Two Competitive but Switchable Organocatalytic Cascade Reaction Pathways: The Diversified Synthesis of Chiral Acetal-Containing Bridged Cyclic Compounds

Article abstract of DOI:10.1021/acs.orglett.8b03654

The organocatalytic enantioselective synthesis of methanobenzodioxepine derivatives bearing a 6,6,5-bridged ring system is presented. The m-CPBA-triggered in situ α-oxidation of β-oxoesters to provide the required but unstable α-hydroxy-β-dicarbonyl substrates is the key to this three-step sequence, providing the desired cyclic acetals with excellent stereoselectivities containing two bridgehead and one fully substituted stereocenters. It is noteworthy that the absence of m-CPBA furnished the acetal products bearing a 6,6,6-bridged ring system with similar good results from the same starting materials.

Full text of DOI:10.1021/acs.orglett.8b03654

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Two Competitive but Switchable Organocatalytic Cascade Reaction
Pathways: The Diversified Synthesis of Chiral Acetal-Containing
Bridged Cyclic Compounds
†
†
,†,‡
Xue-Jiao Lv, Ying-Han Chen, and Yan-Kai Liu*
†Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China,
Qingdao 266003, China
‡
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao
2
66003, China
*
S Supporting Information
ABSTRACT: The organocatalytic enantioselective synthesis
of methanobenzodioxepine derivatives bearing a 6,6,5-bridged
ring system is presented. The m-CPBA-triggered in situ α-
oxidation of β-oxoesters to provide the required but unstable
α-hydroxy-β-dicarbonyl substrates is the key to this three-step
sequence, providing the desired cyclic acetals with excellent
stereoselectivities containing two bridgehead and one fully
substituted stereocenters. It is noteworthy that the absence of
m-CPBA furnished the acetal products bearing a 6,6,6-bridged
ring system with similar good results from the same starting
materials.
he chiral methanobenzodioxepine scaffold, containing
two bridgehead carbon stereogenic centers, constitutes a
Scheme 1. Retrosynthetic Analysis for the Synthesis of the
Methanobenzodioxepine Scaffold
T
privileged structural unit in many bioactive natural products
1
and pharmaceuticals. As a result, it has received considerable
attention from chemists for the synthesis of this bridged cyclic
2
acetal skeleton. However, although a number of strategies
have been developed, it has been found that the
enantioselective construction of such a cyclic acetal moiety is
quite challenging since almost no asymmetric catalytic
approaches have been reported, which may be ascribed to
the structural complexity and rigidity of the bridged cyclic
3
dehyde to a hydroxy-containing nucleophile followed by the
acid-catalyzed intramolecular acetal formation.
system.
In 2016, Jørgensen and co-workers reported the first
example of an asymmetric iminium-catalytic Friedel−Crafts
We recently focused on the application of hemiacetals in
5
4
asymmetric organocatalysis and found that 2-hydroxycinna-
reaction to prepare chiral methanobenzodioxepine scaffolds.
maldehyde could serve as a precursor of the 6,6-fused ring
system in the synthesis of chiral polycyclic architectures via
However, the reaction was demonstrated as a competitive
process between the synthesis of fused cyclic ketal and bridged
cyclic acetal and thus limited to particular substrates bearing an
aryl side chain for the regioselectivity. To the best of our
knowledge, there is no other report on the enantioselective
construction of chiral methanobenzodioxepine derivatives.
Therefore, given their biological relevance, asymmetric
synthetic strategies to construct chiral methanobenzodioxepine
scaffold in a practical and efficient manner are still in great
demand.
As shown in Scheme 1, a general retrosynthetic analysis of
the methanobenzodioxepine scaffold possessing 6,6,5-bridged
ring system leads to the key intermediate bearing a hemiacetal
moiety and a free hydroxy group, which can be accessed by
iminium-catalyzed conjugate addition of 2-hydroxycinnamal-
6
hemiacetal-containing intermediates. We thus proposed that
the application of α-hydroxy-β-dicarbonyl compounds as
hydroxy-containing nucleophiles to react with 2-hydroxycinna-
7
maldehyde seemed promising, since α-hydroxy-β-dicarbonyl
compounds have emerged as valuable synthons in many
8
important chemical transformations. It should be noted that
α-hydroxy-β-dicarbonyl compound has never been used as a
9
competent nucleophile in analogous reactions pathways.
However, from the outset of our studies, the concept is
considered to be particularly challenging because we found
Received: November 15, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
that α-hydroxy-β-dicarbonyl compound 2 was quite unstable
toward air oxidation and easily converted into α,β-
dioxocarbonyl 7 during the purification process by silica gel
column chromatography (Scheme 2). We envisioned that the
TMS = trimethylsilyl) at 25 °C in DCE did not provide the
expected key intermediate hemiacetal 5a. Meanwhile, most of
2a was oxidized into 7a. However, this is rather surprising
because the electron induction of the hydroxy moiety could be
expected to increase the acidity of the hydrogen atom at the α-
12
Scheme 2. Design of Synthetic Strategies
position and the propensity toward an alkylation pathway.
Indeed, when the preformed α-hydroxy-β-dicarbonyl 2b,
which was somewhat stable because of the strong electron-
donating effect of the methoxy group, was used in the
sequential reaction with 3a in the presence of catalyst 4 and
without acidic or basic additives (Scheme 3b, Ar = 4-
MeOC H ), the desired product 6b was obtained in 80%
6
4
yield with excellent stereoselectivity (97% ee, dr >20:1). When
m-CBA (20 mol %) was used as the acidic additive, the
reaction became sluggish (19 h, 33% yield), albeit with a high
level of stereocontrol (97% ee, dr >20:1). Almost no reaction
occurred (>48 h) when 100 mol % of m-CBA was used.
Additionally, it is proposed that an active aminal intermediate
8 was formed from the reaction of 3a with catalyst 4 in an
challenging issue could be addressed via the in situ oxidation of
10
13
β-oxoesters 1 by m-chloroperbenzoic acid (m-CPBA), where
the byproduct m-chlorobenzoic acid (m-CBA) can further act
as an acidic additive in the aminocatalyst 4 triggered iminium
almost quantitative yield, and we also found that the
preformed 2b could be converted cleanly into 6b by the
reaction with aminal 8 (Scheme 3c, Ar = 4-MeOC H ), and
6 4
1
1
catalysis to promote the reaction of 2-hydroxycinnamalde-
hyde 3a and the in situ formed 2, thus enabling a milder access
to target the chiral methanobenzodioxepine scaffold 6 after
oxocarbenium ion induced ring closure of the key intermediate
similar good results were obtained as compared to the direct
sequential reaction path, which indicates that aminal 8 is
involved in the catalytic process. However, to our surprise, a
large amount of acidic additives, such as 100 mol % of m-CBA,
significantly suppressed the reaction rate for the generation of
the active aminal intermediate 8, while the reaction between 3a
and catalyst 4 led to a mixture of 8 and o-quinone methides
5. Herein, we report our efforts to address this issue, which led
to chiral methanobenzodioxepine scaffolds with a wide
substrate scope in good yields and with excellent stereo-
selectivities. Nevertheless, there are still several issues with this
design: (1) the undesired side reaction Baeyer−Villiger-type
oxidation of β-oxoesters; (2) the oxidation of aminocatalyst
resulting in complete loss of catalytic activity; and (3) the
stereocontrolled creation of two bridgehead and one fully
substituted stereocenters.
With these considerations in mind, we initially investigated
the in situ oxidation of ethyl benzoylacetate 1a with m-CPBA
in 1,2-dichoroethane (DCE) at 60 °C (Scheme 3a). However,
upon complete consumption of 1a, the subsequent conjugate
addition of 3a and 2a catalyzed by aminocatalyst 4 (20 mol %,
14
8′, which is inactive for the conjugate addition with α-
hydroxy-β-dicarbonyl 2 (Scheme 3d). In fact, this could
explain why no hemiacetal 5a was obtained due to the
existence of 2.4 equiv of m-CBA in the reaction mixture as the
byproducts.
Based on the above observations, we envisioned that the use
of base would be essential, which plays two roles: (1)
accelerating the formation of the active aminal intermediate 8
and (2) the deprotonative activation of α-hydroxy-β-
dicarbonyl 2. Much to our delight (Scheme 4), with the
Scheme 4. Sequential Synthesis of Chiral
Scheme 3. Control Experiments
Methanobenzodioxepine Scaffold
addition of N,N-diisopropylethylamine (DIPEA) to neutralize
the byproducts m-CBA, the in situ oxidation triggered
sequential reaction proceeded smoothly, providing the key
intermediate 5a, and the subsequent BF ·Et O-catalyzed acetal
3
2
formation via oxocarbenium ion delivered the desired bridged
cyclic acetal product 6a in good isolated yield with excellent
enantioselectivity as a single diastereoisomer.
Inspired by the success of the above model reaction, we next
explored the substrate scope of the reaction sequence between
2
-hydroxycinnamaldehydes 3 and the in situ formed 2. As
shown in Scheme 5, regardless of the electronic properties and
the position of substituents on the phenyl ring of 1, the
reaction proceeded smoothly, providing products 6a−f in good
yields with good to excellent stereoselectivities. The heteroaryl-
and naphthyl-substituted 1 also worked well in the reaction
B
DOI: 10.1021/acs.orglett.8b03654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Substrate Scope of the Sequential Reaction of 2-
Hydroxycinnamaldehydes 3 and in Situ Formed 2
Scheme 6. Sequential Synthesis of Chiral 6,6,6-Bridged Ring
Scaffold
a
the hemiketal isomer 9′a by NMR spectroscopy (characteristic
15
carbon of the ketone carbonyl moiety at δ 196.2 ppm).
Unexpectedly, when 9a was treated with an excess of BF ·Et O,
3
2
the reaction mixture showed two new spots on TLC, and the
more polar one gradually converted to the less polar one,
which was confirmed to be the expected bridged cyclic acetal
1
0a (92%, 53% ee, dr >20:1), while the more polar
intermediate 11, which was somewhat unstable to isolation,
was characterized to be the dimer of 9a by mass spectroscopy.
Interestingly, we found that, in the presence of BF ·Et O, the
dimer 11 was first hydrolyzed to give 9a, followed by ring-
closure to afford 10a.
3
2
16
Encouraged by these initial results, we next focused on the
scope of this sequential cascade transformation, involving a
Michael addition, ketalization, and dehydration reaction
sequence. As shown in Scheme 7, ethyl benzoylacetate 1,
a
All reactions were carried out using 1 (0.2 mmol, 2.0 equiv) and m-
CPBA (0.24 mmol, 2.4 equiv) in DCE (0.2 mL) at 60 °C for 20 h to
give the required α-hydroxy-β-dicarbonyl compound 2. Then DIPEA
(
0.24 mmol, 2.4 equiv) was added to remove m-chlorobenzoic acid
followed by the addition of 3 (0.10 mmol, 1.0 equiv) and 4 (20 mol
) to afford product 5, which was cyclized in the presence of BF3·
Et O (1.0 equiv) at 0 °C in CH Cl (1 mL) leading to product 6.
Scheme 7. Substrate Scope of the Sequential Reaction of 2-
%
a
Hydroxycinnamaldehydes 3 and β-Oxoesters 1
2
2
2
Isolated yields are given. Enantiomeric excesses (ee) are determined
by chiral HPLC analysis. Diastereomeric ratios (dr) are determined
1
by H NMR spectroscopy of the crude reaction mixture. Boc = tert-
butoxycarbonyl; Ts = 4-toluenesulfonyl.
sequence, delivering the bridged cyclic products 6g and 6h in
good results. It should be noted that 6g was obtained as two
inseparable diastereoisomer (3:1), while by using an alkyl
group instead of an aryl group, the desired product was
obtained as two separable epimers, 6i and 6′i, with slightly
decreased enantioselectivity. Furthermore, the benzyl and tert-
butyl benzoylacetates were tolerated in this sequential process
(
6j and 6k), albeit with slightly lower enantioselectivities. For
a
Performed on 0.2 mmol scale with 1.1 equiv of 1 and 1.0 equiv of 3.
the 2-hydroxycinnamaldehyde substrates, both electron-donat-
ing and electron-withdrawing groups at different positions on
the aromatic rings were compatible with this transformation,
affording the products 6l−q in good yield with excellent
enantioselectivity. It should be noted that no reaction (NR)
was observed with 3-Cl-substituted 3, probably for steric
reasons (6r) Furthermore, Boc- and Ts-protected 2-amino-
cinnamaldehyde 3 were also found to be suitable substrates,
and the desired bridged aminal-containing product 6s and 6t
were obtained with excellent stereoselectivity, albeit in lower
yield.
Indeed, during the optimization of reaction conditions for
the synthesis of 6a, a small amount of the undesired enol-
containing bridged cyclic acetal 10a was observed when there
was an incomplete oxidation of ethyl benzoylacetate 1a, and
this original structure attracted our attention, which possesses a
Isolated yields are given. Enantiomeric excess (ee) are determined by
chiral HPLC analysis. Diastereomeric ratios (dr) are determined by
1
H NMR spectroscopy of the crude reaction mixture.
bearing electronically different substituents at various positions
of the aromatic ring, reacted smoothly with 2-hydroxycinna-
maldehyde 3, affording the enol-containing bridged cyclic
acetal in good yield with high enantioselectivity as a single
diastereoisomer (10a−e). This reaction sequenced is appli-
cable to alkyl-substituted β-dicarbonyl (10f). Similar good
results were also obtained regardless of the substituents on the
aryl moiety of 2-hydroxycinnamaldehyde (10g−j).
As previously mentioned, the β-dicarbonyl moiety has
emerged as a valuable synthon in many important chemical
transformations, and then selected transformations were
performed to demonstrate the synthetic utility of the
corresponding cascade products 6b and 10a (Scheme 8). By
6
,6,6-bridged ring system. We then tested the reaction of 2-
hydroxycinnamaldehyde 3a and ethyl benzoylacetate 1a in the
presence of catalyst 4 in DCE at 25 °C (Scheme 6), leading to
the hemiacetal intermediate 9a, which was distinguished from
using LiAlH in THF at 0 °C, the reduction of 6b gave the
dihydroxy-bridged acetal 12 with an additional stereocenter
4
C
DOI: 10.1021/acs.orglett.8b03654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 8. Useful Transformations
The structure and stereochemistry of 6p (CCDC 1878221)
were unambiguously determined by single-crystal X-ray
analysis (Scheme 5; the H atoms are omitted for clarity). All
other compound structures were assigned by analogy to 6p
assuming a uniform reaction pathway. The absolute config-
uration of compounds 6i, 13, 18, and 20 was determined by
chemical correlation (see the Supporting Information for
details).
In summary, we have developed a highly efficient organo-
catalytic three-step sequence for the construction of chiral
methanobenzodioxepine derivatives containing two bridgehead
and one fully substituted stereogenic centers with a wide
substrate scope and with high stereoselectivity. The key to the
success of this strategy was the in situ formed α-hydroxy-β-
dicarbonyl 2 via the metal-free α-hydroxylation of α-
unsubstituted β-dicarbonyl compounds by using m-CPBA as
the oxidant. For the first time, α-hydroxy-β-keto esters were
used in asymmetric organocatalytic cascade reactions to
construct polyheterocyclic compounds bearing a 6,6,5-bridged
ring system. Interestingly, the reaction sequence could proceed
smoothly in the absence of m-CPBA, leading to different types
of polycyclic acetals that possess a 6,6,6-bridged ring system.
Moreover, based on the dicarbonyl functionality, several
valuable transformations were realized to furnish spiro-bridged
polycyclic acetals with high levels of structural complexity. The
application of this in situ oxidation strategy to construct
complex heterocyclic compounds is currently underway in our
laboratory and will be reported in due course.
ASSOCIATED CONTENT
Supporting Information
■
with complete stereocontrol. Compound 12 reacted with
*
S
(
dimethoxymethyl)benzene and 2,2-dimethoxypropane, re-
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03654.
spectively, in the presence of p-TsOH to produce 13 and 14,
both of which contained a spiro fully substituted stereogenic
center. Notably, 13 was obtained as a single diastereoisomer
with the creation of one new asymmetric center. Additionally,
the regioselective tosylation of the primary hydroxyl group in
Detailed optimization, experimental procedures, spectro-
scopic data for all new compounds, and X-ray data
(PDF)
1
2 followed by n-BuLi-triggered ring closure via intramolecular
O-nucleophilic substitution provided the spirocyclic product15
containing a four-membered oxetane ring in 47% total yield
over three steps. The Bayer−Villiger oxidation of the aryl
ketone functionality with m-CPBA as the oxidant delivered the
acyl-protected ketal 16 in 67% yield, maintaining excellent
stereoselectivity. Moreover, a highly chemo- and stereo-
Accession Codes
CCDC 1878221 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
selective reduction of the ketone group with NaBH resulted
4
in secondary alcohol product 17, followed by TiCl -catalyzed
4
intramolecular transacetalization to generate 6,6,6-benzannu-
lated bridged cyclic acetal 18 containing a fully substituted
stereogenic center with a free hydroxy group. It is noteworthy
that the newly formed bridged stereocenter of 18 can be
introduced with complete stereoselectivity. Furthermore, in the
presence of Et SiH and BF ·Et O, compound 17 was smoothly
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: liuyankai@ouc.edu.cn.
ORCID
3
3
2
dehydroxylated to give enantiopure bridged acetal 19. On the
other hand, Pd/C-catalyzed hydrogenation of the double bond
in 10b yielded 20 as the only stereoisomeric product with two
new chiral centers. Additionally, hydrolysis of 10b afforded
acid 21, and when acid 21 was exposed to blue LED in the
Yan-Kai Liu: 0000-0002-6559-2348
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
presence of PhI(OAc)2 and I , oxidative cross coupling
■
2
between C−H and O−H took place to afford the polycyclic
This work was supported by the NSFC−Shandong Joint Fund
for Marine Science Research Centers (No. U1606403) and the
Scientific and Technological Innovation Project Financially
Supported by Qingdao National Laboratory for Marine
Science and Technology (No. 2015ASKJ02-06).
coumarin-containing product 22 in 57% yield (two steps) with
17
excellent stereoselectivity. It should be noted that, starting
from 3a and 4-hydroxycoumarin 23, product 22 could also be
obtained, however, with poor results (45%, 28% ee).
D
DOI: 10.1021/acs.orglett.8b03654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
5) (a) Liu, Y.-K.; Li, Z.-L.; Li, J.-Y.; Feng, H.-X.; Tong, Z.-P.
REFERENCES
■
Open−close: an alternative strategy to α-functionalization of lactone
via enamine catalysis in one pot under mild conditions. Org. Lett.
(
1) (a) Castagnino, C.; Vercauteren, J. Castavinol, a new series of
polyphenols from Bordeaux red wines. Tetrahedron Lett. 1996, 37,
739. (b) Larsen, L.; Benn, M. H.; Parvez, M.; Perry, N. B. A
2
015, 17, 2022. (b) Cai, P.-W.; You, Z.-H.; Xie, L.-H.; Tan, R.; Tong,
7
Z.-P.; Liu, Y.-K. The attractive application of lactol chemistry: from
cytotoxic triketone−phloroglucinol−bullatenone hybrid from Lopho-
myrtus bullata. Org. Biomol. Chem. 2005, 3, 3236. (c) Luo, W.; Yu, Q.-
S.; Holloway, H. W.; Parrish, D.; Greig, N. H.; Brossi, A. Syntheses of
tetrahydrofurobenzofurans and dihydromethanobenzodioxepines
from 5-hydroxy-3-methyl-3H-benzofuran-2-one. Rearrangement and
ring expansion under reductive conditions on treatment with
hydrides. J. Org. Chem. 2005, 70, 6171. (d) Luo, W. M.; Yu, Q.-S.;
Zhan, M.; Parrish, D.; Deschamps, J. R.; Kulkarni, S. S.; Holloway, H.
W.; Alley, G. M.; Lahiri, D. K.; Brossi, A.; Greig, N. H. Novel
anticholinesterases based on the molecular skeletons of furobenzofur-
an and methanobenzodioxepine. J. Med. Chem. 2005, 48, 986.
racemic lactol to natural product skeleton. Synthesis 2016, 48, 2581.
(c) Li, J.-Y.; Li, Z.-L.; Zhao, W.-W.; Liu, Y.-K.; Tong, Z.-P.; Tan, R.
One-pot, highly efficient, asymmetric synthesis of ring-fused
piperidine derivatives bearing N,O- or N,N-acetal moieties. Org.
Biomol. Chem. 2016, 14, 2444. (d) Li, J.-Y.; Yu, K.-W.; Xie, C.-C.; Liu,
Y.-K. Lactols in an asymmetric aldol-desymmetrization sequence:
access to tetrahydro-4H-furo[2,3-b]pyran-2-one and tetrahydro-4H-
furo[2,3-b]furan-2-one derivatives. Org. Biomol. Chem. 2017, 15, 1407.
(e) Liu, C.; Liu, Y.-K. Asymmetric organocatalytic one-pot, two-step
sequential process to synthesize chiral acetal-containing polycyclic
derivatives from cyclic hemiacetals and enones. J. Org. Chem. 2017,
(e) Luo, W.; Yu, Q.-S.; Kulkarni, S. S.; Parrish, D. A.; Holloway, H.
82, 10450. (f) You, Z.-H.; Chen, Y.-H.; Wu, X.-N.; Liu, Y.-K. Lactols
W.; Tweedie, D.; Shafferman, A.; Lahiri, D. K.; Brossi, A.; Greig, N.
H. Inhibition of human acetyl- and butyrylcholinesterase by novel
carbamates of (−)- and (+)-tetrahydrofurobenzofuran and meth-
anobenzodioxepine. J. Med. Chem. 2006, 49, 2174. (f) Kamal, M. A.;
Qu, X.; Yu, Q.-s.; Tweedie, D.; Holloway, H. W.; Li, Y.; Tan, Y.;
Greig, N. H. Tetrahydrofurobenzofuran cymserine, a potent
butyrylcholinesterase inhibitor and experimental Alzheimer drug
candidate, enzyme kinetic analysis. J. Neural Transm. 2008, 115,
in asymmetric sequential organo- and gold-catalysis: synthesis of
densely functionalized epimeric bicyclic O,O-acetals. Adv. Synth.
Catal. 2017, 359, 4260. (g) Zhao, W.-W.; Liu, Y.-K. Enantio- and
diastereoselective synthesis of tetrahydrofuro[2,3-b]furan-2(3H)-one
derivatives and related oxygen heterocycles via an asymmetric
organocatalytic cascade process. Org. Chem. Front. 2017, 4, 2358.
(h) Pei, J.-P.; Chen, Y.-H.; Liu, Y.-K. Asymmetric organocatalytic
sequential reaction of structurally complex cyclic hemiacetals and
functionalized nitro-olefins to synthesize diverse heterocycles. Org.
Lett. 2018, 20, 3609. (i) Wu, X.-N.; You, Z.-H.; Liu, Y.-K. Different
hybridized oxygen atoms controlled chemoselective formation of
oxocarbenium ions: synthesis of chiral heterocyclic compounds. Org.
Biomol. Chem. 2018, 16, 6507.
889. (g) Woollard, J. M. R.; Perry, N. B.; Weavers, R. T.; van Klink, J.
W. Bullatenone, 1,3-dione and sesquiterpene chemotypes of
Lophomyrtus species. Phytochemistry 2008, 69, 1313. (h) Chaudhaery,
S. S.; Roy, K. K.; Shakya, N.; Saxena, G.; Sammi, S. R.; Nazir, A.;
Nath, C.; Saxena, A. K. Novel carbamates as orally active
acetylcholinesterase inhibitors found to improve scopolamine-induced
cognition impairment: pharmacophore-based virtual screening, syn-
thesis, and pharmacology. J. Med. Chem. 2010, 53, 6490. (i) El Hattab,
(6) (a) Sun, X.-L.; Chen, Y.-H.; Zhu, D.-Y.; Zhang, Y.; Liu, Y.-K.
Substrate-controlled, one-pot synthesis: access to chiral chroman-2-
one and polycyclic derivatives. Org. Lett. 2016, 18, 864. (b) Chen, Y.-
H.; Sun, X.-L.; Guan, H.-S.; Liu, Y.-K. Diversity-oriented one-pot
synthesis to construct functionalized chroman-2-one derivatives and
other heterocyclic compounds. J. Org. Chem. 2017, 82, 4774. (c) You,
Z.-H.; Chen, Y.-H.; Tang, Y.; Liu, Y.-K. Organocatalytic asymmetric
synthesis of spiro-bridged and spiro-fused heterocyclic compounds
containing chromane, indole, and oxindole moieties. Org. Lett. 2018,
M.; Genta-Jouve, G.; Bouzidi, N.; Ortalo-Magne,
́
A.; Hellio, C.;
Marechal, J.-P.; Piovetti, L.; Thomas, O. P.; Culioli, G. Cystophlor-
́
oketals A−E, unusual phloroglucinol−meroterpenoid hybrids from
the brown alga cystoseira tamariscifolia. J. Nat. Prod. 2015, 78, 1663.
(j) Yang, D.; Xie, H.; Jiang, Y.; Wei, X. Phenolics from strawberry cv.
Falandi and their antioxidant and α-glucosidase inhibitory activities.
Food Chem. 2016, 194, 857.
2
(
0, 6682.
(2) (a) Chen, P. N.; Kingston, D. G. I.; Vercellotti, J. R. Reduction
́
7) (a) Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.; Kobbelgaard,
of sterigmatocystin and versicolorin A hemiacetals with sodium
borohydride. J. Org. Chem. 1977, 42, 3599. (b) Graybill, T. L.; Pal, K.;
McGuire, S. M.; Brobst, S. W.; Townsend, C. A. The timing of
aromatic deoxygenation in aflatoxin biosynthesis. J. Am. Chem. Soc.
́
́
S.; Jørgensen, K. A. Organocatalytic asymmetric synthesis of a,a-
disubstituted a-amino acids and derivatives. J. Am. Chem. Soc. 2008,
130, 12031. (b) Lee, Y.; Seo, S. W.; Kim, S.-G. Highly
enantioselective conjugate addition−cyclization cascade reaction of
malonates with o-hydroxycinnamaldehydes: asymmetric synthesis of
4-substituted chromanols. Adv. Synth. Catal. 2011, 353, 2671.
́
1989, 111, 8306. (c) Graybill, T. L.; Casillas, E. G.; Pal, K.;
Townsend, C. A. Silyl triflate-mediated ring-closure and rearrange-
ment in the synthesis of potential bisfuran-containing intermediates of
aflatoxin biosynthesis. J. Am. Chem. Soc. 1999, 121, 7729.
(c) Cruz Cruz, D.; Mose, R.; Villegas Gomez, C.; Torbensen, S. V.;
́
Larsen, M. S.; Jørgensen, K. A. Organocatalytic cascade reactions:
towards the diversification of hydroisochromenes and chromenes
through two different activation modes. Chem. - Eur. J. 2014, 20,
(
d) Schnermann, M. J.; Beaudry, C. M.; Egorova, A. V.; Polishchuk,
R. S.; Sutterlin, C.; Overman, L. E. Golgi-modifying properties of
macfarlandin E and the synthesis and evaluation of its 2,7-
̈
11331. (d) Kim, Y. S.; Kim, S. M.; Wang, B.; Companyo,
́
X.; Li, J.;
dioxabicyclo[3.2.1]octan-3-one core. Proc. Natl. Acad. Sci. U. S. A.
Moyano, A.; Im, S.; Tosner, Z.; Yang, J. W.; Rios, R. Expanding the
̌
2010, 107, 6158. (e) Tan, H.; Liu, H.; Chen, X.; Yuan, Y.; Chen, K.;
scope of the organocatalytic addition of fluorobis(phenylsulfonyl)-
methane to enals: enantioselective cascade synthesis of fluoroindane
and fluorochromanol derivatives. Adv. Synth. Catal. 2014, 356, 437.
(e) Ackrill, T. D.; Sparkes, H. A.; Willis, C. L. Synthesis of
diarylheptanoid scaffolds inspired by calyxins I and J. Org. Lett. 2015,
17, 3884. (f) Næsborg, L.; Tur, F.; Meazza, M.; Blom, J.; Halskov, K.
S.; Jørgensen, K. A. Synergistic catalysis for the asymmetric [3 + 2]
cycloaddition of vinyl aziridines with α,β-unsaturated aldehydes.
Chem. - Eur. J. 2017, 23, 268. (g) Maity, R.; Pan, S. C. Organocatalytic
asymmetric Michael/hemiacetalization/acyl transfer reaction of α-
nitroketones with o-hydroxycinnamaldehydes: synthesis of 2,4-
disubstituted chromans. Org. Biomol. Chem. 2018, 16, 1598.
Qiu, S. Concise construction of the tricyclic core of bullataketals
enabled by a biomimetic intermolecular (3 + 3) type cycloaddition.
Org. Lett. 2015, 17, 4050. (f) Ievlev, M. Y.; Ershov, O. V. Synthesis of
2
,7-dioxabicyclo[3.2.1]octanes (microreview). Chem. Heterocycl.
Compd. 2016, 52, 213. (g) Ivanov, K. L.; Vatsouro, I. M.;
Bezzubov, S. I.; Melnikov, M. Y.; Budynina, E. M. Domino
construction of a bullataketal core via double bond cleavage in
activated dihydrofurans. Org. Chem. Front. 2018, 5, 1655.
(3) Zhu, Y.; Zhou, J.; Jin, S.; Dong, H.; Guo, J.; Bai, X.; Wang, Q.;
Bu, Z. Metal-free diastereoselective construction of bridged ketal
spirooxindoles via a Michael addition-inspired sequence. Chem.
Commun. 2017, 53, 11201.
(8) For a review, see: (a) Christoffers, J.; Baro, A.; Werner, T. α-
Hydroxylation of β-dicarbonyl compounds. Adv. Synth. Catal. 2004,
346, 143. For selected examples of α-hydroxy-β-dicarbonyl
compounds in reactions, see: (b) Zhu, J.; Klunder, A. J. H.;
(4) Paz, B. M.; Klier, L.; Næsborg, L.; Lauridsen, V. H.; Jensen, F.;
Jørgensen, K. A. Enantioselective organocatalytic cascade approach to
different classes of benzofused acetals. Chem. - Eur. J. 2016, 22, 16810.
E
DOI: 10.1021/acs.orglett.8b03654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Zwanenburg, B. Stereospecific total synthesis of (−)-kjellmanianone
and a revision of its absolute configuration. Tetrahedron Lett. 1994,
3
5, 2787. (c) Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.;
Bergquist, P. R. Chemistry of Sponges. 19. Novel Bioactive
Metabolites from Hamigera tarangaensis. J. Nat. Prod. 2000, 63, 79.
(
d) Christoffers, J.; Werner, T.; Frey, W.; Baro, A. Straightforward
synthesis of (R)-(−)-kjellmanianone. Chem. - Eur. J. 2004, 10, 1042.
e) Park, J.-H.; Chang, J.-S.; El-Gamal, M. I.; Choi, W.-K.; Lee, W. S.;
(
Chung, H. J.; Kim, H.-I.; Cho, Y.-J.; Lee, B. S.; Jeon, H.-R.; Lee, Y. S.;
Choi, Y. W.; Lee, J.; Oh, C.-H. Novel amides and esters prodrugs of
olmesartan: Synthesis, bioconversion, and pharmacokinetic evalua-
tion. Bioorg. Med. Chem. Lett. 2010, 20, 5895.
(
9) Companyo, X.; Mazzanti, A.; Moyano, A.; Janecka, A.; Rios, R.
́
First one-pot organocatalytic synthesis of α-methylene-γ-lactones.
Chem. Commun. 2013, 49, 1184.
(
10) Asahara, H.; Nishiwaki, N. Metal-free α-hydroxylation of α-
unsubstituted β-oxoesters and β-oxoamides. J. Org. Chem. 2014, 79,
1735.
11) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. New
1
(
strategies for organic catalysis: the first highly enantioselective
organocatalytic Diels−Alder reaction. J. Am. Chem. Soc. 2000, 122,
4
(
243.
12) Bergonzini, G.; Melchiorre, P. Dioxindole in asymmetric
catalytic synthesis: routes to enantioenriched 3-substituted 3-
hydroxyoxindoles and the preparation of maremycin A. Angew.
Chem., Int. Ed. 2012, 51, 971.
(13) Zu, L.; Zhang, S.; Xie, H.; Wang, W. Catalytic Asymmetric oxa-
Michael−Michael Cascade for Facile Construction of Chiral Chro-
mans via an Aminal Intermediate. Org. Lett. 2009, 11, 1627.
(14) Ramachary, D. B.; Shiva Prasad, M.; Vijaya Laxmi, S.;
Madhavachary, R. Asymmetric synthesis of drug-like spiro[chroman-
3
2
,3′-indolin]-2’-ones through aminal-catalysis. Org. Biomol. Chem.
014, 12, 574.
(
15) See the Supporting Information for more details.
(16) No product formation of 10a from 11 was observed in the
presence of molecular sieves, which indicated H O is crucial for the
2
transformation processes.
(17) (a) Kim, K. E.; Li, J.; Grubbs, R. H.; Stoltz, B. M. Catalytic anti-
markovnikov transformations of hindered terminal alkenes enabled by
aldehyde-selective wacker-type oxidation. J. Am. Chem. Soc. 2016, 138,
13179. (b) Andersen, T. L.; Frederiksen, M. W.; Domino, K.;
Skrydstrup, T. Direct access to α,α-difluoroacylated arenes by
palladium-catalyzed carbonylation of (hetero)aryl boronic acid
derivatives. Angew. Chem., Int. Ed. 2016, 55, 10396. (c) Wang, S.;
Xi, C. Nickel-catalyzed arylative carboxylation of alkynes with
arylmagnesium reagents and carbon dioxide leading to trisubstituted
acrylic acids. Org. Lett. 2018, 20, 4131.
F
DOI: 10.1021/acs.orglett.8b03654
Org. Lett. XXXX, XXX, XXX−XXX