Chiral Phosphoric-Acid-Catalyzed Cascade Prins Cyclization

Article abstract of DOI:10.1021/acs.orglett.9b02714

Asymmetric Prins cyclization of in situ generated quinone methides and o-aminobenzaldehyde has been developed with chiral phosphoric acid as an efficient catalyst. This unconventional method provides a facile access to diverse functionalized trans-fused pyrano-/furo-tetrahydroquinoline derivatives in excellent yield and with excellent diastereo- and enantioselectivities (up to 99% yield and 99% ee). Mechanistic studies suggested that the three adjacent tertiary stereocenters were constructed through the sequential formation of C-O, C-C, and C-N bonds.

Full text of DOI:10.1021/acs.orglett.9b02714

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chiral Phosphoric-Acid-Catalyzed Cascade Prins Cyclization
Huai-Ri Sun,†,§ Qingyang Zhao,‡,§ Hui Yang,† Sen Yang,† Bo-Bo Gou,† Jie Chen,†
and Ling Zhou*,†
†Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, National Demonstration Center for Experimental Chemistry Education, Northwest University, Xi’an 710127, P.
R. China
‡School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, P. R. China
S
* Supporting Information
ABSTRACT: Asymmetric Prins cyclization of in situ generated quinone methides and o-aminobenzaldehyde has been
developed with chiral phosphoric acid as an efficient catalyst. This unconventional method provides a facile access to diverse
functionalized trans-fused pyrano-/furo-tetrahydroquinoline derivatives in excellent yield and with excellent diastereo- and
enantioselectivities (up to 99% yield and 99% ee). Mechanistic studies suggested that the three adjacent tertiary stereocenters
were constructed through the sequential formation of C−O, C−C, and C−N bonds.
the selectivity could be promoted via the interaction between
CPA and substrates/intermediates.
he Prins cyclization is an elegant method for the synthesis
1
Tof various oxygenated heterocycles and is a key reaction
in many natural product syntheses.2 Tremendous progress has
been developed by using strong Brønsted acids or Lewis acids
as catalysts.3 However, the asymmetric variants of Prins
cyclization have lagged far behind.2,4,5 The reason may be due
to the fact that it is difficult to control the carbenium
intermediate. Lalli and van de Weghe developed the first
asymmetric Prins cyclization, affording up to 60% ee by using a
dual bis-phosphoric acid and a CuCl catalytic system.4
Recently, List and coworkers developed a confined chiral
imidodiphosphoric acid (IDP) for the asymmetric Prins
reactions. Highly enantio-enriched trans-tetrahydrofurans
were prepared by using a strong chiral acid with an extreme
steric demand as the catalyst (Scheme 1a).6 Moreover,
employing the same catalyst, they reported the asymmetric
synthesis of trans-tetrahydropyrans (THPs) with an o-quinone
methide (o-QM) intermediate, probably via a [4 + 2]
cycloaddition other than the previous Prins cyclization.7 On
the basis of previous research on the dearomative cyclo-
addition reaction involving o-QM intermediates,8 together with
our recent work9 of vinylphenols/naphthols catalyzed by chiral
phosphoric acids (CPAs), we envisioned that this asymmetric
transformation could be improved if the substrate contains an
electron-rich double bond enhanced by the o-hydroxyphenyl
group, wherein a relative stable o-QM intermediate will be
generated (Scheme 1b). Meanwhile, this may compensate for
the weak acidity of CPA required for the Prins cyclization, and
Chiral tetrahydroquinolines (THQs) are key nitrogen
heterocyclic skeletons of many natural products and bio-
logically active molecules.10 Among them, ring-fused THQs
are more unique and attractive because of their potential
utilization in pharmaceuticals11 as well as their enormous
challenges in methodology, wherein three adjacent tertiary
stereocenters are formed. To date, many catalytic systems have
been developed through aza-Diels−Alder (DA) or Povarov
reactions of imine intermediates and cycloolefins,12 and a few
asymmetric examples have been reported by Sundararajan,13
Jacobsen,14 Akiyama,15 Feng,16 Gong,17 and Masson and
Zhu.18 Notably, only cis-fused THQs were obtained, resulting
from the stereospecificity of the DA reaction.19 To the best of
our knowledge, there has been no facile access to
corresponding chiral trans-fused THQ products. It remains a
significant challenge to develop an unparalleled approach for
trans-fused enantioenriched THQs.
We noted that an insightful investigation of the mechanism
indicates that the diastereoselectivity (trans vs cis) of the Prins
cyclization is dependent on the substrates and corresponding
six-membered or five-membered transition states.6b,20 Thus we
assumed a one-pot cascade process to access trans-fused
THQs: Trans-fused oxygenated heterocycles could be obtained
in the Prins cyclization and then delivered to the chiral THQs
Received: August 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02714
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Previous Asymmetric Prins Reactions and
Cascade Prins Cyclization
Table 1. Optimization of the Reaction Conditions
b
c
entry
cat
solvent
T (°C)
t (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
5a
5b
5b
5b
5b
5b
5b
5b
5b
5b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
toluene
MeCN
hexane
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
40
60
60
60
60
60
60
60
60
60
60
60
60
60
48
24
36
27
37
64
49
44
52
68
54
23
22
11
4
−21
−51
−58
−77
−81
−87
98
98
98
89
45
53
NA
98
98
98
9
10
11
12
13
14
15
by sequential cyclization (Scheme 1b). The challenge
associated with this hypothesis is the control of diastereo-/
enantioselectivities in the Prins cyclization, which could be
enabled by the design and utility of the advantaged six-
membered transition state. Indeed, along with the formation of
C−O, C−C, and C−N bonds, the trans-fused pyrano-/furo-
THQ derivatives were obtained in excellent yield and with
excellent diastereo- and enantioselectivities (up to 99% yield
and 99% ee).
NA
93
98
37
d
CH2Cl2
CH2Cl2
CH2Cl2
d
de
,
16
a
Reactions were carried out with 1a (0.10 mmol), 2a (0.12 mmol),
and catalyst (10 mol %) in solvent (1.0 mL) under N2. No other
b
c
diastereoisomers were observed. Isolated yield. Determined by
chiral HPLC. 0.12 mmol of 1a and 0.10 mmol of 2a were used. 5
mol % of 5b was used.
Considering the reactivity, hydroxyvinylphenol 1a and 2-
amino-3,5-dibromobenzaldehyde (2a) were chosen as the
model substrates because the double bond in 1a is more
electronegative and the carbonyl group in 2a is more
electropositive. The initial result was consistent with our
hypothesis. Trans-fused THQ 3a was obtained as a single
diastereoisomer in moderate yield (46%) by using 10 mol %
diphenyl phosphate (DPP) as the catalyst in dichloromethane
at room temperature. Encouraged by this result, we turned to
screening of CPAs for the asymmetric transformation (Table
1). Simple BINOL-based CPA 4a gave the desired product in
low yield and with low ee (Table 1, entry 1), whereas the
enantioselectivity and yield were obviously improved with
bulky CPAs (Table 1, entries 2−6). To our delight, the key
breakthrough was ultimately achieved when SPINOL-based
CPA 5a was employed (Table 1, entry 7). Excellent
diastereoselectivity and enantioselectivity were observed,
whereas the yield was still far from satisfying (entries 7 and
8). Then, a series of extensive surveys of solvents, substrate
ratios, and temperatures was performed. It was found that the
best result was given in 98% yield with 98% ee when adjusting
the ratio of 1a/2a to 1.2:1 at 40 °C for 24 h (Table 1, entry
15). Lower catalyst loading dramatically decreased the yield
(Table 1, entry 16).
d
e
excellent enantioselectivities (90−99% ee). Even the THQ 3g,
bearing a strong electron-withdrawing group, was obtained in
98% yield and with 98% ee. By contrast, the yields were
obviously decreased when chloro (3h) and methyl (3j) were
installed at the meta position of the phenyl ring. Notably,
products containing multi halogens, such as 3b, 3c, 3d, 3h, and
3i, were potential intermediates for the construction of more
complex THQs via metal-catalyzed cross-coupling reactions.
The difference in the reactivity of the halogens made these
intermediates more diverse in synthesis. Furthermore, the
challenging tertiary alcohol was investigated, which was more
difficult for dehydration with aldehyde than primary alcohol.
Compound 3k was afforded in low yield (37%) but with
excellent enantioselectivity (93% ee) under the standard
conditions, and a 93% yield with 90% ee was obtained when
the reaction was carried out at 60 °C. The absolute
configuration of 3 was assigned on the basis of the X-ray
crystallographic structure of ent-3a, 3b, 3c, 3d, and 3g.21 To
evaluate the practicality of this catalytic process, we carried out
the scale-up reaction of 1a and 2a. As a result, the desired
product 3a was successfully obtained in 95% yield with 98% ee
(Scheme 2).
With the optimized conditions in hand, a series of
substituted 1 was first examined (Scheme 2). In most
reactions, both electron-donating groups and electron-with-
drawing groups of 1 were well-tolerated, and the correspond-
ing THQs were obtained in excellent yield (90−98%) and with
Afterward, the derivatives of 2 were investigated (Scheme
3). For the 3-monosubstituted o-aminobenzaldehyde, different
functional groups were well compatible in nearly quantitative
B
DOI: 10.1021/acs.orglett.9b02714
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Scope of 1a Derivatives
Scheme 3. Scope of 2a Derivatives
a
Reactions were carried out with 1a (0.12 mmol), 2 (0.10 mmol), and
5b (10 mol %) in CH2Cl2 (1.0 mL) under N2 for 24 h. Yields refer to
b
isolated products. At 60 °C.
a
Reactions were carried out with 1 (0.12 mmol), 2a (0.10 mmol), and
5b (10 mol %) in CH2Cl2 (1.0 mL) under N2 for 24 h. Yields refer to
effects of substituents. In addition, N-methyl o-amino-
benzaldehyde provided the target product 3z in 96% yield
and with 99% ee at 60 °C.
b
c
isolated products. 300 mg (1.08 mmol) of 2a was used. At 60 °C.
To gain insight into the mechanism, several control
experiments were designed and carried out. Several derivatives
of 1a were subjected to the reaction under standard conditions.
Methylation of the phenol of 1a leads to no reaction, indicating
that the process was possibly involved with o-QM
intermediates (Scheme 4a). When a mixture of 1a (Z/E 1:1)
was used in the reaction under standard conditions, 3a was
obtained in 50% yield with 98% ee, and the Z-1a was recovered
in nearly quantitative yield (Scheme 4b). This result was
consistent with our hypothesis that the six-membered chair
transition state from Z-1a was disfavored owing to the steric
interactions with axial protons. Probably for the same reason, 5
was afforded moderate diastereoselectivity when 4 was used
instead of 1a (Scheme 4c). In addition, the treatment of excess
1 (2.4 equiv) with 4-cyanobenzaldehyde 2aa returned product
6 in good yield, the structure of which was further determined
by the X-ray analysis of its derivative 7d (Scheme 4d).21
yield and with excellent enantioselectivities (all >98% ee),
including bromo (3l), chloro (3m), fluoro (3n), methyl (3p),
and methoxy (3q). The additional substituents on the five-
position had no influence on the yields and enantioselectivities
(3r−u). By contrast, the 3-nitro group (3o) led to excellent
enantioselectivity (98% ee), albeit with a moderate yield. 4-
Methyl o-aminobenzaldehyde afforded a lower yield and ee
than 3,4-dimethyl o-aminobenzaldehyde (3v vs 3w). For the
further investigation, 4-bromo, 5-bromo, 6-bromo/-methyl,
and unsubstituted o-aminobenzaldehyde were used as
comparisons with 3-bromo o-aminobenzaldehyde. A slight
decrease in the yield was observed for 3x, but a dramatic
decrease was observed for 3y. No desired products were
detected with 6-bromo/-methyl o-aminobenzaldehydes under
the optimal conditions. The tremendous difference resulting
from positions was probably due to the steric and electronic
C
DOI: 10.1021/acs.orglett.9b02714
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Control Experiments
Scheme 5. Proposed Mechanism
reaction involving o-QM intermediates. As we expected, the
Prins reaction probably proceeded through a favored six-
membered chair transition state with low energy. The trans-
fused THQ derivatives bearing three adjacent tertiary stereo-
centers were prepared in excellent yield and with excellent
diastereo-/enantioselectivities through cascade Prins cycliza-
tions and the aza-Michael reaction. Control experiments
suggested that the dearomatization of phenol plays an
important role in the transformation. Further investigations
into the mechanism, development, and application of such
cascade reactions are underway.
Moreover, enantioenriched 6a and 6d were obtained with
good to excellent enantioselectivities under the optimal
reaction conditions, albeit in lower yield. The capture of
product 6 supported the stepwise pathway involved in the
Prins cyclization.
Therefore, a plausible mechanism is proposed in Scheme 5.
At the beginning, complex A is generated via the acid-catalyzed
addition of hydroxyl to aldehyde 2l; subsequently, the release
of water forms an oxocarbenium ion B through the interaction
with CPA. Then, the asymmetric Prins cyclization occurs via
the dearomatization of phenol through the favored six-
membered chair transition state, wherein Ha and Hb are
located at the axial position. The disfavored transition state B′
will be generated if Z-1 is used in this reaction. Finally an aza-
Michael reaction of intermediate C will afford the desired
trans-fused 3l and complete the catalytic cycle.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02714.
Experimental details and spectroscopic and analytical
data for new compounds (PDF)
Accession Codes
CCDC 1937551, 1937553−1937555, 1937717, and 1938892
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
We have also attempted to apply the protocol in the reaction
with salicylaldehyde derivative 8, and preliminary studies have
showed that the desired product 9 can be prepared in good
yield and with excellent ee.
In summary, we reported an unprecedented example of a
chiral phosphoric-acid-catalyzed asymmetric Prins cyclization
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhoul@nwu.edu.cn
D
DOI: 10.1021/acs.orglett.9b02714
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Qingyang Zhao: 0000-0001-8259-4321
Jie Chen: 0000-0001-6745-5534
Ling Zhou: 0000-0002-6805-2961
Author Contributions
§H.-R.S. and Q.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC 21672170, 21602172, 21203148), Natural Science
Basic Research Plan in Shaanxi Province of China (2018JC-
020, 2018JM2029), and China Postdoctoral Science Founda-
tion (2018M643705) for financial support. Q.Z. thanks the
Fundamental Research Funds for the Central Universities.
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DOI: 10.1021/acs.orglett.9b02714
Org. Lett. XXXX, XXX, XXX−XXX