Synthesis of enantiopure dehydropiperidinones from α-amino acids and alkynes via azetidin-3-ones

Article abstract of DOI:10.1021/ol3016447

Chiral dehydropiperidinones were synthesized in enantiopure form from α-amino acids and alkynes via azetidin-3-ones.

Full text of DOI:10.1021/ol3016447

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of Enantiopure
Dehydropiperidinones from r-Amino
Acids and Alkynes via Azetidin-3-ones
Naoki Ishida, Tatsuya Yuhki, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University,
Katsura, Kyoto 615-8510, Japan
murakami@sbchem.kyoto-u.ac.jp
Received June 14, 2012
ABSTRACT
Chiral dehydropiperidinones were synthesized in enantiopure form from R-amino acids and alkynes via azetidin-3-ones.
Substituted piperidines are found in numerous natural
alkaloids, pharmaceuticals, and agrochemicals as a privileged
structural motif.1 Although a wide variety of methods for
their synthesis have been developed,2 new pathways leading
to their enantiopure forms starting from readily available
substances are still in demand. We now report the synthesis
of chiral dehydropiperidinones3 in enantiopure form from
R-amino acids and alkynes via azetidin-3-ones (eq 1).4
carbon single bonds of cyclobutanones to construct com-
plex carbocyclic skeletons. This straightforward synthetic
strategy based on carbonÀcarbon bond activation7 sig-
nificantly improved the step as well as atom economies
of the synthesis of chiral benzobicyclo[2.2.2]octenones.5d
On the basis of these results, we next directed our atten-
tion to azetidin-3-ones, which were readily synthesized
in enantiopure form from R-amino acids according to
Seebach’s method (Scheme 1).8 For example, commer-
cially available N-Boc-(L)-alanine was treated with
ethyl chloroformate/triethylamine, and subsequently
(4) During preparation of this manuscript, Aıssa and Louie indepen-
¨
dently reported a closely related nickel-catalyzed reaction, giving achiral
dehydropiperidinone using nonsubstituted azetidin-3-ones except for
one example: (a) Ho, K. Y. T.; Aıssa, C. Chem.;Eur. J. 2012, 18, 3486.
¨
(b) Kumar, P.; Louie, J. Org. Lett. 2012, 14, 2026.
We previously reported the nickel-5 and rhodium-
catalyzed6 insertion of alkynes and alkenes into carbonÀ
(5) (a) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc.
2005, 127, 6932. (b) Murakami, M.; Ashida, S.; Matsuda, T. J. Am.
Chem. Soc. 2006, 128, 2166. (c) Ashida, S.; Murakami, M. Chem.
Commun. 2006, 4599. (d) Liu, L; Ishida, N.; Murakami, M. Angew.
Chem., Int. Ed. 2012, 51, 2485.
(6) For rhodium-catalyzed alkene insertion reactions into cyclobuta-
nones, see: (a) Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002,
124, 13976. (b) Matsuda, T.; Fujimoto, A.; Ishibashi, M.; Murakami, M.
Chem. Lett. 2004, 33, 876.
(1) (a) Escolano, C.; Amat, M.; Bosch, J. Chem.;Eur. J. 2006, 12,
8198. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. (c) Chemler, S. A.
Curr. Bioact. Compd. 2009, 5, 2.
(2) For recent examples of enantioselective synthesis of substituted
piperidine derivatives, see: (a) Stead, D.; Carbone, G.; O’Brein, P.;
Campos, K. R.; Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010,
132, 7260. (b) Beng, T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010, 132,
12216. (c) Cui, L.; Li, C.; Zhang, L. Angew. Chem., Int. Ed. 2010, 49,
9178. (d) Seki, H.; Georg, G. I. J. Am. Chem. Soc. 2010, 132, 15512.
(e) Nadeau, C.; Aly, S.; Belyk, K. J. Am. Chem. Soc. 2011, 133, 2878.
(f) Seel, S.; Thaler, T.; Takatsu, K.; Zhang, C.; Zipse, H.; Straub, B. F.;
Mayer, P.; Knochel, P. J. Am. Chem. Soc. 2011, 133, 4774. (g) Wong, H.;
Garnier-Amblard, E. C.; Liebeskind, L. S. J. Am. Chem. Soc. 2011, 133,
7517 and references cited therein.
(3) For synthesis of dehydropiperidinones, see: (a) Cassldy, M. P.;
Padwa, A. Org. Lett. 2004, 6, 4029. (b) Donohoe, T. J.; Fishlock, L. P.;
Basutto, J. A.; Bower, J. F.; Procopiou, P. A.; Thompson, A. L. Chem.
Commun. 2009, 3008. (c) Husain, I.; Saquib, M.; Bajpai, V.; Kumar, B.;
Shaw, A. K. J. Org. Chem. 2011, 76, 8930.
(7) For reviews on transition-metal-catalyzed cleavage of carbonÀ
carbon bonds: (a) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005,
ꢀ
14, 1. (b) Kondo, T.; Mitsudo, T. Chem. Lett. 2005, 34, 1462. (c) Necas,
D.; Kotora, M. Curr. Org. Chem. 2007, 11, 1566. (d) Park, Y. J.; Park,
J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (e) Winter, C.; Krause,
N. Angew. Chem., Int. Ed. 2009, 48, 2460. (f) Seiser, T.; Cramer, N. Org.
Biomol. Chem. 2009, 7, 2835. (g) Murakami, M.; Matsuda, T. Chem.
Commun. 2011, 47, 1100. (h) Aıssa, C. Synthesis 2011, 3389.
¨
(8) (a) Podlech, J.; Seebach, D. Helv. Chim. Acta 1995, 78, 1238.
(b) Wang., J; Hou, Y.; Wu, P. J. Chem. Soc., Perkin Trans. 1 1999, 2277.
r
10.1021/ol3016447
XXXX American Chemical Society

Scheme 1. Synthesis of Azetidin-3-ones
Scheme 2. Plausible Mechanism
with diazomethane, to afford the diazomethyl ketone.
Upon treatment of this species with dimeric rhodium(II)
acetate, cyclization spontaneously occurred with the re-
lease of molecular nitrogen to furnish azetidin-3-one 1a
with stereochemical integrity.
The azetidinone 1a thus obtained was next reacted with
4-octyne (2a, 1.5 equiv) in the presence of Ni(cod)2 (5mol%)
and PPh3 (10 mol %)9 in toluene (eq 2). The insertion of 2a
between the carbonyl carbon and the R-methylene carbon
successfully took place at 80 °C to afford (S)-R-methylpiper-
idinone 3a in 73% isolated yield. Analysis of 3a by HPLC
verified that the stereochemical integrity was retained again.
Compound 4, the isomer possibly arising from insertion
between the carbonyl carbon and the other R-carbon having
a methyl substituent on it, was not formed.
i.e., a methylene carbon and a methyl-substituted carbon.
Whereas both are potentially amenable to migration onto
nickel by β-elimination, the methylene carbon selectively
migrates, probably due to steric reasons. As a result, the two
rings are merged to expand into seven-membered nickela-
cycle B.12 Finally, reductive elimination gives six-membered
ring product 3a with regeneration of the nickel(0) catalyst.
Various dehydropiperidinones were synthesized in an
analogous manner to 3a (Table 1). First, N-Boc- and
N-Cbz-azetidin-3-ones 1bÀ1e were prepared in enantiopure
form from the corresponding R-amino acids, i.e., pheny-
lalanine, valine, lysine, and methionine respectively, by
Seebach’s method.8 When subjected to the nickel catalysis,
they all underwent alkyne insertion without any difficul-
ties which the presence of the amino and thio functional-
ities might potentially bring forth. The corresponding
piperidinones 3bÀ3e were obtained in moderate to good
isolated yields (entries 1À4). Stereochemical integrity was
retained with 1c derived from valine, whereas a very slight
but measurable racemization was detected with 1b, 1d,
and 1e. Unsubstituted achiral azetidin-3-ones 1fÀh13 also
underwent the insertion reaction. In addition to carba-
mate-type N-protective groups, benzhydryl and p-tolue-
nesulfonyl groups were also suitable for the nitrogen
substituent (entries 5 and 6). Whereas PPh3 was the choice
of ligand with carbamates 1aÀe,h and sulfonamide 1g, the
use of more electron-donating PCy3 gave better results
with benzhydryl-protected azetidin-3-one 1f. Good to
high regioselectivities were observed with unsymmetrical
alkynes 2bÀe. The bulkier tert-butyl and phenyl groups
were placed selectively at the β-position (entries 2 and 7).
This regioselectivity is explained based on sterics; when
undergoing oxidative cyclization, the sterically demanding
ketonic carbonyl carbon prefers to couple with the sp carbon
attached to a less bulky substituent. Unlike the previous case
with cyclobutanones,5a it was possible to insert alkynylstan-
nanes 2d and 2e to give 2-stannylpiperidinones exclusively
Thus, the single bond between the carbonyl carbon and
the R-methylene carbon was site-selectively cleaved, and the
carbonÀcarbon triple bond was inserted therein. We as-
sume the mechanistic pathway shown in Scheme 2, which
involves oxidative cyclization on nickel(0),10,11 as in the case
of cyclobutanones.5a Initially, the carbonyl group of azeti-
din-3-one 1a and alkyne 2a are coupled on nickel(0) to
afford spirocyclic oxanickelacyclopentene A, which pos-
sesses two kinds of strained carbons located γ to nickel,
(9) The use of NHC and other phosphine ligands including PCy3,
which was the ligand of choice for the reaction of cyclobutanones, gave a
lower yield.
(10) For nickel-catalyzed reactions through oxidative cyclization be-
tween unsaturated hydrocarbons and carbonyl compounds, see: (a) Modern
Organonickel Chemistry; Tamaru, Y., Ed.; Willey-VCH: Weinheim, Germany,
2005. (b) Ikeda, S. Angew. Chem., Int. Ed. 2003, 42, 5120. (c) Montgomery, J.
Angew. Chem., Int. Ed. 2004, 43, 3890. (d) Moslin, R. M.; Miller-Moslin, K.;
Jamison, T. F. Chem. Commun. 2007, 4441 and references cited therein.
(11) For direct observation of oxidative cyclization of carbonyls with
alkenes, see: Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am. Chem. Soc. 2004,
126, 11082.
(12) For related reactions involving β-carbon elimination of spiro-
cyclic metalacycles, see: (a) Murakami, M.; Takahashi, K.; Amii, H.; Ito,
Y. J. Am. Chem. Soc. 1997, 119, 9307. (b) Matsuda, T.; Tsuboi, T.;
Murakami, M. J. Am. Chem. Soc. 2007, 129, 12596. See also ref 5.
(13) An azetidinol to be oxidized to 1f, N-H azetidinol hydrochloride to
be derivatized to 1g, and azetidin-3-one 1h itself are commercially available.
B
Org. Lett., Vol. XX, No. XX, XXXX

(entries 8À10). The selectivity observed with 2d and 2e
can be ascribed to the less electronegative nature of tin,
which renders its R-carbon to be charged negatively. The
positively charged carbonyl carbon prefers to couple with
the negatively charged R-carbon rather than with the β-
carbon.14 The stannyl group thus set at the 2-position
regioselectively could serve as the synthetic basis for
allowing further carbonÀcarbon bond formation (vide
infra). In contrast, less imbalanced unsymmetrical alkyne
2f (R2 = Me, R3 = i-Pr) afforded a mixture of regio-
isomers (entry 11). Terminal alkynes such as 1-octyne and
phenylethyne failed to participate in the insertion reac-
tion because of their facile self-oligomerization.
Table 1. Insertion of Alkynes into Azetidin-3-onesa
Thus, the present insertion reaction renders it possible to
derive dehydropiperidinones with various substituents, even
containing functionalities, from natural R-amino acids.
Further derivatization of the enantiopure products demon-
strated their synthetic utility. Reduction of the piperidinone
3a with sodium borohydride furnished piperidinol 5 stereo-
selectively with the arising hydroxyl group being oriented cis
to the R-methyl substituent (95% yield, dr = >20:1, eq 3).
Further stereoselective hydrogenation of 5 by the well-estab-
lished method using Crabtree’s catalyst afforded tetrasubsti-
tuted piperidine 6in 86% yield.15 The cross-coupling reaction
of the stannyl-substituted dehydropiperidinone 3k with
4-iodoanisole produced 4-anisylpiperidine 7 (77%, 98% ee,
eq 4), which was unavailable with regioselective control from
unsymmetrical anisylphenylethyne. Upon treatment of 3g
with DBU, p-toluenesulfinate was eliminated to give 4,5-
disubstituted 3-hydroxypyridine 8,3b which is the core struc-
ture of both pyridoxines and pyridinolines16 (eq 5).
In summary, we have described the nickel-catalyzed
reaction of azetidin-3-ones that selectively insert a triple
(14) For disscussions on the regioselectivity of oxidative cyclization
on nickel, see: (a) Miller, K. M.; Luanphaisarnnont, T.; Molinaro, C.;
Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130. (b) Miller, K. M.;
Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342. (c) Sa-ei, K.;
Montgomery, J. Org. Lett. 2006, 8, 4441. (d) Saito, N.; Katayama, T.;
Sato, Y. Org. Lett. 2008, 10, 3829. (e) Malik, H. A.; Chaulagain, M. R.;
Montgomery, J. Org. Lett. 2009, 11, 5734.
a Reaction conditions: 1.0 equiv of 1, 1.5 equiv of 2, 5 mol %
Ni(cod)2, 10 mol % PPh3, toluene, 80 °C, 18 h unless otherwise noted.
b Isolated yields. c 1.1 equiv of 2. d Rt, 15 h. e PCy3 was used instead of
PPh3. f 60 °C, 15 h.
Org. Lett., Vol. XX, No. XX, XXXX
C

bond into one of their carbonÀcarbon bonds to furnish
dehydropiperidinones. When combined with Seebach’s
method for azetidinone synthesis, the present reaction
provides a reliable synthetic pathway to enantiopure pi-
peridines with various substituents including functiona-
lized ones starting from R-amino acids.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research on Innovative Areas
“Molecular Activation Directed toward Straightforward
Synthesis” and Grant-in-Aid for Scientific Research (B)
from MEXT and The Asahi Glass Foundation.
Supporting Information Available. Experimental pro-
cedures and spectral data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) The stereochemistry of 6 was assigned based on the premise that
Crabtree’s catalyst hydrogenates a cyclohexenol derivative selectively
from the side cis to the directing hydroxyl group: Crabtree, R. G.; Davis,
M. W. J. Org. Chem. 1986, 51, 2655.
(16) Fujimoto, D.; Moriguchi, T.; Ishida, T.; Hayashi, H. Biochem.
Biophys. Res. Commun. 1978, 84, 52.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX