Enantioselective Lactonization by π-Acid-Catalyzed Allylic Substitution: A Complement to π-Allylmetal Chemistry

Article abstract of DOI:10.1002/anie.202108336

Asymmetric allylic alkylation (AAA) is a powerful method for the formation of highly useful, non-racemic allylic compounds. Here we present a complementary enantioselective process that generates allylic lactones via π-acid catalysis. More specifically, a

Full text of DOI:10.1002/anie.202108336

Angewandte
Communications
Chemie
How to cite:
International Edition: doi.org/10.1002/anie.202108336
German Edition: doi.org/10.1002/ange.202108336
Enantioselective Catalysis
Enantioselective Lactonization by p-Acid-Catalyzed Allylic
Substitution: A Complement to p-Allylmetal Chemistry
Arun Raj Kizhakkayil Mangadan, Ji Liu, and Aaron Aponick*
Abstract: Asymmetric allylic alkylation (AAA) is a powerful
method for the formation of highly useful, non-racemic allylic
compounds. Here we present a complementary enantioselec-
tive process that generates allylic lactones via p-acid catalysis.
More specifically, a catalytic enantioselective dehydrative
lactonization of allylic alcohols using a novel PdII-catalyst
containing the imidazole-based P,N-ligand (S)-StackPhos is
reported. The high-yielding reactions are operationally simple
to perform with enantioselectivities up to 99% ee. This strategy
facilitates the replacement of a poor leaving group with what
would ostensibly be a better leaving group in the product
avoiding complications arising from racemization by equili-
bration.
E
nantioselective catalysis has continued to evolve and serve
as a powerful tool for the preparation of enantioenriched
molecules such as pharmaceuticals, agrochemicals, and fine
chemicals.[1] Among these transformations, catalytic asym-
metric allylic alkylation has been highly successful, owing in
part to the broad range of substrate types and nucleophilic
partners that can be used to generate a plethora of enan-
tioenriched compounds suitable for further functionaliza-
tion.[2] Most of these methods, including the pioneering work
by Tsuji and Trost, utilize an allylic compound bearing a good
leaving group (ester, carbonate, etc.) to form an electrophilic
p-allylmetal intermediate for reaction with a nucleophilic
Scheme 1. Allylic Substitution.
sequently ester-forming Pd-AAA is scarce. Similarly, with Ir-
AAA, Helmchen demonstrates time dependent loss of ee.[5b]
Alternatively, Overman employed a PdII-catalyst with allylic
trichloroacetimidates; but, with this activating group, the
uncatalyzed reaction is problematic for nucleophiles with
pKaꢀs below 4. In these reactions, with acidic substrates, low
yields and eeꢀs of the desired products are observed and the
major products are the linear trichloroacetimidate-substitu-
tion product.[6e]
As esters are the substrates for AAA, a potential strategy
to overcome these issues might be to effect a reverse reaction,
but this would necessitate ionization of a poor leaving group
and result in the incorporation of a good leaving group.
Interestingly, alcohols have been used as starting materials for
AAA,[7] but this typically requires cation stabilizing substitu-
ents[8] or acidic additives to facilitate p-allylmetal formation.[9]
While this provides entry to the reaction manifold from the
traditional product side, it does not readily enable the
enantioselective formation of allyl ester products. Kitamura
reported an elegant enantioselective approach employing
a bifunctional Ru-catalyst that mediates p-allylmetal forma-
tion by proton transfer avoiding the necessity for activated
substrates.[10] While the process requires 1008C, presumably
protonation and ionization of the allylic alcohol substrate is
more facile than it is on the lactone product. Although the
reaction proceeds via a p-allylmetal intermediate, differ-
entiation attributable to a change in mechanism suggests that
À
À
partner in the construction of C X and C C bonds (Sche-
me 1A).[3] Although, these activated alcohols require an
additional synthetic step, activation facilitates ionization
under mild conditions and helps differentiate the electrophile
from its nucleophilic partner. Perhaps more importantly, for
enantioselective transformations the substrate is more easily
ionized than the product, so a kinetically formed non-racemic
product does not suffer racemization by thermodynamic
equilibration.
Considering that esters and lactones are ubiquitous in
biologically active compounds,[4] preparation by AAA would
also be extremely useful, but this is problematic because they
are easily ionized under the conditions and are therefore
prone to racemization.[5] Trost notes that the problem is
“more severe than it appears at first glance”[5a] and con-
[*] A. R. Kizhakkayil Mangadan, J. Liu, Prof. Dr. A. Aponick
Florida Center for Heterocyclic Compounds and, Department of
Chemistry, University of Florida
P.O. Box 117200, Gainesville, FL 32611 (USA)
E-mail: aponick@ufl.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.202108336.
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
ꢀ 2021 Wiley-VCH GmbH
1
These are not the final page numbers!

Angewandte
Communications
Chemie
other enantioselective processes might be possible under mild
conditions if an alternative pathway could be accessed.
Mechanistically, if the p-allylmetal could be avoided,
racemization due to leaving group ability should not be
detrimental to enantioselective processes and an enantiose-
lective reverse reaction, of sorts, should be possible (Sche-
me 1B). Our group has a longstanding interest in dehydrative
transformations[11] and we reported dehydrative allylic lacto-
nization with AuI- and PdII-catalysts.[11e] The reaction pro-
ceeded best under “ligandless” conditions using
(CH3CN)2PdCl2. Added ligand such as phosphine or even
substoichiometric amounts of CH3CN completely shut down
the reaction and ligand inhibition is problematic to an
enantioselective variant. Despite this challenging issue, we
reasoned that a successful reaction would be useful from
a synthetic standpoint, atom- and step-economical[12] and also
desirable from a green chemistry perspective.[8c] Herein we
detail our studies and report a catalyst system that is both high
yielding and highly enantioselective under mild conditions.
The enantioselective synthesis of 3-vinyl phthalides and
butenolides is of interest due to their potential as synthons[13]
towards an array of bioactive compounds.[4] To initiate the
study, we selected 1a for catalyst screening (Scheme 2). Initial
trials focused on the use of Au- and Pd-complexes with P,P-,
N,N-, and P,N-ligands and AgOTf as a halide scavenger.
Consistent with the observations noted above, using PdII-
complexes with P,P-ligands C2,3,5 none of the desired
product 2a was formed. With the di-gold complex C1, 2a
was formed but in low ee (12%). Much to our surprise, with
the C1-symmetric P,N-ligand C4, 2a was formed in a 36%
yield and 60% ee, a marked improvement. However, 3 was
the major product, presumably formed by a Lewis-acidic
mechanism.[11e] Since PHOX is a P,N-ligand, a Pd-complex of
our imidazole-based ligand (S)-StackPhos[14] was prepared
and employed in the reaction to yield 2a in 56% and
remarkably 95% ee. With this excellent selectivity and
reversal in the 2a:3 ratio, other StackPhos-based catalysts
were explored in an attempt to improve the chemoselectivity.
It should be noted that the (S)-ligand was used here, but both
enantiomers are readily available. The corresponding AuI-
complex C6 was ineffective, and no other ligand congeners
provided any significant improvement, so further optimiza-
tion would be needed.
StackPhos has not been used with metals other than Cu[14]
and its efficacy in this Pd-catalyzed transformation is note-
worthy as it seems to be uniquely suited for the reaction. With
this initial high ee result in hand, an optimization was
undertaken to minimize the formation of 3 (Table 1).
During initial experiments, it was observed that the reaction
did not proceed without AgOTf, 5 mol% resulted in complete
loss of the reactivity (entry 2) and using solely AgOTf
Table 1: Optimization Studies.[16]
entry
deviation
t
ee
[%]
Yield
Yield
2a [%][a]
3 [%][a]
1
2
3
none
12 h
36 h
12 h
95
–
56
0
31
AgOTf (5 mol%)
trace
10
No Pd catalyst,
–
0
AgOTf (10 mol%)
4
AgBF4 (12 mol%)
THF (0.05 M)
12 h
36 h
18 h
18 h
6 h
60
–
19
12
62
5
0
5[b]
6
3
THF (0.2 M)
93
n.d.
96
98
25
1
7[b]
8
THF (0.1 M), MS 4 ꢁ
acetone (0.1 M)[c]
59
82
12
6
9
acetone (0.1 M)[c]
H2O (0.5 equiv)
6 h
10[d]
11[e]
acetone (0.1 M)[c]
H2O (0.5 equiv)
7 d
99
99
77
81
9
6
acetone (0.1 M)[c]
H2O (0.5 equiv)
28 h
Scheme 2. Catalyst Screening. aPdCl2(CH3CN)2 and ligand were pre-
[a] Isolated yield.; [b] Yield determined by 1H NMR; [c] Distilled acetone;
mixed before the reaction.
[d] T=À258C; [e] T=08C.
2
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 2: Substrate scope.[16]
provided a 10% yield of 3, but only after a prolonged reaction
time (entry 3). Several other salts were screened but AgOTf
proved optimal.[15,16] These data (no reaction without a Ag-
salt and entries 1–4) suggest that dicationic-PdII is required
and AgOTf likely improves the p-acidity.[15] Further experi-
ments on the solvent showed that molecular sieves diminished
the reactivity (entry 7) and, after an extensive solvent
screen,[16] it was found that use of distilled acetone with
0.5 equiv H2O struck an excellent balance between reactivity
and selectivity to provide 2a in 82% yield and 98% ee
(entry 9). These conditions were deemed optimal. At this
stage, two additional experiments should be mentioned.
Firstly, it should be noted that the corresponding trans-
substrate does not function in the reaction. Perhaps more
importantly, when non-racemic product 2a was subjected to
a Pd0-catalyst, rapidly racemization was observed, consistent
with our expectations.[16,17]
The substrate scope was explored to probe generality
(Table 2). A variety of substituted benzoic acids with varying
electronic and steric properties were competent in the
lactonization process, providing access to phthalides in good
to excellent yields and eeꢀs with minimal exception. Substrates
with both EWGs and EDGs functioned quite well to provide
the products in excellent ee (2b–g,i,l,m). In addition to small
scale experiments, the reaction was also carried out on the
gram scale with 2a and 1 mmol scale with 2l, and both were
formed in comparable yield and ee. This range of substrates is
particularly attractive since phthalides with EDGs are present
in most of the natural products of the family.[4e] Additionally,
it has been reported that EWGs on the phthalide enhance the
biological activity.[4f] It should also be noted that the method
doesnꢀt suffer from the same pKa requirements as the
Overman trichloroacetimidate method[6e] and more acidic
substrates like the salicylic acid derived-substrates leading to
2i and 2e functioned well in the reaction. Despite this, some
limitations are as follows: substrates with 5-substitution (2j),
a fused thiophene (2o), as well as a substituted olefin (2p)
were not tolerated. A substituted allyl alcohol was reactive,
and provided 2k in 88% yield, but a racemic substrate was
employed, and this led to racemic product signifying that a p-
allyl is not formed. It was also possible to form a 6-membered
lactone 2n, but further optimalization will be needed to
increase the selectivity.
[a] 1 g scale; [b] Solvent=distilled MeOAc (0.1 M) at rt; [c] Racemic
allylic alcohol substrate employed. [d] Reaction carried out at 1 mmol
scale. [e] Solvent=distilled acetone:TFE (4:1, 0.1 M); [f] Solvent=dis-
tilled MeOAc (0.1 M) at 08C.
In addition to phthalides, the scope was expanded to g-
lactones widely found in terpenes and alkaloids such as the
guaianolides and others.[4a,18] The reaction functions partic-
ularly well for fused a,b-unsaturated g-lactones (2q–s,u), all
exhibiting > 90% ee. Introduction of a CH3 at the a and b
positions of the aliphatic acid resulted in the nearly optically
pure (98% ee) g-butenolide 2w which is an important plant
germination signalling molecule.[19] In addition, 2x containing
a highly electrophilic exomethylene moiety was isolated in
78% and 90% ee, but this required additional optimization.
This is particularly significant since it is prone to racemiza-
tion.[20]
substrates described above have utilized a hydroxyl group as
a leaving group and we wondered how the reaction might
function with alternative, and perhaps better leaving
groups.[3a,21] To this end, substrates 1aa’–1ad’ were prepared
and subjected to the conditions. As can be seen in Table 3, and
as would be expected, these substrates completely suppressed
formation of 3 and 2a was produced exclusively, albeit with an
erosion of the enantioselectivity. The reactivity of alkoxyl
substrates 1aa’ and 1ab’ (entries 2,3) was decreased and
required 48 hours to proceed to completion but 1ac’ and 1ad’
showed only partial conversion after this prolonged reaction
time (entries 4,5). It should be noted that analyses of the
reaction mixtures show only product and unreacted starting
material, with no other by-products.
These data demonstrate that it is possible to identify
a catalyst system to replace a poor leaving group in an allylic
substrate and enantioselectively form a product containing an
ostensibly better leaving group without racemization. The
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 3: Leaving group studies.
group and the ability of the leaving group to act as a ligand. It
is proposed that the active catalyst 4a is formed in situ from
C7 with 2 equiv AgOTf (Scheme 3). The catalyst likely
maintains a + 2 oxidation state throughout the process and
entry
1
substrate
t
[h]
Yield
2a [%]
ee
[%]
Yield
3 [%]
6
82
90
90
17
98
91
91
91
6
0
0
0
2
3
4
48
48
48
5
48
55
91
0
Scheme 3. Plausible mechanism.
Considering these results, we envisioned that allylic ethers
could serve as alternative substrates when the undesired 7-
membered lactone is predominant or when the synthesis of
the corresponding alcohol substrate is challenging. To briefly
probe this, we considered 1v where a low yield of the 2v was
observed due to the competing direct lactonization (Table 2).
Instead of the allylic alcohol, the methyl ether 1va was
prepared and exposed to the reaction conditions. In this case,
2v was formed in 85% yield and 97% ee, overcoming any
issues of the previous substrate.
the p-acidic Pd-species 4a activates the p-bond of the allylic
alcohol to form the complex 4b before addition and
dehydration to form 4e with release of ROH. Decomplex-
ation then yields 2 and regenerates the catalyst. It is probable
that, when liberated, acetate and phenol, which are better
ligands for Pd than H2O and alcohol,[3a,20] coordinate to 4a
and form a species such as 4 f, inhibiting the catalyst to
produce a much slower overall reaction with incomplete
conversion. At the moment, it is unclear whether the
carboxylic acid in 4b is coordinated to the metal. The
coordinated species could undoubtedly be present and
would likely dictate syn- or anti-addition leading to 4c or
4d, but it is unclear if this interaction is productive. Further
experiments addressing this are underway and will be
reported in due course.
The reaction products contain a synthetically useful
lactone ring and a vinyl group strategically located on the
ring system that we envision will be useful for subsequent
transformations and further functionalization. This was
briefly explored with some preliminary experiments and it
was found that 2a can be efficiently reduced to alkyl product
2aa’ and transformed into a synthon for fused g-pyran
lactones, diol 2ab’, by LAH reduction.[22a] Furthermore, the
chain was extended and reduced by metathesis and hydro-
genation of 2a to afford 3-n-butylpthalide-edaravone hybrid
2ad’ in good yield.[22b] It should be noted that only minimal
While alkoxides functioned well in the reaction, it was
curious that substrates employing phenoxide and acetate as
leaving groups suffered a drastic reduction in reactivity. With
acetate, even though it is a good leaving group for p-
allylpalladium chemistry, after 48 h < 60% conversion was
observed. In contrast, with -OH as leaving group, dehydrative
cyclization proceeds to completion in the presence of
a PdII·StackPhos catalyst at temperatures as low as À258C
(Table 1, entries 9–11). It seems likely that this difference is
correlated to the pKa of the conjugate acid of the leaving
4
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Keywords: allylic compounds · enantioselectivity · lactones ·
StackPhos · p-acid catalysis
[1] a) B. M. Trost, Proc. Natl. Acad. Sci. USA 2004, 101, 5348;
b) M. S. Taylor, E. N. Jacobsen, Proc. Natl. Acad. Sci. USA 2004,
101, 5368; c) A. Fanourakis, P. J. Docherty, P. Chuentragool, R. J.
Phipps, ACS Catal. 2020, 10, 10672; d) L. A. Nguyen, H. He, C.
Pham-Huy, Int. J. Biomed Sci. 2006, 2, 85; e) N. C. P. de Al-
buquerque, D. B. Carrao, M. D. O. Habenschus, J. Pharm.
Biomed. Anal. 2018, 147, 89; f) E. M. Ulrich, C. N. Morrison,
M. R. Goldsmith, W. T. Foreman, Rev. Environ. Contam.
Toxicol. 2012, 217, 1.
[2] For recent reviews see: a) O. Pꢁmies, J. Margalef, S. CaÇellas, J.
James, E. Judge, P. J. Guiry, C. Moberg, J. E. Bꢂchvall, A. Pfaltz,
M. A. Pericꢁs, M. Diꢃguez, Chem. Rev. 2021, 121, 4373; b) Q.
Cheng, H.-F. Tu, C. Zheng, J.-P. Qu, G. Helmchen, S.-L. You,
Chem. Rev. 2019, 119, 1855; c) B. M. Trost, Tetrahedron 2015, 71,
5708; d) B. M. Trost, M. R. Machacek, A. Aponick, Acc. Chem.
Res. 2006, 39, 747; e) B. M. Trost, D. L. Van Vranken, Chem. Rev.
1996, 96, 395.
Scheme 4. Further Synthetic Transformations. Reaction conditions:
a) H2 (1 atm), Pd/C (10 wt%), THF, rt, 24 h. b) LiAlH4, 08C—rt, 6 h.
c) 1-hexene, Grubbs-II, DCM, reflux, 12 h. d) H2 (1 atm), Pd/C
(30 wt%), THF, rt, 16 h.
change in ee was observed and other transformations could be
envisioned.[4e,11e]
In conclusion, we have reported an enantioselective p-
acid catalyzed allylic substitution for the formation of
lactones. This method, whereby a substrate with a poor
leaving group delivers a product containing a better leaving
group, provides a complementary approach to the venerable
enantioselective p-allyl metal chemistry that has proven so
useful to the community. By engaging the allylic substrates in
an alternative mechanism, the process is able to avoid the
complications of traditional p-allylmetal chemistry arising
from racemization of the product through a thermodynamic
equilibration that proceeds via an ionization/recombination
pathway. Furthermore, the method does not appear to have
the same pKa limitations as the trichloroacetimidate method.
The reactions are high yielding, enantioselective, chemo-
selective, operationally simple to perform, and provide
heterocycles with a synthetically useful vinyl group strategi-
cally located on the ring system that facilitates further
transformations for target-oriented synthesis. Interestingly,
substrates bearing the traditional allylic acetate leaving group
can undergo a highly selective reaction with this catalyst
system, but the reaction is very slow, likely due to catalyst
inhibition after release of acetate. The mechanistic details and
expansion of the methodology, including additional synthetic
applications, are under further study in our laboratories.
[3] a) B. M. Trost, J. Org. Chem. 2004, 69, 5813; b) B. M. Trost,
Chem. Pharm. Bull. 2002, 50, 1; c) B. M. Trost, M. L. Crawley,
Chem. Rev. 2003, 103, 2921; d) L. Milhau, P. J. Guiry, Top.
Organomet. Chem. 2011, 38, 95; e) T. Noꢄl, K. Bert, E.
Van der Eycken, J. Van der Eycken, Eur. J. Org. Chem. 2010,
4056; f) M. Kawatsura, K. Uchida, S. Terasaki, H. Tsuji, M.
Minakawa, T. Itoh, Org. Lett. 2014, 16, 1470; g) Y. Shi, B. Jung, S.
Torker, A. H. Hoveyda, J. Am. Chem. Soc. 2015, 137, 8948; h) H.
You, E. Rideau, M. Sidera, S. P. Fletcher, Nature 2015, 517, 351;
i) E. Rideau, H. You, M. Sidera, T. D. W. Claridge, S. P. Fletcher,
J. Am. Chem. Soc. 2017, 139, 5614; j) M. Sidera, S. P. Fletcher,
Nat. Chem. 2015, 7, 935; k) C. Li, B. Breit, Chem. Eur. J. 2016, 22,
14655.
[4] a) B. Mao, M. FaÇanas-Mastral, B. L. Feringa, Chem. Rev. 2017,
117, 10502; b) J. Hur, J. Jang, J. A. Sim, Int. J. Mol. Sci. 2021, 22,
2769; c) L. T. N. Chuc, T. A. H. Nguyen, D.-R. Hou, Org.
Biomol. Chem. 2020, 18, 2758, and references therein; d) J.
Wilent, K. S. J. Petersen, Org. Chem. 2014, 79, 2303; e) R.
Karmakar, P. Pahari, D. Mal, Chem. Rev. 2014, 114, 6213; f) W.
Wang, X.-X. Cha, J. Reiner, Y. Gao, H.-L. Qiao, J.-X. Shen, J.-B.
Chang, Eur. J. Med. Chem. 2010, 45, 1941.
[5] a) B. M. Trost, M. G. Organ, J. Am. Chem. Soc. 1994, 116, 10320;
b) J. Qu, L. Roßberg, G. Helmchen, J. Am. Chem. Soc. 2014, 136,
1272; c) N. Kanbayashi, K. Onitsuka, J. Am. Chem. Soc. 2010,
132, 1206 – 1207.
[6] For an account on PdII-catalyzed reactions of allylic trichlor-
oacetimidates see: a) J. S. Cannon, L. E. Overman, Acc. Chem.
Res. 2016, 49, 2220. For reviews see: b) J. S. Arnold, Q. Zhang,
H. M. Nguyen, Eur. J. Org. Chem. 2014, 4925; c) R. A. Fer-
nandes, P. Kattanguru, S. P. Gholap, D. A. Chaudhari, Org.
Biomol. Chem. 2017, 15, 2672. For reports on allylic ester
synthesis see: d) S. F. Kirsch, L. E. Overman, J. Am. Chem. Soc.
2005, 127, 2866; e) J. S. Cannon, S. F. Kirsch, L. E. Overman, J.
Am. Chem. Soc. 2010, 132, 15185; f) J. S. Cannon, S. F. Kirsch,
L. E. Overman, H. F. Sneddon, J. Am. Chem. Soc. 2010, 132,
15192. For a review of PdII-catalyzed alkene functionalization
see: g) R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111,
2981.
Acknowledgements
The authors thank the University of Florida and The National
Science Foundation (CHE-1900299) for their generous sup-
port of our programs. Mass spectrometry instrumentation was
sup-ported by a grant from the National Institutes of Health
(S10 OD021758-01A1).
[7] a) B. Sundararaju, M. Achard, C. Bruneau, Chem. Soc. Rev.
2012, 41, 4467; b) N. Butt, W. Zhang, Chem. Soc. Rev. 2015, 44,
7929.
Conflict of Interest
[8] a) T. Sandmeier, F. W. Goetzke, S. Krautwald, E. M. Carreira, J.
Am. Chem. Soc. 2019, 141, 12212; b) S. L. Rçssler, D. A.
Petrone, E. M. Carreira, Acc. Chem. Res. 2019, 52, 2657; c) S.-
B. Tang, W. Zhang, H.-F. Tu, S.-L. You, J. Am. Chem. Soc. 2018,
140, 7737; d) M. Dryzhakov, R. Edward, J. Moran, Synthesis
The authors declare no conflict of interest.
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
2016, 48, 935; e) Y. Kita, R. D. Kavthe, H. Oda, K. Mashima,
Angew. Chem. Int. Ed. 2016, 55, 1098; Angew. Chem. 2016, 128,
1110.
Aponick, ACS Catal. 2017, 7, 2133; c) S. Mishra, A. Aponick,
Angew. Chem. Int. Ed. 2019, 58, 9485; Angew. Chem. 2019, 131,
9585; d) L. G. DeRatt, M. Pappoppula, A. Aponick, Angew.
Chem. Int. Ed. 2019, 58, 8416; Angew. Chem. 2019, 131, 8504.
[15] For review of ion pairing in transition metals, see: a) A.
Macchioni, Chem. Rev. 2005, 105, 2039. For selected examples
of counterion effects in asymmetric catalysis, see: b) D. H. T.
Phan, B. Kim, V. M. Dong, J. Am. Chem. Soc. 2009, 131, 15608;
c) M. Bandini, A. Eichholzer, Angew. Chem. Int. Ed. 2009, 48,
9533; Angew. Chem. 2009, 121, 9697; d) Y. Uozumi, K. Kato, T.
Hayashi, J. Org. Chem. 1998, 63, 5071; e) M. Nandi, J. Jin, T. V.
RajanBabu, J. Am. Chem. Soc. 1999, 121, 9899.
[9] a) G. Jiang, B. List, Angew. Chem. Int. Ed. 2011, 50, 9471; Angew.
Chem. 2011, 123, 9643; b) C. Defieber, M. A. Ariger, P. Moriel,
E. M. Carreira, Angew. Chem. Int. Ed. 2007, 46, 3139; Angew.
Chem. 2007, 119, 3200; c) S. Mukherjee, B. List, J. Am. Chem.
Soc. 2007, 129, 11336; d) Z.-L. Tao, W.-Q. Zhang, D.-F. Chen, A.
Adele, L.-Z. Gong, J. Am. Chem. Soc. 2013, 135, 9255; e) D.
Banerjee, K. Junge, M. Beller, Angew. Chem. Int. Ed. 2014, 53,
13049; Angew. Chem. 2014, 126, 13265; f) X. Zhao, D. Liu, H.
Guo, Y. Liu, W. Zhang, J. Am. Chem. Soc. 2011, 133, 19354; g) X.
Huo, G. Yang, D. Liu, Y. Liu, I. D. Gridnev, W. Zhang, Angew.
Chem. Int. Ed. 2014, 53, 6776; Angew. Chem. 2014, 126, 6894;
h) X. Huo, M. Quan, G. Yang, X. Zhao, D. Liu, Y. Liu, W. Zhang,
Org. Lett. 2014, 16, 1570.
[16] See Supporting Information for full details.
[17] It is well known that lactones readily open in the presence of
a Pd0-catalyst: B. M. Trost, T. P. Klun, J. Am. Chem. Soc. 1979,
101, 6756.
[10] Y. Suzuki, T. Seki, S. Tanaka, M. Kitamura, J. Am. Chem. Soc.
2015, 137, 9539.
[18] a) G. Sudhakar, K. Satish, J. Raghavaiah, J. Org. Chem. 2012, 77,
10010; b) Y. Li, K. J. Hale, Org. Lett. 2007, 9, 1267; c) B. Mao, K.
Geurts, M. FaÇanas-Mastral, A. W. Van Zijl, S. P. Fletcher, A. J.
Minnaard, B. L. Feringa, Org. Lett. 2011, 13, 948.
[11] For reviews see: a) P. H. S. Paioti, A. Aponick, Top. Curr. Chem.
2014, 357, 63; b) B. Biannic, A. Aponick, Eur. J. Org. Chem.
2011, 6605. For mechanistic studies see: c) T. Ghebreghiorgis, B.
Biannic, B. H. Kirk, D. H. Ess, A. Aponick, J. Am. Chem. Soc.
2012, 134, 16307; d) T. Ghebreghiorgis, B. H. Kirk, A. Aponick,
D. H. Ess, J. Org. Chem. 2013, 78, 7664. For dehydrative
lactonization see: e) J. Liu, R. J. Miotto, J. Segard, A. M. Erb,
A. Aponick, Org. Lett. 2018, 20, 3034.
ˇ
[19] M. Posta, M. Light, H. B. Papenfus, J. S. Staden, L. Kohout, J.
Plant Physiol. 2013, 170, 1235.
[20] R. R. Gowda, E. Y.-X. Chen, ACS Macro Lett. 2016, 5, 772.
[21] a) Y. Suzuki, S. Iwase, K. Hashimoto, S. Tanaka, M. Kitamura,
Chem. Lett. 2017, 46, 1308; b) A. Tomberg, M. E. Muratore, M. J.
Johansson, I. Terstiege, C. Skçld, P.-O. Norrby, iScience 2019, 20,
373.
[22] a) Z. Li, Y. Gao, Z. Jiao, N. Wu, D. Z. Wang, Z. Yang, Org. Lett.
2008, 10, 5163; b) X. Qiang, Y. Li, X. Yang, L. Luo, R. Xu, Y.
Zheng, Z. Cao, Z. Tan, Y. Deng, Bioorg. Med. Chem. Lett. 2017,
27, 718.
[12] a) B. M. Trost, Science 1991, 254, 1471; b) P. A. Wender, M. P.
Croatt, B. Witulski, Tetrahedron 2006, 62, 7505.
[13] For references on the enantioselective synthesis of chiral
lactones see: a) S.-G. Wang, N. Cramer, ACS Catal. 2020, 10,
8231; b) Y.-L. Pan, H.-L. Zheng, J. Wang, C. Yang, X. Li, J.-P.
Cheng, ACS Catal. 2020, 10, 8069; c) Y.-G. Liu, P. K. Majhi, R.-J.
Song, C. L. Mou, L. Hao, H.-F. Chai, Z.-C. Jin, Y. R. Chi, Angew.
Chem. 2020, 132, 3887; d) J. M. Cabrera, J. Tauber, M. J. Krische,
Angew. Chem. Int. Ed. 2018, 57, 1390; Angew. Chem. 2018, 130,
1404.
Manuscript received: June 23, 2021
[14] a) F. S. P. Cardoso, K. A. Abboud, A. Aponick, J. Am. Chem.
Soc. 2013, 135, 14548; b) P. H. S. Paioti, K. A. Abboud, A.
Accepted manuscript online: August 22, 2021
Version of record online: && &&, &&&&
6
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Enantioselective Catalysis
A. R. Kizhakkayil Mangadan, J. Liu,
A. Aponick*
&&&& — &&&&
Enantioselective Lactonization by p-Acid-
Catalyzed Allylic Substitution: A
Complement to p-Allylmetal Chemistry
A highly enantioselective lactonization of
unactivated allylic alcohols is reported
under mild conditions. The trans-
of a poor leaving group with what would
ostensibly be a better leaving group in the
product without selectivity issues arising
from racemization.
formation is catalyzed by a PdII·StackPhos
complex and facilitates the substitution
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
7
These are not the final page numbers!