Asymmetric ?±-benzoyloxylation of ?2-ketocarbonyls by a chiral primary amine catalyst

Article abstract of DOI:10.1021/ol503592n

The direct asymmetric ?±-benzoyloxylation of ?2-ketocarbonyls catalyzed by a chiral primary amine is described herein. This protocol demonstrates excellent enantioselectivity for a broad range of substrates, which allows convenient access to highly enantioenriched ?±-hydroxy-?2-ketocarbonyls.

Full text of DOI:10.1021/ol503592n

Letter
pubs.acs.org/OrgLett
Asymmetric α‑Benzoyloxylation of β‑Ketocarbonyls by a Chiral
Primary Amine Catalyst
Dehong Wang,† Changming Xu,† Long Zhang,†,‡ and Sanzhong Luo*,†,‡
†Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, 300071, China
S
* Supporting Information
ABSTRACT: The direct asymmetric α-benzoyloxylation of β-
ketocarbonyls catalyzed by a chiral primary amine is described
herein. This protocol demonstrates excellent enantioselectivity for
a broad range of substrates, which allows convenient access to
highly enantioenriched α-hydroxy-β-ketocarbonyls.
α-Hydroxy-β-dicarbonyl is a prominent structural feature in
biologically relevant molecules and drug candidates,1 such as
Kjellmanianone, Hamigeran A, and Doxycycline (Figure 1).2
asymmetric protocol for α-hydroxylation of β-dicarbonyls with
high enantioselectivities for a broad scope, to include
dicarbonyls other than β-ketoesters such as 1,3-diketones and
β-ketoamides, remains to be developed.
α-Benzoyloxylation is a powerful approach for the direct
asymmetric α-oxygenation of carbonyl compounds. Recently,
the groups of Maruoka,8 List,9 and others10 have reported the
catalytic direct asymmetric α-benzoyloxylation of aldehydes and
cyclic ketones employing benzoyl peroxide (BPO) as a readily
available and inexpensive hydroxylation reagent. In this regard,
asymmetric α-benzoyloxylation of α-branched ketones such as
β-ketocarbonyls has not been achieved so far. In fact, α-
branched aldehydes and ketones remain challenging substrates
for this reaction. In a single previous report, the reaction with
α-branched aldehydes has been attempted, affording poor
enantioselectivity.9b
Very recently, we have developed chiral primary amines, e.g.
primary amine 1, as viable catalysts for enamine-based
transformations of β-ketocarbonyls.11 In the process of further
explorations of this catalysis, it was realized that the asymmetric
α-benzoyloxylation of β-ketocarbonyls remained an unsolved
issue, in particular with acyclic ketocarbonyls where the
construction of acyclic chiral quaternary carbons is involved.
Herein we report a chiral primary amine catalyzed direct
asymmetric α-benzoyloxylation of β-ketocarbonyls with broad
scopes and high enantioselectivity (Figure 1).
In the model reaction between acetoacetate 2a and benzoyl
peroxide (BPO), the desired α-benzoyloxylated product 4a was
obtained in 83% yield and 96% ee under the optimized
conditions (Table 1, entry 1). Among the solvents examined,
CHCl3 was found to be the optimal solvent in terms of both
yield and enantioselectivity (Table 1, entries 2−5). The use of a
higher concentration was found to be favorable for the product
yield (Table 1, entry 5 vs 1). It was found that 1.5 equiv of 3
Figure 1. Direct benzoyloxylation for the synthesis of α-hydroxy-β-
dicarbonyls.
Such a functional unit can also serve as a versatile chiral
synthon in many multistep reaction sequences.3 Hence,
asymmetric synthesis of α-hydroxy-β-dicarbonyls via enantio-
selective α-hydroxylation of β-dicarbonyls, the most straightfor-
ward approach, has been much explored.4−6 Davis and co-
workers developed the first enantioselective α-hydroxylation of
β-ketoesters employing stoichiometric amounts of enantiopure
N-sulfonyloxaziridines three decades ago.4 Recently, Togni and
co-workers reported Ti-catalyzed α-hydroxylation of both cyclic
and acyclic β-ketoesters. However, enantioselectivities were
rather poor in the cases with acyclic ketoesters.5b Yamamoto
and co-workers described an elegant asymmetric O-nitro-
socarbonyl aldol reaction of acyclic β-ketothioesters with N-
Boc-hydroxylamine as the nitrosocarbonyl precursor. The
reactions require a sterically demanding ester group for optimal
stereocontrols.7 Despite these advances, a general catalytic
Received: December 14, 2014
© XXXX American Chemical Society
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a
Table 1. Screening and Optimization
Scheme 1. Scope of the Asymmetric α-Benzoyloxylation of
β-Ketocarbonyls
a
b
c
entry
1
variation from standard conditions
yield (%)
ee (%)
none
83
65
53
trace
62
72
68
70
76
57
96
27
73
−
95
96
96
96
96
96
d
2
THF
d
3
toluene
d
4
d
1,4-dioxane
CHCl3
5
6
2a:3a = 2:1
2a:3a = 1.5:1
2a:3a = 1:1.2
without BHT
under air
7
8
9
10
a
Reactions were performed at rt in 0.25 mL of CHCl3 with 2a (0.20
mol), 3 (0.3 mol), 1 (20 mol %), BHT (10 mol %) under N2, 24 h.
Isolated yield. Determined by HPLC analysis. These reactions were
b
c
d
performed at a concentration of 0.2 M. BPO: benzoyl peroxide; BHT:
butylated hydroxytoluene.
was optimal, and larger or smaller ratios of 2a/3 all led to a
decreased yield (Table 1, entries 6−8). Butylated hydrox-
ytoluene (BHT), as a radical inhibitor, was previously
employed to avoid possible benzoyl radical side reactions.9 In
our cases, the use of 10 mol % BHT furnished a slightly better
yield (Table 1, entry 9 vs 1). Finally, the reaction worked more
cleanly under N2 with a higher yield than under aerobic
atmosphere (Table 1, entry 10); thus, all the reactions were
conducted under N2.
With the optimized conditions in hand, we first investigated
the scope of acyclic ketoesters. As shown in Scheme 1, acyclic
acetoacetates bearing various ester moieties (R3 position),
including those with sterically bulky tert-butyl ester, benzyl, and
allyl ester groups, afforded the desired α-benzoyloxylation
products in high yields and excellent enantioselectivities
(Scheme 1, 4a−d). The reactions also tolerated a range of α-
substituents on acetoacetates (R2 position, 4e−k). In particular,
the reaction with acetoacetates bearing either an α-allyl or a
propargyl substituent proceeded smoothly to deliver the
corresponding α-benzoyloxylation products with high yields
and enantioselectivities (4i and 4j), and no oxidation of the
unsaturated bonds was observed. Delightfully, 2k (R2 = Ph) is
also a workable substrate, delivering the corresponding adduct
(4k) in acceptable yield and good ee. The use of α-
unsubstituted acetoacetate (R2 = H) and phenyl ketoester
(R1 = Ph) gave racemic adducts (data not shown), suggesting
these reactions are mainly background enol processes escaping
catalyst control.
The current catalysis worked extremely well with cyclic β-
ketoesters to give the desired α-benzoyloxylation products with
high yields and excellent enantioselectivities (4l−n). The
relatively unstable α-acetybutyrolactone was also amenable to
the mild catalytic conditions, furnishing an 83% yield and 86%
ee (4o). Most delightfully, both cyclic and acyclic 1,3-diketones
are workable substrates under the current conditions. Heptane-
2,4-dione and 2-acetyl-1-cyclohexanone reacted smoothly to
give the desired α-benzoyloxylation products with moderate
yields and excellent enantioselectivities (4p and 4r). In
a
All the reactions were performed at rt in 0.25 mL CHCl3 with 2 (0.2
mmol), 3 (0.3 mmol), 1 (20 mol %), BHT (10 mol %) under N2, 24−
48 h. Yields shown are of isolated products.
contrast, 2-acetyl-1-cyclopentanone was a poor substrate for
the reaction producing a low yield and poor enantioselectivity
(4q); presumably, the two keto moieties in this setting are less
differentiable for the catalyst with coformation of enamine
regioisomers, thus leading to poor chiral induction.
To further explore the synthetic utility of the current α-
benzoyloxylation reaction, β-ketoamides were also examined in
the reactions. As shown in Scheme 1, β-ketoamides with or
without a free N−H bond all worked well in the reaction to
cleanly give α-benzoyloxylation products. Both acyclic and
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Letter
cyclic N-phenyl β-ketoamides reacted to furnish the expected α-
benzoyloxylation with high yields and excellent enantioselectiv-
ities (4s, 4t, and 4v). N-Allyl β-ketoamide was also workable
with excellent enantioselectivity albeit in a reduced yield (4u).
Notably, a cyclohenxenone derived ketoester can also be
applied in the reaction to afford the desired benzoyloxylation
adduct 4w in 54% yield and 98% ee (Scheme 1). Unfortunately,
the reaction with the cyclopentenone derivative, a direct access
to Kjellmanianone, did not work under our conditions.
Other aryl acylperoxides have also been examined under the
reaction conditions, showing comparable performance with
high yields and excellent enantioselectivities (6a−6d) (Scheme
2). The yield of 6d was relatively low due to the poor solubility
of bis(p-bromobenzoyl) peroxide.
Scheme 4. Stoichiometric Experiments
enamine 7 could react with BPO to give product 4a in 70%
yield and 40% ee; however, the product was obtained in an
opposite S-configuration, indicating an alternative reaction
pathway. In this context, an S-selective enamine N-oxide
pathway may be invoked (Scheme 3, TS-III). The stereo-
induction can be restored to R-selective control with 96% ee
upon the addition of TfOH (Scheme 4, eq 2). Taken together,
these observations suggest that the N-oxide pathways (Scheme
3, modes II and III), though not completely ruled out, should
be minor and can be largely disfavored in the presence of acid
additive TfOH and that H-bonding directed addition would be
the major productive pathway under the current conditions.
To probe the utility of our method in preparative synthesis, a
gram-scale reaction of β-ketoesters 2l was performed, delivering
the desired product 4l with a good yield (83%) and excellent
enantioselectivity (96% ee) (Scheme 5, eq 3). Furthermore, O-
a
Scheme 2. Scope of Other Aryl Acylperoxides
a
All the reactions were performed at rt in 0.25 mL of CHCl3, with 2a
(0.2 mmol), 5 (0.3 mmol), 1 (20 mol %), BHT (10 mol %) under N2,
24−48 h. Yields shown are of isolated products.
Scheme 5. Gram Scale Reaction and Synthetic
Transformations
The absolute configuration of the hydroxylated adduct was
determined to be R by comparison of the optical rotation of 4h
with the literature value.12 Based on our previous studies, an H-
bonding transition state was proposed to account for the
observed R-selectivity (Scheme 3, TS-I). Similar H-bonding TS
Scheme 3. Proposed Transition States
deprotection of α-benzoyloxylated products is smooth and
facile, e.g. 4h (Scheme 5, eq 4). Treatment with 1 M NaOH
afforded α-hydroxy-β-ketoester 8 in good yield with maintained
stereoselectivity.
has also recently been proposed in previous studies.9a Since
amines are known to undergo facile N-oxidation in the
presence of BPO,13 the reaction may also occur via a N-oxide
addition pathway to give the major enantiomer (Scheme 3, TS-
II). To further look into this issue, we have carried out
stoichiometric experiments with catalyst 1. When the free
amine catalyst was first treated with BPO in the absence of
TfOH, the hydroxylation barely proceeded with rather low
enantioselectivity due to the oxidation of the aminocatalyst14
(Scheme 4, eq 1), while the same reaction sequence in the
presence of TfOH occurred smoothly to give the desired
adduct with maintained outcomes. The critical role of TfOH in
tuning both activity and selectivity can be further verified in the
stoichiometric reaction of preformed enamine 7. In this case,
In summary, we have developed a highly enantioselective α-
benzoyloxylation of β-ketocarbonyls with benzoyl peroxide
under mild conditions by using a simple chiral primary amine.
The reactions enable the constructions of α-hydroxylated
quaternary β-ketocarbonyls with excellent enantioselectivity
and encompass a wide range of substrates including the elusive
1,3-diketones and β-ketoamides. The current reaction provides
a straightforward access to synthetically useful and important
chiral building blocks and can be scaled up without loss of yield
and enantioselectivity.
C
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Letter
14642. (c) Xu, C.; Zhang, L.; Luo, S. J. Org. Chem. 2014, 79, 11517.
(d) Zhang, L.; Xu, C.; Mi, X.; Luo, S. Chem.Asian J. 2014, 9, 3565.
(12) Hashimoto, T.; Sasaki, K.; Fukumoto, K.; Murase, Y.; Abe, N.;
Ooi, T.; Maruoka, K. Chem.Asian J. 2010, 5, 562.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and copies of
1H and 13C NMR spectra and HPLC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(13) (a) Denney, D. B.; Denney, D. Z. J. Am. Chem. Soc. 1960, 82,
1389. (b) Hasegawa, S.; Kashino, S.; Mukahi, Y. Bull. Chem. Soc. Jpn.
1971, 44, 69. (c) Buckley, D.; Dunstan, S.; Henbest, H. B. J. Chem. Soc.
1957, 4901.
AUTHOR INFORMATION
Corresponding Author
■
(14) ESI-MS clearly indicated the complete conversion of the
aminocatalyst; one oxidized form is O-benzoyl-N-oxide. However, we
were unable to differentiate between the tertiary and primary N-oxide.
In the presence of TfOH, the oxidation of the aminocatalyst has been
found to be minor as also verified by the control experiments (Scheme
4).
* E-mail: luosz@iccas.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (21390400,
21025208, and 21202171) and the National Basic Research
Program of China (2011CB808600) for financial support. S.L.
is supported by the National Program of Top-notch Young
Professionals and CAS Youth Innovation Promotion Associa-
tion.
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