Organocatalytic enantioselective Diels-Alder reaction of dienes with α-(N,N-diacylamino)acroleins

Article abstract of DOI:10.1021/ol8011277

(Chemical Equation Presented) Catalytic and highly enantioselective Diels-Alder reaction of cyclic and acyclic dienes with r-phthalimidoacroleins provides cyclic α-quaternary α-amino acid precursors. The conformationally flexible chiral ammonium salt of H-L-Phe-L-Leu-N(CH ₂CH₂)₂-reduced triamine with pentafluorobenzensulfonic acid is very effective as an asymmetric catalyst for the Diels-Alder reaction.

Full text of DOI:10.1021/ol8011277

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2893-2896
Organocatalytic Enantioselective
Diels-Alder Reaction of Dienes with
r-(N,N-Diacylamino)acroleins
Kazuaki Ishihara,*,† Kazuhiko Nakano,† and Matsujiro Akakura‡
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa, Nagoya
464-8603, Japan, and Department of Chemistry, Aichi UniVersity of Education,
Igaya-cho, Kariya, Aichi 448-0001, Japan
ishihara@cc.nagoya-u.ac.jp
Received May 16, 2008
ABSTRACT
Catalytic and highly enantioselective Diels-Alder reaction of cyclic and acyclic dienes with r-phthalimidoacroleins provides cyclic r-quaternary
r-amino acid precursors. The conformationally flexible chiral ammonium salt of H-L-Phe-L-Leu-N(CH2CH2)2-reduced triamine with pentafluo-
robenzensulfonic acid is very effective as an asymmetric catalyst for the Diels-Alder reaction.
Optically active R-amino acids as well as R-hydroxy acids
are valuable chiral synthons that bear two functional groups.
We have recently developed organocatalytic enantioselective
Diels-Alder (DA)1a–c and [2 + 2]1d cycloaddition reactions
with R-acyloxyacroleins based on acid-base combina-
tion chemistry.2,3 H-L-Phe-L-Leu-N(CH2CH2)2-reduced tri-
amine (1)·2.75HX and (R)-2,2′-diamino-1,1′-binaphthyl
(2)·1.9HNTf2 activate R-acyloxyacroleins as an aldiniminium
cation intermediate 3 to react with dienes or monoalkenes
to provide cycloaliphatic R-quaternary4 R-hydroxy acid
equivalents with high enantioselectivity (Chart 1).2 In
contrast, to the best of our knowledge, there has been only
one example of the enantioselective DA reaction with R-(N-
acylamino)acrolein derivatives: in 1991, Cativiela et al.
reported the Diels-Alder reaction of cyclopentadiene with
methyl R-(N-acetylamino)acrylate promoted by 50 mol %
of chiral titanium(IV) Lewis acid (64% yield, 78% exo, 70%
† Nagoya University.
‡ Aichi University of Education.
Chart 1. Chiral Organoammonium Salt Catalysts 1·2.75HX and
2·HNTf2 and Their Aldiminium Intermediate 3 for Cycloaddition
Reactions with R-(Acyloxy)acroleins
(1) (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504–
10505, and 13079 (additions and corrections). (b) Sakakura, A.; Suzuki,
K.; Nakano, K.; Ishihara, K. Org. Lett. 2006, 8, 2229–2232. (c) Sakakura,
A.; Suzuki, K.; Ishihara, K. AdV. Synth. Catal. 2006, 348, 2457–2465. (d)
Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930–8931.
(2) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243–4244. (b) Northrup, A. B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 2458–2459. For our account, see: (c) Ishihara,
K.; Sakakura, A.; Hatano, M. Synlett 2007, 686–703. For a recent review
of iminium catalysis, see: (d) Erkkila¨, A.; Majander, I.; Pihko, P. M. Chem.
ReV. 2007, 107, 5416–5470
(3) For a recent review of bifunctional acid-base catalysts, see: Kanai,
M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491–1508
.
.
10.1021/ol8011277 CCC: $40.75
Published on Web 06/06/2008
2008 American Chemical Society

Table 1. DA Reaction of 2,3-Dimethylbutadiene with R-(N-Acylamino)- or R-(N,N-Diacylamino)acroleins Catalyzed by 1·2.75HX or
a
2·1.9HNTf2
product
Dienophile
(R1, R2)
Conditions solvent,
Yield
(%)b
Ee
(%)c
entry
catalyst
T (°C), t (h)
1d
2
3
4
5
6
7
8
9
10
11
12
13
4 (Bz, H)
1·2.75C6F5SO3H
1·2.75C6F5SO3H
1·2.75C6F5SO3H
1·2.75C6F5SO3H
1·2.75C6F5SO3H
1·2.75C6F5SO3H
1·2.75C6F5SO3H
1·2.75CF3CO2H
1·2.75ArSO3He
1·2.75TfOH
EtNO2, 0, 36 to rt, 24
EtNO2, rt, 4.5
MeNO2, rt, 4.5
MeCN, rt, 4.5
THF, rt, 4.5
59
97
77
86
71
74
41
43
91
90
<5f
<5f
0
81
92
89
89
93
94
74
42
90
89
5a (phthal)
5a (phthal)
5a (phthal)
5a (phthal)
5a (phthal)
5a (phthal)
5a (phthal)
5a (phthal)
5a (phthal)
5a (phthal)
5a (phthal)
5a (phthal)
DME, rt, 4.5
DMF, rt, 4.5
EtNO2, rt, 84
EtNO2, rt, 4.5
EtNO2, rt, 4.5
EtNO2, rt, 3
EtCN, -78, 31
EtNO2, -78, 24
1·2.75HNTf2
2·1.9HNTf2
2·1.9C6F5SO3H
a Unless otherwise noted, the reaction of 2,3-dimethylbutadiene (0.6 mmol) with R-(N-acyl- or N,N-diacylamino)acroleins (0.5 mmol) was carried out
in a solvent (0.5 mL). b Isolated yield. c Determined by chiral HPLC analysis. d 2,3-Dimethylbutadiene (1.0 mmol) was used in EtNO2 (156 µL). e ArSO3H
) 2,4-(NO2)2C6H3SO3H. f A complex mixture was obtained.
ee (exo)).5,6 We describe here the catalytic and highly
enantioselective DA reaction of dienes with R-(N,N-diacy-
lamino)- or R-(N-acylamino)acroleins to give optically active
cyclic R-quaternary4 R-amino acid precursors. Conforma-
tionally constrained R-amino acids are valuable in biochem-
istry as modified peptides, enzyme inhibitors, and ligands
for probing receptor recognition.5–7
In an initial investigation, the DA reaction of 2,3-dimethyl-
butadiene with R-(N-benzoylamino)acrolein (4)8 was examined
in nitroethane in the presence of 20 mol % of 1·2.75C6F5SO3H.
The reaction was slow even at room temperature, and stirring
for 24 h led to the desired cycloadduct with 81% ee in 59%
yield (Table 1, entry 1). Next, R-phthalimidoacrolein (5a) was
examined instead of 4 under the same conditions as above. Both
the reactivity and the enantioselectivity were increased, and
stirring at room temperature for 4.5 h led to the desired
cycloadduct (6a) with 92% ee in 97% yield (entry 2). Next,
the solvent effect was investigated (entries 2-7): most aprotic
polar solvents except for DMF were suitable, and the best result
was observed with nitroethane. Brønsted acids were also
examined as HX of 1·2.75HX (entries 2, 8-11): most sulfonic
acids were effective, but on the other hand, trifluoroacetic acid
and superacidic triflylimide were not suitable. Another candi-
date, 2·1.9HNTf2, did not catalyze the DA reaction with 5a
because 2 irreversibly reacted with 5a even at -78 °C in the
presence of triflylimide (entry 12). 2·1.9C6F5SO3H did not
catalyze the DA reaction with 5a at -78 °C (entry 13) and did
not induce high enantioselectivity at room temperature.
The absolute configuration of cycloadduct 6a, which was
obtained as a major enantiomer in Table 1, was determined
to be (S) by X-ray crystallographic analysis, as shown in
Figure 1.
(4) R,R-Dialkyl-substituted R-hydroxy- or R-amino acids are often called
“R-quaternary R-hydroxy or R-amino acids”. See refs 5–7.
(5) Cativiela, C.; Lo´pez, P.; Mayoral, J. A. Tetrahedron: Asymmetry
1991, 2, 1295–1304.
(6) For the diastereoselective DA reaction with chiral R-amino acrylic
acid derivatives, see: (a) Cativiela, C.; Lo´pez, P.; Mayoral, J. A. Tetrahe-
dron: Asymmetry 1990, 1, 61-64; (b) 1990, 1, 379-388; (c) 1991, 2,
449-456. (d) Sankhavasi, W.; Kohmoto, S.; Yamamoto, M.; Nishio, T.;
Iida, I.; Yamada, K. Bull. Chem. Soc. Jpn. 1992, 65, 935–937. (e) Cativiela,
C.; Carc´ıa, J. I.; Mayoral, J. A.; Pires, E.; Royo, A. J.; Figueras, F. Appl.
Catal. A-Gen. 1995, 131, 159–166. (f) Cativiela, C.; Carc´ıa, J. I.; Mayoral,
J. A.; Pires, E.; Royo, A. J.; Figueras, F. Tetrahedron 1997, 51, 1295–
1300. (g) Chinchilla, R.; Favello, L. R.; Galindo, N.; Na´jera, C. Tetrahedron:
Asymmetry 1999, 20, 821–825. (h) Abella´n, T.; Na´jera, C.; Sansano, J. M.
Tetrahedron: Asymmetry 2000, 11, 1051–1055. (i) Chinchilla, R.; Falvello,
L. R.; Galindo, N.; Na´jera, C. J. Org. Chem. 2000, 65, 3034–3041. (j) Urkett,
B.; Chai, C. L. L. Tetrahedron Lett. 2001, 42, 2239–2242. (k) Abella´n, T.;
Manchen˜o, B.; Na´jera, C.; Sansano, J. M. Tetrahedron 2001, 57, 6627–
6640. (l) Caputo, F.; Clerici, F.; Gelmi, M. L.; Pellegrino, S.; Pocar, D.
Tetrahedron: Asymmetry 2006, 17, 1430–1436. (m) Cernak, T. A.; Gleason,
J. L. J. Org. Chem. 2008, 73, 102–110.
Figure 1. ORTEP illustration of (S)-6a with thermal ellipsoids
drawn at the 50% probability level (Flack parameter ) 0.1228).
R-Phthalimidoacrolein 5a, which was a novel compound,
was prepared by a one-pot procedure of dehydrative con-
densation between 2-amino-1,3-propanediol and phthalic
2894
Org. Lett., Vol. 10, No. 13, 2008

anhydride and subsequent oxidative dehydration under Swern
conditions (Scheme 1).8 Other substituted R-phthalimidoac-
roleins 5 were synthesized in the same manner as 5a.
2-phenylbutadiene, myrcene, and (E)-ꢀ-farnesene also reacted
smoothly with 5a to give the desired 4-alkyl-substituted
cyclohex-3-enecarboxaldehydes 7a-10a with >99% regi-
oselectivity and 88-94% ee (entries 3-6). Although buta-
diene was less reactive than substituted ones, DA adduct 11a
was obtained in 55% yield with 83% ee (entry 7). The
reaction of cyclopentadiene with R-(tetrafluorophthalimi-
do)acrolein (5b) gave endo-formylbicycloadduct 12b with
72% ds and 90% ee (entry 9). Anthracene, which was much
less reactive, was also usable as a diene, although the
chemical yield and enantioselectivity were moderate (entry
10).
Scheme 1. One-pot Synthesis of 5
Phthalimido groups of DA adducts 6-13 were deprotected
in high yield by the treatment with hydrazine after conversion
to the corresponding methyl esters (Scheme 2). Norbornene
To explore the generality and scope of the 1·2.75C6F5SO3H-
induced enantioselective DA reaction with 5a, representative
dienes were examined with 2.5-10 mol % catalyst loading
in nitroethane at -10 °C to rt (Table 2). The enantioselec-
Scheme 2. Deprotection of the Phthalimido Group of 12a
Table 2. Enantioselective DA Reaction of Dienes with 5a
derivatives are particularly valuable as important optically
active synthetic intermediates of bioactive alkaloids such as
norbornene-2-amino-2-methanol derivatives9 and (-)-al-
temicidin.10
Considering that 1·2C6F5SO3H was much less active than
1·2.75C6F5SO3H as a catalyst for the DA reaction of dienes
with 5 as well as R-(acyloxy)acroleins,1a,d we assumed that
1·3C6F5SO3H might be a real active catalyst, which would
activate 5b as aldiminium salt (16) with 1·3C6F5SO3H.11 The
(Z)-isomeric preference of 16 was supposed based on
theoretical calculations of geometries of its analogous
aldiminium salt (17) derived from R-maleimidoacrolein and
(7) (a) Clerici, F.; Gelmi, M. L.; Gambini, A. J. Org. Chem. 1999, 64,
5764–5767. (b) Kotha, S.; Ganesh, T.; Ghosh, A. K. Bioorg. Med. Chem.
Lett. 2000, 10, 1755–1757. (c) Clerici, F.; Gelmi, M. L.; Gambini, A.; Nava,
D. Tetrahedron 2001, 57, 6429–6438. (d) Yang, B. V.; Doweyko, L. M.
Tetrahedron Lett. 2005, 46, 2857–2860. For a review of the stereoselective
synthesis of cyclic tertiary R-amino acids, see: (e) Cativiela, C.; D´ıaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645–732.
(8) For preparation of 4, see: Harada, H.; Morie, T.; Hirokawa, Y.; Kato,
S. Chem. Pharm. Bull. 1996, 44, 2205–2212.
a Unless otherwise noted, the reaction of diene (0.6 mmol) with 5 (0.5
mmol) was carried out in EtNO2. b Isolated yield. c Ee of major diastereomer
determined by chiral HPLC analysis. d Ratio of 4- and 3-alkyl isomers.
The stereochemistry of 8a was determined by X-ray diffraction analysis.
e THF was used instead of EtNO2. f Diene (2 equiv) was used. g H-L-
[3-(2-Naph)Ala]-L-Leu-N(CH2CH2)2-reduced triamine was used instead of
1. h 54% ee (exo-12a), 57% ee (exo-12b). i The relative and absolute
stereochemistries of major diastereomer of 12b were determined by X-ray
diffraction analysis after its derivation to (R)-N-phenylethylamide. j 11 days.
(9) (a) Iwasaki, T.; Yamazaki, H.; Nishitani, T.; Sato, T. Chem. Pharm.
Bull. 1991, 39, 527–529. (b) Yamazaki, H.; Horikawa, H.; Nishitani, T.;
Iwasaki, T.; Nosaka, K.; Tamaki, H. Chem. Pharm. Bull. 1992, 40, 102–
108.
(10) Kende; Liu, K.; Jos Brands, K. M. J. Am. Chem. Soc. 1995, 117,
10597–10598.
(11) In our previous papers,1a,d it was assumed that (Z)-aldiminium salt
derived from 1·2HX and R-(acyloxy)acrolain would be a key intermediate.
However, an aldiminium salt derived from 1·3HX and R-(acyloxy)acrolain
may be more favorable. Further studies are in progress and will be reported
in the near future.
tivity in the initial model reaction of 2,3-dimethylbutadiene
with 5a was further increased to 96% ee (entry 1). Isoprene,
Org. Lett., Vol. 10, No. 13, 2008
2895

H-L-Phe-L-Leu-NMe2-reduced triamine·3HCl.12 The geom-
etries of 17 were optimized at DFT calculations with
B3LYP,13 using the 6-31+G(d,p) basis set (Figure 2). After
(E)-17, and the re-face of the enimide moiety of (Z)-17 is
sterically shielded by the benzyl substituent.
Cyclopentadiene should approach enantioselectively the
si face of the electron-deficient enimide moiety to give endo-
(2S)-12b as a major isomeric product. Thus, as well as the
(Z)-isomeric preference of 17, it was expected that (Z)-
transition-state (TS) assembly 18 would be preferred to (E)-
TS-18 (Figure 3).
Figure 3. Possible transition-state assemblies (Z)-18 and (E)-18.
In summary, we have developed a catalytic and highly
enantioselective DA reaction of dienes with 5 to provide
cyclic R-quaternary4 R-amino acid precursors for the first
time.5 Chiral triamine 1, which is conformationally more
flexible than 2, could be used as a catalyst ligand for
cycloadditions for not only R-acyloxyacroleins but also 5.
Further mechanistic studies are in progress and will be
reported in the near future.
Figure 2. Relative energy defference between (E)- and (Z)-
geometries of aldiminium salt 17 based on theoretical calculations.
satisfactory geometry optimization, the vibrational spectrum
of each species was calculated. As shown in Figure 2, the
relative energy of (Z)-17 is 2.8 kcal/mol lower than that of
Acknowledgment. Financial support for this project was
provided by MEXT.KAKENHI (20245022, 19020021), the
Toray Science Foundation, and the G-COE in Chemistry,
Nagoya. Calculations were performed at the Research Center
or Computational Science (RCCS), Okazaki Research Facili-
ties, National Institutes of Natural Science (NINS).
(12) Theoretical calculations were performed using the Gaussian 03
programs. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
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Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
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OL8011277
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