Anti-AIDS agents. 60. Substituted 3′R,4′R-di-O-(-)-camphanoyl- 2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) analogues as potent anti-HIV agents

Article abstract of DOI:10.1021/jm0400505

Synthesis of positional isomers is a commonly used technique in drug design. Accordingly, based on prior SAR studies of 3′R,4′R-di-O-(S)- camphanoyl-(+)-cis-khellactone (DCK, 1) analogues, a series of mono- and disubstituted chromone derivatives of 3′R,4′R-di-O-(-)camphanoyl- 2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP, 4) were designed and synthesized. Together with 1 and 4-methyl DCK (2), all newly synthesized DCP analogues (4-21) were screened for anti-HIV-1 activity against a non-drug-resistant strain in H9 lymphocytes and a multiple reverse transcriptase (RT) inhibitor-resistant strain in the MT4 cell line. Several DCP analogues (4, 5, 7, 8, 13, and 17) exhibited extremely high anti-HIV activity in the nondrug-resistant strain assay, with EC₅₀ values ranging from 0.00032 to 0.0057 μM and remarkable therapeutic indexes (TI) ranging from 5.6 × 10³ to 1.16 × 10⁵, which were similar to those of 2 (EC₅₀ 0.0059 μM, TI > 6.6 × 10³) and better than those of 1 (EC₅₀ 0.049 μM, TI > 328). Even more promisingly, some DCP analogues also showed activity against a multi-RT inhibitor-resistant strain, HIV-1 RTMDR1, whereas most DCK analogues did not. The most significant compound was 8, with an EC₅₀ value of 0.06 μM and TI of 718 against the multi-RT inhibitor-resistant HIV-1 strain. Compounds 9 and 10 also showed good activity with an EC₅₀ value of 0.14 μM, and TIs of 272 and >111, respectively. 2-Ethyl DCP (8) exhibited the best anti-HIV activity in both assays. Further development of 8-related compounds as clinical trial candidates is warranted.

Full text of DOI:10.1021/jm0400505

4072
J . Med. Chem. 2004, 47, 4072-4082
An ti-AIDS Agen ts. 60.† Su bstitu ted
3′R,4′R-Di-O-(-)-ca m p h a n oyl-2′,2′-d im eth yld ih yd r op yr a n o[2,3-f]ch r om on e (DCP )
An a logu es a s P oten t An ti-HIV Agen ts
Donglei Yu,‡ Chin-Ho Chen,§ Arnold Brossi,‡ and Kuo-Hsiung Lee*,‡
Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, and
Medical Center, Box 2926, SORF, Duke University, Durham, North Carolina 27710
Received February 26, 2004
Synthesis of positional isomers is a commonly used technique in drug design. Accordingly,
based on prior SAR studies of 3′R,4′R-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK, 1)
analogues, a series of mono- and disubstituted chromone derivatives of 3′R,4′R-di-O-(-)-
camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP, 4) were designed and synthe-
sized. Together with 1 and 4-methyl DCK (2), all newly synthesized DCP analogues (4-21)
were screened for anti-HIV-1 activity against a non-drug-resistant strain in H9 lymphocytes
and a multiple reverse transcriptase (RT) inhibitor-resistant strain in the MT4 cell line. Several
DCP analogues (4, 5, 7, 8, 13, and 17) exhibited extremely high anti-HIV activity in the non-
drug-resistant strain assay, with EC50 values ranging from 0.00032 to 0.0057 µM and
remarkable therapeutic indexes (TI) ranging from 5.6 × 103 to 1.16 × 105, which were similar
to those of 2 (EC50 0.0059 µM, TI > 6.6 × 103) and better than those of 1 (EC50 0.049 µM, TI
> 328). Even more promisingly, some DCP analogues also showed activity against a multi-RT
inhibitor-resistant strain, HIV-1 RTMDR1, whereas most DCK analogues did not. The most
significant compound was 8, with an EC50 value of 0.06 µM and TI of 718 against the multi-RT
inhibitor-resistant HIV-1 strain. Compounds 9 and 10 also showed good activity with an EC50
value of 0.14 µM, and TIs of 272 and >111, respectively. 2-Ethyl DCP (8) exhibited the best
anti-HIV activity in both assays. Further development of 8-related compounds as clinical trial
candidates is warranted.
In tr od u ction
Since first reported in the 1980s, acquired immuno-
deficiency syndrome (AIDS), which is caused by the
human immunodeficiency virus (HIV) and results in life-
threatening opportunistic infections and malignancies,
has spread rapidly through the human population and
become a major worldwide pandemic.1,2 The global AIDS
epidemic claimed more than three million lives in 2003,
and ca. 40 million people were living with HIV or AIDS
at the end of that same year.3
In our previous studies, 3′R,4′R-di-O-(-)-camphanoyl-
(+)-cis-khellactone (DCK, 1) and 4-methyl DCK (2)
(Figure 1) were discovered to be potent against HIV-
F igu r e 1. DCK (1), 4-methyl DCK (2), and hydroxymethyl
DCK analogue (3).
1IIIB replication in H9 lymphocytes with remarkable
EC50 values of 2.56 × 10-4 µM and 1.83 × 10-6
µM, and TI values of 1.37 × 105 and 6.89 × 107,
respectively.4-7 Structure-activity relationship (SAR)
study results with DCK analogues indicated that 3′R,4′R
configurations and planarity of the coumarin nucleus
are essential structural features for anti-HIV activity;
alkyl/O-alkyl substituents at the 3-, 4-, and 5-positions
on the coumarin nucleus are favorable for enhanced
anti-HIV activity and decreased toxicity; and two bulky
(S)-(-)-camphanoyl groups at the 3′- and 4′-positions are
preferred to other substituents.
However, our recent screening determined that most
DCK analogues lack potency against multi-RT inhibitor-
resistant HIV strains. This observation together with
poor water solubility presented two main obstacles to
the development of DCK-related drug candidates. We
recently reported the design and synthesis of 3, which
is more water soluble than 1 and has moderate bio-
availability (F ) 15%).8 However, as with most DCK
analogues, compound 3 did not show antiviral activity
against the multi-RT inhibitor-resistant strain at the
tested concentrations. Therefore, further modification
was necessary to overcome these problems.
* Address correspondence to this author at Natural Products
Laboratory, School of Pharmacy, University of North Carolina, Chapel
Hill, NC 27599. Tel: (919)-962-0066; fax: (919)-966-3893; e-mail:
khlee@unc.edu.
† For part 59, see Lee, K. H. Anti-AIDS Agents. 59. Current
Developments in the Discovery and Design of New Drug Candidates
from Plant Natural Product Leads. J . Nat. Prod., in press.
‡ University of North Carolina.
§ Duke University.
10.1021/jm0400505 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/29/2004

Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16 4073
Sch em e 1. Retrosynthetic Strategy for Substituted DCP Derivatives
In the current study, we modified the coumarin
skeleton in order to identify new drug candidates with
potent anti-HIV activity against drug-resistant strains.
This paper reports their design, syntheses, and bioassay
data.
Design
It is not fully clear why DCK analogues show remark-
ably reduced activity against drug-resistant viral strains.
Mutations of the viral RT could cause conformational
changes directly on the binding sites or other regions
that affect binding. Accordingly, DCK might dissociate
more rapidly from or not fit into the putative mutated
target. Our goal is to improve activity against drug-
resistant strains by modifying the coumarin skeleton.
Preparing ring position isomers is a common principle
of analogue design, as such a change may alter electron
distribution in an aromatic ring system or affect the
complementarity toward in vivo receptors.
In 2003, we first reported that the DCK-related
compound 3′R,4′R-di-O-(-)-camphanoyl-2′,2′-dimethyl-
F igu r e 2. Su bstitu ted DCP d er iva tives 4-21.
dihydropyrano[2,3-f]chromone (DCP, 4), a positional
isomer of DCK, showed potent in vitro anti-HIV activity
in acutely HIV-1IIIB-infected H9 lymphocytes, a non-
drug-resistant strain, with an EC50 of 6.78 × 10-4 µM
and TI of 14500, values similar to those of DCK.9 Thus,
the carbonyl group, which is at position 4 in DCP, is
not restricted to position 2, as found in DCK.
Our next goals were to continue our SAR study on
both DCK and DCP series, explore the structural
requirements of the pyranochromone derivatives as new
anti-HIV agents, and increase the anti-HIV activity in
drug-resistant strains. In our prior modification studies
in the DCK series, incorporating small alkyl group(s)
on the coumarin skeleton led to retained or increased
activity. Thus, in the current study, several analogous
new DCP analogues with chromone ring substitutions
were designed and synthesized asymmetrically by the
same approaches.
On the basis of the structural difference between the
A rings of DCK (1) and DCP (4), we mainly focused our
continued modifications on the chromone A ring. Thus,
3-methyl (5), 3-phenyl (6), 2-methyl (7), 2-phenyl (12),
and 2,3-dimethyl (13) DCP analogues were synthesized
to investigate the impact of different substituents at
these positions (Figure 2). After reviewing bioassay
results, we have now introduced different alkyl groups,
i.e., ethyl, propyl, isopropyl, and ethoxymethyl, at the
2-position of the chromone nucleus (a beneficial position)
to give 2-substituted DCP analogues 8-11. Also, a
6-tert-butyl substitution was introduced into compound
8, the most active compound, to produce analogue 14.
Finally, we designed a series of 2-substituted-3′R-acyl-
4′R-camphanoyl pyranochromone derivatives (15-21)
(Figure 2). Acyl groups with smaller volumes replaced
the 3′-camphanoyl group in order to explore the require-
ments at this position for anti-HIV activity.
For all designed target compounds (4-21), our first
synthetic strategy was to consecutively (a) prepare
variously substituted 7-hydroxychromones (I) from 2,4-
dihydroxyacetophenone and its substituted derivatives,
(b) produce substituted pyranochromones (III), (c) asym-
metrically synthesize dihydroxypyranochromones with
required 3′R,4′R configurations (IV), and (d) finally,
produce substituted DCP derivatives (Scheme 1). A
second synthetic strategy for some 2-substituted DCPs
was to begin with 2,2-dimethyl-5-hydroxy-6-ethanone-
2H-chromene (30) and its derivatives (II) rather than
the 7-hydroxychromones (I). All target compounds were
tested in vitro for suppression of HIV-1IIIB replication
in H9 lymphocytes (non-drug-resistant strain), as well
as against the HIV-1 RTMDR1 multi-RT inhibitor-
resistant viral strain in MT4 cells.

4074 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16
Sch em e 2. Synthesis of 7-Hydroxychromones (24)a
Yu et al.
a
Reagents and conditions: (i) 70% perchloric acid, triethyl orthoformate, 40 min; (ii) H2O, reflux, 5 min; (iii) methanesulfonyl chloride/
DMF; (iv) chloromethyl methyl ether, K2CO3, anhydrous acetone/N2, rt; (v) NaH, ethyl alkanoate, anhydrous THF/Ar; (vi) Amberlyst 15,
2-propanol, reflux; (vii) Ac2O, NaOAc, reflux; viii. NaHCO3/MeOH (1:1, v:v) rt.
Sch em e 3. Synthesis of Substituted Pyranochromones (29)a
a
Reagents and conditions: (i) 3-chloro-3-methyl-1-butyne; K2CO3, kI, DMF/80 °C; (ii) N,N-diethylaniline, reflux; (iii) 4,4-dimethoxy-
2-methyl-2-butanol, anhydrous pyridine, 140 °C; (iv) NaH, ethyl alkanoate, anhydrous THF/Ar; (v) Amberlyst 15, 2-propanol, reflux; (vi)
tert-butyl alcohol, H3PO4, P2O5, 80 °C.
Ch em istr y
ethyl (MOM) ether (26); the C-2 hydroxy group is
unlikely to react because of intramolecular H-bonding
with the adjacent carbonyl moiety. Compound 26 and
ethyl acetate or ethyl butyrate were treated with sodium
hydride in anhydrous THF under nitrogen. Subsequent
hydrolysis of the intermediate mixture with Amberlyst
15 resin in 2-propanol gave 2-methyl- (24d ) and 7-hy-
droxy-2-propylchromone (24f).12 2,3-Dimethyl-7-hydroxy-
chromone (24j) was synthesized in two steps. A mixture
of 23, Ac2O, and anhydrous NaOAc was heated under
reflux to afford 27, which was hydrolyzed in a 1:1
mixture of MeOH and saturated aqueous NaHCO3 at
room temperature to provide 24j.13
The synthesis of 4 was previously described without
full experimental details, which are presented herein.
Scheme 2 shows the syntheses of substituted 7-hydroxy-
chromones (24a -d , 24f, and 24j). Commercially avail-
able 2,4-dihydroxyacetophenone (22) or propiophenone
(23) was treated with triethyl orthoformate and 70%
perchloric acid, followed by hydrolysis in boiling water
to afford 7-hydroxychromone (24a ) or 7-hydroxy-3-
methylchromone (24b).10 7-Hydroxy-3-phenylchromone
(24c) was synthesized from benzyl 2,4-dihydroxyphenyl
ketone (25) by treatment with methanesulfonyl chloride
in dry DMF.11 2-Substituted-7-hydroxychromones (24d
and 24f) were synthesized in three steps from 22.
Compound 22 was first protected as the C-4 methoxym-
Scheme 3 illustrates the synthesis of the 2′,2′-di-
methylpyranochromones (29). As described previously,9

Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16 4075
Sch em e 4. Possible Mechanism for Production of 29h
Sch em e 5. Synthesis of DCP Derivatives 4-21a
a
Reagents and conditions: (i) K2OsO2(OH)4, K3Fe(CN)6, (DHQ)2-Phal, K2CO3, 0 °C; (ii) camphanoyl chloride, DMAP, pyridine/CH2Cl2;
(iii) Ac2O or acyl chloride, DMAP/CH2Cl2.
24a -d , 24f, 24i, and 24j were converted to the corre-
sponding pyranochromones (29) by alkylation with
3-chloro-3-methyl-1-butyne in DMF in the presence of
K2CO3 and KI, followed by cyclization in refluxing N,N-
diethylaniline. Alternatively, compound 22 was heated
with 4,4-dimethoxy-2-methyl-2-butanol in anhydrous
pyridine at 140 °C to afford 30, which was reacted with
various ethyl alkanoates and NaH in anhydrous THF,
followed by hydrolysis with Amberlyst 15 resin in
2-propanol to afford 29e, 29g, and 29h . The 6-tert-butyl
analogue 29k was prepared analogously from 31, which
was synthesized by reacting compound 22 with tert-
butyl alcohol in the presence of H3PO4 and P2O5 at 80
°C. As shown in Scheme 4, when ethyl bromoacetate
was reacted with 30, the product was 2-ethoxymethyl-
dimethylpyranochromone (29h ), rather than 2-bromo-
methylpyranochromone as anticipated. Ethoxymethyl
substitution could occur by attack of ethoxide and
displacement of bromide, which is a good leaving group
and adjacent to the carbonyl moiety.
According to Scheme 5, the asymmetric dihydroxyla-
tion of 29a -k was accomplished using a catalytic
Sharpless asymmetric dihydroxylation (AD),14,15 in which
K2OsO2(OH)4 serves as catalyst and (DHQ)2PYR or
(DHQ)2PHAL as chiral auxiliary.14,16 After being dried
in vacuo overnight, the diols (33a -k ) were reacted with
excess (S)-camphanoyl chloride in pyridine or DMAP
and anhydrous methylene chloride at room temperature
to afford target DCP derivatives (4-14).6 Some 4′-
camphanoyl-3′-hydroxy DCPs (34b-e, 34h , and 34i)
were also isolated. The percent diasteromeric excesses
(% de) ranged from 33 to 90%, as determined from the
1H NMR spectra. These values probably differed due to
the effect of the substituents on the molecular planarity
of 29. Compounds 34d , 34e, 34h , and 34i were reacted
with various acid chlorides or anhydrides to afford 3′-
acyl-4′-camphanoyl DCPs (15-21) with different O-acyl
substitutions on the 3′ and 4′ positions.
Resu lts a n d Discu ssion
The newly synthesized substituted DCPs (4-21) were
tested in vitro for suppression of HIV-1IIIB replication
in H9 lymphocytes (non-drug-resistant strain), as well
as against the HIV-1 RTMDR1 multi-RT inhibitor-
resistant viral strain in MT4 cells. This latter viral
strain contains several mutations in RT amino acid
residues (L74V, M41L, V106A, and T215Y) and is
resistant to AZT, ddI, nevirapine, and other nonnucleo-
side reverse transcriptase inhibitors (NNRTI).17
Against the non-drug-resistant strain, the EC50 and
TI values of compounds 4, 5, 7, 8, and 13 were better
than those of DCK and similar to or better than those
of 4-methyl DCK, which were tested in parallel. Com-
pounds 5 and 8 exhibited extremely high anti-HIV
activity in this assay (Table 1), with EC50 values of
0.00099 µM and 0.00032 µM and remarkable therapeu-
tic indexes (TI) of 1.48 × 104 and 1.16 × 105, respec-
tively. DCP (4), 2-methyl DCP (7), and 2,3-dimethyl
DCP (13) also showed potent anti-HIV activity with
EC50 values of 0.0013, 0.0031, and 0.007 µM and TI
values of 1.1 × 104, 8600, and 1500, respectively.
2-Propyl DCP (9) and 2-isopropyl DCP (10) exhibited
moderate activity, with EC50 values of 0.02 µM and 0.07
µM, respectively. However, 2-ethoxymethyl DCP (11)
and 2-phenyl DCP (12) were much less active (EC50
)
0.1 µM and 0.129 µM) and had lower therapeutic
indexes (151 and 277) than DCK, and 3-phenyl DCP (6)
showed only slight activity. As previously found with

4076 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16
Ta ble 1. Anti-HIV Activity of DCP Analogues 4-14a
Yu et al.
b
HIVIIIB
HIV-1 RTMDR1c
compd
IC50 (µM)
EC50 (µM)
TI
IC50 (µM)
EC50 (µM)
TI
4d
5
6
7
8
14.20
14.70
>35.82
27.30
37.16
>37.65
33.4
15.1
>35.82
11.3
0.0013
0.00099
1.54
0.0031
0.00032
0.020
0.07
11100
14800
NS
1.28
NS
3.14
2.5
23.3
8600
116200
1860
483
11.8
43.08
37.65
>15.04
>12.5
12.2
0.19
0.06
0.14
0.14
0.37
0.17
0.31
7.36
12.06
9.43
0.1
62.5
718
272
>111.1
>34
71
9
10
11
12
13
14
0.1
151
0.129
0.007
1.62
0.049
0.0059
0.044
>277
1500
22
>328
>6660
42700
4.72
15
1.9
1.3
1.7
35.4
>14.15
>16.1
>15.7
>37.5
DCK (1)e
4-MeDCK (2)f
AZT
>16.1
>39.3
1872
>375
a
b
All data presented in this table are averaged from at least two separate experiments. This assay was performed in H9 lymphocytes
by Panacos, Inc., Gaithersburg, MD. c This assay was performed in the MT-4 cell line by Dr. Chin-Ho Chen, Duke University, NC.
Previously obtained and published values: EC50 ) 0.00068 µM and TI ) 14500.9 e Previously obtained and published values: EC50
)
d
0.000256 µM and TI ) 1.37 × 105.4 f Previously obtained and published values: EC50 ) 1.83 × 10-6 µM and TI ) >6.89 × 107.6 NS )
no suppression at 10 µg/mL.
Ta ble 2. Anti-HIV Activity of 3′-Acyl DCP Analogues 15-21a
b
HIVIIIB
HIV-1 RTMDR1c
compd
IC50 (µM)
EC50 (µM)
TI
21.9
46
5600
182
70
20
25.3
>328
6600
IC50 (µM)
EC50 (µM)
TI
15
16
17
18
19
20
21
>50
40.7
2.29
0.88
0.0057
0.25
0.62
2.24
1.68
0.049
0.0059
0.044
>40.2
17.1
13.0
>18.5
>17.5
6.25
2.2
0.30
0.59
0.28
1.09
4.46
NS
12.06
9.43
0.1
18.2
56.3
22
>66.7
>16.1
1.4
>32.2
>46.3
>43.9
>44.6
>42.5
>16.1
39.3
DCK (1) e
4-MeDCK (2)f
AZT
>16.1
>15.7
>37.5
1.3
1.7
>375
1872
42700
a
See Table 1 footnotes.
DCK analogues, compound 14, with tert-butyl on C-6,
lost almost all activity. These data demonstrated that,
in DCP analogues, introducing a small alkyl substituent
(one or two carbons) at the chromone 2- and/or 3-posi-
tion resulted in retained anti-HIV activity, whereas a
large substituent (over three carbons) at these positions
significantly decreased activity against non-drug-resis-
tant HIV in H9 lymphocytes, and substitution at the
6-position is not favorable.
Against the HIV-1 RTMDR1 strain, compound 8 (C-2
ethyl) showed the most promising anti-HIV activity
(EC50 0.06 µM, TI 718), while 9 and 10 (C-2 propyl and
isopropyl, respectively) were slightly less potent (EC50
0.14 µM). Compounds 7 and 12 showed almost identical
activity, with EC50 values of 0.19 and 0.17 µM and TI
values of 63 and 71, respectively, and compound 13 had
an EC50 value of 0.31 µM. Compound 14, with 6-tert-
butyl and 2-ethyl substitution, had an EC50 value of only
7.36 µM, an analogous result to the SAR of DCK
analogues, where 6-substitution is not favorable. The
data also showed that substitution on the DCP 3-posi-
tion is not favorable against the resistant strain.
Compound 5 (3-methyl), although quite active against
the non-drug-resistant strain, had an EC50 value of only
1.28 µM against the drug-resistant strain, and com-
pound 6 (3-phenyl) was inactive at the testing concen-
tration. In addition, the unsubstituted parent compound
4 lost potency against the resistant strain, as did 1
(DCK) and 2 (4-methyl DCK). On the basis of these data,
a hydrophobic moiety, either aliphatic or phenyl, on the
2-position is crucial for anti-HIV activity against the
multi-drug-resistant HIV strain and may increase bind-
ing of these compounds to a putative hydrophobic cleft.
The extremely high anti-HIV activity of 8 indicated that
a C-2 ethyl group probably fits well into the putative
hydrophobic cleft on the active surface of the target,
greatly increasing the affinity of the agent and the
desired pharmacological response. Furthermore, from
comparison of EC50 and IC50 values for compounds 5
(3-methyl) and 7 (2-methyl), substitution on the 2-posi-
tion appears to increase the activity against the multi-
RT inhibitor-resistant strain and also decrease the
cytotoxicity.
Several DCP derivatives (15-21) with different acyl
substituents on the 3′-position were synthesized and
evaluated in both assays (Table 2). Against the non-
drug-resistant strain in H9 lymphocytes, compound 15
(3′-acetyl) showed only slight activity (EC50 2.29 µM, TI
22), 16 (3′-isobutyryl) exhibited moderate activity (EC50
0.88 µM, TI 46), and 17 (3′-isovaleryl) was most potent
(EC50 0.0057 µM, TI > 5600). From this rank order, an
isovaleryl on the 3′-position appears essential for high
anti-HIV potency in H9 lymphocytes, as 17 (3′-isov-
aleryl) showed similar potency to 2 and 7 (in both latter
compounds, an isovaleryl moiety is contained within the
3′-camphanoyl group). In addition, all three 3′-isobutyryl
compounds, 16, 18, and 19, showed weaker activity than
their parent compounds 7, 8, and 11 against the non-
drug-resistant strain. The 2-phenyl, 3′-acetyl, and 3′-

Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16 4077
yield (starting with 3.33 g of 23); mp 155-157 °C; MS-ESI+
(m/z, %): 199 (M+ + Na, 10), 198 (M+ + Na - 1, 100), 176
(M+, 53); 1H NMR δ 10.72 (1H, s, OH-7), 8.11 (1H, s, H-2),
7.88 (1H, d, J ) 9.0 Hz, H-5), 6.89 (1H, dd, J ) 9.0, 2.4 Hz,
H-6), 6.80 (1H, d, J ) 2.4 Hz, H-8), 1.87 (3H, s, CH3-3).
isobutyryl analogues (20 and 21) showed weak activity,
comparable to 15.
Against the HIV-1 RTMDR1 strain, 3′-isobutyryl- or
-isovaleryl-substituted compounds exhibited comparable
or slightly weaker potency than the corresponding 3′-
camphanoyl compounds. Accordingly, 16 and 17 (EC50
0.30 and 0.59 µM, respectively) had slightly weaker
potency than 7 (EC50 0.19 µM), while 18 (EC50 0.28 µM)
was less active than 8 (EC50 0.06 µM), and 19 (EC50 1.09
µM) was less active than 11 (EC50 0.37 µM). 3′-
Isobutyryl-2-phenyl DCK (21) was inactive at the test-
ing concentration. As in the nonresistant strain, acetyl
substitution was not favorable at the 3′-position; 15 and
20 had EC50 values of only 2.2 µM and 4.46 µM,
respectively.
7-Hyd r oxy-3-p h en ylch r om on e (24c).11 The phenol 25
(840 mg, 3.7 mmol) in dry DMF (8 mL) was heated to 50 °C,
and a solution of methanesulfonyl chloride (0.9 mL) in dry
DMF (1 mL) was added slowly. Then the mixture was reacted
at 60-70 °C for 6 h. After cooling, the reaction mixture was
poured into a large volume of ice-cold aq NaOAc (12 g/100 mL).
The crude product 24c was filtered off and purified on a silica
gel column (hexane-EtOAc 10:1): 67% yield; mp 155-157 °C;
1
MS-ESI+ (m/z, %): 239 (M+ + 1, 100); H NMR δ (acetone-
d6): 9.62 (1H, s, OH-7), 8.23 (1H, s, H-2), 8.08 (1H, d, J ) 8.7
Hz, H-5), 7.61∼7.64 (2H, m, H-2′, 6′-phenyl), 7.36∼7.43 (3H,
m, H-3′,4′,5′-phenyl), 7.01 (1H, dd, J ) 8.7, 2.4 Hz, H-6), 6.93
(1H, d, J ) 2.4 Hz, H-8).
In conclusion, this study provided the following
results. (1) DCP analogues are more promising than
DCK analogues, as most DCP analogues are active
against the multiple RT inhibitor-resistant strain.
Although the structurally similar DCK derivatives
exhibit potent anti-HIV activity against the non-drug-
resistant strain, they are generally ineffective against
the multiple RT inhibitor-resistant HIV-1 strain. (2) An
appropriate alkyl substituent at position 2 is critical for
the anti-HIV activity of DCP analogues against both
non-drug-resistant and multi-RT-resistant viral strains.
In addition, most 2-substituted DCP analogues are less
toxic to the cells compared with DCP. (3) DCP analogues
showed different SAR in non-drug-resistant and multi-
RT inhibitor-resistant viral strains. 2- and 3-Substitu-
tions are favorable for activity against the non-drug-
resistant strain, but only 2-substituted DCP analogues
show high activity against a multi-RT inhibitor-resis-
tant strain.
2-Hydr oxy-4-(m eth oxym eth yl)acetoph en on e (26).Chloro-
methyl methyl ether (2.25 mL, 25 mmol) was added dropwise
into a mixture of 22 (2.0 g, 13 mmol) and potassium carbonate
(4.3 g) in anhydrous acetone (12 mL). The reaction mixture
was stirred for 12 h at room temperature. After filtration, the
filtrate was solved in water and extracted with CH2Cl2 (3 ×
20 mL). The organic layer was dried in vacuo to provide 26 as
a white solid: 89% yield; mp 36-38 °C; MS-ESI- (m/z, %) 195
1
(M+ - 1, 100); H NMR δ 7.62 (1H, d, J ) 8.7 Hz, H-6), 6.56
(1H, d, J ) 2.4 Hz, H-3), 6.52 (1H, dd, J ) 8.7, 2.4 Hz, H-5),
5.18 (2H, s, OCH2OCH3-4), 3.45 (3H, s, OCH2OCH3-4), 2.54
(3H, s, COCH3-1).
Syn th esis of 2-su bstitu ted -7-h yd r oxych r om on es.12
A
mixture of 26 (498 mg, 2.5 mmol) and ethyl alkanoate (5.0
mmol) in absolute THF (2 mL) was added slowly to a sodium
hydride (320 mg, 8 mmol)/THF (2 mL) suspension under
nitrogen. The mixture was warmed to reflux temperature for
2 h, cooled and neutralized with 2N HCl, and extracted with
CHCl3 three times. The organic layer was collected and
evaporated in vacuo. The residue and Amberlyst 15 resin (0.5
g) were stirred in 2-propanol (10 mL) at reflux temperature
to give the target 2-substituted-7-hydroxychromone (24d and
24f) in a total yield of 63-75%.
Exp er im en ta l Section
7-Hyd r oxy-2-m eth ylch r om on e (24d ). 75% yield (starting
with 476 mg of 26); mp >185 °C sublimed; MS-ESI+ (m/z, %)
176 (M+, 100); 1H NMR δ (DMSO-d6): 10.73 (1H, s, OH-7),
7.83 (1H, d, J ) 8.4 Hz, H-5), 6.87 (1H, dd, J ) 8.4, 2.1 Hz,
H-6), 6.81 (1H, d, J ) 2.1 Hz, H-8), 6.10 (1H, s, H-3), 2.33 (3H,
s, CH3-2).
Melting points were measured with a Fisher J ohns melting
apparatus without correction. The proton nuclear magnetic
resonance (1H NMR) spectra were measured on a 300 MHz
Varian Gemini 2000 spectrometer using TMS as internal
standard. The solvent used was CDCl3 unless indicated.
Elemental analyses were performed by Atlantic Microlab, Inc.,
Norcross, GA. All target compounds were analyzed for C, H
and gave values within (0.4% of the theoretical values. Optical
rotations were measured with a J asco Dip-1000 digital pola-
rimeter at 25 °C at the sodium D line. The diastereoisomeric
excess percentages were determined from intensity of protons
7-Hyd r oxy-2-p r op ylch r om on e (24f). 63% yield (starting
with 230 mg of 26); mp 140-142 °C; MS-ESI- (m/z, %): 204
1
(M+, 70), 203 (M+ - 1, 95); H NMR δ: 7.92 (1H, d, J ) 8.4
Hz, H-5), 6.88 (1H, dd, J ) 8.4, 2.1 Hz, H-6), 6.80 (1H, d, J )
2.1 Hz, H-8), 6.10 (1H, s, H-3), 2.62 (2H, t, J ) 7.6 Hz,
CH2CH2CH3-2), 1.75 (2H, m, CH2CH2CH3-2), 1.01 (3H, t, J )
1
at the 3′-position in the H NMR spectra. Thin-layer chroma-
7.6 Hz, CH2CH2CH3-2).
7-Acetoxy-2,3-d im eth ylch r om on e (27).
tography (TLC) was performed on PLC silica gel 60 F254 plates
(0.5 mm, Merck). Biotage Flash+ and Isco Companion systems
were used as medium-pressure column chromatography. Silica
gel (200-400 mesh) from Aldrich, Inc., was used for column
chromatography. All other chemicals were obtained from
Aldrich, Inc.
13
A mixture of
23 (1.66 g, 10.0 mmol), Ac2O (7 mL), and anhydrous NaOAc
(0.83 g, 10 mmol) was heated under reflux for 14 h. After
cooling, the reaction mixture was diluted with water and
extracted with CH2Cl2 three times. The organic layer was
evaporated to afford 27 as a yellow solid; 96% yield; mp 99-
100 °C; MS-ESI+ (m/z, %): 233 (M+ + 1, 67); 1H NMR δ 8.19
(1H, d, J ) 8.7 Hz, H-5), 7.18 (1H, d, J ) 2.1 Hz, H-8), 7.07
(1H, dd, J ) 8.7, 2.1 Hz, H-6), 2.39 (3H, s, CH3CO-7), 2.33
(3H, s, CH3-2), 2.04 (3H, s, CH3-3).
7-Hyd r oxych r om on e (24a ).10 70% Perchloric acid (0.66
mL) was slowly added into a suspension of 2,4-dihydroxyac-
etophenone (22, 1 g, 6.7 mmol) in triethyl orthoformate (6 mL)
with stirring. The mixture was stirred continuously until it
cooled to room temperature. Anhydrous diethyl ether (18 mL)
was added to precipitate the intermediate oxonium perchlorate
salt, which was subsequently hydrolyzed in 30 mL of hot water
to provide 7-hydroxychromone (24a ) as a dark brown solid:
60% yield; mp 190-193 °C; MS (ESI+) m/z (%) 163 (M+ + 1,
100); 1H NMR δ 10.76 (1H, s, OH-7), 8.14 (1H, d, J ) 6.3 Hz,
H-2), 7.87 (1H, d, J ) 8.6 Hz, H-5), 6.89 (1H, dd, J ) 8.6, 2.1
Hz, H-6), 6.83 (1H, d, J ) 2.1 Hz, H-8), 6.20 (1H, d, J ) 6.3
Hz, H-3).
2,3-Dim eth yl-7-h yd r oxych r om on e (24j).13 Compound 27
(1.00 g, 4.3 mmol) was stirred in a mixture of MeOH and
saturated sodium bicarbonate (v:v ) 1:1, 100 mL) for 3 h at
room temperature. The reaction mixture was filtered and the
solid washed with water to provide pure 24j as a yellow solid;
76% yield; mp >168 °C sublimed; MS-ESI+ (m/z, %) 213 (M+
1
+ Na, 100), 191 (M+ + 1, 75); H NMR δ (CD3OD): 7.98 (1H,
d, J ) 8.7 Hz, H-5), 6.88 (1H, dd, J ) 8.7, 2.1 Hz, H-6), 6.78
(1H, d, J ) 2.1 Hz, H-8), 2.42 (3H, s, CH3-2), 2.03 (3H, s,
CH3-3).
7-Hyd r oxy-3-m eth ylch r om on e (24b).10 The procedure
was identical to that used for the preparation of 24a : 68%

4078 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16
Yu et al.
6-Acet yl-2,2-d im et h yl-5-h yd r oxy-2H -ch r om en e (30).
Compound 22 (1 g, 6.6 mmol) was reacted with 4,4-dimethoxyl-
2-methyl-2-butanol (1.5 mL) in anhydrous pyridine (2 mL) at
140 °C for 6 h. Another 1 mL 4,4-dimethoxyl-2-methyl-2-
butanol was added and the reaction continued for 4 h. The
reaction mixture was cooled to room temperature, diluted with
EtOAc, and washed with 10% aqueous HCl, water, and brine.
The organic layer was separated, and solvent was removed in
vacuo. The residue was purified by column chromatography
with hexane:EtOAc ) 25:1 to afford 30 as a yellow solid: 40%
yield; mp 90-92 °C; MS-ESI+ (m/z, %): 241 (M+ + Na, 100),
) 10.0 Hz, H-4′), 5.68 (1H, d, J ) 10.0 Hz, H-3′), 2.00 (3H, s,
CH3-3), 1.46, 1.47 (each 3H, s, CH3-2′).
2′,2′-Dim eth yl-3-p h en ylp yr a n o[2,3-f]ch r om on e (29c).
Using method 1, 66% yield (starting with 119 mg of 24c); mp
182 °C sublimed; MS-ESI+ (m/z, %) 305 (M+ + 1, 100); 1H
NMR δ 8.07 (1H, d, J ) 8.7 Hz, H-5), 7.96 (1H, s, H-2),
7.52∼7.56 (2H, m, H-2”,6”-phenyl), 7.36∼7.46 (3H, m, H-3”,4”,5”-
phenyl), 6.86 (1H, d, J ) 8.7 Hz, H-6), 6.81 (1H, d, J ) 9.9 Hz,
H-4′), 5.72 (1H, d, J ) 9.9 Hz, H-3′), 1.50 (6H, s, 2 × CH3-2′).
2,2′,2′-Tr im eth ylp yr a n o[2,3-f]ch r om on e (29d ). Using
method 1, 56% yield (starting with 1.3 g of 24d ); mp 123-125
°C; MS-ESI+ (m/z, %) 243 (M+ + 1, 100); 1H NMR δ 7.90 (1H,
d, J ) 8.6 Hz, H-5), 6.78 (1H, d, J ) 8.6 Hz, H-6), 6.75 (1H, d,
J ) 10.2 Hz, H-4′), 6.06 (1H, s, H-3), 5.67 (1H, d, J ) 10.2 Hz,
H-3′), 2.34 (3H, s, CH3-2), 1.45 (6H, s, 2×CH3-2′).
1
219 (M+ + 1, 78); H NMR δ 7.51 (1H, d, J ) 8.7 Hz, H-7),
6.70 (1H, d, J ) 9.9 Hz, H-4), 6.33 (1H, d, J ) 8.7 Hz, H-8),
5.57 (1H, d, J ) 9.9 Hz, H-3), 2.53 (3H, CH3CO-6), 1.44, 1.56
(each 3H, CH3-2).
5-ter t-Bu tyl-2,4-d ih yd r oxya cetop h en on e (31).18 tert-Bu-
tyl alcohol (3.8 mL) was added to a mixture of 2,4-dihydroxy-
acetophenone (22, 760 mg, 5 mmol), H3PO4 (60 mL), and P2O5
(4.4 g) at 60-70 °C. After the mixture was stirred for 1 h,
additional P2O5 (4.4 g) and tert-butyl alcohol (3.8 mL) were
added, and reaction was continued for an additional 1 h at
the same temperature. The reaction mixture was cooled to
room temperature, poured into 500 mL of ice-water, and
filtered to afford crude product, which was purified by column
chromatography on Si gel with an eluant of hexane:EtOAc )
10:1 to provide pure 31 as a white solid; 56% yield; mp: 148-
150 °C; MS-ESI+ (m/z, %): 209 (M+ + 1, 100); 1H NMR δ 7.58
(1H, s, H-6), 6.23 (1H, s, H-3), 2.56 (3H, CH3CO-1), 1.38 (9H,
(CH3)3C-5).
2′,2′-Dim eth yl-2-eth ylp yr a n o[2,3-f]ch r om on e (29e). Us-
ing method 2, 69% yield (starting with 654 mg of 30); mp 97-
98 °C; MS-ESI+ (m/z, %) 279 (M+ + Na, 100), 257 (M+ + 1,
81); 1H NMR δ 7.92 (1H, d, J ) 8.7 Hz, H-5), 6.80 (1H, d, J )
8.7 Hz, H-6), 6.77 (1H, d, J ) 10.2 Hz, H-4′), 6.10 (1H, s, H-3),
5.69 (1H, d, J ) 10.2 Hz, H-3′), 2.65 (2H, q, J ) 7.5 Hz, CH2-
CH3-2), 1.44, 1.48 (each 3H, s, CH3-2′), 1.30 (3H, t, J ) 7.5
Hz, CH2CH3-2).
2′,2′-Dim eth yl-2-pr opylpyr an o[2,3-f]ch r om on e (29f). Us-
ing method 1, 41% yield (starting with 500 mg of 24f); mp 80-
81 °C; MS-ESI+ (m/z, %) 293 (M+ + Na, 100), 271 (M+ + 1,
57); 1H NMR δ 7.90 (1H, d, J ) 8.7 Hz, H-5), 6.78 (1H, d, J )
8.7 Hz, H-6), 6.75 (1H, d, J ) 9.9 Hz, H-4′), 6.08 (1H, s, H-3),
5.67 (1H, d, J ) 9.9 Hz, H-3′), 2.57 (2H, t, J ) 7.5 Hz, CH2-
CH2CH3-2), 1.74 (2H, m, CH2CH2CH3-2), 1.46 (6H, s, 2×CH3-
2′), 1.01 (3H, t, J ) 7.5 Hz, CH2CH2CH3-2).
6-Ac e t y l-8-t er t -b u t y l-2,2-d im e t h y l-5-h y d r o x y -2H -
ch r om en e (32). The procedure was identical to that used for
the preparation of 30: 40% yield (starting with 416 mg of 31);
mp 64-65 °C; MS-ESI+ (m/z, %): 297 (M+ + Na, 80), 275 (M+
2′,2′-Dim eth yl-2-isopr opylpyr an o[2,3-f]ch r om on e (29g).
Using method 2, 50% yield (starting with 218 mg of 30); mp
1
84-86 °C; MS-ESI+ (m/z, %) 293 (M+ + Na, 100), 271 (M+
+
+ 1, 100); H NMR δ 7.48 (1H, s, H-7), 6.72 (1H, d, J ) 10.0
1, 60); 1H NMR δ 7.88 (1H, d, J ) 8.8 Hz, H-5), 6.75 (1H, d, J
) 8.8 Hz, H-6), 6.73 (1H, d, J ) 10.0 Hz, H-4′), 6.06 (1H, s,
H-3), 5.66 (1H, d, J ) 10.0 Hz, H-3′), 2.82 (1H, m, J ) 5.1 Hz,
CH(CH3)2-2), 1.43 (6H, s, 2 × CH3-2′), 1.27 (3H × 2, d, J ) 5.1
Hz, CH(CH3)2-2).
Hz, H-4), 5.57 (1H, d, J ) 10.0 Hz, H-3), 2.54 (3H, CH3CO-6),
1.56, 1.55 (each 3H, CH3-2), 1.36 (9H, (CH3)3C-8).
Syn th eses of Su bstitu ted 2′,2′-Dim eth ylp yr a n o[2,3-f]-
ch r om on e fr om Su bstitu ted 7-Hyd r oxych r om on e De-
r iva tives. Meth od 1. A mixture of substituted 7-hydroxy-
chromone (24), K2CO3 (2.5 equiv), KI (1 equiv), and excess
3-chloro-3-methyl-1-butyne (2∼3 equiv) in dry DMF was
heated to 70-80 °C with stirring until the reaction was
complete as monitored by TLC. After the solid was filtered,
the filtrate was concentrated in vacuo. Without purification,
the residue (crude product 28) was directly heated to reflux
in 10 mL of N,N-diethylaniline for 4-6 h. The reaction mixture
was cooled to room temperature, diluted with EtOAc, and
washed with 10% aqueous HCl, water, and brine. The organic
layer was separated, and solvent was removed in vacuo. The
residue was purified by column chromatography on TLC with
an eluant of hexane:EtOAc ) 4:1 to afford substituted 29.
Meth od 2. The procedure was similar to that used for
synthesis of 24d from 26. A mixture of 30 and ethyl alkanoate
in absolute THF was added slowly to a sodium hydride/THF
suspension under nitrogen. The mixture was warmed to reflux
temperature for 2-6 h monitored by TLC, followed by neu-
tralization with 2 N HCl, and extraction with CHCl3 three
times. The organic layer was collected and evaporated in vacuo.
The residue and Amberlyst 15 resin were stirred in 2-propanol
at reflux temperature to give 2-substituted dimethylpyrano-
chromone 29.
2 ′, 2 ′-D i m e t h y l -2 -e t h o x y m e t h y l p y r a n o [ 2 , 3 -f ] -
ch r om on e (29h ). Using method 2, 31% yield (starting with
109 mg of 30); yellow oil; MS-ESI+ (m/z, %) 309 (M+ + Na,
100), 287 (M+ + 1, 57); 1H NMR δ 7.91 (1H, d, J ) 8.4 Hz,
H-5), 6.80 (1H, d, J ) 8.4 Hz, H-6), 6.73 (1H, d, J ) 10.2 Hz,
H-4′), 6.32 (1H, s, H-3), 5.68 (1H, d, J ) 10.2 Hz, H-3′), 3.63
(2H, q, J ) 6.6 Hz, CH2OCH2CH3-2), 3.45 (2H, s, CH2OCH2CH3-
2), 1.45 (6H, s, 2 × CH3-2′), 1.27 (3H, t, J ) 6.6 Hz,
CH2OCH2CH3-2).
2′,2′-Dim eth yl-2-ph en ylpyr an o[2,3-f]ch r om on e (29i). Us-
ing method 1, 52% yield (starting with 958 mg of commercially
available 24i); mp 135-137 °C; MS-ESI+ (m/z, %) 327 (M+
+
Na, 100), 304 (M+, 25); 1H NMR δ 7.98 (1H, d, J ) 8.8 Hz,
H-5), 7.89 (2H, m, H-2′′,6′′-phenyl), 7.53 (3H, m, H-3′′, 4′′, 5′′-
phenyl), 6.92 (1H, d, J ) 10.0 Hz, H-4′), 6.85 (1H, d, J ) 8.8
Hz, H-6), 6.75 (1H, s, H-3), 5.75 (1H, d, J ) 10.0 Hz, H-3′),
1.51 (6H, s, 2 × CH3-2′).
2,3,2′,2′-Tetr a m eth ylp yr a n o[2,3-f]ch r om on e (29j). Us-
ing method 1, 44% yield (starting with 270 mg of 24j); mp 148-
149 °C; MS-ESI+ (m/z, %) 257 (M+ + 1, 100); 1H NMR δ 7.95
(1H, d, J ) 8.7 Hz, H-5), 6.79 (1H, d, J ) 8.7 Hz, H-6), 6.78
(1H, d, J ) 10.2 Hz, H-4′), 5.68 (1H, d, J ) 10.2 Hz, H-3′),
2.39 (3H, s, CH3-2), 2.03 (3H, s, CH3-3), 1.47 (6H, s, 2 ×
CH3-2′).
2′,2′-Dim eth ylpyr an o[2,3-f]ch r om on e (29a). Using method
1, 50% yield (starting with 194 mg of 24a ); mp 93-95 °C;
6-t er t -B u t y l-2′,2′-d i m e t h y l-2-e t h y lp y r a n o [2,3-f]-
ch r om on e (29k ). Using method 2, 56% yield (starting with
1
EI-MS (m/z, %) 228 (M+, 70), 213 (M+ - CH3, 100); H NMR
135 mg of 32); mp 86-88 °C; MS-ESI+ (m/z, %) 335 (M+
+
δ 7.95 (1H, d, J ) 8.7 Hz, H-5), 7.78 (1H, d, J ) 6.3 Hz, H-2),
6.83 (1H, d, J ) 8.7 Hz, H-6), 6.76 (1H, d, J ) 10.5 Hz, H-4′),
6.26 (1H, d, J ) 6.3 Hz, H-3), 5.69 (1H, d, J ) 10.5 Hz, H-3′),
1.48 (6H, s, 2 × CH3-2′).
1
Na, 75), 313 (M+ + 1, 82); H NMR δ 7.94 (1H, s, H-5), 6.80
(1H, d, J ) 10.2 Hz, H-4′), 6.10 (1H, s, H-3), 5.68 (1H, d, J )
10.2 Hz, H-3′), 2.65 (2H, q, J ) 7.8 Hz, CH2CH3-2), 1.51 (6H,
s, 2 × CH3-2′), 1.40 (9H, (CH3)3C-6), 1.29 (3H, t, J ) 7.8 Hz,
CH2CH3-2).
3,2′,2′-Tr im eth ylp yr a n o[2,3-f]ch r om on e (29b). Using
method 1, 52% yield (starting with 588 mg of 24b); mp 66-67
°C; MS-ESI+ (m/z, %) 265 (M+ + Na, 15), 264 (M+ + Na - 1,
Asym m etr ic d ih yd r oxyla tion of p yr a n och r om on es. A
mixture of K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv), and (DHQ)2-
PYR or (DHQ)2PHAL (2% equiv), and K2OsO2(OH)4 (2% equiv)
1
100), 242 (M+, 29); H NMR δ 7.95 (1H, d, J ) 8.8 Hz, H-5),
7.72 (1H, s, H-2), 6.81 (1H, d, J ) 8.8 Hz, H-6), 6.75 (1H, d, J

Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16 4079
was dissolved in t-BuOH/H2O (v/v, 1:1) at room temperature.
The solution was cooled to 0 °C and methanesulfonamide (1
equiv) added under stirring. When the solution turned from
light yellow to orange, the substituted pyranochromone
(29a -k ) was added. The mixture was stirred at 0 °C for 1-2
days, monitored by TLC. At completion, Na2S2O5 (excess),
water, and CHCl3 were added and stirring continued for 0.5 h
at room temperature. The mixture was extracted with CHCl3
three times, the combined organic layer was dried over K2-
SO4, and then solvent was removed. The residue was purified
by column chromatography or PTLC with an eluant of hexane:
EtOAc ) 3:1 to afford the pure substituted (+)-cis-3′,4′-
dihydroxypyranochromones (33a -k ).
3 ′R ,4 ′R -D i h y d r o x y -2 ′,2 ′-d i m e t h y l p y r a n o [2 ,3 -f]-
ch r om on e (33a ): 40% yield (starting with 43.7 mg of 29a );
mp 70-71 °C; EI-MS (m/z, %) 262 (M+, 45), 244 (M+ - OH,
15); 1H NMR δ 8.05 (1H, d, J ) 8.8 Hz, H-5), 7.84 (1H, d, J )
6.0 Hz, H-2), 6.89 (1H, d, J ) 8.8 Hz, H-6), 6.33 (1H, d, J )
6.0 Hz, H-3), 5.18 (1H, d, J ) 5.1 Hz, H-4′), 3.87 (1H, d, J )
5.1 Hz, H-3′), 1.43, 1.47 (each 3H, s, CH3-2′).
3′R ,4′R -D ih y d r o x y -3,2′,2′-t r im e t h y lp y r a n o [2,3-f]-
ch r om on e (33b): 55% yield (starting with 242 mg of 29b);
mp 180-182 °C; MS-ESI+ (m/z, %) 277 (M+ + 1, 100); 1H NMR
δ 7.98 (1H, d, J ) 8.7 Hz, H-5), 7.74 (1H, d, J ) 1.0 Hz, H-2),
6.82 (1H, d, J ) 8.7 Hz, H-6), 5.15 (1H, dd, J ) 5.4, 3.6 Hz,
H-4′), 3.85 (1H, dd, J ) 5.7, 5.4 Hz, H-3′), 3.43 (1H, d, J ) 3.6
Hz, OH-4′), 3.19 (1H, d, J ) 5.7 Hz, OH-3′), 1.99 (3H, d, J )
1.0 Hz, CH3-3), 1.41, 1.42 (each 3H, s, CH3-2′).
3′R ,4′R -Dih yd r oxy-2′,2′-d im e t h yl-3-p h e n ylp yr a n o-
ch r om on e (33c): 55% yield (starting with 194 mg of 29c);
mp > 203 °C sublimed; MS-ESI+ (m/z, %) 361 (M+ + Na, 35),
339 (M+ + 1, 100); 1H NMR δ (CD3OD) 8.28 (1H, s, H-2), 8.05
(1H, d, J ) 9.0 Hz, H-5), 7.53∼7.57 (2H, m, H-2′′,6′′-phenyl),
7.32∼7.46 (3H, m, H-3”,4”,5”-phenyl), 6.92 (1H, d, J ) 9.0 Hz,
H-6), 5.15 (1H, d, J ) 5.0 Hz, H-4′), 3.81 (1H, d, J ) 5.0 Hz,
H-3′), 1.46, 1.45 (each 3H, s, CH3-2′).
H-6), 6.31 (1H, s, H-3), 5.20 (1H, dd, J ) 5.1, 3.9 Hz, H-4′),
4.47, 4.35 (1H each, d, J ) 14.1 Hz, CH2OCH2CH3-2), 3.87 (1H,
t, J ) 5.1 Hz, H-3′), 3.71 (1H, d, J ) 3.9 Hz, OH-4′), 3.63 (2H,
q, J ) 7.2 Hz, CH2OCH2CH3-2), 3.08 (1H, d, J ) 5.1 Hz,
OH-3′), 1.48, 1.40 (each 3H, s, CH3-2′), 1.27 (3H, t, J ) 7.2
Hz, CH2OCH2CH3-2).
3′R,4′R-Dih yd r oxy-2′,2′-d im eth yl-2-p h en ylp yr a n o[2,3-
f]ch r om on e (33i): 79% yield (starting with 128 mg of 29i);
mp 238-241 °C; MS-ESI+ (m/z, %) 361 (M+ + Na, 100), 338
(M+, 28); MS-ESI- (m/z, %) 337 (M+ - 1, 100); 1H NMR δ 7.97
(1H, d, J ) 8.7 Hz, H-5), 7.81∼7.88 (2H, m, H-2′′,6′′-phenyl),
7.42∼7.53 (3H, m, H-3′′,4′′,5′′-phenyl), 6.82 (1H, d, J ) 8.7 Hz,
H-6), 6.63 (1H, s, H-3), 5.28 (1H, d, J ) 5.0 Hz, H-4′), 3.89
(1H, d, J ) 5.0 Hz, H-3′), 1.51, 1.46 (each 3H, s, CH3-2′).
3′R,4′R-Dih yd r oxy-2,2,2′,2′-t et r a m et h ylp yr a n o[2,3-f]-
ch r om on e (33j): 52% yield (starting with 150 mg of 29j); mp
>280 °C; MS-ESI+ (m/z, %) 291 (M+ + 1, 100); 1H NMR δ
8.02 (1H, d, J ) 8.8 Hz, H-5), 6.83 (1H, d, J ) 8.8 Hz, H-6),
5.19 (1H, t, J ) 5.1 Hz, H-4′), 3.87 (1H, dd, J ) 6.3, 5.1 Hz,
H-3′), 3.10 (1H, d, J ) 5.1, OH-4′), 2.99 (1H, d, J ) 6.3 Hz,
OH-3′), 2.42 (3H, s, CH3-2), 2.03 (3H, s, CH3-3), 1.46, 1.41 (each
3H, s, CH3-2′).
6-ter t-Bu tyl-3′R,4′R-dih ydr oxy-2′,2′-dim eth yl-2-eth ylpyr -
a n o[2,3-f]ch r om on e (33k ): 35% yield (starting with 75.3 mg
of 29k ); mp >260 °C sublimed; MS-ESI+ (m/z, %) 347 (M+
+
1, 100); 1H NMR δ (CD3OD) 7.97 (1H, s, H-5), 6.18 (1H, s, H-3),
5.15 (1H, d, J ) 4.6 Hz, H-4′), 3.79 (1H, d, J ) 4.6 Hz, H-3′),
2.77 (2H, q, J ) 7.5 Hz, CH2CH3-2), 1.54, 1.49 (each 3H, s,
CH3-2′), 1.42 (9H, s, (CH3)3C-6), 1.35 (3H, t, J ) 7.5 Hz,
CH2CH3-2).
Syn t h eses of Su b st it u t ed DCP Der iva t ives. The
substituted 3′R,4′R-dihydroxypyranochromones (33a -k ), (S)-
(-)-camphanic chloride (3 equiv), and DMAP (3 equiv) were
stirred in CH2Cl2 for 1-2 days at room temperature, monitored
by TLC. At completion, the mixture was concentrated and the
residue was purified by PTLC with an eluant of hexane/EtOAc
) 3:1 to afford the appropriately substituted 3′R,4′R-di-O-
(-)-ca m p h a n oyl-2′,2′-d im et h yld ih yd r op yr a n o[2,3-f]-
chromones (4-14) and 3′R-hydroxy-4′R-O-(-)-camphanoyl-
2′,2′-dimethyldihydropyrano[2,3-f]chromones (34b-e, 34h , and
34i).
3′R ,4′R -D ih y d r o x y -2,2′,2′-t r im e t h y lp y r a n o [2,3-f]-
ch r om on e (33d ): 36% yield (starting with 605 mg of 29d );
mp 176-178 °C; MS-ESI+ (m/z, %) 299 (M+ + Na, 100), 277
(M+ + 1, 12); 1H NMR δ (CD3OD) 7.98 (1H, d, J ) 9.0 Hz,
H-5), 6.98 (1H, d, J ) 9.0 Hz, H-6), 6.17 (1H, s, H-3), 5.12 (1H,
d, J ) 4.6 Hz, H-4′), 3.81 (1H, d, J ) 4.6 Hz, H-3′), 2.46 (3H,
s, CH3-2), 1.46, 1.47 (each 3H, s, CH3-2′).
3′R,4′R-Di-O-(-)-ca m p h a n oyl-2′,2′-d im eth yld ih yd r op y-
r a n o[2,3-f]ch r om on e (DCP , 4): 71% yield (starting with 15
mg of 33a ); mp 90-92 °C; MS-ESI+ (m/z, %) 645 (M+ + Na,
3′R,4′R-Dih yd r oxy-2′,2′-d im eth yl-2-eth ylp yr a n o[2,3-f]-
ch r om on e (33e): 54% yield (starting with 512 mg of 29e);
mp 153-155 °C; MS-ESI+ (m/z, %) 313 (M+ + Na, 100), 291
1
100); H NMR δ 8.15 (1H, d, J ) 9.0 Hz, H-5), 7.69 (1H, d, J
) 6.3 Hz, H-2), 6.94 (1H, d, J ) 9.0 Hz, H-6), 6.72 (1H, d, J )
4.8 Hz, H-4′), 6.32 (1H, d, J ) 6.3 Hz, H-3), 5.37 (1H, d, J )
4.8 Hz, H-3′), 2.46, 2.20, 1.90, 1.74 (each 2H, m, camphanoyl
CH2), 1.52, 1.47 (each 3H, s, CH3-2′), 1.11, 1.10, 1.08, 1.02,
0.99, 0.89 (each 3H, s, camphanoyl CH3); 93% de. [R]D -95.3°
(c ) 0.17, CHCl3). Anal. (C34H38O11‚11/2H2O) C, H.
1
(M+ + 1, 35); H NMR δ 8.01 (1H, d, J ) 9.0 Hz, H-5), 6.85
(1H, d, J ) 9.0 Hz, H-6), 6.14 (1H, s, H-3), 5.20 (1H, dd, J )
4.8, 4.2 Hz, H-4′), 3.87 (1H, dd, J ) 6.6, 4.8 Hz, H-3′), 3.08
(1H, d, J ) 4.2 Hz, OH-4′), 2.99 (1H, d, J ) 6.6 Hz, OH-3′),
2.68 (2H, q, J ) 7.5 Hz, CH2CH3-2), 1.42, 1.47 (each 3H, s,
CH3-2′), 1.32 (3H, t, J ) 7.5 Hz, CH2CH3-2).
3′R,4′R-Di-O-(-)-ca m p h a n oyl-3,2′,2′-tr im eth yld ih yd r o-
p yr a n o[2,3-f]ch r om on e (5): 43% yield (starting with 83 mg
of 33b); mp 233-235 °C; MS-ESI+ (m/z, %) 659 (M+ + Na,
100); 1H NMR δ 8.16 (1H, d, J ) 9.0 Hz, H-5), 7.61 (1H, s,
H-2), 6.91 (1H, d, J ) 9.0 Hz, H-6), 6.70 (1H, d, J ) 4.8 Hz,
H-4′), 5.36 (1H, d, J ) 4.8 Hz, H-3′), 2.56, 2.32, 2.24, 1.85 (each
2H, m, camphanoyl CH2), 2.12 (3H, s, CH3-3), 1.64, 1.59 (each
3H, s, CH3-2′), 1.32, 1.24, 1.22, 1.12, 1.10, 1.00 (each 3H, s,
camphanoyl CH3); 90% de. [R]D -36.2° (c ) 0.23, CHCl3). Anal.
(C35H40O11‚1/4H2O) C, H.
3′R,4′R-Dih yd r oxy-2′,2′-d im eth yl-2-p r op ylp yr a n o[2,3-
f]ch r om on e (33f): 55% yield (starting with 241 mg of 29f);
mp 143-144 °C; MS-ESI+ (m/z, %) 327 (M+ + Na, 86), 305
1
(M+ + 1, 100); H NMR δ 7.95 (1H, d, J ) 9.0 Hz, H-5), 6.82
(1H, d, J ) 9.0 Hz, H-6), 6.09 (1H, s, H-3), 5.17 (1H, dd, J )
5.0, 3.6 Hz, H-4′), 3.86 (1H, dd, J ) 5.8, 5.0 Hz, H-3′), 3.39
(1H, d, J ) 3.6 Hz, OH-4′), 3.20 (1H, d, J ) 5.8 Hz, OH-3′),
2.59 (2H, t, J ) 4.5 Hz, CH2CH2CH3-2), 1.75 (2H, m, J ) 4.5
Hz, CH2CH2CH3-2), 1.48, 1.42 (each 3H, s, CH3-2′), 1.02 (3H,
t, J ) 4.5 Hz, CH2CH2CH3-2).
3′R ,4′R -Di-O-(-)-ca m p h a n oyl-2′,2′-d im e t h yl-3-p h e -
n yld ih yd r op yr a n o[2,3-f]ch r om on e (6): 55% yield (starting
with 17 mg of 33c); mp 103-105 °C; MS-ESI+ (m/z, %) 699
3′R,4′R-Dih yd r oxy-2′,2′-d im et h yl-2-isop r op ylp yr a n o-
[2,3-f]ch r om on e (33g): 72% yield (starting with 126 mg of
29g); mp 152 °C sublimed; MS-ESI+ (m/z, %) 327 (M+ + Na,
1
(M+ + 1, 100); H NMR δ 8.25 (1H, d, J ) 9.0 Hz, H-5), 7.84
1
100), 305 (M+ + 1, 55); H NMR δ (CD3OD) 7.96 (1H, d, J )
(1H, s, H-2), 7.38∼7.51 (5H, m, phenyl), 6.97 (1H, d, J ) 9.0
Hz, H-6), 6.76 (1H, d, J ) 4.6 Hz, H-4′), 5.39 (1H, d, J ) 4.6
Hz, H-3′), 2.50, 2.20, 1.91, 1.73 (each 2H, m, camphanoyl CH2),
1.57 (6H, s, 2 × CH3-2′), 1.24, 1.18, 1.09, 1.02, 0.98, 0.92 (each
3H, s, camphanoyl CH3); 60% de. [R]D -279.5° (c ) 0.15,
CHCl3). Anal. (C40H42O11‚H2O) C, H.
8.8 Hz, H-5), 6.88 (1H, d, J ) 8.8 Hz, H-6), 6.18 (1H, s, H-3),
5.14 (1H, d, J ) 4.6 Hz, H-4′), 3.81 (1H, d, J ) 4.6 Hz, H-3′),
2.99 (1H, m, J ) 6.6 Hz, CH(CH3)2-2), 1.48 (6H, s, 2 × CH3-
2′), 1.39 (6H, t, J ) 6.6 Hz, CH(CH3)2-2).
3′R,4′R-Dih yd r oxy-2′,2′-d im eth yl-2-eth oxym eth ylp yr -
a n o[2,3-f]ch r om on e (33h ): 54% yield (starting with 57 mg
3′R,4′R-Di-O-(-)-ca m p h a n oyl-2,2′,2′-tr im eth yld ih yd r o-
p yr a n o[2,3-f]ch r om on e (7): 35% yield (starting with 206 mg
of 33d ); mp 146-148 °C; MS-ESI+ (m/z, %) 659 (M+ + Na,
1
of 29h ); yellow oil; MS-ESI+ (m/z, %) 321 (M+ + 1, 100); H
NMR δ 8.01 (1H, d, J ) 9.1 Hz, H-5), 6.87 (1H, d, J ) 9.1 Hz,

4080 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16
Yu et al.
48), 658 (M+ + Na - 1, 100), 636 (M+, 12); 1H NMR δ 8.11
(1H, d, J ) 8.8 Hz, H-5), 6.90 (1H, d, J ) 8.8 Hz, H-6), 6.75
(1H, d, J ) 4.6 Hz, H-4′), 6.12 (1H, s, H-3), 5.37 (1H, d, J )
4.6 Hz, H-3′), 2.46, 2.12, 1.92, 1.70 (each 2H, m, camphanoyl
CH2), 2.27 (3H, s, CH3-2), 1.53, 1.46 (each 3H, s, CH3-2′), 1.11,
1.10, 1.07, 1.00, 0.97, 0.94 (each 3H, s, camphanoyl CH3); 60%
de. [R]D -69.6° (c ) 0.25, CHCl3). Anal. (C35H40O11‚1/2H2O) C,
H.
0.91 (each 3H, s, camphanoyl CH3); 92% de. [R]D -76.5° (c )
0.23, CHCl3). Anal. (C36H42O11‚11/2H2O) C, H.
6-ter t-Bu tyl-3′R,4′R-di-O-(-)-cam ph an oyl-2′,2′-dim eth yl-
2-eth yldih ydr opyr an o[2,3-f]ch r om on e (14): 57% yield (start-
ing with 28 mg of 33k ); mp 253-254 °C; MS-ESI+ (m/z, %)
707 (M+ + 1, 100); 1H NMR δ 8.10 (1H, s, H-5), 6.75 (1H, d, J
) 4.8 Hz, H-4′), 6.12 (1H, s, H-3), 5.41 (1H, d, J ) 4.8 Hz,
H-3′), 2.52 (2H, q, J ) 7.5 Hz, CH2CH3-2), 2.47, 2.18, 1.92,
1.70 (each 2H, m, camphanoyl CH2), 1.56, 1.53 (each 3H, s,
CH3-2′), 1.40 (9H, (CH3)3C-6), 1.22 (3H, t, J ) 7.5 Hz,
CH2CH3-2), 1.12, 1.10, 1.07, 1.01, 0.97, 0.95 (each 3H, s,
camphanoyl CH3); 99% de. [R]D -64.8° (c ) 0.29, CHCl3). Anal.
(C40H50O11) C, H.
3′R,4′R-Di-O-(-)-cam ph an oyl-2′,2′-dim eth yl-2-eth yldih y-
d r op yr a n o[2,3-f]ch r om on e (8): 51% yield (starting with 290
mg of 33e); mp 137-139 °C; MS-ESI+ (m/z, %) 673 (M+ + Na,
100), 651 (M+ + 1, 16); 1H NMR δ 8.11 (1H, d, J ) 9.0 Hz,
H-5), 6.90 (1H, d, J ) 9.0 Hz, H-6), 6.74 (1H, d, J ) 4.8 Hz,
H-4′), 6.13 (1H, s, H-3), 5.38 (1H, d, J ) 4.8 Hz, H-3′), 2.56
(2H, q, J ) 7.2 Hz, CH2CH3-2), 2.50, 2.14, 1.94, 1.70 (each 2H,
m, camphanoyl CH2), 1.53, 1.46 (each 3H, s, CH3-2′), 1.23 (3H,
t, J ) 7.2 Hz, CH2CH3-2), 1.11, 1.10, 1.07, 1.00, 0.97, 0.95 (each
3H, s, camphanoyl CH3); 95% de. [R]D -773.3° (c ) 0.16,
CHCl3). Anal. (C36H42O11‚1/4H2O) C, H.
3′R,4′R-Di-O-(-)-ca m p h a n oyl-2′,2′-d im et h yl-2-p r op y-
ld ih yd r op yr a n o[2,3-f]ch r om on e (9): 90% yield (starting
with 46 mg of 33f); mp 113-115 °C; MS-ESI+ (m/z, %) 687
(M+ + Na, 100), 665 (M+ + 1, 78); 1H NMR δ 8.10 (1H, d, J )
8.7 Hz, H-5), 6.89 (1H, d, J ) 8.7 Hz, H-6), 6.72 (1H, d, J )
4.8 Hz, H-4′), 6.14 (1H, s, H-3), 5.38 (1H, d, J ) 4.8 Hz, H-3′),
2.50 (2H, m, J ) 7.2 Hz, CH2CH2CH3-2), 2.48, 2.14, 1.94, 1.68
(each 2H, m, camphanoyl CH2), 1.65 (2H, m, J ) 7.2 Hz,
CH2CH2CH3-2), 1.52, 1.45 (each 3H, s, CH3-2′), 1.23 (3H, t, J
) 7.2 Hz, CH2CH2CH3-2), 1.10, 1.09, 1.00, 0.96, 0.95, 0.94 (each
3H, s, camphanoyl CH3); 60% de. [R]D -56.0° (c ) 0.40, CHCl3).
Anal. (C37H44O11‚3/4H2O) C, H.
3′R,4′R-Di-O-(-)-ca m p h a n oyl-2′,2′-d im et h yl-2-isop r o-
p yld ih yd r op yr a n o[2,3-f]ch r om on e (10): 35% yield (starting
with 42 mg of 33g); mp 181-182 °C; MS-ESI+ (m/z, %) 687
(M+ + Na, 100), 665 (M+ + 1, 15); 1H NMR δ 8.10 (1H, d, J )
9.0 Hz, H-5), 6.88 (1H, d, J ) 9.0 Hz, H-6), 6.74 (1H, d, J )
4.6 Hz, H-4′), 6.13 (1H, s, H-3), 5.39 (1H, d, J ) 4.6 Hz, H-3′),
2.72 (1H, m, J ) 7.5 Hz, CH(CH3)2-2), 2.48, 2.16, 1.94, 1.68
(each 2H, m, camphanoyl CH2), 1.54, 1.45 (each 3H, s,
CH3-2′), 1.24 (6H, d, J ) 7.5 Hz, CH(CH3)2-2), 1.11, 1.10, 1.06,
1.02, 0.97, 0.96 (each 3H, s, camphanoyl CH3); 88% de. [R]D
-60.9° (c ) 0.22, CHCl3). Anal. (C37H44O11‚1/2H2O) C, H.
4′R -O-(-)-Ca m p h a n oyl-3′R -h yd r oxy-3,2′,2′-t r im e t h -
yld ih yd r op yr a n o[2,3-f]ch r om on e (34b): 21% yield (starting
with 83 mg of 33b); mp 222-224 °C; MS-ESI+ (m/z, %) 457
1
(M+ + 1, 80), 456 (M+, 100); H NMR δ 8.13 (1H, d, J ) 8.8
Hz, H-5), 7.64 (1H, s, H-2), 6.88 (1H, d, J ) 8.8 Hz, H-6), 6.54
(1H, d, J ) 5.0 Hz, H-4′), 4.13 (1H, d, J ) 5.0 Hz, H-3′), 2.50,
2.08, 1.90, 1.72 (each 1H, m, camphanoyl CH2), 1.98 (3H, s,
CH3-3), 1.52, 1.39 (each 3H, s, CH3-2′), 1.09, 1.00, 0.94 (each
3H, s, camphanoyl CH3).
4′R-O-(-)-Ca m p h a n oyl-3′R-h yd r oxy-2′,2′-d im et h yl-3-
p h en yld ih yd r op yr a n o[2,3-f]ch r om on e (34c): 50% yield
(starting with 17 mg of 33c); mp 225-227 °C; MS-ESI+ (m/z,
%) 519 (M+ + 1, 100); 1H NMR δ 8.19 (1H, d, J ) 9.0 Hz, H-5),
7.87 (1H, s, H-2), 7.52 (2H, m, H-2”, 6”-phenyl), 7.38-7.43 (3H,
m, H-3”, 4”, 5”-phenyl), 6.92 (1H, d, J ) 9.0 Hz, H-6), 6.58
(1H, d, J ) 5.1 Hz, H-4′), 4.12 (1H, d, J ) 5.1 Hz, H-3′), 2.46,
2.26, 1.85, 1.65 (each 1H, m, camphanoyl CH2), 1.53, 1.41 (each
3H, s, CH3-2′), 1.09, 1.02, 0.97, (each 3H, s, camphanoyl CH3).
4′R -O-(-)-Ca m p h a n oyl-3′R -h yd r oxy-2,2′,2′-t r im e t h -
yld ih yd r op yr a n o[2,3-f]ch r om on e (34d ): 60% yield (starting
with 206 mg of 33d ); mp 223-225 °C; MS-ESI+ (m/z, %) 457
1
(M+ + 1, 100); H NMR δ 8.02 (1H, d, J ) 8.8 Hz, H-5), 6.84
(1H, d, J ) 8.8 Hz, H-6), 6.59 (1H, d, J ) 4.8 Hz, H-4′), 6.10
(1H, s, H-3), 4.11 (1H, d, J ) 4.8 Hz, H-3′), 2.48, 2.02, 1.90,
1.67 (each 1H, m, camphanoyl CH2), 2.26 (3H, s, CH3-2), 1.51,
1.38 (each 3H, s, CH3-2′), 1.07, 0.98, 0.97 (each 3H, s,
camphanoyl CH3).
4′R-O-(-)-Ca m p h a n oyl-3′R-h yd r oxy-2′,2′-t r im et h yl-2-
eth yldih ydr opyr an o[2,3-f]ch r om on e (34e): 35% yield (start-
ing with 290 mg of 33e); mp 186-188 °C; MS-ESI+ (m/z, %)
3′R,4′R-Di-O-(-)-cam ph an oyl-2′,2′-dim eth yl-2-eth oxym -
eth yld ih yd r op yr a n o[2,3-f]ch r om on e (11): 45% yield (start-
ing with 40 mg of 33h ); mp 105-106 °C; MS-ESI+ (m/z, %):
1
493 (M+ + Na, 62), 471 (M+ + 1, 20); H NMR δ 8.06 (1H, d,
J ) 9.0 Hz, H-5), 6.86 (1H, d, J ) 9.0 Hz, H-6), 6.61 (1H, d, J
) 4.6 Hz, H-4′), 6.12 (1H, s, H-3), 4.11 (1H, d, J ) 4.6 Hz,
H-3′), 2.52 (2H, q, J ) 7.2 Hz, CH2CH3-2), 2.45, 2.02, 1.92,
1.68 (each 1H, m, camphanoyl CH2), 1.53, 1.40 (each 3H, s,
CH3-2′), 1.23 (3H, t, J ) 7.2 Hz, CH2CH3-2), 1.09, 1.01, 0.99
(each 3H, s, camphanoyl CH3).
1
681 (M+ + 1, 100); H NMR δ 8.13 (1H, d, J ) 9.0 Hz, H-5),
6.92 (1H, d, J ) 9.0 Hz, H-6), 6.72 (1H, d, J ) 4.8 Hz, H-4′),
6.41 (1H, s, H-3), 5.37 (1H, d, J ) 4.8 Hz, H-3′), 4.28, 4.25
(each 1H, d, J ) 15.3 Hz, CH2OCH2CH3-2), 3.58 (2H, q, J )
7.0 Hz, CH2OCH2CH3-2), 2.50, 2.16, 1.95, 1.65 (each 2H, m,
camphanoyl CH2), 1.53, 1.47 (each 3H, s, CH3-2′), 1.24 (3H, t,
J ) 7.0 Hz, CH2OCH2CH3-2), 1.12, 1.10, 1.07, 0.99, 0.97, 0.94
(each 3H, s, camphanoyl CH3); 90% de. [R]D -66.0° (c ) 0.10,
CHCl3). Anal. (C37H44O12‚3/4H2O) C, H.
4′R-O-(-)-Ca m p h a n oyl-3′R-h yd r oxy-2′,2′-d im et h yl-2-
eth oxym eth yld ih yd r op yr a n o[2,3-f]ch r om on e (34h ): 21%
yield (starting with 40 mg of 33h ); mp 161-163 °C; MS-ESI+
1
(m/z, %) 523 (M+ + Na, 100); H NMR δ 8.06 (1H, d, J ) 8.8
Hz, H-5), 6.87 (1H, d, J ) 8.8 Hz, H-6), 6.56 (1H, d, J ) 4.8
Hz, H-4′), 6.38 (1H, s, H-3), 4.29, 4.24 (each 1H, d, J ) 15.3
Hz, CH2OCH2CH3-2), 4.11 (1H, d, J ) 4.8 Hz, H-3′), 3.58 (2H,
q, J ) 7.0 Hz, CH2OCH2CH3-2), 2.47, 2.06, 1.92, 1.67 (each
1H, m, camphanoyl CH2), 1.52, 1.39 (each 3H, s, CH3-2′), 1.34
(3H, t, J ) 7.0 Hz, CH2OCH2CH3-2), 1.08, 1.00, 0.98 (each 3H,
s, camphanoyl CH3).
3′R ,4′R -Di-O-(-)-ca m p h a n oyl-2′,2′-d im e t h yl-2-p h e -
n yld ih yd r op yr a n o[2,3-f]ch r om on e (12): 52% yield (starting
with 162 mg of 33i); mp 153-155 °C; MS-ESI+ (m/z, %) 721
(M+ + Na, 100), 699 (M+ + 1, 15); 1H NMR δ 8.18 (1H, d, J )
9.0 Hz, H-5), 7.80 (2H, m, H-2′′,6′′-phenyl), 7.49 (3H, m, H-3′′,
4′′, 5′′-phenyl), 6.96 (1H, d, J ) 9.0 Hz, H-6), 6.92 (1H, d, J )
5.0 Hz, H-4′), 6.82 (1H, s, H-3), 5.46 (1H, d, J ) 5.0 Hz, H-3′),
2.54, 2.23, 1.98, 1.78 (each 2H, m, camphanoyl CH2), 1.55, 1.49
(each 3H, s, CH3-2′), 1.13, 1.12, 0.99, 0.96, 0.84, 0.64, (each
3H, s, camphanoyl CH3); 33% de. [R]D +25.5° (c ) 0.13, CHCl3).
Anal. (C40H42O11‚1/4H2O) C, H.
4′R-O-(-)-Ca m p h a n oyl-3′R-h yd r oxy-2′,2′-d im et h yl-2-
p h en yld ih yd r op yr a n o[2,3-f]ch r om on e (34i): 45% yield
(starting with 162 mg of 33i); mp 163-165 °C; MS-ESI+ (m/
1
z, %) 541 (M+ + Na, 100), 519 (M+ + 1, 22); H NMR δ 8.14
(1H, d, J ) 8.5 Hz, H-5), 7.79 (2H, m, H-2′′,6′′-phenyl), 7.47-
7.52 (3H, m, H-3′′, 4′′, 5′′-phenyl), 6.92 (1H, d, J ) 8.5 Hz,
H-6), 6.79 (1H, d, J ) 5.0 Hz, H-4′), 6.77 (1H, s, H-3), 4.20
(1H, d, J ) 5.0 Hz, H-3′), 2.48, 2.20, 1.77, 1.62 (each 1H, m,
camphanoyl CH2), 1.56, 1.42 (each 3H, s, CH3-2′), 1.00, 0.92,
0.77, (each 3H, s, camphanoyl CH3).
3′R,4′R-Di-O-(-)-ca m p h a n oyl-2,3,2′,2′-tetr a m eth yld ih y-
d r op yr a n o[2,3-f]ch r om on e (13): 50% yield (starting with
183 mg of 33j); mp 189-190 °C; MS-ESI+ (m/z, %) 673 (M+
+
Na, 100), 651 (M+ + 1, 35); 1H NMR δ 8.11 (1H, d, J ) 8.8 Hz,
H-5), 6.86 (1H, d, J ) 8.8 Hz, H-6), 6.74 (1H, d, J ) 4.6 Hz,
H-4′), 5.36 (1H, d, J ) 4.6 Hz, H-3′), 2.46, 2.14, 1.92, 1.69 (each
2H, m, camphanoyl CH2), 2.27 (3H, s, CH3-2), 1.98 (3H, s, CH3-
3), 1.51, 1.45 (each 3H, s, CH3-2′), 1.10, 1.08, 1.05, 0.97, 0.96,
Syn th eses of 3′-O-Acyl-4′-O-(-)-ca m p h a n oyl-2′,2′-d im -
et h yld ih yd r op yr a n o[2,3-f]ch r om on es (15-21). The 4′-
camphanoyl-3′-hydroxy-substituted compounds (34d , 34e, 34h ,

Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16 4081
and 34i) were dissolved in DMAP/CH2Cl2 and reacted with
acetic anhydride or an acyl chloride (1.5 equiv) for 1-2 days
at room temperature, monitored by TLC. The reaction mixture
was concentrated and purified by PTLC (eluant: hexane/
EtOAc ) 7:3) and afforded the appropriately substituted 3′-
O-acyl-4′-O-(-)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-
f]chromones (15-21).
3′R -O-Ace t yl-4′R -O-(-)-ca m p h a n oyl-2,2′,2′-t r im e t h -
yld ih yd r op yr a n o[2,3-f]ch r om on e (15): 81% yield (starting
with 70 mg of 34d ); mp 229-230 °C; MS-ESI+ (m/z, %) 521
(M+ + Na, 95), 499 (M+ + 1, 100); 1H NMR δ 8.07 (1H, d, J )
9.1 Hz, H-5), 6.87 (1H, d, J ) 9.1 Hz, H-6), 6.69 (1H, d, J )
4.6 Hz, H-4′), 6.11 (1H, s, H-3), 5.29 (1H, d, J ) 4.6 Hz, H-3′),
2.38, 1.94, 1.88, 1.66 (each 1H, m, camphanoyl CH2), 2.28 (3H,
s, CH3-2), 2.10 (1H, s, CH3CO-3′), 1.49, 1.44 (each 3H, s, CH3-
2′), 1.08, 0.99, 0.94 (each 3H, s, camphanoyl CH3); 20% de. [R]D
+20.0° (c ) 0.20, CHCl3). Anal. (C27H30O9‚1/4H2O) C, H.
3H, s, camphanoyl CH3); 70% de. [R]D +4.4° (c ) 0.54, CHCl3).
Anal. (C32H32O9) C, H.
4′R-O-(-)-Ca m p h a n oyl-3′R-O-isobu tyr yl-2′,2′-d im eth yl-
2-p h en yld ih yd r op yr a n o[2,3-f]ch r om on e (21): 27% yield
(starting with 47 mg of 34i); mp 108-110 °C; MS-ESI+ (m/z,
%) 589 (M+ + 1, 100); 1H NMR δ 8.16 (1H, d, J ) 8.8 Hz, H-5),
7.79 (2H, m, H-2′′,6′′-phenyl), 7.48 (3H, m, H-3′′, 4′′, 5′′-phenyl),
6.95 (1H, d, J ) 8.8 Hz, H-6), 6.88 (1H, d, J ) 4.5 Hz, H-4′),
6.78 (1H, s, H-3), 5.40 (1H, d, J ) 4.5 Hz, H-3′), 2.59 (1H, m,
CH(CH3)2-3′), 2.10, 1.60 (each 2H, m, camphanoyl CH2), 1.51,
1.46 (each 3H, s, CH3-2′), 1.25, 1.24 (each 3H, d, J ) 6.9 Hz,
CH(CH3)2-3′), 0.98, 0.82, 0.68, (each 3H, s, camphanoyl CH3);
70% de. [R]D +8.5° (c ) 0.40, CHCl3). Anal. (C34H36O9‚1/4H2O)
C, H.
HIV-1 In fectivity Assa y in Non -Dr u g-Resista n t Str a in
in H9 Lym p h ocytes. This assay was performed by Panacos,
Inc. The general procedure was described previously.8
HIV-1 In fectivity Assa y in HIV-1 RTMDR1 Str a in in
MT-4 Cell Lin es. A diluted drug-resistant HIV-1 stock, HIV-1
RTMDR1/MT2, at a multiplicity of infection (MOI) of 0.001
TCID50/cell was used to infect MT4 cells. Twenty microliters
of the virus and 20 µL of compounds at various concentrations
in RPMI 1640 containing 10% fetal bovine serum were added
to 20 µL of MT4 cells at 6 × 105 cells/mL in a 96-well microtiter
plate. The cell/virus compound mixture was then incubated
at 37 °C in a humidified CO2 incubator. Fresh medium (180
µL) containing an appropriate concentration of the compound
was added to each well of the cultures on day 2. On day 4
postinfection, supernatant samples were harvested and as-
sayed for P24 using an ELISA kit from ZeptoMetrix Corpora-
tion, Buffalo, NY.
4′R-O-(-)-Ca m p h a n oyl-3′R-O-isob u t yr yl-2,2′,2′-t r im e-
th yld ih yd r op yr a n o[2,3-f]ch r om on e (16): 53% yield (start-
ing with 30 mg of 34d ); mp 160-162 °C; MS-ESI+ (m/z, %)
1
549 (M+ + Na, 48), 527 (M+ + 1, 30); H NMR δ 8.09 (1H, d,
J ) 8.8 Hz, H-5), 6.88 (1H, d, J ) 8.8 Hz, H-6), 6.73 (1H, d, J
) 4.6 Hz, H-4′), 6.11 (1H, s, H-3), 5.31 (1H, d, J ) 4.6 Hz,
H-3′), 2.56 (1H, m, J ) 6.3 Hz, CH(CH3)2-3′), 2.43, 2.01, 1.90,
1.68 (each 1H, m, camphanoyl CH2), 2.26 (3H, s, CH3-2), 1.49,
1.44 (each 3H, s, CH3-2′), 1.23, 1.22 (3H each, d, J ) 6.3 Hz,
CH(CH3)2-3′), 1.09, 0.98, 0.96 (each 3H, s, camphanoyl CH3);
>98% de. [R]D -92.0° (c ) 0.10, CHCl3). Anal. (C29H34O9‚H2O)
C, H.
4′R-O-(-)-Ca m p h a n oyl-3′R-O-isova ler yl-2,2′,2′-tr im eth -
yld ih yd r op yr a n o[2,3-f]ch r om on e (17): 60% yield (starting
with 36 mg of 34d ); mp 135-137 °C; MS-ESI+ (m/z, %) 563
(M+ + Na, 62), 541 (M+ + 1, 100); 1H NMR δ 8.08 (1H, d, J )
9.0 Hz, H-5), 6.88 (1H, d, J ) 9.0 Hz, H-6), 6.70 (1H, d, J )
4.8 Hz, H-4′), 6.10 (1H, s, H-3), 5.33 (1H, d, J ) 4.8 Hz, H-3′),
2.44 (1H, m, CH2CH(CH3)2-3′), 2.26 (3H, s, CH3-2), 2.24 (2H,
d, J ) 6.0 Hz, CH2CH(CH3)2-3′), 2.16, 2.00, 1.90, 1.70 (each
1H, m, camphanoyl CH2), 1.48, 1.44 (each 3H, s, CH3-2′), 1.10,
0.99, 0.97 (each 3H, s, camphanoyl CH3), 1.00 (6H, d, J ) 6.0
Hz, CH2CH(CH3)2-3′); >95% de. [R]D -110.0° (c ) 0.16, CHCl3).
Anal. (C30H36O9) C, H.
4′R-O-(-)-Ca m p h a n oyl-3′R-O-isova ler yl-2′,2′-d im eth yl-
2-eth yld ih yd r op yr a n o[2,3-f]ch r om on e (18): 34% yield
(starting with 30 mg of 34e); mp 214-216 °C; MS-ESI+ (m/z,
%): 541 (M+ + 1, 82); 1H NMR δ 8.09 (1H, d, J ) 9.0 Hz, H-5),
6.88 (1H, d, J ) 9.0 Hz, H-6), 6.73 (1H, d, J ) 4.6 Hz, H-4′),
6.13 (1H, s, H-3), 5.32 (1H, d, J ) 4.6 Hz, H-3′), 2.53 (1H, m,
CH(CH3)2-3′), 2.53 (2H, m, CH2CH3-2), 2.43, 2.01, 1.92, 1.69
(each 1H, m, camphanoyl CH2), 1.50, 1.43 (each 3H, s,
CH3-2′), 1.24 (3H, t, J ) 7.2 Hz, CH2CH3-2), 1.22, 1.21 (3H
each, d, J ) 6.9 Hz, CH(CH3)2-3′), 1.09, 0.98, 0.97 (each 3H, s,
camphanoyl CH3); >98% de. [R]D -80.9° (c ) 0.66, CHCl3).
Anal. (C30H36O9‚1/4H2O), C, H.
4′R-O-(-)-Ca m p h a n oyl-3′R-O-isova ler yl-2′,2′-d im eth yl-
2-eth oxym eth yld ih yd r op yr a n o[2,3-f]ch r om on e (19): 34%
yield (starting with 13 mg of 34h ); mp 113-115 °C; MS-ESI+
(m/z, %) 571 (M+ + 1, 100); 1H NMR δ 8.11 (1H, d, J ) 8.8 Hz,
H-5), 6.90 (1H, d, J ) 8.8 Hz, H-6), 6.70 (1H, d, J ) 4.5 Hz,
H-4′), 6.40 (1H, s, H-3), 5.31 (1H, d, J ) 4.5 Hz, H-3′), 4.29,
4.24 (each 1H, dd, J ) 15.0, 1.0 Hz, CH2OCH2CH3-2), 3.58 (2H,
q, J ) 7.2 Hz, CH2OCH2CH3-2), 2.56 (1H, m, CH(CH3)2-3′),
2.42, 2.00, 1.90, 1.68 (each 1H, m, camphanoyl CH2), 1.50, 1.44
(each 3H, s, CH3-2′), 1.24 (3H, m, CH2OCH2CH3-2), 1.22 (6H,
m, CH(CH3)2-3′), 1.09, 0.97, 0.96 (each 3H, s, camphanoyl CH3);
90% de. [R]D -58.6° (c ) 0.44, CHCl3). Anal. (C31H38O10), C, H.
3′R-O-Acet yl-4′R-O-(-)-ca m p h a n oyl-2′,2′-d im et h yl-2-
p h en yld ih yd r op yr a n o[2,3-f]ch r om on e (20): 40% yield
(starting with 20 mg of 34i); mp 154-156 °C; MS-ESI+ (m/z,
%) 561 (M+ + 1, 100); 1H NMR δ 8.16 (1H, d, J ) 8.8 Hz, H-5),
7.78 (2H, m, H-2′′,6′′-phenyl), 7.48 (3H, m, H-3′′, 4′′, 5′′-phenyl),
6.94 (1H, d, J ) 8.8 Hz, H-6), 6.87 (1H, d, J ) 4.8 Hz, H-4′),
6.77 (1H, s, H-3), 5.38 (1H, d, J ) 4.8 Hz, H-3′), 2.15 (1H, s,
CH3CO-3′), 2.38, 2.23, 1.90, 1.60 (each 1H, m, camphanoyl
CH2), 1.49, 1.48 (each 3H, s, CH3-2′), 1.00, 0.89, 0.77, (each
Ack n ow led gm en t . This investigation was sup-
ported by Grant AI-33066 from the National Institute
of Allergy and Infectious Diseases (NIAID) awarded to
K. H. Lee.
Su p p or tin g In for m a tion Ava ila ble: Elemental analyses
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
Refer en ces
(1) Gottlieb, M. S.; Schroff, R.; Schanker, H. M.; Weisman, J . D.;
Fan, P. T.; Wolf, R. A.; Saxon, A. Pneumocystis Carinii Pneu-
monia and Mucosal Candidiasis in Previously Healthy Homo-
sexual Men. N. Engl. J . Med. 1981, 305, 1425-1431.
(2) Barre-Sinoussi, F.; Chermann, J . C.; Rey, F.; Nugeyre, M. T.;
Chamaret, S.; Gruest, J .; Dauguet, C.; Axler-Blin, C.; Vezinet-
Brun, F.; Rouzioux, C.; Rozenbaum, W.; Montagnier, L. Isolation
of a T-lymphotropic Retrovirus from
a Patient at Risk for
Acquired Immune Deficiency Syndrome (AIDS). Science 1983,
220, 868-871.
(3) UNAIDS. AIDS Epidemic Update: 2003; WHO Library Cata-
loguing-in-Publication Data: UNAIDS and WHO, 2003.
(4) Huang, L.; Kashiwada, Y.; Cosentino, L. M.; Fan, S.; Chen, C.
H.; McPhail, A. T.; Fujioka, T.; Mihashi, K.; Lee, K. H. Anti-
AIDS Agents 15. Synthesis and Anti-HIV Activity of Dihydrose-
selins and Related Analogues. J . Med. Chem. 1994, 37, 3947-
3955.
(5) Xie, L.; Takeuchi, Y.; Cosentino, L. M.; Lee, K. H. Anti-AIDS
Agents 33. Synthesis and Anti-HIV Activity of Monomethyl
Substituted 3′, 4′-Di-O-(-)-Camphanoyl-(+)-cis-Khellactone (DCK)
Analogs. Bioorg. Med. Chem. Lett. 1998, 8, 2151-2156.
(6) Xie, L.; Takeuchi, Y.; Cosentino, L. M.; Lee, K. H. Anti-AIDS
Agents. 37. Synthesis and Structure-Activity Relationships of
(3′R,4′R)-(+)-cis-Khellactone Derivatives as Novel Potent Anti-
HIV Agents. J . Med. Chem. 1999, 42, 2662-2672.
(7) Yu, D.; Suzuki, M.; Xie, L.; Morris-Natschke, S. L.; Lee, K. H.
Recent Progress in the Development of Coumarin Derivatives
as Potent Anti-HIV Agents. Med. Res. Rev. 2003, 23, 322-345.
(8) Xie, L.; Yu, D.; Wild, C.; Allaway, G.; Turpin, J . Smith, P. C.;
Lee, K. H. Anti-AIDS Agents 52. Synthesis and Anti-HIV
Activity of Hydroxymethyl (3′R,4′R)-3′, 4′-Di-O-(S)-Camphanoyl-
(+)-cis-khellactone (DCK) Derivatives. J . Med. Chem. 2004, 47,
756-760.
(9) Yu, D.; Brossi, A.; Kilgore, N.; Wild, C.; Allaway, G.; Lee, K. H.
Anti-HIV Agents 55: 3′R,4′R-Di-O-(-)-Camphanoyl-2′,2′-Dim-
ethyldihydropyrano[2,3-f]chromone (DCP), a Novel Anti-HIV
Agent. Bioorg. Med. Chem. Lett. 2003, 13, 1575-1576.
(10) J aen, J . C.; Wise, L. D.; Heffner, T. G.; Pugsley, T. A.; Meltzer,
L. T. Dopamine Autoreceptor Agonists as Potential Antipsy-
chotics. 2. (Aminoalkoxy)-4H-1-benzopyran-4-ones. J . Med. Chem.
1991, 34, 248-256.

4082 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 16
Yu et al.
(11) Wahala, K.; Hase, T. A. Expedient Synthesis of Polyhydroxy-
isoflavones. J . Chem. Soc., Perkin Trans. 1 1991, 3005-3008.
(12) Patonay, T.; Molnar, D.; Muranyi, Z. Flavonoids 45. A General
and Efficient Synthesis of Hydroxyflavones and Chromones.
Bull. Soc. Chim. Fr. 1995, 132, 233-242.
(13) Rehder, K. S.; Kepler, J . A. Total Synthesis of (()-Calanolide A.
Synth. Commun. 1996, 26, 4005-4021.
(14) Mehltretter, G. M.; Dobler, C.; Sundermeier, U.; and Beller, M.
An Improved Version of the Sharpless Asymmetric Dihydroxy-
lation. Tetrahedron Lett. 2000, 41, 8083-8087.
(15) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Catalytic
Asymmetric Dihydroxylation. Chem. Rev. 1994, 94, 2483-2547.
(16) Xie, L.; Crimmins, M. T.; Lee, K. H. Anti-AIDS Agents 22.
Asymmetric Synthesis of 3′,4′-Di-O-(-)-camphanoyl-(+)-cis-khel-
lactone (DCK), a Potent Anti-HIV Agent. Tetrahedron Lett. 1995,
36, 4529-4532.
(17) Larder, B. A.; Kellam, P.; Kemp, S. D. Convergent Combination
Therapy Can Select Viable Multidrug-resistant HIV-1 in vitro.
Nature (London). 1993, 365, 451-453.
(18) Sebok, P.; Timar, T.; J aszberenyi, J . C.; J eko, J . Synthesis of
Benzopyran Derivatives 6. Synthesis of Analogs of Precocenes
Containing 6-Chloro- or 6-tert-Butyl Substituents. Acta Chim.
Hung. C. 1989, 126, 471-85.
J M0400505