Enantio- and diastereoselective synthesis of substituted tetrahydro-1H-isochromanes through a dynamic kinetic resolution proceeding under dienamine catalysis

Article abstract of DOI:10.1021/ol301602h

Racemic 5-acyloxydihydropyranones react with enolizable α,β-unsaturated aldehydes in the presence of a chiral secondary amine catalyst furnishing a wide range of differently substituted tetrahydro-1H-isochromanes with excellent results. The reaction relies on the activation of the enal by the catalyst through the formation of a dienamine intermediate, which undergoes a Diels-Alder/elimination cascade reaction. Moreover, the overall transformation also results in a highly efficient dynamic kinetic resolution process, furnishing the final adducts in high yields and excellent diastereo- and enantioselectivities.

Full text of DOI:10.1021/ol301602h

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3740–3743
Enantio- and Diastereoselective Synthesis
of Substituted Tetrahydro-1H-isochromanes
through a Dynamic Kinetic Resolution
Proceeding under Dienamine Catalysis
´
Ane Orue, Efraım Reyes, Jose L. Vicario,* Luisa Carrillo, and Uxue Uria
´
ꢀ
´
Departamento de Quımica Organica II, Facultad de Ciencia y Tecnologıa,
Universidad del Paıs Vasco/Euskal Herriko Unibertsitatea UPV/EHU, P.O. Box 644,
´
E-48080 Bilbao, Spain
joseluis.vicario@ehu.es
Received June 11, 2012
ABSTRACT
Racemic 5-acyloxydihydropyranones react with enolizable r,β-unsaturated aldehydes in the presence of a chiral secondary amine catalyst
furnishing a wide range of differently substituted tetrahydro-1H-isochromanes with excellent results. The reaction relies on the activation of the
enal by the catalyst through the formation of a dienamine intermediate, which undergoes a DielsꢀAlder/elimination cascade reaction. Moreover,
the overall transformation also results in a highly efficient dynamic kinetic resolution process, furnishing the final adducts in high yields and
excellent diastereo- and enantioselectivities.
The use of chiral secondary amines for catalyzing a
variety of different chemical transformations in a stereo-
controlled way has been the subject of intense research in
the past decade.1 In particular, the ability of these com-
pounds to activate an aldehyde or a ketone toward its
participation in a chemical reaction through the formation
of an azomethine intermediate has shown to be a powerful
approach for the R- or β-functionalization of aldehydes or
enals via enamine2/iminium-cation radical3 intermediates
or via iminium ion intermediates4 respectively. More re-
cently, the application of the vinylogy concept has allowed
expansion of the scope of this reactivity pattern to the γ-
functionalization of R,β-unsaturated aldehydes or ketones
through the formation of dienamine intermediates.5 This
approach has been exclusively developed in recent years,
and consequently the number of examples reported in the
literature regarding this topic is much more limited. Re-
markably, this activation manifold has plenty of different
possibilities tofunctionalize the starting materialdue tothe
rich reactivity profile presented in these dienamine inter-
mediates, which are able to react through three different
ways: (a) the classical enamine reactivity, where R-functio-
nalization of the enal or enone occurs;6 (b) the vinylogous
reactivity which enables γ-functionalization;7 and (c) diene
(1) For some selected reviews on aminocatalysis, see: (a) Bertelsen,
S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178. (b) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (c) Barbas, C. F., III.
Angew. Chem., Int. Ed. 2008, 47, 42. (d) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (e)
MacMillan, D. W. C. Nature 2008, 455, 304. (f) Special issue on
organocatalysis: Chem. Rev. 2007, 107 (12). (g) List, B. Chem. Commun.
2006, 819. For a review covering mechanistic studies, see: (h) Cheong, P.
€
€
H.-Y.; Legault, C. Y.; Um, J. M.; C-elebi-Olc-um, N.; Houk, K. N. Chem.
Rev. 2011, 111, 5042.
(2) For a review: Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471.
(3) First example: Beeson, T. D.; Mastracchio, A.; Hong, J.-B.;
(5) Reviews: (a) Ramachary, D. B.; Reddy, Y. V. Eur. J. Org. Chem.
2012, 865. (b) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.;
Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632. For
pioneering work, see: (c) Bertelsen, S.; Marigo, M.; Brandes, S.; Diner,
P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582.
€
(4) Reviews: (a) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev.
2007, 107, 5416. (b) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta
2006, 39, 79.
r
10.1021/ol301602h
Published on Web 07/05/2012
2012 American Chemical Society

reactivity, in which the dienamine participates as an elec-
tron-rich diene in standard DielsꢀAlder-type reactivity.8,9
In this latter case, although several examples exist using
enones which react through a 2-amino-1,3-diene struc-
ture intermediate (eq a, Scheme 1),8 the few precedents
available in the literature with respect to the use of R,β-
unsaturated aldehydes are related to their amine-catalyzed
self-condensation,9 which lead to the formation of cyclo-
hexadienes (eq b, Scheme 1). This methodology is very
limited in terms of reaction scope, and moreover the possible
participation of an activated form of the Michael acceptor
as the corresponding iminium ion (formed by condensation
with the catalyst) cannot be ruled out. It is noteworthy to
highlight that one of the main problems associated with this
[4 þ 2]-type reactivity of dienamine intermediates employ-
ing enals is the difficulty of releasing the catalyst, which has
to proceed through an elimination process.
eq c (Scheme 1) as suitable substrates in the reaction with
enolizable enals under dienamine activation proceeding
through a [4 þ 2]-type reactivity. This transformationleads
to the formation of enantiomerically enriched chroman
analogues, which are pharmacologically relevant hetero-
cycles present in a variety of natural products.10 Moreover,
this reaction also involves a dynamic kinetic resolution
process in which the final adduct is obtained as a single
diastereoisomer of high enantiomeric purity starting from
racemic material. Another remarkable feature to be high-
lighted relies on the particular behavior of these dihydro-
pyranones to form products from the [4 þ 2] cycloaddition
pathway, which is in deep contrast with other related
highly electrophilic Michael acceptors such as nitroal-
kenes, which typically react with enolizable enals under
dienamine activation furnishing either R- or γ-functiona-
lization adducts.
We initially selected (E)-pent-2-enal (1a) and pyranone
2a as model substrates. We started our study with the
identification of the best chiral amine catalyst, using
typical reaction conditions which involved working in
CHCl3 at rt and also incorporating benzoic acid as a
cocatalyst which is known to facilitate the formation of
this type of dienamine intermediates. As Table 1 shows,
several diarylprolinol derivatives (3aꢀe) were found to
be competent catalysts for the formation of adduct 4a,
achieving very high levels of enantio- and diasterocontrol,
although in variable yields. From all the catalysts tested,
the best results with respect to both yield and stereocontrol
were obtained with catalyst 3b, with the observation that
simple diphenylprolinol 3a performed very poorly in terms
of conversion (compare entry 1 and 2) and that increasing
the steric bulk too much at either the silyl substituent
(catalyst 3c in entry 3) or at the aryl groups (catalysts 3d
and 3e in entries 4 and 5) led to lower yields of compound
4a. On the other hand, imidazolidinone 3f was inactive
under the reaction conditions tried (entry 6). It should
be pointed out that all catalysts afforded exclusively the
corresponding cycloaddition adduct, without the presence
of acyclic side products coming from R- or γ-additions
being observed in any case.
Scheme 1. Reactions of Enones and Enals Proceeding through
Dienamine Activation via [4 þ 2]-Type Reactivity
In this context, we have studied the behavior of racemic
2-substituted dihydropyranones such as those shown in
(6) (a) Ramachary, D. B.; Ramakumar, K. Eur. J. Org. Chem. 2011,
(8) (a) Xu, D.-Q.; Xia, A.-B.; Luo, S.-P.; Tang, J.; Zhang, S.; Jiang,
J.-R.; Xu, Z.-Y. Angew. Chem., Int. Ed. 2009, 48, 3821. (b) Bencivenni,
G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.;
Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200. (c)
Wu, L.-Y.; Bencivenni, G.; Mancinelli, M.; Mazzanti, A.; Bartoli, G.;
ꢀ
ꢀ
€
2599. (b) Stiller, J.; Marques-Lopez, E.; Herrera, R. P.; Frohlich, R.;
Strohmann, C.; Christmann, M. Org. Lett. 2011, 13, 70. (c) Han, B.;
Xiao, Y.-C.; Yao, Y.; Chen, Y.-C. Angew. Chem., Int. Ed. 2010, 49,
10189. (d) Han, B.; Xiao, Y.-C.; He, Z.-Q.; Chen, Y.-C. Org. Lett. 2009,
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11, 4660. (e) Marques-Lopez, E.; Herrera, R. P.; Marks, T.; Jacobs,
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Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7196. (d) Sunden, H.;
€
W. C.; Konning, D.; de Figueiredo, R. M.; Christmann, M. Org. Lett.
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Rios, R.; Xu, Y.; Eriksson, L.; Cordova, A. Adv. Synth. Catal. 2007, 349,
2009, 11, 4116. (f) Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III.
Angew. Chem., Int. Ed. 2007, 46, 1878. (g) Vesely, J.; Dziedzic, P.;
Cordova, A. Tetrahedron Lett. 2007, 48, 6900. (h) Chen, S.-H.; Hong,
2549. (e) Momiyama, N.; Yamamoto, Y.; Yamamoto, H. J. Am. Chem.
Soc. 2007, 129, 1190. (f) Ramachary, D. B.; Anebouselvy, K.; Chowdari,
N. S.; Barbas, C. F., III. J. Org. Chem. 2004, 69, 5838 and references
therein. (g) Thayumanavan, R.; Ramachary, D. B.; Sakthivel, K.;
Tanaka, F.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 3817.
(9) (a) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Huang, G.-F.; Su,
C.-F.; Liao, J.-H. J. Org. Chem. 2007, 72, 8459. (b) de Figueiredo, R. M.;
Frohlich, R.; Christmann, M. Angew. Chem., Int. Ed. 2008, 47, 1450. (c)
Bench, B. J.; Liu, C.; Evett, C. R.; Watanabe, C. M. H. J. Org. Chem.
2006, 71, 9458.
(10) Some selected examples: (a) Hepworth, J. Comprehensive Het-
erocyclic Chemistry, Vol. 3; Katritzky, A. R., Rees, C. W., Eds.; Elsevier
Science: Oxford, 1984. (b) Chromans and Tocopherols In The Chemistry
of Heterocyclic Compounds, Vol. 36; Ellis, G. P., Lockhart, I. M., Eds.;
Wiley-Interscience: New York, 1981. For a review, see: (c) Larghi, E. L.;
Kaufmann, T. S. Eur. J. Org. Chem. 2011, 5195.
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B.-C.; Su, C. F.; Sarshar, S. Tetrahedron Lett. 2005, 46, 8899.
(7) (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. See
also ref 5c. For examples of cascade processes initiated by dienamine
intermediates which start with a γ-addition reaction on an R,β-unsatu-
rated aldehyde, see: (c) Talavera, G.; Reyes, E.; Vicario, J. L.; Carrillo,
L. Angew. Chem., Int. Ed. 2012, 51, 4104. (d) Albrecht, L.; Dickmeiss,
G.; Acosta, F. C.; Rodrıguez-Escrich, C.; Davis, R. L.; Jørgensen, K. A.
J. Am. Chem. Soc. 2012, 134, 2543. (e) Li, J.-L.; Kang, T.-R.; Zhou,
S.-L.; Li, R.; Wu, L.; Chen, Y.-C. Angew. Chem., Int. Ed. 2010, 49, 6418.
(f) Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C.
Angew. Chem., Int. Ed. 2009, 48, 5474. (g) Liu, K.; Chougnet, A.;
Woggon, W.-D. Angew. Chem., Int. Ed. 2008, 47, 5827.
€
Org. Lett., Vol. 14, No. 14, 2012
3741

has a positive influence, which therefore implies that this
parameter requires a careful optimization. Finally, we also
evaluated the incorporation of a base cocatalyst (entry 14),
but the transformation proceeded with very low conver-
sion and poor diastereoselection. Taking into account all
these results, we chose the conditions shown in entry 11 of
Table 1 as the optimal ones for the projected transforma-
tion, proceeding next to carry out the reaction with a wide
range of different R,β-unsaturated aldehydes in order to
study the scope of the reaction.
Table 1. Optimization of the Reaction Conditionsa
Table 2. Scope of the Reactiona
yield
ee
entry cat.
additive
PhCO2H
solvent (%)b
drc
6:1
(%)d
1
3a
3b
3c
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
THF
37
60
52
47
37
<5
61
28
18
73
67
19
76
21
93
2
PhCO2H
PhCO2H
>10:1 86
4:1 90
3
4
3d PhCO2H
>10:1 86
>10:1 99
5
3e
3f
PhCO2H
TFA
6
n.d.e
3:1
n.d.e
yield
(%)b
ee
7
3b
3b
3b
3b
3b
3b
3b
3b
PhCO2H
PhCO2H
PhCO2H
CH3COOH
88
97
entry
R1
R2
product
(%)c
8
4:1
9
EtOH
CHCl3
>10:1 93
6:1 92
>10:1 97
1
Me
H
4a
4b
4c
4d
4e
4f
67
66
64
68
64
65
66
47
81
72
75
63
55
72
60
75
91
97
97
96
96
95
96
96
97
92
96
96
91
98
76
79
30
35
10
11
12
13
14
2
Et
H
4-NO2C6H4CO2H CHCl3
3
n-Pr
H
p-TsOH
ꢀ
CHCl3
CHCl3
CHCl3
6:1
3:1
2:1
98
88
98
4
n-Bu
H
5
n-C5H11
n-C6H13
n-C7H15
PhCH2
Ph
H
DABCO
6
H
7
H
4g
4h
4i
a Reactions were carried out on a 0.32 mmol scale employing 1.0 equiv
of 1a and 1.0 equiv of 2a in the presence of 20 mol % of catalyst 3 and an
additive in 5.0 mL of solvent (48 h). b Yield of pure major diastereo-
isomer after flash column chromatography purification. c Determined by
NMR analysis of the crude product. d Determined by HPLC analysis (see
Supporting Information). e n.d.: not determined.
8
H
9
H
10
11
12
13
14
15
16
17
4-MeOC6H4
H
4j
4-MeC6H4
H
4k
4l
4-FC6H4
H
(Z)-CH3CH2CHdCHCH2
H
4m
4n
4o
4p
4q
2-thienyl
H
Once the best catalyst was identified, we directed our
efforts to improving the yield of the reaction. We initially
tested the reaction using different solvents (entries 7ꢀ9)
but without obtaining better results than those initially
afforded in CHCl3. Next, we evaluated the influence of
Brønsted acid cocatalysts (entries 10ꢀ12) incorporating
otherdifferent additives instead of the benzoic acidinitially
employed. In this sense, using a weaker carboxylic acid
such as CH3COOH (pKa = 4.76)11 resulted in an increase
in the yield of the reaction but with a slight decrease in the
diastereo- and enantioselectivity. In contrast, a slightly
strongercarboxylicacidsuchas4-NO2C6H4CO2H (pKa =
3.47) furnished cycloadduct 4a with a higher yield and stereo-
selectivity than those obtained initially. Using a stronger
acid such as p-TsOH (pKa = ꢀ2.8) resulted in very low
conversions. We also evaluated the reaction in the absence
of any cocatalyst, and although the yield of the reaction
was higher than in all the preceding cases, the resulting
diastereo- and enantioselectivity weresignificantly affected
(entry 13). All these experiments indicate that there is a
narrowpKa window for whichthe Brønsted acidcocatalyst
(CH3)2CdCHCH2
Me
Me
Ph
H
H
a All reactions were carried out using 0.32 mmol of 1aꢀq and
0.32 mmol of 2a in the presence of catalyst 3b and 4-NO2C6H4CO2H
in 5.0 mL of CHCl3 at rt. b Yield of pure compound 4aꢀq after flash
column chromatography. c Determined by HPLC analysis (see Support-
ing Information).
As summarized in Table 2, all reactions studied pro-
ceeded in a completely regioselective manner and provided
the desired adducts as single diastereoisomers. This meth-
odology was successfully employed for β-alkyl monosub-
stituted R,β-unsaturated aldehydes 1aꢀh, furnishing the
corresponding final adducts with excellent enantioselec-
tivities and good yields (entries 1ꢀ8). The use of γ-aryl
substituted enals 1iꢀl resulted in higher yields (entries
9ꢀ12) which can be explained in terms of their better
ability to form a more stable conjugated dienamine inter-
mediate. Aldehydes containing functionalized side chains
like 1mꢀo also reacted satisfactorily (entries 13ꢀ15).
In addition, several β,β-disubstituted 1oꢀq were also found
to be good substrates in the reaction (entries 15ꢀ17),
delivering the corresponding adducts 4oꢀq in good yield
(11) pKa values measured in water.Perrin, D. D.; Serjeant, E. P.;
Dempsey, B. pKa Predictions for Organic Acids and Bases; Champman
and Hall: London, 1981.
3742
Org. Lett., Vol. 14, No. 14, 2012

in all cases and also giving an excellent enantioselectivity
for enal 4o (entry 15), although a signifficant drop was
observed in this parameter for those cases in which an
unsubstituted dienamine intermediate was participating in
the reaction as is in the case of aldehydes 4p and 4q (entries
16 and 17). Importantly, it should be noted that in most
cases the reaction proceededwithyieldsover 50% and high
enantio- and diastereoselectivies starting from a racemic
material. This indicates that a dynamic kinetic resolution
processistaking place, whereoneenantiomerof2aisreact-
ing faster with the chiral dienamine intermediate, whereas
the other enantiomer quickly racemizes in the reaction
medium before participating in the transformation.
We also surveyed the use of other acyloxy substituents
at the dihydropyranone reagent, and as can be seen in Table 3,
the reaction proceeded with similar levels of eficiency than
those obtained with the model substrate 2a regardless of the
nature of the substituent, obtaining good yields and stereo-
selectivities in all tested cases.
Figure 1. X-ray structure of compound 4w.
outcome reported in the literature for other reactions in
which catalyst 3b has been involved for the activation of the
substrate via dienamine catalysis and in which this type of
intermediates subsequently engage in a DielsꢀAlder-type
reaction.5c
In summary, we have developed an efficient procedure
for the synthesis of isochromanes in good yields and excellent
diastereo- and enantioselectivities, by exploiting the potential
of dienamine catalysis to activate the γ-position of R,β-
unsaturated aldehydes. In this sense, the reaction of a wide
range of enals with racemic 4-acyloxy-substituted dihydro-
pyranones in the presence of a chiral secondary amine
catalyst leads to the formation of highly enantio- and diaster-
eomerically enriched target compounds through a cascade
[4 þ 2]/elimination reaction in a dynamic kinetic resolution
process.
Table 3. Scope of the Reaction Using Different 3-Acyloxy-
Substituted Pyranonesa
yield
(%)b
ee
entry
R1
R2
t-BuO
product
(%)c
Acknowledgment. The authors thank the Spanish MI-
CINN (CTQ2011-22790), the Basque Government (Grupos
IT328-10 and fellowships to A.O. and U.U.), and UPV/EHU
(UFI QOSYC 11/22) for financial support. Membership in
the COST Action CM0905 Organocatalysis (ORCA) is
gratefully acknowledged.
1
2
3
4
5
6
Ph
Ph
Ph
Ph
4r
4s
4t
73
85
88
94
66
68
83
85
87
83
99
97
Ph
4-ClC6H4
4-MeSC6H4
4-MeSC6H4
4-MeSC6H4
4u
4v
4w
4-MeOC6H4
2-thienyl
a All reactions were carried out using 0.32 mmol of 1 and 0.32 mmol
of 2 in the presence of catalyst 3b and 4-NO2C6H4CO2H in 5.0 mL of
CHCl3 at rt. b Yield of pure compound 4rꢀw after flash column chroma-
tography. c Determined by HPLC analysis (see Supporting Information).
Supporting Information Available. Characterization
of all new compounds, copies of their 1H and 13C NMR
spectra and of the HPLC chromatograms used for the
determination of enantiopurity. This material is available
free of charge via the Internet at http://pubs.acs.org.
The absolute configuration was unambiguously asigned
as (1S,8R,8aR) by X-ray analysis of derivative 4w (Figure 1).
This configuration is in agreement with the stereochemical
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3743