Catalytic asymmetric difunctionalization of stable tertiary enamides with salicylaldehydes: Highly efficient, enantioselective, and diastereoselective synthesis of diverse 4-chromanol derivatives

Article abstract of DOI:10.1021/ol5029964

Catalyzed by a chiral BINOL-Ti(OiPr)₄ complex, various stable tertiary enamides reacted with salicylaldehydes to afford diverse cis,trans-configured 4-chromanols that contain three continuous stereogenic centers in good yields with excellent diastereoselectivity and enantioselectivity. The reaction proceeded through the addition of enamide to aldehyde followed by the intramolecular interception of the resulting iminium by the hydroxy group. Oxidation of the resulting 4-chromanols yielded almost quantitatively chroman-4-one derivatives which underwent diastereospecific reduction with NaBH₄ to produce cis,cis-configured 4-chromanols.

Full text of DOI:10.1021/ol5029964

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Difunctionalization of Stable Tertiary Enamides
with Salicylaldehydes: Highly Efficient, Enantioselective, and
Diastereoselective Synthesis of Diverse 4‑Chromanol Derivatives
Ling He,† Liang Zhao,‡ De-Xian Wang,† and Mei-Xiang 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
‡MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing 100184, China
S
* Supporting Information
ABSTRACT: Catalyzed by a chiral BINOL−Ti(OiPr)4 complex,
various stable tertiary enamides reacted with salicylaldehydes to
afford diverse cis,trans-configured 4-chromanols that contain three
continuous stereogenic centers in good yields with excellent
diastereoselectivity and enantioselectivity. The reaction proceeded
through the addition of enamide to aldehyde followed by the
intramolecular interception of the resulting iminium by the
hydroxy group. Oxidation of the resulting 4-chromanols yielded
almost quantitatively chroman-4-one derivatives which underwent diastereospecific reduction with NaBH4 to produce cis,cis-
configured 4-chromanols.
s the members of the dihydrobenzopyran family, 4-
chromanol and chroman-4-one derivatives occur as natural
examples using enamides as a testing ground for the study of
asymmetric hydrogenation of the carbon−carbon double bond.8
Only when reacted with highly electrophilic reagents such as
iminium,10,11 acyl chloride,10 and oxonium,12 tertiary enamides
behave as nucleophiles.
A
and synthetic products of various biological activities.1
Perinadine A, a complex alkaloid isolated recently from
marine-derived fungus Penicillium citrinum, for example, features
a pyrrolidine-fused 4-chromanol core structure.2 Although the
syntheses of 4-chromanols and chroman-4-ones are well
documented,1,3 de novo synthesis of enantiopure 4-chromanol
and chroman-4-one derivatives under asymmetric catalysis is
exceedingly rare. It is challenging and desirable to develop a
diversity-orientated synthesis of functionalized 4-chromanols
and chroman-4-ones that assemble the core structure of natural
products.
However, the notion that tertiary enamides are stable, silent
enamines and marginally valuable chemical entities has been
challenged recently.13−17 We proposed several years ago that the
enabled regulation of a cross conjugation system of an enamide
moiety by means of the electronic and steric effects of the
substituents attached on enamide segment CC−N−CO and
the reaction conditions would rejuvenate the nucleophilicity of a
tertiary enamide. This strategy has guided us to accomplish the
intramolecular nucleophilic reactions of tertiary enamides with
some electrophiles,13−17 providing novel methods for the
synthesis of N-heterocyclic compounds. However, almost all
synthetic applications of tertiary enamides reported to date are
monofunctionalizations via deprotonation of the putative
acylated iminium intermediates which are generated from the
initial nucleophilic reaction of enamides11−17 (Figure 2, previous
works). We envisaged that interception of the iminiums by a
nucleophile would afford difunctionalized products. Various ring
structures would be constructed from difunctionalizations if
amphiphilic reagents were used (Figure 2, this work). To
continue our studies on the exploration of new chemistry for
stable tertiary enamides, we designed an unprecedented tandem
reaction strategy for the construction of the 4-chromanol
framework. The key steps comprise an intermolecular
Enamines4 have found wide applications in organic synthesis
owing to Stork’s landmark work in the 1950s.5 When one of the
N-alkyl groups of enamines is replaced by an electron-
withdrawing group such as acyl, tertiary enamides are generated.
Further substitution of the other N-alkyl by hydrogen gives rise
to the formation of secondary enamides (Figure 1). While
secondary enamides are active aza-ene components,6 tertiary
enamides exhibit diminished nucleophilicity because the N-
electron-withdrawing group alleviates the delocalization of lone-
pair electrons of the nitrogen atom into the carbon−carbon
double bond.7−9 This has been exemplified by a plethora of
Received: October 12, 2014
Figure 1. Enamine and tertiary and secondary enamides.
© XXXX American Chemical Society
A
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Table 1. Optimization of the Chiral BINOL−Ti Complex C8-
a
Catalyzed Reaction of 1a with 2a
3a
temp time 3a+4a
(ee)
b
c
d
e
entry catalyst
solvent
(°C)
(h)
(%)
3a:4a
(%)
1
C8
C8
C8
C8
C8
C8
C8
C8
C8
C8
DCM
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
111
86
52
30
59
72
50
59
74
66
76
80
67
>20:1 57.7
11:1 28.5
10:1 24.3
>20:1 72.1
>20:1 56.8
>20:1 50.8
>20:1 85.2
>20:1 60.8
>20:1 81.1
>20:1 76.7
>20:1 87.2
2
3
MeCN
C6H6
86
Figure 2. Strategic designs based on reactivity of tertiary enamides.
4
110
86
5
PhMe
o-xylene
nucleophilic addition of a tertiary enamide to benzaldehyde
followed by an intramolecular trap for the iminiun by the phenol
group. We were pleased to discover that, in the presence of chiral
BINOL and Ti(OiPr)4, the reaction between tertiary enamides
and salicylaldehydes indeed provides a highly enantio- and
diastereoselective synthesis of diverse 4-chromanol derivatives
which contain three continuous stereogenic centers.
6
70
f
7
o-xylene
p-xylene
p-xylene
48
8
70
f
9
94
f
10
11
m-xylene
o-xylene
110
120
C8:H2O
(5)
As a prelude of asymmetric catalysis, we first tested an achiral
Lewis acid catalyzed reaction of tertiary enamide 1a with
salicyladehyde 2a. After screening and optimization, SnCl2 was
found to catalyze the reaction efficiently under mild conditions,
affording a mixture of cis,trans- and cis,cis-configured pyyrolidine-
fused 4-chromanols 3a and 4a with a dr (3a:4ab) of 15 to 1
(Tables S1 and S2). The SnCl2-catalyzed reaction was extended
to other tertiary enamides and salicylaldehydes, producing
racemic products 3 diastereoselectively in good yields (Table
S3).
12
13
14
15
16
17
18
C8:H2O
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
rt
24
24
24
24
24
64
17
17
17
17
24
48
17
65
67
67
59
53
55
66
98
93
76
89
84
90
>20:1 93.7
>20:1 97.3
>20:1 97.6
>20:1 97.9
>20:1 98.3
>20:1 95.2
>20:1 97.3
>20:1 96.5
>20:1 96.0
>20:1 84.4
>20:1 95.6
>20:1 96.5
>20:1 −96.8
(10)
C8:H2O
(20)
rt
C8:H2O
(40)
rt
C8:H2O
(80)
rt
C8:H2O
(100)
rt
C8:H2O
(20)
−5
30
40
50
60
40
40
40
The outcomes of the SnCl2-catalyzed reaction encouraged us
to attempt asymmetric catalysis with the focus on chiral Pybox-
SnX2 complexes C1 to C4 (Figure 3). Unfortunately, although
C8:H2O
(20)
19 C8:H2O
(20)
20
21
22
23
24
C8:H2O
(20)
C8:H2O
(20)
C8:H O
2g
(20)
C8:H O
2h
(20)
j
C8:H O
2i
(20)
Figure 3. Chiral catalysts used in the study.
a
1a (0.5 mmol), 2a (1 mmol), and Ti-complex (10 mol %) were used.
b
c
d
H2O (x mol % relative to 1a) was used. Isolated yield. Determined
e
f
by 1H NMR. Determined by chiral HPLC analysis. Solvent was used
these metal complexes were able to effect diastereoselective
reaction of 1a with 2a, the enantioselectivity was appallingly low
with product ee’s being 0−31% (entries 1−4, Table S4,
Supporting Information). The chiral salen−metal complexes
C5−C7, efficient catalysts for catalyzing the enantioselective
addition of tertiary enamides to ketones,14a were found to be
entirely inactive for the intermolecular reaction between 1a and
2a (entries 5−7, Table S4, Supporting Information).
We then turned our attention to the catalytic systems derived
from chiral BINOL and Ti(OiPr)4.18 Based on a previous
study,15 a mixture of chiral BINOL and Ti(OiPr)4 (2:1) with a 10
mol % loading was first tested as catalyst C8 under anhydrous
conditions. As tabulated in Table 1, the reaction at ambient
temperature in DCM showed high diastereoselectivity, but
moderate efficiency and enantioselectively were observed (entry
1, Table 1). Catalysts C9 and C10 which were prepared from
modified BINOL derivatives (Figure 3) exhibited disappoint-
g
h
without drying with sodium. Catalyst loading was 5 mol %. Catalyst
loading was 1 mol %. (S)-BINOL was used. Ent-3a was obtained.
i
j
ingly deteriorated catalytic activity and enantioselectivity (entries
8−9, Table S4, Supporting Information). To improve the
catalytic performance of C8, the solvent effect was examined.
While polar solvents such as THF and CH3CN were not
favorable (entries 2 and 3, Table 1), employment of nonpolar
solvents including benzene, toluene, and xylene appeared
beneficial, increasing the yield and enantioselectivity (entries 4
to 6, Table 1). Astonishingly, when moistened o-xylene was used
accidentally, the reaction proceeded rapidly to give 3a with 85.2%
ee (entry 7, Table 1).
Scrutiny of water effect19 as summarized in entries 11 to 16,
Table 1, revealed that addition of water in a range of 5 to 100 mol
% led to a dramatic improvement in enantioselectivity, with the
B
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ee of 3a increasing from 87.2% to 98.3%. It should be noted that
the chemical yield of 3a was slightly corroded if water exceeded
80 mol % in the reaction (entries 15 and 16, Table 1). The
reaction was expectedly facilitated at elevated temperatures.
When the reaction was performed at 40−50 °C, product 3a was
isolated almost quantitatively with ee’s up to 96.5% (entries 19
and 20, Table 1). Higher temperature caused a decrease of
enantioselectivity (entry 21, Table 1) whereas lower temperature
resulted in a slow reaction (entry 17, Table 1). The catalytic
asymmetric reaction could also proceed effectively when the
titanium loading was lowered to 1−5 mol %, albeit an elongated
reaction period was required (entries 22 and 23, Table 1). The
use of (S)-BINOL as a chiral ligand gave rise to the formation of
ent-3a in 90% yield and 96.8% ee (entry 24, Table 1).
selectivities, 4-methoxy-salicyladehyde 2m reacted very slug-
gishly to form product 3m in 39% yield with poor diastereo- and
enantioselectivity. A diminished reaction rate and enantioselec-
tivity were also observed from the reaction of hydroxylated
piperonaldehyde 2n, which gave product 3n in 27% yield and
81.9% ee. Consistent with the SnCl2-catalyzed reaction, a slow
rate observed for substrates 2m and 2n in the asymmetric
catalysis reflecting the strong substituent effect of the electron-
donating alkoxy which reduces the reactivity of aldehyde. It was
observed that the 4-alkoxy group on salicyladehyde decreased
selectivity in the asymmetric catalysis (Scheme 1).
Enamides 1 bearing other N-substituents were also able to
undergo a catalytic asymmetric reaction with salicyladehydes.
The catalytic efficiency, enantioselectivity, and diastereoselectiv-
ity of the reaction were, however, dependent upon the nature of
the N-substituents. All N-aroyl-substituted enamides 1a (R1 =
Ph), 1b (R1 = 4-ClC6H4), and 1c (4-MeOC6H4), irrespective of
the presence of an electron-withdrawing or -donating group on
the benzene ring, reacted efficiently with 2d to yield the
corresponding products 3a, 3p, and 3q with a high level of
enantio- and diastereo-selections. It is worth noting that when
the N-aroyl group (1a−c) was replaced by an N-Ac or N-Cbz
substituent, substrates 1d and 1e led to the highly efficient and
diastereoselective reaction albeit the enantioselectivity was
drastically decreased. Obviously, N-aroyl substituents on tertiary
enamides displayed salient advantages over other groups in
enantiocontrol.
With the optimized conditions in hand, we then tested the
scope and limitations of the catalytic asymmetric synthesis of 4-
chromanol derivatives. The outcomes compiled in Scheme 1
a
Scheme 1. Catalytic Asymmetric Synthesis of 3
The catalytic asymmetric reaction was readily expanded to
other heterocyclic and acyclic enamides. Figure 4 shows for
Figure 4. Catalytic asymmetric synthesis of 3s and 3t.
example the synthesis of piperidine-fused 4-chromanol 3s in 65%
yield with 95.7% ee from a six-membered heterocyclic tertiary
enamide 1f. A longer reaction time was required owing most
likely to the lower nucleophilicity of 1f in comparison to 1a.
Acyclic tertiary enamide 1g reacted analogously with 2d to
produce 2-benzamidochroman-4-ol 3t in 52% yield with 99.1%
ee. The decreased diastereoselectivity (dr 11:1 and dr 7:1
respectively) in these cases was probably due to the steric
difference of these enamides from the five-membered hetero-
cyclic ones. It was notable that, under the reaction conditions, 2-
benzamidochroman-4-ol 3u was stable and it did not undergo a
deamination reaction to form the 4H-chromen-4-ol compound.
The catalytic asymmetric reaction was scalable. This was
evidenced for instance by the high-yielding reaction of 1a (5
mmol) with salicylaldehydes 2a, 2d, and 2h which afforded the
gram-scale products 3a (1.33 g, 96.7% ee), 3d (1.51 g, 95.7% ee),
and 3h (1.29 g, 95.1% ee), respectively, without decreases in
enantio- and diastereoselectivity (Figure 5). To demonstrate the
synthetic potential of the method, synthesis of chroman-4-one
derivatives 5 and their subsequent conversion into compounds 4,
a
Ee values in parentheses are obtained after recrystallization.
show that all salicyladehydes 2a−o underwent an asymmetric
reaction with enamide 1a. When 5-substituted salicyladehydes
2b−i were employed, irrespective of the nature of the 5-
substituents, the reaction proceeded efficiently to yield products
3b−i in high yields with excellent enantio- and diastereose-
lectivity. Functional groups including cyano, ester, and carbon−
halogen bonds were well tolerated. Disubstituted reactants such
as 4,6-dichloro- and 3,5-dibromo-salicyladehydes reacted equally
well to afford 3j and 3k. Product 3o of high enantiomeric purity
was synthesized from 1-hydroxy-2-naphthaldehyde 2o. While the
catalytic reaction of 4-bromo-salicyladehyde 2l with 1a showed
the same level of efficiency and enantio- and diastereo-
C
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ACKNOWLEDGMENTS
We acknowledge NNSFC (21320102002) for financial support.
■
REFERENCES
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BINOL-Ti(OiPr)4-catalyzed reaction of tertiary enamides with
salicylaldehydes under mild conditions. The reaction proceeds
through the enaminic addition of enamide to aldehyde and the
interception of the resulting iminium by the phenolic hydroxy
group to afford diverse 4-chromanol derivatives in high yields
with excellent enantio- and diastereoselectivity. The synthetic
potential of the method has been demonstrated by facile
transformation of cis,trans-configured pyrrolidine-fused 4-
chromanols into chroman-4-ones upon oxidation and then to
cis,cis-configured 4-chromanol diastereomers after diastereose-
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ASSOCIATED CONTENT
* Supporting Information
■
S
Characterization and spectroscopic data, X-ray structures (cif
files). This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wangmx@mail.tsinghua.edu.cn.
Notes
The authors declare no competing financial interest.
D
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