Bifunctional Br?nsted Base Catalyst Enables Regio-, Diastereo-, and Enantioselective Cα-Alkylation of β-Tetralones and Related Aromatic-Ring-Fused Cycloalkanones

Article abstract of DOI:10.1002/anie.201612332

The catalytic asymmetric synthesis of both α-substituted and α,α-disubstituted (quaternary) β-tetralones through direct α-functionalization of the corresponding β-tetralone precursor remains elusive. A designed Br?nsted base-squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or α-monosubstituted β-tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the α-carbon atom of the β-tetralone exclusively, but adducts including all-carbon quaternary centers are also formed in highly diastereo- and enantioselective manner.

Full text of DOI:10.1002/anie.201612332

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International Edition: DOI: 10.1002/anie.201612332
German Edition: DOI: 10.1002/ange.201612332
Organocatalysis
Bifunctional Brønsted Base Catalyst Enables Regio-, Diastereo-, and
Enantioselective Ca-Alkylation of b-Tetralones and Related Aromatic-
Ring-Fused Cycloalkanones
IÇaki Urruzuno, Odei Mugica, Mikel Oiarbide, and Claudio Palomo*
In memory of Josꢀ Barluenga
Abstract: The catalytic asymmetric synthesis of both
a-substituted and a,a-disubstituted (quaternary) b-tetralones
through direct a-functionalization of the corresponding
b-tetralone precursor remains elusive. A designed Brønsted
base-squaramide bifunctional catalyst promotes the conjugate
addition of either unsubstituted or a-monosubstituted
b-tetralones to nitroalkenes. Under these reaction conditions,
not only enolization, and thus functionalization, occurs at the
a-carbon atom of the b-tetralone exclusively, but adducts
including all-carbon quaternary centers are also formed in
highly diastereo- and enantioselective manner.
S
yntheses of many bioactive compounds with polycyclic
structures, including homoerythrina alkaloids,[1] morphan
derivatives,[2] glucocorticoid receptors,[3] and stradiols,[4]
among others,[5] have employed b-tetralones. However, this
interest did not translate into a variety of approaches for the
asymmetric synthesis of substituted b-tetralones. Most
approaches for the a/a’-functionalization of b-tetralones so
far documented exploit the idea of Stork et al.[6] which
involves condensation with a chiral amine and subsequent
C-alkylation of the resulting enamine, typically by addition to
a Michael acceptor.[7] One complication, for any nonsymmet-
ric cycloalkanone, is that enolization may occur at either the
a or a’ site. In this context, Blarer and Seebach[8] reported that
the reaction with nitrostyrenes of the enamine derived from
(S)-2-methoxymethylpyrrolidine, and the respective b-tetra-
lone produced in moderate yields the a’-adduct predomi-
nantly (a/a’ from 1:4 to 1:20) with generally good diastereo-
and enantioselectivity after hydrolysis of the resulting imi-
nium species (Scheme 1a). Alternatively, the groups of Pfau
and dꢀAngelo reported the condensation of b-tetralones with
(S)-1-phenylethylamine and subsequent Michael reaction to
afford the a-substituted adducts preferentially,[9] but with
exceptions.[9a]
Scheme 1. Enantioselective a/a’-functionalization of b-tetralones.
EWG=electron-withdrawing group.
a-functionalization of b-tetralones leading to an all-carbon
quaternary stereocenter.[10] Chen and co-workers have
reported direct reaction of b-tetralones with a,b-unsaturated
aldehydes by iminium activation,[11] but stereogenicity at Ca is
lost upon spontaneous hemiketal formation. Herein we report
the direct site-, diastereo-, and enantioselective Ca-alkylation
of b-tetralones by conjugate addition reaction enabled by
À
newly designed Brønsted base catalysts. The new C C bond is
Apart from these stoichiometric multistep approaches, we
are unaware of catalytic methods for the enantioselective
formed at the a-carbon atom exclusively, and adducts,
including those with an a-quaternary center, are formed in
a highly stereoselective manner.
Our consideration was that the fused aromatic ring in
b-tetralones might induce preferential enolization at Ca
rather than Ca’, and that in the presence of a Brønsted base
relatively high concentrations of the enolic form would be
expected, thus eventually driving the catalytic process for-
ward. Nonetheless, this assumption was accompanied by
a second significant challenge, namely the effective control of
both the absolute and relative stereochemistry during con-
[*] I. Urruzuno, O. Mugica, Prof. M. Oiarbide, Prof. C. Palomo
Departamento de Quꢀmica Orgꢁnica I
Universidad del Paꢀs Vasco UPV/EHU
Manuel Lardizabal 3, 20018 San Sebastiꢁn (Spain)
E-mail: claudio.palomo@ehu.es
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612332.
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struction of the quaternary carbon stereocenter. In fact, while
some success has been achieved in the enantioselective
synthesis of a-quaternary carbonyl compounds by Brønsted
base-catalyzed Michael reactions[12,13] of a-aryl cyclopenta-
nones,[14a] the corresponding a-aryl cyclohexanones behaved
sluggishly.[14,15] We started by screening a set of chiral
bifunctional Brønsted base catalysts for the reaction of 1B
with the nitrostyrene 5a (Scheme 2). It was found that while
find that acceptable selectivity was achieved with the new
catalysts C5 and C6 (85 and 80% ee, respectively). In contrast,
the N-methylated catalyst C7 led to a moderate 60% ee, thus
indicating that the amide NH in the former catalysts is
important. Lowering the reaction temperature allowed fur-
ther improvement in the selectivity (90% ee at À108C for
C6), although C5 behaved sluggishly at subzero temperatures
because of limited solubility. The same trend in the behavior
of C1–C7 was observed for the reaction of 1B with the
nitroalkene 5b.[16]
As Table 2 illustrates, results with differently b-substituted
nitroalkenes[22] were uniformly good when using C6. Thus, the
stereoselectivity of the reactions seems to be independent of
the electronic properties of the nitroalkene, and products
6Ba, 6Bb, 6Bd, and 6Be were formed from the respective
nitrostyrenes 5 in yields around 80% and with ee values in the
range of 90–91%. Nitroalkenes having heteroaromatic or
alkynyl b-substituents (5h, 5i) also led to the corresponding
products (6Bh, 6Bi) with similarly good yield and enantiose-
lectivity. Remarkably, even the less reactive b-alkyl-substi-
tuted nitroalkenes, such as 5j and 5k, afforded the corre-
sponding addition adducts (6Bj, 9Bk) with equally good
yields and ee values. The stereochemical outcome of the
reaction is also independent of the a-substituent of the
b-tetralone employed. The tetralones 1C, 1D, and 1E reacted
with the respective nitroalkenes 5 to afford the adducts 6Ca,
6Dg, and 6Ef, respectively, in good yields and with ee values
of up to 99%. The reaction also tolerates the b-tetralones 2D,
3B, and 4B, bearing, respectively the 6-methoxy-, 6-chloro-,
Scheme 2. Catalytic addition of b-tetralones to nitroalkenes.
BB=Brønsted base.
in each case the a,a-dialkyl b-tetralone 6Ba was formed
exclusively and with essentially perfect diastereoselectivity
regardless of the chiral catalyst employed (Table 1),[16] the
enantioselectivities were highly catalyst-dependent. The
bifunctional squaramide-cinchona Brønsted base catalysts
pioneered by Rawal and co-workers[17,18] were the most
effective. Thus, by using the catalysts C1[17] and C2[19] the
product 6Ba was formed exclusively, albeit in moderate
enantioselectivity (73 and 72% ee, respectively).
Table 2: Scope of the reaction with respect to the a-substituted
b-tetralones 1–4 with nitroalkenes 5 catalyzed by C6.[a]
Table 1: Screening of catalysts for the reaction of 1B with 5a.[a]
[a] Reactions carried out at 0.30 mmol scale, using 1.2 equiv of 5a and
10 mol% catalyst in 0.6 mL CH2Cl2 at room temperature. Yield is that of
the isolated product 6Ba after chromatography. The ee value was
determined by chiral-phase HPLC.
[a] Reactions carried out at 0.30 mmol scale, using 1.2 equiv of trans-
nitroalkene 5 and 10 mol% C6, unless otherwise stated, in 0.6 mL
CH2Cl2. d.r.>20:1 in all entries as determined by 1H NMR (300 MHz)
analysis of the crude reaction mixture. Yield is that of the product
isolated after chromatographic purification. The ee value was determined
by chiral-phase HPLC. [b] Reaction conducted at À208C. [c] Obtained as
a 1.5:1 mixture of diastereomers (94% ee for minor isomer). [d] Using
catalyst C4.
Next we examined the catalysts C3[20]/C4 bearing an
amide unit, which would provide a site not only for catalyst
fine tuning, but also for additional hydrogen bonding
(Table 1).[21] Both C3 and C4 catalyzed the reaction of 1B
with 5a, but produced no improvement in the ee value. After
several variations of the amide group, we were delighted to
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and 7-methoxy groups at the aromatic ring, which were
equally efficient (adducts 7Da, 8Bc, and 9Bk). In the case of
7Da, C4 produced the best reaction outcome. Importantly, in
every case no traces of products from the reaction at the
a’-carbon atom of the b-tetralone were formed.
Next, the behavior of the a-unsubstituted b-tetralone 1A
was investigated and the reactions under similar reaction
conditions were found, again, to be completely regioselective
(Table 3). The products 10–18 were obtained from both aryl-
Table 3: Reaction of the b-tetralone 1A with nitroalkenes catalyzed by
either C2 or C6.[a]
Figure 1. Adducts from the direct reaction of a survey of arene-fused
cycloalkanones with nitroolefins in the presence of 10 mol% C6 (for
details, see the Supporting Information). [a] 2 mol% of catalyst C2
used. Both diastereomers obtained with the same ee value.
Product, R
T [8C]
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
compounds 19 and 20 were obtained as a mixture of two
diastereomers, probably as a result of easy epimerization
under the reaction conditions used. In contrast, in the case of
employing a diketone substrate, the adduct 24 from a sequen-
tial Michael/intramolecular Henry reaction was obtained,
again, as essentially a single diastereomer and very high
enantioselectivity.
The excellent regio- and stereoselectivity achieved in the
above reactions are of particular interest in that several
options for further elaboration of the adducts are now made
feasible. For instance (Scheme 3), the adduct 10 (3:1 ratio of
diastereomers), upon treatment with 5a in the presence of
10 mol% of C2 provided the tricyclic systems 25/25’ in 60%
10, Ph
À20
À20
À20
À20
À20
À20
RT
8
8
8
8
8
83
85
88
80
86
84
81
80
83
4:1
8:1
4:1
99
99
99
99
99
98
99
99
99
11, 4-MeOC6H4
12, 4-BrC6H4
13, 3-MeOC6H4
14, 2-ClC6H4
15, 2-furyl
16, CH3(CH2)2
17, C6H11
18, Ph(CH2)2
4:1
>20:1
1:1
8
16
24
16
5:1
4:1
5:1
RT
RT
[a] Reactions carried out at 0.30 mmol scale, using 1.2 equiv of trans-
nitroalkene and 2 mol% of either C2 or C6 in 0.6 mL CH2Cl2. [b] Yield of
product isolated after chromatographic purification. [c] Determined by
1H NMR (300 MHz) analysis of the crude reaction mixture. [d] Both
diastereomers obtained with the same ee value as determined by chiral-
phase HPLC.
and alkyl-substituted nitroalkenes in yields in the 80–88%
range and, importantly, no products from a sequential addi-
tion of two equivalents of nitroalkene, either at Ca/a’ of the
ketone or at Ca of the nitro group, were detected. With the
exception of the 2-furyl-substituted nitroalkene 5h (product
15), in all other cases diastereoselectivity was good (d.r. ꢀ 4:1)
and enantioselectivity essentially perfect for both diastereo-
mers. For these reactions both C2 and C6 were found to be
equally effective at a 2 mol% loading. It should be noted that
the thus obtained a-monosubstituted b-tetralones were prone
toward epimerization under basic conditions at room temper-
ature. For example, the compound 14, which was isolated
essentially as a single diastereomer (d.r. > 20:1), led, after
exposure to 5 mol% of C2 at room temperature in methylene
chloride for 3 hours, to an almost equimolar mixture of
diastereomers. In the absence of base, however, no epimeri-
zation was observed after a prolonged time (20 h) even at
808C.
Eventually, the suitability of this highly site- and stereo-
selective a-functionalization strategy was also investigated for
related ketone substrates. As results in Figure 1 show,
aromatic ring-fused cycloalkanones with an oxygen hetero-
atom in the cycle, or larger seven-membered cycloalkanones,
were equally competent substrates undergoing the corre-
sponding addition reaction at Ca exclusively, and with very
high stereoselectivity. In particular cases, the enolizable
Scheme 3. Elaboration of adducts into a variety of polycyclic mole-
cules.
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combined yield. Remarkably, only two out of the possible 26
stereoisomers of 25 were formed.[23] An interesting aspect is
that apparently no cyclization product derived from the minor
isomer of 10 was detected. Moreover, the isomeric compo-
sition of isolated product 25/25’ was around 3:1 regardless of
the initial mixture of starting 10 employed (3:1 in first run; 1:1
in second run). These results suggest that formation of the
tricycles 25/25’ through a Michael/Henry cascade[24,25] not only
proceeds in high stereoselectivity, but also involves some
kinetic resolution process. Similarly, treatment of 14 (d.r. >
20:1) with 5j in the presence of C2 afforded the products 26/
26’ in a 2:1 ratio. The absolute configuration of 25 was
determined by single-crystal X-ray structure analysis,[26] and
that of 25’ by NOESY experiments.[16] The configuration of
26/26’ was assigned by analogy. In a different example, when
14 was treated with acrolein in the presence of C2 at room
temperature, the Michael addition product 27 was isolated in
80% yield. The aldol-reaction-mediated cyclization of 27 to
28 could be carried out smoothly at room temperature by
exposure to 10 mol% pyrrolidine. Alternatively, direct trans-
formation of 14 into the spirocyclic aldol 28 was achieved by
treatment with acrolein in the presence of 10 mol% pyrro-
lidine. In both cases 28 was produced as essentially a single
diastereomer. The course of the above cascade reaction is
quite surprising considering that cycloalkanones under similar
reaction conditions are reported to furnish substituted
decalins instead.[27] Importantly, as far as we know, no other
catalytic enantioselective approach that allows regioselective
production of tetralone-derived a-spirocycles are available
until now.[5,28] In addition, hexahydro-benzo[e]indoles, heter-
ocyclic cores present in various biologically active com-
pounds,[29] could also be prepared. For example, reduction of
the nitro group in adduct 6Ba with either Zn/H+ or H2/Pd
provided, respectively, 31 and 32, whilst reduction of 14 led to
29, all with good yields. The absolute configurations for the
compounds 28 and 32 were determined by single-crystal
X-ray structure analysis[26] and that of their precursor adducts
was established by extrapolation.
ment (GV grant No IT-628-13), and Ministerio de Economꢁa
y Competitividad (MEC Grant CTQ2016-78487-C2), Spain.
O.M. thanks MEC, and I.U. thanks GV for fellowships. We
also thank SGIker (UPV/EHU) for providing NMR, HRMS,
and X-Ray resources.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Brønsted bases · heterocycles · organocatalysis ·
polycycles · synthetic methods
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Acknowledgments
Support has been provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Govern-
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[30] Preliminary experiments show that vinyl sulfones are also
competent reaction partners. See the Supporting Information.
Manuscript received: December 20, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Organocatalysis
I. Urruzuno, O. Mugica, M. Oiarbide,
C. Palomo*
&&& — &&&
Bifunctional Brønsted Base Catalyst
Enables Regio-, Diastereo-, and
Enantioselective Ca-Alkylation of b-
Tetralones and Related Aromatic-Ring-
Fused Cycloalkanones
Threefold control: A long-standing prob-
lem in the direct a-functionalization of b-
tetralones, the combined control of site-,
diastereo-, and enantioselectivity, is
solved by Brønsted base (BB) catalysis.
As a result, densely functionalized poly-
cyclic systems with an all-carbon quater-
nary stereocenter are now accessible.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!