Gold-Catalyzed Amide/Carbamate-Linked N, O-Acetal Formation with Bulky Amides and Alcohols

Article abstract of DOI:10.1021/acs.joc.0c02640

A gold-catalyzed N,O-acetal formation was established to construct an amide/carbamate-linked N,O-acetal substructure with bulky alcohols. The acyliminium cation species generated from o-alkynylbenzoic acid ester in the presence of a gold catalyst is highly reactive and underwent nucleophilic attack of various bulky alcohols and phenols at room temperature under neutral conditions, leading to the corresponding N,O-acetals in yields of 34-89% with good functional group tolerance.

Full text of DOI:10.1021/acs.joc.0c02640

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Gold-Catalyzed Amide/Carbamate-Linked N,O‑Acetal Formation
with Bulky Amides and Alcohols
Kosuke Ohsawa, Shota Ochiai, Junya Kubota, and Takayuki Doi*
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ABSTRACT: A gold-catalyzed N,O-acetal formation was established to
construct an amide/carbamate-linked N,O-acetal substructure with bulky
alcohols. The acyliminium cation species generated from o-alkynylben-
zoic acid ester in the presence of a gold catalyst is highly reactive and
underwent nucleophilic attack of various bulky alcohols and phenols at
room temperature under neutral conditions, leading to the correspond-
ing N,O-acetals in yields of 34−89% with good functional group
tolerance.
he N,O-acetal moiety has been well-known as an
Timportant precursor of active iminium cation species in
Mannich and Pictet−Spengler reactions.1 Among these
species, amide/peptide-linked N,O-acetals have been recently
noticed as an important substructure for use in various fields in
biologically active natural products,2 in backbone NH-
protecting groups during peptide synthesis,3 as stable linkers
in antibody−drug conjugates,4 and as prodrugs.5
There have been several reports of acyclic carbonyl-linked
N,O-acetal formation by Mannich-type reactions using amides
and aldehydes/acetals6 and oxidative fragmentation of amino
acids/amino alcohols.7 However, these applications to produce
tertiary amide/carbamate-containing N,O-acetals are limited.
One of the procedures generally used is the alkylation of
chloromethyl adducts. For example, N-chloromethylated
amides, prepared from corresponding secondary amides,
reacted with alcohols including antitumor compounds, such
as SN-38 and auristatin E, under mildly basic conditions to
provide the desired N,O-acetals (Scheme 1a).3−5 Ellman et al.
conducted the N-alkylation of a secondary amide with
potassium hexamethyldisilazide (KHMDS) and chloromethyl
3-methylbutanoate during the total synthesis of tubulysin D
(Scheme 1b).8 A relatively stable N-trialkylsilylmethyl group
has also been employed as a latent form of peptide-linked N,O-
acetals. Additionally, the electrochemical oxidation in the
presence of TBAF or Tamao-type oxidation affords the N,O-
acetal functionality (Scheme 1c).9
installed N,O-acetal moiety on an amide nitrogen of a
backbone peptide, which has rarely been found in natural
and unnatural products. Disappointingly, our initial attempts
based on SN2-type N- and O-alkylation with corresponding
chloromethyl adducts were fruitless owing to the bulkiness of
the tertiary alcohol. To overcome the steric issue, we focused
on o-alkynylbenzoic acid esters as effective alkylation agents in
the presence of cationic gold(I) catalyst, as reported by Asao et
al.10 This substructure has also been known as a precursor of
highly reactive oxonium and carbenium cation species in the
glycosidation11 and the propargylation,12 respectively. Based
on these reports, we envisioned that an acyliminium cation
species, generated from the corresponding o-alkynylbenzoic
acid ester in the presence of a catalytic amount of cationic
gold(I), can work as a sterically less-hindered electrophile to
react with bulky alcohols via SN1-type O-alkylation (Scheme
1d). Herein, we report an amide/carbamate-linked N,O-acetal
formation method that uses a highly reactive acyliminium
cation generated in situ by the Ph3PAuOTf catalyst.
Our study began from the preparation of the acyliminium
cation precursors 3 from 1-aminocyclopropanecarboxylic acid
derivatives 1 as a structurally simplified surrogate of
carnosadine lactam. The initial attempt for the N-chlorome-
thylation of 1a was carried out using TMSCl/(CH2O)n
according to the reported procedure.3b,4,5c Although substrate
1a was not fully consumed within 24 h, the resulting N-
chloromethyl adduct reacted by subsequent addition of o-
Nonetheless, carbonyl-linked N,O-acetal formation at a
sterically hindered position is still a difficult task. Our goal is
synthetic studies on branched-peptide antibiotics, named
stalobacin I (Figure 1).2g A N,O-acetal substructure in
stalobacin I is composed of two non-proteinogenic amino
acids, α,α′-disubstituted carnosadine lactam and 3-hydrox-
yisoleucine, linked via a methylene group. A key challenge for
the total synthesis is the incorporation of a tertiary-alcohol-
Received: November 5, 2020
https://dx.doi.org/10.1021/acs.joc.0c02640
© XXXX American Chemical Society
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Scheme 1. Synthetic Strategy for Tertiary Amide/
Carbamate-Linked N,O-Acetals
Scheme 2. Preparation of the Acyliminium Cation Precursor
3
With the desired acyliminium cation precursor in hand, we
next surveyed a gold-catalyzed N,O-acetal formation of N-
Alloc-protected 3a with a bulky alcohol. The reaction
conditions were optimized using 2-methyl-1-phenylpropan-2-
ol (4a) as a substrate, and the results are shown in Table 1.
Table 1. Gold-Catalyzed N,O-Acetal Formation of 4 with 5a
via Acyliminium Cation Species
a
bc
,
entry Au cat. (x mol %)
solvents
CH2Cl2
CH2Cl2
toluene
toluene/CH2Cl2 (7:1)
toluene
toluene
toluene
toluene
yield of 5a (%)
1
2
3
4
5
6
7
8
Ph3PAuOTf (30)
Ph3PAuOTf (10)
Ph3PAuOTf (10)
Ph3PAuOTf (10)
Ph3PAuOTf (5)
Ph3PAuOTf (2)
Ph3PAuOTf (10)
Ph3PAuNTf2 (10)
63
37
73
73
69
17
57
59
d
a
The Au catalyst was prepared in situ from Ph3PAuCl and the
b
c
corresponding Ag salt. Isolated yield. The isocoumarin 6 was
isolated in 84−99% yields. Performed at 50 °C.
d
According to the gold-catalyzed glycosidation procedure
reported by Yu,11 3a was activated using a catalytic amount
of Ph3PAuOTf (30 mol %) prepared in situ in the presence of
MS4A. The generated acyliminium cation species was
immediately captured by the alcohol 4a to provide the desired
N,O-acetal 5a in a 63% yield with the isocoumarin 6 in a 98%
yield (entry 1). Compared with a one-pot approach from 1a
via the N-chloromethyl adduct, the yield of 5a was dramatically
improved,14 suggesting usefulness of our procedure for bulky
substrates. We next tried to reduce the amounts of the Au
catalyst. However, the N,O-acetal formation led to a significant
decrease in yield when the amount of the Au catalyst was
reduced to 10 mol % (37%, entry 2). After several experiments,
the choice of solvent was found to be important. Using toluene
or mixed toluene/CH2Cl2 (7:1) as a solvent improved the
yield up to 73% (entries 3 and 4). Toluene could stabilize the
generated acyliminium cation species through π-stacking
interactions.15 The N,O-acetal formation led to a slight
decrease in yield when the amount of the Au catalyst was
Figure 1. Chemical structure of stalobacin I. The absolute
configuration of the asymmetric carbons with an asterisk was not
determined. The relative configuration of the trans-cyclopropane
carbons marked by a dagger was clarified, whereas the absolute
configuration of them was unclear.
hexynylbenzoic acid 2 and DIEA in an one-pot operation,
providing the desired o-hexynylbenzoic acid ester 3a in a 36%
yield. After investigation of the HCHO source, solvent, and
base, the N-chloromethylation step was found to be
dramatically improved when using a solution of monomeric
HCHO13 instead of polymeric (CH2O)n, and the subsequent
addition of 2 and DIEA afforded 3a−3d, bearing Alloc, Boc,
Cbz, and Fmoc groups, in moderate yields (Scheme 2).
B
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reduced to 5 mol % (69%, entry 5), whereas further reduction
to 2 mol % resulted in a significant decrease in yield (17%,
entry 6). Upon increasing the reaction temperature, the yield
decreased owing to the decomposition of substrate 3a (entry
7). Other cationic Au(I) species, such as Ph3PAuNTf2, resulted
in a moderate yield (59%, entry 8). Thus, we determined that
the optimized condition is shown in entries 3 and 4.
reaction conditions. Products 5ad and 5ae were afforded in 67
and 75% yields, respectively. Phenols, including sterically
hindered 2,6-disubstituents, also reacted to provide N,O-
acetals 5af (69%) and 5ag (67%). Next, we examined the N,O-
acetal formation using hydroxy-bearing amino acids: serine,
threonine, and 3-hydroxyvaline. Primary, secondary, and
tertiary alcohols on the side chains of these amino acids
reacted to produce N,O-acetal-linked dipeptides 5ah−5aj in
moderate to good yields (67−89%). Additionally, a tertiary
alcohol having a N,O-acetonide moiety was applied, affording
5ak in a 34% yield. Of note, protecting groups, such as Alloc,
Boc, Cbz, Fmoc, and tBu ester, which are used widely in
peptide synthesis, are tolerated under our N,O-acetal formation
protocols.
The substrate scope for our developed N,O-acetal method-
ology is depicted in Scheme 3. When alcohols were not
Scheme 3. Scope of Alcohols 4 in the N,O-Acetal Formation
b
of 3
We next shifted our attention to the synthesis of the amide-
linked N,O-acetal substructure, as presented in stalobacin I,
and the reaction using the dipeptide 7 is illustrated in Scheme
4. Because a N,N-dialkylamine bearing a bulky substituent is
Scheme 4. Gold-Catalyzed N,O-Acetal Formation of the
Dipeptide 9 with 4a
often poorly reactive for activated acylating reagents, such as
acid chlorides and mixed acid anhydrides,9c installing a N,O-
acetal substructure for an amide compound is also worthwhile.
Preparation of the acyliminium cation precursor 9 was
conducted using the established protocol in Scheme 2;
however, the N-chloromethylation of 7 with TMSCl/
monomeric HCHO did not proceed, recovering the substrate.
Given the poorer nucleophilicity of the amide nitrogen than
that of the carbamate nitrogen, we planned the N-alkylation of
7 with the O-chloromethyl adduct 8 according to Ellman’s
report.8 The amide anion of 7, generated with KHMDS at −78
°C, readily reacted with 8, providing 9 in a 47% yield. The
N,O-acetal formation of 9 with 4a was successful under the
optimized conditions, and the desired 10 was obtained in a
72% yield. This result indicates the possibility of our procedure
for application to the synthesis of structurally complex N,O-
acetal compounds.
a
b
Toluene/CH2Cl2 (7:1) was used as a mixed solvent. Yields refer to
isolated yield.
dissolved in toluene, toluene/CH2Cl2 (7:1) was used as a
mixed solvent. The precursors 3a−3d bearing carbamate-type
protecting groups, such as Alloc, Boc, Cbz, and Fmoc groups,
readily reacted with the alcohol 4a under optimized conditions,
providing the corresponding N,O-acetals 5aa−5da in moderate
to good yields (69−79%). Cyclic tertiary alcohols, such as 1-
adamantanol (4b) and 1-methylcyclohexanol (4c), were
transformed into the corresponding products of 5ab (67%)
and 5ac (87%). 4-Iodophenyl and azide groups, which are
effective for transition-metal-catalyzed coupling reactions and
Huisgen cycloaddition, were found to be tolerant under the
Based on the gold-catalyzed glycosidation,11 a plausible
mechanism of gold-catalyzed N,O-acetal formation is shown in
Scheme 5. The triple bond in precursor I is initially activated
by gold(I). Subsequent intramolecular nucleophilic attack of
the proximal carbonyl oxygen in II results in the removal of
isocoumarin IV, providing the acyliminium cation species III.
The resulting III is readily captured by an alcohol to produce
the desired N,O-acetal V. Because an acidic proton derived
C
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doublet), td (triple doublet), brs (broad singlet), brd (broad doublet),
brt (broad triplet), brq (broad quartet), and J (coupling constants in
hertz). High-resolution mass spectra were measured on a Thermo
Scientific Exactive Plus Orbitrap Mass Spectrometer (for ESI). IR
spectra were recorded on a JASCO FTIR-4100 instrument. Only the
strongest and/or structurally important absorptions are reported as
the IR data afforded in wavenumbers (cm−1). Optical rotations were
measured on a JASCO P-1010 polarimeter. Melting points were
measured with a Round Science Inc. RFS-10 instrument and are not
corrected.
Scheme 5. Plausible Mechanism of Au-Catalyzed N,O-Acetal
Formation
Ethyl 1-(((Allyloxy)carbonyl)amino)cyclopropane-1-carbo-xylate
(1a). To a solution of 1-(ethoxycarbonyl)cyclopropane-1-carboxylic
acid16 (1.27 g, 8.03 mmol) in dry (CH2Cl)2 (50 mL) were added
NEt3 (1.5 mL, 10.4 mmol) and DPPA (1.9 mL, 8.83 mmol) at room
temperature under an argon atmosphere, and the mixture was stirred
at the same temperature for 30 min. After being stirred at reflux for 2
h in an oil bath, the reaction mixture was cooled to room temperature,
and allyl alcohol (1.1 mL, 16.1 mmol) was added to the above
mixture. After being stirred at reflux for 3 h in an oil bath, the reaction
mixture was cooled to room temperature, concentrated in vacuo, and
diluted with EtOAc. The organic layer was washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, and filtrated. The
filtrate was concentrated in vacuo, and the resulting residue was
purified by column chromatography on silica gel (eluted with hexane/
EtOAc = 7:1) to afford the N-Alloc amine 1a (1.58 g, 7.41 mmol,
from the alcohol is consumed by proto-demetalation of IV to
afford isocoumarin VI, the reaction proceeds under neutral
conditions with the regeneration of the gold(I) catalyst.
In summary, we have demonstrated the carbamate/amide-
linked N,O-acetal formation using cyclopropaneamino acid
derivatives. An acyliminium cation species generated from o-
ethynylbenzoic acid ester 3 in the presence of 10 mol % of
Ph3PAuOTf is highly reactive, and nucleophilic attack of
alcohols 4, especially even sterically hindered 2,6-disubstituted
phenols and tertiary alcohols, proceeded at room temperature,
leading to the corresponding N,O-acetals 5 in moderate to
good yields. Functional group tolerance for not only
iodophenyl and azido groups but also various protecting
groups, such as Alloc, Cbz, Fmoc, Boc, and the tBu ester,
suggests the effectiveness of the reaction in the synthesis of
highly functionalized peptide compounds. Furthermore, our
procedure was applied to dipeptide-containing precursor 9 to
produce the N,O-acetal 10. This reaction could be widely
useful for the formation of tertiary-alcohol-containing N,O-
acetals, and the synthesis of stalobacin I and its N,O-acetal-
containing analogues is underway.
1
92%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 5.83−5.92
(m, 1H), 5.50 (brs, 1H), 5.27 (dd, 1H, J = 17.2, 1.3 Hz), 5.17 (dd,
1H, J = 10.5, 1.3 Hz), 4.55 (brd, 2H, J = 4.2 Hz), 4.11 (q, 2H, J = 7.2
Hz), 1.50 (dd, 2H, J = 7.9, 4.5 Hz), 1.20 (t, 3H, J = 7.2 Hz), 1.15 (brs,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.7, 156.3, 132.6, 117.6,
65.6, 61.3, 34.4, 17.6, 14.0; IR (neat) 3340, 2984, 1727, 1519, 1298,
1304, 1242, 1161, 1079 cm−1; HRMS[ESI] m/z calcd for C10H16NO4
[M + H]+ 214.1074, found 214.1073.
Ethyl 1-((tert-Butoxycarbonyl)amino)cyclopropane-1-carbo-xy-
late (1b). Compound 1b was prepared using the reported
procedure.17 To a solution of 1-(ethoxycarbonyl)cyclopropane-1-
carboxylic acid16 (1.38 g, 8.74 mmol) in dry tBuOH (25 mL) were
added NEt3 (1.5 mL, 10.5 mmol) and DPPA (2.1 mL, 9.62 mmol) at
room temperature under an argon atmosphere. After being stirred at
100 °C for 21 h in an oil bath, the reaction mixture was cooled to
room temperature, quenched with water, and concentrated in vacuo
to remove tBuOH. The aqueous layer was extracted twice with Et2O.
The combined organic layers were washed with brine, dried over
Na2SO4, and filtrated. The filtrate was concentrated in vacuo, and the
resulting residue was purified by column chromatography on silica gel
(eluted with hexane/EtOAc = 7:1) to afford the N-Boc amine 1b
(1.52 g, 6.81 mmol, 76%) as a colorless oil. The spectral data of
synthetic 1b were in good agreement with those reported.17 1H NMR
(600 MHz, CDCl3) δ 5.13 (brs, 1H), 4.15 (q, 2H, J = 7.1 Hz), 1.50
(brs, 2H), 1.45 (s, 9H), 1.24 (t, 3H, J = 7.1 Hz), 1.15 (brs, 2H);
13C{1H} NMR (150 MHz, CDCl3) δ 173.1, 156.0, 79.9, 61.3, 34.3,
EXPERIMENTAL SECTION
■
General Techniques. All commercially available reagents were
purchased from commercial suppliers and used as received. Dry
tetrahydrofuran (THF) and CH2Cl2 (Kanto Chemical Co.) were
obtained by passing commercially available predried, oxygen-free
formulations through an activated alumina column. All reactions in
the solution phase were monitored by TLC carried out on Merck
silica gel plates (0.2 mm, 60F-254) with UV light and visualized by p-
anisaldehyde/H2SO4/EtOH solution, phosphomolybdic acid/EtOH
solution, or ninhydrin/AcOH/1-BuOH solution. Column chromatog-
raphy was carried out with silica gel 60 N (Kanto Chemical Co. 100−
210 μm). Preparative TLC was performed on 0.75 mm Wakogel B-5F
28.3, 17.5, 14.1; IR (neat) 3357, 2979, 17525, 1509, 1368, 1251,
1183, 1073 cm−1; HRMS[ESI] m/z calcd for C11H19NO4Na [M +
Na]+ 252.1206, found 252.1204.
Ethyl 1-Aminocyclopropane-1-carboxylate Hydrochloride. To a
solution of the N-Boc amine 1b (678 mg, 2.96 mmol) in dry 1,4-
dioxane (3.0 mL) was added 4 M HCl/1,4-dioxane (7.4 mL, 29.6
mmol) at 0 °C under an argon atmosphere. After being stirred at
room temperature for 5 h, the reaction mixture was concentrated in
vacuo to afford the amine (489 mg, 2.95 mmol, quant.) as a yellowish
oil, which was solidified during refrigerated storage. mp 118−119 °C
[lit. 108−110 °C];18 1H NMR (600 MHz, CDCl3) δ 9.07 (brs, 3H),
4.25 (q, 2H, J = 7.1 Hz), 1.76 (dd, 2H, J = 7.9, 5.8 Hz), 1.53 (dd, 2H,
J = 7.9, 5.8 Hz), 1.30 (t, 3H, J = 7.1 Hz); 13C{1H} NMR (150 MHz,
CDCl3) δ 169.2, 62.6, 34.6, 14.2, 14.0; IR (neat) 3416, 2912, 1737,
1594, 1531, 1381, 1210 cm−1; HRMS[ESI] m/z calcd for C6H12NO2
[M + H]+ 130.0863, found 130.0861.
1
PLC plates. H NMR spectra (400 and 600 MHz) and 13C NMR
spectra (100 and 150 MHz) were recorded on JEOL JNMAL400 and
JEOL JNM-ECA600 spectrometers in the indicated solvent. Chemical
shifts (δ) are reported in units of parts per million (ppm) relative to
the signal for internal TMS (0.00 ppm for 1H) for solutions in CDCl3.
NMR spectral data are reported as follows: CHCl3 (7.26 ppm for 1H),
1
CDCl3 (77.0 ppm for 13C), CH3CN (1.94 ppm for H), CD3CN
(118.26 ppm for 13C), when internal standard is not indicated.
Multiplicities are reported by the following abbreviations: s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), dd (double
Ethyl 1-(((Benzyloxy)carbonyl)amino)cyclopropane-1-carboxy-
late (1c). To a solution of ethyl 1-aminocyclopropane-1-carboxylate
hydrochloride (56.9 mg, 344 μmmol) in dry 1,4-dioxane (0.7 mL)
D
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and water (0.7 mL) were added Na2CO3 (130 mg, 1.24 mmol) and
CbzCl (58.6 μL, 412 μmol) at 0 °C. After being stirred at room
temperature for 9 h, the reaction mixture was diluted with EtOAc and
quenched with 1 M aqueous HCl. The organic layer was separated,
and the aqueous layer was extracted twice with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and
filtered. The filtrate was concentrated in vacuo, and the resulting
residue was purified by column chromatography on silica gel (eluted
with hexane/EtOAc = 4:1) to afford the N-Cbz amine 1c (85.4 mg,
324 μmol, 94%) as a colorless oil. The spectral data of synthetic 1c
were in good agreement with those reported.18 1H NMR (600 MHz,
CDCl3) δ 7.30−7.36 (m, 5H), 5.38 (brs, 1H), 5.13 (brs, 2H), 4.13−
4.14 (m, 2H, 1.55 (brs, 2H), 1.20−1.24 (m, 5H); 13C{1H} NMR
(150 MHz, CDCl3) δ 172.7, 156.5, 136.4, 128.5, 128.1, 66.8, 61.4,
34.6, 17.7, 14.1; IR (neat) 3335, 2981, 1741, 1517, 1246, 1183, 1028
cm−1; HRMS[ESI] m/z calcd for C14H18NO4 [M + H]+ 264.1230,
found 264.1227.
Ethyl 1-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-
cyclopropane-1-carboxylate (1d). To a solution of ethyl 1-
aminocyclopropane-1-carboxylate hydrochloride (52.4 mg, 316
μmmol) in dry 1,4-dioxane (0.6 mL) and water (0.6 mL) were
added Na2CO3 (121 mg, 948 μmol) and FmocOSu (128 mg, 380
μmol) at 0 °C. After being stirred at room temperature for 9 h, the
reaction mixture was diluted with EtOAc and quenched with 1 M
aqueous HCl. The organic layer was separated, and the aqueous layer
was extracted twice with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, and filtered. The filtrate was
concentrated in vacuo, and the resulting residue was purified by
column chromatography on silica gel (eluted with hexane/EtOAc =
4:1) to afford the N-Fmoc amine 1d (76.1 mg, 217 μmol, 68%) as a
white solid. mp 136−137 °C; 1H NMR (600 MHz, CDCl3, 3:1
rotamer mixture) δ 7.76 (d, 2H, J = 7.4 Hz), 7.60−7.61 (m, 2H), 7.40
(t, 2H, J = 7.4 Hz), 7.31 (t, 2H, J = 7.4 Hz), 5.37 (brs, 0.7H), 5.04
(brs, 0.3H), 4.41−4.51 (m, 2H), 4.00−4.26 (m, 3H), 1.57 (brs, 2H),
1.22−1.25 (m, 5H); 13C{1H} NMR (150 MHz, CDCl3, 3:1 rotamer
mixture) δ 176.6, 143.9, 141.3, 127.7, 127.0, 125.1, 120.0, 67.0, 61.4,
47.1, 29.7, 17.7, 14.2; IR (neat) 3319, 2980, 1714, 1518, 1337, 1247,
1181, 739 cm−1; HRMS[ESI] m/z calcd for C21H21NO4Na [M +
Na]+ 374.1363, found 374.1356.
2-(Hex-1-yn-1-yl)benzoic Acid (2). Compound 2 was prepared
using the reported procedure.19 To a solution of methyl 2-
iodobenzoate (524 mg, 2.00 mmol) in NEt3 (6.0 mL) were added
hex-1-yne (274 μL, 2.40 mmol), PdCl2(PPh3)2 (28.1 mg, 40.0 μmol),
and CuI (9.1 mg, 48.0 μmol) at room temperature under an argon
atmosphere. After being stirred at the same temperature for 16 h, the
reaction mixture was concentrated in vacuo, and the resulting residue
was diluted with EtOAc. The organic layer was washed with water and
brine, dried over MgSO4, and filtrated. The filtrate was concentrated
in vacuo, and the resulting residue was purified by column
chromatography on silica gel (eluted with hexane/EtOAc = 70:1)
to afford the ethynylbenzene (394 mg, 1.82 mmol, 91%) as a pale
yellow oil. The spectral data of synthetic ethynylbenzene were in good
agreement with those reported.19
To a solution of the ethynylbenzene (398 mg, 1.84 mmol) in dry
THF (7.3 mL) was added a solution of NaOH (147 mg, 3.68 mmol)
in water (15 mL) at 0 °C. After being stirred at 50 °C for 12 h in an
oil bath, the reaction mixture was diluted with water and concentrated
in vacuo to remove THF. The aqueous layer was washed twice with
CH2Cl2, acidified with 10% aqueous citric acid to pH 4, and extracted
three times with CH2Cl2. The combined organic layers were washed
with brine, dried over MgSO4, and filtered. The filtrate was
concentrated in vacuo to afford the carboxylic acid 2 (336 mg, 1.66
mmol, 90%) as a colorless oil. Because the corresponding
isocoumarine 6 was formed during the process of purification by
column chromatography on silica gel, the crude 2 was immediately
used for the next reaction. The spectral data of synthetic 2 were in
good agreement with those reported.19 1H NMR (400 MHz, CDCl3)
δ 7.88 (d, 1H, J = 7.5 Hz), 7.51 (d, 1H, J = 7.5 Hz), 7.42 (t, 1H, J =
7.5 Hz), 7.31 (t, 1H, J = 7.5 Hz), 3.92 (s, 3H), 2.48 (t, 2H, J = 7.1
Hz), 1.48−1.66 (m, 4H), 0.96 (t, 3H, J = 7.2 Hz); 13C{1H} NMR
(100 MHz, CDCl3) δ 167.0, 134.2, 131.9, 131.5, 130.1, 127.1, 124.5,
96.0, 79.2, 52.0, 30.7, 22.0, 19.5, 13.6; IR (neat) 2955, 2871, 2311,
1731, 1485, 1432, 1294, 1130, 1083, 701 cm−1; HRMS[ESI] m/z
calcd for C14H16O2 [M + H]+ 217.1123, found 217.1122.
General Procedure for the Synthesis of Acyliminium Cation
Precursors 3 (GP-1). To a solution of the carbamates 1 (1.0 equiv)
in dry CH2Cl2 (6.0 mL/mmol) were added TMSCl (3.0 equiv) and
monomeric formaldehyde (ca. 0.5−0.6 M in THF solution,13 3.0
equiv) at room temperature under an argon atmosphere, and the
mixture was stirred at the same temperature for 24 h. DIEA (3.0
equiv) and benzoic acid 2 (1.5 equiv) were then added to the above
mixture at room temperature. After being stirred at the same
temperature for 4 h, the reaction mixture was concentrated in vacuo,
and the resulting residue was purified by column chromatography on
silica gel (eluted with hexane/EtOAc) to afford the acyliminium
cation precursors 3.
The Precursor 3a. Compound 3a was prepared from the N-Alloc
amine 1a (70.0 mg, 328 μmol) according to GP-1 and was obtained
in a 65% yield (92.0 mg, 215 μmol) as a colorless oil after purification
by column chromatography on silica gel (eluted with hexane/EtOAc
1
= 8:1). H NMR (400 MHz, CDCl3, rotamer mixture) δ 7.88 (brd,
1H, J = 7.1 Hz), 7.50 (brd, 1H, J = 7.1 Hz), 7.42 (brt, 1H, J = 7.1 Hz),
7.27−7.31 (m, 1H), 5.57−5.94 (m, 3H), 5.29−5.33 (m, 1H), 5.22
(dd, 1H, J = 10.6, 1.1 Hz), 4.67−4.68 (m, 2H), 4.04−4.11 (m, 2H),
2.46 (t, 2H, J = 7.1 Hz), 1.29−1.73 (m, 8H), 1.14 (brt, 3H, J = 6.8
Hz), 0.95 (t, 3H, J = 7.3 Hz); 13C{1H} NMR (100 MHz, CDCl3,
rotamer mixture) δ 172.2, 171.9, 165.6, 165.5, 156.5, 155.5, 141.4,
134.4, 134.3, 132.8, 132.1, 131.6, 131.2, 130.3, 130.2, 129.8, 127.9,
127.0, 124.8, 117.5, 96.4, 74.2, 74.1, 66.8, 66.7, 61.5, 41.6, 41.1, 36.7,
22.0, 20.7, 19.5, 17.2, 14.0, 13.6; IR (neat) 2962, 1728, 1308, 1273,
1238, 1187, 1122 cm−1; HRMS[ESI] m/z calcd for C24H29NO6Na
[M + Na]+ 450.1887, found 450.1882.
Larger Scale Synthesis of 3a. The N-chloromethylation followed
by the O-alkylation with 2 for the N-Alloc amine 1a (263 mg, 1.23
mmol) was carried out according to GP-1. The N,O-acetal 3a was
obtained in a 47% yield (91% brsm, 248 mg, 581 μmol), and the
substrate 1a was recovered in a 49% yield (128 mg, 60.0 μmol).
The Precursor 3b. Compound 3b was prepared from the N-Boc
amine 1b (60.3 mg, 263 μmol) according to GP-1 and was obtained
in a 47% yield (55.2 mg, 124 μmol) as a colorless oil after purification
by column chromatography on silica gel (eluted with hexane/EtOAc
1
= 10:1). H NMR (600 MHz, CDCl3, rotamer mixture) δ 7.88 (brd,
1H, J = 7.3 Hz), 7.49 (brd, 1H, J = 7.6 Hz), 7.41−7.42 (m, 1H),
7.27−7.30 (m, 1H), 5.52−5.80 (m, 2H), 5.29−5.33 (m, 1H), 4.05−
4.13 (m, 2H), 2.47 (t, 2H, J = 7.3 Hz), 1.21−1.69 (m, 17H), 1.16 (t,
3H, J = 7.2 Hz), 0.95 (t, 3H, J = 7.4 Hz); 13C{1H} NMR (150 MHz,
CDCl3, rotamer mixture) δ 172.6, 172.3, 165.8, 165.4, 155.5, 154.7,
1134.5, 134.3, 131.5, 130.3, 130.0, 127.03, 126.98, 124.84, 124.77,
96.3, 81.6, 91.2, 79.1, 74.7, 73.9, 61.4, 41.2, 30.7, 28.2, 22.0, 20.9,
19.5, 17.4, 14.1, 13.6; IR (neat) 2975, 2933, 1722, 1368, 1310, 1283,
1241, 1186, 1122, 756 cm−1; HRMS[ESI] m/z calcd for
C25H33NO6Na [M + Na]+ 466.2200, found 466.2188.
The Precursor 3c. Compound 3c was prepared from the N-CBz
amine 1c (62.4 mg, 237 μmol) according to GP-1 and was obtained
in a 55% yield (62.7 mg, 131 μmol) as a colorless oil after purification
by column chromatography on silica gel (eluted with hexane/EtOAc
1
= 10:1). H NMR (600 MHz, CDCl3, rotamer mixture) δ 7.78−7.89
(m, 1H), 7.29−7.50 (m, 8H), 5.57−7.84 (m, 2H), 5.20−5.24 (m,
2H), 3.99−4.07 (m, 2H), 2.44−2.45 (m, 2H), 0.93−1.59 (m, 17H);
13C{1H} NMR (150 MHz, CDCl3, rotamer mixture) δ 172.2, 171.9,
165.7, 165.5, 156.7, 136.04, 136.01, 134.5, 134.4, 131.7, 131.2, 131.1,
130.4, 130.2, 128.5, 128.3, 128.1, 127.7, 127.0, 124.9, 94.4, 79.1, 74.2,
67.9, 67.7, 61.6, 41.7, 41.1, 30.7, 22.0, 20.8, 19.5, 17.3, 13.9, 13.6; IR
(neat) 2958, 2931, 1726, 1307, 1279, 1239, 1187 cm−1; HRMS[ESI]
m/z calcd for C28H31NO6Na [M + Na]+ 500.2044, found 500.2034.
The Precursor 3d. Compound 3d was prepared from the N-Fmoc
amine 1d (62.2 mg, 177 μmol) according to GP-1 and was obtained
in a 41% yield (41.1 mg, 72.7 μmol) as a colorless oil after purification
by column chromatography on silica gel (eluted with hexane/EtOAc
1
= 10:1). H NMR (600 MHz, CDCl3, 2:1 rotamer mixture) δ 7.14−
E
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Note
7.29 (m, 12H), 5.74 (d, 1H, J = 10.6 Hz), 5,46 (d, 1H, J = 10.6 Hz),
4.11−4.66 (m, 4.6H), 3.82−3.83 (m, 1.4H), 2.43−2.45 (m, 2H),
1.15−1.61 (m, 9H), 0.92−1.01 (m, 4.3H), 0.76 (brs, 0.7H); 13C{1H}
NMR (150 MHz, CDCl3, 2:1 rotamer mixture) δ 171.8, 169.8, 165.6,
156.7, 155.8, 143.8, 143.6, 141.5, 141.2, 134.6, 134.3, 131.9, 131.7,
131.2, 130.4, 127.7, 127.1, 127.0, 125.1, 124.8, 124.5, 124.3, 120.0,
96.4, 79.1, 74.5, 74.0, 68.5, 67.6, 61.6, 61.5, 47.1, 46.9, 40.8, 30.7,
29.7, 22.0, 20.4, 19.5, 17.2, 14.1, 13.9, 13.6; IR (neat) 2957, 2932,
1726, 1451, 1271, 1239, 1188 cm−1; HRMS[ESI] m/z calcd for
C35H35NO6Na [M + Na]+ 588.2357, found 588.2348.
2-(4-Iodophenyl)propan-2-ol (4d). To a solution of the methyl 4-
iodobenzoate (340 mg, 1.30 mmol) in dry THF (10 mL) was added
MeMgBr (3.00 M in Et2O, 1.3 mL, 3.90 mmol) dropwise at 0 °C
under an argon atmosphere. After being stirred at the same
temperature for 3 h, the reaction mixture was quenched with
saturated aqueous NH4Cl and diluted with EtOAc. The organic layer
was separated, washed with brine, dried over MgSO4, and filtered.
The filtrate was concentrated in vacuo, and the resulting residue was
purified by column chromatography on silica gel (eluted with hexane/
EtOAc = 5:1) to afford the alcohol 4d (303 mg, 1.16 mmol, 89%) as a
pale yellow oil. The spectral data of synthetic 4d were in good
agreement with those reported.20
11-Azido-3,6,9-trioxaundecan-1-ol (4e). To a solution of HO-
PEG3-OH (1.00 g, 5.15 mmol) in dry CH2Cl2 (30 mL) were added
Ag2O (1.79 g, 7.22 mmol), NaI (849 mg, 5.66 mmol), and TsCl (1.03
g, 5.41 mmol) at 0 °C under an argon atmosphere. After being stirred
at room temperature for 1 h, the reaction mixture was filtered through
a pad of Celite. The filtrate was concentrated in vacuo, and the
resulting residue was purified by column chromatography on silica gel
(eluted with hexane/EtOAc = 1:4 to EtOAc) to afford the ditosylate
(632 mg, 1.26 mmol, 24%) as a colorless oil and the monotosylate
(1.14 g, 3.28 mmol, 64%) as a colorless oil. The spectral data of
synthetic monotosylate were in good agreement with those
reported.21
To a solution of the monotosylate (1.00 g, 2.87 mmol) in dry
MeCN (20 mL) was added NaN3 (224 mg, 3.44 mmol) at room
temperature under an argon atmosphere. After being stirred at reflux
for 21 h in an oil bath, the reaction mixture was concentrated in vacuo
to remove MeCN. The resulting residue was dissolved in EtOAc. The
organic layer was washed with water, and the aqueous layer was
extracted three times with EtOAc. The combined organic layers were
dried over MgSO4 and filtered. The filtrate was concentrated in vacuo,
and the resulting residue was purified by column chromatography on
silica gel (eluted with hexane/EtOAc = 1:4) to afford the azide 4e
(348 mg, 1.59 mmol, 55%) as a colorless oil. The spectral data of
synthetic 4e were in good agreement with those reported.21
THF (80 mL) was added MeMgBr (3.00 M in Et2O, 13 mL, 39.1
mmol) dropwise at −78 °C under an argon atmosphere. After being
stirred at 0 °C for 7 h, the reaction mixture was quenched with
saturated aqueous NH4Cl and diluted with EtOAc. The organic layer
was separated, washed with brine, dried over MgSO4, and filtered.
The filtrate was concentrated in vacuo, and the resulting residue was
purified by column chromatography on silica gel (eluted with hexane/
EtOAc = 10:1) to afford the alcohol 4k (2.26 g, 8.70 mmol, 89%) as a
pale yellow oil. The spectral data of synthetic 4k were in good
agreement with those reported.25 [α]21 +21 (c 0.95, MeOH) [lit.
D
[α]23 +23 (c 1.0, MeOH)].
D
Boc-Val(3-OH)-OH. To a solution of the oxazolidine 4k (1.56 g,
6.02 mmol) in dry MeOH (50 mL) was added TsOH·H2O (114 mg,
602 μmol) at room temperature under an argon atmosphere. After
being stirred at the same temperature for 30 min, the reaction mixture
was quenched with saturated aqueous NaHCO3 and concentrated in
vacuo to remove MeOH. The aqueous layer was extracted three times
with EtOAc. The combined organic layers were washed with brine,
dried over MgSO4, and filtered. The filtrate was concentrated in
vacuo, and the resulting crude amino alcohol was used for the next
reaction without further purification.
To a solution of the crude alcohol in dry MeCN (13 mL) and pH
6.8 buffer (13 mL) were added NaClO2 (1.96 g, 21.7 mmol),
PhI(OAc)2 (194 mg, 602 μmol), and TEMPO (188 mg, 1.20 mmol)
at 0 °C under an argon atmosphere. After being stirred at room
temperature for 13 h, the reaction mixture was quenched with 1 M
aqueous Na2CO3. The aqueous layer was washed with EtOAc,
acidified with 1 M aqueous HCl to pH 3, and extracted three times
with EtOAc. The combined organic layers were washed with brine,
dried over MgSO4, and filtered. The filtrate was concentrated in
vacuo, and the resulting residue was recrystallized from Et2O/hexane
to afford the carboxylic acid (1.05 g, 4.50 mmol, 75% in two steps) as
a white solid. The spectral data of the synthetic compound were in
good agreement with those reported.26 Mp 121−123 °C [lit. 125−
126 °C]; [α]28D −3.0 (c 1.0, MeOH) [lit. (enantiomer) [α]20D +2.5 (c
1.0, MeOH)].
Fmoc-Val(3-OH)-OtBu (4j). To a solution of Boc-Val(3-OH)-OH
(552 mg, 2.37 mmol) in dry CH2Cl2 (3.0 mL) was added TFA (911
μL, 11.8 mmol, 5.0 equiv) at 0 °C under an argon atmosphere. After
being stirred at the same temperature for 6 h, the reaction mixture was
concentrated in vacuo and azeotroped with toluene/MeOH (1:1) to
remove excess TFA. The resulting crude amine was used for the next
reaction without further purification.
To a solution of the crude amine in 1,4-dioxane (5.0 mL) and
water (5.0 mL) were added Na2CO3 (401 mg, 3.78 mmol, 1.6 equiv)
and FmocOSu (1.28 g, 3.78 mmol) at 0 °C under an argon
atmosphere. After being stirred at room temperature for 12 h, the
reaction mixture was diluted with EtOAc and quenched with 1 M
aqueous HCl. The organic layer was separated, and the aqueous layer
was extracted three times with EtOAc. The combined organic layers
were washed with water and brine, dried over Na2SO4, and filtered.
The filtrate was concentrated in vacuo, and the resulting residue was
purified by column chromatography on silica gel (eluted with CHCl3/
MeOH = 60:1) to afford the N-Fmoc amine S8 (729 mg, 2.05 mmol,
87% in two steps) as a white amorphous solid. The spectral data of
the synthetic compound were in good agreement with those
reported.27 [α]22 −8.0 (c 1.0, CHCl3) [lit. [α]19 −6.7 (c 1.03,
Cbz-Ser-OtBu (4h). To a solution of Cbz-Ser-OH (502 mg, 2.10
mmol, 1.0 equiv) in dry CH2Cl2 (21 mL) was added t-butyl 2,2,2-
trichloroacetimidate (917 mg, 4.20 mmol, 2.0 equiv) at room
temperature under an argon atmosphere. After being stirred at the
same temperature for 4 h, the reaction mixture was diluted with
EtOAc. The organic layer was washed with 1 M aqueous HCl,
saturated aqueous NaHCO3 and brine, dried over MgSO4, and
filtered. The filtrate was concentrated in vacuo, and the resulting
residue was purified by column chromatography on silica gel (eluted
with hexane/EtOAc = 4:1) to afford the tert-butyl ester 4h (484 mg,
1.57 mmol, 74%) as a white solid. The spectral data of synthetic 4h
were in good agreement with those reported.22 Mp 93−94 °C [lit.
89−90 °C]; [α]22 −15 (c 1.0, EtOH) [lit. [α]22 −13.7 (c 1.03,
D
D
CHCl3)].
Compound 4j was prepared from Fmoc-Val(3-OH)-OH (729 mg,
2.05 mmol) according to the procedure described above for 4h and
D
D
EtOH)].
was obtained in a 90% yield (759 mg, 1.85 mmol) as a colorless oil.
Cbz-Thr-OtBu (4i). Compound 4i was prepared from Cbz-Thr-OH
(772 mg, 3.05 mmol) according to the procedure described above for
4h and was obtained in an 83% yield (783 mg, 2.53 mmol) as a
colorless oil. The spectral data of synthetic 4i were in good agreement
with those reported.23 [α]22D −10 (c 1.0, CHCl3) [lit. [α]20D −10.3 (c
1.0, CHCl3)].
tert-Butyl (R)-4-(2-Hydroxypropan-2-yl)-2,2-dimethyloxazoli-
dine-3-carboxylate (4k). Compound 4k was prepared using the
reported procedure.24 To a solution of 3-(tert-butyl) 4-methyl (R)-
2,2-dimethyloxazolidine-3,4-dicarboxylate (2.54 g, 9.78 mmol) in dry
1
[α]22 −13 (c 1.1, CHCl3); H NMR (600 MHz, CDCl3) δ 7.77 (d,
D
2H, J = 7.3 Hz), 7.60 (d, 2H, J = 7.6 Hz), 7.39−7.41 (m, 2H), 7.30−
7.33 (m, 2H), 5.60 (brd, 1H, J = 8.7 Hz), 4.38−4.46 (m, 2H), 4.23 (t,
1H, J = 7.0 Hz), 4.16 (d, 1H, J = 8.7 Hz), 1.50 (s, 9H), 1.29 (s, 3H),
1.25 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.9, 156.4,
143.81, 143.75, 141.3, 127.7, 127.1, 125.1, 125.0, 119.99, 119.98, 81.1,
72.0, 67.1, 61.9, 47.2, 28.0, 26.8, 26.3; IR (neat) 3352, 2979, 1712,
1517, 1370, 1225, 1151, 741 cm−1; HRMS[ESI] m/z calcd for
C24H29NO5Na [M + Na]+ 434.1938, found 434.1931.
F
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Note
General Procedures for the N,O-Acetal Formation of 3 with
Alcohols 4 (GP-2). To a solution of Ph3PAuCl (0.1 equiv) in dry
toluene (3.0 mL/mmol) was added AgOTf (0.1 equiv) at room
temperature under an argon atmosphere. After being stirred at the
same temperature for 1.5 h in the dark, the resulting solution of
Ph3PAuOTf was used for the next reaction without further
purification.
To a solution of the acyliminium cation precursors 3 (1.0 equiv) in
dry toluene (17 mL/mmol) or dry toluene/dry CH2Cl2 (7:1, 17 mL/
mmol) were added MS4A (100 wt %), the alcohols 4 (3.0 equiv), and
the above solution of Ph3PAuOTf in toluene at room temperature
under an argon atmosphere. After being stirred at the same
temperature for 1.5 h, the reaction mixture was diluted with
CH2Cl2 and filtered through a pad of Celite. The filtrate was
concentrated in vacuo, and the resulting residue was purified by
column chromatography (eluted with hexane/EtOAc) on silica gel or
preparative TLC (eluted with hexane/EtOAc) to afford the N,O-
acetals 5 and the isocoumarin 6 (84−99% yields) as a colorless oil.
The spectral data of synthetic 6 were in good agreement with those
reported.28
The N,O-Acetal 5aa. Compound 5aa was prepared from the
acyliminium cation precursor 3a (35.1 mg, 82.1 μmol) and 2-methyl-
1-phenyl-propanol (4a) (38.0 μL, 246 μmol) according to GP-2 and
was obtained in a 73% yield (22.5 mg, 59.9 μmol) as a colorless oil
after purification by preparative TLC (eluted with hexane/EtOAc =
3:1). 1H NMR (600 MHz, CDCl3, rotamer mixture) δ 7.24−7.27 (m,
2H), 7.18−7.22 (m, 3H), 5.86−5.93 (m, 1H), 5.17−5.33 (m, 3H),
4.52−4.63 (m, 3H), 4.13 (brq, 2H, J = 6.8 Hz), 2.76−2.79 (m, 2H),
1.78 (brs, 1H), 1.65 (brs, 1H), 1.29 (brs, 1H), 1.17−1.22 (m, 10H);
13C{1H} NMR (150 MHz, CDCl3, rotamer mixture) δ 172.6, 156.8,
138.1, 132.59, 132.58, 130.6, 3, 130.59, 127.8, 126.2, 126.1, 117.7,
117.0, 75.8, 75.4, 73.8, 73.6, 66.4, 66.2, 61.2, 48.1, 40.7, 25.4, 25.1,
14.24, 14.18; IR (neat) 2976, 2370, 1720, 1396, 1302, 1186, 1044,
702 cm−1; HRMS[ESI] m/z calcd for C21H29NO5Na [M + Na]+
398.1938, found 398.1931.
1122, 1044 cm−1; HRMS[ESI] m/z calcd for C25H31NO5Na [M +
Na]+ 448.2094, found 448.2091.
The N,O-Acetal 5da. Compound 5da was prepared from the
acyliminium cation precursor 3d (29.8 mg, 52.7 μmol) and 2-methyl-
1-phenyl-propanol (4a) (24.4 μL, 158 μmol) according to GP-2 and
was obtained in a 72% yield (19.6 mg, 38.2 μmol) as a colorless oil
after purification by preparative TLC (eluted with hexane/EtOAc =
1
3:1). H NMR (600 MHz, CDCl3, 2:1 rotamer mixture) δ 7.75 (d,
2H, J = 7.6 Hz), 7.66 (d, 0.6H, J = 6.5 Hz), 7.54 (d, 1.4H, J = 6.2 Hz),
7.37−7.40 (m, 2H), 7.28−7.31 (m, 2H), 7.23−7.25 (m, 2H), 7.18−
7.21 (m, 1H), 7.15−7.16 (m, 2H), 5.24 (d, 0.7H, J = 8.9 Hz), 5.09
(brs, 0.3H), 4.42−4.61 (m, 3H), 4.29 (t, 0.3H, J = 6.2 Hz), 4.18 (t,
0.7H, J = 5.1 Hz), 4.12 (q, 0.6H, J = 6.9 Hz), 3.89−3.93 (m, 1.4H),
2.73−2.77 (m, 2H), 1.63 (brs, 1H), 1.09−1.21 (m, 11H), 0.78 (brs,
1H); 13C{1H} NMR (150 MHz, CDCl3, 2:1 rotamer mixture) δ
172.7, 172.6, 156.9, 156.2, 144.0, 141.5, 141.3, 138.1, 137.9, 130.6,
127.7, 127.6, 127.0, 126.9, 126.2, 126.1, 125.0, 124.7, 124.5, 120.0,
119.9, 75.7, 75.2, 73.7, 73.3, 67.4, 67.2, 61.3, 61.2, 48.2, 48.0, 47.2,
47.1, 41.5, 40.5, 25.4, 24.8, 19.1, 16.2, 14.1; IR (neat) 2975, 1718,
1300, 1186, 1122, 1045 cm−1; HRMS[ESI] m/z calcd for
C32H35NO5Na [M + Na]+ 536.2407, found 536.2405.
The N,O-Acetal 5ab. Compound 5ab was prepared from the
acyliminium cation precursor 3a (25.0 mg, 58.5 μmol) and
adamantan-1-ol (4b) (26.7 mg, 175 μmol) according to GP-2 and
was obtained in a 67% yield (14.8 mg, 39.2 μmol) as a pale yellow
solid after purification by column chromatography on silica gel
1
(eluted with hexane/EtOAc = 7:1). Mp 58−59 °C; H NMR (600
MHz, CDCl3, rotamer mixture) δ 5.85−5.97 (m, 1H), 5.16−5.36 (m,
3H), 4.53−4.63 (m, 3H), 4.13 (brq, 2H, J = 6.6 Hz), 2.13 (brs, 3H),
1.91 (brs, 1H), 1.78 (brs, 5H), 1.71 (d, 1H, J = 2.4 Hz), 1.58−1.63
(m, 8H), 1.35 (brs, 1H), 1.22 (t, 3H, J = 7.1 Hz); 13C{1H} NMR
(150 MHz, CDCl3, rotamer mixture) δ 173.0, 172.8, 156.7, 155.9,
132.6, 117.4, 116.9, 72.8, 72.6, 66.3, 66.2, 61.2, 45.4, 41.7, 40.7, 36.3,
36.1, 30.7, 30.5, 19.4, 1.3, 14.24, 14.18; IR (neat) 2909, 2852, 1721,
1200, 1183, 1079, 1041 cm−1; HRMS[ESI] m/z calcd for
C21H31NO5Na [M + Na]+ 400.2094, found 400.2093
Larger Scale Synthesis of 5aa. The N,O-acetal formation for the
acyliminium cation precursor 3a (248 mg, 581 μmol) with the alcohol
4a (269 μL, 1.74 mmol) was carried out according to GP-2, and the
N,O-acetal 5aa was obtained in a 55% yield (121 mg, 322 μmol) after
purification by column chromatography on silica gel (eluted with
hexane/EtOAc = 5:1).
The N,O-Acetal 5ac. Compound 5ac was prepared from the
acyliminium cation precursor 3a (30.8 mg, 72.0 μmol) and 1-
methylcyclohexanol (4c) (24.7 mg, 216 μmol) according to GP-2 and
was obtained in an 87% yield (21.2 mg, 62.5 μmol) as a colorless oil
after purification by column chromatography on silica gel (eluted with
hexane/EtOAc = 5:1). 1H NMR (600 MHz, CDCl3, rotamer mixture)
δ 5.86−5.96 (m, 1H), 5.17−5.34 (m, 3H), 4.46−4.63 (m, 3H), 4.13
(brq, 2H, J = 6.9 Hz), 1.16−1.90 (m, 20H); 13C{1H} NMR (150
MHz, CDCl3, rotamer mixture) δ 173.0, 172.8, 156.8, 156.0, 132.6,
117.6, 116.9, 74.1, 73.7, 73.1, 72.9, 66.3, 66.1, 61.2, 41.5, 40.8, 36.7,
36.5, 25.6, 24.9, 22.1, 19.6, 16.4, 14.23, 14.16; IR (neat) 2932, 2859,
1722, 1393, 1304, 1187, 1052 cm−1; HRMS[ESI] m/z calcd for
C18H29NO5Na [M + Na]+ 362.1938, found 362.1935.
The N,O-Acetal 5ba. Compound 5ba was prepared from the
acyliminium cation precursor 3b (24.9 mg, 56.1 μmol) and 2-methyl-
1-phenyl-propanol (4a) (26.0 μL, 246 μmol) according to GP-2 and
was obtained in a 79% yield (17.3 mg, 44.2 μmol) as a colorless oil
after purification by preparative TLC (eluted with hexane/EtOAc =
3:1). 1H NMR (600 MHz, CDCl3, rotamer mixture) δ 7.24−7.26 (m,
2H), 7.18−7.21 (m, 3H), 5.28 (brd, 1H, J = 1.6 Hz), 4.47 (brd, 1H, J
= 1.6 Hz), 4.13−4.12 (m, 2H), 2.76−2.79 (m, 2H), 1.78 (brs, 1H),
1.60 (brs, 1H), 1.44−1.47 (m, 9H), 1.10−1.25 (m, 11H); 13C{1H}
NMR (150 MHz, CDCl3, rotamer mixture) δ 173.3, 173.0, 155.8,
155.2, 138.3, 138.2, 130.63, 130.59, 127.7, 126.1, 126.0, 80.7, 80.3,
75.6, 75.0, 73.8, 73.1, 61.1, 48.2, 48.0, 40.9, 28.3, 25.5, 25.2, 24.9,
19.5, 16.3, 14.34, 14.32, 14.2; IR (neat) 2977, 2935, 1713, 1366,
1302, 1183, 1122 cm−1; HRMS[ESI] m/z calcd for C22H33NO5Na
[M + Na]+ 414.2251, found 414.2248.
The N,O-Acetal 5ca. Compound 5ca was prepared from the
acyliminium cation precursor 3c (18.1 mg, 37.9 μmol) and 2-methyl-
1-phenyl-propanol (4a) (17.5 μL, 114 μmol) according to GP-2 and
was obtained in a 62% yield (10.0 mg, 22.5 μmol) as a colorless oil
after purification by preparative TLC (eluted with hexane/EtOAc =
3:1). 1H NMR (600 MHz, CDCl3, 2:1 rotamer mixture) δ 7.13−7.33
(m, 10H), 5.32 (brs, 1H), 5.13−5.21 (m, 2H), 4.53 (brs, 1H), 4.10−
4.14 (m, 0.7H), 4.03 (brs, 1.3H), 2.77−2.80 (m, 1.3H), 2.71 (s, 1H),
1.78 (brs, 1H), 1.64 (brs, 1H), 1.10−1.28 (m, 11H); 13C{1H} NMR
(150 MHz, CDCl3, 2:1 rotamer mixture) δ 172.9, 172.7, 156.9, 156.1,
138.1, 136.5, 136.3, 130.61, 130.56, 128.4, 128.0, 127.9, 127.7, 127.5,
126.2, 126.1, 75.8, 75.3, 73.8, 73.5, 67.5, 67.3, 61.3, 48.1, 48.0, 41.5,
40.7, 25.4, 25.0, 19.5, 16.2, 14.1; IR (neat) 2975, 1720, 1301, 1186,
The N,O-Acetal 5ad. Compound 5ad was prepared from the
acyliminium cation precursor 3a (28.8 mg, 67.4 μmol) and 2-(4-
iodophenyl)propan-2-ol (4d) (53.0 mg, 202 μmol) according to GP-2
and was obtained in a 67% yield (22.0 mg, 45.1 μmol) as a colorless
oil after purification by preparative TLC (eluted with hexane/EtOAc
1
= 3:1). H NMR (600 MHz, CDCl3, rotamer mixture) δ 7.66−7.67
(m, 2H), 7.16−7.20 (m, 2H), 5.84−5.94 (m, 1H), 5.16−5.32 (m,
2H), 4.90 (brs, 1H), 4.59 (brd, 2H, J = 4.1 Hz), 4.35 (brs, 1H), 4.10
(brq, 2H, J = 6.9 Hz), 1.77 (brs, 1H), 1.66 (brs, 1H), 1.53−1.59 (m,
7H), 1.38 (brs, 1H), 1.19 (t, 3H, J = 6.9 Hz); 13C{1H} NMR (150
MHz, CDCl3, rotamer mixture) δ 172.7, 172.5, 156.6, 155.8, 145.5,
145.3, 147.3, 132.53, 132.46, 127.8, 117.9, 117.1, 92.7, 76.0, 75.7,
74.5, 74.3, 66.5, 66.3, 61.3, 41.6, 40.9, 28.5, 28.1, 19.8, 16.4, 14.2; IR
(neat) 2979, 1720, 1391, 1304, 1187, 1041, 1004 cm−1; HRMS[ESI]
m/z calcd for C20H26NO5INa [M + Na]+ 510.0748, found 510.0739.
The N,O-Acetal 5ae. Compound 5ae was prepared from the
acyliminium cation precursor 3a (29.8 mg, 69.7 μmol) and N3-PEG3-
OH (4e) (45.8 mg, 209 μmol) according to GP-2 and was obtained
in a 75% yield (23.2 mg, 52.2 μmol) as a colorless oil after purification
by column chromatography on silica gel (eluted with hexane/EtOAc
1
= 1:1). H NMR (600 MHz, CDCl3, rotamer mixture) δ 5.86−5.94
G
https://dx.doi.org/10.1021/acs.joc.0c02640
J. Org. Chem. XXXX, XXX, XXX−XXX

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pubs.acs.org/joc
Note
(m, 1H), 5.28−5.34 (m, 1H), 5.18−5.23 (m, 1H), 5.08 (brs, 1H),
4.76 (brs, 1H), 4.62 (brs, 2H), 4.12−4.13 (m, 2H), 3.60−3.68 (m,
14H), 3.39 (t, 2H, J = 5.2 Hz), 1.74 (brs, 1H), 1.68 (brs, 1H), 1.40
(brs, 1H), 1.20−1.23 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3,
rotamer mixture) δ 172.6, 172.4, 157.5, 156.0, 132.4, 117.8, 117.2,
79.6, 70.7, 70.6, 70.5, 70.4, 70.0, 67.6, 67.4, 66.43, 66.35, 61.3, 50.7,
41.0, 40.4, 29.7, 19.7, 16.3, 14.2; IR (neat) 2873, 2105, 1718, 1303,
1193, 1085, 1033, 938 cm−1; HRMS[ESI] m/z calcd for
C19H32N4O8Na [M + Na]+ 467.2112, found 467.2108.
1157, 1025 cm−1; HRMS[ESI] m/z calcd for C27H38N2O9Na [M +
Na]+ 557.2470, found 557.2463.
The N,O-Acetal 5aj. Compound 5aj was prepared from the
acyliminium cation precursor 3a (36.9 mg, 86.3 μmol) and Fmoc-
Val(3-OH)-OtBu (4j) (107 mg, 259 μmol) according to GP-2 and
was obtained in a 74% yield (40.5 mg, 63.6 μmol) as a colorless oil
after purification by preparative TLC (eluted with hexane/EtOAc =
1
3:1). [α]25 +1.5 (c 1.6, CHCl3); H NMR (600 MHz, CD3CN, 50
D
°C, rotamer mixture) δ 7.84 (t, 2H, J = 7.0 Hz), 7.69 (brs, 2H), 7.41−
7.44 (m, 2H), 7.33−7.36 (m, 2H), 5.93 (brs, 2H), 5.29 (d, 1H, J =
17.2 Hz), 5.17−5.20 (m, 1H), 4.81 (brs, 2H), 4.57 (brs, 2H), 4.38
(brs, 2H), 4.24−4.27 (m, 1H), 4.08−4.11 (m, 2H), 4.03 (brs, 1H),
1.43 (brs, 16H), 1,30 (brs, 3H), 1.18 (t, 3H, J = 7.2 Hz); 13C{1H}
NMR (150 MHz, CD3CN, 50 °C, rotamer mixture) δ 173.7, 170.5,
157.7, 157.4, 145.4, 142.4, 134.2, 128.9, 128.28, 128.27, 126.3, 121.1,
82.7, 77.1, 74.6, 67.6, 67.1, 64.0, 62.3, 43.4, 28.4, 23.9, 14.7; IR (neat)
3354, 2979, 1722, 1335, 1304, 1159, 1042, 741 cm−1; HRMS[ESI]
m/z calcd for C35H44N2O9Na [M + Na]+ 659.2939, found 659.2931.
The N,O-Acetal 5ak. Compound 5ak was prepared from the
acyliminium cation precursor 3a (38.0 mg, 88.9 μmol) and the
alcohol 4k (37.6 mg, 293 μmol) according to GP-2 and was obtained
in a 34% yield (14.7 mg, 30.3 μmol) as a colorless oil after purification
The N,O-Acetal 5af. Compound 5af was prepared from the
acyliminium cation precursor 3a (25.9 mg, 60.6 μmol) and phenol
(4f) (17.1 mg, 182 μmol) according to GP-2 and was obtained in a
69% yield (19.3 mg, 41.6 μmol) as a colorless oil after purification by
1
preparative TLC (eluted with hexane/EtOAc = 3:1). H NMR (600
MHz, CDCl3, rotamer mixture) δ 7.26−7.29 (m, 2H), 6.97 (d, 2H, J
= 7.9 Hz), 6.89−6.91 (m, 1H), 5.88−5.93 (m, 1H), 5.70 (brs, 1H),
5.26−5.31 (m, 1H), 5.20 (d, 1H, J = 10.0 Hz), 5.12 (brs, 1H), 4.64
(brs, 2H), 4.07−4.14 (m, 2H), 1.70 (brs, 1H), 1.43 (brs, 1H), 1.26
(brs, 2H), 1.17 (t, 3H, J = 7.0 Hz); 13C{1H} NMR (150 MHz,
CDCl3, rotamer mixture) δ 172.5, 172.3, 156.8, 156.7, 155.5, 132.2,
129.5, 121.8, 121.6, 117.7, 117.4, 116.0, 115.7, 78.7, 77.9, 66.6, 61.5,
41.5, 40.6, 19.8, 16.6, 14.1; IR (neat) 2927, 1725, 1391, 1307, 1272,
1205, 1029 cm−1; HRMS[ESI] m/z calcd for C17H21NO5Na [M +
Na]+ 342.1312, found 342.1309.
by silica gel (eluted with hexane/EtOAc = 4:1). [α]25 +1.1 (c 0.79,
D
1
CHCl3); H NMR (600 MHz, CD3CN, 50 °C, rotamer mixture) δ
The N,O-Acetal 5ag. Compound 5ag was prepared from the
acyliminium cation precursor 3a (29.9 mg, 69.9 μmol) and 2,6-
dimethylphenol (4g) (25.6 mg, 210 μmol) according to GP-2 and was
obtained in a 67% yield (16.2 mg, 46.6 μmol) as a colorless oil after
purification by preparative TLC (eluted with hexane/EtOAc = 3:1).
1H NMR (600 MHz, CDCl3, 3:2 rotamer mixture) δ 7.00 (d, 2H, J =
7.3 Hz), δ 6.93 (t, 1H, J = 7.3 Hz), 5.88−5.94 (m, 0.6H), 5.79−5.85
(m, 0.4H), 5.17−5.34 (m, 3H), 4.84 (brs, 1H), 4.66 (brs, 1.2H), 4.61
(brs, 0.8H), 4.13 (brq, 2H, J = 6.8 Hz), 2.30 (s, 3.6H), 2.25 (s, 2.4H),
1.36−1.74 (m, 4H), 1.21 (t, 3H, J = 6.8 Hz); 13C{1H} NMR (150
MHz, CDCl3, 3:2 rotamer mixture) δ 172.6, 172.5, 157.0, 156.0,
153.7, 153.2, 132.3, 132.1, 131.4, 131.1, 128.9, 124.34, 124.29, 118.2,
117.3, 81.4, 81.3, 66.7, 66.5, 61.5, 41.3, 20.0, 17.1, 16.7, 16.6, 14.19,
14.16; IR (neat) 2928, 1725, 1304, 1259, 1186, 1120, 982 cm−1;
HRMS[ESI] m/z calcd for C19H25NO5Na [M + Na]+ 370.1625,
found 370.1622.
5.93 (brs, 1H), 5.29 (d, 1H, J = 15.8 Hz), 5.19 (d, 1H, J = 9.7 Hz),
4.81 (brs, 2H), 4.58 (d, 2H, J = 3.8 Hz), 4.04−4.11 (m, 3H), 3.95
(brs, 1H), 3.84 (dd, 1H, J = 9.3, 6.5 Hz), 1.54 (s, 3H), 1.44 (brs,
16H), 1.16−1.22 (m, 9H); 13C{1H} NMR (150 MHz, CD3CN, 50
°C, rotamer mixture) δ 173.7, 157.6, 155.2, 134.3, 117.4, 95.9, 80.9,
74.4, 67.0, 65.2, 64.4, 62.2, 41.7, 30.5, 28.7, 27.5, 24.7, 22.3, 18.1,
14.7; IR (neat) 2979, 1721, 1699, 1367, 1171, 1062, 1035 cm−1;
HRMS[ESI] m/z calcd for C24H40N2O8Na [M + Na]+ 507.2677,
found 507.2669.
Alloc-MeAsp(tBu)-OH. To a suspension of Fmoc-Asp(tBu)-OH
(3.03g, 7.36 mmol) in dry MeCN (15 mL) was added Et2NH (3.7
mL) at 0 °C under an argon atmosphere. After being stirred at room
temperature for 3 h, the reaction mixture was concentrated in vacuo.
The resulting residue was azeotroped three times with toluene and
dried under a vacuum. The crude amine was used for the next
reaction without further purification.
The N,O-Acetal 5ah. Compound 5ah was prepared from the
acyliminium cation precursor 3a (28.0 mg, 65.6 μmol) and Cbz-Ser-
OtBu (4h) (58.1 mg, 197 μmol) according to GP-2 and was obtained
in an 89% yield (30.5 mg, 58.6 μmol) as a colorless oil after
To a solution of the crude amine in dry THF (1.8 mL) were added
saturated aqueous NaHCO3 (7.5 mL) and Alloc-Cl (1.2 mL, 11.0
mmol) at 0 °C. After being stirred at room temperature for 19 h, the
reaction mixture was diluted with EtOAc and quenched with 1 M
aqueous HCl. The organic layer was separated, washed with brine,
dried over MgSO4, and filtered. The filtrate was concentrated in
vacuo, and the resulting residue was purified by column
chromatography on silica gel (eluted with hexane/EtOAc = 1:1) to
afford the N-Alloc amine (1.45 g, 5.32 mmol, 72% in two steps) as a
colorless oil. The spectral data of the synthetic compound were in
purification by preparative TLC (eluted with hexane/EtOAc = 3:1).
1
[α]25 +1.8 (c 0.44, CHCl3); H NMR (600 MHz, CD3CN, 50 °C,
D
rotamer mixture) δ 7.31−7.38 (m, 5H), 5.90−5.96 (m, 1H), 5.83
(brs, 1H), 5.30 (d, 1H, J = 17.2 Hz), 5.19 (d, 1H, J = 10.3 Hz), 5.09
(s, 2H), 4.83 (brs, 2H), 4.59 (d, 2H, J = 5.2 Hz), 4.20−4.23 (m, 1H),
4.06−4.10 (m, 2H), 3.80 (dd, 1H, J = 10.0, 4.8 Hz), 3.74 (dd, 1H, J =
10.0, 3.5 Hz), 1.43 (brs, 13H), 1.17 (t, 3H, J = 7.1 Hz); 13C{1H}
NMR (150 MHz, CDCl3, rotamer mixture) δ 173.6, 170.4, 138.4,
134.1, 129.6, 129.3, 129.1, 128.9, 82.8, 80.8, 69.5, 67.4, 67.2, 62.3,
56.3, 28.4, 14.6; IR (neat) 3351, 2979, 1722, 1305, 1193, 1158, 1098,
1026 cm−1; HRMS[ESI] m/z calcd for C26H36N2O9Na [M + Na]+
543.2313, found 543.2307.
good agreement with those reported.29 [α]29 +18 (c 0.92, CHCl3).
D
To a solution of the carbamate (457 mg, 1.67 mmol) in dry THF
(15 mL) were added MeI (836 μL, 13.4 mmol) and NaH (60% in
mineral, 268 mg, 6.69 mmol) at 0 °C under an argon atmosphere.
After being stirred at room temperature for 9 h, the reaction mixture
was diluted with Et2O and quenched with saturated aqueous NH4Cl.
The organic layer was separated, and the aqueous layer was extracted
twice with EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4, and filtered. The filtrate was concentrated
in vacuo, and the resulting residue was purified by column
chromatography on silica gel (eluted with hexane/EtOAc = 2:1) to
afford the N-methylcarbamate (341 mg, 1.19 mmol, 71%) as a
The N,O-Acetal 5ai. Compound 5ai was prepared from the
acyliminium cation precursor 3a (38.3 mg, 89.6 μmol) and Cbz-Thr-
OtBu (4i) (83.1 mg, 269 μmol) according to GP-2 and was obtained
in a 67% yield (32.2 mg, 60.2 μmol) as a colorless oil after purification
by preparative TLC (eluted with hexane/EtOAc = 3:1). [α]25 −1.6
D
(c 0.29, CHCl3); 1H NMR (600 MHz, CD3CN, 50 °C, rotamer
mixture) δ 7.31−7.38 (m, 5H), 5.93 (brs, 1H), 5.72 (brs, 1H), 5.29
(d, 1H, J = 17.5 Hz), 5.19 (d, 1H, J = 10.0 Hz), 5.10 (d, 1H, J = 14.8
Hz), 5.08 (d, 1H, J = 14.8 Hz), 4.80 (brs, 2H), 4.58 (d, 2H, J = 3.8
Hz), 4.03−4.13 (m, 4H), 1.44 (brs, 13H), 1.16−1.18 (m, 6H);
13C{1H} NMR (150 MHz, CD3CN, 50 °C, rotamer mixture) δ 173.5,
170.9, 157.7, 138.4, 134.1, 129.6, 129.1, 128.9, 82.8, 67.5, 67.2, 62.3,
60.9, 28.4, 17.6, 14.6; IR (neat) 3353, 2979, 1723, 1370, 1306, 1188,
colorless oil. [α]28 −33 (c 1.37, CHCl3); 1H NMR (400 MHz,
D
CDCl3, rotamer mixture) δ 5.85−5.96 (m, 1H), 5.30 (d, 1H, J = 17.2
Hz), 5.19−5.23 (m, 1H), 4.87−4.90 (m, 1H), 4.61−4.63 (m, 2H),
2.98−3.11 (m, 4H), 2.66−2.78 (m, 1H), 1.45 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3, rotamer mixture) δ 175.1, 175.0, 169.8, 169.6,
156.3, 155.8, 132.5, 132.3, 117.7, 117.5, 81.6, 81.4, 66.6, 66.5, 57.2,
56.8, 36.2, 35.6, 33.4, 33.1, 27.89, 27.86; IR (neat) 2980, 2939, 2370,
H
https://dx.doi.org/10.1021/acs.joc.0c02640
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
2320, 1714, 1370, 1317, 1257, 1153, 992 cm−1; HRMS[ESI] m/z
calcd for C13H21NO6Na [M + Na]+ 310.1261, found 310.1257.
The Dipeptide 7. To a solution of Alloc-MeAsp(tBu)-OH (201
mg, 700 μmol) and ethyl 1-aminocyclopropane-1-carboxylate hydro-
chloride (116 mg, 700 μmol,) in dry CH2Cl2 (7.0 mL) were added
DIEA (488 μL, 2.80 mmol), HOBt (129 mg, 840 μmol), and EDCI·
HCl (161 mg, 840 μmol) at 0 °C under an argon atmosphere. After
being stirred at room temperature for 17 h, the reaction mixture was
diluted with EtOAc and quenched with 1 M aqueous HCl. The
organic layer was separated, and the aqueous layer was extracted twice
with EtOAc. The combined organic layers were washed with water
and brine, dried over Na2SO4, and filtered. The filtrate was
concentrated in vacuo, and the resulting residue was purified by
column chromatography on silica gel (eluted with hexane/EtOAc =
80.0, 79.1, 74.1, 66.7, 66.6, 62.5, 61.5, 52.6, 52.1, 41.6, 41.5, 35.3,
35.1, 30.73, 30.69, 29.7, 29.5, 27.9, 22.07, 22.05, 20.9, 20.8, 19.54,
19.53, 19.2, 18.8, 14.0, 13.9, 13.8, 13.7; IR (neat) 2933, 1730, 1690,
1394, 1369, 1300, 1237, 1146, 1037 cm−1; HRMS[ESI] m/z calcd for
C33H44N2O9Na [M + Na]+ 635.2939, found 635.2933.
The N,O-Acetal 10. Compound 10 was prepared from the
acyliminium cation precursor 9 (22.1 mg, 36.1 μmol) and 2-
methyl-1-phenylpropanol (4a) (16.7 μL, 108 μmol) according to GP-
2 and was obtained in a 72% yield (14.5 mg, 25.9 μmol) as a colorless
oil after purification by preparative TLC (eluted with hexane/EtOAc
1
= 3:1). [α]29 −44 (c 0.57, CHCl3); H NMR (600 MHz, CD3CN,
D
50 °C, 2:1 rotamer mixture) δ 7.11−7.27 (m, 5H), 5.92−5.99 (m,
1H), 5.07−5.73 (m, 4H), 4.46−4.68 (m, 3H), 3.95−4.07 (m, 2H),
2.67−2.80 (m, 6H), 2.49 (dd, 0.7H, J = 15.9, 7.5 Hz), 2.37 (brd,
0.3H, J = 15.6 Hz), 1.09−1.60 (m, 22H); 13C{1H} NMR (150 MHz,
CD3CN, 50 °C, 2:1 rotamer mixture) δ 173.1, 173.0, 171.1, 170.6,
139.7, 139.4, 134.44, 134.38, 131.91, 131.85, 128.9, 127.3, 127.2, 81.9,
81.7, 76.8, 76.5, 74.2, 73.8, 67.3, 67.2, 62.1, 54.4, 54.0, 49.3, 48.6,
42.2, 36.5, 30.5, 28.5, 26.1, 25.5, 25.3, 25.2, 20.4, 18.3, 17.1, 14.6,
14.4; IR (neat) 2977, 2374, 2311, 1729, 1679, 1144, 1045, 702 cm−1;
HRMS[ESI] m/z calcd for C30H44N2O8Na [M + Na]+ 583.2990,
found 583.2980.
2:1) to afford the dipeptide 7 (196 mg, 492 μmol, 70%) as a colorless
1
oil. [α]29 −58 (c 0.65, CHCl3); H NMR (600 MHz, CDCl3, 2:1
D
rotamer mixture) δ 6.69 (brs, 0.7H), 6.45 (brs, 0.3H), 5.91−5.98 (m,
1H), 5.33 (d, 1H, J = 17.4 Hz), 5.24 (d, 1H, J = 10.8 Hz), 5.08 (t,
0.7H, J = 7.5 Hz), 5.00 (brs, 0.3H), 4.63−4.65 (m, 2H), 4.10−4.16
(m, 2H), 2.91−3.02 (m, 4H), 2.55 (dd, 1H, J = 15.9, 8.1 Hz), 1.63
(brs, 2.5H), 1.42−1.47 (m, 8.5H), 1.18−1.26 (m, 4H), 1.08−1.12 (m,
1H); 13C{1H} NMR (150 MHz, CDCl3, 2:1 rotamer mixture) δ
172.01, 171.97, 170.7, 169.7, 157.1, 132.5, 118.2, 117.8, 84.1, 66.7,
61.4, 55.4, 34.2, 33.4, 30.1, 28.0, 27.9, 17.7, 17.4, 17.3, 14.1; IR (neat)
ASSOCIATED CONTENT
* Supporting Information
■
3324, 2979, 1729, 1687, 1509, 1370, 1298, 1156, 845 cm−1
;
sı
HRMS[ESI] m/z calcd for C19H30N2O7Na [M + Na]+ 421.1945,
found 421.1938.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02640.
Chloromethyl 2-(Hex-1-yn-1-yl)benzoate (8). To a solution of the
carboxylic acid 2 (204 mg, 1.01 mmol) in dry CH2Cl2 (2.0 mL) and
water (2.0 mL) were added NaHCO3 (254 mg, 3.03 mmol),
Bu4NHSO4 (34.3 mg, 101 μmol), and chloromethyl chlorosulfate
(200 mg, 1.21 mmol) at 0 °C under an argon atmosphere. After being
stirred at room temperature for 15 h, the reaction mixture was diluted
with CH2Cl2 and quenched with water. The organic layer was
separated, washed with water and brine, dried over MgSO4, and
filtered. The filtrate was concentrated in vacuo, and the resulting
residue was purified by column chromatography on silica gel (eluted
with hexane/EtOAc = 7:1) to afford the O-chloromethyl adduct 8
1
Copies of H and 13C NMR spectra for all new and
known compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Takayuki Doi − Graduate School of Pharmaceutical Sciences,
Tohoku University, Sendai 980-8578, Japan; orcid.org/
0000-0002-8306-6819; Email: doi_taka@
mail.pharm.tohoku.ac.jp
1
(207 mg, 824 μmol, 82%) as a colorless oil. H NMR (600 MHz,
CDCl3) δ 7.94 (dd, 1H, J = 7.7, 1.2 Hz), 7.54 (dd, 1H, J = 7.7, 1.2
Hz), 7.47 (td, 1H, J = 7.7, 1.2 Hz), 7.34 (td, 1H, J = 7.7, 1.2 Hz), 5.95
(s, 2H), 2.49 (t, 2H, J = 7.2 Hz), 1.61−1.66 (m, 2H), 1.48−1.54 (m,
2H), 0.96 (t, 3H, J = 7.5 Hz); 13C{1H} NMR (150 MHz, CDCl3) δ
164.1, 134.4, 132.4, 130.6, 130.0, 127.2, 125.4, 97.2, 78.8, 69.1, 30.6,
22.0, 19.5, 13.6; IR (neat) 2958, 2932, 1752, 1279, 1234, 1112, 1064,
756, 718 cm−1; HRMS[ESI] m/z calcd for C14H15O2ClNa [M + Na]+
273.0653, found 273.0657.
Authors
Kosuke Ohsawa − Graduate School of Pharmaceutical
Sciences, Tohoku University, Sendai 980-8578, Japan
Shota Ochiai − Graduate School of Pharmaceutical Sciences,
Tohoku University, Sendai 980-8578, Japan
Junya Kubota − Graduate School of Pharmaceutical Sciences,
Tohoku University, Sendai 980-8578, Japan
The Precursor 9. To a solution of the amide 7 (52.7 mg, 132 μmol)
in dry THF (1.0 mL) was added KHMDS (0.50 M in THF, 317 μL,
159 μmmol) at −78 °C under an argon atmosphere, and the mixture
was stirred at the same temperature for 1.5 h. A solution of the
chloride 8 (82.9 mg, 331 μmol) in dry THF (0.3 mL) was then added
to the above mixture at −78 °C. After being stirred at room
temperature for 1.5 h, the reaction mixture was quenched with water
and diluted with EtOAc. The organic layer was separated, and the
aqueous layer was extracted twice with EtOAc. The combined organic
layers were washed with water and brine, dried over Na2SO4, and
filtered. The filtrate was concentrated in vacuo, and the resulting
residue was purified by column chromatography on silica gel (eluted
with hexane/EtOAc = 7:1) to afford the acyliminium cation precursor
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02640
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
JP19K16310 (Early-Career Scientists) and 15H05837 (Middle
Molecular Strategy). This work was partially supported by the
Platform Project for Supporting in Drug Discovery and Life
Science Research from AMED under Grant Numbers
JP20am0101095 and JP20am0101100.
9 (38.3 mg, 62.5 μmol, 47%) as a colorless oil. [α]23 −79 (c 0.93,
D
1
CHCl3); H NMR (600 MHz, CDCl3, 3:2 rotamer mixture) δ 7.93
(d, 0.6H, J = 7.3 Hz), 7.80 (d, 0.4H, J = 7.5, 3.9 Hz), 7.49−7.52 (m,
1H), 7.39−7.45 (m, 1H), 7.23−7.33 (m, 1H), 5.13−6.05 (m, 6H),
4.42−4.67 (2H, m), 4.00−4.13 (m, 2H), 2.88−3.14 (m, 2.8H), 2.77
(s, 1.2H), 2.45−2.49 (m, 2.6H), 2.34−2.41 (m, 0.4H), 1.60−1.68 (m,
3H), 1.08−1.53 (m, 17H), 0.96 (t, 3H, J = 7.5 Hz); 13C{1H} NMR
(150 MHz, CDCl3, 3:2 rotamer mixture) δ 171.9, 171.3, 170.1, 169.8,
165.3, 164.8, 155.7, 134.5, 134.4, 132.6, 132.4, 131.8, 131.6, 130.3,
127.00, 126.95, 125.3, 124.9, 118.5, 118.3, 117.7, 96.8, 96.4, 81.1,
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