Alkyne zip reaction in the synthesis of a taxoid C-ring

Article abstract of DOI:10.1002/1099-0690(200012)2000:24<4029::AID-EJOC4029>3.0.CO;2-0

Hydrazone 30, precursor of a taxoid C-ring, was synthesized in 7 steps from commercial 2-methyl-1,3-cyclohexanedione. An enantioselective approach to 30 was also investigated, using a reduction of diketone 11 with bakers' yeast to introduce enantioselecti

Full text of DOI:10.1002/1099-0690(200012)2000:24<4029::AID-EJOC4029>3.0.CO;2-0

FULL PAPER
Alkyne Zip Reaction in the Synthesis of a Taxoid C-Ring
[a]
[c]
Damien Bourgeois,[a] Joelle Prunet, Ange Pancrazi,*[b] Thierry Prange, and
´
¨
Jean-Yves Lallemand[a]
Keywords: Antitumor agents / Heterocycles / Natural products / Taxol / Total synthesis
Hydrazone 30, precursor of a taxoid C-ring, was synthesized
in 7 steps from commercial 2-methyl-1,3-cyclohexanedione.
An enantioselective approach to 30 was also investigated, us-
enantioselectivity. During the alkyne isomerization step, an-
ionic cyclizations of alkoxides and enolates onto the triple
bond were observed, and a thorough study of these reactions
ing a reduction of diketone 11 with bakers’ yeast to introduce is reported here.
Introduction
In our studies directed towards the total synthesis of anti-
tumor agents taxol (1) and taxotere (2)[1,2] we planned a
convergent retrosynthesis in which the key step was an ol-
efin metathesis to form the B-ring of these molecules
(Scheme 1). In a preceding paper,[3] we described the pre-
paration of seco-taxane 3 by coupling the vinyllithium de-
rived from hydrazone 5 with aldehyde 4, by a Shapiro reac-
tion. The diol formation was completely diastereoselective
and adduct 3 was obtained with the desired stereochemistry
for taxol at C-1 and C-2. Unfortunately, all attempts at
metathesis with derivatives of diol 3 were unsuccessful.[4]
We then turned our attention to a semiconvergent retro-
synthesis, in which the A-ring would be assembled during
the last steps by a pinacol coupling between ketone moieties
at C11 and C12.[2e] Formation of the eight-membered B-
ring would still be effected by an olefin metathesis reac-
tion.[5] A similar Shapiro reaction between hydrazone 5 and
acyclic aldehyde 7 was envisaged for the formation of seco-
taxane 6 (Scheme 1).
We wish to describe here an efficient, enantioselective
synthesis of ketone 8, precursor of hydrazone 5, from the
easily accessible diketone 11 (Scheme 2). The nontrivial iso-
merization step of 10 into 9, which led to side products
through anionic cyclizations of alkoxide and enolate inter-
mediates onto the alkyne function, is reported in detail.
Results and Discussion
Alkylation of commercial 1,3-diketone 12 furnished di-
keto propargylic derivative 11 (Scheme 3).[6] The expected
Scheme 1
[a]
`
Laboratoire de Synthese Organique, Ecole Polytechnique,
91128 Palaiseau Cedex, France
enantiopure hydroxy ketone 13 was obtained in Ͼ95% ee
according to the method of Brooks,[7] by enantioselective
reduction using bakers’ yeast. The isolated yield of 13 on a
large scale was only 33%, due to an arduous extraction fol-
lowed by a difficult separation from the starting diketone,
the other diastereomer (13/14 ϭ 3:1) and the diol resulting
from overreduction.
Fax: (internat.) ϩ 33 1 69333010
E-mail: Joelle.Prunet@polytechnique.fr
[b]
[c]
`
´
Laboratoire de Synthese Organique Selective et Chimie
´
Organometallique, UCP-ESCOM,
13 Bd de lЈHautil, 95092 Cergy-Pontoise, France
Fax: (internat.) ϩ 33 1 0130756186
´
´
Laboratoire de Chimie Structurale Biomoleculaire, Universite
Paris Nord,
74 rue Marcel Cachin, 93017 Bobigny, France
Eur. J. Org. Chem. 2000, 4029Ϫ4036
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/1224Ϫ4029 $ 17.50ϩ.50/0
4029

´
D. Bourgeois, J. Prunet, A. Pancrazi, T. Prange, J.-Y. Lallemand
FULL PAPER
Scheme 2
silica gel, produced lactol 21.[10] Hence, the intermediate
1
product was assigned, from its H and 13C NMR spectra,
as enol ether 20. The mechanism leading to these products
is discussed later in this paper.
In order to avoid the anionic cyclization of the alkoxide
onto the alkyne during the basic treatment needed for the
isomerization, we decided to protect the free alcohol as a
silyl ether. However, the only reaction observed on treat-
ment of the corresponding TBS ether with tBuOK in
DMSO was deprotection of the silyl ether, followed by an-
ionic cyclization of the resulting alkoxide. We next exam-
ined the case of ketone 15.[11] Treatment of 15 with tBuOK
in DMSO at room temperature required a stoichiometric
amount of base, and afforded the cyclic products 23, 24,
and 25. The desired acetylenic isomer 22 was not detected
(Scheme 6). Use of KH in DMF led to compounds 23, 24,
and 25 in poor yields, because of extensive degradation.
However, when this reaction was carried out under the
same conditions, except with diisopropylamine added as a
proton source, acetylenic product 22 was produced in 52%
yield. Compounds 23 and 24 were isolated in 8% and 4%
yields, respectively, while bicyclo derivative 25 was not de-
tected in this case. Having revealed the importance of the
proton source, we reverted to the previous conditions
(tBuOK in DMSO), with addition of tBuOH. Under these
conditions, reaction was complete within one hour; the ex-
pected acetylenic product 22 was obtained, but only in a
35% yield, along with 35% of 23. The moderate yields ob-
served for these reactions are due to degradation of com-
pound 22 in basic media; 22 has a half-life of 6 hours at
room temperature under tBuOK/DMSO conditions (none
of the other isomers 23, 24, 25, or even 15 were detected in
this case).
Scheme 3
We therefore decided to look into an efficient prepara-
tion, from diketone 11, of the racemic alkoxy derivative 10,
and to explore its conversion into 9. Monoketalization of
11 gave ketone 15; conversion did not exceed 70%, but the
product crystallized out of the reaction mixture and it was
possible to recycle the mother liquors, thus giving the de-
sired product in 85% yield after 3 cycles. This monoketone
was then reduced under various different conditions;[8] the
best result was finally obtained with LiAlH4 in toluene, fur-
nishing a 1:1 mixture of the expected derivative 16 and its
diastereomer 17 (Scheme 4). Both structures were assigned
by extensive NMR study.
Formation of compounds 18 and 20 can be explained by
attack of the oxygen atom of the intermediate alkoxides
onto the triple bond. Cyclizations of alcohols on triple
bonds have been thoroughly studied. The method most of-
ten used to effect such a reaction involves either stoichi-
Scheme 4
When treated with a catalytic amount of tBuOK in ometric salts of (for example) Ag, Hg, or W,[12] or catalytic
DMSO,[9] alcohol 16 did not produce the expected isomer- amounts of palladium catalysts.[13] An anionic cyclization
ized alkyne. However, enol ether 18 could be isolated in similar to ours had already been reported by Heathcock in
90% yield after rapid flash chromatography (Scheme 5). the synthesis of dihydromevinolin[14] and a mechanism has
Hydrolysis of 18 in acidic media led to hydroxy ketone 19 been proposed, for the case of a phenolate, by Kirby.[15]
(existing in an open form). The same treatment was also However, this reaction has seldom been used, although it
applied, at a slightly lower temperature, to isomer 17, and does not require any expensive or toxic reagent and it pro-
resulted in an unstable product which, after hydrolysis on ceeds under mild conditions.
4030
Eur. J. Org. Chem. 2000, 4029Ϫ4036

Alkyne Zip Reaction in the Synthesis of a Taxoid C-Ring
FULL PAPER
Scheme 5
Scheme 6
Compound 23 results from a cyclization of the oxygen (Scheme , path b). To the best of our knowledge, such an
atom of the intermediate enolate 26 onto the triple bond.[16] anionic C-cyclization of an enolate is unprecedented.
Endocyclic alkene 24 is not a product of cyclization of the
We have shown that addition of a proton source prevents
isomerized alkyne 22 (vide supra), but might derive from these cyclization reactions and promotes triple bond iso-
an isomerization of a precursor of 23, or from direct iso- merization. This could be rationalized with the mechanism
merization of 23 (Scheme 7, path a). All attempts to induce proposed below. A proton source appears to be necessary
isomerization of 23 into 24 resulted either in degradation to shift the IϪIIϪIII anionic equilibrium towards forma-
or in recovery of the starting material,[17] and we therefore tion of allene IV; the second anionic equilibrium VϪVI
suppose isomerization occurs on the intermediate vinylic might then lead after protonation to the expected isomeric
anion before reprotonation. For the methyl-1-bicyclo[3.3.1]- compound VII (Scheme 8).[18]
nonane 25, we also assume intermediate formation of the
In order to achieve an efficient preparation of the target
enolate, followed by C-cyclization on the triple bond ketone 8, we decided to protect the secondary alcohol of 16
Eur. J. Org. Chem. 2000, 4029Ϫ4036
4031

´
D. Bourgeois, J. Prunet, A. Pancrazi, T. Prange, J.-Y. Lallemand
FULL PAPER
the triple bond with Lindlar’s catalyst (Scheme 10). Hy-
drazone 30 was then obtained in 92% yield.
It is noteworthy that tBuOH did not facilitate the iso-
merization of 27 much (a temperature of 120 °C was still
necessary). However, in the presence of tBuOH, a substo-
ichiometric amount of tBuOK was sufficient and the reac-
tion was much cleaner, with fewer side products resulting
from DMSO decomposition. The harsh conditions required
for the isomerization process might be attributed to the dif-
ference in conformation between the sp2 and sp3 substituted
cyclohexanes, which might position the methylene moiety
of the propargyl side chain in a hindered position.
Scheme 7
In conclusion, we have shown that anionic cyclizations of
an alkoxide or an enolate onto a triple bond constitute an
Scheme 8
with a benzyl ether: a group commonly used for the C7
alcohol function of taxol.[2a] Protection proved to be tricky;
use of NaH in THF led to less than 10% conversion into
the protected product, while use of KH in DMF led to com-
plete cyclization. Finally, however, protection of a 1:1 mix-
ture of the two alcohols 16 and 17 using KH and BnBr in
refluxing THF with a catalytic amount of TBAI was found
to deliver benzyl derivative 27, as a pure isomer, in 48%
yield (Scheme 9). This result clearly illustrates the difference
in reactivity between the two diastereomers; under these
conditions, isomer 17 produces lactol 21, while the alkoxide
derived from isomer 16 does not cyclize and can hence be
protected in very good yield. This route proved to be prac-
tical on large scale (e.g., 10 g) as the laborious separation
of 16 and 17 by column chromatography was avoided (see
the Experimental Section for details).
Scheme 10
easy route to furan derivatives, and proved that this reaction
could be utilized advantageously for the diastereoselective
synthesis of derivative 27, by differentiating between dias-
tereomers 16 and 17. We have also demonstrated that the
isomerization of alkyne 27 to give alkyne 28 can be effected,
although under harsh conditions, leading to a C-ring pre-
cursor for the synthesis of taxol .
Experimental Section
Scheme 9
General Remarks: All air- and/or water-sensitive reactions were car-
ried out under argon atmosphere with dry, freshly distilled solvents,
using standard syringe-cannula/septa techniques. All correspond-
ing glassware was oven-dried (110 °C) and/or carefully dried in line
with a flameless heat gun.
Compound 27 required drastic conditions (stoichiometric
tBuOK, 120 °C in DMSO) for isomerization, but the ex-
pected acetylenic derivative 28 was produced in 88% yield
after purification. The desired ketone 29 was obtained after
1H NMR spectra were recorded in CDCl3 on a Bruker WP 200
(200 MHz) or on a Bruker AM 400 (400 MHz) instrument. The
hydrolysis of the ketal moiety and partial hydrogenation of chemical shifts are expressed in parts per million ϭ referenced to
4032 Eur. J. Org. Chem. 2000, 4029Ϫ4036

Alkyne Zip Reaction in the Synthesis of a Taxoid C-Ring
FULL PAPER
residual chloroform (δ ϭ 7.27). H,H-COSY and H,H-NOESY ex-
periments were routinely performed to ascertain HϪH connectivi-
ties and configuration assignments, respectively. 13C NMR spectra
were recorded on the same instruments at 50.3 MHz and
100.6 MHz, respectively. 13C NMR chemical shifts are expressed in
parts per million (ppm), reported from the central peak of de-
uteriochloroform (δ ϭ 77.14). J-modulated spin-echo technique (J-
mod) experiments were used for evaluating CH multiplicities.
15 h, then filtered, diluted with ether (100 mL), and quenched with
a saturated, aqueous NaHCO3 solution (15 mL). The aqueous layer
was extracted with ether (50 mL), and the combined organic layers
were washed successively with water (2 ϫ 10 mL) and brine
(10 mL), dried with MgSO4 and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (eluent:
Et2O/petroleum ether, 30:70) to yield 541 mg (71%) of 16 and
1
96 mg (19%) of recovered starting material 13. H NMR (CDCl3,
400 MHz): δ ϭ 4.01 (dt, 1 H, J ϭ 6.9, 3.6 Hz, 8-H), 3.66 (d, 1 H,
J ϭ 11.3 Hz, 2,4-Ha), 3.61 (d, 1 H, J ϭ 11.4 Hz, 2,4-Ha), 3.36 (dd,
1 H, J ϭ 11.3, 2.6 Hz, 2,4-Hb), 3.26 (dd, 1 H, J ϭ 11.4, 2.4 Hz, 2,4-
Hb), 3.30 (brs, 1 H, OH), 2.56 (d, 2 H, J ϭ 2.4 Hz, 1Ј-H), 2.04 (t,
1 H, J ϭ 2.8 Hz, 3Ј-H), 1.76Ϫ1.41 (br. m, 6 H, CH2), 1.25, 1.17 (2s,
6 H, CH3-3, CH3-7), 0.72 (s, 3 H, CH3-3). Ϫ 13C NMR (CDCl3,
100.6 MHz): δ ϭ 101.0 (6), 82.8 (2Ј), 73.5 (8), 70.8, 69.8, 69.1 (2,
4, 3Ј), 46.0 (7), 29.8 (3), 28.6 (1Ј), 23.9 (9), 23.3, 22.2 (2C, CH3-3),
21.1 (10), 17.2 (11), 14.4 (CH3-7). Ϫ IR (thin film): 3519, 3305,
2953, 2869, 2114, 1470, 1395, 1122, 1066, 1027. Ϫ MS (CI, NH3):
m/z 270 (MNH4ϩ), 253 (MHϩ), 235. Ϫ C15H24O3 (252.4): calcd. C
71.39, H 9.58; found C 71.22, H 9.53.
Mass spectra (MS) were obtained on a HewlettϪPackard HP
5989B spectrometer, either by direct introduction (chemical ionis-
ation, CI, NH3) or by GC/MS coupling with a Hewlett-Packard
HP 5890 chromatograph. Ϫ Infrared spectra (IR) were obtained
on a PerkinϪElmer FT 1600 instrument, using NaCl salt plates
(thin film) and are reported in terms of absorption frequency (ν˜,
cmϪ1). Ϫ Microanalyses were performed by the Service de Mic-
roanalyse, Institut de Chimie des Substances Naturelles, C.N.R.S.,
F-91198, Gif sur Yvette. Ϫ Flash chromatography was performed
on E. Merck silica gel Si 60 (40Ϫ63 mm, ref. 9385).
Tetrahydrofuran (THF) and diethyl ether were distilled from so-
dium/benzophenone, methanol from magnesium methoxide.
(7R*,8R*)-3,3,7-Trimethyl-7-prop-2-ynyl-1,5-dioxaspiro[5.5]-
undecan-8-ol (17). ؊ From Alcohol 14: To a solution of hydroxy
3,3,7-Trimethyl-7-prop-2-ynyl-1,5-dioxaspiro[5.5]undecan-8-one
(15): To a solution of diketone 11 (17.1 g, 0.10 mmol) and 2,2-di-
methylpropane-1,3-diol (15.6 g, 0.15 mmol) in CH2Cl2 (300 mL) (375 mg, 3.6 mmol) in CH2Cl2 (6 mL) over 3 A molecular sieves
ketone 14 (300 mg, 1.8 mmol) and 2,2-dimethyl-1,3-propanediol
˚
was added BF3·OEt2 (1.2 mL, 10 mol-%). The pink solution was
stirred at 20 °C for 2 h, quenched with triethylamine (10 mL), and
concentrated in vacuo. The resulting crude solid was triturated with
ether (50 mL), and filtered. The white paste was successively
was added BF3·OEt2 (20 µL, 0.15 mmol). The resulting mixture
was stirred at 20 °C for 15 h, then filtered, diluted with ether
(50 mL) and quenched with a saturated, aqueous NaHCO3 solu-
tion (10 mL). The aqueous layer was extracted with ether (50 mL),
washed with ethanol (2 ϫ 25 mL) and ether (50 mL) to yield 13.3 g and the combined organic layers were washed successively with
(51%) of 15 as a white solid. Repetition of the above procedure on
water (2 ϫ 10 mL) and brine (10 mL), dried with MgSO4 and con-
centrated in vacuo. The crude product was purified by flash chro-
matography on silica gel (Et2O/petroleum ether, 30:70) to yield
the mother liquors yielded successively 5.7 g (22%) and 2.9 g (11%)
1
of 15 (total yield 84%). Ϫ H NMR (CDCl3, 400 MHz): δ ϭ 3.62
(t, 2 H, J ϭ 11.4 Hz, 2-Ha, 4-Ha), 3.34 (dt, 2 H, J ϭ 11.0, 2.5 Hz,
320 mg (70%) of 17 and 59 mg (20%) of recovered starting material
1
2-Hb, 4-Hb), 2.83 (dd, 1 H, J ϭ 17.0, 2.7 Hz, 1Ј-H), 2.58 (dd, 1 H, 14. Ϫ H NMR (CDCl3, 400 MHz): δ ϭ 3.89 (dt, 1 H, J ϭ 10.9,
J ϭ 17.0, 2.8, 1Ј-H), 2.53Ϫ2.36 (br. m, 2 H, CH2), 2.22 (m, 2 H, 3.0 Hz, 8-H), 3.69 (d, 1 H, J ϭ 17.5 Hz, 2,4-Ha), 3.66 (d, 1 H, J ϭ
CH2), 1.95 (t, 1 H, J ϭ 2.7, 3Ј-H), 1.68 (m, 2 H, CH2), 1.37 (s, 3 17.3 Hz, 2,4-Ha), 3.57 (brd, 1 H, J ϭ 10.9 Hz, OH), 3.37 (dd, 1 H,
H, CH3), 1.15 (s, 3 H, CH3), 0.72 (s, 3 H, CH3-3). Ϫ 13C NMR J ϭ 10.3, 2.6 Hz, 2,4-Hb), 3.27 (dd, 1 H, J ϭ 10.3, 2.6 Hz, 2,4-Hb),
(CDCl3, 100.6 MHz): δ ϭ 209.7 (8), 101.9 (6), 81.7 (2Ј), 58.0 (7), 3.07 (dd, 1 H, J ϭ 16.7, 2.8 Hz, 1Ј-H), 2.54 (dt, 1 H, J ϭ 14.0,
70.2 (2, 4), 70.1 (3Ј), 36.8 (9), 29.7 (3), 23.3, 22.3 (2 C, CH3-3), 22.3 2.9 Hz, 9-Heq), 2.50 (dd, 1 H, J ϭ 16.7, 2.7 Hz, 1Ј-H), 1.96 (t, 1 H,
(1Ј), 21.1 (10, 11), 16.1 (CH3-7). Ϫ IR (thin film): 3239, 2870, 1717,
J ϭ 2.7 Hz, 3Ј-H), 1.78Ϫ1.51 (br. m, 4 H, H-10, 11-H), 1.37 (td, 1
1395, 1124, 1080. Ϫ MS (CI, NH3): m/z 268 (MNH4ϩ), 251 H, J ϭ 13.9, 4.5 Hz, 9-Hax), 1.15 (s, 3 H, CH3-3), 1.12 (d, 3 H,
(MHϩ).
J ϭ 0.6 Hz, CH3-7), 0.72 (s, 3 H, CH3-3). Ϫ 13C NMR (CDCl3,
100.6 MHz): δ ϭ 101.4 (6), 82.8 (2Ј), 72.6 (8), 69.7, 69.6, 69.1 (2,
4, 3Ј), 45.0 (7), 29.8 (3), 28.2 (1Ј), 23.3, 22.2 (2C, CH3-3), 21.6, 21.1
(9, 10), 19.0 (CH3-7), 16.5 (11). Ϫ IR (thin film): 3498, 3228, 2958,
2869, 2114, 1469, 1444, 1417, 1114, 1067, 1014, 913. Ϫ MS (CI,
NH3): m/z 270 (MNH4ϩ), 253 (MHϩ), 235. Ϫ C15H24O3 (252.4):
calcd. C 71.39, H 9.58; found C 71.27, H 9.59.
(7R*,8S*)-3,3,7-Trimethyl-7-prop-2-ynyl-1,5-dioxaspiro[5.5]-
undecan-8-ol (16). Starting from Ketone 15. ؊ Sodium Borohydride
Reduction: To a solution of 15 (300 mg, 1.2 mmol) in MeOH/
CH2Cl2, 2:1, (10 mL) was added portionwise sodium borohydride
(90 mg, 2.4 mmol). The resulting solution was stirred at 20 °C for
4 h, then diluted with ether (50 mL) and quenched with a saturated,
aqueous NH4Cl solution (5 mL). The phases were separated, and
the organic layer was washed with water (10 mL) and brine
(10 mL), dried with MgSO4, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (Et2O/
petroleum ether, 10:90) to yield 66 mg (22%) of pure 16 as a white
solid (m.p. 95Ϫ97 °C), 157 mg (52%) of pure 17 as a white solid
(m.p. 110Ϫ112 °C) and 40 mg (13%) of a mixture of 16 and 17.
(3aR*,7aS*)-3a,3Ј,3Ј-Trimethyl-2-methylene-2,3,5,6,7,7a-hexa-
hydrospiro[benzofuran-4,2Ј-[1,3]dioxane] (18): To a solution of 16
(50 mg, 0.2 mmol) in DMSO (1 mL) was added tBuOK (4 mg, ca.
0.2 equiv.). The resulting mixture was stirred at 60 °C for 15 h,
then cooled to room temperature, diluted with ether (50 mL) and
quenched with a saturated, aqueous NH4Cl solution (5 mL). The
layers were separated, and the organic layer was washed with water
(3 ϫ 5 mL) and brine (10 mL), then dried with MgSO4 and concen-
trated in vacuo. The crude product was quickly purified by flash
chromatography on silica gel (Et2O/petroleum ether, 50:50) to yield
Lithium Aluminium Hydride Reduction: See preparation of com-
pound 27.
1
From Alcohol 13: To a solution of hydroxy ketone 13 (500 mg,
45 mg (90%) of 18. Ϫ H NMR (CDCl3, 400 MHz): δ ϭ 4.26 (s, 1
3.0 mmol) and 2,2-dimethyl-1,3-propanediol (626 mg, 6.0 mmol) in
CH2Cl2 (10 mL) over 3-A molecular sieves was added BF3·OEt2
(37 µL, 0.3 mmol). The resulting mixture was stirred at 20 °C for
H, CH2-2), 3.98 (dd, 1 H, J ϭ 18.2, 8.4 Hz, 7a-H), 3.95 (s, 1 H,
CH2-2), 3.63 (d, 1 H, J ϭ 15.1 Hz, 4Ј,6Ј-Ha), 3.60 (d, 1 H, J ϭ
14.6 Hz, 4Ј,6Ј-Ha), 3.35 (dd, 1 H, J ϭ 15.0, 1.3 Hz, 4Ј,6Ј-Hb), 3.30
˚
Eur. J. Org. Chem. 2000, 4029Ϫ4036
4033

´
D. Bourgeois, J. Prunet, A. Pancrazi, T. Prange, J.-Y. Lallemand
FULL PAPER
(dd, 1 H, J ϭ 14.7, 1.2 Hz, 4Ј,6Ј-Hb), 3.05 (d, 1 H, J ϭ 17.2 Hz, 3- brown mixture was stirred at 20 °C for 12 h. It was then diluted
H), 2.51 (d, 1 H, J ϭ 16.7 Hz, 5-H), 2.16 (d, 1 H, J ϭ 17.0 Hz, 3-
with ether (50 mL) and quenched with water (5 mL). The layers
H), 1.88 (m, 1 H, 7-H), 1.69 (m, 1 H, 6-H), 1.60 (m, 1 H, 7-H), were separated, and the organic layer was washed with water (3 ϫ
1.30 (br. m, 2 H, H-5, 6-H), 1.12 (s, 3 H, CH3-5Ј), 0.96 (s, 3 H,
10 mL) and brine (10 mL), dried with MgSO4, and concentrated
CH3-3a), 0.73 (s, 3 H, CH3-5Ј). Ϫ 13C NMR (CDCl3, 100.6 MHz): in vacuo. The resulting crude product was then purified by flash
δ ϭ 162.2 (2), 99.8 (4), 82.0 (7a), 81.3 (CH2-2), 70.2, 70.0 (4Ј, 6Ј), chromatography (Et2O/petroleum ether, 10:90 Ǟ 20:80), giving suc-
49.0 (3a), 36.6 (3), 30.1 (5Ј), 23.8 (5), 22.9, 22.0 (2C, CH3-5Ј), 21.7 cessively 23 (50 mg, 50%), 24 (10 mg, 10%), and 25 (7 mg, 7%).
(7), 19.5 (6), 14.5 (CH3-3a). Ϫ MS (CI, NH3): m/z 252 (Mϩ), 209,
141, 122, 109.
With tBuOK/tBuOH/DMSO: To
a solution of 15 (100 mg,
0.4 mmol) and tBuOH (375 µL, 4.0 mmol, 10 equiv.) at room tem-
perature in dry DMSO (2 mL) was added, portionwise over 2 min,
tBuOK (54 mg, 0.5 mmol, 1.2 equiv.). The resulting brown mixture
(2R*,3aR*,7aR*)-2-Hydroxy-2,3a,3Ј,3Ј-tetramethyl-2,3,5,6,7,7a-
hexahydrospiro[benzofuran-4,2Ј-[1,3]dioxane] (21): To a solution of
17 (60 mg, 0.2 mmol) in DMSO (1 mL) was added tBuOK (5 mg, was stirred at 20 °C for 2 h. It was then diluted with ether (50 mL)
ca. 0.2 equiv.). The resulting mixture was stirred at 40 °C for 5 h,
then cooled to room temperature, diluted with ether (50 mL) and
quenched with a saturated, aqueous NH4Cl solution (5 mL). The
layers were separated, and the organic layer was washed with water
(3 ϫ 5 mL) and brine (10 mL), then dried with MgSO4 and concen-
trated in vacuo. The crude product was diluted with CH2Cl2, and
stirred with SiO2 (500 mg) for 1 h, then filtered, concentrated in
vacuo, and purified by flash chromatography on silica gel (Et2O/
petroleum ether, 50:50) to yield 57 mg (95%) of 21. Ϫ 1H NMR
(CDCl3, 200 MHz): δ ϭ 5.21 (d, 1 H, J ϭ 0.8 Hz, OH), 3.78Ϫ3.61
(bm, 3 H, 2Ј,4Ј-Ha, 7a-H), 3.41 (dd, 1 H, J ϭ 18.7, 2.6 Hz, 2Ј,4Ј-
He), 3.33 (dd, 1 H, J ϭ 18.5, 2.6 Hz, 2Ј,4Ј-He), 2.68 (d, 1 H, J ϭ
14.3 Hz, 3-H), 2.57 (m, 1 H, CH2), 1.97 (m, 1 H, CH2), 1.73 (d, 1
H, J ϭ 14.2 Hz, 3-H), 1.67Ϫ1.49 (bm, 4 H, CH2), 1.46 (d, 2 H, J ϭ
0.9 Hz, CH3-2), 1.22 (s, 3 H, CH3-3Ј), 1.07 (s, 3 H, CH3-3a), 0.75
(s, 3 H, CH3-3Ј). Ϫ 13C NMR (CDCl3, 100.6 MHz): δ ϭ 103.5 (2),
102.0 (4), 83.5 (7a), 69.6, 69.2 (2Ј, 4Ј), 49.5 (3), 43.1 (3a), 29.6 (3Ј),
27.5 (CH3-2), 25.3, 22.1 (5, 7), 23.5, 21.9, 20.7 (CH3-3Ј, CH3-3a),
17.3 (6). Ϫ IR (film): ν˜ (cmϪ1) 3394, 2950, 2670, 1463, 1394, 1377,
and quenched with water (5 mL). The layers were separated, and
the organic layer was washed with water (3 ϫ 10 mL) and brine
(10 mL), dried with MgSO4, and concentrated in vacuo. The re-
sulting crude product was then purified by flash chromatography
(Et2O/petroleum ether, 10:90 Ǟ 20:80), giving successively 23
(35 mg, 35%) and 22 (35 mg, 35%).
3,3,7-Trimethyl-7-prop-1-ynyl-1,5-dioxaspiro[5.5]undecan-8-one
1
(22): H NMR (CDCl3, 400 MHz): δ ϭ 3.73 (d, 1 H, J ϭ 11.4 Hz,
2Ј,4Ј-Ha), 3.47 (d, 1 H, J ϭ 11.3 Hz, 2Ј,4Ј-Ha), 3.45 (dd, 1 H, J ϭ
11.3, 2.6 Hz, 2Ј,4Ј-He), 3.28 (dd, 1 H, J ϭ 11.2, 2.6 Hz, 2Ј,4Ј-He),
2.95 (td, 1 H, J ϭ 13.6, 7.2 Hz, 6-H), 2.67 (dt, 1 H, J ϭ 14.2,
3.0 Hz, 5-H), 2.23 (brd, 1 H, J ϭ 14.0 Hz, 5-H), 2.13 (td, 1 H, J ϭ
13.7, 4.3 Hz, 6-H), 1.80 (s, 3 H, CH3ϪCC-2), 1.49 (dt, 1 H, J ϭ
13.2, 4.5 Hz, 4-H), 1.43 (dt, 1 H, J ϭ 13.4, 4.5 Hz, 4-H), 1.40, 1.12,
0.69 (3s, 9 H, CH3-2, CH3-3Ј). Ϫ 13C NMR (CDCl3, 100.6 MHz):
δ ϭ 205.9 (1), 101.7 (3), 81.0, 79.2 (CC-2), 70.8, 70.0 (2Ј, 4Ј), 55.6
(2), 36.3 (6), 29.6 (3Ј), 22.9, 22.0 (CH3-3Ј), 22.3, 18.5 (4, 5), 14.9
(CH3-2), 3.8 (CH3ϪCC-2). Ϫ IR (film): ν˜ (cmϪ1) 2956, 2869, 2248,
1731, 1454, 1396, 1365, 1237, 1178, 1133, 1084. Ϫ MS (IC, NH3):
m/z 251 (MHϩ), 180, 164, 141.
1265, 1110, 1054, 958, 892. Ϫ MS (IC, NH3): m/z 253 (MHϩ
Ϫ
H2O), 237, 141, 122.
3a,3Ј,3Ј-Trimethyl-2-methylene-3,3a,5,6-tetrahydro-2H-spiro-
[benzofuran-4,2Ј-[1,3]dioxane] (23): 1H NMR (CDCl3, 400 MHz):
δ ϭ 4.82 (t, 1 H, J ϭ 3.5 Hz, 7-H), 4.42 (t, 1 H, J ϭ 2.2 Hz, CH2-
2), 4.06 (t, 1 H, J ϭ 2.0 Hz, CH2-2), 3.75 (d, 1 H, J ϭ 11.3 Hz,
2Ј,4Ј-Ha), 3.67 (d, 1 H, J ϭ 11.3 Hz, 2Ј,4Ј-Ha), 3.44 (dd, 1 H, J ϭ
11.3, 2.7 Hz, 2Ј,4Ј-He), 3.37 (dd, 1 H, J ϭ 11.3, 2.7 Hz, 2Ј,4Ј-He),
3.25 (dt, 1 H, J ϭ 14.8, 1.8 Hz, 3-H), 2.20 (d, 1 H, J ϭ 14.7 Hz, 3-
H), 2.64 (dd, 1 H, J ϭ 14.5, 6.1 Hz, 5-He), 2.18 (dddd, 1 H, J ϭ
17.2, 6.9, 3.8, 1.1 Hz, 6-He), 2.04 (dddd, 1 H, J ϭ 17.2, 11.1, 6.8,
3.2 Hz, 6-Ha), 1.58 (ddd, 1 H, J ϭ 14.5, 11.1, 7.0 Hz, 5-Ha), 1.23
(d, 3 H, J ϭ 1.5 Hz, CH3-3a), 1.15, 0.75 (2s, 6 H, CH3-3Ј). Ϫ 13C
NMR (CDCl3, 100.6 MHz): δ ϭ 160.0, 157.7 (2, 8), 98.7 (4), 92.1
(7), 83.2 (CH2-2), 71.0, 70.3 (2Ј, 4Ј), 47.6 (3a), 34.5 (3), 29.9 (3Ј),
22.9, 22.8, 22.0 (CH3-3Ј, CH3-3a), 20.5, 18.5 (5, 6). Ϫ IR (film): ν˜
(cmϪ1) 2953, 2868, 1725, 1472, 1395, 1254, 1194, 1111, 1054, 954.
Procedures for Anionic Cyclizations. ؊ With KH/DMF: To a sus-
pension of degreased KH (35% in oil, 70 mg, 1.2 equiv.) at room
temperature in dry DMF (2.5 mL) was added, portionwise over
5 min, 15 (125 mg, 0.5 mmol). The resulting pink mixture was then
stirred at 40 °C for 5 h, during which time it turned brown. It was
then diluted with ether (50 mL) and quenched with water (5 mL).
The layers were separated, and the organic layer was washed with
water (3 ϫ 10 mL) and brine (10 mL), dried with MgSO4, and con-
centrated in vacuo. The resulting crude product was then purified
by flash chromatography (Et2O/petroleum ether, 10:90 Ǟ 20:80),
giving successively 23 (8 mg, 6%), 24 (25 mg, 20%), 25 (19 mg,
15%), and 15 (15 mg, 12%).
With KH/DMF/DIPA: To a suspension of degreased KH (35% in
oil, 125 mg, 1.2 equiv.) at room temperature in dry DMF (10 mL)
was added diisopropylamine (285 µL, 2.0 mmol, 2.0 equiv.), drop-
wise over 5 min, and 15 (250 mg, 1.0 mmol), portionwise. The re-
sulting orange mixture was then stirred at 60 °C for 15 h, during
which time it turned brown. It was then diluted with ether (100 mL)
and quenched with water (10 mL). The layers were separated, and
the organic layer was washed with water (3ϫ 10 mL) and brine
(10 mL), dried with MgSO4, and concentrated in vacuo. The re-
sulting crude product was then purified by flash chromatography
(Et2O/petroleum ether, 10:90 Ǟ 20:80), giving successively 23
(20 mg, 8%), 24 (10 mg, 4%), 22 (130 mg, 52%), and 15 (26 mg,
10%).
2,3a,3Ј,3Ј-Tetramethyl-5,6-dihydro-3aH-spiro[benzofuran-4,2Ј-[1,3]-
1
dioxane] (24): H NMR (CDCl3, 400 MHz): δ ϭ 5.05 (t, 1 H, J ϭ
1.1 Hz, 3-H), 4.95 (t, 1 H, J ϭ 3.6 Hz, 7-H), 3.72 (d, 1 H, J ϭ
11.2 Hz, 2Ј,4Ј-Ha), 3.58 (d, 1 H, J ϭ 11.3 Hz, 2Ј,4Ј-Ha), 3.44 (dd, 1
H, J ϭ 11.3, 2.6 Hz, 2Ј,4Ј-He), 3.39 (dd, 1 H, J ϭ 11.2, 2.6 Hz,
2Ј,4Ј-He), 2.61 (ddd, 1 H, J ϭ 14.6, 7.3, 1.3 Hz, 5-He), 2.23 (dddd,
1 H, J ϭ 17.5, 7.9, 3.2, 1.6 Hz, 6-He), 2.12 (dddd, 1 H, J ϭ 17.4,
9.9, 7.4, 4.1 Hz, 6-Ha), 1.61 (ddd, 1 H, J ϭ 14.6, 9.8, 8.0 Hz, 5-Ha),
1.90 (d, 3 H, J ϭ 1.3 Hz, CH3-2), 1.19, 1.16, 0.75 (3s, 9 H, CH3-3Ј,
CH3-3a). Ϫ 13C NMR (CDCl3, 100.6 MHz): δ ϭ 159.3 (7a), 152.1
(2), 103.9 (3), 99.1 (4), 94.1 (7), 70.9, 70.7 (2Ј, 4Ј), 53.4 (3a), 29.9
(3Ј), 25.1 (CH3-2), 22.8, 22.0 (CH3-3Ј), 20.4, 19.0 (5, 6), 13.7 (CH3-
With tBuOK/DMSO: To a solution of 15 (100 mg, 0.4 mmol) at
room temperature in dry DMSO (2 mL) was added, portionwise 3a). Ϫ IR (film): ν˜ (cmϪ1) 2954, 2865, 1715, 1664, 1471, 1454, 1434,
over 2 min, tBuOK (54 mg, 0.5 mmol, 1.2 equiv.). The resulting
1394, 1348, 1258, 1211, 1134, 1092, 1043, 935, 912, 821.
Eur. J. Org. Chem. 2000, 4029Ϫ4036
4034

Alkyne Zip Reaction in the Synthesis of a Taxoid C-Ring
FULL PAPER
(1R*,5S*)-1,3Ј,3Ј-Trimethylspiro[bicyclo[3.3.1]non-6-en-4,2Ј-[1,3]-
dioxane]-9-one (25): H NMR (CDCl3, 200 MHz): δ ϭ 5.77 (dt, 1
successively with water (3 ϫ 10 mL) and brine (20 mL), then con-
centrated in vacuo and dried with MgSO4. Purification by flash
chromatography (Et2O/petroleum ether, 10:90) yielded 380 mg of
1
H, J ϭ 11.4, 3.6 Hz, 8-H), 5.62 (ddt, 1 H, J ϭ 11.4, 6.4, 2.0 Hz, 7-
H), 3.76 (d, 1 H, J ϭ 11.2 Hz, 2Ј,4Ј-Ha), 3.57 (d, 1 H, J ϭ 11.2 Hz, 28 (88%) as a colourless oil. Ϫ 1H NMR (200 MHz, CDCl3): δ 7.43
2Ј,4Ј-Ha), 3.48 (dd, 1 H, J ϭ 11.2, 2.3 Hz, 2Ј,4Ј-He), 3.36 (dd, 1 H,
(d, 2 H, J ϭ 7.3 Hz, Ar-H), 7.34 (t, 2 H, J ϭ 7.4 Hz, Ar-H), 7.27
J ϭ 11.2, 2.3 Hz, 2Ј,4Ј-He), 3.01 (ddd, 1 H, J ϭ 19.0, 3.5, 1.7 Hz, (m, 1 H, Ar-H), 4.86 (d, 1 H, J ϭ 11.7 Hz, ArϪCH2ϪO), 4.66 (d,
4-H), 2.89 (dd, 1 H, J ϭ 5.9, 3.5 Hz, 6-H), 2.72Ϫ2.69 (m, 1 H, 5- 1 H, J ϭ 11.7 Hz, ArϪCH2ϪO), 3.75 (dd, 1 H, J ϭ 11.1, 4.7 Hz,
H), 2.12 (dt, 1 H, J ϭ 19.0, 2.5 Hz, 4-H), 1.79 (dd, 1 H, J ϭ 13.5, 8-H), 3.70 (d, 1 H, J ϭ 11.5 Hz, 2,4-Ha), 3.60 (d, 1 H, J ϭ 11.5 Hz,
4.1 Hz, 9-H), 1.70 (dt, 1 H, J ϭ 13.5, 3.5 Hz, 9-H), 1.61Ϫ1.58 (m, 2,4-Ha), 3.47 (m, 2 H, Hb-2, 4-Hb), 2.48 (d, 1 H, J ϭ 11.7 Hz, CH2),
1 H, 5-H), 1.22, 1.15, 0.72 (3s, 9 H, CH3-2Ј,4Ј,2). Ϫ 13C NMR
1.91 (s, 3 H, CH3-2Ј), 1.84 (m, 1 H, CH2), 1.55 (m, 1 H, CH2),
(CDCl3, 100.6 MHz): δ ϭ 129.4, 127.6 (7, 8), 103.3 (3), 70.6, 69.7 1.37, 1.26 (2s, 6 H, CH3-3, CH3-7), 1.46Ϫ1.21 (br. m, 3 H, CH2),
(2Ј, 4Ј), 55.6 (2), 46.6 (6), 40.5 (9), 29.6 (3Ј), 26.3 (4), 23.2, 22.2
0.75 (s, 3 H, CH3-3). Ϫ 13C NMR (50.3 MHz, CDCl3): δ 139.6
(CH3-3Ј), 19.6 (5), 15.2 (CH3-2). Ϫ IR (film): ν˜ (cmϪ1) 2955, 2869, (CϪCH2ϪO-8), 128.1, 127.5, 127.1 (5C, Ar), 100.8 (2C, 6, 1Ј), 83.5
1726, 1442, 1395, 1369, 1307, 1209, 1102, 1065, 1038, 908.
(2Ј), 81.2 (8), 73.2, 70.3, 69.7 (CH2ϪO-8, 2, 4), 47.7 (7), 30.1 (3),
26.7 (11), 22.8, 22.1 (CH3-3), 20.8 (9), 18.2 (10), 16.0 (CH3-7), 3.9
(CH3-2Ј). Ϫ IR (thin film): 3062, 3029, 2952, 2864, 2237, 1496,
1454, 1395, 1364, 1334, 1281, 1216, 1184, 1127, 1089, 969, 910. Ϫ
MS (CI, NH3): m/z 360 (MNH4ϩ), 343 (MHϩ), 257, 235, 141, 108,
91. Ϫ C22H30O3 (342.5): calcd. C 77.15, H 8.82; found C 77.24,
H 8.83.
(7R*,8S*)-8-Benzyloxy-3,3,7-trimethyl-7-prop-2-ynyl-1,5-dioxa-
spiro[5.5]undecane (27): To a suspension of LiAlH4 (380 mg,
10 mmol, 0.5 equiv.) in toluene (60 mL) was added, portionwise
over 15 min, ketone 15 (5.0 g, 20 mmol). The resulting mixture was
heated for 1 h at 70 °C (reaction was monitored by TLC with
MeOH/CH2Cl2, 2:98 as eluent) and then cooled to 0 °C, and
treated with methanol (10 mL, added carefully). The mixture was (7R*,8S*)-8-Benzyloxy-3,3,7-trimethyl-7-prop-1-enyl-1,5-dioxa-
diluted with ether (100 mL), and stirred overnight with a saturated,
aqueous Na,K-tartrate solution (Rochelle’s salt, 40 mL). The layers
were separated, the aqueous layer was extracted with ether (2 ϫ
100 mL), and the combined organic layers were washed successively
with water (50 mL) and brine (50 mL), then concentrated in vacuo
and dried with MgSO4. The crude product of the reaction was di-
luted with THF (40 mL), and added by cannula to a suspension of
KH (880 mg, 22 mmol, 1.1 equiv, from 2.5 g of a 35% suspension
of KH in mineral oil) in THF (40 mL) at room temperature. Benzyl
bromide (2.9 mL, 1.2 equiv.) and (NBu)4I (ca 500 mg, 10% weight)
were added, and the reaction mixture was heated at reflux for 2 h.
It was cooled to room temperature, and quenched with a saturated,
aqueous NH4Cl solution. The layers were separated, the aqueous
layer was extracted with ether (2 ϫ 100 mL), and the combined
organic layers were washed successively with 1  HCl (2 ϫ 50 mL),
water (50 mL), and brine (50 mL), then concentrated in vacuo and
dried with MgSO4. Purification by flash chromatography (Et2O/
petroleum ether, 10:90) yielded 3.3 g of 27 (48%) as a colourless
spiro[5.5]undecane (29): A solution of 28 (420 mg, 1.6 mmol) in
20 mL of AcOEt was stirred vigorously under a hydrogen atmo-
sphere with a catalytic amount of Lindlar catalyst (40 mg, 10%
weight) for 2 h. The resulting suspension was then filtered through
a pad of Celite and concentrated in vacuo. Purification by flash
chromatography (Et2O/petroleum ether, 20:80) yielded 410 mg
(98%) of 29 as a colourless oil. Ϫ 1H NMR (CDCl3, 200 MHz):
δ ϭ 7.35Ϫ7.25 (bm, 5 H, Ar-H), 5.49 (dq, 1 H, J ϭ 11.3, 7.0 Hz,
2Ј-H), 5.40 (dq, 1 H, J ϭ 11.4, 1.3 Hz, 1Ј-H), 4.59, 4.37 (2d, 2 H,
J ϭ 12.1 Hz, OϪCH2-Ar), 3.68 (m, 1 H, 3-H), 2.66 (m, 1 H, 6-H),
2.28 (m, 1 H, CH2), 1.98 (m, 3 H, CH2), 1.82 (m, 1 H, CH2), 1.48
(dd, 3 H, J ϭ 7.0, 1.3 Hz, CH3-2Ј), 1.26 (s, 3 H, CH3-2). Ϫ 13C
NMR (CDCl3, 100.6 MHz): δ ϭ 213.1 (1), 138.1 (OϪCH2ϪC),
133.1 (1Ј), 128.0, 127.9, 127.2, 126.6 (6 C, 2Ј, Ar), 85.8
(OϪCH2ϪAr), 70.5 (3), 55.6 (2), 38.7 (6), 23.8, 21.8 (4, 5), 19.1
(CH3-3Ј), 13.2 (CH3-2). Ϫ IR (film): ν˜ (cmϪ1) 2941, 1715, 1653,
1455, 1374, 1313, 1103, 949, 801. Ϫ MS (IC, NH3): m/z 276
(MNH4ϩ), 259 (MHϩ), 241, 167, 151, 108, 91.
1
oil. Ϫ H NMR (200 MHz, CDCl3): δ 7.43Ϫ7.25 (br. m, 5 H, Ar-
Triisopropylbenzenesulfonyl Hydrazone 30 Derived from Ketone 29:
To a solution of 29 (420 mg, 1.6 mmol) and triisopropylbenzenesul-
fonylhydrazine (600 mg, 2.0 mmol, 1.25 equiv.) in 4 mL of THF
was added ten drops of concentrated HCl. The resulting solution
was stirred at room temperature for 1 h, then diluted with ether
(80 mL) and quenched with a saturated, aqueous NaHCO3 solu-
tion (10 mL). The layers were separated, and the organic layer was
washed successively with water (2 ϫ 10 mL) and brine (10 mL),
dried with MgSO4, and concentrated in vacuo at 40 °C. The re-
sulting crude product was recrystallized from petroleum ether to
give 590 mg (68%) of trisylhydrazone 30 as a white solid (m.p.
35Ϫ37 °C). Purification of the mother liquors by flash chromato-
graphy (Et2O/petroleum ether, 20:80) yielded a further 210 mg
H), 4.60 (s, 2 H, ArϪCH2ϪO), 3.74 (dd, 1 H, J ϭ 10.6, 4.5 Hz, 8-
H), 3.69 (d, 1 H, J ϭ 11.3 Hz, 2,4-Ha), 3.58 (d, 1 H, J ϭ 11.6 Hz,
2,4-Ha), 3.35 (dd, 1 H, J ϭ 11.5, 2.5 Hz, 2,4-Hb), 3.33 (dd, 1 H,
J ϭ 11.6, 2.4 Hz, 2,4-Hb), 2.78 (dd, 1 H, J ϭ 17.0, 2.7 Hz, 1Ј-H),
2.65 (dd, 1 H, J ϭ 17.0, 2.6 Hz, 1Ј-H), 2.50 (m, 1 H, CH2), 2.00
(m, 1 H, CH2), 1.94 (t, 1 H, J ϭ 2.7 Hz, 3Ј-H), 1.61Ϫ1.19 (m, 4 H,
CH2), 1.26 (s, 3 H, CH3-3), 1.08 (s, 3 H, CH3-7), 0.73 (s, 3 H,
CH3-3). Ϫ 13C NMR (50.3 MHz, CDCl3): δ 140.0 (CϪCH2ϪO-8),
128.3, 127.9, 127.3 (5C, Ar), 101.6 (6), 85.4 (2Ј), 80.4 (8), 72.1, 70.3,
69.7, 68.1 (4C, CH2ϪO-8, 3Ј, 2, 4), 48.0 (7), 29.9 (3), 26.6 (1Ј),
23.9, 22.7 (2C, CH3-3), 23.3 (11), 21.6, 18.7 (2C, 9, 10), 15.0 (CH3-
7). Ϫ IR (thin film): 3299, 2952, 2865, 2115, 1720, 1453, 1394, 1362,
1210, 1163, 1111, 1090, 1047, 1027, 969. Ϫ MS (CI, NH3): m/z 360
(MNH4ϩ), 343 (MHϩ), 257, 235, 197, 150.
1
(24%) of 30. Ϫ H NMR (CDCl3, 400 MHz): δ ϭ 7.47 (brs, 1 H,
NH), 7.29Ϫ7.20 (m, 5 H, Ar-H), 7.16 (s, 2 H, Ar), 5.35 (dq, 1 H,
J ϭ 11.6, 7.2 Hz, 2Ј-H), 5.21 (dq, J ϭ 11.6, 1.7 Hz, 1Ј-H), 4.50 (d,
1 H, J ϭ 12.2 Hz, OϪCH2ϪAr), 4.32 (d, 1 H, J ϭ 12.2 Hz,
OϪCH2ϪAr), 4.26 (sept, 2 H, J ϭ 6.7 Hz, CHϪAr), 3.40 (brs, 1
H, 3-H), 2.92 (sept, 1 H, J ϭ 6.9 Hz, CHϪAr), 2.52 (dt, 1 H, J ϭ
14.0, 4.1 Hz, CH2), 1.97 (td, 1 H, J ϭ 12.5, 5.9 Hz, CH2),
(7R*,8S*)-8-Benzyloxy-3,3,7-trimethyl-7-prop-1-ynyl-1,5-dioxa-
spiro[5.5]undecane (28): To a solution of 27 (430 mg, 1.2 mmol) in
DMSO (5 mL) with tBuOH (1.5 mL) was added tBuOK (40 mg,
30 mol-%), and the resulting mixture was stirred at 120 °C for 2 h.
It was then cooled to room temperature, diluted with ether
(100 mL) and quenched with a saturated, aqueous NH4Cl solution. 1.90Ϫ1.64 (br. m,
4
H, CH2), 1.29, 1.28, 1.28, 1.26
The layers were separated, the aqueous layer was extracted with
ether (2ϫ 50 mL), and the combined organic layers were washed
[(CH3)2ϪCHϪAr], 1.19 (dd, 3 H, J ϭ 7.4, 1.8 Hz, CH3-2Ј), 1.17 (s,
3 H, CH3-2). Ϫ 13C NMR (CDCl3, 100.6 MHz): δ ϭ 160.8 (1),
Eur. J. Org. Chem. 2000, 4029Ϫ4036
4035

´
D. Bourgeois, J. Prunet, A. Pancrazi, T. Prange, J.-Y. Lallemand
FULL PAPER
1997, 119, 2755. P. A. Wender, N. F. Badham, S. P. Conway, P.
E. Floreancig, T. E. Glass, J. B. Houze, N. E. Krauss, D. Lee,
D. G. Marquess, P. L. McGrane, W. Meng, M. G. Natchus, A.
J. Shuker, J. C. Sutton, R. E. Taylor, J. Am. Chem. Soc. 1997,
119, 2757. Ϫ [2e] T. Mukaiyama, I. Shiina, H. Iwadare, M. Sai-
toh, T. Nishimura, N. Ohkawa, H. Sakoh, H. Nishimura, Y.-I.
152.7, 151.4 (Ar), 138.7 (OϪCH2ϪC), 134.2 (1Ј), 132.1 (Ar), 128.0,
127.4, 127.2, 126.0 (Ar), 123.4 (2Ј), 84.4 (OϪCH2ϪAr), 71.1 (3),
50.0 (2), 34.1 (CHϪAr), 29.7 (CHϪAr), 24.7, 23.4
((CH3)2ϪCHϪAr), 24.5, 23.4, 20.0 (4, 5, 6), 21.0 (CH3-2Ј), 13.0
(CH3-2). Ϫ IR (film): ν˜ (cmϪ1) 2959, 1600, 1455, 1361, 1318, 1164,
1107. Ϫ MS (IC, NH3): m/z 539 (MHϩ), 449, 300, 276, 259, 151,
108, 91.
Tani, M. Hasegawa, K. Yamada, K. Saito, Chem. Eur. J. 1999,
[2f]
5, 121. Ϫ
K. Morihara, R. Hara, S. Kawahara, T. Nishi-
mori, N. Nakamura, H. Kusama, I. Kuwajima, J. Am. Chem.
Soc. 1998, 120, 12980.
[3]
[4]
D. Bourgeois, J. Y. Lallemand, A. J. Pancrazi, Prunet, Synlett
1999, 10, 1555Ϫ1558.
Acknowledgments
We gratefully acknowledge financial support from the CNRS
(UMR 7652) and the Ecole Polytechnique.
For recent reviews on RCM see the following for leading refer-
[4a]
ences:
R. H. Grubbs, S. Chang, Tetrahedron 1998, 54,
[4b]
4413Ϫ4450. Ϫ
M. Schuster, S. Blechert, Angew. Chem. Int.
[4c]
Ed. Engl. 1997, 36, 2036Ϫ2056. Ϫ
S. K. Armstrong, J.
Chem. Soc., Perkin Trans. 1 1998, 371Ϫ388.
[1] [1a]
M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon, A. T.
[5]
For preliminary results, see: D. Bourgeois, A. Pancrazi, J.
Prunet, L. Ricard, Angew. Chem. Int. Ed. Engl. 2000, 725Ϫ728.
W. G. Dauben, D. J. Hart, J. Org. Chem. 1977, 42, 3787Ϫ3793.
D. W. Brooks, H. Mazdiyasni, P. G. Grothaus, J. Org. Chem.
1987, 52, 3223Ϫ3232.
[1b]
McPhail, J. Am. Chem. Soc. 1971, 93, 2325Ϫ2327. Ϫ
ACS
Symposium Series 583, Taxane Anticancer Agents: Basic Sci-
ence and Current Status (Eds.: G. I. Georg, T. T. Chen, I.
Ojima, D. M. Vyas); American Chemical Society, Washington
[6]
[7]
´
´
D.C., 1995. F. Lavelle, F. Gueritte-Voegelein, D. Guenard, Bull.
For a discussion of the reduction conditions, see ref.[3]
Isomerization of terminal alkynes under base-catalysed condi-
tions is well documented; see for instance: L. Brandsma, Pre-
parative acetylenic chemistry, Elsevier, 1988, 231.
The data of X-ray structure analysis were deposited as CIS
archive files CCDC-151246 with the Cambridge Crystallo-
graphic Data Centre (CCDC, 12 Union Road, Cambridge CB2
1EZ, UK). They are also available from the authors by E-mail:
prange@lure.u-psud.fr
[8]
[9]
´
´
Cancer 1993, 80, 326Ϫ338. D. Guenard, F. Gueritte-Voegelein,
P. Potier, Acc. Chem. Res. 1993, 26, 160Ϫ167 and references
cited therein.
Total syntheses:
[2]
[2a]
K. C. Nicolaou, Z. Yang, J. J. Liu, H.
[10]
Ueno, P. G. Nantermet, R. K. Guy, C. F. Claiborne, J. Renaud,
E. A. Couladouros, K. Paulvannan, E. J. Sorensen, Nature
1994, 367, 630. K. C. Nicolaou, P. G. Nantermet, H. Ueno, R.
K. Guy, E. A. Couladouros, E. J. Sorensen, J. Am. Chem. Soc.
1995, 117, 624. K. C. Nicolaou, J. J. Liu, Z. Yang, H. Ueno,
E. J. Sorensen, C. F. Claiborne, R. K. Guy, C. K. Hwang, M.
Nakada, P. G. Nantermet, J. Am. Chem. Soc. 1995, 117, 634.
K. C. Nicolaou, Z. Yang, J. J. Liu, P. G. Nantermet, C. F.
Claiborne, J. Renaud, R. K. Guy, K. Shibayama, J. Am. Chem.
Soc. 1995, 117, 645. K. C. Nicolaou, H. Ueno, J. J. Liu, P. G.
[11]
[12]
Alcohol 16 is the compound needing to be isomerized in the
optically pure route envisaged for 8 (see ref.[3]), and therefore
we did not initially investigate ketone 15.
P. Pale, J. Chuche, Tetrahedron Lett. 1987, 28, 6447Ϫ6448, and
references therein; F. E. McDonald, J. L. Bowman, Tetrahedron
Lett. 1996, 37, 4675Ϫ4678.
S. Schalbert, E. Schaumann, Eur. J. Org. Chem. 1998,
1873Ϫ1878, and references therein.
S. J. Hecker, C. H. Heathcock, J. Am. Chem. Soc. 1986, 108,
4586Ϫ4594.
C. M. Evans, A. J. Kirby, J. Chem. Soc., Perkin Trans. 1I
1984, 1269Ϫ1275.
D. I. McGee, J. D. Leach, S. Setiadji, Tetrahedron 1999, 55,
2847Ϫ2856.
Nantermet, Z. Yang, J. Renaud, K. Paulvannan, R. Chadha,
[2b]
[13]
[14]
[15]
[16]
[17]
[18]
J. Am. Chem. Soc. 1995, 117, 653. Ϫ
R. A. Holton, C.
Somoza, H. B. Kim, F. Liang, R. J. Biediger, P. D. Boatman,
M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki, C.
Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentile, J.
H. Liu, J. Am. Chem. Soc. 1994, 116, 1597. R. A. Holton, H.
B. Kim, C. Somoza, F. Liang, R. J. Biediger, P. D. Boatman,
M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki, C.
Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentile, J.
H. Liu, J. Am. Chem. Soc. 1994, 116, 1599. Ϫ [2c] J. J. Masters,
The conditions tested were: cat. PPTS in EtOH, cat. I2 in Et2O,
RhCl(PPh3)4 in THF, and tBuLi in refluxing hexane.
The acetylene/allene isomerization mechanism has been de-
scribed many times. See for example: H. Hopf, Chem. Ber.
1971, 104, 3087Ϫ3095.
J. T. Link, L. B. Snyder, W. B. Young, S. Danishefsky, Angew.
[2d]
Chem. Int. Ed. Engl. 1995, 34, 1723. Ϫ
P. A. Wender, N. F.
Badham, S. P. Conway, P. E. Floreancig, T. E. Glass, C.
Gränicher, J. B. Houze, J. Jänichen, D. Lee, D. G. Marquess, P.
L. McGrane, W. Meng, T. P. Mucciaro, M. Mühlebach, M. G.
Natchus, H. Paulsen, D. B. Rawlins, J. Satkofsky, A. J. Shuker,
J. C. Sutton, R. E. Taylor, K. Tomooka, J. Am. Chem. Soc.
Received May 5, 2000
[O00240]
4036
Eur. J. Org. Chem. 2000, 4029Ϫ4036