Expedient synthesis of (R)-patulolide A

Article abstract of DOI:10.1021/jo951339k

An efficient derivation of the title compound has been formulated from easily accessible 10-undecenoic acid (1). Thus, dodec-11-en-2-ol (3), prepared from 1, was pyranylated and subjected to bromination with NBS followed by acetolysis to furnish (2E)-1-acetoxy-11-(tetrahydropyranyloxy)dodec-2-ene (5). Its hydrolysis, oxidation, and depyranylation afforded the (2E)-hydroxy ester (9). This, on Candida rugosa lipase-catalyzed acetylation, SeO₂ oxidation, hydrolysis, and Yamaguchi macrolactonization, led to (R)-patulolide A (l) with 67.1% ee. The enantiomeric excess was improved to 97% by first resolving the alcohol 3 via porcine pancreatic lipase catalyzed acetylation and converting the corresponding (R)-acetate (13) to I as done above.

Full text of DOI:10.1021/jo951339k

1814
J . Org. Chem. 1996, 61, 1814-1816
Exp ed ien t Syn th esis of (R)-P a tu lolid e A
A. Sharma, S. Sankaranarayanan, and S. Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Bombay-400 085, India
Received J uly 21, 1995X
An efficient derivation of the title compound has been formulated from easily accessible 10-
undecenoic acid (1). Thus, dodec-11-en-2-ol (3), prepared from 1, was pyranylated and subjected
to bromination with NBS followed by acetolysis to furnish (2E)-1-acetoxy-11-(tetrahydropyranyloxy)-
dodec-2-ene (5). Its hydrolysis, oxidation, and depyranylation afforded the (2E)-hydroxy ester (9).
This, on Candida rugosa lipase-catalyzed acetylation, SeO2 oxidation, hydrolysis, and Yamaguchi
macrolactonization, led to (R)-patulolide A (I) with 67.1% ee. The enantiomeric excess was improved
to 97% by first resolving the alcohol 3 via porcine pancreatic lipase catalyzed acetylation and
converting the corresponding (R)-acetate (13) to I as done above.
Construction of macrocyclic lactones is an arduous task
Subsequently, the alcohol was oxidized with MnO2 to
furnish the aldehyde 7. This was then subjected to
Corey’s oxidation13 to furnish the ester 8 directly. Its (E)-
geometry was easily established from the coupling con-
stant (16 Hz) of its olefinic protons. Compound 8 was
subsequently depyranylated to the hydroxy ester 9. For
the resolution, we attempted its trans-acetylation with
vinyl acetate using lipase from Candida rugosa (CRL)
as the catalyst. However, this proceeded with disap-
pointing enantioselection. Best results were obtained in
diisopropyl ether where, at 30% conversion, the (R)-
acetate 10 and the resolved (S)-9 were obtained with 68%
and 61% ee’s, respectively. Allylic oxidation of 10 with
SeO2 gave the keto ester 11 which was hydrolyzed to the
desired acid 12. This was then cyclized following Yamagu-
chi’s method14 to obtain the target compound (R)-I with
67.1% ee. The % ee was ascertained by comparing its
[R]D value with the reported one.11 Since the enantio-
meric purity of the synthetic sample was not satisfactory,
we explored another strategy (Scheme 1).
in organic synthesis. However, these are widely distrib-
uted1 in nature and often possess chiral centers. This
in turn offers a challenge for their synthesis. Recently,
we have devised chemoenzymatic routes for two such
compounds, one with a skipped methylenic group2 and
the other possessing a chiral center.3 The macrolide,
(2E)-4-oxo-2-dodecen-11-olide (I), commonly known as
patulolide A, has been isolated4 from Penicillium urticae.
Its (R)-antipode inhibits IgE-induced release of histamine
for human leukocytes better than the degranulation
inhibitor, theophyline. The reported antifungal, antimi-
crobial, and antiinflammatory activities of I have led to
its several syntheses mainly as a racemate.5-7 More
recently, a few asymmetric syntheses have also been
reported.8-11 However, poor enantiocontrol, multiple
steps, and use of inaccessible materials are some of the
limitations in the existing asymmetric routes. We,
therefore, formulated an expedient synthesis of (R)-I
starting from commercially available 10-undecenoic acid
(1), wherein the asymmetry was induced by a lipase-
catalyzed acetylation.
The aldehyde 2, prepared from the acid 1, was reacted
with methylmagnesium iodide to furnish the alcohol 3
in excellent yield. It was pyranylated to compound 4
which was then subjected to allylic bromination with
NBS. The resultant bromide on reaction with AcONa
furnished the (E)-acetate 5 exclusively via concomitant
rearrangement.12 Its alkaline hydrolysis to the alcohol
6 followed by oxidation with PDC in MeOH led to a
complex mixture of products which was not identified.
Recently, we have extensively studied15 the porcine
pancreatic lipase (PPL)-catalyzed acylation of 2-alkanols
with different acyl donors in various solvents. On this
basis, kinetic resolution of 3 itself seemed more appealing
for the enantiomeric synthesis of (R)-I. This seems all
the more reasonable as the resolution step could then be
incorporated at the initial stage of the synthesis. Hence,
following the above protocol, we first prepared the acetate
(R)-13 (97% ee) and (S)-3 (96% ee). The % ee of both
these compounds were determined by GLC analyses of
their respective MTPA esters. The positive optical rota-
tion of the resolved alcohol indicated its (S)-configuration
by analogy with the sign of [R]D of 2-alkanols.15 This was
also confirmed by its hydrogenation to the known com-
pound 2-dodecanol and comparison of its chirooptical data
with those reported.16 Compound (R)-13 was then con-
verted to the macrolide (R)-I following a procedure
identical to that described earlier.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
(1) Omura, S. Macrolide Antibiotics Chemistry, Biology and Practice;
Academic Press: New York, 1984.
(2) Pawar, A. S.; Chattopadhyay, S.; Chattopadhyay, A.; Mamdapur,
V. R. J . Org. Chem. 1993, 58, 7535.
(3) Pawar, A. S.; Sankaranarayanan S.; Chattopadhyay, S. Tetra-
hedron Asymmetry, in press.
(4) (a) Sekiguchi, J .; Kuroda, H.; Yamada, Y.; Okada, H. Tetrahedron
Lett. 1985, 26, 2341. (b) Rodphaya, D.; Sekiguchi, J .; Yamada, Y. J .
Antibiot. 1986, 39, 629.
(5) Makita, A.; Yamada, Y.; Okada, H. J . Antibiot. 1986, 39, 1257.
(6) Ayyangar, N. R.; Chanda, B.; Wakharkar, R. D.; Kasar, R. A.
Synth. Commun. 1988, 18, 2103.
(7) Yadav, J . S.; Radha Krishna, P.; Gurjar, M. K. Tetrahedron 1989,
45, 6263.
Exp er im en ta l Section
All anhydrous reactions were carried out under Ar using
freshly distilled solvents. For enzymatic reactions, solvents
(8) Mori, K.; Sakai, T. Liebigs Ann. Chim. 1988, 13.
(9) Solladie, G.; Gerber, C. Synlett 1992, 449.
(10) Yang, H.; Kuroda, H.; Miyashita, M.; Irie, H. Chem. Pharm.
Bull. 1992, 40, 1616.
(13) Corey, E. J .; Gilman, N. W.; Ganem, B. E. J . Am. Chem. Soc.
1968, 90, 5616.
(14) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull Chem. Soc. J pn. 1979, 52, 1989.
(11) Bestmann, H. J .; Kellermann, W.; Pecher, B. Synthesis 1993,
149.
(12) Babler, J . H.; Martin, M. J . J . Org. Chem. 1977, 42, 1799.
(15) Sharma, A.; Pawar, A. S.; Chattopadhyay, S. Synth. Commun.,
in press.
(16) Pinyarat, W.; Mori, K. Biosci. Biotech. Biochem. 1992, 56, 1673.
0022-3263/96/1961-1814$12.00/0 © 1996 American Chemical Society

Expedient Synthesis of (R)-Patulolide A
J . Org. Chem., Vol. 61, No. 5, 1996 1815
Sch em e 1a
OTHP
OTHP
OR
iii, iv
i, ii
v
(CH2)7
RO
(CH2)7
(CH2)8R
(CH2)8
3, R = H
OHC
1, R = CO2H
2, R = CHO
5, R = Ac
6, R = H
7
4, R = THP
OR
OAc
ix, iv
viii
vi, vii
(CH2)7
(CH2)7
(S)-9 +
MeO2C
MeO2C
8, R = THP
9, R = H
10
OR2
O
x
(CH2)5
O
O
R1O2C
O
11, R1 = Me, R2 = Ac
12, R1 = R2 = H
(R)-I
OH
OH
OAc
xi
(CH2)8
(S)-3
+
(R)-I
(CH2)8
(CH2)8
(R)-13
3
a
Key: (i) MeMgI/ether; (ii) DHP/PPTS/CH2Cl2; (iii) NBS/AIBN/CCl4/∆, NaOAc/DMF; (iv) alcoholic KOH; (v) MnO2/hexane; (vi) MnO2/
MeOH/NaCN/AcOH; (vii) MeOH/PTS/∆; (viii) vinyl acetate/CRL/diisopropyl ether; (ix) SeO2/dioxane; (x) Yamaguchi’s procedure; (xi) vinyl
acetate/PPL/diisopropyl ether.
were dried by standard procedures and then desiccated over
molecular sieves (4 Å, Linde) for at least 72 h. CRL (Sigma,
specific activity 941 units/mg) and PPL (Sigma, specific activity
54 units/mg) were used as obtained. SeO2 (Fluka) was
recrystallized prior to use. The 1H NMR spectra were recorded
in CDCl3 solvent.
and PPTS (0.2 g) in CH2Cl2 (60 mL) was stirred at room
temperature for 12 h. It was poured into 10% aqueous
NaHCO3 (30 mL), the organic layer separated, and the aqueous
part reextracted with CHCl3. The entire organic extract was
washed with water and brine, dried, and concentrated in
vacuo. The residue was chromatographed over a silica gel
column (0-10% ether/hexane) to furnish pure 4 (5.85 g, 95%):
10-Un d ecen a l (2). To a stirred suspension of LAH (3.8 g,
0.1 mol) in anhydrous ether (300 mL) was added dropwise the
acid 1 (18.4 g, 0.1 mol) in ether (100 mL). After the initial
reaction subsided, the mixture was gently heated to reflux for
3 h when the reaction was complete (cf. TLC). The reaction
mixture was cooled by ice-water and the excess hydride
decomposed with aqueous saturated Na2SO4 solution to get a
crystalline white precipitate. The supernatant was decanted
and the precipitate thoroughly washed with ether. Concentra-
tion of the ether extract followed by distillation gave pure 10-
undecenol (16.3 g, 96%): bp 125-127 °C/10 mm; IR 3360, 3090,
1
IR 3090, 1640, 990, 910, 870, 810 cm-1; H NMR δ 1.18 (d, J
) 6 Hz, 3H), 1.3 (br s, 14H), 1.5-1.7 (m, 6H), 2.1-2.3 (m, 2H),
3.5-3.9 (m, 3H), 4.6 (br s, 1H), 4.8-6.2 (m, 3H). Anal. Calcd
for C17H32O2: C, 76.06; H, 12.02. Found: C, 75.86; H, 12.17.
(2E )-1-Ace t oxy-11-(t e t r a h yd r op yr a n yloxy)d od e c-2-
en e (5). A mixture of compound 4 (5.8 g, 0.022 mol), NBS
(4.63 g, 0.026 mol), and AIBN (24 mg) in CCl4 (60 mL) was
refluxed for 1 h. It was poured into ice-cold water, the
precipitated solid removed by filtration, and the filtrate
extracted with n-pentane. The organic layer was washed with
water and brine and dried. Removal of solvent gave a mixture
containing isomeric bromides along with some unreacted 4
which was directly used in the next step.
1
1640, 990, 910 cm-1; H NMR δ 1.32 (br s, 14H), 1.9-2.1 (m,
2H), 2.8 (br s, D2O exchangeable, 1H), 3.68 (t, J ) 6 Hz, 2H),
4.8-6.2 (m, 3H).
To a stirred and cooled (0 °C) suspension of PCC (15.2 g,
0.07 mol) in CH2Cl2 (70 mL) was added the above alcohol (8.0
g, 0.047 mol) in one lot. After 3 h, the reaction mixture was
diluted with dry ether (100 mL) and the supernatant passed
through a pad (6 in.) of silica gel. The brown residue was
repeatedly extracted with ether and passed through the above
pad. The combined organic layer was concentrated under
vacuum and the residue distilled to get the pure aldehyde 2
(5.8 g, 73%): bp 100-102 °C/0.1 mm; IR 2720, 1640, 990, 910
cm-1; 1H NMR δ 1.3 (br s, 12H), 2.0-2.1 (m, 2H), 2.34 (t, J )
7 Hz, 2H), 4.8-6.2 (m, 3H), 9.78 (t, J ) 1.5 Hz, 1H).
Thus, a mixture of the above product and anhydrous NaOAc
(7.4 g, 0.09 mol) in DMF (20 mL) was stirred at room
temperature for 20 h. Then it was poured into excess ice-
water and the aqueous layer extracted with ether. The
ethereal solution was repeatedly washed with water followed
by brine and dried. After concentration, the residue was
chromatographed over silica gel (0-15% EtOAc/hexane) to get
unreacted 4 (38%) and pure 5 (2.2 g, 49.4% based on conver-
sion): IR 1760, 1650, 1385, 980, 870, 810 cm-1 1H NMR δ
;
1.18 (d, J ) 6 Hz, 3H), 1.3 (br s, 12H), 1.5-1.7 (m, 6H), 2.1-
2.3 (m containing a s at 2.1, 5H), 3.5-3.9 (m, 3H), 4.4 (d, J )
6 Hz, 2H), 4.6 (br s, 1H), 5.3-5.5 (m, 2H). Anal. Calcd for
Dod ec-11-en -2-ol (3). To a stirred and cooled (0 °C)
solution of MeMgI [prepared from MeI (5.3 g, 0.037 mol) and
Mg (0.826 g, 0.034 mol)] in ether (100 mL) was added dropwise
the aldehyde 2 (4.36 g, 0.026 mol) in ether (25 mL). After 3
h, the reaction was quenched with aqueous saturated NH4Cl,
the ether layer separated, and the aqueous portion extracted
with ether. The combined ether extract was washed with
water and brine and finally dried. Removal of solvent followed
by column chromatography of the residue over silica gel (0-
15% EtOAc/hexane) gave pure 3 (4.3 g, 90%): IR 3360, 3090,
C
19H34O4: C, 69.90; H, 10.50. Found: C, 69.72; H, 10.26.
(2E)-11-(Tetr a h yd r op yr a n yloxy)d od ec-2-en -1-ol (6). A
solution of compound 5 (2.0 g, 6.1 mmol) in alcoholic KOH (20
mL, 25%) was stirred for 4 h. Most of the solvent was removed
in vacuo, the mixture diluted with water, and the aqueous
layer extracted with EtOAc. The organic layer was washed
with water and brine and dried. Removal of solvent followed
by column chromatography (silica gel, 0-20% EtOAc/hexane)
gave the alcohol 6 (1.65 g, 95%): IR 3360, 1640, 980, 910, 870,
1
1640, 990, 910 cm-1; H NMR δ 1.16 (d, J ) 6 Hz, 3H), 1.29
1
810 cm-1; H NMR δ 1.18 (d, J ) 6 Hz, 3H), 1.29 (br s, 12H),
(br s, 14H), 2.1 (br s, D2O exchangeable, 1H), 2.2-2.4 (m, 2H),
3.7-3.9 (m, 1H), 4.8-6.2 (m, 3H). Anal. Calcd for C12H24O:
C, 78.19; H, 13.12. Found: C, 78.38; H, 13.01.
1.5-1.7 (m, 6H), 2.0-2.3 (m, 2H), 3.5-3.8 (m, 3H), 3.9-4.0 (m
partially D2O exchangeable, 3H), 4.6 (br s, 1H), 5.5-5.8 (m,
2H). Anal. Calcd for C17H32O3: C, 71.78; H, 11.34. Found:
C, 72.02; H, 11.26.
2-(Tetr a h yd r op yr a n yloxy)d od ec-11-en e (4). A solution
of 3 (4.3 g, 0.023 mol), dihydropyran (DHP) (2.2 g, 0.026 mol),

1816 J . Org. Chem., Vol. 61, No. 5, 1996
Sharma et al.
Meth yl (2E)-11-(Tetr ah ydr opyr an yloxy)dodec-2-en oate
(8). A mixture of 6 (1.65 g, 5.8 mmol) and MnO2 (10.08 g,
0.116 mol) in hexane (30 mL) was stirred at room temperature
for 12 h. The black precipitate was filtered off and the filtrate
concentrated under reduced pressure to afford the pure (cf.
TLC) aldehyde 7 (1.38 g, 84.4%): IR 2700, 1720, 1640, 980,
EtOAc/hexane) to get 11 (0.298 g, 71%): [R]25 -3.1° (c 2.1,
1
CHCl3); IR 1750, 1720, 1640, 1260, 980 cm-1; H NMR δ 1.2
(d, J ) 6 Hz, 3H), 1.25-1.45 (m, 10H), 2.1 (s, 3H), 2.5 (t, J )
6 Hz, 2H), 3.83 (s, 3H), 4.4-4.7 (m, 1H), 6.54 (d, J ) 16 Hz,
1H), 7.1 (d, J ) 16 Hz, 1H). Anal. Calcd for C18H24O5: C,
63.36; H, 8.51. Found: C, 63.48; H, 8.77.
(11R,2E)-4-Oxo-2-d od ecen -11-olid e (I). A solution of 11
(0.284 g, 1.0 mmol) in alcoholic KOH (20 mL, 25%) was stirred
for 6 h. The usual isolation gave the hydroxy acid 12 (0.212
g, 93%): [R]25 -4.31 (c 1.2, CH3OH); IR 3700-3500, 1710, 1640,
1060, 980 cm-1; 1H NMR δ 1.2 (d, J ) 6 Hz, 3H), 1.25-1.4 (m,
10H), 1.8 (s, D2O exchangeable, 1H), 2.34 (t, J ) 6 Hz, 2H),
3.6-3.9 (m, 1H), 6.61 (d, J ) 16 Hz, 1H), 7.2 (d, J ) 16 Hz,
1H), 8.71 (s, D2O exchangeable, 1H).
910, 870, 810 cm-1
.
To a stirred solution of 7 (1.6 g, 5.7 mmol) in MeOH (25
mL) was successively added MnO2 (9.91 g, 0.114 mol), NaCN
(1.4 g, 0.029 mol), and AcOH (0.7 g). After being stirred for
16 h at room temperature, the mixture was concentrated in
vacuo and the residue diluted with EtOAc. The organic layer
was filtered and the filtrate washed with water and brine and
dried. Removal of the solvent and column chromatography
(silica gel, 0-20% EtOAc/hexane) of the residue gave the ester
A mixture of the above compound (41 mg, 0.18 mmol), TEA
(34 µL), and 2,4,6-trichlorobenzoyl chloride (50 mg) in THF
(15 mL) was stirred for 4 h at room temperature. The solution
was filtered under Ar and the filtrate diluted to 100 mL with
toluene and introduced into a refluxing solution of DMAP (150
mg) in toluene (20 mL) over a period of 3 h. After being
refluxed for an additional period of 3 h, it was brought to room
temperature, washed with aqueous 10% NaHCO3, water, and
brine and dried. Solvent removal followed by preparative TLC
gave pure (R)-I (23.0 mg, 61%): mp 83 °C (lit.11 mp 81 °C);
[R]22 +21.4° (c 1.14, EtOH) (lit.11 [R] +28.5° (c 0.83, EtOH));
1
8 (1.08 g, 61%): IR 1720, 1640, 980, 910, 870, 810 cm-1; H
NMR δ 1.2 (d, J ) 6 Hz, 3H), 1.29 (br s, 12H), 1.5-1.7 (m,
6H), 2.0-2.3 (m, 2H), 3.5-3.9 (m containing a s at δ 3.62, 6H),
4.6 (br s, 1H), 5.8 (d, J ) 16 Hz, 1H), 6.91 (dt, J ) 16 Hz, 5.4
Hz, 1H). Anal. Calcd for C18H32O4: C, 69.19; H, 10.32.
Found: C, 69.36; H, 10.17.
Meth yl (2E)-11-Hyd r oxyd od ec-2-en oa te (9). A solution
of 8 (1.08 g, 3.46 mmol) and PTS (0.1 g) in MeOH (20 mL)
was refluxed for 4 h. The usual isolation gave pure 9 (0.71 g,
90%) after column chromatography (silica gel, 0-20%
EtOAc/hexane): IR 3360, 1720, 1640, 980 cm-1 1H NMR δ
;
1
IR 3400, 1710, 1680, 1620, 980 cm-1; H NMR δ 1.22 (d, J )
1.2 (d, J ) 6 Hz, 3H), 1.32 (br s, 12H), 2.1-2.3 (m, 2H), 3.5-
3.9 (m containing a s at δ 3.7, 4H), 4.0 (s, D2O exchangeable,
1H), 5.81 (d, J ) 16 Hz, 1H), 6.91 (dt, J ) 16 Hz, 5.5 Hz, 1H).
Anal. Calcd for C13H24O3: C, 68.38; H, 10.59. Found: C,
68.56; H, 10.83.
7 Hz, 3H), 1.4-1.7 (m, 8H), 1.8-1.9 (m, 2H), 2.4-2.5 (m, 1H),
2.7-2.8 (m, 1H), 4.88 (s, 1H), 6.71 (d, J ) 16 Hz, 1H), 7.21 (d,
J ) 16 Hz, 1H).
(2R)-2-Acetoxyd od ec-11-en e (13). A mixture of (()-3 (7.7
g, 0.042 mol), vinyl acetate (5.8 mL, 0.063 mol), and PPL (5.0
g) in diisopropyl ether (50 mL) was stirred for 48 h. At that
time, 34% conversion was noticed by GLC. The mixture was
then filtered to remove the solid enzyme and the filtrate
concentrated in vacuo. The residue was chromatographed over
silica gel (0-15% EtOAc/hexane) to furnish pure (S)-3 (4.85
g, 63%) and (R)-13 (2.65 g, 28%). The spectral data of (S)-3
and all the subsequent chiral intermediates were identical to
those of their respective (()-samples.
Meth yl (11R,2E)-11-Acetoxyd od ec-2-en oa te (10). A so-
lution of 9 (0.7 g, 3.07 mmol), vinyl acetate (0.6 mL, 6.2 mmol),
and CRL (1.0 g) in diisopropyl ether (20 mL) was stirred at
room temperature until 30% conversion was reached (6 h). The
mixture was filtered, the organic extract was concentrated,
and the products viz. (R)-10 (0.21 g, 25.3%) and (S)-9 (0.31 g,
44%) were isolated by preparative thin layer chromatography.
The spectral data of (S)-9 were identical with those of the
racemic sample.
(S)-3: [R]25 +5.88° (c 1.24, EtOH).
(S)-9: [R]25 +1.48° (c 6.2, CHCl3).
(R)-13: [R]25 -4.18° (c 1.4, Hexane); IR 1730, 1640, 1230,
(R)-10: [R]25 -2.86° (c 4.2, CHCl3); IR 1730, 1720, 1640,
990, 910 cm-1 1H NMR δ 1.2 (d, J ) 6 Hz, 3H), 1.29 (br s,
;
1
1260, 980 cm-1; H NMR δ 1.18 (d, J ) 6 Hz, 3H), 1.32 (br s,
14H), 2.1 (s, 3H), 2.2-2.4 (m, 2H), 4.1-4.4 (m, 1H), 4.8-6.2
(m, 3H). Anal. Calcd for C14H26O2: C, 74.28; H, 11.58.
Found: C, 74.14; H, 11.52.
12H), 2.0 (s, 3H), 2.1-2.3 (m, 2H), 3.6 (s, 3H), 4.4-4.6 (m, 1H),
5.82 (d, J ) 16 Hz, 1H), 6.91 (dt, J ) 16 Hz, 5.4 Hz, 1H). Anal.
Calcd for C15H26O4: C, 66.63; H, 9.69. Found: C, 66.36; H,
9.87.
P a tu lolid e A fr om 13: [R]22 +28.1° (c 1.14, EtOH) (lit.11
[R] +28.5° (c 0.83, EtOH)).
Meth yl (11R,2E)-11-Acetoxy-4-oxod od ec-2-en oa te (11).
A solution of 10 (0.4 g, 1.5 mmol) and SeO2 (0.23 g, 2.07 mmol)
in dioxane (25 mL) was refluxed for 48 h. Then, the mixture
was filtered and the filtrate concentrated. The residue was
diluted with water and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated. The
residue obtained was chromatographed over silica gel (0-15%
Ack n ow led gm en t. The authors wish to thank Dr.
V. R. Mamdapur of this institute for his helpful discus-
sions and active interest in this work.
J O951339K