Controlled site-selective reaction of γ,γ-dialkoxyallylic zirconium species with carbonyl compounds: A new method for the construction of gem-dialkoxycyclopropane derivatives

Full text of DOI:10.1021/ja9808954

J. Am. Chem. Soc. 1998, 120, 6623-6624
6623
Controlled Site-Selective Reaction of
Table 1. Reaction of γ,γ-Dialkoxyallyliczirconium Species with
a
Carbonyl Compound under Lewis Acid Promoted Conditions
γ,γ-Dialkoxyallylic Zirconium Species with Carbonyl
Compounds: A New Method for the Construction of
gem-Dialkoxycyclopropane Derivatives
Hisanaka Ito, Hisayo Kuroi, Hui Ding, and Takeo Taguchi*
Tokyo UniVersity of Pharmacy and Life Science
432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
1
ReceiVed March 17, 1998
Carbon-carbon bond-forming reactions of allylic organome-
tallics with electrophiles have been recognized as one of the most
fundamental means in organic synthesis, and a number of
applications for the construction of biologically active molecules
have been reported.1 Normally, allylic organometallics react with
electrophiles at the R- or γ-position of a metal center. We have
reported the carbon-carbon bond-forming reactions by use of
the allylic and related zirconium species as reactive intermediates.2
These zirconium species can be generated by treating allylic ethers
with a zirconocene-butene complex (“Cp
2
Zr”)3 through the
formation of zirconacyclopropane and the following â-elimination
of the alkoxyl group. Very recently, we reported the preparation
of the γ,γ-dialkoxyallylic zirconium species 2 and its reaction
with aromatic and R,â-unsaturated aldehydes (eq 1).4 In this
a
4
Reaction conditions: 2 (3 mmol based on the ortho ester), carbonyl
compound (3.6 mmol), Lewis acid (3.3 mmol), toluene (26 mL), -78
C to room temperature, 2 h, then NH
Cl(aq). b Relative stereochem-
°
4
istries were not determined. Diastereomeric ratio was 1:1 to 2:1.
c
Isolated yield after column chromatography (neutral silica gel).
compounds selectiVely at the â-position in the first step, followed
by the cyclopropanation reaction to afford the gem-dialkoxycy-
6
clopropane deriVatiVes 4 (eq 2). Furthermore, by treating the
compound 4 with acid (trifluoroacetic acid), the â,γ-unsaturated
carboxylic ester 5 was obtained, which is formally derived when
the γ,γ-dialkoxyallylic zirconium species 2 reacts at the R-position
of the zirconium atom (eq 3); that is, 2 can serve as a homoenolate
anion equivalent.7 We report herein this controlled site-selective
reaction of the γ,γ-dialkoxyallylic zirconium species 2 leading
to a new preparative method for the gem-dialkoxycyclopropane
derivatives 4.
reaction, addition of the γ,γ-dialkoxyallylic zirconium species 2
to the carbonyl group occurred in SEi′ mode; thus, 2 behaved as
an R,â-unsaturated acyl anion equivalent. This zirconium species
2
possibly has two reactive sites: one is the γ-position of the
zirconium atom as an allylic zirconium species as reported
4
previously, and the other is the â-position as a ketene dialkyl
acetal.5 We found that under Lewis acid promoted conditions,
this zirconium species 2 reacts with a Variety of carbonyl
Typical examples are summarized in Table 1. In the presence
of Lewis acid, the γ,γ-diethoxyallylic zirconium species 2,
(
1) For reviews on preparations and reactions of allylic organometallic
reagents, see: (a) Yamamoto, Y.; Maruyama, K. Heterocycles 1982, 18, 357.
b) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1982, 21, 555. (c)
(
(5) For the reaction of ketene dialkylacetal with carbonyl compounds, see:
(a) Scheeren, J. W. Recl. TraV. Chim. Pays-Bas 1986, 105, 71. (b) Mattay, J.;
Buchkremer, K. Heterocycles 1988, 27, 2153. (c) Hofstraat, R. G.; Lange, J.;
Scheeren, H. W.; Nivard, R. J. F. J. Chem. Soc., Perkin Trans. 1 1988, 2315.
(d) Aben, R. W. M.; Smit, R.; Scheeren, J. W. J. Org. Chem. 1987, 52, 365.
(e) Hofstraat, R. G.; Scheeren, H. W.; Nivard, R. J. F. J. Chem. Soc., Perkin
Trans. 1 1985, 561. (f) Aben, R. W. M.; Scheeren, J. W. Tetrahedron Lett.
1983, 24, 4613. (g) Aben, R. W. M.; Scheeren, J. W. Synthesis 1978, 400.
(h) Scheeren, H. W.; Aben, R. W. M.; Ooms, P. H. J.; Nivard, R. J. F. J.
Org. Chem. 1977, 42, 3128. (i) Dauben, W. G.; Krabbenhoft, H. O. J. Org.
Chem. 1977, 42, 282.
(6) For the preparation and synthetic utility of gem-dialkoxycyclopropanes,
see: (a) Kuwajima, I.; Nakamura, E. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter
1.14. (b) Nakamura, E.; Kubota, K. J. Org. Chem. 1997, 62, 792.
(7) For reviews, see: (a) Kuwajima, I.; Nakamura, E. Top. Curr. Chem.
1990, 155, 1. (b) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932. (c)
Syowell, J. C. Chem. ReV. 1984, 84, 409. (d) Werstiuk, N. H. Tetrahedron
1983, 39, 205.
Yamamoto, Y. Acc. Chem. Res. 1987, 20, 243. (d) Roush, W. R. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, Chapter 1.1. (e) Yamamoto, Y. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1
2
991; Vol. 2, Chapter 1.2. (f) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93,
207.
(2) (a) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33, 1295.
(
b) Ito, H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992,
3
7
1
3, 3769. (c) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33,
873. (d) Ito, H.; Motoki, Y.; Taguchi, T.; Hanzawa, Y. J. Am. Chem. Soc.
993, 115, 8835. (e) Ito, H.; Ikeuchi, Y.; Taguchi, T.; Hanzawa, Y.; Shiro,
M. J. Am. Chem. Soc. 1994, 116, 5469. (f) Ito, H.; Nakamura, T.; Taguchi,
T.; Hanzawa, Y. Tetrahedron 1995, 51, 4507. (g) Hanzawa, Y.; Ito, H.;
Taguchi, T. Synlett 1995, 299. (h) Hanzawa, Y.; Kiyono, H.; Tanaka, N.;
Taguchi, T. Tetrahedron Lett. 1997, 38, 4615.
(
3) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986,
7, 2829.
4) Ito, H.; Taguchi, T. Tetrahedron Lett. 1997, 38, 5829.
2
(
S0002-7863(98)00895-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/19/1998

6624 J. Am. Chem. Soc., Vol. 120, No. 26, 1998
Communications to the Editor
Scheme 1
A plausible mechanism for the formation of cyclopropane
derivatives 4 is shown in Scheme 1. In the presence of Lewis
acid, the ketene diethyl acetal character overcomes the allylic
zirconium character, and the aldol-type reaction or Paterno-B u¨ chi
reaction of γ,γ-dialkoxyallylic zirconium species 2 with the
aldehyde first proceeded at the â-position of 2 to afford the
4
2
prepared from triethyl orthoacrylate (1) with “Cp Zr”, smoothly
reacted with aldehydes to afford the gem-diethoxycyclopropane
derivatives 4 as a diastereomeric mixture.8 The use of Lewis
acid brought about a remarkable contrast with respect to not only
the reactivity but also the site-selectivity, since 2 itself did not
react with aliphatic aldehydes and the normal allylic zirconium
reaction (γ-addition) occurred with aromatic or R,â-unsaturated
aldehydes.4 Under the Lewis acid promoted conditions, toluene
was more effective solvent as compared with THF. Regarding
the Lewis acid, when boron trifluoride diethyl ether complex was
employed, the reaction of 2 with 3-phenylpropionaldehyde gave
12
intermediate 8. The in situ generated oxocarbenium intermediate
8 then smoothly reacts intramolecularly with the alkyl zirconium
1
3
species to form the gem-diethoxycyclopropane derivatives 4.
To ascertain the possibility of the existence of the intermediate
8, we examined the deuterium incorporation at the methyl group
in the compound 7. Thus, after stirring the γ,γ-diethoxyallylic
zirconium species 2 with 3-phenylpropionaldehyde in the presence
of TMSOTf at -78 °C for 5 min, 20% deuterium chloride in
2
D O was added to the reaction mixture. After workup, products
4
7
a in 75% yield along with a small amount of uncyclized product
a (entry 1). This result may support the following discussion
4a and 7b were obtained in 44% (diastereomeric ratio, 5:4) and
35% (diastereomeric ratio, 5:3) yield, respectively. Formation
of the compound 7b having a deuterium atom (>85%) at the
R-methyl group should support the preexistence of zirconium at
this position, thereby the reaction pathway to 4 involves the
intermediate 8.
In summary, we have revealed here the interesting reactivity
of the γ,γ-dialkoxyallylic zirconium species 2 in the reaction with
carbonyl compounds. This species reacted with the carbonyl
compound at the â-position of the zirconium atom in the presence
of trimethyl trifluoromethanesulfonate, and the gem-dialkoxycy-
clopropane derivatives could be obtained via the aldol-type or
Paterno-B u¨ chi reaction and the following cyclization. It is
noteworthy that all three carbons in the allylic moiety of this
species can participate in the reaction with the carbonyl com-
pound, and this participation can be controlled by the choice of
reaction conditions.
for the mechanism of this reaction (vide infra). Trimethylsilyl
trifluoromethanesulfonate (TMSOTf) smoothly promoted the
reaction of 2 to afford the compound 4a in 88% yield without
the formation of 7a (entry 3). Similarly, the zirconium species 2
reacted with not only aliphatic aldehydes but also aromatic
aldehyde to give the cyclopropane derivatives (4b, 4c, and 4d)
in good yields (entries 4-6).9 Ketones also reacted with this
reagent to afford the adduct (4e, 4f), while the adduct was
relatively unstable due to the facile elimination of the hydroxyl
group during the acidic silica gel column chromatography (entries
7
and 8).10
We also examined the reaction of γ,γ-dialkoxyallylic zirconium
species 2 with R,â-unsaturated carbonyl compounds. Under
TMSOTf-promoted conditions, the 1,4-addition reaction at the
â-position of 2 with 5-phenylpent-1-en-3-one predominantly
proceeded to afford 6a in good yield (eq 4).11 With cycloal-
kenones, 1,4-adduct 6b and 6c were selectively obtained (eq 5).
Supporting Information Available: Experimental details and char-
acterization for all new compounds (7 pages, print/PDF). See any current
masthead page for ordering information and Web access instructions.
8) All new compounds gave satisfactory 1H NMR, 13C NMR, IR, and
elemental analysis.
(
JA9808954
(9) Molecular design of an HMG CoA reductase inhibitor having a gem-
dihydroxycyclopropyl carbinol moiety was reported: Dowd, P.; Kaufman,
C.; Abeles, R. H. J. Am. Chem. Soc. 1984, 106, 2703.
(12) See ref 5a.
(13) For the intramolecular cyclization of homoenolate anion for construc-
tion of cyclopropane and related reactions, see: (a) R u¨ hlmann, K. Synthesis
1971, 236. (b) Rousseau, G.; Slougui, N. J. Am. Chem. Soc. 1984, 106, 7283.
(c) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am. Chem.
Soc. 1987, 109, 8056. (d) Rieke, R. D.; Sell, M. S.; Xiong, H. J. Am. Chem.
Soc. 1995, 117, 5429. (e) Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36,
6079. (f) Kasatkin, A.; Kobayashi, K.; Okamoto, S.; Sato, F. Tetrahedron
Lett. 1996, 37, 1849.
(10) It would be expected that the ring opening of the compound 4 can be
Easily promoted by acidic treatment. Indeed, when the compounds 4a and 4e
were treated with 50% aqueous trifluoroacetic acid in chloroform at room
temperature, the corresponding â,γ-unsaturated esters 5a (82%, E,Z mixture)
and 5e (86%) were obtained, respectively.
(11) In the case of (E)-2-hexenal, a competitive reaction of 1,2-addition
and 1,4-addition was observed in the presence of TMSOTf.