90
Table 2
Enantioselective hydrogenation of ketopantolactone and ethyl pyruvate on Pt/Al2O3 with cinchona alkaloid modifiers 1, 2 and 3a.
Entry
Ketone
Modifier
Conv. (%)b AcOH
eeb (%) AcOH
Conv. (%)b PhMe
eeb (%) PhMe
1
2
3
4
5
6
KPL
EP
KPL
EP
KPL
EP
1
1
2
2
3
3
100
100
100
100
100
100
67 (R)
90 (R)
16 (R)
42 (R)
9 (R)
100
100
100
100
100
100
66 (R)
82 (R)
54 (R)
60 (R)
45 (R)
20 (R)
25 (R)
a
Conditions: 42 mg Pt/Al2O3, 1.84 mmol substrate (ketopantolactone KPL, ethyl pyruvate EP), 6.5 mol modifier (HCl salt), 5 mL solvent, 20 bar H2, 2 h, 1000 rpm.
Determined by chiral GC analysis.
b
3. Results and discussion
electivities observed using the parent systems (66% vs 57% for the
hydrogenation of ketopantolactone).
Studies were initiated by evaluating the hydrogenation of
ketopantolactone 4 using the fluorocinchonidine derivative 8: the
ously been determined (NCCF torsion angle = −75.3◦) [7] lending
support to our initial supposition. Gratifyingly, the reduction of 4 on
a Pt/Al2O3 surface (20 bar H2) furnished the desired (R)-configured
product 5 in quantitative yield and with reasonable levels of enan-
tioinduction (57% ee, Fig. 4).
4. Conclusions
In summary, we have reported a novel class of fluorinated sur-
face modifiers for the asymmetric heterogeneous hydrogenation
C9 fluorinated analogues, as compared with the 9-deoxy system,
is rationalised by invoking a Fı−–N+ gauche effect that is triggered
upon protonation of the quinuclidine nitrogen, thus rigidifying the
alkaloid scaffold. Efforts to prepare modifiers with enhanced per-
formance based on this principle are currently on-going and will
be reported in due course. Particular emphasis will be placed on
investigating the surface binding mode of species such as 8 and the
ensuing surface bound conformational dynamics.
With this preliminary validation in hand we sought to evaluate
the performance of related fluorinated chiral modifiers (9–13) on
the conversion of ketopantolactone 4 to pantolactone 5 (Table 1).
Interestingly, the efficacy of the ligand appeared to have little
dependence on the configuration at C-9 (entries 1 and 3; 8 and
10, respectively) with both the degree and sense of enantioinduc-
tion being dictated by the C-8 centre (entries 5 and 6; 12 and 13,
respectively). Moreover, the impact of the methoxy group on the
enantioselectivity appears to be case dependent. Whereas hydro-
genations using the (R)-configured derivatives 8 and 13 (entries 1
and 6) lead to notable differences in the optical purity of the product
(57% ee and 27% ee in toluene), the (S)-configured modifiers 9 and
10 (entries 2 and 3, respectively) are comparable (ꢀee = 2%). Yet, in
this analysis, the performance of compound 9 rivals that of the lead
(57% ee and 54% ee respectively; entries 1 and 2). The discrepancies
in enantioinduction are tentatively attributed to subtle differences
in the surface bound conformations of these modifiers; an issue that
is the subject of much conjecture [5(b),11]. Furthermore, reactions
using this ligand class show a clear solvent dependence that man-
ifests itself in the enantiopurity of the product. Acetic acid has a
highly detrimental effect on selectivity; an observation that is con-
sistent with the disruption of the postulated Fı−–N+ electrostatic
effect that is central to our working hypothesis [12]. In extreme
cases the discrepancy in enantiomeric excess can be as much as 44%
(compound 10, entry 3). However, in toluene the catalytic compe-
tence of this class of surface modifiers is encouraging and warrants
further investigation.
Acknowledgments
We gratefully acknowledge generous financial support from the
Alfred Werner Foundation (assistant professorship to R.G.), the
Scholarship Fund of the Swiss Chemical Industry (doctoral fellow-
ship to C.B.) and the ETH Zurich.
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