Construction of enantioenriched [3.1.0] bicycles via a ruthenium-catalyzed asymmetric redox bicycloisomerization reaction

Article abstract of DOI:10.1021/ja510968h

Enantiomerically enriched [3.1.0] bicycles containing vicinal quaternary centers were synthesized from [1,6]-enynes using a cyclopentadienylruthenium catalyst containing a tethered chiral sulfoxide. The reaction was complicated by the fact that the substr

Full text of DOI:10.1021/ja510968h

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Communication
Construction of Enantioenriched [3.1.0] Bicycles via a Ruthenium-
Catalyzed Asymmetric Redox Bicycloisomerization Reaction
Barry M. Trost, Michael C. Ryan, Meera Rao, and Tim Z. Markovic
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Nov 2014
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Journal of the American Chemical Society
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Construction of Enantioenriched [3.1.0] Bicycles
via a Ruthenium-Catalyzed Asymmetric Redox
Bicycloisomerization Reaction
Barry M. Trost,* Michael C. Ryan, Meera Rao, and Tim Z. Markovic
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Department of Chemistry, Stanford University, Stanford, California 94305-5580
Supporting Information Placeholder
O
ABSTRACT: Enantiomerically enriched [3.1.0] bicycles
containing vicinal quaternary centers were synthesized
(a)
Me
TsN
Me
5 mol% CpRu(PPh3)2Cl
Me
OH
Me
3 mol% CSA, 5 mol% In(OTf)3
Acetone, 0.25 M, 16 h
from [1,6]-enynes using cyclopentadienylruthenium
a
N
Ts
85% yield
(CpRu) catalyst containing a tethered chiral sulfoxide. The
reaction was complicated by the fact that the substrates
contained a racemic propargyl alcohol that could affect
the selectivity of the process. Nonetheless, high levels of
enantioinduction were observed, despite complications
arising from the use of racemic substrates. Mechanistic
studies showed that while the utilization of either
enantiomer of propargyl alcohol led to high product e.r.
alcohol
coordination
reductive
elimination
[Ru]
Me
Me
Me
[Ru]
O
H
TsN
N
Ts
O
Me
H
when
conducted
in
acetone,
a
significant
redox
isomerization
[2+2]
cycloaddition
matched/mismatched effect is observed in THF.
Me
Me
[Ru]
O
[Ru]
O
TsN
TsN
Me
Me
In recent years, transition metal-catalyzed
asymmetric cycloisomerization reactions1 are an
important class of reactions for the construction of
enantiomerically enriched complex molecules in an
atom,2 step,3 and redox4 economical fashion. Examples
of gold,5 platinum,6 palladium,7 and rhodium8-catalyzed
simple asymmetric cycloisomerization reactions have
been reported in the literature. While there has been
progress in utilizing chiral ruthenium catalysts for
asymmetric cycloaddition,9 cyclopropanation,10 and
allylic alkylation reactions,11 there have been no
reported examples of using a chiral ruthenium catalyst
for cycloisomerization reactions, to the best of our
knowledge. Ruthenium-catalyzed reactions have
distinguished themselves as an important class of
transformations that can construct complex organic
molecules quickly and efficiently.12 Previously, we
reported the cyclopentadienylruthenium (CpRu)-
catalyzed redox bicycloisomerization of [1,6] and [1,7]
enynes to form structurally complex [3.1.0] and [4.1.0]
bicycles that contain vicinal, quaternary stereocenters
(Figure 1a).13 Intrigued by the possibility of making this
process enantioselective, we hoped that an appropriate
choice of ruthenium catalyst would deliver high levels of
enantioinduction.
-
PF6
R
MeCN
L*
HO
S
L*
(c)
(b)
MeCN
R'
H
O
R
R'
H
MeO
Chiral-at-Ru Complexes
L*= chiral ligand
1
Figure
bicycloisomerization reaction reported by Trost. (b)
Ruthenium catalyst containing tethered chiral
1.
(a)
Ruthenium-catalyzed
redox
1
a
sulfoxide. (c) Possible diastereomeric complexes formed
from propargyl alcohol coordination.
described the conveniently synthesized CpRu complex
1
which does not resort to a resolution of an
intermediate CpRu complex15 and its application
towards asymmetric allylic substitution reactions (Figure
1b).16 It also has the added advantage of having its
asymmetry-inducing element, the chiral sulfoxide, in
close proximity to the metal center. This increases the
possibility of asymmetric induction during the
enantiodetermining step. Our hope was that the
application of 1 would provide a means by which one
could access enantioenriched [3.1.0] and [4.1.0]
bicycles.
Chiral sulfoxides are a relatively unexplored ligand
class for transition metals.14 Very recently, we have
1
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Table 1. Asymmetric Redox Bicycloisomerization with Tris-Substituted Nitrogen
1
2
3
4
-
PF6
O
R'
MeCN
S
MeCN
R
3 mol%
O
R
TrisN
OH
R'
Acetone, 40 °C,
0.25 M, 16 h
N
Tris
MeO
2b-9b
2a-9a
5
6
7
O
O
O
O
Me
i-Pr
Ph
8
Me
Me
Me
Me
8
9
N
Tris
N
Tris
N
Tris
N
Tris
5b
57% yield, 93.0:7.0 e.r
2b
78% yield, 56.0:44.0 e.ra
85% yield, 90.5:9.5 e.r.
3b
47% yield, 64.0:36.0 e.ra
75% yield, 98.5:1.5 e.r.
4b
88% yield, 92.0:8.0 e.rb
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O
O
O
i-Pr
Me
O
4
p-tolyl
Me
Me
N
Tris
N
Tris
N
Tris
N
Tris
6b
48% yield, 90.0:10.0 e.rc
7b
42% yield, 94.0:6.0 e.r
8b
75% yield, 90.0:10.0 e.r
9b
50% yield, 82.5:17.5 e.r
a Reaction conducted in THF.
b 5 mol% of catalyst used.
c 8.5 mol% of catalyst used.
However, the fact that substrates of this type
contain a chiral, racemic stereocenter presents a
complicating aspect to this reaction. One can envision
that coordination of the propargyl alcohol to the metal
center can occur with either one of two possible
Supporting Information).18 However, when these
conditions were applied to [1,6]-enynes, only low levels
of enantioinduction were observed for substrates 2a
and 3a (Table 1). Switching to acetone, a more
coordinating solvent, had a profound effect on the
selectivity of the reaction, boosting the e.r. to 90.5:9.5
and 98.5:1.5 for 2b and 3b, respectively. Encouraged
by these results, substrates containing aromatic (4a),
olefinic (5a), and alkynyl (6a) groups were prepared in
an effort to probe steric and coordinative effects in the
redox bicycloisomerization reaction. This series of
substrates showcased the chemoselectivity of the
redox bicycloisomerization reaction, which can tolerate
both isolated alkenes and alkynes without significantly
impacting the reactivity or enantioselectivity, a degree
of chemoselectivity not reported for any previous metal-
catalyzed asymmetric cycloisomerization to our
knowledge.19 Substrate 7a, which contains a more
bulky cyclopentyl group at the internal position of its
diastereochemical outcomes, thus creating
a
stereocenter at ruthenium (Figure 1c). While the
aforementioned stereocenter is destroyed concomitant
with redox isomerization, it is unclear whether this
transfer of stereochemical information to the metal
would have an adventitious, detrimental, or
inconsequential impact on the selectivity.
Initial optimization efforts were made on [1,7]-
enynes containing racemic propargyl alcohols due to
their product’s similarity to triple-uptake inhibitors
developed by GlaxoSmithKline®.17 From these initial
studies, the use of a 2,4,6-triisopropylbenzenesulfonyl
(Tris) group and THF as the solvent were determined to
be optimal for enantioinduction and yield (see
Table 2. Impact of Enyne Backbone on Enantioselectivity
PF6
-
O
R'
MeCN
MeCN
S
R
n
n
3 mol%
O
R
X
OH
R'
Acetone, 40 °C,
0.25 M, 16 h
X
MeO
10b-19b
10a-19a
O
O
O
O
O
Me
Me
i-Pr
Ph
Ph
Me
Me
Me
Me
N
N
N
N
Ts
N
Ts
P(O)(OPh)2
P(O)(OPh)2
Ts
10b
11b
12b
13b
14b
84% yield, 95.0:5.0 e.ra
61% yield, 97.0:3.0 e.ra
81% yield, 94.0:6.0 e.r.
56% yield, 91.0:9.0 e.r
84% yield, 98.0:2.0 e.r.
O
O
O
i-Pr
Me
O
H
i-Pr
O
Me
Ph
Me
Me
N
Tris
N
N
N
BnO2C
CO2Bn
P(O)(OPh)2
P(O)(OPh)2
P(O)(OPh)2
15b
16b
17b
19b
18b
49% yield, 92.0:8.0 e.r.b
56% yield, 85.0:15.0 e.r.c
64% yield, 96.0:4.0 e.r
51% yield, 96.0:4.0 e.r.
69% yield, 88.0:12.0 e.r.
a 5 mol% of catalyst used.
b 7.5 mol% of catalyst used.
c Reaction performed in THF.
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Scheme 1. Reductive Removal of the Sulfonyl
and Phosphoryl Groups on Nitrogen
alkene, also exhibits excellent enantioselectivity.
1
2
3
4
5
6
7
8
Vinylcyclopropane 8a, a type of substrate prone to
metal-catalyzed reactions, is tolerated under these
conditions, as the corresponding [3.1.0] bicycle 8b
can be obtained in a 75% yield and 90:10 e.r.. Finally,
9a, which contains an aromatic moiety at the internal
position of its olefin, was obtained in a slightly
diminished e.r. (82.5:17.5).
Me
Me
Me
ii
RN
HN
i
if R= -Ts or -Tris
RN
O
O
O
iii
O
O
if R= -P(O)(OPh)2
Me
Me
Me
23
20 R= -Tris, 83% yield
21 R= -Ts, 75% yield
22 R= -P(O)(OPh)2, 70% yield
R= -Tris, 91% yield
R= -Ts, 85% yield
R= -P(O)(OPh)2, 78% yield
During the course of our mechanistic studies (vide
infra), it was observed that less bulky para-
toluenesulfonamides 10a and 11a gave slightly
improved enantiomeric ratios than the analogous Tris-
based substrates 2a and 4a (Table 2). A dependence
of the nature of the nitrogen substituent was noted in
comparing the two sulfonamides; we were intrigued
by the notion that alternate groups on nitrogen may
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11
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13
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16
17
18
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i) TsOH•H2O, (MeO)3CH, (CH2OH)2, r.t., 3h; ii) sodium naphthalide, THF, -78 °C to r.t.,
5 min; iii) LiAlH4, Et2O, r.t., 17 h
propargyl alcohol in both the R and S configurations,
conveniently made utilizing our Prophenol chemistry
(see Supporting Information).20 When these propargyl
alcohols were applied to the standard reaction
conditions
in
acetone,
a
very
slight
improve
the
enantioselectivity
of
the
matched/mistmatched effect was observed (entries 1-
3). However, when run in THF, a less coordinating
bicycloisomerization reaction. Indeed, we discovered
that the diphenylphosphoramidate backbone gave
even higher selectivities when compared to the two
sulfonamide backbones as well as improve the yield in
some cases. Thus, bicyclic products 13b through
16b were all obtained in good yield and greater than
96:4 e.r.. Even the most challenging substrate for the
sulfonamides, 9a, displayed an improved selectivity of
solvent,
a
much more substantial effect was
observed; a 92.0:8.0 e.r. was obtained with the (R)
propargyl alcohol and a 68.0:32.0 e.r. obtained with
the (S) propargyl alcohol. The origin of this effect is
currently unclear, but these mechanistic experiments
suggest that acetone’s ability to compete with the
coordination of the chiral alcohol to the metal center
during the course of the reaction is an important
factor for obtaining high enantioselectivities.
88.0:12.0
when
exchanged
for
a
diphenylphosphoramidate backbone (17a). We have
also shown that this chemistry can be extended
beyond pyrrolidine products, as [3.1.0] carbocycle
18b can be isolated in a 49 percent yield and a
92.0:8.0 e.r.. Finally, [4.1.0] bicyclic piperidine 19b
could be obtained in a 56% yield and 85.0:15.0 e.r.
when the Tris functional group is utilized and when the
reaction is run in THF.
Both sulfonamides can be deprotected to the free
pyrrolidine by using sodium naphthalide in THF after
protection of the ketone as the ketal (Figure 2). The
diphenylphosphoramidate group can also be removed
under reductive conditions with lithium aluminum
hydride in ether. The direction of optical rotation of
pyrrolidine 23 did not depend on the starting
protected pyrrolidine, indicating that 20-22 have the
Intrigued by the high levels of asymmetry induced
by chiral ruthenium catalyst 1, we wondered if the
observed enantioselectivity was at all influenced by
the stereochemistry of the starting alcohol even
though the stereocenter is destroyed in the process.
To test this, we synthesized tosyl-substituted [1,6]-
enynes 10a containing an enantiomerically enriched
same
absolute
configuration.
The
absolute
configuration of ketal 20 was confirmed to be (R,R)
based on single crystal x-ray crystallography (Figure
2).
Table 3. Effect of Propargylic Stereocenter on
Enantioselectivity
-
PF6
O
Me
Ru
MeCN
S
Me
MeCN
Solvent, 40 °C,
3 mol%
O
Me
TsN
OH
Me
0.25 M, 16 h
N
Ts
∗
MeO
alcohol
10b
10a
entry
e.r.
solvent
yield (%)
configuration
rac
1
2
81
84
94.0:6.0
93.5:6.5
Acetone
Acetone
(R)a
Figure 2. X-ray crystal structure of 20
(S)a
3
4
5
6
Acetone
THF
81
52
61
52
96.5:3.5
80.0:20.0
92.0:8.0
68.0:32.0
rac
In conclusion, we have developed the first
(R)a
(S)a
THF
asymmetric
ruthenium-catalyzed
redox
THF
cycloisomerization reaction known to date. This
a Starting alcohol has a 97:3 e.r.
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reported for any other metal-catalyzed
cycloisomerization. It is also important to note that this
new chiral catalyst is effective for two very different
types of processes, allylic alkylation and redox
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bicycloisomerization. Such
a feature encourages
examination of this new chiral catalyst for other
ruthenium-catalyzed reactions. Ongoing studies are
currently being performed to elucidate the mechanism
of this transformation.
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ASSOCIATED CONTENT
Supporting Information. Experimental Details,
crystallographic data, and characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.;
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AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
ACKNOWLEDGMENT
We would like to thank the NSF for their generous
support (NSF-CHE-1145236), Dr. Allen Oliver (X-Ray
Crystallographic Laboratory, Notre Dame University) is
gratefully acknowledged for assistance in growing
crystals and XRD analysis.
(13) Trost, B. M.; Breder, A.; O’Keefe, B. M.; Rao, M.; Franz, A.
W. J. Am. Chem. Soc. 2011, 133, 4766–4769.
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(16) Trost, B. M.; Rao, M.; Dieskau, A. P. J. Am. Chem. Soc.
2013, 135, 18697–18704.
(17) (a) Bertani, B., Di Fabio, R., Micheli, F., Tedesco, G., &
Terreni, S., WO 2008031772A1, 2008. (b) Micheli, F.; Cavanni,
P.; Andreotti, D.; Arban, R.; Benedetti, R.; Bertani, B.; Bettati,
M.; Bettelini, L.; Bonanomi, G.; Braggio, S.; Carletti, R.;
Checchia, A.; Corsi, M.; Fazzolari, E.; Fontana, S.; Marchioro,
C.; Merlo-Pich, E.; Negri, M.; Oliosi, B.; Ratti, E.; Read, K. D.;
Roscic, M.; Sartori, I.; Spada, S.; Tedesco, G.; Tarsi, L.;
Terreni, S.; Visentini, F.; Zocchi, A.; Zonzini, L.; Di Fabio, R. J.
Med. Chem. 2010, 53, 4989–5001.
(18) Other catalyst systems were tried, but catalyst 1 proved to
be the most reactive and enantioselective for the
transformation. See Supporting Information for details.
(19) All of the redox bicycloisomerization reactions presented
proceed to full conversion. The remaining mass balance is a
mixture of acyclic redox isomerization and β-hydride elimination
products. For more information, see ref. 13.
(20) Trost, B. M.; Quintard, A. Angew. Chem. Int. Ed. 2012,
51, 6704–6708.
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Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the
manuscript title, should give the reader a representative idea of one of the following: A key structure, reaction,
equation, concept, or theorem, etc., that is discussed in the manuscript. Consult the journal’s Instructions for
Authors for TOC graphic specifications.
-
PF6
O
R'
Ru
MeCN
S
R
n
MeCN
Acetone, 0.25 M,
3 - 7.5 mol%
O
R
X
OH
R'
40 °C, 16 h
n
10
11
12
13
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15
16
17
18
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X
MeO
Vicinal, quaternary
all-carbon stereocenters,
18 examples,
n =1-2
X = -NTris, -NTs,
-NP(O)(OPh)2,
-C(CO2Bn)2
82.5:17.5 to
98.5:1.5 e.r.
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