Direct catalytic enantioselective vinylogous aldol reaction of α-branched enals with isatins

Article abstract of DOI:10.1021/ol302711w

The direct vinylogous aldol reaction of α-substituted α,β-unsaturated aldehydes with isatins is described. The chemistry provides easy access to valuable 3-substituted 3-hydroxyoxindole derivatives with high stereocontrol and perfect γ-site selectivity. P

Full text of DOI:10.1021/ol302711w

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5590–5593
Direct Catalytic Enantioselective
Vinylogous Aldol Reaction of r‑Branched
Enals with Isatins
Carlo Cassani‡ and Paolo Melchiorre*,†,‡
ꢀ
´
ICREA - Institucio Catalana de Recerca i Estudis Avanc-ats, Pg. Lluıs Companys,
23 08010 Barcelona, Spain, and ICIQ - Institute of Chemical Research of Catalonia,
Av. Paısos Catalans 16, 43007 Tarragona, Spain
¨
pmelchiorre@iciq.es
Received October 2, 2012
ABSTRACT
The direct vinylogous aldol reaction of R-substituted R,β-unsaturated aldehydes with isatins is described. The chemistry provides easy access to
valuable 3-substituted 3-hydroxyoxindole derivatives with high stereocontrol and perfect γ-site selectivity. Preliminary mechanistic studies
suggest that, depending on the nature of the R-branched enal substituents, two divergent reaction mechanisms can be operating, leading to
different products and stereochemical outcomes.
The aldol reaction is one of the most powerful CꢀC
bond-forming technologies in the synthetic repertoire.1 Its
synthetic power has been increased recently by its success-
ful marriage to the principle of vinylogy.2 The vinylogous
aldol reaction3 uses R-enolizable R,β-unsaturated carbonyl
substrates as “extended dienolates” to directly construct
densely adorned δ-hydroxylated R,β-unsaturated carbo-
nyls. These functional arrays are common structural mo-
tifs in biologically relevant natural molecules, in particular
within polyketide structures.4 This has provided the im-
petus for developing highly stereoselective, catalytic, viny-
logous aldol reactions,4 their direct application in the total
synthesis of natural products attesting to their utility.5
These methods mainly rely upon indirect Mukayama-type
strategies, which require the preformation of stable dieno-
late equivalents.
The direct in situ activation of unmodified carbonyl
substrates has recently been recognized as the ultimate
goal in further expanding the synthetic potential and atom
economy of this chemical transformation. Despite recent
advances in direct addition procedures, only cyclic com-
pounds, i.e. 2(5H)-furanone derivatives, have found appli-
cation in asymmetric catalytic vinylogous aldol processes.6
In contrast, the use of acyclic unsaturated carbonyls is to
date limited to a single strategy where the direct vinylogous
‡ ICIQ.
† ICREA.
€
(5) For a review: (a) Brodmann, T.; Lorenz, M.; Schackel, R.;
(1) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Berlin,
2004.
Simsek, S.; Kalesse, M. Synlett 2009, 174. For selected examples: (b)
Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127, 8971. (c)
Nicolaou, K. C.; Guduru, R.; Sun, Y.-P.; Banerji, B.; Chen, D. Y.-K.
Angew. Chem., Int. Ed. 2007, 46, 5896.
(6) (a) Ube, H.; Shimada, N.; Terada, M. Angew. Chem., Int. Ed.
2010, 49, 1858. (b) Luo, J.; Wang, H.; Han, X.; Kwiatkowski, J.; Huang,
K.-W.; Lu, Y. Angew. Chem., Int. Ed. 2011, 50, 1861.
(2) Fuson, R. C. Chem. Rev. 1935, 16, 1.
(3) For a comprehensive review, see: Casiraghi, G.; Battistini, L.;
Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076.
(4) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew.
Chem., Int. Ed. 2005, 44, 4682.
r
10.1021/ol302711w
Published on Web 10/18/2012
2012 American Chemical Society

aldol reaction is integrated at the beginning of a cascade
sequence, the aldol step being followed by an intramole-
cular oxa-Michael reaction.7 Herein, we describe the suc-
cessful realization of a discrete vinylogous aldol reaction
with an unmodified acyclic unsaturated carbonyl substrate
that is not implemented within a cascade sequence. Wehave
found that R-substituted enals 2 directly react with isatins 1
upon in situ activation by a chiral secondary amine catalyst
through dienamine formation. The chemistry secures direct
access to products 3 with high stereocontrol and perfect
γ-site selectivity. Notably, these are complex scaffolds, in
which two biologically relevant molecular elements are
combined: a δ-hydroxyl-R,γ-dialkyl-R,β-unsaturated unit8
linked to an oxindole framework.9
Table 1. Development of the Direct Vinylogous Aldolization of
R-Branched Enals with Isatinsa
Our initial investigations focused on the addition of
(E)-2-methylpent-2-enal 2a to N-benzyl protected isatin
1a (Table 1). The choice of the model reaction was moti-
vated by our interest in devising versatile strategies for
stereoselectivelyaccessing3-substituted3-hydroxyoxindole
derivatives10 and our previous experiences with vinylogous
reactivity.11 We have recently established how the cincho-
na-based primary amine catalysts A and B12 can induce
vinylogous nucleophilicity within a substitution reaction
manifold. They can activate R-substituted enals 2 toward
an SN1-type γ-alkylation pathway by means of a transi-
ently generated dienamine intermediate.11a This persuaded
us to test these primary amine catalysts in the aldol
addition reaction. Despite extensive efforts, we have not
succeeded in translating the R-branched enal/cinchona-
based catalyst system to the vinylogous aldol process. The
use of 20 mol % of catalyst A or B led to 3a as the unique
product, but with a poor stereocontrol (entries 1 and 2
in Table 1). The quest for a more stereoselective system
prompted us to undertake an extensive catalyst screening
(details given in Tables S1ꢀS2). This led to an unexpected
conv
(%)b
ee
entry amine
acid
TFA
solvent
CHCl3
drb
6:1
(%)c
1
A
B
C
E
C
D
D
D
D
D
D
42
<5
42
40
ꢀ
2
TFA
BA
ꢀ
CHCl3
67
2.8:1
1:1
3
toluene
CH2Cl2
EtOH
35
4d
5
<5
ꢀ
BA
BA
BA
BA
BA
>95
>95
>95
30
1.2:1
1.2:1
1.4:1
3:1
75
83
89
92
92
91
90
6
EtOH
7e
8e
9e
10e
11e,g
EtOH
MeCN
MeCN/EtOHf
49
2.7:1
3.2:1
3.2:1
CF3-BA MeCN/EtOHf
CF3-BA MeCN/EtOHf
59
87f
a BA: benzoic acid; CF3-BA: 2,6-bis(trifluoromethyl)benzoic acid.
Catalyst A and B were used with 2 equiv of TFA, while C and D required
a 1:1 combination with the acid. Reactions on a 0.05 mmol scale using
2 equiv of 2a. b Both conversion and dr were determined by H NMR
1
analysis of the crude reaction mixture. c Ee value of the major diaster-
eomer, as determined by HPLC analysis. d 1 equiv of N,N-diethylaceta-
mide (DEA) was used to improve the solubility of E (see ref 15). Reaction
conducted with [1a]0 = 0.25 M and adding 2.8 equiv of H2O. e Reaction
at 25 °C. f Reaction in a 9:1 MeCN/EtOH mixture. g 10 mol % of amine
D and of CF3-BA. Reaction time: 40 h; [1a]0 = 2 M. Yield value refers to
the isolated compound after chromatography.
(7) Liu, K.; Chougnet, A.; Woggon, W.-D. Angew. Chem., Int. Ed.
2008, 120, 5911.
observation: the commercially available diphenylprolinol
silyl ether C13 could indeed catalyze the vinylogous aldol
process (entry 3). This stands in contrast to the catalytic
profiles of secondary amines that are generally unable to
efficiently activate sterically hindered carbonyl compounds,
such as R,β-disubstituted enal of type 2a.14 Interestingly, the
bifunctional squaramide-based aminocatalyst E did not
promote the model vinylogous aldol reaction.15
Despite the moderate level of stereoselectivity initially
achieved with catalyst C, we were encouraged by the un-
anticipated power of secondary amine catalysistodirectthe
reaction manifold toward a γ-site selective aldolization
through dienamine activation of R-branched enals.16 Ex-
amination of the reaction media revealed that the catalytic
process was greatly influenced by polarity, with solvents
(8) Previous asymmetric methods toassemble this molecular unit were
based on Evans’ chiral auxiliary-derived vinylogous Mukaiyama aldol
reactions: Shirokawa, S.-I.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604. For
applications to the synthesis of natural products, see ref 5c.
(9) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003.
(10) (a) Bergonzini, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2012,
51, 971. (b) Retini, M.; Bergonzini, G.; Melchiorre, P. Chem. Commun.
2012, 48, 3336.
(11) (a) Bergonzini, G.; Vera, S.; Melchiorre, P. Angew. Chem., Int. Ed.
2010, 49, 9685. (b) Bencivenni, G.; Galzerano, P.; Mazzanti, A.; Bartoli,
G.; Melchiorre, P. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20642. (c) Tian,
X.; Liu, Y.; Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 6439.
(12) Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748.
(13) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen,
K. A. Acc. Chem. Res. 2012, 45, 248.
(14) The activation of R-branched enals generally requires chiral
primary amines; see: (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc.
2005, 127, 10504. (b) Galzerano, P.; Pesciaioli, F.; Mazzanti, A.; Bartoli,
G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7892. Chiral
secondary amines have found limited applications only in the iminium
ion activation of highly reactive R-branched acroleins; see: (c) Kano, T.;
Tanaka, Y.; Osawa, K.; Yurino, T.; Maruoka, K. Chem. Commun. 2009,
45, 1956. (d) Bondzic, B. P.; Urushima, T.; Ishikawa, H.; Hayashi, Y.
Org. Lett. 2010, 12, 5434. For the sole examples dealing with the
iminium ion activation of R,β-disubstituted enals, see: (e) Deiana, L.;
Dziedzic, P.; Vesely, J.; Ibrahem, I.; Rios, R.; Sun, J.; Cordova, A.
Chem.;Eur. J. 2011, 17, 7904. (f) E.-M. Tanzer, E.-M.; Zimmer, L. E.;
Schweizer, W. B.; Gilmour, R. Chem.;Eur. J. 2012, 18, 11334.
(15) Albrecht, Ł.; Dickmeiss, G.; Cruz Acosta, F.; Rodrıguez-Escrich,
C.; Davis, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134, 2543.
(16) An analog of catalyst C (the 3,5-trifluoromethyl aryl substituted
derivative) has been used to promote the asymmetric γ-amination of
linear unsubstituted enals via dienamine activation; see: Bertelsen, S.;
ꢀ
Marigo, M.; Brandes, S.; Diner, P.; Jørgensen, K. A. J. Am. Chem. Soc.
2006, 128, 12973. It was proposed that this reaction proceeded through a
peculiar pericyclic mechanism.
Org. Lett., Vol. 14, No. 21, 2012
5591

Table 2. Scope of the Direct Vinylogous Aldolizationa
Scheme 1. ORTEP Drawing at 50% Probability18
yield
(%)b
ee
(%)d
entry
R1
R2
R3
R4
3
drc
1
Me
Bn
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Br
a
87(47) 3.2:1 90(76)
2
H
H
H
H
H
b
c
d
e
f
68
89
63
65
28f
92
2.5:1 95(77)
1.6:1 94(70)
3:1 94(74)
1.5:1 90(78)
1.5:1 94
3
CH2-SMe
4
CH2NHCbz Me
5e
6e
7
Bn
Et
Bn
Et
derivatives 1, different substitution patterns were well-toler-
ated, regardless of their electronic properties (entries 7ꢀ14).
Although the vinylogous aldolization proceeds with poor to
moderate control over the relative configuration, it is possible
to easily isolate, by simple chromatography, the two diaster-
eoisomers upon simple NaBH4 reduction of adducts 3. This
testifies to the synthetic utility of the process. Proof-of-
concept has been provided for the alcohol derivatives ob-
tained from 3a, 3h, and 3j (entries 1, 8, and 10). The absolute
and relative configuration for the major diastereoisomer of
compound 3h was determined by anomalous dispersion
X-ray crystallographic analysis: an (S) absolute configura-
tion at the newly formed γ-stereocenter was inferred.18
We then carried out further explorations to fully deline-
ate the reaction scope. Unexpectedly, the presence of an
aryl substituent at the R-branched enal position led to a
different product distribution. As depicted in Scheme 1a,
reacting (E)-2-phenylpent-2-enal 2b with isatin 1b in to-
luene in the presenceof catalyst C gave rise to the formation
of the spirooxindole lactol 4b. Despite the moderate level of
relative stereocontrol (2.3:1 ratio), both diastereoisomers
were formed in enantiomerically pure form and isolated as
a single stereoisomer after chromatography. Simple oxida-
tion of the minor (2S,3R)-4b isomer granted access to the
spirooxindole dihydropyran-2-one 5b (Scheme 1b). X-ray
analyses18 established an (R) absolute configuration at the
γ-stereocenter for both the diastereomeric products 4b, in
contrast with the stereochemistry observed in products 3.
Intrigued by these observations, we carried out preli-
minary mechanistic investigations to understand the
origin of the divergent pathways, which led to different
products and opposite stereochemical outcomes. We used
NMR spectroscopic analyses to gain information on the
conformational behavior of the dienamine intermediate I
(Figure 1a). When mixing the aminocatalyst C with enal 2a
or 2b(bearing a methyl or a phenylR-branched substituent,
respectively) in toluene-d8 and in the presence of 4 A
molecular sieves, the corresponding dienamine intermedi-
ate I was formed (see Figures S1ꢀS10 for details). Inter-
estingly, the nature of the R-branched substituent did not
alter the conformational preference of I, as the s-trans
Me
Bn
Me
Me
Me
Me
Me
Me
Me Cl
g
h
i
1.7:1 86(73)
8
Me Cl
69(35) 1.6:1 92(78)
68 1.9:1 85(78)
76(44) 3.8:1 92(81)
9
Me Br
10
11
12
13
14
Me Me
Me NO2
Me CF3O
Me Me
j
k
l
87
71
65
88
1.5:1 87(75)
2.9:1 89(63)
3.9:1 91(77)
2.4:1 92(71)
m
n
Me
H
a Reactions performed on a 0.2 mmol scale using 2 equiv of 2. E/Z ratio
of 2: >95:5; no double bond scrambling was observed during the catalytic
reaction. Only the (E)-isomer of the aldol products 3 was detected. b Yield
of the isolated product 3 after chromatographic purification on silica gel.
Values between brackets (entries 1, 8, 10) refer to the yield of the isolated
major diastereomer of the alcohols obtained after NaBH4 reduction of
compounds 3. c Determined by 1H NMR of the crude mixture. d Ee value of
the major diastereomer, as determined by HPLC analysis. Values between
brackets refer to the ee’s of the minor diastereomers of 3. e 20 mol % of
catalyst D was used. f Yield of the isolated major diastereomer of 3f.
with a high dielectric constant strongly increasing both
reactivity and stereoselectivity (entries 5ꢀ8). Gratifyingly,
the stereocontrol was also sensitive to catalyst structural
modifications, the bulkier silyl protective group of catalyst
D leading to a significant improvement (compare entries 5
and 6).17 A second cycle of optimization using catalyst D
established a 9:1 acetonitrile/ethanol mixture as the best
reaction medium, while revealing that the nature of the
acidic additives was also crucial for modulating catalyst
efficiency(entries 9 and 10). The use ofa 1:1 combination of
amine D (10 mol %) and 2,6-bis(trifluoromethyl) benzoic
acidand amoreconcentratedreaction system ([1a]0 =2M)
provided the product 3a with synthetically useful results
over a 40-h reaction time and at rt (entry 11: 3a isolated in
87% yield, 3.2:1 dr, and 90% ee). These conditions were
selected to evaluate the scope of the vinylogous aldol process.
As reported in Table 2, different substituents, including
heteroatom-containing moieties, can be accommodated at
the enal γ-position without affecting the site selectivity,
while slightly increasing the enantioselectivity of the viny-
logous aldol process (ee up to 95%, entries 2ꢀ4). More
encumbered aliphatic substituents in the R-position are
well-tolerated (entries 5ꢀ6). Concerning the scope of isatin
(18) Crystallographic data for compounds 3h, (2R,3R)-4b, (2S,3R)-
5b, and 7 are available free of charge from the Cambridge Crystal-
lographic Data Centre, accession numbers CCDC 885390, CCDC
885391, CCDC 885392, and CCDC 885695, respectively.
ꢁ
(17) Groselj, U.; Seebach, D.; Badine, D. M.; Schweizer, W. B.; Beck,
A. K.; Krossing, I.; Klose, P.; Hayashi, Y.; Uchimaru, T. Helv. Chim.
Acta 2009, 92, 1225.
5592
Org. Lett., Vol. 14, No. 21, 2012

Table 3. HDA-Type Reaction To Access Spiroxindolesa
yield (%)b
ee (%)d
entry R1
Ar
R2
4
major/minor drc major/minor
1
Me Ph
H
a
b
c
d
e
f
45/22
47/18
63/19
45/31
36/ꢀ
2.2:1
2.3:1
3.0:1
1.3:1
2.2:1
3.2:1
99/99
99/98
99/98
99/97
99/ꢀ
2
Me Ph
Me Ph
Me Ph
Et Ph
Cl
3e
4e
5e
6e
Me
NO2
H
Me 4-Cl-C6H4
H
69/22
99/98
a Reactions performed on a 0.2 mmol scale using 2 equiv of 2. E/Z
ratio of 2: >95:5; no double bond scrambling was observed under the
reaction conditions. b Yield of the isolated diastereomerically pure
compounds (2R,3R)-4 and (2S,3R)-4, which can be separated by chro-
matography. c Determined by 1H NMR analysis. d Determined by
HPLC analysis. e 20 mol % of C.
Figure 1. Mechanistic investigations.
Although an extensive mechanistic investigation is still
needed, some preliminary interpretation is possible. The
initial observations are in agreement with a hetero-Dielsꢀ
Alder (HDA) process being operative with enal 2b, bearing
a phenyl R-substituent. A simple rotation around the CꢀC
single bond of dienamine I16 would produce intermediate II,
having the required s-cis geometry to engage in a pericyclic
path (Figure 1d). The HDA process with isatin would result
in the labile hemiaminal ether intermediate III, which can
easily hydrolyze to the lactol product 4 while releasing the
catalyst C. It is to be noted that the stable cyclic adduct 7 in
Figure 1b is not amenable to this hydrolysis event.
The HDA-type reaction of R-aryl substituted enals and
isatins provides direct access to valuable spirocyclic oxindole
scaffolds, which are found in a large number of natural and
unnatural compounds.9 We therefore explored the synthetic
potential of this catalytic asymmetric approach. As reported
in Table 3, the reactions proceed readily at rt, and quanti-
tative conversion is obtained at convenient reaction times.
Both the diastereoisomers of the spirolactols 4 can be
individually isolated in almost enantiomerically pure form.
This work offers a rare example of a discrete catalytic
and enantioselective vinylogous aldol reaction of an un-
modified acyclic unsaturated carbonyl substrate.
dienamine with the same geometry of the two double bonds
is the more stable species in both cases. The classical “steric
control approach” generally invoked to rationalize the
stereochemical outcome of a process catalyzed by C13
is consistent with the sense of asymmetric induction ob-
served when using an R-alkyl substituted enal of type 2a
(chemistry reported in Table 2). Indeed, the efficient shield-
ing by the chiral fragment in C determines the selective
engagement of the isatin 1 with the Si face of the dienamine
intermediate I (Figure 1a). In contrast, this model, which is
based on the direct addition of isatin from the unshielded
face of I, cannot account for the (R)-absolute configuration
of the γ-stereocenter observed for products 4.
The striking difference in the stereochemistry between
products 3 and 4, in spite of the similar ground state thermo-
dynamic stability of the intermediates I, led us to consider that
a mechanistically distinct pathway may be operative for enal
2b. In analogy with related studies by Jørgensen and collea-
gues on the γ-functionalization of linear enals via dienamine
activation,16 we envisaged a pericyclic [4 þ 2] cycloaddition
pathway. To test this hypothesis, the two different enal
substrates 2a and 2b were individually mixed with the catalyst
Cand the nitrostyrene derivative 6, a dienophile that can react
in concerted pericyclic processes catalyzed by amine C.19
While the enal bearing a methyl substituent remained totally
unreacted (Figure 1c), aldehyde 2b led to the fast and
quantitative formation of the DielsꢀAlder-type product 7
with perfect stereocontrol (Figure 1b).20 After chromato-
graphic purification, the cyclic adduct 7 was characterized by
X-ray crystallographic analysis.18
Acknowledgment. Research support from the ICIQ
Foundation, MICINN (Grant CTQ2010-15513), and the
European Research Council (Starting Grant no. 278541;
ORGA-NAUT to P.M.) is gratefully acknowledged.
Supporting Information Available. Complete experi-
mental procedures, compound characterization, HPLC
traces, and NMR spectra (PDF). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(19) (a) Talavera, G.; Reyes, E.; Vicario, J. L.; Carillo, L. Angew.
Chem., Int. Ed. 2012, 51, 4104. (b) Liu, Y.; Nappi, M.; Arceo, E.; Vera,
S.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212.
(20) The presence of a phenyl substituent raises the HOMO energy of
electron-rich dienes; see: Sustmann, R. Pure Appl. Chem. 1974, 40, 569.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5593