A novel chiral oxazolidine organocatalyst for the synthesis of an oseltamivir intermediate using a highly enantioselective Diels-Alder reaction of 1,2-dihydropyridine

Article abstract of DOI:10.1039/c0cc00110d

Enantioselective Diels-Alder reactions of 1,2-dihydropyridines with acroleins using a novel chiral oxazolidine organocatalyst afforded chiral isoquinuclidines that is an efficient synthetic intermediate of oseltamivir, with fairly good chemical yield and

Full text of DOI:10.1039/c0cc00110d

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A novel chiral oxazolidine organocatalyst for the synthesis of an
oseltamivir intermediate using a highly enantioselective Diels–Alder
reaction of 1,2-dihydropyridinew
Hiroto Nakano,*a Kenichi Osone,b Mitsuhiro Takeshita,*b Eunsang Kwon,c
Chigusa Seki,a Haruo Matsuyama,a Nobuhiro Takanoa and Yoshihito Koharia
Received 24th February 2010, Accepted 30th April 2010
First published as an Advance Article on the web 26th May 2010
DOI: 10.1039/c0cc00110d
Enantioselective Diels–Alder reactions of 1,2-dihydropyridines
with acroleins using a novel chiral oxazolidine organocatalyst
afforded chiral isoquinuclidines that is an efficient synthetic
intermediate of oseltamivir, with fairly good chemical yield
and excellent enantioselectivity (90%, up to >99% ee).
vincristin, which possess isoquinuclidines, with the aspidos-
perma portion.2 It has recently been indicated that ibogaine
reduces cravings for alcohol and other drugs by means of its
ability
to boost the levels of a growth factor known as glial cell line-
derived neurotrophic factor (GDNF).3 In addition, most recently
it was also shown that the isoquinuclidines can be used as
the synthetic intermediate for the synthesis of oseltamivir
phosphate (Tamiflu) which is an important anti-influenza
drug.4 Tamiflu is a potent inhibitor of neuraminidase, and is
used worldwide as a drug for type A or B influenza. Further-
more, isoquinuclidines are also valuable intermediates in the
synthesis of other alkaloids5 and in medicinal chemistry.6 It is
therefore meaningful to establish an effective asymmetric
The 2-azabicyclo[2.2.2]octanes (isoquinuclidines) are found
widely in natural products such as iboga-type indole alkaloids,
which have varied and interesting biological properties.1
In particular, as shown in Scheme 1, there are pharmaco-
logically important vinca alkaloids such as vinblastine and
synthetic methodology for chiral isoquinuclidines.
A
well-established route to the chiral ring system is through the
asymmetric Diels–Alder (DA) reaction of 1,2-dihydropyridines
with dienophiles. However, only a few examples of employing
organometal catalysts or organocatalysts have been reported
by our group and others.7 Despite the obvious advantages of
the catalytic enantioselective version using an organocatalyst,
to the best of our knowledge, only one example employing a
MacMillan catalyst has been reported for the organocatalytic
asymmetric version of this reaction that was used as the
key reaction for the efficient practical total synthesis of Tamiflu
by Fukuyama and co-workers.4 Nevertheless, this reaction
afforded low chemical yield (26%), but excellent enantio-
selectivity (99% ee).
In the present study, we planned to develop a novel organo-
catalyst that afforded chiral isoquinuclidines at a practical
level with regard to both chemical yield and enantioselectivity.
In designing the planned catalyst, we paid attention to our
previously developed phosphinooxazolidine (POZ) ligand A
(Scheme 2).7 The Pd-POZ organometalic catalyst showed
an excellent catalytic property in the DA reaction with 1,2-
dihydropyridines as a diene.7b,c In the reaction, the substituted
Scheme 1 Utility of isoquinuclidines.
a Division of Applied Science and Engineering, College of Environmental
Technology, Guraduate School of Engineering, Muroran Institute of
Technology, 27-1 Mizumoto, Muroran, Hokkaido 050-8585, Japan.
E-mail: catanaka@mmm.muroran-it.ac.jp; Fax: +81 14 346 5727;
Tel: +81 14 346 5727
b Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku,
Sendai 981-8558, Japan. E-mail: catanaka@tohoku-pharm.ac.jp;
Fax: +81 22 727 0146; Tel: +81 22 727 0147
c Research and Analytical Center for Giant Molecules, Graduate
School of Sciences, Tohoku University, 6-3 Aoba, Aramaki,
Aoba-ku, sendai 980-8578, Japan.
E-mail: ekwon@m.tains.tohoku.ac.jp; Fax: +81 22 795 6752;
Tel: +81 22 795 6752
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and spectral data for compounds 5a, 6a,
11a,b, and 12a,b; The absolute stereochemistry assignment for the new
DA adducts 11a, 16, 20, 21. See DOI: 10.1039/c0cc00110d
Scheme 2 Concept of organocatalyst.
ꢀc
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oxazolidine structure of the catalyst worked effectively to give
high enantioselectivity. Given the above, we designed a series
of oxazolidines, 2,4-substituted 5,5-diphenyloxazolidines, as a
novel organocatalyst for the DA reaction of 1,2-dihydro-
pyridines. The oxazolidine catalyst was easily prepared by
the reaction of an amino alcohol with a carbonyl compound.
The resulting compound contained one covalent site, and the
stability of the oxazolidine ring system could be maintained by
the diphenyl groups at the 5-position.
catalysts 8a and 8b8 were also obtained from the condensations
of 4a,b with acetone in the presence of MS 4A followed
by the treatment with CF3CO2H, respectively. In the seven
compounds 6a–g, the assigned stereochemistry at the 2-position
of the oxazolidine ring was determined by NOE difference
spectra. NOE enhancement was observed between the hydrogen
at the 2-position and the hydrogen at the 4-position when the
2- and 4-positions were irradiated, respectively.6
We first examined the DA reaction of common 1-phenoxy-
carbonyl-1,2-dihydropyridine 9 with acrolein 10. The reaction
was carried out at 0 1C in CH3CN–H2O in the presence of
10 mol% of catalysts 6a,b,e–g to give the DA adduct 11, and
its chemical and optical yields were determined by converting
to the alcohol 12. The results are summarized in Table 1. The
reaction catalyzed by 5-tert-butyl-6a with CF3CO2H gave the
endo-DA adduct 11aw in good chemical yield (71%) and
excellent enantioselectivity (>99% ee) (entry 1). The use of
5-isopropyl-6b with CF3CO2H brought about a slight decrease
in enantioselectivity (97% ee), but the DA adduct was obtained
in 70% (entry 2). In contrast, 2-dimethylated catalysts 8a,b
with tert-butyl or iso-propyl groups at the 5-position afforded
both the endo and exo DA adducts as a mixture in only low
chemical yields and enantioselectivity (entries 3, 4). These
above results indicate that the stereochemistry of the substi-
tuent group at the 2-position of the oxazolidine ring is
important for obtaining a satisfactory enantioselectivity.
Catalysts 6e–g with other organic acids (XCO2H: X = Cl3C,
Br3C, F2CH) also did not give satisfactory results for either
chemical yield or enantioselectivity (entries 5–7). Based on
the above, 2-monosubstituted 6a,b might be better than the
corresponding 2-disubstituted 8a,b in the reaction. Thus, the
substituents at 2- and 4-positions having a cis-configuration on
the oxazolidine ring might act to control the equilibrium
between iminium conformers blocking one iminium face from
attacking of diene to afford high enantioselectivity.
We report herein that 2-phenyl-4-tert-butyl-5,5-diphenyl-
oxazolidine with CF3CO2H exhibits a high degree of enantio-
selectivity (up to >99% ee) and good chemical yield (up to
90%) in the DA reaction of 1,2-dihydropyridines with acroleins.
Although a high chemical yield is not obtained in this reaction
using the MacMillan catalyst, this is the first organocatalyst
that affords the corresponding chiral isoquinuclidines at a
practical level with regard to both high chemical yield and
enantioselectivity.
The catalysts, respectively, were prepared by the condensa-
tion of the corresponding b-amino alcohol with an aldehyde
or a ketone, followed by treatment with an organic acid
(Scheme 3). Thus, the reactions of b-amino alcohols 4a–d with
benzaldehyde, respectively, afforded the precursor oxazolidine
5 in good chemical yields, but the 1H-NMR analysis of the
obtained crystallized products showed a tautomeric mixture of
oxazolidines 5a–d and imines 5a0–d0. However, the treatments
of 5 with XCO2H (X = CF3, CHF2, CCl3, CBr3) afforded the
desired chiral oxazolidine salts 6a–g. Thus, the reactions of the
compounds 5a,b with XCO2H (X = CF3, CCl3, CBr3, CHF2),
respectively, gave the desired catalysts 6a,b,e–g as a single
structure in quantitative yields. However, the reactions of the
compounds 5c,d with CF3COOH afforded compound 6c,d
as a single structure with a decomposed product. Furthermore,
Table 1 Enantioselective DA reaction of 9 with 10 using catalyst 6,8
Yield endo : exob endo-11a exo-11b
Entry Catalyst Product (%)a (11a:11b)
ee(%)c
ee(%)
1
2
3
4
5
6
7
6a
6b
8a
8b
6e
6f
11a
11a
11a,b
11a,b
11a,b
11a
71
70
19
19
73
16
53
endo only >99(S)
endo only 97(S)
12 : 1
51 : 1
75 : 1
27(S)
85(S)
39(S)
29
39
18
endo only 33(S)
endo only 42(S)
6g
11a
Isolated yields. The endo/exo ratio was determined by 1H NMR.
The ee of the endo and exo isomers were determined by chiral HPLC
using a Daicel AD-H column (hexane/2-propanol : 85/15) of 12a,b.
a
b
c
Scheme 3 Synthesis of oxazolidine catalysts.
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Table 2 Enantioselective DA reaction of 13 or 14 with acrolein using
catalysts 6a
Scheme 4 Enantioselective DA reactions of 9 or 13 with 19 using
catalyst 6a.
15,16 endo-
yield 15a,16 exo-15b
Catalyst
Entry (mol%) Time/h Substrate Product (%)a ee(%)b ee(%)b
that provides an efficient methodology for obtaining a pharma-
cologically important compound such as Tamiflu and its
derivative, using a novel oxazolidine organocatalyst 6. The
developed oxazolidine catalyst 6 was easily prepared in two
steps and showed dramatic reactivity and excellent enantio-
selectivity for the reactions of three kinds of 1,2-dihydropyridines
9, 13, 14 with two kinds of acroleins 10, 19, comparable to the
results of the report of the Fukuyama group.4 Further studies
to examine the scope and limitations of this organocatalyst
for the catalytic asymmetric version of the DA reactions of
1,2-dihydropyridines are now in progress.
1
6a(10)
24
13
15a
90
>99(S)
2
3
4
5
6a(5)
6a(5)
6a(2.5) 24
6a(10)
24
48
13
13
13
14
15a
15a
15a,b
16a
61
67
44c
51
97(S)
97(S)
85(S)
73
>99(S)
24
a
b
Isolated yields. The ee of the endo and exo isomers were determined
c
by chiral HPLC using a Daicel chiral column of 17a,b,18. The endo/exo
1
ratio was 67 : 33, which was determined by H NMR.
The activity of the most effective catalyst 6a was
then evaluated in the reaction consisting of 10 mol% catalyst
with 1-benzyloxycarbonyl or 1-tert-butoxycarbonyl-1,2-dihydro-
pyridines (13 and 14) and acrolein 10. The chemical and
optical yields of the DA adducts 15, 16w were determined by
converting to the alcohols 17, 18. The results are shown in
Table 2. The use of 1-benzyloxycarbonyl-diene 13 further
increased efficacy of catalyst 6a (entry 1). In this reaction,
fairly good chemical yield (90%) was observed together with
excellent enantioselectivity (>99% ee). Furthermore, the effect
of reducing the molar ratio of catalyst 6a was examined. At
low catalytic loading to 5 mol% of 6a, equally satisfactory
results (61%, 97% ee, entry 2) were obtained, but 2.5 mol%
greatly decreased both the chemical yield and enantioselectivity
(44%, 85% ee, entry 4). Similarly, 6a was also effective in the
DA reaction using 1-tert-butoxycarbonyl-diene 14 and the
desired DA adduct 16 was obtained with almost complete
enantioselectivity (>99% ee) with a moderate chemical yield
(entry 5).
Notes and references
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in Pharmacology of Ibogaine and Ibogaine-related Alkaloids. The
alkaloids. Chemistry and Biology, ed. G. A. Cordell, Academic,
San Diego, 1999, vol. 52, pp. 197–231; (c) S. D. Glick,
I. M. Maisonneuve and K. K. Szumlinski, in Mechanisms of Action
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We examined the effectiveness of acrolein derivative 19
using superior catalyst 6a (Scheme 4). The reactions of dienes,
9, 13 with dienophile 19, respectively, were carried out at 0 1C
in the presence of 10 mol% of superior catalyst 6a to give the
DA adducts 20,w 21,w and those chemical and optical yields
were determined by converting to the alcohol 22, 23, respec-
tively. The desired DA adducts, 20, 21 were obtained in
good chemical yields and almost complete enantioselectivity
(20: 68%, >99% ee, 21: 83%, >99% ee) in the both reac-
tions. This is the first example of an enantioselective DA
reaction of 1,2-dihydropyridine with substituted dienophile
using an organocatalyst.
In conclusion, we have succeeded in carrying out a highly
enantioselective Diels–Alder reaction of 1,2-dihydropyridines
8 A. D. Gupta, B. Singh and V. K. Singh, Indian J. C., 1994, 3B,
981–983.
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Chem. Commun., 2010, 46, 4827–4829 | 4829