Synthesis of 2-ene-1,4-diols by a new cascade-opening of 1,3-diepoxides: Towards an efficient synthesis of dihydroxytaxoid derivatives

Article abstract of DOI:10.1002/chem.200802621

The synthesis of dihydroxytaxoid derivatives, specially 2-Ene-1,4-diols using a new cascade-opening of 1,3-diepoxides was investigated. The study prepared a framework through a cascade ring-closing dienyne metathesis (RCDEYM) reaction from Dienyne. The me

Full text of DOI:10.1002/chem.200802621

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DOI: 10.1002/chem.200802621
Synthesis of 2-Ene-1,4-diols by a New Cascade-Opening of 1,3-Diepoxides:
Towards an Efficient Synthesis of Dihydroxytaxoid Derivatives
Marꢀa J. Aldegunde, Luis Castedo, and Juan R. Granja*[a]
Dedicated to Professor Josep Font on the occasion of his 70th birthday
The impressive anticancer properties of some taxane-
family members make these molecules and their derivatives
attractive targets for chemical synthesis.[1] Despite the rele-
vant contribution of taxanes, such as taxol 1 or taxotere 2
(Scheme 1), advances still are needed to improve their prop-
we report the transformation of derivatives 4 into taxane-
diols 6 by way of a new and general strategy.
Few methods are known for the regio- and stereoselective
1,4-addition of oxygen functions to conjugated dienes.[5–9]
Moreover, they are rarely successful with dienes that nor-
mally do not adopt the s-cis conformation or when the sub-
strate possesses a constrained structure that does not allow
the formation of the p-allyl complex.
Having failed to prepare the alk-2-ene-1,4-diol moiety (6)
from the diene derivatives of type 4 under the reported con-
ditions,[7–10] we decided to study other alternatives. We envis-
aged that titanoceneACHTNUGRTENUNG(III) chloride could be useful in the
construction of the alk-2-ene-1,4-diol system from diepox-
ides derived from 1,3-dienes (Scheme 2).[11–14] The titanium
complex would react with the oxacyclopropane rings to gen-
erate a b-titanoxy radical, which could then trigger the
second epoxide opening to give the alk-2-ene-1,4-diol
moiety.
Scheme 1. Taxanes, such as taxol (1) and taxotere (2), and taxosteroid
structures (3) and proposed synthetic scheme for taxane like derivatives
6 from dienyne 5.
erties by looking for less toxic analogues with improved
properties.[1f] In the last few years, our research group has
been involved in the development of new taxane ana-
logues[2] and taxosteroids 3.[3] Their framework (4) was pre-
pared through a cascade ring-closing dienyne metathesis
(RCDEYM) reaction from dienyne 5 (Scheme 1).[4] Herein,
Scheme 2. General approach proposed for the preparation of enediols by
radical diepoxide opening.
Thus, taxosteroids 7a and 7b (Scheme 3) were trans-
formed into the corresponding dioxiranes (8 and 9) using 3-
chloroperoxybenzoic acid (mCPBA). When the 4:1 in-
[a] M. J. Aldegunde, Prof. Dr. L. Castedo, Prof. Dr. J. R. Granja
Departamento de Quꢀmica Orgꢁnica
Facultad de Quꢀmica
AHCTUNGTRENNUNG
Universidad de Santiago
15782 Santiago de Compostela (Spain)
Fax : (+34)981-595012
AHCTUNGTRENNUNG
the major isomer reacted to give a new compound, which
was identified as the cis-10a based on its 1D- and 2D-NMR
spectra, while the other isomer remained unaltered. Similar-
ly, when we carried out the reaction on pure diepoxides 8b
E-mail: juanr.granja@usc.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802621.
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4785

the steric hinderance provided by the taxane skeleton,
which somewhat restricts the epoxide accessibility to the ti-
tanium complex, and thus they are recovered unchanged.
The above promising results encouraged us to further ex-
plore the scope of this methodology with simple substrates
(Table 1). The first experiments with epoxides 15 and 16
Table 1. Studies for the transformation of diepoxides into alkenediols.
Entry
Diepoxide
Product
Yield[a]
1
16[b]
2
3
30[c]
21[b]
Scheme 3. a) mCPBA, CH2Cl2, 08C, 71% for 8a/9a (4:1) and 85% for
8b/9b (15:1); b) [TiCl2Cp2], Zn, THF, 08C.
4
51[c]
69
and 9b, only the major isomer (8b) reacted, even in the
presence of the unprotected hydroxyl group (P1 =H), to pro-
vide cis-10b in excellent yield.
In the same way, we subjected separately diepoxides 12
and 13 (Scheme 4), derived from taxane 11, to the same con-
ditions. Once again, only isomer 12 underwent the double
5[b]
6[b]
89
[a] Isolated yields. In the case of entries 2 and 4 the yields are for the two
steps. [b] Reaction conditions: 0.05m in THF, [{TiClCp2}2] (0.2m in THF,
1 equiv), 08C. [c] i) 0.05m in THF, [{TiClCp2}2] (0.2m in THF, 1 equiv),
08C; ii) Ac2O, DIEA, DMAP, RT. [d] Diacetate 20, and consequently its
precursor 19, were identified as the trans isomers by comparison of its
spectroscopic data with those previously reported.[16] [e] Compound 24a
was assigned the Z configuration on the basis of the NOE between H1’
(5.52 ppm) and H3 (2.14 ppm). Consequently, the E configuration was as-
signed to the other isomer (24b).
(entries 1 and 3) gave the corresponding alkenediols (17 and
19) as single stereoisomers but in very low yield,[16] which
was attributed to their isolation difficulties associated to
their low molecular weight and polarity. This was partially
confirmed when compounds 17 and 19 were transformed in
situ into the corresponding diacetates 18 and 20 (entries 2
and 4) with a notable increase of isolated yields. Interesting-
ly, the trans-diepoxide 16[16] can evolve into the correspond-
ing trans-enediol, probably because there is reduced geo-
metrical bias for the radical intermediate to adopt the sp2
hybridization that evolves into the olefin. Better results
were obtained with diepoxide 21 (entry 5), giving the ene-
diol 22 in good yield. Subjecting an inseparable diasteromer-
ic mixture of dioxiranes 23 (see Scheme 1SI in supporting
information for its synthetic preparation scheme)[17] to the
TiIII conditions provided a 2:1 mixture of alkenediols 24a
and 24b (entry 6) in very good yield. The results described
above prove the validity of the proposed strategy for the
preparation of 2-alkene-1,4-diols from conjugated dienes/
Scheme 4. a) mCPBA, CH2Cl2, 08C, 81% for 12/13 (5:1); b) [TiCl2Cp2],
Zn, THF, 08C, 92% for cis-14.
oxirane opening to give diol cis-14 (92%). These results
clearly open the opportunity to efficiently prepare novel
taxane derivatives starting from simple cyclohexenones
through RCDEYM,[2] followed by appropriate functionaliza-
tion of the diols resulting from diepoxide opening.
These results could be mechanistically explained, as
shown in general form in Scheme 2, in terms of a titanium-
induced sequential oxirane opening of diepoxide moiety in-
volving the initial formation of an a-epoxy methinyl radi-
cal.[11,13,16] Epoxide opening is more likely to take place on
the C12–C13 oxirane, because the alternative opening of the
epoxide at C10–C11 would result in the formation of a
bridgehead radical intermediate. The lack of reactivity of
the trans-diepoxide isomers (9 and 13) in comparison with
the cis-diepoxides (8 and 12) can be explained in terms of
4786
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Cascade Reactions
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ing.
In summary, we have successfully functionalized the con-
strained 1,3-olefin system of taxane and taxosteroids frame-
works 4 to the dihydroxylated analogues by means of a new
method that relies on olefin diepoxidations followed by radi-
cal opening of the dioxirane system with titanoceneACTHUNTGRNEUNG(III)
chloride. This methodology has also been extended to other
substrates confirming the general validity of this methodolo-
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this process are currently underway.
Experimental Section
Zinc dust (196 mg, 3 mmol) was added to
a solution of [TiCl2Cp2]
(249.5 mg, 1 mmol) in THF (2.5 mL) and the suspension was vigorously
stirred for 1 h under Ar atmosphere. This freshly prepared solution of
[{TiClCp2}2] (0.2m, 0.6 mL, 0.13 mmol) was added dropwise to a solution
of the inseparable mixture of diepoxides 8a/9a (25 mg, 0.042 mmol) in
THF (2.5 mL) at 08C and the mixture was stirred at the same tempera-
ture. After 1 h, HCl (1m) was added and the aqueous layer was extracted
with Et2O, dried over Na2SO4 and concentrated under reduced pressure.
The crude was subjected to flash chromatography (90% AcOEt/hexanes)
to yield diol cis-10a (21 mg, 81%, Rf =0.2 (100% AcOEt), white solid).
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This work was supported by the Ministerio de Educaciꢃn y Ciencia
[SAF2007-61015, and Consolider Ingenio 2010 (CSD2007-00006)], and
by the Xunta de Galicia (GRC2006/132). M.J.A. thanks the Spanish
M.E.C. for her fellowship (FPU).
Keywords: cascade reactions · diepoxide · hydroxylation ·
radicals · taxanes
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Received: December 12, 2008
Published online: March 25, 2009
Chem. Eur. J. 2009, 15, 4785 – 4787
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4787