Metal-Free, One-Pot Cascade Annulation of 2-Pyrones in Water for the Synthesis of Peptidomimetics

Article abstract of DOI:10.1021/acs.joc.9b01856

A one-pot, metal-free, double cyclization for the synthesis of bicyclic 2-pyridones as peptidomimetics was developed. In this process, the transformation of 2-pyrones bearing a tethered, homochiral α-amino acid started with the removal of the N-Boc protective group under acidic or neutral conditions at elevated temperature, followed by several key transformations, including cyclic enamine formation, decarboxylation or esterification, isomerization, and lactamization, to furnish bicyclic 2-pyridones in up to 98% yield with retention of the chirality at the α-carbon of the amino acid portion of the molecule. Exploration of the substrate scope revealed some selectivity between the decarboxylation and esterification pathways under thermal acidic conditions, while performing the reaction in boiling water yielded the decarboxylation products exclusively.

Full text of DOI:10.1021/acs.joc.9b01856

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Article
Metal-Free, One-Pot Cascade Annulation of 2-
Pyrones in Water for the Synthesis of Peptidomimetics
Wannaporn Disadee, Anek Lekky, and Somsak Ruchirawat
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01856 • Publication Date (Web): 25 Dec 2019
Downloaded from pubs.acs.org on December 25, 2019
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Metal-Free, One-Pot Cascade Annulation of 2-Pyrones in
Water for the Synthesis of Peptidomimetics
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*,†
†
†,‡,§
Wannaporn Disadee, Anek Lekky, and Somsak Ruchirawat
†
‡
§
*
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Lak Si, Bangkok 10210, Thailand
Program on Chemical Biology, Chulabhorn Graduate Institute, Lak Si, Bangkok 10210, Thailand
The Center of Excellence on Environmental Health and Toxicology, PERDO, Bangkok, 10400, Thailand
Email: wannapor@cri.or.th
COR1
R2
R2
Just one operation:
- Deprotection of the Boc group
- Enamine formation
- Decarboxylation or esterification
- Lactamization
(S) NHBoc
H2O
110 o
N
R3
O
R3
(S)
C
COR1
O
O
R1 = OR, NRR'
R3 = H, CO2R, CN, Ar
22 examples
up to 98% yield
- Conservation of chirality
R2 = Ar, Alk, Het
R3 = CO2R, CN, Ar
ABSTRACT: A one-pot, metal-free, double cyclization for the synthesis of bicyclic 2-pyridones
as peptidomimetics was developed. In this process, the transformation of 2-pyrones bearing a
tethered, homochiral -amino acid started with removal of the N-Boc protective group under
acidic or neutral conditions at elevated temperature, followed by several key transformations,
including cyclic enamine formation, decarboxylation or esterification, isomerization and
lactamization, to furnish bicyclic 2-pyridones in up to 98% yield with retention of the chirality at
the α-carbon of the amino acid portion of the molecule. Exploration of the substrate scope
revealed some selectivity between the decarboxylation and esterification pathways under thermal
acidic conditions, while performing the reaction in boiling water yielded the decarboxylation
products exclusively.
INTRODUCTION
The significance of natural and synthetic molecules containing 2-pyridone as a central
structural scaffold and their broad applications in many fields has inspired chemists to develop
novel synthetic methods for these compounds for various purposes. Several research groups have
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developed fused, polycyclic 2-pyridones and related compounds as pharmaceutical lead
peptidomimetics for the development of new drugs, as shown in Figure 1.1,2 Some previous
synthetic methods for accessing these types of peptidomimetics include the first total synthesis of
A58365A by Danishefsky’s group using the aza-[3+3] cycloaddition of vinylogous urethane and
0
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2
a

-methyleneglutaric anhydride as a key step (Scheme 1a). The rhodium-catalyzed 1,3-dipolar
cycloaddition of diazo compounds and dipolarophiles was originally developed by Padwa’s
group and later utilized by Zhang’s and Haffner’s groups for the synthesis of various analogs
(
Scheme 1b).2a,d Clive’s methodology involved an enyne radical cyclization, followed by spiro
rearrangement to construct a bicyclic core (Scheme 1c).2a In the Almqvist approach, the
intermolecular cyclocondensation between in situ-generated acyl-ketenes and preformed cyclic
imines was employed for the synthesis of multi-fused-ring 2-pyridones and several related
2
c
compounds (Scheme 1d). Gembus’s group applied a hydroxyl-L-lysine derivative as a starting
material for double cyclization, followed by dehydration to prepare bicyclic pyrazinones
2d
(
Scheme 1e). An approach involving multistep transformations from commercially available 2-
hydroxy-6-methyl nicotinonitrile and another involving the anodic amide oxidation of
pyrrolidines, followed by several transformations were reported by Dragovich’s and Moeller’s
groups, respectively.2a,b
OH
Ar'
X
n
Ar
N
HO2C
N
R'
O
OH
O
O
OR
O
n = 1: A58365A
n = 2: A58365B
(X = S, SO2)
by Almqvist's group
by Danishefsky's, Moeller's,
Padwa's and Clive's groups
R1
R2
R1 = H, COMe, SO2Me;
R3
R2 = H, Me; R3 = (CH2)3Ph, NHCbz
R4 = NHCbz, NHTs, OH, OR, NHR
N
R4
5
=
O
H
,
O
R
,
N
R
,
H
N
C
H
E
t
B
(
O
R
)
R5
R
O
2
2
O
by Zhang's, Haffner's and Dragovich's groups
R1
N
R1 = Cl, H; R2 = Cl, OH, OAr, NHR
R3 = OR, pyrrolidine
N
R2
R3
O
O
by Gembus's and Haffner's groups
Figure 1. Examples of biologically active 2-pyridones with peptidomimetic cores developed by various groups.
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Scheme 1. Examples of Methodologies for the Construction of Bicyclic 2-Pyridone Cores
a) by Danishefsky's group
CO2Bn
BnO2C
1. benzene, 80 o
C
+
HN
N
2. CH2N2
. DDQ, dioxane, reflux
O
O
O
MeO2C
3
CO2Me
MeO2C
O
b) by Padwa's, Zhang's and Haffner's groups
O
O
COMe
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
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0
COMe
X
N
Rh2(OAc)4
benzene, 80 oC
N
N2
Y
CO2Me
CO2Me
O
X = SO2Ph, CO2t-Bu
Y = OH, CO2t-Bu
c) by Clive's group
OH
1
. Bu3SnH, AIBN
PhMe, reflux
n
n
N
N
n
2. TFA, THF, rt
N
O
O
HO2C
CO2Bn
CO2Bn
O
O
CO2Bn
O
O
O
n = 1, 2
d) by Almqvist's group
R1
OH
R2
R2
R1
S
S
O
O
HCl (g)
+
N
DCE, 64 o
N
C
O
O
CO2Me
O
CO2Me
e) by Gembus's group
O
CO2Me
OH
O
HN
2
Tf O
N
HN
NEt3
MeOH, reflux
N
N
O
DCM, rt
HO
CO2Me
NHFmoc
CO2Me
CO2Me
O
O
2
-Pyrones are well-known versatile molecules for preparing a variety of heterocyclic
systems due to the diversity of chemical reactions, including substitution, addition,
3
photochemistry, and ring transformation, in which they participate. In general, in reactions with
2
-pyrones under defined conditions, various substrates can be converted into reactive
intermediates in which decarboxylation occurs after addition, cyclization, or other
rearrangements, leading to several useful scaffolds. The use of a 2-pyrone core to synthesize 2-
pyridone systems via C-6 addition with the appropriate N-nucleophile, followed by ring opening
4
and ring reclosure sequences, has been reported. These processes require only mild reaction
conditions, including low temperature (<60 °C), for carboxylic activation to avoid the extrusion
4
b,c
of CO from intermediate B, Scheme 2a. To the best of our knowledge, there have been no
2
reported examples of intramolecular nucleophilic additions of 2-pyrones for the synthesis of 2-
pyridones, although the analogous intermolecular reactions have been well documented.4
Therefore, inspired by the successful development of 2-pyridones as peptidomimetics and our
previously reported one-pot method of preparing bicyclic 2-pyridones under basic conditions at
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elevated temperature, herein we expanded this concept to access bicyclic 2-pyridones with
chiral centers from the corresponding 2-pyrones in a facile manner, based on the intramolecular
reaction, Scheme 2b. We envisaged that this process would involve several key steps, including
N-Boc deprotection, intramolecular nucleophilic addition to the cyclic enamine, decarboxylation,
isomerization and lactamization, to furnish the final products.
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Scheme 2. General Concept and Novel Approach for the Conversion of 2-Pyrones to Bicyclic 2-Pyridones
(a) General concept
6
NHR
NHR
OH
R-NH2
activation
of COOH
O
O
NR
RO2C
RO2C
RO2C
RO2C
H
O
A
O
O
O
D
B
C
(b) Attempts in this work:
COR1
decarboxylation R2
COR1
COR1
4
3
6
BocHN
H2N
O
R2
R3
H2N
R3
N
R2
R2
R3
4
6
H
H
isomerization
COR1
Y
-Boc
O
O
H: R2 = Ar, alkyl;
R3 3
R3 = H, Ar;
O
O
OH
E: R2 = Ar, alkyl;
R3 = CO2R, CN, Ar
F
G
lactamization
Y = O, NH
RESULTS AND DISCUSSION
Our initial investigations involved the reaction of chiral 3-alkoxy carbonyl 2-pyrone 4a.
This compound was readily prepared from commercially available methyl N-Boc-(L)-
pyroglutamate (1a) and phenylacetylene (2a) in the presence of lithium hexamethyldisilazane
(LHMDS), which afforded the corresponding internal ynone 3a in 85% yield. The thermal 1,4-
addition of 3a to dimethyl malonate in the presence of substoichiometric NaH in tetrahydrofuran
(
THF) furnished the desired 2-pyrone 4a in good yield (up to 85%, Scheme 3).
Scheme 3. Synthetic Pathway to 2-Pyrones Bearing a Tethered, Homochiral -Amino Acid
CO2Me
(S)
O
Ph
MeO C
CO Me
Ph
4
3
6
2
2
NH-P
(S)
0
.5 equiv NaH
THF, 65 oC, 3 h
85% yield)
O
NHBoc
MeO2C
MeO2C
O
(
3a
4a: P = Boc
deBoc-4a: P = H, H.HX
Ph
LHMDS, THF
-78 oC, 6 h
(85% yield)
stepwise
2a
&
Tables 1 and 2
One pot
Ph
R1
4
3
6
O
N
(S)
NBoc
CO2R2
(S)
O
CO2Me
a: R1 = H, R2 = Me
5
6
7
1a
a: R1 = CO Me, R2 = Me
2
a: R1 = H, R2 = H
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Table 1. Optimization conditions for the stepwise transformation of 4a to bicyclic 2-pyridones.a
Condition
Entry
Yield (%)b
Step 1:
Step 2:
5a
6a
18
14
7
1
2
3
4
5
6
7
8
9
1
1
1
TMSCl (3 equiv), MeOH, 55 °C, 1.5 h
EDCI, cat. DMAP, DMF, rt, 14 h
6
SiO
2
, DCM, rt, 3 h
41
20
25
41
52
40
26
81
92
MS 4 Å, DMAP, MeOH, 60 °C, 2 h
MS 4 Å, DCM, rt, 2 h
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
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9
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6
K
K
2
2
CO
3
3
, MeOH, rt, 3 h
14
5
CO
, MeOH, 60 °C, 1 h
b-Al
2
2
O
3
c, DCM, rt, 3 h
d, DCM, rt, 3 h
14
22
4
n-Al
O
3
Toluene, 150 °C, 1 he
Toluene, 150 °C, 1 he
0
1
2
TFA (3 equiv), DCM, RT, 4 h
0g
85 wt.% aq.H
3
PO
4
(20 equiv), THF, RT, 5 h
-
-
-
nrf
0g
0g
TBAF (10 equiv), THF, 70 °C, 2 h
t
13
NaO Bu (4 equiv), THF, H
2
O (1 equiv), 70 °C, 4 h
a
b
Reaction was conducted in a round-bottom flask using 4a (0.22 mmol) in the indicated anhydrous solvents, except MeOH. Isolated
c
d
e
f
g
yield. Basic. Neutral. Reaction was conducted in a pressurized tube. nr = no reaction. None of product 5a or 6a was observed.
Optimization of the Reaction Conditions. To demonstrate the overall transformation efficiency
of 2-pyrone 4a to various 2-pyridones, both stepwise and one-pot synthetic procedures were
examined (Tables 1 and 2). Several strategies, including the use of acids, bases, and
thermolytically neutral conditions for the deprotection of the tert-butyl carbamate (N-Boc)
6
group, have been reported. Based on our previous experience, the Boc group of amino moieties
in 4a was removed by employing the in situ generation of HCl from trimethyl chlorosilane
5
(
TMSCl) in MeOH; after that, the volatile materials were removed in vacuo by a rotary
7
evaporator. Then, the double cyclization of deBoc-4a was examined under various conditions
(Table 1). According to previously reported conditions for the intermolecular reaction,4b
employing
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI)
and
4-
dimethylaminopyridine (DMAP) as a carboxyl-activating agent gave 6a as the major product, as
expected, in a slightly lower yield (18%), and the decarboxylation product 5a was also detected
even when the reaction was conducted at room temperature (Table 1, entry 1). When testing
other quenching methods, treating a solution of deBoc-4a in DCM with SiO at room
2
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temperature produced 5a as the major product in 41% yield along with 6a in 14%. These results
suggested that deBoc-4a could be converted into intermediates F and G (Scheme 2b) and then
transformed into the cyclized products under mild acidic conditions with SiO , albeit in moderate
2
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yield (Table 1, entry 2). When the reaction was performed in the presence of a base, such as
DMAP, K CO , or b-Al O (Table 1, entries 3, 5–7), or under neutral conditions with molecular
2
3
2
3
sieves (MS 4 Å) and n-Al O (Table 1, entries 4 and 8), in all cases, the desired product 5a was
2
3
obtained as the major product (up to 52% yield, Table 1, entry 6), while 6a was still generated in
significant amounts (up to 24% yield, Table 1, entry 8). Although the unexpected formation of
6
a, which could be obtained under almost neutral conditions without coupling reagents, was
quite interesting, these results did not indicate an improvement in the overall efficiency of this
process. In general, the rate of decarboxylation is strongly solvent dependent, and the use of
nonpolar aprotic solvents facilitates decarboxylation. Thus, we next performed the reaction of
deBoc-4a in toluene at 150 °C for 1 h, and under these conditions, 5a was obtained in high yield
and selectivity (Table 1, entry 9). However, 6a was still detected under these conditions.
6
a
Employment of trifluoroacetic acid (TFA) in DCM for N-Boc removal (Table 1, entry 10) gave
5
a as the sole product in 92% yield, which was a higher yield than that obtained using TMSCl in
MeOH (Table 1, entry 9), regardless of the cyclization method. None of the products were
6b
observed when a milder acid, aqueous phosphoric acid (85 wt.%) in an excess amount, was
employed at room temperature (Table 1, entry 11). In addition, the highly activated N-Boc group
6
c
could be cleaved under basic conditions. The use of a mild base, tetra-n-butylammonium
6c
fluoride (TBAF) in an excess amount, in refluxing THF gave no desired product, and only
complex mixtures of unidentifiable byproducts were observed (Table 1, entry 12). When the
6
c
reaction was performed using a stronger base, NaOtBu in refluxing THF and 1 equiv of water,
nonchemoselective products from the aqueous acid extraction that contained carboxylic acid
derivatives, including 7a, were observed (Table 1, entry 13).
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Table 2. Optimization conditions for the one-pot transformation of 4a to the corresponding bicyclic 2-pyridones.a
Yield (%)b
Temp
(°C)
Time
(h)
Entry
Additive (equiv)
Solvent
4
-
a
5a
37
76
85
81
62
83
91
93
92
75
95
61
-
6a
17
5
-
7a
-
1
2
3
4
5
6
7
8
9
TMSCl (10)
TMSCl (10)
TMSOTf (1.2)
TFA (3)
MeOH
MeOH
100
150
150
150
80
1
1
-
-
Toluene
Toluene
Toluene
Toluene
(20) Toluene
Toluene
DCE
0.5
1
-
-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
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9
0
1
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9
0
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0
1
2
3
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9
0
1
2
3
4
5
6
7
8
9
0
-
-
15
Tracec
TFA (3)
2
35
-
-
p-TsOH.H
2
O (1.2)
PO
150
80
1
-
12
-
Tracec
85 wt.% aq. H
3
4
10
40
20
20
7
-
-
Amberlyst-15 (2)
Amberlyst-15 (2)
Amberlyst-15 (2)
Amberlyst-15 (2)
Amberlyst-15 (2)
Amberlyst-15 (2)
100
100
100
100
100
100
100
100
110
150
150
150
110
150
150
110
110
-
-
Tracec
-
-
1
1
1
0
1
2
THF
-
-
12
Tracec
MeCN
-
-
MeOH
2
-
35
-
-
13
MeCN-H
MeCN
2
O (1:1)
2
-
87(91)d
1
1
1
4
5
6
Dowex-50WX4 (2)
2
-
12
18
72
95
12
20
96
98(96)d
-
52
60
-
Amberlite-IR120H (2)
MeCN
2
-
-
-
-
-
-
-
-
-
-
H
H
2
2
O
O
24
4
25
-
-
-
-
-
-
-
-
-
-
17
-
1
1
2
2
8
9
0
1
MeOH
Ethylene glycol (EG)
10
10
14
1.33
0.67
3.5
4(5)g
85
67
-
-
-
H
H
H
H
H
2
2
2
2
2
O-EG (1:1)
O-EG (1:1)
O-EG (1:1)e
-
-
-
22
-
98(95)d
-
O-EG (1:1)e
97(95)d
2
2
3
4f
-
-
O-EG (1:1)e
-
95(96)g
-
a
b
c
Reaction was conducted in a pressurized tube using 4a (0.22 mmol) in the indicated solvents (1-3 mL). Isolated yield. 7a was
1
d
e
observed in trace amounts, as detected by H NMR, and was difficult to purify. Using 4a (1.1 mmol). Concentration was
diluted 5-fold. Using a conventional round-bottom flask. Using 4a (11 mmol).
f
g
On the basis of the screening results in Table 1, the reaction works well under thermal acid
treatment for the deprotection-cyclization strategy. Thus, a one-pot process was explored (Table
2
1
). When 4a was reacted in a pressurized tube in the presence of acidic MeOH at temperatures of
00 and 150 °C, significantly improved yields and selectivities were clearly observed (Table 2,
entries 1 and 2). At higher temperatures, a better chemical yield (up to 81%) and combined yield
with a ratio of 15:1 were achieved (Table 2, entry 2). Fortunately, no racemization of 5a and 6a
occurred, which was proven by HPLC with a chiral column (ee > 99% for 5a and 6a), even when
the reaction was conducted at high temperatures in polar solvents in the presence of excess acid.
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Selectivity for products 5a and 6a could be improved by avoiding the esterification between
solvent MeOH and the intermediates. Thus, various acids for a one-pot synthesis were screened
under different conditions. Employing a Lewis acid, such as TMSOTf, 6d in a stoichiometric
amount (1.2 equiv) at 150 °C for 0.5 h effectively facilitated this reaction to give 5a in good
yield (85%), while 6a was not observed (Table 2, entry 3). However, a one-pot process using the
strong organic acid TFA in excess (3 equiv) at 150 °C for 1 h gave the desired product 5a and
the hydrolysis product 7a in a ratio of 5.4:1 with an excellent combined yield (96%); these
products could be easily separated by acid-base extractions (Table 2, entry 4). Decreasing the
reaction temperature to 80 °C with a longer reaction time (2 h) resulted in an incomplete
reaction, and 7a was still detectable (Table 2, entry 5). A similar result was obtained when p-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
.
6e
TsOH H O was employed in stoichiometric amounts (Table 2, entry 6). Interestingly, the use of
2
a mild inorganic acid H PO (aqueous, 85 wt.%), even in excess (20 equiv) at 80 °C with a
3
4
longer reaction time (10 h), gave 5a in excellent yield (91%) without 7a (Table 2, entry 7). In
general, the use of solid-supported reagents provides a practical and efficient synthetic method.
Thus, we turned our attention to solid-supported sulfonic acids (Table 2, entries 8–15).
6f
Amberlyst-15 (hydrogen form) serves functions analogous to those of p-TsOH. Because of the
8
physical resistance and swelling properties of Amberlyst-15, all reactions employing this solid-
supported reagent were carried out in various solvents at 100 °C. Using 2 equiv of Amberlyst-15,
one-pot deprotection and cyclization took place completely in toluene, dichloroethane (DCE),
THF, MeCN, and MeOH at different reaction rates (Table 2, entries 8–12). The reaction was
very slow in toluene, DCM, and THF at 100 °C, ranging from 20 h to 40 h (Table 2, entries 8–
10), but in MeCN, complete consumption of 4a occurred in a shorter reaction time (7 h),
providing 5a in excellent yield (95%, Table 2, entry 11). Employment of Amberlyst-15 in a polar
protic solvent, such as MeOH, at 100 °C gave similar results to those for use of TMSCl in
MeOH but with a slightly higher combined yield (96%) and an easier operation (Table 2, entry
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1
2). Although Amberlyst-15 (<2% moisture) was dried under vacuum prior to application in
anhydrous solvents, a trace amount of 7a was still detected (Table 2, entries 8–11). These results
suggest that water is crucial. When the reaction was performed in a solvent mixture of MeCN
and water (1:1), complete hydrolysis of the ester to the carboxylic acid 7a was observed as a
single product in excellent yield (Table 2, entry 13). Other solid-supported sulfonic acids, such
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
g
as Dowex-50WX4 and Amberlite-IR120H, which contain high levels of moisture (>50%), did
not work well, and 7a was obtained as a major product in 52% and 60% yields, respectively
(Table 2, entries 14 and 15). Removal of the N-Boc group using water at elevated temperature
6
h
has been previously reported. The reaction of 4a in water without any additives did not proceed
to completion at 110 °C even after 1 day, affording 5a in 72% yield and recovering 4a in 25%
yield (Table 2, entry 16). Increasing the reaction temperature to 150 °C could potentially drive
the reaction to completion within 4 h to give 5a in excellent yield (95%, Table 2, entry 17).
Surprisingly, the reaction of 5a in wet solvents, such as MeOH and EG, at 150 °C for 10 h also
afforded product 5a, even at low levels of conversion (up to 20%, Table 2, entries 18 and 19).
The effects of the cosolvent, concentration and pressure could enhance the solubility of 4a and
9
reaction rate in water. Employing EG as a green cosolvent reduced the reaction time from 4 h to
1.33 h at 150 °C (Table 2, entries 17 and 21) and from >24 h to 14 h at 110 °C (Table 2, entries
1
6 and 20). Interestingly, when the concentration of the reactant was diluted 5-fold, the reaction
went to completion at 150 °C in 0.67 h and at 110 °C in 3.5 h (Table 2, entries 22 and 23).
Decreasing the pressure of the reaction by changing the reaction apparatus from a pressurized
tube to a conventional round-bottom flask equipped with a condenser had no significant effect on
the reaction rate (Table 2, entry 24). Increasing the scale of 4a (up to 5 g, 11 mmol) required a
longer reaction time (5 h) at 110 °C to furnish the desired product 5a in 96% yield (Table 2,
entry 24). In summary, all reactions carried out in water at elevated temperature (110–150 °C)
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5
5
5
5
5
5
5
6
for defined times produced 5a exclusively in excellent yields (95–98%, Table 2, entries 17 and
0–24).
2
Scope of Substrates. Having established a simple method for the thermal double cyclization
reaction to synthesize bicyclic 2-pyridones, a number of substrates 4 bearing different electronic
and steric variations at C-4, different functional group compatibilities at C-3 of the 2-pyrone
cores, and a tethered homochiral -amino acid were prepared using the abovementioned
procedure. The isolated yields of 4b-v are shown in Scheme 4. In general, pyrones 4 could be
prepared in moderate to excellent yields (53–91%), except for 4u, which was synthesized in low
yield (32%). With respect to the stability of both the starting materials 4 and products 5 and 6,
the results of our investigation of the generality and selectivity obtained with condition A
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(TMSCl in MeOH at 150 °C) and condition B (EG/water at 110 °C) in the one-pot synthesis of
peptidomimetics are summarized in Scheme 5.
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Scheme 4. Scope of Substrates 4
COR1
R2
O
R3
O
MeO C
2
R2
R2
R3
4
3
: R2 = Ar, alkyl
R3 = CN, Ar
6
2
(S) NHBoc
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NBoc
(
S)
O
(
S)
LHMDS, THF
-78 oC, 6 h
NHBoc
0.5 equiv NaH
THF, 65 oC, 3 h
COR1
1
R OC
O
a: R1 = OMe
3a-t
(40-85% yield)
4b-v
1
1b: R1 = NMeOMe
OMe
Oi-Pr
Cl
Br
CO Me
CO Me
2
CO Me
CO Me
2
2
2
(
S) NHBoc
(S) NHBoc
(S) NHBoc
(S) NHBoc
O
O
O
O
MeO C
2
MeO C
2
MeO C
2
MeO C
2
O
O
O
O
4b (73%)
4c (80%)
4d (53%)
4e (54%)
OMe
Cl
NO2
MeO
CO Me
2
CO Me
2
CO Me
2
CO2Me
(
S) NHBoc
(S) NHBoc
(S) NHBoc
(S) NHBoc
O
O
O
O
MeO C
2
MeO C
2
MeO C
2
MeO2C
O
O
O
O
4f (72%)
4g (81%)
4h (90%)
4i (75%)
Cl
O N
MeO C
2
2
BocHN
CO Me
CO Me
2
CO Me
2
2
CO Me
2
(
S) NHBoc
(S) NHBoc
(S) NHBoc
(S) NHBoc
O
O
O
O
O
O
MeO C
MeO C
2
MeO C
2
2
MeO C
2
O
O
4j (84%)
4k (88%)
4l (83%)
4
m (91%)
N
CO Me
2
S
CO Me
2
CO Me
CO2Me
2
n-Bu
(
S) NHBoc
(S) NHBoc
(S) NHBoc
(S) NHBoc
O
O
O
O
MeO C
MeO C
MeO C
MeO2C
2
2
2
O
O
O
O
4n (83%)
4o (75%)
4p (64%)
4q (80%)
CO Me
CO Me
2
CO Me
2
2
CONMeOMe
t-Bu
(
S) NHBoc
TBDMSO
(S) NHBoc
(S)
(S) NHBoc
NHBoc
O
O
O
O
MeO C
2
MeO C
NC
2
MeO C
2
O
O
O
O
4r (85%)
4s (81%)
4
t (86%)
4u (32%)
CO Me
2
(
S) NHBoc
O
O
O N
2
4v (68%)
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5
5
5
5
5
6
Scheme 5. Scope of Reactions using Substrates with Variations at the C3/4-Position and Various Functional Group
Compatibilitiesa
R2
X
COR1
4
3
6
R2
R3
4
3
6
N
(s) NHBoc
(s)
COR1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
condition A, B
O
Y
5
b-u: X = H, Y = O, NH
O
4b-v
6b-v: X = CO2Me, Y = O
OMe
OMe
Oi-Pr
Cl
Br
N
N
N
N
N
(s)
X
(s)
X
(s)
X
(s)
X
(s)
X
CO Me
2
CO Me
2
CO Me
CO Me
CO Me
2
O
O
O
2
O
2
O
A: 5b = 46%, 6b = 17%
B: 5b = 93%, 6b = 0%
A: 5c = 69%, 6c = 13%
B: 5c = 91%, 6c = 0%
A: 5d = 74%, 6d = 15%
B: 5d = 90%, 6d = 0%
A: 5e = 62%, 6e = 11%
B: 5e = 90%, 6e = 0%
A: 5f = 51%, 6f = 23%
B: 5f = 92%, 6f = 0%
Cl
NO2
MeO
Cl
O N
2
N
N
N
N
N
X
(s)
X
(s)
X
(s)
X
(s)
X
(s)
CO Me
2
CO Me
CO Me
2
CO Me
2
CO Me
2
O
O
2
O
O
O
A: 5g = 63%, 6g = 19%
B: 5g = 95%, 6g = 0%
A: 5h = 77%, 6h = 16%
B: 5h = 87%, 6h = 0%
A: 5i = 50%, 6i = 14%
B: 5i = 89%, 6i = 0%
A: 5j = 51%, 6j = 22%
B: 5j = 96%, 6j = 0%
A: 5k = 72%, 6k = 13%
B: 5k = 95%, 6k = 0%
MeO C
2
H2N
S
N
N
N
N
N
N
X
(s)
X
(s)
CO Me
X
(s)
X
(
s)
X
(s)
CO2Me
CO Me
2
CO Me
O
CO2Me
O
O
O
2
O
2
A: 5l = 53%, 6l = 18%
B: 5l = 89%, 6l = 0%
A: 5m = 53%, 6m = 10%
B: 5m = 91%, 6m = 0%
A: 5n = 74%, 6n = 12%
B: 5n = 97%, 6n = 0%
A: 5o = 62%, 6o = 26%
B: 5o = 85%, 6o = 0%
A: 5p = 60%, 6p = 7%
B: 5p = 93%, 6p = 0%
n-Bu
t-Bu
HO
N
N
N
X
(s)
X
(s)
X
(s)
CO Me
2
CO Me
CO Me
2
O
O
2
O
N
X
(s)
A: 5t = 42%, 6t = 9%
B: 5t = 94%, 6t = 0%
A: 5q = 61%, 6q = 11%
B: 5q = 93%, 6q = 0%
A: 5r = 64%, 6r = 21%
B: 5r = 94%, 6r = 0%
A: 5s = 66%, 6s = 15%
B: 5s = 95%, 6s = 0%
CONMeOMe
O
4u
N
+
N
4v
5a
+
N
H
(s)
NC
(s)
(s)
CO Me
2
CO Me
2
CO Me
NH
O
O
2
O N
2
5u
6u
6v
A: 5u = 73%, 6u = 12%
B: 5u = 89%, 6u = 0%
A: 5a = 4%, 6v = 42%
B: 5a = 0%, 6v = 0%
a
Condition A: TMSCl in MeOH at 150 °C, except for 4t (100 °C for 1 h); Condition B: EG/water (1:1) at 110 °C for 4 h (4b-k
and 4n), 3.5 h (4l, 4o and 4t), 1.5 h (4m and 4p), or 2 h (4q-s and 4u) or at 150 °C for 3 h (4v).
Employment of condition A: In most cases, heating TMSCl in MeOH at 150 °C for 1 h
preferentially generated the decarboxylation products 5 in moderate to excellent combined yields
2
(
46–93%), as shown in Scheme 5. When R was an aryl group bearing electron-donating or
electron-withdrawing groups at the ortho-, meta- or para-positions, the decarboxylation products
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(
5b–m) were formed in competition with the esterification products (6b–m) in ratios of 2.2–
i
5
.6:1. In the case of a bulkier electron-donating group, such as ortho-O PrAr in 4c, the combined
yield and selectivity of the decarboxylation product (5c) was higher than that achieved with
ortho-OMeAr (5b). The presence of a Cl-Ar group at the ortho- or meta-positions in 4d and 4g
resulted in higher combined yields and product selectivity (5d/6d and 5g/6g) than the presence
of an OMe-directing group in 4b. An ortho-Br group in 4e was well tolerated, and the substrate
gave the desired products 5e/6e in good yield and selectivity (5.6:1, 73% combined yield). The
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
inductive effect of an NO moiety at the meta-position in 4h did not significantly enhance the
2
reactivity of the C=O group toward decarboxylation over esterification compared to the effect of
the neutral aromatic ring in 4a, despite slightly improving the total chemical yield (4.8:1, 93%
+
combined yield). Having strong electron-withdrawing substituents, NO and NH , at the para-
2
3
position, such as in 4k and 4m, favored the decarboxylation step and afforded the cyclization
products 5k/6k and 5m/6m in 85% and 63% combined yields in ratios of 5.5:1 and 5.3:1,
respectively, while 4l, bearing a moderately electron-withdrawing group (p-CO MeAr), also
2
resulted in a good yield with moderate selectivity (3:1, 72% combined yield). The presence of a
naphthyl group in 4n resulted in good product selectivity and a good combined yield (6.2:1,
86%). Heteroaromatic 2-pyrones bearing 3-thienyl (4o) and 3-pyridinyl (4p) moieties were also
tolerated in this reaction, furnishing the desired products in moderate to good overall yields (88
and 67%, respectively), and the decarboxylation-to-esterification selectivity observed with 3-
pyridinyl 4p was higher by 8.6-fold. The reactions of 2-pyrones bearing long alkyl chains (4q
and 4s) and steric t-Bu groups (4r) also proceeded smoothly and gave both cyclization products
(
5q/6q, 5r/6r and 5s/6s) in moderate to good combined yields (72%, 85%, and 81%,
respectively) in ratios of 3.0–5.5:1. Other 2-pyrone derivatives 4, including the Weinreb amide
-pyrone 4t, cyano 2-pyrone 4u, and 3,4-diaryl 2-pyrone 4v, were also explored. In the case of
2
the Weinreb amide 2-pyrone 4t, the amide was sensitive to the acidic conditions and was
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5
5
5
5
5
5
6
converted to methyl ester products. Fortunately, lowering the reaction temperature to 100 °C
increased the combined yield (89%) and improved the 5t/6t ratio (3.5:1). In the case of the 2-
pyrone bearing a cyano group at C-3 (4u), the decarboxylation product, amidine 5u, was
obtained in good yield (73%) and selectivity (6:1). Notably, the ethyl derivative of 2-pyridone 6u
was selectively synthesized in good yield using our previously developed methodology, but 5u
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
was not observed. We also demonstrated that these conditions were suitable for the preparation
of 3,4-diaryl 2-pyridones. When 4v was employed, the esterification product 6v was obtained in
5
a higher yield than that previously reported for a nonchiral version. Surprisingly, 5a was
obtained, presumably from the loss of the nitroaryl group instead of CO2.10
Employment of condition B: In general, performing a one-pot transformation in water at
1
10 °C produced exclusively the decarboxylation products 5b–u in very good to excellent yields
(85–97%), as shown in Scheme 5. The electronic nature of the substituent at C-4 only slightly
2
affected the reaction rates and yields. When R is an aryl group with substituents such as –Oalkyl
(
4b, 4c, 4f, and 4i), –Cl or –Br (4d, 4e, 4g, and 4j), and –NO (4h and 4k) at the ortho-, meta- or
2
para-positions, the reaction rate was lower than that with 4a, and the reaction was completed in
h to give the corresponding compounds 5 in very good to excellent yields (87–96%). The less
soluble naphthyl group in 4n resulted in a slow reaction rate and required a longer reaction time
4
(4 h) for complete transformation to afford 5n in excellent yield (97%). The introduction of
2
weakly polar groups, such as aryl ester (4l) and 3-thienyl (4o), at R did not significantly
improve the water solubility, and the reaction was completed in 3.5 h to give 5l and 5o in very
2
good yields (89% and 85%, respectively). When R possessed polar functional groups that
enhanced the water solubility, such as amine (4m) and pyridinyl (4p) groups, the reaction rates
were faster than that with 4a, and the reactions were complete within 1.5 h to give 5m and 5p in
2
excellent yields (91% and 93%, respectively). Similarly, when R was a small alkyl group (4q
and 4r), the reaction was completed within 2 h to give 5q and 5r in excellent yields (93% and
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4%, respectively). Surprisingly, the reaction of pyrone possessing a long alkyl chain with an
OTBS group (4s) in boiling water for 2 h unexpectedly afforded the corresponding alcohol (5s)
in excellent yield (95%); the deprotection of OTBS under these conditions has not been
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
previously reported. For pyrone with a weakly polar group at R , such as the Weinreb amide 2-
pyrone 4t, the reaction rate in boiling water was equal to that of 4a, and the reaction was
complete within 3.5 h to give 5t in 94% yield. Other 2-pyrone derivatives 4, including cyano 2-
pyrone 4u and 3,4-diaryl 2-pyrone 4v, gave different results from those of condition A. In the
case of the 2-pyrone bearing a cyano group at C-3 (4u), amidine 5u was obtained as a single
product, without 6u, in very good yield (89%), after heating at 110 °C for 2 h. Due to the
hydrophobicity of 3,4-diaryl 2-pyrone 4v, a longer reaction time (3 h), higher temperature (150
°
C), and cosolvent (EG or MeOH) were required to increase the solubility of 4v in water and the
acidity of the reaction. Although the reaction went to complete conversion, these conditions did
not afford any 2-pyridone products. These results demonstrate that an alcohol could not trap the
carboxyl intermediate G as a more stable ester via the esterification pathway (Scheme 2).
Therefore, condition B was unsuitable for the preparation of 3,4-diaryl 2-pyridones.
Scheme 6. Proposed Transformations of 4a-t to 5/6a-t using Condition A
R
3
HCl
R
3
HCl
5
2
HN
O
MeO
HO
N
O
- CO2
2
major product
COR'
COR'
O
MeO
I'
J'
decarboxylation
pathway
(a)
COR'
(b)
HN
3
R
3
HCl
R
ketene formation
pathway
6
(a)
2
2
(b)
MeO
N
MeO
O
C
minor product
(a)
HCl
O
(b)
COR'
-
H2O
O
O
O
H
K'
G'
addition
pathway
(c)
(d)
+
MeOH
MeO
esterification
pathway
R
2
HCl
6
HN
1
O
minor product
COR'
O
OMe
L'
The proposed mechanisms for the formation of products 5 and 6 using condition A are
depicted in Scheme 6. The driving force of the reaction was the nitrogen-facilitated
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1
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
delocalization of electrons to active carboxylic derivatives of G´ via (a) a decarboxylation
pathway or (b) a ketene formation pathway to generate intermediates J´ or K´, respectively. The
formation of a detectable amount of 6 allowed us to determine the role of the alcoholic media in
the reaction system. We envisaged that this product was generated via the direct intramolecular
cycloaddition of the ketene intermediate K´, the esterification of intermediate G´ (pathway c), or
the nucleophilic addition of intermediate K´ (pathway d) with an alcohol, and these
intermediates could then undergo rotatory isomerization and ring closure to generate the
corresponding 2-pyridone 6. To implement these, 4a was reacted in acidic EtOH instead of
MeOH. Analysis of the crude reaction mixtures by GC/MS revealed high conversion to the
esterification products 8a and 10a at 150 °C. Further studies were carried out to confirm the
stability of 6 under the optimal conditions using 6a and 6p as representatives. No
transformations of 6a/6p to 5a/5p were observed when 6a/6p were subjected to the optimal
conditions. Prolonged heating of 4a for 4 h afforded 5a/6a in a ratio of 13:1 and 72% combined
yield. These results suggest that 5 could not be generated from 6 under condition A.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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5
6
7
8
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1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
CONCLUSION
We have developed a facile and efficient one-pot method for synthesizing bicyclic 2-
pyridones bearing a chiral center as a peptidomimetic core. Unlike other approaches, which
normally employed Lewis acid/base- or metal-mediated cyclizations, our strategy provided mild
condition and required no special treatment for multi-chemical transformations, including Boc
deprotection, cyclic enamine formation, decarboxylation or esterification, isomerization, and
lactamization, to furnish the bicyclic 2-pyridones in a one-pot process. An exploration of the
substrate scope revealed some selectivity between the decarboxylation and esterification
pathways under thermal acidic conditions using TMSCl in MeOH (condition A), while
performing the reaction without any additional reagents in boiling water exclusively yielded the
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decarboxylation products (condition B). Observation of CO Me group at C in 6 would stem
2
3
from the use of alcohol in acidic condition at high temperature for carboxylic activation to avoid
the extrusion of CO from intermediate B. In general, all substrates 4, except pyrone with alkyl-
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
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4
5
6
7
8
9
0
1
2
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5
6
7
8
9
0
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5
6
7
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5
6
7
8
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0
1
2
3
4
5
6
7
8
9
0
OTBS 4s, were tolerated under the applied conditions. The deprotection of OTBS group to the
corresponding alcohol 5s in boiling water has not been previously reported. The reaction in
boiling water was particularly well suited for almost all substrates, except 3,4-diaryl 2-pyrone
4v, and provided the desired products 5 in better yields than those produced by the other tested
solvents. The addition of EG as a cosolvent improved the aqueous solubility of the pyrone 4 and
significantly reduced the reaction time. Both conditions gave products with retention of the
chirality at the α-carbon of the amino acid portion of the molecule.
EXPERIMENTAL SECTION
General Information:
Unless otherwise noted, all commercial-grade reagents and substrates 1a and 2 were ordered
from Sigma Aldrich, Fluka, Merck, TCI, and ACRŌS Organics. These chemicals were used
without further purification. Substrate 1b was prepared according to the literature. Solid-
supported sulfonic acids, Amberlyst-15, Dowex-50WX4 and Amberlite-IR120H were dried
under vacuum at room temperature before use. Anhydrous solvents were purified by a solvent
purification system. MeOH and EG were used without further purification. Column
chromatography was carried out using silica gel. Preparative thin-layer chromatography (PTLC)
was carried out on a glass plate precoated with 0.25 mm of silica gel 60 F . Flash column
2
54
1
chromatography was performed on 230-400 mesh silica gel. H NMR spectra were recorded on a
1
300 MHz NMR spectrometer. Chemical shifts ( values) for H NMR spectra are reported in parts
per million (ppm) downfield from tetramethylsilane ( = 0.00 ppm) as an internal reference, and
1
3
the coupling constants (J values) are in Hz. C spectra were recorded on a 75 MHz NMR
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4
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5
5
5
5
5
5
5
5
6
spectrometer with complete proton decoupling. Infrared (IR) spectra were obtained using the
universal attenuated total reflectance (UATR) technique and are reported in wavenumbers

1
(cm ). High-resolution mass spectrometry (HRMS) was performed using a time-of-flight (TOF)
instrument. Optical rotations were recorded on a polarimeter. Melting points (mp) were
determined and are reported without correction. HPLC analysis was performed on a chiral
column with a UV/VIS detector.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
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0
11
Preparation of 1b. This compound was synthesized according to the literature method. To a
two-neck round-bottom flask containing a suspension of (S)-(-)-2-pyrrolidone 5-carboxylic acid
(2.00 g, 15.5 mmol, 1.0 equiv) in DCM (70 mL) under an argon atmosphere was added dropwise
N,N’-diisopropylethylamine (DIPEA, 6.0 mL, 34.4 mmol, 2.2 equiv). The mixture was cooled on
an ice-bath, N,N’-diisopropylcarbodiimide (DIC, 2.7 mL, 17.2 mmol, 1.1 equiv) was added, and
the reaction was stirred for 30 min. Then, N,O-dimethylhydroxyl amine hydrochloride (3.02 g,
31.0 mmol, 2.0 equiv) was directly added, followed by stirring at room temperature for an
additional 2 days. The volatile material was concentrated to half its volume, and the mixture was
cooled at -18 °C overnight. The urea byproduct was removed by filtration through a celite pad,
and the filtrate was concentrated under reduced pressure. The crude product was dissolved in
DCM (30 mL), and a solution of Boc O (3.38 g, 15.5 mmol) in DCM (10 mL), triethylamine (2.2
2
mL, 15.8 mmol), and DMAP (300 mg, 2.5 mmol) was added. The reaction was stirred at room
temperature for 14 h, quenched with 10% citric acid (20 mL), and extracted with DCM (2 x 30
mL). The combined organic layer was dried over anhydrous Na SO , and the solvent was
2
4
concentrated under reduced pressure. The crude products were purified by column
chromatography on silica gel (hexane/EtOAc = 4:1 to 1:4) to afford 1b as yellow oil (4.23 g,
72% yield).
tert-Butyl (S)-2-(methoxy(methyl)carbamoyl)-5-oxopyrrolidine-1-carboxylate (1b).
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[
α]D28 -11 (c 1.0, CHCl ); IR (UATR) 
2979, 1786, 1754, 1714, 1673, 1458, 1305, 1253,
max
3
-1 1
1
150, 1022, 997, 843, 733 cm ; H NMR (300 MHz, CDCl )  5.01 (dd, J = 9.3, 2.5 Hz, 1H),
3
3
.79 (s, 3H), 3.24 (s, 3H), 2.72–2.57 (m, 1H), 2.45 (ddd, J = 17.3, 9.3, 3.0 Hz, 1H), 2.38–2.22
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
(m, 1H), 1.95 (ddt, J = 9.8, 5.4, 2.7 Hz, 1H), 1.91 (s, 9H); C{ H} NMR (75 MHz, CDCl ) 
3
173.8, 171.4, 149.4, 82.9, 61.3, 56.7, 32.3, 30.9, 27.8, 21.2; HRMS (ESI-TOF) calcd for
+
C H N Na O (M+Na) 295.1264, found 295.1265.
1
2
20
2
1
5
General Procedure for the Synthesis of Internal Ynones 3a–t. Lithium hexamethyldisilazane
LHMDS, 1 M in THF, 6.2 mL, 6.2 mmol, 1.5 equiv) was added dropwise to a two-neck round-
(
bottom flask containing a solution of alkyne 2 (6.2 mmol, 1.5 equiv) in THF (5 mL) under an
argon atmosphere at -78 °C and stirred for 1 h. Then, a solution of the lactam 1 (4.1 mmol, 1.0
equiv) in THF (5 mL) was added dropwise, and the mixture was stirred for an additional 6 h. The
reaction was quenched with sat. NH Cl (10 mL), gradually warmed to room temperature, and
4
extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with water and
dried over anhydrous Na SO , and the solvent was concentrated under reduced pressure. The
2
4
crude products were purified by column chromatography on silica gel using hexane and EtOAc
as eluents to afford compound 3.12
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-5-oxo-7-phenyl-6-heptynoate (3a). Following the
general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 10:1), the product 3a was obtained as a brown solid (1.20 g,
8
5% yield), mp 52.7–53.5 °C; [α]D27 +13.3 (c 1.0, CHCl ); IR (UATR)  3366, 2978, 2200,
3
max
-1 1
1742, 1713, 1674, 1444, 1367, 1248, 1159, 1054, 760, 690 cm ; H NMR (300 MHz, CDCl )
3

7.56 (d, J = 7.5 Hz, 2H), 7.50–7.31 (m, 3H), 5.29 (d, J = 7.9 Hz, 1H), 4.42–4.28 (m, 1H), 3.76
1
3
1
(s, 3H), 2.91–2.69 (m, 2H), 2.36–2.20 (m, 1H), 2.11–1.97 (m, 1H), 1.44 (s, 9H); C{ H} NMR
(75 MHz, CDCl )  185.9, 172.4, 155.2, 132.9, 130.6, 128.5, 119.6, 91.1, 87.4, 79.8, 52.6, 52.2,
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2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
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4
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4
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4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
4
3
1.2, 28.1, 26.5; HRMS (ESI-TOF) calcd for C H N Na O (M+Na) 368.1474, found
19 23 1 1 5
68.1472. These spectroscopic data were identical to those reported previously.12a
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(2-methoxyphenyl)-5-oxo-6-heptynoate (3b).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3b was obtained as yellow oil (1.31 g, 85%
yield), [α]D29 +12.8 (c 1.0, CHCl ); IR (UATR)  3373, 2977, 2196, 1712, 1667, 1596, 1491,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
max
-1
1
1
6
366, 1247, 1161, 1022, 852, 755 cm ; H NMR (300 MHz, CDCl )  7.52–7.37 (m, 2H), 6.98–
3
.88 (m, 2H), 5.38 (d, J = 8.1 Hz, 1H), 4.42–4.29 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 2.92–2.68
1
3
1
(m, 2H), 2.38–2.20 (m, 1H), 2.19–2.04 (m, 1H), 1.44 (s, 9H); C{ H} NMR (75 MHz, CDCl ) 
3
1
85.9, 172.4, 161.2, 155.1, 134.6, 132.4, 120.3, 110.6, 108.6, 91.3, 88.7, 79.6, 55.5, 52.6, 52.4,
+
4
1.2, 27.9, 26.4; HRMS (ESI-TOF) calcd for C H N Na O (M+Na) 398.1580, found
20 25
1
1
6
398.1577.
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(2-isopropoxyphenyl)-5-oxo-6-heptynoate (3c).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 4:1), the product 3c was obtained as brown oil (1.39 g, 84%
yield), [α]D26 +37.1 (c 1.0, CHCl ); IR (UATR)  3367, 2978, 2195, 1739, 1715, 1667, 1486,
3
max
-1 1
1
1
366, 1273, 1161, 1051, 950, 753 cm ; H NMR (300 MHz, CDCl )  7.47 (dd, J = 7.8, 1.8 Hz,
3
H), 7.37 (ddd, J = 8.4, 7.5, 1.8 Hz, 1H), 6.94–6.87 (m, 2H), 5.16 (d, J = 7.4 Hz, 1H), 4.67–4.55
(
m, 1H), 4.40–4.28 (m, 1H), 3.74 (s, 3H), 2.87–2.68 (m, 2H), 2.35–2.20 (m, 1H), 2.17–2.00 (m,
1
3
1
1
1
2
H), 1.43 (s, 9H), 1.38 (d, J = 6.1 Hz, 6H); C{ H} NMR (75 MHz, CDCl )  186.2, 172.5,
3
60.2, 155.2, 135.0, 132.3, 120.4, 113.8, 110.3, 91.4, 89.6, 79.9, 71.5, 52.8, 52.3, 41.4, 28.2,
+
6.8, 21.9; HRMS (ESI-TOF) calcd for C H N Na O (M+Na) 426.1893, found 426.1888.
2
2
29
1
1
6
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(2-chlorophenyl)-5-oxo-6-heptynoate (3d).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 4:1), the product 3d was obtained as brown oil (872 mg, 56%
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yield), [α]D26 +17.9 (c 1.0, CHCl ); IR (UATR)  3368, 2978, 2204, 1739, 1712, 1674, 1503,
3
max
-1 1
1
366, 1247, 1159, 1050, 757, 736 cm ; H NMR (300 MHz, CDCl )  7.58 (dd, J = 7.7, 1.6 Hz,
3
1
H), 7.48–7.36 (m, 2H), 7.28 (ddd, J = 7.5, 7.4, 1.6 Hz, 1H), 5.33 (d, J = 7.4 Hz, 1H), 4.44–4.30
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(m, 1H), 3.76 (s, 3H), 2.95–2.72 (m, 2H), 2.40–2.25 (m, 1H), 2.22–2.00 (m, 1H), 1.45 (s, 9H);
1
3
1
C{ H} NMR (75 MHz, CDCl )  185.8, 172.4, 155.2, 137.3, 134.6, 131.7, 129.5, 126.7, 119.9,
3
9
1.3, 87.4, 79.9, 52.6, 52.3, 41.4, 28.1, 26.7; HRMS (ESI-TOF) calcd for C H Cl N Na O
5
1
9
22
1
1
1
+
(
M+Na) 402.1084, found 402.1089.
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(2-bromophenyl)-5-oxo-6-heptynoate (3e).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 4:1), the product 3e was obtained as brown oil (1.01 g, 58%
yield), [α]D26 +19.6 (c 1.0, CHCl ); IR (UATR)  3368, 2978, 2204, 1739, 1710, 1673, 1468,
3
max
-1
1
1
7
366, 1246, 1160, 1026, 757, 736 cm ; H NMR (300 MHz, CDCl )  7.66–7.55 (m, 2H), 7.37–
3
.27 (m, 2H), 5.33 (d, J = 8.4 Hz, 1H), 4.43–4.30 (m, 1H), 3.76 (s, 3H), 2.95–2.75 (m, 2H),
1
3
1
2.40–2.25 (m, 1H), 2.23–2.00 (m, 1H), 1.45 (s, 9H); C{ H} NMR (75 MHz, CDCl )  185.7,
3
1
2
72.3, 155.1, 134.6, 132.5, 131.7, 127.1, 126.5, 122.0, 90.5, 88.9, 79.7, 52.5, 52.2, 41.3, 28.0,
+
6.5; HRMS (ESI-TOF) calcd for C H Br N Na O (M+Na) 446.0579, found 446.0586.
1
9
22
1
1
1
5
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(3-methoxyphenyl)-5-oxo-6-heptynoate (3f)
.
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3f was obtained as brown oil (1.26 g, 82%
yield), [α]D28 +12.9 (c 1.0, CHCl ); IR (UATR)  3368, 2976, 2192, 1739, 1715, 1670, 1489,
3
max
-1
1
1
1
366, 1207, 1162, 1045, 783, 684 cm ; H NMR (300 MHz, CDCl )  7.28 (dd, J = 8.1, 7.8 Hz,
3
H), 7.15 (d, J = 7.8 Hz, 1H), 7.07 (dd, J = 1.7, 0.9 Hz, 1H), 7.00 (ddd, J = 8.3, 7.8, 1.7 Hz, 1H),
5.46 (d, J = 8.2 Hz, 1H), 4.43–4.30 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.92–2.70 (m, 2H), 2.38–
1
3
1
2
.20 (m, 1H), 2.14–1.97 (m, 1H), 1.45 (s, 9H); C{ H} NMR (75 MHz, CDCl )  185.7, 172.3,
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59.0, 155.1, 129.4, 125.1, 120.3, 117.2, 90.7, 86.9, 79.5, 54.9, 52.4, 52.0, 41.0, 27.9, 26.1;
+
HRMS (ESI-TOF) calcd for C H N Na O (M+Na) 398.1580, found 398.1581.
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0
25
1
1
6
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(3-chlorophenyl)-5-oxo-6-heptynoate (3g).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
8
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7
8
9
0
1
2
3
4
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6
7
8
9
0
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3g was obtained as brown oil (965 mg, 62%
yield), [α] 2 +17.9 (c 1.0, CHCl ); IR (UATR) 
6
3375,2978, 2006, 1744, 1713, 1676, 1503,
D
3
max
-1 1
1
367, 1249, 1163, 1056, 788, 680 cm ; H NMR (300 MHz, CDCl )  7.56–7.54 (m, 1H), 7.48–
3
7.41 (m, 2H), 7.34 (d, J = 7.7 Hz, 1H), 5.20 (d, J = 7.4 Hz, 1H), 4.44–4.30 (m, 1H), 3.77 (s, 3H),
13
1
2
.91–2.69 (m, 2H), 2.35–2.22 (m, 1H), 2.13–1.96 (m, 1H), 1.45 (s, 9H); C{ H} NMR (75
MHz, CDCl )  185.7, 172.5, 155.3, 134.5, 132.6, 130.99, 130.96, 129.8, 121.4, 89.0, 87.9, 80.0,
3
+
52.6, 52.4, 41.3, 28.2, 26.6; HRMS (ESI-TOF) calcd for C H Cl N Na O (M+Na) 402.1084,
1
9
22
1
1
1
5
found 402.1089.
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(3-nitrophenyl)-5-oxo-6-heptynoate (3h).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 10:1), the product 3h was obtained as brown solid (736 mg,
4
6% yield), mp 69.5–71.1 °C; [α]D28 +11.7 (c 1.0, CHCl ); IR (UATR)  3393, 2978, 2208,
3
max
-1 1
1740, 1711, 1675, 1532, 1352, 1252, 1161, 1053, 734, 672 cm ; H NMR (300 MHz, CDCl )
3

8.41 (dd, J = 1.7, 1.7 Hz, 1H), 8.33 (ddd, J = 8.3, 2.3, 1.1 Hz, 1H), 7.91 (ddd, J = 7.8, 1.7, 1.1
Hz, 1H), 7.66 (dd, J = 8.3, 7.8 Hz, 1H), 5.37 (d, J = 8.1 Hz, 1H), 4.47–4.32 (m, 1H), 3.79 (s,
1
3
3H), 3.00–2.77 (m, 2H), 2.40–2.25 (m, 1H), 2.15–2.00 (m, 1H), 1.46 (s, 9H); C{1H} NMR (75
MHz, CDCl )  185.3, 172.3, 155.2, 147.8, 138.2, 129.7, 127.3, 125.0, 121.4, 88.3, 86.9, 79.7,
3
+
5
2.4, 52.2, 41.1, 28.0, 26.2; HRMS (ESI-TOF) calcd for C H N Na O (M+Na) 413.1325,
19 22
2
1
7
found 413.1330.
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(4-methoxyphenyl)-5-oxo-6-heptynoate (3i).
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Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3i was obtained as yellow solid (1.12 g, 73%
yield), mp 63.5–65.1 °C; [α]D27 +105.8 (c 1.0, CHCl ); IR (UATR)  3367, 2979, 2191, 1739,
3
max
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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3
3
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4
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5
5
5
5
5
5
5
6
0
1
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7
8
9
0
1
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7
8
9
0
1
2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1 1
1
715, 1602, 1441, 1366, 1251, 1162, 1026, 834, 735 cm ; H NMR (300 MHz, CDCl )  7.51 (d,
3
J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.43 (d, J = 8.2 Hz, 1H), 4.42–4.30 (m, 1H), 3.83 (s,
3
H), 3.75 (s, 3H), 2.90–2.68 (m, 2H), 2.35–2.20 (m, 1H), 2.13–1.98 (m, 1H), 1.44 (s, 9H);
1
3
1
C{ H} NMR (75 MHz, CDCl )  185.7, 172.3, 161.4, 155.1, 134.8, 114.1, 111.1, 92.2, 87.1,
3
+
7
3
9.5, 55.0, 52.5, 52.0, 40.9, 27.9, 26.3; HRMS (ESI-TOF) calcd for C H N Na O (M+Na)
2
0
25
1
1
6
98.1580, found 398.1587.
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(4-chlorophenyl)-5-oxo-6-heptynoate (3j).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3j was obtained as a brown solid (1.29 g,
8
3% yield), mp 93.5–96.4 °C; [α]D27 +6.5 (c 1.0, CHCl ); IR (UATR) 
3367, 2978, 2202,
max
3
-1 1
1711, 1674, 1489, 1366, 1248, 1160, 1089, 1014, 830, 736 cm ; H NMR (300 MHz, CDCl )
3

7.50 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 5.33 (d, J = 8.3 Hz, 1H), 4.43–4.30 (m, 1H),
1
3
1
3
.76 (s, 3H), 2.92–2.69 (m, 2H), 2.38–2.20 (m, 1H), 2.14–1.97 (m, 1H), 1.45 (s, 9H); C{ H}
NMR (75 MHz, CDCl )  185.6, 172.3, 155.2, 136.9, 134.0, 128.9, 118.0, 89.5, 88.0, 79.7, 52.5,
3
+
52.2, 41.1, 28.0, 26.3; HRMS (ESI-TOF) calcd for C H Cl N Na O (M+Na) 402.1084, found
1
9
22
1
1
1
5
4
02.1088.
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(4-nitrophenyl)-5-oxo-6-heptynoate (3k).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3k was obtained as brown oil (881 mg, 55%
yield), [α]D27 +5.9 (c 1.0, CHCl ); IR (UATR)  3385, 2978, 2208, 1739, 1710, 1676, 1521,
3
max
-1 1
1344, 1268, 1161, 1052, 857, 735 cm ; H NMR (300 MHz, CDCl )  8.27 (d, J = 8.7 Hz, 2H),
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5
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5
5
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7
2
.76 (d, J = 8.7 Hz, 2H), 5.28 (d, J = 7.7 Hz, 1H), 4.45–4.30 (m, 1H), 3.78 (s, 3H), 2.96–2.75 (m,
1
3
1
H), 2.40–2.23 (m, 1H), 2.13–1.98 (m, 1H), 1.45 (s, 9H); C{ H} NMR (75 MHz, CDCl ) 
3
185.4, 172.3, 155.2, 148.4, 133.5, 126.3, 123.6, 90.2, 87.1, 79.9, 52.5, 52.3, 41.2, 28.1, 26.4;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (ESI-TOF) calcd for C H N Na O (M+Na) 413.1325, found 413.1338.
1
9
22
2
1
7
Methyl (S)-4-[6-((tert-butoxycarbonyl)amino)-7-methoxy-3,7-dioxo-1-heptynyl]benzoate (3l).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3l was obtained as a pale yellow solid (1.36
g, 82% yield), mp 73.3–75.5 °C; [α]D27 +23.6 (c 1.0, CHCl ); IR (UATR)  3376, 2954, 2204,
3
max
-1 1
1715, 1674, 1507, 1436, 1366, 1273, 1162, 1095, 769, 694 cm ; H NMR (300 MHz, CDCl )
3

8.05 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 5.24 (d, J = 7.3 Hz, 1H), 4.43–4.30 (m, 1H),
3.94 (s, 3H), 3.77 (s, 3H), 2.93–2.60 (m, 2H), 2.37–2.20 (m, 1H), 2.13–1.95 (m, 1H), 1.45 (s,
1
3
1
9
H); C{ H} NMR (75 MHz, CDCl )  185.6, 172.3, 165.7, 155.2, 132.5, 131.5, 129.4, 124.0,
3
8
9.0, 88.9, 79.7, 52.5, 52.1, 41.2, 28.0, 26.2; HRMS (ESI-TOF) calcd for C H N Na O
7
21 25
1
1
+
(M+Na) 426.1529, found 426.1523.
Methyl
(S)-2-[(tert-butoxycarbonyl)amino]-7-[4-(tert-butoxycarbonyl)amino]phenyl-5-oxo-6-
heptynoate (3m).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 7:3), the product 3m was obtained as a yellow solid (756 mg,
4
0% yield), mp 125.8–127.9 °C; [α]D28 +11.3 (c 1.0, CHCl ); IR (UATR)  3357, 2979, 2191,
3
max
-1 1
1698, 1585, 1518, 1367, 1314, 1229, 1151, 1049, 839, 736 cm ; H NMR (300 MHz, CDCl )
3

7.48 (d, J = 9.2 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 5.28 (d, J = 8.1 Hz, 1H), 4.42–4.30 (m, 1H),
3
9
.76 (s, 3H), 2.89–2.67 (m, 2H), 2.35–2.20 (m, 1H), 2.15–1.97 (m, 1H), 1.52 (s, 9H), 1.44 (s,
1
3
1
H); C{ H} NMR (75 MHz, CDCl )  186.1, 172.5, 155.3, 152.2, 141.2, 134.2, 117.9, 113.0,
3
92.4, 87.4, 81.0, 80.0, 52.7, 52.3, 41.1, 28.1, 28.1, 26.5; HRMS (ESI-TOF) calcd for
+
C H N Na O (M+Na) 483.2107, found 483.2119.
2
4
32
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1
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Methyl (S)-2-[(tert-butoxycarbonyl)amino]-7-(2-naphthalenyl)-5-oxo-6-heptynoate (3n).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 5:1), the product 3n was obtained as brown oil (1.20 g, 74%
yield), [α]D26 +24.7 (c 1.0, CHCl ); IR (UATR)  3365, 2977, 2195, 1739, 1711, 1668, 1501,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
max
-1 1
1
436, 1366, 1161, 1051, 817, 748 cm ; H NMR (300 MHz, CDCl )  8.14 (d, J = 1.0 Hz, 1H),
3
7
3
.87–7.80 (m, 3H), 7.60–7.49 (m, 3H), 5.18 (d, J = 7.5 Hz, 1H), 4.45–4.33 (m, 1H), 3.77 (s,
1
3
1
H), 2.95–2.70 (m, 2H), 2.38–2.23 (m, 1H), 2.15–2.00 (m, 1H), 1.45 (s, 9H); C{ H} NMR (75
MHz, CDCl )  186.1, 172.6, 155.4, 134.4, 133.9, 132.6, 128.4, 128.3, 128.2, 128.0, 127.8,
3
1
27.0, 116.9, 91.8, 87.7, 80.1, 52.8, 52.4, 41.4, 28.2, 26.7; HRMS (ESI-TOF) calcd for
+
C H N Na O (M+Na) 418.1630, found 418.1639.
23 25
1
1
5
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-5-oxo-7-(3-thioenyl)-6-heptynoate (3o).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3o was obtained as a brown solid (720 mg,
5
1

0% yield), mp 60.0–62.1 °C; [α]D28 +4.3 (c 1.0, CHCl ); IR (UATR) 
3372, 2978, 2193,
max
3
-1 1
739, 1709, 1667, 1505, 1365, 1248, 1160, 1053, 787, 735 cm ; H NMR (300 MHz, CDCl )
3
7.77 (dd, J = 3.0, 1.2 Hz, 1H), 7.35 (dd, J = 5.1, 3.0 Hz, 1H), 7.22 (dd, J = 5.1, 1.2 Hz, 1H), 5.30
(d, J = 6.8 Hz, 1H), 4.43–4.29 (m, 1H), 3.76 (s, 3H), 2.90–2.68 (m, 2H), 2.33–2.20 (m, 1H),
13
1
2
1
.13–1.95 (m, 1H), 1.44 (s, 9H); C{ H} NMR (75 MHz, CDCl )  185.9, 172.4, 155.2, 1433.9,
3
30.0, 126.1, 118.8, 87.6, 86.5, 79.8, 52.6, 52.2, 41.0, 28.1, 26.4; HRMS (ESI-TOF) calcd for
+
C H N Na O S (M+Na) 374.1038, found 374.1041.
1
7
21
1
1
5
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-5-oxo-7-(3-pyridinyl)-6-heptynoate (3p).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3p was obtained as brown oil (596 mg, 42%
yield), [α]D28 +12.5 (c 1.0, CHCl ); IR (UATR)  3363, 2977, 2205, 1743, 1709, 1674, 1514,
3
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2
2
2
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3
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3
3
3
3
3
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4
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4
5
5
5
5
5
5
5
5
5
5
6
-1
1
1
366, 1249, 1159, 1024, 808, 703 cm ; H NMR (300 MHz, CDCl )  8.80 (dd, J = 2.1, 0.9 Hz,
3
1H), 8.67 (dd, J = 4.9, 1.7 Hz, 1H), 7.87 (ddd, J = 7.9, 2.1, 1.7 Hz, 1H), 7.35 (ddd, J = 7.9, 4.9,
0
.9 Hz, 1H), 5.15 (d, J = 7.3 Hz, 1H), 4.42–4.30 (m, 1H), 3.77 (s, 3H), 2.95–2.71 (m, 2H), 2.36–
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
2
.20 (m, 1H), 2.11–1.96 (m, 1H), 1.45 (s, 9H); C{ H} NMR (75 MHz, CDCl )  185.6, 172.5,
3
155.3, 153.3, 150.8, 139.9, 123.2, 117.2, 99.0, 87.1, 80.2, 52.7, 52.5, 41.3, 28.3, 26.5; HRMS
+
(
ESI-TOF) calcd for C H N Na O (M+Na) 369.1426, found 369.1428.
1
8
22
2
1
5
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-5-oxo-6-undecynoate (3q).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 4:1), the product 3q was obtained as brown oil (614 mg, 46%
yield), [α]D27 +18.2 (c 1.0, CHCl ); IR (UATR)  3367, 2959, 2211, 1715, 1674, 1502, 1437,
3
max
-1 1
1366, 1247, 1160, 1050, 870, 778 cm ; H NMR (300 MHz, CDCl )  5.25 (d, J = 6.9 Hz, 1H),
3
4
2
.36–4.22 (m, 1H), 3.75 (s, 3H), 2.77–2.53 (m, 2H), 2.37 (t, J = 7.0 Hz, 2H), 2.27–2.10 (m, 1H),
1
3
1
.05–1.87 (m, 1H), 1.63–1.48 (m, 2H), 1.50–1.35 (m, 12H), 0.93 (t, J = 7.2 Hz, 3H); C{ H}
NMR (75 MHz, CDCl )  186.1, 172.4, 155.2, 94.8, 80.4, 79.7, 52.6, 52.1, 41.2, 29.4, 28.0, 26.3,
3
+
2
3
1.7, 18.4, 13.2; HRMS (ESI-TOF) calcd for C H N Na O (M+Na) 348.1787, found
1
7
27
1
1
5
48.1795.
Methyl (S)-2-[(tert-butoxycarbonyl)amino]-8,8-dimethyl-5-oxo-6-nonynoate (3r).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 4:1), the product 3r was obtained as yellow oil (601 mg, 45%
yield), [α]D27 +23.4 (c 1.0, CHCl ); IR (UATR)  3367, 2974, 2213, 1715, 1674, 1501, 1456,
3
max
-1 1
1
366, 1262, 1162, 1053, 867, 779 cm ; H NMR (300 MHz, CDCl )  5.19 (d, J = 7.1 Hz, 1H),
3
4.37–4.24 (m, 1H), 3.75 (s, 3H), 2.77–2.52 (m, 2H), 2.27–2.11 (m, 1H), 2.06–1.89 (m, 1H), 1.45
13
1
(
s, 9H), 1.28 (s, 9H); C{ H} NMR (75 MHz, CDCl )  186.1, 172.3, 155.1, 101.6, 79.5, 78.7,
3
+
5
2.5, 52.0, 41.1, 29.7, 27.9, 26.2; HRMS (ESI-TOF) calcd for C H N Na O (M+Na)
17 27 1 1 5
348.1787, found 348.1797.
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Methyl (S)-2-[(tert-butoxycarbonyl)amino]-10-[(tert-butyldimethylsilyl)oxy]-5-oxo-6-decynoate
(3s).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 4:1), the product 3s was obtained as brown oil (1.18 g, 65%
yield), [α]D29 +16.9 (c 1.0, CHCl ); IR (UATR)  3367, 2954, 2212, 1716, 1676, 1501, 1366,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
max
-1 1
1251, 1162, 1103, 834, 776, 662 cm ; H NMR (300 MHz, CDCl )  5.11 (d, J = 7.4 H, 1H),
3
4
2
.30–4.19 (m, 1H), 3.71 (s, 3H), 3.65 (t, J = 5.8 Hz, 2H), 2.63–2.50 (m, 2H), 2.43 (t, J = 7.1 H,
1
3
H), 2.22–2.08 (m, 1H), 2.00–1.85 (m, 1H), 1.41 (s, 9H), 0.86 (s, 9H), 0.02 (s, 6H); C{1H}
NMR (75 MHz, CDCl )  186.1, 172.5, 155.2, 94.6, 80.5, 79.9, 61.1, 52.7, 52.3, 41.3, 30.6, 28.2,
3
+
2
6.5, 25.8, 18.2, 15.3, -5.5; HRMS (ESI-TOF) calcd for C H N Na O Si (M+Na) 464.2444,
2
2
39
1
1
6
found 464.2442.
tert-Butyl (S)-1-[methoxy(methyl)amino]-1,5-dioxo-7-phenyl-6-heptyn-2-yl-carbamate (3t).
Following the general procedure for the synthesis of internal ynones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 3t was obtained as yellow oil (845 mg, 55%
yield), [α]D27 –1.5 (c 1.0, CHCl ); IR (UATR)  3326, 2976, 2201, 1709, 1665, 1489, 1366,
3
max
-
1 1
1
7
2
248, 1164, 1049, 992, 758, 689 cm ; H NMR (300 MHz, CDCl )  7.61–7.54 (m, 2H), 7.51–
3
.34 (m, 3H), 5.33 (m, 1H), 4.82–4.65 (m, 1H), 3.79 (s, 3H), 3.23 (s, 3H), 2.90–2.70 (m, 2H),
1
3
1
.27–2.10 (m, 1H), 2.09–1.87 (m, 1H), 1.44 (s, 9H); C{ H} NMR (75 MHz, CDCl )  186.1,
3
172.1, 155.3, 132.8, 130.5, 128.4, 119.6, 90.6, 87.4, 79.4, 61.4, 49.5, 41.0, 31.9, 28.1, 26.5;
+
HRMS (ESI-TOF) calcd for C H N Na O (M+Na) 397.1739, found 397.1742.
2
0
26
2
1
5
General Procedure for the Synthesis of 2-Pyrones 4a–v. To a two-neck round-bottom flask
containing a suspension of sodium hydride (20 mg, 60% in oil, 0.5 mmol, 0.5 equiv) in THF (0.2
mL) under an argon atmosphere was added dropwise a solution of dimethyl malonate (159 mg,
1
.20 mmol, 1.2 equiv) in THF (1.7 mL) at room temperature, and the resulting mixture was
stirred for 5 min. Then, a solution of the ynone 3a–t (1.00 mmol, 1.0 equiv) in THF (1.7 mL)
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was added, and the reaction was refluxed at 65 °C for 3 h. The reaction was cooled to room
temperature, quenched with sat. NH Cl (10 mL), and extracted with EtOAc (2 x 20 mL). The
4
combined organic layer was dried over anhydrous Na SO and concentrated under reduced
2
4
0
1
2
3
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0
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0
pressure. The crude products were purified by column chromatography on silica gel using
hexane and EtOAc as eluents to afford the 2-pyrones 4a–t. Compounds 4u and 4v were
synthesized according to the general procedure using 3u or 3v (1.00 mmol) with ethyl
cyanoacetate (136 mg, 1.2 mmol, 1.2 equiv) or ethyl 4-nitrophenylacetate (251 mg, 1.2 mmol,
1
.2 equiv), respectively.
Methyl (S)-6-[3-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl]-2-oxo-4-phenyl-2H-pyran-
3-carboxylate (4a).
Following the general procedure for the synthesis of 2-pyrones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 4a was obtained as yellow oil (1.09 g, 85%
yield), [α]D27 +32.5 (c 1.0, CHCl ); IR (UATR)  3366, 2977, 1708, 1637, 1545, 1435, 1367,
3
max
-1
1
1
249, 1159, 1033, 817, 766, 700 cm ; H NMR (300 MHz, CDCl )  7.50–7.35 (m, 5H), 6.21 (s,
3
1
H), 5.19 (d, J = 7.8 Hz, 1H), 4.45–4.30 (m, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 2.75–2.58 (m, 2H),
1
3
1
2
.35–2.20 (m, 1H), 2.10–1.95 (m, 1H), 1.44 (s, 9H); C{ H} NMR (75 MHz, CDCl )  172.2,
3
1
65.2, 164.4, 159.7, 155.2, 154.9, 135.7, 130.2, 128.7, 127.0, 116.0, 105.8, 80.1, 52.4, 30.0,
+
2
9.7, 28.1; HRMS (ESI-TOF) calcd for C H N O (M+H) 446.1815, found 446.1807.
23 28
1
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Methyl
(S)-6-[3-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl]-4-(2-methoxyphenyl)-2-
oxo-2H-pyran-3-carboxylate (4b).
Following the general procedure for the synthesis of 2-pyrones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 4b was obtained as yellow oil (347 mg, 73%
yield), [α]D28 +41.2 (c 1.0, CHCl ); IR (UATR)  3369, 2951, 1712, 1637, 1541, 1494, 1435,
3
max
-
1 1
1
1
366, 1251, 1161, 1023, 756, 734 cm ; H NMR (300 MHz, CDCl )  7.40 (ddd, J = 8.3, 7.5,
3
.7 Hz, 1H), 7.20 (dd, J = 7.5, 1.7 Hz, 1H), 7.00 (ddd, J = 7.5, 7.5, 0.9 Hz, 1H), 6.95 (d, J = 8.3
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Hz, 1H), 6.15 (s, 1H), 5.21 (d, J = 7.8 Hz, 1H), 4.40–4.29 (m, 1H), 3.81 (s, 3H), 3.75 (s, 3H),
1
3
1
3
.63 (s, 3H), 2.70–2.50 (m, 2H), 2.33–2.18 (m, 1H), 2.08–1.90 (m, 1H), 1.43 (s, 9H); C{ H}
NMR (75 MHz, CDCl )  172.2, 164.9, 163.8, 159.7, 155.7, 155.2, 154.1, 131.3, 128.7, 120.7,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
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6
7
8
9
0
1
16.6, 110.9, 107.1, 80.0, 55.3, 52.6, 52.4, 52.0, 29.9, 29.8, 28.1; HRMS (ESI-TOF) calcd for
+
C H N Na O (M+Na) 498.1740, found 498.1745.
2
4
29
1
1
9
Methyl (S)-6-[3-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl]-4-(2-iso-propoxy phenyl)-
-oxo-2H-pyran-3-carboxylate (4c).
2
Following the general procedure for the synthesis of 2-pyrones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 4c was obtained as yellow oil (403 mg, 80%
yield), [α]D27 +32.6 (c 1.0, CHCl ); IR (UATR)  3363, 2979, 1737, 1712, 1638, 1489, 1451,
3
max
-1 1
1
366, 1248, 1161, 1023, 734, 702 cm ; H NMR (300 MHz, CDCl )  7.41–7.31 (m, 1H), 7.17
3
(dd, J = 7.8, 1.6 Hz, 1H), 7.00–6.90 (m, 2H), 6.18 (s, 1H), 5.30 (d, J = 8.2 Hz, 1H), 4.61–4.48
(m, 1H), 4.45–4.30 (m, 1H), 3.75 (s, 3H), 3.61 (s, 3H), 2.72–2.55 (m, 2H), 2.34–2.18 (m, 1H),
1
3
1
2
.10–1.94 (m, 1H) , 1.43 (s, 9H) , 1.29 (d, J = 6.1 Hz, 6H); C{ H} NMR (75 MHz, CDCl ) 
3
172.1, 164.6, 163.3, 159.6, 155.1, 154.7, 154.0, 130.9, 128.7, 126.3, 120.4, 116.5, 114.0, 107.1,
+
7
9.8, 71.0, 52.5, 52.3, 51.8, 29.7, 29.7, 28.0, 21.6; HRMS (ESI ) calcd for C H N Na O
2
6
33
1
1
9
+
(
M+Na) 526.2053, found 526.2066.
Methyl (S)-6-[3-((tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl]-4-(2-chlorophenyl)-2-oxo-
H-pyran-3-carboxylate (4d).
2
Following the general procedure for the synthesis of 2-pyrones and purification by column
chromatography (hexane/EtOAc = 3:1), the product 4d was obtained as yellow oil (254 mg, 53%
yield), [α]D27 +23.1 (c 1.0, CHCl ); IR (UATR)  3368, 2978, 1713, 1637, 1542, 1435, 1366,
3
max
-1 1
1
249, 1160, 1104, 1021, 760, 734 cm ; H NMR (300 MHz, CDCl )  7.46 (dd, J = 7.8, 1.6 Hz,
3
1H), 7.41–7.28 (m, 2H), 7.21 (dd, J = 7.4, 1.9 Hz, 1H), 6.09 (s, 1H), 5.18 (d, J = 7.8 Hz, 1H),
4
.40–4.29 (m, 1H), 3.76 (s, 3H), 3.60 (s, 3H), 2.74–2.58 (m, 2H), 2.47–2.20 (m, 1H), 2.12–1.95
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