4th EucheMs chemistry congress

Poster Session 1
s1073
chem. Listy 106, s587–s1425 (2012)
Poster session 1 - organic chemistry
P - 0 4 2 3
GoLd And SiLver CAtALySed reACtionS of
ProPArGyLiC ALCohoLS
M. PenneLL 1 , t. ShePPArd 1 , P. turner 2
1 University College London, Chemistry, London, United
Kingdom
2 GlaxoSmithKline, Chemistry, Stevenage, United Kingdom
The 1,3-isomerisation of propargylic alcohols to enones is
known as the Meyer-Schuster rearrangement. We have
demonstrated efficient room temperature reaction conditions for
the gold-catalysed Meyer-Schuster rearrangement (>30 examples)
of a wide array of secondary and tertiary propargylic alcohols to
the corresponding enones in generally excellent yields and with
high E-selectivity. [2, 3] The methodology has also successfully been
applied to the synthesis of two small natural products,
Isoegomaketone (anti-inflammatory properties) and Daphenone
(cytotoxicity against five human tumour cell lines). [3]
Primary propargylic alcohols rearrange to give highly
reactive terminal enones, which can undergo conjugate addition
reactions with nucleophiles to access β-substituted products
through convenient one-pot procedures. [2, 3] The use of silver
as a catalyst, instead of gold, promotes substitution of the
electron-rich propargylic alcohol with various oxygen, carbon and
nitrogen nucleophiles. [3] β-Hydroxyketones can be accessed via a
gold-catalysed hydration, employing phenols as the reaction
additive. [2, 4] This methodology has been developed for the synthesis
of enantiomerically enriched β-hydroxyketones and the synthesis
of a natural nonadecenetriol (antiprotozoal agent against
Tyransome parasites). [4] The gold catalysed hydration offers an
alternative to traditional aldol procedures with the benefit of
tolerating the presence of other enolisable centres.
The full scope of the Meyer-Schuster rearrangement and the
investigation into the role of protic additives in the gold and silver
catalysed reactions of propargylic alcohols will be described in
the presentation.
references:
1. Meyer, H. K.; Schuster, K. Chem. Ber. 1922, 55, 819-823.
2. Pennell, M. N.; Unthank, M.; Turner, P.; Sheppard, T. D.
J. Org. Chem. 2011, 76, 1479-1482.
3. Pennell, M. N.; Turner, P. G.; Sheppard, T. D. Chem. Eur.
J. 2012, DOI: 10.1002/chem.201102830.
4. Pennell, M. N.; Turner, P. G.; Sheppard, T. D. Manuscript
in preparation.
Keywords: Gold; Homogeneous cataylsis; Meyer-Schuster
rearrangement; Propargylic alcohols; Silver;
4 th EucheMs chemistry congress
P - 0 4 2 4
SyntheSiS of fLuorinAted AnALoGueS of
6-hetAryL-7-deAzAPurine nuCLeoSideS
P. PerLiKovA 1
1 Charles University in Prague Faculty of Science, Department
of Organic and Nuclear Chemistry, Prague, Czech Republic
Analogues of nucleosides are an important class of
anti-tumor and anti-viral therapeutics. Recently, nanomolar
cytostatic activity against a panel of cancer cell lines was shown
in 6-hetaryl-7-deazapurine ribonucleosides. [1] The aims of this
project were: a) further modification of the lead structure by
replacement of the 2'-hydroxy group by isosteric fluorine;
b) comparison of cytostatic activities of ribonucleosides and their
fluorinated analogues. A synthetic route to 6-hetaryl-7-
-deazapurine 2'-fluoro-2'-deoxyribonucleosides was developed.
A key intermediate 6-chloro-7-deazapurine 2'-fluoro-2'-
-deoxyribonucleoside 1 was synthesized starting from 6-chloro-
-7-deazapurine ribonucleoside 3 in 9 steps in 18 % overall yield.
The synthesis started with silyl protection of 3'- and 5'-hydroxy
group followed by oxidation of 2'-hydroxy group and
stereoselective reduction to obtain silylated arabinonucleoside 2. [2]
Then, several protection and deprotection steps as well as
fluorination of the 2'-hydroxy group with DAST were used to
synthesize 2'-fluoro-2'-deoxyribonucleoside 3. Fluoroderivative
3 was used as a starting material for Suzuki cross-coupling
reactions with hetarylboronic acids under aqueous conditions.
6-Hetaryl-7-deazapurine 2'-fluoro-2'-deoxyribonucleosides were
obtained in 37–88% yield. All 6 target compounds were tested for
their cytostatic activity against cancer cell lines. None of the
fluorinated analogues showed any cytostatic activity. The results
lead to conclusion that 2'-hydroxy group is esential for cytostatic
activity of 6-hetaryl-7-deazapurine ribonucleosides.
Acknowledgement: This work is a part of the research project
Z4 055 0506 from the Academy of Sciences of the Czech
Republic. It was supported by the Czech Science Foundation
(P207/11/0344) and by Gilead Sciences, Inc.
references:
1. Naus P., Pohl R., Votruba I., Dubák P., Hajdúch M.,
Ameral R., Birkus G., Wang T., Ray A.S., Mackman R.,
Cihlar T., Hocek M.: J. Med. Chem. 53, 460 (2010)
2. Naus P., Perlíková P., Pohl R., Hocek M.: Collect. Czech.
Chem Comm. 79, 957 (2011)
Keywords: nucleosides; fluorination;
AUGUst 26–30, 2012, PrAGUE, cZEcH rEPUbLIc