Modular Design of Chiral Conjugate-Base-Stabilized Carboxylic Acids: Catalytic Enantioselective [4 + 2] Cycloadditions of Acetals

Article abstract of DOI:10.1021/jacs.0c07212

Readily available 1,2-amino alcohols provide the framework for a new generation of chiral carboxylic acid catalysts that rival the acidity of the widely used chiral phosphoric acid catalyst (S)-TRIP. Covalently linked thiourea sites stabilize the carboxyl

Full text of DOI:10.1021/jacs.0c07212

Subscriber access provided by UNIV OF WESTERN ONTARIO
Communication
Modular Design of Chiral Conjugate-Base-Stabilized Carboxylic
Acids: Catalytic Enantioselective [4+2] Cycloadditions of Acetals
Zhengbo Zhu, Minami Odagi, Nantamon Supantanapong, Weici Zhu, Jaan
Saame, Helmi-Ulrika Kirm, Khalil A. Abboud, Ivo Leito, and Daniel Seidel
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07212 • Publication Date (Web): 24 Aug 2020
Downloaded from pubs.acs.org on August 24, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Modular Design of Chiral Conjugate-Base-Stabilized Carboxylic Acids:
Catalytic Enantioselective [4+2] Cycloadditions of Acetals.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Zhengbo Zhu,1 Minami Odagi,1,2 Nantamon Supantanapong,1 Weici Xu,1 Jaan Saame,3 Helmi-Ulrika
Kirm,3 Khalil A. Abboud,4 Ivo Leito,3 and Daniel Seidel1,*
1
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United
States
2
Department of Biotechnology and Life Science, Graduate School of Technology, Tokyo University of Agriculture and
Technology, 2-24-16, Naka-cho, Koganei city, 184-8588, Tokyo, Japan
3 Institute of Chemistry, University of Tartu, Tartu, Estonia.
4
Center for X-ray Crystallography, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United
States.
Supporting Information Placeholder
ABSTRACT: Readily available 1,2-amino alcohols provide the
framework for a new generation of chiral carboxylic acid catalysts
that rival the acidity of the widely used chiral phosphoric acid
catalyst (S)-TRIP. Covalently linked thiourea sites stabilize the
carboxylate conjugate bases of these catalysts via anion-binding,
an interaction that is largely responsible for the low pKa values.
The utility of the new catalysts is illustrated in the context of chal-
lenging [4+2] cycloadditions of salicylaldehyde-derived acetals
with homoallylic and bishomoallylic alcohols, providing polycy-
clic chromanes in highly enantioselective fashion.
The burgeoning field of asymmetric Brønsted acid catalysis
continues to be driven largely by chiral phosphoric acids, first
introduced by Akiyama and Terada in 2004.1,2 Although chiral
carboxylic acids such as tartaric acid and mandelic acid are
abundant in nature, they have only occasionally been used in
asymmetric Brønsted acid catalysis.3 This is likely due to the
rather weak acidity of simple carboxylic acids, significantly
limiting the types of substrates that can be activated.2g Indeed, the
most successful chiral carboxylic acids developed thus far contain
elements that further acidify the catalyst, as exemplified by the
elegant contributions of the Maruoka group (Figure 1).4 In this
context, we recently reported a new class of easily prepared chiral
carboxylic acid catalysts that derive their high acidity from
conjugate-base-stabilization through anion-binding, facilitating a
number of asymmetric transformations (Figure 1).5,6
Computational studies suggest that the catalyst anions can adopt a
bowl-shaped structure, enabling the formation of well-defined ion
pairs with cationic substrate intermediates.5e,7 Our original design
of these catalysts was based on chiral 1,2-diamine backbones,
limiting the structural variety of catalysts that are easily
accessible. We now report second-generation catalysts that are
based on chiral 1,2-amino alcohols. Not only are these backbones
more readily available and offer a range of other advantages, the
resulting catalysts show dramatically enhanced reactivity and
selectivity profiles as illustrated in the catalytic enantioselective
synthesis of polycyclic oxygenated chromanes.
Figure 1. Catalyst Design.
Furanochromanes and
pyranochromanes
are
common
substructures of natural products such as parvinaphthol C,
medicarpin, and siccanin (Scheme 1).8 While there are various
examples of catalytic enantioselective cycloadditions of o-
quinone methide intermediates that provide access to simple
chromane frameworks lacking oxygenation in the 4-position,9,10
direct catalytic enantioselective approaches to 4-oxygenated
chromanes remain extremely rare.11 As the latter cycloadditions
require the intermediacy of oxocarbenium ions or protonated o-
quinone methides, they present
asymmetric catalysis.12,13 Although a number of Brønsted and
Lewis acids have been shown to facilitate
a significant challenge to
condensations/cycloadditions of salicylaldehyde derivatives with
homoallylic and bishomoallylic alcohols to provide
furanochromanes and pyranochromanes in high yields and
diastereoselectivities,14 the only catalytic enantioselective variant
of such a reaction was recently published by the List group
(Scheme 1).11a Specifically, these researchers accomplished
highly enantioselective [4+2] cycloadditions of salicylaldehydes
with dienyl homoallylic alcohols, utilizing an imidodiphosphoric
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
Table 1. Reaction development.a
acid catalyst (IDP). However, under identical conditions, a
simple homoallylic alcohol provided the desired product with
poor levels of stereocontrol, illustrating the need for a conjugated
alkene in this particular approach.
1
2
3
4
5
6
7
Scheme 1. Natural products containing 4-oxychromanes
and previous catalytic enantioselective approach to
furanochromanes.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With the goal of developing an intramolecular [4+2]
cycloaddition with simple alkene substrates, we initiated our
investigations with salicylaldehyde dimethyl acetal 1a and
bishomoallylic alcohol 2a (Table 1). The previously reported
thiourea-carboxylic acid 4a was found to be a highly active
catalyst, furnishing the desired product 3a in good yield albeit low
ee (entry 1). Remarkably, the new 1,2-amino alcohol-based
catalyst 4b, differing from 4a only in the type of linker connecting
the thiourea and carboxylic acid functionalities (ester-linkage vs.
amide-linkage), was not only markedly more active, but also
provided a dramatic boost in enantioselectivity (entry 2). The
corresponding cis-isomeric catalyst 4c exhibited similarly high
activity but furnished the opposite enantiomer of 3a in low ee
(entry 3). Notably, no product was obtained with either of the
catalysts when 1a was replaced with salicylaldehyde (not shown).
Increasing the electron-withdrawing character of the thiourea aryl
group resulted in the even more active and selective catalysts 4d
and 4e (entries 4 and 5). In contrast, catalysts 4f and 4g provided
slightly less favorable results (entries 6 and 7). Thiourea-
carboxylic acids 4h–4k were also prepared from a range of other
chiral 1,2-amino alcohols. Although their evaluation did not
result in further improvements (entries 8–11), these catalysts
appear to hold significant potential for the future use in other
reactions. Finally, a modest reduction in reaction temperature to 0
°C further enhanced the performance of catalyst 4e, providing
product 3a in 89% yield and 99% ee after a reaction time of just
30 min (entry 12). For comparison purposes, the reaction was
conducted with the chiral phosphoric acid catalyst (S)-TRIP (5)15
which was found to be relatively inactive. While low substrate
conversion was observed after 15 h, 3a was obtained in nearly
racemic form (entry 13). No improvement in selectivity was
achieved with IDP, although this catalyst proved to be
significantly more active than (S)-TRIP (5) (entry 14). It should
be noted that all ester-linked thiourea-carboxylic acids prepared in
the course of this study are stable and easily available in two steps
from their corresponding 1,2-amino alcohols, isothiocyanates, and
cheap tetrabromophthalic anhydride.
entry
catalyst
time
yield (%)
ee (%)
1
2
30 min
15 min
15 min
10 min
5 min
86
89
80
97
96
95
96
92
75
83
88
89
19
89
25
94
–30
95
96
90
92
–69
19
71
55
99
6
4a
4b
3
4c
4
4d
5
4e
6
5 min
4f
7
30 min
30 min
50 min
50 min
30 min
30 min
15 h
4g
8
4h
9
4i
10
11
12b
13
14
4j
4k
4e
S-TRIP (5)
4 h
2
IDP
a Reactions were performed with 0.1 mmol of 1a and 1.2 equiv of
2a. All yields correspond to yields of isolated product. The ee
values were determined by SFC analysis.
performed at 0 °C.
b
Reaction was
The scope of the catalytic enantioselective [4+2] cycloaddition
reaction is summarized in Scheme 2. While the use of catalyst 4e
was optimal for the synthesis of product 3a from bishomoallylic
alcohol 2a (Table 1), catalyst 4b (readily prepared on scale in just
two steps from commercial materials) was found to be more
general and was therefore used for all other substrates. The
corresponding homoallylic alcohol also participated in this
transformation, providing furanochromane 3b in high ee.
A
benzylic alcohol was also efficiently converted into the
corresponding product 3c. Different substituents on the alkene
moiety were well tolerated. Salicylaldehyde acetals containing
electronically diverse substituents in the 3-, 4-, 5-, and 6-positions
were readily accommodated. Excellent enantioselectivities and
good yields were generally achieved. In all cases, only the trans-
fused diastereomers of products 3 were observed.16
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
Scheme 2. Reaction scope.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To gain insights into the stereospecificity of the [4+2]
cycloaddition and possibly its nature (concerted vs. stepwise),
reactions of 1a were conducted with the two E/Z-isomeric
bishomoallylic alcohols 6 and 8. Diastereomeric products 7 and 9
were formed as the only observable isomers in high albeit
nonidentical levels of enantioselectivity (Scheme 2). As pointed
out recently by Spivey and coworkers in an elegant
mechanistic/computational paper involving closely related
stereogenic centers by utilizing readily available racemic starting
materials.17
To further improve the overall efficiency of the [4+2]
cycloaddition, we evaluated the synthesis of pyranochromane 3a
at different substrate concentrations and catalyst loadings.
Gratifyingly, using only 0.5 mol% of catalyst 4e at a tenfold
increased substrate concentration in toluene solution allowed for
the preparation of product 3a in excellent yield and ee (Scheme
3). Even at this low catalyst loading, the reaction went to
completion within 1.5 hours at room temperature. Thus, the
amount of solvent needed for conducting the reaction on a 0.1
mmol scale is the same as for a 1 mmol scale.
substrates,14g this does not necessarily imply
a concerted
cycloaddition pathway. Therefore, a Prins-like process with a
tertiary carbocation intermediate cannot be ruled out at present
and may in fact be more likely.
The possibility of achieving kinetic resolution or
diastereodivergent reactions was explored with representative,
racemic bishomoallylic alcohols 10 and 12 (Scheme 2).17
Interestingly, while the α-stereogenic center in substrate 10
dictates the diastereoselectivity of the reaction, consistent with
what has been observed in the corresponding non-asymmetric
reaction,14a,e one enantiomer of 10 reacts significantly faster,
leading to an efficient kinetic resolution process and the formation
of product 11 as a single observable diastereomer in 71% yield
and 92% ee. In contrast, the β-stereogenic center in substrate 12
seems to not greatly bias the innate diastereoselectivity of the
reaction. Here a diastereodivergent process was observed with
each enantiomer of 12 providing a different product diastereomer,
both of which were obtained in excellent enantioselectivity.18
Judging from the fact that the product dr is 3.8:1 (rather than 1:1),
a kinetic resolution process also took place simultaneously. These
transformations illustrate the ability to install additional
Scheme 3. Reaction at low catalyst loading
Detailed acidity measurements in acetonitrile were conducted for
several thiourea-carboxylic acid catalysts and control compounds
(Figure 2).19 As reported previously, the amide-linked catalyst 4a
has a pKa value of 12.4.5f Comparison of this value to the pKa
values of truncated versions of the catalyst, namely thiourea 14
and carboxylic acid 15, suggests that conjugate-base-stabilization
is responsible for an increase in acidity of nearly seven orders of
magnitude. To gauge the potential role of the amide NH in
stabilizing or destabilizing the conjugate base of the catalyst, we
subsequently prepared ester 16. Interestingly, 16 was found to be
two orders of magnitude more acidic than amide 15, suggesting
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
that stabilization of the carboxylate anion via hydrogen bonding to
Notes
the amide NH is unlikely to play a significant role. Rather, the
increase in acidity when replacing the amide substituent with an
ester group can be attributed to inductive effects. It was in fact
this observation that provided some of the motivation for pursuing
1,2-amino alcohol based catalysts as a potential avenue to more
acidic catalysts. However, the expected acidity trend does not
hold. The pKa value of 4b was determined to be 13.6. Clearly,
the model compounds do not fully capture all aspects that are
responsible for the overall pKa values of the actual catalysts.
Coincidentally, the acidities of 4b and (S)-TRIP (5) are
identical.20 Their vastly different performances in the [4+2]
cycloaddition nicely illustrate that the acidity of a Brønsted acid
catalyst is not necessarily correlated with its activity in a given
transformation. Comparing once again catalysts 4a and 4b, it is
clear that this consideration also applies to catalysts that are
structurally closely related. Finally, the cis-configured catalyst 4c
was found to be the most acidic catalyst in the series with a pKa
value of 11.8, close to the pKa values of typical
imidodiphosphoric acids (pKa values ~ 11.5)2i and significantly
more acidic than trifluoroacetic acid.21 Presumably, the relative
spatial arrangement of the carboxylic acid and thiourea moieties
enables a more efficient stabilization of the conjugate base in the
cis-isomer 4c than is possible in the trans-isomer 4b.
1
2
3
4
5
6
7
8
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
This material is based upon work supported by the National Sci-
ence Foundation under CHE–1856613 (grant to D.S.) M.O.
thanks the Program for Advancing Strategic International Net-
works to Accelerate the Circulation of Talented Researchers
(R2801) from the Japan Society for the Promotion of Science
(JSPS). We further acknowledge the National Science Founda-
tion (grant# 1828064 to K.A.A.) and the University of Florida for
funding the purchase of the X-ray equipment. Mass spectrometry
instrumentation was supported by a grant from the NIH (S10
OD021758-01A1). The work at Tartu was supported by the EU
through the European Regional Development Fund (TK141 “Ad-
vanced materials and high-technology devices for energy recuper-
ation systems”) and by the research grant PRG690 from the Esto-
nian Research Council.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1)
a) Enantioselective Mannich-type reaction catalyzed by a chiral
Brønsted acid. Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem. Int. Ed. 2004, 43, 1566–1568; b) Chiral Brønsted Acid-Catalyzed
Direct Mannich Reactions via Electrophilic Activation. Uraguchi, D.;
Terada, M. J. Am. Chem. Soc. 2004, 126, 5356–5357.
(2)
Selected reviews on asymmetric Brønsted acid catalysis: a)
"Designer acids": Combined acid catalysis for asymmetric synthesis.
Yamamoto, H.; Futatsugi, K. Angew. Chem. Int. Ed. 2005, 44, 1924–1942;
b) Stronger Brønsted Acids. Akiyama, T. Chem. Rev. 2007, 107, 5744–
5758; c) Chiral Phosphoric Acids as Versatile Catalysts for Enantioselec-
tive Transformations. Terada, M. Synthesis 2010, 1929-1982; d) Complete
Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and
Metal Catalysis: History and Classification by Mode of Activation;
Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates.
Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114,
9047-9153; e) Stronger Brønsted Acids: Recent Progress. Akiyama, T.;
Mori, K. Chem. Rev. 2015, 115, 9277-9306; f) Rueping, M.; Parmar, D.;
Sugiono, E. Asymmetric Brønsted Acid Catalysis; Wiley-VCH: Weinheim,
2015; g) Asymmetric Brønsted acid catalysis with chiral carboxylic acids.
Min, C.; Seidel, D. Chem. Soc. Rev. 2017, 46, 5889-5902; h) Dual
Brønsted acid Organocatalysis: Cooperative Asymmetric Catalysis with
Combined Phosphoric and Carboxylic Acids. Mitra, R.; Niemeyer, J.
ChemCatChem 2018, 10, 1221-1234; i) IDPi Catalysis. Schreyer, L.;
Properzi, R.; List, B. Angew. Chem. Int. Ed. 2019, 58, 12761-12777.
Figure 2. pKa values of thiourea-carboxylic acid catalysts and
comparison to other acids.
In conclusion, we have achieved highly efficient [4+2]
cycloadditions of salicylaldehyde-derived acetals with
homoallylic and bishomoallylic alcohols to provide polycyclic
furanochromanes and pyranochromanes in good to excellent
yields and enantioselectivities. This advance was enabled through
the development of a new generation of conjugate-base-stabilized
carboxylic acid catalysts. The observation that Brønsted acids
with identical pKa values can exhibit vastly different catalytic
activities makes a compelling case for the continued exploration
of more structurally diverse catalysts.
(3)
a) Hypervalent iodine(V)-induced asymmetric oxidation of
sulfides to sulfoxides mediated by reversed micelles: Novel nonmetallic
catalytic system. Tohma, H.; Takizawa, S.; Watanabe, H.; Fukuoka, Y.;
Maegawa, T.; Kita, Y. J. Org. Chem. 1999, 64, 3519-3523; b) Brønsted
acid catalysis of achiral enamine for regio- and enantioselective nitroso
aldol synthesis. Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2005,
127, 1080-1081; c) Enantioselective aza-Friedel-Crafts reaction catalyzed
by a water inclusion complex of O,O '-diacyl tartaric acid. Ube, H.; Fuku-
chi, S.; Terada, M. Tetrahedron: Asymmetry 2010, 21, 1203-1205; d)
Enantioselective Boronate Additions to N-Acyl Quinoliniums Catalyzed
by Tartaric Acid. Kodama, T.; Moquist, P. N.; Schaus, S. E. Org. Lett.
2011, 13, 6316-6319; e) Enantioselective Synthesis of 1,2-
Dihydronaphthalene-1-carbaldehydes by Addition of Boronates to Iso-
chromene Acetals Catalyzed by Tartaric Acid. Luan, Y.; Barbato, K. S.;
Moquist, P. N.; Kodama, T.; Schaus, S. E. J. Am. Chem. Soc. 2015, 137,
3233-3236.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data, including X-
ray crystal structure of product 3n. This material is available free
of charge via the Internet at http://pubs.acs.org.
(4)
a) Design of axially chiral dicarboxylic acid for asymmetric
Mannich reaction of arylaldehyde N-Boc imines and diazo compounds.
Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054-10055;
b) Asymmetric imino aza-enamine reaction catalyzed by axially chiral
dicarboxylic acid: Use of arylaldehyde N,N-dialkylhydrazones as acyl
anion equivalent. Hashimoto, T.; Hirose, M.; Maruoka, K. J. Am. Chem.
Soc. 2008, 130, 7556-7557; c) In Situ Assembled Boronate Ester Assisted
Chiral Carboxylic Acid Catalyzed Asymmetric Trans-Aziridinations.
AUTHOR INFORMATION
Corresponding Author
* E-mail: seidel@chem.ufl.edu
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
Hashimoto, T.; Gálvez, A. O.; Maruoka, K. J. Am. Chem. Soc. 2013, 135,
17667-17670.
al-Free Catalysis. Jaworski, A. A.; Scheidt, K. A. J. Org. Chem. 2016, 81,
10145-10153; g) ortho-Quinone methides as key intermediates in cascade
heterocyclizations. Osipov, D. V.; Osyanin, V. A.; Klimochkin, Y. N.
Russ. Chem. Rev. 2017, 86, 625-687; h) Recent advances in the applica-
tion of Diels–Alder reactions involving o-quinodimethanes, aza-o-quinone
methides and o-quinone methides in natural product total synthesis. Yang,
B.; Gao, S. Chem. Soc. Rev. 2018, 47, 7926-7953; i) Stereoselective Reac-
tions of ortho-Quinone Methide and ortho-Quinone Methide Imines and
Their Utility in Natural Product Synthesis. Nielsen, C. D. T.; Abas, H.;
Spivey, A. C. Synthesis 2018, 50, 4008-4018; j) Applications of Bifunc-
tional Organocatalysts on ortho-Quinone Methides. Mukhopadhyay, S.;
Gharui, C.; Pan, S. C. Asian J. Org. Chem. 2019, 8, 1970-1984.
1
2
3
4
5
6
7
8
(5)
a) Conjugate-Base-Stabilized Brønsted Acids as Asymmetric
Catalysts: Enantioselective Povarov Reactions with Secondary Aromatic
Amines. Min, C.; Mittal, N.; Sun, D. X.; Seidel, D. Angew. Chem. Int. Ed.
2013, 52, 14084-14088; b) Conjugate-Base-Stabilized Brønsted Acids:
Catalytic Enantioselective Pictet-Spengler Reactions with Unmodified
Tryptamine. Mittal, N.; Sun, D. X.; Seidel, D. Org. Lett. 2014, 16, 1012-
1015; c) Enantioselective A3 Reactions of Secondary Amines with a
Cu(I)/Acid–Thiourea Catalyst Combination. Zhao, C.; Seidel, D. J. Am.
Chem. Soc. 2015, 137, 4650-4653; d) Catalytic Enantioselective Intramo-
lecular Aza-Diels–Alder Reactions. Min, C.; Lin, C.-T.; Seidel, D. Angew.
Chem. Int. Ed. 2015, 54, 6608-6612; e) Insights into the Structure and
Function of a Chiral Conjugate-Base-Stabilized Brønsted Acid Catalyst.
Odagi, M.; Araki, H.; Min, C.; Yamamoto, E.; Emge, T. J.; Yamanaka,
M.; Seidel, D. Eur. J. Org. Chem. 2019, 2019, 486-492; f) Highly Acidic
Conjugate-Base-Stabilized Carboxylic Acids Catalyze Enantioselective
oxa-Pictet–Spengler Reactions with Ketals. Zhu, Z.; Odagi, M.; Zhao, C.;
Abboud, K. A.; Kirm, H. U.; Saame, J.; Lõkov, M.; Leito, I.; Seidel, D.
Angew. Chem. Int. Ed. 2020, 59, 2028-2032.
9
(10)
Examples of catalytic enantioselective [4+2] cycloadditions of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o-quinone methides: a) Asymmetric Cycloadditions of o-Quinone Methi-
des Employing Chiral Ammonium Fluoride Precatalysts. Alden-Danforth,
E.; Scerba, M. T.; Lectka, T. Org. Lett. 2008, 10, 4951-4953; b) Catalytic
Asymmetric Inverse-Electron-Demand Oxa-Diels–Alder Reaction of In
Situ Generated ortho-Quinone Methides with 3-Methyl-2-Vinylindoles.
Zhao, J.-J.; Sun, S.-B.; He, S.-H.; Wu, Q.; Shi, F. Angew. Chem. Int. Ed.
2015, 54, 5460-5464; c) Ortho-Quinone Methides as Reactive Intermedi-
ates in Asymmetric Brønsted Acid Catalyzed Cycloadditions with Unacti-
vated Alkenes by Exclusive Activation of the Electrophile. Hsiao, C.-C.;
Raja, S.; Liao, H.-H.; Atodiresei, I.; Rueping, M. Angew. Chem. Int. Ed.
2015, 54, 5762-5765; d) Merging Chiral Brønsted Acid/Base Catalysis:
An Enantioselective [4 + 2] Cycloaddition of o-Hydroxystyrenes with
Azlactones. Zhang, Y.-C.; Zhu, Q.-N.; Yang, X.; Zhou, L.-J.; Shi, F. J.
Org. Chem. 2016, 81, 1681-1688; e) Brønsted Acid-Catalyzed, Diastereo-
and Enantioselective, Intramolecular Oxa-Diels–Alder Reaction of ortho-
Quinone Methides and Unactivated Dienophiles. Ukis, R.; Schneider, C. J.
Org. Chem. 2019, 84, 7175-7188.
(6)
Selected reviews on asymmetric anion-binding catalysis: a)
(Thio)urea organocatalysis - What can be learnt from anion recognition?
Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187-1198; b) The
progression of chiral anions from concepts to applications in asymmetric
catalysis. Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4,
603-614; c) Asymmetric Counteranion-Directed Catalysis: Concept, Defi-
nition, and Applications. Mahlau, M.; List, B. Angew. Chem. Int. Ed.
2013, 52, 518-533; d) Asymmetric Ion-Pairing Catalysis. Brak, K.; Jacob-
sen, E. N. Angew. Chem. Int. Ed. 2013, 52, 534-561; e) The Anion-
Binding Approach to Catalytic Enantioselective Acyl Transfer. Seidel, D.
Synlett 2014, 25, 783-794; f) Applications of Supramolecular Anion
Recognition. Busschaert, N.; Caltagirone, C.; Van Rossom, W.; Gale, P.
A. Chem. Rev. 2015, 115, 8038-8155; g) Anion-binding catalyst designs
for enantioselective synthesis. Visco, M. D.; Attard, J.; Guan, Y.; Mattson,
A. E. Tetrahedron Lett. 2017, 58, 2623-2628; h) Silanediol Anion Binding
and Enantioselective Catalysis. Attard, J. W.; Osawa, K.; Guan, Y.; Hatt,
J.; Kondo, S.-i.; Mattson, A. Synthesis 2019, 51, 2107-2115.
(11)
a) Catalytic Asymmetric Intramolecular [4+2] Cycloaddition of
In Situ Generated ortho-Quinone Methides. Xie, Y.; List, B. Angew.
Chem. Int. Ed. 2017, 56, 4936-4940; b) Asymmetric Induction via a Heli-
cally Chiral Anion: Enantioselective Pentacarboxycyclopentadiene
Brønsted Acid-Catalyzed Inverse-Electron-Demand Diels–Alder Cy-
cloaddition of Oxocarbenium Ions. Gheewala, C. D.; Hirschi, J. S.; Lee,
W.-H.; Paley, D. W.; Vetticatt, M. J.; Lambert, T. H. J. Am. Chem. Soc.
2018, 140, 3523-3527.
(7)
Selected reviews on asymmetric ion pairing and cooperative
catalysis: a) Multiple Catalysis with Two Chiral Units: An Additional
Dimension for Asymmetric Synthesis. Piovesana, S.; Scarpino Schietro-
ma, D. M.; Bella, M. Angew. Chem., Int. Ed. 2011, 50, 6216-6232; b)
Synergistic catalysis: A powerful synthetic strategy for new reaction de-
velopment. Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633-
658; c) Recent advances in cooperative ion pairing in asymmetric organo-
catalysis. Brière, J.-F.; Oudeyer, S.; Dalla, V.; Levacher, V. Chem. Soc.
Rev. 2012, 41, 1696-1707; d) Cooperative Catalysis; Peters, R., Ed.;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2015; e)
Hydrogen Bonding and Internal or External Lewis or Brønsted Acid As-
sisted (Thio)urea Catalysts. Gimeno, M. C.; Herrera, R. P. Eur. J. Org.
Chem. 2020, 2020, 1057-1068.
(12)
Selected reviews covering aspects of catalytic enantioselective
reactions involving oxocarbenium ions: a) Asymmetric Organocatalytic
Cyclization and Cycloaddition Reactions. Moyano, A.; Rios, R. Chem.
Rev. 2011, 111, 4703-4832; b) Catalytic Stereoselective SN1-Type Reac-
tions Promoted by Chiral Phosphoric Acids as Brønsted Acid Catalysts.
Gualandi, A.; Rodeghiero, G.; Cozzi, P. G. Asian J. Org. Chem. 2018, 7,
1957-1981; c) Catalytic Enantioselective Approaches to the oxa-Pictet–
Spengler Cyclization and Other 3,6-Dihydropyran-Forming Reactions.
Zhu, Z.; Adili, A.; Zhao, C.; Seidel, D. SynOpen 2019, 03, 77-90.
(13)
Examples of catalytic enantioselective reactions involving the
intermediacy of oxocarbenium ions: a) Titanium(IV)-Catalyzed Dynamic
Kinetic Asymmetric Transformation of Alcohols, Silyl Ethers, and Acetals
under Carbon Allylation. Braun, M.; Kotter, W. Angew. Chem. Int. Ed.
2004, 43, 514-517; b) Catalytic Enantioselective Aldol-type Reaction of
β-Ketosters with Acetals. Umebayashi, N.; Hamashima, Y.; Hashizume,
D.; Sodeoka, M. Angew. Chem. Int. Ed. 2008, 47, 4196-4199; c) Enanti-
oselective Thiourea-Catalyzed Additions to Oxocarbenium Ions. Reisman,
S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198–
7199; d) Enantioselective Direct Aldol-Type Reaction of Azlactone via
Protonation of Vinyl Ethers by a Chiral Brønsted Acid Catalyst. Terada,
M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc. 2009, 131, 3430-3431;
e) Enantioselective Addition of Boronates to Chromene Acetals Catalyzed
by a Chiral Brønsted Acid/Lewis Acid System. Moquist, P. N.; Kodama,
T.; Schaus, S. E. Angew. Chem. Int. Ed. 2010, 49, 7096-7100; f) Catalytic
Asymmetric Transacetalization. Čorić, I.; Vellalath, S.; List, B. J. Am.
Chem. Soc. 2010, 132, 8536-8537; g) Dual Catalysis in Enantioselective
Oxidopyrylium-Based 5+2 Cycloadditions. Burns, N. Z.; Witten, M. R.;
Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 14578-14581; h) Copper-
Catalyzed Enantioselective Additions to Oxocarbenium Ions: Alkynyla-
tion of Isochroman Acetals. Maity, P.; Srinivas, H. D.; Watson, M. P. J.
Am. Chem. Soc. 2011, 133, 17142-17145; i) Asymmetric spiroacetaliza-
tion catalysed by confined Brønsted acids. Coric, I.; List, B. Nature 2012,
483, 315-319; j) Catalytic Asymmetric Addition of Aldehydes to Oxo-
carbenium Ions: A Dual Catalytic System for the Synthesis of Chromenes.
Rueping, M.; Volla, C. M. R.; Atodiresei, I. Org. Lett. 2012, 14, 4642-
4645; k) Chiral Phosphoric Acid-Catalyzed Enantioselective and Dia-
stereoselective Spiroketalizations. Sun, Z.; Winschel, G. A.; Borovika, A.;
(8)
a) Studies on antibiotics from Helminthosposium sp. fungi.
VII. Siccanin, a new antifungal antibiotic produced by Helminthosposium
siccans. Ishibashi, K. J. Antibiot., A 1962, 15, 161-167; b) Biomimetic
Enantioselective Total Synthesis of (−)-Siccanin via the Pd-Catalyzed
Asymmetric Allylic Alkylation (AAA) and Sequential Radical Cycliza-
tions. Trost, B. M.; Shen, H. C.; Surivet, J.-P. J. Am. Chem. Soc. 2004,
126, 12565-12579; c) Naphthalene Derivatives from the Roots of Pentas
parvifolia and Pentas bussei. Abdissa, N.; Pan, F.; Gruhonjic, A.; Gräfen-
stein, J.; Fitzpatrick, P. A.; Landberg, G.; Rissanen, K.; Yenesew, A.;
Erdélyi, M. J. Nat. Prod. 2016, 79, 2181-2187; d) Total Synthesis of (+)-
Medicarpin. Yang, X.; Zhao, Y.; Hsieh, M.-T.; Xin, G.; Wu, R.-T.; Hsu,
P.-L.; Horng, L.-Y.; Sung, H.-C.; Cheng, C.-H.; Lee, K.-H. J. Nat. Prod.
2017, 80, 3284-3288.
(9)
Selected reviews on the chemistry of o-quinone methides: a) o-
Quinone methides: intermediates underdeveloped and underutilized in
organic synthesis. Van De Water, R. W.; Pettus, T. R. R. Tetrahedron
2002, 58, 5367-5405; b) ortho-Quinone Methides in Natural Product Syn-
thesis. Willis, N. J.; Bray, C. D. Chem. Eur. J. 2012, 18, 9160-9173; c)
The Domestication of ortho-Quinone Methides. Bai, W.-J.; David, J. G.;
Feng, Z.-G.; Weaver, M. G.; Wu, K.-L.; Pettus, T. R. R. Acc. Chem. Res.
2014, 47, 3655-3664; d) Recent Advances in Catalytic Asymmetric Reac-
tions of o-Quinone Methides. Wang, Z.; Sun, J. Synthesis 2015, 47, 3629-
3644; e) The Emergence of Quinone Methides in Asymmetric Organoca-
talysis. Caruana, L.; Fochi, M.; Bernardi, L. Molecules 2015, 20, 11733-
11764; f) Emerging Roles of in Situ Generated Quinone Methides in Met-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
Nagorny, P. J. Am. Chem. Soc. 2012, 134, 8074-8077; l) The Catalytic
4550-4562. See also b) Stereochemically Rich Polycyclic Amines from
the Kinetic Resolution of Indolines through Intramolecular Povarov Reac-
tions. Min, C.; Seidel, D. Chem. Eur. J. 2016, 22, 10817-10820 and refer-
ences cited therein.
Asymmetric Acetalization. Kim, J. H.; Čorić, I.; Vellalath, S.; List, B.
Angew. Chem. Int. Ed. 2013, 52, 4474-4477; m) Catalytic Enantioselective
Oxidative Cross-Coupling of Benzylic Ethers with Aldehydes. Meng, Z.;
Sun, S.; Yuan, H.; Lou, H.; Liu, L. Angew. Chem. Int. Ed. 2014, 53, 543-
547; n) Enantioselective Copper(I)‐ Catalyzed Alkynylation of Oxocarbe-
nium Ions to Set Diaryl Tetrasubstituted Stereocenters. Dasgupta, S.;
Rivas, T.; Watson, M. P. Angew. Chem. Int. Ed. 2015, 54, 14154-14158;
o) Organocatalytic Enantio- and Diastereoselective Synthesis of 1,2-
Dihydronaphthalenes from Isobenzopyrylium Ions. Qian, H.; Zhao, W.;
Wang, Z.; Sun, J. J. Am. Chem. Soc. 2015, 137, 560-563; p) An aromatic
ion platform for enantioselective Brønsted acid catalysis. Gheewala, C. D.;
Collins, B. E.; Lambert, T. H. Science 2016, 351, 961-965; q) Direct For-
mation of Oxocarbenium Ions under Weakly Acidic Conditions: Catalytic
Enantioselective Oxa-Pictet–Spengler Reactions. Zhao, C.; Chen, S. B.;
Seidel, D. J. Am. Chem. Soc. 2016, 138, 9053-9056; r) Nitrated Confined
Imidodiphosphates Enable a Catalytic Asymmetric Oxa-Pictet–Spengler
Reaction. Das, S.; Liu, L.; Zheng, Y.; Alachraf, M. W.; Thiel, W.; De, C.
K.; List, B. J. Am. Chem. Soc. 2016, 138, 9429-9432; s) A General Cata-
lytic Asymmetric Prins Cyclization. Liu, L.; Kaib, P. S. J.; Tap, A.; List,
B. J. Am. Chem. Soc. 2016, 138, 10822-10825; t) Silanediol-Catalyzed
Chromenone Functionalization. Hardman-Baldwin, A. M.; Visco, M. D.;
Wieting, J. M.; Stern, C.; Kondo, S.-i.; Mattson, A. E. Org. Lett. 2016, 18,
3766-3769; u) Organocatalytic Enantioselective Acyloin Rearrangement
of α-Hydroxy Acetals to α-Alkoxy Ketones. Wu, H.; Wang, Q.; Zhu, J.
Angew. Chem. Int. Ed. 2017, 56, 5858-5861; v) Asymmetric Catalysis via
Cyclic, Aliphatic Oxocarbenium Ions. Lee, S.; Kaib, P. S. J.; List, B. J.
Am. Chem. Soc. 2017, 139, 2156-2159; w) A Cooperative Hydrogen Bond
Donor–Brønsted Acid System for the Enantioselective Synthesis of Tetra-
hydropyrans. Maskeri, M. A.; O'Connor, M. J.; Jaworski, A. A.; Davies,
A. V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2018, 57, 17225-17229; x)
Helical Multi-Coordination Anion-Binding Catalysts for the Highly Enan-
tioselective Dearomatization of Pyrylium Derivatives. Fischer, T.; Bam-
berger, J.; Gómez-Martínez, M.; Piekarski, D. G.; García Mancheño, O.
Angew. Chem. Int. Ed. 2019, 58, 3217-3221; y) A Facile Enantioselective
Alkynylation of Chromones. DeRatt, L. G.; Pappoppula, M.; Aponick, A.
Angew. Chem. Int. Ed. 2019, 58, 8416-8420; z) Copper Bis(oxazoline)-
Catalyzed Enantioselective Alkynylation of Benzopyrylium Ions. Guan,
Y.; Attard, J. W.; Mattson, A. E. Chem. Eur. J. 2020, 26, 1742-1747.
1
2
3
4
5
6
7
8
(18)
diastereoselective. See the Supporting Information for details.
(19) Acetonitrile offers multiple advantages for establishing a pKa
Interestingly, the racemic version of this reaction is highly
scale: pKa values in organic chemistry – Making maximum use of the
available data. Kütt, A.; Selberg, S.; Kaljurand, I.; Tshepelevitsh, S.; Heer-
ing, A.; Darnell, A.; Kaupmees, K.; Piirsalu, M.; Leito, I. Tetrahedron
Lett. 2018, 59, 3738-3748.
(20)
On the Acidity and Reactivity of Highly Effective Chiral
9
Brønsted Acid Catalysts: Establishment of an Acidity Scale. Kaupmees,
K.; Tolstoluzhsky, N.; Raja, S.; Rueping, M.; Leito, I. Angew. Chem. Int.
Ed. 2013, 52, 11569-11572.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(21)
Prediction of acidity in acetonitrile solution with COSMO-RS.
Eckert, F.; Leito, I.; Kaljurand, I.; Kütt, A.; Klamt, A.; Diedenhofen, M. J.
Comput. Chem. 2009, 30, 799-810.
(14)
Examples of non-asymmetric [4+2] cycloadditions of salic-
ylaldehyde derivatives with homoallylic and bishomoallylic alcohols: a) A
Facile Synthesis of Angularly-Fused 3,4,4a,10b-Tetrahydro-2H,5H-
pyrano[3,2-c][1]benzopyrans by the One-pot Condensation between Sa-
licylaldehydes and Unsaturated Alcohols. Seiichi, I.; Masatoshi, A.; Kiyo-
shi, H.; Hidekazu, M. Chem. Lett. 1996, 25, 889-890; b) Stereoselective
Synthesis of Pyrano[3,2-c]benzopyrans via Intramolecular Cycloaddition
of o-Quinonemethides Generated from Salicylaldehydes and Unsaturated
Alcohols under Very Mild Conditions. Miyazaki, H.; Honda, K.; Asami,
M.; Inoue, S. J. Org. Chem. 1999, 64, 9507-9511; c) A Facile Synthesis of
trans-Fused Pyrano[3,2-c]benzopyrans Catalyzed by Scandium Triflate.
Yadav, J. S.; Reddy, B. V. S.; Aruna, M.; Thomas, M. Synthesis 2002,
2002, 0217-0220; d) Stereoselective Synthesis of cis- and trans-2,3-
Disubstituted Tetrahydrofurans via Oxonium−Prins Cyclization: Access to
the Cordigol Ring System. Spivey, A. C.; Laraia, L.; Bayly, A. R.; Rzepa,
H. S.; White, A. J. P. Org. Lett. 2010, 12, 900-903; e) Diastereoselective
Synthesis of Angularly Fused Pyranochromenes. Sarmah, B.; Baishya, G.;
Hazarika, N.; Das, P. J. Synlett 2015, 26, 2151-2155; f) Synthesis of Fu-
ro[3,2-c]benzopyrans via an Intramolecular [4 + 2] Cycloaddition Reac-
tion of o-Quinonemethides. Zhao, L.-M.; Zhang, A.-L.; Gao, H.-S.;
Zhang, J.-H. J. Org. Chem. 2015, 80, 10353-10358; g) Reversibility and
reactivity in an acid catalyzed cyclocondensation to give furanochromanes
– a reaction at the ‘oxonium-Prins’ vs. ‘ortho-quinone methide cycloaddi-
tion’ mechanistic nexus. Nielsen, C. D. T.; Mooij, W. J.; Sale, D.; Rzepa,
H. S.; Burés, J.; Spivey, A. C. Chem. Sci. 2019, 10, 406-412.
(15)
a) A Powerful Brønsted Acid Catalyst for the Organocatalytic
Asymmetric Transfer Hydrogenation of Imines. Hoffmann, S.; Seayad, A.
M.; List, B. Angew. Chem. Int. Ed. 2005, 44, 7424-7427; b) Synthesis of
TRIP and Analysis of Phosphate Salt Impurities. Klussmann, M.; Ratjen,
L.; Hoffmann, S.; Wakchaure, V.; Goddard, R.; List, B. Synlett 2010,
2010, 2189-2192.
(16)
Terminal mono-substituted olefins including dienyl homoal-
lylic alcohols are relatively poor substrates in this transformation. See the
Supporting Information for details.
(17)
For a leading review on this topic, see: a) Divergent reactions
on racemic mixtures. Miller, L. C.; Sarpong, R. Chem. Soc. Rev. 2011, 40,
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
1
2
Table of Contents artwork
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment