SpinPhox/iridium(I)-catalyzed asymmetric hydrogenation of cyclic α-alkylidene carbonyl compounds

Article abstract of DOI:10.1002/anie.201309521

Optically active medium-sized cyclic carbonyl compounds bearing an α-chiral carbon center are of interest in pharmaceutical sciences and asymmetric synthesis. Herein, SpinPhox/Ir^I catalysts have been demonstrated to be highly enantioselective in the asymmetric hydrogenation of the Ci￡C bonds in the exocyclic α,β-unsaturated cyclic carbonyls, including a broad range of α-alkylidene lactams, unsaturated cyclic ketones, and lactones. It is noteworthy that the procedure can be successfully used in the asymmetric hydrogenation of the challenging α-alkylidenelactam substrates with six- or seven-membered rings, thus affording the corresponding optically active carbonyl compounds with an α-chiral carbon center in generally excellent enantiomeric excesses (up to 98 % ee). Synthetic utility of the protocol has also been demonstrated in the asymmetric synthesis of the anti-inflammatory drug loxoprofen and its analogue, as well as biologically important ε-aminocaproic acid derivatives. Take it for a spin: SpinPhox/Ir^I complexes are highly efficient and versatile in the enantioselective hydrogenation of a broad spectrum of exocyclic α,β-unsaturated carbonyl compounds, especially the challenging α-alkylidene lactam substrates with six- or seven-membered rings. The synthetic utility of the present protocol is demonstrated in the asymmetric synthesis of biologically important loxoprofen and ε-aminocaproic acid derivatives. Copyright

Full text of DOI:10.1002/anie.201309521

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DOI: 10.1002/anie.201309521
Asymmetric Catalysis
SpinPhox/Iridium(I)-Catalyzed Asymmetric Hydrogenation of Cyclic
a-Alkylidene Carbonyl Compounds**
Xu Liu, Zhaobin Han, Zheng Wang, and Kuiling Ding*
Dedicated to Professor Chengye Yuan on the occasion of his 90th birthday
Abstract: Optically active medium-sized cyclic carbonyl
compounds bearing an a-chiral carbon center are of interest
in pharmaceutical sciences and asymmetric synthesis. Herein,
SpinPhox/IrI catalysts have been demonstrated to be highly
=
enantioselective in the asymmetric hydrogenation of the C C
bonds in the exocyclic a,b-unsaturated cyclic carbonyls,
including a broad range of a-alkylidene lactams, unsaturated
cyclic ketones, and lactones. It is noteworthy that the procedure
can be successfully used in the asymmetric hydrogenation of
the challenging a-alkylidenelactam substrates with six- or
seven-membered rings, thus affording the corresponding
optically active carbonyl compounds with an a-chiral carbon
center in generally excellent enantiomeric excesses (up to
98% ee). Synthetic utility of the protocol has also been
demonstrated in the asymmetric synthesis of the anti-inflam-
matory drug loxoprofen and its analogue, as well as biolog-
ically important e-aminocaproic acid derivatives.
Figure 1. Examples of biologically active molecules derived from
medium-sized cyclic carbonyl compounds.
O
ptically active medium-sized cyclic carbonyl compounds
bearing an a-chiral carbon center are recurring structural
motifs in pharmaceutical sciences and versatile chiral building
blocks in asymmetric synthesis (Figure 1).[1] An attractive
synthetic route to these compounds would be the catalytic
high activity and good stereocontrol in the rhodium- or
ruthenium-catalyzed AH.[6] The iridium complexes of chiral
P,N ligands are particularly noteworthy in overcoming these
limitations,[7] and demonstrated excellent enantioselectivities
in the AH of a wide range of largely unfunctionalized
olefins,[8] including olefins with weakly coordinating groups[9]
and tetrasubstituted olefins.[10] In this context, a few excellent
iridium catalysts have been developed recently for AH of
=
asymmetric hydrogenation (AH) of the C C bonds in the
exocyclic a,b-unsaturated cyclic carbonyls, by virtue of the
high efficiency, atom-economy, and cost-effectiveness of the
methodology. While a great number of chiral catalysts have
been developed over the years for AH of various acyclic and
endocyclic unsaturated carbonyl compounds,[2] documented
=
C C bonds in a,b-unsaturated carbonyl compounds as well,
as exemplified by the independent pioneering studies of the
groups of Bolm, Hou, and Zhou.[11] Nevertheless, challenges
still remain in the AH of exocyclic a,b-unsaturated cyclic
carbonyls with regard to the limited substrate scope, and the
enantioselectivities are often strongly dependent on the ring
size of the substrates in the AH of a-alkylidene lactams and
lactones,[3–5] as indicated by BiphPhox/IrI catalysts
(Figure 2).[12] We previously reported a class of chiral
iridium(I) complexes, SpinPhox/IrI (Figure 2), with spiro
P,N ligands[13] for efficient AH of ketimines, a,b-unsaturated
carboxylic acids, and Weinreb amides, as well as a,a’-bis(2-
examples which are especially effective for the AH of the
exocyclic C C bonds of a-alkylidene lactams, lactones,[4]
[3]
=
and/or cyclic ketones[5] are still quite rare. The difficulty
associated with this type of substrate in asymmetric hydro-
genation is probably due to the exocyclic nature of the C C
bond which may hamper substrate bonding to the metal
center, and has been assumed to be a key factor in achieving
=
[*] X. Liu, Dr. Z. Han, Dr. Z. Wang, Prof. Dr. K. Ding
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P.R. China)
E-mail: kding@mail.sioc.ac.cn
[**] We thank the NSFC (grant nos.21232009, 21172237, 21032007,
21121062) and the Major Basic Research Development Program of
China (grant no. 2010CB833300) for support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309521.
Figure 2. BiphPhox/IrI and SpinPhox/IrI catalysts.
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hydroxyarylidene)ketones.[14] Herein, we communicate the
successful application of SpinPhox/IrI catalysts in the AH of
the challenging six- and seven-membered a-alkylidene car-
bonyls with a focus on the lactam derivatives. The synthetic
utility of the protocol is also showcased in the asymmetric
synthesis of the nonsteroidal anti-inflammatory drug loxo-
profen and an e-aminocaproic acid derivative.
Encouraged by the excellent preliminary results attained
in the hydrogenation of the six-membered substrate 2a with
1c, we extended this catalyst system to the hydrogenation 3-
alkylidene caprolactams, a class of seven-membered exocyclic
a,b-unsaturated lactams which have almost been neglected in
AH studies.[15] A quick survey with (E)-3-benzylidene azepin-
2-one (4a) as the model substrate revealed that (R,S)-1c is the
chirality-matched catalyst (Table 1, entry 11 versus 10). Other
(R,S) isomers of the catalysts 1a,b and 1d,e only showed
inferior results to those of (R,S)-1c (entries 12–15).
The optimized catalyst, (S,S)-1c, was subsequently used in
the AH of various N-Boc-protected (E)-3-alkylidenepiper-
idin-2-ones (2b–p; Table 2). The reactions were conducted at
room temperature under 1 atm of H2 in the presence of
1 mol% of (S,S)-1c, and the results are summarized in the left
column of Table 2. Except for the substrate 2d, having
a sterically demanding ortho-tolyl group (entry 4), the
reactions of 3-alkylidene-2-piperidones having an aryl sub-
stituent were generally successful and afforded high ee values
(89–95%) for substrates with a para- (2b, and 2e–i), meta-
(2c,2j, and 2k), or disubstituted phenyl ring (2l), irrespective
of the electron-donating or electron-withdrawing nature of
the substituent (entries 3–12). Furthermore, the substrates
with heteroaryl substituents (2m–o) were also hydrogenated
in quantitative conversions with excellent enantioselectivities
(entries 13–15). Unfortunately, the AH of piperidone sub-
strates containing an aliphatic group (2p) was less successful,
with a somewhat lower ee value being attained at an elevated
catalyst loading (entries 16).
The hydrogenation of a range of N-Boc-protected alkli-
denecaprolactams having various aryl substituents was fur-
ther carried out with (R,S)-1c as the catalyst under the
optimized reaction conditions mentioned above, and the
results are shown in the right column of Table 2. All the
reactions proceeded smoothly at room temperature under
5 atm of H2 to afford the corresponding chiral caprolactams
5a–q with full conversion of the substrates and excellent
ee values (95–98%; entries 1–17). For these substrates, it
appears that the reactions are quite general and less
influenced by the electronic nature or the steric bulk of the
aryl substituents in the substrates.
To test the viability of the catalysis, a preliminary screen-
ing of the SpinPhox/IrI complexes (R,S)-1a–e and (S,S)-1a–
d,[12a] and of the reaction conditions were performed using
AH of (E)-3-benzylidenepiperidin-2-one, and its N-benzyl-,
N-phenyl-, N-methyl-, or N-Boc-protected derivatives as the
model reactions (see Table S2 in the Supporting Information).
It turns out that the N-Boc-protected derivative 2a appears to
be optimal in terms of the reactivity and enantioselectivity
(up to 93% ee). The AH of 2a was performed under an
ambient pressure of H2 at room temperature in CH2Cl2 for
6 hours in the presence of 1 mol% of different SpinPhox/IrI
complexes. As shown in Table 1, the catalysts (R,S)-1c and
(S,S)-1c, bearing a (S)-sBu group on the oxazoline moiety,
turned out to be favorable for the enantiocontrol of the
reaction, thus affording the piperidone 3a with an ee value
much higher than that of their counterparts (entries 3 and 8).
It is also noteworthy that both (R,S)-1c and (S,S)-1c gave 3a
in excellent optical purity but as opposite enantiomers, thus
indicating that the spirochirality of the ligand controls the
sense of asymmetric induction in the catalysis.
Table 1: Iridium(I) catalysts for AH of the N-Boc-protected 2a and (E)-3-
benzylideneazepin-2-one (4a).[a]
Entry
Subs.
Cat.
Conv. [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
4a
4a
4a
4a
4a
4a
(R,S)-1a
(R,S)-1b
(R,S)-1c
(R,S)-1d
(R,S)-1e
(S,S)-1a
(S,S)-1b
(S,S)-1c
(S,S)-1d
(S,S)-1c
(R,S)-1c
(R,S)-1a
(R,S)-1b
(R,S)-1d
(R,S)-1e
75
>99
60
54
40
77 (S)
19 (S)
91 (S)
70 (S)
6 (S)
73 (R)
37 (R)
93 (R)
70 (R)
31 (R)
97 (S)
77 (S)
89 (S)
94 (S)
95 (S)
Having established the applicability of SpinPhox/IrI
catalysts in the hydrogenation of six- and seven-membered
cyclic amides with a-alkylidene substituents, we further
examined their adaptability in AH of some other medium-
sized cyclic a,b-unsaturated carbonyls. As shown in Table 3,
a variety of lactones, ketones, and lactams with an exocyclic
28
>99
>99
70
=
C C bond (6a–g) have also been hydrogenated smoothly with
9
high enantioselectivity under 5 atm of H2 by suitable choice of
the iridium(I) catalyst, (S,S)-1c or (R,S)-1b (1 mol%). The
catalyst (S,S)-1c was found to be highly enantioselective for
the reaction of the six-membered-ring lactone 6a and ketones
6b,c, as well as seven-membered-ring ketone 6d, having an a-
benzylidene substituent, to give the corresponding hydro-
genation products 7a–d in excellent ee values (entries 1–4).
All these facts further attest to the versatility of the present
catalyst system, although the catalyst (R,S)-1b only showed
moderate to good enantioselectivities (81–83%) in the AH of
substrates 6e–g having five-membered rings (entries 5–7).
10
11
12
13
14
15
86
>99
>99
>99
>99
>99
[a] Unless otherwise noted, all reactions were conducted under 1 or 5
atm of H2 at 258C for 6 or 10 h with [2a] and [4a]=0.1m and [1]=1 mm
(1 mol%). [b] Determined by 1H NMR spectroscopy. [c] The ee values
were determined by HPLC analysis on a chiral stationary phase, and the
absolute configurations were determined according to the method
specified in footnote [c] of Table 2. Boc=tert-butoxycarbonyl.
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Table 2: AH of the N-Boc-protected 2a–p and 4a–q catalyzed by
iridium(I) catalysts (S,S)-1c and (R,S)-1c, respectively.[a]
Table 3: AH of exocyclic a,b-unsaturated ketones, lactams, and lactones
catalyzed by the iridium(I) complexes 1.[a]
Entry
1
Substrate
Catalyst
Conv. [%][b]
ee [%][c]
92 (S)
(S,S)-1c
>99
Entry
R
Conv. ee [%][c]
R
Conv. ee [%][c]
[%][b]
[%][b]
2
3
4
(S,S)-1c
(S,S)-1c
(R,S)-1c
>99
>99
>99
97 (R)
93 (R)
96 (S)
1
Ph
(2a)
4-MeC6H4
(2b)
3-MeC6H4
(2c)
2-MeC6H4
(2d)
4-MeOC6H4 >99 89 (R)
(2e)
4-ClC6H4
(2 f)
4-BrC6H4
(2g)
4-FC6H4
(2h)
4-CF3C6H4
(2i)
3-CF3C6H4
(2j)
3-ClC6H4
(2k)
>99 93 (R)
>99 91 (R)
>99 91 (R)
50 73 (R)
Ph
(4a)
4-MeC6H4
(4b)
3-MeC6H4
(4c)
2-MeC6H4
(4d)
4-MeOC6H4 >99
(4e)
4-ClC6H4
(4 f)
4-BrC6H4
(4g)
4-FC6H4
(4h)
4-CF3C6H4
(4i)
3-CF3C6H4
(4j)
3-ClC6H4
(4k)
3,4-Cl2C6H3 >99
(4l)
3-FC6H4
(4m)
2-furyl
(4n)
2-thienyl
(4o)
>99
>99
>99
97(S)
98 (S)
97 (S)
2
3
4[d]
5
>99[d] 98 (S)
98 (S)
95 (S)
98 (S)
97 (S)
98 (S)
98 (S)
97 (S)
98 (S)
97 (S)
97 (+)
96 (+)
98 (S)
98 (S)
6
>99 93 (R)
>99 93 (R)
>99 93 (R)
>99 95 (R)
>99 95 (R)
>99 94 (R)
>99
>99
>99
>99
>99
>99
5
6
7
(R,S)-1b
(R,S)-1b
(R,S)-1b
>99
>99
>99
83 (À)
83 (À)
81 (S)
7
8
9
10
11
12
3,4-Cl2C6H3 >99 95 (R)
(2l)
[a] Reaction conditions: 0.15 mmol of 6a–g, CH2Cl2 (1.5 mL), P(H2)=
5 atm, 1 mol% of iridium(I) complex 1, RT, 10 h. [b] Determined by
1H NMR spectroscopy. [c] Determined by HPLC analysis on a chiral
stationary phase. The absolute configurations were assigned by
comparing their specific rotations with the literature reported values.
13[e] 3-furyl
(2m)
>99 93 (+)
>99 96 (+)
>99 93 (+)
79 79 (+)
>99
>99
>99
>99
14[e] 2-furyl
(2n)
15[e] 2-thienyl
(2o)
16[e] cyclohexyl
(2p)
2-FC6H4
(4p)
3-PhOC6H4 >99
(4q)
catalytic system. As shown in Figure 3, the hydrogen bonding
between the lactam carbonyl moieties and the upper Ir H
probably has significant impact on the approach of the C C
À
17
=
double bond to the iridium center during the catalysis. The
opposite asymmetric induction observed in AH of 2a using
(R,S)-1c and (S,S)-1c (Table 1) can be rationalized on the
basis of this model, thus indicating the critical role of the
spirochirality in the ligand for the control of asymmetric
induction, even though the chirality of the oxazoline moiety
might influence the level of enantioselectivity as well.
To illustrate the synthetic application of the present
methodology, the enantioenriched caprolactams (S)-5a and
(S)-5b (Table 2) were readily hydrolyzed to the correspond-
ing chiral aminocaproic acids without loss of optical purity,
which are homologues of e-aminocaproic acid (a marketed
enzyme inhibitor used to treat certain bleeding disorders)[17]
and bioisosteres of lysine (Scheme 1A). The synthetic appli-
cation of this protocol was further demonstrated in the
asymmetric synthesis of loxoprofen (10a), a nonsteroidal
[a] Unless otherwise noted, the reactions were performed with
0.15 mmol of 2a–p and 4a–q in CH2Cl2 (1.5 mL) in the presence of
1 mol% of (S,S)-1c and (R,S)-1c at RT, respectively. [b] Determined by
1H NMR spectroscopy. [c] Determined by HPLC on a chiral stationary
phase. The absolute configurations of 3g and 5g were determined by
X-ray crystallographic analyses, while those of the other hydrogenation
products were assigned by comparison of their CD spectra with that of
3g or 5g, respectively. [d] 2 mol% of (S,S)-1c was used with a reaction
time of 10 h. [e] 5 mol% of (S,S)-1c was used with reaction time of 24 h.
On the basis of the the crystal structure information of the
SpinPhox/IrI complexes (R,S)- and (S,S)-1[14e] and the
observed asymmetric induction in the catalysis, as well as
the related mechanism reported by Andersson,[16] a plausible
asymmetric induction model is proposed for the present
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the asymmetric synthesis of the anti-inflammatory drug
loxoprofen and its analogue, as well as biologically important
e-aminocaproic acid derivatives.
Received: November 1, 2013
Published online: January 20, 2014
Keywords: asymmetric catalysis · hydrogenation · iridium ·
.
lactams · synthesis design
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Figure 3. A plausible asymmetric induction model for SpinPhox/IrI-
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Scheme 1. A) Transformation of the optically active caprolactams 5a
and 5b into the corresponding e-aminocaproic acid derivatives:
a) 30% aq HCl, 1008C, 2 h; b) MeOH, H2SO4 (cat), 608C, 2 h;
c) (Boc)2O, Et3N, CH2Cl2, RT, 2 h. B) Asymmetric synthesis of loxopro-
fen (10a) and its analogue 10b by a two-step hydrogenation of 9a,b
using a single catalyst (R,S)-1b: d) (R,S)-1b (1 mol%), 30 atm H2,
Et3N (1 equiv), CH2Cl2, RT, 12 h; e) (R,S)-1b (1–2 mol%), 30 atm H2,
CH2Cl2, RT, 12 h.
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anti-inflammatory drug with medicinal significance and
research interests (Scheme 1b).[18] A two-step AH of the
=
acrylic and alkylidene C C bonds in the (E)-2-{4-[(2-oxocy-
cloalkylidene)methyl]phenyl}acrylic acids 9a,b by using
a (R,S)-1b, afforded (1’S, 2R)-loxoprofen (10a; 98% ee,
82:18 d.r.) and its analogue 10b (99% ee, 91:9 d.r.) in
excellent enantio- and diastereoselectivities (for details see
the Supporting Information).
In summary, we have disclosed that SpinPhox/IrIcatalysts
are highly efficient and versatile in enantioselective hydro-
genation of a broad spectrum of exocyclic a,b-unsaturated
carbonyl compounds with particular merits in addressing the
challenging a-alkylidenelactam substrates with six- or seven-
membered rings, thus affording the corresponding optically
active carbonyl compounds with an a-chiral carbon center in
excellent enantiomeric excesses (up to 98% ee). Synthetic
utility of the present protocol has also been demonstrated in
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