Direct catalytic enantioselective α-aminoxylation of ketones: A stereoselective synthesis of α-hydroxy and α,α′- dihydroxy ketones

Article abstract of DOI:10.1002/anie.200353018

Proline-catalyzed reactions between unmodified ketones and nitrosobenzene proceed with excellent diastereo- and enantioselectivities to provide protected α-hydroxy and α,α′-dihydroxy ketones [Eq. (1)]. Such compounds with chiral α-hydroxy carbonyl units are crucial in natural product synthesis.

Full text of DOI:10.1002/anie.200353018

Angewandte
Chemie
9g,10a,10c]
Asymmetric Catalysis
We believed that the enhanced Brønstedt basicity of
the nitrogen atom would favor O-addition over N-addition.
Hence, we embarked on the quest to develop a novel
enamine-catalyzed asymmetric route for the synthesis of a-
hydroxy-containing molecules.[17]
Herein, we present a method for the direct catalytic a-
oxidation of ketones. This new transformation yields pro-
tected a-hydroxy ketones with excellent regioselectivity and
> 99% ee. In addition, unsubstituted cyclic ketones were
a,a’-dioxylated with remarkable high selectivity affording the
corresponding C2-symmetric ketodiols in > 99% ee.
In an initial experiment, we treated cyclohexanone (1a)
(10 mmol) with nitrosobenzene (2) (1 mmol) in the presence
Direct Catalytic Enantioselective
a-Aminoxylation of Ketones: A Stereoselective
Synthesis of a-Hydroxy and a,a’-Dihydroxy
Ketones**
Anders Bøgevig, Henrik SundØn, and
Armando Córdova*
One of the ultimate goals and challenges in chemistry is to
develop catalytic stereoselective transformations for the
creation of optically active molecules from simple
and easily available starting materials.[1] Optically
active a-hydroxy carbonyl moieties are commonly
found in numerous important natural products. This
has led to extensive research to find new diaster-
eoselective and enantioselective routes for their
syntheses.[2] One way of preparing these compounds
is the asymmetric a-hydroxylation of enolates.[3]
Despite extensive research in this area it was not
until recently that Yamomoto et al. reported a more
efficient catalytic system based on AgX/binap com-
plexes (binap = 2,2’-bis(diphenylphosphanyl)-1,1’-
binaphthyl), which mediate indirect a-oxidation of
activated tin enolates.[4]
Asymmetric reactions catalyzed by metal-free
organic catalysts have received increased attention
in recent years.[5] Interestingly, following the dis-
covery of amino acid catalyzed stereoselective Robinson
annulations in the early 1970s,[6] there was no intensive
of a catalytic amount of (S)-proline (20 mol%) in CHCl3
(4 mL) at room temperature [Eq. (2)]. The initial light blue
solution changed first to light green, then to dark green, and
finally to orange within 30 min. The reaction was quenched
after 2 h, and NMR analysis of the crude product revealed
that no starting material remained and only a-aminooxylated
ketone 3a had formed. Most satisfying we could not observe
the N-addition product, and ketone 3a was isolated in 91%
yield and > 99% ee as determined by chiral HPLC analysis.
The reactions also proceed with only two equivalents of
cyclohexanone and 10 mol% of the catalyst.
Next, we tested a number of solvents (THF, CHCl3,
dimethylformamide (DMF), Et2O, N-methylpyrrolidinone
(NMP), toluene, dimethyl sulfoxide (DMSO), CH3CN, and
neat) for the proline-catalyzed a-aminoxylation with 1a as
the donor and found that the best solvents with regard to
the reactivity of proline were CHCl3 and DMSO. In all
cases tested, the corresponding product 3a was isolated with
> 95% ee. For example, the reaction in DMSO was complete
within 30 min providing not only ketone 3a in 70% yield and
> 99% ee but also the corresponding C2-symmetric a,a’-
diaminoxy ketone 4 in 22% yield and > 99% ee. The
formation of 4 could be circumvented by slow addition of
3a (1m solution in DMSO) with a syringe pump to the
reaction mixture. The second O-addition exhibited remark-
able selectivity, since no meso-diol adduct was detected either
by NMR or HPLC analyses during the course of the reaction.
This is the first time that this type of double stereoselective
nucleophilic attack to an electrophile has been reported in a
À
research on this concept for other C C bond-forming
reactions for several decades even though the reaction is
frequently used to prepare building blocks in natural products
synthesis.[7] It was not until recently that researchers demon-
strated that amino acid derivatives function as catalysts for
direct asymmetric intermolecular reactions.[8–16]
Based on the elegant work of Yamomoto et al. and our
previous research on amine-catalyzed asymmetric synthesis,
we envisioned that an amino acid could catalyze the a-
oxyamination of unmodified ketones [Eq. (1)].[4,8d,f,g,i,9b–
[*] Dr. A. Bøgevig, H. SundØn, Prof. Dr. A. Córdova
Department of Organic Chemistry
The Arrhenius Laboratory, Stockholm University
10691 Stockholm (Sweden)
Fax: (+46)8-154-908
E-mail: acordova@organ.su.se
acordova1a@netscape.net
[**] We thank Prof. J.-E. Bäckvall and Prof. H. Adolfsson for valuable
discussions and the Swedish National Research council and
Wenner-Gren-Foundation for financial support. We also thank Prof.
Hayashi and the referees for helpful discussions concerning the
absolute configuration.
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DOI: 10.1002/anie.200353018
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Communications
proline-catalyzed reaction, which indicates that nitrosoben-
zene is more reactive and/or provides less steric hindrance
than other electrophiles such as diazocarboxylates or a-imino
glyoxylates.[9,10]
Next, we performed the corresponding reaction with a set
of different aliphatic ketones (Table 1). The reactions were
effective, and the corresponding a-aminoxy ketones 3a–3e
were isolated in good yield with > 99% ee.[18] In addition,
Scheme 1. Direct catalytic asymmetric synthesis of 3 f.
and in the presence of air. In addition, the
Table 1: Proline-catalyzed direct a-aminoxylation of different ketones.[a]
progress of the reaction can be monitored
simply by the human eye since the reaction
mixture changes colors from light blue to
green and finally to orange when the
reaction is complete.
The a-aminoxy ketone 3a was readily
reduced with NaBH4 in situ to the corre-
sponding monoprotected diol 5, which was
isolated in 88% yield over the two steps,
with a d.r. of 2:1 (trans/cis) and > 99% ee
(Scheme 2). Removal of the aniline with
Adams catalyst (PtO2) and H2 furnished the
known (1R,2R)-trans-1,2-cyclohexanediol
(6) and cis-1,2-cyclohexanediol in 96%
combined yield with > 99% ee for the
optically active diol.
As selective reduction of a-hydroxy
ketones to both syn- and anti-1,2-diols is
known, the present procedure is one prac-
tical route for the preparation of all the
possible stereoisomers of chiral 1,2-diols. In
addition, the ketones 3a and 4 were readily
deprotected with CuSO4 to afford the
corresponding a-hydroxy ketone 7 and
a,a’-dihydroxy ketone adducts in > 90%
yield without loss of enantioselectivity.[4]
On the basis of the absolute configura-
tion, which is opposite to adducts 3 derived
from Yamamoto's reaction,[19] we propose
Entry
1
Ketone
R1
R2
Yield [%][b]
70
3:5
ee [%] of 3[c]
>99
ee [%] of 5[c]
-(CH2)3-
>100/1
–
(91)[d]
93
(>100/1)[d]
(>99)[d]
>99
–
2
3
4
5
H
Et
H
H
Me
Me
81:19
11
66
87
64
98:2
8:22
90:10
99
7
n.d.[e]
n.d.[e]
=
CH2CH CH2
>99
>99
iPr
[a] Experimental conditions: A mixture of 1 (10 mmol, 10 equiv), 2 (1 mmol), and (S)-proline was stirred
at room temperature for 2–3 h. The crude product obtained after aqueous workup was purified by
column chromatography. [b] Combined yield of isolated products after silica gel column chromatog-
raphy. [c] Determined by chiral-phase HPLC analyses. [d] The reaction was performed in CHCl3. [e] Not
determined.
excellent regioselectivities were observed for a-aminoxyla-
tion of acyclic ketones and no a,a’-diaminoxylated ketones
were observed. The oxidation occurred exclusively on the
methylene carbon of the ketones. For example, protected
hydroxy ketone 3b was isolated as a single regioisomer in
70% yield with > 99% ee. With regards to the O- or N-
selectivity of the reaction, we found that the reaction was
chemoselective, furnishing no N-addition products for
transformations with cyclic ketones as donors. However, a-
aminoxylation of acyclic ketones afforded small amounts
(< 25%) of the corresponding 2-aminated ketones 5 with the
same regioselectivity as the O-addition adducts with a minor
chiral induction.
Furthermore, the sterically hindered, racemic 2-methyl-
cyclohexanone 1 f was also efficiently a- aminoxylated oxy-
aminated, providing the corresponding keto adduct 3 f as a 3:1
mixture of diastereomers (trans/cis) in > 99% ee (Scheme 1).
In this case, excellent O-selectivity was observed since no N-
addition product was observed. The reactions were readily
performed on gram scale in not strictly anhydrous solvents
Scheme 2. Asymmetric synthesis of (1R,2R)-trans-1,2-cyclohexanediol
(6) and (2R)-hydroxycyclohexanone (7).
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Chemie
transition-state model I to account for the regio- and
enantioselectivity of the a-oxidation reaction of unmodified
substituted ketones (Scheme 3). Hence, (S)-proline forms an
enamine with the ketone, which is attacked by the nitro-
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sobenzene from its se face providing (2R)-a-aminoxylated
ketones. This is in accordance with the transition states of
previously reported proline-catalyzed Mannich and a-amina-
tion reactions, in which a si-facial attack occurs.[9,10,20] The
proposed transition state I also explains how the unprece-
dented second attack of the electrophile could occur for the
monoaminoxylated intermediate (R1 = ONHPh).
In conclusion, we have developed the first direct enantio-
selective method that provides protected a-hydroxy ketones
in > 99% ee. The reactions were performed without tedious
elaboration in wet solvents in the presence of air and are
readily scaled up. In addition, reactions with a-unsubstituted
cyclic ketones as donors in DMSO were remarkably selective,
affording the corresponding C2-symmetric a,a’-dihydroxy
ketones with > 99% ee. Further elaboration of this trans-
formation and its synthetic application is being studied in our
laboratory.[21]
[7] For example, the total synthesis of taxol: S. J. Danishefsky, J.
Am. Chem. Soc. 1996, 118, 2843.
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Barbas III, J. Am. Chem. Soc. 2001, 123, 5260; d) A. Córdova, W.
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C. F. Barbas III, J. Am. Chem. Soc. 2002, 124, 1844; c) A.
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1651; e) A. Córdova, C. F. Barbas III, Tetrahedron Lett. 2002, 43,
7749; f) S.-i. Watanabe, A. Córdova, F. Tanaka, C. F. Barbas III,
Org. lett. 2002, 4, 4519; g) A. Córdova, C. F. Barbas III,
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Experimental Section
Typical experimental procedure (Table 1, entry 1): To a vial contain-
ing 2 (1 mmol) and a catalytic amount of (S)-proline (20 mol%) in
CHCl3 (4 mL) was added the ketone 1a (1 mL, 10 equiv). After 2 h of
vigorous stirring the reaction was quenched by the addition of
aqueous NH4Cl, and the aqueous phase was extracted three times
with EtOAc. The combined organic layers were dried over MgSO4,
the solvent was removed under reduced pressure, and the crude
product mixture was purified by silica gel column chromatography
(EtOAc/pentane 1:8) to afford a-aminooxy ketone 3a in 91% yield as
slightly yellow solid. The enantiomeric excess of 3a was > 99% as
determined by chiral-phase HPLC analysis. 3a: 1H NMR (CDCl3):
d = 1.71–1.79 (m, 4H), 2.00–2.02 (m, 2H), 2.34–2.48 (m, 2H), 4.35 (q,
1H, J = 6.0 Hz), 6.94 (t, 3H, J = 8.1 Hz), 7.25 (t, 2H, J = 8.4 Hz),
7.82 ppm (brs, 1H); 13C NMR: d = 23.7, 27.2, 32.5, 40.8, 86.2, 114.3,
122.0, 128.8, 148.0, 209.9 ppm; HPLC (Daicel Chiralpak AD,
hexanes/iPrOH 90:10, flow rate 0.5 mLminÀ1, l = 242 nm): major
isomer: tR = 30.31 min; minor isomer: tR = 25.79 min; [a]D = + 111.3
(c = 0.15, CHCl3); MALDI-TOF MS: 228.101; C12H15NO2 (M+Na+:
calcd 228.100).
[10] For a-aminations, see: a) A. Bøgevig, K. Juhl, N. Kumaragur-
ubaran, W. Zhuang, K. A. Jørgensen, Angew. Chem. 2002, 114,
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Chem. Soc. 2002, 124, 5656; c) N. Kumaragurubaran, K. Juhl, W.
Zhuang, A. Bøgevig, K. A. Jørgensen, J. Am. Chem. Soc. 2002,
124, 6254.
Received: October 6, 2003 [Z53018]
Published Online: February 9, 2004
[11] For Michael reactions, see: a) B. List, H. Pojarliev, H. J. Martin,
Org. Lett. 2001, 3, 2423; b) M. Yamaguchi, T. Shiraishi, M.
Keywords: asymmetric catalysis · ketones · oxidation · proline
.
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Hirama, J. Org. Chem. 1996, 61, 3520; b) M. Yamaguchi, Y.
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[12] For Diels–Alder reactions, see: a) A. B. Northrup, D. W. C.
MacMillan, J. Am. Chem. Soc. 2002, 124, 2458; b) K. A.
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Thadani, V. H. Rawal, Nature 2003, 424, 146.
[13] For alkylation of electron-rich benzene systems, see: a) N. A.
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b) J. F. Austin, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
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[14] For 1,3-dipolar cycloadditions, see: a) W. S. Jen, J. J. M. Wiener,
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Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012.
[16] For other reactions, see: a) A. E. Taggi, A. M. Hafez, H. Wack,
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[17] During the preparation of this manuscript two excellent
independent reports of proline-catalyzed a-oxidations of alde-
hydes were reported, see: a) G. Zhong, Angew. Chem. 2003, 115,
4379; Angew. Chem. Int. Ed. 2003, 42, 4247; b) S. P. Brown, M. P.
Brochu, C. J. Sinz, D. W. C. MacMillan, J. Am. Chem. Soc. 2003,
125, 10808.
[18] The a-oxy aniline adducts racemize and decompose upon
storage in solution and at room temperature and should
therefore be stored as solids at 48C or reduced to the more
stable corresponding monoprotected diols.
[19] The optical rotation of 3a obtained from the (S)-proline-
catalyzed reaction was [a]D = + 111.3 (c = 0.15, CHCl3);
reported rotation for (À)-3a is [a]D = À53.0 (c = 0.62,
CHCl3).[4] The optical rotation of 3c was [a]D = + 57.7 (c = 2.1,
CHCl3); the reported rotation for (À)-3c is [a]D = À12.8 (c = 0.3,
CHCl3).[4]
[20] S. Bahmanyar, K. N. Houk, Org. Lett. 2003, 5, 1249, and
references therein.
[21] Note added in proof (19.1.2004): Please see the following
communication by Hayashi et al., which describes related
chemistry: Y. Hayashi, J. Yamaguchi, T. Suniya, M. Shoji,
Angew. Chem. 2004, 116, 1132; Angew. Chem. Int. Ed. 2004, 43,
1112.
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