Highly stereoselective asymmetric 6π-azaelectrocyclization utilizing the novel 7-alkyl substituted cis-1-amino-2-indanols: Formal synthesis of 20-epiuleine

Article abstract of DOI:10.1021/ja026464+

Highly stereoselective asymmetric 6π-azaelectrocyclization was achieved with generality, based on the reaction between the (E)-3-carbonyl-2,4,6-trienal compounds and the (-)-7-alkyl-cis-1-amino-2-indanol derivatives as the effective novel chiral amines. F

Full text of DOI:10.1021/ja026464+

Published on Web 07/30/2002
Highly Stereoselective Asymmetric 6π-Azaelectrocyclization Utilizing the
Novel 7-Alkyl Substituted cis-1-Amino-2-indanols: Formal Synthesis of
20-Epiuleine
Katsunori Tanaka and Shigeo Katsumura*
School of Science and Technology, Kwansei Gakuin UniVersity, Gakuen 2-1, Sanda, Hyogo 669-1337, Japan
Received April 8, 2002
The thermal cyclization of 1-azatrienes to 1,2-dihydropyridines,1
which is the so-called 6π-azaelectrocyclization, is one of the well-
known concerted pericyclic reactions,2-4 which proceed in a
disrotatory mode.5 Although a number of examples of the 6π-
azaelectrocyclization have been reported,1,6,7 the process required
a high temperature and a long reaction time; therefore, the
application of this reaction toward natural products synthesis is very
limited in the literature. The recent pioneering work of Okamura
and co-workers elucidated that the introduction of either an electron-
donor or an -acceptor group at the 1-azatriene terminus moderately
accelerated the rate of the electrocyclization.5,8 Quite recently, we
independently succeeded in significantly accelerating the aza-
electrocyclization, based on the remarkable orbital interaction
between the HOMO and LUMO of the 1-azatrienes by the
combination of substituent effects, that is the C4-carbonyl and the
C6-alkenyl or phenyl substituents.9-11 Herein, we report the novel
highly stereoselective asymmetric 6π-azaelectrocyclization based
on the reactions between the (E)-3-carbonyl-2,4,6-trienal compounds
and the chiral cis-1-amino-2-indanol derivatives using a remarkably
simple operation under quite mild conditions (Figure 1).
Figure 1.
Table 1. Selectivity of Azaelectrocyclization Using 7-Substituted
Aminoindanolsa
After trials on almost 20 chiral amines which are effective in
the imine-based asymmetric reactions,12 we fortunately found that
the reaction of 19 containing a bulky 2,6,6-trimethylcyclohexene
moiety with (1S,2R)-(-)-cis-1-amino-2-indanol a13 quantitatively
product
(major isomer)
temp
(°C)
dr
produced the pentacyclic piperidine derivative (-)-1a, [R]24
entry
aldehyde
amine
(at the 2-position)c
D
-45.4° (c 1.1, CHCl3), as a single stereoisomer (Figure 1). The
relative stereochemistry was unambiguously determined by the
X-ray crystallographic analysis of the corresponding carboxylic acid
derived from (-)-1a. The reaction may proceed via the isomer-
ization of the dihydropyridine intermediary14 toward the thermo-
dynamically more stable aminoacetal (-)-1a.15 To the best of our
knowledge, this is the first achievement of the highly stereoselective
6π-azaelectrocyclization of the linear 1-azatrienes.16
Although we found the cis-aminoindanol (-)-a as an encouraging
amine candidate, the reactions with the more general aldehydes 2
and 3,10 which contain linear alkenyl or phenyl substituents, only
gave a 3:1 diastereomixture of the corresponding piperidines at the
2-position, as shown in Table 1 (entries 1 and 2). Fortunately, we
found that the diastereoselectivity was significantly improved by
introducing an alkyl substituent at the 7-position of (-)-a.17 Thus,
the highest selectivity was obtained by utilizing the isopropyl-
substituted aminoindanol (-)-d, and the corresponding piperidine
derivatives (-)-2d and (-)-3d were obtained in the ratio of 10:1
and 24:1 (entries 7 and 8), respectively. Moreover, (-)-3d was
obtained as an almost single isomer at the lower temperature of 13
°C (entry 9). Thus, the highly stereoselective 6π-azaelectrocycliza-
1
2
3
2
3
2
3
2
3
2
3
3
2
3
(-)-a
(-)-a
(-)-b
(-)-b
c
2a
24
24
24
24
24
24
24
24
13
24
24
3:1d
3:1
5:1
12:1
7:1
20:1
10:1
24:1
>40:1
5:1
(-)-3a
(-)-2b
(-)-3b
2c
4
5e
6 f
7
c
3c
(-)-d
(-)-d
(-)-d
e
(-)-2d
(-)-3d
(-)-3d
2e
8
9
10g
11h
e
3e
17:1
a Unless noted, all the reactions quantitatively provided a diastereomeric
mixture of two piperidine derivatives, and the stereochemistry as shown.
The relative stereochemistry of the products was determined based on their
1H NMR and nOe experiments by comparing with that of 1a. The
stereochemistry of the 6-position of the minor isomers was not determined.
b CHCl3, 3 h. c Determined by 1H NMR (400 MHz). d An inseparable
mixture of four piperidine derivatives (15:5:3:1) was obtained. The
diastereomeric ratio at the 2-position was determined after LiAlH4 reduction
of the crude products. e-h The racemic c and e were employed to examine
the diastereoselectivity of the azaelectrocyclization.
tion was achieved by utilizing the novel 7-alkyl substituted cis-
aminoindanol derivatives.
The removal of the chiral indanol moiety in the obtained 1a-
3d was successfully achieved as shown in Table 2. Thus, 1a-3d
were reduced with lithium aluminum hydride to give the corre-
* To whom correspondence should be addressed. E-mail: katsumura@
ksc.kwansei.ac.jp.
9
9660
J. AM. CHEM. SOC. 2002, 124, 9660-9661
10.1021/ja026464+ CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2
Institute for Life Science Research at Asahi Chemical Industry Co.,
Ltd. for his X-ray crystallographic measurements. This study was
supported by a Grant-in-Aid for Scientific Research 09480145 from
the Ministry of Education, Science, Sports and Culture of Japan.
K.T. is grateful to the JSPS for a Research Fellowship for Young
Scientists.
Supporting Information Available: Experimental details, char-
yield of
diol (%)
yield of
amino alcohol (%)
1
acterization data, and copies of H and 13C NMR spectra (PDF). This
entry
substrate
product
material is available free of charge via the Internet at http://pubs.acs.org.
1
2
3
4
(-)-1a
(-)-3a
(-)-3b
(-)-3d
(-)-4
(-)-5
(-)-5
(-)-5
100
76b
91
69
55
55
58
References
91c
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(2) (a)Marvell, E. N.; Caple, G.; Schatz, B.; Pippin, W. Tetrahedron 1973,
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Scheme 1. Formal Synthesis of 20-Epiuleinea
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a Conditions: (a) ethyl (Z)-4-hydroxy-2-iodo-2-butenoate 7, Pd(PPh3)4,
LiCl, DMF, 115 oC, 64%; (b) MnO2, CH2Cl2, 67%; (c) (-)-b, 96%, or
(-)-d, 99%, CHCl3, rt; (d) LiAlH4, ether, 95% for (-)-8b, 83% for (-)-
8d; (e) MnO2, ether, rt, 3 min, then SiO2 c.c., 73% for X ) Me, 74% for
X ) iPr; (f) 37% aq HCHO, NaBH3CN, MeCN, rt, quant; (g) MnO2,
CH2Cl2; (h) MeLi, ether, THF, 55% for two steps; (i) NaOH aq, MeOH;
(j) MnO2, CH2Cl2, 40% for two steps. b (()-10 was reported to be converted
into the racemic 20-epiuleine.20a
(10) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org. Chem. 2001,
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K.; Fidanze, S.; Senanayake, C. H. Synthesis 1998, 937. (c) Groaning,
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subsequent transformation toward 1a were observed. For very close
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C.; Das, B. C. J. Chem. Soc., Chem. Commun. 1991, 625. (b) Wong,
Y.-S.; Marazano, C.; Gnecco, D.; Genisson, Y.; Chiaroni, A.; Das, B. C.
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J. Tetrahedron Lett. 1998, 39, 5089.
(16) We have found that the observed diastereoselectivity was not the result
of the thermodynamic equilibration, see: Sklenicka, H. M.; Hsung, R.
P.; Wei, L.-L.; McLaughlin, M. J.; Gerasyuto, A. I.; Degen, S. J. Org.
Lett. 2000, 2, 1161.
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L. E.; Foster, B. S.; Douglas, A. W.; Larsen, R. D.; Verhoeven, T. R.;
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(18) Husson, H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28, 383.
(19) The mechanistic investigation of this novel phenomenon revealed that
the nitrogen atom of the diols was first oxidized with manganese dioxide
to produce the corresponding intermediary N-oxide, which was followed
by the acid-catalyzed Polonovski-type reaction. The detailed results will
be reported in the full account of this work.
(20) (a) Harris, M.; Besselievre, R.; Grierson, D. S.; Husson, H.-P. Tetrahedron
Lett. 1981, 22, 331. (b) Grierson, D. S.; Harris, M.; Husson, H.-P.
Tetrahedron 1983, 39, 3683. (c) Bosch, J.; Bonjoch, J. Pentacyclic
Strychnos Indole Alkaloids. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1988; Vol. 1, pp 31-88.
sponding diols in 76-100% yields,18 which were then treated with
manganese dioxide in ether at room temperature followed by silica
gel chromatography to provide the corresponding amino alcohols
(-)-4 and (-)-5 in 55-69% yields, respectively.19
Then, the method was successfully applied to the asymmetric
synthesis of the ketone 10, which is the key synthetic intermediate
of the Strychnos indole alkaloid, (()-20-epiuleine20 by Husson and
co-workers,20a as shown in Scheme 1. Thus, aldehyde 8, which was
prepared from the vinylstannane 6 and the vinyl iodide 7 according
to our already established method,10 was reacted with (-)-b or
(-)-d to provide the corresponding piperidine derivatives (-)-8b
or (-)-8d in an almost quantitative yield and with a 10:1
diastereoselectivity, respectively. After the minor isomers were
separated, the compounds were reduced with lithium aluminum
hydride followed by the treatment of the produced diols with
manganese dioxide to afford the desired amino alcohol (-)-9 in
73 and 74% yields, respectively. Finally, (-)-9 was converted into
(-)-10, whose spectral data were good agreement with those already
reported,20a by the simple functional group manipulations as shown
in Scheme 1. Thus, the asymmetric 6π-azaelectrocyclization
established herein can be regarded as one of the new synthetic
strategies. Further application of the method for natural products
syntheses is now in progress in our laboratory.
Acknowledgment. We thank Dr. Kayoko Saiki at the Kobe
Pharmaceutical University for her high-resolution mass spectra
measurements. We also thank Mr. Tamotsu Yamamoto at the
JA026464+
9
J. AM. CHEM. SOC. VOL. 124, NO. 33, 2002 9661