Direct Enantio- and Diastereoselective Oxidative Homocoupling of Aldehydes

Article abstract of DOI:10.1002/chem.201803506

A novel strategy for the direct enantioselective oxidative homocoupling of α-branched aldehydes is presented. The methodology employs open-shell intermediates for the construction of chiral 1,4-dialdehydes by forming a carbon–carbon bond connecting two quaternary stereogenic centers in good yields and excellent stereoselectivities for electron-rich aromatic aldehydes. The 1,4-dialdehydes were transformed into synthetically valuable chiral pyrrolidines. Experimental mechanistic investigations based on competition experiments combined with computational studies indicate that the reaction proceeds through a radical cation intermediate and that reactivity and stereoselectivity follow different trends.

Full text of DOI:10.1002/chem.201803506

A Journal of
Accepted Article
Title: Direct Enantio- and Diastereoselective Oxidative Homo-Coupling
of Aldehydes
Authors: Karl Anker Jørgensen, Line Næsborg, Lars Astrup Leth,
Gabriel José Reyes-Rodríguez, Teresa Ann Palazzo, and
Vasco Corti
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To be cited as: Chem. Eur. J. 10.1002/chem.201803506
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Direct Enantio- and Diastereoselective Oxidative Homo-Coupling
of Aldehydes
Line Næsborg, Lars A. Leth, Gabriel J. Reyes-Rodríguez, Teresa A. Palazzo, Vasco Corti, and Karl
Anker Jørgensen*[a]
Abstract: A novel strategy for the direct enantioselective oxidative
homo-coupling of -branched aldehydes is presented. The
methodology employs open-shell intermediates for the construction of
chiral 1,4-dialdehydes by forming a carbon-carbon bond connecting
two quaternary stereogenic centers in good yields and excellent
stereoselectivities for electron-rich aromatic aldehydes. The 1,4-
dialdehydes have been transformed into synthetically valuable chiral
pyrrolidines. Experimental mechanistic investigations based on
competition experiments combined with computational studies
carbons. Strategies for the stereoselective generation of such
carbon-carbon bonds are underdeveloped. Literature cites a
variety of reasons for this including steric repulsion and the
difficulties in selectively activating coupling partners.[2]
We envisioned a concept based on the direct coupling of -
branched aldehydes for the stereoselective construction of vicinal
quaternary stereocenters in succinic 1,4-dialdehydes. An open-
shell species of a catalytically generated enamine intermediate
was anticipated to overcome the immense energetic hill required
to form the bond connecting two quaternary stereogenic
centers.[8] Herein, we disclose the first oxidative organocatalytic
strategy for the diastereo- and enantioselective coupling of -
branched aldehydes (Scheme 1b).
indicate that the reaction proceeds through
a radical cation
intermediate and that reactivity and stereoselectivity follow different
trends.
The oxidative organocatalytic concept relies on an aldehyde
condensing with an aminocatalyst forming enamine I, which is
oxidized to generate radical cation I’. Intermediate I’ is proposed
to stereoselectively react with enamine-nucleophile I constructing
a carbon-carbon bond (Scheme 1b). In the following, we present
the development and scope of the catalytic -coupling of -
branched aldehydes affording enantioenriched 1,4-dialdehydes
with vicinal quaternary carbons, and their transformation into
Introduction
The direct stereoselective -coupling of two carbonyl moieties
into chiral 1,4-dicarbonyl compounds is a challenge due to the
dual nucleophilicity of the reacting species and has, according to
our knowledge, not been achieved. Indirect carbon-carbon
couplings have traditionally been performed by oxidation of pre-
formed enolates.[1] This elegant approach has been pursued by
Baran et al. in the coupling of e.g. oxazolidinones and oxindoles
with ketones applying LDA with copper(II) or iron(III).[2]
Furthermore, Thomson et al. disclosed a related oxidative
coupling of cyclic ketones via silyl-bis-enol ethers.[3] These
synthetically
valuable
chiral
pyrrolidines.
Mechanistic
investigations via competition experiments and computational
studies were carried out to obtain information about the reactivity
and selectivity of the presented methodology.
reactions
generated
racemic
products
with
low
diastereoselectivitities and moderate yields. To further investigate
7
these reactions Flowers et al. applied Li NMR to elucidate the
mechanism for the oxidative coupling of lithium enolates.[4] Finally,
Hirao et al. demonstrated that oxo-vanadium(V) induces coupling
between boron- and silyl-enolates.[5]
Aldehydes are a cornerstone of organocatalysis which have
been applied in HOMO and LUMO attenuating strategies and
extended to SOMO activation via single-electron transfer (SET)
using various oxidants.[6] Of particular interest, MacMillan et al.
reported an oxidative -coupling of aldehydes between an
enamine-based radical cation and a pre-formed silyl-enol ether
(Scheme 1a).[7]
An important aspect of the -coupling of aldehydes is the
potential for stereoselective construction of vicinal quaternary
Scheme 1. (a) Organocatalytic -coupling of aldehydes with silyl-enol
ethers; (b) direct organocatalytic -coupling of aldehydes mediating
the construction of vicinal quaternary stereogenic centers.
[a]
L. Næsborg, L. A. Leth, Dr. G. J. Reyes-Rodríguez, Dr. T. A.
Palazzo, V. Corti, Prof. K. A. Jørgensen
Department of Chemistry,
Results and Discussion
Aarhus University
8000 Aarhus (Denmark)
E-mail:kaj@chem.au.dk
Recently, we reported that -unsaturated aldehydes undergo
stereoselective -couplings in the presence of Cu(II), an
aminocatalyst, and air (O2) as terminal oxidant.[9] Under these
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conditions linear aldehydes afford a product containing a carbon-
carbon double bond connecting the two aldehydes.[10]
These optimized reaction conditions were used to investigate a
representative scope of the enantioselective homo-coupling of -
branched aldehydes (Table 2).
Encouraged by the observed reactivity, we envisioned that -
branched aldehydes might circumvent double-bond formation,
allowing for the formation of vicinal quaternary carbons in a
stereoselective manner. Subjecting 2-(6-methoxynaphthalen-2-
yl)propanal 1a to air/Cu(II)[9] provided 1-(6-methoxynaphthalen-2-
yl)ethan-1-one as an oxidative byproduct (Table 1, entry 1). To
avoid this undesired reaction, a search for different conditions was
initiated applying Ag2CO3 as the oxidant with various
aminocatalysts (entries 2-4). Employing Ag2CO3 increased
conversion to 1,4-dialdehyde 3a, and catalyst 2 led to superior
yields and stereoselectivities. A short screening of metal salts
revealed that Ag2CO3 was the optimal oxidant (entries 5, 6).
Introduction of 4-NO2-PhCO2H (150 mol%) led to a dramatic
increase of yield and stereoselectivity (entry 7). If lower loadings
of 4-NO2-PhCO2H were employed, an increased amount of the
oxidative byproduct 1-(6-methoxynaphthalen-2-yl)ethan-1-one
was observed. Control experiments in the absence of
aminocatalyst or Ag2CO3 displayed no reactivity (entries 8, 9).
This screening revealed that Ag2CO3 displayed the best oxidative
properties and in combination with aminocatalyst 2 (20 mol% per
equiv. of 1a) afforded 3a in the presence of 4-NO2-PhCO2H in
CH2Cl2.
Table 2. Organocatalytic enantioselective oxidative homo-coupling of
α-branched aldehydes.[a]
[a] Reactions were performed on a 0.1 mmol scale. Diastereomeric ratio (d.r.)
determined by 1H NMR after FC. Enantiomeric excess (ee) determined by a
chiral stationary phase UPC2. Absolute stereochemistry determined by analogy
to X-ray crystallography analysis of 4c∙HBr (vide infra).
Table 1. Screening results for the oxidative homo-coupling of -
branched aldehyde 1a.
Table 2 demonstrates that the stereoselective -coupling of
electron-rich aromatic aldehydes proceeds smoothly. Reaction of
an aldehyde carrying a methoxy-naphthyl moiety 1a provided 3a
in 78% yield and excellent stereoselectivity (92% ee, 12:1 d.r.). It
should be noted that the minor diastereoisomer is the meso-
product. Comparable results were obtained for the naphthyl
substituted aldehyde 1b. Aldehydes with methoxy-phenyl
substituents (1c,d) provided the -coupled products 3c,d in
similar yields and stereoselectivities. We were pleased to observe
that 3e was obtained in 75% yield, 94% ee and 5:1 d.r. despite
possible incompatibilities of the thioether due to potential
oxidation events.[11] Furthermore, the reaction of 2-(p-
tolyl)propanal 1f afforded 3f in 63% yield, 94% ee and 5:1 d.r. The
results in entries 3g-i reflect that electron-poor aromatic
aldehydes are less suited for this oxidative homo-coupling as they
display lower yields and stereoselectivities.
To demonstrate the synthetic potential of the 1,4-dialdehydes 3
obtained from this stereoselective coupling, reductive aminations
of 3a-c were performed (Table 3). Reaction of 3a-c with (S)-1-
phenylethan-1-amine provided the corresponding pyrrolidines 4a-
c. This class of interesting pyrrolidine core structures has been
applied as ligands and catalysts in methodology development.[12]
Additionally, pyrrolidines are privileged heterocycles in bioactive
molecules.[13]
Acid
Entry
Oxidant
Conv. (%) d.r. ee (%)
(mol%)
1[a],[b]
2[b]
3[c]
4
0
0
Cu(OAc)2/air
Ag2CO3
4
1:1
1:1
1:1
2:1
2:1
-
-
46
0
90
0
Ag2CO3
89
0
Ag2CO3
96
60
>99
-
[d]
5
0
AgNO3
27
[d]
6
0
FeCl3
0
7[e]
8[f]
9
150
150
150
Ag2CO3
Ag2CO3
-
>95 (78)
7:1
-
92
-
0
0
-
-
Reactions were carried out on a 0.05 mmol scale with 2.0 equiv. of 1a and 40
mol% of the aminocatalyst 2 (it should be noted that this corresponds to 20
mol% per equiv. of aldehyde) in 0.4 mL of solvent. Isolated yield is given in
brackets. Diastereomeric ratios are measured in the crude 1H NMR. [a]20 mol%
Cu(OAc)2 was employed in an open-air system.[b]The catalyst 2’was employed.
[c] L-Proline was employed as catalyst. [d] 3 equiv. of metal salt used. [e]
Reactions were carried out on a 0.1 mmol scale. [f] Control experiment
performed in the absence of organocatalyst.
Table 3. Reductive amination of homo-coupling products 3a-c for the
formation of chiral pyrrolidines 4a-c.[a]
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10.1002/chem.201803506
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react with enamine I providing adduct II, from which the 1,4-
dialdehyde 3 is formed by subsequent SET-oxidation by Ag(I) and
hydrolysis. It is also possible that an enol species reacts with an
oxidized enamine I’. Additionally, we cannot rule out radical
recombination in this mechanism, though the reaction times and
product distributions might suggest radical recombination as
unlikely (see Supporting Information).
[a] Reactions were performed on a 0.1-0.14 mmol scale. d.r. determined by 1H
NMR after FC.
The present reaction concept allows for unprecedented
enantioselective coupling of -branched aldehydes. This
methodology overcomes the difficulties in connecting two
quaternary stereogenic carbons and affords the homo-coupled
products in good yields and high stereoselectivities for electron-
rich aldehydes. Encouraged by these results, we sought to obtain
insight into the reaction mechanism to understand the factors that
govern reactivity. Density functional theory (DFT) was used to
determine the ionization potentials (IPs) of all relevant species
(Scheme 2). The calculations support a chemoselective pathway
by revealing enamine I to be more susceptible to oxidation than
the -branched aldehydes, enols or organocatalyst, in
accordance with prior results.[6c,14] Oxidation of I’ to a dicationic
system I’’ is calculated to be higher in energy. The IPs reflect the
energy required to remove one electron from the species below
which they are listed. The IP values for oxidizing I’ to I’’ are
additive (e.g. oxidation of I bearing a hydrogen to I’’ requires 10.5
eV).
Scheme 3. Proposed reaction mechanism (Pathway 1) and another
conceivable reaction pathway for the oxidative homo-coupling of -
branched aldehydes (Pathway 2).
The following sections describe the experiments performed to
obtain information discerning these two conceivable pathways,
and provide insight into this oxidative homo-coupling. We set out
to gain additional evidence for the proposed pathway proceeding
through radical cation I’ rather than dication I’’ (i.e. differentiating
Pathways 1 and 2). A Newcomb radical-clock experiment could
distinguish between these intermediates,[15] however, no radical-
adducts were observed. Traditional kinetic methods could be
employed to distinguish these pathways, unfortunately, they were
not suitable due to the heterogeneity of the reaction mixture.[16]
Competition experiments proved effective as a means of
evaluating linear free energy relationships to discern the nature of
the oxidized enamine intermediate.
We have measured relative rates of the oxidative coupling in
binary mixtures of para-substituted 2-phenyl propanals 1 by
carrying out separate experiments under the same reaction
conditions. These were measured by a competitive method based
on product ratios and determined by 1H NMR.[17-19] Relative
reactivities can provide valid rate measurements given that the
reaction being analysed is under kinetic control and that the
competing processes are of the same kinetic order.[18,19] It should
be noted that the coupling of I and I’ (Scheme 3) is not proposed
to be rate-determining, but product determining. The rate-
determining step is likely the SET-oxidation generating I’, which
is affected not only by the electronics of the substrate (as in the
case of the calculated IPs, Scheme 2), but also by the insolubility
of the oxidant.[16]
Scheme 2. Calculated IPs of -branched aldehydes, truncated
organocatalyst 2 (pyrrolidine) and intermediates.
Two conceivable reaction pathways for this oxidative coupling
of -branched aldehydes are considered: 1) radical cation I’
reacting with neutral enamine I, and 2) dication I’’ reacting with
neutral enamine I (Scheme 3).
IPs and observed reactivity could support the mechanism
proposed in Pathway 1 (Scheme 3). It relies on the assumption
that two equivalents of enamine I are formed by the reaction of
the -branched aldehyde with organocatalyst 2. One of the
formed intermediates undergoes SET-oxidation by Ag(I)
generating radical cation I’. This intermediate is envisioned to
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Product ratios from the competition experiments and full
details regarding relative rate determination via direct and indirect
methods can be found in the Supporting Information. The
following general trend is observed: enamines having more
radical-stabilizing substituents undergo faster oxidative couplings
compared to their less-stabilized counterparts. E.g. the para-
methoxy-substituted enamine reacts 4.7 times as fast as the
unsubstituted species (Table 4, line 1). Despite the disparity in the
rate- and product-determining steps, this trend is reflected by the
calculated enamine IPs (I
IP(OMe)<IP(H)<IP(CF3).
 I’, Scheme 2) in which
Figure 1. Hammett-type plots for para-substituted 2-phenyl propanals.
(a) log(kR-Ph/kPh)vs σ+ values; (b) log(kR-Ph/kPh)vs σ• values; (c) log(d.r.)
vs σ+ values; (d) log(e.r.) vs σ+ values.
Table 4. Relative reactivities of enamines kR-Ph/kR-Ph in oxidative
couplings. The values presented in italics are averages of four indirect
measurements.
The results suggest that reactivity of the homo-coupling is
governed by radical stabilizing ability. Through the course of the
competition experiments we found an interesting trend in
stereoselectivity for the 1,4-dialdehyde products (d.r. relative to
1): MeO 3c: 5.0±0.4 (96% ee); MeS 3e: 3.7±0.7 (94% ee); Me 3f:
2.9±0.6 (94% ee); H 3i: 1.5±0.3 (66% ee); Br 3g: 1.6±0.3 (32%
ee); CF3 3h: 1.15±0.06 (6% ee). For the electron-rich 1,4-
dialdehydes 3c,e,f, high diastereomeric ratios[22] and
enantiomeric excesses were obtained, while the 1,4-dialdehyde
3h having an electron-withdrawing substituent resulted in poor
stereoselectivity. While the reactivity correlates in a linear fashion
with σ• values which are relative to radical stabilizing ability, the
logarithm of diastereomeric and enantiomeric ratios correlate
linearly with σ+ values (Figure 1c,d).[23] These systems are
mechanistically complex. The data suggest that as the electron-
donating ability of the substituent increases, the energetic profile
between the pathways distinguishing the two enantiomers must
favor the experimentally obtained major product (R,R). This
complexity might originate from the presence of an intermediate
bearing both radical and cationic character.
Calculated IPs and linear free energy analysis support the
claim that the homo-coupling of -branched aldehydes occurs via
a radical cationic intermediate. Additionally, calculated energy
barriers - if located - could provide further evidence for the
proposed reaction pathway. It should be noted that potential
energy profiles of radical species can be challenging as they often
proceed on high-energy surfaces with shallow minima.[24]
DFT (Gaussian09)[25] was used to calculate transition-state
structures (TSSs) for the para-substituted 2-phenyl propanals
1c,f,g,h,i employing the unrestricted-B97X-D[26] functional with
a 6-31+G(d,p) basis set and the SMD solvent continuum model
(see Supporting Information for details).[27] DFT, which is known
to struggle with calculation of absolute barriers, can be quite
useful in predicting trends. Unfortunately, all attempts at
effectively modeling the trend in our relative rate ratios have been
R
MeS
1.2
Me
3.1
Br
2.6
F3C
2.7
H
4.7
MeO
1.0±0.1 2.4±0.8 3.0±0.8 3.4±0.9 6±1
3.0
2.1±0.3 2.8±0.8 3±1
1.3 1.5
2.6
3.0
4.4
5±1
2.3
MeS
Me
1
1
1.1±0.3 1.1±0.2 2.1±0.7
1.0 2.1
1.1±0.1 1.9±0.4
Br
1
1.7
1.7±0.3
F3C
1
The relative reactivities presented in red in Table 4 enable a
Hammett analysis allowing for more specific information
regarding which of the two intermediates (I’ or I’’) is involved.[18]
Figure 1 shows four Hammett-type plots for the oxidative coupling
of para-substituted 2-phenyl propanals 1. Figure 1a shows poor
linear correlation between log(kR-Ph/kPh) and the substituent
parameter σ+ (R2 = 0.46).[20] Gratifyingly, a linear correlation
between log(kR-Ph/kPh) and the substituent parameter σ• was
obtained (R2 = 0.98, Figure 1b).[21] This supports that radical
cation I’ is the reactive species, rather than dication I’’ and
distinguishes Pathways 1 and 2 (Scheme 3). In addition, the plot
in Figure 1b has a value of ρ = 2.8 suggesting that the reactive
intermediate I’ is highly sensitive to substituents.[18] Despite the
compatibility of thio-ether 1e for the synthetic approach, it is
excluded from the linear fit as the sulfur could be prone to
participate in other oxidation events.[11] This is supported by spin-
density calculations in which a large radical contribution was
observed at the sulfur atom in comparison to other substrates
(see Supporting Information).
unsuccessful. Overall, it was found that 1h having
trifluoromethyl substituent had the highest reactivity barrier and 1f
bearing methyl substituent had the lowest barrier.
a
a
Conformational analysis revealed that small changes in geometry
led to significant energy differences in TSSs and intermediates,
unfortunately not improving the correlation to experimental data.
The relative rates account for the complete reaction conditions
(e.g., heterogeneity, solvated silver species, full catalyst species,
etc.) which necessarily affect the energetic profile, and these
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10.1002/chem.201803506
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[8]
[9]
(a) J. J Murphy, D. Bastida, S. Paria, M. Fagnoni, P. Melchiorre, Nature
2016, 532, 218. (b) L. Ye, Q.-S. Gu, Y. Tian, X. Meng, G.-C. Chen, X.-Y.
Liu, Nature Comm. 2018, 9, 227.
factors are not modeled by the DFT calculations. The predicted
barriers, while not representative of the absolute barriers of this
reaction, indicate that it is more energetically favorable for the
homo-coupling reaction to occur, than for the second oxidation
leading to I’’ to take place (Scheme 2).
L. Næsborg, V. Corti, L. A. Leth, P. H. Poulsen, K. A. Jørgensen, Angew.
Chem. Int. Ed. 2018, 57, 1606.
[10] S. Manna, A. P. Antonchick, Angew. Chem. Int. Ed. 2016, 55, 5290.
[11] M. Madesclaire, Tetrahedron 1986, 42, 5459.
[12] (a) S. Cicchi, G. Ghini, L. Lascialfari, A. Brandi, F. Betti, D. Berti, S.
Ferrati, P. Baglioni, Chem. Commun. 2007, 1424. (b) B. S. Donslund, A.
Monleón, J. Larsen, L. Ibsen, K. A. Jørgensen, Chem. Commun. 2015,
51, 13666. (c) M. Shi, Y. Satoh, T. Makihara, Y. Masaki, Tetrahedron:
Asymmetry 1995, 6, 2109.
Conclusions
In conclusion, a novel strategy for the direct enantioselective
oxidative homo-coupling of -branched aldehydes has been
developed yielding succinic 1,4-dialdehydes. These products
have been transformed into synthetically valuable chiral
pyrrolidines. Calculated IPs in addition to competition
experiments used to construct Hammett plots support that the
homo-coupling proceeds through a radical cation intermediate.
Based on the mechanistic analysis, the reactivity is governed by
radical character (σ•), while the diastereo- and enantioselectivities
are influenced by cationic character (σ+).
[13] E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257.
[14] K. Müller, F. Previdoli, H. Desilvestrio, Helv. Chim. Acta 1981, 64, 2497.
[15] M.-H. Le Tadic-Biadatti, M. Newcomb, J. Chem. Soc. Perkin Trans. 2
1996, 1467.
[16] J. J. Devery III, J. C. Conrad, D. W. C. MacMillan, R. A. Flowers II, Angew.
Chem. Int. Ed. 2010, 49, 6106.
[17] R. J. Mullins, A. Vedernikov, R. Viswanathan, J. Chem. Educ. 2004, 81,
1357.
[18] E. V. Anslyn, D. A. Dougherty, Modern Physical Organic Chemistry.
University Science, Sausalito, CA, 2006.
[19] F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry Part A:
Structure and Mechanisms. Springer, New York, NY, 2007.
[20] (a) H. C. Brown, Y. Okamoto, J. Am. Chem. Soc. 1958, 80, 4979. (b) C.
G. Swain, E. C., Jr. Lupton, J. Am. Chem. Soc. 1968, 90, 4328.
[21] X. Creary, M. E. Mehrsheikh-Mohammadi, S. McDonald, J. Org. Chem.
1987, 52, 3254.
Experimental Section
Experimental and computational details (PDF), and crystallographic data
(CIF) can be found in Supporting Information.
[22] The diastereomeric ratios are slightly different from those provided in
Table 1; this difference is due to that the ratios in Table 1 are obtained
after flash column chromatography.
Acknowledgements
[23] (a) A. E. Wendlandt, P. Vangal, E. N. Jacobsen, Nature 2018, 556, 447.
(b) S. E. Shockley, J. C. Holder, B. M. Stoltz, Org. Lett. 2014, 16, 6362.
[24] N. J. Saettel, J. Oxgaard, O. Wiest, Eur. J. Org. Chem. 2001, 1429.
[25] Gaussian09, Revision B.01, M. J. Frisch et al., Gaussian, Inc.,
Wallingford, CT, 2009 (for full Gaussian09 reference, see Supporting
Information).
This work was made possible by grants from Carlsberg
Foundation’s ‘Semper Ardens’ programme, FNU, Aarhus
University and DNRF. V.C. acknowledges the Alma Mater
Studiorum-University of Bologna for financial support.
[26] (a) J.-D. Chai, M. Head-Gordon, J. Chem. Phys. 2008, 128, 084106-1.
(b) J.-D. Chai, M. Head-Gordon, Phys. Chem. Chem. Phys. 2008, 10,
6615. (c) M. Li, Y. Sang, X.-S. Xue, J.-P. Cheng, Org. Chem. 2018, 83,
3333.
Keywords: Organocatalysis • Oxidative coupling of aldehydes •
Pyrrolidines • Hammett analysis • DFT
[27] A. V. Manerich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B., 2009,
113, 6378.
[1]
(a) M. W. Rathke, A. Lindert, J. Am. Chem. Soc. 1971, 93, 4605. (b) M.
Schmittel, A. Burghart, W. Malisch, J. Reising, R. Sollner, J. Org. Chem.
1998, 63, 396. (c) P. S. Baran, M. P. DeMartino, Angew. Chem. Int. Ed.
2006, 45, 7083. (d) H.-Q. Do, H. Tran-Vu, O. Daugulis, Organometallics
2012, 31, 7816. (e) M. D. Clift, C. N. Taylor, R. J. Thomson, Org. Lett.
2007, 9, 4667. (f) Y. Kohno, K. Narasaka, Bull. Chem. Soc. Jpn. 1995,
68, 322. (g) For relevant review, see: F. Guo, M. D. Clift, R. J. Thomson,
Eur. J. Org. Chem. 2012, 4881.
[2]
M. P. DeMartino, K. Chen, P. S. Baran, J. Am. Chem. Soc. 2008, 130,
11546.
[3]
[4]
[5]
E. E. Robinson, R. J. Thomson, J. Am. Chem. Soc. 2018, 140, 1956.
B. M. Casey, R. A. Flowers II, J. Am. Chem. Soc. 2011, 133, 11492.
T. Amaya, Y. Maegawa, T. Masuda, Y. Osafune, T. Hirao, J. Am. Chem.
Soc. 2015, 137, 10072.
[6]
(a) Comprehensive Enantioselective Organocatalysis: Catalysts,
Reactions, and Applications (Ed. P. I. Dalko), Wiley-VCH, Weinheim,
2013. (b) B. Donslund, T. K. Johansen, P. H. Poulsen, K. S. Halskov, K.
A. Jørgensen, Angew. Chem. Int. Ed. 2015, 54, 13860. (c) T. D. Beeson,
A. Mastracchio, J.-B. Hong, K. Ashton, D. W. C. MacMillan, Science 2007,
316, 582.
[7]
H-Y. Jang, J.-B. Hong, D. W. C. MacMillan, J. Am. Chem. Soc. 2007,
129, 7004.
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10.1002/chem.201803506
Chemistry - A European Journal
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FULL PAPER
Homo-coupling? That’s radical!
L. Næsborg, L. A. Leth, G. J. Reyes-
Rodríguez, T. A. Palazzo, V. Corti, and
K. A. Jørgensen*
Page No. – Page No.
Direct Enantio- and
Diastereoselective Oxidative Homo-
Coupling of Aldehydes
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Organocatalytic
Enantioselective
Vicinal quaternary
stereogenic centers
Competition Experiments
Hammett plots
Density Functional Theory
Radical reactivity
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This article is protected by copyright. All rights reserved.