Total synthesis of (+)-camptothecin

Article abstract of DOI:10.1016/S0040-4020(02)00633-6

A total synthesis of (+)-camptothecin is described. The approach is based on a room temperature LUMO_diene-controlled Diels-Alder cycloaddition of the electron deficient N-sulfonyl-1-aza-1,3-butadiene 6 with the electron rich dienophile 1,1,3,3-tetraethoxypropene (7) for assembly of a pyridine precursor to the D-ring pyridone. The 20(S) tertiary alcohol was installed through a Sharpless asymmetric dihydroxylation reaction on the methyl vinyl ether 12, using the 3,4,5-trimethoxyphenyl-derived pyrimidine DHQ dimer ligand 16. In a single reaction vessel, the C and E rings were closed using an acid-catalyzed deprotection of the benzylic ethers to afford the corresponding benzylic bromides (18) which underwent intramolecular nucleophilic displacement by the carboxylate and pyridone nitrogen to furnish (+)-camptothecin.

Full text of DOI:10.1016/S0040-4020(02)00633-6

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 6343±6349
Total synthesis of (1)-camptothecin
p
Brian S. J. Blagg and Dale L. Boger
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, CA 92037, USA
Received 4 February 2002; accepted 25 May 2002
AbstractÐAtotal synthesis of ( 1)-camptothecin is described. The approach is based on a room temperature LUMOdiene-controlled Diels±
Alder cycloaddition of the electron de®cient N-sulfonyl-1-aza-1,3-butadiene 6 with the electron rich dienophile 1,1,3,3-tetraethoxypropene
(
7) for assembly of a pyridine precursor to the D-ring pyridone. The 20(S) tertiary alcohol was installed through a Sharpless asymmetric
dihydroxylation reaction on the methyl vinyl ether 12, using the 3,4,5-trimethoxyphenyl-derived pyrimidine DHQ dimer ligand 16. In a
single reaction vessel, the C and E rings were closed using an acid-catalyzed deprotection of the benzylic ethers to afford the corresponding
benzylic bromides (18) which underwent intramolecular nucleophilic displacement by the carboxylate and pyridone nitrogen to furnish (1)-
camptothecin. q 2002 Elsevier Science Ltd. All rights reserved.
4
(1)-Camptothecin (CPT, 1, Fig. 1) is a pentacyclic alkaloid
isolated and characterized by Wall and co-workers in 1966
isomerase I. Topoisomerase I is responsible for the
cleavage of double-stranded DNAto produce a covalently
0
5
bound 3 -phosphate-enzyme complex and is enlisted to
unwind supercoiled DNAahead of the replication fork.
from Camptotheca acuminata and shown to exhibit potent
cytotoxic activity against a range of tumor cell lines.
1
±3
6
Subsequent to its discovery, CPT was shown to stabilize
the cleavable complex of double-stranded DNAand topo-
Recent modeling studies of a ternary complex suggest
camptothecin intercalates from the minor groove side of
DNAforming key hydrogen bond interactions between its
7
lactone and arginine 364 of human topoisomerase I. This
prevents religation of double-stranded DNA, provides stabi-
lization of the single strand break, and results in a permanent
8
±10
DNAlesion that leads to cell death.
is not used clinically for the treatment of cancer, two closely
Although CPT itself
related analogues Topotecan (2) and Irinotecan (3) have
proven effective in the clinic.
1
1,12
Since its discovery, camptothecin has been the subject of
extensive research especially for the design of water soluble
1
1±18
derivatives
analogues.
and more recently, stable lactone
At physiological pH, the lactone is easily
1
9±23
hydrolyzed to the biologically inactive carboxylate, which
binds to human serum albumin, lowering the effective
2
4,25
concentration of CPT.
This facile hydrolysis of the
lactone represents a challenging problem and its labile
nature has been attributed to the a-hydroxy group which
is believed to accelerate the hydrolysis through intra-
2
1
molecular hydrogen bonding. Recently, the development
of new analogues of CPT which are more stable has been
pursued and culminated in the development of homo-
1
9,20
camptothecin (4, Fig. 2).
Homocamptothecin contains
a methylene spacer between the tertiary alcohol and the
lactone carbonyl, resulting in prolonged activity in cellular
assays.
Figure 1.
2
1
Keywords: (1)-camptothecin; Diels±Alder cycloaddition; N-sulfonyl-1-
aza-1,3-butadiene.
p
Although numerous analogues of CPT containing modi®ca-
tions in the lactone ring have been prepared, none have
Corresponding author. Tel.: 11-858-784-7522; fax: 11-858-784-7550;
e-mail: boger@scripps.edu
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00633-6

6344
B. S. J. Blagg, D. L. Boger / Tetrahedron 58 (2002) 6343±6349
chemistry of the tertiary a-hydroxy group of the E-ring
lactone was envisioned to be set by a Sharpless asymmetric
dihydroxylation reaction of the corresponding vinyl ether
12. Finally, the C and E ring closures were expected to
come from simultaneous pyridone deprotection and conver-
sion of the benzylic ethers in 17 to the corresponding
benzylic bromides, followed by intramolecular displace-
ment upon the addition of base to furnish (1)-camptothecin
Figure 2.
(Scheme 1).
2
7
proven to be as active as CPT itself. Herein we detail the
development of a versatile route for the asymmetric
Methane sulfonamide was condensed with trans-ketone 5
under dehydrating conditions utilizing TiCl and Et N to
furnish the N-sulfonyl-1-aza-1,3-butadiene 6 as previously
4
3
2
6
synthesis of CPT, which allows for modi®cation of the
E-ring permitting access to new analogues that may help
to de®ne the key interactions between CPT/DNA/topo-
isomerase I and ultimately aid in the development of second
generation CPT derivatives.
2
7,31
detailed, Scheme 2.
The inverse electron demand Diels±
Alder cycloaddition between the electron rich 1,1,3,3-tetra-
3
2
ethoxypropene (7) and the electron de®cient N-sulfonyl-1-
aza-1,3-butadiene 6 proceeded at room temperature and
ambient pressure within 4 h to give the desired [412]
cycloadduct 8. Addition of sodium ethoxide to the sensitive
Diels±Alder cycloadduct resulted in the sequential elimina-
tion of methanesul®nic acid and ethanol to provide the
highly substituted 2-ethoxypyridine 9 under mild conditions
(08C, 1±1.5 h). Because of the hydrolysis sensitive nature of
both the azadiene 6 and the cycloadduct 8, the three steps
enlisted for the conversion of 6 to pyridine 9 were carried
out in higher conversions (60±70% overall) without puri®-
cation of the intermediates. Due to the labile nature of the
diethyl acetal 9, it was converted to the corresponding ethyl
ether using ZnI and Et SiH which cleanly gave 10 without
The approach is based on the implementation of a room
temperature inverse electron demand Diels±Alder reaction
2
7
of the N-sulfonylimine 6,
butadiene,
a
with the electron rich dienophile 7 for
N-sulfonyl-1-aza-1,3-
2
8±30
introduction of the D-ring pyridone. The azadiene 6
incorporates a noncomplementary C4 electron-withdrawing
substituent which is known to lower the diene LUMO
accelerating its rate of reaction in an inverse electron
demand Diels±Alder reaction without altering the inherent
3
0
regioselectivity of the cycloaddition. Base-catalyzed
aromatization of cycloadduct 8 would provide the highly
substituted pyridine 9 bearing four of the ®ve pyridone
exocyclic substituents, two of which could be further
elaborated for introduction of the E-ring. The stereo-
2
3
any competing lactonization products resulting from capture
Scheme 1.
Scheme 2.

B. S. J. Blagg, D. L. Boger / Tetrahedron 58 (2002) 6343±6349
6345
of the oxonium intermediate by the adjacent ester. In
contrast, treatment of 9 with NaCNBH and Bu SnCl
3
3
3
3
3
4
provided such a lactone in 85% yield (t-BuOH, 808C,
Eq. (1)). Although not extensively investigated, the use of
ZnI /Et SiH was more effective than either ZnI2/
2
3
3
5
36
NaCNBH3 (20±65%) or TMSOTf/Et SiH for conversion
3
of 9 to 10. In addition, the diethyl acetal of 9 was easily
deprotected to provide the corresponding aldehyde (TFA,
3
7
CH Cl ±H O, 08C, 5±10 min or TsOH, acetone±H O, 11 h,
2
2
2
2
quantitative), but alternative routes proceeding through this
intermediate have not yet proven competitive.
ꢀ
1†
The ethyl ester 10 was directly converted to ethyl ketone 11
by addition of EtMgBr in the presence of excess Et N. The
3
8
3
vinyl ethers 12 were formed through a Wittig reaction of
ethyl ketone 11 and methoxymethenetriphenylphosphorane
to furnish a 3:1 mixture of trans/cis isomers (98%), which
could be easily separated providing E-12 (74%), Scheme 3.
2
6s,v,y
Analogous to the two additional total syntheses of CPT
3
9
that utilized a Sharpless asymmetric dihydroxylation, the
AD reaction of trans vinyl ether 12 proved to be dif®cult
initially. Using the commercially available b-AD mix
containing ligand 14, the desired a-hydroxy aldehyde 13
was obtained in low yields and poor enantiomeric excess.
Instead of 13 as the major product, ketone 11 was predomi-
nately formed resulting from the subsequent oxidative
cleavage of the corresponding C±C bond. Reducing the
amount of K Fe(CN) to 1.3 equiv. and supplementing the
Scheme 3.
Although unanticipated, alternative approaches to campto-
thecin employing the readily available and more advanced,
but more sterically hindered and less electron de®cient,
N-sulfonyl-1-azadiene 19 employing a full range of electron
3
6
reaction with an additional equivalent at a later time while
increasing the amount of ligand 14 and OsO led to an
improved yield of the desired product. However, the
4
4
0
enantiomeric excess remained low (23% ee). The enantio-
meric excess of the reaction was increased remarkably by
utilization of the (DHQ) -pyrimidine ligand 15 resulting in
2
8
8
0% ee. The enantioselectivity was further increased to
6% with the 4,6-(DHQ) -5-phenyl-1,3-pyrimidine-2-
2
(
3,4,5-trimethoxyphenyl) ligand 16 providing material
suitable for incorporation into the total synthesis of 1.
When the cis vinyl ether was used with the (DHQD)2
version of 16, 13 was obtained in lower ee's (60±70%
ee). Interestingly, when the (DHQD) variant of this ligand
2
was used with the trans isomer, greater than 99% ee of the
corresponding unnatural 20(R) enantiomer was obtained.
Once formed, a-hydroxy aldehyde 13 was immediately
oxidized to the corresponding carboxylic acid 17 with
4
1
sodium chlorite in a buffered solution containing resorci-
nol, Scheme 4. The aryl ethyl ether and the two benzylic
ethers were cleaved upon exposure to a saturated solution of
2
7,29a
HBr(g) in a 2,2,2-tri¯uoroethanol at 808C
to give the
corresponding pyridone 18 containing two benzyl bromides.
Addition of potassium carbonate to the reaction mixture
catalyzed the intramolecular nucleophilic ring closures to
give 1, without detection of competing elimination
products.
Scheme 4.

6346
B. S. J. Blagg, D. L. Boger / Tetrahedron 58 (2002) 6343±6349
8
1
.11 (d, Jˆ8.3 Hz, 1H), 7.84 (d, Jˆ8.3 Hz, 1H), 7.82 (s,
H), 7.68 (apparent t, Jˆ7.5 Hz, 1H), 7.53 (apparent t,
Jˆ7.5 Hz, 1H), 5.75 (s, 1H), 5.02 (s, 2H), 4.49 (q,
Jˆ7.0 Hz, 2H), 4.37 (q, Jˆ7.0 Hz, 2H), 3.70 (dq, Jˆ8.8,
7
.0 Hz, 2H), 3.60 (dq, Jˆ7.6, 8.7 Hz, 2H), 3.47 (s, 3H), 1.42
(
t, Jˆ7.0 Hz, 3H), 1.38 (t, Jˆ7.0 Hz, 3H), 1.23 (t, Jˆ7.0,
1
H); C NMR (CDCl , 150 MHz) d 168.4, 160.1, 155.8,
3
6
1
1
6
2
3
53.7, 146.5, 143.2, 134.2, 131.1, 129.4, 129.2, 127.8,
27.3, 127.0, 117.6, 115.8, 97.9, 72.1, 63.1 (2C), 62.4,
1.5, 58.6, 15.0 (2C), 14.7, 14.0; IR (KBr) n
919, 1731, 1560 cm ; MALDI-HRMS (dihydroxybenzyl
2978,
max
2
1
1
alcohol, DHB) m/z 469.2353 (M1H , C H N O requires
6
2
6
32
2
m/z 469.2333).
1.1.2. 2-Ethoxy-3-ethoxymethyl-6-(3-methoxymethyl-
quinolin-2-yl)isonicotinic acid ethyl ester (10). Aslurry
of ZnI (136 mg, 0.42 mmol), 9 (100 mg, 0.21 mmol), and
2
Et SiH (409 mL, 2.56 mmol) in CH Cl (750 mL) was stir-
3
2
2
red for 5 days at 258C. The slurry was ®ltered through a plug
of silica gel (1£5 cm) and eluted with 30% EtOAc±hexane.
Chromatography (SiO , 2.5£10 cm, 20% EtOAc±hexane)
2
afforded 10 (83 mg, 92%) as a colorless solid: mp 75±
7
1
78C; H NMR (CDCl , 400 MHz) d 8.43 (s, 1H), 8.13
3
(
7
d, Jˆ8.5 Hz, 1H), 8.03 (s, 1H), 7.85 (d, Jˆ8.2 Hz, 1H),
.69 (apparent t, Jˆ7.9 Hz, 1H), 7.54 (apparent t,
Jˆ7.6 Hz, 1H), 5.02 (s, 2H), 4.81 (s, 2H), 4.46 (q,
Jˆ7.0 Hz, 2H), 4.40 (q, Jˆ7.0 Hz, 2H), 3.56 (t, Jˆ7.0 Hz,
Scheme 5.
2
3
H), 3.47 (s, 3H), 1.43 (t, Jˆ7.0 Hz, 3H), 1.40 (t, Jˆ7.0 Hz,
1
3
H), 1.20 (t, Jˆ7.0 Hz, 3H); C NMR (CDCl , 100 MHz)
3
rich dienophiles have not proven successful, Scheme 5.
Similarly surprising, the intramolecular cycloaddition of
the N-sulfonyl-1-azadiene 20 was also not successful.
d 167.1, 160.8, 155.4, 154.0, 146.5, 142.7, 134.4, 131.1,
129.3, 129.3, 127.8, 127.4, 127.0, 119.2, 116.7, 72.2, 66.2,
63.0, 62.5, 61.5, 58.6, 15.1, 14.7, 14.1; IR (®lm) n
2
2976,
868, 1723, 1596, 1562, 1440 cm ; MALDI-HRMS
max
2
1
1
DHB) m/z 425.2071 (M1H , C H N O requires m/z
(
425.2071).
24 28 2 5
1.Experimental
1
1
.1. General
1.1.3. 1-[2-Ethoxy-3-ethoxymethyl-6-(3-methoxymethyl-
quinolin-2-yl)pyridin-4-yl]propan-1-one (11). EtMgBr
.1.1. 3-Diethoxymethyl-2-ethoxy-6-(3-methoxymethyl-
(380 mL, 3.0 M in Et
10 (220 mg, 0.52 mmol) and Et
2
O) was added to a solution of ester
N (2.89 mL, 20.8 mmol) in
quinolin-2-yl)isonicotinic acid ethyl ester (9). TiCl4
1.0 M in CH Cl , 4.2 mL) and Et N (1.4 mL) was added
to a solution of ketone 5 (630 mg, 2.1 mmol) and methane
3
(
toluene (10.4 mL) at 258C and the solution was stirred at
258C for 5 h. The reaction was quenched by the addition of
2
2
3
2
7
sulfonamide (400 mg, 4.2 mmol) in CH Cl (63 mL) at
2
saturated aqueous NH
removed and the aqueous layer washed with EtOAc. The
combined organic layers were dried (Na SO ), ®ltered, and
concentrated. PTLC (SiO , 20% EtOAc±hexane) afforded
11 (141 mg, 66%) as a colorless solid: mp 102±1058C; H
NMR (CDCl
4
Cl (5 mL). The organic layer was
2
2
4
428C. The brown solution was stirred at 2428C for
0 min, warmed to 258C, and stirred for an additional
2
4
6
0 min. The crude mixture was poured over a plug of Celite
2
1
(
(
2.5£7.5 cm) and eluted with a 50% EtOAc±hexane
250 mL). The eluent was concentrated and poured over a
3
, 500 MHz) d 8.44 (s, 1H), 8.12 (d, Jˆ8.5 Hz,
plug of silica gel (2.5£7.5 cm) and eluted with 50%
EtOAc±hexane (250 mL). The eluent was concentrated
and redissolved in benzene (10.5 mL). 1,1,3,3-Tetraethoxy-
1H), 7.85 (d, Jˆ8.1 Hz, 1H), 7.74 (s, 1H), 7.69 (dt, Jˆ8.1,
8.4 Hz, 1H), 7.54 (dt, Jˆ8.1, 8.1 Hz, 1H), 5.04 (s, 2H), 4.65
(s, 2H), 4.45 (q, Jˆ7.4 Hz, 2H), 3.52 (q, Jˆ7.0 Hz, 2H),
3.48 (s, 3H), 2.92 (q, Jˆ7.3 Hz, 2H), 1.42 (t, Jˆ7.4 Hz,
3
2
propene (7, 1.82 g, 8.4 mmol) was added and the solution
was stirred for 4 h. The reaction mixture was concentrated
in vacuo and the residue was redissolved in THF (21 mL).
NaOEt (3.0 M in EtOH, 5.6 mL, 16.8 mmol) was added to
the solution at 08C. The mixture was stirred at 08C for
1
3
3H), 1.22 (t, Jˆ7.4 Hz, 3H), 1.19 (t, Jˆ7.0 Hz, 3H);
NMR (CDCl , 125 MHz) d 206.0, 160.1, 155.2, 154.0,
3
C
151.5, 146.5, 134.4, 131.2, 129.3 (2C), 127.8, 127.4,
127.0, 117.0, 114.3, 72.3, 66.6, 63.7, 62.4, 58.6, 36.1,
15.0, 14.7, 7.6; IR (®lm) 2970, 2860, 1701, 1596, 1555,
7
5 min and then diluted with EtOAc (50 mL) and H O
2
2
1
(
30 mL). The organic layer was removed and the aqueous
1437, 1378, 1331 cm ; MALDI-HRMS (DHB) m/z
1
layer was washed with EtOAc. The combined organic layers
were dried (Na SO ), ®ltered, and concentrated. Chromato-
409.2134 (M1H , C24H N O requires m/z 409.2122).
28 2 4
2
4
graphy (SiO , 2.5£20 cm, 5±10% EtOAc±hexane gradient
1.1.4. 2-[6-Ethoxy-5-ethoxymethyl-4-(1-methoxymethyl-
enepropyl)pyridin-2-yl]-3-methoxymethylquinoline
(12). KHMDS (0.5 M in toluene, 6.61 mL) was added to a
2
elution) afforded 9 (664 mg, 68%) as a colorless solid: mp
1
1
09±1138C; H NMR (CDCl , 600 MHz) d 8.43 (s, 1H),
3

B. S. J. Blagg, D. L. Boger / Tetrahedron 58 (2002) 6343±6349
6347
slurry of methoxymethyltriphenylphosphonium chloride
1.18 g, 3.31 mmol) in THF (10 mL) at 08C. The red
solution was stirred at 08C for 30 min before ketone 11
270 mg, 0.66 mmol) was added in THF (1 mL). The
Jˆ7.0 Hz, 1H), 7.55 (apparent t, Jˆ7.0 Hz, 1H), 5.49 (br s,
1H), 5.02 (s, 2H), 4.89 (d, Jˆ11.4 Hz, 1H), 4.65 (d,
Jˆ11.4 Hz, 1H), 4.44 (q, Jˆ7.0 Hz, 2H), 3.60 (q,
Jˆ7.0 Hz, 2H), 3.48 (s, 3H), 2.27 (m, 2H), 1.42 (t,
Jˆ7.0 Hz, 3H), 1.27 (t, Jˆ7.0 Hz, 3H), 1.01 (t, Jˆ7.0 Hz,
(
(
solution was warmed to 258C and stirred for 10 h. Saturated
aqueous NH Cl (5 mL) was added and the organic layer
1
3
3H); C NMR (CDCl , 150 MHz) d 200.6, 161.6, 155.3,
4
3
removed. The aqueous layer was washed with EtOAc and
the combined organic layers were dried (Na SO ),
154.3, 150.7, 146.6, 134.4, 131.2, 129.5, 129.3, 127.8,
127.4, 127.0, 117.9, 116.4, 82.7, 72.3, 66.2, 63.5, 62.6,
58.7, 29.6, 14.9, 14.7, 7.4; IR (®lm) 3389, 2919, 2848,
2
4
®
ltered, and concentrated. Chromatography (SiO2,
.5£10 cm, 5±10% EtOAc±hexane gradient elution)
afforded a high R oil (213 mg, 74%) and a lower R oil
2
1
2
1731, 1549, 1378, 1331 cm ; MALDI-HRMS (DHB) m/z
439.2219 (M1H , C H N O requires m/z 439.2227).
1
f
f
25 30
2
5
(
76 mg, 26%).
1
.1.6. 2-[2-Ethoxy-3-ethoxymethyl-6-(3-methoxymethyl-
1
High R product (trans-12): H NMR (CDCl , 400 MHz) d
quinolin-2-yl)pyridin-4-yl]-2-hydroxybutyric acid (17).
Aldehyde 13 (10 mg, 0.023 mmol) and resorcinol (25 mg,
0.23 mmol) were dissolved in DMSO (600 mL). NaH PO
(18 mg, 0.115 mmol) in H O (200 mL) was added and the
2
mixture cooled to 08C before NaClO2 (10.3 mg,
0.115 mmol) was added. The purple mixture was stirred
f
3
8
1
.42 (s, 1H), 8.12 (d, Jˆ8.5 Hz, 1H), 7.84 (d, Jˆ8.2 Hz,
H), 7.68 (apparent t, Jˆ7.6 Hz, 1H), 7.63 (s, 1H), 7.52
2
4
(
4
apparent t, Jˆ7.6 Hz, 1H), 6.35 (s, 1H), 5.03 (s, 2H),
.48 (s, 2H), 4.44 (q, Jˆ7.3 Hz, 2H), 3.70 (s, 3H), 3.65 (q,
Jˆ6.8 Hz, 2H), 3.48 (s, 3H), 2.55 (q, Jˆ7.6 Hz, 2H), 1.43 (t,
Jˆ6.8 Hz, 3H), 1.28 (t, Jˆ7.0 Hz, 3H), 0.96 (t, Jˆ7.3 Hz,
for 1 h at 08C before saturated aqueous NH Cl (1 mL) was
4
1
3
H); C NMR (CDCl , 150 MHz) d 162.1, 155.1, 154.4,
3
1
1
5
2
added. The solution was extracted with EtOAc (4£500 mL)
3
52.8, 147.5, 146.5, 134.0, 131.4, 129.3, 129.0, 127.7,
27.4, 126.7, 118.2, 117.8, 117.7, 72.3, 65.8, 64.8, 62.0,
9.9, 58.6, 21.8, 15.4, 14.8, 12.9; IR (®lm) 2968, 2926,
and the combined organic layers were dried (NaSO ),
4
®ltered, and concentrated. Chromatography (SiO , 50±
2
100% EtOAc±hexane, followed by 15% MeOH±CH Cl )
2
afforded 27 (9.6 mg, 93%) as an amorphous solid:
2
2
1
864, 1651, 1594, 1547, 1444, 1372, 1330 cm ; MALDI-
1
25
1
HRMS (DHB) m/z 437.2435 (M1H , C H N O requires
2
[a]D ˆ129 (c 0.010, MeOH); H NMR (d -DMSO,
6
32
2
4
6
m/z 437.2435).
400 MHz) d 8.49 (s, 1H), 8.12 (s, 1H), 8.08 (d, Jˆ8.2 Hz,
1
H), 8.05 (d, Jˆ7.6 Hz, 1H), 7.75 (apparent t, Jˆ7.0 Hz,
1
Low R product (cis-12): H NMR (CDCl , 400 MHz) d
1H), 7.62 (t, Jˆ7.0 Hz, 1H), 4.99 (m, 3H), 4.69 (d,
Jˆ10.0 Hz, 1H), 4.38 (q, Jˆ7.0 Hz, 2H), 3.53 (q,
Jˆ7.0 Hz, 2H), 3.41 (s, 3H), 3.25±3.40 (br s, 1H), 2.04
(m, 2H), 1.37 (t, Jˆ7.0 Hz, 3H), 1.14 (t, Jˆ6.8 Hz, 3H),
f
3
8
1
.43 (s, 1H), 8.11 (d, Jˆ8.5 Hz, 1H), 7.84 (d, Jˆ8.2 Hz,
H), 7.61 (apparent t, Jˆ8.2 Hz, 1H), 7.61 (s, 1H), 7.51
(
apparent t, Jˆ8.2 Hz, 1H), 6.01 (s, 1H), 5.08 (s, 2H),
1
3
4
2
1
.51 (s, 2H), 4.45 (q, Jˆ7.0 Hz, 2H), 3.57 (q, Jˆ7.0 Hz,
H), 3.54 (s, 3H), 3.50 (s, 3H), 2.33 (q, Jˆ7.3 Hz, 2H),
.43 (t, Jˆ7.0 Hz, 3H), 1.22 (t, Jˆ7.0 Hz, 3H), 1.03 (t,
0.82 (t, Jˆ7.0 Hz, 3H); C NMR (d -DMSO, 100 MHz)
6
d 174.5, 161.9, 154.9, 152.8, 145.9, 134.1, 131.1, 129.5,
128.7, 127.7, 127.1, 126.9 (2C), 118.8, 116.2, 79.1, 71.6,
65.3, 63.3, 61.5, 58.1, 32.2, 15.3, 14.8, 8.8; IR (®lm) 3334,
2974, 2922, 1644, 1691, 1510, 1592, 1548, 1372,
1
3
Jˆ7.4 Hz, 3H); C NMR (CDCl , 100 MHz) d 161.6,
3
1
1
6
2
54.9, 154.5, 151.0, 146.5, 142.3, 133.8, 131.4, 129.3,
29.0, 127.7, 127.4, 126.6, 118.5, 118.3, 117.5, 72.4, 65.9,
4.4, 61.9, 59.6, 58.6, 26.8, 15.3, 14.8, 13.3; IR (®lm) 2968,
2
1
1333 cm ; MALDI-HRMS (DHB) m/z 455.2172
(M1H , C H N O requires m/z 455.2177).
1
2
5
30
2
6
2
1
919, 2860, 1661, 1590, 1548, 1437, 1378, 1331 cm ;
437.2423
1
(M1H ,
MALDI-HRMS (DHB)
C H N O requires m/z 437.2435).
m/z
1.1.7. (1)-Camptothecin (1). Asample of 17 (9.4 mg,
0.021 mmol) was added to a freshly prepared solution of
concentrated HBr(g) in 2,2,2-tri¯uoroethanol (1.88 mL).
The mixture was warmed at re¯ux for 24 h in a sealed
vial, cooled to 258C, and stirred for an additional 14 h.
K CO (14 mg, 0.1 mmol) was added to the solution and
2
6
32
2
4
1.1.5. 2-[2-Ethoxy-3-ethoxymethyl-6-(3-methoxymethyl-
quinolin-2-yl)pyridin-4-yl]-2-hydroxybutyraldehyde (13).
Aslurry of (DHQ) -Pyr(OMe) (16, 4.1 mg, 0.0047 mmol),
2
3
2
3
K CO (12.3 mg, 0.09 mmol), K Fe(CN) , and OsO (23 mL
2
the mixture was stirred for 1 h. The mixture was ®ltered
through a plug of silica gel (1£5 cm) and eluted with 10%
MeOH±CH Cl . The eluent was concentrated and puri®ed
3
3
6
4
of 4% wt in H O, 0.0035 mmol) in H O (300 mL) was stir-
2
2
red at 08C for 5 min before trans-12 (13 mg, 0.030 mmol) in
t-BuOH (300 mL) was added. After 4 h at 08C, additional
K Fe(CN) (10 mg, 0.03 mmol) was added and the solution
2
2
by chromatography (SiO , 0±10% MeOH±CH Cl ) to
2
2
2
afford 1 (5.2 mg, 72%) as an off-white solid identical in
3
6
2
D
5
was stirred at 08C for 4 h. Solid sodium sul®te (40 mg,
.3 mmol) was added and the solution stirred for 30 min
at 08C. CH Cl (600 mL) was added and the organic layer
all respects with authentic material: [a] ˆ 130 (c
2
5
0
0.001, MeOH±CH Cl , 1:4), lit [a] ˆ132 (c 0.4,
2
2
D
1
1
MeOH±CH Cl , 1:4);
2
H
NMR (CD Cl /CD OD,
2
2
2
2
2
3
was removed. The aqueous layer was extracted (3£600 mL)
600 MHz) d 8.48 (s, 1H), 8.18 (d, Jˆ8.3 Hz, 1H), 7.98 (d,
Jˆ7.9 Hz, 1H), 7.82 (apparent t, Jˆ7.0 Hz, 1H), 7.67 (t,
Jˆ7.0 Hz, 1H), 7.67 (s, 1H), 5.63 (d, Jˆ16.2 Hz, 1H),
5.30 (d, Jˆ16.2 Hz, 1H), 5.28 (s, 2H), 1.90 (m, 2H), 0.99
with CH Cl and the combined organic layers were passed
2
2
through a small plug of silica gel (1£4 cm) and eluted with
0% EtOAc±hexane. The eluent was concentrated by a
steady stream of N . Chromatography (SiO , 20%
5
1
3
(t, Jˆ7.4 Hz, 3H); C NMR (CD Cl /CD OD, 150 MHz) d
2
2
2
2
3
EtOAc±hexane) afforded 13 (11 mg, 84%) as a colorless
174.1, 158.4, 152.8, 151.5, 149.0, 146.5, 132.2, 131.2,
129.5, 129.4, 128.8, 128.8, 1128.5, 119.6, 99.0, 73.3, 66.4,
50.7, 31.7, 7.8; MALDI-HRMS (DHB) m/z 349.1185
2
5
1
oil: [a]D ˆ120 (c 0.011, CH Cl ); H NMR (CDCl ,
2
2
3
6
00 MHz) d 9.74 (s, 1H), 8.44 (s, 1H), 8.13 (d, Jˆ8.3 Hz,
H), 7.90 (s, 1H), 7.86 (d, Jˆ7.9 Hz, 1H), 7.70 (apparent t,
1
1
(M1H , C H N O requires m/z 349.1183).
2
0
16
2
4

6348
B. S. J. Blagg, D. L. Boger / Tetrahedron 58 (2002) 6343±6349
20. Lavergne, O.; Lesueur-Ginot, L.; Rodas, F. P.; Bigg, D.
Acknowledgements
Bioorg. Med. Chem. Lett. 1997, 7, 2235.
We gratefully acknowledge the ®nancial support of the
National Institute of Health (CA42056) and the award of
a National Institute of Health postdoctoral fellowship to B.
S. J. B. (CA86475), as well as the Sharpless laboratories for
providing ligands for the asymmetric dihydroxylation.
21. Bom, D.; Curran, D. P.; Chavan, A. J.; Kruszewski, S.;
Zimmer, S. G.; Fraley, K. A.; Burke, T. G. J. Med. Chem.
1999, 42, 3018.
22. Leseur-Ginot, L.; Demarquay, D.; Kiss, R.; Kasprzyk, P. G.;
Dassonneville, L.; Bailly, C.; Camara, J.; Lavergne, O.; Bigg,
D. C. H. Cancer Res. 1999, 59, 2939.
2
3. Urasaki, Y.; Takebayashi, Y.; Pommier, Y. Cancer Res. 2000,
60, 6577.
4. Mi, Z.; Burke, T. G. Biochemistry 1994, 33, 12540.
References
2
1
2
. Wall, M. E.; Wani, M. C.; Cook, K. H.; McPhail, A. T.; Sim,
G. A. J. Am. Chem. Soc. 1966, 88, 3888.
. Wall, M. E.; Wani, M. C.; Taylor, H. Cancer Chemother. Rep.
25. Burke, T. G.; Mi, Z.; Jiang, Y.; Munshi, C. B. J. Pharm. Sci.
1995, 84, 518.
2
6. Previous synthesis of CPT: (a) Stork, G.; Schultz, A. G. J. Am.
Chem. Soc. 1971, 93, 4074. (b) Volkman, R.; Danishefsky,
S. J.; Eggler, J.; Soloman, D. M. J. Am. Chem. Soc. 1971,
1976, 60, 1011.
3
. Wall, M. E.; Wani, M. C. Cancer Res. 1995, 55, 753.
. Hsiang, Y.-H.; Hertzberg, R.; Hecht, S.; Liu, L. F. J. Biol.
Chem. 1985, 260, 14873.
4
9
3, 5576. (c) Winterfeldt, E.; Korth, T.; Pike, D.; Boch, M.
Angew. Chem., Int. Ed. Engl. 1972, 11, 289. (d) Wani, M. C.;
Campbell, H. F.; Brine, G. A.; Kepler, J. A.; Wall, M. E.;
Levine, W. G. J. Am. Chem. Soc. 1972, 94, 3631. (e) Tang,
C.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 8615.
5
. Pommier, Y.; Leteurtre, F.; Fesen, M. R.; Fujimori, A.;
Bertrand, R.; Solary, E.; Kohlhagen, G.; Kohn, K. W. Cancer
Invest. 1994, 12, 530.
6
7
. Liu, L. F. Annu. Rev. Biochem. 1989, 58, 351.
(
f) Sugasawa, T.; Toyoda, T.; Sasakura, K. Tetrahedron
. (a) Kerrigan, J. E.; Pilch, D. S. Biochemistry 2001, 40, 9792.
For alternative models see: (b) Laco, G. S.; Collins, J. R.;
Luke, B. T.; Kroth, H.; Sayer, J. M.; Jerina, D. M.; Pommier,
Y. Biochemistry 2002, 41, 1428. (c) Redindo, M. R.; Stewart,
L.; Kuhn, P.; Champoux, J. J.; Hol, W. G. Science 1998, 279,
Lett. 1972, 5109. (g) Meyers, A. I.; Nolen, R. L.; Collington,
E. W.; Narwid, T. A.; Strickland, R. C. J. Org. Chem. 1973,
3
8, 1974. (h) Kende, A. S.; Bentley, T. J.; Draper, R. W.;
Jenkins, J. K.; Joyeux, M.; Kubo, J. Tetrahedron Lett. 1973,
307. (i) Shamma, M.; Smithers, D. A.; St. Georgiev, V.
1
1504.
Tetrahedron 1973, 29, 1949. (j) Corey, E. J.; Crouse, D. N.;
Anderson, J. C. J. Org. Chem. 1975, 40, 2140. (k) Kametani,
T.; Ohsawa, T.; Masataka, I. J. Chem. Soc., Perkin Trans. 1
8
. Nitiss, J. L.; Beck, W. T. Eur. J. Cancer 1996, 32, 958.
. Kim, J. S.; Sun, Q.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.;
Lavoie, E. J. Bioorg. Med. Chem. Lett. 1996, 4, 621.
9
1
981, 1563. (l) Ihara, M.; Noguchi, K.; Ohsawa, T.;
Fukumoto, K.; Kametani, T. J. Org. Chem. 1983, 48, 3150.
m) Earl, R. A.; Volhardt, K. P. C. J. Org. Chem. 1984, 49,
786. (n) Wani, M. C.; Nicholas, A. W.; Wall, M. E. J. Med.
1
0. Wall, M. E.; Wani, M. C. In The Alkaloids Chemistry and
Biology; Cordell, G. A., Ed.; Academic: San Diego, 1998.
1. Kingsbury, W. D.; Boehm, J. C.; Jakas, D. R.; Holden, K. G.;
Hecht, S.; Gallagher, G.; Cavanfa, M. J.; McCabe, F. L.;
Faucette, L. F.; Johnson, R. K.; Hertzberg, R. J. Med. Chem.
(
1
4
Chem. 1987, 30, 2317. (o) Ejima, A.; Terasawa, H.; Sugomori,
M.; Tagawa, H. J. Chem. Soc., Perkin Trans. 1 1990, 27.
1991, 34, 98.
(
p) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114,
863. (q) Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am.
1
2. Sawada, S.; Okajima, S.; Aiyama, R.; Nokata, K.-I.; Furuta,
T.; Yokokura, T.; Sugino, E.; Yamaguchi, K.; Miyasaka, T.
Chem. Pharm. Bull. 1991, 39, 1446.
5
Chem. Soc. 1992, 114, 10971. (r) Shen, W.; Coburn, C. A.;
Bornman, W. G.; Danishefsky, S. J. J. Org. Chem. 1993, 58,
1
1
3. Camptothecin: New Anticancer Agents; Potmesil, M., Pinedo,
H., Eds.; CRC: Boca Raton, 1995.
6
11. (s) Fang, F. G.; Xie, S.; Lowery, M. W. J. Org. Chem.
994, 59, 6142. (t) Rama Rao, A. V.; Yadav, J. S.; Valluri, M.
1
4. Luzzio, M. J.; Besterman, J. M.; Emerson, D. L.; Evans, M. G.;
Lackey, K.; Leitner, P. L.; McIntyre, G.; Morton, B.; Myers,
P. L.; Peel, M.; Sisco, J. M.; Sternbach, D. D.; Tong, W.-Q.;
Truesdale, A.; Uehling, D. E.; Vuong, A.; Yates, J. J. Med.
Chem. 1995, 38, 395.
Tetrahedron Lett. 1994, 35, 3613. (u) Comins, D. L.; Hong,
H.; Jianhua, G. Tetrahedron Lett. 1994, 35, 5331. (v) Jew, S.;
Ok, K.; Kim, H.; Kim, M. G.; Kim, J. M.; Hah, J. M.; Cho, Y.
Tetrahedron: Asymmetry 1995, 6, 1245. (w) Ciufolini, M. A.;
Roschanger, F. Tetrahedron 1997, 53, 11049. (x) Murata, N.;
Sugihara, T.; Kondo, Y.; Sakamoto, T. Synlett 1997, 298.
1
5. Hertzberg, R. P.; Caranfa, M. J.; Holden, K. G.; Jakas, D. R.;
Gallagher, G.; Mattern, M. R.; Mong, S.-M.; O'Leary Bartus,
J.; Johnson, R. K.; Kingsbury, W. D. J. Med. Chem. 1989, 32,
(
y) Josien, H.; Ko, S.-B.; Bom, D.; Curran, D. P. Chem.
Eur. J. 1998, 4, 67. (z) Imura, A.; Itoh, M.; Miyadera, A.
Chem. Pharm. Bull. 1998, 46, 1878. (aa) Tagami, K.;
Nakazawa, N.; Sano, S.; Nagao, Y. Heterocycles 2000, 53,
7
15.
1
6. Giovanella, B. C.; Stehlin, J. S.; Wall, M. E.; Wani, M. C.;
Nicholas, A. W.; Manikumar, G.; Kirschenbaum, S.; Siliber,
R.; Potmesil, M. Science 1989, 246, 1046.
7
71. (bb) Bennasar, M.-L.; Juan, C.; Busch, J.
Chem. Commun. 2000, 2459. (cc) Comins, D. L.; Nolan,
J. M. Org. Lett. 2001, 3, 4255.
1
1
7. Pantazis, P.; Early, J. A.; Kozielski, A. J.; Mendoza, J. T.;
Hinz, H. R.; Giovanella, B. Cancer Res. 1993, 53, 1577.
8. Okuno, S.; Harada, M.; Yano, T.; Yano, S.; Kiuchi, S.; Tsuda,
N.; Sakamura, Y.; Imai, J.; Kawaguchi, T.; Tsujihara, K.
Cancer Res. 2000, 60, 2988.
27. Boger, D. L.; Hong, J. J. Am. Chem. Soc. 1998, 120, 1218.
28. (a) Boger, D. L. Chemtracts: Org. Chem. 1996, 9, 149.
(b) Boger, D. L.; Patel, M. Progress in Heterocyclic
Chemistry; Suschitzky, H., Scriven, E. F. V., Eds.; Pergamon:
London, 1989; Vol. 1. p 30. (c) Boger, D. L. Chem. Rev. 1986,
86, 781. (d) Boger, D. L. Bull. Soc. Chim. Belg. 1990, 99, 599.
(e) Boger, D. L.; Weinreb, S. M. Hetero Diels±Alder
1
9. Lavergne, O.; Leseur-ginot, L.; Rodas, F. P.; Kasprzyk, P. G.;
Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.;
Rolland, A.; Schiano-Liberatore, A.-M.; Harnett, J.; Pons,
D.; Camara, J.; Bigg, D. J. Med. Chem. 1998, 41, 5410.

B. S. J. Blagg, D. L. Boger / Tetrahedron 58 (2002) 6343±6349
6349
Methodology in Organic Synthesis; Academic: San Diego,
987. (f) Boger, D. L. Tetrahedron 1983, 39, 2869.
35. Lau, C. K.; Dufresne, C.; Belanger, P. C.; Pietre, S.; Scheigetz,
J. J. Org. Chem. 1986, 51, 3038.
36. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1979,
1
2
3
9. (a) Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem.
Soc. 1993, 115, 10733. (b) Boger, D. L.; Nakahara, S. J. Org.
Chem. 1991, 56, 880. (c) Boger, D. L.; Huter, O.; Mbiya, K.;
Zhang, M. J. Am. Chem. Soc. 1995, 117, 11839. (d) Boger,
D. L.; Zhang, M. J. Org. Chem. 1992, 57, 3974.
48, 4679.
37. For the aldehyde: H NMR (CDCl
1
3
, 400 MHz) d 10.44 (s,
1H), 8.47 (s, 1H), 8.13 (d, Jˆ8.5 Hz, 1H), 8.05 (s, 1H), 7.86
(d, Jˆ7.9 Hz, 1H), 7.70 (apparent t, Jˆ8.2 Hz, 1H), 7.58
(apparent t, Jˆ7.9 Hz, 1H), 5.06 (s, 2H), 4.58 (q, Jˆ7.0 Hz,
2H), 4.46 (q, Jˆ7.0 Hz, 2H), 3.48 (s, 3H), 1.49 (t, Jˆ7.0 Hz,
0. (a) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M.
J. Am. Chem. Soc. 1991, 113, 1713. (b) Boger, D. L.; Corbett,
W. L. J. Org. Chem. 1993, 58, 2068. (c) Boger, D. L.; Curran,
T. T. J. Org. Chem. 1990, 55, 5439. (d) Boger, D. L.; Kasper,
A . M.J. Am. Chem. Soc. 1989, 111, 1517.
1
3
3H), 1.40 (t, Jˆ7.0 Hz, 3H); C NMR (CDCl
3
, 100 MHz) d
188.5, 167.3, 162.7, 160.9, 152.5, 146.5, 144.0, 134.9, 131.3,
129.7, 128.0, 127.7, 127.5, 116.2, 114.9, 72.2, 63.3, 62.3, 58.7,
14.6, 13.9; IR (®lm) nmax 2974, 2902, 1733, 1662, 1553,
1333 cm ; MALDI-HRMS (DHB) m/z 395.1592 (M1H ,
requires m/z 395.1601).
3
3
1. Jennings, W. B.; Lovely, C. J. Tetrahedron Lett. 1988, 29,
2
1
1
3
725.
2. Lounasmaa, M.; Hanhinen, P.; Jokela, R. Tetrahedron 1995,
1, 8623.
3. Srikrishna, A.; Viswajanani, R. Synlett 1995, 95.
22 23 2 5
C H N O
5
38. Kikkawa, I.; Yorifuji, T. Synthesis 1980, 877.
39. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
3
3
1
3
4. For the lactone: H NMR (CDCl , 600 MHz) d 8.34 (s, 1H),
8
7
1
3
1
1
.20 (s, 1H), 8.03 (d, Jˆ8.8 Hz, 1H), 7.78 (d, Jˆ8.4 Hz, 1H),
40. Enantiomeric excess was determined by HPLC using a Diacel
Chiralcel AD column (4.6£250 mm) and eluting isocratically
with 1% isopropanol in hexanes (1 mL/min). Racemic 13 was
used as a standard with retention times of 25 and 28 min for
the S and R enantiomers, respectively.
.64 (apparent t, Jˆ7.0 Hz, 1H), 7.48 (apparent t, Jˆ7.5 Hz,
H), 5.25 (s, 2H), 4.94 (s, 2H), 4.47 (q, Jˆ7.0 Hz, 2H), 3.36 (s,
1
3
H), 1.37 (t, Jˆ7.0 Hz, 3H); C NMR (CDCl
3
, 150 MHz) d
69.6, 157.9, 157.6, 153.7, 146.7, 137.4, 135.0, 130.8, 129.6,
29.5, 128.1, 127.9, 127.4, 127.3, 72.3, 68.2, 63.0, 58.6, 14.6;
41. Boger, D. L.; Kim, S. H.; Mori, Y.; Weng, J.-H.; Rogel, O.;
Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc. 2001, 123, 1862.
21
IR (®lm) nmax 2964, 2913, 1774, 1553, 1339, 1092 cm
;
1
MALDI-HRMS (DHB) m/z 351.1329 (M1H , C H N O
requires m/z 351.1339).
2
0
19
2
4