A practical synthesis of 5-functionalized thieno[2,3-d]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2015.05.104

Abstract The synthesis of 5-hydroxymethyl-, 5-acetoxymethyl-, 5-formyl- and 5-cyanothieno[2,3-d]pyrimidines, the (methyl)-5-carboxylate, and the respective amide functionality was accomplished by building up the functionalized molecule starting from appropriately substituted thiophene precursors. A similar strategy starting from the pyrimidine precursor and subsequent direct functionalization (formylation and cyanation) of the thieno[2,3-d]pyrimidine parent compound in position 5 was found to be less feasible.

Full text of DOI:10.1016/j.tetlet.2015.05.104

Accepted Manuscript
A practical synthesis of 5-functionalized thieno[2,3-d]pyrimidines
Birgit Wilding, Stefan Faschauner, Norbert Klempier
PII:
S0040-4039(15)00946-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.104
TETL 46376
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 March 2015
21 May 2015
27 May 2015
Please cite this article as: Wilding, B., Faschauner, S., Klempier, N., A practical synthesis of 5-functionalized
thieno[2,3-d]pyrimidines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.05.104
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
A practical synthesis of 5-functionalized
thieno[2,3-d]pyrimidines
Leave this area blank for abstract info.
Birgit Wilding, Stefan Faschauner, Norbert Klempier*
OAc
MeOOC
MeOOC
H2N
S
S
H2N
O
N
COOMe
S
R'
N
O
HN
N
R''
MeOOC
H2N
HN
H2N
N
Cl
S
S
R
R = H, NH2, NHPiv
R' = OH, OCH3, Cl
R'' = H, CH2OH, CH2OAc,
COOMe, CONH2, CN

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A practical synthesis of 5-functionalized thieno[2,3-d]pyrimidines
Birgit Wildinga, Stefan Faschaunerb and Norbert Klempiera,b,*
a Austrian Centre of Industrial Biotechnology (acib) c/o Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria
b Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria
ARTICLE INFO
ABSTRACT
Article history:
Received
The synthesis of 5-hydroxmethyl-, 5-acetoxymethyl-, 5-formyl- and 5-cyanothieno[2,3-d]pyrimidines,
the (methyl)-5-carboxylate and the respective amide functionality was accomplished by building up
the functionalized molecule starting from appropriately substituted thiophene precursors. A similar
strategy starting from the pyrimidine precursor and subsequent direct functionalization (formylation
and cyanation) of the thieno[2,3-d]pyrimidine parent compound in position 5 was found to be less
feasible.
Received in revised form
Accepted
Available online
Keywords:
Thieno[2,3-d]pyrimidine
Thiophene
Gewald reaction
Functionalization
Thieno[2,3-d]pyrimidine derivatives show a wide variety of
biological activities. Thieno[2,3-d]pyrimidines have been
evaluated as analgesics, anti-inflammatory, antipyretic, antiviral,
antidepressant, antidiabetic, antihistaminic, antibacterial and
antihypertensive agents, as pesticides, and also as herbicides, and
plant growth regulators. Most important is the inhibition of
protein kinase1, dihydrofolate reductase2 and thymidylate
synthase.2,3 Expectably, the scientific literature dealing with their
synthesis is vast, nevertheless only few review articles have
appeared until now.4
compounds.14 Cu, Ni and Pd-catalyzed nucleophilic cyanation of
aromatic halides,15 and electrophilic cyanation of reactive
organometallic species16 have made tremendous progress in the
past few years, and the cyanation of some more acidic
heterocycles has been accomplished by C-H-functionalization.17
No cyanation in the thiophene moiety has been reported for
thieno[2,3-d]pyrimidines so far.
We have been interested in the biocatalytic synthesis and
transformations of nitriles since several years.5 The recent
discovery of an unprecedented nitrile bioreduction6 and the
investigation concerning their biocatalytic potential for organic
synthesis7 has required the synthesis of 5-cyanothieno[2,3-
d]pyrimidine-4-one. Given the wide variety of other possible
biocatalytic (consecutive) transformations besides nitriles, in
particular by hydrolytic enzymes,8 we extended our work to the
synthesis of other functionalities. Here, we wish to report our
results on a general practical approach to 5-functionalized
thieno[2,3-d]pyrimidin-4-ones.
Scheme 1. Synthesis of thieno[2,3-d]pyrimidines starting from a
pyrimidine precursor. a) NaSH, ethylene glycol, 130°C, b) NaBH4,
DMF c), d) NaSH, ethylene glycol, 130°C, then chloroacetaldehyde,
aq. K2CO3, 40°C (yield 22% in a two step, one pot procedure), e)
pivaloylchloride, DMF, pyridine, Et3N, 0°C to 50°C (yield 33%), f)
POCl3, DMF, 55°C (yield 23%).
In this work, we investigated the synthesis of substituted
thieno[2,3-d]pyrimidines starting from pyrimidines as well as
from thiophene precursors. As pyrimidine precursor, we chose
commercially available 2-amino-6-chloro-4-hydroxypyrimidine
(Scheme 1). Reaction to the mercaptopyrimidine with sodium
hydrosulfide in ethylene glycol18 was accompanied by
dimerization of the mercapto group, which could be avoided by
carrying out the reaction under inert conditions and by
proceeding with the next synthetic step without isolation of the
mercapto compound. We investigated chloroacetaldehyde19 and
chloroformyl acetonitrile7a,20 for the formation of the thiophene
ring. The condensation reaction of 2-amino-6-mercapto-4-
hydroxypyrimidine with chloroacetaldehyde was successful with
The general strategy of thienopyrimidine synthesis follows a
ring annulation either of pyrimidine9 or thiophene rings10. 2-
aminothiophene precursors are frequently synthesized by Gewald
reaction11 from the corresponding α-methylene carbonyl
compound, α-cyanoester and sulfur. Several synthetic routes to
synthesize 5-cyano substituted thieno[2,3-d]pyrimidines were
investigated, such as the ring annulation using a 3-cyano or 3-
carboxylate substituted thiophene precursor and the introduction
of the cyano group in the 5-unsubstituted thieno[2,3-d]pyrimidine
by direct cyanation methods. Besides the classical Sandmeyer12
and Rosenmund - von Braun13 reactions using stoichiometric
amounts of CuCN, chlorosulfonylisocyanate has been reported to
act efficiently as
a cyanation reagent for heterocyclic
* Corresponding author. Tel.: 43-316-873-32445; fax: +43-316-873-32402; e-mail: klempier@tugraz.at

2
Tetrahedron
either KHCO3 in DMF19 or sodium acetate in water (see
Gewald reaction from the corresponding keto-compound 3-
chloro-2-oxopropionyl acetate (11)29, methylcyanoacetate and
Na2S30 (Scheme 3). We received a mixture of methyl 2-amino-4-
acetoxymethyl thiophene-3-carboxylate (12) and its deprotection
supporting information). Ethylene glycol as solvent and sodium
methoxide as base were reported previously in this reaction.21
product
methyl
2-amino-4-hydroxymethyl
thiophene-3-
carboxylate (13) in different ratios depending on the base used
(triethylamine or morpholine) and the ratio of the reactants in
methanol (2/8 in case of the conditions given in ref. 31).
Complete deprotection of methyl 2-amino-4-acetoxymethyl
thiophene-3-carboxylate (Scheme 3) was achieved by dropwise
addition of triethylamine to the reaction mixture and subsequent
heating of the reaction mixture to 65°C overnight. Upon ring
condensation with formamide and ammonium formate, 5-
hydroxymethylthieno[2,3-d]pyrimidin-4-one (15) was obtained
as the desired precursor for further transformations.
Conveniently, the product mixture from the Gewald reaction can
also be directly subjected to the following condensation step,
since the acetoxy group is cleaved upon condensation with
formamide under the high temperature conditions. Oxidation of
the alcohol to the aldehyde, formation of the oxime and
dehydratization under standard conditions23 gave the desired
nitrile, though in an overall unsatisfying yield.
Scheme 2. Synthesis of thieno[2,3-d]pyrimidines starting from a
commercially available thiophene precursor. a) formamide,
ammonium formate, 150°C (yield 57%), b) POCl3, Et3N, acetonitrile,
100°C (yield 70%), c) NaOCH3, methanol, reflux (yield 89%), d)
Hg(OAc)2, acetic acid, 100°C, then brine, e) iodine, chloroform,
50°C.
Given the low overall yields of the first two steps we decided
to pursue a condensation reaction starting from the commercially
available thiophene precursor methyl 2-aminothiophene-3-
carboxylate (Scheme 2). Condensation with formamide10b in
presence of ammonium formate22 occurred straightforward to
give thieno[2,3-d]pyrimidine-4-one (4). The next step was the
introduction of a substituent to the 5-position of the thieno[2,3-
Therefore we investigated a different synthetic route, shorter
in reaction steps and with the option of an even more versatile 4-
substituent in the 2-aminothiophene-3-carboxylate precursor.
d]pyrimidine.
A cyano-substituent can be introduced by
formylation of the thienopyrimidine, subsequent transformation
of the resulting aldehyde into its oxime and dehydratisation of the
oxime.23 Formylation reaction on a thieno[2,3-d]pyrimidine could
not be found in literature and all attempts to introduce the 5-
formyl group by using the Vilsmeier reagent24 resulted in the
preparation of 4-chlorothieno[2,3-d]pyrimidine (9), even when
the 4-hydroxy group was protected as methoxy ether (10). This
can be attributed to the ease of substitution of the 4-oxo-position
in the pyrimidine ring and to the fact that the Vilsmeier reaction
works best with electron rich aromatic heterocycles.
Scheme 3 Synthesis of thieno[2,3-d]pyrimidines starting from a
thiophene precursor. a) potassium acetate, glacial acetic acid, 85°C,
24h, vacuum distillation (bp17mbar 85°C, yield 28%), b) methyl
cyanoacetate, Na2S nonahydrate, MeOH, Et3N, 2d, r.t. (yield 80% of
13), c) formamide, ammonium formate, 120°C, 2-3d (yield 21% of
15). See supporting information for experimental details.
Palladium catalyzed reductive formylation was considered as
alternative formylation method.25 Following the relative
reactivity of aryl halides in palladium catalyzed cross-couplings:
I ~ OTf > Br > Cl, 5-iodothieno[2,3-d]pyrimidin-4-one was
prepared. Direct iodination of thieno[2,3-d]pyrimidin-4-one with
N-iodosuccinimide in THF was not successful, probably due to
the limited solubility of the starting material in THF. During the
iodination by chloromercuration2a,26 and subsequent substitution
with iodine we obtained a mixture of mono-iodinated and di-
iodinated products in a ratio of 1/0.6. Dibromination was also
observed in the bromination of thieno[2,3-d]pyrimidin-4-one
using bromine in acetic acid, and selective debromination then
gave a mono-bromo-substitution in position 5.27
We thus synthesized methyl 2-aminothiophene-3,4-
dicarboxylate (16)31 from methyl-2-oxo-propanoate, methyl
cyanoacetate and sulfur (S8) in DMF using triethylamine as base
in 71% yield (Scheme 4). The condensation of the Gewald
product with formamide and ammonium formate10b resulted in a
mixture of acid, amide and ester in position 5, which were then
separated by silica gel chromatography. Formation of the amide
can likely be attributed to reaction of the ester with the ammonia
formed by decomposition of the condensing reagent formamide
applied in excess at high temperature. The dehydratization of the
amide (19) to the nitrile (20) was accomplished using
trifluoroacetic acid anhydride in triethylamine or pyridine
(Scheme 4).32 It is noteworthy, that chloro-containing
dehydrating
PPh3/tetrachloromethane were unusable since they would lead to
agents,
such
as
thionylchloride
and
Palladium catalyzed reductive carbonylation was recently
successfully applied to the formylation of pyrrolo[2,3-
the undesired 4-chloro substituted thieno[2,3-d]pyrimidine.
d]pyrimidine
nucleosides,28
but
a
formylation
of
thienopyrimidines has not been reported so far. Our attempts
using bis(dibenzylideneacetone)palladium or tris(dibenzylidene)
di-palladium as catalyst were not successful. Optimization of the
reaction conditions and ligands of the palladium catalyst for this
particular reaction would be necessary.
Facing these challenges, we anticipated that a thiophene
precursor which carries the cyano group (or any group which can
be easily converted into a cyano group) in the appropriate
position, and can then be used in the condensation reaction to
give the 5-substituted thieno[2,3-d]pyrimidine, would be a more
convenient choice. We thus prepared methyl 2-amino-4-
acetoxymethyl-thiophene-3-carboxylate (12) by the one pot
Scheme 4. Synthesis of thieno[2,3-d]pyrimidines starting from a
thiophene precursor. a) methylpyruvate, sulphur, Et3N, DMF, 75°C,
overnight (yield 71%), b) formamide, 120-180°C, 2d (yield 30% of

3
19), c) trifluoroacetic anhydride, pyridine, 0°C to 60°C, 4h (yield
55%). See supporting information for experimental details.
9. (a) Clark, J.; Shahhet, M. S.; Korakas, D.; Varvounis, G. J. Heterocycl.
Chem. 1993, 30, 1065-1072.
In conclusion, we have accomplished the synthesis of 5-
hydroxy (acetoxy) methyl-, 5-formyl-, 5-cyanothieno[2,3-
d]pyrimidines, the 5-carboxylates and the respective amide by
building up the functionalized molecule starting from
appropriately substituted thiophene precursors. A similar strategy
starting from the pyrimidine precursor is less feasible since the
respective functionalized condensing agent is usually difficult to
synthesize. Direct functionalization (formylation and cyanation)
of the thieno[2,3-d]pyrimidine parent compound in position 5
turned out to be unsuccessful. The substituted thieno[2,3-
d]pyrimidines can be subjected to biocatalytic functional group
transformations.
10. (a) Kanawade, S. B.; Toche, R. B.; Rajani, D. P. Eur. J. Med. Chem.
2013, 64, 314-320; (b) Bugge, S.; Kaspersen, S. J.; Sundby, E.; Hoff, B. H.
Tetrahedron 2012, 68, 9226-9233; (c) Fernandez-Mato, A.; Peinador, C.;
Quintela, J. M. Synthesis 2011, 20, 3323-3331; (d) Zhang, H.; Bednarz, M.
S.; Lim, N.-K.; Hernandez, G.; Wu, W. Org. Lett. 2014, 16, 2522-2525.
11. (a) Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94-100;
(b) Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem.
1999, 36, 333-345; (c) Sabnis, R. W. Sulfur Rep. 1994, 16, 1-17.
12. (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 2650-; (b) Hodgson,
H. H. Chem. Rev. 1947, 40, 251-277; (c) Galli, C. Chem. Rev. 1988, 88, 765.
13. (a) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. 1919, 52, 1749;
(b) Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779-794.
14. Vorbrüggen, H.; Krolikiewicz, K. Tetrahedron 1994, 50, 6549-6558.
15. For some leading references see: (a) Wen, Q.; Jin, J.; Zhang, L.; Luo, Y.;
Lu, P.; Wang, Y. Tetrahedron Lett. 2014, 55, 1271-1280; (b) Sakakibara, Y.;
Okuda, F.; Shimobayashi, A.; Kirino, K.; Sakai, M.; Uchino, N., Takagi, K.
Bull. Chem. Soc. Jpn. 1988, 61, 1985-1990; (c) Butler, R. S.; Myers, A. K.;
Bellarmine, P.; Abboud, K. A.; Castellano, R. K. J. Mater. Chem. 2007, 17,
1863-1865; (d) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem.
2003, 3513-3526; (e) Schareina, T.; Jackstell, R.; Schultz, T.; Zapf, A.; Cotté,
A.; Gotta, M.; Beller, M. Adv. Synth. Catal. 2009, 351, 643-648; (f)
Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2001, 40, 5049-
5067; (g) Kim, J.; Kim, H. J.; Chang, S. Angew. Chem. Int. Ed. 2012, 51,
11948-11959.
Supplementary data
Synthetic procedures and characterization data (including
graphical NMR spectra) can be found in the supplementary
information.
Acknowledgments
The authors would like to thank Christoph Staudinger and
Melanie Zechner for skillful assistance in the laboratory. This
work has been supported by the Federal Ministry of Science,
Research and Economy (BMWFW), the Federal Ministry of
Traffic, Innovation and Technology (bmvit), the Styrian Business
Promotion Agency SFG, the Standortagentur Tirol and ZIT -
Technology Agency of the City of Vienna through the COMET-
Funding Program managed by the Austrian Research Promotion
Agency FFG.
16. (a) Wu, Y.; Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S.; Org. Lett.
2000, 2, 795-797; (b) Klement, I.; Lennick, K.; Tucker, C. E., Knochel, P.
Tetrahedron Lett. 1993, 34, 4623-4626.
17. (a) Reddy, B. V. S.; Begum, Z.; Reddy, Y. J.; Yadav, J. S. Tetrahedron
Lett. 2010, 51, 3334-3336; (b) Do, H.-Q.; Daugulis, O. Org. Lett. 2010, 12,
2517-2519; (c) Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 5608-
5611.
18. Hevener, K. E.; Yun, M.-K.; Qi, J.; Kerr, I. D.; Babaoglu, K.; Hurdle, J.
G.; Balakrishna, K.; White, S.W.; Lee, R. E. J. Med. Chem. 2010, 53, 166-
177.
19. (a) Rosowsky, A.; Papoulis, A. T.; Queener, S. F. J. Med. Chem. 1997,
40, 3694-3699; (b) corrections: Rosowsky, A.; Papoulis, A. T.; Queener, S. F.
J. Med. Chem. 2003, 46, 3424-3424.
References and notes
20. (a) Migawa, M.T.; Hinkley, J.M.; Hoops, G.C.; Townsend, L.B. Synth.
Commun. 1996, 26 (17), 3317-3322; (b) Gangjee, A.; Vidwans, A.; Elzein,
E.; McGuire, J.J.; Queener, S.F.; Kisliuk, R.L. J. Med. Chem. 2001, 44 (12),
1993-2003; (c) Gibson, C.L.; Ohta, K.; Paulini, K.; Suckling, C.J. J. Chem.
Soc., Perkin Trans. 1, 1998, 3025-3032; (d) Gibson, C.L.; La Rosa, S.; Ohta,
K.; Boyle, P.H.; Leurquin, F.; Lemacon, A.; Suckling. C.J. Tetrahedron 2004,
60 (4), 943-959; (e) Llona-Minguez, S.; Mackay, S. P. Beilstein J. Org.
Chem. 2014, 10, 1333-1338.
21. Roth, B.; Laube, R.; Tidwell, M. Y.; Rauckman, B. S. J. Org. Chem.
1980, 45, 3651-3657.
22. addition of ammonium formate to formamide resulted in improved yields:
Nunokawa, Y.; Nakatsuka,T.; Saitoh, M. Patent, EP 1018514, 2000.
23. March, J. Advanced Organic Chemistry, John Wiley & Sons: New York,
1992.
1. (a) Kjær, S.; Linch, M.; Purkiss, A.; Kostelecky, B.; Knowles, P. P.; Rosse,
C.; Riou, P.; Soudy, C.; Kaye, S.; Patel, B.; Soriano, E.; Murray-Rust, J.;
Barton, C.; Dillon, C.; Roffey, J.; Parker, P. J.; McDonald, N. Q. Biochem. J.
2013, 451, 329-342; (b) Horiuchi, T.; Takeda, Y.; Haginoya, N.; Miyazaki,
M.; Nagata, M.; Kitagawa, M.; Akahane, K.; Uoto, K. Chem. Pharm. Bull.
2011, 59, 991-1002; (c) Horiuchi, T.; Nagata, M.; Kitagawa, M.; Akahane,
K.; Uoto, K. Bioorg. Med. Chem. 2009, 17, 7850-7860; (d) McClellan, W. J. ;
Dai, Y.; Abad-Zapatero, C.; Albert, D. H.; Bouska, J. J.; Glaser, K. B.;
Magoc, T. J.; Marcotte, P. A.; Osterling, D. J.; Stewart, K. D.; Davidsen, S.
K. Bioorg. Med. Chem. Lett. 2011, 21, 5620-5624.
2 (a) Gangjee, A.; Li, W.; Kisliuk, R. L.; Cody, V.; Pace, J.; Piraino, J.;
Makin, J. J. Med Chem. 2009, 52, 4892-4902; (b) .Gangjee, A.; Qiu, Y.; Li,
W.; Kisliuk, R. W. J. Med. Chem. 2008, 51, 5789-5797.
24. (a) Marson, C. M.; Giles, P. R. Synthesis using Vilsmeier Reagents, CRC
Press: 1994; (b) Tasneem, Synlett 2003, 1, 138-139; (c) for formylation of e.
g. indoles using the Vilsmeier reaction see: Jiang, B.; Smallheer, J. M.;
Amaral-Ly, C.; Wuonola, M. A. J. Org. Chem. 1994, 59, 6823-6827.
25. (a) Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 7761-7764;
(b) Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed. Eng.
2009, 48, 4114-4133; (c) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc.
1986, 108, 452-461.
3. Gangjee, A.; Qiu, Y.; Kisliuk, R. L. J. Heterocycl. Chem. 2004, 41, 941-
946.
4. (a) Ibrahim, Y. A.; Elwahy, A. H. M. Adv. Heterocycl. Chem. 1996, 65,
235-281; (b) Varvounis, G.; Giannopoulos, T. Adv. Heterocycl. Chem. 1996,
66, 193-283; (c) Litvinov, V.P. Adv. Heterocycl. Chem. 2006, 92, 83-143.
5. selected examples: (a) Klempier, N.; de Raadt, A.; Griengl, H.; Heinisch,
G. J. Heterocycl. Chem. 1992, 29, 93-95; (b) Schmidt, M.; Hervé, S.;
Klempier, N.; Griengl, H. Tetrahedron 1996, 52, 7833-7840; (c) Winkler, M.;
Martínková, L.; Knall, A. C.; Krahulec, S.; Klempier, N. Tetrahedron 2005,
61, 4249-4260; (d) Winkler, M.; Knall, A. C.; Kulterer, M. R.; Klempier, N.
J. Org. Chem. 2007, 72, 7423-7426.
6. (a) Van Lanen, S. G.; Reader, J. S.; Swairjo, M. A.; De Crecy-Lagard, V.;
Lee, B.; Iwata-Reuyl, D. Proc. Nat. Acad. Sci. USA 2005, 102(12), 4264-
4269; (b) Lee, B.; Van Lanen, S. G.; Iwata-Reuyl, D. Biochemistry 2007, 46,
12844-12854.
26. Taylor, E. C.; Young, W. C.; Chaudhari, R.; Patel, H. H. Heterocycles
1993, 36, 1897-1908.
27. Bowers, S.; Truong, A. P.; Neitz, R. J.; Hom, R. K.; Sealy, J. M.; Probst,
G. D.; Quincy, D.; Peterson, B.; Chan, W.; Galemmo Jr., R. A.; Konradi,
A.W.; Sham, H. L.; Tóth, G.; Pan, H.; Lin, M.; Yao, N.; Artis, D. R.; Zhang,
H.; Chen, L.; Dryer, M.; Samant, B.; Zmolek, W.; Wong, K.; Lorentzen, C.;
Goldbach, E.; Tonn, G.; Quinn, K. P.; Sauer, J.-M.; Wright, S.; Powell, K.;
Ruslim, L.; Ren, Z.; Bard, F.; Yednock, T. A.; Griswold-Prenner, I. Bioorg.
Med. Chem. Lett. 2011, 21, 5521-5527.
28. Brückl, T.; Thoma, I; Wagner, A. J.; Knochel, P.; Carell, T. Eur. J. Org.
Chem. 2010, 34, 6517-6519.
29. (a) Hess, K.; Fink, H. Chem. Ber. 1915, 48, 2003; (b) Pero, R. W.;
Babiarz-Tracy, P.; Fondy, T. P. J. Med. Chem. 1977, 20, 644-647.
30. (a) Buchstaller, H.-P.; Siebert, C. D.; Lyssy, R. H.; Frank, I.; Duran, A.;
Gottschlich, R.; Noe, C. R. Monatsh. Chem. 2001, 132, 279-293; (b) Pratt, J.
7. (a) Wilding, B.; Winkler, M.; Kratzer, R.; Petschacher, B.; Glieder, A.;
Klempier, N. Adv. Synth. Catal. 2012, 354, 2191-2198; (b) Wilding, B.,
Winkler, M., Petschacher, B., Kratzer, R., Egger S., Steinkellner, G.,
Lyskowski, A. Nidetzky, B., Gruber, K., Klempier, N. Chem. Eur. J. 2013,
19, 7007-7012.
8. (a) Bornscheuer, U.; Kazlauskas, R. J. Hydrolases in Organic Synthesis,
Wiley-VCH: Weinheim, 1999; (b) Busto, B.; Gotor-Fernández, V.; Gotor, V.
Chem. Soc. Rev. 2010, 39, 4504-4523.
* Corresponding author. Tel.: 43-316-873-32445; fax: +43-316-873-32402; e-mail: klempier@tugraz.at

4
Tetrahedron
K.; Betebenner, D. A.; Donner, P. L.; Green, B. E.; Kempf, D. J.; McDaniel,
K. F.; Maring, C. J.; Stoll, V. S.; Zhang, R. U. S. Patent 162285, 2004.
31. Berrouard, P.; Grenier, F.; Pouliot, J.-R.; Gagnon, E.; Tessier, C.; Leclerc,
M. Org. Lett. 2011, 13, 38-41.
32. Campagna, F.; Carotti, A.; Casini, G. Tetrahedron Lett. 1977, 21, 1813-
1816.