Highly Enantioselective Synthesis of Cyclic Aminals with a Cyclopentadiene-Based Chiral Carboxylic Acid

Article abstract of DOI:10.1002/ejoc.201701561

A highly enantioselective aminalization of 2-aminobenzenesulfonamides and aldehydes catalyzed by a novel cyclopentadiene-based chiral carboxylic acid has been realized. The cost-effective and readily synthesized cyclopentadiene-based chiral carboxylic aci

Full text of DOI:10.1002/ejoc.201701561

A Journal of
Accepted Article
Title: Highly Enantioselective Synthesis of Cyclic Aminals with a
Cyclopentadiene-Based Chiral Carboxylic Acid
Authors: Yuebo Sui, Peng Cui, Sensheng Liu, Yanmei Zhou, Peng Du,
and haifeng zhou
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701561
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10.1002/ejoc.201701561
European Journal of Organic Chemistry
COMMUNICATION
Highly Enantioselective Synthesis of Cyclic Aminals with a
Cyclopentadiene-Based Chiral Carboxylic Acid
Yuebo Sui, Peng Cui, Sensheng Liu, Yanmei Zhou, Peng Du, and Haifeng Zhou*
Abstract:
A
highly enantioselective aminalization of 2-
Since the pioneering works of Akiyama[8] and Terada[9] in
aminobenzenesulfonamides and aldehydes catalyzed by a novel discovering the chiral BINOL-based phosphoric acids as efficient
cyclopentadiene-based chiral carboxylic acid has been realized. The Brønsted acid catalysts were reported in 2004, independently.
cost-effective and readily synthesized cyclopentadiene-based chiral The asymmetric Brønsted acid catalysis has attracted increasing
carboxylic acid was found to be a highly reactive Brønsted acid for attention in organocatalysis.[10] For example, numerous BINOL-
this transformation, affording benzothiadiazine class of cyclic
aminals with up to 98% ee.
derived Brønsted acids, such as nitrogen,[11] thiol,[12] and carbon
acids[13], have been developed. Moreover, chiral phosphoric
acids based on other frameworks like VAPOL [2,2′-diphenyl-
(3,3′-biphenanthrene)-4,4′-diol][14] and SPINOL[15] have also been
reported. However, the preparation of the above mentioned
chiral Brønsted acids requires multiple steps, chiral resolution,
and hypothermic reaction, which restrains their practical
application due to their limited commercial availability and high
price. Therefore, it is highly desirable to develop new generation
of chiral Brønsted acid catalysts to overcome these drawbacks.
Introduction
Cyclic aminals are common structural elements of diverse
commercial drugs. Among which, the benzothiadiazine class of
cyclic aminals, such as Aquamox, Thiabutazide and
Bendroflumethiazide (Figure 1), are often used as effective
diuretics for the treatment of high blood pressure.[1] It has been
established that their enantiomers have different bioactivities.[2]
However, the clinical drugs are still supplied by racemic mixture
form due to lacking of effective asymmetric synthetic methods.
Therefore, the development of catalytic asymmetric method is
highly attractive. The pioneering works in the synthesis of
enantiomerically pure 2,4-dihydroquinazolinones were reported
by List and Reuping respectively, starting from 2-aminoamides
and aldehydes with BINOL-based (BINOL= [1,1′-binaphthalene]-
2,2′-diol) chiral phosphoric acids as the catalysts.[3]
Subsequently, Tian et al. developed a modified procedure to
prepare the same cyclic aminals by employing the preformed N-
sulfonamide imines instead of aldehydes.[4] Lin and coworkers
reported the same asymmetric acetalization with SPINOL-based
Figure 1. Some examples of benzo(thia)diazine drugs.
Chiral carboxylic acids are easy available in nature, but their
application in organocatalysis is undeveloped due to the weak
acidity.[16] Fortunately, the acidity of carboxylic acids can be
strengthened by rational catalyst design.[17] In 2016, Lambert’s
group designed a new generation of carboxylic acid catalysts
based on 1,2,3,4,5-pentacarboxycyclopentadiene (PCCP). As
(SPINOL=
[2,2′,3,3′-tetrahydro-1,1-spirobi(indene)-7,7′-diol])
chiral spirocyclic phosphoric acids as the catalysts.[5] In all cases,
the axially chiral phosphoric acids bearing sterically hindered
groups play an essential role in achieving high enantioselectivity.
In addition to organocatalysis, the Sc(III)-inda-Pybox complexes
catalyzed asymmetric synthesis of 2,4-dihydroquinazolinones
has also been achieved by Kesavan′s group.[6] Compared to the
preparation of chiral 2,4-dihydroquinazolinones, very limited
reports about the asymmetric synthesis of benzothiadiazine
class of cyclic aminals have appeared. List et al. originally
mentioned the synthesis of this kind of chiral cyclic aminals in
their pioneering work about the asymmetric synthesis of 2,4-
dihydroquinazolinones.[3a] To date, the another report focused on
the asymmetric synthesis of benzothiadiazine class of cyclic
aminals has been realized by using Sc(III)-inda-pybox
complexes as the catalysts.[7] For a possible second generation
of chiral benzothiadiazine drugs, it is highly attractive to develop
shown
in
scheme
1,
the
corresponding
aromatic
cyclopentadienyl anion of PCCP is very stable by releasing a
proton, which exhibits comparable acidity to mineral acids.
Further modification of PCCP with chiral alcohols or amines
afforded a series of chiral carboxylic acids, which were also
demonstrated to be effective chiral Brønsted acid catalysts by
asymmetric Mukiyama-Mannich reaction[18] and transfer
hydrogenation.[19] This novel chiral carboxylic acids impress us
with the merits of modular synthesis, natural chirality, and well-
priced. In this paper, we report
a highly enantioselective
synthesis of benzothiadiazine class of cyclic aminals with as low
as 2 mol % chiral PCCP as a catalyst.
novel
catalytic
asymmetric
methods
for
preparing
benzothiadiazine class of cyclic aminals.
Hubei Key Laboratory of Natural Products Research and Development,
College of Biological and Pharmaceutical Sciences, China Three Gorges
University, Yichang 443002, China
E-mail: zhouhf@ctgu.edu.cn
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
Scheme 1. Lambert′s catalyst design
1
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10.1002/ejoc.201701561
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COMMUNICATION
Results and Discussion
The initial studies were carried out with the reaction of 2-
aminobenzenesulfonamide (1a) and isovaleraldehyde (2a) as a
o
model reaction at −20 C in dichloromethane in the presence of
2 mol % catalyst. First, the chiral Brønsted acids including
BINOL-based chiral phosphoric acids (S)-PA1 and (S)-PA2, and
chiral PCCP were screened (Figure 2). The chiral PCCP as a
new generation of chiral Brønsted acid afforded the best results
with regard to enantioselectivity and reactivity (Table 1, entries
1−3). Then, the effect of different reaction parameters was
investigated with chiral PCCP as a catalyst. A solvent screen
revealed that toluene provided the highest yield and best
enantioselectivity (entry 11). Other solvents, such as CH2Cl2,
CHCl3, ClCH2CH2Cl, THF, MTBE, EtOAc, hexane, and
benzotrifluoride, also gave the desired product 3a with
acceptable yields but lower enantioselectivities (entries 3−10).
Reducing the amount of catalyst from 2 mol % to 1 mol %, the
yield decreased to 73% with slightly lower ee (entry 12). It was
observed that the enantioselectivity decreased slightly in the
absence of molecular sieves, which act as desiccants to trap the
water generated during the condensation step (entry13). Next,
the reaction was performed at different temperature. Raising the
temperature results in lower enantioselectivity (entry 15; 25 oC,
Figure 2. Structures of chiral Brønsted acids
With the optimized reaction conditions in hand, the substrate
scope was examined (Table 2). In general, the results are better
than the previous works in terms of yields and
enantioselectivities.[21] First, the branched aliphatic aldehydes
including isovaleraldehyde (2a), 3,3-dimethylbutyraldehyde (2b),
and isobutyraldehyde (2c) were subjected to the reaction with 1a.
All the reactions proceeded smoothly to afford the corresponding
products 3a−3c with 93−98% ee’s. Interestingly, the less
sterically hindered linear aliphatic aldehydes like valeraldehyde
(2d), butyraldehyde (2e), and propionaldehyde (2f) also gave
the desired products 3d−3f in 92−94% yields and 90−94% ee′s.
Comparatively, the shorter chain acetaldehyde (2g) gave
relatively lower ee (3g; 85% ee). Next, the cyclopropyl (2h),
cyclopentyl (2i), and cyclohexyl (2j) carboxaldehydes were
investigated. It was found that the ring size of the cycloalkyl
aldehydes has a remarkable effect on the enantioselectivity. For
example, the cyclic aminals 3i and 3j were obtained with 93%
and 88% ee, respectively. However, the three-member ring
aldehyde 2h gave moderate ee (3h; 72% ee). In addition, the
aralkyl aldehydes 2k and 2l were also tested, affording good to
excellent yields and ee′s (3k: 83% yield, 93% ee; 3l: 86% yield,
89% ee). Furthermore, the benzyloxyacetaldehyde (2m) was
also applicable to this reaction, and 72% ee of 3m was obtained.
Finally, the aromatic aldehydes, such as 2-bromobenzaldehyde
(2n) and 3-bromobenzaldehyde (2o), were employed as
substrates. The results showed that the less sterically hindered
substrate 2o gave higher ee comparing to 2n (3n: 50% ee; 3o:
81% ee).
o
78% ee). Delightedly, up to 98% ee was achieved at −45 C with
98% yield (entry16).[20] Notably, the results are better than the
previous works with regard to the yield and enantioselectivity (3a:
80% yield and 96% ee in ref.3; 65% yield and 92% ee in ref.7).
o
Finally, 2 mol % of chiral PCCP, 1 mL toluene, −45 C, and 70
mg 4Å molecular sieves were set as the optimal reaction
conditions.
.
Table 1. Optimization of the reaction conditions[a]
temp.
[oC]
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
-20
yield
ee
entry
cat.
solvent
[%][b] [%][c]
1
2
3
4
5
6
7
8
(S)-PA1 CH2Cl2
(S)-PA2 CH2Cl2
83
82
96
97
97
73
77
81
74
75
98
73
86
99
99
97
43
38
64
51
55
49
65
53
83
90
96
93
90
90
78
98
PCCP
PCCP
PCCP
PCCP
PCCP
PCCP
PCCP
PCCP
PCCP
PCCP
PCCP
PCCP
PCCP
PCCP
CH2Cl2
CHCl3
ClCH2CH2Cl
THF
MTBE
EtOAc
hexane
C6H5CF3
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12[d]
13[e]
14
15
16
Scheme 2 Gram-scale reaction
To showcase the practicality of this methodology, a gram-
scale reaction was carried out. As shown in Scheme 2, the
asymmetric aminalization of 1a ( 5 mmol) and 2a (5.5 mmol)
gave the desired product 3a with 98% ee and 90% yield (1.08 g).
Furthermore, the asymmetric synthesis of antihypertensive
−20
0
25
−45
[a]Reaction conditions: 2-aminobenzenesulfonamide (1a) (0.2
mmol), isovaleraldehyde (2a) (0.22 mmol), catalyst (2 mol %),
4Å MS (powdered, 70 mg), solvent (1.0 mL), 24 h. [b]Isolated
yields. [c]Determined by chiral HPLC. [d]1 mol % PCCP was used.
[e]In the absence of molecular sieves.
pharmaceutical Thiabutazide
was
also attempted
in
o
dichloromethane at 25 C for 72 h in the presence of 10 mol %
chiral PCCP. The (R)-Thiabutazide was obtained with 61% yield
and 45% ee.[22]
2
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COMMUNICATION
Table 2. Substrate scope for the synthesis of cyclic aminals[a]
Scheme 3. A proposed reaction pathway
Conclusions
In summary, we have developed an efficient asymmetric
synthesis of benzothiadiazine class of cyclic aminals from the
readily available starting materials with cyclopentadiene-based
chiral carboxylic acid as a catalyst. A series of chiral cyclic
aminals were obtained in good to excellent yields and up to 98%
ee. Further studies focused on the asymmetric synthesis of
chiral benzothiadiazine drugs by cooperative catalysis of chiral
PCCP and Lewis acids to enhance the reactivity are underway.
Experimental Section
General Procedure for Asymmetric Synthesis of Cyclic Aminals:
In a 20 mL Schlenk tube, 2-aminobenzenesulfonamide (1a) (34 mg,
0.2 mmol, 1 equiv), aldehyde 2 (0.22 mmol, 1.1 equiv), chiral PCCP
(3.9 mg, 0.004 mmol, 2 mol %), 4 Å molecular sieves (70 mg,
powdered) and 1 mL toluene were added. Then the mixture was
stirred at −45 oC for 24 h under nitrogen atmosphere. Then 0.05 mL
of reaction mixture was taken and filtered through Celite with ethyl
acetate as eluent. The sample was subjected to HPLC analysis. The
rest reaction mixture was concentrated to dryness and purified by
silica gel chromatography with PE/EA (4:1, v/v) as eluent to give the
desired product 3.
[a]Reaction conditions: PCCP (2 mol %), 1a (0.2 mmol), 2 (0.22
mmol), toluene (1.0 mL), 4Å MS (powdered, 70 mg), −45 oC, 24
h.
Acknowledgements
To understand the origin of the stereochemistry, a possible
reaction pathway is proposed as shown in Scheme 3. The initial
We are grateful for financial support from the National Natural
Science Foundation of China (21202092) and for a Startup
Foundation from the China Three Gorges University
(KJ2012B080, KJ2014H008).
protonation of aldehyde
1
with chiral PCCP produces
intermediate A. And then the condensation of protonated
aldehyde with amine group of compound 2 leads to intermediate
B and releases an equimolar of H2O. The enantioselectivity is
determined by the step of intramolecular amidation of imine. In
the transition state B, the chiral PCCP brings the sulfonamide
and imine groups together through hydrogen bonding. The
sulfonamide attacks the imine from the Re face preferentially as
a result of less steric hindrance, furnishing product 3 in R
configuration and regenerating chiral PCCP for the next catalytic
cycle.
Keywords: cyclic aminals • benzothiadiazine • chiral carboxylic
acid • cyclopentadiene
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4
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
An asymmetric aminalization of 2-
Asymmetric Organocatalysis*
aminobenzenesulfonamides
and
Yuebo Sui, Peng Cui, Sensheng
Liu, Yanmei Zhou, Peng Du, and
Haifeng Zhou*
aldehydes with cyclopentadiene-
based chiral carboxylic acid as a
catalyst has been developed.
Page No. – Page No.
Highly
Enantioselective
Synthesis of Cyclic Aminals
with a Cyclopentadiene-Based
Chiral Carboxylic Acid
5
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