Asymmetric vinylogous diels-alder reactions catalyzed by a chiral phosphoric acid

Article abstract of DOI:10.1002/anie.201310487

An unprecedented way to extend the synthetic utility of the Diels-Alder reaction to include a vinylogous reactivity space is described. A commercially available chiral phosphoric acid catalyst effectively activates cyclic 2,4-dienones towards a vinylogous [4+2] cycloaddition with 2-vinylindoles, which leads to stereochemically dense tetrahydrocarbazoles. The reaction proceeds with a high level of remote stereocontrol and exclusive chemoselectivity for the more distant double bond of the dienone.

Full text of DOI:10.1002/anie.201310487

Angewandte
Chemie
DOI: 10.1002/anie.201310487
Synthetic Methods
Asymmetric Vinylogous Diels–Alder Reactions Catalyzed by a Chiral
Phosphoric Acid**
Xu Tian, Nora Hofmann, and Paolo Melchiorre*
Abstract: An unprecedented way to extend the synthetic utility
of the Diels–Alder reaction to include a vinylogous reactivity
space is described. A commercially available chiral phosphoric
acid catalyst effectively activates cyclic 2,4-dienones towards
a vinylogous [4+2] cycloaddition with 2-vinylindoles, which
leads to stereochemically dense tetrahydrocarbazoles. The
reaction proceeds with a high level of remote stereocontrol
and exclusive chemoselectivity for the more distant double
bond of the dienone.
Figure 1. Design of a Brønsted acid catalyzed asymmetric vinylogous
Diels–Alder reaction.
T
he Diels–Alder (DA) reaction is among the most powerful
methods for the rapid and predictable construction of
stereochemically dense cyclohexenyl rings.[1] Research that
is aimed at further expanding the synthetic potential of the
DA approach is still fascinating the chemical community.
Avenues for new progress have mainly been provided by the
emergence of asymmetric catalytic variants[2] and the desire to
identify unprecedented diene–dienophile combinations. In
contrast, the use of DA chemistry to stereoselectively shape
the reactivity space that is remote from the catalyst point of
action has remained largely underdeveloped.[3] This is prob-
ably due to the inherent difficulties of achieving remote
stereoinduction, as a close spatial contact between the chiral
catalyst and the reaction site is generally required.[4] Herein,
we describe an effective method to carry out a catalytic
vinylogous DA reaction with high control over the remote
stereochemistry. This transformation relies upon the LUMO-
lowering activation of the more distant double bond of
a,b,g,d-unsaturated cyclic ketones 1 (Figure 1). Specifically,
we used chiral Brønsted acid catalysis[5] to increase the
tendency of the distant g,d-olefinic moiety in 1 to react as
a chiral dienophile, an activation principle that has never
served to induce vinylogous reactivity to date. The reaction
with 2-vinylindoles 2, which can readily participate in [4+2]
cycloaddition processes as electron-rich dienes,[6] allowed the
direct synthesis of stereochemically dense tetrahydrocarba-
zoles 3[7] with very high regio-, diastereo-, and enantioselec-
tivity.
We began our investigations by examining the reaction
between cyclic 2,4-dienone 1a and styryl-1H-indole 2a
(Table 1). The choice of substrates was based on our previous
experiences with vinylogous reactivity.[8] We recently estab-
lished that cinchona-alkaloid-based primary amines of
type A[9] can condense with b-substituted cyclic dienones 1,
which facilitates the formation of an extended iminium ion
intermediate while lowering the LUMO energy level of the
distant unsaturated p system. The resulting activated vinyl-
ogous iminium ion activation allowed for d-site-selective and
enantioselective nucleophilic 1,6-additions[8a] and vinylogous
cascade transformations to be realized.[8b] As the same
activation principle underlies the Diels–Alder chemistry, we
tested the ability of quinidine derivative A to catalyze this
model reaction in an asymmetric vinylogous fashion (entries 1
and 2). Unfortunately, this catalytic system was ineffective,
and provided the desired product 3a only with poor yield and
stereoinduction. However, the vinylogous DA reaction is
amenable not only to aminocatalysis, but also to a different
activation mode. We found that a Brønsted acid[10] could
promote the reaction by effectively activating the carbonyl
moiety of dienone 1a.[5] An array of chiral 1,1’-bi-2-naphthol
(BINOL)-derived phosphoric acids[11] were screened as
catalysts for the model reaction. Commercially available 4d
was the best catalyst, as its use led to the formation of product
3a with complete control over the relative configuration and
94% ee (entry 6).[12] The more acidic[13] chiral phosphor-
amide 4e[10a] induced an appreciable level of stereo- and
regioselectivity, but could not parallel the efficacy of 4d
(entry 7). A control experiment confirmed that the Brønsted
acid catalyst is needed for the DA reaction to occur (entry 8),
[*] Prof. Dr. P. Melchiorre
ICREA—Instituciꢀ Catalana de Recerca i Estudis AvanÅats
Passeig Lluꢁs Companys 23, 08010 Barcelona (Spain)
X. Tian, Dr. N. Hofmann, Prof. Dr. P. Melchiorre
ICIQ—Institute of Chemical Research of Catalonia
Avenida Paꢂsos Catalans 16, 43007 Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.es/portal/862/default.aspx
[**] Research support from the Institute of Chemical Research of
Catalonia (ICIQ) Foundation and the European Research Council
(ERC Starting Grant 278541 “ORGA-NAUT” to P.M.) is gratefully
acknowledged. N.H. is grateful to the German Academic Exchange
Service (DAAD) for a postdoctoral fellowship. We thank E.
Escudero-Adꢃn (X-ray Diffraction Unit, ICIQ) for determining the
structure of compound 3e.
À
while protection of the N H indole moiety in 2 greatly
decreased the stereoselectivity of the process (entry 9).
Mechanistically, the last result is consistent with a specific
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310487.
Angew. Chem. Int. Ed. 2014, 53, 2997 –3000
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2997

.
Angewandte
Communications
Table 1: Explorative studies.[a]
Table 2: Scope of the vinylogous DA reaction: variation of the cyclic 2,4-
dienone.[a]
Conv.[b] [%]
d.r.[c]
ee[d] [%]
Entry
R
n
3
Yield[b] [%]
ee[c] [%]
Entry
Catalyst
R
1[d]
2
3
Ph
1
1
1
1
1
1
1
1
1
0
3a
3b
3c
3d
3e
3 f
3g
3h
3i
86
70
84
78
80
86
63
78
85
60
97
92
92
92
93
92
90
88
89
91
1[e]
2[e]
3
4
5
6
7
8
A
A
H
Me
H
H
H
H
H
H
Me
H
<5
55
20
40
<5
74
n.d.
1:1
>20:1
>20:1
n.d.
>20:1
>20:1
n.d.
n.d.
27
77
79
n.d.
94
81
n.d.
5
4-F-C6H4
4-Cl-C6H4
3-Cl-C6H4
2-Br-C6H4
4-Me-C6H4
4-MeO-C6H4
3-furyl
4a
4b
4c
4d
4e
–
4
5[e]
6
7[f]
8
67
<5
55
9
10
Me
Ph
9
4d
4d
2:1
>20:1
10[f]
88[g]
94
3j
[a] Reactions performed in air, without any precautions to exclude
moisture, on a 0.1 mmol scale with 2a (1.5 equiv). For all of the
reactions, a d.r. of >20:1 was inferred by 1H NMR analysis of the crude
reaction mixture. [b] Yield of isolated 3 after purification by column
chromatography. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] 1 mmol scale. [e] 4d (10 mol%). [f] 72 h.
[a] Reactions performed on a 0.05 mmol scale for 16 h with a catalyst
(10 mol%), 2a or 2a’ (1.2 equiv), and [1a]0 =0.25m in PhMe. [b] Con-
version of 1a determined by 1H NMR analysis of the crude mixture using
1,3,5-trimethoxybenzene as the internal standard. [c] d.r. determined by
1H NMR analysis of the crude reaction mixture. [d] ee determined by
HPLC analysis on a chiral stationary phase. [e] Performed at 608C with A
(20 mol%) and TFA (30 mol%) as the acid co-catalyst. [f] 4d (5 mol%),
2a (1.5 equiv), [1a]0 =0.5m, 48 h. [g] Yield of isolated 3a. n.d.=not
determined, Tf=trifluoromethanesulfonyl, TFA=trifluoroacetic acid.
final product. Remarkably, this transformation can be
extended to include substrates that bear an aliphatic sub-
stituent (R = Me, entry 9). Furthermore, a five-membered
cyclic scaffold was a competent dienophile of this vinylogous
DA reaction, providing the corresponding cycloadduct 3j
with high stereocontrol and a slightly decreased chemical
yield (entry 10). As a limitation of this system, acyclic 2,4-
dienones did not react at all under the optimized reaction
conditions. From a synthetic standpoint, it is worth mention-
ing that for all of the reactions described in Table 2,
products 3 were selectively formed as single diastereomers
(complete control over the relative stereochemistry). Crystals
that were obtained for compound 3e (entry 5) were suitable
for X-ray crystallographic analysis. Thus, the stereochemical
outcome of the Diels–Alder reaction as well as the absolute
configurations of the three stereogenic centers could be
established.[14]
We then evaluated the generality of this transformation by
varying the structure of 2-vinylindole 2, which is the diene
component of the vinylogous DA reaction (Table 3). In
general, different substitution patterns on the aryl ring that is
attached to the exocyclic double bond (R1 = aryl) were well
tolerated (entries 1–5), although electron-withdrawing groups
required the use of 10 mol% of catalyst for synthetically
useful chemical yields (entries 1–3). The same behavior was
observed for electron-withdrawing or -donating groups at the
5-position of the indole core (entries 6–8), the latter being
more reactive towards the vinylogous cycloaddition pathway.
Importantly, the exocyclic double bond could also bear an
aliphatic substituent (R1 = Me; entry 9). In this case, a slightly
modified procedure was needed: The diene was added
portionwise to prevent a tandem homo-Diels–Alder cycliza-
tion/aromatization reaction of 2.[15] This experiment afforded
and crucial interaction between substrate 2 and the catalyst,
which productively adds to the acid-induced activation of the
enone (see below for further discussions).
During a second round of optimization it was found that
the use of 5 mol% of phosphoric acid 4d, a slight excess of 2a
(1.5 equiv), and stirring in toluene at 408C for 48 hours
provided adduct 3a with excellent conversion and selectivity
(entry 10; 88%, > 20:1 d.r., 94% ee). These reaction condi-
tions were thus chosen for evaluating the synthetic potential
and the generality of the vinylogous DA reaction. This
method is synthetically useful, as a slightly higher efficiency
was observed when running the model reaction on a 1 mmol
scale (Table 2, entry 1).
A wide range of substituents at the d-position of the
dienone are compatible with the catalytic system. Different
substitution patterns at the aromatic moiety were well
tolerated, regardless of the electronic properties of the
substituents, as the corresponding adducts 3 were obtained
in good yields and with enantioselectivities of ꢀ 90% ee
(entries 1–7). The synthesis of furyl derivative 3h (entry 8)
confirmed that a heteroaryl framework can be included in the
2998 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 2997 –3000

Angewandte
Chemie
Table 3: Scope of the vinylogous DA reaction: variation of the 2-
alkenylindole.[a]
Entry
R1
R2
3
Yield[b] [%]
ee[c] [%]
1[d,e]
2[d,e]
3[d]
4
4-Cl-C6H4
4-Br-C6H4
2-Br-C6H4
4-Me-C6H4
3,5-(MeO)2-C6H3
Ph
Ph
Ph
Me
H
H
H
H
H
Cl
Me
MeO
H
3k
3l
64
53
95
74
94
80
70
59
61
93
92
90
93
95
92
93
92
99
3m
3n
3o
3p
3q
3r
5
6[d,e]
7
8[e]
9[d,f]
3s
[a] Reactions performed on a 0.1 mmol scale using 2 (1.5 equiv). For all
of the reactions, a d.r. of >20:1 was inferred by 1H NMR analysis of the
crude reaction mixture. [b] Yield of isolated 3 after purification by column
chromatography. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] 4d (10 mol%). [e] 72 h. [f] Diene 2 was added portionwise to
the reaction mixture; using the standard procedure, 3s was isolated in
only 20% yield.
the corresponding adduct 3s with an excellent enantiomeric
excess (99% ee, > 20:1 d.r.).
Figure 2. a) NLE study. b) Proposed stereochemical model.
We then focused on the mechanism of the transformation.
As alluded to above, the decrease in stereoselectivity that is
À
observed when the N H group of diene 2 is protected
(Table 1, entry 9) could suggest the requirement for a key
interaction with the Brønsted basic (P = O) moiety of the
catalyst 4d, alongside a concomitant Brønsted acid activation
À
=
of the carbonyl group of dienophile 1 (P OH···O C). We
have performed a nonlinear effect (NLE) study[16] of the
model reaction to examine whether the optical purity of
catalyst 4d directly correlated with the optical purity of
product 3a.[17] A significant and positive NLE was observed,
as shown by the convexity of the curve in Figure 2a, which
indicates that more than one molecule of the chiral acid 4d is
likely to be involved in the transition state of the enantio-
differentiating step. A mechanistic model that accounts for
these experimental observations is proposed in Figure 2b.[18]
One peculiar feature of this catalytic asymmetric vinyl-
ogous DA reaction is that it provides direct and rapid access
to tetrahydrocarbazoles 3 while preserving an a,b-unsatu-
rated system. This functional group could be used as a suitable
chemical handle for easily increasing the molecular and
stereochemical complexity of the products by simple follow-
up transformations. To illustrate this synthetic potential, the
cyclohexenone moiety of 3a was stereoselectively converted
into epoxyketone 5 by means of a protection/epoxidation
sequence (Scheme 1a). Furthermore, we could perform
a palladium-catalyzed Suzuki–Miyaura cross-coupling with
tetrahydrocarbazole 3m without requiring an additional pro-
tection step, which led to product 6 (Scheme 1b).
Scheme 1. Synthetic manipulations of the DA adducts. Boc=tert-
butoxycarbonyl, DMAP=4-dimethylaminopyridine, DME=1,2-dime-
thoxyethane, dppf=diphenylphosphinoferrocene.
lyzed by a commercially available chiral phosphoric acid. A
range of structurally diverse complex tetrahydrocarbazoles
could be synthesized with high chemical yield and excellent
stereoselectivity. It was revealed that cyclic dienones can be
activated towards a cycloaddition pathway by means of
phosphoric acid catalysis. Furthermore, it was demonstrated
that the synthetic utility of the Diels–Alder reaction can be
extended to include a vinylogous reactivity space.
In summary, we have developed a highly stereo- and
regioselective vinylogous Diels–Alder reaction that is cata-
Angew. Chem. Int. Ed. 2014, 53, 2997 –3000
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2999

.
Angewandte
Communications
[9] P. Melchiorre, Angew. Chem. 2012, 124, 9886; Angew. Chem. Int.
Ed. 2012, 51, 9748.
Received: December 3, 2013
Revised: December 19, 2013
Published online: February 6, 2014
[10] For Diels–Alder reactions of enones that are catalyzed by
Brønsted acids, see: a) D. Nakashima, H. Yamamoto, J. Am.
Chem. Soc. 2006, 128, 9626; b) D. Nakashima, H. Yamamoto,
Org. Lett. 2005, 7, 1251; c) T. Schuster, M. Bauch, G. Durner,
M. W. Gçbel, Org. Lett. 2000, 2, 179; for an asymmetric catalytic
version that is based on iminium ion activation, see: d) A. B.
Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
2458.
[11] a) T. Akiyama, Chem. Rev. 2007, 107, 5744; b) M. Terada,
Synthesis 2010, 1929; for pioneering studies on chiral BINOL-
derived phosphoric acid catalysis, see: c) T. Akiyama, J. Itoh, K.
Yokota, K. Fuchibe, Angew. Chem. 2004, 116, 1592; Angew.
Chem. Int. Ed. 2004, 43, 1566; d) D. Uraguchi, M. Terada, J. Am.
Chem. Soc. 2004, 126, 5356.
Keywords: asymmetric catalysis · Brønsted acids · Diels–
.
Alder reactions · organocatalysis · synthetic methods
[1] a) O. Diels, K. Alder, Justus Liebigs Ann. Chem. 1926, 450, 237;
b) E. J. Corey, Angew. Chem. 2002, 114, 1724; Angew. Chem. Int.
Ed. 2002, 41, 1650; c) K. C. Nicolaou, S. A. Snyder, T. Mon-
tagnon, G. Vassilikogiannakis, Angew. Chem. 2002, 114, 1742;
Angew. Chem. Int. Ed. 2002, 41, 1668.
[2] Y. Hayashi, “Catalytic asymmetric Diels – Alder reactions” in
Cycloaddition reactions in organic synthesis (Eds.: S. Kobayashi,
K. A. Jørgensen), Wiley-VCH, Weinheim, 2001.
[12] A reactivity- and selectivity-enhancing effect of Ca2+ ions in
combination with phosphoric acid catalysts has been reported;
see: M. Hatano, K. Moriyama, T. Maki, K. Ishihara, Angew.
Chem. 2010, 122, 3911; Angew. Chem. Int. Ed. 2010, 49, 3823. We
performed a control experiment using a sample of commercially
available catalyst 4d that had been further purified by a careful
extraction with HCl. This experiment provided a similar reac-
tivity and stereoselectivity (3a obtained in 88% yield, 88% ee),
indicating that metals are not involved in the reported reaction.
[13] For information on the acidity of chiral phosphoric acids, see:
a) P. Christ, A. G. Lindsay, S. S. Vormittag, J.-M. Neudçrfl, A.
Berkessel, A. C. OꢀDonoghue, Chem. Eur. J. 2011, 17, 8524;
b) K. Kaupmees, N. Tolstoluzhsky, S. Raja, M. Rueping, I. Leito,
Angew. Chem. 2013, 125, 11783; Angew. Chem. Int. Ed. 2013, 52,
11569.
[14] CCDC 973586 contains the supplementary crystallographic data
for this paper (3e). These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[15] This pathway can be catalyzed by a strong Brønsted acid as
previously reported; see: C. B. Chen, X. F. Wang, Y. J. Cao, H. G.
Cheng, W.-J. Xiao, J. Org. Chem. 2009, 74, 3532.
[3] A viable strategy towards catalytic enantioselective vinylogous
DA reactions has recently been identified; it involves the
transient formation of chiral trienamine intermediates that can
readily participate in DA processes as activated chiral dienes;
see: a) Z. J. Jia, H. Jiang, J.-L. Li, B. Gschwend, Q.-Z. Li, X. Yin,
J. Grouleff, Y.-C. Chen, K. A. Jørgensen, J. Am. Chem. Soc.
2011, 133, 5053; b) X.-F. Xiong, Q. Zhou, J. Gu, L. Dong, T.-Y.
Liu, Y.-C. Chen, Angew. Chem. 2012, 124, 4477; Angew. Chem.
Int. Ed. 2012, 51, 4401; c) Y. Liu, M. Nappi, E. Arceo, S. Vera, P.
Melchiorre, J. Am. Chem. Soc. 2011, 133, 15212.
[4] J. Clayden, Chem. Soc. Rev. 2009, 38, 817.
[5] Sporadic examples have demonstrated the potential of chiral
Brønsted acid catalysis for activating unsaturated ketones
towards conjugate additions; see: a) H.-Y. Tang, A.-D. Lu, Z.-
H. Zhou, G.-F. Zhao, L.-N. He, C.-C. Tang, Eur. J. Org. Chem.
2008, 1406; b) M. Rueping, B. J. Nachtsheim, S. A. Moreth, M.
Bolte, Angew. Chem. 2008, 120, 603; Angew. Chem. Int. Ed. 2008,
47, 593; c) T. Akiyama, T. Katoh, K. Mori, Angew. Chem. 2009,
121, 4290; Angew. Chem. Int. Ed. 2009, 48, 4226; d) Z. Zhang,
J. C. Antilla, Angew. Chem. 2012, 124, 11948; Angew. Chem. Int.
Ed. 2012, 51, 11778.
[6] For Diels–Alder reactions with 2-vinylindole derivatives, see:
a) S. B. Jones, B. Simmons, D. W. C. MacMillan, J. Am. Chem.
Soc. 2009, 131, 13606; b) C. Zheng, Y. Lu, J. Zhang, X. Chen, Z.
Chai, W. Ma, G. Zhao, Chem. Eur. J. 2010, 16, 5853; c) X.-F.
Wang, J.-R. Chen, Y.-J. Cao, H.-G. Cheng, W.-J. Xiao, Org. Lett.
2010, 12, 1140; for an early example of the use of 3-vinylindoles,
see: d) C. Gioia, A. Hauville, L. Bernardi, F. Fini, A. Ricci,
Angew. Chem. 2008, 120, 9376; Angew. Chem. Int. Ed. 2008, 47,
9236.
[7] Tetrahydrocarbazoles have been recognized as important struc-
tural motifs and are found in a variety of natural products and
pharmacologically active compounds; see: a) J. E. Saxton, Nat.
Prod. Rep. 1997, 14, 559; b) A. Nikitenko, D. Evrard, A. L. Sabb,
R. L. Vogel, G. Stack, M. Young, M. Lin, B. L. Harrison, J. R.
Potoski, Org. Process Res. Dev. 2008, 12, 76, and references
therein.
[16] For a review, see: a) T. Satyanarayana, S. Abraham, H. B. Kagan,
Angew. Chem. 2009, 121, 464; Angew. Chem. Int. Ed. 2009, 48,
456; for a recent report on a negative NLE associated with chiral
phosphoric acid catalysis, see: b) C. K. De, F. Pesciaioli, B. List,
Angew. Chem. 2013, 125, 9463; Angew. Chem. Int. Ed. 2013, 52,
9293.
[17] Both the optically pure phosphoric acid 4d and its racemic
mixture proved completely soluble under the reaction conditions
(toluene, [4d]0 = 0.025m, stirring at 408C for 16 h). A positive
NLE was also observed when performing the experiments in
chloroform. For a pertinent discussion, see: N. Li, X.-H. Chen,
S.-M. Zhou, S.-W. Luo, J. Song, L. Ren, L.-Z. Gong, Angew.
Chem. 2010, 122, 6522; Angew. Chem. Int. Ed. 2010, 49, 6378.
[18] Further investigations are needed to fully clarify the reaction
mechanism. Specifically, we are making use of a combination of
experimental and theoretical mechanistic studies to ascertain
whether a concerted or a stepwise mechanism is operative in our
model reaction.
[8] a) X. Tian, Y. Liu, P. Melchiorre, Angew. Chem. 2012, 124, 6545;
Angew. Chem. Int. Ed. 2012, 51, 6439; b) X. Tian, P. Melchiorre,
Angew. Chem. 2013, 125, 5468; Angew. Chem. Int. Ed. 2013, 52,
5360.
3000 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 2997 –3000