Intramolecular reductive ketone-alkynoate coupling reaction promoted by (η2-propene)titanium

Article abstract of DOI:10.1039/c2ob07049a

Intramolecular reductive coupling of cycloalkanones tethered to alkynoates in the presence of (η²-propene)titanium was successfully performed to provide hydroxy-esters in a diastereoselective manner. Subsequent lactonization afforded angularly

Full text of DOI:10.1039/c2ob07049a

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PAPER
Intramolecular reductive ketone–alkynoate coupling reaction promoted by
(η2-propene)titanium†
Christian Schäfer, Michel Miesch* and Laurence Miesch*
Received 7th December 2011, Accepted 7th February 2012
DOI: 10.1039/c2ob07049a
Intramolecular reductive coupling of cycloalkanones tethered to alkynoates in the presence of
(η2-propene)titanium was successfully performed to provide hydroxy-esters in a diastereoselective
manner. Subsequent lactonization afforded angularly fused unsaturated tricyclic lactones which represent
relevant substructures of numerous bioactive compounds.
Introduction
Angularly fused 5-6-5 and 6-6-5 tricyclic fused lactones are rel-
evant substructures for numerous bioactive compounds such as
alliacolide,1 alliacol A,2 alliacol B3 and arteannuin B4 (Fig. 1).
The challenge associated with the synthesis of such tricyclic
skeletons, combined with their pharmacological activities,3 has
elicited considerable synthetic interest. As part of our studies of
the reactivity of acetylenic ω-ketoesters,5 we planned an intra-
molecular ketone–alkynoate coupling reaction promoted by (η2-
propene)Ti(OiPr)2 (Sato’s reagent) for the construction of poly-
cyclic skeletons (Scheme 1).
The generation of divalent dialkyloxytitanium complexes and
their utilization in organic synthesis have attracted considerable
interest over a number of years.6 Among these titanium com-
plexes, the highly practical divalent (η2-propene)Ti(OiPr)2
reagent, was introduced as an equivalent of Ti(OiPr)2.7 Reac-
Fig. 1 Natural products containing tricyclic fused lactones.
tions of various acyclic alkynes with (η2-propene)Ti(OiPr)2 have
been intensively investigated,6b,f,g,8 although the reaction with
activated alkynes is less documented.9 Indeed to the best of our
knowledge, only one preliminary study has been published by
Sato et al. involving a titanium-mediated cyclization, starting
from 2-en-7-ynoates for the preparation of bicyclic systems.10
Marek and coworkers reported an intramolecular cyclization,
with a keto group at the γ- or δ-position affording four- and five-
Scheme 1
membered cycloalkanols.11
Thus reaction of an alkyne with a titanium(II) species should
generate (η2-alkynoate)Ti(OiPr)2 by ligand exchange of the co-
ordinated propene in (η2-propene)Ti(OiPr)2. That is, in situ
reductive coupling reaction of the carbonyl group with the
alkynoate complex could proceed to provide an oxytitanacycle.
The hydrolysis of the latter would afford a bicyclic compound
that includes an allylic alcohol at the bridgehead carbon. Thus,
we prepared various cycloalkanones bearing an ynoate side
chain.
Université de Strasbourg, Institut de Chimie, UMR 7177, Laboratoire de
Chimie Organique Synthétique, 1 rue Blaise Pascal, BP 296/R8, 67008
Strasbourg-Cedex, France. E-mail: lmiesch@unistra.fr, m.miesch@
unistra.fr; Fax: +33 3 68 85 17 54; Tel: +33 3 68 17 51
Results and discussion
†Electronic supplementary information (ESI) available: Detailed exper-
imental procedures, characterization of compounds and crystallographic
data. CCDC 784204–784206. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c2ob07049a
Acetylenic ω-ketoesters 19–24 were synthesized starting from
the corresponding N,N-dimethylhydrazones according to our pre-
viously developed reaction sequence (Scheme 2).12
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Scheme 2 Reagents and conditions: (a) H2NNMe2, TFA, benzene,
reflux; (b) (1) nBuLi, (2) I(CH2)n+1CCH, (3) 10% HCl, THF, −40 °C to
rt; (c) HOCH2CH2OH, PTSA, benzene, reflux; (d) (1) nBuLi, (2) ethyl
chloroformate, (3) 10% HCl, −78 °C to rt.
Scheme 4 Reagents and conditions: (a) 2 equiv. Ti(OiPr)4, 6 equiv.
iPrMgBr, Et2O, −30 °C, 2 h.
Scheme 5 Proposed mechanism.
cyclization to give bicyclic alcohols 28–30 in a stereoselective
Scheme 3 Reagents and conditions: (a) 2 equiv. Ti(OiPr)4, 6 equiv.
iPrMgBr, Et2O, −30 °C, 2 h.
fashion in moderate to good yields (Scheme 4).14
To examine the feasibility of our synthetic strategy, we first
investigated the carbometallation reaction of cycloalkanones
bearing 7-ynoates. Compounds 19–21 (m = 1–3, n = 1) were
treated with (η2-propene)Ti(OiPr)2, which was readily prepared
by reacting Ti(OiPr)4 with 2 equivalents of iPrMgBr. The reduc-
tive cyclization took place in a diastereoselective manner, provid-
ing exclusively cis-bicyclic ring systems bearing an E-
substituted exocyclic electrophilic double bond (Scheme 3).
This reaction outlines an “umpolung” reaction of the ethoxy-
carbonyl substituted alkynes, since the titanocyclopropene gener-
ated in situ creates a nucleophilic center β to the ester.13
Homologous 8-ynoates 22–24 underwent a similar syn selective
Mechanistic investigations
A possible reaction mechanism of cyclization is shown in
Scheme 5. First, coordination of the alkyne moiety of 19 to the
titanium(II) complex, followed by an intramolecular cyclization
generates titanacycle 31 in a stereoselective fashion. Hydrolysis
leads to the hydroxy exo-methylene ester compound 25.
In order to probe the existence of a carbon–titanium bond as
depicted in the oxatitanacycle 31, iodine was added at the end of
the reaction. The iodinolysis gave exclusively the Z-isomer of
the corresponding alkenyl iodide 32 (Scheme 6).11
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Asymmetric version
reaction using sodium ethanolate in refluxing ethanol starting
from bicyclic compounds (25–27 and 51–52) issued from
ω-ketoesters bearing a two carbon tether remained fruitless. In
contrast, bicyclic compounds (28–29 and 53–54) derived from a
three carbon tether afforded the corresponding unsaturated lac-
tones in high yields (Scheme 9).
Because of the great importance of asymmetric synthesis and to
broaden the scope of this cyclization, the optimal reaction con-
ditions were extended to enantiomerically pure ynoates. Prep-
aration of optically pure alkynoates 49 and 50 has already been
described.15
The synthesis of compounds 43 and 44 was carried out as
follows: after protection of the carbonyl group, of enantio-
enriched ketoester derivatives 37 and 38,15 the ester functions
were reduced to aldehydes 39 and 40. A modified Corey–Fuchs
reaction involving the addition of ethyl chloroformate prior to
aqueous work-up afforded acetylenic ω-keto esters 43 and 44
with good yields (Scheme 7).
Lactonization reactions were also performed with enantiomeri-
cally pure compounds affording the corresponding lactones in
Treatment of 43–44 and 49–50 with Sato’s reagent provided
various bicyclic compounds having two consecutive stereogenic
centres including a tetrasubstituted carbon in a stereoselective
fashion. The carbometallation reaction worked well and isolated
yields were good (Scheme 8). The structure of compounds 53
and 54 were unambiguously confirmed by X-ray crystallographic
analysis (Fig. 2) though providing evidence for the exclusive for-
mation of E-alkenes.
Lactonization reactions
The bifunctional molecules obtained provided an opportunity to
approach tricyclic unsaturated lactones. The lactonization
Scheme 6 Reagents and conditions: (a) (1) 2 equiv. Ti(OiPr)4, 6 equiv.
iPrMgBr, Et2O, −30 °C, 2 h, (2) I2, −78 °C to 0 °C, 25 min, (3) 1 N
HCl.
Scheme 8 Reagents and conditions: (a) 2 equiv. Ti(OiPr)4, 6 equiv.
iPrMgBr, Et2O, −30 °C, 2 h.
Scheme 7 Reagents and conditions: (a) (R)-α-methylbenzylamine, toluene, reflux; (b) methyl acrylate, PTSA, toluene, 40 °C; (c) ethylene glycol,
nBu4NBr3, HC(OEt)3, rt; (d) DIBAL-H, DCM, rt; (e) CBr4, PPh3, NEt3, DCM, rt; (f) nBuLi, ethyl chloroformate, THF, −78 °C; (g) 10% HCl, THF,
rt; (h) LAH, THF, rt; (i) TsCl, NEt3, DMAP, DCM, rt; ( j) lithium acetylide–ethylenediamine complex, DMSO, 0 °C to rt; (k) nBuLi, ethyl chlorofor-
mate, THF, −78 °C to rt then 10% HCl, rt.
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Scheme 10 Lactonization reactions: Asymmetric version. Reagents
and conditions: (a) 4 equiv. NaOEt, EtOH, reflux, 16 h.
Fig. 2 ORTEP depiction of compounds 53 (top) and 54 (bottom) with
thermal ellipsoids at the 50% probability level.16
Fig. 3 ORTEP depiction of compound 58 with thermal ellipsoids at
the 50% probability level.17
observed for the hydroxyl-esters. Based on this precedence, we
hypothesized a double bond isomerization prior to lactonization
via a Michael retro–Michael addition of ethanolate on the allylic
ester or the reversible formation of an epoxide by intramolecular
Michael reaction.
Conclusions
In conclusion, (η2-propene)titanium promoted intramolecular
reductive coupling reaction of cycloalkanones bearing activated
alkynes provide bicyclic allylic alcohols in a stereoselective
manner. This synthetically useful method was extended to
various cycloalkanones bearing a 7-ynoate or 8-ynoate side
chain. Although the lactonization reaction starting from m-5
bicyclic systems (compounds 25–27 and 51–52) failed, unsatu-
rated tricyclic lactones could be obtained starting from hydroxy-
esters 28–29 and 53–54. Thus the tricyclic compounds obtained
are present in numerous bioactive natural products. Further
studies on synthetic applications of this methodology are under
investigation.
Scheme 9 Lactonization reactions. Reagents and conditions: (a) 4
equiv. NaOEt, EtOH, reflux, 16 h.
good yields (Scheme 10). The structure of compound 58 was
unambiguously confirmed by X-ray crystallographic analysis
(Fig. 3).
Although the lactonization reaction was successful, the for-
mation of the lactones stands in contrast with the stereochemistry
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Polytechnique, Paris) for helpful discussions and Dr Jennifer
Wytko for assistance in preparing the manuscript. C.S. thanks
MRT for a research fellowship.
Experimental section
Typical procedure for the preparation of bicyclic γ-hydroxy
α,β-unsaturated esters
The starting material (0.6 mmol, 1 equiv.) was dissolved in
10 mL of dry Et2O and cooled to −30 °C. Ti(OiPr)4 (1.2 mmol,
2 equiv.) was added under vigorous stirring. Then iPrMgBr
(3.6 mmol, 6 equiv.) was added dropwise. The reaction mixture
was stirred at −30 °C for 2 h, then hydrolysed with 10 mL of
10% HCl at −30 °C, warmed to rt and stirred for 30 min. The
aqueous phase was extracted with 2 × 25 mL of Et2O and 2 ×
25 mL of EtOAc. The combined organic layers were consecu-
tively washed with 25 mL of a saturated aqueous solution of
NaHCO3, 15 mL of a saturated aqueous solution of NaCl, dried
over anhydrous Na2SO4 and concentrated in vacuum (15 mbar).
The pure product was obtained by column chromatography
(petroleum ether–EtOAc 95 : 5).
Notes and references
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Chem., 2010, 6944–6948; (b) L. Miesch, T. Welsch, V. Rietsch and
M. Miesch, Chem.–Eur. J., 2009, 15, 4394–4401.
(E)-Ethyl-2-((4aS,8aR)-8a-hydroxy-4a-methyloctahydronapht-
halen-1(2H)-ylidene)acetate 54. Yield: 78%; colourless oil; 1H
NMR (300 MHz, CDCl3) δ 0.83 (s, 3H), 1.07–1.25 (m, 2H),
1.27 (t, J = 7.1 Hz, 3H), 1.45–1.77 (m, 9H), 1.93–2.21 (m, 3H),
3.90 (d, J = 14.3 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 6.11 (d, J =
1.8 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 14.4, 21.0,
21.5, 22.3, 22.7, 26.6, 33.6, 34.0, 35.9, 39.7, 59.8, 77.4, 112.4,
166.3, 167.5 ppm; IR (neat) 3516, 2926, 2864, 1696,
1638 cm−1; HRMS Cal for [M + Na]+: C15H24O3: 275.1618
Found: 275.1611; [α]2D0 = +39.24 (c = 0.576, CHCl3).
6 (a) J. K. Chan and O. G. Kulinkovich, in Organic Reactions, ed.
S. E. Denmark, John Wiley & Sons, Inc., Hoboken, New Jersey, 2012,
vol. 77; (b) A. Wolan and Y. Six, Tetrahedron, 2010, 66, 15–61;
(c) A. Wolan and Y. Six, Tetrahedron, 2010, 66, 3097–3133; (d) P. Setzer,
A. Beauseigneur, M. S. M. Pearson-Long and P. Bertus, Angew. Chem.,
Int. Ed., 2010, 49, 8691–8694; (e) O. Kulinkovich, Eur. J. Org. Chem.,
2004, 4517–4529; (f) I. Marek, Titanium and Zirconium in Organic Syn-
thesis, Wiley-VCH Verlag GmbH, Weinheim, Germany, 2002;
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2886; (h) O. G. Kulinkovich and A. de Meijere, Chem. Rev., 2000, 100,
2789–2834; (i) O. G. Kulinkovich, S. V. Sviridov and D. A. Vasilevski,
Synthesis, 1991, 234; ( j) O. G. Kulinkovich, S. V. Sviridov, D.
A. Vasilevski and T. S. Pritytskaya, Zh. Org. Khim., 1989, 25, 2244–
2245.
Typical procedure for the preparation of tricyclic
α,β-unsaturated lactons
7 K. Harada, H. Urabe and F. Sato, Tetrahedron Lett., 1995, 36, 3203–
3206.
8 (a) F. Sato and S. Okamoto, Adv. Synth. Catal., 2001, 343, 759–784;
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920; (c) F. Sato, H. Urabe and S. Okamoto, Pure Appl. Chem., 1999, 71,
1511–1519; (d) C. Averbuj, J. Kaftanov and I. Marek, Synlett, 1999,
1939–1941; (e) S. Okamoto, A. Kasatkin, P. K. Zubaidha and F. Sato, J.
Am. Chem. Soc., 1996, 118, 2208–2216.
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H. Imahori, J. Org. Chem., 2008, 73, 5139–5142; (b) Y. Matano,
T. Miyajima, T. Nakabuchi, Y. Matsutani and H. Imahori, J. Org. Chem.,
2006, 71, 5792–5795; (c) R. Tanaka, A. Yuza, Y. Watai, D. Suzuki,
Y. Takayama, F. Sato and H. Urabe, J. Am. Chem. Soc., 2005, 127, 7774–
7780; (d) R. Tanaka, S. Hirano, H. Urabe and F. Sato, Org. Lett., 2002, 5,
67–70; (e) R. Tanaka, Y. Nakano, D. Suzuki, H. Urabe and F. Sato, J.
Am. Chem. Soc., 2002, 124, 9682–9683.
A solution of sodium (4 equiv.) in dry EtOH (10 mL) was added
to a solution of the bicyclic γ-hydroxy α,β-unsaturated esters
(0.5 mmol, 1 equiv.) in 6 mL of dry EtOH. The resulting
mixture was refluxed for 16 h. After cooling to rt the solvent was
removed. The resulting slime was dissolved in 15 mL of Et2O
and treated with 8 mL of a saturated aqueous solution of NH4Cl.
The aqueous phase was extracted with 3 × 15 mL of Et2O. The
combined organic layers were washed with 20 mL of a saturated
aqueous solution of NaCl, dried over anhydrous Na2SO4 and
concentrated in vacuum (15 mbar). The pure product was
obtained by column chromatography (petroleum ether–EtOAc
95 : 5).
10 (a) H. Urabe, K. Suzuki and F. Sato, J. Am. Chem. Soc., 1997, 119,
10014–10027; (b) K. Suzuki, H. Urabe and F. Sato, J. Am. Chem. Soc.,
1996, 118, 8729–8730.
11 N. Morlender-Vais, N. Solodovnikova and I. Marek, Chem. Commun.,
2000, 1849–1850.
12 (a) A. J. Mota, A. Klein, F. Wendling, A. Dedieu and M. Miesch,
Eur. J. Org. Chem., 2005, 4346–4358; (b) A. Klein and M. Miesch,
Tetrahedron Lett., 2003, 44, 4483–4485.
13 D. Suzuki, H. Urabe and F. Sato, Angew. Chem., Int. Ed., 2000, 39,
3290–3292.
14 Similar compounds were recently described by Sato and coworkers using
a nickel-catalyzed intramolecular cyclization in the presence of Et3SiH
using NHC ligand: N. Saito, Y. Sugimura and Y. Sato, Org. Lett., 2010,
12, 3494–3497.
(6aS,10aR)-6a-Methyl-4,5,6,6a,7,8,9,10-octahydro-2H-naphtho-
[8a,1-b]furan-2-one 58. Yield: 70%; colourless solid; H NMR
1
(300 MHz, C6D6) δ 0.61 (s, 3H), 0.84–1.27 (m, 6H), 1.28–1.43
(m, 4H), 1.43–1.69 (m, 3H), 1.93 (ddt, J = 13.9, 4.6, 1.8Hz,
1H), 5.35 (d, J = 2.0 Hz, 1H) ppm;13C NMR (75 MHz, C6D6) δ
20.8, 21.2, 22.2, 22.6, 25.9, 30.2, 32.3, 36.5, 39.6, 88.6, 113.4,
172.0, 172.7 ppm; IR (neat) 2927, 2864, 1731, 1235 cm−1
;
HRMS Cal for [M + Na]+: C13H18O2: 229.1199 Found:
229.1205; [α]2D0 = −40.17 (c = 0.605, CHCl3).
15 P. Geoffroy, M.-P. Ballet, S. Finck, E. Marchioni, C. Marcic and
M. Miesch, Synthesis, 2010, 171–179.
16 CCDC-784204 contains the supplementary crystallographic data for com-
pound 53. CCDC-784206 contains the supplementary crystallographic
data for compound 54.
17 CCDC-784205 contains the supplementary crystallographic data for com-
pound 58.
Acknowledgements
Support for this work was provided by CNRS and Université de
Strasbourg. The authors are grateful to Dr Yvan Six (Ecole
This journal is © The Royal Society of Chemistry 2012
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