Phosphoric Acid Catalyzed Aldehyde Addition to in Situ Generated o-Quinone Methides: An Enantio- and Diastereoselective Entry toward cis-3,4-Diaryl Dihydrocoumarins

Article abstract of DOI:10.1021/acs.orglett.8b01865

A highly stereoselective, phosphoric acid catalyzed synthesis of cis-3,4-diarylchromanols through reaction of o-hydroxybenzhydryl alcohols and aryl acetaldehydes is reported. The products can be further manipulated to 3,4-dihydrocoumarins, 4H-chromenes, and chromanes with good overall yields and very good diastereo- and enantiocontrol. This reaction is based upon the concept of enol catalysis and comprises the in situ generation of hydrogen-bonded o-quinone methides and their formal [4 + 2]-cycloaddition with aldehyde enols.

Full text of DOI:10.1021/acs.orglett.8b01865

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Phosphoric Acid Catalyzed Aldehyde Addition to in Situ Generated
o‑Quinone Methides: An Enantio- and Diastereoselective Entry
toward cis-3,4-Diaryl Dihydrocoumarins
Matthias Spanka and Christoph Schneider*
Institut fur Organische Chemie, Universitat Leipzig, Johannisallee 29, 04103 Leipzig, Deutschland
̈
̈
S
* Supporting Information
ABSTRACT: A highly stereoselective, phosphoric acid catalyzed synthesis of cis-3,4-diarylchromanols through reaction of o-
hydroxybenzhydryl alcohols and aryl acetaldehydes is reported. The products can be further manipulated to 3,4-
dihydrocoumarins, 4H-chromenes, and chromanes with good overall yields and very good diastereo- and enantiocontrol.
This reaction is based upon the concept of enol catalysis and comprises the in situ generation of hydrogen-bonded o-quinone
methides and their formal [4 + 2]-cycloaddition with aldehyde enols.
3,4-Diarylchromans have been widely studied for their potential
use against mammary cancer as well as for their estrogenic and
antiestrogenic activities (Figure 1). For example, DL-centchro-
mans,3 4H-chromenes,4 and hydrocoumarins,5 an enantiose-
lective access to all these compound classes by one common
intermediate, ideally generated by a chiral catalyst, appears to be
highly desirable. We report herein a Brønsted acid catalyzed
enantio- and diastereoselective synthesis of cis-3,4-diarylchro-
manols and the corresponding dihydrocoumarins through a
formal [4 + 2]-cycloaddition of in situ generated o-quinone
methides and aryl acetaldehydes. Moreover, the chromanol
products 3 were easily converted into a variety of other chroman
derivatives by modification of the lactol moiety.
We and others have recently studied in detail the chiral
phosphoric acid (CPA) catalyzed addition of π-nucleophiles
toward o-quinone methides (o-QMs), which are generated in
situ by dehydration of the corresponding o-hydroxy benzhydryl
alcohols.6 A broad range of benzannulated oxygen heterocycles
were prepared in excellent yield and enantioselectivity based
upon this strategy. In particular, β-dicarbonyl compounds were
shown to readily participate in conjugate addition reactions
proceeding with exceptional levels of enantioselectivity. As a
model to account for the high selectivity, we have proposed a
bifunctional activation mode of the phosphoric acid to both the
o-QM and the enol tautomer of the β-dicarbonyl compound via
two hydrogen bonds.
Figure 1. Examples of bioactive compounds containing the 3,4-
diarylchroman skeleton.1,2
man is an oral nonsteroidal contraceptive sold in India as a
selective estrogen receptor modulator (SERM). It has also been
intensively studied for the treatment of dysfunctional uterine
bleeding (DUB), breast, head, and neck cancer, chronic myeloid
leukemia cells, and mastalgia.1 In addition to centchroman itself,
various derivatives thereof have been carefully studied for their
activity against osteoporosis and cancer among others.2
Even though many studies suggest that L-centchroman is far
more active than its D-enantiomer or the DL-mixture in many
indications, most of the strategies employed to date to
synthesize centchroman and derivatives provide them as
racemic material or include a resolution step through
crystallization.1 In order to broaden the scope of already existing
enantio- and diastereoselective strategies to synthesize chro-
Following this concept ,we envisioned the addition of aryl
acetaldehydes 2 as nucleophiles toward o-QMs, thereby
expanding the scope of these reactions. Given the enol-rich
nature of these aldehydes, we expected them to behave as
competent nucleophiles being able to form a crucial second
Received: June 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01865
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hydrogen bond to the phosphoric acid by enol catalysis, thereby
assembling a highly ordered transition state (Figure 2). In the
groups within the BINOL backbone were shown to provide the
highest enantioselectivity with PA1 (Ar = 2,6-Me2-4-t-Bu-Ph)
being the optimal chiral catalyst (entry 4). Quite interestingly,
phosphoric triflylamide NPA furnished the product only in trace
amounts, while the corresponding acetal was formed as the
major product in this reaction (entry 8). Reducing the catalyst
loading to 5 mol % or running the reaction without 3 Å MS
diminished the yield of the reaction, while the enantioselectivity
was almost completely retained (entries 9 and 10).
With the optimized reaction conditions (Table 1, entry 4), the
substrate scope was next examined (Scheme 1 and 2). For this
Scheme 1. Substrate Scope for the Benzhydryl Alcohol
a
Component 1
Figure 2. Conceptualization of the reaction and the assumed transition
state.
past, hydrogen-bonded enols have been employed as
nucleophiles in a number of enantioselective Brønsted acid
catalyzed reactions, however, exclusively with ketone-derived
enols.7
We began our studies with the model reaction shown in Table
1. Benzhydryl alcohol 1a and phenylacetaldehyde 2a were
a
Table 1. Catalyst and Reaction Screening
b
c
entry
PA
solvent
time (h)
yield (%)
er
1
2
3
4
5
6
7
8
9
1
1
1
1
2
3
4
NPA
toluene
CH2Cl2
THF
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
16
16
48
16
16
16
48
16
16
16
84
81
79:21
84:16
a
Conditions: catalyst PA1 (0.02 mmol, 0.1 equiv), 1a (0.20 mmol, 1
equiv), and 2a (0.40 mmol, 2 equiv) in 1 mL of CHCl3, isolated yield
over two steps and for both diastereomers. The er is of the major
diastereomer. 3 Å MS added.
no conversion
85
66
67
87:13
60:40
85:15
b
no conversion
a
d
Scheme 2. Substrate Scope for the Aldehyde Component 2
traces
74
71
nd
86:14
85:15
e
1
1
f
10
a
Conditions: catalyst PA (0.02 mmol, 0.1 equiv), 1a (0.20 mmol, 1
equiv), 2a (0.40 mmol, 2 equiv), and 50 mg of 3 Å MS in 1 mL of
b
c
solvent. Yield for two-step procedure. Determined by chiral HPLC.
d
e
f
Acetal obtained in 46% yield. No 3 Å MS added. Catalyst loading
reduced to 5 mol %.
treated with various CPAs (10 mol %)8 in the presence of
molecular sieves at rt. To our delight, the cycloaddition turned
out to be the dominant reaction pathway despite some concerns
that the starting diol might well undergo an acetalization
reaction (product not shown here). In order to simplify the
reaction analysis in the initial stages of our investigations, we
isolated the product as chromene 4a after acid-induced
dehydration.
Generally good yields of chromene 4a were isolated with
PA1−3 and in various solvents (Table 1). Chlorinated solvents
proved to be superior to toluene and THF both in terms of
overall yield and enantioselectivity (entries 1−4). Bulky 3,3′-aryl
a
Conditions: catalyst PA1 (0.02 mmol, 0.1 equiv), 1a (0.20 mmol, 1
equiv), 2 (0.40 mmol, 2 equiv), and 50 mg of 3 Å MS in 1 mL of
CHCl3, isolated yield over two steps and for both diastereomers. No
3 Å MS added.
b
B
DOI: 10.1021/acs.orglett.8b01865
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
purpose, the initial cycloaddition product, the lactol 3, was
routinely oxidized to the corresponding lactone, the 3,4-
dihydrocoumarin 5, with PCC from which the diastereoselec-
tivity of the reaction could then be determined.
4). The sense of asymmetric induction is analogous to our
previous studies on a phosphoric acid catalyzed reaction of o-
The β-aryl substituent of the o-QM ends up at the 4-position
within the dihydrocoumarin 5, which could be readily modified
in all positions to furnish products with generally good yields
and er ranging from 83:17 to 92:8. Better enantioselectivities
were observed for sterically more hindered ortho-substituted β-
aryl groups (e.g., 5i and 5j), while para-substituted aryl groups
gave rise to enantioselectivities at the lower end of that range. As
an overall trend, we observe that more electron-rich benzhydryl
alcohols (e.g., 5a, 5h, and 5i) gave rise to higher degrees of
enantioselectivities, especially if the electron-donating group
was located on the phenol moiety (compare 5e and 5k).
The diastereoselectivity of the reaction was ca. 3−4:1 cis/trans
for most products studied. In that respect, the PMP-substituted
coumarins 5a−d stand out as exceptions as they gave rise to
excellent diastereoselectivities of up to >20:1 cis/trans. To shine
some light on this aspect, we studied the formation and
diastereoselectivity during the reaction of lactols 3a and 3b by
online NMR measurements (see the Supporting Information
(SI) and Figure 3). Compound 3a gave rise to a 6:1 cis/trans
Figure 4. Crystal structure analysis of dihydrocoumarin 5b and 4H-
chromene 4b.
QM with enols and enamides, which supports our assumption of
a bifunctional activation mode of both o-QM and aldehyde enol
through the phosphoric acid catalyst.
In order to document the versatility of this process, the
initially obtained lactol 3a was transformed into a variety of
useful products (Scheme 3). As alluded to before, methane-
a
Scheme 3. Derivatization of Lactol 3a
Figure 3. Proposed dynamic equilibrium between the 3,4-cis and 3,4-
trans diastereomers.
ratio after the usual reaction time in the crude reaction mixture,
whereas 3b gave only a 4:1 cis/trans ratio. More interestingly, the
diastereoselectivity proved to be dynamic and changed over
time. In addition, it could be increased by SiO2 column
chromatography in the case of 3a, suggesting an acid-catalyzed
epimerization. We assume that the lactol moiety easily opens up
and produces a new enol intermediate 6, which can be
protonated on either side. Due to unfavorable steric interactions
on the top side by the Ar group, this proton transfer appears
kinetically favored on the bottom side of the enol, producing the
3,4-cis-diastereomer preferentially (Figure 3).
With 1a as benzhydryl alcohol, the substrate scope on the
aldehyde component was investigated (Scheme 2). Again,
generally good yields, excellent cis-diastereoselectivity, and up to
93:7 er were obtained across a range of substituted α-aryl-
substituted acetaldehydes.
Aliphatic aldehydes, lacking the α-aryl group, did, however,
fail to undergo this transformation, most likely because their
enol content was too low for a successful reaction.9 In addition,
2-phenylpropionaldehyde did not give rise to the corresponding
cycloadducts, even though its enol content should be
comparable. Most likely, steric hindrance around the α-position
prevented a successful reaction here. Thus, our investigations
document the first example of enantioselective enol catalysis
with aldehydes.
a
Conditions: (1) catalyst PA1 (0.02 mmol, 0.1 equiv), 1a (0.20
mmol, 1 equiv), 2a (0.40 mmol, 2 equiv), and 50 mg of 3 Å MS in 1
mL of CHCl3; (2) isolated yield over two steps. For further
information, see the SI.
sulfonic acid mediated dehydration delivered 4H-chromene 4a
in high yield. Reduction with LiAlH4 produced diol 7, whereas
acid-assisted reduction with Et3SiH/BF3·OEt2 produced 3,4-
diarylchroman 8 in 67% yield. In addition, cis-3,4-dihydrocou-
marin 5a was readily epimerized to the thermodynamically more
stable 3,4-trans-dihydrocoumarin trans-5a upon treatment with
DBU in CHCl3 at 40 °C, which produced a 8:1-trans-/cis-
mixture of 5a. Accordingly, 3,4-trans-dihydrocoumarins are also
easily accessible with high enantioselectivity using this strategy.
In conclusion, we have developed a new Brønsted acid-
catalyzed protocol for a formal [4 + 2]-cycloaddition of in situ
generated o-QMs and aldehyde enols furnishing 2-chromanols.
Upon further oxidation, a broad range of cis-3,4-diaryl-3,4-
dihydrocoumarins were produced in good yields and with high
diastereo- and enantioselectivity. In addition, the initially
formed 2-chromanols have been manipulated in numerous
ways to access valuable chroman derivatives. In addition, upon
We have obtained crystal structures of dihydrocoumarin 5b
and of 4H-chromene 4b which unambiguously reveal both the
absolute as well as relative configuration of the products (Figure
C
DOI: 10.1021/acs.orglett.8b01865
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01865.
Detailed experimental procedures, spectral data for all
new compounds, and crystallographic data (PDF)
Accession Codes
CCDC 1843089−1843090 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: schneider@chemie.uni-leipzig.de.
ORCID
Christoph Schneider: 0000-0001-7392-9556
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Deutsche Forschungsgemeinschaft for
their continued generous financial support (SCHN 441/11-2)
and thank the European Social Fund for support in the form of a
doctoral fellowship awarded to M.S. We are grateful to M.Sc.
Oliver Erhardt (University of Leipzig) for the crystal structure
analyses and to BASF and Evonik for the donation of chemicals.
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DOI: 10.1021/acs.orglett.8b01865
Org. Lett. XXXX, XXX, XXX−XXX