Direct Asymmetric α-Hydroxylation of Cyclic α-Branched Ketones through Enol Catalysis

Article abstract of DOI:10.1055/s-0037-1611084

Enantiopure α-hydroxy carbonyl compounds are common scaffolds in natural products and pharmaceuticals. Although indirect approaches towards their synthesis are known, direct asymmetric methodologies are scarce. Herein, we report the first direct asymmetric α-hydroxylation of α-branched ketones through enol catalysis, enabling a facile access to valuable α-keto tertiary alcohols. The transformation, characterized by the use of nitrosobenzene as the oxidant and a new chiral phosphoric acid as the catalyst, delivers a good scope and excellent enantioselectivities.

Full text of DOI:10.1055/s-0037-1611084

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
G. A. Shevchenko et al.
Letter
Synlett
Direct Asymmetric α-Hydroxylation of Cyclic α-Branched Ketones
through Enol Catalysis
F
Grigory A. Shevchenko+
Gabriele Pupo+
F
F
F
F
Benjamin List*
F
F
O
O
O
P
10 mol%
OH
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 Mülheim an der Ruhr, Germany
list@mpi-muelheim.mpg.de
F
F
F
F
O
O
R
F
R
O
N
OH
+ These authors contributed equally to this work.
F
F
+
Ph
n
n
Enol
catalysis
13 examples
up to 98.5:1.5 er
Received: 07.09.2018
Accepted after revision: 10.10.2018
Published online: 14.11.2018
OH
OH
O
Me
O
DOI: 10.1055/s-0037-1611084; Art ID: st-2018-r0580-l
Me
H
Abstract Enantiopure α-hydroxy carbonyl compounds are common
scaffolds in natural products and pharmaceuticals. Although indirect
approaches towards their synthesis are known, direct asymmetric
methodologies are scarce. Herein, we report the first direct asymmetric
α-hydroxylation of α-branched ketones through enol catalysis, enabling
a facile access to valuable α-keto tertiary alcohols. The transformation,
characterized by the use of nitrosobenzene as the oxidant and a new
chiral phosphoric acid as the catalyst, delivers a good scope and excel-
lent enantioselectivities.
O
H
H
Me
O
(a)
OH
Me
O
OH
OH
O
cortisone
Me
OH
O
OH
OH
O
O
OH
O
paeonilactone B
aquayamycin
(b)
O
O
Key words enol catalysis, α-hydroxy ketones, Brønsted acid catalysis,
hydroxylation, chiral phosphoric acid
N
N
N
Ph
O
Me
Ph
NH
R
R
α-Hydroxy carbonyl compounds and their derivatives
are versatile building blocks and can be found in numerous
bioactive molecules and drugs (Figure 1, a).1 Over the last
decades, numerous synthetic strategies towards these mo-
tifs have been developed; however, they have almost exclu-
sively relied on nature’s chiral pool,2 chiral auxiliaries,3 or
chiral reagents (e.g. Davis oxaziridine).4 More recently, cata-
lytic methods initially developed for the dihydroxyl-
ation/epoxidation of olefins, e.g. Sharpless dihydroxyl-
ation,5 Jacobsen–Katsuki,6 and Shi epoxidations7 were suc-
cessfully applied to the oxidation of preformed enol ethers
and esters. Moreover, Yamamoto et al. employed tin eno-
lates and silyl enol ethers as reactants in the Lewis acid-cat-
alyzed α-hydroxylation with nitrosobenzene as the oxi-
dant.8 High O/N selectivity was obtained and subsequent
reduction gave the desired α-hydroxy carbonyl com-
pounds.8c Nevertheless, all these indirect methodologies re-
quire an additional step to pre-functionalize the starting
material toward the corresponding enolate.
82%
Enamine Catalysis
less substituted enamine preferred
er >99:1 [Ref. 9d,f]
O
R
OH
O
O
O
N
P
OH
OH
OH
H
O
H
H
*
P
OH
O
O
OH
R
Ph
R
O
R
this work
Enol Catalysis
more substituted enol preferred
Figure 1 (a) Natural products and drugs bearing the α-hydroxy ketone
moiety; (b) direct catalytic routes toward enantioenriched α-hydroxy
ketones
Efficient direct asymmetric aminoxylation reactions of
linear aldehydes and cyclic ketones have been reported in
the context of enamine catalysis with use of chiral second-
ary amines as the catalysts and nitrosobenzene as the re-
agent.9,1c However, because of the steric constrains of
enamines, α-branched ketones exclusively react through
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
G. A. Shevchenko et al.
Letter
Synlett
the least-substituted enamine intermediate, thus preclud-
ing access to synthetically challenging tetrasubstituted ste-
reocenters (Figure 1, b).9d,e An alternative phase-transfer
catalytic approach has also been reported for the hydroxyl-
ation of α,α'-trisubstituted ketones, yet the regioselectivity
challenge was not addressed.9i We recently proposed a
solution for the direct functionalization of branched ke-
tones through enol catalysis.10 In the presence of catalytic
amounts of a chiral phosphoric acid, the more substituted
enol is formed thus enabling highly selective and enanti-
oselective α-functionalizations. By employing this new ac-
tivation mode, C–C10a,11 and C–N12 and bond forming reac-
tions were successfully developed. Recently, we disclosed
the direct aryloxylation of α-branched cyclic ketones; how-
ever, additional synthetic modifications were required in
order to access the corresponding α-hydroxy ketones.13 We
therefore hypothesized that we could apply enol catalysis in
the presence of an excess of nitrosobenzene thus directly
accessing highly valuable tetrasubstituted α-hydroxy ke-
tones through a tandem asymmetric aminoxylation/depro-
tection sequence (Figure 1, b).14
ents were tested (A5), higher enantioselectivities were ob-
tained (entry 5). Finally, by changing the backbone from
BINOL to SPINOL (B5),15 we were able to isolate 2a in 56%
yield and 98:2 er (entry 6). Noteworthy in all cases, hydrox-
ylation of the nonsubstituted α-carbon of the ketones only
occurred in traces.
In all cases 6-oxo-6-phenylhexanoic acid was obtained
as side product, presumably through two successive oxida-
tions of the substrate (see Supporting Information for de-
tails). However, this could be strongly suppressed by slow
addition of nitrosobenzene without influencing the yield of
the product. Further optimization attempts (e.g. tempera-
ture, equivalents, and concentration) did not further im-
prove the yields while maintaining in all cases very high en-
antioselectivities. Control experiments showed that the de-
sired products were stable under the reaction conditions.
Although kinetic resolution of the starting material is pres-
ent (see Supporting Information for details), this does not
solely account for the moderate yields, and we believe that
the formation of an uncharacterized polymer may be an ad-
ditional cause.
The chiral Brønsted acid catalyst should play multiple
roles in this designed scenario and enable: the enolization
(nucleophile activation), the enantioselective functionaliza-
tion (electrophile activation through protonation of the ni-
trogen atom), and ultimately the cleavage of the N–O bond
to deliver the free alcohol. This transformation presents,
however, multiple challenges: (i) regioselectivity (more vs.
less substituted enol), (ii) N/O selectivity of the attack on ni-
trosobenzene, (iii) enantioselectivity, and (iv) the tandem
sequence of the α-oxidation and reductive cleavage. Never-
theless, if successful, this approach would represent the
first direct, catalytic, and asymmetric α-oxidation of
branched ketones, and provide a single step access to enan-
tioenriched α-hydroxy ketones.
We started our investigation (Table 1) by employing
commercially available 2-phenyl cyclohexanone (1a) as a
model substrate. When a reaction of 1a was performed
with an excess of nitrosobenzene in the presence of a chiral
phosphoric acid catalyst such as (S)-TRIP (A1), the desired
α-hydroxy ketone 2a was indeed obtained albeit in low
yields and very low enantioselectivities (entry 1, 14% yield,
58.5:41.5 er). Initial experiments had immediately shown
that aromatic solvents and the addition of over stoichio-
metric amounts of acetic acid were beneficial in terms of
yield and enantioselectivity (see Supporting Information
for details). More importantly, when electron-withdrawing
groups were included in the 3,3'-positions of the catalyst,
the enantioselectivity increased dramatically. For example,
catalyst A3 afforded 44% of product 2a with an enantiomer-
ic ratio of 82.5:17.5. We screened other nitrosobenzene de-
rivatives, but these resulted only in lower enantioselectivi-
ties. Interestingly, fluorinated catalyst A4 outperformed A3
raising the enantioselectivity to 89:11 er. Indeed, when
new catalysts bearing perfluorinated naphthalene substitu-
Table 1 Optimization of the Catalyst Structure for the Asymmetric
α-Hydroxylation of α-Branched Ketonesa
O
O
A or B (10 mol%)
PhNO (2.5 equiv)
AcOH (3.5 equiv)
Ph
OH
Ph
benzene, r.t., 24 h
1a
2a
Ar
iPr
CF3
CF3
O
O
iPr
Ar =
P
OH
O
iPr
Ar
A1
A2
A3
Ar
O
F
F
A
O
O
F
F
F
F
P
F
F
OH
F
F
Ar
F
A4
A5/B5
F
B
Entry
Catalyst
Yield (%)b
erc
A1
1
2
3
4
5
6
7
14
47
58.5:41.5
55:45
A2
A3
A4
A5
B5
B5
44
82.5:17.5
89:11
55
43
92.5:7.5
98:2
56d
17e
98:2
a Reactions were performed on a 0.025 mmol scale. For full optimization
see Supporting Information.
b Determined by 1H NMR with use of Ph3CH as an internal standard.
c Determined by HPLC on a chiral stationary phase.
d Isolated yield.
e No acetic acid added.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
G. A. Shevchenko et al.
Letter
Synlett
Having the best conditions in hands, we turned our at-
tention towards the generality of the transformation
(Scheme 1). Various cyclohexanones bearing an electron-
neutral, -rich or mildly -poor aromatic substituents in the
2-position were hydroxylated in moderate to good yields
and very high enantioselectivities (2a–j). More electron-de-
ficient substituents on the aromatic ring (-CF3) resulted in
lower yields yet extremely high enantiomeric ratios (2d).
Despite its strong steric hindrance, 2-(1-naphtyl) cyclohex-
anone was also compatible with the protocol (2c, 38% yield,
91:9 er). To our delight, cycloheptanone 2l was also tolerat-
ed (29% yield, 95.5:4.5 er). Finally, 2-alkyl-substituted cy-
clohexanones delivered the desired products in lower yields
and enantioselectivities (2k, 2m, and 2n). Interestingly, in-
danone- and tetralone-derived substrates, which per-
formed well in previous enol catalysis reports,11a either did
not react or resulted in racemic product. Products derived
from 2-substituted cyclopentanones were not stable under
the reaction conditions and decomposed. Acyclic ketones
did not show any reactivity even at higher temperatures
(up to 40 °C tested). The absolute configuration was con-
firmed by X-Ray spectroscopic analysis of 2a and assigned
by analogy for the other substrates.
The robustness of the method was further highlighted
by a scale-up experiment with our model substrate, and 2a
was obtained without deterioration in yield or enantiose-
lectivity by employing a lower catalyst loading (Scheme 2, 5
mol%, 70% recovered). To illustrate the utility of the devel-
oped method, hydroxy ketone 2a was derivatized to diols 3
and 5 by stereoselective reduction or Grignard addition, re-
spectively. Furthermore, reaction with the Bestmann ylide16
afforded lactone 4, giving a straightforward and highly en-
antioselective access to dihydroactinidiolide-type struc-
tures.17 In all cases, no deterioration in enantioselectivity
was observed.
F
F
F
F
PhNO (2.5 equiv)
(R)-B5 (10 mol%)
AcOH (3.5 equiv)
O
O
F
OH
F
F
OH
OH
O
R
O
O
R
P
B5
OH
Ph
F
PhH, r.t.
F
F
n
n
1a–m
2a–m
K-Selectride (5 equiv)
THF, –78 to 0 °C
er 98:2, dr >20:1
F
3 (83%)
F
F
F
O
O
B5 (5 mol%)
O
O
O
C
O
OH
70% recovered)
PhNO (2.5 equiv)
AcOH (3.5 equiv)
O
(2 equiv)
OH
OH
O
OH
C
OH
Ph
CF3
O
Ph
Ph
PPh3
Ph
PhMe,
100 °C
PhH, r.t., 3 d
2a (56%)
er 98:2
2b (58%)
er 97.5:2.5
2c (38%)
er 91:9
2d (29%)
er 98.5:1.5
2a (55%, 2.5 mmol)
1a
4 (70%)
er 97.5:2.5
er 97.5:2.5
O
OH
Me OH
OMe
MeMgCl (4 equiv)
THF, –78 to r.t.
OH
Ph
Ph
OMe
O
O
O
OH
OH
OH
Me
2f (54%)
er 96:4
5 (79%)
er 99.5:0.5, dr > 20:1
2e (54%)
2g (44%)
2h (49%)
er 97.5:2.5
er 97.5:2.5
er 97:3
Scheme 2 Scale-up reaction and derivatization of the products
OMe
O
O
O
O
O
OH
Ph
OH
OH
OH
On the basis of our previous studies10–13 and literature
reports14 we propose the reaction to proceed through the
catalytic cycle depicted in Scheme 3. Phosphoric acid-pro-
moted enolization gives catalyst/enol complex 6. The ob-
served kinetic resolution of the starting material suggests
that this step is rate-determining (see Supporting Informa-
tion for details). Subsequent attack of the enol onto nitroso-
benzene gives aminoxylated ketone 7, which reacts with a
second equivalent of nitrosobenzene to give the targeted α-
hydroxy ketones alongside with azoxybenzene (9)18 pre-
sumably through intermediate 8.14 Initial mechanistic stud-
ies suggest the reversibility of the initial attack of the enol
onto nitrosobenzene and support the existence of aminox-
ylated ketone 7 as a reaction intermediate (see Supporting
Information for details).
O
OMe
2i (46%)
er 97:3
2j (53%)
er 97:3
2k (40%)
er 94:6
2l (29%)
er 95.5:4.5
O
O
OH Ph
OH
2n (23%)
er 92:8
2m (34%)
er 85.5:14.5
Scheme 1 Substrate scope of the catalytic asymmetric α-hydroxyl-
ation of α-branched ketones. Reactions were performed on a 0.2 mmol
scale and run for 24 or 48 h at room temperature. Absolute configura-
tions of the products were assigned according to the crystal structure
of 2a.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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G. A. Shevchenko et al.
Letter
Synlett
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O
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O
O
Ph
Ph
Ph
O
O
O
OH
O
N
H
P
Ph
1a
Ph
7
OH
HO
OH
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N
Ph
6
O
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Ph
OH
Ph
O
N
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+
Ph
OH
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O
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Ph
H
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9
Ph
N
O
Ph
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Scheme 3 Proposed catalytic cycle
In summary, we have developed the first direct asym-
metric α-hydroxylation of α-branched ketones through
enol catalysis.19 By employing nitrosobenzene as both the
oxidant and reductant in a tandem process, various valu-
able cyclic α-hydroxy ketones were obtained in moderate to
good yields and excellent enantioselectivities. We believe
that the presented findings will further broaden the scope
of enol catalysis thus inspiring other highly enantioselec-
tive transformations.
Funding Information
The Max Planck Society, the DFG (Leibnitz award to B.L.) and the
Fonds der Chemischen Industrie (fellowship to G.P.) are acknowledged
for financial support.()
(10) (a) Felker, I.; Pupo, G.; Kraft, P.; List, B. Angew. Chem. Int. Ed.
2015, 54, 1960. (b) Monaco, M. R.; Pupo, G.; List, B. Synlett 2016,
27, 1027. For a non-enantioselective version of the reaction
reported here, see: (c) Shevchenko, G. A.; Dehn, S.; List, B.
Synlett 2018, 29, 2298.
(11) (a) Pupo, G.; Properzi, R.; List, B. Angew. Chem. Int. Ed. 2016, 55,
6099. (b) Burns, A. R.; Madec, A. G. E.; Low, D. W.; Roy, I. D.;
Lam, H. W. Chem. Sci. 2015, 6, 3550. (c) Yang, X.; Toste, F. D.
Chem. Sci. 2016, 7, 2653. (d) Zhang, L.-D.; Zhong, L.-R.; Xi, J.;
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Le Cavalier, F.; Humphreys, L.; Rouden, J.; Blanchet, J. Org. Lett.
2010, 12, 3582.
Acknowledgment
The authors greatly acknowledge the NMR (J. Lingnau), GC, HPLC, and
X-Ray departments of the MPI-Kohlenforschung.
Supporting Information
(12) (a) Shevchenko, G. A.; Pupo, G.; List, B. Synlett 2015, 10, 1413.
(b) Yang, X.; Toste, F. D. J. Am. Chem. Soc. 2015, 137, 3205.
(13) Shevchenko, G. A.; Oppelaar, B.; List, B. Angew. Chem. Int. Ed.
2018, 57, 10756.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611084.
S
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References and Notes
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G. A. Shevchenko et al.
Letter
Synlett
1
(18) Azoxybenzene 9 was both observed by 1H NMR spectroscopy
and isolated from the crude reaction mixture (purification by
FCC).
2a (21.5 mg, 56%, 98:2 er) as an orange oil. H NMR (500 MHz,
C6D6): δ = 7.18–7.12 (m, 2 H), 7.11–7.01 (m, 3 H), 4.61 (s, 1 H),
2.73 (dq, J = 14.3, 3.2 Hz, 1 H), 2.19 (dddd, J = 13.5, 4.1, 2.7, 1.6
Hz, 1 H), 1.95 (td, J = 13.5, 6.3 Hz, 1 H), 1.69–1.61 (m, 1 H), 1.34
(ddt, J = 12.5, 6.3, 3.1 Hz, 1 H), 1.29–1.07 (m, 3 H) ppm. 13C NMR
(125 MHz, C6D6): δ = 211.9, 141.2, 129.1, 126.8, 80.1, 39.2, 38.8,
28.2, 23.1 ppm (one aromatic signal missing because of overlap
with solvent). HRMS (ESI+): m/z [M + Na]+ calcd for C12H14O2Na:
213.0886; found 213.0885. HPLC (Chiralpak AD-3, n-
(19) General Procedure: Catalyst B5 (16.4 mg, 0.02 mmol, 10 mol%)
and 2-phenyl cyclohexanone (1a, 0.2 mmol, 1.0 equiv) were
placed in a plastic GC vial. After the addition of benzene (0.8
mL) and acetic acid (40 μL, 0.7 mmol, 3.5 equiv), nitrosobenzene
(21.4 mg, 0.2 mmol, 1.0 equiv) was added in one portion and
the reaction mixture was stirred for 2 h. Then, additional nitro-
sobenzene (32.1 mg, 0.3 mmol, 1.5 equiv) was added and stir-
ring was continued for additional 22 h. The crude reaction
mixture was directly purified by flash column chromatography
(hexanes/EtOAc gradient 100:0 to 10:1) to give hydroxy ketone
Hept/EtOH = 80:20, flowrate: 1.0 ml/min, λ = 206 nm):
25
tr(major) = 6.88 min, tr(minor) = 9.73 min. [α]D
CHCl3, 98:2 er).
: +166.0 (c 0.20,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E