Application of the molybdenum-catalysed hydrostannation towards a flexible synthesis of substituted unsaturated amino acids

Article abstract of DOI:10.1055/s-2000-6293

Application of the molybdenum catalysed hydrostannation towards propargylic esters of amino acids allows for the regioselective synthesis of α-stannylated allylic esters, suitable substrates for chelate Claisen rearrangements, α-Stannylated allylic carbonates can be subjected to palladium catalysed allylic alkylations using chelated amino acid ester enolates as nucleophiles. The stannylated amino acids obtained can be further modified via crosscoupling reactions.

Full text of DOI:10.1055/s-2000-6293

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SHORT PAPER
Application of the Molybdenum-Catalysed Hydrostannation Towards a
Flexible Synthesis of Substituted Unsaturated Amino Acids
Uli Kazmaier,* Dagmar Schauß, Matthias Pohlman, Stefan Raddatz
Organisch-Chemisches Institut der Universität, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)544205; E-mail: ck1@popix.urz.uni-heidelberg.de
Received 10 December 1999; revised 21 February 2000
Abstract: Application of the molybdenum catalysed hydrostanna-
tion towards propargylic esters of amino acids allows for the regio-
selective synthesis of a-stannylated allylic esters, suitable sub-
strates for chelate Claisen rearrangements. a-Stannylated allylic
carbonates can be subjected to palladium catalysed allylic alkyla-
tions using chelated amino acid ester enolates as nucleophiles. The
stannylated amino acids obtained can be further modified via cross-
coupling reactions.
Key words: allylic alkylation, Claisen rearrangement, cross cou-
pling, hydrostannation, molybdenum
g, d-Unsaturated amino acids are of great interest, not only
Scheme 1
as naturally occurring non proteinogenic amino acids such
as the isoleucine antagonist cyclopentenylglycine1 and the
antibiotic furanomycine,2 but also as important intermedi-
ates for the synthesis of complex amino acids.3 Therefore,
various approaches to the synthesis of this class of amino
acids have been described.4
Recently, we have developed a new variation of the ester
enolate Claisen rearrangement, proceeding via chelated
allylic ester enolates.5 Due to the fixed enolate geometry,
Scheme 2
as a result of chelate formation, the rearrangement pro-
ceeds with a high degree of syn-selectivity, independent
Stannylated allylic alcohols can easily be obtained via hy-
drostannation of propargylic alcohols, although the regio-
selectivity of this process is a significant problem.
Hydrostannation of propargylic alcohol under radical
of the substitution pattern and the protecting group used.6
The corresponding anti-configured products can be ob-
tained by palladium catalysed allylic alkylations, also in a
highly stereoselective fashion (Scheme 1).7 This is espe-
conditions preferentially results in the formation of the
cially interesting with respect to the fact that unsymmetri-
undesired b-substituted products as a E/Z isomeric mix-
cal nucleophiles are used,8 and only a few applications of
ture.12 On the other hand, the catalytic version using
non stabilised ester enolates as nucleophiles in palladium
Pd(0)complexes provides the a- and b-(Z) product as a
catalysed allylic alkylations are described in the literature
nearly 1:1 mixture.13 Unfortunately, the palladium cataly-
so far.9
sed reaction cannot be directly applied to propargylic es-
The disadvantage of this protocol results from the fact that
for each side chain introduced the corresponding allylic
alcohol or ester has to be firstly prepared. For a more flex-
ible approach, a modified allylic ester is desirable, giving
rise to an amino acid which is suitable for further modifi-
cations. As shown by Crisp et al.,10 the Stille coupling
methodology is especially suitable for this purpose, since
these reactions take place under rather mild conditions
and are tolerant of a wide variety of functionalities.11 The
required amino acids with a vinylstannane sidechain B
should be accessible from the corresponding a-stannylat-
ed ester A via Claisen rearrangement or from C via palla-
dium catalysed allylic alkylation (Scheme 2).
ters, which decompose under these reaction conditions.
For these reasons, we developed a new catalyst for regio-
selective hydrostannations. Mo(CO)3(CNtBu)3 (MoBI3),
easily prepared by ligand exchange from Mo(CO)6,14
shows high reactivity and selectivity for various types of
alkynes.15
Excellent yields and a-selectivities16 were obtained in the
hydrostannation of propargylic acetate 1a and carbonate
1b (Scheme 3). The resulting stannylated derivatives 2 are
highly interesting building blocks, bearing two reactive
centers. The vinylstannane subunit should allow coupling
with electrophiles under Stille conditions, and the allyl es-
ter moiety should be suitable for Pd-catalysed allylic
alkylations, allowing nucleophilic substitutions at the ter-
Synthesis 2000, No. 7, 914–916 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Application of the Molybdenum-Catalysed Hydrostannation
915
minal allylic position. Based on the good results obtained Very good results were obtained in reactions using ben-
with chelated enolates, we investigated the palladium ca- zylbromide as an electrophile (8a, b),9 especially in the
talysed allylation of glycine ester 3 in the presence of zinc presence of triphenylarsine as a ligand.17 A comparable
chloride. The reaction proceeded very cleanly, under very result was also obtained with allylbromide under the same
mild conditions, providing the desired stannylated amino reaction conditions (9). Allylic and benzylic halides are
acid derivative 4 as substrate for further modifications at obviously more reactive in comparison to aryl halides.
the vinylstannane moiety.
Therefore o-bromobenzylbromide reacted exclusively at
the benzylic position, and no reaction at the aromatic nu-
cleus was observed. A nearly quantitative yield was ob-
tained in the reaction with iodine, and the vinyl iodide 11a
should be a suitable electrophile for further cross-cou-
pling reactions. Couplings with acyl chlorides such as
benzoyl chloride provided amino acids 12a, b in a very
fast reaction. These reactions can be carried out in acetone
or even better in acetonitrile without additional ligands.
Probably these polar solvents can coordinate to the palla-
dium complexes formed during the reaction, keeping
them in solution.18 The amino acids obtained in these acy-
lation reactions are interesting substrates for further mod-
ifications, e. g. via Michael additions.
Scheme 3
Comparable results were also obtained in the hydrostan-
nation of glycine propargylic esters 5, giving direct access
to 6, ideal substrates for subsequent Claisen rearrange-
ments. These rearrangements proceeded comparable to
non-stannylated allylic esters in a very clean fashion, and
the amino acids obtained were directly converted into the
corresponding methyl esters 7.
a, 3 equiv benzylbromide, 2.5 mol% [allylPdCl]2, 20 mol% AsPh3,
THF, 60 °C, 5 h; b, 3 equiv allylbromide, 2.5 mol% [allylPdCl]2,
20 mol% AsPh3, toluene, 50 °C, 4 h; c, 3 equiv bromobenzyl bromide,
2.5 mol% [allylPdCl]2, 20 mol% AsPh3, THF, 50 °C, 5 h; d, 1.2 equiv
I2, CHCl3, r.t., 30 min; e, 1.05 equiv benzoyl chloride, 2.5 mol% [al-
lylPdCl]2, MeCN, 50 °C, 10 min.
Scheme 4
The moderate isolated yield obtained in the allylation re-
action and the rearrangement, especially in the rearrange-
ment of 6b, resulted from a partially protodestannylation
during workup (flash chromatography on silica). But in
general, the stannylated esters obtained can be used di-
rectly without further purification for the subsequent cross
coupling reactions (Scheme 5). The yields marked with an
asterisk (*) were obtained by this direct conversion, and
are overall yields for two steps (Claisen rearrangement
and cross coupling).
Scheme 5
Molybdenum Catalysed Hydrostannations; General Procedure
The corresponding alkyne (1 mmol) was dissolved in toluene
(1 mL) under Ar, before MoBI3 (2 mol%) and hydroquinone (to
suppress radical hydrostannations) were added, followed by
Bu3SnH (2.5 mmol). The reaction mixture was warmed to 50 °C un-
til all alkyne was consumed (2-5 h). After cooling to r.t., the whole
reaction mixture was subjected to flash chromatography on silica.
Excess of tin hydride was removed using hexanes as eluent, the
Synthesis 2000, No. 7, 914–916 ISSN 0039-7881 © Thieme Stuttgart · New York

916
U. Kazmaier et al.
SHORT PAPER
stannylated products were obtained by switching to a slightly more
polar solvent (hexanes/EtOAc >90:<10). It is recommended to add
1% Et3N to the eluent to suppress protodestannylation during chro-
matography.
(2) Katagiri, K.; Tori, K.; Kimura, Y.; Yoshida, T.; Nagasaki, T.;
Minato, H. J. Med. Chem. 1967 10, 1149.
(3) Bartlett, P. A.; Tanzella, D. J.; Barstow, J. F. Tetrahedron Lett.
1982, 23, 619.
Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1985, 26, 5307.
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1025.
Broxterman, Q. B.; Kaptein, B.; Kamphuis, J.; Schoemaker,
H. E. J. Org, Chem. 1992, 57, 6286.
Palladium Catalysed Allylic Alkylation of Chelated Enolates;
General Procedure
The protected amino acid ester (1 mmol) was dissolved in THF
(4 mL). At -78 °C a freshly prepared solution of LHMDS (2.5
mmol) in THF (2 mL) was added. After 30 min at -78 °C, a solution
of ZnCl2 (1.1 mmol) in THF (2 mL) was added with stirring. 30 min
later a solution of p-allylpalladium chloride dimer (1 mol%), PPh3
(4.5 mol%) and the corresponding stannylated allyl ester
(1.5 mmol) in THF (2 mL) was added. The solution was stirred
overnight while being warmed up to r.t. Subsequently, the solution
was diluted with Et2O and hydrolysed with 1 N KHSO4 solution
(10 mL). The aqueous phase was extracted twice with Et2O (15 mL
each) and the combined organic layers were dried (Na2SO4). After
evaporation of the solvent in vacuo, the crude product was purified
by flash chromatography (hexanes/EtOAc). It is recommended to
add 1% Et3N to the eluent to suppress protodestannylation during
chromatography.
(4) Williams, R. M. In Synthesis of Optically Active a- Amino
Acids, Vol. 7 of Organic Chemistry Series; Baldwin, J. E.;
Magnus, P. D., Eds.; Pergamon Press: Oxford, 1989.
(5) Kazmaier, U. Angew. Chem., Int. Ed. Engl. 1994, 33, 998.
(6) Review: Kazmaier, U. Liebigs Ann. Chem. 1997, 285.
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1468.
Kazmaier, U.; Zumpe, F. L. Angew. Chem. in press.
(8) In general, almost 1:1 diastereomeric mixtures are obtained
with unsymmetrical nucleophiles such as b-keto esters or
imines of amino acid esters (see ref. 7 and literature cited
therein).
(9) Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J. Org.
Chem. 1980, 45, 5193.
Claisen Rearrangement of Chelated Enolates; General Proce-
dure
Hoffmann, H. M. R.; Otte, A. R.; Wilde, A. Angew. Chem.,
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Otte, A. R.; Wilde, A.; Hoffmann, H. M. R. Angew. Chem.,
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A freshly prepared LDA solution (2.5 mmol) in THF (5 mL) was
added to a stirred mixture of the stannylated allylic ester (1 mmol)
and ZnCl2 (1.1 mmol) in dry THF (5 mL) at -78 °C. The mixture
was allowed to warm up to r.t. overnight. The resulting clear solu-
tion was diluted with Et2O (20 mL) and hydrolyzed with 1 N
KHSO4 solution (20 mL). After separation of the aqueous layer, the
crude n-protected amino acids were directly converted into the me-
thyl ester by addition of a solution of diazomethane in Et2O. After
evaporation of the solvent, the crude product was purified by flash
chromatography (EtOAc/hexanes). It is recommended to add 1%
Et3N to the eluent to suppress protodestannylation during chroma-
tography.
Hoffmann, H. M. R.; Otte, A. R.; Wilde, A.; Menzer, S.;
Williams, D. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 100.
(10) Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50, 3213.
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Albers, M. O.; Coville, N. J.; Singleton, E. J. Organomet.
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1017.
Acknowledgement
Financial support by the Deutsche Forschungsgemeinschaft (SFB
247) as well as the Fonds der Chemischen Industrie is gratefully
acknowledged.
(16) Determined by NMR.
(17) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
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Article Identifier:
1437-210X,E;2000,0,07,0914,0916,ftx,en;C00700SS.pdf
Synthesis 2000, No. 7, 914–916 ISSN 0039-7881 © Thieme Stuttgart · New York