The catalytic synthesis of carboniolamide: The role of sp 3 hybridized oxygen

Article abstract of DOI:10.1055/s-0034-1379101

A catalytic synthesis of carboniolamide has been reported. The strategy was straightforward with aldehyde and amide as starting materials. The products can be isolated as precipitates from the reaction mixture. The factor that stabilizes the labile functionality of hemiaminal was elucidated as a sp ³ hybridized oxygen.

Full text of DOI:10.1055/s-0034-1379101

2644▌
LETTER
3
letter
The Catalytic Synthesis of Carboniolamide: The Role of sp Hybridized
Oxygen
Carboniolamide Synthesis
Yi Zhang,a Yuchi Dai,a Guigen Li,a,b Xu Cheng*a
a
Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023,
P. R. of China
b
Department of Chemistry and Biochemistry, Texas Tech University, Memorial Circle & Boston, Lubbock, TX 79409-1061, USA
Fax +86(25)84687372; E-mail: chengxu@nju.edu.cn
Received: 19.07.2014; Accepted after revision: 18.08.2014
IC50 (nM)
cell line
Abstract: A catalytic synthesis of carboniolamide has been report-
ed. The strategy was straightforward with aldehyde and amide as
starting materials. The products can be isolated as precipitates from
the reaction mixture. The factor that stabilizes the labile functional-
ity of hemiaminal was elucidated as a sp3 hybridized oxygen.
O
O
OH
4.3
1.9
2.2
4.0
20
25
14
3.2
7.2
2.9
HL-60
O
O
A2780
A2780AD
MCF-7
OVCAR 8
NCI/ADR
1A9
A549
HCT116
PC-3
N
H
Key words: catalysis, amide, aldehyde, phosphate, nucleophilic
addition
O
(–)-zampanolide
Hemiaminal bears unusual gem-N,OH functionality and
has been supposed to be an unstable intermediate in the
organic chemistry. The half-life of the trapped hemiami-
nal is about 30 minutes as reported by Rebek.1 On the oth-
er hand, carboniolamide, the acylated hemiaminal, does
occur naturally in the marine macrolide (–)-zampanolide
(Figure 1).2 The (–)-zampanolide showed outstanding an-
ticancer potency against ovarian, breast, lung, prostate
and colorectal cancer cell lines.3 The backbone of zampa-
nolide, named as dactylolide, shows reduced inhibitory
activity than that of zampanolide with additional hemiam-
inal group. Recently, a study conducted by Steinetz and
his co-workers revealed that the carbinolamide side chain
plays an important role in the anticancer profile due to its
unique hydrogen bonding ability.4
O
O
IC50 (nM)
cell line
O
O
A2780
602
1236
68
149
249
A2780AD
MCF-7
A549
O
HCT116
(–)-dactylolide
Figure 1 Marine macrolide with carboniolamide side chain
mers. Another strategy towards the carboniolamide uti-
lized the amide preorganized with stochiometric
aluminum20 or boron21 reagent. Toste demonstrated the
enantioselective synthesis of α-fluoro carbinolamide with
enamide as substrate, where excellent enantioselectivity
was obtained.8 In comparison, the direct addition of amide
to aldehyde is a straightforward, atom-economic, and ide-
al synthesis.22 In 2009, Tanaka and his co-workers report-
ed the p-TsOH-catalyzed addition of amide to aldehyde in
their total synthesis of (–)-zampanolide, where carboniol-
amide was generated as a minor product along with the
bisamide as the major outcome.23 The only example of
chemoselective direct addition of amide to aldehyde is
presented by Ghosh employing chiral phosphate as cata-
lyst.24 So far the factor that stabilized the carboniolamide
instead of its overreaction to bisamide is not clear.20,25
The synthesis of gem-diheteroatom functionality has ad-
vanced in the last decade with organo- and organometallic
catalysis. In 2005, Antilla reported the first enantioselec-
tive intermolecular N,N-aminal synthesis.5 Later on, the
intramolecular aminal syntheses were achieved by List,6
Rueping,7 Toste,8 Tian,9 Kurth,10 Masson,11 and Lin.12
Highly related N,OR chiral centers were constructed with
similar protocols in both intermolecular13 and intramolec-
ular manners.14 Meanwhile, several O,O-acetal syntheses
were also presented by List,15 Nagorny,16 Gong,17 and
Aponick.18 Despite these progresses, the synthesis of car-
boniolamide was somehow challenging due to its labile
free hydroxyl group. In the pioneer work of total synthesis
of zampanolide by Smith group, the carboniolamide
group was derived from PMB-protected hemiaminal.19 In
this case, during the course of deprotection, epimerization
happened spontaneously to give a mixture of diastereoiso-
As a part of our ongoing research on the reaction between
amide and aldehyde, we found that the ethyl glyoxylate
reacted with amide (2.0 equiv), yielding the carboniol-
amide instead of commonly observed bisamide products
(Scheme 1).26 Herein, we report our study on the catalytic
addition of amide to aldehyde as well as the stabilizing
factor for carboniolamide.
SYNLETT 2014, 25, 2644–2648
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DOI: 10.1055/s-0034-1379101; Art ID: st-2014-w0612-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carboniolamide Synthesis
2645
aliphatic amides gave the corresponding carboniolamides
as white precipitate (1a–1c) in good yield. The aromatic
products could be obtained efficiently as well (1d–i). The
α,β-unsaturated amide such as cinnamide and acrolamide
gave the desired product 1j and 1k, respectively, without
any significant side reaction. Meanwhile, the heterocyclic
compound 1l was prepared in good yield. Besides these
amides, the carbamates, such as Cbz-NH2 and Fmoc-NH2,
worked in the same way to give the respective adducts 1m
and 1n. When the different glyoxylates were adopted as
the electrophiles, similar reactivities along with easy
workup were retained for both amides and carbamates
(entries 15–21).
O
OH
O
O
OEt
OEt
BF3⋅OEt2
N
NH2
H
+
H
O
O
(2.0 equiv)
stable carboniolamide
X
O
OEt
N
O
HN
O
O
OEt
N
H
O
Table 2 Substrate Scope of the Addition of Amide to Glyoxylatea
Scheme 1 Unexpected carboniolamide synthesis
O
OH
∗
O
O
Our initial reaction was carried out with ethyl glyoxylate
and benzamide as starting materials in the presence of 10
mol% boron trifluoride diethyl etherate (Table 1). Soon it
turned out that the diphenyl phosphate could give superior
reactivity (entries 1–3). So we chose the diphenyl phos-
phate as standard catalyst, and screened different solvents
at room temperature. To our delight, diethyl ether, a rela-
tively green solvent, facilitated the conversion by precip-
itating the target molecule as the only product, which
drove the reaction to the high conversion instead of reach-
ing equilibriums as observed in other solvents such as ac-
etone, ethyl acetate and CH2Cl2. The purity of precipitate
was satisfying in the absence of either chromatography or
recrystallization.27
OR2
OR2
conditions
R1
N
H
R1
NH2
H
+
O
O
1
Entry
1
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Me
i-Pr
Bn
Ph
Et
Et
Et
Et
Et
Et
Et
Et
85
83
81
84b
84
91
80
80
4-MeOC6H4
4-FC6H4
Table 1 Optimization Conditions for the Addition of Amide to Gly-
1g
1h
4-ClC6H4
4-F3CC6H4
oxylatea
O
O
OH
O
catalyst
OEt
OEt
+
H
Ph
N
Ph
NH2
solvent, r.t.
9
1i
Et
73
H
O
O
Entry
Catalyst
Solvent
Yield
10
11
1j
styrenyl
Et
Et
81
81
1
2
3
4
5
6
BF3·OEt2
AcOH
acetone
acetone
acetone
EtOAc
CH2Cl2
Et2O
50%b
20%b
60%b
40%b
35%
1k
vinyl
S
12
13
1l
Et
Et
83
80
(PhO)2POOH
(PhO)2POOH
(PhO)2POOH
(PhO)2POOH
O
1m
O
85%
14
1n
Et
90
a Reaction conditions: ethyl glyoxylate (1.0 equiv), benzamide (1.0
equiv), catalyst (10 mol%), 0.25 M in solvents, r.t., 12 h; the product
was obtained as precipitate.
b The product was obtained after chromatography.
15
16
1o
1p
Ph
i-Pr
i-Pr
80
80
O
With the optimized conditions in hand, we tested different
amides with several glyoxylate derivatives (Table 2).28
With the commercially available ethyl glyoxylate as start-
ing material, different amides were evaluated in the pres-
ence of 10 mol% of diphenyl phosphate. The adducts of
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2644–2648

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Y. Zhang et al.
LETTER
Table 2 Substrate Scope of the Addition of Amide to Glyoxylatea
(continued)
H
H
O
OH
O
O
O
O
O
O
O
O
OH
∗
O
O
R
N
R
N
R
N
H
H
H
OR2
OR2
conditions
OEt
OEt
R1
N
H
R1
NH2
H
O
+
O
O
1
Entry
17
1
R1
R2
Yield (%)
85
sp2
O
O
O
O
O
H
NH
O
+
NH2
1q
i-Pr
O
H
HN
2
3
18
19
1r
1s
4-MeC6H4
Bn
Bn
78
80
H
N
CONH2
(PhO)2POOH
Ph
3-thienyl
BnO
BnO
sp3
+
O
OH
O
O
5
4
20
1t
Bn
88
sp3
OH
O
O
O
O
O
O
O
N
H
R
+
21
1u
Bn
60
O
R
NH2
H
R = Ph
R = Bn
R = styrenyl 7c
7a
7b
55%
55%
58%
a Reaction conditions: glyoxate (1.0 equiv), amide (1.0 equiv), 0.25 M
in Et2O, diphenyl phosphate (10 mol%), r.t., 8–24 h. The precipitate
was collected by filtration.
6
b Amount of amide used was 2.0 equiv.
Scheme 2 The different behavior of aldehydes bearing α-oxygen.
Note: 10 mol% diphenyl phosphate, aldehyde and amide, 0.25 M in
Et2O, r.t., 12 h. The products were collected as single products with
filtration.
It was noteworthy that even with 2.0 equivalents of ben-
zamide as starting material the reaction gave the car-
boniolamide as the only product without any overaddition
to bisamide (Table 2, entry 4). In contrast to the common
bisamide condensation reactions, this phenomenon sug-
gested that the product is too stable to undergo dehydra-
tion to give the imine intermediate. We presumed that the
additional oxygen atom provided by the glyoxylate mole-
cule could stabilize the hydroxyl group along with the car-
bonyl group from the amide part. So in turn, it was needed
to be found which oxygen (sp2 or sp3) accounted for the
major effect (Scheme 2). Thus, substrate 2 with only sp2
α-oxygen and 4 with only sp3 α-oxygen atom were sub-
jected to the phosphate-catalyzed reactions using one
equivalent of benzamide. The distinct chemoselectivity
was observed in that bisamide 3 was the only product
from dicarbonyl compound 2, and carboniolamide 5 gen-
erated specifically from 4. We reasoned that sp3 oxygen is
the effective hydrogen bonding acceptor for the formed
hydroxyl group and prevents the further collapse of car-
boniolamide. We explored additional aldehydes such as
dioxolane aldehyde 6 and the target molecules 7a–c were
obtained as mixtures of diastereoisomers.
tem, we assumed that sulfonamide, where the sulfonyl ad-
opted tetrahedron configuration instead of planar triangle
of carbonyl in amide,29 could fit this protocol as well.
Thus, a reaction between the benzenesulfonamide and
ethyl glyoxylate was established with the standard condi-
tions. The desired molecule 8 was obtained as the single
product in the form of a white precipitate with the yield of
65% (Scheme 3). The compound was inert under the am-
bient condition and could be manipulated in the same
manner.
(PhO)2POOH
(5 mol%)
O
OH
O
O
S
HN
S
OEt
NH2
+
H
OEt
Et2O, r.t., 12 h
O
O
O
O
8
65%
Scheme 3 The reaction between benzenesulfonamide and ethyl gly-
oxylate
In order to take the full advantage of the convenient filtra-
tion, the preparation of 1m was set up at 0.1-mol scale
(Scheme 4). At the beginning of the reaction, a mixture of
glyoxylate, Cbz-NH2, and diphenyl phosphate was ob-
tained as a clear solution. After 20 hours, the desired prod-
uct was obtained as a white crystalline solid by
In contrast to the known mode of hydrogen bonding net-
work focused on the NH···OC,25 an interaction also exists
in the bisamide, and the present results suggested that the
OH.OR interaction plays a unique role in surviving the
hemiaminal. With the rationale of hydrogen bonding sys-
Synlett 2014, 25, 2644–2648
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carboniolamide Synthesis
2647
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Scheme 4 The catalytic synthesis of carboniolamide on a 20-gram
scale
In summary, we have discovered that Brønsted acid can
catalyze the nucleophilic addition of amide to the alde-
hyde to form the carboniolamide as a stable compound
where α-oxygen adopting sp3 hybridization is necessary to
stabilize the generated hydroxyl group. The chemistry can
be extended to sulfonamide. This simple procedure could
be scaled up to 20 grams. We are now working on the en-
antioselective construction of carboniolamide.
Acknowledgment
This work was supported by the National Science Fund for Talent
Training in Basic Science (Grant No. J1103310), the Ph.D. Pro-
grams Foundation of Ministry of Education of China (Grant
20130091120047), and NSFC key Program (Grant 21332005). A
scholarship for Z.Y. (SRTP Grant G1310284037) is highly appre-
ciated.
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(28) General Procedure for the Synthesis of the
Carboniolamide: To a reaction vial charged with amide (1.0
mmol), glyoxylate (1.0 mmol), and diphenyl hydrogen
phosphate (25.0 mg, 0.1 mmol) was added Et2O (4 mL).
Then the sealed reaction mixture was stirred at r.t. for the
specified time. The obtained slurry was then filtered, and the
precipitate was washed with a minimum amount of cold
Et2O to give the compound as a white powder.
1g: mp 106.2–108.1 °C. 1H NMR (400 MHz, DMSO-d6):
δ = 9.46 (d, J = 7.8 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 2 H), 7.56
(d, J = 8.5 Hz, 2 H), 6.63 (d, J = 6.1 Hz, 1 H), 5.64 (t, J = 6.9
Hz, 1 H), 4.15 (q, J = 7.1 Hz, 2 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 170.26, 165.43,
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2644–2648

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Y. Zhang et al.
LETTER
137.01, 132.72, 129.93, 128.92, 72.44, 61.25, 14.49. IR (thin
film): 1015, 1033, 1102, 1155, 1239, 1312, 1345, 1487,
1536, 1598, 1649, 1655, 1746, 3304, 3402 cm–1. MS (ESI):
m/z [M + Na+] calcd for C11H12ClNO4Na: 280; found: 280.
HRMS (ESI): m/z [M + Na+] calcd for C11H12ClNO4Na:
280.0353; found: 280.0356.
H), 1.21 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, DMSO-
d6): δ = 170.04, 155.92, 144.24, 144.14, 141.18, 128.14,
127.54, 125.83, 125.76, 120.59, 73.73, 66.34, 61.25, 46.94,
14.47. IR (thin film): 740, 758, 1042, 1093, 1224, 1267,
1331, 1449, 1530, 1703, 1721, 1753, 3328 cm–1. MS (ESI):
m/z [M – H+] calcd for C19H19NO5: 340; found: 340. HRMS
(ESI): m/z [M + Na+] calcd for C19H19NO5Na: 364.1161;
found: 364.1163.
1n: mp 125.3–127.1 °C. 1H NMR (400 MHz, DMSO-d6): δ
= 8.43 (d, J = 8.6 Hz, 1 H), 7.90 (d, J = 7.5 Hz, 2 H), 7.74 (t,
J = 8.1 Hz, 2 H), 7.32–7.45 (m, 4 H), 6.50 (s, 1 H), 5.29 (d,
J = 8.6 Hz, 1 H), 4.20–4.36 (m, 3 H), 4.13 (q, J = 7.1 Hz, 2
(29) Adsmond, D. A.; Grant, D. J. W. J. Pharm. Sci. 2001, 90,
2058.
Synlett 2014, 25, 2644–2648
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