Dienyne ring-closing metathesis approach for the construction of taxosteroids

Article abstract of DOI:10.1002/chem.200601685

A cascade dienyne ring-closing metathesis approach has been applied to the synthesis of the tetracyclic carbon framework of a new class of hybrid compounds - the taxosteroids - possessing carbon frameworks incorporating moieties characteristic of both tax

Full text of DOI:10.1002/chem.200601685

FULL PAPER
DOI: 10.1002/chem.200601685
Dienyne Ring-Closing Metathesis Approach for the Construction of
Taxosteroids
María J. Aldegunde, Rebeca García-FandiÇo, Luis Castedo, and Juan R. Granja*[a]
Abstract: A cascade dienyne ring-closing metathesis approach has been applied to
the synthesis of the tetracyclic carbon framework of a new class of hybrid com-
Keywords:
medium-ring com-
pounds—the taxosteroids—possessing carbon frameworks incorporating moieties
characteristic of both taxanes (such as AB rings) and steroids (i.e., CD system and
side chain). This tandem cyclization is highly stereoselective, allowing the one-step
pounds · metathesis · ring-closing
dienyne metathesis (RCDEYM) ·
steroid analogues · taxosteroids
formation of the bicyclo[5.3.1]undecene system characteristic of taxol. In this work
G
we describe the scope and limitations of such cyclizations.
Introduction
The creation of molecular entities that blend the structural
characteristics of two or more natural products or pharma-
cophore-derived fragments joined by at least one carbon–
carbon bond is one of the most appealing strategies in drug
discovery.[1] Conceptually, the objective in this approach is
the design of new functional molecules with enhanced or
even new types of properties arising from the combination
of diverse structural features from two or more functionally
active compounds. We have previously reported a molecular
hybrid system, in the form of the taxosteroids (I, Figure 1),[2]
characterized by the presence of the [5.3.1] system (A and
B rings) of taxanes (III) joined in fusion with the [4.3.0] bi-
cyclic unit (rings C and D) of the steroid system (II).[3] Inter-
est in compounds of this type of structure arises both from
their structural novelty and from their potential biological
activity. The recent discovery that some steroid analogues
behave like paclitaxel,[4] increasing tubulin assembly and sta-
bilizing microtubules, further supports this hypothesis with
regard to the potential activity of taxosteroids.[5] Additional-
ly, the structure is ideally suited for the development of new
methodologies for the construction of fused and bridged
Figure 1. Top: General structure of taxosteroids (I), in which the bicyclo-
A
cycle, rings C and D of the steroid system. Bottom: General strategy for
preparation of taxosteroid skeleton.
polycyclic systems.[6] To this end we envisioned, as an alter-
native to other lengthy procedures developed so far, the
direct preparation of the core system through a cascade[7]
metathesis strategy, in which the power of ring-closing meta-
thesis (RCM)[8] would be combined with a sequential bond
formation. In particular, we considered a ring-closing dien-
yne metathesis (RCDEYM)[9] reaction in which the initial
first ring formation by ring-closing enyne metathesis
[a] M. J. Aldegunde, Dr. R. García-FandiÇo, Prof. Dr. L. Castedo,
Prof. Dr. J. R. Granja
Departamento de Química Orgµnica e Unidade Asociada ó C.S.I.C.
Facultade de Química, Universidade de Santiago
15782 Santiago de Compostela (Spain)
Fax : (+34)981-595012
E-mail: qojuangg@usc.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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5135

(RCEYM)[10] between the alkyne and the less substituted
olefin would provide a metal alkylidene intermediate that
would then undergo RCM with the other double bond to
give a second ring. This transformation is very useful for the
construction of two-ring systems from acyclic starting mate-
rials and has even been extended to the construction of
three or four rings: the steroid skeleton, for example, has
been prepared in one step from a linear dienetriyne in this
way.[11] The proposed domino-metathesis approach
(RCDEYM) to taxosteroids implies an initial enyne RCM
of precursor 1a that would form ring B[12] and generate in-
termediate 2, which would cyclize again to form ring A of 3
(Figure 1). Regiocontrol over the first cyclization would be
achieved through appropriate selection of the substituents
R1, R2 and/or R3 such as to ensure that the catalyst would
initially react with the less substituted olefin to form 1b and
then with the alkynyl moiety, so that the formation of the
thermodynamically less stable eight-membered ring would
be favored.[13]
Here we report full details of the application of this
tandem metathesis to the synthesis of novel taxosteroids, in-
cluding the preparation of precursors, the structural require-
ments and the influence of dienyne substituents on the key
tandem process, as well as an enantioselective version. The
preparation of the appropriate precursors is based, as previ-
ously reported, on a combination of enol alkylation and car-
bonyl allylation of the ketone containing the CD frag-
ment.[2,12] The use of a hydrindanone possessing a methylsi-
lyloxyethyl side chain (7 in Scheme 1) would both aid for-
mation of the eight-membered ring[2] and provide a CD
system on which a modified steroid side chain could be in-
troduced.
Scheme 1. Synthesis of dienyne 9a and RCM studies. a) MeI, K2CO3,
DMF, 77%. b) LDA, propargyl bromide, THF, ꢀ608C, 43%. c) LiAlH4,
Et2O, 94%. d) I2, PPh3, imidazole, 85%. e) 1) KHMDS, toluene/DMF,
ꢀ788C, 2) 6a, 79%. f) AllylMgBr, THF, 95%. g) 10a (15%), CH2Cl2, D,
44%. h) TBAF, THF, 97%.
compound 11a, with a global yield of 44% (Scheme 1 and
Table 1, entry 1). Flash chromatography of the crude mix-
ture allowed isolation of compound 12a. The other two
products were easily separated after removal of the tert-bu-
tyldimethylsilyl group by treatment with tetrabutylammoni-
um fluoride. NMR analysis of the deprotected minor com-
pound 14a showed it to be a single isomer, suggesting that
only one of the C10-epimers of 9a can undergo the tandem
RCDEYM reaction, with the geometric impediments to the
second annulation of the other epimer causing it to remain
as 12a.[2,12c,16] This hypothesis was supported by a lack of
conversion of triene 12a into 11a when treated with RCM
catalyst 10a or the more reactive Grubbsꢁ catalyst 10b,[17]
either in methylene chloride or in benzene.
Although the taxosteroid skeleton had only been obtained
as a minor product, the above result had at least demon-
strated the feasibility of the proposed strategy. To improve
the yield, we first tried using the more reactive Grubbsꢁ cat-
alyst 10b, which has been employed in previously reported
RCDEYM reactions.[9a,10a] However, the use of this catalyst
with compound 9a afforded a complex mixture in which no
compound containing an eight-membered ring was ob-
served, the main isolated product being the cyclopentene
16a, in this case in a 20% yield (Table 1, entry 2). This be-
havior was attributed to the catalyst initially reacting with
the acetylene group and then, presumably because of ther-
modynamic preference for 16a over 11a or 12a, with the
more substituted alkene (vide infra).[18]
Results and Discussion
Synthesis of the taxosteroid skeleton by RCDEYM—struc-
tural requirements: Following the synthetic strategy de-
scribed above, we initially prepared the alkylating agent 6a
(Scheme 1). This iodide was obtained in four steps from the
commercially available hex-4-enoic acid, which was esteri-
fied by treatment with methyl iodide in basic DMF. The re-
sulting ester was deprotonated with freshly prepared lithium
diisopropylamide (LDA) at ꢀ608C and the generated eno-
late was trapped with propargyl bromide to afford ester 4 in
43% yield.[14] After reduction with lithium aluminium hy-
dride, the resulting alcohol 5a was treated with triphenyl-
phosphine, imidazole and iodine to give 6a.
Treatment of 6a with the kinetic enolate of 7 (generated
with KHMDS in toluene/DMF 1:1), followed by allylation
of the resulting ketone (8a), gave dienyne 9a in 75% yield
(from 7) as an inseparable 1:1 mixture of C10-epimers.[15]
Treatment of 9a with Grubbsꢁ catalyst 10a (15%) provided
a 2:2:1 mixture of enyne 13a (formed by simple diene RCM
without involvement of the alkynyl moiety), triene 12a (the
product of simple RCEYM without involvement of the
more substituted double bond) and the desired tetracyclic
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Dienyne RCM Approach for the Construction of Taxosteroids
FULL PAPER
Table 1. Results of RCM of dienynes 9a–d.
Entry
9
R1
R2
Cat[a] Relative ratios[b] Global yield[c]
11 12 13 16
Scheme 2. Synthesis of dienynes 9b–d. a) 1) NaOEt, EtOH, Et2O,
1
2
3
4
5
6
7
8
9a
9a
9b10R
9b10S
9c10R
9c10S
9d
9d
Me/H Me/H 10a
Me/H Me/H 10b
1
0
1
0
9
0
0
0
2
0
0
0
1
1
4
0
2
0
1
9
0
0
0
0
0
1
0
1
0
0
1
1
44
20
80
97
90
55
60
20
ꢁ
2) BrCH2C CH, toluene/DMF, D, 86%. b) NaOEt, MeSO3CH2CH=
CR1R2, THF, 35% for 19b and 85% for 19c. c) NaOEt, BrCH2CH=C-
[d]
H
Et
Et
H
10a
10a
10a
10a
10a
10b
[d]
[d]
(CH3)2, THF, 75%. d) NaOEt, EtOH, 32–55%. e) LiAlH4, THF, 89–
H
94%. f) I2, PPh3, imidazole, 85–98%. g) Grundmannꢁs ketone (20) or 7,
KHMDS, toluene/DMF, ꢀ788C, and then 6b–d, 35–78%. h) AllylMgBr,
THF, 70–95%.
iPr
iPr
Me
Me
[d]
H
Me
Me
[a] The amounts of catalysts 10a or 10b were not optimized and 15%
was routinely used. [b] Approximate relative ratios determined by NMR
spectroscopy on the crude mixture. [c] Global yields of products isolated
by chromatography on silica gel or aluminum oxide. [d] C10-epimers sep-
arated by flash chromatography are differentiated by a subscript (10R or
10S).
tion either of the kinetic enolate of 7 with 6b and 6c or of
the enolate of Grundmannꢁs ketone (20)[20] (Scheme 1) with
iodide 6d, followed by allylation of the resulting ketones.
The two C10-epimers of dienynes 9b and 9c were separat-
ed by flash chromatography. In the case of 9c they were not
obtained in equal amounts: the 9c10S/9c10R ratio (the eluci-
dation of the stereochemistry is described below) was 10:1
after use of three equivalents of 6c (overall yield 75%), and
3:1 after use of 1.5 equivalents (overall yield 78%), showing
that one of the enantiomers of 6c [(R)-6c] reacts more rap-
idly than the other with the enolate of 7 to give the 10S dia-
stereomer of dienyne 9. Since it turned out to be the other
isomers (10R) of dienynes 9 that were susceptible to
RCDEYM (see below), we later tried to prepare 9c with
the use of fewer than 1.5 equivalents of 6c, but this reduced
the global yield of the reaction significantly. The two C10-
epimers of 9d could not be separated.
Like the reactive isomer of 9a, which proved to be 10R,
the same isomers (10R) of dienynes 9b and 9c both afford-
ed the desired taxosteroid 11a (R=OTBS) when subjected
to RCDEYM conditions with catalyst 10a. In these cases
the yields of the taxosteroid 11 increased with the steric im-
pediment to the diene RCM (R1 or R2 =Me, Et, iPr; en-
tries 1, 3, and 5, Table 1), as did the overall yields.[21] The
other isomers (10S) of 9b and 9c, like the unreactive
isomer of 9a, failed to afford compound 11a; instead 9b10S
gave mainly the diene RCM product 13a (entry 4, Table 1),
whilst 9c10S gave only triene 12c (entry 6, Table 1). These re-
sults confirm that only one of the isomers of dienynes 9 can
undergo both annulations, and show that for this isomer the
desired annulation sequence can be favored by the presence
of appropriate terminal substituents on the longer olefin
chain. Disubstitution at this position, however, was counter-
productive: when 9d was used as substrate for the
RCDEYM reaction, the major products were triene 12d
Because the use of catalyst 10b had failed to improve the
yield of 11a afforded by catalyst 10a, we prepared a series
of compounds (9b–d) bearing different substituents on the
longer olefin chain (R1 and/or R2) in the hope that these
substrates would be less likely to support conversion into
enynes 13 by diene RCM and/or less likely to give triene in-
termediates 12 that could not cyclize to 11. The alkylating
agents needed to prepare these substrates, compounds 6b–d,
were obtained from triethyl methanetricarboxylate (17) as
shown in Scheme 2. Deprotonation of 17 (EtONa, EtOH/
Et2O), followed by heating of a toluene/DMF (1:1) solution
of the resulting sodium salt at 808C in the presence of prop-
argyl bromide, gave the alkyne triester 18. Decarboxylation
with sodium ethoxide and in situ alkylation of the resulting
anion with the appropriate allyl electrophilic reagents af-
forded compounds 19b–d. Attempted monodecarboxylation
of these malonates by heating in acidic aqueous solution
(HCl/H2O) gave only very poor yields (in the case of 19d,
zero yield after 3 h at reflux), and no improvement was ach-
ieved by treatment with sodium hydroxide followed by heat-
ing in water or DMSO in the presence of NaCl. The best
yields (32–55%) were achieved by heating a solution of mal-
onate in ethanol containing sodium ethoxide, with subse-
quent neutralization.[19] Reduction of the resulting esters
with lithium aluminium hydride in THF afforded the alco-
hols 5b–d, which were transformed into iodides 6b–d in
good yields by treatment with triphenylphosphine, imidazole
and iodine. Finally, dienynes 9b–d were obtained by alkyla-
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Juan R. Granja et al.
(48%) when the catalyst was 10a and cyclopentene 16d
(20%) when the catalyst was 10b (entries 7 and 8, Table 1),
although treatment of isolated 12d with 10b at reflux in di-
chloromethane for 12 h did afford a small yield of 11d
(14%).[22] This last finding supports our earlier conclusion
that the failure of 10b to induce RCDEYM of 9 was due to
the presence of the alkyne moiety, and also suggests that in
the case of 9d there was not only a total stereochemical im-
pediment to RCDEYM of the 10S diastereomer, but also a
somewhat less intractable impediment to RCDEYM of the
10R diastereomer (presumably involving steric hindrance
due to the methyl groups R1 and R2).
lation of the resulting ketone, afforded compounds with
spectroscopic characteristics identical to those of the reac-
tive isomers of 9b and 9c, thus confirming these as 9b10R
[24]
and 9c10R
.
Subjection of these compounds to RCM condi-
tions gave, as expected, results identical to those obtained
with the reactive compounds derived from racemic mixtures
of iodides 6b and 6c (entries 3 and 5, Table 1). Definitive
confirmation of the stereochemistry of the reactive isomers
of 9 was obtained by X-ray crystallography of the methyl
ether 11e (P=Me, Figure 2), which was obtained by alkyla-
Enantioselective synthesis of (10R)-taxosteroids by
RCDEYM: Molecular mechanical calculations suggested
that, as anticipated above, it was the 10R stereoisomers of
compounds 9 that were able to cyclize. To confirm this and
to establish the configurations of the taxosteroids at C10, we
prepared the enantiopure alkylating agents 6b and 6c by
use of (4R,5S)-4-methyl-5-phenyloxazolidin-2-one as chiral
auxiliary (Scheme 3).[23] Treatment of (Z)-hept-4-enoic acid
Figure 2. X-ray structure of compound 11e, confirming the C10-R config-
uration.
tion of 11a with KH and MeI and then crystallized from
chloroform by vapor-phase equilibration with hexane. The
structure calculated from the X-ray data showed the expect-
ed taxane-like bicyclo[5.3.1]undecadiene system with the
G
bridgehead C4=C6 double bond left untouched by the
RCDEYM reaction and with the R configuration at C10, as
a result of which the C10 hydrogen is cis to the C8 methoxy
group and C9 hydrogen (Figure 2).
Enantioselective synthesis of
a 3-methyltaxosteroid by
Scheme 3. Enantioselective synthesis of iodides (S)-6b, (S)-6c, and (S)-
6g. a) 1) Pivaloyl chloride, Et3N, THF, ꢀ788C, 2) (4R,5S)-4-methyl-5-
phenyloxazolidin-2-one, DMPA, room temperature, 59% for 22b, 80%
RCDEYM: Our next step was to use an RCDEYM sub-
strate with an alkyne chain terminated by a methyl group
that should end up at the position corresponding to the C18-
methyl group of taxol (C3 in the taxosteroid skeleton,
Scheme 4). Accordingly, compound 9 f was prepared by
3
3
ꢁ
for 22c. b) LiHMDS, BrCH2C CR , THF, ꢀ788C, 65% (R =TMS) from
22b, 70% (R3 =Me), 65% (R3 =TMS) from 22c. c) LiAlH4, THF, 08C,
90% for (S)-5g. d) TBAF, THF, 80% for (S)-5b, 90% for (S)-5c (two
steps). e) I2, PPh3, imidazole, 75% for (S)-6b, 75% for (S)-6c, 70% for
(S)-6g.
(21b) with pivaloyl chloride, followed in situ by Evansꢁ oxa-
zolidinone, afforded compound 22b, the enolate of which
(generated with LiHMDS) was treated at ꢀ788C with 1-
bromo-3-trimethylsilylprop-2-yne to give the corresponding
propargylated oxazolidinone 23b in >90% de. Reduction of
23b with lithium aluminium hydride and subsequent desily-
lation provided alcohol (S)-5b, and treatment of this alcohol
with iodine, triphenylphosphine and imidazole afforded
iodide (S)-6b in 75% yield. The (E)-isopropyl derivative
(S)-6c was prepared from (E)-6-methylhept-4-enoic acid[23]
(21c) in similar yield by the same strategy. Alkylation of the
kinetic enolate of 7 with (S)-6b or (S)-6c, followed by ally-
Scheme 4. RCDEYM of dienyne 9 f for the synthesis of taxosteroids con-
taining the C18-methyl group of taxol (C3 at taxosteroid skeleton).
a) nBuLi, MeI, THF, 76%. b) 10b (15%), CH2Cl2, D, 38%. c) 10b
(15%), benzene, D.
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Dienyne RCM Approach for the Construction of Taxosteroids
FULL PAPER
treatment of 9d with two equivalents of nBuLi, followed by
methyl iodide (Scheme 4). Although RCDEYM of 9 f was
expected to suffer from steric hindrance from the geminal
methyl groups of the alkene, the formation of 11d by treat-
ment of triene 12d with 10b encouraged us to hope that 9 f
might afford a similar result. However, the desired taxoste-
roid 11 f was obtained neither directly by treatment of 9 f
with 10a or 10b, nor when the product isolated from that re-
action, a 38% yield of triene 12 f, was treated with 10b in
benzene at reflux. Apparently, RCDEYM was impossible
for 9 f not only in the case of the 10S diastereomer but also
in that of its 10R epimer, because of excessive steric hin-
drance due to the combination of the acetylenic methyl
group and the geminal olefinic methyl groups. Unexpected-
ly, the use of 10b did not result in the formation of any
product containing the cyclopentene present in 16, although
this type of derivative had previously always been obtained
when this catalyst had been applied to a dienyne substrate.
In view of the above results, we decided to reduce the
steric hindrance in the substrate by using 6g, in which R1 =
iPr and R2 =H (Scheme 3), and at the same time avoid un-
necessary production of the 10S diastereomer by using only
9g10R (Scheme 5). Accordingly, iodide (S)-6g was prepared
skeleton). This group could be generated by aldol condensa-
tion of the kinetic enolate of 7 and an aldehyde, such as (S)-
24h (Scheme 6), containing the enyne moiety and the iso-
Scheme 6. Synthesis of taxosteroids 11i,j (10S epimers) containing the
C2-hydroxy group of taxol (C19 at taxosteroid skeleton). a) PDC,
CH2Cl2, 72%. b) 7, LDA, THF, ꢀ788C, and then (S)-24h, 92%. c) Al-
lylMgBr, THF, 79%. d) MOMCl, DIEA, CH2Cl2, 80%. e) TBSOTf, Py,
CH2Cl2, 08C to rt, 75%. f) 10b (10%), benzene, D, 80% for 12j10S and
80% for 11j10S. g) 10b (10%), benzene, D, 2 h and then 10b (10%), D,
62%.
propyl group needed for optimal RCDEYM product forma-
tion. It was believed that the well known anti aldol product
selectivity and the enolate axial attack,[25] together with
facial selectivity for alkylation of hydrindinone 7, should
preferentially provide only one (19S) diastereomer. Alde-
hyde (S)-24h was obtained in 72% yield by oxidation of al-
cohol (S)-5g with pyridinium dichromate (PDC), and addi-
tion of the lithium kinetic enolate of 7 to a cooled (ꢀ788C)
solution of aldehyde (S)-24h in THF, followed by carbonyl
allylation of the resulting ketone, provided diol 9h10S in
72% yield (two steps) as a single isomer (Scheme 6).[26] It
was not possible at this point to confirm the expected 19S
configuration by NMR experiments. Unfortunately, treat-
ment of the resulting diol 9h10S with Grubbsꢁ catalysts 10a
or 10b at reflux in either benzene or dichloromethane did
not provide any cyclization products, and the starting dieny-
nediol was not recovered in any of these cases, being com-
pletely decomposed. We have attributed this result to the
presence of the two unprotected hydroxy groups, which has
been claimed to decompose the catalyst.[27]
Protection of those hydroxy groups was only possible as
MOM acetals, by treatment of diol 9h10S with methoxymeth-
yl chloride and N,N’-diisopropylethylamine (DIEA), to give
compound 9i10S in 80% yield. Treatment of MOM deriva-
tive 9i10S under the above optimal RCDEYM conditions
(10% 10b in benzene) afforded a complex mixture of com-
pounds in which the main compound was the triene deriva-
tive 12i10S rather than the desired tetracyclic derivative
11i10S. Furthermore, the monoprotected silyl ether 9j10S
Scheme 5. Synthesis of a taxosteroid containing the C18-methyl group of
taxol (11g). a) 7, KHMDS, toluene/DMF, ꢀ788C, and then (S)-6g, 70%.
b) AllylMgBr, THF, 93%. c) 10b (10%), benzene, D, 69% from 9g10R
and 70% from 12g10R
.
in the same way as (S)-6c (but with use of 1-bromobut-2-
yne instead of 1-bromo-3-trimethylsilylprop-2-yne to alky-
late 22c; Scheme 3). Addition of (S)-6g to the potassium
enolate of 7, followed by allylation of the resulting ketone,
afforded dienyne 9g10R in 70% yield. With this dienyne the
steric hindrance problem still persisted, but was no longer
insurmountable. Although treatment of 9g10R with 10a in di-
chloromethane or benzene afforded 11g10R only as a very
minor product (the major product being the triene 12g10R),
treatment of isolated 12g10R with 10b (10%) at reflux in
benzene for 4 h produced 11g10R almost exclusively (70%).
It was then found that treatment of 9g10R directly with 10b
at reflux in benzene also afforded 11g10R as the major prod-
uct (69%), without any of the cyclopentene formation that
we had initially expected.
Stereoselective synthesis of (19S)-hydroxylated taxosteroids
by RCDEYM: In order to increase the structural complexi-
ty of the taxosteroid hybrids further, we decided to intro-
duce the taxol C2 hydroxy group (C19 in the taxosteroid
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Juan R. Granja et al.
gave mainly triene 12j10S (80%) under the same condi-
tions.[28]
product and no starting material was recovered. Now, how-
ever, the MOM-protected derivative 9i10R was cyclized to
11i10R under optimal RCDEYM conditions in excellent
yield (90%). Interestingly, the ketone 9k10R was also cy-
clized in good yield under the same conditions, to form the
19-ketotaxosteroid derivative 11k10R. Inspection of the two-
dimensional NMR spectra of the two taxosteroids 11i10R
and 11k10R showed clear NOE relationships between H9
(d=2.56 ppm and 2.98 ppm, respectively) and Me18 (d=
0.98 ppm) that can only be explained by the C ring adopting
a boat conformation. Additional structural information was
provided by the observed NOE between the neighbouring
Interestingly, while treatment of isolated 12i10S with 10b
at reflux in benzene had not afforded any 11i10S, the silyl
ether 12j10S was transformed into the tetracyclic derivative
11j10S in good yield. The best conditions for the formation
of the taxosteroid skeleton from dienyne 9j10S required two
additions of catalyst 10b (10%), the second one being after
two hours of heating, when the main product observed by
TLC was the triene precursor 12j10S. Under these conditions
compound 11j10S was obtained in 62% yield. The observed
NOE cross-peaks between the H19 and H9 and H10 in
NMR spectra of 11j10S confirm the proposed 19S configura-
tion.
These results obtained with 19-hydroxylated derivatives
(9i10S and 9j10S) might suggest that the presence of substitu-
ents at position C19 and a protecting group on the tertiary
hydroxy group produces some conformational modification
that might preclude the final cyclization. For that reason we
decided also to study the 10R isomer, hoping that these con-
formational changes might now facilitate its cyclization. To
this end we prepared alcohol (R)-5g in the same way as (S)-
5c (Scheme 3) but with use of (S)-4-benzyloxazolidin-2-one
as chiral auxiliary (Scheme 7).[23,24] Oxidation of alcohol (R)-
5g with PDC afforded the enantiomerically pure aldehyde
(R)-24h, which on condensation with the kinetic enolate of
7 and subsequent allylation produced diol 9h10R in 62%
yield as a single isolated isomer at C19 (Scheme 7). Once
again, treatment of the resulting diol with Grubbsꢁ catalyst
10b at reflux in benzene did not provide any cyclization
protons H19 (d=3.99 ppm) and H9 in spectra of 11i10R
,
which confirms the proposed 19S configuration. Definitive
confirmation of the stereochemistry of the C19-OH taxoste-
roid was again obtained by X-ray crystallography, this time
of 11i10R, which was obtained by crystallization from metha-
nol. The structure calculated from the X-ray data for 11i10R
showed the expected taxane-like bicyclo[5.3.1]undecadiene
G
system fused to a C ring in a boat conformation, together
with the S configuration at C19 (Figure 3).
Figure 3. X-ray structure of compound 11i10R, confirming the C10-R con-
figuration.
Mechanistic conclusions:[18,29] It would appear that, as we
had originally envisaged, the first-generation Grubbsꢁ cata-
lyst 10a initially reacts preferentially with the less substitut-
ed double bond in dienynes 9a–k, forming the correspond-
ing vinylideneruthenium(II) intermediates 26 (Scheme 8).
Diene RCM of 26 affords enynes 13, while RCEYM of 26
gives the secondary vinylideneruthenium(II) intermediates
27. RCM of 27 produces—if there is not too much steric
hindrance—the desired taxosteroids 11, while cross-metathe-
sis of 27 with another molecule of substrate 9 generates
fresh 26 and leaves, as products, the trienes 12. In the case
of the 10S diastereomers of 27, annulation to the taxoste-
roid is stereochemically impossible if the C ring adopts a
chair conformation, but RCM will take place if the confor-
mation of ring C is boat, induced by the presence of a sub-
Scheme 7. Synthesis of taxosteroids 11i and 11k (10R diastereomer) con-
taining the C2-hydroxy group of taxol (C19). a) 1) Pivaloyl chloride,
Et3N, THF, ꢀ788C, 2) (4S)-4-benzyloxazolidin-2-one, DMPA, room tem-
3
ꢁ
perature, 42% from 21b, 94% from 21c. b) LiHMDS, BrCH2C CR ,
THF, ꢀ788C, 77% for 25b and 73% for 25g. c) LiAlH4, Et2O, 0 8C, 87%
for (R)-5g. d) TBAF, THF, 75% for (R)-5b (two steps). e) I2, PPh3, imi-
dazole, 85% for (R)-6b. f) PDC, CH2Cl2, 70%. g) 7, LDA, THF, ꢀ788C,
and then (R)-24h, 91%. h) AllylMgBr, THF, 68%. i) MOMCl, DIEA,
CH2Cl2, 82%. j) PDC, CH2Cl2, 46%. k) 10b (10%), benzene, D, 90% for
stituent (R¼
6
H) at C19 and if there is not too much steric
hindrance. On the other hand, the 10R epimers of 27 can
undergo RCM to afford 11 when the C ring can adopt the
chair conformation. Formation of taxosteroids 11 can also
take place by RCM of conformationally predisposed trienes
11i10R, 54% for 11k10R
.
5140
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5135 – 5150

Dienyne RCM Approach for the Construction of Taxosteroids
FULL PAPER
closing metathesis. This RCDEYM is highly stereoselective,
can be very efficient and allows the introduction of a variety
of substituents characteristic of taxanes (methyl, hydroxy)
into the carbon framework. We anticipate that it should also
be useful for the construction of complex polycyclic systems
from conformationally locked cycloalkanones other than
those used in this study (7 and 20). Work on the introduc-
tion of additional functional groups into the taxosteroid
skeleton and on the biological and pharmacological proper-
ties of this new class of compounds is currently in progress.
Experimental Section
Methyl (E,Z)-hex-4-enoate: Hex-4-enoic acid (3.00 g, 26.28 mmol) and
MeI (5.0 mL, 28.9 mmol) were added successively to a suspension of
K2CO3 (5.40 g, 39.07 mmol) in DMF (15 mL). After having been stirred
for 2 h at room temperature, the mixture was poured into water and ex-
tracted with Et2O (2”10 mL). The organic phases were washed with
water (3”10 mL), dried over Na2SO4, filtered and concentrated under re-
duced pressure. The crude residue was distilled (508C at 1 mmHg) to
afford the target ester (2.60 g, 77%, colorless oil); 1H NMR (250 MHz,
CDCl3, 258C, TMS): d=5.44 (m, 2H), 3.66 (s, 3H), 2.33 (m, 4H),
1.64 ppm (d, 3J=4.9 Hz, 3H); 13C NMR (63 MHz, CDCl3, 258C, TMS):
d=173.0 (CO), 128.9 (trans CH), 128.0 (cis CH), 125.7 (trans CH), 124.9
(cis CH), 50.9 (CH3), 33.6 (CH2), 27.5 (CH2), 22.0 (cis CH3), 17.4 ppm
(trans CH3); EM-IQ+: m/z (%): 128 (11) [M]+, 97 (6) [MꢀOMe]+, 69
(11) [MꢀCO2Me]+; HRMS calcd for C7H12O2 [M]+: 128.08373; found:
128.08376.
Scheme 8. Mechanistic paths for dienyne metathesis compounds.
12. In some cases (such as 11j10S), the formation of tetracy-
clic compound occurs mainly through the RCEYM/RCM se-
quence, probably because cross metathesis to give rise to
the triene 12 takes place before the ring-closing process, due
to conformation restrictions. In any case, success is not guar-
anteed and may require the use of 10b and of relatively
long reaction times and/or relatively high temperatures.
If the acetylene group of 9 is terminal (R3 =H), the
second-generation Grubbsꢁ catalyst 10b appears to react ini-
tially with this group (EYM), forming the conjugated metal-
lovinylidenes 28. Driven by the greater thermodynamic sta-
bility of 16, this intermediate then undergoes RCM to form
these cyclopentene derivatives rather than reacting with the
less substituted double bond to form the eight-membered
ring, even though the formation of the cyclopentene ring re-
quires reaction of the catalyst with the more substituted
olefin. However, the lack of formation of cyclopentenes
from 9 f–k suggests that if the acetylene group is non-termi-
nal (R3 =Me), formation of 28 is blocked and the reaction
proceeds via 27, although steric hindrance due to the block-
ing methyl group may make it necessary to use relatively
long reaction times and/or relatively high temperatures to
achieve the second annulation.
Methyl (E,Z)-2-(prop-2-ynyl)hex-4-enoate (4):
A solution of methyl
(E,Z)-hex-4-enoate (3.09 g, 24.11 mmol) in THF (50 mL) was added at
ꢀ608C to a solution of LDA in THF (1m, 26.6 mL, 26.6 mmol). The mix-
ture was stirred at that temperature for 30 min, propargyl bromide (80%
w/w solution in toluene, 4.6 mL, 41.0 mmol) was added, stirring was con-
tinued at ꢀ608C for 45 min, and the reaction mixture was poured into
NH4Cl (20 mL) and extracted with Et2O. The organic phases were
washed successively with HCl (10%) and NaHCO3, dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (EtOAc/hexanes 5%) to
afford 4 [1.72 g, 43%, Rf =0.5 (EtOAc/hexanes 10%), colorless oil];
1H NMR (250 MHz, CDCl3, 258C, TMS): d=5.38 (m, 2H), 3.69 (s, 3H),
3.60 (m, 1H), 2.37 (m, 4H), 1.96 (t, 3J=2.6 Hz, 1H), 1.62 ppm (m, 3H);
13C NMR (63 MHz, CDCl3, 258C, TMS): d=174.3 (CO), 128.4 (CH),
ꢁ
ꢁ
126.6 (CH), 81.4 (C ), 70.0 (C ), 51.7 (CH3), 44.4 (CH), 34.0 (CH2), 28.2
(CH2), 17.9 ppm (CH3); MS: m/z (%): 167 (8) [M+H]+, 136 (3)
[M+HꢀOMe]+, 108 (9) [M+HꢀCO2Me]+; HRMS calcd for C10H15O2
[M+H]+: 167.10720; found: 167.10703.
A
was added at 08C to a solution of ester 4 (289 mg, 1.49 mmol) in Et2O
(10 mL). The reaction mixture was stirred at that temperature for 30 min,
quenched with H2SO4 (5%, 15 mL) and extracted with Et2O, and the or-
ganic phase was dried over Na2SO4, filtered and concentrated under re-
duced pressure. This concentrate was purified by flash chromatography
on silica gel (EtOAc/hexanes 10%), affording the desired alcohol
1
[213 mg, 94%, Rf =0.3 (EtOAc/hexanes 10%), pale yellow oil]; H NMR
Conclusion
(500 MHz, CDCl3, 258C, TMS): d=5.50 (m, 1H), 5.37 (m, 1H), 3.64 (m,
2H), 2.30–2.18 (m, 2H), 2.06 (dd, 3J=10.8 and 6.5 Hz, 2H), 1.97 (t, 3J=
2.6 Hz, 1H), 1.74 (td, 3J=12.3 and 6.3 Hz, 1H), 1.63 ppm (d, 3J=6.3 Hz,
3H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=128.3 (CH), 127.5
In this work we have successfully used the tandem ring-clos-
ing dienyne metathesis (RCDEYM) reaction to prepare
hybrid compounds: taxosteroids, combining the AB ring sys-
tems of taxanes with the CD ring systems and side chains of
steroids. The strategy described here represents an excep-
tional example of the formation of bridged bicycle systems
with a bridgehead double bond produced by dienyne ring-
ꢁ
ꢁ
(CH), 82.6 (C ), 69.6 (C ), 64.9 (CH2), 39.9 (CH), 33.6 (CH2), 19.9
(CH2), 17.9 ppm (CH3); IR (KBr): n˜ =3306, 3018, 2920, 2855, 2362, 2116,
1716, 1438, 1378, 1292, 1234, 1067, 1032, 968 cmꢀ1; MS: m/z (%): 139 (5)
[M+H]+, 121 (15) [M+HꢀH2O]+; HRMS calcd for C9H15O [M+H]+:
139.11229; found: 139.11241; elemental analysis calcd (%) for C9H14O: C
78.21, H 10.21; found: C 78.35, H 10.42.
Chem. Eur. J. 2007, 13, 5135 – 5150
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5141

Juan R. Granja et al.
(Z)-2-(Prop-2-ynyl)hept-4-en-1-ol (5b): This compound was prepared
from ethyl (Z)-2-(prop-2-ynyl)hept-4-enoate (747 mg, 3.85 mmol, pre-
pared from malonate 19b) in THF, in the same way as 5a from 4
MS: m/z (%): 181 (8) [M+H]+, 165 (7) [M+HꢀMe]+, 163 (14)
+
+
ꢀ
ꢀ
[M+HꢀH2O] , 137 (20) [M+HꢀiPrH] , 128 (11) [M+HꢀCH2 CaC
CH3]+; HRMS: calcd for C12H21O: 181.15924; found: 181.16005.
1
[527 mg, 90%, Rf =0.4 (EtOAc/hexanes 25%), pale yellow oil]; H NMR
A
(250 MHz, CDCl3, 258C, TMS): d=5.41 (m, 1H), 5.25 (m, 1H), 3.61 (m,
2H), 2.25 (m, 2H), 2.13 (m, 4H), 1.96 (t, 3J=2.7 Hz, 1H), 1.75 (m, 1H),
0.93 ppm (t, 3J=7.5 Hz, 3H); 13C NMR (63 MHz, CDCl3, 258C, TMS):
was prepared from oxazolidinone 25g (3.17 g, 8.98 mmol) in the same
way as (R)-5b from 25b [1.3 g, 87%, Rf =0.4 (20% AcOEt/hexanes),
yellow oil]; [a]D20: ꢀ8.01 (c=0.02 in CHCl3).
ꢁ
ꢁ
d=133.9 (CH), 126.0 (CH), 82.5 (C ), 69.7 (C ), 64.7 (CH2), 40.2 (CH),
28.0 (CH2), 20.6 (CH2), 19.8 (CH2), 14.2 ppm (CH3); MS: m/z (%): 153
(36) [M+H]+, 135 (51) [M+HꢀH2O]+; HRMS calcd for C10H17O
[M+H]+: 153.12794; found: 153.12859.
A
10.87 mmol), imidazole (1.85 g, 27.17 mmol) and iodine (2.53 g,
9.96 mmol) were successively added at 08C to a solution of alcohol 5a
(1.25 g, 9.06 mmol) in THF (45 mL). The resulting mixture was stirred at
that temperature for 30 min, and for 30 minutes more at room tempera-
ture, and was then poured into water (30 mL) and extracted with Et2O.
The combined organic phases were dried over Na2SO4 and concentrated
under reduced pressure, and the crude residue was purified by flash chro-
matography on silica gel (hexanes), to yield the desired iodide [1.91 g,
85%, Rf =0.8 (EtOAc/hexanes 10%), colorless oil]; 1H NMR (250 MHz,
CDCl3, 258C, TMS): d=5.56 (m, 1H), 5.31 (m, 1H), 3.33 (m, 2H), 2.23
(m, 4H), 1.99 (t, 3J=2.6 Hz, 1H), 1.65 (m, 3H), 1.55 ppm (m, 1H);
13C NMR (63 MHz, CDCl3, 258C, TMS): d=128.3 (trans CH), 127.3
A
[(R)-5b]:
LiAlH4
(0.32 g,
8.43 mmol) was added at 08C to a solution of oxazolidinone 25b (1.13 g,
8.43 mmol) in Et2O (60 mL), and the reaction mixture was stirred for 1 h
at this temperature and quenched with H2SO4 (5%, 20 mL). The aqueous
layer was extracted with Et2O, and the combined organic phases were
dried over Na2SO4, filtered and concentrated under reduced pressure.
The resulting crude product was dissolved in THF (20 mL), treated with
TBAF (1m, 7.7 mL, 7.7 mmol) and stirred at room temperature for
30 min. The reaction mixture was poured into water and then extracted
with Et2O, the organic phases were dried, filtered and concentrated
under reduced pressure, and the resulting residue was purified by flash
chromatography on silica gel (EtOAc/hexanes7%), affording alcohol
(R)-5b [324 mg, 75%, Rf =0.4 (EtOAc/hexanes 25%), pale yellow oil].
ꢁ
ꢁ
(trans CH),126.9 (cis CH), 126.6 (cis CH), 81.4 (C ), 70.1 (C ), 38.9
(CH), 36.6 (CH2), 23.4 (CH2), 18.0 (CH3), 13.2 (CH2).
(Z)-4-(Iodomethyl)non-6-en-1-yne (6b): This compound was prepared
from 5b (351 mg, 2.31 mmol) in the same way as 6a from 5a [520 mg,
86%, Rf =0.8 (EtOAc/hexanes 10%), colorless oil]; 1H NMR (250 MHz,
CDCl3, 258C, TMS): d=5.49 (m, 1H), 5.23 (m, 1H), 3.34 (m, 2H), 2.35
A
pared from oxazolidinone 23b (9.46 g, 23.83 mmol) in THF, in the same
way as (R)-5b from 25b [2.90 g, 80%, Rf =0.4 (EtOAc/hexanes 25%),
pale yellow oil].
3
3
(m, 2H), 2.27 (dd, J=6.7, 2.6 Hz, 2H), 2.17 (m, 2H), 2.00 (t, J=2.6 Hz,
1H), 1.55 (m, 1H), 0.96 ppm (t, 3J=7.5 Hz, 3H); 13C NMR (63 MHz,
(E)-6-Methyl-2-(prop-2-ynyl)hept-4-en-1-ol (5c): This compound was
prepared from ethyl (E)-6-methyl-2-(prop-2-ynyl)hept-4-enoate (878 mg,
4.22 mmol, prepared from malonate 19c) in THF, in the same way as 5a
from 4 [624 mg, 89%, Rf =0.3 (EtOAc/hexanes 15%), pale yellow oil];
1H NMR (300 MHz, CDCl3, 258C, TMS): d=5.45 (dd, 3J=15.3 and
6.4 Hz, 1H), 5.30 (dt, 3J=15.2 and 7.1 Hz, 1H), 3.62 (m, 2H), 2.24 (m,
1H), 1.96 (t, 3J=2.6 Hz, 1H), 1.76 (m, 1H), 0.95 ppm (d, 3J=6.7 Hz,
6H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=140.3 (CH), 124.0
ꢁ
ꢁ
CDCl3, 258C, TMS): d=134.7 (CH), 125.0 (CH), 81.4 (C ), 70.2 (C ),
39.3 (CH), 31.3 (CH2), 23.5 (CH2), 20.8 (CH2), 14.1 (CH3), 13.0 ppm
(CH2); IR (KBr): n˜ =3302, 3006, 2962, 2929, 2871, 2850, 2360, 2118, 1457,
1426, 1230, 1178, 1069, 968 cmꢀ1; MS: m/z (%): 263 (0.1) [M+H]+, 136
(11) [M+HꢀI]+, 121 (15), 107 (55); HRMS calcd for C10H16 [M+HꢀI]:
136.12520; found: 136.12467.
(4R,6Z)-4-(Iodomethyl)non-6-en-1-yne [(R)-6b]: This compound was
prepared from (R)-5b (361 mg, 2.37 mmol) in the same way as 6a from
5a [529 mg, 85% yield].
ꢁ
ꢁ
(CH), 82.6 (C ), 69.7 (C ), 64.8 (CH2), 40.0 (CH), 33.6 (CH2), 31.0
(CH), 22.6 (CH3), 19.8 ppm (CH2); MS: m/z (%): 167 (31) [M+H]+, 149
(51) [M+HꢀH2O]+; HRMS calcd for C11H19O [M+H]+: 167.14359;
found: 167.14431; elemental analysis calcd (%) for C11H18O: C 78.99, H
11.45; found: C 78.68, H 11.42.
(4S,6Z)-4-(Iodomethyl)non-6-en-1-yne [(S)-6b]: This compound was
prepared from (S)-5b (685 mg, 4.50 mmol) in the same way as 6a from
5a (884 mg, 75%).
(E)-4-(Iodomethyl)-8-methylnon-6-en-1-yne (6c): This compound was
prepared from 5c (933 mg, 5.62 mmol) in the same way as 6a from 5a
[1.32 g, 85%, Rf =0.9 (EtOAc/hexanes 10%), colorless oil]; 1H NMR
(250 MHz, CDCl3, 258C, TMS): d=5.45 (tdd, 3J=15.3, 6.6, 1.1 Hz, 1H),
5.18 (dtd, 3J=15.3, 7.1, 7.1, 1.1 Hz, 1H), 3.27 (ddd, 3J=15.7, 9.8, 5.3 Hz,
2H), 2.3–2.0 (m, 5H), 1.94 (t, 3J=2.7 Hz, 1H), 1.48 (td, 3J=11.5, 5.8 Hz,
1H), 0.91 ppm (d, 3J=6.7 Hz, 6H); 13C NMR (63 MHz, CDCl3, 258C,
G
was prepared from oxazolidinone 23c (5.56 g, 13.52 mmol) in THF, in the
same way as (R)-5b from 25b [2.02 g, 90%, Rf =0.3 (EtOAc/hexanes
15%), pale yellow oil].
5-Methyl-2-(prop-2-ynyl)hex-4-en-1-ol (5d): This compound was pre-
pared from ethyl 5-methyl-2-(prop-2-ynyl)hex-4-enoate (420 mg,
2.17 mmol, prepared from malonate 19d) in THF, in the same way as 5a
from 4 [310 mg, 94%, Rf =0.1 (EtOAc/hexanes 10%), pale yellow oil];
1H NMR (300 MHz, CDCl3, 258C, TMS): d=5.22–4.92 (m, 1H), 3.64 (t,
3J=5.5 Hz, 2H), 2.27 (ddd, 3J=6.3, 4.7, 2.6 Hz, 2H), 2.08 (t, 3J=7.1 Hz,
2H), 1.98 (t, 3J=2.7 Hz, 1H), 1.77 (dd, 3J=12.1, 6.3 Hz, 1H), 1.70 (d,
3J=1.1 Hz, 3H), 1.62 ppm (s, 3H); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=133.7 (C), 121.7 (CH), 82.8 (C ), 69.6 (C ), 64.9 (CH2), 40.5
(CH), 29.0 (CH2), 25.8 (CH3), 19.9 (CH2), 17.8 ppm (CH3); IR (KBr): n˜ =
3307, 2961, 2917, 2855, 2116, 1437, 1377, 1226, 1081, 1032 cmꢀ1; MS: m/z
(%): 153 (15) [M+H]+, 135 (27) [M+HꢀH2O]+; HRMS calcd for
C10H17O [M+H]+: 153.12794; found: 153.12803.
ꢁ
ꢁ
TMS): d=141.1 (CH), 122.8 (CH), 81.4 (C ), 70.1 (C ), 38.9 (CH), 36.5
(CH2), 31.0 (CH), 23.3 (CH2), 22.5 (2”CH3), 13.1 ppm (CH2); MS: m/z
(%): 277 (2) [M+H]+, 150 (2) [M+HꢀI]+.
(4S,6E)-4-(Iodomethyl)-8-methylnon-6-en-1-yne [(S)-6c]: This com-
pound was prepared from (S)-5c (1.69 g, 10.15 mmol) in the same way as
6a from 5a (2.1 g, 75%).
4-(Iodomethyl)-7-methyloct-6-en-1-yne (6d): This compound was pre-
pared from 5d (190 mg, 1.25 mmol) in the same way as 6a from 5a
[320 mg, 98%, Rf =0.8 (EtOAc/hexanes 10%), colorless oil]; 1H NMR
(250 MHz, CDCl3, 258C, TMS): d=5.00 (t, 3J=6.8 Hz, 1H), 3.29 (m,
2H), 2.23 (m, 2H), 2.05 (dd, 3J=12.3, 6.8 Hz, 2H), 1.95 (t, 3J=2.6 Hz,
1H), 1.65 (s, 3H), 1.59 (s, 3H), 1.51 ppm (m, 1H); 13C NMR (63 MHz,
A
was prepared from oxazolidinone 23g (1.4 g, 3.97 mmol) in THF, in the
same way as (R)-5b from 25b [645 mg, 90%, Rf =0.4 (20% EtOAc/hex-
anes), pale yellow oil]; [a]2D0: 8.01 (c=0.02 in CHCl3); 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=5.43 (dd, 3J=15.5, 6.4 Hz, 1H), 5.32
(dt, 3J=15.2, 6.4 Hz, 1H), 3.61 (dd, 3J=5.2, 1.8 Hz, 2H), 2.27–2.13 (m,
ꢁ
ꢁ
CDCl3, 258C, TMS): d=134.4 (C), 120.8 (CH), 81.5 (C ), 70.05 (C ),
39.6 (CH), 32.15 (CH2), 25.8 (CH3), 23.5 (CH2), 18.1 (CH3), 13.2 ppm
(CH2); MS: m/z (%): 263 (0.2) [M+H]+, 136 (2) [M+HꢀI]+; HRMS
calcd for C10H16I [M+H]+: 263.02968; found: 263.03099.
2H), 2.03 (t, J=6.7 Hz, 2H), 1.89 (s, 1H), 1.76 (t, J=2.4 Hz, 3H), 1.75–
A
1.65 (m, 2H), 0.95 ppm (d, J=6.7 Hz, 6H); 13C NMR (125 MHz, CDCl3,
was prepared from (S)-5g (152 mg, 0.84 mmol) in the same way as 6a
from 5a [170 mg, 70%, Rf =0.9 (EtOAc/hexanes 10%), colorless oil];
1H NMR (250 MHz, CDCl3, 258C, TMS): d=5.49 (dd, 3J=15.2 and
258C, TMS): d=140.0 (CH), 124.3 (CH), 77.1 (C ), 65.3 (CH2), 40.3
(CH), 33.8 (CH2), 31.0 (CH), 22.5 (CH3), 20.3 (CH2), 3.4 ppm (CH3);
5142
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5135 – 5150

Dienyne RCM Approach for the Construction of Taxosteroids
FULL PAPER
6.7 Hz, 1H), 5.24 (dt, 3J=15.5 and 7.0 Hz, 1H), 3.38–3.24 (m, 2H), 2.30–
2.00 (m, 5H), 1.77 (t, 3J=2.4 Hz, 3H), 1.46 (m, 1H), 0.96 ppm (d, 3J=
6.7 Hz, 1H); 13C NMR (63 MHz, CDCl3, 258C, TMS): d=140.8 (CH),
35.4 (CH2), 35.2 (CH), 31.1 (CH2), 29.2 (CH2), 27.0 (CH2), 25.9 (CH3),
21.4 (CH2), 20.6 (CH2), 19.0 (CH2), 18.3 (C), 17.0 (CH3), 14.3 (CH3), 12.8
(CH3), ꢀ5.4 (CH3), ꢀ5.5 ppm (CH3); IR (CHCl3): n˜ =3307, 3008, 2961,
123.2 (CH), 77.3 (C ), 76.1 (C ), 39.4 (CH), 36.6 (CH2), 31.0 (CH), 23.7
(CH2), 22.5 (CH3), 13.8 (CH2), 3.5 (CH3); MS (IQ+): m/z (%): 291 (2)
[M+H]+, 164 (3) [M+HꢀI]+, 163 (9) [M+HꢀHI]+, 247 (3)
[M+HꢀiPrH]+, 149 (100) [M+HꢀIꢀCH3]+.
2930, 2868, 2116, 1700, 1462, 1386, 1254, 1213, 1089, 1040, 1006, 972 cmꢀ1
;
ꢁ
ꢁ
MS: m/z (%): 459 (21) [M+H]+, 328 (6) [M+HꢀOTBS]+, 310 (8)
[M+HꢀOTBSꢀH2O]+; HRMS calcd for C29H51O2Si [M+H]+:
459.36584; found: 459.36415.
Ketone 8a: A solution of ketone 7[30] (498 mg, 1.54 mmol) in DMF
(3 mL) was slowly added at ꢀ788C to a mixture of KHMDS (0.5m in tol-
uene, 9.3 mL, 4.6 mmol) and DMF (4 mL), the resulting mixture was
stirred for 0.5 h, and a solution of alkylating agent 6a (1.14 g, 4.61 mmol)
in DMF (2 mL) was added. After 2 h, a saturated solution of NH4Cl was
added and the aqueous layer was extracted with Et2O. The combined or-
ganic extracts were washed with brine, dried over Na2SO4 and concen-
trated under reduced pressure, giving a residue that, when flash chroma-
tographed on silica gel (EtOAc/hexanes 2%), afforded ketone 8a
Ketone 8c: This compound was prepared from 7 (607 mg, 1.87 mmol)
and 6c (775 mg, 2.81 mmol) in the same way as 8a from 7 and 6a
[690 mg, 78%, Rf =0.3 (EtOAc/hexanes 5%), pale yellow oil]; 1H NMR
(250 MHz, CDCl3, 258C, TMS): d=5.41 (dd, 3J=15.3, 6.4 Hz, 1H), 5.22
(m, 1H), 3.53 (dd, 3J=9.7, 2.3 Hz, 1H), 3.30 (dd, 3J=9.5, 5.8 Hz, 1H),
2.56 (dd, 3J=11.2, 7.3 Hz, 1H), 0.87 (s, 9H), 0.62 (s, 3H), 0.01 ppm (s,
6H); 13C NMR (63 MHz, CDCl3, 258C, TMS): d=214.6 (CO), 140.4
ꢁ
ꢁ
(CH), 124.1 (CH), 82.2 (C ), 69.7 (C ), 67.5 (CH2), 57.6 (CH), 53.2
(CH), 50.3 (C), 47.2 (CH), 38.5 (CH), 36.4 (CH2), 35.7 (CH2), 35.4 (CH2),
34.9 (CH), 31.1 (CH), 29.3 (CH2), 27.0 (CH2), 25.9 (CH3), 22.6 (CH3),
21.3 (CH2), 19.0 (CH2), 18.3 (C), 17.0 (CH3), 12.8 (CH3), ꢀ5.4 ppm
(CH3); MS: m/z (%): 473 (100) [M+H]+, 342 (6) [M+HꢀOTBS]+, 341
(28), 323 (12); HRMS calcd for C30H53O2Si [M+H]+: 473.38149; found:
473.38379.
1
[540 mg, 79%, Rf =0.5 (EtOAc/hexanes 10%), pale yellow oil]. H NMR
(300 MHz, CDCl3, 258C, TMS): d=5.46 (m, 1H), 5.30 (m, 1H), 3.56 (dd,
3J=9.5 and 2.6 Hz, 1H), 3.33 (dd, 3J=9.5 and 5.9 Hz, 1H), 1.94 (t, 3J=
3
2.6 Hz, 1H), 1.02 (d, J=6.2 Hz, 3H), 0.90 (s, 9H), 0.65 (s, 3H), 0.04 ppm
(s, 6H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=214.8 (CO), 128.2
ꢁ
ꢁ
(CH), 127.5 (CH), 82.2 (C ), 69.7 (C ), 67.6 (CH2), 57.7 (CH), 53.3
(CH), 50.3 (C), 47.3 (CH), 38.7 (CH), 36.5 (CH2), 35.9 (CH2), 35.4 (CH2),
35.0 (CH), 29.3 (CH2), 27.1 (CH2), 26.0 (CH3), 21.4 (CH2), 19.2 (CH2),
18.5 (C), 18.0 (CH3), 17.1 (CH3), 12.9 (CH3), ꢀ5.2 (CH3), ꢀ5.3 ppm
(CH3); IR (CHCl3): n˜ =3307, 3020, 2956, 2929, 2957, 1699, 1603, 1472,
1386, 1214, 1088, 1006 cmꢀ1; MS: m/z (%): 445 (29) [M+H]+, 314 (15)
Ketone 8c10R: This compound was prepared from 7 (1.37 g, 4.23 mmol)
and (S)-6c (1.75 g, 6.35 mmol) in the same way as 8a from 7 and 6a
[1.40 g, 70%, Rf =0.3 (EtOAc/hexanes 5%), pale yellow oil]; 1H NMR
(250 MHz, CDCl3, 258C, TMS): d=5.41 (dd, 3J=15.3 and 6.4 Hz, 1H),
5.27 (m, 1H), 3.54 (dd, 3J=9.7, 2.3 Hz, 1H), 3.31 (dd, 3J=9.7, 6.1 Hz,
1H), 0.87 (s, 9H), 0.63 (s, 3H), 0.01 ppm (s, 6H); 13C NMR (63 MHz,
[M+HꢀOTBS]+,
312
(5)
[M+HꢀTBSꢀH2O]+,
296
(17)
ꢁ
CDCl3, 258C, TMS): d=214.8 (CO), 140.5 (CH), 124.0 (CH), 82.1 (C ),
[M+HꢀOTBSꢀH2O]+, 294 (2); HRMS calcd for C28H49O2Si [M+H]+:
ꢁ
69.5 (C ), 67.5 (CH2), 57.6 (CH), 53.2 (CH), 50.2 (C), 47.4 (CH), 38.5
445.35018; found: 445.35036.
(CH), 36.3 (CH2), 35.6 (CH2), 35.4 (CH2), 34.9 (CH), 31.0 (CH), 29.2
(CH2), 27.0 (CH2), 25.9 (2”CH3), 22.6 (3”CH3), 21.3 (CH2), 19.0 (CH2),
18.3 (C), 17.0 (CH3), 12.8 (CH3), ꢀ5.4 ppm (2”CH3); IR (KBr): n˜ =3312,
2956, 2928, 2858, 2117, 1709, 1463, 1384, 1362, 1252, 1091, 1040, 1006,
972 cmꢀ1; MS: m/z (%): 473 (13) [M+H]+, 342 (7) [M+HꢀOTBS]+, 341
(28), 323 (33); HRMS calcd for C30H53O2Si [M+H]+: 473.38148; found:
473.38269.
Ketone 8b: This compound was prepared from 7 (309 mg, 0.95 mmol)
and 6b (386 mg, 1.47 mmol) in the same way as 8a from 7 and 6a
[153 mg, 35%, Rf =0.2 (EtOAc/hexanes 5%), pale yellow oil]. 1H NMR
(250 MHz, CDCl3, 258C, TMS): d=5.43 (m, 1H), 5.19 (m, 1H), 3.54 (dd,
3J=9.7, 2.3 Hz, 1H), 3.29 (dd, 3J=9.6, 6.2 Hz, 1H), 2.56 (dd, 3J=11.3,
7.3 Hz, 1H), 0.87 (s, 9H), 0.62 (s, 3H), 0.01 ppm (s, 6H); 13C NMR
(250 MHz, CDCl3, 258C, TMS): d=214.9 (CO), 133.9 (CH), 126.1 (CH),
82.0 (C ), 69.7 (C ), 67.5 (CH2), 57.6 (CH), 53.2 (CH), 50.2 (C), 47.6
(CH), 38.6 (CH), 36.3 (CH2), 35.3 (CH2), 35.1 (CH), 31.05 (CH2), 29.2
(CH2), 27.0 (CH2), 25.9 (3”CH3), 21.3 (CH2), 20.6 (CH2), 19.0 (CH2),
18.3 (C), 17.0 (CH3), 14.2 (CH3), 12.8 (CH3), ꢀ5.4 (CH3), ꢀ5.5 ppm
(CH3); IR (CHCl3): n˜ =3307, 3012, 2958, 2930, 2858, 2117, 1701, 1463,
1386, 1254, 1089, 1006 cmꢀ1; MS: m/z (%): 459 (23) [M+H]+, 328 (2)
[M+HꢀOTBS]+, 310 (3) [M+HꢀOTBSꢀH2O]+; HRMS calcd for
C29H51O2Si [M+H]+: 459.36584; found: 459.36641.
Ketone 8d: This compound was prepared from 20[19] (509 mg, 1.93 mmol)
and 6d (1.52 g, 5.78 mmol) in the same way as 8a from 7 and 6a [530 mg,
69%, Rf =0.6 (EtOAc/hexanes 10%), pale yellow oil]; 1H NMR
ꢁ
ꢁ
3
(300 MHz, CDCl3, 258C, TMS): d=5.03 (t, J=6.8 Hz, 1H), 1.70 (s, 6H),
1.14 (d, 3J=5.7 Hz, 3H), 0.87 (d, 3J=6.6 Hz, 6H), 0.64 ppm (s, 3H);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=215.1 (CO), 133.6 (C), 121.9
ꢁ
ꢁ
(CH), 82.3 (C ), 69.5 (C ), 57.8 (CH), 56.8 (CH), 50.2 (C), 47.2 (CH),
39.3 (CH2), 36.0 (CH2), 35.9 (CH2), 35.5 (CH), 35.4 (CH2), 31.9 (CH2),
29.3 (CH2), 27.9 (CH), 27.5 (CH2), 25.8 (CH), 23.7 (CH2), 22.7 (CH3),
22.5 (CH3), 21.3 (CH2), 18.9 (CH2), 18.6 (CH3), 17.9 (CH3), 12.6 ppm
(CH3); IR (KBr): n˜ =3312, 2952, 2928, 2869, 2113, 1708, 1450, 1383, 1261,
Ketone 8b10S: This compound was prepared from 7 (271 mg, 0.84 mmol)
and (R)-6b (340 mg, 1.30 mmol) in the same way as 8a from 7 and 6a
[296 mg, 77%, Rf =0.5 (EtOAc/hexanes 5%), pale yellow oil]; 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=5.43 (m, 1H), 5.20 (m, 1H), 3.55 (dd,
3J=9.6, 2.7 Hz, 1H), 3.31 (dd, 3J=9.6, 6.2 Hz, 1H), 2.57 (dd, 3J=11.2,
7.1 Hz, 1H), 0.88 (s, 9H), 0.63 (s, 3H), 0.01 ppm (s, 6H); 13C NMR
(63 MHz, CDCl3, 258C, TMS): d=214.8 (CO), 133.9 (CH), 126.1 (CH),
82.0 (C ), 69.7 (C ), 67.5 (CH2), 57.6 (CH), 53.2 (CH), 50.2 (C), 47.2
(CH), 38.6 (CH), 36.0 (CH2), 35.4 (CH2), 35.2 (CH), 31.1 (CH2), 29.2
(CH2), 27.0 (CH2), 25.9 (CH3), 21.4 (CH2), 20.6 (CH2), 19.0 (CH2), 17.8
(C), 17.0 (CH3), 14.2 (CH3), 12.8 (CH3), ꢀ5.4 (CH3), ꢀ5.5 ppm (CH3); IR
(KBr): n˜ =3311, 2957, 2929, 2857, 2362, 2116, 1708, 1462, 1385, 1359,
1251, 1217, 1091, 1040, 1006 cmꢀ1; MS: m/z (%): 459 (38) [M+H]+, 328
(10) [M+HꢀOTBS]+, 310 (11) [M+HꢀOTBSꢀH2O]+; HRMS calcd for
C29H51O2Si [M+H]+: 459.36584; found: 459.36504.
1238, 1121, 969 cmꢀ1
;
MS: m/z (%): 399 (94) [M+H]+, 381 (52)
[M+HꢀH2O]+; HRMS calcd for C28H47O [M+H]+: 399.36269; found:
399.36200.
Ketone 8g10R: This compound was prepared from 7 (107 mg, 0.33 mmol)
and (S)-6g (144 mg, 0.50 mmol) in the same way as 8a from 7 and 6a
[110 mg, 69%, Rf =0.3 (EtOAc/hexanes 5%), pale yellow oil]; 1H NMR
(250 MHz, CDCl3, 258C, TMS): d=5.40 (dd, 3J=15.2, 6.0 Hz, 1H), 5.25
(dt, 3J=15.2, 6.7 Hz, 1H), 3.54 (dd, 3J=9.4, 2.1 Hz, 1H), 3.33 (dd, 3J=
9.7, 5.5 Hz, 1H), 1.76 (t, 3J=2.4 Hz, 3H), 1.01 (d, 3J=5.8 Hz, 3H), 0.95
(d, 3J=6.7 Hz, 6H), 0.88 (s, 9H), 0.63 (s, 3H), 0.02 ppm (s, 6H);
13C NMR (63 MHz, CDCl3, 258C, TMS): d=215.2 (CO), 140.2 (CH),
ꢁ
ꢁ
ꢁ
ꢁ
124.1 (CH), 77.5 (C ), 76.6 (C ), 67.5 (CH2), 57.5 (CH), 53.3 (CH), 50.2
(C), 47.6 (CH), 38.5 (CH), 36.1 (CH2), 35.9 (CH), 35.8 (CH2), 35.3 (CH2),
31.1 (CH), 29.2 (CH2), 27.0 (CH2), 25.9 (2”CH3), 23.0 (CH2), 22.6 (CH3),
19.0 (CH2), 18.3 (C), 17.1 (CH3), 12.8 (CH3), 3.4 (CH3), ꢀ5.5 ppm (CH3);
MS: m/z (%): 487 (20) [M+H]+, 355 (6) [M+HꢀHOTBS]+, 430 (39),
403 (14); HRMS calcd for C31H55O2Si [M+H]+: 487.39714; found:
487.39763.
Ketone 8b10R: This compound was prepared from 7 (270 mg, 0.83 mmol)
and (S)-6b (338 mg, 1.29 mmol) in the same way as 8a from 7 and 6a
[264 mg, 69%, Rf =0.5 (EtOAc/hexanes 5%), pale yellow oil]; 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=5.43 (m, 1H), 5.20 (m, 1H), 3.55 (dd,
3J=9.6, 2.7 Hz, 1H), 3.31 (dd, J=9.6, 6.2 Hz, 1H), 2.57 (m, 1H), 0.88 (s,
3
9H), 0.63 (s, 3H), 0.01 ppm (s, 6H); 13C NMR (63 MHz, CDCl3, 258C,
Compound 8h10S: A solution of ketone 7 (79 mg, 0.23 mmol) in THF
(1.4 mL) was added dropwise at ꢀ788C to a freshly prepared solution of
LDA (1m, 0.7 mL, 0.7 mmol). After having been stirred for 30 min, the
ꢁ
ꢁ
TMS): d=214.9 (CO), 133.9 (CH), 126.1 (CH), 82.0 (C ), 69.7 (C ), 67.6
(CH2), 57.6 (CH), 53.3 (CH), 50.2 (C), 47.2 (CH), 38.6 (CH), 36.0 (CH2),
Chem. Eur. J. 2007, 13, 5135 – 5150
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5143

Juan R. Granja et al.
solution of the enolate was added at ꢀ788C to a solution of the aldehyde
(S)-24h (123 mg, 0.69 mmol) in THF (1.4 mL). The resulting mixture was
stirred at that temperature for 3 h and the reaction was quenched by ad-
dition of NH4Cl (sat., 3 mL). The aqueous layer was extracted with Et2O
and the combined organic extracts were dried over Na2SO4 and concen-
trated under reduced pressure to give an oil, which was purified by flash
chromatography (AcOEt/hexanes 3%), yielding the desired compound
[106 mg, 91%, Rf =0.4 (10% AcOEt/hexanes), yellow oil]; 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=5.45 (dd, 3J=15.3, 6.5 Hz, 1H), 5.33
(dt, 3J=15.3, 6.8 Hz, 1H), 4.14 (ddd, 3J=9.3, 5.8, 2.2 Hz, 1H), 3.62 (m,
1H), 3.54 (dd, 3J=5.8, 2.2 Hz, 1H), 3.33 (dd, 3J=9.6, 6.3 Hz, 1H), 2.75
(dd, 3J=11.4, 7.4 Hz, 1H), 2.46 (m, 1H), 2.32–2.10 (m, 6H), 2.04 (t, 3J=
7.00 Hz, 1H), 1.97–1.83 (m, 3H), 1.77 (dd, 3J=4.0, 2.5 Hz, 1H), 0.99 (d,
3J=6.4 Hz, 3H), 0.95 (d, 3J=6.7 Hz, 6H), 0.87 (s, 9H), 0.66 (s, 3H),
0.01 ppm (s, 6H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=214.0
(CO), 140.3 (CH), 124.7 (CH), 77.7 (C), 77.4 (C), 74.0 (CH), 67.5 (CH2),
65.5 (CH2), 59.1 (CH), 53.4 (CH), 49.0 (CH), 40.6 (C), 38.6 (CH), 33.9
(CH), 31.0 (CH2), 30.2 (CH2), 27.1 (CH2),25.9 (CH3), 25.6 (CH2), 22.5
(CH3), 20.9 (CH2), 20.5 (CH2), 19.1 (C), 18.3 (C), 17.0 (CH3), 13.9 (CH3),
3.5 (CH3), ꢀ5.4 ppm (CH3); MS: m/z (%): 503 (94) [M+H]+, 485 (100)
[M+HꢀH2O]+, 445 (44) [M+HꢀtBuH]+; HMRS: calcd for C31H55O3Si:
503.39205; found: 503.39222.
26.0 (CH3), 23.8 (CH2), 20.7 (CH2), 20.5 (CH2), 20.3 (CH2), 18.4 (C), 16.7
(CH3), 14.3 (CH3), 13.5 (CH3), ꢀ5.3 (CH3), ꢀ5.4 ppm (CH3); IR
(CHCl3): n˜ =3565, 3311, 2961, 2929, 2856, 1729, 1462, 1386, 1363, 1255,
1127, 1089, 1004 cmꢀ1
;
MS: m/z (%): 501 (22) [M+H]+, 370 (7)
[M+HꢀOTBS]+, 352 (31) [M+Hꢀ OTBSꢀH2O]+; HRMS calcd for
C32H57O2Si [M+H]+: 501.41278; found: 501.41329.
Dienyne 9b10R: This compound was prepared from 8b10R or 8b (345 mg,
0.75 mmol) in the same way as 9a from 8a [131 mg, 35%, Rf =0.37
(EtOAc/hexanes 10%), pale yellow oil]; 1H NMR (500 MHz, CDCl3,
258C, TMS): d=5.98 (m, 1H), 5.46 (m, 1H), 5.29 (m, 1H), 5.15 (m, 2H),
3
3
3.56 (dd, J=9.6, 3.2 Hz, 1H), 3.25 (dd, J=9.5, 7.5 Hz, 1H), 0.88 (s, 9H),
0.02 ppm (s, 6H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=133.6
(CH), 133.3 (CH), 126.8 (CH), 119.7 (CH2), 82.5 (C), 75.8 (C), 69.8
(CH2), 67.7 (C), 53.7 (CH), 51.2 (CH), 43.5 (CH2), 43.3 (C), 39.8 (CH),
38.5 (CH), 34.8 (CH), 34.6 (CH2), 32.2 (CH2), 30.8 (CH2), 26.7 (CH2),
26.0 (CH3), 21.1 (CH2), 20.7 (CH2), 20.35 (CH2), 20.3 (CH2), 18.4 (C),
16.7 (CH3), 14.3 (CH3), 13.5 (CH3), ꢀ5.3 (CH3), ꢀ5.4 ppm (CH3); MS: m/
z (%): 501 (0.05) [M+H]+, 352 (2) [M+HꢀOTBSꢀH2O]+; HRMS calcd
for C32H57O2Si [M+H]+: 501.41278; found: 501.41308.
Dienyne 9c10R: This compound was prepared from 8c10R or 8c (1.99 g,
4.20 mmol) in the same way as 9a from 8a [477 mg, 22%, Rf =0.29
(EtOAc/hexanes 10%), pale yellow oil]; 1H NMR (300 MHz, CDCl3,
258C, TMS): d=5.86 (m, 1H), 5.44 (dd, 3J=15.4, 6.3 Hz, 1H), 5.29 (m,
1H), 5.16 (m, 2H), 3.56 (dd, 3J=9.6, 3.4 Hz, 1H), 3.25 (dd, 3J=9.6,
7.3 Hz, 1H), 1.95 (t, 3J=2.6 Hz, 1H), 0.89 (s, 9H), 0.03 ppm (s, 6H);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=140.1 (CH), 133.3 (CH),
124.8 (CH), 119.6 (CH2), 82.6 (C), 75.8 (C), 69.7 (C), 67.7 (CH2), 53.7
(CH), 51.2 (CH), 43.5 (CH2), 43.3 (C), 39.8 (CH), 38.4 (CH), 37.5 (CH2),
34.7 (CH), 34.6 (CH2), 31.0 (CH), 30.4 (CH2), 26.6 (CH2), 26.0 (CH3),
22.7 (CH3), 21.3 (CH2), 20.3 (CH2), 20.2 (CH2), 18.4 (C), 16.6 (CH3), 13.5
(CH3), ꢀ5.4 ppm (2”CH3); IR (CHCl3): n˜ =3565, 3312, 2954, 2930, 2857,
1731, 1634, 1463, 1384, 1352, 1254, 1089, 1004, 972 cmꢀ1; MS: m/z (%):
Compound 8h10R
: This compound was prepared from 7 (75 mg,
0.23 mmol) and (R)-24h (122 mg, 0.69 mmol) in the same way as 8h10s
from
7 and (S)-24h [107 mg, 92%, Rf =0.4 (15% AcOEt/hexanes),
yellow oil]; 1H NMR (400 MHz, CDCl3, 258C, TMS): d=5.51 (dd, 3J=
15.4, 6.5 Hz, 1H), 5.34 (dt, 3J=15.5, 7.0 Hz, 1H), 3.93 (ddd, 3J=9.8, 7.4,
3
3
2.8 Hz, 1H), 3.55 (dd, J=9.6, 2.8 Hz, 1H), 3.34 (dd, J=9.6, 6.1 Hz, 1H),
2.71 (dd, 3J=11.3, 7.4 Hz, 1H), 2.57 (ddd, 3J=9.1, 6.1, 2.6 Hz, 1H), 2.46
(d, 3J=7.3 Hz, 1H), 2.33–2.12 (m, 5H), 2.0–1.80 (m, 2H), 1.78 (t, 3J=
2.6 Hz, 3H), 1.60–1.45 (m,2H), 1.39–1.25 (m, 2H), 1.00 (d, 3J=6.3 Hz,
3H), 0.98 (d, 3J=6.0 Hz, 6H), 0.89 (s, 9H), 0.67 (s, 3H), 0.02 ppm (s,
6H); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=213.8 (CO), 140.6
(CH), 124.6 (CH), 77.9 (C), 77.5 (C), 73.7 (CH), 67.4 (CH2), 59.1 (CH),
53.3 (CH), 52.8 (CH), 49.0 (C), 40.0 (CH), 38.5 (CH), 35.8 (CH2), 34.4
(CH2), 31.1 (CH), 27.1 (CH2), 25.9 (CH3), 25.7 (CH2), 22.6 (CH), 19.0
(CH2), 18.3 (C), 17.3 (CH2), 17.0 (CH), 13.8 (CH3), 3.5 (CH3), ꢀ5.4 ppm
(CH3); MS: m/z (%): 503 (16) [M+H]+, 485 (8) [M+HꢀH2O]+; HRMS:
calcd for C31H55O3Si: 503.39205; found: 503.39202.
515
(14)
[M+H]+,
384
(1)
[M+HꢀOTBS]+,
364
(0.3)
[M+HꢀTBSꢀ2H2O]+; HRMS calcd for C33H59O2Si [M+H]+: 515.42844;
found: 515.42937.
Dienyne 9c10S: This compound was prepared from 8c10S or 8c (1.99 g,
4.20 mmol) in the same way as 9a from 8a [3.77 g, 68%, Rf =0.35
(EtOAc/hexanes 5%), pale yellow oil]; 1H NMR (300 MHz, CDCl3,
258C, TMS): d=5.88 (m, 1H), 5.48 (dd, 3J=15.2, 6.1 Hz, 1H), 5.32 (m,
1H), 5.20 (m, 2H), 3.60 (m, 1H), 3.29 (m, 1H), 1.95 (t, 3J=2.5 Hz, 1H),
0.86 (s, 9H), 0.06 ppm (s, 6H); 13C NMR (75 MHz, CDCl3, 258C, TMS):
d=140.3 (CH), 133.2 (CH), 123.9 (CH), 119.5 (CH2), 83.5 (C), 69.3 (C),
76.0 (C), 67.7 (CH2), 53.6 (CH), 51.1 (CH), 43.5 (CH2), 43.3 (C), 39.5
(CH), 38.5 (CH), 35.3 (CH), 34.9 (CH2), 34.5 (CH2), 31.3 (CH2), 31.1
(CH), 26.7 (CH2), 26.0 (2CH3), 23.7 (CH2), 22.6 (CH3), 20.4 (CH2), 20.3
(CH2), 18.4 (C), 16.7 (CH3), 13.5 (CH3), ꢀ5.4 ppm (CH3); MS: m/z (%):
515 (22) [M+H]+, 497 (9) [M+HꢀH2O]+, 384 (10) [M+HꢀOTBS]+, 383
(41), 365 (100), 323(38); HRMS calcd for C33H59O2Si [M+H]+:
515.42844; found: 515.42810.
Dienyne 9a: A solution of allylMgBr (1m in Et2O, 0.75 mL, 0.75 mmol)
was added dropwise at ꢀ788C to a solution of ketone 8a (115 mg,
0.26 mmol) in THF (2 mL). After the mixture had been stirred for 2 h at
this temperature, a saturated solution of NH4Cl was added, and the re-
sulting mixture was extracted with Et2O. The combined organic extracts
were washed with brine, dried over Na2SO4 and concentrated under re-
duced pressure. The crude alcohol was purified by flash chromatography
(EtOAc/hexanes 2%), yielding dienyne 9a [120 mg, 95%, Rf =0.5
(EtOAc/hexanes 10%), pale yellow oil]; 1H NMR (500 MHz, CDCl3,
258C, TMS): d=5.90 (m, 1H), 5.39 (m, 2H), 5.13 (m, 2H), 3.54 (m, 1H),
3.24 (m, 1H), 0.95 (d, 3J=6.3 Hz, 3H), 0.87 (s, 9H), 0.01 ppm (s, 6H);
13C NMR (125 MHz, CDCl3, 258C, TMS): d=133.2 (CH), 128.3 (CH),
Dienyne 9d: This compound was prepared from 8d (362 mg, 0.91 mmol)
in the same way as 9a from 8a [320 mg, 80%, Rf =0.5 (EtOAc/hexanes
1
ꢁ
ꢁ
127.4 (CH), 119.4 (CH2), 83.3 (C ), 76.0 (C), 67.3 (C ), 67.7 (CH2), 53.6
(CH), 51.1 (CH), 43.4 (CH2), 43.3 (C), 39.5 (CH), 38.5 (CH), 35.2 (CH),
34.8 (CH2), 34.5 (CH2), 31.2 (CH2), 26.7 (CH2), 26.0 (CH3), 23.8 (CH2),
20.3 (CH2), 20.2 (CH2), 18.3 (C), 18.0 (CH3), 16.7 (CH3), 13.5 (CH3),
ꢀ5.4 ppm (CH3); IR (KBr): n˜ =3564, 3525, 3311, 3075, 2943, 2931, 2856,
2116, 1637, 1471, 1386, 1362, 1254, 1128, 1087, 1005 cmꢀ1; MS: m/z (%):
487 (19) [M+H]+, 355 (47), 337 (100); HRMS calcd for C31H55O2Si
[M+H]+: 487.39714; found: 487.39624.
10%), pale yellow oil]; H NMR (300 MHz, CDCl3, 258C, TMS): d=5.83
(m, 1H), 5.03 (m, 3H), 0.88 ppm (s, 3H); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=133.3 (C), 133.2 (CH), 121.1 (CH), 119.3 (CH2), 83.5
ꢁ
ꢁ
(C ), 76.0 (C), 69.2 (C ), 57.1 (CH), 51.3 (CH), 43.3 (C), 43.4 (CH2),
39.6 (CH), 39.5 (CH2), 35.85 (CH), 35.8 (CH2), 35.2 (CH), 34.6 (CH2),
33.0 (CH2), 31.5 (CH2), 30.25 (CH2), 28.0 (CH), 27.2 (CH2), 25.8 (CH3),
23.7 (CH2), 22.8 (CH3), 22.5 (CH3), 20.4 (CH2), 20.0 (CH2), 18.3 (CH3),
17.8 (CH3), 13.4 ppm (CH3); IR (KBr): n˜ =3565, 3311, 3074, 2957, 2931,
2872, 2116, 1731, 1636, 1456, 1382, 1268, 1222, 1168, 1122, 993 cmꢀ1; MS:
m/z (%): 441 (44) [M+H]+, 423 (100) [M+HꢀH2O]+; HRMS calcd for
C31H53O [M+H]+: 441.40964; found: 441.40945.
Dienyne 9b10S: This compound was prepared from 8b10S or 8b (345 mg,
0.75 mmol) in the same way as 9a from 8a [132 mg, 35%, Rf =0.42
(EtOAc/hexanes 10%), pale yellow oil]; 1H NMR (500 MHz, CDCl3,
258C, TMS): d=5.86 (m, 1H), 5.45 (m, 1H), 5.28 (m, 1H), 5.16 (m, 2H),
Dienyne 9 f: A solution of nBuLi in THF (0.13 mL, 2.15m, 0.28 mmol)
was added to a solution of dienyne 9d (50 mg, 0.11 mmol) in THF
(2 mL), the mixture was stirred for 2 h, and MeI (0.02 mL, 0.34 mmol)
was added. The reaction mixture was stirred for 4 h at room temperature
and poured into water. The aqueous layer was extracted with Et2O and
the combined organic phases were dried over Na2SO4, filtered and con-
3
3
3.56 (dd, J=9.6, 3.3 Hz, 1H), 3.26 (dd, J=9.5, 7.2 Hz, 1H), 0.88 (s, 9H),
0.02 ppm (s, 6H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=133.8
ꢁ
ꢁ
(CH), 133.2 (CH), 126.2 (CH), 119.5 (CH2), 83.3 (C ), 76.1 (C ), 69.3
(CH2), 67.7 (C), 53.7 (CH), 51.2 (CH), 43.5 (CH2), 43.4 (C), 39.7 (CH),
38.5 (CH), 35.6 (CH), 34.6 (CH2), 31.6 (CH2), 29.7 (CH2), 26.7 (CH2),
5144
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5135 – 5150

Dienyne RCM Approach for the Construction of Taxosteroids
FULL PAPER
centrated under reduced pressure. This crude product was purified by
flash chromatography on silica gel (EtOAC/hexanes 2%), yielding 9e
[39 mg, 76%, Rf =0.5 (EtOAc/hexanes 10%), yellow oil]; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=5.94–5.77 (m, 1H), 5.15 (m, 2H), 5.09
(t, 3J=6.7 Hz, 1H), 0.94 (s, 3H), 0.89 (d, 3J=6.5 Hz, 3H), 0.87 (d, 3J=
6.5 Hz, 3H), 0.86 ppm (d, 3J=6.5 Hz, 3H); 13C NMR (63 MHz, CDCl3,
258C, TMS): d=133.3 (C=), 133.0 (CH=), 122.1 (CH=), 119.3 (CH2=),
when flash chromatographed (AcOEt/hexanes 2%), afforded compound
9i10R [320 mg, 82%, Rf =0.5 (10%AcOEt/hexanes), yellow oil]; H NMR
1
(500 MHz, CDCl3, 258C, TMS): d=6.06 (m, 1H), 5.41 (dd, 3J=15.3,
6.2 Hz, 1H), 5.31 (dt, 3J=15.3, 7.5 Hz, 1H), 5.02 (dd, 3J=16.9, 2.7 Hz,
1H), 4.98 (dd, 3J=10.0, 1.8 Hz, 1H), 4.82 (d, 3J=6.6 Hz, 1H), 4.67 (d,
3J=6.5 Hz, 1H), 4.61 (d, 3J=6.5 Hz, 1H), 4.58 (d, 3J=6.5 Hz, 1H), 3.99
(d, 3J=8.1 Hz, 1H), 3.58 (dd, 3J=9.6, 3.3 Hz, 1H), 3.41 (s, 3H), 3.37 (s,
3H), 3.25 (dd, 3J=9.6, 7.2 Hz, 1H), 2.72 (dd, 3J=16.1, 6.6 Hz, 1H), 2.37
(dd, 3J=16.1, 6.5 Hz, 1H), 2.30–2.05 (m, 7H), 1.78 (t, 3J=2.4 Hz, 3H),
1.00 (s, 3H), 0.97 (d, 3J=6.7 Hz, 6H), 0.96 (d, 3J=6.7 Hz, 3H), 0.08 (s,
9H), 0.02 ppm (s, 6H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=
139.7 (CH), 136.8 (CH), 125.4 (CH), 115.7 (CH2), 99.2 (CH2), 91.4 (CH2),
82.7 (C), 82.6 (CH), 79.0 (C), 76.6 (C), 67.9 (CH2), 56.6 (CH3), 56.0
(CH3), 53.9 (CH), 53.8 (CH), 44.1 (CH), 43.5(C), 41.6 (CH2), 41.3 (CH),
38.3 (CH), 36.0 (CH2), 32.0 (CH2), 31.1 (CH), 26.8 (CH2), 26.0 (CH3),
22.6 (CH3), 22.1 (CH2), 21.7 (CH2), 20.5 (CH2), 18.4 (C), 16.8 (CH3), 14.1
(CH3), 3.6 (CH3), ꢀ5.3 ppm (CH3); MS: m/z (%): 655 (8) [M+Na]+;
HRMS: calculated for C38H68NaO5Si: 655.47282; found: 655.47536.
ꢁ
ꢁ
85.5 (C ), 78.4 (C ), 62.2 (C), 57.2 (CH), 51.3 (CH), 43.4 (CH2), 39.7
(CH), 39.5 (CH2), 36.4 (CH), 35.9 (CH2), 35.2 (CH), 34.6 (CH2), 31.6
(CH2), 30.7 (CH2), 30.3 (C), 28.0 (CH), 27.2 (CH2), 25.8 (CH3), 24,2
(CH2), 23.7 (CH2), 22.8 (CH3), 22.5 (CH3), 20.4 (CH2), 20.0 (CH2), 18.4
(CH3), 17.8 (CH3), 13.4 (CH3), 3.5 ppm (CH3); MS: m/z (%): 455 (1)
[M+H]+, 437 (3) [M+HꢀH2O]+; HRMS calcd for C32H55O [M+H]+:
455.42529; found: 455.42609.
Compound 9g10R: This compound was prepared from 8g10R (143 mg,
0.29 mmol) in the same way as 9a from 8a [144 mg, 93%, Rf =0.4
(EtOAc/hexanes 10%), pale yellow oil]; 1H NMR (300 MHz, CDCl3,
258C, TMS): d=6.00 (m, 1H), 5.45 (dd, 3J=15.2 and 6.1 Hz, 1H), 5.31
(dt, 3J=15.2, 6.7 Hz, 1H), 5.15 (m, 2H), 3.57 (dd, 3J=9.4, 3.3 Hz, 1H),
3.25 (dd, 3J=9.4, 7.3 Hz, 1H), 1.78 (t, 3J=2.4 Hz, 3H), 0.97 (d, 3J=
9.7 Hz, 3H), 0.95 (d, 3J=5.8 Hz, 6H), 0.89 (s, 9H), 0.02 ppm (s, 6H);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=139.7 (CH), 133.3 (CH),
Compound 9i10S
: This compound was prepared from 9h10S (34 mg,
0.06 mmol) in the same way as 9i10R from 9h10R [30 mg, 80%, Rf =0.5
(10% AcOEt/hexanes), yellow oil]; 1H NMR (500 MHz, CDCl3, 258C,
3
3
TMS): d=6.01 (m, 1H), 5.48 (dd, J=15.4, 6.3 Hz, 1H), 5.30 (dt, J=7.9,
5.4 Hz, 1H), 4.97 (t, 3J=13.4 Hz, 2H), 4.79 (d, 3J=6.5 Hz, 1H), 4.61 (d,
3J=6.4 Hz, 1H), 4.55 (d, 3J=6.5 Hz, 2H), 3.65 (d, 3J=7.8 Hz, 1H), 3.57
(dd, 3J=9.6, 3.2 Hz, 1H), 3.39 (s, 3H), 3.35 (s, 3H), 3.21 (dd, 3J=9.3,
7.8 Hz, 1H), 2.64 (dd, 3J=16.1, 6.9 Hz, 1H), 2.40–2.04 (m, 8H), 1.78 (t,
3J=2.1 Hz, 3H), 0.97 (d, 3J=8.1 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 3H), 0.85
ꢁ
ꢁ
125.1 (CH), 119.6 (CH2), 77.2 (C ), 75.9 (C ), 67.7 (CH2), 53.7 (CH),
51.1 (CH), 43.5 (C), 43.3 (CH2), 39.7 (CH), 38.4 (CH), 37.7 (CH2), 35.0
(CH), 34.6 (CH2), 31.1 (CH), 30.5 (CH2), 26.6 (CH2), 26.0 (CH3), 22.7
(CH3), 21.6 (CH2), 20.2 (CH2), 18.4 (C), 16.6 (CH3), 13.5 (CH3), 3.4
(CH3), ꢀ5.4 ppm (2”CH3); IR (KBr): n˜ =3563, 2954, 2930, 2857, 1727,
1637, 1463, 1383, 1361, 1254, 1123, 1090, 1043, 1004, 971 cmꢀ1; MS: m/z
(%): 529 (1) [M+H]+, 511 (2) [M+HꢀH2O]+, 453 (9), 355 (16), 337 (21).
3
(d, J=6.6 Hz, 6H), 0.02 ppm (s, 6H); 13C NMR (125 MHz, CDCl3, 258C,
TMS): d=140.5 (CH), 136.7 (CH), 125.7 (CH), 115.8 (CH2), 98.9 (CH2),
91.5 (CH2), 81.3 (CH), 78.9 (C), 76.2 (C), 67.7 (CH2), 56.6 (CH3), 56.1
(CH3), 53.9 (CH), 44.3 (CH), 43.5 (C), 42.2 (CH), 41.7 (CH2), 38.5 (CH),
36.1 (CH2), 34.1 (CH2), 31.6 (CH2), 31.1 (CH), 29.1 (CH2), 26.8 (CH2),
26.0 (CH3), 22.6 (CH), 22.1 (CH2), 19.3 (CH2), 18.7 (CH3), 18.4 (C), 16.6
(CH3), 14.1 (CH3), 11.1 (CH3), 3.6 (CH3), ꢀ5.4 ppm (CH3); MS: m/z (%):
655 (8) [M+Na]+; HRMS: calcd for C38H68NaO5Si: 655.47282; found:
655.47328.
Compound 9h10S: This compound was prepared from 8h10S (37 mg,
0.07 mmol) in the same way as 9a from 8a [31 mg, 79%, Rf =0.4 (10%
AcOEt/hexanes), white solid]; 1H NMR (500 MHz, CDCl3, 258C, TMS):
d=6.00 (m, 1H), 5.50 (dd, 3J=15.3, 6.5 Hz, 1H), 5.37 (dt, 3J=15.3,
7.3 Hz, 1H), 5.10 (m, 2H), 3.88 (dd, 3J=9.7, 4.5 Hz, 1H), 3.57 (dd, 3J=
9.6, 3.2 Hz, 1H), 3.24 (dd, 3J=9.4, 7.4 Hz, 1H), 2.50 (s, 1H), 2.39–2.10
(m, 7H), 1.79 (t, 3J=2.2 Hz, 3H), 1.65–1.48 (m, 7H), 1.34–1.13 (m, 5H),
1.00 (s, 3H), 0.97 (d, 3J=6.7 Hz, 6H), 0.93 (d, 3J=6.5 Hz, 3H), 0.89 (s,
9H), 0.02 ppm (s, 6H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=
140.2 (CH), 135.6 (CH), 126.0 (CH), 118.0 (CH2), 78.4 (C), 75.9 (C), 73.0
(CH), 67.6 (CH2), 54.1 (CH), 51.8 (CH), 46.0 (CH), 42.4 (C), 39.9 (CH),
38.6 (CH), 36.9 (CH2), 34.7 (CH2), 31.1 (CH), 30.3 (CH3), 29.7 (CH2),
27.4 (CH2), 26.0 (CH3), 22.6 (CH3), 21.7 (CH2), 20.2 (CH2), 18.4 (C), 16.7
(CH2), 16.6 (CH3), 3.7 (CH3), ꢀ5.3 ppm (CH3); MS: m/z (%): 545 (2)
[M+H]+, 528 (12) [M+HꢀCH4]+, 418 (46) [M+HꢀOTBSꢀH2O]+;
HRMS: calcd for C34H61O3Si: 545.43900; found: 545.43891.
Compound 9j10S
: Pyridine (15 mL, 0.2 mmol) and TBSOTf (39 mL,
0.17 mmol) were added dropwise at 08C to a solution of dienyne 9h10S
(30 mg, 0.05 mmol) in CH2Cl2 (1.7 mL). The final solution was stirred at
that temperature for 30 min and was then allowed to reach room temper-
ature and stirred for another 5 h. The reaction was quenched by addition
of water (2 mL) and the aqueous layer was extracted with CH2Cl2, dried
over Na2SO4 and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography (1% AcOEt/hexanes) to pro-
vide the protected compound [27 mg, 75%, Rf =0.6 (10% AcOEt/hex-
anes), yellow oil]; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=5.97 (m,
1H), 5.42 (dd, 3J=15.3, 6.4 Hz, 1H), 5.26 (dt, 3J=13.9, 6.9 Hz, 1H), 5.10
Compound 9h10R: This compound was prepared from 8h10R (103 mg,
0.20 mmol) in the same way as 9a from 8a [74 mg, 68%, Rf =0.2
(AcOEt/hexanes 10%), white solid]; 1H NMR (500 MHz, CDCl3, 258C,
TMS): d=6.05 (m, 1H), 5.46 (dd, 3J=15.3, 6.4 Hz, 1H), 5.35 (dt, 3J=
15.3, 6.5 Hz, 1H), 5.13 (t, 3J=13.1 Hz, 2H), 4.16 (dd, 3J=10.0, 2.8 Hz,
3
3
(d, J=4.0 Hz, 1H), 5.05 (s, 1H), 4.22 (dd, J=9.9, 3.9 Hz, 1H), 3.55 (dd,
3J=9.6, 3.3 Hz, 1H), 3.22 (dd, 3J=9.5, 7.4 Hz, 1H), 2.44–2.13 (m, 5H),
1.75 (t, 3J=2.3 Hz, 3H), 0.95 (d, 3J=3.2 Hz, 6H), 0.93 (d, 3J=6.4 Hz,
3H), 0.93 (s, 3H), 0.88 (s, 9H), 0.86 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H),
ꢀ0.01 ppm (s, 6H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=140.2
(CH), 135.2 (CH), 125.3 (CH), 118.2 (CH2), 99.9 (C), 78.7 (C), 75.2 (C),
67.7 (CH2), 54.2 (CH), 51.8 (CH), 47.6 (CH), 44.8 (CH), 42.2 (C), 43.7
(CH2), 38.6 (CH), 37.1 (CH2), 31.1 (CH), 30.3 (CH), 29.7 (CH2), 27.2
(CH2), 26.2 (CH3), 26.0 (CH3), 22.6 (CH3), 22.5 (CH3), 21.3 (CH2), 20.8
(CH2), 20.4 (CH2), 18.4 (C), 3.5 (CH3), ꢀ3.4 (CH3), ꢀ3.8 (CH3),
ꢀ5.4 ppm (CH3); MS: m/z (%): 659 (4) [M+H]+, 641 (5) [M+HꢀH2O]+,
527 (15) [M+HꢀOTBS]+; HRMS: calculated for C40H75O3Si2: 659.52548;
found: 659.52374.
3
3
1H), 3.58 (dd, J=9.6, 3.3 Hz, 1H), 3.27 (dd, J=9.6, 7.2 Hz, 1H), 2.37 (s,
1H), 2.40 (s, 1H), 2.33–2.16 (m, 4H), 1.98 (m, 1H), 1.80 (t, 3J=2.5 Hz,
3H), 1.71–1.46 (m, 4H), 1.44 (s, 1H), 1.38–1.21 (m, 4H), 1.01 (s, 3H),
0.98 (d, 3J=6.7 Hz, 6H), 0.96 (d, 3J=6.5 Hz, 3H), 0.90 (s, 9H), 0.03 ppm
(s, 6H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=139.9 (CH), 135.8
(CH), 125.1 (CH), 118.3 (CH2), 77.9 (C), 75.8 (C), 73.4 (CH), 67.7 (CH2),
54.1 (C), 51.7 (CH), 45.9 (CH), 44.1 (CH), 42.8 (CH2), 40.2 (CH), 38.6
(CH), 36.9 (CH2), 31.0 (CH), 30.4 (CH3), 29.8 (CH2), 27.3 (CH2), 26.0
(CH3), 22.5 (CH3), 21.4 (CH2), 20.8 (CH2), 20.2 (CH2), 18.5 (C), 16.6
(CH3), 3.6 (CH3), ꢀ5.3 ppm (CH3); MS: m/z (%): 545 (3) [M+H]+, 527
(46) [M+HꢀH2O]+, 509 (100) [M+Hꢀ2H2O]+; HRMS: calcd for
C34H61O3Si: 545.43900; found: 545.43876.
Compound 9k10R: PDC (29 mg, 0.08 mmol) was added to a solution of di-
enyne 9h10R (28 mg, 0.05 mmol) in CH2Cl2 (1.5 mL) and the suspension
was stirred at rt. After 6 h the reaction mixture was filtered through a
short pad of SiO2/celite (1:1) and washed with Et2O to give a residue
that, upon flash chromatography, afforded the ketone 9k10R [13 mg, 46%,
Compound 9i10R: DIEA (1.3 mL, 7.44 mmol) and ClMOM (0.56 mL,
7.44 mmol) were added to
a solution of dienyne 9h10R (338 mg,
0.62 mmol) in CH2Cl2 (21 mL). The reaction was stirred at room temper-
ature for 15 h and then NH4Cl (sat, 15 mL) was added. The aqueous
layer was extracted with CH2Cl2 and the organic extracts were dried over
Na2SO4 and concentrated under reduced pressure, giving a residue that,
1
Rf =0.4 (10% AcOEt/hexanes), white solid]; H NMR (300 MHz, CDCl3,
258C, TMS): d=5.78 (m, 1H), 5.42 (dd, 3J=15.3, 6.4 Hz, 1H), 5.20 (dt,
3J=15.1, 7.3 Hz, 1H), 5.08 (ddd, 3J=18.6, 13.7, 1.8 Hz, 1H), 3.57 (dd,
Chem. Eur. J. 2007, 13, 5135 – 5150
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5145

Juan R. Granja et al.
3J=9.6, 3.5 Hz, 1H), 3.18 (dd, 3J=9.5, 8.0 Hz, 1H), 2.86 (tt, 3J=9.3,
4.7 Hz, 1H), 2.72 (dd, 3J=6.5, 1.2 Hz, 1H), 2.44 (dd, 3J=14.1, 7.7Hz,
1H), 1.69 (t, 3J=2.5 Hz, 3H), 0.94 (d, 3J=6.5 Hz, 6H), 0.91 (d, 3J=
6.6 Hz, 3H), 0.87 (s, 9H), 0.87 (s, 3H), 0.00 ppm (s, 6H); 13C NMR
(75 MHz, CDCl3, 258C, TMS): d=212.4 (CO), 141.1 (CH), 133.3 (CH),
122.9 (CH), 119.7 (CH2), 77.3 (C), 74.0 (C), 67.7 (CH2), 54.8 (CH), 53.1
(CH), 51.4 (CH), 50.3 (CH), 43.5 (CH2), 43.0 (C), 38.5 (CH), 35.8 (CH2),
34.9 (CH2), 31.0 (CH), 26.7 (CH2), 26.0 (CH3), 22.4 (CH3), 20.8 (CH2),
20.3 (CH2), 19.4 (CH2), 18.4 (C), 16.5 (CH3), 13.1 (CH3), 3.4 (CH3),
ꢀ5.3 ppm (CH3); MS: m/z (%): 543 (25) [M+H]+, 525 (75)
[M+HꢀH2O]+; HRMS: calcd for C34H59O3Si 543.42280; found:
543.42164.
1H), 2.90 (dd, 3J=11.0, 4.0 Hz, 1H), 1.80 (s, 3H), 0.97 (s, 3H), 0.91 (s,
9H), 0.05 ppm (s, 6H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=
142.2 (C), 136.1 (C), 121.0 (CH), 117.3 (CH), 80.9 (C), 67.8 (CH2), 53.9
(CH), 48.5 (CH), 45.3 (CH), 43.7 (C), 40.6 (CH2), 38.6 (CH), 35.8 (CH2),
35.2 (CH2), 34.6 (CH), 33.0 (CH2), 30.5 (CH), 30.4 (CH2), 29.8 (CH2),
26.6 (CH2), 26.1 (CH3), 20.7 (CH2), 18.5 (CH3), 16.6 (CH3), 14.1 (CH3),
ꢀ5.2 ppm (2”CH3); IR (CHCl3): n˜ =3012, 2952, 2929, 2850, 1718, 1603,
1464, 1365, 1255, 1214, 1149, 1086, 1038 cmꢀ1; MS: m/z (%): 459 (2)
[M+H]+, 459 (1) [M+HꢀH2O]+, 383 (8), 307 (3); HRMS calcd for
C29H50O2Si [M+H]+: 458.35801; found: 458.35637.
Compound 11i10R: This compound was prepared from 9i10R (25 mg,
0.04 mmol) in the same way as 11g10R from 9g10R [20 mg, 90%, Rf =0.4
(10% AcOEt/hexanes), white solid]; 1H NMR (500 MHz, CDCl3, 258C,
RCDEYM cyclization—general conditions: Compound 11a: Grubbsꢁ cat-
alyst 10a (0.006 mmol) was added to a solution of dienyne 9c10R (220 mg,
0.43 mmol) in CH2Cl2 (100 mL). The reaction mixture was heated at
reflux for 4 h, allowed to come to room temperature and concentrated
under reduced pressure. The crude residue was purified by chromatogra-
phy on aluminium oxide (8% H2O) to yield 11a [152 mg, 80%, Rf =0.27
(EtOAc/hexanes 10%), yellow oil]; 1H NMR (500 MHz, CDCl3, 258C,
TMS): d=6.18 (d, 3J=10.1 Hz, 1H), 5.43 (m, 1H), 5.34 (t, 3J=8.1 Hz,
1H), 3.61 (dd, 3J=3.5, 9.6 Hz, 1H), 3.20 (m, 1H), 2.87 (dd, 3J=11.4,
3.9 Hz, 1H), 2.01 (d, 3J=11.4 Hz, 1H), 0.91 (s, 9H), 0.05 ppm (s, 6H);
13C NMR (125 MHz, CDCl3, 258C, TMS): d=139.7 (C), 130.5 (CH),
125.8 (CH), 119.1 (CH), 81.2 (C), 67.8 (CH2), 53.8 (CH), 48.5 (CH), 45.2
(CH), 43.7 (C), 40.5 (CH2), 38.6 (CH), 35.6 (CH2), 35.1 (CH2), 34.9 (CH),
33.3 (CH2), 30.4 (CH2), 29.9 (CH2), 26.5 (CH2), 26.0 (CH3), 20.6 (CH2),
18.4 (C), 16.4 (CH3), 14.0 (CH3), ꢀ5.3 ppm (2”CH3); IR (KBr): n˜ =2952,
2927, 2855, 1712, 1462, 1377, 1252, 1091, 1007, 984 cmꢀ1; MS: m/z (%):
445 (4) [M+H]+, 313 (4), 295 (83); HRMS calcd for C28H49O2Si [M+H]+
: 445.35018; found: 445.35141.
3
3
TMS): d=5.68 (t, J=7.6 Hz, 1H), 5.24 (s, 1H), 4.87 (d, J=6.6 Hz, 1H),
4.73 (d, 3J=6.6 Hz, 1H), 4.73 (d, 3J=6.6 Hz, 1H), 4.55 (d, 3J=6.6 Hz,
1H), 3.99 (d, 3J=9.6 Hz, 1H), 3.56 (dd, 3J=9.6, 3.3 Hz, 1H), 3.38 (s,
3H), 3.35 (s, 3H), 3.27 (dd, 3J=9.6, 7.0 Hz, 1H), 2.83 (dd, 3J=11.8,
3.7 Hz, 1H), 2.56 (d, 3J=7.9 Hz, 2H), 2.23 (m, 1H), 2.16 (m, 1H), 1.77
(d, 3J=1.5 Hz, 3H), 0.98 (s, 3H), 0.95 (d, 3J=6.6 Hz, 6H), 0.93 (d, 3J=
7.5 Hz, 3H), 0.89 (s, 9H), 0.03 ppm (s, 6H); 13C NMR (125 MHz, CDCl3,
258C, TMS): d=141.9 (CH), 135.7 (CH), 121.4 (CH), 119.5 (CH), 96.1
(CH2), 91.7 (CH2), 85.8 (C), 78.7 (CH), 67.6 (CH2), 56.6 (CH), 55.9
(CH3), 55.0 (CH3), 54.2 (CH), 50.3 (CH), 41.6 (C), 38.9 (CH2), 38.8 (CH),
38.1 (CH), 33.7(CH2), 29.4 (CH2), 27.2 (CH2), 26.0 (CH2), 26.9 (CH3),
N
21.4 (CH2), 19.5 (CH2), 19.1 (CH3),18.4 (CH3), 16.7 (CH3), ꢀ5.3 ppm
(CH3); MS: m/z (%): 563 (6) [M+H]+, 502 (15) [M+HꢀOMOM]+, 441
(32) [M+Hꢀ2”OMOM]+.
Compound 11j10S
:
Grubbsꢁ catalyst 10b (2 mg, 2.7”10ꢀ3 mmol) was
added to a solution of dienyne 9j10S (18 mg, 0.027 mmol) in benzene
(5.5 mL). The reaction mixture was heated at reflux for 2 h and then an-
other 2 mg of catalyst were added. After having been stirred for 2 h
more at the same temperature, the solution was allowed to reach room
temperature and concentrated under reduced pressure. The crude prod-
uct was purified by chromatography on aluminium oxide (8% H2O) to
yield 11j10S [10 mg, 62%, Rf =0.5 (10% AcOEt/hexanes), white solid];
1H NMR (500 MHz, CDCl3, 258C, TMS): d=5.39 (dd, 3J=11.1, 5.1 Hz,
Compound 11d: This compound was prepared from 12d (25 mg,
0.056 mmol) in the same way as 11a from 9c10R, with use of 10b and
final chromatography on silica gel to yield 11d [3 mg, 14%, Rf =0.5
(EtOAc/hexanes 10%), yellow oil]; 1H NMR (500 MHz, CDCl3, 258C,
3
TMS): d=6.19 (d, J=9.7 Hz, 1H), 5.43 (m, 1H), 5.34 (m, 1H), 2.86 (dd,
3J=11.5 and 4.2 Hz, 1H), 1.99 (d, 3J=11.5 Hz, 1H), 0.85 (d, 3J=6.6 Hz,
6H), 0.85 ppm (s, 3H); IR (CHCl3): n˜ =3020, 2929, 2870, 1603, 1457,
1215, 996 cmꢀ1; MS: m/z (%): 385 (5) [M+H]+, 367 (37) [M+HꢀH2O]+;
HRMS calcd for C27H45O [M+H]+: 385.34704; found: 385.34682.
3
3
1H), 5.10 (s, 1H), 4.13 (dd, J=4.7, 2.6 Hz, 1H), 3.60 (dd, J=9.7, 3.4 Hz,
1H), 3.26 (dd, 3J=9.7, 7.4 Hz, 1H), 2.76 (dd, 3J=12.2, 1.2 Hz, 1H), 2.65
(td, 3J=9.5, 4.7 Hz, 1H), 2.55 (t, 3J=11.8 Hz, 1H), 2.45 (dt, 3J=20.1,
2.4 Hz, 1H), 2.27 (dd, 3J=12.3, 5.1 Hz, 1H), 2.20 (dt, 3J=15.2, 2.1 Hz,
1H), 2.10 (dd, 3J=20.9, 10.2 Hz, 1H), 1.99 (dd, 3J=12.3, 6.0 Hz, 1H),
1.88 (dd, 3J=12.6, 7.7 Hz, 1H), 1.81 (d, 3J=1.6 Hz, 3H), 1.76 (ddd, 3J=
12.9, 8.3, 1.6 Hz, 1H), 1.71–1.61 (m, 4H), 1.57 (m, 3H), 0.94 (s, 3H), 0.93
(d, 3J=5.4 Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H),
0.04 ppm (s, 6H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=144.4
(C), 137.5 (C), 121.7 (CH), 117.6 (CH), 79.2 (C), 73.8 (C), 67.7 (CH2),
55.6 (CH), 54.6 (CH), 51.4 (CH), 43.4 (CH), 41.2 (C), 38.8 (CH), 38.5
(CH2), 38.0 (CH2), 30.7 (CH2), 30.3 (CH), 29.7 (CH2), 27.3 (CH2), 26.0
(CH3), 25.7 (CH3), 24.8 (CH2), 19.6 (CH3), 19.3 (CH2), 18.4 (C), 18.3
(CH3), 17.9 (C), 16.5 (CH3), ꢀ4.8 (CH3), ꢀ5.3 ppm (CH3); MS: m/z (%):
589 (7) [M+H]+, 571 (23) [M+HꢀH2O]+, 527 (66) [M+HꢀOTBS]+;
HRMS: calcd for C35H65O3Si2: 589.44723; found: 589.44705.
Compound 11e: KH (35% dispersion in mineral oil, 10 mg, 0.09 mmol),
crown ether (2 mg) and MeI (10 mL, 0.16 mmol) were added to a solu-
tion of alcohol 11a (20 mg, 0.04 mmol) in THF (2 mL) and the resulting
mixture was heated at reflux for 12 h. The reaction was quenched by ad-
dition of H2O and the resulting mixture was extracted with hexanes. The
combined organic layers were dried over Na2SO4, filtered and concentrat-
ed under reduced pressure, giving a residue that was flash chromato-
graphed (hexanes) to afford compound 11e [14 mg, 68%, Rf =0.80
(EtOAc/hexanes 5%), colorless oil]; 1H NMR (500 MHz, CDCl3, 258C,
TMS): d=6.18 (d, 3J=9.6 Hz, 1H), 5.42 (m, 1H), 5.38 (t, 3J=8.0 Hz,
1H), 3.60 (dd, 3J=9.6, 3.5 Hz, 1H), 3.23 (s, 3H), 3.17 (m, 1H), 2.81 (m,
1H), 1.95 (m, 1H), 0.93 (d, 3J=6.5 Hz, 3H), 0.89 (s, 9H), 0.03 ppm (s,
6H); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=138.7 (C), 130.7
(CH), 125.6 (CH), 119.9 (CH), 84.8 (C), 67.9 (CH2), 54.0 (CH), 49.0
(CH3), 47.5 (CH), 43.5(C), 38.6 (CH), 37.8 (CH), 35.4 (CH2), 35.2 (CH2),
35.1 (CH), 33.3 (CH2), 32.3 (CH2), 30.2 (CH2), 29.8 (CH2), 26.6 (CH2),
26.0 (3”CH3), 20.8 (CH2), 18.4 (C), 16.5 (CH3), 14.3 (CH3), ꢀ5.3 ppm
(CH3); IR (KBr): n˜ =3312, 3019, 2928, 2856, 1738, 1470, 1381, 1361, 1253,
1088, 1036, 1005, 987 cmꢀ1; EM-IQ+: m/z (%): 459 (11) [M+H]+, 411
(11), 369 (5), 295 (7); HRMS calcd for C29H51O2Si [M+H]+: 459.36584;
found: 459.36413.
Compound 11k10R: This compound was prepared from 9k10R (30 mg,
0.055 mmol) in the same way as 11g10R from 9g10R [14 mg, 54%, Rf =0.3
(10% AcOEt/hexanes), white solid]; 1H NMR (500 MHz, CDCl3, 258C,
3
3
TMS): d=5.51 (t, J=6.9 Hz, 1H), 5.23 (s, 1H), 3.55 (dd, J=9.6, 3.2 Hz,
1H), 3.28 (dd, 3J=9.5, 6.9 Hz, 1H), 3.20 (s, 1H), 2.98 (d, 3J=11.6 Hz,
1H), 2.40 (m, 2H), 2.13 (m, 2H), 1.74 (brs, 3H), 0.98 (s, 3H), 0.93 (d,
3J=6.6 Hz, 3H), 0.88 (s, 9H), 0.02 ppm (s, 6H); 13C NMR (125 MHz,
CDCl3, 258C, TMS): d=120.5 (CH), 120.1 (CH), 77.0 (CH), 67.4 (CH2),
65.8 (CH2), 58.7 (C), 54.4 (CH), 38.6 (CH), 37.3 (C), 29.4 (CH), 27.3
(CH2), 26.0 (CH3), 22.1 (CH2), 19.6 (CH2), 18.7 (CH3), 18.4 (C), 16.6
(CH3), 15.2 (CH3), ꢀ5.4 ppm (CH3); MS: m/z (%): 495 (2) [M+Na+]+,
307 (100) [Mꢀ2H2OꢀOTBS]+; HRMS: calcd for C29H48NaO3Si:
495.32649; found: 495.32604.
Compound 11g10R: Grubbsꢁ catalyst 10b (2.8 mg, 3.8”10ꢀ3 mmol) was
added to a solution of dienyne 9g10R (20 mg, 0.038 mmol) in benzene
(8 mL). The reaction mixture was heated at reflux for 2 h, allowed to
reach room temperature and concentrated under reduced pressure. The
crude product was purified by chromatography on aluminium oxide (8%
H2O) to yield 11g10R [12 mg, 69%, Rf =0.2 (EtOAc/hexanes 10%),
yellow oil]; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=5.41 (m, 1H),
5.17 (m, 1H), 3.62 (dd, 3J=9.5, 3.7 Hz, 1H), 3.20 (dd, 3J=9.5, 8.1 Hz,
Triethyl but-3-yne-1,1,1-tricarboxylate (18): A solution of NaOEt (1.93 g,
28.42 mmol) in EtOH (24 mL) was added to a solution of triethyl metha-
netricarboxylate (6.00 g, 25.84 mmol) in Et2O (20 mL), cooled in an ice
5146
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5135 – 5150

Dienyne RCM Approach for the Construction of Taxosteroids
FULL PAPER
bath. The white sodium salt that precipitated was collected, washed with
Et2O and dried in vacuo, affording triethyl sodium methanetricarboxylate
(5.78 g, 22.73 mmol) as a white powder that was dissolved in a toluene/
DMF mixture (1:1, 50 mL) and treated with propargyl bromide (80% w/
w solution in toluene, 5.1 mL, 45.5 mmol). The mixture was stirred at
808C for 1.5 h, cooled and filtered, and the residue was washed with tolu-
ene. The combined filtrates were washed with water, dried over Na2SO4,
filtered and concentrated under reduced pressure. Distillation of the
crude product (978C at 0.2 mmHg) afforded triethyl but-3-yne-1,1,1-tri-
carboxylate [6.03 g, 86%, Rf =0.2 (EtOAc/hexanes 10%), pale yellow
oil]; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=4.25 (q, 3J=7.1 Hz,
6H), 2.98 (d, 3J=2.6 Hz, 2H), 2.01 (t, 3J=2.6 Hz, 1H), 1.26 ppm (t, 3J=
7.1 Hz, 9H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=165.6 (CO),
258C, TMS): d=5.44 (m, 1H), 5.19 (m, 1H), 4.11 (q, 3J=7.1 Hz, 2H),
2.51 (m, 1H), 2.35 (m, 4H), 2.01 (m, 3H), 1.21 (t, 3J=7.1 Hz, 3H),
0.90 ppm (t, 3J=7.5 Hz, 3H); 13C NMR (63 MHz, CDCl3, 258C, TMS):
ꢁ
ꢁ
d=173.8 (CO), 134.6 (CH), 124.3 (CH), 81.4 (C ), 69.8 (C ), 60.5 (CH2),
44.4 (CH), 28.5 (CH2), 20.5 (CH2), 20.3 (CH2), 14.2 (CH3), 14.1 ppm
(CH3); MS: m/z (%): 195 (53) [M+H]+, 167 (27), 149 (17), 121 (100);
HRMS calcd for C12H19O2 [M+H]+: 195.13850; found: 195.13884.
Ethyl (E)-6-methyl-2-(prop-2-ynyl)hept-4-enoate: Malonate 19c (4.2 g,
14.99 mmol) was decarboxylated in 50% yield in the same way as 19b
[Rf =0.5 (EtOAc/hexanes 15%), yellow oil]; 1H NMR (250 MHz, CDCl3,
258C, TMS): d=5.47 (dd, 3J=15.5, 6.3 Hz, 1H), 5.27 (dtd, 3J=15.2, 6.9,
3
1.0 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 2.56 (m, 1H), 2.33 (m, 5H), 1.98 (t,
3J=2.6 Hz, 1H), 1.26 (t, 3J=7.1 Hz, 3H), 0.94 ppm (d, 3J=6.8 Hz, 6H);
13C NMR (63 MHz, CDCl3, 258C, TMS): d=173.5 (CO), 140.7 (CH),
ꢁ
ꢁ
78.6 (C ), 70.6 (C ), 64.4 (C), 62.4 (CH2), 23.1 (CH2), 13.75 ppm (CH3);
MS: m/z (%): 271 (100) [M+H]+, 197 (35), 125 (24); HRMS calcd for
C13H19O6 [M+H]+: 271.11816; found: 271.11868.
ꢁ
ꢁ
122.3 (CH), 81.2 (C ), 69.6 (C ), 60.1 (CH2), 44.3 (CH), 33.8 (CH2), 30.8
(CH), 22.2 (CH3), 19.9 (CH2), 14.0 ppm (CH3); IR (KBr): n˜ =3311, 2959,
2930, 2871, 1736, 1466, 1440, 1259, 1177, 1041, 972 cmꢀ1; MS: m/z (%):
209 (29) [M+H]+, 136 (2) [M+HꢀCO2Et]+; HRMS calcd for C13H21O2
[M+H]+: 209.15416; found: 209.15432.
Malonate 19b: A solution of 18 (3.00 g, 11.10 mmol) in THF (3 mL) was
added by cannula to
a suspension of sodium ethoxide (980 mg,
14.4 mmol) in THF (35 mL) and the mixture was stirred at room temper-
ature for 1.5 h. (Z)-Pent-2-enynyl methanesulfonate (3.64 g, 22.2 mmol)
was added, and stirring was continued for 3 h, after which the mixture
was poured into brine (30 mL) and extracted with Et2O. The combined
organic phases were dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash chromatogra-
phy on silica gel (EtOAc/hexanes 4%), affording the dialkylmalonate
19b [1.03 g, 35%, Rf =0.4 (EtOAc/hexanes 10%), yellow oil]; 1H NMR
(250 MHz, CDCl3, 258C, TMS): d=5.48 (m, 1H), 4.97 (m, 1H), 4.11 (m,
4H), 2.70 (m, 4H), 2.07 (m, 2H), 1.94 (t, 3J=2.7 Hz, 1H), 1.18 (t, 3J=
7.2 Hz, 6H), 0.88 ppm (t, 3J=7.5 Hz, 3H); 13C NMR (63 MHz, CDCl3,
Ethyl 5-methyl-2-(prop-2-ynyl)hex-4-enoate: Malonate 19d (7.34 g,
27.59 mmol) was decarboxylated in the same way as 19b [32%, Rf =0.6
(EtOAc/hexanes 10%), yellow oil]; 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=5.04 (t, 3J=1.4 Hz, 1H), 4.15 (q, 3J=7.1 Hz, 2H), 2.54 (m,
1H), 2.39 (m, 4H), 1.96 (t, 3J=2.6 Hz, 1H), 1.68 (s, 3H), 1.61 (s, 3H),
1.24 ppm (t, 3J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C, TMS):
ꢁ
ꢁ
d=174.1 (CO), 134.6 (C), 120.1 (CH), 81.7 (C ), 69.7 (C ), 60.5 (CH2),
44.7 (CH), 29.6 (CH2), 25.8 (CH3), 20.3 (CH2), 17.8 (CH3), 14.2 ppm
(CH3); MS: m/z (%): 195 (1) [M+H+]+.
(4R,5S)-3-[(Z)-Hept-4-enoyl]-4-methyl-5-phenyloxazolidin-2-one (22b):
ꢁ
ꢁ
258C, TMS): d=169.7 (CO), 136.4 (CH), 121.6 (CH), 78.9 (C ), 71.1 (C
), 61.4 (CH2), 61.1 (CH2), 56.5 (C), 29.5 (CH2), 22.2 (CH2), 20.5 (CH2),
14.0 (CH3), 13.9 (CH3), 13.6 ppm (CH3); IR (KBr): n˜ =3285, 2979, 2936,
2875, 1736, 1465, 1447, 1367, 1325, 1289, 1243, 1208, 1188, 1137, 1096,
Pivaloyl chloride (3.3 mL, 27.2 mmol) was slowly added at ꢀ788C to a
flask containing (Z)-hept-4-enoic acid[33] (21b, 2.09 g, 16.3 mmol) and
Et3N (3.8 mL, 27.1 mmol) in THF (8 mL). The thick white paste was
stirred at 08C for 1 h. In a separate flask, a solution of (4R,5S)-(+)-4-
methyl-5-phenyloxazolidin-2-one (4.37 g, 24.66 mmol) in THF (11 mL)
was treated at room temperature with a catalytic amount of DMAP
(10 mol%, 302 mg, 2.46 mmol), followed by Et3N (3.4 mL, 24.6 mmol).
This solution was then added at ꢀ788C over 5 min to the above mixed
anhydride, and the mixture was stirred for 12 h at room temperature to
ensure complete reaction. Volatiles were removed in vacuo, and the re-
sulting white paste was dissolved in CH2Cl2 (11 mL) and NaOH (1m,
6 mL). The aqueous phase was removed and the organic phase was
washed with brine and then dried, filtered and concentrated under re-
duced pressure. This concentrate was purified by flash chromatography
on silica gel (12% EtOAc/hexanes), yielding 22b [4.18 g, 59%, Rf =0.5
(EtOAc/hexanes 15%), pale yellow oil]; 1H NMR (300 MHz, CDCl3,
258C, TMS): d=7.35 (m, 5H), 5.64 (d, 3J=7.3 Hz, 1H), 5.40 (m, 2H),
4.75 (m, 1H), 2.99 (m, 2H), 2.42 (m, 2H), 2.09 (m, 2H), 0.96 (t, 3J=
7.6 Hz, 3H), 0.85 ppm (m, 3H); 13C NMR (75 MHz, CDCl3, 258C, TMS):
d=172.4 (CO), 152.9 (CO), 133.3 (C), 133.1 (CH), 128.64 (CH), 128.60
(CH), 126.7 (CH), 125.5 (CH), 78.9 (CH), 54.6 (CH), 35.6 (CH2), 22.0
(CH2), 20.4 (CH2), 14.5 (CH3), 14.2 ppm (CH3); IR (KBr): n˜ =3063, 2965,
2934, 2874, 1784, 1700, 1456, 1369, 1345, 1279, 1218, 1195, 1145, 1122,
1067, 1031, 990 cmꢀ1; MS: m/z (%): 288 (96) [M+H]+, 273 (4), 178 (62);
HRMS calcd for C17H22NO3 [M+H]+: 288.15997; found: 288.16074; ele-
mental analysis calcd (%) for C17H21NO3: C 70.81, H 7.69, N 4.86; found:
C 70.68, H 7.75, N 5.18.
1070, 1054, 1016 cmꢀ1 MS: m/z (%): 267 (100) [M+H]+, 194 (5)
;
[M+HꢀCO2Et]+, 121 (5) [M+Hꢀ
(CO2Et)2]+; HRMS calcd for C15H23O4
[M+H]+: 267.15963; found: 267.16007.
Malonate 19c: This compound was prepared in the same way as 19b
with (E)-4-methylpent-2-enyl methanesulfonate[31] (3.18 g, 17.85 mmol) to
afford 19c [2.2 g, 88%, Rf =0.5 (EtOAc/hexanes 15%), yellow oil];
1H NMR (300 MHz, CDCl3, 258C, TMS): d=5.52 (dd, 3J=15.2, 6.9 Hz,
1H), 5.15 (m, 1H), 4.17 (q, 3J=7.1 Hz, 4H), 2.75 (d, 3J=2.6 Hz, 2H),
2.70 (d, 3J=7.5 Hz, 2H), 2.21 (m, 1H), 1.98 (t, 3J=2.6 Hz, 1H), 1.23 (t,
3J=7.1H, z6H), 0.92 ppm (d, 3J=6.8 Hz, 6H); 13C NMR (75 MHz,
ꢁ
CDCl3, 258C, TMS): d=169.8 (CO), 143.2 (CH), 119.7 (CH), 79.1 (C ),
ꢁ
71.2 (C ), 61.5 (CH2), 57.0 (C), 35.0 (CH2), 31.1 (CH), 22.0 (CH3), 21.7
(CH2), 14.1 ppm (CH3); IR (KBr): n˜ =3202, 3006, 2962, 2929, 2871, 2850,
2360, 2118, 1457, 1426, 1230, 1178, 1069 cmꢀ1; MS: m/z (%): 281 (58)
[M+H]+, 207 (25), 133 (17); HRMS calcd for C16H25O4 [M+H]+:
281.17528; found: 281.17564.
Malonate 19d:[32] This compound was prepared in the same way as 19b
with 1-bromo-3-methylbut-2-ene (3.90 g, 26.15 mmol) to afford 19d
[2.61 g, 75%, Rf =0.4 (EtOAc/hexanes 15%), yellow oil]; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=4.89 (t, 3J=1.4 Hz, 1H), 4.17 (m,
4H), 2.75 (m, 4H), 1.97 (t, 3J=2.7 Hz, 1H), 1.65 (s, 3H), 1.64 (s, 3H),
1.23 ppm (t, 3J=7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3, 258C, TMS):
ꢁ
ꢁ
d=170.0 (CO), 136.6 (C), 117.1 (CH), 71.1 (C ), 79.4 (C ), 61.5 (2”
CH2), 57.0 (C), 30.6 (CH2), 26.0 (CH3), 22.4 (CH2), 18.0 (CH3), 14.0 ppm
(2”CH3); MS: m/z (%): 267 (1) [M+H]+, 205 (5); HRMS calcd for
C15H23O4 [M+H]+: 267.15963; found: 267.15882.
A
one (22c): This compound was prepared from (E)-6-methylhept-4-enoic
acid (21c, 1.83 g, 12.87 mmol of crude mixture)[23] in the same way as 22b
from 21b [3.1 g, 80%, Rf =0.75 (30% EtOAc/hexanes), pale yellow oil];
1H NMR (500 MHz, CDCl3, 258C, TMS): d=7.36 (m, 5H), 5.65 (d, 3J=
7.3 Hz, 1H), 5.43 (m, 2H), 4.75 (m, 1H), 3.01 (m, 2H), 2.35 (m, 2H),
2.22 (m, 1H), 0.95 (d, 3J=6.7 Hz, 6H), 0.87 ppm (d, 3J=6.5 Hz, 3H);
13C NMR (125 MHz, CDCl3, 258C, TMS): d=172.5 (CO), 153.0 (CO),
133.3 (C), 138.9 (CH), 128.7 (CH), 128.6 (CH), 125.6 (CH), 124.8 (CH),
78.9 (CH), 54.7 (CH), 35.6 (CH2), 30.9 (CH), 27.2 (CH2), 22.4 (CH3),
14.5 ppm (CH3); IR (KBr): n˜ =3526, 3383, 3066, 3035, 2957, 2869, 1777,
Ethyl (Z)-2-(prop-2-ynyl)hept-4-enoate:
A solution of malonate 19b
(3.20 g, 12.01 mmol) and NaOEt (1.23 g, 18.07 mmol) in EtOH (50 mL)
was heated at reflux for 2 days, allowed to come to rt, poured into NaCl
(40 mL) and treated with HCl (10%, 20 mL). The aqueous layer was ex-
tracted with Et2O, and the combined organic phases were dried over
Na2SO4, filtered and concentrated under reduced pressure. The crude res-
idue was purified by flash chromatography on silica gel (EtOAc/hexanes,
1%), yielding ethyl (Z)-2-(prop-2-ynyl)hept-4-enoate [1.30 g, 55%, Rf =
0.6 (EtOAc/hexanes 10%), yellow oil]; 1H NMR (250 MHz, CDCl3,
1700, 1498, 1457, 1382, 1345, 1197, 1146, 1120, 1091, 1067, 1032, 970 cmꢀ1
;
Chem. Eur. J. 2007, 13, 5135 – 5150
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5147

Juan R. Granja et al.
MS: m/z (%): 302 (28) [M+H]+, 206 (28), 178 (43), 134 (100); HRMS
calcd for C18H24NO3 [M+H]+: 302.17562; found: 302.17632.
[M+HꢀCH4]+, 178 (100) [M+HꢀCHO
U
G
A
G
was prepared from (Z)-hept-4-enoic acid (21b, 6.14 g, 48.01 mmol) in the
same way as 22b from 21b but with use of (4S)-4-benzyloxazolidin-2-one
(8.68 g, 48.97 mmol) [5.79 g, 42%, Rf =0.4 (20% EtOAc/hexanes), pale
yellow oil]; 1H NMR (250 MHz, CDCl3, 258C, TMS): d=7.29 (m, 5H),
5.42 (m, 2H), 4.67 (m, 1H), 4.15 (m, 2H), 3.29 (dd, 3J=13.4, 3.2 Hz,
1H), 3.01 (m, 2H), 2.79 (dd, 3J=13.3, 9.5 Hz, 1H), 2.43 (m, 2H), 2.09
methyl-5-phenyloxazolidin-2-one (23b): LiHMDS (1m, 4.3 mL,
4.3 mmol) was added at ꢀ788C to a solution of oxazolidinone 22b
(1.14 g, 3.99 mmol) in THF (25 mL), the resulting mixture was stirred for
0.5 h, and
a solution of 3-bromo-1-trimethylsilylprop-2-yne (2.29 g,
11.97 mmol) in toluene (5 mL) was added. The reaction mixture was
stirred at 08C for 3 h, poured into NH4Cl (30 mL) and extracted with
CH2Cl2. The combined organic phases were dried over Na2SO4, filtered
and concentrated under reduced pressure, and the concentrate was puri-
fied by flash chromatography on silica gel (EtOAc/hexanes 5%), afford-
ing the desired product [1.03 g, 65%, Rf =0.55 (EtOAc/hexanes 15%),
pale yellow oil]; 1H NMR (500 MHz, CDCl3, 258C, TMS): d=7.37 (m,
5H), 5.64 (d, 3J=7.3 Hz, 1H), 5.47 (m, 1H), 5.27 (m, 1H), 4.78 (m, 1H),
4.01 (m, 1H), 2.47 (m, 4H), 2.04 (m, 2H), 0.93 (t, 3J=7.5 Hz, 3H), 0.86
(d, 3J=6.6 Hz, 3H), 0.06 ppm (s, 9H); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=173.8 (CO), 152.5 (CO), 134.75 (CH), 133.3 (C), 128.6, 125.5
3
(m, 2H), 0.99 ppm (t, J=7.5 Hz, 3H); 13C NMR (63 MHz, CDCl3, 258C,
TMS): d=172.7 (CO), 153.4 (CO), 135.2 (C), 133.1 (CH), 129.3 (CH),
128.8 (CH), 127.2 (CH), 126.7 (CH), 66.1 (CH2), 55.0 (CH), 37.8 (CH2),
35.5 (CH2), 21.9 (CH2), 20.4 (CH2), 14.2 ppm (CH3); IR (KBr): n˜ =3527,
3383, 3085, 3029, 3007, 2962, 2903, 2871, 1979, 1784, 1696, 1604, 1496,
1458, 1391, 1359, 1251, 1210, 1126, 1110, 1065, 988 cmꢀ1; MS: m/z (%):
288 (100) [M+H]+, 206 (46), 178 (74); HRMS calcd for C17H22NO3
[M+H]+: 288.15997; found: 288.16032; elemental analysis calcd (%) for
C17H21NO3: C 70.81, H 7.69, N 4.86; found: C 70.94; H 7.58, N 4.99.
Compound (R)-24h: PDC (3.1 g) and molecular sieves (4 Š, 0.5 g,
8.34 mmol) were added to a solution of alcohol (R)-5g (1.0 g, 5.56 mmol)
in CH2Cl2 (55 mL). The suspension was stirred at room temperature for
6 h and then filtered through a pad of silica gel/celite (1:1) and washed
with Et2O. The crude was flash chromatographed to give a yellow oil that
upon distillation (958C, 0.2 mbar) afforded the aldehyde (R)-24h
[692 mg, 70%, Rf =0.8 (AcOEt/hexanes 20%), colorless oil]; [a]2D0: ꢀ7.9
ꢁ
ꢁ
(CH), 124.3 (CH), 103.6 (C ), 86.2 (C ), 78.7 (CH), 54.8 (CH), 42.3
(CH), 28.7 (CH2), 21.7 (CH2), 20.4 (CH2), 14.5 (CH3), 14.1 (CH3),
ꢀ0.1 ppm (CH3); IR (KBr): n˜ =3520, 3400, 3061, 3006, 2960, 2874, 2177,
1765, 1708, 1456, 1346, 1250, 1225, 1198, 1148, 1125, 1032, 979 cmꢀ1; MS:
m/z (%): 398 (3) [M+H]+, 382 (10), 354 (14), 250 (70), 221 (17), 206
(38); HRMS calcd for C23H32NO3Si [M+H]+: 398.21515; found:
398.21396.
1
(c=0.02 in CHCl3); H NMR (300 MHz, CDCl3, 258C, TMS): d=9.69 (s,
(4R,5S)-3-{(2S,4E)-6-Methyl-2-[3-(trimethylsilyl)prop-2-ynyl]hept-4-
1H), 5.49 (dd, 3J=15.3 and 6.6 Hz, 1H), 5.29 (dt, 3J=15.3 and 6.6 Hz,
enoyl}-4-methyl-5-phenyloxazolidin-2-one (23c): This compound was pre-
pared from 22c (3.77 g, 12.52 mmol) in the same way as 23b from 22b
[3.45 g, 67%, Rf =0.6 (EtOAc/hexanes 15%), pale yellow oil]; 1H NMR
(500 MHz, CDCl3, 258C, TMS): d=7.36 (m, 5H), 5.61 (d, 3J=7.3 Hz,
1H), 5.47 (dd, 3J=15.3, 6.6 Hz, 1H), 5.32 (m, 1H), 4.77 (m, 1H), 4.05
(m, 1H), 2.52 (m, 2H), 2.38 (m, 1H), 2.25 (m, 2H), 0.95 (d, 3J=6.8 Hz,
6H), 0.89 (d, 3J=6.6 Hz, 3H), 0.08 ppm (s, 9H); 13C NMR (75 MHz,
CDCl3, 258C, TMS): d=174.1 (CO), 152.6 (CO), 141.2 (CH), 133.3 (C),
128.7, 125.6 (CH), 122.6 (CH), 103.9 (C ), 86.1 (C ), 78.8 (CH), 54.9
(CH), 42.5 (CH), 34.6 (CH2), 31.0 (CH), 22.5 (CH3), 21.7 (CH2), 14.6
(CH3), 0.01 ppm (CH3); IR (CHCl3): n˜ =3673, 3549, 3032, 3009, 2961,
2871, 2457, 2363, 2175, 1779, 1699, 1456, 1385, 1344, 1250, 1195, 1145,
1121, 975 cmꢀ1; MS: m/z: 412 [M+H]+ (10), 397 (12), 250 (100); HRMS
calcd for C24H34NO3Si [M+H]+: 412.23080; found: 412.23204.
3
3
1H), 2.45–2.24 (m, 6H), 1.79 (t, J=2.6 Hz, 3H), 0.97 ppm (d, J=7.0 Hz,
6H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=203.5 (CO), 141.1
(CH), 122.2 (CH), 77.7 (C), 75.5 (C), 50.7 (CH), 31.2 (CH2), 30.4 (CH),
22.5 (CH3), 17.9 (CH2), 3.6 ppm (CH3); MS: m/z (%): 179 (17) [M+H]+,
163 (12) [M+HꢀCH4]+, 161 (23) [M+HꢀH2O]+, 149 (62)
[M+HꢀCH2O]+; HRMS: calcd for C12H19O 179.14359; found: 179.14375.
Compound (S)-24h: This compound was prepared from alcohol (S)-5g
(960 mg, 5.33 mmol) in the same way as (R)-24h from (R)-5g [682 mg,
72%, Rf =0.8 (20% AcOEt/hexanes), colorless oil]; [a]2D0: 7.9 (c=0.02 in
CHCl3).
ꢁ
ꢁ
(4S)-4-Benzyl-3-{(2R,4Z)-2-[3-(trimethylsilyl)prop-2-ynyl]hept-4-enoy-
l}oxazolidin-2-one (25b): This compound was prepared from (4S)-4-
benzyl-3-((Z)-hept-4-enoyl)oxazolidin-2-one (4.70 g, 16.37 mmol) in the
same way as 23b from 22b [5.02 g, 77%, Rf =0.4 (EtOAc/hexanes 15%),
pale yellow oil]; 1H NMR (500 MHz, CDCl3, 258C, TMS): d=7.28 (m,
5H), 5.49 (m, 1H), 5.28 (m, 1H), 4.68 (td, 3J=6.2 and 3.5 Hz, 1H), 4.16
(m, 2H), 3.98 (m, 1H), 3.30 (dd, 3J=13.4 and 2.9 Hz, 1H), 2.76 (dd, 3J=
13.4 and 9.5 Hz, 1H), 2.59 (d, 3J=6.5 Hz, 2H), 2.44 (m, 2H), 2.07 (m,
2H), 0.95 (t, 3J=7.5 Hz, 3H), 0.12 ppm (s, 9H); 13C NMR (125 MHz,
CDCl3, 258C, TMS): d=173.9 (CO), 152.9 (CO), 135.2 (C), 134.8 (CH),
134.7 (CH), 129.3 (CH), 128.8 (CH), 127.2 (CH), 124.4 (CH), 124.3
(4R,5S)-3-[(2S,4E)-2-(But-2-ynyl)-6-methylhept-4-enoyl]-4-methyl-5-
phenyloxazolidin-2-one (23g): This compound was prepared from 22c
(1.5 g, 4.8 mmol) and 1-bromobut-2-yne (1.75 mL, 19.2 mmol) in the
same way as 23b from 22b [1.2 g, 70%, Rf =0.5 (EtOAc/hexanes 15%),
pale yellow oil]; 1H NMR (400 MHz, CDCl3, 258C, TMS): d=7.38–7.26
(m, 5H), 5.58 (d, 3J=7.4 Hz, 1H), 5.45 (dd, 3J=15.2, 6.2 Hz, 1H), 5.30
3
(dt, J=15.6, 7.0 Hz, 1H), 4.75 (m, 1H), 3.98 (m, 1H), 2.48–2.16 (m, 5H),
1.67 (s, 3H), 0.92 (d, 3J=6.6 Hz, 6H), 0.86 ppm (d, 3J=6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3, 258C, TMS): d=174.4 (CO), 152.6 (CO),
140.9 (CH), 133.3 (C), 128.6 (CH), 125.5 (CH), 122.8 (CH), 78.7 (CH),
ꢁ
ꢁ
(CH), 103.6 (C ), 86.5 (C ), 65.9 (CH2), 55.2 (CH), 42.3 (CH), 37.9
(CH2), 28.4 (CH2), 21.8 (CH2), 20.5 (CH2), 14.1 (CH3), ꢀ0.1 ppm (CH3);
IR (KBr): n˜ =3010, 2962, 2925, 2868, 2358, 2176, 1782, 1699, 1456, 1387,
1350, 1288, 1250, 1208, 1105, 1053, 1011 cmꢀ1; MS: m/z (%): 398 (28)
[M]+, 206 (49), 222 (9), 178 (68); HRMS calcd for C23H32NO3Si [M]+:
398.21515; found: 398.21645.
ꢁ
ꢁ
77.0 (C ), 75.9 (C ), 54.7 (CH), 42.7 (CH), 34.4 (CH2), 30.9 (CH), 22.5
(CH3), 22.4 (CH3), 20.8 (CH2), 14.4 (CH3), 3.3 ppm (CH3); MS: m/z (%):
354 (88) [M+H]+, 338 (16) [M+HꢀCH4]+, 310 (70) [M+HꢀiPrH]+, 177
(100); HRMS calcd for C22H28NO3 [M+H]+: 354.20692; found:
354.20777.
A
din-2-one (25g): This compound was prepared from (4S)-4-benzyl-3-
[(E)-methylhept-4-enoyl]oxazolidin-2-one (4.98 g, 16.54 mmol) and 1-bro-
mobut-2-yne (3.0 mL, 33.08 mmol) in the same way as 23b from 22b to
yield compound 25g [4.28 g, 73%, Rf =0.5 (20% AcOEt/hexanes),
yellow oil]; 1H NMR (250 MHz, CDCl3, 258C, TMS): d=7.31 (m, 6H),
5.47 (dd, 3J=15.4, 6.31 Hz, H), 5.32 (dt, 3J=15.4, 6.6 Hz, 1H), 4.70 (m,
1H), 4.20 (d, 3J=5.2 Hz, 2H), 4.00 (q, 3J=7.0 Hz, 1H), 3.28 (dd, 3J=
(4S)-4-Benzyl-3-[(4E)-methylhept-4-enoyl]oxazolidin-2-one: This com-
pound was prepared from 21c (2.55 g, 17.93 mmol) in the same way as
22b from 21b but with use of (4S)-4-benzyloxazolidin-2-one [4.98 g,
94%, Rf =0.6 (30% AcOEt/hexanes), pale yellow oil]; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.35–7.19 (m, 5H), 5.52–5.36 (m,
2H), 4.66 (tdd, 3J=10.3, 6.9, 3.5 Hz, 1H), 4.21–4.12 (m, 2H), 3.28 (dd,
3J=13.4, 3.1 Hz, 1H), 3.11–2.89 (m, 2H), 2.76 (dd, 3J=13.3, 9.6 Hz, 1H),
2.41–2.34 (m, 2H), 2.24 (dc, 3J=13.1, 6.6 Hz, 1H), 0.96 ppm (d, 3J=
6.8 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=172.6 (CO),
153.3 (CO), 138.9 (CH), 135.2 (C), 129.3 (CH), 128.8 (CH), 127.2 (CH),
124.7 (CH), 66.0 (CH2), 55.0 (CH), 37.8 (CH2), 35.5 (CH2), 30.8 (CH),
27.1 (CH2), 22.4 ppm (CH3); MS: m/z (%): 302 (61) [M+H]+, 286 (6)
3
13.3, 3.2 Hz, 1H), 2.80 (dd, J=13.4, 9.2 Hz, 1H), 2.53–2.16 (m, 5H), 1.76
3
3
(t, J=2.5 Hz, 3H), 1.40 (s, 2H), 0.94 ppm (d, J=6.7 Hz, 6H); 13C NMR
(63 MHz, CDCl3, 258C, TMS): d=174.6 (CO), 153.0 (CO), 141.0 (CH),
135.2 (C), 129.4 (CH), 128.9 (CH), 127.3 (CH), 122.8 (CH), 77.2 (C), 76.1
(C), 65.9 (CH2), 55.2 (CH), 42.8 (CH), 37.8 (CH2), 34.5 (CH2), 30.9 (CH),
26.3 (CH3), 22.5 (CH3), 20.8 (CH2), 3.5 ppm (CH3); MS: m/z (%): 150 (1)
5148
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 5135 – 5150

Dienyne RCM Approach for the Construction of Taxosteroids
FULL PAPER
[M+H]+, 91 (100) [M+HꢀBn]+; HRMS: calcd for C21H28NO3:
Chem. 2005, 117, 4564–4601; Angew. Chem. Int. Ed. 2005, 44, 4490–
4527.
354.20692; found: 354.20704.
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CCDC-282836 (11e) and CCDC-624627 (11i10R) contain the supplemen-
tary crystallographic data for this paper. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgement
This work was supported by the Ministerio de Ciencia y Tecnología
(SAF2001—3120, SAF2004—01044) and the Xunta de Galicia (PGI-
DIT02PXIC20902PN). R.G.-F. thanks the Ministerio de Educación y
Ciencia (FPI) and M.J.A. the Ministerio de Educación y Ciencia (FPU)
for fellowships awarded.
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greater when neutral alumina was used to purify the crude reaction
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Juan R. Granja et al.
mixture than when silica gel was used; only a 9% yield of com-
pound 11a was obtained from 9b10R
[22] After purification on silica gel (see Ref. [21]).
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[24] Dienyne 9b10S was also prepared to confirm that configuration at
C10 is crucial for reactivity and that the 10S epimer is not suscepti-
ble to RCDEYM. To this end, iodide (R)-6b was prepared from al-
cohol (R)-5b (see Scheme 7) and used to alkylate the potassium ki-
netic enolate of 7, which, after allylation of resulting ketone, gave a
dienyne with spectroscopic characteristics identical to those of the
unreactive epimer of 9b obtained from the racemic mixture of 6b.
Subjection of this 9b10S derivative to RCM conditions with 10a as
catalyst afforded 13b in 87% yield together with a small amount of
triene 16b; no 11a was observed (Table 1, Entry 4).
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[28] All the conditions applied to obtain the diprotected silyl ether
failed, only affording the monoprotected silyl ether 9j10S
.
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[26] Note that the 10S series in 9h–j corresponds to the 10R series in
9a–g due to the presence of the C19 hydroxy group.
Received: November 24, 2006
Published online: March 23, 2007
5150
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Chem. Eur. J. 2007, 13, 5135 – 5150