Synthesis of optically active trifluoromethylated indolizidine derivatives via stereoselective radical cyclization.

Article abstract of DOI:10.1021/ol025792b

[reaction: see text]. Asymmetric Michael reaction of lithiated trifluoroacetone SAMP-hydrazone with alkylidenemalonates gave addition products stereoselectively. Hydrolyzed enantiomerically pure ketoacids were cyclized to dihydropyridinones. N-Iodopropylation followed by radical cyclization gave optically active trifluoromethylated indolizidinones stereoselectively.

Full text of DOI:10.1021/ol025792b

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1571-1573
Synthesis of Optically Active
Trifluoromethylated Indolizidine
Derivatives via Stereoselective Radical
Cyclization
Takashi Okano,* Masataka Fumoto, Takahiro Kusukawa, and Makoto Fujita
Department of Applied Chemistry, Graduate School of Engineering,
Nagoya UniVersity, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
okano@apchem.nagoya-u.ac.jp
Received February 28, 2002
ABSTRACT
Asymmetric Michael reaction of lithiated trifluoroacetone SAMP-hydrazone with alkylidenemalonates gave addition products stereoselectively.
Hydrolyzed enantiomerically pure ketoacids were cyclized to dihydropyridinones. N-Iodopropylation followed by radical cyclization gave optically
active trifluoromethylated indolizidinones stereoselectively.
Fluorinated heterocycles1 are of current interest as a class
of potentially biologically active compounds.2 Compared to
the common approaches for trifluoromethylated aromatic
heterocycles,3 fewer syntheses of trifluoromethylated ali-
phatic nitrogen heterocycles have been reported, even though
the introduction of a trifluoromethyl group into the alkaloid-
related heterocycle is a hopeful modification procedure to
develop new biologically active compounds.4 Particularly,
synthesis of optically active trifluoromethylated aliphatic
nitrogen heterocycles has been rarely reported. Jiang et al.
reported the synthesis of optically active trifluoromethylated
piperidine and quinolidine from 6,6,6-trifluoro-5-oxohexanoic
acid.5 Previously, we prepared the ketoacid in an awkward
way that involved the low-yield cross Claisen condensation
of trifluoroacetate and glutarate.6 Usually, such 1,5-dicar-
bonyl compounds are prepared by the Michael reaction of
ketone and R,â-unsaturated carboxylic acid derivatives, and
if an asymmetric conjugate addition is possible, a versatile
optically active building block for the potential biologically
active aliphatic nitrogen heterocycles is available. We report
here the asymmetric Michael reaction of Enders’s SAMP7
((S)-N-amino-2-methoxymethylpyrrolidine) hydrazone of tri-
fluoroacetone and alkylidenemalonate esters to give chiral
3-alkyl-6,6,6-trifluoro-5-oxohexanoic acids 1 and the fol-
lowing radical cyclization to optically active indolizidine
derivatives bearing a trifluoromethyl group at the bridgehead
carbon.
(1) For recent reviews of the synthesis of trifluoromethylated compounds,
see: (a) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635-3671. (b) Elguero,
J.; Fruchier, A.; Jagerovic, N.; Werner, A. Org. Prep. Proced. Int. 1995,
27, 33-74.
(2) (a) Fluoroorganic Chemistry: Synthetic Challenge and Biomedical
Rewards; Resnati, G., Soloshonok, V. A., Eds.; Tetrahedron Symposium-
in-Print N 58; Tetrahedron 1996, 52, 1-330. (b) Welch, J. T.; Eswar-
akrishnan, A. In Fluorine in Bioorganic Chemistry; Wiley: New York,
1991. (c) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. In Biomedical Aspects
of Fluorine Chemistry; Elsevier: Amsterdam, 1993.
(3) Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56, 7267-7272 and
references therein.
(4) Bravo, P.; Crucianelli, M.; Farina, A.; Meille, S. V.; Volonterio, A.;
Zanda, M. Eur. J. Org. Chem. 1998, 435-440.
Reed and Katzenellenbogen8 reported the preparation of
SAMP-hydrazone 2 and the following Michael addition of
(5) Jiang, J.; DeVita, R. J.; Doss, G. A.; Goulet, M. T.; Wyvratt, M. J.
J. Am. Chem. Soc. 1999, 121, 593-594.
(6) Okano, T.; Sakaida, T.; Eguchi, S. J. Org. Chem. 1996, 61, 8826-
8830.
(7) Enders, D.; Papadopoulas, K. Tetrahedron Lett. 1983, 24, 4967-
4970. Enders, D.; Rendenbach, B. E. M. Tetrahedron 1986, 42, 2235-
2242.
10.1021/ol025792b CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/02/2002

lithiated hydrazone 3 with methyl cinnamate followed by
alkaline hydrolysis to an “unstable” ketoacid 1a, which was
not purified. However, in our hands this reaction failed
completely. Probably because of the unusually stable nature
of the lithiated hydrazone 3, the reverse Michael reaction
prevents obtaining the addition product. Successful Michael
addition of 3 was achieved by employing activated alkyli-
denemalonate esters 4a1,2-e1,2 as Michael acceptors at -78
°C to give diastereomer mixtures of (E)-hydrazones 5a1,2-
e1,2 in 58-84% yields (Table 1).9 To avoid the reverse
comparison of the HPLC retention times on a chiral column
1
and the H and 19F NMR spectra of (3R)-5a1 and (3S)-5a1
with those of the products 5b1,2-e1,2. Interestingly, for the
products from arylmethylenemalonates 4a1,2 and 4b1,2, the
stereoselectivities of the methyl esters 4a2 and 4b2 were better
than those of ethyl esters 4a1 and 4b1, whereas ethyl esters
4c1-e1 gave Michael products more stereoselectively than
methyl esters 4c2-e2 for alkylidenemalonates. Particularly,
the stereoselectivity of 3-anisyl ethyl ester 4b1 was reversed
to give preferentially (3S)-5b1. Except for the methyl
derivatives 5e1,2, the Michael products 5a1-d1 were separated
by simple SiO2 column chromatography.
The acidic hydrolysis of the isolated major ethyl esters
5a1-d1 was conducted by heating in formic acid in the
presence of sulfuric acid to give the desired enantiomerically
pure 3-substituted (+)-6,6,6-trifluoro-5-oxohexanoic acids
1a,c,d and (-)-acid 1b (Table 2) as stable forms.
Table 1. Asymmetric Michael Reaction of Lithiated
Hydrazone 3 with Alkylidenemalonates 4
Table 2. Preparation of Enatiomerically Pure 3-Substituted
6,6,6-Trifluoro-5-oxohexanoic Acids 1a-d
yield products ratio
substrate product
R
R1
(%)
(3R):(3S)a
yield
(%)
[R]16
D
(c 0.4, CHCl3)
product
R1
C6H5
R2
4a 1
4a 2
4b1
4b2
4c1
4c2
4d 1
4d 2
4e1
4e2
5a 1
5a 2
5b1
5b2
5c1
5c2
5d 1
5d 2
5e1
5e2
C6H5
C6H5
C2H5
CH3
75
77
64
70
77
75
84
58
80
83
79:21
92:8
(3R)-1a
(3S)-1b
(3R)-1c
(3R)-1d
H
92
90
97
97
+24.5
-18.4
+40.5
+35.4
4-CH3OC6H4 C2H5
4-CH3OC6H4 CH3
(CH3)2CH
(CH3)2CH
C4H9
38:62
83:17
74:26b
68:32b
68:32
61:39
72:28
56:44
H
4-CH3OC6H4
(CH3)2CH
C4H9
H
H
C2H5
CH3
C2H5
CH3
C2H5
CH3
C4H9
CH3
CH3
The dehydration reaction of chiral acids 1a-d with
ammonium carbonate under refluxing in toluene followed
by addition of a catalytic amount of p-toluenesulfonic acid
gave dihydropyridinones 6a-d in 74-80% yields, presum-
ably through the hemiaminal intermediates 7. An iodopropyl
group as a tether for the radical cyclization was attached by
deprotonation of enamide 6a-d with NaH in anhydrous
DMF followed by addition of an excess amount of 1,3-
diiodopropane at room temperature in 52-70% yields
(Scheme 1).
The reaction of triethylborane and a small amount of
oxygen is a promising route to generate an ethyl radical that
abstracts iodine from alkyl iodides to give another alkyl
radical at low temperature.11 After radical addition to a C-C
double bond, the generated alkyl radical is reduced by usually
trialkyltin hydrides. However, for environmental reasons, tris-
(trimethylsilyl)silane12 was employed as the radical chain
transfer reagent despite the lower reactivity compared to that
a The ratios of diastereomers were estimated by integrating the 19F NMR
signals of the crude reaction mixtures. b The formal configurations of these
products are (3S) and (3R), respectively.
Michael reaction during warming up, the reaction mixture
was quenched by addition of an ethereal solution of hydrogen
chloride at -78 °C. X-ray crystallography of the major
isomer of 3-phenyl product 5a2 revealed that the configu-
ration of the 3-position was R, similar to the results of the
acetone SAMP-hydrazone and benzylidenemalonates re-
ported by Enders.10 The diastereomeric ratios and the
configurations of the other products were established by
(8) Instead of the reported procedure, SAMP-hydrazone 2 was prepared
by dehydrative heating in toluene with a Dean-Stark apparatus in the
presence of a catalytic amount of p-toluenesulfonic acid in 90% yield after
mixing trifluoroacetone and SAMP at room temperature for 2 days. Reed,
P. E.; Katzenellenbogen, J. A. J. Med. Chem. 1991, 34, 1162-1176.
(9) All new compounds were characterized by spectroscopic and
elemental analyses.
(11) Fujita, K.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem.
Soc. 2001, 123, 3137-3138.
(12) Ikeda, M.; Hamada, M.; Yamashita, T.; Matsui, K.; Sato, T.;
Ishibashi, H. J. Chem. Soc., Perkin Trans. 1 1999, 1949-1956.
(10) Enders, D.; Demir, A. S.; Rendenbach, B. E. M. Chem. Ber. 1987,
120, 1731-1735.
1572
Org. Lett., Vol. 4, No. 9, 2002

Scheme 1
Table 3. Radical Cyclization of Iodoenamides 8 to Optically
Active Indolizidinones 9 and 10
products (yield, %)
products ratio
9
10
R1
R2
(syn:anti)
9a (46)
9b (10)
9c (44)
10a (14)
10b (32)
10c (16)
C6H5
H
(CH3) 2CH
H
71:29
74:26
70:30
61:39
4-CH3OC6H4
H
H
9d (46) 10d (23) C4H9
cyclization of a six-membered ring was also observed in the
radical cyclization of a more rigid cyclohexenyl ester.14
of tin hydrides. Thus, the radical cyclization of the iodopro-
pylpyridinones 8a-d (0.1 mmol) was achieved by the
reaction with triethylborane (0.2 mmol) and slow addition
of oxygen (3 mL) using a syringe pump in the presence of
tris(trimethylsilyl)silane (0.2 mmol) at room temperature. The
desired optically active indolizidines 9a-d and 10a-d,
which have a trifluoromethyl group at the bridgehead
position, were obtained as syn/anti (R/CF3) mixtures (Table
3). The minor isomer of isopropyl derivative 10c was
crystallized, and the molecular structure was analyzed by
X-ray crystallography to reveal that the relative configuration
was anti.13 Since the structural similarities among each series
of the major and minor products were evident from both the
1H and 19F NMR spectra, all major products can be
speculated to have the syn relative configurations. Although
the origin of this moderate stereoselectivity in the radical
cyclization of 8a-d is not clearly understood, as illustrated
in Figure 1, in the transition states for the anti products,
unfavorable 1,3-di-pseudoaxial interaction between the alkyl
group attached on the carbon at the 4-position of the
dihydropyridine ring and the developing C-C bond is
possible. This type of 1,3-stereoselection of the radical
Figure 1. Transition states for the syn and anti radical products.
In summary, optically active indolizidinones having a
trifluoromethyl group on the bridgehead carbon were pre-
pared via stereoselective radical cyclization, starting from
asymmetric Michael addition of trifluoroacetone SAMP-
hydrazone with alkylidenemalonate esters.
Supporting Information Available: Crystallographic
data in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL025792B
(13) The absolute configuration of 10c was deduced from the (3R)-
configuration of the starting 1c.
(14) Srikrishna, A.; Kumar, P. P.; Reddy, T. J. Tetrahedron Lett. 1998,
39, 5815-5818.
Org. Lett., Vol. 4, No. 9, 2002
1573