Arabinosylamine in asymmetric syntheses of chiral piperidine alkaloids

Article abstract of DOI:10.1055/s-2004-817775

The stereodifferentiating potential of arabinosyl aldimines was utilized in stereoselective syntheses of 2-substituted dehydropiperidinones and their further transformation to 2,6-cis-substituted piperidinones. The absolute configuration was proven by X-r

Full text of DOI:10.1055/s-2004-817775

LETTER
671
Arabinosylamine in Asymmetric Syntheses of Chiral Piperidine Alkaloids
A
rabinosylamine
i
in
A
sy
r
m
metric
g
S
yntheses
o
i
f
Chira
t
l
P
iperidine
A
K
lkaloids ranke, Dominique Hebrault, Martin Schultz-Kukula, Horst Kunz*
Institut für Organische Chemie, Johannes Gutenberg-Universität Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
Fax +49(6131)3924786; E-mail: hokunz@uni-mainz.de
Received 27 November 2003
galactosylamine 1 was replaced with its pseudoenantio-
mer, D-arabinosylamine 3, and employed in the described
reactions leading to nitrogen heterocycles with opposite
stereochemical configuration.
Abstract: The stereodifferentiating potential of arabinosyl ald-
imines was utilized in stereoselective syntheses of 2-substituted
dehydropiperidinones and their further transformation to 2,6-cis-
substituted piperidinones. The absolute configuration was proven
by X-ray analysis and by the synthesis of the enantiomerically pure
alkaloid (+)-dihydropinidine. The presented method offers the
possibility to synthesize piperidine derivatives enantiomeric to
those obtained by the application of the corresponding galactosyl-
amine auxiliary.
Although arabinosylamine 3 belongs to the D-series of
carbohydrates it displays almost the mirror image of the
D-galactosylamine 1. In aldimines derived from these
glycosylamines the opposite enantiotopic sides are effec-
tively shielded by the C-2 pivaloyl group. While in the
galactosylimine 2 the re-side is blocked, it is readily
accessible in the arabinosylimine 4 (Scheme 1).
Key words: carbohydrate auxiliaries, arabinosylamine, domino
Mannich–Michael reaction, piperidine alkaloids, conjugate cuprate
addition
OPiv
OPiv
OPiv
PivO
PivO
Due to their extensive diversity in biological activity,1
alkaloids and synthetic analogs containing the piperidine
ring system are considered interesting targets for drug
development. Therefore, these heterocyclic structures are
subjects of numerous stereoselective approaches such as
ex-chiral pool syntheses2 and methods using enantio-
selective catalysis3 or chiral auxiliaries.2,4
O
O
H2N
NH2
PivO
OPiv
1
3
RCHO
RCHO
During the past years, we developed a strategy for the
enantioselective synthesis of piperidine alkaloids using
glycosylamines as chiral auxiliaries.4,5 In this approach,
steric, stereoelectronic and complexing effects of carbo-
hydrates are exploited for diastereofacial differentiation
of nucleophilic additions to glycosyl aldimines.
OPiv
O
OPiv
OPiv
PivO
PivO
O
O
O
R
N
N
R
O
O
H
H
2
4
2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyranosylamine (1)
proved an efficient auxiliary for Strecker syntheses of
aminonitriles,6 Ugi reactions giving amino acid amides7
and syntheses of homoallylamines.8 In addition, aldimines
2, obtained from the condensation of galactosylamine 1
with several aldehydes, react with 1-methoxy-3-trimeth-
ylsiloxy-butadiene (Danishefsky’s diene)9 5 to give 2-
re-side
si-side
Scheme 1 A pair of pseudoenantiomeric chiral auxiliaries.
N-Arabinopyranosylimines 4 are formed in analogy to N-
galactopyranosylimines 2 via the reaction of the glyco-
sylamine 3 with aliphatic aldehydes in the presence of
molecular sieves or with aromatic aldehydes under acid
catalyzis. These aldimines 4 react with Danishefsky’s
diene 5 in a domino Mannich–Michael5 reaction promot-
ed by zinc chloride to N-(2,3,4-tri-O-pivaloyl-a-D-ara-
binopyranosyl)-5,6-didehydropiperidin-4-ones (6), which
are obtained in high yields and high diastereoselectivity
(Scheme 2, Table 1).
substituted
N-glycosyl-5,6-didehydropiperidin-4-ones
with high yield and high stereoselectivity.4 These consti-
tute useful precursors for highly substituted piperidines
and more complex alkaloids such as indolizidines and
decahydroquinolines. This was demonstrated e.g. in the
syntheses of 2,6-disubstituted piperidines such as dihy-
dropinidine,4 the indolizidine gephyrotoxine 167B4 and
the decahydroquinoline trans-epi-pumiliotoxin C.10
In comparison to the N-galactosyl dehydropiperidinones
reported earlier,4 the N-arabinosyl dehydropiperidinones
6 bear the opposite configuration at position 2 of the nitro-
gen heterocycle. Thus, by using either galactosylamine or
its pseudoenantiomer, arabinosylamine, the epimeric de-
hydropiperidinones are accessible offering the possibility
to synthesize both enantiomeric classes of piperidines by
choosing the appropriate auxiliary.
Herein, we describe the application of a different carbo-
hydrate auxiliary, in order to establish a route to synthe-
size the corresponding enantiomeric alkaloids. Therefore,
SYNLETT 2004, No. 4, pp 0671–0674
0
9.
0
3.
2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817775; Art ID: G33603ST.pdf
© Georg Thieme Verlag Stuttgart · New York

672
B. Kranke et al.
LETTER
PivO
PivO
OPiv
OPiv
a or b
OPiv
OPiv
O
O
N
R
O
NH2
O
PivO
PivO
O
O
OPiv
OPiv
rotation
N
N
O
O
4
H
O
3
O
O
6d
B
6d
A
OSiMe3
PivO
OPiv
5
MeO
Scheme 3 Preferred conformation of 2-substituted N-arabinosyl
dehydropiperidinone 6d according to Figure 1.
OPiv
O
N
c
R
6
N-Arabinosyl dehydropiperidinones 6 represent precur-
sors for highly substituted nitrogen heterocycles. The
reactivity of these a,b-unsaturated carbonyl compounds
as Michael acceptor is reduced because of the vinylogous
amide structure. However, cuprate additions were
successful in combination with hard electrophiles, e. g.
Yamamoto cuprates12 activated by boron trifluoride di-
ethyletherate (RCu·BF3), and Gilman cuprates13 (R2CuLi)
in combination with chlorotrimethylsilane14 resulting in
the formation of 2,6-cis-disubstituted piperidinones 7 in
high diastereoselectivity (Scheme 4, Table 2).
Scheme 2 Synthesis of 2-substituted N-arabinosyl-5,6-didehydro-
piperidin-4-ones (6) from arabinosylamine 3. Conditions: a) RCHO,
molecular sieves, pentane (for aliphatic aldehydes); b) RCHO,
HOAc, i-PrOH (for aromatic aldehydes); c) ZnCl2·Et2O, 5, THF,
–78 °C, 10 min; –20 °C, 48 h.
Table 1 Diastereoselective Synthesis of 2-Substituted Dehydro-
piperidinones 6 According to Scheme 2
Product
6a
R
Yield (%)
dra
p-ClPh
p-NO2Ph
Ph
96
74
84
76
73
97:3c
PivO
R'
O
6b
86:14,b 96:4c
92:8b
OPiv
a or b
OPiv
O
N
6
6c
R
6d
Pr
91:9b
7
Scheme 4 Diastereoselective synthesis of 2,6-disubstituted piperi-
dinones 7 from N-arabinosyl dehydropiperidinones 6. Conditions: a)
R′Cu·BF3 (from CuX, R′MgBr), THF, –78 °C, 16 h; b) 1. R′2CuLi
(from CuX, R′Li), Me3SiCl, THF, –78 °C, 14 h; 2. TBAF, THF, r.t.
6e
i-Pr
95:5,b 99:1c
a Diastereomeric ratio was determined by HPLC.
b HPLC of the crude product.
c HPLC after flash chromatography.
Table 2 Diastereoselective Synthesis of 2,6-Disubstituted Piperidi-
nones 7 According to Scheme 4
The absolute configuration of the dehydropiperidinones
was proven by X-ray analysis showing 6d to have (S)-
configuration (Figure 1).11 The compound prefers a con-
formation in which the planes of the nitrogen heterocycle
and the carbohydrate are perpendicular to each other
(according to the exo-anomeric effect). In addition, a
minimization of the steric hindrance between the sub-
stituent in position 2 and the pivaloyl group at C-2 of the
carbohydrate is observed (Scheme 3, rotamer B).
Ketone Cuprate
Product Yield
(%)
drd
cis/trans
99:1f
a
6a
6a
6d
6d
6d
PhCu·BF3
7a
72
51
44
59
88
98:2f
b
(CH2=CH-CH2)Cu·BF3 7b
99:1f
a
PhCu·BF3
7c
94:6,e 95:5f
91:9,e 93:7f
b
(CH2=CH-CH2)Cu·BF3 7d
Me2CuLi/Me3SiClc
7e
a Cuprate formation: CuI, PhMgBr, THF, –78 °C, 1 h.
b Cuprate formation: CuCN, AllylMgBr, THF, –40 °C, 0.5 h.
c Cuprate formation: CuI, MeLi, THF, –25 °C, 2 h.
d Diastereomeric ratio was determined by HPLC.
e HPLC of the crude product.
f HPLC after flash chromatography.
The cis-configuration was confirmed by a X-ray analysis
of 7a (Figure 2).15 The nitrogen heterocycle adopts a
twisted conformation with the smaller substituent in
equatorial and the larger substituent in axial position and
a pyramidally configured nitrogen atom.
Figure 1 X-ray structure of N-arabinosyl dehydropiperidinone 6d.
Synlett 2004, No. 4, 671–674 © Thieme Stuttgart · New York

LETTER
Arabinosylamine in Asymmetric Syntheses of Chiral Piperidine Alkaloids
673
S
PivO
OPiv
S
OPiv
b
a
O
N
7e
8
PivO
Cl
OPiv
c
OPiv
O
N
N
H
H
9
10
PivO
OPiv
O
OPiv
OH
Scheme 5 Synthesis of enantiopure (+)-(2S,6R)-dihydropinidine
hydrochloride. Conditions: a) HSCH2CH2SH, BF3·OEt2, CH2Cl2, r.t.,
12 h, 81%; b) Raney nickel, H2, i-PrOH, 70 °C, 12 h, 73%; c) 1 N
HCl, MeOH, r.t., 48 h, quantitative.
Figure 2 X-ray structure of N-arabinosyl piperidinone 7a.
The observed cis-stereoselectivity of the 1,4-addition can
be explained considering the X-ray structure of 6d (see
Figure 1) showing its preferred conformation. Compared
to rotamer A, rotamer B (see Scheme 3) benefits from less
steric hindrance between the substituent in position 2 of
the heterocycle and the pivaloyl group at C-2 of the carbo-
hydrate. The front-side attack of the cuprate results in a
cis-substitution pattern.
References
(1) (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The
Alkaloids – Chemistry and Pharmacology, Vol. 43; Cordell,
G. A., Ed.; Academic Press: San Diego, 1993, 185.
(b) Daly, J. W. Nat. Prod. 1998, 61, 162. (c) Daly, J. W.;
Garraffo, H. M.; Spande, T. F. In Alkaloids – Chemical and
Biological Perspectives, Vol. 13; Pelletier, S. W., Ed.;
Pergamon: New York, 1999, 1.
(2) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 1915.
(3) (a) Kobayashi, S.; Ishitani, H. Angew. Chem. Int. Ed. 1998,
37, 979. (b) Reding, M. T.; Buchwald, S. L. J. Org. Chem.
1998, 63, 6344.
Employing the reactions presented above, 2,6-disubsti-
tuted piperidine alkaloid (+)-dihydropinidine 1016 was
synthesized, which has already been a target of many
studies.17 For this purpose, the piperidinone derivative 7e
was converted into dithiolane 8 and subsequently treated
with Raney nickel to give the N-arabinosyl piperidine 9.
The enantiomerically pure alkaloid hydrochloride 10 was
released from the carbohydrate by mild acidolyzis with
dilute hydrochloric acid in methanol (Scheme 5). The
optical rotation value of 10 {[a]D25 +11.1, c 1, EtOH} was
in agreement with literature data17 {[a]D +11.6 to +14.2 in
EtOH for 10 and [a]D –9.1 to –12.7 in EtOH for the
enantiomer}17 and confirmed the absolute configuration.
(4) Weymann, M.; Pfrengle, W.; Schollmeyer, D.; Kunz, H.
Synthesis 1997, 1151.
(5) Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. Engl. 1989,
28, 1067.
(6) (a) Kunz, H.; Sager, W. Angew. Chem., Int. Ed. Engl. 1987,
26, 557. (b) Kunz, H.; Sager, W.; Schanzenbach, D.;
Decker, M. Liebigs Ann. Chem. 1991, 649.
(7) (a) Kunz, H.; Pfrengle, W. J. Am. Chem. Soc. 1988, 110,
651. (b) Kunz, H.; Pfrengle, W.; Rück, K.; Sager, W.
Synthesis 1991, 1039.
Further transformations of N-arabinosyl dehydropiperidi-
nones to highly substituted chiral nitrogen heterocycles
are under investigation.
Acknowledgment
(8) (a) Laschat, S.; Kunz, H. Synlett 1990, 51. (b) Laschat, S.;
Kunz, H. J. Org. Chem. 1991, 56, 5883.
We wish to thank Dr. D. Schollmeyer, Institut für Organische
Chemie, Universität Mainz, for the X-ray analyses. B. K. is grateful
for being awarded the Adolf-Todt-Preis of the Adolf-Todt-Stiftung
of the Universität Mainz.
(9) Danishefsky, S. J. Am. Chem. Soc. 1974, 96, 7807.
(10) Weymann, M.; Schultz-Kukula, M.; Knauer, S.; Kunz, H.
Monatsh. Chem. 2002, 133, 571.
(11) Compoumd 6d: [a]D25 +66.6 (c 1, CHCl3). 1H NMR (200
MHz, CDCl3): d = 6.90 (d, 1 H, JH-6,H-5 = 7.3 Hz, CH=CH),
5.55 (t, 1 H, JH-2′,H-1′ = 9.5 Hz, JH-2′,H-3′ = 9.5 Hz, H-2′),
5.30–5.20 (m, 1 H, H-4′), 5.13 (dd, 1 H, JH-3′,H-2′ = 10.0 Hz,
JH-3′,H-4¢= 3.2 Hz, H-3′), 4.93 (d, 1 H, JH-5,H-6 = 7.3 Hz,
CH=CH), 4.44 (d, 1 H, JH-1′,H-2′ = 9.3 Hz, H-1′), 4.02 (dd, 1
H, JH-5′a,H-5¢b = 13.2 Hz, JH-5¢a,H-4¢ = 2.0 Hz, H-5′a), 3.80–3.70
(m, 1 H, PrCHN), 3.67 (d, 1 H, JH-5′b,H-5′a = 13.2 Hz, H-5′b),
2.60 (dd, 1 H, JH-3a,H-3b = 16.6 Hz, JH-3a,H-2 = 6.3 Hz,
CHHC=O), 2.34 (d, 1 H, JH-3b,H-3a = 16.6 Hz, CHHC=O),
Synlett 2004, No. 4, 671–674 © Thieme Stuttgart · New York

674
B. Kranke et al.
LETTER
2.00–1.75 [m, 1 H, (CHH)2CH3], 1.65–1.50 (m, 1 H,
(CHH)2CH3), 1.30–1.10 (m, 27 H, piv CH3), 0.86 [t, 3 H,
J = 7.3 Hz, (CH2)CH3] ppm. 13C NMR (50.3 MHz, CDCl3):
d = 192.15 (C=O), 177.21, 176.76 (pivC=O), 149.92
(CH=CH), 99.79 (CH=CH), 92.13 (C-1′), 71.13, 67.97,
66.06 (C-2′, C-3′, C-4′), 66.22 (C-5′), 53.48 (PrCHN), 38.97
(CH2C=O), 38.89, 38.82, 38.77 (pivCquart.), 32.66
[(CH2)CH3], 27.21, 27.13, 27.02 (piv-CH3), 18.90
[(CH2)CH3], 13.81 [(CH2)CH3] ppm; X-ray analysis:
P212121(orthorhombic), a = 9.8895(13) Å, b = 10.1820(11)
Å, c = 30.614(4) Å, V = 3082.7(6) Å3, z = 4, F(000) = 1136,
CAD4 Enraf Nonius, Cu-Ka, SIR-92, SHELXL-97. Further
details of the crystal structure analysis are available on
request from the Cambridge Crystallographic Data Centre
quoting the deposit number CCDC 229785.
(12) Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986, 25, 947.
(13) Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952,
17, 1630.
(14) Corey, E. J.; Boaz, W. Tetrahedron Lett. 1985, 26, 6019.
(15) X-ray analysis: P1(triclinic), a = 10.1869(6) Å,
b = 13.1017(12) Å, c = 15.5126(12) Å, V = 1901.1(3) Å3,
z = 2, F(000) = 716, CAD4 Enraf Nonius, Cu-Ka, SIR-92,
SHELXL-97. Further details of the crystal structure analysis
are available on request from the Cambridge
Crystallographic Data Centre quoting the deposit number
CCDC 229786.
(16) Compound 10: [a]D25 +11.1 (c 1, EtOH). 1H NMR (200
MHz, DMSO): d = 9.07 (br s, 1 H, NH), 8.68 (1 H, NH),
3.15–2.80 (m, 2 H, H-1, H-6), 1.90–1.00 (m, 13 H, CH2,
CH3), 0.87 [t, 3 H, J = 7.1 Hz, (CH2)2CH3] ppm. 13C NMR
(50.3 MHz, DMSO): d = 55.98, 52.52 (C-2, C-6), 34.82,
29.78, 27.05, 22.01, 18.75, 17.86 (CH2, CH3), 13.68
[(CH2)2CH3] ppm.
(17) Ciblat, S.; Besse, P.; Papastergiou, V.; Veschambre, H.;
Canet, J.-L.; Troin, Y. Tetrahedron: Asymmetry 2000, 11,
2221; and references therein.
Synlett 2004, No. 4, 671–674 © Thieme Stuttgart · New York