiomeric purity of 2 f, and the fact that its major
diastereomer could be obtained in better yield of isolated
Scheme 3. Mechanistic rationale.
3678
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Angew. Chem. Int. Ed. 2011, 50, 3677 –3680

nitrogen atom only (para to the nitro group). This result, at
first glance surprising, can be rationalized considering a
preferred formation of intermediate 9 (Scheme 2). In this
intermediate, the cationic nitrogen atom is stabilized by the
para-OMe group while the electron-density on the other
nitrogen atom is efficiently delocalized towards the nitro
substituent.
In conclusion, this paper reports the one-step rhodi-
um(II)-catalyzed reaction of methano-bridged Trꢀger bases
and diazo esters to yield highly enantioenriched, configura-
tionally stable ethano-bridged Trꢀger derivatives. The process
is general, enantiospecific (up to 99% ee, retention of
configuration), diastereoselective (quaternary carbon center
introduction, up to 49:1 d.r.), and represents an interesting
regioselective outcome.
Experimental Section
Figure 1. Experimental IR absorption (top) and VCD (bottom) spectra
(CCl4, 298 K) of (À)-2 f (red) and (+)-2 f (blue). Calculated spectrum
of (5SN,11RN,14RC)-2 f (green).
Representative procedure: In a 5 mL screw-cap vial equipped with a
magnetic stirring bar, Trꢀger base (À)-(R,R)-1 (0.40 mmol, 100.0 mg)
was introduced along with dry toluene (1.0 mL) and 1.76 mg [Rh2-
(OAc)4] (1 mol%). Diazo compound 3 f (0.40 mmol) was added in
one portion and the cap was placed at the top (unscrewed). The
reaction mixture was introduced into an already-heated oil bath
(1008C) and stirred for 1 h. Then, 3 f (0.40 mmol) was added in one
portion again and the resulting solution stirred for another 5 h at
1008C. The reaction was monitored by ESI-MS. After completion, the
mixture was cool to 208C and the solvent removed under reduced
pressure. After NMR spectroscopic analysis of the crude reaction
mixture, the desired product was purified by column chromatography
on silica gel (eluent: hexanes/acetone = 20:1) to give (À)-2 f as a white
solid (113 mg, 71%).
optimizations, vibrational frequencies, IR absorption; and
VCD intensities were calculated by using density functional
theory (DFT).[25] Overall, a good agreement between the
experimental and theoretical spectra was observed, thus
allowing the assignment of a (5SN,11RN,14RC) configuration
for (+)-2 f. The enantiospecific rearrangement occurs, there-
fore, with retention of configuration.
An electron-rich Trꢀger base was also used as a substrate
(X = OMe, 98% ee; Table 2, entry 13) and its treatment with
3 f afforded product 7 with excellent diastereoselectivity
(16:1 d.r.) and enantiospecificity (97% ee). Finally, an unsym-
metrically substituted Trꢀger base was prepared carrying
electron-donating and electron-withdrawing substituents on
the two aromatic rings, respectively (OMe and NO2;
Scheme 4).[26] A single regioisomer was obtained from its
reaction with diester 3b. Interestingly, product 8 (> 49:1 d.r.,
71% yield) arises from the reaction of the electron-poor
CCDC 806457 (2 f) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
Received: January 7, 2011
Published online: March 18, 2011
Keywords: carbenoids · diazo compounds · rearrangement ·
.
rhodium · Trꢀger bases
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Angew. Chem. Int. Ed. 2011, 50, 3677 –3680
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www.angewandte.org 3679

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[25] B3LYP and CAM-B3LYP functionals combined with 6-311 +
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B3LYP. Infrared absorption and VCD spectra were constructed
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Lorentzian band shape with a half-width at half maximum of
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Revision A02.
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Angew. Chem. Int. Ed. 2011, 50, 3677 –3680