Organocatalytic, Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa-Michael Addition Sequence

Article abstract of DOI:10.1002/anie.201607039

An unprecedented enantioselective oxa-Michael reaction of α-tertiary alcohols using cinchona-alkaloid-based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa-Michael addition s

Full text of DOI:10.1002/anie.201607039

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607039
German Edition: DOI: 10.1002/ange.201607039
Enantioselective Synthesis
Organocatalytic, Enantioselective Synthesis of Cyclohexadienone
Containing Hindered Spirocyclic Ethers through an Oxidative
Dearomatization/Oxa-Michael Addition Sequence
Reddy Rajasekhar Reddy, Satish Sonbarao Gudup, and Prasanta Ghorai*
Abstract: An unprecedented enantioselective oxa-Michael
reaction of a-tertiary alcohols using cinchona-alkaloid-based
chiral bifunctional squaramide catalysts is reported. An
oxidative dearomatization of phenol followed by an enantio-
selective oxa-Michael addition sequence provided a broad
array of chiral sterically hindered tetrahydrofurans and
tetrahydropyrans attached to a cyclohexadienone moiety in
spiro fashion. In general, good yields and excellent enantiose-
lectivities (up to 99%) were observed. The chiral oxo-cycles
obtained have easily been transformed into chromans without
disturbing the enantioselectivity.
Figure 1. a) Natural products that have a cyclohexadienone-containing
spiro-THF moiety. b) Natural products that have a chroman moiety.
E
nantioselective synthesis of sterically hindered ethers such
as tetrahydrofurans/-pyrans is a long-standing challenge in
organic chemistry.[1] Nevertheless, such moieties are ubiqui-
tous in natural products and pharmaceuticals. Although,
enantioselective intramolecular oxa-Michael addition is one
of the most straightforward routes to chiral oxa-cycles,[2,3] the
enantioselective synthesis of sterically hindered tetrahydro-
furans/-pyrans through the oxa-Michael addition of a-tertiary
alcohols constitutes a daunting, yet unsolved, challenge owing
to their a-crowding and thereby reduced nucleophilicity.[4]
Cyclohexadienone connected to a tetrahydrofuran moiety
in a spiro-fashion (CHD-spiro-THF) is a fascinating skeleton
found in natural products aculeatins A–D and an aculeatin
analogue A, which are active antimalarial agents against the
P. falciparum 3D7 strain (Figure 1a).[5] There have been many
attempts to synthesize such a CHD-spiro-THF moiety; most
are achiral[6a–g] or from chiral substrates.[6h–j] To the best of our
knowledge, a catalytic enantioselective synthesis of such
a moiety is elusive. Therefore, the development of catalytic
enantioselective methods to construct such moieties should
be significantly rewarding.
a tethered alcohol attached to a cyclohexadienone moiety for
the synthesis of fused oxa-cycle II was described (Sche-
me 1a).[10] We presumed a direct use of a-tertiary alcohols,
attached to a cyclohexadienone moiety and with a tethered
enone (shown in III, Scheme 1b), to participate in asymmetric
oxa-Michael reactions to the tethered enone for the synthesis
of sterically hindered tetrahydrofuran/tetrahydropyran IV.
Furthermore, the spiro-cyclohexadienone moiety in the
product would remain untouched, which would potentially
À
allow further functionalization induced by the chiral C O
center.
Development of a sequential organocatalysis remains an
active area of research.[11] In recent years, asymmetric oxa-
Michael reactions using bifunctional organocatalysts bearing
an H-bond donor moiety and a tertiary amino group on
a chiral scaffold,[12] has gained considerable momentum in
Oxidative dearomatization (OD) of phenols[7] to provide
cyclohexadienone, followed by an enantioselective desym-
metrization of a cyclohexadienone (DC)[8] moiety remained
a powerful strategy for the synthesis of architecturally
complex molecules. To the best of our knowledge, only
Gaunt et al. have reported performing both steps in
sequence.[9] Recently, the enantioselective desymmetrization
of cyclohexadienone I through the oxa-Michael addition of
[*] R. R. Reddy, Dr. S. S. Gudup, Prof. P. Ghorai
Department of Chemistry, Indian Institute of Science Education and
Research (IISER) Bhopal
Bhopal By-pass Road, Bhauri, Bhopal-462066 (India)
E-mail: pghorai@iiserb.ac.in
Scheme 1. a) Dearomatization/enantioselective oxa-Michael reaction
on cyclohexadienone. b) Dearomatization/enantioselective oxa-Michael
reaction on tethered enone.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607039.
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catalytic endeavors.[2,3] As a part of our effort to extend the
power of these transformations,[3] we decided to utilize
a similar mode of action for the present reaction. First, an
OD of substituted phenol 1b was performed using PhI(OAc)2
as an oxidant to prepare the desired 4-hydroxy cyclohex-
adienone Ib, which was used for the asymmetric oxa-Michael
addition in the presence of various organocatalysts as shown
in Table 1 (for details, see the Supporting Information). The
Table 1: Optimization of the reaction conditions.[a]
Entry
2
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
2e
2e
Toluene
Toluene
Toluene
Toluene
Toluene
44
86
66
59
93
91
53
94
85 (70)[g]
77
95 (97)[d]
55
Toluene
Other solvents[f]
Toluene
<92
82
<94
96[e]
Scheme 2. Substrate scope for CHD-spiro-THF.[a,b,g] [a] Reaction con-
ditions: (i) 1 (0.1 mmol, 1 equiv), PhI(OAc)2 (0.1 mmol, 1 equiv), in
MeCN:H2O (9:1, 1.0 mL) at 08C for 10 min. (ii) Toluene (1 mL) at 08C
and then 2e (0.005 mmol, 5 mol%). [b] Isolated yield. [c] Step 2 was
carried out at rt. [d] Step 2 was carried out at À208C. [e] Step 2 was
carried out at 408C. [f] After single recrystallization. [g] The ee’s were
determined by chiral HPLC analysis.
[a] Reaction conditions: (i) 1b (0.6 mmol, 1 equiv), PhI(OAc)2
(0.6 mmol, 1 equiv), MeCN:H2O (9:1), 08C for 10 min. (ii) Ib
(0.02 mmol, 1 equiv), catalyst (5 mol%) in solvent (0.3 mL, 0.1m) at rt,
9 h. [b] The conversion/yield was calculated based on 1H NMR spec-
troscopy of the crude reaction mixture using diphenylacetonitrile as an
internal standard. [c] The ee’s were determined by chiral HPLC analysis.
[d] Sequential synthesis. [e] at 08C. [f] See the Supporting Information.
[g] Isolated yield.
Replacement of the phenyl ring with bi-phenyl (3l, 97% ee)
and 1-naphthyl rings (3m, 90% ee) was equally successful.
Instead of an aryl moiety, heteroaryl groups such as 2-furyl
(3n) and 2-thiophenyl (3o) moieties underwent cyclization
and gave high enantioselectivities (90% ee and 95% ee,
respectively). Furthermore, substitutions on the phenol ring
were also tolerated, for example, the corresponding 2,6-di-
tert-butyl and 2,6-dibromo substituted phenols provided the
corresponding products 3p (84% ee) and 3q (93% ee),
respectively. Not only aryl and heteroaryl ketones but also
aliphatic ketones such as methyl ketone (3r) worked well
under these reaction conditions and provided 90% ee with
a 75% yield. Notably, the ester (3s) and thioester (3t)
functionalities were also equally effective and gave 98% ee
and 95% ee, respectively. Finally, compound (3b) was
synthesized in a higher scale (2 mmol scale) with only
a small loss of selectivity (from 97% ee to 93% ee).
optimal catalyst 2e provided a yield of 85% and 95% ee
(entry 5). The screening of the solvents (see the Supporting
Information) revealed that toluene was the optimal solvent
(entry 5). When the reaction temperature was lowered to
08C, the selectivity was enhanced to 96% ee (entry 8). Once
the optimized reaction conditions were established, a sequen-
tial reaction was carried out, which yielded an even better
selectivity (97% ee, entry 5).
Various phenol derivatives were tested using the opti-
mized sequential reaction conditions to examine the general-
ity of the reaction. The results are summarized in Scheme 2.
Electron-rich substituents such as p-Me (3b), p-OMe (3c), o-
OMe (3d), m,p-diOMe (3e), and m,p-OCH2O (3 f) worked
smoothly, resulting high stereo-controlled products with
excellent selectivity (90–97% ee). Electron-deficient sub-
stituents such as p-Cl (3g), o-Br (3h), p-Br (3i), p-I (3j), and
p-F3C (3k) showed a similar effect on selectivity (87–99% ee).
The absolute configuration of the spiro-dienone 3j was
unambiguously determined to be (S) by single-crystal X-ray
diffraction analysis (Figure 2).
This protocol can also be applied to the asymmetric
synthesis of substituted tetrahydropyrans (THP, Scheme 3).
The electronic and steric effects on the a,b-enone moiety of 4
were examined; for example, Ph (5a), p-tol (5b), biphenyl
(5c), 2- thiophenyl (5d), and 2-furyl (5e) provided good
yields and high enantioselectivities (78–93% ee). Substitution
2
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Unfortunately, a lower selectivity was obtained for product 9
owing to the inseparable E/Z-isomers (4:1) in the parent
substrate 8.[14a] However, the enantioselectivity remained
unchanged during the rearrangement step. This provides an
excellent opportunity to expand the synthesis of hindered
spiro-cyclic ethers having both a-tertiary carbons.
To expand further the synthetic utility of our method,
functionalization of the cyclohexadienone moiety of 3b or 3s
was performed without losing much enantioselectivity
(Scheme 5). Pd/C-catalyzed hydrogenation of 3b (93% ee)
Figure 2. Crystal structure of compound 3j (CCDC 1488175 contains
the supplementary crystallographic data for this paper. These data can
be obtained free of charge by The Cambridge Crystallographic Data
Centre).
Scheme 3. Substrate scope for CHD-spiro-pyrans.[a] [a] Reaction con-
ditions remained the same as given in Scheme 2.
Scheme 5. Functionalization of cyclohexadienone moiety.[a–c] [a] 3b or
3s (0.1 mmol, 1 equiv), (i) Pd/C (10 mol%), H2 gas (1 atm), MeOH
(2 mL), rt, 12 h. (ii) DIBAl-H (2.2 equiv), THF (1 mL), À788C, N2 atm,
20 min. (iii) cyclopentadiene (10 equiv), CF3CH2OH (2 mL), rt, 16 h.
(iv) N-methyl indole (1.2 equiv), FeCl3 (10 mol%), CH2Cl2 (2 mL), rt,
18 h. [b] Isolated yield. [c] The ee’s were determined by chiral HPLC
analysis.
on the phenol moiety (for example, Br in 5 f) was well
tolerated. To illustrate the further synthetic utility of the
developed method, chiral spiro-oxocycle 3 and 5 were tested
for an efficient Lewis-acid-mediated ring expansion into the
chiral chromans (6a–6e) and homochroman (7a), respec-
tively (Scheme 4a). To our delight, the desired chromans
were obtained in good yields, albeit a slight decrease in
enantioselectivity. To the best of our knowledge, this is the
first synthesis of a chiral homochroman with good enantio-
selectivity. Chromans are an important structural motif in
several natural products such as nebivolol, vitamin-E, and
Trolox (Figure 1b).[13] However, the reports on the enantio-
selective synthesis of such motifs are very limited.[1a,2j,14] The
prevalence of a-tertiary centers to oxygen in chromans (as
shown in Figure 1b) prompted us carry out the current
oxidative oxa-Michael addition of substrate 8 (Scheme 4b).
gave the corresponding cyclohexanone derivative 11a in
excellent yield and nearly the same ee (90% ee). A ketone
functionality of the cyclohexadienone moiety of 3b was
selectively reduced over benzyl ketone with DIBAL-H to
provide 11b with 2.9:1 d.r. and 91% ee. The unsaturation of
3b was utilized as a dienophile in a Diels–Alder reaction with
cyclopentadiene as a diene to provide 11c with the same
selectivity. Interestingly, nucleophilic addition of the indole to
a cyclohexadienone moiety using a FeCl3·6H20 catalyst
À
resulted in a unique C O bond breaking, which did not
affect enantioselectivities to provide the b-hydroxy ester
(11d) and thioester (11e) attached to a d-phenol moiety.[15]
A bifunctional mechanism similar to those previously
proposed for the squaramide/thiourea-based amino catalysts
in the oxa-Michael reaction of enone[2,3] may be cited to
explain the observed absolute stereochemistry.
In summary, a sequential dearomatization/enantioselec-
tive intramolecular oxa-Michael reaction of in situ generated
4-hydroxyl cyclohexadienones has been developed using
a chiral bifunctional organocatalyst. This process provides
the first and promising approach for the enantioselective
synthesis of tetrahydrofurans and tetrahydropyrans, attached
to a cyclohexadienone moiety in spiro-fashion, with excellent
enantioselectivity and a broad substrate scope. Furthermore,
a Lewis-acid-mediated ring expansion of the chiral spiro-
THFs/pyrans has been demonstrated to provide the corre-
sponding chromans and homochroman without disturbing the
enantioselectivities. Overall, this methodology contributes to
Scheme 4. Ring expansion: synthesis of chiral chromans and homo-
chromans.[a–c] [a] Reaction conditions: a) 3 or 5 (0.1 mmol), BF3·OEt2
(8.0 equiv), dry CH2Cl2, 08C, 10 min. [b] Isolated yield. [c] The ee’s
were determined by chiral HPLC analysis.
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hindered ethers, which, though ubiquitous in natural products,
were a long-standing challenge to the synthetic community.
Acknowledgements
This work has been funded by the Council of Scientific and
Industrial Research (CSIR), New Delhi and IISER Bhopal.
Keywords: asymmetric synthesis · chromans · organocatalysis ·
oxa-Michael addition · tetrahydrofurans
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[12] For recent reviews on chiral amino-thiourea catalysis, see: a) S. J.
Connon, Chem. Commun. 2008, 2499; b) Y. Takemoto, Chem.
Pharm. Bull. 2010, 58, 593; On chiral amino-squaramide
catalysis: c) J. Malerich, K. Hagihara, V. H. Rawal, J. Am.
Chem. Soc. 2008, 130, 14416; d) R. I. Storer, C. Aciro, L. H.
Jones, Chem. Soc. Rev. 2011, 40, 2330.
[15] For the reaction mechanism, see: Y. Ye, H. Wang, R. Fan, Synlett
2011, 0923.
[13] J. M. Grisar, M. A. Petty, F. N. Bolkenius, J. Dow, J. Wagner,
E. R. Wagner, K. D. Haegele, W. D. Jong, J. Med. Chem. 1991,
34, 257.
Received: July 20, 2016
Revised: August 24, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Enantioselective Synthesis
R. R. Reddy, S. S. Gudup,
P. Ghorai*
&&&& — &&&&
Organocatalytic, Enantioselective
Synthesis of Cyclohexadienone
Containing Hindered Spirocyclic Ethers
through an Oxidative Dearomatization/
Oxa-Michael Addition Sequence
An asymmetric oxa-Michael reaction of a-
tertiary alcohols using chiral squaramide
catalysts is reported. The reaction pro-
vided a broad array of sterically hindered
tetrahydrofurans and tetrahydropyrans
attached to a cyclohexadienone moiety in
spiro fashion. Good yields and enantio-
selectivities were observed. The oxo-
cycles obtained were transformed into
chromans without disturbing the enan-
tioselectivity.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!