Esterification by Redox Dehydration Using Diselenides as Catalytic Organooxidants

Article abstract of DOI:10.1021/acs.joc.8b02765

Ortho-functionalized aryl diselenides are catalytic (5.0 mol %) oxidants for the construction of esters from carboxylic acids and alcohols in the presence of stoichiometric triethyl phosphite and dioxygen in air as the terminal redox reagents (redox dehydration conditions). The reaction proceeds through the intermediacy of the anhydride and requires the presence of 10% DMAP to drive the esterification.

Full text of DOI:10.1021/acs.joc.8b02765

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Featured Article
Esterification by Redox Dehydration using
Diselenides as Catalytic Organooxidants
Thomas C Pickel, Srirama Murthy Akondi, and Lanny S. Liebeskind
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02765 • Publication Date (Web): 11 Feb 2019
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The Journal of Organic Chemistry
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Esterification by Redox Dehydration using Diselenides as Catalytic Or-
ganooxidants
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Thomas C. Pickel, Srirama Murthy Akondi† and Lanny S. Liebeskind*
Emory University, Department of Chemistry, 1515 Dickey Drive, Atlanta, Georgia 30322
Supporting Information Placeholder
ABSTRACT: Ortho functionalized aryl diselenides are catalytic (5.0 mol %) oxidants for the construction of esters from carboxylic
acids and alcohols in the presence of stoichiometric triethylphosphite and dioxygen in air as the terminal redox reagents (redox
dehydration conditions). The reaction proceeds through the intermediacy of the anhydride and requires the presence of 10% DMAP
to drive the esterification.
Introduction. Redox dehydration, which removes H2O
from two reaction partners through the action of an oxidant
to accept [2H] and a reductant to accept [O],1-5 has been
used to carry out both alkylative 2-4 and acylative1, 6-7 bond
formation. Recent efforts have focused on developing cata-
lytic versions of both alkylative8-12 and acylative13-14 redox
dehydration reactions. For the latter, we have described the
use of benzoisothiazolones15 and ortho functionalized
diselenides16 as catalytic oxidants linked to O2 in air for ef-
ficient and economical amidation and peptidation reactions.
In these reactions triethylphosphite serves as an inexpen-
sive terminal reductant. Herein we disclose a follow-up
study where ortho functionalized aryl diselenides are used
as oxidation organocatalysts for O-esterification reactions17
proceeding through a redox dehydration mechanism.
Taniguchi published a related aerobic, iron-catalyzed pro-
duction of acyloxytriphenylphosphonium intermediates that
that effectively esterify alcohols.18
Results and Discussion. Treatment of 1 equiv of p-toluic
acid and 1.2 equiv of 4-methoxyphenethyl alcohol under the
conditions previously established for effective amidation
and peptidation16 (2.5 mol % diaryldiselenide 1, 1.5 equiv
triethylphosphite, dry air, freshly dried and activated 4Å mol
sieves, room temp in MeCN) over 14 h generated predomi-
nantly p-toluic anhydride (50%) along with 31% of the de-
sired ester product, traces of recovered p-toluic acid, and
10% of ethyl -p-toluate (Table 1). Inclusion of 10 mol % of
the acyl transfer catalyst DMAP19 within the reaction mix-
ture avoided buildup of the anhydride; the desired ester was
formed in 65% yield along with quantities of unreacted p-
toluic acid (16%) and ethyl p-toluate (11%). Raising the re-
action temperature to 50 °C improved the conversion to ester
(80%) leaving similar quantities of ethyl p-toluate (10%) and
only minor traces of unreacted p-toluic acid.
Table 1. Optimization of Aerobic, Diselenide-Catalyzed
Esterification Conditions
% 1
2.5
°C
25
additives
---
% ester
31
other*
10, 50,
trace
11, 0, 16
10, 0, trace
trace, 0, 14
2.5
2.5
2.5
25
50
50
10% DMAP
10% DMAP
10% DMAP,
1.1 equiv Et3N
10% DMAP,
1.1 equiv Et3N
65
80
74
5.0
50
84
trace, 0,
trace
*yields of ethyl ester, p-toluic anhydride, recovered p-toluic
acid, respectively
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The undesired ethyl ester can be formed in one of two
5
EtOAc,
10 h, 75%
1
ways: either by carboxylate reacting in an SN2 reaction with
active Arbuzov-like intermediates that are generated during
the reaction process when triethylphosphite cleaves the
diselenide (i.e. ArSeP+(OEt)3), or by liberation of free etha-
nol during the reaction through the very rapid, acid-cata-
lyzed hydrolysis20 (or transesterification) of tri-
ethylphosphite. Addressing the latter possibility, 1.1 equiv
of Et3N was added to buffer the carboxylate acidity. While
this tactic slightly slowed the rate of overall reaction, it ef-
fectively mitigated formation of the undesired ethyl ester
pointing to acid-catalyzed hydrolysis/alcoholysis of tri-
ethylphosphite as the problematic side reaction. Thus, after
14 h the desired ester was formed in 74% yield with 14% of
p-toluic acid remaining. Optimum conditions were achieved
by raising the diselenide loading to 5 mol %. Thus, at 5 mol
% diselenide, 10 mol % DMAP and 1.1 equiv of Et3N amine
at 50 °C in 14 h, the ester was generated in 84% yield. Only
very minor traces of the ethyl ester and p-toluic acid were
evident. For comparison, the same reactants generated the
ester in 78% yield when treated under the Steglich condi-
tions21-22 with 1.5 equiv of EDCI (N-(3-Dimethylaminopro-
pyl)-N′-ethylcarbodiimide hydrochloride), 1.5 equiv of Et3N
and catalytic DMAP in CH2Cl2 at room temperature for 3 hr.
The Taniguchi procedure mentioned above18 provided the
ester in only 48% yield.
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EtOAc,
10 h, 82%
MeCN,
12 h, 74%
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9
MeCN,
12 h, 79%
DMF,
14 h, 88%
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11
MeCN,
11 h, 86%
Having identified the optimal conditions for the esterifica-
tion of toluic acid and p-methoxyphenethyl alcohol, the
scope of the reaction was investigated (Table 2). Citronellic
acid (entry 2, triethylamine not required) and biphenyl-4-
carboxylic acid (entry 3) reacted smoothly with p-methoxy-
phenethyl alcohol to provide the desired esters in 92% and
84% yield, respectively
MeCN,
12 h, 72%
Table 2. Esterifications using Aerobic, Diselenide Catalyzed Re-
dox Dehydration
12
13
EtOAc,
10 h, 79%
EtOAc,
10 h, 82%
entry
1
product
solv, time
isol. yield
MeCN,
12 h, 83%
14
15
EtOAc,
10 h, 77%
2
3
MeCN,
10 h, 86%a
EtOAc,
10 h, 83%b
MeCN,
12 h, 84%
4
16
MeCN,
MeCN,
14 h, 85%
12 h, 0%
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Scheme 1. Phenol Reaction Pathway
17
MeCN, 8 h,
41%a
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2
3
4
5
6
7
8
Reaction conditions: 1.0 equiv of carboxylic acid, 1.1 equiv of
alcohol, 1.5 equiv of P(OEt)3, 10 mol % DMAP, 1.1 equiv Et3N,
5.0 mol % catalyst, solvent, dry air balloon and 4 Å mol sieves (1.0
x wt % of acid). Solvent, temperature and reaction time are given
b
in the Table entries. a Reaction in the absence of triethylamine.
Mixture of diastereomers (1:0.6 dr).
Attempted esterification of cholesterol with N-Boc-tryp-
tophan was unsuccessful in MeCN, owing to the poor solu-
bility of cholesterol in this solvent. Fortunately, a switch to
EtOAc as solvent gave the anticipated ester in 75% yield
(entry 5). An attempted coupling of N-Boc-serine methyl
ester with N-Boc-proline in MeCN was seriously compro-
mised by competitive dehydration of serine to dehydroa-
lanine. Again, switching from MeCN to the less polar
EtOAc as solvent was beneficial and delivered the desired
product in 82% yield (entry 6) with no trace of the dehydro-
alanine byproduct. The esterification of biotin was challeng-
ing because of its poor solubility in MeCN. Switching to
DMF provided product in 88% yield (entry 9).
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Entries 12, 14, and 15 of Table 2 were first attempted in
MeCN, but in each case the ester products were partially epi-
merized. Changing the solvent from MeCN to EtOAc com-
pletely suppressed the epimerization in entries 12 and 14, re-
sulting in the formation of single diastereomers, although
partial epimerization was unavoidable in entry 15. Attempts
to engage a tertiary alcohol in esterification (entry 16) was
unsuccessful.
In the absence of triethylamine, transesterification of the
phenol with selenophosphonium species does not occur and
the diselenide does not undergo ethylation. Therefore, the
esterification of phenol and citronellic acid was carried out
in the absence of triethylamine, providing 41% yield of the
phenolic ester after 8 hr (Table 2, entry 17). No attempt was
made to optimize this reaction.
The mechanism of the aerobic, diselenide catalyzed O-es-
terification of carboxylic acids and alcohols differs from the
previously described amidation/peptidation protocols
(Scheme 2).15-16, 23 In the latter, both 1° and 2° amines are
sufficiently nucleophilic to react with the in situ acyl elec-
trophiles (activated thio/selenoester or an acyloxyphospho-
nium salt), to rapidly produce amides/peptides. In the for-
mer, where the rates of electrophile trapping by the neutral
alcohol are much slower, the carboxylate preferentially at-
tacks the implicit acyl electrophile producing the carboxylic
acid anhydride, preferentially. Thus, the O-esterification re-
action requires DMAP to catalyze the reaction of the anhy-
dride with the reactant alcohol.
The esterification of phenols was briefly investigated. At-
tempts to esterify phenol or methyl-4-hydroxybenzoate with
citronellic acid resulted in substantial disappearance of the
phenol, full consumption of triethylphosphite, and destruc-
tion of the diselenide catalyst, but none of the desired ester
was generated. To determine how the diselenide and phenol
were decaying, a control experiment was conducted with 1.0
equivalent of methyl-4-hydroxybenzoate, 0.5 equivalents of
diselenide, 10 mol % DMAP, 1.1 equivalents of triethyla-
mine, and 1.5 equivalents of triethylphosphite (Scheme 1).
The reaction was monitored by 31P for changes in tri-
ethylphosphite concentration and then concentrated after 8
hr. After chromatographic separation of the reaction constit-
uents, selenoether 2 was obtained in 68 % yield along with
methyl-4-((ethoxy(ethoxymethyl)phosphoryl)oxy)benzoate
(3) in 80% yield. It appears that the selenophosphonium in-
termediate 4, generated from triethylphosphite and the
diselenide, undergoes exchange with the phenol under basic
reaction conditions to generate aryloxyphosphonium inter-
mediate 5 and arylselenide 6. Together these react to gener-
ate the observed products 2 and 3.
Scheme 2. Amidation vs Esterification. Mechanism Change
Conclusions. We have demonstrated an aerobic,
diselenide-catalyzed redox dehydrative generation of O-es-
ters from carboxylic acids and 1° and 2° alcohols; 3° alco-
hols do not react. The terminal redox reagents are tri-
ethylphosphite as reductant and O2 in air as oxidant.
EXPERIMENTAL SECTION
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General information. All solvents were purchased from
after 14 h, at which time the reaction mixtures were con-
centrated under reduced pressure and analyzed by 1H
NMR. Reported yields are based on NMR integration of
product peaks versus the internal standard.
1
2
3
4
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Fisher Scientific and dried over 4Å mol sieves. Mol sieves
were activated via heating in a microwave oven for three
minutes and dried under reduced pressure for five minutes.
Unless otherwise noted, all commercially available reagents
and substrates were used directly as received. Compressed
dry air was obtained from Nexair and used as received. Thin
layer chromatography was performed on Merck silica gel
plates and visualized by UV light/KMnO4. 1H, 13C{1H}, and
31P NMR spectra were recorded on Brucker 600, Varian
INOVA 600, INOVA 500, INOVA 400, and Mercury 300
spectrometers. In the spectra, the residual solvent absorb-
ances were treated as internal reference signals (CDCl3: 1H-
7.26 ppm and 13C- 77.16 ppm). Abbreviations for 1H NMR
coupling is as follows: singlet = s, doublet = d, triplet = t,
quartet = q, pentet = p. IR spectra were recorded on a Nicolet
iS10 FT-IR spectrometer and the absorption peaks were re-
ported in cm-1. A Thomas capillary melting point apparatus
was used to determine the melting points (uncorrected).
High resolution mass spectra were obtained with a Thermo
LTQ-FTMS instrument equipped with tandem ion trap - ICR
mass analyzers at the Emory University Mass Spec Facility
4-Methoxyphenethyl 4-methylbenzoate - (Table 2, entry
1). A mixture of p-toluic acid (29 mg, 0.21 mmol),
diselenide 1 (7.2 mg, 0.011 mmol), 4-dimethylamino-
pyridine (2.6 mg, 0.021 mmol), and 4 Å molecular sieves
(100 mg) in dry CH3CN (1 mL, 0.2M) was treated with p-
methoxy-phenethyl alcohol (35 mg, 0.231 mmol), triethyla-
mine (33 µL, 0.231 mmol), and P(OEt)3 (54 µL, 0.32
mmol) according to the general procedure. The coupling re-
action was stirred for 10 h under dry air at 50 °C and puri-
fied by flash column chromatography using SiO2 and 7%
EtOAc in hexanes to give the pure ester as a colorless oil
(47 mg, 83% yield). 1H NMR (400 MHz, chloroform-d) δ
7.95 – 7.87 (m, 2H), 7.25 – 7.22 (m, 2H), 7.22 – 7.18 (m,
2H), 6.88 – 6.84 (m, 2H), 4.47 (t, J = 7.0 Hz, 2H), 3.80 (s,
3H), 3.01 (t, J = 7.0 Hz, 2H), 2.41 (s, 3H). 13C{1H} NMR
(150 MHz, chloroform-d) δ 166.7, 158.5, 143.7, 130.2,
130.1, 129.7, 129.2, 127.8, 114.1, 65.7, 55.4, 34.5, 21.8. IR
(neat, cm-1): 1710. HRMS (ESI) Calcd for C17H19O3
[M+H]+: 271.1329. Found: 271.1328.
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Inc.
8-(4-Chlorophenylsulfonamido)-4-(3-(pyridin-3-
yl)propyl)octanoic acid was obtained from Novartis (as a
gift to the Emory University Center for C-H Functionaliza-
tion).
O-Esterification Comparison Results.
Steglich Conditions.21-22 To a test tube under N2 contain-
ing a magnetic stir bar and p-toluic acid (29 mg, 0.21
mmol), p-methoxyphenethyl alcohol (0.231, 0.231 mmol),
and DMAP (2.5 mg, 0.021 mmol) in dichloromethane (1
mL, 0.2 M), Et3N (44 uL, 0.315 mmol) was added N-(3-di-
methylaminopropyl)-N′-ethylcarbodiimide hydrochloride
(60 mg, 0.315 mmol) under a stream of nitrogen. The reac-
tion was stirred at room temperature for 3 h and determined
to be complete by TLC (7% EtOAc in hexanes). The crude
reaction mixture was filtered over silica and the silica
washed with dichloromethane to furnish the pure ester as a
colorless oil (44 mg, 78% yield).
General Experimental Procedure for Ester Bond For-
mation. A 12 mL test tube was charged with 4 Å molecular
sieves (100 mg) previously activated in a microwave oven
for three minutes and dried under reduced pressure for five
minutes. Then the carboxylic acid (0.21 mmol), diselenide 1
(0.011 mmol), and 4-dimethylaminopyridine (2.6 mg, 0.021
mmol) were added followed by dry CH3CN, EtOAc, or DMF
(1.0 mL, 0.2M, moisture content <25 ppm). The alcohol
(0.23 mmol), 4-dimethylaminopyridine (0.021 mmol), tri-
ethylamine, (0.23 mmol) and triethylphosphite (0.32 mmol)
were added sequentially. The reaction mixture was stirred
for 10 – 18 h at 50 °C (temperature controlled with an alu-
minum block on a hot plate) under a dry air atmosphere (bal-
loon). Upon complete conversion of carboxylic acid as mon-
itored by TLC, the reaction mixture was filtered, and the mo-
lecular sieves thoroughly washed with CH2Cl2 (DCM). The
combined filtrate was concentrated under reduced pressure
and the crude product was purified by flash column chroma-
tography using the eluents mentioned below to obtain the es-
ter product.
Experimental Procedure for Reactions Reported in
Scheme 1. A 12 mL test tube was charged with 4 Å molec-
ular sieves (100 mg) previously activated in a microwave
oven for three minutes and dried under reduced pressure for
five minutes. Then toluic acid (29 mg, 0.21 mmol) and
diselenide 1 (3.6 mg, 0.0055 mmol or 7.2 mg, 0.011 mmol)
were added. For the reactions in which 4-dimethylamino-
pyridine (2.6 mg, 0.021 mmol) was employed, it was added
followed by dry CH3CN (1.0 mL, 0.2M, moisture content
<25 ppm) and p-methoxy-phenethyl alcohol (35 mg, 0.23
mmol). If triethylamine (33 µL, 0.23 mmol) was employed,
it was added followed by triethylphosphite (0.32 mmol).
Lastly, 1,3,5-trimethoxybenzene was added and used as an
internal standard. The reaction was stirred at either 25 or 50
°C (temperature controlled with an aluminum block on a
hot plate) under a dry air atmosphere (balloon) and stopped
Taniguchi Conditions. Following the procedure reported by
Taniguchi and coworkers,18 a mixture of p-toluic acid (29
mg, 0.21 mmol), p-methoxyphenethyl alcohol (0.231,
0.231 mmol), triphenylphosphine (110 mg, 0.42 mmol),
iron(II) phthalocyanine (6.2 mg, 0.011 mmol), and 4-meth-
oxypyridine N-oxide (2.6 mg, 0.021 mmol) in MeCN (0.5
mL, 0.5 M) was heated at reflux with an aluminum block
on hot plate under dry air (balloon) for 24 h. The mixture
was filtered, and the solvent was removed under reduced
pressure. The residue was purified by filtration over silica
gel, eluting with dichloromethane to give the pure ester as a
colorless oil (27 mg, 48% yield).
4-Methoxyphenethyl 3,7-dimethyloct-6-enoate - (Table
2, entry 2). A mixture of racemic citronellic acid (36 mg,
0.21 mmol, 94% pure), diselenide 1 (7.2 mg, 0.011 mmol),
4-dimethylaminopyridine (2.6 mg, 0.021 mmol), and 4 Å
molecular sieves (100 mg) in dry CH3CN (1 mL, 0.2M)
was treated with p-methoxyphenethyl alcohol (35 mg,
0.231 mmol), triethylamine (33 µL, 0.23 mmol), and
P(OEt)3 (54 µL, 0.32 mmol) according to the general pro-
cedure. The coupling reaction was stirred for 10 h under
dry air at 50 °C and purified by flash column chromatog-
raphy using SiO2 and 5% EtOAc in hexanes to give the
pure ester as a colorless oil (55 mg, 86% yield). 1H NMR
(600 MHz, chloroform-d) δ 7.14 (AA’ of AA’XX’, 2H),
6.84 (XX’ of AA’XX’, 2H), 5.08 (tp, J = 7.1, 1.4 Hz, 1H),
4.25 (t, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.88 (t, J = 7.1 Hz,
4
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2H), 2.30 (dd, J = 14.7, 5.9 Hz, 1H), 2.10 (dd, J = 14.7, 8.2
Hz, 1H), 2.04 – 1.89 (m, 3H), 1.68 (q, J = 1.3 Hz, 3H), 1.60
(d, J = 1.3 Hz, 3H), 1.36 – 1.29 (m, 1H), 1.20 (dddd, J =
13.6, 9.4, 7.8, 5.9 Hz, 1H), 0.91 (d, J = 6.7 Hz, 3H).
13C{1H} NMR (150 MHz, chloroform-d) δ 173.4,158.4,
131.7, 130.04, 129.98, 124.4, 114.1, 65.0, 55.4, 42.0, 36.9,
34.4, 30.2, 25.9, 25.6, 19.7, 17.8. IR (CDCl3, cm-1): 1733.
HRMS (ESI) Calcd for C19H32NO3 [M+NH4]+: 322.2377.
Found: 322.2379.
diselenide 1 (7.2 mg, 0.011 mmol), 4-dimethylamino-
pyridine (2.6 mg, 0.021 mmol), and 4 Å molecular sieves
(100 mg) in dry EtOAc (1 mL, 0.2M) was treated with cho-
lesterol (89 mg, 0.23 mmol), triethylamine (33 µL, 0.23
mmol), and P(OEt)3 (54 µL, 0.32 mmol) according to the
general procedure. The coupling reaction was stirred for 14
h under dry air at 50 °C and purified by flash column chro-
matography using SiO2 and 3% EtOAc in DCM to give the
pure ester as a white foam (106 mg, 75% yield). 1H NMR
(600 MHz, chloroform-d) δ 8.05 (s, 1H), 7.59 (d, J = 6.9
Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.19 (ddd, J = 8.1, 7.0,
1.1 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 2.4 Hz,
1H), 5.33 (d, J = 5.7 Hz, 1H), 5.07 (d, J = 8.3 Hz, 1H), 4.67
– 4.49 (m, 2H), 3.38 – 3.18 (m, 2H), 2.20 (d, J = 10.1 Hz,
2H), 2.00 (dt, J = 12.6, 3.5 Hz, 1H), 1.99 – 1.93 (m, 1H),
1.82 (dtd, J = 13.2, 6.3, 3.5 Hz, 2H), 1.75 – 1.67 (m, 1H),
1.61 – 1.23 (m, 21H), 1.19 – 0.89 (m, 16H), 0.87 (d, J = 2.8
Hz, 3H), 0.86 (d, J = 2.7 Hz, 3H), 0.67 (s, 3H). 13C{1H}
NMR (150 MHz, chloroform-d) δ 171.8, 155.4, 139.6,
136.2, 128.1, 122.9, 122.8, 122.3, 119.7, 119.2, 111.2,
110.7, 79.8, 75.2, 56.8, 56.3, 54.6, 50.1, 42.5, 39.9, 39.7,
38.0, 37.1, 36.7, 36.3, 35.9, 32.04, 31.99, 28.5, 28.4, 28.2,
27.7, 24.4, 24.0, 23.0, 22.7, 21.2, 19.4, 18.9, 12.0. IR
(CDCl3, cm-1): 3415, 3349, 1696. HRMS (ESI) Calcd for
C43H63N2O4 [M-H]-: 671.4793. Found: 671.4799. Melting
point: 87-89 °C (recrystallized from ether/hexanes).
2-((S)-2-((tert-Butoxycarbonyl)amino)-3-methoxy-3-ox-
opropyl) 1-(tert-butyl) (S)-pyrrolidine-1,2-dicarboxylate
- (Table 2, entry 6). A mixture of N-Boc-L-proline (45 mg,
0.21 mmol), diselenide 1 (7.2 mg, 0.011 mmol), 4-dimethyl-
aminopyridine (2.6 mg, 0.021 mmol), and 4 Å molecular
sieves (100 mg) in dry EtOAc (1 mL, 0.2M) was treated with
N-Boc-L-serine methyl ester (51 mg, 0.23 mmol), triethyla-
mine (33 µL, 0.23 mmol), and P(OEt)3 (54 µL, 0.32 mmol)
according to the general procedure. The coupling reaction
was stirred for 10 h under dry air at 50 °C and purified by
flash column chromatography using SiO2 and 30% EtOAc
in hexanes to give the pure ester as a colorless oil (70 mg,
82% yield). 1H NMR (400 MHz, chloroform-d) δ 5.60, 5.24
(d, J = 8.6 Hz, 1H, rotamers), 4.63 – 4.50 (m, 2H), 4.41 (dtd,
J = 33.9, 11.2, 3.8 Hz, 2H), 4.29, 4.21 (dd, J = 8.6, 4.0 Hz,
1H, rotamers), 3.75 (s, 3H), 3.60 – 3.31 (m, 2H), 2.20 (ddq,
J = 16.0, 12.4, 8.2 Hz, 1H), 2.05 – 1.81 (m, 3H), 1.48, 1.40
(s, 9H rotamers), 1.44 (s, 9H). 13C{1H} NMR (150 MHz,
chloroform-d) δ 172.8, 172.5, 170.4, 170.2, 155.5, 155.2,
154.7, 153.7, 80.5, 80.2, 80.1, 64.9, 64.8, 59.2, 59.0, 53.05,
53.02, 52.8, 52.7, 46.7, 46.4, 31.0, 30.1, 28.6, 28.42, 28.38,
24.5, 23.6.
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8
4-methoxyphenethyl [1,1'-biphenyl]-4-carboxylate - (Ta-
ble 2, entry 3). A mixture of biphenyl-4-carboxylic acid (42
mg, 0.21 mmol, 95% pure), diselenide 1 (7.2 mg, 0.011
mmol), 4-dimethylaminopyridine (2.6 mg, 0.021 mmol),
and 4 Å molecular sieves (100 mg) in dry CH3CN (1 mL,
0.2M) was treated with p-methoxyphenethyl alcohol (35
mg, 0.231 mmol), triethylamine (33 µL, 0.23 mmol), and
P(OEt)3 (54 µL, 0.32 mmol) according to the general pro-
cedure. The coupling reaction was stirred for 12 h under
dry air at 50 °C and purified by flash column chromatog-
raphy using SiO2 and 7% EtOAc in hexanes to give the
pure ester as a crystalline white solid (56 mg, 84% yield).
1H NMR (600 MHz, chloroform-d) δ 8.10 – 8.07 (m, 2H),
7.68 – 7.64 (m, 2H), 7.64 – 7.61 (m, 2H), 7.50 – 7.45 (m,
2H), 7.40 (ddt, J = 8.1, 6.7, 1.3 Hz, 1H), 7.25 – 7.20 (m,
2H), 6.90 – 6.86 (m, 2H), 4.52 (t, J = 7.0 Hz, 2H), 3.80 (s,
3H), 3.04 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (150 MHz,
chloroform-d) δ 166.6, 158.5, 145.8, 140.2, 130.2, 130.1,
129.2, 129.1, 128.3, 127.4, 127.2, 114.1, 65.9, 55.4, 34.6.
IR (CDCl3, cm-1): 1711. HRMS (ESI) Calcd for C22H21O3
[M+H]+: 333.1485. Found: 333.1490. Melting point: 127-
128 °C (recrystallized from EtOAc/hexanes).
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5-(tert-Butyl) 1-((1S,2R,4S)-1,7,7-trimethylbicy-
clo[2.2.1]heptan-2-yl) (tert-butoxycarbonyl)-D-gluta-
mate - (Table 2, entry 4). A mixture of Boc-L-glutamic
acid 1-tert-butyl ester (64 mg, 0.21 mmol), diselenide 1
(7.2 mg, 0.011 mmol), 4-dimethylaminopyridine (2.6 mg,
0.021 mmol), and 4 Å molecular sieves (100 mg) in dry
CH3CN (1 mL, 0.2M) was treated with (1S,2R,4S)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ol (36 mg, 0.23 mmol), tri-
ethylamine (33 µL, 0.23 mmol), and P(OEt)3 (54 µL, 0.32
mmol) according to the general procedure. The coupling re-
action was stirred for 14 h under dry air at 50 °C and puri-
fied by flash column chromatography using SiO2 and 10%
EtOAc in hexanes to give the pure ester as a colorless oil
(78 mg, 85% yield). 1H NMR (600 MHz, chloroform-d) δ
5.09 (d, J = 8.4 Hz, 1H), 4.94 (ddd, J = 10.0, 3.5, 2.2 Hz,
1H), 4.38 – 4.28 (m, 1H), 2.35 (ddd, J = 16.3, 8.6, 6.7 Hz,
2H), 2.27 (ddd, J = 16.3, 8.6, 6.3 Hz, 1H), 2.18 – 2.10 (m,
1H), 1.97 – 1.88 (m, 2H), 1.75 (ddq, J = 12.2, 8.1, 4.0 Hz,
1H), 1.69 (t, J = 4.6 Hz, 1H), 1.45 (s, 9H), 1.44 (s, 9H),
1.34 – 1.23 (m, 2H), 1.02 (dd, J = 13.8, 3.4 Hz, 1H), 0.90
(s, 3H), 0.88 (s, 3H), 0.83 (s, 3H). 13C{1H} NMR (150
MHz, chloroform-d) δ 172.8, 172.2, 155.5, 81.4, 80.8, 80.0,
53.5, 49.1, 48.1, 45.0, 36.7, 31.8, 28.5, 28.2, 28.13, 28.11,
27.3, 19.8, 19.0, 13.7.IR (CDCl3, cm-1): 3361, 1734, 1717,
1700. HRMS (ESI) Calcd for C24H42NO6 [M+H]+:
IR (CDCl3, cm-1): 3347, 1755, 1737, 1712, 1693. HRMS
(ESI) Calcd for C19H36N3O8 [M+NH4]+: 434.2497. Found:
434.2492.
(Z)-4-((tert-Butyldimethylsilyl)oxy)but-2-en-1-yl (tert-
butoxycarbonyl)-L-methioninate - (Table 2, entry 7). A
mixture of N-Boc-L-methionine (52 mg, 0.21 mmol),
diselenide 1 (7.2 mg, 0.011 mmol), 4-dimethylamino-
pyridine (2.6 mg, 0.021 mmol), and 4 Å molecular sieves
(100 mg) in dry CH3CN (1 mL, 0.2M) was treated with (Z)-
4-((tert-butyldimethylsilyl)oxy)but-2-en-1-ol (47 mg, 0.23
mmol), triethylamine (33 uL, 0.231 mmol), and P(OEt)3
(54 µL, 0.32 mmol) according to the general procedure.
The coupling reaction was stirred for 12 h under dry air at
50 °C and purified by flash column chromatography using
SiO2 and 15% EtOAc in hexanes to give the pure ester as a
440.3007. Found: 440.3013.
(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-((R)-6-
methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl (tert-
butoxycarbonyl)-D-tryptophanate - (Table 2, entry 5). A
mixture of N-α-Boc-D-tryptophan (64 mg, 0.21 mmol),
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colorless oil (68 mg, 74% yield). 1H NMR (600 MHz, chlo-
Page 6 of 9
mmol), and 4 Å molecular sieves (100 mg) in dry CH3CN
(1 mL, 0.2M) was treated with ((2S,3S)-3-methyl-3-(4-
methylpent-3-en-1-yl)oxiran-2-yl)methanol (39 mg, 0.23
mmol), triethylamine (33 µL, 0.23 mmol), and P(OEt)3 (54
µL, 0.32 mmol) according to the general procedure. The
coupling reaction was stirred for 11 h under dry air at 50 °C
and purified by flash column chromatography using SiO2
and 15% EtOAc in hexanes to give the pure ester as a pale
yellow oil (93 mg, 86% yield). 1H NMR (500 MHz, Chlo-
roform-d) δ 7.69 – 7.63 (m, 2H), 7.50 – 7.43 (m, 2H), 6.97
(d, J = 2.5 Hz, 1H), 6.87 (dd, J = 9.0, 0.5 Hz, 1H), 6.67 (dd,
J = 9.0, 2.5 Hz, 1H), 5.06 (ddq, J = 8.6, 5.7, 1.5 Hz, 1H),
4.36 (dd, J = 12.1, 4.0 Hz, 1H), 4.07 (dd, J = 12.1, 7.1 Hz,
1H), 3.84 (s, 3H), 3.72 (s, 2H), 2.98 (dd, J = 7.1, 4.0 Hz,
1H), 2.39 (s, 3H), 2.11 – 1.96 (m, 2H), 1.68 (d, J = 1.3 Hz,
3H), 1.67 – 1.61 (m, 1H), 1.59 (d, J = 1.2 Hz, 3H), 1.45
(ddd, J = 13.8, 9.7, 6.8 Hz, 1H), 1.28 (s, 3H). 13C{1H}
NMR (150 MHz, Chloroform-d) δ 170.8, 168.4, 156.2,
139.4, 136.2, 134.0, 132.4, 131.3, 131.0, 130.7, 129.3,
123.3, 115.1, 112.4, 111.9, 101.4, 64.2, 60.7, 59.7, 55.9,
38.4, 30.3, 25.8, 23.7, 17.8, 17.0, 13.5. IR (neat, cm-1):
1737, 1681. HRMS (ESI) Calcd for C29H33ClNO5 [M+H]+:
510.2042. Found: 510.2048.
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3
4
5
6
7
8
roform-d) δ 5.75 (dtt, J = 11.5, 5.8, 1.5 Hz, 1H), 5.56 (dtt, J
= 11.3, 6.8, 1.8 Hz, 1H), 5.11 (d, J = 8.2 Hz, 1H), 4.78 –
4.70 (m, 2H), 4.44 – 4.38 (m, 1H), 4.28 (ddt, J = 5.8, 1.8,
0.9 Hz, 2H), 2.57 – 2.50 (m, 2H), 2.17 – 2.10 (m, 1H), 2.09
(s, 3H), 1.92 (dq, J = 14.6, 7.6 Hz, 1H), 1.44 (s, 9H), 0.90
(s, 9H), 0.08 (s, 6H). 13C{1H} NMR (150 MHz, chloro-
form-d) δ 172.2, 155.4, 134.7, 123.6, 80.2, 61.5, 59.7, 52.3,
32.4, 30.1, 28.5, 26.1, 18.5, 15.7, -5.1. IR (neat, cm-1):
3351, 1714. HRMS (ESI) Calcd for C20H40NO5SSi
9
[M+H]+: 434.2391. Found: 434.2389.
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(R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl (E)-3-(fu-
ran-3-yl)acrylate - (Table 2, entry 8). A mixture of (E)-3-
(furan-3-yl)acrylic acid (29 mg, 0.21 mmol), diselenide 1
(7.2 mg, 0.011 mmol), 4-dimethylaminopyridine (2.6 mg,
0.021 mmol), and 4 Å molecular sieves (100 mg) in dry
CH3CN (1 mL, 0.2M) was treated with (R)-3-hydroxy-4,4-
dimethyldihydrofuran-2(3H)-one (30 mg, 0.23 mmol), tri-
ethylamine (33 µL, 0.23 mmol), and P(OEt)3 (54 µL, 0.32
mmol) according to the general procedure. The coupling re-
action was stirred for 12 h under dry air at 50 °C and puri-
fied by flash column chromatography using SiO2 and 30%
EtOAc in hexanes to give the pure ester as a colorless oil
(40 mg, 79% yield). 1H NMR (400 MHz, chloroform-d) δ
7.76 – 7.62 (m, 2H), 7.45 (ddd, J = 2.1, 1.5, 0.8 Hz, 1H),
6.61 (dt, J = 1.9, 0.7 Hz, 1H), 6.25 (dd, J = 15.8, 0.5 Hz,
1H), 5.49 (s, 1H), 4.09 (d, J = 9.0 Hz, 1H), 4.06 (d, J = 9.3
Hz, 2H), 1.24 (s, 3H), 1.16 (s, 3H). 13C{1H} NMR (150
MHz, chloroform-d) δ 172.7, 165.8, 145.3, 144.8, 137.0,
122.6, 116.2, 107.5, 76.4, 75.2, 40.6, 23.3, 20.1. IR
1-(tert-Butyl) 2-(((3aR,4R,6R,6aR)-6-(2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydro-
furo[3,4-d][1,3]dioxol-4-yl)methyl) (2S,4R)-4-(ben-
zyloxy)pyrrolidine-1,2-dicarboxylate - (Table 2, entry
11). A mixture of (2S,4R)-4-(benzyloxy)-1-(tert-butoxycar-
bonyl)pyrrolidine-2-carboxylic acid (68 mg, 0.21 mmol),
diselenide 1 (7.2 mg, 0.011 mmol), 4-dimethylamino-
pyridine (2.6 mg, 0.021 mmol), and 4 Å molecular sieves
(100 mg) in dry CH3CN (1 mL, 0.2M) was treated with 1-
((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahy-
drofuro[3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-di-
one (66 mg, 0.23 mmol), triethylamine (33 µL, 0.23
mmol), and P(OEt)3 (54 µL, 0.32 mmol) according to the
general procedure. The coupling reaction was stirred for 12
h under dry air at 50 °C and purified by flash column chro-
matography using SiO2 and 70% EtOAc in hexanes to give
the pure ester as a white foam (89 mg, 72% yield). 1H
NMR (600 MHz, chloroform-d) δ 8.17, 8.14 (s, 1H, rota-
mers), 7.38 – 7.27, 7.21– 7.18 (m, 6H rotamers), 5.76 –
5.71, 5.59 – 5.57 (m, 2H rotamers), 5.01, 4.86 (dd, J = 6.4,
1.8 Hz, and dd, J = 6.4, 2.6 Hz, 1H rotamers), 4.79 (dt, J =
6.6, 3.7 Hz, 1H), 4.55 – 4.26 (m, 6H), 4.20 – 4.13 (m, 1H),
3.74 – 3.70, 3.61 – 3.54 (m, 2H), 2.47 – 2.33 (m, 1H), 2.11
– 2.02 (m, 1H), 1.56 (s, 3H), 1.45, 1.40 (s, 9H, rotamers),
1.35 (s, 3H). 13C{1H} NMR (150 MHz, chloroform-d) δ
172.8, 172.6, 162.7, 162.5, 154.6, 153.9, 149.9, 149.7,
142.6, 141.7, 137.8, 137.9, 128.70, 128.67, 128.1, 128.0,
127.8, 127.7, 114.9, 114.9, 103.0, 102.8, 95.4, 93.5, 85.5,
84.6, 84.5, 84.4, 81.3, 80.7, 80.6, 76.1, 71.4, 71.3, 64.8,
64.5, 58.2, 57.8, 52.1, 51.5, 37.0, 35.9, 28.6, 28.4, 27.4,
27.3, 25.54, 25.48. IR (neat, cm-1): 3194, 1746, 1687.
HRMS (ESI) Calcd for C29H36N3O10 [M-H]-: 586.2406.
Found: 586.2415. Melting point: 74-78 °C (recrystallized
from EtOAc/hexanes).
(CDCl3, cm-1): 1781, 1716, 1684. HRMS (ESI) Calcd for
C13H15O5 [M+H]+: 251.0914. Found: 251.0913.
4-(Trimethylsilyl)but-3-yn-2-yl 5-((3aS,4S,6aR)-2-
oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentano-
ate - (Table 2, entry 9). A mixture of biotin (51 mg, 0.21
mmol), diselenide 1 (7.2 mg, 0.011 mmol), 4-dimethyla-
minopyridine (2.6 mg, 0.021 mmol), and 4 Å molecular
sieves (100 mg) in dry DMF (1 mL, 0.2M) was treated with
racemic 4-(trimethylsilyl)but-3-yn-2-ol (33 mg, 0.23
mmol), triethylamine (33 µL, 0.23 mmol), and P(OEt)3 (54
µL, 0.32 mmol) according to the general procedure. The
coupling reaction was stirred for 14 h under dry air at 50 °C
and purified by triturating the crude mixture with H2O to
remove triethylphosphate, followed by flash column chro-
matography using SiO2 and 7% MeOH in DCM to give the
ester as white gummy semi-solid (68 mg, 88% yield, 1:1
mixture of diastereomers). 1H NMR (400 MHz, chloro-
form-d) δ 5.95 (s, 1H), 5.46 (q, J = 6.7 Hz, 1H), 5.36 (s,
1H), 4.58 – 4.44 (m, 1H), 4.30 (ddd, J = 7.9, 4.6, 1.5 Hz,
1H), 3.15 (ddd, J = 8.2, 6.3, 4.5 Hz, 1H), 2.90 (dd, J = 12.8,
4.9 Hz, 1H), 2.75 (d, J = 12.8 Hz, 1H), 2.35 (td, J = 7.5, 2.2
Hz, 2H), 1.80 – 1.57 (m, 4H), 1.51– 1.39 (m, 5H), 0.16 (s,
9H). 13C{1H} NMR (100 MHz, chloroform-d) δ 172.6,
163.7, 103.7, 89.6, 62.1, 60.7, 60.2, 55.6, 40.7, 34.0, 28.40,
28.38, 28.35, 28.33, 24.8, 24.8, 21.7. IR (CDCl3, cm-1):
3206, 1737, 1695. HRMS (ESI) Calcd for C17H29N2O3SSi
[M+H]+: 369.1663. Found: 369.1660.
((2S,3S)-3-Methyl-3-(4-methylpent-3-en-1-yl)oxiran-2-
yl)methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-
1H-indol-3-yl)acetate - (Table 2, entry 10). A mixture of
2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-
yl)acetic acid (75 mg, 0.21 mmol), diselenide 1 (7.2 mg,
0.011 mmol), 4-dimethylaminopyridine (2.6 mg, 0.021
((3aS,5aR,8aR,8bS)-2,2,7,7-Tetramethyltetrahydro-
3aH-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methyl
(tert-butoxycarbonyl)-D-phenylalaninate - (Table 2, en-
try 12). A mixture of N-Boc-D-phenylalanine (58 mg, 0.21
mmol), diselenide 1 (7.2 mg, 0.011 mmol), 4-dimethyla-
minopyridine (2.6 mg, 0.021 mmol), and 4 Å molecular
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The Journal of Organic Chemistry
sieves (100 mg) in dry EtOAc (1 mL, 0.2M) was treated
(600 MHz, chloroform-d) δ 7.39 – 7.28 (m, 5H), 7.16 –
7.11 (m, 2H), 7.01 – 6.96 (m, 2H), 5.26 (d, J = 8.1 Hz, 1H),
5.10 (s, 2H), 4.70 (td, J = 10.9, 4.4 Hz, 1H), 4.61 (dt, J =
8.1, 5.9 Hz, 1H), 3.13 (dd, J = 14.0, 6.0 Hz, 1H), 3.07 (dd,
J = 14.0, 5.8 Hz, 1H), 2.28 (s, 3H), 1.94 – 1.83 (m, 1H),
1.73 (pd, J = 6.9, 2.2 Hz, 1H), 1.69 – 1.63 (m, 2H), 1.51 –
1.41 (m, 1H), 1.34 (ddt, J = 14.4, 11.2, 3.2 Hz, 1H), 1.02
(qd, J = 13.4, 12.7, 3.7 Hz, 1H), 0.96 – 0.80 (m, 8H), 0.71
(d, J = 6.9 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ
171.0, 169.5, 155.7, 149.8, 136.4, 133.5, 130.6, 128.6,
128.3, 128.3, 121.7, 76.0, 67.1, 54.8, 46.9, 40.8, 37.7, 34.1,
31.5, 26.2, 23.4, 22.1, 21.3, 20.8, 16.3. IR (CDCl3, cm-1):
3362, 1751, 1721, 1688. HRMS (ESI) Calcd for C29H38NO6
[M+H]+: 496.2694. Found: 496.2687.
((3aS,5aR,8aR,8bS)-2,2,7,7-Tetramethyltetrahydro-
3aH-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methyl
2-acetoxy-2-phenylacetate - (Table 2, entry 15). A mix-
ture of (S)-(+)-O-acetylmandelic acid (40 mg, 0.21 mmol),
diselenide 1 (7.2 mg, 0.011 mmol), 4-dimethylamino-
pyridine (2.6 mg, 0.021 mmol), and 4 Å molecular sieves
(100 mg) in dry EtOAc (1 mL, 0.2M) was treated with
((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-
bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methanol (60
mg, 0.23 mmol), triethylamine (33 µL, 0.23 mmol), and
P(OEt)3 (54 µL, 0.32 mmol) according to the general pro-
cedure. The coupling reaction was stirred for 10 h under
dry air at 50 °C and purified by flash column chromatog-
raphy using SiO2 and 25% EtOAc in hexanes to give the
pure ester as a colorless oil (76 mg, 83% yield, 1:0.6 mix-
ture of diastereomers based on integration of 1H NMR
spectrum). 1H NMR (400 MHz, chloroform-d) δ 7.51 –
7.34 (m, 5H), 6.04, 5.96 (s, 1H, mixture of diastereomers),
4.59, 4.53 (dd, J = 7.9, 2.7 Hz, 1H, mixture of diastere-
omers), 4.46 – 4.02 (m, 4H), 3.89, 3.86 (d, J = 1.9 Hz, 1H,
diastereomers), 3.73, 3.70 (dd, J = 4.6, 0.8 Hz, 1H mixture
of diastereomers), 2.18, 2.17 (s, 3H, mixture of
1
with ((3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-
3aH-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-3a-yl)methanol
(60 mg, 0.23 mmol), triethylamine (33 µL, 0.23 mmol),
and P(OEt)3 (54 µL, 0.32 mmol) according to the general
procedure. The coupling reaction was stirred for 10 h under
dry air at 50 °C and purified by flash column chromatog-
raphy using SiO2 and 20% EtOAc in hexanes to give the
pure ester a colorless oil (84 mg, 79% yield). 1H NMR (600
MHz, chloroform-d) δ 7.31 (t, J = 7.3 Hz, 2H), 7.26 (t, J =
7.4 Hz, 1H), 7.15 (d, J = 6.9 Hz, 2H), 5.02 (d, J = 8.4 Hz,
1H), 4.69 (dt, J = 8.6, 5.6 Hz, 1H), 4.63 (dd, J = 7.9, 2.7
Hz, 1H), 4.29 (d, J = 11.7 Hz, 1H), 4.28 – 4.24 (m, 2H),
4.20 (d, J = 11.6 Hz, 1H), 3.95 (dd, J = 13.0, 1.9 Hz, 1H),
3.80 (d, J = 13.0 Hz, 1H), 3.22 – 3.08 (m, 2H), 1.57 (s,
3H), 1.43 (s, 9H), 1.42 (s, 3H), 1.37 (s, 3H). 13C{1H} NMR
(150 MHz, chloroform-d) δ 171.3, 155.1, 135.9, 129.6,
128.8, 127.2, 109.4, 109.1, 101.3, 80.1, 70.9, 70.5, 70.1,
66.3, 61.5, 54.5, 38.4, 28.5, 26.7, 26.1, 25.5, 24.2. IR
(CDCl3, cm-1): 3355, 1746, 1711. HRMS (ESI) Calcd for
C26H38NO9 [M+H]+: 508.2541. Found: 508.2543.
(3a'R,4S,7'S,7a'R)-2,2,2',2'-Tetramethyltetrahydro-
spiro[[1,3]dioxolane-4,6'-[1,3]dioxolo[4,5-c]pyran]-7'-yl
(tert-butoxycarbonyl)-L-valinate - (Table 2, entry 13). A
mixture of N-Boc-L-valine (46 mg, 0.21 mmol), diselenide
1 (7.2 mg, 0.011 mmol), 4-dimethylaminopyridine (2.6 mg,
0.021 mmol), and 4 Å molecular sieves (100 mg) in dry
EtOAc (1 mL, 0.2M) was treated with (3a'R,4S,7'S,7a'S)-
2,2,2',2'-tetramethyltetrahydrospiro[[1,3]dioxolane-4,6'-
[1,3]dioxolo[4,5-c]pyran]-7'-ol (60 mg, 0.23 mmol), tri-
ethylamine (33 µL, 0.23 mmol), and P(OEt)3 (54 µL, 0.32
mmol) according to the general procedure. The coupling
reaction was stirred for 10 h under dry air at 50 °C and pu-
rified by flash column chromatography using SiO2 and
20% EtOAc in hexanes to give the pure ester as a white
solid (79 mg, 82% yield). 1H NMR (500 MHz, chloroform-
d) δ 5.15 (d, J = 7.7 Hz, 1H), 5.04 (d, J = 9.2 Hz, 1H), 4.34
(dd, J = 9.2, 4.4 Hz, 1H), 4.29 (dd, J = 7.8, 5.4 Hz, 1H),
4.25 – 4.21 (m, 1H), 4.13 (dd, J = 13.5, 2.5 Hz, 1H), 4.07
(d, J = 13.4 Hz, 1H), 3.96 (d, J = 9.3 Hz, 1H), 3.82 (d, J =
9.3 Hz, 1H), 2.21 (pd, J = 6.9, 4.6 Hz, 1H), 1.54 (s, 3H),
1.47 (s, 3H), 1.44 (s, 9H), 1.41 (s, 3H), 1.35 (s, 3H), 1.00
(d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H). 13C{1H}
NMR (100 MHz, chloroform-d) δ 171.7, 155.5, 112.1,
109.8, 103.6, 79.9, 74.8, 73.8, 72.2, 71.3, 60.8, 58.9, 31.6,
28.4, 27.8, 26.48, 26.46, 26.2, 19.4, 17.3. IR (neat, cm-1):
3393, 1746, 1688. HRMS (ESI) Calcd for C22H38NO9
[M+H]+: 460.2541. Found: 460.2542. Melting point: 106 –
108 °C (recrystallized from ether/hexanes).
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disatereomers), 1.50, 1.46 (s, 3H, mixture of
disatereomers), 1.45 (s, 3H,), 1.33, 1.31 (s, 3H, mixture of
diastereomers), 1.26, 1.05 (s, 3H, mixture of diastere-
omers). 13C{1H} NMR (100 MHz, chloroform-d) δ 196.4,
170.4, 170.1, 168.3, 168.3, 133.9, 133.5, 129.56, 129.55,
129.03, 128.98, 128.21, 128.15, 109.30, 109.25, 109.1,
109.0, 101.23, 101.16, 74.6, 74.4, 70.9, 70.8, 70.3, 70.12,
70.09, 70.05, 65.61, 65.56, 61.42, 61.38, 26.60, 26.57,
26.01, 26.00, 25.2, 25.0, 24.19, 24.17, 20.9. IR (CDCl3, cm-
1): 1743. HRMS (ESI) Calcd for C22H27O9 [M-H]-:
435.1661. Found: 435.1660.
Phenyl 3,7-dimethyloct-6-enoate - (Table 2, entry 17). A
mixture of racemic citronellic acid (36 mg, 0.21 mmol),
diselenide 1 (7.2 mg, 0.011 mmol), 4-dimethylamino-
pyridine (2.6 mg, 0.021 mmol), and 4 Å molecular sieves
(100 mg) in dry CH3CN (1 mL, 0.2M) was treated with
phenol (22 mg, 0.23 mmol) and P(OEt)3 (54 µL, 0.32
mmol) according to the general procedure. The coupling re-
action was stirred for 9 h under dry air at 50 °C and puri-
fied by flash column chromatography using SiO2 and 10%
EtOAc in hexanes to give the pure ester as a colorless oil
(21 mg, 41% yield). 1H NMR (400 MHz, chloroform-d) δ
7.42 – 7.34 (m, 2H), 7.25 – 7.19 (m, 1H), 7.11 – 7.05 (m,
2H), 5.13 (tp, J = 10.7, 2.2 Hz, 1H), 2.57 (dd, J = 14.7, 6.0
Hz, 1H), 2.37 (dd, J = 14.8, 8.2 Hz, 1H), 2.16 – 1.99 (m,
3H), 1.70 (q, J = 1.3 Hz, 3H), 1.62 (d, J = 1.2 Hz, 3H), 1.46
(dddd, J = 13.5, 9.2, 6.7, 5.7 Hz, 1H), 1.32 (dddd, J = 13.6,
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl (S)-3-(4-ace-
toxyphenyl)-2-(((benzyloxy)carbonyl)amino)propanoate
- (Table 2, entry 14). A mixture of (S)-3-(4-acetoxy-
phenyl)-2-(((benzyloxy)carbonyl)amino)propanoic acid (75
mg, 0.21 mmol), diselenide 1 (7.2 mg, 0.011 mmol), 4-di-
methylaminopyridine (2.6 mg, 0.021 mmol), and 4 Å mo-
lecular sieves (100 mg) in dry EtOAc (1 mL, 0.2M) was
treated (1R,2S,5R)-2-isopropyl-5-methylcyclohexan-1-ol
(36 mg, 0.23 mmol), triethylamine (33 µL, 0.23 mmol),
and P(OEt)3 (54 µL, 0.32 mmol) according to the general
procedure. The coupling reaction was stirred for 10 h under
dry air at 50 °C and purified by flash column chromatog-
raphy using SiO2 and 20% EtOAc in hexanes to give the
pure ester as a colorless oil (80 mg, 77% yield). 1H NMR
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9.1, 7.8, 6.2 Hz, 1H), 1.06 (d, J = 6.7 Hz, 3H). 13C{1H}
NMR (100 MHz, chloroform-d) δ 171.8, 150.9, 131.9,
129.5, 125.9, 124.3, 121.8, 77.5, 77.2, 76.8, 41.9, 36.9,
30.3, 25.9, 25.6, 19.8, 17.8. IR (neat, cm-1): 1755. HRMS
(ESI) Calcd for C16H22O2 [M+H]+: 247.1693. Found:
247.1691.
This work has been supported by the National Science Foundation,
Grants CHE-1362281 and CHE-1531620. We thank Dr. Ritwika
Ray and Dr. Pavankumar Gangireddy for their early contributions
to the project.
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Mukaiyama, T., Oxidation-Reduction Condensation. Angew.
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A mixture of methyl-4-hydroxybenzoate (15 mg, 0.099
mmol), diselenide 1 (32 mg, 0.049 mmol), 4-dimethyla-
minopyridine (1.0 mg, 0.001 mmol), and 4 Å molecular
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= 6.9 Hz, 1H), 3.20 (t, J = 6.8 Hz, 1H), 3.14, 2.91 (s, 3H,
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2H), 7.27 (XX’ of AA’XX’, 2H), 4.22 (dqd, J = 8.2, 7.1,
2.0 Hz, 4H), 3.90 (s, 3H), 1.35 (td, J = 7.1, 1.1 Hz, 6H).
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6.89. IR (CDCl3, cm-1): 1721. HRMS (ESI) Calcd for
C12H18O6P [M+H]+: 289.0836. Found: 289.0832.
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ASSOCIATED CONTENT
Supporting Information
1H and 13C{1H} spectra are provided (pdf file) free of charge via
the Internet at http://pubs.acs.org.
16.
Akondi, S. M.; Gangireddy, P.; Pickel, T. C.; Liebeskind, L. S.,
Aerobic, Diselenide-Catalyzed Redox Dehydration: Amides and Peptides.
Org. Lett. 2018, 20 (3), 538-541.
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Synthesis of Carboxylic Acid Esters. In Carboxylic Acid. Key Role in Life
Sciences, Badea, G. I.; Radu, G. L., Eds. Intech Open: 2018; Vol.
https://www.intechopen.com/books/carboxylic-acid-key-role-in-life-
sciences/recent-advances-in-the-synthesis-of-carboxylic-acid-esters.
The Supporting Information is available free of charge on the ACS
Publications website.
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Taniguchi, T.; Hirose, D.; Ishibashi, H., Esterification via Iron-
Catalyzed Activation of Triphenylphosphine with Air. ACS Catal. 2011, 1
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AUTHOR INFORMATION
19.
Spivey, A. C.; Arseniyadis, S., Amine, Alcohol and Phosphine
Corresponding Author
* Professor Lanny S. Liebeskind, Email: chemLL1@emory.edu.
Catalysts for Acyl Transfer Reactions. In Asymmetric Organocatalysis,
List, B., Ed. Springer Berlin Heidelberg: Berlin, Heidelberg, 2009; Vol.
291, pp 233-280.
Present Addresses
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Westheimer, F. H.; Huang, S.; Covitz, F., Rates and
Mechanisms of Hydrolysis of Esters of Phosphorous Acid. J. Am. Chem.
Soc. 1988, 110, 181-185.
† Department of Organic Synthesis & Process Chemistry,
CSIR−Indian Institute of Chemical Technology, Hyderabad-
500007, India
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Author Contributions
Basic Carbodiimides in Peptide Synthesis. J. Org. Chem. 1956, 21, 439-
441.
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the manu-
script. /
23.
Gangireddy, P.; Patro, V.; Lam, L.; Morimoto, M.; Liebeskind,
L. S., Mechanism of Acylative Oxidation-Reduction-Condensation
Reactions Using Benzoisothiazolones as Oxidant and Triethylphosphite as
Stoichiometric Reductant. J. Org. Chem. 2017, 82 (7), 3513-3529.
ACKNOWLEDGMENT
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