SCHEME 1. Eight-Step Formal Total Synthesis of
22-Hydroxyacuminatine (3)
FIGURE 2. Retrosynthesis of 22-hydroxyacuminatine (3) and luotonin
A (4) using a common cascade strategy.
hydroxyacuminatine (3), luotonin A (4), and other new CPT
derivatives, is of great value.
More recently, we reported a mild cascade methodology to
construct variously substituted indolizino[1,2-b]quinolin-9(11H)-
ones,thetetracyclicA/B/C/D-ringcoreofCPT-familyalkaloids.6d,13
This highly efficient cascade reaction triggered by bis(triphenyl)-
oxodiphosphonium trifluoromethanesulfonate under mild condi-
tions has been successfully applied in total synthesis of
camptothecin (1).13 In order to examine the power of this
methodology, two additional naturally occurring alkaloids, 22-
hydroxyacuminatine (3) and luotonin A (4) were selected for
its further applications. Both of them are notable with structural
similarities to camptothecin (1) in identical A-C rings. Herein,
we report our results of total syntheses of 22-hydroxyacumi-
natine (3) and luotonin A (4) using the above-mentioned cascade
reaction as a common strategy. These two targets were suc-
cessfully achieved in very short steps and high overall yields.
Figure 2 illustrates their general retrosynthetic analysis. With
the consideration of employing our cascade reaction conditions,
chemically stable amides 5 and 6 have to be prepared at first,
respectively.
Condensation of 2,6-dicyanotoluene 9 with diethyl oxalate in
the presence of potassium tert-butoxide, followed by a basic
treatment, yielded 5-cyano-1-oxo-1,2-dihydroisoquinoline-3-
carboxylic acid (10) in 63% yield.14 Treatment of 10 with oxalyl
chloride followed by reaction with excess methanol afforded
ester 11 (88%). N-Propargylation of 11 was carried out with
propargyl bromide, K2CO3, LiBr, and a catalytic amount of
tetrabutylammonium bromide in toluene, giving a new pyridone
8 in 91% yield.15 Basic hydrolysis of methyl ester 8 afforded
acid 7 in 98% yield. Conversion of acid 7 to its corresponding
acid chloride followed by treatment with aniline afforded amide
5 (70% yield in two steps). Amide precursor 5 was then treated
with bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate
(prepared in situ) at room temperature for half an hour.13 The
known advanced intermediate 128b was finally obtained (91%
yield), containing the whole skeleton of 22-hydroxyacuminatine
(3). Conversion of 12 to 22-hydroxyacuminatine (3) has been
previously carried out by Cushman and co-workers using a two-
step DIBAL-H reduction procedure (51% yield).8b Thus, using
our mild cascade reaction, we accomplished a straightforward
synthesis of the known key intermediate 12 (six steps and 31%
yield) starting from commercially available 2,6-dicyanotoluene
9. This represents a formal total synthesis of 22-hydroxyacumi-
natine (3) in eight steps and 16% overall yield.
Synthesis of 22-hydroxyacuminatine (3) started from the
commercially available 2,6-dicyanotoluene 9 (Scheme 1).
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Employing a similar strategy, total synthesis of luotonin A
(4) was accomplished in five steps (Scheme 2). Reaction of the
commercially available anthranilamide 13 with diethyl oxalate
yielded a quinazolinone derivative 14 in 81% yield.16 Ethyl ester
14 was then hydrolyzed with LiOH to give acid 15.17 Conversion
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J. Org. Chem, Vol. 72, No. 16, 2007 6271