Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of Azomethine Ylides with Methacrylonitrile

Article abstract of DOI:10.1021/acs.orglett.5b03171

Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.

Full text of DOI:10.1021/acs.orglett.5b03171

Letter
pubs.acs.org/OrgLett
Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of
Azomethine Ylides with Methacrylonitrile
Mary C. Walton,† Yun-Fang Yang,‡ Xin Hong,‡ K. N. Houk,*,‡ and Larry E. Overman*,†
†Department of Chemistry, University of California, Irvine, California 92697-2025, United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
ABSTRACT: Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the
endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.
e recently reported that analogues 1 of epidithiodioxo-
piperazine (ETP) alkaloids exhibit promising activity
motifs in many bioactive natural products7 and synthetic
pharmaceuticals,8 and nitriles are important pharmacophores,9
we chose to examine metal catalysis of cycloadditions of the
type illustrated in Scheme 1. We report herein salient features
of these investigations, which discovered that either the endo or
exo cycloadduct can be formed with high selectivity by
changing only the ligand of a Cu(I) catalyst. Computational
studies that shed light on the origin of the observed
diastereoselectivities are also reported.
Our studies began by examining copper complexes formed
from Cu(MeCN)4BF4 in the reaction of imine 3a and
methacrylonitrile (Table 1), because several examples of
copper-catalyzed cycloadditions of azomethine ylides with
nitrile-containing dipolarophiles had been reported by the
Carretero group10 and others.6e,j,k We initially investigated a
variety of ligand types. Reactions using Ph3P or tricyclohexyl-
phosphine (Cy3P) afforded pyrrolidine products in high yield;
however, only the reaction with Cy3P was diastereoselective
giving the exo cycloadduct 4a with 9:1 selectivity (entry 2). In
contrast, the reaction using 1,2-bis(diphenylphosphino)ethane
(dppe) as the ligand resulted in 88:12 diastereoselectivity
favoring the endo cycloadduct 2a (entry 3). Endo stereo-
selectivity was improved to 50:1 by using tris(2,2,2-trifluoro-
ethyl) phosphite [P(OCH2CF3)3] as the ligand (entry 4). The
HASPO ligand L1 provided the endo cycloadduct 2a with
modest stereoselectivity; however, the yield of this reaction was
low (entry 5). The P,N-ligand DavePhos (2-dicyclohexylphos-
phino-2′-(N,N-dimethylamino)biphenyl) resulted in a 41:59
mixture of cycloadducts in a high yield of 85% (entry 6). The
use of the NHC ligand L2 or 1,10-phenanthroline resulted in
no reaction (entries 7, 8).
W
against both solid and blood tumors in vitro and that a lead
member of this series having a methylenedioxyphenyl-5-yl
substituent suppresses tumor growth in mouse xenograft
models of melanoma and lung cancer.1 Pyrrolidine 2-
carboxylates 2, which are pivotal intermediates in the synthesis
of 1, were prepared by 1,3-dipolar cycloadditions of azomethine
ylides derived from glycine imines 3 with methacrylonitrile.2
Using the commonly employed conditions of Tsuge (Scheme
1),2b endo cycloadducts 2 were formed with 2:1−10:1
Scheme 1. Dipolar Cycloaddition Step in the Synthesis of
Antitumor ETP Alkaloid Analogues 1
diastereoselectivity. Although the construction of 2-pyrrolidine
esters by 1,3-dipolar cycloadditions is well-developed, with
many advances in metal and enantioselective catalysis having
been recorded, cycloadditions in which the dipolarophile is
activated by a nitrile rather than an ester substituent are much
less common.3 For example, prior to our disclosure,1 there was
only one report4 of a 1,3-dipolar cycloaddition of an
azomethine ylide derived from a glycine imine and
methacrylonitrile.5,6 As substituted pyrrolidines are structural
Three ligandsP(OCH2CF3)3, Cy3P, and DavePhoswere
selected to test the generality of the ligand effects observed in
Received: November 2, 2015
© XXXX American Chemical Society
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Table 1. Investigation of Ligands for the Cu(I)-Catalyzed
Reaction of Imine 3a and Methacrylonitrile
Table 2. Investigation of Ligands for the Cu(I)-Catalyzed
Reaction of Imines 3 and Methacrylonitrile
a
a
a
Reactions were performed using imine 3a (0.20 mmol), meth-
acrylonitrile (0.30 mmol), Cu(MeCN)4BF4 (10 mol %), and Et3N
b
(0.12 mmol) at a concentration of 0.20 M in THF. The reactions
c
were conducted using 22 mol % of the ligand. The reactions with
bidentate ligands were performed using 11 mol % of the ligand.
d
Ligand L2 was generated from the corresponding HBF4 by stirring
with 1.1 equiv of potassium tert-butoxide for 10 min before adding
e
Cu(MeCN)4BF4. GC yields using 1,3,5-trimethoxybenzene as
f
external standard. Ratios were determined by GC-FID analysis. nd
= not determined.
our initial survey.11 As summarized in Table 2, good yields and
very high diastereoselectivities (>94:6) favoring formation of
the endo cycloadducts were observed for eight aryl imine
substrates in Cu-catalyzed cycloadditions using P(OCH2CF3)3
(initial imine concentration of 0.6 M, 5 h reaction time).12,13
The sole exception was the 3-pyridinyl substrate, which reacted
with slightly lower diastereoselectivity and in poor yield.14 Exo
cycloadducts were accessed in high stereoselectivity (>86:14)
and good yield in similar reactions using Cy3P (imine
concentration of 1 M, reaction time 1 h).15 As in our
preliminary survey, Cu-catalyzed cycloadditions using Dave-
Phos were nonstereoselective. Yields of isolated products and
stereoselectivities were similar in reactions conducted on a
larger scale (entries 1, 2, 10, 11, 19, 20, 25, and 26).
The origins of the ligand-controlled diastereoselectivity were
studied through DFT calculations, using a truncated model of
imine 3 and methacrylonitrile. B3LYP-D3/SDD-6-311+G(d,p)
energies from B3LYP geometries are given here.16 Extensive
conformational searching has been performed to find the most
stable conformer. With the P(OCH2CF3)3 ligand, the
computation results show that the endo transition state, TS5,
is 0.9 kcal/mol more stable than the exo transition state, TS6.
This is consistent with the experimental diastereoselectivity
(entry 4, Table 1). In TS5, the negative electrostatic potential
(ESP) region of methacrylonitrile (N terminal) is proximal to
a
Reactions were performed using imine 3 (0.20 mmol), methacryloni-
trile (0.22 mmol), and Cu(MeCN)4BF4 (5 mol %) at the indicated
concentration in THF. Reactions run at 0.6 M for 5 h using 11 mol %
b
c
ligand. Reactions run at 1.0 M for 1 h using 11 mol % ligand.
d
e
Reactions run at 0.4 M for 3 h using 5.5 mol % ligand. GC yields
determined using 1,3,5-trimethoxybenzene as an internal standard
(average of two experiments). Isolated yields from reactions run on a
0.5 mmol scale. Ratios determined by GC-FID analysis (average of
two experiments). Ratios of isolated products.
f
g
h
B
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Letter
the ESP-positive region of the phosphite ligand (ligand
methylene group),17 as highlighted in Figure 1, and the
provide the first diastereoselective access to cyano-substituted
pyrrolidines of this type. The DFT transition state structures
that rationalize the observed selectivity trends provide a basis
for future studies to render such reactions enantioselective.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03171.
■
Figure 1. Structures and relative Gibbs free energies of transition
states of copper-catalyzed cycloaddition between model azomethine
ylide and methacrylonitrile (Gibbs free energies are in kcal/mol; the
hydrogens of the Cy3P ligands are omitted for clarity).
S
electrostatic interaction stabilizes this endo transition state,
leading to the diastereoselectivity. With the Cy3P ligand, this
electrostatic stabilization no longer exists, and the steric
repulsions favor the exo transition state. The nitrile group of
methacrylonitrile has greater repulsion of the Cy3P ligand as
compared to the methyl group. Therefore, the exo transition
state, TS8, is 1.1 kcal/mol more stable than the endo transition
state, TS7, and the diastereoselectivity is reversed.
Two additional observations are consistent with the
computational model proposed in Figure 1. The stabilizing
electrostatic interactions between the nitrile nitrogen and
P(OCH2CF3)3 in endo transition structure TS5 would not be
expected if a less electron-deficient phosphite ligand was
employed. This prediction is confirmed by the reaction of imine
3a with methacrylonitrile using triethyl phosphite as the ligand,
which proceeded nonstereoselectively to give the exo and endo
cycloadducts 4a and 2a in a 2:1 ratio (eq 1). In addition, endo
stereoselection in the reaction of acrylonitrile with imine 3d
using P(OCH2CF3)3 as the ligand occurred with eroded endo
stereoselectivity (dr = 69:31, eq 2) compared to cycloaddition
with methacrylonitrile under identical conditions. The lack of
substitution at the α-position of acrylonitrile results in exo
transition structure TS6 being less disfavored. As would be
expected, high exo stereoselectivity was seen in this reaction
using Cy3P as the ligand (eq 2).
Experimental procedures, characterization data for new
compounds, supplementary computational results, com-
putational details, Cartesian coordinates and Gibbs free
energies of the calculated structures (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: houk@chem.ucla.edu.
*E-mail: leoverma@uci.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.C.W. thanks the National Science Foundation for a graduate
fellowship (DGE-1321846) and Professor Vy Dong for routine
access to GC-FID instrumentation. We are grateful to the
National Science Foundation (CHE-1361104) for financial
support of this research. Calculations were performed on the
Hoffman2 cluster at UCLA and the Extreme Science and
Engineering Discovery Environment (XSEDE), which is
supported by the NSF (OCI-1053575).
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■
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ligand, 1,3-dipolar cycloaddition reactions of glycine ester
arylimines and methacrylonitrile provide either the endo or exo
cycloadduct with high diastereoselectivity. These reactions
C
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Letter
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1
assigned as described in ref 1 and are supported by 2D H NMR
(see the Supporting Information for details).
(13) Optimization experiments that defined the preferred solvent and
reaction concentration for each catalyst can be found in the
Supporting Information.
(14) Yields of products 2e and 4e were increased when a higher
catalyst loading of 10 mol % was used. The pyridinyl substituent
undoubtedly reduces catalyst activity, as the addition of 1 equiv of
pyridine to the reaction reported in Table 2, entry 10 resulted in <5%
formation of cycloadduct 2d.
(15) Whereas the use of 5.5 mol % of P(OCH2CF3)3 and Cy3P
resulted in the formation of an effective catalyst, the use of 11 mol %
resulted in increased catalyst solubility and elevated yields.
(16) (a) Computational details and references are included in the
Supporting Information. (b) For a related DFT study, see: Wang, M.;
Wang, C.-J.; Lin, Z. Organometallics 2012, 31, 7870.
(17) ESP diagrams of methacrylonitrile and the copper complex in
TS5 are included in the Supporting Information.
D
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