Enantioselective synthesis of hindered cyclic dialkyl ethers via catalytic oxa-Michael/Michael desymmetrization

Article abstract of DOI:10.1039/c3sc51022k

An asymmetric oxa-Michael/Michael cascade reaction of p-quinols and α,β-unsaturated aldehydes provides access to hindered dialkyl ethers. A highly enantioselective oxa-Michael addition of a tertiary alcohol precedes an intramolecular cyclohexadienone desymmetrization, which allows for the concomitant formation of four contiguous stereocenters in a single step. The highly functionalized bicyclic frameworks are rapidly obtained from simple starting materials with good diastereoselection and serve as valuable precursors for further manipulation.

Full text of DOI:10.1039/c3sc51022k

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Enantioselective synthesis of hindered cyclic dialkyl
ethers via catalytic oxa-Michael/Michael
desymmetrization†
Cite this: DOI: 10.1039/c3sc51022k
*
Michael T. Corbett and Jeffrey S. Johnson
An asymmetric oxa-Michael/Michael cascade reaction of p-quinols and a,b-unsaturated aldehydes
provides access to hindered dialkyl ethers. A highly enantioselective oxa-Michael addition of a tertiary
alcohol precedes an intramolecular cyclohexadienone desymmetrization, which allows for the
concomitant formation of four contiguous stereocenters in a single step. The highly functionalized
bicyclic frameworks are rapidly obtained from simple starting materials with good diastereoselection
and serve as valuable precursors for further manipulation.
Received 17th April 2013
Accepted 14th May 2013
DOI: 10.1039/c3sc51022k
www.rsc.org/chemicalscience
challenges limiting its broad utility as a general method for the
construction of hindered ethers: poor nucleophilicity, compet-
Introduction
itive acetal/ketal formation, and reversibility.6 Consequently,
phenols and oximes are typically employed in asymmetric
intermolecular oxa-Michael additions due to their heightened
reactivity.7 Applications of secondary and tertiary alcohols in
oxa-Michael reactions are scarce due to their a-stereogenicity
and reduced nucleophilicity; generally limiting their applica-
tion to intramolecular kinetic resolutions.8 Based on recent
Sterically hindered ethers are ubiquitous in natural products
and their asymmetric preparation is a long-standing challenge
to the synthetic community. Limitations of classical methods
for the preparation of tertiary ethers, such as the Williamson
ether synthesis, include undesirable racemization and elimi-
nation pathways.1 Current C–O bond forming methodologies to
address these limitations include metal-mediated alkene func-
tionalizations,2 carbonyl ylide cycloadditions,3 among others;4
intramolecular C–O bond formation with creation of a single
a-stereocenter is common. A more powerful method for
complexity-building synthesis could arise from intermolecular
C–O bond formation allowing the preparation of a-tertiary
ethers where both a-stereocenters are set in a single operation,
but examples of these are rare.4j Herein, we report a direct
metal-free synthesis of hindered tert/sec ethers via an organo-
catalytic oxa-Michael/Michael sequence involving tertiary alco-
hols and a,b-unsaturated aldehydes with concomitant
formation of four contiguous stereocenters.
´
work by Cordova, we believed carefully selected tertiary alcohols
could be effective participants in oxa-Michael additions in
conjunction with an ensuing intramolecular complexity
building transformation.8c
The strategy described above implicitly relies on simple
access to the achiral tertiary alcohol; dearomatization is a
valuable method that is relevant in the present context.9 In
particular, oxidative dearomatization of 4-substituted phenols
with an oxygen nucleophile provides access to p-quinols,10
a
As conceptualized in Scheme 1a, we sought to develop an
asymmetric CÀO bond construction involving achiral tertiary
carbinols bearing enantiotopic groups that would undergo
subsequent diastereoselective desymmetrization to establish
the tertiary stereogenic center. The illustrated (3 + 2)-annula-
tion5 was targeted as an attractive embodiment of this strategy
and would require initiation by oxa-Michael addition to an a,b-
unsaturated carbonyl (Scheme 1b). Despite increasing attention
in the literature, the oxa-Michael addition retains key
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel
Hill, NC 27599-3290, USA. E-mail: jsj@unc.edu
† Electronic supplementary information (ESI) available: Experimental procedures,
NMR spectra, and HPLC/SFC traces. CCDC 926927. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3sc51022k
Scheme 1 Asymmetric approach to hindered ether synthesis.
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Table 1 Reaction optimizationa
Entry
3
Additive
Solvent
Yield (%)b
drc
erd
1
2
3
4
5
6
7
8
9e
3b
3b
3b
3b
3a
3c
3d
3e
3b
PhCO2H
NaHCO3
PhCO2H
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
CH2Cl2
CH2Cl2
61
Tracec
78
82
0
72
0
75
81
15 : 1
—
15 : 1
16 : 1
—
7 : 1
—
9 : 1
15 : 1
99.5 : 0.5
—
>99.5 : 0.5
>99.5 : 0.5
—
>99.5 : 0.5
—
>99.5 : 0.5
>99.5 : 0.5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Scheme 2 Select cyclohexadienone desymmetrization strategies.
a
Reactions were performed on 0.30 mmol scale, using 3.0 equiv.
b
aldehyde unless otherwise noted.
Isolated yield of major
unique cyclohexadienone subclass that has been applied in
various desymmetrization processes.11 Gaunt demonstrated the
potential to perform direct enantioselective dearomatization
reactions of phenols employing PhI(OAc)2 in conjunction with
enamine catalysis (Scheme 2a),11d while Rovis developed enan-
tioselective synthesis of endoperoxide acetals by desymmetri-
zation of the achiral hydroperoxides (Scheme 2b).11j p-Quinol 1
possesses both a tertiary alcohol capable of participating in
intermolecular oxa-Michael addition and enantiotopic p-elec-
trophiles for subsequent intramolecular desymmetrization. We
proposed that these attributes could establish p-quinol 1 as a
competent substrate class for iminium/enamine oxa-Michael/
Michael cascade reactions under secondary amine catalysis.12
diastereomer. Determined by 1H NMR analysis of crude reaction
c
d
e
mixture. Determined by chiral SFC analysis. Employing 1.5 equiv.
aldehyde.
yield, but lower levels of diastereoselection (entries 6 and 8).
Optimized conditions were realized using commercially avail-
able 3b with 1.5 equivalents of cinnamaldehyde affording 4a in
81% yield with 15:1 dr and >99.5:0.5 er (entry 9).
The feasibility of employing other quinol and aldehyde
reactants was examined as the reaction's scope was probed
(Table 2). Excellent levels of enantioselection were observed
for all substrates irrespective of the steric and electronic
features of the nucleophile and electrophile. In addition to the
parent product 4a, products can be obtained bearing strongly
Results and discussion
We commenced our investigation by examining the reaction of electron-releasing and withdrawing para-substituents with
p-quinol 1a with cinnamaldehyde (2a) employing Jørgensen– slightly reduced diastereocontrol (4b and 4c). Aromatic alde-
Hayashi diarylprolinol ether catalysts 3 due to their applicability hydes bearing ortho-substituents were found to provide
in a variety of aldehyde functionalization reactions.13 Gratify- excellent levels of diastereocontrol regardless of electronic
ingly, silyl ether 3b in conjunction with benzoic acid as an features (4d, 4e, and 4f). The bulky mesityl-group could be
additive provided 4a in 61% yield with good diastereocontrol incorporated providing 4g in good chemical yield and enan-
and excellent enantioselection (Table 1, entry 1). The use of tioselectivity, but with low diastereocontrol (4 : 1 dr). Thien-
basic additives like NaHCO3 was found to be detrimental to the 2-yl and indol-3-yl functionality was amenable to the reaction
reaction (entry 2). Switching the solvent to toluene and utilizing providing access to heteroaromatic substrates 4h and 4i.
4-nitrobenzoic acid (PNBA) increased the yield to 82% with no Aldehydes bearing a g-enolizable site are also compatible
loss in stereocontrol (entry 4). Although high levels of enantio- under the reaction conditions as crotonaldehyde provides
selectivity were observed in the initial oxa-Michael addition, access to Me-substituted 4j in 58% yield and 7 : 1 dr with 99 : 1
efforts to increase the diastereoselection of the subsequent enantioselection. Only trace byproducts were observed from
intramolecular Michael addition through structural modica- undesired dienamine formation. In addition to methyl-
tions of the catalyst 3 were largely unsuccessful. Both free substituted 1a, a variety of p-quinols were tolerated bearing
alcohol 3a and 3,5-(CF3)2Ph-derived 3d completely shut down linear aliphatic substituents allowing for the incorporation of
the reaction (entries 5 and 7). Catalysts possessing a bulkier TES pendant siloxy and ester functionality (4k, 4m, and 4n). The
group (3c) or 3,5-Me2Ph aryl groups (3e) provided 4a in good bulkier iPr-derived p-quinol provided 4l in 71% yield, but with
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Table 2 Substrate scopea
4a 81% yield
4b 80% yield
4cb 77% yield
4d 93% yield
15 : 1 dr, >99.5 : 0.5 er
9 : 1 dr, 98 : 2 er
7 : 1 dr, >99.5 : 0.5 er
17 : 1 dr, >99.5 : 0.5 er
4e 86% yield
4f 91% yield
4g 76% yield
4hb 73% yield
14 : 1 dr, >99.5 : 0.5 er
>20 : 1 dr, 99.5 : 0.5 er
4 : 1 dr, 99 : 1 er
5 : 1 dr, 98 : 2 er
4i 65% yield
4j 58% yield
4k 77% yield
4lc 71% yield
7 : 1 dr, 97 : 3 er
7 : 1 dr, 99 : 1 er
12 : 1 dr, >99.5 : 0.5 er
6 : 1 dr, 99 : 1 er
4m 82% yield
4n 75% yield
13 : 1 dr, 99 : 1 er
6 : 1 dr, >99.5 : 0.5 er
a
Reactions were performed on 1.00 mmol scale, using 1.5 equiv. aldehyde. Isolated yields of analytically pure major diastereomer are reported.
Diastereomer ratios were determined by 1H NMR analysis of the crude reaction mixtures; enantiomer ratios were determined by chiral HPLC/
SFC analysis. b Toluene:CH2Cl2 (1 : 1) (0.25 M). c Isolated yield of 10 : 1 dr mixture.
modest diastereoselection in the intramolecular Michael
addition.
In addition to providing complex fused bicyclic frameworks
with good stereocontrol, the products contain synthetically
In order to further highlight the potential applicability of useful aldehyde and enone functional handles for further
this methodology, the reaction of 1a and 2d was performed on orthogonal manipulations (Scheme 4). Chemoselective reduc-
20 mmol scale employing commercially available catalyst 3b tion of aldehyde 4a afforded alcohol 5a (92% yield), which was
with technical grade reagents under ambient atmosphere subsequently converted to the p-nitrobenzoate 6. The absolute
providing 4d in 82% yield aer a single recrystallization stereochemistry of the product was assigned by an X-ray
(Scheme 3).
diffraction study of 6 and others were assigned by analogy.14 The
illustrated X-ray structure reveals a rigidied structure that was
projected to engender excellent stereocontrol in manipulations
of p-functional groups. Indeed, Weitz–Scheffer reaction of 4d
afforded epoxide 7 as a single diastereomer bearing six contig-
uous stereocenters. Chemoselective Horner–Wadsworth–
Emmons olenation of 4n provided diester 8 in 96% yield. A
one-pot TBS-cleavage/oxa-Michael cyclization of 4m gave access
to aldehyde 9 bearing a tricyclic framework found in the phys-
alins.15 Exposure of 4d to benzylamine and NaBH3CN generated
tricycle 10 presumably via sequential epimerization, reductive
Scheme 3 Gram scale synthesis.
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Acknowledgements
The project described was supported by Award No. R01
GM084927 from the National Institute of General Medical
Sciences. M.T.C. acknowledges the University of North Carolina
at Chapel Hill Department of Chemistry for an Ernest L. Eliel
Graduate Fellowship. X-ray crystallography performed by Dr
Peter S. White.
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~
´
´
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