Catalytic asymmetric Exo-selective [C+NC+CC] reaction

Article abstract of DOI:10.1021/ol500474a

A catalytic asymmetric version of the exo-selective [C+NC+CC] reaction is reported. This multicomponent reaction utilizes a readily prepared achiral glycyl sultam as the "NC" component and commercially available catalyst components. The method can be applied to a variety of aldehydes ("C" component) and activated alkenes ("CC" component) to provide substituted pyrrolidines in good yields and high enantioselectivities. Of particular note is the ability to employ labile enolizable aldehydes (e.g., acetaldehyde and propionaldehyde) in this reaction.

Full text of DOI:10.1021/ol500474a

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Exo-Selective [C+NC+CC] Reaction
Ryan Joseph, Charles Murray, and Philip Garner*
Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, United States
S
* Supporting Information
ABSTRACT: A catalytic asymmetric version of the exo-
selective [C+NC+CC] reaction is reported. This multi-
component reaction utilizes a readily prepared achiral glycyl
sultam as the “NC” component and commercially available
catalyst components. The method can be applied to a variety
of aldehydes (“C” component) and activated alkenes (“CC”
component) to provide substituted pyrrolidines in good yields
and high enantioselectivities. Of particular note is the ability to
employ labile enolizable aldehydes (e.g., acetaldehyde and propionaldehyde) in this reaction.
Scheme 1. Asymmetric [C+NC+CC] Reaction Manifold
he pyrrolidine ring is found at the core of a diverse range
Tof biologically active and structurally intriguing molecules.
As a consequence, the synthesis of pyrrolidine-containing
targets has been the focus of intense research. The foremost
method for the synthesis of substituted pyrrolidines, namely the
[3 + 2] cycloaddition of azomethine ylides and olefins, has
undergone considerable development since its initial classi-
fication by Huisgen.1,2 Grigg’s seminal work in this area,
utilizing stoichiometric Lewis acid metal salts together with
chiral ligands and tertiary amine bases, first suggested the
possibility of asymmetric catalysis in this reaction.3 Since that
time, a plethora of catalytic asymmetric versions of this reaction
have been developed.4 Despite these important advances, a
critical limitation of current methods is that, except for a few
isolated examples,5 they are largely restricted to stable imine
precursors derived from nonenolizable (usually aromatic)
aldehydes. Most of the aliphatic examples have employed
branched imines that may be conformationally protected from
tautomerization. Very few groups have reported the use of
more labile unbranched aliphatic imines in catalytic asymmetric
azomethine ylide cycloadditions.5b,i,k,l,n
Our interest in this problem, necessitated by our desire to
synthesize several target molecules possessing pyrrolidine cores
with aliphatic substituents, led to the development of the
asymmetric [C+NC+CC] reaction. In this multicomponent
cycloaddition reaction, an aldehyde (“C” component), chiral
glycyl sultam (“NC” component), and dipolarophile (“CC”
component) combine to form functionalized pyrrolidines
(Scheme 1).6−9 Oppolzer’s chiral glycyl sultam serves both to
control the developing absolute stereochemistry and activate
the α-proton for rapid dipole formation. The latter point is of
particular significance because it enables the in situ generation
of azomethine ylides derived from enolizable aliphatic
aldehydes, thus differentiating this method from existing
azomethine ylide cycloadditions that require one to preform
an unstable imine.
enantioselective synthesis of a variety of substituted pyrroli-
dines using a catalytic Cu(I)/chiral ligand system. This atom-
economical method utilizes a readily prepared achiral glycyl
sultam “NC” component derived from the commodity chemical
saccharine, allowing the in situ generation of azomethine ylides
starting from enolizable unbranched aliphatic aldehydes.
Although not the focus of this study, the reaction is also
shown to proceed with aromatic and olefinic aldehydes. It is
notable that no external base beyond the glycyl sultam amine
component is required nor is the addition of any dehydrating
agent.
Our initial design for a catalytic asymmetric variant of the [C
+NC+CC] reaction required the identification of an achiral
auxiliary for the “NC” component. Based on our experience
with Oppolzer’s chiral glycyl sultam, we decided on a sultam-
We now report a catalytic asymmetric version of the exo-
selective [C+NC+CC] reaction in which we demonstrate the
Received: November 19, 2013
Published: March 6, 2014
© 2014 American Chemical Society
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Letter
a
containing auxiliary that could be easily accessed from
inexpensive, commercially available starting materials. The
commodity chemical saccharine, which is readily reduced to the
corresponding benzosultam, met our criteria and served as a
starting point for our studies. The synthesis of the achiral glycyl
benzosultam “NC” component is outlined below (Scheme 2).
Table 1. Ligand Screening and Reaction Optimization
d
Scheme 2. Synthesis of the Glycyl Benzosultam
entry
ligand
solvent
yield of 8 (%)
er
b
1
Fesulphos
THF
62
52:48
50:50
50:50
52:48
67:33
>99:1
58:42
55:45
>99:1
55:45
b
2
Taniaphos
THF
58
b
3
Walphos
THF
60
b
4
DM-Segphos
DTBM-Segphos
DTBM-Segphos
DTBM-Segphos
DTBM-Segphos
DTBM-Segphos
DM-Segphos
THF
65
b
5
THF
55
b
6
toluene
DMSO
CH2Cl2
toluene
70
b
7
60
b
8
25
c
9
81
b
10
toluene
63
a
b
X = saccharine-derived sultam. Cu(MeCN)4PF6 (10 mol %), (R)-
c
ligand (10 mol %). Cu(MeCN)4PF6 (5 mol %), (R)-ligand (5 mol
%). (R/S) as determined from chiral HPLC analysis.
d
Reduction of saccharine gave benzosultam 2 in excellent
yield.10 Subsequent acylation with bromoacetyl bromide,
followed by azide formation and reduction, was accomplished
using adaptations of conditions developed for the camphor-
derived auxiliary.11 The resulting ammonium salt 4 was stable
for storage and was conveniently converted to its more labile
free amine form just before use.
(entry 9). This combination defined our optimal reaction
conditions. Somewhat surprisingly, switching to toluene did not
improve the enantioselectivity associated with the DM-Segphos
ligand (entry 10).
With optimized conditions in hand, we next sought to
explore the scope of the catalytic asymmetric exoselective [C
+NC+CC] reaction with various aldehydes and activated
alkenes (Table 2). To aid in purification and analysis, the
cycloadducts were converted to their corresponding methyl
esters. As shown in this collection of examples, the optimal
reaction conditions enable the enantioselective catalytic
asymmetric [CC+NC+CC] synthesis of substituted pyrroli-
dines using a variety of aliphatic enolizable aldehydes. These
reactions were all exo-selective with the relative configuration
assignments being made through NOE experiments. The
absolute configurations were based on a combination of
chemical correlation and chiral HPLC relative retention
times. Entries 1−3 demonstrate [C+NC+CC] cycloadditions
of hydrocinnamaldehyde with standard dipolarophiles, giving
excellent enantioselectivities and good overall yields with only
trace levels of detectable diastereomers.13 Cinnamaldehyde also
gave excellent enantio- and diastereoselectivity (entry 4). The
reaction with 1-nonanal exhibited very good enantioselectivity
(entry 5). Entries 6−8 explored the catalytic-asymmetric [CC
+NC+CC] reaction with the more synthetically useful
benzyloxyacetaldehyde while also expanding the scope to
several other dipolarophiles. These reactions proceeded with
slightly lower but still very good enantioselectivities. Finally, we
successfully demonstrated the catalytic asymmetric [C+NC
+CC] cycloaddition protocol using the volatile enolizable
aliphatic aldehydes propionaldehyde and acetaldehyde (entries
9 and 10, respectively). Both of these reactions gave very good
enantioselectivities. To our knowledge, this is the first example
of the use of acetaldehyde in this class of cycloadditions, clearly
illustrating the utility of the catalytic asymmetric [C+NC+CC]
reaction.
Our next step involved evaluation of the achiral glycyl sultam
employing our previously established exo-selective [C+NC
+CC] reaction conditions.7 An initial control experiment was
performed in which the glycyl sultam was mixed with
hydrocinnamaldehyde and methyl acrylate in DMSO in the
presence of an achiral Cu(I) catalyst. We were pleased to find
that the achiral saccharine-derived auxiliary participated in an
exo-selective [C+NC+CC] reaction. Having demonstrated that
the saccharine-derived achiral glycyl sultam was a viable “NC”
component, we began our search for a chiral ligand and optimal
reaction conditions for the catalytic asymmetric [C+NC+CC]
reaction. This initial study was performed with benzaldehyde
rather than enolizable aliphatic aldehydes such that we might
more readily compare our results with the literature. A survey
of known successful catalytic asymmetric azomethine ylide
cycloadditions guided our selection of chiral ligands. The
screening of commercially available ligands along with
optimization of the reaction conditions is summarized in
Table 1.
To evaluate ligand enantioselectivity, we converted the
initially formed cycloadduct to the known methyl ester 8 by
adapting Ohfune’s conditions12 for methanolysis. As entries 1−
4 demonstrate, the Fesulphos, Taniaphos, Walphos, and DM-
Segphos ligands showed little to no enantioselectivity in THF.
However, an initial observation of enantioselectivity occurred
when the more sterically demanding DTBM-Segphos was
tested in THF (entry 5). With this promising result in hand, we
wondered whether a simple change to a noncoordinating
solvent might result in increased enantioselectivity. Indeed,
changing the solvent to toluene resulted in a substantial
improvement in enantioselectivity (entry 6) while DMSO did
not (entry 7), lending support to our hypothesis. The use of
CH2Cl2 as a solvent resulted in both poor yield and
enantioselectivity (entry 8). Using DTBM-Segphos as ligand
and toluene as the solvent, we found that high enantioselectiv-
ities could be achieved with catalyst levels as low as 5 mol %
In conclusion, we have developed a unique catalytic
asymmetric exo-selective [C+NC+CC] reaction for the stereo-
controlled synthesis of substituted pyrrolidines. By utilizing a
readily prepared achiral glycyl sultam and a commercially
available metal salt + chiral ligand catalyst, [C+NC+CC]
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a
Table 2. Catalytic−Asymmetric [C+NC+CC] Reaction
a
b
c
d
X = saccharine-derived sultam. Isolated yield over two steps. Methanolysis performed with Mg(OMe)2. An excess of aldehyde was used.
cyclizations can be performed with a variety of enolizable
aliphatic aldehydes and electron-deficient alkenes producing
functionalized pyrrolidines with very good to excellent
enantioselectivity. The reaction augments existing methods
and should prove useful in synthetic applications.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ppg@wsu.edu.
■
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
■
S
ACKNOWLEDGMENTS
* Supporting Information
■
Experimental procedures and characterization data for all new
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
This research was supported by a grant from the National
Science Foundation (CHE-1149327). We thank Dr. Frank
Dyer (Washington State University) for helpful discussions.
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