Hydroxyacyl derivatives of forskolin - Their positive inotropic activity

Article abstract of DOI:10.1016/S0968-0896(98)00123-0

Using appropriate protection and deprotection sequence novel hydroxyacyl chains of the type CO(CH₂)(n)OH are synthesized and are utilized to develop new analogues of forskolin. Several compounds showed good positive inotropic activity. Compound

Full text of DOI:10.1016/S0968-0896(98)00123-0

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 2061±2073
Hydroxyacyl Derivatives of ForskolinÐtheir Positive
Inotropic Activity
Bansi Lal,a,* Ashok Kumar Gangopadhyay,a Ramanujam Rajagopalanb,y
and Anil Vasantrao Ghateb
aDepartment of Chemistry, Research Centre, Hoechst Marion Roussel Limited, Mulund (W), Mumbai 400 080, India
bDepartment of Pharmacology, Research Centre, Hoechst Marion Roussel Limited, Mulund (W), Mumbai 400 080, India
Received 2 March 1998; accepted 16 June 1998
AbstractÐUsing appropriate protection and deprotection sequence novel hydroxyacyl chains of the type CO(CH2)nOH
are synthesized and are utilized to develop new analogues of forskolin. Several compounds showed good positive ino-
tropic activity. Compound 12 is almost 10 times more active than forskolin (EC50=0.002 mg/ml).]. # 1998 Elsevier
Science Ltd. All rights reserved.
Introduction
modi®cation at 6b position through 7b to 6b acyl
migration step. Direct modi®cation at 6b position was
rather dicult due to steric hindrance. It was decided to
modify the acetyl group of forskolin to hydroxyacyl
functionality of the type CO(CH2)nOH, in which the
hydroxyl group was incorporated in the terminal pos-
ition with a varying chain length. The main assumption
was that when this group was attached at the 7b pos-
ition it may retain or enhance the activity of forskolin,
and further allow subsequent derivatization in a regio-
selective manner due to the presence of a more reactive
primary OH group. Secondly, when migrated to 6b
position, it could act as a new `spacer' for subsequent
modi®cation at 6b.
Forskolin, a polyhydroxylated labdane diterpenoid was
isolated from Coleus forskolii.1 It exhibited interesting
biological properties such as positive inotropic, anti-
hypertensive, lowering of intraoccular pressure and
adenylate cyclase activator activities.2 Our involvement
on forskolin was to improve its positive inotropic activity.
Earlier observation on forskolin derivatization indicated
following SAR status: (a) importance of free 1a-OH and
9a-OH groups,3 (b) replacement of 7b-acetyl group by
various other amino acyl chains lead to water soluble
derivatives without loss of activity,4 (c) substitution of
acyl group at 6b-position which is achieved through the
migration of 7b-acyl group to 6b position in both alka-
line as well as acidic conditions,5,6 not only retains but,
in several cases, enhances the activity of forskolin
molecule.4
This paper reports the chemistry and SAR on the
introduction of a number of novel hydroxyacyl chain in
the forskolin molecule.
Results and Discussion
Chemistry
In order to improve the positive inotropic activity of
forskolin molecule we were looking for acyl `spacer'
which are novel and also wanted to exploit the chemical
Our initial task was to devise a synthetic route for OH-
protected acid chain in such a fashion that when
required the deprotection could be achieved under mild
condition without disturbing 7b-acetyl group. Thus we
chose p-methoxybenzyl group for OH protection which
could be removed by mild treatment with DDQ without
disturbing acyl function as reported in the literature.7
Key words: Forskolin; 2-hydroxyacetyl; positive inotropic
activity.
*Corresponding author. Tel: +91 22 564 0748; fax: +91 22 564
1953; e-mail: bansilal@hoechstres.rpgms.ems.vsnl.net.in
yPresent address: Department of Pharmacology, Dr. Reddy's
Research Foundation, Bollaram Road Miyapur, Hyderabad-
500138, India.
0968-0896/98/$ - see front matter # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00123-0

2062
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
Hence the required p-methoxybenzyloxyacetic acid was
prepared by reacting ethyl bromoacetate with p-meth-
oxybenzyl alcohol in presence of NaH followed by
alkaline hydrolysis (see Experimental).
from 2a, 2b and 6 by treatment with DDQ in a dichloro-
methane±water system7 to obtain compounds 9, 5 and
13, respectively. Thus the above method enabled us to
introduce hydroxyacetyl chain in the forskolin skeleton
at 7b-, 6b-, and 1a,7b-positions corresponding to the
compounds 9, 13 and 5. In a similar fashion ethoxy and
phenoxy acetyl chains were introduced using the
required acid as shown in Scheme 1.
7-Deacetyl forskolin (1)1,5b was reacted with p-methoxy-
benzyloxy acetic acid in presence of DCC±DMAP to
give 7b-acyl substituted product 2a with a small amount
of diacyl substituted product 2b. When 2a was treated
with diluted NaOH in acetonitrile (pHꢀ8.5) 6b-acyl
derivative 6 was obtained in 42% yield. During the
migration reaction, partial hydrolysis of acyl chain also
occurred. The p-methoxybenzyl group was removed
Another alternative approach to introduce hydroxy-
acetyl at the 7b-position was attempted as shown in
Scheme 1. The compound 1 was treated with bromo-
acetyl bromide and pyridine in dichloromethane at 0 ꢁC
Scheme 1. 1. DCC, DMAP, EtOAc; 2. DDQ, CH2Cl2, H2O; 3. lN NaOH, CH3CN, H2O; 4. BrCH2COBr, pyridine, CH2Cl2, 0 ꢁC; 5.
Sodium formate, HMPA; 6. Neutral alumina, MeOH, CH2Cl2.

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
2063
to obtain 7b-bromoacetyl 11a and 1a,7b-dibromoacetyl
11b derivatives, respectively, as reported earlier.5b,8
When 11a and 11b were treated with sodium formate in
HMPA9 in separate reactions, the corresponding for-
mate derivatives 12 and 16 were formed, which were
puri®ed by silica gel ¯ash column chromatography.
Subsequently these compounds were passed through
neutral alumina9 in order to generate 7b-hydroxyacetyl
and 1a,7b-bis(hydroxyacetyl) derivatives. To our sur-
prise, in both the cases the resultant hydroxyacetyl chain
had migrated from 7b- to 6b-position exclusively, lead-
ing to the formation of 6b-hydroxyacetyl-7b-deacetyl
forskolin (13) and 1a,6b-bis(hydroxyacetyl)-7b-deacetyl
forskolin (17), respectively. This transformation clearly
indicated that even neutral alumina was enough to e€ect
the migration of the acyl group. Although it was not an
intended result, however, it was found to be an excellent
method to introduce hydroxyacetyl chain at 6b-position.
Further derivatization of more reactive primary OH
group of compounds 9 and 13 were demonstrated by
converting them into acetyl and/or formyl derivatives
10, 14 and 15 after a coupling reaction with acetic acid
or formic acid in presence of DCC and DMAP (Scheme
1) in a regioselective manner.
The synthetic strategy for the introduction of b-hydroxy-
propanoyl chain is outlined in Scheme 2. The OH
group of 3-hydroxypropionic acid was protected by
t-butyldimethylsilyl (TBDMS) group. The required acid
was prepared from propionolactone by a ring opening
reaction with NaOMe under anhydrous condition
followed by silylation in situ with TBDMS-Cl and
imidazole.10 The isolated ester was hydrolyzed with
1N NaOH in methanol to provide the required
Scheme 2. 1. NaOMe; 2. TBDMS-Cl, imidazole; 3. lN NaOH, MeOH; 4. DCC, DMAP, EtOAc; 5. 1M nBu4N+F , THF; 6. PTSA,
MeOH.

2064
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
TBDMS-protected hydroxypropionic acid chain which
was used without further puri®cation. The crude acid
was reacted with 1 in presence of DCC and DMAP to
yield 7b-(3-tertbutyldimethylsilyloxypropanoyloxy)-7b-
deacetyl forskolin (18). The TBDMS-group from 18 was
removed by DDQ-water in dichloromethane,7 to obtain
1a-t-butyldimethylsilyloxy-6b-hydroxy-acetylforskolin
(30). The TBDMS-group from 30 was removed by
10
nBu4N+F
in THF to obtain the required compound
31 in which the hydroxyacetyl chain was in 6b-position
of forskolin. Further derivatization on primary hydroxy
group at 6b-position was demonstrated by the reaction
of 31 with AcOH and formic acid separately in presence
of DCC and DMAP to obtain the corresponding acetyl
(32) and formyl (33) derivatives, respectively, in excel-
lent yield. None of the analogues were found to be
soluble in water.
10
removed with the use of nBu4N+F- in THF with the
formation of 7b-(3-hydroxypropanoyloxy)-7b-deacetyl
forskolin (19a) in ꢀ50% yield, also 6b acyl migration
product 19b in 10% yield and a small amount of
hydrolysis product 1 were also isolated.
Another novel chain, 2,3-dihydroxypropionic acid was
introduced in its optically pure form. The corresponding
optically pure R- and S-form of acetonide protected
acids were prepared from mannitol11,12 and l-ascorbic
acid,12,13 respectively, according to the reported proce-
dure. These two acids were separately reacted with 1 by
DCC-DMAP method as shown in Scheme 2 with the
formation of compounds 20 and 21, respectively. The
deprotection of the acetonide was best achieved with the
use of p-toluene sulfonic acid in methanol14 leading to
the formation of 7b-(R)-(2,3-dihydroxypropanoyloxy)-
7b-deacetyl forskolin (22a), with a small amount of acyl
migrated product 22b from the starting material 20.
Biological activity
The blood pressure lowering activity of forskolin deri-
vatives was evaluated by intravenous administration to
anaesthetized normotensive cats. The positive inotropic
activity of forskolin analogues was tested in sponta-
neously beating isolated guinea pig atrial preparation.
The minimum concentration of the compound required
to obtain an increase in the force of contraction by 50%
(EC50) was determined and compared with forskolin.
The experimental details for the evaluation of biological
activity could be found in an earlier publication.16
Similarly
7b-(S)-(2,3-dihydroxypropanoyloxy)-7b-de-
acetyl forskolin (23) was also prepared starting from 21.
While we had completed our synthesis of both R- and S-
isomers, a paper appeared in the literature which
described the synthesis and adenylate cyclase stimulat-
ing activity of R-isomer, however S-isomer was not
reported in the publication.15
The results of blood pressure lowering activity and
positive inotropic activity are summarized in Table 1.
Some of the intermediates were also tested to obtain
some SAR correlation.
All the compounds reported here failed to show better
blood pressure lowering activity in comparison to for-
skolin. Particularly when the 1a-OH group was func-
tionalized, complete loss of activity was observed in
conformity with the earlier results by others.3 Substitu-
tion of hydroxy acyl chain at 7b-position (viz. 9, 19a,
22a, 23) or at 6b-position (13, 31) showed relatively
better blood pressure lowering activity. Introduction of
alkoxy acyl group at 7b- or 6b-positions (viz. 2a, 3a, 4,
6±8), 3-silyloxypropanoyl (18) and acetonide protected
(R) or (S)-2,3-dihydroxypropanoyl (20, 21) failed to
show desired level of blood pressure lowering or positive
inotropic activity. Incorporation of hydroxyacetyl chain
at 7b-position (9), 6b-position (13) of deacetyl forskolin
and substitution of hydroxy acetyl chain at 6b-position
of forskolin (31) lead to improved positive inotropic
activities, viz. EC50=1.0 mg/ml, 0.72 mg/ml and
EC50=0.16 mg/ml, respectively, However when the
terminal OH-group in the chain of these compounds 9,
13 and 31 were converted into formyl and/or acetyl
derivatives such as 10, 12, 14, 15, 32 and 33 interesting
positive inotropic activity resulted. Except two com-
pounds 14 and 15, the remaining four, showed sig-
ni®cant increase in positive inotropic activity. While
compound 32 (EC50=0.16 mg/ml) was eight times less
In order to introduce the hydroxyacetyl chain at the 1a-
position, the p-methoxybenzyloxyacetic acid was reac-
ted with forskolin as described earlier (Scheme 3) fol-
lowed by deprotection of p-methoxybenzyl-group with
DDQ-water in dichloro-methane. The required com-
pound 25 was obtained in good yield.
We next targeted our attention to keep the 7b-acetyl
group of forskolin intact and introduce hydroxyacetyl
chain at 6b-position. To achieve our objective, we
adopted the synthetic strategy as shown in Scheme 3.
1a-t-Butyldimethylsilyloxy-7b-deacetyl forskolin (26)4
was converted into 1a-t-butyldimethylsilyloxy-7b-p-
methoxybenzyloxy acetyl derivative 27 in high yield.
The protected group was then migrated to 6b- position
to obtain compound 28 in 60±70% yield after treating
27 with aqueous NaOH in acetonitrile (pHꢀ8.5) for
30 min. The unreacted starting material and some
amount of hydrolyzed product formed during the reac-
tion could be recycled in the ®rst step. The compound
28 was reacted with AcOH in presence of DCC and
DMAP to give 1a-t-butyldimethylsilyloxy-6b-p-meth-
oxybenzyloxy-acetylforskolin (29) in near quantitative
yield. The p-methoxybenzyl-protecting group was

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
2065
active than forskolin (EC50=0.02 mg/ml), the remaining
three compounds 10, 12 and 33 were found to be 2.5-fold
(EC50=0.008 mg/ml), 10-fold (EC50=0.002 mg/ml) and
twofold (EC50=0.01 mg/ml) more active than forskolin,
respectively.
group at 2-position which means additional polarity)
further improved the positive inotropic activity (22a;
EC50=0.065 mg/ml) when compared with hydroxyacetyl
derivative (9; EC50=1.0 mg/ml) and 3-hydroxy-
propanoyl derivative (19a; inactive). On the other hand
the incorporation of (S)-2,3-dihydroxypropanoyl chain
at 7b-position (23) had less potency (EC50= 0.22 mg/ml)
and at 6b-position (22b), the compound did not show
any activity.
The increase of chain length at 7b-position (19a) and at
6b-position (19b) lead to loss of activity. Introduction of
(R)-2,3-dihydroxypropanoyl chain (i.e. additional OH
Scheme 3. 1. DCC, DMAP, EtOAc; 2. DDQ, CH2Cl2, H2O; 3. TBDMS-Cl, imidazole; 4. lN NaOH, MeOH; 5. 1N NaOH, CH3CN,
H2O; 6. 1M nBu4N+
in THF, THF.
F

2066
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
Table 1. Biological activity of forskolin derivatives
In short, we have synthesized novel compounds with
superior positive inotropic activity than parent forskolin
molecule.
Compound
no.
EC50
(GP atrium)
BP lowering activity (cat)*
(mg/mL)
Dose (iv) Fall in BP Duration
(mg/kg) (mm of Hg) (in min)
Experimental
General procedures
2a
2b
3a
3b
4
NA
NA
10
10
30
30
>90
10
Melting points were determined with a Ko¯er hot stage
apparatus and are uncorrected. IR spectra were deter-
mined with a Perkin±Elmer 157 Spectrophotometer as
>10
NA
Ð
Ð
Ð
Ð
Ð
Ð
Ð
10
10
60
20
>60
60
1
KBr ®lm unless otherwise mentioned. H NMR spectra
5
NA
3.7
were recorded in CDCl3 unless otherwise mentioned on
a Jeol FT-90 Spectrometer with TMS as internal stan-
dard, chemical shift values were expressed in d and
coupling constant values are expressed in Hz. The four
protons corresponding to 2a-H, 2b-H, 3a-H and 3b-H
positions of forskolin appears at d 1.43 (doublet of
quartets), 2.17 (triplet of dd), 1.77 (triplet of doublets)
and 1.10 (doublet of triplets), respectively, in 270 MHz
1H NMR spectrum. However in routine 90 MHz 1H
NMR spectrum of forskolin and its derivatives, the sig-
nals of 2-H and 3-H are hidden under the strong methyl
peaks and are not correctly recognized. Therefore we
have not included the assignment of these peaks in the
experimental section. Petroleum ether refers to the
fraction of b.p. 60±80 ꢁC. For ¯ash column chromatog-
raphy silica gel (®ner than 0.08 mm particle size) was
used. Precoated (silica gel 60 F254) TLC plates were used
for checking purity of compounds. Vaniline-50%
orthophosphoric acid or anisaldehide-H2SO4 spray
reagent were used and heated the plates at 110 ꢁC for
visualization. All compounds were homogeneous on
TLC and gave proper spectral characteristics.
6
Ð
Ð
Ð
Ð
Ð
7
3.7
NA
Ð
Ð
Ð
Ð
8
9
1.0
0.5
1.0
0.3
3.0
Ð
60
90
55
60
60
10
12
13
14
15
16
17
18
19a
19b
20
22a
22b
23
25
30
31
32
33
Forskolin
0.008
0.002
0.72
NA
>120
60
20
Ð
Ð
Ð
Ð
1.0
Ð
Ð
Ð
Ð
Weak activity
NA
Ð
NA
3.0
1.0
3.0
0.1
1.0
10
20
110
100
40
>120
NA
>120
>120
60
>30
0.14
0.065
>30
0.22
NA
70
90
>180
180
50
0.3
NA
10
60
Ð
NA
Ð
NA
NA
120
Ð
0.16
0.16
0.01
0.02
0.3
Ð
50
Ð
Ð
Ð
0.1
Ð
55.0‹3.9
63.7‹5.5
p-Methoxybenzyloxy acetic acid. Sodium hydride (55±
65% in oil; 20 g; ꢀ0.5 mol) was washed with dry toluene
(3Â50 mL) and then suspended in dry dioxane
(1000 mL). To this suspension p-methoxybenzyl alcohol
(68 g; 0.5 mol) was slowly added (1 h) under stirring at
room temperature. Stirring continued until the evolution
of H2 ceased. Ethyl bromoacetate (55 mL; 0.5 mol) was
added dropwise at 0 ꢁC (1 h). After the addition was
over the reaction mixture was slowly brought to room
temperature and stirring was continued for 16 h. The
reaction mixture was diluted with EtOAc (1500 mL) and
slowly poured over crushed ice (ꢀ2 kg) containing
ammonium chloride (50 g). The ethyl acetate layer was
separated and washed with brine. It was dried over
anhydrous Na2SO4. Solvent was removed and the resi-
due was dried in a vacuum pump for 3 h. The crude
ester was dissolved in methanol (1500 mL) and 1N
NaOH (500 mL; 0.5 mol) was added. The mixture was
stirred for 1 h at room temperature. Methanol was
removed under reduced pressure. The residue was dilu-
ted with water (500 mL) and was extracted with EtOAc
(3Â50 mL). The aqueous layer was acidi®ed with dilute
NA, not active; Ð not done.
*No signi®cant e€ect below the dose mentioned.
Conclusion
We have achieved the target of introducing a `spacer'
hydroxyacetyl/acyl chain at di€erent positions of for-
skolin skeleton such as 1a-position (25), 6b-position (31)
of forskolin molecule and 6b-position (13), 7b-position
(9), 1a,6b-positions (17), 1a,7b-positions (5) of deacetyl
forskolin. Some of these derivatives, 9, 13 and 31,
showed excellent regioselectivity towards acetylation/
formylation reaction. We have shown that these groups
can be used as a novel pharmacophore since their
introduction in forskolin molecule selectively enhances
the positive inotropic activity without a€ecting too
much the blood pressure lowering activity. When the
terminal OH group of these chains was substituted with
acetyl/formyl group the positive inotropic activity
increased sharply while alkyl substitution did not show
desired activity.

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
2067
HCl. The oily layer separated, was extracted with
EtOAc. The organic layer was washed with brine, dried
over anhydrous Na2SO4. Solvent was removed. It was
crystallized from light petroleum containing trace
amount of EtOAc and kept in a freezer overnight.
Yield: 68.6 g (70%); m.p. 54±56 ꢁC; IR (KBr): 3500 (br),
Compounds 3a and 3b were prepared from 1 and ethoxy
acetic acid by the same method and the products were
puri®ed by ¯ash chromatography with 10% CH3CN±
CHCl3.
8,13-Epoxy-7ꢀ-ethoxyacetoxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-
14-en-11-one (3a). Yield: 76.23%, m.p. 165±166 ꢁC
(EtOAc±light petroleum); IR (KBr): 3540, 3440 (br),
1
1772, 1750, 1628, 1530 cm 1; H NMR (60 MHz): 3.74
(s, 3H, OCH3), 4.32 (s, 2H, OCH2COOH), 4.75 (s, 2H,
OCH2Ph), 6.85 (d, 2H, J=8.6, Ar H3,5), 7.35 (d, 2H,
J=8.6, ArH 2,6), 9.75 (br, 1H, COOH, exchangeable);
Anal. calcd for C10H12O4: C, 61.21; H, 6.17. Found: C,
61.19; H, 6.10%.
1
2950 (br), 1730 (br), 1710 cm
;
1H NMR: 1.03, 1.24
(2Âs, 6H, 2ÂCH3), 1.24 (t, 3H, J=7.5 CH2CH3), 1.31,
1.43, 1.70 (3Âs, 9H, 3ÂCH3), 2.19 (d, 1H, J=2.54, 5H),
2.44 (d, 1H, Jgem=17.2, 12bH), 2.87 (br, 1H, exchange-
able OH), 3.16 (d, 1H, Jgem=17.21, 12aH), 3.60 (quar-
tet, 2H, J=7.5, CH2CH3), 4.13 (s, 2H, COCH2OEt),
4.40±4.57 (m, 2H, 1H and 6H), 4.91 (dd, 1H, Jcis=10.13,
Jgem=1.6, 15Hcis), 5.21 (dd, 1H, Jtrans=17.2, Jgem=1.6,
15Htrans), 5.51 (d, 1H, J=4.05, 7H), 5.90 (dd, 1H,
Jtrans=17.2 Jcis=10.13, 14H). Anal. calcd for C24H38O8:
C, 63.41; H, 8.43. Found: C, 63.43; H, 8.33%.
8,13-Epoxy-7ꢀ-[(4-methoxybenzyloxy)acetoxy]-1ꢁ,6ꢀ,9ꢁ-
trihydroxylabd-14-en-11-one (2a) and 1ꢁ,7ꢀ,-bis[(4-
methoxybenzyloxy)acetoxy]-6ꢀ,9ꢁ-dihydroxy-8,13-epoxy
labd-14-en-11-one (2b). Deacetyl forskolin 1 (7.36 g;
20 mmol) and DCC (5.15 g; 25 mmol) were dissolved in
EtOAc (90 mL). A solution of p-methoxybenzyloxy
acetic acid (4.31 g; 22 mmol) in EtOAc (10 mL) was
added slowly followed by DMAP (2.4 g; 20 mmol). The
mixture was stirred at room temperature for 3 h. DCU
was ®ltered o€. The ®ltrate was transferred into a
separating funnel and washed successively with water
and brine. The EtOAc layer was dried over anhydrous
Na2SO4 and the solvent was removed under reduced
pressure. The residue was puri®ed by ¯ash chromato-
graphy on silica gel with 2.5% CH3CN±CHCl3. Com-
pound 2a was eluted ®rst, followed by the compound
2b. 2a. Yield: 10 g (91.4%); m.p. 96 ꢁC (EtOAC±light
petroleum). IR (KBr): 3470, 3310. 1762, 1740, 1715,
1ꢁ,7ꢀ-Bis-ethoxyacetoxy-6ꢀ,9ꢁ-dihydroxy-8,13-epoxy-
labd-14-en-11-one (3b). Yield: 11%, m.p. 138 ꢁC (EtOAc±
light petroleum); IR (KBr): 3490, 2970, 2930, 1750 (br),
1720, 1670 (br) cm 1; 1H NMR: 1.04 (s, 3H, CH3), 1.12±
1.33 (m, 14H, 2ÂCH3, 2ÂCH2CH3,CH2), 1.52, 1.69
(2Âs, 6H, 2ÂCH3), 2.26 (d, 1H, J=2.6, 5H), 2.36 (d, 1H,
Jgem=16.2, 12bH), 3.08 (d, 1H, Jgem=16.2, 12aH),
3.34±3.71 (m, 4H, 2ÂCH2CH3), 3.93 (s, 2H, 1a-OCO-
CH2OEt), 4.14 (s, 2H, 7b-OCOCH2OEt), 4.47 (t, 1H,
J=3.54, 6H), 4.84 (dd, 1H, Jcis=10, Jgem=1.62. 15Hcis),
5.15 (dd, 1H, Jtrans=17.2, Jgem=1.62, 15 Htrans), 5.46
(br, 1H, 1H), 5.58 (d, 1H, J=4.05, 7H), 5.87 (dd, 1H,
Jtrans=17.2, Jcis=10, 14H). Anal. calcd for C28H45O11:
C, 62.13; H, 8.38. Found: C, 62.18; H, 8.18%.
1
1613 cm 1; H NMR: 1.03, 1.24, 1.31, 1.43, 1.70 (5Âs,
15H, 5ÂCH3), 2.18 (d, 1H, J=2.54, 5H), 2.42 (d, 1H,
Jgem=17.21, 12bH), 3.18 (d, 1H, Jgem=17.21, 12aH),
3.76 (s, 3H, OCH3), 4.11 (s, 2H, COCH2O-), 4.37±4.56
(m, 2H, 1H and 6H), 4.57 (s, 2H, O-CH2-Ar), 4.93 (dd,
1H, Jcis=10.18, Jgem=1.5, 15Hcis), 5.24 (dd, 1H,
Jtrans=17.21, Jgem=1.5, 15Htrans), 5.53 (d, 1H, J=4.05,
7H), 5.91 (dd, 1H, Jtrans=17.21, Jcis=10.18, 14H), 6.81
(d, 2H, J=8.6, Ar H3,5), 7.23 (d, 2H, J=8.6, ArH 2,6).
Anal. calcd for C30H42O9: C, 65.91; H, 7.75. Found: C,
65.71; H, 8.26%.
8,13-Epoxy-7ꢀ-phenoxyacetoxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-
14-en-11-one (4). The compound 4 was also prepared
by this method after reacting 1 with phenoxy acetic acid.
The crude product obtained after workup was puri®ed
by ¯ash chromatography with 10% CH3CN/CHCl3.
Yield: 82.2%; m.p. 179 ꢁC (EtOAc±light petroleum). IR
(KBr): 3520 (br), 2950 (br), 1760, 1730, 1510, 1220
1
(br) cm
;
1H NMR: 1.0, 1.20, 1.26, 1.39, 1.56 (5Âs,
2b, Yield: 0.46 g (3.1%), oil; IR (neat): 3408, 2941, 1724,
1
15H, 5ÂCH3), 2.15 (d, 1H, J=2.54, 5H), 2.40 (d, 1H,
Jgem=17.2, 12bH), 3.16 (d, 1H, Jgem=17.2, 12 aH), 4.33
(t, 1H, J=3.04, 6H), 4.49 (br, 1H, 1H), 4.71 (s, 2H,
1695, 1600 cm 1. H NMR: 1.03, 1.26, 1.30, 1.53, 1.70
(5Âs, 15H, 5ÂCH3), 2.25 (d, J=3.04, 5H), 2.36 (d, 1H,
Jgem=17.2, 12bH), 3.09 (d, 1H, Jgem=17.2, 12aH), 3.79
(s, 6H, 2ÂOCH3), 3.91 (s, 2H, 1a-OCOCH2-), 4.14 (s,
2H, 7b-OCOCH2), 4.47±4.60 (m, 5H, 2ÂCH2-Ar+6H),
4.89 (dd, 1H, Jcis=11.14, Jgem=1.6, 15Hcis), 5.19 (dd,
1H, Jtrans=17.2, Jgem=1.6, 15 H trans), 5.51 (br, 1H,
1H), 5.62 (d, 1H, J=4.0, 7H), 5.89 (dd, 1H, Jtrans=17.2,
Jcis=11.14, 14 H), 6.64 (d, 4H, J=8.1, 2ÂArH3,5), 7.23,
7.25 (2Âd, 4H, J=8.1, 2ÂAr-H2,6). Anal. calcd for
C40H52O12: C, 66.28; H, 7.23. Found: C, 66.75; H,
7.42%.
OCOCH2O), 4.91 (dd, 1H, Jcis=10.1, Jgem=2.0, 15 Hcis
)
5.21 (dd, 1H, Jtrans=17.2, Jgem=2.0, 15Htrans), 5.53 (d,
1H, J=4.05, 7H), 5.89 (dd, 1H, Jtrans=17.2, Jcis=10.1
14H), 6.80±7.30 (m, 5H, 5ÂPhH). Anal. calcd for
C28H38O8: C, 66.91; H, 7.62. Found: C, 67.22; H, 7.65%.
1ꢁ,7ꢀ-Bis-hydroxyacetyloxy-6ꢀ,9ꢁ-dihydroxy-8,13-epoxy-
labd-14-en-11-one (5). Compound 2b (2.0 g; 2.75 mmol)
was dissolved in a heterogenous mixture of dichloro-
methane (144 mL) and water (8 mL). To this soln,

2068
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
DDQ (2.27 g; 10 mmol) was added and the reaction
mixture was stirred vigorously at room temperature for
16 h. The reaction mixture was transferred into a separ-
ating funnel and shaken well with 5% aq sodium
dithionate till the colour of organic layer became light
pink. The dichloromethane layer was successfully
washed with water and brine. It was dried over anhy-
drous Na2SO4 and the solvent was evaporated. The
residue was puri®ed by ¯ash chromatography with 20%
CH3CN/CHCl3. Yield: 0.98 g (73.7%); m.p. 102±104 ꢁC.
IR (KBr): 3490 (br), 2950 (br), 1755, 1745 (br),
2.33 (d, 1H, J=2.5, 5H), 2.48 (d, 1H, Jgem=17.2,
12bH), 3.17 (d, 1H, Jgem=17.2, 12aH), 3.56 (quartet,
2H, J=7.09, CH2CH3), 4.06 (s, 2H, COCH2-OEt), 4.25
(d, 1H, J=4.56, 7H), 4.95 (dd, 1H, Jcis=10.13,
Jgem=1.1, 15Hcis), 5.14 (dd, 1H, Jtrans=17.21, Jgem=1.1,
15Htrans), 5.89 (t, 1H, J=2.54, 6H), 6.80 (dd, 1H,
Jtrans=17.21, Jcis=10.13, 14H). Anal. calcd for
C24H38O8: C, 63.41; H, 8.42. Found: C, 63.64; H, 8.55%.
8,13-Epoxy-6ꢀ-phenoxyacetoxy-1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-
14-en-11-one (8). The compound 8 was prepared as
described for the synthesis of 6. The reaction time was
20 min. After workup the crude product was puri®ed by
¯ash chromatography with 10% CH3CN/CHCl3. Yield:
32%; m.p. 180±182 ꢁC (EtOAc-light petroleum); IR
(KBr): 3490 (br), 2970, 1750, 1725, 1610, 1505 cm 1; 1H
NMR: 0.96, 1.09, 1.36, 1.39, 1.53 (5Âs, 15H, 5ÂCH3),
2.34 (d, 1H, J=2.54, 5H), 2.46 (d, 1H, Jgem=17.2,
12bH), 3.16 (d, 1H, Jgem=17.2, 12aH), 4.26 (d, 1H,
J=4.56, 7H), 4.63 (br, 3H, 1H and COCH2OPh), 4.94
(dd, 1H, Jcis=10.13, Jgem=1.02, 15Hcis), 5.12 (dd, 1H,
Jtrans=17.21, Jgem 1.02, 15Htrans), 5.94 (t, 1H, J=2.54,
6H), 6.06 (dd, 1H, Jtrans=17.21, Jcis=10.13, 14H), 6.77±
7.29 (m, 5H, 5ÂArH). Anal. calcd for C28H38O8: C,
67.91; H, 7.62. Found: C, 67.62; H, 7.38%.
1
1715 cm 1; H NMR: 1.04, 1.27, 1.33, 1.52, 1.71 (5Âs,
15H, 5ÂCH3), 2.21 (d, 1H, J=2.54, 5H), 2.45 (d, 1H,
J=17.2, 12bH), 3.04 (d, 1H, Jgem=17.2, 12aH), 4.02 (s,
2H, 1a-OCOCH2OH), 4.23 (s, 2H, 7b-OCOCH2OH),
4.46 (t, 1H, J=3.54, 6H), 4.94 (dd, 1H, Jcis=10.13,
Jgem=1.52, 15Hcis), 5.19 (dd, 1H, Jtrans=17.2,
Jgem=1.52, 15Htrans), 5.45 (d, 1H, J=4.05, 7H), 5.60
(br, 1H, 1H), 5.84 (dd, 1H, Jtrans=17.21, Jcis=10.13;
14H). Anal. calcd for C24H36O10,1/2 H2O: C, 58.40; H,
7.56. Found: C,58.38; H, 7.95%.
8,13-Epoxy-6ꢀ-[(4-methoxybenzyloxy)acetoxy]-1ꢁ,7ꢀ,9ꢁ-
trihydroxylabd-14-en-11-one (6). To a solution of com-
pound 2a (0.17 g; 1.3 mmol) in acetonitrile (26 mL) and
water (32 mL), 1N NaOH (2.3 mL; 2.3 mmol) was
added. The mixture was stirred for 20 min. Acetonitrile
was removed under reduced pressure after neutralizing
the reaction mixture with diluted HCl. The oil separated
was extracted with ethyl acetate. The EtOAc layer was
washed successively with water and brine. The solvent
was removed after drying over anhydrous Na2SO4. The
crude product thus obtained was puri®ed by ¯ash chro-
matography over silica gel with 5% CH3CN±CHCl3.
8,13-Epoxy-7ꢀ-hydroxyacetoxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-
14-en-11-one (9). Compound 2a (12 g; 22 mmol) was
dissolved in a heterogenous mixture of dichloromethane
(810 mL) and water (45 mL). To the vigorously stirred
soln at room temperature, DDQ (6.09 g; 26.4 mmol) was
added. The reaction mixture was stirred at room tem-
perature for 16 h. The solid was ®ltered o€ and the ®l-
trate was washed with 5% aq. soln of sodium dithionate
until the organic layer was almost colourless. It was
washed with brine and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure. The resi-
due was puri®ed by ¯ash chromatography over silica gel
with 30% EtOAc±light petroleum. The product was
®nally crystallized from hot EtOAc±light petroleum.
Yield: 0.3 g (42.2%), oil; IR (neat): 3420 (br), 2950,
1
2870, 1710 (br) 1650 cm
;
1H NMR: 0.97, 1.09, 1.37,
1.40, 1.56 (5Âs, 15H, 5ÂCH3), 2.36 (d, 1H, J=2.5, 5H),
2.45 (d, 1H, J=17.2, 12bH), 3.19 (d, 1H, Jgem=17.2,
12aH), 3.79 (s, 3H, OCH3), 4.06 (s, 2H, OCOCH2-O),
4.29 (d, 1H, J=4.05, 7H), 4.56 (br, 1H, 1H), 4.61 (s, 2H,
OCH2Ph), 4.96 (dd, 1H, Jcis=10.13, Jgem=1.6, 15Hcis),
5.14 (d, 1H, Jtrans=17.2, Jgem=1.6, 15Htrans), 5.91 (br,
1H, 6H), 6.11 (dd, 1H, Jtrans=17.2, Jcis=10.13, 14H),
6.84 (d, 2H, J=8.1, Ar-H3,5), 7.26 (d, 2H, J=8.1 Ar-H
2,6). Anal. calcd for C30H42O9: C, 65.91; H, 7.45. Found:
C, 66.02; H, 7.61%.
Yield: 6.8 g (72.5%); m.p. 189 ꢁC; IR (KBr): 3535, 3430,
1
3290, 1730, 1698 cm 1; H NMR: 1.04, 1.25, 1.33, 1.44,
1.69 (5Âs, 15H, 5ÂCH3), 2.18 (d, 1H, J=2.54, 5H), 2.46
(d, 1H, Jgem=16.7, 12bH), 3.20 (d, 1H, Jgem=16.7,
12aH), 4.23 (s, 2H, COCH2OH), 4.37±4.63 (m, 2H, 1H
and 6H), 4.93 (dd, 1H, Jcis=10.13, Jgem=1.01, 15Hcis),
5.21 (dd, 1H, Jtrans=17.2, Jgem=1.01, 15Htrans), 5.56 (d,
1H, J=4.05, 7H), 5.93 (dd, 1H, Jtrans=17.21,
Jcis=10.13; 14H). Anal. calcd for C22H34O8,H2O: C,
59.44; H, 8.09. Found: C, 59.91; H, 8.20%.
8,13-Epoxy-6ꢀ-ethoxyacetoxy-1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-
14-en-11-one (7). This compound was prepared from 3a
according to the method described for the synthesis of 6.
The reaction time was 30 min and the crude product was
puri®ed by ¯ash chromatography over silica gel with
10% CH3CN/CHCl3. Yield: 28.33% (semi solid); IR
(KBr): 3470 (br), 3000, 2960, 1770, 1750, 1055 cm 1; 1H
NMR: 0.97, 1.08 (2Âs, 6H, 2ÂCH3), 1.22 (t, 3H,
J=7.09, CH2CH3), 1.40, 1.41, 1.60 (3Âs, 9H, 3ÂCH3),
7ꢀ-Acetoxyacetoxy-8,13-epoxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-
14-en-11-one (10). To a well-stirred soln of compound 9
(0.424 g; 1 mmol) and DCC (0.23 g; 1.1 mmol) in EtOAc
(15 mL), AcOH (0.07 mL; 1.22 mmol) in EtOAc (1 mL)

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
2069
was added followed by DMAP (0.12 g; 1 mmol). The
reaction mixture was stirred for 3 h at room tempera-
ture. The DCU was ®ltered o€ and the ®ltrate was
washed with brine. The EtOAc layer was dried over
anhydrous Na2SO4. The solvent was removed under
reduced pressure. The residue was crystallized from
EtOAc±light petroleum. Yield: 0.44 g (94.5%); m.p.
5.45 (d, 1H, J=4.05, 7H), 5.92 (dd, 1H, Jtrans=17.21,
Jcis=10.63; 14H), 8.11 (s, 2H, 2ÂOCH). Anal. calcd for
C26H36O12: C, 57.87; H, 6.71. Found: C, 58.15; H,
6.68%.
8,13-Epoxy-6ꢀ-hydroxyacetoxy-1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-
14-en-11-one (13). The compound 12 (0.2 g; 0.44 mmol)
was dissolved in 1% MeOH±CH2Cl2 (20 mL) and was
passed through a column of neutral alumina (20 g). The
column was eluted with 5% MeOH±CH2Cl2. All the
fractions containing the product were evaporated to
dryness. The crude product thus obtained was puri®ed
by ¯ash chromatography over silica gel with 20%
CH3CN±CHCl3. It was ®nally crystallized from EtOAc±
142±143 ꢁC; IR (KBr): 3548, 3470, 2940 (br), 1760, 1730
1
(br), 1705 cm
;
1H NMR: 1.03, 1.25, 1.34, 1.42, 1.69
(5Âs, 15H, 5ÂCH3) 2.16 (br, 4H, COCH3+5H), 2.44
(d, 1H, Jgem=16.7, 12bH), 3.19 (d, 1H, Jgem=16.71,
12aH), 4.44±4.60 (m, 2H, 1H and 6H), 4.64 (s, 2H,
COCH2OAc), 4.93 (dd, 1H, Jcis=10.13, Jgem=2.03,
15Hcis), 5.19 (dd, 1H, Jtrans=17.21, Jgem=2.03,
15HJtrans), 5.41 (d, 1H, J=4.05, 7H), 5.94 (dd, 1H,
Jtrans=17.21, Jcis=10.13; 14H). Anal. calcd for
C24H36O9: C, 61.52; H, 7.75. Found: C, 61.71; H, 7.63%.
light petroleum. Yield: 0.15 g (80%); m.p. 221±223 ꢁC;
1
IR (KBr): 3500, 3440 (br), 2940, 1755, 1705, 1400 cm
;
1H NMR (CDCl3+CD3OD): 0.94, 1.06, 1.36, 1.40, 1.53
(5Âs, 15H, 5ÂCH3), 2.34 (d, 1H, J=3.04, 5H), 2.40 (d,
1H, Jgem=16.2, 12bH), 3.24 (d, 1H, Jgem=16.2, 12aH),
4.11 (br, 2H, OCOCH2OH), 4.27 (d, 1H, J=4.56, 7H),
4.49 (br, 1H, 1H), 4.93 (dd, 1H, Jcis=10.6, Jgem=1.01,
15Hcis), 5.11 (dd, 1H, Jtrans=17.2, Jgem= 1.01, 15Htrans),
5.87 (dd, 1H, J=4.56 and 2.54, 6H), 6.11 (dd, 1H,
Jtrans=17.2, Jcis=10.6, 14H). Anal. calcd for C22H34O8:
C, 61.95; H, 8.03. Found: C, 62.27; H, 7.92%.
8,13-Epoxy-7ꢀ-formyloxyacetoxy-1ꢁ,6ꢀ,9ꢁ-trihydroxy-
labd-14-en-11-one (12). To a soln of compound 11a5b
(0.5 g; 1 mmol) in HMPA (6 mL, freshly distilled over
CaH2), dry sodium formate (0.136 g; 2 mmol) was added
under dry N2. The reaction mixture was stirred at room
temperature for 16 h. It was diluted with ether
(ꢀ100 mL) and quickly washed with cold water followed
by brine. The organic layer was dried over anhydrous
Na2SO4. The solvent was removed under reduced pres-
sure. The crude product was puri®ed by ¯ash chroma-
tography with 5% CH3CN±CHCl3. The pure product
was ®nally crystallized from hot EtOAc±light petroleum.
1ꢁ,6ꢀ-Bis-hydroxyacetoxy-7ꢀ,9ꢁ-dihydroxy-8,13-epoxy-
labd-14-en-11-one (17). The above mentioned method
was utilized to prepare compound 17. The crude prod-
uct was puri®ed by ¯ash chromatography over silica gel
with 20% CH3CN±CHCl3 followed by crystallization
from CHCl3±light petroleum. Yield: 67%; m.p. 121±
Yield: 0.435 g (94.5%); m.p. 199±201 ꢁC; IR (KBr):
1
3510, 3440, 3280, 2970, 1740, 1730, 1705 cm
;
1H
NMR: 1.03, 1.26, 1.35, 1.43, 1.69 (5Âs,15H, 5ÂCH3),
2.17 (d, 1H, J=2.54, 5H), 2.43 (d, 1H, Jgem=17.21,
12bH), 3.18 (d, 1H, Jgem=17.21, 12aH), 4.44±4.57 (m,
2H, 1H and 6H), 4.75 (s, 2H, CH2OCOH), 4.91 (dd, 1H,
Jcis=10.63, Jgem=1.62, 15Hcis), 5.18 (dd, 1H,
Jtrans=17.21, Jgem=1.62, 15Htrans), 5.45 (d, 1H,
J=4.05, 7H), 5.93 (dd, 1H, Jtrans=17.21, Jcis=10.63,
14H), 8.11 (s, 1H, ±CHO). Anal. calcd for C23H34O9: C,
60.78; H, 7.54. Found: C, 60.38; H, 7.36%.
123 ꢁC; IR (KBr): 3450 (br), 2920 (br), 1730 (br),
1
1705 cm
;
1H NMR (CDCl3+CD3OD): 0.98, 1.09,
1.41, 1.47, 1.58 (5Â15H, 5ÂCH3), 2.42 (d, 1H, J=2.6,
5H), 2.43 (d, 1H, Jgem=16.61, 12bH), 3.13 (d, 1H,
Jgem=16.61, 12aH), 4.03±4.12 (2Âs, 4H, COCH2OH),
4.23 (d, 1H, J=4.56, 7H), 4.96 (dd, 1H, Jcis=10.13,
Jgem=2.03, 15Hcis), 5.15 (dd, 1H, Jtrans=16.41,
Jgem=2.03, 15Htrans), 5.51 (br, 1H, 1H), 5.87 (t, 1H,
J=3.5, 6H), 6.04 (dd, 1H, Jtrans=16.41, Jcis=10.13,
14H). Anal. calcd for C24H36O10: C, 59.49; H, 7.49.
Found: C, 59.01; H, 7.28%.
1ꢁ, 7ꢀ-Bis -formyloxyacetoxy-6ꢀ, 9ꢁ -dihydroxy-8,13-
epoxylabd-14-en-11-one (16). The compound was pre-
pared from 11b by the above mentioned method. The
molar ratio of 11b to sodium formate was 1:4. After the
workup, the crude product was puri®ed by ¯ash chro-
matography over silica gel with 30% EtOAc±light pet-
roleum. Yield: 94.3%, m.p. 159 ꢁC (EtOAc±light
petroleum); IR (KBr): 3530, 3410, 2920, 1770, 1745,
6ꢀ-Acetoxyacetoxy-8,13-epoxy-1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-
14-en-11-one (14). This compound was prepared from
13 by the method similar to the synthesis of compound
10 as described earlier. The crude product was puri®ed
by crystallization from EtOAc±light petroleum. Yield:
89.3%; m.p. 173±175 ꢁC; IR (KBr): 3479, 2940 (br),
1
1
1710, 1415 cm 1; H NMR: 1.03, 1.25, 1.34, 1.42, 1.69
1785, 1750 (br), 1730 cm 1; H NMR: 1.01, 1.09, 1.40,
(5Âs, 15H, 5ÂCH3), 2.16 (d, 1H, J=2.54, 5H), 2.43 (d,
1H, Jgem=17.21, 12bH), 3.18 (d, 1H, Jgem=17.21,
12aH), 4.40±4.62 (br, 2H, 1H and 6H), 4.74 (s, 2H,
COCH2O±), 4.81 (dd, 1H, Jcis=10.13, Jgem=1.5,
15Hcis), 5.17 (dd, 1H, Jtrans=17.21, Jgem=1.5, 15Htrans),
1.42, 1.60 (5Âs, 15H, 5ÂCH3), 2.14 (s, 3H, ±COCH3),
2.36 (d, 1H, J=3.04, 5H), 2.49 (d, 1H, Jgem=17.2,
12bH), 3.19 (d, 1H, Jgem=17.2, 12aH), 4.28 (d, 1H,
J=4.05, 7H), 4.60 (s, 3H, COCH2OAc+1H), 4.95 (dd,
1H, Jcis=10.13, Jgem=1.5, 15Hcis), 5.14 (dd, 1H,

2070
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
Jtrans=17.21, Jgem=1.5, 15Htrans), 5.90 (dd, 1H,
J=3.04, 4.05, 6H). 6.08 (dd, 1H, Jtrans=17.21,
Jcis=10.13; 14H). Anal. calcd for C24H36O9: C, 61.52;
H, 7.75. Found: C, 61.61; H, 7.69%.
4.51 (m, 2H, 1H and 6H), 4.84 (dd, 1H, Jcis=10.63,
Jgem=2.03, 15Hcis), 5.11 (dd, 1H, Jtrans=17.21,
Jgem=2.03, 15Htrans), 5.22 (d, 1H, J=4.05, 7H), 5.86
(dd, 1H, Jtrans=17.21, Jcis=10.63, 14H). Anal. calcd for
C29H49O8Si: C, 62.78; H, 9.09. Found: C, 63.48; H,
9.12%.
6ꢀ-Formyloxyacetoxy-8,13-epoxy-1ꢁ,7ꢀ,9ꢁ-trihydroxy-
labd-14-en-11-one (15). Compound 15 was prepared
from compound 13 and formic acid using DCC method
as described for the synthesis of compound 10. Yield:
86.8%, m.p. 160±161 ꢁC; IR (KBr): 3555, 3455, 2990,
8,13-Epoxy-7ꢀ-(3-hydroxypropanoyloxy)-1ꢁ,6ꢀ,9ꢁ-tri-
hydroxylabd-14-en-11-one (19a) and 8,13-epoxy-6ꢀ-(3-
hydroxypropanoyloxy)-1ꢁ,7ꢀ,9ꢁ-trihydroxylabd-14-en-
11-one (19b). To a soln of compound 18a (1.4 g;
2.52 mmol) in freshly distilled THF (over LAH)
(60 mL), 1M nBu4N+F in THF (3 mL, 3 mmol) was
added at room temperature. The reaction mixture was
stirred at room temperature for 15 min. Solvent was
removed under reduced pressure and the residue was
quickly puri®ed by ¯ash chromatography over silica gel
with 10% CH3CN±CHCl3. The compound 19a was
eluted ®rst, followed by compound 19b.
1
1785, 1773, 1750 1710 cm 1; H NMR: 1.03, 1.11, 1.41,
1.43, 1.61 (5Âs, 15H, 5ÂCH3), 2.37 (d, 1H, J=3.04,
5H), 2.51 (d, 1H, Jgem=17.2, 12bH), 3.19 (d, 1H,
Jgem=17.2, 12aH), 4.30 (d, 1H, J=4.05, 7H), 4.66 (br,
1H, 1H), 4.76 (s, 2H, COCH2O), 4.97 (dd, 1H,
Jcis=10.13, Jgem=1.01, 15Hcis), 5.16 (dd, 1H,
Jtrans=17.2, Jgem=1.01, 15Htrans), 5.97 (m, 1H, 6H),
6.11 (dd, 1H, Jtrans=17.2, Jcis=10.13, 14H), 8.14 (s, 1H,
O±CHO). Anal. calcd for C23H34O9: C, 60.78; H, 7.54.
Found: C, 61.07; H, 7.67%.
19a. Yield: 0.53 g (47.8%); m.p. 165 ꢁC (EtOAc-light
petroleum); IR (KBr): 3440, 3290, 2895, 1735,
8,13-Epoxy-7ꢀ-(3-tertiarybutyldimethylsilyloxy)propanoyl-
oxy-1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (18). Propio-
lactone (12.6 g; 175 mmol) in dry DMF (20 mL) was
added to a well-stirred suspension of NaOMe (12.8 g;
237 mmol) in DMF (130 mL) at 0 ꢁC. After the addition
was over, the mixture was stirred at room temperature
for 1 h. Tertiarybutyldimethylsilyl chloride (30 g;
196 mmol) and imidazole (5 g) were added and the stir-
ring was continued overnight. The solvent (DMF) was
distilled and the residue was taken up in ether. The
ethereal layer was washed with cold diluted HCl fol-
lowed by brine. The solvent was removed and the resi-
due was dissolved in MeOH (330 mL). 1N NaOH
(110 mL, 110 mmol) was added at room temperature
and stirring was continued for 1 h. Methanol was
removed under reduced pressure and the residue was
extracted with ether (2Â50 mL). The aqueous layer was
acidi®ed with cold diluted HCl. The oily residue was
extracted with ether and washed with brine. The ethe-
real layer was dried over anhydrous Na2SO4. The sol-
vent was removed to give chromatographically pure 3-
tertiarybutyl dimethylsilyloxypropionic acid.
1
1695 cm 1; H NMR: 1.04, 1.25, 1.36, 1.44, 1.74 (5Âs,
15H, 5ÂCH3), 2.12 (d, 1H, J=3.04, 5H), 2.43 (d, 1H,
Jgem=16.7, 12bH), 2.64 (t, 2H, J=6.08, COCH2CH2),
3.21 (d, 1H, Jgem=16.7, 12aH), 3.90 (t, 2H, J=6.08,
OCOCH2CH2±OH), 4.47±4.60 (br, 2H, 1H and 6H),
4.93 (dd, 1H, Jcis=10.13, Jgem=2.03, 15Hcis), 5.18 (dd,
1H, Jtrans=17.2, Jgem=2.03, 15Htrans), 5.41 (d, 1H,
J=4.05, 7H)), 5.96 (dd, 1H, Jtrans=17.21, Jcis=10.13;
14H). Anal. calcd for C23H36O8: C, 62.71; H, 8.24.
Found: C, 62.54; H, 8.03%.
19b. Yield: 0.12 g (10.8%), m.p. 204±206 ꢁC (EtOAc-
light petroleum); IR (KBr): 3400 (br), 2950, 1745, 1715
1
(br) cm
;
1H NMR: 1.0, 1.11, 1.40, 1.41, 1.62 (5Âs,
15H, 5ÂCH3), 2.36 (d, 1H, J=5.04, 5H), 2.48 (d, 1H,
Jgem=17.2, 12bH), 2.58 (t, 2H, J=5.60, ±COCH2
CH2OH), 3.20 (d, 1H, Jgem=17.2, 12aH), 3.89 (t, 2H,
J=5.60, ±COCH2CH2OH), 4.29 (d, 1H, J=5.06, 7H),
4.63 (br, 1H, 1H), 4.96 (dd, 1H, Jcis=10.1, Jgem=1.6;
15Hcis), 5.14 (dd, 1H, Jtrans=17.2, Jgem=1.6, 15Htrans),
5.91 (t, 1H, J=2.5, 6H), 6.09 (dd, 1H, Jtrans=17.2,
Jcis=10.1, 14H). Anal. calcd for C23H36O8: C, 62.71; H,
8.24. Found: C, 62.63; H, 7.98%.
The compound 1 was treated with the above acid in the
presence of DCC±DMAP in EtOAc as described for the
preparation of 2a. The crude material was puri®ed by
¯ash chromatography over silica gel with 5% CH3CN±
CHCl3. Yield: 45%; m.p. 150±153 ꢁC. (from light pet-
roleum with a trace of EtOAc). IR (KBr), 3460, 2960,
2930, 1715, 1705 cm 1; 1H NMR: 0.08 [s, 6H, Si(CH3)2],
0.89 [(s, 9H, SiC(CH3)3], 1.01, 1.24, 1.37, 1.43, 1.73
(5Âs, 15H, 5ÂCH3), 1.60 (s, 1H, OH exchangable), 2.16
(d, 1H, J=3.04, 5H), 2.35 (d, 1H, Jgem=16.71, 12bH),
7ꢀ-[(R)-2,3-O-Isopropylidinopropanoyloxy]-8,13-epoxy-
1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (20). This com-
pound was prepared from compound 1 and (R)-2,3-O-
isopropilidino propionic acid by DCC method as
described for the synthesis of compound 18. The crude
product was puri®ed by ¯ash chromatography over
silica gel with 10% CH3CN±CHCl3. Yield: 55%, m.p.
173±175 ꢁC (EtOAc±light petroleum); IR (KBr): 3500,
3200, 2990, 1745, 1735, 1720 cm 1; 1H NMR: 1.03, 1.26,
1.31, 1.41, 1.44, 1.52, 1.74 (7Âs, 21H, 7ÂCH3), 2.17 (d,
.
2.51 (t, 2H, J=5.06, COCH2 CH2±), 3.09 (d, 1H,
Jgem=16.71, 12aH), 3.83, (m, 2H, CH2±CH2±OSi), 4.27-

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
2071
1H, J=3.04, 5H), 2.41 (d, 1H, Jgem =16.7, 12bH), 3.17
(d, 1H, Jgem=16.7, 12aH), 4.06±4.38 (m, 2H, 30-CH2),
4.43±4.73 (m, 3H, 1H, 6H and 20-CH), 4.90 (dd, 1H,
Jcis=10.13, Jgem=2.03, 15Hcis), 5.18 (dd, 1H,
Jtrans=16.71, Jgem=2.03, 15Htrans), 5.51 (d, 1H,
J=4.05, 7H), 5.89 (dd, 1H, Jtrans=16.71, Jcis=10.13,
14H). Anal. calcd for C26H40O9: C, 62.88; H, 8.12.
Found: C, 63.21; H, 8.42%.
7ꢀ-[(S)-2,3-dihydroxypropanoyloxy]-8,13-epoxy-1ꢁ,6ꢀ,9ꢁ-
trihydroxylabd-14-en-11-one (23). The compound was
prepared from crude 21 using the method described
above. Yield: 79.5%, m.p. 191±193 ꢁC (EtOAc±light
petroleum); IR (KBr): 3425 (br), 3300, 2920 (br), 1748,
1
1700, 1655 cm 1; H NMR: 1.03, 1.24, 1.37, 1.43, 1.74
(5Âs, 15H, 5ÂCH3), 2.18 (d, 1H, J=3.04, 5H), 2.40 (d,
1H, Jgem=16.2, 12bH), 3.23 (dd, 1H, Jgem=16.2,
12aH), 3.78, 3.96 (2Âdd, 2H, Jgem=14.11, J2±3=3.04,
±CH2OH), 4.31 (t, 1H, J=3.04, ±CHOH), 4.47±4.60 (m,
2H, 1H and 6H), 4.93 (dd, 1H, Jcis=10.13, Jgem=1.6,
15Hcis), 5.14 (dd, 1H, Jtrans=17.21, Jgem=1.6, 15Htrans),
5.45 (d, 1H, J=4.05, 7H), 5.99 (dd, 1H, Jtrans=17.21,
Jcis=10.13, 14H). Anal. calcd for C23H36O9: C, 60.51;
H, 7.95. Found: C, 60.64; H, 8.13%.
7ꢀ-[(S)-2,3-O-Isopropylidinopropanoyloxy]-8,13-epoxy-
1ꢁ,6ꢀ,9ꢁ-trihydroxylabd-14-en-11-one (21). This com-
pound was prepared from compound 1 and (S)-2,3,-O-
isopropilidinopropionic acid. The crude product was
directly used for deblocking of acetonide ring.
7ꢀ-[(R)-2,3-dihydroxypropanoyloxy]-8,13-epoxy-1ꢁ,6ꢀ,9ꢁ-
trihydroxylabd-14-en-11-one (22a) and 6ꢀ-[(R)-2,3-
dihydroxypropanoyloxy]-8,13-epoxy-1ꢁ,7ꢀ,9ꢁ-trihydroxy-
labd-14-en-11-one (22b). Compound 20 (0.496 g;
1 mmol) was dissolved in methanol (15 mL) and p-
toluene sulfonic acid (0.17 g; 1 mmol) was added at
room temperature. After stirring the reaction mixture
for 2 h, methanol was evaporated under reduced pres-
sure and the residue was taken up in EtOAc. The EtOAc
layer was washed with diluted aq NaHCO3, followed by
brine. Organic layer was dried over anhydrous Na2SO4.
The solvent was removed and the residue was puri®ed
by ¯ash chromatography over silica gel with 20%
CH3CN±CHCl3. Compound 22a was eluted ®rst, fol-
lowed by 22b.
7ꢀ-Acetoxy-6ꢀ,9ꢁ-dihydroxy-8,13-epoxy-1ꢁ-[(4-methoxy-
benzyloxy)acetoxy]labd-14-en-11-one (24). The proce-
dure of getting this compound was the same as described
for the synthesis of 2a. The crude product was puri®ed by
¯ash chromatography over silica gel with 10%,
CH3CN±CHCl3. Yield: 92% (oil); IR (neat): 3490, 2935,
1
1740 (br), 1712, 1615 cm 1; H NMR: 1.04, 1.25, 1.31,
1.53, 1.68 (5Âs, 15H, 5ÂCH3), 2.15 (s, 3H, COCH3),
2.25 (d, 1H, J=2.54, 5H), 2.36 (d, 1H, Jgem=17.2,
12bH), 3.08 (d, 1H, Jgem=17.2, 12bH), 3.76 (s, 3H,
OCH3), 3.89 (s, 2H, ±COCH2±O±), 4.45 (br, 3H,
PhCH2O, 6H), 4.85 (dd, 1H, Jcis=10.13, Jgem=1.5,
15Hcis), 5.18 (dd, 1H, Jtrans=17.21, Jgem=1.5, 15Htrans),
5.47±5.51 (m, 2H, 1H and 7H), 5.85 (dd, 1H, Jtrans=17.2,
Jcis=10.13, 14H), 6.82 (d, 2H, J=9.1, ArH3,5), 7.20 (d,
2H, J=9.1, ArH2,6). Anal. calcd for C32H44O10: C, 65.29;
H, 7.53. Found: C, 65.59; H, 7.66%.
22a. Yield: 0.35 g (75.2%); m.p. 166±168 ꢁC (EtOAc±
light petroleum); IR (KBr): 3440 (br), 2940 (br), 1735,
1
1725, 1695 cm 1; H NMR: 0.99, 1.10, 1.40, 1.41, 1.57
(5Âs, 15H, 5ÂCH3), 2.38 (d, 1H, J=3.04, 5H), 2.41(d,
1H, Jgem=16.71, 12bH), 3.24 (d, 1H, Jgem=16.71,
12aH), 3.82 (d, 2H, J=4.05, ±CH2OH), 4.23 (t, 1H,
J=4.05, CH(OH)±CH2), 4.25 (d, 1H, J =4.6, 7H), 4.51
(br, 1H, 1H), 4.94 (dd, 1H, Jcis=10.13, Jgem=1.6,
15Hcis), 5.13 (dd, 1H, Jtrans=17.7, Jgem=1.6, 15Htrans),
5.89 (t, 1H, J=2.5, 6H), 6.09 (dd, 1H, Jtrans=17.7,
Jcis=10.13, 14H). Anal. calcd for C23H36O9,0.5 H2O: C,
59.33; H, 8.01. Found: C, 59.25; H, 8.21%.
7ꢀ-Acetoxy-6ꢀ,9ꢁ-dihydroxy-8,13-epoxy-1ꢁ-hydroxy-
acetoxylabd-14-en-11-one (25). The compound 24 (4.4 g;
6.4 mmol) was dissolved in a heterogenous mixture of
CH2Cl2 (180 mL) and water (10 mL) and DDQ (2.18 g;
9.6 mmol) was added under vigorous stirring conditions.
The reaction mixture was stirred at room temperature
for 5 h. The reaction was worked up in a manner similar
to the synthesis of compound 5. The crude product was
puri®ed by ¯ash chromatography over silica gel with
20% CH3CN±CHCl3. Yield: 2.41 g (83%); m.p. 196 ꢁC
(EtOAc-light petroleum). IR (KBr): 3571, 2899, 1754,
22b. Yield: 0.025 g (5.4%), m.p. 217±219 ꢁC (EtOAc±
light petroleum). IR (KBr): 3450±3300, 2950, 1735,
1
1709 cm 1; H NMR: 1.05, 1.29, 1.34, 1.54, 1.73 (5Âs,
1
1720 cm
;
1H NMR: 0.99, 1.1, 1.40, 1.41, 1.57 (5Âs,
15H, 5ÂCH3), 2.16 (s, 3H, ±COCH3), 2.19 (d, 1H,
J=2.54, 5H), 2.45 (d, 1H, Jgem=17.2, 12bH), 2.57 (t,
1H, J=5.06, exchangable ±CH2OH), 3.04 (d, 1H,
Jgem=17.2, 12aH), 4.03 (d, 2H, J=5.06, singlet in D2O
exchange, COCH2±OH), 4.39 (t, 1H, J=3.04, 6H), 4.95
(dd, 1H, Jcis=10.13, Jgem =1.01, 15Hcis), 5.23 (dd, 1H,
Jtrans=17.21, Jgem=1.5, 15Htrans), 5.35 (d, 1H, J=4.05,
7H), 5.61 (br, 1H, 1H), 5.83 (dd, 1H, Jtrans=17.21,
Jcis=10.13, 14H). Anal. calcd for C24H36O9: 61.52; H,
7.75. Found: C, 61.76; H, 7.69%.
15H, 5ÂCH3), 2.38 (d, 1H, J=3.04, 5H), 2.41 (dd, 1H,
Jgem =16.71, 12bH), 3.24 (d, 1H, Jgem=16.71, 12aH),
3.82 (d, 2H, J=4.05, ±CH2OH), 4.23 (t, 1H, J=4.05,
CH(OH)±), 4.25 (d, 1H, J=4.6, 7H), 4.51 (br, 1H, 1H),
4.94 (dd, 1H, Jcis=10.13, Jgem=1.62, 15Hcis), 5.13, (dd,
1H, Jtrans=17.7, Jgem=1.62, 15Htrans), 5.89 (t, 1H,
J=2.5, 6H), 6.09 (dd, 1H, Jtrans=17.72, Jcis=10.13,
14H). Anal. calcd for C23H36O9: C, 60.51; H, 7.95.
Found: C, 60.31; H, 8.12%.

2072
B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
1
6ꢀ,9ꢁ-Dihydroxy-8,13-epoxy-7ꢀ-[(4-methoxybenzyloxy)-
acetoxy]-1ꢁ-tertbutyldimethylsilyloxylabd-14-en-11-one
(27). Compound 26 (24.8 g; 51.4 mmol) and 4-methoxy-
benzyloxyacetic acid (11.1 g, 56.6 mmol) were coupled
together with DCC (13.03 g; 63.3 mmol) and DMAP
(6.27 g; 51.4 mmol) in a manner similar to the synthesis
of 2a. The crude material was puri®ed by ¯ash chroma-
tography over silica gel with 3% CH3CN±CHCl3. Yield:
2940, 1760, 1755, 1718, 1615, 1515 cm ;
1H NMR:
0.06, 0.13 [2Âs, 6H, Si(CH3)2], 0.86 [s, 9H, Si C(CH3)3],
0.93, 1.03, 1.30, 1.39, 1.54 (5Âs, 15H, 5ÂCH3), 2.0 (s,
3H, ±(COCH3), 2.33 (d, 1H, Jgem= 16.2, 12bH), 2.41
(br, 1H, 5H), 3.21 (d, 1H, Jgem=16.2, 12aH), 3.77 (s,
3H, OCH3), 4.03 (s, 2H, OCH2±Ar), 4.51 (s, 2H,
COCH2±), 4.58 (br, 1H, 1H), 4.84 (dd, 1H, Jcis=10.6;
Jgem=1.6, 15Hcis), 5.07 (dd, 1H, Jtrans=17.21,
Jgem=1.6, 15Htrans), 5.57 (d, 1H, J=4.56, 7H), 5.87 (br,
1H, 6H), 5.98 (dd, 1H, Jtrans= 17.21, Jcis= 10.6, 14H),
6.82 (d, 2H, J=8.6, Ar±H3,5), 7.22 (d, 2H, J=8.6,
ArH2,6). Anal. calcd for C38H61O10Si: C, 64.65; H, 8.71.
Found: C, 65.06; H, 8.50%.
33 g (97.3%), oil; IR (neat): 3510 (br), 3310 (br), 2942
1
(br), 1750 (br), 1718, 1615 cm
;
1H NMR: 0.01, 0.13
[2Âs, 6H, Si(CH3)2], 0.86 [s, 9H, SiC(CH3)3], 1.02, 1.23,
1.29, 1.44, 1.63 (5Âs, 15H, 5ÂCH3), 2.2 (d, 1H, J=2.5,
5H), 2.31 (d, 1H, Jgem=16.7, 12bH), 3.22 (d, 1H,
Jgem=16.7, 12(aH), 3.77 (s, 3H, OCH3), 4.11 (s, 2H,
±CH2±Ar(OMe)], 4.57 (br, 3H, COCH2O, 1H), 4.46 (t,
1H, J=3.5, 6H), 4.81 (dd, 1H, Jcis=10.13, Jgem=1.6,
15Hcis), 5.10 (dd, 1H, Jtrans=17.21, Jgem=1.6, 15Htrans),
5.59 (d, 1H, J=4.05, 7H), 5.98 (dd, 1H, Jtrans=17.21,
Jcis=10.13, 14H), 6.82 (d, 2H, J=8.1, ArH3,5), 7.24 (d,
2H, J=8.1, ArH2,6). Anal. calcd for C36H56O9Si: C,
65.42; H, 8.54. Found: C, 65.12; H, 8.82%.
7ꢀ-Acetoxy-8,13-epoxy-9ꢁ-hydroxy-6ꢀ-[(hydroxyacet-
oxy)]-1ꢁ-tertbutyldimethylsilyloxylabd-14-en-11-one (30).
Compound 29 (16.5 g; 22.79 mmol) was dissolved in a
heterogeneous mixture of CH2Cl2, 55 mL) and water
(36.5 mL), DDQ (9.2 g; 40.6 mmol) was added to the
soln with vigorous stirring at room temperature. The
reaction mixture was stirred at room temperature for
16 h. The reaction was worked up in a manner similar to
9 (Scheme 1). The crude product was puri®ed by ¯ash
chromatography over silica gel with 10% CH3CN±
CHCl3. Yield: 12.3 g (92.8%), m.p. 162 ꢁC (EtOAc±light
7ꢀ,9ꢁ-Dihydroxy-8,13-epoxy-6ꢀ-[(4-methoxybenzyloxy)-
acetoxy]-1ꢁ-tertbutyldimethylsilyloxylabd-14-en-11-one
(28). To a soln of 27 (7.5 g; 11.36 mmol) in CH3CN
(190 mL) and water (300 mL), 1N NaOH (20 mL;
20 mmol) was added. The reaction mixture was stirred
at room temperature for 45 min. It was neutralized with
1N HCl and acetonitrile was removed under reduced
pressure. The oil separated was extracted with EtOAc.
The organic layer was washed with water, dried over
anhydrous Na2SO4. The solvent was removed and the
residue was puri®ed by ¯ash chromatography over silica
gel with 15% EtOAc±light petrolium. Yield: 6.5 g
(87%)*, oil (* with varying batch sizes the yield varies
from 60±87%). IR (neat): 3465 (br), 3290 (br), 2940 (br),
petroleum); IR (KBr): 3450, 3320, 2940, 1760, 1715,
1
1705 cm
;
1H NMR: 0.03, 0.14 [2Âs, 6H, Si(CH3)2],
0.86 [s, 9H, SiC(CH3)3], 0.92, 1.02, 1.31, 1.39, 1.52
(5Âs, 15H, 5ÂCH3), 2.0 (s, 3H, ±COCH3), 2.34 (d, 1H,
Jgem=16.2, 12bH), 2.44 (d, 1H, J=2.03, 5H), 3.22 (d,
1H, Jgem=16.2, 12aH), 4.11 (d, 2H, J=4.05,
COCH2OH, singlet after D2O exchange)*, 4.58 (br, 1H,
1H), 4.84 (dd, 1H, Jcis=10.6; Jgem=1.6, 15Hcis), 5.06
(dd, 1H, Jtrans=17.21, Jgem= 1.6, 15Htrans), 5.56 (d, 1H,
J=5.06, 7H), 5.89 (t, 1H, J=2.5, 6H), 5.98 (dd, 1H,
Jtrans=17.21, Jcis=10.6, 14H). Anal. calcd for C24H36O9:
C, 61.54; H, 7.75. Found: C, 61.41; H, 7.68%.
1
1758, 1713, 1612 cm 1; H NMR: 0.03, 0.14 [2Âs, 6H,
Si(CH3)2], 0.87 [s, 9H, SiC(CH3)3], 0.94, 1.07, 1.38, 1.39,
1.51 (5Âs, 15H, 5ÂCH3), 2.36 (d, 1H, J=3.04, 5H), 2.41
(d, 1H, Jgem=17.21, 12bH), 3.21 (d, 1H, Jgem=17.21,
12aH), 3.79 (s, 3H, OCH3), 4.04 (s, 2H, OCH2±Ar), 4.33
(d, 1H, J=4.56, 7H), 4.57 (s, 2H, COCH2±O±), 4.64 (br,
1H, 1H), 4.93 (dd, 1H, Jcis=11.14, Jgem=1.62, 15Hcis),
5.07 (dd, 1H, Jtrans=16.71, Jgem=1.62, 15Htrans), 5.93
(br, 1H, 6H), 6.17 (dd, 1H, Jtrans=16.71, Jcis=11.14,
14H), 6.80 (d, 2H, J=8.6, Ar±H3,5) 7.21 (d, 2H, J=8.6,
ArH2,6). Anal. calcd for C36H59O9Si: C, 65.42; H, 8.54.
Found: C, 65.84; H, 8.55%.
7ꢀ-Acetoxy-1ꢁ,9ꢁ-dihydroxy-8,13-epoxy-6ꢀ-(hydroxy-
acetoxy)-labd-14-en-11-one (31). To a solution of com-
pound 30 (5.82 g; 10 mmol) in THF (freshly distilled
over LAH) (300 mL), 1M nBu4N+F in THF (kept
over molecular seive 4A type for 3 h before use) (10 mL;
10 mmol) was added. The soln was stirred for 5 min at
room temperature. Solvent was removed under reduced
pressure. The residue was puri®ed by ¯ash chroma-
tography over silica gel with 15% CH3CN±CHCl3 as
eluent. The product was ®nally crystallized from hot
EtOAc. Yield: 4.47 g (95.5%), m.p. 258±260 ꢁC; IR
1
7ꢀ-Acetoxy-8,13-epoxy-9ꢁ-hydroxy-6ꢀ-[(4-methoxybenzyl-
oxy)acetoxy]-1ꢁ-tertbutyldimethylsilyloxylabd-14-en-11-
one (29). This compound was prepared according to the
method discribed for the synthesis of compound 14
(Scheme 1). The crude product was puri®ed by ¯ash
chromatography over silica gel with 15% EtOAc±light-
petroleum. Yield: 98%, semi solid; IR (neat): 3300 (br),
(KBr) 3495, 3210, 1745, 1724, 1400 cm
;
1H NMR:
(CDCl3+CD3OD): 0.94, 1.03, 1.34, 1.39, 1.57 (5Âs,
15H, 5ÂCH3), 2.01 (s, 3H, ±COCH3), 2.37 (d, 1H,
Jgem=16.2, 12bH), 2.41 (d, 1H, J=2.54, 5H), 3.25 (d,
1H, Jgem=16.2, 12aH), 4.11 (s, 2H, COCH2OH), 4.47
(br, 1H, 1H), 4.89 (dd, 1H, Jcis=10.1, Jgem =1.62,
15Hcis), 5.14 (dd, 1H, Jtrans=17.2, Jgem=1.62 15Htrans),

B. Lal et al./Bioorg. Med. Chem. 6 (1998) 2061±2073
2073
5.51 (d, 1H, J=4.56, 7H), 5.85 (t, 1H, J=3.04, 6H),
5.95 (dd, 1H, Jtrans=17.2, Jcis =10.1, 14H). Anal. calcd
for C24H36O9Si: C, 61.54; H, 7.75. Found: C, 61.41; H,
7.68%.
the late Dr. A. N. Dohadwalla and Dr. N. K. Dadkar,
for their help in pharmacological screening, and also
Dr. P. K. Inamdar and his group for analytical data.
References and Notes
7ꢀ-Acetoxy-6ꢀ-acetoxyacetoxy-1ꢁ,9ꢁ-dihydroxy-8,13-
epoxylabd-14-en-11-one (32) and 7ꢀ-acetoxy-1ꢁ,9ꢁ-
dihydroxy-8,13-epoxy-6ꢀ-(formyloxy)acetoxylabd-14-en-
11-one (33). These two compounds were prepared from
31 by using the same method as described for the
synthesis of compound 14 (Scheme 1) with appropriate
acid EtOAc:DMF (5:1) as reaction solvent. The crude
products were puri®ed by ¯ash chromatography over
silica gel with 8% CH3CN±CHCl3 as eluent.
1. Bhat, S. V.; Bajwa, B. S.; Dornauer, H.; deSouza, N. J.;
Fehlhaber, H. W. Tetrahedron Lett. 1977, 1669.
2. (a) deSouza, N. J.; Dohadwalla, A. N.; Reden, J. Med. Res.
Rev. 1983, 3, 201; (b) Caprioli, J.; Sears, M.; Baussher, L.;
Gregory, D.; Mead, A. Invest. Ophthelmol. Vis. Sci. 1984, 25,
268; (c) Seamon, K. B.; Daily, J. W. Adv. Cyclic Nucleotide
Protein Phosphorylation Res. 1986, 20, 1.
3. (a) deSouza, N. J. In ForskolinÐits chemical biological and
medicinal potential; Rupp, R. H.; deSouza, N. J.; Dohadwalla,
A. N., Eds.; Hoechst India Ltd: Bombay, 1986; pp 39; (b)
Seamon, K. B.; Daly, J. W.; Metzger, H.; deSouza, N. J.;
Reden, J. J. Med. Chem. 1983, 26, 436; (c) O'Malley, G. J.;
Spahl, B.; Cherill, R. J.; Kosley Jr., R. W. J. Org. Chem. 1990,
55, 1102.
32. Yield: 98%, m.p. 190±191 ꢁC (EtOAc±light petro-
leum). IR (KBr): 3400, 3340, 3270, 2940 (br), 1755,
1
1720, 1630 cm 1; H NMR: 0.99, 1.04, 1.35, 1.41, 1.63
(5Âs, 15H, 5ÂCH3), 2.03, 2.14 (2Âs, 6H, 2ÂCOCH3),
2.42 (d, 1H, J=2.54, 5H), 2.45 (d, 1H, Jgem=17.21,
12bH), 3.21 (d, 1H, J=17.21, 12aH), 4.48, 4.70 (2Âd,
2H, Jgem=16.1, COCH2O), 4.6 (br, 1H, 1H), 4.91 (dd,
1H, Jcis=10.13; Jgem=1.68, 15Hcis), 5.19 (dd, 1H,
Jtrans=17.21, Jgem=1.68 15Htrans), 5.48 (d, 1H, J=4.05,
7H), 5.82 (t, 1H, J=3.04, 6H), 5.83 (dd, 1H, Jtrans
=17.21, Jcis= 10.13, 14H). Anal. calcd for C26H38O10:
C, 61.16; H, 7.50. Found: C, 61.32; H, 7.60%.
4. Khandelwal, Y.; Rajeshwari, K.; Rajagopalan, R.; Swamy,
L.; Dohadwalla, A. N.; deSouza, N. J.; Rupp, R. H. J. Med.
Chem. 1988, 31, 1872.
5. (a) Bhat, S. V.; Bajwa, B. S.; Dornauer, H.; deSouza, N. J. J.
Chem. Soc. Perkin Trans. 1. 1982, 767; (b) Kosley Jr., R. W.;
Cherill, R. J. J. Org. Chem. 1989, 54, 2972.
6. Lal, B.; Gangopadhyay, A. K. J. Chem. Soc. Perkin Trans.
1. 1992, 1993.
7. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885.
33. Yield: 92.5%, m.p. 197±200 ꢁC (EtOAc±light petro-
leum); IR (KBr) 3360 (br), 2982, 2955, 1775, 1755, 1745,
8. Laurenza, A.; Morris, D.; Seamon, K. B. Mol. Pharmacol.
1990, 37, 69.
1
1707 cm 1; H NMR: 0.99, 1.04, 1.35, 1.41, 1.62 (5Âs,
9. Harris, M.; Bull, M. J. Synth. Commun. 1985, 15, 1225.
15H, 5ÂCH3), 2.03 (s, 3H, COCH3), 2.44 (d, 1H,
J=2.54, 5H), 2.45 (d, 1H, Jgem=16.7, 12bH), 3.21 (d,
1H, J=16.7, 12aH), 4.56, 4.79 (2Âd, 2H, Jgem=15.2,
COCH2O), 4.93 (dd, 1H, Jcis= 10.13; Jgem= 2.03,
15Hcis), 5.19 (dd, 1H, Jtrans=17.21, Jgem=2.03,
15Htrans), 5.50 (d, 1H, J=4.56, 7H), 5.84 (t, 1H,
J=3.04, 6H), 5.93 (dd, 1H, Jtrans =17.21, Jcis = 10.13,
14H), 8.07 (s, 1H, CHO). Anal. calcd for C25H36O10: C,
60.47; H, 7.31. Found: C, 60.63; H, 7.29%.
10. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190.
11. Jackson, D. Y. Synth. Commun. 1988, 18, 337.
12. Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S.
Tetrahedron Lett. 1986, 27, 4537.
13. Marco, J. L.; Rodriguez, B. Tetrahedron Lett. 1988, 29,
1997.
14. Ichihara, A.; Ubukata, M.; Sakamura, S. Tetrahedron Lett.
1977, 3473.
15. Seguin, E.; Ferry, N.; Hanoune, J.; Koch, M. Planta Med-
ica, 1988, 54, 4.
Acknowledgements
The authors gratefully acknowledge Dr. R. H. Rupp for
his interest and encouragement. We also acknowledge
16. Bhat, S. V.; Dohadwalla, A. N.; Bajwa, B. S.; Dadkar, N.
K.; Dornauer, H.; deSouza, N. J. J. Med. Chem. 1983, 26, 486.