Oxy-Allyl Cation Catalysis: An Enantioselective Electrophilic Activation Mode

Article abstract of DOI:10.1021/jacs.5b13041

A generic activation mode for asymmetric LUMO-lowering catalysis has been developed using the long-established principles of oxy-allyl cation chemistry. Here, the enantioselective conversion of racemic α-tosyloxy ketones to optically enriched α-indolic ca

Full text of DOI:10.1021/jacs.5b13041

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Communication
Oxy-Allyl Cation Catalysis: An Enantioselective Electrophilic Activation Mode
Chun Liu, E. Zachary Oblak, Mark N. Vander Wal, Andrew
K. Dilger, Danielle K. Almstead, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b13041 • Publication Date (Web): 21 Jan 2016
Downloaded from http://pubs.acs.org on January 21, 2016
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Oxy-Allyl Cation Catalysis: An Enantioselective Electrophilic Activation Mode
Chun Liu, E. Zachary Oblak, Mark N. Vander Wal, Andrew K. Dilger, Danielle K. Almstead,and David W. C.
MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA
dmacmill@princeton.edu
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Abstract.A generic activation mode for asymmetric LUMOꢀlowering catalysis has been developed using the longꢀestablished principles
of oxyꢀallyl cation chemistry. In this application, the enantioselectiveconversion of racemic αꢀtosyloxy ketonesto optically enrichedαꢀ
indolic carbonylshas been accomplished using a new amino alcohol catalystin the presence of electronꢀrich indole nucleophiles.Kinetic
studiesreveal that the rateꢀdetermining stepin this SN1 pathway is the catalystꢀmediated αꢀtosyloxy ketone deprotonation step to form an
enantiodiscriminant oxyꢀallyl cation prior to the stereodefiningnucleophilic addition event.The utility of this activation mode is further
demonstrated by the rapid and enantioselective construction of natural productꢀlike pyrroloindoline scaffolds.
Over the last two decades, the field of asymmetric
organocatalysis has grown at a rapid pace, fueled largely by the
development of generic modes of substrate activation.
Indeed,electrophile activation via hydrogen bonding1 or iminium
catalysis2has provided more than 60 novel transformations that
allow for the enantioselective construction of C–C, C–X, and C–
H bonds. In more recent years, urea or thioureaꢀmediated anionꢀ
binding has found widespread utility for the generation of
enantiodifferentiated ion pairs, another LUMOꢀlowering
platform that offers a vast array of unique applications.3HOMOꢀ
raising asymmetric induction has been widely accomplished with
enamine catalysis, an activation mode thatenables aldehydes and
ketones to readily undergo αꢀcarbonyl functionalization with a
variety of electrophilic coupling partners.4The utility of enamine
catalysis is readily appreciated given the prevalence ofαꢀ
aromatic, αꢀaminated, and αꢀoxygenated carbonyls within the
fields of pharmaceutical, fine chemical, and natural product
synthesis. With this consideration in mind, we recently
questioned whether enantioselectiveαꢀcarbonyl functionalizꢀ
ation might be accomplished using LUMOꢀloweringcatalysis,
specifically founded upon a new oxyꢀallyl cation activation
mode. As a critical design element, we recognized that the use
of
a
LUMOꢀloweringpathway would allow for the
implementation of nucleophilecoupling partnersin lieu of
electrophiles,a strategy that should enablea dramaticincrease in
the structure and scope ofαꢀcarbonyl products that would
beaccessible using asymmetric organocatalysis.
Oxyꢀallyl cations have been long known as transient
electrophilic species since they were first employed as
intermediates in the Favorskii rearrangement in 1894.5Since that
time, they have also been used as an activation mode for [4 + 3]
cycloadditions6and Nazarov cyclizations7in a variety of natural
product syntheses. In 2013, our laboratory found that oxyꢀallyl
cations generated under mild conditions from αꢀtosyloxy ketones
(using weak base) do not readily undergo Favorskii contraction
and, more importantly, can be trapped by a large array of σꢀor πꢀ
nucleophiles to directly furnish αꢀ heteroaromatic, αꢀaromatic, αꢀ
Results.As shown in Figure 1, we hypothesized that chiral
hydrogen bondꢀdonating catalysts should reversibly bind withαꢀ
tosyloxy ketones and thereby enable them to undergo softꢀ
enolization/fragmentation to formenantiodiscriminantoxyꢀallyl
cations.In this vein, we elected to evaluate a variety of amino
alcoholsgiven their capacity to function as carbonyl LUMOꢀ
lowering catalysts while at the same time being compatible with
mildly basic conditions. Preliminary studies from our lab
demonstrated that commercially available phenyl prolinolꢀ
derived amino alcohol 1 can induce enantiocontrol in the
coupling of αꢀtosyloxy cyclopentanone and Nꢀmethyl indolein
the presence of the mild base K2HPO4 and benzene, albeit with
poor levels of selectivity (Table 1, entry 1).10The effect of
changing to the bisꢀnaphthylꢀsubstituted catalyst 2 and extending
the prolinol core to an octahydroindolinol framework (catalyst
3)11 further improved the enantioselectivity to 55% and 73% ee,
Table 1. Initial studies and reaction optimization.
,
aminated, and αꢀoxygenated carbonyl products.8 9Anticipating
that this generic mode of αꢀcarbonyl activation might be
rendered enantioselective, we subsequently sought to find chiral
organocatalysts that might a)enable αꢀtosyloxy ketones to readily
undergo soft catalyst enolization/fragmentationand b)
subsequently form enantiodiscriminant oxyꢀallyl cations. Herein
we report the successful execution of these ideals and describe a
new amino alcohol catalyst that allows the enantioselective
coupling of indoles with racemic αꢀtosyloxy ketones.
Figure 1. Accessing novel organocatalytic platforms of catalysis.
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X
O
O
X
N
20 mol% catalyst 4
1
N
OTs
K2HPO4, H2O
Y
2
3
4
5
Y
C6F6, 23 ºC
48 - 72 h
indole
product, yield, eea
ketone
α-heteroaryl ketone
product, yield, eea
6
7
8
1
2
Me
Me
N
Me
O
O
N
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Br
74% yield, 90% ee
76% yield, 94% ee
3
5
7
9
4
Me
Me
O
O
N
N
1
2
1
2
3
C6H6
C6H6
K2HPO4
K2HPO4
58%
50%
54%
55%
33%
91%
0%
37%
55%
73%
79%
81%
92%
ꢀꢀ
F
3
C6H6
K2HPO4
77% yield
94% ee
CO2Me
78% yieldb, 84% ee
4
3
1:1 C6H6: C6F6
C6F6
K2HPO4
5
6c
3
4
K2HPO4
6
Bn
C6F6
K2HPO4, H2Od
K2HPO4, H2Od
H2O
N
N
O
O
7
None
C6F6
8
4
C6F6
4%
ꢀꢀ
aYield determined by 1H NMR. bEnantioselectivities determined by chiral HPLC.
cReaction time of 48 h. d1 equiv. of H2O.
79% yield, 92% eec
85% yield, 92% ee
8
Bn
Bn
respectively (entries 2 and 3). We propose that this net increase
in enantiocontrol is due to enhanced cationꢀπ stabilization
between the oxyꢀallyl cation and the aryl substituents on the
catalyst framework. On this basis we next examined the use of
perfluorobenzene instead of benzene as the reaction medium,
achange that should disfavor any competing cationꢀπ interactions
between the solvent and the critical oxyꢀallyl cation
intermediate.12Indeed, the perfluorobenzene system exhibited a
marked increase in asymmetric induction (entries 3–5). Finally,
incorporation of methyl groups at the 1ꢀ and 4ꢀpositions of the
naphthalene rings (catalyst 4) increased the selectivity to 92%
ee, while the presence of water further augmented the yield
(entry 6, 91% yield). Control experiments revealed that the
presence of the amino alcohol catalystiscritical forthe reaction to
proceed (entry 7), while the absence of K2HPO4 severely inhibits
the overall efficiency (entry 8, 4% yield), indicating thesoft
enolization step requires both catalyst and mild base.
With optimal conditions in hand, we next examined the scope
of this new and enantioselective oxyꢀallyl cation addition
protocol with respect to the indole component. As revealed in
Figure 2, this transformation is amenable to changes in both
sterics and electronics of the nucleophilic partner, with the
caveat that electronꢀdeficient indoles require extended reaction
times. Gratifyingly, substitution at the indole 2ꢀposition is
tolerated (entry 1, 74% yield,90% ee) despite the attendant
increase in nucleophile steric demand.13 Electronꢀdeficient Nꢀ
methyl indoles can also be implemented and provide the desired
indole addition adducts in high yield and enantioselectivity
(entries 2–4, 76% – 78% yield, 84% – 94% ee). It should be
noted that this asymmetric coupling operates equally well with
allylꢀ and benzylꢀprotected indoles (entries 5 and 6, 79% yield,
92% ee; 85% yield, 92% ee respectively).14 Moreover, a series
of Nꢀbenzyl indoles of varying electronic description perform
with almost uniform levels of efficiency and enantiocontrol,
including electronꢀrich methoxyꢀ, neutral methylꢀ, and electronꢀ
deficient bromoꢀsubstituted systems (entries 7–10, 70–87%
yield, 90%–92% ee). Finally, we were able to extend this oxyꢀ
allyl cation activation mode to an iminium cascade sequence that
Figure 2. Scope of the indole nucleophile coupling partner.
O
O
N
N
OMe
83% yield
OMe
90% ee
70% yield, 92% ee
10
Bn
Bn
O
O
N
N
87% yield
Me
81% yieldb
Br
92% ee
91% ee
11
Me
N
O
H
N
N
Me
Ts
NHTs
92% yield, 84% ee, 4:1 dr
aIsolated yields,see SI for experimental details.bReaction time of 96 h. cUsing 1,4ꢀ
diOMeꢀ2ꢀnaphthyloctahydroindolinol catalyst.
allows the rapid construction of a complex pyrroloindolines
architecture, a motif commonly found among a variety of natural
product classes.15 As revealed in entry 11, the use of a tryptamine
nucleophile with αꢀtosyloxy cyclopentanone in the presence of
catalyst
4
leads
to
facile
formation
of
the
correspondingpyrroloindoline in 92% yield, 84% ee, and 4:1 dr.
We next evaluated the scope of αꢀtosyloxy ketones that are
amenable to this new asymmetric oxyꢀallyl cation mechanism
(Figure 3). The reaction is tolerant to substitution at the 4ꢀ
position
of
the
cyclopentyl
substrate,including
benzyl,dialkyl,and spirocyclic ring functionalities (entries 2–4,
70–84% yield, 90–92% ee). Interestingly, the use of
enantioenriched methylꢀsubstituted αꢀtosyloxy cyclopentanones
provided an indolic adduct as a single regioisomer with excellent
diastereoselectivity (>20:1 dr) using the matched (S)ꢀprolinol
catalyst(entries 5 and
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Figure 3. Scope of the ketone electrophile coupling partner.
additionto the oxyꢀallyl cation. Moreover, as demonstrated in
1
Scheme 1,
2
Figure 4. Plot of initial rate (M/s) versus [ketone] (M).
3
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Figure 5. Plot of initial rate (M/s) versus [organocatalyst] (M).
Figure 6. Plot of initial rate (M/s) versus [indole] (M).
Scheme 1. Kinetic isotope effect studies on soft enolization.
aIsolated yields, see SI for experimental details.b1:1 dr of product. cReaction time
of 96 h. dUsing 1,4ꢀdiOMeꢀ2ꢀnaphthyloctahydroindolinol catalyst.
6, 70% and 62% respectively). Not surprisingly, use of the
mismatched (R)ꢀcatalyst lowers the diastereoselectivity (2.4:1 dr
and 3.5:1 dr respectively), while regiocontrol remains high. As a
useful mechanistic probe, the formation of the identical
indoleaddition adduct is observed from the 3ꢀmethyl as well as
the 4ꢀmethylꢀsubstituted αꢀtosyloxy cyclopentanone system,
reaffirming that the transformation proceeds through a common
oxyꢀallyl cation intermediate.16
Mechanistic Studies. To gain a better understanding of the
mechanistic details of this new oxyꢀallyl cation activation mode,
initial rate kinetics experiments were performed to elucidate the
reaction order for both the ketone and indole coupling partners
and for the prolinol catalyst.17 As revealed in Figures 4, 5, and
6,respectively, a first order dependence in both ketone and
organocatalyst and a zero order dependence in Nꢀmethyl indole
was observed. These experiments are consistent with a pathway
wherein the rateꢀdetermining step occurs prior to indole
a primary KIE of 3.5 was found for αꢀtosyloxy ketones
withproton vs. deuterium labels at the αꢀcarbonyl positions.
These studies provide insight that the deprotonation in the
initialenolization step is rateꢀdetermining. At this stage we
cannot state whether the fragmentation/ionization step happens
inconcert with the deprotonation event.
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Having found that the soft enolization step is rateꢀ
cation2(Scheme 3). DFT minimization19 of the catalystꢀbound
1
2
3
4
5
6
7
8
determining, we reasoned that there might be an opportunity to
demonstrate chemoselectivity for functionalization of αꢀtosyloxy
Scheme 2. Competition study conducted in common vessel.
oxyꢀallyl cation2(DFTꢀ2) suggests that enantiodiscrimination is
achieved via shielding of the oxyꢀallyl cation top face (as shown)
by way of acationꢀπꢀinteraction with one of the naphthalene
rings on the catalyst framework. Subsequent addition of the
indole 3nucleophile to the less sterically encumbered lower face
should provide the enantioenriched αꢀheteroaryl ketone 5.20
Acknowledgement.Financial support was provided by
NIHGMS (R01 GM078201ꢀ05) and gifts from Merck.
9
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.
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References
(1) (a) Miyabe, H.; Takemoto, Y. Carbonyl and Imine Activation. In
Comprehensive Organic Synthesis (2nd Edition); Knochel, P.; Molander, G.
A., Eds.; Elsevier: Amsterdam, 2014, p. 751. For seminal papers, see: (b)
Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (c)
Scheme 3. Proposed mechanism of the substitution reaction.
Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed.2000, 39
1279.
,
H
Ar
H
O
Ar
(2) (a) MacMillan, D. W. C. Nature 2008, 455, 304. For seminal papers, see: (b)
Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000,
122, 4243. (c) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 9874.
(3) (a) Brak, K.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2013, 52, 534. (b) Zhang,
Z.; Schreiner, P. R. Chem. Soc. Rev.2009, 38, 1187.For seminal papers, see:
(c) Kotke, M.; Schreiner, P. R. Tetrahedron2006, 62, 434. (d) Kotke, M.;
Schreiner, P. R. Synthesis 2007, 779. (e) Raheem, I. T.; Thiara, P. S.;
Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (f)
Ar
N
O
–H+ (RDS)
OTs
H
Ar
H
H
N
H
H
O
OH
–OTs
catalyst 4
ketone 1
2
Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130
7198. (g)Zuend, S. J.; Coughlin, M. P.; Lalonde, M.; Jacobsen, E. N. Nature
2009, 461, 968.
,
Me
Me
N
O
N
(4) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107
,
5471. For seminal paper, see: Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974,
39, 1615.
(5) (a) Favorskii, A. E. J. Russ. Phys.ꢀChem. Soc.1894, 26, 559. (b) Loftfield, R.
B. J. Am. Chem. Soc. 1951, 73, 4707.
(6) (a) Harmata, M. Chem. Commun. 2010, 46, 8886. (b) Harmata, M. Chem.
Commun. 2010, 46, 8904.
(7) (a) West, F. G.; Scadeng, O.; Wu, Y. –K.; Fradette, R. J.; Joy, S. The Nazarov
Cyclization. In Comprehensive Organic Synthesis (2nd Edition); Knochel, P.;
Molander, G. A., Eds.; Elsevier: Amsterdam, 2014, p. 827.For examples in
recent total syntheses, see: (b) Shvartsbart, A.; Smith, A. B. J. Am. Chem. Soc.
2015, 137, 3510. (c) Shi, Y.; Yang, B.; Cai, S.; Gao, S. Angew. Chem. Int. Ed.
2014, 53, 9539.
indole 3
enantioenriched
α-heteroaryl ketone 5
DFT-2
cyclopentanones in the presence of an almost identical aliphatic
cyclohexanone derivative. More specifically, we were aware
that fiveꢀmembered cyclic ketones undergo rapid αꢀ
deprotonation in comparison to their cyclohexanone
counterpartsdue to the unfavorable strain energy that arises from
introducing unsaturation into sixꢀmembered over fiveꢀmembered
rings. Indeed, when both ketones were subjected to this
asymmetric catalytic protocol in the same vessel, complete
selectivity forαꢀtosyloxy cyclopentanone functionalizationwas
observed, yielding 91% of thesmaller ring adduct and near
quantitative recovery of the αꢀtosyloxy cyclohexanone (Scheme
2).18
Finally, a series of experiments were conducted using αꢀBr
and αꢀOMs cyclopentanones to discriminate between two
possible pathways forasymmetric induction, namely a) catalyst
bound enantiodiscriminant oxyꢀallyl cation formation and b)an
ionic catalystꢀsubstrate anionꢀbinding activation mode. While
the use of different anion leaving groups on the cyclopentyl
moiety should have no effect on the enantioselectivity conferred
via a common oxyꢀallyl cation intermediate, we were aware that
anionꢀbinding catalysis typically exhibits large variations in
enantiocontrol as a function of the halide or tosylate leaving
group employed.3e In the event, the observed selectivities were
92% and 90% ee, respectively for the bromo and mesylate
groups, strongly suggesting thatthe catalyst is hydrogen bonded
to the oxyꢀallyl cation in the enantiodetermining step.
(8) (a) Vander Wal, M. N.; Dilger, A. K.; MacMillan, D. W. C. Chem. Sci.2013,
4
, 3075. The Chi group concurrently reported a similar transformation: (b)
Tang, Q.; Chen, X.; Tiwari, B.; Chi, R. C. Org. Lett. 2012, 14, 1922.
(9) For other reports employing oxyꢀallyl, siloxyꢀallyl, or azaoxyꢀallyl cations
towards racemic electrophilic activation, see: (a) Jeffrey, C. S.; Barnes, K. L.;
Eickhoff, J. A.; Carson, C. R. J. Am. Chem. Soc. 2011, 133, 7688. (b)
Acharya, A.; Eickhoff, J. A.; Jeffrey, C. S. Synthesis 2013, 45, 1825. (c) Li,
H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288. (d) Ayala, C. E.;
Dange, N. S.; Fronczek, F. R.; Kartika, R. Angew. Chem. Int. Ed. 2015, 54
4641. (e) Dange, N. S.; Stepherson, J. R.; Ayala, C. E.; Fronczek, F. R.;
Kartika, R. Chem. Sci. 2015, , 6312. (f) Acharya, A.; Anumandla, D.; Jeffrey,
C. S. J. Am. Chem. Soc. 2015, 137, 14858 (g) DiPoto, M. C.; Hughes, R. P.;
Wu, J. J. Am. Chem. Soc. 2015, 137, 14861.
,
6
(10) The use of Nꢀmethylation or alcohol methylation analogues of catalyst 1 gave
product formation with 0% and 16% ee respectively.
(11) A similar catalyst scaffold was employed in the following works: (a) Arceo,
E.; Jurberg, I. D.; AlvarezꢀFernandez, A.; Melchiorre, P. Nat. Chem. 2013, 5,
750. (b) Luo, R.; Weng, J.; Ai, H.; Lu, G.; Chan, A. S. C. Adv. Synth. Catal.
2009, 351, 2449.
(12) (a) Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303. (b) Dougherty, D.
A. Science1996, 271, 163.
(13) The use of 1,3ꢀdimethyl indole result in [3+2] cycloaddition adducts (78%
yield, 72% ee, 9:1 dr); major diastereomer as observed in reference 9c.
(14) The use of NꢀH indole in this reaction provided the corresponding product in
32% yield and 70% ee.
(15) For a review on the synthesis of pyrroloindolines and their reactivity, see: (a)
Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151. For a review of
pyrroloindolineꢀbearing natural products, see: (b) Steven, A.; Overman, L. E.
Angew. Chem. Int. Ed. 2007, 46, 5488.
(16)Labeling studies employing catalyst 1 and H218O revealed no incorporation of
18O into the product ketone, thus ruling out the possibility of enamine
formation with subsequent tosylate ionization to furnish an aminoꢀallyl cation.
(17) RPKA experiments were initially performed, but catalyst deactivation was
observed (see SI for experimental results), thus necessitating the use of the
method of initial rates. For a review on RPKA studies, see: Blackmond, D. G.
Angew. Chem. Int. Ed. 2005, 44, 4302.
Taking into account the combined results of our mechanistic
studies, we believe the following catalytic pathway is operative.
Hydrogen bonding of amino alcohol 4toαꢀtosyloxy ketone
1induces
a
rateꢀdetermining deprotonation step with
subsequentor concomitant ionization to form the highly reactive
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(18) At the current time, catalyst 4 is selective only for 5ꢀmembered ring ketones;
work is ongoing to develop a suitable catalyst for ketones of other ring sizes.
(19) DFT optimization used a B3LYP 6ꢀ31G basis set with benzene as the solvent.
1
2
3
4
(20) The absolute configuration of the
pꢀbromobenzyl derivative of (S)ꢀ5 was
unambiguously determined by Xꢀray crystallographic analysis, which lends
further support for the proposed mechanism; see SI for crystallographic data.
5
6
7
8
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ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
Graphical Abstract
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ACS Paragon Plus Environment