Iridium-catalyzed asymmetric hydrogenation of α-substituted α,β-unsaturated acyclic ketones: Enantioselective total synthesis of (-)-mesembrine

Article abstract of DOI:10.1021/ol302842h

A highly efficient asymmetric hydrogenation of α-substituted α,β-unsaturated acyclic ketones catalyzed by chiral spiro iridium complexes for the preparation of chiral 2-substituted allylic alcohols has been developed (ee up to 99.7%). This method provides a concise route to (-)-mesembrine (34% yield, 12 steps).

Full text of DOI:10.1021/ol302842h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iridium-Catalyzed Asymmetric
Hydrogenation of r‑Substituted
r,β-Unsaturated Acyclic Ketones:
Enantioselective Total Synthesis
of (À)-Mesembrine
Qian-Qian Zhang, Jian-Hua Xie,* Xiao-Hui Yang, Jian-Bo Xie, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China
jhxie@nankai.edu.cn; qlzhou@nankai.edu.cn
Received October 16, 2012
ABSTRACT
A highly efficient asymmetric hydrogenation of r-substituted r,β-unsaturated acyclic ketones catalyzed by chiral spiro iridium complexes for the
preparation of chiral 2-substituted allylic alcohols has been developed (ee up to 99.7%). This method provides a concise route to (À)-mesembrine
(34% yield, 12 steps).
Chiral allylic alcohols are popular subunits of a variety
of chiral natural products and pharmaceuticals. The asym-
metric catalysis provides a highly efficient and environ-
mentally benign method for the synthesis of chiral allylic
alcohols.1 Among the catalytic asymmetric preparations of
chiral allylic alcohols, the selective reduction ofthe carbon-
yl group of R,β-unsaturated ketones by catalytic asym-
metric hydrogenations is one of the most direct methods.2
With chiral ruthenium diphosphine/diamine catalysts,
pioneered by Noyori et al.,3 a series of R,β-unsaturated
acyclic and cyclic ketones has been hydrogenated to the
corresponding chiral allylic alcohols with high yields
and high enantioselectivities.4 Our recent investigations
showed that the chiral iridium complexes of spiro amino-
phosphine ligands SpiroAP were efficient catalysts for the
(3) (a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 2675.
(4) For selected recent papers, see: (a) Ohkuma, T.; Koizumi, M.;
~
Muniz, K.; Hilt, G.; Kabuto, C.; Noyori, R. J. Am. Chem. Soc. 2002,
(1) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 6A. (b)
Katsuki, T. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, p 621. (c)
Tsuji, J. Palladium Reagents and Catalysis; VCH: Chichester, 1997;
Chapter 4.
124, 6508. (b) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.;
Duan, H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404. (c) Wu, J.;
Ji, J.-X.; Guo, R.; Yeung, C.-H.; Chan, A. S. C. Chem.;Eur. J. 2003, 9,
2963. (d) Ohkuma, T.; Hattori, T.; Ooka, H.; Inoue, T.; Noyori, R. Org.
Lett. 2004, 6, 2681. (e) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin,
~
Q.; Wei, Y.; Munz, K.; Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288. (f)
(2) (a) Ohkuma, T.; Noyori, R. In The Handbook of Homogeneous
Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim,
2007; p 1106. (b) Noyori, R.; Okuma, T. Angew. Chem., Int. Ed. 2001, 40,
40. (c) Xie, J.-H.; Zhou, Q.-L. Acta Chim. Sinica 2012, 70, 1427.
Arai, N.; Suzuki, K.; Sugizaki, S.; Sorimachi, H.; Ohkuma, T. Angew.
Chem., Int. Ed. 2008, 47, 1770. (g) Arai, N.; Azuma, K.; Nii, N.;
Ohkuma, T. Angew. Chem., Int. Ed. 2008, 47, 7475. (h) Li, W.; Sun,
X.; Zhou, L.; Hou, G.; Yu, S.; Zhang, X. J. Org. Chem. 2009, 74, 1397.
r
10.1021/ol302842h
XXXX American Chemical Society

hydrogenation of R-arylmethylene cycloalkanones, a type
of exo-cyclic R,β-unsaturated ketone, providing chiral
cyclic allylic alcohols in up to 97% ee and TONs of as
high as 10000.5 However, the asymmetric catalytic hydro-
genation of R,β-unsaturated acyclic ketones is still a chal-
lengingtaskifthe substrateshaveanR-substituent.6 Onthe
other hand, the products of asymmetric hydrogenation of
R-substituted R,β-unsaturated acyclic ketones, the chiral
2-substituted acyclic allylic alcohols are core structures in a
number of natural products such as jerangolids A and D,7
tedanolide,8 and epothilones A and B9 (Figure 1).
enantioselective preparation of chiral 2-substituted acyclic
allylic alcohols. The catalyst iridiumÀSpiroPAP (IrÀ(S)-1a)
offered the corresponding chiral 2-substituted acyclic
allylic alcohols 6 in excellent enantioselectivities (up to
99.7% ee) and TONs of as high as 100000 (Scheme 1). We
herein report the details of the asymmetric hydrogenation
of R-substituted R,β-unsaturated acyclic ketones 5 with
catalysts IrÀ(S)-1 and its application in the asymmetric
total synthesis of (À)-mesembrine, a natural alkaloid
containing a chiral arylated quaternary carbon center.11
Scheme 1. Asymmetric Hydrogenation of R-Substituted
R,β-Unsaturated Acyclic Ketones 5
Figure 1. Examples of natural products containing a chiral
2-substituted allylic alcohol structure.
Encouraged by our recent successes in the asymmetric
hydrogenation of ketones catalyzed by chiral iridium
catalysts of spiro pyridineÀaminophosphine ligands
(1, SpiroPAP)10 and the asymmetric hydrogenation of
R-arylmethylene cycloalkanones catalyzed by iridium
catalysts of spiro aminophosphine ligands (2, SpiroAP),5
we attempted the asymmetric hydrogenation of R-substi-
tuted R,β-unsaturated acyclic ketones 5 toward the
Initially, (E)-3,4-diphenylbut-3-en-2-one (5a) was se-
lected as a standard substrate, and the hydrogenation was
performed in nPrOH under 6 atm of H2 at room tempera-
ture in the presence of KOtBu as a base. When the catalyst
IrÀ(S)-1a was used, the product (R)-6a was obtained in
98% yield and 99.4% ee within 15 min (Table 1, entry 1).
The catalyst IrÀ(S)-2 also gave high enantioselectivity
(95% ee), albeit requiring a longer reaction time (entry 2).
The chiral rutheniumÀdiphosphine/diamine catalysts such
as (Sa,R,R)-3 and (Ra,R,R)-4, which have been demon-
strated to be highly efficient for the hydrogenation of
R,β-unsaturated acyclic ketones without R-substituent,2a
were also evaluated, and only moderate enantioselectivities
(69 and 60% ee, respectively) were obtained after a very
long reaction time (ca. 15 h) under 50 atm of H2, although
the yields are also high (entries 3 and 4). The solvent
experiments showed MeOH and EtOH were suitable sol-
(5) Xie, J.-B; Xie, J.-H; Liu, X.-Y; Kong, W.-L; Li, S.; Zhou, Q.-L.
J. Am. Chem. Soc. 2010, 132, 4538.
(6) For selected papers of asymmetric reduction of R-substituted
R,β-unsaturated acyclic ketones, see: (a) Nolin, K. A.; Ahn, R. W.;
Kobayashi, Y.; Kennedy-Smith, J. J.; Toste, F. D. Chem.;Eur. J. 2010,
ꢀ
16, 9555. (b) Moser, R.; Boskovic, Z. V.; Crowe, C. S.; Lipshutz, B. H.
J. Am. Chem. Soc. 2010, 132, 7852. (c) Yokoyama, R.; Matsumoto, S.;
Nomura, S.; Higaki, T.; Yokoyama, T.; Kiyooka, S.-i. Tetrahedron
2009, 65, 5181. For selected papers of asymmetric hydrogenation of
R-substituted R,β-unsaturated cyclic ketones, see: (d) 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. (e) Burk, M. J.; Hems, W.; Herzberg, D.; Malan,
C.; Zanotti-Gerosa, A. Org. Lett. 2000, 2, 4173. (f) Junge, K.; Wendt,
B.; Addis, D.; Zhou, S.-L.; Das, S.; Fleischer, S.; Beller, M. Chem.;
Eur. J. 2011, 17, 101.
€
(7) Gerth, K.; Washausen, P.; Hofle, G.; Irschik, H.; Reichenbach,
H. J. Antibiot. 1996, 49, 71.
(8) Schmitz, F. J. S.; Gunasekera, P.; Yalamanchili, G.; Hossain,
M. B.; Vanderhelm, D. J. Am. Chem. Soc. 1984, 106, 7251.
i
vents (entries 6 and 7 vs 1), but PrOH and toluene were
inferior, giving low conversions (entries 5 and 8). Base also
plays an important role in the reaction, with KOtBu being
€
(9) (a) Gerth, K.; Bedorf, N.; Hofle, G.; Irschik, H.; Reichenbach, H.
€
J. Antibiot. 1996, 49, 560. (b) Hofle, G.; Bedorf, N.; Steinmetz, H.;
Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1567.
(10) (a) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2011, 50, 7329. (b) Xie, J.-H.; Liu, X.-Y.; Yang,
X.-H.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2012,
51, 201.
(11) (a) Popelak, A.; Haack, E.; Lettenbauer, G.; Spingler, H.
Naturwissenschaften 1960, 47, 156. (b)Smith, E.;Hosansky, N.;Shamma,
M.; Moss, J. B. Chem. Ind. 1961, 402.
B
Org. Lett., Vol. XX, No. XX, XXXX

the choice of base. KOH also offered the desired product
(R)-6a in 98% yield with 97% ee, although the reaction
became slow (15 h, entry 9). When K2CO3 was used, the
conversion of the reaction dropped to 50% (entry 10). The
organic base NEt3 was inert for this reaction (entry 11).
Subsequently, we screened the chiral SpiroPAP ligands
((S)-1) and found that the substituent on the pyridine
group of the catalyst has almost no effect on the reactions
(entries 1 and 12À14). In addition, when the catalyst
loading was lowered to 0.001 mol % (S/C = 100000) the
reaction still performed very well under 50 atm of H2 in
excellent enantioselectivity (99.7% ee) with 100% conver-
sion (entry 15).
catalyst IrÀ(S)-1a, although a longer reaction time was
required (12 h, entry 17). It is worthy of mention that the
spiro iridium catalyst IrÀ(S)-1a was also efficient for the
hydrogenation of tetrasubstituted R,β-unsaturated acyclic
ketones such as 5r and 5s, giving the corresponding chiral
tetrasubstituted allylic alcohols 6r and 6s in excellent yields
with 98 and 97% ee, respectively (entries 18 and 19).
Table 2. Asymmetric Hydrogenation of R-Substituted
R,β-Unsaturated Acyclic Ketones 5 with Ir-(S)-1aa
Table 1. Optimization of the Hydrogenation Conditionsa
time yieldb
entry
R
R1
R2
R3
C6H5
6
(min) (%)
eec (%)
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
6a 15
6b 15
6c 15
6d 15
6e 15
98
98
98
97
99
98
97
98
99
98
98
98
98
99
99
90
98
97
96
99.4 (R)
99.5
99.6
98
2
2-ClC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
C6H5
C6H5
3
C6H5
4
C6H5
convb yieldc
5
C6H5
99
entry
cat.
base
solvent
time
(%)
(%)
eed (%)
6
C6H5
6f
15
99
7
2-ClC6H4
3-MeC6H4
4-MeC6H4
6g 15
6h 15
99.6
97
1
Ir-(S)-1a
Ir-(S)-2
(Sa,R,R)-3 tBuOK iPrOH
(Ra,R,R)-4 tBuOK iPrOH
tBuOK nPrOH 15 min 100
98
95
98
97
42
98
98
25
98
48
2
99.4 (R)
95 (R)
8
C6H5
2
tBuOK nPrOH 3 h
100
100
100
44
9
C6H5
6i
15
15
99.1
99.4
97
3e
4e
5
15 h
15 h
15 h
69 (S)
10
11
12
13
14
15
C6H5
4-MeOC6H4 6j
60 (S)
C6H5
4-ClC6H4
C6H5
C6H5
Me
6k 15
6l 15
Ir-(S)-1a
Ir-(S)-1a
Ir-(S)-1a
Ir-(S)-1a
Ir-(S)-1a
Ir-(S)-1a
Ir-(S)-1a
Ir-(S)-1b
Ir-(S)-1c
Ir-(S)-1d
Ir-(S)-1a
tBuOK iPrOH
97 (R)
C6H5
99.7
98
6
tBuOK MeOH 20 min 100
tBuOK EtOH
20 min 100
tBuOK Toluene 15 h
KOH
nPrOH 15 h
K2CO3 nPrOH 15 h
NEt3
nPrOH 15 h
99 (R)
iPr
Me
Me
C6H5
6m 15
6n 15
6o 15
6p 30
6q 12 h
7
99.2 (R)
96 (R)
C6H5
99.1(R)
99 (R)
99
8
30
100
50
C6H5
Et
9
97 (R)
16d Me
Me
Me
10
11
12
13
14
15f
99.2 (R)
12 (R)
17
Me
À(CH2)4À
99 (R)
98
3
18
Me Me C6H5
Me
6r
6s
15
60
tBuOK nPrOH 15 min 100
tBuOK nPrOH 15 min 100
tBuOK nPrOH 15 min 100
98
97
97
98
99.4 (R)
99.5 (R)
99.1 (R)
99.7 (R)
19d Me C6H5
À(CH2)4À
97
a Reaction conditions: 1.5 mmol scale, [substrate] = 2.1 M, 0.15
mmol % of catalyst, [KOtBu] = 0.04 M, solvent (2.0 mL), 6 atm of H2,
rt (25À30 °C). b Isolated yield. c Determined by HPLC or SFC with
chiral column. d Using ligand (R)-1b.
tBuOK EtOH
10 h
100
a Reaction conditions: 1.5 mmol scale, [substrate] = 2.1 M, 0.15
mmol % of catalyst, [KOtBu] = 0.04 M, solvent (2.0 mL), 6 atm of H2,
rt (25À30 °C). b Determined by 1H NMR. c Isolated yield. d Determined
by HPLC. e 50 atm of H2, 4 mL of iPrOH, [KOtBu] = 0.05 M. f 50 atm
of H2, S/C = 100000.
To demonstrate the utility of this highly efficient asym-
metric hydrogenation, a Sceletium alkaloid (À)-mesembrine11
bearing a quaternary carbon center was synthesized.
(À)-Mesembrine has been found to have potent serotonin
reuptake inhibitor activity12 and has received extensive
synthetic studies over the past decades.13 The challenge
of synthesis of (À)-mesembrine is the construction of
the unique congested chiral arylated quaternary carbon
center. Among the total syntheses of (À)-mesembrine or
its enantiomer, a few successful examples used asymmetric
catalysis.13gÀl Our synthetic strategy is outlined in Scheme 2,
employing iridium-catalyzed asymmetric hydrogenation
and JohnsonÀClaisen rearrangement to install the chiral
arylated quaternary carbon center.
Under the optimized reaction conditions, a series of
R-substituted R,β-unsaturated ketones 5 were hydroge-
nated to chiral allylic alcohols 6 in high yields (90À99%)
and excellent enantioselectivities (97À99.7% ee) with
catalyst IrÀ(S)-1a at S/C = 1000 (Table 2). Either the
electron-withdrawing group or the electron-donating
group on the phenyl ring of the substrates (5aÀm) has
little effect on the reactivity and enantioselectivity of the
reaction; the reactions were completed within 15 min
and yielded the corresponding products (6aÀm) in excellent
yields and enantioselectivities (97À99.7% ee, entries 1À13).
When the R-substituent R3 in the substrates 5 was changed
from phenyl to alkyl groups such as methyl and ethyl the
hydrogenation reactions also showed excellent enantioselec-
tivities (99% ee, entries 14À16). The cycloalkenyl ketone 5q
could be hydrogenated to allylic alcohol 6q in 99% ee by
Starting with commercially available 1,4-dioxaspiro-
[4.5]decan-8-one (7), the unsaturated ester 8 was prepared
(12) Gericke, N. P.; Van Wyk, B.-E. PCT Int. Appl. WO 9746234.
Org. Lett., Vol. XX, No. XX, XXXX
C

in 83% yield via three steps according to literature
method.14 The ester 8 was converted to R,β-unsaturated
methyl ketone 9 in 84% yield (two steps) via a Weinreb
amide and subsequent treatment with methylmagnesium
bromide.15 With catalyst IrÀ(R)-1b, the methyl ketone 9
was hydrogenated to chiral tetrasubstituted allylic alcohol
(S)-10 in 93% yield with 98% ee under 6 atm of H2.
Subsequently, chiral allylic alcohol (S)-10 was subjected
to a JohnsonÀClaisen rearrangement16 to generate (R)-11
with a chiral arylated quaternary carbon center in 84%
yield. The treatment of compound (R)-11 with an ozonyl-
sis/reduction procedure to cleave the carbonÀcarbon
double bond, base-promoted ester hydrolysis and lacto-
nization with ethyl chloroformate and subsequent tri-
ethylamine-assisted additionÀelimination yielded lactone
(S,S)-12 in 78% yield (three steps).17 Amination of
(S,S)-12 with methylamine at 70 °C in THF for 12 h and
subsequent reduction with LiAlH4 at the same tempera-
ture for another 12 h and deprotection of the carbonyl
group with aqueous HCl at room temperature for 2 h
offered (À)-mesembrine in 80% yield (two steps). The
Scheme 2. Catalytic Enantioselective Synthesis of
(À)-Mesembrine
NMR spectroscopic data and the optical rotation ([R]20
D
À61.6 (c 0.25, MeOH); lit.13e [R]20D À61.6 (c 0.20, MeOH);
lit.13l [R]20 À61.0 (c 0.20, MeOH)) of our synthetic
D
(À)-mesembrine are identical to those reported in a pre-
vious synthesis.
In conclusion, a highly efficient asymmetric hydrogena-
tion of R-substituted R,β-unsaturated acyclic ketones
catalyzed by chiral iridium complexes of spiro pyridineÀ
aminophosphine ligands has been developed for the
preparation of chiral 2-substituted allylic alcohols in excel-
lent enantioselectivities. A highly efficient catalytic enantio-
selective total synthesis of the Sceletium alkaloid (À)-
mesembrine was achieved in 34% overall yield over 12
steps from commercially available material by using this
asymmetric hydrogenation as a key step.
(13) For a review, see: (a) Zhao, Y.-H.; Zhou, Y.-Y; Du, F.-X.;
Liang, L.-L; Zhang, H.-B. Chin. J. Org. Chem. 2010, 30, 47. For selected
papers of enantioselective synthesis of (À)-mesembrine or its enantio-
mer, see: (b) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66, 143. (c)
Paul, T.; Malachowski, W. P.; Lee, J. Org. Lett. 2006, 8, 4007. (d) Saito,
M.; Matsuo, J.-i.; Ishibashi, H. Tetrahedron 2007, 63, 4865. (e) Ilardi,
E. A.; Isaacman, M. J.; Qin, Y.-C.; Shelly, S. A.; Zakarian, A. Tetra-
hedron 2009, 65, 3261. (f) Tuan, L. A.; Kim, G. Tetrahedron Lett. 2010,
51, 2354. (g) Nemoto, H.; Tanabe, T.; Fukumoto, K. J. Org. Chem. 1995,
60, 6785. (h) Yoshimitsu, T.; Ogasawara, K. Heterocycles 1996, 42, 135.
(i) Mori, M.; Kuroda, S.; Zhang, C.-S.; Sato, Y. J. Org. Chem. 1997, 62,
3263. (j) Yamada, O.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 7747.
(k) Taber, D. F.; He, Y. J. Org. Chem. 2005, 70, 7711. (l) Gu, Q.; You,
S.-L. Chem. Sci. 2011, 2, 1519.
Acknowledgment. We thank the National Natural
Science Foundation of China, the National Basic Research
Program of China (973 Program) (2012CB821600), and
the “111” project (B06005) of the Ministry of Education of
China for financial support.
(14) Su, J.; Tang, H.-Q.; Mckittrick, B. A. Tetrahedron Lett. 2011, 52,
3382.
(15) Kanazawa, Y.; Tsuchiya, Y.; Kobayashi, K.; Shiomi, T.; Itoh, J.-i.;
Kikuchi, M.; Yamamoto, Y.; Nishiyama, H. Chem.;Eur. J. 2006, 12, 63.
(16) (a) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brockson,
T. J.; Li, T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741. (b) For a review, see: Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
(17) After the ozonylsisÀreduction, the formed hydroxy ester product
was very reluctant to cyclize to lactone (S,S)-12 via an intramolecular
transesterification, and the subsequent ester hydrolysis and activation of
the carboxylic acid for the formation of the lactone were required.
Supporting Information Available. Experimental pro-
cedures, characterization data, and HPLC and SFC
spectra for the products. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX