Asymmetric synthesis of (-)-indolizidines 167B and 209D based on stereocontrolled allylation of a chiral tricyclic N-acyl-N,O-acetal

Article abstract of DOI:10.1021/ol990389z

(Formula presented) The tricyclic N-acyl-N,O-acetal incorporating (S)-2-(1-aminoethyl)phenol as a chiral auxiliary underwent TiCl₄-mediated allylation to give the chiral (5S)-allylpyrrolidinone with retention of configuration in high yield and diastereoselectivity. On the bases of this methodology, the asymmetric syntheses of the dendrobatid alkaloids (-)-indolizidines 167B and 209D were achieved.

Full text of DOI:10.1021/ol990389z

ORGANIC
LETTERS
2000
Vol. 2, No. 4
465-467
Asymmetric Synthesis of
(−)-Indolizidines 167B and 209D Based
on Stereocontrolled Allylation of a
Chiral Tricyclic N-Acyl-N,O-acetal
Naoki Yamazaki, Toshimasa Ito, and Chihiro Kibayashi*
School of Pharmacy, Tokyo UniVersity of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
kibayasi@ps.toyaku.ac.jp
Received December 7, 1999
ABSTRACT
The tricyclic N-acyl-N,O-acetal incorporating (S)-2-(1-aminoethyl)phenol as a chiral auxiliary underwent TiCl4-mediated allylation to give the
chiral (5S)-allylpyrrolidinone with retention of configuration in high yield and diastereoselectivity. On the bases of this methodology, the
asymmetric syntheses of the dendrobatid alkaloids (−)-indolizidines 167B and 209D were achieved.
Bicyclic lactams incorporating chiral cyclic N,O-acetals 1
have been the subject of current interest due to their potential
use in asymmetric synthesis.1 In this context, Meyers2 has
demonstrated the utility of 1 (n ) 1) in the asymmetric
synthesis of 2-substituted pyrrolidines involving the use of
diastereoselective Lewis acid-mediated allylation, which has
subsequently been applied to the asymmetric preparation of
2-substituted piperidines (eq 1).3 In these investigations, the
chiral auxiliaries that allowed for the successful implementa-
tion of asymmetric induction. However, N-dealkylation of
2 to yield the corresponding N-nor compounds requires the
use of phenylglycinol as the only auxiliary capable of
allowing the cleavage of the N-benzyl group under the
reductive conditions, which seems to limit the utility of this
asymmetric protocol.
We recently demonstrated4 that 2-(1-aminoethyl)phenol (5)
is a notably effective chiral auxiliary for the tricyclic N,O-
acetal-based allylation, leading to higher reactivity and
selectivity (compared with the amino alcohols employed) in
the formation of a chiral piperidinone; the higher reactivity
can be attributed to the fact that phenoxide ions are much
better leaving groups than alkoxide ions in nucleophilic
displacement reactions. In this paper, we report the extension
of this allylation reaction using the chiral aminophenol
auxiliary (S)-5 to the asymmetric synthesis of a 5-substituted
pyrrolidinone and the application of this methodology to the
enantioselective synthesis of simple dendrobatid alkaloids,
amino acid-derived amino alcohols such as phenylglycinol,
alaninol, valinol, and tert-leucinol proved to be effective
(1) For a recent review, see: Romo, D.; Meyers, A. I. Tetrahedron 1991,
47, 9503.
(2) (a) Burgess, L. E.; Meyers, A. I. J. Am. Chem. Soc. 1991, 113, 9858.
(b) Meyers, A. I.; Burgess, L. E. J. Org. Chem. 1991, 56, 2294.
(3) Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett. 1994, 35, 2223.
(4) (a) Yamazaki, N.; Ito, T.; Kibayashi, C. Synlett 1999, 37. (b)
Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron Lett. 1999, 40, 739.
10.1021/ol990389z CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/26/2000

(-)-indolizidines 167B (3)5 and 209D (4)6 bearing a single
We next examined the allylation of the chiral tricyclic N,O-
acetal 7 by treatment with allyltrimethylsilane and titanium
tetrachloride, and the results are summarized in Table 1. The
substituent at C(5).7
Table 1. Allylation of Tricyclic N-Acyl-N,O-acetal 7a
The requisite chiral tricyclic N-acyl-N,O-acetal 7 was
prepared by the sequence given in Scheme 1. Condensation
Scheme 1a
entry
solvent
CH2Cl2
chlorobenzene
benzene
toluene
ethylbenzene
p-xylene
8/9 ratiob
yieldc (%)
1
2
3
4
5
6
3.1:1
3.9:1
6.3:1
7.2:1
8.0:1
8.7:1
95
99
91
90
93
92
a All reactions were carried out using allyltrimethylsilane (3 equiv) and
TiCl4 (3 equiv) at 40 °C. b Estimated by the 1H NMR spectrum. c Isolated
yield after chromatography.
a (a) Benzene, reflux, then AcCl, reflux; (b) Red-Al, then HCl.
results clearly demonstrated that these reactions proceed in
high yield (>90%) and lead to the (5S)-allylated product 8
as a major diastereomer with retention of configuration at
the reaction center. Because of difficulty of the stereochem-
ical assignment of the products 8 and 9 based on NMR
spectra, crystallization of these compounds was attempted
for X-ray analysis, but it failed. However, recrystallization
of racemic 9, prepared using the racemic aminophenol (()-5
by the same reaction sequence as shown in Scheme 1 and
then the allylation, provided crystals (mp 107-109 °C, from
benzene) suitable for X-ray crystallography which allowed
assignment of the relative stereochemistry of the two chiral
centers as shown (Figure 1), thus leading to formal establish-
ment of the absolute stereochemistry of chiral 8 and 9. The
of succinic anhydride (1.2 equiv) with (S)-2-(1-aminoethyl)-
phenol [(S)-5] (reflux in benzene and then reflux with AcCl)
gave the corresponding imide 6 (81%). Partial reduction of
6 with Red-Al and subsequent acid treatment of the resulting
5-hydroxylactam allowed formation of the N,O-acetal 7 as
a single isomer in 95% yield. The relative stereochemistry
of hydrogen at C(3a) in 7 was confirmed by NMR NOE
experiments which showed interaction between the hydrogen
at C(3a) and the C(9)-methyl.
(5) For enantioselective syntheses of indolizidine 167B, see: (a)
Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55, 4688. (b) Jefford,
C. W.; Tang, Q.; Zaslona, A. J. Am. Chem. Soc. 1991, 113, 3513. (c)
Fleurant, A.; Ce´le´rier, J. P.; Lhommet, G. Tetrahedron: Asymmetry 1992,
3, 695. (d) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 3119.
(e) Fleurant, A.; Saliou, C.; Ce´le´rier, J. P.; Platzer, N.; Moc, T. V.; Lhommet,
G. J. Heterocycl. Chem. 1995, 32, 255. (f) Takahata, H.; Bandoh, H.;
Momose, T. Heterocycles 1995, 41, 1797. (g) Lee, E.; Li, K. S. Lim, J.
Tetrahedron Lett. 1996, 37, 1445. (h) Weymann, M.; Pfrengle, W.;
Schollmeyer, D.; Kunz, H. Synthesis 1997, 1151. (i) Angle, S. R.; Henry,
R. M. J. Org. Chem. 1997, 62, 8549. (j) Chalard, P.; Remuson, R.; Gelas-
Mialhe, Y.; Gramain, J.-C.; Canet, I. Tetrahedron Lett. 1999, 40, 1661. (k)
Cheˆnevert, R.; Ziarani, G. M.; Dasser, M. Heterocycles 1999, 51, 593.
(6) For enantioselective syntheses of indolizidine 209D, see: (a) A° hman,
J.; Somfai, P. Tetrahedron Lett. 1995, 36, 303. A° hman, J.; Somfai, P.
Tetrahedron 1995, 51, 9747. (b) Nukui, S.; Sodeoka, M.; Sasai, H.;
Shibasaki, M. J. Org. Chem. 1995, 60, 398. (c) Jefford, C. W.; Sienkiewicz,
K. Thornton, S. R. HelV. Chim. Acta 1995, 78, 1511. (d) Takahata, H.;
Kubota, M.; Ihara, K.; Okamoto, N.; Momose, T.; Azer, N.; Eldefrawi, A.
T.; Eldefrawi, M. E. Tetrahedron: Asymmetry 1998, 9, 3289. See also refs
5a, 5d, and 5g.
(7) These indolizidine alkaloids 167B and 209D were detected once as
a very minor trace components in unidentified dendrobatid frogs found in
a single population [(a) Daly, J. W. Fortschr. Chem. Org. Naturst. 1982,
41, 205. (b) Aronstam, R. S.; Daly, J. W.; Spande, T. F.; Narayanan, T. K.;
Albuquerque, E. X. Neurochem. Res. 1986, 11, 1227]. Their structures have
been tentatively assigned as 3 and 4 on the basis of mass spectral evidence
whereas their absolute configurations were simply inferred as 5R,9R by
analogy to the structurally related indolizidine 223AB whose absolute
stereochemistry is known.
Figure 1. X-ray crystallographic structure of racemic 9 represented
by one enantiomer.
466
Org. Lett., Vol. 2, No. 4, 2000

results summarized in Table 1 also demonstrated that the
selectivity is significantly influenced by the solvent used.
The reaction temperature of 40 °C proved to be optimal for
the reaction: lower temperature (e.g., 20 °C) resulted in a
very slow reaction, while higher temperature (50 °C) caused
decomposition. Thus, the allylation using CH2Cl2 as a solvent
at 40 °C afforded a mixture of 8 and 9 in a 3.1:1 ratio and
95% yield (entry 1). Changing the solvent from CH2Cl2 to
chlorobenzene showed a small increase in diastereoselectivity
(3.9:1, entry 2). The use of benzene and its alkyl derivatives
such as toluene and ethylbenzene as solvents afforded
significant improvements in the selectivity of up to 6.3:1,
7.2:1, and 8.0:1, respectively (entries 3-5), and when
p-xylene was used, a much higher selectivity (8.7:1) was
obtained (entry 6).
Scheme 2a
The preference of the retentive isomer 8 over the inversive
isomer 9 in this allylation reaction is inconsistent with an
SN2 pathway and therefore is consistent with the reaction
proceeding by an SN1 process via the presumed intermediacy
of an N-acyl iminium ion. Thus, the initially formed N-acyl
iminium ion 10 is expected to adopt conformation A with
the hydrogen atom in the inside position which minimizes
the 1,3-allylic strain with the CdN bond. In this conforma-
tion, a coordination of the titanium(IV) phenoxide with the
carbonyl oxygen atom is possible. In such a stereochemical
arrangement, silane approach occurs from the face opposite
the phenyl group to generate 8 with retention of configuration
at the reaction center.
a (a) MeI, K2CO3 acetone; (b) OsO4, NaIO4, dioxane-H2O (3:
1); (c) (EtO)2P(O)CH2C(O)R, NaH, THF; (d) H2, Pd-C, MeOH;
(e) LiAlH4, THF, reflux; (f) Dess-Martin periodinate, CH2Cl2; (g)
H2, Pd-C, MeOH.
-119.1 (c 0.24, CH2Cl2) [lit.5a [R]20 -111.3 (c 1.3, CH2-
D
Cl2)]. The spectral data (1H and 13C NMR, and MS) of the
synthetic material are identical to those reported5a for
(5R,9R)-(-)-indolizidine 167B.
The same reaction sequence starting from aldehyde 12 as
that described above for (-)-indolizidine 167B was then
applied to the synthesis of (-)-indolizidine 209D (4). Thus
12 was subjected to Horner-Emmons condensation with
(EtO)2P(O)CH2C(O)C6H13 to give the single (E)-enone 13b
in 99% yield. Conversion of 13b to 15b was achieved
through sequential hydrogenation, LiAlH4 reduction, and
Dess-Martin oxidation in 76% overall yield. Hydrogenation
of 15b exclusively provided (-)-indolizidine 209D (4), with
spectral data (1H and 13C NMR, and MS) identical to those
reported,5a in 85% yield: [R]20D -87.6 (c 0.45, CH2Cl2) [lit.6d
With the (5S)-allylated product 8 in hand, O-methylation
afforded the methoxy derivative 11, which underwent
oxidative cleavage of the olefin moiety using OsO4-NaIO4
to give aldehyde 12 in 61% overall yield (Scheme 2). The
Horner-Emmons olefination with the phosphonate [(EtO)2P-
(O)CH2C(O)Pr] provided (E)-enone 13a as a single isomer,
which was converted to propyl ketone 14a by olefin
hydrogenation in 95% overall yield. Reduction of 14a with
LiAlH4, followed by Dess-Martin oxidation of the resulting
amino alcohol, afforded amino ketone 15a (84% yield for
two steps). Upon catalytic hydrogenation of 15a using
palladium on carbon, hydrogenolytic cleavage of the N-
benzyl moiety and subsequent intramolecular reductive
amination occurred as a one-pot reaction to furnish (-)-
[R]20 -89.64 (c 1.880, CH2Cl2)].
D
In conclusion, the tricyclic lactam incorporating a chiral
cyclic N,O-acetal derived from (S)-2-(1-aminoethyl)phenol
underwent TiCl4-mediated allylation with allyltrimethylsilane
to give the chiral (5S)-allylpyrrolidinone in high yield and
diastereoselectivity. This methodology was successfully
applied to the asymmetric syntheses of the dendrobatid
alkaloids (-)-indolizidines 167B and 209D.
indolizidine 167B (3) in 93% yield as a single isomer: [R]20
OL990389Z
D
Org. Lett., Vol. 2, No. 4, 2000
467