New taxane derivatives: Synthesis of baccatin[14,1-d]furan-2-one nucleus and its condensation with the norstatine side chain

Article abstract of DOI:10.1021/jo0493018

New taxanes 15 and 18, containing the unsaturated and saturated baccatin[14,1-d]furan-2-one nucleus, respectively, were prepared starting from the readily available 13-oxo-7-Tes-baccatin III (3). Sequential formation of the enolate of 3 and reaction with

Full text of DOI:10.1021/jo0493018

New Ta xa n e Der iva tives: Syn th esis of Ba cca tin [14,1-d ]fu r a n -2-on e
Nu cleu s a n d Its Con d en sa tion w ith th e Nor sta tin e Sid e Ch a in
Eleonora Baldelli,† Arturo Battaglia,† Ezio Bombardelli,‡ Giacomo Carenzi,§
Gabriele Fontana,‡ Maria Luisa Gelmi,*,§ Andrea Guerrini,† and Donato Pocar§
Istituto di Chimica Organica “A. Marchesini” Facolta` di Farmacia, Universita` di Milano,
via Venezian 21, 20133, Milano, Italy, Istituto CNR per la Sintesi Organica e Fotoreattivita` “ISOF”,
Area della Ricerca di Bologna, Via P. Gobetti 101, I-40129 Bologna, Italy,
and Indena SPA, via Ripamonti 99, 20141 Milano, Italy
marialuisa.gelmi@unimi.it
Received April 27, 2004
New taxanes 15 and 18, containing the unsaturated and saturated baccatin[14,1-d]furan-2-one
nucleus, respectively, were prepared starting from the readily available 13-oxo-7-Tes-baccatin III
(3). Sequential formation of the enolate of 3 and reaction with ethyl glyoxylate gave the 13-oxo-
7-Tes-baccatin[14,1-d]-3,4-dehydrofuran-2-one 4. The reduction of 4 can result in the formation of
a mixture of compounds corresponding to 13-hydroxy alcohol 5 and 13-enol derivative 6. Both 5
and 6 were transformed into 13-oxo-7-Tes-baccatin[14,1-d]furan-2-one 8 by treatment with a base.
Further reduction of 8 gave 13-hydroxy compound 9. Esterification of 6 and 9 with N,O-protected
norstatine 12, followed by deprotection, gave the new promising anticancer taxanes 15 and 18,
respectively.
CHART 1. Ba cca tin Der iva tives a n d Or ta ta xel
In tr od u ction
Paclitaxel (Taxol), a complex natural diterpene ex-
tracted from Taxus brevifolia, is one of the most efficient
anticancer agents for the treatment of ovarian and breast
cancer. A major limitation is the development of multi-
drug resistance (MDR) during the therapy.1
For this reason, recent research is targeted toward
discovery of more effective and less toxic analogues of
paclitaxel by modifying its basic structure. In fact, it is
well established from structure-activity studies of sev-
eral research groups that changes to the “southern
hemisphere”, comprising the C-14 and C-1 to C-5 posi-
tions, exert a major effect on Taxol’s activity.2 These
studies were supported by the discovery of a potent
“second-generation” of taxoid anticancer agents, which
have been prepared3 from the scarcely available 14â-
hydroxy-10-deacetylbaccatin III 1 (Chart 1), isolated from
the needles of Taxus wallichiana Zucc.4 The presence of
the 14â-OH functionality in a form of 1,14-carbonate
moiety displays improved pharmacological properties
such as a remarkably better bioavailability than pacli-
taxel and docetaxel after oral administration and a wide
activity spectrum against various cancer types (human
ovarian, non-small-cell-lung, colon, and breast cancer cell
lines). One of these new taxanes, ortataxel (Chart 1) has
been selected for preclinical development.5
We have recently developed a semisynthetic protocol
for the preparation of 14â-OH-baccatin III 1,14 carbon-
ates 2 (Chart 1). The key step of this synthesis was the
* Corresponding author. Phone: +390250314481. Fax: +39025031-
4476.
† CNR “ISOF”, Bologna.
‡ Indena SPA.
§ Universita` di Milano.
(1) (a) Verweij, J .; Clavel, M.; Chevalier, B. Ann. Oncol. 1994, 5,
495-505. (b) Casazza, A. M.; Fairchild, C. R. In Drug Resistance Cancer
Treatment and Research; Freidreich, E. J ., Series Ed.; Hait, W. N.,
Ed.; Kluwer Academic Publishers: New York, 1996; Chapter 6, pp
149-171. (c) Horwitz, S. B. Taxol: Mechanism of Action and Resis-
tance. In Stony Brook Symposium on Taxol and Taxote`re; May 14-
15, 1993; The State University of New York at Stony Brook: Stony
Brook, NY, 1993; Abstracts 23-24. (d) Gottesmann, M. M.; Pastan, I.
Annu. Rev. Biochem. 1993, 62, 385-427. (e) Rose, W. C.; Clark, J . L.;
Lee, F. Y.; Casazza, A. M. Cancer Chemother. Pharmacol. 1997, 39,
446.
(3) (a) Ojima, I.; Slater, J . C.; Kuduk, S. D.; Takeuchi, C. S.; Gimi,
R. I.; Sun, C.-M.; Park, Y. H.; Pera, P.; Veith, J . M.; Bernacki, R. J . J .
Med. Chem. 1997, 40, 267-278. (b) Ojima, I.; Fenoglio, I.; Park, Y. H.;
Pera, P.; Bernacki, R. J . Bioorg. Med. Chem. Lett. 1994, 37, 1408. (c)
Ojima, I.; Park, Y. H.; Sun, C.-M.; Fenoglio, I.; Appendino, G.; Pera,
P.; Bernacki, R. J . J . Med Chem. 1994, 37, 1408. (d) Distefano, M.;
Scambia, G.; Ferlini, C.; Gaggini, C.; DeVincenzo, R.; Riva, A.;
Bombardelli, E.; Ojima, I.; Fattorossi, A.; Panici, P. B.; Mancuso, S.
Int. J . Cancer 1997, 72, 844-850.
(2) See,for example: Kingston, D. J . I. J . Nat. Prod. 2000, 63, 726-
734 and references therein.
10.1021/jo0493018 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/26/2004
6610
J . Org. Chem. 2004, 69, 6610-6616

New Taxane Derivatives
SCHEME 1. Syn th esis of Ba cca tin [14,1-d ]d eh yd r ofu r a n -2-on e Nu cleu sa
a
Reagents and conditions: (i) THF, -60 °C, t-BuOK.
selective â-hydroxylation of the enolates of protected 13-
oxobaccatins with oxaziridines, followed by 1,14-carbo-
nylation and reduction of the 13-oxo group.6 It is worth
noting that 13-oxobaccatins are prepared in high yields
from 10-deacetylbaccatin III, a readily available com-
pound from natural sources. The simplicity of the enolate
route for the stereoselective insertion of the OH group
at C-14 prompted us to test this methodology with other
electrophilic reagents to access to novel antitumor tax-
oids.
Since bioisosters are known in many cases to improve
the efficacy of a drug, new promising anticancer agents
were designed and developed in our laboratory. Our
project focused on the synthesis of compounds 15 and 18,
containing the unsaturated and saturated baccatin[14,1-
d]furan-2-one nucleus, respectively, which differ from
ortataxel for the presence of a carbon atom linked to C-14
instead of the oxygen atom. For their preparation the 13-
oxo-7-Tes-baccatin III 3 and ethyl glyoxylate were used
as the starting materials.
agent since this hydride gave the best R-diasterocontrol
in the reduction of isosteric 14â-OH 1,14-carbonates.6
Instead, the target 13R-OH epimer of 7-Tes-baccatin-
[14,1-d]-3,4-dehydrofuran-2-one 5 was obtained as the
minor product (33%) of a mixture with the enol 6 (66%)
(Scheme 2). The last compound was formed by 1,4-
addition of the hydride ion to the R,â-unsaturated car-
bonyl group of 4. Other reducing agents such as Bu4-
NBH4/CeCl3 and DIBAL-H failed to reduce the 13-oxo
group, while NaBH4 in EtOH, NaBH4/CeCl3, and NaBH4/
CuCl only gave compound 6. This enol was also obtained
by catalytic hydrogenation in the presence of Pd/C in
quantitative yield, so this last protocol must be consid-
ered the best one to prepare this compound. These results
clearly showed that the double bond is more reactive than
the keto group, probably for steric reasons.
The enol derivative 6 is stable in a solid state but was
quantitatively transformed into hydroperoxide 7 on
standing in solution (toluene/THF, 70 °C, 8 h; CHCl3, 25
°C, 24 h) (Scheme 2). This air-induced hydroperoxidation
is typical for compounds bearing a stable enol group.8a
It is worth noting that an identical air-induced hydro-
peroxidation of the enolic function also occurred in 12,-
13-isobaccatin III, a baccatin III analogue of 6.8b
Attempts to carry out a direct reduction of the alcohol
5, or the enol 6 to the saturated analogue 9 probing
several reducing agents, failed.9 Instead, this target was
efficiently achieved by inducing with a base (DMAP in
CH2Cl2) a tautomerization process between the enol 6
and the keto compound 8 which was then reduced to 9
(Scheme 2). Very important, the tautomerization of 6
must be performed in an inert medium since the presence
of air associated to a basic medium favored a competitive
oxidation of 6 into 410 through the hydroperoxide 7
(Scheme 2). An independent experiment confirmed the
quantitative conversion of pure 7 into 4 in the presence
of DMAP (Scheme 2). Despite our attempts to avoid the
Resu lts a n d Discu ssion
Previous studies showed that the 13-oxo compound 3
is the key starting material for the functionalization of
the C-14 position via its enolate,6,7 which was efficiently
obtained using potassium tert-butoxide as the base in the
polar mixed solvent THF/DMPU at -60 °C.6 In the
present case, the reaction of the enolate of 3 with ethyl
glyoxylate (2 equiv) was performed using THF as the
solvent and selectively gave the 13-oxo-7-Tes-baccatin-
[14,1-d]-3,4-dehydrofuran-2-one 4 in 79% yield (Scheme
1). For its formation it is assumed that the aldol reaction
occurred between the enolate A and the aldehyde group
of glyoxylate, giving intermediate B, followed by a
sequential lactonization reaction between the ester func-
tion and the hydroxy group at C-1 and water elimination.
The reduction of the 13-keto function of 4 was studied
in order to obtain both the 13-hydroxy unsaturated
lactone 5 and the saturated analogue 9 (Scheme 2).
Bu4NBH4 in methanol was selected as the reducing
(8) (a) Hayakawa, K.; Ueyama, K.; Kanematsu, K. J . Org. Chem.
1985, 50, 1963-1969. (b) Kelly, R. C.; Wicnienski, N. A.; Gebhard, I.;
Qualls, S. J .; Han, F.; Dobrowolski, P. J .; Nidy, E. G.; J ohnson, R. A.
J . Am. Chem. Soc. 1996, 118, 919-920.
(9) The alcohol 5 was hydrogenated both with Pd/C and Pt2O as the
catalysts operating at room temperature both at 1 atm and under
pressure, but the starting material was recovered. When 6 was treated
both with (i-PrO)3Al in i-PrOH at 60 °C and NaBH4 in EtOH (-20 to
25 °C), the unreacted starting material was recovered.
(10) When 6 was treated in the presence of air with a base such as
(dimethylamino)pyridine (DMAP) or N-methylimidazole or diisopro-
pylethylamine (DIPEA) in a solvent such as CH2Cl2, toluene/THF,
toluene/CH2Cl2 both at room temperature and reflux, a mixture of the
keto compound 8 and the unsaturated starting ketone 4 was obtained
in a different ratio (Scheme 2). The oxidized compound 4 was the major
one in most cases i.e., when different amounts of one of the above bases
(from 0.2 to 1 eq.) and a mixture of toluene/THF were used (4/8 )
4-4.5:1). Instead, performing the reaction in CH2Cl2 and using DMAP
(1 equiv), operating at 25 °C for 2 h, compounds 8 and 4 were obtained
in a 4:1 ratio.
(4) Appendino, G.; Gariboldi, P.; Gabetta, B.; Pace, R.; Bombardelli,
E.; Viterbo, D. J . Chem. Soc., Perkins Trans. 1 1992, 2925-29296.
(5) (a) Nicoletti, M. I.; Colombo, T. Rossi, C.; Monardo, C.; Stura,
S.; Zucchetti, M.; Riva, A.; Morazzoni, P.; Donati, M. B.; Bombardelli,
E.; D’Incalci, M.; Giavazzi, R. Cancer Res. 2000, 60, 842-846. (b)
Polizzi, D.; Pratesi, G.; Monestiroli, S.; Tortoreto, M.; Zunino, F.;
Bombardelli, E.; Riva, A.; Morazzoni, P.; Colombo, T.; D’Incalci, M.;
Zucchetti, M. Clin. Cancer Res. 2000, 6, 2070-2074. (c) Polizzi, D.;
Pratesi, G.; Tortoreto, M.; Supino, R.; Riva, A.; Bombardelli, E.; Zunino,
F. Cancer Res. 1999, 59, 1036-1040.
(6) Baldelli, E.; Battaglia, A.; Bombardelli, E.; Carenzi, G.; Fontana,
G.; Gambini, A.; Gelmi, M. L.; Guerini, A.; Pocar, D. J . Org. Chem.
2003, 68, 9773-9779.
(7) Fang, W. S.; Fang, Q. C.; Liang, X. T. Chinese Chem. Lett. 2001,
12, 675-678.
J . Org. Chem, Vol. 69, No. 20, 2004 6611

Baldelli et al.
SCHEME 2. Oxid or ed u ction Rea ction sa
a
Reagents and conditions: (i) 5/6 (1:2): Bu4NBH4, MeOH, -10 °C; (ii) 6: H2, Pd/C, AcOEt; (iii) CH2Cl2, DMAP, 25 °C; (iv) O2, CHCl3,
25 °C; (v) NaBH4, DMAP, EtOH/CH2Cl2; (vi) NaBH4, EtOH, from 0 to 25 °C; (vii) CH2Cl2, DMAP, 25 °C, then (vi).
presence of air in the reaction medium, trace amounts
of 4 were always formed. The best result obtained was a
16:1 mixture of 8/4 operating in CH2Cl2 and using DMAP
(1 equiv) at 25 °C for 2 h.
The reduction of the keto function, starting from both
4 and 8, occurred with high stereocontrol. Unlike the
reduction of 13-oxobaccatin III 1,14-carbonate,6 which
gave a mixture of 13R- (major stereomer) and 13â-
hydroxybaccatin III derivatives, only the single 13R-
hydroxy epimers (i.e., 5 from 4 and 9/10 from 8) were
isolated. A favored approach of the hydride ion from the
less hindered â-face of the C-13 keto group of the folded
structure of the taxane skeleton, or the double bond of
the lactone ring, well accounts for such selectivity.6,12 In
the present case, the presence of the furanone ring
increased the steric demand, thus allowing a high steric
control in the reduction process. Furthermore, the R-OH
isomers are probably the more thermodinamically stable
compounds, as evinced when an equilibration occurred
between 6 and 5 (see below, Scheme 3).
Derivative 5 showed the same reactivity of 6 under
basic conditions, giving a mixture of compounds 4 and 8
(1H NMR analysis) (Scheme 2).
The formation of compound 8 from 5 may be accounted
by a prototropic allylic shift, giving intermediate 6,
followed by a base-induced anionotropic rearrangement.11
Noteworthy, compounds 5 and 6 can equilibrate in basic
medium, and in the absence of other reactants (see below)
the equilibrium is in favor of 6 and then transformed into
8.
Compound 8 was then reduced to the 13R-hydroxy
derivative 9 (Scheme 2). Bu4NBH4 did not work, while a
mixture of the expected alcohol 9 and the 4,13-dihydroxy
derivative 10 (4:1 ratio by 1H NMR analysis) was
obtained using NaBH4 in EtOH. Compound 9 was
isolated in 70% yield after chromatography. As confirmed
by an independent experiment, compound 10 is formed
by a competitive C4-O deacetylation of 9 when reacted
with NaBH4 in EtOH (48 h). The same behavior was
observed using MeOH as the solvent at low temperature.
The reductive 4-O deacetylation was previously ob-
served.6
To increase the yield of the 13-hydroxy compound 9, a
“one-pot reaction” was attempted both starting from 6
and 4. After the DMAP-induced tautomerization of the
enol 6 into 8 (traces of the oxidized compound 4 were
present), the reaction mixture was directly reduced with
NaBH4 (8 equiv) at 25 °C in EtOH. The R-diastereomer
9 was formed as the major product (71%) besides a minor
amount of compound 10 (14%). The whole protocol was
more feasible, and yields of 9 increased. When the same
protocol was carried out in the presence of air, we noticed
1
that the H NMR spectrum revealed consistent amounts
(11) Di Giacomo, M.; Leggeri, P.; Azzolina, O.; Pirillo, D.; Traverso,
G. J . Chem. Res., Synop. 1990, 16-17.
(12) Wigfield, D. C.; Phelpss, D. J . Can. J . Chem. 1972, 50, 388-
394.
6612 J . Org. Chem., Vol. 69, No. 20, 2004

New Taxane Derivatives
SCHEME 3. Syn th esis of Ta xa n e Der iva tive 15a
a
Reagents and conditions: (i) DCC, DMAP, CH2Cl2, 25 °C; (ii) PyHF, MeCN/Py, 25 °C; (iii) AcCl/MeOH cat., CH2Cl2.
of a new compound 11 (9/11 ) 1.25:1) which derived from
4 (see below).
formation of a mixture of 4 (15%), ketone 8 (10%), and
the taxoid derivative 13 (57%) (Scheme 3). The DMAP-
promoted formation of compounds 4 and 8 from the
reagent 6 (Scheme 2) was avoided with a slight modifica-
tion of esterification protocol. When compound 6 (1 equiv)
was reacted with 12 (1.5 equiv) in high concentration in
CH2Cl2, in the presence of DCC (2 equiv) and DMAP (0.1
equiv) and operating at room temperature under argon,
compound 13 was isolated in 88% yield.
Clearly, compound 13 derived from the condensation
of 12 with 5 which is formed from enol 6 via a 1,3-
sigmatropic proton shift induced by the base. As reported
above, this process is reversible: in fact, 5 is transformed
into 8 via enol 6 in the presence of a base. In the present
case, the equilibrium is shifted toward compound 5 that
is removed during the esterification with the amino acid
12 (Scheme 3).
In fact, the same compound 11 was the sole reaction
product when 4 was reduced with the couple NaBH4/
DMAP (8 equiv/1 equiv) at 0 °C (Scheme 2). The reaction
was monitored by 1H NMR. After 2 h, the starting
material 4 disappeared and the 1H NMR spectrum
showed the presence of the enol 6 and traces of the new
compound 11. Prolonging the reaction time (18 h) to favor
1
the complete transformation of 6, the H NMR spectrum
showed only the presence of 11 (74% after column
chromatography). The same results (TLC, 1H NMR
analyses) were observed when starting from pure 6 by
reduction with a mixture of NaBH4/DMAP (8 equiv/1
equiv). In all cases neither TLC nor 1H NMR analyses
showed the presence of 9. On the basis of the above
observations, it must be concluded that compound 4 was
reduced to 6, which was transformed into 11. The
structure of compound 11 stemmed from their 1H and
13C NMR spectra which showed the presence of the 13-
keto group, the [14,1-d]furan-2-one ring, the enol group
at C-9-C-10, and the absence of the 10-acetoxy group. The
reduction of acyloins to ketones13 is a known procedure,
but to our knowledge, this protocol was for the first time
applied to taxane chemistry.
The esterification of baccatin derivative 9 with 12 using
the new protocol gave the taxoid derivative 16 in 94%
yield (Scheme 4).
Both compounds 13 and 16 were desilylated with
pyridinium hydrogen fluoride in MeCN/pyridine solvents
at room temperature. Compounds 14 (Scheme 3) and 17
(Scheme 4) were isolated in 75 and 87% yield, respec-
tively. The N,O-deprotection of the oxazolidine ring of the
side chain of 14 and 17 was carried out in CH2Cl2 with
catalytic HCl, obtained by methanolysis of a MeOH
solution of acetyl chloride. The final compounds 15
(Scheme 3) and 18 (Scheme 4) were obtained in 85 and
70% yield, respectively.
Both compounds 6 and 9 were esterified with the
suitable N,O-protected norstatinic acid 12. The esterifi-
cation of 6 with acid 12 was carried out under standard
conditions,14 i.e., dicyclohexylcarbodiimide (DCC, 1.2
equiv) and DMAP (0.4 equiv), in a mixture of toluene/
CH2Cl2 (2:1) at 70 °C. The reaction resulted in the
Con clu sion s
(13) (a) Ueki, M.; Okamura, A.; Yamaguchi, J . Tetrahedron Lett.
1995, 36, 7467-7470 and references therein. (b) He Y.; Pan, X.; Zhao,
H.; Wang, S. Synthetic Comm. 1989, 19, 3051-3054. (c) Hurnaus, R.;
Reiffen, M.; Sauter, R.; Grell, W.; Rupprecht, E. GWXXB DE 3718638
A1 19881222. Chem. Abstr. 1989, 111, 77643.
(14) Pontiroli, A.; Bombardelli, E. PCT Int. Appl. 20020444161;
Chem Abstr. 2002, 137, 6295.
In conclusion, the synthesis of two new taxoid deriva-
tives 15 and 18, containing the baccatin[14,1-d]dehydro-
furan-2-one and -furan-2-one nucleus, respectively, was
performed starting from the readily available 13-oxo-7-
J . Org. Chem, Vol. 69, No. 20, 2004 6613

Baldelli et al.
SCHEME 4. Syn th esis of Ta xa n e Der iva tive 18a
by column chromatography (silica, EtOAc/cyclohexane ) 1:9-
2:8) to give lactone 4 (503 mg, 79%) as a yellow solid: Rf )
0.55 (silica, EtOAc/cyclohexane ) 1:1); mp 252-253 °C (Et2O/
n-pentane); [R]20D +72 (c 1, CHCl3); IR (CDCl3) νmax 1771, 1728,
1661, 1221; 1H NMR (200 MHz, CDCl3) δ 7.97 (d, 2H, J ) 8.4
Hz), 7.43-7.62 (m, 3H), 6.87 (s, 1H), 6.66 (s, 1H), 6.16 (d, 1H,
J ) 6.9 Hz), 4.88 (d, 1H, J ) 8.8 Hz), 4.50 (dd, 1H, J 1 ) 6.6,
Hz, J 2 ) 3.6 Hz), 4.22 (d, 1H, J ) 8.8 Hz), 4.15 (d, 1H, J ) 8.8
Hz), 3.98 (d, 1H, J ) 6.9 Hz), 2.49-2.64 (m, 1H), 2.39 (s, 3H),
2.27 (s, 3H), 2.14 (s, 3H), 1.84-1.98 (m, 1H), 1.75 (s, 3H), 1.45
(s, 3H), 1.27 (s, 3H), 0.95 (t, 9H, J ) 8.4 Hz), 0.56-0.68 (m,
6H); 13C NMR (300 MHz, CDCl3) δ 199.4, 182.9, 171.0, 169.5,
168.5, 165.2, 158.7, 156.3, 143.1, 134.7, 130.5, 129.4, 128.7,
127.4, 94.3, 84.4, 77.3, 77.1, 76.4, 72.8, 68.6, 60.8, 47.3, 45.2,
37.9, 32.9, 22.3, 21.4, 20.8, 14.6, 10.3, 7.4, 5.3. Anal. Calcd for
C39H48O12Si: C, 63.57; H, 6.57. Found: C, 63.49; H, 6.66.
7-TE S-13,14-d eh yd r ob a cca t in [14,1-d ]fu r a n -2-on e (6).
Compound 4 (90 mg, 0.12 mmol) was dissolved in EtOAc (10
mL) and hydrogenated with Pd/C as the catalyst (90 mg, 10%)
for 45 min at room temperature and 1 atm. After removal of
Pd/C by filtration over Celite and evaporation of the solvent,
the residue was purified by column chromatography (EtOAc/
cyclohexane ) 1:4 to 1:1) to give enol derivative 6 (85 mg, 93%)
as a white solid: Rf ) 0.3 (silica, EtOAc/cyclohexane ) 1:1);
mp 235-236 °C (EtOAc/n-hexane); [R]20 -15 (c 0.6, CHCl3);
D
1
IR (CDCl3) νmax 3432, 1771, 1743, 1695, 1222; H NMR (200
MHz, CDCl3) δ 8.01 (d, 2H, J ) 6.9 Hz), 7.44-7.62 (m, 3H),
6.43 (s, 1H), 6.10 (d, 1H, J ) 6.6 Hz), 4.98 (d, 1H, J ) 5.9 Hz),
4.44 (dd, 1H, J 1 ) 6.6 Hz, J 2 ) 3.6 Hz), 4.35 (d, 1H, J ) 8.4
Hz), 4.19 (d, 1H, J ) 8.4 Hz), 3.76 (d, 1H, J ) 7.0 Hz), 3.35 (d,
1H, J ) 22.0 Hz), 3.19 (d, 1H, J ) 21.6 Hz), 2.49-2.64 (m,
1H), 2.23 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H), 1.84-1.98 (m, 1H),
1.74 (s, 3H), 1.27 (s, 3H), 1.16 (s, 3H), 0.94 (t, 9H, J ) 8.1 Hz),
0.56-0.68 (m, 6H); 13C NMR (300 MHz, CDCl3) δ 201.5, 175.0,
170.1, 169.6, 164.9, 148.7, 136.8, 134.9, 133.8, 129.6, 128.8,
128.7, 102.2, 92.4, 84.1, 80.8, 76.1, 75.9, 72.2, 70.4, 58.4, 45.0,
39.6, 37.3, 32.0, 28.1, 21.3, 20.9, 19.6, 13.5, 10.0, 6.7, 5.3. Anal.
Calcd for C39H50O12Si: C, 63.39; H, 6.82. Found: C, 63.44; H,
6.76.
7-TES-ba cca tin [14,1-d ]-3,4-d eh yd r ofu r a n -2-on e (5) a n d
(6). A solution of Bu4NBH4 (180 mg, 0.7 mmol) in MeOH (10
mL) was cooled to -30 °C. Then compound 4 (200 mg, 0.28
mmol) was dissolved in THF (1 mL) and added dropwise. After
30 min. the reaction mixture was quenched with citric acid
(180 mg) and warmed to room temperature. After addition of
water (10 mL), it was extracted with EtOAc (2 × 10 mL) and
the organic layers were washed with water (5 mL), dried over
Na2SO4 and evaporated. The residue was purified by chroma-
tography (silica, EtOAc/cyclohexane ) 1:4 to 1:2) giving two
fractions containing 6 (103 mg, 52%) and 5 (52 mg, 26%) as
white solids. 5: Rf ) 0.25 (silica, EtOAc/cyclohexane ) 1:1);
a
Reagents and conditions: (i) DCC, DMAP, CH2Cl2, 25 °C; (ii)
PyHF, MeCN/Py, 25 °C; (iii) AcCl/MeOH cat., CH2Cl2.
Tes-baccatin III 3. The protocol followed for the prepara-
tion of the above nucleus consists of two (compound 15)
or three (compound 18) steps, i.e., (i) condensation of 3
with ethyl glyoxylate (compound 4), (ii) reduction of the
double bond (intermediate 6), and (iii) reduction of the
keto group of 6 to 9. Both 6 and 9 were successfully
condensed with N,O-protected isoserinic acid 12 giving
compounds 13 and 16, respectively, transformed into the
final products 15 (45% overall yield from 3) and 18 (32%
overall yield from 3) after deprotection.
mp 235 °C (Et2O/n-pentane); [R]20 -23 (c 0.7, CHCl3); IR
D
(CDCl3) νmax 3455, 1768, 1740, 1668, 1223; 1H NMR (200 MHz,
CDCl3) δ 8.02 (d, 2H, J ) 6.9 Hz), 7.40-7.63 (m, 3H), 6.47 (s,
1H), 6.25 (s, 1H), 6.12 (d, 1H), 5.14 (m, 1H), 4.92 (d, 1H, J )
8.1 Hz), 4.55 (dd, 1H, J 1) 7.0 Hz, J 2 ) 3.6 Hz), 4.27 (d, 1H, J
) 8.0 Hz), 4.27(d, 1H, J ) 8.0 Hz), 4.16 (d, 1H, J ) 8.0 Hz),
2.49-2.56 (m, 1H), 2.28 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H), 1.84-
1.97 (m, 1H), 1.80 (s, 3H), 1.35 (s, 3H), 1.27 (s, 3H), 0.90-0.99
(t, 9H, J ) 8.1 Hz), 0.58-0.65 (m, 6H); 13C NMR (300 MHz,
CDCl3) δ 200.1, 171.0, 170.3, 169.2, 165.4, 165.0, 140.0, 134.2,
133.7, 129.8, 128.8, 128.6, 122.8, 93.7, 84.3, 80.4, 75.8, 75.5,
72.3, 69.8, 66.8, 59.1, 48.5, 40.8, 37.1, 29.2, 22.7, 21.0, 20.8,
15.7, 10.1, 6.7, 5.2. Anal. Calcd for C39H50O12Si: C, 63.39; H,
6.82. Found: C, 63.46; H, 6.74.
Exp er im en ta l Section
7-TE S-13-oxob a cca t in [14,1-d ]-3,4-d e h yd r ofu r a n -2-
on e (4). A solution of 13-oxo-7-TES-baccatin 3 (600 mg, 0.86
mmol) in anhydrous THF (15 mL) was cooled to -70 °C and
stirred under nitrogen. Potassium tert-butoxide (2.16 mL, 1
M in THF, 2.16 mmol) was added dropwise and the solution
stirred at -65 °C for 45 min. Then ethyl glyoxylate (0.36 mL,
50% in toluene, 1.29 mmol) was added and the reaction
monitored by TLC: after 2 h, the conversion was not complete,
so a further amount of ethyl glyoxylate (0.12 mL, 0.43 mmol)
was added. After 1 h (total reaction time: 3 h), the reaction
mixture was quenched with anhydrous citric acid and warmed
to room temperature, and then it was immediately purified
7-TES-14-h yd r op er oxy-13-oxoba cca tin [14,1-d ]fu r a n -2-
on e (7). Enol 6 (50 mg, 0.07 mmol) was dissolved in CHCl3 (3
mL) and stirred for 18 h, and then the solvent was evaporated
to give compound 7 (50 mg, 100%): Rf ) 0.4 (silica, EtOAc/
cyclohexane ) 1:1); mp 152-155 °C (Et2O/n-pentane); [R]20
D
-28 (c 0.8, CHCl3); IR (CDCl3) νmax 3425, 1790, 1724, 1226;
1H NMR (200 MHz, CDCl3) δ 9.59 (s, 1H), 7.96 (d, 2H, J ) 7.4
6614 J . Org. Chem., Vol. 69, No. 20, 2004

New Taxane Derivatives
Hz), 7.47-7.65 (m, 3H), 6.55 (s, 1H), 6.33 (d, 1H, J ) 6.6 Hz),
4.84 (d, 1H, J ) 8.6 Hz), 4.54 (dd, 1H, J 1 ) 6.6 Hz, J 2 ) 3.7
Hz), 4.38 (d, 1H, J ) 8.3 Hz), 4.30 (d, 1H, J ) 8.2 Hz), 4.15 (d,
1H, J ) 6.5 Hz), 3.55 (d, 1H, J ) 20.0 Hz), 2.96 (d, 1H, J )
20.0 Hz), 2.49-2.59 (m, 1H), 2.26 (s, 3 H), 2.22 (s, 3H), 2.21
(s, 3H), 1.84-1.98 (m, 1H), 1.81 (s, 3H), 1.38 (s, 3H), 1.09 (s,
3H), 0.94 (t, 9H, J ) 8.4 Hz), 0.55-0.63 (m, 6H); 13C (300 MHz,
CDCl3) δ 199.8, 193.6, 172.1, 171.5, 169.1, 165.5, 149.2, 139.3,
134.5, 129.9, 129.5, 128.8, 93.5, 91.9, 86.0, 81.3, 76.9, 74.6, 72.6,
70.1, 60.2, 45.2, 43.7, 37.7, 37.4, 33.8, 22.6, 21.1, 21.0, 13.8,
10.1, 7.1, 5.6; MS m/z 770. Anal. Calcd for C39H50O14Si: C,
60.76; H, 6.54. Found: C, 60.49; H, 6.68.
7-TES-13-oxoba cca tin [14,1-d ]fu r a n -2-on e (8). Enol 6
(200 mg, 0.27 mmol) was dissolved in outgassed dry CH2Cl2
(10 mL) under argon, and p-(dimethylamino)pyridine (33 mg,
0.27 mmol) was added. The reaction mixture was stirred for 4
h, and then it was quenched with saturated NH4Cl solution
(15 mL). The organic layer was separated, dried over Na2SO4,
and evaporated. The residue was purified by column chroma-
tography (EtOAc/cyclohexane ) 1:9-1:4) to afford compound
4 (10 mg) and compound 8 (180 mg, 90%) as a white solid: Rf
) 0.5 (silica, EtOAc/cyclohexane ) 1:1); mp 256 °C (Et2O/n-
pentane); [R]20D +3 (c 0.25, CHCl3); IR (CDCl3) νmax 1790, 1731,
1687, 1223; 1H NMR (200 MHz, CDCl3) δ 7.98 (d, 2H, J ) 7.4
Hz), 7.45-7.62 (m, 3H), 6.54 (s, 1H), 6.06 (d, 1H, J ) 6.8 Hz),
4.95 (d, 1H, J ) 8.3 Hz), 4.50 (dd, 1H, J 1 ) 6.6 Hz, J 2 ) 4.0
Hz), 4.34 (d, 1H, J ) 8.4 Hz), 4.23 (d, 1H, J ) 8.4 Hz), 3.91 (d,
1H, J ) 6.7 Hz), 3.34 (t, 1H, J ) 10.1 Hz), 2.90 (d, 2H), 2.49-
2.64 (m, 1H), 2.23 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H), 1.84-1.98
(m, 1H), 1.74 (s, 3H), 1.35 (s, 3H), 1.27 (s, 3H), 0.94 (t, 9H, J
) 8.4 Hz), 0.56-0.64 (m, 6H); 13C NMR (300 MHz, CDCl3) δ
199.9, 198.7, 172.9, 170.2, 169.2, 164.8, 149.9, 140.1, 134.5,
130.2, 129.4, 128.7, 89.3, 84.3, 81.2, 76.3, 75.4, 72.4, 70.8, 59.3,
46.0, 45.7, 42.7, 37.3, 33.1, 32.5, 22.0, 21.1, 19.9, 14.3, 10.3,
7.1, 5.6. Anal. Calcd for C39H50O12Si: C, 63.39; H, 6.82.
Found: C, 63.48; H, 6.77.
compound 4 (104 mg, 0.14 mmol) and DMAP (16 mg, 0.14
mmol) were dissolved in CH2Cl2 (1.5 mL) and added dropwise.
The reaction mixture was raised to room temperature and
stirred for 18 h, and then acetone (1 mL) and finally NH4Cl
saturated solution (5 mL) were added. Organic solvents were
evaporated, and after addition of water (5 mL) the residue was
extracted with CH2Cl2 (2 × 5 mL). The organic layer was dried
over Na2SO4 and evaporated. The residue was purified by
chromatography (EtOAc/cyclohexane ) 1:4-3:7) to give 11 (70
mg, 74%) as a white solid: Rf ) 0.3 (silica, EtOAc/cyclohexane
) 1:1); mp 238 °C (Et2O); [R]20 +105 (c 0.5, CHCl3); 1H NMR
D
(200 MHz, CD3COCD3) δ 8.00 (d, 2H, J ) 7.2 Hz), 7.69 (s, 1H,
exch.), 7.49-7.66 (m, 3H), 6.10 (s, 1H), 5.83 (d, 1H, J ) 5.0
Hz), 4.90 (d, 1H, J ) 8.3 Hz), 4.41 (dd, 1H, J 1 ) 7.1 Hz, J 2
)
3.3 Hz), 4.25 (d 1H, J ) 4.9 Hz,), 4.11 (d, 1H, J ) 8.2 Hz),
4.11 (d, 1H, J ) 8.1 Hz), 2.99-3.05 (m, 3H, 14-H), 2.35-2.55
(m, 1H), 2.26 (s, 3H), 1.98 (s, 3H), 1.62-1.81 (m, 1H), 1.58 (s,
3H), 1.23 (s, 3H), 0.96 (t, 9H, J ) 8.1 Hz), 0.89 (s, 3H), 0.55-
0.66 (m, 6H); 13C NMR (300 MHz, CD3COCD3) δ 210.7, 171.4,
170.8, 164.7, 159.2, 142.3, 134.0, 130.2, 129.4, 129.0, 111.7,
90.1, 84.6, 80.7, 76.9, 73.5, 68.4, 57.3, 49.3, 40.3, 40.2, 39.2,
37.8, 28.5, 22.7, 22.3, 20.2, 15.3, 8.8, 6.5, 5.3; MS m/z 680. Anal.
Calcd for C37H48O10Si: C, 65.27; H, 7.11. Found: C, 65.38; H,
6.99.
Gen er a l P r oced u r e for th e Syn th esis of 13-[N-Boc-
N,O-(2,4-d im eth oxyben zilid en )-â-isobu tylisoser in oyl]-7-
TES-ba cca tin [14,1-d ]-3,4-d eh yd r ofu r a n -2-on e (13) a n d
13-[N-Boc-N,O-(2,4-d im eth oxyben zilid en )-â-isobu tyliso-
ser in oyl]-7-TES-ba cca tin [14,1-d ]fu r a n -2-on e (16). (i) Gen -
er a tion of F r ee Acid 12 fr om Its Sod iu m Sa lt. To a solution
of the sodium salt of 12 (72 mg, 0.168 mmol) in water (5 mL)
was added CH2Cl2 (3 mL). A solution of NaHSO4 (2 M, 0.15
mL) was added dropwise until pH 3.0. After being stirred for
a few minutes, the organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (2 mL). The com-
bined organic layers were washed with water (5 mL) and with
brine (5 mL), dried over Na2SO4, and evaporated to give free
acid 12 (68 mg, 100%) as a white solid. (ii) Cou p lin g of 6 or
9 w ith P r otected Sid e Ch a in 12. To a solution of compounds
6 or 9 (0.1 mmol) in CH2Cl2 (1.2 mL) under argon were added
in sequence compound 12 (free acid) (61 mg, 0.15 mmol)
dissolved in CH2Cl2 (0.5 mL), N,N-(dimethylamino)pyridine
(DMAP) (1.2 mg, 0.01 mmol), and dicyclohexylcarbodiimmide
(DCC) (41 mg, 0.2 mmol). The reaction mixture was stirred
for 1.5 h, and then it was cooled until precipitation of
dicyclohexylurea (DCU) was complete. The precipitate (DCU)
was filtered and washed with toluene (2 × 2 mL), and then
the filtrate was diluted with CH2Cl2 (5 mL) and washed first
with a saturated solution of NaHCO3 (5 mL) and then with
HCl (0.4 M, 5 mL) to remove DMAP, and finally with a
saturated solution of NaHCO3 (5 mL). The organic layer was
dried over Na2SO4 and evaporated. The residue was purified
by column chromatography (EtOAc/cyclohexane ) 1:9-1:4) to
afford compound 13 (99 mg, 88%) or 16 (106 mg, 94%) as a
white solid. 13: Rf ) 0.55 (silica, EtOAc/cyclohexane ) 1:1);
mp 150-153 °C (i-Pr2O/n-pentane); [R]20D +44 (c 0.25, CHCl3);
7-TES-ba cca tin [14,1-d ]fu r a n -2-on e (9). (i) A solution of
NaBH4 (108 mg, 2.88 mmol) in EtOH (10 mL) was cooled to 0
°C. Then compound 8 (264 mg, 0.36 mmol) was dissolved in
THF (2 mL) and added dropwise. The reaction mixture was
raised to room temperature and stirred for 4 h, and then
acetone (2 mL) and finally NH4Cl saturated solution (10 mL)
were added. The organic phase was evaporated, and after
addition of water (10 mL) the residue was extracted with CH2-
Cl2 (2 × 10 mL) and the organic layer was dried over Na2SO4
and evaporated. The residue was purified by chromatography
(EtOAc/cyclohexane ) 1:4-1:3) to give 9 (185 mg, 70%) as a
white solid. A second fraction was isolated containing the
corresponding 4-deacetyl derivative 10. (ii) Compound 6 (200
mg, 0.27 mmol) was dissolved in outgassed dry CH2Cl2 (4 mL)
under argon, and p-(dimethylamino)pyridine (33 mg, 0.27
mmol) was added. The reaction mixture was stirred for 4 h,
and then it was added to a solution of NaBH4 (81 mg, 2.16
mmol) in EtOH (8 mL) and the reaction stirred, quenched,
extracted, and purified as described in method i to obtain 9
(141 mg, 71%): Rf ) 0.2 (silica, EtOAc/cyclohexane ) 1:1); mp
246 °C (Et2O/n-pentane); [R]20D -34 (c 0.7, CHCl3); IR (CDCl3)
1
IR (CDCl3) νmax 1788, 1741, 1699, 1265, 1224; H NMR (200
ν
max 3469, 1791, 1743, 1705, 1228; 1H NMR (200 MHz, CDCl3)
MHz, CDCl3) relevant resonances at δ 7.97 (d, 2H, J ) 7.0
Hz), 7.42-7.60 (m, 3H), 7.19-7.25 (m, 1H), 6.68 (s, 1H), 6.46-
6.54 (m, 2H), 6.03 (s, 1H), 5.98 (d, 1H, J ) 5.1 Hz), 5.81 (s,
1H), 4.91 (d, 1H, J ) 7.0 Hz), 4.40-4.47 (m, 1H), 4.28 (s, 2H),
3.95 (d, 1H, J ) 5.5 Hz), 3.89 (s, 3H), 3.85 (s, 3H), 2.81 (s,
1H), 2.49-2.64 (m, 1H), 2.34 (s, 3H), 2.22 (s, 3H), 2.08 (s, 3H),
1.84-1.98 (m, 1H), 1.69 (s, 3H), 1.27 (s, 3H), 1.24 (s, 3H), 1.03-
δ 8.03 (d, 2H, J ) 7.3 Hz), 7.44-7.62 (m, 3H), 6.45 (s, 1H),
6.01 (d, 1H, J ) 7.4 Hz), 4.97 (d, 1H, J ) 8.1 Hz), 4.67 (m,
1H), 4.50 (dd, 1H, J 1 ) 6.9 Hz, J 2 ) 3.7 Hz), 4.30 (d, 1H, J )
8.1 Hz), 4.23 (d, 1H, J ) 8.4 Hz), 3.86 (d, 1H, J ) 7.3 Hz),
2.94-3.07 (m, 2H), 2.47-2.59 (m, 2H), 2.32 (s, 3H), 2.20 (s,
3H), 2.19 (s, 3H), 1.79-1.98 (m, 1H), 1.74 (s, 3H), 1.32 (s, 3H),
1.27 (s, 3H), 0.95 (t, 9H, J ) 8.1 Hz), 0.58-0.66 (m, 6H); 13C
NMR (300 MHz, CDCl3) δ 201.6, 174.6, 170.8, 169.7, 165.1,
153.0 144.0, 134.2, 132.8, 130.0, 129.1, 91.4, 84.5, 81.1, 76.6,
75.7, 75.6, 72.5, 72.2, 58.9, 46.8, 42.5, 42.3, 37.5, 36.8, 30.0,
26.7, 22.8, 22.3, 21.2, 15.1, 10.5, 7.1, 5.6. Anal. Calcd for
1.13 (m, 9H), 0.94 (t, 9H, J ) 7.7 Hz), 0.54-0.62 (m, 6H); 13
C
NMR (300 MHz, CDCl3) δ 203.5, 170.6, 170.2, 168.8, 164.5,
161.7, 159.1, 155.7, 139.0, 138.5, 133.9, 130.0, 129.6, 129.0,
128.7, 128.3, 127.8, 118.8, 104.3, 98.6, 90.0, 87.0, 84.3, 81.3,
80.8, 79.5, 75.0, 73.6, 72.9, 72.1, 67.7, 60.1, 58.9, 56.9, 55.4,
50.9, 50.1, 45.4, 43.7, 39.3, 38.3, 37.4, 29.7, 29.1, 28.2, 26.9,
25.5, 22.8, 22.6, 22.5, 21.1, 19.8, 15.9, 9.5, 6.8, 5.6. Anal. Calcd
for C60H79NO18Si: C, 63.75; H, 7.04. Found: C, 63.67; H, 6.99.
C
39H52O12Si: C, 63.22; H, 7.07. Found: C, 63.37; H, 6.99.
Syn th esis of 11. A solution of NaBH4 (45 mg, 1.13 mmol)
in EtOH (6 mL) was cooled to 0 °C under argon. Then
J . Org. Chem, Vol. 69, No. 20, 2004 6615

Baldelli et al.
16: Rf ) 0.5 (silica, EtOAc/cyclohexane ) 1:1); mp 193 °C (i-
3H), 2.28 (s, 3H), 2.03 (s, 3H), 1.84-1.98 (m, 1H), 1.73 (s, 3H),
Pr2O); [R]20 -28 (c 1, CHCl3); IR (CDCl3) νmax 1786, 1738,
13C
1.34 (s, 3H), 1.29 (s, 3H), 1.26 (s, 9H), 1.07-1.13 (m, 9H);
D
1698, 1260, 1231; 1H NMR (200 MHz, CDCl3) relevant
resonances at δ 8.00 (d, 2H, J ) 7.3 Hz), 7.42-7.61 (m, 3H),
7.23-7.27 (m, 1H), 6.57 (s, 1H), 6.46-6.54 (m, 2H), 6.20 (d,
1H), 6.05 (d, 1H, J ) 7.3 Hz), 4.96 (d, 1H, J ) 7.7 Hz), 4.42
(m, 1H), 4.32 (d, 1H, J ) 8.4 Hz), 4.24 (d, 1H, J ) 8.4 Hz),
3.95 (d, 1H, J ) 5.5 Hz), 3.90 (s, 3H), 3.85 (s, 3H), 2.99 (d,
1H), 2.68-2.75 (m, 2H), 2.49-2.64 (m, 1H), 2.31 (s, 3H), 2.21
(s, 3H), 2.06 (s, 3H), 1.84-1.98 (m, 1H), 1.62 (s, 9H), 1.36 (s,
3H), 1.27 (s, 3H), 1.21 (s, 3H), 0.94 (t, 9H, J ) 7.7 Hz), 0.54-
0.62 (m, 6H); 13C NMR (300 MHz, CDCl3) δ 200.9, 173.4, 171.3,
170.0, 164.8, 161.8, 159.3, 153.3, 140.0, 134.1, 133.9, 129.8,
129.0, 128.9, 128.1, 119.2, 104.5, 98.7, 91.7, 87.0, 84.3, 81.0,
80.9, 80.1, 77.0, 76.2, 74.7, 72.2, 72.1, 58.7, 58.6, 57.9, 55.6,
50.3, 49.3, 46.4, 43.9, 42.6, 40.1, 37.3, 34.1, 29.9, 28.5, 28.4,
26.4, 25.5, 25.1, 24.8, 23.0, 22.4, 22.1, 20.9, 14.7, 10.5, 6.9, 5.5.
Anal. Calcd for C60H81NO18Si: C, 63.64; H, 7.21. Found: C,
63.60; H, 7.09.
NMR (300 MHz, CDCl3) δ 203.1, 173.3, 171.4, 170.2, 164.8,
161.8, 159.3, 153.3, 142.2, 134.2, 133.1, 129.8, 129.1, 128.8,
127.9, 119.1, 104.4, 98.7, 91.8, 87.0, 84.6, 81.2, 80.9, 79.8, 76.8,
76.2, 75.3, 72.2, 72.0, 68.3, 58.8, 58.7, 55.7, 55.6, 45.2, 42.5,
40.4, 35.8, 35.0, 34.1, 28.4, 26.6, 25.7, 25.1, 23.2, 23.1, 22.5,
22.1, 21.0, 15.2, 10.0. Anal. Calcd for C54H67NO18: C, 63.70;
H, 6.63. Found: C, 63.59; H, 6.69.
Gen er a l P r oced u r e for th e Syn th esis of 13-(N-Boc-â-
isobu tylisoser in oyl)ba cca tin [14,1-d ]-3,4-d eh yd r ofu r a n -
2-on e (15) a n d 13-(N-Boc-â-isobu tylisoser in oyl)ba cca tin -
[14,1-d ]fu r a n -2-on e (18). Compound 14 or 17 (0.08 mmol)
was dissolved in CH2Cl2 (3 mL) and cooled to 0 °C. Acetyl
chloride solution in MeOH (0.01 M, 1 mL) was added dropwise.
The reaction mixture was stirred at room temperature and
monitored by TLC. After 24 h, it was quenched with saturated
NH4Cl solution (5 mL), and the organic layer was dried over
Na2SO4 and evaporated. The residue was purified by column
chromatography (EtOAc/cyclohexane ) 1:3-1:2) to afford
compound 15 (54 mg, 85%) or 18 (45 mg, 70%) as a white solid.
15: Rf ) 0.2 (silica, EtOAc/cyclohexane ) 1:1); mp. 149-154
Gen er a l P r oced u r e for th e Syn th esis of 13-[N-Boc-
N,O-(2,4-dim eth oxyben ziliden )-â-isobu tylisoser in oyl]bac-
ca tin [14,1-d ]-3,4-d eh yd r ofu r a n -2-on e (14) a n d 13-[N-Boc-
N,O-(2,4-d im et h oxyb en zilid en )-â-isob u t ylisoser in oyl]-
ba cca tin [14,1-d ]fu r a n -2-on e (17). A solution of 13 or 16
(0.09 mmol) in acetonitrile (3 mL) and pyridine (3 mL) was
cooled to 0 °C. HF-pyridine (0.5 mL) was slowly added under
stirring, and then the reaction mixture was raised to room
temperature and stirred for 24 h. Then it was poured into ice-
water (10 mL) and extracted with CH2Cl2 (2 × 5 mL). The
organic layer was washed with NaHSO4 2 M until pH 2 and
then with NaHCO3 5% (5 mL) and finally with brine (5 mL),
and then it was dried (Na2SO4) and evaporated. The residue
was purified by column chromatography (EtOAc/cyclohexane
) 1:3-1:2) to afford compounds 14 (71 mg, 80%) or 17 (80 mg,
87%) as white solids. 14: Rf ) 0.3 (silica, EtOAc/cyclohexane
°C (CH2Cl2/iPr2O); [R]20 +58 (c 0.9, CHCl3); IR (CDCl3) νmax
D
3514, 3305, 1791, 1758, 1733, 1710, 1695, 1239; 1HNMR (200
MHz, CDCl3) δ 7.95 (d, 2H, J ) 7.4 Hz), 7.42-7.60 (m, 3H),
6.16 (s, 1H), 5.99 (d, 1H, J ) 5.5 Hz), 5.57 (s, 1H), 4.90 (dd, J
) 3.7, 6.2 Hz, 1H), 4.77 (d, 1H, J ) 10.2 Hz), 4.30-4.47 (m,
4H), 3.81 (d, 1H, J ) 5.5 Hz), 3.00 (s, 1H), 2.49-2.61 (m, 1H),
2.45 (s, 3H), 2.27 (s, 3H), 1.84-1.97 (m, 1H), 1.83 (s, 3H), 1.69
(s, 3H), 1.44 (s, 9H), 1.27 (s, 3H), 1.24 (s, 3H), 1.07 (m, 9H);
13C NMR (300 MHz, CDCl3) δ 205.4, 172.0, 171.6, 171.3, 170.0,
164.8, 156.1, 154.8, 139.7, 136.3, 134.0, 130.3, 128.9, 128.4,
115.5, 90.1, 84.6, 81.2, 81.0, 77.8, 76.7, 73.3, 71.9, 68.1, 58.3,
57.4, 51.2, 42.3, 39.1, 38.1, 35.7, 29.9, 29.1, 28.5, 25.0, 23.4,
23.3, 22.4, 21.2, 20.6, 16.4, 9.3. Anal. Calcd for C45H57NO16
:
) 1:1); mp 154-158 °C (i-Pr2O-n-pentane); [R]20 +82 (c 0.9,
D
CHCl3); IR (CDCl3) νmax 3435, 1781, 1738, 1697, 1231; 1H NMR
(200 MHz, CDCl3) δ 7.95 (d, 2H, J ) 7.5 Hz), 7.43-7.59 (m,
3H), 7.22-7.27 (m, 1H), 6.66 (s, 1H), 6.51-6.54 (m, 2H), 5.99
(d, 1H, J ) 5.5 Hz), 5.84 (s, 1H), 5.57 (s, 1H), 5.05-5.13 (m,
1H), 4.90 (d, 1H, J ) 7.0 Hz), 4.70 (s, 1H), 4.42 (m, 1H), 4.32
(d,, 1H J ) 8.8 Hz), 4.28 (d, 1H, J ) 8.8 Hz), 3.89 (s, 3H), 3.86
(d, 1H, J ) 5.5 Hz), 3.84 (s, 3H), 3.03 (s, 1H), 2.49-2.64 (m,
1H), 2.34 (s, 3H), 2.27 (s, 3H), 1.88 (s, 3H), 1.84-1.98 (m, 1H),
1.69 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 1.09 (s, 9H). 13C NMR
(300 MHz, CDCl3) δ 205.6, 172.2, 171.2, 170.1, 169.0, 164.9,
162.1, 159.4, 155.6, 153.5, 139.2, 137.6, 134.3, 130.3, 129.3,
129.1, 128.5, 127.9, 119.0, 114.2, 104.6, 98.9, 90.5, 87.2, 84.7,
81.6, 81.2, 79.8, 76.8, 72.0, 68.3, 59.2, 58.4, 57.5, 55.9, 55.8,
44.0, 39.4, 38.1, 35.8, 30.0, 29.3, 28.5, 25.8, 23.2, 22.9, 22.8,
21.3, 20.8, 16.3, 9.5. Anal. Calcd for C54H65NO18: C, 63.83; H,
6.45. Found: C, 63.69; H, 6.59.
C, 62.27; H, 6.62. Found: C, 62.19; H, 6.70. 18: Rf ) 0.15 (silica,
EtOAc/cyclohexane ) 1:1); mp. 181 °C (i-Pr2O-n-pentane);
[R]20D -36.11 (c 4.32, CHCl3); IR (CDCl3) νmax 3510, 3302, 1790,
1
1756, 1732, 1710, 1698, 1241; H NMR (200 MHz, CDCl3) δ
8.02 (d, 2H, J ) 7.4 Hz), 7.47-7.63 (m, 3H), 6.27 (s, 1H), 6.12
(d, 1H), 6.00 (d, 1H, J ) 7.3 Hz), 4.96 (d, 1H, J ) 7.4 Hz), 4.60
(d, 1H, J ) 9.9 Hz), 4.38 (dd, 1H, J 1 ) 10.6 Hz, J 2 ) 7.3 Hz),
4.27 (s, 2H), 4.20 (s, 1H), 4.15 (d, 1H, J ) 7.0 Hz), 4.11 (d, 1H,
J ) 7.0 Hz), 3.79 (d, 1H, J ) 7.0 Hz), 2.99-3.18 (m, 3H), 2.48-
2.64 (m, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.04 (s, 3H), 1.84-1.97
(m, 1H), 1.89 (s, 3H), 1.72 (s, 3H), 1.32 (s, 9H), 1.25 (s, 3H),
1.22 (s, 3H), 0.95-1.01 (m, 9H); 13C NMR (300 MHz, CDCl3) δ
203.0, 174.0, 173.9, 171.3, 170.2, 164.9, 155.9, 142.1, 134.0,
133.1, 139.9, 129.1, 128.8, 91.4, 84.5, 81.2, 80.4, 78.1, 75.4, 73.0,
72.2, 72.1, 60.6, 58.7, 51.4, 45.2, 42.6, 42.1, 39.8, 35.7, 28.5,
26.6, 25.0, 23.8, 23.5, 22.8, 22.2, 21.0, 15.0, 10.0. Anal. Calcd
for C45H69NO16: C, 62.13; H, 6.84. Found: C, 62.00; H, 6.89.
17: Rf ) 0.25 (silica, EtOAc/cyclohexane ) 1:1); mp 149-
155 °C (i-Pr2O-n-pentane); [R]20 -35 (c 0.6, CHCl3); IR
D
(CDCl3) νmax 3441, 1785, 1741, 1685, 1228; 1H NMR (200 MHz,
CDCl3) δ 8.00 (d, 2H, J ) 7.3 Hz), 7.43-7.62 (m, 3H), 7.22-
7.28 (m, 1H), 6.51-6.58 (m, 2H), 6.23 (d, 1H), 6.04 (d, 1H, J )
7.3 Hz), 4.99 (d, 1H, J ) 7.0 Hz), 4.48-4.54 (m, 2H), 4.33 (d,
1H, J ) 8.8 Hz), 4.25 (d, 1H, J ) 8.8 Hz), 3.90 (s, 3H), 3.85 (s,
3H), 3.84 (d, 1H), 3.00 (m, 1H), 2.56-2.76 (m, 2H), 2.32 (s,
Su p p or tin g In for m a tion Ava ila ble: General techniques
and spectroscopic data for compounds 4-9 and 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0493018
6616 J . Org. Chem., Vol. 69, No. 20, 2004