Organocatalytic Asymmetric Dearomatization Reaction for the Synthesis of Axial Chiral Allene-Derived Naphthalenones Bearing Quaternary Stereocenters

Article abstract of DOI:10.1021/acs.orglett.1c01849

The highly regio-, diastereo-, and enantioselective dearomatization reaction of 1-substituted 2-naphthols and β,γ-alkynyl-α-imino esters with complete atom economy is disclosed via chiral phosphoric acid catalysis. This protocol provides facile and effici

Full text of DOI:10.1021/acs.orglett.1c01849

pubs.acs.org/OrgLett
Letter
Organocatalytic Asymmetric Dearomatization Reaction for the
Synthesis of Axial Chiral Allene-Derived Naphthalenones Bearing
Quaternary Stereocenters
Alemayehu Gashaw Woldegiorgis, Zhao Han, and Xufeng Lin*
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ABSTRACT: The highly regio-, diastereo-, and enantioselective
dearomatization reaction of 1-substituted 2-naphthols and β,γ-
alkynyl-α-imino esters with complete atom economy is disclosed
via chiral phosphoric acid catalysis. This protocol provides facile
and efficient access to asymmetric construction of a broad range of
axially chiral allene-derived naphthalenones bearing quaternary
stereocenters in good yields with high diastereoselectivities and
enantioselectivities.
atalytic asymmetric dearomatization (CADA) reactions
electrophilic substrates such as azo-dicarboxylates, propargylic
Chave been widely recognized as a powerful approach for ketones, aziridine, alkoxyallenes, allylic carbonates, internal
alkynes, and hydroxylamine-o-sulfonic acid using a metal
catalyst and chiral ligands was successfully achieved.4 In
addition, asymmetric dearomatization reaction of β-naphthols
through an amination reaction catalyzed by Rh metal and a
chiral phosphoric acid, bifunctional thiourea-catalyzed Michael
reaction (Scheme 1a)5 and Rh-catalyzed C(sp2)−H function-
alization/annulation reaction4f were performed (Scheme 1b).
Moreover, most of these dearomatization protocols have
focused only on the construction of naphthalenones bearing a
single chirality. Therefore, the formation of both central and
axial chirality by catalytic asymmetric dearomatization of 2-
naphthol, which is far less developed and challenging, is highly
desirable (Scheme 1c).
Recently, the enantioenriched allenes have attracted the
attention of chemists due to their versatile applications.6 They
are well-known frameworks that are widely present in natural
products, bioactive molecules, ligands, organocatalysts, and
functional materials.7 In addition, they exemplify a class of
valuable starting materials for a wide range of synthetic
applications8 and their introduction into bioactive molecules
(e.g., steroids and prostaglandins) increases metabolic stability,
bioavailability, and potency.7a Regardless, ample endeavors
have been made to develop methodologies for the asymmetric
synthesis of axially chiral allenes through metal catalysis9 and
organocatalysis.10 Although significant progress has been
transforming planar aromatic structures into stereoselective
chiral frameworks.1 In this regard, metal and organo-catalyti-
cally dearomatized electron rich aromatic structures (phenols
and naphthols) and heteroaromatics (indoles, pyrroles, and
benzofurans) readily undergo alkylation reactions with electro-
philes to provide synthetically useful compounds that
constitute key moieties of bioactive natural products and
pharmaceuticals. Among numerous electron rich aromatic
moieties, dearomative naphthols represent a novel enabling
method for the rapid construction of highly functionalized
three-dimensional naphthalenone cores.2 As a privileged
structural motif, these enantioenriched naphthalenones are of
great importance in various biologically active natural products
and therapeutic reagents, such as HCV polymerase inhibitor,
(−)-N-methylguattescidine, cyclosordyriolone, and lacinilenes
(Figure 1).3 Recently, enormous effort has been devoted by
various researchers to the construction of the naphthalenone
core. For example, dearomatization of 2-naphthols using
Received: June 3, 2021
Figure 1. Natural products and bioactive molecules bearing a β-
naphthalenone skeleton.
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chiral phosphoric acid catalysis,16,17 we postulated that a
double-activation mode by hydrogen bonding interaction
could be practical for promoting the asymmetric γ-addition
of 1-substituted β-naphthol to β,γ-alkynyl-α-imino esters. In
addition, the chiral environment of CPA and the alkyl group
attached at position 1 of 2-naphthol play a vital role in the
preferential attack at the γ-position of β,γ-alkynyl-α-imino
esters because of steric demand (Scheme 1c).
Scheme 1. Asymmetric Dearomatization of β-Naphthols
Our study started by utilizing the nucleophile 1-methyl-2-
naphthol (1a) and an electrophile β,γ-alkynyl-α-imino ester
(2a) as the model substrates to optimize the asymmetric
dearomatization reaction conditions (Table 1). The initial test
a
Table 1. Optimization of Reaction Conditions
b
c
c
entry
catalyst
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
PhCl
DCM
CHCl3
CHCl3/DCM
CHCl3/DCM
CHCl3/DCM
CHCl3/DCM
yield (%)
dr
ee
1
2
3
4
5
6
7
8
A1
A2
A3
A4
A5
A6
B1
C1
A1
A1
A1
A1
A1
A1
A1
78
66
38
55
56
81
44
71
63
72
25
60
72
72
69
70:30
71:29
54:46
60:40
57:43
59:41
66:34
69:31
90:10
96:4
50
14
4
6
28
26
4
46
68
68
78
82
84
90
54
9
10
11
98:2
98:2
98:2
99:1
d
12
d
d
d
,e
achieved in asymmetric syntheses of chiral allenes through
metal catalysis, general and practical protocols for the
organocatalyzed synthesis of axially chiral allenes from readily
available starting materials remain rare in organic synthesis.11
Here, we develop an organocatalytic asymmetric dearoma-
tization reaction of 1-substituted β-naphthols with β,γ-alkynyl-
α-imino esters12 with complete atom economy to provide axial
chiral allene-derived naphthalenones bearing quaternary
stereocenters. Because steric hindrance may have an impact
on the regioselectivity of the reaction,13 we introduced a
substituent at position 1 of β-naphthol with the aim of
constructing axially chiral allene via dearomatization reaction
by undergoing γ-addition with β,γ-alkynyl-α-imino esters.
However, several significant challenges should be considered
during this asymmetric transformation: (1) selecting suitable
chiral catalysts to control regioselectivity and stereoselectivity,
(2) generation of vicinal axially chiral tetrasubstituted allene
and an all-carbon quaternary stereogenic center, (3) formation
of a highly enantioenriched naphthalenone scaffold, and (4)
energy barriers associated with dearomatization. Relying on the
valuable contribution of chiral phosphoric acids in asymmetric
catalysis14,15 and as part of our ongoing interest in the field of
13
14
15
−
f
,
g
95:05
a
Unless otherwise noted, the reactions were carried out with 1a (0.07
mmol), 2a (0.07 mmol), a catalyst (10 mol %), and an additive (70
mg, 3 Å molecular sieves) in 1.4 mL of solvent for 12 h. Isolated
yield. Determined by chiral phase HPLC analysis. With 1:1 CHCl3/
DCM. With 4 Å molecular sieves. At 0 °C. Without molecular
sieves.
b
c
d
e
f
g
was performed in the presence of the CPA catalyst (R)-A1, 3 Å
molecular sieves, and dichloroethane as the solvent. The
reaction proceeded smoothly to afford the desired product 3a,
having both central and axial chirality, in moderate yield (78%)
and promising stereoselectivity (70:30 dr and 50% ee) with
complete atom economy (Table 1, entry 1). To further
improve the yield and stereoselectivity, a range of chiral
phosphoric acids with different substituents and backbones
were evaluated (Table 1, entries 2−8). Indeed, the majority of
these catalysts could promote all of the reactions smoothly to
afford allene-derived naphthalenone 3a with variable stereo-
selectivity (see Table S1). Compared to BINOL- and H8-
B
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BINOL-derived chiral phosphoric acids, SPINOL-based chiral
phosphoric acids (SPAs) showed low catalytic activity (entries
1, 7, and 8). Because this reaction generated both axial chirality
and a quaternary stereocenter, the control of diastereoselec-
tivity was a crucial part of this reaction in addition to
enantioselectivity. As a result, after evaluation of catalysts, the
BINOL bearing a 9-phenanthryl group, (R)-A1, exhibited the
best performance, providing high enantioselectivity and
diastereoselectivity (Table 1, entry 1).
Scheme 2. Substrate Scope with Respect to β,γ-Alkynyl-α-
imino Esters
a
Encouraged by these promising results, we then evaluated
various solvents, and a significant solvent effect was observed
(entries 9−12). Among the solvents evaluated, DCM was
found to be the best solvent in terms of yield (72%) (Table 1,
entry 10) and CHCl3 is preferred in terms of stereoselectivity
(98:2 dr and 78% ee) (Table 1, entry 11). No reaction
occurred when this transformation was conducted using
tetrahydrofuran and ethyl acetate as a solvent (Table S2).
Consequently, to improve the yield and stereoselectivity, DCM
and CHCl3 were mixed in different proportions. Among the
mixing ratios of the solvents tested, an equal proportion (1:1)
afforded the desired product in moderate yield (60%) with
good enantioselectivity (82% ee) and excellent diastereose-
lectivity (98:2 dr) (Table 1, entry 12). Additionally, when the
3 Å molecular sieves (MS) were replaced with 4 Å MS, the
reaction performed better to afford the desired product 3 in
good yield (72%), high ee (84%), and excellent dr (98:2)
(Table 1, entry 16). However, without an additive, the reaction
gave a low enantioselectivity (54% ee) (Table 1, entry 15).
Further investigations revealed that decreasing the reaction
temperature was beneficial for improving the enantioselectivity.
Fortunately, when the reaction temperature was decreased to 0
°C with a prolonged reaction time, high enantioselectivity
(90% ee) and high diastereoselectivity (99:1) were achieved
(Table 1, entry 14).
a
Unless otherwise noted, all reactions were carried out with (R)-A1
(10 mol %), 1a (0.07 mmol), 2a (0.07 mmol), and 4 Å molecular
sieves (70 mg) in 1.4 mL of 1:1 DCM/CHCl3 at 0 °C for 12 h. The
ee and dr values were determined by chiral phase HPLC analysis. The
yield refers to the isolated product. Using (R)-C1 (10 mol %). At
−20 °C.
b
c
(Scheme 3). To our delight, 6-aryl-substituted 2-naphthol
derivatives with different substitution groups (1n−1u) bearing
a
Scheme 3. Substrate Scope with Respect to 2-Naphthols
With the optimized asymmetric dearomatization reaction
conditions in hand, we first investigated the substrate scope
with respect to β,γ-alkynyl-α-imino esters and explored the
generality of this substrate by employing various substituents
on the aryl ring, protecting group, and ester groups (Scheme
2). In general, aromatic rings of Ar with either electron-
withdrawing or electron-donating groups at different positions
were all well tolerated and the corresponding products,
tetrasubstituted α-amino allenoates, were obtained in moderate
yields (56−74%) and good to excellent enantioselectivities
(86−92% ee) and diastereoselectivities (97:3−99:1 dr) (3a−
3j). When Ar was a naphthalene ring, a moderate yield (56%),
high enantioselectivity (90% ee), and high diastereoselectivity
(99:1) were obtained (3d). It is also noted that, when catalyst
(R)-C1 was used instead of (R)-A1 for the m-Me-substituted
aryl ring of 2a, the stereoselectivity of the product was 86% ee
and 98:2 dr (3i).
a
Unless otherwise noted, the reactions were carried out with 1a (0.07
In addition, our method could be applied to β,γ-alkynyl-α-
imino esters 2a bearing CO2Me, CO2Bn, and N-Cbz
substitution and gave the corresponding products allene-
derived naphthalenone 3 in moderate to high yields (64−82%)
and good stereoselectivities (83−92% ee and 96:4 to >99:1 dr)
(3k−3m). The β,γ-alkynyl-α-imino esters bearing CO2Et (3a)
and CO2Bn (3l) have higher stereoselectivity than CO2Me
(3k), presumably due to the generation of spatial steric
hindrance by bulkier groups.
mmol), 2a (0.07 mmol), (R)-A1 (10 mol %), and 4 Å molecular
sieves (70 mg) in 1.4 mL of 1:1 DCM/CHCl3 for 12 h. The dr and ee
values were determined by HPLC analysis on chiral stationary phases.
The yield refers to the isolated product.
various electron-donating and electron-withdrawing substitu-
ents could undergo γ-addition with 2a and afforded the desired
chiral allene-derived naphthalenones in 51−80% yields, good
enantioselectivity (78−93% ee), and good diastereoselectivity
(93:7−99:1 dr) [3n−3u (Scheme 3)]. β-Naphthols bearing
different alkyl groups such as ethyl and propyl at position 1
proceeded smoothly, leading to the corresponding dearomative
Next, we examined the substrate scope of the asymmetric
dearomatization reaction of various 1-substituted 2-naphthols
to β,γ-alkynyl-α-imino esters under standard conditions
C
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chiral allene-derived naphthalenone in moderate yields with
high enantioselectivity (3v, 67%, 83% ee; 3w, 44%, 79% ee)
and excellent diastereoselectivity (99:1 dr). However, low-yield
formation of the naphthol substrate bearing a propyl group
(3w) as compared to methyl and ethyl groups (3a and 3v,
respectively) was observed probably due to steric hindrance at
the position. In addition, β-naphthols with methyl substitu-
tions at positions 1 and 3 were also tested and well tolerated in
the reaction, providing the desired dearomative products 3x−
3za in good yields and stereoselectivities (60−76% yields, 76−
94% ee, 94:6 to >99:1 dr).
protocol provides facile and efficient access to highly
functionalized allene-derived naphthalenone derivatives bear-
ing both a quaternary stereocenter and axial chirality in good
yields with high diastereoselectivities and enantioselectivities.
Control experiments suggested that the high to excellent
stereoselectivity arose from dual hydrogen bonding interaction
with chiral phosphoric acid, and the substituent at position 1 of
β-naphthol plays a crucial role in controlling regioselectivity.
ASSOCIATED CONTENT
* Supporting Information
■
sı
To demonstrate the utility of the chiral phosphoric acid-
catalyzed asymmetric dearomatization reaction of 1-substituted
2-naphthols, we performed a 1 mmol scale synthesis of product
3a (Scheme 4a). This large scale reaction proceeded smoothly
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01849.
Experimental procedures, characterization of all new
compounds, and X-ray structure and crystal data of 3a
(PDF)
Scheme 4. Scale-up and Control Experiments
Accession Codes
CCDC 2060010 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.
AUTHOR INFORMATION
Corresponding Author
■
Xufeng Lin − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China; orcid.org/0000-0003-4611-
0507; Email: lxfok@zju.edu.cn
Authors
Alemayehu Gashaw Woldegiorgis − Department of
Chemistry, Zhejiang University, Hangzhou 310027, China
Zhao Han − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
and efficiently afforded the chiral allene-derived naphthalenone
without erosion of diastereoselectivity or enantioselectivity
with nearly the same good yields as those obtained in the small
scale reaction. The absolute configuration of the stereogenic
center in compound 3a was determined by X-ray diffraction
analysis of a single crystal.18
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01849
Notes
To gain insight into the mechanism of the dearomative γ-
addition of 1-substituted 2-naphthols with β,γ-alkynyl-α-imino
esters, some related control experiments were performed.
Under the optimized reaction conditions, when 2-naphthol 1b
was utilized in the reaction, the α-addition reaction occurred
and gave the corresponding product (4b) in moderate yield
(53%) and poor enantioselectivity (<5% ee) (Scheme 4b).
This indicated that the steric hindrance of the substituent at
position 1 of 2-naphthols played important roles both in the
regioselectivity of the addition reaction to β,γ-alkynyl-α-imino
esters and in controlling enantioselectivity because of the
formation of dual hydrogen bonds with the CPA catalyst. On
the contrary, when 2-methoxynaphthol was employed, the
reaction did not occur [4c (Scheme 4b)], which revealed that
the naphthol O−H group in substrates 1a played a significant
role in controlling the reactivity, possibly due to the formation
of hydrogen-bonding interactions with CPA, as shown in
Scheme 1c.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (22071213), the Leading Talents of
Special Support Program of Zhejiang Province High-level
Talents (2020R52008), and the Center of Chemistry for
Frontier Technologies of Zhejiang University is gratefully
acknowledged.
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D
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Letter
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ac.uk/data_request/cif.
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