Ru(CO)-salen-catalyzed synthesis of enantiopure aziridinyl ketones and formal asymmetric synthesis of (+)-PD 128907

Article abstract of DOI:10.1021/ol302095r

Aziridination of vinyl ketones using SESN₃ in the presence Ru(CO)-salen complex 1 provides the enantiopure aziridinyl ketones that can serve as useful chiral building blocks. A formal asymmetric synthesis of (+)-PD 128907 was achieved in an eight-step sequence via aziridination.

Full text of DOI:10.1021/ol302095r

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4658–4661
Ru(CO)-salen-Catalyzed Synthesis of
Enantiopure Aziridinyl Ketones and
Formal Asymmetric Synthesis of
(þ)-PD 128907
Yasuaki Fukunaga,† Tatsuya Uchida,†,‡ Yutaro Ito,† Kenji Matsumoto,§ and
Tsutomu Katsuki*,‡
Department of Chemistry, Faculty of Science, Graduate School, and International
Institute for Carbon-Neutral Energy Research (I2CNER), Kyushu University,
Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
katsuscc@chem.kyushu-univ.jp
Received July 30, 2012
ABSTRACT
Aziridination of vinyl ketones using SESN3 in the presence Ru(CO)-salen complex 1 provides the enantiopure aziridinyl ketones that can serve as
useful chiral building blocks. A formal asymmetric synthesis of (þ)-PD 128907 was achieved in an eight-step sequence via aziridination.
Optically active aziridinyl ketones and esters, especially
ones N-protected with an electron-withdrawing group, are
versatile building blocks because they undergo nucleo-
philic and reductive ring-opening to provide various chiral
amine derivatives.1,2 Thus, many methods for their enan-
tioenriched synthesis have been developed.1,3 Asymmetric
aziridination of readily available enones and enoates is a
simple and direct method for synthesis and is the method
that has been explored most thoroughly.4 Evans et al. have
reported highly enantioselective copper-catalyzed aziridi-
nation using N-(p-toluenesulfonyl)iminophenyliodinane.4a
Scott et al. also reported highly enantioselective aziridina-
tion using copper complexes of biaryl Schiff bases.4b Sub-
sequently, Xu et al. reported that a particular copper-
(AnBOX) complex is an excellent catalyst for asymmetric
aziridination.4c Good substrates for these reactions are,
however, largely limited to cinnamate and chalcone deriv-
atives, and few methods can be applied to asymmetric
aziridination of vinyl ketones that are polymerizable.5
Moreover, use of arenesulfonyliminophenyliodinane
† Department of Chemistry.
‡ International Institute for Carbon-Neutral Energy Research (I2CNER).
§ Current address: Department of Applied Science, Faculty of Science,
Kochi University, 2-5-1 Akebono-cho, Kochi 780-8520, Japan.
(1) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (b)
McCoull, W.; Davis, F. A. Synthesis 2000, 1347. (c) Sweeney, J. B. Chem.
Soc. Rev. 2002, 31, 247. (d) Hu, X. E. Tetrahedron 2004, 60, 2701.
(2) (a) Molander, G. A.; Stengel, P. J. J. Org. Chem. 1995, 60, 6660.
(b) Molander, G. A.; Stengel, P. J. Tetrahedron 1997, 53, 8887. (c)
Ogawa, Y.; Kuroda, K.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2005, 78,
1309.
(3) (a) Osborn, H. M. I.; Sweeney, J. B. Tetrahedron: Asymmetry
1997, 8, 1693. (b) Jacobsen, E. N. In Comprehensive Asymmetric
Catalysis II; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999; Vol. 2, Chap. 17, p 607. (c) Sweeney, J. B. In Aziridination
and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley: Weinheim,
2005; p 117. (d) Katsuki, T. In Comprehensive Coodination Chemistry II;
McCleverty, J., Ed.; Elsevier: Oxford, 2003; Vol. 9, Chap. 9.4, p 207. (e)
(4) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.;
Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328. (b) Gillespie, K. M.;
Sanders, C. J.; O’Shaughnessy, P.; Westmoreland, I.; Thickitt, C. P.;
Scott, P. J. Org. Chem. 2002, 67, 3450. (c) Xu, J.; Ma, L.; Jiao, P. Chem.
Commun. 2004, 1616.
(5) Copper-mediated aziridination of acrolein has been reported,
though nonenantioselectively: Dauban, P.; Dodd, R. H. J. Org. Chem.
1999, 64, 5304.
€
Muller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905. (f) Dauban, P.; Dodd,
R. H. Synlett 2003, 1571.
r
10.1021/ol302095r
Published on Web 08/28/2012
2012 American Chemical Society

derivatives as nitrenoid precursors reduces the atom
economy of the reactions6 and causes problems with
N-arenesulfonyl deprotection from the products.7 Nucleo-
philic addition of diazo compounds or ylides to aldimines
is another promising approach for obtaining optically
active aziridino carbonyl compounds,8,9 but unstable
formaldimine derivatives have not yet been used as the
substrate for these reactions. Recently, organocatalytic
asymmetric aziridination of R,β-unsaturated carbonyl
compounds using N-protected hydroxylamine or chloro-
amine derivatives via an additionꢀcyclization pathway
has been developed.10,11 This method has been success-
fully applied to the aziridination of acrolein showing high
enantioselectivity of up to 94% ee.11b However, these
reactions require high catalyst loading. Still, the enan-
tioenriched and atom-economic synthesis of unsubsti-
tuted aziridinyl ketones, which are highly reactive to
nucleophiles, remains a challenging problem.
modest enantioselectivity.13ꢀ15 We discovered that
Ru(CO)-salen complexes catalyze enantioselective aziridina-
tion of simple olefins using N-toluenesulfonyl azides at
room temperature without irradiation.16 Moreover,
Ru(CO)-salen complex 1 bearing a robust ligand could
catalyze aziridination using p-NsN3 and SESN3.16bꢀe
Zhang et al. also reported on asymmetric aziridination using
azide compounds as nitrenoid sources.17 During our study,
we observed that 1 catalyzes aziridination of benzyl acrylate
with excellent enantioselectivity.16d Although metal nitre-
noids are isoelectronic species of metal oxenoids that are an
electrophilic species, they undergo aziridination of electron-
deficient olefins smoothly (vide supra).4 Considering the mild
Lewis acidity of Ru(CO)-salen complexes,18 we expected that
complex 1 would serve as a good catalyst for aziridination
of unstable vinyl ketones. Thus, we first examined the
intramolecular competitive aziridination of p-vinylphenyl
vinyl ketone 2 using SESN3. Although the styrene and
the acroyl moieties of 2 reacted at almost equal rates,
the enantioselectivity of aziridination of the acroyl
moieties was much better than that of the styrene moiety
(Scheme 1). No polymerization of the vinyl ketone was
observed.
Azide compounds,12 in particular, the ones bearing a
readily removable N-sulfonyl group such as p-nitroben-
zenesulfonyl (p-Ns)7a,b and 2-(trimethylsilyl)ethanesulfonyl
(SES) groups,7c are an ideal nitrenoid precursor in terms
€
of atom efficiency and synthetic application. Muller et al.
reported that p-NsN3 serves as a nitrenoid precursor
for Rh-mediated aziridination under UV-irradiation with
Scheme 1. Intramolecular Competitive Aziridination Using 1 as
Catalyst
(6) For examples of asymmetric aziridination using p-NsNdIPh as
.
the nitrene precursor, see: (a) Sodergren, M. J.; Alonso, D. A.;
Andersson, P. G. Tetrahedron: Asymmetry 1997, 8, 3563. (b) Taylor,
S.; Gullick, J.; McMorn, P.; Bethell, D.; Bulman Page, P. C.; Hancock,
F. E.; King, F.; Hutchings, G. J. J. Chem. Soc., Perkin Trans. 2 2001,
1714.
(7) For examples of a readily removable N-protecting group, see: (a)
Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831. (c) Weinreb, S. M.; Demko, D. M.;
Lessen, T. A.; Demers, J. P. Tetrahedron Lett. 1986, 27, 2099.
(8) (a) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1995, 34, 676. (b) Juhl, K.; Hazell, R. G.; Jørgensen, K. A.
J. Chem. Soc., Perkin Trans. 1 1999, 2293. (c) Antilla, J. C.; Wulff, W. D.
J. Am. Chem. Soc. 1999, 121, 5099. (d) Antilla, J. C.; Wulff, W. D.
Angew. Chem., Int. Ed. 2000, 39, 4518. (e) Hashimoto, T.; Uchiyama, N.;
Maruoka, K. J. Am. Chem. Soc. 2008, 130, 14380. (f) Zeng, X.; Zeng, X.;
Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009, 11, 3036.
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Ferrara, M.; O’Brien, C. J.; Thompson, A.; Jones, R. V. H.; Fieldhouse,
R. J. Chem. Soc., Perkin Trans. 1 2001, 1635.
Encouraged by these results, we investigated the asym-
metric aziridination of various vinyl ketones using a com-
plex 1/SESN3 system (Table 1). As expected, the reaction
of phenyl vinyl ketone 3a proceeded with almost complete
(10) For WeitzꢀScheffer-type asymmetric aziridination, see: (a)
Fioravanti, S.; Mascia, M. G.; Pellacani, L.; Tardella, P. A. Tetrahedron
2004, 60, 8073. (b) Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y. Angew.
Chem., Int. Ed. 2006, 45, 8005. (c) Armstrong, A.; Baxter, C. A.; Lamont,
S. G.; Pape, A. R.; Wincewicz, R. Org. Lett. 2007, 9, 351. (d) Minakata,
S.; Murakami, Y.; Tsuruoka, R.; Kitanaka, S.; Komatsu, M. Chem.
Commun. 2008, 6363. (e) Pesciaioli, F.; De Vincentiis, F.; Galzerano,
P.; Bencivenni, G.; Bartoli, G.; Mazzanti, A.; Melchiorre, P. Angew.
Chem., Int. Ed. 2008, 47, 8703. (f) De Vincentiis, F.; Bencivenni, G.;
Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Galzerano, P.; Melchiorre, P.
Chem.;Asian. J. 2010, 5, 1652. (g) Jiang, H.; Holub, N.; Jørgensen,
K. A. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20630. (h) Menjo, Y.;
Hamajima, A.; Sasaki, N.; Hamada, Y. Org. Lett. 2011, 13, 5744. (i) Cruz,
(15) Asymmetric aziridination using arenesulfonyl azide under irra-
diation has been reported: Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am.
Chem. Soc. 1995, 117, 5889.
(16) (a) Omura, K.; Murakami, M.; Uchida, T.; Irie, R.; Katsuki, T.
Chem. Lett. 2003, 32, 354. (b) Omura, K.; Uchida, T.; Irie, R.; Katsuki,
T. Chem. Commun. 2004, 2060. (c) Kawabata, H.; Omura, K.; Katsuki,
T. Tetrahedron Lett. 2006, 47, 1571. (d) Kawabata, H.; Omura, K.;
Uchida, T.; Katsuki, T. Chem.;Asian J. 2007, 2, 248. (e) Kim, C.;
Uchida, T.; Katsuki, T. Chem. Commun. 2012, 48, 7188.
ꢀ
D. C.; Sanchez-Murcia, P.-A.; Jøgensen, K. A. Chem. Commun. 2012, 48,
6112.
(11) For asymmetric aziridination based on iminium-enamine cata-
ꢀ
Angew. Chem., Int. Ed. 2007, 46, 778. (b) Arai, H.; Sugaya, N.; Sasaki,
N.; Makino, K.; Lectard, S.; Hamada, Y. Tetrahedron Lett. 2009, 50,
3329.
(17) (a) Jones, J. E.; Ruppel, J. V.; Gao, G.-Y.; Moore, T. M.; Zhang,
X. P. J. Org. Chem. 2008, 73, 7260. (b) Subbarayan, V.; Ruppel, J. V.;
Zhu, S.; Perman, J. A.; Zhang, X. P. Chem. Commun. 2009, 4266.
(18) Complex 1 does not catalyze the hetero Diels-Alder reaction
(unpublished result), though Ru(NO)-salen complexes do. Mihara, J.;
Hamada, T.; Takeda, T.; Irie, R.; Katsuki, T. Synlett 1999, 1160.
(19) CCDC 771523 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
lysis, see: (a) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Cordova, A.
(12) Driver, T. G. Org. Biomol. Chem. 2010, 8, 3831.
€
€
(13) Muller, P.; Baud, C.; Jacquier, Y.; Moran, M.; Nageli, I. J. Phys.
Org. Chem. 1996, 9, 341.
(14) For the first aziridination using azide compounds, see: Kwart,
H.; Kahn, A. A. J. Am. Chem. Soc. 1967, 89, 1951.
Org. Lett., Vol. 14, No. 17, 2012
4659

enantioselectivity (entry 1). Furthermore, the catalyst
loading could be reduced to 0.5 mol % without decreasing
the enantioselectivity and the yield (entry 3). Under the
conditions, the reactions of various aryl vinyl ketones
3bꢀf gave the corresponding aziridinyl ketones also
with almost complete enantioselectivity and high yields,
irrespective of the location and electronic nature of the
substituents (entries 4ꢀ8). The reactions of alkyl and
cycloalkenyl vinyl ketones 3g and 3h were slower, and
1 mol % of 1 was required to ensure high yields (entries 9
and 10). The reactions of alkenyl vinyl ketones 3h and 3i
occurred only at the vinyl moiety with almost complete
enantioselectivity (entries 10 and 11).
Scheme 2. Deprotection of the N-SES Group of Aziridinyl
Ketones
syntheses22 and one chiral synthesis via resolution22b have
been reported and no asymmetric synthesis based on the
enantioselective method has been reported. With the pres-
ent asymmetric aziridination as a key step, we achieved
the formal but highly enantioenriched synthesis of (þ)-PD
128907 (Scheme 3). The synthesis started with vinylation
of commercial 5-methoxysalicylaldehyde 6. The resulting
vinyl alcohol is unstable, and oxidation using PCC, PDC,
CrO3/TBHP, or TEMPO/PhI(OAc)2 did not give the de-
sired product. The oxidation with excess MnO2 (20 equiv)
provided product 7 in moderate yield (37%). However, 6
was converted in one pot into vinyl ketone 7 at a yield of
52% via vinylation and subsequent Ru-catalyzed aerobic
oxidation.23 Aziridination of 7 gave almost enantiopure
(R)-aziridinyl ketone 8 (>99% ee) in an acceptable yield
(87%),24 without protecting the phenolic hydroxyl group.
Table 1. Asymmetric Aziridination of Vinyl Ketones with
SESN3 in the Presence of Ru(CO)-salen Complex 1a
cat.
yield
(%)b
entry
vinyl ketone (R)
(mol %)
% eec
>99
1
Ph (3a)
2.0
1.0
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
0.5
99
2
Ph (3a)
99
>99
3
Ph (3a)
99
>99
4
p-ClC6H4 (3b)
m-ClC6H4 (3c)
o-ClC6H4 (3d)
p-MeOC6H4 (3e)
m-MeOC6H4 (3f)
PhCH2CH2 (3g)
1-cyclohexenyl (3h)
(E)-PhCHdCH (3i)
96
>99
5
96
>99
6
98
>99
7
92
>99
€
Treatment of 8 with a catalytic amount of Hunig’s base at
8
99
>99
0 °C gave cyclic ketone 9, though a slight decrease of the
enantioselectivity to 96% ee was observed. Recrystallization
of 9 from CH2Cl2/hexane gave enantiopure 9.24 Reduction
9
99 (64)d
92 (67)d
95
>99
10
11
>99 (R)e
>99
a The reaction was carried out on a 0.5 mmol scale at 25 °C under a
N2 atmosphere, unless otherwise noted. b Isolated yield. c Determined by
HPLC analysis with a chiral stationary phase, as described in the
Supporting Information. d Catalyst loading was 0.5 mol %. e Absolute
configuration was determined to be R by X-ray analysis (ref 19).
Scheme 3. Formal Asymmetric Synthesis of (þ)-PD 128907
The N-SES group of phenyl aziridinyl ketone 4a was
deprotected by exposure to tris(dimethylamino)sulfonium
difluorotrimethylsilicate (TASF)20 in tetrahydrofuran
(THF) with little racemization to give the corresponding
aziridines 5a with good yield (Scheme 2). Treatment of
2-phenylethyl aziridinyl ketone 4g under the same condi-
tions also gave 5g without racemization, but in a modest
yield. However, the reaction using 1.1 equiv of TASF in1/1
THF/dimethylformamide (DMF) gave 5g in a better yield
with little racemization.
(þ)-PD 128907 is a potent dopamin D3 receptor
agonist.21 Although its structure is simple, only two racemic
(20) Nishimura, M.; Minakata, S.; Takahashi, T.; Oderaotoshi, Y.;
Komatsu, M. J. Org. Chem. 2002, 67, 2101.
(21) (a) Sokoloff, P.; Schwartz, J.-C. Trends Pharmacol. Sci. 1995, 16,
270. (b) Pugsley, T. A.; Davis, M. D.; Akunne, H. C.; Mackenzie, R. G.;
Shih, Y. H.; Damsma, G.; Wikstrom, H.; Whetzel, S. Z.; Georgic, L. M.;
Cooke, L. W.; Demattos, S. B.; Corbin, A. E.; Glase, S. A.; Wise, L. D.;
Dijkstra, D.; Heffner, T. G. J. Pharmacol. Exp. Ther. 1995, 275, 1355.
4660
Org. Lett., Vol. 14, No. 17, 2012

of 9 with NaBH4 gave the desired trans-hydroxy amine 10
preferentially, while the reduction with L-selectride afforded
cis-hydroxy amine 10 exclusively. The mixture of trans- and
cis-products 10 was converted without separation to the
corresponding 4-protected 1,4-oxazine derivatives 11 by
annulation using a diphenyl vinyl sulfonium reagent,25
and the product mixture was chromatographed to give
trans- and cis-oxazines 11, respectively. Deprotection of the
respective SES group in trans- and cis-oxazines 11 with
TBAF and subsequent treatment of the resulting amines
with 1-bromopropane gave the corresponding trans- and
cis-oxazines 12 in good yields, respectively.26 Since trans-12
has been converted to (þ)-PD 128907 in one step,22 a formal
asymmetric total synthesis of (þ)-PD 128907 was achieved
in eight steps with the synthesis of 12.
In summary, we have demonstrated that ruthenium-
(CO)-salen complex 1 is an efficient catalyst for enantio-
selective aziridination of acid-sensitive vinyl ketones using
SESN3 as the nitrene precursor. The reaction proceeded
with high yields even at a 0.5ꢀ1 mol % catalyst loading to
give almost enantiopure aziridinyl ketones. The high syn-
thetic utility of this aziridination was shown by the short
step synthesis of (þ)-PD 128907.
Acknowledgment. Financial support from Nissan Chem-
ical Industries, Ltd.; World Premier International Re-
search Center Initiative (WPI); and JSPS KAKENHI
Grant No. 23245009 from MEXT, Japan is gratefully
acknowledged.
Supporting Information Available. X-ray crystallo-
graphic data of compounds 4h, 9, and trans-12 in CIF
format; experimental procedures, spectroscopic and ana-
lytical data for the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) For the synthesis of PD 128907, see: (a) Dijkstra, D.; Mulder,
T. B. A.; Rollema, H.; Tepper, P. G.; Van der Weide, J.; Horn, A. S.
J. Med. Chem. 1988, 31, 2178. (b) DeWald, H. A.; Heffner, T. G.; Jaen,
J. C.; Lustgarten, D. M.; McPhail, A. T.; Meltzer, L. T.; Pugsley, T. A.;
Wise, L. D. J. Med. Chem. 1990, 33, 445.
(23) Miyata, A.; Murakami, M.; Irie, R.; Katsuki, T. Tetrahedron
Lett. 2001, 42, 7067.
(24) Recrystallization of 9 from CH2Cl2/hexane gave a single crystal.
The structure of 9 was confirmed to be R by X-ray analysis of the crystal.
Accordingly, the configuration of 8 was determined to be R. CCDC
813702 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(25) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2008, 47, 3784.
(26) Recrystallization of trans-12 from EtOH gave a single crystal.
The stereochemistry of trans-12 was confirmed by X-ray analysis.
CCDC 813700 contains the supplementary crystallographic data for
this paper. These data are also available from The Cambridge Crystal-
lographic Data Centre.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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