Bio-Based Amides from Renewable Isosorbide by a Direct and Atom-Economic Boric Acid Amidation Methodology

Article abstract of DOI:10.1002/ejoc.201600186

The functionalization of bio-sourced isohexides has proved challenging over the last number of years, especially in polymer and medicinal chemistry. We report herein the synthesis of bio-based amido-isohexides by the known boric acid catalysed amidation reaction. The coupling reaction was successfully performed with aliphatic and aromatic carboxylic acids. The extension of the scope of the reaction to eight Boc-protected amino acids is also described, the products being obtained in moderate to good yields. A preliminary screening of these new potential organocatalysts was carried out for the aldolization of isatin. We describe herein the formation of the amide bond between amines derived from dianhydrohexitols and carboxylic or amino acids mediated by a catalytic quantity of boric acid.

Full text of DOI:10.1002/ejoc.201600186

DOI: 10.1002/ejoc.201600186
Full Paper
Amidation of Isohexides
Bio-Based Amides from Renewable Isosorbide by a Direct and
Atom-Economic Boric Acid Amidation Methodology
Marine Janvier,[a] Sylvie Moebs-Sanchez,*[a] and Florence Popowycz*[a]
Abstract: The functionalization of bio-sourced isohexides has The extension of the scope of the reaction to eight Boc-pro-
proved challenging over the last number of years, especially in
polymer and medicinal chemistry. We report herein the synthe-
sis of bio-based amido-isohexides by the known boric acid cata-
lysed amidation reaction. The coupling reaction was success-
fully performed with aliphatic and aromatic carboxylic acids.
tected amino acids is also described, the products being ob-
tained in moderate to good yields. A preliminary screening of
these new potential organocatalysts was carried out for the al-
dolization of isatin.
Introduction
hexides make them attractive as chiral auxiliaries[5] or chiral li-
gands.[6] Challenging applications in organocatalysis have also
been explored through the synthesis of chiral ammonium/imid-
azolium ionic liquids,[7] phase-transfer catalysts[8] and more re-
cently thioureas or imines.[9]
Biomass represents an attractive renewable resource for an al-
ternative production of chemicals and high-value-added mol-
ecules. As a continuation of on-going projects in the field of
green and sustainable chemistry, the chemical transformation
of bio-sourced molecules represents a challenge that still de-
mands attention. Isosorbide, a chiral dianhydrohexitol, is a ma-
jor product of the starch industry produced by Roquette Frères
(Lestrem, France), which expanded its production to several
thousands of tons in 2015. This renewable platform molecule is
produced from
process.
D-sorbitol, following a double dehydration
Figure 1. Structures of isosorbide and main diastereoisomers.
The two hydroxy groups display different reactivity due to
the geometry of the molecule. The hydroxy group at C-6 has
an exo configuration, pointing outwards from the cycle,
whereas the hydroxy group at C-3 with an endo configuration
points inwards (Figure 1). A hydrogen bond between the endo-
hydroxy group and the endocyclic oxygen atom also influences
the geometry of the isosorbide, increasing the steric hindrance
at the endo-hydroxy group. Two other diastereoisomers com-
plete the family of 1,4:3,6-dianhydrohexitols: isomannide, the
endo/endo isomer, and isoidide, the exo/exo isomer, derived
With our aim of inducing enantioselectivity mediated by iso-
hexide derivatives as an alternative to other organocatalysts de-
rived from the carbohydrate chiral pool,[10] the 1,2-diamino
moiety appears to be a valuable target that could be intro-
duced by the coupling of amino acids to amino isohexides. Nev-
ertheless, there are only a few reports of the formation of an
amide bond on an isohexide scaffold using ꢀ-amino acids (with
DCC, DMAP or EDCI, HOBt),[11] acid chlorides (with triethyl-
amine, DMAP),[12] symmetric anhydrides or oxazolones (by ring-
opening in an Erlenmeyer–Plöchl reaction).[13] The amide bond,
present in about 25 % of the top-selling pharmaceuticals, is
largely formed by classical coupling reactions between amines
and carboxylic acids or their derivatives (acyl chlorides, anhy-
drides or esters).[14] Recently, alternative strategies have been
developed using alcohols or aldehydes (oxidative amidation)[15]
and considerable effort is still being made to develop more
convenient procedures suitable for industrial applications. Most
of the well-established methods, which use a coupling agent
(EDC, DCC, HOBt), are relatively inefficient with large quantities
of potentially hazardous waste products being produced, lead-
ing to difficulties in the purification of the desired amide prod-
ucts.[16] More recently, the discovery of effective catalysts
(ZrCl4,[17] [ZrCp2Cl2],[18] [Hf(Cp)2Cl2],[19] silica gel,[20] triphenyl-
phosphine[21]) for the direct amidation of carboxylic acids has
from
D-mannitol and L-iditol, respectively (Figure 1). Readily
available and inexpensive isosorbide and isomannide have
been used as starting materials for the preparation of mono-
mers for the production of various copolymers[1] as well as
pharmaceutical compounds[2] such as Xa inhibitors,[3] vasodilat-
ors or drugs treating vascular diseases, for example, isosorbide
dinitrate, which is marketed under the trademark Isordil®.[4] The
spatial arrangement combined with the intrinsic rigidity of iso-
[a] Université Lyon1, CNRS, INSA, CPE-Lyon, ICBMS, UMR 5246, Equipe Chimie
Organique et Bioorganique,
20 Avenue Albert Einstein, 69621 Villeurbanne Cedex, France
E-mail: florence.popowycz@insa-lyon.fr
http://www.icbms.fr/cob
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600186.
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led to processes that offer increased efficiency.[22] All these cata- placement of the leaving group by sodium azide was per-
lysts have been used for the coupling of simple aliphatic carb- formed efficiently despite requiring a high temperature and a
oxylic acids or benzoic acids with benzylamine, aniline and long reaction time. Compound 2 was then submitted to
simple aliphatic amines. Adolfsson[17,19] and Mecinović[18] and hydrogenation under an atmospheric pressure of H2 in the pres-
their co-workers extended the methodology to amino acids. ence of 10 mol-% of Pd/C (10 %), allowing chemoselective hy-
Notably, the work carried out by Adolfsson involved the use of drogenolysis to afford 3 in 98 % yield without any trace of the
ZrCl4 in THF at reflux and more recently [Hf(Cp)2Cl2] at room debenzylated product.
temperature.
A mixture of the amine 3 and p-toluic acid (1.5 equiv.) was
The ability of boric acid or boronic acids to promote direct heated at reflux in toluene in a Dean–Stark apparatus with dif-
amidation reactions has also been known for a long time,[23] ferent amounts of boric acid ranging from 0 to 30 mol-%
but it has become frequently used only in recent years.[24] Boric (Table 1). In the absence of catalyst, no trace of amide was
acid, as a cheap, readily available, stable reagent, has attracted detected, whereas an excellent isolated yield of 93 % was ob-
our attention as a sustainable resource for amidation reactions. tained for the highest load of boric acid.
An additional benefit of the use of this substrate stems from a
Table 1. Optimization of the amount of boric acid required for the amidation
simple purification procedure with easy removal by basic aque-
ous workup. A literature survey of the reports from international
of 3.[a]
laboratories disclosed a few examples of enantiopure sub-
strates, but in most cases with laboratory-prepared synthetic
catalysts, which thus require additional synthetic steps. As an
example, the coupling of N-Boc-alanine with benzyl-
amine was performed with B(OMe)3 or synthetic B(OCH2CF3)3
to give product yields of 49 and 81 %, respectively, with low
levels of racemization.[24c] Hall and co-workers also reported the
Entry
Boric acid [mol-%]
Reaction time [h]
Yield [%]
amidation of (S)-ibuprofen with benzylamine using substituted
phenylboronic acids.[24d] Recent and efficient applications in di-
peptide synthesis have been reported by Whiting and co-work-
ers using the more expensive 3,4,5-trifluorophenylboronic
acid.[24k] Today, economic and environmental guidelines and re-
strictions have had a significant influence on the evolution of
synthetic strategies. Anticipation of the real chances of a poten-
tial industrialization is now, at least, considered earlier in the
process, which argues in favour of the use of boric acid, albeit
toxic, in the synthesis of active pharmaceutical ingredients.[24b]
Considering all the criteria, we decided to combine the well-
known boric acid methodology with the original reactivity of
isohexide substrates for direct access to novel structures based
on the isohexide skeleton with convenient purification proce-
dures.
1
2
3
4
0
72
24
24
24
–
<10
78
10
20
30
93
[a] Reagents and conditions: amine 3 (100 mg, 0.43 mmol, 1 equiv.), p-toluic
acid (0.65 mmol, 1.5 equiv.), boric acid (x mol-%), toluene, azeotropic distilla-
tion in a Dean–Stark apparatus.
The relative stoichiometry of amine and carboxylic acid in
the reaction was then investigated (Table 2). A molar equivalent
of p-toluic acid only led to partial conversion and a modest
isolated yield of 49 %. Using 1.2 equiv. increased the yield to
75 %, but the best results were still obtained with 1.5 equiv. of
the carboxylic acid. As a simple basic workup allowed the easy
removal of excess acid, the crude product could be obtained
1
with quite good H NMR purity.
Table 2. Optimization of the stoichiometric ratio of substrates in the amid-
Results and Discussion
ation of 3.[a]
6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-amine (3) was first
chosen as a model substrate, synthesized in four steps from
isosorbide (Scheme 1). Following the conditions previously de-
veloped by Loupy and co-workers (CsOH, BnCl, 80 °C, water,
72 h),[25] isosorbide was converted into monobenzylated com-
pound 1, isolated in 28 % yield by simple crystallization on a
10 gram scale. After tosylation under classical conditions, dis-
Entry
p-Toluic acid [equiv.]
Yield [%]
1
2
1
1.0
1.2
1.5
49
75
93
[a] Reagents and conditions: amine 3 (100 mg, 0.43 mmol, 1 equiv.), p-toluic
acid (x equiv.), boric acid (30 mol-%), toluene, azeotropic distillation in a
Dean–Stark apparatus, 48 h.
Scheme 1. Synthesis of amine model substrate 3.
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Other drying agents (magnesium sulfate, sodium sulfate or factory purity, probably due to its well-known tendency to
4 Å molecular sieves) were tested instead of the Dean–Stark polymerize.
apparatus. Under these conditions the amide bond was barely
or not detected. In some attempts, MgSO4 did provide the ex-
pected compound, but there were significant problems with
reproducibility.
With the goal of designing original organocatalysts, we then
focused on coupling reactions with amino acids (Table 3). This
would offer access to original diamino derivatives based on the
isohexide scaffold as promising candidates for amino organoca-
The scope of the boric acid catalysed amidation was next talysis. However, the methodology had to be tested for the pos-
investigated by studying the reaction of the model substrate sible racemization suffered by other classical methods.
3 with a range of aliphatic and aromatic carboxylic acids; the
Table 3. The boric acid-catalysed coupling of isohexide with N-Boc amino
acids.
corresponding amides 5–18 were obtained in isolated yields of
76–96 % (Figure 2).
The reaction conditions could be successfully applied to a
wide range of benzoic acids substituted at the ortho, meta and
para positions. The amidation was compatible with an aromatic
halogen substituent (7–9) without a significant decrease in the
yield. Poor electron-donating groups, such as methyl (4, 5, 10),
and strong electron-withdrawing nitro groups (11), were well
tolerated. However, 4-hydroxybenzoic acid was coupled with
compound 3 to give an isolated yield of only 17 %. The reac-
tions with benzyloxybenzoic acid and 2-amino-3-methylbenzoic
acid were not successful, with only traces of the corresponding
amides detected and conversions of less than 5 %, even after
48 h. According to these preliminary results, the use of strong
electron-donating substituents on the phenyl ring seems to
prevent the coupling reaction. Heteroaromatic indole-2-carb-
oxylic acid and cinnamic acid were used to give 12 and 13 in
Entry
Amino acid
Boc- -proline
Boc-glycine
Product
Isolated yield [%]
1
2
3
4
5
6
7
8
L
19
20
21
22
23
24
25
26
85
71
69
72
67
64
34
38
Boc-
Boc-
Boc-
Boc-
Boc-
Boc-
L
-leucine
-phenylalanine
-serine
-serine
-valine
-valine
L
D
L
L
D
Boc-L-proline was first introduced with an excellent 85 %
yields of 77 and 85 %, respectively. The scope of the reaction yield (19). The methodology was then successfully extended
was also successfully extended to aliphatic carboxylic acids. The to Boc-glycine, Boc- -leucine, Boc- -phenylalanine, Boc- -serine
treatment of 3 with butyric, isobutyric and isovaleric acids con- and Boc- -serine to yield 20–24, respectively, with the yields
L
L
D
L
firmed the robustness of the protocol with excellent isolated ranging from 64 to 72 %. These lower yields could in part be
yields of 14–16 (86, 96 and 89 %, respectively). The reaction explained by the difficult purification of the highly polar final
with cyclohexanecarboxylic acid or 4-phenylbutyric acid also products, as their crude yields were good. L- and D-Valine were
afforded the amides 17 and 18 in excellent yields. Acrylic acid also coupled with 3 to yield 25 and 26, albeit in modest iso-
was coupled in a moderate yield of 39 %, but with an unsatis- lated yields of 34 and 38 %, respectively. This series of products
Figure 2. Scope of the boric acid catalysed amidation with respect to carboxylic acid structure.·Reagents and conditions: amine 3 (100 mg, 0.43 mmol,
1 equiv.), carboxylic acid (1.5 equiv.), boric acid (30 mol-%), toluene, azeotropic distillation in a Dean–Stark apparatus, 24 h.
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offers a very interesting, diverse functionalization for future
screening as organocatalysts precursors. As expected, a direct
attempt to couple a non-protected amino acid led to the com-
plete recovery of the starting material.
Careful examination of the NMR spectra did not show any
evidence of racemization, except for compounds 23 and 24, for
which a splitting of signals is perceptible in their 13C NMR spec-
tra (in both cases, racemization was evaluated to be 10 %). In
2015, Lundberg and Adolfsson reported no reaction with Boc-
protected valine, or isoleucine with the [HfCp2Cl2] catalyst, even
after different modification of the reaction parameters.[19]
We then examined the influence of the substrate scaffold by
investigating the reactions of the new and known mono amines
27 and 28[11] and diamine 29,[26] each synthesized from iso-
mannide (in four steps for 27 and 28, and in three steps for
29). They were coupled with p-toluic acid under the optimized
conditions to give the products 30–32 in moderate to good
yields (61–80 %; Table 4).
Figure 3. Less or unreactive substrates.[27] [a] Isolated yields in amide prod-
ucts.
through the reaction of acetone with isatin (37) (Scheme 2). Ten
potential organocatalysts were evaluated under the following
conditions, a mixture of acetone/water (80:20) with a 10 mol-%
loading of organocatalyst in the presence of dinitrophenol
(DNP) as additive (20 mol-%). The development of the boric
acid methodology with the isohexide substrate 3 has provided
a family of amido acids, which, upon deprotection (HCl, DCM),
provided prospective organocatalysts quantitatively. The prod-
uct of the reaction with leucinamide 36, derived from 21, was
identified as the first promising hit, with the product obtained
in 73 % yield and 33 % ee in favour of the R isomer. To confirm
both the importance of the isohexide skeleton and the amide
Table 4. Influence of the isohexide configuration.[a]
bond, the reaction of L-leucine was tested without success: the
racemate was obtained in only 10 % yield. Studies specifically
concerning asymmetric synthesis are currently under investiga-
tion.
[a] Reagents and conditions: isohexide derivative (1 equiv.), p-toluic acid (1.5
or 3 equiv. for entry 3), boric acid (30 mol-%), toluene, azeotropic distillation
in a Dean–Stark apparatus, 24 h.
Despite these encouraging results, some derivatives re-
mained unreactive under our experimental conditions.
exo/endo-Diamine 33[26] reacted with p-toluic acid to give a
poor yield of 18 %. No significant yield was obtained from the
new mono amino ether 34 either. The presence of a hydrogen
bond between the endo NH2 and the endocyclic oxygen of the
furanyl ring could explain this lack of reactivity. The starting
compound 35,[8] with a secondary amine, was completely re-
covered (Figure 3).
Scheme 2. Preliminary result of the screening of the laboratory-prepared iso-
hexide organocatalysts in the aldolization reaction of acetone with isatin.
Conclusions
We have proved the successful application of the boric acid
catalysed peptidic coupling methodology to amino/diamino
These laboratory-prepared organocatalysts were evaluated in isohexide derivatives. A broad range of carboxylic acids and
an asymmetric aldol reaction, performed in accordance with amino acids could thus be introduced into the isohexide skele-
the sustainable philosophy of our projects, targeting some of ton in good to excellent yields, leading to a variety of new
the 12 principles of green chemistry of Anastas and Warner:[28] functionalized isohexide derivatives. This undoubtedly enriches
the use of bio-sourced isohexides as organocatalyst (Princi- the chemical library for this scaffold and opens the way for
ple 7), atom economy (Principle 2) and catalysis (Principle 9). future investigation of its under-exploited potential as a chiral
Thus, we wished to explore for the first time the potential of inducer. Some success has been achieved by using our organo-
highly functionalized isohexides in asymmetric synthesis catalyst 36 in asymmetric synthesis.
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under reduced pressure. The resulting oil was dissolved in water
(100 mL) and EtOAc (150 mL). After extraction with EtOAc (4 ×
150 mL), the combined organic phases were dried with Na2SO4,
filtered and concentrated. The resulting yellow oil was purified by
flash chromatography using petroleum ether/ethyl acetate (7:3) as
Experimental Section
General: Reagents and solvents were obtained from Aldrich, Acros,
Lancaster, Alfa Aesar, Fluka or TCI and purchased at the highest
commercial quality to be used without further purification. NMR
spectra were recorded with Bruker 300 (1H: 300 MHz; 13C: 75 MHz),
400 (1H: 400 MHz; 13C: 100 MHz), or 500 (1H: 500 MHz; 13C: 125 MHz)
spectrometers at 293 K using CDCl3, CD3OD and [D6]DMSO as sol-
vents. The chemical shifts (δ) are referenced to the residual solvent
peak and coupling constants (J) are reported in the standard fash-
ion. The following abbreviations are used to denote the multiplici-
ties: s = singlet, d = doublet, t = triplet, q = quadruplet, quint. =
quintuplet, sext = sextuplet, sept = septuplet, m = multiplet, br. =
broad. Electrospray ionization (ESI) mass spectrometry (MS) was
performed with a Thermo Finnigan LCQ Advantage mass spectrom-
eter. High-resolution mass spectra (HRMS) were recorded with a
Finnigan Mat 95xL mass spectrometer using the electrospray tech-
nique. Analytical TLC was carried out on silica gel Merck 60 D254
(0.25 mm). Flash chromatography was performed on Merck Si 60
silica gel (40–63 μm). IR spectra were recorded with an IRAffinity-1
Shimadzu spectrometer using attenuated total reflectance (ATRMir-
acle). Optical rotations were measured with a Perkin–Elmer 241 or
Jasco P1010 polarimeter with a 10 cm cell (concentration c ex-
pressed as g/100 mL). Melting points were measured by using a
Büchi B-540 apparatus.
eluent to give compound 2 as a colourless oil (2.29 g, 73 %). [α]D23
+39.5 (c = 1.12, CHCl3). IR (ATR): ν = 2947, 2876, 2102, 1718, 1454,
=
˜
1
3
1263, 1082 cm–1. H NMR (400 MHz, CDCl3): δ = 3.85 (dd, J5H,6H
=
2
3
2
4.1, J = 10.1 Hz, 1 H, 5-H), 3.87 (dd, J2H,3H = 3.7, J = 10.4 Hz, 1 H,
2-H), 3.93 (dd, J2′H,3H = 1.6, 2J = 10.4 Hz, 1 H, 2′-H), 3.95 (dd,
3
3J5′H,6H = 1.7, J = 10.1 Hz, 1 H, 5′-H), 4.03 (br. d, J3H,2H = 3.7 Hz, 1
2
3
3
2
H, 3-H), 4.08 (br. d, J6H,5H = 4.1 Hz, 1 H, 6-H), 4.59 (AB system, J =
3
11.8 Hz, 2 H, CH2Ph), 4.66 (d, J3aH,6aH = 3.9 Hz, 1 H, 3a-H), 4.69 (d,
3J6aH,3aH = 3.9 Hz, 1 H, 6a-H), 7.29–7.38 (m, 5 H, HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 65.8 (C-3), 71.5 and 71.7 (C-2, CH2Ph), 72.8
(C-5), 82.9 (C-6), 85.8 (C-6a), 86.0 (C-3a), 127.9 (2 CHAr), 128.1 (CHAr),
128.7 (2 CHAr ), 137.5 (Cq, A r) ppm. HMRS (ESI): calcd. for
C
13H15N3NaO3 [M + Na]+ 284.1006; found 284.1008.
(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
amine (3): Compound 2 (500 mg, 1.91 mmol) was dissolved in
anhydrous methanol (40 mL) under argon before adding Pd/C
(10 %) (50 mg, 0.1 mass. equiv.). After three vacuum–argon cycles
and three vacuum–hydrogen cycles, the suspension was stirred at
room temperature under an atmospheric pressure of H2. After 20 h,
the reaction mixture was filtered through Celite® and then washed
three times (3 × 30 mL) with methanol. After concentration, the
residue was purified by short-column flash chromatography using
dichloromethane/methanol (9:1) as eluent to give 3 as a colourless
(3R,3aR,6S,6aR)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-ol
(1): A solution of CsOH (50 % in water) (11.7 mL, 67 mmol, 1 equiv.),
followed by benzyl chloride (7.72 mL, 67 mmol, 1 equiv.) after com-
plete solubilization, were added to a solution of isosorbide (10 g,
67 mmol, 1 equiv.) in water (30 mL). The biphasic reaction mixture
was stirred at 80 °C for 3 d. After completion, the pH was neutral-
oil (444 mg, 98 %). [α]D22 = +15.9 (c = 1.00, CHCl3). IR (ATR): ν = 3356,
˜
2933, 2870, 1670, 1454, 1365, 1072 cm–1. 1H NMR (300 MHz, CDCl3):
3
δ = 1.68 (br. s, 2 H, NH2), 3.52 (d, J3H,2′H = 4.1 Hz, 1 H, 3-H), 3.65
ized with 2 HCl
N until pH 1. The aqueous phase was extracted with
3
2
3
3
(dd, J2H,3H = 1.1, J = 9.5 Hz, 1 H, 2-H), 3.86 (dd, J2′H,3H ≈ J5H,6H
=
EtOAc (3 × 150 mL). The organic phases were combined, dried with
Na2SO4, filtered and concentrated. The resulting yellow solid was
washed with cold Et2O and filtered to give compound 1 as a white
solid (7.31 g, 28 %), m.p. 97–99 °C (Et2O). [α]D23 = +28.5 (c = 0.52,
4.1, 2J ≈ 2J = 9.5 Hz, 2 H, 2′-H, 5-H), 3.91 (dd, J5H,6H = 2.4, 2J =
3
3
10.1 Hz, 1 H, 5′-H), 4.06 (m, 1 H, 6-H), 4.42 (d, J3aH,6aH = 3.9 Hz, 1
H, 3a-H), 4.59 (AB system, 2J = 11.9 Hz, 2 H, CH2Ph), 4.71 (d,
3J6aH,3aH = 3.9 Hz, 1 H, 6a-H), 7.29–7.39 (m, 5 H, HAr) ppm. 13C NMR
(75 MHz, CDCl3): δ = 57.8 (C-3), 71.5 (CH2Ph), 72.3 (C-5), 74.7 (C-2),
83.1 (C-6), 85.3 (C-6a), 89.3 (C-3a), 127.7 (2 CHAr), 127.9 (CHAr), 128.5
(2 CHAr), 137.6 (Cq,Ar) ppm. HRMS (ESI): calcd. for C13H18NO3 [M +
H]+ 236.1281; found 236.1283.
CHCl3). IR (ATR): ν = 3417, 2907, 1452, 1425, 1400, 1317, 1109, 1066,
˜
1041, 738 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.70 (d, JOH,3H
=
3
3
2
7.1 Hz, 1 H, OH), 3.55 (dd, J2H,3H = 5.9, J = 9.4 Hz, 1 H, 2-H), 3.85
(dd, J2′H,3H = 5.9, J = 9.4 Hz, 1 H, 2′-H), 3.89 (dd, 3J5H,6H = 3.9, J =
10.1 Hz, 1 H, 5-H), 4.09 (br. d, 2J = 10.1 Hz, 1 H, 5′-H), 4.12 (br. d,
3J6H,5H = 3.9 Hz, 6-H), 4.28 (m, 1 H, 3-H), 4.52 (d, J6aH,3aH = 4.5 Hz, 1
H, 6a-H), 4.58 (AB system, 2J = 11.9 Hz, 2 H, CH2Ph), 4.63 (app. t,
3
2
2
Representative Procedure for Boric Acid Catalysed Amidation
Reaction: Carboxylic acid (1.5 equiv.) and then boric acid
3J3aH,6aH 3J3aH,3H = 5 Hz, 1 H, 3a-H), 7.28–7.38 (m, 5 H, HAr) ppm.
,
(0.3 equiv.) were added to a 0.085
M
solution of 3 (100 mg,
13C NMR (100 MHz, CDCl3): δ = 71.7 (CH2Ph), 72.3 (C-3), 73.5 (C-5),
73.7 (C-2), 81.9 (C-3a), 83.6 (C-6), 86.1 (C-6a), 127.8 (2 CHAr), 128.1
(CHAr), 128.6 (2 CHAr), 137.6 (Cq,Ar) ppm. HRMS (ESI): calcd. for
C13H16NaO4 [M + Na]+ 259.0941; found 259.0936.
0.425 mmol) in toluene. After azeotropic distillation for 24 h in a
Dean–Stark apparatus, the mixture was diluted in ethyl acetate
(80 mL) and water (50 mL). After extraction with EtOAc (3 × 60 mL),
the organic phase was washed with a saturated solution of NaHCO3
(2 × 50 mL) and brine (50 mL), and then dried with Na2SO4. After
filtration and concentration, the crude residue was purified by flash
chromatography on silica gel.
(3S,3aR,6S,6aR)-3-Azido-6-benzyloxyhexahydrofuro[3,2-b]furan
(2): A solution of 1 (4.57 g, 19.33 mmol) and tosyl chloride (4.06 g,
21.3 mmol, 1.1 equiv.) in anhydrous pyridine (20 mL) was stirred at
room temperature for 16 h under argon. After completion, the reac-
tion mixture was acidified with HCl (2
M
) until pH 1. After the addi-
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
yl]-4-methylbenzamide (4): The general procedure was followed
using 4-methylbenzoic acid (87 mg, 0.638 mmol, 1.5 equiv.) to give
a brown solid (144 mg, 96 % crude yield). The crude product was
tion of water (75 mL), the aqueous phase was extracted with EtOAc
(3 × 150 mL). The combined organic phases were dried with
Na2SO4, filtered and concentrated. The resulting colourless oil was
purified by flash column chromatography in pentane/EtOAc (6:4) to purified by flash chromatography using petroleum ether/ethyl acet-
give the tosylate intermediate as a white solid (6.84 g, 17.5 mmol, ate (1:1) as eluent to afford compound 4 as a white solid (140 mg,
94 %). Sodium azide (2.35 g, 36 mmol, 3 equiv.) was added to a
solution of the tosylate (4.69 g, 12 mmol, 1 equiv.) in anhydrous
DMF (40 mL) under argon and the suspension was stirred at 140 °C
for 3 d. After completion, the mixture was cooled to room tempera-
ture, water was added (10 mL) and the mixture was concentrated
93 %), m.p. 140–142 °C (Et2O). [α]D22 = +29.6, (c = 1.02, CHCl3). IR
(ATR): ν = 3302, 2943, 2872, 1631, 1537, 1502, 1454, 1284,
˜
1078 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.39 (s, 3 H, CH3), 3.87
(dd, 3J2H,3H = 1.5, 2J = 9.7 Hz, 1 H, 2-H), 3.94 (m, 2 H, 5-H, 5′-H), 4.00
(dd, J2′H,3H = 4.4, J = 9.7 Hz, 1 H, 2′-H), 4.10 (t, J6H,5H ≈ J6H,5′H
3
2
3
3
=
Eur. J. Org. Chem. 2016, 2308–2318
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2312 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3
3
3.6 Hz, 1 H, 6-H), 4.58 (AB system, 2J = 11.8 Hz, 2 H, CH2Ph), 4.62 3J6aH,6H = 1.0, J6aH,3aH = 4.1 Hz, 1 H, 6a-H), 4.74 (app. d, J3aH,6aH
=
3
3
3
(m, 1 H, 3-H), 4.68 (dd, J6aH,6H = 1.0, J6aH,3aH = 4.2 Hz, 1 H, 6a-H),
4.1 Hz, 1 H, 3a-H), 6.14 (d, JNH,3H = 7.4 Hz, 1 H, NH), 7.25–7.37 (m,
3
3
4
3
4.70 (d, J3aH,6aH = 4.2 Hz, 1 H, 3a-H), 6.17 (d, JNH,3H = 7.1 Hz, 1 H,
7 H, HAr), 7.54 (dd, J = 1.8, J = 7.6 Hz, 1 H, HArortho-C=O), 7.58 (dd,
4J = 1.1, 3J = 8.0 Hz, 1 H, HArortho-Br) ppm. 13C NMR (100 MHz, CDCl3):
δ = 56.8 (C-3), 71.8 (CH2Ph), 72.0 (C-2), 72.6 (C-5), 83.3 (C-6), 86.1
(C-6a), 86.3 (C-3a), 119.3 (Cq,Ar-Br), 127.8 (CHAr), 127.9 (2 CHAr), 128.1
(CHAr), 128.7 (2 CHAr), 130.0 (CHAr), 131.7 (CHAr), 133.5 (CHAr), 137.2
NH), 7.22–7.24 (d, 3J = 7.9 Hz, 2 H, HAr), 7.27–7.38 (m, 5 H, HAr),
3
7.63–7.65 (d, J = 7.9 Hz, 2 H, HAr) ppm. 13C NMR (75 MHz, CDCl3):
δ = 21.6 (CH3), 56.7 (C-3), 71.7 (CH2Ph), 72.4 and 72.5 (C-2, C-5), 83.3
(C-6), 86.0 (C-6a), 86.6 (C-3a), 127.1 (2 CHAr), 127.8 (2 CHAr), 128.0
(CHAr), 128.7 (2 CHAr), 129.4 (2 CHAr), 131.2 (Cq,Ar), 137.6 (Cq,Ar), 142.4 (Cq,Ar), 137.6 (Cq,Ar), 167.1 (C=O) ppm. HRMS (ESI): calcd. for
(Cq,Ar), 167.1 (C=O) ppm. HRMS (ESI): calcd. for C21H23NNaO4 [M +
C20H20BrNNaO4 [M + Na]+ 440.0468; found 440.0458.
Na]+ 376.1519; found 376.1519.
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
yl]-2-iodobenzamide (8): The general procedure was followed us-
ing 2-iodobenzoic acid (158 mg, 0.638 mmol, 1.5 equiv.) to give a
brown oil (198 mg, 99 % crude yield). The crude residue was puri-
fied by flash chromatography using pentane/ethyl acetate (1:1) as
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
yl]-2-methylbenzamide (5): The general procedure was followed
using 2-methylbenzoic acid (87 mg, 0.638 mmol, 1.5 equiv.) to give
a brown oil purified by flash chromatography using pentane/ethyl
acetate (1:1) as eluent to give 5 (pale-yellow solid, 122 mg, 82 %), eluent to give 8 (white solid, 187 mg, 94 %), m.p. 91–92 °C (iPr2O).
m.p. 104–106 °C (Et2O). [α]22 = +30.1 (c = 0.99, CHCl3). IR (ATR): ν = [α]D22 = +9.4 (c = 1.07, CHCl3). IR (ATR): ν = 3266, 2952, 2868, 1642,
˜
˜
D
3277, 3258, 2926, 2854, 1633, 1532, 1453, 1325, 1205, 1099, 1079,
1586, 1535, 1454, 1320, 1078, 1016, 909, 841, 734 cm–1
.
1H NMR
1057, 1047, 959, 904, 798, 758 cm–1. 1H NMR (400 MHz, CDCl3): δ = (400 MHz, CDCl3): δ = 3.90 (dd, J2H,3H = 1.4, J = 9.8 Hz, 1 H, 2-H),
3
2
2.43 (s, 3 H, CH3), 3.84 (dd, 3J2H,3H = 1.3, 2J = 9.7 Hz, 1 H, 2-H), 3.90–
3.91–3.93 (m, 2 H, 5-H, 5′-H), 3.96 (dd, J2′H,3H = 4.2, J = 9.8 Hz, 1
3
2
3
2
3
3
3.94 (m, 2 H, 5-H, 5′-H), 3.98 (dd, J2′H,3H = 4.4, J = 9.7 Hz, 1 H, 2′-
H, 2′-H), 4.08 (app. t, J6H,5H ≈ J6H,5′H = 3.3 Hz, 1 H, 6-H), 4.58 (s, 2
H), 4.08 (app. t, 3J6H,5H ≈ 3J6H,5′H = 3.1 Hz, 1 H, 6-H), 4.58 (AB system, H, CH2Ph), 4.60–4.63 (m, 1 H, 3-H), 4.67 (dd, 3J6aH,6H = 0.9, 3J6aH,3aH
=
2J = 12.1 Hz, 2 H, CH2Ph), 4.59–4.61 (m, 1 H, 3-H), 4.63 (d, 3J6aH,3aH
=
4.1 Hz, 1 H, 6a-H), 4.78 (app. d, J3aH,6aH = 4.1 Hz, 1 H, 3a-H), 5.92
(d, JNH,3H = 7.6 Hz, 1 H, NH), 7.08–7.12 (m, 1 H, HAr), 7.28–7.40 (m,
3
3
3
4.1 Hz, 1 H, 6a-H), 4.68 (d, J3aH,6aH = 4.1 Hz, 1 H, 3a-H), 5.88 (d,
3JNH,3H = 7.2 Hz, 1 H, NH), 7.17–7.24 (m, 2 H, HAr), 7.28–7.38 (m, 7 7 H, HAr), 7.84 (d, 3J = 7.8 Hz, 1 H, HAr) ppm. 13C NMR (100 MHz,
H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.9 (CH3), 56.6 (C-3), CDCl3): δ = 56.8 (C-3), 71.8 (CH2Ph), 72.0 (C-2), 72.6 (C-5), 83.4 (C-6),
71.8 (CH2Ph), 72.4 and 72.5 (C-2, C-5), 83.3 (C-6), 86.0 (C-6a), 86.6
86.1, 86.2 (C-3a, C-6a), 92.5 (Cq,Ar), 127.9 (2 CHAr), 128.1 (CHAr), 128.4
(C-3a), 125.9 (CHAr), 126.8 (CHAr), 127.9 (2 CHAr), 128.1 (CHAr), 128.7 (CHAr), 128.6 (CHAr), 128.7 (2 CHAr), 131.5 (CHAr), 137.6 (Cq,Ar), 140.0
(2 CHAr), 130.3 (CHAr), 131.3 (CHAr), 135.9 (Cq,Ar), 136.3 (Cq,Ar), 137.6 (CHAr), 141.7 (Cq,Ar), 168.9 (C=O) ppm. HRMS (ESI): calcd. for C20H21I-
(Cq,Ar), 169.7 (C=O) ppm. HRMS (ESI): calcd. for C21H24NO4 [MH]+ NO4 [M + H]+ 466.0510; found 466.0507.
354.1700; found 354.1700.
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
yl]benzamide (6): The general procedure was followed using
yl]-4-bromobenzamide (9): The general procedure was followed
using 4-bromobenzoic acid (129 mg, 0.638 mmol, 1.5 equiv.) to af-
benzoic acid (78 mg, 0.638 mmol, 1.5 equiv.) to give a brown solid ford a brown solid (173 mg, 98 % crude yield). The crude product
(144 mg, 99 % crude yield). The crude product was purified by flash was purified by flash chromatography using petroleum ether/ethyl
chromatography using petroleum ether/ethyl acetate (1:1) as eluent acetate (1:1) as eluent to afford compound 9 as a white solid
to afford compound 6 (white solid, 122 mg, 85 %), m.p. 105–107 °C
(155 mg, 88 %), m.p. 166–168 °C (Et2O). [α]D22 = +27.5 (c = 1.01,
(Et2O). [α]22 = +28.7 (c = 1.01, CHCl3). IR (ATR): ν = 3302, 2929, 2872, CHCl3). IR (ATR): ν = 3292, 2941, 2872, 1635, 1589, 1535, 1481, 1271,
˜
˜
D
3
1637, 1531, 1489, 1454, 1265, 1076 cm–1. 1H NMR (400 MHz, CDCl3): 1070, 735 cm–1 1H NMR (400 MHz, CDCl3): δ = 3.86 (dd, J2H,3H
. =
3
2
2
3
2
δ = 3.87 (dd, J2H,3H = 1.5, J = 9.7 Hz, 1 H, 2-H), 3.93 (m, 2 H, 5-H,
1.4, J = 9.8 Hz, 1 H, 2-H), 3.91 (dd, J5H,6H = 4.1, J = 10.2 Hz, 1 H,
5′-H), 4.00 (dd, J2′H,3H = 4.5, 2J = 9.7 Hz, 1 H, 2′-H), 4.09 (app. t,
5-H), 3.94 (dd, J5′H,6H = 2.9, 2J = 10.2 Hz, 1 H, 5′-H), 3.99 (dd,
3
3
3J6H,5H ≈ J6H,5′H = 3.4 Hz, 1 H, 6-H), 4.58 (AB system, J = 11.9 Hz,
3J2′H,3H = 4.5, 2J = 9.8 Hz, 1 H, 2′-H), 4.09 (t, 3J6H,5H ≈ 3J6H,5′H = 3.3 Hz,
3
2
3
3
2
2 H, CH2Ph), 4.62 (m, 1 H, 3-H), 4.68 (dd, J6aH,6H = 0.8, J6aH,3aH
=
1 H, 6-H), 4.58 (AB system, J = 11.8 Hz, 2 H, CH2Ph), 4.60 (m, 1 H,
3
4.2 Hz, 1 H, 6a-H), 4.70 (d, J3aH,6aH = 4.2 Hz, 1 H, 3a-H), 6.33 (d,
3-H), 4.67 (d, 3J6aH,3aH = 4.2 Hz, 1 H, 6a-H), 4.70 (d, 3J3aH,6aH = 4.2 Hz,
3JNH,3H = 7.0 Hz, 1 H, NH), 7.28–7.37 (m, 5 H, HAr), 7.40–7.44 (m, 2 1 H, 3a-H), 6.34 (d, JNH,3H = 7.2 Hz, 1 H, NH), 7.27–7.37 (m, 5 H,
3
H, HAr), 7.48–7.52 (m, 1 H, HAr), 7.73–7.75 (m, 2 H, HAr) ppm. 13C
HAr), 7.55 (m, 2 H, HAr), 7.61 (m, 2 H, HAr) ppm. 13C NMR (100 MHz,
NMR (100 MHz, CDCl3): δ = 56.9 (C-3), 71.7 (CH2Ph), 72.3, 72.5 (C-2,
CDCl3): δ = 56.9 (C-3), 71.7 (CH2Ph), 72.2 (C-2), 72.5 (C-5), 83.2 (C-6),
C-5), 83.2 (C-6), 86.0 (C-6a), 86.6 (C-3a), 127.1 (2 CHAr), 127.8 (2 CHAr), 86.0 (C-6a), 86.5 (C-3a), 126.7 (Cq,Ar), 127.8 (2 CHAr), 128.1 (CHAr),
128.0 (CHAr), 128.6 (2 CHAr), 128.7 (2 CHAr), 131.9 (CHAr), 134.0, 137.6 128.6 (2 CHAr), 128.8 (2 CHAr), 132.0 (2 CHAr), 132.8 (Cq,Ar), 137.6
(2 Cq,Ar), 167.3 (C=O) ppm. HRMS (ESI): calcd. for C20H21NNaO4 [M (Cq,Ar), 166.4 (C=O) ppm. HRMS (ESI): calcd. for C20H20BrNNaO4 [M
+ Na]+ 362.1363; found 362.1362.
+ Na]+ 440.0468; found 440.0461.
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
yl]-2-bromobenzamide (7): The general procedure was followed
using 4-bromobenzoic acid (129 mg, 0.638 mmol, 1.5 equiv.) to give
a brown oil (170 mg, 96 % crude yield). The crude product was
purified by flash chromatography using petroleum ether/ethyl acet-
ate (1:1) as eluent to afford 7 (white solid, 154 mg, 87 %), m.p. 93–
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
yl]-3-methylbenzamide (10): The general procedure was followed
using 3-methylbenzoic acid (87 mg, 0.638 mmol, 1.5 equiv.) to give
a brown oil (149 mg). The crude residue was purified by flash chro-
matography using pentane/ethyl acetate (1:1) as eluent to give 10
(white solid, 131 mg, 88 %), m.p. 99–101 °C (Et2O). [α]D22 = +27.5 (c =
94 °C (Et2O). [α]25 = +10.3 (c = 1.18, CHCl3). IR (ATR): ν = 3321, 2930, 1.01, CHCl3). IR (ATR): ν = 3346, 3286, 2940, 2862, 1643, 1630, 1524,
˜
˜
D
2866, 1725, 1644, 1519, 1333, 1285, 1097, 1074, 1044, 923, 909, 842,
1333, 1296, 1209, 1091, 1081, 1042, 929, 813, 789, 747 cm–1
.
1H
737 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.88 (dd, 3J2H,3H = 1.2, 2J =
9.8 Hz, 1 H, 2-H), 3.92–3.93 (m, 2 H, 5-H, 5′-H), 3.97 (dd, J2′H,3H
4.3, J = 9.8 Hz, 1 H, 2′-H), 4.09 (app. t, J6H,5H ≈ J6H,5′H = 3.0 Hz, 1
NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H, CH3), 3.87 (dd, 3J2H,3H = 1.5,
2J = 9.7 Hz, 1 H, 2-H), 3.93–3.94 (m, 2 H, 5-H, 5′-H), 3.99 (dd,
3
=
2
3
3
2
3
3
3J2′H,3H = 4.4, J = 9.7 Hz, 1 H, 2′-H), 4.09 (app. t, J6H,5H ≈ J6H,5′H
=
H, 6-H), 4.58 (app. s, 2 H, CH2Ph), 4.62 (m, 1 H, 3-H), 4.65 (dd,
3.4 Hz, 1 H, 6-H), 4.58 (AB system, 2J = 11.9 Hz, 2 H, CH2Ph), 4.62
Eur. J. Org. Chem. 2016, 2308–2318
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Full Paper
3
3
(m, 1 H, 3-H), 4.68 (dd, J6aH,6H = 0.9, J6aH,3aH = 4.2 Hz, 1 H, 6a-H),
H, 2′-H), 4.08 (m, 1 H, 6-H), 4.57 (AB system, 2J = 11.9 Hz, 2 H,
3
4.70 (d, J3aH,6aH = 4.2 Hz, 1 H, 3a-H), 6.28 (d, JNH,3H = 7.2 Hz, 1 H,
CH2Ph), 4.59 (m, 1 H, 3-H), 4.67 (app. s, 2 H, 6a-H, 3a-H), 6.05 (d,
NH), 7.27–7.37 (m, 7 H, HAr), 7.50–7.53 (m, 1 H, HAr), 7.55–7.58 (m, 3JNH,3H = 7.5 Hz, 1 H, NH), 6.40 (d, JCH=CH,trans = 15.6 Hz, 1 H, C=C-
3
1 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 56.8 (C-
H), 7.27–7.36 (m, 8 H, HAr), 7.47–7.49 (m, 2 H, HAr), 7.65 (d,
3), 71.7 (CH2Ph), 72.3 (C-2), 72.5 (C-5), 83.2 (C-6), 86.0 (C-6a), 86.6 3JCH=CH,trans = 15.6 Hz, 1 H, C=C-H) ppm. 13C NMR (100 MHz, CDCl3):
(C-3a), 124.1 (CHAr), 127.8 (3 CHAr), 128.0 (CHAr), 128.6 (3 CHAr), 132.6 δ = 56.4 (C-3), 71.7 (CH2Ph), 72.3 (C-2), 72.5 (C-5), 83.2 (C-6), 85.9,
(CHAr), 134.0 (Cq,Ar), 137.6 (Cq,Ar), 138.6 (Cq,Ar), 167.5 (C=O) ppm.
86.6 (C-3a, C-6a), 120.0 (C=C), 127.8 (2 CHAr), 127.98 (2 CHAr), 128.02
(CHAr), 128.6 (2 CHAr), 129.0 (2 CHAr), 130.0 (CHAr), 134.7 (Cq,Ar), 137.7
(Cq,Ar), 142.0 (C=C), 165.6 (C=O) ppm. HRMS (ESI): calcd. for
C22H23NNaO4 [M + Na]+ 388.1519; found 388.1526.
HRMS (ESI): calcd. for C21H24NO4 [M + H]+ 354.1700; found 354.1694.
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
yl]-3,5-dinitrobenzamide (11): The general procedure was fol-
lowed using 3,5-dinitrobenzoic acid (135 mg, 0.638 mmol, N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
1.5 equiv.) to give a brown oil (206 mg). The crude product was
purified by flash chromatography using petroleum ether/ethyl acet-
ate (1:1) as eluent to afford 11 (white solid, 138 mg, 76 %), m.p.
yl]butanamide (14): The general procedure was followed using bu-
tyric acid (59 μL, 0.638 mmol, 1.5 equiv.) to give a brown oil
(127 mg, 98 % crude yield). The crude product was purified by flash
157–159 °C (Et2O). [α]22 = +26.1 (c = 0.99, CHCl3). IR (ATR): ν = 3304, chromatography using petroleum ether/ethyl acetate (3:7) as eluent
˜
D
2970, 2881, 1647, 1535, 1342, 1078, 912 cm–1
.
1H NMR (400 MHz, to afford 14 (colourless oil, 111 mg, 86 %). [α]D22 = +11.2 (c = 0.99,
CDCl3): δ = 3.91 (m, 2 H, 5-H, 5′-H), 3.94 (dd, J2H,3H = 1.6, 2J =
CHCl3). IR (ATR): ν = 3282, 2966, 2900, 1643, 1541, 1454, 1259,
3
˜
10.1 Hz, 1 H, 2-H), 4.02 (dd, J2′H,3H = 4.5, 2J = 10.1 Hz, 1 H, 2′-H), 1076 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.93 (t, JCH3,CH2CH3
=
=
3
3
4.09 (app. t, 3J6H,5H ≈ 3J6H,5′H = 3.3 Hz, 1 H, 6-H), 4.55 (s, 2 H, CH2Ph),
7.4 Hz, 3 H, CH3), 1.64 (app. sext, JCH2CH3,CH3
7.4 Hz, 2 H, CH2CH3), 2.14 (t, JCOCH2,CH2CH3 = 7.4 Hz, 2 H, COCH2),
3.73 (dd, J2H,3H = 1.5, J = 9.6 Hz, 1 H, 2-H), 3.85–3.92 (m, 3 H, 2′-
H, 5-H, 5′-H), 4.05 (m, 1 H, 6-H), 4.42 (m, 1 H, 3-H), 4.53–4.56 (m, 3
H, CH2Ph, 3a-H), 4.59 (d, J6aH,3aH = 3.1 Hz, 1 H, 6a-H), 5.70 (d,
≈
3JCH2CH3,CH2CO
3
3
3
3
4.62 (m, 1 H, 3-H), 4.69 (dd, J6aH,6H = 0.9, J6aH,3aH = 4.3 Hz, 1 H,
6a-H), 4.72 (d, 3J3aH,6aH = 4.3 Hz, 1 H, 3a-H), 7.09 (d, 3JNH,3H = 7.0 Hz,
1 H, NH), 7.25–7.35 (m, 5 H, HAr), 8.98 (d, J = 2.1 Hz, 2 H, HAr), 9.10
(t, J = 2.1 Hz, 1 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 57.6
3
2
3
(C-3), 71.8 (CH2Ph, C-2), 72.6 (C-5), 83.1 (C-6), 86.1 (C-6a), 86.3 (C- 3JNH,3H = 7.0 Hz, 1 H, NH), 7.27–7.37 (m, 5 H, HAr) ppm. 13C NMR
3a), 121.5 (CHAr), 127.5 (2 CHAr), 127.8 (2 CHAr), 128.1 (CHAr), 128.6 (100 MHz, CDCl3): δ = 13.8 (CH3), 19.2 (CH2CH3), 38.6 (COCH2), 56.2
(2 CHAr), 137.3 (Cq,Ar), 137.4 (Cq,Ar), 148.7 (2 Cq,Ar), 162.9 (C=O) ppm. (C-3), 71.7 (CH2Ph), 72.4 (C-2, C-5), 83.2 (C-6), 85.9 (C-6a), 86.5 (C-
HRMS (ESI): calcd. for C20H19N3NaO8 [M + Na]+ 452.1064; found
452.1060.
3a), 127.8 (2 CHAr), 128.0 (CHAr), 128.6 (2 CHAr), 137.6 (Cq,Ar), 172.7
(C=O) ppm. HRMS (ESI): calcd. for C17H23NNaO4 [M + Na]+ 328.1519;
found 328.1534; calcd. for C17H24NO4 [M + H]+ 306.1700; found
306.1705.
N-[(3S,3aR,6S,6aS)-6-Benzyloxyhexahydrofuro[3,2-b]furan-3-yl]-
1H-indole-2-carboxamide (12): The general procedure was fol-
lowed with indole-2-carboxylic acid (87 mg, 0.638 mmol, 1.5 equiv.) N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
to give a yellow solid (160 mg, 99 % crude yield). The crude product yl]-3-methylbutanamide (15): The general procedure was fol-
was purified by flash chromatography using diethyl ether as eluent
lowed using isovaleric acid (70 μL, 0.638 mmol, 1.5 equiv.) to give
to afford 12 (white solid, 125 mg, 77 %), m.p. 152–153 °C (Et2O).
a yellow oil (135 mg, 99 % crude yield). The crude product was
[α]D25 = +72.4 (c = 1.03, MeOH). IR (ATR): ν = 3318, 3227, 2928, 1628, purified by flash chromatography using petroleum ether/ethyl acet-
˜
1545, 1308, 1265, 1074, 1045, 817 cm–1
.
1H NMR (400 MHz, ate (1:1) as eluent to afford 15 (white solid, 131 mg, 96 %), m.p. 77–
[D6]DMSO): δ = 3.80 (dd, J2H,3H = 2.8, 2J = 9.3 Hz, 1 H, 2-H), 3.84
78 °C (iPr2O). [α]22 = +10.9 (c = 1.01, CHCl3). IR (ATR): ν = 3275, 2956,
3
˜
D
(dd, 3J5H,6H = 1.9, 2J = 10.1 Hz, 1 H, 5-H), 3.88 (dd, 3J5′H,6H = 3.8, 2J = 2870, 1641, 1541, 1454, 1369, 1259, 1078 cm–1. H NMR (400 MHz,
1
10.1 Hz, 1 H, 5′-H), 3.95 (dd, J2′H,3H = 5.3, 2J = 9.3 Hz, 1 H, 2′-H), 4.07
CDCl3): δ = 0.94 [d, 3J = 6.5 Hz, 6 H, CH(CH3)2], 2.01 (d, JCH2,CH
=
3
2
3
(m, 1 H, 6-H), 4.35 (m, 1 H, 3-H), 4.57 (AB system, J = 12.0 Hz, 2 H,
2.2 Hz, 2 H, CH2CO), 2.10 [m, 1 H, CH(CH3)2], 3.73 (dd, J2H,3H = 1.4,
CH2Ph), 4.63 (dd, 3J3aH,3H = 0.7, J3aH,6aH = 4.1 Hz, 1 H, 3a-H), 4.68 (d,
2J = 9.6 Hz, 1 H, 2-H), 3.86–3.92 (m, 3 H, 2′-H, 5-H, 5′-H), 4.06 (app.
3
J
6aH,3aH = 4.1 Hz, 1 H, 6a-H), 7.03 (ddd, J = 0.9, J = 7.0 Hz, J = 8.0 Hz,
t, J6H,5H = 3.3 Hz, 1 H, 6-H), 4.43 (m, 1 H, 3-H), 4.54–4.60 (m, 4 H,
1 H, Hindole), 7.18 (ddd, J = 1.1, J = 7.0 Hz, J = 8.0 Hz, 1 H, Hindole), 3a-H, 6a-H, CH2Ph), 5.57 (d, 3JNH,3H = 6.9 Hz, 1 H, NH), 7.29–7.37 (m,
7.22–7.24 (m, 1 H, Hindole), 7.27–7.38 (m, 5 H, HAr), 7.43 (dd, J = 0.8,
J = 8.3 Hz, 1 H, Hindole), 7.62 (d, J = 8.2 Hz, 1 H, Hindole), 8.58 (d,
3JNH,3H = 6.6 Hz, 1 H, NH), 11.59 (s, 1 H, NHindole) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 56.3 (C-3), 70.4 (CH2Ph), 71.6, 71.7 (C-2,
5 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.6 (2 CH3), 26.3
[CH(CH3)2], 46.0 (CH2CO), 56.2 (C-3), 71.8 (CH2Ph), 72.38, 72.40 (C-2,
C-5), 83.3 (C-6), 86.0, 86.6 (C-3a, C-6a), 127.8 (2 CHAr), 128.1 (CHAr),
128.6 (2 CHAr), 137.6 (Cq,Ar), 172.2 (C=O) ppm. HRMS (ESI): calcd. for
C-5), 82.6 (C-6), 85.1 (C-6a), 86.2 (C-3a), 103.4 (CHindole), 112.3 C18H25NNaO4 [M + Na]+ 342.1676; found 342.1679.
(CHindole), 119.8 (CHindole), 121.6 (CHindole), 123.5 (CHindole), 127.0
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
(Cq,indole), 127.6 (CHAr), 127.7 (2 CHAr), 128.3 (2 CHAr), 131.2 (Cq,indole),
yl]-2-methylpropanamide (16): The general procedure was fol-
136.5 (Cq,indole), 138.0 (Cq,Ar), 161.1 (C=O) ppm. HRMS (ESI): calcd.
lowed using isobutyric acid (88 μL, 0.638 mmol, 1.5 equiv.) to give
for C22H22N2NaO4 [M + Na]+ 401.1472; found 401.1471.
a brown solid (137 mg). The crude product was purified by flash
(2E)-N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-
b]furan-3-yl]-3-phenylprop-2-enamide (13): The general proce-
dure was followed using trans-cinnamic acid (95 mg, 0.638 mmol,
1.5 equiv.) to give a brown oil (161 mg). The crude product was
chromatography using petroleum ether/ethyl acetate (4:6) as eluent
to afford 16 (white solid, 116 mg, 89 %), m.p. 84–86 °C (iPr2O).
[α]D22 = +9.0 (c = 1.01, CHCl3). IR (ATR): ν = 3290, 2968, 2873, 1647,
˜
1541, 1456, 1247, 1080 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.13
3
3
purified by flash chromatography using petroleum ether/ethyl acet- [d, JCH3,CH = 6.9 Hz, 6 H, CH(CH3)2], 2.32 [sept, JCH,C3H = 6.9 Hz, 1
ate (1:1) as eluent to afford 13 (white solid, 131 mg, 85 %), m.p. H, CH(CH3)2], 3.73 (dd, 3J2H,3H = 1.5, J = 9.6 Hz, 1 H, 2-H), 3.85–3.92
2
146–147 °C (Et2O). [α]22 = +32.5 (c = 1.00, CHCl ). IR (ATR): ν = 3269, (m, 3 H, 2′-H, 5-H, 5′-H), 4.06 (m, 1 H, 6-H), 4.40 (m, 1 H, 3-H), 4.55
˜
3
D
2968, 2879, 1654, 1618, 1541, 1450, 1338, 1211, 1076 cm–1. 1H NMR (d, J6aH,3aH = 3.8 Hz, 1 H, 3a-H), 4.57 (m, 2 H, CH2Ph), 4.60 (d,
3
3
2
3
(400 MHz, CDCl3): δ = 3.83 (dd, J2H,3H = 1.6, J = 9.7 Hz, 1 H, 2-H),
3.91–3.92 (m, 2 H, 5-H, 5′-H), 3.95 (dd, J2′H,3H = 4.4, J = 9.7 Hz, 1
3J6aH,3aH = 3.8 Hz, 1 H, 6a-H), 5.67 (d, JNH,3H = 7.0 Hz, 1 H, NH),
3
2
7.27–7.36 (m, 5 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.6,
Eur. J. Org. Chem. 2016, 2308–2318
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Full Paper
19.7 [CH(CH3)2], 35.6 [CH(CH3)2], 56.1 (C-3), 71.7 (CH2Ph), 72.3 (C-2, (NHCOO), 171.7 (NHCO) ppm. HRMS (ESI): calcd. for C23H32N2NaO6
C-5), 83.2 (C-6), 85.9 (C-6a), 86.6 (C-3a), 127.8 (2 CHAr), 128.0 (CHAr), [M + Na]+ 455.2153; found 455.2144.
128.6 (2 CHAr), 137.6 (Cq,Ar), 176.7 (C=O) ppm. HRMS (ESI): calcd. for
tert-Butyl (2-{[(3S,3aR,6S,6aS)-6-Benzyloxyhexahydrofuro[3,2-
C17H23NNaO4 [M + Na]+ 328.1519; found 328.1512.
b]furan-3-yl]amino}-2-oxoethyl)carbamate (20): The general pro-
cedure was followed using N-Boc glycine (112 mg, 0.638 mmol,
1.5 equiv.) to give a yellow oil (169 mg). The crude product was
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
yl]cyclohexanecarboxamide (17): The general procedure was fol-
purified by flash chromatography using petroleum ether/ethyl acet-
lowed using cyclohexanecarboxylic acid (79 μL, 0.638 mmol,
ate (2:8) as eluent to afford 20 (white solid, 118 mg, 71 %), m.p.
1.5 equiv.) to give a rather pure brown solid (144 mg, 98 % crude
yield). The crude product was purified by flash chromatography us-
116–117 °C (Et2O). [α]22 = +10.8 (c = 1.03, CHCl3). IR (ATR): ν = 3309,
˜
D
2978, 1707, 1668, 1514, 1368, 1265, 1167, 1080, 1055, 1028 cm–1
.
ing petroleum ether/ethyl acetate (1:1) as eluent to afford 17 (white
1H NMR (400 MHz, CDCl3): δ = 1.45 [s, 9 H, C(CH3)3], 3.73–3.76 (m,
3 H, CH2NH, 2-H), 3.74–3.76 (m, 2 H, CH2NH), 3.86–3.93 (m, 3 H, 2′-
H, 5-H, 5′-H), 4.06 (m, 1 H, 6-H), 4.39–4.42 (m, 1 H, 3-H), 4.56 (AB
system, 2J = 12.0 Hz, 2 H, CH2Ph), 4.56–4.57 (m, 1 H, 3a-H), 4.60–
4.61 (m, 1 H, 6a-H), 5.27 (br. s, 1 H, NHCOO), 6.52 (br. s, 1 H, NHCO),
7.26–7.36 (m, 5 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.4
[C(CH3)3], 44.6 (CH2NH), 56.2 (C-3), 71.7 (CH2Ph), 72.1 (C-2), 72.5 (C-
5), 80.6 [C(CH3)3], 83.1 (C-6), 85.8 (C-6a), 86.4 (C-3a), 127.8 (2 CHAr),
128.0 (CHAr), 128.6 (2 CHAr), 137.6 (Cq,Ar), 156.4 (NHCOO), 169.5
(NHCO) ppm. HRMS (ESI): calcd. for C20H28N2NaO6 [M + Na]+
415.1840; found 415.1835.
solid, 134 mg, 92 %), m.p. 113–115 °C (iPr2O). [α]D22 = +13.4 (c = 1.00,
CHCl3). IR (ATR): ν = 3308, 2983, 2900, 1647, 1521, 1454, 1265,
˜
1078 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.20–1.25, 1.37–1.45,
3
1.64–1.66, 1.76–1.82 (m, 10 H, CH2,cyclohexyl), 2.05 (tt, Jax,eq = 3.3,
3Jax,ax = 11.6 Hz, 1 H, CH,cyclohexyl), 3.71 (dd, 3J2H,3H = 1.5, 2J = 9.6 Hz,
1 H, 2-H), 3.84–3.91 (m, 3 H, 2′-H, 5-H, 5′-H), 4.05 (m, 1 H, 6-H), 4.39
(m, 1 H, 3-H), 4.54 (d, J3aH,6aH = 3.6 Hz, 1 H, 3a-H), 4.52–4.56 (m, 2
H, CH2Ph), 4.59 (d, J6aH,3aH = 3.6 Hz, 1 H, 6a-H), 5.75 (d, JNH,3H
3
3
3
=
7.4 Hz, 1 H, NH), 7.28–7.36 (m, 5 H, HAr) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.70, 25.72, 29.6, 29.7 (5 CH2,cyclohexyl), 45.3
(CH,cyclohexyl), 56.0 (C-3), 71.6 (CH2Ph), 72.29, 72.34 (C-2, C-5), 83.2
(C-6), 85.8 (C-6a), 86.6 (C-3a), 127.8 (2 CHAr), 128.0 (CHAr), 128.6 (2
CHAr), 137.6 (Cq,Ar), 175.9 (C=O) ppm. HRMS (ESI): calcd. for
C20H27NNaO4 [M + Na]+ 368.1832; found 368.1827.
tert-Butyl [(2S)-1-{[(3S,3aR,6S,6aS)-6-Benzyloxyhexahydro-
furo[3,2-b]furan-3-yl]amino}-4-methyl-1-oxopentan-2-yl]-
carbamate (21): The general procedure was followed using N-Boc-
L
-leucine (148 mg, 0.638 mmol, 1.5 equiv.) to give a brown oil
N-[(3S,3aR,6S,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
yl]-4-phenylbutanamide (18): The general procedure was fol-
lowed using 4-phenylbutyric acid (105 mg, 0.638 mmol, 1.5 equiv.)
to give a yellow oil (169 mg). The crude product was purified by
flash chromatography using petroleum ether/ethyl acetate (4:6) as
eluent to afford 18 (white solid, 145 mg, 90 %), m.p. 118–119 °C
(159 mg, 84 % crude yield). The crude product was purified by flash
chromatography using petroleum ether/ethyl acetate (1:1) as eluent
to afford 21 (pale-yellow oil, 130 mg, 69 %). [α]D23 = –7.6 (c = 0.97,
CHCl3). IR (ATR): ν = 3289, 2955, 2871, 1680, 1651, 1526, 1366, 1248,
˜
1167, 1080, 1045, 910 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.92,
0.94 [2 d, 3J = 4.7 Hz, 6 H, CH(CH3)2], 1.44 [s, 9 H, C(CH3)3], 1.43–
1.53 [m, 1 H, CH2CH(CH3)2], 1.59–1.67 [m, 2 H, CH2CH(CH3)2,
(Et2O). [α]22 = +11.1 (c = 1.00, CHCl3). IR (ATR): ν = 3282, 2968, 2900,
˜
D
1
1643, 1541, 1454, 1251, 1078 cm–1. H NMR (400 MHz, CDCl3): δ =
CH(CH3)2], 3.72 (dd, J2H,3H = 1.3, 2J = 9.6 Hz, 1 H, 2-H), 3.86–3.93
3
3
3
1.97 (app. quint, J = 7.5 Hz, 2 H, CH2CH2CH2), 2.16 (t, J = 7.5 Hz,
(m, 3 H, 2′-H, 5-H, 5′-H), 4.01–4.07 (m, 2 H, CHNHCOO, 6-H), 4.39 (m,
1 H, 3-H), 4.53–4.58 (m, 3 H, 3a-H, CH2Ph), 4.60 (d, 3J6aH,3aH = 4.5 Hz,
1 H, 6a-H), 4.88 (d, JNH,CHNH = 6.6 Hz, 1 H, NHCOO), 6.45 (br. s, 1 H,
NHCO), 7.27–7.37 (m, 5 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ =
22.1, 23.1 [CH(CH3)2], 24.9 [CH(CH3)2], 28.4 [C(CH3)3], 40.9
[CH2CH(CH3)2], 53.0 (CHNHCOO), 56.2 (C-3), 71.7 (CH2Ph), 72.2 (C-2),
72.5 (C-5), 80.5 [C(CH3)3], 83.2 (C-6), 85.8 (C-6a), 86.5 (C-3a), 127.8 (2
CHAr), 128.1 (CHAr), 128.6 (2 CHAr), 137.6 (Cq,Ar), 156.0 (NHCOO),
172.4 (NHCO) ppm. HRMS (ESI): calcd. for C24H36N2NaO6 [M + Na]+
471.2466; found 471.2461.
2 H, COCH2), 2.65 (t, J = 7.5 Hz, 2 H, CH2CH2Ph), 3.71 (dd, 3J2H,3H
=
3
1.4, 2J = 9.6 Hz, 1 H, 2-H), 3.85–3.92 (m, 3 H, 2′-H, 5-H, 5′-H), 4.05
3
(m, 1 H, 6-H), 4.41 (m, 1 H, 3-H), 4.54 (d, J3aH,6aH = 4.0 Hz, 1 H, 3a-
3
H), 4.57–4.60 (m, 3 H, 6a-H, CH2Ph), 5.58 (d, JNH,3H = 7.3 Hz, 1 H,
NH), 7.16–7.21 (m, 3 H, HAr), 7.26–7.37 (m, 7 H, HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 27.0 (CH2CH2CH2), 35.2 (CH2CH2Ph), 35.7
(COCH2), 56.2 (C-3), 71.7 (CH2Ph), 72.3, 72.4 (C-2, C-5), 83.2 (C-6),
85.9 (C-6a), 86.5 (C-3a), 126.2 (CHAr), 127.8 (2 CHAr), 128.0 (CHAr),
128.5 (2 CHAr), 128.61 (2 CHAr), 128.62 (2 CHAr), 137.6 (Cq,Ar), 141.4
(Cq,Ar), 172.4 (C=O) ppm. HRMS (ESI): calcd. for C23H27NNaO4 [M +
Na]+ 404.1832; found 404.1840.
tert-Butyl [(2S)-1-{[(3S,3aR,6S,6aS)-6-Benzyloxyhexahydro-
furo[3,2-b]furan-3-yl]amino}-1-oxo-3-phenylpropan-2-yl]-
carbamate (22): The general procedure was followed using N-Boc-
tert-Butyl (2S)-2-{[(3S,3aR,6S,6aS)-6-Benzyloxyhexahydro-
furo[3,2-b]furan-3-yl]carbamoyl}pyrrolidine-1-carboxylate (19):
L-phenylalanine (170 mg, 0.638 mmol, 1.5 equiv.) to give a brown
The general procedure was followed using N-Boc-L-proline (138 mg,
oil (195 mg, 95 % crude yield). The crude product was purified by
0.638 mmol, 1.5 equiv.) to give a brown oil (182 mg, 98 % crude flash chromatography using petroleum ether/ethyl acetate (1:1) as
yield). The crude product was purified by flash chromatography us-
eluent to afford 22 (pale-yellow oil, 148 mg, 72 %). [α]D25 = +16.9
ing petroleum ether/ethyl acetate (4:6) as eluent to afford 19 (col-
(c = 1.00, CHCl3). IR (ATR): ν = 3287, 3063, 2976, 2874, 1651, 1526,
˜
ourless oil, 155 mg, 85 %). [α]D25 = –40.5 (c = 0.99, CHCl3). IR (ATR): 1454, 1366, 1167, 1080, 910 cm–1
.
1H NMR (400 MHz, CDCl3): δ =
3
2
ν = 3296, 2974, 2874, 1682, 1661, 1543, 1395, 1366, 1161, 1082,
1.42 [s, 9 H, C(CH3)3], 2.96, 3.07 (2 dd, J = 6.2, 8.8, J = 13.2 Hz, 2
H, CHCH2Ph), 3.61 (app. dd, 3J2H,3H = 1.0, 2J = 9.6 Hz, 1 H, 2-H), 3.76–
3.88 (m, 3 H, 2′-H, 5-H, 5′-H), 3.97 (m, 1 H, 6-H), 4.16–4.27 (m, 3 H,
˜
912 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.46 [s, 9 H, C(CH3)3], 1.75–
2
2.45 (m, 4 H, CH2CH2), 3.20–3.42 (m, 2 H, NCH2), 3.70 (app. d, J =
9.4 Hz, 1 H, 2-H), 3.85–3.90 (m, 3 H, 2′-H, 5-H, 5′-H), 4.05 (m, 1 H, 6- 3a-H, 6a-H, CHCH2Ph), 4.33 (m, 1 H, 3-H), 4.54 (AB system, 2J =
H), 4.23 (m, 1 H, NCHCO), 4.38 (m, 1 H, 3-H), 4.50–4.65 (m, 4 H,
11.9 Hz, 2 H, OCH2Ph), 5.13 (m, 1 H, NHCOO), 5.72 (d, JNH,3H = 7.4 Hz,
1 H, NHCO), 7.20–7.23 (m, 3 H, HAr), 7.28–7.39 (m, 7 H, HAr) ppm.
CH2Ph, 3a-H, 6a-H), 6.14 (br. s, 1 H, NH), 7.28–7.36 (m, 5 H, HAr) ppm.
13C NMR (100 MHz, CDCl3): δ = 24.7 (CH2CH2), 27.6 (CH2CH2), 28.5 13C NMR (100 MHz, CDCl3): δ = 28.4 [C(CH3)3], 39.1 (CHCH2Ph), 56.0
[C(CH3)3], 47.3 (NCH2CH2), 56.1 (C-3), 59.9 (CHCH2CH2), 71.7 (CH2Ph),
72.3, 72.6 (C-2, C-5), 80.8 [C(CH3)3], 83.1 (C-6), 85.8, 86.5 (C-3a, C-6a),
127.8 (2 CHAr), 128.0 (CHAr), 128.6 (2 CHAr), 137.6 (CqAr), 156.3
(C-3), 56.2 (NHCHCO), 71.6 (OCH2Ph), 71.8 (C-2), 72.6 (C-5), 80.5
[C(CH3)3], 83.1 (C-6), 85.5, 86.2 (C-3a, C-6a), 127.3 (CHAr), 127.7 (2
CHAr), 128.0 (CHAr), 128.6 (2 CHAr), 129.0 (2 CHAr), 129.4 (2 CHAr),
Eur. J. Org. Chem. 2016, 2308–2318
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136.8 (Cq,Ar), 137.7 (Cq,Ar), 155.5 (NHCOO), 170.8 (NHCO) ppm. HRMS tert-Butyl [(2R)-1-{[(3S,3aR,6S,6aS)-6-Benzyloxyhexahydro-
(ESI): calcd. for C27H34N2NaO6 [M + Na]+ 505.2309; found 505.2303.
furo[3,2-b]furan-3-yl]amino}-3-methyl-1-oxobutan-2-yl]carb-
amate (26): The general procedure was followed using N-Boc-
D
-
tert-Butyl [(2R)-3-Hydroxy-1-{[(3S,3aR,6S,6aS)-6-benzyloxyhexa-
hydrofuro[3,2-b]furan-3-yl]amino}-1-oxopropan-2-yl]carbamate
(23): The general procedure was followed using N-Boc-D-serine
valine (139 mg, 0.638 mmol, 1.5 equiv.) to give a brown oil (195 mg,
95 % crude yield). The crude product was purified by flash chroma-
tography using petroleum ether/ethyl acetate (1:1) as eluent to af-
(131 mg, 0.638 mmol, 1.5 equiv.) to give a brown oil (207 mg). The
crude product was purified by flash chromatography using diethyl
ether/ethanol (96:4) as eluent to afford 23 (colourless oil, 121 mg,
ford 26 (white solid, 69 mg, 38 %), m.p. 156–157 °C (iPr2O). [α]D25
=
+15.7 (c = 0.99, CHCl3). IR (ATR): ν = 3331, 3302, 2965, 2876, 1709,
˜
1634, 1551, 1514, 1366, 1275, 1236, 1163, 1076, 1053, 1016, 916,
881 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.90, 0.94 [2 d, 3J = 6.6 Hz,
6 H, CH(CH3)2], 1.43 [s, 9 H, C(CH3)3], 2.09–2.16 [m, 1 H, CH(CH3)2],
3.74 (app. d, 2J = 9.6 Hz, 1 H, 2-H), 3.82 (app. t, 3J = 7.6 Hz, 1 H,
CHNH), 3.86–3.93 (m, 3 H, 2′-H, 5-H, 5′-H), 4.05–4.07 (m, 1 H, 6-H),
4.39–4.43 (m, 1 H, 3-H), 4.54–4.63 (m, 4 H, 6a-H, CH2Ph, 3a-H), 5.03
67 %). [α]D23 = +24.2 (c = 1.02, CHCl3). IR (ATR): ν = 3294, 2974, 2932,
˜
1
2878, 1657, 1524, 1497, 1366, 1248, 1163, 1074, 1028, 908 cm–1. H
NMR (400 MHz, CDCl3): δ = 1.45 [s, 9 H, C(CH3)3], 3.60–3.66 (m, 1 H,
3
2
CH2OH), 3.75 (dd, J2H,3H = 1.4, J = 9.6 Hz, 1 H, 2-H), 3.85–3.94 (m,
3 H, 2′-H, 5-H, 5′-H), 4.05–4.12 (m, 3 H, 6-H, CH2OH, NCHCH2OH),
4.39 (m, 1 H, 3-H), 4.51–4.63 (m, 4 H, 3a-H, CH2Ph, 6a-H), 5.61 (d,
3J = 7.2 Hz, 1 H, NHCOO), 6.99 (d, 3J = 6.1 Hz, 1 H, NHCO), 7.27–
7.37 (m, 5 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.4
[C(CH3)3], 54.9 (CHCH2OH), 56.2 (C-3), 62.6 (CH2OH), 71.6 (CH2Ph),
72.1 (C-2), 72.5 (C-5), 80.9 [C(CH3)3], 83.0 (C-6), 85.8 (C-6a), 86.5 (C-
3a), 127.8 (2 CHAr), 128.0 (CHAr), 128.6 (2 CHAr), 137.6 (Cq,Ar), 156.6
(NHCOO), 171.5 (NHCO) ppm. HRMS (ESI): calcd. for C21H30N2NaO7
[M + Na]+ 445.1945; found 445.1955.
3
(d, 1 H, JNH,CHNH = 8.5 Hz, NHCOO), 6.21 (d, 3JNHCO,3H = 7.0 Hz, 1 H,
NHCO), 7.28–7.36 (m, 5 H, HAr) ppm. 13C NMR (125 MHz, CDCl3): δ =
17.9, 19.5 [CH(CH3)2], 28.4 [C(CH3)3], 30.6 [CH(CH3)2], 56.2 (C-3), 60.2
(CHNH), 71.7 (CH2Ph), 72.1 (C-2), 72.5 (C-5), 80.3 [C(CH3)3], 83.0 (C-
6), 85.7 (C-6a), 86.4 (C-3a), 127.9 (2 CHAr), 128.1 (CHAr), 128.6 (2
CHAr), 137.5 (Cq,Ar), 156.1 (NHCOO), 171.5 (NHCO) ppm. HRMS (ESI):
calcd. for C23H34N2NaO6 [M + Na]+ 457.2309; found 457.2310.
N-[(3S,3aR,6R,6aS)-6-Methoxyhexahydrofuro[3,2-b]furan-3-yl]-
4-methylbenzamide (30): The general procedure was followed us-
ing 27 (70 mg, 0.44 mmol), 4-methylbenzoic acid (90 mg,
0.66 mmol, 1.5 equiv.) and boric acid (8 mg, 0.132 mmol, 0.3 equiv.)
in xylene (5 mL) to give a brown oil (87 mg, 71 % crude yield). The
crude product was purified by flash chromatography using petro-
leum ether/ethyl acetate (2:8) as eluent to afford 30 (pale-yellow
solid, 73 mg, 61 %), m.p. 122–123 °C (Et2O). [α]D25 = +79.3 (c = 1.07,
tert-Butyl [(2S)-3-Hydroxy-1-{[(3S,3aR,6S,6aS)-6-benzyloxyhexa-
hydrofuro[3,2-b]furan-3-yl]amino}-1-oxopropan-2-yl]carbamate
(24): The general procedure was followed using N-Boc-L-serine
(131 mg, 0.638 mmol, 1.5 equiv.) to give a brown oil (179 mg). The
crude product was purified by flash chromatography using ether/
ethanol (98:2) as eluent to afford 24 (white solid, 115 mg, 64 %),
m.p. 122–123 °C (iPr2O). [α]23 = –3.2 (c = 1.03, CHCl3). IR (ATR): ν =
˜
D
3431, 3337, 2972, 2935, 2883, 1705, 1637, 1533, 1506, 1366, 1265,
1084, 1053, 912, 843 cm–1. H NMR (500 MHz, CDCl3): δ = 1.45 [s, 9
1
CHCl3). IR (ATR): ν = 3289, 2941, 2878, 1636, 1535, 1503, 1325, 1138,
˜
1
1096, 1055 cm–1. H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H, CH3),
H, C(CH3)3], 2.04–2.17 (br. s, 1 H, OH), 3.63 (m, 1 H, CH2OH), 3.73 (d,
2J = 8.9 Hz, 1 H, 2-H), 3.86–3.93 (m, 3 H, 2′-H, 5-H, 5′-H), 4.05–4.12
(m, 3 H, 1 CH2OH, 6-H, CHCH2OH), 4.39 (m, 1 H, 3-H), 4.57 (AB
3.47 (s, 3 H, OCH3), 3.64–3.70 (m, 1 H, 5-H), 3.92–3.98 (m, 3 H, 2-H,
3
2
5′-H, 6-H), 4.11 (dd, J2′H,3H = 4.4, J = 9.8 Hz, 1 H, 2′-H), 4.58–4.62
3
2
(m, 2 H, 3a-H, 3-H), 4.66–4.69 (m, 1 H, 6a-H), 6.28 (d, JNHCO,3H
=
system, J = 12.0 Hz, 2 H, CH2Ph), 4.59 (m, 1 H, 3a-H), 4.62 (m, 1 H,
7.0 Hz, 1 H, NH), 7.20–7.22 (d, 3J = 8.0 Hz, 2 H, HAr), 7.63–7.65 (d,
3J = 8.0 Hz, 2 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6
(CH3), 57.6 (C-3), 58.5 (OCH3), 70.6 (C-5), 73.7 (C-2), 80.2 (C-6a), 81.8
(C-6), 87.2 (C-3a), 127.1 (2 CHAr), 129.4 (2 CHAr), 131.1 (Cq,Ar), 142.4
(Cq,Ar), 167.2 (C=O) ppm. HRMS (ESI): calcd. for C15H19NNaO4 [M +
Na]+ 300.1206; found 300.1210.
6a-H), 5.59 (d, 3J = 6.4 Hz, 1 H, NHCOO), 6.99 (br. s, 1 H, NHCO),
7.28–7.36 (m, 5 H, HAr) ppm. 13C NMR (125 MHz, CDCl3): δ = 28.4
[C(CH3)3], 54.8 (NCHCH2OH), 56.3 (C-3), 62.7 (CH2OH), 71.7 (OCH2Ph),
72.1 (C-2), 72.6 (C-5), 80.9 [C(CH3)3], 83.1 (C-6), 85.8 (C-6a), 86.5 (C-
3a), 127.9 (2 CHAr), 128.1 (CHAr), 128.7 (2 CHAr), 137.6 (Cq,Ar), 156.6
(NHCOO), 171.4 (NHCO) ppm. HRMS (ESI): calcd. for C21H30N2NaO7
[M + Na]+ 445.1945; found 445.1949.
N-[(3S,3aR,6R,6aS)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-
tert-Butyl [(2S)-1-{[(3S,3aR,6S,6aS)-6-Benzyloxyhexahydro- yl]-4-methylbenzamide (31): The general procedure was followed
furo[3,2-b]furan-3-yl]amino}-3-methyl-1-oxobutan-2-yl]carb-
amate (25): The general procedure was followed using N-Boc-
using 28 (100 mg, 0.425 mmol), 4-methylbenzoic acid (87 mg,
0.638 mmol, 1.5 equiv.) and boric acid (8 mg, 0.128 mmol,
0.3 equiv.). The crude brown oil was purified by flash chromatogra-
phy using petroleum ether/ethyl acetate (1:1) as eluent to afford 31
(white solid, 119 mg, 80 %), m.p. 130–131 °C (Et2O). [α]D22 = +75.8
L-
valine (139 mg, 0.638 mmol, 1.5 equiv.) to give a brown oil (139 mg,
75 % crude yield). The crude product was purified by flash chroma-
tography using petroleum ether/ethyl acetate (1:1) as eluent to af-
ford 25 (colourless oil, 63 mg, 34 %). [α]D25 = +5.8 (c = 1.00, CHCl3). (c = 1.03, CHCl3). IR (ATR): ν = 3296, 2972, 2856, 1631, 1531, 1506,
˜
IR (ATR): ν = 3294, 2965, 2932, 2874, 1680, 1649, 1526, 1366, 1248,
1334, 1160, 1070, 1042, 957, 839, 759, 735 cm–1. 1H NMR (400 MHz,
˜
1
3
2
1080, 1047, 910 cm–1. H NMR (400 MHz, CDCl3): δ = 0.91, 0.95 [2 CDCl3): δ = 2.38 (s, 3 H, CH3), 3.70 (dd, J5H,6H = 7.5, J = 9.0 Hz, 1
3
3
2
d, J = 6.8 Hz, 6 H, CH(CH3)2], 1.44 [s, 9 H, C(CH3)3], 2.04–2.17 [m, 1
H, 5-H), 3.88 (dd, J5′H,6H = 6.6, J = 9.0 Hz, 1 H, 5′-H), 3.98 (app. d,
3
2
3
3
H, CH(CH3)2], 3.73 (dd, J2H,3H = 1.4, J = 9.6 Hz, 1 H, 2-H), 3.83 (dd,
2J′ = 9.8 Hz, 1 H, 2-H), 4.08 (ddd, J6H,6aH = 4.9, J6H,5H 3J6H,5′H
≈ =
7.0 Hz, 1 H, 6-H), 4.15 (dd, J2′H,3H = 4.4, J = 9.8 Hz, 1 H, 2′-H), 4.57
(AB system, J = 11.8 Hz, 1 H, CH2Ph), 4.55–4.62 (m, 2 H, 3a-H, 3-H),
4.66 (app. t, J6aH,6H ≈ J6aH,3aH = 4.6 Hz, 6a-H), 4.76 (AB system, J =
11.8 Hz, 1 H, CH2Ph), 6.35 (d, 3JNH,3H = 7.5 Hz, 1 H, NH), 7.21 (d, 3J =
8.0 Hz, 2 H, HAr), 7.28–7.38 (m, 5 H, HAr), 7.65 (d, 3J = 8.0 Hz, 2 H,
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6 (CH3), 57.6 (C-3), 70.9
(C-5), 72.7 (CH2Ph), 73.6 (C-2), 79.2 (C-6), 80.5 (C-6a), 87.2 (C-3a),
3
3
2
3J = 6.6, J = 8.4 Hz, 1 H, NCH), 3.87–3.92 (m, 3 H, 2′-H, 5-H, 5′-H),
2
4.06 (m, 1 H, 6-H), 4.42 (m, 1 H, 3-H), 4.54–4.60 (m, 4 H, CH2Ph, 3a-
3
2
H, 6a-H), 5.04 (d, JNH,CHNH = 8.4 Hz, 1 H, NHCOO), 6.17 (d, JNHCO,3H
=
5.5 Hz, 1 H, NHCO), 7.27–7.37 (m, 5 H, HAr) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.1, 19.5 [CH(CH3)2], 28.4 [C(CH3)3], 31.0 [CH(CH3)2], 56.2
(C-3), 60.1 (CHNH), 71.7 (CH2Ph), 72.1 (C-2), 72.5 (C-5), 80.1 [C(CH3)3],
83.2 (C-6), 85.8 (C-6a), 86.5 (C-3a), 127.8 (2 CHAr), 128.0 (CHAr),
128.6 (2 CHAr), 137.6 (Cq,Ar), 156.1 (NHCOO), 171.6 (NHCO) ppm. 127.1 (2 CHAr), 128.0 (2 CHAr), 128.1 (CHAr), 128.6 (2 CHAr), 129.4 (2
HRMS (ESI): calcd. for C23H34N2NaO6 [M + Na]+ 457.2309; found
457.2292.
CHAr), 131.1 (Cq,Ar), 137.8 (Cq,Ar), 142.4 (Cq,Ar), 167.2 (C=O) ppm.
HRMS (ESI): calcd. for C21H23NaNO4 [M + Na]+ 376.1519;
Eur. J. Org. Chem. 2016, 2308–2318
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found 376.1511; calcd. for C21H24NO4 [M + H]+ 354.1700; found
354.1692.
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N,N′-(3S,3aR,6S,6aR)-Hexahydrofuro[3,2-b]furan-3,6-diylbis(4-
methylbenzamide) (32): The general procedure was followed us-
ing 29 (100 mg, 0.693 mmol) and 4-methylbenzoic acid (283 mg,
2.08 mmol, 3 equiv.) and boric acid (26 mg, 0.416 mmol, 0.6 equiv.)
in xylene (7 mL) to give a rather pure brown solid (226 mg, 86 %
crude yield). The crude product was purified by flash chromatogra-
phy using petroleum ether/ethyl acetate (3:7) as eluent to afford 32
(white solid, 175 mg, 67 %), m.p. 234–237 °C (Et2O). [α]D25 = +60.8
[7]
(c = 0.24, CHCl3). IR (ATR): ν = 3320, 2942, 1641, 1634, 1533, 1508,
˜
1337, 1091, 1065, 910 cm–1. H NMR (400 MHz, CDCl3): δ = 2.37 (s,
1
3
3
2
6 H, 2 CH3), 3.89 (dd, J2H,3H = J5H,6H = 2.0, J = 9.8 Hz, 2 H, 2-H, 5-
H), 4.08 (dd, J2′H,3H
[8]
[9]
=
3J5′H,6H = 4.8, 2J = 9.8 Hz, 2 H, 2′-H, 5′-H),
3
4.61–4.64 (m, 2 H, 3-H, 6-H), 4.72 (s, 2 H, 3a-H, 6a-H), 6.28 (d, 3JNH,H
=
6.9 Hz, 2 H, 2 NH), 7.18 (d, 3J = 8.0 Hz, 4 H, HAr), 7.62 (d, 3J = 8.0 Hz,
4 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.5 (2 CH3), 57.3 (C-
3, C-6), 72.7 (C-2, C-5), 86.7 (C-3a, C-6a), 127.2 (4 CHAr), 129.4 (4
CHAr), 131.3 (2 Cq,Ar), 142.4 (2 Cq,Ar), 167.4 (2 C=O) ppm. HRMS (ESI):
calcd. for C22H24NaN2O4 [M + Na]+ 403.1628; found 403.1619; calcd.
for C22H25N2O4 [M + H]+ 381.1809; found 381.1801.
[10]
[11]
Supporting Information (see footnote on the first page of this
1
article): H and 13C NMR spectra.
[12]
[13]
Acknowledgments
The Ministère de l'Enseignement Supérieur et de la Recherche
is gratefully acknowledged for a grant to M. J.
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Keywords: Organocatalysis · Carbohydrates · Amino acids ·
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Received: February 18, 2016
Published Online: April 13, 2016
Eur. J. Org. Chem. 2016, 2308–2318
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2318
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim