A Photochemical Route to Optically Active Hexahydro-4 H-furopyranol, a High-Affinity P2 Ligand for HIV-1 Protease Inhibitors

Article abstract of DOI:10.1021/acs.joc.9b01361

We describe here the syntheses of optically pure (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol and (3aR,4R,7aS)-hexahydro-4H-furo[2,3-b]pyran-4-ol. These stereochemically defined heterocycles are important high-affinity P2 ligands for a variety of highl

Full text of DOI:10.1021/acs.joc.9b01361

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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
A Photochemical Route to Optically Active
Hexahydro‑4H‑furopyranol, a High-Affinity P2 Ligand for HIV‑1
Protease Inhibitors
Arun K. Ghosh* and William L. Robinson
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana
47907, United States
S
* Supporting Information
ABSTRACT: We describe here the syntheses of optically
pure (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol and
(3aR,4R,7aS)-hexahydro-4H-furo[2,3-b]pyran-4-ol. These
stereochemically defined heterocycles are important high-
affinity P2 ligands for a variety of highly potent HIV-1
protease inhibitors. The key steps involve an efficient
̀
Paterno−Buchi [2 + 2] photocycloaddition, catalytic hydrogenation, acid-catalyzed cyclization to form the racemic ligand
̈
alcohol, and an enzymatic resolution with immobilized Amano Lipase PS-30. Optically active ligands (−)-6 and (+)-6 were
obtained with high enantiomeric purity. Enantiomer (−)-6 has been converted to potent HIV-1 protease inhibitor 3.
tructure-based design is enabling innovations in modern
S
drug discovery and medicinal chemistry.1,2 This is
particularly evident in the design and syntheses of HIV-1
protease inhibitor drugs.3,4 HIV-1 protease inhibitors are an
important component of combined antiretroviral therapy
which has dramatically transformed HIV/AIDs from a fatal
disease to a manageable chronic disorder.5,6 In our efforts to
develop resistance-proof protease inhibitors (PIs), we have
designed a range of exceedingly potent PIs incorporating
bicyclic polyether templates that are inherent to many
bioactive natural products.7,8 Many such PIs exhibited broad-
spectrum activity against multidrug-resistant HIV-1 variants.
For example, we have designed and developed fused bicyclic
(3R,3aS,6aR)-bis-tetrahydrofuran (bis-THF) as a nonpeptide,
high-affinity P2 ligand, and utilized this ligand to create
Darunavir (1, Figure 1), a highly potent FDA approved PI
drug.9,10
Figure 1. Structures of HIV-1 protease inhibitors 1−3.
bonding interactions with the backbone atoms in the S2
pocket.14,15 Furthermore, the extra methylene group appears to
have favorable van der Waals interactions with hydrophobic
residues in the S2 subsite.14
The hexahydro-4H-furopyranol ligand has been incorpo-
rated in the design and synthesis of a host of potent PIs.14 Our
initial synthesis of optically active ligand alcohol 6 involved
known, enantiomerically pure lactone 4 as the key starting
material.14,16,17 However, the synthetic route is lengthy, and
the synthesis of lactone 4 requires several steps. Our more
recent synthesis of optically active ligand alcohol utilized
optically active alcohol 5 that was obtained by an enzymatic
desymmetrization strategy using 1,2-di(acetoxymethyl)-
cyclohex-4-ene as the key starting material.18 To further
Darunavir has emerged as a frontline therapy for HIV/AIDS
patients.11,12 The X-ray structures of Darunavir (1) and its
methoxy derivative (2) bound to HIV-1 protease revealed that
both PIs are involved in extensive interactions, particularly
with the backbone atoms throughout the enzyme active site.13
The bis-THF P2 ligand of Darunavir is an intriguing
pharmacophore that is responsible for its robust drug
resistance profiles.7 To further improve binding properties,
particularly to enhance both backbone binding and van der
Waals interactions, we sought to fine-tune ligand interactions
based upon X-ray structures. Therefore, we designed a
stereochemically defined hexahydrofuropyranol-based P2
ligand that improved the dihedral angle of the bicyclic acetal
to form enhanced hydrogen bonding interactions with the
backbone NHs of Asp29 and Asp30. Indeed, X-ray structural
analysis of inhibitors bearing the (3aS,4S,7aR)-hexahydro-4H-
furo[2,3-b]pyran-4-ol ligand indicated stronger hydrogen
Received: May 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b01361
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
establish structure−activity relationships, we planned to
synthesize both ligand enantiomers efficiently. We planned to
utilize a photocycloaddition of furan and an aldehyde as the
key step. Similar photocycloadditions were recently reported
for the synthesis of bis-THF ligands.19,20 Herein, we describe
an efficient photochemical route to the hexahydro-4H-
furopyranol ligand in racemic form followed by enzymatic
resolution to provide optically active ligands with high
enantiomeric purity. The route is amenable to gram quantities
of enantiomeric ligands. We have converted the optically active
ligand (−)-6 to potent HIV-1 protease inhibitor 3.
this synthetic route due to their prior use in photochemical
routes for the synthesis of the bis-THF ligand.19,20 However,
we chose to use a THP protecting group due to the stability of
the THP-ether as well as the low cost of the requisite
precursor, 3,4-dihydro-2H-pyran. Thus, (tetrahydropyranyl-
oxy)propionaldehyde 10 was prepared on multigram scale by
monoprotection of propane-1,3-diol with 3,4-dihydro-2H-
pyran in the presence of a catalytic amount of p-
toluenesulfonic acid (p-TsOH·H2O) in CH2Cl2 followed by
́
Swern oxidation of the resulting alcohol.27 The Paterno−Bu
̈
chi
reaction was carried out as shown in Scheme 2. A solution of
Our strategy for the synthesis of optically pure (3aS,4S,7aR)-
hexahydro-4H-furo[2,3-b]pyran-4-ol (−)-6 is outlined in
Scheme 1. Enantiomerically pure ligand alcohol (−)-6 would
Scheme 2. Synthesis of Optically Active Hexahydro-4H-
a
furo[2,3-b]pyran-4-ol
Scheme 1. Photochemical Route to Optically Active
Hexahydro-4H-furopyranol
a
Reagents and conditions: (a) furan, UV light (300 nm), 23 °C,
be obtained from an enzymatic resolution of the racemic
hexahydro-4H-furopyranol 6. The synthesis of a racemic 6,5-
fused ring heterocycle is envisioned from racemic oxetane 7.
An appropriate acid-catalyzed reaction is expected to promote
deprotection of the THP-ether followed by transacetalization
to provide racemic bicyclic alcohol 6. The racemic saturated
oxetane 7 would be obtained by a catalytic hydrogenation of
oxetane derivative 8. Oxetane 8 can be prepared by the
(91%); (b) H2, Rh/Al2O3, Et2O, 23 °C; (c) p-TsOH·H2O, MeOH,
55 °C, (63% for 2 steps); (d) immobilized Amano Lipase PS-30, vinyl
acetate, THF, 23 °C, ((−)-6, 49%), acetate 11, (50%); (e) K2CO3,
MeOH, 23 °C, (97%); (f) p-(NO2)PhOCOCl, pyridine, CH2Cl2, 0 to
23 °C, 2 h, (99%).
furan 9 and aldehyde 10 was stirred vigorously and irradiated
with UV light (300 nm) for 48 h in a Rayonet photochemical
reactor to afford the racemic photoadduct 8 in 91% yield. The
1H NMR (400 MHz) analysis revealed 99% conversion after
48 h. It is important to note that the reaction mixture must be
degassed by sparging with argon prior to irradiation.
Additionally, high yields were obtained only after purification
of aldehyde 10 by chromatography. Photocyclization provided
exclusively the exo-oxetane 8.21,22 The product was isolated
and analyzed as a 1:1 mixture of inconsequential diastereomers
due to the presence of the stereocenter in the THP protecting
group. The photoadduct was dissolved in ether and hydro-
genated over a catalytic amount of Rh on Al2O3 under a
hydrogen-filled balloon at 23 °C for 6 h. The resulting
́
Paterno−Buchi photocycloaddition of inexpensive furan 9 and
̈
(tetrahydropyranyloxy)propionaldehyde 10.
Our key strategy for the synthesis of hexahydro-4H-
́
furopyranol involved the Paterno−Buchi reaction with
̈
furan.21,22 Photoadditions of aldehydes and furan leading to
substituted oxetanes have been investigated by Sakurai and co-
workers.23,24 Schreiber and co-workers demonstrated the
utility of such photocyclizations of aldehydes and furan during
the synthesis of (+)-avenaciolide.25,26 The exo-oxetane was
formed exclusively, and three contiguous chiral centers were
́
formed in the reaction. The Paterno−Buchi reaction was
̈
recently utilized for the synthesis of a related bis-THF ligand.
Initially, we considered CBz and TBS protecting groups for
B
DOI: 10.1021/acs.joc.9b01361
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The Journal of Organic Chemistry
Note
saturated oxetane 7 was not purified due to instability on silica
gel and Al2O3. The crude saturated oxetane was then dissolved
in MeOH and heated to 55 °C in the presence of a catalytic
amount of p-TsOH to afford racemic hexahydro-4H-
furopyranol 6 in 63% yield over 2 steps after chromatography
on Al2O3. The racemic alcohol was then subjected to
enzymatic resolution with immobilized Amano Lipase PS-30
on Celite14 in the presence of 10 equiv of vinyl acetate in THF
Further applications of this photochemical cyclization are in
progress.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out under an
atmosphere of argon in oven-dried (120 °C) glassware with magnetic
stirring unless otherwise noted. Solvents, reagents and chemicals were
purchased from commercial suppliers. Solvents were purified as
follows: CH2Cl2 was distilled from calcium hydride or purified using a
solvent purification system; furan was shaken with aqueous 5% KOH,
dried with Na2SO4, and distilled from KOH immediately before use;
ether was purified using a solvent purification system; methanol was
used without further purification; tetrahydrofuran was distilled from
sodium/benzophenone; acetonitrile was purified with a solvent
purification system. Purification of reaction products was carried
out by flash chromatography using either silica gel 230−400 mesh (60
Å pore diameter) or alumina 80−200 mesh. Photochemical reactions
were carried out in a Rayonet photochemical reactor (RPR-100)
equipped with 300 nm bulbs (lamp model: RPR-3000A) and a
cooling fan. Analytical thin layer chromatography was performed on
glass-backed silica gel thin-layer chromatography plates (0.25 mm
thickness, 60 Å, F-254 indicator) or alumina thin-layer chromatog-
raphy plates (0.25 mm thickness, UV254). Optical rotations were
measured by using a digital polarimeter with a sodium lamp. 1H NMR
spectra were recorded at 23 °C on a 400 MHz spectrometer and are
reported in ppm relative to solvent signals (CDCl3 at δ = 7.26 ppm)
as an internal standard. Data are reported as (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, ddd =
doublet of doublet of doublets, dddd = doublet of doublet of doublets
of doublets, td = triplet of doublets, qd = quartet of doublets, dt =
doublet of triplets, dq = doublet of quartets, brs = broad singlet;
coupling constant(s) in Hz; integration). Proton-decoupled 13C NMR
spectra were recorded on a 100 MHz spectrometer and are reported
in ppm by using the solvent as the internal standard (CDCl3 at δ =
77.16 ppm). Low resolution mass spectra were obtained using a
Quadrupole LCMS instrument under ESI+. High resolution mass
spectra were obtained by the Mass Spectrometry Center at Purdue
University. These experiments were performed under ESI+ and APCI
+ conditions using an Orbitrap XL instrument.
1
at 23 °C. The reaction was monitored by TLC and by H
NMR analysis of a small aliquot until a 50% conversion of
acylation was observed (120 h). The enzymatic resolution
afforded (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol li-
gand (−)-6 [(α)2D3 −31.1(c 0.52, CHCl3)] in 49% yield.
Acylated ligand (+)-11 was isolated in 50% yield. The optical
purity of alcohol (−)-6 was determined after its conversion to
p-nitrocarbonate 12.14 Thus, exposure of (−)-6 to p-
nitrophenylchloroformate in the presence of pyridine in
CH2Cl2 at 0 to 23 °C for 2 h provided nitrocarbonate 12 in
near-quantitative yield.
Chiral HPLC analysis of 12 on a CHIRALPAK IC-3 column
revealed an enantiomeric purity of 99% ee. Acetate derivative
11 was converted to the enantiomeric ligand alcohol (+)-6 by
treatment with K2CO3 in MeOH at 23 °C for 2 h to provide
(+)-6 in 97% yield. Enantiomerically pure ligand alcohol (−)-6
was converted into HIV-1 protease inhibitor 3.14 As shown in
Scheme 3, treatment of carbonate 12 with the known (R)-
a
Scheme 3. Synthesis of HIV Protease Inhibitor (−)-3
exo-6-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2,7-dioxa-
bicyclo[3.2.0]hept-3-ene ( )-(8). To a flame-dried quartz flask were
added aldehyde 10 (3.36 g, 21.24 mmol) and furan 9 (53 mL, 728.8
mmol) at 23 °C. The mixture was degassed by sparging with argon for
15 min, and then the flask was quickly sealed. The flask was placed in
the photoreactor. The reaction was run in a Rayonet photoreactor
equipped with 300 nm bulbs and a cooling fan. The distance from
lamps to irradiation vessel was approximately 3.5 in., and no
additional filter was used. The reaction mixture was irradiated and
stirred vigorously for 48 h at 23 °C. The reaction mixture was
concentrated under reduced pressure to afford a crude oil. Analysis by
1H NMR shows 99% conversion of the aldehyde substrate. The crude
a
Reagents and conditions: (a) DIPEA, MeCN, 23 °C, 5 days (76%).
(hydroxyethyl)-sulfonamide isostere 1314 in the presence of
diisopropylethylamine (DIPEA) at 23 °C for 5 days furnished
HIV-1 protease inhibitor 3 in 76% yield. Inhibitor 3 showed a
Ki value of 10 pM in the HIV-1 protease inhibitory assay.28
In summary, we described an efficient synthesis of racemic
hexahydro-4H-furopyranol, a high affinity P2 ligand for a
variety of potent HIV-1 protease inhibitors. The racemic ligand
oil is then purified by flash chromatography on alumina using 20%
EtOAc/hexanes as the eluent to yield the purified photoadduct ( )-8
(4.36 g, 91%) as a white amorphous solid. Rf = 0.50 (25% EtOAc/
1
hexanes, alumina). H NMR (400 MHz, CDCl3) δ 6.61 (d, J = 2.7
Hz, 2H), 6.34−6.26 (m, 2H), 5.32 (q, J = 2.8 Hz, 2H), 4.75−4.65 (m,
2H), 4.59 (t, J = 3.2 Hz, 1H), 4.54 (t, J = 3.4 Hz, 1H), 3.94−3.75 (m,
4H), 3.60−3.42 (m, 6H), 2.18−2.05 (m, 4H), 1.86−1.64 (m, 4H),
1.62−1.44 (m, 8H); 13C{1H} NMR (101 MHz, CDCl3) δ 148.2,
108.3, 104.5, 99.4, 98.7, 90.3, 90.1, 63.3, 63.1, 62.6, 62.1, 49.4, 49.2,
37.2, 37.1, 30.8, 30.7, 25.5, 19.8, 19.5. HRMS (ESI) m/z: [M + Na]+
calcd for C12H18O4Na 249.1097, found 249.1100.
6-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2,7-dioxabicyclo-
[3.2.0]heptane ( )-7. To a flame-dried flask was added photoadduct
( )-8 (4.36 g, 19.27 mmol) in ether (96 mL) followed by 5% Rh/
Al2O3 (872 mg, 20% w/w). The reaction flask was flushed with argon
and evacuated under vacuum three times. The flask was then flushed
with H2 and evacuated under vacuum three times before leaving the
mixture to stir under a hydrogen-filled balloon at 23 °C for 6 h. The
́
alcohol was synthesized using a Paterno−Buchi reaction of
̈
(tetrahydropyranyloxy)propionaldehyde and furan as the key
step. The photocycloaddition reaction was carried out on a
multigram scale. Racemic ligand alcohol 6 was resolved by an
enzymatic resolution using immobilized Amano Lipase PS-30
on Celite. This provides convenient access to optically active
ligand alcohols (−)-6 and (+)-6 in high enantiomeric purity
(99% ee). The overall process utilized inexpensive starting
materials and has the potential for large-scale synthesis of
optically pure ligands for medicinal chemistry development.
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The Journal of Organic Chemistry
Note
reaction mixture was then filtered through a small Celite plug and
concentrated under reduced pressure to yield racemic oxetane 7 (4.3
g) as a colorless oil. The crude oxetane was used for the next reaction
without further purification due to its instability on silica gel or
under argon and cooled to 0 °C. To the mixture was quickly added 4-
nitrophenyl chloroformate (130 mg, 0.65 mmol), and the resulting
reaction was stirred at 0 to 23 °C for 2 h. After this period, the
mixture was concentrated under reduced pressure and purified by
flash chromatography (15% EtOAc/hexanes, then 33% EtOAc/
hexanes) to yield carbonate 12 (70 mg, 99% yield) as an amorphous
white solid. Rf = 0.50 (50% EtOAc/hexanes, silica). [α]2D3 −41.8 (c
1
alumina. Rf = 0.70 (50% EtOAc/hexanes, alumina). H NMR (400
MHz, CDCl3) δ 5.88 (d, J = 3.8 Hz, 2H), 4.57 (t, J = 3.4 Hz, 1H),
4.54 (t, J = 3.6 Hz, 1H), 4.32−4.18 (m, 6H), 3.92−3.76 (m, 4H),
3.55−3.41 (m, 4H), 3.20−3.10 (m, 2H), 2.14−1.43 (m, 20H);
13C{1H} NMR (101 MHz, CDCl3) δ 106.3, 99.4, 98.9, 79.8, 79.5,
67.7, 67.7, 63.5, 63.41, 62.6, 62.3, 46.5, 46.4, 37.2, 37.1, 30.78, 30.77,
28.8, 28.8, 25.6, 19.8, 19.6; HRMS (ESI) m/z: [M + Na]+ calcd for
C12H20O4Na 251.1254, found 251.1253.
1
0.12, CHCl3). H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 9.0 Hz,
2H), 7.39 (d, J = 9.0 Hz, 2H), 5.31−5.17 (m, 1H), 5.07 (d, J = 3.2
Hz, 1H), 4.28 (td, J = 10.6, 10.1, 2.4 Hz, 1H), 4.09−3.94 (m, 2H),
3.42 (td, J = 12.6, 4.1 Hz, 1H), 2.83−2.66 (m, 1H), 2.28−2.09 (m,
1H), 2.03−1.91 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.5,
151.9, 145.6, 125.5, 121.9, 101.32, 75.6, 68.7, 60.7, 43.3, 26.0, 22.6.
(3aS,4S,7aR)-Hexahydro-4H-furo[2,3-b]pyran-4-yl((2S,3R)-3-hy-
droxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenyl-
butan-2-yl)carbamate 3. To a flame-dried flask was added a solution
of amine 13 (30 mg, 0.07 mmol) in MeCN (1 mL). The reaction
mixture was placed under argon and cooled to 0 °C. To the flask was
added DIPEA (42 μL, 0.24 mmol) followed by carbonate 12 (15 mg,
0.05 mmol). The resulting mixture was stirred at 0 °C for 10 min, and
then it was stirred for 5 days at 23 °C. After this period, the reaction
mixture was concentrated under reduced pressure to afford a crude
solid that was purified by flash chromatography using 33% EtOAc/
hexanes and then 50% EtOAc/hexanes as the eluent to yield inhibitor
3 (21.3 mg, 76% yield) as an amorphous white solid. Rf = 0.25 (50%
Hexahydro-4H-furo[2,3-b]pyran-4-ol [( )-6]. To a stirred solution
of crude oxetane 7 (4.34 g, 19.01 mmol) in MeOH (152 mL) at 23
°C p-TsOH·H2O (362 mg, 1.90 mmol) was added. The flask was
then equipped with a reflux condenser, and the reaction mixture was
stirred under argon for 12 h at 55 °C (heat source, oil bath). After this
period, the reaction mixture was concentrated under reduced pressure
to yield a crude residue. The residue was adsorbed onto alumina and
purified by flash chromatography on alumina using 66% EtOAc/
hexanes as the eluent to yield the racemic alcohol 6 (1.75 g, 63% over
2 steps) as an amorphous white solid. Rf = 0.36 (100% EtOAc,
1
alumina). H NMR (400 MHz, CDCl3) δ 4.97 (d, J = 3.4 Hz, 1H),
4.24−4.14 (m, 2H), 3.98−3.86 (m, 2H), 3.33 (td, J = 12.0, 2.6 Hz,
1H), 2.50 (dddd, J = 11.6, 8.7, 5.9, 3.5 Hz, 1H), 2.12−1.97 (m, 1H),
1.97−1.84 (m, 2H), 1.80−1.64 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 101.5, 68.6, 67.5, 61.2, 46.5, 29.5, 22.0.
EtOAc/hexanes, silica). [α]2D3 −13.9 (c 0.12, CHCl3). H NMR (400
1
MHz, CDCl3) δ 7.71 (d, J = 8.9 Hz, 2H), 7.32−7.18 (m, 5H), 6.98
(d, J = 8.9 Hz, 2H), 4.98 (dt, J = 11.5, 5.8 Hz, 1H), 4.93 (d, J = 3.4
Hz, 1H), 4.84 (d, J = 8.7 Hz, 1H), 4.15 (td, J = 9.7, 2.5 Hz, 1H),
3.95−3.88 (m, 1H), 3.87 (s, 3H), 3.86−3.71 (m, 3H), 3.32 (td, J =
11.8, 2.2 Hz, 1H), 3.15 (dd, J = 15.2, 8.2 Hz, 1H), 3.09−2.93 (m,
3H), 2.90−2.74 (m, 2H), 2.49−2.35 (m, 1H), 1.91−1.44 (m, 5H),
0.92 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 163.2, 155.7, 137.8, 129.9, 129.6, 128.6, 126.7,
114.5, 101.3, 73.0, 70.3, 68.6, 60.9, 59.0, 55.8, 55.0, 53.9, 43.6, 35.6,
27.4, 26.3, 22.4, 20.3, 20.0. LRMS-ESI: m/z = 577.2 [M + H]+, 599.2
[M + Na]+. HRMS-ESI (m/z): [M + Na]+ calcd for C29H40N2O8NaS
599.2403, found 599.2406; the purity of the inhibitor was determined
to be 98.1% by HPLC (YMC-Pack ODS-A column; 20 min gradient,
MeCN/H2O/TFA 20:80:0.1 to MeCN/H2O/TFA 90:10:0.1, then 20
min MeCN/H2O/TFA 90:10:0.1; 1.5 mL/min; 254 nm; 25 °C; tR =
14.4 min).
(3aS,4S,7aR)-Hexahydro-4H-furo[2,3-b]pyran-4-ol [(−)-6]. Im-
mobilized Amano Lipase PS-30 was prepared according to a known
procedure.14 To a flame-dried flask containing distilled THF (173
mL) at 23 °C racemic alcohol 6 (1.75 g, 12.14 mmol), vinyl acetate
(11.2 mL, 121.4 mmol), and immobilized Amano Lipase PS-30 (875
mg, 50% w/w) were added. The mixture was stirred under argon at 23
°C for 120 h. Aliquots of the reaction were analyzed by 1H NMR, and
the reaction was stopped once 50% of the alcohol was acylated (about
120 h). The mixture was then filtered through a small plug of Celite
and concentrated under reduced pressure to yield a crude oil. The
crude mixture was purified by flash chromatography on silica gel using
50% EtOAc/hexanes to 100% EtOAc as the eluent to afford
enantiomerically pure ligand alcohol (−)-6 (849 mg, 49%) and
acylated ligand (+)-11 (1.13 g, 50%) as amorphous solids. Ligand
alcohol (−)-6: 1H and 13C NMR spectra are identical to those of the
racemic ligand alcohol. Rf = 0.36 (100% EtOAc, alumina). [α]D23
−31.3 (c 0.52, CHCl3). An enantiomeric purity of 99% ee for the
alcohol was determined by analysis of the corresponding carbonate 12
on chiral HPLC (CHIRALPAK IC-3 column; 15% IPA/hexanes; 1.0
mL/min; 254 nm; 23 °C; tR minor = 89.0 min, tR major = 81.9 min).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b01361.
1
Acylated Ligand Alcohol (+)-11. H NMR (400 MHz, CDCl3) δ
1H and 13C NMR spectra for all new compounds (PDF)
5.23 (dt, J = 11.5, 5.9 Hz, 1H), 5.01 (d, J = 3.4 Hz, 1H), 4.27−4.16
(m, 1H), 3.97−3.87 (m, 2H), 3.47−3.31 (m, 1H), 2.59 (dddd, J =
11.6, 8.8, 6.0, 3.4 Hz, 1H), 2.28−2.08 (m, 1H), 2.06 (s, 3H), 1.87−
1.70 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.5, 101.3,
69.8, 68.6, 61.0, 43.4, 26.2, 22.7, 21.3. TLC: Rf = 0.90 (100% EtOAc,
alumina). [α]2D3 +54.0 (c 0.32, CHCl3). HRMS (ESI) m/z: [M + Na]+
calcd for C9H14O4Na 209.0784, found 209.0786.
AUTHOR INFORMATION
Corresponding Author
*E-mail: akghosh@purdue.edu.
■
ORCID
(3aR,4R,7aS)-Hexahydro-4H-furo[2,3-b]pyran-4-ol (+)-6. To a
flask was added (3aR,4R,7aS)-hexahydro-4H-furo[2,3-b]pyran-4-yl
acetate (+)-11 (1.13 g, 6.04 mmol). Methanol (121 mL) was
added, followed by addition of anhydrous K2CO3 (1.25 g, 9.1 mmol).
The solution was stirred at 23 °C under argon for 2 h, and then the
reaction mixture was filtered and concentrated to yield a crude white
solid that was purified by column chromatography on silica using 50%
EtOAc/hexanes and then 100% EtOAc/hexanes as the eluent to
Arun K. Ghosh: 0000-0003-2472-1841
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this work was provided by the National
Institutes of Health (GM53386). NMR and mass spectrometry
were all performed using shared resources which are partially
supported by the Purdue Center for Cancer Research through
an NIH grant (P30CA023168). We would like to thank Mr.
1
afford ligand alcohol (+)-6 (844 mg, 97%) as a white solid. H and
13C NMR spectra are identical to those of the racemic Tp-THF
ligand. Rf = 0.30 (100% EtOAc). [α]2D3 +28.9 (c 0.36, CHCl3).
(3aS,4S,7aR)-Hexahydro-4H-furo[2,3-b]pyran-4-yl (4-Nitrophen-
yl) Carbonate 12. To a flame-dried flask were added optically active
alcohol (−)-6 (31 mg, 0.22 mmol) and CH2Cl2 (1.8 mL) followed by
addition of pyridine (64 μL, 0.80 mmol). The mixture was stirred
́
Josh Born and Mr. Emilio Cardenas (Purdue University) for
helpful discussions.
D
DOI: 10.1021/acs.joc.9b01361
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
[2,3-b]furan-3-ol: A Key Component of Current HIV Protease
Inhibitors. J. Org. Chem. 2017, 82, 1218−1223.
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J. Org. Chem. XXXX, XXX, XXX−XXX