Direct Asymmetric Synthesis of β-Amino Ketones from Sulfinimines (N-Sulfinylimines). Synthesis of (-)-Indolizidine 209B

Article abstract of DOI:10.1021/ol035981+

(Equation presented) N-Sulfinyl β-amino ketones, prepared directly from the potassium enolates of methyl ketones and enantiopure sulfinimines, are transformed in one pot to protected amino ketones, which are valuable chiral building blocks for the assembl

Full text of DOI:10.1021/ol035981+

ORGANIC
LETTERS
2003
Vol. 5, No. 26
5011-5014
Direct Asymmetric Synthesis of
â-Amino Ketones from Sulfinimines
(N-Sulfinylimines). Synthesis of
(−)-Indolizidine 209B
Franklin A. Davis* and Bin Yang
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received October 11, 2003
ABSTRACT
N-Sulfinyl â-amino ketones, prepared directly from the potassium enolates of methyl ketones and enantiopure sulfinimines, are transformed
in one pot to protected amino ketones, which are valuable chiral building blocks for the assembly of piperidines. The utility of this methodology
is illustrated in a concise asymmetric synthesis of (−)-indolizidine 209B.
Recently, we introduced a new and general methodology for
the asymmetric syntheses of â-amino aldehydes and ketones
2 via the addition of hydride and Grignard reagents to
nonracemic N-sulfinyl â-amino Weinreb amides 1 (Scheme
1).1 The Weinreb amides 1 were prepared either by the
by the reaction of the corresponding â-amino ester with
lithium N,O-dimethylhydroxyamine.1 â-Amino carbonyl
moieties are found not only as structural units of natural
products2 but also as useful chiral building blocks for Wittig-
type condensations3-7 and natural product,1,4,5 1,3-amino
alcohol,1,8 and â-amino acid syntheses. We describe herein
a direct method for the asymmetric synthesis of â-amino
ketones via the addition of the methyl ketone enolates to
sulfinimines and its application to the concise synthesis of
piperidine and indolizidine alkaloids.
Scheme 1
The methyl ketone enolates were generated from the
corresponding ketones, acetophenone, acetone, 2-butanone,
and 2-hexanone and the appropriate base at -78 °C. A
solution of 1.0 equiv of (S)-(+)-N-benzylidine-p-toluene-
(2) Davis, F. A.; Szewczyk J. M. Tetrahedron Lett. 1998, 39, 5951.
(3) Louis, C.; Mill, S.; Mancuso, V.; Hootele, C. Can. J. Chem. 1994,
72, 1347.
(4) Davies, S. B.; McKervey, M. A. Tetrahedron Lett. 1999, 40, 1229.
(5) (a) Rodriguez, M.; Aumelas, A.; Martinez, J. Tetrahedron Lett. 1990,
31, 5153. (b) Rodriguez, M.; Heitz, A.; Martinez, J. Tetrahedron Lett. 1990,
31, 7319. (c) Limal, D.; Quesnel, A.; Briand, J.-P. Tetrahedron Lett. 1998,
39, 4239.
addition of the potassium enolate of N-methoxy-N-methyl-
acetamide to enantiopure sulfinimines (N-sulfinylimines) or
(6) Toujas, J.-L.; Toupet, L.; Vaultier, M. Tetrahedron 2000, 56, 2665.
(7) For a review see Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957.
(8) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 2911.
(1) Davis, F. A.; Prasd, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5,
925.
10.1021/ol035981+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/04/2003

The availability of small, easily manipulated chiral building
blocks and templates has had a significant impact on the
asymmetric syntheses of biologically and pharmaceutically
valuable molecules.11,12 Toward this objective, Troin and co-
workers introduced the ketal of (S)-(+)-4-amino-2-pentanone
5 and its enantiomer for the asymmetric synthesis of cis-
2,6-disubstituted protected 4-oxo piperidines 6.13 On treat-
ment with various aldehydes, followed by acid, 5 undergoes
a facile intramolecular Mannich reaction to afford 6 in good
yield and high diastereoselectivity (Scheme 3). However, the
Scheme 2
Scheme 3
sulfinamide (3)9 was added, via cannula and at -78 °C, to
1.8 equiv of the enolates. The reaction mixture was quenched
after 30 min by addition of saturated NH4Cl solution. Flash
chromatography afforded the N-sulfinyl â-amino ketones
(SS,R)-(+)-4a-d as single diastereoisomers (Scheme 2).
These results are summarized in Table 1.
multistep synthesis of 5 requires either a classical resolution
or a microbiological reduction as key steps.13a,e Moreover,
their methodology does not provide convenient access to
diversely substituted derivatives, which are needed for the
synthesis of more complex piperidines.
The Troin chiral building block is readily prepared using
our new â-amino ketone synthesis. Thus, treatment of (S)-
(+)-acetylidene-N-p-toluenesulfinimide (7)9 with the potas-
sium enolate of acetone in ether gave (SS,S)-(+)-N-(p-
toluenesulfinyl)-4-aminopentane-2-one (8) in 70% isolated
yield of the major diastereoisomer following chromatography
(Scheme 4). The diastereoselectivity of the addition was 64%.
Table 1. Addition of Methyl Ketone Enolates to Sulfinimine
(S)-(+)-3 at -78 °C
ketone
% isolated yielda
(% de)b
entry
(R ))
base
LDA
solvent
1
2
3
4
5
6
7
8
9
Ph
THF
THF
THF
THF
THF
THF
Et2O
Et2O
THF
Et2O
(SS,R)-(+)-4a 53 (>96)
59 (>96)
<10
95 (>96)
(SS,R)-(+)-4b <10
40 (62)
LiHMDS
NaHMDS
KHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
Me
72(70)
Et
n-Bu
(SS,R)-(+)-4c 90 (90)
(SS,R)-(+)-4d 65 (80)
83 (90)
10
a Isolated yield of major diastereoisomer. b Determined from the 1H NMR
of the crude reaction mixture.
Scheme 4
The results summarized in Table 1 reveal that the potas-
sium enolates of the methyl ketones afford the highest
yields and diastereoselectivity. While the lithium enolate of
acetophenone gave high diastereoselectivity (>96% de), the
yields were modest (Table 1, entries 1 and 2). Sodium eno-
lates gave complex reaction mixtures (Table 1, entries 3 and
5). Improved diastereoselectivities and yields were also noted
in ether solvent (Table 1, entries 7, 8, and 10). The absolute
stereochemistry of the newly created stereocenter for the
addition of enolates to (S)-(+)-3 was established as R by
comparison of the rotation of (+)-4a with an authentic sam-
ple.1 These results are consistent with the usual model for
addition of organometallic reagents to sulfinimines: the metal
ion coordinates to the sulfinyl oxygen and addition to the
C-N double bond occurs via six-membered chairlike transi-
tion states.11
Initial attempts to convert (+)-8 into (+)-5 using 1,3-
propanediol and catalytic p-toluenesulfonic acid (TsOH, 5
(10) For reviews on the chemistry of sulfinimines, see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. In AdVances in Sulfur Chemistry; Rayner, C. M.,
Ed.; JAI Press: Stamford, CT, 2000; Vol. 2, pp 249-282. (b) Davis, F.
A.; Zhou, P.; Chen. B.-C. Chem. Soc. ReV. 1998, 27, 13. (c) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(9) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1043. (b) Fanelli, D. L.; Szewczyk,
J. M.; Zhang, Y.; Reddy, G. V.; Burns, D. M.; Davis, F. A. Org. Synth.
1999, 77, 50.
(11) For a review on sulfinimine derived polyfunctionalized chiral
building blocks, see: Davis, F. A.; Chao, B.; Andemichael, Y. W.; Mohanty,
P. K.; Fang, T.; Burns, D. M.; Rao, A.; Szewczyk, J. M. Heteroto. Chem.
2002, 13, 48.
5012
Org. Lett., Vol. 5, No. 26, 2003

mol %) resulted in low conversions. However, when (+)-8
was heated in benzene or toluene with 1.5 equiv of TsOH
and 5.0 equiv of 1,3-propanediol, (+)-5 was obtained directly
in 72% yield for the two-step, one-pot reaction. Comparison
of its rotation with literature values indicated that epimer-
ization had not occurred.13a
A further illustration of the utility of our methodology is
the asymmetric synthesis of (-)-indolizidine 209B (18).14
This 5,8-disubstituted indolizidine is member of a large
family of indolizidine alkaloids isolated from the toxic skin
of the dendrobatide frog and many of these alkaloids exhibit
interesting biological activities.15 Our synthesis begins with
the preparation of (R)-(-)-N-(hexanylidine)-p-toluenesulfin-
amide (10), in 79% yield, by condensation of hexanal with
commercially available (R)-(-)-p-toluenesulfinamide (9)
using Ti(OEt)4 (Scheme 5).9 Next, treatment of the sulfin-
anhydrous MgSO4 in DCM was attempted, but complex
mixtures occurred, apparently from aldol condensation of
the aldehyde. Alternatively, treating this aldehyde with 4 Å
molecular sieves without heating did seem to give some of
the imine, but the aldol product was also present. This
problem was avoided by stirring (-)-12 at room temperature
with anhydrous MgSO4 and (E)-4-benzyloxy-but-2-enal (13)
for 2-3 h (Scheme 6). The crude imine 14, obtained in nearly
Scheme 6
Scheme 5
imine with the potassium enolate of 2-butanone afforded the
â-amino ketone (RS,R)-(-)-11 in 85% yield and >96% de.
The one-pot deprotection-protection sequence gave (R)-
(-)-12 in 87% yield following chromatography.
With the requisite protected â-amino ketone (-)-12 in
hand, heating it with 4-benzyloxybutanal in the presence of
quantitative yield was heated with dry TsOH, 2.0 equivalents,
in benzene at 75 °C for 3 h to afford the Mannich product
(-)-15 as a single diastereoisomer in 61% yield for the two
steps. The relative configuration was unambiguously assigned
(12) For applications of N-sulfinyl δ-amino â-ketoesters to the asym-
metric synthesis of piperidine and pyrrolidine alkaloids, see: (a) Davis, F.
A.; Chao, Fang, T.; Szewczyk, J. M. Org. Lett. 1999, 1, 1041. (b) Davis,
F. A.; Chao, B. Org. Lett. 2000, 2, 2623. (c) Davis, F. A.; Fang, T.; Chao,
B.; Burns, D. M. Synthesis 2000, 2106. (d) Davis, F. A.; Chao, B.; Rao, A.
Org. Lett. 2001, 3, 3169. (e) Davis, F. A.; Fang, T.; Goswami, R. Org.
Lett. 2002, 4, 1599. (f) Davis, F. A.; Yang, B.; Deng, J. J. Org. Chem.
2003, 68, 5147. (g) Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5,
3855.
(13) (a) Ripoche, I.; Canet, J.; Gelas, J.; Troin, Y. Tetrahedron:
Asymmetry 1999, 10, 2213. (b) Ciblat, S.; Besse, P.; Canet, J.; Troin, Y.;
Veschambre, H.; Gelas J. Tetrahedron: Asymmetry 1999, 10, 2225. (c)
Besse, P.; Ciblat, S.; Canet, J.; Troin, Y.; Veschambre H. Tetrahederon:
Asymmetry 2000, 11, 2211. (d) Glasson, S. R.; Canet, J.-L.; Troin, Y.
Tetrahedron Lett. 2000, 41, 9797. (e) Ciblat, S.; Calinaud, P.; Canet, J.-L.;
Troin, Y. J. Chem. Soc., Perkin Trans. 1 2000, 353. (f) Carbonnel, S.; Troin,
Y. Heterocycles 2002, 57, 1807. (g) Lamazzi, C.; Carbonnel, S.; Calinaud,
P.; Troin Y. Heterocycles 2003, 60, 1447.
1
based on the H NMR and COSY spectra and is consistent
with a transition state where all the substituents occupy
equatorial positions.13b Initial attempts to hydrogenate the
alkene and remove the benzyl group using Pd/C/H2 resulted
(14) For earlier syntheses of (-)-indolizidine 209B and leading refer-
ences, see: (a) Ma, D.; Pu, X.; Wang, J. Tetrahedron: Asymmetry 2002,
13, 2257. (b) Song, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2002, 43,
8635. (c) Shu, C.; Alcudia, A.; Yin, J.; Liebeskind, L. S. J. Am. Chem.
Soc. 2001, 123, 12477. (d) Back, T. G.; Nakajima, K. J. Org. Chem. 2000,
65, 4543. (e) Michael, J. P.; Gravestock, D. J. Chem. Soc., Perkin Trans.
1 2000, 1919.
(15) For a review, see Daly, J. W.; Carraffo, H. M.; Spande, T. F. In
Alkaloids: Chemical & Biological PerspectiVes; Pelletier, S. W., Ed.;
Pergamon Press: Oxford, 1999; Vol. 13, pp 1-161.
Org. Lett., Vol. 5, No. 26, 2003
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in only reduction of the alkene even after 3 days. Subsequent
reaction of the crude alkane with Pd(OH)2/H2 gave the
alcohol, which was subjected to cyclization using CBr4/Ph3P/
Et3N and afforded the indolizidine (-)-16 in 74% yield for
the four steps. With ethane dithiol/BF3, (-)-16 gave the
thioketal (-)-17, which on Ra-Ni desulfurization gave (-)-
indolizidene 209B (18) with properties consistent with
literature values.14
demonstrated in the asymmetric synthesis of (-)-indolizidene
209B (18).
Acknowledgment. We thank Dr. Joanna Szewczyk for
early studies and Jianghe Deng and Dr. Charles DeBrosse,
director of NMR, for helpful discussions. This work was
supported by a grant from the National Institute of General
Medical Sciences (GM51982).
In summary, the direct asymmetric synthesis of N-sulfinyl
â-amino ketones 4 from the potassium enolate of methyl
ketones and sulfinimines is described. These compounds are
efficiently transformed in one pot to protected â-amino
ketones, which are valuable chiral building blocks for the
assembly of piperidines. The utility of this methodology was
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035981+
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Org. Lett., Vol. 5, No. 26, 2003