Construction of Chiral-Fused Tricyclic γ-Lactams via a trans-Perhydroindolic Acid-Catalyzed Asymmetric Domino Reaction

Article abstract of DOI:10.1021/acs.orglett.7b01160

An asymmetric domino reaction was developed utilizing readily available cyclic α-dehydroamino ketones and aldehydes, which when subjected a 2-iodoxybenzoic acid (IBX)-mediated oxidation gives pyrrolidinone-containing tricyclic derivatives. trans-Perhydroi

Full text of DOI:10.1021/acs.orglett.7b01160

Letter
pubs.acs.org/OrgLett
Construction of Chiral-Fused Tricyclic γ‑Lactams via a trans-
Perhydroindolic Acid-Catalyzed Asymmetric Domino Reaction
Qianjin An,†,§ Jiefeng Shen,†,§ Delong Liu,*,† Yangang Liu,† and Wanbin Zhang*,†,‡
‡
†School of Pharmacy and School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, China
S
* Supporting Information
ABSTRACT: An asymmetric domino reaction was developed
utilizing readily available cyclic α-dehydroamino ketones and
aldehydes, which when subjected a 2-iodoxybenzoic acid
(IBX)-mediated oxidation gives pyrrolidinone-containing
tricyclic derivatives. trans-Perhydroindolic acid proved to be
an efficient organocatalyst in this reaction (up to 94% yield,
99% ee, and >20:1 dr). The product could be conveniently
converted to synthetically useful intermediates via simple
transformations. A possible stereocontrolled process has been
suggested according to X-ray crystallography studies.
za-heterocyclic γ-lactams and pyrrolidines are important
skeletons and exist in numerous natural products,
approach.8 Although satisfactory to good yields and excellent
regioselectivities could be obtained, the above-mentioned
methodologies either utilize substrates that are not readily
available or provide somewhat low reaction activities. Fur-
thermore, substrate scope is limited, and only one example of an
asymmetric catalytic strategy for the synthesis of enantioenriched
pyrrolidine-containing tricycles has been reported by Zhou.9
Recently, we reported an efficient Rh-catalyzed asymmetric
hydrogenation of cyclic α-dehydroamino ketones for the
synthesis of chiral α-amino ketones and trans-β-amino
alcohols.10 The cyclic α-dehydroamino ketone substrates can
be easily prepared from benzaldehyde via a simple aldol
condensation followed by an intramolecular Friedel−Crafts
reaction. Furthermore, our group previously disclosed an
efficient synthetic route for the preparation of trans-perhy-
droindolic acids, a key intermediate used in the synthesis of
trandolapril and its isomeric byproducts.11 These proline-like
molecules subsequently proved to be excellent organocatalysts
for several types of asymmetric cascade reactions.12 Herein, we
report the application of trans-perhydroindolic acid IV to the
asymmetric domino reaction of cyclic α-dehydroamino ketones
and simple aldehydes for the synthesis of biologically active γ-
lactam and pyrrolidine-containing tricyclic derivatives (Scheme
1).
A
physiologically active compounds, and catalysts.1 The con-
struction of such motifs has therefore been intensively
investigated. In comparison, even though they can serve as
“privileged structures” in medical and pharmaceutical chemistry,2
γ-lactam and pyrrolidine-containing tricyclic derivatives have
received less attention because the synthesis of such function-
alized tricycles remains challenging.3 In 1991, Marson reported a
one-pot stereocontrolled synthesis of a few substituted tricyclic
γ-lactams via the condensation of 3-alkenamides with benzalde-
hyde in acidic media (Figure 1, the same below).4 In 2004,
Figure 1. Tricyclic γ-lactams and pyrrolidines.
Scheme 1. Asymmetric Domino Reaction
Okamoto synthesized a pyrrolidine-containing tricycle using a
divalent titanium reagent.5 The following year, Feldman
prepared similar products using a cascade cyclization sequence
evolving from the thermolyses of allenyl azides.6 The You group
combined a tandem NHC-catalyzed aza-benzoin and Michael
reaction to produce dihydroindenones, which can then be
transformed to pyrrolidinone-containing tricycles.7 More
recently, Nicewicz realized the only reported example of the
synthesis of a tricyclic γ-lactams using a photoredox-mediated
Received: April 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Initial studies began with the asymmetric domino reaction of
cyclic α-dehydroamino ketone 1a with propanal 2a in benzene at
25 °C in the presence of DABCO, using different chiral proline-
like catalysts I−IV (Table 1).
reducing the dosage of DABCO to 0.1 equiv resulted in a sharp
decrease in reaction activity with the reaction failing to go to
completion even after 3 days. The ORTEP drawing of the desired
product 3a indicates that a cis-fused bicyclic structure bearing
four S-configuration chiral centers is formed in our reaction.13
We next investigated the influence of solvent on the reaction
(Table 2). The reaction proceeded smoothly in the protic alcohol
a
Table 1. Screening of Catalysts and Additives
a
Table 2. Screening of Solvents
b
d
yield
ee
c
entry
time
2 h
additive (equiv)
(%)
dr
(%)
e
1
DABCO (1)
DABCO (1)
DABCO (1)
DABCO (1)
−
98
70
94
89
26
32
86
70
85
90
38
91
90
89/7/2/2
0
77
4
f
2
7 days
71/9/19/1
86/9/4/1
g
3
1.0 days
1.0 days
7 days
b
time
yield
(%)
4
84/5/5/6
93
93
87
93
91
88
67
89
93
93
c
d
entry
(days)
solvent
CH3OH
dr
ee (%)
5
52/4/19/25
56/8/17/19
77/4/8/11
78/5/16/1
74/9/15/2
83/3/13/1
67/15/15/3
86/3/5/6
1
2
3
4
5
6
7
8
0.5
7
77
69
90
90
81
94
94
95
93
88
61/21/11/7
71/11/14/4
62/9/19/10
88/3/8/1
72/6/15/7
82/6/9/3
87/4/6/3
90/4/5/1
90/10
68
88
86
93
91
93
92
96
94
94
6
7 days
benzoic acid (1)
DMAP (1)
Et3N (1)
THF
7
1.5 days
1.5 days
1.5 days
1.5 days
7 days
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
DCM
8
benzene
9
DIPEA (1)
TMEDA (1)
Na2CO3 (1)
DABCO (0.5)
DABCO (0.2)
bromobenzene
toluene
10
11
12
13
m-xylene
mesitylene
mesitylene
mesitylene
1.5 days
2.0 days
88/3/8/1
e
9
f
10
88/12
a
Using the optimal reaction conditions shown in Table 1 (entry 13) in
b
different solvent. Isolated yields of the products 3a containing the
major and minor isomers. Determined by chiral HPLC using a chiral
IE-H column with products containing four isomers. With the major
configuration. Product 4a; IBX, CH3CN, 80 °C. Product 5; Et3SiH/
c
a
Reactions of 1a (0.2 mmol) with 2a (2 mmol) were catalyzed by
catalyst IV (10 mol %) in the presence of an additive (1 equiv) in
d
e
f
b
benzene (2.0 mL) at 25 °C. Isolated yields of the products containing
BF3·Et2O, DCM, −78 to 25 °C.
c
the major and minor isomers. Determined by chiral HPLC using a
d
chiral IE-H column with products containing four isomers. With the
e
f
g
major configuration. Catalyst I. Catalyst II. Catalyst III.
CH3OH to give the desired product 3a in only moderate yield
and enantioselectivity (entry 1). When aprotic solvents such as
THF, DCM, benzene, bromobenzene, toluene, m-xylene, and
mesitylene were used, good to excellent yields and enantiose-
lectivities were obtained (entries 2−8). Mesitylene was found to
be the best solvent according to a combination of chemical yield
and enantioselectivity (entry 8). To obtain the terminal tricyclic
γ-lactam product, 3a was oxidized using 2-iodoxybenzoic acid
(IBX) to give the desired product 4a in 93% yield, 94% ee, and
90/10 dr (entry 9). Additionally, the hydroxyl group and the
carbonyl group of 3a could be removed in the presence of
Et3SiH/BF3·Et2O, affording the reduced product 5 in high yield
and with good diastereoselectivity and excellent enantioselectiv-
ity (entry 10).
With the optimal reaction conditions in hand, the substrate
scope of the reaction between different cyclic α-dehydroamino
ketones 1 with several aldehydes 2 was explored (Scheme 2).
Cyclic α-dehydroamino ketones bearing one or two Me groups
on the phenyl ring were first examined. We were pleased to
discover that asymmetric catalytic behavior was mostly
unaffected, and all reactions proceeded smoothly with the
desired products being obtained in more than 90% yield and ee
and 90/10 dr (4b−4e). The effect of different electron-
withdrawing substituents on the phenyl ring was next examined
(4f−4n). Excellent asymmetric catalytic behavior was still
observed and 4n was obtained in 97% ee. When the phenyl
ring was replaced by a naphthalene group, the tetracyclic γ-lactam
Commonly used proline (I) is able to promote smooth
reaction, with the desired product being obtained in almost
quantitative yield but as a racemic mixture (entry 1). Moderate
yield and enantioselectivity were observed when (S)-indoline-2-
carboxylic acid (II) was used as a catalyst (entry 2). Very high
yield and low ee were also obtained using cis-perhydroindolic
acid (III) as a catalyst (entry 3). To our delight, when trans-
perhydroindolic acid (IV) was applied in the above reaction, high
reaction activity as well as good diastereo- and excellent
enantioselectivity were achieved (entry 4). We next investigated
the influence of additives on the reaction (entries 5−11). When
no additive or an acidic additive such as benzoic acid was added,
the reaction proceeded slowly, giving the tricyclic product 3a
with good enantioselectivities but in low yields, even after 7 days
(entries 5 and 6). In contrast, organic bases significantly
promoted the reaction, with 3a being obtained in high yields
and enantioselectivities (entries 7−10). However, inorganic
bases such as Na2CO3 were unable to provide high reaction
activity, with 3a being obtained in only 38% yield after 7 days
(entry 11). DABCO provided somewhat better catalytic
behavior than others and was used for further optimization of
the reaction conditions. Finally, the dosage of DABCO was
examined. Lowering the amount of DABCO to 0.5 or 0.2 equiv
had no obvious effect on the reaction outcome, although reaction
activities were slightly lower (entries 12 and 13). Further
B
DOI: 10.1021/acs.orglett.7b01160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of Substrates
Scheme 3. Transformation of 4a
also be simply converted to give hydrozone 8 in 90% yield with
no effect on enantioselectivity.15 The carbonyl group can also be
partially reduced in the presence of a RuCl2(PPh3)3 catalyst
under 40 bar H2 at room temperature to give the corresponding
chiral cyclic β-amino alcohol 9 in good yield. Alcohol 9 is a
potentially important building block for the synthesis of several
biologically active molecules and chiral catalysts.10b
Based on the absolute configuration of 3a and detailed reaction
results, we believe that the reaction may undergo the following
stereocontrolled process (Scheme 4). First, an enamine A is
Scheme 4. Proposed Reaction Pathway
a
Using the optimal reaction conditions shown in Table 2 (entry 9)
followed by treatment with IBX in CH3CN at 80 °C. Yields of isolated
products of the major and minor isomers are presented. The
diastereomeric ratio was determined by 1H NMR of the crude
product; ee values were determined by chiral HPLC.
generated in situ via the reaction of trans-perhydroindolic acid VI
with one molecule of propanal 2a. A H-bond interaction between
the amide (1a) and carboxyl group (A) directs the attack of the
enamine moiety of A from the top side of 1a due to the steric
hindrance of the six-membered fused ring system of the catalyst;
intermediate B is subsequently formed. In the presence of a base,
B undergoes a nucleophilic addition via back surface attack of the
acetyl amino group to the aldehyde group. The desired tricyclic
product 3a is obtained after a further hydrolysis, and the chiral
catalyst is released.
To summarize, we have developed an efficient asymmetric
domino reaction of readily available cyclic α-dehydroamino
ketones and aldehydes for the synthesis of chiral γ-lactam-
containing tricyclic derivatives. The previously synthesized trans-
perhydroindolic acid proved to be an efficient organocatalyst for
this reaction. Under the optimal reaction conditions, the reaction
provided the desired products in up to excellent yield (up to
94%), with excellent diastereoselectivities (up to >20:1) and
product 4o was obtained in 94% yield and with 99% ee. Finally,
several aldehydes 2 were investigated, and good to excellent
results were also obtained (4p−4r). A BnO-substituted aldehyde
gave its corresponding product (4r) with 99% ee and more than
20/1 dr. The reaction was also carried out with other aliphatic
aldehydes, such as n-butyl aldehyde and iso-pentaldehyde;
however, no reaction occurred.
The tricyclic γ-lactam products have the potential to
participate in a variety of transformations (Scheme 3). For
example, the carbonyl group of 4a can be removed using a Pd/C
and H2 system in AcOH to give the corresponding lactam 6. N-
Deprotection of 6 with trimethylsilyl iodide (TMSI) in
chloroform affords 7.14 Structures such as 7 not only are
medicinally interesting but also represent a synthetically
challenging family of intermediates owing to the presence of
three stereogenic centers.3 Alternatively, the carbonyl group can
C
DOI: 10.1021/acs.orglett.7b01160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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enantioselectivities (up to 99%). A stereocontrolled process has
been proposed, and the tricyclic products could be converted to
structurally useful scaffolds using simple transformations.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01160.
Experimental procedures and characterization details
(PDF)
X-ray data for 3a (CIF)
X-ray data for 4c (CIF)
X-ray data for 4h (CIF)
X-ray data for 4j (CIF)
X-ray data for 4l (CIF)
AUTHOR INFORMATION
Corresponding Authors
(12) (a) Zhao, L.; Shen, J.; Liu, D.; Liu, Y.; Zhang, W. Org. Biomol.
Chem. 2012, 10, 2840. (b) Shen, J.; An, Q.; Liu, D.; Liu, Y.; Zhang, W.
Chin. J. Chem. 2012, 30, 2681. (c) An, Q.; Shen, J.; Liu, D.; Butt, N.; Liu,
Y.; Zhang, W. Synthesis 2013, 45, 1612. (d) An, Q.; Shen, J.; Butt, N.;
Liu, D.; Liu, Y.; Zhang, W. Org. Lett. 2014, 16, 4496. (e) An, Q.; Li, J.;
Shen, J.; Butt, N.; Liu, D.; Liu, Y.; Zhang, W. Chem. Commun. 2015, 51,
885. (f) An, Q.; Shen, J.; Butt, N.; Liu, D.; Liu, Y.; Zhang, W. Adv. Synth.
Catal. 2015, 357, 3627.
(13) CCDC 1486267, 1506126, 1506127, 1506128, and 1506129
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(14) (a) Miller, R. D.; Goelitz, P. J. Org. Chem. 1981, 46, 1616.
(b) Chen, Y. L.; Nielsen, J.; Hedberg, K.; Dunaiskis, A.; Jones, S.; Russo,
L.; Johnson, J.; Ives, J.; Liston, D. J. Med. Chem. 1992, 35, 1429.
(15) Cranwell, P. B.; Russell, A. T. J. J. Chem. Educ. 2016, 93, 949.
■
*E-mail: dlliu@sjtu.edu.cn.
*E-mail: wanbin@sjtu.edu.cn.
ORCID
Wanbin Zhang: 0000-0002-4788-4195
Author Contributions
§Q.A. and J.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by the National Natural
Science Foundation of China (Nos. 21372152, 21402117,
21672142, and 21232004), Program of Shanghai Subject Chief
Scientists (Nos. 14XD1402300 and 15JC1402200), and the
Instrumental Analysis Center of SJTU for characterization.
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DOI: 10.1021/acs.orglett.7b01160
Org. Lett. XXXX, XXX, XXX−XXX