Proline-tetrazole-catalyzed enantioselective N-nitroso aldol reaction of aldehydes with in situ generated nitrosocarbonyl compounds

Article abstract of DOI:10.1002/anie.201311069

A highly enantioselective method (up to 98% ee) for the preparation of β-amino alcohols was achieved by using the readily available proline-tetrazole as the catalyst for the N-nitroso aldol reaction of aldehydes with in situ generated nitrosocarbonyl compounds. The key to success of this reaction is the use of MnO₂ as an oxidant and catechol as a Bronsted acid additive.

Full text of DOI:10.1002/anie.201311069

Angewandte
Chemie
DOI: 10.1002/anie.201311069
Organocatalysis
Proline-Tetrazole-Catalyzed Enantioselective N-Nitroso Aldol
Reaction of Aldehydes with In Situ Generated Nitrosocarbonyl
Compounds**
Biplab Maji* and Hisashi Yamamoto*
Dedicated to the centennial of the MPI fꢀr Kohlenforschung
Abstract: A highly enantioselective method (up to 98% ee) for
the preparation of b-amino alcohols was achieved by using the
readily available proline-tetrazole as the catalyst for the N-
nitroso aldol reaction of aldehydes with in situ generated
nitrosocarbonyl compounds. The key to success of this reaction
is the use of MnO2 as an oxidant and catechol as a Brønsted
acid additive.
Catalytic enantioselective oxidation, including hydroxyl-
ation and amination, in a complex molecular structure
represents a central goal in organic synthesis.[1] Stable
arylnitroso compounds[2] have been widely utilized for this
purpose as a useful source of oxygen[3] and nitrogen[4]
functionalities. However, a limitation resulting from N-aryl
bond cleavage has become apparent,[5] and the search for
a new source of nitroso compounds is in demand. The
nitrosocarbonyl compounds 1 (Scheme 1), which can easily be
manipulated, have turned out to serve this purpose.[6] Because
of their high reactivities, the transient nitrosocarbonyl species
1 are usually generated in situ by the oxidation of hydroxamic
acid derivatives (2).[7] The designs of catalytic enantioselec-
tive processes utilizing 1 are often made challenging by the
incompatibility of the catalytic conditions with their forma-
tion. Recently, we introduced manganese dioxide as a mild
oxidant in the copper-catalyzed enolate formation from 1,3-
diketo compounds for the enantioselective O-nitroso aldol
(O-NA) reaction.[8] Read de Alaniz and co-workers utilized
air as an oxidant for highly efficient copper-catalyzed racemic
N-nitroso aldol (N-NA)[5] and asymmetric O-NA reactions of
b-ketoesters (Scheme 1).[9]
Scheme 1. Previous work with nitrosocarbonyl compounds. PG=pro-
tecting group.
compounds.[10] They are also used as chiral ligands and
auxiliaries in asymmetric synthesis.[11] Hence, significant
efforts have been devoted to developing enantioselective
methods for their preparation.[12] However, catalytic enantio-
selective methods for their syntheses were often complicated
by the use of a suitable source of nitrogen and the need to
avoid postreaction racemization of acid- or base-sensitive
products.[12] Herein, we report the utilization of in situ
generated nitrosocarbonyl compounds 1 in N-NA reactions
of aldehydes, catalyzed by proline-tetrazole, as a method for
the synthesis of a-amino derivatives.[13]
During the preparation of this manuscript Maruoka and
co-workers reported a binapthol-modified secondary amine
catalyst for hydroxyamination of aldehydes with N-protected
hydroxamic acids (2) as the nitrosocarbonyl precursor, and
a combination of 2,2,6,6-tetramethylpiperidine N-oxyl and
dibenzoyl peroxide as the oxidant (Scheme 2).[14] Although
the preparation of the catalyst requires several steps and the
use of N-oxyl compounds and peroxides as oxidants requires
additional precaution, high yield and enantioselectivities of
the N-NA products 3 were achieved.
Optically active a-amino acids, a-amino aldehydes, and b-
amino alcohols represent valuable structural motifs because
of their abundance in natural products and pharmaceutical
[*] Dr. B. Maji, Prof. Dr. H. Yamamoto
Molecular Catalyst Research Center, Chubu University
1200 Matsumoto-cho, Kasugai, Aichi 487-8501 (Japan)
E-mail: biplabmaji@isc.chubu.ac.jp
hyamamoto@isc.chubu.ac.jp
Homepage: http://www3.chubu.ac.jp/catalyst/
We envisioned that the development of a method for the
N-NA reaction of aldehydes with relatively simple and
commercially available proline-tetrazole as a catalyst, the
N-protected hydroxylamine 2 as the nitrosocarbonyl precur-
sor, and manganese dioxide as a mild oxidant[15] would open
a new direction for nitrosocarbonyl chemistry en route to
a diverse range of a-amino compounds.
[**] This work is supported by a Grant-in-Aid for Scientific Research (No.
23225002), the Advance Catalytic Transformation Program for
Carbon Utilization, the Uehara Memorial Foundation, Nippon
Pharmaceutical Chemicals Co., Ltd, and Advance Electric Co., Inc.
We thank Dr. M. Baidya and Dr. S. Bhadra for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311069.
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reaction of preformed enamines with nitrosobenzene was not
only important to control the regioselectivity but also
enantioselectivity.[3j] To test whether BA affected our catalytic
system we performed the proline-tetrazole-catalyzed N-NA
reactions in the presence of several BAs (Table 1, entries 7–
12). While aliphatic alcohols are not efficient (entries 7 and
8), the use of aromatic alcohols as a BA additive resulted in
improved enantioselectivities and maintained similar yields
and regioselectivities (entries 9–12). We were pleased to find
that catechol could serve as an optimal BA additive for this
reaction as it gave 65% of the desired N-NA product with
98% ee.[18]
Scheme 2. Enantioselective N-nitroso aldol reactions of aldehydes.
Bz=benzoyl, TES=triethylsilyl.
With the optimal reaction conditions in hand, we exam-
À
ined the scope of this novel C N bond-forming protocol and
To our delight, when a solution of commercially available
N-CbzNHOH (2a) was added slowly by syringe pump to
a mixture of 3-phenylpropanal, MnO2, and 10 mol% of
proline-tetrazole in CH2Cl2 at room temperature (238C), the
desired N-NA product 3a was obtained in 65% yield and
88% ee after reduction with NaBH4, and the undesired
aminoxylated product was not observed by TLC (Table 1,
entry 1).[16] The structure of 3a was confirmed by X-ray
crystallography.[17] Screening of other solvents resulted in
diminished yields and enantioselectivities (entries 2–5). Grat-
ifyingly, when N-BocNHOH (2b) was used as the source of
nitrosocarbonyl compound, higher yield and enantioselectiv-
ity of the N-NA product 3b was obtained while maintaining
same level of regioselectivity (entry 6).
the results are shown in Scheme 3. With 10 mol% of the
readily available proline-tetrazole catalyst, catechol as a BA
additive, and MnO2 as oxidant, this protocol accommodates
a wide range of substituents on the aldehyde component,
including aromatics, alkane chains of various steric bulk,
ethers, halides, amines, esters, alkenes, and readily oxidizable
thioethers (51–69% yield and 92–98% ee). However, more
sterically demanding 3,3-dimethylbutanal, phenylacetalde-
hyde, and a-branched aldehydes were not useful substrates
in this transformation. Other N-protected hydroxy amines
were also tolerated in this reaction, thus providing the
corresponding N-NA products in 41–62% yields and 91–
97% ee.
To test the synthetic utility of the present hydroxyamina-
tion of aldehydes we performed the reaction on a multigram
scale (10 mmol). With 10 mol% of the catalyst under the
optimized reaction conditions the N-NA reaction proceeded
smoothly and the corresponding hydroxy amino alcohol 3a
was obtained in 62% yield (1.66 g) and 98% ee (Scheme 4).
To further demonstrate the synthetic utility of this
protocol, we have illustrated a representative procedure to
convert these enantioenriched N-NA products into the
corresponding N-Boc-protected 1,2-amino alcohol 4 and 1,2-
hydroxyamino alcohol 5 (Scheme 5). Thus, [Mo(CO)6] treat-
In our previous study with nitrosobenzene, we observed
that the use of a Brønsted acid (BA) catalyst for the aldol
Table 1: Optimization of reaction conditions.[a]
À
Entry
2
Solvent
Brønsted acid (BA)
Yield
[%][b]
ee
ment of 3a cleanly cleaved the N O bond and provided 4 in
[%][c]
excellent yield with complete retention of the enantioselec-
tivity.[19] In contrast, when a dichloromethane solution of 3a
was treated with TFA, 5 was obtained in good yield without
affecting the enantioselectivity. The absolute configuration of
4 (and hence 3a) was established to be R by comparing the
optical rotation of 4 with that reported in the literature.[20] The
absolute configurations of the compounds in Scheme 3 were
assigned by analogy to the absolute configuration of 3a.
In conclusion, we have developed an organocatalytic
method to the N-nitroso aldol reaction of aldehydes with N-
protected hydroxamic acid using easily handled MnO2 as the
oxidant and commercially available proline-tetrazole as the
catalyst. This facile and robust method provides access to b-
amino alcohols in moderate to good yields with excellent
enantioselectivities. A detailed mechanistic study, including
the beneficial effect of Brønsted acids on enantioselectivities,
and further investigations aimed at applying this method to
the synthesis of complex target structures containing a chiral
amine fragment is underway in this laboratory.
1[d]
2[e]
3[e]
4
2a
2a
2a
2a
2a
2b
2a
2a
2a
2b
2b
2b
CH2Cl2
THF
–
–
–
–
–
–
65
53
56
58
33
67
58
60
61
67
65
69
88
76
84
86
13
91
83
83
91
96
98
96
1,4-dioxane
(CH2Cl)2
THF/H2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5[e]
6
7[f]
8[f]
9[f]
10[f]
11
12
(CH2OH)2
(4S,5S)-taddol
(S)-binol
(S)-binol
catechol
phenol
[a] Reaction of hydroxamic acids 2 (0.2 mmol) with 3-phenylpropanal
(0.8 mmol) was carried out in the presence of proline-tetrazole
(0.02 mmol), BA (0.02 mmol), and MnO2 (1.0 mmol). [b] Yield of the
isolated product. [c] Determined by HPLC using a chiral stationary
phase. [d] 79% hydrocinnamyl alcohol and 8% of an aldol dimer was
isolated. [e] Used 0.04 mmol of the catalyst, and the THF/H2O ratio was
5:1. [f] Used 0.04 mmol of BA. binol=2,2’-dihydroxy-1,1’-binaphthyl,
Boc=tert-butoxycarbonyl, Cbz=carbobenzyloxy, taddol=a,a,a’,a’-tet-
raphenyl-1,3-dioxolane-4,5-dimethanol, THF=tetrahydrofuran.
2
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Scheme 5. Synthesis of the N-Boc-protected 1,2-amino alcohol 4 and
1,2-hydroxyamino alcohol 5. TFA=trifluoroacetic acid.
(0.02 mmol), MnO2 (1.0 mmol), and aldehyde (0.8 mmol) in CH2Cl2
(4 mL). The mixture was stirred for an additional 1 h before it was
placed into an ice bath. MeOH (2 mL) and NaBH4 (1.6 mmol) was
added and the mixture was stirred vigorously for another 40 min. The
reaction was quenched with saturated NH4Cl solution (0.2 mL) and
filtered through a small pad of MgSO4 and celite. After concentrating,
the residue was purified by silica gel flash chromatography to afford
the N-NA product.
Received: December 20, 2013
Published online: && &&, &&&&
Keywords: aldol reaction · amino alcohol · organocatalysis ·
.
oxidation · synthetic methods
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Scheme 3. Scope of enantioselective N-nitroso aldol reaction. Reaction
conditions: 2 (0.2 mmol), aldehyde (0.8 mmol), proline-tetrazole
(0.02 mmol), catechol (0.02 mmol), MnO2 (1.0 mmol). Yield of iso-
lated products are given. The ee value was determined by HPLC using
a chiral stationary phase. [a] 76% hydrocinnamyl alcohol and 9% of an
aldol dimer were isolated. [b] 74% 5-(benzyloxy)pentan-1-ol and 8% of
an aldol dimer were isolated. Ad=1-adamantyl, Fmoc=9-fluorenyl-
methoxycarbonyl, NPhth=1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl.
Scheme 4. Scale-up of the N-nitroso aldol reaction.
Experimental Section
General procedure of the N-nitroso aldol reaction: A solution N-
protected hydroxamic acid (0.2 mmol) in CH2Cl2 (2 mL) was added
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Organocatalysis
B. Maji,* H. Yamamoto*
&&&& — &&&&
Proline-Tetrazole-Catalyzed
Enantioselective N-Nitroso Aldol
Reaction of Aldehydes with In Situ
Generated Nitrosocarbonyl Compounds
Sturdy as it gets: A highly enantioselec-
tive, robust, and scalable method for the
synthesis of b-hydroxyamino alcohols
were achieved by using the title reaction.
MnO2 serves as the oxidant and catechol
as Brønsted acid additive. PG=protect-
ing group.
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