Diastereoselective Iridium-Catalyzed Amination of Biosourced Isohexides Through Borrowing Hydrogen Methodology

Article abstract of DOI:10.1021/acs.joc.8b01162

A novel direct and diastereoselective amination of biosourced monobenzylated isohexides has been developed through borrowing hydrogen methodology using a cooperative catalysis between an iridium complex and a phosphoric acid. We also report herein the first regio- and diastereoselective direct amination of isosorbide.

Full text of DOI:10.1021/acs.joc.8b01162

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Note
Diastereoselective Iridium-Catalyzed Amination of Biosourced
Isohexides Through Borrowing Hydrogen Methodology
Maïwenn Jacolot, Sylvie Moebs-Sanchez, and Florence Popowycz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01162 • Publication Date (Web): 11 Jun 2018
Downloaded from http://pubs.acs.org on June 11, 2018
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Diastereoselective Iridium-Catalyzed Amination of Biosourced
Isohexides Through Borrowing Hydrogen Methodology
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Maïwenn Jacolot,* Sylvie Moebs-Sanchez, Florence Popowycz*
Université Lyon 1, CNRS, INSA, CPE, UMR 5246, ICBMS, Bâtiment Lederer, Campus Lyon Tech La Doua, F-69621
Villeurbanne Cedex, France
ABSTRACT: A novel direct and diastereoselective amination of biosourced monobenzylated isohexides has
been developed through borrowing hydrogen methodology using a cooperative catalysis between an iridium
complex and a phosphoric acid. We also report herein the first regio- and diastereoselective direct amination
of isosorbide.
Isosorbide, a major product of the starch industry,1 is a renewable platform chemical able to significantly
contribute to the future replacement of fossil resource-based products.2 This isohexide is a V-shaped chiral
molecule of two cis-connected tetrahydrofuran rings with secondary hydroxyl groups in C-3 and C-6 positions
with endo and exo configurations respectively. Isomannide (endo/endo), produced from D-mannitol, and non-
commercial isoidide (exo/exo) are two other diastereoisomers (Figure1).
Figure 1. Chemical structure of bio-based isohexides
Isosorbide and isomannide have been used for the synthesis of biogenic polymers3 as well as pharmaceutical
compounds4 such as isosorbide dinitrate (Isordil®).5 Over the last decades, functionalization of these
biosourced isohexides into corresponding amines has also attracted considerable interest for polymer
applications6 and for asymmetric induction in organic synthesis7 (auxiliaries,8 ligands9 and organocatalysts10).
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Reported synthesis of isohexide-based amines involved the use of highly reactive leaving groups, such as
tosylates as a given example (Scheme 1, a). Although effective, this process has low atom efficiency and high
amount of waste is generated. The advent of green chemistry has promoted innovative methodologies
considering atom economy parameter. With respect to this point, borrowing hydrogen (BH) methodology has
emerged as an important tool in organic chemistry for the construction of C-C and C-N bonds.11 In the case of
amination of alcohols, a first step of catalytic dehydrogenation converts an unreactive alcohol into the
corresponding carbonyl compound. Subsequent reaction with an amine leads to the imine in situ which upon
hydrogenation affords the desired product. This one pot strategy benefits from metal catalysis and affords
water as the sole by-product. We thus proposed to apply this atom-efficient transformation for the synthesis of
isohexide-based amines as an alternative to classical reported methods (Scheme 1, b).
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Scheme 1. Two-step reported amination of isohexides (a) and proposed catalytic amination using BH
methodology (b)
Already used for homogeneous catalyzed diamination of isosorbide and isomannide with ammonia,12 this
approach led to diamines with excellent conversions but as a mixture of three diastereoisomers (in an optimal
distribution endo/exo, endo/endo, exo/exo 45:15:35 when determined).
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The exo-monobenzylated isosorbide 4 was first chosen as a model substrate. The number of possible products,
inherent to the involved mechanism, should be limited and the analysis of the reaction outcome be simplified.
This choice was also consistent with calculations reporting that the oxidation of the hydroxyl group in endo
position was slightly favored towards the one in exo position ((G#) = 2 kcal.mol-1).13
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Table 1. Preliminary screening for reactions conditions
Entry Cat. (mol%)
T (°C)
140
120
170c
170
120
120
120
120
120
120
120
120
additive (mol%)
KOH (20)
solvent
tamyl alcohol
toluene
ratio 4 : 5 : 6 : 7a
25 : 0 : 0 : 75
100 : 0 : 0 : 0
22 : 8 : 8 : 62
20 : 30 : 30 : 20
100 : 0 : 0 : 0
100 : 0 : 0 : 0
55 : 45 : 0 : 0
62 : 38 : 0 : 0
57 : 11 : 0 : 31
62 : 0 : 0 : 38
20 : 18 : 0 : 62
40 : 60 : 0 : 0
5 (%)b
1
2
8 (5)
9 (5)
-
-
Xantphos (5)
Xantphos (10)
Xantphos (10)
DPE-phos (10)
11 (10), tBuOK (30)
NaHCO3 (5)
-
3
9 (10)
tamyl alcohol
xylene
nd
17d
-
4
9 (10)
5
10 (5)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
6
10 (5)
-
7
8
9
10
11e
12
12 (1.5)
12 (1.5)
12 (1.5)
12 (1.5)
12 (1.5)
13 (5)
34
nd
nd
-
nd
50
NaHCO3 (50)
K2CO3 (5)
NaHCO3 (5)
14 (5)
Reaction conditions: 4 (1 equiv), amine (1 equiv), catalyst, additive, solvent [2M], 24 h. a) conversion rate and diastereoisomeric ratio were determined
by 1H NMR b) isolated yields, c) reaction was also performed at 140 °C and same results were obtained, d) isolated yield of 6 : 16%, e) with 3Å MS -
nd : not determined
We started our investigations with RuCl2(PPh3)3 8 and KOH catalytic system for the reaction from 4, taking
advantage of the recent results obtained in our group using a borrowing hydrogen reaction between 4-
hydroxycoumarin and benzylic alcohol14 (Table 1, entry 1). Despite a 75% conversion rate, no amination
product was detected and only epimerized isohexide 7 was observed. The use of the previously reported
catalytic system by Beller et al. using RuClH(CO)(PPh3)3 / Xantphos12a was then shown to be strongly
dependent from the solvent. (Table 1, entries 2-4). While no reaction occurred in toluene at 120 °C, the
formation of a diastereoisomeric mixture of amines 5 and 6 in a 1:1 ratio15 was observed in amyl alcohol or
t
xylene at 140-170 °C, along with the isomer 7 in non negligible amount (20 to 62%). Amines 5 and 6 were
isolated with 17 and 16% yields respectively (Table 1, entry 4).16 No conversion was observed using the
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dimeric [RuCl2(p-cymene)]2 catalyst 10 either with oxydi-2,1-phenylene)bis(diphenylphosphine (DPE-Phos)
5
6
or phenyl phenyl alaninamide trifluoroacetic acid as additive (Table 1, entries 5 and 6).
7
8
9
Because of the disappointing results obtained with ruthenium complexes, we decided to radically switch to
iridium catalysts. [Cp*IrCl2]2 12 has specially proven to be efficient for amination of primary or secondary
alcohols using borrowing hydrogen methodology under basic conditions.17 The use of 1.5 mol% of 12 and 5
mol% of sodium bicarbonate in toluene at 120 °C led to the formation of a single diastereoisomer 5 with 45%
conversion rate and 34% isolated yield (Table 1, entry 7). Following this very promising result, optimization
of the reaction parameters was pursued. The absence of base did not seem to influence conversion rate (about
40%, entries 7-10) but the use of either 50 mol% of NaHCO3 (Table 1, entry 9) or 5 mol% of K2CO3 (Table
1, entry 10) mainly led to the formation of compound 7. The obtention of this epimerized product via the
formation of the intermediate ketone led us to speculate that the limiting step was the imine formation. To
displace the equilibrium, the reaction was thus performed with molecular sieves that unfortunately promoted
epimerization (Table 1, entry 11). In the work reported by Zhao on enantioselective amination of secondary
alcohols,18 phosphoric acids proved to promote the condensation of ketones with aniline using iridium catalyst
13. Gratifyingly, the combination of diphenylphosphate 14 (5 mol%) with 13 (5 mol%) in toluene at 120 °C
improved indeed significantly the results. Conversion rate reached 60% and amine 5 was isolated in 50% yield
(Table 1, entry 12). It is noticeable that without acid, 28% of epimerized isohexide 7 was formed with only
2% of expected compound 5.
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To investigate more thoroughly the cooperative catalysis between IrIII complex and phosphoric acid, a new
optimization of iridium catalysis was carried out (Table 2). First, a slightly positive synergistic effect of
molecular sieves was noticed as conversion rate increased to 70% (Table 2, entry 2). Replacing the
organometallic catalyst 13 by its pentamethyl analog 15 led satisfyingly to the formation of 5 with 95%
conversion and 67% isolated yield (Table 2, entry 4). Zhao et al. had also reported the use of a racemic
iridacycle 16 as an efficient catalyst for the synthesis of tetrahydroquinolines by borrowing hydrogen
methodology under acidic conditions.19
Table 2. Optimization of the iridium-based catalysis
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Entry
Ir
T (°C)
5 (%)a
ratio
4 : 5 : 6 : 7
40 : 60 : 0 :
1b
2
120
120
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50
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67
-
0
30 : 70 : 0 :
0
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120
120
90
26 : 74 : 0 :
3b
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0
5 : 95 : 0 :
0
18 : 1 : 0 :
81
0 : 90 : 0 :
5c
6
71
nd
nd
0
45 : 55 : 0 :
7
0
140
0 : 60 : 0 :
8
0
Reaction conditions: 4 (1 equiv), amine (1 equiv), metal
catalyst (5 mol%), 14 (5 mol%), toluene, 24 h. a) isolated
yields b) without 3Å MS c) without phosphoric acid
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We thus decided to examine the reactivity of 16.HCl simply obtained in one step from [Cp*IrCl2]2 and
tritylamine. When performing the reaction with 16.HCl, released HCl was not sufficient to promote the
formation of imine and led to 7 as the major compound after 82% conversion (Table 2, entry 5). When 5
mol% of acid 14 was added, total conversion led to a 9/1 mixture of 5 and 7 and 5 was isolated with 71%
yield (Table 2, entry 6). Interestingly, reaction temperature had a strong influence on the selectivity: at 90 °C,
conversion into 5 decreased to 55% but no epimerized isohexide 7 was formed (Table 2, entry 7) while at 140
°C, total conversion led to a mixture of 5/7 in a 3/2 ratio (Table 2, entry 8). Best results were thus obtained
with 5 mol% of iridium catalyst (15 or 16.HCl), 5 mol% of phosphoric acid 14 with molecular sieves in
toluene at 120 °C for 24 h. The conversion was slightly better with catalyst 16.HCl, whereas catalyst 15
offered a total selectivity without epimerization product. The isolated yields were also roughly in the same
range.
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The scope of the reaction was examined and first studied with various amines using optimized conditions
combining 15 and phosphoric acid 14 (Scheme 2).20
Scheme 2. Scope of amines reacting with 4
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Reactions with benzylamine and p-methylbenzylamine provided the corresponding amines in yields of 69%
(5b) and 56% (5c) respectively. With less nucleophilic benzylamines, such as chloro and phenyl
electronwithdrawing groups in para position, some epimerization of starting material (10-20%) and moderate
conversion rates into amines 5d and 5e (60-70%) were observed. More hindered amines such as
cyclohexylamine and α-methylbenzylamine provided the expected compounds in 55 and 44 % respectively.
Unfortunately, no reaction occurred with aniline. In the case of tertbutylamine, only epimerized isohexide 7
was formed with a conversion rate of 50%.
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To better understand the scope of application of the reaction, it was interesting to study the influence of the
unreacted C-6 position. The amination via borrowing hydrogen methodology was thus also studied on
monobenzylated isomannide 17 which differs from 4 only by the orientation of the benzyloxy group. Under
the above optimized conditions, reacting 17 with p-methoxybenzylamine also provided a single
diastereoisomer 18a with an excellent conversion rate and a 58% isolated yield (Scheme 3).
Scheme 3. Scope of amines reacting with 17
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Confirming the robustness of the process, this result also pointed out the non-assistance of the C-6 position in
the control of the diastereoselectivity. A scope of benzylic and aliphatic amines was then investigated. The use
of benzylamine afforded chiral amine 18b with an excellent conversion rate and 77% isolated yield. The less
nucleophilic 4-phenylbenzylamine provided 18c in 44% isolated yield (vs 46% for 5e). Using aliphatic amines
gave very satisfying results. Indeed, total conversions were observed affording amines 18d and 18e in 79%
and 72% yield respectively. As from 4, the amination with cyclohexylamine also led to the concurrent
formation of the isomerized by-product and expected amine isolated in a more moderate yield of 52%. The
same range of yields was globally measured for amines obtained from 4 or 17, only differing from the
stereocenter in C-6 position.
Considering Gibbs free energies calculated for oxidation of isohexides,13 oxidation of the hydroxyl in exo
position appeared to be disfavoured. This was confirmed by submitting endo-benzyloxy-isosorbide (with an
exo alcohol) to our amination reaction using our optimized conditions. No amination product was formed and
starting material was recovered. To take benefit from this selectivity, we then envisaged the direct and more
challenging transformation of isosorbide into a chiral amino-alcohol. Our optimised conditions using iridium
complex 15 / acid cooperative catalysis were first tested. We were delighted to observe the formation of a
single stereoisomer with 70% conversion (Scheme 4).21 Increasing the catalytic loading to 7.5 mol% made the
conversion rate reach 90% and the chiral amino-alcohol 19 was isolated in 65% yield in one step from
isosorbide.
Scheme 4. Regio- and diastereoselective amination of IS-1
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To conclude, we developed an efficient methodology for the diastereoselective direct amination of biobased
isohexides. In each case examined, the sense of diastereoselectivity corresponds to an exo attack of the [Ir]-H
species onto an imine intermediate. Optimized conditions allowed very good conversion rates and excellent
selectivity towards the formation of valuable chiral amino-isohexides. Moreover, the regioselectivity of the
oxidation step was proved and we could propose the first regio- and diastereoselective direct amination of the
biosourced unprotected isosorbide using BH methodology. The scope of application of this approach is
currently being further explored in conjunction with mechanistic investigations.
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EXPERIMENTAL SECTION
Reagents and solvents were supplied by Aldrich, Acros or Alfa Aesar and purchased at the highest
commercial quality to be used without further purification. NMR spectra were recorded on a Bruker DPX-300
(1H: 300 or 400 MHz; 13C: 75 or 100 MHz) spectrometer using CDCl3. The chemical shifts (δ ppm) and
coupling constants (Hz) are reported in the standard fashion. The following abbreviations are used to explain
the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. NMR peak
assignments was performed for each compound using classical 1D and 2D NMR (COSY, HSQC, HMBC and
NOESY). For better clarity, a mean of close measured coupling constants for correlated protons are displayed
in NMR assignments. High-resolution mass spectra (HRMS) were recorded on a Bruker MicrOTOF-Q II XL
spectrometer using ESI as ionization source. Analytical thin-layer chromatographies were carried out on silica
gel Merck 60 D254 (0.25 mm). Flash chromatographies were performed on Merck Si 60 silica gel (40–63
μm). Infra-red (IR) spectra were recorded with an IRAffinity-1 Shimadzu spectrometer using attenuated total
reflectance (ATRMiracle), and the wavenumbers were expressed in cm–1. Optical rotations were measured
with a Perkin–Elmer 241 polarimeter with a 10 cm cell (concentration c expressed in g/100 mL).
General procedure for isohexide amination. To a solution of isohexide 4 or 17 (60 mg, 0.25 mmol, 1
equiv), diphenylphosphate 14 (3.1 mg, 0.0125 mmol, 0.05 equiv), iridium catalyst 15 (9.3 mg, 0.0125 mmol,
0.05 equiv) and 3Å molecular sieves in anhydrous toluene (130 μL) was added amine (0.25 mmol, 1 equiv).
The vial was sealed and the reaction mixture was stirred under heating at 120 °C for 24 h. After cooling down
to rt, the mixture was filtered through Celite® and the solvent was evaporated. After NMR analyses of the
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crude mixture, purification by column chromatography on silica gel (EtOAc/Pentane as eluent) afforded the
targeted amines as yellow oils.
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(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-(4-methoxybenzyl)hexahydrofuro[3,2-b]furan-3-amine (5a). The crude
product was purified by column chromatography on silica gel using EtOAc/Pentane 7/3 as eluent affording 5a
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1
(60 mg, 68%) as a pale yellow oil. H NMR (CDCl3, 300 MHz) δ 3.26 (dd, J = 7.8 and 10.0, 1H, H2), 3.30-
3.41 (m, 1H, H3), 3.72 (d, J = 13.0, 1H, CH2N), 3.79 (s, 3H, OMe), 3.87 (d, J = 13.0, 1H, CH2N), 3.83-3.89
(m, 1H, H5), 3.96-4.01 (m, 2H, H2 and H5), 4.06-4.07 (m, 1H, H6), 4.52-4.62 (m, 3H, H6a and CH2O), 4.64
(app. t, J = 4.0, 1H, H3a), 6.86 (d, J = 8.3, 2H, 2 Hc), 7.27 (d, J = 8.3, 2H, 2 Hb), 7.31-7.40 (m, 5H, HAr); 13C
NMR (CDCl3, 75 MHz) δ 51.7 (CH2N), 55.2 (OMe), 61.7 (C3), 71.1 (C2), 71.5 (CH2O), 73.0 (C5), 79.9 (C3a),
84.2 (C6), 86.4 (C6a), 113.7 (2 Cc), 127.6 (2 CAr), 127.8 (CAr), 128.4 (2 CAr), 129.3 (2 Cb), 132.0 (Ca), 137.6
(CqAr), 158.7 (Cd); IR (ATR) ν 2953, 2932, 1611, 1510, 1456, 1244, 1076, 1032, 820, 733 cm-1 ; [휶]푫ퟐퟏ
=
+42.3° (c 1.35 CHCl3); HRMS (ESI) [M+Na]+: calcd for C21H25NNaO4: 378.1676; found 378.1695; [M+H]+:
calcd for C21H26NO4: 356.1856 ; found 356.1842
(3R,3aR,6S,6aS)-N-Benzyl-6-(benzyloxy)hexahydrofuro[3,2-b]furan-3-amine (5b). The crude product was
purified by column chromatography on silica gel using EtOAc/Pentane 6/4 as eluent affording 5b (56 mg,
69%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 3.28 (dd, J = 8.0 and 10.0, 1H, H2), 3.34-3.39 (m,
1H, H3), 3.78 (d, J = 12.9, 1H, CH2N), 3.88 (dd, J = 4.2 and 10.0, 1H, H5), 3.94 (d, J = 12.9, 1H, CH2N), 3.98-
4.02 (m, 2H, H2 and H5), 4.06-4.08 (m, 1H, H6), 4.57 and 4.60 (2 d, J = 11.9, 2H, CH2O), 4.60 (d, J = 4.1, 1H,
13
H6a), 4.65 (app. t, J = 4.1, 1H, H3a), 7.24-7.38 (m, 10H, HAr); C NMR (CDCl3, 100 MHz) δ 52.3 (CH2N),
61.8 (C3), 71.1 (C2), 71.5 (CH2O), 73.0 (C5), 79.9 (C3a), 84.2 (C6), 86.5 (C6a), 127.1 (CAr), 127.7 (2 CAr), 127.8
(CAr), 128.1 (2 CAr), 128.4 (2 CAr), 128.4 (2 CAr), 137.6 (CqAr), 139.9 (CqAr); [휶]ퟐ푫ퟏ = +29.9° (c 0.936 CHCl3);
IR (ATR) ν 2932, 2864, 1454, 1080, 1067, 733 cm-1; HRMS (ESI) [M+Na]+: calcd for C20H23NNaO3:
348.1570; found 348.1564; [M+H]+: calcd for C20H24NO3: 326.1751; found 326.1738
(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-(4-methylbenzyl)hexahydrofuro[3,2-b]furan-3-amine (5c). The crude
product was purified by column chromatography on silica gel using EtOAc/Pentane 6/4 as eluent affording 5c
(48 mg, 56%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H, Me), 3.27 (dd, J = 8.1 and 9.9,
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1H, H2), 3.32-341 (m, 1H, H3), 3.75 (d, J = 12.7, 1H, CH2N), 3.85-3.93 (m, 2H, H5 and CH2N), 3.96-4.03 (m,
2H, H2 and H5), 4.04-4.09 (m, 1H, H6), 4.57 (d, J = 12.0, 1H, CH2O), 4.59 (d, J = 4.2, 1H, H6a), 4.60 (d, J =
12.0, 1H, CH2O), 4.65 (app. t, J = 4.2, 1H, H3a), 7.14 (d, J = 7.8, 2H, HAr), 7.25 (d, J = 8.0, 2H, HAr), 7.28-
7.39 (m, 5H, HAr); 13C NMR (CDCl3, 100 MHz) δ 21.1 (Me), 52.0 (CH2N), 61.7 (C3), 71.1 (C2), 71.5
(CH2O), 73.0 (C5), 79.9 (C3a), 84.2 (C6), 86.5 (C6a), 127.7 (2 CAr), 127.8 (CAr), 128.1 (2 Cb), 128.4 (2 CAr),
129.1 (2 Cc), 136.7 (Cd), 136.8 (Ca), 137.7 (CqAr); [휶]ퟐ푫ퟏ = +49.7° (c 1.11 CHCl3); IR (ATR) ν 2924, 2866,
1456, 1078, 733 cm-1; HRMS (ESI) [M+H]+: calcd for C21H26NO3: 340.1907; found 340.1903
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(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-(4-chlorobenzyl)hexahydrofuro[3,2-b]furan-3-amine (5d). The crude
product was purified by column chromatography on silica gel using EtOAc/Pentane 7/3 to 8/2 as eluent
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affording 5d (45 mg, 50%) as a pale yellow oil. H NMR (CDCl3, 400 MHz) δ 3.26 (dd, J = 7.8 and 10.0,
1H, H2), 3.30-3.37 (m, 1H, H3), 3.74 (d, J = 13.1, 1H, CH2N), 3.87 (dd, J = 4.2 and 10.0, 1H, H5), 3.89 (d, J =
13.1, 1H, CH2N), 3.96-4.02 (m, 2H, H2 and H5), 4.05-4.08 (m, 1H, H6), 4.56 (d, J = 11.9, 1H, CH2O), 4.59 (d,
J = 4.2, 1H, H6a), 4.60 (d, J = 11.9, 1H, CH2O), 4.63 (app. t, J = 4.2, 1H, H3a), 7.26-7.37 (m, 9H, HAr); 13C
NMR (CDCl3, 100 MHz) δ 51.6 (CH2N), 61.9 (C3), 71.1 (C2), 71.6 (CH2O), 73.1 (C5), 79.8 (C3a), 84.2 (C6),
86.5 (C6a), 127.7 (2 CAr), 127.8 (CAr), 128.5 (2 CAr), 128.5 (2 Cc), 129.4 (2 Cb), 132.7 (Cd), 137.6 (CqAr), 138.5
(Ca); [휶]ퟐ푫ퟏ = +47.7° (c 0.99 CHCl3); IR (ATR) ν 2924, 2870, 1456, 1265, 1080, 700 cm-1; HRMS (ESI)
[M+Na]+: calcd for C20H22ClNNaO3: 382.1180; found 382.1180; [M+H]+: calcd for C20H23ClNO3: 360.1361;
found 360.1349
(3R,3aR,6S,6aS)-N-([1,1'-Biphenyl]-4-ylmethyl)-6-(benzyloxy)hexahydrofuro[3,2-b]furan-3-amine (5e).
The crude product was purified by column chromatography on silica gel using EtOAc/Pentane 6/4 as eluent
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affording 5e (46 mg, 46%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 3.30 (dd, J = 8.2 and 10.0,
1H, H2), 3.37-3.44 (m, 1H, H3), 3.83 (d, J = 13.1, 1H, CH2N), 3.90 (dd, J = 4.2 and 10.0, 1H, H5), 3.98 (d, J =
13.1, 1H, CH2N), 4.00-4.05 (m, 2H, H2 and H5), 4.07-4.10 (m, 1H, H6), 4.57 and 4.60 (2 d, J = 11.9, 2H,
CH2O), 4.62 (d, J = 4.1, 1H, H6a), 4.68 (app. t, J = 4.1, 1H, H3a), 7.27-7.67 (m, 14H, HAr); 13C NMR (CDCl3,
100 MHz) δ 52.0 (CH2N), 61.9 (C3), 71.2 (C2), 71.6 (CH2O), 73.1 (C5), 79.9 (C3a), 84.2 (C6), 86.5 (C6a), 127.0
(2 CAr), 127.2 (3 CAr), 127.7 (2 CAr), 127.8 (CAr), 128.5 (2 CAr), 128.6 (2 CAr), 128.7 (2 CAr), 137.6 (CqAr),
139.0 (CqAr), 140.0 (CqAr), 140.9 (CqAr); IR (ATR) ν 2926, 2870, 1456, 1265, 1076, 733 cm-1; [휶]푫ퟐퟏ = +45.7°
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(c 1.09 CHCl3); HRMS (ESI) [M+Na]+: calcd for C26H27NNaO3: 424.1883; found 424.1890; [M+H]+: calcd
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for C26H28NO3: 402.2064; found 402.2053
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(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-(3-phenylpropyl)hexahydrofuro[3,2-b]furan-3-amine (5f). The crude
product was purified by column chromatography on silica gel using EtOAc/Pentane 7/3 as eluent affording 5f
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(55 mg, 62%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 1.77-1.88 (m, 2H, H2’), 2.60 (dt, J = 7.2
and 11.3, 1H, H1’), 2.67 (t, J = 7.5, 2H, H3’), 2.80 (dt, J = 7.2 and 11.3, 1H, H1’), 3.25 (dd, J = 7.7 and 10.0,
1H, H2), 3.28-3.35 (m, 1H, H3), 3.87 (dd, J = 4.2 and 10.0, 1H, H5), 3.96-4.04 (m, 2H, H5 and H2), 4.05-4.09
(m, 1H, H6), 4.56 and 4.59 (2 d, J = 11.9, 2H, CH2O), 4.60 (d, J = 3.9, 1H, H6a), 4.63 (app. t, J = 3.9, 1H, H3a),
7.16-7.37 (m, 10H, HAr); 13C NMR (100 MHz, CDCl3) δ 32.0 (C2’), 33.5 (C3’), 48.0 (C1’), 62.7 (C3), 71.1
(C2), 71.5 (CH2O), 73.0 (C5), 80.1 (C3a), 84.2 (C6), 86.5 (C6a), 125.7 (CAr), 127.7 (2 CAr), 127.8 (CAr), 128.3 (2
CAr), 128.3 (2 CAr), 128.4 (2 CAr), 137.6 (CqAr), 141.9 (CqAr); IR (ATR) ν 2928, 2862, 1454, 1084, 733 cm-1;
[휶]ퟐ푫ퟏ = +27.1° (c 0.92 CHCl3); HRMS (ESI) [M+H]+: calcd for C22H28NO3: 354.2064; found 354.2053
(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-hexylhexahydrofuro[3,2-b]furan-3-amine (5g). The crude product was
purified by column chromatography on silica gel using EtOAc/Pentane 7/3 to 8/2 as eluent affording 5g (54
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mg, 68%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 6.9, 3H, H6’), 1.23-1.36 (m, 6H,
H5’, H4’ and H3’), 1.42-1.56 (m, 2H, H2’), 2.55 and 2.74 (2 ddd, J = 6.4, 8.3 and 11.1, 2H, H1’), 3.24 (dd, J =
7.7 and 10.1, 1H, H2), 3.28-3.35 (m, 1H, H3), 3.86 (dd, J = 4.2 and 10.0, 1H, H5), 3.97 (dd, J = 2.0 and 10.0,
1H, H5), 4.01 (dd, J = 7.1 and 7.7, 1H, H2), 4.04-4.08 (m, 1H, H6), 4.55 and 4.58 (2 d, J = 11.9, 2H, CH2O),
4.60 (d, J = 4.0, 1H, H6a), 4.62 (app. t, J = 4.0, 1H, H3a), 7.26-7.36 (m, 5H, HAr); 13C NMR (CDCl3, 100
MHz) δ 14.0 (C6’), 22.5 (C4’ or C5’), 26.9 (C3’), 30.4 (C2’), 31.7 (C4’ or C5’), 48.6 (C1’), 62.8 (C3), 71.1 (C2),
71.5 (CH2O), 73.0 (C5), 80.0 (C3a), 84.2 (C6), 86.5 (C6a), 127.6 (2 CAr), 127.8 (CAr), 128.4 (2 CAr), 137.6
(CqAr); IR (ATR) ν 2953, 2926, 2857, 1456, 1084, 737 cm-1; [휶]푫ퟐퟏ = +46.9° (c 0.96 CHCl3); HRMS (ESI)
[M+Na]+: calcd for C19H29NNaO3: 342.2040; found 342.2048; [M+H]+: calcd for C19H30NO3: 320.2220; found
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(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-pentylhexahydrofuro[3,2-b]furan-3-amine (5h). The crude product was
purified by column chromatography on silica gel using EtOAc/Pentane 7/3 as eluent affording 5h (58 mg,
76%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J = 6.9 Hz, 3H, H5’), 1.25-1.37 (m, 4H, H3’
and H4’), 1.44-1.56 (m, 2H, H2’), 1.75 (bs, NH), 2.55 and 2.74 (2 ddd, J = 6.2, 8.4 and 11.1, 2H, H1’), 3.24 (dd,
J = 7.5 and 10.4, 1H, H2), 3.32 (dd, J = 7.5 and 10.4, 1H, H3), 3.86 (dd, J = 4.2 and 10.0, 1H, H5), 3.98 (dd,
J = 1.9 and 10.0, 1H, H5), 4.02 (app. t, J = 7.5, 1H, H2), 4.05-4.07 (m, 1H, H6), 4.56 and 4.59 (2 d, J = 11.9,
2H, CH2O), 4.61 (d, J = 4.0, 1H, H6a), 4.63 (app. t, J = 4.0, 1H, H3a), 7.26-7.38 (m, 5H, HAr); 13C NMR
(CDCl3, 100 MHz) δ 14.0 (C5’), 22.5 (C3’), 29.4 (C4’), 30.1 (C2’), 48.6 (C1’), 62.8 (C3), 71.1 (C2), 71.5 (CH2O),
73.0 (C5), 80.0 (C3a), 84.1 (C6), 86.5 (C6a), 127.7 (2 CAr), 127.8 (CAr), 128.4 (2 CAr), 137.6 (CqAr); IR (ATR) ν
2953, 2928, 2860, 1456, 1084, 735 cm-1; [휶]푫ퟐퟏ = +50.1° (c 1.00 CHCl3); HRMS (ESI) [M+H]+: calcd for
C18H28NO3: 306.2064; found 306.2053
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(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-octylhexahydrofuro[3,2-b]furan-3-amine (5i). The crude product was
purified by column chromatography on silica gel using EtOAc/Pentane 7/3 as eluent affording 5i (72 mg,
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83%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 6.9 Hz, 3H, H8’), 1.16-1.33 (m, 10H,
H7’, H6’, H5’, H4’ and H3’), 1.41-1.54 (m, 2H, H2’), 1.78 (bs, NH), 2.55 and 2.73 (2 ddd, J = 6.4, 8.3 and 11.1,
2H, H1’), 3.24 (dd, J = 7.5 and 10.5, 1H, H2), 3.31 (ddd, J = 3.9, 7.5 and 10.5, 1H, H3), 3.86 (dd, J = 4.2 and
10.0, 1H, H5), 3.97 (dd, J = 1.9 and 10.0, 1H, H5), 4.01 (app. t, J = 7.5, 1H, H2), 4.04-4.07 (m, 1H, H6), 4.55
and 4.59 (2d, J = 11.9, 2H, CH2O), 4.60 (d, J = 3.9, 1H, H6a), 4.63 (app. t, J = 3.9, 1H, H3a), 7.27-7.36 (m, 5H,
HAr); 13C NMR (CDCl3, 100 MHz) δ 14.1 (C8’), 22.7 (C6’ or C7’), 27.3 (C3’), 29.3 (C4’ or C5’), 29.5 (C4’ or
C5’), 30.5 (C2’), 31.8 (C6’ or C7’), 48.7 (C1’), 62.8 (C3), 71.2 (C2), 71.6 (CH2O), 73.1 (C5), 80.1 (C3a), 84.2 (C6),
86.5 (C6a), 127.7 (2 CAr), 127.9 (CAr), 128.5 (2 CAr), 137.6 (CqAr); IR (ATR) ν 2924, 2855, 1456, 1084,
737 cm-1; [휶]ퟐ푫ퟏ = +43.3° (c 0.95 CHCl3); HRMS (ESI) [M+H]+: calcd for C21H34NO3: 348.2533; found
348.2523.
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(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-isopentylhexahydrofuro[3,2-b]furan-3-amine (5j). The crude product
was purified by column chromatography on silica gel using EtOAc/Pentane 7/3 as eluent affording 5j (54 mg,
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71%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 0.91 (2 d, J = 6.6 Hz, 6H, H4’), 1.41 (app. q, J =
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7.3, 2H, H2’), 1.57-1.71 (m, 1H, H3’), 1.81 (bs, NH), 2.59 and 2.78 (2 dt, J = 7.3 and 11.1, 2H, H1’), 3.26 (dd,
J = 7.7 and 10.1, 1H, H2), 3.30-3.38 (m, 1H, H3), 3.88 (dd, J = 3.9 and 10.0, 1H, H5), 3.99 (dd, J = 1.9 and
10.0, 1H, H5), 4.03 (app. t, J = 7.7, 1H, H2), 4.07 (dd, J = 1.9 and 3.9, 1H, H6), 4.57 and 4.61 (2 d, J = 11.9,
2H, CH2O), 4.62 (d, J = 4.0, 1H, H6a), 4.65 (app. t, J = 4.0, 1H, H3a), 7.26-7.37 (m, 5H, HAr); 13C NMR
(CDCl3, 100 MHz) δ 22.4 (C4’), 22.8 (C4’), 26.1 (C3’), 39.4 (C2’), 46.7 (C1’), 62.8 (C3), 71.1 (C2), 71.5 (CH2O),
73.0 (C5), 80.0 (C3a), 84.2 (C6), 86.5 (C6a), 127.7 (2 CAr), 127.8 (CAr), 128.4 (2 CAr), 137.6 (CqAr); IR (ATR) ν
2953, 2926, 2888, 1456, 1366, 1082, 1051, 735 cm-1; [휶]푫ퟐퟏ = +44.8° (c 1.01 CHCl3) ; HRMS (ESI) [M+H]+:
calcd for C18H28NO3: 306.2064; found 306.2052
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(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-cyclohexylhexahydrofuro[3,2-b]furan-3-amine (5k). The crude product
was purified by column chromatography on silica gel using EtOAc/Pentane 7/3 as eluent affording 5k (44 mg,
55%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.00-1.65 (m, 6H, CH2-cyclohexyl), 1.68-1.77 (m,
2H, CH2-cyclohexyl), 1.80-1.88 (m, 2H, CH2-cyclohexyl), 2.52 (tt, J = 3.7 and 10.4, 1H, CH-cyclohexyl),
3.22 (dd, J = 8.2 and 10.3, 1H, H2), 3.41-3.49 (m, 1H, H3), 3.86 (dd, J = 4.2 and 10.0, 1H, H5), 3.94-4.03 (m,
2H, H2 and H5), 4.03-4.07 (m, 1H, H6), 4.55 and 4.58 (2 d, J = 11.9, 2H, CH2O), 4.57-4.61 (m, 2H, H6a and
H3a), 7.27-7.39 (m, 5H, HAr); 13C NMR (CDCl3, 100 MHz) δ 24.9 (CH2-cyclohexyl), 25.0 (CH2-cyclohexyl),
26.0 (CH2-cyclohexyl), 33.4 (CH2-cyclohexyl), 34.1 (CH2-cyclohexyl), 55.3 (CH-cyclohexyl), 59.4 (C3), 71.4
(C2), 71.5 (CH2O), 72.9 (C5), 80.5 (C3a), 84.2 (C6), 86.4 (C6a), 127.7 (2 CAr), 127.8 (CAr), 128.4 (2 CAr), 137.6
(CqAr); IR (ATR) ν 2924, 2853, 1456, 1084, 1051, 737 cm-1; [휶]푫ퟐퟏ = +49.2° (c 0.93 CHCl3); HRMS (ESI)
[M+H]+: calcd for C19H28NO3: 318.2064; found 318.2051
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(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-((S)-1-phenylethyl)hexahydrofuro[3,2-b]furan-3-amine (5l). The crude
product was purified by column chromatography on silica gel using EtOAc/Pentane 6/4 to 7/3 as eluent
affording 5l (37 mg, 44%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 1.36 (d, J = 6.5, 3H, Me), 1.89
(bs, NH), 3.10-3.17 (m, 1H, H3), 3.21 (dd, 7.5 and 10.4, 1H, H2), 3.81 (app. t, J = 7.5, 1H, H2), 3.89 (dd, 4.2
and 10.0, 1H, H5), 3.96 (q, J = 6.5, 1H, CHN), 4.00 (dd, J = 1.8 and 10.0, 1H, H5), 4.03-4.06 (m, 1H, H6), 4.51
(d, J = 3.9, 1H, H6a), 4.54 and 4.57 (2 d, J = 11.9, 2H, CH2O), 4.59 (app. t, J = 3.9, 1H, H3a), 7.23-7.37 (m,
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10H, HAr); C NMR (CDCl3, 100 MHz) δ 25.2 (Me), 56.6 (CHN), 60.2 (C3), 70.9 (C2), 71.5 (CH2O), 73.0
(C5), 79.6 (C3a), 84.3 (C6), 86.5 (C6a), 126.7 (2 CAr), 127.1 (CAr), 127.7 (2 CAr), 127.8 (CAr), 128.4 (2 CAr),
128.5 (2 CAr), 137.6 (CqAr), 145.2 (CqAr); IR (ATR) ν 2955, 2928, 2864, 1456, 1090, 1055, 764, 739; [휶]푫ퟐퟏ
=
+103.8° (c 0.87 CHCl3); HRMS (ESI) [M+Na]+: calcd for C21H25NNaO3: 362.1727; found 362.1722;
[M+H]+: calcd for C21H26NO3: 340.1907; found 340.1893.
(3R,3aR,6R,6aS)-6-(Benzyloxy)-N-(4-methoxybenzyl)hexahydrofuro[3,2-b]furan-3-amine (18a). The
crude product was purified by column chromatography on silica gel using EtOAc/Pentane 6/4 to 8/2 as eluent
affording 18a (52 mg, 58%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.33-3.40 (m, 1H, H3), 3.44
(dd, J = 8.0 and 10.3, 1H, H2) ; 3.64 (dd, J = 8.3 and 8.5, 1H, H5), 3.71 (d, J = 12.7, 1H, CH2N), 3.79 (s, 3H,
OMe), 3.83 (d, J = 12.7, 1H, CH2N), 3.92 (dd, J = 6.7 and 8.5, 1H, H5), 4.05-4.14 (m, 2H, H2 and H6), 4.45
(app. t, J = 4.4, 1H, H3a), 4.54 (d, J = 11.9, 1H, CH2O), 4.59 (app. t, J = 4.4, 1H, H6a), 4.75 (d, J = 11.9, 1H,
CH2O), 6.85 (d, J = 8.7, 2H, Hc), 7.26 (d, J = 8.7, 2H, Hb), 7.29-7.36 (m, 5H, HAr); 13C NMR (CDCl3, 100
MHz) δ 51.8 (CH2N), 55.2 (OMe), 62.0 (C3), 71.2 (C5), 72.4 (CH2O), 72.7 (C2), 79.9 (C6), 80.3 (C3a), 81.1
(C6a), 113.8 (2 Cc), 127.8 (CAr), 127.9 (2 CAr), 128.4 (2 CAr), 129.3 (2 Cb), 132.1 (Ca), 137.8 (CqAr), 158.7 (Cd);
IR (ATR) ν 2932, 2870, 1512, 1456, 1248, 1136, 1082, 1072, 1030, 826, 741 cm-1 [휶]푫ퟐퟏ = +112.2° (c 0.93
CHCl3) ; HRMS (ESI) [M+Na]+: calcd for C21H25NNaO4: 378.1676; found 378.1676; [M+H]+: calcd for
C21H26NO4: 356.1856; found 356.1848
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(3R,3aR,6R,6aS)-N-Benzyl-6-(benzyloxy)hexahydrofuro[3,2-b]furan-3-amine (18b). The crude product
was purified by column chromatography on silica gel using EtOAc/Pentane 7/3 to 8/2 as eluent affording 18b
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(63 mg, 77%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 3.34-3.42 (m, 1H, H3), 3.46 (dd, J = 7.8
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and 10.3, 1H, H2), 3.65 (app. t, J = 8.3, 1H, H5), 3.77 (d, J = 12.9, 1H, CH2N), 3.87-3.97 (m, 2H, CH2N and
H5), 4.04-4.10 (m, 1H, H6), 4.13 (dd, J = 7.4 and 7.8, 1H, H2), 4.46 (app. t, J = 4.4, 1H, H3a), 4.55 (d, J = 11.9,
1H, CH2O), 4.59 (app. t, J = 4.4, 1H, H6a), 4.75 (d, J = 11.9, 1H, CH2O), 7.21-7.42 (m, 10H, HAr); 13C NMR
(CDCl3, 100 MHz) δ 52.3 (CH2N), 62.1 (C3), 71.2 (C5), 72.4 (CH2O), 72.7 (C2), 79.8 (C6), 80.3 (C3a), 81.1
(C6a), 127.0 (CAr), 127.8 (CAr), 127.9 (2 CAr), 128.1 (2 CAr), 128.4 (2 CAr), 128.4 (2 CAr), 137.7 (CqAr), 140.0
(CqAr); IR (ATR) ν 2928, 2870, 1454, 1134, 1070, 1026, 737 cm-1; [휶]푫ퟐퟏ = +83.0° (c 0.96 CHCl3); HRMS
(ESI) [M+Na]+: calcd for C20H23NNaO3: 348.1570; found 348.1582; [M+H]+: calcd for C20H24NO3: 326.1751;
found 326.1755
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(3R,3aR,6R,6aS)-N-([1,1'-Biphenyl]-4-ylmethyl)-6-(benzyloxy)hexahydrofuro[3,2-b]furan-3-amine
(18c). The crude product was purified by column chromatography on silica gel using EtOAc/Pentane 7/3 as
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eluent affording 18c (44 mg, 44%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 3.39-3.46 (m, 1H,
H3), 3.49 (dd, J = 7.7 and 10.2, 1H, H2), 3.67 (app. t, J = 8.3, 1H, H5), 3.82 (d, J = 13.0, 1H, CH2N), 3.93-3.96
(m, 2H, CH2N and H5), 4.07-4.13 (m, 1H, H6), 4.16 (app. t, J = 7.7, 1H, H2), 4.49 (app. t, J = 4.4, 1H, H3a),
4.56 (d, J = 11.9, 1H, CH2O), 4.61 (app. t, J = 4.4, 1H, H6a), 4.76 (d, J = 11.9, 1H, CH2O), 7.30-7.60 (m, 14
13
HAr) ; C NMR (CDCl3, 100 MHz) δ 52.0 (CH2N), 62.1 (C3), 71.2 (C5), 72.4 (CH2O), 72.7 (C2), 79.8 (C6),
80.3 (C3a), 81.2 (C6a), 127.0 (2 CAr), 127.1 (3 CAr), 127.8 (CAr), 127.9 (2 CAr), 128.4 (2 CAr), 128.5 (2 CAr),
128.7 (2 CAr), 137.7 (CqAr), 139.0 (CqAr), 140.0 (CqAr), 140.9 (CqAr); IR (ATR) ν 2934, 2870, 1487, 1454,
1134, 1071, 1026, 827, 760, 737 cm-1; [휶]푫ퟐퟏ = +93.5° (c 1.17 CHCl3); HRMS (ESI) [M+H]+: calcd for
C26H28NO3 402.2064; found 402.2055.
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(3R,3aR,6R,6aS)-6-(Benzyloxy)-N-hexylhexahydrofuro[3,2-b]furan-3-amine (18d). The crude product was
purified by column chromatography on silica gel using EtOAc/Pentane 7/3 to 8/2 as eluent affording 18d (63
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mg, 79%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 0.86 (t, J = 6.8, 3H, H6’), 1.20-1.37 (m, 6H,
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H3’, H4’ and H5’), 1.41-1.51 (m, 2H, H2’), 1.87 (bs, NH), 2.54 and 2.69 (2 ddd, J = 6.5, 8.1 and 11.1, 2H, H1’),
3.29-3.36 (m, 1H, H3), 3.41 (dd, J = 7.8 and 10.4, 1H, H2), 3.63 (dd, J = 8.2 and 8.5, 1H, H5), 3.90 (dd, J = 6.7
and 8.5, 1H, H5), 4.04-4.10 (m, 1H, H6), 4.13 (app. t, J = 7.8, 1H, H2), 4.46 (app. t, J = 4.4, 1H, H3a), 4.53 (d,
J = 11.9, 1H, CH2O), 4.60 (app. t, J = 4.4, 1H, H6a), 4.74 (d, J = 11.9, 1H, CH2O), 7.25-7.40 (m, 5H, HAr);
13C NMR (CDCl3, 100 MHz) δ 14.0 (C6’), 22.5 (C4’), 26.9 (C3’), 30.4 (C2’), 31.7 (C5’), 48.6 (C1’), 63.0 (C3),
71.2 (C5), 72.4 (CH2O), 72.7 (C2), 79.8 (C6), 80.4 (C3a), 81.1 (C6a), 127.8 (CAr), 127.9 (2 CAr), 128.4 (2 CAr),
137.7 (CqAr); IR (ATR) ν 2928, 2957, 1454, 1141, 1084, 1072, 1026, 737 cm-1; [휶]푫ퟐퟏ = +106.4° (c 0.97
CHCl3); HRMS (ESI) [M+Na]+: calcd for C19H29NNaO3342.2040; found 342.2036; [M+H]+: calcd for
C19H30NO3: 320.2220; found 320.2206
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(3R,3aR,6R,6aS)-6-(Benzyloxy)-N-isopentylhexahydrofuro[3,2-b]furan-3-amine (18e). The crude product
was purified by column chromatography on silica gel using EtOAc/Pentane 8/2 as eluent affording 18e (55
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mg, 72%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 0.88 (2 d, J = 6.6, 6H, H4’), 1.39 (app. q, J =
7.4, 2H, H2’), 1.56-1.65 (m, 1H, H3’), 2.13 (bs, NH), 2.56 and 2.72 (2 dt, J = 7.4 and 11.0, 2H, H1’), 3.30-3.38
(m, 1H, H3), 3.42 (d, J = 7.8 and 10.3, 1H, H2), 3.63 (dd, J = 8.2 and 8.6, 1H, H5), 3.91 (dd, J = 6.7 and 8.6,
1H, H5), 4.04-4.11 (m, 1H, H6), 4.14 (app. t, J = 7.8, 1H, H2), 4.47 (app. t, J = 4.4, 1H, H3a), 4.54 (d, J = 11.9,
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1H, CH2O), 4.61 (app. t, J = 4.4, 1H, H6a), 4.75 (d, J = 11.9, 1H, CH2O), 7.27-7.37 (m, 5H, HAr); C NMR
(CDCl3, 100 MHz) δ 22.4 (C4’), 22.7 (C4’), 26.0 (C3’), 39.4 (C2’), 46.6 (C1’), 63.0 (C3), 71.2 (C5), 72.4 (CH2O),
72.7 (C2), 79.8 (C6), 80.4 (C3a), 81.2 (C6a), 127.8 (CAr), 127.9 (2 CAr), 128.4 (2 CAr), 137.7 (CqAr); IR (ATR)
ν 2951, 2924, 2868, 1456, 1134, 1082, 1026, 737 cm-1; [휶]푫ퟐퟏ = +99.7° (c 1.07 CHCl3); HRMS (ESI)
[M+Na]+: calcd for C18H27NNaO3 328.1883; found 328.1882; [M+H]+: calcd for C18H28NO3 306.2064; found
306.2055.
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(3R,3aR,6S,6aS)-6-(Benzyloxy)-N-cyclohexylhexahydrofuro[3,2-b]furan-3-amine (18f). The crude product
was purified by column chromatography on silica gel using EtOAc/Pentane 6/4 to 7/3 as eluent affording 18f
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(41 mg, 52%) as a pale yellow oil. H NMR (400 MHz, CDCl3) δ 1.00-1.29 (m, 5H, CH2-cyclohexyl), 1.57-
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1.64 (m, 1H, CH2-cyclohexyl), 1.67-1.76 (m, 2H, CH2-cyclohexyl), 1.79-1.91 (m, 3H, CH2-cyclohexyl and
NH), 2.47 (tt, J = 3.7 and 10.4, 1H, CH-cyclohexyl), 3.39 (dd, J = 7.8 and 10.5, 1H, H2), 3.47 (m, 1H, H3),
3.62 (dd, J = 8.3 and 8.6, 1H, H5), 3.90 (dd, J = 6.8 and 8.6, 1H, H5), 4.02-4.10 (m, 1H, H6), 4.12 (app. t,
J = 7.8, 1H, H2), 4.42 (app. t, J = 4.4, 1H, H3a), 4.54 (d, J = 11.9, 1H, CH2O), 4.60 (app. t, J = 4.4, 1H, H6a),
4.74 (d, J = 11.9, 1H, CH2O), 7.27-7.41 (m, 5H, HAr); 13C NMR (CDCl3, 100 MHz) δ 24.8 (CH2-cyclohexyl),
24.9 (CH2-cyclohexyl), 25.9 (CH2-cyclohexyl), 33.5 (CH2-cyclohexyl), 34.0 (CH2-cyclohexyl), 55.2 (CH-
cyclohexyl), 59.6 (C3), 71.2 (C5), 72.4 (CH2O), 73.0 (C2), 79.8 (C6), 80.9 (C3a), 81.0 (C6a), 127.8 (CAr), 127.9
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(2 CAr), 128.4 (2 CAr), 137.7 (CqAr); IR (ATR) ν 2926, 2853, 1452, 1134, 1083, 1070, 1026, 737 cm-1; [휶]푫ퟐퟏ
+121.7° (c 0.92 CHCl3) ; HRMS (ESI) [M+H]+: calcd for C19H28NO3: 318.2064; found 318.2068
=
(3S,3aR,6R,6aR)-6-(Hexylamino)hexahydrofuro[3,2-b]furan-3-ol (19). To a solution of isosorbide IS-1
(36.5 mg, 0.25 mmol, 1 equiv), diphenylphosphate 14 (4.8 mg, 0.019 mmol, 0.075 equiv), iridium catalyst 15
(14.2 mg, 0.019 mmol, 0.075 equiv) and 3Å molecular sieves in anhydrous toluene (250 μL) was added n-
hexylamine (33 μL, 0.25 mmol, 1 equiv). The vial was sealed and the reaction mixture was stirred and heated
to 120 °C for 24 h. After cooling down to rt, the mixture was filtered through Celite® and the solvent was
evaporated. After NMR analyses of the crude mixture, purification by column chromatography on silica gel
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using Et2O/acetone 1/1 as eluent afforded 19 as a pale yellow oil in 65% yield (37 mg). H NMR (400 MHz,
CDCl3) δ 0.86 (t, J = 6.8, 3H, H6’), 1.19-1.34 (m, 6H, H3’, H4’ and H5’), 1.40-1.57 (m, 2H, H2’), 2.54 (ddd, J =
6.7, 8.2 and 11.1, 1H, H1’), 2.54 (bs, 1H, NH), 2.71 (ddd, J = 6.7, 8.2 and 11.1, 1H, H1’), 3.21 (dd, J = 7.8 and
10.1, 1H, H2), 3.24-3.37 (m, 1H, H3), 3.79-3.91 (m, 2H, H5), 4.01 (app. t, J = 7.8, 1H, H2), 4.18-4.33 (m, 1H,
H6), 4.44 (d, J = 3.8, 1H, H6a), 4.64 (app. t, J = 3.8, 1H, H3a); 13C NMR (CDCl3, 100 MHz) δ 14.0 (C6’), 22.5
(C4’ or C5’), 26.9 (C3’), 30.3 (C2’), 31.7 (C4’ or C5’), 48.6 (C1’), 62.7 (C3), 71.2 (C2), 75.5 (C5), 76.9 (C6), 79.8
(C3a), 88.6 (C6a); IR (ATR) ν 3362, 3285, 2953, 2926, 2857, 1458, 1078, 1049, 775, 735 cm-1; [휶]푫ퟐퟏ = +48.9°
(c 0.94 CHCl3) ; HRMS (ESI) [M+Na]+: calcd for C12H23NNaO3: 252.1570; found 252.1574; [M+H]+: calcd
for C12H24NO3: 230.1751; found 230.1743
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website. NMR spectra for all
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compounds are provided.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: maiwenn.jacolot@insa-lyon.fr
* E-mail: florence.popowycz@insa-lyon.fr
ORCID
Maïwenn Jacolot: 0000-0003-4788-423X
Florence Popowycz: 0000-0002-0297-295X
ACKNOWLEDGMENT
The authors are grateful for the access to the MS analysis at the CCSM and NMR facilities at the Université
Lyon 1.
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Amines 5 and 6 could be easily distinguished by H NMR. For amine 5, H3a appears as a triplet
considering the cis-coupling JH3a 3 = 4Hz while for amine 6, H3a turns to be a doublet because of the trans-
-H
coupling JH3a
= 0Hz. This observation was confirmed by NMR NOESY experiments. See spectra in
-H
3
supporting information - page S4.
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1H NMR spectrum of reaction mixture resulting from entry 4 (Table 1) detailed in supporting
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a) Fujita, K.; Yamamoto, K.; Yamaguchi, R. Oxidative cyclization of amino alcohols catalyzed by a
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The Journal of Organic Chemistry
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Zhang, Y.; Lim, C. S.; Sim, D. S. B.; Pan, H. J.; Zhao, Y. Catalytic enantioselective amination of
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Lim, C. S.; Quach, T. T.; Zhao, Y. Enantioselective synthesis of tetrahydroquinolines by borrowing
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The scope of the reaction with catalyst 16.HCl is depicted in supporting information - page S6.
Analytical standard was synthesized according procedure reported in the thesis of Dr M. Janvier.
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