A highly enantioselective one-pot synthesis of spirolactones by an organocatalyzed michael addition/cyclization sequence

Article abstract of DOI:10.1002/anie.201104819

Spiroring in control: A novel organocatalytic Michael addition/cyclization sequence based on the bis(electrophilic) properties of vinyl selenones has been successfully employed for the synthesis of densely functionalized spirocyclic compounds (see scheme). By using a simple one-pot procedure and mild reaction conditions, spirocyclic compounds were synthesized in high yields and with high levels of enantioselectivity (90-98% ee).

Full text of DOI:10.1002/anie.201104819

Communications
DOI: 10.1002/anie.201104819
Organocatalysis
A Highly Enantioselective One-Pot Synthesis of Spirolactones by an
Organocatalyzed Michael Addition/Cyclization Sequence**
Silvia Sternativo, Antonella Calandriello, Ferdinando Costantino, Lorenzo Testaferri,
Marcello Tiecco, and Francesca Marini*
Spirocyclic compounds are attractive targets in organic
synthesis because of their broad distribution in biologically
active natural products and pharmaceuticals,[1] as well as their
increasing use in a range of important chemical and techno-
logical processes, such as asymmetric synthesis and organic
optoelectronics.[2] On this basis the development of novel
methods for the construction of spirocyclic frameworks is of
considerable importance, particularly when these methods
give rise to the enantioselective formation of an all-carbon
quaternary stereocenter, which itself is considered to be a
challenging transformation.[3,4] Over the past decade, exten-
sive work on organocatalyzed asymmetric conjugated addi-
tions of trisubstituted carbon nucleophiles to electron-defi-
cient alkenes demonstrated that these reactions represent an
attractive solution to the problem of selectively generating
quaternary stereocenters.[4] Recently several organocatalytic
cascade processes involving Michael additions have been
successfully applied to the synthesis of spirocyclic com-
pounds.[5] These methods, are based on Michael or Michael/
aldol-type sequences and provide access to spiro-oxindoles,
spirobenzofuranones, or spiro-3,4-dihydropyrans with high
stereocontrol. The use of novel substrate combinations and
the development of new cascade or one-pot reactions are
significant advances in this field, thus making the asymmetric
assembly of structurally diverse spirocyclic compounds pos-
sible from simple and readily available precursors. In this field
and in continuation of our efforts to expand the scope of
privileged organocatalysts in the field of selenium chemis-
try,[6,7] we herein report the first highly enantioselective
synthesis of spirolactones starting from racemic cyclic b-
ketoesters and the vinyl selenone catalyzed by bifunctional
cinchona-alkaloid-derived catalysts. The operationally
simple, one-pot Michael addition/cyclization sequence is
based on the peculiar properties of the phenylselenonyl
substituent, which plays a dual role as an electron-withdraw-
ing group, during the addition step, and as a leaving group,
during the cyclization by intramolecular nucleophilic substi-
tution.
Initial studies were performed with an excess of the tert-
butyl b-ketoester 1a and the easily available vinyl selenone 2
in toluene in the presence of a catalytic amount of anhydrous
Na2CO3 (Scheme 1).
Scheme 1. Reaction of tert-butyl b-ketoester 1a and the vinyl selenone
2: a one-pot Michael addition/cyclization sequence.
The formation of the Michael intermediate 3a was clearly
demonstrated by 1H, 13C, and 77Se NMR spectra of the crude
reaction mixture. Particularly indicativeare the 13C peak at
d = 56 ppm, characteristic of a methylene linked to a sele-
nonyl group,[6b,8] and the 77Se signal at d = 994 ppm typical of a
phenyl alkyl selenone.[9] This signal is deshielded in compar-
ison with that of the starting conjugated selenone 2, for which
a signal is seen at d = 961 ppm. We were delighted to observe
that the Michael adduct was smoothly converted in 2 hours
into the spirolactone 4a by stirring at room temperature with
silica gel. The excellent leaving ability of the selenone group
in intramolecular nucleophilic substitutions is well known,[6,10]
thus, plausibly this unprecedented ring-closure reaction
occurs through nucleophilic displacement of -SeO2Ph by the
ester group. The tert-butyl group can be easily cleaved by the
free silanol groups of the silica[11] and the released PhSeO2H is
partially trapped by the excess of the b-ketoester.[12] The
presence of the tert-butyl residue seems to be crucial for the
cyclization. In fact the reaction carried out with the corre-
sponding ethyl b-ketoester gave 4a in very poor yield. To
assess the feasibility of an asymmetric organocatalytic strat-
egy, we focused on the use of the easily accessible compounds
5a–g (Scheme 2), which have recently emerged as potentially
general catalysts for a range of 1,4-addition reactions.[4,13]
These organocatalysts, bearing an hydrogen-bond-donor
group together witha basic site on a chiral scaffold, are typical
bifunctional catalysts. They improve yields and stereoselec-
tivities of 1,4-additions by simultaneous activation of both the
Michael acceptor and the pronucleophile. Treatment of the
vinyl selenone 2 with the tert-butyl b-ketoester 1a in the
presence of 20 mol% of the ureidic or thioureidic catalysts
5a–c, which have been successfully employed for the activa-
[*] Dr. S. Sternativo, A. Calandriello, Prof. L. Testaferri, Prof. M. Tiecco,
Prof. F. Marini
Dip. Chimica e Tecnologia del Farmaco, Universitꢀ di Perugia
Via del Liceo, 06123 Perugia (Italy)
E-mail: marini@unipg.it
Dr. F. Costantino
Dipartimento di Chimica, Universitꢀ di Perugia
Via Elce di Sotto, 06123 Perugia (Italy)
[**] Financial support from MIUR, National Projects PRIN 2007 and the
University of Perugia and Consorzio CINMPIS, Bari is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104819.
9382
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principle, the presence of water can affect the outcome of the
reaction by interactions with the catalyst or by nucleophilic
displacement of the selenonyl group of 3a,[9b] the reactions
carried out in the presence and absence of molecular sieves
(4 ꢀ) gave comparable results in terms of yield and enantio-
selectivity (Table 1, entries 6 and 7). The 6’-OH 9-O-(9’-
phenanthryl)ether quinine derived catalyst 5 f exhibited the
best levels of enantioselectivity and catalytic activity. Com-
parable results were still achieved when the loading of 5 f was
reduced to 5 mol%, albeit an extended reaction time was
required to reach complete conversion (Table 1, entries 11–
13). Both the enantiomers of the spirolactone are accessible,
in fact ent-4a was prepared in good yield and with a similar
ee value with the quinidine-derived catalyst 5g (Table 1,
entry 14).
With the optimized reaction conditions established, we
explored the scope and limitations of the asymmetric
Michael/cyclization sequence. As summarized in Scheme 4,
indanone-derived tert-butyl b-ketoesters 1b–f, having various
substituents, were found to be suitable for this catalytic
transformation and provided products in high yields and
excellent enantioselectivities in short reaction times. The
presence of either electron-withdrawing or electron-donating
groups on the aromatic ring gave comparable results. Cyclo-
pentanone-derived tert-butyl b-ketoesters 1g and 1h were
also successfully employed in the one-pot sequence, thus
generating, under the same reaction conditions, the spirolac-
tones 4g and 4h. On the contrary, reactions carried out
starting from b-ketoesters with a cyclohexanone core were
unsuccessful. The Michael additions to the selenone 2
proceeded very slowly and the adducts formed could not be
transformed into the corresponding spirolactones by treat-
ment with silica gel.
Scheme 2. Catalysts screened for the spirocylic compound formation.
tion of the selenone moiety,[6b–c,7] resulted in clean reactions
but low selectivity (Table 1, entries 2–4). Thus, we turned our
attention on the use of the 6’-OH cinchona alkaloid deriva-
tives 5d–g.[14] These catalysts gave 4a with high yield and
excellent enantiocontrol (Table 1, entries 5–14). Experiments
carried out with different solvents demonstrated that toluene
is the solvent of choice. In fact the desired spirolactone is
formed in high yield and excellent selectivity even at room
temperature and in a short reaction time. Although, in
Table 1: Selected examples of catalyst screening and optimization of
reaction conditions.
Recrystallization of the spirolactone 4c followed by
single-crystal X-ray analysis allowed the S configuration to
be assigned (Scheme 3).[15] The absolute stereochemical
configurations of the other products were assigned by
analogy. The step responsible for the enantioselectivity of
Entry
Cat.
[mol%]
Solvent
T
[8C]
t
[h]
Yield
ee
[%][a,b]
[%][c]
1
2
3
4
5
6
7
8
Na2CO3
5a
5b
5c
5d
5e
5e
5e
5e
5e
5 f
20
20
20
20
20
20
20
20
20
20
20
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
CH2Cl2
toluene
toluene
toluene
toluene
RT
24
10
7
8
6
6
6
22
72
53
5
71
–
RT
RT
RT
RT
RT
RT
0
À45
À45
RT
RT
RT
RT
90[d]
99[d]
99[d]
99
42
20
28[e]
76
90
91
92
88
94
96
96
96
97[e]
99[d]
99
94
85
94
96
82
93
80
9
10
11
12
13
14
5 f
5 f
5g
5
24
5
5
20
[a] The reactions were performed on a 0.1 mmol scale in the indicated
solvent (0.4 mL) with 2 equivalents of the b-ketoester 1a. The indicated
temperatures and times refer to the addition step. Then silica gel (0.5 g)
was added and the reaction mixtures were stirred at room temperature
for additional 2 h. [b] Yield of the isolated product after flash chroma-
tography on silica gel. [c] The ee values were determined by HPLC
analysis using a chiral column. [d] The reaction was carried out in the
presence of molecular sieves (4 ꢁ). [e] The opposite enantiomer was
formed. THF=tetrahydrofuran.
Scheme 3. Absolute configuration of 4c (thermal ellipsoids are shown
at 50% probability) and the proposed stereochemical model for the
reaction of 1c and 2 with the catalyst 5 f.
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Communications
Scheme 5. Organocatalytic one-pot Michael addition/cyclization
sequence of 1i and 1k. [a] The relative configuration was assigned by a
NOESY experiment and the absolute configuration was assigned by
analogy. [b] Reaction performed with the catalyst 5g. [c] The ee value
after a single crystallization (EtOAc).
addition step regardless of the stereochemistry of the other
stereogenic center, thus each of the diastereomeric com-
pounds is generated with high enantioselectivity.
Although several examples of stereodivergent reactions
catalyzed by enzymes are known, those with organocatalysts
are less common.[17,18]
Scheme 4. Scope of the one-pot Michael addition/cyclization reaction.
[a] Unless otherwise specified, the reactions were performed at RT on a
0.2 mmol scale in toluene (0.8 mL) with 2 equivalents of the b-
ketoesters 1a–h and 20 mol% of the catalyst 5 f. [b] The ee values of
4a–h were determined by HPLC analysis using a chiral stationary
phase. [c] The ee value obtained after a single crystallization (EtOAc) is
reported in brackets. [d] Reaction performed with the catalyst 5g. [e] By
single-crystal X-ray analysis (+)-4c was determined to be S-configured
and the absolute configurations of all the other products were
assigned by analogy.
From the reaction of rac-1k the compound 4k was
obtained as the single cis isomer in 83% yield and 92% ee,
thus demonstrating that, in this case, one of the enantiomers is
preferentially converted into the spirocyclic compound
(Scheme 5).[19] Attempts to recover unreacted 1k failed and
only a mixture containing 6 as the main product was isolated
by column chromatography.[12] Compound ent-4k was pre-
pared with a high enantiomeric excess using the pseudo-
enantiomeric catalyst 5g under the optimized reaction con-
ditions.
In conclusion, an organocatalytic protocol for the syn-
thesis of spirolactones from cyclic b-ketoesters and an easily
accessible vinyl selenone by a one-pot Michael addition/
cyclization reaction has been described.[20] The novelty of the
transformation, the simplicity of the procedure, and the high
levels of efficiency and stereoselectivity (ee values range from
90 to 98%) are the most attractive aspects of this trans-
formation. The enantioselective formation of spirolactones is
a challenging task[1c] requiring control in the construction of a
sterically constrained quaternary carbon center. Moreover,
the spirolactone skeleton is present in natural products and
biologically important compounds such as bakkenolides[1] and
structural analogues of the antitumoral podophyllotoxin.[21]
The present method also confirms the synthetic value of the
vinyl selenone as a 1,2-bis(electrophilic) synthon and expands
its applicability in the field of asymmetric organocatalysis,
introducing a novel Michael-initiated ring-closure process
that has no parallel in the related sulfur chemistry.[22]
the sequence is the addition step, and the stereochemical
models previously reported for other conjugate additions
catalyzed by C6’-OH cinchona alkaloid derivatives correctly
predict the observed stereochemistry.[14] As shown in
Scheme 3 the active gauche open conformer of the quinine-
derived catalyst 5 f in the transition state orients and activates
simultaneously both the enolic tautomer of the pronucleo-
phile and the electrophilic vinyl selenone by a network of
hydrogen-bonding interactions.
To extend the method, Michael donors containing an
additional stereocenter, such as racemic trans-1i and trans-1k
were also investigated (Scheme 5). The reactions were carried
out under the optimized reaction conditions with two
equivalents of the pronucleophile. Compound rac-1i gave
the two highly enantioenriched diastereomeric spirolactones
cis-4i and trans-4j, which were easily separated by flash
column chromatography on silica gel.[16] This is an example of
a stereodivergent parallel kinetic resolution (PKR)[17] or, as it
is nowadays more properly defined, of a stereodivergent
reaction of a racemic mixture (stereodivergent RRM),[18] and
in this transformation both the enantiomers of a racemic
substrate are transformed at similar rates into enantioen-
riched diastereomeric products by effect of a chiral reagent or
catalyst.
Experimental Section
General procedure for the enantioselective formation of spirocyclic
compounds 4: In a vial equipped with a Teflon-coated stir bar, catalyst
5 f or 5g (0.04 mmol, 20 mol%) and vinyl selenone 2 (0.2 mmol) were
dissolved in undistilled toluene (0.8 mL) under air. The b-ketoesters
In the present case the chiral catalyst strictly controls the
configuration of the stereogenic center formed during the
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1a–i, k (0.4 mmol, 2 equiv) were added at room temperature and the
resulting solution was stirred for 5–20 h. When 2 was completely
consumed, as indicated by TLC analysis, silica gel (1 g) and toluene
(0.8 mL) were added and the reactions were stirred for 2 h. The crude
mixtures were directly submitted to flash column chromatography on
silica gel using n-hexane/ethyl acetate mixtures as the eluent. The
fractions were collected and concentrated in vacuo to give the
products 4a–k.
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boxylate by column chromatography on silica gel. Benzensele-
ninic acid derivatives are known to react with enolates and the
resulting a-ketoselenoxide in some cases eliminates PhSeOH
and forms a double bond: a) H. J. Reich, J. M. Renga, I. L.
Reich, J. Am. Chem. Soc. 1975, 97, 543; for benzenseleninic acid
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[15] For X-ray analysis details see the Supporting information.
CCDC 833150 (4c) 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.
[16] Racemic samples of 4i and 4j were obtained in overall 87%
yield and 55:45 diastereomeric ratio from the reaction with
Na2CO3 (20 mol%). The products were easily separated by flash
column chromatography on silica gel.
[17] For a review concerning parallel kinetic resolution, see: a) J. R.
Dehli, V. Gotor, Chem. Soc. Rev. 2002, 31, 365; see also b) P. J.
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[19] A racemic sample of 4k was obtained as a single cis isomer in
76% yield from the reaction with Na2CO3 (20 mol%).
[20] Michael reactions between 1a and an alkyl- or aryl-substituted
b-vinyl selenone, were unsuccessful and the addition products
were not formed even after prolonged reaction times.
[21] L. L. Klein, C. M. Yeung, D. T. Chu, E. J. McDonald, J. J.
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Received: July 11, 2011
Published online: August 19, 2011
Keywords: cyclization · nucleophilic addition · organocatalysis ·
.
selenium · spiro compounds
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