Selective access to both diastereoisomers in an enantioselective intramolecular michael reaction by using a single chiral organocatalyst and application in the formal total synthesis of (-)-epibatidine

Article abstract of DOI:10.1002/chem.201202353

Two in one: Both diastereoisomers of 4-nitro-3-substituted cyclohexanones are accessed selectively by an intramolecular Michael reaction using a single chiral aminocatalyst (see scheme). Mechanistic studies show that the reaction is selective for the cis-diastereoisomer and that the trans-diastereoisomer arises over time. DFT calculations suggest that the cis-selectivity is due to a favorable electrostatic interaction between the iminium ion and the nucleophile. Copyright

Full text of DOI:10.1002/chem.201202353

COMMUNICATION
DOI: 10.1002/chem.201202353
Selective Access to Both Diastereoisomers in an Enantioselective
Intramolecular Michael Reaction by Using a Single Chiral Organocatalyst
and Application in the Formal Total Synthesis of (À)-Epibatidine
Kim L. Jensen, Christian F. Weise, Gustav Dickmeiss, Fabio Morana,
Rebecca L. Davis, and Karl Anker Jørgensen*[a]
The development of enantioselective and diastereoselec-
tive reactions, utilizing simple prochiral precursors and gen-
erating multiple stereocenters in one step, plays a major role
in synthesis.[1] One significant limitation of asymmetric catal-
ysis is the lack of access to the full array of stereoisomers of
a complex chiral molecule. While complementary enantiose-
lectivity can be obtained by using the enantiomeric pair of
the catalyst, modulation of the enforced sense of diastereo-
selectivity is a challenge.
Controlling the diastereoselectivity by applying a single
catalyst is an interesting but largely unmet challenge. In
terms of transition-metal catalysis, a change in diastereose-
lectivity can be obtained by substrate modifications,[2] chang-
ing the Lewis acid[3] or tuning the electronic properties of
Scheme 1. Enantio- and diastereoselective formation of cis- and trans-
stereoisomers by an intramolecular Michael reaction.
the ligand.[4] Organocatalysis[5] has made a significant impact
on asymmetric catalysis and is an attractive and complemen-
tary approach to transition-metal catalysis. While several ex-
amples in which different organocatalytic systems induce op-
posite diastereoselectivity exist,[6] examples relying on a
single catalyst to provide complementary diastereoisomers
remain scarce. Recently, it was demonstrated that a cincho-
na-based primary amine is able to catalyze a highly diaster-
eoselective addition of alkyl thiols to a range of a-branched
enones.[7] Through the use of different combinations of addi-
tives[8] and solvents, the diastereoselectivity could be switch-
ed to favor either the syn- or the anti-stereoisomer.
showed that the reaction is selective for the cis-diaster-
eoisomer and DFT calculations suggested that the selectivity
arises from a favorable electrostatic interaction between the
iminium ion and the nucleophile. The results of these inves-
tigations also indicated that the trans-isomer is generated
through catalyst-induced epimerization of the labile nitro
stereocenter.[9] The mechanistic studies enabled the rational
development of reaction conditions that allowed for the iso-
lation of either the cis- or trans-diastereoisomer in high
yields and stereoselectivities for a broad range of substrates.
The concept was used in the enantioselective synthesis of all
stereoisomers of 4-nitro-3-phenylcyclohexanone. Finally, the
synthetic utility of the reaction was demonstrated by the
formal total synthesis of (À)-epibatidine in only seven steps
from a commercially available aldehyde.
Herein, we present our efforts in the development of an
enantio- and diastereoselective reaction toward the forma-
tion of both the cis- and trans-diastereoisomers in an intra-
molecular Michael reaction by using a single chiral organo-
catalyst (Scheme 1). Initial results indicated that either the
cis- or trans-diastereoisomer could be obtained selectively
depending on the reaction conditions. This led us to investi-
We started our study by examining the asymmetric intra-
molecular Michael addition[10] of (E)-6-nitro-1-phenylhex-1-
en-3-one (1a) by using the cinchona-alkaloid-based primary
aminocatalyst 2a (Scheme 2).[11] Despite numerous reports
1
gate the mechanism of the reaction. H NMR spectroscopy
[a] K. L. Jensen, Dr. C. F. Weise, Dr. G. Dickmeiss, F. Morana,
Dr. R. L. Davis, Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45) 8619 6199
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202353.
Scheme 2. Optimized conditions for the selective formation of the trans-
diastereoisomer.
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Figure 1. Conversion and diastereomeric excess (d.e.) as a function of time for the intramolecular Michael reaction of 1a in a) CH3OH/CHCl3 (4:1) and
b) tBuOH at 408C (see the Supporting Information for details).
on organocatalyzed Michael additions of nitronates to
enones,[12] this catalytic, enantioselective, intramolecular var-
iant has not been described previously.[13] Preliminary reac-
tions indicated that the trans-diastereoisomer 4a was fa-
vored upon cyclization. A screening of reaction conditions
showed that the best result was obtained with the (S)-N-
Boc-phenylglycine salt of catalyst 2a (see the Supporting In-
formation for details). Accordingly, by employing this cata-
lyst in tBuOH at 758C, the product was obtained in 86%
yield, 96% ee, and a 8:1 d.r. in favor of the trans-isomer.
However, it is worth noting that the diastereoselectivity
dropped to a 4:1 and 1.2:1 ratio in favor of 4a when the
temperature was lowered to 50 and 408C, respectively. Inter-
estingly, a dramatic change was observed when CH3OH was
applied as the solvent; after 24 h, cis-4-nitro-3-phenylcyclo-
hexanone (3a) was formed in 67% conversion and a 7:1 d.r.
with 90% ee.
estingly, the diastereoselectivity was excellent in favor of the
cis-diastereosiomer 3a (>20:1 d.r., >99% d.e.)[15] after 6 h
and then slowly reduced to 7:1 d.r. (78% d.e.) after 24 h.
The same study was performed for the reaction in tBuOH
at 408C. In this solvent the reaction proceeded faster, giving
69 and 94% conversion after 6 and 24 h, respectively (Fig-
ure 1b). Interestingly, the reaction was also selective in
tBuOH, affording the cis-diastereoisomer 3a exclusively at
41% conversion in 2 h, after which the d.e. was reduced to
74 (6.7:1 d.r.) and À10% (1:1.2 d.r.) at 6 and 24 h, respec-
tively. These experiments suggest that the organocatalyzed
intramolecular Michael reaction is cis-diastereoselective in-
dependent of the solvent. The corresponding trans-
diastereoACTHNUTRGENUGiN somer 4a is then likely to arise from catalyst-pro-
moted epimerization of the labile nitro stereocenter.[16] It is
worth noting that heating of the cis-diastereoisomer 3a to
758C in tBuOH and in the absence of catalyst 2a did not
provide the trans-diastereoisomer 4a.
To further understand the change in diastereoselectivity,
we monitored the reaction (CH3OH/CHCl3 at 408C) by
1H NMR spectroscopy (Figure 1a).[14] The conversion slowly
increased to 36 and 72% at 6 and 24 h, respectively. Inter-
Theoretical calculations (M06-2x/6-31+GACTHNUTRGNEUNG
(d,p))[17] provide
an explanation for the observed diastereoselectivity in the
reaction. A simplified model system (Figure 2) was used to
Figure 2. Optimized structures and relative energies (kcalmolÀ1) for the two cyclization pathways leading to the cis- and trans-diastereoisomers. Distances
are in ꢁngstrøm. Reported values are free energies at 408C.
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Asymmetric Organocatalysis
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Table 1. Scope of the intramolecular Michael reaction for the cis-diaster-
eoisomers 3.[a]
study the cyclization pathways for both the cis- and trans-di-
astereoisomers.[18,19] The lowest energy productive conform-
er of the zwitterionic intermediate A was found to have a
weak interaction between the lone pair of the electron-rich
oxygen atom (lpO) of the nitro group and the anti-bonding
orbital of the electron-deficient carbon atom of the iminium
ion (p*C). This interaction preorganizes the substrate into a
conformation that, upon cyclization, leads to the cis-
diastereoACHTUNGTRENNUNGisomer C. This nitro–iminium-ion interaction is not
present in B, the conformer which leads to the trans-diaster-
eoisomer D, and, as a result, this conformer is 2.3 kcalmolÀ1
higher in energy. As the cyclization of A progresses, the
lpO–p*C interaction diminishes. This can be seen by a
change in the distance between the oxygen atom of the
nitro group and the iminium-ion carbon atom when going
from A to TS-C. Comparison of the transition-state energies
for both the cis- and trans-selective pathways shows that the
transition-state structure on the pathway leading to the cis-
diastereoisomer TS-C is favored over the transition-state
structure on the trans-selective pathway TS-D by 2.2 kcal
molÀ1. Inspection of the products of both pathways reveals
that the trans-product D is favored over the cis-diastereo-
ACHTUNGTRENNUNG
isomer C by 1.7 kcalmolÀ1. This data suggests that the cis-di-
[a] All reactions were performed on a 0.2 mmol scale (see the Supporting
Information). Yield after isolation by flash chromatography is given, and
yield based on recovered starting material is provided in parentheses.
The d.r. was determined by 1H NMR spectroscopy. The ee was deter-
mined by chiral stationary phase (CSP)-HPLC. [b] The reaction was per-
formed in tBuOH.
astereoisomer is kinetically favored, while the trans-diaster-
eoisomer is thermodynamically favored. In both pathways
the cyclization is highly exergonic, suggesting that the cyclo-
reversion reaction is much slower and unlikely to occur to a
significant degree. This lends further support to our hypoth-
esis that the trans-diastereoisomer is formed by epimeriza-
tion.
The fact that the reaction is cis-selective and the product
only slowly epimerizes over time makes it possible to access
the kinetically favored isomer if the reaction is stopped at a
time when conversion and selectivity are both high. Initially,
owing to the higher enantioselectivity observed (98% ee),
tBuOH was employed as the solvent for the enantioselective
formation of the cis-diastereoisomer. However, an insepara-
ble byproduct, presumably arising from the intermolecular
dimerization of the starting material, was also formed. Inter-
estingly, this byproduct was not observed at elevated tem-
peratures, suggesting that it forms reversibly at high temper-
atures.
the solvent to tBuOH solved this problem, and product 3i
was formed in 62% yield, 6:1 d.r., and 97% ee. In all cases,
the unreacted starting material could be recovered.
Having successfully demonstrated that the developed re-
action conditions could be applied for the synthesis of the
kinetically favored cis-diastereoisomer, we wanted to
expand the methodology to include the formation of the
trans-diastereoisomer. As observed in the initial screening
and the kinetic studies, trans-diastereoisomer 4 is formed at
prolonged reaction times. Accordingly, by increasing the re-
action temperature and performing the reaction in tBuOH,
the trans-diastereoisomers 4 were afforded in excellent
yields, diastereo-, and enantioselectivities (Table 2). As with
the scope of the cis-diastereoisomer 3, a series of aromatic
substrates with different substitution patterns and electronic
properties performed well, affording the products 4a–k.
Heterocycles were also tolerated, which was illustrated by
the furan, thiophene, and chloropyridine substrates that un-
derwent cyclization to afford products 4l–n with very good
results. An aliphatic substrate could also be applied, as
shown by the formation of homobenzyl product 4o. Finally,
it was demonstrated that the catalyst loading could be re-
duced to 5 mol%, giving product 4a in 80% yield, 8:1 d.r.,
and 96% ee after 48 h (not shown).
Owing to the abovementioned issues, the asymmetric syn-
thesis of the cis-diastereoisomers 3 was conducted in a 4:1
[14]
mixture of CH3OH/CHCl3 (Table 1). Because it was not
possible to achieve full conversion without eroding the cis-
diastereoselectivity, the reactions were stopped after 24 h,
ensuring a good yield and selectivity. The developed reac-
tion concept showed good tolerance toward a series of sub-
strates, affording the products in good yields and stereose-
lectivities. In general, the substituent and the electronic
nature of the aromatic ring had little effect on the outcome
of the reaction, as demonstrated for the products 3a–g. Het-
erocycles were also tolerated, as shown by thiophene-substi-
tuted product 3h. Initial attempts to expand the substrate
scope to aliphatic substituents were not successful, owing to
acetal formation of the starting material. However, changing
The absolute and relative stereochemistry of the products
was determined by X-ray crystallographic analysis of com-
pounds 3b and 4b.[20]
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K. A. Jørgensen et al.
Table 2. Scope of the intramolecular Michael reaction for the trans-dia-
stereoisomer 4.[a]
Scheme 3. Accessing the full array of stereoisomers of 4-nitro-3-phenylcy-
clohexanone.
[a] All reactions were performed on a 0.2 mmol scale (see the Supporting
Information). Yield after isolation by flash chromatography is given. The
1
d.r. was determined by H NMR spectroscopy. The ee was determined by
CSP-HPLC.
After having demonstrated that both diastereoisomers
can be accessed by the application of a single chiral organo-
catalyst, we wanted to demonstrate that the full array of
stereoisomers, derived from 1a, can be obtained
(Scheme 3). By reacting 1a with the pseudo-enantiomeric
catalyst 2b, derived from quinidine, in CH3OH/CHCl3 (4:1)
at 408C, product ent-3a was isolated in 63% yield with a
d.r. of 7:1 and 84% ee. Likewise, treating the substrate with
the catalyst in tBuOH at 758C afforded product ent-4a in a
higher yield (91%), higher d.r. (9:1), and slightly lower
enantioselectivity (94% ee) compared to 4a.
To demonstrate the synthetic utility of the reaction, prod-
uct 4n was applied in the formal total synthesis of the natu-
ral alkaloid (À)-epibatidine 6, an analgesic approximately
200 times more potent than morphine and a highly potent
agonist of the nicotinic acetylcholine receptor.[21] To achieve
this synthesis, a stereoselective reduction of the ketone func-
tionality of product 4n was performed (Scheme 4).
Scheme 4. Stereoselective reduction of ketone 4n and its application in
the formal total synthesis of (À)-epibatidine 6.
tive, organocatalytic, formal total synthesis of (À)-epibati-
dine.[23]
In summary, we have demonstrated that both diaster-
eoisomers of 4-nitro-3-substituted cyclohexanones can be ac-
cessed selectively by an intramolecular Michael reaction
using a single chiral aminocatalyst. Mechanistic studies
1
based on H NMR spectroscopy showed that the reaction is
selective for the cis-diastereoisomer and that the trans-dia-
stereoisomer arises over time. DFT calculations suggest that
the high selectivity toward the formation of the cis-diaster-
eoisomer is due to a favorable electrostatic interaction be-
tween the iminium ion and the nucleophile. These combined
mechanistic studies enabled the rational development of re-
action conditions that allow for the isolation of either the
cis- or trans-diastereoisomer in high yields and stereoselec-
tivities for a broad range of substrates. Furthermore, the
strategy was used for the enantioselective synthesis of all
four stereoisomers of 4-nitro-3-phenylcyclohexanone. Final-
Treating the pure trans-isomer with two equivalents of
NaBH4 in CH3OH at 08C afforded the corresponding alco-
hol 5 in 87% yield and 10:1 d.r. From alcohol 5, only four
additional synthetic steps (mesylation, reduction/cyclization,
and epimerization) are needed to reach the target 6.[22]
Starting from chloropyridine aldehyde 7, this is, to the best
of our knowledge, the shortest (seven steps) and most selec-
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Acknowledgements
This work was supported by Aarhus University, FNU and the Carlsberg
Foundation. Dr. Jacob Overgaard is gratefully acknowledged for per-
forming X-ray analysis.
Keywords: asymmetric synthesis · total synthesis · reaction
mechanisms · organocatalysis
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[15] While these numbers do not directly correlate, they refer to the fact
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[16] Retro-Michael/Michael seems unlikely, because treatment of the
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of the cis-product.
[17] Calculations were performed with Gaussian 09 (Gaussian 09, Revi-
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level of theory and basis set (Y. Zhao, D. Truhlar, Theor. Chem.
Acc. 2008, 120, 215.) by using a Polarizable Continuum Model with
a dielectric for CH3OH (e=32.613). See the Supporting Information
for full details and complete references on theoretical methods.
[18] For coordinates and energies of all intermediates and transition
state structures, see the Supporting Information.
[19] Cyclization through a tautomerization pathway was also considered.
However, tautomerization of I to reactive intermediate II was found
to be energetically unfavorable, with II being 7.7 kcalmolÀ1 higher
in energy than I. Cyclization of II to III was also found to be ener-
getically unfavorable. Thus, it seems unlikely that the reaction pro-
ceeds through this cyclization pathway..
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K. A. Jørgensen et al.
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[21] For a comprehensive review, see: H. F. Olivo, M. S. Hemenway, Org.
Prep. Proced. Int. 2002, 34, 1.
[22] C. Szꢄntay, Z. Kardos-Balogh, I. Moldvai, C. Szꢄntay Jr., E. Te-
mesvꢄri-Major, G. Blaskꢃ, Tetrahedron 1996, 52, 11053.
[23] For another epibatidine synthesis (10 steps) by using hydrogen-
bonding catalysis (75% ee), see: Y. Hoashi, T. Yabuta, Y. Takemoto,
Tetrahedron Lett. 2004, 45, 9185.
[20] CCDC 878386 (3b) and 878387 (ent-4b) contain the supplementary
Received: July 2, 2012
Published online: && &&, 0000
crystallographic data for this paper. These data can be obtained free
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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Asymmetric Organocatalysis
COMMUNICATION
Organocatalysis
K. L. Jensen, C. F. Weise, G. Dickmeiss,
F. Morana, R. L. Davis,
K. A. Jørgensen* ............. &&&& — &&&&
Selective Access to Both Diaster-
eoisomers in an Enantioselective Intra-
molecular Michael Reaction by Using
a Single Chiral Organocatalyst and
Application in the Formal Total
Synthesis of (À)-Epibatidine
Two in one: Both diastereoisomers of
4-nitro-3-substituted cyclohexanones
are accessed selectively by an intramo-
lecular Michael reaction using a single
chiral aminocatalyst (see scheme).
Mechanistic studies show that the reac-
tion is selective for the cis-diastereo-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
tions suggest that the cis-selectivity is
due to a favorable electrostatic interac-
tion between the iminium ion and the
nucleophile.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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