The Chiron Approach to (3 R,3 aS,6 aR)-Hexahydrofuro[2,3- b]furan-3-ol, a Key Subunit of HIV-1 Protease Inhibitor Drug, Darunavir

Article abstract of DOI:10.1021/acs.joc.0c02396

We describe an enantioselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol which is a key subunit of darunavir, a widely used HIV-1 protease inhibitor drug for the treatment of HIV/AIDS patients. The synthesis was achieved in optically pure form utilizing commercially available sugar derivatives as the starting material. The key steps involve a highly stereoselective substrate-controlled hydrogenation, a Lewis acid catalyzed anomeric reduction of a 1,2-O-isopropylidene-protected glycofuranoside, and a Baeyer-Villiger oxidation of a tetrahydrofuranyl-2-aldehyde derivative. This optically active ligand alcohol was converted to darunavir efficiently.

Full text of DOI:10.1021/acs.joc.0c02396

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The Chiron Approach to (3R,3aS,6aR)‑Hexahydrofuro[2,3‑b]furan-3-
ol, a Key Subunit of HIV‑1 Protease Inhibitor Drug, Darunavir
Arun K. Ghosh,* Shivaji B. Markad, and William L. Robinson
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ABSTRACT: We describe an enantioselective synthesis of
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol which is a key
subunit of darunavir, a widely used HIV-1 protease inhibitor
drug for the treatment of HIV/AIDS patients. The synthesis was
achieved in optically pure form utilizing commercially available
sugar derivatives as the starting material. The key steps involve a
highly stereoselective substrate-controlled hydrogenation, a Lewis
acid catalyzed anomeric reduction of a 1,2-O-isopropylidene-
protected glycofuranoside, and a Baeyer−Villiger oxidation of a tetrahydrofuranyl-2-aldehyde derivative. This optically active ligand
alcohol was converted to darunavir efficiently.
he development of combination antiretroviral therapies
(cART) has transformed Acquired Immunodeficiency
Syndrome (AIDS) from a fatal disease into a manageable
chronic condition.1,2 The Human Immunodeficiency Virus
Type-1 (HIV-1) protease inhibitor drugs are an important
component of cART regimens.3,4 Darunavir (1, Figure 1) is
Darunavir received full approval in 2008 for all HIV/AIDS
patients including pediatrics.5,9 Darunavir is a widely used
protease inhibitor drug, and it has become the front-line
therapy for treatment of HIV/AIDS. Darunavir was specifically
designed to promote “backbone binding” through extensive
hydrogen bonding interactions with the HIV-1 protease active
site backbone atoms.8,10 One of the key features of darunavir is
the stereochemically defined bicyclic (3R,3aS,6aR)-bis-tetrahy-
drofuran (bis-THF) heterocycle as the P2-ligand.7,10 Our
extensive structure−activity studies and X-ray crystallographic
studies established the bis-THF ligand as the privileged ligand
for the S2 subsite of HIV-1 protease for a variety of very potent
HIV-1 protease inhibitors with clinical potential.11−13
T
Darunavir is readily synthesized by formation of the
urethane between the bis-THF ligand alcohol 2 and amino-
alcohol derivative 3.14 The bis-THF ligand structure contains
three contiguous stereocenters. We and others reported a
number of syntheses of bis-THF ligand alcohol 2 in optically
active form.14 Our initial synthesis of bis-THF alcohol was
achieved utilizing (3R)-diethyl malate as the key starting
material.15 We reported an efficient racemic synthesis of bis-
THF alcohol which was resolved by using a lipase-catalyzed
enzymatic resolution to provide the optically active ligand.16
We also investigated the stereoselective photochemical route
to bis-THF alcohol where 1,3-dioxolane was added to a chiral
furanone derivative.17 These procedures provided access to
Figure 1. Structure of darunavir (1), bis-THF (2), and aminoalcohol
3.
the most recent FDA approved HIV-1 protease inhibitor drug
for the treatment of patients with HIV-1 infection and AIDS.5,6
It is exceedingly potent and has exhibited broad-spectrum
activity against highly multidrug-resistant HIV-1 variants.7,8 It
received FDA approval in 2006 for the treatment of HIV/
AIDS patients who are harboring multidrug-resistant HIV-1
variants and do not respond to other approved therapies.
Received: October 9, 2020
https://dx.doi.org/10.1021/acs.joc.0c02396
© XXXX American Chemical Society
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optically active bis-THF ligand alcohol. However, the optical
purity of ligand alcohol was in the range 92−96% ee.
Quaedflieg and co-workers reported a large-scale synthesis of
bis-THF ligand alcohol utilizing a diastereoselective Michael
addition as the key step.18 Black and co-workers reported an
asymmetric synthesis of bis-THF ligand alcohol using a
Mukaiyama aldol reaction with a silyl ketene acetal.19 Yu and
co-workers reported a large-scale synthesis of a racemic bis-
THF ligand from glycolaldehyde dimer and 2,3-dihydrofuran
using Yb(fod)3 catalyst.20 Xie and co-workers also reported a
similar Lewis acid catalyzed synthesis of racemic bis-THF
alcohol.21 For our continued interest in optically pure bis-THF
ligand, we have investigated the feasibility of a carbohydrate-
based synthesis of bis-THF alcohol. Herein, we report an
optically active synthesis of bis-THF utilizing inexpensive D-
xylofuranose or D-glucose as the starting materials. The overall
route may furnish convenient access to quantities of optically
pure bis-THF ligand alcohol.
silica gel chromatography in 85% yield over two steps.
Catalytic hydrogenation of olefin 6 over 10% Pd/C in ethanol
at 23 °C under a hydrogen-filled balloon afforded saturated
derivative 7 as the only isolated product in 96% yield.
Saturated ester 7 was converted to γ-lactone derivative 8 by
exposure to BF3·OEt2 (8 equiv) followed by Et3SiH (3 equiv)
in CH2Cl2 at −78 to 23 °C for 6 h.24,25 Bicyclic lactone 8 was
isolated in 87% yield. Presumably, the reaction of the
isopropylidene derivative with a Lewis acid resulted in the
formation of an oxocarbenium ion intermediate. Silane
reduction then provided the corresponding alcohol which
formed the γ-lactone under the acidic conditions. The overall
transformation is quite efficient. The reaction was carried out
on gram scale to provide an excellent yield of γ-lactone 8.
Hydrolysis of the benzoate ester using K2CO3 in MeOH at 23
°C for 15 min furnished bicyclic alcohol 9 in 85% yield.
Alcohol 9 was converted to methyl acetal 10 in a three-step
sequence involving (1) Dess-Martin oxidation of the primary
alcohol to the corresponding aldehyde, (2) m-CPBA-promoted
Baeyer−Villiger oxidation at 0 °C for 2 h, and (3) exposure of
the resulting formate to 6% HCl in MeOH at 0 °C. Acetal 10
was obtained in 41% yield over three steps. Reduction of
lactone 10 by LiAlH4 in THF at −78 to 23 °C for 1 h followed
by exposure of the resulting diol to aqueous HCl at 0 to 23 °C
furnished bis-THF alcohol 2 [α]2D3 = −12.3° (c 0.73, MeOH;
lit17 [α]2D3 = −12.4° (c 1.16, MeOH)) in 63% yield over two
steps.18 The optical purity of alcohol (−)-2 was determined
after its conversion to p-nitrocarbonate 11.26 The reaction of
(−)-2 with p-nitrophenylchloroformate in the presence of
pyridine in CH2Cl2 at 0 to 23 °C for 12 h provided
nitrocarbonate 11 in 92% yield. Chiral HPLC analysis of 11 on
a CHIRALPAK OD-H column revealed an enantiomeric
purity of 99% ee (please see Supporting Information).
Our chiron approach22,23 to the synthesis of optically active
bis-THF alcohol 2 begins with commercially available 1,2-O-
isopropylidine-α-D-xylofuranose 4 as shown in Scheme 1.
Scheme 1. Synthesis of Optically Active bis-THF Ligand
from D-Xylose
We have also converted commercially available 1,2:5,6-di-O-
isopropylidene-α-D-glucofuranose 12 to bis-THF ligand
alcohol 2. As shown in Scheme 2, Swern oxidation of 12
followed by Horner−Wadsworth−Emmons reaction of the
resulting ketone provided α,β-unsaturated ester derivative 13
as a 4:1 Z/E mixture in 48% yield over two steps.27 The
isomers were separated, and the Z-ester 13 was treated with
80% aqueous AcOH at 23 °C for 60 h to provide the
corresponding diol.28 The resulting diol was hydrogenated
over 10% Pd/C under a hydrogen-filled balloon at 23 °C for
24 h to afford the saturated diol 14 in 66% yield over two
steps. Diol 14 was converted to alcohol 15 by exposure to
NaIO4 in MeOH at 0 to 23 °C for 2 h.28 The resulting
aldehyde was reacted with NaBH4 in MeOH at 0 °C for 1 h to
furnish 15 in 88% yield over two steps.25 Protection of the
primary alcohol as benzoate ester 7 was carried out with
benzoyl chloride in the presence of Et3N. Benzoate derivative 7
has been converted to bis-THF alcohol 2 as described in
Scheme 1. Alcohol 2 was converted to mixed activated
carbonate 16 by treatment with N,N′-disuccinimidyl carbonate
in the presence of Et3N in CH2Cl2 at 23 °C.17,29 The synthesis
of darunavir is shown in Scheme 3. Commercially available
epoxide 17 was reacted with isobutylamine in 2-propanol at 60
°C for 22 h. Reaction of the resulting amino alcohol with 4-
nitrobenzenesulfonyl chloride in CH2Cl2 in the presence of
Et3N at 23 °C for 5 h afforded Cbz-containing sulfonamide
derivative 18 in 71% yield over two steps.30 For the synthesis
of darunavir, the Cbz-derivative 18 was subjected to catalytic
hydrogenation with mixed activated carbonate 16 in the
presence of Et3N in THF under a hydrogen-filled balloon at 23
Selective protection of the primary alcohol as a benzoate
derivative with 1.1 equiv of benzoyl chloride in the presence of
pyridine and a catalytic amount of DMAP in CH2Cl2 at 0 °C
for 30 min furnished 5 in 95% yield. Swern oxidation of 5
provided the corresponding ketone which was subjected to
Wittig olefination with commercially available (carbethoxy-
methylene)triphenylphosphorane in CH2Cl2 at 23 °C for 24 h
to afford α,β-unsaturated ester 6 along with a small amount of
its isomer in a 8:1 mixture. The Z-isomer 6 was separated by
B
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involves more steps than other published syntheses. However,
the main advantage of the current route is the enantioselective
synthesis using inexpensive sugars as the starting materials,
efficient reaction steps, and high optical purity of the bis-THF
alcohol. The route has the potential for scale-up. The bis-THF
alcohol was converted to mixed activated succinimidyl
carbonate. Catalytic hydrogenation of this carbonate with a
Cbz-derivative of a dipeptide isostere furnished darunavir.
Scheme 2. Synthesis of Optically Active bis-THF Ligand
from D-Glucose
EXPERIMENTAL PROCEDURES
■
General Methods. All chemical and reagents were purchased
from commercial suppliers and used without further purification
unless otherwise noted. Solvents were purified as follows: CH2Cl2 was
distilled from calcium hydride or purified using a solvent purification
system; methanol was used without further purification; tetrahy-
drofuran was distilled from sodium/benzophenone. The flasks were
fitted with rubber septa and kept under a positive pressure of argon.
Heated reactions were ran using an oil bath on a hot plate equipped
with a temperature probe. TLC analysis was conducted using glass-
backed thin-layer silica gel chromatography plates (60 Å, 250 μm
thickness, F-254 indicator). Flash chromatography was done using a
230−400 mesh, a 60 Å pore diameter silica gel. 1H NMR spectra were
recorded on 400 and 500 MHz spectrometers. 13C NMR spectra were
recorded at 100 MHz NMR. Chemical shifts are reported in parts per
million and referenced to the deuterated residual solvent peak
1
(CDCl3, 7.26 ppm for H and 77.16 ppm for 13C). NMR data are
reported as δ value (chemical shift), J-value (Hz), and integration,
where s = singlet, bs = broad singlet, d = doublet, t = triplet, q =
quartet, p = quintet, m = multiplet, dd = doublet doublets, and so on.
Optical rotations were recorded on a digital polarimeter. Low
resolution mass spectra (LRMS) spectra were recorded using a
quadrupole LCMS under positive electrospray ionization (ESI+).
High-resolution mass spectrometry (HRMS) spectra were recorded at
the Purdue University Department of Chemistry Mass Spectrometry
Center. These experiments were performed under ESI+ and positive
atmospheric pressure chemical ionization (APCI+) conditions using
an Orbitrap XL Instrument.
Scheme 3. Synthesis of Darunavir (1)
((3aR,5R,6aR)-6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl)methyl Benzoate (5). A solution of commer-
cially available 1,2-O-isopropylidene-α-D-xylofuranose 4 (3 g, 15.8
mmol) in dry CH2Cl2 (40 mL) was cooled to 0 °C. To the mixture
were added 1.90 mL (23.6 mmol) pyridine and a catalytic amount
(192 mg) of N,N-dimethylaminopyridine. The resulting mixture was
stirred at 0 °C for 10 min, at which time 2 mL (17.3 mmol) benzoyl
chloride were added to it dropwise over a period of 30 min. The
reaction mixture was stirred at 0 °C for an additional 30 min and then
quenched by the addition of 20 mL of a saturated solution of NH4Cl.
The reaction was allowed to warm to 23 °C, the layers were separated,
and the aqueous layer was extracted with CH2Cl2 (3×). The
combined organic extracts were washed with an aqueous solution of
CuSO4, water, and brine. The organic solution was dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography (50% EtOAc in hexane) to afford 5 as an oil (4.43 g,
95%). Rf = 0.2 (50% EtOAc/hexanes, SiO2 plate). [α]2D3 = +15.5 (c
°C for 17 h to provide carbamate 1 (darunavir) in 53% yield.
The hydrogenation condition accomplished deprotection of
Cbz-group, reaction of the resulting amine with mixed
succinimidyl carbonate to form the carbamate, and reduction
of the aromatic nitro group to the amine.31
In conclusion, we describe here a convenient synthesis of
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (2) in optically
pure form using commercially available glucose or xylose
derivatives. The key synthetic steps involved a highly
diastereoselective substrate controlled hydrogenation of an
α,β-unsaturated ester, an efficient BF3·OEt2-catalyzed depro-
tection of an isopropylidene group and subsequent silane
reduction, a Baeyer−Villiger oxidation, and an acid-catalyzed
cyclization. Overall, the synthesis of the bis-THF ligand alcohol
1
0.15, CHCl3). H NMR (400 MHz, CDCl3) δ 8.08−8.01 (m, 2H),
7.62−7.54 (m, 1H), 7.49−7.40 (m, 2H), 5.95 (d, J = 3.6 Hz, 1H),
4.83−4.73 (m, 1H), 4.59 (d, J = 3.6 Hz, 1H), 4.43−4.34 (m, 2H),
4.18 (dd, J = 4.2, 2.3 Hz, 1H), 3.36−3.31 (m, 1H), 1.50 (s, 3H), 1.32
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.3, 133.5, 129.8
(2C), 129.1, 128.4 (2C), 111.8, 104.6, 84.9, 78.4, 74.3, 61.2, 26.7,
26.0. LRMS (ESI) m/z: [M + H]+ 295.1. HRMS (ESI) m/z: [M +
Na]+ calcd C15H18O6Na 317.0996; found 317.0998.
(3aR,5R,6aS)-2,2-Dimethyl-6-oxotetrahydrofuro[2,3-d][1,3]-
dioxol-5-yl)methyl Benzoate (6). A solution of oxalyl chloride
(2.42 mL, 28.5 mmol) in 40 mL of anhydrous CH2Cl2 was cooled to
−78 °C under an argon atmosphere. To the mixture was added
DMSO (4 mL, 57.1 mmol) dropwise over a period of 15 min. After
the resulting solution had been stirred at the same temperature for 10
C
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min, a solution of alcohol 5 (4.2 g, 14.2 mmol) in anhydrous CH2Cl2
(10 mL) was added to it dropwise over a period of 15 min. Stirring
was continued at −78 °C for an additional 30 min. Then, Et3N (9.9
mL, 71.3 mmol) was added. The temperature of the reaction mixture
was maintained at −78 °C for 10 min, and then the mixture was
allowed to stir for 30 min while warming to 23 °C. The reaction was
then quenched by 30 mL of water and extracted with (3×) CH2Cl2.
The CH2Cl2 layer was washed with saturated aqueous NaHCO3 and
then brine and was dried over anhydrous Na2SO4. Filtration and
solvent removal under reduced pressure afforded crude product which
was used in the next step without further purification.
To a stirred solution of the above ketone (14.3 mmol) in dry
CH2Cl2 (30 mL) was added (carbethoxymethylene)triphenyl-
phophorane (5.96 g, 17.1 mmol). The reaction mixture was stirred
under argon at 23 °C for 24 h. The reaction mixture was concentrated
under reduced pressure, and the resulting residue was purified by flash
chromatography on silica (5% EtOAc/hexanes to 10% EtOAc/
hexane) to yield the ester as an 8:1(Z/E) mixture of separable
isomers. Z-isomer of ester 6 (4.4 g, 85% over 2 steps), yellow oil. Rf =
0.4 (20% EtOAc/hexanes, SiO2 plate). [α]2D3 = +240 (c 0.5, CHCl3).
1H NMR (400 MHz, CDCl3) δ 8.05−7.92 (m, 2H), 7.62−7.53 (m,
(3aR,4S,6aR)-4-(Hydroxymethyl)tetrahydrofuro[3,4-b]-
furan-2(3H)-one (9). To a stirred solution of the lactone 8 (1.2 g,
4.6 mmol) in MeOH (15 mL) at 0 °C was added K2CO3 (695 mg, 5
mmol), and the mixture was stirred for 15 min. The reaction mixture
was concentrated under reduced pressure to remove MeOH. The
obtained residue was dissolved in water (10 mL) and CH2Cl2 (10
mL), and the aqueous layer was extracted with (3×) 10% MeOH/
CH2Cl2. The combined organic layer was washed with brine and
dried over anhydrous Na2SO4. The solvent was evaporated, and the
residue was purified by by silica gel column chromatography (10%
MeOH/CH2Cl2) to afford 9 (690 mg, 85%) as a colorless oil. Rf = 0.2
(80% EtOAc/hexanes, SiO2 plate). [α]2D3 = −11.1 (c 0.02, CHCl3). 1H
NMR (400 MHz, CDCl3) δ 5.09 (ddd, J = 6.9, 4.8, 2.0 Hz, 1H), 4.17
(dd, J = 11.0, 4.7 Hz, 1H), 4.02 (dt, J = 11.4, 2.4 Hz, 1H), 3.86−3.70
(m, 2H), 3.64−3.56 (m, 1H), 2.98−2.88 (m, 1H), 2.82 (ddd, J =
18.1, 9.3, 1.4 Hz, 1H), 2.46 (dd, J = 18.1, 1.8 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 175.6, 85.2, 84.3, 72.7, 62.4, 40.0, 32.8. LRMS
(ESI) m/z: [M + H]+ 159. HRMS (ESI) m/z: [M + Na]+ calcd
C7H10O4Na 181.0471; found 181.0470.
(3aS,6aR)-4-Methoxytetrahydrofuro[3,4-b]furan-2(3H)-one
(10). To a solution of alcohol 9 (200 mg, 1.3 mmol) in anhydrous
CH2Cl2 (3 mL) were added Na2HPO4 (369 mg, 2.6 mmol) and DMP
(1.10 g, 2.6 mmol) at 0 °C. The reaction mixture was stirred at 0 to
23 °C for 3 h and then cooled to 0 °C and quenched with a saturated
solution of NaHCO3 (10 mL). The aqueous layer was extracted with
CH2Cl2 (3×), and the organic layer was washed with water (10 mL)
and brine. The organic solution was dried over anhydrous NaSO4,
filtered, and concentrated under reduced pressure to afford the
aldehyde. The crude aldehyde was used in the next step without
further purification.
1H), 7.44 (dd, J = 8.4, 7.2 Hz, 2H), 6.03−5.95 (m, 2H), 5.78 (dt, J =
4.2, 1.5 Hz, 1H), 5.16 (ddt, J = 5.3, 3.7, 1.8 Hz, 1H), 4.57 (dd, J =
11.9, 3.5 Hz, 1H), 4.43 (dd, J = 11.9, 5.0 Hz, 1H), 4.24 (q, J = 7.1 Hz,
2H), 1.51 (s, 3H), 1.44 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 166.0, 164.5, 154.5, 133.2, 129.6 (2C),
129.4, 128.4 (2C), 117.1, 112.9, 105.0, 78.1, 77.8, 65.1, 60.8, 27.3,
27.0, 14.0. LRMS (ESI) m/z: [M + Na]+ 385.0. HRMS (ESI) m/z:
[M + Na]+ calcd C19H22O7Na 385.1258; found 385.1247.
((3aR,5S,6R,6aR)-6-(2-Ethoxy-2-oxoethyl)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl Benzoate (7). To
a solution of Z-ester 6 (4.2 g, 11.6 mmol) in anhydrous ethanol (70
mL) 10% Pd/C (147 mg, 5% w/w) was added. The resulting mixture
was stirred under a hydrogen filled balloon for 6 h. Upon completion
of the reaction, the mixture was filtered through Celite, and the filter
cake was washed with EtOAc. Evaporation of solvent yielded a
colorless oil that was purified by flash chromatography on silica (15%
EtOAc/hexane) to provide ester 7 (4.02 g, 96%) as a colorless oil and
as a single diastereomer. Rf = 0.4 (20% EtOAc/hexanes, SiO2 plate).
To a stirred solution of the above crude aldehyde in anhydrous
CH2Cl2 (10 mL) at 0 °C were added NaHCO3 (211 mg, 2.52 mmol)
and m-CPBA (577 mg, 2.5 mmol). The reaction mixture was stirred
for 2 h at 0 °C and quenched with a saturated aqueous solution of
NaHCO3. The aqueous layer was extracted with (3×) CH2Cl2. The
combined organic solvent was washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure
to afford the formate. The crude formate was used in the next step
without further purification.
[α]2D3 = +52.7 (c 0.584, CHCl3). H NMR (400 MHz, CDCl3) δ
1
To a stirred solution of the above crude formate (1.2 mmol) in
MeOH (5 mL) at 0 °C was added slowly 6% HCl/MeOH (5 mL),
and the mixture was stirred for 12 h at 0 to 23 °C. The reaction
mixture was then neutralized with a saturated solution of NaHCO3,
concentrated under reduced pressure to remove MeOH, extracted
with CH2Cl2, and washed with brine. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure
to yield a crude residue that was purified by flash chromatography on
silica (50% ether/hexane) to yield lactone 10 (82 mg, 41% over 3
steps) as an amorphous solid with a 3:1 mixture of separable anomers.
8.15−8.00 (m, 2H), 7.60−7.52 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H),
5.87 (d, J = 3.7 Hz, 1H), 4.82 (t, J = 4.2 Hz, 1H), 4.56 (dd, J = 12.3,
2.9 Hz, 1H), 4.34 (dd, J = 12.3, 5.0 Hz, 1H), 4.19−4.08 (m, 3H), 2.75
(dd, J = 17.0, 9.8 Hz, 1H), 2.54−2.33 (m, 2H), 1.53 (s, 3H), 1.32 (s,
3H), 1.25 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
171.7, 166.3, 133.1, 129.7 (2C), 129.6, 128.3 (2C), 111.7, 104.8, 80.8,
78.6, 63.9, 60.7, 41.4, 29.6, 26.6, 26.2, 14.0. LRMS (ESI) m/z: [M +
Na]+ 387.0. HRMS (ESI) m/z: [M + Na]+ calcd C19H24O7Na
387.1414; found 387.1421.
Major Anomer: Rf = 0.4 (40% EtOAc/hexanes, SiO2 plate). [α]D23
=
((3aR,4S,6aR)-2-Oxohexahydrofuro[3,4-b]furan-4-yl)methyl
benzoate (8). To a flask containing ester 7 (2.3 g, 6.3 mmol) in dry
CH2Cl2 (20 mL) at −78 °C was added BF3·OEt2 (6.18 mL, 50.5
mmol) dropwise over 5 min, and then Et3SiH (3.01 mL, 18.9 mmol)
was added. The reaction mixture was stirred at −78 to 23 °C for 6 h.
The reaction mixture was cooled to 0 °C, quenched with a saturated
solution of NaHCO3 (20 mL), and extracted with (3×) CH2Cl2. The
combined organic layer was washed with water and brine. The organic
solution was dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The product was purified by silica gel column
chromatography (50% EtOAc/hexane) to afford 8 as an oil (1.44 g,
87%). Rf = 0.3 (30% EtOAc/hexanes, SiO2 plate). [α]2D3 = +9.6 (c
+70.3 (c 0.05, CHCl3). 1H NMR (400 MHz, CDCl3) δ 5.13 (dd, J =
7.1, 3.9 Hz, 1H), 4.87 (s, 1H), 4.09 (d, J = 10.9 Hz, 1H), 3.94 (dd, J =
10.9, 3.9 Hz, 1H), 3.31 (s, 3H), 3.02 (ddd, J = 11.2, 7.1, 4.0 Hz, 1H),
2.83 (dd, J = 18.6, 11.3 Hz, 1H), 2.50 (dd, J = 18.6, 4.0 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3) δ 175.9, 109.9, 82.9, 70.6, 54.5,
45.0, 31.7. LRMS (ESI) m/z: [M + H]+ 159.1. HRMS (ESI) m/z: [M
+ Na]+ calcd C7H10O4Na 181.0471; found 181.0472.
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol (2).17 To a
flame-dried flask was added LiAlH4 (734 mg, 19.33 mmol). The
flask was evacuated by vacuum and then flushed with argon. To the
flask was added dry THF (38 mL). The mixture was stirred and
cooled to −78 °C prior to the addition of a solution of lactone 10
(1.02 g, 6.44 mmol) in THF (38 mL). The reaction mixture was then
allowed to warm to 23 °C over 1 h. The reaction mixture was cooled
to 0 °C, and then H2O (0.7 mL), 2.0 M NaOH (0.7 mL), and H2O
(2.1 mL) were added sequentially and slowly. The mixture was stirred
vigorously at 0 °C for 1.5 h, and then it was filtered through Celite
with MeOH. The filtrate was concentrated under reduced pressure to
afford a residue containing the crude diol.
1
0.015, CHCl3). H NMR (400 MHz, CDCl3) δ 8.06−7.97 (m, 2H),
7.65−7.54 (m, 1H), 7.52−7.35 (m, 2H), 5.15 (ddd, J = 6.7, 4.8, 1.9
Hz, 1H), 4.53−4.35 (m, 2H), 4.24 (ddd, J = 11.2, 4.8, 0.5 Hz, 1H),
4.17−4.04 (m, 2H), 2.99−2.84 (m, 2H), 2.57 (dd, J = 17.8, 1.7 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 175.3, 166.1, 133.3,
129.6(2C), 129.3, 128.4(2C), 83.9, 82.9, 72.9, 64.6, 41.4, 33.0. LRMS
(ESI) m/z: [M + H]+ 263.0. HRMS (ESI) m/z: [M + H]+ calcd
C14H15O5 263.0914; found 263.0920.
D
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Note
To the flask containing the above crude diol (6.44 mmol) was
added 1.0 M HCl (15 mL). The mixture was cooled to 0 °C and
stirred prior to slow addition of concentrated HCl (1.5 mL). The
mixture was allowed to warm to 23 °C over 1 h, and then the mixture
was cooled back down to 0 °C and neutralized by portionwise
addition of solid Na2CO3. The aqueous layer was extracted with a
10% MeOH/CH2Cl2 solution (5 × 150 mL). The organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to yield the crude ligand alcohol 2 that was purified
by flash chromatography on SiO2 (70% ether/hexanes) to yield ligand
alcohol 2 (533 mg, 63% over 2 steps) as a colorless oil. Rf = 0.56
(100% EtOAc, SiO2 plate). [α]2D3 = −12.3 (c 0.732, MeOH). 1H
NMR (400 MHz, CDCl3) δ 5.70 (d, J = 5.8 Hz, 1H), 4.45 (dtd, J =
8.0, 6.6, 5.2 Hz, 1H), 4.03−3.96 (m, 2H), 3.90 (ddd, J = 10.0, 8.6, 6.3
Hz, 1H), 3.64 (dd, J = 9.2, 7.0 Hz, 1H), 2.86 (dddd, J = 10.1, 7.9, 5.2,
2.5 Hz, 1H), 2.36−2.27 (m, 1H), 1.88 (dtd, J = 12.9, 9.9, 8.4 Hz, 1H),
1.79 (d, J = 5.3 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 109.7,
73.3, 71.1, 70.0, 46.7, 25.0.
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (4-nitrophen-
yl) Carbonate (11).26 To a flame-dried flask were added optically
active bis-THF alcohol (−)-2 (6 mg, 0.046 mmol) and CH2Cl2 (1.0
mL) followed by pyridine (7.5 μL, 0.092 mmol). The mixture was
stirred under argon and cooled to 0 °C. To the mixture was quickly
added 4-nitrophenyl chloroformate (19 mg, 0.092 mmol), and the
resulting reaction was stirred at 23 °C for 12 h. After this period, the
mixture was concentrated under reduced pressure and purified by
flash chromatography (20% EtOAc/hexanes) to yield carbonate 11
(12 mg, 92% yield) as an amorphous white solid. Rf = 0.15 (30% ethyl
acetate/hexanes). 1H NMR (400 MHz, CDCl3) δ 8.34−8.25 (m,
2H), 7.43−7.35 (m, 2H), 5.77 (d, J = 5.1 Hz, 1H), 5.32−5.20 (m,
1H), 4.15 (dd, J = 10.0, 6.1 Hz, 1H), 4.05 (td, J = 8.4, 2.6 Hz, 1H),
3.97 (tt, J = 10.0, 6.1 Hz, 2H), 3.15 (dddd, J = 10.2, 7.9, 5.1, 2.4 Hz,
1H), 2.17 (ddt, J = 13.2, 5.4, 2.5 Hz, 1H), 2.00 (dtd, J = 13.2, 10.0,
8.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 155.1, 151.9, 145.5,
125.3, 121.6, 109.1, 77.5, 70.3, 69.5, 44.9, 25.9.
Ethyl 2-((3aR,5S,6aR)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-
yl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(5H)-ylidene)-
acetate (13).28 To a flame-dried flask was added CH2Cl2 (210 mL).
The CH2Cl2 was stirred under argon and cooled to −78 °C prior to
addition of oxalyl chloride (5.47 mL, 64.6 mmol). After 5 min, DMSO
(9.18 mL, 129.2 mmol) was added dropwise to the reaction mixture.
After 10 min, a solution of commercially available 1,2:5,6-di-O-
isopropylidene-α-D-glucofuranose 12 (8.41 g, 32.3 mmol) in CH2Cl2
(20 mL) was added dropwise to the reaction mixture, and then the
mixture was stirred at −78 °C for 1 h. At this time, Et3N (22.5 mL,
161.6 mmol) was added. The temperature of the reaction mixture was
maintained at −78 °C for 10 min, and then the cooling bath was
removed. The mixture was allowed to stir for 30 min while warming
to 23 °C. The reaction mixture was then quenched with H2O and
transferred to a separatory funnel. The organic layer was washed with
saturated aqueous NaHCO3 and then with brine. The organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to yield the crude ketone as a brown oil. The crude
ketone was used without further purification.
To a flame-dried flask was added NaH (60% in oil) (2.37 g, 59
mmol). The flask was evacuated and placed under argon prior to
addition of dry THF (91 mL). The mixture was stirred and cooled to
0 °C prior to the dropwise addition of triethyl phosphonoacetate
(12.3 mL, 62.2 mmol). After 15 min, a solution of the above crude
ketone (31.1 mmol) in dry THF (31 mL) was added slowly at 0 °C.
The reaction mixture was kept at a temperature of 0 °C for 30 min,
and then the reaction mixture was allowed to warm to 23 °C over 30
min. The reaction was quenched by the addition of saturated aqueous
NH4Cl, extracted with Et2O, and washed with brine. The organic
layer was then dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to yield a brown oil that was
purified by flash chromatography on SiO2 (15% ether/hexanes to 25%
ether/hexanes) to yield α,β-unsaturated ester 13 as a 4:1 (Z/E)
mixture of separable isomers (combined yield for mixture of isomers,
48% over 2 steps). Z-isomer of ester 13: (3.95 g, 39% over 2 steps),
amorphous solid. Rf = 0.60 (50% ether/hexanes, SiO2 plate). 1H
NMR (400 MHz, CDCl3) δ 6.32 (dd, J = 2.2, 1.4 Hz, 1H), 5.82 (d, J
= 4.2 Hz, 1H), 5.73 (dt, J = 4.2, 1.4 Hz, 1H), 4.66 (ddt, J = 6.0, 2.2,
1.4 Hz, 1H), 4.28−4.19 (m, 2H), 4.12−4.06 (m, 1H), 4.03−3.97 (m,
2H), 1.49 (s, 3H), 1.43 (s, 3H), 1.39 (s, 3H), 1.35 (s, 3H), 1.30 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.3, 155.8, 118.0,
112.9, 110.3, 105.0, 80.0, 78.5, 76.9, 67.4, 60.8, 27.4, 27.2, 26.8, 25.5,
14.3. E-isomer of ester 13E: (963 mg, 9% over 2 steps). Rf = 0.65
(50% ether/hexanes, SiO2 plate). 1H NMR (400 MHz, CDCl3) δ 6.21
(t, J = 1.9 Hz, 1H), 5.92 (d, J = 4.8 Hz, 1H), 5.75 (q, J = 1.9 Hz, 1H),
5.09 (dt, J = 4.8, 1.9 Hz, 1H), 4.34 (ddd, J = 7.9, 6.3, 2.6 Hz, 1H),
4.17 (qt, J = 7.4, 3.8 Hz, 2H), 3.96 (dd, J = 8.8, 6.3 Hz, 1H), 3.56 (dd,
J = 8.8, 7.9 Hz, 1H), 1.42 (s, 3H), 1.37 (s, 3H), 1.32−1.27 (m, 9H).
13C{1H} NMR (100 MHz, CDCl3) δ 165.7, 158.1, 118.2, 113.8,
109.2, 103.9, 82.3, 80.1, 79.1, 65.5, 60.9, 27.99, 27.96, 26.2, 25.8, 14.3.
Ethyl-2-((3aR,5S,6R,6aR)-5-((R)-1,2-dihydroxyethyl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)acetate (14).28
To a flask were added Z-ester 13 (1.77 g, 5.4 mmol) and 80%
AcOH/H2O (20 mL). The mixture was stirred at 23 °C for 60 h. The
reaction mixture was then concentrated under reduced pressure, and
the resultant crude orange oil was purified by flash chromatography
on SiO2 (50% EtOAc/hexanes) to yield the deprotected α,β-
unsaturated ester (1.14 g, 74%) as a colorless oil. Rf = 0.45 (75%
1
EtOAc/hexanes, SiO2 plate). H NMR (400 MHz, CDCl3) δ 6.30
(dd, J = 2.2, 1.5 Hz, 1H), 5.86 (d, J = 4.2 Hz, 1H), 5.74 (dt, J = 4.2,
1.5 Hz, 1H), 4.79 (ddd, J = 6.6, 2.2, 1.4 Hz, 1H), 4.23 (q, J = 7.1 Hz,
2H), 3.80−3.67 (m, 3H), 2.95 (d, J = 6.6 Hz, 1H), 2.45 (s, 1H), 1.48
(s, 3H), 1.41 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 165.3, 155.7, 117.7, 113.0, 104.9, 80.0, 78.4, 73.5,
63.5, 60.9, 27.4, 27.2, 14.3.
To a flame-dried flask was added a solution of the above α,β-
unsaturated ester (1.06 g, 3.68 mmol) in anhydrous ethanol (16 mL)
followed by 10% Pd/C (53 mg, 5% w/w). The flask containing the
mixture was evacuated by vacuum and flushed with argon three times,
and then it was evacuated by vacuum and flushed with hydrogen three
times. The reaction mixture was then left to stir under an atmosphere
of hydrogen (1 atm) for 24 h. The reaction mixture was then filtered
through Celite with EtOAc and concentrated under reduced pressure
to yield a crude colorless oil that was purified by flash
chromatography on SiO2 (3% MeOH/CH2Cl2) to yield the saturated
diol 14 (950 mg, 89%) as a colorless syrup. Rf = 0.45 (75% EtOAc/
hexanes, SiO2 plate). 1H NMR (400 MHz, CDCl3) δ 5.76 (d, J = 3.7
Hz, 1H), 4.76 (dd, J = 4.8, 3.7 Hz, 1H), 4.13 (qd, J = 7.1, 3.2 Hz,
2H), 3.82−3.60 (m, 4H), 3.24 (d, J = 5.4 Hz, 1H), 2.91 (t, J = 5.6 Hz,
1H), 2.77−2.63 (m, 2H), 2.42−2.31 (m, 1H), 1.46 (s, 3H), 1.28 (s,
3H), 1.24 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
172.9, 111.9, 104.8, 81.6, 81.1, 73.7, 63.9, 60.8, 43.2, 30.5, 26.7, 26.4,
14.3.
(3aR,4S,6aR)-6-Hydroxy-4-(hydroxymethyl)tetrahydrofuro-
[3,4-b]furan-2(3H)-one (15).28 To a flask were added saturated diol
14 (866 mg, 3.0 mmol) and MeOH (15 mL). The mixture was stirred
and cooled to 0 °C prior to portionwise addition of NaIO4 (1.28 g,
6.0 mmol). The reaction mixture was then allowed to warm to 23 °C
over 2 h while stirring vigorously. The reaction mixture was filtered
through Celite with MeOH and concentrated under reduced pressure
to yield a residue that was dissolved in H2O and CH2Cl2 and
extracted with CH2Cl2. The organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure to yield
the crude aldehyde that was used without further purification.
The above crude aldehyde was dissolved in MeOH (15 mL) and
cooled to 0 °C prior to portionwise addition of NaBH4 (226 mg, 6.0
mmol). The reaction mixture was stirred at 0 °C for 1 h. The mixture
was then concentrated under reduced pressure to remove MeOH.
Saturated aqueous NH4Cl was added, and the organics were extracted
with CH2Cl2. The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to yield a colorless
oil that was purified by flash chromatography on SiO2 (40% EtOAc/
hexanes) to yield ester 15 (683 mg, 88% over 2 steps) as a colorless
oil and as a single diastereomer. Rf = 0.25 (40% EtOAc/hexanes, SiO2
plate). [α]2D3 = +65.8 (c 1.31, CHCl3) 1H NMR (400 MHz, CDCl3) δ
E
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Note
5.81 (d, J = 3.8 Hz, 1H), 4.77 (t, J = 3.9 Hz, 1H), 4.15 (dttd, J = 10.8,
7.4, 3.7, 1.2 Hz, 2H), 3.91−3.83 (m, 2H), 3.60−3.52 (m, 1H), 2.69
(ddd, J = 16.8, 8.3, 1.1 Hz, 1H), 2.48−2.33 (m, 2H), 2.05 (s, 1H),
1.48 (s, 3H), 1.31 (s, 3H), 1.26 (td, J = 7.1, 1.2 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 172.4, 111.9, 104.8, 81.7, 81.5, 61.5, 60.9,
39.8, 29.9, 26.8, 26.4, 14.3.
2H), 7.38−7.12 (m, 10H), 4.99 (td, J = 18.2, 17.1, 10.6 Hz, 3H),
3.92−3.80 (m, 2H), 3.62 (s, 1H), 3.26−3.11 (m, 2H), 3.05−2.84 (m,
4H), 1.85 (dt, J = 13.8, 6.8 Hz, 1H), 0.86 (m, 6H). 13C{1H} NMR
(100 MHz, CDCl3) δ 156.7, 150.1, 144.8, 137.3, 136.3, 129.5, 128.8,
128.7, 128.6, 128.3, 128.0, 126.9, 124.4, 72.3, 67.0, 57.9, 55.6, 52.8,
35.6, 27.1, 20.1, 19.9.
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-((2S,3R)-4-((4-
amino-N-isobutylphenyl)-sulfonamido)-3-hydroxy-1-phenyl-
butan-2-yl)carbamate (1). To a flask were added carbamate
derivative 18 (48 mg, 0.1 mmol) and THF (1 mL). To the mixture
were added triethylamine (24 μL, 0.17 mmol), succinimidyl carbonate
16 (26 mg, 0.1 mmol), and then 10% Pd/C (10 mg). The mixture
was placed under a hydrogen balloon. The flask containing the
mixture was evacuated under vacuum briefly and then flushed with
hydrogen. This was repeated two more times, and then the mixture
was left to stir under a balloon of hydrogen at 23 °C for 17 h. The
mixture was then filtered through Celite with ethyl acetate,
concentrated under reduced pressure, and purified by flash
chromatography on SiO2 using 50% EtOAc/CH2Cl2 as the eluent
to yield compound 1 (Darunavir) (25 mg, 53%) as an amorphous
2,5-Dioxopyrrolidin-1-yl ((3R,3aS,6aR)-hexahydrofuro[2,3-
b]furan-3-yl) Carbonate (16).17 To a flame-dried flask were
added bis-THF ligand alcohol 2 (84 mg, 0.65 mmol) and acetonitrile
(2.5 mL). To the mixture was added triethylamine (180 μL, 1.29
mmol) followed by commercially available N,N′-disuccinimidyl
carbonate (248 mg, 0.97 mmol). The mixture was stirred under
argon at 23 °C for 16 h, and then saturated aqueous NaHCO3 was
added. The organics were extracted with a solution of 10% MeOH/
CH2Cl2, dried over anhydrous Na2SO4, filtered, concentrated under
reduced pressure, and purified by flash chromatography on SiO2 using
EtOAc to yield 16 (51 mg, 29% yield (quantitative yield brsm)) as a
1
white solid. Rf = 0.85 (EtOAc, SiO2 plate). H NMR (400 MHz,
CDCl3) δ 5.71 (d, J = 5.1 Hz, 1H), 5.22 (dt, J = 8.2, 6.0 Hz, 1H),
4.13−4.05 (m, 1H), 4.00 (td, J = 8.4, 2.5 Hz, 1H), 3.91 (ddd, J = 10.6,
8.8, 5.9 Hz, 2H), 3.16−3.04 (m, 1H), 2.82 (s, 4H), 2.11 (ddt, J =
13.5, 5.4, 2.4 Hz, 1H), 1.95 (dddd, J = 13.4, 10.3, 9.5, 8.1 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 168.6, 151.3, 109.3, 79.7, 70.1, 69.7,
1
solid. Rf = 0.5 (75% EtOAc/hexanes, SiO2 plate). H NMR (400
MHz, CDCl3) δ 7.57 (d, J = 7.8 Hz, 2H), 7.23 (m, 5H), 6.77 (d, J =
8.3 Hz, 2H), 5.64 (d, J = 5.1 Hz, 1H), 5.04 (dd, J = 20.8, 8.5 Hz, 2H),
3.87 (td, J = 20.4, 16.5, 8.6 Hz, 5H), 3.78−3.60 (m, 3H), 3.22−2.75
(m, 8H), 1.85−1.74 (m, 1H), 1.62 (t, J = 10.7 Hz, 1H), 1.45 (d, J =
13.4 Hz, 1H), 0.92 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 155.6, 149.8, 137.8, 129.6,
129.5, 128.6, 127.1, 126.7, 115.0, 109.5, 73.5, 72.9, 71.1, 69.8, 58.9,
55.3, 53.8, 45.6, 35.8, 27.4, 25.9, 20.3, 20.1. HRMS (APCI) m/z; [M
+ H]+ calcd C27H38N3O7S, 548.2425; found 548.2430.
45.2, 26.0, 25.5.
((3aR,5S,6R,6aR)-6-(2-Ethoxy-2-oxoethyl)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl Benzoate (7,
from 12). To a flame-dried flask was added a solution of 15 (16
mg, 0.1 mmol) in CH2Cl2. To the mixture was added triethylamine
(42 μL, 0.3 mmol), and the mixture was then cooled to 0 °C prior to
addition of benzoyl chloride (35 μL, 0.3 mmol). The mixture was
then allowed to warm to 23 °C, and it was stirred under argon for 18
h. The mixture was then diluted with water, extracted with CH2Cl2,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. Purification by flash chromatography on SiO2 with
20% EtOAc/hexanes provided the desired benzoate ester 7 (15 mg,
65% yield) as a colorless oil. Rf = 0.30 (20% EtOAc/hexanes, SiO2
plate). [α]2D3 = +52.7 (c 0.55, CHCl3). 1H NMR (400 MHz, CDCl3) δ
8.15−8.00 (m, 2H), 7.60−7.52 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H),
5.87 (d, J = 3.7 Hz, 1H), 4.82 (t, J = 4.2 Hz, 1H), 4.56 (dd, J = 12.3,
2.9 Hz, 1H), 4.34 (dd, J = 12.3, 5.0 Hz, 1H), 4.19−4.08 (m, 3H), 2.75
(dd, J = 17.0, 9.8 Hz, 1H), 2.54−2.33 (m, 2H), 1.53 (s, 3H), 1.32 (s,
3H), 1.25 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
171.7, 166.3, 133.1, 129.7 (2C), 129.6, 128.3 (2C), 111.7, 104.8, 80.8,
78.6, 63.9, 60.7, 41.4, 29.6, 26.6, 26.2, 14.0. LRMS (ESI) m/z: [M +
Na]+ 387.0. HRMS (ESI) m/z: [M + Na]+ calcd C19H24O7Na
387.1414; found 387.1421.
Benzyl-((2S,3R)-3-hydroxy-4-((N-isobutyl-4-nitrophenyl)-
sulfonamido)-1-phenylbutan-2-yl)carbamate (18).17 To a flask
were added commercially available benzyl (1S)-1-[(2S)-2-oxiranyl]-2-
phenylethylcarbamate (17) (200 mg, 0.7 mmol) and isopropanol (2.8
mL). To the mixture was added isobutylamine (0.43 mL, 4.26 mmol).
A reflux condenser was attached, and the mixture was stirred and
heated at 60 °C for 22 h. The mixture was concentrated under
reduced pressure to afford the corresponding aminoalcohol as an
amorphous solid that was used in the next step without further
purification.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02396.
1H and 13C NMR spectra for all new compounds; HPLC
data for compound 11 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Arun K. Ghosh − Department of Chemistry and Department
of Medicinal Chemistry, Purdue University, West Lafayette,
Indiana 47907, United States; orcid.org/0000-0003-
2472-1841; Email: akghosh@purdue.edu
Authors
Shivaji B. Markad − Department of Chemistry and
Department of Medicinal Chemistry, Purdue University,
West Lafayette, Indiana 47907, United States
William L. Robinson − Department of Chemistry and
Department of Medicinal Chemistry, Purdue University,
West Lafayette, Indiana 47907, United States
The crude aminoalcohol (0.71 mmol) was dissolved in CH2Cl2 (7
mL) and transferred to a flame-dried flask. The mixture was cooled to
0 °C prior to the addition of triethylamine (0.3 mL, 2.1 mmol) and
then 4-nitrobenzenesulfonyl chloride (236 mg, 1.1 mmol). The
mixture was placed under argon and stirred at 0 °C for 5 min. The
cooling bath was removed, and the reaction was warmed to 23 °C and
stirred for 5 h. The mixture was transferred to a separatory funnel, and
1.0 M HCl was added. The organics were extracted with CH2Cl2,
dried over anhydrous Na2SO4, filtered, concentrated under reduced
pressure, and purified by flash chromatography on SiO2 using 20%
EtOAc/hexane and then 30% EtOAc/hexane as the eluent to yield the
desired CBz-protected amine 18 (231 mg, 71% over 2 steps) as an
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02396
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this work was provided by the National
Institutes of Health (Grant AI150466). The authors would like
to thank the Purdue University Center for Cancer Research,
which supports the shared NMR and mass spectrometry
facilities.
1
amorphous solid. Rf = 0.30 (30% EtOAc/hexanes, SiO2 plate). H
NMR (400 MHz, CDCl3) δ 8.35−8.24 (m, 2H), 7.92 (d, J = 8.5 Hz,
F
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Note
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