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Journal ArticleDOI

A short and convenient way to produce the Taxol A-ring utilizing the Shapiro reaction

11 Mar 2002-Tetrahedron (Pergamon)-Vol. 58, Iss: 11, pp 2175-2181

AbstractThe Shapiro reaction was utilized in an efficient route to a Taxol™ A-ring building block. Commercially available 2-methyl-1,3-cyclohexanedione was converted in three simple steps to various arenesulfonylhydrazones and then to the target molecule with the Shapiro reaction. Remarkable differences were observed in the reactivity and stability of different hydrazones and their dianions in the Shapiro reaction. This pathway is the shortest one reported to give the target molecule in good overall yield. The use of different electrophiles in the final Shapiro reaction step allows alternative ways to prepare the target alcohol.

Topics: Shapiro reaction (70%)

Summary (1 min read)

1. Introduction

  • The authors have earlier reported their entries to the side chain 2 6 and the C-ring precursor 4.
  • The use of intramolecular electrophiles allows preparation of cyclic products with high stereoselectivity.
  • The route involves only four steps and proceeds with high yields.

2. Results and discussion

  • Methylation (13a!14a) was incomplete in these experiments.
  • Also, TMEDA/hexane was impracticable here because of strong salt formation between CH 3 I and TMEDA.

3. Conclusions

  • Taxole A-ring building block 10 was synthesized with a novel and short method consisting of only four steps with high 38% overall yield.
  • Tosylhydrazone 9a was found to be the best of the studied arylhydrazones in Shapiro reaction allowing the formation of stable dianions and complete methylation.
  • Evidence of the possible effect of steric hindrance was observed in the preparation and reactivity of hydrazones.
  • Protonation of the vinyl anion by THF remained problematic to some extent giving always some protonated vinyl anion.
  • This can be minimized with rapid decomposition of dianion 15a at room temperature followed by immediate addition of the electrophile.

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Törmäkangas, O.P.; Toivola, R.J.; Karvinen, E.K.; Koskinen, A.M.P.
A short and convenient way to produce Taxol A-ring utilizing the Shapiro-reaction
Published in:
Tetrahedron
DOI:
/10.1016/S0040-4020(02)00089-3
Published: 01/01/2002
Document Version
Peer reviewed version
Published under the following license:
CC BY-NC-ND
Please cite the original version:
Törmäkangas, O. P., Toivola, R. J., Karvinen, E. K., & Koskinen, A. M. P. (2002). A short and convenient way to
produce Taxol A-ring utilizing the Shapiro-reaction. Tetrahedron, 58, 2175-2181. https://doi.org//10.1016/S0040-
4020(02)00089-3

A short and convenient way to produce the Taxole A-ring
utilizing the Shapiro reaction
Olli P. To
È
rma
È
kangas,
a
Reijo J. Toivola,
b
Esko K. Karvinen
c
and Ari M. P. Koskinen
a,p
a
Laboratory of Organic Chemistry, Helsinki University of Technology, P.O. Box 6100, FIN-02015 Espoo, HUT, Finland
b
Department of Chemistry, University of Oulu, P.O. Box 3000, FIN-90014 Oulu, Finland
c
Neste Chemicals Oy, Technology Center, P.O. Box 310, FIN-06101 Porvoo, Finland
AbstractÐThe Shapiro reaction was utilized in an ef®cient route to a Taxole A-ring building block. Commercially available 2-methyl-1,3-
cyclohexanedione was converted in three simple steps to various arenesulfonylhydrazones and then to the target molecule with the Shapiro
reaction. Remarkable differences were observed in the reactivity and stability of different hydrazones and their dianions in the Shapiro
reaction. This pathway is the shortest one reported to give the target molecule in good overall yield. The use of different electrophiles in the
®nal Shapiro reaction step allows alternative ways to prepare the target alcohol. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Synthetic preparation of Taxol 1 is still under intensive
investigation due to its extremely low availability from
nature (bark of Paci®c yew tree Taxus brevifolia) and
growing shortage in treatment against a number of mam-
malian cancers.
1
Semisynthesis of Taxole from 10-
deacetylbaccatin III, readily available from the needles of
Taxus baccata, has provided some amelioration against lack
of Taxol.
2
Several different strategies to Taxole A-ring
fragments have been developed utilizing Diels±Alder
reaction,
3
modi®cation of cyclohexanones
4
and ene-
reaction
5
as the most common methods.
Our retrosynthetic strategy for Taxole is shown in
Scheme 1. We have earlier reported our entries to the side
chain 2
6
and the C-ring precursor 4.
7
Compound 5 has been
utilized successfully as an A-ring precursor in the total
synthesis of Taxole by Nicolaou et al.
8
The Shapiro reaction is an ef®cient way to create a new C±C
bond to the carbonyl carbon of ketones simultaneously
introducing a vinylic moiety into the product. In the Shapiro
reaction the ketone derived hydrazone is converted to a
dianion using an alkyl lithium base and then decomposed
directly to the vinyl anion.
9
The vinyl anion can also be
alkylated to introduce a substituent to the neighboring
Keywords: Shapiro reaction; Taxol; shortest synthetic pathway.
Ph
CO
2
R
NHBz
OH
OHC
O
O
X
OHC
MeO
2
C
OPh
O
OH
AcO
HO OBz
OAc
O
O
BzHN
OH
O
RO
1
2
3
4
5
Scheme 1. Retrosynthetic analysis of Taxole and the role of A-ring building block.
Author's accepted manuscript, published in Tetrahedron 58 (2002) 2175-2181

carbon atom. The lithiated vinyl anion reacts readily with
electrophiles allowing an easy entry to the ®nal product. The
use of intramolecular electrophiles allows preparation of
cyclic products with high stereoselectivity.
10
In this paper we report the shortest and simplest synthesis of
a Taxole A-ring fragment utilizing the Shapiro reaction as
the key step. The route involves only four steps and
proceeds with high yields.
2. Results and discussion
The synthesis plan for the A-ring precursor 10 is shown in
Scheme 2. We have earlier reported the ®rst two steps in a
complementary and longer route to the Taxole A-ring
block.
4d
Herein we optimized those steps and the product,
monoketal 8, was used as the starting material in the
preparation of the hydrazones 9a±c. The Shapiro reaction
of 9a±c and related hydrazones 12a±b was investigated
carefully.
Methylation of commercially available 2-methyl-1,3-cyclo-
hexanedione 6 was carried out with K
2
CO
3
/CH
3
Iin
acetone.
11
The product mixture contained 85% of the
desired 7 and 15% of 3-methoxy-2-methyl-cyclohex-2-
enone as the side product (ratios based on GC analysis).
The crystalline side product was ®ltered off and recycled
to the enol form of the starting material 6 by treatment with
2 M HCl in CH
2
Cl
2
. Diketone 7 was isolated in 99% purity
when CH
2
Cl
2
was used as the solvent in the extraction. If
toluene was used instead of CH
2
Cl
2
the product had to be
distilled (103±1048C; 13 mmHg) in order to obtain suf®-
cient purity. Dimethylation of cyclohexane-1,3-dione
directly to 7 was also attempted but the yield was rather
low (40%) and more side products were observed.
Selective monoketalization of pure 2,2-dimethyl-1,3-cyclo-
hexadione 7 was achieved by treatment with 2,2-dimethyl-
1,3-propanediol and 1 mol% of p-TsOH in CH
2
Cl
2
with
azeotropic removal of water.
12
Traces of two side products
were observed but no diketalized dione.
In the beginning of this work, we wanted to study the
reactivity of different electrophiles in the Shapiro reaction.
The aim was to use tosyl 12a and trisylhydrazone 12b
(Scheme 3) as model compounds. Ketone 8 was ®rst
converted (LDA/CH
3
I) to the methylated ketone 11 in
66% yield. However, preparation of the arylsulfonylhydra-
zones from ketone 11 proved to be impossible or extremely
slow. No product was observed in the case of 12b and only
traces of product was formed in the case of 12a even after
24 h. The steric hindrance caused by the methyl groups in
the a-position obviously retards the reaction. With HCl as
acid catalyst, only deketalization of 11 was observed.
We decided to use sterically less hindered hydrazones 9a±c
(of ketone 8) as model compounds (Scheme 2) in order to
uncover the limitations in the Shapiro reaction. Addition-
ally, the use of hydrazones 9a±c instead of hydrazones
12a±b provides one step shorter reaction pathway. All
stable hydrazones 9a±c were prepared in excellent yields.
Typically hydrazones are prepared under concentrated
conditions so that all starting material and reagent hardly
O
O
OO
O
O
O
N
O
O
H
N
S
O
O
R
O
O
HO
R'
R'
ab
c
d
67(69%) 8 (94%)
9a R=CH
3
, R'=H
b R=R'=CH
3
c R=R'=CH
(
CH
3
)
10 (62% from 9a)
(92%
)
(79%
)
(94%
)
Scheme 2. Synthesis of Taxole A-ring block via tosylhydrazone 9a. Reagents and conditions: (a) K
2
CO
3
,CH
3
I, acetone, rfx, 8 h; (b) CH
2
Cl
2
,
Me
2
C(CH
2
OH)
2
, p-TsOH£H
2
O, CH
2
Cl
2
, rfx, 7 h; (c) EtOH (THF in 9b), hydrazide, 1408C 16 min, then rt 6 h; (d) THF, 2508C, n-BuLi, 30 min, CH
3
I,
30 min, n-BuLi, from 2508C to rt, 25 min, paraformaldehyde, 30 min.
RS
O
O
H
N
N
O
O
O
O
O
R'
R'
8
a
b
11
12 a R=CH
3
, R'=H
b R=R'=CH
(
CH
3
)
2
Scheme 3. Reagents and conditions: (a) LDA, THF, 2788C, CH
3
I, 08C then rt; (b) hydrazide, EtOH, (HCl).

dissolve in the solvent.
13
Also a small excess of hydrazine
(105±110 mol%) is usually required to run the reaction to
completion. If the ketone used is sterically hindered,
addition of a catalytic amount of HCl, re¯uxing the reaction
mixture and longer reaction time are sometimes needed.
14
Here, under optimized reaction conditions to prepare 9a±c,
the reaction mixture is ®rst heated up to 130 to 1408C until
complete dissolution is achieved and then allowed to react at
room temperature (too high reaction temperatures caused
partial decomposition of the product even at 1508C). The
use of acid catalyst was not necessary. Absolute EtOH was
found to be the best solvent in the preparation of tosyl-
hydrazone 9a and trisylhydrazone 9c allowing a
spontaneous crystallization of the hydrazones from the
reaction mixture. The preparation of 9a was carried out
also in THF and MeOH successfully but in lower yields.
Additionally, the reaction was slightly slower and the
hydrazone did not crystallize out from the reaction mixture.
Mesitylhydrazone 9b was prepared only in THF.
Differences in the stabilities of hydrazones 9a±c during
storage were also observed. Tosylhydrazone 9a seems to
be very stable and can be stored at 148C for a few years
under argon. Trisylhydrazone 9c decomposed partly under
similar conditions giving yellowish color in a few months.
The stability of mesitylhydrazone 9b during the storage was
close to that of tosylhydrazone 9a.
Detailed description of the Shapiro reaction is described in
Scheme 4. Hydrazone 9 was ®rst treated with 220 mol% of
n-BuLi in order to prepare dianion 13. The ®rst hydrogen
removed is the one located on nitrogen and this monoanion
is usually colorless. Addition of another equivalent of butyl
lithium gives a beautiful deep red color. The dianion was
methylated quantitatively to 14 with CH
3
Iat2508C
(internal temperature). The second addition of n-BuLi at
2508C gives dianion 15 which can be observed as a slightly
orange color. When this dianion is heated to room
temperature it slowly decomposes to vinyl anion 16. The
decomposition can be easily observed as the formation of
small bubbles when N
2
is liberated. An electrophile must be
added immediately when the gas formation has ceased
especially if THF is used as the solvent in order to avoid
possible protonation of vinyl anion 16 by THF.
The strength of the used alkyl lithium base in the
Shapiro reaction is also crucial.
15
Stronger bases like
t-BuLi are sometimes required in the deprotonation. In
our case the formation of dianion 15 from 14 can be carried
out easily with n-BuLi. However, t-BuLi gave similar
results.
We initially studied the Shapiro reaction with trisylhydra-
zone 9c which was treated with t-BuLi at 2788C in THF and
formation of the ®rst dianion 13c was observed as a red
color (Scheme 4). The dianion of trisylhydrazone was
found to be too labile even at 2788C and decomposition
was observed. Methylation of the dianion was carried out at
2788C as well as the preparation of the second dianion 15c,
followed by heating to 08C and quenching by D
2
O. In the
product mixture there was only 7.5% of compound 17 where
methylation proceeded successfully at the a-carbon and
then decomposed to vinyl anion and captured with
deuterium. The main product was 19 (57% of product
mixture) which indicates that the dianion had not reacted
with CH
3
I at all but decomposed to vinyl anion and was
trapped later with deuterium. The presence of product 20
was a clear evidence of premature decomposition of dianion
13c to its vinyl anion. N
2
evolution was also observed
already at 2458C which indicates the decomposition of
the dianion to the vinyl anion.
RS
O
O
H
N
N
O
O
RS
O
O
NN
O
O
RS
O
O
NN
O
O
RS
O
O
NN
O
O
O
O
Li
R'
R'
R'
R'
R'
R'
R'
R'
9a-c
13a-c
14a-c
15a-c
16
a
b
c
d
Scheme 4. Detailed steps of Shapiro reaction from hydrazones to vinyl anion 16. Reagents and reaction conditions: (a) n-BuLi (220 mol%), THF, 2558C,
30 min; (b) CH
3
I (250 mol%), 2508C, 30 min; (c) n-BuLi (400 mol%), THF, 2508C, 30 min; (d) rt, 25 min.

O
O
D
O
O
H
3
C
O
O
D
O
O
H
19 20
17
18
The ®nal proof of the premature decomposition of the
dianion of 9c was obtained when dianion 13c was prepared
at 2788C and quenched after 45 min with D
2
O. Both
deuterated trisylhydrazone 21 (85%) and deuterated vinyl
anion 19 (15%) were observed in the product mixture
(Scheme 5). At higher temperature (2488C) and shorter
stirring before quench (15 min) the product mixture
contained 96% of 19 with H/D ratio 22:78.
Mesitylhydrazone 9b was assumed to be a better choice
because a possible deprotonation of aromatic ortho-protons
is avoided and the vinyl anion could be stable enough for
methylation. Also the decomposition of dianion 15b could
be fast enough in order to avoid protonation of 16 by the
solvent. The reaction proceeded as described in Scheme 4.
Methylation was complete but the step 15b!16 was slow
and the vinyl anion was protonated by THF.
Tosylhydrazone 9a proved to be the best choice. Steps
9a!14a (Scheme 4) were carried out uneventfully. After
formation of the second dianion 15a the solution was
warmed to room temperature. The decomposition (evolu-
tion of N
2
) was complete in 25 min. A shorter reaction
time or lower decomposition temperature gives a signi®cant
amount of hydrazone as a side product. Paraformaldehyde
(10 mol equiv.) was added to give allylic alcohol 10 in 62%
isolated yield. Protonated vinyl anion was still obtained as a
side product (,10%). Immediate protonation of vinyl anion
16 can occur either by reaction with the solvent
16
or due to
the MeOH liberated during monomerization of para-
formaldehyde. Thus, other forms of formaldehyde were
also investigated. Gaseous formaldehyde was generated
from paraformaldehyde by heating at 1308C and then led
into the reaction with an argon ¯ow.
17
This method gave
28% isolated yield of 10 at best. The use of excess 1,3,5-
trioxane in THF gave 22% isolated yield.
These results with Shapiro reaction of 9a±c are in
accordance with the results reported by Shapiro et al.
originally. They observed that the ortho-position of the
aromatic ring of tosylhydrazones can be deprotonated with
strong alkyllithium bases to give a trianion. Vinyl anions
related to 16 have also been reported to be basic enough to
deprotonate the aromatic ortho-position.
18
The problem of
vagrant deprotonation could be overcome by using
300±400 mol% of BuLi in the preparation of dianions.
However, we observed no difference in the product distribu-
tion when the amount of used BuLi was varied from 220 to
400 mol%. Furthermore, dianions of tosylhydrazones
decompose extremely slowly to the vinyl anion as compared
to the corresponding trisylhydrazones.
19
Therefore decom-
position of the dianion should be fast and the electrophile
should be added immediately after complete decomposition
of dianion.
A few additional experiments with carefully dried electro-
philes were conducted to ®nd out whether the protonation
was caused by the solvent (THF) or by moisture. The
reaction of benzylchloromethylether with 16 to the BOM
protected alcohol 10 was unsuccessful. Methylchloro-
formate and dimethylcarbonate were also examined to
create an ester functionality which could be reduced to the
target compound, alcohol 10. However, the yield of 22 was
very low with both electrophiles and again, protonated vinyl
anion was obtained as the main product.
When DMF was employed as the electrophile (Scheme 6)
N
O
O
D
N
S
O
O
D
9c
21
1) t-BuLi
-78˚C
2) D
2
O
+
1
9
Scheme 5.
O
O
CH
3
OCOCl
O
H
3
CO
O
O
HO
LiAlH
4
DMF
O
O
O
H
LiAlH
4
16
or
(CH
3
O)
2
CO
22
10 (73%)
r.t.
23 (61%)
Scheme 6.

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