Enantioselective organo-singly occupied molecular orbital catalysis: The carbo-oxidation of styrenes

Article abstract of DOI:10.1021/ja8075633

The first enantioselective organocatalytic carbo-oxidation of styrenes has been accomplished using singly occupied molecular orbital (SOMO) catalysis. Geometrically constrained radical cations are generated from the one-electron oxidation of enamines formed from the condensation of aldehydes with a secondary amine catalyst. These SOMO-activated radical cations are susceptible to attack by commercially available styrenes, forming γ-oxyaldehyde products with uniformly high levels of asymmetric induction. Broad latitude in both the aldehyde and styrene scope is readily tolerated. This report highlights the potential of SOMO catalysis to enable the development of entirely new classes of asymmetric reactions that have no traditional catalytic equivalents. Copyright

Full text of DOI:10.1021/ja8075633

Published on Web 11/17/2008
Enantioselective Organo-Singly Occupied Molecular Orbital Catalysis: The
Carbo-oxidation of Styrenes
Thomas H. Graham, Casey M. Jones, Nathan T. Jui, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton UniVersity, Princeton, New Jersey 08544
Received September 23, 2008; E-mail: dmacmill@princeton.edu
Table 1. Organocatalytic Carbo-oxidation: Aldehyde Scope
A critical objective for the continued advancement of the field
of asymmetric catalysis is the design and implementation of novel
activation modes that allow the invention of unprecedented trans-
formations.1 Recently, our laboratory introduced a new mode of
organocatalytic activation, termed (singly occupied molecular
orbital) SOMO catalysis,2 that is founded upon the transient
production of a 3π-electron radical-cation3 species that can function
as a generic platform of induction and reactivity. As part of these
studies, we documented the first direct and enantioselective allylic
alkylation,2 enolation,4 and vinylation5 of aldehydes, three protocols
that were not previously known in a chiral or achiral format.
Continuing this theme, we recently questioned whether feedstock
olefins, such as styrenes, might be exploited in this SOMO pathway
to allow the enantioselective R-homobenzylation of aldehydes, a
new C-C bond-forming reaction between functional groups that
are generally inert to chemical combination. In this context, we
disclose the first asymmetric SOMO-catalyzed carbo-oxidation of
styrenes to provide γ-nitrate-R-alkyl aldehydes, a valuable synthon
for the production of enantioenriched butyrolactones, pyrrolidines,
and R-formyl homobenzylation adducts. Most important, this new
organo-SOMO reaction allows simple styrenes to function as
R-alkylation partners for aldehydes, a transformation that to our
knowledge is without precedent.6
entry
R
% yield
anti:syn
% eea, b
1
2
3
4
5
6
hexyl
cyc-hexyl
91
88
94
81
90
82
3:1
3:1
3:1
3:1
3:1
2:1
96
96
96
96
95
94
(CH2)6C≡CEt
Bn
(CH2)3OBn
4-N-BOC piperidinyl
a Enantiomeric excess determined by chiral HPLC or SFC analysis.
b Stereochemistry assigned by single crystal X-ray analysis or analogy.
3π-electron system away from the bulky tert-butyl group, while the
carbon-centered radical will selectively populate an (E)-configuration
to avoid nonbonding interactions with the catalyst framework. More-
over, the calculated structure of DFT-2 reveals that the methyl group
on the catalyst system will effectively shield the Si-face of the SOMO-
activated π-system, leaving the Re-face exposed to styrene addition.
Design Plan. In our previous SOMO catalysis studies, we exploited
the capacity of the aldehyde-derived radical cation DFT-27 to rapidly
engage electron-rich olefins that incorporate traceless activation handles
(e.g., enolsilanes, allylsilanes, vinyl trifluoroborate salts).2,4,5 A com-
mon mechanistic feature of these coupling reactions is the transient
production of a ꢀ-silyl or ꢀ-borato cation intermediate that can
regioselectively collapse to render an olefinic or carbonyl containing
product. With this in mind, we questioned whether a simple, nonac-
tivated olefin, such as styrene, might also undergo addition to the radical
cation DFT-2 to form a benzylic radical 3 that upon further oxidation
will generate a similar carbocation 4 (eq 1). As a key design element,
the benzylic cation 4 cannot readily participate in an E1 elimination
mechanism (the salient pathway of our previous studies) as the styrene
precursor does not incorporate a ꢀ-activation/leaving group. Instead
we hoped to capture the value of this high energy intermediate via
intermolecular addition of an anionic or neutral heteroatom addend
(e.g., NO3-, Cl-, H2O), a step that would create a second stereogenic
center while increasing the relative molecular complexity of the
alkylation product. In accord with our previous studies, we expected
high levels of enantiocontrol on the basis that catalyst 1 should
selectively form a SOMO-activated cation 2 (DFT-2) that projects the
The proposed enantioselective R-formyl homobenzylation was first
examined using octanal and styrene, with imidazolidinone 1 as the
SOMO catalyst and ceric ammonium nitrate (CAN)8 as the stoichio-
metric oxidant (Table 1, entry 1). Notably, the desired aldehyde
R-alkylation was successful along with intermolecular trapping of the
putative cation 4 by the nitrate anion arising from reduction of the
Ce(IV) oxidant. Indeed, the resulting homoaldol-type product was
formed in excellent yield and enantioselectivity, while diastereocontrol
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16494 J. AM. CHEM. SOC. 2008, 130, 16494–16495
10.1021/ja8075633 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Organocatalytic Carbo-oxidation: Scope of the Styrene
the benzylic nitrate ester without reduction of the aldehyde moiety or
loss in enantiopurity (eq 2).9 This mild two-stage protocol allows the
enantioselective R-homobenzylation of aldehydes using a variety of
styrenyl substrates (eq 2, 82-92% yield, g91% ee). Second, the nitrate
ester products can be utilized for the rapid construction of enantioen-
riched heterocyclic rings (eqs 3-6). For example, in situ treatment
with sodium borohydride leads directly to tetrahydrofuran products,10
while a reductive amination sequence using allylamine provides rapid
access to optically active pyrrolidines. While direct oxidation of the
aldehyde moiety provides the corresponding trans-γ-lactone, the
enantioenriched cis-γ-lactone can be accessed via zinc reduction to
the corresponding lactol and subsequent oxidation.11 Notably, the
stereochemical purity of the carbo-oxidation adducts is retained in all
of these ring forming steps and the resulting heterocycles are readily
isolated in isomerically pure form.12
a The benzylic stereocenter was formed in all cases with 3:1 R,γ-anti
diastereocontrol. b Values of ee determined by SFC or HPLC analysis.
c Stereochemistry assigned by X-ray analysis or by analogy. d With
trans-ꢀ-methyl styrene, dr ) 6:1 R,ꢀ-syn. e With cis-ꢀ-methyl styrene,
dr ) 4:1 R,ꢀ-anti.
Acknowledgment. Financial support was provided by the NIH-
GMS (R01 GM078201-01-01) and kind gifts from Merck.
for the cation trapping step was moderate (∼75:25 anti:syn). As
revealed in Table 1, substantial variation in the steric contribution of
the aldehyde component is possible (entries 1, 2 and 6, R ) n-hexyl,
cyc-hexyl, 4-piperidinyl, 82-91% yield, 94-96% ee). Moreover, a
variety of functionalities appear to be inert to these mild oxidative
conditions including alkynes, aryl rings, ethers, and carbamates (entries
3-6, 81-94% yield, 94-96% ee).
As highlighted in Table 2, a wide array of styrenes readily participate
as SOMOphiles in this new catalytic carbo-oxidation (entries 1-10).
For example, electron-rich and electron-deficient styrenes are readily
tolerated (entries 1-8, 88-95% yield, 92-97% ee). Notably, the
implementation of ꢀ-substituted styrenes in this coupling reaction
allows the stereospecific formation of carbo-oxidation products that
incorporate three stereogenic centers. As exemplified in Table 2, the
use of trans-ꢀ-methyl styrene allows selective formation of the
syn-anti stereochemical triad (entry 9, 6:1 dr, 94% ee), while the cis-
ꢀ-methyl styrene leads to the corresponding anti-syn isomer (entry
10, 4:1 dr, 89% ee).
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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(6) It is important to note that a noncatalytic, non-enantioselective intermo-
lecular alkylation of malonate esters using styrene has been accomplished
under oxidative conditions: Citterio, A.; Sebastiano, M.; Nicolini, R.; Santi,
R. Synlett 1990, 42.
(7) DFT calculations performed using B3LYP/6-311+G(2d,p)//B3LYP/6-
31G(d) (see ref 2).
(8) Nair, V.; Deepthi, A. Chem. ReV. 2007, 107, 1862.
(9) (a) Auricchio, S.; Ricca, A. Tetrahedron 1987, 43, 3983. (b) Baldwin, S. W.;
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(10) Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
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(12) We were unable to separate the nitrate ester diastereomeric adducts prior
to heterocyclic ring formation.
The utility of this new enantioselective carbo-oxidation and the
accompanying γ-nitrate-R-alkyl aldehyde products is highlighted in
eqs 2-6. First, we have found that the crude product of our SOMO
catalysis step can be subjected to hydrogenation to selectively cleave
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