Asymmetric hydrogenation of bicyclic ketones catalyzed by BINAP/IPHAN-Ru(II) complex

Article abstract of DOI:10.1021/ol101200z

(Equation Presented). Hydrogenation of 3-quinuclidinone and bicyclo[2.2.2]octan-2-one with a combined catalyst system of RuCl ₂[(S)-binap][(R)-iphan] and t-C₄H₉OK in 2-propanol afforded the chiral alcohols in 97-98% ee. 2-Diphenylmethyl-3- quinuclidinone was hydrogenated with the same catalyst to the cis alcohol with perfect diastereo-and enantioselectivity. The reaction of unsymmetrical ketones with a bicyclo[2.2.1] or-[2.2.2] skeleton gave the corresponding alcohols with high stereoselectivity.

Full text of DOI:10.1021/ol101200z

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3380-3383
Asymmetric Hydrogenation of Bicyclic
Ketones Catalyzed by BINAP/
IPHAN-Ru(II) Complex
Noriyoshi Arai,† Masaya Akashi,‡ Satoshi Sugizaki,† Hirohito Ooka,†,‡
Tsutomu Inoue,‡ and Takeshi Ohkuma*,†
DiVision of Chemical Process Engineering, Faculty of Engineering, Hokkaido
UniVersity, Sapporo, Hokkaido 060-8628, Japan, and Odawara Research Center,
Nippon Soda Co., Ltd., 345 Takada, Odawara 250-0280, Japan
ohkuma@eng.hokudai.ac.jp
Received May 25, 2010
ABSTRACT
Hydrogenation of 3-quinuclidinone and bicyclo[2.2.2]octan-2-one with a combined catalyst system of RuCl2[(S)-binap][(R)-iphan] and t-C4H9OK
in 2-propanol afforded the chiral alcohols in 97-98% ee. 2-Diphenylmethyl-3-quinuclidinone was hydrogenated with the same catalyst to the
cis alcohol with perfect diastereo- and enantioselectivity. The reaction of unsymmetrical ketones with a bicyclo[2.2.1] or -[2.2.2] skeleton gave
the corresponding alcohols with high stereoselectivity.
Asymmetric hydrogenation of ketones is one of the most
direct and reliable methods to produce synthetically useful
chiral secondary alcohols.1 We have developed highly active
and enantioselective Ru catalysts with a chiral diphosphine
and a nitrogen-based bidentate ligand for this reaction.2
Appropriate combination of these two ligands is crucial to
achieve high catalyst performance. For instance, a Ru
complex bearing XylBINAP and DAIPEN, a chiral 1,2-
diamine, catalyzes hydrogenation of a series of acyclic
aromatic, heteroaromatic, amino, and R,ꢀ-unsaturated ketones
in base-containing 2-propanol to afford the corresponding
chiral alcohols in >99% ee in the best cases.2-4 The
TolBINAP/chiral 1,4-diamine-Ru complexes show high
catalytic activity and enantioselectivity in the hydrogenation
of 1-tetralones, a kind of cyclic aromatic ketone.3,5
Asymmetric hydrogenation of aliphatic ketones with a
bicyclo[2.2.2] or -[2.2.1] skeleton is a challenging subject from
the following academic and practical points of view: (1) the
(3) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. TolBINAP ) 2,2′-
bis(di-4-tolylphosphino)-1,1′-binaphthyl. XylBINAP ) 2,2′-bis(di-3,5-xylylphos-
phino)-1,1′-binaphthyl. DAIPEN ) 1,1-di(4-anisyl)-2-isopropyl-1,2-ethylenedi-
amine. (S)-IPBAN ) (2S,3S)-2,3-O-isopropylidenehexane-1,4-diamine. (R)-IPHAN
) (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine.
† Hokkaido University.
‡ Nippon Soda Co., Ltd.
(1) Resent reviews: (a) Ohkuma, T.; Noyori, R. In Transition Metals
for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 2004; Vol. 2, pp 29-113. (b) Ohkuma, T.; Noyori, R. In The
Handbook of Homogeneous Hydrogenation; de Vries, J. G., Elsevier, C. J.,
Eds.; Wiley-VCH: Weinheim, 2007; Vol. 3, pp 1105-1163.
(2) Reviews: (a) Ohkuma, T. Proc. Jpn. Acad. Ser. B 2010, 86, 202–
219. (b) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40–73.
(4) (a) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.;
Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1998, 120, 13529–13530. (b) Ohkuma, T.; Koizumi, M.; Mun˜iz, K.;
Hilt, G.; Kabuto, C.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508–6509
(5) Ohkuma, T.; Hattori, T.; Ooka, H.; Inoue, T.; Noyori, R. Org. Lett.
2004, 6, 2681–2683
.
.
10.1021/ol101200z  2010 American Chemical Society
Published on Web 07/12/2010

sterically congested framework requires highly active catalytic
species, (2) precise discrimination between primary alkyl and
secondary alkyl groups is crucial to achieve high enantioselec-
tivity, (3) and the obtained chiral alcohols are key intermediates
for the synthesis of biologically active compounds, including
solifenacin, an M3 receptor antagonist.6 We expected that the
BINAP/chiral 1,4-diamine-Ru catalysts would be appropriate
for this hydrogenation because the medium-sized diamine-Ru
chelate structure has enough space for an approach of the
bicyclic ketones to the reaction site. The chiral environment of
the Ru catalyst constructed from chiral diphosphine and diamine
ligands can be tuned by changing the combination.
Scheme 1
We recently reported asymmetric hydrogenation of 3-qui-
nuclidinone (1a) catalyzed by an (S,S)-XylSkewphos/R-
picolylamine-Ru complex.7 The high catalytic activity achieved
complete conversion in the reaction with a substrate-to-catalyst
molar ratio (S/C) of 100 000 (15 atm H2, 30-40 °C, 4 h) to
give (R)-3-quinuclidinol [(R)-2a] in 88% ee. A patent described
that 97% ee of 2a was obtained in the reaction by using the
(R)-DM-SEGPHOS/(S)-DM-DAIPEN-Ru catalyst, but the
reactivity was insufficient for practical use (S/C ) 1000, 30
atm of H2, rt, 16 h, 97.5% conversion).8 Therefore, we aimed
to develop a Ru catalyst with both high activity and enantiose-
lectivity for the hydrogenation of bicyclic ketones.
We selected 1a as a typical substrate for optimization of
the catalyst structure due to the synthetic importance of
product 2a (Table 1).6 When 1a (1.63 g, 13 mmol) was
hydrogenated with RuCl2[(R)-binap][(S)-ipban] [(R,S)-3a]3
(S/C ) 10 000) in t-C4H9OK containing 2-propanol under
20 atm of H2, (S)-3-quinuclidinol [(S)-2a] was obtained in
92% ee quantitatively (entry 1). The reaction with the
diastereomeric (S,S)-3a gave (R)-2a in 88% ee (entry 2). The
enantioselection was primarily dependent on the configura-
tion of BINAP, and the (R)-BINAP/(S)-diamine combination
was preferable to the R/R diastereomer. The use of (S)-
BINAP/(R)-IPHAN-Ru complex (S,R)-3b3 resulted in an
excellent ee of 97% (entry 3). Introduction of two methyl
groups at the R-carbons of the amino groups with an R
configuration appeared to fix the diamine-Ru chelate ring
appropriately. The high catalytic activity of the (S,R)-3b-t-
C4H9OK system achieved complete conversion in the reaction
with an S/C of 50 000 under 50 atm of H2 without
loss of enantioselectivity (entry 4). The (S)-TolBINAP/(R)-
IPHAN-Ru complex [(S,R)-3c] exhibited catalyst efficiency
comparable to that of (S,R)-3b (entry 5). The acetonide
moiety of the 1,4-diamine was also important for attaining
high catalyst performance. Thus, the ee value of 2a in the
reaction with the (S)-BINAP/(2R,5R)-2,5-hexanediamine-Ru
complex [(S,R)-3d] decreased to 95%, and high pressure
conditions (80 atm) were required for completion of the
hydrogenation with an S/C of 20 000 (entries 6 and 7). High
enantioselectivity was gained by using a combination of
Table 1. Asymmetric Hydrogenation of Ketones with
Bicyclo[2.2.2] Skeletons 1a
entry ketone 1 Ru cat. 3 S/Cb H2 (atm) time (h) % ee of 2c
1
1a
1a
1a
1a
1a
1a
1a
1a
1b
(R,S)-3a 10000
(S,S)-3a 10000
(S,R)-3b 10000
(S,R)-3b 50000
(S,R)-3c 50000
(S,R)-3d 10000
(S,R)-3d 20000
(R,S)-3e 10000
20
20
20
50
50
20
80
20
20
5
5
92 (S)
2
88 (R)
97 (R)d
97 (R)d
97 (R)d
95 (R)
95 (R)d
97 (S)
3
5
4e
5e
6
24
24
5
16
5
2
7f
8
9g
(S,R)-3b
1000
98 (S)h
a Unless otherwise stated, reactions were conducted at 25 °C using 13
mmol of 1 in 2-propanol (2.7 mL) containing 3 and t-C4H9OK (20 mM).
Complete conversion was observed in all cases. b Substrate/catalyst molar
ratio. c Determined by chiral HPLC analysis after conversion to the benzoate.
d The isolated yield was 99%. e 1a (18.8 g, 150 mmol) and 2-propanol (49
mL) were used. f 1a (3.3 g, 26 mmol) and 2-propanol (8.4 mL) were used.
g 1b (168 mg, 1.35 mmol) and a 3:1 2-propanol-t-C4H9OH (6.4 mL)
mixture were used. h The isolated yield was 90%.
(6) Naito, R.; Yonetoku, Y.; Okamoto, Y.; Toyoshima, A.; Ikeda, K.;
Takeuchi, M. J. Med. Chem. 2005, 48, 6597–6606.
(7) Tsutsumi, K.; Katayama, T.; Utsumi, N.; Murata, K.; Arai, N.;
Kurono, N.; Ohkuma, T. Org. Process Res. DeV. 2009, 13, 625–628.
(8) Takenaka, M. Chem. Abstr. 2005, 143, 422509; Jpn. Kokai Tokkyo
Koho 2005306804 A 20051104, 2005.
Org. Lett., Vol. 12, No. 15, 2010
3381

with a bicyclic[2.2.1] skeleton in the presence of (S,R)-3b
gave an 11.6:88.4 mixture of exo-8 (95% ee) and endo-9
(13% ee), showing that the stereoselectivity of (1R,4S)-7 was
high, but the diastereomeric face selection of (1S,4R)-7 was
insufficient by this catalyst (Scheme 1, eq 3).
The (S,R)-3b-t-C4H9OK catalyst system was fairly ef-
fective for hydrogenation of racemic 2-diphenylmethyl-3-
quinuclidinone (10) through dynamic kinetic resolution
(Scheme 1, eq 4).9,10 The reaction with an S/C of 5000 ([t-
C4H9OK] ) 20 mM) in a 6:1 2-propanol-CH3CON(CH3)2
under 10 atm of H2 for 20 h quantitatively gave the (2S,3S)-
11 (cis/trans ) >99:1) in >99% ee. Interestingly, the sense
of enantioselection was the opposite of that in the reaction
of 1a. The obtained alcohol is a useful intermediate for the
synthesis of a series of human NK1 antagonists.11
Our recent mechanistic studies on the BINAP/diamine-Ru-
catalyzed hydrogenation of ketones revealed that the trans-
RuH2(binap)(diamine) is the active species with a structure
closely related to that of the precatalyst, the trans-RuCl2
complex (see the Supporting Information).12,13 Figure 1
shows the distorted octahedral structure of the (S)-BINAP/
(R)-IPHAN-RuCl2 complex, (S,R)-3b, determined by a
single-crystal X-ray analysis. The torsion angle of
Cl(1)-Ru-N(1)-H(1) (6°) was much smaller than that of
Cl(1)-Ru-N(1)-H(2) (110°), indicating that two amino
protons H(1) and H(2) are discriminated to be axial (Hax)
and equatorial (Heq), respectively, by the skewed (R)-
IPHAN-Ru chelate ring.12,13 On the basis of the (S,R)-3b
structure, molecular models of trans-RuH2[(S)-binap][(R)-
iphan] and diastereomeric transition states (TSs) TSA and
TSB in the hydrogenation of 1 are schematically illustrated
in Figure 2. The hydrogenation of ketones proceeds through
the six-membered TS, TSA or TSB, in which the
Figure 1. ORTEP drawing of (S,R)-3b. All protons except those
on the diamine ring are omitted for clarity.
TolBINAP and the simple-shaped diamine (entry 8). It is
noteworthy that hydrogenation of bicyclo[2.2.2]octan-2-one
(1b) with (S,R)-3b afforded (S)-2b [same sense as (R)-2a]
in 98% ee (entry 9), suggesting that the nitrogen atom in
the ketone 1a did not affect the enantioselection.
The catalyst system was also effective for hydrogenation
of unsymmetrical ketones. When a racemic bicyclo[2.2.2]
ketone 4 was hydrogenated with (S,R)-3b (S/C ) 1000,
[t-C4H9OK] ) 20 mM, 20 atm H2), the exo alcohol
(1R,2S,4R)-5 in 48% yield and 99% ee, and the endo isomer
(1S,2S,4S)-6 in 52% yield and 96% ee were obtained
(Scheme 1, eq 2). These results indicated that both enanti-
omers of 4 were reduced with high stereoselectivity. The
stereoselective manner was highly dependent on the substrate
structure. The hydrogenation of racemic 2-norbornanone (7)
δ+
Hδ--Ruδ+-Nδ--Hax quadrupole of the Ru complex
interacts with the Cδ+dOδ- dipole of the ketone.12,13 TSA is
Figure 2. Molecular models of the (S,R)-RuH2 complex (O ) Ru) derived from 3b and diastereomeric transition states (TSs) in the
hydrogenation of 1 (X ) N or CH). The structures are simplified for clarity.
3382
Org. Lett., Vol. 12, No. 15, 2010

(Phax) of BINAP and a bridged alkyl moiety of 1 in TSB
exists. This interpretation is consistent with the results that
1a (X ) N) and 1b (X ) CH) were hydrogenated with the
same degree and sense of enantioselectivity.
The mode of enantioselection in hydrogenation of 10 is
explained by using two TS models, TSC and TSD (Figure
3). The steric repulsion between the (C6H5)2CH group of 10
and the Phax of BINAP in TSD is large enough to cancel the
repulsive interaction caused by the bridged alkyls of 10 and
the BINAP’s Phax in TSC. The (C6H5)2CH group connected
at the configurationally interconvertible R-carbon locates anti
to the nucleophilic RuH2 complex. Therefore, (2S,3S)-11 was
obtained with perfect diastereo- and enantioselectivity.10
In summary, the BINAP/IPHAN-Ru complex 3b with
t-C4H9OK catalyzes asymmetric hydrogenation of bicy-
clo[2.2.2] ketones 1 to afford the chiral alcohols 2 in
97-98% ee. The high catalytic activity achieves a turnover
as high as 50 000. Unsymmetrical bicyclo[2.2.1] and -[2.2.2]
ketones 4 and 7 are also hydrogenated with high stereose-
lectivity. A 2-substituted bicyclic ketone 10 is converted to
the cis alcohol in perfect diastereo- and enantioselectivity.
The mode of enantioselection is interpreted by using mo-
lecular models based on the X-ray structure of 3b.
Figure 3. Molecular models of diastereomeric TSs in the hydro-
genation of 10 with (S,R)-3b.
Acknowledgment. This work was supported by a Grant-
in-Aid from the Japan Science and Technology Agency (JST)
and the Japan Society for the Promotion of Science (JSPS)
(No. 21350048).
favored over TSB, resulting in (R)-1a or (S)-1b selectively,
because repulsive interaction between an axial P-phenyl ring
(9) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995,
68, 36–56.
(10) (a) Ohkuma, T.; Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori, R.
J. Org. Chem. 1996, 61, 4872–4873. (b) Ohkuma, T.; Li, J.; Noyori, R.
Synlett 2004, 1383–1386.
Supporting Information Available: Preparative methods
and properties of chiral Ru complexes 3, procedures for
asymmetric hydrogenation of bicyclic ketones, NMR, GC,
and HPLC behavior, [R]D values of products, X-ray structure
of 3b (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Swain, C. J.; Seward, E. M.; Cascieri, M. A.; Fong, T. M.; Herbert,
R.; MacIntyre, D. E.; Merchant, K. J.; Owen, S. N.; Owens, A. P.; Sabin,
V.; Teall, M.; VanNiel, M. B.; Williams, B. J.; Sadowski, S.; Strader, C.;
Ball, R. G.; Baker, R. J. Med. Chem. 1995, 38, 4793–4805.
(12) Sandoval, C. A.; Ohkuma, T.; Mun˜iz, K.; Noyori, R. J. Am. Chem.
Soc. 2003, 125, 13490–13503.
(13) Ooka, H.; Arai, N.; Azuma, K.; Kurono, N.; Ohkuma, T. J. Org.
Chem. 2008, 73, 9084–9093.
OL101200Z
Org. Lett., Vol. 12, No. 15, 2010
3383