Hydrogen-bond-directed enantioselective decarboxylative mannich reaction of β-ketoacids with ketimines: Application to the synthesis of anti-HIV drug DPC 083

Article abstract of DOI:10.1002/anie.201210361

Key to success: The title reaction provides facile access to enantioenriched 3,4-dihydroquinazolin-2(1H)-ones containing a quaternary stereogenic center in high yields with excellent enantioselectivities. Subsequent transformations lead to the convenient preparation of the anti-HIV drug DPC 083 and N-fused polycyclic compounds without loss of enantiomeric excess.

Full text of DOI:10.1002/anie.201210361

Angewandte
Chemie
DOI: 10.1002/anie.201210361
Organocatalysis
Hydrogen-Bond-Directed Enantioselective Decarboxylative Mannich
Reaction of b-Ketoacids with Ketimines: Application to the Synthesis
of Anti-HIV Drug DPC 083**
Hai-Na Yuan, Shuai Wang, Jing Nie, Wei Meng, Qingwei Yao, and Jun-An Ma*
The decarboxylative Mannich reaction (DMR) of b-ketoacids
with imines has emerged as a very important tool for the
synthesis of natural products and biologically active com-
pounds. The elegant work of Robinson on the total synthesis
of (Æ)-tropinone represents the first practical example of
utilizing the DMR as a key step in organic synthesis.[1]
Herbert and co-workers[2] and Mangla and Bhakuni[3] then
developed a similar decarboxylative Mannich condensations
of b-ketoacids with D1-pyrroline and D1-piperideine for the
synthesis of biologically relevant alkaloids, such as septicine,
phenanthroindolizidines, and cryptopleurine. Despite these
notable achievements, little progress has been made in the
development of an asymmetric version for this important
reaction. Recently, the group of Tian developed a chiral-
auxiliary-based method in which b-ketoacids undergo highly
diastereoselective decarboxylative Mannich transformation
with optically active 2-(tert-butanesulfinyl-imino)glyoxyla-
tes,[4a] and Lu and co-workers described a catalytic asymmet-
ric DMR of b-ketoacids with aldimines to afford b-amino
ketones with a maximum of ee value of 83%.[4b] However, all
such studies have focused on the aldimine-based electro-
philes. In contrast, the use of ketimines as the electrophilic
acceptors for the decarboxylative Mannich reactions of b-
ketoacids still remains a formidable challenge and there has
been no report in the literature, to date, of such a potentially
useful transformation.[5]
reaction of b-ketoacids by employing cyclic N-acyl ketimines
as the electrophilic acceptor (Figure 1). This new reaction was
cooperatively promoted by saccharide-based bifunctional
organocatalysts. The catalysts contain a tertiary amine and
thiourea moieties which simultaneously activate the sub-
strates and are responsible for excellent overall stereochem-
ical control. The potential application of this catalytic
asymmetric decarboxylative Mannich reaction was further
exemplified in a highly enantioselective synthesis of the anti-
HIV drug DPC 083.
The obvious benefits that hydrogen-bonding catalysis can
offer in asymmetric synthesis have been recognized in recent
years.[6] Aunique characteristic of hydrogen-bonding catalysis
is that the catalyst not only activates the reaction partners
through hydrogen-bond interactions, but also positions them
in close proximity with the desired relative geometry, and as
such, the reaction is often facilitated in a synergistic manner,
a manner similar to that of enzymatic catalysis. Herein, we
report the results of our efforts in developing a hydrogen-
bond-directed enantioselective decarboxylative Mannich
Figure 1. Hydrogen-bond-directed enantioselective Mannich reaction of
b-ketoacids with ketimines.
Our initial investigation began with the enantioselective
decarboxylative Mannich condensation of model substrates 3-
oxo-3-phenylpropanoic acid (1a) and ketimine 2a (Table 1)
in the presence of the saccharide-derived amino thioureas
Aa–c (Figure 2), which were developed previously in our
laboratory,[7] as chiral catalysts . To drive the reaction to
completion, the b-ketoacid was used in excess as significant
amounts of acetophenone, formed from a competing decarb-
oxylation pathway, was recovered during the course of the
reaction.[8] Under these reaction conditions, the Mannich
adduct 3a was obtained in high yield with moderate to good
enantioselectivity (Table 1, entries 1–3), with catalyst Ab
giving the best performance. Mindful of a detrimental back-
ground reaction which could lead to the observed low
enantioselectivity, the reaction was performed at a lower
temperature, and as expected, the enantioselectivity was
improved from 80% ee to 89% ee at 08C and to 92% ee at
[*] H.-N. Yuan, S. Wang, J. Nie, W. Meng, Prof. J.-A. Ma
Department of Chemistry, Tianjin University
Tianjin 300072 (China)
E-mail: majun_an68@tju.edu.cn
Dr. Q. Yao
Sphinx Scientific Laboratory Corporation
Sycamore, IL 60178 (USA)
[**] This work was supported financially by the NSFC (No. 21172170 and
21225208).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201210361.
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Table 1: Screening of ligands and optimization of the reaction conditions
for DMR of 1a with 2a.[a]
(entry 10) with the same sense of stereochemical induction as
Ad. The same is true for the 1,2-diphenylethane-1,2-diamine-
based catalyst C which gave 92% ee (entry 11). In addition,
the solvent was found to have an important effect on the
reactivity (entries 12–16). Among the solvents tested, THF
was found to be the choice solvent for this reaction with
respect to both catalytic activity and asymmetric induction.
When the catalyst loading of Ad was reduced to 5 mol%, the
reaction performed equally well with high enantioselectivity
(entry 17). Even at a loading of 1 mol%, Ad still delivered
comparable results (92% yield and 90% ee) if the reaction
was run for extended reaction time (entry 18). To corroborate
the activity and enantioselectivity of Ad, its enantiomer, the
l-glucose-derived catalyst D was prepared and tested under
similar reaction conditions. Not surprisingly, D exhibited
almost identical activity and stereoselectivity with those of Ad
except for the opposite sense of asymmetric induction
(entry 19).
By using the optimized protocol, we explored the scope of
this catalytic enantioselective decarboxylative Mannich con-
densation with a variety of b-ketoacids and cyclic N-acyl
ketimines, and the results are summarized in Scheme 1. In the
presence of 10 mol% Ad, the reaction of ortho-, meta-, and
para-substituted phenyl b-ketoacids with trifluoromethyl-
ketimine 2a all proceeded smoothly, thus generating the
desired adducts 3a–i in consistently high yield (94–99%) and
enantioselectivity (91–99% ee). 2-Naphthyl- and 2-thio-
phenyl-substituted b-ketoacids were also found to be good
substrates, thus delivering the products 3j and 3k, respec-
tively, in high yield and enantioselectivity. Additionally, it was
found that linear, branched, and cyclic alkyl substituted b-
ketoacids could also be used as the nucleophilic partners, and
excellent results were obtained for the Mannich adducts 3l–q.
To further define the scope of our methodology, the reactions
of other cyclic N-acyl trifluoromethylketimines bearing
electron-withdrawing, electron-donating, or electron-neutral
groups on the phenyl ring with 1a were tested. The
decarboxylative Mannich condensations of these substrates
all proceeded efficiently to give the products 3r–x in 92–99%
yield and high enantioselectivity. It is worth noting that the
presence of an N-protecting group at the ketimine substrate
proved to be essential for achieving high level of asymmetric
induction, as poor enantioselectivity was observed for 3y
(38% ee) wherein the protecting group was absent. In
addition, when the trifluoromethyl group on the quinazolin-
2(1H)-one ring was replaced with a difluoromethyl group, the
decarboxylative Mannich product 3z was also obtained in
91% yield with 93% ee. However, when the trifluoromethyl
group was replaced with a methyl or phenyl group, no
condensation products were observed. These results indicated
that the strong electron-withdrawing di- and trifluoromethyl
groups are critical for this DMR to occur.[9]
Entry Catalyst (mol%) Solvent
T
t
Yield ee
[8C] [h]
[%][b] [%][c]
1
2
3
4
5
6
7
8
Aa (10)
Ab (10)
Ac (10)
Ab (10)
Ab (10)
Ab (10)
Ad (10)
Ae (10)
Af (10)
B (10)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
CHCl3
Et2O
25 12
25 12
25 12
90
96
92
90
92
57 (+)
80 (+)
63 (+)
89 (+)
92 (+)
90 (+)
>99 (+)
98 (+)
95 (+)
98 (+)
92 (+)
79 (+)
72 (+)
68 (+)
85 (+)
90 (+)
95 (+)
90 (+)
96 (À)
0
24
À20 48
À40 120 44
À20 48
À20 48
À20 48
À20 48
À20 48
À20 48
À20 72
À20 72
99
99
99
99
99
61
97
41
90
66
99
9
10
11
12
13
14
15
16
17
18
19
C (10)
Ad (10)
Ad (10)
Ad (10)
Ad (10)
Ad (10)
Ad (5)
1,4-dioxane À20 72
toluene
THF
À20 72
À20 72
Ad (1)
D (10)
THF
THF
À20 120 92
À20 48
99
[a] General reaction conditions: 1a (1.2 mmol for entries 1–4; 0.6 mmol
for entries 5–19), 2a (0.3 mmol), catalyst (1–10 mol%) in solvent for the
stated time. [b] Yield of isolated product. [c] Determined by HPLC
analysis on a chiral stationary phase. PMB=para-methoxybenzyl,
THF=tetrahydrofuran.
Figure 2. Structures of saccharide-derived organocatalysts tested.
À208C (entries 4 and 5). The amount of b-ketoacid can also
be reduced to two equivalents at these temperatures. How-
ever, further decrease in the reaction temperature (À408C)
led to a sluggish reaction and the yield dropped to 44%, even
after a prolonged reaction time (entry 6). Subsequently,
a series of other thioureas bearing a cyclic tertiary amine
moiety were designed and synthesized. To our delight, the
catalysts Ad, Ae, and Af displayed higher catalytic activity as
To demonstrate the practical applicability of this highly
efficient catalytic asymmetric DMR, the condensation of 1a
and 2a was repeated on a one gram (6 mmol) scale
(Scheme 2a) and the reaction delivered the desired product
3a with results almost identical to that of the model reaction.
Additional synthetic transformations of the keto carbonyl
moiety of 3a, through reduction with NaBH4 and subsequent
well as delivered
a superior level of stereoselectivity
(entries 7–9). Interestingly, the amino-thiourea B, a diastereo-
mer of Ad with the opposite configuration (R,R) on the
diamine moiety could also induce high enantioselectivity
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Scheme 1. Scope of Ad-catalyzed DMR of the b-ketoacids 1 with the ketimines 2. TMB=2,4,6-trimethylbenzyl, Anth-M=9-anthracenylmethyl.
reaction of the resulting diastereomeric alcohol 4 with TsCl/
KOH in THF under reflux, led to the isolation of the unique
and enaniomerically pure tricyclic 5,9b-dihydro-1H-azeto-
[1,2-c] quinazolin-4(2H)-ones 5 and 6. X-ray crystallographic
analysis of 6 allowed the absolute configuration of the two
stereogenic centers to be assigned as (2R, 9bR).[10] The
determination of the stereochemistry of 6 was thereafter used
as the basis for the assignment of absolute configuration
reported in Table 1 and Scheme 1. Compound ent-6, synthe-
sized in a similar way in 57% overall yield and 99.9% ee by
using D, was found to possess the opposite configuration
through X-ray crystallographic analysis.
We next turned our attention to the application of this
highly enantioselective catalytic DMR to the synthesis of the
anti-HIV drug DPC 083.[11] Under the above-optimized
reaction conditions, the (L, R, R)-D-catalyzed DMR of 3-
cyclopropyl-3-oxopropanoic acid with 2a gave the S-config-
ured adduct 3p’ with 90% ee in quantitative yield (Sche-
me 2b). The enantiopurity was further improved to 96% ee
after a single recrystallization. Reduction of the carbonyl
group with NaBH4 gave the alcohol 7 in 98% yield as a 71:29
mixture of diastereomers. Direct dehydration of the diaste-
reomeric mixture in HMPA and subsequent removal of the
PMB group afforded (E)- and (Z)-DPC 083 in 53 and 26%
yield, respectively. The optical rotation data of (E)-DPC 083
are in full agreement with those described in the literature.[12]
To cast some light on the mechanism, NMR and ESI/MS
methods were used to study this decarboxylative Mannich
reaction. 19F NMR analysis of the reaction progress for b-
ketoacid 1a and 2a in CDCl3 revealed the appearance of two
new peaks at d = À84.4 and À84.6 ppm, which were tenta-
tively assigned as the addition intermediates (see the Sup-
porting Information). However, all attempts to isolate the
putative intermediate failed. Notably, an ESI/MS analysis of
this reaction allowed further identification of the addition
intermediate using the high-resolution mass data [HRMS
(ESI) calcd for C26H20ClF3N2O5Na+ [M+Na+] 555.0910,
found 555.0904]. A control experiment where acetophenone
was used as a surrogate of the b-ketoacid 1a under otherwise
identical reaction conditions did not give adduct 3a. These
experimental results suggest that nucleophilic addition to the
ketimine occur prior to the decarboxylation of the b-ketoacid
during this decarboxylative Mannich reaction.
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Scheme 2. a) Additional transformations of the products and X-ray crystal structures of 6 and ent-6. b) Preparation of the anti-HIV drug DPC 083.
HMPA=hexamethylphosphoramide, Ts=4-toluenesulfonyl. F green, N blue, O red.
The interactions between substrates and catalyst were
probed computationally by examining the bond critical points
(BCPs) with Baderꢀs atoms in molecules (AIM) analysis.[13]
The calculations revealed that the cyclic N-acyl ketimine was
activated and oriented by hydrogen bonding with the NH
groups of the organocatalyst. A H–p bonding interaction
between the aromatic-substituted protecting group on the
ketimine substrate and the saccharide moiety of organo-
catalyst may also play an important role in stabilizing the
transition state (Figure 3a). This is in agreement with the
observation that substrate 2y, which is lacking an aromatic
protecting group on its nitrogen atom exhibited only low
enenatioselectivity in forming the product 3y. Additionally,
the tertiary amine moiety of organocatalyst electrostatically
bonds to the b-ketoacid 1 (in its enol form[14]) through a salt
bridge. Based on this analysis, the nucleophile can only be
=
delivered to the Si face of the C N group, thus giving
predominantly the R enantiomer of the Mannich products 3
after decarboxylation of the initial adduct (Figure 3b).
In summary, we have successfully developed the first
hydrogen-bond-directed enantioselective decarboxylative
Mannich reaction of b-ketoacids with ketimines. This new
method affords a wide range of enantioenriched 3,4-dihydro-
quinazolin-2(1H)-one derivatives containing a quaternary
stereogenic center in high yields and excellent enantioselec-
tivities in the presence of saccharide-based amino-thiourea
catalysts. The potential application of this catalytic asymmet-
ric decarboxylative Mannich reaction was demonstrated as
a key step in a new and efficient asymmetric synthesis of the
anti-HIV drug DPC 083. Preliminary mechanistic investiga-
tions indicate that the reaction proceeds through direct
addition of b-ketoacids to the ketimines with subsequent
decarboxylation. A more systematic study on the mechanistic
details and further application of the b-ketoacid-derived
enolate synthons to other catalytic asymmetric reactions are
ongoing in our laboratories.
Received: December 30, 2012
Published online: && &&, &&&&
Figure 3. a) Hydrogen-bonding complex between organocatalyst and
ketamine. F green, N blue, O red, S yellow. b) Proposed reaction
pathway.
Keywords: enantioselectivity · heterocycles · ketimines ·
organocatalysis · synthetic methodology
.
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Communications
Organocatalysis
H.-N. Yuan, S. Wang, J. Nie, W. Meng,
Q. Yao, J.-A. Ma*
&&&& — &&&&
Hydrogen-Bond-Directed
Enantioselective Decarboxylative
Mannich Reaction of b-Ketoacids with
Ketimines: Application to the Synthesis of
Anti-HIV Drug DPC 083
Key to success: The title reaction pro-
vides facile access to enantioenriched
3,4-dihydroquinazolin-2(1H)-ones con-
taining a quaternary stereogenic center in
high yields with excellent enantioselec-
tivities. Subsequent transformations lead
to the convenient preparation of the anti-
HIV drug DPC 083 and N-fused polycyclic
compounds without loss of enantiomeric
excess.
6
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