Direct regio-, diastereo-, and enantioselective vinylogous Michael addition of prochiral 3-alkylideneoxindoles to nitroolefins

Article abstract of DOI:10.1002/adsc.201300168

3-Alkylidene-2-oxindoles represent a simple, yet enabling subfamily of indole alkaloids, and their ability to react as electron-poor acceptors has largely been investigated. In contrast, their utility as pronucleophilic synthons remains elusive. In this context, the present article describes the successful execution of the direct, organocatalytic asymmetric Michael addition of prochiral 3-alkylideneoxindoles to nitroolefins. A variety of γ-substituted alkylideneoxindoles carrying two stereocenters at both the γ- and δ-carbon sites was assembled with excellent stereoselectivity and without olefin isomerization or stereochemical ablation. Copyright

Full text of DOI:10.1002/adsc.201300168

UPDATES
DOI: 10.1002/adsc.201300168
Direct Regio-, Diastereo-, and Enantioselective Vinylogous
Michael Addition of Prochiral 3-Alkylideneoxindoles to
Nitroolefins
Gloria Rassu,a,* Vincenzo Zambrano,a Luigi Pinna,b Claudio Curti,c,*
Lucia Battistini,c Andrea Sartori,c Giorgio Pelosi,d Franca Zanardi,c
and Giovanni Casiraghic,*
a
Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, I-07100 Li Punti Sassari, Italy
Fax : (+39)-079-2841299; phone: (+39)-079-2841226; e-mail: gloria.rassu@icb.cnr.it
Dipartimento di Chimica e Farmacia, Universitꢀ degli Studi di Sassari, Via Vienna 2, I-07100 Sassari, Italy
Dipartimento di Farmacia, Universitꢀ degli Studi di Parma, Parco Area delle Scienze 27A, I-43124 Parma, Italy
b
c
Fax : (+39)-0521-905006; phone: (+39)-0521-905079; e-mail: claudio.curti@unipr.it or giovanni.casiraghi@unipr.it
Dipartimento di Chimica, Universitꢀ degli Studi di Parma, Parco Area delle Scienze 17A, I-43124 Parma, Italy
d
Received: February 21, 2013; Revised: May 2, 2013; Published online: June 4, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300168.
Abstract:
3-Alkylidene-2-oxindoles
represent
where a Brønsted base and a proton donor moiety
synergistically conspire to activate both the donor and
acceptor reaction components.[4]
a simple, yet enabling subfamily of indole alkaloids,
and their ability to react as electron-poor acceptors
has largely been investigated. In contrast, their utili-
ty as pronucleophilic synthons remains elusive. In
this context, the present article describes the suc-
cessful execution of the direct, organocatalytic
asymmetric Michael addition of prochiral 3-alkyli-
deneoxindoles to nitroolefins. A variety of g-substi-
tuted alkylideneoxindoles carrying two stereocen-
ters at both the g- and d-carbon sites was assembled
with excellent stereoselectivity and without olefin
isomerization or stereochemical ablation.
Continuing on this theme, we questioned whether
this organocatalytic conjugate addition might be ex-
tended to the addition of 3-alkylideneoxindoles
having a prostereogenic site at the g-position, which
could potentially proceed by an enantio- and diaste-
reoselective process to deliver nitro adducts carrying
two vicinal stereocenters at both the g- and d-posi-
tions (compounds D in Scheme 1). Herein we de-
scribe the first example of this transformation where
indolinones of type C provide adducts D efficiently,
with perfect regio- and geometry control and with
outstanding levels of enantioselectivity and good dia-
stereoselectivity.
Keywords: asymmetric catalysis; Cinchona alka-
loids; nitroolefins; organocatalysis; oxindoles; vinyl-
ogous Michael addition
We initiated our investigations by synthesizing a set
of pronucleophilic oxindole candidates varying in
shape and substitution (Scheme 2). The scaffold diver-
sity encompassed “symmetrical” N-methoxycarbonyl-
protected oxindoles 1a and 1b, benzo-ring substituted
Vinylogy and reactions inspired by this principle[1] are chloro, fluoro, and methoxy compounds 1c, 1d, and
rapidly growing research themes that have significant- 1e, as well as an “unsymmetrical” E-configured repre-
ly widened the organic synthesis landscape over the sentative 1f. From a synthetic point of view, it is note-
last decades.[2] In this context, our laboratory has re- worthy that these olefinic oxindoles are very stable
cently described the direct regio- and enantioselective compounds, which are readily synthesized from the
vinylogous Michael addition of b-substituted alkyli- parent oxindoles in two steps and in good yields (for
ACHTUNGTRENNUNG
adducts bearing a d-carbon stereocenter (compounds trans-b-nitrostyrene 2a was selected as the model re-
B in Scheme 1).[3] The key advance enabling this re- action to evaluate the ability of the dihydroquinine-
markable transformation was the use of the Cinchona derived catalyst I to control both the preference of
alkaloid thiourea catalyst I (or II), a dual system the substitution site (g vs. a) and the product topology
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Gloria Rassu et al.
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Scheme 2. Pronucleophilic oxindole substrates used in this
study. Moc=methoxycarbonyl.
tween yield and selectivity were obtained using tolu-
ene at 0.2M substrate concentration. The transforma-
tion was productive in several polar and apolar sol-
vents such as CH2Cl2, THF, Et2O, and MeCN, but the
stereochemical outcome was substantially less per-
forming as compared to reactions conducted in tolu-
ene (see the Supporting Information for further de-
Scheme 1. Previous and current asymmetric vinylogous Mi-
chael approaches of oxindole pronucleophiles A and C.
(Z vs. E; anti vs. syn), as well as the efficiency of the tails, Table S1).
chirality transmittal from the catalyst to the product.
With these results established, we next explored the
Gratifyingly, the expected product 3aa could be ob- generality of the reaction with regards to variation of
tained in 97% isolated yield, with exclusive g-site- the olefin acceptor using 1a as a probe. All reactions
and Z-selectivities, and with excellent stereocontrol were completed after 24 h at room temperature (18–
after brief optimization studies [95:5 anti/syn dr; 208C) and returned the expected adducts in very
99.9:0.1 er for the major (R,R)-configured diastereo- good isolated yields, with excellent levels of g-site se-
isomer, Table 1, entry 1]. As expected, quasi-enantio- lectivity, enantioselectivity, and diastereoselectivity
meric catalyst II derived from quinidine showed an with respect to the geometry of the exocyclic olefin
equal reactivity profile and furnished the opposite linkage (Table 1).
enantiomer of 3aa with quite similar dr and er values.
Good anti:syn diastereoselectivities were also at-
To clarify the role of the catalyst structure, we also tained, favouring the (R,R)-configured isomers. In
checked, in addition to I and II, bifunctional thioureas particular, for the use of b-aryl nitroolefins, the posi-
III and IV as well as Cinchona-squaramide V and di- tion and the electronic properties of the aromatic ring
hydroquinidine VI. Catalysts IV, V, and VI proved to- substituent did not alter the reaction performance sig-
tally unproductive, while Takemotoꢂs catalyst III re- nificantly and, regardless of their nature, be the neu-
sulted in very low conversion with only trace amount tral, electron-withdrawing, or electron-donating
of adduct 3aa recovered. We then performed a solvent groups, good yields and excellent enantioselectivities
screening, and the best results in terms of balance be- were uniformly attained. Nitroolefins bearing elec-
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Direct Regio-, Diastereo-, and Enantioselective Vinylogous Michael Addition
Table 1. Generality of the reaction with respect to the nitroolefin acceptor.[a]
Entry
R (2)
Product (3)
Yield [%][b]
dr[c]
er[d,e]
1
2
3
4
5
6
7
8
Ph (2a)
3aa
3ab
3ac
3ad
3ae
3af
97
88
98
92
96
97
94
97
95:5
99.9:0.1 (98.5:1.5)
99.9:0.1 (98.5:0.5)
99.9:0.1 (97.0:3.0)
99.0:1.0 (98.5:1.5)
99.5:0.5[f] (98.5:1.5)[f]
99.9:0.1 (99.7:0.3)
99.0:1.0 (98.0:2.0)
99.0:1.0 (83.0:17.0)
4-BrC6H4 (2b)
4-MeOC6H4 (2c)
2-FC6H4 (2d)
C6F5 (2e)
4-MeC6H4 (2f)
3,5-(MeO)2C6H3 (2g)
2-furyl (2h)
80:20
80:20
82:18
78:22
75:25
80:20
88:12
3ag
3ah
[a]
Unless otherwise specified, reactions were carried out using oxindole 1a (0.19 mmol) and nitroolefins 2a–h (0.19 mmol)
in toluene (950 mL) with 10 mol% catalyst I (or II) at room temperature (18–208C) for 24 h.
Yield of isolated 3 after chromatography.
[b]
[c]
1
The anti:syn diastereomeric ratio was determined by integration of key signals in the H NMR spectra of the reaction
crude. No E-configured isomers or a-addition adducts were detected.
Values in parentheses refer to reactions with catalyst II, with S,S-isomers as the major products.
Determined by HPLC analysis using a stationary phase chiral column, for the major isomers.
Determined on N-deprotected products.
[d]
[e]
[f]
tron-rich heteroaromatic groups, like 2-furyl deriva- this asymmetric transformation, and afforded the cor-
tive 2h, also afforded the desired product with superb responding adduct 3fa with good results in terms of
enantio- and geometry control and with a 88:12
anti:syn isomeric ratio. Interestingly, the reaction of
1a with 2a proved to be equally reliable on
a 1.0 mmol scale, returning the product 3aa in 98%
yield, 95:5 dr, and 99.9:0.1 er.
Since the reactions could not be initiated by achiral
amine catalysts, like Et3N, DABCO, or pyrrolidine, all
reactions were performed with equal success with
both catalysts I and II, to obtain racemates of the
products for use in the er measurements.
Disappointingly, alkyl nitroolefins such as b-cyclo-
hexyl- and b-n-hexyl-1-nitroethenes, which have
a modest repute as Michael acceptors under similar
reaction conditions, did not give any clean conversion,
even when forcing conditions or different catalysts
III–VI were employed.[5]
Variation of the alkylidene donor was then sur-
veyed in reactions with olefin 2a (Figure 1). The pres-
ence of different indole substrates was compatible
with this vinylogous reaction. Indolinones 1a and 1b,
as well as benzo-ring substituted congeners 1c, 1d,
and 1e were found to be competent substrates, and re-
turned the expected g-substituted Michael adducts
Figure 1. Products of the reactions with various indole sub-
3aa and 3ba, as well as 3ca, 3da, and 3ea in high
strates. Reactions were performed with 10 mol% catalyst I
yields, with moderate to good dr and excellent er
(or II). For all products site-selectivity (g/a) was >99:1 and
values, and with the same sense of stereoinduction as
dictated by the Cinchona catalyst employed.
the geometry selectivity (Z/E or E /Z) was >99:1. Values in
parentheses (er) refer to reactions with catalyst II, with S,S-
isomers as the major products. For conditions and details,
Alkylidene derivative 1f bearing a phenyl group at
the b-position could also be productively engaged in see Table 1 and the Supporting Information.
Adv. Synth. Catal. 2013, 355, 1881 – 1886
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Gloria Rassu et al.
UPDATES
yield, enantioselectivity, and geometry control, albeit
with modest diastereoselectivity (ca. 2:1 anti/syn
ratio). The diminished diastereoselectivity for unsym-
metrical oxindole 1f could likely be ascribed to poor
geometry control during the generation of the active
dienolate by means of the catalyst employed, with
both Z,Z- and Z,E-disposed dienolates competitively
involved. That is, the ratio between the Z,Z- and Z,E
dienolates would determine the anti/syn ratio of the
products. As subjecting the major and minor stereo-
isomers of 3fa to the reaction conditions did not
result in any interconversion or epimerization, the
low dr observed with this oxindole cannot be ascribed
to thermodynamic equilibration of the products.
Protection-free NH oxindoles, as well as oxindoles
having alkyl, allyl, or benzyl groups on the nitrogen
did not exhibit any sign of reactivity toward the
model substrates; and this suggests that a proper N-
substituent able to engender a supplementary anchor-
age to the catalyst through hydrogen bonding is cru-
cial for these organocatalytic conditions (vide infra).[6]
The relative and absolute configuration of 3ab,
bearing a heavy atom substituent, was unambiguously
determined as 3Z,2’R,3’R[7] by resonant-scattering X-
ray crystallographic analysis (Figure 2, top),[8] while
that of ent-3ac, which was obtained with catalyst II,
revealed the same 3Z-2’,3’-anti topology and, argua-
bly,
a
2’S,3’S absolute configuration (Figure 2,
bottom).[9,10] The geometry of the exocyclic olefin link-
ages in both major and minor isomers was further cor-
roborated by 2D NOESY NMR experiments (see Fig-
ure S3 in the Supporting Information). Assuming
a uniform stereochemical outcome of the reactions,
the configuration of the other Michael adducts in
Table 1 and Figure 1 were assigned by analogy.
To explain the stereochemical outcome of this vi-
nylogous addition, a plausible mechanistic pathway
was proposed, taking into account the observed ste-
Figure 2. Relative and absolute stereochemistry of bromi-
nated product 3ab (top) and relative stereochemistry of ent-
3ac (bottom) as determined by single crystal X-ray analyses.
reoselectivity of the reactions and capitalizing on pre- HOMO-raising activation and the nitroolefin acceptor
vious proposals for Cinchona catalysts-promoted acti- via LUMO-lowering.[12]
vation models, as well as theoretical calculations for
similar transformations (Figure 3).
Also, reactants are positioned in close spatial prox-
imity within a chiral pocket, and this facilitates the vi-
According to the general pathway proposed by nylogous addition step along the Si,Re-face trajectory,
Takemoto et al.,[4a,11] it is postulated that initial inter- through which (3Z,2’R,3’R)-configured (R2 =alkyl), or
action of the quinuclidine base of the Cinchona cata- (3E,2’R,3’R)-configured (R2 =aryl)[13] oxindole prod-
lyst with the oxindole pronucleophile, followed by de- ucts preferentially form. Moreover, the preferred 1’Z-
protonation at the g-methylene site, leads to the for- geometry of the dienolate, which dictates the 2’,3’-
mation of the active dienolate species, which prefer- anti-diastereoselectivity of the products, is likely due
entially reacts in s-cis conformation and with a 2Z,1’Z to a favourable steric disposition of the R2 and R3
geometry. The nucleophile is bonded to the protonat- substituents, as opposed to steric congestion of 1’E-
ed base via bidentate H-bonding, with both the hy- configured dienolates (see Figure 3). This behaviour is
droxy anion and N-carbamoyl groups involved. Mean- in keeping with the experimental results.
while, the nitroalkene acceptor is recognized by the
Alternative dual activation channels cannot, howev-
thiourea moiety of the catalyst through double H- er, in principle be excluded. As recently proposed by
bond interaction with its nitro functionality. In such Wang et al. for similar Cinchona-thiourea-catalyzed
a manner, the two reactants are independently, yet transformations,[14] nucleophile activation is the result
synergistically activated: the indole donor via of dual H-bonding to both the protonated quinucli-
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Direct Regio-, Diastereo-, and Enantioselective Vinylogous Michael Addition
ers involved in organic synthesis and pharmaceutical
chemistry disciplines.
Experimental Section
General Comments
Survey of catalysts and conditions, compound characteriza-
tion data of products 1 and 3, HPLC traces, stereochemical
assessment, and copies of 1H and 13C NMR spectra are
given in the Supporting Information.
Representative Procedure. Synthesis of (Z)-1-
Methoxycarbonyl-3-[(4R,5R)-4-methyl-6-nitro-5-
phenylhexan-3-ylidene)indolin-2-one (3aa)
To a solution of oxindole 1a (50 mg, 0.19 mmol) and nitro-
styrene 2a (28 mg, 0.19 mmol) in toluene (950 mL) at room
temperature (18–208C), was added thiourea-catalyst
I
(11 mg, 0.019 mmol). The reaction mixture was kept under
vigorous stirring at room temperature for 24 h. The reaction
mixture was then concentrated in vacuum and the crude ma-
terial was purified by silica gel flash chromatography (80:20
petroleum ether/EtOAc) to afford pure (3Z,4’R,5’R)-3aa as
white crystals; yield: 71 mg (92%) ; mp 166–1678C; [a]2D0:
+249.2 (c 1.0, CHCl3). Chiral HPLC (Chiralcel OD-H,
hexane/EtOH 90:10, 1.0 mLminÀ1, 254 nm): Rt 11.16 min
(99.9:0.1 er).
Minor isomer (3Z,4’S,5’R)-3aa’ was obtained as a colorless
glass; yield: 3.9 mg (5%); [a]2D0: +72.4 (c 0.9, CHCl3). Chiral
HPLC (Chiralcel OD-H, hexane/EtOH 90:10, 1.0 mLminÀ1,
254 nm); Rt 10.11 min (99.1:0.9 er).
Figure 3. Possible pathways for the dual activation mecha-
nism on the formation of the major and minor (2’R,3’R)-
and (2’S,3’R)-configured diastereomeric products. The s-cis
orientation of the indole dienolate dictates the geometry of
the olefin linkage of the oxindole products. Simple diaster-
eoselection (anti vs syn) is governed by the Z/E configura-
tion of the remote olefin of the reacting dienolate. Facial se-
lectivity is imparted by the catalyst environment.
dine nitrogen of the catalyst and one NH of the thio-
urea moiety, while the other thiourea NH activates
the nitroolefin via bifurcate H-bonding. According to
the proposal of Pꢃpai[15] and Zhong[16] instead, the nu-
cleophile is activated by the thiourea group of the cat-
alyst, while the protonated quinuclidine nitrogen en-
genders a bifurcate H-bonding with the nitroolefin. In
truth, an exact understanding of the mechanism of
the present vinylogous transformation via DFT calcu-
lations and NMR determinations is desirable, and this
issue is a current research theme in our laboratories.
In summary, to complement our previous results
with methyl-substituted alkylideneoxindoles,[3] we
have herein provided a limpid testimony to the
unique capability of enolizable 3-alkylideneoxindoles
to serve as pronucleophiles for the direct, asymmetric
vinylogous Michael addition to nitroolefins. With
prostereogenic oxindole substrates and employing the
consecrated bifunctional Cinchona alkaloid-based
Acknowledgements
We thank the Universitꢀ degli Studi di Parma and the Re-
gione Autonoma della Sardegna (L.R. 07.08.2007, n.7) for
funding. Thanks are due to Centro Interdipartimentale
Misure “G. Casnati” for instrumental facilities.
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Adv. Synth. Catal. 2013, 355, 1881 – 1886
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UPDATES
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