Taxoid C-ring building blocks from Hajos-Parrish ketone. Practical synthesis of an enantiomerically pure taxoid ABC ring system

Article abstract of DOI:10.1016/S0957-4166(99)00062-2

A synthesis and characterization of conveniently functionalized taxoid C-ring building blocks to be used in an A+C approach is presented. Subsequently, a four-step entry to the tricyclic taxoid ABC skeleton, which allows for a high degree of convergency and is highlighted by a stannylene- mediated coupling to link the left- and right-half moieties, followed by an intramolecular aldol reaction to effect the B-ring closure, is described.

Full text of DOI:10.1016/S0957-4166(99)00062-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 783–797
Taxoid C-ring building blocks from Hajos–Parrish ketone.
Practical synthesis of an enantiomerically pure taxoid ABC ring
system
José Ignacio Martín Hernando, José Quílez del Moral, Maria del Rosario Rico Ferreira,
José Ignacio Candela Lena and Siméon Arseniyadis ∗
Institut de Chimie des Substances Naturelles,32+13 CNRS, F-91198 Gif-sur-Yvette, France
Received 27 January 1999; accepted 19 February 1999
Abstract
A synthesis and characterization of conveniently functionalized taxoid C-ring building blocks to be used in an
A+C approach is presented. Subsequently, a four-step entry to the tricyclic taxoid ABC skeleton, which allows for
a high degree of convergency and is highlighted by a stannylene-mediated coupling to link the left- and right-half
moieties, followed by an intramolecular aldol reaction to effect the B-ring closure, is described. © 1999 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Ongoing efforts, directed towards enantioselective construction of the taxoid1 ABC core I, required
methodology for the construction of the enantiomerically-pure cyclohexane derivative 1 containing
four adjacent substituents and a quaternary center. Prior studies from our laboratories2 have realized
significant progress towards this end, including the development of a new ring-expansion/rearrangement
sequence that afforded 1, in only three steps from the Hajos–Parrish3 ketone-derived unsaturated diol
2. The heavily substituted cyclohexane derivative 1, constitutes an excellent right-half building block
providing 10 out of 20 carbons of the taxoid diterpene skeleton with the correct absolute stereochemistry
at C-8; this stereocenter then controls the relative (and consequently the absolute) configuration of the
remaining stereocenters. Therefore, we sought to exploit the synthetic methodology developed in our
laboratories and designed a convenient route to the taxoid C-ring moiety offering linking possibilities at
C-2 and C-10. Our objective was to devise an efficient A+C route to taxoid diterpene skeleton I from 1
and commercially available 4-oxoisophorone 3, that would allow the introduction of required substituents
∗
Corresponding author. Fax: +33-1-69-07-72-47; e-mail: simeon.arseniyadis@icsn.cnrs-gif.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00062-2

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at the C-1, C-5, C-9 and C-13 positions. Model studies designed to test the feasibility of this strategy
have been published recently.4 From the foregoing results, it seemed desirable to generate a tricyclic
intermediate that incorporates all carbon atoms of the final taxoid skeleton; therefore, modifications of
the C-ring were addressed. The latter has to contain a functional moiety that could ultimately be used to
introduce the C-20 carbon offering further elaboration, thereby ensuring access into oxirane-, oxetane-
or olefin-containing taxoid families. Reported herein are the complete details of various C-ring building
blocks, as well as a synthetic approach which culminated in a concise synthesis of the 20 carbon taxoid
ABC subunit 25 in its enantiomerically pure form. In this paper, we also report that the organotin–acetal
functionality can be used as a versatile protective group which is compatible with several protective-
group manipulations commonly employed in synthesis.
2. Synthetic planning
Our synthetic plan involved the union of two fragments of unequal complexity, two six-membered ring
subunits, II and III (the A- and C-ring precursors respectively) which, taken together, constitute the 20
carbon atoms of taxoid diterpene skeleton I (shown in the box, Scheme 1).
Scheme 1. A+C strategies based on 4-oxoisophorone 3 and the Hajos–Parrish ketone derived diol 2
Investigations would start with the ‘A+C’ coupling reactions, carried out according to the protocol
developed by Still5 which involves a stannylation–destannylation process to afford the corresponding
top-linked B-secotaxanes, thus setting the stage for the C1–C2 bottom linking. In the ensuing discussion
we describe in sequence the construction and characterization of right-half fragments of type IIIa and
IIIb (F stands for MOM-protected tributyltin acetal) placing emphasis on 5, 8, 14, and 20, protected α-
hydroxy organostannanes to be used as C-10 nucleophiles via transmetallation. The left-half fragments
of type IIa were described elsewhere; IIb is only one step away from commercially available 4-oxo-
isophorone4 and could be used as either C-11 electrophile or C-1 nucleophile in a top or bottom side (a
Kende like approach)6 linking strategy, respectively. We then show how the method of Still can be used
to join these two fragments and finally we connect C1–C2 carbons using intramolecular aldol chemistry
for the crucial B-ring closure. One of the fundamental assumptions of our synthetic plan is that all newly
created stereogenic centers in the left-half moiety of the B-secotaxane unit have no long-term significance
as they are programmed to be destroyed in later steps. The oxetane D-ring construction is deferred to the

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785
end of the synthetic scheme, and so is the C-3 stereochemistry. A concise route to either ‘top’ (such as
IV) or ‘bottom’ (such as V) linked B-secotaxoid frameworks, is retrosynthetically outlined in Scheme 1.
3. Results and discussion
3.1. Synthesis of the right-half segments
The key synthetic intermediate 1 has been synthesized in multigram quantities in three steps and 82%
overall yield from diol 2 according to our previous work.7 Enantiomeric purity was secured via our
lipase-catalyzed hydrolysis8 rather than using the proline-catalyzed asymmetric Robinson annelation.3
A series of α-alkoxyorganostannanes of the general type III were prepared using Still’s procedure from
the corresponding aldehydes by treatment with lithium tributylstannylate, followed by protection of
the resulting alcohol using chloromethyl methyl ether in the presence of Hünig’s base (iPr2NEt). The
assembly of C-ring fragments such as α-alkoxyorganostannanes 5, 8, 14, and 20 to be used as C-10
nucleophiles for the synthesis of type IV B-secotaxane derivatives, and aldehyde 16 or its acetal 17 to be
used as C-2 electrophiles for type V B-secotaxane synthesis is outlined in Schemes 2–4.
Scheme 2. (a) DMSO, (COCl)2, Et3N, CH2Cl2, −60°C. (b) Bu3SnLi, THF, −70°C then MOMCl, iPr2NEt, CH2Cl2, rt. (c) BzCl,
Et3N, CH2Cl2, rt, 1 h. (d) pTosOH, EtOH–H2O, rt, 0.5 h. (e) TBDMSCl, DMAP, CH2Cl2, 0°C to rt, 2 h. (f) MOMCl, iPr2NEt,
CH2Cl2, rt. (g) LiAlH4, THF, 0°C, 0.5 h
Scheme 3. (a) BnBr, NaH, DMF, rt, 15 h. (b) 5% HCl–THF, 1:1, rt, 4 h. (c) TBDMSCl, DMAP, CH2Cl2, 0°C to rt. (d) DMSO,
(COCl)2, Et3N, CH2Cl2, −60°C. (e) Tebbe reagent, THF, 0°C, 40 min. (f) Li–NH3 liq., tBuOH, THF, −78°C. (g) Bu3SnLi, THF,
−70°C then MOMCl, iPr2NEt, CH2Cl2, rt

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Scheme 4. (a) nBu4NF, THF, rt, 5 h. (b) DMSO, (COCl)2, Et3N, CH2Cl2, −60°C. (c) HOCH2CH2OH, pTosOH. (d) Li–NH3
liq., tBuOH, THF, −78°C. (e) Bu3SnLi, THF, −70°C then MOMCl, iPr2NEt, CH2Cl2, rt
Thus, as shown in Scheme 2, type 5 organostannane was obtained as a diastereomeric mixture (C-10
epimers) starting from isopropylidene alcohol 1, as follows. Swern oxidation of the latter afforded the
required aldehyde 4 which was subsequently umpoled by treatment with tri-n-butylstannyllithium (1.1
equiv., prepared from equimolar quantities of Bu3SnH and LDA) in dry THF and protected immediately
after with chloromethyl methyl ether (MOMCl) in the presence of iPr2NEt at room temperature in dry
CH2Cl2 to afford 5a (faster eluting isomer) and 5b (slower eluting isomer), easily separable by SiO2
flash column chromatography, in 88% isolated yield and an 1:1 ratio (C-10 configuration undefined). The
second requisite building block, type 8 organostannane, was readily accessed carrying out the sequence
described in Scheme 2. First, the free hydroxyl group at C-10 of 1 was protected as its benzoate ester by
treatment with BzCl in methylene chloride, in the presence of triethylamine. C10–O–Benzyl derivative 6
thus obtained, was then converted to organostannane 8 in six straightforward steps as follows. Acetonide
cleavage using pTosOH in ethanol–water furnished the free diol (98%) which was then stirred in dry
methylene chloride with tert-butyldimethylsilyl chloride (TBDMSCl) in the presence of 4-DMAP at
0°C to rt for 2 h to effect the preferential protection of the primary hydroxyl group at C-2 as its tert-
butyldimethylsilyl ether, in the presence of the free secondary alcohol at C-4. The resulting C10–OBz,
C2–OTBS protected alcohol (98%) was subsequently subjected to MOM-protection of the secondary
hydroxyl group at C-4, using MOMCl, in the presence of Hünig’s base in dry CH2Cl2 to give a 98%
yield of the desired MOM-ether. Treatment of the latter with excess of LiAlH4 in dry THF at 0°C
for 30 min yielded quantitatively the corresponding C-10 free hydroxy compound. Swern oxidation of
the latter afforded aldehyde 7 in 95% yield. Finally, addition of nBu3SnLi followed by etherification
with chloromethylmethyl ether furnished the C-ring subunit 8a (faster eluting isomer) and 8b (slower
eluting isomer) in ca. 75% yield and a 1:1 ratio (epimeric at C-10 position). Attention was then turned to
preparation of the target 14, a more conveniently functionalized variant to be used as a C-ring nucleophile,
containing C-20 carbon and offering better possibilities for further elaboration. Scheme 3 depicts the
synthesis of type 14 organostannane.
Starting from 1, exposure to benzyl bromide in the presence of sodium hydride in dry DMF afforded
9, which upon treatment with dilute hydrochloric acid in THF, and subsequent selective protection of
the resulting diol as above, furnished C-4 alcohol 10 in 88% combined yield (3 steps). The C-20 carbon
atom was then introduced via a Swern oxidation (96%) which was followed by a Tebbe olefination9
cleanly affording 12a. This material was converted into organotin acetal 14 in a straightforward three-
step sequence. Thus, cleavage of the benzyl protective group in 12a, using Li–NH3 liq. at −78°C,
quantitatively afforded 12b. Swern oxidation gave the required aldehyde 13 (91%) which, upon treatment
as above with nBu3SnLi and protection of the secondary hydroxyl groups as their MOM ethers, gave α-

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787
alkoxyorganostannanes 14a:14b in a 1:2.5 ratio and 92% yield. It should be pointed out, that attempted
Wittig olefination under various literature conditions failed to produce the desired olefin, leading mainly
to TBS deprotection and retro-aldol fragments.
Our next goal was to design a substrate, the precursors of which could be easily incorporated into one of
several distinct types of taxane construction, as shown retrosynthetically in Scheme 1. Scheme 4 provides
an outline for the synthesis of such a target, compound 20, along with its precursors 16, 17, 18 and 19
which could be used as either C-ring nucleophiles or C-ring electrophiles depending upon the nature of
the substituents at C-10 and C-2 and the type of A+C coupling (top or bottom side linking). Starting
from 12a, fluoride promoted deprotection using nBu4NF in THF, and furnished 15 (99%), which was
subjected to a Swern oxidation to afford 16 (which could be used as a C-2 electrophile) in 93% isolated
yield. Following protection of C-2 carbonyl as its acetal (17) and removal of the benzyl group with
lithium in ammonia at −70°C, the intermediate alcohol 18 thus obtained (98%, two steps) was oxidized
to aldehyde 19 (could be used as a C-10 electrophile) in 93% yield using the Swern protocol.
The latter was then converted into 20 (C-10 nucleophile), obtained as a diastereomeric mixture in
ca. 1:1.4 ratio for the faster 20a and slower eluting isomer 20b, respectively, using the same protocol
as above, in 78% isolated yield. At this point, the C-10 configuration remained unknown for all the
α-alkoxyorganostannanes synthesized.
3.2. The A+C coupling and B-ring closure
In our previous work,4 B-secotaxoids of type IV (Scheme 1) were synthesized to gain familiarity with
the proposed chemistry and also to check its feasibility. Accordingly, the key fragment coupling was
accomplished by transmetallation of the major organostannane 14b followed by addition of the A-ring
electrophile, racemic 21, which was prepared according to the literature.10 The addition product 22 was
obtained in 90% yield as a 7:1:1 mixture of diastereoisomers favoring the one depicted in Scheme 5. In
fact, this reaction, like that of 5a, 5b,4a 8a and 8b4b with 21 was regioselective, with nucleophilic attack
of the α-alkoxy carbanion occurring exclusively at the C-11 electophilic terminus. It was satisfying to
find that the A+C coupling of organostannane 14b gave a higher yield than did organostannanes 5 and
8 in the model studies. At this stage (22) the absolute stereochemistry of diastereomers at C-10, C-11
could not be assigned, nor could the products be separated in a synthetically useful way. Although we
were unable to synthesize 22 with the level of stereoselectivity previously obtained on B-secotaxanes
originating from 5 and 8, we progressed in anticipation that this stereochemical imperfection would not
pose any problems at subsequent stages of the synthesis. Nevertheless, at least initially, we separated
the major isomer by flash chromatography and used isomerically homogeneous 23 in the subsequent
exploratory steps for characterization purposes. Finishing the synthesis of the tricyclic core of taxoid
diterpene 25 from the intermediate 22 required an adjustment of the oxidation states of the A- and C-
rings. This was attempted by a two-step approach that had been successful in model studies.4 The first
step involved fluoride-promoted deprotection of the bis-tert-butyldimethylsilyl ether 22 affording the
corresponding diol 23 in quantitative yield. The intermediate possessing functionality for the final C1–C2
coupling was then accessed in an additional step via a tetrapropylammonium perruthenate (TPAP)-
catalyzed oxidation11 of the C-14 and C-2 alcohols. Treatment of diol 23 with NMO and catalytic TPAP
(0.025 equiv.) in dry MeCN in the presence of 4Å MS, at room temperature led to the desired enone-
aldehyde 24, in 86% yield. This conversion not only set the conditions for the following transformation,
the C1–C2 bond formation, but also helped to elucidate the location of the stereoisomers (Scheme 5).
The resulting enone-aldehyde was then subjected to standard aldol conditions (LDA, THF, −78°C, 5
min) to give the desired aldol 25 in an unoptimized 31% isolated yield along with the unreacted starting

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material (50%). In all cases quasi-quantitative recovery of the unreacted starting material was possible
via column chromatography and the recovered compound, which appeared spectroscopically identical to
the original material (no epimerization at C-3 was detected), could be reused. Our strategy, as illustrated
in Scheme 5, is exemplified by a four-step construction of the enantiopure taxoid ABC tricyclic core 25,
thus demonstrating the potential of this methodology.
Scheme 5. (a) nBuLi–THF, −70°C. (b) nBu4NF, THF, 50°C, 2.5 h. (c) TPAP–NMO, 4Å MS, MeCN, rt, 0.5 h. (d) LDA–THF,
−78°C, 10 min
The structure of ABC tricyclic intermediate 25 was assigned on the basis of coupling patterns and
spatial proximity measurements in the proton NMR spectrum. The stereochemistry of the C-ring moiety
was known prior to the NMR investigations. The remaining four unknown stereogenic centers of 25 (C-
1, C-2, C-10, C-11) have been determined with a high degree of reliability as follows. After a complete
assignment of the proton and carbon resonances, exhaustive NOEDIFF experiments were performed at
300 and 800 MHz to explore spatial relationships. This secured the relative configuration of all the chiral
centers. The map of diagnostic NOEs is depicted in Fig. 1 (see Experimental) for the most significant
effects. By far the most important were the observed enhancements at the C-10 proton on irradiation of
the C-16 methyl group at δ 1.42, of the C-19 methyl group at δ 0.98 and of the bridgehead proton at C-3
at δ 2.57 which provided evidence that they are all on the same face of the molecule as shown in Fig. 1.
Observation of an enhancement of the signal for the bridgehead proton at C-3 upon irradiation of the C-8
angular methyl group (Me-19) protons confirmed a syn-geometry, consistent with lack of epimerization
at C-3 during the aldol process. Turning now to the concave face of the ABC tricycle 25, upon irradiation
of the C-2 hydrogen at δ 4.38 we see a strong NOE to the α-face hydrogens such as C-7 proton at δ 3.19,
and C-5α axial proton at δ 2.30, confirming that the C-2 proton is on the α-face of the molecule. This
assignment confirmed the threo-aldol formation as expected.12 The absence of vicinal coupling for H-1
at δ 2.80 is consistent with an endo-orientation for H-2 at δ 4.38 based upon the near 90° dihedral angle
relationship for H-1 and H-2. This justifies the two-way NOE, observed upon irradiation of either H-1 or
H-2 even though the two dipoles do not possess a syn-geometry. Finally, NOEs upon irradiation of C-7
proton strong NOEs were observed for the C-9α proton at δ 1.52, the C-2 proton as well as for the C-5α
axial proton, thus confirming the conformations adopted from the C and B-rings of the molecule.
3.3. Assignment of C-10 absolute configurations based on 14b; correlation studies
A series of protecting group manipulations and functional group interconversions were performed to
correlate the known (vide supra) C-10 absolute stereochemistry of 14b with the undefined C-10 centers of
all the remaining organotin acetals and also demonstrate the versatility of organotin acetal functionality

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Figure 1. Diagnostic NOEs shown separately on the β (left) and α (right) faces of 25. The observed NOEs were used as
restraints (r) for the simulations in MM3 studies (lowest energy conformer shown)
as a protecting group. Assignment of the absolute configuration to (10S)-14b is based on relative
stereochemistry of the C-10 stereocenter in 25 and assumption of the retentive transmetallation,13 which
by inference, proved the C-10 stereochemistry of organostannanes 5a,b, 8a,b and 20a,b (Scheme 6).
Scheme 6. (a) pTosOH, EtOH–H2O, rt, 0.5 h. (b) TBDMSCl, DMAP, CH2Cl2, 0°C to rt, 2 h. (c) MOMCl, iPr2NEt, CH2Cl2, rt.
(d) LiAlH4, THF, −30°C, 0.5 h
Organostannanes 5, 8, 14, and 20, that can be stored for long periods and are stable unless expo-
sed to acid, could be incompatible with many protective group manipulations and functional group
interconversion protocols. The compatibility map generated during functional group interconversions
on organotin–acetal containing substrates is outlined in Scheme 6, which served for correlation studies,
and was further extended to several common transformations. Thus, the tributyltin–MOM grouping was
perfectly stable in fluoride-promoted TBS deprotection as well as in Swern conditions but not in the
formation of acetal. For example, 14a was desilylated with tetrabutylammonium fluoride to afford the
corresponding alcohol which was further oxidized using the Swern protocol to the resulting aldehyde
in nearly quantitative yield. Attempts to protect the aldehyde as its corresponding acetal under various
conditions failed, thus revealing incompatibility of the organotin acetal with standard acetal formation
conditions. The primary hydroxyl at C-2 of α-alkoxyorganostannane 14a could thus be deprotected,
reacetylated or oxidized, but the resulting aldehyde could not stand conditions for acetal formation. The
C-10 absolute configurations of the organostannanes were assigned through the correlation sequence
outlined in Scheme 6. Organostannane 5a was taken to the final ABC tricyclic compound 25, by coupling
with 21 according to our previous work.14 Removal of the acetonide protection in the B-secotaxoid deri-
vative thus obtained Swern oxidation, followed by TBS-monoprotection, and Tebbe olefination furnished

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22 which was processed to 25 as above (Scheme 5). This unambiguously proved its C-10 stereochemistry
as (S). Selective removal of the isopropylidene group in (10S)-5a resulted in the corresponding diol which
was converted to 8b in a two-step sequence. Selective deprotection in the presence of a tributyltin–MOM
protecting group was carried out by room temperature treatment in EtOH with catalytic pTosOH while
the two remaining steps, selective TBS protection at C-2 and MOM-protection at C-4 were performed as
above. On the other hand, acetal deprotection proceeded smoothly on 20b affording the corresponding
aldehyde which was reduced with lithium aluminum hydride in THF at −30°C. The primary hydroxyl
thus formed was protected by reaction with TBDMSCl and imidazol in DMF or by treatment with
TBS–triflate in toluene in the presence of collidine to give organotin acetal 14a. These transformations
permitted correlation of organostannanes 5a, 8b and 20a with 14b which served as reference.
4. Conclusion
These studies further establish the synthetic utility of Pb(OAc)4 mediated one-pot multi-stage transfor-
mations of bicyclic unsaturated 1,2-diols for the construction of taxoid C-ring building blocks, offering
C-10 and C-2 linking possibilities. Stereochemistry of the originally unknown C-10 stereocenter in
a series of C-ring building blocks thus synthesized, was confirmed by reaction of racemic 21 with
enantiopure 14b, which furnished 22; the latter following a deprotection–oxidation–intramolecular
aldol protocol provided 25 as a single diastereoisomer. The reactions portrayed in Scheme 6 are of
special significance since not only the unknown C-10 absolute configurations of all new organostan-
nanes were established, but compatibility of MOM–Bu3Sn grouping is also proved in various oxi-
dation–reduction–protection–deprotection operations. In summary, synthetically useful taxoid C-ring
segments were synthesized and fully characterized, and conditions have been found for the direct
assembly of the eight-membered B-ring.15 Improvements to the intramolecular aldol reaction (C1–C2
linking) and completion of the synthesis will be the subject for further focus in this area.
5. Experimental
5.1. General
General experimental details were as previously described.16 NMR spectra were run in CDCl3 and
specific rotations were measured in chloroform. ‘Usual work up’ means washing of the organic layer
with brine, drying over anhydrous magnesium sulfate, and evaporating in vacuo with a rotary evaporator
at aspirator pressure. Flash chromatographies were run on silica gel (230–400 mesh).
5.2. Preparation of right-half segments
5.2.1. Preparation of α-alkoxyorganostannanes 5
Starting from the known aldehyde 4,7 and according to the procedure developed by Still,5 α-
alkoxyorganostannanes 5 were synthesized uneventfully as follows. To a magnetically stirred solution of
diisopropylamine (0.72 mL, 5.11 mmol) in dry THF (9 mL) under argon at 0°C, nBuLi (1.9 mL of a 2.5
M hexane solution, 4.69 mmol) was added dropwise. The solution was stirred for 15 min, nBu3SnH (1.3
mL, 4.69 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 4 (1.27 g, 4.26 mmol) in dry THF (5 mL) was added dropwise. After

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791
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 (15
mL). To this solution was added, under argon, iPrNEt2 (13.3 mL, 77 mmol) and after 10 min at 0°C
addition of MOMCl (3.9 mL, 51 mmol) followed. The reaction mixture was stirred overnight at room
temperature then quenched with H2O (at 0°C) and extracted with CH2Cl2. The combined organic layers
were washed with 1 N HCl, sat. NaHCO3, and following usual work up, chromatography (heptane:ether,
99:1 as eluent) afforded 1.16 g of the faster eluting isomer 5a (44%), and 1.16 g of the slower eluting
isomer 5b (44%), in 88% combined yield. 5a: [α]D +72.2 (c 2.00). IR (film): 2957, 2925, 2871, 2866,
1465, 1379, 1362, 1276, 1249, 1226, 1193, 1164, 1149, 1104, 1047, 1028, 1002, 967, 935, 920 cm−1. 1H
NMR (300 MHz): 0.85–0.93 (15H, m), 0.95 (3H, s), 1.16 (9H, s), 1.25–1.62 (16H, m), 1.38 (3H, s), 1.44
(3H, s), 2.06 (1H, dd, J=1.6, 16.2), 2.13 (1H, dd, J=1.8, 9.5), 2.73 (1H, dd, J=10.9, 16.2), 3.37 (3H, s),
3.86 (1H, d, J=12.5), 3.94 (1H, d, J=5.4), 3.97 (1H, dd, J=4.2, 12.5), 4.11 (1H, m), 4.27 (1H, dd, J=1.6,
10.9), 4.53 (1H, d, J=6.8), 4.55 (1H, d, J=6.8). 13C NMR (50.3 MHz): 9.5 (3C), 13.6 (3C), 18.8, 23.2
(2C), 25.3, 27.5 (3C), 29.0 (3C), 29.2 (3C), 30.0, 38.4, 41.2, 41.7, 55.9, 60.8, 67.2, 70.9, 71.7, 72.7, 96.4,
97.8. CIMS: 635 ([M+H]+, 3), 577 (100), 545 (50), 515 (87), 503 (57). Anal. calcd for C31H62O5 Sn C
58.77 H 9.86, found: C 59.02 H 9.57. 5b: [α]D −2.3 (c 1.45). IR (film): 2956, 2925, 2874, 2856, 1463,
1378, 1362, 1250, 1226, 1194, 1163, 1147, 1104, 1064, 1047, 1029, 1002 cm−1. 1H NMR (300 MHz):
0.87–0.96 (15H, m), 1.07 (3H, s), 1.18 (9H, s), 1.26–1.58 (15H, m), 1.37 (3H, s), 1.44 (3H, s), 1.74 (1H,
m), 2.12 (1H, m), 2.29 (1H, dd, J=11.0, 16.2), 2.49 (1H, bd, J=14.7), 3.36 (3H, s), 3.68 (1H, d, J=3.5),
3.96–4.06 (2H, m), 4.10 (1H, dd, J=3.4, 6.6), 4.27 (1H, dd, J=1.9, 11.0), 4.55 (1H, d, J=6.5), 4.58 (1H,
d, J=6.5). 13C NMR (75 MHz): 9.4 (3C), 13.6 (3C), 19.3, 23.6, 24.0, 25.4, 27.5 (3C), 28.9 (3C), 29.2
(3C), 29.9, 39.1, 40.7, 41.1, 56.0, 60.6, 67.1, 70.5, 70.9, 72.9, 96.7, 97.8. CIMS: 635 ([M+H]+, 35), 603
(9), 577 (56), 545 (65), 515 (13), 291 (15), 151 (43), 125 (56), 73 (100). Anal. calcd for C31H62O5 Sn C
58.77, H 9.86, found: C 58.34, H 9.91.
5.2.2. Preparation of α-alkoxyorganostannanes 8
Benzoyl protection of 1 (1.285 g, 4.28 mmol) was carried out under standard conditions using BzCl
(1.09 g, 7.75 mmol), in the presence of Et3N (1.02 g, 10.04 mmol) in 30 mL of dry CH2Cl2. Following
room temperature stirring for 1–5 h (TLC monitoring) usual work up and filtration on silica gel afforded
quantitatively the desired benzoate ester 6: [α]D +52.8 (c 1.06). IR (film): 2974, 2927, 2907, 1719, 1382,
1
1276, 1251, 1193, 1159, 1069, 1002, 910 cm−1. H NMR (200 MHz): 1.06 (3H, s), 1.14 (9H, s), 1.38
(3H, s), 1.46 (3H, s), 1.20–1.60 (3H, m), 1.96–2.34 (3H, m), 2.60 (1H, td, J=7.6, 15.2), 3.60 (1H, d,
J=3.2), 3.93–4.06 (2H, m), 4.15 (1H, bs), 4.28 (2H, t, J=7.6), 7.38–7.58 (3H, m), 8.04 (2H, dd, J=7.0,
1.6). 13C NMR (50.3 MHz): 18.7, 23.0 (2C), 25.0, 28.7 (3C), 29.6, 35.4, 37.8, 38.8, 60.6, 62.2, 66.9,
71.3, 72.9, 97.8, 128.1 (2C), 129.3 (2C), 130.3, 132.5, 166.3. EIMS: 404 (M+, 4), 389 (15), 333 (17),
328 (9), 291 (47), 273 (16), 233 (47), 193 (24), 111 (100). Anal. calcd for C24H36O5 C, 71.26; H, 8.97;
found: C, 71.19, H, 8.85.
Acetonide cleavage on 6 was catalyzed by pTosOH (0.1 equiv.), in 95% EtOH in H2O (5 mL per
mmol), at room temperature. After stirring for 0.5 h, the reaction mixture was diluted with CH2Cl2 and
worked up as usual which furnished the corresponding diol in 98% isolated yield after filtration on silica
gel. Selective protection of the primary hydroxyl group at was then effected as follows. A solution of
1,3-diol thus obtained (1.285 g, 3.53 mmol), DMAP (1.39 g, 11.39 mmol), and tert-butyldimethylsilyl
chloride (845 mg, 5.60 mmol), in CH2Cl2 (15 mL), was stirred at 0°C to room temperature for 1.5 h. The
reaction mixture was then diluted with CH2Cl2, washed with 1 N HCl, then sat. aq. NaHCO3 and worked
up as usual to give the title compound as a white solid in 98% isolated yield after filtration on silica gel
(heptane:EtOAc, 4:1 as eluent). The OBz–TBS protected alcohol thus obtained was then MOM-protected

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J. I. Martín Hernando et al. / Tetrahedron: Asymmetry 10 (1999) 783–797
on C-4 secondary hydroxyl group as follows. A solution of the latter (1.55 g, 3.24 mmol), was treated
with methoxymethyl chloride (0.8 mL, 10.5 mmol) and diisopropylethylamine (2.0 mL, 11.48 mmol)
in CH2Cl2 (15 mL) at room temperature for 12 h. The reaction was stopped by addition of water and
extracted with CH2Cl2. Following the usual work up, the resulting oil was purified by chromatography
(heptane:EtOAc, 2:1 as eluent) to give the corresponding MOM-ether (1.66 g, 98%). Target aldehyde 7
was then prepared in two straightforward steps. Lithium aluminium hydride (946 mg, 24.92 mmol) was
suspended in dry THF (40 mL) and the mixture cooled to −70°C. To this, C-10 OBz (1.66 g, 3.18 mmol)
in THF (10 mL) was slowly added, then the reaction mixture was allowed to reach 0°C within 30 min,
after which water (0.9 mL) and aq. NaOH (15%, 0.9 mL) were added and the mixture stirred for 30 min.
After dilution with technical ether, the white solid was filtered off and the filtrate concentrated under
reduced pressure to quantitatively give the C-10 free hydroxy compound which was taken to aldehyde
7 using a Swern protocol. Thus, to dimethyl sulfoxide (1.4 mL, 19.7 mmol) in dichloromethane (15
mL) was added oxalyl chloride dropwise (4.0 mL, 8.0 mmol, 2 M in dichloromethane) at −60°C. The
reaction mixture was stirred for 30 min at −60°C and then the C-10 alcohol (1.32 g, 3.15 mmol) in
dichloromethane (15 mL) was slowly added. Following additional stirring for 30 min, triethylamine (5.0
mL, 35.8 mmol) was added then the reaction flask was placed in an ice bath and stirring continued for
1–2 h. The organic layer was washed with 1 N HCl, sat. aq. NaHCO3 and worked up as usual to give
(heptane:EtOAc, 9:1) after chromatography, a 95% isolated yield of 7.
For the preparation of α-alkoxyorganostannanes 8, Still’s procedure was repeated as above using 2.26
mmol of 7 to afford, after chromatography using heptane:EtOAc (92:8 as eluent), a 75% combined yield
of 8a:8b as a 1:1 mixture. 8a (faster eluting isomer): [α]D +34.7 (c 1.05). IR (film): 2929, 1464, 1362,
1265, 1192, 1145, 1042, 837, 775, 742 cm−1. 1H NMR (300 MHz): 0.03 (3H, s), 0.04 (3H, s), 0.85–0.93
(24H, m), 0.99 (3H, s), 1.17 (9H, s), 1.25–2.06 (18H, m), 2.58 (1H, dd, J=11.5, 16.1), 3.37 (6H, s),
3.64–3.70 (2H, m), 3.81 (1H, d, J=3.2), 3.97 (1H, m), 4.21 (1H, bd, J=11.5), 4.51 (1H, d, J=6.4), 4.54
(1H, d, J=6.4), 4.63 (1H, d, J=7.3), 4.66 (1H, d, J=7.3). 13C NMR (62.9 MHz): −5.4 (2C), 9.6 (3C),
13.6, 13.7 (3C), 18.2, 26.0 (3C), 26.8, 27.5 (3C), 27.8, 29.2 (6C), 39.9, 41.8, 47.4, 55.2, 56.0, 59.5, 71.9,
72.1, 72.6, 73.9, 96.5, 97.1. CIMS: 753 ([M+H]+, 21), 721 (26), 707 (14), 695 (24), 691 (38), 665 (24),
647 (10), 573 (12), 515 (12), 477 (36), 133 (83), 113 (67), 73 (100). 8b (slower eluting isomer): [α]D
1
−18.9 (c 1.05). IR (film): 2956, 2928, 1464, 1361, 1254, 1193, 1147, 1099, 1060, 1041, 836 cm−1. H
NMR (300 MHz): 0.06 (6H, s), 0.87–0.93 (24H, m), 1.05 (3H, s), 1.18 (9H, s), 1.32 (6H, sext, J=7.2),
1.46–1.90 (12H, m), 2.31 (1H, m), 3.34 (3H, s), 3.35 (3H, s), 3.68–3.97 (4H, m), 4.30 (1H, d, J=11.6),
4.50 (1H, d, J=6.5), 4.53 (1H, d, J=6.5), 4.64 (2H, s). 13C NMR (62.9 MHz): −5.4 (2C), 9.5 (3C), 13.7
(4C), 18.2, 26.0 (4C), 27.6 (3C), 29.2 (7C), 39.7 (2C), 48.1, 55.1, 56.2, 59.6, 71.1, 71.6, 72.9, 73.9, 96.5,
97.1. CIMS: 753 ([M+H]+, 52), 721 (100), 695 (50), 665 (21), 253 (50), 133 (48), 73 (44).
5.2.3. Preparation of α-alkoxyorganostannanes 14
Sodium hydride (60% w/w in mineral oil; 530 mg, 13.3 mmol) was washed twice with dry hexane
under argon atmosphere and the remainder of the hexane removed via syringe and the flask vacuumed
then filled with argon. N,N-Dimethylformamide (30 mL) and alcohol 1 (2.0 g, 6.6 mmol) were added.
After stirring for 0.5 h the reaction mixture was cooled to 0°C and BnBr (1.25 g, 7.3 mmol) and N,N-
dimethylformamide (10 mL) were added and the mixture stirred for 20 h. Water and ether were added,
the two phases separated and the organic phase was worked up as usual. Chromatography of the residue
(hexane:EtOAc, 1:1) gave 9 (2.57 g, 99%). Acetonide cleavage as above afforded the corresponding diol
which was monoprotected on C-2 primary hydroxyl group using the standard method (vide supra) to give
10 in 88% combined yield. Swern oxidation as above on alcohol 10 (2.82 g, 6.1 mmol) afforded after
chromatography (heptane:EtOAc, 10:1) 2.70 g (96%) of the required 11: [α]D +2.8 (c 2.48). IR (film):

J. I. Martín Hernando et al. / Tetrahedron: Asymmetry 10 (1999) 783–797
793
2958, 2931, 2882, 2855, 1714, 1472, 1390, 1360, 1251, 1194, 1145, 1102, 1079, 834, 778, 740, 698
cm−1. 1H NMR (300 MHz): 0.04 (3H, s), 0.05 (3H, s), 0.88 (9H, s), 1.07 (3H, s), 1.21 (9H, s), 1.45–1.70
(2H, m), 1.85–2.07 (2H, m), 2.28 (1H, dt, J=5.6, 13.6), 2.64 (1H, ddd, J=6.5, 10.2, 13.6), 2.79 (1H,
dd, J=4.1, 6.8), 3.43–3.54 (2H, m), 3.63 (1H, dd, J=4.1, 10.3), 3.73 (1H, dd, J=3.0, 5.2), 4.06 (1H, dd,
J=6.8, 10.3), 4.46 (2H, s), 7.27–7.38 (5H, m). 13C NMR (62.9 MHz): −5.7, −5.6, 18.0, 21.5, 25.7 (3C),
28.7 (3C), 29.0, 34.6, 37.1, 44.7, 58.5 (2C), 66.0, 70.9, 72.8, 73.2, 127.1 (2C), 127.2, 128.1 (2C), 138.1,
211.4. EIMS: 462 (M+, 3), 405 (4), 388 (4), 373 (4), 349 (22), 331 (99), 257 (13), 242 (29), 239 (74), 225
(35), 223 (37), 215 (36), 197 (33), 165 (27), 153 (24), 92 (58), 91 (100), 75 (79), 73 (76). Anal. calcd for
C27H46O4Si C, 70.08; H, 10.02; found: C, 69.73; H, 10.11.
Methylenation of C-4 ketone 11 (9.84 g, 21.3 mmol) was carried out using Tebbe’s reagent (0.5 M
solution, 25 mL, 12.5 mmol) in dry THF (90 mL), at 0°C, under argon. The reaction mixture was
stirred at rt 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, 20:1–10:1) afforded 4.94 g (50%) of 12a and 4.66 g (47%) of recovered starting ketone.
12a: [α]D −15.6 (c 3.89). IR (film): 3064, 3030, 2960, 2928, 2859, 1649, 1464, 1365, 1252, 1192, 1105,
1071, 1030, 1008, 887, 777, 732 cm−1. 1H NMR (200 MHz): 0.05 (6H, s), 0.91 (9H, s), 0.92 (3H, s), 1.19
(9H, s), 1.49–1.67 (2H, m), 1.77 (1H, m), 2.02 (1H, ddd, J=6.5, 9.1, 15.5), 2.15–2.28 (3H, m), 3.55–3.62
(3H, m), 3.72–3.85 (2H, m), 4.53 (2H, s), 4.62 (1H, d, J=2.2), 4.77 (1H, d, J=2.2), 7.28–7.40 (5H, m).
13C NMR (62.9 MHz): −5.4 (2C), 18.2, 19.5, 25.9 (3C), 29.1 (3C), 30.6 (2C), 35.8, 40.4, 53.9, 62.1,
67.0, 72.7, 72.9, 73.0, 110.2, 127.4, 127.5 (2C), 128.2 (2C), 138.6, 147.3. CIMS: 461 ([M+H]+, 64), 405
(62), 387 (100), 329 (29), 297 (25), 273 (21), 255 (18), 237 (14). Anal. calcd for C28H48O3Si C, 72.99;
H, 10.50; found: C, 72.80; H, 10.54.
To a stirred solution of 12a (1.86 g, 4.04 mmol) in liquid ammonia (150 mL) and THF (44 mL)
in the presence of tBuOH (3.7 mL) 280 mg of lithium metal was added portionwise at −78°C. The
mixture was stirred for 10 min (blue color). Ammonia was evaporated while technical heptane was
added periodically. Evaporation to dryness dilution with ether and the usual work up afforded, after
chromatography (heptane:EtOAc, 5:1), 1.49 g (100%) of the required debenzylated compound 12b. [α]D
−20.1 (c 1.47). IR (film): 3319, 2957, 2930, 2885, 1648, 1472, 1389, 1362, 1255, 1193, 1102, 1070, 1020,
1006, 887, 836 cm−1. 1H NMR (300 MHz): 0.05 (6H, s), 0.89 (9H, s), 0.92 (3H, s), 1.19 (9H, s), 1.50–1.64
(2H, m), 1.78 (1H, m), 1.93 (1H, dt, J=7.1, 14.2), 2.16–2.25 (3H, m), 2.47 (1H, bs, OH), 3.55 (1H, dd,
J=4.3, 10.1), 3.66–3.79 (3H, m), 3.84 (1H, dd, J=4.8, 10.2), 4.63 (1H, bs), 4.74 (1H, bs). 13C NMR (75
MHz): −5.5 (2C), 18.2, 18.6, 25.9 (3C), 29.1 (3C), 30.6, 30.7, 39.1, 40.6, 55.5, 59.3, 62.9, 72.8, 73.4,
110.3, 147.3. CIMS: 371 ([M+H]+, 43), 353 (12), 315 (13), 297 (100). Anal. calcd for C21H42O3Si C,
68.05; H, 11.42; found: C, 68.31; H, 11.44. The latter (1.58 g, 4.27 mmol) was then subjected to Swern
conditions as above to give after chromatography (heptane:EtOAc, 6:1) 1.43 g (91%) of 13: IR (film):
3072, 2953, 2861, 2725, 1712, 1647, 1484, 1387, 1360, 1257, 1197, 1094, 1067, 1002, 888, 829, 764,
682 cm−1. 1H NMR (300 MHz): 0.04 (6H, s), 0.89 (9H, s), 1.15 (3H, s), 1.17 (9H, s), 1.54 (1H, m), 1.81
(1H, m), 2.16–2.35 (2H, m), 2.27 (1H, d, J=4.9), 2.31 (1H, dd, J=2.1, 15.8), 2.64 (1H, dd, J=3.2, 15.8),
3.77 (1H, m), 3.79 (2H, d, J=4.9), 3.66–3.79 (3H, m), 4.68 (1H, bs), 4.79 (1H, bs), 9.90 (1H, dd, J=2.1,
3.2). 13C NMR (62.9 MHz): −5.7, −5.6, 18.0, 19.4, 25.8 (3C), 28.9 (3C), 30.3, 31.0, 41.2, 51.4, 55.3,
63.7, 72.1, 73.4, 111.0, 147.1, 203.4.
For the preparation of α-alkoxyorganostannanes 14, Still’s procedure was repeated as above using
2.26 mmol of 13 to afford 75% combined yield of 14a and 14b as a 1:2.5 mixture. Purification on silica
gel (heptane:ether, 99:1 as eluent) furnished 14a (faster eluting isomer): [α]D −62.1 (c 1.49). IR (film):
3068, 2956, 2927, 2855, 1652, 1471, 1464, 1398, 1376, 1361, 1254, 1194, 1145, 1097, 1055, 1039, 1006,
884, 859, 836, 774 cm−1. 1H NMR (300 MHz): 0.04 (6H, s), 0.84–0.94 (15H, m), 0.90 (9H, s), 0.93 (3H,

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J. I. Martín Hernando et al. / Tetrahedron: Asymmetry 10 (1999) 783–797
s), 1.19 (9H, s), 1.27–1.39 (6H, m), 1.44–1.58 (6H, m), 1.64 (1H, m), 1.77 (1H, m), 1.93–2.05 (2H, m),
2.20 (1H, dt, J=4.9, 13.6), 2.36 (1H, ddd, J=5.6, 12.6, 13.6), 2.46 (1H, dd, J=3.5, 7.6), 3.38 (3H, s),
3.68 (1H, dd, J=4.5, 9.7), 3.91 (1H, dd, J=3.5, 9.8), 4.01 (1H, dd, J=7.6, 9.8), 4.37 (1H, dd, J=6.3, 8.0),
4.53 (2H, s), 4.57 (1H, bs), 4.73 (1H, bs). 13C NMR (75 MHz): −5.4 (2C), 9.6 (3C, J=286.8), 13.6 (3C),
18.2, 18.7, 26.0 (3C), 27.5 (3C, J=53.5), 29.3, 30.8, 31.2, 39.5, 43.1, 54.2, 56.2, 62.9, 71.7 (J=390.9),
72.2, 72.9, 97.2, 109.6, 148.5. CIMS: 705 ([M+H]+, 4), 673 (91), 647 (100), 573 (9), 541 (12), 291
(17). Anal. calcd for C35H72O4SiSn C, 59.73; H, 10.31; found: C, 59.61; H, 10.44. 14b (slower eluting
isomer): [α]D +25.7 (c 2.08). IR (film): 3078, 2955, 2927, 2873, 2856, 1652, 1464, 1398, 1377, 1362,
1255, 1195, 1148, 1097, 1068, 1056, 1032, 1006, 993, 886, 837, 774 cm−1. 1H NMR (300 MHz): 0.03
(6H, s), 0.86–0.92 (15H, m), 0.88 (9H, m), 1.03 (3H, s), 1.18 (9H, s), 1.26–1.38 (6H, m), 1.46–1.63 (8H,
m), 1.80 (1H, m), 2.13–2.36 (3H, m), 2.45 (1H, dd, J=3.4, 8.2), 3.37 (3H, s), 3.57–3.63 (2H, m), 3.72
(1H, dd, J=8.2, 9.8), 4.28 (1H, d, J=11.8), 4.52 (1H, d, J=6.6), 4.55 (1H, d, J=6.6), 4.62 (1H, d, J=2.0),
4.78 (1H, bs). 13C NMR (75 MHz): −5.3 (2C), 9.6 (3C, J=286.8), 13.6 (3C), 18.2, 20.7, 25.9 (3C), 27.5
(3C, J=53.8), 29.0 (3C), 29.2 (3C), 30.4, 30.8, 40.3, 43.0, 52.0, 56.1, 61.4, 71.1 (J=386.4), 72.7, 73.1,
97.1, 109.4, 147.3. CIMS: 705 ([M+H]+, 21), 673 (64), 647 (100), 631 (53), 559 (34), 291 (34). Anal.
calcd for C35H72O4SiSn C, 59.73; H, 10.31; found: C, 59.61; H, 10.36.
5.2.4. Preparation of α-alkoxyorganostannanes 20
Starting from 12a, the target organostannanes were synthesized in five steps as follows. Tetrabutyl-
ammonium fluoride (1 M in THF, 11.7 mL, 11.7 mmol) was added to the TBS-protected alcohol 12a
(1.80 g, 3.91 mmol) in dry THF (15 mL) and the reaction mixture stirred at room temperature for 5 h.
Dilution with ethyl acetate and the usual work up followed by chromatography (heptane:EtOAc, 4:1 to
2:1) afforded 1.34 g (99%) of 15: [α]D −13.8 (c 2.12). IR (film): 3451, 3069, 3029, 2978, 2878, 1646,
1458, 1390, 1366, 1258, 1191, 1097, 1076, 1030, 949, 890, 737, 696 cm−1. 1H NMR (200 MHz): 0.90
(3H, s), 1.15 (9H, s), 1.42–1.68 (2H, m), 1.77 (1H, m), 1.97 (1H, dt, J=3.5, 7.0), 2.08–2.32 (4H, m),
3.41 (1H, dd, J=4.2, 9.5), 3.55 (2H, dd, J=7.2, 7.6), 3.62 (1H, dt, J=3.0, 10.4), 3.77 (1H, ddd, J=3.5,
4.7, 10.4), 4.49 (2H, s), 4.72 (1H, bs), 4.89 (1H, bs), 7.26–7.34 (5H, m). 13C NMR (50.3 MHz): 19.2,
28.9 (3C), 29.4, 30.3, 35.5, 40.1, 54.5, 59.1, 66.6, 72.2, 72.8, 73.0, 111.8, 127.4, 127.5 (2C), 128.2 (2C),
138.2, 146.0. CIMS: 347 ([M+H]+, 54), 291 (100), 273 (89), 261 (23), 255 (13), 243 (21), 183 (60),
165 (43), 107 (33). Alcohol 15 (1.31 g, 3.79 mmol) was then oxidized to the corresponding aldehyde
using the Swern protocol as above to give, after SiO2 flash chromatography (heptane:EtOAc, 10:1), 1.28
g (98%) of 16: [α]D −194.0 (c 3.49). IR (film): 3070, 3031, 2973, 2935, 2874, 2724, 1720, 1643, 1455,
1389, 1363, 1254, 1192, 1100, 1071, 1046, 1027, 898, 736, 697 cm−1. 1H NMR (250 MHz): 0.90 (3H,
s), 1.17 (9H, s), 1.57 (1H, m), 1.79 (1H, m), 1.89–1.97 (2H, m), 2.07 (1H, m), 2.25 (1H, dt, J=4.8, 14.1),
3.22 (1H, d, J=2.5), 3.50–3.64 (2H, m), 3.91 (1H, dd, J=4.2, 9.8), 4.41 (1H, d, J=11.9), 4.47 (1H, d,
J=11.9), 4.75 (1H, bs), 4.95 (1H, bs), 7.24–7.33 (5H, m), 9.56 (1H, d, J=2.5). 13C NMR (62.9 MHz):
18.2, 29.0 (3C), 30.2 (2C), 35.1, 40.5, 64.7, 66.8, 72.1, 72.9, 73.1, 113.9, 127.4 (2C), 127.5 (2C), 128.2,
138.2, 141.0, 200.4. CIMS: 345 ([M+H]+, 23), 327 (4), 289 (100), 271 (15), 181 (58), 107 (13). Standard
acetal formation (ethyleneglycol, pTosOH, molecular sieves, rt) afforded 17 (1.26 g, 3.25 mmol) which,
upon debenzylation with lithium metal in liquid ammonia as above, furnished after chromatography
(heptane:EtOAc, 1:1) 969 mg (100%) of 18: [α]D −36.2 (c 0.95). IR (film): 3405, 2973, 2886, 1648,
1473, 1459, 1439, 1389, 1363, 1254, 1228, 1192 1141, 1122, 1067, 1049, 1023, 969, 942, 889 cm−1. 1H
NMR (250 MHz): 0.92 (3H, s), 1.20 (9H, s), 1.58 (1H, ddt, J=5.5, 10.7, 13.0), 1.66–1.88 (3H, m), 2.03
(1H, dt, J=7.1, 14.2), 2.20 (1H, m), 2.31 (1H, dt, J=5.2, 13.2), 2.43 (1H, d, J=4.7), 3.72–4.03 (7H, m),
4.65 (1H, bs), 4.85 (1H, t, J=2.2), 5.14 (1H, d, J=4.7). 13C NMR (62.9 MHz): 18.0, 29.0, 30.6, 31.2,
38.6, 40.7, 56.0, 59.1, 64.3, 64.4, 72.1, 73.3, 103.5, 112.4, 144.8. CIMS: 299 ([M+H]+, 46), 281 (3), 237

J. I. Martín Hernando et al. / Tetrahedron: Asymmetry 10 (1999) 783–797
795
(39), 225 (34), 181 (100), 163 (11). Anal. calcd for C17H30O4 C, 68.42; H, 10.13; found: C, 68.25; H,
10.19.
Swern oxidation of 18 (1.74 g, 5.83 mmol) produced, after chromatography (heptane:EtOAc, 5:1),
1.60 g (92.7%) of 19: [α]D −22.0 (c 1.16). IR (film): 3076, 2975, 2938, 2887, 1716, 1654, 1476, 1389,
1
1379, 1363, 1255, 1223, 1191 1146, 1115, 1069, 1049, 1026, 995, 972, 944, 891 cm−1. H NMR (250
MHz): 1.11 (3H, s), 1.14 (9H, s), 1.50 (1H, ddt, J=5.7, 10.9, 12.7), 1.81 (1H, m), 2.14–2.33 (2H, m),
2.41 (1H, bd, J=16.7), 2.51 (1H, d, J=4.9), 2.60 (1H, dd, J=3.0, 16.7), 3.70–3.95 (5H, m), 4.69 (1H, bs),
4.87 (1H, bs), 5.04 (1H, dd, J=1.2, 4.9), 9.84 (1H, m). 13C NMR (62.9 MHz): 19.1, 29.0 (3C), 30.5, 31.2,
40.5, 51.2, 56.0, 64.1, 64.6, 71.8, 73.6, 103.7, 113.3, 144.2, 203.5. CIMS: 297 ([M+H]+, 55), 297 (100),
223 (40), 198 (11), 179 (11), 113 (18), 73 (26), 71 (14).
The procedure developed by Still was repeated as above on 19 (1.6 g, 5.41 mmol) to afford after
chromatography (heptane:EtOAc, 20:1) a 78% epimeric mixture of 20a:20b in a 1:1.4 ratio. 20a (faster
eluting isomer): [α]D +12.2 (c 0.93). IR (film): 2956, 2926, 2873, 2855, 1650, 1465, 1459, 1388, 1377,
1
1362, 1194, 1171, 1147, 1128, 1095, 1066, 1052, 1032, 990, 939, 887 cm−1. H NMR (200 MHz):
0.83–0.94 (15H, m), 1.02 (3H, s), 1.19 (9H, s), 1.21–1.68 (13H, m), 1.78 (1H, m), 1.82 (1H, d, J=15.5),
2.20–2.27 (2H, m), 2.41 (1H, dd, J=11.2, 15.5), 2.58 (1H, d, J=5.1), 3.38 (3H, s), 3.70 (1H, dd, J=4.3,
10.1), 3.73–3.84 (2H, m), 3.86–3.99 (2H, m), 4.36 (1H, d, J=11.2), 4.52 (1H, d, J=6.5), 4.57 (1H, d,
J=6.5), 4.69 (1H, d, J=2.3), 4.87 (1H, d, J=2.3), 4.92 (1H, d, J=5.1). 13C NMR (50.3 MHz): 9.6 (3C),
13.6 (3C), 19.4, 27.6 (3C), 29.0 (3C), 29.2 (3C), 30.7, 31.6, 41.0, 42.6, 53.7, 56.3, 64.3, 64.4, 71.7,
72.5, 73.0, 97.2, 103.4, 111.9, 145.2. CIMS: 633 ([M+H]+, 100), 601 (21), 575 (70), 559 (24), 527 (82),
486 (17). Anal. calcd for C31H60O5Sn C, 58.96; H, 9.58; found: C, 58.82; H, 9.51. 20b (slower eluting
isomer): [α]D −83.7 (c 1.19). IR (film): 3050, 2956, 2926, 2873, 2856, 1648, 1465, 1459, 1388, 1377,
1
1362, 1193, 1145, 1098, 1052, 1028, 1007, 935 cm−1. H NMR (250 MHz): 0.86–0.94 (6H, m), 0.90
(9H, t, J=7.5), 0.93 (3H, s), 1.19 (9H, s), 1.25–1.39 (6H, m), 1.45–1.66 (7H, m), 1.80 (1H, m), 2.05 (1H,
dd, J=3.2, 15.2), 2.16 (1H, m), 2.17 (1H, dd, J=11.7, 15.2), 2.44 (1H, dt, J=6.0, 12.5), 2.75 (1H, bs),
3.38 (3H, s), 3.72–3.98 (5H, m), 4.39 (1H, dd, J=3.2, 11.7), 4.50 (1H, d, J=7.5), 4.53 (1H, d, J=7.5),
4.61 (1H, bs), 4.85 (1H, t, J=2.1), 5.48 (1H, d, J=2.6). 13C NMR (62.9 MHz): 9.5 (3C), 13.6 (3C), 17.3,
27.4 (3C), 29.1 (6C), 31.1, 32.5, 39.2, 42.8, 54.5, 56.0, 63.9, 64.8, 71.5, 71.6, 72.8, 97.0, 104.6, 112.6,
145.1. Anal. calcd for C31H60O5Sn C, 58.96; H, 9.58; found: C, 58.84; H, 9.63.
5.3. The A+C linking
5.3.1. Preparation of B-secotaxoid 22 and setting the stage for the eight-membered B-ring formation
To a magnetically stirred solution of 14b (510 mg, 0.725 mmol) in 3.5 mL of anhydrous THF cooled
at −78°C under argon, nBuLi (2.5 M in hex, 0.3 mL, 1.05 equiv.) was added and the mixture was stirred
at this temperature for 10 min before (ꢀ)-21 (388 mg, 1.45 mmol) was added. After stirring for 20
min at −78°C, the reaction mixture was diluted with ether, and quenched with a saturated solution of
NH4Cl. Following the usual work up, SiO2 column chromatography (eluent heptane:ether, 96:4) gave an
unseparable mixture of A+C adducts 22 (435 mg, 90%, only the major isomer is shown) along with an
unreacted 21. For the deprotection of tert-butyldimethylsilyl ethers at C-14 and C-2, this mixture was
heated at 50°C in 4 ml of THF in the presence of nBu4NF (1 M solution in THF 3 mL, 3 mmol) for 2.5
h. Dilution with ethyl acetate, the usual work up and SiO2 flash chromatography (heptane:EtOAc, 1:3)
furnished 261 mg of a mixture of triols (90%). The major isomer (obtained pure after chromatography,
shown in Scheme 5) 23: [α]D +41.1 (c 1.04). IR (film): 3416, 3075, 2975, 2881, 1640, 1460, 1391, 1367,
1250, 1196, 1165, 1144, 1062, 1016, 943, 906, 889, 741 cm−1. 1H NMR (300 MHz): 1.01 (3H, s), 1.03
(3H, s), 1.07 (3H, s), 1.19 (9H, s), 1.62 (1H, dd, J=5.4, 13.6), 1.60–1.94 (8H, m), 1.76 (3H, t, J=1.6), 2.11

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J. I. Martín Hernando et al. / Tetrahedron: Asymmetry 10 (1999) 783–797
(1H, dt, J=5.1, 13.3), 2.44 (1H, m), 2.54 (1H, m), 3.46 (3H, s), 3.53 (1H, dd, J=2.7, 5.1), 3.80 (1H, dd,
J=7.5, 11.3), 3.86–3.92 (2H, m), 4.17 (1H, m), 4.67 (1H, d, J=5.7), 4.73 (1H, bs), 4.78 (1H, d, J=5.7),
4.90 (1H, s), 5.55 (1H, bs). 13C NMR (75 MHz): 19.4, 22.2, 25.3, 26.2, 29.2 (3C), 29.4, 30.8, 38.5, 39.5,
42.6, 44.6, 50.7, 56.9, 60.1, 65.3, 72.2, 73.1, 77.8, 83.0, 100.0, 107.9, 128.2, 138.3, 147.9. CIMS: 455
([M+H]+, 30), 437 (90), 419 (31), 405 (36), 387 (21), 301 (40), 237 (34), 181 (50), 163 (100). Anal. calcd
for C26H46O6 C, 68.69; H, 10.20; found: C, 68.49; H, 9.97.
To a stirred solution of 23 (159 mg, 0.35 mmol) in 3.5 mL of dry acetonitrile under argon at room
temperature, was added 200 mg of powdered 4Å molecular sieves followed by NMO (123 mg, 1.05
mmol) and a catalytic amount of nPr4NRuO4 (TPAP, 19.7 mg, 0.056 mmol). After 30 min the solvent
was removed under reduced pressure and the reaction mixture was taken up in CH2Cl2 prior to filtration
through a short silica gel column (eluted with heptane:EtOAc, 1:1) to furnish the desired enone-aldehyde
(86%). 24: [α]D −33.7 (c 2.92). IR (film): 3463, 2971, 2937, 1720, 1663, 1470, 1388, 1364, 1310, 1252,
1
1192, 1069, 1026, 908, 734 cm−1. H NMR (200 MHz): 1.03 (3H, s), 1.08 (3H, s), 1.13 (9H, s), 1.14
(3H, s), 1.57–2.43 (7H, m), 2.00 (3H, bs), 2.71 (1H, d, J=18.6), 3.24 (1H, s, OH), 3.34 (1H, bs), 3.46
(3H, s), 3.69 (1H, dd, J=3.2, 6.4), 3.94 (1H, dd, J=2.1, 10.1), 4.68 (1H, bs), 4.68 (1H, d, J=6.2), 4.78
(1H, d, J=6.2), 4.92 (1H, bs), 5.91 (1H, s), 9.65 (1H, d, J=1.9). 13C NMR (50.3 MHz): 20.3, 21.0, 24.0,
27.7, 29.1 (3C), 29.6, 30.6, 37.0, 42.0, 50.0 (2C), 56.9, 62.0, 72.1, 73.3, 78.7, 85.5, 100.2, 112.5, 128.2,
141.7, 163.0, 198.1, 201.8.
5.3.2. The C1–C2 linking: synthesis of the ABC taxoid 25
LDA (0.27 mmol, 2 equiv.) was prepared at −20°C in 9 ml of dry THF, cooled at −78°C and stirred
at this temperature for 15 min. Then the enone-aldehyde 24 (60 mg, 0.13 mmol) was added in 10 ml
of THF. After 5 min, the solution was diluted with heptane and the reaction was quenched at −78°C by
careful addition of a sat. aq. NH4Cl solution. The organic layer was then separated and washed with brine
until pH 7. Usual work up followed by chromatography (heptane:EtOAc, 3:1) furnished 18.6 mg of the
aldol 25 (31%), and 30 mg of starting material (50%). 25: mp: 168–170°C (heptane–ether). [α]D −66.3
(c 0.9). IR (film): 3546, 3075, 2854, 1717, 1656, 1460, 1363, 1266, 1190, 1150, 1090, 1068, 1047, 1039,
911 cm−1. 1H NMR (800 MHz): 0.98 (3H, s, Me-19), 1.08 (9H, s, tBu), 1.22 (3H, s, Me-17), 1.42 (3H, s,
Me-16), 1.52 (1H, dd, J=6.3, 17.5, H-9ax), 1.53 (1H, dddd, J=5.1, 11.1, 12.5, 14.4, H-6ax), 1.70 (1H, d,
J=17.5, H-9eq), 1.79 (1H, dddd, J=2.0, 4.7, 5.6, 12.5, H-6eq), 2.04 (3H, t, J=1.1, Me-18), 2.18 (1H, bdd,
J=5.1, 14.4, H-5eq), 2.30 (1H, tdt, J=2.0, 5.6, 14.4, H-5ax), 2.57 (1H, d, J=11.2, H-3), 2.80 (1H, s, H-1),
3.19 (1H, dd, J=4.7, 11.1, H-7), 3.47 (3H, s, OMe), 3.89 (1H, s, OH), 4.06 (1H, d, J=6.3, H-10), 4.38
(1H, d, J=11.2, H-2), 4.64 (1H, d, J=6.8, OCH2O), 4.77 (1H, d, J=6.8, OCH2O), 4.87 (1H, bs, H-20a),
5.02 (1H, t, J=2.0, H-20b), 6.13 (1H, dq, J=1.1, 1.1, H-13). 13C NMR (75 MHz): 20.0 (Me-16), 20.5
(Me-19), 21.5 (Me-18), 28.9 (tBu), 30.9 (C-5), 31.0 (C-6), 31.8 (Me-17), 39.1 (Cq-8), 40.2 (C-9), 40.9
(Cq-15), 56.1 (OMe), 56.8 (C-3), 61.4 (C-1), 69.4 (C-2), 71.7 (C-7), 73.5 (Cq-tBu), 76.8 (C-10), 79.6
(C-11), 94.3 (–OCH2O–), 115.3 (C-20), 127.9 (C-13), 147.4 (C-4), 163.3 (C-12), 198.3 (C-14). CIMS:
451 ([M+H]+, 100), 433 (23), 419 (37), 401 (5), 389 (25), 377 (45). HRCIMS: calcd for C26H43O6 m/z
451.3059, found 451.3052.
Acknowledgements
The authors thank the Ministerio de Educacion y Cultura (Spain) for fellowships to Dr. J. Quílez del
Moral and Dr. J. I. Martín Hernando, the European Commission for a Research Training Grant to Dr. J.
I. Candela Lena, and Professor Pierre Potier for his kind interest and constant encouragements.

J. I. Martín Hernando et al. / Tetrahedron: Asymmetry 10 (1999) 783–797
797
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