Gold-catalyzed synthesis of enantioenriched furfurylamines from amino acids

Article abstract of DOI:10.1016/j.tetasy.2015.06.014

Abstract A convenient gold-catalyzed asymmetric synthesis of polysubstituted furfurylamines starting from amino acids has been achieved. The cyclization proceeded under mild conditions and generally provided the furan or iodofuran derivatives in good to e

Full text of DOI:10.1016/j.tetasy.2015.06.014

Tetrahedron: Asymmetry 26 (2015) 868–875
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Gold-catalyzed synthesis of enantioenriched furfurylamines
from amino acids
⇑
Benjamin Guieu, Myriam Le Roch, Michèle David, Nicolas Gouault
Equipe PNSCM, UMR 6226, Université de Rennes 1, 2 avenue du Pr. Léon Bernard, 35043 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient gold-catalyzed asymmetric synthesis of polysubstituted furfurylamines starting from
amino acids has been achieved. The cyclization proceeded under mild conditions and generally provided
the furan or iodofuran derivatives in good to excellent yields and with high enantiomeric excess.
Iodofurans were validated as good intermediates for classical organometallic coupling reactions.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 23 May 2015
Accepted 24 June 2015
Available online 21 July 2015
1. Introduction
2. Results and discussion
Polysubstituted furans are key structural units found in many
natural products1 and pharmaceuticals.2 Thus, several methods for
their synthesishave been developed in the past fewyears,3 including
transition-metal-mediated cyclizations and cycloisomerizations.4
Optically active 2-aminomethyl-furans have important applica-
tions as chiral ligands or organocatalysts,5 and as building blocks
for various biologically active molecules,6 and provide access to
many nitrogen containing compounds such as piperidines or aza-
sugars, by the aza-Achmatowicz rearrangement,7 or amino acids
by oxidative cleavage.8 However, few stereoselective syntheses of
chiral furfurylamines have been described and most of them
involve the modification of substituted furans, such as the asym-
metric aminohydroxylation of vinylfuran or the enantioselective
reduction of furanyl ketones.9 Thus, the search for efficient, conve-
nient, and highly stereoselective alternative synthetic routes is of
great interest.
Our initial efforts focused on the synthesis of the key interme-
diates acetylenic diols 3, precursors of chiral 2-aminomethylfurans
1 and 2 by gold-catalyzed dehydrative cyclization. We first pre-
pared aldehydes 4a–d on a gram scale in two steps from commer-
cially available N-Boc protected amino acids. Amino acids were
converted into their corresponding Weinreb amides using TBTU,
DIEA, and N,O-dimethylhydroxylamine hydrochloride in DMF, then
reduced without any racemization using lithium aluminum
hydride in diethylether at ꢀ15 °C according to the literature.11
The observed specific rotations of these derivatives 4 were in
agreement with the literature.12
Intermediate enynes 6 were obtained from aldehydes 4 in one
(Wittig reaction, Method A) or two steps (Takai iodovinylation13
then Sonogashira coupling reaction, Method B) routes (Scheme 2).
Wittig reaction of 4a–b with 2-pentynyltriphenylphosphonium
bromide and n-BuLi in THF afforded amino enynes 6a–b in moder-
ate yield as a mixture of diastereoisomers (E/Z: 80/20).14 Method B
is a more general strategy due to the wide variety of commercially
available terminal alkynes. trans-Vinyl iodides 5 were obtained by
treatment of aldehydes 4 with iodoform in the presence of CrCl2,15
and Sonogashira coupling16 of 1-pentyne or phenylacetylene in the
presence of PdCl2(PPh3)2 yielded enynes 6c–d (51–67% yield over
two steps). The trans-geometry of vinyl iodides 5 was confirmed
by the coupling constant of the two vinylic protons (J = 14.5 Hz).
We next focused on the dihydroxylation17 of alkenes 6a–d to
obtain dihydroxy alkynes 3 (Scheme 3). Osmium tetroxide and N-
methylmorpholine N-oxide failed to deliver the expected diols 3,
but modified Sharpless asymmetric dihydroxylation conditions
with additional methane sulfonamide18 allowed the isolation of
diols 3a–d in a range of 72–79% yield. The use of AD-mix-b (easier
We have previously reported diverse gold-catalyzed approaches
to nitrogen containing 5-or 6-membered heterocycles from amino
acids.10 Herein we report an efficient synthetic route to some chiral
di- and tri-substituted
a-aminomethylfuran derivatives from a-
aminoalkynyl-1,2-diols prepared from commercially available
amino-acids. Our synthetic approach is outlined in Scheme 1.
The structural diversity of commercially available enantiopure
amino acids and the opportunity for late-stage diversification at
intermediate diol 3 should allow rapid generation of enantioen-
riched 2-amino furan libraries by this strategy. One major advan-
tage of gold catalyzed cyclization is minimal racemization under
the very mild conditions.
⇑
Corresponding author.
E-mail address: nicolas.gouault@univ-rennes1.fr (N. Gouault).
http://dx.doi.org/10.1016/j.tetasy.2015.06.014
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

B. Guieu et al. / Tetrahedron: Asymmetry 26 (2015) 868–875
869
R3
N
R2
R1
R4
O
[Au]
OH
R3
1
O
Boc
R3
R2
HO
R2
HO
Boc
2-aminomethyl furans
I
N
R1
N
R1
[Au]
Boc
R4
R3
+
"I "
R2
R4
3
amino acids
O
N
R1
2
Boc
Scheme 1. Retrosynthetic strategy.
Method A (Wittig Reaction)
Br
O
Et
R3
Et
Ph3P
R3
N
R2
R2
R1
H
N
nBuli, THF
-78°C to rt, 3.5 h
R1
Boc
4a-b
Boc
6a-b
4a: R1, R3 = H, R2 = CH2OBn
4b: R1, R2 = H, R3 = CH2OBn
: 56%, E/Z = 80/20
: 56%, E/Z = 80/20
6a
6b
Method B (Iodovinylation and Sonogashira coupling reaction)
PdCl2(PPh3)2
(10 mol%)
R4
O
R3
R3
N
R3
R2
R2
R1
CuI (10 mol%)
CrCl2, CHI3
THF, rt, 2 h
R2
I
H
N
TEA, EtOH, rt
N
R1
Boc
R1
Boc
4c-d
Boc
5
6c-d
: R4 = nPr, 51%, E/Z = 90/10
6d: R4 = Ph, 67%, E/Z = 90/10
4c: R1, R2 = H, R3 = Bn
6c
4d: R1, R2 = -(CH2)3-, R3 = H
Scheme 2. Synthesis of enyne intermediates 6.
R4
OH
R4
3a: 76%
R3
R2
β
R3
N
AD-mix-
R2
R1
OsO4, NaHCO3
methane sulfonamide
3b
3c
: 72%
: 75%
N
OH
Boc
R1
Boc
t-BuOH:H2O (1:1),
0°C, 48 h
6a-d
3d: 79%
3a-d
Scheme 3. Dihydroxylation of intermediates 6.
to manipulate) and methane sulfonamide in t-BuOH/H2O (1:1) gave
best yields.
With these diols 3 in hand, we next turned our attention to their
gold-catalyzed dehydrative cyclization into di-substituted furans 1
and 4-iodofurans 2 using reaction conditions that were successful
in our previous work (Scheme 4).10
PPh3AuCl (1 mol %) in the presence of AgSbF6 (1 mol %), with NIS
(1.2 equiv) as an electrophile, in 1,2-DCE at room temperature,
afforded furan 2a in 62% yield in 1 h (Scheme 3). Similar treatment
of enantiomeric 3b allowed purity measurement of 1a–b and 2a–b
(93–96% ee) by chiral HPLC, which indicated minimal ee erosion
during the sequence.
In order to validate this cyclization, diol 3a was treated with
Ph3PAuCl (1 mol %) and AgSbF6 (1 mol %) in 1,2-dichloroethane
(1,2-DCE) at room temperature to afford furan 1a in 89% yield in
1 h. As expected, no reaction was observed when AgSbF6 or
Ph3PAuCl catalysts were used separately.
Iodocyclization was next investigated. The reaction of 3a with
NIS or I2 as electrophilic halogen sources in the absence of a cata-
lyst gave either starting 3a or complex mixtures with only trace
amounts of 2a. Catalytic iodocyclization under conditions previ-
ously developed in our laboratory19 revealed that the use of
Various a,b-dihydroxyalkynes 3 were submitted to our reaction
conditions to generate a series of disubstituted furans 1 and iod-
ofurans 2 in moderate to excellent yields (Scheme 4).
The value of iodofurans 2 as chiral building blocks was demon-
strated by further manipulations using Suzuki–Miyaura,20 Heck,21
Sonogashira,22 and Buchwald–Hartwig23 couplings (Scheme 5).
Compounds 7–9 were obtained in excellent isolated yields
(87–94%) by Suzuki–Miyaura cross-coupling reaction of 2 with
arylboronic acids. Heck and Sonogashira reactions of 2c with ethyl
acrylate or phenylacetylene respectively provided adducts 10 and

870
B. Guieu et al. / Tetrahedron: Asymmetry 26 (2015) 868–875
R4
I
OH
R3
R2
R3
R3
R2
R2
PPh3AuCl (1 mol%)
AgSbF6 (1 mol%)
PPh3AuCl (1 mol%)
AgSbF6 (1 mol%)
R4
R4
O
O
OH
N
N
N
R1
R1
Boc
R1
NIS (1.2 eq)
1,2-DCE
rt, 1 h
1,2-DCE
rt, 1 h
Boc
Boc
3
1
2
I
I
BnO
H
BnO
H
H
H
BnO
BnO
Et
Et
Et
O
Et
O
O
O
HN
HN
HN
HN
Boc
Boc
Boc
Boc
1a
1b
89% (93% ee)
2b
2a
89% (94% ee)
62% (96% ee)
62% (94% ee)
I
I
H
H
HN
nPr
nPr
Ph
O
O
O
HN
N
Boc
Boc
Boc
1c
2c
56%
2d
46%
84%
Scheme 4. Gold-catalyzed cyclization of substrates 3 to furans 1 and 2.
F
CO2Me
H
BnOH2C
H
nPr
Et
O
O
HN
HN
Boc
Boc
10
7
87% (96% ee)
60% (99% ee)
i
ii
F
Ph
I
2 R3
N
R
Bn
H
H
nPr
i
iii
R4
O
O
nPr
O
HN
Boc
R1
HN
Boc
Boc
2
8
11
94% (99% ee)
95% (99% ee)
i
iv
NHBoc
NHBoc
H
H
Ph
Ph
O
O
N
N
Boc
Boc
94% (83% ee)
9
12
20% (97% ee)
Scheme 5. Reagents and conditions: Suzuki–Miyaura coupling reaction (i) Ar-B(OH)2, K3PO4, S-Phos (10 mol %), Pd(OAc)2 (5 mol %), toluene, 80 °C, 3 h; Heck coupling
reaction (ii) methyl acrylate, TEA, Pd(PPh3)4 (10 mol %), DMF, 80 °C, 2 h; Sonogashira coupling reaction (iii) phenylacetylene, PdCl2(PPh3)2 (1 mol %), CuI (2 mol %), TEA, rt, 4 h;
Buchwald–Hartwig coupling reaction (iv) tert-butyl carbamate, Cs2CO3, CuI (20 mol %), N,N0-DMEDA (40 mol %), toluene, 90 °C, 18 h.
11 in 60% and 94% isolated yields. Finally, Buchwald–Hartwig ami-
nation of 2d with tert-butylcarbamate gave the corresponding
aminofuran 12, albeit in low yield.
benzyl groups in 1a and 7 was accomplished with cyclohexene in
the presence of Pearlman’s catalyst to give 13 and 14 with an
excellent enantiomeric excess (Scheme 6).
Access to fully deprotected b-amino alcohol derivatives by our
strategy was then investigated. Efficient hydrogenolysis of the
Finally, N-Boc deprotection of 13 with 4 M HCl in dioxane pro-
ceeded smoothly to give b-amino alcohol 15 in 72% yield.

B. Guieu et al. / Tetrahedron: Asymmetry 26 (2015) 868–875
871
R1
R1
R1
cyclohexene,
HCl/dioxane
(4M)
H
H
H
Pd(OH)2/C (25% w/w)
Et
Et
Et
.HCl
BnO
HO
HO
O
O
O
EtOH,
reflux, 18 h
rt, 1 h
HN
HN
NH2
Boc
Boc
15 R1 = H, 72%
1a R1 = H
13 R1 = H, 93% (96% ee)
1 = p-F-Ph
1 = p-F-Ph, 94% (97% ee)
7
14
R
R
Scheme 6. Removal of the protecting groups and access to amino-alcohol derivatives.
CDCl3): d 155.0, 145.5, 136.7, 129.6, 128.7, 126.9, 80.0, 77.5, 55.9,
41.2, 28.4; HRMS (ESI, m/z): calcd for C15H20NO2INa: 396.0437;
found [M+Na]+: 396.0437.
3. Conclusion
In conclusion, we have reported a convenient gold-catalyzed
approach for the synthesis of polysubstituted aminomethyl-furan
derivatives from chiral acetylenic diol intermediates. The reaction
proceeds under mild conditions, generally providing furan prod-
ucts in good to excellent yields and enantiopurity. Such com-
pounds may have applications as chiral ligands, organocatalysts,
and pharmaceuticals.
4.2.2. (S,E/Z)-2-(2-Iodovinyl)pyrrolidine-1-carboxylic acid tert-
butyl ester 5d
870 mg (67%), pale yellow oil. Data of the mixture of isomers: IR
(UATR): 1687, 1607 cmꢀ1; spectroscopic data for the unseparated
major isomer E: 1H NMR (300 MHz, CDCl3, 50 °C): d 6.42 (dd,
J = 14.4 Hz, J = 6.5 Hz, 1H), 6.14 (d, J = 14.4 Hz, 1H), 4.24 (br s,
1H), 3.38 (t, J = 6.6 Hz, 2H), 2.05–1.90 (m, 1H), 1.89–1.69 (m, 3H),
1.44 (s, 9H); 13C NMR (75 MHz, CDCl3, 50 °C): d 154.5, 146.5,
79.7, 76.1, 61.3, 46.4, 31.4, 28.7, 23.3; HRMS (ESI, m/z): calcd for
4. Experimental
4.1. General
C
11H18NO2INa: 346.0280; found [M+Na]+: 346.0283.
All reagents of high quality were purchased from commercial
suppliers, and used without further purification. All reactions
requiring anhydrous conditions were performed under an argon
atmosphere using oven dried glassware. DMF and THF were dis-
tilled from CaH2 and Na/benzophenone, respectively. 1H and 13C
NMR were recorded at 300 and 75 MHz respectively on a Bruker
AM 300 spectrometer, using CDCl3 (and TMS as internal standard).
d values are given in parts per million (ppm), coupling constants (J
values) are given in Hertz (Hz), and multiplicity of signals are
reported as follows: s, singlet; d, doublet; t, triplet; q, quadruplet;
m, multiplet; br s, broad singlet. Thin layer chromatography was
performed using precoated silica gel plate (0.2 mm thickness).
Infrared spectra were recorded using a Universal Attenuated
Total Reflectance Accessory (UATR). All melting points are uncor-
rected. Optical rotations were measured at the sodium D line on
a digital polarimeter at ambient temperature.
4.3. Typical procedure for the preparation of enynes 6
4.3.1. From aldehydes 4 (Method A)
To a stirred suspension of 2-pentynyltriphenylphosphonium
bromide14 (1.43 g, 3.5 mmol) in 18 mL of dry THF at ꢀ78 °C under
argon atmosphere was added dropwise 1.7 mL (3.5 mmol) of a
2.1 M solution of n-butyllithium in hexane. After stirring at
ꢀ78 °C for 1 h, a solution of N-Boc-
L-serinal 4a or N-Boc-D-serinal
4b (0.98 g, 3.5 mmol) in 15 mL of dry THF was added. After stirring
at ꢀ78 °C for 30 min, the mixture was allowed to warm to room
temperature over 2 h. Next 40 mL of H2O was added and the mix-
ture was extracted with diethylether (3 ꢁ 40 mL). The combined
organic extracts were washed with brine, dried over magnesium
sulfate, and concentrated. Chromatography on silica gel, eluting
with 2% diethylether in dichloromethane gave 6a or 6b.
4.3.1.1. tert-Butyl (S,E)-(1-(benzyloxy)oct-3-en-5-yn-2-yl)carba-
4.2. Typical procedure for the preparation of vinyl iodides 5
mate 6a.
650 mg (56%), pale yellow oil, as a mixture of E/Z
isomers, ratio: 80/20. Data of the separated major E isomer:
Chromium(II) chloride (2.22 g, 18.0 mmol) was suspended in
dry THF (25 mL) at room temperature under argon. A solution of
aldehyde 4c or 4d (4.0 mmol) and iodoform (2.37 g, 6.0 mmol) in
THF (25 mL) was added dropwise. After stirring in the dark at room
temperature for 2 h, the reaction mixture was hydrolyzed with a
saturated solution of NH4Cl (50 mL) and extracted with diethy-
lether (3 ꢁ 40 mL). The combined organic layers were washed with
brine, then dried over magnesium sulfate, concentrated, and puri-
fied by silica gel chromatography (2% ethyl acetate in dichloro-
methane) to afford products 5c and 5d as a mixture of isomers
E/Z, ratio: 90/10.
[
a
]
D
22 = ꢀ29.0 (c 1.05, CHCl3); IR (HATR): 3337, 2216, 1698,
1633 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.39–7.27 (m, 5H), 6.03
(dd, J = 15.9 Hz, J = 6.1 Hz, 1H), 5.68 (dm, J = 15.9 Hz, 1H), 4.88 (br
s, 1H), 4.52 (s, 2H), 4.34 (br s, 1H), 3.54 (dd, J = 9.5 Hz, J = 4.4 Hz,
1H), 3.47 (dd, J = 9.5 Hz, J = 4.5 Hz, 1H), 2.30 (qd, J = 7.5 Hz,
J = 2.1 Hz, 1H), 1.44 (s, 9H), 1.15 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 155.3, 139.7, 137.9, 128.6, 127.9, 127.8, 111.8,
92.7, 79.8, 77.8, 73.4, 72.0, 52.1, 28.5, 14.0, 13.2; HRMS (ESI,
m/z): calcd for C20H27NO3Na: 352.1888; found [M+Na]+: 352.1884.
4.3.1.2. tert-Butyl (R,E)-(1-(benzyloxy)oct-3-en-5-yn-2-yl)carba-
mate 6b.
major E isomer: [
650 mg (56%), pale yellow oil. Data of the separated
4.2.1. tert-Butyl (R,E)-(4-iodo-1-phenylbut-3-en-2-yl)carbamate
5c
a
]
D
22= +27.1 (c 0.93, CHCl3); spectroscopic data
and HRMS are identical with those reported for 6a.
970 mg (65%). Data of the separated major isomer E: white
solid, mp = 108–109 °C; [
a]
22 = +23.8 (c 1.04, CH2Cl2); IR (UATR):
D
3351, 1687, 1612 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.34–7.21
;
4.3.2. From vinyl iodides 5 (Method B)
To a degassed solution of vinyl iodide 5c or 5d (2.5 mmol) and
triethylamine (0.7 mL, 5 mmol) in 25 mL of EtOH were added suc-
cessively under an argon atmosphere, PdCl2(PPh3)2 (17.5 mg,
(m, 3H), 7.17–7.14 (m, 2H), 6.47 (dd, J = 14.5 Hz, J = 5.9 Hz, 1H),
6.19 (dd, J = 14.5 Hz, J = 1.2 Hz, 1H), 4.47 (br s, 1H), 4.39 (br s,
1H), 2.82 (br d, J = 6.6 Hz, 2H), 1.40 (s, 9H); 13C NMR (75 MHz,

872
B. Guieu et al. / Tetrahedron: Asymmetry 26 (2015) 868–875
0.025 mmol, 1 mol %), CuI (23.8 mg, 0.125 mmol, 5 mol %), and the
appropriate alkyne (2.75 mmol). The mixture was stirred for 72 h
for 6c and 24 h for 6d at room temperature. After the reaction
was completed (1H NMR analysis), 50 mL of H2O was added and
the mixture was extracted with diethylether (3 ꢁ 40 mL). The com-
bined organic extracts were washed with brine, dried over magne-
sium sulfate, and concentrated. Chromatography on silica gel,
eluting with 20% cyclohexane in dichloromethane gave 6c–d as a
mixture of E/Z isomers, ratio:90/10.
4.4.2. tert-Butyl ((2R)-(1-(benzyloxy)-3,4-dihydroxyoct-5-yn-2-
yl)carbamate 3b
520 mg (72%), pale yellow oil. Data of the separated major dihy-
droxylated product: [
a]
;
22 = +3.4 (c 1.35, CHCl3); IR (HATR): 3400,
D
2287, 2233, 1682 cmꢀ1
1H NMR (300 MHz, CDCl3): d 7.40–7.28
(m, 5H), 5.29 (br d, J = 7.4 Hz, 1H), 4.57 (AB System, JAB = 11.7 Hz,
1H), 4.51 (AB System, JAB = 11.7 Hz, 1H), 4.48–4.43 (m, 1H), 3.95
(d, J = 9.5 Hz, 1H), 3.73–3.61 (m, 3H), 3.02 (br s, 2H), 2.24 (qd,
J = 7.5 Hz, J = 2.0 Hz, 2H), 1.44 (s, 9H), 1.15 (t, J = 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 157.1, 137.8, 128.6, 128.0, 127,8, 88.2,
80.7, 74.1, 73.7, 69.2, 62.9, 51.6, 28.4, 13.8, 12.6; HRMS (ESI,
m/z): calcd for C20H29NO5Na: 386.1943; found [M+Na]+: 386.1945.
4.3.2.1. tert-Butyl (R,E)-(1-phenylnon-3-en-5-yn-2-yl)carba-
mate 6c.
brown solid, mp = 84–85 °C; IR (UATR): 3354, 2219, 1687,
1603 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.33–7.16 (m, 5H), 5.96
780 mg (78%). Data of the separated major E isomer:
;
4.4.3. tert-Butyl ((2R)-3,4-dihydroxy-1-phenylnon-5-yn-2-
yl)carbamate 3c
(dd, J = 15.9 Hz, J = 5.5 Hz, 1H), 5.56 (dm, J = 15.9 Hz, 1H), 4.44 (br
s, 2H), 2.82 (br d, J = 5.9 Hz, 2H), 2.25 (td, J = 7.0 Hz, J = 2.1 Hz,
2H), 1.53 (sext, J = 7.2 Hz, 2H), 1.39 (s, 9H), 0.97 (t, J = 7.3 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 155.1, 141.3, 137.2, 129.6,
128.6, 126.7, 111.0, 91.2, 79.7, 78.5, 53.0, 41.6, 28.5, 22.3, 21.5,
13.7; HRMS (ESI, m/z): calcd for C20H27NO2Na: 336.1939; found
[M+Na]+: 336.1938.
520 mg (75%). Data of the separated major dihydroxylated pro-
duct: cream solid, mp = 108–109 °C; [
a]
22 = +23.9 (c 0.78, CH2Cl2);
D
IR (UATR): 3566, 3348, 2227, 1688 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 7.35–7.22 (m, 5H), 4.60 (br d, J = 8.6 Hz, 1H), 4.46–4.42
(m, 1H), 3.96–3.82 (m, 1H), 3.82 (br d, J = 4.4 Hz, 1H), 3.47–3.38
(m, 1H), 3.09 (dd, J = 14.0 Hz, J = 4.1 Hz, 1H), 2.97–2.90 (m, 1H),
2.91 (br d, J = 6.0 Hz, 1H), 2.22 (td, J = 7.1 Hz, J = 2.0 Hz, 2H), 1.55
(sext, J = 7.3 Hz, 2H), 1.37 (s, 9H), 0.98 (t, J = 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 157.1, 137.4, 129.6, 128.8, 126.8, 87.1, 80.7,
78.0, 76.0, 63.1, 52.6, 36.5, 28.4, 22.1, 20.9, 13.7; HRMS (ESI,
m/z): calcd for C20H29NO4Na:370.1994; found [M+Na]+: 370.1991.
4.3.2.2.
acid tert-butyl ester 6d.
(S,E)-2-Hept-1-en-3-yn-1-yl)pyrrolidine-1-carboxylic
740 mg (100%), orange solid,
mp = 86–87 °C. Data of the mixture of isomers: IR (UATR): 1688,
1594 cmꢀ1; spectroscopic data for the unseparated major E isomer:
1H NMR (300 MHz, CDCl3, 50 °C): d 7.42–7.40 (m, 2H), 7.30–7.25
(m, 3H), 6.10 (dd, J = 15.7 Hz, J = 6.2 Hz, 1H), 5.74 (d, J = 15.9 Hz,
1H), 4.36 (br s, 1H), 3.49–3.32 (m, 2H), 2.08–2.01 (m, 1H), 1.92–
1.79 (m, 2H), 1.77–1.72 (m, 1H), 1.46 (s, 9H); 13C NMR (75 MHz,
CDCl3, 50 °C): d 154.6, 144.1, 131.7, 128.4, 128.2, 123.8, 109.8,
89.9, 87.8, 79.6, 58.8, 46.5, 32.2, 28.7, 23.4; HRMS (ESI, m/z): calcd
for C19H23NO2Na: 320.1626; found [M+Na]+: 320.1622.
4.4.4. (2R)-2-(1,2-Dihydroxyhept-3-yn-1-yl)pyrrolidine-1-
carboxylic acid tert-butyl ester 3d
520 mg (79%), pale yellow oil. Data of the separated major dihy-
droxylated product: [
a
]
;
22 = ꢀ100.2 (c 1.31, CH2Cl2); IR (UATR):
D
3381, 2243, 1658 cmꢀ1
1H NMR (300 MHz, CDCl3): d 7.47–7.43
(m, 2H), 7.32–7.27 (m, 3H), 5.21 (br s, 1H), 4.62–4.53 (m, 1H),
4.13 (td, J = 7.6 Hz, J = 3.6 Hz, 1H), 3.73–3.67 (m, 2H), 3.57–3.49
(m, 1H), 3.38–3.30 (m, 1H), 2.12–1.80 (m, 4H), 1.46 (s, 9H); 13C
NMR (75 MHz, CDCl3): d 158.4, 132.0, 128.5, 128.3, 122.7, 88.2,
85.3, 81.2, 78.2, 64.5, 59.6, 47.7, 29.2, 28.5, 24.3; HRMS (ESI,
m/z): calcd for C19H25NO4Na: 354.1681; found [M+Na]+: 354.1681.
4.4. Typical procedure for the preparation of diols 3
To a solution of enynes 6a–d (2.0 m mol) in t-BuOH/H2O (1:1,
26 mL) were added successively at 0 °C AD-mix-b (2.8 g,
1.4 g/mmol of substrate), a solution of 0.05% (w/v) OsO4 in t-
BuOH (6 mL, 0.012 mmol), NaHCO3 (0.5 g, 6.0 mmol), and
methanesulfonamide (0.38 g, 4 mmol). The mixture was stirred
vigorously at 0 °C 48 h for 3a–c and 24 h for 3d. The reaction was
quenched with Na2S2O3 (3 g) while maintaining vigorous agitation
for 30 min at 0 °C. Diethylether (20 mL) was added and the mixture
was warmed to room temperature under constant agitation. The
organic layer was separated and the aqueous layer was extracted
with diethylether (3 ꢁ 40 mL). The combined organic layers were
washed with brine, dried over magnesium sulfate, and concen-
trated. Chromatography on silica gel (20% ethyl acetate in dichlor-
omethane for 3a, 3b, and 3d, 30% ethyl acetate in dichloromethane
for 3c) afforded the dihydroxylated derivatives 3a–d as a mixture
of diastereomers used in the next step without separation.
4.5. Typical procedure for the synthesis of furans 1
To a degassed solution of dihydroxylated derivatives 3a–c
(0.6 mmol) in 1,2-dichloroethane (4 mL) were added under an
argon atmosphere 0.4 mL of
a freshly prepared solution of
PPh3AuCl (14.8 mg, 0.03 mmol) and AgSbF6 (10.3 mg, 0.03 mmol)
in 2 mL of degassed 1,2-dichloroethane. After stirring for 1 h at
room temperature, the reaction mixture was concentrated and
purified by silica gel chromatography eluting with dichloro-
methane to afford the 2,5-disubstitued furans 1a–c.
4.5.1. tert-Butyl (S)-(2-(benzyloxy)-1-(5-ethylfuran-2-yl)ethyl)-
carbamate 1a
184 mg (89%), colorless oil. [
a
;
]
22 = ꢀ35.1 (c 1.00, CH2Cl2), 94%
D
4.4.1. tert-Butyl ((2S)-(1-(benzyloxy)-3,4-dihydroxyoct-5-yn-2-
yl)carbamate 3a
ee; IR (UATR): 3336, 1705 cmꢀ1
1H NMR (300 MHz, CDCl3): d
7.38–7.24 (m, 5H), 6.11 (d, J = 3.1 Hz, 1H), 5.89 (dt, J = 3.1 Hz,
J = 0.9 Hz, 1H), 5.08 (br s, 1H), 4.93 (br s, 1H), 4.55 (AB System,
JAB = 12.1 Hz, 1H), 4.49 (AB System, JAB = 12.1 Hz, 1H), 3.76 (dd,
J = 9.7 Hz, J = 4.9 Hz, 1H), 3.70 (dd, J = 9.7 Hz, J = 5.0 Hz, 1H), 2.60
(q, J = 7.5 Hz, 2H), 1.44 (s, 9H), 1.20 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 157.3, 155.4, 151.1, 138.1, 128.5, 127.8, 127.7,
107.2, 104.7, 79.8, 73.2, 71.0, 48.9, 28.5, 21.5, 12.2; HRMS (ESI,
550 mg (76%), pale yellow oil. Data of the separated major dihy-
droxylated product: [a]
22 = +31.6 (c 1.01, CH2Cl2); IR (HATR): 3389,
D
2289, 2232, 1682 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 7.38–7.28 (m,
5H), 5.15 (br d, J = 8.7 Hz, 1H), 4.54 (s, 2H), 4.34 (br d, J = 7.5 Hz,
1H), 4.12–4.01 (m, 1H), 3.84 (br d, J = 6.2 Hz, 1H), 3.74–3.56 (m,
2H), 3.51 (br s, 1H), 2.94 (br s, 1H), 2.22 (qd, J = 7.5 Hz, J = 1.8 Hz,
2H), 1.44 (s, 9H), 1.13 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 156.3, 137.7, 128.6, 128.0, 127,8, 89.1, 80.0, 76.9, 75.1,
73.5, 71.2, 64.0, 50.7, 28.5, 13.8, 12.6; HRMS (ESI, m/z): calcd for
m/z): calcd for
C
20H27NO4Na: 368.1832; found [M+Na]+:
368.1833; HPLC analysis (Chiralpak IA column, heptane/2-propa-
nol = 95:5, flow rate = 1 mL/min, wavelength = 230 nm): Rt = 7.42
(major) and 8.22 (minor).
C
20H29NO5Na: 386.1943; found [M+Na]+: 386.1945.

B. Guieu et al. / Tetrahedron: Asymmetry 26 (2015) 868–875
873
4.5.2. tert-Butyl (R)-(2-(benzyloxy)-1-(5-ethylfuran-2-yl)ethyl)-
4.76 (br s, 1H), 3.07 (br d, J = 6.5 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H),
1.65 (sext, J = 7.4 Hz, 2H), 1.40 (s, 9H), 0.95 (t, J = 7.4 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 156.0, 155.0, 153.7, 136.9, 129.5, 128.5,
126.8, 113.9, 80.0, 62.7, 49.9, 40.4, 29.4, 28.4, 21.8, 13.7; HRMS
(ESI, m/z): calcd for C20H26NO3INa: 478.0855; found [M+Na]+:
478.0854.
carbamate 1b
184 mg (89%), colorless oil. [a]
22 = +33.4 (c 0.99, CH2Cl2), 93%
D
ee; spectral data and HRMS are identical with those reported for
1a; HPLC analysis (Chiralpak IA column, heptane/2-propa-
nol = 95:5, flow rate = 1 ml/min, wavelength = 230 nm): Rt = 7.40
(minor) and 8.19 (major).
4.6.4. (S)-2-(4-Iodo-5-phenylfuran-2-yl)pyrrolidine-1-carboxylic
acid tert-butyl ester 2d
4.5.3. tert-Butyl (R)-(2-phenyl-1-(5-propylfuran-2-yl)ethyl)-
121 mg (46%), yellow solid, mp = 71–72 °C; [
a]
D
22 = ꢀ101.0 (c
carbamate 1c
1.04, CH2Cl2); IR (UATR): 1690 cmꢀ1
;
1H NMR (500 MHz, CDCl3,
166 mg (84%), colorless oil. [
a]
22 = +43.4 (c 1.07, CH2Cl2), P99%
D
;
ee; IR (UATR): 3343, 1701 cmꢀ1
1H NMR (300 MHz, CDCl3): d
55 °C): d 7.92 (d, J = 7.3 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.30 (t,
J = 7.4 Hz, 1H), 6.29 (s, 1H), 4.90 (br s, 1H), 3.59–3.41 (m, 2H),
2.23–2.13 (m, 1H), 2.12–2.00 (m, 2H), 1.96–1.88 (m, 1H), 1.40 (s,
9H); 13C NMR (125 MHz, CDCl3, 55 °C): d 157.1, 154.5, 150.8,
130.6, 128.5, 128.1, 126.3, 116.5, 79.9, 61.2, 54.8, 46.5, 32.4, 28.6,
23.9; HRMS (ESI, m/z): calcd for C19H22NO3INa: 462.0542; found
[M+Na]+: 462.0540.
7.25–7.17 (m, 3H), 7.06–7.03 (m, 2H), 5.88 (d, J = 3.0 Hz, 1H),
5.84 (d, J = 3.0 Hz, 1H), 4.93 (br s, 1H), 4.82 (br s, 1H), 3.09 (br d,
J = 6.6 Hz, 2H), 2.57 (t, J = 7.4 Hz, 2H), 1.65 (sext, J = 7.4 Hz, 2H),
1.40 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
155.7, 155.1, 151.9, 137.5, 129.6, 128.3, 126.5, 107.0, 105.5, 79.7,
50.3, 40.8, 30.2, 28.5, 21.6, 13.8; HRMS (ESI, m/z): calcd for
C
20H27NO3Na: 352.1889; found [M+Na]+: 352.1887; HPLC analysis
4.7. Typical procedure for the Suzuki–Miyaura coupling of
iodofurans 2 with 4-substituted phenylboronic acid
(Chiralpak IA column, heptane/2-propanol = 99:1, flow rate =
1 mL/min, wavelength = 220 nm): Rt = 10.08.
To a degassed solution of iodofurans 2a, 2c, or 2d (0.25 mmol)
and the appropriate aryl boronic acid (0.375 mmol) in toluene
(2.5 mL) were added successively under an argon atmosphere,
K3PO4 (106.0 mg, 0.50 mmol), S-Phos (10.3 mg, 0.025 mmol,
10 mol %), and Pd(OAc)2 (2.8 mg, 0.0125 mmol, 5 mol %). The
resulting mixture was heated to 80 °C for 3 h. After cooling, the
mixture was diluted with diethylether, filtered over a CeliteÒ plug,
which was washed with diethylether. After removal of the solvents
in vacuo, the crude product was purified by silica gel chromatogra-
phy eluting with 20% diethylether in petroleum ether for 7, 8 and
25% ethyl acetate in cyclohexane for 9.
4.6. Typical procedure for the synthesis of iodofurans 2
To a degassed solution of dihydroxylated derivatives 3a–d
(0.6 mmol) in 1,2-dichloroethane (4 mL) were added successively
under an argon atmosphere, NIS (0.16 g, 0.72 mmol) and 0.4 mL
of a freshly prepared solution of PPh3AuCl (14.8 mg, 0.03 mmol)
and AgSbF6 (10.3 mg, 0.03 mmol) in 2 mL of degassed 1,2-dichlor-
oethane. After stirring for 1 h at room temperature, 20% Na2S2O3
(5 mL) was added and the mixture was extracted with diethylether
(3 ꢁ 10 mL). The combined organic extracts were washed with
brine, dried over magnesium sulfate, and concentrated.
Chromatography on silica gel eluting with dichloromethane
afforded the 2,5-disubstituted 3-iodofurans 2a–d.
4.7.1. tert-Butyl (S)-(2-(benzyloxy)-1-(5-ethyl-4-(4-fluorophenyl)-
furan-2-yl)ethyl)carbamate 7
96 mg (87%), colorless oil; [
a
]
D
22 = ꢀ36.4 (c 0.99, CH2Cl2), 96% ee;
4.6.1. tert-Butyl (S)-(2-(benzyloxy)-1-(5-ethyl-4-iodofuran-2-
IR (UATR): 3336, 1711 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.36–
yl)ethyl)carbamate 2a
7.24 (m, 7H), 7.10–7.02 (m, 2H), 6.28 (s, 1H), 5.14 (br s, 1H), 4.97
(br s, 1H), 4.58 (AB System, JAB = 12.2 Hz, 1H), 4.52 (AB System,
JAB = 12.2 Hz, 1H), 3.81 (dd, J = 9.7 Hz, J = 4.6 Hz, 1H), 3.75 (dd,
J = 9.7 Hz, J = 4.8 Hz, 1H), 272 (q, J = 7.5 Hz, 2H), 1.46 (s, 9H), 1.24
175 mg (62%), pale yellow oil. [
a
;
]
22 = ꢀ36.5 (c 1.02, CH2Cl2), 96%
D
ee; IR (UATR): 3332, 1704 cmꢀ1
1H NMR (300 MHz, CDCl3): d
7.37–7.24 (m, 5H), 6.20 (s, 1H), 511 (br s, 1H), 4.91 (br s, 1H),
4.55 (AB System, JAB = 12.1 Hz, 1H), 4.48 (AB System,
JAB = 12.1 Hz, 1H), 3.75 (dd, J = 9.6 Hz, J = 4.4 Hz, 1H), 3.68 (dd,
J = 9.6 Hz, J = 4.7 Hz, 1H), 2.64 (q, J = 7.6 Hz, 2H), 1.45 (s, 9H), 1.17
(t, J = 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 157.1, 155.3,
152.8, 137.9, 128.6, 127.9, 127.8, 114.1, 80.1, 73.3, 70.6, 61.7,
48.8, 28.5, 21.1, 12.6; HRMS (ESI, m/z): calcd for C20H26NO4INa:
494.0804; found [M+Na]+: 494.0806; HPLC analysis (Chiralpak IA
column, heptane/2-propanol = 97:3, flow rate = 1 ml/min, wave-
length = 230 nm): Rt = 9.06 (major) and 9.89 (minor).
(t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d
161.7
(J1CF = 245.3 Hz), 155.4, 152.1, 151.0, 138.1, 130.4 (JC4F = 3.3 Hz),
129.3 (J3CF = 7.9 Hz), 128.5, 127.8, 127.7, 120.2, 115.5 (JC2F = 21.4 Hz),
108.3, 80.0, 73.3, 70.9, 48.9, 28.5, 20.4, 13.1; HRMS (ESI, m/z): calcd
for C26H30NO4FNa: 462.2057; found [M+Na]+: 462.2059; HPLC anal-
ysis (Chiralpak IA column, heptane/2-propanol = 95:5, flow rate =
1 mL/min, wavelength = 220 nm): Rt = 10.01 (minor) and 10.70
(major).
4.7.2. tert-Butyl (R)-(1-(4-(4-fluorophenyl)-5-propylfuran-2-yl)-
4.6.2. tert-Butyl (R)-(2-(benzyloxy)-1-(5-ethyl-4-iodofuran-2-
2-phenylethyl)carbamate 8
a]
22 = +36.6 (c 1.00, CH2Cl2), P99%
D
;
yl)ethyl)carbamate 2b
103 mg (95%), colorless oil; [
175 mg (62%), pale yellow oil. [a]
22= +36.3 (c 1.03, CH2Cl2), 94%
ee; IR (UATR): 3345, 1700 cmꢀ1
1H NMR (300 MHz, CDCl3): d
D
ee; spectral data and HRMS are identical with those reported for
2a; HPLC analysis (Chiralpak IA column, heptane/2-propa-
nol = 97:3, flow rate = 1 ml/min, wavelength = 230 nm): Rt = 9.09
(minor) and 9.91 (major).
7.26–7.16 (m, 5H), 7.10–7.01 (m, 4H), 6.07 (s, 1H), 4.99 (br s,
1H), 4.85 (br s, 1H), 3.13 (br d, J = 6.5 Hz, 2H), 2.69 (t, J = 7.5 Hz,
2H), 1.71 (sext, J = 7.4 Hz, 2H), 1.41(s, 9H), 0.96 (t, J = 7.4 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 161.7 (JC1F = 245.5 Hz), 155.1, 151.8,
151.0, 137.3, 130.4 (J4CF = 3.2 Hz), 129.6, 129.3 (JC3F = 7.9 Hz), 128.4,
126.7, 120.7, 115.5 (J2CF = 21.4 Hz), 108.1, 79.9, 50.1, 40.7, 28.9,
4.6.3. tert-Butyl (R)-(1-(4-iodo-5-propylfuran-2-yl)-2-phenyl-
ethyl)carbamate 2c
28.5, 22.1, 14.0; HRMS (ESI, m/z): calcd for
C26H30NO3FNa:
153 mg (56%), white solid, mp = 79–80 °C; [a]
22 = +38.3 (c 1.08,
D
446.2107; found [M+Na]+: 446.2107; HPLC analysis (Chiralpak IA
column, heptane/2-propanol = 98:2, flow rate = 1 mL/min, wave-
length = 220 nm): Rt = 10.65.
CH2Cl2); IR (UATR): 3316, 1685 cmꢀ1; 1H NMR (300 MHz, CDCl3): d
7.28–7.17 (m, 3H), 7.06–7.03 (m, 2H), 6.02 (s, 1H), 4.95 (br s, 1H),

874
B. Guieu et al. / Tetrahedron: Asymmetry 26 (2015) 868–875
4.7.3. (S)-2-(4-(4-((tert-Butoxycarbonyl)amino)phenyl)-5-phen-
ylfuran-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 9
(ESI, m/z): calcd for C28H31NO3Na: 452.2202; found [M+Na]+:
452.2205; HPLC analysis (Chiralpak IA column, heptane/2-propa-
nol = 98:2, flow rate = 1 mL/min, wavelength = 280 nm): Rt =
10.63.
119 mg (94%), white solid, mp = 220–221 °C; [
a]
D
22 = ꢀ86.3 (c
0.91, CH2Cl2), 83% ee; IR (UATR): 3247, 1726, 1672 cmꢀ1
;
1H
NMR (300 MHz, DMSO, 80 °C): d 9.13 (br s, 1H), 7.48–7.43 (m,
4H), 7.35–7.30 (m, 2H), 7.27–7.22 (m, 3H), 6.32 (s, 1H), 4.88 (dd,
J = 7.7 Hz, J = 2.5 Hz, 1H), 3.52–3.36 (m, 2H), 2.29–2.16 (m, 1H),
2.11–1.86 (m, 3H), 1.50 (s, 9H), 1.36 (s, 9H); 13C NMR (75 MHz,
DMSO, 80 °C): d 155.1, 153.1, 152.4, 145.5, 138.4, 130.6, 128.1,
128.0, 127.1, 127.0, 125.1, 122.2, 118.2, 109.1, 78.8, 78.2, 53.9,
45.7, 31.1, 27.8, 27.7, 23.0; HRMS (ESI, m/z): calcd for
4.10. (S)-2-(4-((tert-Butoxycarbonyl)amino)-5-phenylfuran-2-
yl)pyrrolidine-1-carboxylic acid tert-butyl ester 12
To a degassed mixture of iodofuran 2d (110 mg, 0.25 mmol),
tert-butyl carbamate (35 mg, 0.3 mmol), cesium carbonate
(122 mg, 0.37 mmol), and CuI (9.5 mg, 0.05 mmol, 20 mol %) in
dry toluene (2.5 mL), was added under an argon atmosphere,
C
30H36N2O5Na: 527.2522; found [M+Na]+: 527.2519; HPLC analy-
sis (Chiralpak IA column, heptane/2-propanol = 90:10, flow
rate = 1 mL/min, wavelength = 250 nm): Rt = 7.51 (minor) and
10.27 (major).
N,N0-DMEDA (11
lL, 0.1 mmol, 40 mol %). The mixture was heated
to 90 °C for 18 h. After cooling, the mixture was diluted with
dichloromethane, filtered over a Celite plug, which was washed
with dichloromethane. After removal of solvents in vacuo, the
crude product was purified by silica gel chromatography eluting
with 5% ethyl acetate in dichloromethane to afford the pure pro-
4.8. (R,E)-3-(5-(1-((tert-Butoxycarbonyl)amino)-2-phenylethyl)-
2-propylfuran-3-yl)acrylic acid methyl ester 10
duct 12 as a colorless oil: 22 mg (20%); [
a
]
D
22 = ꢀ89.0 (c 1.23,
To a degassed solution of iodofuran 2c (114 mg, 0.25 mmol) in
CH2Cl2), 97% ee; IR (UATR): 3291, 1720, 1679 cmꢀ1
;
1H NMR
dry DMF (2 mL) were added successively under an argon atmo-
sphere, methyl acrylate (45 lL, 0.5 mmol), triethylamine (70 lL,
(300 MHz, DMSO, 80 °C): d 8.38 (br s, 1H), 7.61 (d, J = 8.3 Hz, 2H),
7.40 (t, J = 7.7 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 6.28 (s, 1H), 4.83
(dd, J = 7.8 Hz, J = 2.3 Hz, 1H), 3.49–3.35 (m, 2H), 2.26–2.13 (m,
1H), 2.06–1.88 (m, 3H), 1.43 (s, 9H), 1.37 (s, 9H); 13C NMR
(75 MHz, DMSO, 80 °C): d 153.6, 153.4, 153.1, 141.4, 130.0, 128.0,
126.3, 123.8, 121.0, 107.2, 78.6, 78.3, 54.0, 45.7, 31.0, 27.7, 22.9;
0.5 mmol), and Pd(PPh3)4 (29 mg, 0.025 mmol, 10 mol %). The mix-
ture was heated to 80 °C for 2 h. After cooling, H2O (3 mL) was
added and the mixture was extracted with diethylether
(3 ꢁ 5 mL). The combined organic extracts were washed with
brine, dried over magnesium sulfate, and concentrated.
Chromatography on silica gel eluting with 2% diethylether in
dichloromethane afforded the pure product 10 as a yellow solid:
HRMS (ESI, m/z): calcd for
C24H32N2O5Na: 451.2209; found
[M+Na]+: 451.2207; HPLC analysis (Chiralpak IA column, heptane/
2-propanol = 95:5, flow rate = 1 mL/min, wavelength = 291 nm):
Rt = 10.55 (major) and 17.67 (minor).
62 mg (60%), mp = 104–105 °C; [
a]
22 = +31.7 (c 0.94, CH2Cl2), 99%
D
ee; IR (UATR): 3343, 1714, 1688, 1634 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 7.48 (d, J = 15.7 Hz, 1H), 7.27–7.17 (m, 3H), 7.06–7.04
(m, 2H), 6.12 (s, 1H), 5.95 (d, J = 15.7 Hz, 1H), 4.97 (br s, 1H),
4.80 (br s, 1H), 3.76 (s, 3H), 3.09 (br d, J = 6.6 Hz, 2H), 2.69 (t,
J = 7.4 Hz, 2H), 1.68 (sext, J = 7.4 Hz, 2H), 1.41 (s, 9H), 0.95 (t,
J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 167.9, 158.0, 155.0,
153.6, 136.9, 135.4, 129.5, 128.5, 126.8, 118.1, 115.8, 104.4, 80.1,
51.6, 50.0, 40.4, 28.5, 28.3, 22.1, 13.8; HRMS (ESI, m/z): calcd for
4.11. Typical procedure for O-debenzylation
To a solution of furan 1a or 7 (0.2 mmol) in ethanol (2.4 mL) and
cyclohexene (1.2 mL) was added 20% palladium hydroxide on car-
bon (25% catalyst/substrate by weight). The suspension was stirred
at reflux for 18 h. After cooling, the catalyst was filtered over a
Celite plug, washed with dichloromethane, and the volatiles were
removed by evaporation in vacuo. The residue was purified by sil-
ica gel chromatography eluting with a mixture of cyclohex-
ane/ethyl acetate/methanol (75:25:1).
C
24H31NO5Na: 436.2100; found [M+Na]+: 436.2101; HPLC analysis
(Chiralpak IA column, heptane/2-propanol = 98:2, flow rate =
1 mL/min, wavelength = 290 nm): Rt = 20.29 (major), 27.17
(minor).
4.11.1. (S)-(1-(5-Ethylfuran-2-yl)-2-hydroxyethyl)carbamic acid
tert-butyl ester 13
4.9.
(R)-(2-Phenyl-1-(4-(phenylethynyl)-5-propylfuran-2-yl)-
ethyl)carbamic acid tert-butyl ester 11
47 mg (93%), colorless oil; [
a]
22 = ꢀ51.1 (c 1.00, CH2Cl2), 96% ee;
D
IR (UATR): 3396, 1693 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 6.13 (d,
To a degassed solution of iodofuran 2c (114 mg, 0.25 mmol) in
triethylamine (2 mL) were added under an argon atmosphere,
PdCl2(PPh3)2 (1.8 mg, 0.0025 mmol, 1 mol %) and CuI (1.0 mg,
0.005 mmol, 2 mol %). The reaction mixture was stirred for
15 min at room temperature. Then a solution of phenylacetylene
J = 3.1 Hz, 1H), 5.91 (d, J = 3.1 Hz, 1H), 5.16 (br s, 1H), 4.82 (br s,
1H), 3.90 (dd, J = 11.2 Hz, J = 5.4 Hz, 1H), 3.83 (dd, J = 11.2 Hz,
J = 4.7 Hz, 1H), 2.61 (q, J = 7.5 Hz, 2H), 1.45 (s, 9H), 1.21 (t,
J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 157.8, 156.0, 150.3,
107.7, 104.7, 80.2, 64.9, 51.1, 28.5, 21.5, 12.1; HRMS (ESI, m/z):
calcd for C13H21NO4Na: 278.1363; found [M+Na]+: 278.1363;
HPLC analysis (Chiralpak IA column, heptane/2-propanol = 97:3,
flow rate = 1 mL/min, wavelength = 220 nm): Rt = 21.60 (minor)
and 23.26 (major).
(69 lL, 0.63 mmol) in triethylamine (0.4 mL) was added dropwise
and the mixture was stirred for 4 h at room temperature.
Subsequently, the mixture was diluted with diethylether (10 mL)
and washed with brine. The organic extract was separated, dried
over magnesium sulfate, and concentrated. Chromatography on
silica gel eluting with 20% diethylether in petroleum ether afforded
the pure product 11 as a pale yellow solid: 101 mg (94%), mp = 96–
4.11.2. (S)-(1-(5-Ethyl-4-(4-fluorophenyl)furan-2-yl)-2-hydroxy-
ethyl)carbamic acid tert-butyl ester 14
97 °C; [
a
]
D
22 = +34.2 (c 1.04, CH2Cl2), P99% ee; IR (UATR): 3389,
66 mg (94%), colorless oil; [
a]
22 = ꢀ49.4 (c 0.50, CH2Cl2), 97% ee;
D
2223, 1687 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.45–7.43 (m,
IR (UATR): 3410, 1689 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.32–
2H), 7.35–7.17 (m, 10H), 7.08–7.05 (m, 2H), 6.06 (s, 1H), 4.96 (br
s, 1H), 4.79 (br s, 1H), 3.10 (br d, J = 6.7 Hz, 2H), 2.74 (t,
J = 7.4 Hz, 2H), 1.74 (sext, J = 7.4 Hz, 2H), 1.41 (s, 9H), 0.99 (t,
J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 159.5, 155.0, 152.1,
137.0, 131.4, 129.5, 128.5, 128.4, 128.0, 126.7, 123.8, 109.4,
103.7, 91.8, 81.9, 80.0, 50.0, 40.5, 29.3, 28.5, 21.6, 13.9; HRMS
7.25 (m, 2H), 7.11–7.03 (m, 2H), 6.32 (s, 1H), 5.18 (br s, 1H), 4.88
(br s, 1H), 4.00–3.85 (m, 2H), 2.74 (q, J = 7.5 Hz, 2H), 2.14 (br s,
1H), 1.47 (s, 9H), 1.25 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3):
d
161.8 (J1CF = 245.5 Hz), 155.9, 152.5, 150.2, 130.0,
(J4CF = 3.3 Hz), 129.3 (JC3F = 7.8 Hz), 120.3, 115.6 (JC2F = 21.4 Hz), 108.7,
80.3, 64.8, 51.1, 28.5, 20.4, 13.0; HRMS (ESI, m/z): calcd for

B. Guieu et al. / Tetrahedron: Asymmetry 26 (2015) 868–875
875
C19H24NO4FNa: 372.1587; found [M+Na]+: 372.1585; HPLC analysis
(Chiralpak IA column, heptane/2-propanol = 95:5, flow rate =
1 mL/min, wavelength = 220 nm): Rt = 15.26 (minor) and 17.42
(major).
Weibel, J.-M.; Pale, P. J. Org. Chem. 2009, 74, 5342–5348; (i) Kotikalapudi, R.;
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Rudolph, M.; Hashmi, A. S. K. Adv. Synth. Catal. 2014, 356, 2337–2342; (k)
Wang, T.; Shi, S.; Hansmann, M. A.; Rettenmeier, E.; Rudolph, M.; Hashmi, A. S.
K. Angew. Chem. Int. Ed. 2014, 53, 3715–3719; (l) Hashmi, A. S. K.; Schwarz, L.
Chem. Ber. 1997, 130, 1449–1456; (m) Hashmi, A. S. K.; Ruppert, T. L.; Knöfel, T.;
Bats, J. W. J. Org. Chem. 1997, 62, 7295–7304.
4.12. (S)-2-Amino-2-(5-ethylfuran-2-yl)ethan-1-ol, hydrochloride
15
5. Paolucci, C.; Rosini, G. Tetrahedron Asymmetry 2008, 18, 2923–2946.
6. (a) Zhou, W.-S.; Lu, Z.-H.; Xu, Y.-M.; Liao, L.-X.; Wang, Z.-M. Tetrahedron 1999,
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To product 13 (47 mg, 0.18 mmol) was added 4 M HCl in diox-
ane (0.5 mL), which was then left to stir for 1 h. The reaction mix-
ture was concentrated in vacuo, taken up with a mixture of
diethylether/ethyl acetate (4:1). The solid part was separated by
filtration, washed with diethylether, and dried in vacuum desicca-
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a
]
;
22= ꢀ16.2
D
(c 0.50, MeOH); IR (UATR): 3550–2400 (br), 2034 cmꢀ1
1H NMR
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105; (b) Bushey, M. L.; Hankaas, M. H.; O’Doherty, G. A. J. Org. Chem. 1999, 64,
2984–2985; (c) Alvaro, G.; Martelli, G.; Savoia, D.; Zuffoli, A. Synthesis 1998,
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12744; (e) Zhou, W. S.; Lu, Z. H.; Wang, Z. M. Tetrahedron 2009, 65, 1919–1927.
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P.; Gouault, N. Beilstein J. Org. Chem. 2013, 9, 2042–2047.
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12. (a) Alfaro, R.; Yuste, F.; Ortiz, B.; Sanchez-Obregon, R.; Garcıa Ruano, J. L.
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14. (a) Fu, Y.; Bieschke, J.; Kelly, J. W. J. Am. Chem. Soc. 2005, 127, 15366–15367; (b)
Kaltenbronn, J.; Hudspeth, J. P.; Lunney, E. A.; Michniewicz, B. M.; Nicolaides, E.
D.; Repine, J. T.; Roark, W. H.; Stier, M. A.; Tinney, F. J.; Woo, P. K. W.;
Essenburg, A. D. J. Med. Chem. 1990, 33, 838–845.
(300 MHz, CD3OD): d 6.43 (d, J = 3.2 Hz, 1H), 6.07 (d, J = 3.2 Hz,
1H), 4.41 (ABX System, JAX = 8.2 Hz, JBX = 4.9 Hz, 1H), 3.94 (ABX
System, JAB = 11.6 Hz, JBX = 4.9 Hz, 1H), 3.88 (ABX System,
JAB = 11.6 Hz, JAX = 8.3 Hz, 1H), 2.66 (q, J = 7.5 Hz, 2H), 1.23 (t,
J = 7.5 Hz, 3H); 13C NMR (75 MHz, CD3OD): d 160.4, 146.9, 111.4,
106.3, 61.9, 51.9, 22.1, 12.5; HRMS (ESI, m/z): calcd for C8H11O2:
139.0759; found [MꢀNH3+H]+: 139.0760.
Acknowledgments
This research was financially supported by the French Ministry
of Higher Education and Research (MESR) and CNRS.
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