Highly enantioselective decarboxylative Mannich reaction of malonic acid half oxyesters with cyclic trifluoromethyl ketimines: Synthesis of β-amino esters and anti-HIV drug DPC 083

Article abstract of DOI:10.1002/chem.201303307

An organocatalytic enantioselective decarboxylative Mannich reaction of malonic acid half oxyesters with cyclic ketimines was developed for the preparation of enantioenriched β-amino esters with a quaternary stereogenic center and the anti-HIV drug DPC 083 (see scheme). Copyright

Full text of DOI:10.1002/chem.201303307

DOI: 10.1002/chem.201303307
Highly Enantioselective Decarboxylative Mannich Reaction of Malonic Acid
Half Oxyesters with Cyclic Trifluoromethyl Ketimines: Synthesis of b-Amino
Esters and Anti-HIV Drug DPC 083
Hai-Na Yuan, Shen Li, Jing Nie, Yan Zheng, and Jun-An Ma*[a]
Optically active b-amino esters are an important class of
molecules in biological systems and organic synthesis.[1]
Direct asymmetric Mannich reaction[2] of simple esters with
imines provides an ideal approach toward the construction
of these useful building-blocks. However, such transforma-
tion remains a great challenge due to the high pKa value of
the a-proton in carboxylic acid derivatives. In this context,
the enantioselective decarboxylative Mannich reaction of
malonic acid half esters with imines has emerged as a very
important tool for the asymmetric synthesis of optically
active b-amino esters.[3] For example, this process generally
employs an ester equivalent, such as a malonic acid half
oxyester or thioester, to participate in the reaction under
very mild conditions and thereby circumvent the problems
with strong bases and self-condensation. Catalytic asymmet-
ric decarboxylative Mannich reactions with a wide range of
aldimine-based electrophiles have proven to be highly effec-
tive.[4–6] However, expansion of the electrophilic acceptors to
ketimines for the synthesis of b-amino esters with a quater-
nary stereogenic center seems to be more challenging, since
controlling the ketimine geometry in combination with the
p-facial selectivity of electrophilic attack is critical for the
stereochemical outcome. Only one recent report by Shibata
and co-workers has addressed a decarboxylative addition of
malonic acid half thioesters (MAHTs) to ketimines derived
from isatins to offer the b-amino thioesters with a maximum
of 83% ee.[7,8] Obviously, there is still plenty of room for the
development of efficient protocols for the enantioselective
decarboxylative Mannich reactions with ketimines. More-
over, the asymmetric decarboxylative Mannich reaction
using the less reactive malonic acid half oxyesters
(MAHOs), which directly leading to b-amino oxyesters, has
not been documented yet.
asymmetric decarboxylative Mannich reaction of MAHOs,
providing products in excellent yields and enantioselectivi-
ties. The cyclic structure of these ketimines, in which the
C=N bond is constrained in the E geometry, appears to be
important for the success of the reactions. Furthermore, the
potential application of this catalytic asymmetric
decarboxylACTHNUGRTNEUNGative Mannich reaction was further exemplified
in a highly enantioselective synthesis of the anti-HIV drug
DPC 083.
We initiated our study from the decarboxylative Mannich
condensation of 3-oxo-3-phenoxypropanoic acid (1a) with
cyclic trifluoromethylketimine 2a in THF at room tempera-
ture. The reaction hardly occurs without the use of a catalyst
(Table 1, entry 1). Then we focused on the catalytic perfor-
mance of the saccharide-derived amino-thioureas, developed
previously in our laboratory (Figure 1).[9] The amine moiety
of the catalyst was found to have a significant effect on the
catalytic activity as well as the enantioselectivity: a poor
result was attained with catalyst (d, S, S)-Aa bearing a pri-
mary amine function (entry 2), whereas remarkable im-
provement in the yields and enantioselectivities of the Man-
nich adduct 3a could be observed when tertiary amine-thio-
urea catalysts were employed (entries 3–10). Among them,
catalyst (d, S, S)-Bd exhibited the best catalytic activity and
chiral induction ability (entry 8). Solvent screening revealed
that THF remains to be the solvent of choice, and other sol-
vents such as chloroform, dichloromethane, toluene, and
1,4-dioxane diminish the yield and/or enantioselectivity (en-
tries 11–14). The catalyst loading can be reduced to as low
as 1 mol% without a significant decrease in the product
yield and enantioselectivity, although a prolonged time was
required (entries 15 and 16). Reducing the amount of
MAHO to 1.5 or even 1.2 equivalents gave comparable re-
sults under standard reaction conditions (entries 17 and 18).
Interestingly, the catalyst (d, R, R)-C, a diastereoisomer of
(d, S, S)-Bd with the opposite configuration on the diamine
moiety, could give the Mannich adduct 3a with the retained
configuration in high enantioselectivity as well (entry 19).
There is no doubt that the use of catalyst (l, R, R)-D led to
the other enantiomer of the b-amino oxyester in comparable
yield and ee value (entry 20). These results demonstrated
that the reversal of enantioselectivity is directly related to
the saccharide moiety of organocatalysts.
Herein, we demonstrate that cyclic trifluoromethylketi-
mines are highly effective substrates for organocatalytic
[a] H.-N. Yuan, Dr. S. Li, Dr. J. Nie, Dr. Y. Zheng, Prof. J.-A. Ma
Department of Chemistry, Key Laboratory of Systems
Bioengineering (The Ministry of Education), State Synergetic
Innovation Center of Chemical Science and Engineering
Tianjin University, Tianjin 300072 (P. R. of China)
Fax: (+86)22-2740-3475
E-mail: majun_an68@tju.edu.cn
Under the optimal conditions, the scope of the reaction
was explored with a variety of MAHOs 1 and cyclic keti-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303307.
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Chem. Eur. J. 2013, 19, 15856 – 15860

COMMUNICATION
Table 1. Screening of catalysts and conditions optimization for the decar-
boxylative Mannich reaction of MAHO 1a with ketimine 2a.
sired adducts 3h–o in 93–99% yields and 91–99% ee. The
N-TMB-protected cyclic ketimine (TMB=2,4,6-trimethyl-
benzyl) was found to be an equally effective substrate, deliv-
ering 3p in 98% yield with 99% ee. A dramatic decrease in
enantioselectivity was observed (3q, 55% ee) when N-pro-
tecting group-free substrate was subjected to the reaction,
which indicates the protecting group was indispensable.
Good results could also be obtained when the trifluorometh-
Entry[a] Catalyst [mol%] Solvent Time [h] Yield [%][b] ee [%][c]
yl group on the quinazolin-2ACTHNUTRGNEUGN(1H)-one ring was replaced
1
2
3
4
5
6
7
8
–
A
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CHCl3
CH2Cl2 72
toluene 48
dioxane 48
THF
THF
THF
THF
THF
THF
96
96
48
48
48
48
48
48
48
48
72
0
28
95
94
97
70
84
99
94
90
65
72
84
93
98
96
98
98
99
97
–
with an analogous electron-withdrawing difluoromethyl
group (3r in 90% yield with 92% ee). However, other sub-
strates that replaced the trifluoromethyl group with
a methyl or phenyl group were ineffective in this reaction
system. These results indicated that the strong electron-with-
drawing di- and trifluoromethyl groups are critical for the
reactivity and selectivity of this decarboxylative Mannich re-
action.[10]
The utility of this decarboxylative Mannich products was
demonstrated by the following transformations (Scheme 2).
Starting from the adduct (R)-3i, a simple reduction of the
ester moiety with NaBH4, followed by cyclization to the
55 (R)
94 (R)
98 (R)
96 (R)
98 (R)
91 (R)
99 (R)
97 (R)
91 (R)
75 (R)
82 (R)
95 (R)
93 (R)
96 (R)
94 (R)
98 (R)
97 (R)
98 (R)
97 (S)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
ACHTUNGTRENNUNG
10
11
12
13
14
15[d]
16[d]
17[e]
18[f]
19
20
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
R
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
N
72
96
48
48
48
48
ACHTUNGTRENNUNG
amide nitrogen, gave 5,9b-dihydro-1H-azetoACHTUNGTRENUN[NG 1,2-c]quinazo-
ACHTUNGTRENNUNG
lin-4(2H)-one (5) containing an azetidine moiety, which is
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
a key subunit found in a number of bioactive natural prod-
ucts (Scheme 2a).[11] Our efficient enantioselective decar-
boxylative Mannich reaction also provides an attractive ap-
proach to the anti-HIV drug DPC 083 (Scheme 2b).[12] Com-
pound (S)-3a, which was used as the key intermediate for
the synthesis of DPC 083, was obtained in 97% yield with
97% ee upon the decarboxylative Mannich reaction of
MAHO 1a with ketimine 2a in the presence of (l, R, R)-D.
The enantiopurity of (S)-3a was further improved to
99% ee after a single recrystallization from THF. Reduction
of the phenol ester group with NaBH4 and powdered anhy-
drous CaCl2 in methanol yielded the alcohol 6 in 85% yield
with 99% ee. Subsequently, a simple oxidation using pyridi-
nium chlorochromate (PCC) afforded the corresponding al-
dehyde 7 in 72% yield. Treatment of 7 with cyclopropyl-
magnesium bromide in THF at 08C gave the adduct 8 in
81% yield with a diastereomeric ratio of 1:1. The final prod-
uct 10 could be easily obtained after dehydration and depro-
tection of the mixture 8. The optical rotation data of DPC
083 (10) are entirely consistent with those described in the
literature.[13] Thus, the determination of the stereochemistry
of 10 was used as the basis for the assignment of absolute
configuration reported in Table 1 and Scheme 1.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] General reaction conditions: 2a (0.1 mmol), 1a (0.2 mmol), and cata-
lyst (1–10 mol%) in solvent for the stated time. PMB=para-methoxy-
benzyl, THF=tetrahydrofuran. [b] Isolated yield. [c] Determined by
HPLC analysis on a chiral stationary phase. The absolute configuration
was determined by comparison of the optical rotation value of its deriva-
tive with the literature data (vide infra). [d] 2a (0.3 mmol) and 1a
(0.6 mmol) were used; [e] 1.5 equiv of 1a was used; [f] 1.2 equiv of 1a
was used.
Figure 1. Structures of saccharide-derived amino-thiourea catalysts
tested.
To gain some insights into the mechanism, a 19F NMR
study was undertaken on the decarboxylative Mannich reac-
tion of MAHO 1a with ketimine 2a in the presence of (d, S,
S)-Bd in [D8]THF (see the Supporting Information for fur-
ther details). As shown in Figure 2a, two new signals at
À80.39 and À80.52 ppm could be detected after a few hours,
which implied the formation of two diastereoisomers of the
addition intermediate 12. Although such proposed inter-
mediate could not be isolated directly, these experimental
results provide supportive evidence that nucleophilic addi-
tion of MAHOs to the ketimines could occur prior to the
mines
2 in the presence of 10 mol% (d, S, S)-Bd
(Scheme 1). The use of MAHOs with different phenolic-
ester substituents afforded the corresponding b-amino esters
3a–g in high yields (90–99%) with excellent enantioselectiv-
ities (90–99% ee). Next studies showed that the decarboxy-
lative Mannich reaction could be extended to a series of
cyclic ketimines. The substituents on the aromatic ring of
the ketimines had a negligible influence, generating the de-
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J. -A. Ma et al.
Scheme 1. Scope of the decarboxylative Mannich reaction of MAHOs 1 with cyclic ketimines 2.
Scheme 2. a) Further transformation of the decarboxylative Mannich product. b) Synthesis of anti-HIV drug DCP 083.
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Chem. Eur. J. 2013, 19, 15856 – 15860

Enantioselective Decarboxylative Mannich Reaction
COMMUNICATION
Figure 2. a) Stack plot of 19F NMR spectra. (Spectra A, B, and C: 19F NMR spectrum of ketimine 2a, Mannich product 3a, and the hydration by-product
11; Spectrum D: 19F NMR spectra of the reaction mixture collected at certain hours). b) Hydrogen-bonding complex between organocatalyst and keta-
mine; F green, N blue, O red, S yellow. c) Proposed mechanism for the organocatalytic decarboxylative Mannich reaction of MAHOs 1 with cyclic keti-
mines 2.
decarboxylation step during the decarboxylative Mannich
reaction. On the other hand, the interactions between sub-
strate and organocatalyst were probed computationally by
examining the bond critical points (BCPs) with Baderꢁs
atoms in molecules (AIM) analysis.[14] The calculations re-
vealed that the cyclic ketimine was activated and oriented
by H-bonding with the NH groups of the organocatalyst.[15]
The potential application of this catalytic asymmetric decar-
boxylative Mannich reaction was demonstrated as a key
step in a new and efficient asymmetric synthesis of the anti-
HIV drug DPC 083. Efforts are currently underway to eluci-
date the mechanistic details and the application of MAHOs-
derived synthons to other transformations, the results of
which will be reported in due course.
À
A H p bonding interaction between the aromatic-substitut-
ed protecting group on the ketimine substrate and the sac-
charide moiety of organocatalyst may also play an important
role in stabilizing the transition state (Figure 2b). This is in
agreement with the observation that substrate 2q lacking an
aromatic protection group on its nitrogen exhibited only
moderate enenatioselectivity in forming product 3q. Addi-
tionally, the tertiary amine moiety of organocatalyst electro-
statically bonds to the MAHOs 1 through a salt bridge.
From the above analysis and the absolute configurations of
the products 3, a transition state (TS) for the reaction of
MAHOs 1 with ketimines 2 in the presence of chiral orga-
nocatalyst Bd is proposed in Figure 2c. Because the nucleo-
phile approaches the Si-face of the C=N group, the R enan-
tiomer of the Mannich products 3 is preferentially formed.
Experimental Section
General procedure for decarboxylative Mannich reactions of malonic
acid half oxyesters with ketimines: A mixture of cyclic N-acyl ketimine 2
(0.1 mmol), amino-thiourea catalyst (d, S, S)-Bd (0.01 mmol), and malon-
ic acid half oxyester 1 (0.2 mmol) in THF (1.0 mL) was added into
a 10 mL Schlenk flask equipped with a stirring bar. The reaction was
then stirred at room temperature for the corresponding time. After com-
pletion of the reaction (monitored by TLC), solvent was removed under
reduced pressure, the residue was treated with 1N NaHCO3 (8 mL) and
extracted with ethyl acetate (3ꢂ10 mL). The combined organic layers
were washed with saturated brine (8 mL), dried over MgSO4 and concen-
trated under reduced pressure. The residue was purified by column chro-
matography on silica gel (eluting with petroleum ether/ethyl acetate or
ethyl acetate/CH2Cl2) to give the product 3.
Conclusion
Acknowledgements
This work was supported by the National Natural Science Foundation of
China, and the National Basic Research Program of China (973 Program,
2014CB745100).
In summary, we have developed a highly efficient enantiose-
lective decarboxylative Mannich reaction of MAHOs with
cyclic trifluoromethylketimines. With the aid of saccharide-
derived amino-thiourea catalysts, a series of enantioenriched
b-amino oxyesters containing a chiral b-quaternary center
were obtained in very high yields and enantioselectivities.
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J. -A. Ma et al.
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Keywords: asymmetric catalysis
decarboxylative Mannich reaction
oxyesters · saccharide-derived amino-thioureas
·
b-amino esters
· malonic acid half
·
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Received: August 23, 2013
Published online: October 21, 2013
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Chem. Eur. J. 2013, 19, 15856 – 15860