Intramolecular [4+2]-cycloaddition of 5-amino-substituted oxazoles as an approach toward the left-hand segment of haplophytine

Article abstract of DOI:10.1055/s-0030-1259302

The [4+2]-cycloaddition chemistry of several 5-amino-substituted oxazoles has been examined as an approach toward the construction of the left-half segment of the aspidosperma alkaloid haplophytine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259302

LETTER
215
Intramolecular [4+2]-Cycloaddition of 5-Amino-Substituted Oxazoles as an
Approach toward the Left-Hand Segment of Haplophytine
C
onstruction of Left-H
a
and
S
egm
e
j
nt of
H
i
a
ploph
d
ytine Chughtai, James M. Eagan, Albert Padwa*
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Fax +1(404)7276629; E-mail: chemap@emory.edu
Received 30 August 2010
Dedicated to Alberto Brandi on the occasion of his 60th birthday
ally intriguing and synthetically demanding aspidosperma
alkaloids is haplophytine (1).6 The haplophytine molecule
consists of a central indole moiety onto which two tetra-
cyclic heterocycles are attached. Acid cleavage of haplo-
phytine (1) led to aspidophytine (2; Scheme 1), a lactonic
aspidospermine-type of alkaloid which has been suggest-
ed to be not only a biosynthetic precursor of 1 but also a
possible intermediate to be used in its synthesis.7 Because
of its novel structure, aspidophytine (2) has attracted the
attention of several major research groups,7 including our
own.8 Prompted by our initial work dealing with aspido-
phytine (2),8 we decided to initiate a synthetic project em-
ploying the cycloaddition chemistry of 5-amino oxazoles
as an approach toward the construction of the left-half
segment of haplophytine (1).
Abstract: The [4+2]-cycloaddition chemistry of several 5-amino-
substituted oxazoles has been examined as an approach toward the
construction of the left-half segment of the aspidosperma alkaloid
haplophytine.
Key words: 5-aminooxazoles, intramolecular, Diels–Alder reac-
tion, pyridines, haplophytine
Construction of azapolyheterocycles through [4+2]-cy-
cloaddition chemistry has been a particularly fruitful area
of exploration, and the synthesis of various types of alka-
loids by this approach has been carried out by numerous
investigators.1 During the course of our research dealing
with the cycloaddition chemistry of push-pull dipoles2
and 2-amidofurans,3 we began studies geared toward a
synthesis of several aspidosperma alkaloids.4 This family
of indole alkaloids contains over 250 members that share
in their molecular structure a common pentacyclic ABCDE
framework, with the C-ring being of critical importance
because all six stereocenters and most of the functional-
ities are located in this ring.5 One of the more architectur-
The recently completed synthesis of haplophytine (1) car-
ried out by the Fukuyama9 and Nicolaou10 groups made
use of a novel oxidative rearrangement of a tetracyclic b-
carboline derivative to furnish the left-hand portion of the
alkaloid.11 These authors took advantage of an inherent
skeletal rearrangement of haplophytine (1) that occurred
Me
N
N
O
O
N
N
O
O
O
O
HO
H+
MeO
N
Me
N
Me
H
MeO
H
OMe
OMe
haplophytine (1)
aspidophytine (2)
Scheme 1 Acid degradation of haplophytine
Me
N
Me
+
N
O
HO
+
N
O
N
N
N
O
O
HBr
NaHCO3
O
HO
2 Br
CO2H
HO
N
N
Me
H
MeO
MeO
H
Me
OMe
OMe
haplophytine (1)
3
Scheme 2 Skeletal rearrangement of haplophytine using HBr
SYNLETT 2011, No. 2, pp 0215–0218
x
x.
x
x.
2
0
1
1
Advanced online publication: 05.01.2011
DOI: 10.1055/s-0030-1259302; Art ID: G26310ST
© Georg Thieme Verlag Stuttgart · New York

216
M. Chughtai et al.
LETTER
upon treatment with HBr. The rearranged isomer 3 that on oxazole precursors can be tolerated during the cycliza-
formed was converted back into haplophytine under basic tion step.17 Following the Lipshutz procedure, the prepa-
conditions by means of a semipinacol-type rearrangement ration of our model oxazole 18 commenced with the
(Scheme 2).
coupling of N-tert-butoxycarbonylalanine (12) with o-
iodoaniline to give 14 in 73% yield. The N-Boc group was
removed with TFA and then acetylated with acetic anhy-
dride to afford 16 in 64% yield (Scheme 4). Although the
path to 16 may seem a bit round-about, we found that an
initial protection of alanine’s nitrogen with acetic anhy-
dride greatly inhibited the peptide coupling. With 16 in
Based on this observation, both teams found that the char-
acteristic left-hand segment (i.e. 7) could be formed by the
epoxidation of a tetrahydro-b-carboline derivative (i.e. 4).
The resulting diamino epoxide intermediate 5 underwent
a facile epoxide ring opening to give iminium ion 6. A
subsequent 1,2-shift of the C–N bond furnished the de-
sired left-hand skeleton (i.e. 7) of haplophytine
(Scheme 3). Our synthetic approach to the left-hand por-
tion of haplophytine is also shown in Scheme 3. We
planned to construct the related tetracyclic structure 11
(X = halo, SiR3, SnR3, etc.), a possible precursor to haplo-
phytine, by an intramolecular Diels–Alder cycloaddition
of 5-amido oxazole 8. We envisaged that the resulting
[4+2]-cycloadduct 9 would undergo ready ring opening to
give zwitterion 10. An ensuing semipinacol-type rear-
rangement analogous to the conversion of 6 to 7 could fur-
nish the desired tetracycle 11.
O
I
NHBoc
H
o-iodoaniline
DCC, DMAP
BocHN
N
OH
R
R
O
12; R = Me
13; R = Ph
14; R = Me; 73%
15; R = Ph; 70%
1. TFA, CH2Cl2
2. Ac2O, pyridine
I
O
O
I
The Diels–Alder reaction of oxazoles with olefins has be-
come a useful tool for the preparation of nitrogen-contain-
ing heterocycles,12 since the first example of this
cycloaddition reaction was reported by Kondratèva in
1957.13 Although numerous studies have described the
utility of oxazoles for the construction of pyridines,14
there have been few reports exploiting the intramolecular
Diels–Alder reactions of oxazole-olefins for the synthesis
of natural products.15 The feasibility of our approach to-
ward haplophytine that is outlined in Scheme 3 clearly
hinged upon a 5-amido oxazole undergoing an intramo-
lecular [4+2]-cycloaddition with a tethered styrene deriv-
ative. Since this tactic was the focal point of our plan, we
opted to first verify the viability of this reaction using sim-
pler model substrates.
O
TFAA
TFA
NH
N
N
H
N
H
R
R
16; R = Me; 64%
17; R = Ph; 62%
18; R = Me; 92%
19; R = Ph; 82%
Bu3SnCH=CH2
PdCl2(PPh3)2
DMF, 100 °C
CH2
O
N
– H2O
N
N
H
R
N
H
The pioneering work of Fleury and co-workers16 showed
that a-acyl amino acids readily undergo cyclization upon
treatment with acid anhydrides in the presence of strong
R
21; R = Me; 70%
22; R = Ph; 54%
20
acids to furnish 5-(acetamido)oxazoles. In subsequent Scheme 4 Synthesis and [4+2]-cycloaddition chemistry of 5-aza
oxazoles
work, Lipshutz demonstrated that a variety of appendages
Ar
Ar
Ar
Ar
[Ox]
O
O
N
N+
N
N
N
N
N
R
N
R
R
R
–O
O
O
O
O
7
5
6
4
+
X
Ar
Ar
Ar
Ar
X
X
N
O
O
X
N
N
O
N
N
N
N
N
–O
O
O
O
O
8
9
10
11
Scheme 3 Semipinacol-type rearrangement for synthesis of the left-half segment of haplophytine
Synlett 2011, No. 2, 215–218 © Thieme Stuttgart · New York

LETTER
Construction of Left-Hand Segment of Haplophytine
217
I
R = H
Bu3SnCH=CH2
PdCl2(PPh3)2
O
H+
N
N
N
N
N
N
R
H
CH2CH2CO2Me
CH2CH2CO2Me
O
29; 75%
26; R = H; 60%
27; R = Me; 62%
28; R = Bn; 56%
23; R = H
24; R = Me
25; R = Bn
Scheme 5 A linked Stille cross-coupling–cycloaddition cascade
hand, cyclodehydration using the Lipshutz protocol gave sults obtained are outlined in Scheme 6. The two-step syn-
5-anilino oxazole 18 in 92% yield. Stille coupling of 18 thesis of oxazole 32 from the known amide 30 worked
with n-tributylvinylstannane did not produce the expected well furnishing 32 in 80% overall yield. Acylation of 32
cross-coupled styryl oxazole 20. Instead, the initially with but-3-enoyl chloride gave 33 in 57% yield. The ther-
formed oxazole 20 spontaneously underwent an intramo- molysis of 33 at 120 °C in toluene afforded pyridine 34 in
lecular [4+2]-cycloaddition followed by ring opening and 61% yield. This product is formed by an intramolecular
loss of water to give the 9H-pyrido[3,4-b] indole system Diels–Alder cycloaddition followed by the ready loss of
21 in 70% yield (Scheme 4). A corresponding set of reac- water.
tions also occurred when the closely related 5-anilinoox-
azole 19 (R = Ph) was treated with n-tributylvinylstannane
in the presence of a palladium catalyst at 100 °C in DMF
affording 9H-pyridoindole 22 in 54% yield.
In summary, we have developed a cycloaddition protocol
to construct various substituted pyridines by an intramo-
lecular Diels–Alder reaction of a 5-amino-substituted ox-
azole. The potential value of this approach toward a total
Somewhat more relevant examples of the 5-amido ox- synthesis of haplophytine is under active investigation
azole cycloaddition reaction concern those systems pos- and will be reported in due course.
sessing a CH2CH2CO2Me appendage at the C-4 position
of the heterocyclic ring. We expected that N-acylation at
the anilino nitrogen would eventually lead to a 6,7-dihy-
drooxazolo[5,4-b]pyridin-5(4H)-one such as structure 8
in Scheme 3. To establish the viability of this approach,
spectral data for all compounds.
oxazoles 23–25 were prepared using standard synthetic
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
1
experimental procedures and H NMR, 13C NMR, HRMS, and IR
reactions similar to those outlined in Scheme 4. After
some experimentation, we found that a linked Stille cou-
Acknowledgment
pling–thermolysis cascade provided 9H-pyrido[3,4-b]in-
doles 26–28 in good yield (ca. 60%). In the case of 26,
treatment with p-TsOH at 120 °C gave rise to 4H-indo-
lo[3,2,1-de][1,5]naphthyridin-6(5H)-one 29 in 75% yield
(Scheme 5).
The financial support provided by the National Science Foundation
(CHE-0742663) is greatly appreciated.
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CO2Et
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Synlett 2011, No. 2, 215–218 © Thieme Stuttgart · New York

218
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LETTER
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