Stereoselective enol tosylation: Preparation of trisubstituted α,β-unsaturated esters

Article abstract of DOI:10.1021/ol047854z

(Chemical Equation Presented) The stereoselective preparation of (E)- or (Z)-trisubstituted α,β-unsaturated esters in three steps from N-protected glycine is presented. The key step in the synthesis is the highly selective enol tosylation of γ-amino β-keto esters. The enol tosylates are stable, crystalline compounds that undergo smooth and effective Suzuki-Miyaura coupling reaction with a variety of aryl boronic acids.

Full text of DOI:10.1021/ol047854z

ORGANIC
LETTERS
2005
Vol. 7, No. 2
215-218
Stereoselective Enol Tosylation:
Preparation of Trisubstituted
r,â-Unsaturated Esters
Jenny M. Baxter,* Dietrich Steinhuebel,* Michael Palucki, and Ian W. Davies
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
jenny_baxter@merck.com; dietrich_steinhuebel@merck.com
Received October 18, 2004
ABSTRACT
The stereoselective preparation of (E)- or (Z)-trisubstituted
key step in the synthesis is the highly selective enol tosylation of
that undergo smooth and effective Suzuki Miyaura coupling reaction with a variety of aryl boronic acids.
r,
â
-unsaturated esters in three steps from N-protected glycine is presented. The
γ
-amino -keto esters. The enol tosylates are stable, crystalline compounds
â
−
γ-Aminobutyric acid (GABA) analogues have received
considerable attention as important target molecules in the
pharmaceutical industry due to their profound effects on the
various central nervous system functions. GABA analogues
have been used as antispastic agents, mood enhancement
agents, and tranquilizers. The common structural motif of
these biologically active molecules is the γ-amino carbonyl
group. In this context, the selective formation of γ-amino
R,â-unsaturated esters is of significant interest. 1,2 Similarly,
the trisubstituted R,â-unsaturated ester core is also a useful
synthetic building block given the relatively straightforward
method to incorporate it in a given synthesis, as well as the
ability to perform asymmetric reductions of the double
bond.3,4 The reduction of the ester to afford a valuable
difunctionalized allylic fragment has also been reported.5
We recently required access to both geometric isomers of
a γ-amino R,â-unsaturated ester. There are no general
methods for accessing both the (Z)- and (E)-esters of this
type. Consequently, our interests centered on developing an
efficient and highly selective route for the formation of
compounds of the general structure 5 and 6. Intermediates
lacking the key amino functionality have been prepared by
utilizing Horner-Emmons chemistry6 or a Reformatsky
reaction/elimination protocol.7 These transformations usually
involve multiple steps and poor selectivity and result in low
overall yields. Other methods include the addition of
(3) Tang, W.; Wang, W.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42,
943-946.
(1) Becht, J.; Meyer, O.; Helmchen, G. Synthesis 2003, 18, 2805-2810.
Allan, R. D.; Bates, M. C.; Drew, C. A.; Duke, R. K.; Hambley, T. W.;
Johnston, G. A. R.; Mewett, K. N.; Spence, I. Tetrahedron 1990, 46, 2511-
2524. Silverman, R. B.; Invergo, B. J.; Levy, M. A.; Andrew, C. R. J. Bio.
Chem. 1987, 262, 3192-3195. Karla, R.; Ebert, B.; Thorkildsen, C.; Herdeis,
C.; Johansen, T. N.; Nielsen, B.; Krogsgaard-Larsen, P. J. Med. Chem. 1999,
42, 2053-2059 and references therein.
(4) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473-9474.
(5) Zahn, T. J.; Weinbaum, C.; Gibbs, R. A. Bio. Med. Chem. Lett. 2000,
10, 1763-1766. Martin, R.; Islas, G.; Moyano, A.; Pericas, M. A.; Riera,
A. Tetrahedron 2001, 57, 6367-6374. Mu, Y.; Gibbs, R. A. Tetrahedron
Lett. 1995, 36, 5669-5672. Srikrishna, A.; Reddy, T. J.; Kumar, P. P.;
Vijaykumar, D. Synlett 1996, 1, 67-68.
(2) Hjeds, H.; Honore´, T. Acta Chem. Scand. B 1978, 32, 187-192.
10.1021/ol047854z CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/17/2004

organocuprates to alkynes,8 asymmetric addition of aryl
boronic acids to unsaturated esters,9 and Heck coupling of
aryl halides with acrylates.10 The alkyne substrates can be
difficult to prepare, and both other methods provide access
to only the (E)-isomer.
Although it was known that the selectivity of â-keto ester
enolization could be controlled by the choice of base and/or
solvent,11,12 to our knowledge there are no reports of the
selective enolization of γ-amino â-keto esters.13 It was
uncertain what effect, if any, an adjacent NH group would
have on the selectivity of the enolization step. Herein, we
describe the stereoselective formation of both the (Z)- and
(E)-γ-amino R,â-unsaturated esters in three steps from
N-protected glycine derivatives. In this letter, we also
highlight the use of enol tosylates as a practical alternative
to enol triflates.
research groups have circumvented stability issues of triflates
by preparing the nonaflate equivalents; however, these
compounds were used in cross-coupling reactions with
organozinc reagents17 or under Stille coupling conditions.13
We desired a process that did not require a separate
transmetalation step or involve the use of tin reagents.
Therefore, we turned our attention toward the stereoselective
preparation of enol tosylates and their potential use as cross-
coupling partners with readily available aryl boronic acids.
While cross-coupling reactions of enol tosylates are much
less developed and under-utilized relative to enol triflates,
there has been much recent interest in the transition metal-
catalyzed cross-coupling reactions of aryl and vinyl tosy-
lates.18
Although the (Z)-enol tosylate 3 is selectively formed
under kinetic conditions and Ts2O is much less reactive than
Tf2O, treatment of 1b with LHMDS followed by Ts2O
addition afforded ∼20:1 ratio of the (Z)-:(E)-isomers and a
67% assay yield.19 An optimization study identified LDA
as the ideal base for deprotonation of 1b, while n-BuLi is
optimal for 1a (20:1, 80% assay yield). Use of NaHMDS
degrades the selectivity for formation of (Z)-isomer, while
KHMDS reverses the selectivity, resulting in the formation
of the (E)-isomer as the major product (Table 1). If KHMDS
Scheme 1
Table 1. Examination of Various Bases on the Formation of
Enol Tosylates from â-Keto Ester 1b
The requisite â-keto esters were prepared from N-protected
glycine derivatives via a Masamune homologation protocol
in good yield.2,14 Our initial focus was on the development
of an enolization process for the stereoselective preparation
of enol triflates and the subsequent cross-coupling of these
substrates to aryl boronic acids. The selective formation of
the (Z)-enol triflate15 from the â-keto ester was achieved in
86% isolated yield with 1.1 equiv of n-BuLi in MTBE at
-60 °C. Investigation of the subsequent Suzuki-Miyaura
coupling step indicated that the enol triflate was unstable to
the reaction conditions. Substrate decomposition was reduced
in the presence of LiBr and LiCl,16 but the yields were
typically less than 50% and difficult to reproduce. Other
base
solvent
3b:4b
% assay yielda
LHMDSb
LHMDSb
n-BuLib
LDAb
NaHMDSb
KHMDSb
KHMDSb,c
Et3Nd
THF
24:1
7:1
30:1
12:1
2:1
1:7
16:1
1:25
63
23
65
93
52
72
46
83
THF/30 mol % DMF
THF
THF
THF
THF
THF
CH2Cl2
(6) Song, Y.; Clizbe, L.; Bhakta, C.; Teng, W.; Li, W.; Wu, Y.; Jia, Z.
J.; Zhang, P.; Wang, L. Doughan, B.; Su, T.; Kanter, J.; Woolfrey, J.; Wong,
P.; Huang, B.; Tran, K.; Sinha, U.; Park, G.; Reed, A.; Malinowski, J.;
Hollenbach, S.; Scarborough, R. M.; Zhu, B. Bio. Med. Chem. Lett. 2002,
12, 1511-1515.
a Assay yield determined by HPLC analysis of the reaction mixture with
comparison to a purified standard. b Reaction conditions: keto ester 1b (200
mg, 0.85 mmol) was dissolved in 5 mL of THF cooled to -50 °C; the
reaction was aged for 3 h after base (1.1 equiv) addition, and then Ts2O
(1.1 equiv) was added and the reaction allowed to warm to room
temperature. c LiBr (1 equiv) was added. d Reaction conditions: keto ester
1b (7.88 g, 32.1 mmol) and Ts2O (1.02 equiv) in 100 mL CH2Cl2 at 0 °C
were added followed by Et3N, and the reaction was allowed to warm to
room temperature.
(7) Thakur, V. V.; Nikalje, M. D.; Sudalai, A. Tetrahedron: Asymmetry
2003, 14, 581-586.
(8) Dieter, R. K.; Lu, K. J. Org. Chem. 2002, 67, 847-855. Dieter, R.
K.; Lu, K.; Velu, S. E. J. Org. Chem. 2000, 65, 8715-8724.
(9) Meyer, O.; Becht, J.; Helmchen, G. Synlett 2003, 10, 1539-1541.
(10) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989-7000.
(11) Harris, F. L.; Weiler, L. Tetrahedron Lett. 1984, 25, 1333-1336.
Gebauer, O.; Bru¨ckner, R. Synthesis 2000, 4, 588-602.
(12) Shao, Y.; Eummer, J. T.; Gibbs, R. A. Org. Lett. 1999, 1, 627-
630.
(13) Example of selective enolization of a trisubstituted amino keto
ester: Bo¨sche, U.; Nubbemeyer, U. Tetrahedron 1999, 55, 6883-6904.
(14) Jones, R. C. F.; Bhalay, G.; Carter, P. A.; Duller, K. A. M.; Dunn,
S. H. J. Chem. Soc., Perkin Trans. 1 1999, 7, 765-776.
(15) Geometry was assigned on the basis of NOE studies, and the (E)-
isomer was not observed by HPLC in the reaction mixture.
is used as the base in the presence of 1 equiv of LiBr, good
selectivity for the formation of the (Z)-isomer is maintained,
but the yield is diminished. These results are consistent with
a substantial counterion effect on the reaction. We were also
interested in preparing the (E)-enol tosylate isomer. Although
literature reports describe the use of a strong base in polar
216
Org. Lett., Vol. 7, No. 2, 2005

Table 2. Suzuki-Miyaura Cross-Coupling of (Z)-Enol
Tosylates with Aryl Boronic Acids
Table 3. Suzuki-Miyaura Cross-Coupling of (E)-Enol
Tosylates with Aryl Boronic Acids
With access to both stereodefined enol tosylates, we began
to investigate the coupling of these intermediates with a
variety of aryl boronic acids. Results from optimization
studies show catalytic PdCl2(PPh3)2 with aqueous Na2CO3
aprotic solvents (KHMDS in DMF)20 to afford the (E)-
isomer,12 a much simpler procedure was developed using
Et3N in CH2Cl2.21 This protocol affords both 4a and 4b in
good yield and purity. An important property of these enol
tosylates is that they are stable crystalline solids that may
be readily purified by crystallization. Also, unlike Tf2O, a
liquid that is readily hydrolyzed to triflic acid, Ts2O is a
stable solid that can be easily weighed on the benchtop.
Scheme 2
(16) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-
2208 and references therein.
(17) Bellina, F.; Ciucci, D.; Rossi, R.; Vergamini, P. Tetrahedron 1999,
55, 2103-2112. Romero, D. L.; Manninen, P. R.; Han, F.; Romero, A. G.
J. Org. Chem. 1999, 64, 4980-84.
Org. Lett., Vol. 7, No. 2, 2005
217

in THF to be the best reaction conditions for cross-coupling
of both enol tosylate isomers. Cross-coupling works ef-
ficiently for aryl boronic acids containing electron-withdraw-
ing groups (Table 2, entries 1-3, 5, and 6) and electron-
neutral groups (entry 8). Aryl boronic acids containing an
electron-donating group are also tolerated (entries 4 and 7),
as is an ortho-substituted aryl boronic acid. Control experi-
ments performed in the absence of Pd catalyst show no
starting material conversion, thereby ruling out an addition/
elimination pathway. In addition, the fact that the reactions
provide pure geometrical isomers also argues against an
addition/elimination pathway.22 The (E)-enol tosylates also
undergo cross-coupling reactions with a range of aryl boronic
acids. As shown in Table 3, electron-withdrawing groups
are still tolerated in the reaction, although lower yields are
observed with some of the N-CBz derivatives (entry 2). The
reaction works effectively with a variety of electron-donating
substituents (entries 4-6), and once again, an ortho sub-
stituent on the aryl boronic acid is tolerated. In general, lower
yields are obtained with the (E)-enol tosylate than with the
(Z)-isomer in these cross-coupling reactions.23
In conclusion, a rapid and highly selective approach for
the preparation of aromatic trisubstituted R,â-unsaturated
esters from readily available glycine derivatives has been
achieved. This approach is highlighted by the selective
enolization of keto esters 1a,b and formation of the corre-
sponding enol tosylates. Both geometric enol tosylate deriva-
tives undergo efficient cross-coupling reactions with elec-
tronically diverse aryl boronic acids to afford a wide variety
of aromatic trisubstituted R,â-unsaturated esters. We antici-
pate that these esters will be useful synthetic derivatives and
that enol tosylates will continue to emerge as viable synthetic
alternatives to enol triflates.
(18) Huffman, M. A.; Yasuda, N. Synlett 1999, 4, 471-473. Lakshman,
M. K.; Thomson, P. F.; Nuqui, M. A.; Hilmer, J. H.; Sevova, N.; Boggess,
B. Org. Lett. 2002, 4, 1479-1482. Wu, J.; Zhu, Q.; Wang, L.; Fathi, R.;
Yang, Z. J. Org. Chem. 2003, 68, 670-673. Nguyen, H. N.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818-11819. Lakshman,
M.; Thomson, P.; Nuqui, M.; Hilmer, J.; Sevova, N.; Boggess, B. Org.
Lett. 2002, 4, 1479-1482. Zim, D.; Lando, V. R.; Dupont, J.; Monteiro,
A. L. Org. Lett. 2001, 3, 3049-3051. Percec, V.; Golding, G. M.; Smidrkal,
J. Weichold, O. J. Org. Chem. 2004, 69, 3447-3452.
(19) Assignment of (E)- and (Z)-isomers was made on the basis of NMR
and NOE studies. (E)-Enol tosylate geometry confirmed by X-ray crystal-
lography.
(20) From Table 1, the presence of 30 mol % DMF in THF with LHMDS
results in a degradation of the Z/E ratio. However, there are multiple products
and low yields of enol tosylates.
Acknowledgment. We thank Robert Reamer and Dr.
Peter Dormer for assistance in NMR interpretation.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972-6975.
(22) From Table 3, entry 2a gives 5% isomerization and entry 1a gives
3% isomerization. In all other examples, <3% isomerization is observed.
Control experiments: 4a, phenyl boronic acid and Na2CO3 solution were
heated for 12 h at 40 °C; 4b, 4-thiomethyl phenyl boronic acid and Na2-
CO3 were heated for 12 h at 40 °C. In both cases, no conversion to product
was observed by HPLC.
OL047854Z
(23) The major byproduct for some of these reactions is the homocoupled
biaryl product, which is consistent with competitive decomposition of the
boronic acid. However, some of the lower yielding reactions contain multiple
byproducts that were not characterized.
218
Org. Lett., Vol. 7, No. 2, 2005