Multi-component assembly of the bicyclic core associated with the tRNA synthetase inhibitors SB-203207 and SB-203208. Application to the synthesis of biologically active analogues

Article abstract of DOI:10.1039/b104890m

The ketone (±)-5, which embodies the bicyclic core associated with the title tRNA synthetase inhibitors 1 and 2, has been prepared via a three-component coupling reaction involving 2-(hydroxymethyl)cyclopent-2-enone (15), methylamine (6) and propiolamide

Full text of DOI:10.1039/b104890m

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Multi-component assembly of the bicyclic core associated with the
tRNA synthetase inhibitors SB-203207 and SB-203208. Application to
the synthesis of biologically active analogues†
Martin G. Banwell,*a Curtis F. Crasto,a Christopher J. Easton,*a Tomislav Karoli,a Darren R.
March,a Michael R. Nairn,a Peter J. O’Hanlon,b Mark D. Oldham,a Anthony C. Willisa and
Weimin Yuea
a Research School of Chemistry, Institute of Advanced Studies, The Australian National
University, Canberra, ACT 0200, Australia. E-mail: mgb@rsc.anu.edu.au
b GlaxoSmithKline, New Frontiers Science Park, Harlow, UK CM19 5AW
Received (in Cambridge, UK) 4th June 2001, Accepted 21st June 2001
First published as an Advance Article on the web 11th October 2001
The ketone ( )-5, which embodies the bicyclic core asso-
ciated with the title tRNA synthetase inhibitors 1 and 2, has
been prepared via a three-component coupling reaction
involving 2-(hydroxymethyl)cyclopent-2-enone (15), methy-
lamine (6) and propiolamide (10); straightforward elabora-
tion of the readily derived acetates (2)-21 and (+)-21 has
provided the biologically active analogues 23 and 24,
respectively, of the title compounds.
The emergence of ‘superbugs’ such as vancomycin-resistant
Staphylococcus aureus has prompted extensive efforts to
Fig. 1
identify new anti-infective agents.1 High throughput screening
regimes have led to the discovery of a number of novel leads
which would then react, through nitrogen in a hetero-Michael-
including SB-203207 (1) and SB-203208 (2) which are potent
inhibitors of both bacterial and mammalian isoleucyl tRNA
synthetases.2 The structurally related natural product altemici-
din (3),3 a novel acaricidal and anti-tumour agent, has been the
subject of an elegant total synthesis.4 However, the methods4,5
currently available for construction of the hexahydroazaindene
core associated with such compounds are unlikely to be
practical in providing a broad range of analogues of 1 and 2 for
testing as anti-infective agents. On this basis we now describe a
multi-component and potentially highly flexible method for
construction of the azabicyclic ketones ( )-4 and ( )-5 as well
as conversion of the latter into biologically active analogues of
the title compounds.
addition reaction, with 9 or 10. The enamine–cyclopentenone
conjugate thus formed might then be expected to undergo an
intra-molecular Michael-addition reaction,7 thereby providing
the target ketones ( )-4 and ( )-5. In the event, mixing the four
components 6–9 with DABCO, a proven catalyst for the Baylis–
Hillman reaction, in water at room temperature (CAUTION—
highly exothermic!) resulted in a complex mixture of products
from which the 1,5-diazacycloocta-2,6-diene 13 could be
isolated and the structure of which follows from spectroscopic
analysis. Clearly, 6, 7 and 9 but not 8 have been incorporated
into this product and further studies revealed that simply mixing
the former compounds in water (Scheme 1) provided diene 13
in 45% yield. Presumably, a key intermediate in this conversion
In our initial approach to ( )-4 and ( )-5 we envisaged that
these might be constructed in a one-pot process from methyla-
mine (6), formaldehyde (7), cyclopent-2-enone (8) and the
appropriate propiolic acid derivative 9 or 10 (Fig. 1). In
particular, it seemed possible that in the presence of a suitable
catalyst the Schiff-base (imine) derived from condensation of 6
and 7 could participate in an ‘aza-Baylis–Hillman’ reaction6
with 8 to give N-methyl-2-(aminomethyl)cyclopent-2-enone
† Electronic supplementary information (ESI) available: spectral data for 5,
crystal data for ( )-21 (CCDC 165269), HPLC for (+)- and (2)-21. See
http://www.rsc.org/suppdata/cc/b1/b104890m/
Scheme 1 Conditions: (i) H2O, DABCO (cat.), ca. 18 °C, 16 h.
2210
Chem. Commun., 2001, 2210–2211
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104890m

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Scheme 2 Reagents and conditions: (i) DABCO (ca. 0.25 mol% wrt 8), aq. HCHO (1.5 mole equiv.), THF, 18 °C, 23 h; (ii) Ac2O (2 mole equiv.), Et3N (1.65
mole equiv.), DMAP (cat.), CH2Cl2; (iii) 6 (1.5 mole equiv.), 9 (1.5 mole equiv.), DABCO (1.25 mole equiv.), H2O, 18 °C, 5–7 days; (iv) 14 (1.6 mole equiv.),
DABCO (1 mole equiv.), EtOH, 18 °C, 15 h; (v) 14 (1.7 mole equiv.), EtOH, 18 °C, 15 h; (vi) 11 (1 mole equiv.), Pd(PPh3)4 (10 mol%), THF, 18 °C, 10–14
days; (vii) L-Selectride® (1.0 mole equiv. of a 1 M solution in THF), THF, 217 °C, 0.5 h; (viii) 22 (2 mole equiv,), Et3N (2 mole equiv.), ClCOCOCl (2
mole equiv.), 0 °C, 0.5 h then (+)- or (2)- 20, Et3N (1 mole equiv.), DMAP (cat.), DMF, 0 to 18 °C, 1.5 h; (ix) H2 (1 atm), 10% Pd on C (cat.), MeOH, 18 °C,
4 h.
is the enamine 118,9 (resulting from Michael addition of
methylamine to methyl propiolate) which condenses with 7 to
give the 1-aza-3-methoxycarbonylbuta-1,3-diene 12 that, in
turn, undergoes cyclodimerisation to the observed product. An
analogous sequence starting with amide 10, and which would
have been presumed to involve intermediate 14,8 failed to
deliver the bis(carboxamide) analogue of compound 13.
gave, after hydrogenolytic deprotection, the target molecules 23
[from (2)-21] and 24 [from (+)-21]. Independent testing of 23
and 24 as inhibitors of S. aureus-derived IRS12 revealed that the
former compound shows an IC50 of 3.7 mM while the analogous
value for the ‘unnatural’ diastereoisomer 24 is 12.4 mM.
Interestingly, this difference in activity is even more pro-
nounced with S. aureus-derived LRS (0.42 mM vs. no inhibition
at 100 mM), S. aureus-derived VRS (6.35 mM vs. no inhibition
at 100 mM) and rat liver IRS (0.57 mM vs. 13.5 mM).
The above-mentioned and ready condensation of 7 with 11,
rather than its participation in an initial Baylis–Hillman reaction
with 8, clearly thwarted attempts to implement the proposed
four-component coupling approach to targets ( )-4 and ( )-5.
To circumvent such problems, 7 and 8 were subject to a
dedicated Baylis–Hillman reaction then an aqueous solution of
the resulting 2-(hydroxymethyl)cyclopent-2-enone (15)10
(Scheme 2) was treated with 6 and 9 in the presence of
stoichiometric amounts of DABCO. In this manner the unstable
ketone ( )-4 was eventually obtained (ca. 20% after ca. 5 days).
An analogous reaction using propiolamide 10 afforded the more
stable congener ( )-5 (ca. 20%). A superior method (40% yield
after ca. 15 h) for producing ( )-5 involved treating an ethanolic
solution of the acetate 16, derived from alcohol 15, with 148
(resulting from Michael addition of methylamine to propiola-
mide) in the presence of DABCO. Surprisingly, the same
reaction when carried out in the absence of DABCO afforded
the isomeric hexahydroazaindene ( )-17 (40%) as the major
product of reaction. Similarly, when a THF solution of 16 was
treated with 11 in the presence of (Ph3P)4Pd the structurally
related ester ( )-18 (ca. 20%) was obtained.
Diastereofacially selective reduction of ketone ( )-5 with
L-Selectride® yielded the alcohol ( )-20 (96%), the readily
available acetate derivative, ( )-21 (63%), of which proved
suitable for single-crystal X-ray analysis. Alcohol ( )-20 was
readily coupled with the acid chloride derived from 22 and the
resulting diastereomeric mixture of esters was subjected to
hydrogenolytic deprotection to produce an inseparable and ca.
1+1 mixture of 23 and 24. In an effort to obtain diastereomer-
ically pure samples of these materials several methods for
preparing the monochiral forms of ketone 5 were examined but
none of the several chiral catalysts that have been used to effect
asymmetric Baylis–Hillman reactions11 proved effective in
promoting the enantioselective coupling of 14 and 15. While
various chiral ester derivatives of 15 participated in reaction
with 14 to produce ketone 5 in acceptable chemical yield, the
observed diastereomeric excesses were disappointing ( < 17%).
As a consequence, the racemic acetate ( )-21 was resolved
using chiral HPLC techniques (see ESI†). Coupling of each of
the enantiopure alcohols with the acid chloride derivative of 22
We thank GlaxoSmithKline (Australia) Pty Ltd for financial
support and Dr Brian Metcalf (formerly of SmithKline
Beecham US) for his encouragement and advice. Lucy M.
Mensah (GSK, Harlow) is thanked for carrying out the reported
enzyme inhibition assays.
Notes and references
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