Enantioselective synthesis of 4-hydroxytetrahydropyridine derivatives by intramolecular addition of tertiary enamides to aldehydes

Article abstract of DOI:10.1002/anie.201200459

Stable tertiary enamides and enecarbamates undergo highly enantioselective intramolecular nucleophilic addition to aldehyde units catalyzed by chiral binol-Ti complexes under mild conditions to produce the title compounds in up to 99.5% or greater enantiomeric excess. A positive nonlinear effect was detected and the formation of binol-Ti aggregates suggests an intricate asymmetric catalytic pathway. Copyright

Full text of DOI:10.1002/anie.201200459

Angewandte
Chemie
DOI: 10.1002/anie.201200459
Asymmetric Catalysis
Enantioselective Synthesis of 4-Hydroxytetrahydropyridine
Derivatives by Intramolecular Addition of Tertiary Enamides to
Aldehydes**
Shuo Tong, De-Xian Wang, Liang Zhao, Jieping Zhu, and Mei-Xiang Wang*
Chiral 4-hydroxypiperidine rings constitute the core struc-
tures of natural products[1–5] such as dendrobate alka-
loid 241D,[1] lasubine I,[2] and 13a-hydroxy-4-oxasparteine.[3]
Furthermore, a large number of 4-hydroxypiperidine deriv-
atives have interesting bioactivity,[6–9] ranging from activation
of 5-hydroxytryptamine (5-HT1F) receptors[6] to inhibition of
g-secretase[7] and the mammalian target of rapamycin.[8]
Despite their importance in varied disciplines, general
synthetic methods for producing 4-hydroxypiperidine deriv-
atives have remained scarcely explored.[2,6–10]
ever, has been challenged recently after the discovery of
intramolecular nucleophilic addition of tertiary enamides to
an oxirane in the biomimetic synthesis of clausena alka-
loids.[14] The nucleophilicity of tertiary enamides has been
exploited in the (R,R)-salen-CrIIICl-catalyzed intramolecular
addition to activated ketones, which produces (S)-3-hydroxy-
1H-pyrrol-2(3H)-one derivatives in excellent yields and with
high enantioselectivity (Scheme 2).[15] We envisioned that
tertiary enamides would act as general and unique nucleo-
Enamides are enamine variants that contain an electron-
withdrawing carbonyl group on the nitrogen atom
(Scheme 1). As a result of the electronic effect of the carbonyl
group, the delocalization of the lone pair of electrons from the
Scheme 1. Structure of an enamine as well as secondary and tertiary
enamides.
Scheme 2. Catalytic asymmetric reactions of tertiary enamides.
=
nitrogen atom into the C C bond is reduced, which decreases
the electron density and the nucleophilicity of the enaminic
philic reagents. Moreover, the nucelophilicity of enamides is
amenable to regulation by the nature of the substituent R
(Scheme 1). Changes in the electronic and steric effects of the
substituent, for instance, would control the conjugation of the
enamine segment and tune the reactivity of enamides. Herein,
we present the efficient synthesis of highly enantiopure 4-
hydroxy-1,2,3,4-tetrahydropyridine derivatives from the
intramolecular nucleophilic addition of tertiary enamides to
aldehydes catalyzed by a chiral Lewis acid (Scheme 2).
Mechanistic insight into the asymmetric catalysis by the
chiral binol–Ti complex that was used in this reaction was also
obtained. Reduction of the resulting addition products
completes preparation of chiral 4-hydroxypiperidine com-
pounds.
We examined the transformation of enamides into 4-
hydroxy-1,2,3,4-tetrahydropyridines (Table 1) by using Jacob-
senꢀs salen-metal complexes (10 mol%) as chiral catalysts[16]
(Scheme 3). Whereas (R,R)-salen-FeCl (Cat-2), -Co (Cat-3)
and -MnCl (Cat-4) complexes had virtually no catalytic
activity (Table 1, entries 2–4), (R,R)-salen-CrCl (Cat-1)
(Table 1, entry 1) and -AlCl (Cat-5) (Table 1, entry 5) com-
plexes catalyzed the conversion of 1d effectively at room
temperature in dichloromethane. However, asymmetric
carbon atom.[11] Whereas secondary enamides, which contain
À
an N H moiety, are aza-ene components that undergo
reactions with active electrophiles,[11,12] tertiary enamides
are known as stable species in nucleophilic reactions.[11,13] The
notion of tertiary enamides as inert chemical entities, how-
[*] S. Tong, Dr. D.-X. Wang, Prof. Dr. M.-X. Wang
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
Dr. L. Zhao, Prof. Dr. J. Zhu, Prof. Dr. M.-X. Wang
Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (China)
E-mail: wangmx@mail.tsinghua.edu.cn
Prof. Dr. J. Zhu
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne (Switzerland)
[**] We thank NNSFC (20820102034), MOST (2009CB724704), and
Tsinghua University for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200459.
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Table 1: Reaction optimization.
Cat-6-catalyzed reaction of 1d by using either different
solvents, including acetonitrile, benzene, or toluene, or
adding additives, such as molecular sieve (4 ꢁ), Na2SO4,
AgOTf, or LiCl, led to the ee values not exceeding 80%,
albeit high conversion was achieved in some cases (see
Table S1 in the Supporting Information).
We then turned our attention to binol–metal complexes.[17]
To our delight, the complex formed in situ between (R)-binol
and Ti(OiPr)4 (2:1, Cat-11) was a highly active and enantio-
selective catalyst. With a 5 mol% catalyst loading, complete
conversion of 1b into 2b was effected within 1 h at 58C, to
afford a 96% yield of isolated product in 72.0% ee (Table 1,
entry 14). Decreasing the reaction temperature from 58C to
À358C gave rise to the dramatic improvement in ee value
from 72.0% to 97.6% (Table 1, entries 14–18). The reaction
became extremely slow when temperature was further
reduced to À408C (Table 1, entry 19). It is also interesting
to note that other solvents, including acetonitrile, benzene,
toluene, and carbon tetrachloride had a detrimental effect on
the asymmetric catalysis, which resulted in either low
conversion even over an elongated reaction period at room
temperature, or diminished enantioselectivity (see Table S1 in
the Supporting Information). A higher loading of catalyst
(10 mol%) gave the same level of enantiocontrol (Table 1,
entry 22), whereas a lower loading caused a decrease in the
reaction velocity and selectivity (Table 1, entry 21).
Entry
Catalyst
(mol%)
T [8C]
t [h]
2
ee [%][b]
(Yield [%])[a]
1
2
3
4
5
6
7
8
Cat-1 (10)
Cat-2 (10)
Cat-3 (10)
Cat-4 (10)
Cat-5 (10)
Cat-5 (10)
Cat-6 (10)
Cat-7 (10)
Cat-8 (10)
Cat-8 (10)
Cat-9 (10)
Cat-9 (10)
Cat-10 (10)
Cat-11 (5)
Cat-11 (5)
Cat-11 (5)
Cat-11 (5)
Cat-11 (5)
Cat-11 (5)
Cat-11 (2.5)
Cat-11 (10)
RT
RT
RT
RT
5
2a (92)
2a (15)
2a (0)
3.3
2.1
-
120
120
120
72
120
13.5
9
12
36
12
36
19
1
3
6
13.5
35
>96
>96
12
2a (0)
-
RT
2a (81)
2a (75)
2a (89)
2a (93)
2a (91)
2a (51)
2a (90)
2a (42)
2a (93)
2b (96)
2b (96)
2b (96)
2b (98)
2b (92)
2b (trace)
2b (27)
2b (96)
35.4
52.1
69.3
59.4
31.8
72.6
28.0
60.0
60.6
72.0
90.1
93.0
97.0
97.6
n.d.
89.7
97.4
À30
RT
RT
RT
9
10
11
12
13
14
15
16
17
18
19
21
22
À40
RT
À10
RT
5
À10
À20
À30
À35
À40
À35
À35
Catalyzed by (R)-binol–Ti complex Cat-11 under opti-
mized conditions, a range of enamides underwent efficient
intramolecular nucleophilic addition to an aldehyde group to
afford (S)-4-hydroxy-1,2,3,4-tetrahydropyridine products 2 in
excellent yields and high ee values. As shown in Table 2,
phenyl-substituted enamide 1a and its analogues 1b–f, which
contain electron-withdrawing halogen atoms at different
[a] Yield of isolated product. [b] Determined by HPLC analysis. n.d.=not
determined.
Table 2: Synthesis of chiral 4-hydroxy-1,2,3,4-tetrahydropyridine deriva-
tives 2.
Entry
1
R
Ar
T [8C] t [h] (S)-2
(Yield [%])[a]
ee [%][b]
1
2
3
4
5
6
7
1a Ph
1b Ph
1c Ph
1d Ph
1e Ph
1 f Ph
1g Ph
Ph
À30 24 2a (89)
À35 35 2b (92)
92.8
97.6
92.6
Scheme 3. Chiral catalysts used in this study.
4-Cl-C6H4
4-F-C6H4
4-Br-C6H4
2-Cl-C6H4
2,4-Cl2C6H3
3,4-
À20
6
2c (97)
À30 40 2d (99)
À30 14 2e (96)
À30 20 2 f (97)
97.6
induction was very low, with the ee values for the product 2d
of 3.3% and 35.4%, respectively. When the reaction cata-
lyzed by Cat-1 was performed at À308C, which led to
a sluggish transformation, only a slight improvement in
enantioselectivity to 52.1% was obtained (Table 1, entry 6).
Screening of salen-AlCl catalysts Cat-6 to Cat-10, which are
derived from the modified chiral salen ligands (Table 1,
entries 7–13), indicated that Cat-6 was a promising hit in
terms of catalytic efficiency and enantioselectivity, as product
2d was obtained in 89% yield with an ee value of 69.3%
within 13.5 h (Table 1 entry 7). Further optimization of the
>99.5
>99.5
91.4
À20
4
2g (94)
(OCH2O)C6H3
4-Me-C6H4
8
9
10
11
12
1h Ph
À20 42 2h (77)
2i (90)
>99.5
80.0
88.6
n.d.
93.5
95.9
1i Me Ph
1i Me Ph
1i Me Ph
1j BnO Ph
À10
5
À20 50 2i (82)
À30 96 2i (trace)
À30 42 2j (69)
À30 22 (R)-2a (91)
13[c] 1a Ph
Ph
[a] Yield of isolated product. [b] Determined by HPLC analysis. [c] (S)-
binol–Ti complex was used. n.d.=not determined.
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positions on the benzene ring, were transformed into the
corresponding heterocyclic products in 89–99% yields with
ee values ranging from 92.6% to more than 99.5% (Table 2,
entries 1 to 6). A high conversion and good enantioselectivity
was also obtained from the reaction of 1g, which has an
electron-rich phenyl moiety (Table 2, entry 7). In the case of
enamide 1h, which contains a 4-tolyl group, the highly
enantioselective cyclization proceeded slowly at À208C, and
2h was obtained in 77% yield after 42 h with an ee value of
more than 99.5% (Table 2, entry 8). It is noteworthy that N-
acetyl substituted enamide 1i and enecarbamate 1j were also
tolerated by the (R)-binol–Ti catalytic system, and these
reactions proceeded analogously to yield products 2i and 2j,
respectively (Table 2, entries 10 and 12). The comparable
ee values of the products reflect the consistent level of
enantiocontrol of the chiral catalyst. The different reaction
rates for substrates 1a, 1I, and 1j, however, indicate the
tuning effect of the electron-withdrawing group on the
nitrogen atom on the nucleophilic reactivity of the enamides.
The absolute configuration of the products (S)-2 was deter-
mined by X-ray crystallographic analysis of (S)-2e and (S)-2h
(Figure S1 in the Supporting Information).[18] When the (S)-
binol–Ti complex was applied as a chiral catalyst, the reaction
gave (R)-2a, the enantiomer of (S)-2a, in excellent yield and
enantioselectivity (Table 2, entry 13).
(R)-binol protons, additional proton signals were detected
downfield in the 1H NMR spectrum (Figure S3–S5 in the
Supporting Information) in a mixture of the chiral ligand and
Ti(OiPr)4 at a 2:1 ratio, which indicates a slow exchange of
ligand and ligand–Ti complexes on the NMR time scale. The
high intensity of proton signals of the free (R)-binol ligand
also suggests a low conversion of the ligand into (R)-binol–Ti
complexes. The diffusion coefficients of the (R)-binol–Ti
complex (7.81 ꢂ 10À10 m2 sÀ1) and free (R)-binol (1.33 ꢂ
10À9 m2 sÀ1) were then measured in CD2Cl2 by using the
DOSY technique (Figure S6 and S7 in the Supporting
Information). On the assumption that the molecules are
spherical, the ratio of the molecular weights of two species
Mcomplex/Mbinol calculated from (Dbinol/Dcomplex)3 is 4.9:1.[21] This
calculation suggests that the complex has an approximate
structure of [(R)-binol–Ti(OiPr)2]3, which co-exists in equi-
librium with free (R)-binol in solution. Computer simulation
shows that the nonlinear effect fits well to a trimeric (ML)3
model[19a] (Figure S8–S10 in the Supporting Information).
Although the exact mechanism awaits further study, the
aforementioned outcomes support the involvement of [(R)-
binol–Ti(OiPr)2]3 as the most probable catalytic species.
The chiral hydroxylated 1,2,3,4-tetrahydropyridines 2 are
conceivably invaluable building blocks in organic synthesis.
As a demonstration, the hydrogenation of 2a in the presence
of the Crabtree catalyst[22] produced 4-hydroxypiperidine
derivatives trans-5 and cis-5 almost quantitatively in a 5:1
ratio (Scheme 5).
The asymmetric catalysis was readily extended to alkyl-
substituted enamides. For example, the reaction of enamide 3,
which contains a cyclohexenyl substituent is shown in
Scheme 4. The bicyclic product, 1-benzoyl-4-hydroxy-octahy-
droquinoline (4), was conveniently obtained in 66% yield in
more than 99.5% ee.
Scheme 5. Catalytic hydrogenation of 2a.
In summary, we have demonstrated a general and efficient
method for the synthesis of highly enantiopure 4-hydroxy-
1,2,3,4-tetrahydropyridine derivatives from the intramolecu-
lar nucleophilic addition of tertiary enamides to aldehydes
catalyzed by a chiral binol–Ti complex. The outcomes, along
with our previous discoveries, show convincingly that tertiary
enamides are stable and versatile nucleophiles that are useful
in organic synthesis. The study of various enaminic reactions
of tertiary enamides in synthesis is being actively pursued and
the results will be reported in due course.
Scheme 4. Synthesis of enantiopure bicyclic compound 4.
Although combinations of binol and Ti(OiPr)4 have been
used widely as chiral Lewis acid catalysts in asymmetric
syntheses, an understanding of the reaction mechanisms still
remains elusive, with different catalytic species being pro-
posed depending upon the reactions and reaction condi-
tions.[18] To provide mechanistic insight into the reaction of
enamides, we examined the transformation of 1d into 2d as
a model reaction. Almost identical, positive nonlinear
effects[19] were obtained with different catalyst concentrations
(0.5 mm and 0.25 mm, Figure S2 in the Supporting Informa-
tion). However, a higher catalyst loading (5 mol%) led to
a faster conversion than a lower catalyst loading (2.5 mol%).
These results are contrary to the (R)-binol–Ti complex-
catalyzed enantioselective glyoxylate-ene reaction reported
by Mikami and co-workers.[20] These results clearly indicate
that the monomeric (R)-binol–Ti complex is not responsible
for the asymmetric catalysis of enamides. To shed light on the
catalytic species, 1H NMR spectroscopy and diffusion-
ordered spectroscopy (DOSY) were used. Except for free
Received: January 17, 2012
Published online: March 22, 2012
Keywords: asymmetric catalysis · binol · enamides ·
.
nonlinear effects · tetrahydropyridines
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