Selective preparation of benzyltitanium compounds by the metalative reppe reaction. Its application to the first synthesis of alcyopterosin A

Article abstract of DOI:10.1021/ja027008o

Dialkoxytitanacyclopentadienes, prepared from two different acetylenes and a divalent titanium alkoxide reagent, Ti(O-i-Pr)₄/2 i-PrMgCl, reacted with propargyl bromide to give directly benzyltitanium compounds. The resultant benzyltitanium comp

Full text of DOI:10.1021/ja027008o

Published on Web 07/26/2002
Selective Preparation of Benzyltitanium Compounds by the Metalative Reppe
Reaction. Its Application to the First Synthesis of Alcyopterosin A
Ryoichi Tanaka,† Yoshitaka Nakano,† Daisuke Suzuki,‡,§ Hirokazu Urabe,† and Fumie Sato*,‡
Departments of Biological Information and Biomolecular Engineering, Graduate School of Bioscience and
Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8501, Japan
Received May 22, 2002
Benzylmetal compounds occupy an important position among
organometallic compounds that allow the introduction of an
aromatic moiety into organic molecules.1 While the preparation of
benzylmetals continues to utilize metalation of appropriate aromatic
compounds,1 a conceptually different method, starting from non-
aromatic precursors, could be a useful alternative. Herein we report
such a novel transformation based on the metalative Reppe reaction
of acetylenes and a titanium(II) reagent, which directly and
regioselectively produces benzyltitanium compounds as shown in
Scheme 1.2
A proposed mechanism of this reaction is also drawn in eq 1,
where the propargyl bromide is incorporated into the titanacycle 4
in a regioselective manner8 and, perhaps, in equilibrium to form 6
as a transient species. However, elimination of the leaving group
(Br) from this intermediate 6 should make the whole reaction
irreversible, to lead to the formation of benzyltitanium compound
8 via the aromatization of 7.
Other results are summarized in Table 1. The benzyltitanium 8
in eq 1 could be iodinated (with iodine) or oxygenated (with dry
oxygen gas under atmospheric pressure) to afford benzyl iodide
10 or alcohol 11, respectively (entries 3 and 4). Such synthetic
applications of the resulting titanium compounds would broaden
the utility of this method.9 Enyne 12 gave the desired aromatic
compound 14 after hydrolysis of 13 without any complication (entry
5). Acetylene 15 underwent the cyclotrimerization with 16 and 5
as well to give a mixture of benzyltitanium compounds 17-19, as
evidenced by hydrolysis and deuteriolysis (entry 6).3 Nonetheless,
as 17 and 18 have the same structure except for the arylmetal portion
(Si or Ti),10 the regioselectivity regarding the uptake of propargyl
bromide ((17 + 18)/19 ) 94:6) did prove very high. Hydrolysis of
a mixture of 17-19, subsequent desilylation with CF3CO2H, and
purification on silica gel furnished the major aromatic compound
20 in pure form, as shown in entry 6.3
Scheme 1. New Metalative Reppe Reaction Producing
Benzyltitanium Compounds
Equation 1 illustrates the actual transformation of Scheme 1.3
Thus, titanacyclopentadiene 4 was first prepared from two different,
Tethered acetylenes (i.e., diynes) are also feasible substrates in
this reaction to give bicyclic compounds (Table 1, entries 7-14).
The acetylene-titanium complex generated from acetylenic ester
21 underwent orderly coupling with each of the two acetylenic
bonds of diyne 22 to give a single benzyltitanium intermediate 23,
which, upon hydrolysis, gave aromatic ester 24 in good yield (entry
7). The smooth generation of a sterically hindered benzylmetal
species such as 23 is an interesting application of this method.
Similarly, the cyclotrimerization of acetylenic amide 25 and diyne
26 afforded aromatic amide 28 (entry 8). Alternatively, oxygenation
of the intermediate titanium species 30 with O2 produced a benzyl
alcohol, which was then lactonized to give tricyclic phthalide
derivative 31 (entry 9). As precedented in entry 6, the assembly of
acetylene 15 and diyne 26 afforded a mixture of two benzyltitanium
species, 32 and 33 (entry 10), which finally led to a single aromatic
compound 34 by the same treatment as described in entry 6. On
the other hand, entries 11-14 show that diyne 35 worked as the
first and second acetylenes to give benzyltitanium compound 36,
which was subsequently hydrolyzed, iodinated, oxygenated, or
alkylated to give the corresponding products 37-40 in good yields.
It should be noted that the silicon-titanium crossing observed in
the aforementioned entries 6 and 10 was not seen at all in this
combination of acetylenes.
unsymmetrical acetylenes, 2 and 3 (as the first and second
acetylenes), and a divalent titanium alkoxide, Ti(O-i-Pr)4/2 i-PrMgCl
(1),4 at -50 °C.5 Propargyl bromide (5)6 was then added as the
third acetylene. The reaction mixture was allowed to warm to room
temperature to give a single benzyltitanium compound 8, the
presence of which was confirmed by its hydrolysis and deuteriolysis
to give 9 as the sole aromatic compound. It should be noted that
this method achieved the selective cyclotrimerization of three
different, unsymmetrical acetylenes to a single aromatic compound,
which has been only scarcely precedented.2,7 Another synthetic
advantage is that the ester group in acetylene 2 survived the reaction
conditions to allow the generation of a functionalized benzylmetal
species.
* Corresponding author. E-mail: fsato@bio.titech.ac.jp.
† Department of Biological Information.
The convenient preparation of bicyclic aromatic compounds as
shown above prompted us to explore the first concise synthesis of
‡ Department of Biomolecular Engineering.
§ Research Fellow of the Japan Society for the Promotion of Science.
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10.1021/ja027008o CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Total Synthesis of Alcyopterosin Aa
Table 1. Preparation of Benzyltitanium Compounds
a Reagents and conditions: (i) Ti(O-i-Pr)4/2 i-PrMgCl, then H+, 73%;
(ii) LiAlH4, 91%; (iii) PCC, 96%; (iv) Ph3PdCH2, 86%; (v) BH3‚THF,
then H2O2/OH-, 67%; (vi) SOCl2, LiCl, pyridine, 70%.
three acetylenes and the titanium alkoxide has been reported. Further
extension and application of this method are under active investiga-
tion.
Acknowledgment. We thank the Japan Society for the Promo-
tion of Science for financial support.
Supporting Information Available: Experimental procedures,
physical properties of products, and a proposed reaction course (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) For a recent survey on the preparation of benzylmetal compounds, see:
(a) Kim, S.-H.; Rieke, R. D. J. Org. Chem. 2000, 65, 2322-2330 and
references therein. (b) Trost, B. M., Fleming, I., Eds. ComprehensiVe
Organic Synthesis; Pergamon Press: Oxford, 1991; Vol. 1.
(2) For the metalative Reppe reaction giving aryltitanium compounds and
pertinent references on acetylene cyclotrimerization, see: Suzuki, D.;
Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123, 7925-7926.
(3) For details, see the Supporting Information.
(4) (a) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835-2886.
(b) Kulinkovich, O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789-
2834. (c) Eisch, J. J. J. Organomet. Chem. 2001, 617-618, 148-157.
(d) Sato, F.; Okamoto, S. AdV. Synth. Catal. 2001, 343, 759-784. (e)
Sato, F.; Urabe, H. In Titanium and Zirconium in Organic Synthesis;
Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; pp 319-354.
(5) (a) Urabe, H.; Sato, F. J. Am. Chem. Soc. 1999, 121, 1245-1255. (b)
Hamada, T.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 1999,
121, 7342-7344.
(6) Propargyl chloride or phosphate gave inferior results to the bromide.
Reaction of allyl phenyl ether with diaryloxytitanacyclopentadienes,
generating (cyclohexadienylmethyl)titanium species, was reported: (a)
Balaich, G. J.; Rothwell, I. P. Tetrahedron 1995, 51, 4463-4470. Copper-
mediated coupling of propargyl bromide with zirconacycles is known,
but the formation of benzylmetal reagents has not been evidenced: (b)
Takahashi, T.; Tsai, F.-Y.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka, M.;
Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 5059-5067.
(7) Gevorgyan, V.; Radhakrishnan, U.; Takeda, A.; Rubina, M.; Rubin, M.;
Yamamoto, Y. J. Org. Chem. 2001, 66, 2835-2841.
a Structure deduced by spectroscopic analysis of the products resulting
from hydrolysis, deuteriolysis, and other reactions with electrophiles. TiX3
is likely Ti(O-i-Pr)2Br. b No other isomer(s) detected in a crude reaction
mixture, unless otherwise stated. c Isolated, overall yields from acetylenes.
d After desilylation with CF3CO2H. See text. e After lactonization with
p-MeC6H4SO3H. f Yield of a purified mixture of protonated 32 and 33 (6:
4) before desilylation. g Yield not optimized.
(8) Rationale of this regioselection so far remains unclear and should await
further study. Other possible paths from 4 to 8 are shown in the Supporting
Information.
(9) For general synthetic application of organotitanium compounds, see: (a)
Ferreri, C.; Palumbo, G.; Caputo, R. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1,
pp 139-172. (b) Reetz, M. T. In Organometallics in Synthesis; Schlosser,
M., Ed.; Wiley: Chichester, 1994; pp 195-282.
(10) A plausible mechanism of the formation of 18 during the cyclotrimerization
and its basis are provided in the Supporting Information.
alcyopterosin A (41) (Scheme 2). Its isolation, characterization, and
mild cytotoxicity toward human tumor cell lines were quite recently
reported.11,12 The cyclotrimerization of acetylenic ester 21 and diyne
42 afforded the properly substituted aromatic ring 43 in one step
and in 73% yield after hydrolysis. Modification of the ester portion
of 43 to an alcohol (44), vinyl group (45), hydroxyethyl group (46),
and, finally, the chloroethyl group by standard methods completed
the first synthesis of alcyopterosin A (41).
(11) Palermo, J. A.; Brasco, M. F. R.; Spagnuolo, C.; Seldes, A. M. J. Org.
Chem. 2000, 65, 4482-4486.
(12) For reviews on the synthesis of illudalane sesquiterpenoids, to which
alcyopterosin A belongs, see: (a) Terpenoids and Steroids; The Royal
Society of Chemistry: London, 1971-1983; Vols. 1-12. A synthesis of
illudalanes based on Rh-catalyzed cyclotrimerization of three acetylenes
was reported, where all acetylenes were tethered to eliminate the
regiochemical ambiguity. (b) Neeson, S. J.; Stevenson, P. J. Tetrahedron
1989, 45, 6239-6248.
In conclusion, a novel preparation of benzyltitanium compounds,
which may have a functional group such as ester or amide, from
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