Synthesis and evaluation of 14-nor-a-secotaxoids

Article abstract of DOI:10.1002/1099-0690(20021)2002:2<277::AID-EJOC277>3.0.CO;2-F

A series of 14-nor-A-secotaxoids has been prepared from 10-deacetyl-14β-hydroxybaccatin III (3a) and some unexpected and new reactivity of the taxane system has been revealed. The observation that the final compounds were considerably less active than taxol and their 1,10-oxygen-bridged ana-logues shows that the 1,10-oxygen tether can partially compensate for the opening of ring A, and suggests that 14-norA-secotaxoids warrant further investigation as simplified taxol mimics. WILEY-VCH Verlag GmbH 2002.

Full text of DOI:10.1002/1099-0690(20021)2002:2<277::AID-EJOC277>3.0.CO;2-F

FULL PAPER
Synthesis and Evaluation of 14-Nor-A-secotaxoids
Giovanni Appendino,*[a] Emanuela Belloro,[a] Erika Del Grosso,[b] Alberto Minassi,[a] and
Ezio Bombardelli[c]
Keywords: Antitumor agents / Natural products / StructureϪactivity relationships / Terpenoids
A series of 14-nor-A-secotaxoids has been prepared from 10-
deacetyl-14β-hydroxybaccatin III (3a) and some unexpected
and new reactivity of the taxane system has been revealed.
The observation that the final compounds were considerably
less active than taxol and their 1,10-oxygen-bridged ana-
logues shows that the 1,10-oxygen tether can partially com-
pensate for the opening of ring A, and suggests that 14-nor-
A-secotaxoids warrant further investigation as simplified
taxol mimics.
With the combined sales of taxol (1a) and taxotere (1b)
approaching two billion dollars in 2000,[1] taxoids are the
most successful anticancer agents ever, and no other class
of natural products has received such worldwide and multi-
disciplinary attention over the past fifteen years.[2] In the
chemical arena, the focus of taxoid research has gradually
moved from the total synthesis of the natural product to
the discovery of more powerful, better tolerated, and easier
to administer newer-generation analogues.[3] Non-oncolog-
ical potential applications of taxoids have also been disco-
vered,[4] with powerful activity against severe conditions
such as Alzheimer’s disease,[4a] polycystic kidney disease,[4b]
arthritis,[4c] and multiple sclerosis.[4d]
The emergence of new clinical targets suggests that the
pharmacological potential of taxoids is still underexploited.
This, as well as the uncertainties still shrouding the mechan-
ism of the anticancer activity of these compounds[5] and the
definition of a taxane pharmacophore,[6] has continued to
inspire the search for new taxane leads. In this context, we
have explored changes of connectivity within the taxane
skeleton, a rigid scaffold, perturbation of which is expected
to have profound effects on the biological activity.[7] The
early observation that the cleavage of the oxetane D ring
results in inactive compounds[8] has long deterred studies in
this area. Nevertheless, both tubulin binding and cytotox-
icity are substantially retained in 7,8-secotaxoids bearing
norstatin-type side-chains,[9] while the A-seco analogue 2
maintains a considerable degree of activity, especially
against multiply drug-resistant cell lines.[10]
The B-ring of 2 is constrained in a rigid conformation by
the 1,10-oxido bridge, and it was therefore interesting to
assess the contribution of this conformational lock to the
overall activity of 14-nor-A-secotaxoids. The key reaction
to cleave ring A is the periodate oxidation of 10-deacetyl-
14β-hydroxybaccatin III (3a), a naturally occurring baccatin
available from the Himalayan yew.[11] This generates a 1-
one, which is trapped by the 10-hydroxy group with forma-
tion of a γ-lactol ring (Scheme 1). Acetylation of the 10-
hydroxy group before the periodate oxidation would pre-
vent formation of the oxido bridge, and further simplify
comparison with taxol, in which the 10-hydroxy function is
acetylated. The synthesis of ring B unconstrained A-nor-A-
secobaccatins and their esterification with side-chains of the
phenylisoserine and the norstatin types became the target
of our investigation. As usual with highly functionalized
molecules like taxoids, the synthesis of these compounds
was plagued by unexpected reactions and complications.
10-Deacetyl-14β-hydroxybaccatin III (3a) has four
acetylable hydroxy groups, the order of esterification of
which under basic or nucleophilic catalysis conditions is 7
Ͼ 14 Ͼ 10 ϾϾ 13.[11] However, we were delighted to ob-
serve that the acyloin hydroxy group could be chemoselec-
tively acetylated by Lewis acid catalysis under the
ScheerenϪHolton conditions (cat. CeCl3, Ac2O, THF).[12]
[a]
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche
e Farmacologiche,
V.le Ferrucci 33, 28100 Novara, Italy
E-mail: appendin@pharm.unito.it
[b]
Dipartimento di Scienza e Tecnologia del Farmaco,
Via Giuria 9, 10125 Torino, Italy
[c]
Indena S.p.A.,
V.le Ortles 12, 20139 Milano, Italy
Eur. J. Org. Chem. 2002, 277Ϫ283
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1434Ϫ193X/02/0102Ϫ0277 $ 17.50ϩ.50/0
277

G. Appendino, E. Belloro, E. Del Grosso, A. Minassi, E. Bombardelli
FULL PAPER
Scheme 1. Periodate cleavage of 10-deacetyl-14β-hydroxybaccatin
III[10]
This gave the 10-acetyl derivative 3b in 90% yield
(Scheme 2). Remarkably, protection of the 7-hydroxy func-
tion as a silyl group changed the selectivity of the reaction,
affording, in low yield (10%), the 14-acetyl derivative 3d as
the only reaction product (Scheme 2). A possible explana-
tion for these observations is that the Lewis acid forms a
chelate with the 10-hydroxy and the 9-carbonyl moieties
and that formation of this complex somewhat activates the
10-hydroxy group toward esterification, possibly by coor-
dination of the acetylating reagent to cerium and intramole-
cular acyl delivery. The capacity of Lewis acids to promote
the esterification of acyloin-type hydroxy groups, even ter-
tiary ones, had been observed previously,[13] and silylation
of the 7-hydroxy group apparently prevents formation of
the acyloinϪLewis acid complex, possibly because of
steric hindrance.
Scheme 2. Synthesis of the 14-nor-A-secobaccatins 6؊8
Treatment of 3b with periodic acid in dioxane/water gave
the unstable nor-dioxoaldehyde 4a (Scheme 2), which was
contaminated by a more polar by-product (ca. 20%, 1H
NMR analysis). The amount of the more polar impurity
increased when the reaction was allowed to proceed after tone 1,9-ether 5 was preferred over the alternative arrange-
complete consumption of the starting material, suggesting ment, namely a 13,1-γ-lactone 9,15-ether, because the chem-
that further oxidation and/or rearrangement of 4a was tak- ical shift of C-13 (δ ϭ 172.7) was typical of a δ-lactone
ing place. After silylation, a mixture amenable to chromato- and not of a γ-lactone, which would have resonated at δ ഠ
graphic purification was obtained, and the silylated dioxoal- 178Ϫ180.[14] The very low field resonance of C-1 [δ ϭ 101.1
dehyde 4b and the A-seco-14-nor-11(15Ǟ1)-abeo derivative (s)] could also be more easily accommodated in a tetrahy-
1
5 were obtained as pure compounds. The H NMR spec- drofuran rather than in a tetrahydropyran structure.[15]
trum of 5 (Scheme 3) was at first glance similar to that of Formation of the by-product 5 is presumably triggered by a
a baccatin derivative, lacking the signals of the 13- and 14- WagnerϪMeerwein rearrangement of 4a. Closure of a 1,9-
protons. However, the 13C NMR spectrum revealed dra- hemiacetal bridge, quenching of the 15-cation by the hy-
matic differences. Thus, in comparison with the starting drate form of the 13-aldehyde carbonyl group and eventual
material, the endocyclic double bond was replaced by two lactol-to-lactone oxidation (Scheme 3) would then afford
oxygenated quaternary carbon atoms [δ ϭ 88.2 and 88.3 the final structure. It is not clear at what stage the dihy-
(s)], the 9-carbonyl by an acetal group [δ ϭ 106.3 (s)], and droxylation of the endocyclic double bond takes place.
the oxymethine groups at C-13 and C-14 by an ester car- While the WagnerϪMeerwein rearrangement of 1-oxygen-
bonyl group [δ ϭ 172.7 (s)]. HRMS confirmed the nor- ated taxanes is well documented,[7,8] the dihydroxylation of
taxoid nature of the compound and established the molecu- a carbonyl-conjugated double bond under the conditions of
lar formula as C36H50O14Si, while HMBC experiments cla- periodate cleavage is, to the best of our knowledge, unpre-
rified the carbonϪcarbon connectivity and the 11Ǟ15-abeo cedented. Also remarkable is the observation that no over-
nature of the nortaxane skeleton. Analysis of the long- oxidation took place during the periodate cleavage of 3a,
1
range H-13C correlations left the location of the two pos- the 10-deacetyl derivative of 3b. The compact shape of the
sible oxygen bridges required by the molecular formula un- rearranged product 5 resulted in many diagnostic NOE ef-
defined, since all potentially involved carbon atoms were fects, which were instrumental in the assignment of its con-
nonprotonated. Of the possible alternatives, the 13,15-δ-lac- figuration. Especially useful were the NOE correlations be-
278
Eur. J. Org. Chem. 2002, 277Ϫ283

Synthesis and Evaluation of 14-Nor-A-secotaxoids
FULL PAPER
tween the 18-methyl group and 10-H and between the 15β- process.[17] Treatment of 7 and 8 with activated MnO2 took
methyl group and 2-H.
a very different course. While 7 afforded the crystalline δ-
lactone 9 in almost quantitative yield, its isomer 8 gave a
complex mixture that was not further investigated.
With the three A-secobaccatins 6, 7, and 8 to hand, their
esterification with compact synthons of the aminoacyl side
chains of first- and second-generation anticancer taxoids
was investigated.[18] Treatment with the N,O-(2,4-dimethoxy-
benzal) derivatives 10a and 10b[19] was uneventful with all
three compounds, the presence of the tautomeric equilib-
rium in 6 and of a free secondary hydroxy group at C-1 in
7 notwithstanding (Scheme 4).
Scheme 3. Possible mechanism of the formation of the 14-nor-A-
seco-11(15Ǟ1)-abeo-taxane 5
The aldehyde carbonyl group of 4b could be chemoselec-
tively reduced with NaBH3CN in the presence of the ketone
carbonyl groups at C-1 and C-9, affording the correspond-
ing 13-ol. This was shown by NMR to be a tautomeric mix-
ture (4:1 in CDCl3 at room temp.) of the δ-lactol 6a and
the hydroxy ketone 6b (Scheme 2). The former was anomer-
ically pure, because only one face of the cyclooctanone car-
bonyl group can be approached intramolecularly by the
primary 13-hydroxy group. Reduction of the tautomeric
mixture gave different compounds depending on the sol-
vent. Thus, when the reaction was carried out in methanol,
the 1-hydroxy derivative 7 was obtained as the only reaction
product, and the same result was observed in ethanol and
in 2-propanol. However, the hemiacetal 8 was selectively
formed when methanol was replaced with dioxane. The re-
duction products 7 and 8 share the same molecular formula
(C36H52O10Si). The major difference in their 13C NMR
spectra was the replacement of the 9-carbonyl signal with
an acetal carbon signal in 8 [δ ϭ 97.9 (s)], showing that
an acetal bridge had formed between C-9 and the hydroxy
function at C-1. Since 7 and 8 did not interconvert in solu-
tion or in acidic medium, they thus had different configura-
tions at C-1. The splitting pattern of 1-H was indeed differ-
ent [δ ϭ 3.40 (s) in 7; δ ϭ 4.01 (d, J ϭ 9.0 Hz) in 8], but not
diagnostic for a configurational assignment, which could,
however, be done with the aid of NOE difference experi-
ments. Thus, the detection in 8 of NOE effects between 7-
H and 10-H and between 3-H and the α-methyl group at
C-15 (17-H3)[16] showed that these atoms were syn-oriented,
a condition requiring a β-oxygen bridge between C-1 and
C-9. Conversely, these NOE effects were absent in the α-
Scheme 4. Esterification of the 14-nor-A-secobaccatins 6؊8 with
amino acid side chains
Deprotection with acidic methanol or formic acid eventu-
alcohol 7, the NOE effects pattern of which (16-H3,19-H3; ally afforded the taxoids 11a, 11b, 12, 13a, and 13b, which
2-H,19-H3; 10-H,3-H) showed an overall shape more sim- were evaluated for cytotoxicity in MCF7 breast cancer cells
ilar to that of ring B of taxanes. We do not at present have (Table 1). Compounds 11a, 11b, 13a, and 13b showed mark-
a compelling explanation for the complementary stereo- edly decreased activities compared not only to taxol
chemical courses of the borohydride reduction in alcohol (500Ϫ800fold) but also to its 1,9-oxygen bridged A-seco
and in dioxane. The poor solubility and solvation of analogue 2 (10Ϫ20fold),[10] while 12, despite substantial re-
NaBH4 in dioxane means that a 13-alkoxyborohydride tention of the taxane conformation in rings B and C, was
might actually be the reducing species in dioxane, resulting inactive. These data show that the 1,10-oxygen bridge has
in intramolecular hydride delivery from the α-face of the C- an important effect on activity, acting as a partial surrogate
1 carbonyl group, the only one available for this type of for ring A. In sharp contrast to C-secotaxoids,[9] no major
Eur. J. Org. Chem. 2002, 277Ϫ283
279

G. Appendino, E. Belloro, E. Del Grosso, A. Minassi, E. Bombardelli
FULL PAPER
3.81 (d, J ϭ 8.0 Hz, 3-H), 4.01 (br. d, J ϭ 4.0 Hz, 14-H), 4.20 (d,
J ϭ 8.0 Hz, 20b-H), 4.29 (d, J ϭ 8.0 Hz, 20a-H), 4.44 (m, 7-H),
4.76 (br. s, 13-H), 4.98 (br. d, J ϭ 8.0 Hz, 5-H), 5.81 (d, J ϭ 8.0 Hz,
2-H), 6.31 (s, 10-H), 7.44 (BBЈ-Bz); 7.61 (C-Bz); 8.08 (AAЈ-Bz).
HRMS (70 eV): m/z ϭ 602.2371 (calcd. for C31H38O12 602.2363).
differences in activity were observed between compounds
bearing phenylisoserine and norstatin chains.
Table 1. Biological evaluation of the 14-nor-A-secotaxoids
11a,bϪ13a,b
Acetylation of 10-deacetyl-7-triethylsilyl-14β-hydroxybaccatin III
(3c): Ac2O (110 µL, 1.1 mmol, 4 mol-equiv.) and CeCl3·7H2O (ca.
5 mg) were added to a solution of 3c (200 mg, 0.28 mmol) in dry
THF (3 mL). After stirring at room temp. for 24 h, the reaction
mixture was worked up by dilution with EtOAc and washing with
sat. NaHCO3. Removal of the solvent left a paste, which was puri-
fied by column chromatography (3 g of silica gel; hexane/EtOAc,
4:6, as eluent) to give 21 mg (10%) of 3d and 149 mg of recovered
3c. Compound 3d was obtained as a white powder, m.p. 235 °C.
Compound
IC50 [n]
Taxol (1a)
2
11a
11b
12
13a
13b
1.7
79
800
900
Ͼ 10000
1500
1100
[α]2D5 ϭ Ϫ56 (c ϭ 0.60, CH2Cl2). IR (KBr): ν ϭ 3490, 1760, 1740,
˜
1530, 1220, 1100, 1025, 830 cmϪ1. 1H NMR (CDCl3): δ ϭ 0.63 (m,
TES), 0.94 (m, TES), 1.07 (s, 16-H3), 1.14 (s, 17-H3), 1.77 (s, 19-
H3), 1.90 (m, 6b-H), 1.99 (s, OAc), 2.18 (br. s, 18-H3), 2.37 (s, OAc),
2.50 (m, 6a-H), 2.71 (s, OH), 3.14 (s, OH), 3.95 (d, J ϭ 8.0 Hz, 3-
H), 4.24 (d, J ϭ 8.0 Hz, 20b-H), 4.28 (d, J ϭ 8.0 Hz, 20a-H), 4.30
(s, OH), 4.43 (dd, J ϭ 10.3, 6.2 Hz, 7-H), 4.73 (br. s, 13-H), 4.95
(br. d, J ϭ 9.0 Hz, 5-H), 5.20 (s, 10-H), 5.35 (d, J ϭ 5.1 Hz, 14-H),
5.79 (d, J ϭ 8.0 Hz, 2-H), 7.46 (BBЈ-Bz); 7.60 (C-Bz); 8.03 (AAЈ-
Bz). HRMS (70 eV): m/z ϭ 602.2371 (calcd. for C31H38O12
Conclusions
A series of five 14-nor-A-secotaxoids has been prepared
from 10-deacetyl-14β-hydroxybaccatin III (3a), revealing
some new and unexpected reactivity of taxane derivatives.
The final compounds were either inactive or considerable
less cytotoxic than their 1,10-bridged analogue 2 and taxol. 602.2363).
Nevertheless, the preservation of a lower micromolar cyto-
Periodate Cleavage of 14β-Hydroxybaccatin III (3b): Aq.
toxicity and the existence of definite structureϪactivity re-
lationships show that 14-nor-A-secotaxoids warrant further
investigation as simplified taxol analogues.
H5IO6·2H2O (0.5 , 34.3 mL, 17.20 mmol, 2.4 mol-equiv.⁾ was ad-
ded to a solution of 3b (4.31 g, 7.14 mmol) in dioxane (40 mL).
After stirring overnight, the reaction mixture was worked up by
dilution with sat. NaHCO3 (100 mL) and extraction with EtOAc.
The organic phase was sequentially washed with 5% Na2S2O3 and
brine, and then dried. The solvents were evaporated to give 4.1 g
of crude 4a as an unstable, amorphous powder, containing ca. 20%
(1H NMR analysis) of the overoxidation product. 1H NMR
(CDCl3): δ ϭ 1.38 (s, 16-H3), 1.44 (s, 19-H3), 1.48 (s, 17-H3), 1.88
(s, 18-H3), 1.88 (m, 6b-H), 2.06 (s, 4-OAc), 2.20 (s, 10-OAc), 2.55
Experimental Section
General: Column chromatography: Merck silica gel. IR: Shimadzu
DR 8001 spectrophotometer. Optical rotations: PerkinϪElmer 192
polarimeter, equipped with a sodium lamp (λ ϭ 589 nm) and a 10-
cm microcell. NMR: Bruker AM 500 (500 MHz and 125 MHz for (m, 6a-H), 3.06 (d, J ϭ 4.4 Hz, OH), 3.74 (d, J ϭ 11.1 Hz, 3-H),
1H and 13C, respectively). For 1H NMR, CDCl3 as solventand ref-
4.42 (d, J ϭ 11.2 Hz, 20a-H), 4.69 (d, J ϭ 11.2 Hz, 20b-H), 4.74
erence (δ ϭ 7.26). For 13C NMR, CDCl3 as solvent and reference (m, 7-H), 4.93 (dd, J ϭ 10.2 Hz, 5-H), 5.87 (d, J ϭ 11.1 Hz, 2-H),
(δ ϭ 77.0). The 1H and 13C NMR spectra of all final products and 6.44 (s, 10-H), 7.51 (BBЈ-Bz), 7.64 (C-Bz), 7.94 (AAЈ-Bz), 10.54 (s,
the key intermediates were fully assigned by a combination of 1D
H-13). HRMS (70 eV): m/z ϭ 570.2100 (calcd. for C30H34O11
and 2D (COSY, HMBC, HMQC, ROESY) techniques. CH2Cl2 was 570.2101).
dried by distillation from CaH2, and THF by distillation from Na/
Silylation of the Secotaxoid 4a: Imidazole (2.35 g, 34.50 mmol, 5
benzophenone. Na2SO4 was used to dry solutions before concen-
tration. Reactions were monitored by TLC on Merck 60 F254
(0.25 mm) plates, which were viewed by UV inspection and/or
staining with 5% H2SO4 in ethanol and heating. All compounds
were crystallized from ether, unless indicated otherwise. Cytotox-
icity assays were carried out according to an established literature
procedure.[20]
mol-equiv.) and triethylsilyl chloride (TES-Cl, 5.80 mL, 5.21 g,
34.51 mmol, 5 mol-equiv.) were added to a mixture of 4a and its
overoxidation product (3.94 g, 6.90 mmol based on the molecular
mass of 4a) in dry DMF (25 mL). After stirring at room temp. for
12 h, the reaction mixture was worked up by dilution with water
(100 mL) and addition of Celite (2 g). The reaction mixture was
then filtered through a bed of Celite, and the cake was washed
several times with water to remove DMF, and eventually with
Acetylation of 10-Deacetyl-14β-hydroxybaccatin III (3a): Ac2O
(2.68 mL, 28.6 mmol, 4 mol-equiv.) and CeCl3·7H2O (266 mg, EtOAc to recover the silylated products. After drying and concen-
0.71 mmol, 0.1 mol-equiv.) were added to a solution of 3a (4.0 g, tration, the residue was purified by column chromatography (hex-
7.14 mmol) in dry THF (25 mL). After stirring at room temp. for ane/EtOAc gradient, from 9:1 to 7:3) to give 4b (3.4 g, 72%) and 5
18 h, the reaction mixture was worked up by dilution with EtOAc (779 mg, 15%). Compound 4b was obtained as a white powder,
˜
and washing with sat. NaHCO3. The solid residue obtained after
removal of the solvent was washed with ether to give 3.6 g (90%)
of 3b as a white powder, m.p. 230Ϫ234 °C. [α]2D5 ϭ Ϫ48 (c ϭ 0.42,
m.p. 143Ϫ147 °C. [α]2D5 ϭ Ϫ10 (c ϭ 0.46; CH2Cl2). IR (KBr): ν ϭ
3453, 1755, 1738, 1732, 1728, 11689, 1675, 1586, 1376, 1227, 1090
1
cmϪ1. H NMR (CDCl3): δ ϭ 0.63 (m, TES), 0.91 (m, TES), 1.44
˜
CH2Cl2). IR (KBr): ν ϭ 3475, 1740, 1717, 1401, 1240, 1049, 716 (s, 16-H), 1.46 (s, 19-H3), 1.50 (s, 17-H3), 1.98 (s, 18-H3), 2.11 (s,
cmϪ1. 1H NMR (CDCl3): δ ϭ 1.13 (s, 16-H3), 1.16 (s, 17-H3), 1.68 4-OAc), 2.16 (s, 10-OAc), 3.94 (d, J ϭ 8.5 Hz, 3-H), 4.52 (d, J ϭ
(s, 19-H3), 1.87 (m, 6b-H), 2.06 (br. s, 18-H3), 2.26 (s, OAc), 2.31 8.6 Hz, 20b-H), 4.62 (m, 7-H), 4.63 (d, J ϭ 8.6 Hz, 20a-H), 4.92
(s, OAc), 2.55 (m, 6a-H), 2.68 (s, OH), 3.05 (s, OH), 3.30 (s, OH), (dd, J ϭ 8.3 Hz, 5-H), 5.72 (d, J ϭ 8.5 Hz, 2-H), 6.77 (s, 10-H),
280
Eur. J. Org. Chem. 2002, 277Ϫ283

Synthesis and Evaluation of 14-Nor-A-secotaxoids
10.24 (s, 13-H), 7.50 (BBЈ-Bz), 7.66 (C-Bz), 7.94 (AAЈ-Bz). HRMS the solvents were evaporated to give a white powder. Purification
FULL PAPER
(70 eV): m/z ϭ 684.2956, (calcd. for C36H48O11Si, 684.2966). Com-
by column chromatography (5 g of silica gel; hexane/EtOAc, 8:2,
pound 5 was obtained as a white powder, m.p. 117Ϫ123 °C. [α]2D5
ϭ
as eluent) gave 7 (147 mg, 74%) as white crystals, m.p. 90Ϫ96 °C
ϩ1 (c ϭ 0.42; CH2Cl2). IR (KBr): ν˜ ϭ 3429, 3228, 1777, 1738, (toluene/ether). [α]2D5 ϭ Ϫ72 (c ϭ 0.58; CH2Cl2). IR (KBr): ν˜ ϭ
1
1453, 1375, 1267, 1244, 1200, 1088, 999 cmϪ1. H NMR (CDCl3): 3432, 1748, 1721, 1603, 1561, 1372, 1273, 111, 1016, 993, 713.7;
δ ϭ 0.68 (m, TES), 0.97 (t, J ϭ 7.0 Hz, TES), 1.14 (s, 17-H3), 1.38 993 cmϪ1 1H NMR (CDCl3) δ ϭ 0.63 (q, TES), 0.92 (t, J ϭ
.
(s, 16-H3), 1.56 (s, 18-H3), 1.82 (s, 19-H3), 2.01 (m, 6b-H), 2.26 (s, 7.4 Hz, TES), 1.19 (s, 17-H3), 1.35 (s, 16-H3), 1.53 (s, 19-H3), 1.92
OAc), 2.35 (s, OAc), 2.41 (m, 6a-H), 3.41 (br. d, J ϭ 9.0 Hz, 3-H), (m, 6b-H), 2.12 (s, 18-H3), 2.15 (s, 4-OAc), 2.22 (s, 10-OAc), 2.63
4.09 (d, J ϭ 8.0 Hz, 20b-H), 4.68 (dd, J ϭ 10.8 Hz, 7-H), 4.88 (d, (m, 6a-H), 3.40 (s, 1-H), 3.69 (s, OH), 4.11 (d, J ϭ 9.0 Hz, 3-H),
J ϭ 8.0 Hz, 20a-H), 4.91 (dd, J ϭ 9.2 Hz, 5-H), 5.74 (s, 10-H), 6.75
4.22 (d, J ϭ 12.0 Hz, 13b-H), 4.35 (d, J ϭ 8.0 Hz, 20b-H), 4.53
(d, J ϭ 9.0 Hz, 2-H), 7.53 (BBЈ-Bz), 7.60 (br. s, OH), 7.67 (C-Bz), (dd, J ϭ 10.8 Hz, 7-H), 4.54 (d, J ϭ 8.0 Hz, 20a-H), 4.85 (d, J ϭ
8.12 (AAЈ-Bz). Selected HMBC correlations: 2-H,C-3; 2-H,C-8; 2-
H,CϭOBz; 3-H,C-19; 5-H,C-4; 5-H,C-7; 6a-H,C-8; 6b-H,C-7; 7-
12.0 Hz, 12a-H), 4.99 (br. d, J ϭ 8.0 Hz, 5-H), 5.35 (d, J ϭ 9.0 Hz,
2-H), 6.56 (s, 10-H), 7.47 (BBЈ-Bz), 7.61 (CBz), 7.98 (AAЈ-Bz). Se-
lected NOEs: 2-H,1-H; 3-H,7-H; 10-H,7-H; 10-H,18-H3; 16-H3,1-
H,C-19; 10-H,C-11; 10-H,C-12; 10-H,C-1; 10-H,C-9; 10-H,CϭOAc
;
16-H3,C-17; 16-H3,C-15; 16-H3,C-1; 18-H3,C-11; 18-H3,C-12; 18- H; 16-H3,13a-H; 16-H3,13b-H; 17-H3,1-H; 2-H,10-OAc; 18-H3,2-
H3,C-13; 19-H3,C-4; 19-H3,C-8; 19-H3,C-7; 19-H3,C-9; OH,C-10.
H; 6a-H,20a-H. 13C NMR (CDCl3): δ ϭ 5.5 (t, TES), 7.0 (q, TES),
13C NMR (CDCl3): δ ϭ 5.0 (t, TES), 6.5 (q, TES), 9.9 (q, C-19), 9.6 (q, C-17), 19.6 (q, C-18), 21.0 (q, Ac), 22.1 (q, Ac), 27.4 (q, C-
14.7 (q, C-18), 19.3 (q, C-17), 21.0 (q, Ac), 21.5 (q, Ac), 22.8 (q, 19), 31.2 (q, C-16), 38.0 (t, C-6), 38.1 (d, C-3), 43.1 (s, C-15), 57.8
C-16), 36.4 (t, C-6), 42.6 (d, C-3), 48.5 (s, C-8), 68.8 (d, C-2), 70.4 (s, C-8), 65.4 (t, C-13), 72.4 (d, C-7), 72.7 (d, C-2), 77.3 (t, C-20),
(d, C-10), 72.8 (d, C-7), 75.6 (t, C-20), 79.3 (s, C-4), 83.6 (d, C-5), 77.9 (d, C-10), 81.0 (d, C-1), 81.0 (s, C-4), 84.5 (d, C-5), 128.7 (d,
88.3 (s, C-11*), 88.3 (s, C-12*), 90.5 (s, C-15), 101.1 (s, C-1), 106.3 Bz), 129.0 (s, Bz), 129.6 (d, Bz), 132.4 (s, C-11), 133.8 (d, Bz), 146.2
(s, C-9), 128.7 (d, Bz), 128.9 (s, Bz), 130.2 (d, Bz), 134.3 (d, Bz), (s, C-12), 164.3 (s, Ac), 164.3 (s, Bz), 172.1 (s, Ac), 206.1 (s, C-9).
165.3 (s, Bz), 167.6 (s, Ac), 169.8 (s, Ac), 172.7 (s, C-13). HRMS HRMS (70 eV): m/z ϭ 688.3280 (calcd. for C36H52O11Si, 688.3279).
(70 eV): m/z ϭ 734.2984 (calcd. for C36H50O14Si 734.2970).
Ϫ B) With NaBH4 in Dioxane: An excess of NaBH4 (825 mg) was
added to a solution of 6 (658 mg, 0.96 mmol) in dioxane (7 mL).
The suspension was stirred at room temp. for 48 h, and then
worked up by washing with sat. NH4Cl and extraction with EtOAc.
The organic phase was washed with brine and dried, and the solv-
ents were evaporated to give recovered 6 (127 mg) and 8 (365 mg,
55%) as a white powder, m.p. 168Ϫ171 °C. [α]2D5 ϭ Ϫ49 (c ϭ 0.67;
CH2Cl2). IR (KBr): ν˜ ϭ 3453, 1748, 1721, 1603, 1372, 1273, 1235,
Reduction of 4b with NaBH3CN: An excess of NaBH3CN (3.4 g)
was added portionwise over 2 h to a solution of 4b (3.4 g,
5.01 mmol) in MeOH (22 mL)/acetate buffer (22 mL). After stir-
ring at room temp. for an additional 4 h, the reaction mixture was
worked up by dilution with sat. NaHCO3 and extraction with
EtOAc. After having been washed with brine, the residue was con-
centrated and the residue was purified by column chromatography
(25 g of silica gel; hexane/EtOAc, 9:1, as eluent) to afford 6 (1.73 g,
51%) as a white powder, m.p. 134Ϫ139 °C. [α]2D5 ϭ Ϫ49 (c ϭ 0.5;
CH2Cl2). IR (KBr): ν˜ ϭ 3432, 1748, 1721, 1372, 1109, 826, 710;
1
1112, 1017, 996, 714 cmϪ1. H NMR (CDCl3) δ ϭ 0.76 (m, TES),
1.06 (t, J ϭ 7.0 Hz, TES), 1.38 (s, 16-H3), 1.43 (s, 17-H3), 1.65 (s,
19-H3), 1.95 (m, 6b-H), 2.04 (s, 18-H3), 2.09 (s, OAc), 2.12 (s, OAc),
2.55 (m, 6a-H), 3.38 (d, J ϭ 12.0 Hz, 3-H), 3.98 (d, J ϭ 10.0 Hz,
13b-H), 4.01 (d, J ϭ 9.0 Hz, 1-H), 4.31 (d, J ϭ 8.0 Hz, 20b-H),
4.38 (d, J ϭ 8.0 Hz, 20a-H), 4.55 (d, J ϭ 10.0 Hz, 13a-H), 4.60
(dd, J ϭ 10.8 Hz, 7-H), 4.68 (s, OH), 4.92 (d, J ϭ 8.0 Hz, 5-H),
5.83 (dd, J ϭ 12.0, 9 Hz, 2-H), 6.14 (s, 10-H), 7.46 (BBЈ-Bz), 7.59
(C-Bz), 8.03 (AAЈ-Bz). 13C NMR (CDCl3): δ ϭ 5.5 (t, TES), 6.9
(q, TES), 9.4 (q, C-17), 20.1 (q, C-18), 21.2 (q, Ac), 21.5 (q, Ac),
27.7 (q, C-19), 32.2 (q, C-16), 36.6 (t, C-6), 39.9 (d, C-3), 40.1 (s,
C-15), 46.7 (s, C-8), 63.9 (t, C-13), 69.2 (d, C-7), 69.7 (d, C-2), 71.8
(d, C-10), 73.4 (d, C-10), 80.6 (d, C-1), 84.0 (s, C-4), 84.0 (d, C-5),
98.0 (s, C-9), 128.9 (d, Bz), 129.0 (s, Bz), 129.6 (d, Bz), 133.4 (s, C-
11), 134.7 (d, Bz), 137.5 (s, C-12), 165.5 (s, Bz), 170.0 (s. OAc),
825 cmϪ1 1H NMR (CDCl3): Tautomer 6a: δ ϭ 0.58 (m, TES),
.
0.94 (m, TES), 1.19 (s, 17-H3), 1.29 (s, 16-H3), 1.69 (s, 19-H3), 1.90
(m, 6b-H), 2.14 (br. s, 18-H3), 2.20 (s, 4-OAc), 2.28 (s, 10-OAc),
2.57 (m, 6a-H), 3.87 (d, J ϭ 7.2 Hz, 3-H), 3.99 (d, J ϭ 16.1 Hz,
13a-H), 4.21 (d, J ϭ 8.2 Hz, 20b-H), 4.29 (d, J ϭ 8.2 Hz, 20a-H),
4.48 (dd, J ϭ 10.0, 8.3 Hz, 7-H), 4.83 (d, J ϭ 16.1 Hz, 13b-H), 4.98
(d, J ϭ 7.9 Hz, 5-H), 5.67 (d, J ϭ 7.2 Hz, 2-H), 6.43 (s, 10-H), 7.48
(BBЈ-Bz), 7.61 (C-Bz), 8.12 (AAЈ-Bz). Tautomer 6b: δ ϭ 0.58 (m,
TES), 0.94 (m, TES), 1.35 (s, 16-H3), 1.52 (s, 17-H3), 1.62 (s, 19-
H3), 2.12 (br. s, 18-H3), 2.19 (s, 4-OAc), 2.48 (s, 10-OAc), 4.14 (d,
J ϭ 8.0 Hz, 20b-H), 4.21 (d, J ϭ 8.0 Hz, 20a-H), 4.54 (m, 7-H),
4.62 (d, J ϭ 9.0 Hz, 13b-H), 4.74 (d, J ϭ 9.0 Hz, 13a-H), 5.49 (d,
J ϭ 8.0 Hz, 5-H), 5.52 (d, J ϭ 6.2 Hz, 2-H), 6.71 (s, 10-H), 7.49
(BBЈ-Bz), 7.61 (C-Bz); 8.03 (AAЈ-Bz).13C NMR (CDCl3): Tauto-
mer 6a: δ ϭ 5.4 (t, TES), 6.9 (q, TES), 10.1 (q, C-19), 17.2 (q, C-
18), 20.9 (q, C-16), 21.6 (q, Ac), 22.0 (q, Ac), 25.4 (q, C-17), 38.0
(t, C-6), 42.4 (s, C-15), 45.0 (d, C-3), 59.1 (s, C-8), 69.8 (t, C-13),
72.8 (d, C-7), 72.9 (d, C-2), 75.1 (d, C-10), 76.6 (t, C-20), 80.9 (s,
C-4), 84.1 (d, C-5), 102.2 (s, C-1), 128.6 (d, Bz), 129.0 (s, Bz), 130.2
(d, Bz), 132.6 (s, C-11), 133.6 (s, Bz), 134.2 (d, Bz), 146.6 (s, C-12),
165.6 (s, Ac), 170.4 (s, Ac), 202.2 (s, C-9). Diagnostic signal of
tautomer 6b: δ ϭ 204.6 (s, C-1). HRMS (70 eV): m/z ϭ 686.3118
(calcd. for C36H50O11Si 686.3122).
170.3 (s, Ac). HRMS (EI): m/z
ϭ 688.3288 (calcd. for
C36H52O10Si 688.3279).
Oxidation of the Diol 7 to the Lactone 9: Commercial (Merck) ac-
tivated MnO2 (1.4 g) was added to a solution of 7 (140 mg,
2.02 mmol) in toluene (5 mL). After stirring overnight at room
temp., the reaction mixture was worked up by filtration to give 9
(136 mg, 98%) as a white powder, m.p. 122Ϫ124 °C. [α]2D5 ϭ Ϫ129
˜
(c ϭ 0.50; CH2Cl2). IR (KBr): ν ϭ 1725, 1603, 1586, 1279, 1250,
1
1165, 1065, 984, 714 cmϪ1. H NMR (CDCl3) δ ϭ 0.58 (q, TES),
0.92 (t, J ϭ 7.4 Hz, TES), 1.23 (s, 17-H3), 1.31 (s, H-16/3), 1.67
(s,19-H3), 1.89 (m, 6b-H), 2.21 (s, OAc), 2.25 (s, OAc), 2.36 (br. s,
18-H3), 2.60 (m, 6a-H), 3.72 (d, J ϭ 7.0 Hz, 3-H), 4.13 (d, J ϭ
Reduction of 6. ؊ A) With NaBH4 in Methanol: An excess of 8.0 Hz, H-20b), 4.24 (s, 1-H), 4.40 (d, J ϭ 8.0 Hz, H-20a), 4.53 (dd,
NaBH4 (100 mg) was added to a solution of 6 (200 mg, 0.29 mmol) J ϭ 10.8 Hz, H-7), 4.54 (dd, J ϭ 10.5, 8.0 Hz, H-7), 5.01 (br. d,
in MeOH (5 mL). After stirring for 10 min at room temp., the reac- J ϭ 9.0 Hz, H-5), 5.55 (d, J ϭ 7.0 Hz, H-2), 6.46 (s, H-10), 7.47
tion mixture was worked up by quenching with NH4Cl and extrac-
(BBЈ-Bz), 7.61 (CBz), 8.09 (AAЈ-Bz). 13C NMR (CDCl3) δ ϭ 5.2
tion with EtOAc. The organic phase was washed with brine and (t, TES), 7.0 (q, TES), 10.0 (q, C-19), 15.3 (q, C-18), 20.7 (q, Ac),
Eur. J. Org. Chem. 2002, 277Ϫ283
281

G. Appendino, E. Belloro, E. Del Grosso, A. Minassi, E. Bombardelli
21.07 (q, C-16), 21.6 (q, Ac), 33.9 (q, C-17), 37.1 (s, C-15), 37.5 (t, Compound 13a: White powder, m.p. 115Ϫ120 °C. [α]2D5 ϭ Ϫ31 (c ϭ
FULL PAPER
˜
C-6), 43.0 (d, C-3), 60.1 (s, C-8), 69.1 (d, C-7), 72.3 (d, C-10), 75.2 0.42; CH2Cl2) IR (KBr): ν ϭ 3432, 1736, 1725, 1659, 1520, 1487,
1
(t, C-20), 79.9 (s, C-1), 83.8 (d, C-5), 85.2 (s, C-1), 128.6 (d, Bz), 1372, 1273, 1107, 1065, 713 cmϪ1. H NMR (CDCl3): δ ϭ 1.28 (s,
129.0 (s, Bz), 130.0 (d, Bz), 133.2 (d, Bz), 133.9 (s, C-12), 145.3 (s,
16-H3), 1.42 (s, 17-H3), 1.66 (s, 19-H3), 1.87 (s, 18-H3), 2.10 (s,
C-11), 164.7 (s, C-13), 165.3 (s, Bz), 168.9 (s, OAc), 170.9 (s, Ac), OAc), 2.16 (s, OAc), 3.19 (d, J ϭ 12.0 Hz, 3-H), 4.02 (d, J ϭ 4.0 Hz,
200.1 (s, C-9). HRMS (70 eV): m/z ϭ 684.2990 (calcd. for
C36H48O11Si 684.2966).
1-H), 4.32 (d, J ϭ 8.0 Hz, 20b-H), 4.37 (d, J ϭ 8.0 Hz, 20a-H),
4.58 (dd, J ϭ 10.8 Hz, 7-H), 4.95 (d, J ϭ 8.0 Hz, 5-H), 5.22 (d,
J ϭ 12.0 Hz, 13a-H), 5.74 (dd, J ϭ 8.5, 2 Hz, 3Ј-H), 5.82 (dd, J ϭ
12.4 Hz, 2-H), 6.21 (s, 10-H), 6.90 (d, J ϭ 8.5 Hz, NH), 7.30 (m,
arom.), 7.60 (m, arom), 7.73 (AAЈ-NHBz), 8.02 (AAЈ-OBz).
HRMS (70 eV): m/z ϭ 825.3351 (calcd. for C46H51NO13 825.3360).
Coupling of Secobaccatins 6؊8 with Amino Acid Side-Chains: Syn-
thesis of 13a as representative: (4S,5R)-N-Benzoyl-2-(2,4-dime-
thoxyphenyl)-4-phenyl-5-oxazolinecarboxylic acid (10a; 428 mg,
1.06 mmol, 2 mol-equiv.), DCC (219 mg, 1.06 mmol, 2 mol-equiv.),
and DMAP (catalytic amount: 30 mg) were added to a solution of
8 (365 mg, 0.53 mmol) in dry toluene (4 mL). After stirring at room
temp. for 1 h, the reaction mixture was filtered and dissolved in a
solution of HCl in methanol (10 mL, obtained by addition of 140
µL of Ac2O to 20 mL of MeOH). The reaction mixture was worked
up by washing with sat. NaHCO3 and extraction with EtOAc.
After having been washed with brine and concentrated, the residue
was purified by column chromatography (hexane/EtOAC gradient
from 8:2 to 6:4) to afford 206 mg (46%) of 13a. The taxanes 11a,
11b, 12, and 13b were obtained in a similar way, in yields of 54%,
61%, 38%, and 45%, respectively.
Compound 13b: White powder, m.p. 122Ϫ125 °C. [α]2D5 ϭ Ϫ39 (c ϭ
0.5, CH2Cl2). IR (KBr): ν˜ ϭ 3453, 1721, 1509, 1370, 1272, 1248,
1161, 1107, 1065, 715 cmϪ1 1H NMR (CDCl3): δ 0.92 (d, J ϭ
.
7.4 Hz, iBu), 0.94 (d, J ϭ 7.4 Hz, iBu), 1.28 (s, 16-H), 1.35 (s, Boc),
1.42 (s, 17-H3), 1.64 (s, 19-H3), 1.89 (s, 18-H3), 2.11 (s, OAc), 2.15
(s, OAc), 2.50 (m, 6a-H), 3.10 (d, J ϭ 6.0 Hz, 2Ј-OH), 3.20 (d, J ϭ
3.0 Hz, 7-OH), 3.21 (d, J ϭ 11.0 Hz, 3-H), 4.01 (d, J ϭ 4.0 Hz, 1-
H), 4.10 (s, 2Ј-H), 4.12 (d, J ϭ 8.0 Hz, 3Ј-H), 4.33 (d, J ϭ 8.0 Hz,
20b-H), 4.36 (d, J ϭ 8.0 Hz, 20a-H), 4.58 (d, J ϭ 12.0 Hz, 13b-H),
4.60 (m, 7-H), 4.60 (d, J ϭ 8.0 Hz, NH), 4.97 (d, J ϭ 8.0 Hz, 5-
H), 5.23 (d, J ϭ 12.0 Hz, 13a-H), 5.81 (dd, J ϭ 11.0, 4 Hz, 2-H),
6.23 (s, 10-H), 7.45 (BBЈ-Bz), 7.59 (C-Bz), 8.01 (AAЈ-Bz). HRMS
(70 eV): m/z ϭ 817.3880 (calcd. for C42H59NO15 817.3885).
Compound 11a: White powder, m.p. 61Ϫ65 °C. [α]2D5 ϭ ϩ32 (c ϭ
˜
0.58; CH2Cl2). IR (KBr): ν ϭ 3513, 3430, 1732, 1665, 1518, 1487,
1265, 1244, 1088, 1076, 988, 712 cmϪ1. 1H NMR (CDCl3) δ ϭ 1.35
(s, 17-H3), 1.44 (s, 19-H3), 1.50 (s, 16-H3); 1.81 (s, 18-H3), 2.03 (s,
OAc), 2.21 (s, OAc), 2.54 (m, 6a-H), 3.13 (d, J ϭ 4.0 Hz, 2Ј-OH),
3.37 (d, J ϭ 4.0 Hz, 7-OH), 3.78 (d, J ϭ 10.0 Hz, 3-H), 4.44 (d,
J ϭ 8.0 Hz, 20b-H), 4.68 (m, 7-H), 4.72 (d, J ϭ 12.0 Hz, 13b-H),
4.72 (d, J ϭ 8.0 Hz, 20a-H), 4.72 (m, 2Ј-H), 4.90 (br. d, J ϭ 9.0 Hz,
5-H), 5.58 (d, J ϭ 12.0 Hz, 13a-H), 5.80 (dd, J ϭ 8, 1.8 Hz, 3Ј-H),
5.85 (d, J ϭ 10.0 Hz, 2-H), 6.40 (s, 10-H), 6.92 (d, J ϭ 8.0 Hz,
NH), 7.32 (m, arom), 7.58 (m, arom), 7.76 (AAЈ-NHBz), 7.96
Acknowledgments
We are very grateful to Dr. Jasmin Jakupovic (AnalytiCon Discov-
ery GmbH, Potsdam, Germany) for the 500 MHz NMR spectra
and his useful suggestions for the structural elucidation of the vari-
ous secobacatins and their rearrangement products.
(AAЈ-OBz). HRMS (70 eV): m/z
C46H49NO14 839.3153).
ϭ 839.3131 (calcd. for
[1]
A. M. Thayer, Chem. Eng. News 2000, 78(45), 20Ϫ21.
Three books have been devoted to the chemistry and medicinal
[2]
chemistry of taxol: Taxol: Science and Applications (Ed.: M.
Suffness), CRC, Boca Raton, FL, 1995; Taxane Anticancer
Agents: Basic Science and Current Status (Eds.: G. I. Georg, T.
T. Chen, I. Ojima, D. M. Vyas), American Chemical Society,
Washington, DC, 1995; The Chemistry and Pharmacology of
Taxol and its Derivatives (Ed.: V. Farina), Elsevier, Amster-
dam, 1995.
Compound 11b: White powder, m.p. 100Ϫ103 °C. [α]2D5 ϭ ϩ13 (c ϭ
0.5 MeOH). IR (KBr): ν˜ ϭ 3524, 3389, 1732, 1603, 1508, 1452,
1370, 1246, 1173, 1090, 1050, 711.8; 1049.4. 1H NMR (CDCl3):
δ ϭ 0.97 (d, J ϭ 7.4 Hz, iBu), 0.99 (d, J ϭ 7.4 Hz, iBu), 1.35 (s,
16-H3), 1.38 (s, Boc), 1.44 (s, 17-H3), 1.79 (s, 19-H3), 2.06 (br. s,
18-H3), 2.21 (s, OAc ϫ 2), 2.55 (m, 6a-H), 3.10 (br. s, 2Ј-OH), 3.14
(d, J ϭ 4.0 Hz, 7-OH), 3.79 (d, J ϭ 9.9 Hz, 3-H), 4.12 (br. d, J ϭ
8.0 Hz, 3Ј-H), 4.16 (br. s, 2Ј-H), 4.44 (d, J ϭ 8.2 Hz, 20b-H), 4.60
(d, J ϭ 12.2 Hz, 13b-H), 4.63 (d, J ϭ 8.0 Hz, NH), 4.69 (m, 7-H),
4.73 (d, J ϭ 8.2 Hz, 20a-H), 4.93 (br. d, J ϭ 7.9 Hz, 5-H), 5.58 (d,
J ϭ 12.2 Hz, 13a-H), 5.87 (d, J ϭ 9.9 Hz, 2-H), 6.42 (s, 10-H), 7.54
(BBЈ-Bz), 7.63 (C-Bz), 7.98 (AAЈ-Bz). HRMS (EI): m/z ϭ 815.3712
(calcd. for C42H57NO15 815.3728).
[3]
These properties are exemplified by IDN-5109, an orally active
taxane currently undergoing clinical development. For the syn-
thesis of IDN-5109, see: I. Ojima, J. C. Slater, S. D. Kuduk, C.
S. Takeuchi, R. H. Gimi, C.-M. Sun, Y. H. Park, P. Pera, J. M.
Veith, R. J. Bernacki, J. Med. Chem. 1997, 40, 267Ϫ278. For a
bioavailability study, see: M. I. Nicoletti, T. Colombo, C. Rossi,
C. Monardo, S. Stura, M. Zucchetti, A. Riva, P. Morazzoni,
M. B. Donati, E. Bombardelli, M. D’Incalzi, R. Giavazzi, Can-
cer Res. 2000, 60, 842Ϫ846.
Compound 12: White powder, m.p. 158Ϫ161 °C. [α]2D5 ϭ Ϫ12 (c ϭ
[4] [4a]
M. L. Michaelis, N. Ranciat, Y. Chen, M. Bechtel, R. Ra-
˜
0.58 CHCl3). IR (KBr): ν ϭ 3444, 1723, 1603, 1505, 1370, 1273,
gan, M. Hepperle, Y. Liu, G. Georg, J. Neurochem. 1998, 70,
1
1248, 1175, 1094, 713 cmϪ1. H NMR (CDCl3): δ ϭ 0.94 (d, J ϭ
[4b]
1623Ϫ1627.
D. D. L. Woo, S. Y. P. Miao, J.C. Pelayo,
[4c]
7.4 Hz, iBu), 0.96 (d, J ϭ 7.4 Hz, iBu), 1.19 (s, 16-H3), 1.38 (s, 17-
H3), 1.42 (s, Boc), 1.56 (s, 19-H3), 2.04 (br. s, 18-H3), 2.18 (s, OAc),
2.24 (s, OAc), 2.61 (m, 6a-H), 2.9 (br. s, 1-OH), 3.21 (br. d, J ϭ
4.0 Hz, 7-OH), 3.42 (br. s, 2Ј-OH), 3.85 (d, J ϭ 4.0 Hz, 3-H), 4.31
(d, J ϭ 8.0 Hz, 20b-H), 4.34 (d, J ϭ 8.0 Hz, 20a-H), ca 4.15 (m,
1-H, 2Ј-H, 3Ј-H), 4.54 (d, J ϭ 12.2 Hz, 13b-H), 4.65 (d, J ϭ 8.0 Hz,
NH), 5.08 (dd, J ϭ 7.9, 2.9 Hz, 5-H), 5.37 (br. d, J ϭ 4.0 Hz, 2-
H), 5.74 (d, J ϭ 12.2 Hz, 13a-H), 6.43 (s, 10-H), 7.49 (BBЈ-Bz),
7.62 (C-Bz), 7.98 (AAЈ-Bz). HRMS (70 eV): m/z ϭ 817.3892 (calcd.
for C42H59NO15 817.3885).
A. S. Woolf, Nature 1994, 368, 750Ϫ753.
S. Lhotak, W. L. Hunter, M. L. C. Banquerigo, E. Brahn,
Clin. Immunol. Immunopathol. 1998, 86, 280Ϫ289.
http://www.pslgroup.com/dg/1748a2.htm
A. L. Arsenault,
[4d]
See:
[5]
D. J. Rodi, R. W. James, H. J. Sanganee, R. A. Holton, B. A.
Wallace, L. Makovski, J. Mol. Biol. 1999, 80, 337Ϫ343.
[6] [6a]
L. Barboni, C. Lambertucci, G. Appendino, D. G. Vander
Velde, R. H. Himes, E. Bombardelli, M. Wang, J. P. Snyder, J.
Med. Chem. 2001, 44, 1576Ϫ1587. [6b] J. P. Snyder, J. H. Nettles,
B. Cornett, K. H. Downing, E. Nogales, Proc. Natl. Acad. Sci.
USA 2001, 98, 5312Ϫ5316.
282
Eur. J. Org. Chem. 2002, 277Ϫ283

Synthesis and Evaluation of 14-Nor-A-secotaxoids
FULL PAPER
[7]
[16]
S. H. Chen, V. Farina, in: The Chemistry and Pharmacology of
Since C-15 is a reentrant angle in 8, the meaning of thickened
and broken lines is reversed. For a discussion, see: G. Ap-
pendino, in: The Chemistry and Pharmacology of Taxol and its
Derivatives (Ed: V. Farina), Elsevier, Amsterdam, 1995, pp.
13Ϫ18.
We have also observed the remarkable properties of the
NaBH4/dioxane system in a non-taxoid context: G. Ap-
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