New route to natural camptothecin through isomünchnone cycloaddition

Article abstract of DOI:10.1055/s-2008-1078205

A novel approach to camptothecin by [3+2] cycloaddition of an isomünchnone intermediate is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078205

LETTER
2275
New Route to Natural Camptothecin through Isomünchnone Cycloaddition
New
R
oute to Natu
l
ral Cam
i
ptoth
c
e
cin throug
eh Isomünchnone
Cycloaddition anazawa,* Mauro N. Muniz, Barbora Baumlová, Natalie Ljungdahl, Andrew E. Greene
Département de Chimie Moléculaire (SERCO), UMR 5250, ICMG FR 2650, CNRS Université Joseph Fourier, BP 53, 38041 Grenoble,
France
Fax +33(4)76635754; E-mail: Alice.Kanazawa@ujf-grenoble.fr
Received 23 May 2008
Abstract: A novel approach to camptothecin by [3+2] cycloaddi-
tion of an isomünchnone intermediate is described.
Key words: camptothecin, antitumor natural product, isomünch-
none cycloaddition, Suzuki coupling, cyanosilylation
Camptothecin (1; Figure 1) was first isolated in 1966 by
Wall et al. from extracts of Camptotheca acuminata (‘Xi
Shu’or tree of joy), a plant native to China, and found to
possess strong antitumor activity.1 The biological activity
of this pentacyclic alkaloid was subsequently attributed to
a unique mechanism, the selective poisoning of DNA to-
Figure 1 Camptothecin and analogues [PipPip = 4-(1-piperidino)-
1-piperidino]
poisomerase I, which is an enzyme essential for the relax-
ation of DNA during important cellular processes.2
alkaloid through an isomünchnone [3+2] cycloaddition
has been developed and is described herein.
Several structure–activity studies have been performed
since the isolation of this natural product and a number of
more active and less severely toxic camptothecinoids
have been identified. These research efforts, focused pri-
marily on the synthesis of derivatives bearing substituents
on the A and B rings, have led to the discovery of irinote-
can [Camptosar (2)] and topotecan [Hycamtin (3)], which
are used for the treatment of ovarian and colon cancers, re-
spectively.3,4 Several others analogues are in different
phases of clinical evaluation.5,6
We envisaged that a diazoester could be obtained from the
easily accessible tricyclic lactam 49 and used to generate
the corresponding isomünchnone intermediate; this, in
turn, could undergo a [3+2] cycloaddition10 with an ap-
propriate olefin to produce an adduct with suitable func-
tionality for constructing the D and E rings of the natural
product (Scheme 1). Acylation of lactam 4 with ethyl 2-
diazomalonyl chloride11 did indeed provide, after forma-
tion of the corresponding lithium amide with LHMDS in
THF, the desired diazoester 512 in 68% yield. Subsequent
exposure of the diazoester to excess benzyl vinyl ether13
in the presence of a catalytic amount of rhodium acetate
dimer in refluxing benzene cleanly produced the desired
tetracycle 714 in excellent yield. As expected, an efficient
[3+2]-cycloaddition reaction had occurred to give the
bridged ether 6, which then suffered ring opening to gen-
Numerous syntheses of camptothecin and its derivatives
have been reported in the literature.6e,j,7 However, due to
the pharmacological importance of the camptothecinoids
and their challenging structural features, new synthetic
approaches remain of considerable interest. As part of a
program to explore new approaches toward camptothecin
and its analogues,8 a novel, enantioselective route to this
O
O
a
b
NH
N
OEt
N
N
N2
O
O
4
5
O
O
N
O
N
OH
CO2Et
N
N
CO2Et
OBn
OBn
6
7
Scheme 1 Reagents and conditions: (a) LHMDS, THF, then ethyl diazomalonyl chloride (68%); (b) [Rh(OAc)2]2, benzyl vinyl ether, benzene
(91%).
SYNLETT 2008, No. 15, pp 2275–2278
1
5
.0
9
.2
0
0
8
Advanced online publication: 21.08.2008
DOI: 10.1055/s-2008-1078205; Art ID: G17008ST
© Georg Thieme Verlag Stuttgart · New York

2276
A. Kanazawa et al.
LETTER
erate 7. This step, however, was not spontaneous and was generated from glucose-derived 13, which gave a 2:1 mix-
1
therefore followed by H NMR to ensure complete con- ture of (–)-1225 and (+)-12 in 66% yield (Scheme 4).26
version (91% yield).
Separation of the mixture by chiral HPLC efficiently pro-
vided the enantiomers in high purity (≥ 99.8% ee).27 Since
it was found that the undesired minor enantiomer (+)-12
was converted back into ketone 11 in excellent yield on
careful treatment with one equivalent of TBAF in THF at
–80 °C, ketone 11 could be, at least in theory, completely
transformed into the desired enantiomer (–)-12.
In the presence of DBU, tetracycle 7 underwent smooth
dehydration to afford pyridone 8a15 in high yield
(Scheme 2). Having thus rapidly and efficiently complet-
ed the A–D rings of camptothecin, the next and final goal
was to elaborate the lactone. To this end, pyridone 8a was
debenzylated in the usual way and the derived hydroxy
pyridone 8b16 was then transformed, also conventionally, The major enantiomer (–)-12 was successfully converted
into triflate 8c17 (84%, 2 steps).
into natural camptothecin by an intramolecular Pinner re-
action on treatment with HCl in hot ethanol (92%). The
20
O
N
synthetically derived material {[a]D +40.7 (c 0.27,
O
N
CHCl3–MeOH, 4:1); mp 257–258 °C (dec.)} was spectro-
scopically and chromatographically identical with an au-
thentic sample of (20S)-camptothecin.28
OH
a
N
N
CO2Et
CO2Et
OBn
OR
7
8a R = Bn
8b R = H
8c R = Tf
b
c
O
O
N
N
a
+
(+)-12
N
N
Scheme 2 Reagents and conditions: (a) DBU, CH2Cl2 (94%);
(b) H2, Pd/C, EtOH (88%); (c) Tf2O, pyridine, CHCl3 (96%).
OTBDMS
OTBDMS
TMSO
11
O
CN
(–)-12
With this triflate in hand, a study was effected to evaluate
palladium-mediated coupling reactions for introducing a
vinylic substituent. While different Stille and Heck reac-
tions proved ineffectual, Suzuki coupling with phenyl-
vinylboronic acid in the presence of tetrakis(tri-
phenylphosphine)palladium and sodium carbonate pro-
ceeded smoothly to furnish the styrene derivative 918 in
89% yield (Scheme 3). The ethoxycarbonyl group in 9
was next selectively reduced to produce the correspond-
ing hydroxymethyl derivative 10a,19 which was protected
as the tert-butyldimethylsilyl ether.20 Oxidative cleavage
of the styryl group then readily produced aldehyde 10c,21
which was efficiently transformed into ethyl ketone 1122
simply by treatment with diazoethane.23 The crude mate-
rial was used directly in the next step.
Ph
O
N
P
Ph
b
O
HO
N
O
O
F
F
(+)-1
OH
O
HO
13
Scheme 4 Reagents and conditions: (a) Gd(Oi-Pr)3 (10 mol%), 13
(20 mol%), TMSCN (3 equiv), CH2Cl2, –20 °C, 60 h (66% from 10c);
(b) chiral HPLC separation, then for (–)-12 [→ (+)-1]: 2 M HCl in
Et2O, EtOH (92%); for (+)-12 (→ 11): TBAF (1 equiv), THF, –80 °C
(92%).
In summary, a new synthesis of natural camptothecin
from a readily available starting material has been devel-
oped that employs a [3+2] cycloaddition, a Suzuki cou-
pling, and a Shibasaki enantioselective cyanosilylation as
Introduction of the 20S stereocenter was addressed
through application of Shibasaki’s methodology.24 Thus,
ketone 11 was submitted to S-enantioselective cyanosi-
lylation with TMSCN in the presence of the Gd complex
O
O
N
a
N
b
N
CO2Et
N
CO2Et
OTf
O
8c
9
Ph
O
N
N
e
N
N
OR1
OTBDMS
R2
11
O
10a R1 = H, R2 = CH=CHPh
10b R1 = TBDMS, R2 = CH=CHPh
10c R1 = TBDMS, R2 = CHO
c
d
Scheme 3 Reagents and conditions: (a) PhCH=CHB(OH)2, Pd(PPh3)4, aq Na2CO3, toluene (89%); (b) DIBAL-H, CH2Cl2, then NaBH4, Me-
OH; (c) TBDMSCl, imidazole, DMF (89%); (d) OsO4 (cat.), NaIO4, t-BuOH, THF–H2O (99%); (e) MeCHN2, Et2O–CHCl3.
Synlett 2008, No. 15, 2275–2278 © Thieme Stuttgart · New York

LETTER
New Route to Natural Camptothecin through Isomünchnone Cycloaddition
2277
(10) For reviews on isomünchnone cycloadditions, see:
the key transformations. The synthesis requires 12 steps
and proceeds in an overall yield of >15%.
(a) McMills, M. C.; Wright, D. In The Chemistry of
Heterocyclic Compounds: Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products; Padwa, A.; Pearson, W. H., Eds.; John
Wiley and Sons: New York, 2002, 253–314. (b) Mehta, G.;
Muthusamy, S. Tetrahedron 2002, 58, 9477. (c) Padwa, A.
Top. Curr. Chem. 1997, 189, 121. (d) Padwa, A.;
Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(e) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis
1994, 123.
Acknowledgment
We would like to express special gratitude to Prof. M. Shibasaki and
Dr. M. Kanai (University of Tokyo) for kindly providing Gd(Oi-
Pr)3 and the ligand 13 and to Prof. C. Roussel and Dr. N. Vanthuyne
(Université Paul Cézanne-Marseille) for the enantiomeric separa-
tion of enriched 12. We also thank Prof. P. Dumy (UJF) for his in-
terest in our work, the Swedish Foundation for Strategic Research
and Chalmers University of Technology for a study grant (to N.L.),
and the Université Joseph Fourier and the CNRS for financial sup-
port.
(11) (a) Marino, J. P.; Osterhout, M. H.; Price, A. T.; Sheehan,
S. M.; Padwa, A. Tetrahedron Lett. 1994, 35, 849. (b) For
the use of this reagent for similar cyclizations, see: Padwa,
A.; Prein, M. J. Org. Chem. 1997, 62, 6842.
(12) Compound 5: mp 215–216 °C (dec.). 1H NMR (300 MHz,
CD2Cl2): d = 1.29 (t, J = 7.1 Hz, 3 H), 4.31 (q, J = 7.1 Hz, 2
H), 5.08 (s, 2 H), 7.69 (pseudo t, J = 7.5 Hz, 1 H), 7.82
(pseudo t, J = 7.2 Hz, 1 H), 7.93 (d, J = 7.9 Hz, 1 H), 8.36 (d,
J = 7.2 Hz, 2 H). 13C NMR (75 MHz, CD2Cl2): d = 14.6,
46.8, 62.5, 71.0, 128.6, 129.6, 130.0, 130.9, 131.2, 131.4,
132.2, 149.4, 150.1, 161.0, 161.5, 165.0. IR: 2142, 1736,
1717, 1655 cm–1. MS: m/z = 325 [M + H+]. HRMS: m/z
[M + H+] calcd for C16H13N4O4: 325.0937; found: 325.0952.
(13) Guy, R. K.; DiPietro, R. A. Synth. Commun. 1992, 22, 687.
(14) Compound 7: mp 169–170 °C. 1H NMR (300 MHz, CDCl3):
d = 1.14 (t, J = 7.1 Hz, 3 H), 4.17–4.29 (m, 3 H), 4.81–4.94
(m, 3 H), 5.01 (s, 2 H), 6.30 (d, J = 2.7 Hz, 1 H), 7.25–7.40
(m, 5 H), 7.58 (pseudo t, J = 8.0 Hz, 1 H), 7.75 (pseudo t,
J = 8.5 Hz, 1 H), 7.83 (d, J = 8.2 Hz, 1 H), 8.12–8.14 (m, 2
H). 13C NMR (75 MHz, CDCl3): d = 14.1, 48.4, 62.8, 73.1,
80.5, 81.1, 101.7, 127.5, 127.9, 128.0 (2 ×), 128.2, 128.5,
128.6, 129.7, 130.3, 130.8, 137.1, 137.9, 149.0, 152.4,
166.6, 168.6. IR: 3428, 1744, 1659 cm–1. MS: m/z = 431
[M + H+]. Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.16; N,
6.51. Found: C, 69.48; H, 5.04; N, 6.41.
References and Notes
(1) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.;
McPhail, A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88,
3888.
(2) Hsiang, Y.-H.; Hertzberg, R.; Hecht, S.; Liu, L. J. Biol.
Chem. 1985, 260, 14873.
(3) Saltz, L. B.; Cox, J. V.; Blanke, C.; Rosen, L. S.;
Fehrenbacher, L.; Moore, M. J.; Maroun, J. A.; Ackland,
S. P.; Locker, P. K.; Pirotta, N.; Elfring, G. L.; Miller, L. L.
N. Engl. J. Med. 2000, 343, 905.
(4) Gore, M.; ten Bokkel Huinink, W.; Carmichael, J.; Gordon,
A.; Davidson, N.; Coleman, R.; Spaczynski, M.; Heron,
J. F.; Bolis, G.; Malmstrom, H.; Malfetano, J.; Scarabelli, C.;
Vennin, P.; Ross, G.; Fields, S. Z. J. Clin. Oncol. 2001, 19,
1893.
(5) (a) Butler, M. S. Nat. Prod. Rep. 2008, 25, 475. (b) Butler,
M. S. Nat. Prod. Rep. 2005, 22, 162. (c) Cragg, G. M.;
Newman, D. J. J. Nat. Prod. 2004, 67, 332.
(6) For reviews on camptothecin and its derivatives, see:
(a) Cuendet, M.; Pezzuto, J. M. In Modern Alkaloids:
Structure, Isolation, Synthesis and Biology; Fattorusso, E.;
Taglialatela-Scafati, O., Eds.; Wiley-VCH: Weinheim,
2008, Chap. 2, 29–33. (b) Lorence, A.; Nessler, C. I.
Phytochemistry 2004, 65, 2735. (c) Thomas, C. J.; Rahier,
N. J.; Hecht, S. M. Bioorg. Med. Chem. 2004, 12, 1585.
(d) Pizzolato, J. F.; Saltz, L. B. Lancet 2003, 361, 2235.
(e) Du, W. Tetrahedron 2003, 59, 8649. (f) Lansiaux, A.;
Bailly, C. Bull. Cancer 2003, 90, 239. (g) Torck, M.;
Pinkas, M. J. Pharm. Belg. 1996, 51, 200.
(15) Compound 8a: mp 201–203 °C. 1H NMR (300 MHz,
CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H), 4.42 (q, J = 7.1 Hz, 2
H), 5.22 (s, 2 H), 5.35 (s, 2 H), 7.17 (s, 1 H), 7.30–7.50 (m,
5 H), 7.66 (pseudo t, J = 7.6 Hz, 1 H), 7.82 (pseudo t, J = 8.3
Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 8.20 (d, J = 8.5 Hz, 1 H),
8.32 (s, 1 H). 13C NMR (100 MHz, CDCl3): d = 14.2, 49.2,
61.4, 71.1, 89.6, 109.6, 127.1, 128.1, 128.2, 128.31, 128.34,
128.7, 129.2, 129.6, 130.6, 131.2, 135.3, 147.8, 148.7,
152.0, 159.0, 164.9, 166.2. IR: 1718, 1651, 1602 cm–1. MS:
m/z = 413 [M + H+]. Anal. Calcd for C25H20N2O4: C, 72.81;
H, 4.89; N, 6.80. Found: C, 72.70; H, 4.84; N, 6.59.
(16) (a) Compound 8b: mp 246–248 °C. 1H NMR (300 MHz,
CDCl3): d = 1.49 (t, J = 7.0 Hz, 3 H), 4.50 (q, J = 7.1 Hz, 2
H), 5.23 (s, 2 H), 7.03 (s, 1 H), 7.67 (pseudo t, J = 7.3 Hz, 1
H), 7.83 (pseudo t, J = 7.2 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 1
H), 8.24 (d, J = 8.5 Hz, 1 H), 8.37 (s, 1 H). 13C NMR (75
MHz, CDCl3–MeOH, 4:1): d = 14.1, 50.0, 61.9, 94.6, 128.0,
128.3, 128.4, 129.2, 129.3, 130.6, 131.4, 148.5, 149.7,
151.3, 155.9, 159.3, 171.5, 175.6. IR: 3447, 1660, 1616
cm–1. MS: m/z = 323 [M + H+]. Anal. Calcd for C18H14N2O4:
C, 67.08; H, 4.38; N, 8.70. Found: C, 67.23; H, 4.37; N,
8.71. (b) For an alternative synthesis, see: Liao, T. K.;
Nyberg, W. H.; Cheng, C. C. J. Heterocycl. Chem. 1971, 8,
373.
(h) Camptothecins: New Anticancer Agents; Potmesil, M.;
Pinedo, H., Eds.; CRC Press: Boca Raton, 1995.
(i) Sawada, S.; Yokokura, T.; Miyasaka, T. Curr. Pharm.
Des. 1995, 1, 113. (j) Hutchinson, C. R. Tetrahedron 1981,
37, 1047.
(7) For recent syntheses of (20S)-camptothecin, see: (a) Zhou,
H.-B.; Liu, G.-S.; Yao, Z.-J. Org. Lett. 2007, 9, 2003.
(b) Chavan, S. P.; Pathak, A. B.; Kalkote, U. R. Synlett 2007,
2635. (c) Peters, R.; Althaus, M.; Nagy, A.-L. Org. Biomol.
Chem. 2006, 4, 498. (d) Chavan, S. P.; Venkatraman, M. S.
ARKIVOC 2005, (iii), 165.
(8) (a) Raolji, G. B.; Garçon, S.; Greene, A. E.; Kanazawa, A.
Angew. Chem. Int. Ed. 2003, 42, 5059. (b) Anderson, R. J.;
Raolji, G. B.; Kanazawa, A.; Greene, A. E. Org. Lett. 2005,
7, 2989. (c) Babjak, M.; Kanazawa, A.; Andersen, R. J.;
Greene, A. E. Org. Biomol. Chem. 2006, 4, 407. (d) Tang,
C.-J.; Babjak, M.; Anderson, R. J.; Greene, A. E.;
Kanazawa, A. Org. Biomol. Chem. 2006, 4, 3557.
(9) (a) Danishefsky, S.; Bryson, T. A.; Puthenpurayil, J. J. Org.
Chem. 1975, 40, 796. (b) Boger, D. L.; Hong, J. J. Am.
Chem. Soc. 1998, 120, 1218.
(17) Compound 8c: mp 205–207 °C (dec.). 1H NMR (300 MHz,
CDCl3): d = 1.42 (t, J = 7.2 Hz, 3 H), 4.46 (q, J = 7.2 Hz, 2
H), 5.28 (s, 2 H), 7.28 (s, 1 H), 7.70 (pseudo t, J = 8.1 Hz, 1
H), 7.85 (pseudo t, J = 8.4 Hz, 1 H), 7.95 (d, J = 7.7 Hz, 1
H), 8.23 (d, J = 8.4 Hz, 1 H), 8.41 (s, 1 H). 13C NMR (75
MHz, CDCl3): d = 13.7, 50.8, 62.5, 94.8, 115.7, 116.2,
120.5, 128.1, 128.5, 128.7, 129.5, 131.1, 131.6, 148.7,
Synlett 2008, No. 15, 2275–2278 © Thieme Stuttgart · New York

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A. Kanazawa et al.
LETTER
149.0, 150.4, 156.9, 158.1, 161.6. IR: 1730, 1654, 1616
cm–1. MS: m/z = 455 [M + H+]. Anal. Calcd for
C19H13F3N2O6S: C, 50.23; H, 2.89; N, 6.17. Found: C, 50.11;
H, 2.99; N, 6.10.
[M + H+]. Anal. Calcd for C23H26N2O3Si: C, 67.95; H, 6.45;
N, 6.90. Found: C, 68.12; H, 6.43; N, 6.89.
(22) Compound 11: mp 200–201 °C. 1H NMR (300 MHz,
CDCl3): d = 0.12 (s, 6 H), 0.91 (s, 9 H), 1.22 (t, J = 7.2 Hz,
3 H), 2.91 (q, J = 7.2 Hz, 2 H), 4.91 (s, 2 H), 5.28 (s, 2 H),
7.16 (s, 1 H), 7.65 (pseudo t, J = 7.0 Hz, 1 H), 7.81 (pseudo
t, J = 7.7 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 8.20 (d, J = 8.4
Hz, 1 H), 8.37 (s, 1 H). 13C NMR (75 MHz, CDCl3): d = –5.6,
7.6, 18.6, 25.8, 36.2, 50.3, 58.5, 98.5, 127.7, 127.8, 127.9,
128.0, 128.6, 129.6, 130.4, 130.9, 144.5, 148.7, 150.3,
152.5, 159.9, 205.6. IR: 1708, 1649, 1596 cm–1. MS: m/z =
435 [M + H+]. Anal. Calcd for C25H30N2O3Si: C, 69.10; H,
6.96; N, 6.45. Found: C, 69.19; H, 7.07; N, 6.55.
(18) Compound 9: mp 261–263 °C (dec.). 1H NMR (300 MHz,
CDCl3): d = 1.46 (t, J = 7.2 Hz, 3 H), 4.52 (q, J = 7.1 Hz, 2
H), 5.30 (s, 2 H), 7.20–7.70 (m, 9 H), 7.84 (pseudo t, J = 7.7
Hz, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), 8.26 (d, J = 8.4 Hz, 1 H),
8.40 (s, 1 H). 13C NMR (75 MHz, CDCl3): d = 14.4, 49.9,
61.8, 97.1, 122.5, 122.9, 127.4, 127.9, 128.1, 128.2, 128.8,
129.0, 129.3, 129.5, 130.5, 131.0, 135.8, 136.8, 145.7,
147.1, 148.7, 152.4, 158.7, 166.3. IR: 1723, 1640, 1603
cm–1. MS: m/z = 409 [M + H+]. Anal. Calcd for C26H20N2O3:
C, 76.46; H, 4.94; N, 6.86. Found: C, 76.37; H, 4.99; N, 6.67.
(19) Compound 10a: mp 261–263 °C (dec.). 1H NMR (300 MHz,
DMSO-d6): d = 4.74 (d, J = 5.1 Hz, 2 H), 4.99 (t, J = 5.1 Hz,
1 H), 5.25 (s, 2 H), 7.30–7.50 (m, 3 H), 7.60–7.90 (m, 7 H),
8.10–8.25 (m, 2 H), 8.67 (s, 1 H). 13C NMR (100 MHz,
CDCl3–MeOH, 4:1): d = 49.8, 55.9, 99.4, 122.5, 126.4,
127.1, 127.6, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5,
128.6, 128.9, 130.5, 131.3, 135.8, 136.3, 143.5, 147.4,
148.2, 152.3, 161.9. IR: 3310, 1652, 1580, 1566 cm–1. MS:
m/z = 367 [M + H+]. HRMS: m/z [M + H+] calcd for
C24H19N2O2: 367.1447; found: 367.1455.
(23) Warner, C. R.; Walsh, E. J.; Smith, R. F. J. Chem. Soc. 1962,
1232.
(24) (a) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.;
Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 9908. (b) Yabu, K.; Masumoto, S.;
Kanai, M.; Shibasaki, M. Heterocycles 2003, 59, 369.
(25) Compound (–)-12: mp 228–231 °C (dec.); [a]D22 –18 (c 1.3,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 0.19 (s, 3 H), 0.20
(s, 3 H), 0.28 (s, 9 H), 0.93 (s, 9 H), 1.09 (t, J = 7.3 Hz, 3 H),
2.37 (q, J = 7.3 Hz, 2 H), 5.05 (ABq, J = 10.8 Hz, 1 H), 5.21
(ABq, J = 10.8 Hz, 1 H), 5.26 (s, 2 H), 7.58–7.66 (m, 2 H),
7.80 (pseudo t, J = 7.7 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H),
8.23 (d, J = 8.4 Hz, 1 H), 8.34 (s, 1 H). 13C NMR (75 MHz,
CDCl3): d = –5.4, –5.3, 1.0, 8.5, 18.5, 25.9, 37.2, 50.2, 56.6,
76.0, 99.1, 120.0, 127.5, 127.7, 128.0, 128.7, 129.8, 130.3,
130.7, 144.4, 148.9, 151.2, 152.7, 161.2. IR: 1652, 1598 cm–1.
MS: m/z = 534 [M + H+]. HRMS: m/z [M + H+] calcd for
C29H40N3O3Si2: 534.2608; found: 534.2616.
(20) Compound 10b: mp 247–248 °C (dec.). 1H NMR (300 MHz,
CDCl3): d = 0.16 (s, 6 H), 0.93 (s, 9 H), 5.02 (s, 2 H), 5.27
(s, 2 H), 7.27–7.47 (m, 5 H), 7.59–7.73 (m, 4 H), 7.82
(pseudo t, J = 7.7 Hz, 1 H), 7.92 (d, J = 7.4 Hz, 1 H), 8.24 (d,
J = 8.5 Hz, 1 H), 8.35 (s, 1 H). 13C NMR (75 MHz, CDCl3):
d = –5.1, 18.3, 26.0, 49.9, 56.6, 88.4, 98.4, 124.5, 127.2,
127.4, 127.5, 128.0, 128.1, 128.7, 128.8, 129.0, 129.6,
130.3, 130.9, 134.9, 136.6, 143.6, 147.7, 148.6, 153.2,
161.0. IR: 1656, 1651, 1593 cm–1. MS: m/z = 481 [M + H+].
Anal. Calcd for C30H32N2O2Si: C, 74.87; H, 6.71; N, 5.83.
Found: C, 74.87; H, 6.76; N, 5.89.
(26) Dichloromethane was used as the solvent for this reaction
instead of a more usual one (THF or EtCN) because of
solubility problems. The reaction was performed at –20 °C
for the same reason.
(21) Compound 10c: mp 262–265 °C (dec.). 1H NMR (300 MHz,
CDCl3): d = 0.14 (s, 6 H), 0.90 (s, 9 H), 5.15 (s, 2 H), 5.27
(s, 2 H), 7.63–7.66 (m, 2 H), 7.80 (pseudo t, J = 8.4 Hz, 1 H),
7.90 (d, J = 8.1 Hz, 1 H), 7.90 (d, J = 8.1 Hz, 1 H), 8.20 (d,
J = 8.5 Hz, 1 H), 8.34 (s, 1 H). 13C NMR (75 MHz, CDCl3):
d = –5.4, 18.3, 25.7, 50.3, 57.2, 97.4, 127.8, 127.9, 128.5,
129.8, 130.4, 130.9, 134.6, 143.5, 145.1, 149.0, 152.6,
160.7, 192.2. IR: 1697, 1651, 1600 cm–1. MS: m/z = 407
(27) Analytical HPLC of 12 was performed on a Chiralpak® IA
column (250 × 4.6 mm) using hexane–i-PrOH (9:1) as the
eluent with a flow rate of 1.0 mL/min and UV monitoring at
l = 254 nm [tR (+)-12 = 10.2 min; tR (–)-12 = 7.5 min]. The
separation was performed using the same chiral support
(250 × 10 mm) and eluent with a flow rate of 5 mL/min.
(28) (20S)-Camptothecin was purchased from Sigma-Aldrich.
Synlett 2008, No. 15, 2275–2278 © Thieme Stuttgart · New York

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