One-pot synthesis of spirooxazino derivatives via enzyme- Initiated multicomponent reactions

Article abstract of DOI:10.1002/adsc.201300965

A novel enzyme-initiated multicomponent reaction from readily available aldehyde, nitrostyrene, cyclohexanone and acetamide substrates was discovered, enabling the facile construction of six new C-C/-N bonds and two rings in single step, one-pot operation, for the synthesis of spirooxazino derivatives in moderate to high yields. Several methods such as isotope labelling and enzyme mutation were used to probe the possible mechanism of this complex synthesis.

Full text of DOI:10.1002/adsc.201300965

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DOI: 10.1002/adsc.201300965
One-Pot Synthesis of Spirooxazino Derivatives via Enzyme-
Initiated Multicomponent Reactions
Jun-Liang Wang,+a Xiao-Yang Chen,+a Qi Wu,a,* and Xian-Fu Lina,*
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, Peopleꢀs Republic of China
Fax : (+86)-571-8795-2618; e-mail: wuqi1000@163.com or llc123@zju.edu.cn
+
These authors contributed equally to this work.
Received: October 30, 2013; Published online: March 12, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300965.
Abstract: A novel enzyme-initiated multicompo-
nent reaction from readily available aldehyde, nitro-
styrene, cyclohexanone and acetamide substrates
was discovered, enabling the facile construction of
(Scheme 1).[4] The development of more efficient ap-
proaches, which combine two or more ring-forming
reactions into a single synthetic operation and allow
the concomitant formation of several bonds with
a rapid increase in molecular complexity, represents
one of the most attractive subjects in synthetic organ-
ic chemistry.[5]
In comparison with stepwise processes, multicom-
ponent reactions (MCRs) are more powerful ap-
proaches for the preparation of structurally complex
heterocyclic spiro compound.[6,7] So far, most reported
MCRs were chemically catalyzed, and the enzymatic
MCRs have been generally less investigated.[8] How-
ever, as more and more new enzymes with new activi-
ties, and new functions of old enzymes (enzymatic
promiscuities) are being found, the application poten-
tial of biocatalysts in synthetic chemistry can be ex-
À À
six new C C/ N bonds and two rings in single step,
one-pot operation, for the synthesis of spirooxazino
derivatives in moderate to high yields. Several
methods such as isotope labelling and enzyme mu-
tation were used to probe the possible mechanism
of this complex synthesis.
Keywords: enzyme catalysis; multicomponent reac-
tions; one-pot procedure; spirooxazino derivatives
Heterocyclic spiro motifs are found in a wide variety pected to be exciting. Especially enzymatic promiscui-
of pharmacological agents and agricultural products, ties endow one enzyme with catalytic multi-functions,
which are used as anticancer agents, anticonvulsant allowing multistep reactions catalyzed by one or two
agents, antimicrobial agents.[1] In addition to their
medical and agricultural uses, non-natural heterocy-
clic spiro compounds have also been widely employed
in industrial fields as fluorescent probes and electrolu-
minescent devices because of their special rigid struc-
tures.[2] The spirooxazine motif (I) is the most popular
group of photochromic materials and the best repre-
sentative of heterocyclic spiro compounds with photo-
chromic properties. In this context, efforts to design
and develop new reactions that easily access this
structural motif have continued to attract much atten-
tion. The synthesis of heterocyclic spiro compounds
typically relies on the sequential construction of each
ring in a stepwise fashion.[3,4] For example, the synthe-
sis of fluorescent spiro-oxazino-quinoline derivatives
(II) involves a complicated synthetic sequence includ-
ing Knoevenagel condensation, reduction of nitro to
amino group, and cyclocondensation of substituted 2-
aminoquinoline-3-carobonitriles and cyclic ketones rivatives (II)
Scheme 1. Spirooxazine (I) and spiro-oxazino-quinoline de-
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Recently, our group reported a lipase/acetamide-
catalyzed Michael addition of ketones to nitroole-
fins,[12] and then we found that this co-catalyst system
was also efficient for the aldol reaction (Table S1 in
the Supporting Information). In order to extend the
application of this system and introduce further struc-
tural complexity, olefin (1a) with an electron-with-
drawing group, cyclohexanone (2a) and 4-nitrobenzal-
dehyde (3a) were shaken in one pot catalyzed by
lipase/acetamide. However, the designed product of
the aldol–Michael cascade reaction was not detected.
Unexpectedly, when Candida antarctica lipase B
(CAL-B) was used as catalyst, an orange crystalline
material was obtained, but other enzymes could not
catalyze this reaction (Table S2 in the Supporting In-
formation). The structure of this product was con-
Figure 1. X-ray crystallographic ORTEP drawing of com-
pound 5a.
enzymes in an MCR manner.[9,10] We have reported firmed by NMR, HR-MS (please see the Supporting
several cases of cascade reactions or MCRs in one- Information) and X-ray single crystal diffraction
pot catalyzed by one enzyme.[11] However, the more (Figure 1). Interestingly the product 5a is a spirooxazi-
complicated cases of enzymatic MCRs, especially for no derivative, and the whole reaction process is an ap-
accessing heterocyclic spiro compounds with a rapidly parent five-component reaction as shown in Eq. (1)
À
À
increasing molecular complexity are still highly desir- (Table 1). Six new C C/C N bonds and two rings are
able. Herein, we report an unprecedented lipase-initi- constructed in a single step, in one pot, leading to
ated five-component reaction for the one-pot synthe- a rapid increase in molecular complexity. This seren-
sis of complicated spirooxazino derivatives.
dipitous success inspired us to go forward, and some
Table 1. Optimization of the reaction conditions.[a]
Entry
Amide
Temperature [oC]
Yield [%]
1
2
3
4
5
6
7
8
acetamide (4a)
propanamide (4b)
benzamide (4c)
acrylamide (4d)
acetamide (4a)
acetamide (4a)
acetamide (4a)
acetamide (4a)
acetamide (4a)
acetamide (4a)
acetamide (4a)
50
50
50
50
50
50
50
50
50
25
60
15/25[g]
3
1
5
38[b,g]
43[c,g]
55[d,g]
69[d,e,g]
72[c,d,e,f,g]
21[d,e,f,g]
60[d,e,f,g]
9
10
11
[a]
Unless otherwise noted, reactions conditions were 1a (0.5M), 3a (0.5M), enzyme (50 mg), amide (1M), in 2a (1 mL) at
508C for 72 h.
1M 1a was used.
1.5M 1a was used.
0.25M 3a was used.
70 mg enzyme were used.
1.25M acetamide was used.
The reaction time was 144 h.
[b]
[c]
[d]
[e]
[f]
[g]
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One-Pot Synthesis of Spirooxazino Derivatives
Table 2. Multicomponent reaction catalyzed by CAL-B.[a]
Entry
R1
R2
Product
Yield [%]
1
2
3
4
5
6
7
8
4-CH3O-C6H4
4-HO-C6H4
3-HO-C6H4
C6H5
4-CH3-C6H4
4-i-Pr-C6H4
H
H
H
H
H
H
H
H
p-CH3
p-CH3
p-CH3
p-CH3
5a
5b
5c
5d
5e
5f
5g
5h
5i
72
84
85
30
34
21
41
47
25
25
38
36
4-N
N
4-F-C6H4
C6H5
4-F-C6H4
4-HO-C6H4
4-CH3O-C6H4
9
10
11
12
5j
5k
5l
[a]
Experimental conditions: 0.25M aldehyde, 1.5M nitroalkene, 1 mL monocarbonyl compound, 1.25M acetamide, 70 mg
CAL-B, 508C, 144 h.
reaction conditions were screened based on the in the transformation, with acceptable yields (en-
model reaction of aldehyde (3a), olefin (1a) and cy- tries 9-12, Table 2). Concerning other aldehyde sub-
clohexanone (2a) to see whether it was possible to im- strates, the spiro compound was formed most effi-
prove the enzymatic MCR. Firstly, control reactions ciently in the presence of 4-nitrobenzaldehyde (3a).
under the catalysis of BSA or denatured CAL-B con- Unfortunately, when other aldehydes were used, al-
firmed the essentially catalytic roles of active lipase in though the corresponding products could be detected,
the MCR (entries 11 and 12, Table S2 in the Support- the reaction yields were very low.
ing Information). Further screening of structurally dif-
In order to probe the possible mechanism of this
ferent amides indicated that acetamide was the ideal multicomponent reaction, several important questions
choice for this transformation, while three other should be considered. (i) When starting from 1a, 2a,
amides including propanamide, benzamide and acryl- and 3a, is the reaction process proceeding via a Mi-
amide displayed almost no effects (entries 1–4, chael addition or an aldol reaction? (ii) Is the N atom
Table 1). The molar ratio of substrates, the amounts of the spiro product from the acetamide molecule 4
of enzyme and amide, and the temperature were then or the NO2 group in 1a? (iii) What are the roles of
examined carefully. The reaction was found to pro- acetamide and CAL-B in the MCR. Regarding item
ceed with 1.5M nitroalkene, 0.25M 4-nitrobenzalde- 1, we synthesized the intermediate of the Michael ad-
hyde, 1.25M acetamide, and 70 mg CAL-B in cyclo- dition or aldol reaction, respectively, from 1a+2a and
hexanone at 508C giving spirocompound 5a in the 3a+2a, and used them independently as the new
highest (72%) yield (entries 5–11, Table 1).
starting molecules with the addition of other necessa-
Under the above optimized conditions, the sub- ry materials, and checked the final spiro-product of
strate scope and generality of this new MCR process the MCR catalyzed by CAL-B. It was discovered that
were examined, typical results are summarized in the spiro compound could also be formed from the
Table 2. Various nitrostyrenes were subjected to the MCR using aldol intermediate as the starting material
reaction, and the corresponding products were ob- [Eq. (3) in Scheme 2]. However, no reaction was ob-
tained in moderate to high yields. Substituted nitro- served when using the Michael addition intermediate
styrenes bearing oxy-groups afforded the spiro com- as the substrate [Eq. (4) in Scheme 2]. Thus it is clear
pounds in better yields, compared with other nitro- that the first step is the aldol reaction, supported by
styrenes (entries 1–3, Table 2). Concerning the struc- the observation that a small amount of this intermedi-
ture of the cyclohexanone, substituted cyclohexanones ate was also detected in the MCR.
such as 4-methylcyclohexanone could also be applied
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Scheme 2. MCRs under the different reaction conditions.
For the item 2, the source of N atom in the final trobenzaldehyde (3a) and cyclohexanone (2a). Ac-
product is very important. Initially, we suspected that cordingly, a 62% yield was obtained under the cataly-
the N(NH) fragment was the reduction product of sis of CAL-B with acetamide, while CAL-B almost
NO2 from substrate 1a. However, this is almost im- could not catalyze this aldol reaction in the absence
possible because lipases have never been reported to of acetamide (Table S1 in the Supporting Informa-
be able to catalyze a reduction reaction. Another pos- tion). A similar synergistic effect of acetamide on
sible source is the acetamide. In a previous report of CAL-B was also found in our previous work,[12] and
an acetamide-based enzymatic Hantzsch reaction, the we speculated that acetamide played a role as co-cata-
acetamide was involved as a novel ammonia sour- lyst to activate the substrates in this aldol reaction.
ce.[11c] It seemed useful to us to use 15N-acetamide in Such effects of small organic molecules on the syn-
the MCR and to see whether the acetamide is also an thetic performance of enzymes need more studies for
ammonia source. Interestingly the 15N labelled prod- the insight into the inherent mechanisms.
uct was obtained in good yield [Eq. (5) in Scheme 2].
In this complicated MCR, the catalytic role of
The presence of acetamide was critical to the MCR CAL-B should be strictly confirmed. Considering that
not only as the source of the N(NH) fragment, but the used commercial CAL-B are crude and immobi-
also as a synergistic catalytic molecule. It is clear that lized enzyme preparations, we excluded the possible
acetamide cannot catalyze any reaction process in this catalytic activity of the immobilization carrier, the
MCR, after checking some control reactions. But we acidic or basic amino acids on the protein surface and
found that acetamide had an important synergistic also the impurity of the preparation using some con-
effect on the CAL-B-catalyzed aldol reaction of 4-ni- trol experiments. The first one is that the completely
1002
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One-Pot Synthesis of Spirooxazino Derivatives
Scheme 3. Mechanistic proposal and possible reaction process.
denatured CAL-B with the immobilization carrier tected except for some intermediate of the aldol reac-
could not catalyze the aldol reaction of 4-nitrobenzal- tion [Eq. (7) in Scheme 2]. This implies that some
dehyde with cyclohexanone (entry 5 of Table S1 in natural reaction activity of CAL-B such as hydrolysis
the Supporting Information), as well as the whole or esterification was also involved in the MCR pro-
MCR of route 1 (entry 11 of Table S2 in the Support- cess, because CAL-B S105A cannot catalyze a natural
ing Information), ruling out the catalytic possibility of hydrolysis or esterification reaction due to the lack of
both denatured protein and the immobilization carri- the essential residue 105Ser. All these results suggest
er. Actually, the catalytic promiscuity of CAL-B for that the tertiary structure and the specific active site
the aldol reaction or the Michael addition has been of CAL-B are responsible for the MCR process.
confirmed by many publications to some extent.[13]
At this stage, based on these data and some previ-
The control experiment of BSA catalysis further ex- ous references, we could propose a tentative mecha-
cluded the catalytic role of some amino acids on the nism illustrating the internal reaction sequence
protein surface (entry 12 of Table S2 in the Support- (Scheme 3). In this mechanism, CAL-B is responsible
ing Information). Another important control experi- for the early steps forming the possible intermediates
ment is using the purified CAL-B protein as the cata- A–C. The aldol reaction catalyzed by lipase was well
lyst to rule out the catalytic role of any impurity in investigated recently and also confirmed by some
commercial CAL-B preparation and confirm what is data in the reaction sequence of this MCR, thus b-hy-
really the catalyst. The purification of CAL-B is droxy ketone A was produced. In the presence of
shown in the Supporting Information. Purified CAL- CAL-B, b-hydroxy ketone A could react with activat-
B provided the final product with 25% yield [Eq. (6) ed acetamide through a tandem condensation/hydrol-
in Scheme 2], which was a bit lower than that from ysis reaction to afford the enamine intermediate C.[16]
the catalysis with commercial CAL-B, possibly ascrib- Similar activation of acetamide by CAL-B was also
able to the beneficial effect of immobilization. In the observed in another report of an acetamide-attending
pioneering works on the mechanism of CAL-B pro- CAL-B-catalyzed Hantzsch reaction.[11c] The hydroly-
miscuity by Berglund and co-workers, the S105A sis process was also partially confirmed by the pres-
mutant of CAL-B showed higher promiscuous activity ence of a small amount acetic acid and the above con-
than WT CAL-B because the S105A mutation breaks trol reaction catalyzed by CAL-B S105A mutant [Eq.
the hydrogen bond between S105–H224 and thus (7) in Scheme 2]. Next, the reaction of nitroolefins
strengthens the deprotonation ability of His 224, sup- with enamine derivatives C at room temperature can
porting the catalytic role of the H224–D187 diad for afford the intermediate D efficiently via a sequential
promiscuous reactions.[13a,b,14] Herein, the S105A Michael addition/intramolecular Nef reaction.[17] The
mutant of CAL-B was prepared and purified accord- final spiro compound product was obtained from the
ing to the previous literature[15] (details are shown in condensation of intermediate D and cyclohexan-
the Supporting Information), and used for the whole
MCR process, however no spiro compound was de-
one.[18]
ACHTUNGTRENNUNG
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acknowledged. We thank Professor Manfred T. Reetz for
helpful discussion.
As can be seen in Table 2, all spiro products have
at least two stereocenters (formed from reactions of
cyclohexanone, while >2 when using substituted cy-
clohexanones). We tried to examine the ee value of
these products by chiral HPLC. To our disappoint-
ment, no enantioselectivity could be observed. Ac-
tually, we found that the first step (aldol reaction)
where the stereocenters of the final spiro-products
were produced, failed to provide any enantioselectivi-
ty, thus it would be not expected to have good stereo-
selectivity in the whole MCR process. To the best of
our knowledge, a CAL-B-catalyzed asymmetric aldol
reaction has never been reported. Similarly for the
CAL-B-catalyzed Michael addition, a possible reason
is that the active site of CAL-B is too voluminous to
have clearly distinguished binding modes for formed
enantiomers.[19] In order to improve the stereoselectiv-
ity of this MCR process and overcome the structure
defect of the active site of CAL-B, directed evolution
and site-mutagenesis of CAL-B for the asymmetric
aldol reaction are in progress in our lab.
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In conclusion, we have developed a novel enzyme-
initiated multicomponent reaction for the one-pot
synthesis of spirooxazino derivatives starting from
readily available aldehydes, activated olefins, cyclo-
hexanone and acetamide. 12 various spiro compounds
with different substitutions could be prepared in mod-
erate to high yields. The ability of the MCR to con-
À
À
struct six new C C/C N bonds and two rings in
a single step strongly proves its important application
potential in complicated organic synthesis. The pre-
liminary investigation of the reaction mechanism re-
vealed the source of the N atom in the final spiro
products and the important catalytic roles of the
active site of Candida antarctica lipase B in the
domino process.
Experimental Section
General Procedure for the Multicomponent
Reactions
4-Nitrobenzaldehyde (0.25M), nitroalkene (1.5M), acet-
amide (1.25M), and CAL-B (Novozym435) (70 mg) in 1 mL
monocarbonyl compound were allowed to react at 508C for
144 h. The reaction was terminated by filtering off the
enzyme. The crude residue was purified by silica gel column
chromatography with an eluent consisting of petrol ether/
acetone (20/1 v/v). Product-contained fractions were com-
bined, concentrated, and dried to give 5a–5l.
Acknowledgements
The financial support from the National Natural Science
Foundation of China (No. 21072172, 21272208) is gratefully
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