Enantioselective organo-SOMO cycloadditions: A catalytic approach to complex pyrrolidines from olefins and aldehydes

Article abstract of DOI:10.1021/ja305076b

A new method to rapidly generate pyrrolidines via a SOMO-activated enantioselective (3 + 2) coupling of aldehydes and conjugated olefins has been accomplished. A radical-polar crossover mechanism is proposed wherein olefin addition to a transient enamine

Full text of DOI:10.1021/ja305076b

Communication
pubs.acs.org/JACS
Enantioselective Organo-SOMO Cycloadditions: A Catalytic
Approach to Complex Pyrrolidines from Olefins and Aldehydes
Nathan T. Jui, Jeffrey A. O. Garber, Fernanda Gadini Finelli, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
S
* Supporting Information
ABSTRACT: A new method to rapidly generate
pyrrolidines via a SOMO-activated enantioselective (3 +
2) coupling of aldehydes and conjugated olefins has been
accomplished. A radical-polar crossover mechanism is
proposed wherein olefin addition to a transient enamine
radical cation and oxidation of the resulting radical furnish
a cationic intermediate which is vulnerable to nucleophilic
addition of a tethered amine group. A range of olefins,
including styrenes and dienes, are shown to provide
stereochemically complex pyrrolidine products with high
chemical efficiency and enantiocontrol.
he pyrrolidine ring system is central to a broad range of
T
bioactive natural products,1 is increasingly present in
pharmaceutical agents,2 and recently has become ubiquitous in
catalysis, finding use as organocatalysts as well as ligands for a
wide range of metal-mediated enantioselective protocols.3 Not
surprisingly, this high value heterocyclic framework has become
an attractive target for new reaction invention,4 with (3 + 2)
cycloadditions5 and the aza-Cope Mannich rearrangement6
providing elegant solutions to access stereochemically complex
variants. Recently, we sought to develop a new catalytic
approach to pyrrolidines via the modular combination of β-
amino aldehydes and simple olefins using an enantioselective
SOMO-activation/cycloaddition mechanism. Herein we de-
scribe the successful execution of these ideals and demonstrate
a simple yet powerful pyrrolidine forming reaction that we hope
will be of significant utility to practitioners of medicinal agent
synthesis and asymmetric catalysis.
activation studies,7−12 we presumed that high levels of
enantiocontrol would be achieved on the basis of 3π-electron
geometry control in catalyst−substrate adduct 3 and selective
benzyl group shielding of the radical cation Si-face on the same
system. As an important design criterion, we recognized that
this new pyrrolidine forming reaction should be possible using
readily accessible starting materials, such as simple olefins and
β-amino aldehydes.
Results. As revealed in Table 1, the proposed design plan
was rendered successful via the exposure of a variety of N-
protected β-amino aldehydes to styrene and 2 equiv of
iron(III)trisphenanthroline in the presence of amine catalysts
1 and 2. Notably, high levels of enantiocontrol could be
achieved using various protecting groups on the aldehydic
nitrogen; however, the degree of diastereocontrol ranged from
poor with Cbz to synthetically useful with nosyl (Table 1,
entries 1−5, 62−86% yield, 1.2−6:1 dr, 82−90% ee).
Interestingly, the more electron-withdrawing amine substitu-
ents (Cbz < Ts < Ns) clearly provide increased diastereocon-
Design Plan. Within the past few years, our laboratory has
introduced a new mode of activation termed SOMO-catalysis
that has enabled the direct enantioselective allylic alkylation,7
enolation,8 vinylation,9 nitro-alkylation,10 and carbo-oxidation11
of aldehydes, as well as a new (4 + 2) cycloaddition to generate
complex cyclohexyl rings.12 Recently, we questioned if this
radical-polar crossover mechanism might be employed to
design a (3 + 2) cycloaddition to enantioselectively build
complex pyrrolidine rings.13,14 As outlined in eq 1, we
hypothesized that exposure of β-amino aldehydes to SOMO-
activation using imidazolidinone catalyst 1 and an oxidant
would transiently form the radical cation 3, which should
rapidly engage an olefinic substrate in an enantioselective
coupling to deliver the alkyl radical 4. Oxidative radical-polar
crossover would then furnish a carbocation that should trigger a
stereoselective nitrogen addition−ring closure to deliver a
complex pyrrolidine motif. In accord with previous SOMO-
Received: June 1, 2012
Published: July 5, 2012
© 2012 American Chemical Society
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Communication
Table 1. Effect of Amine Protecting Group and Catalyst
Structure
Table 2. Enantioselective SOMO-Cycloaddition: Styrene
Scope
a b
,
a
b
c
entry
PG
equiv. ald.
cat. (R)
% yield
dr
% ee
1
2
3
4
5
6
Cbz
Boc
Ts
3.0
3.0
3.0
3.0
1.5
1.5
1 (Me)
1 (Me)
1 (Me)
1 (Me)
1 (Me)
2 (Bn)
66
62
86
79
75
77
1.2:1
1.4:1
4:1
82
86
90
90
90
92
Ns
6:1
Ns
6:1
Ns
9:1
a
b
Isolated yield. Determined by 1H NMR analysis of crude reaction or
c
isolated mixture. Determined by chiral HPLC or SFC analysis of
corresponding alcohol; absolute stereochemistry assigned by X-ray
crystal structure or by analogy. Boc = t-butoxycarbonyl, Cbz =
carboxybenzyl, Ts = 4-toluenesulfonyl, Ns = 4-nitrophenylsulfonyl.
trol, suggesting a more ordered (later) transition state with less
nucleophilic tethered amines. Finally, changing the methyl
group of the catalyst 1 to the more traditional benzyl-
substituted imidazolidinone 2 further increased the relative
stereoselectivities (Table 1, entry 6, 92% ee, 9:1 dr), a
significant outcome given the propensity of five-membered ring
cyclizations to be less diastereoselective than their six- and
seven-membered counterparts.15
With the optimized conditions in hand, we next examined
the scope of the olefinic component. As shown in Table 2, a
range of electron-rich (entries 2, 4, and 6, 71−75% yield, 7−
10:1 dr, 89−92% ee) and electron-poor (entries 7 and 8, 61−
81% yield, 5−8:1 dr, 89−91% ee) styrenes are viable in this
new cycloaddition reaction. Moreover, the enantioselectivity
and efficiency are maintained for the o-, m-, and p-
bromostyrenes (entries 1, 3, and 5, 72−76% yield, 93−94%
ee), all useful substrates for further diversification in metal-
catalyzed cross-coupling protocols. To our delight, varying the
olefin substitution pattern is readily achieved. For example, the
use of α-methyl styrene provides tertiary amino substituted
pyrrolidines with excellent enantiocontrol (entry 9, 92% ee)
and in 3:1 diastereocontrol (presumably due to the decreased
preference for a pseudoequatorial phenyl group in the
cyclization transition state). The diastereoselectivity improves
significantly, to >20:1, when using trans-β-methyl styrene to
stereoselectively build the pyrrolidine framework with three
contiguous stereocenters (entry 10, 50% yield, 96% ee).
Given the importance of heteroaryl-substituted pyrrolidines
in medicinal chemistry, we recognized an attractive prospect
might be the replacement of styrene with vinyl heteroaromatics
in this protocol (Table 3). As representative examples, both
benzyl pyrazole (entry 1, 75% yield, 3:1 dr, 91% ee) and
isoxazole (entry 2, 55% yield, 6:1 dr, 95% ee) were successfully
incorporated in this manner. Importantly, this process is not
limited to vinyl arenes. A full range of electron-neutral dienes
were also competent in this transformation (entries 3−6, 62−
85% yield, 1.5−4:1 dr, 87−92% ee), forming both bicyclic
structures and fully substituted carbon stereocenters. Enantio-
selectivities and yields remained high in all cases; however,
diasterocontrol was observed to be moderate relative to other
olefinic substrates.
a
Results listed as product, yield, diastereomeric ratio (dr),
b
enantiomeric excess (% ee). Diastereomeric ratio, % ee determined
as in Table 1. Reaction conducted at −20 °C using THF and
Fe(phen)3(PF6)3.
c
Finally, the use of indene as the π-coupling partner (eq 2)
allows the production of unique tricyclic pyrrolidines in high
yield and diastereoselectivity (75% yield, 9:1 dr, 85% ee).
Perhaps even more notable, the use of optically active β-methyl
β-amino aldehydes has enabled the construction of all four
carbon stereocenters on the pyrrolidine ring while achieving
excellent levels of diastereocontrol (eqs 3 and 4, 65−66% yield,
≥99% ee, 5−19:1 dr). Importantly, in these cases catalyst
control appears to dominate for the formation of the formyl-
bearing stereocenter, as well as the amine−carbocation
cyclization event. As a result, various pyrrolidine isomers can
be formed enantioselectively via the judicious choice of
substrate and catalyst antipodes.
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Communication
feature, the starting materials and catalysts are commercial
materials or easily prepared, allowing rapid and modular
production of a variety of pyrrolidine cores. We anticipate that
this transformation will be valuable for catalyst development,
natural product synthesis, and in the identification of new
medicinal agents. Given this conceptual advance, future work
will focus on the development of alternative oxidants of lower
molecular weight for this protocol.
Table 3. Enantioselective Cascade Cycloaddition: Olefin
Scope
a b
,
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, structural proofs, and spectral data
for all new compounds are provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
dmacmill@princeton.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
F.G.F. thanks CNPq-Brazil for a postdoctoral fellowship. N.T.J.
thanks Bristol-Myers Squibb for a graduate fellowship. Financial
support was provided by NIHGMS (R01 01 GM078201-06),
and kind gifts were provided by Merck, Amgen, and Abbott.
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