Stereoselective formation of (E)-β-alkoxy acrylates from fischer carbene complexes and chelated amino acid ester enolates

Article abstract of DOI:10.1055/s-0033-1340496

Chelated amino acid ester enolates react with alkyl Fischer carbene complexes via nucleophilic attack on the electrophilic carbene center. Subsequent elimination of the metal fragment and trifluoroacetamide results in the formation of β-alkoxy-α,β-unsaturated esters in a highly E-stereoselective fashion. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340496

LETTER
▌693
lSettteer reoselective Formation of (E)-β-Alkoxy Acrylates from Fischer Carbene
Complexes and Chelated Amino Acid Ester Enolates
Stereoselective Formation of (E)-β-Alkoxy Acrylates
Rupsha Chaudhuri, Uli Kazmaier*
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received: 29.10.2013; Accepted after revision: 06.12.2013
carbene 1a.9 Interestingly, not the expected metalated
Abstract: Chelated amino acid ester enolates react with alkyl
amino acid 4 was obtained, but a mixture of various com-
Fischer carbene complexes via nucleophilic attack on the electro-
pounds, including the β-methoxylated α,β-unsaturated es-
philic carbene center. Subsequent elimination of the metal fragment
ter 5a. Attempts to improve the purity and yield of this
product by variation of the N-protecting group (Boc or
Cbz) or the chelating metal salt [ClTi(Oi-Pr)3] failed,
while an exchange of the carbene metal brought the de-
sired success. With the molybdenum complex 2a ester 5a
was obtained in 61% yield as a single stereoisomer. Only
the formation of the E-configured product could be ob-
served. With the tungsten complex 3a the yield could be
improved further.
and trifluoroacetamide results in the formation of β-alkoxy-α,β-
unsaturated esters in a highly E-stereoselective fashion.
Key words: acrylates, amino acids, carbene complexes, enolates,
Fischer carbenes, α,β-unsaturated esters
Since their first description by Fischer and Maasböl in
1964,1 Fischer carbene complexes developed to very pow-
erful tools in organic synthesis.2 In general, group 6 met-
als are incorporated into Fischer carbenes, while
chromium is the most popular metal with the most appli-
cations. But also the chemistry of the analogous molybde-
num and tungsten complexes is rich and complex. While
alkenyl- and alkynyl carbene complexes are excellent
substrates for cycloadditions, alkyl carbene complexes are
isolobal analogues of Lewis acid complexed esters.2 Nu-
cleophilic attack on the carbene carbon results in an ex-
change of the alkoxy group and the formation of modified
carbene complexes, and on deprotonation, the carbene
complexes form enolates which can be reacted with a
wide range of electrophiles.2
LHMDS (2.4 equiv)
ZnCl2 (1.2 equiv)
Ot-Bu
TFAHN
COOt-Bu
N
O
THF, –50 °C
TFA
Zn
OMe
n-Bu
1a M = Cr
2a M = Mo
3a M = W
–78 to –50 °C, 1.5 h
0 °C, 1.5 h
(OC)5M
n-Bu
COOt-Bu
carbene yield (%)
Since a couple of years, our group is involved in the de-
velopment of synthetic protocols towards new amino ac-
ids based on reactions of chelated amino acid ester
enolates.3 These enolates show a higher thermal stability
compared to unchelated enolates, and in addition chelate
formation causes high selectivities in a wide range of
reactions.4 Especially good results are obtained with tri-
fluoroacetylated (TFA) tert-butyl glycinate, which is an
almost perfect nucleophile for transition-metal-catalyzed
allylic alkylations,5 Michael additions,6 and Michael addi-
tion induced ring closures (MIRC).7 Very recently, we
also reported the 1,4-addition of chelated enolates towards
alkynyl carbene complexes, resulting in the formations of
substituted pyrroles.8
n-Bu
COOt-Bu
(OC)5M
TFAHN
1a
2a
3a
20
61
73
MeO
5a
4
Scheme 1 Reactions of chelated enolates with Fischer carbene com-
plexes
Although these results were not expected, it should be
mentioned that such a reaction behavior of Fischer car-
bene complexes is not unprecedented. Similar compounds
5 have been obtained previously in reactions of Fischer
carbenes with stabilized ester enolates bearing electron-
withdrawing groups, which can also act as leaving group.
Sierra et al. investigated the reaction of chromium car-
benes with ester-substituted sulfur ylides.10 While under
thermal conditions E/Z selectivities of around 1:1 were
obtained, on irradiation the selectivity for the E-isomer
could be increased to about 4:1 to 5:1. Concellon and
Bernard obtained high yields (up to 95%) of 1:1 E/Z mixtures
in reactions of α-bromo esters with aryl-substituted chro-
mium carbenes, but this protocol seems to be limited to ar-
yl- and heteroaryl-substituted carbenes.11 Last, but not
least, Barluenga et al. reported an interesting coupling of
Therefore, we were interested to see if these enolates are
also suitable nucleophiles for 1,2-additions towards alkyl
carbene complexes 1–3 (Scheme 1), giving rise to amino
acids with a carbene complex in the side chain 4. We start-
ed our investigations with the butyl-substituted chromium
SYNLETT 2014, 25, 0693–0695
Advanced online publication: 13.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340496; Art ID: ST-2013-B1012-L
© Georg Thieme Verlag Stuttgart · New York

694
R. Chaudhuri, U. Kazmaier
LETTER
chromium carbene complex 1a with diazoacetates in the To determine the configuration of the double bond gener-
presence of copper salts. They could show that under their ated, we subjected the β-methylated ester 7b to saponifi-
conditions copper carbene complexes are formed in situ, cation. The free carboxylic acid obtained gave crystals
but also these gave 1:1 E/Z mixtures.12
suitable for X-ray structure analysis (Figure 1), which
clearly shows the formation of the E-isomer.
Therefore, the selective formation of the E-isomer forced
us to investigate the scope and limitations of this reaction.
Based on our experience made in the initial experiments,
we focused on the corresponding tungsten complexes 3
and varied the substituent on the carbene carbon and also
on the oxygen. While the TFA protecting group seems to
be essential for the success of the reaction we varied the
ester functionality of the amino acid (Table 1). Both mod-
ifications, the variation of the O-substituent and of the es-
ter, had no significant influence neither on the yield nor
the stereoselectivity. With all alkyl-substituted carbene
complexes the E-configured product was formed exclu-
sively in yields between 63% and 71%, independent of the
chain length of the alkyl substituent. With phenyl-substi-
tuted carbenes 3d and 3f slightly higher yields could be
obtained, but in this case always E/Z mixtures (1:1 to 2:1)
were formed, comparable to the other ester enolates inves-
tigated before.10–12
Figure 1 X-ray structure of (E)-3-methoxybut-2-enoic acid
To explain the outcome of this reaction, we assume that
the formation of the β-alkoxylated α,β-unsaturated ester is
initially triggered by an 1,2-addition of the chelated eno-
late onto the electrophilic carbon of the carbene complex.
This results in the formation of a zwitterionic intermediate
913 which undergoes a Wittig-like process, resulting in the
elimination of the trifluoroacetamide (Scheme 2).10
Table 1 Syntheses of Unsaturated Ester 5–8
LHMDS (2.4 equiv)
OR3
R2
R3O
COOR1
ZnCl2 (1.2 equiv)
COOR1
+
(OC)5W
TFAHN
THF
R2
–78 to –50 °C, 1.5 h
0 °C, 1.5 h
5–8
3
Entry
3
R1
R2
R3
Product 5–8
Yield (%)
E/Z
1
2
3a
3b
3c
3d
3e
3f
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
n-Bu
Me
Me
Me
Me
Et
5a
5b
5c
5d
5e
5f
73
67
69
67
65
69
65
64
67
77
63
71
71
74
63
64
66
66
E
Me
Et
E
3
E
4
Ph
2.3:1
E
5
Me
Ph
6
Et
1.5:1
E
7
3a
3b
3c
3d
3a
3b
3c
3d
3e
3f
n-Bu
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Et
6a
6b
6c
6d
7a
7b
7c
7d
7e
7f
8
Me
E
9
Me
E
10
11
12
13
14
15
16
17
18
Me
Ph
1.3.1
E
Bn
n-Bu
Me
Et
Bn
E
Bn
E
Bn
Ph
1.1:1
E
Bn
Me
Ph
Bn
Et
2.1:1
E
3b
3d
2-butenyl
2-butenyl
Me
Ph
Me
Me
8b
8d
1.5:1
Synlett 2014, 25, 693–695
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Formation of (E)-β-Alkoxy Acrylates
695
Rearrangements; Hiersemann, M.; Nubbemayer, U., Eds.;
Wiley-VCH: Weinheim, 2007, 233.
R2
1,2-addition
+
OR1
OR3
R2
R3O
–
W(CO)5
(OC)5W
(4) (a) Grandel, R.; Kazmaier, U. Tetrahedron Lett. 1997, 38,
8009. (b) Grandel, R.; Kazmaier, U.; Rominger, F. J. Org.
Chem. 1998, 63, 4524. (c) Kazmaier, U.; Mues, H.; Krebs,
A. Chem. Eur. J. 2002, 8, 1850. (d) Kazmaier, U.; Maier, S.
Tetrahedron 1996, 52, 941.
(5) Palladium: (a) Kazmaier, U.; Pohlman, M. Synlett 2004,
623. (b) Kazmaier, U.; Lindner, T. Angew. Chem. Int. Ed.
2005, 44, 3303; Angew. Chem. 2005, 117, 3368.
(c) Kazmaier, U.; Stolz, D.; Krämer, K.; Zumpe, F. L. Chem.
Eur. J. 2008, 14, 1322. Rhodium: (d) Kazmaier, U.; Stolz, D.
Angew. Chem. Int. Ed. 2006, 45, 3072; Angew. Chem. 2006,
118, 3143. (e) Stolz, D.; Kazmaier, U. Synthesis 2008, 2288.
Ruthenium: (f) Bayer, A.; Kazmaier, U. Org. Lett. 2010, 12,
4960.
N
O
TFAN
CO2R1
TFA
Zn
Zn+
9
H2O/H+
– NH2TFA
R3O
R2
+
W(CO)5X
CO2R1
Scheme 2 Proposed reaction mechanism
(6) (a) Mendler, B.; Kazmaier, U. Org. Lett. 2005, 7, 1715.
(b) Mendler, B.; Kazmaier, U.; Huch, V.; Veith, M. Org.
Lett. 2005, 7, 2643.
(7) (a) Pohlman, M.; Kazmaier, U. Org. Lett. 2003, 5, 2631.
(b) Schmidt, C.; Kazmaier, U. Eur. J. Org. Chem. 2008, 887.
(c) Schmidt, C.; Kazmaier, U. Org. Biomol. Chem. 2008, 6,
4643. (d) Kazmaier, U.; Schmidt, C. Synlett 2009, 1136.
(e) Kazmaier, U.; Schmidt, C. Synthesis 2009, 2435.
(8) Chaudhuri, R.; Kazmaier, U. Organometallics 2013, 32,
5546.
This would also explain why this reaction works only well
with the strong electron-withdrawing TFA group (rela-
tively good leaving group), but not with other standard N-
protecting groups such as carbamates. It should be men-
tioned that although we investigated a wide range of reac-
tions of the TFA-protected glycine esters so far,3–7 this is
the very first time that we observed a cleavage of the ami-
no acids C-N bond, with the trifluoroacetamides acting as
a leaving group. When the reaction is quenched with D2O,
no deuterium incorporation into the product is found. This
observation also supports the mechanism proposed.
(9) All carbene complexes were prepared according to: Fischer,
E. O.; Maasböl, A. Chem. Ber. 1967, 100, 2445.
(10) Alcaide, B.; Casarrubios, L.; Domínguez, G.; Sierra, M. A.
Organometallics 1996, 15, 4612.
In conclusion, we developed a straightforward protocol
for the stereoselective synthesis of (E)-β-alkoxy-α,β-un-
saturated esters based on the nucleophilic attack of chelat-
ed ester enolates on Fischer carbene complexes.14 The
reactions work well with alkyl- and aryl-substituted car-
benes, but only with the alkyl derivatives the E-isomers
were formed exclusively. Synthetic applications and
mechanistic aspects are currently under investigation.
(11) Concellón, J. M.; Bernad, P. L. Jr. Tetrahedron Lett. 1998,
7967.
(12) Barluenga, J.; López, L. A.; Löber, O.; Tomás, M.; Gracía-
Granda, S.; Alvarez-Rúa, C. Angew. Chem. Int. Ed. 2001,
40, 3392; Angew. Chem. 2001, 113, 3495.
(13) For comparable intermediates and mechanistic proposals,
see: (a) Casey, C. P.; Burkhardt, T. J. Am. Chem. Soc. 1972,
94, 6543. (b) Casey, C. P.; Burkhardt, T.; Bunnell, C. A.;
Calabrese, J. C. J. Am. Chem. Soc. 1977, 99, 2127.
(c) Alcaide, B.; Dominguez, G.; Plumet, J.; Sierra, M. A.
Organometallics 1991, 10, 11.
Acknowledgment
(14) Preparation of (E)-tert-Butyl 3-Methoxyhept-2-enoate
(5a)
This work was supported by the Deutsche Forschungsgemeinschaft.
R. Chaudhuri greatfully acknowledges a fellowship of the Alexan-
der von Humboldt Foundation. We also thank Dr. V. Huch for X-
ray structure analysis.
To a solution of trifluoroacetylated (TFA) tert-butyl
glycinate (75 mg, 0.33 mmol) and ZnCl2 (54 mg, 0.39 mmol)
in THF was added LHMDS (1 M, 0.79 mL, 0.79 mmol)
dropwise at –78 °C and the reaction mixture was stirred for
30 minutes at the same temperature. Then the Zn-chelated
enolate formed was added dropwise to a solution of
methoxybutyl carbene complex 3a (140 mg, 0.33 mmol) in
THF at –78 °C. The reaction mixture was stirred for 1.5 h
while the temperature rose to –50 °C. Stirring was continued
for another 1.5 h at 0 °C to complete the reaction, before it
was quenched with distilled water. The organic phase was
extracted with EtOAc, dried over anhydrous Na2SO4, and
was evaporated in vacuo. The crude product was purified by
column chromatography (PE) affording the title compound
5a (51.4 mg, 0.24 mmol, 73%) as a colorless liquid. [TLC:
Rf (5a) = 0.8 (PE)]. 1H NMR (400 MHz, CDCl3): δ = 0.89 (t,
3J9,8 = 7.2 Hz, 3 H, 9-H), 1.29–1.38 (m, 2 H, 8-H), 1.46 (s, 9
H, 1-H), 1.48–1.54 (m, 2 H, 7-H), 2.69 (t, 3J6,7 = 7.6 Hz, 2 H,
6-H), 3.58 (s, 3 H, 10-H), 4.89 (s, 1 H, 4-H). 13C NMR (100
MHz, CDCl3): δ = 13.9 (q, C-9), 22.5 (t, C-8), 28.3 (q, C-1),
29.6 (t, C-7), 31.5 (t, C-6), 55.1 (q, C-10), 79.0 (s, C-2), 92.2
(d, C-4), 167.1 (s, C-3), 175.5 (s, C-5). GC–MS (EI): m/z (%)
= 214 (2) [M], 158 (24) [M – 56], 141 (44) [M – 73], 116
(100) [M – 98].
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
(1) Fischer, E. O.; Maasböl, A. Angew. Chem., Int. Ed. Engl.
1964, 3, 580; Angew. Chem. 1964, 76, 645.
(2) Recent reviews: (a) Dötz, K. H.; Stendel, J. Jr. Chem. Rev.
2009, 109, 3227. (b) Santamaria, J. Curr. Org. Chem. 2009,
13, 31. (c) Herndon, J. W. Coord. Chem. Rev. 2009, 253, 86.
(d) Herndon, J. W. Coord. Chem. Rev. 2009, 253, 1517.
(e) Herndon, J. W. Coord. Chem. Rev. 2010, 254, 103.
(f) Herndon, J. W. Coord. Chem. Rev. 2011, 255, 3.
(g) Herndon, J. W. Coord. Chem. Rev. 2012, 256, 1281; and
references cited therein.
(3) (a) Kazmaier, U. Amino Acids 1996, 11, 283. (b) Kazmaier,
U. Liebigs Ann./Recl. 1997, 285. (c) Kazmaier, U. In Claisen
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 693–695

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