Stereoselective synthesis of acetoacetate-derived enol triflates

Article abstract of DOI:10.1021/ol8010002

(Chemical Equation Presented) A highly stereoselective method for preparing (Z)- and (E)-enol triflates derived from substituted acetoacetate derivatives is described. The salient feature of this methodology is the use of Schotten-Baumann-type conditions

Full text of DOI:10.1021/ol8010002

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2901-2904
Stereoselective Synthesis of
Acetoacetate-Derived Enol Triflates
David Babinski, Omid Soltani, and Doug E. Frantz*
Department of Biochemistry, UniVersity of Texas Southwestern Medical Center at
Dallas, 5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
douglas.frantz@utsouthwestern.edu
Received May 1, 2008
ABSTRACT
A highly stereoselective method for preparing (Z)- and (E)-enol triflates derived from substituted acetoacetate derivatives is described. The
salient feature of this methodology is the use of Schotten-Baumann-type conditions to control enolate geometry using either aqueous LiOH
(Z-selective) or aqueous (Me)4NOH (E-selective) in combination with triflic anhydride to provide a practical and predictable approach to these
valuable substrates.
Enol triflates have served as strategic precursors to a number
of elegant syntheses toward important target molecules
including isoprenoids,1 R,ꢀ-butenolides,2 carbapenems,3 phor-
moidrides,4 leptofuranin D,5 agelasimines,6 the latrunculin
macrolides,7 and angiotensin II receptor antagonists.8 In
addition, they continue to serve as indispensable substrates
toward the development of new cross-coupling methodolo-
gies9 and more recently in carbon-carbon bond fragmenta-
tion reactions.10
In particular, we were most eager to utilize enol triflates
derived from acetoacetate derivatives since the starting
materials are obtainable in bulk quantities and easy to
functionalize through standard alkylation chemistry en route
to fully substituted substrates (Scheme 1). We assumed (as
Scheme 1
We have been interested in utilizing enol triflates as
valuable precursors in our own methodology development.
(1) (a) Shao, Y.; Eummer, J. T.; Gibbs, R. A. Org. Lett. 1999, 1, 627.
(b) Mu, Y.; Gibbs, R. A. Tetrahedron Lett. 1995, 36, 5669. (c) Gibbs, R. A.;
Krishnan, U.; Dolence, J. M.; Poulter, C. D. J. Org. Chem. 1995, 60, 7821.
(2) Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972.
(3) (a) Jensen, M. S.; Yang, C.; Hsiao, Y.; Rivera, N.; Wells, K. N.;
Chung, J. Y. L.; Yasadu, N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2000,
2, 1081. (b) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1986, 27, 3119.
(4) (a) Leighton, J. L.; Bio, M. M. J. Org. Chem. 2003, 68, 1693. (b)
Bio, M. M.; Leighton, J. L. Org. Lett. 2000, 2, 2905. (c) Bio, M. M.;
Leighton, J. L. J. Am. Chem. Soc. 1999, 121, 890.
(5) Marshall, J. A.; Schaaf, G. M. J. Org. Chem. 2003, 68, 7428.
(6) Ohba, M.; Kawase, N.; Fujii, T. J. Am. Chem. Soc. 1996, 118, 8250.
(7) (a) Fu¨rstner, A.; De Souza, D.; Parra-Rapado, L.; Jensen, J. T. Angew.
Chem., Int. Ed. 2003, 42, 5358. (b) Fu¨rstner, A.; De Souza, D.; Turet, L.;
Fenster, M. D. B.; Parra-Rapado, L.; Wirtz, C.; Mynott, R.; Lehmann, C. W.
Chem.-Eur. J. 2007, 13, 115.
others have)11 that we could readily obtain in a stereoselec-
tive fashion both (Z)- and (E)-enol triflates derived from
various acyclic ꢀ-keto esters with relative ease and in high
yields given their aforementioned historical precedence.
However, we were surprised after a thorough survey of the
literature that a general and practical method to stereoselec-
(8) Keenan, R. M.; Weinstock, J.; Finkelstein, J. A.; Franz, R. G.;
Gaitanopoulos, D. E.; Girard, G. R.; Hill, D. T.; Morgan, T. M.; Samanen,
J. M.; Hempel, J.; Eggleston, D. S.; Aiyar, N.; Griffin, E.; Ohlstein, E. H.;
Stack, E. J.; Weidley, E. F.; Edwards, R. J. Med. Chem. 1992, 35, 3858.
10.1021/ol8010002 CCC: $40.75
Published on Web 06/10/2008
2008 American Chemical Society

tively synthesize both geometric isomers on a broad range
of acyclic acetoacetate derivatives has yet to fully emerge.
We did come across sporadic reports on methods to
selectively generate both enolate isomers on isolated ex-
amples.12 Nonetheless, these methods appear to be optimized
specifically for those substrates and have not been demon-
strated on a range of substituted acetoacetates. As a
consequence, many are left to employ processes that are
poorly selective or, in the worse case scenario, selective for
the undesired isomer.
The synthetic utility of new methodology should be gauged
not only by the products that are produced but also by the
availability of the starting materials that feed into it. It is
not surprising that if starting materials are neither com-
mercially available nor accessible in a few short, practical
steps the methodology will suffer limited application. Thus,
we realized that any methodology we develop which employs
enol triflates as entry points will be of little value if we cannot
first practically access these substrates with high stereose-
lectivity and yields. In this Letter, we wish to report our
findings toward achieving this goal.
Given the precedence of successfully using triflic anhy-
dride to synthesize aryl triflates under Schotten-Baumann-
type conditions,13 our efforts initially focused on using
various aqueous bases as a means of controlling enolate
geometry by judicious choice of the counterion. A summary
of our most encouraging results from our screening efforts
using ethyl acetoacetate (1) is presented in Table 1. We
quickly identified the combination of hydrocarbon-based
solvents and saturated aqueous LiOH (∼5 N) as a convenient
route to the (Z)-isomer 2a with high selectivity (>150:1)
and assay yield (94% in hexanes). In constrast, aqueous
Table 1. Screening of Various Bases and Solvents for the
Stereoselective Formation of (Z)- and (E)-Enol Triflates from
Ethyl Acetoacetatea
aqueous base
solvent
2a:2bb
assay yieldc
2 N NaOH
2 N NaOH
2 N NaOH
2 N KOH
2 N CsOH
2 N LiOH
sat. LiOHd
THF
MTBE
N/A
N/A
<5%
<5%
35%
63%
76%
81%
91%
94%
30%
61%
79%
82%
84%
toluene
toluene
toluene
toluene
toluene
hexanes
toluene
toluene
hexanes
toluene
hexanes
1:2.6
1:9.5
1:6.1
34:1
>150:1
>150:1
1:39
1:20
1:23
1:18
1:24
(Bu)4NOHe
(Me)3BnNOHe
(Me)4NOHf
(Me)4NOHg
a Reaction conditions: ethyl acetoacetate (260 mg, 2.0 mmol) was
dissolved in 10 mL of solvent and cooled to 5 °C; aqueous base (5 equiv)
was then added, and the biphasic mixture was stirred for 5 min. Then triflic
anhydride (2.5 equiv) was added dropwise to maintain the internal reaction
temperature < 10 °C. b Isomeric ratios determined by HPLC analysis.
c Assay yield determined by HPLC analysis of the reaction mixture using
d
a purified standard of each isomer. ∼5.0 N. e 40 wt % solution in water.
f 25 wt % solution. g 15 wt % solution.
solutions of tetraalkylammonium hydroxides were highly
E-selective. We found that (Me)4NOH (15 wt % in water)
was superior providing the (E)-enol triflate 2b with good
E-selectivity (24:1) and assay yield (84% in hexanes).14
With two predictable methods in hand to selectively access
either the (Z)-enol triflate (via aqueous LiOH) or the (E)-
enol triflate (via aqueous (Me)4NOH), we set out to challenge
the methodology on a range of acetoacetate derivatives
(Table 2). From our results, some general comments can be
made. First, the stereoselectivities and yields are consistently
higher for (Z)-enol triflates than the corresponding (E)-enol
triflates. Second, in many cases, the crude enol triflates are
obtained in >98% purity by simply removing the aqueous
phase from the reaction followed by concentration of the
organic phase. Finally, increasing substitution at the 4-posi-
tion has a dramatic impact on obtaining the (E)-enol triflates
selectively and significantly reduces the overall conversion.
The most dramatic example is seen with ethyl benzoylacetate
where the (Z)-enol triflate 8a is the sole isomer isolated
regardless of the base employed.15
(9) For a general review of enol triflate coupling reactions, see: (a) Scott,
W. J.; McMurry, J. E. Acc. Chem. Res. 1988, 21, 47. (b) For recent
examples, see: Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner, A. J.
Org. Chem. 2004, 69, 3943. (c) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.;
Volante, R. P. Org. Lett. 2003, 5, 4749. (d) Li, S.; Dieter, K. J. Org. Chem.
2003, 68, 969. (e) Dillinger, S.; Bertus, P.; Pale, P. Org. Lett. 2001, 3,
1661. (f) Movassaghi, M.; Ondrus, A. E. J. Org. Chem. 2005, 70, 8638.
(10) (a) Tummatorn, J.; Dudley, G. B. J. Am. Chem. Soc. 2008, 130,
5050. (b) Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175. (c) Kamijo,
S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028.
(11) Although many methods that utilized enol triflates make reference
to the ease of accessibility of both acyclic stereoisomers, most substrate
tables in these reports are filled with cyclic examples providing evidence
to the contrary.
(12) (a) Baxter, J. M.; Steinhuebel, D.; Palucki, M.; Davies, I. W. Org.
Lett. 2005, 7, 215. (b) Harris, F. L.; Weiler, L. Tetrahedron Lett. 1984, 25,
1333. (c) Gebauer, O.; Bru¨ckner, R. Synthesis 2000, 4, 588. See also ref 1a.
(13) Frantz, D. E.; Weaver, D. G.; Carey, J. P.; Kress, M. H.; Dolling,
U. H. Org. Lett. 2002, 4, 4717.
(14) Although the results in Table 1 suggest hexanes is the preferred
solvent in both cases, toluene provides a suitable alternative for substrates
with limited solubility in hexanes.
(15) We surveyed a number of different conditions (both published and
unpublished) in an attempt to obtain the (E)-enol triflate derived from ethyl
benzoylacetate under basic conditions. In every experiment, we could only
obtain the (Z)-isomer. For a report on obtaining the (E)-isomer under acidic
conditions, see: (a) Vasilyev, A. V.; Walspurger, S.; Chassaing, S.; Pale,
P.; Sommer, J. Eur. J. Org. Chem. 2007, 5470.
We next set out to explore the scope on a selected series
of 2-substituted acetoacetate derivatives in an attempt to
access fully substituted ꢀ-keto enol triflates in a stereose-
lective fashion.16 The results are summarized in Table 3.
(16) Reports of gaining access to both enol triflates stereoisomers
stereoselectively on 2-substituted derivatives are scarce. See ref 2. Other
selected examples: (a) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem.
1999, 64, 8770. (b) Lipshutz, B. H.; Alami, M. Tetrahedron Lett. 1993,
34, 1433. (c) Yao, M.-L.; Deng, M.-Z. Tetrahedron Lett. 2000, 41, 9083.
(d) Ide, M.; Nakata, M. Synlett 2001, 1511. (e) Molander, G. A.; Ito, T.
Org. Lett. 2001, 3, 393. (f) Bobeck, D. R.; Warner, D. L.; Vedejs, E. J.
Org. Chem. 2007, 72, 8506.
(17) The (E)-isomer (12b) derived from ethyl 2-phenylacetoacetate was
a notable exception. Multiple attempts at achieving complete conversion
by increasing the amounts of either base and/or Tf2O did not provide any
improvements. In addition, regardless of the conditions we tried, we could
not separate the enol triflate isomers away from the unreacted starting
material via column chromatography.
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Org. Lett., Vol. 10, No. 13, 2008

Table 2. Stereoselective Synthesis of Enol Triflates Derived
Table 3. Stereoselective Synthesis of Enol Triflates Derived
from Acetoacetate Derivativesa
from 2-Substituted Acetoacetate Derivativesa
a All reactions were performed with 2.5 equiv of Tf2O and either 7.5
equiv of sat. LiOH or 5.0 equiv of 15 wt % (Me)4NOH in water in an
open-air flask. b Stereochemistry assigned by comparison with literature
values or by NOE studies. c Ratios determined by 1H NMR analysis of the
crude reaction mixture. d Isolated yields. e No purification required. f Isomers
could not be separated by column chromatography. Contaminated with
∼10% unreacted starting material.
a All reactions were performed with 2.5 equiv of Tf2O and either 7.5
equiv of sat. LiOH or 5.0 equiv of 15 wt % (Me)4NOH in water in an
open-air flask. b Stereochemistry assigned by comparison with literature
values or by NOE studies. c Ratios determined by 1H NMR analysis of the
crude reaction mixture. d Isolated yields. e No purification required.
higher selectivities than the corresponding (E)-enol triflates.
The only exception is ethyl 2-methylacetoacetate where we
see slightly higher selectivity for the (E)-enol triflate (11b)
compared to the corresponding (Z)-isomer (11a). Again, most
of the products are obtained in >98% purity by a simple
extractive workup followed by concentration.17
Again, some general comments can be made based on the
results we observed. The same trend was observed as before
where we routinely obtain the (Z)-enol triflates with much
In its current state of development, there are several limita-
tions that we would like to mention. We noticed in some cases
that viscous and/or heterogeneous solutions were obtained
Org. Lett., Vol. 10, No. 13, 2008
2903

during the course of these reactions. This does not appear to
impact yields on a small scale (<10 mmol) with vigorous
magnetic stirring. Nonetheless, on a larger scale we recommend
using mechanical overhead stirring to ensure proper mixing.
In addition, all attempts to access either enol triflate isomer from
ꢀ-keto amide 14 failed to give acceptable yields (<10%).
Finally, we found that although the 1,3-diketone 15 serves as a
viable substrate to (Z)-enol triflate 16a with high selectivity (50:
1) and good yield (74%) we were unable to obtain the (E)-
enol triflate 16b selectively even when (Bu)4NOH was em-
ployed as the base (Scheme 2).
from substituted acetoacetate derivatives. The salient
featureofthismethodologyistheuseofSchotten-Baumann-
type conditions to dictate enolate geometry either by using
LiOH (Z-selective) or (Me)4NOH (E-selective) in com-
bination with triflic anhydride and hydrocarbon-based
solvents. The reactions do not require an inert atmosphere,
and more notably in many cases the crude products are
isolated in >98% purity obviating the need for chromato-
graphic purification. The ease of accessing both enol
triflate isomers in a stereoselective and predictable fashion
on a broad range of substrates should significantly increase
the utility of prior methodologies and inspire new methods
toward stereodefined olefinic products.
Scheme 2
Acknowledgment. This work was supported in part by a
program project grant from the National Cancer Institute (P01
CA95471). We would like to thank Dr. Michael H. Kress
and Dr. Todd D. Nelson of Merck Research Laboratories
for helpful discussions. We would also like to thank the
Department of Process Research at Merck & Co., Inc. for a
generous donation of various equipment to our laboratory.
Supporting Information Available: General experimental
procedures and characterization data (1H and 13C NMR, ESI-
MS) for all products reported. This material is available free
of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed a practical process
to stereoselectively obtain both (Z)- and (E)-enol triflates
OL8010002
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Org. Lett., Vol. 10, No. 13, 2008