Asymmetric syntheses of (+)-camptothecin and (+)-7-ethyl-10- methoxycamptothecin

Article abstract of DOI:10.3987/com-00-8853

Total syntheses of (+)-camptothecin (1a) and (+)-7-ethyl-10- methoxycamptothecin (1b) from racemic ethyl 1-ethoxycarbonyl-3-oxopyrrolidin- 2-ylacetate (7) were accomplished via asymmetric hydroxylation onto C20 of racemic 20-deoxycamptothecin derivatives (3a,b) employing a chiral Davis reagent, (2R, 8aS)-(+)-(camphorylsulfonyl)oxaziridine.

Full text of DOI:10.3987/com-00-8853

HETEROCYCLES, Vol. 53, No. 4, 2000, pp. 771 - 775, Received, 14th January, 2000
ASYMMETRIC SYNTHESES OF (+)-CAMPTOTHECIN AND
(
+)-7-ETHYL-10-METHOXYCAMPTOTHECIN
a
b
b
Keiko Tagami, Norio Nakazawa, Shigeki Sano,
b
and Yoshimitsu Nagao*
a
Faculty of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68
Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179, Japan
b
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi,
Tokushima 770-8505, Japan
Abstract- Total syntheses of (+)-camptothecin (1a) and (+)-7-ethyl-10-methoxy-
camptothecin (1b) from racemic ethyl 1-ethoxycarbonyl-3-oxopyrrolidin-2-
ylacetate (7) were accomplished via asymmetric hydroxylation onto C20 of
racemic 20-deoxycamptothecin derivatives (3a,b) employing a chiral Davis
reagent, (2R, 8aS)-(+)-(camphorylsulfonyl)oxaziridine.
Since discovery of (+)-camptothecin (1a) as a potent antitumor-active alkaloid from Campthotheca
1
acuminata by Wall and co-workers in 1966, its synthesis and chemical modification have extensively been
2
2l,3
performed in the world. Irinotecan (1c) and (2'S, 3 'R)- and (2'R, 3 'S)-dihydroxybutanoylcamptothecin
4
derivatives (2a,b) have proved to be more superior tumor inhibitors as compared to (+)-camptothecin (1a)
itself. Thus, we have investigated and estasblished a new synthetic procedure for (+)-camptothecin (1a) and
(+)-7-ethyl-10-methoxycamptothecin (1b), a key intermediate toward the synthesis of irinotecan like
compounds.
R1
9
O
R2 10
7
5
8
6
4
O
N
N
N
1
1
16
2
17
1
3
3
N
1
2
1
O
2
0
1
4
1
1
5
9
O
2
0
OR O
Me
OH O
Me 18
1
2
1
1
1
a R = R = H (+)-camptothecin
HO
HO
H
H
1
2
2a R =Me
2b R =Me
b R = Et, R = OMe
H
H
1
2
OHO
OHO
c R = Et, R = O C
N
N
⋅HCl 3H O irinotecan
2
O

As shown in Figure 1, enolization of 20-deoxycamptothecin derivatives (3a,b) followed by asymmetric
hydroxylation at the C20 position is featured in our synthetic access to the goal because this strategy will be
applicable to the development of various C20-functionalized camptothecin analogs (4a,b) by exploiting
+
+
+
suitable electrophiles [E = RS , X (X = Br, I), etc.]. The 20-deoxycamptothecin derivatives (3a,b) can be
2
h
synthesized by intermolecular dehydrative condensation between compounds (5a,b) and 6, respectively.
R1
N
R1
R2
R2
O
O
N
N
N
O
O
HO
E
1a, b
O
O
Me
Me
4a, b
asymmetric
electrophile
hydroxylation
E+
OH+
enolization
R1
base
R1
R2
O
R2
NH2
O
O
5a, b
dehydrative
N
condensation
N
N
O
2
0
O
H
O
O
Me
Me
Base
O
1
2
3a, b
a R = R = H
6
1
2
b R = Et, R = OMe
Figure 1. Synthetic strategy of camptothecin derivatives (1a,b and 4a,b)
2
h
5
The key compound (6) was successfully synthesized starting from known pyrrolidinone (7) as shown in
Scheme 1. Ketalization of 7 with ethylene glycol under the conventional conditions gave dioxolane (8) in
8
4% yield. Alkaline hydrolysis of 8 with 20% KOH - EtOH (1:1) under reflux followed by protection of
pyrrolidine amino group with Boc O and 1M NaOH in dioxane and then treatment of the resulting N-Boc
2
6
carboxylic acid with the Masamune reagent system afforded keto ester (9) in 71% overall yield from 8.
After ethylation of 9 with EtI - NaH in DMF, the resulting compound (1 0) (75% yield) was subjected to the
usual deprotection of the N-Boc group and then treated with ethyl malonyl chloride in the presence of
Et N-DMAP in benzene to give N-malonyl amide (1 1) in 88% yield. Selective Dieckmann-type
3
condensation of 1 1 with a catalytic amount of EtONa smoothly proceeded in refluxing EtOH to furnish the

desired cyclized product (1 2) in 71% yield as a diastereomeric mixture. Oxidative dehydrogenation of 1 2
with DDQ in dioxane under reflux afforded pyridone (1 3) (87% yield), which was subjected to alkaline
hydrolysis with 10% NaOH in EtOH at 0˚C to give selectively monocarboxylic acid (1 4) as a colorless
solid [mp 148-150˚C (AcOEt)] in 81% yield. Treatment of 1 4 with ethyl chloroformate in the presence of
Et N in THF at 0˚C followed by aminolysis of the resulting mixed anhydride with piperidine gave amide
3
(
1 5) in 70% yield. Reduction of 1 5 with LiBH in dioxane turned out to be alcohol (1 6) (55% yield),
4
which was treated with 6N HCl under reflux to provide the desired δ-lactone (6) [mp 160-161˚C (AcOEt);
2
h
lit., mp 162-163˚C (AcOEt)] as colorless needles in 60% yield.
Scheme 1
O
O
O
O
O O
O
O O
CO Et
a
b,c,d
e
2
CO Et
2
CO Et
CO Et
2
2
N
N
N
N
CO Et
Boc
2
CO Et
2
Boc
Me
7
8
9
10
O
O
O
O
O
O O
O
O
CO Et
2
j
f,g
h
i
N
N
O
N
N
Me
Me
CO H
O
Me
Me
O
O
CO Et
CO Et
EtO C
CO2Et
EtO2C
2
EtO C
2
2
2
2
11
12
13
14
O
O
O
O
O
k,l
m
n
N
O
N
O
N
O
Me
O
N
O
N
Me
EtO C
O
O
2
OH Me
15
16
6
Reagents and conditions : a) ethylene glycol (1.1 mol eq), TsOH (cat.), benzene, reflux, 4 h;
b) 20% aq. KOH / EtOH (1:1), reflux, 12 h; c) Boc O (1.5 mol eq), 1M NaOH (1.5 mol eq),
2
dioxane, rt, 12 h; d) CO(Im) (1.2 mol eq), EtO CCH CO K (2.2 mol eq), MgCl (1.2 mol eq),
2
2
2
2
2
Et N (2.4 mol eq), THF, rt, 24 h; e) NaH (1.2 mol eq), EtI (1.2 mol eq), DMF, rt, 3 h; f) TFA /
3
anisole (2:1), 0 ˚C, 30 min; g) ClCOCH CO Et (1.2 mol eq), Et N (2.5 mol eq), DMAP (0.4
2
2
3
mol eq), benzene, rt, 1 h; h) EtONa (0.05 mol eq), EtOH, reflux, 1 h; i) DDQ (1.0 mol eq),
dioxane, reflux, 4 h; j) 10% NaOH (3.0 mol eq), EtOH, 0 ˚C, 6 h; k) ClCO Et (1.5 mol eq),
2
Et N (3.0 mol eq), THF, 0 ˚C, 30 min; l) piperidine (1.5 mol eq), THF, rt, 1 h; m) LiBH (4.0
3
4
mol eq), dioxane, rt, 30 min; n) 6N HCl, reflux, 30 min

Dehydrative condensation of 6 with 2-aminobenzaldehyde (5a) in the presence of morpholine in refluxing
2
b
toluene afforded racemic 20-deoxycamptothecin (3a) [mp 256-260˚C (CHCl -AcOEt); lit., mp
3
2
58-264˚C] as a yellow solid in 64% yield as shown in Scheme 2. Similar condensation of 6 with
'-amino-5'-methoxypropiophenone (5b) [ yellow needles, mp 58˚C (CH Cl -hexane)] obtained from the
2
2
2
7
reaction of p-anisidine with propionitrile utilizing the Sugasawa method, was done in the presence of a
catalytic amount of TsOH in toluene under reflux to give racemic
-ethyl-10-methoxy-20-deoxycamptothecin (3b) [mp 276-278˚C (CHCl -AcOEt)] as yellow needles in
7
6
3
0% yield. Davis and Weismiller reported that the enolate generated by treatment of 3-isochromanone with
NHMDS, was allowed to react with (2R,8aS)-(+)-(camphorylsulfonyl)oxaziridine to give the S-hydroxy
8
derivative in 77% ee. The δ-lactone moiety of 3a,b seemed to be similar to that of 3-isochromanone.
Thus, asymmetric hydroxylation at C20 of 3a,b was attempted by exploiting a chiral Davis reagent,
N-sulfonyloxaziridine as follows. After enolization of 3a,b with LHMDS in THF at -78˚C, each resulting
8
enolate was treated with (2R,8aS)-(+)-(camphorylsulfonyl)oxaziridine to furnish the corresponding
2
5
(
+)-camptothecin (1a) {mp 264-266˚C decomp (MeCN-MeOH), [α]D +14.2˚ [c 0.34, CHCl -MeOH (4 :
3
1
25
1
)]; lit., mp 264-267˚C decomp (MeCN-MeOH), [α]D +31.3˚ [CHCl -MeOH (4 : 1)]} as a pale yellow
3
2
5
solid in 53% yield and (+)-7-ethyl-10-methoxycamptothecin (1b) {mp 276-278˚C (CHCl -AcOEt), [α]
3
D
9
25
+
+
27.4˚ [c 0.46, CHCl -MeOH (4 : 1)]; the authentic compound mp 279-281˚C (CHCl -AcOEt), [α]
3
3
D
38.7˚ [c 0.51, CHCl -MeOH (4 : 1)]} as pale yellow needles in 40% yield, respectively, as shown in
3
1
Scheme 2. Spectroscopic data ( H NMR, IR, and MS) of synthetic compounds (1a,b) were identical with
9
those of the authentic (+)-camptothecin and (+)-7-ethyl-10-methoxycamptothecin.
Scheme 2
R1
N
R1
N
O
R2
R2
N
O
O
O
N
N
c, d
a or b
O
Me
O
O
Me
O
Me
O
OH O
6
3a, b
1a, b
Reagents and conditions: a) 2-aminobenzaldehyde (5a) (1.5 mol eq), morpholine (1.5 mol
eq), toluene, reflux, 3 h; b) 2'-amino-5'-methoxypropiophenone (5b) (1 mol eq), TsOH (0.1
mol eq), toluene, reflux, 3 h; c) [(CH ) Si] NLi (1.5 mol eq), THF, -78 ˚C, 30 min; d) (2R,
3
3
2
8aS)-(+)-(camphorylsulfonyl)oxaziridine (1.5 mol eq), THF, -78 ˚C, 3 h

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authentic (+)-camptothecin and (+)-7-ethyl-10-methoxycamptothecin.