TiF4-mediated biomimetic alkylation-cyclization cascade reaction of 2-trimethylsilylmethyl-1,5-dienes with aldehydes

Article abstract of DOI:10.1016/j.tetlet.2005.06.149

TiF₄ has proven to be the Lewis acid of choice for promoting the biomimetic addition of 2-trimethylsilylmethyl-1,5-dienes to aliphatic aldehydes with concomitant cyclization. 1,3-cis-Disubstituted methylenecyclohexanes are thus produced in good yields and high diastereoselectivity. The reaction appears to proceed via a highly concerted mechanism involving a chair-like transition state.

Full text of DOI:10.1016/j.tetlet.2005.06.149

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5803–5806
TiF4-mediated biomimetic alkylation–cyclization cascade
reaction of 2-trimethylsilylmethyl-1,5-dienes with aldehydes
Luigi Anastasia, Elios Giannini, Giuseppe Zanoni and Giovanni Vidari*
`
Dipartimento di Chimica Organica, Universita di Pavia, via Taramelli 10, 27100 Pavia, Italy
Received 6 May 2005; revised 24 June 2005; accepted 28 June 2005
Available online 14 July 2005
Abstract—TiF4 has proven to be the Lewis acid of choice for promoting the biomimetic addition of 2-trimethylsilylmethyl-1,5-
dienes to aliphatic aldehydes with concomitant cyclization. 1,3-cis-Disubstituted methylenecyclohexanes are thus produced in good
yields and high diastereoselectivity. The reaction appears to proceed via a highly concerted mechanism involving a chair-like tran-
sition state.
ꢀ 2005 Elsevier Ltd. All rights reserved.
In the suggested biosynthesis of several terpenoids, such
as saponaceolides1 and mispyric acid,2 core structures
are assembled by cyclization of a 1,5-diene moiety pro-
moted by the electrophilic addition of a formal terpe-
noid carbocation species. The coupling has been
proposed to occur through a highly ordered arrange-
ment leading to a cis-1,3-alkylated six-membered ring.
Early sporadic attempts to reproduce this elegant bio-
chemical process in vitro, though imaginative, were,
however of limited synthetic applicability. In fact,
a mixture of cyclized and non-cyclized products were
usually attained,3 with unsatisfactory regio- and
diastereoselectivity.
The latter results were still rather a proof of concept
than a real tool for the synthetic community, due to
the cyclization modest yields (635% based on the start-
ing aldehyde) and variable amounts of contaminating
protodesilylated and chlorinated adducts. Therefore,
with the goal to develop a new useful approach to the
total synthesis of natural products, we decided to further
screen several combinations of the three reaction com-
ponents, namely, a Lewis acid, diene 2, and aldehyde
1, with respect to which yields were optimized. The
results obtained with different aromatic and aliphatic
aldehydes, Lewis acids (LA = Me2AlCl, Me2AlCl–TiCl4,
Me3SiOTf, TiF4, SnCl4, Sc(OTf)3, and Yb(OTf3)) and
substituted dienes (R2 = CH2OAc, CH2OH, and
COOR) indicated that the course of the reaction, though
rather unpredictably, varied with the electron density of
the allylsilane moiety, imparted by the R2 substituent,
and the hardness of the complexed aldehyde, mainly
determined by the Lewis acid used (Scheme 1). Extensive
experimentation was thus needed to finely tune the elec-
tronic characteristic of the reactants to drive the cycliza-
tion to a useful preparative method. At last we
Along this line, in a preliminary study, we first reported
the cyclization of a 1,5-diene (2, R2 = CH2OAc) pro-
moted by electrophilic addition of TiCl4-complexed ali-
phatic aldehydes (Scheme 1).4
SiMe3
LA
O
5
R1
discovered that TiF4 efficiently promotes the addi-
R2
R1
tion–cyclization of 1-alkoxycarbonyl-2-trimethylsilyl-
methyl-1,5-dienes 2 (R2 = CO2R0) to aliphatic aldehydes
(1), affording 1,3-disubstituted methylenecyclohexane
derivatives (3) in good yields and high cis-diastereoselec-
tivity (Scheme 1 and Table 1). The optimal molar ratio
of 1, 2, and TiF4 was eventually adjusted to 1:2:4,
respectively, with initial exposure of the aldehyde to
R2
OH
H
1
2
3
Scheme 1.
Keywords: Biomimetic reactions; Cyclization; TiF4; Aldehydes;
Allylsilane.
*
TiF4 at ꢀ40 ꢁC for 10 min prior to diene
2
Corresponding author. Tel.: +39 0382987322; fax: +39
0382987323; e-mail: vidari@unipv.it
(R2 = CO2Me)6,7 addition at 0 ꢁC.8 Addition of diene
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.149

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L. Anastasia et al. / Tetrahedron Letters 46 (2005) 5803–5806
Table 1. Results of the reactions of diene 2 (R2 = CO2Me) with aldehydes
Entry
Aldehyde
Yielda
cis/trans Ratiob
Carbinol diastereomeric ratiob
cis 5a+6a:6b
transc 7
1
2
3
4
5
6
PhCH2CH2CHO (8)
Cy-CH2CHO
Me2CHCH2CHO
n-Hexyl-CHO
Cy-CHO
50
64
82
85
42
40
87:13
87:13
85:15
94:6
ND
ND
69:31
73:27
75:25
80:20
ND
66:34
61:39
70:30
ND
ND
ND
Me3C–CH2CHO
ND
a Combined isolated yields of products 5+6+7 with respect to the aldehyde.
b 5+6:7, determined by GC for entries 1 and 2, and by NMR and isolated yields for entries 3 and 4.
c The stereochemistry at C01 of carbinols 7a,b was not established.
2 to aldehydes 1 competed with its concurrent proton-
initiated cyclization to exo-methylenecyclohexane 4.
In fact, the addition was minimal at ꢀ40 ꢁC, while it
occurred readily at 0 ꢁC with an excess diene.
exposure to a catalytic amount of p-TsOH in CH2Cl2
overnight. Indeed, for preparative purposes, the crude
reaction mixture was treated with p-TsOH, so that lac-
tones 5a,b were easily separated from unreacted trans-
hydroxyesters 7a,b by column chromatography.8
Structure assignments to the cis (6a,b) and the trans
(7a,b) stereoisomers were based on the highly diagnostic
1H NMR signals of the exo olefin protons,9 while
NOESY experiments on lactones 5a and b, respectively,
indicated the structure of each cis-hydroxyester, 6a and
b, respectively.
COOMe
R
R'
O
O
4
5a R=H, R'=alkyl
5b R=alkyl, R'=H
5c R=H, R'=isobutyl
5d R=isobutyl, R'=H
The ratio of diastereomers 6+5 to 7 did not change sig-
nificantly on prolonged exposure to TiF4 or p-TsOH,
HO
COOMe
R
R'
according to
a kinetic control of the reaction
diastereoselectivity.
6a R=H, R'=alkyl
6b R'=H, R=alkyl
HO
COOMe
R
R'
The results obtained from cyclization of the model alde-
hydes suggest that major cis-compounds 6a,b likely arise
from a highly concerted mechanism involving a chair-
like transition state (TS-A in Scheme 2). A synclinal
arrangement of aldehyde and olefin double bonds, with
an anti orientation of the approaching aldehyde R group
with respect to the bulky geminal dimethyl group, would
thus explain the preferential stereochemistry at C-10 of
the cis-compounds, namely that of 6a.10,11 Conversely,
a higher energy boat-like TS (TS-B in Scheme 2) may
account for the formation of the minor trans-stereoiso-
mers 7a,b.
7a R=H, R'=alkyl
7b R'=H, R=alkyl
On the other hand, TiF4-induced self-condensation of
aldehyde 1 was negligible when the complex with the
Lewis acid was formed at ꢀ40 ꢁC.
MeCN was the solvent of choice given the insolubility of
TiF4 in other aprotic solvents. This medium had the
additional advantage to tune the Lewis acid strength
so finely that polymerization of TiF4-complexed alde-
hyde was unimportant at ꢀ40 ꢁC. By contrast, in a
non-coordinating solvent, like DCM, aldehyde polymer-
ization occurred readily, even at ꢀ78 ꢁC.
_
_
SiMe3
The superior reactivity of TiF4 with respect to other
Lewis acid catalysts has been attributed to the high elec-
tronegativity of fluorine.5 Moreover, the high strength
of the Ti–F bond5 was an additional bonus to avoid
the formation of halogenated side-products, which, in-
stead, contaminated analogous TiCl4 or SnCl4-pro-
moted cyclization products.3,4
F4Ti
O
R
COOMe
R
H
OH
OH
COOMe
SiMe3
cis (6a)
TS-A
_
_
F4Ti
H
R
O
R
Both the cis- and the trans-products comprised the two
epimers at the newly formed carbinol stereocenter,
namely alcohols 6a,b and 7a,b, respectively. Compound
6a, the more abundant of the two epimeric alcohols in
the cis-pair, slowly gave lactone 5a under reaction con-
ditions, whereas carbinol 6b lactonized to 5b only upon
COOMe
COOMe
H
H
TS-B
trans (7)
Scheme 2.

L. Anastasia et al. / Tetrahedron Letters 46 (2005) 5803–5806
5805
References and notes
TiF4
O
SiMe3
a
7a-b
6a-b
a
1. (a) Vidari, G.; Vita Finzi, P. Tetrahedron 1991, 47, 7109–
7116; (b) De Bernardi, M.; Garlaschelli, L.; Gatti, G.;
Vidari, G.; Vita Finzi, P. Tetrahedron 1988, 44, 235–240;
(c) Yoshikawa, K.; Kuroboshi, M.; Arihara, S.; Miura,
N.; Tujimura, N.; Sakamoto, K. Chem. Pharm. Bull. 2002,
50, 1603–1606.
H
H
+
R
COOMe
b
b
Scheme 3.
2. Sun, D.-A.; Deng, J.-Z.; Starck, R. S.; Hecht, S. M. J. Am.
Chem. Soc. 1999, 121, 6120–6124.
3. (a) Takahashi, T.; Iwamoto, H.; Nagashima, K.; Okabe,
T.; Doi, T. Angew. Chem., Int. Ed. Engl. 1977, 36, 1319–
An alternative non-concerted mechanism (Scheme 3),
involving a fully developed tertiary carbenium ion spe-
cies arising from addition of the distant double bond
of 2 to the TiF4-complexed aldehyde, prior to cycliza-
tion, was ruled out on the basis of the results obtained
by substituting diene 2 (R2 = CO2Me) with methyl ger-
aniate 9 under standard conditions.8 In fact, the reaction
with 3-phenylpropanal 8 afforded, as the main products,
methyl cyclogeraniate 10 (50% from 9), arising from
proton-initiated cyclization of the diene, and unsatu-
rated aldehyde 11 (42% from 8), due to the aldol self-
condensation of the aldehyde.
´ ´
1321; (b) Ferezou, J. P.; Julia, M. Tetrahedron 1990, 46,
475–486; (c) Julia, M.; Schmitz, C. Tetrahedron 1986, 42,
2491–2500; (d) Kumagai, T.; Ise, F.; Uyehara, T.; Kato, T.
Chem. Lett. 1981, 25–28; (e) Kato, T.; Takayanagi, H.;
Suzuki, T.; Uyehara, T. Tetrahedron Lett. 1978, 19, 1201–
1204; (f) Kumazawa, S.; Nakano, Y.; Kato, T.; Kitahara,
Y. Tetrahedron Lett. 1974, 15, 1757–1760; (g) Smit, W. A.;
Semenovsky, A.; Kucherov, V. F.; Chernova, T. N.;
Krimer, M. Z.; Lubinskaya, O. V. Tetrahedron Lett. 1971,
12, 3101–3106, and references therein.
4. Vidari, G.; Bonvicelli, M. P.; Anastasia, L.; Zanoni, G.
Tetrahedron Lett. 2000, 41, 3471–3474.
5. For the use of TiF4 in the enantioselective addition of
allyltrimethylsilane to aldehydes, see: Gauthier, D. R., Jr.;
Carreira, E. M. Angew. Chem., Int. Ed. 1996, 35, 2363–
2365.
CHO
CO2Me
CO2Me
Ph
6. (a) Beszant, S.; Giannini, E.; Zanoni, G.; Vidari, G.
Tetrahedron: Asymmetry 2002, 13, 1245–1255; (b) Arm-
strong, R. J.; Weiler, L. Can. J. Chem. 1986, 64, 584–596;
(c) Armstrong, R. J.; Weiler, L. Can. J. Chem. 1983, 61,
214–215.
9
10
11
By contrast, under these conditions, the expected prod-
ucts of the alkylation–cyclization reaction, namely, lac-
tone 5a (R0 = PhCH2CH2) and hydroxy esters 6 and 7
R or (R0 = PhCH2CH2), were produced in only 4%
and 2% yields, respectively (carbinol stereochemistry
undetermined).
7. Similar results were obtained with other simple esters
(R2 = Et or Pr).
8. The reaction with isovaleraldehyde (1, R1 = isobutyl)
describes the general preparative procedure. A solution of
isovaleraldehyde (1, R1 = isobutyl) (67.2 mg, 0.786 mmol)
˚
in dry CH3CN (8 mL) containing 4 A MS (about 40 mg),
under an Ar atmosphere, was cooled to ꢀ40 ꢁC and TiF4
390 mg, (3.14 mmol) was added in one portion. After
10 min, a solution of 1,5-diene 2 (R2 = CO2Me)6 in
MeCN (400 mg in 1 mL, 1.57 mmol) was added and the
temperature was raised to 0 ꢁC. The reaction was stirred
for 4 h at the same temperature, then quenched with
20 mL of a 1:1 mixture of 5% aqueous NaHCO3 and
brine, and diluted with diethyl ether (20 mL). The
aqueous phase was extracted with diethyl ether
(3 · 30 mL) and the combined organic layers were dried
over MgSO4, filtered, and concentrated. The crude
residue (412 mg), dissolved in CH2Cl2 (70 mL), was
exposed to p-TsOH (13 mg) under stirring at rt overnight.
The reaction mixture was washed with satd aqueous
NaHCO3, brine, and dried over MgSO4. The salt was
filtered off and the filtrate was concentrated in vacuo. The
resulting residue was separated by flash chromatography
on silica gel. Elution with a hexane–EtOAc gradient
(from 99:1 to 90:10) afforded, in the order, lactone 5c
(87 mg, 47% with respect to isovaleraldehyde) and 5d
(28 mg, 15% with respect to isovaleraldehyde), each
uncontaminated by the epimeric trans-hydroxyesters 7
(R1 = isobutyl). Lactone 5c: IR (neat) m (tilde) 2955,
2970, 1740, 1748, 1650, 1467, 1368, 1254, 1224, 1069,
It thus appears evident that the allylsilyl group of diene
2 (R2 = CO2Me), in addition to being an effective termi-
nating unit and controlling the cyclization regioselectiv-
ity,4,6,12 possibly increases the electron density of the
distant olefin, via through space interaction of the dou-
ble bonds.13
In conclusion, in this letter we have described the first
example of an efficient and stereoselective biomimetic
1,5-diene cyclization promoted by an external electro-
philic carbenium species, namely, a Lewis acid com-
plexed aliphatic aldehyde. In comparison with other
Lewis acids, the use of TiF4 appears to be crucial for
attaining good yields with respect to the starting alde-
hyde and high cis-diastereoselectivity of the products.
This new methodology can become a useful tool for
the synthesis of different natural products. Our own
applications in total synthesis will be reported in due
time.
Acknowledgements
1
1029, 920, 897 cmꢀ1; H NMR (300 MHz, CDCl3, TMS)
d 0.96 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H), 1.04
(s, 3H), 1.18 (s, 3H), 1.3–1.45 (m, 2H), 1.7–1.95 (m, 4H),
2.15–2.28 (m, 2H), 2.95 (br s, 1H), 4.75 (m, 1H), 4.91 (br
s, 2H); 13C NMR (75 MHz CDCl3, TMS) d 172.1 (s),
142.2 (s), 112.2 (t), 79.0 (d), 59.3 (d), 41.5 (t), 39.6 (d),
The authors thank the Italian MIUR (funds COFIN)
and the University of Pavia (funds FAR) for financial
support. We are indebted to Dr. Mariella Mella for
NMR spectra acquisition.

5806
L. Anastasia et al. / Tetrahedron Letters 46 (2005) 5803–5806
34.9 (s), 27.9 (t), 26.9 (q), 25.1 (q), 24.2 (d), 22.9 (q), 22.1
10. Denmark, S. E.; Almstead, N. G. In Modern Carbonyl
Chemistry In Allylation of Carbonyls: Methodology and
Stereochemistry; Otera, J., Ed.; Wiley-VCH: Weinheim
(FDR), 2000, pp 299–401.
11. In the alternative antiperiplanar arrangement of double
bonds10 leading to 6a, the R group would develop an
unfavorable allylic strain with the pseudoequatorial
methyl group on the distal double bond of diene 2.
12. Fleming, I.; Pearce, A. J. Chem. Soc., Perkin Trans. 1
1981, 251–255.
13. In the Lewis acid-promoted addition to aldehydes, the
distant double bond of 1,5-dienes of type 2 (R2 = CO2Me)
appears to be activated by the allylsilyl group in the same
manner as in 1,3-dienylsilanes; see: Fleming, I.; Kindon,
N. D.; Sarkar, A. K. Tetrahedron Lett. 1987, 28, 5921–
5924, and references cited therein.
(q), 21.3 (t); GC–MS m/z (relative intensity) 236 (M+,
6.5), 193 (23.9), 177 (3.0), 149 (2.0), 135 (4.3), 121 (100),
107 (11.2), 93 (11.7), 79 (10.8), 67 (5.1), 55 (5.9).
C15H24O2 calcd: C, 76.23; H, 10.24. Found: C, 76.33;
H, 10.12. Lactone 5d: 1H NMR (300 MHz, CDCl3,
TMS), d 0.96 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.5 Hz,
3H), 0.98 (s, 3H), 1.14 (s, 3H), 1.4–1.56 (m, 2H), 1.75–2.1
(m, 4H), 2.18–2.36 (m, 2H), 2.91 (br s, 1H), 4.42 (m, 1H),
4.92 (br s, 2H); 13C NMR (75 MHz CDCl3, TMS) d 171.8
(s), 141.5 (s), 113.6 (t), 84.0 (d), 58.5 (d), 46.7 (t), 40.3 (d),
33.8 (s), 29.1 (t), 28.4 (q), 27.1 (t), 25.5 (q), 24.8 (d), 22.8
(q), 21.9 (q). C15H24O2 calcd: C, 76.23; H, 10.24. Found:
C, 76.38; H, 10.32.
9. Organ, M. G.; Winkle, D. D.; Huffmann, J. J. Org. Chem.
1997, 62, 5254–5266.