Asymmetric a-hydroxylation of a lactone with vinylogous pyridone by using a guanidine-urea bifunctional organocatalyst: Catalytic enantioselective synthesis of a key intermediate for (20S)-camptothecin analogues

Article abstract of DOI:10.1002/chem.201303633

We have developed a catalytic asymmetric synthesis of (S)-4-ethyl-6,6- (ethylenedioxy)-7,8-dihydro-4-hydroxy- 1H-pyrano[3,4-f]indolizine-3,10(4H)dione (5a), a synthetic intermediate for (20S)-camptothecin analogues. A key step in this synthesis is an asym

Full text of DOI:10.1002/chem.201303633

DOI: 10.1002/chem.201303633
Full Paper
&
Asymmetric Synthesis
Asymmetric a-Hydroxylation of a Lactone with Vinylogous
Pyridone by Using a Guanidine–Urea Bifunctional Organocatalyst:
Catalytic Enantioselective Synthesis of a Key Intermediate for
(20S)-Camptothecin Analogues
Tatsuya Watanabe, Minami Odagi, Kota Furukori, and Kazuo Nagasawa*[a]
Abstract: We have developed a catalytic asymmetric synthe-
sis of (S)-4-ethyl-6,6-(ethylenedioxy)-7,8-dihydro-4-hydroxy-
1H-pyrano[3,4-f]indolizine-3,10(4H)dione (5a), a synthetic in-
termediate for (20S)-camptothecin analogues. A key step in
this synthesis is an asymmetric a-hydroxylation of a lactone
with a vinylogous pyridone structure (8a) by using a guani-
dine–urea bifunctional organocatalyst. The present oxidation
was successfully applied to the synthesis of C20-modified
derivatives of (+)-C20-desethylbenzylcamptothecin (13).
Introduction
In the synthesis of 1 and its analogues, construction of the
stereogenic center at C20 is an important issue,[6,7] and syn-
thetic studies of the key intermediates 4a,[8,10d,12] 6,[9,10a–c,11] and
7[13] have mainly employed one of four approaches, that is,
1) chiral auxiliary-mediated alkylation,[8,9] 2) asymmetric dihy-
droxylation,[10] 3) asymmetric cyanosilylation,[11] 4) chemical
and/or enzymatic optical resolutions,[12] and 5) enzymatic de-
symmetrization.[13] The intermediates 4a and 6 have been ob-
tained with high selectivity. However, there are some disadvan-
tages to these approaches, such as the need for stoichiometric
usage of a chiral auxiliary, use of highly toxic reagents, or a re-
quirement for low temperature. Moreover, the undesired
isomer is wasted in the case of the optical resolution methods.
Ciufolini and co-workers have developed a very efficient strat-
egy for the synthesis of the key intermediate 7 by enzymatic
desymmetrization.[13] Recently, a more straightforward ap-
proach to direct a-hydroxylation of 8a with chiral oxaziridine
in the presence of potassium hexamethyl disilazide (KHMDS)
has been investigated by Chen and co-workers (Scheme 1),[7b]
and the hydroxylation product 4a was obtained in 82% yield
with 72% ee.
Camptothecin (CPT 1), a pentacyclic alkaloid, was isolated from
Camptotheca acuminata by Wall and co-workers in 1966
(Figure 1).[1] CPT (1) shows significant antitumor activity
Figure 1. Structures of camptothecin (1) and its water-soluble analogues 2
and 3.
through inhibition of topoisomerase I (Topo I),[2] which is over-
expressed in some types of solid tumors. Early clinical trials of
1 carried out in the mid 1970s achieved partial success, but
were subsequently discontinued due to serious toxicity con-
cerns.[3] Since then, extensive structure–activity relationship
studies have been conducted, especially focusing on improv-
ing the solubility of 1 in water. Currently, two camptothecin
derivatives, topotecan (2)[4] and irinotecan (3),[5] are in clinical
use for treatment of solid tumors.
We have recently developed an asymmetric a-hydroxylation
of b-ketoesters by using a guanidine–urea bifunctional organo-
catalyst 10a in the presence of cumene hydroperoxide (CHP)
and K2CO3.[14] In this reaction, guanidine and urea in the cata-
lyst are suggested to interact with b-ketoester and oxidant, re-
spectively (Scheme 2). The chiral spacer in the catalyst serves
to control the transition state for the asymmetric induction,
and is believed to accelerate the reaction by a synergistic prox-
imity effect.[15]
[a] T. Watanabe, M. Odagi, K. Furukori, Prof. Dr. K. Nagasawa
Department of Biotechnology and Life Science
Tokyo University of Agriculture and Technology
2-24-16 Naka-cho, Koganei
Based upon the plausible interacting model shown in
Scheme 2, we envisaged applying this catalytic asymmetric oxi-
dation to the synthesis of the key intermediate 5 for campto-
thecins. Thus, a-hydroxylation of 8 was planned in the pres-
ence of guanidine–urea bifunctional organocatalyst 10. Com-
Tokyo 184-8588 (Japan)
Fax: (+81)42-388-7295
E-mail: knaga@cc.tuat.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303633.
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Table 1. Asymmetric a-hydroxylation of lactone 8a by using guanidine–
urea bifunctional organocatalysts 10a–j.[a]
Entry
Cat.
R2
5a
R1
R3
R4
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
9
10
10a
10b
10c
10d
10e
10 f
10g
10h
10i
Bn
Me
iPr
Ph
iBu
H
Me
Me
Me
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Et
(CH2)17Me
(CH2)17Me
(CH2)17Me
(CH2)17Me
(CH2)17Me
(CH2)17Me
Et
99
70
89
93
97
95
94
99
97
92
22
52
49
20
37
10
65
66
76
56
À(CH2)3À
À(CH2)4À
À(CH2)5À
10j
Scheme 1. Retrosynthetic approach to camptothecin (1) and its analogues.
[a] Reactions were performed with 8a (0.1 mmol), CHP (0.15 mmol),
K2CO3 (0.1 mmol), and catalyst (0.01 mmol) in toluene at 08C for 24 h.
[b] Racemic 5a and (S)-5a were prepared according to ref. [8b] and [8c],
respectively. The enantiomeric excess and the absolute stereochemistry
were determined by chiral HPLC analysis.
pound 8 does not have a simple 1,3-dicarbonyl moiety; in-
stead, C20 in 8 is regarded as a vinylogous position to the car-
bonyl group at C16a in the 2-pyridone structure (Scheme 3).
Therefore, we planned to generate an enolate efficiently from
8 by using an appropriate base to promote a-hydroxylation in
the presence of a guanidine–urea bifunctional organocatalyst
10 and an oxidant. Here, we described enantioselective orga-
nocatalytic a-hydroxylation of 8a. We also examined the sub-
strate scope of the oxidation by using a variety of C20 sub-
stituents in 8. These results will be helpful for the synthesis of
C20-modified camptothecin derivatives.
Results and Discussion
At the outset, we investigated a-hydroxylation of 8a
with cumene hydroperoxide (CHP)[16] and K2CO3 in
toluene in the presence of guanidine–urea bifunc-
tional organocatalyst 10a[15f] (10 mol%). In this reac-
tion, hydroxylation proceeded efficiently at 08C, and
compound 5a was obtained in 99% yield with
22% ee (Table 1, entry 1). Although the selectivity
was low, the catalytic system was effective for the
oxidation reaction of 8a, so we next carried out
a structure–activity relationship study of the catalyst
by varying the R1 and R2 groups on the chiral spacer
in 10a (Table 1, entries 2–6). In the case of catalysts
10b[15f] (R1 =Me) and 10c[15f] (R1 =iPr), compound 5a
Scheme 2. Asymmetric a-hydroxylation of b-ketoesters catalyzed by guanidine–urea bi-
functional organocatalyst 10a, and a plausible interacting model of the reaction.
was obtained with 52 and 49% ee, respectively (en-
tries 2 and 3). On the other hand, the reaction with
catalysts 10d bearing an aromatic group (R1 =Ph) and 10e
bearing a bulky substituent (R1 =iBu) resulted in lower enantio-
selectivity (entries 4 and 5). Interestingly, the catalyst 10 f, with
a methyl group at another position in the chiral spacer, gave
5a in good yield, but the enantioselectivity was considerably
reduced compared to that with catalyst 10b (entry 6 vs. 2).
Next, we examined the effects of substituents on the guani-
dine group (R3 and R4) of the catalysts (entries 7–10). Changing
Scheme 3. Asymmetric a-hydroxylation of a lactone with vinylogous pyri-
dine 8 for the synthesis of 5, a key intermediate of camptothecin (1) and its
derivatives, by using guanidine–urea bifunctional organocatalyst 10.
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the octadecylamino group to a disubstituted diethylamino
10g or an azetidino group 10h increased the enantioselectivi-
ty to 65 and 66% ee, respectively, with high yield (entries 7
and 8). Furthermore, catalyst 10i bearing a pyrrolidine sub-
stituent on guanidine gave 5a in 97% yield with 76% ee
(entry 9). On the other hand, piperidine-substituted deriva-
tive 10j gave decreased enantioselectivity (56% ee, entry 10).
We further optimized the catalyst structure based upon the
catalyst 10i, especially focusing on the aromatic group at-
tached to the urea moiety (Table 2). In the case of phenyl urea
10k, the enantioselectivity decreased slightly to 70% ee
(Table 2, entry 1 vs. Table 1, entry 9). On the other hand, 3,5-di-
F-substituted 10l showed a similar level of selectivity to cata-
lyst 10i (Table 2, entry 2). Catalysts bearing a CF3 group at the
2- or 3-position on the phenyl group of urea 10m and 10n
also showed comparable enantioselectivity to catalyst 10i (en-
tries 3 and 4). Interestingly, 4-CF3-substituted phenyl urea 10o
gave increased selectivity, and 5a was obtained in 95% yield
with 84% ee (entry 5). Since substitution at the 4-position on
the aromatic ring seemed to be effective for obtaining high
enantioselectivity, substituent effects at this position were fur-
ther explored. Catalysts 10p (4-F), 10q (4-OCF3), and 10r (4-
NO2) showed a similar level of enantioselectivity to catalyst
10o (entries 6–8). On the other hand, the reaction with catalyst
10s (4-OMe) resulted in lower enantioselectivity (entry 9). The
catalyst loading was examined with 10o, and it was found
that loading could be reduced to 5 mol% without affecting
the yield or selectivity (entry 10). Furthermore, enantiomeric
Table 3. Asymmetric a-hydroxylation of lactones 8b–e by using a guani-
dine–urea bifunctional organocatalyst 10i or 10o.[a]
Entry
Substrate
Cat.
Product[b]
Yield [%]
ee [%][c,d]
1
2
3
4
8b
8c
8d
8e[e]
10i
5b
5c
5d
5e
99
95
90
99
75
82
82
80, 90[f]
10o
10o
10i
[a] Reactions were performed with 8 (0.1 mmol), CHP (0.15 mmol), K2CO3
(0.1 mmol), and catalyst (0.005 mmol) in toluene at 08C for 24 h. [b] Race-
mic a-hydroxy lactones 5b–e for HPLC analysis were derived from lacto-
nes 8b–e by reaction with NaHMDS and (Æ)-N-tosyl-phenyloxaziridine[19]
in THF. [c] The enantiomeric excess was determined by chiral HPLC analy-
sis. [d] Absolute stereochemistries were deduced from the results of oxi-
dation of 5a. [e] Oxidation did not proceed in the case of 8 f with ethyl-
ene dioxide-derived acetal at C2 because of its insolubility.[20] Thus, we ex-
amined the reaction with 8e bearing neopentyl glycol-derived acetal.
[f] Enantiomeric purity was increased into 90% ee by a single recrystalliza-
tion from ethanol.
purity was increased to 93% ee by a single recrystallization
from ethanol (entry 10).
Next, a series of lactones 8b–e[17] bearing a methyl, n-butyl,
1-phenylethyl, or benzyl group as R, respectively, were tested
by using the guanidine–urea catalyst 10i or 10o.[18] In these re-
actions, the corresponding products 5b–e were obtained in
high yields with good ee (Table 3, entries 1–4).
Table 2. Asymmetric a-hydroxylation of lactone 8a by using guanidine–
urea bifunctional organocatalysts 10k–s.[a]
The cytotoxicity of 1 is modified by variation of the substitu-
ent at C20,[21] thus product 5e was applied to a synthesis of
(+)-C20-desethylbenzyl camptothecin (13)[22,23] (Scheme 4). De-
protection of the acetal in 5e (80% ee) with 80% trifluoroace-
tic acid (TFA) afforded ketone 5e. This ketone was subjected to
the Friedlander reaction with aniline 12[24] in the presence of
p-toluenesulfonic acid to give (+)-C20-desethylbenzyl campto-
thecin (13). Optically pure compound (+)-13 was isolated in
16% yield from 5e by means of a single recrystallization from
methanol/acetonitrile.
Entry
Cat.
5a
X
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
9
10
10k
10l
H
93
86
89
93
95
99
85
96
70
93
70
76
75
78
84
82
83
82
3,5-di-F
2-CF3
3-CF3
4-CF3
4-F
4-OCF3
4-NO2
4-OMe
4-CF3
10m
10n
10o
10p
10q
10r
Elucidation of a catalytic reaction mechanism based upon
structure–activity relationship studies
To gain insight into the cooperative roles of the guanidine and
urea groups and the chiral spacer in the catalysts 10, we per-
formed the following control experiments using as catalysts
the carbamate 14[25] (lacking urea), triurea 15[26] (lacking guani-
dine), and unsymmetrical 16[26] (lacking C2 symmetry) bearing
a monomethyl chiral spacer under the conditions used in
Table 2, entry 5 (Table 4). In the case of catalyst 14, no reaction
took place, but addition of urea 17[27] (10 mol%) under catalyt-
ic conditions effectively promoted the reaction, and 5a was
10s
10o[c]
78
84, 93[d]
[a] Reactions were performed with 8a (0.1 mmol), CHP (0.15 mmol),
K2CO3 (0.1 mmol), and catalyst (0.01 mmol) in toluene at 08C for 24 h.
[b] Racemic 5a and (S)-5a were prepared according to ref. [8b] and [8c],
respectively. The enantiomeric excess and the absolute stereochemistry
were determined by chiral HPLC analysis. [c] Reaction was carried out
with 5 mol% of catalyst 10o. [d] Enantiomeric purity was increased to
93% ee by a single recrystallization from ethanol.
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high yield, but enantioselectivity was drastically reduced to
20% ee (entry 5 versus 2 in Table 1). Thus, these results clearly
show that both the guanidine center as a base site and the H-
bond sites of the urea moiety are mandatory for promoting
the reaction effectively. Moreover, C2-symmetrical structure was
crucial to achieve high enantioselectivity in the a-hydroxyl-
ation of lactones 8.
Based upon those findings together with the absolute ste-
reochemistry of (S)-5a at C20, a possible transition state for
this reaction in the presence of catalyst 10 was proposed to
account for the enantioselectivity, as shown in Figure 2. Sub-
Scheme 4. Synthesis of (+)-C20-desethylbenzyl camptothecin (13).[24]
obtained in 85% yield, although its enantioselectivity was low
(entries 1 and 2). Triurea 15 only showed low catalytic activity,
but the yield of 5a was increased to 64% by addition of
10 mol% of tetramethyl guanidine (18), although enantioselec-
tivity was low in both cases (entries 3 and 4). In the case of un-
symmetrical catalyst 16, the product 5a was obtained with
Figure 2. Plausible transition state of the a-hydroxylation catalyzed by 10.
strate 8a coordinates with guanidine as an enolate form, while
at the same time, the urea part of the catalyst interacts with
CHP, which is activated via a double hydrogen-bonding inter-
action. Then nucleophilic attack of the enolate takes place on
CHP from the preferential transition state TS-1, which avoids
the steric repulsion between the ethyl group in 8a and the
urea moiety in the catalyst, resulting in the formation of (S)-5a.
Table 4. Cooperative effects of guanidine and urea and the chiral spacer
in a-hydroxylation catalysts.[a]
Conclusion
In summary, we have developed a catalytic asymmetric a-hy-
droxylation of a vinylogous-type lactone 8a utilizing guani-
dine–urea bifunctional organocatalyst 10 for synthesis of 5a,
which is a key synthetic intermediate of (20S)-camptothecin
and its analogues. The functional groups of guanidine and
urea and the chiral spacer in 10 act cooperatively to give 5a in
high yield (up to 99%) with high enantioselectivity (up to
84% ee). This new catalytic oxidation was efficiently applied to
the synthesis of C20-modified camptothecin analogue (+)-13.
Entry
Cat.
Additive (equiv)
5a
ee [%][b]
Experimental Section
Yield [%]
R or S
General remarks
1
2
3
4
5
14
14
15
15
16
–
trace
85
25
64
92
–
8
7
5
20
–
R
S
S
S
17 (0.1)
–
18 (0.1)
–
Flash chromatography was performed using silica gel 60 (spherical,
particle size 0.040–0.100 mm. Kanto Co., Japan) or NH silica gel
(spherical, particle size 0.06 mm, Fuji Silysia Chemical, Japan). Opti-
1
cal rotations were measured on a JACO P-2200 polarimeter. H and
13C NMR spectra were recorded on AL300 (JEOL), ECX400 (JEOL),
JNM500 (JEOL), or AVANCE400 (Bruker) instruments. Chemical shifts
in [D]chloroform, [D4]MeOH, or [D6]dimethylsulfoxide were report-
ed in the scale relative to [D]chloroform (d=7.26 ppm), [D4]MeOH
[a] Reactions were performed with 8a (0.1 mmol), CHP (0.15 mmol),
K2CO3 (0.1 mmol), and catalyst (0.01 mmol) in toluene at 08C for 24 h.
[b] The enantiomeric excess and the absolute stereochemistry were de-
termined by chiral HPLC analysis.
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(d=3.30 ppm), and [D6]dimethylsulfoxide (d=2.50 ppm) for
1H NMR spectroscopy, respectively. For 13C NMR spectra, chemical
shifts were reported in the scale relative to [D]chloroform (d=
77.0 ppm), [D4]MeOH (d=49.0 ppm), or [D6]dimethylsulfoxide (d=
39.5 ppm) as internal references, respectively. Mass spectra were
recorded on a JMS-T100LC (JEOL) spectrometer. Melting points
were measured on a Bꢁchi model B-545 instrument without correc-
tion. Elemental analyses were performed by using a Perkin–Elmer
2400 CHN-Analyzer and Yokogawa IC7000S ion chromatograph
(oxygen flask method).
13C NMR (75 MHz, CDCl3): d=29.5, 33.8, 39.6, 44.8, 65.5, 65.6, 66.2,
72.1, 96.6, 112.9, 118.3, 126.2, 128.2, 128.4, 140.0, 149.4, 149.6,
157.4, 173.5 ppm; HRMS (ESI): calcd for C21H21NO6Na: 406.1266
[M+Na]+; found: 406.1222; enantiomeric excess of 5d was deter-
mined to be 82% ee by chiral HPLC analysis: DAICEL Chiralpak IA
column (250ꢂ4.6 mm), n-hexane/2-propanol 70:30, flow rate:
1 mLminÀ1, l=220 nm, t1 =32.06 (major), t2 =25.84 (minor).
a-Hydroxy lactone 5e: 99% yield; [a]2D5 = +26.7 (c=0.55 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.90 (s, 3H), 1.26 (s, 3H),
2.48–2.58 (m, 2H), 3.09 (q, J=13.2, 30.9 Hz, 2H), 3.65 (s, 2H), 3.67
(s, 2H), 4.09–4.19 (m, 2H), 4.63 (d, J=16 Hz, 1H), 5.46 (d, J=16 Hz,
1H), 6.72 (s, 1H), 7.06–7.08 (m, 2H), 7.26–7.27 ppm (m, 3H);
13C NMR (75 MHz, CDCl3): d=22.1, 22.5, 29.8, 30.3, 45.4, 46.0, 66.2,
72.2, 72.3, 72.8, 97.6, 105.0, 119.2, 127.6, 128.2, 130.1, 132.8, 148.2,
149.2, 157.0, 172.9 ppm; HRMS (ESI, [M+Na]+): calcd for
C23H25NO6Na: 434.1580; found: 434.1561; enantiomeric excess of
5e was determined to be 80% ee by chiral HPLC analysis: DAICEL
Chiralpak IA column (250ꢂ4.6 mm), n-hexane/ethanol 60:40; flow
rate: 1 mLminÀ1, l =220 nm, t1 =19.52 (major), t2 =11.60 (minor).
General procedure for catalytic asymmetric a-hydroxylation
of pyranoindolizine derivatives 8 by using guanidine–urea
bifunctional organocatalysts 10
A test tube equipped with a magnetic stirring bar was charged
with catalyst 10 (0.01 mmol), pyranoindolizine derivative
8
(0.1 mmol), K2CO3 (0.1 mmol), and toluene (1.0 mL) at room tem-
perature. The mixture was cooled to 08C and stirred for 10 min.
Then, cumene hydroperoxide (0.15 mmol) was added to it, and the
whole was stirred at 08C for 24 h. The reaction was quenched by
addition of Na2S2O3 solution (10%, 2 mL) and acetic acid (0.2 mL),
and the mixture was vigorously stirred at room temperature for
1 h. The organic layer was separated and the aqueous layer was
extracted three times with CHCl3. The combined organic solution
was concentrated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel (n-hexane/ethyl ace-
tate 1:1 to CHCl3/CH3OH 100:1) to give the product 6. The enantio-
meric excess and the absolute configuration were determined by
HPLC analysis of the product by using a chiral column (DAICEL
Chiralpak IA) with n-hexane/ethanol as the eluent.
Synthesis of guanidine–urea bifunctional organocatalysts
(10d–s)
Compounds 10d–s were synthesized according to the known pro-
cedure[15f,25] with minor modifications. See the Supporting Informa-
tion for details.
Compound 10d: [a]D29 = +39.4 (c=1.2 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=0.89 (t, J=6.9 Hz, 3H), 1.13–1.40 (m, 32H),
1.52–1.67 (m, 2H), 3.09–3.50 (m, 4H), 4.91–4.98 (m, 2H), 7.30–7.56
(m, 12H), 8.00 ppm (s, 4H); 13C NMR (100 MHz, CD3OD): d=14.4,
23.7, 27.9, 29.8, 30.3, 30.5, 30.56, 30.58, 30.66, 30.72, 30.75, 30.78,
a-Hydroxy lactone 5a: For details of the spectral data of a-hy-
droxy lactone 5a, see the ref. [8b]. Enantiomeric excess of 5a was
determined by chiral HPLC analysis: DAICEL Chiralpak IA column
33.1, 43.3, 48.5, 55.2, 115.9 (br), 119.1 (br), 124.8 (q, J
=
CÀF
(250ꢂ4.6 mm), n-hexane/ethanol 60:40, flow rate 1 mLminÀ1
l =220 nm, t1 =18.93 (major), t2 =24.92 (minor).
,
272.0 Hz), 128.2, 129.5, 130.2, 133.3 (q, J CÀF =33.1 Hz), 140.2, 143.0,
156.5, 157.5 ppm; HRMS (ESI, [M+H]+): calcd for C53H66F12N7O2:
1060.5086; found: 1060.5097.
a-Hydroxy lactone 5b: 99% yield; [a]2D5 = +66.6 (c=1.0 in CHCl3/
CH3OH 1:1);1H NMR (500 MHz, CDCl3): d=1.27 (d, J=7.3 Hz, 3H),
2.4 (t, J=6.9 Hz, 2H), 3.5 (q, J=6.9 Hz, 1H), 4.10–4.21 (m, 6H), 5.24
(d, J=15.6 Hz, 1H), 5.43 (d, J=15.6 Hz, 1H), 6.19 ppm (s, 1H);
13C NMR (75 MHz, CDCl3): d=25.9, 33.9, 44.8, 65.5, 65.8, 66.0, 95.8,
113.0, 118.1, 149.8, 150.2, 157.4, 174.5 ppm; HRMS (ESI): calcd for
C14H15N1O6Na: 316.0797 [M+Na]+; found: 316.0784; enantiomeric
excess of 5b was determined to be 75% ee by chiral HPLC analy-
sis: DAICEL Chiralpak IA column (250ꢂ4.6 mm), n-hexane/2-propa-
nol 70:30, flow rate: 1 mLminÀ1, l =220 nm, t1 =20.20 (major),
t2 =15.91 (minor).
Compound 10e: [a]D27 = +1.7 (c=1.5 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=0.89 (t, J=6.7 Hz, 3H), 0.92 (d, J=6.2 Hz,
6H), 0.98 (d, J=6.7 Hz, 6H), 1.10–1.37 (m, 30H), 1.40–1.58 (m, 4H),
1.58–1.71 (m, 2H), 1.72–1.85 (m, 2H), 3.21 (t, J=7.2 Hz, 2H), 3.24–
3.34 (m, 4H), 3.9 (br, 2H), 7.5 (s, 2H), 8.04 ppm (s, 4H); 13C NMR
(100 MHz, CD3OD): d=14.6, 22.1, 23.9, 26.2, 28.0, 29.9, 30.3, 30.59,
30.64, 30.66, 30.74, 30.80, 30.82, 30.87, 30.90, 33.2, 42.5, 43.2, 48.6,
115.9 (br), 119.2 (br), 124.9 (q, JCÀF =272.0 Hz), 133.4 (q, JCÀF
=
33.1 Hz), 143.3, 156.5, 158.2 ppm; HRMS (ESI): calcd for
C49H74F12N7O2: 1020.5712 [M+H]+; found: 1020.5738.
a-Hydroxy lactone 5c: 95% yield; [a]2D5 = +75.9 (c=0.91 in
CHCl3); H NMR (500 MHz, CDCl3): d=0.87 (t, J=7.6 Hz, 3H), 1.22–
Compound 10 f: [a]D30 = +39.2 (c=1.2 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=0.89 (t, J=6.9 Hz, 3H), 1.14–1.32 (m, 30H),
1.35 (d, J=6.7 Hz, 6H), 1.60–1.73 (m, 2H), 3.10–3.31 (m, 4H), 3.35–
3.48 (m, 2H), 3.73–3.84 (m, 2H), 7.49 (s, 2H), 8.04 ppm (s, 4H);
13C NMR (100 MHz, CD3OD): d=14.6, 18.4, 23.9, 28.0, 29.8, 30.3,
30.6, 30.66, 30.68, 30.76, 30.84, 30.88, 30.91, 33.2, 43.3, 46.7, 50.0,
115.9 (br), 119.2 (br), 125.0 (q, JCÀF =271 Hz), 133.3 (q, JCÀF =33 Hz),
143.3, 155.5, 158.5 ppm; HRMS (ESI): calcd for C43H62F12N7O2:
936.4773 [M+H]+; found: 936.4737.
Compound 10g: [a]D27 =À42.4 (c=1.3 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.18 (t, J=6.9 Hz, 6H), 1.26 (d, J=7.2 Hz,
6H), 3.26–3.34 (m, 2H), 3.35–3.49 (m, 6H), 4.04–4.15 (m, 2H), 7.47
(s, 2H), 8.02 (s, 4H); 13C NMR (100 MHz, CD3OD): d=12.9, 18.7,
44.3, 47.3, 52.0, 115.8 (br), 119.1 (br), 124.8 (q, JCÀF =272 Hz), 133.2
1
1.39 (m, 3H), 1.67–1.81 (m, 3H), 2.42 (t, J=6.9 Hz, 2H), 3.74 (s, 1H),
4.07–4.23 (m, 6H), 5.17 (d, J=16 Hz, 1H), 5.61 (d, J=16 Hz, 1H),
6.57 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=13.7, 22.3, 25.2,
33.8, 37.8, 44.7, 65.4, 65.5, 66.1, 72.2, 96.6, 112.9, 118.2, 149.2, 150.0,
157.4, 173.7 ppm; HRMS (ESI, [M+Na]+): calcd for C17H21NO6Na:
358.1267; found: 358.1222; enantiomeric excess of 5c was deter-
mined to be 82% ee by chiral HPLC analysis: DAICEL Chiralpak IA
column (250ꢂ4.6 mm), n-hexane/2-propanol 70:30, flow rate:
1 mLminÀ1, l =220 nm, t1 =26.51 (major), t2 =17.35 (minor).
a-Hydroxy lactone 5d: 90% yield; [a]2D5 = +13.3 (c=0.92 in
1
CHCl3); H NMR (500 MHz, CDCl3): d=1.96–2.12 (m, 2H), 2.42 (t, J=
6.9 Hz, 2H), 2.66–2.76 (m, 2H), 3.87 (s, 1H), 4.08–4.25 (m, 6H), 5.19
(d, J=16 Hz, 1H), 5.64 (d, J=16 Hz, 1H), 6.62 (s, 1H), 7.12 (d, J=
6.9 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.25 ppm (d, J=8.6 Hz, 2H);
(q,
JCÀF =32 Hz), 143.2, 157.6, 160.7; HRMS (ESI): calcd for
C29H34F12N7O2: 740.2582 [M+H]+; found: 740.2597.
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Compound 10h: [a]D29 =À22.2 (c=1.3 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.27 (d, J=6.7 Hz, 6H), 2.32–2.44 (m, 2H),
3.23–3.35 (m, 4H), 3.96–4.09 (m, 2H), 4.22–4.37 (m, 4H), 7.48 (s,
2H), 7.99 ppm (s, 4H); 13C NMR (100 MHz, CD3OD): d=16.9, 18.4,
47.1, 50.0, 54.2, 115.9 (br), 119.2 (br), 124.9 (q, JCÀF =271.9 Hz),
133.3 (q, JCÀF =33.3 Hz), 143.3, 157.77, 157.82, 163.3, 163.7 ppm;
HRMS (ESI): calcd for C28H30F12N7O2: 724.2269 [M+H]+; found:
724.2257.
157.76, 157.84 ppm; HRMS (ESI): calcd for C27H34F6N7O2: 602.2678
[M+H]+; found: 602.2650.
Compound 10p: [a]D27 =À40.8 (c=1.3 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.22 (d, J=6.7 Hz, 6H), 1.80–2.00 (m, 4H),
3.24 (dd, J=8.7, 13 Hz, 2H), 3.40–3.54 (m, 4H), 3.42 (dd, J=4.4,
13 Hz, 2H), 3.94–4.09 (m, 2H), 6.92–7.01 (m, 4H), 7.29–7.35 ppm
(m, 4H); 13C NMR (100 MHz, CD3OD): d=18.6, 26.3, 47.1, 50.3, 51.5,
116.3 (d, JCÀF =22.3 Hz), 122.1 (d, JCÀF =7.7 Hz), 136.8 (d, JCÀF
=
Compound 10i: [a]D29 =À34.6 (c=1.1 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.26 (d, J=6.7 Hz, 6H), 1.83–2.03 (m, 4H),
3.26–3.37 (m, 2H), 3.42 (dd, J=4.9, 13 Hz, 2H), 3.43–3.58 (m, 4H),
3.98–4.14 (m, 2H), 7.49 (s, 2H), 8 ppm (s, 4H); 13C NMR (100 MHz,
CD3OD): d=18.6, 26.3, 47.3, 50.3, 51.5, 115.8 (br), 119.1 (br), 124.9
2.3 Hz), 157.8, 158.4, 160 ppm (d, JCÀF =240 Hz); HRMS (ESI): calcd
for C25H34F2N7O2: 502.2742 [M+H]+; found: 502.2724.
Compound 10q: [a]D27 =À43.5 (c=1.1 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.23 (d, J=6.7 Hz, 6H), 1.80–2.03 (m, 4H),
3.27 (dd, J=8.2, 13 Hz, 2H), 3.42 (dd, J=4.6, 13 Hz, 2H), 3.42–3.54
(m, 4H), 3.97–4.09 (m, 2H), 7.14 (brd, J=8.2 Hz, 4H), 7.38–
7.45 ppm (m, 4H); 13C NMR (100 MHz, CD3OD): d=18.6, 26.3, 47.1,
50.3, 51.5, 121.1, 122.0 (q, JCÀF =255 Hz), 122.8, 140.0, 145.3 (br),
157.8, 158.1 ppm; HRMS (ESI): calcd for C27H34F6N7O4: 634.2577
[M+H]+; found: 634.2576.
Compound 10r: [a]D30 =À73.4 (c=1.1 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.26 (d, J=7.2 Hz, 6H), 1.86–2.07 (m, 4H),
3.33 (dd, J=8.2, 13 Hz, 2H), 3.42 (dd, J=4.6, 13 Hz, 2H), 3.46–3.56
(m, 4H), 3.96–4.11 (m, 2H), 7.50–7.60 (m, 4H), 8.07–8.14 ppm (m,
4H); 13C NMR (100 MHz, CD3OD): d=18.5, 26.4, 47.3, 50.4, 51.4,
118.6, 126.0, 143.3, 147.4, 157.3, 157.8 ppm; HRMS (ESI): calcd for
C25H34N9O6: 556.2632 [M+H]+; found: 556.2673.
Compound 10s: [a]D27 =À56.9 (c=1.1 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.22 (d, J=6.7 Hz, 6H), 1.78–2.01 (m, 4H),
3.22 (dd, J=8.5, 13 Hz, 2H), 3.41–3.55 (m, 4H), 3.43 (dd, J=4.1,
13 Hz, 2H), 3.73 (s, 6H), 3.95–4.07 (m, 2H), 6.75–6.86 (m, 4H), 7.13–
7.22 ppm (m, 4H); 13C NMR (100 MHz, CD3OD): d=18.7, 26.3, 47.1,
50.3, 51.4, 55.9, 115.2, 122.8, 133.4, 157.3, 157.8, 158.7 ppm; HRMS
(ESI): calcd for C27H40N7O4: 526.3142 [M+H]+; found 526.3174.
(q,
J CÀF =271.7 Hz), 133.2 (q, J CÀF =33.1 Hz), 143.2, 157.6,
157.9 ppm; HRMS (ESI): calcd for C29H32F12N7O2: 738.2426 [M+H]+;
found: 738.2401.
Compound 10j: [a]D29 =À40.5 (c=1.1 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.25 (d, J=7.2 Hz, 6H), 1.64 (m, 6H), 3.25–
3.39 (m, 6H), 3.42 (dd, J=4.3, 13 Hz, 2H), 4.03–4.15 (m, 2H), 7.48
(s, 2H), 8.01 ppm (s, 4H); 13C NMR (100 MHz, CD3OD): d=18.8, 25.0,
26.7, 47.3, 50.5, 51.5, 115.8 (br), 119.2 (br), 125.0 (q, JCÀF =271.5 Hz),
133.3 (q, JCÀF =33.3 Hz), 143.3, 157.5, 161.0 ppm; HRMS (ESI): calcd
for C30H34F12N7O2: 752.2582 [M+H]+; found: 752.2594.
1
Compound 10k: [a]2D7 =À50.6 (c=1.2, CH3OH); H NMR (400 MHz,
CD3OD): d=1.22 (d, J=7.2 Hz, 6H), 1.78–1.98 (m, 4H), 3.24 (dd, J=
8.7, 13 Hz, 2H), 3.42–3.54 (m, 4H), 3.43 (dd, J=4.4, 13 Hz, 2H),
3.96–4.11 (m, 2H), 6.93–7.00 (m, 2H), 7.18–7.26 (m, 4H), 7.30–
7.36 ppm (m, 4H); 13C NMR (100 MHz, CD3OD): d=18.6, 26.3, 47.0,
50.3, 51.5, 120.3, 123.7, 129.9, 140.7, 157.8, 158.3 ppm; HRMS (ESI):
calcd for C25H36N7O2: 466.2931 [M+H]+, found: 466.2910.
Compound 10l: [a]D27 =À51.3 (c=1.2 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.24 (d, J=6.7 Hz, 6H), 1.85–2.05 (m, 4H),
3.27 (dd, J=8.7, 14 Hz, 2H), 3.41 (dd, J=4.6, 14 Hz, 2H), 3.43–3.55
(m, 4H), 3.95–4.09 (m, 2H), 6.46–6.54 (m, 2H), 6.96–7.06 ppm (m,
4H); 13C NMR (100 MHz, CD3OD): d=18.6, 26.4, 47.2, 50.3, 51.5,
97.9 (t, JCÀF =26 Hz), 102.2 (d, JCÀF =30 Hz), 143.7 (t, JCÀF =14 Hz),
157.6, 157.8, 164.8 ppm (dd, JCÀF =15, 244 Hz); HRMS (ESI): calcd
for C25H32F4N7O2: 538.2554 [M+H]+; found: 538.2509.
Synthesis of (+)-C20-desethylbenzyl camptothecin (13)
A solution of compound 5e (822 mg, 2.0 mmol, 80% ee) in 80%
aqueous TFA (25 mL) was stirred at room temperature for 1 h. The
mixture was diluted with water and then extracted with CHCl3. The
organic extract was dried over MgSO4, filtered, and then concen-
trated under reduced pressure to give ketone 4e, which was used
in the next step without purification. A mixture of crude ketone
4e, 2-aminobenzaldehyde dimethylacetal (12) (6.0 mmol), pTsOH
(0.02 mmol), and toluene (40 mL) was refluxed for 18 h by using
a Dean–Stark trap under a nitrogen atmosphere, and then the re-
action mixture was concentrated under reduced pressure. The re-
sulting residue was purified by column chromatography on silica
gel (CHCl3/ethyl acetate 2:1 to 1:1) to give a brown solid. The solid
was recrystallized from methanol/acetonitrile to give (+)-C20-dese-
thylbenzyl camptothecin (13) (130 mg, 16%, 2 steps). M.p. 247–
2508C (dec.); [a]2D6 = +54.8 (c=0.5 in DMF); 1H NMR (400 MHz,
[D6]DMSO): d=3.19 (dd, J=13.3, 61.8 Hz, 2H), 3.51 (s, 1H), 4.77 (d,
J=16.0 Hz, 1H), 5.23–5.36 (m, 3H), 6.81 (s, 1H), 7.06–7.07 (m, 2H),
7.18–7.20 (m, 3H), 7.71 (t, J=7.8 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H),
8.13 (t, J=7.8 Hz, 2H), 8.68 ppm (s, 1H); 13C NMR (100 MHz,
[D6]DMSO): d=44.3, 50.1, 65.3, 72.9, 96.9, 119.6, 127.0, 127.6, 127.8,
128.4, 129.0, 129.6, 130.3, 130.4, 131.5, 134.0 ppm; HRMS (ESI):
calcd for C25H18N2O4Na: 433.1164 [M+Na]+; found: 434.1208; enan-
tiomeric excess of 13 was determined to be >99% ee by chiral
HPLC analysis: DAICEL Chiralpak IA column (250ꢂ4.6 mm), n-
hexane/ethanol 60:40, flow rate: 0.2 mLminÀ1, l =220 nm, t1 =
24.72 (major), t2 =23.61 (minor).
Compound 10m: [a]D27 =À10.8 (c=1.2 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.24 (d, J=7.2 Hz, 6H), 1.86–2.02 (m, 4H),
3.28 (dd, J=8.2, 13 Hz, 2H), 3.39 (dd, J=4.6, 13 Hz, 2H), 3.44–3.52
(m, 4H), 3.93–4.14 (m, 2H), 7.24 (t, J=7.7 Hz, 2H), 7.54 (t, J=
8.2 Hz, 2H), 7.62 (d, J=7.7 Hz, 2H), 7.82 ppm (d, J=8.2 Hz, 2H);
13C NMR (100 MHz, CD3OD): d=18.6, 26.3, 47.2, 50.3, 51.6, 122.9 (q,
J
CÀF =29 Hz), 125.3, 125.5 (q, JCÀF =272 Hz), 127.1 (q, JCÀF =5.8 Hz),
127.3, 133.8, 137.6, 157.7, 158.3 ppm; HRMS (ESI): calcd for
C27H34F6N7O2: 602.2678 [M+H]+; found: 602.2728.
Compound 10n: [a]D27 =À40.6 (c=1.2 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.24 (d, J=6.7 Hz, 6H), 1.81–2.02 (m, 4H),
3.27 (dd, J=8.2, 13 Hz, 2H), 3.40–3.55 (m, 4H), 3.43 (dd, J=4.4,
13 Hz, 2H), 3.99–4.12 (m, 2H), 7.24 (brd, J=7.2 Hz, 2H), 7.37–7.43
(m, 2H), 7.46 (brd, J=8.7 Hz, 2H), 7.85 (s, 2H); 13C NMR (100 MHz,
CD3OD): d=18.5, 26.3, 47.1, 50.3, 51.6, 116.1 (q, JCÀF =3.9 Hz), 119.7
(q, JCÀF =3.9 Hz), 123.0, 125.7 (q, JCÀF =271 Hz), 130.7, 132.0 (q,
J
CÀF =32 Hz), 141.8, 157.9, 158.0 ppm; HRMS (ESI): calcd for
C27H34F6N7O2: 602.2678 [M+H]+; found: 602.2723.
Compound 10o: [a]D29 =À52.5 (c=1.2 in CH3OH); 1H NMR
(400 MHz, CD3OD): d=1.24 (d, J=7.2 Hz, 6H), 1.80–2.02 (m, 4H),
3.29 (dd, J=8.7, 14 Hz, 2H), 3.43 (dd, J=4.4, 14 Hz, 2H), 3.43–3.55
(m, 4H), 3.98–4.11 (m, 2H), 7.47–7.56 ppm (m, 8H); 13C NMR
(100 MHz, CD3OD): d=18.6, 26.3, 47.2, 50.4, 51.4, 119.3, 125.0 (q,
J
CÀF =32 Hz), 125.9 (q, JCÀF =271 Hz), 127.1 (q, JCÀF =3.9 Hz), 144.5,
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Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Transfor-
mations by Organocatalysts” (no. 23105013) from the Ministry
of Education, Culture, Sports, Science and Technology, Japan,
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Keywords: camptothecin · guanidine · natural products ·
organocatalysis · urea
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Received: September 14, 2013
Published online on November 28, 2013
Chem. Eur. J. 2014, 20, 591 – 597
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