Regio-and enantioselective synthesis of pyrrolidines bearing a quaternary center by palladium-catalyzed asymmetric [3 + 2] cycloaddition of trimethylenemethanes

Article abstract of DOI:10.1021/ja312351s

Herein we describe the first use of disubstituted donors in the palladium-catalyzed trimethylenemethane (TMM) cycloaddition resulting in an enantioselective synthesis of highly substituted pyrrolidines. These cyanoalkyl donors 1 form all-carbon quaternary centers in a catalytic, asymmetric, and intermolecular manner uniquely using diamidophosphite ligands L2 and L3, generating synthetically important chiral building blocks in good yields and selectivities.

Full text of DOI:10.1021/ja312351s

Communication
pubs.acs.org/JACS
Regio- and Enantioselective Synthesis of Pyrrolidines Bearing a
Quaternary Center by Palladium-Catalyzed Asymmetric [3 + 2]
Cycloaddition of Trimethylenemethanes
Barry M. Trost,* Tom M. Lam, and Melissa A. Herbage†
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S
* Supporting Information
ABSTRACT: Herein we describe the first use of
disubstituted donors in the palladium-catalyzed trimethy-
lenemethane (TMM) cycloaddition resulting in an
enantioselective synthesis of highly substituted pyrroli-
dines. These cyanoalkyl donors 1 form all-carbon
quaternary centers in a catalytic, asymmetric, and
intermolecular manner uniquely using diamidophosphite
ligands L2 and L3, generating synthetically important
chiral building blocks in good yields and selectivities.
substituents on the donor, thereby increasing the generality of
he transition-metal-catalyzed trimethylenemethane
this methodology.8 The difficulty of this prospect, however, lies
T
(TMM) cycloaddition is a powerful tool in the synthesis
in the donor−catalyst system, as increased substitution reduces
both reactivity and selectivity. Herein, we describe the
realization of such a process and its application to the synthesis
of functionalized pyrrolidines. These products serve as useful
chiral building blocks bearing stereodefined quaternary centers
which can be further functionalized to complex structures.
We began our investigation by identifying the best coupling
partners for the reaction. Tosyl imines were chosen as a
substrate class due to their previous success in TMM
cycloadditions as well as the importance of pyrrolidines in
nature.4a Given the success of cyano-subsituted donors in the
TMM methodology, we designed a disubstituted donor
including this functional group to potentially increase the
reactivity of the donor as well as to provide a functional handle
for further elaborations of the cycloadducts. Our initial screen
with phosphoramidite ligand L1 and methylcyano donor 1a led
to trace amounts of product (Table 1). On the other hand,
switching to L2, we were able to isolate the desired product in
66% yield, 6:1 dr, and 89% ee (entry 2). Increasing the steric
bulk about the ligand from the (S,S)-cyclohexanediamine
backbone in L2 to the (R,R)-stilbene diamine in L3 led to a
slight increase in enantioselectivity (entry 3).9 Extending the
methyl group in the donor to an ethyl group 1b increased the
diastereoselectivity while retaining high levels of enantioselec-
tivity. We decided to continue our exploration with the
ethylcyano donor 1b due to its superior selectivity.
of various ring systems. Since its inception, the method has
shown its versatility in the synthesis of five-, seven-, and nine-
membered rings.1,2 In our efforts to develop asymmetric
catalysts for the TMM reaction, our ligand designs simulta-
neously expanded the types of substitution tolerated in the
acceptor. For example, using chiral phosphoramidite ligands3
not only delivered good enantioselectivity but also allowed both
aldimines and ketimines to be used as acceptors for
cycloaddition.3c,4a To further expand this methodology, we
have been interested in employing substituted-TMM donors.
These donors, when performed in an asymmetric fashion,
would allow us to generate highly substituted ring systems
enantioselectively. We have found that the choice of ligands
may be crucial to the success of these transformations from a
reactivity point of view as well as an enantioselectivity
perspective. For example, while the phosphoramidite ligand
L1 performed well for the cyano-substituted donor,4,5 we had
to turn to a new class of ligands, diamidophosphites such as L2,
for success with vinyl substituted donors.6
We became intrigued by the possibility of generating
quaternary stereocenters with the use of disubstituted-TMM
donors, a process that heretofore has not been done. The
synthesis of all-carbon quaternary stereocenters remains a
challenge in organic chemistry.7 The intrinsic steric bulk of this
structural entity complicates its synthesis from both a reactivity
and enantioselectivity standpoint. We have been able to
synthesize quaternary stereocenters using the TMM method-
ology by reacting with tri- or tetrasubstituted π-system
acceptors (eq 1).3d,5 In those cases, the formation of the
quaternary center resides on the acceptor, which limits the
types of products formed. We envisioned that placement of the
stereogenic center on the donor coupling partner (eq 2, 1)
would allow us to generate molecular complexity by varying the
During our substrate screen, we realized that the conditions
set out in entry 4 led to good yields and selectivities for
electron-poor tosyl imines. However, when a more electron-
rich imine was employed (R′ = NMe2), the reaction completely
Received: December 18, 2012
Published: January 30, 2013
© 2013 American Chemical Society
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Communication
a
Table 1. Selected Optimization Studies
Scheme 1. Palladium-Catalyzed [3 + 2] Reactions of
a
Ethylcyano-TMM Donor with Tosyl Imines
yield
ee
(%)
entry
1
R
R′
Pd source
Pd(dba)2
Ln
(%)
dr
Me
(1a)
Cl
L1
trace
2
3
4
5
6
7
Me
Me
Cl
Cl
Pd(dba)2
Pd(dba)2
Pd(dba)2
L2
L3
L3
L3
L2
L2
66
74
68
NR
45
63
6:1
4:1
89
−92
−93
Et (1b) Cl
13:1
Et
Et
Et
N(Me)2 Pd(dba)2
N(Me)2 Pd(dba)2
N(Me)2 CpPd
9:1
75
85
16:1
(η3-C3H5)
b
8
Et
Et
N(Me)2 CpPd
(η3-C3H5)
L2
L3
88
40
14:1
9:1
83
b
9
N(Me)2 CpPd
(η3-C3H5)
−73
a
All reactions were conducted for 18 h at 0.2 M in toluene with 1.4
equiv of 1, 5% palladium precatalyst, and 6% ligand. Yields are
combined isolated values; ee’s were determined by HPLC with a chiral
b
stationary phase column. Concentration increased to 0.5 M.
a
All reactions were conducted for 18 h at 0.5 M in toluene with 1.4
equiv of 1a, 5% CpPd(η3- C3H5), and 6% ligand. Yields are combined
isolated values; ee’s were determined by HPLC with a chiral stationary
phase column.
dr and 84% ee in 3m. This decrease in enantioselectivity can
also be observed in 3n and 3o, where the products are isolated
in 81% and 74% ee, respectively.
Variations in the alkyl substituent on the donor are also
tolerated. We have seen that methyl and ethyl groups function
well in this cycloaddition (Scheme 2). Further extension of the
shut down (Table 1, entry 5). Switching to L2 provided the
desired product, albeit in 45% yield (entry 6). Trying to
increase this yield, we tested the more reactive palladium
precatalyst CpPd(η3-C3H5), and an increase in yield to 63% was
observed (entry 7). The increased yield obtained from this
precatalyst is likely due to the removal of dibenzylidene acetone
from the system, which could act as a competitive ligand for the
metal center. Increasing the concentration of the system from
0.2 to 0.5 M further increased the yield to 88% with 83% ee
(entry 8). However, using these optimized conditions with L3,
only 40% of the product was isolated with a decrease in
selectivity (entry 9). While L2 was selected as the optimal
ligand for this transformation, L3 sometimes performed better
depending upon the exact acceptor.
Scheme 2. Exploration of Other Alkyl Substituents on Donor
1
With conditions in hand, we proceeded to evaluate the scope
of the reaction (Scheme 1). Various pyrrolidines were
synthesized in good yields and diastereo- and enantioselectivity.
Assignment of the absolute and relative stereochemistry was
achieved through both nOe analysis and X-ray crystallogra-
phy.10 Several aromatic groups are well tolerated (3a−3j),
regardless of the position of substitution around the aromatic
ring (3b−3d). Both electron-withdrawing and -donating groups
serve well in the transformation, although, as mentioned before,
L2 is preferred for more electron-rich cases. Five-membered
heterocycles show no significant difference in yield and
selectivity as well (3i−3j). Gratifyingly, alkyl side chains also
perform well in the cycloaddition (3k−3o).11 With the alkyl
variants, it was found that the steric bulk of the side chain
affects the selectivity of the reaction. As the alkyl branching is
further removed from the reaction center, both diastereo- and
enantioselectivity drop from >19:1 dr and 92% ee in 3k to 6:1
chain to an isobutyl group led to formation of 3q in good yields
and diastereoselectivity; however, the enantioselectivity was
greatly reduced to 32% ee. Attaching an alkyne functionality to
the ethyl chain restored the enantioselectivity of the donor
catalyst system, although it was slightly reduced to 74% ee in
3r. Again, using L3 increases the enantioselectivity to 83% ee
but with a drop in yield to 45%.
These pyrrolidines are versatile chiral building blocks that are
easily elaborated to synthetically important structures. The
cyano group can be reduced to both the aldehyde and free
amine with no erosion of enantiopurity (Scheme 3, 4 and 5).
Desulfonylation with magnesium in methanol gave the
unprotected pyrrolidine 6 as a single diastereomer. In our
previous work using the cyano-substituted TMM donor,
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Journal of the American Chemical Society
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Scheme 3. Further Functionalizations of Cycloadducts 3
REFERENCES
■
(1) (a) Trost, B. M. Pure Appl. Chem. 1988, 60, 1615. (b) Lautens,
M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. (c) Chan, D. M. T.
Recent Advances in Palladium-Catalyzed Cycloadditions Involving
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(2) For TMM reactions that do not involve transition metal catalysis,
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(3) (a) Trost, B. M.; Bringley, D. A.; Seng, P. S. Org. Lett. 2012, 14,
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derivatization of the substrate was required prior to
deprotection, which we proposed underwent base-catalyzed
double bond isomerization which was responsible for
producing multiple products.4a The current results, which
proceeded quantitatively on the direct cycloadduct, support
that contention. The alkynyl side chain in 3r can also react with
the exocyclic methylene using a palladium-catalyzed reductive
ring closing reaction.12 The reaction proceeds with catalytic
palladium in the presence of formic acid and triethylsilane as a
reducing agent. Diastereoselectivity of the C−C bond forming
ring closure reaction is controlled by the nature of the substrate,
forming the cis-fused [5,5] ring system 7 as a single olefin
isomer with stereodefined vicinal quaternary centers, a
synthetically challenging structural entity.7b
In summary, we have described the synthesis of substituted
pyrrolidines bearing quaternary centers using a TMM cyclo-
addition. The reaction was made possible by the utility of
diamidophosphite ligands L2 and L3, allowing us to perform
the cycloaddition with disubstituted-TMM donors for the first
time. The products are formed in good yields and selectivities
and are readily functionalized to diverse architectures. Further
investigation into the full scope of the reaction is underway and
will be reported in due time.
Silverman, S. M.; Schworer, U. J. Am. Chem. Soc. 2006, 128, 13328.
̈
(4) (a) Trost, B. M.; Silverman, S. M. J. Am. Chem. Soc. 2012, 134,
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(7) (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
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Sci. U.S.A. 2004, 101, 11943. (c) Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2001, 40, 4591.
(8) While disubstituted TMM donors have been successful
previously using a cyclopropyl donor (see Trost, B. M.; Parquette, J.
R.; Nubling, C. Tetrahedron Lett. 1995, 36, 2917 ) the quaternary
center produced was not chiral, and the process was only carried out in
a racemic fashion.
(9) Ligands L2 and L3 are derived from diamines of opposite
chiralities; thus the products observed possess opposite enantiose-
lectivities, as reflected in Table 1.
(10) All products were isolated as a single regioisomer. The absolute
and relative stereochemistry of the product was determined by the
crystal structure of 3d (see Supporting Information). All other
products were assigned by analogy.
(11) L3 was not tested more broadly due to the lowered yields
experienced by this ligand in these reactions.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental details, compound characterization data,
and spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(12) (a) Trost, B. M.; Krische, M. J. Synlett 1998, 1, 1. (b) Trost, B.
M.; Li, Y. J. Am. Chem. Soc. 1996, 118, 6625. (c) Trost, B. M.; Fleitz, F.
J.; Watkins, W. J. J. Am. Chem. Soc. 1996, 118, 5146. (d) Trost, B. M.;
Rise, F. J. Am. Chem. Soc. 1987, 109, 3161. (e) Trost, B. M.; Braslau, R.
Tetrahedron Lett. 1988, 29, 1231.
AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
■
Present Address
†Chemical Development, Boehringer Ingelheim Pharmaceut-
icals Inc., 900 Ridgebury Road/P.O. Box 368, Ridgefield,
Connecticut 06877-0368, United States
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding was provided by NSF Grant CHE-1145236. We thank
the NSF for their generous support of our programs. We thank
Dr. Allen Oliver from the University of Notre Dame for the X-
ray crystal structures and Johnson-Matthey for generous gifts of
palladium salts.
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