Asymmetric total synthesis of (20R)-homocamptothecin, substituted homocamptothecins and homosilatecans

Article abstract of DOI:10.1016/S0040-4020(02)00632-4

An efficient asymmetric synthesis of a key DE lactone pyridone intermediate in the synthesis of homocamptothecin is reported. The synthesis is scalable and features a Stille coupling and a Sharpless asymmetric epoxidation as the key steps. The key intermediate has been parleyed into homocamptothecin and an assortment of fluorinated homocamptothecins and homosilatecans (7-silylhomocamptothecins), thereby providing the first asymmetric entry to this important new class of antitumor agents.

Full text of DOI:10.1016/S0040-4020(02)00632-4

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 6329±6341
Asymmetric total synthesis of (20R)-homocamptothecin,
substituted homocamptothecins and homosilatecans
Ana E. Gabarda, Wu Du, Thomas Isarno, Raghuram S. Tangirala and Dennis P. Curranp
Department of Chemistry, University of Pittsburgh, Parkman Abenue University Drive, Pittsburgh, PA 15260, USA
Dedicated to Professor Yoshito Kishi in recognition of his receipt of the Tetrahedron Prize
Received 6 May 2002; accepted 28 May 2002
AbstractÐAn ef®cient asymmetric synthesis of a key DE lactone pyridone intermediate in the synthesis of homocamptothecin is reported.
The synthesis is scalable and features a Stille coupling and a Sharpless asymmetric epoxidation as the key steps. The key intermediate has
been parleyed into homocamptothecin and an assortment of ¯uorinated homocamptothecins and homosilatecans (7-silylhomocampto-
thecins), thereby providing the ®rst asymmetric entry to this important new class of antitumor agents. q 2002 Published by Elsevier Science
Ltd.
1. Introduction
ene group on the other side of the lactone carbonyl gives a
keto ether analog 4 that is inactive.8
(20S)-Camptothecin 1 is the parent of an important class of
anticancer agents that act on the so-called cleavable
complex of DNA and the enzyme topoisomerase I.1 All
camptothecins are dynamic drugs and exist in equilibrium
with their open carboxylate forms in blood and other bio-
logical milieu (Fig. 1).2 Of late, advances in the total syn-
thesis of camptothecins have driven medicinal chemistry
and pharmacology research by providing many new analogs
for biological testing. For example, we have prepared a
diverse assortment of 7-silylcamptothecins, or silatecans,
by a ¯exible and general total synthesis that features a
cascade isonitrile radical annulation.3 DB-67 2 has emerged
from the pack of silatecans as a potential candidate for
cancer chemotherapy by virtue of its high activity, high
blood stability and other interesting properties.4
To facilitate the synthesis of analogs, Lavergne and
co-workers developed a fully synthetic route to racemic
homocamptothecin based on the powerful Comins route to
camptothecins.9 Key intermediate 7 (Fig. 2) is alkylated
with quinoline 6 to give 8 followed by Pd-catalyzed cycli-
zation to give homocamptothecin 3. Resolution of a pre-
cursor of 7 then opened the door to the corresponding
enantioenriched homocamptothecin analogs. Several highly
active ¯uorinated analogs of homocamptothecin were
prepared from suitably substituted quinolines 6.10
In 1999, we communicated the adoption of our cascade
radical annulation route to camptothecins for the prepara-
tion of homocamptothecins.11 Racemic 9 was prepared and
reacted with a number of silyl propargyl halides to provide
precursors rac-10a, which were then reacted with isonitriles
11 to provide a small collection of silatecan/homocamp-
tothecin hybrids rac-12 called homosilatecans (Fig. 3).
Several of these compounds exhibited potent anticancer
properties coupled with exceptionally high human blood
stabilities.11 Compared to the hybrid Comins/Lavergne
route, the radical annulation route allows for a more diverse
range of A-ring substituents and incorporates B-ring sub-
stituents with equal ease. The generality of the approach has
been shown by making a library of over 100 analogs of
homosilatecans.12
In 1997, Lavergne and coworkers described a semi-syn-
thesis of racemic homocamptothecin rac-3 (BN 80245,
abbreviated hcpt) from camptothecin 1,5 and showed that
this E-ring expanded analog was more potent than camp-
tothecin in a number of assays. In contrast to the lactone ring
of camptothecin 1, which opens rapidly and reversibly, the
lactone ring of homocamptothecin 3 opens slowly and
irreversibly.6 Resolution of the open hydroxyl carboxylate
form of homocamptothecin provided the ®rst sample of the
active (20R)-enantiomer 3 (Fig. 1).7 The insertion of a
methylene group (C20a) between the stereocenter at C20
and the lactone carbonyl is crucial; insertion of the methyl-
Collectively, the early results suggest that analogs of homo-
camptothecin and homosilatecans may often possess similar
or even better anticancer activities than the parent while
at the same time exhibiting very different pharmaco-
dynamic properties due to the reactivity difference of the
Keywords: homosilatecans; topoisomerase; antitumor.
Corresponding author. Tel.: 11-412-624-8240; fax: 11-412-624-9861;
e-mail: curran@pitt.edu
p
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)00632-4

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A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
Figure 1. Camptothecin, silatecans and homocamptothecin.
seven-membered lactone ring compared to the parent six-
membered ring. To facilitate progress in this exciting area,
we undertook the development of an asymmetric synthesis,
and we report here the preparation of enantioenriched 9
and its conversion to a number of known and new homo-
camptothecin and homosilatecan analogs. In addition, we
report an asymmetric synthesis of lactone 7 (Fig. 2), the
key intermediate in the Comins/Lavergne route.
2. Results and discussion
After brie¯y evaluating a number of possible asymmetric
strategies to lactone pyridone 9, we set out to explore
a classical Sharpless asymmetric expoxidation route, as
shown in Scheme 1. As in our previous routes to both camp-
tothecin and homocamptothecin, a trimethylsilyl group was
used as a place holder for the radical precursor (iodine).
Figure 2. Comins/Lavergne route to hcpt.

A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
6331
Figure 3. Cascade radical annulation route to racemic homosilatecans.
The synthesis of allylic alcohols 18E and 18Z began with
iodoformyl pyridine 13, which is an early intermediate in
the total synthesis of camptothecin.3 Treatment of 13 with
NaBH4 in EtOH at 2408C afforded hydroxymethyl pyridine
14 in 80% yield. Exposure of this alcohol to MOMCl and
iPr2EtN in CH2Cl2 at 08C provided MOM ether 15 in 88%
yield. The cuprate reagent derived from pyridine 15 was
prepared by iodine±magnesium exchange reaction13 with
iPrMgCl at 2408C, followed by addition of CuCN and
LiCl.14 Quenching with propionyl chloride provided
the ketone 1615 in 69% isolated yield. The Horner±
Wadsworth±Emmons16 ole®nation of this ketone with
trimethyl phosphonoacetate (tBuOK, THF, 558C) provided
esters 17E (27%) and 17Z (43%) after separation on silica
gel. LAH reduction gave the corresponding alcohols 18Z
(92%) and 18E (96%).
The Sharpless asymmetric epoxidation of allylic alcohols
18E and 18Z to install the key C20 stereocenter was
attempted under standard conditions.17 Epoxidation of 18Z
with 1 equiv. of d-(2)-diethyl tartrate, tBuOOH and
80 mol% of Ti(OiPr)4 in CH2Cl2 at 2208C was sluggish.
Warming the reaction mixture to 08C led to epoxide
19-cis in 12% yield and 31% ee, based on chiral HPLC
analysis. The starting allylic alcohol 18Z was also recovered
in 38% yield. In contrast, treatment of alcohol 18E
t
with BuOOH/Ti(OiPr)4 and a stoichiometric amount of
l-(1)-diethyl tartrate in CH2Cl2 at 2208C for 2 h followed
by workup and ¯ash chromatography provided epoxide
19-trans in 79% yield and 93% ee.
The highly selective Sharpless epoxidation makes ester 18E
and alcohol 19-trans key intermediates, thus their selective
preparation was necessary. Attempts to increase the E-selec-
tivity of the Horner±Emmons ole®nation were unsuccess-
ful, and the isomerization of 17Z into the desired isomer
17E was inef®cient at best.12a Accordingly, focus shifted
towards the preparation of 18E by means of a palladium-
catalyzed cross-coupling reaction starting from iodopyri-
dine 15 and ethyl (E)-3-(tributylstannyl)-2-pentenoate 2018
(Scheme 2). This was achieved by using Corey's protocol19
(LiCl, CuCl, Pd(Ph3P)4, DMSO, 608C, 17 h) to provide 21E
Scheme 1.

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A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
Scheme 2.
t
of aldehyde 23 with NaClO2 in BuOH, buffered with an
(the ethyl ester analog of 19E) in 80% isolated yield. Treat-
ment of ethyl ester 21E with LAH provided alcohol 18E,
which was subjected to Sharpless epoxidation as above to
give 19-trans.
aqueous solution of sodium dihydrogen phosphate and in
the presence of 2-methyl-2-butene, provided acid 24.
Finally, MOM ether deprotection and in situ lactonization
to 25 were accomplished by treatment of acid 24 with TFA
at room temperature for 16 h. The overall isolated yield for
the ®ve-step process to convert the allylic alcohol 18E into
the TMS-lactone 25 was 44%. The enantiomeric excess of
25 was estimated to be 90% by chiral HPLC analysis.
With a satisfactory route to epoxide 19-trans in hand, we
next identi®ed a straightforward route to parlay this inter-
mediate into the needed iodopryridone (R)-10b (Scheme 2).
Regioselective opening20 was accomplished quantitatively
by treatment of 19-trans with LAH. Oxidation of the result-
ing alcohol 22 with Dess±Martin periodinane21 in CH2Cl2 at
room temperature for 3 h afforded 23. Immediate oxidation
Completion of the preparation of the central iodopyri-
done (R)-9 followed the established racemic route.11
Scheme 3.

A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
Table 1. Fluorinated homocamptothecins prepared from iodopyridone (R)-10b
6333
Cmpd
R9
R10
R11
R12
Yield (%)
Isonitrile
Comments
27a
27b
27c
27d
28a
28b
H
H
F
H
F
H
F
H
H
F
H
H
H
F
H
F
F
49
38
16
16
33
35
2-FC6H4NC
4-FC6H4NC
3-FC6H4NC
3-FC6H4NC
3,4-diFC6H3NC
3,4-diFC6H3NC
Single siomer
Single isomer
1/1 Mix with 27d
1/1 Mix with 27c
1/1 Mix with 28b
1/1 Mix with 28a
H
H
H
H
H
H
F
TMS-lactone 25 was subjected to ICl mediated iododesilyl-
ation in CH2Cl2/CCl4 at room temperature. Iodolactone 26
was isolated by column chromatography in 38% yield and
the starting TMS-lactone 25 was recovered (56%) for
recycling. Demethylation was achieved in 61% yield by
adding TMSCl to a mixture of iodolactone 26 and NaI in
CH3CN at 658C for 5 h. The route in Scheme 3 is an ef®cient
means for the stereocontrolled preparation of the key iodo-
pyridone (R)-9 in 7% overall yield from the iodoaldehyde
13.
Several homosilatecans were also prepared from (R)-9, and
the synthesis DB-91 31b shown in Scheme 3 is representa-
tive. This compound is the homocamptothecin version of
DB-67 2 and is an important touchstone between the two
series since the behavior of DB-67 is now relatively well
understood. For detailed chemical and pharmacological
studies, we prepared 805 mg of DB-91 31b by total syn-
thesis. N-Propargylation of (R)-9 with 29 provided 30 in
reproducible 60% yields on gram scale. The ditin photolysis
was deemed inconvenient for larger scales and a standard tin
hydride syringe pump procedure (see Section 4) was used
instead. This provided acetate 31a in reliable 50% yields on
200±500 mg scale. Finally, deacylation provided DB-91
31b in 70±80% yields on 50±500 mg scale. The ee of
DB-91 was measured by chiral hplc and was the same as
the ee of precursor 9. 7-TBS-hcpt 31c, 10-Boc-amino-7-
TBS-hcpt 31d and 10-amino-7-TBS-hcpt 31c were prepared
by analogous strategies (see Section 4). All these com-
pounds were identical to the corresponding racemic
samples,3 except for optical rotation.
The ®nal steps to assemble the homocamptothecin ring
system also followed the established route (Scheme 2).
N-Alkylation of (R)-9 with propargyl bromide gave
(R)-10b, which in turn provided (20R)-homocamptothecin
3 in 61% yield on irradiation in the presence of phenyl
isonitrile and hexamethylditin. Likewise, all possible
A-ring mono ¯uorinated isomers of homocamptothecin
were made by a series of reactions with ¯uorinated iso-
nitriles. The structures of these known analogs7,10 are
shown in Table 1. 2-Fluoroisonitrile provided 12-¯uoro-
homocamptothecin 27a, 4-¯uoroisonitrile provided the
10-¯uoroisomer 27b, and 3-¯uoroisonitrile provided a
separable 1/1 mixture of 9-¯uoro- and 11-¯uoroisomers
27c,d.22 Reaction of 3,4-di¯uoroisonitrile provided a separ-
able 1/1 mixture of 9,10-di¯uorohcpt and 10,11-di¯uoro-
hcpt 28a,b (BN80915).7,10
Recognizing that the Comins/Lavergne route7,10 to homo-
camptothecins also provides powerful synthetic options, we
decided to apply the chemistry in Scheme 2 towards the
preparation of (R)-7, which is currently made by classical
resolution of a racemic intermediate (Fig. 2). This synthesis
is outlined in Scheme 4. Pyridine 34 is the requisite
Scheme 4.

6334
A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
substrate for the key Stille coupling, and this was prepared
from readily available iodoaldehyde23 32 by NaBH4 reduc-
tion and protection of the resulting alcohol 33 as its MOM
ether. Stille coupling of ethyl (E)-3-(tributylstannyl)-2-
pentenoate18 with iodopyridine 34, under Corey's con-
ditions,19 followed by reduction with LAH, gave allylic
alcohol 36. Stoichiometric Sharpless asymmetric epoxi-
dation of 36 with l-(1)-diethyl tartrate led to 37 in 96%
ee.24 This epoxide was then converted to pyridone (R)-7 via
a ®ve-step sequence: (1) regioselective opening of the
epoxide 37 with LAH; (2) Dess±Martin oxidation of the
resulting alcohol 38; (3) further oxidation of aldehyde 39
with NaClO2; (4) MOM ether deprotection and in situ cycli-
zation of 40 with TFA; and ®nally, (5) demethylation. Over-
all, the route provided easy access to pyridone (R)-7 in 4%
overall yield from the aldehyde 32 and with 96% ee.25 Many
of the later steps of the sequence were only conducted once
or twice, so prospects for yield improvement are still open.
(trimethylsilanyl)pyridine (15). MOMCl (2.0 mL, 26.7
mmol) was added dropwise to a 08C solution of 14 (3 g,
8.9 mmol) and iPr2EtN (4.6 mL, 26.7 mmol) in dry
CH2Cl2 (35 mL). The resulting mixture was allowed to
warm to room temperature and stirred overnight. The reac-
tion was quenched with 5% aqueous NaHCO3 solution and
the product was extracted with CH2Cl2. The combined
organic phases were washed with brine, dried over MgSO4
and concentrated under reduced pressure to give 3.0 g (88%
yield) of the crude product 15 as an orange oil. The crude
product was suf®ciently pure for the subsequent reaction: 1H
NMR (300 MHz, CDCl3) d 0.27 (s, 9H), 3.46 (s, 3H), 3.98
(s, 3H), 4.71 (s, 2H), 4.75 (s, 2H), 7.51 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 22.1, 53.8, 55.5, 67.9, 96.4, 113.8,
122.6, 133.0, 161.4, 166.4; IR (®lm, NaCl, cm21) 2946,
1528, 1340, 1042, 840; LRMS (70 eV, EI) m/z (rel int %)
381 (M1), 366, 336, 320, 306, 169, 128, 84 (100), 73;
HRMS m/z calcd for C12H20NO3SiI (M1) 381.0257, found
381.0241.
4.1.3.
1-[2-Methoxy-3-methoxymethoxymethyl-6-(tri-
3. Conclusions
methylsilanyl)pyridin-4-yl]propan-1-one (16). To a solu-
tion of 15 (4.0 g, 10.5 mmol) in THF (25 mL) at 2408C was
added dropwise PrMgCl (7.0 mL, 2.0 M in THF). The
The ®rst asymmetric synthesis of (20R)-homocampto-
thecins and homosilatecans has been developed. A con-
venient and enantioselective synthetic route to the
DE-fragment (R)-9 has been achieved. The synthetic
strategy relies on the application of a Stille reaction and a
Sharpless asymmetric epoxidation to establish the R con-
®guration at C20. A similar route is used to make the key
intermediate (R)-7 in the Comins/Lavergne homocampto-
thecin total synthesis.
i
mixture was stirred at 2408C for 1 h, and then CuCN´2LiCl
(prepared from CuCN (1.2 g, 13.4 mmol) and LiCl (1.2 g,
27.4 mmol)) in THF (30 mL) was added. After 15 min
propionyl chloride (2.7 mL, 31.5 mmol) was added, then
the reaction mixture was stirred 1 h at 2408C and 15 min
at room temperature. The reaction was quenched with brine
and extracted with Et2O. The combined organic layers were
washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The residue was puri®ed by ¯ash
chromatography (gradient hexanes to hexanes/Et2O 95:5)
The asymmetric process to the DE-fragment has the scope
to produce homocamptothecin and many derivatives in an
enantioenriched form. Looking ahead towards the develop-
ment of a homocamptothecin analog as a promising anti-
cancer drug, this process can be of signi®cant importance.
1
to afford 16 (2.2 g, 69%) as a yellowish oil: H NMR
(300 MHz, CDCl3) d 0.28 (s, 9H), 1.98 (t, Jˆ7.1 Hz, 3H),
2.82 (q, Jˆ7.1 Hz, 2H), 3.37 (s, 3H), 3.99 (s, 3H), 4.62 (s,
2H), 4.64 (s, 2H), 6.94 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 25.6, 22.0, 7.7, 36.4, 53.5, 61.1, 96.4, 115.2, 118.4,
148.5, 161.1, 165.5, 206.8; IR (®lm, NaCl, cm21) 2951,
1708, 1451, 1342, 1046, 839; LRMS (70 eV, EI) m/z (rel
int %) 296 (M1215), 266 (100), 248, 234, 100, 89, 73, 591;
HRMS m/z calcd for C14H22NO4Si (M12CH3) 296.1318,
found 296.1313.
4. Experimental
4.1. General
4.1.1. 4-Iodo-2-methoxy-6-(trimethylsilanyl)pyridin-3-yl]-
methanol (14). To a solution of NaBH4 (1.1 g, 26.4 mmol)
in EtOH (100 mL) at 2408C was slowly added a solution of
4-iodo-2-methoxy-6-trimethylsilanyl-3-pyridinecarboxalde-
hyde3a 13 (31.8 g, 94.9 mmol) in EtOH (50 mL). After stir-
ring for 1 h, the reaction mixture was carefully quenched
with brine and then extracted three times with Et2O. The
combined organic extracts were dried over MgSO4. The
solvent was removed under reduced pressure and the residue
puri®ed by ¯ash chromatography (gradient hexanes to
hexanes/EtOAc 91:9) to afford 14 (25.1 g, 78% yield) as a
4.1.4.
3-[2-Methoxy-3-methoxymethoxymethyl-6-(tri-
methylsilanyl)pyridin-4-yl]pent-2-enoic acid methyl
ester (17E/Z). To a mixture of trimethyl phosphonoacetate
(2.5 mL, 15.3 mmol) and tBuOK(1.7 g, 15.3 mmol) in THF
(20 mL) at 08C (1 h) was added a THF (10 mL) solution of
16 (1.2 g, 3.7 mmol). The mixture was stirred at re¯ux for
36 h. Puri®cation of the crude residue by ¯ash chroma-
tography (hexanes/EtOAc 92:8) followed by preparative
HPLC (hexanes/EtOAc 92:8, Novapak normal phase
cartridge column, 10 mL/min), afforded in order of elution;
16 (123.3 mg, 10%), 17E (387.0 mg, 27%) and 17Z
1
clear oil: H NMR (300 MHz, CDCl3) d 0.28 (s, 9H), 2.5
(bs, 1H), 4.01 (s, 3H), 4.8 (s, 2H), 7.5 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 22.0, 53.8, 65.3, 11.6, 125.3, 133.2,
160.9, 165.8; IR (®lm, NaCl, cm21) 3485, 2960, 1580, 1450,
1039, 839; LRMS (70 eV, EI) m/z (rel int %) 337 (M1), 322
(100), 306, 194, 180, 73; HRMS m/z calcd for C10H16NO2SiI
(M1) 336.9996, found 337.000.
1
(609.3 mg, 43%) as clear oils: 17E; H NMR (300 MHz,
CDCl3) d 0.28 (s, 9H), 0.99 (t, Jˆ7.6 Hz, 3H), 2.99 (q,
Jˆ7.6 Hz, 2H), 3.42 (s, 3H), 3.75 (s, 3H), 4.02 (s, 3H),
4.47 (s, 2H), 4.72 (s, 2H), 5.8 (s, 1H), 6.84 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 22.0, 12.3, 26.6, 51.2, 53.4,
55.3, 61.9, 96.7, 115.4, 118.9, 121.1, 150.9, 160.3, 162.2,
164.9, 166.2; IR (®lm, NaCl, cm21) 2949, 1723, 1341, 1042,
4.1.2. 4-Iodo-2-methoxy-3-methoxymethoxymethyl-6-

A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
6335
840; LRMS (70 eV, EI) m/z (rel int %) 367 (M1), 352, 322,
308 (100), 290, 276, 246, 232, 99, 57; HRMS m/z calcd for
C18H29NO5Si (M1) 367.1815, found 367.1802. 17Z: 1H
NMR (300 MHz, CDCl3) d 0.26 (s, 9H), 1.11 (t, Jˆ
7.2 Hz, 3H), 2.38±2.48 (m, 2H), 3.4 (s, 3H), 3.53 (s, 3H),
3.99 (s, 3H), 4.35 (d, Jˆ10.2 Hz, 1H), 4.51 (d, Jˆ10.2 Hz,
1H), 4.66 (dd, Jˆ6.3, 14.2 Hz, 2H), 5.94 (s, 1H), 6.72 (s,
1H); 13C NMR (75 MHz, CDCl3 d 21.9, 11.4, 33.1, 51.1,
53.2, 55.2, 61.9, 96.5, 114.5, 116.3, 120.6, 150.0, 159.0,
161.7, 164.3, 165.6; IR (®lm, NaCl, cm21) 2941, 1732,
1559, 1457, 1342, 1054, 836; LRMS (70 eV, EI) m/z (rel
int %) 367 (M1), 322, 290, 278, 262, 139 (100), 89, 73;
HRMS m/z calcd for C18H29NO5Si (M1) 367.1815, found
367.1820.
(19.0 mg, 34%), and 19-cis (6.0 mg, 11%) as a clear oil.
Epoxide 19-cis was analyzed for enantiomeric purity
by using a Regis (S,S) Whelk-O1 column with 99.5:0.5
hexanes/iPrOH as the eluent (2 mL/min), and the racemate
as the standard. The enantiomeric excess was shown to be
30% ((2S, 3R) major, Rt 9.3 min, (2R, 3S) minor Rt
1
10.5 min): H NMR (300 MHz, CDCl3) d 0.28 (s, 9H),
0.88 (t, Jˆ7.3 Hz, 3H), 1.62±1.73 (m, 1H), 2.02±2.13 (m,
1H), 2.94±3.03 (m, 1H), 3.36±3.45 (m, 2H), 3.47 (s, 3H),
4.01 (s, 3H), 4.61 (d, Jˆ10.9 Hz, 1H), 4.74 (d, Jˆ10.9 Hz,
1H), 4.73 (d, Jˆ6.5 Hz, 1H), 4.85 (d, Jˆ6.5 Hz, 1H), 7.13
(s, 1H); 13C NMR (75 MHz, CDCl3) d 21.9, 8.4, 30.4, 53.4,
55.9, 60.5, 61.3, 62.7, 65.4, 97.1, 114.8, 122.1, 145.9, 161.8,
165.7; IR (®lm, NaCl, cm21) 3502, 2953, 1562, 1451, 1343,
1042, 839; LRMS (70 eV, EI) m/z (rel int %) 355 (M1), 340,
4.1.5.
(trimethylsilanyl)pyridin-4-yl]pent-2-en-1-ol
(Z)-3-[2-Methoxy-3-methoxymethoxymethyl-6-
(18Z).
323, 310, 278, 262 (100), 250, 220, 73; HRMS m/z calcd for
C17H29NO5Si (M1) 355.1815, found 355.1827; [a]D
18.2 (cˆ0.5, MeOH).
23
ˆ
LAH (0.25 mL, 1 M solution in Et2O) was slowly added
to a 2788C solution of 17Z (100 mg, 0.3 mmol) in Et2O
(3 mL). The resulting mixture was allowed to warm to
08C. Then, the reaction was quenched with a saturated
aqueous solution of potassium sodium tartrate. The aqueous
layer was extracted three times with Et2O. The combined
organic phases were washed with brine, dried over MgSO4
and concentrated under reduced pressure to give the crude
product 18Z (86.0 mg, 93% yield) as colorless oil. The
crude product was suf®ciently pure for the subsequent
4.1.7.
(E)-3-[2-Methoxy-3-methoxymethoxymethyl-6-
(trimethylsilanyl)pyridin-4-yl]pent-2-enoic acid ethyl
ester (21E). A round bottom ¯ask was charged with LiCl
(66.6 mg, 1.6 mmol) and ¯amed dried under vacuum.
Pd(PPh3)4 (32.6 mg, 0.03 mmol), CuCl (129.6 mg, 1.3
mmol) and DMSO (2.0 mL) were added and the mixture
was degassed. Ketone 15 (100 mg, 0.26 mmol) was added,
followed by ethyl (E)-3-(tri-n-butylstannyl)-2-pentenoate15
20 (131.4 mg, 0.31 mmol) and the resulting mixture was
degassed. The reaction mixture was then heated at 608C
for 17 h. After cooling, the reaction was diluted with Et2O
(30 mL) and washed with a mixture of brine (40 mL) and
5% aqueous NH4OH (8 mL). The aqueous layer was
extracted 3 times with Et2O. The combined organic extracts
were dried over MgSO4 and concentrated under reduced
pressure. The crude product was puri®ed by ¯ash chroma-
tography (gradient hexanes to hexanes/EtOAc 95:5) to yield
1
reaction: H NMR (300 MHz, CDCl3) d 0.28 (s, 9H), 1.05
(t, Jˆ7.4 Hz, 3H), 2.25 (q, Jˆ7.4 Hz, 2H), 3.43 (s, 3H),
3.63±3.81 (m, 2H), 4.01 (s, 3H), 4.31 (d, Jˆ10.3 Hz, 1H),
4.64±4.81 (m, 3H), 5.76±5.92 (m, 1H), 6.76 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 21.9, 11.9, 31.6, 53.3, 55.6, 59.2,
61.5, 96.5, 115.8, 122.7, 126.2, 142.8, 150.1, 162.1, 164.9;
IR (®lm, NaCl, cm21) 3393, 2962, 1552, 1340, 1042, 839;
LRMS (70 eV, EI) m/z (rel int %) 339 (M1), 324, 308, 292,
277, 262, 248 (100), 234, 73; HRMS m/z calcd for
C17H29NO4Si (M1) 339.1865, found 339.1864.
1
21E (80 mg, 80%) as a clear oil: H NMR (300 MHz,
CDCl3) d 0.28 (s, 9H), 0.99 (t, Jˆ7.5 Hz, 3H), 1.3 (t, Jˆ
7.1 Hz, 3H), 2.98 (q, Jˆ7.5 Hz, 2H), 3.42 (s, 3H), 4.02 (s,
3H), 4.2 (q, Jˆ7.1 Hz, 2H), 4.47 (s, 2H), 4.72 (s, 2H), 5.79
(s, 1H), 6.84 (s, 1H); 13C NMR (75 MHz, CDCl3) d 22.0,
12.3, 14.3, 26.6, 53.6, 55.4, 60.0, 62.0, 96.7, 115.5, 119.5,
121.2, 151.2, 159.9, 162.2, 164.8, 165.8; IR (®lm, NaCl,
cm21) 2; LRMS (70 eV, EI) m/z (rel int %) 381 (M1),
366, 336, 320, 308 (100), 290, 262, 246, 89, 73; HRMS
m/z calcd for C19H31NO5Si (M1) 381.1976, found
381.19667.
4.1.6. (1)-{3-Ethyl-3-[2-methoxy-6-(trimethylsilanyl)-
pyridin-4-yl]oxiranyl} methanol (19-cis). To a solution
Ê
of 18Z (50.0 mg, 0.1 mmol) and activated 4 A molecular
sieves (25.0 mg) in CH2Cl2 (1.5 mL) at 2208C was added
d-(2)-diethyl tartrate (30.0 mg, 0.1 mmol) and Ti(OiPr)4
(33.5 mg, 0.1 mmol). After stirring for 1 h, tBuOOH
Ê
(60.0 mL, 5.0±6.0 M in decane, predried over 4 A molecular
sieves for 1 h) was added with a syringe. The reaction
mixture was kept in the freezer at 2208C for 12 h and
next warmed to 08C. After stirring for 1 week at 08C, the
solution was diluted with Et2O (0.2 mL) and quenched with
a saturated Na2SO4 solution (0.1 mL). The resulting hetero-
geneous mixture was allowed to warm to room temperature
and stirred for 2 h. Then it was ®ltered through a celite pad
(washing with hot EtOAc several times). The combined
®ltrates were concentrated under vacuum. The residue was
dissolved in Et2O (0.7 mL) at 08C and a 1N NaOH solution
saturated with NaCl was added (0.5 mL). The two-phase
mixture was vigorously stirred at 08C for 1 h and then
transferred to a separatory funnel. The aqueous layer was
separated and extracted three times with EtOAc. The
combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure. The crude residue
was puri®ed by ¯ash chromatography (hexanes/EtOAc,
70:30) to give, in order of elution, starting alcohol 18Z
4.1.8.
3-[2-Methoxy-3-methoxymethoxymethyl-6-(tri-
methylsilanyl)pyridin-4-yl]pent-2-en-1-ol (18E). To a
2788C mixture of 21E (100 mg, 0.26 mmol) in Et2O
(3 mL) was slowly added LAH (0.26 mL, 0.26 mmol,
1.0 M solution in Et2O). The resulting mixture was allowed
to warm to 08C and then quenched by addition of a chilled
saturated aqueous solution of potassium sodium tartrate.
The aqueous layer was extracted three times with Et2O.
The combined organic extracts were dried over MgSO4
and concentrated under reduced pressure. The crude product
was puri®ed by ¯ash chromatography (hexanes/EtOAc
1
75:25) to yield 18E (80 mg, 90%) as a colorless oil: H
NMR (300 MHz, CDCl3) d 0.27 (s, 9H), 0.91 (t, Jˆ
7.5 Hz, 3H), 2.43 (q, Jˆ7.5 Hz, 2H), 3.43 (s, 3H), 4.01 (s,
3H), 4.33 (d, Jˆ6.9 Hz, 2H), 4.53 (s, 2H), 4.69 (s, 2H), 5.61

6336
A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
(t, Jˆ6.9 Hz, 1H), 6.87 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 22.0, 13.0, 25.3, 53.4, 55.3, 58.8, 61.6, 95.9, 115.9, 122.3,
4.71 (s, 2H), 4.89 (d, Jˆ10.6 Hz, 1H), 5.09 (d, Jˆ10.6 Hz,
1H), 6.91 (s, 1H); 13C NMR (75 MHz, CDCl3) d 21.9, 7.6,
36.4, 43.7, 53.6, 55.7, 60.1, 70.0, 80.9, 96.2, 116.7, 121.2,
153.7, 162.6, 164.1; IR (®lm, NaCl, cm21) 3383, 2962,
1545, 1342, 1038, 839; LRMS (70 eV, EI) m/z (rel int %)
339 (M12H2O), 324, 308, 294, 266, 250, 85, 73 (100), 57;
HRMS m/z calcd for C17H29NO4Si (M12H2O) 339.1866,
128.7, 142.4, 152.2, 162.3, 164.3; IR (®lm, NaCl, cm21
)
3388, 2949, 1576, 1450, 1340, 1042, 854; LRMS (70 eV,
EI) m/z (rel int %) 339 (M1), 324, 308, 294, 277, 262 (100),
248, 232, 218, 188, 174, 117, 89, 73, 59; HRMS m/z calcd
for C17H29NO2Si (M1) 339.1866, found 339.1861.
23
found 339.1876; [a]D ˆ21.9 (cˆ1.05, CH2Cl2).
4.1.9. (1)-{3-Ethyl-3-[2-methoxy-6-(trimethylsilanyl)-
pyridin-4-yl]-oxiranyl}methanol (19-trans). To a solution
Ê
of 18E (937 mg, 2.76 mmol) and activated 4 A molecular
4.1.11. (2)-3-Hydroxy-3-[2-methoxy-3-methoxymethoxy-
methyl-6-(trimethylsilanyl)pyridin-4-yl]pentanoic acid
(24). To a mixture of 22 (0.75 g, 2.1 mmol) in CH2Cl2
(30 mL) was added Dess±Martin periodinane (1.4 g,
3.3 mmol). The mixture was stirred at room temperature
for 3 h and then poured into a well-stirred mixture of sat.
Na2S2O3 (15 mL) and sat. NaHCO3 (15 mL). The layers
were separated after 30 min. The aqueous layer was
extracted three times with Et2O. The combined organic
extracts were washed with sat. NaHCO3, brine, dried over
MgSO4 and concentrated under vacuum to give the
crude aldehyde 23 (750 mg, 2.1 mmol), which was used
immediately after workup.
sieves (280 mg) in CH2Cl2 (26 mL) at 2208C was added
diethyl-l-(1)-tartrate (568 mg, 2.75 mmol), and Ti(OiPr)4
(629 mg, 2.2 mmol). After stirring for 1 h, tBuOOH
Ê
(1.1 mL, 5.0±6.0 M in decane, predried over 4 A molecular
sieves for 1 h) was added with a syringe. The reaction
mixture was kept in the freezer at 2208C for 2 h. The solu-
tion was removed from the freezer, diluted with Et2O
(5.2 mL) and quenched with a saturated Na2SO4 solution
(2.6 mL). The resulting heterogeneous mixture was stirred
and allowed to warm to room temperature for 2 h. Then it
was ®ltered through a celite pad (washing with hot EtOAc
several times). The combined ®ltrates were concentrated
under vacuum. The residue was dissolved in Et2O (13 mL)
at 08C and a 1N NaOH solution saturated with NaCl was
added (8 mL). The two-phase mixture was vigorously
stirred at 08C for 1 h and then transferred to a separatory
funnel. The aqueous layer was separated and extracted three
times with EtOAc. The combined organic extracts were
dried over MgSO4 and concentrated under reduced pressure
to give 651 mg (66% yield) of the crude product 19-trans as
a clear oil with 92% ee and suf®ciently pure for the subse-
quent reaction. Epoxide 19-trans was analyzed for enantio-
purity using a Chiralcel OD-H column with 98.5:1.5
hexanes/iPrOH as the eluent, using the racemate as the
To a solution of the aldehyde 23 (750 mg, 2.11 mmol) in
tert-butyl alcohol (40 mL) was added 2-methyl-2-butene
(12 mL). To this mixture was added dropwise a solution
containing sodium chlorite (1.7 g, 18.8 mmol) and sodium
dihydrogen phosphate (2.0 g, 14.5 mmol) in H2O (20 mL).
The resulting mixture was stirred at room temperature for
16 h, concentrated under vacuum, diluted with water and
extracted with EtOAc. The aqueous layer was acidi®ed
(pH 3.5) with 5% HCl and extracted with EtOAc. The
combined organic layers were washed with brine, dried
over Na2SO4 and concentrated under vacuum to give the
crude acid 24 (740 mg, 94%) as a clear oil and suf®ciently
pure for the subsequent reaction: 1H NMR (300 MHz,
CDCl3) d 0.27 (s, 9H), 0.84 (t, Jˆ7.3 Hz, 3H), 1.91 (q,
Jˆ7.3 Hz, 2H), 2.89 (d, Jˆ15.8 Hz, 1H), 3.1 (d, Jˆ
15.8 Hz, 1H), 3.43 (s, 3H), 3.97 (s, 3H), 4.73 (s, 2H), 4.9
(d, Jˆ10.6 Hz, 1H), 5.0 (d, Jˆ10.6 Hz, 1H), 6.95 (s, 1H);
13C NMR (75 MHz, CDCl3) d 22.0, 8.0, 35.6, 45.7, 53.6,
55.6, 61.1, 77.3, 96.3, 116.1, 120.4, 152.5, 162.9, 164.7,
175.2; IR (®lm, NaCl, cm21) 3474, 1712, 1345, 1036,
840; LRMS (70 eV, EI) m/z (rel int %) 353 (M12H2O),
326, 308 (100), 294, 280, 262, 250, 236, 190, 89, 73, 571;
HRMS m/z calcd for C17H27O5Si (M12H2O) 353.1659,
1
standard: H NMR (300 MHz, CDCl3) d 0.27 (s, 9H), 0.9
(t, Jˆ7.5 Hz, 3H), 1.79 (m, 1H), 1.97 (m, 1H), 3.23 (t, Jˆ
5.8 Hz, 1H), 3.45 (s, 3H), 3.9 (m, 2H), 3.99 (s, 3H), 4.67 (d,
Jˆ10.6 Hz, 2H), 4.72 (d, Jˆ10.6 Hz, 2H) 7.09 (s, 1H) (±OH
proton resonance not detected); 13C NMR (75 MHz, CDCl3)
d 21.9, 9.2, 25.6, 53.4, 55.6, 60.6, 61.2, 63.5, 64.6, 96.4,
115.5, 121.3, 148.4, 161.9, 165.2; IR (®lm, NaCl, cm21
)
3463, 2945, 1562, 1451, 1345, 1041, 840; LRMS (70 eV,
EI) m/z (rel int %) 355 (M1), 340, 324, 310, 294, 280,
262, 250, 89, 73, 57; HRMS m/z calcd for C17H29NO5Si
(M1) 355.1815, found 355.1812, [a]D ˆ128 (cˆ0.25,
23
23
CH2Cl2).
found 353.1655; [a]D ˆ26.8 (cˆ0.54, CH2Cl2).
4.1.10. (2)-3-[2-Methoxy-3-methoxymethoxymethyl-6-
(trimethylsilanyl)pyridin-4-yl]pent-2-en-1-ol (22). LAH
(0.3 mL, 0.3 mmol) was slowly added to a 08C mixture of
19-trans (144 mg, 0.4 mmol) in Et2O (9 mL). The resulting
mixture was allowed to warm to room temperature and
stirred overnight. The reaction was quenched with a satu-
rated aqueous solution of potassium sodium tartrate. The
aqueous layer was extracted three times with Et2O. The
combined organic phases were washed with brine, dried
over MgSO4 and concentrated under reduced pressure to
give (144 mg, 99% yield) of the crude product 22 as color-
less oil. The crude product was suf®ciently pure for the
4.1.12. (1)-5-Ethyl-5-hydroxy-1-methoxy-3-(trimethyl-
silanyl)-5,9-dihydro-6H-8-oxa-2-aza-benzocyclohepten-
7-one (25). To a round bottom ¯ask was added 24 (0.74 g,
1.99 mmol) followed by TFA (50 mL). The mixture was
stirred at room temperature for 16 h and then concentrated
under reduced pressure. The residue was dissolved in Et2O
and neutralized with sat. NaHCO3. The organic phase was
dried over MgSO4 and concentrated under reduced pressure.
The crude product was puri®ed by ¯ash chromatography
(hexanes/EtOAc 75:25) to yield 25 (0.43 g, 70%) with
90% ee as a white foam. Spectroscopic data agreed
23
well with the reported values;4 [a]D ˆ145.1 (cˆ0.86,
1
subsequent reaction: H NMR (300 MHz, CDCl3) d 0.28
(s, 9H), 0.78 (t, Jˆ7.4 Hz, 3H), 1.9 (m, 2H), 2.13 (m,
CH2Cl2). Lactone 25 was analyzed for enantiomeric purity
using a Chiralcel OD-H column with 92:8 hexanes/iPrOH as
the eluent, using the racemate as the standard.
2H), 3.43 (s, 3H), 3.59 (m, 1H), 3.7 (m, 1H), 4.0 (s, 3H),

A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
6337
4.1.13. (1)-5-Ethyl-5-hydroxy-3-iodo-1-methoxy-5,9-di-
hydro-6H-8-oxa-2-aza-benzocyclohepten-7-one (26). A
sonicated solution of ICl (160 mg, 0.98 mmol) in CCl4
(0.7 mL) at 08C was added to a solution of 25 (77.5 mg,
0.25 mmol) in CH2Cl2 (1 mL) at 08C. The resulting mixture
was stirred and allowed to warm to room temperature in the
dark for 24 h. The solution was diluted with CH2Cl2 and
washed with aqueous Na2S2O3. The organic phase was
washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The residue was puri®ed by ¯ash
chromatography (hexanes/EtOAc 75:25) to yield recovered
25 (44 mg, 56%) and 26 (35 mg, 38%) as a white foam.
Spectroscopic data agreed well with the reported values;4
the two phases, the aqueous phase was extracted with ethyl
acetate. The organic phases were dried over magnesium
sulfate. Filtration and evaporation of the solvents gave a
thick yellow oil. The crude product was puri®ed by
chromatography on silica gel (chloroform/ethyl acetate 75/
25) to yield iodopyridone 30 as a yellow solid (905 mg,
60%): Spectroscopic data agreed well with reported values.4
23
[a]D ˆ165 (cˆ0.74 CH2Cl2) eeˆ97% (NMR shift
experiment with Eu(hfc)3).
4.2. General procedure for synthesis of homocampto-
thecins by tandem radical cyclization
23
[a]D ˆ134.1 (cˆ0.6, CH2Cl2).
A solution of the iodopyridone 10b or 30 (0.03 mmol) in
benzene (0.5 mL) was added to an NMR tube under argon.
Then, a 1 M solution of the isonitrile in benzene (0.1 mL,
0.1 mmol) and hexamethylditin (15 mL) were added succes-
sively. The NMR tube was sealed with a cap and irradiated
with 275 W GE sunlamp for 1.5 h. The reaction turned to
dark brown. Then, the reaction mixture was applied directly
on silica gel column. The column was ®rst washed with
dichloromethane to remove less polar impurities. Elution
with 5±20% acetone in dichloromethane gave the desired
homocamptothecins in 30±60% yield.
4.1.14. (1)-5-Ethyl-5-hydroxy-3-iodo-2,5,6,9-tetrahydro-
8-oxa-2-aza-benzocycloheptene-1,7-dione ((R)-9). Chloro-
trimethylsilane (112 mL, 0.88 mmol) and H2O (5 mL,
0.27 mmol) were added to a solution of 26 (200 mg,
0.55 mmol) and NaI (132 mg, 0.88 mmol) in CH3CN
(1.8 mL). The mixture was heated in the dark at 658C for
5 h. After cooling, the reaction was diluted with CH2Cl2 and
washed with a 1:1 mixture of brine and 5% aqueous
Na2S2O3. The aqueous layer was extracted 3 times with
EtOAc. The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure. The
crude product was puri®ed by ¯ash chromatography
(CH2Cl2/MeOH 95:5) affording (R)-9 (97 mg, 50%) as a
white foam. Spectroscopic data agreed well with the
4.2.1. (20R)-Homocamptothecin (3). Using the general
procedure, the title compound (5.7 mg, 61% yield) was
23
prepared as yellow solid: [a]D ˆ154 (cˆ0.1, CHCl3/
1
MeOH 4:1); H NMR (300 MHz, CDCl3/CD3OD) d 0.95
reported values;4 [a]D ˆ143.7 (cˆ0.54, MeOH).
23
(t, Jˆ8.7 Hz, 3H), 1.99 (m, 2H), 3.18 (d, Jˆ13.7 Hz, 1H),
3.39 (d, Jˆ13.7 Hz, 1H), 5.25 (s, 2H), 5.40 (d, Jˆ15.4 Hz,
1H), 5.48 (d, Jˆ15.4 Hz, 1H), 7.63±7.64 (m, 2H), 7.79 (t,
Jˆ7.6 Hz, 1H), 7.95 (d, Jˆ7.7 Hz, 1H), 8.13 (d, Jˆ7.7 Hz,
1H), 8.46 (s, 1H); HRMS m/z calcd for C21H18N2O4
362.1267, found 362.1268.
4.1.15. (1)-5-Ethyl-hydroxy-3-iodo-2-prop-2-ynyl-2,5,6,
9-tetrahydro-8-oxa-2-aza-benzocycloheptene-1,7-dione
((R)-10b). This was prepared with (R)-9 and propargyl bro-
mide following the procedure for 30 listed below: 1H NMR
(300 MHz, CD3OD) d 0.93 (t, Jˆ7.4 Hz, 3H), 1.71±1.86
(m, 2H), 3.09 (d, Jˆ13.8 Hz, 1H), 3.31 (s, 1H), 3.36 (d,
Jˆ13.8 Hz, 1H), 5.88 (s, 2H), 5.28 (d, Jˆ15.3 Hz, 1H),
5.41 (d, Jˆ15.3 Hz, 1H), 7.18 (s, 1H); 13C NMR
(75 MHz, CD3OD) d 6.9, 35.4, 41.8, 44.0, 61.9, 72.4,
73.2, 76.9, 100.2, 119.7, 122.1, 155.4, 160.5, 172.8;
LRMS (70 eV, EI) m/z (rel int %) 387 (M1), 327, 316,
4.2.2. (R)-12-Fluorohomocamptothecin (27a). Using the
general procedure, the title compound was prepared in
1
49% yield. H NMR (300 MHz, CDCl3/CD3OD) d 0.95 (t,
Jˆ7.4 Hz, 3H), 1.98 (q, Jˆ7.4 Hz, 2H), 3.18 (d, Jˆ13.7 Hz,
1H), 3.38 (d, Jˆ13.7 Hz, 1H), 5.20 (d, Jˆ19.7 Hz, 1H), 5.30
(d, Jˆ19.7 Hz, 1H), 5.35 (d, Jˆ15.5 Hz, 1H), 5.61 (d, Jˆ
15.5 Hz, 1H), 7.42 (m, 1H), 7.54 (m, 1H), 7.66 (s, 1H), 7.69
(d, Jˆ8.3 Hz, 1H), 8.40 (s, 1H); HRMS m/z calcd for
C21H17N2O4F 380.1172, found 380.1187.
288, 167, 149, 128 (100), 57; HRMS m/z calcd for
ˆ
23
C14H14NO4I (M1) 386.9967, found 386.9961; [a]D
158.3 (cˆ0.18, 3/1 CH2Cl2/MeOH).
4.1.16. (1)-5-Ethyl-1,4,5-trihydro-5-hydroxy-7-iodo-8-
(tert-butyldimethylsilyl-2-propynol)-oxepino[3,4,c]pyri-
dine-3,9-dione (30). In a 25 mL round bottom ¯ask,
equipped with a stirbar, were successively introduced the
iodopyridone (R)-9 (1.05 g, 3 mmol), DME (9 mL) and
DMF (3 mL). The reaction ¯ask was put under argon and
allowed to cool at 08C (ice bath) before sodium hydride 60%
in mineral oil (150 mg, 3.3 mmol) was added in one portion.
After 10 min at 08C, ¯ame-dried LiBr (521 mg, 6 mmol)
was added and the reaction mixture was allowed to warm
to room temperature. After 15 min the propargyl bromide 29
(2.1 g, 9 mmol) was added next (weighed in the syringe) and
the reaction mixture was immediately warmed to 708C. The
reaction was run in the dark to avoid any possible decom-
position of the starting material (¯ask covered with alu-
minum foil). After 20 h, the reaction mixture was
quenched with brine and ethyl acetate. After separation of
4.2.3. (R)-10-Fluorohomocamptothecin (27b). Using the
general procedure, the title compound was prepared in 38%
yield. 1H NMR (300 MHz, CDCl3/CD3OD) d 0.97 (t,
Jˆ7.4 Hz, 3H), 1.98 (m, 2H), 3.22 (d, Jˆ13.7 Hz, 1H),
3.42 (d, Jˆ13.7 Hz, 1H), 5.15 (d, Jˆ19.5 Hz, 1H), 5.31
(d, Jˆ19.5 Hz, 1H), 5.33 (d, Jˆ15.5 Hz, 1H), 5.66 (d,
Jˆ15.5 Hz, 1H), 7.45 (m, 2H), 7.49 (s, 1H), 7.92 (m, 1H),
8.28 (s, 1H); HRMS m/z calcd for C21H17N2O4F 380.1172,
found 380.1165.
4.2.4. Compounds 27c,d. Using the general procedure, the
two title compounds were prepared in 32% combined yield
and in 1:1 ratio. The two compounds were separated by
careful chromatography on a silica gel column.
1
(R)-9-Fluorohomocamptothecin 27c. H NMR (300 MHz,
CDCl3/CD3OD) d 0.96 (t, Jˆ7.5 Hz, 3H), 2.02 (m, 2H),

6338
A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
3.18 (d, Jˆ13.7 Hz, 1H), 3.41 (d, Jˆ13.7 Hz, 1H), 5.23 (dd,
Jˆ19.1, 1.2 Hz, 1H), 5.31 (dd, Jˆ19.1, 1.2 Hz, 1H), 5.36 (d,
Jˆ15.4 Hz, 1H), 5.64 (d, Jˆ15.4 Hz, 1H), 7.28 (m, 1H),
7.58 (s, 1H), 7.70 (td, Jˆ8.6, 6.0 Hz, 1H), 7.90 (d, Jˆ
8.6 Hz, 1H), 8.63 (d, Jˆ1 Hz, 1H); HRMS m/z calcd for
C21H17N2O4F 380.1172, found 380.1177.
residue was puri®ed by chromatography on silica gel
(CH2Cl2/acetone 95/5±75/25) to yield 31a as a brown
1
solid (280 mg, 52%): H NMR (300 MHz, CDCl3) d 0.73
(s, 3H), 0.74 (s, 3H) 0.97 (t, Jˆ7 Hz, 3H), 1.07 (s, 9H),
1.94±2.08 (m, 2H), 2.42 (s, 3H) 3.29 (d, Jˆ14 Hz, 1H),
3.44 (d, Jˆ14 Hz, 1H), 3.78 (br s, 1H), 5.16 (d, Jˆ18 Hz,
1H), 5.37 (d, Jˆ15 Hz, 1H), 5.48 (d, Jˆ18 Hz, 1H), 5.65 (d,
Jˆ15 Hz, 1H), 7.33 (dd, Jˆ9 Hz, 2 Hz, 1H), 7.36 (s, 1H),
7.70 (d, Jˆ9 Hz, 1H), 7.97 (d, Jˆ2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 20.7, 20.5, 8.4, 19.3, 21.5, 27.2,
35.8, 42.8, 52.9, 62.2, 73.9, 100.5, 120.0, 122.8, 124.7,
131.1, 133.1, 133.1, 136.5, 143.0, 145.0, 145.4, 148.9,
149.9, 156.3, 159.9, 169.0, 171.5; HRMS (EI) m/z calcd
for C29H34N2O6Si (M1) 534.2186, found 534.2187;
LRMS (EI) m/z 534 (M1), 516, 488, 477, 459, 435, 417,
393, 375, 335, 320, 291, 275, 234, 164, 137, 125, 111, 97,
(R)-11-Fluorohomocamptothecin 27d. 1H NMR (300 MHz,
CDCl3/CD3OD) d 0.96 (t, Jˆ7.4 Hz, 3H), 2.02 (m, 2H),
3.20 (d, Jˆ13.7 Hz, 1H), 3.40 (d, Jˆ13.7 Hz, 1H), 5.19
(d, Jˆ19.0 Hz, 1H), 5.29 (d, Jˆ19.1 Hz, 1H), 5.35 (d,
Jˆ15.5 Hz, 1H), 5.63 (d, Jˆ15.4 Hz, 1H), 7.41 (td, Jˆ
9.3, 2.5 Hz, 1H), 7.54 (s, 1H), 7.65 (dd, Jˆ9.9, 2.4 Hz,
1H), 7.90 (dd, Jˆ9.1, 5.8 Hz, 1H), 8.38 (s, 1H); HRMS
m/z calcd for C21H17N2O4F 380.1172, found 380.1176.
23
4.2.5. Compounds 28a,b. Using the general procedure, the
two title compounds were prepared in 68% yield as a 1:1
mixture. Separation by ¯ash chromatography on silica gel
column (20% acetone in dichloromethane), in the order of
elution, gave pure 28a (3.4 mg, 33% yield) and 28b (3.6 mg,
35%).
83, 69 57; [a]D ˆ198 (cˆ0.5, CH2Cl2).
4.2.7. (R)-10-Hydroxy-12-tert-butyldimethylsilylhomo-
camptothecin (31b, DB-91). To a solution of 31a
(272 mg, 0.5 mmol) in methanol (10 mL) and distilled
water (10 mL) was added K2CO3 (700 mg, 5 mmol). The
solution became dark and stirring was maintained for 3 h.
The solvents were removed under vacuum. The ®nal
removal of water was effected by adding toluene and
evaporating under vacuum twice. The solid brown residue
was taken up in CH2CL2 (10 mL) and tri¯uoroacetic acid
(5 mL, 65 mmol) was carefully added dropwise with
stirring. After stirring at room temperature for 4 h, the
solvent and excess tri¯uoroacetic acid were removed
under vacuum and the resulting brown residue was puri®ed
by ¯ash chromatography on silica gel (CH2Cl2/acetone 80/
20) to yield 31b as a brown solid (203 mg, 82%): 1H NMR
(300 MHz, CD3OD/CDCl3 1:1) d 0.65 (s, 6H), 0.90±0.99
(m, 12H), 1.89±2.06 (m, 2H), 3.14 (d, Jˆ14 Hz, 1H), 3.33
(d, Jˆ14 Hz, 1H), 5.25 (s, 2H), 5.37 (d, Jˆ15 Hz, 1H), 5.56
(d, Jˆ15 Hz, 1H), 7.42 (dd, Jˆ9 Hz, 2 Hz, 1H), 7.58 (d,
Jˆ2 Hz, 1H), 7.70 (s, 1H), 8.15 (d, Jˆ9 Hz 1H); 13C
NMR (75 MHz, CD3OD/CDCl3 1:1) d 21.0, 8.1, 19.3,
26.9, 36.2, 42.2, 52.9, 62.1, 73.5, 101.9, 111.5, 122.7,
123.6, 127.5, 129.0, 135.0, 136.5, 139.8, 143.0, 145.4,
156.7, 157.0, 159.7, 172.7; LRMS (EI) m/z 588, 548, 491
(M21), 474, 448, 434, 391, 377, 363, 333, 320, 306, 291,
23
(R)-9,10-Di¯uorohomocamptothecin (28a). [a]D ˆ141.3
(cˆ1.03, CH2Cl2/MeOH 4:1); IR 3355, 2923, 1746, 1646,
1590, 1507, 1253, 1061, 826: 1H NMR (500 MHz, CDCl3) d
1.00 (t, Jˆ7.1 Hz, 3H), 1.95 (m, 1H), 2.06 (m, 1H), 3.32 (d,
Jˆ13.6 Hz, 1H), 3.43 (d, Jˆ13.6 Hz, 1H), 5.11 (d, Jˆ
19.0 Hz, 1H), 5.32 (d, Jˆ15.6 Hz, 1H), 5.42 (d, Jˆ
19.0 Hz, 1H), 5.64 (d, Jˆ15.6 Hz, 1H), 7.44 (s, 1H), 7.49
(m, 1H), 7.60 (m, 1H), 8.46 (s, 1H); The aromatic region
(7±9 ppm) in 19F-decoupled 1H NMR (500 MHz, CDCl3) d
7.45 (s, 1H), 7.49 (d, Jˆ9.0 Hz, 1H), 7.61 (d, Jˆ9.0 Hz,
1H), 8.47 (s, 1H); 13C NMR (125 MHz, CDCl3/CD3OD) d
7.9, 36.1, 42.1, 50.4, 62.0, 73.3, 101.7, 119.8 (d, Jˆ
12.5 Hz), 121.0 (d, Jˆ21.1 Hz), 123.2, 124.4, 125.8,
129.4, 143.9 (dd, Jˆ254, 13.8 Hz), 143.9, 144.9, 147.1
(dd, Jˆ250, 12.5 Hz), 152.5, 156.6, 159.8, 172.6; HRMS
m/z calcd for C21H16N2O4F2 398.1078, found 398.1070.
23
(R)-10,11-Di¯uorohomocamptothecin (28b). [a]D ˆ144.3
(cˆ0.58, CH2Cl2/MeOH 4:1); 1H NMR (500 MHz, CDCl3)
d 0.87 (t, Jˆ7.4 Hz, 3H), 2.0 (m, 2H), 3.10 (d, Jˆ13.8 Hz,
1H), 3.30 (d, Jˆ13.8 Hz, 1H), 5.14 (d, Jˆ19.3 Hz, 1H), 5.19
(d, Jˆ19.3 Hz, 1H), 5.31 (d, Jˆ15.4 Hz, 1H), 5.52 (d,
Jˆ15.4 Hz, 1H), 7.50 (s, 1H), 7.63 (m, 1H), 7.80 (m, 1H),
8.32 (s, 1H); the aromatic region (7±9 ppm) in 19F-
23
277, 264, 249, 235, 221, 205, 227, 91, 73, 57; [a]D ˆ148
(cˆ0.47 CHCl3/MeOH 1:1).
4.2.8. (R)-7-tert-Butyldimethylsilyl homocamptothecin
(31c). To a solution of 30 (7.0 mg, 0.014 mmol) in benzene
(0.5 mL) was added phenyl isonitrile3a (4.3 mg, 0.042
mmol, 1 M in benzene) and hexamethylditin (9.1 mg,
5.7 mL, 0.15 mmol). The mixture was irradiated with a
275 W GE sunlamp for 1 h. The solvent was evaporated
and the residue puri®ed by ¯ash chromatography (gradient
CH2Cl2 to CH2Cl2/acetone 85:15) to yield 31a (2.8 mg,
42%) as a pale yellow solid. Spectroscopic data agreed
1
decoupled H NMR (500 MHz, CDCl3) d 7.51 (s, 1H),
7.64 (s, 1H), 7.81 (s, 1H), 8.32 (s, 1H); HRMS m/z calcd
for C21H16N2O4F2 398.1078, found 398.1083.
4.2.6. (R)-10-Acetoxy-12-tert-butyldimethylsilylhomo-
camptothecin (31a). In a 25 mL round bottom ¯ask
equipped with a stirbar were successively introduced
the TBDMS propargylated iodopyridone 30 (502 mg,
1 mmol), 4-acetoxyphenylisonitrile (805 mg, 5 mmol) and
benzotri¯uoride (BTF, 8 mL). The reaction ¯ask was sealed
with a septum and put under argon, warmed to 808C, and a
solution of AIBN (246 mg, 1.5 mmol) and tributyltin
hydride (0.4 mL, 1.5 mmol) in BTF (4 mL) was slowly
added over a period of 4 h by the means of a syringe pump.
well with the reported values;4 [a]D ˆ153 (cˆ0.1,
23
CDCl3).
4.2.9. (R)-12-tert-Butyldimethylsilyl-10-(tert-butyloxy-
carbonylamino)homocamptothecin (31d). To a solution
of 30 (15.0 mg, 0.03 mmol) in benzene (0.5 mL) was
added 4-tert-butyloxycarbonylaminophenyl isonitrile3a
(19.5 mg, 0.09 mmol) and hexamethylditin (19.5 mg,
The solvent was then removed under vacuum and the brown

A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
i
6339
12.4 mL, 0.06 mmol). The mixture was irradiated with a
275 W GE sunlamp for 1 h. The solvent was evaporated
and the residue puri®ed by ¯ash chromatography (gradient
CH2Cl2 to CH2Cl2/acetone 85:15) to yield 31c (10.4 mg,
59%) as a pale brown solid. Spectroscopic data agreed
20 mmol) and Pr2EtN (3.49 mL, 20 mmol) in dry CH2Cl2
(40 mL) to afford 34 as an orange-yellow oil (2.06 g, 100%).
The crude product was suf®ciently pure for the subsequent
1
reaction. H NMR (300 MHz, CDCl3) d 3.45 (s, 3H), 3.96
(s, 3H), 4.72 (s, 2H), 4.75 (s, 2H), 7.35 (d, Jˆ5.4 Hz, 1H),
7.71 (d, Jˆ5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 54.4,
55.8, 67.89, 96.7, 114.2, 124.0, 128.1, 147.1, 162.4; IR
(CH2Cl2, NaCl, cm21) 2949, 1561, 1459, 1380, 1265,
1039, 741; LRMS (70 eV, EI) m/z (rel int %) 309 (M1,
19), 277 (20), 264 (45), 248 (100), 218 (68), 152 (39), 92
(50), 79 (35); HRMS m/z calcd for C9H12NO3I (M1)
308.9862, found 308.9860.
well with the reported values;4 [a]D ˆ1123 (cˆ0.2,
23
CH2Cl2).
4.2.10. (1)-10-Amino-12-tert-butyldimethylsilylhomo-
camptothecin (31e). To a solution of 31d (7.5 mg,
0.013 mmol) in CH2Cl2 (0.5 mL) was added TFA
(0.3 mL). The mixture was stirred at room temperature for
6 h and then concentrated under reduced pressure. The resi-
due was puri®ed by ¯ash chromatography (gradient CH2Cl2
to CH2Cl2/acetone 4:1) to yield 31e (3.8 mg, 61%) as a
yellow solid. Spectroscopic data agreed well with the
4.2.14. 3-(2-Methoxy-3-methoxymethoxymethylpyridin-
4-yl)pent-2-enoic acid ethyl ester (35). Following the
procedure in 21E, the reaction was carried out with 34
(1.0 g, 3.23 mmol), LiCl (0.82 g, 19.4 mmol), predried
under vacuum at 1208C for a period of 24 h CuCl (1.60 g,
16.2 mmol), Pd(PPh3)4 (0.19 g, 0.16 mmol) and ethyl (E)-3-
(tributylstannyl)-2-pentenoate (1.62 g, 3.88 mmol) in dry
DMSO (35 mL). The crude product was subjected to ¯ash
chromatography (hexanes/ethyl acetate 95:5) to afford 35 as
23
reported values;11 [a]D ˆ136.2 (cˆ0.23, CD3OD).
4.2.11. 4-Iodo-2-methoxypyridine-3-carboxaldehyde (32).
Methyllithium in diethyl ether (1.4 M, 23.5 mL, 33 mmol)
was added to a solution of 2-methoxypyridine (1.93 mL,
18.3 mmol) in THF (120 mL) at 2408C. To this mixture
was added diisopropylamine (0.13 mL, 0.9 mmol) upon
which the mixture turned yellowish orange. After warming
to 08C and stirring for 3 h, the mixture was cooled to 2788C
and N,N,N0-trimethyl-N0-formylethylenediamine (2.62 g,
20 mmol) was added slowly. The mixture was allowed to
warm to 2408C. nBuLi in hexanes (1.6 M, 22.9 mL,
36.6 mmol) was injected and the mixture was stirred for
3 h at 2308C. A solution of I2 (11.2 g, 44 mmol) in THF
(70 mL) was then added dropwise through a dropping
funnel at 2788C with vigorous stirring. After 30 min, the
resulting mixture was allowed to warm slowly to 08C (1 h),
poured into 5% Na2SO3 (250 mL) and extracted with Et2O
(3£150 mL) and the residue obtained after removal of the
solvents was subjected to ¯ash chromatography (hexanes/
ethyl acetate 95:5) to provide 32 as a yellow oil (1.9 g,
1
a yellow oil (0.82 g, 82%). H NMR (300 MHz, CDCl3) d
0.99 (t, Jˆ7.6 Hz, 3H), 1.30 (t, Jˆ7.1 Hz, 3H), 2.99 (q,
Jˆ7.6 Hz, 2H), 3.43 (s, 3H), 4.01 (s, 3H), 4.21 (q, Jˆ
7 Hz, 2H), 4.49 (s, 2H), 4.73 (s, 2H), 5.81 (s, 1H), 6.69
(d, Jˆ5 Hz, 1H), 8.11 (d, Jˆ5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 12.5, 14.4, 26.6, 54.1, 55.6, 60.3,
62.1, 97.0, 116.3, 116.9, 120.0, 146.4, 153.3, 159.4, 163.4,
165.9; IR (CH2Cl2, NaCl, cm21) 2982, 1713, 1640, 1593,
1560, 1453, 1392, 1266, 1186, 1040, 743; LRMS (70 eV,
EI) m/z (rel int %) 309 (M1, 32), 277 (42), 236 (100), 190
(84), 174 (73), 160 (22), 77 (10); HRMS (EI) m/z calcd for
C16H23NO5 (M1) 309.1576, found 309.1587.
4.2.15. 3-(2-Methoxy-3-methoxymethoxymethylpyridin-
4-yl)pent-2-en-1-ol (36). Following the procedure in 18E,
the reaction was carried out with 35 (1.2 g, 3.88 mmol) and
a 1 M solution of LAH in diethyl ether (9.7 mL, 9.7 mmol)
to afford 36 as a very pale yellow oil (0.84 g, 81%). The
crude product was suf®ciently pure for the subsequent
reaction. 1H NMR (300 MHz, CDCl3) d 0.92 (t, Jˆ
7.6 Hz, 3H), 2.44 (q, Jˆ7.6 Hz, 2H), 3.44 (s, 3H), 4.00 (s,
3H), 4.33 (dd, Jˆ5.6, 6.7 Hz, 2H), 4.55 (s, 2H), 4.70 (s, 2H),
5.63 (t, Jˆ6.8 Hz, 1H), 6.68 (d, Jˆ5.2 Hz, 1H), 8.07 (d,
Jˆ5.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 13.2, 15.5,
25.4, 54.0, 55.6, 59.0, 61.8, 96.3, 117.3, 129.4, 142.1, 146.1,
154.6, 163.6; IR (CH2Cl2, NaCl, cm21) 3383, 2945, 1594,
1555, 1452, 1391, 1320, 1268, 1148, 1038, 739, 541; LRMS
(70 eV, EI) m/z (rel int %) 268 (M11H, 38), 249 (31), 236
(62), 190 (48), 176 (100), 160 (35), 91 (16), 77 (15); HRMS
m/z calcd for C13H18NO3 (M12CH3O) 236.1287, found
236.1292.
1
40%); H NMR (300 MHz, CDCl3) d 4.06 (s, 3H), 7.54
(d, Jˆ5.3 Hz, 1H), 7.86 (d, Jˆ5.3 Hz, 1H), 10.21 (s, 1H);
13C NMR (75 MHz, CDCl3) d 54.6, 108.8, 119.4, 130.5,
151.0, 164.4, 190.4; IR (CH2Cl2, NaCl, cm21) 1703, 1551,
1462, 1368, 1298, 1265, 1017, 847, 736; LRMS (70 eV, EI)
m/z (rel int %) 263 (M1, 100), 234 (80), 205 (30), 127 (30),
93 (28), 78 (72); HRMS m/z calcd for C7H6INO2 (M1)
262.9443, found 262.9431.
4.2.12. (4-Iodo-2-methoxy-pyridin-3-yl)methanol (33).
Following the procedure in 14, the reaction was carried
out with 32 (1.88 g, 7.1 mmol) and NaBH4 (0.135 g,
3.56 mmol) in EtOH (40 mL) to afford 33 as a pale yellow
oil (1.83 g, 97%). The crude product was suf®ciently pure
for the subsequent reaction. 1H NMR (300 MHz, CDCl3) d
2.43 (t, Jˆ7 Hz, 1H), 3.99 (s, 3H), 4.82 (d, Jˆ7 Hz, 2H),
7.35 (d, Jˆ5.4 Hz, 1H), 7.7 (d, Jˆ5.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 54.3, 64.9 112.1, 126.5, 128.2, 146.6,
161.7; IR (CH2Cl2, NaCl, cm21) 3391, 2946, 1561, 1459,
1380, 1019, 805; LRMS (70 eV, EI) m/z (rel int %) 265
(M1, 53), 250 (84), 138 (30), 84 (100), 78 (30); HRMS
m/z calcd for C7H8NO2I (M1) 264.9600, found 264.9598.
4.2.16. (1)-[3-Ethyl-3-(2-methoxy-3-methoxymethoxy-
methylpyridin-4-yl)oxiranyl]methanol (37). Following
the procedure in 19-trans, the reaction was carried out
with 36 (161 mg, 0.6 mmol), Ti(OiPr)4 (0.14 mL, 0.48
mmol), diethyl-l-(1)-tartrate (0.1 mL, 0.6 mmol), tBuOOH
Ê
(0.19 mL, 5.0±6.0 M in decane) and 4 A molecular sieves
4.2.13. 4-Iodo-2-methoxy-3-methoxymethoxymethylpyri-
dine (34). Following the procedure in 15, the reaction was
carried out with 33 (1.77 g, 6.68 mmol), MOMCl (1.52 mL,
(48 mg) in dry CH2Cl2 for 24 h to afford 37 as a yellow oil
(144 mg, 84%) with 96% ee. The crude product was suf-
®ciently pure for the subsequent reaction. Epoxide 37 was

6340
A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
analyzed for enantiomeric purity using a Chiralcel OD-H
column with 98:2 hexanes/iPrOH as the eluent with the
racemate as the standard. H NMR (300 MHz, CDCl3) d
9H-8-oxa-2-aza-benzocyclohepten-7-one (40). To a solu-
tion of the aldehyde 39 (0.13 g, 0.46 mmol) in tert-butyl
alcohol (7.1 mL) was added 2-methyl-2-butene (2.13 mL).
To this mixture was added dropwise a solution of sodium
chlorite (0.37 g, 4.13 mmol) and sodium dihydrogen
phosphate (0.44 g, 3.2 mmol) in H2O (3.8 mL). The result-
ing mixture was stirred at room temperature for 36 h. The
crude mixture was extracted with ethyl acetate. The aqueous
layer was then acidi®ed (pH<3.5) with dropwise addition of
5% HCl and subsequently extracted with ethyl acetate (in
cases where a yellow coloration was observed, the mixture
was washed with 5% sodium sul®te solution). The com-
bined organic extracts were washed with brine, dried over
sodium sulfate and concentrated under vacuum to give the
crude product 40 (0.12 g, 84%) as a light green oil which
was used immediately after the workup.
1
0.92 (t, Jˆ7.6 Hz, 3H), 1.81 (dq, Jˆ7.4 Hz, 14.8 Hz, 1H),
2.01 (dq, Jˆ7.6 Hz, 15.0 Hz, 1H), 3.24 (t, Jˆ5.8 Hz, 1H),
3.46 (s, 3H), 3.90 (m, 2H), 3.99 (s, 3H), 4.71 (s, 2H), 4.73 (s,
2H), 6.93 (d, Jˆ5.2 Hz, 1H), 8.12 (d, Jˆ5.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 9.4, 25.7, 54.1, 55.8, 60.8, 61.3,
63.7, 64.7, 96.7, 116.5, 116.8, 146.6, 151.0, 163.1; IR
(CH2Cl2, NaCl, cm21) 3408, 2980, 1765, 1607, 1457,
1410, 1393, 1266, 1040, 742, 546; LRMS (70 eV, EI) m/z
(rel int %) 284 (M11H, 58), 190 (100), 178 (73), 162 (27),
148 (27), 77 (13); HRMS m/z calcd for C14H22NO5 (M11H)
23
284.1498, found 284.1507; [a]D ˆ165.6 (cˆ0.25,
CH2Cl2).
4.2.17. (1)-3-(2-Methoxy-3-methoxymethoxymethylpyri-
din-4-yl)pentane-1,3-diol (38). Following the procedure in
22, the reaction was carried out with 37 (0.71 g, 2.5 mmol)
and LAH in dry ether (50 mL) for 24 h to afford 38 as color-
less oil (0.54 g, 76%). The crude product was suf®ciently
pure for the subsequent reaction. 1H NMR (300 MHz,
CDCl3) d 0.79 (t, Jˆ7.3 Hz, 3H), 1.91 (q, Jˆ7.3 Hz, 2H),
2.15 (m, 2H), 3.42 (s, 3H), 3.60 (m, 1H), 3.74 (m, 1H), 3.98
(s, 3H), 4.71 (s, 2H), 4.89 (d, Jˆ10.7 Hz, 1H), 5.10 (d,
Jˆ10.7 Hz, 1H), 6.77 (d, Jˆ5.5 Hz, 1H), 8.05 (d, Jˆ
5.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 7.8, 36.7,
43.8, 54.1, 55.9, 60.2, 61.1, 80.9, 96.5, 116.3, 117.9,
146.2, 156.5, 163.8; IR (CH2Cl2, NaCl, cm21) 3391, 3056,
2984, 1593, 1446, 1382, 1265, 1037, 743, 546; LRMS
(70 eV, EI) m/z (rel int %) 286 (M11H, 39), 235 (23),
222 (86), 205 (52), 194 (74), 178 (100), 150 (49), 92 (30),
77 (15); HRMS m/z calcd for C14H24NO5 (M11H)
4.2.20. (1)-5-Ethyl-5-hydroxy-2,5,6,9-tetrahydro-8-oxa-
2-aza-benzocycloheptene-1,7-dione ((R)-7)). To a round-
bottom ¯ask was added 40 (0.11 g, 0.38 mmol) followed by
TFA (8 mL). The mixture was stirred for 24 h at room
temperature. The mixture was then neutralized with sat.
NaHCO3 (pH<8) and extracted with diethyl ether
(3£6 mL). The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure to afford
the crude lactone as a yellowish brown oil (72 mg, 80%) and
suf®ciently pure for the subsequent reaction. 1H NMR
(300 MHz, CD3OD) d 0.84 (t, Jˆ7.4 Hz, 3H), 1.85 (q, Jˆ
7.4 Hz, 2H), 3.01 (d, Jˆ13.9 Hz, 1H), 3.41 (d, Jˆ13.9 Hz,
1H), 3.94 (s, 3H), 5.29 (d, Jˆ15.2 Hz, 1H), 5.44 (d, Jˆ
15.2 Hz, 1H), 7.15 (d, Jˆ5.5 Hz, 1H), 8.13 (d, Jˆ5.5 Hz,
1H); 13C NMR (75 MHz, CD3OD) d 9.01, 38.48, 43.81,
54.97, 61.36, 62.66, 74.68, 117.12, 147.84, 155.98,
161.91, 173.06; IR (MeOH, NaCl, cm21) 3390, 2958,
1725, 1683, 1596, 1377, 1204, 1140, 1041; LRMS (70 eV,
EI) m/z (rel int %) 237 (M1, 75), 208 (22), 166 (100), 136
(25), 106 (7), 77 (7); HRMS m/z calcd for C12H15NO4 (M1)
23
286.1654, found 286.1658; [a]D ˆ10.185 (cˆ1.08,
CH2Cl2).
4.2.18. (2)-3-Hydroxy-3-(2-Methoxy-3-methoxymethoxy-
methylpyridin-4-yl)pentanal (39). To a mixture of 38
(0.5 g, 1.78 mmol) in CH2Cl2 (20 mL) was added Dess±
Martin periodinane (1.2 g, 2.85 mmol). The mixture was
stirred at room temperature for 3 h and then poured into a
well-stirred mixture of sat. Na2S2O3 (10 mL) and sat.
NaHCO3 (10 mL). The layers were separated after 30 min.
The aqueous layer was extracted three times with diethyl
ether. The combined organic extracts were washed with sat.
NaHCO3, brine, dried over MgSO4 and concentrated under
vacuum to give the crude aldehyde 39 (0.47 g, 89%) as pale
yellow oil. The crude product was suf®ciently pure for the
subsequent reaction. 1H NMR (300 MHz, CDCl3) d 0.82 (t,
Jˆ7.4 Hz, 3H), 1.91 (m, 2H), 2.85 (dd, Jˆ2.1, 16.4 Hz, 1H),
3.10 (dd, Jˆ2.2, 16.3 Hz, 1H), 3.41 (s, 3H), 3.96 (s, 3H),
4.74 (s, 2H), 4.98 (q, Jˆ10.9 Hz, 2H), 6.74 (d, Jˆ5.5 Hz,
1H), 8.06 (d, Jˆ5.5 Hz, 1H), 9.73 (t, Jˆ2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 7.9, 36.4, 54.2, 55.3, 56.0,
60.9, 77.90, 96.5, 115.8, 117.4, 146.6, 155.6, 163.9, 202.2;
IR (CH2Cl2, NaCl, cm21) 3380, 3057, 2982, 1763, 1655,
1596, 1422, 1264, 895, 735, 547; LRMS (70 eV, EI) m/z
(rel int %) 284 (M11H, 15), 265 (25), 192 (20), 178 (72),
148 (24), 84 (100), 57 (26); HRMS m/z calcd for C14H22NO5
23
237.1001, found 237.0996; [a]D ˆ13.0 (cˆ0.1, MeOH).
To a dry round-bottom ¯ask was added the crude lactone
(70 mg, 0.3 mmol) followed by dry acetonitrile (1 mL).
Sodium iodide (0.07 g, 0.49 mmol) was added followed
by chlorotrimethylsilane (0.06 mL, 0.49 mmol). The result-
ing mixture was stirred at room temperature for 15 min at
which point H2O was added (2.7 mL, 0.15 mmol) and the
reaction mixture was heated to 608C for 7 h. The mixture
was then poured into a 1:1 solution of 5% sodium sul®te/
brine (7 mL) and then quickly extracted with ethyl acetate
(4£5 mL). The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The crude product
was subjected to ¯ash chromatography (MeOH/CH2Cl2
5:95) to afford pure 33 as pale yellow oil (10.4 mg, 16%).
1H NMR (300 MHz, CD3OD) d 0.91 (t, Jˆ7.5 Hz, 3H), 1.82
(m, 2H), 3.10 (d, Jˆ13.8 Hz, 1H), 3.40 (d, Jˆ13.8 Hz, 1H),
5.30 (d, Jˆ15.2 Hz, 1H), 5.46 (d, Jˆ15.2 Hz, 1H), 6.57 (d,
Jˆ7 Hz, 1H), 7.35 (d, Jˆ7 Hz, 1H); 13C NMR (75 MHz,
CDCl3/CD3OD) d 6.76, 35.22, 41.46, 60.98, 72.43,
105.93, 122.42, 132.76, 156.35, 161.60, 172.57; IR
(MeOH, NaCl, cm21) 3370 (br), 1655, 1049, 1025, 823,
768; LRMS (70 eV, EI) m/z (rel int %) 224 (M11H, 32),
195 (21), 163 (43), 153 (100), 91 (40), 77 (19), 55 (24);
HRMS m/z calcd for C11H13NO4 (M1) 223.0845, found
(M11H) 284.1498, found 284.1498; [a]D ˆ211.5
23
(cˆ0.125, CH2Cl2).
23
4.2.19. (1)-5-Ethyl-5-hydroxy-1-methoxy-5,6-dihydro-
223.0851; [a]D ˆ135.0 (cˆ0.08, MeOH).

A. E. Gabarda et al. / Tetrahedron 58 (2002) 6329±6341
6341
12. (a) Gabarda, A. PhD Thesis, University of Pittsburgh, 2001.
(b) Curran, D. P.; Josien, H.; Bom, D.; Gabarda, A.; Du, W.
The Camptothecins: Unfolding their Anticancer Potential.
Liehr, J. G., Giovanella, B. C., Verschraegen, C. F., Eds.,
Ann. NY Acad. Sci. 2000, 922, 112.
Acknowledgements
We thank the National Institutes of Health for funding this
work.
È
13. (a) Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P.
Angew. Chem., Int. Ed. 1998, 37, 1701. (b) Berillon, L.;
Â
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 Â
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