New Class of Anion-Accelerated Amino-Cope Rearrangements as Gateway to Diverse Chiral Structures

Article abstract of DOI:10.1021/jacs.7b07319

We report useful new lithium-assisted asymmetric anion-accelerated amino-Cope rearrangement cascades. A strategic nitrogen atom chiral auxiliary serves three critical roles, by (1) enabling in situ assembly of the chiral 3-amino-1,5-diene precursor, (2) facilitating the rearrangement via a lithium enolate chelate, and (3) imparting its influence on consecutive inter- or intramolecular C-C or C-X bond-forming events via resulting chiral enamide intermediates or imine products. The mechanism of the amino-Cope rearrangement was explored with density functional theory. A stepwise dissociation-recombination mechanism was found to be favored. The stereochemistry of the chiral auxiliary determines the stereochemistry of the Cope product by influencing the orientation of the lithium dienolate and sulfinylimine fragments in the recombination step. These robust asymmetric anion-accelerated amino-Cope enabled cascades open the door for rapid and predictable assembly of complex chiral acyclic and cyclic nitrogen-containing motifs in one pot.

Full text of DOI:10.1021/jacs.7b07319

Article
pubs.acs.org/JACS
New Class of Anion-Accelerated Amino-Cope Rearrangements as
Gateway to Diverse Chiral Structures
Isaac Chogii,‡ Pradipta Das,‡ Jason S. Fell,† Kevin A. Scott,§ Mark N. Crawford,‡ K. N. Houk,*,†
and Jon T. Njardarson*,‡
§
‡Department of Chemistry and Biochemistry and Department of Pharmacology and Toxicology, University of Arizona, Tucson,
Arizona 85721, United States
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: We report useful new lithium-assisted asym-
metric anion-accelerated amino-Cope rearrangement cascades.
A strategic nitrogen atom chiral auxiliary serves three critical
roles, by (1) enabling in situ assembly of the chiral 3-amino-
1,5-diene precursor, (2) facilitating the rearrangement via a
lithium enolate chelate, and (3) imparting its influence on
consecutive inter- or intramolecular C−C or C−X bond-
forming events via resulting chiral enamide intermediates or
imine products. The mechanism of the amino-Cope rearrange-
ment was explored with density functional theory. A stepwise
dissociation−recombination mechanism was found to be
favored. The stereochemistry of the chiral auxiliary determines
the stereochemistry of the Cope product by influencing the orientation of the lithium dienolate and sulfinylimine fragments in
the recombination step. These robust asymmetric anion-accelerated amino-Cope enabled cascades open the door for rapid and
predictable assembly of complex chiral acyclic and cyclic nitrogen-containing motifs in one pot.
Three research groups have briefly investigated the anion-
accelerated amino-Cope reaction, but as of yet these
contributions have not captured the attention of the broader
synthetic chemistry community. Insights from these early
contributions help paint a picture of why adaptation of Evans’
observations in regard to the 3-amino variant is not as
straightforward as one might gather. The first report from a
team of Merck−Frosst scientists demonstrated, for a specific
series of N-alkyl-substituted substrates,5 the feasibility of this
reaction and that it proceeded at far lower temperatures than
the anionic-oxy Cope rearrangement. These low-yielding
reactions (9−44%) were mainly plagued by a competing
[1,3]-rearrangement, which strongly suggested a nonconcerted
pathway (Scheme 1). Inspired by this study, Meyers and Houk
evaluated the anionic rearrangement behavior of several 3-
amino-Cope substrates.6 These substrates failed to rearrange;
instead, they either did not react, decomposed, or deallylated. A
rigorous computational investigation concluded that the
anionic 3-amino-Cope rearrangement proceeds via a stepwise
mechanism wherein the 3-amino-1,5-diene dissociates and then
recombines.
INTRODUCTION
■
The oxy-Cope rearrangement1 is an important transformation
in organic chemistry whose applications and impact grew
rapidly following the disclosure of an anion-accelerated variant
by the David Evans group2 in 1975.3 The corresponding 3-
amino-Cope rearrangement has not received much attention in
the last 40 years4 despite the obvious opportunities for
designing asymmetric variants and the attractive bond-forming
potential of the resulting enamine products (Figure 1).
Allin reported that a chiral auxiliary could be used for the
anion-accelerated amino-Cope rearrangement (Scheme 2).7
Unfortunately, elevated temperatures were required and
Figure 1. Anion-accelerated amino-Cope rearrangement: a neglected
class of sigmatropic rearrangements.
Received: July 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b07319
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
selectively add to the chiral imine and that the resulting α-
adduct would then undergo an anion-accelerated 3-amino-
Cope rearrangement (Scheme 3). The resulting chiral enamide
Scheme 1. First Anion-Accelerated Amino-Cope
Rearrangements Example (Merck−Frosst, 1993)5
Scheme 3. Anion-Accelerated Amino-Cope Rearrangement
Cascade Proposal
Scheme 2. Only Reported Asymmetric Anion-Accelerated
Amino-Cope Rearrangement Studies (Professor Allin)7
could then be trapped in the same pot by an electrophile in an
inter- or intramolecular fashion. The chiral auxiliary could at
this point be used to control a fourth consecutive step by
treatment of the chiral imine with a nucleophile. In this
proposed anionic cascade, the chiral auxiliary strategically
directs all four steps (α-addition, rearrangement, enamide
trapping, and imine addition) enabling access to a diverse array
of complex chiral cyclic and acyclic products with multiple
useful functional group handles.
RESULTS AND DISCUSSION
■
significant stereochemical erosion was observed when chiral N-
benzyl substituents were employed. Optimizations revealed that
amino-alcohol chiral auxiliaries could somewhat improve this
erosion challenge, but this was accomplished at a cost of using
excess n-butyl lithium and much higher (reflux) temperatures.
Reaction outcomes varied greatly when substrate substituents
were altered.8 Allin also concluded that the rearrangement
proceeded through a nonconcerted pathway. Neither the
Merck−Frosst group nor Allin attempted to harness the
reactivity of the resulting enamide intermediate or imine
product.
It is evident that the anion-accelerated amino-Cope
rearrangement can be realized, but multiple significant obstacles
need to be addressed for it to be a useful synthetic tool. Perhaps
the most challenging of these obstacles is highlighted by
experimental and computational data that strongly suggest a
nonconcerted mechanism, wherein the amino-diene undergoes
a heterolytic cleavage followed by reunification in one of two
ways (net [3,3]- or [1,3]-rearrangement) or fully dissociating.
Arguably, the most impactful substituent for this reaction is the
nitrogen atom substituent. To date, only a handful of alkyl
substituents have been evaluated, none of which have proven to
be a good match. We propose that judicious choice of the
appropriate chiral N-substituent could not only address the
aforementioned rearrangement challenges but also enable
assembly of the chiral 1,5-amino-diene Cope precursor in
situ. Inspired by the success of our recent one-pot asymmetric
synthesis of 3-pyrrolines,9 we postulated that a chiral
sulfinamide10 group might represent a suitable nitrogen atom
substituent. The auxiliaries used to form such imines are stable,
inexpensive,11 and readily available in both enantiomeric forms.
We envisioned that anion-stabilized nucleophiles could
We have put the anion-accelerated amino-Cope rearrangement
hypothesis to the test and are pleased to report that it has
exceeded our most optimistic expectations (Scheme 4). When
conjugated chiral imines are treated with lithium bis-
(trimethylsilyl)amide (LiHMDS) in the presence of ethyl β-
methyl cinnamate, at low temperature, selective enolate α-
addition takes place immediately followed by the proposed
anion-accelerated amino-Cope rearrangement upon slight
warming of the reaction mixture. Unexpectedly, the anionic
cascade proceeded to cleanly undergo an intramolecular 6-exo-
trig cyclization wherein the chiral enamide attacked a Z-enoate
to form the six-membered ring products shown (Scheme 4) in
excellent yields as single stereoisomers. Both aryl and alkyl
imine substituents are tolerated. The nitrogen atom chiral
auxiliary suppressed the previously deleterious competing [1,3]-
rearrangement pathway, and regardless of the exact nature of
the mechanism, the rearrangement proceeded without stereo-
chemical erosion.12 This new anion-accelerated amino-Cope
rearrangement cascade affords complex chiral cyclohexenone
products in high yields as single stereoisomers.13 An X-ray
crystal structure of one of the cyclization products (1)
unambiguously established the overall structure and the
absolute configuration of the newly formed stereocenter. An
attractive practical application of this anion-accelerated amino-
Cope rearrangement is its ability to provide ready access to
either enantiomeric series (1 and 2). These examples represent
the first useful asymmetric anion-accelerated amino-Cope
rearrangement reaction. This new anionic reaction cascade is
not limited to cinnamate nucleophiles (1−17). For example,
ethyl 3,3-dimethyl acrylate and its trifluoromethyl derivative are
also well-matched. The fluorinated nucleophile performs
particularly well, affording chiral cyclohexenone products
B
DOI: 10.1021/jacs.7b07319
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 4. One-Pot Anion-Accelerated Amino-Cope Rearrangement Cascade
Scheme 5. Altering Nucleophile Substitution Diverts Anion-Accelerated Amino-Cope Rearrangement Cascade
C
DOI: 10.1021/jacs.7b07319
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 6. Alternative Enamide Cyclizations (3- and 5-exo-tet)
(18−26) decorated with a trifluoromethyl group in 60−82%
yields. The success of this particular nucleophile is noteworthy
given the importance of trifluoromethyl groups in drug
discovery as evident from our recent pharmaceutical structure
analysis.14 Ethyl 3,3-dimethyl acrylate (27−31) also performs
well, affording the chiral products in good to very good yields.
When comparing the reactivity of the nucleophiles, we observe
that the trifluoromethyl-substituted nucleophile (R2 = CF3)
affords the rearrangement products more rapidly, at lower
temperature, and in uniformly high yields. Aryl-substituted
nucleophiles perform well with the methyl-substituted
nucleophile being the slowest. The product enamide moiety
has the potential to react in a variety of useful ways. For
example, treatment with N-bromo succinimide (NBS) stereo-
selectively incorporates a bromine atom (32) in 78% yield.
We postulated that if the acrylate nucleophile was substituted
with an α-substituent the enamide cyclization scenarios
observed for the β-substituted nucleophile (Scheme 4) could
be suppressed, thus opening the door for diverting the
rearrangement toward formation of chiral acyclic products.
Toward that end, when ethyl tiglate (34, Scheme 5) is
employed as nucleophile, the anion-accelerated amino-Cope
rearrangement proceeds at −78 °C to afford a product (37)
wherein the resulting enoate is of the E- instead of Z-
configuration, which shuts down cyclohexenone formation and
affords an acyclic product instead. This promising reaction
outcome creates opportunities for designing synthetic routes
toward an incredible diversity of chiral acyclic products.
Remarkably, we can isolate the intermediate enamine (37),
which then readily converts to an imine (38). This has allowed
us to confirm that both intermediate double bonds (enamine
and enoate) are of E-configuration. The intermediate chiral
enamide anion (36) can be trapped in situ with electrophiles.
For example, exposure to allyl bromide results in exclusive N-
allylation (40), while addition of an electrophilic bromide traps
at carbon (39). Bromination affords exclusively an α,α-dibromo
product. We have demonstrated this one-pot anionic cascade
for nine E-conjugate imines (38 and 41−48), all of which
afford chiral acyclic products15 as single stereoisomer in
generally excellent yields. When a Z-conjugated imine (49) is
employed, a single stereoisomer of a product (50) with
opposite configuration at the newly created stereocenter (R) is
obtained.16 In our original hypothesis (Scheme 3), we
postulated that the anionic cascade could be pushed even
further by adding a second nucleophile to the imine resulting
from trapping of the intermediate enamide. This second in situ
nucleophilic addition step would add another stereocenter, thus
significantly increasing the complexity of the products. We have
realized this reaction outcome as part of our efforts to
unambiguously confirm the stereochemistry of the products
presented in Scheme 5. Indium-mediated allylation of imine
4217 and reduction of the resulting ester provided separable
diastereomers of the amino alcohols (dr 3:1). Diene ring-
closing metathesis reaction using second-generation Hoveyda-
Grubbs (HG-II)18 catalyst afforded cycloheptenes 51 and 52.
Crystals of sufficient quality (52) enabled X-ray analysis, which
surprisingly revealed that the absolute configuration of the
newly formed stereocenter was opposite to that observed for β-
substituted nucleophiles (Scheme 4).19 The most plausible
explanation for this outcome is that the initial nucleophilic
attack onto the chiral imine proceeded from the opposite
face.20
We were curious to learn how the intermediate enamide,
which we have already demonstrated can undergo an in situ 6-
exo-trig cyclization (Scheme 4) or be trapped in an
intermolecular fashion (Scheme 5), would behave if presented
with alternative cyclization choices. For this adventure, we
postulated that γ-brominated 3,3-dimethyl acrylate (53) would
present the intermediate rearrangement product (an enamide)
with a competing 3-exo-tet cyclization scenario. Treatment of
the imines shown in Scheme 6 with the lithium enolate of 53
triggered an anionic cascade wherein the amino-Cope
rearrangement proceeded at −78 °C followed by 3-exo-tet
cyclization to form a cyclopropane imine, which then further
proceeded to react with the enolate again affording the
products shown as single isomer (54−57).21 Incredibly, seven
stereocenters were established in this one-pot amino-Cope-
enabled anionic cascade. Finally, to further highlight the wide
range of cyclization pathways the intermediate chiral enamide
offers, we designed a substrate (58) with a strategic leaving
group being part of the imine instead of the nucleophile.
Treatment of this substrate with ethyl tiglate proceeded as
D
DOI: 10.1021/jacs.7b07319
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 2. DFT-calculated mechanism of the anion-accelerated amino-Cope rearrangement. The structures of the recombination TS and the R and S
products as shown. Distances and energies are given in units of Ångstroms and kcal mol−1, respectively. Hydrogens on the THF solvent molecules
were omitted for clarity.
expected with the anionic cascade being initiated with selective
α-addition (59) followed by anion-accelerated amino-Cope
rearrangement (60). We were excited to see that the enamide
rearrangement product did indeed engage the benzylic bromide
in a 5-exo-tet cyclization as proposed to afford a chiral indane
product (61) in very good yield.
Density functional theory (DFT) with the M06-2X func-
tional and 6-311+G(d,p) basis set was employed to elucidate
the mechanism of the amino-Cope rearrangement (Figure 2).
The model includes a lithium counterion and two explicit THF
solvent molecules as well as a polarizable continuum model for
THF solvent.22
The favored mechanism was found to be a stepwise
dissociative mechanism. The first step (TS1) in the rearrange-
ment mechanism is the cleavage of the C3−C4 to form a lithium
dienolate and sulfinylimine. The sulfinylimine can be formed as
the E- (shown in Figure 2) or Z-imine; the E-imine is more
stable by 5.0 kcal mol−1. These fragments recombine in a chair
transition state (TS2) to form the new carbon−carbon bond,
which we calculate to have a slightly higher energy than TS1 by
1.2 kcal mol−1. Additionally, there is a 1.5 kcal mol−1 preference
for the transition structure that forms the observed S-product.
The reaction is calculated to be exergonic for the formation of
both product isomers, with a 1.8 kcal mol−1 (nearly 16:1 S/R
product ratio) preference for the observed S-product. The
origin of this preference arises from the conformation of the
sulfinamide required to coordinate to the lithium counterion. In
the R transition state, the sulfur and nitrogen atom lone pairs
are syn to one another while in the S transition state they are
anti to one another. The lone pair repulsion in the R transition
state and product is also found in the corresponding
conformers of the isolated imine (2.5 kcal mol−1). A smaller
lone pair repulsion on conformations has been observed in
iminyl anions23 and is well-known for peroxides and hydroxyl-
amines. Our model shows that there is a kinetic and
thermodynamic preference for the formation of the observed
S-product due to the stereochemistry of the sulfinamide and the
coordination geometry of the transition state (TS2).
CONCLUSIONS
■
In summary, we have developed useful new asymmetric anion-
accelerated amino-Cope rearrangement reactions. A chiral
sulfinamide nitrogen atom substituent ensures that the
rearrangement is stereoselective and high yielding. This same
E
DOI: 10.1021/jacs.7b07319
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(6) (a) Yoo, H. Y.; Houk, K. N.; Lee, J. K.; Scialdone, M. A.; Meyers,
A. I. J. Am. Chem. Soc. 1998, 120, 205. (b) Haeffner, F.; Houk, K. N.;
Schulze, S. M.; Lee, J. K. J. Org. Chem. 2003, 68, 2310.
(7) (a) Allin, S. M.; Button, M. A. C. Tetrahedron Lett. 1998, 39,
3345. (b) Allin, S. M.; Button, M. A. C.; Baird, R. D. Synlett 1998,
1998, 1117. (c) Allin, S. M.; Button, M. A. C. Tetrahedron Lett. 1999,
40, 3801. (d) Allin, S. M.; Baird, R. D.; Lins, R. J. Tetrahedron Lett.
2002, 43, 4195. (e) Allin, S. M.; Essat, M.; Horro-Pita, C. H.; Baird, R.
D.; McKee, V.; Elsegood, M.; Edgar, M.; Andrews, D. M.; Shah, P.;
Aspinall, I. Org. Biomol. Chem. 2005, 3, 809.
chiral auxiliary enables assembly of the amino-Cope substrate in
situ and imparts its influence on both the enamide rearrange-
ment product and the resulting chiral imine. We have
demonstrated that this amino-Cope enabled anionic cascade
can be controlled to afford either chiral cyclic or acyclic
products by use of appropriate nucleophiles and electrophiles.
The possibilities for programming this fertile new anionic
cascade for synthetic target purposes seem plentiful. Our efforts
are currently focused on further deciphering the stepwise
dissociation−recombination reaction mechanism as well as
investigating and applying this new asymmetric anion-
accelerated amino-Cope rearrangement cascade.
(8) Allin, S. M.; Horro-Pita, C.; Essat, M.; Aspinall, I.; Shah, P. Synth.
Commun. 2010, 40, 2696.
(9) Chogii, I.; Njardarson, J. T. Angew. Chem., Int. Ed. 2015, 54,
13706.
(10) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600.
(11) Su, X.; Zhou, W.; Li, Y.; Zhang, J. Angew. Chem., Int. Ed. 2015,
54, 6874.
(12) The initial α-enolate imine adducts can be isolated at low
temperature and resubjected to alternative bases. Our preliminary
investigations have revealed that Na and Li counterions (generated
from treating the amino alcohol adduct with LiHMDS, NaH, BuLi, or
NaHMDS) are critical for the success of the rearrangement while K is
detrimental. This suggests that the Na and Li counterions are playing a
key role, most likely by suppressing the dissociations that plagued
earlier investigations.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b07319.
■
S
Experimental procedures and characterization data for all
new compounds as well as computational methods
(PDF)
Crystallographic data for 1 (CCDC 1451254) (CIF)
Crystallographic data for 52 (CCDC 1556649) (CIF)
(13) Interestingly, when the imine is unsubstituted, two products are
obtained in a 2:1 ratio in 86% yield. The minor product is the [3,3]-
rearrangement product and major is the [1,3]-rearrangement product
(2:1 dr).
(14) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med. Chem. 2014, 57,
2832.
(15) Protonation of the intermediate enamine results in E/Z-imine
product mixtures, which result in a single compound when reduced
with NaBH4.
AUTHOR INFORMATION
■
Corresponding Authors
*houk@chem.ucla.edu
*njardars@email.arizona.edu
ORCID
K. N. Houk: 0000-0002-8387-5261
Jon T. Njardarson: 0000-0003-2268-1479
(16) To further confirm this result, we have separately reduced the
imines of 42 and 50 and then oxidized the chiral auxiliary of the
resulting product to its Bus-substituted amine to afford products that
are enantiomeric as evident from optical rotation measurements (see
Supporting Information, Scheme S5B, S52).
(17) Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10,
1259.
(18) (a) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160. (b) Cho, J. H.; Kim, B. M. Org. Lett.
2003, 5, 531.
(19) This stereochemical assignment has been further validated by
subjecting a common chiral imine separately to the ethyl esters of β-
methyl (Scheme S5C, Part A, S56 ) and α-methyl (Scheme S5C Part
B, S61 ) crotonate and then chemically converting the resulting amino-
Cope rearrangement products to a common chiral structure. Chemical
characterization revealed that these products were identical in all
respects (NMR, IR, mass-spec) but had opposite optical rotation
values (see Supporting Information).
(20) The main competing pathway for this new class of anionic
cascades is a retro-Mannich reaction ( Davis, F. A.; Zhang, Y.; Qiu, H.
Org. Lett. 2007, 9, 833 ). It is plausible that the α-substituted
nucleophiles add from the same face as the nucleophiles in Scheme 4
but then fail to undergo the rearrangement and instead undergo a
retro-Mannich reaction before then adding from the opposite face and
rearranging..
Author Contributions
I.C. and P.D contributed equally to the creation of this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1266365 to
J.T.N. and CHE-1361104 to K.N.H.) for financial support of
this research. We are grateful for the computational resources
provided by UCLA Institute for Digital Research and Education
and the National Science Foundation through XSEDE Science
Gateways Program (TG-CHE040013N).
REFERENCES
■
(1) (a) Berson, J. A.; Jones, M. J. J. Am. Chem. Soc. 1964, 86, 5019.
(b) Wilson, S. R. Org. React. 1993, 43, 93.
(2) (a) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765.
(b) Evans, D. A.; Baillargeon, D. J.; Nelson, J. V. J. Am. Chem. Soc.
1978, 100, 2242. (c) Steigerwald, M. L.; Goddard, W. A., III; Evans, D.
A. J. Am. Chem. Soc. 1979, 101, 1994.
(3) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Paquette, L.
A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609. (c) Haffner, F.; Houk, K.
N.; Reddy, Y. R.; Paquette, L. A. J. Am. Chem. Soc. 1999, 121, 11880.
(4) (a) Stogryn, E. L.; Brois, S. J. J. Org. Chem. 1965, 30, 88.
(b) Wender, P. A.; Schaus, J. M.; Torney, D. C. Tetrahedron Lett. 1979,
20, 2485. (c) Jemison, R. W.; Ollis, D. W.; Sutherland, I. O.; Tannock,
J. J. Chem. Soc., Perkin Trans. 1 1980, 7, 1462. (d) Dollinger, M.;
Henning, W.; Kirmse, W. Chem. Ber. 1982, 115, 2309.
(21) Maintaining the reaction temperature at −78 °C is critical for
success.
(22) Essafi, S.; Tomasi, S.; Aggarwal, V. K.; Harvey, J. N. J. Org.
Chem. 2014, 79, 12148.
(23) Zhang, H.; Wu, W.; Ahmed, B. M.; Mezei, G.; Mo, Y. Chem. -
Eur. J. 2016, 22, 7415.
(5) (a) Sprules, T. J.; Galpin, J. D.; Macdonald, D. Tetrahedron Lett.
1993, 34, 247. (b) Dobson, H. K.; LeBlanc, R.; Perrier, H.;
Stephenson, C.; Welch, T. R.; Macdonald, D. Tetrahedron Lett.
1999, 40, 3119.
F
DOI: 10.1021/jacs.7b07319
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX