A new cobalt-salen catalyst for asymmetric cyclopropanation. Synthesis of the serotonin-norepinephrine repuptake inhibitor (+)-synosutine

Article abstract of DOI:10.1021/ol501549x

A new C₂ symmetric cobalt(II)-salen catalyst based on cis-2,5-diaminobicyclo[2.2.2]octane as the chiral scaffold was prepared which, in the presence of potassium thioacetate as the promoter, catalyzed the formation of cyclopropanes from 1,1-dis

Full text of DOI:10.1021/ol501549x

Letter
pubs.acs.org/OrgLett
A New Cobalt−Salen Catalyst for Asymmetric Cyclopropanation.
Synthesis of the Serotonin−Norepinephrine Repuptake Inhibitor
(+)-Synosutine
James D. White* and Subrata Shaw
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, United States
S
* Supporting Information
ABSTRACT: A new C2 symmetric cobalt(II)−salen catalyst
based on cis-2,5-diaminobicyclo[2.2.2]octane as the chiral
scaffold was prepared which, in the presence of potassium
thioacetate as the promoter, catalyzed the formation of
cyclopropanes from 1,1-disubstituted ethylenes and ethyl
diazoacetate in high yield and with excellent diastereo- and
enantioselectivity. Asymmetric cyclopropanation with the
catalyst was used in a short, efficient synthesis of the dual
serotonin−epinephrine reuptake inhibitor (+)-synosutine.
hiral cyclopropanes represent an important class of
Ccarbocycles found in a wide range of naturally occurring
structures.1 Furthermore, the high degree of strain in a three-
membered ring permits expansion, fragmentation, and
rearrangement to other chiral cyclic and acyclic systems.2 The
most general method for enantioselective synthesis of
substituted cyclopropanes is via addition of a carbene−
transition metal complex (carbenoid) to an alkene where a
Figure 1. Diamine 1 and metal complexes 2−5 based on a cis-2,5-
chiral ligand surrounding the metal sets the stage for
diaminobicyclo[2.2.2]octane scaffold.
stereogenesis.3 Catalytic methods based on this concept have
employed chiral complexes of copper,4 rhodium,5 ruthenium,6
and cobalt,7 as well as species derived from late transition
Copper complexes have been widely employed as catalysts
metals such as gold,8 iron,9 iridium,10 and osmium.11 Although
for asymmetric cyclopropanation since an initial report of this
some of these carbenoid complexes afford chiral cyclopropanes
reaction by Noyori appeared in 1965,4a and we therefore
from alkenes and diazo compounds in highly enantio-enriched
assumed that copper(II)−salen complex 4 would be a good
form, others are strongly substrate dependent and many give
candidate for catalysis of cyclopropanation in our system.
poor (E)/(Z) diastereoselectivity in trisubstituted cyclo-
However, no cyclopropane formation was detected when α-
propanes. In an effort to extend and improve existing methods
for asymmetric synthesis of cyclopropanes, we have examined
the reaction of ethyl diazoacetate with 1,1-disubstituted alkenes
methylstyrene (6) was exposed to ethyl diazoacetate in the
presence of 20 mol % of 4 (Table 1, entry 1). On the other
hand, the cobalt(II)−salen complex 512 did produce trisub-
catalyzed by a new metal−salen complex in which cis-2,5-
diaminobicyclo[2.2.2]octane (1) provides the chiral scaffold.12
Our previous studies with chiral metal-salen systems based
on 1 found that chromium(II) complex 2 was an excellent
catalyst for asymmetric hetero-Diels−Alder cycloaddition and
for asymmetric Nozaki−Hiyama−Kishi addition of an allyl
halide to aldehydes (Figure 1).12 A copper(I) complex derived
from a tetrahydro version of the same salen ligand was shown
to be an efficient catalyst for the Henry reaction.13 Recently, we
found that iron(III) complex 3 catalyzed the highly
enantioselective conjugate addition of thiols to α,β-unsaturated
ketones (asymmetric sulfa-Michael reaction)14 and we reasoned
that a carbenoid unit embedded in a similar chiral architecture
could be used to catalyze asymmetric cyclopropanation.
stituted cyclopropanes 7 and 8, although in very low yield and
with no (E)/(Z) selectivity (Table 1, entry 2). The presence of
nucleophilic promoters has been shown by Katsuki to improve
stereoselectivity in catalytic cyclopropanation,7a−c,g and addi-
tion of N-methylimidazole and 4-(dimethylamino)pyridine to
the reaction of 6 with ethyl diazoacetate was found to increase
the yield of 7 and 8 while decreasing the reaction time (Table 1,
entries 3 and 4). Unfortunately, the stereoselectivity favoring
(E)-cyclopropane 7 was low and a catalyst loading of at least 20
mol % of 5 was necessary for a practical preparation of this
cyclopropane.
Received: May 29, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
Table 1. Enantioselective Cyclopropanation of α-
Table 2. Enantioselective Cyclopropanation of α-
Methylstyrene (6) Catalyzed by Metal−Salen Complexes
Methylstyrene (6) Catalyzed by Cobalt−Salen Complex
a
a
(+)-4 and (+)-5
(+)-12
b
b
c
d
(+)-12
additive
dr
yield
d
ee
entry
metal complex
additive
t (h)
dr E/Z
yield [%]
c
e
entry (mol %)
(mol %)
solvent t (h) E/Z
[%]
[%]
1
2
3
4
(+)-4
(+)-5
(+)-5
(+)-5
−
−
NMI
48
48
18
16
−
nr
1
2
3
4
5
5
5
5
5
5
−
THF
THF
THF
THF
THF
48
30
36
48
50
2:1
3:1
3:1
2:1
4:1
63
82
91
46
51
nd
nd
nd
nd
nd
1:1
1:1
2:1
trace
52
NMI (5)
DMAP (5)
pyridine (5)
DMAP
64
a
The reactions were carried out on a 0.3 mmol scale in a 0.2 M
solution with 1.5 equiv of 6 in the presence of 20 mol % catalyst. The
2,6-lutidine
(5)
b
catalyst was stirred with the additive (20 mol %) for 1 h prior to the
6
5
5
5
5
5
5
5
5
5
5
5
5
5
2.5
1
Ph3P (5)
THF
39
39
40
40
36
36
27
27
20
29
29
28
48
60
60
4:1
3:1
9:1
39
95
89
68
49
97
56
53
87
95
93
90
77
67
58
nd
nd
72
68
nd
73
54
59
67
84
93
91
86
88
85
c
d
addition of 6. Determined by 1H NMR analysis. lsolated yields of E
7
Ph3As (5)
DMF (5)
DMSO (5)
NaOAc (5)
KSAc (5)
HMPA (5)
DMPU (5)
Br2 (5)
THF
and Z isomers; nr = no reaction.
8
THF
9
THF
12:1
3:1
Katsuki has reported that the presence of an electron-
donating substituent in the benzenoid rings of the salen
framework of a metal complex can increase both the diastereo-
and enantioselectivity of asymmetric cyclopropanation.7a,b This
prompted us to modify our salen ligand in 5 by incorporating
methoxy substituents at the C5 and C5′ positions of the
benzenoid rings. Synthesis of our modified ligand began with
formylation of 2-(tert-butyl)-4-methoxyphenol (9) with para-
formaldehyde and triethylamine in the presence of magnesium
chloride to give aldehyde 10 (Scheme 1).15 Condensation of 10
10
11
12
13
14
15
16
17
18
19
20
THF
THF
21:1
6:1
THF
THF
6:1
THF
9:1
KSAc (5)
KSAc (5)
KSAc (5)
KSAc (5)
KSAc (2.5)
KSAc (1)
DCE
28:1
31:1
30:1
17:1
22:1
17:1
CH2Cl2
CHCl3
PhMe
CH2Cl2
CH2Cl2
Scheme 1. Synthesis of the Second Generation Cobalt(II)
Complex (+)-12
a
The reactions were carried out on a 0.3 mmol scale in a 0.2 M
solution with 1.5 equiv of 6 in the presence of catalyst and additive.
b
The catalyst was stirred with the additive for 1 h prior to the addition
c
d
of 6. Determined by 1H NMR analysis. lsolated yields of (E) and (Z)
e
isomers. Determined by HPLC using a Chiralcel OD-H column.
of 7 was shown to be (1R,2R) by comparison of its optical
rotation with the literature value.6a,d
The optimized conditions developed for asymmetric cyclo-
propanation of 6 were tested on a range of 1,1-disubstituted
ethylenes (Table 3). 1-Alkyl-1-aryl ethylenes (13, Table 3,
entries 1−13) afforded (E) cyclopropanes 14−26 in 89−97%
yield and >20:1 diastereoselectivity. The enantiomeric excess of
the major cyclopropane from these reactions was 90−98%. A
1,1-dialkyl ethylene gave (E) cyclopropane 27 in good yield but
with lower stereoselectivity (Table 3, entry 14), and a thioenol
ether also led to a cyclopropane (28) with diminished
stereoselectivity (Table 3, entry 15). These results are
consistent with a mechanistic model for cyclopropanation
with 12 where stereoelectronic effects play a prominent role
(vide infra).
A practical application of asymmetric cyclopropanation with
12 was demonstrated in a synthesis of (+)-synosutine (29), a
cyclopropyl homologue of the commercial antidepressant
duloxetine (Cymbalta) and itself a powerful dual inhibitor
(1−2 nM) of serotonin and norepinephrine reuptake (Figure
2).16 A previous synthesis of 29 installed the cyclopropane core
via Charette asymmetric cyclopropanation17 of an allylic
alcohol using a chiral boronate catalyst in a process that
required separation of (E) and (Z) allylic alcohols and was
expensive to scale up.
with (−)-diamine 1 using magnesium sulfate as the catalyst
afforded salen ligand 11 which was reacted with rigorously
dried cobalt(II) acetate in refluxing ethanol to furnish second
generation cobalt−salen complex 12.
The catalytic properties of 12 were first examined in the
cyclopropanation of 6 with ethyl diazoacetate using 5 mol % of
the catalyst in the presence of several additives (Table 2, entries
2−20). Without an additive, the reaction in THF produced
cyclopropanes 7 and 8 in modest yield and with only 2:1
stereoselectivity favoring (E) isomer 7 (Table 2, entry 1) while
certain additives (Table 2, entries 2−7) showed only a marginal
gain in diastereoselectivity. However, the addition of DMF and
DMSO to the reaction, each at 5 mol %, markedly improved
the ratio of cyclopropanes in favor of 7 which exhibited a
promising enantiomeric excess (Table 2, entries 8 and 9). After
further experimentation with a series of electron-donor
additives (Table 2, entries 10−20), it was found that
cyclopropanation in a chlorinated solvent containing potassium
thioacetate at 5 mol % gave 7 and 8 in >90% yield with a 7:8
ratio of ca. 30:1 (Table 2, entries 15−17). In chloroform or
dichloromethane as solvent, the enantiomeric excess of 7 was
>90% (Table 2, entries 16 and 17). The absolute configuration
The new route to 29 began with acylation of 1-naphthol (30)
with thiophen-2-carbonyl chloride (31) to give ester 32 which
after Tebbe methylenation18 afforded enol ether 33 (Scheme
B
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Organic Letters
Letter
Table 3. Asymmetric Cyclopropanation of 1,1-Disubstituted
Ethylenes (13) Catalyzed by (+)-12
Scheme 2. Enantioselective Synthesis of Synosutine (29)
a b
,
t
dr
E/Z
yield
e
ee
[%]
c
d
f
entry
Ar
R
(h) product
[%]
1
2
3
4
5
Ph
Ph
Et
32
32
26
36
28
14
15
16
17
18
26:1
23:1
30:1
23:1
25:1
94
91
90
89
91
92
90
96
92
91
nBu
Me
Me
2-OMeC6H4
2-furyl
Ph
CH2CO2
Et
6
7
(2-CO2Me)-
C6H4
Me
19
22
19
20
30:1
32:1
92
96
95
94
Scheme 3. Catalytic Cycle for the Formation of (E)-7 via
Asymmetric Cyclopropanation of 6 in the Presence of (+)-12
3,4-Di-
OMeC6H3
Me
8
2-thiophenyl
1-naphthyl
4-MeC6H4
Me
Me
33
26
28
21
22
23
25:1
33:1
27:1
93
97
96
90
96
94
9
10
(CH2)2
CO2Me
11
3-(CO2Et)-
5-C6H5-
2-furyl
Me
39
24
26:1
92
97
12
13
14
4-CF3C6H4
nPr
26
20
36
25
26
27
21:1
95
90
95
92
98
83
4-OMeC6H3
(CH2)3-
Me
>50:1
18:1
CH2-
(1-naphthyl)
15
SC6H5
nPr
48
28
16:1
87
88
a
The reactions were carried out on a 0.3 mmol scale in a 0.2 M
solution with 1.5 equiv of 13 in the presence of (+)-12 and KSAc each
b
at 5 mol %. Catalyst (+)-12 was stirred with KSAc for 1 h prior to the
c
d
addition of 13. See Supporting Information. Determined by 1H
e
f
NMR analysis. lsolated yields of (E) and (Z) isomers. Determined by
HPLC using a Chiralcel OD, AD, OD-H or AS-H column.
undergoes prior activation by a thiol before catalyzing the
asymmetric sulfa-Michael reaction,14 the nucleophilic promoter
potassium thioacetate is believed to activate the cobalt complex
by reacting with 12 to produce the new complex 37. This
activated complex19 then reacts with ethyl diazoacetate to
generate cobalt carbenoid 38 which undergoes stereoselective
cycloaddition with 6 to furnish transiently four-membered
cobaltocycle 40. The formation of cobaltocycles of this type is
well documented, as is their collapse to cyclopropanes by
stereospecific extrusion of the complexed cobalt species.20
The relative and absolute configuration of the trisubstituted
cyclopropane 7 generated in this process can be explained by
the approach of the alkene toward the cobalt carbenoid 38
along the trajectory shown in Figure 3. With the carbenoid
ligand situated in the more open lower right quadrant under the
Figure 2. Synosutine, a balanced dual inhibitor of serotonin and
norepinephrine reuptake.
2). Exposure of 33 to ethyl diazoacetate in the presence of 12
(5 mol %) and potassium thioacetate (5 mol %) in
dichloromethane at room temperature resulted in smooth
cyclopropanation to furnish (Z) ester 34 with a (Z)/(E) ratio
17:1. The major (Z) isomer 34 was formed in 94%
enantiomeric excess. Saponification of 34 produced the
known (1R,2S) carboxylic acid 3516 which was condensed
with methylamine to give amide 36. Final reduction of 36 with
lithium aluminum hydride led to (+)-synosutine (29) in a five-
step sequence from commercial materials. This route shortens
our previous synthesis of 29 by four steps and circumvents the
separation of (E) and (Z) allylic alcohols required for Charette
cyclopropanation.
A catalytic cycle that rationalizes the formation of cyclo-
propane 7 from 6 and ethyl diazoacetate in the presence of
cobalt complex 12 and a promoter (Y) is shown in Scheme 3.
As noted previously with iron−salen complex 3 which
Figure 3. Proposed transition state for the enantioselective cyclo-
propanation of α-methylstyrene (6) with ethyl diazoacetate catalyzed
by cobalt(II)−salen complex (+)-12.
C
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Organic Letters
Letter
Angew. Chem., Int. Ed. 1992, 31, 430. (c) Lesma, G.; Cattenati, C.;
Pilati, T.; Sacchetti, A.; Silvani, A. Tetrahedron: Asymmetry 2007, 18,
659 and references cited therein.
bicyclic scaffold of 12 and with the ester oriented to minimize
steric interaction with a neighboring tert-butyl group of the
salen framework, the si face of the carbenoid is obstructed by
benzenoid ring “a” whereas the re face is exposed to attack by
the alkene π system. Approach to this cobalt carbenoid by the si
face of α-methylstyrene is dictated by steric bulk around the
cobalt, which determines the regioselectivity of cycloaddition,
and by the geometry of the carbenoid, which aligns the ester
group with the smaller methyl substituent of 6. This leads to
(E) cobaltocycle 40. When the steric size of substituents in a
1,1-disubstituted ethylene is more closely matched, diminished
(E/(Z) stereoselectivity of cyclopropane formation, as in 27
and 34, is to be expected with this model.
(5) For cyclopropanation reactions catalyzed by rhodium complexes,
see: (a) Bykowski, D.; Wu, K. H.; Doyle, M. P. J. Am. Chem. Soc. 2006,
128, 16038. (b) Denton, J. R.; Sukumaran, D.; Davies, H. M. L. Org.
Lett. 2007, 9, 2625. (c) Shibata, Y.; Noguchi, K.; Tanaka, K. J. Am.
Chem. Soc. 2010, 132, 7896 and references cited therein.
(6) For cyclopropanation reactions catalyzed by ruthenium
complexes, see: (a) Berkessel, A.; Kaiser, P.; Lex, J. Chem.Eur. J.
2003, 9, 4746. (b) Charette, A. B.; Bouchard, J. E. Can. J. Chem. 2005,
83, 533. (c) Miller, J. A.; Gross, B. A.; Zhuravel, M. A.; Jin, W. C.;
Nguyen, S. T. Angew. Chem., Int. Ed. 2005, 44, 3885. (d) Bonaccorsi,
C.; Mezzetti, A. Organometallics 2005, 24, 4953 and references cited
therein.
In summary, a new cobalt−salen complex 12 based on a
chiral cis-2,5-diaminobicyclo[2.2.2]octane scaffold has been
prepared in which the salen ligand is modified by incorporating
an electron-donating methoxy substituent in each benzenoid
ring. In the presence of the additive potassium thioacetate, 12
was found to catalyze the reaction of α-methylstyrene and other
1,1-disubstituted ethylenes with ethyl diazoacetate to give
trisubstituted cyclopropanes with high diastereo- and enantio-
selectivity. The reaction was applied to a 1,1-disubstituted enol
ether to produce a cyclopropane that was carried forward to
(+)-synosutine, a dual inhibitor of serotonin and norepinephr-
ine reuptake in five steps with 57% overall yield. A rationale for
the stereochemical outcome of cyclopropanation with
(1R,2R,4R,5R)-12 is proposed in which an initially formed
activated cobalt carbenoid undergoes re face cycloaddition with
the alkene at its si face to generate a four-membered
cobaltocycle regio- and stereoselectively. Cobalt is extruded
stereospecifically from the metallocycle to furnish a cyclo-
propane and regenerate the catalyst.
(7) For cyclopropanation reactions catalyzed by cobalt complexes,
see: (a) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron Lett.
2000, 41, 3647. (b) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Adv.
Synth. Catal. 2001, 343, 79. (c) Uchida, T.; Saha, B.; Katsuki, T.
Tetrahedron Lett. 2001, 42, 2521. (d) Huang, L.; Chen, Y.; Gao, G.-Y.;
Zhang, X. P. J. Org. Chem. 2003, 68, 8179. (e) Chen, Y.; Fields, K. B.;
Zhang, X. P. J. Am. Chem. Soc. 2004, 126, 14718. (f) Chen, Y.; Zhang,
X. P. Synthesis 2006, 1697. (g) Uchida, T.; Katsuki, T. Synthesis 2006,
1715. (h) Chen, Y.; Zhang, X. P. J. Org. Chem. 2007, 72, 5931.
(i) Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc. 2007, 129,
12074. (j) Morandi, B.; Mariampillai, B.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2011, 50, 1101 and references cited therein.
(8) For cyclopropanation reactions catalyzed by gold complexes, see:
(a) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 18002. (b) Watson, I. D. G.; Ritter, S.; Toste, F.
D. J. Am. Chem. Soc. 2009, 131, 2056.
(9) For cyclopropanation reactions catalyzed by iron complexes, see:
(a) Morandi, B.; Cheang, J.; Carreira, E. M. Org. Lett. 2011, 13, 3080.
(b) Morandi, B.; Dolva, A.; Carreira, E. M. Org. Lett. 2012, 14, 2162.
(c) Morandi, B.; Carreira, E. M. Science 2012, 335, 1471. (d) Kaschel,
J.; Schneider, T. F.; Weirz, D. B. Angew. Chem., Int. Ed. 2012, 51, 7085.
(10) For cyclopropanation reactions catalyzed by iridium complexes,
see: (a) Kanchiku, S.; Suematsu, H.; Matsumoto, K.; Uchida, T.;
Katsuki, T. Angew. Chem., Int. Ed. 2007, 46, 3889. (b) Ichinose, M.;
Suematsu, H.; Katsuki, T. Angew. Chem., Int. Ed. 2009, 48, 3121.
(c) Anding, B. J.; Ellern, A.; Woo, L. K. Organometallics 2012, 31, 3628
and references cited therein.
(11) Zhang, J.; Liang, J. L.; Sun, X. R.; Zhou, H. B.; Zhu, N. Y.; Zhou,
Z. Y.; Chan, P. W. H.; Che, C. M. Inorg. Chem. 2005, 44, 3942.
(12) White, J. D.; Shaw, S. Org. Lett. 2011, 13, 2488.
(13) White, J. D.; Shaw, S. Org. Lett. 2012, 14, 6270.
(14) White, J. D.; Shaw, S. Chem. Sci. 2014, 5, 2200.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: James.white@oregonstate.edu.
Notes
(15) Theaker, G. W.; Morton, C.; Scott, P. Dalton Trans. 2008, 48,
6883.
(16) White, J. D.; Juniku, R.; Huang, K.; Yang, J.; Wong, D. T. J. Med.
Chem. 2009, 52, 5872.
The authors declare no competing financial interest.
(17) Charette, A. B.; Juteau, H. J. Am. Che. Soc. 1994, 116, 2651.
(18) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611.
(19) The “trans effect” associated with sulfur−metal coordination
which enhances reactivity at the metal center is documented. For a
review, see: Coe, B. J.; Glenwright, S. J. Coord. Chem. Rev. 2000, 203,
5.
(20) (a) Klein, H. F.; Beck, R.; Florke, U.; Haupt, H. J. Eur. J. Inorg.
Chem. 2002, 3305. (b) Klein, H. F.; Beck, R.; Florke, U.; Haupt, H. J.
Eur. J. Inorg. Chem. 2003, 1380.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the National
Science Foundation (CHE-0834862). Support for the Oregon
State University NMR facility used in this work was provided
by the National Science Foundation (CHE-0722319) and by
the M. J. Murdock Charitable Trust (Grant 2005265).
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dx.doi.org/10.1021/ol501549x | Org. Lett. XXXX, XXX, XXX−XXX