S. Christou et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5066–5069
5067
The pivotal intermediate in our approach to the target com-
pounds was -oxygenated cyclohexenone 8 which was prepared
Despite the unpredictable nature of these reactions, preparative
quantities of all principal adducts could be obtained by fractional
crystallisation (chromatographic separation of diastereoisomers
was unsuccessful). In the first instance, stereochemical assignment
of the adducts was based on examination of the respective vicinal
c
in 4 steps and 79% overall yield from (À)-quinic acid (7) using
the conditions reported previously by ourselves (Scheme 1).5d
Conjugate addition to 8 may occur either syn or anti to the C4-
substituent to give syn-9 or anti-9, respectively: despite a num-
ber of relevant investigations over the years, a reliable model
for predicting the stereochemical outcome of transformations
such as this remains illusive. This is exemplified by a report by
Corey6 which describes the outcome of investigations of the reac-
tion of spirocyclic enone 10 with lithiumdialkyl cuprates—in
which a preference was observed for conjugate addition syn to
the oxygen substituent in the presence of TMSCl (to give
syn-11) and a reversal in selectivity in the absence of the
additive (to give anti-11). In contrast, Danishefsky7 reported that
addition of lithiumdimethyl cuprate in the presence of TMSCl to
3
3
coupling constants for C(4)H (e.g. syn-9b: J3,4 = 5.1; J4,5 = 10.4:
3
3
anti-9b: J3,4 = 11.0: J4,5 = 9.5). The assignment was supported by
the observation of nOe enhancements between C(5)H and C(3)H
for anti-9b and between C(5)H and the aromatic CH’s of syn-9b.
Ultimately, structural confirmation was possible by X-ray analysis
of crystalline samples of the two isomeric adducts (Fig. 4).9,10
Our preferred approach to the preparation of the target com-
pounds is illustrated in Scheme 2 for the synthesis of phenyl-
substituted compound 17. Thus, eliminative removal of the BDA
protecting group of anti-9b proceeded effectively in aqueous med-
ium and in the presence of a catalytic amount of a Bronsted acid
surfactant catalyst (dodecylbenzenesulphonic acid) to give 14.11
Subsequent protection of the liberated hydroxyl group as its trieth-
ylsilyl (TES) ether proceeded cleanly at low temperature to give 15
in a reproducible 48% yield over the two steps from 9b. Following
extensive investigations of a variety of reaction conditions, it was
found that introduction of a hydroxymethyl group at C2 of 15
could be accomplished quite efficiently, and in a relatively short
time, using Williams’ surfactant-based procedure for the Morita–
Baylis–Hillman (M–B–H) reaction.12 Finally, the target compound
17, which possesses a crotonate ester side-chain similar to that
in COTC (1), was prepared by esterification of the primary hydroxyl
of 16 followed by acid-mediated removal of the silyl protecting
group.
c
-oxygenated cyclohexenone 12 gave solely the anti adduct 13
(Fig. 3).
The rigid ‘trans-decalin’ nature of 8 results in there being little
steric differentiation between the two faces of the enone moiety
and the C4-oxygen substituent, which is pseudo-equatorially dis-
posed, would be expected to have negligible stereoelectronic influ-
ence on diastereofacial selectivity. It was our conjecture, therefore,
that conjugate addition to 8 would proceed via an ‘axial’ trajectory
to give syn-9.8 Unfortunately, however, the stereochemical
outcome of reactions of 8 with a range of Gilman cuprates proved
to be wholly unpredictable as illustrated by the results in Table 1.
Thus, under standard conditions, addition of di-(2-propenyl)-cup-
rate proceeded with reasonable facial selectivity to give anti-9a:
the product ratio was unaffected by the presence of TMSCl
however it was notably increased at low temperature. Contrarily,
diphenylcuprate, in the presence of TMSCl, furnished the syn-
isomer in excess at 0 °C, however, at room temperature anti-9b
becomes the major product isomer. Di-(4-fluorophenyl)-cuprate
displayed a similar preference for formation of the syn-isomer
(syn-9c) at 0 °C, however there was no discernible facial
discrimination at room temperature.
Both the diastereoisomeric phenyl-substituted compound 18
and the 2-propylcompound 1913 were prepared in a similar man-
ner to 17 whereas diol 20 was obtained by hydrolytic deprotection
of the 2-propyl-substituted analogue of M–B–H adduct 16 (Fig. 5).
The four analogues 17-20 were assessed for their in vitro toxic-
ity towards the non-small-cell lung cancer cell line A549. The as-
says were carried out by exposing cells to varying concentrations
of each compound for 4 days and the number of surviving cells
Scheme 1.
Figure 3. Conjugate addition reactions of organo-cuprates to c-oxygenated cyclohexenones.
Christou, Stephania
