Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P2 ligands: Structure-activity studies and biological evaluation

Article abstract of DOI:10.1021/jm1012787

The design, synthesis, and evaluation of a new series of hexahydrofuropyranol-derived HIV-1 protease inhibitors are described. We have designed a stereochemically defined hexahydrofuropyranol-derived urethane as the P2-ligand. The current ligand is designed based upon the X-ray structure of 1a-bound HIV-1 protease. The synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b] pyran-4-ol, (-)-7, was carried out in optically active form. Incorporation of this ligand provided inhibitor 35a, which has shown excellent enzyme inhibitory activity and antiviral potency. Our structure-activity studies have indicated that the stereochemistry and the position of oxygens in the ligand are important to the observed potency of the inhibitor. Inhibitor 35a has maintained excellent potency against multidrug-resistant HIV-1 variants. An active site model of 35a was created based upon the X-ray structure of 1b-bound HIV-1 protease. The model offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived novel P2-ligand.

Full text of DOI:10.1021/jm1012787

622 J. Med. Chem. 2011, 54, 622–634
DOI: 10.1021/jm1012787
Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-Derived
High Affinity P2 Ligands: Structure-Activity Studies and Biological Evaluation
,^
Arun K. Ghosh,*,†,‡ Bruno D. Chapsal,† Abigail Baldridge,† Melinda P. Steffey,† D. Eric Walters,§ Yasuhiro Koh,
,^,#
Masayuki Amano, ,^ and Hiroaki Mitsuya
†Department of Chemistry, and ‡Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States,
§Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, United
States, Department of Hematology, and ^Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan,
and #Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland 20892, United States
Received October 4, 2010
The design, synthesis, and evaluation of a new series of hexahydrofuropyranol-derived HIV-1 protease
inhibitors are described. We have designed a stereochemically defined hexahydrofuropyranol-derived
urethane as the P2-ligand. The current ligand is designed based upon the X-ray structure of 1a-bound
HIV-1 protease. The synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b]pyran-4-ol, (-)-7, was carried out
in optically active form. Incorporation of this ligand provided inhibitor 35a, which has shown excellent
enzyme inhibitory activity and antiviral potency. Our structure-activity studies have indicated that the
stereochemistry and the position of oxygens in the ligand are important to the observed potency of the
inhibitor. Inhibitor 35a has maintained excellent potency against multidrug-resistant HIV-1 variants. An
active site model of 35a was created based upon the X-ray structure of 1b-bound HIV-1 protease. The model
offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived
novel P2-ligand.
Introduction
resistance to 1a is significantly delayed compared to other
approved PIs.19-21
HIV-1 protease inhibitors are critical components of highly
active antiretroviral therapy (HAARTa).1-3 The HAART
treatment regimens significantly reduced HIV/AIDS-related
mortality.4,5 However, the rapid emergence of drug-resistant
HIV-1 strains and the appearance of cross-resistance are
severely limiting long-term treatment options.6-8 An esti-
mated 10-25% of newly infected patients harbor at least
one viral strain that is resistant to current medications.9-11 In
addition, PI regimens suffer from a number of other draw-
backs including high pill burden, treatment cost, poor AD-
MET properties, debilitating side effects, and toxicity issues.12
Therefore, the development of novel PIs with broad-spectrum
activity against multidrug-resistant HIV-1 variants remains a
major therapeutic objective.13
In our continuing interest to develop novel protease inhi-
bitors (PI) with broad-spectrum activity against multidrug-
resistant HIV-1 variants, we have reported a series of PIs
including PIs 1a, 1b, 2, and 3.14-16 These inhibitors exhibited
excellent antiviral activity against multidrug-resistant HIV-1
variants. Darunavir (TMC-114, Figure 1) has been recently
approved by the FDA.17,18 It has displayed a high genetic
barrier to resistance and retained high potency against multi-
drug resistant HIV-1 strains. It has been demonstrated that
Our structure-based design of 1a and other PIs is inspired
by the premise that an inhibitor engaged in multiple interac-
tions, especially hydrogen bonding with the HIV protease
backbone atoms, should retain these affinities with mutant
strains.22 As the enzyme backbone conformation is only mini-
mally distorted when mutations occur, backbone atoms-PI
interactions are likely maintained, therefore sustaining the
inhibitor affinity and potency. Inhibitor 1a’s superb resistance
profile likely originates from the extensive interactions the
inhibitor makes within the HIV-1 protease’s binding site and
particularly with the backbone atoms of the enzyme.22-24
Extensive studies of 1a-bound HIV-1 protease crystal struc-
tures have consistently revealed tight hydrogen bonding be-
tween the inhibitor and the protease backbone.23-25 The
stereochemically defined bis-tetrahydrofuran (bis-THF) P2
ligand in 1a forms a strong hydrogen bonding network between
its two cyclic ether oxygens and the backbone amide NH bonds
of the protease residues, Asp29 and Asp30.22 These observa-
tions likely provide explanations for 1a’s outstanding antiviral
activity. Not surprisingly, several other protease inhibitors
featuring the bis-THF as the P2 ligand have exhibited equally
impressive antiviral activities and resistance profiles.22,26
The bis-THF ligand represents an intriguing pharmaco-
phoric scaffold for the development of PIs to combat drug
resistance. To further optimize the bis-THF structural tem-
plate, we have now investigated ligands that could enhance the
backbone-binding as well as improve hydrophobic interactions
with the protease active site. The X-ray structure of 1a-bound
*To whom correspondence should be addressed. Phone: (765)-494-
5323. Fax: (765)-496-1612. E-mail: akghosh@purdue.edu.
a Abbreviations: bis-THF, bis-tetrahydrofuran; Cp-THF, cyclopen-
tanyltetrahydrofuran; Tp-THF, tetrahydropyranyltetrahydrofuran; PI,
protease inhibitor; HAART, highly active antiretroviral therapy; APV,
amprenavir; DRV, darunavir; SQV, saquinavir; IDV, indinavir; LPV,
lopinavir; RTV, ritonavir; ATV, atazanavir.
˚
HIV-1 protease has shown a distance of about 3.0-3.2 A
r
pubs.acs.org/jmc
Published on Web 12/31/2010
2010 American Chemical Society

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 623
Scheme 1. Synthesis of Ligand (-)-7 and Its Respective
Enantiomer (þ)-7
diol using lithium aluminum hydride in 95% yield. Selective
monoacetylation at the primary alcohol using AcCl and 2,4,6-
collidine at -78 ꢀC 28 and subsequent silylation of the remain-
ing free hydroxyl furnished intermediate 5 in 86% yield
(two steps). Removal of the acetate group, followed by
ozonolysis of the olefin, furnished a bicyclic bis-acetal
intermediate. Reduction of the hemiacetal moiety using
Et3SiH and BF3-Et2O afforded bicyclic intermediate 6 in
55% yield in three steps. Removal of the silyl group with
TBAF in THF furnished the desired hexahydrofuropyran-
4-ol ligand (-)-7.
To demonstrate the importance of the absolute stereochem-
istry of the bicyclic structure of ligand (-)-7, its corresponding
enantiomer (þ)-7 was synthesized starting from intermediate
8 (Scheme 1). Intermediate 8 was synthesized by an enzyme-
catalyzed desymmetrization of cyclopentene meso-diacetate
followed by a Claisen rearrangement step.27b,29 The resulting
diester was reduced by LAH to provide 8. It was used for the
synthesis of (þ)-7 and subjected to the same synthetic
sequence applied from lactone (-)-4 in the synthesis of (-)-7
(Scheme 1). To examine the importance of each of the two
cyclic ether oxygens in the furopyranol ligand (-)-7, we
prepared the corresponding cyclohexane and cyclopentane
derivatives (Schemes 2 and 3).
The synthesis of 4-hydroxyoctahydrobenzofuran ligand
(-)-12 is shown in Scheme 2. Reaction of diazocyclohexane-
dione 930 with ethyl vinyl ether in presence of a catalytic
amount of Rh2(OAc)4 at 23 ꢀC gave derivative 10.31 Hydro-
genation of the ketofuran in the presence of Pd/C under H2
(1 atm) furnished the corresponding crude ketone 11 as a 9:1
mixture of diastereoisomers. A one-pot procedure involving
L-selectride reduction of the ketone followed by Et3SiH/
TMSOTf-promoted reduction of the acetal furnished the
racemic alcohol (()-12 (71% from 10). Enzymatic resolution
of (()-12 using lipase Amano PS-30 provided the desired
enantiopure alcohol (-)-12 (98.8% ee by chiral HPLC anal-
ysis of the 2,4-dinitrobenzoate derivative), after ∼55% con-
version to the acetate.
Figure 1. Structures of inhibitors 1-3 and 35a.
between the bis-THF cyclic oxygens and the Asp30 NH amide
˚
bond, while a shorter 2.9 A distance was observed with the
Asp29 NH bond.23,25 In order to maximize and promote closer
hydrogen bonding with the Asp30 backbone NH bond, we
thought a larger ring on the P2 ligand should increase the
dihedral angle of the bicyclic acetal, bring the oxygen closer,
give more flexibility to the structure, and offer a more optimal
alignment of the cyclic oxygen with the Asp30 NH bond. Such
factors could realistically promote tighter hydrogen bonding
with the Asp30 backbone NH bond. Besides, this extra methy-
lene group in the “inner” ring would also provide more
favorable van der Waals interactions within the hydrophobic
pocket created by Ile47, Val32, Ile84, Leu76, and Ile500 residues
in the protease S2 subsite. In addition, a larger ring could
potentially lead to better flexibility and adaptability to protease
mutations. Herein, we report the design, synthesis, and bio-
logical evaluation of a series of highly potent PIs that combined
a (R)-hydroxyethylsulfonamide isostere with the furopyranol
ligand (-)-7. Among all inhibitors of the series, 35a showed the
most impressive inhibitory and antiviral activity (Ki=2.7 pM,
IC50=0.5 nM). Moreover, inhibitor 35a was evaluated against
a panel of multidrug-resistant HIV-1 viruses. It retained potent
activity against a variety of multidrug-resistant clinical HIV-1
strains with EC50 values in low nanomolar range, which is
superior to other PIs and comparable to 1a. Modeling of 35a
based upon the X-ray structure of 1b-bound HIV-1 protease
active site has provided critical molecular insight into the
ligand-binding site interactions.
Chemistry
The synthesis of enantiomerically pure (3aS,4S,7aR)-hex-
ahydro-2H-furo[2,3-b]pyran-4-ol is shown in Scheme 1. It
was achieved starting from known enantiomerically pure
lactone 4.27 Lactone 4 was reduced into the corresponding
The synthesis of cyclopentapyranol ligand (-)-18 is shown
in Scheme 3. Pentanone 14 was treated with LDA and then
reacted with tert-butyldimethylsilyloxypropionaldehyde32

624 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2
Scheme 2. Synthesis of Furocyclohexanol P2 Ligand (-)-12
Ghosh et al.
Scheme 4. Synthesis of Hexahydrofuro[3,4-b]pyran-4-ol
Ligand 25
ketone provided the corresponding alcohol (dr = 10:1, as
observed by 1H and 13C NMR). Lipase-mediated resolution
of the major cis-alcohol gave the respective chiral ligand (-)-19
(90% ee determined by chiral HPLC).
Scheme 3. Syntheses of Ligands (-)-18 and (-)-19
Since the introduction of a six-membered ring in the P2
ligand structure may introduce more structural flexibility, we
set out to explore ligands in which the cyclic oxygens were
moved to adjacent positions. Such ligands would also demon-
strate the importance of the oxygen positions in the bicyclic
structure of ligand (-)-7. Thus, isomeric ligand 25 was synthe-
sized with the furan oxygen moved to its vicinal position. The
synthesis of 4-hydroxyhexahydro-2H-furo[3,4-b]pyran 25 is
shown in Scheme 4. Iodoalkoxylation of the 2,5-dihydrofuran
22 using propanediol in the presence of N-iodosuccinimide and
catalytic NH4OAc provided iodo alcohol 23. Swern oxidation
gave aldehyde 24 in 86% yield. An intramolecular Barbier-type
reaction was then conducted using indium in the presence of
copper(I) iodide and iodine to furnish a mixture of diastereoi-
someric alcohols.34 Oxidation followed by stereoselective reduc-
tion using NaBH4 furnished the racemic cis,cis-bicyclic
alcohol (()-25 as the sole product. Lipase-mediated resolution
finally gave the enantiomerically pure alcohol 25.
To ascertain the importance of the position of the urethane
in (-)-7, we have synthesized hexahydrofuropyran-5-ol ligand
30 shown in Scheme 5. The free hydroxyl on the pyran ring was
moved to the C3 position. The synthesis was accomplished
starting from enantiomerically pure bis-THF ligand 27 synthe-
sized by us previously.35 Dess-Martin oxidation of 27 pro-
vided the corresponding ketone. Homologation of the resulting
ketone using trimethylsilyldiazomethane in the presence of
AlMe3 followed by treatment of the crude mixture with TBAF
and acetic acid provided furanopyranone 29. Stereoselective
reduction of ketone 29 using L-selectride furnished alcohol 30
as a mixture of inseparable diastereoisomers (dr=5:1). Both
isomers were separated after formation of the corresponding
activated mixed carbonate 31g.
to furnish intermediate 15 (dr 3:1) in 95% yield. A DMSO-
TFAA promoted oxidation of the free hydroxy group fol-
lowed by TFA-promoted cyclocondensation furnished the
bicyclic R,β-unsaturated ketone 16. Hydrogenation in pre-
sence of 10% Pd/C followed by L-selectride reduction of the
ketone gave racemic alcohol (()-18 as a single diastereomer in
68% yield over two steps. Lipase-catalyzed resolution of the
alcohol provided enantiomerically pure alcohol (-)-18. For
the synthesis of a P2 ligand devoid of any cyclic oxygen,
known tetrahydroindanone 1733 was similarly hydrogenated
in presence of 10% Pd/C to give the corresponding bicyclic
ketone. Accordingly, L-selectride-promoted reduction of the
The synthesis of the protease inhibitors was accomplished
in a two-step sequence shown in Schemes 6 and 7. Each ligand
alcohol synthesized above was reacted with 4-nitrophenyl

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 625
Scheme 7. Syntheses of Inhibitors 35a-g, 36, and 37
Scheme 5. Synthesis of Hexahydrofuro[2,3-b]pyran-5-ol
Ligand 30
Scheme 6. Synthesis of Activated Mixed Carbonates 31a-g
with Tp-THF (-)-7, exhibited an enzyme Ki value of 2.7 pM.
Antiviral activity of 35a and other inhibitors were determined
in MT-2 human-T-lymphoid cells exposed to HIV-1LAI.
19 As
shown, 35a has displayed remarkable antiviral potency
(IC50 = 0.5 nM), comparable to those of PIs 1a and 1b. The
bicyclic ring stereochemistry of the P2 ligand proved to be
important as inhibitor 35b, with enantiomeric ligand (þ)-7,
displayed a significant reduction in enzyme inhibitory po-
tency (>20-fold increase in Ki) as well as antiviral activity
(IC50=19 nM).
To probe the importance of the cyclic ether oxygens in the
bicyclic structure of (-)-7, inhibitors 35c-e were synthesized
and evaluated. As shown, inhibitor 35c, with a cyclohexane
ring in place of the tetrahydropyran ring, only displayed a
2-fold reduction in Ki values but a 16-fold decrease in antiviral
activity compared to inhibitor 35a. A more dramatic loss of
enzymatic potency was observed with compound 35d with a
cyclopentane ring in place of a THF ring in the P2 ligand. The Ki
value dropped to 1.43 nM. Inhibitor 35e, which lacks both
cyclic ether oxygens, displayed even lower Ki and no appreci-
able antiviral activity. Those results clearly demonstrated the
critical role of both cyclic ether oxygens in ligand (-)-7.
Furthermore, the difference of activity observed between
35a and 35c suggests that the O1 oxygen on the THF-ring
of (-)-7 exerts a stronger interaction with the enzyme com-
pared to the pyran oxygen. Inhibitor 35f, in which the THF-
oxygen of the P2 ligand is located at a vicinal position, also
exhibited a substantial loss of potency (i.e., Ki = 5.3 nM) and
no antiviral activity. These results corroborated our previous
observations with the bis-THF ligand in PIs 1a and 1b. The
THF-oxygen in (-)-7 likely has a stronger hydrogen bonding
interaction with the Asp29 backbone NH and may form a
weak hydrogen bond with Asp30, in the S2 subsite of the HIV
protease. We have investigated the position of the urethane
oxygen on the bicyclic ligand in inhibitor 35g. This has
resulted in a substantial loss of protease inhibitory activity.
Furthermore, we have examined the potency enhancing effect
of the Tp-THF ligand with various hydroxyethylsulfonamide
isosteres to give inhibitors 36 and 37. The 4-methoxysulfona-
mide derivative 35a appears to be the most potent inhibitor in
chloroformate in the presence of pyridine to form mixed
activated carbonates 31a-g in 70-99% yield. The syntheses
of the corresponding protease inhibitors were achieved by
coupling the mixed activated carbonates with previously reported
hydroxyethylsulfonamide isosteres 32-34 (Scheme 7).15,35 The
syntheses of various HIV-PIs containing the Tp-THF (-)-7were
achieved by respectively treating the Boc-protected isosteres
32-34 with TFA in CH2Cl2 and subsequently by coupling
the resulting free amine isosteres with activated mixed car-
bonate 31a in THF/CH3CN in the presence of Et3N. The
corresponding inhibitors 35a, 36, and 37 were obtained in
good yields (Scheme 7). Inhibitors 35b-g were made in a
similar manner.
Results and Discussion
As mentioned above, our preliminary modeling suggested
that a hexahydrofuropyranol (-)-7 ligand may interact with
backbone atoms and residues in the protease S2-site. All
inhibitors in Table 1 were evaluated in enzyme inhibitory
assays following a protocoldescribedby Tothand Marshall.36
Inhibitors thatshowedpotentKi valueswerefurther evaluated
through in vitro antiviral assays. As can be seen, inhibitor 35a,

626 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2
Ghosh et al.
Table 1. Enzymatic Inhibitory and Antiviral Activity of Compounds 35a-g, 36, and 37b
a Values are the mean of at least two experiments. b Human T-lymphoid (MT-2) cells (2 ꢀ 103) were exposed to 100 TCID50 of HIV-1LAI and cultured
in the presence of each PI, and IC50 values were determined using the MTT assay. The IC50 values of amprenavir (APV), saquinavir (SQV), and indinavir
(IDV) were 0.03, 0.015, and 0.03 μM, respectively.

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 627
Table 2. Comparison of the Antiviral Activity of 35a and Other PIs against Multidrug Resistant Clinical Isolates in PHA-PBMs Cellsa
EC50 (μM)
virus
35a
ATV
LPV
DRV (1a)
HIV-1ERS104pre (X4)
HIV-1MDR/B (X4)
HIV-1MDR/C (X4)
HIV-1MDR/G (X4)
HIV-1MDR/TM (X4)
HIV-1MDR/MM (R5)
HIV-1MDR/JSL (R5)
0.0019 ( 0.0015
0.0027 ( 0.0006
0.031 ( 0.004
>1 (>32)
0.004 ( 0.001
0.0145 ( 0.0001 (8)
0.0037 ( 0.0018 (2)
0.0026 ( 0.0004 (1)
0.0275 ( 0.0055 (14)
0.0050 ( 0.0023 (3)
0.0275 ( 0.0009 (14)
0.470 ( 0.007 (174)
0.039 ( 0.003 (14)
0.019 ( 0.008 (7)
0.075 ( 0.003 (28)
0.205 ( 0.024 (76)
0.293 ( 0.099 (109)
0.034 ( 0.008 (9)
0.009 ( 0.005 (2)
0.026 ( 0.009 (7)
0.022 ( 0.015 (6)
0.017 ( 0.005 (4)
0.023 ( 0.005 (6)
0.437 ( 0.004 (14)
0.181 ( 0.023 (6)
0.423 ( 0.082 (14)
0.762 ( 0.115 (25)
>1 (>32)
a The amino acid substitutions identified in the protease-encoding region of HIV-1ERS104pre, HIV-1B, HIV-1C, HIV-1G, HIV-1TM, HIV-1MM, HIV-
1JSL compared to the consensus type B sequence cited from the Los Alamos database include L63P; L10I, K14R, L33I, M36I, M46I, F53I, K55R, I62V,
L63P, A71V, G73S, V82A, L90M, I93L; L10I, I15V, K20R, L24I, M36I, M46L, I54V, I62V, L63P, K70Q,V82A, L89M; L10I, V11I, T12E, I15V, L19I,
R41K, M46L, L63P, A71T, V82A, L90M; L10I, K14R, R41K, M46L, I54V, L63P, A71V, V82A, L90M; I93L, L10I, K43T, M46L, I54V, L63P, A71V,
V82A, L90M, Q92K; and L10I, L24I, I33F, E35D, M36I, N37S, M46L, I54V, R57K, I62V, L63P, A71V, G73S, V82A, respectively. HIV-1ERS104pre
served as a source of wild-type HIV-1. The EC50 values were determined by using PHA-PBMs as target cells, and the inhibition of p24 Gag protein
production by each drug was used as an end point. The numbers in parentheses represent the fold changes of EC50 values for each isolate compared to the
EC50 values for wild-type HIV-1ERS104pre. All assays were conducted in duplicate, and the data shown represent mean values ((1 standard deviations)
derived from the results of two or three independent experiments.
Figure 2. Stereoview of inhibitor 35a modeled into the active site of HIV-1 protease and superimposed on the X-ray crystal structure of 1b
(PDB code 3I7E).
the series comparable to inhibitor 2. However, the 4-amino
derivative 36 exhibited very comparable enzyme inhibitory
and antiviral potency similar to 1a.
field,37 as implemented in Molecular Operating Environment
(version 2009.10, Chemical Computing Group, Montreal,
Canada). The modeled structure maintains the important
binding interactions (hydroxyl group with Asp25 and Asp250
carboxylates; cyclic ether oxygens with Asp29 and Asp30 back-
bone NH bonds; methoxy oxygen with the Asp300 backbone
NH bond; carbonyl oxygen and sulfonamide oxygen with a
water molecule binding to Ile50 and Ile500) that are observed in
the crystal structure of 1b-bound HIV-1 protease.
We have examined inhibitor 35a for its activity against a
panel of multidrug-resistant HIV-1 variants and compared it
with that of other clinically available PIs including 1a. The
results are shown in Table 2. All inhibitors showed high antiviral
activity against an HIV-1 clinical strain isolated from a drug-
naive patient (wild-type).19 Compound 35a displayed the most
potent activity with an EC50 of 1.9 nM. When tested against
multidrug-resistant HIV-1 variants, compound 35a re-
tained impressively high activity to all variants with EC50 values
ranging from 2.6 to 27.5 nM. In contrast, other inhibitors,
except 1a, exhibited substantial loss of activity. Interestingly, 1a
and 35a showed similar fold-change of EC50 against most
multidrug-resistant HIV strains. The results indicated that 35a
is highly active against multidrug-resistant HIV-1 variants. This
inhibitor outperformed the clinically available PIs with exceed-
ingly high antiviral activity and compared well with 1a,
which currently stands as the leading PI for the treatment of
drug-resistant HIV infection.
Conclusions
We have reported the structure-based design of novel HIV-1
protease inhibitors incorporating a stereochemically defined
4-hexahydrofuropyranol-derived urethanes as the P2-ligand.
The inhibitors were designed to make extensive interactions
including hydrogen bonding with the protein backbone of the
HIV-1 protease active site. The synthesis of (3aS,4S,7aR)-
hexahydro-2H-furo[2,3-b]pyran-4-ol [(-)-7, Tp-THF] was car-
ried out in optically active form using (3aR,6aS)-3,3a,6,6a-
tetrahydro-2H-cyclopenta[b]furan-2-one as the starting material.
Inhibitor 35a has shown excellent enzyme inhibitory activity
and antiviral potency comparable to that of approved PI 1a.
Furthermore, it has shown excellent activity against multi-PI-
resistant variants, superior to other FDA approved inhibitors
examined. The data are comparable to those of 1a. We have
carried out detailed structure-activity studies that indicated
that the stereochemistry of the Tp-THF ligand and position
of its oxygens are critical to the ligand’s high enzyme affinity.
In order to obtain molecular insights into the enzyme-
inhibitor interactions of 35a in the protease active site, an
active model of 35a was created. A stereoview of the overlaid
structure of 35a with the X-ray structure of inhibitor 1b-
bound HIV-1 protease is shown in Figure 2. Inhibitor 35a was
modeled starting from the X-ray crystal structure of 1b. The
conformation of 35a was optimized using the MMFF94 force

628 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2
Ghosh et al.
An active model of 35a was created based upon the X-ray
crystal structure of 1b-bound HIV-1 protease. The overlaid
structures revealed that both oxygens of the Tp-THF ligand
can interact withthe Asp29and Asp30 backboneNHs, similar
to the bis-THF ligand oxygens. Furthermore, the extra
methylene unit in the Tp-THF ligand appears to fill in the
hydrophobic pocket in the S2-site more effectively compared
to the bis-THF in 1a. The design of an inhibitor targeting the
protein backbone may serve as an important guide to combat
drug resistance. Further design and chemical modifications
are currently underway.
J = 17.1 Hz, 1H), 2.06 (s, 3H), 2.04-1.88 (m, 1H), 1.87-1.73 (m,
1H). 13C NMR (CDCl3, 75 MHz) δ 171.1, 132.4, 128.4, 72.7, 63.9,
47.2, 42.1, 26.8, 21.0. HRMS-ESI (m/z): [M þ H]þ calcd for
C9H15O3 171.1021; found 171.1020.
To a stirred solution of the above acetate (54 mg, 0.32 mmol) and
2,6-lutidine (74 μL, 0.63 mmol) in CH2Cl2 (1 mL) was added tert-
butyldimethylsilyl trifluoromethanesulfonate (125 mg, 108 μL) at
-78 ꢀC under argon. The mixture was stirred for 10 min, at which
point reaction completion was observed. Saturated aqueous NaH-
CO3 solution (1 mL) and additional CH2Cl2 (2 mL) were added.
The two layers were separated, and the aqueous layer was further
extracted with CH2Cl2 (2 ꢀ 2 mL). The combined organic layer was
washed with brine, dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude oil was purified by column chroma-
tography on silica gel using hexanes/EtOAc (20:1) as the eluent to
afford silylated product 5 (90 mg, > 99%) as a colorless oil. TLC:
Rf = 0.68 (hexanes/EtOAc = 3:1). 1H NMR (CDCl3, 300 MHz) δ
5.68 (s, 2H), 4.45 (dt, J = 5.1, 6.3 Hz, 1H), 4.14 (t, J = 6.9 Hz, 2H),
2.67-2.55 (m, 1H), 2.47 (dd, J = 6.9, 15.4 Hz, 1H), 2.23 (dd, J =
4.8, 15.4 Hz, 1H), 2.04 (s, 3H), 2.01-1.85 (m, 1H), 1.72-1.56 (m,
1H), 0.88 (s, 9H), 0.06 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ171.2,
132.7, 128.4, 73.6, 63.8, 45.9, 41.0, 27.4, 25.8, 21.0, 18.1, -4.6, -5.0.
(4S,4aS,7aR)-4-(tert-Butyldimethylsilyloxy)hexahydrofuro-
[2,3-b]pyrane (6). To a stirred solution of 5 (76 mg, 0.27 mmol) in
MeOH (2 mL) was added K2CO3 (37 mg, 0.27 mmol). The solution
was stirred at 23 ꢀC for 2 h. Then saturated aqueous NH4Cl solution
(2 mL) was added to the mixture. EtOAc was added, and the two
layers were separated. The aqueous layer was extracted with EtOAc
(4 ꢀ 3 mL). The combined organic layer was washed with brine,
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The resulting oil was purified by flash chromatography on silica gel
using hexanes/EtOAc (7:1) as the eluent to give the corresponding
alcohol (64 mg, 98%) as a colorless oil. This intermediate was used
immediately for the subsequent reaction. TLC: Rf = 0.29 (hexanes/
EtOAc = 5:1). 1H NMR (CDCl3, 300 MHz) δ 5.72.5.62 (m, 2H),
4.52 (dt, J = 6.0, 6.9 Hz, 1H), 3.74-3.60 (m, 2H), 2.80-2.68 (m,
1H), 2.49 (ddt, J = 1.8, 7.2, 16.3 Hz, 1H), 2.34-2.29 (m, 1H), 2.06
(brs, 1H), 1.90-1.62 (m, 2H). 13CNMR(CDCl3, 75MHz) δ132.9,
128.3, 74.0, 61.1, 46.5, 40.6, 31.2, 25.8, 18.2, -4.7, -5.0.
Experimental Section
General Experimental Methods. All anhydrous solvents were
obtained according to the following procedures: diethyl ether and
tetrahydrofuran (THF) were distilled from sodium/benzophenone
under argon; toluene, methanol, acetonitrile, and dichloromethane
were distilled from calcium hydride; benzene was distilled from
sodium. Other solvents were used without purification. All moist-
ure-sensitive reactions were carried out in flame-dried flasks under
argon atmosphere. Reactions were monitored by thin layer chro-
matography (TLC) using Silicycle 60A-F254 silica gel precoated
plates. Flash column chromatography was performed using Sili-
cycle 230-400 mesh silica gel. Yields refer to chromatographically
and spectroscopically pure compounds. Optical rotations were
1
recorded on a Perkin-Elmer 341 polarimeter. H NMR and 13C
NMR spectra were recorded on a Varian Inova-300 (300 and 75
MHz), Bruker Avance ARX- 400 (400 and 100 MHz), or DRX-
500 (500 and 125 MHz). High and low resolution mass spectra
were carried out by the Mass Spectroscopy Center at Purdue
University. The purity of all test compounds was determined by
HRMS and HPLC analysis in the different solvent systems. All test
compounds showed g95% purity.
(1S,2R)-2-[1-(tert-Butyldimethylsilyloxy)cyclopent-3-en-2-yl]-
ethyl Acetate (5). To a stirred suspension of lithium aluminum
hydride (93 mg, 2.45 mmol) in dry Et2O (6 mL) was added
dropwise a solution of (-)-(1S,5R)-2-oxabicyclo[3.3.0]oct-6-en-
3-one (4) (150 mg, 1.19 mmol) in Et2O (4 mL þ 1 mL rinse) at 0 ꢀC
under argon. The reaction mixture was vigorously stirred at this
temperature for 1.5 h. Water (0.1 mL) was then carefully added
followed by addition of 3 M NaOH (0.1 mL) and then water (0.3 mL).
The solution was stirred until formation of a white precipitate was
complete. EtOAc (3 mL) and then Na2SO4 were added, and the
resulting suspension was filtered out. The amorphous solid was
washed several times with EtOAc (5 ꢀ 5 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated
in vacuo. The crude oil was purified by flash chromatography on
silica gel using hexanes/EtOAc (1:1) as the eluent to give the
resulting diol (145 mg, 95%) as a colorless oil. TLC: Rf = 0.28
(hexanes/EtOAc = 1:2). 1H NMR (CDCl3, 300 MHz) δ 5.74 (m,
1H), 5.56 (m, 1H), 4.48 (dt, J = 2.4, 6.6 Hz, 1H), 3.84 (m, 1H), 3.71
(ddd, J = 3.6, 8.7, 10.0 Hz, 1H), 2.75 (m, 1H), 2.67 (m, 1H), 2.36
(d, J = 17.1 Hz, 1H), 1.98-1.75 (m, 1H).
To a stirred solution of the diol (76 mg, 0.59 mmol) in CH2Cl2
(3 mL) was added 2,4,6-collidine (1.2 mmol, 155 μL) followed by
acetyl chloride (50 μL, 0.71 mmol) at -78 ꢀC under argon. The
resulting solution was stirred at this temperature for 5 h at which
point additional acetyl chloride (0.25 μL, 0.24 mmol) was added.
The solution was stirred for 2 h, and then saturated aqueous
NaHCO3 solution was added. The two layers were separated, and
the aqueous layer was washed with CH2Cl2 (3 ꢀ 5 mL). The
combined organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The crude oil was purified by flash chro-
matography on silica gel using hexanes/EtOAc (6:1, then 4:1) as the
eluent to give the monoacetate (88 mg, 87%) as a colorless oil.
TLC: Rf = 0.26 (hexanes/EtOAc = 2:1). 1H NMR (CDCl3, 300
MHz) δ 5.80-5.72 (m, 1H), 5.64-5.58 (m, 1H), 4.40 (dt, J = 2.4,
5.6 Hz, 1H), 4.20 (t, J = 7.2 Hz, 2H), 2.74-2.56 (m, 2H), 2.33 (d,
A stream of ozonized oxygen was bubbled through a solution
of the above alcohol (63.8 mg, 0.26 mmol) in CH2Cl2 (15 mL)
at -78 ꢀC until the blue color persisted (5 min). After the
solution was flushed with nitrogen, Me2S (0.5 mL) was added.
The solution was warmed to 0 ꢀC and stirred over a 2 h period
following which anhydrous Na2SO4 was added. The solution was
left at room temperature overnight and then filtered and concen-
trated in vacuo. The resulting solid was quickly passed through a
short column of silica gel using hexanes/EtOAc (3:1) as the eluent
to afford the hemiacetal (99 mg) as a white-solid mixture of isomers
which was submitted directly to the next step. TLC: Rf = 0.26
(hexanes/EtOAc = 3:1). To an ice-cold solution of the crude
diacetal (∼0.25 mmol) and Et3SiH (0.16 mL, 1.0 mmol) in CH2Cl2
(3 mL) under argon, was slowly added BF3-Et2O (60 μL, 0.5
mmol). The mixture was stirred at 0 ꢀC for 10 min. Saturated
aqueous NaHCO3 solution (2 mL) and additional CH2Cl2 were
added. The two phases were separated and the aqueous layer was
further extracted with CH2Cl2 (3 ꢀ 2 mL). The combined organic
layer was washed with brine, dried (MgSO4), filtered, and con-
centrated in vacuo. The crude oil was purified by column chroma-
tography on silica gel using hexanes/EtOAc (7:1) as the eluent to
give bicyclic acetal 6 (38 mg, 55% 3 steps) as an amorphous solid.
TLC: Rf = 0.50 (hexanes/EtOAc = 3:1). 1H NMR (CDCl3, 300
MHz) δ 4.95 (d, J = 3.4 Hz, 1H), 4.24-4.08 (m, 2H), 3.92 (dt, J =
8.1, 9.1 Hz, 1H), 3.85 (ddd, J = 2.0, 4.5, 12.2 Hz, 1H), 3.30 (dt, J =
2.0, 12.3 Hz, 1H), 2.39 (m, 1H), 2.07 (tt, J = 9.4, 12.0 Hz, 1H),
1.91-1.66 (m, 2H), 1.58-1.48 (m, 1H), 0.89 (s, 9H), 0.07 (s, 3H),
0.067 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 101.2, 68.4, 67.8, 61.1,
47.2, 30.3, 25.7, 22.4, 18.2, -4.6, -4.8.
(3aS,4S,7aR)-Hexahydro-2H-furo[2,3-b]pyran-4ol [(-)-7].
Bicyclic compound 6 (36 mg, 0.139 mmol) was dissolved in

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 629
THF (1 mL), and tetrabutylammonium fluoride (1 M solution
THF, 0.21 mL, 0.21 mmol) was added to the solution. The mixture
was stirred for 2 h at 23 ꢀC. Saturated aqueous NH4Cl solution was
added (2 mL), followed by EtOAc (2 mL). The two phases were
separated, and the aqueous layer was further extracted with EtOAc
(4 ꢀ 3 mL). The combined organic layer was washed with brine,
dried (Na2SO4), filtered, and concentrated in vacuo. The resulting
compound was purified by flash chromatography on silica gel
using hexanes/EtOAc (1:2 then 1:3) as the eluent to afford pure
alcohol (-)-7 (19 mg, 94%) as an amorphous solid. TLC: Rf1=
0.15 (hexanes/EtOAc = 1:3). [R]2D3 -29.6 (c 1.06, CHCl3). H
NMR (CDCl3, 300 MHz) δ 4.99 (d, J = 2.7 Hz, 1H), 4.25-4.16
(m, 2H), 3.96 (q, J = 7.5 Hz, 1H), 3.90 (ddd, J = 2.4, 4.8, 12.3 Hz,
1H), 3.34 (td, J = 3.0, 11.7 Hz, 1H), 2.58-2.45 (m, 1H), 2.14-1.98
(m, 1H), 1.96-1.82 (m, 1H), 1.80-1.62 (m, 2H). 13C NMR
(CDCl3, 75 MHz) δ 101.4, 68.4, 67.5, 61.0, 46.3, 29.4, 21.8.
HRMS-CI (m/z): [M þ H]þ calcd for C9H15O3 127.0759; found
127.0757.
(3aS,4S,7aR)-Octahydrobenzofuran-4-ol [(-)-12]. Racemic
alcohol 12 (70 mg, 0.5 mmol) was dissolved in THF (5 mL),
and vinyl acetate (120 μL, 1.25 mmol) was added. Amano lipase
PS-30 (30 mg) was added, and the resulting suspension was
stirred at 15-17 ꢀC. After 48 h, 30 mg of additional enzyme was
added and the mixture was left for additional 48 h until ∼54%
conversion was reached (NMR and GC). The resulting suspension
was diluted with Et2O and filtered on Celite and the filter cake
rinsed with Et2O. After evaporation of the remaining solvent, the
residue was purified by column chromatography using hexanes/
EtOAc (5:1, 3:1, then 2:1) as the eluent to yield acetyl furanol 13
(38 mg, 41%) and the desired enantioenriched (-)-hexahydrobenzo-
furanol (-)-12 (24 mg, 35%). The enantiomeric excess of the 2,4-
dinitrobenzoate derivative of (-)-12 was determined to be 98.8% ee
by chiral HPLC: column ChiralPak IA, hexane/isopropanol
(90/10 to 50/50, 40 min), 1 mL/min, 35 ꢀC, λ= 254 nm, tR major =
16.54 min, tR minor = 37.1 min.
2-[3-(tert-Butyldimethylsilyl)oxy)-1-hydroxypropyl]cyclopenta-
none (15). A solution of lithium diisopropylamide (14 mmol),
freshly prepared by adding n-BuLi (1.6 M solution in hexanes,
8.75 mL, 14 mmol) to diisopropylamine (1.97 mL, 1.42 g, 14 mmol)
in THF (30 mL) at 0 ꢀC under argon followed by stirring for 30 min,
was cooled to -78 ꢀC, and cyclopentanone 14 (1.12 mL, 1.07 g,
12.7 mmol) in THF (5 mL) was added dropwise over 10 min. After
being stirred at -78 ꢀC for 1.5 h, 3-tert-butyldimethylsilyloxypro-
pionaldehyde (1.55 g, 8.2 mmol) in THF (20 mL) was added
dropwise over 5 min. The mixture was stirred for an additional 2 h,
and the reaction was quenched by addition of saturated aqueous
NH4Cl solution (10 mL). Following dilution with Et2O, the two
phases were separated, and the aqueous phase was extracted with
Et2O (2ꢀ). The combined organic phase was washed with brine,
dried (MgSO4), filtered, and evaporated. The residue was quickly
purified by column chromatography on silica gel using hexanes/
EtOAc (20:1 to 10:1) as the eluent to give 15 as a 3:1 mixture of
diastereoisomers (2.13 g, 95%). Light yellow oil. TLC: Rf = 0.37
and 0.23 (hexanes/EtOAc = 5:1). 1H NMR (CDCl3, 400 MHz) δ
4.27 (dt, J = 3.1, 9.3 Hz, 0.3H), 4.10 (s, 1H), 3.91 (m, 1H), 3.87 (m,
0.3H), 3.85-3.75 (m, 2.6H), 2.38-2.30 (m, 6.5H), 1.80-1.56 (m,
5.2H), 0.88 (brs, 12H), 0.06 (s, 2H), 0.05 (s, 6H). 13C NMR
(CDCl3, 100 MHz) δ 222.8, 220.4, 70.4, 70.2, 62.6, 60.5, 54.5,
53.9, 39.1, 38.7, 37.0, 36.6, 26.4, 25.9, 25.8, 23.5, 20.7, 20.5, 18.2,
-5.5, -5.6. HRMS-CI (m/z): [M - OH]þ calcd for C14H27O2Si
255.1780; found 255.1785.
2,3,6,7-Tetrahydrocyclopenta[b]pyran-4(5H)-one (16). To a
solution of DMSO (425 μL, 468 mg, 6 mmol) in CH2Cl2 (3 mL)
was added (CF3CO)2O (406 μL, 609 mg, 2.9 mmol) dropwise at
-78 ꢀC under argon. The resulting mixture was stirred at that tem-
perature for 45 min. Then a precooled solution of ketone 15 (272mg,
1 mmol) in CH2Cl2 (3 mL) was added. The reaction mixture was
stirred at -78 ꢀC for 30 min, then at -15 ꢀC for 15 min and cooled
back to -78 ꢀC. Et3N (1.25 mL, 911 mg, 9 mmol) was added, and
the mixture was stirred at -78 ꢀC for 45 min. The reaction was
quenched by addition of saturated aqueous NH4Cl solution and the
mixture warmed to room temperature. The two phases were
separated and the aqueous phase was extracted with CH2Cl2 (3ꢀ)
and then EtOAc (1ꢀ). The combined organic phase was washed
with brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
using hexanes/EtOAc (20:1, then 15:1 with a few drops of acetic
acid) as the eluent to give the corresponding diketone (221 mg, 82%)
as a light orange oil. TLC: Rf = 0.37 (hexanes/EtOAc = 10:1). 1H
NMR (CDCl3, 400 MHz) δ 12.7 (br s, 1H), 3.90 (t, J = 6.2 Hz,
0.66H), 3.89 (t, J = 6.5 Hz, 2H), 3.46 (t, J = 7.8 Hz, 0.33H), 2.86
(dt, J= 3.0, 6.2 Hz, 0.66H), 2.58 (t, J= 7.2 Hz, 2H), 2.45 (t, J= 6.5
hz, 2H), 2.40 (t, J = 7.9 Hz, 2H), 2.31-2.19 (m, 0.66H), 2.10-1.97
(m, 0.66H), 1.95-1.82 (m, 2H), 0.86 (s, 9H), 0.86 (s, 3H), 0.04 (s,
1H), 0.03 (s, 1H), 0.03 (s, 6H). 13C NMR (CDCl3, 100 MHz) δ
212.9, 206.1, 203.6, 175.4, 110.9, 62.4, 59.6, 58.5, 45.6, 38.7, 37.8,
37.0, 25.7, 25.6, 25.0, 20.6, 20.3, 18.1, -5.6. HRMS-CI (m/z):
[M þ H]þ calcd for C14H26O3Si 271.1729; found 271.1733.
(3aR,4R,7aS)-Hexahydro-2H-furo[2,3-b]pyran-4-ol [(þ)-7].
Cyclopentenediol 8 was prepared as described previously.27b
The same synthetic sequence was the applied on the diol as for
the synthesis of (-)-7. Ligand (þ)-7 was obtained in high
enantiomeric purity [99% ee, [R]2D3 þ22.3 (c 0.22, CHCl3)].
2-Ethoxy-2,3,6,7-tetrahydrobenzofuran-4(5H)-one (10). To a
stirred solution of 2-diazo-1,3-cyclohexanedione (300 mg, 2.17
mmol) in freshly distilled ethyl vinyl ether (5 mL) was added
[Rh2(OAc)4] (10 mg, 0.02 mmol). The mixture was stirred at
room temperature for 5 h, after which the reaction was diluted
with Et2O and a few drops of pyridine were added. A red
precipitate formed. The solution was filtered on a short pad of
silica, flushing with Et2O/THF (4:1) as eluent. After evapora-
tion, the residue was purified by column chromatography on
silica gel using hexanes/CH2Cl2/THF (8:1:1) as the eluent to
furnish benzofuranone derivative 17 (347 mg, 88%). TLC: Rf =
1
0.29 (hexanes/EtOAc = 1:1). H NMR (CDCl3, 400 MHz) δ
5.72 (dd, J = 3.3, 7.4 Hz, 1H), 3.88 (m, 1H), 3.62 (m, 1H), 2.92
(ddt, J = 2.2, 7.4, 15.8 Hz, 1H), 2.70-2.62 (m, 1H), 2.52-2.37
(m, 2H), 2.33 (t, J = 6.5 Hz, 2H), 2.12-1.95 (m, 2H), 1.24 (t, J =
7.1 Hz, 3H). 13C NMR (CDCl3, 100 Hz) δ 195.2, 175.7, 112.3,
108.5, 65.0, 36.3, 32.7, 23.8, 21.5, 14.9.
2-Ethoxyhexahydrobenzofuran-4(2H)-one (11). To a solution
of the ketone 10 (140 mg, 0.77 mmol) in EtOAc (9 mL) was
added 5% Pd/C (128 mg, 60 μmol), and the mixture was stirred
under H2 (1 atm) for 1.5 h at room temperature. The mixture was
then filtered on Celite and the pad washed with EtOAc. Eva-
poration of the solvent furnished the corresponding crude
ketone 11 as an essentially pure mixture of diastereoisomers
(130 mg, dr = 9:1). The ketone was directly submitted to the
next step without purification. TLC major isomer: Rf = 0.35
(hexanes/EtOAc = 2:1).
cis-Octahydrobenzofuran-4-ol [(()-12]. A solution of ketone 11
(130 mg, ca. 0.7 mmol) in CH2Cl2 (10 mL) was cooled to -78 ꢀC
under Ar. L-Selectride (1 M solution, 0.9 mL, 0.9 mmol) was
slowly added to the solution over 5 min and the reaction mixture
was stirred for 1.5 h at -78 ꢀC. Upon complete conversion, Et3SiH
(0.6 mL, 437 mg, 3.7 mmol) was added followed by dropwise
addition of TMSOTf (380 μL, 466 mg, 2.1 mmol). The solution
was stirred for 2.5 h while slowly warming to 0 ꢀC. The reaction was
quenched by addition of saturated aqueous NaHCO3 solution
(5 mL). The two phases were separated, and the aqueous phase was
extracted with Et2O (5ꢀ). The combined organic layer was washed
with brine, dried (MgSO4), and evaporated under vacuum. The
residue was purified by column chromatography on silica gel using
hexanes/EtOAc (3:1 to 2:1) as the eluent to yield the desired alcohol
(()-12 (78 mg, 71% over two steps) as a colorless oil. TLC: Rf =
0.25 (hexanes/EtOAc = 1:2). 1H NMR (CDCl3, 400 MHz) δ 4.01
(dt, J = 4.6, 8.8 Hz, 1H), 3.88-3.82 (m, 2H), 3.78 (dt, J = 7.1, 8.7
Hz, 1H), 2.31 (m, 1H), 2.12-1.90 (m, 2H), 1.74-1.50 (m, 5H),
1.32-1.22 (m, 1H). 13C NMR (CDCl3, 100 Hz) δ 77.6, 69.1, 66.7,
43.2, 30.2, 26.9, 25.9, 16.2.

630 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2
Ghosh et al.
Diketone (54 mg, 0.2 mmol) was dissolved in CH2Cl2 (2 mL)
and cooled to 0 ꢀC under argon. Trifluoroacetic acid (90 μL, 134
mg, 1.2 mmol) was then added dropwise. The mixture was
stirred at 0 ꢀC for 30 min and then warmed to room temperature
and stirred for 4 h. As completion was reached, solid NaHCO3
(∼150 mg) was then added and the mixture diluted with EtOAc.
After being stirred for 10 min, the suspension was filtered on a
small Celite pad. The solvent was evaporated under reduced
pressure and the residue purified by column chromatography on
silica gel using hexanes/EtOAc (4:1) as the eluent to furnish R,β-
unsaturated ketone 16 (26 mg, 94%) as a colorless oil. TLC:
Rf = 0.23 (hexanes/EtOAc = 3:1). 1H NMR (CDCl3, 400 MHz)
δ 4.49 (t, J = 6.9 Hz, 2H), 2.59-2.45 (m, 6H), 1.89 (m, 2H). 13C
NMR (CDCl3, 100 MHz) δ 189.6, 178.5, 114.5, 69.5, 35.4, 32.6,
25.6, 19.0.
Octahydrocyclopenta[b]pyran-4-ol [(()-18]. A solution of R,β-
unsaturated ketone 16 (109 mg, 0.79 mmol) in EtOAc (6 mL)
was loaded with 10% Pd/C (50 mg, 0.047 mmol) and carefully
placed under H2 (1 atm). The mixture was stirred at room
temperature for 12 h. The suspension was then filtered over a
Celite pad, the pad washed with EtOAc, and the resulting solu-
tion evaporated under reduced pressure. The essentially pure
ketone (81 mg) was directly carried out to the next step without
further purification. TLC: Rf = 0.37 (hexanes/EtOAc = 3:1).
1H NMR (CDCl3, 400 MHz) δ 4.22-4.15 (m, 2H), 3.69 (td, J =
2.8, 12.0 Hz, 1H), 2.71 (ddd, J = 7.2, 12.3, 15.7 Hz, 1H), 2.48 (dt,
J = 4.0, 9.0 Hz, 1H), 2.23 (ddt, J = 1.4, 2.8, 15.7 Hz, 1H),
2.00-1.80 (m, 5H), 1.71-1.63 (m, 1H). 13C NMR (CDCl3, 100
MHz) δ 210.2, 82.8, 65.9, 55.1, 38.5, 33.3, 28.4, 22.8.
The ketone was diluted in CH2Cl2 (5 mL) under argon and
cooled to -78 ꢀC. L-Selectride (1 M solution in THF, 0.80 mL,
0.8 mmol) was added dropwise, and the resulting mixture was
stirred at this temperature for 2 h. Hydrogen peroxide (30%
aqueous solution, 3 mL) and 3 N NaOH aqueous solution were
added, and the mixture was warmed to 23 ꢀC and stirred for 5 h.
The phases were separated and the aqueous phase extracted with
CH2Cl2 (4ꢀ). The combined organic phase was washed with
brine, dried (Mg2SO4), filtered, and evaporated under reduced
pressure. The residue was purified by column chromatography
on silica gel using hexanes/EtOAc (4:1, then 1.5:1) as the eluent
to yield cis-bicyclic alcohol (()-18 (77 mg, 68% two steps) as a
colorless oil. TLC: Rf = 0.13 (hexanes/EtOAc = 2:1). 1H NMR
(CDCl3, 400 MHz) δ 4.11 (dt, J = 5.6, 11.1 Hz, 1H), 3.91 (ddd,
J = 2.0, 4.5, 11.7 Hz, 1H), 3.84-3.81 (m, 1H), 3.33 (dt, J = 2.3,
11.9 Hz, 1H), 2.17-2.08 (m, 1H), 1.92-1.81 (m, 1H), 1.79-1.55
(m, 7H). 13C NMR (CDCl3, 125 MHz) δ 80.5, 68.3, 65.4, 47.0,
32.6, 29.7, 21.6, 21.3.
(4S,4aS,7aS)-Octahydrocyclopenta[b]pyran-4-ol [(-)-18].
Racemic alcohol (()-18 (68 mg, 0.48 mmol) was dissolved in
THF (5 mL), and vinyl acetate (225 μL, 2.4 mmol) was added.
Amano lipase PS-30 (30 mg) was added, and the resulting
suspension was stirred at 15-20 ꢀC. The mixture was left stirring
for >48 h until around 50% conversion was reached (as seen by
NMR). The resulting suspension was diluted with Et2O and
filtered on Celite, and the filter cake was rinsed with Et2O. After
evaporation of the remaining solvent, the residue was purified
by column chromatography using hexanes/EtOAc (5:1, 3:1,
then 1.5:1) to yield the desired enantio enriched pyranol (-)-18
(25 mg, 37%). [R]2D0 -47.5 (c 1.32, CHCl3). An enantiopurity
of 94.1% ee for the alcohol was measured by chiral HPLC
analysis of the corresponding activated carbonate 31d: column
ChiralPak IA, 0.7 mL/min, hexanes/IPA (98:2 to 85:15, from 0
to 45 min), λ = 210 nm, T = 30 ꢀC, tR minor = 22.4 min, tR
major = 23.3 min.
followed by slow formation of the reduced cis-product. After
12 h, the solution was filtered on a pad of Celite and the
solvent removed in vacuo. The residue was purifed by flash
column chromatography on silica gel using hexanes/EtOAc
(30:1 to 10:1) to give the reduced ketone (98 mg, 92%). TLC:
Rf = 0.65 (hexanes/EtOAc = 5:1). 1H NMR (CDCl3, 400 MHz)
δ 2.62-2.54 (m, 1H), 2.48-2.38 (m, 1H), 2.38-2.23 (m, 2H),
2.08-1.98 (m, 1H), 1.94-1.30 (m, 9H). 13C NMR (CDCl3, 100
MHz) δ 214.6, 53.1, 42.9, 39.6, 31.0, 27.2, 26.6, 23.8, 23.0. A
solution of the ketone (135 mg, 0.98 mmol) in CH2Cl2 (3 mL)
was cooled to -78 ꢀC under argon. L-Selectride (1 M solution
THF, 1.2 mL) was added dropwise to the solution, and the
reaction mixture was stirred at -78 ꢀC for 1 h. Hydrogen
peroxide solution (30% solution, 1.5 mL) and then NaOH
(3 M solution, 1.5 mL) were added, and the mixture was warmed to
23 ꢀC and stirred for 1 h. After dilution with water (2 mL) and
then addition of Na2SO3 saturated aqueous solution (3 mL), the
aqueous phase was successively extracted with CH2Cl2 (4ꢀ).
The combined organic phase was dried (Na2SO4), filtered, and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel using hexanes/EtOAc (6:1) to
yield racemic alcohol (()-19 (92 mg, 66%) as a colorless oil.
1
TLC: Rf = 0.25 (hexanes/EtOAc = 5:1). H NMR (CDCl3,
500 MHz) δ 3.96 (m, 1H), 2.26-2.17 (m, 1H), 1.93 (m, 1H),
1.79-1.53 (m, 7H), 1.47-1.15 (5 H), 0.96 (dq, J = 3.3, 13.0 Hz,
1H). 13C NMR (CDCl3, 125 MHz) δ 71.6, 46.4, 40.1, 31.5,
29.5, 27.0, 23.9, 21.4, 21.2. HRMS-EI (m/z): [M - OH]- calcd
for C9H15 122.1096, found 122.1097.
(1R,2S,6R)-Bicyclo[4.3.0]nonan-2-ol [(-)-19]. Racemic 19 (86
mg, 0.62 mmol) was dissolved in THF (5 mL), and vinyl acetate
(0.5 mL) was added. Amano lipase PS-30 (60 mg) was added,
and the resulting suspension was stirred at 23 ꢀC until 50%
conversion was reached (NMR) in ∼6 h. The resulting suspen-
sion was diluted with Et2O and filtered on Celite, and the filter
cake was rinsed with Et2O. After evaporation of the remaining
solvent, the residue was purified by column chromatography
using hexanes/EtOAc (8:1, 6:1, then 4:1) to yield acetate 21 and
the desired enantioenriched (-)-indanol (-)-19 (38.5 mg, 45%
yield). [R]2D0 -28.3ꢀ (c 1.02, CHCl3), ([R]2D0 lit.-27.2ꢀ (c 1.0,
CHCl3).38 The enantiomeric excess of the 2,4-dinitrobenzoate
derivative was determined to be 89.9% ee by chiral HPLC,
column ChiralPak IA, hexane/isopropanol (100/0 to 90/10,
15 min; 90/10 to 80/20, 15 min), 1 mL/min, tR minor=16.58 min,
tR major = 19.5 min.
3-[(4-Iodotetrahydrofuran-3-yl)oxy]propan-1-ol (23). To a so-
lution of freshly distilled 2,5-dihydrofuran (700 mg, 0.740 mL,
10 mmol), in a mixture of dry 1,3-propanediol/dimethoxyethane
(1:1, 5 mL) at 0 ꢀC under argon was successively added NH4OAc
(77 mg, 1 mmol), followed by N-iodosuccinimide (11 mmol,
2.47 g). The mixture was warmed to 23 ꢀC and stirred for 12 h
protected from light. The reaction was quenched by addition of
saturated aqueous Na2SO3 and then diluted with water. The
mixture was extracted with Et2O/EtOAc (1:1). The combined
organic phase was dried (Na2SO4), filtered, and evaporated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel using hexanes/EtOAc
(4:1, 3:1, then 2.5:1) to give iodo alcohol 23 (1.2 g, 45%) as a
pale yellow oil. TLC: Rf = 0.3 (hexanes/EtOAc = 1:1). 1H
NMR (CDCl3, 400 MHz) δ 4.33 (m, 1H), 4.29-4.19 (m, 3H),
4.04 (dd, J = 2.2, 9.8 Hz, 1H), 3.79 (dd, J = 1.5, 9.8 Hz, 1H),
3.76-3.69 (m, 3H), 3.60 (m, 1H), 1.81 (m, 2H). 13C NMR
(CDCl3, 100 MHz) δ 88.2, 76.1, 71.8, 67.9, 60.6, 32.3, 23.4.
3-[(4-Iodotetrahydrofuran-3-yl)oxy]propanal (24). Oxalyl
chloride (580 mg, 392 μL, 4.6 mmol) was diluted in CH2Cl2
(12 mL) under argon, and the solution was cooled to -78 ꢀC.
Dry DMSO (715 mg, 650 μL, 9.15 mmol) in CH2Cl2 (3 mL) was
added to the cold solution dropwise, and the mixture was stirred
for 30 min. A solution of alcohol 23 (500 mg, 1.83 mmol) in
CH2Cl2 (4 mL) was then added slowly, and the mixture was kept
stirring for an additional hour at -78 ꢀC. Et3N (1.3 g, 1.8 mL,
(()-endo,cis-Bicyclo[4.3.0]nonan-2-ol [(()-19]. Enone 1733
(106 mg, 0.77 mol) was dissolved in THF (10 mL), and the flask
was purged with argon. Pd/C 10% (60 mg, 0.06 mmol) was
added to the solution, and the resulting suspension was stirred
under hydrogen (1 atm). TLC monitoring first shows isomerization
of the enone, through migration of the olefin to the internal position,

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 631
12.8 mmol) was then introduced. The white suspension was
stirred at -78 ꢀC for 20 min and slowly warmed to room tem-
perature. A 0.5 M phosphate buffer solution pH 5.5 (20 mL)
was added. The two phases were separated, and the resulting
aqueous phase was extracted with Et2O (4ꢀ). The combined
organic phase was dried (MgSO4), filtered, and evaporated. The
residue was purified by flash column chromatography using
hexanes/EtOAc (6:1 to 4:1) to yield the desired aldehyde 24
(433 mg, 86%) as a light yellow oil. TLC: Rf = 0.76 (hexanes/
EtOAc = 1:1). 1H NMR (CDCl3, 300 MHz) δ 9.77 (t, J = 1.3
Hz, 1H), 4.35 (m, 1H), 4.30-4.19 (m, 3H), 4.04 (dd, J = 2.3,
9.8 Hz, 1H), 3.92 (ddd, J = 5.3, 6.7, 9.5 Hz, 1H), 3.77 (dd, J =
1.7, 10.1 Hz, 1H), 3.75 (ddd, J = 5.2, 6.2, 9.5 Hz, 1H), 2.69
(m, 2H). 13C NMR (CDCl3, 75 MHz) δ 200.1, 88.3, 76.1, 71.8,
63.1, 43.7, 23.3.
(3aR,6aR)-Tetrahydrofuro[2,3-b]furan-3(2H)-one (28). Enan-
tiomerically pure (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol
(bis-THF) 27 (85 mg, 0.65 mmol) was diluted in dry CH2Cl2
(6 mL) under argon. The solution was cooled to 0 ꢀC, and
anhydrous Na2HPO4 (52 mg, 0.36 mol) was added. Dess-
Martin periodinane (360 mg, 0.85 mmol) was added at once at
0 ꢀC and the resulting suspension warmed to 23 ꢀC and stirred
for 3 h. The reaction was then quenched by successive addition
of saturated aqueous NaHCO3 and saturated aqueous Na2SO3
solutions (1.5 þ 1.5 mL). The phases were separated, and the
aqueous phase was extracted with CH2Cl2 and then EtOAc. The
combined organic phases were dried (Na2SO4), filtered on a
small pad of silica gel, and evaporated to dryness. The residue
was purified by column chromatography on silica gel using
hexanes/EtOAc (3:1) to furnish ketone 28 (73 mg, 87%) as a
white crystalline solid. TLC: Rf = 0.57 (hexanes/EtOAc = 1:1).
Spectral data corresponded to those previously reported in the
literature.35
(3aS,7aR)-Tetrahydro-2H-furo[2,3-b]pyran-5(3H)-one (29).
AlMe3 (25% w/w hexanes, 250 μL, 0.6 mmol) was diluted in
dry CH2Cl2 (5 mL) under argon, and the solution was cooled to
-78 ꢀC. A solution of ketone 28 (64 mg, 0.5 mmol) in dry CH2Cl2
(5 mL) was slowly added dropwise. After 10 min, TMSCHN2 (2 M
solution in Et2O, 275 μL, 0.55 mmol) was added. The mixture was
stirred for 2 h while warming to -30 ꢀC. Saturated Rochelle’s salt
solution (5 mL) was added, and the mixture was stirred for 1 h. The
phases were separated. The aqueous phase was extracted with
CH2Cl2, and the combined organic phase was dried (MgSO4). The
solution was filtered on a small silica gel pad, flushing with Et2O,
and the collected organic phase was evaporated. A crude mixture
of the desired ketone along with R-silylated derivatives and isomers
was then obtained. The mixture was redissolved in THF (5 mL).
AcOH (6 drops) and TBAF (0.5 mL, 0.5 mmol) were successively
added. The resulting mixture was stirred at 23 ꢀC for 3 h and
evaporated to dryness. The residue was purified by flash column
chromatography on silica gel using hexanes/EtOAc (5:1) as the
eluent to give ketone 29 (45 mg, 63%). TLC: Rf = 0.35 (hexanes/
EtOAc = 2:1). 1H NMR (CDCl3, 400 MHz) δ 5.49 (d, J = 6.8 Hz,
1H), 4.11 (d, J = 18.2 Hz, 1H), 4.10 (m, 1H), 3.92 (d, J = 18.2 Hz,
1H), 3.74 (dt, J = 6.5, 8.9 Hz, 1H), 2.85 (m, 1H), 2.71 (d, J = 6.3,
15.6 Hz, 1H), 2.48 (d, J = 3.9, 15.6 Hz, 1H), 2.15 (m, 1H), 1.55
(ddt, J = 7.7, 8.9, 12.7 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ
210.7, 100.9, 67.5, 67.1, 39.2, 36.2, 31.3.
(3aS,5R,7aR)-Hexahydro-2H-furo[2,3-b]pyran-5-ol (30). A
solution of ketone 29 (25 mg, 0.173 mmol) dissolved in CH2Cl2
(5 mL) was cooled to -78 ꢀC under argon. L-Selectride (1 M in
THF, 200 μL, 0.2 mmol) was added dropwise. The solution was
stirred at this temperature for 3 h and quenched by addition of
saturated aqueous NH4Cl solution. The aqueous phase was
extracted with EtOAc. The combined organic extract was dried
(Na2SO4), filtered, and evaporated. The crude was purified by
column chromatography on silica gel using hexanes/EtOAc (2:1,
1:1, then 1:2) to yield alcohol 30 as a 5:1 mixture of diastereoi-
somers (18 mg, cis major). The stereoisomers were separated in the
subsequent synthesis of the mixed activated carbonate 31g. TLC:
Rf = 0.25 (hexanes/EtOAc = 1:2). 1H NMR (CDCl3, 300 MHz) δ
5.08 (d, J = 3.8 Hz, 0.2H), 5.05 (d, J = 3.3 Hz, 1H), 4.16-4.11 (m,
1.2H), 3.95-3.84 (m, 1.6H), 3.81-3.70 (m, 2H), 3.63 (m, 1H), 3.27
(dd, J = 7.9, 11.2 Hz, 0.2H), 2.35-1.70 (m, 6H).
(3aS,4S,7aR)-Hexahydro-2H-furo[2,3-b]pyran-4-yl (4-Nitro-
phenyl) Carbonate (31a). Furopyranol ligand (-)-7 (9 mg,
0.063 mmol) was diluted in CH2Cl2 (0.5 mL) under argon.
The solution was cooled to 0 ꢀC, and dry pyridine (17 μL,
∼0.21 mmol) was added. 4-Nitrophenyl chloroformate (24 mg,
0.12 mmol) was added at once to the solution, upon which a
white precipitate formed. The mixture was stirred for 2 h while
warming to room temperature. Upon completion, the mixture
was concentrated under reduced pressure and the residue was
purified by column chromatography on silica gel using hexanes/
EtOAc (6:1, then 3:1) as the eluent to give the corresponding
Hexahydro-2H-furo[3,4-b]pyran-4-ol [(()-25]. To a solution
of aldehyde 24 (100 mg, 0.37 mmol) in DME (10 mL) was
successively added indium (60 mg, 0.55 mmol), CuI (48 mg, 0.25
mmol), and a catalytic amount of iodine (10 mg, 0.037 mmol).
After the suspension was stirred for 5 min, water (4 mL) was
added and the mixture was stirred at room temperature for 4 h.
The suspension was filtered on a Celite pad, washing the pad
with THF. The solvent was reduced under vacuum and the
resulting aqueous phase acidified with 1 M HCl and saturated
with NaCl. The aqueous phase was extracted with EtOAc, and
the combined organic phase was dried over MgSO4. After
filtration and evaporation, the crude was purified by flash
column chromatography on silica gel using hexanes/EtOAc
(1:1 to 1:5) to provide the bicyclic alcohol (()-25 (25 mg,
47%) as a mixture of diastereoisomers. TLC: Rf = 0.28
(EtOAc 100%). Pyridinium chlorochromate (74 mg, 0.346
˚
mmol) was added to a suspension of flame-dried 4 A molecular
sieves in CH2Cl2 (2 mL) at room temperature under argon. A
solution of the above alcohol (25 mg, 0.173 mmol) in CH2Cl2
(1.5 mL) was transferred to the suspension at 0 ꢀC, and the
solution was stirred for 1 h at 0 ꢀC. The reaction was quenched
by addition of isopropanol, and the mixture was filtered on a
silica pad, flushing with Et2O. After evaporation of the solvent,
the corresponding ketone thus obtained was used directly in the
next step. TLC: Rf = 0.45 (hexanes/EtOAc = 1:1). The ketone
was redissolved in EtOH (1.5 mL). The solution was cooled to-
-20 ꢀC, and NaBH4 (25 mg, 0.66 mmol) was added at once.
After being stirred at this temperature for 30 min, the reac-
tion was quenched by addition of saturated aqueous NH4Cl
solution (1.5 mL). The solution was extracted with EtOAc and
the combined organic phase dried (Na2SO4), filtered, and
evaporated. The corresponding racemic alcohol (()-25 was
purified by flash column chromatography using hexanes/EtOAc
(1:1 to 1:5) as the eluent. Colorless oil (12 mg, 50% two steps).
TLC: Rf = 0.25 (100% EtOAc). 1H NMR (CDCl3, 300 MHz) δ
4.26 (m, 1H), 4.05 (t, J = 3.0 Hz, 1H), 4.04-3.95 (m, 3H),
3.94-3.85 (m, 2H), 3.40 (dt, J = 2.5, 11.8 Hz, 1H), 2.60 (m, 1H),
1.94 (d, J = 4.0 Hz, 1H), 1.80 (ddt, J = 4.6, 11.5, 12.5 Hz, 1H),
1.74 (m, 1H). 13C NMR (CDCl3, 75 MHz) δ 78.3, 74.5, 67.1,
66.4, 65.0, 45.5, 30.0.
To a solution of racemic (()-25 (10 mg, 0.07 mmol) in dry
THF (1 mL) under an argon atmosphere was added vinyl acetate
(60 mg, 65 μL, 0.7 mmol) followed by addition of immobilized
Amano Lipase PS-30 (10 mg) on Celite-545. The mixture was
stirred at 15-20 ꢀC for 2 days until >50% conversion could be
observed by NMR of aliquots. The resulting suspension was
diluted in Et2O and filtered on a small Celite pad. The solvents
were evaporated and the residue was purified by flash chroma-
tography using hexanes/EtOAc (1:1 to 1:5) as the eluent to give
enantiomeric alcohol 25 (4.6 mg, 46%) as a colorless oil.
An enantiopurity of >99.5% ee for the alcohol was measured
by analysis of the corresponding activated carbonate 31f
on chiral HPLC (column ChiralPak IC, hexane/isopropanol
52:48, 1 mL/min, λ = 215 nm, T = 24 ꢀC, tR minor = 14.4 min,
tR major = 15.5 min).

632 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2
Ghosh et al.
activated carbonate 31a (18 mg, >99%). TLC: Rf = 0.25
(hexanes/EtOAc = 3:1). H NMR (CDCl3, 300 MHz) δ 8.29
solvent was evaporated under reduced pressure. The correspond-
ing Boc-deprotected intermediate (0.08 mmol) was then diluted in
dry acetonitrile (0.8 mL) at 0 ꢀC under argon and Et3N(0.3mL, 0.2
mmol) was added. A solution of activated carbonate 31a (18.6 mg,
0.06 mmol) in acetonitrile or THF (0.5 mL) was then added to the
mixture. The reaction was stirred at 23 ꢀC until completion was
reached (2-3 days). The solution was then evaporated in vacuo and
the resulting residue purified by flash chromatography on silica gel
using hexanes/EtOAc (2:1 then 1:1) as the eluent to afford the
inhibitor 35a as a amorphous solid (19.8 mg, 55%). TLC Rf =0.35
(hexanes/EtOAc = 1:1). 1H NMR (CDCl3, 300 MHz) δ 7.71 (d,
J = 8.9 Hz, 2H), 7.33-7.17 (m, 5H), 6.97 (d, J = 8.9 Hz, 2H),
5.05-4.90 (m, 1H), 4.93 (d, J = 3.6 Hz, 1H), 4.84 (d, J = 8.4 Hz,
1H), 4.15 (dt, J= 2.4, 9.0 Hz, 1H), 3.87 (s, 3H), 3.98-3.76 (m, 4H),
3.31 (t, J = 11.7 Hz, 1H), 3.22-2.90 (m, 4H), 2.90-2.78 (m, 2H),
2.48-2.32 (m, 1H), 1.96-1.25 (m, 5H), 0.92 (d, J = 6.6 Hz, 3H),
0.87 (d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 75 MHz) δ 163.1,
155.5, 137.6, 129.8, 129.4, 128.4, 126.5, 114.3, 101.1, 72.9, 70.2,
68.5, 60.9, 58.9, 55.7, 54.9, 53.8, 43.5, 35.6, 27.3, 26.2, 22.3, 20.2,
19.9. HRMS-ESI (m/z): [M þ Na]þ calcd for C29H40N2O8NaS
599.2403, found 599.2406.
(3aS,4S,7aR)-Hexahydro-2H-furo[2,3-b]pyran-4-yl (2S,3R)-
4-(4-Amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenyl-
butan-2-yl Carbamate (36). The title compound was obtained
from 31a and sulfonamide isostere 33 as described for inhibitor
35a, in 64% yield following purification by flash chromatogra-
phy using CHCl3/2% MeOH as the eluent. TLC: Rf = 0.45
(hexanes/EtOAc = 1:3). 1H NMR (CDCl3, 300 MHz) δ 7.55 (d,
J = 8.7 Hz, 2H), 7.32-7.16 (m, 5H), 6.67 (d, J = 8.7 Hz, 2H),
4.97 (m, 1H), 4.93 (d, J = 3.4 Hz, 1H), 4.85 (d, J = 8.7 Hz, 1H),
4.20-4.11 (m, 3H), 3.92-3.80 (m, 5H), 3.31 (dt, J = 2.2, 11.9
Hz, 1H), 3.15 (dd, J = 8.1, 15.2 Hz, 1H), 3.05 (dd, J = 4.2, 14.1
Hz, 1H), 3.01-2.80 (m, 3H), 2.75 (dd, J = 6.6, 13.4 Hz, 1H),
2.40 (m, 1H), 1.97-1.60 (m, 4H), 1.46 (m, 1H), 0.92 (d, J = 6.6
Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz)
δ 155.5, 150.7, 137.7, 129.5, 129.5, 128.4, 126.5, 126.2, 114.1,
101.1, 72.8, 70.1, 68.5, 60.8, 58.9, 54.8, 53.8, 43.4, 35.5, 27.3,
26.2, 22.2, 20.2, 19.9. HRMS-ESI (m/z): [M þ Na]þ calcd for
C28H39N3O7NaS 584.2406; found 584.2402.
1
(d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 5.30-5.19 (m, 1
H), 5.07 (d, J = 2.7 Hz, 1H), 4.28 (dt, J = 3 Hz, 1H), 4.04-3.95
(m, 2H), 3.47-3.37 (m, 1H), 2.80-2.68 (m, 1H), 2.30-2.10 (m,
1H), 2.05-1.90 (m, 3H). 13C NMR (CDCl3, 75 MHz) δ 155.3,
151.7, 145.4, 125.3, 121.7, 101.1, 75.4, 68.5, 60.5, 43.2, 25.8, 22.5.
(3aR,4R,7aS)-Hexahydro-2H-furo[2,3-b]pyran-4-yl (4-
Nitrophenyl) Carbonate (31b). The title compound was obtained
from (þ)-7 as described for (-)-7 in 86% yield after purification
by column chromatography on silica gel using hexanes/EtOAc
(6:1, then 3:1). Spectral data were consistent with those recorded
for 31a.
(3aR,4S,7aR)-Octahydrobenzofuran-4-yl (4-Nitrophenyl) Car-
bonate (31c). The title compound was obtained from (-)-12 as
described for (-)-7 in 83% yield after purification by column
chromatography on silica gel using hexanes/EtOAc (8:1 to 6:1).
1
TLC: Rf = 0.7 (hexanes/EtOAc = 3:1). H NMR (CDCl3, 400
MHz) δ8.28 (d, J= 9.2 Hz, 2H), 7.39 (d, J= 9.2 Hz, 2H), 5.07 (m,
1H), 4.13-4.05 (m, 2H), 3.90 (q, J = 8.2 Hz, 1H), 2.72 (m, 1H),
2.10-2.00 (m, 2H), 1.90-1.68 (m, 4H), 1.55-1.45 (m, 1H),
1.34-1.23 (m, 1H). 13C NMR (CDCl3, 100 MHz) δ 155.4,
151.9, 145.2, 125.2, 121.7, 77.7, 77.1, 66.5, 41.2, 27.0, 26.2,
25.4, 18.0.
((4S,4aR,7aS)-Octahydrocyclopenta[b]pyran-4-yl) (4-Nitrophe-
nyl) Carbonate (31d). The title compound was obtained from
(-)-18 as described for (-)-7 in 85% yield after purification by
column chromatography on silica gel using hexanes/CH2Cl2/
THF (4:1:0 then 4:1:0.1) as the eluent. TLC: Rf = 0.31 (hexanes/
EtOAc = 1:1). 1H NMR (CDCl3, 400 MHz) δ 8.28 (d, J = 9.1 Hz,
2H), 7.38 (d, J = 9.1 Hz, 2H), 5.21 (m, 1H), 4.00 (ddd, J = 1.8, 4.7,
12.0 Hz, 1H), 3.93 (dt, J = 2.5, 2.7 Hz, 1H), 3.43 (dt, J = 2.1, 12.0
Hz, 1H), 2.36 (m, 1H), 2.04-1.82 (m, 4H), 1.82-1.62 (m, 4H). 13C
NMR (CDCl3, 100 MHz) δ 155.5, 151.9, 145.3, 125.3, 121.8, 80.7,
77.3, 65.0, 43.7, 32.6, 26.3, 22.3, 21.7.
(3aR,4S,7aR)-Octahydro-1H-inden-4-yl (4-Nitrophenyl) Car-
bonate (31e). The title compound was obtained from (-)-19 as
described for (-)-7 in 90% yield after purification by column
chromatography on silica gel using hexanes/EtOAc (20:1 to
10:1) as the eluent. 1H NMR (CDCl3, 400 MHz) δ 8.27 (d, J =
9.1 Hz, 2H), 7.38 (d, J = 9.1 Hz, 2H), 5.05 (m, 1H), 2.41 (m, 1H),
2.05 (m, 1H), 1.98-1.24 (m, 11H), 1.05 (dq, J = 3.4, 12.7 Hz,
1H). 13C NMR (CDCl3, 100 MHz) δ 155.7, 151.9, 145.2, 125.2,
121.8, 80.7, 42.8, 40.2, 31.3, 26.6, 25.7, 23.4, 22.4, 21.3.
(4S,4aS,7aR)-Hexahydro-2H-furo[3,4-b]pyran-4-yl (4-Nitro-
phenyl) Carbonate (31f). The title was obtained from (-)-25 as
described for (-)-7 in >99% yield following column chroma-
tography purification on silica gel using hexanes/EtOAc (3:1,
then 2:1) as the eluent. 1H NMR (CDCl3, 400 MHz) δ 8.29
(d, J = 9.1 Hz, 2H), 7.38 (d, J = 9.1 Hz, 2H), 5.32 (m, 1H), 4.20-
3.88 (m, 6H), 3.50 (m, 1H), 2.81 (m, 1H), 2.10-1.90 (m, 2H).
[(3aS,5R,7aR)-Hexahydro-2H-furo[2,3-b]pyran-5-yl] (4-Nitro-
phenyl) Carbonate (31g). The title compound was obtained from
30 as described for (-)-7 in 70% yield. Purification and separation
from the 5-epi diastereoisomer were performed following flash
column chromatography on silica gel using hexanes/EtOAc (3:1,
2:1, then 1:1) as the eluent. Amorphous solid (70% from a 5:1
mixture of diastereoisomers). TLC: Rf = 0.16 (hexanes/EtOAc =
2:1). 1H NMR (C6D6, 800 MHz) δ 7.64 (d, J = 9.0 Hz, 2H), 6.69
(d, J = 9.0 Hz, 2H), 4.76 d, J = 3.6 Hz, 1H), 4.35 (m, 1H), 4.02 (dt,
J = 3.8, 8.6 Hz, 1H), 3.94 (dt, J = 2.8, 13.0 Hz, 1H), 3.60 (q, J =
8.0 Hz, 1H), 3.12 (dd, J= 2.0, 13.0 Hz), 2.04 (m, 1H), 1.67 (dq, J=
3.1, 15.1 Hz, 1H), 1.50 (m, 1H), 1.46-1.38 (m, 2H). 13C NMR
(C6D6, 200 MHz) δ 154.9, 151.9, 145.2, 124.9, 121.2, 100.7, 72.0,
67.4, 63.8, 35.9, 27.9, 27.3.
(3aS,4S,7aR)-Hexahydro-2H-furo[2,3-b]pyran-4-yl (2S,3R)-
3-Hydroxy-4-(4-(hydroxymethyl)-N-isobutylphenylsulfonamido)-1-
phenylbutan-2-yl Carbamate (37). The title compound was ob-
tained from 31a and sulfonamide isostere 34 as described for
inhibitor 35a in 72% yield following purification by flash chroma-
tography on silica gel using CHCl3/2% MeOH as the eluent.
1
Amorphous solid. TLC: Rf = 0.23 (hexanes/EtOAc = 1:2). H
NMR (CDCl3, 400 MHz) δ 7.76 (d, J = 8.1 Hz, 2H), 7.52 (d, J =
8.1 Hz, 2H), 7.32-7.17 (m, 5H), 4.96 (m, 1H), 4.93 (d, J = 3.2 Hz,
1H), 4.85 (d, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.15 (t, J = 8.5 Hz, 1H),
3.92-3.80 (m, 4H), 3.70 (s, 1H), 3.31 (t, J= 11.6 Hz, 1H), 3.16 (dd,
J = 8.0, 15.0 Hz, 1H), 3.10-2.95 (m, 3H), 2.88-2.76 (m, 2H), 2.41
(m, 1H), 2.04 (m, 1H), 1.95-1.78 (m, 2H), 1.76-1.56 (m, 2H), 1.47
(m, 1H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 1H). 13C
NMR (CDCl3, 100 MHz) δ 155.6, 146.2, 137.6, 137.1, 129.4 128.5,
127.6, 127.1, 126.5, 101.1, 72.8, 70.2, 68.4, 64.2, 60.8, 58.8, 54.9,
53.7, 43.4, 35.5, 27.3, 26.2, 22.2, 20.1, 19.9. HRMS-ESI (m/z):[Mþ
Na]þ calcd for C29H40N2O8NaS 599.2403, found 599.2414.
(3aR,4R,7aS)-Hexahydro-2H-furo[2,3-b]pyran-4-yl ((2S,3R)-
3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenyl-
butan-2-yl)carbamate (35b). The title compound was obtained from
31b and sulfonamide isostere 32 in 65% yield as described for
inhibitor 35a, following purification by column chromatography
on silica gel using hexanes/EtOAc (3:1, then 1.5:1) as the eluent.
White amorphous solid. TLC: Rf = 0.44 (hexanes/EtOAc = 1:1).
1H NMR (CDCl3, 400 MHz) δ 7.70 (d, J = 8.9 Hz, 2H), 7.31-7.26
(m, 2H), 7.25-7.20 (m, 3H), 6.98 (d, J = 8.9 Hz, 2H), 5.00 (m, 1H),
4.97 (d, J = 2.7 Hz, 1H), 4.88 (d, J = 8.0 Hz, 1H), 4.17 (t, J = 7.7
Hz, 1H), 3.99-3.72 (m, 6H), 3.87 (s, 3H), 3.31 (dt, J = 1.9, 12.0 Hz,
1H), 3.13 (dd, J = 8.4, 15.0 Hz, 1H), 3.08-2.84 (m, 4H), 2.79 (dd,
J= 6.7, 13.4 Hz, 1H), 2.53 (m, 1H), 2.00 (m, 1H), 1.83 (m, 1H), 1.73
(3aS,4S,7aR)-Hexahydro-2H-furo[2,3-b]pyran-4-yl-(2S,3R)-
4-(N-isobutyl-4-methoxyphenyl sulfonamido)-3-hydroxy-1-phenyl-
butan-2-yl Carbamate (35a). . Sulfonamide isostere 32 (42 mg,
0.08 mmol) was dissolved in a 30% TFA solution in CH2Cl2
(3 mL), the solution was stirred at 23 ꢀC for 2 h after which the

Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 633
(m, 1H), 1.68-1.54 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ 163.1,
155.7, 137.7, 129.8, 129.5, 128.5, 126.5, 114.3, 101.2, 72.6, 70.2, 68.4,
60.8, 58.7, 55.6, 55.1, 53.7, 43.6, 35.3, 27.3, 26.2, 22.5, 20.1, 19.9.
HRMS-ESI (m/z):[M þ Na]þ calcd for C29H40N2O8NaS 599.2403,
found 599.2407.
0.95 (m, 1H), 0.90 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H).
13C NMR (CDCl3, 100 MHz) δ 163.0, 156.4, 137.7, 129.9, 129.5,
129.4, 128.5, 126.4, 114.3, 74.9, 72.8, 58.8, 55.6, 54.8, 53.8, 43.1,
39.9, 35.7, 31.3, 27.2, 26.9, 26.1, 23.5, 22.2, 21.3, 20.1, 19.9.
HRMS-ESI (m/z): [M þ Na]þ calcd for C31H44N2O6NaS
595.2818, found 595.2816.
(3aR,4S,7aR)-Octahydrobenzofuran-4-yl (2S,3R)-3-Hydroxy-
4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl
Carbamate (35c). The title compound was obtained from 31c
and sulfonamide isostere 32 in 75% yield as described for
inhibitor 35a, following purification by column chromatogra-
phy on silica gel using hexanes/EtOAc (3:1, then 2.5:1) as the
eluent. TLC: Rf = 0.39 (hexanes/EtOAc = 1:1). 1H NMR
(CDCl3, 400 MHz) δ 7.72 (d, J = 8.9 Hz, 2H), 7.311-7.16 (m,
5H), 6.98 (d, J = 8.9 Hz, 2H), 4.83 (m, 2H), 3.95-3.75 (m, 5H),
3.87 (s, 3H), 3.68 (q, J = 8.1 Hz, 1H), 3.14 (dd, J = 8.4, 15.2 Hz,
1H), 3.08 (dd, J = 4.1, 14.1 Hz, 1H), 3.05-2.99 (m, 1H), 2.96
(dd, J = 8.4, 13.4 Hz, 1H), 2.87-2.75 (m, 2H), 2.35 (m, 1H), 1.83
(m, 1H), 1.70-1.40 (m, 7H), 1.20 (m, 1H), 0.92 (d, J = 6.6 Hz,
3H), 0.87 (d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ
163.0, 156.1, 137.7, 129.7, 129.5, 129.4, 128.4, 126.4, 114.3, 73.0,
71.8, 66.6, 58.8, 55.6, 54.7, 53.7, 41.2, 35.6, 27.3, 27.2, 27.0,
25.7, 20.1, 19.9, 17.7. HRMS-ESI (m/z): [M þ Na]þ calcd for
C30H42N2O7NaS 597.2610, found 597.2621.
(4S,4aR,7aS)-Octahydrocyclopenta[b]pyran-4-yl ((2S,3R)-3-
Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenyl-
butan-2-yl)carbamate (35d). The title compound was obtained
from 31d and sulfonamide isostere 32 in 81% yield as described
for inhibitor 35a, following purification by column chromatog-
raphy on silica gel using hexanes/EtOAc (3:1, then 2.5:1) as the
eluent. TLC: Rf = 0.58 (hexanes/EtOAc = 1:1). 1H NMR
(CDCl3, 400 MHz) δ 7.70 (d, J = 8.9 Hz, 2H), 7.30-7.17 (m,
5H), 6.96 (d, J = 8.9 Hz, 2H), 4.94 (m, 1H), 4.81 (d, J = 8.1 Hz,
1H), 3.86 (s, 3H), 3.90-3.76 (m, 4H), 3.33 (t, J = 11.9 Hz, 1H),
3.13 (dd, AB, J = 8.3, 15.0 Hz, 1H), 3.08-2.91 (m, 3H), 2.85 (m,
1H), 2.79 (dd, J = 6.8, 13.5 Hz, 1H), 2.04 (m, 1H), 1.81 (m, 2H),
1.76-1.64 (m, 3H), 1.64-1.49 (m, 3H), 0.90 (d, J = 6.6 Hz, 3H),
0.86 (d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ 163.0,
156.0, 137.7, 129.8, 129.4, 128.4, 126.4, 114.3, 80.5, 72.7, 71.7,
65.2, 58.7, 55.6, 54.8, 53.7, 44.1, 35.6, 32.5, 27.2, 26.6, 22.0, 21.6,
20.1, 19.8. HRMS-ESI (m/z): [M þ Na]þ calcd for C30H42N2-
O7S 597.2610, found 597.2612.
(4S,4aS,7aR)-Hexahydro-2H-furo[3,4-b]pyran-4-yl ((2S,3R)-
3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phe-
nylbutan-2-yl)carbamate (35f). The title compound was obtained
from 31f and sulfonamide isostere 32 in 75% yield as described for
inhibitor 35a, following purification by column chromatography
using hexanes/EtOAc (3:1, then 2.5:1) as the eluent. TLC: Rf = 0.24
(hexanes/EtOAc = 1:1). 1H NMR (CDCl3, 800 MHz) δ 7.70 (d,
J = 8.8 Hz, 2H), 7.30 (m, 2H), 7.24-7.20 (m, 3H), 6.97 (d, J = 8.8
Hz, 2H), 5.05 (m, 1H), 4.83 (d, J = 8.5 Hz, 1H), 4.03 (t, J = 3.2 Hz,
1H), 3.96 (m, 1H), 3.87 (s, 3H), 3.87 (s, 3H), 3.88-3.81 (m, 5H), 3.62
(t, J=8.3Hz, 1H), 3.39(t,J= 11.5 Hz, 1H), 3.14 (dd, J= 8.4, 15.0
Hz, 1H), 3.02 (dd, J = 4.0, 14.1 Hz, 1H), 2.99-2.94 (m, 2H), 2.84
(dd, J = 8.7, 14.1 Hz, 1H), 2.77 (dd, J = 6.6, 13.4 Hz, 1H), 2.51 (m,
1H), 1.81 (m, 1H), 1.78 (dq, J= 4.5, 12.4 Hz, 1H), 1.71 (dd, J=5.4,
12.4 Hz, 1H), 0.91 (d J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). 13
C
NMR (CDCl3, 200 MHz) δ 163.0, 155.5, 137.5, 129.6, 129.45,
129.38, 128.5, 126.6, 114.3, 78.4, 74.4, 72.6, 70.0, 66.1, 64.9, 58.8,
55.6, 54.9, 53.7, 42.7, 35.4, 27.2, 26.9, 20.1, 19.8. HRMS-ESI (m/z):
[M þ Na]þ calcd for C29H40N2O8S 599.2403, found 599.2397.
(3aS,5R,7aR)-Hexahydro-2H-furo[2,3-b]pyran-5-yl ((2S,3R)-
3-Hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phe-
nylbutan-2-yl)carbamate (35g). The title compound was ob-
tained from 31g and sulfonamide isostere 32 in 86% yield as
described for inhibitor 35a, following purification by column
chromatography on silica gel using hexanes/EtOAc (gradient 3:1
to 1.5:1) as the eluent. TLC: Rf = 0.33 (hexanes/EtOAc = 1:1). 1H
NMR (CDCl3, 400 MHz) δ 7.72 (d, J = 8.9 Hz, 2H), 7.32-7.26
(m, 2H), 7.25-7.17 (m, 3H), 6.98 (d, J = 8.9 Hz, 2H), 4.98 (d, J =
3.5 Hz, 1H), 4.89 (d, J = 8.7 Hz, 1H), 4.54 (m, 1H), 4.11 (dt, J =
3.5, 8.3 Hz, 1H), 3.87 (s, 3H), 3.90-3.77 (m, 4H), 3.74 (m, 1H),
3.56 (d, J = 12.7 Hz, 1H), 3.12 (dd, J = 8.5, 15.1 Hz, 1H),
3.09-2.91 (m, 3H), 2.84 (dd, J = 8.5, 14.1 Hz, 1H), 2.79 (dd, J =
6.8, 13.4 Hz, 1H), 2.08 (m, 1H), 2.04-1.93 (m, 2H), 1.90-1.76 (m,
3H), 0.91 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). 13C NMR
(CDCl3, 100 MHz) δ 163.4, 155.7, 137.6, 129.7, 129.5, 128.5, 126.5,
114.4, 101.0, 72.5, 68.0, 67.1, 65.4, 58.8, 55.6, 54.9, 53.8, 36.2, 35.8,
28.3, 27.8, 27.2, 20.1, 19.9. HRMS-ESI (m/z): [M þ Na]þ calcd for
C29H40N2O8NaS 599.2403, found 599.2397.
(3aR,4S,7aR)-Octahydro-1H-inden-4-yl-(2S,3R)-3-hydroxy-
4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl
Carbamate (35e). The title compound was obtained from 31e
and sulfonamide isostere 32 as described for inhibitor 35a.
Following preliminary purification by flash chromatography
using hexanes/CH2Cl2/THF (8:1:1) as the eluent, the inhibitor
was obtained as a mixture of unseparable isomeric compounds.
Compound 35e was derivatized into the corresponding N,O-
isopropylidene compound by treatment of 35e (20 mg) with 2,2-
dimethoxypropane (0.1 mL) and a catalytic amount of pTSA
(1.5 mg) in dry CH2Cl2 (1 mL) for 8 h at 23 ꢀC. After
neutralization with Et3N, the organic phase was evaporated to
dryness. Following a quick silica gel column (hexanes/EtOAc =
8:1), the resulting inhibitor was purified by HPLC: preparative
HPLC column Sunfire Prep C18 OBD, 30 mm ꢀ 100 mm, eluent
MeOH/H2O 85:15 (30 min) and then 90:10 (15 min), flow rate
Acknowledgment. The research was supported by the
National Institutes of Health (Grant GM53386). This work
was also supported by the Intramural Research Program of
the Center for Cancer Research, National Cancer Institute,
National Institutes of Health, and in part by a Grant-in-Aid
for Scientific Research (Priority Areas) from the Ministry
of Education, Culture, Sports, Science, and Technology of
Japan (Monbu Kagakusho), a Grant for Promotion of AIDS
Research from the Ministry of Health, Welfare, and Labor of
Japan (Kosei Rohdosho), and a Grant to the Cooperative
Research Project on Clinical and Epidemiological Studies of
Emerging and Reemerging Infectious Diseases (Renkei Jigyo)
of Monbu-Kagakusho.
15 mL min-1, tR = 42 min. The isopropylidene derivative was
3
then obtained as a colorless oil (24 mg). The product was then
taken into MeOH (2 mL). pTSA H2O (36 μmol, 1.5 mg) was
3
added, and the resulting solution was refluxed for 6 h. After
neutralization with a few drops of Et3N, the solution was
evaporated and the residue purified by column chromatography
on silica gel using hexanes/CH2Cl2/THF (8:1:1) to give inhibitor
35e (15 mg, 43% from 31e). TLC: Rf = 0.35 (hexanes//EtOAc =
5:1). 1H NMR (CDCl3, 400 MHz) δ 7.71 (d, J = 8.9 Hz, 2H),
7.32-7.18 (m, 5H), 6.97 (d, J = 8.9 Hz, 2H), 4.79 (m, 1H), 4.70
(d. J = 8.1 Hz, 1H), 3.90 (m, 1H), 3.87 (s, 3H), 3.81 (m, 1H),
3.18-3.02 (m, 3H), 2.98-2.82 (m, 2H), 2.78 (dd, J = 6.6, 13.2 Hz,
1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.82 (m, 1H), 1.74-1.19 (m, 11H),
Supporting Information Available: HPLC and HRMS data of
inhibitors 35a-g, 36, and 37. This material is available free of
charge via the Internet at http://pubs.acs.org.
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