A practical access into conveniently functionalized, homochiral C-ring system of taxuyunnanine C

Article abstract of DOI:10.1016/S0957-4166(01)00549-3

The preparation of a homochiral 7-nor taxoid C-ring framework, to be used in an A+C approach for the synthesis of low oxygenation pattern taxoids with an exocyclic olefin at C(4)-(20) and oxygenation at C(14), is described. Retrosynthetic analysis associated with the preparation of 3 has been designed around the targets 11 and 15 which could be produced by functional group manipulation starting from the known hydrindenone 4, obtained with a moderate e.e. (ca. 70%). A lipase was used to perform clean and high yield saponification on its corresponding acetoxy enone, while chemical resolution of the resulting acyloins allowed straightforward access to diastereomerically pure material.

Full text of DOI:10.1016/S0957-4166(01)00549-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3281–3291
A practical access into conveniently functionalized, homochiral
C-ring system of taxuyunnanine C
Jose´ I. Candela Lena, Maria del R. Rico Ferreira, Jose´ I. Mart´ın Hernando and
Sime´on Arseniyadis*
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette, France
Received 28 November 2001; accepted 4 December 2001
Abstract—The preparation of a homochiral 7-nor taxoid C-ring framework, to be used in an A+C approach for the synthesis of
low oxygenation pattern taxoids with an exocyclic olefin at C(4)–(20) and oxygenation at C(14), is described. Retrosynthetic
analysis associated with the preparation of 3 has been designed around the targets 11 and 15 which could be produced by
functional group manipulation starting from the known hydrindenone 4, obtained with a moderate e.e. (ca. 70%). A lipase was
used to perform clean and high yield saponification on its corresponding acetoxy enone, while chemical resolution of the resulting
acyloins allowed straightforward access to diastereomerically pure material. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Our initial interest in this area was stimulated by the
need for rapid entry to a variety of heavily substituted
optically homogeneous six-membered ring systems as
precursors of the taxoid left-half and right-half building
blocks.4 The key element of our retrosynthetic strategy
was the use of a new ring expansion/rearrangement
methodology developed in our laboratory.5 The utility
of these domino transformations6 with regard to the
synthesis of biologically active natural products was
demonstrated by the practical syntheses of skeleton-
modified steroids,7 by the construction of a fully func-
Taxoids have been the subject of immense interest and
six total syntheses of taxol have been published to
date.1 We reported recently a concise synthesis of 1a,
corresponding to a taxoid ABC building block common
to various taxoid representatives.2 This ‘A+C’ strategy3
is exemplified by the seven-step construction of 1a and
further by a modular approach which provides a conve-
nient handle for the step-efficient preparation of vari-
ous representatives of the taxane family (Scheme 1).
Scheme 1.
* Corresponding author. Fax: 33-1-69.07.72.47; e-mail: simeon.arseniyadis@icsn.cnrs-gif.fr
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00549-3

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2. Results and discussion
tional taxoid C-ring intermediate and its use in the
synthesis of advanced taxoid ABC frameworks.8 The
C-ring has to contain a functional moiety that could
ultimately be used to introduce the C(20) carbon offer-
ing further elaboration towards oxirane-, oxetane- or
olefin-containing taxoid families. To extend this
methodology to natural taiwanxan type 7-nor taxoids,9
such as taxuyunnanine C I,10 2,7-deacetoxyaustrospi-
catine 1011 and taiwanxan 11,12 modification of the
C-ring had to be addressed based on our earlier models
(Scheme 2).
The problem to be addressed was the construction of
two appropriately functionalized cyclohexane deriva-
tives such as (14S)-2 and (10S)-3, the left- and right-
half of the taxoid diterpene skeleton, respectively. To
accomplish this task, we took advantage of the strategy
developed previously, in which the C-ring precursor
was derived from the 7-nor Hajos–Parrish ketone
derivative 9 by means of a one-pot Pb(OAc)4-mediated
multistage transformation. Our right-half targets were
analogues of the Hajos–Parrish ketone-derived19 series,
for which a successful synthetic route to taxanes was
described.2 a-Alkoxystannanes20 were investigated as
readily available and function-reach substrates. Analy-
sis of structure 1b in terms of the route summarized in
Scheme 1 shows that the appropriate starting materials
are the known (14S)-O-TBDMS-protected phorenol 221
and the hydrindene diol 9, which, to the best of our
knowledge, is not described in the literature. As for the
identical protecting groups on both segments, previous
work had showed that a TBS protecting group at C(2)
(right-half moiety) and C(14) (left-half moiety) was
suitable, as they are removed simultaneously before the
crucial intramolecular aldol step. The substrates were
prepared according to the general route shown in
Scheme 3. The first step involved acetoxylation of the
enone with Pb(OAc)4. Conversion of the resultant ace-
toxyenones 5 into the corresponding diols 9 under
lithium aluminium hydride reduction conditions and
treatment with Pb(OAc)4 then provided the ring-
expanded intermediate 15, to be used as a taxoid C-ring
precursor.
Taxoids related to taxuyunnanine C, differing only in
their C(2), C(3), C(4) and C(14) ester parts (either H,
acetyl, propionyl or 2-methylbutyryl) have NGF-like
activity and have been claimed to be useful for the
treatment of Alzheimer’s disease.13 On the other hand,
2,7-deacetoxyaustrospicatine 10 is reported to be a
potent inhibitor of the P-glycoprotein efflux-function,
acting as MDR-resistance reversing agents.14 Closely
related taxoids such as taxuspine C and 2-deacetoxy
taxinine15 are also highly effective for binding to the
glycoprotein, thus inhibiting the influx of the antitumor
drug from the cancer cells. These taxoid diterpenes
differ from the representatives of the oxetane family,
for the D-ring has not been formed. Our retrosynthetic
analysis calls for taxoid 1b to be assembled from the
left- and right-half fragments 2 and 3, respectively.
Fragment 2, (S)-phorenol is a versatile intermediate
used in the synthesis of carotenoids, degraded
carotenoids16 and (+)-absicic acid.17 We considered that
a-alkoxyorganostannane 3 should be available from 418
by treatment of its derivative, the unsaturated 1,2-diol
9, with Pb(OAc)4 and subsequent elaboration of the
resulting ring-expanded intermediate 15 according to
our published procedure (Scheme 1). The need to gen-
erate large quantities of diastereomerically pure 3 dic-
tated the way advance was made towards its
acquisition. To this end, we attempted enzymatic
hydrolysis on scalemic 5 to circumvent problems
encountered during acetate hydrolysis and classical
techniques of resolution of the resulting acyloins 7, with
the aim to ensure enantiomeric purity as early as possi-
ble in the synthetic scheme. Herein, we report addi-
tional studies which further establish the synthetic
utility of the Pb(OAc)4-mediated oxidative cleavage of
selected unsaturated 1,2-diols for the construction of
the taxoid C-ring precursor 3, offering C(10) and C(2)
linking possibilities, for the top and bottom side link-
ing, respectively.
The synthesis of initial substrates 5 began with (S)-
hydrindenone 4, available in 72% e.e. through deracem-
izing alkylation catalyzed by (R)-(1)-phenylethyl-
amine.22 The low e.e. obtained and the tedious recrys-
tallizations needed to increase the e.e. to acceptable
levels led us to develop a practical alternative route
where enzymatic hydrolysis is used as a simple basic
reagent to promote clean high-yielding saponification,
while enantiomeric purity is ensured on the derived
acyloins by chemical resolution using lactate deriva-
tives. Thus, rather than proceeding as described in the
literature,23 to increase the low e.e. of 4, we went
on subjecting the scalemic mixture to Pb(OAc)4-
mediated a-acetoxylation (3.5 equiv., 4 days at reflux
in dry benzene, under argon). Scalemic 10a- and
10b-acetoxyenones 5 were obtained in 78% yield
Scheme 2.

J. I. Candela Lena et al. / Tetrahedron: Asymmetry 12 (2001) 3281–3291
3283
Scheme 3. (a) Pb(OAc)4, PhH, reflux; (b) HLE, pH 7, rt; (c) (S)-2-acetoxypropionyl chloride, Et3N, DMAP, CH2Cl2, 0°C; (d)
LiAlH4, Et2O, 0°C; (e) Pb(OAc)4, MeCN, rt.
(epimeric mixture of a- and b-acetates, ca. 60:40 ratio)
along with side product 6 arising from acetate elimina-
tion.24 The acetoxyenones thus obtained formed an
epimeric mixture which was difficult to separate in large
scale preparations. However, the corresponding
acyloins 7 were easily separated at larger scale by silica
gel column chromatography as were the corresponding
lactate derivatives 8. This was suggestive of a resolution
at the acyloin level, provided that acetate hydrolysis
could be accomplished in high yields on a large scale.
Both chemical and enzymatic hydrolysis protocols have
been described to access a-ketols. Chemical hydrolysis
(K2CO3–MeOH) performed on small scales led to some
epimerization leading at room temperature mainly to
the 10a-alcohol, while at 0°C to a 4:1 mixture of a- and
b-alcohols was obtained. A further drawback of chemi-
cal hydrolysis is that upon scale-up a considerable
amount of unidentified rearrangement products were
obtained. Difficulties in saponifying acetyl esters having
a carbonyl group in the a-position have been noted
previously, but were circumvented by us using a lipase.
We thus focused on a lipase-mediated hydrolysis and
therefore started screening a number of relatively inex-
pensive lipases, searching simply for a high-yield
hydrolysis.25 Horse liver esterase (HLE, acetone pow-
der) cleaved the acetates cleanly, affording the desired
acyloins in quantitative yield. Even though enantiose-
lective hydrolysis was possible by varying the experi-
mental conditions, we preferred chemical resolution via
the lactate derivatives 8,26 which are easily separable by
chromatography, thus affording diastereomerically pure
material straightforwardly. The scalemic a-ace-
toxyenones 5 were first purified by silica gel column
chromatography to remove the side product 6 formed
during the acetoxylation process. Lipase-catalyzed
hydrolysis of scalemic acetoxy enone 5 was then carried
out under various conditions. We found that a 10:1
ratio of substrate to lipase was enough to hydrolyze
both (R)- and (S)-acetates at room temperature in
phosphate buffer after overnight stirring (only 10% of
the starting material was left unreacted). Using equal
masses of the substrate and the enzyme preparation did
not affect the result to an appreciable extent. In a
typical experiment 10 g of substrate and 2 g of the
lipase (20% HLE by weight) were stirred magnetically
on the bench (no need for an incubator/shaker) in 1 L
of phosphate buffer pH 7, in the presence of a small
amount of toluene to solubilize the sample (but this is
not even necessary) to afford quantitative yields of the
acyloins 7. A key feature of this combined enzymatic
hydrolysis/chemical resolution, where the enzyme is
used as a simple basic reagent to perform saponifica-
tion, is that multigram quantities can be easily prepared
and excellent chemical yields are obtained, without any
detectable formation of side products. Enantiodifferen-
tiation of scalemic secondary alcohols 7a and 7b was
carried out following chromatographic separation by
diastereoselective derivatization with (S)-O-acetyllactyl
chloride as a chiral auxiliary.27 Thus, starting from 7a,
diastereomeric derivatization with (S)-2-acetoxypropi-
onyl chloride in the presence of triethylamine and
DMAP in dry CH2Cl2 at 0°C under an inert atmo-
sphere afforded the corresponding esters 8a (steroid
series) and d-ent-8a (anti-steroid series) as a mixture of
diastereomers, which were then separated by flash chro-
matography using toluene–ether (8:1) as eluent. Start-
ing from 7b and proceeding as above, lactates 8b
(steroid series) and d-ent-8b (anti-steroid series) were
obtained and portions used for small-scale characteriza-
tion purposes, while the remaining amounts were taken
through to the next steps. All of the possible acyloins
and a-acetoxy enones were obtained in diastereomeri-
cally pure form using the combined enzymatic hydroly-
sis/chemical resolution sequence outlined in Scheme 4.
Small quantities of the lactate derivatives 8 were care-
fully saponified (K2CO3, MeOH–H2O, 10:1, −20°C)
affording the corresponding acyloins 7, while the major
lactates 8a and 8b (steroid series) were reduced directly
to the required unsaturated diols 9 (LiAlH4, Et2O, 0°C)
prior to oxidative cleavage. On the other hand, acetyla-
tion at C(10) of the homochiral acyloins 7 thus
obtained (Ac2O, Py, DMAP, 0°C, 1 h) afforded 90–
95% yields of the corresponding C(10) acetates 5, for
characterization.
Treatment of diastereomerically pure 9 (steroid series)
with 2 equivalents of Pb(OAc)4 in acetonitrile (room
temperature, 15 h) followed by filtration through Celite
and silica gel cleanly afforded the conveniently substi-
tuted cyclohexane (C-ring precursor) 15 in 82% isolated
yield. This is a reliable procedure, which we have
carried out several times on a multigram scale. The
mechanism of this one-pot multistage transformation,
resulting in ring expansion and functionality redistribu-
tion, has not been unequivocally established, but one
reasonable possibility is outlined in Scheme 5. The
presence of 2 equivalents of Pb(OAc)4 is required for

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J. I. Candela Lena et al. / Tetrahedron: Asymmetry 12 (2001) 3281–3291
Scheme 4. (a) HLE, pH 7, rt; (b) (S)-2-acetoxypropanoyl chloride, Et3N, DMAP, CH2Cl2, 0°C; (c) K2CO3, MeOH–H2O, 10:1,
−20°C; (d) Ac2O, Py, DMAP, 0°C; (e) LiAlH4, Et2O, 0°C. L*=CH3CH(OAc)CO.
Scheme 5.
the synthesis of the ring-expanded product 15; the first
equivalent is used for the cleavage while the second is
used in the oxyplumbation, which promotes ring expan-
sion. A mechanistic rationale involves initial formation
of 12 which collapses to 13 setting the stage for the next
transformation, electrophilic attack of the metal to the
olefin, leading to the formation of a carbonꢀlead bond
in the transient organolead intermediate 14. The strain
associated with the ring system and the geometry in the
transient organolead intermediate then favor ring
expansion, with concomitant loss of a Pb(OAc)2 unit
and acylation. All of this occurs in one-pot, which
makes an average 96% yield per transformation. The
ability of Pb4+ to perform different tasks, acting as an
oxidizing agent and as a Lewis acid, the low dissocia-
tion energy of the CꢀPb bond (31 Kcal/mol) and the
thermodynamically favorable valence change (redox
potential of Pb4+/Pb2+ is 1.7 V) account well for the
proposed mechanism of the cascade transformation,
even though this has not been convincingly
established.28
was realized straightforwardly starting from the ring
enlarged key intermediate 15 as follows. Conversion of
15 to 16+17 was accomplished by reduction with excess
LiAlH4 to the corresponding triol (epimeric mixture)
and subsequent selective acetonide formation (acetone,
pTosOH, rt, 24 h) in 78% combined yield and 3.5:1
ratio. Part of the mixture of acetonides thus obtained
was easily purified on silica gel (eluent: ethyl acetate–
heptane, 1:1) to afford pure syn-acetonide 16 (major
isomer) and anti-acetonide 17 (minor isomer) for char-
acterization, while the remaining crude was used in the
next step without separation. Exposure of isopropyli-
dene acetals 16+17 to benzyl bromide in the presence of
sodium hydride at room temperature in dry DMF
afforded a diastereomeric mixture of the corresponding
C(10)-O-benzyl ethers 18+19 in 88% combined yield.
This mixture was then converted to the aldehyde 24,
precursor of organostannanes 3 in five steps as follows.
Acetonide cleavage on 18 and 19, by treatment with 2N
aqueous HCl–THF, 1:1, at 0°C to room temperature
furnished the C(2),C(4) free diol (93%) as an epimeric
mixture, which was used directly in the next reaction in
the sequence. Subsequent selective protection of the
latter by stirring in dry methylene chloride with tert-
The assembly of the target a-alkoxyorganostannanes 3
to be used as C(10) nucleophiles for the A+C linking

J. I. Candela Lena et al. / Tetrahedron: Asymmetry 12 (2001) 3281–3291
3285
butyldimethylsilyl chloride (TBDMSCl) in the presence
of 4-DMAP at 0°C to room temperature for 2 h
converted the primary hydroxyl group at C(2) to its
tert-butyldimethylsilyl ether, in the presence of the free
secondary alcohol at C(4) (98%). The C(20) carbon
atom was then introduced via Swern oxidation (92%)
which was followed by Tebbe29 olefination (0.6 equiva-
lents of commercial Tebbe reagent, THF, 0°C to room
temperature) affording cleanly 22 (50% along with
unreacted starting material, 47%) bearing the exocyclic
C(4)–(20) olefin. Cleavage of the benzyl protective
group using Li-NH3(liq.) at −78°C afforded the corre-
sponding alcohol 23 quantitatively. Swern oxidation
provided the required aldehyde 24 in 93% yield. This
material was converted to the organotin acetal in a
two-step sequence using the Still protocol. Addition of
n-Bu3SnLi (1.1 equiv. prepared from equimolar quanti-
ties of n-Bu3SnH and LDA) in dry THF followed by
etherification with chloromethyl methyl ether in the
presence of i-Pr2NEt at room temperature in dry
CH2Cl2, furnished the requisite a-alkoxyorganostan-
nanes (10S)-3 and (10R)-3 as a diastereomeric mixture
(C(10) epimers) in ca. 1:1 ratio and 75% combined yield
(Scheme 6).
C-ring construction. The original aim of our investiga-
tions in this area was to determine if implementation of
the Pb(OAc)4-mediated cascade methodology could
lead to solutions of the length-problems in synthesizing
stereodefined polysubstituted cyclic systems. The prepa-
ration of the desired C-ring precursor 3 in dia-
stereomerically pure form demonstrates the appli-
cability of this approach to various taxoid representa-
tives. Furthermore, we provide complete characteriza-
tion of all intermediates. The enantiomeric purity of
(S)-hydrindenone 4 rests on that of (R)-hydrindenone;
that compound was reported to have an e.e. of 90%.18
Our route gives more reliable exact values as it is based
on diastereomeric separation of lactate derivatives.
4. Experimental
Experiments which required an inert atmosphere were
carried out under dry argon in a flame dried glass
system. Solvents and reagents used in this work were
purified according to standard literature techniques and
stored under argon. THF and benzene were freshly
distilled from LiAlH4 and CaH2, respectively, and were
transferred via syringe. Methylene chloride was distilled
from P2O5. Acetonitrile was distilled from CaH2. Com-
mercial reagents were purchased from Aldrich Chemi-
cals and used as received. ‘Usual work up’ means
washing of the organic layer with brine, drying over
anhydrous MgSO4, filtering and evaporating the filtrate
in vacuo with a rotary evaporator at aspirator pressure.
Optical rotations were recorded in CHCl3 solution in a
1 dm cell using a JASCO P-1010 polarimeter. IR spec-
tra were recorded on a Perkin Elmer BX FTIR instru-
ment, neat or in chloroform. Melting points were taken
on a Bu¨chi B-540 melting point apparatus and are
The specific rotations of all non-racemic substrates
obtained in this process were in good agreement with
those values measured on the Hajos–Parrish ketone
derived analogues of known absolute stereochemistry.
The configurations at C(10) were assigned by analogy
to the Hajos–Parrish series on the basis of our previous
work, where the C(10) absolute stereochemistry of the
C(7)-O-tBu analogues was established by their conver-
sion to the taxoid ABC-ring system.
3. Conclusion
1
reported uncorrected. H NMR spectra were obtained
on Bruker AM300 instrument in CDCl3. Chemical
shifts are expressed in ppm downfield from TMS; the
This paper reports the synthesis and characterization of
new hydrindene derivatives and their use in taxoid
Scheme 6. (a) LiAlH4, THF, reflux, then acetone, pTosOH, rt; (b) BnBr, NaH–DMF; (c) 2N HCl–THF, 1:1, 0°C then DMAP,
TBSCl, CH2Cl2, 0°C to rt; (d) DMSO, oxalyl chloride, Et3N, CH2Cl2, −60°C; (e) Tebbe reagent, THF, 0°C to rt; (f) Li-NH3(liq),
THF, tBuOH, −78°C; (g) n-Bu3SnLi, THF, −78°C then MOMCl, i-Pr2NEt, 0°C to rt.

3286
J. I. Candela Lena et al. / Tetrahedron: Asymmetry 12 (2001) 3281–3291
1H NMR data, measured at 300 MHz, is presented in
the order: l 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. 13C NMR
spectra were measured at 75 MHz and the chemical
shifts are reported relative to CDCl3 triplet centered
at 77.00 ppm. For all compounds investigated, multi-
plicities of 13C resonances were assigned by the SEFT
technique.30 Mass spectra (MS) are abbreviated as
follows: electron impact spectra, EI, chemical ioniza-
tion spectra, CI, fast atom bombardment FAB, spec-
tra acquired in the positive ion mode under electron
spray ionization (ES+) using a mobile phase of
methanol, ESIMS (MeOH), high resolution mass
spectra, HR and are reported in the form: ‘m/z
(intensity relative to base peak=100%)’. Microanaly-
ses were performed by the microanalytical laboratory
of this institute. 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. Horse liver esterase was pur-
chased from Sigma Chemical Co.
4.2. General procedure for horse liver esterase-cata-
lyzed hydrolysis of the acetates
The enone acetates 5, obtained pure after silica gel
column chromatography, were first recrystallized in
ether, at 0°C. This precipitates only the a-acetate in
quasi-racemic form ([h]D +5), thus increasing the e.e.
of the scalemic mixture. To a mixture of acetates (100
mg) in phosphate buffer (20 mM, pH 7, 30 mL) and
toluene (1 mL) as co-solvent was added commercially
available horse liver esterase (20 mg acetone powder)
at room temperature. The mixture was stirred (mag-
netic stirrer) for 12 h monitoring the reaction by
TLC. Typically the reaction was complete after 24 h.
The mixture was diluted with ethyl acetate and
filtered through Celite. The extract was washed with
brine, dried over magnesium sulfate filtered and the
filtrate concentrated in vacuo. The residue was chro-
matographed on silica gel.
This procedure can be scaled up without problem; the
ratio of enzyme to substrate can in many cases be
lowered to 0.1 without a marked effect on the rate of
the reaction (nearly 90% hydrolysis along with unre-
acted starting material). We did not attempt enan-
tioselective hydrolysis as chromatographic separation
of the lactate derivatives was practical enough.
4.1. General procedure for the preparation of a-
acetoxyenones
4.3. General procedure for preparation of the unsatu-
rated diols by LAH reduction
To enone 4 (68.5 mmol) in a three-neck flask,
equipped with a Dean–Stark apparatus, was added
Pb(OAc)4 (225 mmol) and the reaction vessel was
vacuum dried while flushed with argon. Freshly dis-
tilled benzene (240 mL) was then added and the reac-
tion mixture was refluxed for 4 days under an inert
atmosphere. After cooling to room temperature, a
large volume of ether was added (five times the vol-
ume of the solvent) and the reaction mixture was
stirred for an additional 1 h, filtered and the filtrate
was washed with brine and water. The organic layer
was then dried over anhydrous magnesium sulfate,
concentrated under reduced pressure and chro-
matographed on silica gel. Yields for the acetoxyla-
tion were nearly quantitative, taking into account that
byproduct 6 (22%; e.e. 72%) was formed from the
acetoxy enones 5. Dienone 6 was known in its
racemic form, synthesized by treating the also known
hydrindenone 4 with selenium dioxide according to
the method of Bloom.24 Later, Caine et al.18 resynthe-
To a suspension of LiAlH4 (4 mmol) in anhydrous
Et2O (5 mL), cooled at 0°C, was added dropwise a
solution of the acetoxyenone (1 mmol) in anhydrous
ether (2 mL). After stirring at 0°C for 30–40 min
(TLC monitoring) the mixture was diluted with wet
Et2O and treated with a small amount of 15% aq.
NaOH solution. The organic layer was worked up as
usual to give the desired diols after silica gel chro-
matography (ethyl acetate–heptane, 1:1). The same
procedure was used to directly reduce the lactates 8
into the diols 9.
4.4. General procedure for the acetylation of the
stereopure a-ketols 7
Acetic anhydride (0.3 mL) was added to a stirred
mixture of the acyloins 7 (95 mg, 0.57 mmol) and
DMAP (catalytic) in pyridine (2.0 mL) at 0°C under
argon. After 50 min, the mixture was diluted with
CH2Cl2 quenched with satd aq. NaHCO3, washed
with aqueous hydrochloric acid (1N), saturated
sodium bicarbonate, water, brine and dried over mag-
nesium sulfate. The solvent was evaporated under
reduced pressure and the residue was chro-
matographed (SiO2, eluent heptane–EtOAc, 3:1) to
give 113 mg (95%) of 5. 5a: mp: 53–55°C (heptane–
ether). [h]D +114 (c 2.28). IR (Nujol): 2970, 2867,
1753, 1696, 1635, 1463, 1380, 1227, 1145, 1110, 1070,
1046, 895, 875, 840, 704 cm−1. 1H NMR: 1.30 (3H,
s), 1.55 (1H, dt, J=8.1, 11.6), 1.78–2.03 (3H, m), 1.99
(1H, dd, J=12.1, 13.4), 2.18 (3H, s), 2.30 (1H, dd,
J=5.3, 12.1), 2.50 (1H, m), 2.74 (1H, m), 5.59 (1H,
1
sized racemic 6 and described its 60 MHz H NMR
spectrum in CCl4. 6: [h]D −54 (c 1.42). IR (film):
2968, 1664, 1637, 1603, 1460, 1391, 1095, 981, 912,
1
866, 732 cm−1. H NMR: 1.20 (3H, s), 1.58 (1H, dd,
J=9.5, 11.2), 1.75–2.13 (3H, m), 2.48 (1H, ddd, J=
5.9, 9.5, 15.2), 2.80 (1H, dddd, J=2.4, 5.4, 7.7, 11.0),
6.02 (1H, q, J=1.8), 6.13 (1H, dd, J=1.7, 9.8), 7.02
(1H, d, J=9.8). 13C NMR: 20.9, 25.6, 29.0, 34.8,
46.4, 121.9, 127.7, 153.5, 174.3, 186.8. EIMS: 148
([M]+, 92), 147 (46), 133 (54), 122 (38), 120 (79), 119
(47), 106 (32), 105 (99), 104 (56), 103 (46), 93 (29), 92
(95), 91 (100), 90 (52), 79 (76), 77 (84), 76 (36), 67
(21), 65 (71), 63 (61), 55 (59). HREIMS: calcd for
C10H12O 148.0888, found 148.0882.

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3287
dd, J=5.3, 13.4), 5.84 (1H, t, J=1.9). 13C NMR: 20.6,
20.8, 22.9, 30.3, 40.8, 42.0, 44.0, 70.7, 119.9, 170.2,
177.6, 193.3. EIMS: 208 ([M]+, 1), 166 (2), 123 (14), 122
(100), 121 (28), 107 (16), 79 (34), 77 (23). Anal. calcd
for C12H16O3 C, 69.21; H, 7.74%; found: C, 69.04; H,
7.81%. Ent-5a: [h]D −112 (c 2.24). 5b: [h]D +32 (c 1.55).
IR (film): 2963, 1744, 1675, 1639, 1462, 1372, 1296,
1229, 1155, 1099, 1028, 972, 887, 863, 736, 702 cm−1. 1H
NMR: 1.24 (3H, s), 1.46 (1H, dt, J=8.2, 11.8), 1.75–
2.04 (3H, m), 1.98 (1H, dd, J=5.7, 14.9), 2.08 (3H, s),
2.31 (1H, dd, J=1.9, 14.9), 2.54 (1H, m), 2.77 (1H, m),
5.21 (1H, dd, J=1.9, 5.7), 5.90 (1H, t, J=1.9). 13C
NMR: 20.7, 21.0, 26.0, 30.8, 40.1, 40.4, 41.8, 69.7,
119.9, 169.6, 180.3, 192.5. EIMS: 208 ([M]+, 16), 166
(47), 123 (69), 122 (100), 121 (87), 120 (34), 108 (19),
107 (79), 106 (30), 95 (42), 94 (69), 91 (72), 80 (57), 79
(92), 77 (82), 67 (52), 65 (63), 55 (70). Ent-5b: [h]D −31
(c 1.18).
equiv.) were added at 0°C. After 25 min at this temper-
ature (TLC monitoring) the reaction mixture was
quenched with
a saturated solution of aqueous
NaHCO3. Extraction with CH2Cl2, washing with 1N aq
HCl, NaHCO3, water and brine and finally drying over
MgSO4 afforded a crude residue from which the lac-
tates were separated on silica gel (eluent toluene–ether,
8:1 to 6:1) to give 1.67 g (96% combined yield) of a
mixture of lactates 8a (steroid series, 952 mg, 89%) and
d-ent-8a (anti-steroid series, 115 mg, 11%). 8a: [h]D +46
(c 4.16). IR (film): 2940, 1744, 1686, 1638, 1454, 1372,
1307, 1236, 1132, 1101, 1067, 1051, 1018, 949, 877
1
cm−1. H NMR: 1.22 (3H, s), 1.49 (1H, m), 1.49 (3H, d,
J=7.1), 1.72–1.98 (4H, m), 2.04 (3H, s), 2.23 (1H, dd,
J=5.4, 12.1), 2.45 (1H, m), 2.67 (1H, m), 5.12 (1H, q,
J=7.1), 5.47 (1H, dd, J=5.4, 13.4), 5.75 (1H, t, J=
1.8). 13C NMR: 16.9, 20.5 (2C), 22.8, 30.2, 40.7, 41.6,
43.9, 68.6, 71.4, 119.7, 169.9 (2C), 177.7, 192.1. EIMS:
280 ([M]+, 1), 187 (2), 166 (2), 123 (28), 122 (100), 121
(56), 115 (26), 107 (26), 94 (18), 93 (21), 91 (25), 87 (60),
79 (49), 77 (35), 67 (14), 65 (17), 56 (14), 55 (48), 44
(26), 43 (96), 41 (25). d-Ent-8a: mp: 68–69°C (heptane–
ether). [h]D −93 (c 1.98). IR (film): 2966, 2940, 2871,
1743, 1687, 1639, 1455, 1425, 1373, 1307, 1241, 1197,
4.5. General procedure for mild hydrolysis of C(10)
lactyl functionality: preparation of stereopure a-ketols
Diastereopure lactate derivative 8a (377 mg, 1.34
mmol) was dissolved in MeOH (7 mL), K2CO3 (742
mg, 5.38 mmol, 4 equiv.) and then water (0.7 mL) were
added at −25°C. After stirring for 55 min at this
temperature (TLC monitoring) MeOH was evaporated
under reduced pressure without heating and the residue
was taken into ethyl acetate. Following washing with
brine, the organic layer was dried over MgSO4 and
flash chromatographed (eluent heptane–EtOAc, 3:1) to
yield 7a (204 mg, 92%): [h]D +122 (c 2.15). IR (film):
3475, 2964, 2936, 2864, 1674, 1637, 1463, 1422, 1379,
1275, 1218, 1169, 1110, 1074, 963, 922, 877, 840 cm−1.
1H NMR: 1.23 (3H, s), 1.50 (1H, dt, J=7.9, 11.6),
1.67–2.10 (4H, m), 2.41 (1H, dd, J=5.4, 12.2), 2.51
(1H, m), 2.71 (1H, m), 3.65 (1H, d, J=1.6), 4.34 (1H,
ddd, J=1.6, 5.4, 13.1), 5.83 (1H, t, J=1.9). 13C NMR:
20.2, 22.7, 30.5, 40.9, 44.0, 44.7, 69.2, 118.4, 179.7,
199.7. EIMS: 166 ([M]+, 3), 123 (24), 122 (100), 121
(77), 120 (25), 107 (38), 94 (28), 93 (29), 91 (23), 80 (24),
79 (85), 78 (50), 77 (49), 76 (26), 66 (30), 65 (41), 55
(41). Ent-7a: [h]D −121 (c 1.98). 7b: mp: 71–73°C (hep-
tane–ether). [h]D +25 (c 1.35). IR (film): 3434, 3055,
2964, 1660, 1422, 1378, 1266, 1236, 1209, 1169, 1103,
1
1134, 1102, 1067, 1052, 1017, 878, 735 cm−1. H NMR:
1.38 (3H, s), 1.68 (1H, m), 1.71 (3H, d, J=7.1), 1.90–
2.15 (3H, m), 2.24 (3H, s), 2.36–2.49 (2H, m), 2.60 (1H,
m), 2.83 (1H, m), 5.20 (1H, q, J=7.1), 5.72 (1H, dd,
J=5.4, 13.6), 5.91 (1H, bs). 13C NMR: 16.9, 20.6 (2C),
22.9, 30.3, 40.8, 41.8, 44.0, 68.6, 71.2, 119.7, 170.3 (2C),
177.9, 192.5. EIMS: 280 ([M]+, 2), 166 (3), 123 (35), 122
(100), 121 (53), 115 (15), 107 (34), 94 (20), 93 (25), 91
(31), 87 (45), 79 (54), 77 (41), 65 (19), 55 (40). Anal.
calcd for C15H20O5 C, 64.27; H, 7.19; found: C, 64.22;
H, 7.27%. 8b: [h]D +39 (c 4.16). IR (film): 2964, 1749,
1675, 1637, 1456, 1373, 1296, 1239, 1194, 1133, 1099,
1
1052, 1018, 958, 918, 868, 733 cm−1. H NMR: 1.28
(3H, s), 1.49 (1H, m), 1.50 (3H, d, J=7.1), 1.77–2.01
(3H, m), 2.02 (1H, dd, J=5.9, 14.9), 2.13 (3H, s), 2.37
(1H, dd, J=1.9, 14.9), 2.56 (1H, m), 2.81 (1H, m), 4.99
(1H, q, J=7.1), 5.25 (1H, dd, J=1.9, 5.9), 5.92 (1H, t,
J=1.9). 13C NMR: 16.6, 20.5, 20.9, 26.3, 31.0, 40.0,
40.4, 41.9, 68.7, 70.5, 119.9, 169.9, 170.3, 180.8, 191.8.
EIMS: 280 ([M]+, 1), 166 (2), 123 (25), 122 (100), 121
(49), 115 (16), 107 (22), 94 (16), 93 (21), 91 (25), 87 (38),
79 (46), 77 (36), 67 (14), 65 (17), 55 (38). d-Ent-8b: [h]D
−42 (c 2.11). IR (film): 2965, 1747, 1675, 1639, 1456,
1373, 1267, 1240, 1168, 1132, 1098, 1051, 1018, 958,
1
1050, 963, 893, 846, 739, 704 cm−1. H NMR: 1.25 (3H,
s), 1.51 (1H, dt, J=8.3, 11.6), 1.75–2.03 (3H, m), 2.01
(1H, dd, J=6.6, 14.4), 2.19 (1H, dd, J=3.2, 14.4), 2.52
(1H, m), 2.75 (1H, m), 3.04 (1H, m), 4.08 (1H, m), 5.89
(1H, t, J=1.8). 13C NMR: 20.8, 27.0, 30.7, 40.1, 40.6,
42.3, 69.1, 118.6, 180.1, 198.6. EIMS: 166 ([M]+, 4), 123
(25), 122 (100), 121 (60), 107 (50), 94 (33), 91 (29), 80
(27), 79 (85), 77 (60), 66 (31), 65 (39), 55 (28). Anal.
calcd for C10H14O2 C, 72.26; H, 8.49; found: C, 71.99;
H, 8.47%. Ent-7b: [h]D −24 (c 1.33).
1
884, 738, 704 cm−1. H NMR: 1.19 (3H, s), 1.47 (3H, d,
J=7.1), 1.50 (1H, m), 1.74–2.17 (4H, m), 2.06 (3H, s),
2.24 (1H, dd, J=1.9, 15.1), 2.53 (1H, m), 2.74 (1H, m),
5.12 (1H, q, J=7.1), 5.28 (1H, dd, J=1.9, 5.8), 5.89
(1H, t, J=1.9). 13C NMR: 16.8, 20.6, 20.9, 26.4, 31.0,
40.2, 40.4, 41.8, 68.6, 70.1, 120.1, 169.6, 170.0, 180.4,
191.6. EIMS: 280 ([M]+, 1), 166 (2), 123 (16), 122 (100),
121 (29), 107 (16), 94 (10), 93 (14), 91 (19), 87 (33), 79
(34), 77 (26), 65 (10), 55 (19).
4.6. Resolution of scalemic acyloins: preparation of lac-
tate derivatives 8
4.7. General procedure for the preparation of the
unsaturated diols 9
Scalemic 7a (6.64 g, 40 mmol) was dissolved in dry
CH2Cl2 (400 mL) at 0°C; Et3N (33 mL, 240 mmol, 6
equiv.), DMAP (9.77 g, 80 mmol, 2 equiv.) and 10 min
later (S)-O-acetyllactyl chloride (18 mL, 160 mmol, 4
To a suspension of LiAlH4 (855 mg, 22.5 mmol) in
anhydrous ether (20 mL), cooled at 0°C, was added

3288
J. I. Candela Lena et al. / Tetrahedron: Asymmetry 12 (2001) 3281–3291
dropwise a solution of diastereomerically pure lactate
8a (1.57 g, 5.62 mmol) in anhydrous ether (10 mL). The
reaction mixture was stirred at 0°C for 1 h at which
point no starting material remained (TLC monitoring),
and then diluted with wet ether and treated with a small
amount of 15% aq. NaOH solution. The organic layer
was worked up as usual to give diols 9a and 9b as an
epimeric mixture (915 mg, 97% combined yield) after
filtration on silica gel (ethyl acetate–heptane, 1:1). 9a:
[h]D +159 (c 0.60). IR (film): 3368, 2957, 2929, 1676,
1459, 1434, 1262, 1164, 1119, 1059, 1025, 1000, 980,
reaction was quenched with water, and after addition of
15% NaOH and water, stirred at room temperature for
1 h. Filtration and concentration under reduced pres-
sure yielded a mixture of alcohols. A portion of the
thus obtained alcohols (7.14 g, 38.0 mmol) was dis-
solved in dry acetone (310 mL) and pTosOH (723 mg,
3.8 mmol) was added. The mixture was stirred under
argon at 0°C for 1 h. The reaction mixture was filtered
through a pad of alumina using EtOAc–MeOH (9:1) as
solvent, the filtrate was concentrated under reduced
pressure and the residue was purified by flash chro-
matography on silica gel. Elution with heptane–ethyl
acetate (1:1) afforded a 78% combined yield (in a 3.5:1
ratio). First eluting major-syn acetonide 16: [h]D +21 (c
1.74). IR (film): 3414, 2991, 2936, 2874, 1642, 1459,
1384, 1362, 1281, 1259, 1229, 1173, 1145, 1103, 1074,
1048, 1026, 1000, 984, 933, 869, 859, 756 cm−1. 1H
NMR: 0.92 (3H, s), 0.93 (1H, m), 1.28–2.20 (6H, m),
1.34 (3H, s), 1.40 (3H, s), 1.50 (1H, td, J=4.2, 13.1),
1.84 (1H, quintet, J=7.5), 2.34 (1H, quintet, J=7.5),
3.61 (2H, t, J=7.7), 3.88–4.02 (2H, m), 4.09 (1H, dd,
J=3.5, 6.5). 13C NMR: 17.0, 19.0, 27.5, 29.5, 31.9, 34.3,
36.9, 38.2, 44.1, 59.6, 60.6, 67.0, 98.0. CIMS: 229
([MH]+, 39), 225 (14), 213 (79), 199 (4), 183 (10), 171
(60), 153 (100), 151 (44), 135 (28). Second eluting minor
anti-acetonide 17: [h]D +17 (c 1.08). IR (film): 3402,
2992, 2938, 2881, 1652, 1461, 1382, 1265, 1199, 1165,
1123, 1100, 1073, 1050, 1021, 944, 894, 853, 755 cm−1.
1H NMR: 0.94 (3H, s), 1.08 (1H, dt, J=3.4, 13.2),
1.24–1.66 (7H, m), 1.37 (3H, s), 1.45 (3H, s), 1.80–1.95
(2H, m), 3.64 (2H, t, J=6.9), 3.77–3.86 (2H, m), 3.92
(1H, ddd, J=4.4, 10.6, 15.0). 13C NMR: 19.4, 20.0,
26.5, 29.8, 32.5, 34.3, 34.9, 36.9, 50.7, 58.9, 60.2, 68.8,
98.1. CIMS: 229 ([MH]+, 39), 225 (14), 213 (79), 199
(4), 183 (10), 171 (60), 153 (100), 151 (44), 135 (28).
HRCIMS calcd for C13H25O3 229.1803, found
229.1802.
1
908, 894, 855 cm−1. H NMR: 1.02 (3H, s), 1.17–1.43
(2H, m), 1.39 (1H, t, J=12.1), 1.65–1.88 (4H, m), 1.81
(1H, dd, J=3.7, 12.1), 2.26 (1H, m), 2.45 (1H, m), 3.94
(1H, td, J=4.0, 12.5), 4.08 (1H, bs), 5.50 (1H, bs). 13C
NMR: 20.3, 23.9, 28.5, 39.8, 40.9, 43.5, 66.3, 67.6,
116.6, 154.5. 9b: mp: 80–82°C (heptane–ether). [h]D +3
(c 1.14). IR (film): 3350, 2957, 2930, 2858, 1680, 1460,
1
1375, 1113, 1058, 1022, 944, 877, 841 cm−1. H NMR
(300 MHz): 1.04 (3H, s), 1.29 (1H, q, J=10.7), 1.47
(1H, t, J=12.4), 1.57–1.85 (3H, m), 1.91 (1H, dd,
J=3.6, 12.4), 2.14 (1H, m), 2.38 (1H, m), 3.88 (1H, m),
4.08 (1H, bs), 4.37 (2H, bs), 5.18 (1H, bs). 13C NMR:
20.6, 24.5, 28.0, 40.9, 43.1, 43.5, 72.2, 75.2, 117.9, 151.3.
CIMS: 169 ([MH]+, 29), 152 (10), 151 (100), 147 (7),
133 (92), 130 (10), 124 (25), 119 (10). Anal. calcd for
C10H16O2 C, 71.39; H, 9.59; found: C, 71.31; H, 9.52%.
Ent-9a: [h]D −152 (c 0.85). Ent-9b: [h]D −3 (c 1.08).
4.8. Cascade transformations in acetonitrile
A dry flask was charged with the mixture of diols 9a+9b
(16.6 g, 99 mmol) and Pb(OAc)4 (131.5 g, 297 mmol, 3
equiv.) the flask was placed under vacuum, flushed with
argon and cooled to nearly 0°C. Acetonitrile (400 mL)
was added, the ice bath was removed soon after and the
mixture was stirred at room temperature for 24 h,
diluted with acetonitrile, filtered through Celite, the
filtrate was concentrated and purified by silica gel chro-
matography using ethyl acetate–heptane (1:2) as eluent
to give 15 (24.5 g, 87%). Proceeding similarly but in
different solvents, such as acetic acid, toluene or
dichloromethane, the ring expanded compound was
obtained in 75–85% isolated yields. 15: mp: 77–79°C
(heptane–ether). [h]D −83 (c 1.08). IR (film): 2941, 1733,
1445, 1368, 1256, 1224, 1191, 1071, 1035, 981, 913, 840,
4.10. C(10) O-Bn protection
Sodium hydride (60% w/w in mineral oil; 0.71 g, 29.6
mmol) was washed twice with dry hexane under an
argon atmosphere and the remainder of the hexane
removed via syringe and the flask vacuumed, then filled
with argon. DMF (2 mL) at 0°C and then isopropyli-
dene alcohols 16+17 (1.02 g, 4.47 mmol) in DMF (6
mL) were added dropwise. After stirring for 0.5 h at
room temperature, the reaction mixture was cooled to
0°C and BnBr (1.59 mL, 13.4 mmol) was added drop-
wise and the mixture was stirred for 4 h. Water and
ether were added, the two phases separated and the
organic phase was worked up as usual. Chromatogra-
phy of the residue (eluent: heptane–EtOAc, 8:1 to 3:1)
gave 18 and 19 in 88% combined yield. C(10)-O-Bn
minor trans-acetonide 18: [h]D +8 (c 2.27). IR (film):
2936, 1455, 1381, 1265, 1199, 1165, 1102, 1074, 855, 736
1
733, 648 cm−1. H NMR: 1.28 (3H, s), 1.31–1.87 (5H,
m), 1.69 (1H, dd, J=1.5, 14.0), 1.84 (1H, dd, J=2.8,
14.0), 2.11 (3H, s), 2.12 (3H, s), 2.28 (1H, m), 2.75 (1H,
s), 5.31 (1H, dd, J=1.5, 2.8), 6.47 (1H, d, J=1.0). 13C
NMR: 18.8, 21.2, 22.5, 27.8, 31.7, 33.4, 38.0, 39.6, 41.3,
90.6, 92.2, 104.1, 169.6 (2C). ESIMS (MeOH): 323
([MK]+, 5), 307 ([MNa]+, 68). Anal. calcd for C14H20O6
C, 59.14; H, 7.09; found: C, 58.97; H, 7.11%. Ent-15:
[h]D +82 (c 1.08).
1
4.9. Reduction of 15 and selective acetonide formation
cm−1. H NMR: 0.95 (3H, s), 1.07 (1H, ddd, J=4.4,
14.3, 18.5), 1.20–1.66 (5H, m), 1.38 (3H, s), 1.45 (3H, s),
1.77–2.02 (3H, m), 3.46 (2H, m), 3.76–3.91 (2H, m),
3.93 (1H, ddd, J=4.4, 10.3, 15.0), 4.50 (2H, s), 7.26–
7.40 (5H, m). 13C NMR: 19.4, 20.0, 26.4, 29.8, 31.8,
32.5, 34.3, 36.9, 50.7, 60.2, 66.7, 68.7, 73.2, 98.0, 127.5
(3C), 128.3 (2C), 138.2. CIMS: 319 ([MH]+, 52), 303
To a stirred suspension of lithium aluminum hydride
(11.9 g, 313 mmol) in THF (500 mL) a solution of 15
(17.8 g, 63 mmol) in THF (20 mL) was added at room
temperature. The mixture was heated under reflux for 4
h and then stirred at room temperature for 6 h, the

J. I. Candela Lena et al. / Tetrahedron: Asymmetry 12 (2001) 3281–3291
3289
(22), 261 (100), 243 (30), 231 (18), 211 (7), 153 (98), 135
(18), 123 (8), 109 (7), 91 (34). HRCIMS calcd for
C20H31O3 319.2273, found 319.2281. C10-O-Bn major
cis-acetonide 19: [h]D +13 (c 2.35). IR (film): 2935, 1455,
1380, 1362, 1259, 1229, 1198, 1145, 1104, 1027, 969, 861,
828, 735, 698 cm−1. 1H NMR: 0.99 (3H, s), 0.99 (1H, m),
1.42 (1H, m), 1.43 (3H, s), 1.48 (3H, s), 1.57 (1H, td,
J=3.7, 13.2), 1.67–1.90 (4H, m), 1.99 (1H, quintet,
J=7.4), 2.51 (1H, quintet, J=7.4), 3.57 (2H, dd, J=6.6,
8.1), 4.00–4.05 (2H, m), 4.16 (1H, dd, J=3.5, 6.5), 4.54
(2H, s), 7.28–7.38 (5H, m). 13C NMR: 17.2, 19.2, 27.6,
29.6, 32.0, 34.4, 34.5, 36.7, 44.2, 60.6, 67.1, 67.6, 72.5,
97.9, 127.2, 127.3 (2C), 128.2 (2C), 138.9. HRCIMS calcd
for C20H31O3 319.2273, found 319.2277.
argon. We found it more economically favourable to
proceed using half of the required amount, as using even
large excesses of such an expensive reagent gave repro-
ducibly yields not exceeding 50%. The reaction mixture
was stirred at room temperature for 40 min, then cooled
at 0°C, diluted with ether and 0.1 M NaOH was added
dropwise until gas evolution ceased. Filtration through
a pad of Celite and MgSO4 followed by chromatography
(heptane–EtOAc, 6:1) afforded 22 (413 mg, 50%) and
recovered starting ketone 21 (391 mg, 47%). 22: [h]D −18
(c 2.25). IR (film): 3018, 2930, 2885, 2857, 1648, 1472,
1463, 1378, 1364, 1257, 1216, 1100, 1028, 1006, 939, 891,
838, 814, 758, 698, 668 cm−1. 1H NMR: 0.04 (6H, s), 0.90
(9H, s), 0.98 (3H, s), 1.29 (1H, m), 1.50–1.73 (5H, m),
2.01 (1H, dd, J=4.8, 7.7), 2.06–2.20 (2H, m), 3.56 (2H,
t, J=6.8), 3.73 (1H, dd, J=8.2, 10.0), 3.83 (1H, dd,
J=4.7, 10.1), 4.52 (2H, s), 4.46 (1H, bs), 4.80 (1H, bs),
7.28–7.38 (5H, m). 13C NMR: −5.4 (2C), 18.2, 23.0, 25.2,
25.9 (3C), 33.1, 35.1, 35.9, 37.8, 55.6, 61.4, 66.9, 73.0,
110.0, 127.4, 127.5 (2C), 128.3 (2C), 138.6, 147.6. ESIMS
(MeOH): 427 ([MK]+, 15), 411 ([MNa]+, 75), 389 ([MH]+,
42).
4.11. Installation of the C(4)–(20) exocyclic olefin
Acetonide cleavage (2N HCl–THF, 1:1, 0°C to room
temperature, 4 h) of 18+19 (2.62 g, 8.23 mmol) afforded
the corresponding diol (2.13 g, 93%) which was
monoprotected at the C(2) primary hydroxyl group as
follows. A crude solution of 1,3-diol thus obtained (2.27
g, 8.16 mmol), DMAP (3.21 g, 26.3 mmol), and tert-
butyldimethylsilyl chloride (1.95 g, 12.9 mmol), in
CH2Cl2 (35 mL), was stirred at 0°C to room temperature
for 4 h. The reaction mixture was then diluted with
CH2Cl2, washed with 1N HCl, then saturated aq.
NaHCO3 and worked up as usual. Filtration of the crude
product on silica gel (heptane–EtOAc, 6:1 as eluent)
afforded 20 as a white solid (3.14 g, 98%) (C(4) epimeric
mixture), which was used without diastereomeric separa-
tion for the Swern oxidation. To a stirred solution of
dimethyl sulfoxide (1.41 mL, 19.9 mmol) in CH2Cl2 (10
mL) cooled at −60°C, was added dropwise a solution of
oxalyl chloride (2 M in CH2Cl2, 4.97 mL, 9.93 mmol) in
CH2Cl2 (45 mL) under argon. The reaction mixture was
stirred for 30 min and then a solution of alcohol 20 (1.95
g, 4.97 mmol) in CH2Cl2 (40 mL) was added slowly. The
reaction mixture was stirred for 30 min, triethylamine
(3.46 mL, 24.8 mmol) was added and the reaction
mixture was allowed to warm quickly to 0°C and stirred
for 1.5 h before water was added. The organic layer was
diluted with CH2Cl2, washed with 1N HCl, satd
NaHCO3 and brine, dried over MgSO4 and concentrated
under reduced pressure. Silica gel flash column chro-
matography (heptane–EtOAc, 20:1 to 6:1) afforded 92%
of 21: [h]D −22 (c 2.43). IR (film): 3065, 3031, 2931, 2856,
1716, 1496, 1472, 1463, 1382, 1363, 1310, 1256, 1214,
1090, 1028, 1006, 940, 886, 838, 814, 777, 736, 698 cm−1.
1H NMR: 0.04 (6H, s), 0.87 (9H, s), 1.05 (3H, s),
1.45–1.62 (3H, m), 1.79–1.89 (3H, m), 2.24–2.27 (3H, m),
3.48 (2H, t, J=7.1), 3.73 (1H, dd, J=4.8, 10.2), 4.02 (1H,
dd, J=7.9, 10.2), 4.47 (2H, s), 7.25–7.38 (5H, m). 13C
NMR: −5.6 (2C), 18.1, 22.2, 25.5, 25.8 (3C), 34.8, 35.8,
39.8, 40.3, 59.5, 63.2, 66.2, 73.0, 127.4 (3C), 128.3 (2C),
138.2, 211.9. CIMS: 391 ([MH]+, 10), 335 (10), 283 (19),
259 (10), 241 (16), 225 (8), 199 (8), 167 (19), 151 (8), 125
(12), 91 (100). HRCIMS: calcd for C23H39O3Si 391.2668,
found 391.2671.
4.12. Preparation of the C(10) aldehyde
To a stirred solution of 22 (783 mg, 2.02 mmol) in
liquid ammonia (150 mL) and THF (22 mL), in the
presence of tBuOH (1.85 mL), lithium metal (140 mg)
was added portionwise at −78°C. The mixture was
stirred for 10 min (blue color). Ammonia was evapo-
rated while heptane (technical grade) was added period-
ically. Evaporation to dryness, dilution with ether and
usual work up, afforded after chromatography (hep-
tane–EtOAc, 6:1) 601 mg (100%) of the C(10) O-deben-
zylated compound 23: [h]D −36 (c 1.36). IR (film): 3350,
2929, 2856, 1648, 1471, 1462, 1388, 1377, 1360, 1255,
1
1102, 1041, 1005, 887, 836, 773 cm−1. H NMR: 0.06
(6H, s), 0.89 (9H, s), 0.98 (3H, s), 1.16–1.30 (1H, m),
1.40–1.60 (4H, m), 1.68 (1H, t, J=7.9), 1.72 (1H, t,
J=7.9), 1.95–2.13 (2H, m), 2.18 (1H, t, J=5.9), 3.65
(1H, dd, J=6.0, 10.2), 3.68–3.80 (2H, m), 3.89 (1H, dd,
J=6.0, 10.2), 4.65 (1H, bs), 4.75 (1H, bs). 13C NMR:
−5.4 (2C), 18.3, 22.8, 24.3, 25.9 (3C), 32.7, 35.0, 35.9,
41.3, 55.4, 59.2, 62.8, 109.8, 148.1. ESIMS (MeOH):
337 ([MK]+, 32), 321 ([MNa]+, 100). This was converted
to the aldehyde 24 using a Swern protocol as above. To
a stirred solution of dimethyl sulfoxide (1.18 mL, 16.6
mmol, 6 equiv.) in CH2Cl2 (7 mL) cooled at −60°C, was
added dropwise a solution of oxalyl chloride (2 M in
CH2Cl2, 4.15 mL, 8.31 mmol, 3 equiv.) under argon.
The reaction mixture was stirred for 30 min and a
solution of the alcohol 23 (825 mg, 2.77 mmol) in
CH2Cl2 (20 mL) was added slowly. The reaction mix-
ture was stirred for 30 min, triethylamine (3.86 mL,
27.7 mmol) was added and the reaction mixture was
allowed to warm quickly to 0°C and stirred for 1.5 h
before water was added. The organic layer was diluted
with CH2Cl2, washed with 1N HCl, satd NaHCO3 and
brine, dried over MgSO4 and concentrated under
reduced pressure. Silica gel flash column chromatogra-
phy (heptane–EtOAc, 15:1 to 5:1) afforded 763 mg
(93%) of 24: [h]D −16 (c 1.36). IR (film): 2929, 2856,
1732, 1721, 1716, 1651, 1471, 1463, 1389, 1361, 1256,
Methylenation of the C(4) ketone 21 (831 mg, 2.13 mmol)
was carried out using Tebbe’s reagent (0.5 M solution,
2.5 mL, 1.25 mmol) in dry THF (9 mL), at 0°C, under
1
1099, 1005, 890, 837, 775 cm−1. H NMR: 0.02 (6H, s),

3290
J. I. Candela Lena et al. / Tetrahedron: Asymmetry 12 (2001) 3281–3291
Acknowledgements
0.85 (9H, s), 1.12 (3H, s), 1.33 (1H, td, J=4.6, 13.1),
1.50–1.77 (3H, m), 2.09 (2H, t, J=5.9), 2.18 (1H, t,
J=5.7), 2.28 (1H, dd, J=3.1, 15.2), 2.45 (1H, dd,
J=2.4, 15.2), 3.68 (1H, dd, J=5.6, 10.4), 3.86 (1H, dd,
J=5.9, 10.4), 4.67 (1H, bs), 4.78 (1H, bs), 9.85 (1H, t,
J=2.8). 13C NMR: −5.5 (2C), 18.2, 22.6, 25.4, 25.9
(3C), 33.0, 35.2, 36.8, 52.2, 55.2, 63.0, 110.4, 147.5,
203.6.
The authors thank Ministerio de Educacion y Cultura
(Spain) for a fellowship to Dr. J. I. Martin Hernando,
the European Commission for a Research Training
Grant to Dr. J. I. Candela Lena and the Hoffmann-
La-Roche company (Basel) for a generous gift of
phorenol.
4.13. Preparation of the taxoid C-ring precursor
References
According to the procedure developed by Still, a-
alkoxyorganostannanes 3 were synthesized as follows:
To a magnetically stirred solution of diisopropylamine
(0.9 mL, 6.28 mmol) in dry THF (6 mL) under argon at
0°C, n-BuLi (3.6 mL of a 1.6 M hexane solution, 5.76
mmol) was added dropwise. The solution was stirred
for 15 min, n-Bu3SnH (1.6 mL, 5.76 mmol) was added
and stirring continued for 15 min at 0°C. The reaction
mixture was chilled to −78°C before a solution of
aldehyde 24 (1.55 g, 5.24 mmol) in dry THF (16 mL)
was added dropwise. After 20 min the cold reaction
mixture was quenched with saturated NH4Cl, diluted
with Et2O and extracted. The combined organic layers
were worked up as usual and the residue dissolved in
dry CH2Cl2 (40 mL). To this solution was added, under
argon, i-Pr2NEt (13.7 mL, 78.6 mmol) and after 10 min
at 0°C addition of MOMCl (4.0 mL, 52.4 mmol) fol-
lowed. The reaction mixture was stirred overnight at
room temperature then quenched with H2O (at 0°C)
and extracted with CH2Cl2. The combined organic lay-
ers were washed with 1N HCl, satd NaHCO3 and,
following usual work up, chromatography (hep-
tane:ether, 150:1 as eluent) afforded 1.25 g of the faster
eluting isomer (10R)-3 (35%) and 1.32 g of the slower
eluting isomer (10S)-3 (40%), in 75% combined yield.
The absolute stereochemistry of the C(10) stereocenter
was confirmed by analogy with the a-alkoxyorganos-
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