Desymmetrization of meso-cyclic imides via enantioselective monohydrogenation

Article abstract of DOI:10.1021/ja105783u

meso-Cyclic imides are monohydrogenated to form the corresponding hydroxy lactams in 88-97% ee using trans-[Ru((R)-BINAP)(H)₂((R,R)-dpen)] and related compounds as catalysts with base in THF. The hydrogenation proceeds with high enantiogroup-and chemoselectivity, and it is a desymmetrization reaction, forming up to five stereogenic centers in one reaction. Conversion of a hydroxy lactam into the corresponding iminium ion followed by addition of indene extended the number of stereogenic centers from 5 to 7.

Full text of DOI:10.1021/ja105783u

Published on Web 08/24/2010
Desymmetrization of meso-Cyclic Imides via Enantioselective
Monohydrogenation
Satoshi Takebayashi, Jeremy M. John, and Steven H. Bergens*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
Received June 30, 2010; E-mail: steve.bergens@ualberta.ca
catalyzes the hydrogenation of esters in THF to give the alcohol
Abstract: meso-Cyclic imides are monohydrogenated to form the
corresponding hydroxy lactams in 88-97% ee using trans-
[Ru((R)-BINAP)(H)2((R,R)-dpen)] and related compounds as
catalysts with base in THF. The hydrogenation proceeds with high
enantiogroup- and chemoselectivity, and it is a desymmetrization
reaction, forming up to five stereogenic centers in one reaction.
Conversion of a hydroxy lactam into the corresponding iminium
ion followed by addition of indene extended the number of
stereogenic centers from 5 to 7.
products under mild conditions, and it stoichiometrically adds
lactones at -80 °C to form the corresponding Ru hemiacetoxides.15
This unexpectedly high reactivity in THF led us to explore the
enantioselective monohydrogenation of meso-cyclic imides using
1c and related complexes as catalysts under mild conditions.
We prepared solutions containing 1c and related catalysts for
this study by reacting mixtures of trans-[Ru((R)-BINAP)(H)(L)((R,R)-
dpen)](BF4) (2, L ) η2-H2 or THF), KOt-Bu, and H2 (∼2 atm) at
-78 °C in THF.14a As 1 equiv of base is consumed to prepare 1,
the amount of base quoted in this text is that remaining after 1 is
prepared. Catalysts containing other diamine ligands (Scheme 1)
were prepared similarly. The common catalyst precursor trans-
[Ru((R)-BINAP)(Cl)2((R,R)-dpen)]16 was inactive toward this imide
hydrogenation.
We report the first enantioselective desymmetrization of meso-
cyclic imides by monohydrogenation to form hydroxy lactams.
Hydroxy lactams and their derivatives are versatile building blocks
that have been used to prepare numerous heterocyclic compounds,1
including vitamins, antibiotics, ACE inhibitors, and anticancer drugs
such as (+)-biotin,2 loracarbef,3 (-)-A58365A,4 and swainsonine.5
Hydroxy lactams are readily converted into the corresponding
lactones or lactams,6 and they are precursors to N-acyliminium
ions.1 N-Acyliminium ions undergo a myriad of C-C bond-forming
reactions.1 Recent reports include organocatalytic enantioselective
Morita-Baylis-Hillman-type reactions7 and Pictet-Spengler-type
cyclizations.8
Scheme 1. Structures of Catalysts and Cyclic Imides
Desymmetrization is an efficient method for multiplying the
enantioselectivity of a catalytic reaction.9 Multiple stereogenic
centers are formed simultaneously and in identical ee in one reaction
from simple substrates. Desymmetrizations are typically enantio-
group-selective reactions, with relatively few examples among
catalytic hydrogenations.9d Of these, most are dihydrogenations of
meso-cyclic anhydrides to form the corresponding lactones.2e,10
There exists only one report of the enantioselective desymmetri-
zation of meso-cyclic imides by catalytic hydrogenation: Ikariya
and co-workers11 showed that certain meso-cyclic imides were
dihydrogenated (30 atm H2, 80 °C, 24 h, 10 mol % Ru catalyst,
and 10 mol % KOt-Bu in 2-PrOH) to form the ring-opened
alcohol-amides in 64-98% ee. Dihydrogenation presumably
occurred via hydrogenation of the more reactive aldehyde-amide
tautomer of the hydroxy lactam. Although enantioselective monore-
ductions of meso-cyclic imides with chiral B-H or Al-H reagents
that trap the hydroxy lactam are known,2c,d,12 there are no reports
of enantioselective monohydrogenations.13 We hypothesized that
monohydrogenation should occur when the catalyst is sufficiently
active to reduce the imide under mild conditions that disfavor the
tautomerization.
Table 1. Achiral Hydrogenation of Imidesa
entry
catalyst
imide
3 (%)b
4 (%)b
5 (%)b
1
1a
1b
1a
1a
1a
1a
1c
1c
3a
3a
3a
3b
3c
3d
3b
3b
0
100
100
30
24
34
0
0
0
70
76
66
55
30
100
0
0
0
0
0
0
20
2
3c
4
5d
6
7
45
50
8e
We recently reported the low-temperature preparation and study
of the Noyori ketone hydrogenation catalyst trans-[Ru((R)-
BINAP)(H)2((R,R)-dpen)] (1c) (Scheme 1).14 The dihydride 1c is
a remarkably active carbonyl reducing agent in THF. For example,
we showed that 1c rapidly adds acetophenone at -80 °C to form
trans-[Ru((R)-BINAP)(H)(OCH(CH3)(Ph))((R,R)-dpen)].14c 1c also
a [Imide] ) 0.33 M, unless otherwise noted. b Determined by 1H
NMR. c Imide/1a/KOt-Bu ) 200:1:9, [imide] ) 0.5 M in 3:1 THF/
2-PrOH. d [Imide]
)
0.11
M in 2:1 THF/CH2Cl2 because of the
solubility of 3c. e At 60 °C.
Table 1 summarizes our results for achiral hydrogenations in
THF at 30 °C. N-Methylsuccinimide (3a) was exclusively dihy-
9
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10.1021/ja105783u  2010 American Chemical Society

C O M M U N I C A T I O N S
drogenated to the alcohol-amide product (entry 1). The N-
substituted phthalimides (3b-d) were monohydrogenated under
moderate conditions to yield the corresponding hydroxy lactams
(entries 4-6). Increasing the reaction temperature resulted in partial
dihydrogenation (entry 8). Thus, monohydrogenation occurs at
lower temperatures when the imide structure disfavors ring-opening
tautomerization. Use of 2-PrOH (entry 3) and secondary diamine
ligands (entry 2 vs entries 4 and 7) disabled the catalyst system.
Table 2 summarizes our results for enantioselective hydrogena-
tions using mainly 1c as catalyst. We chose imide 3e (Scheme 1)
to evaluate the extent of hydrogenation (mono/di), and the chemo-
(CdC/CdO), diastereo- (cis/trans), and enantiogroup selectivity of
the hydrogenation. Also, the product hydroxy lactam 4e (Figure 1)
contains five stereogenic centers.
Figure 1. Addition reaction between 4e and indene and an ORTEP drawing
of 6 with 20% probability ellipsoids. The absolute configuration was not
determined.
Table 2. Enantioselective Hydrogenation of meso-Cyclic Imidesa
entry
imide
T (°C)
time (h)
4 (%)b
5 (%)b
d.r. of 4b
ee of 4 (%)c
tization.18 Analogues of 4e were also used in the literature to prepare
indolizidine and pyrrolizidine alkaloids.19
1d
2e
3
3e
3e
3f
3g
3h
3i
22
0
0
0
0
0
0
0
3
17
17
17
17
57
6
70
98
99
92
98
90
97
44
12
0
0
0
>99:1
>99:1
>99:1
>99:1
>99:1
97:3
83
96
97
97
95
88
92
92
This paper has presented the first chemo-, diastereo-, and
enantiogroup-selective monohydrogenations of meso-cyclic imides.
These desymmetrization reactions formed up to five stereogenic
centers in high ee with one hydrogenation. N-Acyliminium ion
chemistry readily increases the number of stereogenic centers. The
cis/trans selectivity at the hydroxy carbon was not preserved during
the hydrogenation, and the trans isomer is strongly favored by
thermodynamics. The scope of these hydrogenations, the origins
of the enantioselectivity, and the cis/trans selectivity of these catalyst
systems are under study in our laboratory.
4
5
0
6f
7g
8
trace
trace
0
3j
3k
93:7
>99:1
17
a Imide/1c/KOt-Bu ) 500:1:9, [imide] ) 0.625 M, 50 atm H2 in
THF, unless otherwise noted. b Determined by 1H NMR spectroscopy;
d.r. ) diastereomeric ratio. c Determined by HPLC analysis using a
Daicel CHIRALPAK IB column. d Imide/1c/KOt-Bu ) 100:1:4, [imide]
) 0.125 M. e Imide/1c/KOt-Bu ) 1000:1:9, [imide] ) 1.25 M. f Imide/
1c/KOt-Bu ) 1000:1:99, [imide] ) 0.25 M. g Imide/1d/KOt-Bu )
100:1:4, [imide] ) 0.125 M.
Acknowledgment. This work was supported by the Natural
Sciences and Engineering Research Council of Canada (NSERC),
the Government of Trinidad and Tobago (GoRTT), and the
University of Alberta. We greatly appreciate the assistance of the
University of Alberta High Field NMR Laboratory and X-ray
Crystallography Laboratory.
Hydrogenation (50 atm) of 3e at 22 °C formed a mixture of
mono- and dihydrogenation products in a ∼6:1 ratio with 83% ee
for hydroxy lactam 4e and without olefin hydrogenation16 (entry
1). At 0 °C, 3e reacted to yield only 4e in 98% yield with 96% ee
using 0.1% catalyst (entry 2). One recrystallization increased the
ee to >99%. The p-F, -NMe2, and -OMe variants 3f-h reacted in
92-99% yield with 95-97% ee using 0.2% 1c as the catalyst
(entries 3-5). The meso-cyclohexane imide 3i reacted in 90% yield
with 88% ee (entry 6), and the O-bridging imide 3j reacted with
catalyst 1d in 97% yield with 92% ee (entry 7). The norbornane
imide 3k reacted in 44% yield with 92% ee (entry 8). This imide
is also relatively unreactive toward Al-H reduction,6 most likely
as a result of steric hindrance by the norbornane backbone.17 The
stereochemistry at the hydroxy carbon of the hydroxy lactam
products was almost exclusively trans (see the Supporting Informa-
tion for the solid-state structure of 4e). Control experiments with
the cis isomer of 4e6 showed that cis-trans isomerization is
catalyzed by base under the conditions of these hydrogenations.
Thus, the enantiogroup selectivity is preserved under the conditions
of these hydrogenations, but the cis/trans selectivity at the hydroxy
carbon is not.
Supporting Information Available: Experimental procedures,
characterization of compounds, and crystallographic data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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