Organocatalytic asymmetric domino Michael-Henry reaction for the synthesis of substituted bicyclo[3.2.1]octan-2-ones

Article abstract of DOI:10.1039/c3cc39165e

The first organocatalytic asymmetric reaction between 1,4-cyclohexanedione and nitroalkenes has been studied, affording bicyclo[3.2.1]octane derivatives containing four continuous stereogenic centres. The products were obtained through a domino Michael-Henry process as a single diastereoisomer with excellent enantioselectivities.

Full text of DOI:10.1039/c3cc39165e

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Organocatalytic asymmetric domino Michael–Henry
reaction for the synthesis of substituted
bicyclo[3.2.1]octan-2-ones†
Cite this: Chem. Commun., 2013,
49, 2219
Received 22nd December 2012,
Accepted 28th January 2013
Michail Tsakos,a Mark R. J. Elsegoodb and Christoforos G. Kokotos*a
DOI: 10.1039/c3cc39165e
www.rsc.org/chemcomm
The first organocatalytic asymmetric reaction between 1,4-cyclo- encountered in numerous natural products and biologically
hexanedione and nitroalkenes has been studied, affording bicyclo- active molecules,11 and any enantioselective synthetic route to
[3.2.1]octane derivatives containing four continuous stereogenic this structural motif could be of great importance.
centres. The products were obtained through
a
domino
Michael–Henry process as a single diastereoisomer with excellent
enantioselectivities.
(1)
In recent years, domino and cascade reactions have attracted
the interest of organic chemistry researchers, as they constitute
a powerful tool for the formation of several bonds in a one-step
process.1 The application of these reactions in the field of We initiated our study by choosing as a model reaction the
organocatalysis2 is particularly appealing because it can lead addition of 1,4-cyclohexanedione 1 to phenyl nitrodiene 2a in
to the formation of complex structures with high stereo- the presence of L-proline as the chiral catalyst. The use of
selectivities, in an operationally simple and straightforward nitrodienes as the Michael acceptors is far less documented
manner. Amongst the numerous strategies employed in this and it remains underdeveloped in comparison to the exten-
category,3 domino Michael–Henry reactions4 play a pivotal role sively studied nitroolefins. Indeed, proline enabled the reaction
as these reactions constitute two of the most widely used forming bicyclic compound 3a in excellent yield but in a nearly
reactions in organic asymmetric synthesis.5,6
racemic form. This result led us to the assumption that the
In line with our latest studies on the asymmetric Michael domino Michael–Henry reaction proceeds through an enamine
addition of ketones to nitroalkenes using bifunctional organo- activation mode,12 as opposed to the existing protocols8,10 that
catalysts,7 we became interested in the use of 1,4-cyclohexane- suggest the formation of the enolic tautomer of the 1,2-cyclo-
dione as the Michael donor. Rueping et al. and Zhao et al. hexanedione by a cinchona-alkaloid derived catalyst. To sup-
reported the tandem Michael–Henry reaction of 1,2-cyclohexane- port our hypothesis, we repeated the reaction using catalytic
dione with nitroalkenes leading to bicyclo[3.2.1] octanes.8,9 Also, amounts of tertiary amines that cannot form an enamine
Zhong and co-workers used 2,5-dioxocyclohexanecarboxylate intermediate with the dione. Thus, we tested an achiral base,
esters with nitroolefins.10 Bearing in mind these literature such as DABCO, and a bifunctional base, like quinine, and in
reports, we envisaged that 1,4-cyclohexanedione could be used both cases no reaction took place. The difference in the pKa of
and could undergo a similar reaction sequence to assemble a 1,2-cyclohexanedione in comparison to 1,4-cyclohexanedione
multifunctionalized bicyclo[3.2.1]octane structure [eqn (1)]. could explain this difference in reactivity.
Our design plan was to use an unprecedented enamine activa-
Based on these observations, we set out to develop an
tion of 1,4-diketones in order to obtain a skeleton which is asymmetric version of this domino reaction. Several bifunc-
tional catalysts were screened, but only the proline derived
a Laboratory of Organic Chemistry, Department of Chemistry, University of Athens,
Panepistimiopolis 15771, Athens, Greece. E-mail: ckokotos@chem.uoa.gr;
Fax: +30 210 7274761; Tel: +30 210 7274281
catalysts I–III displayed noteworthy effects on the outcome of
the reaction (Table 1, entries 1–3, see ESI† for full optimization
study). Catalysts I and II developed by us,7b bearing a thioxo-
tetrahydropyrimidinone or a thiohydantoin ring, respectively,
delivered the product in excellent enantioselectivity, but the
size of the ring exhibited a tremendous impact on the activity of
the catalyst (Table 1, entry 1 vs. 2). Catalyst III led to high yield
b Loughborough University, Loughborough, LE11 3TU, UK
† Electronic supplementary information (ESI) available: Full optimization studies,
proposed mechanism, characterization of the products, NMR, HPLC and crystallo-
graphic data. CCDC 916313. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3cc39165e
c
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Table 1 Catalyst screening and optimization studies for the asymmetric domino
Michael–Henry reactiona
Table 2 Domino Michael–Henry reaction between dione 1 and nitrodienes 2a–f
using catalyst Ia
Entry
Ar, R
Yieldb (%)
eec (%)
1
2
3
4
5
6
Ph, H (2a)
3a, 91
3b, 56
3c, 72
3d, 89
3e, 73
3f, 70
96
94
91
86
97
95
4-OMe-Ph, H (2b)
4-Cl-Ph, H (2c)
2-NO2-Ph, H (2d)
4-NO2-Ph, H (2e)
Ph, Me (2f)
Entry
Catalyst
Additives (10 mol%)
Yieldb (%)
eec (%)
1
2
3
4
I
4-NBA, H2Od
4-NBA, H2Od
—
91
22
92
58
Traces
72
75
96
90
75
89
—
96
96
II
III
I
I
I
4-CBA, H2Od
4-NBA
Reactions were performed using 1 (0.2 mmol), 2 (0.1 mmol) in the
presence of catalyst I (10 mol%), 4-NBA (10 mol%) and H2O (50 mL) in
a
5
6e
7f
4-NBA, H2Od
4-NBA, H2Od
dry THF (0.25 mL) at r.t. for 24 hours. Isolated yield. The enantio-
meric excess (ee) was determined by chiral HPLC.
b
c
I
a
Reactions were performed using 1 (0.2 mmol), 2a (0.1 mmol) with
10 mol% of catalyst and additive in dry THF (0.25 mL) for 24 hours at
Table 3 Domino Michael–Henry reaction between dione 1 and nitroolefins
4a–h using catalyst Ia
b
c
r.t. Isolated yield. The enantiomeric excess (ee) was determined by
d
e
chiral HPLC. 50 mL of water were used. 5 mol% of I was used.
f
0.11 mmol (1.1 equiv.) of 1 was used. 4-NBA: 4-nitrobenzoic acid,
4-CBA: 4-cyanobenzoic acid.
but the selectivity dropped significantly (Table 1, entry 3). It has
to be highlighted that compound 3a was formed as a single
diastereoisomer in all cases, demonstrating the excellent
stereocontrol of this protocol on four continuous stereogenic
centres. To optimize the reaction conditions, several solvents
and additives were examined in the presence of 10 mol% of
catalyst I (Table 1 and ESI†). Polar solvents that could solubilise
efficiently the dione favoured the reaction, with THF being the
optimum both in terms of yield and selectivity. On the other
hand, it is well documented that a careful selection of additives
can play a significant role in the activity of the catalyst.13 Thus,
4-nitrobenzoic acid made an ideal pair with our catalyst pro-
viding the best results (Table 1, entry 1 vs. 4), while a controlled
amount of water proved to be essential for the catalyst’s turn-
over (Table 1, entry 1 vs. 5). Moreover, reducing the catalyst
loading to 5 mol%, or the ratio of dione to nitrodiene to 1.1 : 1
Entry
R
Yieldb (%)
eec (%)
1d
2
3
4
5
6
7
8
9
Ph (4a)
Ph (4a)
5a, 38
5a, 86
5b, 81
5c, 75
5d, 80
5e, 70
5f, 83
5g, 82
5h, 78
93
93
95
93
96
93
94
91
90
4-Cl-Ph (4b)
4-F-Ph (4c)
3-NO2-Ph (4d)
4-NO2-Ph (4e)
4-OMe-Ph (4f)
2-Furyl (4g)
2-Naphthyl (4h)
a
Reactions were performed using 1 (0.2 mmol), 4 (0.1 mmol) in the
presence of catalyst I (20 mol%), 4-NBA (20 mol%) and H2O (50 mL) in
b
c
dry THF (0.25 mL) at r.t. for 24 hours. Isolated yield. The enantio-
meric excess (ee) was determined by chiral HPLC. 10 mol% of catalyst
I and 4-NBA were used.
d
led to decreased yields, but excellent enantioselectivity (Table 1, closing step experienced difficulties in advancing (10% of
entries 6 and 7). the Michael adduct from the initial Michael addition of the
1
With optimal conditions in hand, the scope and limitations diketone to nitrostyrene was detected in H-NMR of the crude
of our method were studied. An array of aromatic nitrodienes reaction mixture) (Table 3, entry 1). The latter was probably due
bearing electron-donating or electron withdrawing substituents to steric repulsion and/or stabilizing factors from the adjacent
on the phenyl ring could be well tolerated, delivering the bulky phenyl group. To overcome this obstacle, 20 mol% of
bicyclic products 3a–e in good to high yields and excellent catalyst I was used and the desired product 5a was delivered as
enantioselectivity (Table 2, entries 2–5). Nitrodiene 2f bearing a a single diastereoisomer in 86% yield and 93% ee (Table 3,
methyl group at the a-position with respect to the phenyl ring entry 2). Having established the optimal reaction protocol, a
was also successfully employed (Table 2, entry 6).
variety of substituted aromatic nitroolefins was investigated.
To broaden the scope of our methodology, nitrodienes were Aromatic groups with electron-rich and electron-deficient sub-
replaced by aromatic nitroolefins as the electrophilic partner. stituents were successfully utilized to form the bicyclic products
Unfortunately, when we employed the same reaction conditions in high yield and with excellent ee values (Table 3, entries 3–7).
used for nitrodienes, we encountered a significant handicap In addition, nitroolefins bearing heteroaromatics as well as
with trans-b-nitrostyrene 4a. The reaction rate was much slower other aromatic groups were also well tolerated (Table 3,
(a reaction time of 4 days was required in order to reach comple- entries 8 and 9). It should be noted that a small percentage
tion), while simultaneously the second, intramolecular ring of the Michael adduct was observed in all cases (3–6%),
c
2220 Chem. Commun., 2013, 49, 2219--2221
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4 For selected examples on organocatalyzed domino Michael–Henry
reaction, see: (a) Y. Hayashi, T. Okano, S. Aratake and D. Hazelard,
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Fig. 1 X-ray structure of enantiopure 3a.
lowering the yield of the desired product. All attempts to force
the second ring closing step by adding a base in the product
mixture resulted either in degradation or in the epimerization
of the a-nitro carbon centre of 5a–h (B95 : 5 dr) possibly
through a retro-Henry reaction.
The absolute configuration of the products was indicated by
X-ray crystallographic analysis14 of a crystal of compound 3a
(Fig. 1). On the basis of this result, a plausible mechanistic
pathway is proposed to account for the stereochemical outcome
of this reaction (see ESI†).
In conclusion, we have developed an unprecedented organo-
catalytic asymmetric addition of 1,4-cyclohexanedione to aromatic
nitrodienes and nitroolefins, leading to complex bicyclo[3.2.1]-
octan-2-one derivatives containing four continuous stereogenic
centres as a single diastereoisomer and with excellent enantio-
selectivities. The products were delivered through a domino
Michael–Henry process using a proline-based bifunctional
organocatalyst.
M.T. and C.G.K. acknowledge COST Action CM0905 (ORCA) and
Prof. A. Malkov (Loughborough University) for initiating the
cooperation between the Universities of Athens and Loughborough.
C.G.K. would like to acknowledge the Operational Program
‘‘Education and Lifelong Learning’’ for financial support
through the NSRF program ‘‘METADIDAKTORES (PE 2431)’’
co-financed by ESF and the Greek State.
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Enantioselective Organocatalysis Reactions and Experimental Proce- 14 X-ray data for 3a: C16H17NO4, M = 278.30, colourless block, 0.70 Â
dure, Wiley-VCH, Weinheim, 2007.
0.21 Â 0.17 mm3, orthorhombic, P21212, a = 10.3329(10), b =
19.6202(19), c = 7.1804(7) Å, V = 1455.7(2) Å3, Z = 4, m(Mo-Ka) =
0.10 mmÀ1, T = 150 K, 17 114 reflections measured on a Bruker
APEX 2 CCD diffractometer, 4410 unique, Rint = 0.033, R1[F2 > 2s(F2)] =
0.041, wR2 (all data) = 0.107, Flack x = À0.6(4); not reliably determined,
but gives an indication. H atoms freely refined. CCDC 916313†.
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 2219--2221 2221