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dipyranocoumarin. The anti-HIV activity of (
þ
)-cordatolide A was lower than that
of (
þ
)-calanolide A and (
þ
)-inophyllum B.
The synthetic procedure of (
)-cordatolide A
47
was carried out similar to that of
(
)-calanolide A. We used phloroglucinol as a starting material and then con-
structed the 5,7-dihydroxy-4-methyl coumarin by Pechman reaction in the presence
of concentrated sulfuric acid in 98% yield. The acylation and ring closure of the
coumarin in a one-step reaction using tigloyl chloride in the presence of AlCl
3
formed a key intermediate 15 in 57% yield. The chromene ring was then con-
structed by the same procedure mentioned above to obtain chromanone of (
)16
and its stereoisomer (
)17 with a ratio of 1.5 : 1 in 72% yield. (
)16 was separated
by column chromatography in 50% yield. Finally, Luche reaction reduced the chro-
manone (
)-16 to obtain (
)-cordatolide A in 60% yield as shown in Scheme 8-5.
The spectral data including
1
H NMR, IR, and MS of (
)-cordatolide A were
identical to those of natural product (
þ
)-cordatolide A. This four-step synthesis
of (
)-cordatolide A was accomplished in about 24% overall yield.
8.4.1.4 General Procedure of the Total Synthesis of Racemic
Calophyllum Coumarins
Palmer and Josephs
48
reported on a general method for preparation of (
)-calano-
lide A, (
)-inophyllum B, and (
)-cordatolide A as shown in Scheme 8-6.
Starting from 8-(2-methylbutyryl) coumarin (18a-c), which was prepared by
phloroglucinol through two steps (Scheme 8-6), treatment of 18a-c with 3-
methyl-3-hydroxybutyraldehyde in pyridine, followed by methylation with methyl
iodide, gave 19a-c. The conversion of the 2-methyl butyryl side chain in 19a-c into
the (E)-2-methylbut-2-enoyl (tigloyl) group to form coumarins 22a-c by a four-
step hydrobromiration-bromination-double dehydrobromination (20,21) sequence.
Dimethylation of 8-acylcoumarins (21) with magnesium iodide in the presence
of ether afforded the 7-hydroxy coumarins (22). Treatment of 22 with triethylamine
gave the desired trans-and cis-dipyranocoumarins (23) and (24) that were separated
by chromatography. Finally, reduction of 23 with NaBH
4
/potassium biphthalate
reduction gave (
)-calanolide A, (
)-cordatolide B, and (
)-inophyllum B
(25a-c), respectively. This general method starting either from 8-(2-methylbutyryl)-5,
7-dihydroxycoumarins (18a-c) via 9-step sequence or from phloroglucinol via
11-step sequence for the synthesis of the racemic Calophyllum coumarins.
8.4.2 Preparation of Optically Active Calophyllum Coumarins
8.4.2.1 Synthesis of Optically Active Calanolide A (1) and Calanolide B (2)
(
þ
)-Calanolide A (1) and (
)-calanolide B (15) have been shown to be potent inhi-
bitors of HIV-1 RT. Synthesis of both optically active calanolide A and calanolide B
have been accomplished by Deshpande et al. (Scheme 8-7).
49,50
They reported on
the first enantioselective total synthesis of (
þ
)-calanolide A (1) and (
þ
)-calanolide
B(2) and their (
)enantiomers, (
)-calanolide A (a new compound) and (
)-cala-
nolide B (15), using a process that generated all three contiguous chiral centers
(the (
)-calanolide B is also known as costatolide), respectively.
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