A highly diastereo- and enantioselective synthesis of tetrahydroquinolines: Quaternary stereogenic center inversion and functionalization

Article abstract of DOI:10.1021/ja4040945

Tetrahydroquinolines containing two quaternary stereogenic centers were synthesized with excellent ee and dr via a four-component cyclization reaction catalyzed by a chiral phosphoric acid. High chemoselectivity was achieved by differentiating anilines with similar reactivities to yield diverse hybrid products. The chirality of the quaternary C4 atom of the 4-aminotetrahydroquinoline products was found to undergo highly stereoselective inversion, enabling facile functionalization using a wide range of nucleophiles (C, O, N, and S).

Full text of DOI:10.1021/ja4040945

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Communication
A Highly Diastereo- and Enantioselective Synthesis of Tetrahydroquinolines:
Quaternary Stereogenic Center Inversion and Functionalization
Chaosheng Luo, and Yong Huang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4040945 • Publication Date (Web): 16 May 2013
Downloaded from http://pubs.acs.org on May 16, 2013
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Journal of the American Chemical Society
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A Highly Diastereo- and Enantioselective Synthesis of Tetra-
hydroquinolines: Quaternary Stereogenic Center Inversion
and Functionalization
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Chaosheng Luo, Yong Huang*
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peꢀ
king University, Shenzhen, China, 518055
Supporting Information Placeholder
ABSTRACT: Tetrahydroquinolines containing two quaternary
stereogenic centers were synthesized with excellent ee and dr via
a fourꢀcomponent cyclization reaction catalyzed by chiral phosꢀ
phoric acid. High chemoselectivity was achieved by differentiatꢀ
ing the anilines with similar reactivities to yield diverse “hybrid”
products. The chirality of the quaternary C4 of the 4ꢀ
aminotetrahydroquinoline products was found to undergo highly
stereo selective inversion, which enables facile functionalization
using a wide range of nucleophiles (C, O, N and S).
Our group has been interested in developing methods that allow
direct access to 4ꢀamino THQs due to their pharmacological releꢀ
vance.5 However, the biological data for the 2,4ꢀdiquaternized
Tetrahydroquinolines (THQs) belong to a class of heterocycles
of high pharmacological value; they have attracted attention from
medicinal and synthetic chemists due to their abundance in both
natural products and drug molecules that possess various biologiꢀ
cal activities.1 The rapid assembly of the chiral THQs resulted
primarily from recent advances in enantioselective organocatalytꢀ
ic cascade reactions and cooperative catalysis (Scheme 1).2,3
THQs are scarce, which is largely due to the inaccessibility of
these compounds. Thus, developing practical methods for preparꢀ
ing 2,4ꢀdiquaternized THQs through diastereoꢀ and enantioselecꢀ
tive synthesis is highly desirable. Inspired by the abovementioned
work of Akiyama, Zhu, and Masson, we challenged the chiral
Brønstedꢀacidꢀcatalyzed Povarov reaction with pairs of pyruvates
and anilines. To the best of our knowledge, no other example of
an organocatalytic Povarov reaction involving enolizable ketones
can be found in the literature.4 The successful use of these subꢀ
strates could immediately lead to THQ analogues bearing 2,4ꢀ
quaternary centers and diversified functionalities.
One particular strategy, developed by Gong, employed the reꢀ
lay catalysis of a gold(I)ꢀcatalyzed hydroamination and a chiral
Brønsted acidꢀcatalyzed transfer hydrogenation to enantioselecꢀ
tively synthesize 2ꢀsubstituted THQs in one pot.3k The chiral
phosphoric acidꢀcatalyzed enantioselective Povarov reactions and
the inverse electronꢀdemand heteroꢀDielsꢀAlder (IEHDA) reacꢀ
tions, developed by Akiyama, Zhu, and Masson, permit the synꢀ
thesis of 2,4ꢀdisubstituted THQs.3aꢀ3j However, the substrate scope
of these reactions is limited to preformed aldimines or aldehydes.
In contrast, the asymmetric Povarov reaction involving ketones is
rare,4 limiting access to the THQs that contain quaternary chiral
centers. The multicomponent condensation of two anilines and
two enolizable ketones is potentially complicated and unclean
because rapid enamine/iminium equilibrium may lead to a number
of reaction pathways and combination cascades such as aldol,
Mannich, Claisen, Michael, etc. We describe a highly diastereoꢀ
and enantioselective synthesis of THQs with two quaternary steꢀ
reogenic centers and rich functionalities using pairs of anilines
and pyruvates. The phenylamino substituted C4 quaternary center
of the products was found to be extraordinary synthetic versatile,
through an acid catalyzed elimination and addition mechanism.
This PMPNH group could be replaced by a wide range of C, O, N
and S based nucleophiles in a formal “SN2 substitution”.
Our preliminary studies revealed that activated ketones, i.e., pyꢀ
ruvates, are viable substrates for direct condensation with equal
equivalents of anilines to generate THQ products with 2,4ꢀfully
substituted carbon centers. This transformation was racemically
catalyzed by Mg(ClO4)2 at room temperature to provide a quantiꢀ
tative yield and a poor dr (cis/trans = 1:2). Various chiral phosꢀ
phoric acids6 were then examined to improve the dr and induce
facial discrimination (Table 1). Although the nonꢀsubstituted
BINOLꢀderived phosphoric acid 4a failed to promote this reaction,
its 3,3′ꢀdisubstituted analogues significantly enhanced the catalytꢀ
ic activity. Both the dr and ee increased proportionally with the
size of these substituents. The helical VAPOLꢀderived phosphoric
acid 57 was less effective and enantioselective, although the dr
remained high. The more acidic Tfꢀsubstituted phosphoramide 6a8
promoted an interesting racemic reaction, favoring the transꢀ
isomer. The corresponding Mg and Ca phosphate salts did not
catalyze this reaction, ruling out the previously documented metal
contamination effects.9 As with other chiral phosphoricꢀacidꢀ
catalyzed processes, the enantioselectivity of the reaction was
strongly influenced by the polarity of the solvent. Less polar solꢀ
vents led to an improved ee by attenuating the solvation of the
hydrogenꢀbonded catalyst–substrate complex. Both the dr and ee
were further enhanced by switching to the corresponding H8ꢀ
Scheme 1. Representative asymmetric strategies for the
synthesis of substituted THQs
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BINOLꢀbased phosphoric acids,10 which have slightly larger diꢀ
aniline pairs with moderate differences in reactivity considering
hedral angles than their BINOL counterparts.11 Catalyst 7, with
two bulky 9ꢀanthracenyl groups, afforded 88% conversion to the
single cisꢀproduct 3b with a 95% ee for the unꢀsubstituted aniline
substrate.
both steric and electronic influence. The orthoꢀsubstituted anilines
were tolerated in these reactions. Interestingly, for a reaction beꢀ
tween two different carbonyl components, i.e., methyl pyruvate
and glyoxylate, a γꢀlactam product 8g was obtained in 90% yield
with 72% ee.
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4
Table 1. Catalyst screening and reaction optimizationa
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Table 2. Substrate scope for the enantioselective synthesis
of cisꢀ2,4ꢀdiquaternized THQsa
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entry cat solvent
product conv (%)b cis/transc ee (%)d
1
4a
4b
4c
4d
5
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
3a
3a
3a
3a
3a
3a
3a
4
3.5:1
1:1.2
4.6:1
> 20:1
> 20:1
1:2.7
ꢀ
11
60
57
85
46
4
2
81
75
66
38
83
< 5
82
83
86
79
85
88
aThe reactions were performed with 0.2 mmol aniline and 0.2
mmol methyl pyruvate in 1 mL solvent at 25 °C for 24 h. Isolated
yields; dr determined via 1H NMR of the crude mixture; ee deterꢀ
mined via chiral HPLC. bRegioselectivity determined by 2Dꢀ
NMR. See SI for spectra.
3
4
5
6
6a
6b
4d
4d
4d
4d
7
Table 3. “Hybrid” reactions using two anilinesa
7
ꢀ
8
dioxane 3a
> 20:1
1:2.6
> 20:1
> 20:1
> 20:1
> 20:1
77
10
70
78
89
95
9
MeCN
DCM
IPACe
PhMe
PhMe
3a
3a
3a
3a
3b
10
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13
7
aThe reactions were performed with 0.2 mmol aniline and 0.2
b
mmol methyl pyruvate in 1 mL solvent at 25 °C for 24 h. The
conversion percentage was determined via 1H NMR integration of
c
1
the crude mixture. The dr was determined via H NMR integraꢀ
tion of the crude mixture. dThe percent ee was determined via
chiral HPLC. eIPAC = isopropyl acetate.
aThe reactions were performed by mixing anilines 1, 1′ and pyꢀ
The substrate scope was examined and the results are summaꢀ
rized in Table 2. Both the electronꢀrich and electronꢀpoor anilines
were tolerated, although the rates for electron deficient anilines
were slower. The reactions involving anilines with strong elecꢀ
tronꢀwithdrawing substituents, e.g., NO2, proceeded slowly with
low conversion rates. The paraꢀ, metaꢀ and diꢀsubstituted anilines
in this fourꢀcomponent condensation reaction achieved good
yields and high selectivities. As observed by Akiyama, Gong, Zhu,
and Masson, the orthoꢀsubstituted anilines were ineffective except
for orthoꢀhydroxy analogues where the substituent provided an
additional Hꢀbond.3aꢀ3e Under these conditions, the cis isomer was
consistently the only product. The relative and absolute stereoꢀ
chemistry was unambiguously assigned using singleꢀcrystal Xꢀray
diffraction.12 Other activated enolizable ketones were examined.
The reaction was messy for 2,3ꢀbutadione and acetyl cyanide.
Ethyl pyruvate led to a diastereomeric mixture at C3.
1
ruvate 2 in a 1:1:2 ratio. Isolated yields; dr determined via H
NMR of the crude mixture; ee determined via chiral HPLC. bThis
reaction was performed by mixing aniline 1c, methyl pyruvate 2,
and tꢀbutyl glyoxylate 2′ in a 2:1:1 ratio. PMP = pꢀmethoxyphenyl.
During our preliminary catalyst screening, we observed that the
dr and ee of the products changed over time (Table 4). This timeꢀ
dependent cis/trans isomerization was particularly facile for the
electronꢀrich aniline substrates when less sterically hindered chiral
phosphoric acids were utilized. The electronꢀdeficient aniline
substrates did not isomerize at room temperature. With catalyst 4b,
the reaction between 1c and 2 yielded a cis/trans ratio of 5.2/1
after 5 hours. The ee of the minor isomer transꢀ3c was poor
(34%). In contrast, the major cisꢀ3c isomer exhibited a high ee
(98%). Over time, the dr of the products slowly changed to 1:1.4,
favoring the transꢀ3c. The ee for the accumulating trans-product
steadily increased (95% after 4 days), accompanied by a small
loss in the optical purity for cisꢀ3c isomer (98% to 92%).
In recognizing the discrepancies in the reactivities for the difꢀ
ferent anilines, we were encouraged to examine whether a “hybrid”
product could be obtained with two different anilines. As exꢀ
pected, high chemoselectivity was achieved for a number of aniꢀ
line pairs (Table 3). Detailed studies of the various aniline combiꢀ
nations revealed that “hybrid” reactions could be achieved using
Table 4. Cis/trans isomerization and ee vs. reaction time
correlationa
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We analyzed the mechanism of this reaction based on these
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findings. Due to the structure of the “hybrid” aniline products, the
Povarov reaction likely proceeds in a stepꢀwise manner as opꢀ
posed to a concerted IEDHDA mechanism, which would yield the
wrong isomer. These “hybrid” THQ products from the aniline
pairs were assembled via an “abnormal” Mannich reaction. The
enamine derived from the more electronꢀdeficient aniline reacted
as a nucleophile, while the electrophile imine was derived from
the more electronꢀrich aniline. This electronically unmatched
Mannich step was compensated by the more facile FꢀC ring cloꢀ
sure. In this step, the electronꢀrich aniline served as the nucleoꢀ
phile to react with an imine from the more electronꢀdeficient aniꢀ
line.
entry time (h) trans/cis transꢀee (%) cisꢀee (%) conv (%)
1
2
3
4
5
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5
1:5.2
1:3.4
1:3.4
1:2.2
1:1.6
1:1.4
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95
98
98
98
96
93
92
76
83
89
92
92
94
11
20
44
72
96
9
10
11
12
aSix parallel reactions were carried out using 0.1 mmol aniline,
0.1 mmol methyl pyruvate, and 0.005 mmol catalyst in 0.5 mL
toluene at room temperature; the dr was determined via crude H
Table 5. Stereogenic center inversion and functionalizatioꢀ
na
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NMR; the ee was determined via chiral HPLC; and the conversion
was estimated via 1H NMR integration of the crude mixture.
The cis/trans isomerization was further validated by another
independent experiment: stirring a solution of pure cis-3a or
transꢀ3a in the presence of 5 equiv HOAc at room temperature
led to a thermodynamic mixture of the cis/trans isomers (1:1.5)
and a small quantity of a dihydroquinoline byꢀproduct 11.13 This
dihydroquinoline can be the dominant product when large excess
pyruvate was used.14 At 50 °C, this equilibrium favored the trans
isomer only through an intramolecular lactamization to assemble
a novel bridged benzodiazepine scaffold (Scheme 2). This process
can be carried out in one pot with a 50% overall yield from the
aniline and methyl pyruvate, allowing the rapid biological evaluaꢀ
tion of this class of pharmacophores.15
aThe reaction condition was not fully optimized. Excess nucleoꢀ
b
philes were used (20 equiv.). MeNO2 was used as solvent in the
Scheme 2. Stereoinversion of quaternary carbon C4 folꢀ
lowed by lactamization
c
d
absence of an external nucleophile. MeOH used as solvent. The
nucleophile is NaN3.
Scheme 3. Proposed reaction mechanism
The cis/trans isomerization likely resulted from a C4 aniline
elimination/reꢀaddition pathway (Table 5, eq. 1). Taking this
mechansim into account, we speculated that the transient eliminaꢀ
tion product 10 might be trapped by an external nucleophile to
yield the THQ analogues with diversified functionalities at the C4.
The success of this “SN2ꢀlike substitution” requires that the exterꢀ
nal NucꢀH is a better nucleophile and/or a worse leaving group
than the internal nucleophilic PMPꢀNH2. To our delight, we were
able to displace the NHꢀPMP with both hard and soft nucleophiles
(Table 5). Intermediate 10 was susceptible to additions by various
Cꢀ, Nꢀ, Oꢀ, and Sꢀbased nucleophiles, which leads to sophisticated
THQ analogues difficult to access using other methods. Indoles
engaged in a FriedelꢀCrafts reaction with 10 to generate indole
substituted THQs. Treatment with alcohols and azides led to 4ꢀ
alkoxy and 4ꢀazido substituted analogues in high yields. For priꢀ
mary amines, an intramolecular lactamization occurred to yield
bridged benzodiazepines. Interestingly, MeNO2 facilitated reꢀ
aromatization to afford the corresponding dihydroquinoline (DHQ)
product 11 with 94% yield. These reactions were not restricted to
electronꢀrich substrates. An example using 3b derived from the
nonꢀsubstituted aniline was also effective (Table 5, product 13). In
all cases, the chirality of C2 and newly functionalized C4 were
highly enantioꢀenriched, suggesting a substrateꢀcontrolled stereoꢀ
specificity.
This fourꢀcomponent condensation reaction cascade began with
an irreversible chiral protonꢀcatalyzed Mannich reaction,16 which
established the C2 quaternary center with high enantioselectivity.
The dr of the subsequent FriedelꢀCraft cyclization was also conꢀ
trolled by the catalyst. A simplified illustration is provided in
Scheme 3 (the transition states for the FꢀC cyclization are presentꢀ
ed in brackets) in which the dark ovals represent a hindered cataꢀ
lyst sidearm that protrudes out of the paper, and the light ovals
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Luo, S.ꢀW.; Tu, S.ꢀJ.; Gong, L.ꢀZ. J. Org. Chem. 2012, 77, 6970. (e) He,
represent an identical substituent that points inward. To adopt a
halfꢀchair conformation for the FriedelꢀCraft cyclization, the subꢀ
strate backbone must fold forward as dictated by the chirality of
the C2. The corresponding transꢀ transition state would cause a
severe steric repulsion between the substrate and the catalyst
flanks. However, the cisꢀ cyclization precursor is strongly favored
given its ability to dock next to the helical catalyst. The cis/trans
isomerization suggests that the cisꢀ product is the kinetic, but
thermodynamically less stable product (an axial–axial dipole reꢀ
pulsion between the two axial ester groups), which leads to the
elimination of PMPNH2 under the influence of a weak Brønsted
acid to yield an unstable species 10. This product can be further
converted to the trans product (via aniline reꢀaddition), a dihydroꢀ
quiniline product (via reꢀaromatization), and various C4ꢀ
functionalized THQ derivatives.
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In summary, we present a highly diastereoselective and enantiꢀ
oselective protocol to access the cisꢀ2,4ꢀdiꢀquaternized tetrahyꢀ
droquinolines using anilines, methyl pyruvates, and a chiral phosꢀ
phoric acid catalyst. This method enabled the use of aniline pairs
to generate “hybrid” Povarov products with excellent chemoselecꢀ
tivity. The C4 quaternary center of the product allowed for a verꢀ
satile synthetic manipulation with a wide range of Cꢀ, Nꢀ, Oꢀ, and
Sꢀbased nucleophiles. Apply this method to the synthesis of strucꢀ
ture related bioactive molecules or natural products are currently
undergoing.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, product characterizations, copies of all
NMR spectra, HPLC traces, and crystallographic data. This mateꢀ
rial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
huangyong@pkusz.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work is financially supported by grants of Shenzhen special
funds for the development of biomedicine, Internet, new energy
and new material industries (JC201104210111A and
JC201104210112A),
Shenzhen
innovation
funds
(GJHZ20120614144733420), and the Shenzhen Peacock Program
(KQTD201103). The Shenzhen municipal development and reꢀ
form commission is thanked for a public service platform proꢀ
gram.
(12) See supporting information for Xꢀray crystal structure data.
(13) Synthesis of the racemic dihydroquinoline under strong acid conꢀ
ditions has been reported, see: (a) Waldmann, H.; Karunakar, G. V.; Kuꢀ
mar, K. Org. Lett. 2008, 10, 2159. (b) Hu, X.ꢀY.; Zhang, J.ꢀC.; Wei, W.;
Ji, J.ꢀX. Tetrahedron Lett. 2011, 52, 2903. (c) Zhang, J.ꢀC.; Ji, J.ꢀX. Catal.
2011, 1, 1360. (d) Zhu, Y.ꢀW.; Qian, J.ꢀL.; Yi, W.ꢀB.; Cai, C. Tetrahedron
Lett. 2013, 54, 638.
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