TiCl4 promoted reaction of aldehydes with 1,5-dienyl allylsilanes: Addition accompanied by cyclization

Article abstract of DOI:10.1016/S0040-4039(00)00400-7

TICl₄ readily promotes the addition of 1,5-dienyl allylsilanes to aliphatic aldehydes with concomitant cyclization to afford 1,3-cis- disubstituted methylenecyclohexanes with remarkable stereoselectivity. The trimethylsilyl group exerts a strong activating and directing influence on the regioselectivity and stereoselectivity of this biomimetic cyclization. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00400-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3471–3474
TiCl4 promoted reaction of aldehydes with 1,5-dienyl allylsilanes:
addition accompanied by cyclization
Giovanni Vidari,∗ Maria Pia Bonicelli, Luigi Anastasia and Giuseppe Zanoni
Dipartimento di Chimica Organica, Universita’ di Pavia, Via Taramelli 10, 27100 Pavia, Italy
Received 5 January 2000; revised 1 March 2000; accepted 7 March 2000
Abstract
TiCl4 readily promotes the addition of 1,5-dienyl allylsilanes to aliphatic aldehydes with concomitant cyclization
to afford 1,3-cis-disubstituted methylenecyclohexanes with remarkable stereoselectivity. The trimethylsilyl group
exerts a strong activating and directing influence on the regioselectivity and stereoselectivity of this biomimetic
cyclization. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: biomimetic reactions; cyclization; aldehydes; dienes.
Many isoprenoid natural products are biosynthesized via a polyolefinic electrophilic cyclization. The
initiation of ring closure is usually caused either by protonation of the terminal double bond or by opening
of a terminal epoxide.1 However, there is an increasing number of compounds for which biogenetic
cyclization of an acyclic precursor is achieved by C–C bond formation of the terminal double bond
with a carbenium ion. For example, the structural framework of saponaceolides suggests that their
biosynthesis may involve direct coupling of two farnesyl units accompanied by cyclization (Scheme
1).2,3 A similar pathway has been recently proposed for the monocyclic triterpenoid mispyric acid.4 An
intramolecular variant of this mechanism gives rise to the verticillane skeleton, a putative intermediate
Scheme 1.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00400-7
tetl 16680

3472
along the biosynthetic pathway to Taxol®.5 From a synthetic point of view, early studies have shown
that Friedel–Crafts reactions of geranyl derivatives with acyl chlorides may mimic this kind of diene
cyclization rather efficiently; however, diastereo- and regioselectivity were far from being satisfactory.6–8
In parallel studies, Julia carried out a prenylation–cyclization reaction of isoprenoid polyolefins that was
initiated by alkylation of the distal double bond with isoprene epoxide under anhydrous ZnCl2/MeNO2
conditions9 or with an allylic alcohol under CF3COOH catalysis;10 unfortunately, under these condi-
tions a mixture of stereoisomeric prenylated compounds are also produced. We reasoned that the low
stereoselectivity was possibly due to a non-concerted mechanism for the alkylation–cyclization steps and
better diastereomeric excesses could therefore be achieved if the carbenium species developing at the
tertiary carbon of the terminal double bond could be readily intercepted by the other double bond of the
diene system. To this purpose, in principle an allyl silane could function adequately. In fact, the allyl silyl
group has been used as an effective terminating unit in electrophilic polyolefinic cyclizations by a number
of groups11 even if, to the best of our knowledge, none of them involved cyclizations promoted by an
external carbenium species. In addition to providing a reactive electron-rich double bond, a trialkylsilyl
moiety can efficiently control the regioselectivity of the cyclization to yield the exocyclic olefin. Here, we
report our preliminary results on the Lewis acid promoted alkylation–cyclization reaction of aldehydes
with 1,3-dienyl allylsilanes (Scheme 2).
Scheme 2.
We started our experiments by examining the reaction between the easily available dienyl ester 212
and aldehyde 3, taken as model compounds. It was readily found that a C–C bond formation with a
concomitant ring closure occurred smoothly using TiCl4 as Lewis acid; however, the desired compound
4 (mixture ca. 2:1 of stereoisomers at the carbinol centers)13 was obtained in only 5% yield, while the
ene compound 5 (30%, dr >10) and the corresponding chloride 6 (10%, dr >10) were the most abundant
products (Scheme 3).13 Looking for a more electron-rich allyl silane, we then considered the reaction
between 3 and dienyl acetate 7 in the presence of TiCl4. After some optimization, we found that the
biomimetic-like cyclization could be effected in a still moderate but more satisfactory 35% yield (40%
Scheme 3.

3473
on recovered starting aldehyde). The C-10 epimers 8 (ratio of 2.3:1, undetermined stereochemistry at
the carbinol center) having the two 1,3-substituents cis oriented (NOE experiments), constituted the
90% of the cyclization products, while the corresponding trans disubstituted diastereoisomeric alcohols
accounted for the remaining 10%.
In order to explore the generality of the method, the reaction was then extended to diene 914 and other
aldehydes, including hexanal, nonanal, isovaleraldehyde and benzaldehyde. With the exception of the
latter compound, for which no alkylation was observed, the other aldehydes gave the expected cyclic
products of general formula 1 (R and R0 substituents as appropriate) in consistent yields (30–35%) and
diastereomeric excesses (80–85%).
A general procedure follows: TiCl4 (freshly distilled from CaH2) in anhydrous CH2Cl2 (1 M solution,
2 equiv.) was added by syringe to a solution of aldehyde (1.5 equiv.) in anhydrous CH2Cl2 at −78°C
under an argon atmosphere. The mixture was kept at −78°C for 10 min, then a solution of the allyl
silane (1 equiv.) in anhydrous CH2Cl2 was added. Stirring was continued at −78°C until disappearance
of the diene (30 min–1 h). The solution was quenched with saturated NaHCO3, diluted with CH2Cl2,
and washed with saturated NaCl. Drying (Na2SO4) and concentration of the organic layer gave a crude
mixture that was separated by flash silica gel column chromatography (gradient of EtOAc in hexanes) to
afford the desired cyclic products.
Interesting results were obtained when boron trifluoride etherate was used as a Lewis acid promoter
instead of TiCl4. The reaction of aldehyde 3 with diene 9 was much slower and afforded the acyclic
compounds 10 (26% yield; dr 4) and 11(17% yield, undetermined dr) (Scheme 4).13 The former is the
product of the Sakurai reaction15 of the allyl silane unit, while the latter is formed by the ene reaction on
the electron rich double bond of 9. If the free alcohol 12 was used as diene component of the reaction,
the ene product 13 (12% yield, dr 3.8) was accompanied by the tetrahydrofuran derivative 14 (20%
yield, undetermined dr) arising from interception of the developing carbenium species by the nucleophilic
hydroxy group.13
Scheme 4.

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At present, we have no firm explanation for the strikingly different directing influence of the two Lewis
acids on the regioselectivity of these reactions; we assume it to be due, at least in part, to the different
hardness of the carbon of the coordinated carbonyl group and to the well-known diverse coordinative
properties of TiCl4 and BF3.
In order to confirm the essential role of the allyltrimethylsilyl group in promoting the cyclization
step, we performed the reaction between aldehyde 3 and geranyl acetate 15 under the above standard
conditions (Scheme 5). As anticipated, no cyclization occurred; instead, the product of the ene reaction
16 (dr >10) and chloride 17 were formed in 46 and 14% yield, respectively.13
Scheme 5.
In conclusion, the preliminary results described here show clearly that TiCl4 promotes a quite efficient
biomimetic-like addition–cyclization reaction of aliphatic aldehydes with 1,3-dienyl allyl silanes. 1,3-
cis-Disubstituted methylenecyclohexanes are thus produced with remarkable stereoselectivity. Further
studies on the optimization of the reaction as well as on the application in the biomimetic synthesis of
natural products will be reported in due course.
Acknowledgements
We thank Dr. Mariella Mella for NMR spectra, the Italian CNR and MURST (ex 40%), and the EU
Commission (Contract No. ERBFAIRCT961781) for financial support.
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