Studies towards the total synthesis of taxoids: A rapid entry into bicyclo[6.4.0]dodecane ring system. Part 1

Article abstract of DOI:10.1016/S0957-4166(98)00434-0

We report a short and stereocontrolled synthesis of the taxoid BC- subunit (+)-5 embodying the whole carbon framework and most of the required oxygen functionalities for further elaboration. Enantiomeric purity was secured at an early stage by resolution

Full text of DOI:10.1016/S0957-4166(98)00434-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4055–4071
Studies towards the total synthesis of taxoids: a rapid entry into
bicyclo[6.4.0]dodecane ring system. Part 1
a,∗
a
a
Siméon Arseniyadis, María del Rosario Rico Ferreira, José Quílez del Moral,
a
a
b
José Ignacio Martín Hernando, Pierre Potier and Loïc Toupet
Institut de Chimie des Substances Naturelles, CNRS, F-91198, Gif-sur-Yvette, France
a
b
URA 804 au CNRS, Université de Rennes I, F-35042, Rennes, France
Received 5 October 1998; accepted 26 October 1998
Abstract
We report a short and stereocontrolled synthesis of the taxoid BC-subunit (+)-5 embodying the whole carbon
framework and most of the required oxygen functionalities for further elaboration. Enantiomeric purity was secured
at an early stage by resolution involving derivatization with (S)-2-acetoxypropionyl chloride on (ꢀ)-10b. © 1998
Elsevier Science Ltd. All rights reserved.
1. Introduction
Previous studies from this laboratory concerned with the synthesis of taxoid analogues have revealed
1
a three-reaction based strategy, the aldol–annulation–fragmentation methodology, for stereoselectively
2
constructing taxoid BC-subunits. These early studies have established the feasibility of producing the
2
0-carbon framework of the taxoid diterpene skeleton I in relatively few steps from inexpensive starting
materials.
We detail herein a full account of our approach, built around methylcyclopentenone, to which were
attached the atoms destined to become the taxoid subunit embodying the whole carbon framework and
suitable oxygen functionalities. Methyl acetoacetate, methyllithium, benzoic acid, methyl iodide and
formalin together with methylcyclopentenone would provide the entire taxoid diterpene skeleton using
our three-reaction sequence.
∗
Corresponding author. E-mail: simeon.arseniyadis@icsn.cnrs-gif.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00434-0

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2. Synthetic planning
In the light of the results obtained during our synthetic studies aimed at the preparation of a homochiral
3
taxoid BC-subunit, the general strategy for the formation of the target molecule (+)-5, centered around
the generation of fragmentation precursor 4 which would provide the A-seco taxoid skeleton in a step-
efficient manner. Working backwards, the key tricyclic system 4 could, in principle, be assembled from
an intramolecular annulation of 3a which, in turn, could be derived from the left and right half aldol
partners 1 and 2. Recognition that tricyclic intermediate 4 could be derived from a close derivative of
threo aldol 3a via a 5-exo-trig cyclization was a key element of the synthetic scheme. According to the
strategy formulated in Scheme 1 it was necessary to evaluate several issues. First, it was mandatory
to establish the feasibility of the key annulation step. Critical to the success of this approach was the
construction of the ‘folded’ cis-syn-cis annulated intermediate 4 that would guarantee the stereoselective
production of the requisite relationship between the centers at C-1 and C-8. This retrosynthesis did not
account for the stereogenic center at C-3; however, we anticipated that this center could be controlled
2
by equilibration after closure to the taxoid ABC system (for precedents see literature ). As it was
necessary to define those stereochemical control elements that would ensure a series of ‘single isomer’
transformations, we chose to use achiral aldol partners to simplify stereochemical issues. Had we used
chiral aldol partners as in our previous approach, any lack of selectivity in the aldol process could have
been magnified during the annulation step, producing a complex mixture of isomers. Single threo aldol
formation 3a, set the stage for a single cis-syn-cis annulated tricyclic enone 4, which in turn secured a
single fragmentation precursor 17. The sequence begins with the aldol partners 1 and 2 and leads in four
steps to the annulated intermediate 4. Five straightforward steps are required for the incorporation of the
C-20 hydroxymethyl substituent and the required oxygen functionalities at C-1 and C-7. Installation of
the appropriate leaving group at C-9 and subsequent Grob type fragmentation completes the synthesis
of the target bicyclo[6.4.0]dodecane (+)-5 in its enantiomerically pure arrangement in three additional
steps. In the present letter we document the ease with which the 6+8 fused substructure of taxoids can be
constructed with complete stereocontrol.
Scheme 1. Target, ingredients, bond forming operations and the three-reaction sequence

S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
4057
3
. Results and discussion
.1. Preparation of the aldol partners: the C9–C10 bond formation (aldolization)
The first stage of the synthesis required the left-half aldol partner 1, the right-half aldol partner 2 being
3
3
already reported in our earlier work. To that end we undertook the synthesis of aldehyde 6 which was
synthesized in 85% yield from methyl acetoacetate by a three-step sequence using literature conditions.
Protection of the ketone carbonyl (ethylene glycol, pTosOH, PhMe, reflux, 1 h, 90%) followed by LiAlH4
reduction in THF (rt, 10 min, 100%) and oxidation of the resulting primary alcohol via the usual Swern
protocol (DMSO, (COCl) , CH Cl , −78°C, then Et N, 95%) afforded 6. Coupling of the latter with the
2
2
2
3
4
methyl cuprate generated enolate 7 (MeLi, CuI, Et O, −10°C, 15 min, then methylcyclopentenone, 0°C,
2
2
0 min) at −20°C, in the presence of 1.6 equiv. of ZnCl (1.0 M in ether) gave the corresponding aldol
2
(as a 7:1 mixture) which was directly acetylated (Ac O, Py, DMAP, rt) and crotonized immediately after
2
(DBU) in one-pot to afford the desired enone 1 in 75% overall yield. With the two carbonyl components
from methylcyclopentenone and benzoic acid methyl ester (conveniently prepared on a 100 g scale), we
proceeded to the aldol reaction in order to join the left and right half fragments (C10–C9 bonding) as
outlined in Scheme 2. Aldol condensation was carried out at −78°C, by addition of the aldehyde 2 to a
5
solution of the threo-selective E-enolate generated from 1 [LDA, THF, −40°C, 2 h for enolate formation,
and a further 15 min stirring upon tetramethylethylenediamine (TMEDA) addition]. 5 min after addition
the reaction was quenched with a saturated solution of NaHCO to give, exclusively, the required threo
3
aldol 3a as the sole product in 90% isolated yield (EtOAc:heptane, 1:3).
Scheme 2. (a) HO(CH
DMAP, then DBU. (f) LDA, THF, −78°C, 5 min. (g) Ac
2
)
2
OH, pTsOH. (b) LiAlH
4
, THF. (c) Swern. (d) Me
2
CuLi, Et
2
O. (e) ZnCl
2
, Et
2
O, −20°C, Ac
2
O, Py,
2
O, Py, DMAP. (h) CrO
3
–DMP, tBuOOH, CH
2
Cl , 0°C to rt
2
Acetylation at C-9 of the aldol thus obtained (Ac O, Py, DMAP, 0°C, 1 h) afforded 95% of the
2
corresponding C-9 acetate 3b. For the conversion of the latter to the annulation precursor 8, a site
selective allylic oxidation at C-5 was required. This was efficiently accomplished by the CrO –dimethyl
3
6
pyrazole (DMP) protocol. Thus, treatment of 3b with CrO , in the presence of 3,5-dimethyl pyrazole,
3
and tBuOOH, in CH Cl , at 0°C to room temperature for 5 h, afforded the desired annelation precursor
2
2
8, in 85% isolated yield, while no trace of the undesired C-13 oxidation was detected.
3.2. The C2–C3 bond formation (annulation) and the installation of C-20
Having successfully achieved the threo-selective aldol reaction and the regioselective allylic oxidation,
which sets up conditions for the annulation sequence (C2–C3 bonding), we turned our attention to the
subsequent ring closure. In principle, this step could occur via two stereoisomeric transition states; that
is, the closure could occur from either the conformation in which the angular methyl at C-8 (Me-
19) and the C-9 acetate are in gauche relationship, leading to the desired cis-syn-cis product, or in

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S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
severe eclipsing relationship, leading to the unwanted cis-anti-cis product. Annulation was achieved by
7
samarium diiodide promoted intramolecular reductive coupling via a 5-exo-trig process according to
1
our previous work. Treatment of 8 with SmI in THF in the presence of HMPA and MeOH at −85°C
2
for 15 min followed by quenching with aqueous NaHCO (2 ml/mmol) gave, after flash chromatography
3
(
EtOAc:heptane, 1:1) the cis-syn-cis tricyclic enone 4 as the sole product in 70% isolated yield. Within
1
the limits of detection by 400 MHz H NMR spectroscopy, no stereoisomer was produced. The single
isomer formation could be rationalized from a consideration of the developing eclipsing interactions
between the angular methyl group at C-8 and the C-9 acetoxy group.
Incorporation of the last carbon (C-20) of the diterpene skeleton was first achieved by deprotonation
of the tricyclic enone 4 with LDA at −78°C followed by cyanomethyl formate addition at −78°C in
the presence of HMPA, and further reduction (LAH, THF, −20°C). This sequence afforded low yields
and a number of by-products and thus was abandoned. An alternative route for the introduction of the
C-20 was then established in which the enone 4 was transformed into the aldol 10 in a sequence of
reactions involving generation of its silylenol ether 9 (Scheme 3) (by quenching its LDA generated
lithium enolate with TMS-Cl) and subsequent aldol condensation in the presence of Yb(OTf) , a water
3
tolerant Lewis acid catalyst, affording ca. 70% isolated yield of the target aldol. In a search for other
routes to TMS-dienol ethers aiming at practicality and better yields, we investigated the TMSOTf
(trimethylsilyl trifluoromethane sulfonate) protocol; however, attempted TMS-dienol formation using
TMSOTf in CH Cl was complicated by enolization of the O-acetyl group and, more importantly,
2
2
opening of the ketal at C-12 to give an enol ether. To circumvent this problem, the tricyclic enone
reacted smoothly with TMSOTf (1.5 equiv.) in the presence of collidine (4.4 equiv.) in dry toluene
4
(
6.5 ml/mmol), at −40°C under argon, cleanly affording the desired TMS-dienol ether 9, in quantitative
yield. Regular TLC monitoring of the TMS-dienol ether formation reaction was required since extended
reaction times led to lower yields because of the possible formation of the earlier cited side products.
Nevertheless, by carrying out the reaction in toluene and operating at −40°C, complications can be easily
1
avoided. The H NMR of the crude material indicated no side products (such as enol ether formation at
C-12 or silylation on the methyl of the C-9 acetate), and the desired product 9 was easily purified by silica
gel flash chromatography and could be safely stored under argon for long periods. The conversion of 9
to 10 proceeds cleanly through the Yb(OTf) catalyzed aldol condensation with formalin (37% HCH_O
3
in water), and subsequent desilylation (nBu NF, THF, rt) with the only by-product observed being the
4
starting enone, resulting from TMS-enol hydrolysis. SiO flash chromatography (EtOAc:heptane, 1:1)
2
removed the unreacted starting enone and provided 10b in 85% yield. The relative stereochemistry of
10b was assigned on the basis of the observed diagnostic NOEs.
Scheme 3. (a) SmI
2
–MeOH/THF/HMPA, −85°C, 15 min. (b) TMSOTf, collidine, PhMe, −40°C. (c) Yb(OTf)
3
, HCH_O, rt,
then nBu NF, THF, rt
4

S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
4059
3.3. Introduction of enantiomeric purity
Aldol 10b, embodying the whole carbon framework of the taxoid diterpene skeleton, was obtained in
its enantiomerically pure arrangement through a resolution sequence outlined in Scheme 4 as follows:
8
diastereomeric derivatization with (S)-2-acetoxypropionyl chloride in the presence of triethylamine and
DMAP in dry CH Cl at 0°C afforded the corresponding esters 11a and 11b as a mixture of diastereomers
2
2
which were then separated by HPLC using heptane:ethyl acetate, 2:1 and 0.1% AcOH as eluent.
Scheme 4. (a) (S)-O-Acetyllactyl chloride, DMAP, CH
NaBH , CH Cl –EtOH
2
Cl
2
, 0°C. (b) K
2
CO
3
, MeOH:H
2
O, 10:1, −30°C. (c) CeCl3·7H
2
O,
4
2
2
The absolute configuration of the (S)-O-acetyllactyl derivative 11a was assigned by a single crystal
X-ray crystallographic study (Fig. 1).
Thus, 11b having the required absolute stereochemistry, was used in the synthetic scheme towards
taxoid series in the transformation sequence: 11b-→12-→13-→14-→17. To this end, the C-9 acetyl group
had to be removed selectively in the presence of the C-9 acetate; this was successfully achieved using
potassium carbonate in methanol:water, 10:1, at −30°C. A non-selective one step reduction would free
the C-9 OAc, the C-20 lactate and would also reduce the C-5 carbonyl, thus saving two additional steps.
However, low yields obtained through this way were discouraging and thus we adopted the somehow
longer but more efficient method portrayed in Scheme 4.
3.4. Preparation of fragmentation precursor and B-ring formation: C2–C10 fragmentation
In order to prepare intermediates in which the C2–C10 bond could provide access to cleavage, we
have studied several alternative strategies portrayed in Scheme 5. Reports from this laboratory have
demonstrated the feasibility of an ozonolytic approach (type I cleavage) for the preparation of an
Figure 1. Perspective drawing of the X-ray structure of 11a (dioxolane part omitted to simplify the presentation)

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S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
9
advanced, enantiomerically pure, taxoid BC-substructure. Attempted ozonolytic cleavage of several A
type substrates failed; proceeding as in our previous studies, ozonolysis has repeatedly proved to be
complex and not synthetically valuable. The retro-aldol fragmentation on B-like substrates, which are
obtained as recyclable by-products during Sharpless epoxidation (type II cleavage) was attempted next,
unsuccessfully. Various conditions targeting retroaldolization failed, affording instead the corresponding
crotonized A-like compounds, used in the unsuccessful ozonolytic type I fragmentation mode. At this
point an alternative approach to the B-ring formation through a C2–C10 diol fragmentation (type III
cleavage) was attempted. In principle, treatment of an enolate derived from B-like substrates with one
of the known electrophilic hydroxylation reagents could produce the C-like diol, a logical precursor for
the construction of BC-subunit via a lead tetra-acetate mediated oxidative cleavage. Despite an extensive
search for suitable reaction conditions that would accommodate the C-like C2–C10 diol, none were found
to be synthetically useful.
Scheme 5. Looking for the appropriate C2–C10 fragmentation mode; the B-ring formation
These unpromising results forced a change in strategy for the construction of the eight-membered B-
ring. The objective became to effect a Grob fragmentation (type IV cleavage)10 to construct the fully
functional eight-membered B-ring. Thus we needed an efficient route which targeted the elaborated
D-like analogues as key intermediates. The proposed route to the target compound 17 is outlined in
Scheme 6. Chemoselective saponification of 11b hydrolyzed the C-20 lactate, while the C-9 acetate
remained intact (K CO , MeOH,H O, 10:1, −30°C) affording 10. Further elaboration of the resulting
2
3
2
enantiomerically pure (−)-10b to the acetonide (−)-13, common intermediate for all fragmentation
precursors was achieved through diol (−)-12 in two steps. Enone reduction of 10b with NaBH , (4 molar
4
equiv.) in the presence of CeCl (1.2 equiv.), in EtOH:CH Cl (1:1, 5 ml/mmol), at −78°C afforded 12
3
2
2
(98%). Subsequent treatment with acetone, 2,2-dimethoxy propane (DMP), and a catalytic amount of
pTsOH, at 0°C, for 20 min under argon, furnished the corresponding acetonide 13 (88%).
As the stereochemistry of the fragmentation precursor 13 should ensure that the stereogenic centers
at C-8, C-1 have the desired configuration, we relied on the hydroxyl group-directed epoxidation
protocol for the introduction of the C-1 oxygen to secure the correct stereochemistry at C-1 stereocenter.
Moreover, by carrying out the hydroxyl directed epoxidation after saponification at C-9, we could expect
an increased functionalization. This was achieved by using Sharpless conditions; thus VO(acac) (0.03
2
equiv.), tBuOOH (5 M solution in decane, 1.15 equiv.), benzene (25 ml/mmol), 15 min reflux, afforded
the target compound, the bis-epoxide 17 (C1–C14 β- and C6–C7 α-epoxide, 61%) along with the
corresponding bis-epoxy aldol 16 (20%) where the C-9 OH position was oxidized to the ketone, and
the mono-epoxy aldol 15 (14%) in high combined yield (95%). The bis-epoxy aldol, once reduced at C-9
(
LiAlH , Et O, 0°C, 10 min, 96%) afforded the desired compound 17. However, 15 was also recycled
4 2
via two additional steps (reduction and Sharpless epoxidation as above), thus increasing the yield.

S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
4061
Scheme 6. (a) Acetone, 2,2-DMP, cat. pTsOH, 0°C. (b) 2 N NaOH, MeOH–H
PhH, reflux. (d) LiAlH , Et O, 0°C
2
O, 0°C to rt. (c) VO(acac)
2
, tBuOOH in decane,
4
2
The overall sequence portrayed in Scheme 6 can be readily modified to produce the required car-
bon/oxygen skeleton offering several distinct ways for further elaboration. The stereochemical outcome
1
13
of the epoxidation process was assessed by extensive NMR studies. The H and C NMR features of 17
are well resolved and readily amenable to assignment on the basis of 1 and 2D experiments, which
allowed the tracing of the entire atomic connectivity. In particular, diagnostic NOEs established the
spatial proximities and confirmed the folded cis-syn-cis relationship in the key tricyclic intermediate,
and the stereochemistry of the two epoxides (α-configuration of the epoxide at C6–C7, β-configuration
of the epoxide at C1–C14). The α-stereochemistry of C6–C7 epoxide was confirmed by 1D-NOEDIFF
experiments. Irradiation of the C-8 angular methyl group, Me-19, singlet at 1.39 ppm, showed NOE
to H-7 at 3.19 ppm (confirms epoxide stereochemistry) as well as to H-9, H-3 at 4.26 and 1.51
ppm, respectively (confirms cis-syn-cis ring junction) and H-5 proton at 3.99 ppm. No enhancement
was observed for the H-4 proton confirming the β-stereochemistry of the C-20 hydroxymethyl group.
Likewise, when H-9 was irradiated, an NOE was seen to the epoxidic proton H-7 at 3.19 ppm, to H-10 at
2
.61 ppm and Me-19 at 1.39 ppm. Irradiation of both α- and β-methyl groups at C-15, showed NOE to
H-14 at 3.20 ppm. These data, along with additional information given in the experimental part, establish
the stereochemical relationship of all ring substituents. 17 can also serve for resolution purposes using
(S)-O-acetyllactyl chloride as above, even though the former resolution, carried out four steps earlier, is
synthetically more interesting.
The C-9 mesylate 18 obtained quantitatively using standard procedures (MsCl, pyridine, DMAP
cat., 0°C, 30 min) was efficiently fragmented to the BC-taxoid substructure. Thus, treatment with
tBuOK:tBuOH (6 equiv. of 1 M solution of tBuOK in tBuOH), in dry THF (10 ml/mmol), at 70°C
(
oil bath temperature), for 1.5 h, afforded after SiO flash chromatography (ethyl acetate:heptane, 1:2)
2
an 88% isolated yield of (+)-5 (Scheme 7). Similarly, upon subjection to fragmentation conditions using
NaH (4 equiv.), in THF (10 ml/mmol), at reflux for 1 h, led to the desired eight-membered ring containing
BC-subunit (+)-5 in comparable yields, so establishing the viability of this approach for taxoid synthesis.
4. Conclusion
We developed a three reaction sequence of [6+8]-fused taxoid BC-system based on the aldol-
annulation sequence as the critical steps. The synthetic strategy relied on the simple diastereoselection
offered by the enolate geometry during the aldol reaction and the feasibility of efficient 5-exo-trig

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S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
Scheme 7. (a) MsCl, pyridine, DMAP cat., 0°C. (b) tBuOK/tBuOH–THF, 70°C
annulation using SmI . A kinetic aldol reaction created the stereogenic center at C-9 leading to 3a, whilst
2
a highly stereoselective 5-exo-trig cyclization provided the folded cis-syn-cis tricyclic enone 4, which
in turn secured the installation of the quaternary centers at C-8 and C-1 with the required relative and
absolute configuration. From the standpoint of efficiency of stereocontrolled bond construction, the result
is truly remarkable: note that during the aldol–annelation sequence, starting from two achiral precursors,
two new bonds are formed, five chiral centers are generated, and only one diastereomer is obtained out
of 16 possible enantiomeric pairs of diastereoisomers. The flexibility of the current method to efficiently
introduce and further modify various substituents around the core tricyclic intermediate allows scope for
novel fragmentation precursors, while opening up routes to new functionalized [6+8]-fused bicyclics.
5. Experimental section
5.1. General
1
Experimental evidence favoring the structures investigated came from a comprehensive range of H
and 1 C NMR data (400 and 75 MHz, respectively, 1D and 2D experiments) and were corroborated by
spatial proximity (NOE) studies. Molecular mechanics calculations were run using Still’s Macromodel
program version 5.5 operated on a Silicon Graphics workstation. Structures were constructed by means
of the interactive graphics input and then subjected to the MM3 minimization using the Monte Carlo
option of the program for the search of all conformers and the evaluation of their energy (indicated
solvent: chloroform). Experiments which required an inert atmosphere were carried out under dry argon
3
or nitrogen in a flame dried glass system. THF and benzene were freshly distilled from LiAlH and
4
sodium wire, respectively, and were transferred via syringe. Methylene chloride was distilled from P O .
2
5
Triethyl and diisopropyl amines were distilled from KOH pellets. Commercial reagents were purchased
from Aldrich Chemicals and used as received. ‘Usual work up’ means washing of the organic layer
with brine, drying on anhydrous MgSO , and evaporating in vacuo with a rotary evaporator at aspirator
4
pressure. Optical rotations were recorded in CHCl solution in a 1 dm cell using a Perkin–Elmer 241
3
polarimeter. IR spectra were recorded on a Nicolet 205 FTIR instrument, neat or in chloroform. Melting
1
points are uncorrected. H NMR spectra were obtained on Bruker AM400, AM300, AC250 (400, 300
and 250 MHz, respectively) instruments in CDCl . Chemical shifts are expressed in ppm downfield
3
1
from TMS The H NMR data are presented in the order: δ value of the signal, integrated number of
protons, peak multiplicity (abbreviations used are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet) and coupling constants in hertz. Nuclear Overhauser enhancements by the NOEDIFF method11
were obtained with the aid of the Aspect 3000 microprograms, which allow direct accumulations of
difference FIDs. NOEs were successfully obtained with extremely low irradiating power levels (40 dB);
3
20 transients were acquired in NOE experiments, and an exponential line broadening of 0.3 Hz was used.
13
C spectra were measured at 62.5 and 75 MHz and the chemical shifts are reported relative to CDCl
3
13
triplet centered at 77.00 ppm. For all compounds investigated, multiplicities of C resonances were

S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
4063
assigned by the SEFT technique.12 Two-dimensional homo and heteronuclear correlation experiments
were performed with standard Bruker software. Mass spectra (MS), recorded on an AEI MS-50 (electron
impact spectra, EI), an AEI MS-9 (chemical ionization spectra, CI), or a Kratos MS-50 (high resolution
mass spectra, HR) instruments are reported in the form: ‘m/z (intensity relative to base peak)=100%’.
Flash chromatographies were run on silica gel (Merck 60, 230–400 mesh) with the solvent mixture
indicated. Thin layer chromatography was performed on commercial silica gel glass plates that were
developed by immersion in 5% phosphomolybdic acid in 95% ethanol.
5.2. Preparation of left-half aldol partner 1
A dry flask was charged with copper(I) iodide (17.7 g, 93.15 mmol) which was dried under high
vacuum pressure for 12 h. Methyllithium (120 ml of a 1.55 M solution in ether, 186 mmol) was added
dropwise to a stirring suspension of the copper(I) iodide in ether (180 ml) at −20°C under argon. After
20 min, the mixture was allowed to warm to 0°C and 3-methylcyclopent-2-enone (6.72 g, 69.9 mmol)
was added. After a further 20 min, the mixture was cooled to −20°C and zinc chloride (95.12 ml of a
1.0 M solution in ether, 95.12 mmol) was added. After 5 min, the aldehyde 6 (8.65 g, 66.54 mmol) was
added and the mixture was stirred for a further 20 min. The reaction mixture was quenched by addition
of a saturated solution of ammonium chloride and diluted with EtOAc. After being allowed to warm
to room temperature, ammonia was added to solubilize the precipitate. The organic layer was washed
with 1 N hydrochloric acid, water and brine, and then dried (MgSO ). The solvent was evaporated under
4
reduced pressure to give 16 g of crude product which, upon chromatography, furnished 81% yield of the
corresponding aldol as a mixture of two diastereomers, used as such in the next step.
Acetic anhydride (26.4 g, 258.6 mmol) was added dropwise to a stirring solution of the latter crude
(
1
(
12.2 g, 50.4 mmol) and DMAP (1.3 g, 10.8 mmol) in pyridine (50 ml) at 0°C under argon. After
5 min the mixture was allowed to warm to room temperature and stirred for an additional 1 h. DBU
24.84 g, 163.2 mmol) was added to the mixture and it was then stirred overnight. The mixture was ice
cooled, diluted with CH Cl , washed with dilute hydrochloric acid, saturated with sodium bicarbonate
2
2
and brine, and then dried (MgSO ). The solvent was evaporated under reduced pressure and the residue
4
was chromatographed (SiO , heptane:EtOAc, 4:1) to give 10.49 g of 1 (93%) along with a small amount
2
(
1
0.45 g, 4%) of the Z-isomer, separable by chromatography. 1: IR (film): 2957, 2864, 1716, 1643, 1457,
−1 1
377, 1291, 1218, 1111, 1058, 870 cm . H NMR (250 MHz): 1.18 (6H, s), 1.31 (3H, s), 1.74 (2H, t,
13
J=7.8), 2.33 (2H, t, J=7.8), 3.08 (2H, d, J=7.4), 3.96 (4H, bs), 5.90 (1H, t, J=7.4). C NMR (62.9 MHz):
3.8, 28.9 (2×Me), 34.8, 36.4 (2×CH ), 40.4 (Cq-15), 64.5 (OCH CH O, 2×C), 109.3 (C-12), 132.3
2
2
2
2
+
(C-14), 146.5 (C-1), 208.6 (C-2). EIMS: 224 (M , 2), 209 (65), 190 (14), 175 (18), 163 (14), 149 (18),
1
37 (12), 123 (26), 87 (100). HREIMS: calcd for C H O m/z 224.1412, found: 224.1398.
13 20 3
5.3. Preparation of 3a: aldol condensation
A solution of diisopropylamine (5.12 g, 50.64 mmol) in 80 ml of dry THF was cooled to −78°C
and nBuLi (2.5 M in hexanes, 18.6 ml, 46.4 mmol) was added dropwise under argon. After 30 min, 1
9.45 g, 42.2 mmol) was added dropwise. The solution was allowed to stir for 2 h (enolate formation)
at −78°C, and TMEDA (11.5 ml, 76.0 mmol) was added in one portion. After 15 min the aldehyde 2
(
(
5.12 g, 76.6 mmol) was added dropwise. The mixture was allowed to stir for 5 min at −78°C and the
reaction was quenched with 45 ml of saturated aqueous NaHCO . The mixture was rapidly extracted in
3
EtOAc, washed with ice-cold 1% HCl and then a NaHCO solution. After drying and removal of solvent
3
the aldol was obtained as a light yellow oil. Purification was effected by flash chromatography only for

4064
S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
characterization purposes, (SiO , heptane:EtOAc, 4:1 as eluent) to give a single threo aldol (ꢀ)-3a as the
2
sole product in nearly quantitative yield. The crude reaction profile of the aldol reaction step showed a
1
single product by 400 MHz H NMR without any detectable trace of an erythro aldol.
(
ꢀ)-3a: IR (film): 3440, 3018, 2958, 2924, 2863, 2820, 1692, 1623, 1451, 1425, 1382, 1304, 1279,
−1 1
1
210, 1158, 1115, 1037, 1020, 943, 900, 865, 719 cm . H NMR (400 MHz): 1.07 (3H, s), 1.16 (3H,
s), 1.19 (3H, s), 1.31 (3H, s), 1.39 (1H, t, J=12.6), 1.87 (1H, dd, J=8.5, 12.6), 2.49 (1H, dt, J=8.5, 12.6),
2
.65 (2H, bd, J=1.0), 3.07 (2H, d, J=7.4), 3.54 (1H, dd, J=1.5, 8.5), 3.92–3.99 (4H, m), 5.27 (1H, d,
13
J=1.5, OH), 5.43 (1H, dd, J=1.0, 10.2), 5.65 (1H, dt, J=2.8, 10.2), 5.80 (2H, bs), 5.98 (1H, t, J=7.4).
C
NMR (75 MHz): 24.0, 26.6, 26.7, 28.6, 29.9, 37.0, 38.6, 41.1, 41.4, 49.7, 64.7 (OCH CH O, 2×C), 79.4,
2
2
+
1
09.3, 123.3, 124.1, 129.7, 133.0, 134.9, 146.3, 213.3. CIMS: 347 ([M+H] , 60), 343 (10), 329 (40), 253
(
20), 225 (10), 191 (11), 105 (6), 87 (76). HRCIMS: calcd for C H O m/z 347.2222, found: 347.2231.
21
31
4
5.4. Acetylation of the aldol
Acetic anhydride (27.05 g 265 mmol) was added to a stirring mixture of aldol (ꢀ)-3a (14.6 g, 42.2
mmol) and DMAP (0.5 g, 4.1 mmol) in pyridine (80 ml) at 0°C under argon. After 30 min, the mixture
was diluted with DCM and washed with dilute hydrochloric acid, saturated sodium bicarbonate, water,
brine and dried (MgSO ). The solvent was evaporated under reduced pressure and the residue was
4
chromatographed (SiO , heptane:EtOAc, 4:1) to give 14.4 g of (ꢀ)-3b (88%) along with 7% of the
2
corresponding crotonized product which was discarded.
(
ꢀ)-3b: IR (film): 2960, 2932, 2872, 1742, 1711, 1639, 1450, 1151, 1369, 1243, 1138, 1115, 1051,
−1 1
1
029, 949 cm . H NMR (300 MHz) 1.03 (3H, s), 1.05 (3H, s), 1.18 (3H, s), 1.29 (3H, s), 1.65 (1H,
t, J=12.5, H-11), 1.84 (1H, dd, J=8.6, 12.5, H-11), 2.12 (3H, s, OCOMe), 2.58 (1H, ddd, J=7.3, 8.5,
1.8, H-10), 2.63 (2H, m, H-5), 2.99 (2H, m, H-13), 3.95 (4H, m, OCH CH O), 4.86 (1H, d, J=7.3,
1
2
2
13
H-9), 5.45 (1H, dd, J=1.7, 10.0), 5.7–5.9 (4H, m). C NMR (75 MHz) 21.0 (CH CO), 23.7 (Me), 26.3
3
(C-5), 26.7 (Me), 28.6 (Me), 29.7 (Me), 36.5 (C-13), 38.0 (Cq), 40.5 (Cq), 41.1 (C-11), 47.8 (C-10), 64.5
(
OCH CH O, 2×C), 79.0 (C-9), 107.4 (C-12), 124.2, 124.5, 129.6, 131.3, 132.4, 146.5, 170.7, 205.7.
2
2
+
EIMS: 388 (M , 2), 328 (8), 237 (16), 221 (10), 191 (26), 175 (30), 105 (43), 91 (51), 87 (100). CIMS:
3
+
89 ([M+H] , 9), 343 (34), 329 (100), 285 (11), 214 (9), 87 (46). HRCIMS: calcd for C H O m/z
33 33 5
389.2328, found: 389.2333.
5.5. Allylic oxidation
t-Butylhydroperoxide (60 ml of a 70% w/v solution in water, 435.6 mmol) was added to a stirring
solution of 3,5-dimethylpyrazol (4.19 g, 43.56 mmol) and chromium trioxide (1.74 g, 17.42 mmol) in
dichloromethane (200 ml) at 0°C. (ꢀ)-3b (16.9 g, 43.56 mmol) in dichloromethane (50 ml) was added
dropwise and the mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was
diluted with ether, washed with dilute hydrochloric acid, dilute sodium hydroxide, water, brine and dried
(
MgSO ). The solvent was evaporated under reduced pressure and the residue was chromatographed
4
(
SiO , heptane:EtOAc, 2:1 to 1:3) to give 14.89 g (85%) of of the fragmentation precursor (ꢀ)-8: IR
2
(film): 3058, 2969, 2884, 1744, 1710, 1666, 1628, 1457, 1371, 1267, 1236, 1141, 1053, 1030, 864, 738,
−1 1
7
03 cm . H NMR (300 MHz): 0.99 (3H, s), 1.15 (3H, s), 1.23 (3H, s), 1.29 (3H, s), 1.45 (1H, t,
J=12.3), 1.67 (1H, dd, J=8.5, 12.3), 2.19 (3H, s), 2.44 (1H, ddd, J=7.1, 8.5, 12.3), 2.99 (2H, d, J=7.4),
.92–4.00 (4H, m), 5.20 (1H, d, J=7.1), 5.89 (1H, t, J=7.4), 6.30 (1H, dd, J=1.8, 10.1), 6.39 (1H, dd,
3
13
J=1.8, 10.2), 6.88 (1H, dd, J=3.0, 10.1), 7.18 (1H, dd, J=3.0, 10.2). C NMR (75 MHz): 20.7, 23.7
2×Me), 28.3, 29.5, 36.5, 37.9, 40.2, 45.4, 47.7, 64.4 (OCH CH O, 2×C), 76.1, 109.0, 129.1, 129.5,
(
2
2

S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
4065
+
1
2
4
33.7, 145.6, 151.2, 151.7, 170.2, 185.3, 204.2. CIMS: 403 ([M+H] , 1), 343 (98), 295 (33), 281 (30),
51 (40), 191 (41), 109 (13), 105 (14), 87 (100). HRCIMS: calcd for C H O m/z 403.2120, found
23
31
6
+
03.2132, calcd for m/z 343.1909 ([MH] –AcOH) found: 343.1892.
5.6. Annelation
HMPA (30 ml, 172.5 mmol) was added dropwise to a stirring solution of samarium iodide (330 ml of
a 0.1 M solution in THF, 33 mmol) at −85°C under argon (the dark blue coloration turns to purple). After
3
0 min at this temperature, a solution of (ꢀ)-8 (2.98 g, 7.41 mmol) in dry methanol (6 ml) and THF (18
ml) was added dropwise over 5 min. After a further 10 min at −85°C, the mixture was quenched by the
addition of a saturated solution of potassium sodium tartrate (60 ml) followed by dilution with EtOAc.
Water was added and the organic layer was separated. The aqueous layer was re-extracted with EtOAc
and the combined organic layers were washed with 1 N HCl, water, brine and dried (MgSO ). The crude
4
residue was chromatographed (SiO , heptane:EtOAc, 1:1) to give 2.093 g of the required product (ꢀ)-4
2
(
70% isolated yield).
−1 1
(
ꢀ)-4: IR (CHCl ) 3436, 2951, 3938, 2878, 1736, 1682, 1377, 1238, 1045, 952, 746 cm ; H NMR
3
(400 MHz) 1.10 (3H, s, Me-17), 1.18 (3H, s, Me-16), 1.37 (3H, s, Me-18), 1.56 (3H, s, Me-19), 1.59
(
1H, d, J=9.9, H-11α), 1.60 (1H, d, J=11.1, H-11β), 1.97 (3H, s, OCOMe), 2.15 (1H, dd, J=13.4, 16.8,
H-4βax), 2.25 (1H, dd, J=6.2, 16.8, H-4αequiv.), 2.52 (2H, m, H-13), 2.56 (1H, dd, J=6.2, 13.4, H-3),
3
.27 (1H, ddd, J=8.1, 9.9, 11.1, H-10), 3.85–4.01 (4H, m, OCH CH O−), 4.58 (1H, OH-2), 5.16 (1H,
2
2
d, J=8.1, H-9), 5.39 (1H, dd, J=6.5, 10.7, H-14), 5.98 (1H, d, J=10.1, H-6), 6.55 (1H, d, J=10.1, H-7).
Diagnostic NOEs: {Me-17}: Me-16 (NOE gem), H-11α, H-14; {Me-16}: Me-17 (NOE gem), H-11β,
H-10, H-14; {Me-19}: H-3, H-9, H-7; {H-10}: H-11β, Me-16, H-9; {H-9}: H-10, Me-19, H-7; {H-14}:
13
Me-16, Me-17, Me-18; C NMR (75 MHz) 20.9 (CH CO), 24.9 (Me-18), 27.1 (Me-19), 27.5 (Me-17),
3
3
6
2.1 (Me-16), 38.8 (C-11), 39.2 (C-13), 39.5 (C-4), 44.9 (C-15), 51.3 (C-8), 54.9 (C-3), 55.4 (C-10), 65.1,
5.2 (OCH CH O), 79.8 (C-9), 92.4 (C-2), 109.7 (C-12), 117.3 (C-14), 128.5 (C-6), 153.3 (C-7), 157.5
2
2
+
(
7
C-1), 169.8 (MeC_O), 199.3 (C-5); EIMS: m/z 404 (M , 3), 389 (M−Me, 13), 371 ([M−Me]−H O,
2
), 191 (39), 121 (59), 87 (100). HRCIMS: calcd for C H O m/z 405.2276, found 405.2249. Anal.
23 33 6
calcd for C H O : C 68.29, H 7.97, found: C 68.16, H 7.90.
23
32
6
5.7. Incorporation of C-20 via TMS-dienol ether (ꢀ)-9
To a stirred solution of 3.71 g (9.18 mmol) of (ꢀ)-4 and 24.3 ml (184 mmol) of collidine in dry toluene
(
−
60.0 ml) at −40°C under argon, was added 8.1 ml (45 mmol) of TMSOTf. The mixture was stirred at
40°C for 20 min, diluted with heptane, washed with 1 M hydrochloric acid, water and brine, dried
over sodium sulfate, and concentrated under reduced pressure to give a crude, which upon purification
on silica gel (heptane:EtOAc, 1:1 as eluent), yielded 4.76 g (94%) of (ꢀ)-9: IR (film): 3050, 2957, 2897,
−1 1
1
741, 1665, 1457, 1413, 1375, 1252, 1215, 1156, 1099, 1066, 949, 903, 843, 751 cm . H NMR (300
MHz): 0.18 (9H, s), 0.19 (9H, s), 0.99 (3H, s), 1.07 (3H, s), 1.23 (3H, s), 1.38 (3H, s), 1.58 (2H, t, J=5.9),
.08 (3H, s), 2.59 (1H, dd, J=7.3, 15.8), 2.78 (1H, dd, J=6.2, 15.8), 2.91 (1H, d, J=5.4), 2.98 (1H, dt,
2
J=5.9, 6.5), 3.90–4.02 (4H, m), 4.86 (1H, dd, J=1.9, 5.4), 5.17 (1H, d, J=6.5), 5.37 (1H, dd, J=6.2, 7.3),
5
2
1
3
.54 (1H, dd, J=1.9, 10.1), 5.66 (1H, d, J=10.1). 13C NMR (75 MHz): 0.2 (3×Me), 1.8 (3×Me), 20.8,
4.5, 28.4, 31.2, 32.2, 36.7, 38.1, 41.7, 43.0, 52.1, 59.2, 64.6 (OCH CH O, 2×C), 84.8, 96.6, 102.5,
2
2
+
09.8, 119.1, 122.0, 133.1, 144.4, 154.0, 170.4. CIMS: 548 (M , 3), 533 (3), 488 (3), 473 (4), 440 (9),
68 (49), 308 (20), 223 (14), 195 (16), 180 (14), 165 (33), 73 (100).

4066
S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
(
ꢀ)-9 (4.67 g, 8.5 mmol) thus obtained was dissolved in 100 ml of THF at room temperature. 50 ml
of 37% aqueous HCHO and 4.7 g (7.65 mmol) of Yb(OTf) were added and the reaction mixture stirred
3
for 40 h. Quenching with a saturated aqueous solution of sodium bicarbonate (2 ml per mmol) followed
by extraction with EtOAc, washing with 1 N aqueous HCl, water and brine afforded 4.8 g of crude,
containing partially silylated compounds of type (ꢀ)-10a, the desired (ꢀ)-10b and the starting material
(
ꢀ)-4, which was then desilylated. Thus, the crude material was dissolved in THF (100 ml); 1 M Bu NF
4
in THF (13 ml, 13 mmol) was added at room temperature and the mixture stirred for 10 min. Dilution
with EtOAc, washing with brine and drying over MgSO furnished a residue which was subsequently
4
purified on silica gel (heptane:EtOAc, 1:2 to 1:4) to yield 0.368 g (11%) of recovered (ꢀ)-4 and 2.95 g
(
80%) of (ꢀ)-10b. Spectral data for enantiomerically pure 10b will follow after the resolution step (vide
infra).
5.8. Resolution of (ꢀ)-10b: preparation of lactate derivatives 11a and 11b
Racemic 10b (708 mg, 1.63 mmol) was dissolved in dry CH Cl (24 ml) at 0°C; Et N (1.6 ml, 11.5
2
2
3
mmol), DMAP (500 mg, 4.1 mmol) and 10 min later (S)-O-acetyllactyl chloride ((S)-2-acetoxypropionyl
chloride, 1.2 ml, 10.4 mmol) were added at 0°C. After 25 min at this temperature (TLC monitoring), the
reaction mixture was quenched with a saturated solution of aqueous NaHCO . Extraction with CH Cl ,
3
2
2
washings with 1 N aq. HCl, NaHCO , water and brine and finally drying over MgSO afforded a crude
3
4
residue which was purified on silica gel (heptane:EtOAc, 1:1) to yield 832 mg (93%) of a mixture of
lactates 11a and 11b along with 28 mg (4%) of the starting alcohol (ꢀ)-10b. The lactates 11a and 11b
were separated by HPLC (heptane:ethyl acetate 2:1, in the presence of 0.1% acetic acid).
1
1a (ent-taxoid series): mp 54–57°C (ether:heptane). [α] 36.5 (c 1.15). IR (film): 3454, 3055, 2987,
D
−1 1
2
(
962, 2894, 1742, 1671, 1422, 1375, 1266, 1240, 1195, 1136, 1101, 1066, 1051, 895 cm . H NMR
400 MHz): 0.91 (3H, s), 1.06 (3H, s), 1.28 (1H, dd, J=8.4, 13.4), 1.36 (3H, s), 1.43 (3H, s), 1.50 (3H,
d, J=7.1), 1.57 (1H, t, J=13.4), 2.12 (3H, s), 2.14 (3H, s), 2.43 (1H, dd, J=5.5, 13.6), 2.65 (1H, bs), 2.86
1H, dd, J=11.7, 13.5), 2.88–2.96 (2H, m), 3.85–3.96 (4H, m), 4.13 (1H, s, OH), 4.19 (1H, dd, J=6.0,
(
1
5
3
1
0.7), 4.42 (1H, dd, J=7.7, 10.7), 5.03 (1H, q, J=7.1), 5.24 (1H, d, J=7.0), 5.52 (1H, dd, J=5.5, 11.7),
.99 (1H, d, J=10.5), 6.99 (1H, dd, J=1.0, 10.5). 13C NMR (75 MHz): 16.9, 20.5, 20.8, 24.7, 28.1, 28.7,
3.5, 37.6, 38.7, 41.9, 44.4, 45.8, 54.1, 55.7, 64.9, 65.0, 66.6, 68.6, 81.7, 91.3, 109.5, 121.5, 126.9, 154.7,
57.5, 170.1, 170.3, 170.5, 196.4. Anal. calcd for C H O : C 63.49, H 7.35, found: C 63.32, H 7.56.
29
40 10
X-Ray structure determination of 11a: C H O , C H O: Mr=621.75, monoclinic, P2 ,
2
9
39 10
4
10
1
−3
a=13.434(9), b=10.461(9), c=12.381(5) Å, β=95.33(5)°, V=1735(2) Å , Z=2, D =1.190 Mg
x
−3
−1
m , λ(MoKα)=0.71073 Å, µ=0.828 cm , F(000)=670, T=294 K. The sample (0.25×0.25×0.30 mm)
was studied on an automatic diffractometer CAD4 ENRAF–NONIUS with graphite monochromatized
MoKα radiation. The cell parameters were obtained by fitting a set of 25 high-theta reflections. The
data collection (2θmax=50°, scan ω/2θ=1, tmax=60 s, range HKL: H −17,17 K 0,13 L 0,15, intensity
controls without appreciable decay (0.2%) gave 4175 reflections from which 2457 were independent
(Rint=0.013) with I>3.0σ(I). After Lorenz and polarization corrections the structure was solved with
SIR-92 which revealed the non-hydrogen atoms of the structure and the solvent molecule. After
anisotropic refinement, the hydrogen atoms were found with a Fourier difference (between 0.56 and 0.24
−3
e Å ). The whole structure was refined by the full-matrix least-square techniques (use of F magnitude;
x, y, z, β for C and O atoms and x, y, z fixed for H atoms; 489 variables and 2457 observations;
ij
2
2
2 2 −1/2
) with the resulting R=0.052, R =0.049 and S =0.778 (residual
o
w=1/σ(F ) =[σ (I)+(0.04F ) ]
o
w
w
−
3
∆
ρ=0.23 e Å ). Atomic scattering factors are from International Tables for X-Ray Crystallography

S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
4067
(1974). All the calculations were performed on a Silicon Graphics Indy computer with the MOLEN
package (Enraf–Nonius, 1990).
1
1b (taxoid series): [α] −73.3 (c 0.85). IR (film): 3444, 2962, 2919, 2856, 1744, 1669, 1462, 1375,
D
−1 1
1
1
225, 1200, 1110, 1050 cm . H NMR (400 MHz): 0.91 (3H, s), 1.06 (3H, s), 1.27 (1H, dd, J=8.6,
3.5), 1.36 (3H, s), 1.43 (3H, s), 1.50 (3H, d, J=7.0), 1.58 (1H, t, J=13.5), 2.12 (6H, s), 2.44 (1H, dd,
J=5.5, 13.5), 2.65 (1H, bs), 2.84 (1H, dd, J=11.8, 13.5), 2.88–2.96 (2H, m), 3.84–3.97 (4H, m), 4.12 (1H,
s, OH), 4.30 (1H, dd, J=7.0, 10.9), 4.34 (1H, dd, J=7.4, 10.9), 5.08 (1H, q, J=7.0), 5.24 (1H, d, J=7.1),
5
2
9
.52 (1H, dd, J=5.5, 11.8), 5.97 (1H, d, J=10.5), 6.96 (1H, dd, J=1.1, 10.5). 13C NMR (62.9 MHz): 16.8,
0.5, 20.7, 24.6, 27.9, 28.5, 33.5, 37.6, 38.7, 41.8, 44.4, 46.0, 54.0, 55.6, 64.8, 64.9, 66.1, 68.4, 81.6,
1
1.1, 109.4, 121.4, 126.9, 154.3, 157.3, 170.0, 170.2, 170.3, 196.4. The 400 MHz H NMR spectra were
easily integrated, and compared to the racemic mixture; enantiomeric excesses were measured with ꢀ2%
precision.
5.9. Selective hydrolysis of C-20 lactyl functionality in the presence of C-9 acetate
1
1b (1.33 g, 2.4 mmol) was dissolved in MeOH (60 ml), K CO (840 mg, 6.1 mmol) and then water (6
2
3
ml) were added at −30°C. After stirring for 55 min at −30°C (TLC monitoring), MeOH was evaporated
under reduced pressure and the residue was taken into CH Cl . Following washing with brine, the organic
2
2
layer was dried over MgSO and flash chromatographed (heptane:EtOAc, 1:3) to yield 920 mg (88%)
4
of 10b along with 30 mg (2%) of recovered starting material. 10b: [α] −73, (c 2.1). IR (film) 3449,
D
−1 1
2
959, 2934, 2884, 1741, 1664, 1376, 1240, 1053 cm . H NMR (400 MHz) 0.92 (3H, s, Me-17), 1.06
(
3H, s, Me-16), 1.29 (1H, dd, J=8.4, 13.2, H-11b), 1.35 (3H, s, Me-18), 1.39 (3H, s, Me-19), 1.57 (1H,
t, J=13.2, H-11a), 2.12 (3H, s, OCOMe), 2.49 (1H, dd, J=5.8, 13.7, H-13), 2.56 (1H, br s, H-3), 2.61
1H, OH-20), 2.74 (1H, ddd, J=1.5, 6.1, 8.3, H-4), 2.85 (1H, dd, J=11.2, 13.7, H-13), 2.94 (1H, ddd,
J=7.0, 8.4, 12.8, H-10), 3.80 (2H, m, H-20), 3.94 (4H, m, OCH CH O−), 5.25 (1H, d, J=7.0, H-9),
(
2
2
5
.54 (1H, dd, J=5.8, 11.2, H-14), 5.98 (1H, d, J=10.4, H-6), 7.00 (1H, dd, J=0.6, 10.4, H-7). Diagnostic
NOEs: {Me-17}: Me-16 (NOE gem), H-11α, H-14; {Me-16}: Me-17 (NOE gem), H-11β, H-10, H-14;
Me-19}: H-3, H-9, H-7; {H-11α}: H-11β (NOE gem), Me-17, H-7; {H-9}: H-3, H-10, Me-19. 13
NMR (75 MHz) 20.8 (CH CO), 24.8 (Me-18), 28.1 (Me-17), 29.0 (Me-19), 33.5 (Me-16), 37.6 (C-11),
{
C
3
3
8.7 (C-13), 41.8 (C-15), 44.5 (C-8), 49.3 (C-4), 54.2 (C-10), 56.0 (C-3), 64.9, 65.0 (OCH CH O), 65.9
2 2
(
C-20), 81.8 (C-9), 91.5 (C-2), 109.5 (C-12), 121.3 (C-14), 126.6 (C-6), 155.0 (C-7), 157.3 (C-1), 170.1
+
(MeC_O), 200.0 (C-5); EIMS: m/z 434 (M , 4), 419 (9), 401 (7), 313 (29), 295 (40), 191 (43), 151 (47),
8
7 (100). HRCIMS: calcd for C H O m/z 435.2382, found 435.2359.
24 35 7
5.10. Reduction of the C-5 carbonyl and preparation of the isopropylidene derivative (−)-13
Cerium chloride heptahydrate (0.51 g, 1.36 mmol) was added to a solution of 10b (536 mg, 1.24
mmol) in CH Cl (15 ml) and ethanol (15 ml) at −78°C. After 5 min, sodium borohydride (117 mg, 3.1
2
2
mmol) was added and the mixture was stirred for 1.5 h at −78°C and then quenched by careful addition
of brine followed by dilution with ether. After being allowed to warm to room temperature, the organic
layer was separated and the aqueous layer was extracted with ether (×3). The combined organic fractions
were washed with brine and dried over MgSO , the solvent was evaporated under reduced pressure to
4
give a crude residue which was purified by SiO flash chromatography, eluent EtOAc, 534 mg (98%) of
2
(
1
−)-12. [α] −128 (c 2.35). IR (film): 3429, 3046, 2966, 2923, 2892, 1737, 1663, 1465, 1379, 1249,
D
−1 1
140, 1045, 950, 852, 730 cm . H NMR (300 MHz): 1.08 (3H, s), 1.11 (3H, s), 1.16 (3H, s), 1.20–1.35
(1H, m), 1.36 (3H, s), 1.66–1.79 (3H, m), 2.12 (3H, s), 2.48 (1H, dd, J=6.3, 13.8), 2.70–2.82 (1H, m),

4068
S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
3
3
.10 (1H, dd, J=10.6, 13.8), 3.16 (1H, bs, OH), 3.51–3.65 (1H, m), 3.56 (1H, s, OH), 3.72 (1H, bs, OH),
.94–4.05 (5H, m), 4.29 (1H, bd, J=6.6), 5.12 (1H, d, J=6.5), 5.52 (1H, dd, J=6.3, 10.6), 5.69 (1H, d,
13
J=10.1), 6.04 (1H, dd, J=2.5, 10.1). C NMR (75 MHz): 21.0, 24.8, 28.6, 29.6, 34.0, 37.1, 38.2, 41.5,
4.6, 46.7, 55.6, 55.7, 64.9, 65.0, 68.5, 71.5, 81.0, 91.9, 109.8, 120.5, 129.3, 132.7, 157.7, 170.6. CIMS:
4
+
(419 [(M+H)−H O] , 100), 401 (6), 375 (56), 359 (24), 357 (27), 87 (98).
2
Diol (−)-12 thus obtained was dissolved in 22 ml of acetone and 2.2 ml of 2,2-DMP, and catalytic
pTsOH·H O was added at 0°C. After 20 min stirring, the mixture was first filtered on Al O which was
2
2
3
rinsed with EtOAc. The residue was purified by chromatography on silica gel (heptane:EtOAc, 3:1) to
give 512 mg (88%) of (−)-13: [α] −141 (c 2.03). IR (film): 3441, 2954, 2895, 1733, 1675, 1463, 1364,
D
−1 1
1
240, 1193, 1111, 1047, 875 cm . H NMR (300 MHz): 1.10 (3H, s), 1.18 (3H, s), 1.22–1.32 (1H,
m), 1.32 (3H, s), 1.35 (3H, s), 1.40 (3H, s), 1.47 (3H, s), 1.54–1.67 (3H, m), 1.92 (1H, d, J=12.3), 2.10
3H, s), 2.32 (1H, dd, J=5.3, 13.5), 2.76–2.90 (1H, m), 3.04 (1H, dd, J=12.0, 13.5), 3.58 (1H, t, J=10.9),
(
3.84–3.94 (4H, m), 4.01 (1H, bs, OH), 4.10–4.22 (2H, m), 5.13 (1H, d, J=7.0), 5.45 (1H, dd, J=5.3,
1
2.0), 5.66 (1H, d, J=10.6), 5.85 (1H, dd, J=2.6, 10.6). 13C NMR (75 MHz): 18.9, 21.0, 24.8, 28.3, 29.7,
31.1, 33.3, 37.6, 38.4, 41.7, 41.8, 46.8, 56.4, 56.7, 64.9, 65.0, 69.1, 81.5, 90.8, 98.1, 109.6, 119.8, 127.6,
132.9, 158.5, 170.5.
5.11. Hydrolysis of the C-9 acetate
Sodium hydroxide (54 mmol, 9 ml of a 6 N solution) was added dropwise to a stirring solution of (−)-
3 (2.45 g, 5.15 mmol) in methanol (110 ml) at 0°C. After 1 h, the mixture was allowed to warm to room
1
temperature and then stirred for an additional 1 h (TLC monitoring). Methanol was evaporated under
reduced pressure and the residue was taken up in ethyl acetate. The solution was washed with water,
saturated aqueous NaHCO and brine, and then dried over MgSO to give 2.3 g (100%) of (−)-14. An
3
4
analytical sample was purified on SiO gel (heptane:EtOAc, 1:2). (−)-14: [α] −163 (c 2.11). IR (film):
2
D
3
451, 3050, 2989, 2957, 2927, 1652, 1460, 1381, 1293, 1267, 1223, 1199, 1149, 1107, 1052, 997, 950,
−1 1
870, 737 cm . H NMR (200 MHz): 1.08 (3H, s), 1.15 (3H, s), 1.24 (3H, s), 1.32 (3H, s), 1.30–1.60
(3H, m), 1.36 (3H, s), 1.44 (3H, s), 1.84 (1H, d, J=12.0), 2.10 (1H, OH, bs), 2.29 (1H, dd, J=5.4, 13.5),
2
.51–2.65 (1H, m), 2.99 (1H, dd, J=12.0, 13.5), 3.55 (1H, t, J=10.8), 3.81–3.94 (4H, m), 4.03–4.16 (3H,
13
m), 4.15 (1H, d, J=6.9), 5.42 (1H, dd, J=5.4, 12.0), 5.69 (1H, d, J=10.0), 6.02 (1H, dd, J=2.5, 10.0).
C
NMR (50.33 MHz): 19.0, 24.8, 28.3, 29.7, 31.0, 33.5, 36.8, 38.5, 41.7, 42.4, 46.7, 56.8, 58.7, 64.9, 65.0,
+
6
5.4, 69.1, 79.9, 90.2, 98.1, 109.7, 119.3, 128.2, 132.8, 158.8. CIMS: 435 ([M+H] , 6), 417 (23), 377
(100), 373 (31), 359 (24), 315 (33), 227 (11), 87 (99).
5.12. Sharpless epoxidation
A mixture of diol (−)-14 (1.9 g, 4.2 mmol) and VO(acac) (16 mg, 0.06 mmol) in benzene (100 ml)
2
was refluxed for 10 min under argon. Addition of 5–6 M tBuOOH in decane (1.0 ml, 5.5 mmol) followed,
and stirring continued at this temperature for 15 min. After cooling, dilution with EtOAc, and washing
with a saturated aqueous solution of NaHCO , water and brine, the residue was dried, concentrated and
3
chromatographed on silica gel (heptane:EtOAc, 1:1 to 1:3) to yield 265 mg (14%) of 15, 390 mg (20%)
of 16 and 1.19 g (61%) of the desired bisepoxy-1,3-diol 17. The C-9 oxidized derivatives 15 and 16 were
then easily recycled by LiAlH reduction in dry Et O, at 0°C, (10 min, 96%) for the latter and LiAlH
4
2
4
reduction followed by Sharpless epoxidation as above for the former, thus considerably increasing the
yield.

S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
4069
Elution with heptane:ethyl acetate, 2:1, afforded first the C-9 oxidized derivatives 15 and 16 which
served as B-like substrates (Scheme 5) in, otherwise unsuccessful, retro-aldol type II fragmentation
experiments.
1
5: mp: 188–190°C (heptane:ether). IR (film): 2987, 2967, 2939, 2875, 1737, 1460, 1381, 1372, 1226,
−1 1
1
199, 1112, 1001, 871 cm . H NMR (400 MHz): 0.92 (3H, s), 1.19 (3H, s), 1.41 (3H, s), 1.42 (3H, s),
1.45 (3H, s), 1.51 (3H, s), 1.72 (1H, t, J=13.8), 1.86 (1H, dd, J=9.5, 13.8), 1.92–2.08 (1H, m), 2.11–2.14
(
2H, m), 2.22 (1H, dd, J=1.9, 13.6), 2.76 (1H, ddd, J=1.9, 9.5, 13.8), 3.31 (1H, bs, OH), 3.33 (1H, dd,
J=4.5, 8.3), 3.77 (1H, t, J=11.1), 3.96–4.03 (4H, m), 4.16–4.24 (2H, m), 5.66 (1H, d, J=10.0), 5.84
1H, dd, J=2.4, 10.0). 13C NMR (62.9 MHz): 18.9, 24.3, 25.7, 27.2, 28.3, 29.6, 37.1, 39.3, 39.5, 41.5,
2.4, 53.8, 57.5, 59.9, 64.6, 64.7, 65.3, 69.6, 72.7, 85.3, 98.5, 109.2, 128.1, 131.6, 218.1. Anal. calcd for
C H O : C 66.94, H 8.09, found: C 66.89, H 8.12.
(
5
25
36
7
1
6: mp: 224–226°C (heptane:ether). [α] −14.3 (c 1.29). IR (film): 3469, 2987, 2968, 2939, 2876,
D
1
8
1
2
737, 1465, 1382, 1374, 1301, 1268, 1230, 1219, 1200, 1168, 1115, 1084, 1052, 1000, 948, 918, 896,
−1 1
57 cm . H NMR (300 MHz): 0.93 (3H, s), 1.20 (3H, s), 1.44 (6H, s), 1.45 (3H, s), 1.51 (3H, s),
.76 (1H, dd, J=9.1, 13.9), 1.94 (1H, dd, J=1.8, 13.4), 2.03 (1H, dd, J=13.5, 13.9), 2.04–2.09 (2H, m),
.39 (1H, dddd, J=4.1, 9.5, 11.1, 13.5), 2.71 (1H, ddd, J=1.8, 9.1, 13.5), 3.19 (1H, OH, s), 3.29 (1H,
dd, J=3.7, 9.1), 3.33 (1H, d, J=4.5), 3.37 (1H, d, J=4.5), 3.64 (1H, t, J=11.1), 3.96–4.04 (4H, m), 4.03
13
(
1H, d, J=9.5), 4.11 (1H, dd, J=4.1, 11.1). C NMR (62.9 MHz): 18.8, 24.3, 25.2, 25.6, 27.3, 29.5, 33.7,
3
6.3, 37.1, 39.3, 50.7, 52.7, 54.3, 57.2, 57.3, 60.1, 64.6, 64.8, 64.9, 70.7, 72.5, 86.1, 98.7, 109.2, 218.4.
+
CIMS: 465 ([M+H] , 100), 447 (24), 407 (24), 403 (53), 389 (30), 345 (40), 87 (99). HRCIMS: calcd for
C H O m/z 465.2488, found: 465.2479. Anal. calcd for C H O : C 64.64, H 7.81, found: C 64.39,
25
37
8
25 36
8
H 7.97.
1
7: mp: 210–212°C (heptane:EtOAc). [α] −45 (c 1.31). IR (film): 3451, 2991, 2981, 2875, 1460,
D
−1 1
1
384, 1374, 1268, 1255, 1230, 1217, 1196, 1170, 1101, 1055, 1039, 996, 755 cm . H NMR (300
MHz): 0.91 (3H, s, Me-16), 1.17 (3H, s, Me-17), 1.39 (3H, s, Me-19), 1.42 (3H, s, Me-18), 1.43 (3H,
s, Me-eq acetonide), 1.45–1.52 (2H, m, H-11, H-3), 1.48 (3H, s, Me-ax acetonide), 1.94 (1H, t, J=13.4,
H-11), 1.98–2.05 (2H, m, H-13), 2.35 (1H, m, H-4), 2.61 (1H, ddd, J=7.4, 8.0, 13.4, H-10), 2.89 (1H,
s, OH), 3.20 (1H, d, J=4.7, H-7), 3.22 (1H, dd, J=4.5, 8.1, H-14), 3.33 (1H, d, J=4.7, H-6), 3.53 (1H,
t, J=11.1, H-20ax), 3.92–4.03 (4H, m, -OCH CH O-), 3.98 (1H, d, J=9.8, H-5), 3.99 (1H, dd, J=4.7,
2
2
11.1, H-20eq), 4.27 (1H, d, J=7.4, H-9). Diagnostic NOEs: {Me-16}: Me-17 (NOE gem), H-14, H-11β,
H-10; {Me-19}: H-3, H-9, H-7, H-5; {Me-βax of acetonide}: H-20β-ax, H-5; {H-5}: H-3, H-6, Me-ax
acetonide, H-20ax; {H-6}: H-7, H-5; {H-7}: Me-19, H-6; {H-14}: Me-16, Me-17, H-13. 13C NMR (62.9
MHz): 18.7 (Me-ax acetonide), 24.1 (Me-18), 25.4 (Me-17), 27.5 (Me-16), 29.4 (Me-eq acetonide), 29.6
(Me-19), 34.2 (C-4), 34.7 (C-11), 37.0 (C-13), 37.9 (Cq), 46.3 (Cq), 53.6 (C-6), 54.3 (C-3), 56.8 (C-14),
5
8
3
7.0 (C-10), 57.6 (C-7), 64.4, 64.6 (-OCH CH O-), 65.0 (C-20), 70.6 (C-5), 72.6 (Cq-O), 82.2 (C-9),
2 2
+
7.3 (Cq-O), 98.4 (C-12), 109.2 (Cq-acetonide). CIMS: 467 ([M+H] , 96), 449 (54), 409 (17), 405 (79),
91 (57), 347 (55), 329 (23), 87(100). HRCIMS: calcd for C H O m/z 467.2645, found: 467.2640.
25
37
8
Anal. calcd for C H O : C 64.36, H 8.21, found: C 64.31, H 8.29.
25
38
8
5.13. Setting the stage for the B-ring formation: mesylation protocol
To a stirred solution of 17 (550 mg, 1.18 mmol) in pyridine (10 ml), in the presence of DMAP as
catalyst (few crystals), methanesulfonyl chloride (MsCl, 0.8 ml, 8.2 mmol) was added at 0°C and stirring
continued for 1 h at this temperature (TLC monitoring, CH Cl :MeOH, 96:4 as eluent). The reaction
2
2
was quenched with a saturated aqueous solution of sodium bicarbonate, and extracted with methylene
chloride. The combined extracts were washed with 1 N hydrochloric acid, water, sodium bicarbonate and

4070
S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
brine, and then dried over sodium sulfate, and concentrated under reduced pressure to give 642 mg of
the required mesylate 18. As a sensitive compound it was taken into the next step without purification.
Spectral characteristics of this crude material (purified on silica gel, heptane:EtOAc, 1:1 to 1:1.5 as
eluent) are as follows: [α] −32.3 (c 1.16). IR (film): 3387, 3035, 2985, 2872, 1655, 1461, 1384, 1342,
D
−1 1
1
331, 1271, 1234, 1220, 1200, 1172, 1116, 1104, 1056, 961, 896, 861 cm . H NMR (300 MHz): 0.90
(3H, s), 1.18 (3H, s), 1.41 (3H, s), 1.43 (3H, s), 1.46 (3H, s), 1.48 (3H, s), 1.56 (1H, dd, J=7.8, 13.8),
1
7
.57 (1H, d, J=13.1), 1.97–2.06 (2H, m), 2.13 (1H, t, J=13.8), 2.32–2.51 (1H, m), 2.71 (1H, ddd, J=7.5,
.8, 13.8), 2.97 (1H, s, OH), 3.08 (3H, s), 3.19 (1H, d, J=4.7), 3.23 (1H, dd, J=3.6, 8.8), 3.28 (1H, d,
13
J=4.7), 3.53 (1H, t, J=11.1), 3.94–4.02 (6H, m), 5.14 (1H, d, J=7.5). C NMR (75 MHz): 18.6, 24.1,
2
5.2, 27.4, 28.8, 29.3, 33.9, 35.3, 36.9, 37.8, 37.9, 46.0, 52.9, 54.2, 55.4, 56.6, 56.9, 64.4, 64.5, 64.7,
+
70.3, 72.3, 87.7, 87.8, 98.3, 109.0. CIMS: 545 ([M+H] , 6), 527 (7), 483 (28), 449 (100), 425 (28), 391
(18), 347 (11), 329 (13), 143 (7), 103 (98), 87 (37).
5.14. Fragmentation
For the synthesis of the BC fragment 5 we report two routes, both of which are efficient and allow
access to multigram quantities of material.
a) Mesylate 18 (1.15 mmol) was dissolved in THF (15 ml) and tBuOK (1 M in tBuOH, 3.5 ml,
.5 mmol) was added at room temperature. The temperature was then raised to 70°C (bath temp.) and
(
3
the reaction mixture was stirred for 45 min. After cooling, then dilution with ether, water was added.
Extraction with EtOAc, followed by washing with brine, drying of the organic layer on MgSO and
4
concentration under reduced pressure furnished 529 mg (92%) of (+)-5 as a crude. A rapid filtration on
SiO (heptane:EtOAc, 2:1 to 1:1) gave pure (+)-5 in 88% isolated yield.
2
(
b) Sodium hydride (60% suspension in oil) was washed with dry hexane (3×5 ml) under inert
atmosphere (septum), vacuum dried and then slurried in anhydrous THF. Mesylate 18 (1.1 mmol) in
THF (12 ml) was added to a suspension of NaH (4 mmol) in THF (8 ml). The resulting slurry was heated
at reflux for 1 h, quenched with water and extracted with methylene chloride. The organic layer was
washed with brine, dried over MgSO and concentrated under reduced pressure. Purification as above
4
gave 75% of the desired compound (+)-5: mp 168–170°C (heptane:ether). [α] +21 (c 1.29). IR (film):
D
2
989, 2968, 2937, 2877, 2853, 1702, 1476, 1459, 1442, 1382, 1370, 1320, 1305, 1268, 1239, 1229,
−1 1
1199, 1177, 1156, 1118, 1106, 1062, 1036, 1020, 951, 937, 917, 888, 857, 765, 741 cm . H NMR
(300 MHz): 0.82 (3H, s, Me-16), 1.19 (3H, s, Me-17), 1.20 (1H, dd, J=7.9, 14.7, H-13), 1.33 (3H, s,
Me-18), 1.40 (3H, s, Me-acetonide), 1.41 (3H, s, Me-acetonide), 1.68 (1H, dd, J=3.2, 14.7, H-13), 1.70
(
(
1H, dd, J=8.8, 13.8, H-11), 1.78 (3H, s, Me-19), 2.38 (1H, dddd, J=4.3, 10.5, 10.6, 12.2, H-4), 2.75
1H, d, J=12.2, H-3), 2.80 (1H, dd, J=8.8, 13.8, H-11), 2.95 (1H, d, J=4.4, H-7), 3.16 (1H, t, J=10.5,
H-20ax), 3.18 (1H, dd, J=3.2, 7.9, H-14), 3.31 (1H, d, J=4.4, H-6), 3.80 (1H, dd, J=4.3, 10.5, H-20eq),
.91–3.97 (4H, m, OCH CH O), 4.04 (1H, d, J=10.6, H-5), 5.68 (1H, dt, J=8.8, 12.2, H-10), 5.77 (1H,
3
2
2
dd, J=1.3, 12.2, H-9). Diagnostic NOEs: {Me-16}: Me-17 (NOE gem), H-14; {Me-19}: H-3, H-9, H-7;
Me-βax of acetonide}: H-20β-ax, H-5; {H-3}: Me-19, H-5, H-20ax; {H-5}: H-3, H-6, Me-ax acetonide,
{
1
3
H-20ax; {H-6}: H-7, H-5; {H-7}: Me-19, H-6, H-9; {H-14}: Me-16, H-13. C NMR (75 MHz): 18.9
Me ax acetonide), 24.0 (Me-17), 24.4 (Me-18), 25.0 (Me-16), 26.1 (Me-19), 29.6 (Me-eq acetonide),
0.4 (C-4), 37.0 (Cq), 38.0 (C-11), 38.5 (Cq), 38.6 (C-13), 55.2 (C-6), 55.6 (C-3), 56.2 (C-14), 61.3
C-7), 63.7 (C-20), 64.7, 64.8 (OCH CH O), 69.7, 70.5 (C-5), 98.7, 108.4, 129.9 (C-10), 135.6 (C-9),
(
3
(
2
2
2
+
05.1 (C-2). CIMS: 449 ([M+H] , 49), 391 (93), 387 (16), 329 (31), 261 (51), 87 (100). HRCIMS: calcd
for C H O : 449.2539, found: 449.2544. Anal. calcd for C H O : C 66.94, H 8.09, found: C 66.68,
25
37
7
25 36
7
H 7.91.

S. Arseniyadis et al. / Tetrahedron: Asymmetry 9 (1998) 4055–4071
4071
Acknowledgements
The authors thank the A.R.C. (Association pour la Recherche sur le Cancer, France) for a fellowship
to Maria del Rosario Rico Ferreira and the Ministerio de Educacion y Cultura (Spain) for scholarships to
José Quílez del Moral and José Ignacio Martín Hernando.
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. Arseniyadis, S.; Brondi Alves, R.; Pereira de Freitas, R.; Muñoz-Dorado, M.; Yashunsky, D. V.; Potier, P.; Toupet, L.
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989, 72, 101–109.
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4. Lipshutz, B. H.; Sengupta, S. Organic Reactions, Paquette, L. et al., Eds; John Wiley & Sons, 1992; Vol. 41.
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9
1
8
1
0. (a) Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594. (b) Clayton, R. B.; Henbest, H. B.; Smith, M. J. Chem.
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Chem. 1965, 30, 3254.
11. Hall, L. D.; Sanders, J. K. M. J. Am. Chem. Soc. 1980, 102, 5703–5711.
12. LeCocq, C.; Lallemand, J. Y. J. Chem. Soc., Chem. Commun. 1981, 150–152.