Catalytic enantioselective O -nitrosocarbonyl aldol reaction of β-dicarbonyl compounds

Article abstract of DOI:10.1021/ja309311z

The first example of a Cu-catalyzed asymmetric O-nitrosocarbonyl aldol reaction is described. This novel protocol allows convenient access to highly enantioenriched α-hydroxy-β-ketoesters including the antibacterial natural product kjellmanianone (up to 99% ee). MnO₂ was introduced as a mild efficient oxidant for the in situ generation of nitrosocarbonyl species from hydroxamic acid derivatives.

Full text of DOI:10.1021/ja309311z

Communication
pubs.acs.org/JACS
Catalytic Enantioselective O‑Nitrosocarbonyl Aldol Reaction of
β‑Dicarbonyl Compounds
Mahiuddin Baidya, Kimberly A. Griffin, and Hisashi Yamamoto*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
S
* Supporting Information
to chiral α-hydroxy-β-dicarbonyl products is the asymmetric
ABSTRACT: The first example of a Cu-catalyzed
asymmetric O-nitrosocarbonyl aldol reaction is described.
This novel protocol allows convenient access to highly
enantioenriched α-hydroxy-β-ketoesters including the
antibacterial natural product kjellmanianone (up to 99%
ee). MnO2 was introduced as a mild efficient oxidant for
the in situ generation of nitrosocarbonyl species from
hydroxamic acid derivatives.
oxidation of β-dicarbonyl compounds. The first enantioselective
α-hydroxylation of β-ketoesters was developed by Davis and co-
workers three decades ago, where a stoichiometric amount of
enantiopure N-sulfonyloxaziridines (Davis reagent) was
employed.10 Despite considerable efforts in this area, to the
best of our knowledge there are only a few methods dealing
with asymmetric catalysis.11,12 All of these catalytic processes
are good, but only highly enolizable cyclic β-ketoesters are
demonstrated to give high yields and enantioselectivities,
indicating limited substrate scopes. Recently Ti-catalyzed α-
hydroxylation reported by Togni and co-workers employed
both cyclic and acyclic β-ketoesters as substrates; however,
asymmetric induction was considerably low.11b Further, these
transformations rely on oxaziridines and peroxides as oxygen
atom sources, for which extra precaution is needed. Thus, the
development of a mild, robust, and highly enantioselective
catalytic protocol with a wide substrate scope is necessary.
We envisioned that development of an enantioselective O-
nitrosocarbonyl aldol reaction of β-dicarbonyl compounds
would open a new direction of nitroso chemistry, and
subsequent selective N−O bond heterolysis could be a facile
route to enantioenriched α-hydroxy-β-dicarbonyl compounds
(Scheme 1b). Herein, we will report the first example of a Cu-
catalyzed enantioselective O-nitrosocarbonyl aldol reaction of
β-dicarbonyl compounds with commercially available N-Boc-
hydroxylamine as the nitrosocarbonyl precursor and manganese
dioxide as a mild oxidant.13 In addition, for preliminary
demonstration of the utility of this strategy, a concise
enantioselective synthesis of antibacterial natural product
kjellmanianone was accomplished.8a
ince the pioneering work by Kirby in 1973, nitrosocarbonyl
S
compounds have occupied a prominent position in organic
chemistry.1−3 Yet, these species are very unstable and highly
reactive, posing a significant challenge to the synthetic chemist.
Traditionally, they are generated in situ as a transient
intermediate via oxidation of hydroxamic acid derivatives.4,5
During the past few years, aerobic oxidizing processes have
emerged, allowing convenient use of these intermediates for
organic synthesis.6 However, despite their high synthetic
potential, the success of nitrosocarbonyl compounds is still
immature and limited to hetero-Diels−Alder and ene
reactions.2,3 Heretofore, the more exciting nitrosocarbonyl
aldol reaction is not known and no catalytic enantioselective
reactions utilizing nitrosocarbonyl compounds have been
reported. In this report we describe our progress addressing
these challenges (Scheme 1).
Scheme 1. Reactions of Nitrosocarbonyl Compounds
Among the β-dicarbonyl compounds, we preferred β-
ketothioesters 1 for these studies. The choice of thioesters
relative to oxoesters is advantageous because the thioester
moiety can be easily functionalized, allowing straightforward
access to the products with a series of functional groups such as
ketones, aldehydes, esters, and amides upon a single trans-
formation.14 Most importantly, the key to the success of this
process is the identification of MnO2 as an oxidizing reagent
compatible with the catalytic cycle. This extremely mild oxidant
efficiently generates nitrosocarbonyl compounds in situ through
the oxidation of hydroxamic acid derivatives and also avoids
overoxidation of the products.
The α-hydroxy-β-dicarbonyl moiety is an important struc-
tural feature found in many biologically relevant molecules and
drug candidates.7 Examples include the antibacterial kjellma-
nianone, hamigeran A, and doxycycline.8 Moreover, this
functional unit appears in key intermediates in the synthesis
of complex molecules, such as indoline alkaloids vindoline and
11-demethoxyvindoline.9 The most convenient synthetic route
We began our investigation using acyclic β-ketothioester 1a
as a model substrate with Cu(OTf)2 as the catalyst in
Received: September 19, 2012
Published: October 29, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
combination with commercially available bidentate bisoxazoline
was improved up to 88% (entry 7). Addition of 4 Å molecular
sieves reduced the yield significantly (entry 8).
ligands (Table 1).15 Gratifyingly, when a solution of N-Boc-
Next, we turned our attention to modification of the
thioester moiety using ligands L1 and L2 while keeping other
reaction conditions unchanged. Replacement of S-ethyl
thioester 1a with S-phenyl thioester 1b significantly improved
the outcome delivering the O-nitrosocarbonyl aldol product 2b
in 76% yield and 90% ee when L1 was used as a ligand (Table
1, entry 12). In contrast, this reaction became sluggish for
ligand L2, which performed better for S-ethyl thioester 1a
(entry 13 vs 7). When S-tert-butyl thioester 1d was used with
ligand L1, both yields and ee dropped drastically (entry 14 vs
15). Moreover, the aldol product 2c was crystallized and X-ray
analysis unambiguously confirmed the O-selectivity. These
results suggest that the S-phenyl unit in the β-ketothioester is
very important. Encouraged by this result, we have further
tuned the β-ketothioester by introducing S-2,6-xylyl moiety. To
our delight, S-2,6-xylyl thioester 1e produced desired O-
nitrosocarbonyl aldol product 2e in very good yield (73%) with
almost complete enantioselectivity (99%, entry 16). Thus, S-
2,6-xylyl substituted β-ketothioesters are most appropriate for
this reaction with the ligand L1.
Experiments probing the scope of this process under
optimized conditions are summarized in Table 2. A broad
spectrum of β-ketothioesters, cyclic and acyclic, could be
employed to afford tertiary O-nitrosocarbonyl aldol products 2
in very good yields and excellent stereoselectivities. While
substitution at the position R1 with aliphatic (2f−h), aromatic
(2j−l), and vinyl (2i) groups in β-ketothioesters 1 has little
effect on enantioselectivity, substitution at the position R3 is
sensitive. Moving from methyl (2e, Table 1) to ethyl (2o) and
benzyl (2p), a slight drop in enantioselectivity was observed,
yet it remained high (≥90%). In order to extend the reaction
scope further, we also integrated commonly used β-ketoesters
(1q−z). Gratifyingly, β-ketoesters are also efficient for this
reaction and the desired products were isolated in better yields
with similar asymmetric inductions (2q−t). At this point, we
questioned whether the enantioselectivity of the aldol product
2 with ethyl and benzyl substitution at the R3 position might be
further improved via revision of the ester moiety (R2). Thus,
substituted β-ketoesters of various commercially available 2,6-
disubstituted phenols were considered. Altering the methyl
group at R2 with isopropyl in β-ketoesters improved the
enantioselctivity (2q vs 2u); however, when the more bulky
tBu-group was installed (2v), both the yield and enantiose-
lectivity decreased significantly. Thus, β-ketoesters (1w−z) of
2,6-diisopropyl phenol were employed and the desired products
(2w−z) were isolated with improved enantioselectivities (up to
97%).
Table 1. Screening of Reaction Conditions
2
3
yield
b
ee
(%)
yield
b
ee
a
c
c
entry
1
L
solvent
(%)
(%)
(%)
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1e
L1
L1
L1
L1
L1
L1
L2
L2
L3
L4
L5
L1
L2
L1
L1
L1
CH2Cl2
CHCl3
CH3CN
toluene
70
46
34
25
48
31
71
11
31
37
28
76
15
65
8
79
79
75
74
75
70
88
87
0
<1
14
28
6
N.D.
14
9
14
d
THF
10
48
<1
<1
14
7
6
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
N.D.
N.D.
2
e
8
9
10
11
12
13
14
15
16
81
36
90
83
89
69
99
0
26
<1
<1
<1
N.D.
<1
17
N.D.
N.D.
N.D.
N.D.
N.D.
73
a
b
All reactions were performed at 0.1 mmol scale. Yield of the isolated
c
d
product. Determined by HPLC on chiral stationary phase. Reaction
did not proceed at −40 °C in THF. Reaction was performed with 100
mg of 4 Å molecular sieves as additive. N.D. = not determined.
e
hydroxylamine was slowly injected via a syringe pump into the
mixture of 10 mol % Cu(OTf)2 and 12 mol % (R, R)-PhBox
ligand L1 in the presence of substrate 1a and oxidant MnO2 (5
equiv) in CH2Cl2 at room temperature, the O-nitrosocarbonyl
aldol product 2a was formed in 70% yield with 79% ee (Table
1, entry 1).
Only trace amounts of N-nitrosocarbonyl aldol product 3a
were observed. The high preference for O-selectivity over N-
selectivity is rather remarkable. Slow addition of N-Boc-
hydroxylamine is crucial to avoid condensation between the
in situ formed nitrosocarbonyl species and excess N-Boc-
hydroxylamine, a strong nucleophile. Screening of other
solvents resulted in diminished yields and enantioselectivities
with poor O- vs N-selectivity (entries 2−6). Notably, in MeOH,
selectivity was inverted favoring the N-nitrosocarbonyl aldol
product. The reaction completely shut down upon lowering the
temperature to −40 °C in THF. In order to improve
enantioselectivity further, various substituted ligands were
tested. Box-ligands L3−L5 were not particularly effective for
this reaction (entries 9−11). The semicorrin ligand L2 showed
similar reactivity as observed for L1; however, enantioselectivity
The transformation from α-aminooxy-β-ketoester 2 to α-
hydroxy-β-ketoesters 4 is smooth and facile. Treatment of
Mo(CO)6 cleanly cleaved the N−O bond for both carboxylate
ester and thioesters affording α-hydroxy products 4 in very
good yields without affecting enantioselectivities (Scheme 2).16
To highlight further the chemical utility, we applied this new
catalytic O-nitrosocarbonyl aldol reaction to the enantioselec-
tive synthesis of kjellmanianone, a member of the cyclo-
pentanoid class of antibiotics, which shows moderate activity
against gram positive bacteria such as E. coli K12 and Bacillus
subtilis var. niger.17 As illustrated in Scheme 3, exposure of β-
ketothioester 5 (prepared in two steps from commercial
materials) to our oxidation protocol, followed by N−O bond
heterolysis, and then silver trifluoroacetate promoted trans-
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Journal of the American Chemical Society
Communication
Table 2. Enantioselective O-Nitrosocarbonyl Aldol
Reactions of β-Dicarbonyl Compounds
Scheme 3. Rapid Enantioselective Synthesis of Antibacterial
(S)-Kjellmanianone
a d
−
esterification, rapidly furnished the antibiotic kjellmanianone 8
in 53% yield over three steps and 97% ee.14a,b The absolute
configuration of the product was determined by comparing the
optical rotation with literature data, and the stereochemistries
of the other α-hydroxy-β-ketoesters were tentatively assigned
by analogy.17b
In conclusion, we have developed the first catalytic
asymmetric O-nitrosocarbonyl aldol reaction of both β-
ketothioesters and β-ketoesters using a readily accessible Cu-
catalyst and PhBox ligand. The value of this transformation has
been highlighted via the expedient synthesis of antibacterial
(S)-kjellmanianone. MnO2 was introduced as a mild oxidant to
generate transient nitrosocarbonyl species from a hydroxamic
acid derivative. Further investigations are underway to clarify
the mechanism of this transformation and to explore the scope
of nitrosocarbonyl chemistry in catalytic asymmetric synthesis.
ASSOCIATED CONTENT
* Supporting Information
Complete experimental details and characterization data for
prepared compounds described. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
yamamoto@uchicago.edu
■
Notes
The authors declare no competing financial interest.
a
b
ACKNOWLEDGMENTS
All reactions were performed at 0.1 mmol scale. Yield of the isolated
■
c
product. Determined by HPLC on chiral stationary phase.
We gratefully acknowledge the NIH (2R01GM068433) for
support of this research. We would also like to thank Dr.
Antoni Jurkiewicz, Dr. Ian Steele, and Dr. Jin Qin for their
expertise in NMR, X-ray crystallography, and mass spectrom-
etry, respectively.
d
Stereochemistries were assigned by analogy to compound 8.
Scheme 2. Mo(CO)6 Mediated N−O Bond Heterolysis and
the Synthesis of α-Hydroxy-β-Ketoesters
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Journal of the American Chemical Society
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