Olefinic-ester cyclizations using Takai-Utimoto reduced titanium alkylidenes

Article abstract of DOI:10.1016/j.tetlet.2005.08.071

The scope and limitations of the Takai-Utimoto reagent to induce the cyclization of olefinic-esters is described. Critical is the steric environment about both the ester and the olefin. Mechanistically, these results support the hypothesis that cyclized p

Full text of DOI:10.1016/j.tetlet.2005.08.071

Tetrahedron
Letters
Tetrahedron Letters 46(2005) 7209–7211
Olefinic-ester cyclizations using Takai–Utimoto
reduced titanium alkylidenes
Utpal Majumder and Jon D. Rainier*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA
Received 8 August 2005; revised 15 August 2005; accepted 16August 2005
Available online 6September 2005
Abstract—The scope and limitations of the Takai–Utimoto reagent to induce the cyclization of olefinic-esters is described. Critical is
the steric environment about both the ester and the olefin. Mechanistically, these results support the hypothesis that cyclized product
comes from an olefin metathesis, carbonyl-olefination sequence.
Ó 2005 Elsevier Ltd. All rights reserved.
Because they serve as precursors to a number of interest-
ing heterocyclic compounds, cyclic enol ethers have gar-
nered the attention of the chemical synthesis
community. Among the various routes to their synthe-
sis, there has been considerable interest in the conver-
sion of olefinic-esters into cyclic enol ethers via the
two-step metathesis sequence outlined in Scheme 1.1,2
directly from an olefinic-ester.4 Finally, Nicolaou and
co-workers reported olefinic-ester cyclization reactions
using the Tebbe and Petasis reagents to generate fused
ether compounds.5
Our interest in cyclic enol ethers directed our attention
to the generation of acyclic enol ethers from the corre-
sponding olefinic-esters using the Takai–Utimoto tita-
nium alkylidene.6 We were attracted to this reagent
primarily because of its in situ preparation and its
diminished Lewis acidity relative to the more commonly
employed Tebbe reagent. Important to the generation of
highly substituted targets, substrates having functional-
ity sensitive to the Tebbe reagent often stand up to the
Takai–Utimoto reagent. For example, in our hands we
were unable to isolate either acyclic or cyclic enol ethers
from the reaction of 4 with the Tebbe reagent but were
with the Takai–Utimoto reagent (Table 1).7
Clearly, a more efficient method of transforming 1 into 3
would bypass acyclic enol ether intermediates (e.g., 2).
Along these lines, successes have been reported. In the
mid-1980s Grubbs and co-workers successfully synthe-
sized capnellene by utilizing norbornenes in a ring-
opening metathesis, carbonyl-olefination sequence.3
Subsequently, Fu and Grubbs reported the use of a
tungsten alkylidene to generate cyclic enol ethers
O
R
O
R
"M="
O
CH2
In addition to demonstrating the mild nature of the
Takai–Utimoto protocol, the example in Table 1 illus-
trates that this reagent can affect the cyclization of
olefinic-esters.8 However, Scheme 2 also points to a sig-
nificant problem; to the best of our knowledge, the
exclusive formation of cyclic enol ethers from olefinic-
esters using this reagent has not been reported. A better
understanding of the ability of the Takai–Utimoto
reagent to convert olefinic-esters into cyclic enol ethers
would be significant; the results of our initial attempts
to attain this goal are described here.
"Mo="
or
"Ru="
1
2
O
R
i-Pr
i-Pr
Ph
MesN
NMes
Ph
3
"Mo=":
N
Me(F3C)2CO
(F3C)2MeCO
Cl
Cl
"Ru=":
Ru
Mo
PCy3
Scheme 1.
Keywords: Metathesis; Cyclization; Enol ether; Polycyclic ether;
Titanium.
*
In their work, Nicolaou and co-workers found that cyclic
enol ethers resulted from acyclic enol ether intermediates
Corresponding author. Tel.: +1 801 581 4954; fax: +1 801 581 8433;
e-mail: rainier@chem.utah.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.071

7210
U. Majumder, J. D. Rainier / Tetrahedron Letters 46 (2005) 7209–7211
Table 1.
Table 2.
PMBO
CH3
OBn
H
H
R
R
O
OBn
OBn
O
OBn
TiCl4, Zn,PbCl2,
CH2Br2, THF,
BnO
BnO
CH2
5
PMBO
H
H
H
O
H
O
CH3
O
R
O
OBn
H
H
H
H
C
"Ti="
TMEDA, CH Cl2 65˚C
OBn
H
O
OBn
2
PMBO
O
CH3
BnO
O
O
OBn
H
O
H
4
O
H
CH2
OBn
O
H
O
H
H
H
A
6
Entry
Ester
R
Enol
ether(s)
Yield
(%)a
C:Ab
ÔTi =Õ
Yield (%)
5:6
a
Tebbe
Takai
—
—
1:1
1
2
3
10
11
12
CH3
i-Pr
CH2OTBDPS
14
15
16
80
88
862.1:1
5:3
2.4:1
77b
a Products included hydrolyzed ester.
b Yield after a subsequent RCM reaction using the 2nd generation
O
H
GrubbÕs catalyst.
4
13
17
71
>95:5
O
a Isolated yields after chromatography.
b From the crude 1H NMR of the reaction mixture.
OR'
OR'
H
H
H
H
H
H
R
O
OR"
OR"'
R
O
OR"
OR"'
"Ti="
O
O
O
O
Interestingly, the steric environment on the pyranyl side
of the ester played an even larger role in the generation
of cyclic enol ether (Table 3). Substrates having C(3)
TBDPS ethers gave exclusively cyclic products even
when relatively unhindered esters were employed.
H
H
8
Ti
OR'
7
H
H
H
R
O
OR"
OR"'
O
H
Cyclizations of a-allyl C-glycosidic esters are also sensi-
tive to the steric environment about the ester (Table 4).12
That is, 23 gave exclusively cis-fused bicyclic enol ether
25 while 22 (R = CH3) gave a mixture of cyclic and acy-
clic enol ethers.
"Ti=O"
9
Scheme 2.
and a subsequent enol ether-olefin RCM sequence.5 In
contrast, we found that acyclic enol ethers are not pre-
cursors to cyclic enol ethers when the Takai–Utimoto
reagent is used.9 Based upon this, we proposed that
cyclic material from the Takai–Utimoto reagent was
the result of an olefin metathesis, carbonyl-olefination
sequence (Scheme 2). Mechanistically, this proposal is
similar to the initial Grubbs hypothesis;3 the difference
being that Grubbs had only reported the use of strained
olefins.
To determine the extent to which a TBDPS ether at C(3)
was capable of influencing the cyclization, we examined
glycosides having dialkyl substitution at the anomeric
position (C-ketosides, Table 5). Based upon our mecha-
nistic hypothesis, it was not surprising that C-ketosides
gave relatively lower yields of cyclic products. However,
as was observed previously, the dimethyldioxolane-
substituted ester 27 gave cyclic enol ether 29 as the only
observed enol ether product (entry 2). Because both the
olefin and ester are hindered in 27, it is not surprising
that the reaction was sluggish; the remainder of the iso-
lable material (26%) consisted of the recovered starting
material.
If our hypothesis were accurate, one would predict that
the relative steric environment about the ester would
influence the amount of cyclic material produced. To
test this, we turned to b-C-glycosides derived from
tris-benzylidene-D-glucal.10 Surprisingly, with acetate
(R = CH3), isobutyrate (R = i-Pr), and TBDPS pro-
tected glycolate (R = CH2OTBDPS) esters 10–12, sub-
stitution had no effect on the relative amount of cyclic
and acyclic products 14–16 (entries 1–3). In contrast,
when dimethyldioxolane ester 13 was exposed to the
Takai–Utimoto reagent, cyclic enol ether 17 was formed
exclusively (entry 4). To the best of our knowledge,
the cyclization of 13 represents the first highly selective
olefinic-ester cyclization reaction utilizing the Takai–
Utimoto reagent. As the dimethyldioxolane ester is
larger than the other esters, we believe that this
result is consistent with our mechanistic hypothesis
(Table 2).11
Table 3.
OTBDPS
OTBDPS
H
H
t-Bu
Si
H
H
H
TiCl4, Zn,PbCl2,
CH2Br2, THF,
t-Bu
R
O
O
R
O
O
Si
t-Bu
t-Bu
O
O
O
TMEDA, CH2Cl2
O
O
H
H
65˚C
H
Entry
Ester
R
Enol ether
Yield (%)a
C:Ab
1
2
18
19
CH3
i-Pr
20
21
84
89
>95:5
>95:5
a Isolated yields after chromatography.
b From the crude 1H NMR of the reaction mixture.

U. Majumder, J. D. Rainier / Tetrahedron Letters 46 (2005) 7209–7211
7211
Table 4.
Rachlin for help in obtaining mass spectra. The authors
would also like to thank Professor Ilya Zharov for his
help with calculations.
OBn
H
H
R
R
O
O
OBn
OBn
OBn
H
TiCl4, Zn,PbCl2,
CH2Br2, THF,
O
H
OBn
H
H
H
R
O
OBn
OBn
H
H
C
Supplementary data
O
TMEDA, CH2Cl2
O
H
OBn
65˚C
Experimental procedures and spectroscopic data for all
new compounds. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.08.071.
OBn
O
H
H
A
Entry
Ester
R
Enol ether(s)
Yield (%)a
C:Ab
1
2
22
23
CH3
t-Bu
24
25
84
70
1:2.8
>95:5
References and notes
a Isolated yields after chromatography.
b From the crude 1H NMR of the reaction mixture.
1. Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
2199.
2. (a) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem.
1994, 59, 4029; (b) Clark, J. S.; Kettle, J. G. Tetrahedron
Lett. 1997, 38, 123; (c) Clark, J. S.; Kettle, J. G.
Tetrahedron Lett. 1997, 38, 127; (d) Postema, M. H. D.
J. Org. Chem. 1999, 64, 1770; (e) Clark, J. S.; Hamelin, O.
Angew. Chem., Int. Ed. 2000, 39, 372; (f) Chatterjee, A. K.;
Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2000, 122, 3783; (g) Postema, M. H. D.; Calimente,
D.; Liu, L.; Behrmann, T. J. Org. Chem. 2000, 65, 6061;
(h) Rainier, J. D.; Cox, J. M.; Allwein, S. P. Tetrahedron
Lett. 2001, 42, 179; (i) Liu, L.; Postema, M. H. D. J. Am.
Chem. Soc. 2001, 123, 8602.
3. (a) Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1986,
108, 855; (b) Stille, J. R.; Santarsiero, B. D.; Grubbs, R. H.
J. Org. Chem. 1990, 55, 843.
4. Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115,
3800.
Table 5.
OTBDPS
H
H
R
R
O
O
O
Si(t-Bu)2
O
OTBDPS
TiCl4, Zn,PbCl2,
CH2Br2, THF,
O
CH3
H
H
H
R
O
O
C
Si(t-Bu)2
OTBDPS
TMEDA, CH2Cl2
O
O
H
H
O
65˚C
O
CH3
H
Si(t-Bu)2
O
O
CH3
H
A
Entry
Ester
R
Enol
ether(s)
Yield
(%)a
C:Ab
1
2
26
27
CH2OTBDMS
28
77
1.3:1
5. (a) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F.
J. Am. Chem. Soc. 1996, 118, 1565; (b) Nicolaou, K. C.;
Postema, M. H. D.; Yue, E. W.; Nadin, A. J. Am. Chem.
Soc. 1996, 118, 10335.
O
H
29
66c
>95:5
O
6. Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org.
Chem. 1994, 59, 2668.
a Isolated yields after chromatography.
b From the crude 1H NMR of the reaction mixture.
7. Cox, J. M.; Rainier, J. D. Org. Lett. 2001, 3, 2919.
8. We recently reported the use of the Takai–Utimoto
reagent in olefinic-ester cyclizations to generate oxepenes.
See: Johnson, H. W. B.; Majumder, U.; Rainier, J. D.
J. Am. Chem. Soc. 2003, 125, 11893.
c 26% recovered 27.
In summary, we have shown that olefinic-ester cycliza-
tion reactions using the Takai–Utimoto reagent proto-
col are dependent upon the steric environment about
both the ester and olefin. These observations are consis-
tent with the olefin metathesis, carbonyl-olefination
reaction mechanism that was proposed previously. We
are continuing to explore these reactions including their
use in total synthesis problems.
9. Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W.
B.; Rainier, J. D. Tetrahedron 2002, 58, 1997.
10. Available from the corresponding glycal using an epoxi-
dation/propenyl MgBr coupling sequence. See: (a) Rain-
ier, J. D.; Allwein, S. P. J. Org. Chem. 1998, 63, 5310; (b)
Majumder, U.; Cox, J. M.; Rainier, J. D. Org. Lett. 2003,
5, 913.
11. As an estimation of the steric bulk of the substituents, we
have calculated the relative A-values of dimethyldioxolane
and isopropyl substituted cyclohexanes using GaussianÒ
03W version 6.0 (Dreiding force field). This predicts an
energy difference of 1.1 kcal/mol thus accounting for the
observed reactivity. Gaussian 03, Revision A.1, Gaussian,
Pittsburgh, PA, 2003.
Acknowledgments
We are grateful to the National Institutes of Health,
General Medical Sciences (GM56677) for support of
this work. We would like to thank Dr. Charles Mayne
for help with NMR experiments and Dr. Elliot M.
12. Available from the corresponding glycal using an epoxi-
dation/triallylborane coupling sequence. See: Rainier, J.
D.; Cox, J. M. Org. Lett. 2000, 2, 2707.