Asymmetric Heck cyclization route to indolizidine and azaazulene alkaloids: Synthesis of (+)-5-epiindolizidine 167B and indolizidine 223AB

Article abstract of DOI:10.1016/S0040-4039(01)01361-2

Asymmetric intramolecular Heck cyclization of endocyclic enamides occurs at room temperature to give indoloizidine and azaazulene ring systems in up to 86% enantiomeric excess. A synthesis of (+)-epiindolizidine 167B and formal synthesis of 5E,9Z-indolizidine 223AB is described.

Full text of DOI:10.1016/S0040-4039(01)01361-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6621–6623
Asymmetric Heck cyclization route to indolizidine and
azaazulene alkaloids: synthesis of (+)-5-epiindolizidine 167B and
indolizidine 223AB
Kurt Kiewel, Mathew Tallant and Gary A. Sulikowski*
Department of Chemistry, Texas A&M University, PO Box 30012, College Station, TX 77842, USA
Received 4 July 2001; revised 23 July 2001; accepted 25 July 2001
Abstract—Asymmetric intramolecular Heck cyclization of endocyclic enamides occurs at room temperature to give indoloizidine
and azaazulene ring systems in up to 86% enantiomeric excess. A synthesis of (+)-epiindolizidine 167B and formal synthesis of
5E,9Z-indolizidine 223AB is described. © 2001 Elsevier Science Ltd. All rights reserved.
The intramolecular Heck reaction has proven to be a
powerful method for the construction of heterocyclic
and carbocyclic ring systems.1 Asymmetric variations of
this process are useful for the production of non-
racemic compounds as demonstrated by the many
applications of this reaction to the total synthesis of
natural products.2 Strategically, the enantioselective
Heck reaction provides a method for the introduction
of either a chiral tertiary or quaternary carbon center.3
The former variation of the enantioselective Heck reac-
tion has been applied to syntheses of decalin, hydrindan
and indolizidine ring systems.3,4 As part of a program
directed towards the enantioselective production of
nitrogen heterocycles, we envisioned Heck cyclization
of endocyclic enamides related to substrates studied by
Shibasaki5 and shown in Fig. 1 to afford pyrrolizidine,
indolizidine and azaazulene heterocycles as reaction
products. These ring systems are frequent structural
features of many alkaloids and thus would provide a
potentially expedient entry into these complex natural
products. Furthermore, we hoped PCP-type6 catalysts
would prove effective and provide an opportunity to
develop a new class of catalysts for asymmetric Heck
cyclizations.7 Herein, we describe the results of these
investigations that culminated in syntheses of (+)-5-epi-
indolizidine 167B and indolizidine 223AB.
Endocyclic enamides, such as 2a–c, are typically gener-
ated by the in situ acylation of the corresponding cyclic
imine. For example 2,3,4,5-tetrahydropyridine (n=1)
has been produced from N-chloropiperidine by base-
promoted elimination of hydrochloric acid and
acylation to afford the corresponding enamide.8 How-
ever, in our hands this procedure was somewhat capri-
cious and not readily applicable to other cyclic
N-chloro amines (n=0 and n=2).9 In contrast, N-for-
myl enamides (1a–c) are readily available starting from
the corresponding N-formyl amine by electrochemical
methoxylation followed by thermal elimination of
methanol.10 We reasoned that simple deformylation of,
for example, 1b should provide 2,3,4,5-tetra-
hydropyridine or its equivalent. To this end, enamide
1b on treatment with phenylmagnesium bromide (1.2
equiv.) followed by the addition of (Z)-3-bromo-
propenoyl chloride gave cyclic enamide 2b in 40–54%
yield.11 In a similar fashion enamides 2a and 2c were
also prepared starting from formyl enamides 1a and 1c,
respectively (Scheme 1).
H
N
H
H
N
N
pyrrolizidine
indolizidine
azaazulene
H
Asymmetric
N
O
N
O
Heck Reaction
Br
Figure 1.
* Corresponding author.
Heck cyclization of enamide 2b using Ag3PO4 as a
halide scavenger in combination with Pd·(R)-BINAP
complex in DMF at room temperature provided 3 in
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01361-2

6622
K. Kiewel et al. / Tetrahedron Letters 42 (2001) 6621–6623
neotropical dart-poison frogs.14 Due to their biological
O
Br
i. PhMgBr
THF, 0 ˚C
activity these alkaloids have been the subject of numer-
ous total synthesis investigations. In a recent publication
5-epiindolizidine 167B (13) was produced by reduction
of indolizidone 11.15 Also, in 1982 Hart and co-workers
described the conversion of racemic 11 to 5E,9Z-
indolizidine 223AB (13), one of the less abundant
diastereomers of indolizidine 223AB.16 In order to illus-
trate the synthetic utility of Heck cyclization product
indolizidone (+)-3 we prepared (+)-11 as outlined in
Scheme 4. First, reduction of 3 with L-selectride gave
lactam 8. Introduction of the C5 propyl group was
accomplished by treatment of 8 with acidic methanol to
give aminal 9 which on allylation afforded 10 as the only
detectable diastereomer in accord with a earlier publica-
tion by Stevenson and co-workers.17 Finally, hydrogena-
tion of 10 afforded indolizidone 11 in near quantitative
yield. Reduction of 11 with lithium aluminumhydride
gave (+)-5-epiindolizine 167B (12).
N
NCHO
ii.
Br
n
n
COCl
1a n = 0
1b n = 1
1c n = 2
2a n = 0 (30-36%)
2b n = 1
(40-54%)
2c n = 2 (14-42%)
Scheme 1.
85% enantiomeric excess, while reactions conducted in
tetrahydrofuran gave dieneamide 4 as the major product
(Scheme 2). Additives such as Tl(I) and Ag(I) salts failed
to suppress double bond migration or led to no reac-
tion.12 In all cases the primary Heck product (with no
double bond migration) was not observed. Other palla-
dium complexes (including PCP-type6 catalysts) proved
completely ineffective in promoting cyclization, led to the
elimination of HBr to afford the corresponding alkyn-
amide or resulted in incomplete reaction. The absolute
stereochemistry of 3 was assigned by hydrogenation to
(−)-indolizidone and comparison of optical rotation to a
sample of known absolute configuration.13 The sense of
asymmetric induction for the cyclization of 2b to 3 is in
accord with models proposed by Overman for cationic
Heck reactions.3b
An unusual feature of the enantioselective Heck cycliza-
tion of endocyclic enamides 2b and 2c is the effect of
solvent on the distribution of isomeric cyclization prod-
ucts. For example, Heck cyclization of enamide 2b using
DMF as a solvent afforded enamide 3 as the only
product, the result of double bond migration following
the initial Heck vinylation reaction. On the other hand
We also examined Heck cyclization of endocyclic enam-
ide 2c. Using reaction conditions developed in the
context of enamide 2b and THF as a solvent we observed
the production of three isomeric products (+)-5 (42%
yield), (−)-6 (7% yield), and 7 (12% yield) (Scheme 3). The
optically active isomers, (+)-5 and (−)-6, were isolated in
73 and 86% ee, respectively. The absolute stereochem-
istry of (+)-5 and (−)-6 were assigned following hydro-
genation to identical levorotatory products and based on
analogy to the sense of enantioselectivity established in
Heck cyclization of 2b (Scheme 2). Next, reaction of 2c
using the identical palladium catalyst system and now
DMF as a solvent-promoted double bond isomerization
and provided a mixture of (+)-5 (9% yield) and enamide
(−)-6 (29% yield) in low enantiomeric excess, 27 and 28%
ee, respectively. The sense of asymmetric induction was
identical to that observed using THF as a solvent.
O
O
O
N
N
N
H
H
(+)-5
7
(-)-6
Scheme 3.
O
O
L-selectride
TFA
N
H
N
H
THF, 0 ˚C
MeOH
(95%)
(93%)
( +)-3
8
The indolizidine ring system is a common structural
motif among dendrobatid alkaloids isolated from
OMe
N
TMS
O
O
H2, Pd-C
N
EtOH
TiCl4, CH2Cl2
-30→0 ˚C
(97%)
(>98%)
H
H
O
9
10
N
Pd•(R)-BINAP
Ag3PO4, DMF
O
Br
H
(64%)
O
LiAlH4
3 (85% ee)
N
O
N
N
N
THF (>98%)
N
2b
Pd•(R)-BINAP
Ag3PO4, THF
(69%)
H
H
H
13 (from 11)16
11
12
4
Scheme 2.
Scheme 4.

K. Kiewel et al. / Tetrahedron Letters 42 (2001) 6621–6623
6623
the same substrate afforded dienamide 4 when THF
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Scheme 6.