Enantioselective organo-SOMO catalysis: The α-vinylation of aldehydes

Article abstract of DOI:10.1021/ja077212h

The first enantioselective organocatalytic α-vinylation of aldehydes has been accomplished. Selective oxidation of chiral enamines, derived from the condensation of aldehydes and a chiral secondary amine catalyst, leads to the production of highly reactive radical cations that exist in an asymmetric environment. These SOMO-activated species undergo direct coupling with readily available potassium organotrifluoroborate salts to yield enantioenriched α-vinyl aldehydes. The described reaction procedure achieves carbon-carbon bond formation in an efficient manner with consistently high levels of enantioinduction and geometrical control for the trans-olefin product. A wide range of both aldehydes and potassium organotrifluoroborate salts, including those typically susceptible to oxidative conditions, are accommodated under the reaction conditions. Results herein further demonstrate the capacity of the SOMO catalysis platform to achieve asymmetric carbon-carbon bond formations that are difficult to access via traditional methods. Copyright

Full text of DOI:10.1021/ja077212h

Published on Web 12/21/2007
Enantioselective Organo-SOMO Catalysis: The r-Vinylation of Aldehydes
Hahn Kim and David W. C. MacMillan*
Merck Center for Catalysis at Princeton UniVersity, Princeton, New Jersey 08544
Received September 17, 2007; E-mail: dmacmill@princeton.edu
Table 1. Organocatalytic Vinylation: Scope of Aldehyde Substrate
The catalytic union of nascent enolates with aryl or vinyl coupling
partners has become a mainstay transformation in organic synthesis,
primarily driven by advances in transition metal chemistry.1 In
particular, the seminal work of Buchwald and Hartwig has provided
a number of enantioselective enolate R-arylations that enable
quaternary carbon formation directly adjacent to both ketone and
lactone moieties.2 Surprisingly, however, the asymmetric R-viny-
lation of enolates has been slow to develop and thus far is restricted
to the production of stereogenicity that cannot epimerize or be
destroyed via olefin isomerization to an R,â-unsaturated product.3
Recently, our laboratory introduced a new mode of organocatalytic
activation, termed SOMO catalysis, that is founded upon the
mechanistic hypothesis that one-electron oxidation of a transient
enamine intermediate (derived from aldehydes and chiral amine
catalyst 1) will render a 3π-electron SOMO-activated species 2 that
can readily participate in a range of unique asymmetric bond
constructions (eq 1).4 In this communication, we demonstrate that
organo-SOMO catalysis has been successfully exploited to achieve
the first asymmetric R-vinylation of aldehydes using vinyl trifluo-
roborate salts and a commercial amine catalyst. Notably, these mild
catalytic conditions allow the production of R-formyl, R-vinyl,
methine stereogenic centers without olefin transposition or subse-
quent erosion in enantiopurity.
a Stereochemistry assigned by chemical correlation or by analogy. b Only
(E)-olefin isomer observed by 1H NMR (400 MHz). c Isolated yield of the
corresponding alcohols. d Enantiomeric excess determined by chiral SFC
analysis.
and regioselective carbon-carbon bond formation with DFT-2 to
form a â-borato-stabilized radical 3 (eq 2), which in the presence
of a suitable oxidant will undergo rapid electron transfer to render
the â-cation 4. Subsequent Peterson elimination7,8 of the trifluo-
roborate group with trans-selectivity followed by iminium hydroly-
sis would then reveal an optically enriched R-(E)-vinyl aldehyde.
Central to this design plan, we anticipated that our imidazolidinone
catalyst would be inert to enamine formation with the R-vinyl
aldehyde product, an essential criterion if we hoped to preclude
product epimerization, olefin conjugation, and bisvinylation path-
ways. In terms of enantiocontrol, we presumed that the activated
radical DFT-2 would position the 3π-electron system away from
the bulky tert-butyl group, while adopting an (E)-configuration to
minimize nonbonding interactions. In this topography, the benzyl
group on the imidazolidinone framework effectively shields the Re
face leaving the Si face exposed toward asymmetric bond formation.
Our organocatalytic SOMO vinylation was first evaluated using
potassium styryltrifluoroborate, imidazolidinone catalyst 1, and a
series of R-substituted aldehydes (Table 1, eq 3).9 Initial optimiza-
tion experiments revealed that high levels of enantiocontrol, trans-
olefin selectivity, and reaction efficiency are possible when the
reaction is performed in DME using 2.5 equiv of oxidant (ceric
ammonium nitrate (CAN)), 4.0 equiv of H2O, and 2.0 equiv of
sodium bicarbonate (NaHCO3). As summarized in Table 1, these
mild oxidative conditions are tolerated by a wide range of functional
groups including aromatic rings, olefins, benzyl ethers, and car-
bamates (entries 2, 4-6, 76-79% yield, 93-96% ee). Moreover,
the steric demands of the aldehyde substrate have little influence
Design Plan. In our previous reports,4 we advocated that the
aldehyde-derived radical cation DFT-25 should function as a generic
platform of induction and reactivity for a variety of unprecedented
transformations. Continuing this theme, we hypothesized that vinyl
potassium trifluoroborate salts6 should readily participate in enantio-
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10.1021/ja077212h CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Vinyl Potassium Trifluoroborate Salt
Scheme 1. Aldehyde-1,2-Bisvinylation Anionic Oxy-Cope Strategy
step) conversion of simple aldehydes to enantioenriched oxy-Cope
products.10 As highlighted in Scheme 1, exposure of octanal to our
asymmetric olefin coupling followed by in situ vinyl Grignard
addition provided the corresponding 1,5-dienyl alcohol in good yield
but with no diastereocontrol (6, anti/syn 1:1). Subsequent exposure
of this isomeric mixture to Evans’ anionic oxy-Cope protocol,
however, allows rapid and stereoconvergent [3,3]-rearrangement
to provide the quaternary carbon-bearing aldehyde 7 with complete
enantioretention (94% ee) and as a single diastereomer.11 Given
that oxy-Cope substrates are typically produced via the allylation
of R,â-unsaturated aldehydes, we present this new operationally
simple aldehyde 1,2-bisvinylation sequence as an alternative oxy-
Cope retron.
Last, the sense of enantioinduction for all cases presented is in
complete accord with our calculated model DFT-2. To our
knowledge, this is (i) the first enantioselective catalytic R-vinylation
of aldehydes and (ii) the first use of boron salts as coupling reagents
for radical-based processes. Full details of this organo-SOMO
catalysis technology will be forthcoming.
Acknowledgment. Financial support was provided by the
NIHGMS (R01 GM078201-01-01) and kind gifts from Merck and
Amgen. H.K. thanks NIHGMS/NCI for a postdoctoral fellowship
(1F32 CA128210-01). The authors thank Sandra Lee for the
preparation of BF3K substrates.
Supporting Information Available: Experimental procedures and
spectral data are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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a Solvent: entries 1-6 ) DME; entries 7-10 ) acetone. b Stereochem-
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(5) Performed using B3LYP/6-311+G(2d,p)// B3LYP/6-31G(d). See ref 4a.
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on yield or enantiocontrol (X ) c-hexyl, 4-piperidinyl, entries 3
and 6, 76-82% yield, 96% ee).
As revealed in Table 2, an extensive range of trifluoroborate
coupling partners are suitable for this enantioselective vinylation
protocol (eq 4).9 For example, para-substituted styryl systems that
incorporate electron-donating, -withdrawing, or -neutral groups
undergo addition with near identical selectivities (entries 1-5, 61-
81% yield, 92-95% ee). Furthermore, trisubstituted olefins can be
successfully utilized with stereoselective formation of the trans-
geometrical isomer (entry 6, 93% yield, 94% ee). Perhaps most
important, this technology can produce γ-alkyl-substituted â,γ-
unsaturated aldehydes without olefin isomerization to the R,â-
conjugated adduct, a true testament to the mild reaction conditions
that are operable in this organocatalytic process (entries 7-9, 71-
84% yield, 89-91% ee).
(7) Elimination of boron via a â-radical intermediate (e.g., 3, eq 2) is a highly
endothermic pathway and thereby presumed unlikely; see: Walton, J. C.;
McCarroll, A. J.; Chen, Q.; Carboni, B.; Nziengui, R. J. Am. Chem. Soc.
2000, 122, 5455.
(8) Kano, N.; Kawashima, T. In Modern Carbonyl Olefination; Takeda, T.,
Ed; Wiley-VCH: Weinheim, Germany, 2004; Chapter 2.
(9) All products were characterized as the corresponding alcohols after NaBH4
reduction. See Supporting Information for details.
(10) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765.
(11) Only the major diastereomer was observed by 1H NMR (400 MHz).
A demonstration of the utility of this organocatalytic vinylation
and the accompanying products is presented in the two-stage (three-
JA077212H
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