Efficient total synthesis of (S)-14-azacamptothecin

Article abstract of DOI:10.1002/asia.201000073

An efficient total synthesis of (S)-14-azacamptothecin has been accomplished in 10 steps and 56% overall yield from 5H-pyrano[4, 3-d]pyrimidine 8.A mild Hendrickson reagent-triggered intramolecular cascade cyclization, a highly enantioselective dihydroxylation, and an efficient palladium-catalyzed transformation of an O-allyl into N-allyl group are the key steps in the synthesis. This work provides a much higher overall yield than the previous achievement and shows sound flexibility for the further applications that will lead to new bioactive analogues.

Full text of DOI:10.1002/asia.201000073

FULL PAPERS
DOI: 10.1002/asia.201000073
Efficient Total Synthesis of (S)-14-Azacamptothecin
Guan-Sai Liu,[a, b] Yuan-Shan Yao,[a, b] Peng Xu,[a, b] Shaozhong Wang,[a] and
Zhu-Jun Yao*[a, b]
Abstract: An efficient total synthesis of (S)-14-azacamptothecin has been accom-
plished in 10 steps and 56% overall yield from 5H-pyranoACHTNUTRGNEUNG[4,3-d]pyrimidine 8. A
mild Hendrickson reagent-triggered intramolecular cascade cyclization, a highly
enantioselective dihydroxylation, and an efficient palladium-catalyzed transforma-
tion of an O-allyl into N-allyl group are the key steps in the synthesis. This work
provides a much higher overall yield than the previous achievement and shows
sound flexibility for the further applications that will lead to new bioactive ana-
logues.
Keywords: 14-azacamptothecin · al-
lyl migration · asymmetric dihy-
droxylation
synthesis
· cyclization · total
Introduction
Camptothecin (CPT, 1) is a representative of the unique
pentacyclic alkaloids isolated from Chinese medicinal plant
Camptotheca acumunata.[1] The potent anticancer activities
and unusual action mechanisms by inhibiting DNA topoiso-
merase I[2] have made CPT an excellent and successful lead
for drug discovery and development in the past several de-
cades.[3] Other natural alkaloids in this family, including 22-
hydroxyacuminatine (3)[4] and luotonin A (4),[5] have also
been found to display similar inhibitory properties against
DNA Top I. Unfortunately, camptothecin itself could not be
used in clinical treatments because of its poor water solubili-
ty and high toxicity. Initial clinical trials of CPT in the early
1970s were administered with its more toxic and less potent
sodium salt 2. Continuous endeavors in the medicinal
chemistry of CPT in the past decades have made great suc-
cesses. The semi-synthetic, more water-soluble analogues
topotecan (1a) and irinotecan (1b) have now been success-
fully applied in the clinical treatments of a number of can-
cers.[6,7] Several additional CPT analogues have also been
developed and studied in different stages of clinical
trials.[8]14-Azacamptothecin (5) is one of the water-soluble
CPT analogues recently developed by Hecht and co-work-
ers,[9] in which the C-14 carbon atom of natural camptothe-
cin (1) is replaced with a nitrogen atom. It was firstly syn-
thesized by utilizing a radical cyclization strategy by the
same group.[10] Such aza modification greatly improves the
water solubility of the compound and thus facilitates the
corresponding biomedical research. Furthermore, evidence
has shown that 14-azacamptothecin can stabilize the topo-
[a] G.-S. Liu, Y.-S. Yao, P. Xu, Dr. S. Wang, Prof. Dr. Z.-J. Yao
Nanjing National Laboratory of Microstructures
School of Chemistry and Chemical Engineering
Nanjing University
22 Hankou Road, Nanjing, Jiangsu 210093 (China)
E-mail: yaoz@sioc.ac.cn
yaoz@nju.edu.cn
[b] G.-S. Liu, Y.-S. Yao, P. Xu, Prof. Dr. Z.-J. Yao
Joint Laboratory of Green Chemistry
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000073.
AHCTUNGTREGiNNUN somerase I-DNA complex at the same sites as CPT with a
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Chem. Asian J. 2010, 5, 1382 – 1388

somewhat more potent IC50 value.[9] Therefore, 14-azacamp-
tothecin shows great potential as a new lead structure for
the future design and development of anticancer drugs.
For a significant difference from the basic skeleton of
camptothecin, total synthesis is now the only entrance to ac-
quire the samples of 14-azacamptothecin[10] and other relat-
ed derivatives.[11] However, the relatively low overall yield
(0.6% yield in 10 total steps) and the inefficient radical cyc-
lization (28% yield in a single step) in the previously ach-
ieved total synthesis of 14-azacamptothecin[10] encumber the
progress of further applications. In the synthesis of another
the resulting hemiacetal intermediate were employed to es-
tablish the lactone moiety and its C-20 stereochemistry. Our
recently developed aza Diels–Alder approach[14] via the For-
tunak intermediate[15] was considered to construct both the
B and C rings of key cyclic enol ether 6 from the simple
amide 7 in a one-pot fashion.
Results and Discussion
Synthesis of the stable amide 7: Following the above retro-
synthesis (Scheme 1), the chemically stable amide 7 was syn-
thesized at first. Chloropyrimidine 8, a known common in-
termediate in the previous syntheses of 14-azacamptothe-
cin[10] and 10,11-methylenedioxy-14-azacamptothecin,[11] was
utilized in this work again (Scheme 2). Catalytic carbonyla-
tion of chloropyrimidine 8 was smoothly accomplished
under a CO atmosphere (120 psig) in the presence of
derivative, 10,11-methylenedioxy-14-azacamptothecin,
a
much lower yield (6%) has been achieved in the key radical
cyclization.[11] Undoubtedly, the development of a more effi-
cient total synthesis of 14-azacamptothecin would be helpful
in acquiring more clinically useful derivatives of 14-aza-
camptothecin. Prompted by our recent achievements in the
total syntheses of camptothecin (1), luotonin A (4), and 22-
hydroxyacuminatine (3) by using an efficient Hendrickson
reagent-triggered mild cascade reaction,[12–14] we attempted
to extend our methodology to the synthesis of 14-azacamp-
tothecin. Herein, we wish to report our recent results in the
total synthesis of (S)-14-azacamptothecin (5) by utilizing the
mild cascade methodology, and our exploration in the enan-
tioselective dihydroxylation of multiple nitrogen-containing
cyclic enol ethers.
2 mol% of [PdCl2ACHTNUGRTENNUG(CH2Cl2)ACHUTGNTREN(NUGN dppf)] (dppf=1,1’-bis(diphenyl-
phosphino)ferrocene) and Et3N in methanol at 908C afford-
ing the corresponding methyl ester 9 (92%). O-Demethyla-
tion of 9 with trimethylsilyl chloride (TMSCl) and sodium
iodide[16] in acetonitrile and a catalytic amount of water
gave pyrimidinone 10 (79%) and another minor decarboxy-
lation byproduct 11 (14%). Treatment of 10 with propargyl
bromide, K2CO3, and LiBr in the presence of a catalytic
amount of tetrabutylammonium bromide in toluene[17] pro-
vided N-propargylation product 12 (77%) and O-propargy-
lation product 13 (12%), respectively. Unfortunately, further
hydrolysis of methyl ester 12 with LiOH did not afford the
The formation of the a-hydroxyl lactone moiety of 14-aza-
camptothecin was devised in the final stages of the total syn-
thesis in our initial retrosynthesis (Scheme 1). Sharpless
asymmetric dihydroxylation (Sharpless AD) of the cyclic
enol ether 6 and subsequent iodine-mediated oxidation of
Scheme 1. Initial retrosynthesis of 14-azacamptothecin (5).
Abstract in Chinese:
Scheme 2. Attempts to synthesize carboxylic acid 15. DIEPA=diisopro-
pylethylamine.
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Z.-J. Yao et al.
FULL PAPERS
expected carboxylic acid 15. Instead, a decarboxylation
product 14 (92%) was provided.
To avoid the undesired decarboxylation, two protocols,
slightly altering the reaction order, were explored
(Scheme 3). In method A, basic hydrolysis of the methyl
step. Treatment of this mixture with freshly prepared Hen-
drickson reagent (bis(triphenyl)oxodiphosphonium trifluoro-
methanesulfonate) for 30 min at 08C to room temperature
afforded the needed cyclic enol ether 6 (56% overall yield
from amide 17, Scheme 4) and the unreacted 20 after sepa-
ration by silica-gel flash chromatography. The corrected
yield of converting 7 to 6 is 91% with consideration of the
ratio of reactants.
Scheme 4. Cascade synthesis of pentacyclic precursor 6.
Oxidations of cyclic enol ethers: With the entire pentacyclic
skeleton 6 in hand, oxidations towards the final target 5
were then attempted. Sharpless dihydroxylation was de-
signed as a crucial step to establish the stereochemistry of
14-azacamptothecin
(5)
in
this
synthesis
(Sche-
me 1).[14a,16,18–19] Treatment of the enol ether 6 with the stan-
dard Sharpless asymmetric dihydroxylation conditions
(K2OsO4, K3[Fe(CN)6], K2CO3, hydroquinidine-2,5-diphen-
yl-4,6-pyrimidinediyl diether ((DHQD)2-PYR), MeSO2NH2,
tBuOH/H2O, 0 8C, 24 h)[20] and followed by further treat-
ment with iodine and CaCO3 afforded a satisfactory yield of
lactone 5. To our surprise, chiral HPLC analysis of the ob-
tained sample 5 indicated that it was completely racemic
(Table 1, entry 1). The use of another commonly used chiral
ligand, (DHQD)2-PHAL, also provided the negative results
(entry 2). Additional optimizations of reaction conditions all
failed, including altering the solvents and temperatures and
Scheme 3. Synthesis of amides 17 and 7.
ester 10 with LiOH in THF/MeOH/H2O 2:2:1 at room tem-
perature gave the acid 16 (90%). To our delight, the decar-
boxylation was not detected in this case. Further treatment
of 16 with aniline in the presence of N’-(3-dimethylamino-
propyl)-N-ethylcarbodiimide (EDCI) and 1-hydroxybenzo-
triazole (HOBt) in dichloromethane at room temperature
afforded the corresponding amide 17 (71%). In another par-
allel method, B, basic hydrolysis of the methyl ester 9 gave
the corresponding carboxylic acid 18 in 99% yield. Conver-
sion of acid 18 to its corresponding acid chloride followed
by treatment with aniline afforded amide 19 (93%). O-De-
methylation of 19 was then carried out with TMSCl and
sodium iodide[16] in acetonitrile, giving the corresponding
amide 17 (97%). Relatively, method B (89% yield from 9)
is more efficient than A (50% yield from 9) for the synthe-
sis of amide 17. Unfortunately, further N-propargylation by
treatment of amide 17 with propargyl bromide provided an
inseparable mixture of the desired product 7 and the by-
Table 1. Dihydroxylations of the pentacyclic intermediate 6.
Entry Conditions
Yield
[%][a]
ee [%][b]
1
2
3
K2OsO4, K3[Fe(CN)6], K2CO3,
(DHQD)2PYR, MeSO2NH2, tBuOH, H2O,
08C, 24 h
K2OsO4, K3[Fe(CN)6], K2CO3,
(DHQD)2PHAL, MeSO2NH2, tBuOH, H2O,
08C, 24 h
65
68
85
0
1
product 20 (7/20 1.9:1, determined by H NMR spectrosco-
py) in a combined yield of 94%.
0
0
Synthesis of pentacyclic precursor 6: Because the byproduct
20 (Scheme 3) is inert under the subsequent reaction condi-
tions, the mixture of 7 and 20 was directly used for the next
K2OsO4, NMO, THF, H2O
[a] The overall isolated yields of rac-5. [b] Determined by chiral HPLC.
NMO=N-methylmorpholine-N-oxide.
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Efficient Total Synthesis of (S)-14-Azacamptothecin
the use of different amounts of the catalyst and ligand.
More interestingly, the ligand-free conditions gave the high-
est yield of rac-5 (85%, entry 3).
see the Supporting Information) (Scheme 6). Its S configura-
tion was further confirmed by an X-ray single-crystal analy-
sis of the bromoacetate 25 (see the Supporting Information).
Failure in the enantioselective dihydroxylations suggested
to us that certain structural factors in substrate 6 prevented
the Sharpless AD from achieving satisfactory enantioselec-
tivity. Comparison with similar substrates in previous suc-
cessful syntheses of camptothecin[14a,18–19] indicated that the
two spatially-close nitrogen atoms (N-14 and N-1, see
Table 1) in the cyclic enol ether 6 might disrupt the effective
coordination of osmium with the chiral ligand during the
AD reactions.[20] To overcome the above drawback, two al-
ternatives could be considered in introducing the required
oxygenated stereogenic center. One is to apply metal-free
oxidations upon the cyclic enol ether 6 and the other is to
use ligand-ability-free olefin precursors as the substrate of
Sharpless AD. Since the enol ether 6 was available, we first-
ly examined Shiꢁs asymmetric epoxidation (Scheme 5).
Scheme 6. Dihydroxylation of enol ethers 19 and 17.
However, the parallel reaction of 17 was quite slow and
gave only a 19% yield of 26 (97% ee determined by HPLC)
after four days, along with a substantial amount of starting
material 17. The use of larger amounts of chiral ligand and
K2OsO4 could not improve the results in the later case.
N-Propargylation and cascade cyclization: Treatment of a-
hydroxylactone 24 with TMSCl and sodium iodide[16] in ace-
tonitrile afforded the amide 26 in 98% yield (Scheme 7).
Because of its poor solubility in many regular organic sol-
vents, tertiary alcohol 26 was then converted to the more
soluble acetate 27 (93%) by using acetic anhydride, pyri-
Scheme 5. Shiꢁs epoxidation of cyclic enol ether 6 and subsequent trans-
fomations to 5.
Treatment of 6 with Shiꢁs epoxidation conditions[21] by using
a catalytic amount of ketone 21 afforded an unstable epox-
ide 22, which was immediately converted to the diol 23 with
water in the presence of silica gel. Further oxidation of 23
with iodine and CaCO3 provided 14-azacamptothecin (5) in
47% overall yield in 3 steps from 6. Unfortunately, the opti-
cal purity of this product was again unsatisfactory (38% ee
(ee=enantiomeric excess) as measured by chiral HPLC
analysis). Further efforts in optimizing the reaction tempera-
tures, solvents, amounts of catalyst 21, and pH of reaction
media could not improve the enantioselectivity.
Because both Sharpless dihydroxylation and Shi epoxida-
tion could not achieve satisfactory enantioselectivities when
using the cyclic enol ether 6 as the oxidation substrate, two
early-stage cyclic enol ethers 17 and 19 (Scheme 3) were
then taken into our consideration. In both amide com-
pounds, their N-1 atom lacks strong coordinating ability
with osmium in the Sharpless dihydroxylations. To our de-
light, treatment of enol ether 19 with previously used Sharp-
less AD conditions followed by further oxidation with I2
and CaCO3 successfully afforded the required lactone 24 in
91% yield and with 94% ee (determined by HPLC analysis,
Scheme 7. N-Propargylation and the subsequent cascade cyclization.
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Z.-J. Yao et al.
FULL PAPERS
dine, and a catalytic amount of 4-dimethylaminopyridine
(DMAP) in dichloromethane. Again, propargylation of 27
with prop-2-ynyl methanesulfonate provided an inseparable
mixture of N-propargylation product 28 and O-propargyla-
tion byproduct 29 in 96% yield (ratio 1.5:1 as measured by
1H NMR spectroscopy), and no N-propargylation product
on the aniline amide nitrogen atom was observed. All at-
tempts failed to improve the ratio between the required
compound 28 and the byproduct 29 by optimizing reaction
temperatures, solvents, and bases.
Although poor selectivity of N- and O-propargylation was
achieved, exploration of the subsequent intramolecular cyc-
lization continued. The above mixture of 28 and 29 was im-
mediately treated with bis(triphenyl)oxodiphosphonium tri-
fluoromethanesulfonate at 08C and at room temperature for
2 h. The desired pentacyclic product 30 was obtained in
52% yield (from 27) after purification by silica-gel column
chromatography. By adjustment of the reactants ratio of 28
and 29 (1.5:1), the actual yield of this cascade reaction
(from 28 to 30) was approximately 90%.
Reaction of 27 with allyl methanesulfonate provided an
inseparable mixture of 31 and 32 (ratio 1.35:1 as measured
1
by H NMR spectroscopy) in 95% combined yield.[17] Treat-
ment of this mixture with [PdCl2ACHTNUTRGNE(NUG PhCN)2] (5 mol%) in
CH2Cl2 for 2 h at RT afforded the N-allyl product 31 in a
quantitative yield. Obviously, treatment with simple allyla-
tion conditions followed by Pd-catalyzed O-allyl migration
provides a new high-yield entrance to the sole N-allyl 2-pyri-
done derivatives, which have been frequently involved as
the key intermediates in the syntheses of many camptothe-
cin-family alkaloids.[3e] Treatment of 31 with bis(triphenyl)-
oxodiphosphonium trifluoromethanesulfonate at 08C and
room temperature[24] followed by oxidation with freshly pre-
pared MnO2 provided (S)-30 in 89% yield. Final deacetyla-
tion of 30 was carried out with concentrated HCl in ethanol,
providing (S)-14-azacamptothecin (5, 95%, >99% ee by
HPLC analysis).
Conclusions
Pd-catalyzed allyl transformation and completion of the
total synthesis: As mentioned above, poor selectivities of N-
and O-alkylations (12/13 6.4:1 in Scheme 2, 7/20 1.9:1 in
Scheme 3, 28/29 1.5:1 in Scheme 7) were often given under
the previous propargylation conditions. Although our work
was very close to the target 5, further improvement on the
N-alkylation selectivity was needed for a satisfactory synthe-
sis. An internal transformation of the O-allyl derivative to
the corresponding N-allyl derivative was considered by
using the palladium-catalyzed conditions.[22,23] Since uncer-
tain allenic intermediates might be produced in the reaction
of O-propargyl derivative 29, rearrangement of an alterna-
tive O-allyl compound 32 to the N-allyl compound 31 was
examined (Scheme 8).
A new enantioselective total synthesis of (S)-14-azacampto-
thecin has been accomplished from a known 5H-pyranoACHTUNGTRENNUNG[4,3-
d]pyrimidine intermediate. A mild Hendrickson reagent-
triggered cascade cyclization, an efficient Pd-catalyzed trans-
formation of O-allyl to N-allyl, and a highly enantioselective
dihydroxylation successfully served as the key steps in the
synthesis. Relative to the previous achievement, this work
(10 steps, 56% yield from 8) presents a much higher overall
yield and shows sound flexibility for further applications
that may lead to new bioactive analogues with pharmaceuti-
cal interests.
Experimental Section
General: Unless stated otherwise, all reactions were carried out in dried
glassware under a dry nitrogen atmosphere. All melting points were un-
corrected. All solvents were purified and dried prior to use. Optical rota-
tions were measured at the sodium D line (589 nm) with a 1.00 dm path
length cell. IR spectra were recorded on an FT-IR instrument. 1H NMR
spectra were recorded at 300 MHz, and 13C NMR spectra were recorded
at 75 MHz, and assigned in parts per million (d). Reference peaks for
chloroform in 1H NMR and 13C NMR spectra were set at 7.27 ppm and
77.0 ppm, respectively. For [D6]DMSO, the reference peaks in 1H NMR
and 13C NMR spectra were set at 2.50 ppm and 40.0 ppm, respectively.
Flash column chromatographies were performed on silica gel H (10–
40 m).
Methyl 8-ethyl-4-methoxy-5H-pyrano
An autoclave vessel containing 8 (2.69 g, 11.9 mmol), [PdCl
(dppf)] (0.19 g, 0.24 mmol, 2 mol%), Et3N (4.15 mL, 29.7 mmol), and
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
CH3OH (50 mL) was purged with nitrogen and then with carbon monox-
ide (120 psig) and heated to 908C. The reaction mixture was vigorously
stirred for 5 h, and then allowed to cool down to room temperature and
vented. The solids were removed by filtration through a pad of Celite
and washed with EtOAc (100 mL). The filtrate and washings were com-
bined and concentrated. The residue was purified by silica-gel flash chro-
matography (CH2Cl2) to afford 9 (2.74 g, 92%) as a white solid. M.p.
114–1168C; IR (KBr): n˜ =3012, 2987, 2964, 2512, 1745, 1639, 1575, 1550,
1475, 1464, 1446, 1397, 1368, 1256, 1205, 1134, 1063, 968, 937, 827,
1
Scheme 8. Pd-catalyzed allyl transformation and completion of the total
synthesis.
759 cmÀ1; H NMR (CDCl3, 300 MHz): d=6.74 (1H, s), 5.16 (2H, s), 4.07
(3H, s), 4.00 (3H, s), 2.49 (2H, q, J=7.5 Hz), 1.15 ppm (3H, t, J=
1386
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Chem. Asian J. 2010, 5, 1382 – 1388

Efficient Total Synthesis of (S)-14-Azacamptothecin
7.4 Hz); 13C NMR (CDCl3, 75 MHz): d=164.4, 164.3, 158.4, 155.4, 149.9,
117.4, 107.1, 62.4, 54.1, 53.0, 19.2, 13.2 ppm; MS (ESI): m/z: 251
2.01–1.87 (2H, m), 0.84 ppm (3H, t, J=7.4 Hz); 13C NMR ([D6]DMSO,
75 MHz): d=170.5, 165.6, 163.1, 160.4, 157.8, 138.4, 129.2, 124.8, 120.8,
112.1, 74.1, 63.3, 55.3, 31.4, 8.2 ppm; MS (ESI): m/z: 366 [M+Na]+; ele-
mental analysis calcd (%) for C17H17N3O5: C 59.47, H 4.99, N 12.24;
found: C 59.21, H 5.07, N 11.97.
ACHTUNGTRENNUNG
[M+H]+; elemental analysis calcd (%) for C12H14N2O4·0.2H2O: C 56.78,
H 5.72, N 11.04; found: C 56.67, H 5.56, N 11.19.
8-Ethyl-4-methoxy-5H-pyrano[4,3-d]pyrimidine-2-carboxylic acid (18):
AHCTUNGTRENNUNG
lithium hydroxide monohydrate (0.38 g, 9 mol) was added to a solution
of ester 9 (1.50 g, 6 mmol) in THF (20 mL) and water (10 mL) at 08C.
After the reaction had been stirred at the same temperature for 30 min,
the whole mixture was concentrated in vacuo and the residue was re-dis-
solved into water (10 mL). The pH was adjusted to 4–5 by the addition
of 1n HCl. The resultant precipitation was collected by filtration and
dried, giving 18 (1.40 g, 99%) as a white solid. M.p. 137–1398C; IR
(S)-8-Ethyl-8-hydroxy-4,7-dioxo-N-phenyl-4,5,7,8-tetrahydro-3H-pyrano-
AHCTUNGTERG[NNUN 4,3-d]pyrimidine-2-carboxamide (26): Chlorotrimethylsilane (0.21 mL,
2.43 mmol) was slowly added to a solution of 24 (0.52 g, 1.52 mmol) and
NaI (0.41 g, 2.43 mmol) in CH3CN (15 mL) and water (14 mL,
0.76 mmol). The mixture was heated in the dark at 658C and monitored
by TLC. The reaction mixture was quenched by adding a mixture of 5%
Na2SO3 and brine (1:1, 10 mL). The mixture was quickly extracted with
AcOEt (3ꢂ20 mL), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated. Purification by flash chromatography
(CH2Cl2/CH3OH 60:1) on silica gel gave 26 (0.48 g, 98%) as a yellow
solid. [a]1D9 =29 (c=1.0 in CHCl3/CH3OH 3:1). M.p. 176–1788C; IR
(KBr): n˜ =3406, 3228, 1678, 1547, 1446, 1252, 1162, 1047, 948, 827,
(KBr): n˜ =3469, 2968, 1709, 1574, 1375, 1240, 1071, 941, 729 cmÀ1
;
1H NMR ([D6]DMSO, 300 MHz): d=13.40 (1H, s), 7.00 (1H, s), 5.15
(2H, s), 3.97 (3H, s), 2.40–2.33 (2H, m), 1.07 ppm (3H, t, J=7.5 Hz);
13C NMR ([D6]DMSO, 75 MHz): d=165.2, 164.2, 157.9, 156.8, 151.0,
116.8, 106.6, 62.3, 54.5, 19.2, 14.0 ppm; MS (ESI): m/z: 235 [MÀH]À; ele-
mental analysis calcd (%) for C11H12N2O4: C 55.93, H 5.12, N 11.86;
found: C 56.07, H 5.14, N 11.89.
760 cmÀ1 1H NMR ([D6]DMSO, 300 MHz): d=13.30 (1H, brs), 10.70
;
(1H, s), 7.80–7.77 (2H, m), 7.44 (2H, t, J=7.8 Hz), 7.24–7.19 (1H, m),
6.12 (1H, s), 5.31 (1H, AB, J=16.8 Hz), 5.25 (1H, AB, J=16.8 Hz),
2.01–1.84 (2H, m), 0.85 ppm (3H, t, J=7.4 Hz); 13C NMR ([D6]DMSO,
75 MHz): d=170.4, 159.2, 157.2, 156.6, 150.4, 137.6, 129.3, 125.3, 121.0,
118.1, 73.0, 64.2, 31.6, 8.2 ppm; MS (ESI): m/z: 328 [MÀH]À; elemental
analysis calcd (%) for C16H15N3O5·2H2O: C 52.60, H 5.24, N 11.50;
found: C 52.74, H 5.10, N 11.49.
8-Ethyl-4-methoxy-N-phenyl-5H-pyranoACTHNUGTRNEUNG[4,3-d]pyrimidine-2-carboxamide
(19): The acid 18 (0.83 g, 3.51 mmol) in CH2Cl2 (18 mL) was treated with
(COCl)2 (0.92 mL, 10.52 mmol) and catalytic amount of DMF at 08C.
After gas evolution ceased, the reaction mixture was concentrated and
dried in vacuo. The residue was redissolved in CH2Cl2 (10 mL) and intro-
duced into a suspension of aniline (0.32 mL, 3.51 mmol) and NaHCO3
(0.88 g, 10.52 mmol) in CH2Cl2 (8 mL). After 2 h, water was added to the
reaction mixture. The aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over Na2SO4, fil-
tered, and concentrated. Purification by silica-gel flash chromatography
(EtOAc/hexane 1:6) gave 19 (1.01 g, 93%) as a white solid. M.p. 134–
(S)-8-Ethyl-4,7-dioxo-2-(phenylcarbamoyl)-4,5,7,8-tetrahydro-3H-pyrano-
AHCTUNGTRENNUNG
a
0.61 mmol) in dichloromethane (5 mL). The above solution was stirred at
room temperature for 2 h. The solvents were removed in vacuo and the
residue was purified by silica-gel flash chromatography (CH2Cl2/CH3OH
80:1) to afford 27 (0.20 g, 93%) as a white solid. [a]1D9 =À29 (c=1.0 in
CHCl3/CH3OH 3:1). M.p. 204–2068C; IR (KBr): n˜ =3358, 3232, 1753,
1368C; IR (KBr): n˜ =3419, 2360, 1637, 1533, 1385, 1130, 750, 617 cmÀ1
;
1H NMR (CDCl3, 300 MHz): d=9.95 (1H, s), 7.80–7.77 (2H, m), 7.44–
7.39 (2H, m), 7.20–7.15 (1H, m), 6.80 (1H, t, J=1.2 Hz), 5.22 (2H, s),
4.17 (3H, s), 2.54 (2H, dq, J=7.5, 1.2 Hz), 1.24 ppm (3H, t, J=7.2 Hz);
13C NMR (CDCl3, 75 MHz): d=165.0, 159.9, 157.5, 156.2, 150.3, 137.5,
129.0, 124.4, 119.5, 116.7, 106.6, 62.5, 54.3, 19.4, 13.4 ppm; MS (ESI): m/z:
334 [M+Na]+; elemental analysis calcd (%) for C17H17N3O3: C 65.58, H
5.50, N 13.50; found: C 65.54, H 5.37, N 13.48.
1689, 1540, 1460, 1257, 1147, 1076, 1032, 944, 825, 760, 692 cmÀ1
;
1H NMR ([D6]DMSO, 300 MHz): d=10.38 (1H, s), 7.78–7.75 (2H, m),
7.45–7.39 (2H, m), 7.23–7.18 (1H, m), 5.38 (1H, AB, J=17.1 Hz), 5.30
(1H, AB, J=17.1 Hz), 2.33–2.09 (5H, m), 0.87 ppm (3H, t, J=7.5 Hz);
13C NMR ([D6]DMSO, 75 MHz): d=170.3, 167.7, 158.9, 157.6, 153.8,
151.3, 137.5, 129.2, 125.4, 121.4, 118.8, 76.2, 64.8, 29.4, 20.6, 7.7 ppm; MS
(ESI): m/z: 370 [MÀH]À; elemental analysis calcd (%) for C18H17N3O6: C
58.22, H 4.61, N 11.32; found: C 58.28, H 4.64, N 11.27.
(S)-8-Ethyl-8-hydroxy-4-methoxy-7-oxo-N-phenyl-7,8-dihydro-5H-
pyrano
PYR (14 mg, 0.016 mmol, 5 mol%), K3[Fe(CN)6] (317 mg, 0.96 mmol),
K2CO3 (133 mg, 0.96 mmol), 2A[OsO2(OH)4] (1.18 mg, 3.21 mmol,
ACHTUNGTRENNUNG[4,3-d]pyrimidine-2-carboxamide (24): A mixture of (DHQD)2-
K CHTUNGTRENNUNG
1.0 mol%), and CH3SO2NH2 (61 mg, 0.64 mmol) in water (1.5 mL) and
tert-butanol (1.5 mL) was stirred at room temperature until both phases
were clear. The mixture was then cooled down to 08C, and enol ether 19
(100 mg, 0.32 mmol) was added in one portion. The reaction was allowed
to warm to RT and was stirred for 20 h. The reaction was quenched at
the same temperature by adding sodium sulfite (0.5 g), and stirred for an
additional 30 min. The aqueous layer was extracted with a mixture of
CH2Cl2 and CH3OH (10 mLꢂ2, 10:1). The combined organic layers were
dried over Na2SO4 and concentrated.
(S)-3-Allyl-8-ethyl-4,7-dioxo-2-(phenylcarbamoyl)-4,5,7,8-tetrahydro-3H-
pyranoACTHNUGRTENUNG[4,3-d]pyrimidin-8-yl acetate (31): Potassium carbonate (37 mg,
0.27 mmol) was added to a suspension of 27 (50 mg, 0.14 mmol) in water
(0.01 mL) and toluene (1 mL) at 08C. After the mixture had been stirred
at the same temperature for 10 min, lithium bromide (28 mg, 0.27 mmol)
and tetrabutylammonium bromide (4 mg, 0.014 mmol) were added. The
whole mixture was stirred for 10 min at room temperature. Allyl metha-
nesulfonate (30 mg, 0.22 mmol) was then added. The reaction mixture
was heated to 808C and stirred for 2 h. The inorganic residue was re-
moved by filtration over a pad of Celite and washed with CH2Cl2. The fil-
trate and washings were combined and concentrated under reduced pres-
sure. Flash chromatography on silica gel (CH2Cl2/CH3OH 80:1) gave a
mixture of 31 and 32 (53 mg, 95%).
Crystalline iodine (1.22 g, 4.8 mmol, 15 equiv) and CaCO3 (160 mg,
1.6 mmol, 5 equiv) were added to the above residue in a mixture of
CH3OH and H2O (15 mL, 2:1). The whole mixture was stirred at 408C
for 15 h. Na2SO3 (1.3 g) was then added slowly. CH3OH was removed
under reduced pressure, and then CH2Cl2 (10 mL), CH3OH (1 mL), and
H2O (10 mL) were added. The aqueous layer was extracted with a mix-
ture of CH2Cl2 and CH3OH (10:1, 10 mLꢂ2). The combined organic
layers were dried over Na2SO4 and concentrated. Purification by flash
column chromatography on silica gel (CH2Cl2/CH3OH 60:1) afforded 24
(100 mg, 91%) in 94% ee (HPLC conditions: Chiralcel AD-H column
(0.46ꢂ15 cm), n-hexane/iPrOH 80:20 as mobile phase, flow rate:
1 mLminÀ1, UV detection at 254 nm; tR ((S)-isomer): 19.9, tR ((R)-
isomer): 30.4 min). M.p. 147–1498C; [a]1D9 =44 (c=1.0 in CHCl3/CH3OH
3:1); IR (KBr): n˜ =3440, 2978, 1751, 1603, 1542, 1373, 1155, 1037, 874,
ACHUNTRGEN[NUG PdCl2CAHTUNGTRNEN(UGN PhCN)2] (2.5 mg, 6.5 mmol) was added to the mixture of 31 and 32
(53 mg, 0.13 mmol) in CH2Cl2 (1.3 mL) under a N2 atmosphere. The reac-
tion mixture was stirred at RT for 2 h. The solvent was evaporated. The
residue was purified by flash chromatography on silica gel (CH2Cl2/
CH3OH 80:1) to afford 31 as a white solid (53 mg, 100%). M.p. 84–868C;
[a]1D9 =9 (c=1.8 in CHCl3/CH3OH 3:1); IR (KBr): n˜ =3302, 2933, 1168,
1750, 1687, 1599, 1537, 1491, 1435, 1368, 1236, 1094, 1055, 985, 945, 758,
695 cmÀ1 1H NMR (CDCl3, 300 MHz): d=9.34 (1H, s), 7.64–7.61 (2H,
;
m), 7.46–7.41 (2H, m), 7.28–7.23 (1H, m), 6.08–5.99 (1H, m), 5.51–5.26
(6H, m), 2.31–2.17 (5H, m), 0.98 ppm (3H, t, J=7.5 Hz); 13C NMR
(CDCl3, 75 MHz): d=170.0, 167.0, 158.2, 156.9, 151.7, 150.7, 136.2, 131.6,
129.3, 125.7, 120.0, 119.6, 118.2, 75.7, 64.9, 46.7, 30.2, 20.4, 7.5 ppm;
761 cmÀ1 1H NMR ([D6]DMSO, 300 MHz): d=10.67 (1H, s), 7.82 (2H,
;
dd, J=8.7, 0.9 Hz), 7.45–7.40 (2H, m), 7.20–7.15 (1H, m), 6.38 (1H, s),
5.53 (1H, AB, J=16.2 Hz), 5.44 (1H, AB, J=16.2 Hz), 4.14 (3H, s),
Chem. Asian J. 2010, 5, 1382 – 1388
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1387

Z.-J. Yao et al.
FULL PAPERS
HRMS (MALDI): m/z: calcd for C21H22N3O6: 412.1503 [M+H]+; found:
412.1521.
509; b) “The Camptothecins: from Discovery to the Patient,” P. Pan-
taziz, B. C. Giovanella, Ann. N. Y. Acad. Sci. 1996, 803, 1–335;
c) “Antitumor Alkaloids in Clinical Use or in Clinical Trials,” M.
Cuendet, J. M. Pezzuto in Modern Alkaloids: Structure, Isolation,
Synthesis and Biology (Eds.: E. Fattorusso, O. Taglialatela-Scafati),
Wiley-VCH, Weinheim, 2008, pp. 29–33; d) C. J. Thomas, N. J.
Rahier, S. M. Hecht, Bioorg. Med. Chem. 2004, 12, 1585; e) W. Du,
Tetrahedron 2003, 59, 8649.
(S)-20-O-acetyl-14-aza-camptothecin (30): Trifluoromethanesulfonic an-
hydride (0.055 mL, 0.33 mmol) was slowly added to a solution of triphe-
nylphosphane oxide (0.18 g, 0.66 mmol) in dry CH2Cl2 (2 mL) at 08C.
After this mixture had been stirred at 08C for 15 min, 31 (0.090 g,
0.22 mmol) in dry CH2Cl2 (1 mL) was added at the same temperature.
The reaction was allowed to warm to room temperature and was then
stirred for 6 h. Freshly prepared MnO2 (0.038 g, 0.44 mmol) was then
added, and the mixture was stirred at RT for 0.5 h. The solid was re-
moved by filtration over a pad of Celite and was washed with CH2Cl2.
The filtrate and washings were combined and concentrated under re-
duced pressure. The residue was purified by flash chromatography on
silica gel (CH2Cl2/CH3OH 80:1) to afford 30 (76 mg, 89%). M.p. 295–
2978C (dec.); [a]1D9 =À27 (c=0.4 in CHCl3/CH3OH 3:1); IR (KBr): n˜ =
[4] L. Z. Lin, G. A. Cordell, Phytochemistry 1989, 28, 1295.
[5] Z. Z. Ma, Y. Hano, T. Nomura, Y. J. Chen, Heterocycles 1997, 46,
541.
[6] W. D. Kingsbury, J. C. Boehm, D. R. Jakas, K. G. Holden, S. M.
Hecht, G. Gallagher, M. J. Caranfa, F. L. McCabe, L. F. Faucette,
R. K. Johnson, R. P. Hertzberg, J. Med. Chem. 1991, 34, 98.
[7] a) S. Negoro, M. Fukuoka, N. Masuda, M. Takada, Y. Kusunoki, K.
Matsui, N. Takifuji, S. Kudoh, H. Niitani, T. Taguchi, J. Natl. Cancer
Inst. 1991, 83, 1164; b) Y. Kawato, M. Aonuma, Y. Hirota, H. Kuga,
K. Sato, Cancer Res. 1991, 51, 4187.
[8] a) G. M. Cragg, D. J. Newman, J. Nat. Prod. 2004, 67, 232; b) M. S.
Butler, Nat. Prod. Rep. 2005, 22, 162.
[9] K. J. Cheng, N. J. Rahier, B. M. Eisenhauer, R. Gao, S. J. Thomas,
S. M. Hecht, J. Am. Chem. Soc. 2005, 127, 838.
[10] N. J. Rahier, K. J. Cheng, R. Gao, B. M. Eisenhauer, S. M. Hecht,
Org. Lett. 2005, 7, 835.
[11] M. A. Elban, W. Y. Sun, B. M. Eisenhauer, R. Gao, S. M. Hecht,
Org. Lett. 2006, 8, 3513.
3442, 2987, 1691, 1624, 1560, 1385, 1248, 1051, 777, 735 cmÀ1 1H NMR
;
(CDCl3, 300 MHz): d=8.51–8.48 (2H, m), 8.01 (1H, d, J=7.8 Hz), 7.90
(1H, t, J=7.4 Hz), 7.76 (1H, t, J=7.4 Hz), 5.64 (1H, AB, J=17.1 Hz),
5.38 (1H, AB, J=17.1 Hz), 5.27 (2H, s), 2.41 (2H, q, J=7.2 Hz), 2.33
(3H, s), 1.00 ppm (3H, t, J=7.5 Hz); 13C NMR (CDCl3, 75 MHz): d=
170.5, 167.7, 157.9, 157.2, 156.7, 150.1, 149.4, 131.6, 131.0, 130.7, 129.05,
129.01, 128.7, 128.0, 115.7, 76.7, 64.7, 47.5, 30.2, 20.5, 7.5 ppm; MS (ESI):
m/z: 414 [M+Na]+; elemental analysis calcd (%) for C21H17N3O5: C
64.45, H 4.38, N 10.74; found: C 64.21, H 4.34, N 10.99.
(S)-14-Aza-camptothecin (5): Concentrated hydrochloric acid (0.3 mL)
was added to a solution of 30 (30 mg, 0.077 mmol) in EtOH (1.2 mL).
The reaction was stirred at 808C for 24 h. The solvents were removed in
vacuo and the residue was purified by silica-gel flash chromatography to
afford 5 (25 mg, 95%) in >99% ee (HPLC conditions: Chiralcel AD-H
column (0.46ꢂ15 cm), n-hexane/iPrOH 50:50 as mobile phase, flow rate:
1 mLminÀ1, UV detection at 254 nm; tR ((S)-isomer): 11.1, tR ((R)-
isomer): 12.5 min). M.p. 272–2948C (dec.); [a]2D0 =24 (c=1.2 in CHCl3/
CH3OH 3:1).[25] IR (KBr): n˜ =3358, 2927, 1757, 1649, 1596, 1542, 1500,
[12] J. B. Hendrickson, S. M. Schwartzman, Tetrahedron Lett. 1975, 16,
277.
[13] For representative applications of the Hendrickson reagent, see:
a) S. L. You, H. Razavi, J. W. Kelly, Angew. Chem. 2003, 115, 87;
Angew. Chem. Int. Ed. 2003, 42, 83; b) S. L. You, J. W. Kelly, J. Org.
Chem. 2003, 68, 9506; c) S. L. You, J. W. Kelly, Org. Lett. 2004, 6,
1681; d) Q. L. Dong, G. S. Liu, H. B. Zhou, L. Chen, Z. J. Yao, Tetra-
hedron Lett. 2008, 49, 1636.
1431, 1349, 1206, 1157, 1100, 924, 776 cmÀ1 1H NMR (CDCl3, 300 MHz):
;
[14] a) H. B. Zhou, G. S. Liu, Z. J. Yao, Org. Lett. 2007, 9, 2003; b) H. B.
Zhou, G. S. Liu, Z. J. Yao, J. Org. Chem. 2007, 72, 6270.
[15] For Fortunakꢁs synthesis of the core structure of camptothecin, see:
J. M. D. Fortunak, A. R. Mastrocola, M. Mellinger, N. J. Sisti, J. L.
Wood, Z. P. Zhuang, Tetrahedron Lett. 1996, 37, 5679.
[16] H. Josien, S. B. Ko, D. Bom, D. P. Curran, Chem. Eur. J. 1998, 4, 67.
[17] I. Ricoh, K. Halvorsen, C. Dubrule, A. J. Lattes, J. Org. Chem. 1994,
59, 415.
d=8.55 (1H, s), 8.47 (1H, d, J=8.4 Hz), 8.02 (1H, d, J=8.7 Hz), 7.92
(1H, dt, J=6.9, 1.2 Hz), 7.78 (1H, dt, J=8.1, 1.2 Hz), 5.63 (1H, AB, J=
16.8 Hz), 5.32 (2H, s), 5.30 (1H, AB, J=16.8 Hz), 4.11 (1H, s), 2.10–2.02
(2H, m), 1.10 ppm (3H, t, J=7.5 Hz); 13C NMR ([D6]DMSO, 75 MHz):
d=171.9, 159.4, 157.8, 157.4, 151.3, 148.6, 132.3, 131.3, 131.0, 130.0,
128.87, 128.85, 128.77, 114.9, 73.7, 63.9, 48.4, 30.8, 8.5 ppm; MS (ESI):
m/z: 348 [MÀH]À; elemental analysis calcd (%) for C19H15N3O4: C 65.32,
H 4.33, N 12.03; found: C 65.37, H 4.31, N 11.89.
[18] S. P. Chavan, M. S. Venkatraman, ARKIVOC 2005, 165.
[19] G. S. Liu, Q. L. Dong, Y. S. Yao, Z. J. Yao, Org. Lett. 2008, 10, 5393.
[20] a) H. C. Kolb, M. S. Vannieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483; b) G. A. Crispino, K. S. Jeong, H. C. Kolb, Z. M.
Wang, D. Xu, K. B. Sharpless, J. Org. Chem. 1993, 58, 3785.
[21] Z. X. Wang, Y. Tu, M. Frohn, J. R. Zhang, Y. A. Shi, J. Am. Chem.
Soc. 1997, 119, 11224.
[22] K. Itami, D. Yamazaki, J. I. Yoshida, Org. Lett. 2003, 5, 2161.
[23] N. Ototake, M. Nakamura, Y. Dobashi, H. Fukaya, O. Kitagawa,
Chem. Eur. J. 2009, 15, 5090.
Acknowledgements
Financial support from MOST (2010CB833200), MOH (2009ZX09501),
and CAS (KSCX2-YW-R23, KJCX2-YW-H08) are greatly appreciated.
[1] a) M. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail,
G. A. Sim, J. Am. Chem. Soc. 1966, 88, 3888; b) M. E. Wall, Med.
Res. Rev. 1998, 18, 299.
[2] a) C. G. Moertel, A. J. Schutt, R. J. Reitemeier, R. G. Hahn, Cancer
Chemother. Rep. 1972, 56, 95; b) Y. H. Hsiang, L. F. Liu, M. E. Wall,
M. C. Wani, A. W. Nicholas, G. Manikumar, S. Kirschenbaum, R.
Silber, M. Potmesil, Cancer Res. 1989, 49, 4385.
[24] X. Q. Dai, C. Cheng, C. Y. Ding, Q. Z. Yao, A. Zhang, Synlett 2008,
19, 2989.
[25] The optical rotation of (S)-14-azacamptothecin was not reported in
reference [10].
Received: January 26, 2010
Published online: May 18, 2010
[3] For recent reviews on the chemistry and biology of the camptothe-
cin alkaloids, see: a) M. E. Wall, M. C. Wani, Alkaloids 1998, 50,
1388
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Chem. Asian J. 2010, 5, 1382 – 1388