First synthesis of aza-calanolides - A new class of anti-HIV active compounds

Article abstract of DOI:10.1016/S0040-4020(02)01456-4

First synthesis of (±)-aza-calanolides, starting from dimethoxy aniline, is achieved. These new compounds exhibited potent in vitro anti-HIV reverse transcriptase activity.

Full text of DOI:10.1016/S0040-4020(02)01456-4

Tetrahedron 59 (2003) 95–99
First synthesis of aza-calanolides—a new class of anti-HIV
active compoundsq
a
b
c
G. V. Madhava Sharma,a A. Ilangovan, Ven L. Narayanan and Mukund K. Gurjar
,
*
aDiscovery Laboratory D-211, Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bDrug Synthesis and Chemistry Branch, National Cancer Institute, Bethesda, MD 20692, USA
cDivision of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 2 September 2002; revised 14 October 2002; accepted 7 November 2002
Abstract—First synthesis of (^)-aza-calanolides, starting from dimethoxy aniline, is achieved. These new compounds exhibited potent in
vitro anti-HIV reverse transcriptase activity. q 2002 Elsevier Science Ltd. All rights reserved.
An urge to identify non-nucleoside reverse transcriptase
inhibitors (NNRTI)1,2 resulted in isolation of a novel class
of pyranocoumarin derivatives from Calophyllum
lanigerum.3 One such compound, calanolide A (1) is in
clinical testing and hence arose unprecedented interest
particularly in developing its analogues.4–6 But so far, most
of the analogues were either less potent or devoid of anti-
HIV activity. The limitations associated with 1 are its
instability and bio-availability in physiological medium. We
envisaged that replacing oxygen in ring B with a nitrogen
atom would lead to aza-calanolide A (2), which might
circumvent these limitations due to the presence of stable
quinolinone ring system. Herein, we describe the first
synthesis, characterization, optical resolution and in vitro
biological evaluation of (^) aza-calanolide A 2.
The target molecule 2 was visualized as a hexa-substituted
aromatic system (ring A) fused on either side with 2-(1-H)-
quinolinone (ring B), chromene (ring C) and dimethyl-
chromanol (ring D) rings. Successive introduction of these
three rings on commercially available 3,5-dimethoxyaniline
forms the basic strategy of our synthetic endeavor.
The synthesis was first initiated with the construction of
quinolinone system (ring B) onto 3,5-dimethoxyaniline (3)
by reacting with ethyl 3-oxo-hexanoate under reflux to give
the acetanilide intermediate (4), albeit in low yield with
number of products. However, by adopting the modified
approach described by Avendano et al.7 wherein 3 was
treated with 2,2-dimethyl-6-n-propyl-4H-1,3-dioxin-4-one8,9
1
in xylene at 1308C, 4 was obtained in 77% yield. The H
NMR spectrum of 4 revealed H-20 and H-60 at a downfield
region d 6.75 and 6.76 compared to H-40 located at d 6.20.
Subsequent treatment of 4 with conc. H2SO4 at room
temperature effected cyclisation to afford the quinolinone
derivative 5 in 90% yield. The two aromatic protons H-6
and H-8 of 5 appeared at d 6.22 and 6.50 respectively in its
1H NMR spectrum. This confirmed the fusion of ring B on
the centrally located ring A. The demethylation of both the
methoxyl groups was conveniently effected with AlCl3 in
chlorobenzene at 1008C to give the substituted resorcinol
derivative 6 (Scheme 1).
The next step was to build the dimethylchromanone ring
(ring D) on the intermediate 6, for which the Friedel–Crafts
acylation with tigloyl chloride–AlCl3 was sought. How-
ever, the issue of regioselectivity was our main concern,
although literature10 published during the synthesis of
calanolide A clearly indicated that the acylation at C-8
was highly preferred. Accordingly, 6 was treated with
tigloyl chloride and AlCl3 in CS2-nitrobenzene at 508C
followed by exposure of the crude reaction mixture to Et3N
q IICT Communication 4421
Keywords: pyranocoumarin; calanolide; aza-calanolide; anti-HIV;
quinolinone synthesis.
*
Corresponding author. Fax: þ91-40-717-3387;
e-mail: esmvee@iict.ap.nic.in
0040–4020/03/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01456-4

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G. V. M. Sharma et al. / Tetrahedron 59 (2003) 95–99
Scheme 1. Reagents: (a) 2,2-Dimethyl-6-n-propyl-4H-1,3-dioxin-4-one, xylene, 1308C, 3 h; (b) conc. H2SO4, rt, 1 h; (c) AlCl3, C6H5Cl, 1208C, 16 h;
(d) CH3CHv(Me) COCl, AlCl3, CS2, C6H5NO2, 508C, 48 h; (e) Et3N, CHCl3, rt, 16 h; (f) uC(Me)2–Cl, K2CO3, n-Bu4NI, ZnCl2, EtCOMe–DMF (9:1),
708C, 16 h.
in CHCl3 at room temperature and gave compound 7 in 23%
yield as a cis and trans diastereomeric mixture in 1:2 ratio.
The regioselectivity of the above acylation reaction was
amply indicated by the 1H NMR spectrum of the mixture in
which the resonances due to H-8, as expected, were missing
from the region of d 6.5 while those of H-6 were present at d
6.20.
NMR spectrum of the trans-ketone (8), the methyl groups in
ring D resonated at separately at d 1.22 (d, J¼6.9 Hz) and
1.78 (multiplet) while H-6 appeared at d 4.20–4.40
(J5,6¼11.1 Hz). For the cis-ketone (9), the resonances due
to two methyl groups appeared at d 1.22 and 1.50 as
doublets (J¼6.1 Hz each) while H-6 appeared at d 4.60–
4.75 (J5,6¼3.0 Hz). Individually both ketones 8 and 9 were
reduced with NaBH4 in EtOH to give 2 (78%) and 11 (73%),
respectively. Whereas, the corresponding reduction of 8
with NaBH4–CeCl3 under Luche condition11 at 2308C
afforded a 8:1 mixture of (^)-aza-calanolide A (2) and (^)-
aza-calanolide B (10) respectively which were separated by
The chromene segment (ring C) was fused on 7 by
essentially adopting the procedure described by Dreyer
et al.10 Thus the reaction of 7 with 3-chloro-3-methyl-1-
butyne in 2-butanone–DMF in the presence of K2CO3,
n-Bu4NI and ZnCl2 at 708C afforded a mixture of trans and
cis ketones (8 and 9) in 42% yield. The trans–cis mixture
was separated by silica gel chromatography and analysed by
1H NMR spectroscopy; particularly important were the
coupling constants between H-5 and H-6 of ring D. In the 1H
1
silica gel chromatography. In the H NMR spectrum of
compound 2, the chemical shift of H-8 was localized at d
4.59 and the observed J value of 9.0 Hz clearly indicated the
trans relationship with H-7. The protons H-3 and H-4
resonated as doublets at d 5.49 and 6.63 (J¼9.9 Hz). The
Scheme 2. Reagents: (a) NaBH4, EtOH, 08C to rt, 1 h; (b) NaBH4 CeCl3, EtOH, 2308C, 10 h.

G. V. M. Sharma et al. / Tetrahedron 59 (2003) 95–99
97
Scheme 3. (a) Chiral HPLC.
1
minor isomer 10 showed in its H NMR spectrum a signal
due to H-8 at d 4.78 (J7,8¼3.1 Hz) indicating a cis
relationship with H-7 (Scheme 2).
oxo-hexanamide 4 (18.87 g) in 77% yield as an oily liquid.
nmax (Neat) 3325, 2960, 2925, 1710, 1650 cm21; dH
(200 MHz, CDCl3) 0.96 (t, 3H, J¼6.2 Hz, CH2CH3),
1.55–1.75 (m, 2H, CH2CH2), 2.54 (t, 2H, J¼6.2 Hz,
CH2CH2), 3.50 (s, 2H, COCH2), 3.80 (s, 6H, 2-OCH3),
6.20 (s, 1H, H-40), 6.75, 6.76 (2s, 2H, H-20 and H-60); m/z
(EI) 265 (Mþ, 62), 203 (20), 186 (10), 179 (21), 153
(100%); HRMS: found 265.1315. C14H19NO4 requires
265.1314.
The optical resolution of racemic 2 (Scheme 3) was
conveniently carried out by chiral HPLC (Chiracel (OD),
9:1 isopropanol–hexane, 1 mL/min) to afford (þ)-aza-
calanolide A (þ)-2 {[a]D¼þ50.7 (c 2.2, CHCl3)} and
(2)-aza-calanolide A (2)-2 {[a]D¼248.4 (c 1.65,
CHCl3)}. The absolute stereochemistry was defined based
on the correlation of their sign of rotation with those of
natural calanolides.3 The spectral data of (þ)-2 and (2)-2
were in agreement with the structures assigned.
1.1.2. 1,2-Dihydro-5,7-dimethoxy-4-n-propyl-2-quinoli-
none (5). Compound 4 (19 g, 71.69 mmol) was cooled to
08C, Conc. H2SO4 (88.298 g, 901 mmol) added dropwise
for 10 min and allowed to raise to room temperature over a
period of 30 min. After completion of the reaction (TLC,
hexane–EtOAc, 1:1, Rf¼0.3) it was poured into water
(200 mL) and the solid which separated was filtered, washed
with water to a neutral pH and dried under vacuum to give
product 1,2-dihydro-5,7-dimethoxy-4-n-propyl-2-quinoli-
none 5 (15.93 g) in 90% yield as a white solid, mp 193–
1968C; nmax (Neat) 1670, 1625, 1605 cm21;dH (200 MHz,
CDCl3þDMSO-d6) 1.00 (t, 3H, J¼6.3 Hz, CH2CH3), 1.54–
1.74 (m, 2H, CH2CH2), 2.90 (t, 2H, J¼6.3 Hz, CH2CH2),
3.80 (s, 3H, –OCH3), 3.90 (s, 3H, –OCH3), 6.15 (s, 1H, H-
3), 6.22 (s, 1H, H-6), 6.50 (s, 1H, H-8), 11.70 (br.s, 1H, NH);
m/z (EI) 247 (Mþ, 95), 230 (22), 219 (44), 204 (100%);
HRMS: found 247. 1219. C14H17NO3 requires 247. 1208.
Compound (^)-2 was evaluated12,13 for anti-HIV reverse
transcriptase activity using CEM-SS cell line at a maximum
concentration of 100 mM. The assay basically involves the
killing of T-4 lymphocytes by HIV. The EC50 value of (^)-
2 (0.12 mM) is much lower than that of the natural product
(þ)-1 (0.27 mM). Similarly, the IC50 values for (^)-2 and
(þ)-1 are IC50¼15 and IC50¼23, respectively. The EC50
and IC50 values infer that (^)-2 is active and cytotoxic at
lesser concentrations when compared to (þ)-1. Thus, the
higher therapeutic index value observed for (^)-aza-
calanolide (2) (TI¼126) over naturally occurring (þ)
calanolide A 1 (TI¼82) indicates that (þ)-2 could certainly
be a better choice for further pre-clinical development.
In conclusion, a new class of synthetic NNRTI, e.g. aza-
calanolide A (2), has been synthesized evaluated and
optically resolved. Its enhanced anti-HIV activity compared
to the natural product calanolide A has been demonstrated.
The detailed synthetic work on other analogues of aza-
calanolides and their anti-HIV activity will be dealt with
separately.
1.1.3. 8,9-Dimethyl-5-hydroxy-4-n-propyl-1,8,9,10-tetra-
hydro-2H-pyrano[2,3-h]quinolin-2,10-dione (7). To a
stirred solution of 5 (12 g, 48.58 mmol) in chlorobenzene
(100 mL), was added aluminium chloride (25.8 g,
195.45 mmol) in portions over a period of 10 min. and
heated at 1008C for 12 h (TLC, chloroform–methanol, 9:1,
Rf¼0.2). The reaction mixture was cooled to room
temperature, poured on crushed ice (300 g) and stirred
well for 30 min. The solid precipitate was filtered, washed
with water to a neutral pH then washed with hexane (50 mL)
and dried at 608C for 1 h to give 1,2-dihydro-5,7-dihydroxy-
4-n-propyl-2-quinolinone 6 (10.32 g) in 97% yield as a dark
brown solid, mp (3008C; nmax (KBr): 3280, 3220, 3140,
1. Experimental
1.1. General
1650 cm21
.
1.1.1. 1N-(3,5-Dimethoxyphenyl)-3-oxo-hexanamide (4).
A
solution of 3, 5-dimethoxy aniline (3; 14.15 g,
A mixture of the above crude 6 (7.0 g, 31.96 mmol), AlCl3
(21.60 g, 162 mmol) and CS2 (140 mL) was taken in a
500 mL round bottom flask equipped with a mechanical
stirrer and a reflux condenser. The reaction mixture was
heated at 508C for 30 min. Nitrobenzene (45 mL) was added
dropwise in 30 min. and stirred for additional 30 min. to get
a homogeneous mixture. Tigloyl chloride (4.621 g,
92.48 mmol) in xylene (50 mL) was heated at 1308C
under nitrogen atmosphere and treated with 2,2-dimethyl-
6-n-propyl-4H-1,3-dioxin-4-one (17.3 g, 101.7 mmol) drop-
wise for 25 min. After 6 h, the reaction mixture was cooled
to 508C and xylene removed under vacuum and the residue
obtained was purified by column chromatography (silica gel
hexane–EtOAc, 4:1) to give 1N-(3,5-dimethoxyphenyl)-3-

98
G. V. M. Sharma et al. / Tetrahedron 59 (2003) 95–99
39 mmol) in nitrobenzene (20 mL) was added dropwise in
30 min and stirred at 508C for 48 h. The reaction mixture
was cooled to room temperature after completion of
reaction (TLC, chloroform–MeOH, 9:1, Rf¼0.4), poured
on crushed ice (500 g) and stirred for 30 min. The solid
separated was filtered and washed with water till neutral to
pH. It was dried under vacuum to get the compound, which
was used as such for next reaction.
yield as a syrupy liquid. dH (200 MHz, CDCl3) 1.05 (t,
3H, J¼7.3 Hz, CH2CH3), 1.22 (d, 3H, J¼6.1 Hz, CHCH3),
1.50 (d, 3H, J¼6.1 Hz, CHCH3), 1.60 (s, 3H, CH3), 1.62 (s,
3H, CH3), 1.63–1.69 (m, 2H, CH2CH2), 2.60–2.74 (m, 1H,
J¼3.4, 6.0 Hz, H-7), 2.95 (t, 2H, J¼8.1 Hz, CH2CH2),
4.60–4.75 (m, 1H, J¼3.0, 6.2 Hz, H-6), 5.55 (d, 1H,
J¼10.2 Hz, H-3), 6.28 (s, 1H, H-11), 6.64 (d, 1H,
J¼10.2 Hz, H-4), 12.9 (br. s, 1H, NH); m/z (EI) 367 (Mþ,
22); HRMS: found: 367.1766. C22H25NO4 requires
367.1783.
A dispersion of the above crude solid in chloroform
(150 mL) was treated with triethylamine (4.97 mL, 3.61 g,
35.7 mmol) and stirred at room temperature for 12 h. The
reaction mixture was filtered and residue was extracted with
hot chloroform (3£200 mL). Combined chloroform extracts
were evaporated and the residue was purified by column
chromatography (silica gel, chloroform–methanol, 9:1) to
afford 8,9-dimethyl-5-hydroxy-4-n-propyl-1,8,9,10-tetra-
hydro-2H-pyrano[2,3-h]quinolin-2,10-dione 7 (2.212 g) in
23% yield as a solid, mp 295–2968C; nmax (Neat): 3425,
2958, 2920, 2860, 1595 cm21; dH (200 MHz, CDCl3þ
DMSO-d6) 1.00 (t, 3H, J¼7.2 Hz, CH2CH3), 1.16–1.30 (m,
3H, CHCH3), 1.44 (d, 1.2H, J¼6.5 Hz, CHCH3), 1.52 (d,
1.8H, J¼6.7 Hz, CHCH3), 1.60–1.68 (m, 2H, CH2CH2),
2.50–2.70 (m, 1H, H-9), 2.95 (t, 2H, J¼6.3 Hz, CH2CH2),
4.20–4.38 (m, 0.6H, J¼6.4 Hz, 11.4 Hz, H-8), 4.62–4.78
(m, 0.4H, J¼3.4 Hz, 6.2 Hz, H-8), 6.12 (s, 1H, H-3), 6.20
(s, 1H, H-6), 11.32 (br. s, 1H, OH), 12.88 (br. s, 1H, NH);
m/z (EI) 301 (Mþ, 46), 286 (15), 273 (41), 245 (12), 217
(15%); HRMS: found 301.1317. C17H19NO4 requires
301.1314.
1.1.5. (6)-8-Hydroxy-12-n-propyl-7,8,9,10-tetrahydro-
2,2,6,7-tetramethyl-2H,6H-dipyrano[2,3-f:2,3-h] quino-
lin-10-one (2). To a solution of compound 8 (0.15 g,
0.408 mmol) in ethanol (3 mL), cooled to 08C, NaBH4
(0.015 g, 0.408 mmol) was added and the reaction mixture
allowed to raise to room temperature over a period of 1 h.
After completion of reaction (TLC, hexane–EtOAc, 6:4,
Rf¼0.2)), water (2 mL) was added and extracted with
EtOAc (3£5 mL). The combined organic layers were
successively washed with water (4 mL), brine (4 mL),
dried (Na2SO4) and evaporated. The residue was subjected
to chromatographic purification (silica gel, hexane–EtOAc,
1:8) to afford product (^)-8-hydroxy-12-n-propyl-7,8,9,10-
tetrahydro-2,2,6,7-tetramethyl-2H,6H-dipyrano[2,3-f:2,3-
h]quinolin-10-one 2 (0.117 g) in 78% yield as a white solid,
mp 164–1668C; nmax (neat): 3250, 2988, 2945, 2875,
1660 cm21; dH (200 MHz, CDCl3) 1.0 (t, 3H, J¼7.3 Hz,
CH2CH3), 1.19 (d, 3H, J¼6.6 Hz, CHCH3), 1.45–1.52 (br.
s, 9H, J¼7.1 Hz, 3CH3), 1.50–1.70 (m, 2H, CH2CH2), 2.0–
2.15 (m, 1H, H-7), 2.80–3.05 (m, 2H, CH2 CH2), 3.88–4.04
(m, 1H, J¼6.4, 11.2 Hz, H-6), 4.59 (d, 1H, J¼9.0 Hz, H-8),
5.49 (d, 1H, J¼9.9 Hz, H-3), 6.10 (s, 1H, H-11), 6.63 (d, 1H,
J¼9.9 Hz, H-4); m/z (EI) 352 (Mþ2OH, 17), 351
(Mþ2H2O, 17), 336 (100), 284 (10%); HRMS: found:
369.1922. C22H27NO4 requires 369.1940.
1.1.4. (6)-12-n-Propyl-7,8,9,10-tetrahydro-2,2,6,7-tetra-
methyl-2H,6H-dipyrano[2,3-f:2,3-h]quinoline-8,10-
dione (8 trans and 9 cis). To a solution of 7 (2.0 g,
6.64 mmol) in mixture of 2-butanone-DMF (35 mL, 9:1),
3-chloro-3-methyl-1-butyne (3.40 g, 33.2 mmol), K2CO3
(2.292 g, 16.6 mmol), n-Bu4NþI- (2.45 g, 6.63 mmol) and
ZnCl2 (1.128 g, 8.27 mmol) were added sequentially and
heated at 708C for 12 h (TLC, hexane–EtOAc, 7:3, Rf¼0.4).
It was cooled to room temperature, water (20 mL) added
and 2-butanone was evaporated under reduced pressure. The
residue was extracted with EtOAc (3£30 mL) and combined
organic layers were washed with water (20 mL), dried
(Na2SO4) and evaporated. The residue obtained was purified
through column chromatography (silica gel, finer than
200 mesh, hexane–EtOAc, 4:1) first to afford (^)-trans-12-
n-propyl-7,8,9,10-tetrahydro-2,2,6,7-tetramethyl-2H,6H-
dipyrano[2,3-f:2,3-h]quinoline-8,10-dione 8 (0.67 g) in
27.5% yield as a white solid, mp 120–1218C; nmax (KBr):
3180, 2986, 2963, 2892, 1690, 1664 cm21; dH (200 MHz,
CDCl3) 1.04 (t, 3H, J¼7.1 Hz, CH2CH3), 1.22 (d, 3H,
J¼6.9 Hz, CHCH3), 1.54 (s, 3H, CH3), 1.58 (s, 3H, CH3),
1.69–1.78 (m, 5H, CHCH3 and CH2CH2), 2.50–2.65 (m,
1H, J¼6.9 Hz, 11.1 Hz, H-7), 2.91 (t, 2H, J¼6.9 Hz,
CH2CH2), 4.20–4.40 (dq, 1H, J¼6.3, 11.1 Hz, H-6), 5.55
(d, 1H, J¼10.1 Hz, H-3), 6.24 (s, 1H, H-11), 6.62 (d, 1H,
J¼10.1 Hz, H-4), 12.95 (br. s, 1H, NH); m/z (EI) 367 (Mþ,
22), 352 (100), 296 (39%); HRMS: found: 367.1767.
C22H25NO4 requires 367.1783.
1.1.6. (6)-8-Hydroxy-12-n-propyl-7,8,9,10-tetrahydro-
2,2,6,7-tetramethyl-2H,6H-dipyrano [2,3-f:2,3-h] quino-
lin-10-one (2 and 10). A solution of 8 (0.1 g, 0.272 mmol)
and CeCl3·7H2O (0.202 g, 0.54 mmol) in ethanol (5 mL)
was stirred at room temperature for 2 h. The reaction
mixture was cooled to 2308C, NaBH4 (0.01 g, 0.272 mmol)
was added and stirred for 10 h (TLC, hexane–EtOAc, 3:2,
Rf¼0.2). The reaction mixture was allowed to rise to room
temperature, quenched with water (3 mL) and extracted
with ethyl acetate (3£5 mL). Combined organic layers were
washed with brine (5 mL), dried (Na2SO4) and evaporated
to get a gummy residue. The residue was purified by column
chromatography (silica gel, finer than 200 mesh, hexane–
EtOAc, 3:7) first to give 10 (0.006 g) in 6% yield, as a solid,
m. p. 183–1858C; dH (200 MHz, CDCl3) 1.02 (t, 3H,
J¼7.3 Hz, CH2CH3), 1.20 (d, 3H, J¼6.5 Hz, CHCH3),
1.35–1.59 (m, 9H, 3CH3), 1.60–1.78 (m, 3H, CH2CH2 and
H-7), 2.90–3.08 (m, 2H, CH2CH2), 4.18–4.30 (m, 1H,
J¼10.5, 6.2 Hz, H-6), 4.78 (d, 1H, J¼3.1 Hz, H-8), 5.49 (d,
1H, J¼9.8 Hz, H-3), 6.18 (s, 1H, H-11), 6.64 (d, 1H,
J¼9.9 Hz, H-4), 11.55 (br. s, 1H, NH); HRMS: found:
369.1923. C22H27NO4 requires 369.1940.
Second eluted was compound (^)-cis-12-n-propyl-
7,8,9,10-tetrahydro-2,2,6,7-tetramethyl-2H,6H-dipyrano-
[2,3-f:2,3-h]quinoline-8,10-dione 9 (0.356 g) in 14.6%
Second eluted was compound 2 (0.047 g) in 46.7% yield,
which was identical in all respect with the material prepared
in the earlier experiment.

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99
II., J. H.; McMahon, J. B.; Currens, M. J.; Buckheit, Jr. R. W.;
Hughes, S. H.; Cragg, G. M.; Boyd, M. R. J. Med. Chem. 1992,
35, 2735–2743. (b) Patil, A. D.; Freyer, A. J.; Eggleston, D. S.;
Haltiwagner, R. C.; Bean, M. F.; Taylor, P. B.; Caranfa, M. J.;
Breen, A. L.; Bartus, H. R.; Johnson, R. K.; Hertzberg, R. P.;
Westley, J. W. J. Med. Chem. 1993, 36, 4131–4138. (c) Kling,
J. Modern Drug Discovery 1999, 2(6), 31–36.
1.1.7. (6)-8-Hydroxy-12-n-propyl-7,8,9,10-tetrahydro-
2,2,6,7-tetramethyl-2H,6H-dipyrano [2,3-f:2,3-h] quino-
lin-10-one (11). Compound 9 (0.15 g, 0.408 mmol) in
ethanol (3 mL) was treated with NaBH4 (0.015 g,
0.408 mmol) for a period of 1 h. Worked up and purified
as described for 2 to afford 11 (0.11 g) in 73% yield as a
white solid, mp 185–1888C; dH (200 MHz, CDCl3) 1.05 (t,
3H, J¼7.2 Hz, CH2CH3), 1.12 (d, 3H, J¼6.5 Hz, CHCH3),
1.42 (d, 3H, J¼6.5 Hz, CHCH3), 1.46 (s, 3H, CH3), 1.48 (s,
3H, CH3), 1.64–1.68 (m, 2H, CH2CH2), 2.35–2.4 (m, 1H,
H-7), 2.95–3.08 (m, 2H, CH2CH2), 4.30–4.42 (m, 1H,
J¼3.0, 6.1 Hz, H-6), 5.34 (d, 1H, J¼7.6 Hz, H-8), 5.47 (d,
1H, J¼10.0 Hz, H-3), 6.19 (s, 1H, H-11), 6.62 (d, 1H,
J¼10.0 Hz, H-4); HRMS: found: 369.1923. C22H27NO4
requires 369.1940.
4. Zembower, D. E.; Liao, S.; Flavin, M. T.; Xu, Z. Q.; Stup,
T. L.; Buckheit, Jr. R. W.; Khilevich, A.; Mar, A. A.;
Sheinkman, A. K. J. Med. Chem. 1997, 40, 1005–1017.
5. Xu, Z. Q.; Buckheit, Jr. R. W.; Stup, T. L.; Flavin, M. T.; Liao,
S.; Khilevich, A.; Rizzo, J. D.; Lin, L.; Zembower, D. E.
Bioorg. Med. Chem. Lett. 1998, 8, 2179–2183.
6. Newman, R. A.; Chen, W.; Madden, T. L. J. Pharm. Sci. 1998,
87, 1077–1080.
7. Avendano, C. E de la Cuesta; Gesto, C. Synthesis 1991,
727–730.
Acknowledgements
8. Sato, M.; Ogasawara, H.; Komatsu, S.; Kato, T. Chem. Pharm.
Bull. 1984, 32, 3848–3856.
Authors wish to thank DST, New Delhi and the Government
of USA for the award of PL-480 scheme.
9. Sato, M.; Ogasawara, H.; Oi, K.; Kato, T. Chem. Pharm. Bull.
1983, 31, 1896–1901.
10. (a) Chenera, B.; West, M. L.; Finkelstein, J. A.; Dreyer, G. B.
J. Org. Chem. 1993, 58, 5605–5606. (b) Pedersen, O. S.;
Pedersen, E. B. Synthesis 2000, 479–495.
References
11. Germal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 34,
5454–5459.
1. Barre-Sinoussi, F.; Chermann, J. C.; Rey, F.; Chameret, M. T.;
Guruest, J.; Dauguet, C.; Axler-Blin, C.; Veinet-Brun, F.;
Rouzioux, C.; Rosenbaum, W.; Montaigner, L. Science 1983,
220, 868–871.
12. Weislo, O. W.; Kiser, R.; Fine, D.; Bader, J.; Shoemaker,
R. H.; Boyd, M. R. J. Natl Cancer Inst. 1989, 81, 586.
13. Gurjar, M. K.; Sharma, G. V. M.; Ilangovan, A.; Narayanan,
V. L.; Indian Patent Application No. 1441/DEL/98; US Patent
6,191,279, 2001.
2. De Clerq, E. J. Med. Chem. 1995, 38, 2491–2517.
3. (a) Kashman, Y.; Gustafson, K. R.; Fuller, R. W.; Cardellina,