Enantioselective organocatalytic singly occupied molecular orbital activation: The enantioselective α-enolation of aldehydes

Article abstract of DOI:10.1021/ja0719428

The first enantioselective organocatalytic ∞-enolation of aldehydes has been accomplished using singly occupied molecular orbital (SOMO) catalysis. Chiral secondary amines react with aldehydes to form transient enamines that undergo selective one-electron

Full text of DOI:10.1021/ja0719428

Published on Web 05/12/2007
Enantioselective Organocatalytic Singly Occupied Molecular Orbital
Activation: The Enantioselective r-Enolation of Aldehydes
Hye-Young Jang,† Jun-Bae Hong, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton UniVersity, Princeton, New Jersey 08544, and DiVision of Chemistry and
Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received March 19, 2007; E-mail: dmacmill@princeton.edu
Over the last 40 years, thousands of asymmetric catalytic reac-
tions have been invented in accord with the increasing need for
enantiopure medicinal agents and the rapid advancement of the field
of chemical synthesis.1 Remarkably, however, the vast majority of
these enantioselective processes are derived from a small number
of long-established activation modes (e.g., Lewis acid catalysis,2
σ-bond insertion,3 π-bond insertion,4 atom-transfer catalysis,5 and
hydrogen-bonding catalysis6). A critical objective, therefore, for
the continued advancement of the field of asymmetric catalysis is
the design and implementation of novel activation modes that enable
the invention of unprecedented transformations. Recently, our labor-
atory introduced a new mode of organocatalytic activation, termed
singly occupied molecular orbital (SOMO) catalysis,7-9 that is
founded upon the mechanistic hypothesis that one-electron oxidation
of a transient enamine intermediate (derived from aldehydes and
chiral amine catalysts) will render a 3π-electron SOMO-activated
species that can readily participate in a range of unique asymmetric
bond constructions.10 In our original SOMO studies,7 we docu-
mented the first direct and enantioselective allylic alkylation of
aldehydes (eq 1). In this Communication, we further advance this
activation concept to describe the first asymmetric aldehyde
R-enolation, a protocol that allows direct access to enantioenriched
γ-ketoaldehydes from simple aldehydes, enolsilanes and a com-
mercial catalyst (eq 2).
form a SOMO-activated cation (DFT-2) that projects the 3π-electron
system away from the bulky tert-butyl group, while the carbon-
centered radical will selectively populate an (E)-configuration to
minimize nonbonding interactions with the imidazolidinone ring.
In terms of enantiofacial discrimination, the calculated structure
of DFT-2 reveals that the benzyl group on the catalyst system will
effectively shield the Re-face of the radical cation, leaving the Si-
face exposed to enolsilane addition.
Our enantioselective organocatalytic SOMO enolation was first
evaluated using enolsilane 3, imidazolidinone catalyst 1, and a series
of R-substituted aldehydes (Table 1, eq 3). Initial investigations
revealed that the introduction of 2 equiv of the oxidant ceric
Table 1. Organocatalytic Enolation: Scope of the Aldehyde
Substrate
Design Plan. We proposed that condensation of imidazolidinone
catalyst 1 with a simple aldehyde (e.g., propanal) in the presence
of a suitable oxidant should provide the putative radical cation 2.
Addition of an accompanying enolsilane to the R-position of 2
would then render an R-OTMS carbon-centered radical that should
rapidly participate in a second oxidation event11 to generate an
oxocarbenium ion that, upon hydrolysis of the silyl group, will
furnish the requisite R-substituted-γ-ketoaldehyde. On the basis of
DFT calculations12 we proposed that catalyst 1 should selectively
† Ajou University, Suwon, Korea.
a Enantiomeric excess determined by chiral SFC analysis.
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C O M M U N I C A T I O N S
Table 2. Organocatalytic Enolation: Scope of the Enolsilane
Substrate
asymmetric induction observed in all cases (Tables 1 and 2) is
consistent with addition of the enolsilane to the Si-face of the radical
cation 2, in complete accord with the calculated structure DFT-2.
Last, we have observed that the capacity of the putative radical
cation species to undergo intermolecular enolation is dramatically
superior to that of intramolecular cyclohexyl ring formation with
π-neutral olefins (cf. eqs 5 and 6). This finding again demonstrates
the remarkable ability of electron deficient radical cations to
participate in highly chemoselective transformations, a mechanistic
feature not traditionally associated with radical activation.
In summary, the first enantioselective organocatalytic R-enolation
of aldehydes has been accomplished using SOMO catalysis. Further
applications of this new organocatalytic activation mode will be
reported shortly.
Acknowledgment. Financial support was provided by the
NIHGMS (Grant R01 GM078201-01-01) and kind gifts from
Amgen and Merck. Robert A. Pascal is thanked for his assistance
in carrying out DFT calculations.
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
a Enantioselectivity determined by GLC or SFC analysis. b Stereochem-
istry assigned by chemical correlation or by analogy. c Performed in acetone.
d Performed at -50 °C.
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(7) Beeson, T. D.; Mastracchio, A.; Hong, J. B.; Ashton, K.; MacMillan, D.
W. C. Science 2007, 316, 582.
(8) The studies outlined in this manuscript were first described in a NIH
submission to SBCA October 1st, 2005 and reported widely by D.W.C.M.
in public presentations including the following: March 31st, Amgen,
Thousand Oaks, CA; April 27th, 2006, Manchester U.K.; June 13th, 2006,
IUPAC, Merida, Mexico; July 25th, 2006 IUPAC Kyoto, Japan; Sept 11th,
2006, ACS, San Francisco, CA.
ammonium nitrate (CAN), 2 equiv of H2O and 2 equiv of 2,6 di-
tert-butyl pyridine (DTBP) is necessary to achieve high levels of
enantioselectivity and reaction efficiency.13 As revealed in Table
1, variation in the steric contribution of the radical cation substituent
(R ) hexyl, cyc-hexyl, 4-piperdyl entries 1, 3, and 6) is pos-
sible without substantial loss in yield or enantiocontrol (74-85%
yield, 90-95% ee). Moreover, a variety of chemical functionalities
appear to be inert to these mild oxidative conditions including
olefins, aryl rings, and carbamates (entries 2, 4, and 6, 77-92%
yield, 91-95% ee).
As highlighted in Table 2, a wide array of π-rich enolsilanes
will readily participate as somophiles in this new catalytic enolation
protocol (entries 1-8). For example, alkyl, vinyl, and aryl substi-
tuted silyl enolethers can be tolerated without loss in reaction
efficiency or enantiocontrol (entries 1-8, 55-85% yield, 86-96%
ee). Moreover, significant latitude in the steric demand of the somo-
philic substituent can be accommodated (entry 7, R ) Me, 67%
yield, 86% ee; entry 8, R ) t-Bu, 55% yield, 92% ee). Interestingly,
the incorporation of bulky silyl groups to prevent substrate hydroly-
sis (in the case of alkyl substituted enolsilanes) provides slightly
higher enantioselectivities.14 Perhaps most striking, electron rich
heteroaromatic systems that are often susceptible to mild oxidants
are compatible with these organocatalytic conditions (entries 2-3,
70-77% yield, g92% ee). It is important to note that the sense of
(9) For prior work related to the chemistry of oxidized enamines, see: (a)
Chiba, T.; Okimoto, H.; Hamaguchi, H.; Imanishi, T.; Yoshida, K. J. Org.
Chem. 1979, 44, 3519. (b) Cossy, J.; Bouzide, A.; Leblanc, C. Synlett
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1993, 1218.
(10) Shortly before submission of this manuscript, studies on the R-oxidation
of radical cations with moderate enantioselectivity were reported, see:
Sibi, M.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124.
(11) Narasaksa, K.; Okauchi, T.; Tanaka, K.; Murakami, M. Chem. Lett. 1992,
2099.
(12) DFT calculations performed using B3LYP/6-311+G(2d,p)//B3LYP/
6-31G(d).
(13) The use of alternative bases (NaHCO3, Na2CO3, pyridine) or lower
equivalents of oxidant or H2O resulted in useful levels of enantio-selectivity
(g90% ee) but diminished yields (25-68% yield). Products arising from
enamine-aldehyde aldol were not observed in this study.
(14) The use of TMS enolethers in Table 2, entries 7 and 8, provides the
corresponding products in 39% yield, 73% ee and e10% yield, 0% ee.
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