Table 1. Hydrogenation of Lactic Acid Derivatives 4
substrates 4
entry
P
FG
CO2Et
1
H2 (bar)
syn/antia (crude material)
1
2
3
4
5
6
7
8
a
b
c
H
R
S
R
S
R
S
R
S
50
50
5
5
5
5
20
20
1.0:2.0
61:1.0
1.0:10
27:1.0
1.0:10
16:1.0
1.0:1.2
14:1.0
MOM
MOM
MOM
CO2Et
CH2OH
d
CH2OTBDPS
a Reactions run to >99% conversion. Conversions and enantiomeric excesses determined via GC on a chiral column.
tree’s Ir-complexes7-12 like (S)-1.13,14 Stereoselective hy-
drogenations of chiral allylic alcohols were investigated
extensively about two decades ago.15- However, those
reactions were all substrate-controlled, so it was not possible
to obtain syn- and anti-aldol fragments by varying the catalyst
chirality. Here it was possible to do that; hence, some
important chirons were produced with high levels of catalyst
control using 0.5 mol % of complex 1; the syntheses are
practical and potentially scalable with minimal optimization.
Before the current studies began, we had already reported
moderate enantioselectivities for ethyl tiglate C and the
corresponding alcohol D; both these substrates have an
R-methyl group adjacent to the ester or hydroxymethylene
group.18 In the current work, we discovered that much better
enantioselectivities were obtained for substrates 2 and 3
where the methyl group is attached to the ꢀ-carbon of the
alkene (100% conversion at 0.5 mol% (S)-1, 25 °C, 6 h; 2,
5 bar H2; 3: 25 bar H2), as outlined below.
to optimize the diastereoselectivities in either direction, i.e.,
so that either the syn or the anti diastereomers could be
obtained. Pressure can influence enantioselectivities in
hydrogenations of some substrates with catalyst 1, but that
was not the case here; the main objective of varying it for
substrates 4 was to achieve >99% conversion within 12 h.
All of the data in Table 1 indicate hydrogenation of 4 is
catalyst controlled, but the substrate vector is also influential.
Excellent syn selectivities could be obtained, with entry 2
being best of those studied. After flash chromatography of
the material corresponding to entry 2, the syn/anti ratio was
>99:1.0 (75% yield). The best crude selectivity for the anti
isomer was 10:1.0 (entries 3 and 5); the material from the
experiment represented by entry 3 was purified by flash
chromatography giving 68% isolated yield of 1.0:31 syn/
anti material.17
An interesting difference emerges when comparing the
data for the “ꢀ-methyl” substrates in Table 1 (cf. Figure 1a)
with similar “R-methyl” alkenes. Relatively many com-
pounds of the latter type have been studied in our group,18-21
and two illustrative examples are given in Figure 1b. In all
cases of the later type, carbonyl derivatives (like the ester
shown) give opposite face selectivities relative to primary
alcohol and ether compounds. This has been explained in
terms of a catalyst vector (usually dominant) that involves
(12) Cheruku, P.; Diesen, J.; Andersson, P. G. J. Am. Chem. Soc. 2008,
130, 5595–5599.
Substrates 4a-d were prepared to expand the scope of
the discovery outlined above in the context of preparing
chirons A (Table 1). Largely inconsequential changes were
made to the protecting group “P” and the functional group
(13) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies,
J. H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113–123.
(14) Powell, M. T.; Hou, D.-R.; Perry, M. C.; Cui, X.; Burgess, K. J. Am.
Chem. Soc. 2001, 123, 8878–8879.
(15) Brown, J. M.; Cutting, I. J. Chem. Soc., Chem. Commun. 1985,
578–579.
(7) Crabtree, R. H.; Felkin, H.; Fillebeen-Khan, T.; Morris, G. E. J.
Organomet. Chem. 1979, 168, 183–198.
(16) Evans, D. A.; Morrissey, M. M. J. Am. Chem. Soc. 1984, 106, 3866–
3868.
(8) Markert, C.; Roesel, P.; Pfaltz, A. J. Am. Chem. Soc. 2008, 130,
3234–3235.
(17) Holscher, B.; Braun, N. A.; Weber, B.; Kappey, C.-H.; Meier, M.;
Pickenhagen, W. HelV. Chim. Acta 2004, 87, 1666–1680.
(18) Zhou, J.; Ogle, J. W.; Fan, Y.; Banphavichit, V.; Zhu, Y.; Burgess,
K. Chem.sEur. J. 2007, 13, 7162–7170.
(9) Wang, A.; Wustenberg, B.; Pfaltz, A. Angew. Chem., Int. Ed. 2008,
47, 2298–2300.
(10) Dieguez, M.; Mazuela, J.; Pamies, O.; Verendel, J. J.; Andersson,
P. G. J. Am. Chem. Soc. 2008, 130, 7208–7209.
(11) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345.
(19) Zhou, J.; Burgess, K. Org. Lett. 2007, 9, 1391–1393.
(20) Zhou, J.; Burgess, K. Angew. Chem., Int. Ed. 2007, 46, 1129–1131
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(21) Zhu, Y.; Burgess, K. J. Am. Chem. Soc. 2008, 130, 8894–8895
.
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Org. Lett., Vol. 11, No. 10, 2009